Menopause

TOPLINE:

Various surgical approaches to treat vaginal vault prolapse may be similarly safe and effective and can produce high rates of patient satisfaction.

METHODOLOGY:

• A randomized clinical trial at nine sites in the United States included 360 women with vaginal vault prolapse after hysterectomy (average age, 66 years).
• The women were randomly assigned to undergo native tissue repair (transvaginal repair using the sacrospinous or uterosacral ligament), sacrocolpopexy (mesh repair placed abdominally via open or minimally invasive surgery), or transvaginal mesh repair.

TAKEAWAY:

• At 36 months, a composite measure of treatment failure — based on the need for retreatment, the presence of symptoms, or prolapse beyond the hymen — had occurred in 28% of the women who received sacrocolpopexy, 29% who received transvaginal mesh, and 43% who underwent native tissue repair.
• Sacrocolpopexy was superior to native tissue repair for treatment success (adjusted hazard ratio, 0.57; P = .01), and transvaginal mesh was noninferior to sacrocolpopexy, the researchers found.
• All of the surgical approaches were associated with high rates of treatment satisfaction and improved quality of life and sexual function.
• Adverse events and mesh complications were uncommon.

IN PRACTICE:

“All approaches were associated with high treatment satisfaction; improved symptoms, quality of life, and sexual function; and low rates of regret,” the authors of the study wrote. “As such, clinicians counseling patients with prolapse can discuss the ramifications of each approach and engage in shared, individualized decision-making.”

SOURCE:

The study was led by Shawn A. Menefee, MD, Kaiser Permanente San Diego in San Diego, California. It was published online in JAMA Surgery.

LIMITATIONS:

The US Food and Drug Administration in April 2019 banned transvaginal mesh for pelvic organ prolapse because of concerns about complications such as exposure and erosion. Five trial participants who had been assigned to receive transvaginal mesh but had not yet received it at that time were rerandomized to one of the other surgical approaches.

DISCLOSURES:

The study was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institutes of Health Office of Research on Women’s Health. Researchers disclosed consulting for companies that market medical devices.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Various surgical approaches to treat vaginal vault prolapse may be similarly safe and effective and can produce high rates of patient satisfaction.

METHODOLOGY:

• A randomized clinical trial at nine sites in the United States included 360 women with vaginal vault prolapse after hysterectomy (average age, 66 years).
• The women were randomly assigned to undergo native tissue repair (transvaginal repair using the sacrospinous or uterosacral ligament), sacrocolpopexy (mesh repair placed abdominally via open or minimally invasive surgery), or transvaginal mesh repair.

TAKEAWAY:

• At 36 months, a composite measure of treatment failure — based on the need for retreatment, the presence of symptoms, or prolapse beyond the hymen — had occurred in 28% of the women who received sacrocolpopexy, 29% who received transvaginal mesh, and 43% who underwent native tissue repair.
• Sacrocolpopexy was superior to native tissue repair for treatment success (adjusted hazard ratio, 0.57; P = .01), and transvaginal mesh was noninferior to sacrocolpopexy, the researchers found.
• All of the surgical approaches were associated with high rates of treatment satisfaction and improved quality of life and sexual function.
• Adverse events and mesh complications were uncommon.

IN PRACTICE:

“All approaches were associated with high treatment satisfaction; improved symptoms, quality of life, and sexual function; and low rates of regret,” the authors of the study wrote. “As such, clinicians counseling patients with prolapse can discuss the ramifications of each approach and engage in shared, individualized decision-making.”

SOURCE:

The study was led by Shawn A. Menefee, MD, Kaiser Permanente San Diego in San Diego, California. It was published online in JAMA Surgery.

LIMITATIONS:

The US Food and Drug Administration in April 2019 banned transvaginal mesh for pelvic organ prolapse because of concerns about complications such as exposure and erosion. Five trial participants who had been assigned to receive transvaginal mesh but had not yet received it at that time were rerandomized to one of the other surgical approaches.

DISCLOSURES:

The study was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institutes of Health Office of Research on Women’s Health. Researchers disclosed consulting for companies that market medical devices.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Various surgical approaches to treat vaginal vault prolapse may be similarly safe and effective and can produce high rates of patient satisfaction.

METHODOLOGY:

• A randomized clinical trial at nine sites in the United States included 360 women with vaginal vault prolapse after hysterectomy (average age, 66 years).
• The women were randomly assigned to undergo native tissue repair (transvaginal repair using the sacrospinous or uterosacral ligament), sacrocolpopexy (mesh repair placed abdominally via open or minimally invasive surgery), or transvaginal mesh repair.

TAKEAWAY:

• At 36 months, a composite measure of treatment failure — based on the need for retreatment, the presence of symptoms, or prolapse beyond the hymen — had occurred in 28% of the women who received sacrocolpopexy, 29% who received transvaginal mesh, and 43% who underwent native tissue repair.
• Sacrocolpopexy was superior to native tissue repair for treatment success (adjusted hazard ratio, 0.57; P = .01), and transvaginal mesh was noninferior to sacrocolpopexy, the researchers found.
• All of the surgical approaches were associated with high rates of treatment satisfaction and improved quality of life and sexual function.
• Adverse events and mesh complications were uncommon.

IN PRACTICE:

“All approaches were associated with high treatment satisfaction; improved symptoms, quality of life, and sexual function; and low rates of regret,” the authors of the study wrote. “As such, clinicians counseling patients with prolapse can discuss the ramifications of each approach and engage in shared, individualized decision-making.”

SOURCE:

The study was led by Shawn A. Menefee, MD, Kaiser Permanente San Diego in San Diego, California. It was published online in JAMA Surgery.

LIMITATIONS:

The US Food and Drug Administration in April 2019 banned transvaginal mesh for pelvic organ prolapse because of concerns about complications such as exposure and erosion. Five trial participants who had been assigned to receive transvaginal mesh but had not yet received it at that time were rerandomized to one of the other surgical approaches.

DISCLOSURES:

The study was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institutes of Health Office of Research on Women’s Health. Researchers disclosed consulting for companies that market medical devices.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

This transcript has been edited for clarity. 

Rachel S. Rubin, MD: As a sexual medicine specialist, I treat a lot of menopause. Why? Because menopausal complaints are not just hot flashes and night sweats; we see so many sexual health problems: genital urinary syndrome of menopause (GUSM), low libido, pain with sex, arousal disorders, orgasm disorders. I am joined today with a superstar in the menopause field, Dr. Stephanie Faubion. Introduce yourself to our amazing listeners.

Stephanie S. Faubion, MD, MBA: I am Stephanie Faubion, director of the Mayo Clinic Center for Women’s Health and medical director for the Menopause Society.

Dr. Rubin: That is a very short introduction for a very impressive person who really is an authority, if you’ve ever read an article about menopause. I asked Dr. Faubion if she spends all her time talking to reporters. But it’s very important because menopause is having a moment. We can’t go a day without seeing a headline, an Instagram story, or something; my feed is full of menopause information. Why do you think menopause is having a moment right now?

Dr. Faubion: It’s a well-deserved moment and should have happened a long time ago. It’s having a moment for several reasons. The generation of women experiencing perimenopause and menopause is different now; they are less willing to suffer in silence, which is a great thing. We’ve also created a little bit of a care vacuum. The Women’s Health Initiative (WHI) study came out in 2002, and after that, we really left women with few choices about what to take to manage their symptoms. That created a vacuum. 

After that, clinicians decided they no longer needed to worry about being educated about menopause because there was really nothing to do for menopause if we weren’t going to use hormone therapy. Where we’ve come to now is women are having symptoms; they’re having a problem. It’s affecting all aspects of their lives: their relationships, their quality of life, their ability to work. And they’re saying, “Hey, this isn’t right. We need to do something about this.” There’s still very little research in this area. We have a lot more to do. They’re demanding answers, as they should. 

Dr. Rubin: We have quite a lot of tools in our toolbox that are evidence based, that really work and help people. I always say to my patients, “You have a generation of clinicians who were not taught how to do this well. Hormones are not all good or all bad, all right or all wrong, but they require some understanding of when to use them and how to safely use them.” That way, you can avoid your patients going to the snake oil salesmen down the street selling non–evidence-based treatments. 

One article that came out this year that I thought was really fascinating was about what we are calling NFLM: not feeling like myself. I will tell you, I think it’s brilliant because there is not a woman aged 40 or above who doesn’t deeply connect with the idea of NFLM. Can you speak to the symptoms of perimenopause and menopause beyond hot flashes and night sweats? I named a few sexual symptoms earlier. We’re really learning about all these new areas to understand, what is perimenopause? 

Dr. Faubion: Very rarely does a woman come in and say, “I have hot flashes” and I say, “Well, is that all you have?” “Yep. That’s all I have. I just have a couple of hot flashes.” That almost never happens, as you know. Menopause is not just about hot flashes, although that’s one of the most common symptoms. Hot flashes also occur at night. We call them night sweats when that happens. But there’s the sleep disturbance, which is probably not just related to night sweats but a lot of other things as well. Mood symptoms can be crazy. A lot of women come in with descriptions of irritability, just not feeling right, or feeling anxious. Another common symptom that we’re learning about is joint aches. 

It’s important to remember when we’re talking about these symptoms that estrogen affects every tissue and organ system in the body. And when you lose it, you have effects in pretty much every tissue and organ system in the body. So, it’s not just about hot flashes and night sweats. We’ve also learned recently that women in perimenopause can have the same symptoms that women have after menopause. It’s not just that it starts at menopause. 

Dr. Rubin: This is really important because we are speaking to the primary care world. The way medicine is set up, you’re allowed to have one problem. If you have more than one problem, I don’t know what to do. You go in the crazy bucket of we’re not interested or we don’t have time to take care of you. But menopause is never one problem. So, the disaster here is that these women are getting diagnosed with a mental health condition, with fibromyalgia, with dry eye, with sexual dysfunction, with depression or anxiety. They’re getting 10 diagnoses for what is actually one underlying hypogonadal problem. 

Dr. Faubion: That’s exactly right. I’ve seen a woman at the Mayo Clinic, who came to me as a general internist, not even knowing I did menopause. She traveled across the country to see me. She’s gaining weight, she’s losing her hair, she’s sweating. She thinks there is something horribly wrong with her, like she must have cancer or something. When you put it all together — the palpitations and the rest — it was all menopause. Think of the expense to come to the Mayo Clinic and be evaluated for that. But no one, including her, had put together the fact that all of these symptoms were related to menopause. You’re exactly right. Sometimes women don’t even recognize that it’s all related. 

Dr. Rubin: For the primary care viewers, we were raised on the idea that hormones cause cancer. Can you speak to that? What are the data in 2024? Am I going to die if I take hormone therapy? Am I going to risk blood clots and horrible cancers? 

Dr. Faubion: To be brief, we now know who the best candidates are for hormone therapy, and we can really minimize risk. We also know that there are differences between the formulations that we use, the route of delivery, and the dose. We can really individualize this for the woman. 

When it comes down to cancer risk, the WHI found that if you have a uterus and you’re taking both an estrogen and a progestogen (specifically conjugated equine estrogen and medroxyprogesterone acetate), the risk for breast cancer was increased slightly. When I say “slightly,” I’m talking the same as the increase in breast cancer risk of drinking one to two glasses of wine a night, or being overweight, or being inactive. We are really talking about less than one case per thousand women per year after about 5 years of hormone therapy. So, it’s a very small increased risk.

In contrast, the data showed that the risk for breast cancer did not appear to be increased in women who did not have a uterus and were using conjugated equine estrogen alone, either during the study or in the 18-year follow-up. The blood clot risk associated with estrogen-containing hormone therapy can be minimized with transdermal preparations of estrogen, particularly with lower doses. Overall, we don’t see that these risks are prohibitive for most women, and if they are having bothersome symptoms, they can use an estrogen-containing product safely. 

Dr. Rubin: We can learn new things, right? For example, the new GLP-1 drugs, which is also very fascinating — using those in perimenopause and menopause. A GLP-1 deficiency may be increased as you go to perimenopause and menopause. By adding back hormones, maybe we can help keep muscle around, keep mental health better, and keep bones stronger, because osteoporosis and fractures kill more people than breast cancer does. 

So, as a primary care clinician, how do we learn to write prescriptions for hormone therapy? How do we learn how to counsel patients properly? Do we have to go back and take a fellowship? How do I learn how to integrate the evidence into my practice? 

Dr. Faubion: An easy thing to do to gain confidence is take a course. The North American Menopause Society has an annual meeting in Chicago in September, and we do a Menopause 101 course for clinicians there. It’s also available online. There are ways to get this information in a digestible way to where you can learn the basics: Here’s where I start; here’s how I need to follow it up. It’s really not that difficult to get into this. 

As to your point about the GLP-1 drugs, we all have to learn new things every day because treatments change, drugs change, etc. Although hormones have been out there for a long time, many clinicians haven’t had the experience of treating menopausal women. I would put a plea out to my primary care colleagues in internal medicine and family medicine that you need to be doing this. Think about it — you already are the expert on brain health and bone health and heart health. You should be the most comfortable in dealing with hormone therapy that has effects throughout the entire body. It’s important for us as primary care providers to really have a handle on this and to be the owners of managing menopause for women in midlife. 

Dr. Rubin: I couldn’t agree more. As a sexual medicine doctor, treating menopausal women is actually what fuels my soul and stops all burnout because they get better. My clinic is full of a fifty-something-year-old people who come back and they say sex is good. “My relationship is good.” “I’m kicking butt at work.” I have a patient who just started law school because she feels good, and she says, “I’m keeping up with the 20-year-olds.” It is incredible to see people who feel terrible and then watch them blossom and get better. There’s nothing that fuels my soul more than these patients. 

What is exciting you in the menopause world? What are you hopeful for down the road with some of these new initiatives coming out? 

Dr. Faubion: The fact that we have a president of the United States and a National Institutes of Health who are more interested in looking at menopause is amazing. It’s an exciting time; there’s more interest, and more research funding seems to be available for the United States. 

In terms of clinical management, we now have so many options available to women. We’ve been talking about hormone therapy, but we now have nonhormonal medications out there as well that are on the market, such as fezolinetant, a neurokinin 3 inhibitor that came out last year. There’s probably another one coming out in the next year or so. So, women have lots of options, and for the first time, we can really individualize treatment for women and look at what symptoms are bothering them, and how best to get them back to where they should be. 

We’re also starting a menopause-in-the-workplace initiative with the Menopause Society and really kind of tackling that one. We know that a lot of women are missing work, not taking a promotion, or avoiding a leadership role because of their menopause symptoms. Women should never be in the position of compromising their work lives because of menopause symptoms. This is something we can help women with. 

Dr. Rubin: Our big takeaway today is: Believe your patients when they come to you, and they’ve driven and parked and arranged childcare, and showed up to your office and waited to see you. When they’re telling you that they have all these symptoms and they’re not feeling like themselves, maybe before you jump straight to the SSRI or just say, “Do some yoga and deep breathing,” maybe really dive into the menopause literature and understand the pros and cons, and the risks and benefits of hormone therapy. We do it with so many other things. We can do it with hormone therapy as well. It is not a one-size-fits-all. We do need to talk to our patients, customize their care, and really figure out what they care about and what they want. Patients are able to understand risks and benefits and can make good decisions for themselves.

Dr. Rubin is an assistant clinical professor, Department of Urology, at Georgetown University, Washington, DC. She reported conflicts of interest with Sprout, Maternal Medical, Absorption Pharmaceuticals, GSK, and Endo.

A version of this article first appeared on Medscape.com.

This transcript has been edited for clarity. 

Rachel S. Rubin, MD: As a sexual medicine specialist, I treat a lot of menopause. Why? Because menopausal complaints are not just hot flashes and night sweats; we see so many sexual health problems: genital urinary syndrome of menopause (GUSM), low libido, pain with sex, arousal disorders, orgasm disorders. I am joined today with a superstar in the menopause field, Dr. Stephanie Faubion. Introduce yourself to our amazing listeners.

Stephanie S. Faubion, MD, MBA: I am Stephanie Faubion, director of the Mayo Clinic Center for Women’s Health and medical director for the Menopause Society.

Dr. Rubin: That is a very short introduction for a very impressive person who really is an authority, if you’ve ever read an article about menopause. I asked Dr. Faubion if she spends all her time talking to reporters. But it’s very important because menopause is having a moment. We can’t go a day without seeing a headline, an Instagram story, or something; my feed is full of menopause information. Why do you think menopause is having a moment right now?

Dr. Faubion: It’s a well-deserved moment and should have happened a long time ago. It’s having a moment for several reasons. The generation of women experiencing perimenopause and menopause is different now; they are less willing to suffer in silence, which is a great thing. We’ve also created a little bit of a care vacuum. The Women’s Health Initiative (WHI) study came out in 2002, and after that, we really left women with few choices about what to take to manage their symptoms. That created a vacuum. 

After that, clinicians decided they no longer needed to worry about being educated about menopause because there was really nothing to do for menopause if we weren’t going to use hormone therapy. Where we’ve come to now is women are having symptoms; they’re having a problem. It’s affecting all aspects of their lives: their relationships, their quality of life, their ability to work. And they’re saying, “Hey, this isn’t right. We need to do something about this.” There’s still very little research in this area. We have a lot more to do. They’re demanding answers, as they should. 

Dr. Rubin: We have quite a lot of tools in our toolbox that are evidence based, that really work and help people. I always say to my patients, “You have a generation of clinicians who were not taught how to do this well. Hormones are not all good or all bad, all right or all wrong, but they require some understanding of when to use them and how to safely use them.” That way, you can avoid your patients going to the snake oil salesmen down the street selling non–evidence-based treatments. 

One article that came out this year that I thought was really fascinating was about what we are calling NFLM: not feeling like myself. I will tell you, I think it’s brilliant because there is not a woman aged 40 or above who doesn’t deeply connect with the idea of NFLM. Can you speak to the symptoms of perimenopause and menopause beyond hot flashes and night sweats? I named a few sexual symptoms earlier. We’re really learning about all these new areas to understand, what is perimenopause? 

Dr. Faubion: Very rarely does a woman come in and say, “I have hot flashes” and I say, “Well, is that all you have?” “Yep. That’s all I have. I just have a couple of hot flashes.” That almost never happens, as you know. Menopause is not just about hot flashes, although that’s one of the most common symptoms. Hot flashes also occur at night. We call them night sweats when that happens. But there’s the sleep disturbance, which is probably not just related to night sweats but a lot of other things as well. Mood symptoms can be crazy. A lot of women come in with descriptions of irritability, just not feeling right, or feeling anxious. Another common symptom that we’re learning about is joint aches. 

It’s important to remember when we’re talking about these symptoms that estrogen affects every tissue and organ system in the body. And when you lose it, you have effects in pretty much every tissue and organ system in the body. So, it’s not just about hot flashes and night sweats. We’ve also learned recently that women in perimenopause can have the same symptoms that women have after menopause. It’s not just that it starts at menopause. 

Dr. Rubin: This is really important because we are speaking to the primary care world. The way medicine is set up, you’re allowed to have one problem. If you have more than one problem, I don’t know what to do. You go in the crazy bucket of we’re not interested or we don’t have time to take care of you. But menopause is never one problem. So, the disaster here is that these women are getting diagnosed with a mental health condition, with fibromyalgia, with dry eye, with sexual dysfunction, with depression or anxiety. They’re getting 10 diagnoses for what is actually one underlying hypogonadal problem. 

Dr. Faubion: That’s exactly right. I’ve seen a woman at the Mayo Clinic, who came to me as a general internist, not even knowing I did menopause. She traveled across the country to see me. She’s gaining weight, she’s losing her hair, she’s sweating. She thinks there is something horribly wrong with her, like she must have cancer or something. When you put it all together — the palpitations and the rest — it was all menopause. Think of the expense to come to the Mayo Clinic and be evaluated for that. But no one, including her, had put together the fact that all of these symptoms were related to menopause. You’re exactly right. Sometimes women don’t even recognize that it’s all related. 

Dr. Rubin: For the primary care viewers, we were raised on the idea that hormones cause cancer. Can you speak to that? What are the data in 2024? Am I going to die if I take hormone therapy? Am I going to risk blood clots and horrible cancers? 

Dr. Faubion: To be brief, we now know who the best candidates are for hormone therapy, and we can really minimize risk. We also know that there are differences between the formulations that we use, the route of delivery, and the dose. We can really individualize this for the woman. 

When it comes down to cancer risk, the WHI found that if you have a uterus and you’re taking both an estrogen and a progestogen (specifically conjugated equine estrogen and medroxyprogesterone acetate), the risk for breast cancer was increased slightly. When I say “slightly,” I’m talking the same as the increase in breast cancer risk of drinking one to two glasses of wine a night, or being overweight, or being inactive. We are really talking about less than one case per thousand women per year after about 5 years of hormone therapy. So, it’s a very small increased risk.

In contrast, the data showed that the risk for breast cancer did not appear to be increased in women who did not have a uterus and were using conjugated equine estrogen alone, either during the study or in the 18-year follow-up. The blood clot risk associated with estrogen-containing hormone therapy can be minimized with transdermal preparations of estrogen, particularly with lower doses. Overall, we don’t see that these risks are prohibitive for most women, and if they are having bothersome symptoms, they can use an estrogen-containing product safely. 

Dr. Rubin: We can learn new things, right? For example, the new GLP-1 drugs, which is also very fascinating — using those in perimenopause and menopause. A GLP-1 deficiency may be increased as you go to perimenopause and menopause. By adding back hormones, maybe we can help keep muscle around, keep mental health better, and keep bones stronger, because osteoporosis and fractures kill more people than breast cancer does. 

So, as a primary care clinician, how do we learn to write prescriptions for hormone therapy? How do we learn how to counsel patients properly? Do we have to go back and take a fellowship? How do I learn how to integrate the evidence into my practice? 

Dr. Faubion: An easy thing to do to gain confidence is take a course. The North American Menopause Society has an annual meeting in Chicago in September, and we do a Menopause 101 course for clinicians there. It’s also available online. There are ways to get this information in a digestible way to where you can learn the basics: Here’s where I start; here’s how I need to follow it up. It’s really not that difficult to get into this. 

As to your point about the GLP-1 drugs, we all have to learn new things every day because treatments change, drugs change, etc. Although hormones have been out there for a long time, many clinicians haven’t had the experience of treating menopausal women. I would put a plea out to my primary care colleagues in internal medicine and family medicine that you need to be doing this. Think about it — you already are the expert on brain health and bone health and heart health. You should be the most comfortable in dealing with hormone therapy that has effects throughout the entire body. It’s important for us as primary care providers to really have a handle on this and to be the owners of managing menopause for women in midlife. 

Dr. Rubin: I couldn’t agree more. As a sexual medicine doctor, treating menopausal women is actually what fuels my soul and stops all burnout because they get better. My clinic is full of a fifty-something-year-old people who come back and they say sex is good. “My relationship is good.” “I’m kicking butt at work.” I have a patient who just started law school because she feels good, and she says, “I’m keeping up with the 20-year-olds.” It is incredible to see people who feel terrible and then watch them blossom and get better. There’s nothing that fuels my soul more than these patients. 

What is exciting you in the menopause world? What are you hopeful for down the road with some of these new initiatives coming out? 

Dr. Faubion: The fact that we have a president of the United States and a National Institutes of Health who are more interested in looking at menopause is amazing. It’s an exciting time; there’s more interest, and more research funding seems to be available for the United States. 

In terms of clinical management, we now have so many options available to women. We’ve been talking about hormone therapy, but we now have nonhormonal medications out there as well that are on the market, such as fezolinetant, a neurokinin 3 inhibitor that came out last year. There’s probably another one coming out in the next year or so. So, women have lots of options, and for the first time, we can really individualize treatment for women and look at what symptoms are bothering them, and how best to get them back to where they should be. 

We’re also starting a menopause-in-the-workplace initiative with the Menopause Society and really kind of tackling that one. We know that a lot of women are missing work, not taking a promotion, or avoiding a leadership role because of their menopause symptoms. Women should never be in the position of compromising their work lives because of menopause symptoms. This is something we can help women with. 

Dr. Rubin: Our big takeaway today is: Believe your patients when they come to you, and they’ve driven and parked and arranged childcare, and showed up to your office and waited to see you. When they’re telling you that they have all these symptoms and they’re not feeling like themselves, maybe before you jump straight to the SSRI or just say, “Do some yoga and deep breathing,” maybe really dive into the menopause literature and understand the pros and cons, and the risks and benefits of hormone therapy. We do it with so many other things. We can do it with hormone therapy as well. It is not a one-size-fits-all. We do need to talk to our patients, customize their care, and really figure out what they care about and what they want. Patients are able to understand risks and benefits and can make good decisions for themselves.

Dr. Rubin is an assistant clinical professor, Department of Urology, at Georgetown University, Washington, DC. She reported conflicts of interest with Sprout, Maternal Medical, Absorption Pharmaceuticals, GSK, and Endo.

A version of this article first appeared on Medscape.com.

This transcript has been edited for clarity. 

Rachel S. Rubin, MD: As a sexual medicine specialist, I treat a lot of menopause. Why? Because menopausal complaints are not just hot flashes and night sweats; we see so many sexual health problems: genital urinary syndrome of menopause (GUSM), low libido, pain with sex, arousal disorders, orgasm disorders. I am joined today with a superstar in the menopause field, Dr. Stephanie Faubion. Introduce yourself to our amazing listeners.

Stephanie S. Faubion, MD, MBA: I am Stephanie Faubion, director of the Mayo Clinic Center for Women’s Health and medical director for the Menopause Society.

Dr. Rubin: That is a very short introduction for a very impressive person who really is an authority, if you’ve ever read an article about menopause. I asked Dr. Faubion if she spends all her time talking to reporters. But it’s very important because menopause is having a moment. We can’t go a day without seeing a headline, an Instagram story, or something; my feed is full of menopause information. Why do you think menopause is having a moment right now?

Dr. Faubion: It’s a well-deserved moment and should have happened a long time ago. It’s having a moment for several reasons. The generation of women experiencing perimenopause and menopause is different now; they are less willing to suffer in silence, which is a great thing. We’ve also created a little bit of a care vacuum. The Women’s Health Initiative (WHI) study came out in 2002, and after that, we really left women with few choices about what to take to manage their symptoms. That created a vacuum. 

After that, clinicians decided they no longer needed to worry about being educated about menopause because there was really nothing to do for menopause if we weren’t going to use hormone therapy. Where we’ve come to now is women are having symptoms; they’re having a problem. It’s affecting all aspects of their lives: their relationships, their quality of life, their ability to work. And they’re saying, “Hey, this isn’t right. We need to do something about this.” There’s still very little research in this area. We have a lot more to do. They’re demanding answers, as they should. 

Dr. Rubin: We have quite a lot of tools in our toolbox that are evidence based, that really work and help people. I always say to my patients, “You have a generation of clinicians who were not taught how to do this well. Hormones are not all good or all bad, all right or all wrong, but they require some understanding of when to use them and how to safely use them.” That way, you can avoid your patients going to the snake oil salesmen down the street selling non–evidence-based treatments. 

One article that came out this year that I thought was really fascinating was about what we are calling NFLM: not feeling like myself. I will tell you, I think it’s brilliant because there is not a woman aged 40 or above who doesn’t deeply connect with the idea of NFLM. Can you speak to the symptoms of perimenopause and menopause beyond hot flashes and night sweats? I named a few sexual symptoms earlier. We’re really learning about all these new areas to understand, what is perimenopause? 

Dr. Faubion: Very rarely does a woman come in and say, “I have hot flashes” and I say, “Well, is that all you have?” “Yep. That’s all I have. I just have a couple of hot flashes.” That almost never happens, as you know. Menopause is not just about hot flashes, although that’s one of the most common symptoms. Hot flashes also occur at night. We call them night sweats when that happens. But there’s the sleep disturbance, which is probably not just related to night sweats but a lot of other things as well. Mood symptoms can be crazy. A lot of women come in with descriptions of irritability, just not feeling right, or feeling anxious. Another common symptom that we’re learning about is joint aches. 

It’s important to remember when we’re talking about these symptoms that estrogen affects every tissue and organ system in the body. And when you lose it, you have effects in pretty much every tissue and organ system in the body. So, it’s not just about hot flashes and night sweats. We’ve also learned recently that women in perimenopause can have the same symptoms that women have after menopause. It’s not just that it starts at menopause. 

Dr. Rubin: This is really important because we are speaking to the primary care world. The way medicine is set up, you’re allowed to have one problem. If you have more than one problem, I don’t know what to do. You go in the crazy bucket of we’re not interested or we don’t have time to take care of you. But menopause is never one problem. So, the disaster here is that these women are getting diagnosed with a mental health condition, with fibromyalgia, with dry eye, with sexual dysfunction, with depression or anxiety. They’re getting 10 diagnoses for what is actually one underlying hypogonadal problem. 

Dr. Faubion: That’s exactly right. I’ve seen a woman at the Mayo Clinic, who came to me as a general internist, not even knowing I did menopause. She traveled across the country to see me. She’s gaining weight, she’s losing her hair, she’s sweating. She thinks there is something horribly wrong with her, like she must have cancer or something. When you put it all together — the palpitations and the rest — it was all menopause. Think of the expense to come to the Mayo Clinic and be evaluated for that. But no one, including her, had put together the fact that all of these symptoms were related to menopause. You’re exactly right. Sometimes women don’t even recognize that it’s all related. 

Dr. Rubin: For the primary care viewers, we were raised on the idea that hormones cause cancer. Can you speak to that? What are the data in 2024? Am I going to die if I take hormone therapy? Am I going to risk blood clots and horrible cancers? 

Dr. Faubion: To be brief, we now know who the best candidates are for hormone therapy, and we can really minimize risk. We also know that there are differences between the formulations that we use, the route of delivery, and the dose. We can really individualize this for the woman. 

When it comes down to cancer risk, the WHI found that if you have a uterus and you’re taking both an estrogen and a progestogen (specifically conjugated equine estrogen and medroxyprogesterone acetate), the risk for breast cancer was increased slightly. When I say “slightly,” I’m talking the same as the increase in breast cancer risk of drinking one to two glasses of wine a night, or being overweight, or being inactive. We are really talking about less than one case per thousand women per year after about 5 years of hormone therapy. So, it’s a very small increased risk.

In contrast, the data showed that the risk for breast cancer did not appear to be increased in women who did not have a uterus and were using conjugated equine estrogen alone, either during the study or in the 18-year follow-up. The blood clot risk associated with estrogen-containing hormone therapy can be minimized with transdermal preparations of estrogen, particularly with lower doses. Overall, we don’t see that these risks are prohibitive for most women, and if they are having bothersome symptoms, they can use an estrogen-containing product safely. 

Dr. Rubin: We can learn new things, right? For example, the new GLP-1 drugs, which is also very fascinating — using those in perimenopause and menopause. A GLP-1 deficiency may be increased as you go to perimenopause and menopause. By adding back hormones, maybe we can help keep muscle around, keep mental health better, and keep bones stronger, because osteoporosis and fractures kill more people than breast cancer does. 

So, as a primary care clinician, how do we learn to write prescriptions for hormone therapy? How do we learn how to counsel patients properly? Do we have to go back and take a fellowship? How do I learn how to integrate the evidence into my practice? 

Dr. Faubion: An easy thing to do to gain confidence is take a course. The North American Menopause Society has an annual meeting in Chicago in September, and we do a Menopause 101 course for clinicians there. It’s also available online. There are ways to get this information in a digestible way to where you can learn the basics: Here’s where I start; here’s how I need to follow it up. It’s really not that difficult to get into this. 

As to your point about the GLP-1 drugs, we all have to learn new things every day because treatments change, drugs change, etc. Although hormones have been out there for a long time, many clinicians haven’t had the experience of treating menopausal women. I would put a plea out to my primary care colleagues in internal medicine and family medicine that you need to be doing this. Think about it — you already are the expert on brain health and bone health and heart health. You should be the most comfortable in dealing with hormone therapy that has effects throughout the entire body. It’s important for us as primary care providers to really have a handle on this and to be the owners of managing menopause for women in midlife. 

Dr. Rubin: I couldn’t agree more. As a sexual medicine doctor, treating menopausal women is actually what fuels my soul and stops all burnout because they get better. My clinic is full of a fifty-something-year-old people who come back and they say sex is good. “My relationship is good.” “I’m kicking butt at work.” I have a patient who just started law school because she feels good, and she says, “I’m keeping up with the 20-year-olds.” It is incredible to see people who feel terrible and then watch them blossom and get better. There’s nothing that fuels my soul more than these patients. 

What is exciting you in the menopause world? What are you hopeful for down the road with some of these new initiatives coming out? 

Dr. Faubion: The fact that we have a president of the United States and a National Institutes of Health who are more interested in looking at menopause is amazing. It’s an exciting time; there’s more interest, and more research funding seems to be available for the United States. 

In terms of clinical management, we now have so many options available to women. We’ve been talking about hormone therapy, but we now have nonhormonal medications out there as well that are on the market, such as fezolinetant, a neurokinin 3 inhibitor that came out last year. There’s probably another one coming out in the next year or so. So, women have lots of options, and for the first time, we can really individualize treatment for women and look at what symptoms are bothering them, and how best to get them back to where they should be. 

We’re also starting a menopause-in-the-workplace initiative with the Menopause Society and really kind of tackling that one. We know that a lot of women are missing work, not taking a promotion, or avoiding a leadership role because of their menopause symptoms. Women should never be in the position of compromising their work lives because of menopause symptoms. This is something we can help women with. 

Dr. Rubin: Our big takeaway today is: Believe your patients when they come to you, and they’ve driven and parked and arranged childcare, and showed up to your office and waited to see you. When they’re telling you that they have all these symptoms and they’re not feeling like themselves, maybe before you jump straight to the SSRI or just say, “Do some yoga and deep breathing,” maybe really dive into the menopause literature and understand the pros and cons, and the risks and benefits of hormone therapy. We do it with so many other things. We can do it with hormone therapy as well. It is not a one-size-fits-all. We do need to talk to our patients, customize their care, and really figure out what they care about and what they want. Patients are able to understand risks and benefits and can make good decisions for themselves.

Dr. Rubin is an assistant clinical professor, Department of Urology, at Georgetown University, Washington, DC. She reported conflicts of interest with Sprout, Maternal Medical, Absorption Pharmaceuticals, GSK, and Endo.

A version of this article first appeared on Medscape.com.

TOPLINE:

Accurately diagnosing recurrent urinary tract infections (rUTIs) in older women is challenging and requires careful weighing of the risks and benefits of various treatments, according to a new clinical insight published in JAMA Internal Medicine.

METHODOLOGY:

• Women aged > 65 years have double the rUTI rates compared with younger women, but detecting the condition is more complicated due to age-related conditions, such as overactive bladder related to menopause.
• Overuse of antibiotics can increase their risk of contracting antibiotic-resistant organisms and can lead to pulmonary or hepatic toxic effects in women with reduced kidney function.
• Up to 20% of older women have bacteria in their urine, which may or may not reflect a rUTI.
• Diagnosing rUTIs is complicated if women have dementia or cognitive decline, which can hinder recollection of symptoms.

TAKEAWAYS:

• Clinicians should consider only testing older female patients for rUTIs when symptoms are present and consider all possibilities before making a diagnosis.
• Vaginal estrogen may be an effective treatment, although the authors of the clinical review note a lack of a uniform formulation to recommend. However, oral estrogen use is not supported by evidence, and clinicians should instead consider vaginal creams or rings.
• The drug methenamine may be as effective as antibiotics but may not be safe for women with comorbidities. Evidence supports daily use at 1 g.
• Cranberry supplements and behavioral changes may be helpful, but evidence is limited, including among women living in long-term care facilities.

IN PRACTICE:

“Shared decision-making is especially important when diagnosis of an rUTI episode in older women is unclear ... in these cases, clinicians should acknowledge limitations in the evidence and invite patients or their caregivers to discuss preferences about presumptive treatment, weighing the possibility of earlier symptom relief or decreased UTI complications against the risk of adverse drug effects or multidrug resistance.”

SOURCE:

The paper was led by Alison J. Huang, MD, MAS, an internal medicine specialist and researcher in the Department of Medicine at the University of California, San Francisco.

LIMITATIONS:

The authors reported no limitations.

DISCLOSURES:

Dr. Huang received grants from the National Institutes of Health. Other authors reported receiving grants from the Agency for Healthcare Research and Quality, the US Department of Veterans Affairs, the Kahn Foundation, and Nanovibronix.

Cranberry supplements and behavioral changes may be helpful, but evidence is limited, including among women living in long-term care facilities.

A version of this article first appeared on Medscape.com.

TOPLINE:

Accurately diagnosing recurrent urinary tract infections (rUTIs) in older women is challenging and requires careful weighing of the risks and benefits of various treatments, according to a new clinical insight published in JAMA Internal Medicine.

METHODOLOGY:

• Women aged > 65 years have double the rUTI rates compared with younger women, but detecting the condition is more complicated due to age-related conditions, such as overactive bladder related to menopause.
• Overuse of antibiotics can increase their risk of contracting antibiotic-resistant organisms and can lead to pulmonary or hepatic toxic effects in women with reduced kidney function.
• Up to 20% of older women have bacteria in their urine, which may or may not reflect a rUTI.
• Diagnosing rUTIs is complicated if women have dementia or cognitive decline, which can hinder recollection of symptoms.

TAKEAWAYS:

• Clinicians should consider only testing older female patients for rUTIs when symptoms are present and consider all possibilities before making a diagnosis.
• Vaginal estrogen may be an effective treatment, although the authors of the clinical review note a lack of a uniform formulation to recommend. However, oral estrogen use is not supported by evidence, and clinicians should instead consider vaginal creams or rings.
• The drug methenamine may be as effective as antibiotics but may not be safe for women with comorbidities. Evidence supports daily use at 1 g.
• Cranberry supplements and behavioral changes may be helpful, but evidence is limited, including among women living in long-term care facilities.

IN PRACTICE:

“Shared decision-making is especially important when diagnosis of an rUTI episode in older women is unclear ... in these cases, clinicians should acknowledge limitations in the evidence and invite patients or their caregivers to discuss preferences about presumptive treatment, weighing the possibility of earlier symptom relief or decreased UTI complications against the risk of adverse drug effects or multidrug resistance.”

SOURCE:

The paper was led by Alison J. Huang, MD, MAS, an internal medicine specialist and researcher in the Department of Medicine at the University of California, San Francisco.

LIMITATIONS:

The authors reported no limitations.

DISCLOSURES:

Dr. Huang received grants from the National Institutes of Health. Other authors reported receiving grants from the Agency for Healthcare Research and Quality, the US Department of Veterans Affairs, the Kahn Foundation, and Nanovibronix.

Cranberry supplements and behavioral changes may be helpful, but evidence is limited, including among women living in long-term care facilities.

A version of this article first appeared on Medscape.com.

TOPLINE:

Accurately diagnosing recurrent urinary tract infections (rUTIs) in older women is challenging and requires careful weighing of the risks and benefits of various treatments, according to a new clinical insight published in JAMA Internal Medicine.

METHODOLOGY:

• Women aged > 65 years have double the rUTI rates compared with younger women, but detecting the condition is more complicated due to age-related conditions, such as overactive bladder related to menopause.
• Overuse of antibiotics can increase their risk of contracting antibiotic-resistant organisms and can lead to pulmonary or hepatic toxic effects in women with reduced kidney function.
• Up to 20% of older women have bacteria in their urine, which may or may not reflect a rUTI.
• Diagnosing rUTIs is complicated if women have dementia or cognitive decline, which can hinder recollection of symptoms.

TAKEAWAYS:

• Clinicians should consider only testing older female patients for rUTIs when symptoms are present and consider all possibilities before making a diagnosis.
• Vaginal estrogen may be an effective treatment, although the authors of the clinical review note a lack of a uniform formulation to recommend. However, oral estrogen use is not supported by evidence, and clinicians should instead consider vaginal creams or rings.
• The drug methenamine may be as effective as antibiotics but may not be safe for women with comorbidities. Evidence supports daily use at 1 g.
• Cranberry supplements and behavioral changes may be helpful, but evidence is limited, including among women living in long-term care facilities.

IN PRACTICE:

“Shared decision-making is especially important when diagnosis of an rUTI episode in older women is unclear ... in these cases, clinicians should acknowledge limitations in the evidence and invite patients or their caregivers to discuss preferences about presumptive treatment, weighing the possibility of earlier symptom relief or decreased UTI complications against the risk of adverse drug effects or multidrug resistance.”

SOURCE:

The paper was led by Alison J. Huang, MD, MAS, an internal medicine specialist and researcher in the Department of Medicine at the University of California, San Francisco.

LIMITATIONS:

The authors reported no limitations.

DISCLOSURES:

Dr. Huang received grants from the National Institutes of Health. Other authors reported receiving grants from the Agency for Healthcare Research and Quality, the US Department of Veterans Affairs, the Kahn Foundation, and Nanovibronix.

Cranberry supplements and behavioral changes may be helpful, but evidence is limited, including among women living in long-term care facilities.

A version of this article first appeared on Medscape.com.

Two decades after the landmark Women’s Health Initiative (WHI) changed the way clinicians thought about hormone therapy and cancer, new findings suggest this national health study is "the gift that keeps on giving."

Follow-up from two of the WHI’s randomized trials have found that estrogen alone in women with prior hysterectomy significantly increased ovarian cancer incidence and mortality in postmenopausal women. Estrogen and progesterone together, meanwhile, did not increase ovarian cancer risk, and significantly reduced the risk of endometrial cancer. Rowan T. Chlebowski, MD, PhD, of The Lundquist Institute in Torrance, California, presented these results from the latest WHI findings, at the annual meeting of the American Society of Clinical Oncology in Chicago.

Dr. Chlebowski and his colleagues conducted an analysis from two randomized, placebo-controlled trials, which between 1993 and 1998 enrolled nearly 28,000 postmenopausal women aged 50-79 years without prior cancer from 40 centers across the United States. (The full WHI effort involved a total cohort of 161,000 patients, and included an observational study and two other non-drug trials.)

In one of the hormone therapy trials, 17,000 women with a uterus at baseline were randomized to combined equine estrogen plus medroxyprogesterone acetate, or placebo. In the other trial, about 11,000 women with prior hysterectomy were randomized to daily estrogen alone or placebo. Both trials were stopped early: the estrogen-only trial due to an increased stroke risk, and the combined therapy trial due to findings of increased breast cancer and cardiovascular risk.

Mean exposure to hormone therapy was 5.6 years for the combined therapy trial and 7.2 years for estrogen alone trial.
 

Ovarian Cancer Incidence Doubles with Estrogen

At 20 years’ follow up, with mortality information available for nearly the full cohort, Dr. Chlebowski and his colleagues could determine that ovarian cancer incidence doubled among women who had taken estrogen alone (hazard ratio = 2.04; 95% CI 1.14-3.65; P = .01), a difference that reached statistical significance at 12 years’ follow up. Ovarian cancer mortality was also significantly increased (HR = 2.79 95% CI 1.30-5.99, P = .006). Absolute numbers were small, however, with 35 cases of ovarian cancer compared with 17 in the placebo group.

Combined therapy recipients saw no increased risk for ovarian cancer and significantly lower endometrial cancer incidence (106 cases vs. 140 HR = 0.72; 95% CI, 0.56-0.92; P = .01).

Conjugated equine estrogen, Dr. Chlebowski said during his presentation at the meeting, “was introduced in US clinical practice in 1943 and used for over half a century, yet the question about hormone therapy’s influence on endometrial and ovarian cancer remains unsettled. Endometrial cancer and ovarian cancer are the fourth and fifth leading causes of cancer deaths in women ... and there’s some discordant findings from observational studies.”

Care of Ovarian Cancer Survivors Should Change

The new findings should prompt practice and guideline changes regarding the use of estrogen alone in ovarian cancer survivors, Dr. Chlebowski said.

In an interview, oncologist Eleonora Teplinsky, MD, of Valley-Mount Sinai Comprehensive Cancer Care in Paramus, New Jersey, said that apart from this subgroup of ovarian cancer survivors, the findings would not likely have much impact on how clinicians and patients approach hormone replacement therapy today.

“Twenty years ago the Women’s Health Initiative showed that hormone replacement therapy increases breast cancer risk, and everyone stopped taking HRT. And now people pushing back on it and saying wait a second – it was the estrogen plus progesterone that increased breast cancer, not estrogen alone. And now we’ve got these newer [estrogen] formulations.

“Yes, there’s a little bit of an increased risk [for ovarian cancer]. Patients should be aware. They should know the symptoms of ovarian cancer. But if they have indications and have been recommended HRT, this is not something that we would advise them against because of this very slightly increased risk,” Dr. Teplinsky said.

Oncologist Allison Kurian, MD of Stanford University in Stanford, California, who specializes in breast cancer, also noted that the duration of hormone treatment, treatment timing relative to age of menopause onset, and commonly used estrogen preparations had indeed changed since the time the WHI trials were conducted, making it harder to generalize the findings to current practice. Nonetheless, she argued, they still have real significance.

“WHI is an incredibly complex but also incredibly valuable resource,” said Dr. Kurian, who has conducted studies using WHI data. “The first big results came out in 2002, and we’re still learning from it. These are randomized trials, which offer the strongest form of scientific evidence that exists. So whenever we see results from this study, we have to take note of them,” she said.

Because the WHI trials had shown combined therapy, not estrogen alone, to be associated with breast cancer risk, clinicians have felt reassured over the years about using estrogen alone.

“You can’t give it to a person unless they have their uterus removed, because we know it will cause uterine cancer if the uterus is in place. But if the uterus is removed, the feeling was that you can give estrogen alone. I think the new piece that is going to get everyone’s attention is this signal for ovarian cancer.”

Something else the new findings show, Dr. Kurian said, is that WHI is “the gift that keeps on giving,” even after decades. “Some of the participants had a relatively short-term exposure to HRT. They took a medication for just a little while. But you didn’t see the effects until you followed people 12 years. So we’re now going to be a little more worried about ovarian cancer in this setting than we used to be. And that’s going to be something we’re all going to keep an eye on and think twice about in terms of talking to patients.”

These results help demonstrate what happens when a society invests in science on a national scale, Dr. Kurian said. “Here we have a really long-term, incredibly informative study that keeps generating knowledge to help women.”

When the WHI began, it “really was the first time that people decided it was important to systematically study women at midlife. It was a remarkable thing then that society got mobilized to do this, and we’re still seeing the benefits.”

Dr. Chlebowski disclosed receiving consulting or advisory fees from Pfizer. Dr. Teplinsky and Dr. Kurian disclosed no financial conflicts of interest.

Two decades after the landmark Women’s Health Initiative (WHI) changed the way clinicians thought about hormone therapy and cancer, new findings suggest this national health study is "the gift that keeps on giving."

Follow-up from two of the WHI’s randomized trials have found that estrogen alone in women with prior hysterectomy significantly increased ovarian cancer incidence and mortality in postmenopausal women. Estrogen and progesterone together, meanwhile, did not increase ovarian cancer risk, and significantly reduced the risk of endometrial cancer. Rowan T. Chlebowski, MD, PhD, of The Lundquist Institute in Torrance, California, presented these results from the latest WHI findings, at the annual meeting of the American Society of Clinical Oncology in Chicago.

Dr. Chlebowski and his colleagues conducted an analysis from two randomized, placebo-controlled trials, which between 1993 and 1998 enrolled nearly 28,000 postmenopausal women aged 50-79 years without prior cancer from 40 centers across the United States. (The full WHI effort involved a total cohort of 161,000 patients, and included an observational study and two other non-drug trials.)

In one of the hormone therapy trials, 17,000 women with a uterus at baseline were randomized to combined equine estrogen plus medroxyprogesterone acetate, or placebo. In the other trial, about 11,000 women with prior hysterectomy were randomized to daily estrogen alone or placebo. Both trials were stopped early: the estrogen-only trial due to an increased stroke risk, and the combined therapy trial due to findings of increased breast cancer and cardiovascular risk.

Mean exposure to hormone therapy was 5.6 years for the combined therapy trial and 7.2 years for estrogen alone trial.
 

Ovarian Cancer Incidence Doubles with Estrogen

At 20 years’ follow up, with mortality information available for nearly the full cohort, Dr. Chlebowski and his colleagues could determine that ovarian cancer incidence doubled among women who had taken estrogen alone (hazard ratio = 2.04; 95% CI 1.14-3.65; P = .01), a difference that reached statistical significance at 12 years’ follow up. Ovarian cancer mortality was also significantly increased (HR = 2.79 95% CI 1.30-5.99, P = .006). Absolute numbers were small, however, with 35 cases of ovarian cancer compared with 17 in the placebo group.

Combined therapy recipients saw no increased risk for ovarian cancer and significantly lower endometrial cancer incidence (106 cases vs. 140 HR = 0.72; 95% CI, 0.56-0.92; P = .01).

Conjugated equine estrogen, Dr. Chlebowski said during his presentation at the meeting, “was introduced in US clinical practice in 1943 and used for over half a century, yet the question about hormone therapy’s influence on endometrial and ovarian cancer remains unsettled. Endometrial cancer and ovarian cancer are the fourth and fifth leading causes of cancer deaths in women ... and there’s some discordant findings from observational studies.”

Care of Ovarian Cancer Survivors Should Change

The new findings should prompt practice and guideline changes regarding the use of estrogen alone in ovarian cancer survivors, Dr. Chlebowski said.

In an interview, oncologist Eleonora Teplinsky, MD, of Valley-Mount Sinai Comprehensive Cancer Care in Paramus, New Jersey, said that apart from this subgroup of ovarian cancer survivors, the findings would not likely have much impact on how clinicians and patients approach hormone replacement therapy today.

“Twenty years ago the Women’s Health Initiative showed that hormone replacement therapy increases breast cancer risk, and everyone stopped taking HRT. And now people pushing back on it and saying wait a second – it was the estrogen plus progesterone that increased breast cancer, not estrogen alone. And now we’ve got these newer [estrogen] formulations.

“Yes, there’s a little bit of an increased risk [for ovarian cancer]. Patients should be aware. They should know the symptoms of ovarian cancer. But if they have indications and have been recommended HRT, this is not something that we would advise them against because of this very slightly increased risk,” Dr. Teplinsky said.

Oncologist Allison Kurian, MD of Stanford University in Stanford, California, who specializes in breast cancer, also noted that the duration of hormone treatment, treatment timing relative to age of menopause onset, and commonly used estrogen preparations had indeed changed since the time the WHI trials were conducted, making it harder to generalize the findings to current practice. Nonetheless, she argued, they still have real significance.

“WHI is an incredibly complex but also incredibly valuable resource,” said Dr. Kurian, who has conducted studies using WHI data. “The first big results came out in 2002, and we’re still learning from it. These are randomized trials, which offer the strongest form of scientific evidence that exists. So whenever we see results from this study, we have to take note of them,” she said.

Because the WHI trials had shown combined therapy, not estrogen alone, to be associated with breast cancer risk, clinicians have felt reassured over the years about using estrogen alone.

“You can’t give it to a person unless they have their uterus removed, because we know it will cause uterine cancer if the uterus is in place. But if the uterus is removed, the feeling was that you can give estrogen alone. I think the new piece that is going to get everyone’s attention is this signal for ovarian cancer.”

Something else the new findings show, Dr. Kurian said, is that WHI is “the gift that keeps on giving,” even after decades. “Some of the participants had a relatively short-term exposure to HRT. They took a medication for just a little while. But you didn’t see the effects until you followed people 12 years. So we’re now going to be a little more worried about ovarian cancer in this setting than we used to be. And that’s going to be something we’re all going to keep an eye on and think twice about in terms of talking to patients.”

These results help demonstrate what happens when a society invests in science on a national scale, Dr. Kurian said. “Here we have a really long-term, incredibly informative study that keeps generating knowledge to help women.”

When the WHI began, it “really was the first time that people decided it was important to systematically study women at midlife. It was a remarkable thing then that society got mobilized to do this, and we’re still seeing the benefits.”

Dr. Chlebowski disclosed receiving consulting or advisory fees from Pfizer. Dr. Teplinsky and Dr. Kurian disclosed no financial conflicts of interest.

Two decades after the landmark Women’s Health Initiative (WHI) changed the way clinicians thought about hormone therapy and cancer, new findings suggest this national health study is "the gift that keeps on giving."

Follow-up from two of the WHI’s randomized trials have found that estrogen alone in women with prior hysterectomy significantly increased ovarian cancer incidence and mortality in postmenopausal women. Estrogen and progesterone together, meanwhile, did not increase ovarian cancer risk, and significantly reduced the risk of endometrial cancer. Rowan T. Chlebowski, MD, PhD, of The Lundquist Institute in Torrance, California, presented these results from the latest WHI findings, at the annual meeting of the American Society of Clinical Oncology in Chicago.

Dr. Chlebowski and his colleagues conducted an analysis from two randomized, placebo-controlled trials, which between 1993 and 1998 enrolled nearly 28,000 postmenopausal women aged 50-79 years without prior cancer from 40 centers across the United States. (The full WHI effort involved a total cohort of 161,000 patients, and included an observational study and two other non-drug trials.)

In one of the hormone therapy trials, 17,000 women with a uterus at baseline were randomized to combined equine estrogen plus medroxyprogesterone acetate, or placebo. In the other trial, about 11,000 women with prior hysterectomy were randomized to daily estrogen alone or placebo. Both trials were stopped early: the estrogen-only trial due to an increased stroke risk, and the combined therapy trial due to findings of increased breast cancer and cardiovascular risk.

Mean exposure to hormone therapy was 5.6 years for the combined therapy trial and 7.2 years for estrogen alone trial.
 

Ovarian Cancer Incidence Doubles with Estrogen

At 20 years’ follow up, with mortality information available for nearly the full cohort, Dr. Chlebowski and his colleagues could determine that ovarian cancer incidence doubled among women who had taken estrogen alone (hazard ratio = 2.04; 95% CI 1.14-3.65; P = .01), a difference that reached statistical significance at 12 years’ follow up. Ovarian cancer mortality was also significantly increased (HR = 2.79 95% CI 1.30-5.99, P = .006). Absolute numbers were small, however, with 35 cases of ovarian cancer compared with 17 in the placebo group.

Combined therapy recipients saw no increased risk for ovarian cancer and significantly lower endometrial cancer incidence (106 cases vs. 140 HR = 0.72; 95% CI, 0.56-0.92; P = .01).

Conjugated equine estrogen, Dr. Chlebowski said during his presentation at the meeting, “was introduced in US clinical practice in 1943 and used for over half a century, yet the question about hormone therapy’s influence on endometrial and ovarian cancer remains unsettled. Endometrial cancer and ovarian cancer are the fourth and fifth leading causes of cancer deaths in women ... and there’s some discordant findings from observational studies.”

Care of Ovarian Cancer Survivors Should Change

The new findings should prompt practice and guideline changes regarding the use of estrogen alone in ovarian cancer survivors, Dr. Chlebowski said.

In an interview, oncologist Eleonora Teplinsky, MD, of Valley-Mount Sinai Comprehensive Cancer Care in Paramus, New Jersey, said that apart from this subgroup of ovarian cancer survivors, the findings would not likely have much impact on how clinicians and patients approach hormone replacement therapy today.

“Twenty years ago the Women’s Health Initiative showed that hormone replacement therapy increases breast cancer risk, and everyone stopped taking HRT. And now people pushing back on it and saying wait a second – it was the estrogen plus progesterone that increased breast cancer, not estrogen alone. And now we’ve got these newer [estrogen] formulations.

“Yes, there’s a little bit of an increased risk [for ovarian cancer]. Patients should be aware. They should know the symptoms of ovarian cancer. But if they have indications and have been recommended HRT, this is not something that we would advise them against because of this very slightly increased risk,” Dr. Teplinsky said.

Oncologist Allison Kurian, MD of Stanford University in Stanford, California, who specializes in breast cancer, also noted that the duration of hormone treatment, treatment timing relative to age of menopause onset, and commonly used estrogen preparations had indeed changed since the time the WHI trials were conducted, making it harder to generalize the findings to current practice. Nonetheless, she argued, they still have real significance.

“WHI is an incredibly complex but also incredibly valuable resource,” said Dr. Kurian, who has conducted studies using WHI data. “The first big results came out in 2002, and we’re still learning from it. These are randomized trials, which offer the strongest form of scientific evidence that exists. So whenever we see results from this study, we have to take note of them,” she said.

Because the WHI trials had shown combined therapy, not estrogen alone, to be associated with breast cancer risk, clinicians have felt reassured over the years about using estrogen alone.

“You can’t give it to a person unless they have their uterus removed, because we know it will cause uterine cancer if the uterus is in place. But if the uterus is removed, the feeling was that you can give estrogen alone. I think the new piece that is going to get everyone’s attention is this signal for ovarian cancer.”

Something else the new findings show, Dr. Kurian said, is that WHI is “the gift that keeps on giving,” even after decades. “Some of the participants had a relatively short-term exposure to HRT. They took a medication for just a little while. But you didn’t see the effects until you followed people 12 years. So we’re now going to be a little more worried about ovarian cancer in this setting than we used to be. And that’s going to be something we’re all going to keep an eye on and think twice about in terms of talking to patients.”

These results help demonstrate what happens when a society invests in science on a national scale, Dr. Kurian said. “Here we have a really long-term, incredibly informative study that keeps generating knowledge to help women.”

When the WHI began, it “really was the first time that people decided it was important to systematically study women at midlife. It was a remarkable thing then that society got mobilized to do this, and we’re still seeing the benefits.”

Dr. Chlebowski disclosed receiving consulting or advisory fees from Pfizer. Dr. Teplinsky and Dr. Kurian disclosed no financial conflicts of interest.

Premenopausal patients with hormone receptor positive and human epidermal growth factor receptor 2 negative invasive breast cancer were significantly more likely to respond to chemotherapy plus endocrine therapy if their baseline anti-Müllerian hormone levels were10 pg/mL or higher, a new analysis shows.

The new findings also show that women with low baseline anti-Müllerian hormone (AMH) of less than 10 pg/mL do not benefit from chemotherapy. In fact, AMH levels were a better predictor of chemotherapy benefit than self-reported premenopausal status, age, and other hormone levels.

“We may be overtreating some of our patients” with invasive breast cancer and low AMH levels, Kevin Kalinsky, MD, of the Winship Cancer Institute of Emory University, Atlanta, said in a presentation at the annual meeting of the American Society of Clinical Oncology (ASCO).

The potential implication of the study is that clinicians may be able to stop giving chemotherapy to a subset of breast cancer patients who will not benefit from it, he said in the presentation.
 

New Analysis Singles Out AMH Levels

In a new analysis of data from the RxPONDER trial, Dr. Kalinsky shared data from 1,016 patients who were younger than 55 years of age and self-reported as premenopausal.

The original RxPONDER trial (also known as SWOG S1007) was a randomized, phase 3 trial designed to evaluate the benefit of endocrine therapy (ET) alone vs. ET plus chemotherapy in patients with hormone receptor positive and human epidermal growth factor receptor 2 negative (HR+/HER2-) invasive breast cancer and low recurrence scores (25 or less with genomic testing by Oncotype DX), Dr. Kalinsky said in his presentation.

The researchers found no improvement in invasive disease-free survival (IDFS) with the addition of chemotherapy to ET overall, but significant IDFS improvement occurred with added chemotherapy to ET in the subgroup of self-reported premenopausal women (hazard ratio 0.60).

To better identify the impact of menopausal status on patients who would benefit or not benefit from chemotherapy in the new analysis, the researchers assessed baseline serum samples of serum estradiol, progesterone, follicular stimulating hormone(FSH), luteinizing hormone, AMH, and inhibin B.

The primary outcomes were associations of these markers (continuous and dichotomized) with IDFS and distant relapse-free survival with prognosis and prediction of chemotherapy benefit, based on Cox regression analysis.

Of the six markers analyzed, only AMH showed an association with chemotherapy benefits. “AMH is more stable and reliable during the menstrual cycle” compared to other hormones such as FSH and estradiol. Also, AMH levels ≥ 10 pg/mL are considered a standard cutoff to define normal ovarian reserve, Dr. Kalinsky said in his presentation.

A total of 209 patients (21%) had low AMH (less than 10 pg/mL) and were considered postmenopausal, and 806 (79%) were considered premenopausal, with AMH levels of 10 pg/mL or higher.

Chemotherapy plus ET was significantly more beneficial than ET alone in the premenopausal patients with AMH levels ≥ 10 pg/mL (hazard ratio 0.48), Dr. Kalinsky said. By contrast, no chemotherapy benefit was seen in the patients deemed postmenopausal, with low AMH levels (HR 1.21).

In the patients with AMH of 10 pg/mL or higher, the absolute 5-year IDFS benefit of chemotherapy was 7.8%, compared to no notable difference for those with low AMH levels.

Similarly, 5-year DRFS with chemotherapy in patients with AMH of 10 pg/mL or higher was 4.4% (HR 0.41), with no benefit for those with low AMH (HR 1.50).

The findings were limited by the post hoc design and lack of longitudinal data, Dr. Kalinsky said.

During the question-and-answer session, Dr. Kalinsky said that he hoped the data could be incorporated into a clinical model “to further refine patients who need chemotherapy or don’t.” The results suggest that the reproductive hormone AMH can be used to identify premenopausal women with HR+/HER2- invasive breast cancer and intermediate risk based on oncotype scores who would likely benefit from chemotherapy, while those with lower AMH who could forgo it, Dr. Kalinsky concluded.
 

AMH May Ultimately Inform Chemotherapy Choices

The findings are “thoughtful and intriguing” and may inform which patients benefit from adjuvant chemotherapy and which may not, said Lisa A. Carey, MD, of Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, who served as discussant for the abstract.

Dr. Carey noted as a caveat that AMH is not currently recommended by the American College of Obstetricians and Gynecologists for menopause prediction. However, AMH is “a very credible biomarker of ovarian reserve,” she said in her presentation.

As for clinical implications, the lack of chemotherapy benefit in patients with low AMH at baseline suggests that at least part of the benefits of chemotherapy come from ovarian suppression, Dr. Carey said.

Current assessments of menopausal status are often crude, she noted, and AMH may be helpful when menopausal status is clinically unclear.

Dr. Carey agreed the findings were limited by the post hoc design, and longitudinal data are needed. However, the clinical implications are real if the results are validated, she said, and longitudinal data will be explored in the currently enrolling NRG BR009 OFSET trial.
 

Clinical Challenges of Menopausal Status

Since the original RxPONDER showed a benefit of chemotherapy for premenopausal women, but not for postmenopausal women with the same low recurrence score, the medical oncology community has worked to determine how much of the benefit seen was related to the ovarian suppression associated with chemotherapy, Megan Kruse, MD, of the Cleveland Clinic, said in an interview.

“Determining a woman’s menopausal status can be challenging in the clinic, as many women have had hysterectomy but have intact ovaries or may have significantly irregular periods, which can lead to confusion about the best endocrine therapy to recommend and how to categorize risk when it comes to Oncotype DX testing,” said Dr. Kruse. She was not involved in the RxPONDER study, but commented on the study in a podcast for ASCO Daily News in advance of the ASCO meeting.

“I was surprised that only AMH showed an association with chemotherapy benefit, as we often obtain estradiol/FSH levels in clinic to try to help with the menopausal assessment,” Dr. Kruse said in an interview. However, in clinical practice, the data may help discuss systemic therapy in patients who are near clinical menopause and trying to decide whether the potential added benefit of chemotherapy is worth the associated toxicity, she said.

“My hope is that new data allow for a more informed, individualized decision-making process,” she added.

Potential barriers to incorporate AMH into chemotherapy decisions in clinical practice include the need for insurance coverage for AMH levels, Dr. Kruse said in an interview. “The [AMH] levels also can be dynamic, so checking one point in time and making such a significant clinical decision based on one level is also a bit concerning,” she said.

Looking ahead, Dr. Kruse emphasized the need to complete the NRG BR-009 OFSET trial. That trial is designed to answer the question of whether adjuvant chemotherapy added to ovarian suppression (OS) plus ET is superior to OS plus ET for premenopausal women with early stage high-risk node negative or 1-3 lymph nodes positive breast cancer with an RS score of 25 or lower, she said.

“This extra analysis of the RxPONDER trial helps to further understand how premenopausal women may best benefit from adjuvant treatments,” Malinda T. West, MD, of the University of Wisconsin, Madison, said in an interview. The new study is important because it shows the ability of serum AMH to help predict ovarian reserve and imminent menopause, said Dr. West, who was not involved in the study.

In clinical practice, the study provides further insight into how premenopausal women may benefit from added chemotherapy and the role of ovarian suppression, Dr. West said.

The study was supported by the Breast Cancer Research Foundation, the National Institutes of Health/National Institute of General Medical Sciences/National Cancer Institute, Exact Sciences Corporation (previously Genomic Health), and the Hope Foundation for Cancer Research.

Dr. Kalinsky disclosed that immediate family members are employed by EQRx and GRAIL, with stock or other ownership interests in these companies. He disclosed consulting or advisory roles with 4D Pharma, AstraZeneca, Cullinan Oncology, Daiichi Sankyo/AstraZeneca, eFFECTOR Therapeutics, Genentech/Roche, Immunomedics, Lilly, Menarini Silicon Biosystems, Merck, Mersana, Myovant Sciences, Novartis, Oncosec, Prelude Therapeutics, Puma Biotechnology, RayzeBio, Seagen, and Takeda. Dr. Kalinsky further disclosed research funding to his institution from Ascentage Pharma, AstraZeneca, Daiichi Sankyo, Genentech/Roche, Lilly, Novartis, and Seagen, and relationships with Genentech and Immunomedics.

Dr. Carey disclosed research funding to her institution from AstraZeneca, Genentech/Roche, Gilead Sciences, Lilly, NanoString Technologies, Novartis, Seagen, and Veracyte. She disclosed an uncompensated relationship with Seagen, and uncompensated relationships between her institution and Genentech/Roche, GlaxoSmithKline, Lilly, and Novartis.

Dr. Kruse disclosed consulting or advisory roles with Novartis Oncology, Puma Biotechnology, Immunomedics, Eisai, Seattle Genetics, and Lilly.

Dr. West had no financial conflicts to disclose.

Premenopausal patients with hormone receptor positive and human epidermal growth factor receptor 2 negative invasive breast cancer were significantly more likely to respond to chemotherapy plus endocrine therapy if their baseline anti-Müllerian hormone levels were10 pg/mL or higher, a new analysis shows.

The new findings also show that women with low baseline anti-Müllerian hormone (AMH) of less than 10 pg/mL do not benefit from chemotherapy. In fact, AMH levels were a better predictor of chemotherapy benefit than self-reported premenopausal status, age, and other hormone levels.

“We may be overtreating some of our patients” with invasive breast cancer and low AMH levels, Kevin Kalinsky, MD, of the Winship Cancer Institute of Emory University, Atlanta, said in a presentation at the annual meeting of the American Society of Clinical Oncology (ASCO).

The potential implication of the study is that clinicians may be able to stop giving chemotherapy to a subset of breast cancer patients who will not benefit from it, he said in the presentation.
 

New Analysis Singles Out AMH Levels

In a new analysis of data from the RxPONDER trial, Dr. Kalinsky shared data from 1,016 patients who were younger than 55 years of age and self-reported as premenopausal.

The original RxPONDER trial (also known as SWOG S1007) was a randomized, phase 3 trial designed to evaluate the benefit of endocrine therapy (ET) alone vs. ET plus chemotherapy in patients with hormone receptor positive and human epidermal growth factor receptor 2 negative (HR+/HER2-) invasive breast cancer and low recurrence scores (25 or less with genomic testing by Oncotype DX), Dr. Kalinsky said in his presentation.

The researchers found no improvement in invasive disease-free survival (IDFS) with the addition of chemotherapy to ET overall, but significant IDFS improvement occurred with added chemotherapy to ET in the subgroup of self-reported premenopausal women (hazard ratio 0.60).

To better identify the impact of menopausal status on patients who would benefit or not benefit from chemotherapy in the new analysis, the researchers assessed baseline serum samples of serum estradiol, progesterone, follicular stimulating hormone(FSH), luteinizing hormone, AMH, and inhibin B.

The primary outcomes were associations of these markers (continuous and dichotomized) with IDFS and distant relapse-free survival with prognosis and prediction of chemotherapy benefit, based on Cox regression analysis.

Of the six markers analyzed, only AMH showed an association with chemotherapy benefits. “AMH is more stable and reliable during the menstrual cycle” compared to other hormones such as FSH and estradiol. Also, AMH levels ≥ 10 pg/mL are considered a standard cutoff to define normal ovarian reserve, Dr. Kalinsky said in his presentation.

A total of 209 patients (21%) had low AMH (less than 10 pg/mL) and were considered postmenopausal, and 806 (79%) were considered premenopausal, with AMH levels of 10 pg/mL or higher.

Chemotherapy plus ET was significantly more beneficial than ET alone in the premenopausal patients with AMH levels ≥ 10 pg/mL (hazard ratio 0.48), Dr. Kalinsky said. By contrast, no chemotherapy benefit was seen in the patients deemed postmenopausal, with low AMH levels (HR 1.21).

In the patients with AMH of 10 pg/mL or higher, the absolute 5-year IDFS benefit of chemotherapy was 7.8%, compared to no notable difference for those with low AMH levels.

Similarly, 5-year DRFS with chemotherapy in patients with AMH of 10 pg/mL or higher was 4.4% (HR 0.41), with no benefit for those with low AMH (HR 1.50).

The findings were limited by the post hoc design and lack of longitudinal data, Dr. Kalinsky said.

During the question-and-answer session, Dr. Kalinsky said that he hoped the data could be incorporated into a clinical model “to further refine patients who need chemotherapy or don’t.” The results suggest that the reproductive hormone AMH can be used to identify premenopausal women with HR+/HER2- invasive breast cancer and intermediate risk based on oncotype scores who would likely benefit from chemotherapy, while those with lower AMH who could forgo it, Dr. Kalinsky concluded.
 

AMH May Ultimately Inform Chemotherapy Choices

The findings are “thoughtful and intriguing” and may inform which patients benefit from adjuvant chemotherapy and which may not, said Lisa A. Carey, MD, of Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, who served as discussant for the abstract.

Dr. Carey noted as a caveat that AMH is not currently recommended by the American College of Obstetricians and Gynecologists for menopause prediction. However, AMH is “a very credible biomarker of ovarian reserve,” she said in her presentation.

As for clinical implications, the lack of chemotherapy benefit in patients with low AMH at baseline suggests that at least part of the benefits of chemotherapy come from ovarian suppression, Dr. Carey said.

Current assessments of menopausal status are often crude, she noted, and AMH may be helpful when menopausal status is clinically unclear.

Dr. Carey agreed the findings were limited by the post hoc design, and longitudinal data are needed. However, the clinical implications are real if the results are validated, she said, and longitudinal data will be explored in the currently enrolling NRG BR009 OFSET trial.
 

Clinical Challenges of Menopausal Status

Since the original RxPONDER showed a benefit of chemotherapy for premenopausal women, but not for postmenopausal women with the same low recurrence score, the medical oncology community has worked to determine how much of the benefit seen was related to the ovarian suppression associated with chemotherapy, Megan Kruse, MD, of the Cleveland Clinic, said in an interview.

“Determining a woman’s menopausal status can be challenging in the clinic, as many women have had hysterectomy but have intact ovaries or may have significantly irregular periods, which can lead to confusion about the best endocrine therapy to recommend and how to categorize risk when it comes to Oncotype DX testing,” said Dr. Kruse. She was not involved in the RxPONDER study, but commented on the study in a podcast for ASCO Daily News in advance of the ASCO meeting.

“I was surprised that only AMH showed an association with chemotherapy benefit, as we often obtain estradiol/FSH levels in clinic to try to help with the menopausal assessment,” Dr. Kruse said in an interview. However, in clinical practice, the data may help discuss systemic therapy in patients who are near clinical menopause and trying to decide whether the potential added benefit of chemotherapy is worth the associated toxicity, she said.

“My hope is that new data allow for a more informed, individualized decision-making process,” she added.

Potential barriers to incorporate AMH into chemotherapy decisions in clinical practice include the need for insurance coverage for AMH levels, Dr. Kruse said in an interview. “The [AMH] levels also can be dynamic, so checking one point in time and making such a significant clinical decision based on one level is also a bit concerning,” she said.

Looking ahead, Dr. Kruse emphasized the need to complete the NRG BR-009 OFSET trial. That trial is designed to answer the question of whether adjuvant chemotherapy added to ovarian suppression (OS) plus ET is superior to OS plus ET for premenopausal women with early stage high-risk node negative or 1-3 lymph nodes positive breast cancer with an RS score of 25 or lower, she said.

“This extra analysis of the RxPONDER trial helps to further understand how premenopausal women may best benefit from adjuvant treatments,” Malinda T. West, MD, of the University of Wisconsin, Madison, said in an interview. The new study is important because it shows the ability of serum AMH to help predict ovarian reserve and imminent menopause, said Dr. West, who was not involved in the study.

In clinical practice, the study provides further insight into how premenopausal women may benefit from added chemotherapy and the role of ovarian suppression, Dr. West said.

The study was supported by the Breast Cancer Research Foundation, the National Institutes of Health/National Institute of General Medical Sciences/National Cancer Institute, Exact Sciences Corporation (previously Genomic Health), and the Hope Foundation for Cancer Research.

Dr. Kalinsky disclosed that immediate family members are employed by EQRx and GRAIL, with stock or other ownership interests in these companies. He disclosed consulting or advisory roles with 4D Pharma, AstraZeneca, Cullinan Oncology, Daiichi Sankyo/AstraZeneca, eFFECTOR Therapeutics, Genentech/Roche, Immunomedics, Lilly, Menarini Silicon Biosystems, Merck, Mersana, Myovant Sciences, Novartis, Oncosec, Prelude Therapeutics, Puma Biotechnology, RayzeBio, Seagen, and Takeda. Dr. Kalinsky further disclosed research funding to his institution from Ascentage Pharma, AstraZeneca, Daiichi Sankyo, Genentech/Roche, Lilly, Novartis, and Seagen, and relationships with Genentech and Immunomedics.

Dr. Carey disclosed research funding to her institution from AstraZeneca, Genentech/Roche, Gilead Sciences, Lilly, NanoString Technologies, Novartis, Seagen, and Veracyte. She disclosed an uncompensated relationship with Seagen, and uncompensated relationships between her institution and Genentech/Roche, GlaxoSmithKline, Lilly, and Novartis.

Dr. Kruse disclosed consulting or advisory roles with Novartis Oncology, Puma Biotechnology, Immunomedics, Eisai, Seattle Genetics, and Lilly.

Dr. West had no financial conflicts to disclose.

Premenopausal patients with hormone receptor positive and human epidermal growth factor receptor 2 negative invasive breast cancer were significantly more likely to respond to chemotherapy plus endocrine therapy if their baseline anti-Müllerian hormone levels were10 pg/mL or higher, a new analysis shows.

The new findings also show that women with low baseline anti-Müllerian hormone (AMH) of less than 10 pg/mL do not benefit from chemotherapy. In fact, AMH levels were a better predictor of chemotherapy benefit than self-reported premenopausal status, age, and other hormone levels.

“We may be overtreating some of our patients” with invasive breast cancer and low AMH levels, Kevin Kalinsky, MD, of the Winship Cancer Institute of Emory University, Atlanta, said in a presentation at the annual meeting of the American Society of Clinical Oncology (ASCO).

The potential implication of the study is that clinicians may be able to stop giving chemotherapy to a subset of breast cancer patients who will not benefit from it, he said in the presentation.
 

New Analysis Singles Out AMH Levels

In a new analysis of data from the RxPONDER trial, Dr. Kalinsky shared data from 1,016 patients who were younger than 55 years of age and self-reported as premenopausal.

The original RxPONDER trial (also known as SWOG S1007) was a randomized, phase 3 trial designed to evaluate the benefit of endocrine therapy (ET) alone vs. ET plus chemotherapy in patients with hormone receptor positive and human epidermal growth factor receptor 2 negative (HR+/HER2-) invasive breast cancer and low recurrence scores (25 or less with genomic testing by Oncotype DX), Dr. Kalinsky said in his presentation.

The researchers found no improvement in invasive disease-free survival (IDFS) with the addition of chemotherapy to ET overall, but significant IDFS improvement occurred with added chemotherapy to ET in the subgroup of self-reported premenopausal women (hazard ratio 0.60).

To better identify the impact of menopausal status on patients who would benefit or not benefit from chemotherapy in the new analysis, the researchers assessed baseline serum samples of serum estradiol, progesterone, follicular stimulating hormone(FSH), luteinizing hormone, AMH, and inhibin B.

The primary outcomes were associations of these markers (continuous and dichotomized) with IDFS and distant relapse-free survival with prognosis and prediction of chemotherapy benefit, based on Cox regression analysis.

Of the six markers analyzed, only AMH showed an association with chemotherapy benefits. “AMH is more stable and reliable during the menstrual cycle” compared to other hormones such as FSH and estradiol. Also, AMH levels ≥ 10 pg/mL are considered a standard cutoff to define normal ovarian reserve, Dr. Kalinsky said in his presentation.

A total of 209 patients (21%) had low AMH (less than 10 pg/mL) and were considered postmenopausal, and 806 (79%) were considered premenopausal, with AMH levels of 10 pg/mL or higher.

Chemotherapy plus ET was significantly more beneficial than ET alone in the premenopausal patients with AMH levels ≥ 10 pg/mL (hazard ratio 0.48), Dr. Kalinsky said. By contrast, no chemotherapy benefit was seen in the patients deemed postmenopausal, with low AMH levels (HR 1.21).

In the patients with AMH of 10 pg/mL or higher, the absolute 5-year IDFS benefit of chemotherapy was 7.8%, compared to no notable difference for those with low AMH levels.

Similarly, 5-year DRFS with chemotherapy in patients with AMH of 10 pg/mL or higher was 4.4% (HR 0.41), with no benefit for those with low AMH (HR 1.50).

The findings were limited by the post hoc design and lack of longitudinal data, Dr. Kalinsky said.

During the question-and-answer session, Dr. Kalinsky said that he hoped the data could be incorporated into a clinical model “to further refine patients who need chemotherapy or don’t.” The results suggest that the reproductive hormone AMH can be used to identify premenopausal women with HR+/HER2- invasive breast cancer and intermediate risk based on oncotype scores who would likely benefit from chemotherapy, while those with lower AMH who could forgo it, Dr. Kalinsky concluded.
 

AMH May Ultimately Inform Chemotherapy Choices

The findings are “thoughtful and intriguing” and may inform which patients benefit from adjuvant chemotherapy and which may not, said Lisa A. Carey, MD, of Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, who served as discussant for the abstract.

Dr. Carey noted as a caveat that AMH is not currently recommended by the American College of Obstetricians and Gynecologists for menopause prediction. However, AMH is “a very credible biomarker of ovarian reserve,” she said in her presentation.

As for clinical implications, the lack of chemotherapy benefit in patients with low AMH at baseline suggests that at least part of the benefits of chemotherapy come from ovarian suppression, Dr. Carey said.

Current assessments of menopausal status are often crude, she noted, and AMH may be helpful when menopausal status is clinically unclear.

Dr. Carey agreed the findings were limited by the post hoc design, and longitudinal data are needed. However, the clinical implications are real if the results are validated, she said, and longitudinal data will be explored in the currently enrolling NRG BR009 OFSET trial.
 

Clinical Challenges of Menopausal Status

Since the original RxPONDER showed a benefit of chemotherapy for premenopausal women, but not for postmenopausal women with the same low recurrence score, the medical oncology community has worked to determine how much of the benefit seen was related to the ovarian suppression associated with chemotherapy, Megan Kruse, MD, of the Cleveland Clinic, said in an interview.

“Determining a woman’s menopausal status can be challenging in the clinic, as many women have had hysterectomy but have intact ovaries or may have significantly irregular periods, which can lead to confusion about the best endocrine therapy to recommend and how to categorize risk when it comes to Oncotype DX testing,” said Dr. Kruse. She was not involved in the RxPONDER study, but commented on the study in a podcast for ASCO Daily News in advance of the ASCO meeting.

“I was surprised that only AMH showed an association with chemotherapy benefit, as we often obtain estradiol/FSH levels in clinic to try to help with the menopausal assessment,” Dr. Kruse said in an interview. However, in clinical practice, the data may help discuss systemic therapy in patients who are near clinical menopause and trying to decide whether the potential added benefit of chemotherapy is worth the associated toxicity, she said.

“My hope is that new data allow for a more informed, individualized decision-making process,” she added.

Potential barriers to incorporate AMH into chemotherapy decisions in clinical practice include the need for insurance coverage for AMH levels, Dr. Kruse said in an interview. “The [AMH] levels also can be dynamic, so checking one point in time and making such a significant clinical decision based on one level is also a bit concerning,” she said.

Looking ahead, Dr. Kruse emphasized the need to complete the NRG BR-009 OFSET trial. That trial is designed to answer the question of whether adjuvant chemotherapy added to ovarian suppression (OS) plus ET is superior to OS plus ET for premenopausal women with early stage high-risk node negative or 1-3 lymph nodes positive breast cancer with an RS score of 25 or lower, she said.

“This extra analysis of the RxPONDER trial helps to further understand how premenopausal women may best benefit from adjuvant treatments,” Malinda T. West, MD, of the University of Wisconsin, Madison, said in an interview. The new study is important because it shows the ability of serum AMH to help predict ovarian reserve and imminent menopause, said Dr. West, who was not involved in the study.

In clinical practice, the study provides further insight into how premenopausal women may benefit from added chemotherapy and the role of ovarian suppression, Dr. West said.

The study was supported by the Breast Cancer Research Foundation, the National Institutes of Health/National Institute of General Medical Sciences/National Cancer Institute, Exact Sciences Corporation (previously Genomic Health), and the Hope Foundation for Cancer Research.

Dr. Kalinsky disclosed that immediate family members are employed by EQRx and GRAIL, with stock or other ownership interests in these companies. He disclosed consulting or advisory roles with 4D Pharma, AstraZeneca, Cullinan Oncology, Daiichi Sankyo/AstraZeneca, eFFECTOR Therapeutics, Genentech/Roche, Immunomedics, Lilly, Menarini Silicon Biosystems, Merck, Mersana, Myovant Sciences, Novartis, Oncosec, Prelude Therapeutics, Puma Biotechnology, RayzeBio, Seagen, and Takeda. Dr. Kalinsky further disclosed research funding to his institution from Ascentage Pharma, AstraZeneca, Daiichi Sankyo, Genentech/Roche, Lilly, Novartis, and Seagen, and relationships with Genentech and Immunomedics.

Dr. Carey disclosed research funding to her institution from AstraZeneca, Genentech/Roche, Gilead Sciences, Lilly, NanoString Technologies, Novartis, Seagen, and Veracyte. She disclosed an uncompensated relationship with Seagen, and uncompensated relationships between her institution and Genentech/Roche, GlaxoSmithKline, Lilly, and Novartis.

Dr. Kruse disclosed consulting or advisory roles with Novartis Oncology, Puma Biotechnology, Immunomedics, Eisai, Seattle Genetics, and Lilly.

Dr. West had no financial conflicts to disclose.

TOPLINE:

Women with low bone density are more likely to report their first fragility hip fracture in their 60s rather than at older ages.

METHODOLOGY:

• Researchers used hip fracture data from the National Health and Nutrition Examination Survey for 2009-2010, 2013-2014, and 2017-2018.
• They included women older than 60 years with a bone mineral density T score ≤ −1 at the femur neck, measured by dual-energy x-ray absorptiometry.
• Fragility fractures are defined as a self-reported hip fracture resulting from a fall from standing height or less.

TAKEAWAY:

• The number of women in their 60s who reported their first hip fracture grew by 50% from 2009 to 2018.
• The opposite was true for women in their 70s and 80s who reported fewer first hip fractures over the study period.
• Reported fragility hip fractures in women overall decreased by half from 2009 to 2018.
• The prevalence of women with osteoporosis (T score ≤ −2.5) grew from 18.1% to 21.3% over 10 years.

IN PRACTICE:

The decrease in fractures overall and in women older than 70 years “may be due to increasing awareness and utilization of measures to decrease falls such as exercise, nutrition, health education, and environmental modifications targeted toward the elderly population,” the authors wrote. The findings also underscore the importance of earlier bone health awareness in primary care to curb the rising trend in younger women, they added.

SOURCE:

The study was led by Avica Atri, MD, of Albert Einstein Medical Center in Philadelphia. She presented the findings at ENDO 2024: The Endocrine Society Annual Meeting.

LIMITATIONS:

The study was retrospective in nature and included self-reported health data.

DISCLOSURES:

The study received no commercial funding. The authors have reported no relevant financial relationships.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Women with low bone density are more likely to report their first fragility hip fracture in their 60s rather than at older ages.

METHODOLOGY:

• Researchers used hip fracture data from the National Health and Nutrition Examination Survey for 2009-2010, 2013-2014, and 2017-2018.
• They included women older than 60 years with a bone mineral density T score ≤ −1 at the femur neck, measured by dual-energy x-ray absorptiometry.
• Fragility fractures are defined as a self-reported hip fracture resulting from a fall from standing height or less.

TAKEAWAY:

• The number of women in their 60s who reported their first hip fracture grew by 50% from 2009 to 2018.
• The opposite was true for women in their 70s and 80s who reported fewer first hip fractures over the study period.
• Reported fragility hip fractures in women overall decreased by half from 2009 to 2018.
• The prevalence of women with osteoporosis (T score ≤ −2.5) grew from 18.1% to 21.3% over 10 years.

IN PRACTICE:

The decrease in fractures overall and in women older than 70 years “may be due to increasing awareness and utilization of measures to decrease falls such as exercise, nutrition, health education, and environmental modifications targeted toward the elderly population,” the authors wrote. The findings also underscore the importance of earlier bone health awareness in primary care to curb the rising trend in younger women, they added.

SOURCE:

The study was led by Avica Atri, MD, of Albert Einstein Medical Center in Philadelphia. She presented the findings at ENDO 2024: The Endocrine Society Annual Meeting.

LIMITATIONS:

The study was retrospective in nature and included self-reported health data.

DISCLOSURES:

The study received no commercial funding. The authors have reported no relevant financial relationships.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Women with low bone density are more likely to report their first fragility hip fracture in their 60s rather than at older ages.

METHODOLOGY:

• Researchers used hip fracture data from the National Health and Nutrition Examination Survey for 2009-2010, 2013-2014, and 2017-2018.
• They included women older than 60 years with a bone mineral density T score ≤ −1 at the femur neck, measured by dual-energy x-ray absorptiometry.
• Fragility fractures are defined as a self-reported hip fracture resulting from a fall from standing height or less.

TAKEAWAY:

• The number of women in their 60s who reported their first hip fracture grew by 50% from 2009 to 2018.
• The opposite was true for women in their 70s and 80s who reported fewer first hip fractures over the study period.
• Reported fragility hip fractures in women overall decreased by half from 2009 to 2018.
• The prevalence of women with osteoporosis (T score ≤ −2.5) grew from 18.1% to 21.3% over 10 years.

IN PRACTICE:

The decrease in fractures overall and in women older than 70 years “may be due to increasing awareness and utilization of measures to decrease falls such as exercise, nutrition, health education, and environmental modifications targeted toward the elderly population,” the authors wrote. The findings also underscore the importance of earlier bone health awareness in primary care to curb the rising trend in younger women, they added.

SOURCE:

The study was led by Avica Atri, MD, of Albert Einstein Medical Center in Philadelphia. She presented the findings at ENDO 2024: The Endocrine Society Annual Meeting.

LIMITATIONS:

The study was retrospective in nature and included self-reported health data.

DISCLOSURES:

The study received no commercial funding. The authors have reported no relevant financial relationships.
 

A version of this article appeared on Medscape.com.

For years, scientists have sought to create a human artificial ovary, restoring fertility in patients without other options. The first cellular map of a human ovary, recently developed at the University of Michigan, Ann Arbor, represents a big leap forward in that quest.

“You cannot build something if you don’t have the blueprint,” said biomedical engineer Ariella Shikanov, PhD, associate professor at University of Michigan, who helped create what she and colleagues call an atlas of the ovary. “By creating a map or an atlas, we can now follow what nature created and engineer the building blocks of an ovary — and build a nature-like structure.”

So far, the concept of an artificial ovary has been successful only in mice, with the development of a 3D-printed prosthetic ovary that enabled sterilized mice to have pups. Researchers hope that artificial human ovary technology could someday help women left infertile after cancer treatment, as well as patients who don›t respond to fertility treatments and those with premature ovarian failure.

But Dr. Shikanov believes this research will go even further, providing a valuable resource to scientists studying diseases and other conditions related to the ovary.

“Whenever people think about the ovary, if they think about it at all, they usually think about fertility,” said Dr. Shikanov. The ovary is so much more.

Besides producing and carrying a woman’s unfertilized eggs during her lifetime, the ovary is also responsible for endocrine function — the production of estrogen and progesterone, which in addition to supporting reproductive health, help maintain a woman’s cardiovascular, bone, and mental health.

“We don’t really understand everything that is happening in the ovary yet,” Dr. Shikanov said. “But we know it is an important organ.”
 

Mapping the Ovary

Because people don’t typically donate their ovaries, there are not many available for research, especially from younger reproductive age women, said Dr. Shikanov. So, the scientists set out to build a resource. They described their work in Science Advances.

To create their atlas, the researchers studied two premenopausal donor ovaries, profiling 18,000 genes in 257 regions. From three additional donor ovaries, they also generated single-cell RNA sequencing data for 21,198 cells.

“We identified four major cell types and four immune cell subtypes in the ovary,” said Dr. Shikanov. Taking samples from different areas of the ovary revealed distinct gene activities for oocytes, theca cells, and granulosa cells — expanding scientists’ understanding of the molecular programs driving ovarian follicle development.

What’s unique about their work is the focus on both single cell and spatial analysis, said study coauthor Jun Z. Li, PhD, associate chair of the University of Michigan’s department of computational medicine and bioinformatics. Specifically, they used a relatively new method called spatial transcriptomics, which allows them to see which genes are being activated and where.

“We are constructing the spatial arrangement of the cells in the ovary,” said Dr. Li. “This spatial analysis is like saying, ‘Let me look at where you are and who your neighbor is.’ ”

Their findings are built on other genetic and cellular research in the field, Dr. Li noted. Biomedical engineers in other areas of medicine are applying similar technologies to other organs including the heart, the breast, and bone — part of a larger project called the Human Cell Atlas.
 

Advancing Women’s Health Research

Historically, women’s health research has been underfunded and underrepresented, but the authors believe their atlas of the ovary is a significant step forward.

“There are a lot of biological questions that we don’t know the answers to about the ovary,” said Dr. Shikanov.

One of the biggest mysteries is why so many eggs never become fertilizable. Each human female is born with about one to two million ovarian follicles. Each follicle carries one immature egg. Around puberty, two thirds of these follicles die off. And most that are left never develop into fertilizable eggs.

“The majority of these follicles either just grow and secrete hormones or undergo atresia,” Dr. Shikanov said. “One question that we wanted to understand is, what determines an egg that can grow, ovulate, and become a fertilizable egg and potentially develop into a new human being from one that does not?”

Another big question researchers have is, what’s happening with other types of cells in the ovary — the supporting cells that produce endocrine hormones? Where are they located and what proteins and RNA are they making? Their research begins to unravel some of these questions and lays a foundation for future studies.

“We wanted to analyze the transcriptional signatures from specific regions and then do bioinformatical analysis and really combine structure, function, and transcriptional signatures,” Dr. Shikanov said.

Knowing the transcriptional signatures can help researchers understand disease mechanisms and then go on to develop treatments for these diseases.

Winifred Mak, MD, PhD, a reproductive endocrinologist and infertility specialist at Dell Medical School, University of Texas, Austin, studies cancer fertility preservation. “For me, it is interesting to see that there are so many different clusters of cells in the ovary that have been identified by this study that we were not necessarily aware of before,” said Dr. Mak, who is not involved in the new research. “Also, the identification of new genes not previously studied in the human ovary.”
 

What’s Next

Dozens of scientists who study reproductive health are already reaching out to the researchers about their work, Dr. Shikanov said.

“We get contacted almost every day from researchers all around the world asking for data sets or asking for details from this paper,” she said, “from people who study ovarian cancer, for example.”

Dr. Mak said having a map of a normal ovary could also help researchers who study premature ovarian insufficiency — why the ovary sometimes goes into premature menopause — and polycystic ovarian syndrome.

Another big area of research interest is ovarian aging. “Women live so much longer now, but we still reach menopause at the age of 50,” Dr. Shikanov said. “So, there are efforts going toward understanding ovarian aging and maybe preventing it to extend ovarian longevity.”

Dr. Mak said it will enable scientists to “look at different age women and see what genes change across the reproductive lifespan.”

The atlas may also eventually lead to treatments that help restore fertility in individuals who had and were treated for cancer as children, people who undergo sex transitions, and those whose reproductive organs have been impacted by trauma in conflict settings or accidents, Dr. Li said.

The applications are numerous and exciting, Dr. Shikanov said. “Our atlas is like a benchmark. Now researchers can collect ovaries from individuals with these diseases and conditions and try to compare what’s different.”

A version of this article appeared on Medscape.com.

For years, scientists have sought to create a human artificial ovary, restoring fertility in patients without other options. The first cellular map of a human ovary, recently developed at the University of Michigan, Ann Arbor, represents a big leap forward in that quest.

“You cannot build something if you don’t have the blueprint,” said biomedical engineer Ariella Shikanov, PhD, associate professor at University of Michigan, who helped create what she and colleagues call an atlas of the ovary. “By creating a map or an atlas, we can now follow what nature created and engineer the building blocks of an ovary — and build a nature-like structure.”

So far, the concept of an artificial ovary has been successful only in mice, with the development of a 3D-printed prosthetic ovary that enabled sterilized mice to have pups. Researchers hope that artificial human ovary technology could someday help women left infertile after cancer treatment, as well as patients who don›t respond to fertility treatments and those with premature ovarian failure.

But Dr. Shikanov believes this research will go even further, providing a valuable resource to scientists studying diseases and other conditions related to the ovary.

“Whenever people think about the ovary, if they think about it at all, they usually think about fertility,” said Dr. Shikanov. The ovary is so much more.

Besides producing and carrying a woman’s unfertilized eggs during her lifetime, the ovary is also responsible for endocrine function — the production of estrogen and progesterone, which in addition to supporting reproductive health, help maintain a woman’s cardiovascular, bone, and mental health.

“We don’t really understand everything that is happening in the ovary yet,” Dr. Shikanov said. “But we know it is an important organ.”
 

Mapping the Ovary

Because people don’t typically donate their ovaries, there are not many available for research, especially from younger reproductive age women, said Dr. Shikanov. So, the scientists set out to build a resource. They described their work in Science Advances.

To create their atlas, the researchers studied two premenopausal donor ovaries, profiling 18,000 genes in 257 regions. From three additional donor ovaries, they also generated single-cell RNA sequencing data for 21,198 cells.

“We identified four major cell types and four immune cell subtypes in the ovary,” said Dr. Shikanov. Taking samples from different areas of the ovary revealed distinct gene activities for oocytes, theca cells, and granulosa cells — expanding scientists’ understanding of the molecular programs driving ovarian follicle development.

What’s unique about their work is the focus on both single cell and spatial analysis, said study coauthor Jun Z. Li, PhD, associate chair of the University of Michigan’s department of computational medicine and bioinformatics. Specifically, they used a relatively new method called spatial transcriptomics, which allows them to see which genes are being activated and where.

“We are constructing the spatial arrangement of the cells in the ovary,” said Dr. Li. “This spatial analysis is like saying, ‘Let me look at where you are and who your neighbor is.’ ”

Their findings are built on other genetic and cellular research in the field, Dr. Li noted. Biomedical engineers in other areas of medicine are applying similar technologies to other organs including the heart, the breast, and bone — part of a larger project called the Human Cell Atlas.
 

Advancing Women’s Health Research

Historically, women’s health research has been underfunded and underrepresented, but the authors believe their atlas of the ovary is a significant step forward.

“There are a lot of biological questions that we don’t know the answers to about the ovary,” said Dr. Shikanov.

One of the biggest mysteries is why so many eggs never become fertilizable. Each human female is born with about one to two million ovarian follicles. Each follicle carries one immature egg. Around puberty, two thirds of these follicles die off. And most that are left never develop into fertilizable eggs.

“The majority of these follicles either just grow and secrete hormones or undergo atresia,” Dr. Shikanov said. “One question that we wanted to understand is, what determines an egg that can grow, ovulate, and become a fertilizable egg and potentially develop into a new human being from one that does not?”

Another big question researchers have is, what’s happening with other types of cells in the ovary — the supporting cells that produce endocrine hormones? Where are they located and what proteins and RNA are they making? Their research begins to unravel some of these questions and lays a foundation for future studies.

“We wanted to analyze the transcriptional signatures from specific regions and then do bioinformatical analysis and really combine structure, function, and transcriptional signatures,” Dr. Shikanov said.

Knowing the transcriptional signatures can help researchers understand disease mechanisms and then go on to develop treatments for these diseases.

Winifred Mak, MD, PhD, a reproductive endocrinologist and infertility specialist at Dell Medical School, University of Texas, Austin, studies cancer fertility preservation. “For me, it is interesting to see that there are so many different clusters of cells in the ovary that have been identified by this study that we were not necessarily aware of before,” said Dr. Mak, who is not involved in the new research. “Also, the identification of new genes not previously studied in the human ovary.”
 

What’s Next

Dozens of scientists who study reproductive health are already reaching out to the researchers about their work, Dr. Shikanov said.

“We get contacted almost every day from researchers all around the world asking for data sets or asking for details from this paper,” she said, “from people who study ovarian cancer, for example.”

Dr. Mak said having a map of a normal ovary could also help researchers who study premature ovarian insufficiency — why the ovary sometimes goes into premature menopause — and polycystic ovarian syndrome.

Another big area of research interest is ovarian aging. “Women live so much longer now, but we still reach menopause at the age of 50,” Dr. Shikanov said. “So, there are efforts going toward understanding ovarian aging and maybe preventing it to extend ovarian longevity.”

Dr. Mak said it will enable scientists to “look at different age women and see what genes change across the reproductive lifespan.”

The atlas may also eventually lead to treatments that help restore fertility in individuals who had and were treated for cancer as children, people who undergo sex transitions, and those whose reproductive organs have been impacted by trauma in conflict settings or accidents, Dr. Li said.

The applications are numerous and exciting, Dr. Shikanov said. “Our atlas is like a benchmark. Now researchers can collect ovaries from individuals with these diseases and conditions and try to compare what’s different.”

A version of this article appeared on Medscape.com.

For years, scientists have sought to create a human artificial ovary, restoring fertility in patients without other options. The first cellular map of a human ovary, recently developed at the University of Michigan, Ann Arbor, represents a big leap forward in that quest.

“You cannot build something if you don’t have the blueprint,” said biomedical engineer Ariella Shikanov, PhD, associate professor at University of Michigan, who helped create what she and colleagues call an atlas of the ovary. “By creating a map or an atlas, we can now follow what nature created and engineer the building blocks of an ovary — and build a nature-like structure.”

So far, the concept of an artificial ovary has been successful only in mice, with the development of a 3D-printed prosthetic ovary that enabled sterilized mice to have pups. Researchers hope that artificial human ovary technology could someday help women left infertile after cancer treatment, as well as patients who don›t respond to fertility treatments and those with premature ovarian failure.

But Dr. Shikanov believes this research will go even further, providing a valuable resource to scientists studying diseases and other conditions related to the ovary.

“Whenever people think about the ovary, if they think about it at all, they usually think about fertility,” said Dr. Shikanov. The ovary is so much more.

Besides producing and carrying a woman’s unfertilized eggs during her lifetime, the ovary is also responsible for endocrine function — the production of estrogen and progesterone, which in addition to supporting reproductive health, help maintain a woman’s cardiovascular, bone, and mental health.

“We don’t really understand everything that is happening in the ovary yet,” Dr. Shikanov said. “But we know it is an important organ.”
 

Mapping the Ovary

Because people don’t typically donate their ovaries, there are not many available for research, especially from younger reproductive age women, said Dr. Shikanov. So, the scientists set out to build a resource. They described their work in Science Advances.

To create their atlas, the researchers studied two premenopausal donor ovaries, profiling 18,000 genes in 257 regions. From three additional donor ovaries, they also generated single-cell RNA sequencing data for 21,198 cells.

“We identified four major cell types and four immune cell subtypes in the ovary,” said Dr. Shikanov. Taking samples from different areas of the ovary revealed distinct gene activities for oocytes, theca cells, and granulosa cells — expanding scientists’ understanding of the molecular programs driving ovarian follicle development.

What’s unique about their work is the focus on both single cell and spatial analysis, said study coauthor Jun Z. Li, PhD, associate chair of the University of Michigan’s department of computational medicine and bioinformatics. Specifically, they used a relatively new method called spatial transcriptomics, which allows them to see which genes are being activated and where.

“We are constructing the spatial arrangement of the cells in the ovary,” said Dr. Li. “This spatial analysis is like saying, ‘Let me look at where you are and who your neighbor is.’ ”

Their findings are built on other genetic and cellular research in the field, Dr. Li noted. Biomedical engineers in other areas of medicine are applying similar technologies to other organs including the heart, the breast, and bone — part of a larger project called the Human Cell Atlas.
 

Advancing Women’s Health Research

Historically, women’s health research has been underfunded and underrepresented, but the authors believe their atlas of the ovary is a significant step forward.

“There are a lot of biological questions that we don’t know the answers to about the ovary,” said Dr. Shikanov.

One of the biggest mysteries is why so many eggs never become fertilizable. Each human female is born with about one to two million ovarian follicles. Each follicle carries one immature egg. Around puberty, two thirds of these follicles die off. And most that are left never develop into fertilizable eggs.

“The majority of these follicles either just grow and secrete hormones or undergo atresia,” Dr. Shikanov said. “One question that we wanted to understand is, what determines an egg that can grow, ovulate, and become a fertilizable egg and potentially develop into a new human being from one that does not?”

Another big question researchers have is, what’s happening with other types of cells in the ovary — the supporting cells that produce endocrine hormones? Where are they located and what proteins and RNA are they making? Their research begins to unravel some of these questions and lays a foundation for future studies.

“We wanted to analyze the transcriptional signatures from specific regions and then do bioinformatical analysis and really combine structure, function, and transcriptional signatures,” Dr. Shikanov said.

Knowing the transcriptional signatures can help researchers understand disease mechanisms and then go on to develop treatments for these diseases.

Winifred Mak, MD, PhD, a reproductive endocrinologist and infertility specialist at Dell Medical School, University of Texas, Austin, studies cancer fertility preservation. “For me, it is interesting to see that there are so many different clusters of cells in the ovary that have been identified by this study that we were not necessarily aware of before,” said Dr. Mak, who is not involved in the new research. “Also, the identification of new genes not previously studied in the human ovary.”
 

What’s Next

Dozens of scientists who study reproductive health are already reaching out to the researchers about their work, Dr. Shikanov said.

“We get contacted almost every day from researchers all around the world asking for data sets or asking for details from this paper,” she said, “from people who study ovarian cancer, for example.”

Dr. Mak said having a map of a normal ovary could also help researchers who study premature ovarian insufficiency — why the ovary sometimes goes into premature menopause — and polycystic ovarian syndrome.

Another big area of research interest is ovarian aging. “Women live so much longer now, but we still reach menopause at the age of 50,” Dr. Shikanov said. “So, there are efforts going toward understanding ovarian aging and maybe preventing it to extend ovarian longevity.”

Dr. Mak said it will enable scientists to “look at different age women and see what genes change across the reproductive lifespan.”

The atlas may also eventually lead to treatments that help restore fertility in individuals who had and were treated for cancer as children, people who undergo sex transitions, and those whose reproductive organs have been impacted by trauma in conflict settings or accidents, Dr. Li said.

The applications are numerous and exciting, Dr. Shikanov said. “Our atlas is like a benchmark. Now researchers can collect ovaries from individuals with these diseases and conditions and try to compare what’s different.”

A version of this article appeared on Medscape.com.

In a recent article in the American Journal of Obstetrics & Gynecology, Rebecca C. Thurston, PhD, and Pauline Maki, PhD, leading scientists in the area of menopause’s impact on brain function, presented data from their assessment of 248 late perimenopausal and postmenopausal women who reported hot flashes, also known as vasomotor symptoms (VMS).

Hot flashes are known to be associated with changes in brain white matter, carotid atherosclerosis, brain function, and memory. Dr. Thurston and colleagues objectively measured VMS over 24 hours, using skin conductance monitoring. Plasma concentrations of Alzheimer’s disease biomarkers, including the amyloid beta 42–to–amyloid beta 40 ratio, were assessed. The mean age of study participants was 59 years, and they experienced a mean of five objective VMS daily.

A key finding was that VMS, particularly those occurring during sleep, were associated with a significantly lower amyloid beta 42–to–beta 40 ratio. This finding suggests that nighttime VMS may be a marker of risk for Alzheimer’s disease.

Previous research has found that menopausal hormone therapy is associated with favorable changes in Alzheimer’s disease biomarkers. Likewise, large observational studies have shown a lower incidence of Alzheimer’s disease among women who initiate hormone therapy in their late perimenopausal or early postmenopausal years and continue such therapy long term.

The findings of this important study by Thurston and colleagues provide further evidence to support the tantalizing possibility that agents that reduce nighttime hot flashes (including hormone therapy) may lower the subsequent incidence of Alzheimer’s disease in high-risk women.
 

Dr. Kaunitz is a tenured professor and associate chair in the department of obstetrics and gynecology at the University of Florida College of Medicine–Jacksonville, and medical director and director of menopause and gynecologic ultrasound services at the University of Florida Southside Women’s Health, Jacksonville. He disclosed ties to Sumitomo Pharma America, Mithra, Viatris, Bayer, Merck, Mylan (Viatris), and UpToDate.

A version of this article appeared on Medscape.com.

In a recent article in the American Journal of Obstetrics & Gynecology, Rebecca C. Thurston, PhD, and Pauline Maki, PhD, leading scientists in the area of menopause’s impact on brain function, presented data from their assessment of 248 late perimenopausal and postmenopausal women who reported hot flashes, also known as vasomotor symptoms (VMS).

Hot flashes are known to be associated with changes in brain white matter, carotid atherosclerosis, brain function, and memory. Dr. Thurston and colleagues objectively measured VMS over 24 hours, using skin conductance monitoring. Plasma concentrations of Alzheimer’s disease biomarkers, including the amyloid beta 42–to–amyloid beta 40 ratio, were assessed. The mean age of study participants was 59 years, and they experienced a mean of five objective VMS daily.

A key finding was that VMS, particularly those occurring during sleep, were associated with a significantly lower amyloid beta 42–to–beta 40 ratio. This finding suggests that nighttime VMS may be a marker of risk for Alzheimer’s disease.

Previous research has found that menopausal hormone therapy is associated with favorable changes in Alzheimer’s disease biomarkers. Likewise, large observational studies have shown a lower incidence of Alzheimer’s disease among women who initiate hormone therapy in their late perimenopausal or early postmenopausal years and continue such therapy long term.

The findings of this important study by Thurston and colleagues provide further evidence to support the tantalizing possibility that agents that reduce nighttime hot flashes (including hormone therapy) may lower the subsequent incidence of Alzheimer’s disease in high-risk women.
 

Dr. Kaunitz is a tenured professor and associate chair in the department of obstetrics and gynecology at the University of Florida College of Medicine–Jacksonville, and medical director and director of menopause and gynecologic ultrasound services at the University of Florida Southside Women’s Health, Jacksonville. He disclosed ties to Sumitomo Pharma America, Mithra, Viatris, Bayer, Merck, Mylan (Viatris), and UpToDate.

A version of this article appeared on Medscape.com.

In a recent article in the American Journal of Obstetrics & Gynecology, Rebecca C. Thurston, PhD, and Pauline Maki, PhD, leading scientists in the area of menopause’s impact on brain function, presented data from their assessment of 248 late perimenopausal and postmenopausal women who reported hot flashes, also known as vasomotor symptoms (VMS).

Hot flashes are known to be associated with changes in brain white matter, carotid atherosclerosis, brain function, and memory. Dr. Thurston and colleagues objectively measured VMS over 24 hours, using skin conductance monitoring. Plasma concentrations of Alzheimer’s disease biomarkers, including the amyloid beta 42–to–amyloid beta 40 ratio, were assessed. The mean age of study participants was 59 years, and they experienced a mean of five objective VMS daily.

A key finding was that VMS, particularly those occurring during sleep, were associated with a significantly lower amyloid beta 42–to–beta 40 ratio. This finding suggests that nighttime VMS may be a marker of risk for Alzheimer’s disease.

Previous research has found that menopausal hormone therapy is associated with favorable changes in Alzheimer’s disease biomarkers. Likewise, large observational studies have shown a lower incidence of Alzheimer’s disease among women who initiate hormone therapy in their late perimenopausal or early postmenopausal years and continue such therapy long term.

The findings of this important study by Thurston and colleagues provide further evidence to support the tantalizing possibility that agents that reduce nighttime hot flashes (including hormone therapy) may lower the subsequent incidence of Alzheimer’s disease in high-risk women.
 

Dr. Kaunitz is a tenured professor and associate chair in the department of obstetrics and gynecology at the University of Florida College of Medicine–Jacksonville, and medical director and director of menopause and gynecologic ultrasound services at the University of Florida Southside Women’s Health, Jacksonville. He disclosed ties to Sumitomo Pharma America, Mithra, Viatris, Bayer, Merck, Mylan (Viatris), and UpToDate.

A version of this article appeared on Medscape.com.

Charles Powell, MD, said he sometimes has a hard time persuading patients to start on low-dose vaginal estrogen, which can help prevent urinary tract infections and ease other symptoms of menopause.

Many women fear taking these vaginal products because of what Dr. Powell considers excessively strong warnings about the risk for cancer and cardiovascular disease linked to daily estrogen pills that were issued in the early 2000s.

He is advocating for the US Food and Drug Administration (FDA) to remove the boxed warning on low-dose estrogen. His efforts are separate from his roles as an associate professor of urology at the Indiana University School of Medicine, and as a member of the American Urological Association (AUA), Dr. Powell said.

In his quest to find out how to change labeling, Dr. Powell has gained a quick education about drug regulation. He has enlisted Representative Jim Baird (R-IN) and Senator Mike Braun (R-IN) to contact the FDA on his behalf, while congressional staff guided him through the hurdles of getting the warning label changed. For instance, a manufacturer of low-dose estrogen may need to become involved.

“You don’t learn this in med school,” Dr. Powell said in an interview.

With this work, Dr. Powell is wading into a long-standing argument between the FDA and some clinicians and researchers about the potential harms of low-dose estrogen.

He is doing so at a time of increased interest in understanding genitourinary syndrome of menopause (GSM), a term coined a decade ago by the International Society for the Study of Women’s Sexual Health and the North American Menopause Society to cover “a constellation of conditions” related to urogenital atrophy.

Symptoms of GSM include vaginal dryness and burning and recurrent urinary tract infections.

The federal government in 2022 began a project budgeted with nearly $1 million to review evidence on treatments, including vaginal and low-dose estrogen. The aim is to eventually help the AUA develop clinical guidelines for addressing GSM.

In addition, a bipartisan Senate bill introduced in May calls for authorizing $125 million over 5 years for the National Institutes of Health (NIH) to fund research on menopause. Senator Patty Murray (D-WA), the lead sponsor of the bill, is a longtime advocate for women’s health and serves as chairwoman for the Senate Appropriations Committee, which largely sets the NIH budget.

“The bottom line is, for too long, menopause has been overlooked, underinvested in and left behind,” Sen. Murray said during a May 2 press conference. “It is well past time to stop treating menopause like some kind of secret and start treating it like the major mainstream public health issue it is.”

Evidence Demands

Increased federal funding for menopause research could help efforts to change the warning label on low-dose estrogen, according to JoAnn Manson, MD, chief of preventive medicine at Brigham and Women’s Hospital in Boston.

Dr. Manson was a leader of the Women’s Health Initiative (WHI), a major federally funded research project launched in 1991 to investigate if hormone therapy and diet could protect older women from chronic diseases related to aging.

Before the WHI, clinicians prescribed hormones to prevent cardiovascular disease, based on evidence from earlier research.

But in 2002, a WHI trial that compared estrogen-progestin tablets with placebo was halted early because of disturbing findings, including an association with higher risk for breast cancer and cardiovascular disease.

Compared with placebo, for every 10,000 women taking estrogen plus progestin annually, incidences of cardiovascular disease, stroke, pulmonary embolism, and invasive breast cancer were seven to eight times higher.

In January 2003, the FDA announced it would put a boxed warning about cardiovascular risk and cancer risk on estrogen products, reflecting the WHI finding.

The agency at the time said clinicians should work with patients to assess risks and benefits of these products to manage the effects of menopause.

But more news on the potential harms of estrogen followed in 2004: A WHI study comparing estrogen-only pills with placebo produced signals of a small increased risk for stroke, although it also indicated no excess risk for breast cancer for at least 6.8 years of use.

Dr. Manson and the North American Menopause Society in 2016 filed a petition with the FDA to remove the boxed warning that appears on the front of low-dose estrogen products. The group wanted the information on risks moved to the usual warning section of the label.

Two years later, the FDA rejected the petition, citing the absence of “well-controlled studies,” to prove low-dose topical estrogen poses less risk to women than the high-dose pills studied in the WHI.

The FDA told this news organization that it stands by the decisions in its rejection of the petition.

Persuading the FDA to revise the labels on low-dose estrogen products likely will require evidence from randomized, large-scale studies, Dr. Manson said. The agency has not been satisfied to date with findings from other kinds of studies, including observational research.

“Once that evidence is available that the benefit-risk profile is different for different formulations and the evidence is compelling and definitive, that warning should change,” Dr. Manson told this news organization.

But the warning continues to have a chilling effect on patient willingness to use low-dose vaginal estrogen, even with the FDA’s continued endorsement of estrogen for menopause symptoms, clinicians told this news organization.

Risa Kagan, MD, a gynecologist at Sutter Health in Berkeley, California, said in many cases her patients’ partners also need to be reassured. Dr. Kagan said she still sees women who have had to discontinue sexual intercourse because of pain. In some cases, the patients will bring the medicine home only to find that the warnings frighten their spouses.

“The spouse says, ‘Oh my God, I don’t want you to get dementia, to get breast cancer, it’s not worth it, so let’s keep doing outercourse’,” meaning sexual relations without penetration, Dr. Kagan said.

Difficult Messaging

From the initial unveiling of disappointing WHI results, clinicians and researchers have stressed that women could continue using estrogen products for managing symptoms of menopause, even while advising strongly against their continued use with the intention of preventing heart disease.

Newly published findings from follow-ups of WHI participants may give clinicians and patients even more confidence for the use of estrogen products in early menopause.

According to the study, which Dr. Manson coauthored, younger women have a low risk for cardiovascular disease and other associated conditions when taking hormone therapy. Risks attributed to these drugs were less than one additional adverse event per 1000 women annually. This population may also derive significant quality-of-life benefits for symptom relief.

Dr. Manson told this news organization that estrogen in lower doses and delivered through the skin as a patch or gel may further reduce risks.

“The WHI findings should never be used as a reason to deny hormone therapy to women in early menopause with bothersome menopausal symptoms,” Dr. Manson said. “Many women are good candidates for treatment and, in shared decision-making with their clinicians, should be able to receive appropriate and personalized healthcare for their needs.”

But the current FDA warning label makes it difficult to help women understand the risk and benefits of low-dose estrogen, according to Stephanie Faubion, MD, MBA, medical director at the North American Menopause Society and director of Mayo Clinic’s Center for Women’s Health in Jacksonville, Florida.

Clinicians now must set aside time to explain the warnings to women when they prescribe low-dose estrogen, Dr. Faubion said.

“The package insert is going to look scary: I prepare women for that because otherwise they often won’t even fill it or use it.”
 

A version of this article appeared on Medscape.com .

Charles Powell, MD, said he sometimes has a hard time persuading patients to start on low-dose vaginal estrogen, which can help prevent urinary tract infections and ease other symptoms of menopause.

Many women fear taking these vaginal products because of what Dr. Powell considers excessively strong warnings about the risk for cancer and cardiovascular disease linked to daily estrogen pills that were issued in the early 2000s.

He is advocating for the US Food and Drug Administration (FDA) to remove the boxed warning on low-dose estrogen. His efforts are separate from his roles as an associate professor of urology at the Indiana University School of Medicine, and as a member of the American Urological Association (AUA), Dr. Powell said.

In his quest to find out how to change labeling, Dr. Powell has gained a quick education about drug regulation. He has enlisted Representative Jim Baird (R-IN) and Senator Mike Braun (R-IN) to contact the FDA on his behalf, while congressional staff guided him through the hurdles of getting the warning label changed. For instance, a manufacturer of low-dose estrogen may need to become involved.

“You don’t learn this in med school,” Dr. Powell said in an interview.

With this work, Dr. Powell is wading into a long-standing argument between the FDA and some clinicians and researchers about the potential harms of low-dose estrogen.

He is doing so at a time of increased interest in understanding genitourinary syndrome of menopause (GSM), a term coined a decade ago by the International Society for the Study of Women’s Sexual Health and the North American Menopause Society to cover “a constellation of conditions” related to urogenital atrophy.

Symptoms of GSM include vaginal dryness and burning and recurrent urinary tract infections.

The federal government in 2022 began a project budgeted with nearly $1 million to review evidence on treatments, including vaginal and low-dose estrogen. The aim is to eventually help the AUA develop clinical guidelines for addressing GSM.

In addition, a bipartisan Senate bill introduced in May calls for authorizing $125 million over 5 years for the National Institutes of Health (NIH) to fund research on menopause. Senator Patty Murray (D-WA), the lead sponsor of the bill, is a longtime advocate for women’s health and serves as chairwoman for the Senate Appropriations Committee, which largely sets the NIH budget.

“The bottom line is, for too long, menopause has been overlooked, underinvested in and left behind,” Sen. Murray said during a May 2 press conference. “It is well past time to stop treating menopause like some kind of secret and start treating it like the major mainstream public health issue it is.”

Evidence Demands

Increased federal funding for menopause research could help efforts to change the warning label on low-dose estrogen, according to JoAnn Manson, MD, chief of preventive medicine at Brigham and Women’s Hospital in Boston.

Dr. Manson was a leader of the Women’s Health Initiative (WHI), a major federally funded research project launched in 1991 to investigate if hormone therapy and diet could protect older women from chronic diseases related to aging.

Before the WHI, clinicians prescribed hormones to prevent cardiovascular disease, based on evidence from earlier research.

But in 2002, a WHI trial that compared estrogen-progestin tablets with placebo was halted early because of disturbing findings, including an association with higher risk for breast cancer and cardiovascular disease.

Compared with placebo, for every 10,000 women taking estrogen plus progestin annually, incidences of cardiovascular disease, stroke, pulmonary embolism, and invasive breast cancer were seven to eight times higher.

In January 2003, the FDA announced it would put a boxed warning about cardiovascular risk and cancer risk on estrogen products, reflecting the WHI finding.

The agency at the time said clinicians should work with patients to assess risks and benefits of these products to manage the effects of menopause.

But more news on the potential harms of estrogen followed in 2004: A WHI study comparing estrogen-only pills with placebo produced signals of a small increased risk for stroke, although it also indicated no excess risk for breast cancer for at least 6.8 years of use.

Dr. Manson and the North American Menopause Society in 2016 filed a petition with the FDA to remove the boxed warning that appears on the front of low-dose estrogen products. The group wanted the information on risks moved to the usual warning section of the label.

Two years later, the FDA rejected the petition, citing the absence of “well-controlled studies,” to prove low-dose topical estrogen poses less risk to women than the high-dose pills studied in the WHI.

The FDA told this news organization that it stands by the decisions in its rejection of the petition.

Persuading the FDA to revise the labels on low-dose estrogen products likely will require evidence from randomized, large-scale studies, Dr. Manson said. The agency has not been satisfied to date with findings from other kinds of studies, including observational research.

“Once that evidence is available that the benefit-risk profile is different for different formulations and the evidence is compelling and definitive, that warning should change,” Dr. Manson told this news organization.

But the warning continues to have a chilling effect on patient willingness to use low-dose vaginal estrogen, even with the FDA’s continued endorsement of estrogen for menopause symptoms, clinicians told this news organization.

Risa Kagan, MD, a gynecologist at Sutter Health in Berkeley, California, said in many cases her patients’ partners also need to be reassured. Dr. Kagan said she still sees women who have had to discontinue sexual intercourse because of pain. In some cases, the patients will bring the medicine home only to find that the warnings frighten their spouses.

“The spouse says, ‘Oh my God, I don’t want you to get dementia, to get breast cancer, it’s not worth it, so let’s keep doing outercourse’,” meaning sexual relations without penetration, Dr. Kagan said.

Difficult Messaging

From the initial unveiling of disappointing WHI results, clinicians and researchers have stressed that women could continue using estrogen products for managing symptoms of menopause, even while advising strongly against their continued use with the intention of preventing heart disease.

Newly published findings from follow-ups of WHI participants may give clinicians and patients even more confidence for the use of estrogen products in early menopause.

According to the study, which Dr. Manson coauthored, younger women have a low risk for cardiovascular disease and other associated conditions when taking hormone therapy. Risks attributed to these drugs were less than one additional adverse event per 1000 women annually. This population may also derive significant quality-of-life benefits for symptom relief.

Dr. Manson told this news organization that estrogen in lower doses and delivered through the skin as a patch or gel may further reduce risks.

“The WHI findings should never be used as a reason to deny hormone therapy to women in early menopause with bothersome menopausal symptoms,” Dr. Manson said. “Many women are good candidates for treatment and, in shared decision-making with their clinicians, should be able to receive appropriate and personalized healthcare for their needs.”

But the current FDA warning label makes it difficult to help women understand the risk and benefits of low-dose estrogen, according to Stephanie Faubion, MD, MBA, medical director at the North American Menopause Society and director of Mayo Clinic’s Center for Women’s Health in Jacksonville, Florida.

Clinicians now must set aside time to explain the warnings to women when they prescribe low-dose estrogen, Dr. Faubion said.

“The package insert is going to look scary: I prepare women for that because otherwise they often won’t even fill it or use it.”
 

A version of this article appeared on Medscape.com .

Charles Powell, MD, said he sometimes has a hard time persuading patients to start on low-dose vaginal estrogen, which can help prevent urinary tract infections and ease other symptoms of menopause.

Many women fear taking these vaginal products because of what Dr. Powell considers excessively strong warnings about the risk for cancer and cardiovascular disease linked to daily estrogen pills that were issued in the early 2000s.

He is advocating for the US Food and Drug Administration (FDA) to remove the boxed warning on low-dose estrogen. His efforts are separate from his roles as an associate professor of urology at the Indiana University School of Medicine, and as a member of the American Urological Association (AUA), Dr. Powell said.

In his quest to find out how to change labeling, Dr. Powell has gained a quick education about drug regulation. He has enlisted Representative Jim Baird (R-IN) and Senator Mike Braun (R-IN) to contact the FDA on his behalf, while congressional staff guided him through the hurdles of getting the warning label changed. For instance, a manufacturer of low-dose estrogen may need to become involved.

“You don’t learn this in med school,” Dr. Powell said in an interview.

With this work, Dr. Powell is wading into a long-standing argument between the FDA and some clinicians and researchers about the potential harms of low-dose estrogen.

He is doing so at a time of increased interest in understanding genitourinary syndrome of menopause (GSM), a term coined a decade ago by the International Society for the Study of Women’s Sexual Health and the North American Menopause Society to cover “a constellation of conditions” related to urogenital atrophy.

Symptoms of GSM include vaginal dryness and burning and recurrent urinary tract infections.

The federal government in 2022 began a project budgeted with nearly $1 million to review evidence on treatments, including vaginal and low-dose estrogen. The aim is to eventually help the AUA develop clinical guidelines for addressing GSM.

In addition, a bipartisan Senate bill introduced in May calls for authorizing $125 million over 5 years for the National Institutes of Health (NIH) to fund research on menopause. Senator Patty Murray (D-WA), the lead sponsor of the bill, is a longtime advocate for women’s health and serves as chairwoman for the Senate Appropriations Committee, which largely sets the NIH budget.

“The bottom line is, for too long, menopause has been overlooked, underinvested in and left behind,” Sen. Murray said during a May 2 press conference. “It is well past time to stop treating menopause like some kind of secret and start treating it like the major mainstream public health issue it is.”

Evidence Demands

Increased federal funding for menopause research could help efforts to change the warning label on low-dose estrogen, according to JoAnn Manson, MD, chief of preventive medicine at Brigham and Women’s Hospital in Boston.

Dr. Manson was a leader of the Women’s Health Initiative (WHI), a major federally funded research project launched in 1991 to investigate if hormone therapy and diet could protect older women from chronic diseases related to aging.

Before the WHI, clinicians prescribed hormones to prevent cardiovascular disease, based on evidence from earlier research.

But in 2002, a WHI trial that compared estrogen-progestin tablets with placebo was halted early because of disturbing findings, including an association with higher risk for breast cancer and cardiovascular disease.

Compared with placebo, for every 10,000 women taking estrogen plus progestin annually, incidences of cardiovascular disease, stroke, pulmonary embolism, and invasive breast cancer were seven to eight times higher.

In January 2003, the FDA announced it would put a boxed warning about cardiovascular risk and cancer risk on estrogen products, reflecting the WHI finding.

The agency at the time said clinicians should work with patients to assess risks and benefits of these products to manage the effects of menopause.

But more news on the potential harms of estrogen followed in 2004: A WHI study comparing estrogen-only pills with placebo produced signals of a small increased risk for stroke, although it also indicated no excess risk for breast cancer for at least 6.8 years of use.

Dr. Manson and the North American Menopause Society in 2016 filed a petition with the FDA to remove the boxed warning that appears on the front of low-dose estrogen products. The group wanted the information on risks moved to the usual warning section of the label.

Two years later, the FDA rejected the petition, citing the absence of “well-controlled studies,” to prove low-dose topical estrogen poses less risk to women than the high-dose pills studied in the WHI.

The FDA told this news organization that it stands by the decisions in its rejection of the petition.

Persuading the FDA to revise the labels on low-dose estrogen products likely will require evidence from randomized, large-scale studies, Dr. Manson said. The agency has not been satisfied to date with findings from other kinds of studies, including observational research.

“Once that evidence is available that the benefit-risk profile is different for different formulations and the evidence is compelling and definitive, that warning should change,” Dr. Manson told this news organization.

But the warning continues to have a chilling effect on patient willingness to use low-dose vaginal estrogen, even with the FDA’s continued endorsement of estrogen for menopause symptoms, clinicians told this news organization.

Risa Kagan, MD, a gynecologist at Sutter Health in Berkeley, California, said in many cases her patients’ partners also need to be reassured. Dr. Kagan said she still sees women who have had to discontinue sexual intercourse because of pain. In some cases, the patients will bring the medicine home only to find that the warnings frighten their spouses.

“The spouse says, ‘Oh my God, I don’t want you to get dementia, to get breast cancer, it’s not worth it, so let’s keep doing outercourse’,” meaning sexual relations without penetration, Dr. Kagan said.

Difficult Messaging

From the initial unveiling of disappointing WHI results, clinicians and researchers have stressed that women could continue using estrogen products for managing symptoms of menopause, even while advising strongly against their continued use with the intention of preventing heart disease.

Newly published findings from follow-ups of WHI participants may give clinicians and patients even more confidence for the use of estrogen products in early menopause.

According to the study, which Dr. Manson coauthored, younger women have a low risk for cardiovascular disease and other associated conditions when taking hormone therapy. Risks attributed to these drugs were less than one additional adverse event per 1000 women annually. This population may also derive significant quality-of-life benefits for symptom relief.

Dr. Manson told this news organization that estrogen in lower doses and delivered through the skin as a patch or gel may further reduce risks.

“The WHI findings should never be used as a reason to deny hormone therapy to women in early menopause with bothersome menopausal symptoms,” Dr. Manson said. “Many women are good candidates for treatment and, in shared decision-making with their clinicians, should be able to receive appropriate and personalized healthcare for their needs.”

But the current FDA warning label makes it difficult to help women understand the risk and benefits of low-dose estrogen, according to Stephanie Faubion, MD, MBA, medical director at the North American Menopause Society and director of Mayo Clinic’s Center for Women’s Health in Jacksonville, Florida.

Clinicians now must set aside time to explain the warnings to women when they prescribe low-dose estrogen, Dr. Faubion said.

“The package insert is going to look scary: I prepare women for that because otherwise they often won’t even fill it or use it.”
 

A version of this article appeared on Medscape.com .

Sherrie Palm, a patient advocate in Mukwonago, Wisconsin, learned in her 30s that she needed to educate herself about her own health. So when she discovered a walnut-sized lump coming out of her vagina in her mid-50s, she was stunned when her primary care provider (PCP) told her it was pelvic organ prolapse (POP), where one or more organs descend into the vaginal cavity.

“I was shocked,” Ms. Palm said. After searching online and discovering how prevalent POP was, her shock turned to anger. “I was blown away that it could be this common and I’d never heard of it,” she said. “I knew within 2 weeks that I had to do something to change the status quo.”

Ms. Palm eventually founded the nonprofit Association for Pelvic Organ Prolapse Support, or APOPS, complete with a forum where women can learn about POP and support one another. She said awareness has improved substantially since her diagnosis in 2007, but “we have a long way to go” because POP and vaginal health in general are so stigmatized.

Her website notes that about half of women with incontinence do not seek help, largely because of stigma. “The status quo is that PCPs do not POP screen,” she said. ObGyns may screen but often “because the patient has asked to be screened, they say it’s not that bad, come back and see me in a year, and do your Kegels,” Ms. Palm said.

Doctors who diagnose POP agree that the issue is often off PCPs’ radar.

“Primary care doctors are really in a time crunch, so this is one of the things that may not get addressed,” Jill Rabin, MD, vice chair of education and development in obstetrics and gynecology at Northwell Health in New York, said. Dr. Rabin is also head of urogynecology at Long Island Jewish Medical Center.

Ann Nwabuebo, PT, DPT, owner and founder of Body Connect Physical Therapy in Bethesda, Maryland, said social media has been shifting the attitude that pelvic health is a taboo subject. “It’s empowering people to seek care if they’re not finding physicians who are helping.”

But social media is also a double-edged sword, said Jenny LaCross, PT, DPT, PhD, a physical therapist at MOVE PT in Monroe, Michigan, and a postdoctoral research fellow with Michigan Medicine’s Pelvic Floor Research Group. “Pelvic health in general is talked about a lot more, but there’s also a lot more misinformation,” she said.

Part of that misinformation is the idea that pelvic prolapse is solely about weakness in the pelvic floor when it can also result from a widening of natural openings within the pelvis, Dr. LaCross said. She pointed to the two definitions of pelvic organ prolapse by the International Urogynecologic Consultation and the International Continence Society, both of which have been updated in recent years.

“This is why this is challenging for primary care providers,” Dr. LaCross said. “Even urogynecologists who are the specialists that treat prolapse and incontinence have changed how they assess it and the terminology and criteria that they use.”

What hasn’t changed is the substantial negative impact POP can have on quality of life. “This is the second most common reason that women enter nursing homes,” primarily because of urinary incontinence, Dr. Rabin said. “It’s very debilitating, but a lot of it is preventable and a lot is treatable.”

Dr. Rabin estimated that three out of every five women older than 60 and one or two out of every five women younger than 60 experience POP. Prevalence studies vary widely, from nearly a quarter of women to more than half, and racial and ethnic disparities in diagnosis further complicate the statistics.

PCPs therefore have an important role to play in screening for POP. The evidence shows that “patients want their providers to bring this up,” Dr. LaCross said. “They want to talk about it, but they want the provider to ask the questions first.”
 

Causes, Risk Factors, and Symptoms

Many causes contribute to POP, with gravity, aging, childbirth, and menopause at the top of the list.

“As people get older, their pelvic muscles and connective tissue get weaker, and the nerves don’t function as well,” Dr. Rabin said. Meanwhile, the body is losing estrogen, which affects how well the muscles contract and how easily the connective tissue can tear, she said.

With menopause, when baseline estrogen is lower, the tissue integrity is not as supportive as it should be and women are going to be at an increased risk of prolapse, Dr. Nwabuebo said.

POP has a range of risk factors:

• Increasing age, as muscle mass decreases and connective tissue hardens.
• Menopause.
• Vaginal delivery with complications, such as long second-stage labor, instrument-assisted delivery, multiple vaginal lacerations, and improperly repaired episiotomy.
• Multiple vaginal deliveries.
• Birthing large babies.
• Family history of pelvic organ prolapse (genetics can play a role in POP risk).
• Previous pelvic/abdominal surgery, including cesarean delivery and hysterectomy.
• Smoking (largely because of associated coughing).
• Chronic lung conditions that cause a lot of coughing.
• Chronic constipation or irritable bowel syndrome.
• Some types of high-impact activity, such as jogging or marathon running.
• Early menopause, for younger women.
• Repetitive heavy lifting in daily activities, such as occupational lifting (though not necessarily weight lifting as an exercise).
• Higher body mass index.
• Connective tissue disorders, such as joint hypermobility syndrome or Ehlers-Danlos syndrome.

Roger Dmochowski, MD, professor of urology and surgery at Vanderbilt University Medical Center, groups POP symptoms into two groups: anatomic and functional ones. A common anatomic symptom is bulging. “They’ll describe sitting on a ball, feeling like their bladder or something’s falling out, feeling a pressure or a heaviness,” Dr. Dmochowski said.

Functional symptoms can include vaginal dryness, vaginal irritation, painful intercourse, contact of the vaginal tissues with underclothes, and associated urinary symptoms, such as stress incontinence, urge incontinence, and incomplete emptying of the bladder. Dr. Dmochowski noted that women who report urinary incontinence may be at risk for being prescribed a medication without the necessary referral to a specialist for a full gynecologic evaluation.

Two other groups of functional symptoms include bowel-related disorders – primarily fecal incontinence and ongoing constipation – and pelvic pain or discomfort.

There can also be asymptomatic cases. “A lot of women have what we call silent prolapse,” Dr. Dmochowski said. That is, “they have some degree of loss of support to the bladder, vagina, or uterus, but they’re not symptomatic.” These women may be particularly good candidates for pelvic health physical therapy.
 

Screening and Diagnosis

Because many postmenopausal women stop seeing their ob.gyn, it’s often up to their primary care physician to determine whether their patients are experiencing POP symptoms.

“Women sometimes don’t bring this up with their doctor because they think there’s not enough time, or they’ll be laughed at, or their friends told them this is normal,” Dr. Rabin said. But primary care providers are really in a unique position to be able to ask the key symptom questions.

Dr. Rabin recommends a couple of questions to cover all the bases: “Do you leak urine when you cough or sneeze or on the way to the bathroom? Do you notice a bulge coming out of the vagina, or are you bothered by pelvic pressure?”

Dr. Dmochowski offered a single question that can open the conversation to more questions: “Are you bothered by any urinary or bowel or vaginal issues that we should talk about?” He also suggests asking how bothersome the symptoms are, which can help in directing treatment or prevention options. A physical exam can reveal signs of POP as well.

Diagnosis involves a detailed history, a comprehensive physical exam, and assessment with the Pelvic Organ Prolapse Quantification (POP-Q) tool. A urogynecologist can diagnose the type of POP – such as cystocele, rectocele, enterocele, uterine prolapse, or vaginal vault prolapse – and its grade (0-4).
 

Treatment: Physical Therapy, Pessary, and Surgery

No medications can treat prolapse, though some can treat downstream effects, such as hormonal vaginal creams for vaginal dryness and irritation, and medications for urinary incontinence. However, two mistakes PCPs can make are sending someone straight to surgery or prescribing them medication for symptoms without referring them for a diagnostic evaluation, Dr. Rabin said. “You have to have a diagnosis first to know what type of prolapse is there,” she said.

Because there can be long waiting lists for a urogynecologist or urologist, PCPs should also refer their patients to a pelvic health physical therapist (PT) who can help patients begin addressing the symptoms while they await a specialist who can diagnose them.

Though PT is often thought of as preventive, it’s also a conservative first-line intervention for prolapse, Dr. Nwabuebo said. Strong evidence shows pelvic floor muscle training from pelvic health PT can reduce symptoms of prolapse and reduce the severity by one grade in those with a grade 1 or 2 prolapse. Stage 3 is trickier, where PT may or may not be able to shift the symptom presentation, Dr. Nwabeubo said, and stage 4 is usually a surgical candidate.

“If you have a grade 4 prolapse, or the tissues are really visible outside the body, physical therapy and pelvic floor muscle training is not going to elevate that tissue back up into your body, but it can sometimes help with symptoms,” Dr. LaCross said.

The PT conducts a thorough pelvic muscle assessment, discusses lifestyle, and may teach breathing and bracing strategies for lifting, for example.

“A lot of what we’re talking about with pelvic floor therapy is lifestyle modifications,” Dr. Nwabuebo said. “If I have a patient with a history of chronic constipation, it doesn’t matter how much we do pelvic floor exercises; if we don’t manage the constipation issues by addressing their nutrition, then straining when using the bathroom will keep putting pressure on the pelvic floor.”

PTs can also recommend appropriate vaginal weights and dilators to help with pelvic floor strengthening and teach patients how to use them properly.

Even if women ultimately opt for surgery, PT prior to surgery can be beneficial. Dr. Rabin cited three reasons she recommends first-line PT: It may elevate the bladder enough to reduce stress incontinence and thicken the pelvic muscles, it can improve the effectiveness of a pessary or surgery if the woman chooses one of those options, and it can quiet bladder contractions, potentially obviating the need for pharmacologic treatment for overactive bladder.

The next nonsurgical option is a pessary, a device that fits into the vagina to provide support to the tissues displaced by prolapse. There’s a wide range of pessary types: some are short-term, worn only daily, or disposable, while others can be worn longer. Some women can self-insert and remove the pessary, and others may need a clinician to do so. Dr. Dmochowski recommends patients try a pessary to see if it benefits them. About a third of women will find them comfortable enough to wear regularly, but others will feel more sensitive to the pessary’s presence, he said.

One of the newest, most innovative pessary options for women is Gynethotics, which received Food and Drug Administration (FDA) clearance in March, as the first 3D-printed, customizable pessary capable of nearly 10 million configurations based on a person’s body.

Nearly all stage 4 prolapses and most of stage 3 prolapses can be addressed only through transvaginal or transabdominal surgery.

“We tell patients, if you can get 10 years out of your operation, you’re lucky,” Dr. Dmochowski said. A major reason for the short-lived durability is the poor quality of the tissue that needs to be pulled together. Serious complications resulting from use of polypropylene mesh during prolapse surgery led the FDA to halt sales of the devices and recommend discontinuing their use. However, one type of vaginal mesh is still considered safe to use in sacral colpopexy surgery.

Three things can shorten the durability of the surgery, Dr. Dmochowski said: heavy lifting, particularly anything over 30 pounds; chronic coughing, such as in those with chronic lung conditions; and chronic constipation.

Ms. Palm tried a pessary for her grade 3 prolapse with cystocele, rectocele, and enterocele but didn’t feel she had the time to use it regularly, so she opted for surgery. After a week on the couch recovering, she took it easy for another 12 weeks. Since then, she’s dedicated much of her time to educating and supporting women with POP and combating stigma associated with it. The APOPS website that she started has become a valuable resource for PCPs to send patients to, and the forum includes more 27,000 women from around the world.

“We encourage women to share what they’re experiencing. Tell your family, tell your friends, tell the people you work with about it,” Ms. Palm said. But many still feel uncomfortable speaking up, making PCPs’ role even more important.

*This story was updated on May 14, 2024.

Sherrie Palm, a patient advocate in Mukwonago, Wisconsin, learned in her 30s that she needed to educate herself about her own health. So when she discovered a walnut-sized lump coming out of her vagina in her mid-50s, she was stunned when her primary care provider (PCP) told her it was pelvic organ prolapse (POP), where one or more organs descend into the vaginal cavity.

“I was shocked,” Ms. Palm said. After searching online and discovering how prevalent POP was, her shock turned to anger. “I was blown away that it could be this common and I’d never heard of it,” she said. “I knew within 2 weeks that I had to do something to change the status quo.”

Ms. Palm eventually founded the nonprofit Association for Pelvic Organ Prolapse Support, or APOPS, complete with a forum where women can learn about POP and support one another. She said awareness has improved substantially since her diagnosis in 2007, but “we have a long way to go” because POP and vaginal health in general are so stigmatized.

Her website notes that about half of women with incontinence do not seek help, largely because of stigma. “The status quo is that PCPs do not POP screen,” she said. ObGyns may screen but often “because the patient has asked to be screened, they say it’s not that bad, come back and see me in a year, and do your Kegels,” Ms. Palm said.

Doctors who diagnose POP agree that the issue is often off PCPs’ radar.

“Primary care doctors are really in a time crunch, so this is one of the things that may not get addressed,” Jill Rabin, MD, vice chair of education and development in obstetrics and gynecology at Northwell Health in New York, said. Dr. Rabin is also head of urogynecology at Long Island Jewish Medical Center.

Ann Nwabuebo, PT, DPT, owner and founder of Body Connect Physical Therapy in Bethesda, Maryland, said social media has been shifting the attitude that pelvic health is a taboo subject. “It’s empowering people to seek care if they’re not finding physicians who are helping.”

But social media is also a double-edged sword, said Jenny LaCross, PT, DPT, PhD, a physical therapist at MOVE PT in Monroe, Michigan, and a postdoctoral research fellow with Michigan Medicine’s Pelvic Floor Research Group. “Pelvic health in general is talked about a lot more, but there’s also a lot more misinformation,” she said.

Part of that misinformation is the idea that pelvic prolapse is solely about weakness in the pelvic floor when it can also result from a widening of natural openings within the pelvis, Dr. LaCross said. She pointed to the two definitions of pelvic organ prolapse by the International Urogynecologic Consultation and the International Continence Society, both of which have been updated in recent years.

“This is why this is challenging for primary care providers,” Dr. LaCross said. “Even urogynecologists who are the specialists that treat prolapse and incontinence have changed how they assess it and the terminology and criteria that they use.”

What hasn’t changed is the substantial negative impact POP can have on quality of life. “This is the second most common reason that women enter nursing homes,” primarily because of urinary incontinence, Dr. Rabin said. “It’s very debilitating, but a lot of it is preventable and a lot is treatable.”

Dr. Rabin estimated that three out of every five women older than 60 and one or two out of every five women younger than 60 experience POP. Prevalence studies vary widely, from nearly a quarter of women to more than half, and racial and ethnic disparities in diagnosis further complicate the statistics.

PCPs therefore have an important role to play in screening for POP. The evidence shows that “patients want their providers to bring this up,” Dr. LaCross said. “They want to talk about it, but they want the provider to ask the questions first.”
 

Causes, Risk Factors, and Symptoms

Many causes contribute to POP, with gravity, aging, childbirth, and menopause at the top of the list.

“As people get older, their pelvic muscles and connective tissue get weaker, and the nerves don’t function as well,” Dr. Rabin said. Meanwhile, the body is losing estrogen, which affects how well the muscles contract and how easily the connective tissue can tear, she said.

With menopause, when baseline estrogen is lower, the tissue integrity is not as supportive as it should be and women are going to be at an increased risk of prolapse, Dr. Nwabuebo said.

POP has a range of risk factors:

• Increasing age, as muscle mass decreases and connective tissue hardens.
• Menopause.
• Vaginal delivery with complications, such as long second-stage labor, instrument-assisted delivery, multiple vaginal lacerations, and improperly repaired episiotomy.
• Multiple vaginal deliveries.
• Birthing large babies.
• Family history of pelvic organ prolapse (genetics can play a role in POP risk).
• Previous pelvic/abdominal surgery, including cesarean delivery and hysterectomy.
• Smoking (largely because of associated coughing).
• Chronic lung conditions that cause a lot of coughing.
• Chronic constipation or irritable bowel syndrome.
• Some types of high-impact activity, such as jogging or marathon running.
• Early menopause, for younger women.
• Repetitive heavy lifting in daily activities, such as occupational lifting (though not necessarily weight lifting as an exercise).
• Higher body mass index.
• Connective tissue disorders, such as joint hypermobility syndrome or Ehlers-Danlos syndrome.

Roger Dmochowski, MD, professor of urology and surgery at Vanderbilt University Medical Center, groups POP symptoms into two groups: anatomic and functional ones. A common anatomic symptom is bulging. “They’ll describe sitting on a ball, feeling like their bladder or something’s falling out, feeling a pressure or a heaviness,” Dr. Dmochowski said.

Functional symptoms can include vaginal dryness, vaginal irritation, painful intercourse, contact of the vaginal tissues with underclothes, and associated urinary symptoms, such as stress incontinence, urge incontinence, and incomplete emptying of the bladder. Dr. Dmochowski noted that women who report urinary incontinence may be at risk for being prescribed a medication without the necessary referral to a specialist for a full gynecologic evaluation.

Two other groups of functional symptoms include bowel-related disorders – primarily fecal incontinence and ongoing constipation – and pelvic pain or discomfort.

There can also be asymptomatic cases. “A lot of women have what we call silent prolapse,” Dr. Dmochowski said. That is, “they have some degree of loss of support to the bladder, vagina, or uterus, but they’re not symptomatic.” These women may be particularly good candidates for pelvic health physical therapy.
 

Screening and Diagnosis

Because many postmenopausal women stop seeing their ob.gyn, it’s often up to their primary care physician to determine whether their patients are experiencing POP symptoms.

“Women sometimes don’t bring this up with their doctor because they think there’s not enough time, or they’ll be laughed at, or their friends told them this is normal,” Dr. Rabin said. But primary care providers are really in a unique position to be able to ask the key symptom questions.

Dr. Rabin recommends a couple of questions to cover all the bases: “Do you leak urine when you cough or sneeze or on the way to the bathroom? Do you notice a bulge coming out of the vagina, or are you bothered by pelvic pressure?”

Dr. Dmochowski offered a single question that can open the conversation to more questions: “Are you bothered by any urinary or bowel or vaginal issues that we should talk about?” He also suggests asking how bothersome the symptoms are, which can help in directing treatment or prevention options. A physical exam can reveal signs of POP as well.

Diagnosis involves a detailed history, a comprehensive physical exam, and assessment with the Pelvic Organ Prolapse Quantification (POP-Q) tool. A urogynecologist can diagnose the type of POP – such as cystocele, rectocele, enterocele, uterine prolapse, or vaginal vault prolapse – and its grade (0-4).
 

Treatment: Physical Therapy, Pessary, and Surgery

No medications can treat prolapse, though some can treat downstream effects, such as hormonal vaginal creams for vaginal dryness and irritation, and medications for urinary incontinence. However, two mistakes PCPs can make are sending someone straight to surgery or prescribing them medication for symptoms without referring them for a diagnostic evaluation, Dr. Rabin said. “You have to have a diagnosis first to know what type of prolapse is there,” she said.

Because there can be long waiting lists for a urogynecologist or urologist, PCPs should also refer their patients to a pelvic health physical therapist (PT) who can help patients begin addressing the symptoms while they await a specialist who can diagnose them.

Though PT is often thought of as preventive, it’s also a conservative first-line intervention for prolapse, Dr. Nwabuebo said. Strong evidence shows pelvic floor muscle training from pelvic health PT can reduce symptoms of prolapse and reduce the severity by one grade in those with a grade 1 or 2 prolapse. Stage 3 is trickier, where PT may or may not be able to shift the symptom presentation, Dr. Nwabeubo said, and stage 4 is usually a surgical candidate.

“If you have a grade 4 prolapse, or the tissues are really visible outside the body, physical therapy and pelvic floor muscle training is not going to elevate that tissue back up into your body, but it can sometimes help with symptoms,” Dr. LaCross said.

The PT conducts a thorough pelvic muscle assessment, discusses lifestyle, and may teach breathing and bracing strategies for lifting, for example.

“A lot of what we’re talking about with pelvic floor therapy is lifestyle modifications,” Dr. Nwabuebo said. “If I have a patient with a history of chronic constipation, it doesn’t matter how much we do pelvic floor exercises; if we don’t manage the constipation issues by addressing their nutrition, then straining when using the bathroom will keep putting pressure on the pelvic floor.”

PTs can also recommend appropriate vaginal weights and dilators to help with pelvic floor strengthening and teach patients how to use them properly.

Even if women ultimately opt for surgery, PT prior to surgery can be beneficial. Dr. Rabin cited three reasons she recommends first-line PT: It may elevate the bladder enough to reduce stress incontinence and thicken the pelvic muscles, it can improve the effectiveness of a pessary or surgery if the woman chooses one of those options, and it can quiet bladder contractions, potentially obviating the need for pharmacologic treatment for overactive bladder.

The next nonsurgical option is a pessary, a device that fits into the vagina to provide support to the tissues displaced by prolapse. There’s a wide range of pessary types: some are short-term, worn only daily, or disposable, while others can be worn longer. Some women can self-insert and remove the pessary, and others may need a clinician to do so. Dr. Dmochowski recommends patients try a pessary to see if it benefits them. About a third of women will find them comfortable enough to wear regularly, but others will feel more sensitive to the pessary’s presence, he said.

One of the newest, most innovative pessary options for women is Gynethotics, which received Food and Drug Administration (FDA) clearance in March, as the first 3D-printed, customizable pessary capable of nearly 10 million configurations based on a person’s body.

Nearly all stage 4 prolapses and most of stage 3 prolapses can be addressed only through transvaginal or transabdominal surgery.

“We tell patients, if you can get 10 years out of your operation, you’re lucky,” Dr. Dmochowski said. A major reason for the short-lived durability is the poor quality of the tissue that needs to be pulled together. Serious complications resulting from use of polypropylene mesh during prolapse surgery led the FDA to halt sales of the devices and recommend discontinuing their use. However, one type of vaginal mesh is still considered safe to use in sacral colpopexy surgery.

Three things can shorten the durability of the surgery, Dr. Dmochowski said: heavy lifting, particularly anything over 30 pounds; chronic coughing, such as in those with chronic lung conditions; and chronic constipation.

Ms. Palm tried a pessary for her grade 3 prolapse with cystocele, rectocele, and enterocele but didn’t feel she had the time to use it regularly, so she opted for surgery. After a week on the couch recovering, she took it easy for another 12 weeks. Since then, she’s dedicated much of her time to educating and supporting women with POP and combating stigma associated with it. The APOPS website that she started has become a valuable resource for PCPs to send patients to, and the forum includes more 27,000 women from around the world.

“We encourage women to share what they’re experiencing. Tell your family, tell your friends, tell the people you work with about it,” Ms. Palm said. But many still feel uncomfortable speaking up, making PCPs’ role even more important.

*This story was updated on May 14, 2024.

Sherrie Palm, a patient advocate in Mukwonago, Wisconsin, learned in her 30s that she needed to educate herself about her own health. So when she discovered a walnut-sized lump coming out of her vagina in her mid-50s, she was stunned when her primary care provider (PCP) told her it was pelvic organ prolapse (POP), where one or more organs descend into the vaginal cavity.

“I was shocked,” Ms. Palm said. After searching online and discovering how prevalent POP was, her shock turned to anger. “I was blown away that it could be this common and I’d never heard of it,” she said. “I knew within 2 weeks that I had to do something to change the status quo.”

Ms. Palm eventually founded the nonprofit Association for Pelvic Organ Prolapse Support, or APOPS, complete with a forum where women can learn about POP and support one another. She said awareness has improved substantially since her diagnosis in 2007, but “we have a long way to go” because POP and vaginal health in general are so stigmatized.

Her website notes that about half of women with incontinence do not seek help, largely because of stigma. “The status quo is that PCPs do not POP screen,” she said. ObGyns may screen but often “because the patient has asked to be screened, they say it’s not that bad, come back and see me in a year, and do your Kegels,” Ms. Palm said.

Doctors who diagnose POP agree that the issue is often off PCPs’ radar.

“Primary care doctors are really in a time crunch, so this is one of the things that may not get addressed,” Jill Rabin, MD, vice chair of education and development in obstetrics and gynecology at Northwell Health in New York, said. Dr. Rabin is also head of urogynecology at Long Island Jewish Medical Center.

Ann Nwabuebo, PT, DPT, owner and founder of Body Connect Physical Therapy in Bethesda, Maryland, said social media has been shifting the attitude that pelvic health is a taboo subject. “It’s empowering people to seek care if they’re not finding physicians who are helping.”

But social media is also a double-edged sword, said Jenny LaCross, PT, DPT, PhD, a physical therapist at MOVE PT in Monroe, Michigan, and a postdoctoral research fellow with Michigan Medicine’s Pelvic Floor Research Group. “Pelvic health in general is talked about a lot more, but there’s also a lot more misinformation,” she said.

Part of that misinformation is the idea that pelvic prolapse is solely about weakness in the pelvic floor when it can also result from a widening of natural openings within the pelvis, Dr. LaCross said. She pointed to the two definitions of pelvic organ prolapse by the International Urogynecologic Consultation and the International Continence Society, both of which have been updated in recent years.

“This is why this is challenging for primary care providers,” Dr. LaCross said. “Even urogynecologists who are the specialists that treat prolapse and incontinence have changed how they assess it and the terminology and criteria that they use.”

What hasn’t changed is the substantial negative impact POP can have on quality of life. “This is the second most common reason that women enter nursing homes,” primarily because of urinary incontinence, Dr. Rabin said. “It’s very debilitating, but a lot of it is preventable and a lot is treatable.”

Dr. Rabin estimated that three out of every five women older than 60 and one or two out of every five women younger than 60 experience POP. Prevalence studies vary widely, from nearly a quarter of women to more than half, and racial and ethnic disparities in diagnosis further complicate the statistics.

PCPs therefore have an important role to play in screening for POP. The evidence shows that “patients want their providers to bring this up,” Dr. LaCross said. “They want to talk about it, but they want the provider to ask the questions first.”
 

Causes, Risk Factors, and Symptoms

Many causes contribute to POP, with gravity, aging, childbirth, and menopause at the top of the list.

“As people get older, their pelvic muscles and connective tissue get weaker, and the nerves don’t function as well,” Dr. Rabin said. Meanwhile, the body is losing estrogen, which affects how well the muscles contract and how easily the connective tissue can tear, she said.

With menopause, when baseline estrogen is lower, the tissue integrity is not as supportive as it should be and women are going to be at an increased risk of prolapse, Dr. Nwabuebo said.

POP has a range of risk factors:

• Increasing age, as muscle mass decreases and connective tissue hardens.
• Menopause.
• Vaginal delivery with complications, such as long second-stage labor, instrument-assisted delivery, multiple vaginal lacerations, and improperly repaired episiotomy.
• Multiple vaginal deliveries.
• Birthing large babies.
• Family history of pelvic organ prolapse (genetics can play a role in POP risk).
• Previous pelvic/abdominal surgery, including cesarean delivery and hysterectomy.
• Smoking (largely because of associated coughing).
• Chronic lung conditions that cause a lot of coughing.
• Chronic constipation or irritable bowel syndrome.
• Some types of high-impact activity, such as jogging or marathon running.
• Early menopause, for younger women.
• Repetitive heavy lifting in daily activities, such as occupational lifting (though not necessarily weight lifting as an exercise).
• Higher body mass index.
• Connective tissue disorders, such as joint hypermobility syndrome or Ehlers-Danlos syndrome.

Roger Dmochowski, MD, professor of urology and surgery at Vanderbilt University Medical Center, groups POP symptoms into two groups: anatomic and functional ones. A common anatomic symptom is bulging. “They’ll describe sitting on a ball, feeling like their bladder or something’s falling out, feeling a pressure or a heaviness,” Dr. Dmochowski said.

Functional symptoms can include vaginal dryness, vaginal irritation, painful intercourse, contact of the vaginal tissues with underclothes, and associated urinary symptoms, such as stress incontinence, urge incontinence, and incomplete emptying of the bladder. Dr. Dmochowski noted that women who report urinary incontinence may be at risk for being prescribed a medication without the necessary referral to a specialist for a full gynecologic evaluation.

Two other groups of functional symptoms include bowel-related disorders – primarily fecal incontinence and ongoing constipation – and pelvic pain or discomfort.

There can also be asymptomatic cases. “A lot of women have what we call silent prolapse,” Dr. Dmochowski said. That is, “they have some degree of loss of support to the bladder, vagina, or uterus, but they’re not symptomatic.” These women may be particularly good candidates for pelvic health physical therapy.
 

Screening and Diagnosis

Because many postmenopausal women stop seeing their ob.gyn, it’s often up to their primary care physician to determine whether their patients are experiencing POP symptoms.

“Women sometimes don’t bring this up with their doctor because they think there’s not enough time, or they’ll be laughed at, or their friends told them this is normal,” Dr. Rabin said. But primary care providers are really in a unique position to be able to ask the key symptom questions.

Dr. Rabin recommends a couple of questions to cover all the bases: “Do you leak urine when you cough or sneeze or on the way to the bathroom? Do you notice a bulge coming out of the vagina, or are you bothered by pelvic pressure?”

Dr. Dmochowski offered a single question that can open the conversation to more questions: “Are you bothered by any urinary or bowel or vaginal issues that we should talk about?” He also suggests asking how bothersome the symptoms are, which can help in directing treatment or prevention options. A physical exam can reveal signs of POP as well.

Diagnosis involves a detailed history, a comprehensive physical exam, and assessment with the Pelvic Organ Prolapse Quantification (POP-Q) tool. A urogynecologist can diagnose the type of POP – such as cystocele, rectocele, enterocele, uterine prolapse, or vaginal vault prolapse – and its grade (0-4).
 

Treatment: Physical Therapy, Pessary, and Surgery

No medications can treat prolapse, though some can treat downstream effects, such as hormonal vaginal creams for vaginal dryness and irritation, and medications for urinary incontinence. However, two mistakes PCPs can make are sending someone straight to surgery or prescribing them medication for symptoms without referring them for a diagnostic evaluation, Dr. Rabin said. “You have to have a diagnosis first to know what type of prolapse is there,” she said.

Because there can be long waiting lists for a urogynecologist or urologist, PCPs should also refer their patients to a pelvic health physical therapist (PT) who can help patients begin addressing the symptoms while they await a specialist who can diagnose them.

Though PT is often thought of as preventive, it’s also a conservative first-line intervention for prolapse, Dr. Nwabuebo said. Strong evidence shows pelvic floor muscle training from pelvic health PT can reduce symptoms of prolapse and reduce the severity by one grade in those with a grade 1 or 2 prolapse. Stage 3 is trickier, where PT may or may not be able to shift the symptom presentation, Dr. Nwabeubo said, and stage 4 is usually a surgical candidate.

“If you have a grade 4 prolapse, or the tissues are really visible outside the body, physical therapy and pelvic floor muscle training is not going to elevate that tissue back up into your body, but it can sometimes help with symptoms,” Dr. LaCross said.

The PT conducts a thorough pelvic muscle assessment, discusses lifestyle, and may teach breathing and bracing strategies for lifting, for example.

“A lot of what we’re talking about with pelvic floor therapy is lifestyle modifications,” Dr. Nwabuebo said. “If I have a patient with a history of chronic constipation, it doesn’t matter how much we do pelvic floor exercises; if we don’t manage the constipation issues by addressing their nutrition, then straining when using the bathroom will keep putting pressure on the pelvic floor.”

PTs can also recommend appropriate vaginal weights and dilators to help with pelvic floor strengthening and teach patients how to use them properly.

Even if women ultimately opt for surgery, PT prior to surgery can be beneficial. Dr. Rabin cited three reasons she recommends first-line PT: It may elevate the bladder enough to reduce stress incontinence and thicken the pelvic muscles, it can improve the effectiveness of a pessary or surgery if the woman chooses one of those options, and it can quiet bladder contractions, potentially obviating the need for pharmacologic treatment for overactive bladder.

The next nonsurgical option is a pessary, a device that fits into the vagina to provide support to the tissues displaced by prolapse. There’s a wide range of pessary types: some are short-term, worn only daily, or disposable, while others can be worn longer. Some women can self-insert and remove the pessary, and others may need a clinician to do so. Dr. Dmochowski recommends patients try a pessary to see if it benefits them. About a third of women will find them comfortable enough to wear regularly, but others will feel more sensitive to the pessary’s presence, he said.

One of the newest, most innovative pessary options for women is Gynethotics, which received Food and Drug Administration (FDA) clearance in March, as the first 3D-printed, customizable pessary capable of nearly 10 million configurations based on a person’s body.

Nearly all stage 4 prolapses and most of stage 3 prolapses can be addressed only through transvaginal or transabdominal surgery.

“We tell patients, if you can get 10 years out of your operation, you’re lucky,” Dr. Dmochowski said. A major reason for the short-lived durability is the poor quality of the tissue that needs to be pulled together. Serious complications resulting from use of polypropylene mesh during prolapse surgery led the FDA to halt sales of the devices and recommend discontinuing their use. However, one type of vaginal mesh is still considered safe to use in sacral colpopexy surgery.

Three things can shorten the durability of the surgery, Dr. Dmochowski said: heavy lifting, particularly anything over 30 pounds; chronic coughing, such as in those with chronic lung conditions; and chronic constipation.

Ms. Palm tried a pessary for her grade 3 prolapse with cystocele, rectocele, and enterocele but didn’t feel she had the time to use it regularly, so she opted for surgery. After a week on the couch recovering, she took it easy for another 12 weeks. Since then, she’s dedicated much of her time to educating and supporting women with POP and combating stigma associated with it. The APOPS website that she started has become a valuable resource for PCPs to send patients to, and the forum includes more 27,000 women from around the world.

“We encourage women to share what they’re experiencing. Tell your family, tell your friends, tell the people you work with about it,” Ms. Palm said. But many still feel uncomfortable speaking up, making PCPs’ role even more important.

*This story was updated on May 14, 2024.