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CHICAGO – Management of fertility and reproduction for women with prolactin-secreting pituitary tumors is a balancing act, often in the absence of robust data to support clinical decision making. So judgment, communication, and paying attention to the patient become paramount considerations, said endocrinologist Mark Molitch, MD, speaking at the annual meeting of the Endocrine Society.
The first step: restoring fertility
“Remember that our patients that have hyperprolactinemia are generally infertile,” said Dr. Molitch, Martha Leland Sherwin Professor of Medicine at Northwestern University, Chicago. “You really need to restore prolactin levels to close to normal, or normal, to allow ovulation to occur,” he said.
Dr. Molitch noted that up to 94% of women with hyperprolactinemia will initially have anovulation, amenorrhea, and infertility, but restoration of normal prolactin levels usually corrects these.
“If you have a patient where you are unable to restore prolactin levels to normal, there are other methods” to consider. Patients may end up using clomiphene, gonadotropin-releasing hormone (GnRH) or gonadotropins, or even moving to in vitro fertilization in these cases, said Dr. Molitch.
Preferable to any of these, though, is achieving normal prolactin levels.
In patients who are hyperprolactinemic, “the major action is occurring at the hypothalamic level,” with decreases in pulsatile secretion of GnRH, said Dr. Molitch. Next, there are resultant decreases in gonadotropin secretion, which in turn interrupt the ovary’s normal physiology. “There’s also an interruption in positive estrogen feedback in this cycle,” he said.
“So what’s new in this area is kisspeptin,” Dr. Molitch said, adding that the peptide activates the G-protein coupled receptor GPR54, found in the hypothalamus and pituitary. Infusion of kisspeptin stimulates secretion of luteinizing hormone, follicle stimulating hormone, and testosterone. Conversely, mutations that inactivate GPR43 result in hypogonadotropic hypogonadism, while activating mutations are associated with centrally caused precocious puberty (Biol Reprod. 2011 Oct;85[4]:650-60; Mol Cell Endocrinol. 2011 Oct 22;346[1-2]:29-3).
From this and other work, endocrinologists now know that kisspeptin is “very likely involved in puberty initiation and in response to fasting,” said Dr. Molitch. It’s now thought that high prolactin levels alter kisspeptin levels, “which then causes the further downstream effects,” said Dr. Molitch.
Dopamine agonists and pregnancy
Dopamine agonists are the primary therapies used for patients with prolactinomas and hyperprolactinemia. In patients seeking fertility, the dopamine agonist is usually continued just through the first few weeks of pregnancy, until the patient misses her first menstrual period, he said.
Establishing the menstrual interval is key to knowing when to stop the dopamine agonist, though. “We often use barrier contraceptives, so we can tell what the menstrual interval is – so we can tell when somebody’s missed her period,” Dr. Molitch explained.
“Most of the safety data on these drugs … are based on that relatively short period of exposure,” said Dr. Molitch. “As far as long-term use during pregnancy, only about 100 patients who took bromocriptine throughout pregnancy have been reported,” with two minor fetal anomalies reported from this series of patients, he said.
Though fewer than 20 cases have been reported of cabergoline being continued throughout a pregnancy, “there have not been any problems with that,” said Dr. Molitch.
Overall, over 6,000 pregnancies with bromocriptine exposure, as well as over 1,000 with cabergoline, have now been reported.
Dr. Molitch summarized the aggregate safety data for each dopamine agonist: “When we look at the adverse outcomes that occurred with either of these drugs, as far as spontaneous abortions or terminations, premature deliveries, multiple births, and, of course, the most important thing here being major malformations … in neither drug is there an increase in these adverse outcomes” (J Endocrinol Invest. 2018 Jan;41[1]:129-41).
“In my own mind now, I think that the number of cases with cabergoline now is quite sufficient to justify the safety of its use during pregnancy,” Dr. Molitch said. “However, this is sort of an individualized decision between you – the clinician – as well as your patient to make”: whether to trust the 1,000-case–strong data for cabergoline. “I no longer change patients from cabergoline to bromocriptine because of safety concerns. I think that cabergoline is perfectly safe,” he added.
What if the tumor grows in pregnancy?
During pregnancy, high estrogen levels from the placenta can stimulate prolactinoma growth, and the dopamine agonist’s inhibitory effect is gone once that medication’s been stopped. This means that “We have both a ‘push’ and a decrease in the ‘pull’ here, so you may have tumor enlargement,” said Dr. Molitch.
The risk for tumor enlargement in microadenomas is about 2.4%, and ranges to about 16% for enlargement of macroadenomas during pregnancy. For macroadenomas, “you might consider a prepregnancy debulking of the tumor,” Dr. Molitch said.
It’s reasonable to stop a dopamine agonist once pregnancy’s been established in a patient with a prolactinoma, and “follow the patient symptomatically every few months,” letting suspicious new symptoms like visual changes or headaches be the prompt for visual field exam and magnetic resonance imaging without contrast, said Dr. Molitch.
Though it’s not FDA approved, consideration can be given to continuing a dopamine agonist in a patient with a large prepregnancy adenoma throughout pregnancy – and if the tumor is enlarging significantly, the dopamine agonist should be restarted if it’s been withheld, said Dr. Molitch. Finally, surgery is the option if an enlarging tumor doesn’t respond to a dopamine agonist, unless the pregnancy is far enough along that delivery is a safe option.
“It’s important to actually document that there’s tumor enlargement, because if you’re going to do something like restarting a drug or even surgery, you really want to make sure that it’s the enlarging tumor that’s causing the problem,” said Dr. Molitch.
Postpartum prolactinoma considerations
Postpartum, even though prolactin secretion is upped by nursing, “there are no data to show that lactation stimulates tumor growth,” said Dr. Molitch. “I don’t see that there’s any problem with somebody nursing if they choose to do so.” However, “You certainly cannot restart the dopamine agonist, because that will lower prolactin levels and prevent that person from being able to nurse,” he said.
For reasons that are not clear, prolactin levels often drop post partum. Accordingly, it’s a reasonable approach in a nursing mother with mildly elevated prolactin levels to wait until nursing is done to see if menses resume spontaneously before restarting the dopamine agonist, said Dr. Molitch.
Dr. Molitch reported receiving fees and research funding from several pharmaceutical companies. He also disclosed that his spouse holds stock in Amgen.
SOURCE: Molitch M ENDO 2018. Abstract M02-2.
CHICAGO – Management of fertility and reproduction for women with prolactin-secreting pituitary tumors is a balancing act, often in the absence of robust data to support clinical decision making. So judgment, communication, and paying attention to the patient become paramount considerations, said endocrinologist Mark Molitch, MD, speaking at the annual meeting of the Endocrine Society.
The first step: restoring fertility
“Remember that our patients that have hyperprolactinemia are generally infertile,” said Dr. Molitch, Martha Leland Sherwin Professor of Medicine at Northwestern University, Chicago. “You really need to restore prolactin levels to close to normal, or normal, to allow ovulation to occur,” he said.
Dr. Molitch noted that up to 94% of women with hyperprolactinemia will initially have anovulation, amenorrhea, and infertility, but restoration of normal prolactin levels usually corrects these.
“If you have a patient where you are unable to restore prolactin levels to normal, there are other methods” to consider. Patients may end up using clomiphene, gonadotropin-releasing hormone (GnRH) or gonadotropins, or even moving to in vitro fertilization in these cases, said Dr. Molitch.
Preferable to any of these, though, is achieving normal prolactin levels.
In patients who are hyperprolactinemic, “the major action is occurring at the hypothalamic level,” with decreases in pulsatile secretion of GnRH, said Dr. Molitch. Next, there are resultant decreases in gonadotropin secretion, which in turn interrupt the ovary’s normal physiology. “There’s also an interruption in positive estrogen feedback in this cycle,” he said.
“So what’s new in this area is kisspeptin,” Dr. Molitch said, adding that the peptide activates the G-protein coupled receptor GPR54, found in the hypothalamus and pituitary. Infusion of kisspeptin stimulates secretion of luteinizing hormone, follicle stimulating hormone, and testosterone. Conversely, mutations that inactivate GPR43 result in hypogonadotropic hypogonadism, while activating mutations are associated with centrally caused precocious puberty (Biol Reprod. 2011 Oct;85[4]:650-60; Mol Cell Endocrinol. 2011 Oct 22;346[1-2]:29-3).
From this and other work, endocrinologists now know that kisspeptin is “very likely involved in puberty initiation and in response to fasting,” said Dr. Molitch. It’s now thought that high prolactin levels alter kisspeptin levels, “which then causes the further downstream effects,” said Dr. Molitch.
Dopamine agonists and pregnancy
Dopamine agonists are the primary therapies used for patients with prolactinomas and hyperprolactinemia. In patients seeking fertility, the dopamine agonist is usually continued just through the first few weeks of pregnancy, until the patient misses her first menstrual period, he said.
Establishing the menstrual interval is key to knowing when to stop the dopamine agonist, though. “We often use barrier contraceptives, so we can tell what the menstrual interval is – so we can tell when somebody’s missed her period,” Dr. Molitch explained.
“Most of the safety data on these drugs … are based on that relatively short period of exposure,” said Dr. Molitch. “As far as long-term use during pregnancy, only about 100 patients who took bromocriptine throughout pregnancy have been reported,” with two minor fetal anomalies reported from this series of patients, he said.
Though fewer than 20 cases have been reported of cabergoline being continued throughout a pregnancy, “there have not been any problems with that,” said Dr. Molitch.
Overall, over 6,000 pregnancies with bromocriptine exposure, as well as over 1,000 with cabergoline, have now been reported.
Dr. Molitch summarized the aggregate safety data for each dopamine agonist: “When we look at the adverse outcomes that occurred with either of these drugs, as far as spontaneous abortions or terminations, premature deliveries, multiple births, and, of course, the most important thing here being major malformations … in neither drug is there an increase in these adverse outcomes” (J Endocrinol Invest. 2018 Jan;41[1]:129-41).
“In my own mind now, I think that the number of cases with cabergoline now is quite sufficient to justify the safety of its use during pregnancy,” Dr. Molitch said. “However, this is sort of an individualized decision between you – the clinician – as well as your patient to make”: whether to trust the 1,000-case–strong data for cabergoline. “I no longer change patients from cabergoline to bromocriptine because of safety concerns. I think that cabergoline is perfectly safe,” he added.
What if the tumor grows in pregnancy?
During pregnancy, high estrogen levels from the placenta can stimulate prolactinoma growth, and the dopamine agonist’s inhibitory effect is gone once that medication’s been stopped. This means that “We have both a ‘push’ and a decrease in the ‘pull’ here, so you may have tumor enlargement,” said Dr. Molitch.
The risk for tumor enlargement in microadenomas is about 2.4%, and ranges to about 16% for enlargement of macroadenomas during pregnancy. For macroadenomas, “you might consider a prepregnancy debulking of the tumor,” Dr. Molitch said.
It’s reasonable to stop a dopamine agonist once pregnancy’s been established in a patient with a prolactinoma, and “follow the patient symptomatically every few months,” letting suspicious new symptoms like visual changes or headaches be the prompt for visual field exam and magnetic resonance imaging without contrast, said Dr. Molitch.
Though it’s not FDA approved, consideration can be given to continuing a dopamine agonist in a patient with a large prepregnancy adenoma throughout pregnancy – and if the tumor is enlarging significantly, the dopamine agonist should be restarted if it’s been withheld, said Dr. Molitch. Finally, surgery is the option if an enlarging tumor doesn’t respond to a dopamine agonist, unless the pregnancy is far enough along that delivery is a safe option.
“It’s important to actually document that there’s tumor enlargement, because if you’re going to do something like restarting a drug or even surgery, you really want to make sure that it’s the enlarging tumor that’s causing the problem,” said Dr. Molitch.
Postpartum prolactinoma considerations
Postpartum, even though prolactin secretion is upped by nursing, “there are no data to show that lactation stimulates tumor growth,” said Dr. Molitch. “I don’t see that there’s any problem with somebody nursing if they choose to do so.” However, “You certainly cannot restart the dopamine agonist, because that will lower prolactin levels and prevent that person from being able to nurse,” he said.
For reasons that are not clear, prolactin levels often drop post partum. Accordingly, it’s a reasonable approach in a nursing mother with mildly elevated prolactin levels to wait until nursing is done to see if menses resume spontaneously before restarting the dopamine agonist, said Dr. Molitch.
Dr. Molitch reported receiving fees and research funding from several pharmaceutical companies. He also disclosed that his spouse holds stock in Amgen.
SOURCE: Molitch M ENDO 2018. Abstract M02-2.
CHICAGO – Management of fertility and reproduction for women with prolactin-secreting pituitary tumors is a balancing act, often in the absence of robust data to support clinical decision making. So judgment, communication, and paying attention to the patient become paramount considerations, said endocrinologist Mark Molitch, MD, speaking at the annual meeting of the Endocrine Society.
The first step: restoring fertility
“Remember that our patients that have hyperprolactinemia are generally infertile,” said Dr. Molitch, Martha Leland Sherwin Professor of Medicine at Northwestern University, Chicago. “You really need to restore prolactin levels to close to normal, or normal, to allow ovulation to occur,” he said.
Dr. Molitch noted that up to 94% of women with hyperprolactinemia will initially have anovulation, amenorrhea, and infertility, but restoration of normal prolactin levels usually corrects these.
“If you have a patient where you are unable to restore prolactin levels to normal, there are other methods” to consider. Patients may end up using clomiphene, gonadotropin-releasing hormone (GnRH) or gonadotropins, or even moving to in vitro fertilization in these cases, said Dr. Molitch.
Preferable to any of these, though, is achieving normal prolactin levels.
In patients who are hyperprolactinemic, “the major action is occurring at the hypothalamic level,” with decreases in pulsatile secretion of GnRH, said Dr. Molitch. Next, there are resultant decreases in gonadotropin secretion, which in turn interrupt the ovary’s normal physiology. “There’s also an interruption in positive estrogen feedback in this cycle,” he said.
“So what’s new in this area is kisspeptin,” Dr. Molitch said, adding that the peptide activates the G-protein coupled receptor GPR54, found in the hypothalamus and pituitary. Infusion of kisspeptin stimulates secretion of luteinizing hormone, follicle stimulating hormone, and testosterone. Conversely, mutations that inactivate GPR43 result in hypogonadotropic hypogonadism, while activating mutations are associated with centrally caused precocious puberty (Biol Reprod. 2011 Oct;85[4]:650-60; Mol Cell Endocrinol. 2011 Oct 22;346[1-2]:29-3).
From this and other work, endocrinologists now know that kisspeptin is “very likely involved in puberty initiation and in response to fasting,” said Dr. Molitch. It’s now thought that high prolactin levels alter kisspeptin levels, “which then causes the further downstream effects,” said Dr. Molitch.
Dopamine agonists and pregnancy
Dopamine agonists are the primary therapies used for patients with prolactinomas and hyperprolactinemia. In patients seeking fertility, the dopamine agonist is usually continued just through the first few weeks of pregnancy, until the patient misses her first menstrual period, he said.
Establishing the menstrual interval is key to knowing when to stop the dopamine agonist, though. “We often use barrier contraceptives, so we can tell what the menstrual interval is – so we can tell when somebody’s missed her period,” Dr. Molitch explained.
“Most of the safety data on these drugs … are based on that relatively short period of exposure,” said Dr. Molitch. “As far as long-term use during pregnancy, only about 100 patients who took bromocriptine throughout pregnancy have been reported,” with two minor fetal anomalies reported from this series of patients, he said.
Though fewer than 20 cases have been reported of cabergoline being continued throughout a pregnancy, “there have not been any problems with that,” said Dr. Molitch.
Overall, over 6,000 pregnancies with bromocriptine exposure, as well as over 1,000 with cabergoline, have now been reported.
Dr. Molitch summarized the aggregate safety data for each dopamine agonist: “When we look at the adverse outcomes that occurred with either of these drugs, as far as spontaneous abortions or terminations, premature deliveries, multiple births, and, of course, the most important thing here being major malformations … in neither drug is there an increase in these adverse outcomes” (J Endocrinol Invest. 2018 Jan;41[1]:129-41).
“In my own mind now, I think that the number of cases with cabergoline now is quite sufficient to justify the safety of its use during pregnancy,” Dr. Molitch said. “However, this is sort of an individualized decision between you – the clinician – as well as your patient to make”: whether to trust the 1,000-case–strong data for cabergoline. “I no longer change patients from cabergoline to bromocriptine because of safety concerns. I think that cabergoline is perfectly safe,” he added.
What if the tumor grows in pregnancy?
During pregnancy, high estrogen levels from the placenta can stimulate prolactinoma growth, and the dopamine agonist’s inhibitory effect is gone once that medication’s been stopped. This means that “We have both a ‘push’ and a decrease in the ‘pull’ here, so you may have tumor enlargement,” said Dr. Molitch.
The risk for tumor enlargement in microadenomas is about 2.4%, and ranges to about 16% for enlargement of macroadenomas during pregnancy. For macroadenomas, “you might consider a prepregnancy debulking of the tumor,” Dr. Molitch said.
It’s reasonable to stop a dopamine agonist once pregnancy’s been established in a patient with a prolactinoma, and “follow the patient symptomatically every few months,” letting suspicious new symptoms like visual changes or headaches be the prompt for visual field exam and magnetic resonance imaging without contrast, said Dr. Molitch.
Though it’s not FDA approved, consideration can be given to continuing a dopamine agonist in a patient with a large prepregnancy adenoma throughout pregnancy – and if the tumor is enlarging significantly, the dopamine agonist should be restarted if it’s been withheld, said Dr. Molitch. Finally, surgery is the option if an enlarging tumor doesn’t respond to a dopamine agonist, unless the pregnancy is far enough along that delivery is a safe option.
“It’s important to actually document that there’s tumor enlargement, because if you’re going to do something like restarting a drug or even surgery, you really want to make sure that it’s the enlarging tumor that’s causing the problem,” said Dr. Molitch.
Postpartum prolactinoma considerations
Postpartum, even though prolactin secretion is upped by nursing, “there are no data to show that lactation stimulates tumor growth,” said Dr. Molitch. “I don’t see that there’s any problem with somebody nursing if they choose to do so.” However, “You certainly cannot restart the dopamine agonist, because that will lower prolactin levels and prevent that person from being able to nurse,” he said.
For reasons that are not clear, prolactin levels often drop post partum. Accordingly, it’s a reasonable approach in a nursing mother with mildly elevated prolactin levels to wait until nursing is done to see if menses resume spontaneously before restarting the dopamine agonist, said Dr. Molitch.
Dr. Molitch reported receiving fees and research funding from several pharmaceutical companies. He also disclosed that his spouse holds stock in Amgen.
SOURCE: Molitch M ENDO 2018. Abstract M02-2.
REPORTING FROM ENDO 2018