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PSA testing: When it’s useful, when it’s not
Do not routinely screen all men over the age of 50 for prostate cancer with the prostate-specific antigen (PSA) test. Consider screening men younger than 75 with no cardiovascular or cancer risk factors—the only patient population for whom PSA testing appears to provide even a small benefit.1,2
STRENGTH OF RECOMMENDATION
B: Based on a meta-analysis of 6 randomized controlled trials (RCTs) with methodological limitations, and a post hoc analysis of a large RCT.
Djulbegovic M, Beyth RJ, Neuberger MM, et al. Screening for prostate cancer: systematic review and meta-analysis of randomized controlled trials. BMJ. 2010;341:c4543.
Crawford ED, Grubb R 3rd, Black A, et al. Comorbidity and mortality results from a randomized prostate cancer screening trial. J Clin Oncol. 2011;29:355-361.
ILLUSTRATIVE CASES
A 65-year-old obese man with high blood pressure comes in for a complete physical and asks if he should have the “blood test for cancer.” He had a normal prostate specific antigen (PSA) the last time he was tested, but that was 10 years ago. What should you tell him?
A 55-year-old man schedules a routine check-up and requests a PSA test. His last test, at age 50, was normal. The patient has no known medical problems and no family history of prostate cancer, and he exercises regularly and doesn’t smoke. How should you respond to his request for a PSA test?
Prostate cancer is the second leading cause of cancer deaths among men in the United States, after lung cancer. One in 6 American men will be diagnosed with prostate cancer; for about 3% of them, the cancer will be fatal.3,4
Widespread testing without evidence of efficacy
The PSA test was approved by the US Food and Drug Administration (FDA) in 1986.5 Its potential to detect early prostate cancer in the hope of decreasing morbidity and mortality led to widespread PSA screening in the 1990s, before data on the efficacy of routine screening existed.
By 2002, only one low-quality RCT that compared screening with no screening had been published. The investigators concluded that screening resulted in lower mortality rates, but a subsequent (and superior) intention-to-treat analysis showed no mortality benefit.6 Two large RCTs, both published in 2009, reported conflicting results.7,8
The European Randomized Study of Screening for Prostate Cancer (ERSPC) enrolled 182,000 men ages 50 to 74 years and randomized them to either PSA screening every 4 years or no screening. Prostate cancer-specific mortality was 20% lower for those in the screening group compared with the no-screening group; however, the absolute risk reduction was only 0.71 deaths per 1000 men.7
The US Prostate, Lung, Colorectal, Ovarian Cancer (PLCO) Screening Trial randomized 77,000 men ages 55 to 74 years to either annual PSA and digital rectal examination (DRE) screening or usual care. After 7 years of follow-up, no significant difference was found in prostate cancer deaths or all-cause mortality in the screening group vs the control group. It is important to note, however, that 52% of the men in the control group had ≥1 PSA screening during the study period, which decreased the researchers’ ability to fully assess the benefits of screening.8
PSA’s limitations and potential harmful effects
The PSA test’s significant limitations and potentially harmful effects counter the potential benefits of screening. About 75% of positive tests are false positives, which are associated with psychological harm in some men for up to a year after the test.6 In addition, diagnostic testing and treatment for what may be nonlife-threatening prostate cancer can cause harm, including erectile dysfunction (ED), urinary incontinence, bowel dysfunction, and death. Rates of ED and incontinence 18 months after radical prostatectomy are an estimated 59.9% and 8.4%, respectively.9
Do the benefits of PSA testing outweigh the harms—and for which men? The meta-analysis and post hoc analysis detailed in this PURL help clear up the controversy.
STUDY SUMMARY: Widespread screening doesn’t save lives
Djulbegovic et al examined 6 RCTs, including the ERSPC and PLCO studies described earlier, that compared screening for prostate cancer (PSA with or without DRE) with no screening or usual care.1 Together, the studies included nearly 390,000 men ages 45 to 80 years, and had 4 to 15 years of follow-up. The results showed that routine screening for prostate cancer had no statistically significant effect on all-cause mortality (relative risk [RR]=0.99; 95% confidence interval [CI], 0.97-1.01), death from prostate cancer (RR=0.88; 95% CI, 0.71-1.09), or diagnosis of stage III or IV prostate cancer (RR=0.94; 95% CI, 0.85-1.04). Routine screening did, however, increase the probability of being diagnosed with prostate cancer at any stage, especially at stage I. For every 1000 men screened, on average, 20 more cases of prostate cancer were diagnosed.
Healthy men may benefit from screening
Crawford et al conducted a post hoc analysis of the PLCO trial, which had found no benefit to annual PSA testing and serial DRE compared with usual care for the general population.2 Their analysis compared the mortality benefits (both prostate cancer–specific and overall) of annual PSA screening for healthy men with no or minimal comorbidities vs the mortality benefits for men with any risk factor for the 2 leading causes of death: cancer and cardiovascular disease.
Annual PSA testing yielded more diagnoses of prostate cancer in both healthy and at-risk men. Deaths from prostate cancer were infrequent in both groups, occurring in 0.22% (164/73,378) of all participants.
Men with ≥1 risk factor had similar prostate cancer–specific deaths with both yearly screening and usual care (62 vs 42 deaths, adjusted hazard ratio [AHR]=1.43; 95% CI, 0.96-2.11); their prostate cancer–specific mortality rate was 0.27% (95% CI, 0.21-0.34) and 0.19% (95% CI, 0.14-0.25), respectively.
However, healthy men younger than 75 years had fewer prostate cancer–specific deaths with annual PSA screenings (22 vs 38; AHR=0.56; 95% CI, 0.33-0.95; P=.03). Specifically, the prostate cancer mortality rate was 0.17% (95% CI, 0.11-0.25) in the group that received screening vs 0.31% (95% CI, 0.22-0.42) in the usual care group. Thus, the absolute risk reduction for prostate cancer-specific mortality in men without comorbidities who received yearly screening instead of usual care was 0.14% (0.31% vs 0.17%, P=.03), with a number needed to screen of 723 to prevent one death from prostate cancer. There was a non-significant reduction in all-cause mortality in the intervention group vs the control group (AHR=0.93; 95% CI, 0.86-1.02; P=.11).
WHAT’S NEW: At best, screening has a small benefit
These trials indicate that only a small group of men will potentially benefit from PSA screening. Prior to this meta-analysis, a Cochrane review published in 2006 had concluded that there was insufficient evidence to support or refute the routine use of mass screening for prostate can-cer.10 The meta-analysis by Djulbegovic et al, which included 4 additional trials, 2 of them large, found no benefit of PSA screening in reducing mortality from prostate cancer for the general population.1
Annual screening does appear to provide a small reduction in prostate cancer deaths but no significant reduction in all-cause mortality in men younger than age 75 who have no risk factors for cancer or cardiovascular disease.
CAVEATS: Study limitations, some unknowns
These studies did not address whether certain groups at higher risk of developing prostate cancer, such as African American men and those with a family history of prostate cancer, would benefit from PSA screening. In addition, both of the studies detailed in this PURL had substantive weaknesses.
Methodological limitations of the studies in the meta-analysis included the lack of intention-to-treat analysis and allocation concealment, which favors finding a benefit for the screening arm, and PSA screening in the nonscreening arm, which biases the results toward not finding a screening benefit that might exist. Despite these weaknesses, this meta-analysis brings together the best available evidence of the value of screening for prostate cancer.
In addition, there was no quantitative assessment of complication rates included in the meta-analysis. None of the 6 trials collected data on the effect of screening or treatment on participants’ quality of life.
In the post hoc study showing a benefit for screening healthy men, the decrease in prostate cancer deaths was small in magnitude, did not have an impact on all-cause mortality, and was of marginal statistical significance. Although the data came from the largest multicenter study to date of prostate cancer screening, the results of a post hoc analysis of a single trial should be interpreted with caution. The study was initially designed to test the effect of screening on a general population. Whenever a study deviates from the original hypothesis to evaluate a subset of the study population, the investigators increase the risk of finding a difference where none exists. Thus, it is possible that the findings of benefit for healthy men may not truly be present.
What’s more, the risk factors identified by the authors could be interpreted as arbitrary. They included diverticulosis, which is not known to increase the likelihood of cancer or heart disease, as a risk factor. By the same token, smoking—a known risk factor for both cancer and cardiovascular disease—was not addressed. Finally, potential harms associated with false-positive tests and prostate cancer treatment were not addressed in these studies.
CHALLENGES TO IMPLEMENTATION: Old habits die hard
Clinicians have recommended PSA screening for men >50 years, and men have requested such screening, for more than 2 decades. Physicians often opt to order a PSA test rather than to take the time to explain potential harms and benefits and listen to the patient’s thoughts and feelings about the value of screening. In addition, physicians who believe the lack of benefit from screening does not apply to their patients will continue to order the PSA test. (See “The perils of PSA screening”.)
Patients may opt to continue to be screened although they have developed a risk factor for cardiovascular disease. Also, a decision not to screen directly contradicts the recommendation of the American Urological Association, which calls for annual PSA testing for asymptomatic men with a life expectancy >10 years starting at 40 years of age.11
Shared decision-making
The US Preventive Services Task Force (USPSTF) provides a basis for shared decision-making between physicians and patients concerning prostate cancer screening. The USPSTF states that there is insufficient evidence to recommend for or against prostate cancer screening for the general male population younger than age 75 and recommends against screening men age 75 and older or those with a life expectancy of less than 10 years.12
Decisions regarding PSA screening should be shared and documented for all men between the ages of 50 and 75 years. Advise patients with risk factors that the evidence shows little value and possible harm from screening. Tell healthier men that PSA testing appears to offer a small benefit, at best.
Acknowledgement
The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources; the grant is a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.
1. Djulbegovic M, Beyth RJ, Neuberger MM, et al. Screening for prostate cancer: systematic review and meta-analysis of randomized controlled trials. BMJ. 2010;341:c4543.-
2. Crawford ED, Grubb R, 3rd, Black A, et al. Comorbidity and mortality results from a randomized prostate cancer screening trial. J Clin Oncol. 2011;29:355-361.
3. American Cancer Society. Cancer facts & figures 2010. Atlanta, Ga: American Cancer Society; 2010. Available at: http://www.cancer.org/acs/groups/content/@nho/documents/document/acspc-024113.pdf. Accessed April 13, 2011.
4. American Cancer Society. Prostate cancer. Last medical review November 22, 2010. Available at: http://www.cancer.org/cancer/prostatecancer/detailedguide/prostate-cancer-key-statistics. Accessed April 13, 2011.
5. National Institutes of Health. Prostate cancer. Last updated February 14, 2011. Available at: http://report.nih.gov/NIHfactsheets/ViewFactSheet.aspx?csid=60. Accessed May 9, 2011.
6. Lin K, Lipsitz R, Miller T, et al. Benefits and harms of prostate-specific antigen screening for prostate cancer: an evidence update for the U.S. Preventive Services Task Force. Ann Intern Med. 2008;149:192-199.
7. Schroder FH, Hugosson J, Roobol MJ, et al. Screening and prostate-cancer mortality in a randomized European study. N Engl J Med. 2009;360:1320-1328.
8. Andriole GL, Crawford ED, Grubb RL, 3rd, et al. Mortality results from a randomized prostate-cancer screening trial. N Engl J Med. 2009;360:1310-1319.
9. Stanford JL, Feng Z, Hamilton AS, et al. Urinary and sexual function after radical prostatectomy for clinically localized prostate cancer: the Prostate Cancer Outcomes Study. JAMA. 2000;283:354-360.
10. Ilic D, O’Connor D, Greens, Wilt T. Screening for prostate cancer. Cochrane Database Syst Rev. 2006;(3):CD004720.-
11. American Urological Association. Prostate-specific antigen best practice statement: 2009 update. Available at: http://www.auanet.org/content/guidelines-and-quality-care/clinical-guidelines/main-reports/psa09.pdf. Accessed March 16, 2011.
12. US Preventive Services Task Force. Screening for prostate cancer: US Preventive Services Task Force recommendation statement. Ann Intern Med. 2008;149:185-191.
Do not routinely screen all men over the age of 50 for prostate cancer with the prostate-specific antigen (PSA) test. Consider screening men younger than 75 with no cardiovascular or cancer risk factors—the only patient population for whom PSA testing appears to provide even a small benefit.1,2
STRENGTH OF RECOMMENDATION
B: Based on a meta-analysis of 6 randomized controlled trials (RCTs) with methodological limitations, and a post hoc analysis of a large RCT.
Djulbegovic M, Beyth RJ, Neuberger MM, et al. Screening for prostate cancer: systematic review and meta-analysis of randomized controlled trials. BMJ. 2010;341:c4543.
Crawford ED, Grubb R 3rd, Black A, et al. Comorbidity and mortality results from a randomized prostate cancer screening trial. J Clin Oncol. 2011;29:355-361.
ILLUSTRATIVE CASES
A 65-year-old obese man with high blood pressure comes in for a complete physical and asks if he should have the “blood test for cancer.” He had a normal prostate specific antigen (PSA) the last time he was tested, but that was 10 years ago. What should you tell him?
A 55-year-old man schedules a routine check-up and requests a PSA test. His last test, at age 50, was normal. The patient has no known medical problems and no family history of prostate cancer, and he exercises regularly and doesn’t smoke. How should you respond to his request for a PSA test?
Prostate cancer is the second leading cause of cancer deaths among men in the United States, after lung cancer. One in 6 American men will be diagnosed with prostate cancer; for about 3% of them, the cancer will be fatal.3,4
Widespread testing without evidence of efficacy
The PSA test was approved by the US Food and Drug Administration (FDA) in 1986.5 Its potential to detect early prostate cancer in the hope of decreasing morbidity and mortality led to widespread PSA screening in the 1990s, before data on the efficacy of routine screening existed.
By 2002, only one low-quality RCT that compared screening with no screening had been published. The investigators concluded that screening resulted in lower mortality rates, but a subsequent (and superior) intention-to-treat analysis showed no mortality benefit.6 Two large RCTs, both published in 2009, reported conflicting results.7,8
The European Randomized Study of Screening for Prostate Cancer (ERSPC) enrolled 182,000 men ages 50 to 74 years and randomized them to either PSA screening every 4 years or no screening. Prostate cancer-specific mortality was 20% lower for those in the screening group compared with the no-screening group; however, the absolute risk reduction was only 0.71 deaths per 1000 men.7
The US Prostate, Lung, Colorectal, Ovarian Cancer (PLCO) Screening Trial randomized 77,000 men ages 55 to 74 years to either annual PSA and digital rectal examination (DRE) screening or usual care. After 7 years of follow-up, no significant difference was found in prostate cancer deaths or all-cause mortality in the screening group vs the control group. It is important to note, however, that 52% of the men in the control group had ≥1 PSA screening during the study period, which decreased the researchers’ ability to fully assess the benefits of screening.8
PSA’s limitations and potential harmful effects
The PSA test’s significant limitations and potentially harmful effects counter the potential benefits of screening. About 75% of positive tests are false positives, which are associated with psychological harm in some men for up to a year after the test.6 In addition, diagnostic testing and treatment for what may be nonlife-threatening prostate cancer can cause harm, including erectile dysfunction (ED), urinary incontinence, bowel dysfunction, and death. Rates of ED and incontinence 18 months after radical prostatectomy are an estimated 59.9% and 8.4%, respectively.9
Do the benefits of PSA testing outweigh the harms—and for which men? The meta-analysis and post hoc analysis detailed in this PURL help clear up the controversy.
STUDY SUMMARY: Widespread screening doesn’t save lives
Djulbegovic et al examined 6 RCTs, including the ERSPC and PLCO studies described earlier, that compared screening for prostate cancer (PSA with or without DRE) with no screening or usual care.1 Together, the studies included nearly 390,000 men ages 45 to 80 years, and had 4 to 15 years of follow-up. The results showed that routine screening for prostate cancer had no statistically significant effect on all-cause mortality (relative risk [RR]=0.99; 95% confidence interval [CI], 0.97-1.01), death from prostate cancer (RR=0.88; 95% CI, 0.71-1.09), or diagnosis of stage III or IV prostate cancer (RR=0.94; 95% CI, 0.85-1.04). Routine screening did, however, increase the probability of being diagnosed with prostate cancer at any stage, especially at stage I. For every 1000 men screened, on average, 20 more cases of prostate cancer were diagnosed.
Healthy men may benefit from screening
Crawford et al conducted a post hoc analysis of the PLCO trial, which had found no benefit to annual PSA testing and serial DRE compared with usual care for the general population.2 Their analysis compared the mortality benefits (both prostate cancer–specific and overall) of annual PSA screening for healthy men with no or minimal comorbidities vs the mortality benefits for men with any risk factor for the 2 leading causes of death: cancer and cardiovascular disease.
Annual PSA testing yielded more diagnoses of prostate cancer in both healthy and at-risk men. Deaths from prostate cancer were infrequent in both groups, occurring in 0.22% (164/73,378) of all participants.
Men with ≥1 risk factor had similar prostate cancer–specific deaths with both yearly screening and usual care (62 vs 42 deaths, adjusted hazard ratio [AHR]=1.43; 95% CI, 0.96-2.11); their prostate cancer–specific mortality rate was 0.27% (95% CI, 0.21-0.34) and 0.19% (95% CI, 0.14-0.25), respectively.
However, healthy men younger than 75 years had fewer prostate cancer–specific deaths with annual PSA screenings (22 vs 38; AHR=0.56; 95% CI, 0.33-0.95; P=.03). Specifically, the prostate cancer mortality rate was 0.17% (95% CI, 0.11-0.25) in the group that received screening vs 0.31% (95% CI, 0.22-0.42) in the usual care group. Thus, the absolute risk reduction for prostate cancer-specific mortality in men without comorbidities who received yearly screening instead of usual care was 0.14% (0.31% vs 0.17%, P=.03), with a number needed to screen of 723 to prevent one death from prostate cancer. There was a non-significant reduction in all-cause mortality in the intervention group vs the control group (AHR=0.93; 95% CI, 0.86-1.02; P=.11).
WHAT’S NEW: At best, screening has a small benefit
These trials indicate that only a small group of men will potentially benefit from PSA screening. Prior to this meta-analysis, a Cochrane review published in 2006 had concluded that there was insufficient evidence to support or refute the routine use of mass screening for prostate can-cer.10 The meta-analysis by Djulbegovic et al, which included 4 additional trials, 2 of them large, found no benefit of PSA screening in reducing mortality from prostate cancer for the general population.1
Annual screening does appear to provide a small reduction in prostate cancer deaths but no significant reduction in all-cause mortality in men younger than age 75 who have no risk factors for cancer or cardiovascular disease.
CAVEATS: Study limitations, some unknowns
These studies did not address whether certain groups at higher risk of developing prostate cancer, such as African American men and those with a family history of prostate cancer, would benefit from PSA screening. In addition, both of the studies detailed in this PURL had substantive weaknesses.
Methodological limitations of the studies in the meta-analysis included the lack of intention-to-treat analysis and allocation concealment, which favors finding a benefit for the screening arm, and PSA screening in the nonscreening arm, which biases the results toward not finding a screening benefit that might exist. Despite these weaknesses, this meta-analysis brings together the best available evidence of the value of screening for prostate cancer.
In addition, there was no quantitative assessment of complication rates included in the meta-analysis. None of the 6 trials collected data on the effect of screening or treatment on participants’ quality of life.
In the post hoc study showing a benefit for screening healthy men, the decrease in prostate cancer deaths was small in magnitude, did not have an impact on all-cause mortality, and was of marginal statistical significance. Although the data came from the largest multicenter study to date of prostate cancer screening, the results of a post hoc analysis of a single trial should be interpreted with caution. The study was initially designed to test the effect of screening on a general population. Whenever a study deviates from the original hypothesis to evaluate a subset of the study population, the investigators increase the risk of finding a difference where none exists. Thus, it is possible that the findings of benefit for healthy men may not truly be present.
What’s more, the risk factors identified by the authors could be interpreted as arbitrary. They included diverticulosis, which is not known to increase the likelihood of cancer or heart disease, as a risk factor. By the same token, smoking—a known risk factor for both cancer and cardiovascular disease—was not addressed. Finally, potential harms associated with false-positive tests and prostate cancer treatment were not addressed in these studies.
CHALLENGES TO IMPLEMENTATION: Old habits die hard
Clinicians have recommended PSA screening for men >50 years, and men have requested such screening, for more than 2 decades. Physicians often opt to order a PSA test rather than to take the time to explain potential harms and benefits and listen to the patient’s thoughts and feelings about the value of screening. In addition, physicians who believe the lack of benefit from screening does not apply to their patients will continue to order the PSA test. (See “The perils of PSA screening”.)
Patients may opt to continue to be screened although they have developed a risk factor for cardiovascular disease. Also, a decision not to screen directly contradicts the recommendation of the American Urological Association, which calls for annual PSA testing for asymptomatic men with a life expectancy >10 years starting at 40 years of age.11
Shared decision-making
The US Preventive Services Task Force (USPSTF) provides a basis for shared decision-making between physicians and patients concerning prostate cancer screening. The USPSTF states that there is insufficient evidence to recommend for or against prostate cancer screening for the general male population younger than age 75 and recommends against screening men age 75 and older or those with a life expectancy of less than 10 years.12
Decisions regarding PSA screening should be shared and documented for all men between the ages of 50 and 75 years. Advise patients with risk factors that the evidence shows little value and possible harm from screening. Tell healthier men that PSA testing appears to offer a small benefit, at best.
Acknowledgement
The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources; the grant is a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.
Do not routinely screen all men over the age of 50 for prostate cancer with the prostate-specific antigen (PSA) test. Consider screening men younger than 75 with no cardiovascular or cancer risk factors—the only patient population for whom PSA testing appears to provide even a small benefit.1,2
STRENGTH OF RECOMMENDATION
B: Based on a meta-analysis of 6 randomized controlled trials (RCTs) with methodological limitations, and a post hoc analysis of a large RCT.
Djulbegovic M, Beyth RJ, Neuberger MM, et al. Screening for prostate cancer: systematic review and meta-analysis of randomized controlled trials. BMJ. 2010;341:c4543.
Crawford ED, Grubb R 3rd, Black A, et al. Comorbidity and mortality results from a randomized prostate cancer screening trial. J Clin Oncol. 2011;29:355-361.
ILLUSTRATIVE CASES
A 65-year-old obese man with high blood pressure comes in for a complete physical and asks if he should have the “blood test for cancer.” He had a normal prostate specific antigen (PSA) the last time he was tested, but that was 10 years ago. What should you tell him?
A 55-year-old man schedules a routine check-up and requests a PSA test. His last test, at age 50, was normal. The patient has no known medical problems and no family history of prostate cancer, and he exercises regularly and doesn’t smoke. How should you respond to his request for a PSA test?
Prostate cancer is the second leading cause of cancer deaths among men in the United States, after lung cancer. One in 6 American men will be diagnosed with prostate cancer; for about 3% of them, the cancer will be fatal.3,4
Widespread testing without evidence of efficacy
The PSA test was approved by the US Food and Drug Administration (FDA) in 1986.5 Its potential to detect early prostate cancer in the hope of decreasing morbidity and mortality led to widespread PSA screening in the 1990s, before data on the efficacy of routine screening existed.
By 2002, only one low-quality RCT that compared screening with no screening had been published. The investigators concluded that screening resulted in lower mortality rates, but a subsequent (and superior) intention-to-treat analysis showed no mortality benefit.6 Two large RCTs, both published in 2009, reported conflicting results.7,8
The European Randomized Study of Screening for Prostate Cancer (ERSPC) enrolled 182,000 men ages 50 to 74 years and randomized them to either PSA screening every 4 years or no screening. Prostate cancer-specific mortality was 20% lower for those in the screening group compared with the no-screening group; however, the absolute risk reduction was only 0.71 deaths per 1000 men.7
The US Prostate, Lung, Colorectal, Ovarian Cancer (PLCO) Screening Trial randomized 77,000 men ages 55 to 74 years to either annual PSA and digital rectal examination (DRE) screening or usual care. After 7 years of follow-up, no significant difference was found in prostate cancer deaths or all-cause mortality in the screening group vs the control group. It is important to note, however, that 52% of the men in the control group had ≥1 PSA screening during the study period, which decreased the researchers’ ability to fully assess the benefits of screening.8
PSA’s limitations and potential harmful effects
The PSA test’s significant limitations and potentially harmful effects counter the potential benefits of screening. About 75% of positive tests are false positives, which are associated with psychological harm in some men for up to a year after the test.6 In addition, diagnostic testing and treatment for what may be nonlife-threatening prostate cancer can cause harm, including erectile dysfunction (ED), urinary incontinence, bowel dysfunction, and death. Rates of ED and incontinence 18 months after radical prostatectomy are an estimated 59.9% and 8.4%, respectively.9
Do the benefits of PSA testing outweigh the harms—and for which men? The meta-analysis and post hoc analysis detailed in this PURL help clear up the controversy.
STUDY SUMMARY: Widespread screening doesn’t save lives
Djulbegovic et al examined 6 RCTs, including the ERSPC and PLCO studies described earlier, that compared screening for prostate cancer (PSA with or without DRE) with no screening or usual care.1 Together, the studies included nearly 390,000 men ages 45 to 80 years, and had 4 to 15 years of follow-up. The results showed that routine screening for prostate cancer had no statistically significant effect on all-cause mortality (relative risk [RR]=0.99; 95% confidence interval [CI], 0.97-1.01), death from prostate cancer (RR=0.88; 95% CI, 0.71-1.09), or diagnosis of stage III or IV prostate cancer (RR=0.94; 95% CI, 0.85-1.04). Routine screening did, however, increase the probability of being diagnosed with prostate cancer at any stage, especially at stage I. For every 1000 men screened, on average, 20 more cases of prostate cancer were diagnosed.
Healthy men may benefit from screening
Crawford et al conducted a post hoc analysis of the PLCO trial, which had found no benefit to annual PSA testing and serial DRE compared with usual care for the general population.2 Their analysis compared the mortality benefits (both prostate cancer–specific and overall) of annual PSA screening for healthy men with no or minimal comorbidities vs the mortality benefits for men with any risk factor for the 2 leading causes of death: cancer and cardiovascular disease.
Annual PSA testing yielded more diagnoses of prostate cancer in both healthy and at-risk men. Deaths from prostate cancer were infrequent in both groups, occurring in 0.22% (164/73,378) of all participants.
Men with ≥1 risk factor had similar prostate cancer–specific deaths with both yearly screening and usual care (62 vs 42 deaths, adjusted hazard ratio [AHR]=1.43; 95% CI, 0.96-2.11); their prostate cancer–specific mortality rate was 0.27% (95% CI, 0.21-0.34) and 0.19% (95% CI, 0.14-0.25), respectively.
However, healthy men younger than 75 years had fewer prostate cancer–specific deaths with annual PSA screenings (22 vs 38; AHR=0.56; 95% CI, 0.33-0.95; P=.03). Specifically, the prostate cancer mortality rate was 0.17% (95% CI, 0.11-0.25) in the group that received screening vs 0.31% (95% CI, 0.22-0.42) in the usual care group. Thus, the absolute risk reduction for prostate cancer-specific mortality in men without comorbidities who received yearly screening instead of usual care was 0.14% (0.31% vs 0.17%, P=.03), with a number needed to screen of 723 to prevent one death from prostate cancer. There was a non-significant reduction in all-cause mortality in the intervention group vs the control group (AHR=0.93; 95% CI, 0.86-1.02; P=.11).
WHAT’S NEW: At best, screening has a small benefit
These trials indicate that only a small group of men will potentially benefit from PSA screening. Prior to this meta-analysis, a Cochrane review published in 2006 had concluded that there was insufficient evidence to support or refute the routine use of mass screening for prostate can-cer.10 The meta-analysis by Djulbegovic et al, which included 4 additional trials, 2 of them large, found no benefit of PSA screening in reducing mortality from prostate cancer for the general population.1
Annual screening does appear to provide a small reduction in prostate cancer deaths but no significant reduction in all-cause mortality in men younger than age 75 who have no risk factors for cancer or cardiovascular disease.
CAVEATS: Study limitations, some unknowns
These studies did not address whether certain groups at higher risk of developing prostate cancer, such as African American men and those with a family history of prostate cancer, would benefit from PSA screening. In addition, both of the studies detailed in this PURL had substantive weaknesses.
Methodological limitations of the studies in the meta-analysis included the lack of intention-to-treat analysis and allocation concealment, which favors finding a benefit for the screening arm, and PSA screening in the nonscreening arm, which biases the results toward not finding a screening benefit that might exist. Despite these weaknesses, this meta-analysis brings together the best available evidence of the value of screening for prostate cancer.
In addition, there was no quantitative assessment of complication rates included in the meta-analysis. None of the 6 trials collected data on the effect of screening or treatment on participants’ quality of life.
In the post hoc study showing a benefit for screening healthy men, the decrease in prostate cancer deaths was small in magnitude, did not have an impact on all-cause mortality, and was of marginal statistical significance. Although the data came from the largest multicenter study to date of prostate cancer screening, the results of a post hoc analysis of a single trial should be interpreted with caution. The study was initially designed to test the effect of screening on a general population. Whenever a study deviates from the original hypothesis to evaluate a subset of the study population, the investigators increase the risk of finding a difference where none exists. Thus, it is possible that the findings of benefit for healthy men may not truly be present.
What’s more, the risk factors identified by the authors could be interpreted as arbitrary. They included diverticulosis, which is not known to increase the likelihood of cancer or heart disease, as a risk factor. By the same token, smoking—a known risk factor for both cancer and cardiovascular disease—was not addressed. Finally, potential harms associated with false-positive tests and prostate cancer treatment were not addressed in these studies.
CHALLENGES TO IMPLEMENTATION: Old habits die hard
Clinicians have recommended PSA screening for men >50 years, and men have requested such screening, for more than 2 decades. Physicians often opt to order a PSA test rather than to take the time to explain potential harms and benefits and listen to the patient’s thoughts and feelings about the value of screening. In addition, physicians who believe the lack of benefit from screening does not apply to their patients will continue to order the PSA test. (See “The perils of PSA screening”.)
Patients may opt to continue to be screened although they have developed a risk factor for cardiovascular disease. Also, a decision not to screen directly contradicts the recommendation of the American Urological Association, which calls for annual PSA testing for asymptomatic men with a life expectancy >10 years starting at 40 years of age.11
Shared decision-making
The US Preventive Services Task Force (USPSTF) provides a basis for shared decision-making between physicians and patients concerning prostate cancer screening. The USPSTF states that there is insufficient evidence to recommend for or against prostate cancer screening for the general male population younger than age 75 and recommends against screening men age 75 and older or those with a life expectancy of less than 10 years.12
Decisions regarding PSA screening should be shared and documented for all men between the ages of 50 and 75 years. Advise patients with risk factors that the evidence shows little value and possible harm from screening. Tell healthier men that PSA testing appears to offer a small benefit, at best.
Acknowledgement
The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources; the grant is a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.
1. Djulbegovic M, Beyth RJ, Neuberger MM, et al. Screening for prostate cancer: systematic review and meta-analysis of randomized controlled trials. BMJ. 2010;341:c4543.-
2. Crawford ED, Grubb R, 3rd, Black A, et al. Comorbidity and mortality results from a randomized prostate cancer screening trial. J Clin Oncol. 2011;29:355-361.
3. American Cancer Society. Cancer facts & figures 2010. Atlanta, Ga: American Cancer Society; 2010. Available at: http://www.cancer.org/acs/groups/content/@nho/documents/document/acspc-024113.pdf. Accessed April 13, 2011.
4. American Cancer Society. Prostate cancer. Last medical review November 22, 2010. Available at: http://www.cancer.org/cancer/prostatecancer/detailedguide/prostate-cancer-key-statistics. Accessed April 13, 2011.
5. National Institutes of Health. Prostate cancer. Last updated February 14, 2011. Available at: http://report.nih.gov/NIHfactsheets/ViewFactSheet.aspx?csid=60. Accessed May 9, 2011.
6. Lin K, Lipsitz R, Miller T, et al. Benefits and harms of prostate-specific antigen screening for prostate cancer: an evidence update for the U.S. Preventive Services Task Force. Ann Intern Med. 2008;149:192-199.
7. Schroder FH, Hugosson J, Roobol MJ, et al. Screening and prostate-cancer mortality in a randomized European study. N Engl J Med. 2009;360:1320-1328.
8. Andriole GL, Crawford ED, Grubb RL, 3rd, et al. Mortality results from a randomized prostate-cancer screening trial. N Engl J Med. 2009;360:1310-1319.
9. Stanford JL, Feng Z, Hamilton AS, et al. Urinary and sexual function after radical prostatectomy for clinically localized prostate cancer: the Prostate Cancer Outcomes Study. JAMA. 2000;283:354-360.
10. Ilic D, O’Connor D, Greens, Wilt T. Screening for prostate cancer. Cochrane Database Syst Rev. 2006;(3):CD004720.-
11. American Urological Association. Prostate-specific antigen best practice statement: 2009 update. Available at: http://www.auanet.org/content/guidelines-and-quality-care/clinical-guidelines/main-reports/psa09.pdf. Accessed March 16, 2011.
12. US Preventive Services Task Force. Screening for prostate cancer: US Preventive Services Task Force recommendation statement. Ann Intern Med. 2008;149:185-191.
1. Djulbegovic M, Beyth RJ, Neuberger MM, et al. Screening for prostate cancer: systematic review and meta-analysis of randomized controlled trials. BMJ. 2010;341:c4543.-
2. Crawford ED, Grubb R, 3rd, Black A, et al. Comorbidity and mortality results from a randomized prostate cancer screening trial. J Clin Oncol. 2011;29:355-361.
3. American Cancer Society. Cancer facts & figures 2010. Atlanta, Ga: American Cancer Society; 2010. Available at: http://www.cancer.org/acs/groups/content/@nho/documents/document/acspc-024113.pdf. Accessed April 13, 2011.
4. American Cancer Society. Prostate cancer. Last medical review November 22, 2010. Available at: http://www.cancer.org/cancer/prostatecancer/detailedguide/prostate-cancer-key-statistics. Accessed April 13, 2011.
5. National Institutes of Health. Prostate cancer. Last updated February 14, 2011. Available at: http://report.nih.gov/NIHfactsheets/ViewFactSheet.aspx?csid=60. Accessed May 9, 2011.
6. Lin K, Lipsitz R, Miller T, et al. Benefits and harms of prostate-specific antigen screening for prostate cancer: an evidence update for the U.S. Preventive Services Task Force. Ann Intern Med. 2008;149:192-199.
7. Schroder FH, Hugosson J, Roobol MJ, et al. Screening and prostate-cancer mortality in a randomized European study. N Engl J Med. 2009;360:1320-1328.
8. Andriole GL, Crawford ED, Grubb RL, 3rd, et al. Mortality results from a randomized prostate-cancer screening trial. N Engl J Med. 2009;360:1310-1319.
9. Stanford JL, Feng Z, Hamilton AS, et al. Urinary and sexual function after radical prostatectomy for clinically localized prostate cancer: the Prostate Cancer Outcomes Study. JAMA. 2000;283:354-360.
10. Ilic D, O’Connor D, Greens, Wilt T. Screening for prostate cancer. Cochrane Database Syst Rev. 2006;(3):CD004720.-
11. American Urological Association. Prostate-specific antigen best practice statement: 2009 update. Available at: http://www.auanet.org/content/guidelines-and-quality-care/clinical-guidelines/main-reports/psa09.pdf. Accessed March 16, 2011.
12. US Preventive Services Task Force. Screening for prostate cancer: US Preventive Services Task Force recommendation statement. Ann Intern Med. 2008;149:185-191.
Copyright © 2011 The Family Physicians Inquiries Network.
All rights reserved.
What’s the best way to manage athletes with amenorrhea?
Ruling out secondary causes of amenorrhea is, of course, the first step. Once that’s done, you can make a presumptive diagnosis of hypothalamic amenorrhea and advise the patient to increase caloric intake or decrease energy expenditure to promote the return of normal menses (strength of recommendation: C, expert consensus).1
I err on the side of hormone supplementatio
Roberta VanZant, MD
UICOMP/MMCI Family Residency, Peoria, Ill
The menstrual cycle is a finely balanced orchestra of events; amenorrhea means that something is out of tune. In athletes, amenorrhea signals that the body is sacrificing the menses to provide energy for more important daily functions.2
Because of the potential negative long-term consequences of hypoestrogenism, I err on the side of hormone supplementation while encouraging the patient to modify her eating pattern and exercise routine to promote the return of menses. For women who desire birth control, I use hormonal contraception.
If pregnancy is not a concern, I prefer to cycle the patient on low-dose estradiol and progesterone that are chemically identical to her own hormones. I believe this gently prods the body’s own hypothalamic-pituitary axis (HPA) to re-engage without overriding the internal HPA-ovarian drive.
Evidence summary
Little evidence and no specific guidelines exist to guide the clinician in evaluating and managing exercise-induced amenorrhea. All athletes with amenorrhea should have a pregnancy test, because pregnancy is the most common cause of secondary amenorrhea.1 After ruling it out, the clinician may choose to exclude other causes of secondary amenorrhea before presuming a diagnosis of hypothalamic amenorrhea.
Useful tests (TABLE) include:
- serum prolactin to rule out prolactinoma
- follicle-stimulating hormone to rule out premature ovarian failure
- thyroid-stimulating hormone to evaluate for thyroid problems.
If all these tests are negative, consider a progesterone challenge test.3 Typically, athletes with hypothalamic amenorrhea don’t experience withdrawal bleeding after progesterone challenge, because of inadequate endogenous estrogen stimulation.
Greater calorie and micronutrient intake—plus rest—is best
A 1999 study in the International Journal of Sport Nutrition found that chronic energy deficit in amenorrheic athletes (N=4) could be reversed in a 20-week program using a sport nutrition supplement, 1 rest day per week, and a dietician to help with food selection.4 A 2002 review similarly recommends 1 rest day per week, increasing caloric intake by 200 to 300 Kcal/d, and increasing intake of calcium, B vitamins, iron, and zinc.5
TABLE
Is it hypothalamic amenorrhea, or something else?
| DIFFERENTIAL DIAGNOSIS | CLINICAL CLUE | POTENTIALLY USEFUL TEST |
|---|---|---|
| Pregnancy | Sexual history | Urine hCG |
| Polycystic ovary syndrome | Obesity, hirsutism | Progesterone challenge |
| Ovarian failure | Family history | Serum FSH |
| Thyroid dysfunction | Physical exam, history | Serum TSH |
| Prolactinoma, psychiatric medications | Galactorrhea | Serum prolactin |
| Asherman’s syndrome | History of pelvic instrumentation | Estrogen/progesterone challenge |
| FSH, follicle-stimulating hormone; hCG, human chorionic gonadotropin; TSH, thyroid-stimulating hormone. | ||
Oral contraceptives to prevent bone loss? Too little information
Bone loss in amenorrheic athletes may have long-term consequences, even if amenorrhea is only temporary. Some theoretical and disease-based research suggests a possible role for oral contraceptives to prevent bone loss in pre- and postmenopausal women,6 but little research has investigated younger women with hypothalamic amenorrhea. A recent open-label study that did examine bone mineral density (BMD) in women with hypothalamic amenorrhea before and after 13 cycles of oral contraceptives found a significant increase in BMD in the spine, but not at the hip.7
No published study has demonstrated clinically significant advantages for oral contraceptive therapy in women with secondary amenorrhea. These women should take adequate calcium and vitamin D. Bisphosphonates are not appropriate for women of reproductive age, because of their potential teratogenicity.1
Recommendations
The Committee on Sports Medicine and Fitness of the American Academy of Pediatrics (AAP) encourages exercise to help maintain lean body mass and protect against obesity, diabetes, hypertension, and cardiovascular disease. Athletes with amenorrhea, however, may be at risk for sequelae such as osteopenia, fractures, and dyslipidemia. Amenorrhea during adolescence may inhibit the accretion of BMD, and the lost density may not be re-gained. Amenorrheic athletes are also at risk for the “female athlete triad”—disordered eating, amenorrhea, and osteoporosis.8
The potential negative sequelae of amenorrhea are best prevented with measures that restore physiologic menses.3 For exercise-induced hypothalamic bone loss, the AAP recommends decreased exercise, increased caloric intake, or both.
1. Warren MP, Perlroth NE. The effects of intense exercise on the female reproductive system. J Endocrinol. 2001;170:3-11.
2. Master-Hunter T, Heiman DL. Amenorrhea: evaluation and treatment. Am Fam Physician. 2006;73:1374-1382.
3. American College of Obstetricians and Gynecologists Amenorrhea. (ACOG Technical Bulletin 128). Washington, DC: American College of Obstetricians and Gynecologists; 1989.
4. Kopp-Woodroffe SA, Manore MM, Dueck CA, et al. Energy and nutrient status of amenorrheic athletes participating in a diet and exercise training intervention program. Int J Sport Nutr. 1999;9:70-88.
5. Manore MM. Dietary recommendations and athletic menstrual dysfunction. Sports Med. 2002;32:887-901.
6. DeCherney A. Bone sparing properties of oral contraceptives. Am J Obstet Gynecol. 1996;v:15-20.
7. Warren MP, Miller KK, Olson WH, et al. Effects of an oral contraceptive (norgestimate/ethinyl estradiol) on bone mineral density in women with hypothalamic amenorrhea and osteopenia: an open-label extension of a double-blind, placebo-controlled study. Contraception. 2005;72:206-211.
8. American Academy of Pediatrics Committee on Sports Medicine and Fitness Medical concerns in the female athlete. Pediatrics. 2000;106:610-613.
Ruling out secondary causes of amenorrhea is, of course, the first step. Once that’s done, you can make a presumptive diagnosis of hypothalamic amenorrhea and advise the patient to increase caloric intake or decrease energy expenditure to promote the return of normal menses (strength of recommendation: C, expert consensus).1
I err on the side of hormone supplementatio
Roberta VanZant, MD
UICOMP/MMCI Family Residency, Peoria, Ill
The menstrual cycle is a finely balanced orchestra of events; amenorrhea means that something is out of tune. In athletes, amenorrhea signals that the body is sacrificing the menses to provide energy for more important daily functions.2
Because of the potential negative long-term consequences of hypoestrogenism, I err on the side of hormone supplementation while encouraging the patient to modify her eating pattern and exercise routine to promote the return of menses. For women who desire birth control, I use hormonal contraception.
If pregnancy is not a concern, I prefer to cycle the patient on low-dose estradiol and progesterone that are chemically identical to her own hormones. I believe this gently prods the body’s own hypothalamic-pituitary axis (HPA) to re-engage without overriding the internal HPA-ovarian drive.
Evidence summary
Little evidence and no specific guidelines exist to guide the clinician in evaluating and managing exercise-induced amenorrhea. All athletes with amenorrhea should have a pregnancy test, because pregnancy is the most common cause of secondary amenorrhea.1 After ruling it out, the clinician may choose to exclude other causes of secondary amenorrhea before presuming a diagnosis of hypothalamic amenorrhea.
Useful tests (TABLE) include:
- serum prolactin to rule out prolactinoma
- follicle-stimulating hormone to rule out premature ovarian failure
- thyroid-stimulating hormone to evaluate for thyroid problems.
If all these tests are negative, consider a progesterone challenge test.3 Typically, athletes with hypothalamic amenorrhea don’t experience withdrawal bleeding after progesterone challenge, because of inadequate endogenous estrogen stimulation.
Greater calorie and micronutrient intake—plus rest—is best
A 1999 study in the International Journal of Sport Nutrition found that chronic energy deficit in amenorrheic athletes (N=4) could be reversed in a 20-week program using a sport nutrition supplement, 1 rest day per week, and a dietician to help with food selection.4 A 2002 review similarly recommends 1 rest day per week, increasing caloric intake by 200 to 300 Kcal/d, and increasing intake of calcium, B vitamins, iron, and zinc.5
TABLE
Is it hypothalamic amenorrhea, or something else?
| DIFFERENTIAL DIAGNOSIS | CLINICAL CLUE | POTENTIALLY USEFUL TEST |
|---|---|---|
| Pregnancy | Sexual history | Urine hCG |
| Polycystic ovary syndrome | Obesity, hirsutism | Progesterone challenge |
| Ovarian failure | Family history | Serum FSH |
| Thyroid dysfunction | Physical exam, history | Serum TSH |
| Prolactinoma, psychiatric medications | Galactorrhea | Serum prolactin |
| Asherman’s syndrome | History of pelvic instrumentation | Estrogen/progesterone challenge |
| FSH, follicle-stimulating hormone; hCG, human chorionic gonadotropin; TSH, thyroid-stimulating hormone. | ||
Oral contraceptives to prevent bone loss? Too little information
Bone loss in amenorrheic athletes may have long-term consequences, even if amenorrhea is only temporary. Some theoretical and disease-based research suggests a possible role for oral contraceptives to prevent bone loss in pre- and postmenopausal women,6 but little research has investigated younger women with hypothalamic amenorrhea. A recent open-label study that did examine bone mineral density (BMD) in women with hypothalamic amenorrhea before and after 13 cycles of oral contraceptives found a significant increase in BMD in the spine, but not at the hip.7
No published study has demonstrated clinically significant advantages for oral contraceptive therapy in women with secondary amenorrhea. These women should take adequate calcium and vitamin D. Bisphosphonates are not appropriate for women of reproductive age, because of their potential teratogenicity.1
Recommendations
The Committee on Sports Medicine and Fitness of the American Academy of Pediatrics (AAP) encourages exercise to help maintain lean body mass and protect against obesity, diabetes, hypertension, and cardiovascular disease. Athletes with amenorrhea, however, may be at risk for sequelae such as osteopenia, fractures, and dyslipidemia. Amenorrhea during adolescence may inhibit the accretion of BMD, and the lost density may not be re-gained. Amenorrheic athletes are also at risk for the “female athlete triad”—disordered eating, amenorrhea, and osteoporosis.8
The potential negative sequelae of amenorrhea are best prevented with measures that restore physiologic menses.3 For exercise-induced hypothalamic bone loss, the AAP recommends decreased exercise, increased caloric intake, or both.
Ruling out secondary causes of amenorrhea is, of course, the first step. Once that’s done, you can make a presumptive diagnosis of hypothalamic amenorrhea and advise the patient to increase caloric intake or decrease energy expenditure to promote the return of normal menses (strength of recommendation: C, expert consensus).1
I err on the side of hormone supplementatio
Roberta VanZant, MD
UICOMP/MMCI Family Residency, Peoria, Ill
The menstrual cycle is a finely balanced orchestra of events; amenorrhea means that something is out of tune. In athletes, amenorrhea signals that the body is sacrificing the menses to provide energy for more important daily functions.2
Because of the potential negative long-term consequences of hypoestrogenism, I err on the side of hormone supplementation while encouraging the patient to modify her eating pattern and exercise routine to promote the return of menses. For women who desire birth control, I use hormonal contraception.
If pregnancy is not a concern, I prefer to cycle the patient on low-dose estradiol and progesterone that are chemically identical to her own hormones. I believe this gently prods the body’s own hypothalamic-pituitary axis (HPA) to re-engage without overriding the internal HPA-ovarian drive.
Evidence summary
Little evidence and no specific guidelines exist to guide the clinician in evaluating and managing exercise-induced amenorrhea. All athletes with amenorrhea should have a pregnancy test, because pregnancy is the most common cause of secondary amenorrhea.1 After ruling it out, the clinician may choose to exclude other causes of secondary amenorrhea before presuming a diagnosis of hypothalamic amenorrhea.
Useful tests (TABLE) include:
- serum prolactin to rule out prolactinoma
- follicle-stimulating hormone to rule out premature ovarian failure
- thyroid-stimulating hormone to evaluate for thyroid problems.
If all these tests are negative, consider a progesterone challenge test.3 Typically, athletes with hypothalamic amenorrhea don’t experience withdrawal bleeding after progesterone challenge, because of inadequate endogenous estrogen stimulation.
Greater calorie and micronutrient intake—plus rest—is best
A 1999 study in the International Journal of Sport Nutrition found that chronic energy deficit in amenorrheic athletes (N=4) could be reversed in a 20-week program using a sport nutrition supplement, 1 rest day per week, and a dietician to help with food selection.4 A 2002 review similarly recommends 1 rest day per week, increasing caloric intake by 200 to 300 Kcal/d, and increasing intake of calcium, B vitamins, iron, and zinc.5
TABLE
Is it hypothalamic amenorrhea, or something else?
| DIFFERENTIAL DIAGNOSIS | CLINICAL CLUE | POTENTIALLY USEFUL TEST |
|---|---|---|
| Pregnancy | Sexual history | Urine hCG |
| Polycystic ovary syndrome | Obesity, hirsutism | Progesterone challenge |
| Ovarian failure | Family history | Serum FSH |
| Thyroid dysfunction | Physical exam, history | Serum TSH |
| Prolactinoma, psychiatric medications | Galactorrhea | Serum prolactin |
| Asherman’s syndrome | History of pelvic instrumentation | Estrogen/progesterone challenge |
| FSH, follicle-stimulating hormone; hCG, human chorionic gonadotropin; TSH, thyroid-stimulating hormone. | ||
Oral contraceptives to prevent bone loss? Too little information
Bone loss in amenorrheic athletes may have long-term consequences, even if amenorrhea is only temporary. Some theoretical and disease-based research suggests a possible role for oral contraceptives to prevent bone loss in pre- and postmenopausal women,6 but little research has investigated younger women with hypothalamic amenorrhea. A recent open-label study that did examine bone mineral density (BMD) in women with hypothalamic amenorrhea before and after 13 cycles of oral contraceptives found a significant increase in BMD in the spine, but not at the hip.7
No published study has demonstrated clinically significant advantages for oral contraceptive therapy in women with secondary amenorrhea. These women should take adequate calcium and vitamin D. Bisphosphonates are not appropriate for women of reproductive age, because of their potential teratogenicity.1
Recommendations
The Committee on Sports Medicine and Fitness of the American Academy of Pediatrics (AAP) encourages exercise to help maintain lean body mass and protect against obesity, diabetes, hypertension, and cardiovascular disease. Athletes with amenorrhea, however, may be at risk for sequelae such as osteopenia, fractures, and dyslipidemia. Amenorrhea during adolescence may inhibit the accretion of BMD, and the lost density may not be re-gained. Amenorrheic athletes are also at risk for the “female athlete triad”—disordered eating, amenorrhea, and osteoporosis.8
The potential negative sequelae of amenorrhea are best prevented with measures that restore physiologic menses.3 For exercise-induced hypothalamic bone loss, the AAP recommends decreased exercise, increased caloric intake, or both.
1. Warren MP, Perlroth NE. The effects of intense exercise on the female reproductive system. J Endocrinol. 2001;170:3-11.
2. Master-Hunter T, Heiman DL. Amenorrhea: evaluation and treatment. Am Fam Physician. 2006;73:1374-1382.
3. American College of Obstetricians and Gynecologists Amenorrhea. (ACOG Technical Bulletin 128). Washington, DC: American College of Obstetricians and Gynecologists; 1989.
4. Kopp-Woodroffe SA, Manore MM, Dueck CA, et al. Energy and nutrient status of amenorrheic athletes participating in a diet and exercise training intervention program. Int J Sport Nutr. 1999;9:70-88.
5. Manore MM. Dietary recommendations and athletic menstrual dysfunction. Sports Med. 2002;32:887-901.
6. DeCherney A. Bone sparing properties of oral contraceptives. Am J Obstet Gynecol. 1996;v:15-20.
7. Warren MP, Miller KK, Olson WH, et al. Effects of an oral contraceptive (norgestimate/ethinyl estradiol) on bone mineral density in women with hypothalamic amenorrhea and osteopenia: an open-label extension of a double-blind, placebo-controlled study. Contraception. 2005;72:206-211.
8. American Academy of Pediatrics Committee on Sports Medicine and Fitness Medical concerns in the female athlete. Pediatrics. 2000;106:610-613.
1. Warren MP, Perlroth NE. The effects of intense exercise on the female reproductive system. J Endocrinol. 2001;170:3-11.
2. Master-Hunter T, Heiman DL. Amenorrhea: evaluation and treatment. Am Fam Physician. 2006;73:1374-1382.
3. American College of Obstetricians and Gynecologists Amenorrhea. (ACOG Technical Bulletin 128). Washington, DC: American College of Obstetricians and Gynecologists; 1989.
4. Kopp-Woodroffe SA, Manore MM, Dueck CA, et al. Energy and nutrient status of amenorrheic athletes participating in a diet and exercise training intervention program. Int J Sport Nutr. 1999;9:70-88.
5. Manore MM. Dietary recommendations and athletic menstrual dysfunction. Sports Med. 2002;32:887-901.
6. DeCherney A. Bone sparing properties of oral contraceptives. Am J Obstet Gynecol. 1996;v:15-20.
7. Warren MP, Miller KK, Olson WH, et al. Effects of an oral contraceptive (norgestimate/ethinyl estradiol) on bone mineral density in women with hypothalamic amenorrhea and osteopenia: an open-label extension of a double-blind, placebo-controlled study. Contraception. 2005;72:206-211.
8. American Academy of Pediatrics Committee on Sports Medicine and Fitness Medical concerns in the female athlete. Pediatrics. 2000;106:610-613.
Evidence-based answers from the Family Physicians Inquiries Network