Introduction 

When it comes to hormone replacement therapy (HRT), menopausal women often find themselves navigating a maze of warnings and claims. Among the most alarming is the FDA's black box warning on progesterone, stating that it increases the risk of breast cancer. But is there solid evidence to back up this bold idea? The controversy surrounding this claim is not only confusing but also potentially misleading, especially for those who are considering HRT to manage their menopause symptoms.

In this post, I'll dive into the details of the FDA's black box warning and expose the truth behind the idea that progesterone increases breast cancer risk. We will explore the research, scrutinize the evidence, and highlight the significant differences between the progesterone made by human ovaries and synthetic progestins that aren't exactly the same as progesterone. By the end of this article, you'll have a clearer understanding of the real risks involved and be better equipped to make informed decisions about your health.

Understanding Progesterone and Progestins

Before we delve deeper into the controversy surrounding the FDA's black box warning, it's crucial to understand the fundamental differences between hormones made by humans and hormones with similar sounding names that aren't exactly the same.

Human ovaries make progesterone

Progesterone: Hormone Made In Human Ovaries

Progesterone is a hormone naturally produced by the ovaries during the menstrual cycle. (Technically, progesterone is mostly made by the corpus luteum, a leftover piece of tissue within the ovary that results from ovulation.) Progesterone is often referred to as "natural progesterone," "micronized progesterone," or "bioidentical progesterone." This hormone plays a vital role in regulating the menstrual cycle, preparing the body for pregnancy, and maintaining pregnancy. Progesterone helps to prepare the uterine lining for a fertilized egg and supports early pregnancy, maintaining that uterine lining.

Progesterone imitation progestin vs the real thing

Progestins: The Imitators Are Not the Original

Progestins are hormones that are chemically altered versions of progesterone. Many have just one tiny change that makes a world of difference. That makes them not identical to the progesterone produced by human ovaries. Progestins are often used in hormone replacement therapy (HRT) and in oral contraceptives. While they can perform some of the same functions as progesterone, their chemical structure differs, leading to different effects and side effects.

Similarities and Differences Between Progesterone and Progestins

  1. Endometrial Growth Control: Both progestins and progesterone slow the growth of the uterine lining, called the endometrium. A natural consequence of the presence of estrogen is that the uterine lining can grow out of control. Both progesterone and progestins can help with that.
  2. Insomnia Relief: Progesterone, but not progestins, makes a dramatic difference in post-menopausal insomnia, as this post explains.
  3. Bone Health: Progesterone, but not progestins, can augment the bone-building effects of estradiol and help with the prevention of osteoporosis.
  4. Hot Flashes and Night Sweats: While not as effective as estradiol, progesterone, but not progestins, can also help reduce hot flashes and night sweats.
  5. Cardiovascular Health: Long-term use of medroxyprogesterone acetate (MPA) in post-menopausal women has several implications for cardiovascular health. MPA negatively affects blood lipids and causes weight gain. But long-term use of progesterone in post-menopausal women does not appear to adversely affect cardiovascular health. Progesterone has neutral effects on endothelial function, lipid profiles, and other cardiovascular risk factors.

Understanding these differences is essential for making informed decisions about hormone replacement therapy. In the next section, we'll explore the FDA's black box warning and the evidence (or lack thereof) supporting the claim that progesterone increases breast cancer risk.

Let's unravel the facts and myths about progesterone and breast cancer risk, starting with a closer look at what the FDA's black box warning actually says.

FDA Black Box Warning progesterone

FDA Black Box Warning: A Bold Claim

The FDA's black box warning on progesterone is a bold and alarming statement. The warning claims that progesterone increases the risk of breast cancer, but this claim is based entirely on the results of the Women's Health Initiative (WHI) clinical trial. To understand the implications of this warning, it's essential to examine the details and context of the WHI study.

Womens Health Initiative study

The Women's Health Initiative (WHI) Study

The WHI was the largest, most expensive, multi-center clinical trial ever conducted. It focused on the potential for preventing heart disease, breast and colorectal cancer, and osteoporosis in postmenopausal women. The hormone therapy trial, which investigated the effects of estrogen alone and estrogen combined with a specific progestin on health outcomes in the women who participated.

Origins of FDA Black Box Warning

FDA has required a "Black Box Warning" on all progesterone-containing products for many years. The text of the warning makes it abundantly clear that the FDA assumes progesterone and progestins are essentially the same.

Here are some direct quotes from the Black Box Warning:

"The WHI estrogen plus progestin substudy reported an increased risk of invasive breast cancer in women who took a combination of conjugated equine estrogens (CEE) and medroxyprogesterone acetate (MPA)."

"The most important randomized clinical trial providing information about breast cancer is the Women’s Health Initiative (WHI) substudy of daily CE (0.625 mg) plus MPA (2.5 mg). In the estrogen plus progestin substudy, after a mean follow-up of 5.6 years, the WHI substudy reported an increased risk of breast cancer in women who took daily CE plus MPA. In this substudy, prior use of estrogen alone or estrogen plus progestin therapy was reported by 26 percent of the women. The relative risk of invasive breast cancer was 1.24 (95 percent nCI 1.01-1.54), and the absolute risk was 41 versus 33 cases per 10,000 women-years, for estrogen plus progestin compared with placebo."

The Controversy: Progesterone vs. Progestins

It's crucial to note that patients recruited into the WHI study did not receive progesterone. A slightly increased risk of breast cancer reported in the WHI study was associated with progestins, specifically medroxyprogesterone acetate (MPA), and not progesterone. Despite this, the FDA's black box warning still applies to any and all progesterone-containing hormones.

No Evidence That Progesterone Increases Risk

The FDA's warning about progesterone increasing breast cancer risk lacks direct evidence against progesterone. Research indicates that progesterone doesn't carry the same risks as progestins. This misattribution of risk has led to confusion and fear among women considering hormone replacement therapy for menopause symptoms. Clearly, the fear of hormones doesn't come out of nowhere.

Research Insights on Progesterone and Breast Cancer Risk

To gain a clearer understanding of the actual risks involved with progesterone versus progestins, it is essential to look into various research studies that differentiate the effects of these hormones. The following studies provide valuable insights:

Progesterone vs. Progestins and the Risk of Breast Cancer

This comprehensive meta-analysis examined the risk of breast cancer associated with progesterone compared to progestins. It found that progestins are more likely to be associated with an increased risk of breast cancer, whereas progesterone does not show the same level of risk. The study highlights the importance of distinguishing between the two types of hormones when considering hormone replacement therapy (HRT).

Effects of Estradiol and Micronized Progesterone vs. Conjugated Equine Estrogens and Medroxyprogesterone Acetate on Breast Cancer Gene Expression

Next, we'll look at a study comparing the effects of estradiol combined with micronized progesterone to conjugated equine estrogens (CEE) combined with medroxyprogesterone acetate (MPA) on breast cancer gene expression. Findings indicated that the combination of estradiol and micronized progesterone had a significantly different impact on gene expression related to breast cancer risk compared to the combination of CEE and MPA. The results suggest that progesterone may be a safer alternative in terms of breast cancer risk.

Unequal Risks for Breast Cancer Associated with Different Hormone Replacement Therapies: Results from the E3N Cohort Study

The French E3N-Epic cohort study investigated the risks of breast cancer associated with various hormone replacement therapies in tens of thousands of women. The study concluded that the risk of breast cancer varies significantly depending on the type of hormone used. Women using progesterone in combination with estradiol had a lower risk of breast cancer compared to those using progestins. This reinforces the idea that progesterone and progestins should not be treated as equivalent in terms of breast cancer risk.

The Impact of Micronized Progesterone on Breast Cancer Risk: A Systematic Review

A systematic review focused on the impact of micronized progesterone on breast cancer risk. The review found that progesterone does not increase breast cancer risk to the same extent as progestins. This comprehensive analysis supports the notion that progesterone is a safer option for women considering HRT.

Micronized Progesterone and Its Impact on the Endometrium and Breast vs. Progestogens

This study examined the effects of micronized progesterone compared to various progestogens on the endometrium and breast tissue. The research demonstrated that progesterone does not increase cell proliferation in breast tissue, unlike progestogens such as medroxyprogesterone acetate (MPA). The findings suggest that micronized progesterone may have a more favorable safety profile regarding breast cancer risk.

Progestogens in Postmenopausal Hormone Therapy and the Risk of Breast Cancer

This study analyzed the risk of breast cancer associated with different progestogens (progesterone-like hormones) used in postmenopausal hormone therapy. The research indicated that progesterone and dydrogesterone are associated with a lower risk of breast cancer compared to other progestins. The findings highlight the importance of selecting the appropriate type of progestogen in hormone therapy.

Use of Different Postmenopausal Hormone Therapies and Risk of Histology- and Hormone Receptor-Defined Invasive Breast Cancer

This study investigated the impact of various postmenopausal hormone therapies on the risk of different types of invasive breast cancer. The results showed that the risk varies depending on the hormone regimen used. Specifically, the use of progesterone was associated with a lower risk of hormone receptor-positive breast cancer compared to progestins. This emphasizes the need for personalized hormone therapy plans based on individual risk factors and hormone receptor status.

These research studies collectively demonstrate that progesterone has a different risk profile compared to progestins, particularly concerning breast cancer. Understanding these differences is crucial for making informed decisions about hormone replacement therapy. In the next section, we'll discuss the practical implications of these findings for menopausal women.

The Real Culprit: Progestins, Not Progesterone

The distinction between progesterone and progestins is crucial in understanding the real risks associated with hormone replacement therapy (HRT). Research consistently shows that the increased risk of breast cancer linked to HRT is primarily associated with progestins, not progesterone.

FDA US Food and Drug Administration black box warning progesterone

The Impact of Misattribution

The FDA's black box warning on progesterone has led to significant confusion among women and healthcare providers. By failing to differentiate between progesterone and progestins, the warning perpetuates the myth that all variations of progesterone carry the same risks. This misattribution can have several negative consequences:

  1. Fear and Hesitation: Many women may avoid HRT altogether due to the fear of increased breast cancer risk, depriving them of the benefits of progesterone, such as improved sleep, better bone health, and reduced hot flashes and night sweats.
  2. Suboptimal Treatment: Women may be prescribed synthetic progestins instead of progesterone, potentially exposing them to higher risks of adverse effects and breast cancer.
  3. Informed Decision-Making: Accurate information is essential for women to make informed decisions about their health. The conflation of progesterone with progestins hinders the ability to make such decisions based on the true risks and benefits.

A Call for Clarity

It's time to set the record straight and ensure that women and healthcare providers understand the crucial differences between progesterone and progestins. By distinguishing between these hormones, we can make more informed choices about HRT and reduce unnecessary fears about breast cancer risk.

In the next section, we'll discuss the practical implications of these findings for menopausal women and how to approach hormone replacement therapy with a clear understanding of the actual risks and benefits.

Practical Implications for Menopausal Women

Understanding the differences between progesterone and progestins has significant practical implications for menopausal women considering hormone replacement therapy (HRT). Here’s how these insights can guide you in making informed decisions about your health:

Individualized Treatment Plans

Hormone therapy should be tailored to your specific health needs and risks. Given the distinct safety profiles of progesterone and progestins, it’s essential to discuss with your healthcare provider the most appropriate hormone regimen for you. Factors such as your medical history, risk factors for breast cancer, and overall health goals should be considered when deciding on HRT.

Sleep Progesterone benefits

Benefits of Progesterone

Progesterone offers several benefits that progestins do not. These include:

  1. Improved Sleep: Progesterone has been shown to help with post-menopausal insomnia. For more details, see this post.
  2. Bone Health: Progesterone augments the bone-building effects of estradiol, helping to prevent osteoporosis.
  3. Relief from Hot Flashes and Night Sweats: While not as effective as estradiol, progesterone can still help reduce the frequency and severity of hot flashes and night sweats.
  4. Cardiovascular Health: Long-term use of progesterone does not appear to adversely affect cardiovascular health. Progesterone has neutral effects on endothelial function, lipid profiles, and other cardiovascular risk factors, unlike some progestins which can negatively impact these areas.
Hormone Optimization Specialist helps with progesterone and breast cancer

Consulting with a Qualified, Trained Hormone Optimization Specialist

Given the complexities and nuances of hormone replacement therapy, it’s crucial to consult with a specialist who understands the risks and benefits of progesterone and progestins. A hormone optimization specialist can provide personalized advice and tailor a treatment plan that aligns with your health needs and goals.

You can find qualified hormone optimization practitioners through my patient referral form. Visit SimpleHormones.com/referral to connect with specialists who are experienced in hormone optimization and can provide personalized care tailored to your unique needs.

Monitoring and Adjusting Your Therapy

Regular follow-ups with your healthcare provider are essential to monitor your symptoms and adjust your treatment plan as needed. Hormone levels can fluctuate, and individual responses to HRT can vary, so it's important to have a plan that can be fine-tuned over time. Comprehensive lab panels can track your hormone levels and overall health, ensuring your HRT is working effectively and safely.

Conclusion

The distinction between progesterone and progestins is more than a matter of semantics; it’s a critical factor that influences the safety and effectiveness of hormone replacement therapy (HRT). The FDA's black box warning on progesterone, which stems from studies involving synthetic progestins like medroxyprogesterone acetate (MPA), has unfortunately led to widespread confusion and fear. However, a growing body of research indicates that progesterone does not carry the same risks as progestins.

What You Can Do

To address your fears about hormone replacement therapy and breast cancer, and to learn more about managing menopause symptoms effectively, consider enrolling in my comprehensive course, "The Menopause Solution". This course is designed to provide you with the clarity and confidence to make an informed decision about whether to take hormones for your menopause.

Ensuring you’re getting the best advice involves consulting with a qualified, trained hormone specialist who understands the nuances of progesterone and progestins. A specialist understands your personal health history and unique risks. Visit SimpleHormones.com/referral to find a hormone practitioner who can provide precision medicine, tailored to your specific needs.

Staying informed is crucial. Keep yourself updated with the latest research and insights about hormone replacement therapy and menopause by visiting my blog and YouTube channel. Accurate information is your best tool for navigating the complexities of HRT and ensuring your health and well-being during menopause.

By distinguishing between progesterone and progestins, you can make more informed choices about HRT, reducing unnecessary fears about breast cancer risk and optimizing your health and well-being during menopause. Take control of your health with the right information and support.

References

  1. Prometrium® (progesterone) patient package insert. https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/019781s013lbl.pdf
  2. Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women: Principal Results From the Women's Health Initiative Randomized Controlled Trial. Rossouw JE, Anderson GL, Prentice RL, et al. Jama. 2002;288(3):321-33. doi:10.1001/jama.288.3.321.
  3. Progesterone vs. Synthetic Progestins and the Risk of Breast Cancer: A Systematic Review and Meta-Analysis. Asi N, Mohammed K, Haydour Q, et al. Systematic Reviews. 2016;5(1):121. doi:10.1186/s13643-016-0294-5. Copyright License: CC BY
  4. Effects of Estradiol/Micronized Progesterone vs. Conjugated Equine Estrogens/Medroxyprogesterone Acetate on Breast Cancer Gene Expression in Healthy Postmenopausal Women. Lalitkumar PGL, Lundström E, Byström B, et al. International Journal of Molecular Sciences. 2023;24(4):4123. doi:10.3390/ijms24044123. Copyright License: CC BY
  5. Unequal Risks for Breast Cancer Associated With Different Hormone Replacement Therapies: Results From the E3N Cohort Study. Fournier A, Berrino F, Clavel-Chapelon F. Breast Cancer Research and Treatment. 2008;107(1):103-11. doi:10.1007/s10549-007-9523-x.
  6. The Impact of Micronized Progesterone on Breast Cancer Risk: A Systematic Review. Stute P, Wildt L, Neulen J. Climacteric : The Journal of the International Menopause Society. 2018;21(2):111-122. doi:10.1080/13697137.2017.1421925.
  7. Micronized Progesterone and Its Impact on the Endometrium and Breast vs. Progestogens. Gompel A. Climacteric : The Journal of the International Menopause Society. 2012;15 Suppl 1:18-25. doi:10.3109/13697137.2012.669584. 
  8. Progestogens in Postmenopausal Hormone Therapy and the Risk of Breast Cancer. Lambrinoudaki I. Maturitas. 2014;77(4):311-7. doi:10.1016/j.maturitas.2014.01.001. 
  9. Use of Different Postmenopausal Hormone Therapies and Risk of Histology- And Hormone Receptor-Defined Invasive Breast Cancer. Fournier A, Fabre A, Mesrine S, et al. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2008;26(8):1260-8. doi:10.1200/JCO.2007.13.4338. 
  10. Oral Micronized Progesterone for Vasomotor Symptoms--a Placebo-Controlled Randomized Trial in Healthy Postmenopausal Women. Hitchcock CL, Prior JC. Menopause (New York, N.Y.). 2012;19(8):886-93. doi:10.1097/gme.0b013e318247f07a.
  11. Progesterone for Hot Flush and Night Sweat Treatment--Effectiveness for Severe Vasomotor Symptoms and Lack of Withdrawal Rebound. Prior JC, Hitchcock CL. Gynecological Endocrinology : The Official Journal of the International Society of Gynecological Endocrinology. 2012;28 Suppl 2:7-11. doi:10.3109/09513590.2012.705390.
  12. Progesterone for Treatment of Symptomatic Menopausal Women. Prior JC. Climacteric : The Journal of the International Menopause Society. 2018;21(4):358-365. doi:10.1080/13697137.2018.1472567.
  13. Efficacy of Micronized Progesterone for Sleep: A Systematic Review and Meta-Analysis of Randomized Controlled Trial Data. Nolan BJ, Liang B, Cheung AS. The Journal of Clinical Endocrinology and Metabolism. 2021;106(4):942-951. doi:10.1210/clinem/dgaa873.
  14. Progesterone for the Prevention and Treatment of Osteoporosis in Women. Prior JC. Climacteric : The Journal of the International Menopause Society. 2018;21(4):366-374. doi:10.1080/13697137.2018.1467400. 
  15. Acute Effects of Estradiol and Progesterone on Insulin, Lipids and Lipoproteins in Postmenopausal Women: A Pilot Study. Cheung AP. Maturitas. 2000;35(1):45-50. doi:10.1016/s0378-5122(00)00091-8.
  16. Impact of Micronized Progesterone on Body Weight, Body Mass Index, and Glucose Metabolism: A Systematic Review. Coquoz A, Gruetter C, Stute P. Climacteric : The Journal of the International Menopause Society. 2019;22(2):148-161. doi:10.1080/13697137.2018.1514003.
  17. Hormone Replacement Therapy, Insulin Sensitivity, and Abdominal Obesity in Postmenopausal Women. Ryan AS, Nicklas BJ, Berman DM. Diabetes Care. 2002;25(1):127-33. doi:10.2337/diacare.25.1.127.
  18. Metabolic Characterization of Menopause: Cross-Sectional and Longitudinal Evidence. Wang Q, Ferreira DLS, Nelson SM, et al. BMC Medicine. 2018;16(1):17. doi:10.1186/s12916-018-1008-8. Copyright License: CC BY
  19. The Impact of Medroxyprogesterone Acetate on Lipid Profiles in Women: A Time and Dose-Response Meta-Analysis of Randomized Controlled Trials. Feng L, Wang L, Hernández-Wolters B, et al. Diabetes Research and Clinical Practice. 2024;209:111073. doi:10.1016/j.diabres.2023.111073.
  20. The Effects of Estrogen Therapy and Estrogen Combined With Different Androgenic Progestins on Carbohydrate and Lipid Metabolism in Overweight-Obese Younger Postmenopausal Women.
    Demir B, Ozturkoglu E, Solaroglu A, et al. Gynecological Endocrinology : The Official Journal of the International Society of Gynecological Endocrinology. 2008;24(6):347-53. doi:10.1080/01443610802043066.
  21. Addition of Medroxyprogesterone Acetate to Conjugated Equine Estrogens Results in Insulin Resistance in Adipose Tissue. Shadoan MK, Kavanagh K, Zhang L, Anthony MS, Wagner JD. Metabolism: Clinical and Experimental. 2007;56(6):830-7. doi:10.1016/j.metabol.2007.01.014.
  22. Short-Term Effects of Hormone Therapy on Serum C-Reactive Protein Levels in Postmenopausal Women. Kiran H, Kiran G. Archives of Gynecology and Obstetrics. 2006;274(1):9-12. doi:10.1007/s00404-005-0111-1.
  23. Cardiovascular and Metabolic Effects of Medroxyprogesterone Acetate Versus Conjugated Equine Estrogen After Premenopausal Hysterectomy With Bilateral Ovariectomy. Kalyan S, Hitchcock CL, Sirrs S, Pudek M, Prior JC. Pharmacotherapy. 2010;30(5):442-52. doi:10.1592/phco.30.5.442.
  24. Progestogens and Cardiovascular Disease. A Critical Review. Clarkson TB. The Journal of Reproductive Medicine. 1999;44(2 Suppl):180-4.6.
  25. Progesterone Therapy, Endothelial Function and Cardiovascular Risk Factors: A 3-Month Randomized, Placebo-Controlled Trial in Healthy Early Postmenopausal Women. Prior JC, Elliott TG, Norman E, Stajic V, Hitchcock CL. PloS One. 2014;9(1):e84698. doi:10.1371/journal.pone.0084698. Copyright License: CC BY
  26. Progesterone Does Not Influence Vascular Function in Postmenopausal Women. Honisett SY, Pang B, Stojanovska L, Sudhir K, Komesaroff PA. Journal of Hypertension. 2003;21(6):1145-9. doi:10.1097/00004872-200306000-00014.
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About the Author

With over 26 years of experience as a licensed pharmacist in Utah and Colorado, I specialize in hormone optimization and menopause management. I hold certifications in Advanced Bioidentical Hormone Replacement Therapy (ABHRT) from Worldlink Medical, C4 Hormone Replacement Therapy from the Professional Compounding Centers of America and the American Academy of Anti-Aging Medicine, and I am a Brain Health Coach certified by Amen Clinics.

I also share my expertise on my Simple Hormones YouTube channel where my over 100 videos have been viewed over 1,000,000 times and over 19,000 viewers have subscribed.

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