Progesterone vs Progestin: Why You Can’t Afford to Not Know The Difference

Key Takeaways

• Progesterone vs progestin is one of the most important distinctions in menopause and hormone medicine.
• Bioidentical progesterone is structurally identical to the progesterone naturally produced by the body, while a synthetic progestin has been chemically altered.
• Research suggests bioidentical progesterone and synthetic progestin products may have significantly different effects on breast cancer risk, blood clot risk, cardiovascular health, and overall outcomes.[1-9]
• For women receiving estradiol, progesterone is often an essential component of treatment.
• Understanding the risks and benefits of bioidentical hormone therapy can help providers make more informed clinical decisions.

One of the main female hormones that is commonly overlooked and confused with its synthetic imposters is progesterone. When discussing progesterone versus progestin, it is important to recognize that these terms are not interchangeable. Bioidentical progesterone is structurally identical to the hormone naturally produced by the ovaries, whereas a synthetic progestin has been chemically modified and may produce very different biological effects.[1,3]

• Progesterone vs Progestin: Understanding the Difference
• Bioidentical Progesterone vs Synthetic Progestin
• Progesterone, Breast Cancer, and Blood Clot Risk
• Additional Benefits of Progesterone Therapy
• Frequently Asked Questions About Progesterone vs Progestin
• Conclusion

Progesterone vs Progestin: Understanding the Difference

Natural progesterone (progesterone) is primarily produced by the ovaries and, to a lesser extent, by the adrenal glands in women.[1] Its origin is steeped in a rich historical context as early researchers noted its necessity for pregnancy implantation, maintenance, and ovulation.[1,2]

When prepared exogenously, this steroid hormone is derived from cholesterol to align with the 21-carbon structure in its natural form.[1,3] This bioidentical preparation is the only hormone replacement that should be called progesterone.[1] Any other mixture is technically termed a progestogen or progestin (having some of the same qualities as progesterone) and has been structurally and chemically altered from the original form.[1] 

The most common progestin prescribed and confused with natural progesterone is medroxyprogesterone acetate (MPA) which has been linked with a gross amount of side effects, yet for some reason, remains the primary choice of hormone replacement therapy (HRT) from The Menopause Society (previously known as NAMS) to oppose estrogen.[1-6]

Bioidentical Progesterone vs Synthetic Progestin

In their 2022 position statement, NAMS stated that the effectiveness and safety of bioidentical progesterone has not been studied, and their recommendation for replacement for women experiencing symptoms associated with menopause is the progestin, MPA.[1]

This is interesting as there have been studies dating back to 1949 when progesterone was given to women with a history of miscarriages who were unable to conceive or maintain the pregnancy.[2] Once they were given natural/bioidentical progesterone, they went on to deliver healthy babies.[2] NAMS also held the position that there is “...insufficient evidence to support overall clinical use of compounded bioidentical hormone therapy (BHRT) for treatment of menopause symptoms.”[4,7]

Whereas there may not be clinical trials that look at the safety and efficacy of these compounded BHRT products, they are quickly becoming a more accepted form of HRT nationwide. In fact, the authors of the REPLENISH trial concluded compounded hormonal therapy was quickly becoming the standard of care for menopausal treatment, based on prescription counts for compounded BHRT far surpassing those of the FDA-approved products.[7] That study was published in 2018, years before NAMS released their latest position statement.[7]

These differing recommendations highlight the ongoing debate surrounding bioidentical hormone therapy, hormone therapy, and the role of progesterone in menopause care.[4,7] Providers are generally taught in their respective academic programs to look to the guidelines for evidence-based practice to best treat their patients. Yet as risks and benefits of bioidentical progesterone and MPA are tallied, progesterone is the safer and more efficacious choice.[1-3,5-9]

Progesterone, Breast Cancer, and Blood Clot Risk

Breast Cancer Risk and Progesterone vs Progestin

One of the most important considerations when evaluating progesterone vs progestin is the difference in breast cancer risk reported in the literature. On a cellular level, MPA induces mitosis while natural progesterone inhibits carcinogenesis by stimulating apoptosis and further has an antiproliferative effect.[1] Alarmingly, NAMS recognizes this increased risk for breast cancer and still promotes MPA.[4] There are no studies that indicate the replacement of natural progesterone increases women’s risk for breast cancer, and in fact, many have corroborated that it is actually preventative.[1-3,5,6,8,9]

Deep Vein Thrombosis (DVT) and Synthetic Progestins

Another key distinction between bioidentical progesterone and synthetic progestin products involves the risk of deep vein thrombosis (DVT). The incidence and prevalence of DVTs were found only in women who were exposed to progestins such as MPA, not progesterone.[1-4,8] NAMS recognized this risk with MPA and further stated this risk is higher in older women or in those who start HRT ten years after their final menses.[4] Conversely, there is no increased risk of DVTs in the literature when a woman initiates progesterone replacement at any age.

Progesterone and Estradiol in Hormone Replacement Therapy

For any woman who has reached menopause (cessation of menses for at least twelve months) with an intact uterus and who is prescribed estradiol, progesterone is needed to prevent excessive endometrial stimulation.[7] Other organizations recommend a progestin as long as therapy is initiated within the ten-year window of menopause.[4]

In contrast to progestins, bioidentical progesterone can be initiated at any time.[7] In fact, in a randomized control trial of over 1255 women, there was no evidence of any endometrial hyperplasia in any woman given oral progesterone. Along with this incredible protection against endometrial cancer, these women also reported relief of their vasomotor symptoms.[7] It is important to note even women who have had a hysterectomy can greatly benefit from progesterone replacement.

Progesterone and other Cancer Protection

Besides protection against breast and endometrial cancers, progesterone has been shown to decrease risks of cancers in other parts of the body.[6,7] Progesterone’s apoptotic effects have proven to decrease the risk of ovarian, colon, and non-small cell lung cancers, as well as malignant melanoma.[1,9]  These life-saving benefits are not seen with its synthetic counterparts.

To understand estrogen versus estradiol, it is important to understand the different types of estrogen available for menopause treatment.

Risks and Side Effects of Synthetic Progestin

MPA has been found to have androgenic, mineralocorticoid, and glucocorticoid activity.[2,3] This can lead to women experiencing symptoms such as:

• Weight gain
• Bloating
• Mood swings
• Acne[2,3] 

As if negative symptoms aren’t enough to deter a woman from using the synthetic versions or encourage a provider to choose the better alternative, because of this receptor activity, MPA can also lead to insulin resistance and worsening of lipid parameters, both of which can lead to heart disease.[3]

Additional Benefits of Progesterone Therapy

Beyond its role in hormone replacement therapy, research has identified numerous benefits associated with progesterone therapy that are not seen with synthetic alternatives.

Menses and Pregnancy Benefits

Progesterone can be helpful for women who experience irregular menses. It has been shown to improve cycles over time and provide relief for young women who struggle with heavy menstrual cycles.[8] Furthermore, it is an essential hormone for women trying to maintain a healthy pregnancy, as progesterone deficiencies have been linked to higher rates of miscarriage.[2,3]

Women reporting night sweats, vaginal dryness, brain fog, hot flushes, and insomnia who were prescribed estradiol reported better symptom relief when compared to CEE.[5-6]

Cardiovascular Benefits

Progesterone does not possess any glucocorticoid or androgenic activity that leads to bothersome symptoms, and has been found to be cardioprotective.[2,3] This was assessed in several studies where progesterone replacement was found to decrease the risk of congestive heart failure, myocardial ischemia, cerebral ischemia, and dementia.[2,3,8,9] Besides these cardiovascular benefits of progesterone over MPA, supplementing with natural progesterone reduced all-cause mortality by 22% while taking a progestin such as MPA increased all-cause mortality by 11%![9]

Bone Health Benefits

The role of progesterone therapy in bone health is often overlooked compared to estradiol replacement. In addition to increasing cardiovascular risks as they age, women are also disproportionately affected by bone loss.[5] It may be common knowledge that restoration of a woman’s estradiol level to her youthful range helps with bone loss and fractures. However, what’s not so commonly known is that progesterone replacement plays a pivotal role in bone health as well. 

As estradiol helps to slow the resorption rate, progesterone stimulates new bone formation. This degenerative bone activity that is normally not screened for until well past menopause is now known to begin with the first irregularity seen in the menstrual cycle. Younger women in perimenopause can safely be prescribed oral progesterone to decrease fracture risk and improve overall bone density.[5]

Sleep, Brain Health, and Cognitive Function

Women who are in perimenopause or menopause and who experience insomnia or sleep difficulties can be prescribed progesterone to aid in restful, restorative slumber.[8] Not only were these women able to sleep better, but they also saw improvement in their of vasomotor symptoms, which are quite common in women in this age range. 

Progesterone replacement has also been shown to be neuroprotective.[2,8] Studies show it can slow down cognitive decline, improve brain function, reduce memory fog, and even be helpful after an ischemic event. It has even been implicated in helping with other inflammatory conditions, such as multiple sclerosis.[2,8]

Conclusion

Understanding the distinction between progesterone vs progestin is essential for providers evaluating the risks and benefits of modern bioidentical hormone therapy and individualized menopause treatment. Natural progesterone exerts a protective effect on almost all body systems, including the breasts, uterus, ovaries, heart, lungs, bones, and brain.[5,9] This protective effect can be seen in young women who are trying to maintain pregnancy, perimenopausal women experiencing side effects, and older women who want to experience the multitude of benefits it offers.[1-3,5-9]

Replacing valuable hormones that balance risk reduction and symptom management is crucial to practicing evidence-based optimal health medicine. Although there are societies attempting to guide providers to treat patients in a less-than-optimal way, we must educate ourselves in academies that place patients' needs and health first. 

Progesterone is a safe and efficacious therapy and should be offered to all women in place of dangerous and synthetic progestins such as medroxyprogesterone acetate.

Ready to Learn More About BHRT?

Understanding the differences between bioidentical progesterone and synthetic progestin products is just one part of delivering evidence-based hormone care. To deepen your understanding of menopause management, hormones, and bioidentical hormone replacement therapy, consider joining WorldLink Medical's Optimal Medicine Training Series.

Start with Mastering the Foundations of BHRT, a comprehensive course designed to help providers confidently implement evidence-based hormone optimization strategies in clinical practice.

Learn more:
https://worldlinkmedical.com/education/conferencecourses/optimal-medicine-training-series/mastering-the-foundations-of-bhrt

References

1. Lieberman A. In defense of progesterone: a review of the literature. Alternative Therapies. 2017; 23(6):24-32.PMID: 29055286. https://pubmed.ncbi.nlm.nih.gov/29055286/
2. Piette P. The history of natural progesterone, the never-ending story. Climacteric. 2018; 21(4):308-314. doi:10.1080/13697137.2018.1462792. PMID: 29806794. https://pubmed.ncbi.nlm.nih.gov/29806794/
3. Garcia-Saenz M, Ibarra-Salce R, Pozos-Varela J, Mena-Ureta TS, Flores-Villagomez S, Sanatana-Mata M, De Los Santos-Aguilar RG, Uribe-Cortes D, Ferreira-Hermosillo A. Understanding progestins: from basics to clinical applicability. Journal of Clinical Medicine. 2023; 12(10): 3388. doi:10.3390/jcm12103388. PMID: 37240495. https://pubmed.ncbi.nlm.nih.gov/37240495/
4. The North American Menopause Society. The 2022 hormone therapy position statement of the north american menopause society. Menopause. 2022; 29(7):767-794. doi:10.1097/GME.0000000000002028. PMID: 35797481. https://pubmed.ncbi.nlm.nih.gov/35797481/
5. Prior JC. Progesterone for the prevention and treatment of osteoporosis in women. Climacteric. 2018;21(4):366-374. doi:10.1080/13697137.2018.1467400. PMID: 29962257. https://pubmed.ncbi.nlm.nih.gov/29962257/
6. Gompel A, Plu-Bureau G. Progesterone, progestins and the breast in menopause treatment. Climacteric. 2018;21(4):326-332. doi:10.1080/13697137.2018.1476483. PMID: 29852797. https://pubmed.ncbi.nlm.nih.gov/29852797/
7. Lobo RA, Archer DF, Kagan R, Kaunitz AM, Constatine GD, Pickar JH, Graham S, Bernick B, Mirkin S. A 17beta-estradiol-progesterone oral capsule for vasomotor symptoms in postmenopausal women. Obstetrics & Gynecology. 2018;132(1):161-170. doi: 10.1097/AOG.0000000000002645. Erratum in: Obstet Gynecol. 2018;132(3):786. doi: 10.1097/AOG.0000000000002859. PMID: 29889748. https://pubmed.ncbi.nlm.nih.gov/29889748/
8. Mirkin S. Evidence on the use of progesterone in menopausal hormone therapy. Climacteric. 2018; 21(4): 346-354. doi:10.1080/13697137.2018.1455657. PMID: 29630427. https://pubmed.ncbi.nlm.nih.gov/29630427/
9. Baik SH, Baye F, McDonald CJ. Use of menopausal hormone therapy beyond age 65 years and its effects on women’s health outcomes by types, routes, and doses. Menopause. 2022;31(5): 363-371. doi:10.1097/GME.0000000000002335. PMID: 38595196. https://pubmed.ncbi.nlm.nih.gov/38595196/