Progesterone and Progestins: Is there a difference?
Progesterone’s Key Role
Progesterone is created when we ovulate during our monthly menstrual cycles — here is how. And, when hormonal patterns start to shift in our late 30s/early 40s, fewer ovulations lead to lower levels of progesterone. See how things change during the menopause transition here. Progesterone is also made during pregnancy, but since we are focused on perimenopause, we won’t get into that.
Progesterone v. progestin v. progestogens: terms cause confusion!
This is another case of confusing terminology. In many places, you will see the term “progestins” used to encompass three things, but it’s technically incorrect!
Here are definitions to know:
- progesterone — the hormone made by our bodies when we ovulate. Products that are made to be identical to this naturally occurring molecule are sometimes referred to as bioidentical; Prometrium®— is the brand name of the FDA-approved oral progesterone product. Crinone® is the name of the vaginal gel, FDA-approved product.
- progestins — all “progesterone-like” products that are not exactly like the molecule made by our bodies but are made to act on our progesterone receptors. Most of these are more potent than progesterone.
- progestogens — any steroid hormone that binds to and activates the progesterone receptor — this includes progesterone (bioidentical) and progesterone-like products (i.e. progestins).
These umbrella terms confuse the non-medical among us and mask the fact that these products may have different ways of interacting in the body and different safety profiles.
A GRAPHIC TO CLARIFY
Note: Prometrium® and Crinone® (above left) are FDA-approved hormone therapy products available by prescription. The progestins listed on the right are generic names. Our menopausal hormone therapy chart shows all of the available products.
Molecular structures differ: progesterone and progestins are not the same!
Progestins are a class of drugs manufactured in a lab by pharmaceutical companies to act like the progesterone our bodies make. However, the chemical structure of the synthesized molecule is not the same as the naturally occurring one, which has an impact on the way these progesterone-like molecules bind to progesterone receptors in our bodies. Progesterone dissipates quickly in the body, so progestins were designed to be more potent and have a longer-lasting effect. As such, progestins are more potent than natural progesterone.
Progesterone USP (in Promentrium®), is also manufactured in a lab and derived from plants. It is said to be “bioidentical” — that is, molecularly identical to the progesterone made in our bodies.
Looking at the chemical structure of a progestin and progesterone, it is clear they are not the same.1
Below are the chemical structures of Progesterone USP (Prometrium®), Medroxyprogesterone Acetate (Provera®) and Progesterone as made each time we ovulate by the corpus luteum, the place on the ovary where the egg pops out. Provera® often referred to as MPA is one of the oldest synthetic progesterone-like products, found in many birth control pills.https://womenlivingbetter.org/progesterone-and-progestins/
Progesterone (PrometriumTM) Chemical Structure
National Center for Biotechnology Information (2022). PubChem Compound Summary for CID 1807214, Progesterone (PrometriumTM). Retrieved October 31, 2022 from this link.
Medroxyprogesterone acetate (Depo-ProveraTM) Chemical Structure
National Center for Biotechnology Information (2022). PubChem Compound Summary for CID 6279, Medroxyprogesterone acetate. Retrieved October 31, 2022 from this link.
Progesterone
Chemical Structure
Source: National Center for Biotechnology Information (2022). PubChem Compound Summary for CID 5994, Progesterone. Retrieved October 31, 2022 from this link.
Research Suggests: There might safety and tolerability differences between progesterone and progestin products
In 1995, a randomized-controlled trial compared different estrogen and progestogen (products that have progesterone-like effects) combinations on markers of cardiovascular health in 875 postmenopausal women. The trial demonstrated that bioidentical progesterone (Progesterone USP) had a more favorable impact on cholesterol and was better tolerated than Provera® (medroxyprogesterone acetate) — a synthetic (i.e. non-bioidentical) form.3
Early evidence in studies about the differential breast cancer risk with progesterone versus progestin.
1.) a French study, estrogen plus progesterone had no increased breast cancer risk, but estrogen with progestin increased risk by 69%. 4
2.) Another finding: controlled studies and most observational studies published over the last five years suggest that the addition of synthetic progestins to estrogen in hormone replacement therapy, particularly in a continuous-combined regimen, increases the breast cancer risk compared to estrogen alone. By contrast, a recent study suggests that the addition of natural progesterone in cyclic regimens does not affect breast cancer risk.5
October 2020 Update
In terms of comparing safety, there has not yet been a randomized trial that demonstrates that bioidentical progesterone is safer than progestins (synthetic, non-bioidentical). However, recent reviews of observational studies have raised the question of whether bioidentical progesterone is safer with respect to breast cancer risk than progestins like Provera (medroxyprogesterone acetate).6,7
January 2024 Update
More research has investigated whether the risk of breast cancer is dependent on the type of progestogen used with estrogen in menopausal hormone therapy. This new research from 2022, concluded that the formulations that included a progestin versus progesterone were associated with an increased risk of breast cancer. Not surprisingly, this research concludes by suggesting the use of progesterone in menopausal hormone therapy rather than a progestin.8
We’ve been watching this research for several (7) years or so. It’s becoming clear that progesterone and progestins have different effects on breast tissue and in our cardiovascular systems. Most health care providers that we talk to use progesterone and not progestins when they can.
Two FDA-approved progesterone products
There are two FDA-approved progesterone products on the market: Prometrium™ is an oral capsule and is formulated in peanut oil. Crinone™ is a vaginal gel. You can see where these fit in out hormone therapy chart here.
Developing a drug and getting it approved by the FDA is a multi-stage, multi-million dollar investment that takes 5-10 years on average, and most drugs do not make it to approval. For drugs that do, they are granted seven years of patent protection, a time when no other company can copy their product so that they can make back the costs of developing the drug and hopefully a bit more for profit. Because progesterone is made from naturally occurring plant-based sources, it is difficult to claim the product is unique in order to qualify for a patent and protect the investment in developing the drug. Prometrium™ was granted patent protection because of its unique formulation in peanut oil.
We find it curious that Prometrium™ — even though it is structurally the same (bioidentical) to the progesterone made by our bodies — has the same FDA warning label as progestins.
Here is why: the developers of Prometrium™ developed it as a bioidentical progesterone option for women who were taking estrogen for uterine protection. Anyone who takes estrogen and has a uterus needs progesterone to protect her uterus from the overgrowth of endometrial cells caused by added estrogen which can lead to uterine cancer. We’ve spoken to physicians who believe that Prometrium™ has less risk because it is bioidentical. This is not yet proven, but some studies, like those in the section above, seem to be showing a safety difference between the two.
REFERENCES
1. All progestins are not created equal. Frank Z. Stanczyk. Steroids 68 (2003) 879–890.
2. Molecular mechanisms of steroid receptor-mediated actions by synthetic progestins used in HRT and contraception. Donita Africander, Nicolette Verhoog, Janet P. Hapgood. Steroids 76 (2011) 636–652
3. Barrett-Connor E, Slone S, Greendale G, Kritz-Silverstein D, Espeland M, Johnson SR, Waclawiw M, Fineberg SE. The Postmenopausal Estrogen/Progestin Interventions Study: primary outcomes in adherent women. Maturitas. 1997 Jul;27(3):261-74. doi: 10.1016/s0378-5122(97)00041-8. PMID: 9288699.
4. Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study. Breast Cancer Res Treat. 2008 Jan;107(1):103-11. Epub 2007 Feb 27.
5. Progestins and progesterone in hormone replacement therapy and the risk of breast cancer. J Steroid Biochem Mol Biol. 2005 Jul; 96(2): 95–108.
6. Asi N, Mohammed K, Haydour Q, et al. Progesterone vs. synthetic progestins and the risk of breast cancer: a systematic review and meta-analysis. Syst Rev. 2016;5(1):121. Published 2016 Jul 26. doi:10.1186/s13643-016-0294-5
7. Stute P, Wildt L, Neulen J. The impact of micronized progesterone on breast cancer risk: a systematic review. Climacteric. 2018;21(2):111-122. doi:10.1080/13697137.2017.1421925
8. Abenhaim HA, Suissa S, Azoulay L, Spence AR, Czuzoj-Shulman N, Tulandi T. Menopausal Hormone Therapy Formulation and Breast Cancer Risk. Obstet Gynecol. 2022 Jun 1;139(6):1103-1110. doi: 10.1097/AOG.0000000000004723. Epub 2022 May 3. PMID: 35675607.