Progesterone and Progestins and Progestogens: What do these terms mean? And what is are the differences?
What does progesterone do?
Progesterone is created from the place on the ovary where an egg pops out when we ovulate during our monthly menstrual cycles — here is how. If we do not ovulate, we do not produce progesterone.
And so, 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.
What is the difference between progesterone, progestin and progestogens?
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).
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.
Mounting research suggests safety and tolerability differences between progesterone and progestin products
Impact on cholesterol is different between progesterone and progestins
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
Breast cancer risk is different with progesterone and progestins
A French study demonstrated that estrogen plus progesterone had no increased breast cancer risk, but estrogen with progestin increased breast cancer risk by 69%. 4
Controlled studies and observational studies suggest that the addition of synthetic progestins to estrogen in menopausal hormone 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
Recent reviews of observational studies have raised the question of whether progesterone is safer with respect to breast cancer risk than progestins like Provera (medroxyprogesterone acetate).6,7
Additional research (2022) concluded that formulations that include a progestin versus progesterone were associated with an increased risk of breast cancer. 8
Venous thromboembolism (VTE) risk is different with progesterone and progestins
The risk of VTE was higher in those using hormone therapy than placebo in the Women’s Health Initiative trial. The hormone therapy products used in the WHI trial were for estrogen: conjugated equine estrogen (CEE) and for a progestogen: medroxyprogesterone acetate (MPA). A 2023 study investigated the occurrence of VTE in 2+ years of medical claims data comparing those who took oral CEE/MPA (what was used in the WHO) with those who took oral 17-beta estradiol/micronized progesterone. The rate of VTE was significantly lower in the oral 17-beta estradiol/micronized progesterone group.9
What are the 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.
What are progestins used for?
Progestins are used when we aren’t getting periods, to regulate menstrual cycles, for abnormal uterine bleeding are included in many forms of birth control. They can be stand alone or used in combination with an estrogen.
Find a list of types of products and their brand names here.
Progesterone and progestins are not the same. Their molecular structures differ.
Progestins are a class of drugs manufactured 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 (Prometrium®), Medroxyprogesterone Acetate (Provera®) and Progesterone made when we ovulate. Provera® often referred to as MPA is one of the oldest synthetic progesterone-like products, found in many birth control pills.
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.
REFERENCES
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.
9. Panay N, Nappi RE, Stute P, Palacios S, Paszkowski T, Kagan R, Archer DF, Héroux J, Boolell M. Oral estradiol/micronized progesterone may be associated with lower risk of venous thromboembolism compared with conjugated equine estrogens/medroxyprogesterone acetate in real-world practice. Maturitas. 2023 Jun;172:23-31. doi: 10.1016/j.maturitas.2023.04.004. Epub 2023 Apr 13. PMID: 37084589.