Progesterone and Progestins and Progestogens: What do these terms mean? And what is are the differences?
What is a progestogen?
A progestogen is any steroid hormone that is or acts similarly to progesterone by binding to and activating the progesterone receptors throughout our bodies. This includes:
- Progesterone that our bodies make when we ovulate
- Progesterone products that are synthesized/made in a laboratory/manufactured to act just like it (e.g., Prometrium® or Crinone®)
- Progestin products also synthesized/made in a laboratory/manufactured made to be progesterone-like products
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.
Using the visual, here is more detail.
Progesterone and progestins: what is the difference?
What is progesterone?
Progesterone is created from the place on the ovary where an egg pops out after we ovulate in the middle of our menstrual cycle. If we do not ovulate, we do not produce progesterone.
When hormonal patterns begin to change in our late 30s/early 40s, both less frequent ovulation and less progesterone produced when we do ovulate lead to lower levels of progesterone overall. 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 go into that.
Products that are made to be exactly the same as this naturally occurring molecule are sometimes referred to as bioidentical. As shown in the image above, Prometrium® — is the brand name of the FDA-approved oral progesterone product. Crinone® is the name of the vaginal gel, FDA-approved product.
What does progesterone do in perimenopause and menopause?
In menopausal hormone therapy, Progesterone is used in women with a uterus to prevent he the overgrowth that estrogen alone can cause. Although research is incomplete progesterone is linked to mood and sleep. In some people progesterone has a calming effect. In others it can cause depressive feelings. It also sometimes causes bloating and dizziness. One expert said that 10% of her patients refer to progesterone as “PMS in a bottle”. Many women report sleep benefits to progesterone taken at night.
What is progestin? What are progestins?
Progestins are all “progesterone-like” products that are not exactly like the molecule made by our bodies but are made to act on the progesterone receptors in our bodies. Most progestins are more potent than progesterone.
What are progestins used for generally? What are progestins used for in perimenopause and menopause?
Progestins are used when we aren’t getting periods, to regulate menstrual cycles, for abnormal uterine bleeding and are included in many forms of birth control. They are also used as a part of menopausal hormone therapy in those with a uterus to protect the uterus from cancerous overgrowth that can occur with estrogen use.
Here is a table listing the most common progestins. A few things to note
- Prometrium® (oral micronized progesterone) is the progestogen used in perimenopausal and menopausal women as part of menopausal hormone therapy with an estradiol patch.
- Prometrium® is made in a base of peanut oil which prevents those with peanut allergies from taking it.
- The progestins typically used in perimenopause and menopause are bolded below.
- Note there is significant variability in individual responses to progesterone.
- There are also transdermal patches that combine a progestin and estrogen (e.g. Combipatch and Climara). While the combination is convenient, you can’t alter the relative amounts of estrogen to progestogen and they don’t come in low doses of estrogen like the individual estradiol patch. (.05 and .045 vs patch alone which starts at .0125)
- Find a list of types of products and their side effects here.
Generic name of progestin(by family) |
Brand names |
How it’s used |
|---|---|---|
| Medroxyprogesterone acetate (MPA) | Provera®, Depo-Provera® |
Abnormal uterine bleeding, absence of periods Contraceptive (Depo shot) |
|
Norethindrone Norethindrone acetate |
Aygestin®, Camila®, Errin®, Ortho Micronor® Aygestin®, Activella® (with estrogen) |
Oral contraception, endometriosis, abnormal bleeding Menopausal hormone therapy, endometriosis, abnormal uterine bleeding |
|
Levonorgestrel Norgestrel |
Mirena®, (Skyla®, Kyleena®) Plan B One-Step® Ovrette® |
IUDs for contraception and heavy bleeding Used in emergency contraception Progestin-only contraception (mini-pill) |
|
Norgestimate Desogestrel |
Ortho Tri-Cyclen®, Sprintec® Apri®, Desogen®, Mircette® |
Combined oral contraceptives |
| Drospirenone | Yasmin®, Yaz®, Slynd® (progestin-only) | Contraception, Premenstrual dysphoric disorder (PMDD), acne (in combination with estrogen or alone) |
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 may be 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%. (Observational)
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.
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.