Progestogens Used in Postmenopausal Hormone Therapy: Differences in Their Pharmacological Properties, Intracellular Actions, and Clinical Effects
Open accessAbstract
The safety of progestogens as a class has come under increased scrutiny after the publication of data from the Women's Health Initiative trial, particularly with respect to breast cancer and cardiovascular disease risk, despite the fact that only one progestogen, medroxyprogesterone acetate, was used in this study. Inconsistency in nomenclature has also caused confusion between synthetic progestogens, defined here by the term progestin, and natural progesterone. Although all progestogens by definition have progestational activity, they also have a divergent range of other properties that can translate to very different clinical effects. Endometrial protection is the primary reason for prescribing a progestogen concomitantly with postmenopausal estrogen therapy in women with a uterus, but several progestogens are known to have a range of other potentially beneficial effects, for example on the nervous and cardiovascular systems. Because women remain suspicious of the progestogen component of postmenopausal hormone therapy in the light of the Women's Health Initiative trial, practitioners should not ignore the potential benefits to their patients of some progestogens by considering them to be a single pharmacological class. There is a lack of understanding of the differences between progestins and progesterone and between individual progestins differing in their effects on the cardiovascular and nervous systems, the breast, and bone. This review elucidates the differences between the substantial number of individual progestogens employed in postmenopausal hormone therapy, including both progestins and progesterone. We conclude that these differences in chemical structure, metabolism, pharmacokinetics, affinity, potency, and efficacy via steroid receptors, intracellular action, and biological and clinical effects confirm the absence of a class effect of progestogens.
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Progesterone itself has its major effects on the progesterone receptor with negligible effects on the glucocorticoid receptor, androgen receptor, and it is an antagonist of the mineralocorticoid receptor.
“Progesterone itself has its major effects on the progesterone receptor (PR) with negligible effects on the glucocorticoid receptor (GR), androgen receptor (AR), and it is an antagonist of the mineralocorticoid receptor (MR).”
From Clinical practice guidelines for the care of girls and women with Turner syndrome. (2024) · cites this paper as [298]
Evidence shows a consistent association between level of risk and duration and strength of the estrogen dose.
“evidence shows a consistent association between level of risk and duration and strength of the estrogen dose.”
From Clinical practice guidelines for the care of girls and women with Turner syndrome. (2024) · cites this paper as [298]
Natural progesterone has poor oral bioavailability but this can be greatly improved by micronizing.
“Natural progesterone has poor oral bioavailability but this can be greatly improved by micronizing.”
From Clinical practice guidelines for the care of girls and women with Turner syndrome. (2024) · cites this paper as [298]
Medroxyprogesterone acetate has been widely used in hormone replacement therapy because its oral bioavailability is >90%, it has high potency, and its half-life is 24 hours, allowing for daily dosing.
“Medroxyprogesterone acetate has been widely used in HRT because its bioavailability orally is >90%, it has high potency and its half-life is 24 h, allowing for daily dosing.”
From Clinical practice guidelines for the care of girls and women with Turner syndrome. (2024) · cites this paper as [298]
All synthetic progestins bind to the progesterone receptor effectively but differ in their binding affinities and effects on the glucocorticoid, androgen, and mineralocorticoid receptors, giving rise to different profiles of actions and side effects.
“All synthetic progestins bind to the PR effectively but differ in their binding affinities and effects on the GR, AR, and MR giving rise to different profiles of actions and side effects.”
From Clinical practice guidelines for the care of girls and women with Turner syndrome. (2024) · cites this paper as [298]
Progesterone has other effects being crucially important for the implantation of the fertilized ovum, the maintenance of pregnancy, and some psychopharmacological actions including anxiolytic, antidepressant, and analgesic effects.
“Progesterone has other effects being crucially important for the implantation of the fertilized ovum, the maintenance of pregnancy,298 and some psychopharmacological actions including anxiolytic, antidepressant, and analgesic effects.”
From Clinical practice guidelines for the care of girls and women with Turner syndrome. (2024) · cites this paper as [298]
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- Authors
- Stanczyk, F. Z., Hapgood, J. P., Winer, S., & Mishell, D. R.
- Affiliations
- University of Southern California (US)
- University of Cape Town (ZA)
- Departments of Obstetrics and Gynecology (F.Z.S., S.W., D.R.M.) Los Angeles, California, 90033
- Corresponding author
- Stanczyk, Frank Z.
- Venue
- Endocrine Reviews
- Publisher
- The Endocrine Society
- Published
- 2012-12-13
- Volume
- 34
- Issue
- 2
- Pages
- 171-208
- ISSN
- 0163-769X (ISSN-L)
- 1945-7189
- PMC
- PMC3610676
- OpenAlex
- W2030555662
- Cited by
- 429
- References
- 21
- Citations by year
- 2026: 29 · 2025: 35 · 2024: 28 · 2023: 33 · 2022: 41 · 2021: 41 · 2020: 38 · 2019: 35 · 2018: 37 · 2017: 24 · 2016: 32 · 2015: 22 · 2014: 15 · 2013: 18
- FWCI
- 2.44
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Endocrine Reviews (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Menopause: Health Impacts and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Reproductive Health and Contraception
- Keywords
- progestogens, hormone replacement therapy, progestins, natural progesterone, medroxyprogesterone acetate, Women's Health Initiative, breast cancer risk, cardiovascular risk, endometrial protection, steroid hormone receptors, pharmacokinetics, bone metabolism, nervous system effects
- MeSH terms
- Female, Humans, Receptors, Steroid, Structure-Activity Relationship, Estrogen Replacement Therapy, Postmenopause, Progesterone Congeners
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