All progestins are not created equal
Abstract
A variety of progestins are available for therapeutic use. It is convenient to classify them into those related in chemical structure to progesterone or testosterone. Progestins related to progesterone can be subdivided into pregnanes and 19-norpregnanes, whereas those related to testosterone can be subdivided into those with and without a 17-ethinyl group. 17-Ethinylated progestins consist of the families of norethindrone (estranes) and levonorgestrel (13-ethylgonanes). Progestins administered orally undergo extensive hepatic first pass metabolism primarily by reduction and conjugation, and in most instances, relatively high progestin doses are required for therapeutic use. There are limited reliable data on the pharmacokinetics of most progestins. Some progestins are prodrugs, requiring transformation prior to exhibiting progestational activity. Qualitative and quantitative tests utilizing either human or animal species have been used to establish progestin potency. However, profound differences in progestational activity are often observed between human and animal tissues. Also, there is a misconception about androgenicity of progestins due largely to extrapolation of data from rat studies to the human. Progestins differ widely in their chemical structures, structure-function relationships, metabolism, pharmacokinetics, and potencies; they are not created equal.
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Progestogens are primarily metabolized by the liver largely to form pregnanediols and pregnanolones.
“Progestogens are primarily metabolized by the liver largely to form pregnanediols and pregnanolones [336,337].”
From Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: a comprehensive review (2019) · cites this paper as [337]
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BackgroundBray, J. D., Jelinsky, S. A., Ghatge, R. P., Bray, J. A., Tunkey, C. D., Saraf, K. A., Jacobsen, B. M., Richer, J. K., Brown, E. L., Winneker, R. C., et al. (2005) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2005.06.032 · Cited by 59 · see citing works
Influence of Oral Contraceptive Use on Adaptations to Resistance Training
Dalgaard, L. B., Dalgas, U., Andersen, J. L., Rossen, N. B., Møller, A. B., Stødkilde-Jørgensen, H., Jørgensen, J. O., Kovanen, V., Couppé, C., Langberg, H., et al. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.00824 · Cited by 58 · see citing works
“Depending on brand name and OC “generation,” the formulation of EE typically varies between 20 and 50 µg daily dose, while the different types of progestins differ in dose depending on potency (Stanczyk, 2003; Burrows and Peters, 2007).”
BackgroundThe other side of progestins: effects in the brain.
Giatti, S., Melcangi, R., & Pesaresi, M. (2016) · Journal of Molecular Endocrinology · doi:10.1530/jme-16-0061 · Cited by 53 · see citing works
“…plasma binding proteins that bind steroids (i.e., albumin, corticosteroid-binding globulin (CBG), and sex hormone binding globulin (SHBG)) (Hammond 2002, Schindler et al. 2003) as well as by the metabolism of progestins, which can result in compounds that have different activities (Stanczyk 2003).”
InfluentialMenopausal Hormone Therapy Formulation and Breast Cancer Risk
Abenhaim, H. A., Suissa, S., Azoulay, L., Spence, A. R., Czuzoj‐Shulman, N., & Tulandi, T. (2022) · Obstetrics and Gynecology · doi:10.1097/aog.0000000000004723 · Cited by 57 · see citing works
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Degradation of Norgestrel by Bacteria from Activated Sludge: Comparison to Progesterone
Liu, S., Ying, G., Liu, Y.-S., Peng, F., & He, L.-Y. (2013) · Environmental Science & Technology · doi:10.1021/es304688g · Cited by 53 · see citing works
Tsilidis, K. K., Allen, N. E., Key, T. J., Dossus, L., Kaaks, R., Bakken, K. S., Lund, E., Fournier, A., Dahm, C. C., Overvad, K., et al. (2011) · Cancer Causes & Control · doi:10.1007/s10552-011-9782-z · Cited by 52 · see citing works
“For estrogen-only users, analyses were performed by constituent (estradiol compounds, conjugated equine estrogens) and route of administration (cutaneous, oral), and for estrogen plus progestin users, by progestin constituent (micronized [natural] progesterone, progesterone derivatives, testosterone derivatives) [8],…”
Sonneveld, E., Pieterse, B., Schoonen, W. G. E. J., & van der Burg, B. (2010) · Toxicology in Vitro · doi:10.1016/j.tiv.2010.11.018 · Cited by 51 · see citing works
Norethisterone and its acetate – what’s so special about them?
Huvinen, E., Holopainen, E., & Heikinheimo, O. (2020) · BMJ Sexual & Reproductive Health · doi:10.1136/bmjsrh-2020-200619 · Cited by 50 · see citing works
Meendering, J. R., Torgrimson, B. N., Miller, N. P., Kaplan, P., & Minson, C. T. (2008) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.01314.2007 · Cited by 47 · see citing works
“The androgenic nature of MPA compared with progesterone provides additional support to the notion that different progestogens may have divergent effects on vascular function (43).”
BackgroundPharmacodynamics of combined estrogen-progestin oral contraceptives: 2. effects on hemostasis
Farris, M., Bastianelli, C., Rosato, E., Brosens, I. A., & Benagiano, G. (2017) · Expert Review of Clinical Pharmacology · doi:10.1080/17512433.2017.1356718 · Cited by 46 · see citing works
“This concept was elaborated by Stanczyk [44] who stressed the existence of major differences in their chemical structures, structure-function relationships, metabolism, pharmacokinetics, pharmacodynamic, and potencies, concluding that “they are not created equal”.”
BackgroundBraden, B. B., Andrews, M. G., Acosta, J. I., Mennenga, S. E., Lavery, C. N., & Bimonte‐Nelson, H. A. (2016) · Behavioural Brain Research · doi:10.1016/j.bbr.2016.06.053 · Cited by 46 · see citing works
Polycystic ovary syndrome: A review for dermatologists
Buzney, E. A., Sheu, J., Buzney, C. D., & Reynolds, R. V. (2014) · Journal of the American Academy of Dermatology · doi:10.1016/j.jaad.2014.05.009 · Cited by 47 · see citing works
Perry, G. A. (2011) · Journal of Animal Science · doi:10.2527/jas.2011-4572 · Cited by 46 · see citing works
Salazar, M. G. S., Lerma-Ortiz, A., Hooks, G. M., Ashley, A. K., & Ashley, R. L. (2016) · Gene · doi:10.1016/j.gene.2016.06.044 · Cited by 45 · see citing works
“Indeed, the pharmacological properties of progestins vary depending on their parent compound in which they were synthesized from, leading to disparities in biological activities (Schindler, Campagnoli, Druckmann et al., 2003, Stanczyk, 2003).”
BackgroundEthinyl estradiol-to-desogestrel ratio impacts endothelial function in young women
Meendering, J. R., Torgrimson, B. N., Miller, N. P., Kaplan, P., & Minson, C. T. (2008) · Contraception · doi:10.1016/j.contraception.2008.07.025 · Cited by 45 · see citing works
“Each progestin can have dramatically different effects on the body based on the parent molecule from which it was created, its chemical structure, pharmacokinetics, activity and specificity to given receptors [24–27].”
Naturally Occurring and Melengestrol Acetate-associated Reproductive Tract Lesions in Zoo Canids
Moresco, A., Munson, L., & Gardner, I. A. (2009) · Veterinary Pathology · doi:10.1354/vp.08-vp-0293-m-fl · Cited by 43 · see citing works
Association of Estrogen and Progestin Potency of Oral Contraceptives With Ovarian Carcinoma Risk
Lurie, G., Thompson, P. J., McDuffie, K., Carney, M. E., Terada, K. Y., & Goodman, M. T. (2007) · Obstetrics and Gynecology · doi:10.1097/01.aog.0000255664.48970.e6 · Cited by 44 · see citing works
Effects of Female Reproductive Hormones on Sports Performance
Lebrun, C. M., Joyce, S., & Constantini, N. (2013) · Humana Press eBooks · doi:10.1007/978-1-62703-314-5_16 · Cited by 43 · see citing works
Contraceptive progestins with androgenic properties stimulate breast epithelial cell proliferation
Shamseddin, M., Martino, F. D., Constantin, C., Scabia, V., Lancelot, A., László, C., Ayyanan, A., Battista, L., Raffoul, W., Gailloud‐Matthieu, M., et al. (2021) · EMBO Molecular Medicine · doi:10.15252/emmm.202114314 · Cited by 43 · see citing works
“They also vary in bioavailability, efficacy, and have different binding affinities for the sex hormone-binding globulin (SHBG) and corticosteroid-binding globulin (CBG) bound to which these hydrophobic substances travel in the bloodstream (Stanczyk, 2002, 2003 ) .”
Petit-Topin, I., Turque, N., Fagart, J., Fay, M., Ulmann, A., Gainer, E., & Rafestin-Oblin, M. E. (2009) · Molecular Pharmacology · doi:10.1124/mol.108.054312 · Cited by 43 · see citing works
“Many progestins have been developed for contraception, menopausal hormone therapy, and treatment of gynecological diseases (Schindler et al., 2003; Stanczyk, 2003; SitrukWare, 2004, 2007).”
BackgroundCardiovascular effects of medroxyprogesterone acetate and progesterone: a case of mistaken identity?
Hermsmeyer, R. K., Thompson, T. L., Pohost, G. M., & Kaski, J. C. (2008) · Nature Clinical Practice Cardiovascular Medicine · doi:10.1038/ncpcardio1234 · Cited by 40 · see citing works
“There is, however, only one unique, naturally occurring hormone known as progesterone, which is a specific chemical entity that belongs to the class of progestins”
BackgroundWillibald, M., Bayer, G., Stahlhut, V., Poschmann, G., Stühler, K., Gierke, B., Pawlak, M., Seeger, H., Mueck, A. O., Niederacher, D., et al. (2017) · Oncotarget · doi:10.18632/oncotarget.19819 · Cited by 38 · see citing works
“However, they differ from their molecule of origin and from each other in metabolism, pharmacokinetics, pharmacodynamics, potency and binding affinity to progesterone receptor (PR), causing different effects in breast cells [13,14].”
The neurosteroid system: an emerging therapeutic target for hepatic encephalopathy
Ahboucha, S., & Butterworth, R. F. (2007) · Metabolic Brain Disease · doi:10.1007/s11011-007-9065-2 · Cited by 38 · see citing works
“Some precursors of NS, including pregnenolone and progesterone, are normally metabolized by the liver (Stanczyk 2003).”
BackgroundMagnetic Resonance Imaging (MRI) of hormone-induced breast changes in young premenopausal women
Clendenen, T. V., Kim, S., Moy, L. P., Wan, L. S., Rusinek, H., Stanczyk, F. Z., Pike, M. C., & Zeleniuch‐Jacquotte, A. (2012) · Magnetic Resonance Imaging · doi:10.1016/j.mri.2012.06.022 · Cited by 38 · see citing works
“We studied a single OC formulation because the type and dose of hormones differ across formulations [29] and may have variable effects on the breast tissue.”
BackgroundFu, X., Giretti, M. S., Goglia, L., Flamini, M. I., Sanchez, A. M., Baldacci, C., Garibaldi, S., Sitruk-Ware, R. L., Genazzani, A. R., & Simoncini, T. (2008) · BMC Cancer · doi:10.1186/1471-2407-8-166 · Cited by 37 · see citing works
“The pharmacological properties of progestins vary depending on the parent molecule from which they are derived, leading to considerable variations of the full spectrum of biological activities [2,6].”
BackgroundMeendering, J. R., Torgrimson, B. N., Miller, N. P., Kaplan, P., & Minson, C. T. (2010) · Contraception · doi:10.1016/j.contraception.2010.03.009 · Cited by 36 · see citing works
The role of progestins in treating the pain of endometriosis
Surrey, E. S. (2006) · Journal of Minimally Invasive Gynecology · doi:10.1016/j.jmig.2006.06.008 · Cited by 36 · see citing works
Oral progesterone for the prevention of recurrent preterm birth: systematic review and metaanalysis
Boelig, R. C., Corte, L. D., Ashoush, S. A., McKenna, D. S., Saccone, G., Rajaram, S., & Berghella, V. (2019) · American Journal of Obstetrics & Gynecology MFM · doi:10.1016/j.ajogmf.2019.03.001 · Cited by 35 · see citing works
Progress in progestin-based therapies for neurological disorders
Sitruk-Ware, R. L., Bonsack, B., Brinton, R. D., Schumacher, M., Kumar, N., Lee, J.-Y., Castelli, V., Corey, S., Coats, A. B., Sadanandan, N., et al. (2020) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2020.12.007 · Cited by 35 · see citing works
Do progestins contribute to (anti-)androgenic activities in aquatic environments?
Šauer, P., Bořík, A., Golovko, O., Grabic, R., Staňová, A. V., Valentová, O., Stará, A., Šandová, M., & Kroupová, H. K. (2018) · Environmental Pollution · doi:10.1016/j.envpol.2018.06.104 · Cited by 33 · see citing works
Effects of Combination Oral Contraceptives on Strength Development in Women Athletes
Nichols, A. W., Hetzler, R. K., Villanueva, R. J., Stickley, C. D., & Kimura, I. F. (2008) · The Journal of Strength and Conditioning Research · doi:10.1519/jsc.0b013e31817ae1f3 · Cited by 33 · see citing works
“For example, levonorgestrol and norethindrone have been shown to have both androgenic and antiandrogenic properties (36).”
BackgroundBasis of melengestrol acetate action as a progestin
Perry, G. A., Welshons, W. V., Bott, R. C., & Smith, M. F. (2004) · Domestic Animal Endocrinology · doi:10.1016/j.domaniend.2004.07.002 · Cited by 33 · see citing works
Fournier, A., Berrino, F., & Clavel‐Chapelon, F. (2007) · Breast Cancer Research and Treatment · doi:10.1007/s10549-007-9604-x · Cited by 33 · see citing works
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Neuroactive steroids and fatigue severity in patients with primary biliary cirrhosis and hepatitis C
Ahboucha, S., Butterworth, R. F., Pomier–Layrargues, G., Vincent, C., Hassoun, Z., & Baker, G. B. (2008) · Neurogastroenterology & Motility · doi:10.1111/j.1365-2982.2007.01080.x · Cited by 31 · see citing works
Influence of Progestin Bioactivity on Cutaneous Vascular Responses to Passive Heating
Houghton, B. L., Holowatz, L. A., & Minson, C. T. (2005) · Medicine & Science in Sports & Exercise · doi:10.1249/01.mss.0000150075.81511.fe · Cited by 31 · see citing works
Malik, M., Britten, J., Cox, J. M., Patel, A. D., & Catherino, W. H. (2015) · Fertility and Sterility · doi:10.1016/j.fertnstert.2015.09.006 · Cited by 30 · see citing works
Tsilidis, K. K., Allen, N. E., Key, T. J., Sanjoaquin, M. A., Bakken, K. S., Berrino, F., Fournier, A., Lund, E., Overvad, K., Olsen, A., et al. (2010) · International Journal of Cancer · doi:10.1002/ijc.25504 · Cited by 30 · see citing works
Impact of Metabolism on the Safety of Estrogen Therapy
Prókai-Tátrai, K., & Prókai, L. (2005) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1347.018 · Cited by 30 · see citing works
Hormonal contraception and breast cancer
Westhoff, C. L., & Pike, M. C. (2018) · Contraception · doi:10.1016/j.contraception.2018.05.002 · Cited by 30 · see citing works
Mishra, R. G., Hermsmeyer, R. K., Miyagawa, K., Sarrel, P. M., Uchida, B. T., Stanczyk, F. Z., Burry, K. A., Illingworth, D. R., & Nordt, F. J. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2004-1557 · Cited by 29 · see citing works
“bioidentical (54,55), will greatly enhance these preventive and therapeutic strategies.”
BackgroundModeling hormonal contraception in female rats: a framework for studies in behavioral neurobiology.
Lacasse, J. M., Gomez-Perales, E., & Brake, W. (2022) · Frontiers in neuroendocrinology (Print) · doi:10.1016/j.yfrne.2022.101020 · Cited by 24 · see citing works
Does the Progestogen Used in Combined Hormonal Contraception Affect Venous Thrombosis Risk?
Han, L. L., & Jensen, J. T. (2015) · Obstetrics and Gynecology Clinics of North America · doi:10.1016/j.ogc.2015.07.007 · Cited by 27 · see citing works
Romualdi, D., Cicco, S. D., Busacca, M., Gagliano, D., Lanzone, A., & Guido, M. (2013) · Journal of Endocrinological Investigation · doi:10.1007/bf03346756 · Cited by 26 · see citing works
- Authors
- Stanczyk, F. Z.
- Affiliations
- University of Southern California (US)
- Corresponding author
- Stanczyk, Frank Z
- ORCID
- Stanczyk, Frank Z
- Venue
- Steroids
- Publisher
- Elsevier BV
- Published
- 2003-11
- Volume
- 68
- Issue
- 10-13
- Pages
- 879-890
- ISSN
- 0039-128X (ISSN-L)
- OpenAlex
- W2037043326
- Cited by
- 226
- References
- 37
- Citations by year
- 2026: 5 · 2025: 11 · 2024: 5 · 2023: 5 · 2022: 13 · 2021: 7 · 2020: 11 · 2019: 15 · 2018: 15 · 2017: 9 · 2016: 9 · 2015: 11 · 2014: 11 · 2013: 15 · 2012: 8
- FWCI
- 2.47
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Steroids (publishedVersion)
- PubMed (publishedVersion)
- Topics
- 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
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Keywords
- progestins, progesterone derivatives, testosterone derivatives, pregnane derivatives, norethisterone, levonorgestrel, hepatic first-pass metabolism, prodrugs, structure-function relationship, androgenic activity, pharmacokinetics
- MeSH terms
- Animals, Female, Humans, Liver, Models, Chemical, Norethindrone, Pregnanes, Progestins, Structure-Activity Relationship, Time Factors, Levonorgestrel, Rats
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