Progesterone is by far the most controversial hormone in transgender HRT. Almost bizarrely so, the amount of clinical misinformation, dis-information, gaslighting, and just straight ignorance is astounding. So let’s look in to it!
I’ve been told that progesterone has “no benefits”, which from personal experience is not true (“no proven benefits” is technically correct, but we’ll get in to that later), and others I know have been told that it’s “risky” - though without specifying the risks - and even that it’s a carcinogen, which would be pretty astonishing if true given that progesterone is part of every healthy human’s system!
What is progesterone?
Progesterone is a human sex hormone, like testosterone and oestrogen (yes there’s an oestrone, but oestrogen always seems to be used instead, perhaps because oestrone isn’t the most clinically important oestrogen). Biologically progesterone is the main precursor to testosterone, which itself is the main precursor to oestradiol.
The broader class of similar hormones is called progestogens, all progestogens have similar behaviour with varying degrees of potency, as do oestrogens (oestrone, oestradiol etc) and androgens (testosterone, dihydrotestosterone etc). There are also many synthetic progestogens, collectively known as progestins. These are often used in contraceptive pills, among other uses.
Progestogens play an important role in the reproductive system, it’s well known as the hormone that regulates the menstrual cycle but progesterone is also important for spermatogenesis and has effects on sleep, appetite, and the immune system1.
For people with an active menstrual cycle progesterone has monthly spikes up to 1200% of the baseline 2, but everyone else over 16 will have a serum level between 0.3-3nmol/L 3.
So what does it do?
As with everything we’re still discovering everything, but these are some of the functions that have been shown in research several times.
Progesterone is involved in breast tissue maturation4. While progesterone does not have any effect on initial breast growth, once Tanner stage IV is reached progesterone causes lobuloalveolar development, filling out the breast, increasing the size of the areola, and preparing the tissue for milk production. So progesterone does have a function in breast growth.
Heart health is also impacted, particularly the QT interval. Oestrogens increase the QT interval whereas androgens and progesterone shorten it5. This isn’t a significant thing for most people, but it’s definitely an effect. Additionally 100mg-300mg has been shown to lower blood pressure6.
Sleep is another area that’s affected, with progesterone being shown to reduce stress hormone levels, increase deep sleep, and prevent sleep disruptions 2. Again not a huge thing clinically, but it’s not “nothing”.
The form of progesterone generally considered the best among the transgender community is micronised bio-identical progesterone. This is identical to natural human progesterone that has been processed to make the powder as fine as possible and then suspended in a food oil (generally sunflower from what I’ve read). As this is identical to natural progesterone it has no known negative side effects in regular oral doses7, and only site-related side effects in other forms (eg injection site pain).
A lot of literature mentions an increase in drowsiness or memory function, but the paper that seems to be the source mentions this is with 300-1200mg per day, with symptoms increasing with dose6. The paper seems to suggest that this is due to the metabolism of progesterone to 5𝛼- and 5𝛽- pregnanolone in the liver, which is due to the administration route. Oral administration always results in a high level of liver metabolism.
So for bioidentical micronised progesterone the risks seem minimal, even if there are no effects.
Progestins are synthetic drugs that mimic progesterone. They are used because progestins can be designed to avoid liver metabolism, which supposedly reduces the risk of side-effects and greatly reduces the dose required. The most referenced one in HRT is medroxyprogesterone acetate (most common brand is depro-provera), but there’s another one that’s much more common in New Zealand.
Cyproterone Acetate, or CPA, is the most common anti-androgen prescribed for feminising hormone therapy in New Zealand. CPA is a progestogen and is said to be 1000 times more potent than progesterone itself. So if you’re on 12.5mg/day of cyproterone acetate it will be stronger than 100mg of progesterone daily in terms of progesterone receptor activation.
No evidence of effect?
This is technically correct. There have been very few studies on the effects of progestogens in transfeminine hormone therapy. Medroxyprogesterone Acetate in Gender-Affirming Therapy for Transwomen: Results From a Retrospective Study uses a synthetic progestogen and was inconclusive, and the only clinical article I have found that takes a deeper look recommends using progesterone as it’s important to cis women (Progesterone Is Important for Transgender Women’s Therapy—Applying Evidence for the Benefits of Progesterone in Ciswomen 8).
Unfortunately all this evidence hasn’t been enough to sway clinicians from their desire to deny treatment which, while it may have limited effects, is demonstrably safe. Personally I have found it helpful for my mental health and sleep quality at the very least.
I also really wish it wasn’t necessary to become an amateur endocrinologist to know whether doctors are telling us the truth about the medication we’re prescribed, but here we are.
Also Jerilynn C Prior has done some some amazing work on the way progesterone has been (and continues to be) ignored as an essential part of woman’s health. I wish I could talk to her and get more background, but alas I’m not a real endocrinologist.
Jerilynn C. Prior (2020), Women’s reproductive system as balanced estradiol and progesterone actions—A revolutionary, paradigm-shifting concept in women’s health, Drug Discovery Today: Disease Models, Vol 32, Part B, 31-40 DOI: 10.1016/j.ddmod.2020.11.005
Christine L. Clarke, Robert L. Sutherland, Progestin Regulation of Cellular Proliferation, Endocrine Reviews, Volume 11, Issue 2, 1 May 1990, Pages 266–301, DOI: 10.1210/edrv-11-2-266
Tara Sedlak, Chrisandra Shufelt, Carlos Iribarren, and C. Noel Bairey Merz. Sex Hormones and the QT Interval: A Review. Journal of Women’s Health. Sep 2012.933-941. DOI: 10.1089/jwh.2011.3444
Goletiani, N. V., Keith, D. R., & Gorsky, S. J. (2007). Progesterone: Review of safety for clinical studies. Experimental and Clinical Psychopharmacology, 15(5), 427–444. doi:10.1037/1064-12184.108.40.2067
Kuhl, H. (2005). Pharmacology of estrogens and progestogens: influence of different routes of administration. Climacteric, 8(sup1), 3–63. doi:10.1080/13697130500148875
Gräf KJ, Brotherton J, Neumann F (1974). “Clinical Uses of Antiandrogens”. Androgens II and Antiandrogens / Androgene II und Antiandrogene. pp. 485–542. doi:10.1007/978-3-642-80859-3_7