Progesterone - The Big Debate

To use or not to use progesterone?

For people born with testes whose bodies primarily produce testosterone and who want hormonal gender affirming treatment, estrogen (estradiol) has been the treatment workhorse to achieve changes in the body.  Estrogen may be used by itself, or in combination with medication that blocks testosterone (anti-androgens/T blockers.) Historically, most prescribers have not included progesterone in treatment protocols!

For people born with testes whose bodies primarily produce testosterone and who want hormonal gender affirming treatment, estrogen (estradiol) has been the treatment workhorse to achieve changes in the body.  Estrogen may be used by itself, or in combination with medication that blocks testosterone (anti-androgens/T blockers.) Historically, most prescribers have not included progesterone in treatment protocols.

However, if we think about bodies with ovaries, we know that ovaries make both estrogen and progesterone.

Huh? So where is progesterone in gender affirming care?

Ovaries and bodies with ovaries make 3 highly functional forms of estrogen (E1, E2, E3) and 10-15 minor forms of estrogen. They also make 1 highly functional form of progesterone (P4) and about 9 minor forms.

So why don’t we use more progesterone in gender affirming care?

Concerns about risks in post-menopausal cis women, that’s why.

A study done in the 1990s, called the Women’s Health Initiative1, raised some concerns that supplemental progesterone increased the rates of cardiac events, strokes, pulmonary emboli, and invasive breast cancers in post-menopausal cis women. Bad news bears!  HOWEVER, the study used a totally different form of progesterone than we use in gender affirming care, and the population studied was totally different (cis women! Post-menopausal cis women!)

Furthermore, while the increases in adverse health events were clinically significant, the total numbers of adverse events were not large, and they did NOT affect overall rates of death among the study groups. Although applying this data to trans women is questionable at best, it scared providers away from prescribing progesterone to trans women. That research informed gender affirming care (GAC) throughout the 1990s and 2000s. Then, as guidelines were developed for GAC, the commonly used models of care avoided progesterone. So today, most of our current guidelines still lack progesterone!

What we know about progesterone:

The same place as where we are with lots of gender affirming care:

• we don’t have a ton of research,
• we extrapolate data from cis people,
• we utilize expert opinion² and our understanding of pathophysiology to make our best educated guesses.

I know, right? I want more science too!

We know that having enough progesterone during a cis woman’s menstruating years reduces her risk of cardiovascular disease, osteoporosis, and breast cancer later in life. We know estrogen and progesterone work hand-in-hand (sometimes in opposition) to bring these health benefits. We know that progesterone is needed for the later stages of breast development in cis women (Tanner 4-5).  For more information on Tanner Stages, see this chart. We know that progesterone has significant mood effects.

For trans women and trans femme folx, we think progesterone MAY:

• bring about more rapid curviness
• help create larger, more developed breasts
• reduce testosterone production
• improve bone health
• improve cardiovascular health
• improve sleep and hot flashes

Important!  Here’s what we know about risk. Progesterone MAY:

• cause some mood symptoms
• cause increased risk for liver disease and breast cancer
• cause an increased risk for cardiovascular disease (wait, what? It’s protective in cis women, right? Weird, we know. We just don’t have great science here.)
  • We know that progesterone is protective against cardiovascular and cancer risks in people with ovaries (i.e., people with ovaries with less progesterone throughout their life have higher rates of cardiovascular disease and breast/ovarian cancer)
  • We know that SYNTHETIC progestins cause increases in strokes, heart problems, and blood clots, BUT micronized progesterone, which is BIOIDENTICAL, does not seem to have these effects³

This is why we AVOID SYNTHETIC PROGESTERONE!

So how do we use progesterone at QueerDoc?

At QueerDoc, we aim to INDIVIDUALIZE your gender affirming treatments to your gender expression goals. We might not recommend progesterone for everyone, but we do discuss it as one of the potential treatments for all of our patients exploring gender affirming care and wanting to be more curvy and soft. As ever, our practices in gender affirming care are evolving. When we look at the pubertal process fueled by ovaries, progesterone levels rise later in puberty than estrogen levels. There is a theoretical risk of more tubular-shaped, less round breasts when progesterone levels start and peak too early in breast development. Because of this theoretical risk, we generally recommend waiting to start progesterone for about six months after beginning estrogen (especially if rounder boobs are important to you). Furthermore, we recommend staying at a lower dose until Tanner stage 3 breast development has occurred; then, we begin to titrate your dose up to encourage mature breast development (Tanner stages 4 and 5)⁴.

Progesterone is the cheapest in capsules that were designed to be swallowed. We are pretty confident that adequate absorption of progesterone can be achieved via rectal placement. However:

• rectal use may cause higher levels of progesterone in the bloodstream due to avoiding first-pass metabolism in the liver.
• rectal use may cause more swings in blood levels of progesterone. The data we have is actually data for bio-vaginal absorption, so not precisely applicable⁵!
• progesterone does come in suppository form, but most retail pharmacies don’t stock it (hard to find)

You can get progesterone made into a transdermal cream at a specialty pharmacy. A transdermal cream is absorbed directly into the bloodstream through the skin, thus avoiding first-pass liver metabolism, like rectal capsule use.

At QueerDoc, we talk about what fits best for your life – cost, ease of use, etc. – to help pick the dosage and form that works for you. We have also started adding a transdermal progesterone cream a few months after starting the capsules.

THERE IS NO ONE WAY TO BE TRANS. THERE IS NO ONE WAY TO BE A WOMAN OR TO BE A FEMME.

Progesterone may or may not fit with your goals. That being said, we know that ovaries make estrogen and progesterone. If your gender affirming care goals match up with the ways ovaries make things happen, there are plenty of reasons to consider prescribing both estrogen and progesterone.

References

1. Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative randomized trials. JAMA. 2013;310(13):1353-1368. doi:10.1001/jama.2013.278040
2. Jerilynn C Prior, Progesterone Is Important for Transgender Women’s Therapy—Applying Evidence for the Benefits of Progesterone in Ciswomen, The Journal of Clinical Endocrinology & Metabolism, Volume 104, Issue 4, April 2019, Pages 1181–1186, https://doi.org/10.1210/jc.2018-01777
3. Canonico M, Oger E, Plu-Bureau G, Conard J, Meyer G, Lévesque H, Trillot N, Barrellier MT, Wahl D, Emmerich J, Scarabin PY; Estrogen and Thromboembolism Risk (ESTHER) Study Group. Hormone therapy and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration and progestogens: the ESTHER study. Circulation. 2007 Feb 20;115(7):840-5. doi: 10.1161/CIRCULATIONAHA.106.642280. PMID: 17309934.
4. Carolyn A. Bondy, Care of Girls and Women with Turner Syndrome: A Guideline of the Turner Syndrome Study Group, The Journal of Clinical Endocrinology & Metabolism, Volume 92, Issue 1, January 2007, Pages 10–25, https://doi.org/10.1210/jc.2006-1374
5. Richard J. Paulson, Michael G. Collins, Vladimir I. Yankov, Progesterone Pharmacokinetics and Pharmacodynamics With 3 Dosages and 2 Regimens of an Effervescent Micronized Progesterone Vaginal Insert, The Journal of Clinical Endocrinology & Metabolism, Volume 99, Issue 11, 1 November 2014, Pages 4241–4249, https://doi.org/10.1210/jc.2013-3937

Reviewed April 2021