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Commentary and Fact Check of Dr. Jerilynn Prior’s 2019 Review on Progesterone for Transfeminine People

By Aly | First published March 23, 2019 | Last modified November 8, 2022

Abstract / TL;DR

In early 2019, a prominent literature review arguing for the use and benefits of progesterone in transfeminine people was published. This review was by Dr. Jerilynn Prior, a Canadian academic and endocrinologist who has cared for transfeminine people in the past and who among other things was responsible for the adoption of spironolactone in transfeminine hormone therapy in the 1980s. Prior based her claims about progesterone in transfeminine people on research from other areas including progesterone in cisgender women. Going through the review however, it is apparent that many of Prior’s claims are poorly supported or obviously incorrect. In relation to this, a letter to the editor by seven researchers, including major figures in transgender medicine, was published in response to Prior’s review and was critical of her claims. The purpose of this article is to serve as a commentary and fact check on some of the problematic claims made in Prior’s review. It is concluded that Prior’s review on progesterone for transfeminine people should be considered with a great deal of caution and skepticism.

Introduction

In January 2019, a literature review on progesterone in transfeminine people was published by a researcher known as Dr. Jerilynn C. Prior (some biography on Prior is provided below):

  • Prior, J. C. (2019). Progesterone is Important for Transwomen’s Therapy—Applying Evidence for the Benefits of Progesterone in Ciswomen. The Journal of Clinical Endocrinology & Metabolism, 104(4), 1181–1186, [DOI:10.1210/jc.2018-01777]

Prior is notable in that she prioneered the use of spironolactone as an antiandrogen in transfeminine people in the 1980s (Prior et al., 1986; Prior et al., 1989). Today, spironolactone is widely used in transfeminine people, especially in the United States. Prior has also been a longtime researcher into and advocate for use of progesterone in hormone therapy for cisgender women.

In her 2019 review, Prior argues that progesterone has many beneficial effects in women and should be used in all transfeminine people. Reading through the review however, it quickly became clear to me that there were a lot of problematic claims in it. Accordingly, a letter to the editor responding to the review (see below), coauthored by seven researchers in the field of transgender medicine—including major and well-known experts like Guy T’Sjoen and Joshua Safer—was published and was critical of her claims.

Some of Prior’s points regarding progesterone are extrapolated from studies on ovulation in cisgender women. I am not well-acquainted with the literature on the health effects of ovulation in cisgender women, so I am unable to speak for what Prior says in this regard. But I am knowledgeable in other areas relevant to the paper, and I can say that a number of her statements stood out to me as clearly erroneous. As evidenced by the letter to the editor responding to her review, other researchers had qualms with her paper as well. I would like to highlight some of the problems with her review in this article so that others can be aware of them and not unknowingly accept incorrect information.

The format of this article is excerpts from the paper in quote blocks followed by my responses.

Progesterone, Feminization, and Breast Development

It is important to add progesterone to estradiol and an antiandrogen in transgender women’s [cross-sex hormone therapy] (CHT)]. Progesterone may add the following: (i) more rapid feminization, […] (iii) optimal breast maturation to Tanner stages 4/5 […]

In my clinical experience, feminization occurred more rapidly with [estradiol (E2)] and antiandrogens plus progesterone than with E2 and antiandrogens alone.

There is also clinical evidence that breast maturation occurs on progesterone in men (7).

Progesterone plus E2 leads to optimal breast maturation and size. Along with elimination of facial and male pattern body hair, one of the important goals of transgender women is to develop mature and physiological breasts (that are classified as Tanner stage 5) (26). However, currently, the majority seeks breast augmentation surgery (3), because [estrogen/estradiol (E/E2)] plus antiandrogen therapy means the areola stays small (≤2.5 cm, ≤1 inch) and masculine, and breasts remain Tanner stage 3 (27). [Progesterone (P4)] is necessary for the ductal branching within the breast (and hence, for lactation) (28) and eventual maturation leading to the enlargement of the normal ciswoman’s areola diameter of ≥3 cm (7). Currently reviewed evidence (29, 30) is inadequate to assess the breast effects of transgender women’s CHT, because breast size, not areolar diameter (the primary difference between Tanner 3 and 5 stages) (26), has so far gone unreported except by one research group (7).

The following excerpt, from a different earlier literature review by Prior, is also applicable (Prior, 2011):

E2 stimulates breast glandular development in puberty (Tanner stages I-III) while P4 (plus E2) is required for final breast maturation to Tanner stages IV-V as the areolar diameter expands and the ductal system and nipple mature (Prior et al., 1989); […]

There is no evidence at present that progesterone is involved in feminization in either cisgender females or transfeminine people (Aly, 2018; Wiki; Wiki). Prior’s clinical experience that she describes is anecdotal and is not admissible as convincing evidence. Likewise, there is no evidence that progesterone is involved in morphological pubertal breast development in cisgender girls or transfeminine people (Aly, 2018; Aly, 2018; Wiki). That is, there is no evidence that progesterone is involved in breast development when it comes to size and shape at any other time besides pregnancy and lactation. As I’ve described elsewhere, cisgender women with complete androgen insensitivity syndrome (CAIS) have negligible levels of progesterone (<1 ng/mL [<3 nmol/L]) yet are perfectly phenotypically female, including having well-developed breasts and even breasts that are reportedly above average in size (Aly, 2020). Hence, progesterone would appear to not be needed for complete feminization nor morphological pubertal breast development.

Checking Prior’s cited source (“(7)”—Prior et al. (1989)) for her claims about progestogens and breast development, the study used medroxyprogesterone acetate, not progesterone, and there was no actual mention of enhanced breast development or movement to Tanner stage 4 or 5 due to progestogens. I emailed Prior about this and other issues and she did not respond (despite responding to an earlier email I sent her asking about her 1986 paper she published, which she declined to provide). Moreover, the cited study was actually her own 1989 publication, and in her response to the letter to the editor to her 2019 review, which also challenged her on this, she claimed the following:

I appreciate that we currently have no systematic assessments of transgender women’s lobular breast maturation as likely reflected by differences in areolar size. A testable hypothesis is that that the areola will enlarge with estrogen-progesterone therapy; we showed this in early photo-documented clinical observations.3

However, Prior observed areolar enlargement with combined estrogen and medroxyprogesterone acetate therapy. She did not compare estrogen alone versus the combination of estrogen and a progestogen. As estrogens are already known to cause areolar enlargement, it is not possible to conclude to what extent estrogen versus the progestogen was involved in the breast changes, and hence there is no way to know whether medroxyprogesterone acetate provided any additional benefit over estrogen alone.

It is notable that it may also be inadvisable for transfeminine people to take progestogens too early into hormone therapy—before approximately Tanner breast stage 4 or 5—as progesterone and other progestogens hypothetically might interfere with normal puberty-type breast development (Aly, 2019).

Oral versus Non-Oral Progesterone

The recent Endocrine Society clinical practice guidelines for “gender dysphoric/gender incongruous persons” advise clinicians to “maintain sex hormone levels within the normal range for the person’s affirmed gender” (1). Every normal, fertile, menstrual cycle in cisgendered women (whose gender identity as women aligns with their female sex assigned at birth) ideally produces progesterone, as well as estradiol (E2). Therefore, rather than being treated with daily E2 and an antiandrogen, as is the current clinical practice, to follow guidelines, we need to prescribe oral micronized progesterone (referred to in this article as progesterone) as an at least cyclic component of treatment of all transgender women (gender dysphoric men to women).

The 300-mg progesterone dose maintains the P4 blood level in the ciswoman’s luteal phase range (the desired goal) for the full 24 hours (38).

Prior advocates for the use of oral micronized progesterone in all transfeminine people. She furthermore claims that 300 mg/day oral progesterone maintains progesterone levels in the range of the normal luteal phase. However, in actuality, oral progesterone has very poor bioavailability, achieves low levels of progesterone that are far below normal luteal phase levels, and has weak progestogenic effects (Aly, 2018; Wiki). Pharmacokinetic findings of high, luteal-phase progesterone levels with oral progesterone have been from studies that used flawed blood-analytic techniques which cross-reacted with high levels of progesterone metabolites formed during the first pass through the intestines and liver. As such, while oral progesterone has been shown to be effective for protecting the endometrium in cisgender women, it is likely to have poor effectiveness as a progestogen in other regards in transfeminine people.

Oral Estradiol, Doses, and Risks

When E or E2 treatments are prescribed for transgender women, I believe it is important to use physiological dose E2, delivered transdermally (either as a gel or patch). […] transdermal E2 carries less increased risk for venous thromboembolism (VTE) (21). Knowing what we now know about risks for VTE in transgender women (5), I believe that E2 should not be given orally.

I also believe that higher E2 doses (arbitrarily, more than double physiological) carry increased risks (note that the mean dose in the large Goodman study was 4 mg of oral E2, where a physiological ciswoman dose is 0.5 to 1.0 mg/d) (5). […] Both oral E/E2 and higher doses are associated with an increased risk of VTE and pulmonary embolism in transgender women (2, 5, 23), and the recent paper also showed increased ischemic stroke (5). These are life-threatening, adverse effects that can be devastating for a transgender woman and therefore, when possible, using transdermal E2 and lower doses, should be avoided.

[Progesterone] may also facilitate transgender women’s acceptance of physiological (rather than high) E2 doses ideally delivered transdermally.

I agree with Prior that non-oral estradiol is preferable to oral estradiol. It seems clear based on available research that oral estradiol poses a much greater risk of blood clots than does transdermal estradiol (Aly, 2020). Aside from issues related to factors like cost, convenience, and acceptability, there is little reason for oral estradiol to be used in transfeminine people over non-oral estradiol.

Prior argues that instead of the doses of oral estradiol commonly used in transfeminine people, for instance 2 to 8 mg/day, much lower doses, in the range of 0.5 to 1 mg/day, should be used. These doses are about 4- to 8-fold lower in comparison. Prior states that lower doses should be used due to unacceptable risks of blood clots and cardiovascular complications with oral estradiol.

However, the absolute risk of blood clots with even high doses of oral estradiol in actuality is very low in most transfeminine people and shows specificity to those with risk factors for blood clots like older age, smoking, obesity, concomitant progestogen use, and others (Aly, 2020). Hence, while oral estradiol does have greater risks than non-oral estradiol, its risk profile is not unacceptable for most transfeminine people. Accordingly, oral estradiol is widely used in both cisgender women and transfeminine people and is considered to be reasonably safe in these populations (e.g., Stuenkel et al., 2015; Hembree et al., 2017; Coleman et al., 2022). In people with risk factors for blood clots and cardiovascular problems with oral estradiol (e.g., age greater than 40 years or known susceptibility to blood clots), non-oral routes, such as transdermal estradiol, can be used instead (Aly, 2020; Coleman et al., 2022).

Contrary to what Prior says, 0.5 to 1.0 mg/day estradiol is not a physiological dosage of oral estradiol, at least for premenopausal cisgender women. This dose range results in very low menopausal-replacement levels of estradiol that would be around 25 pg/mL (92 pmol/L) or less on average (Aly, 2020). For transfeminine people who have undergone surgical gonadal removal, estradiol levels should generally be in the normal physiological range for premenopausal women. This range is about 50 to 200 pg/mL (184–734 pmol/L), with an integrated average across the menstrual cycle of around 100 pg/mL (367 pmol/L) (Aly, 2018). Only doses of oral estradiol of 2 to 8 mg/day are typically able to achieve such levels.

The relatively high oral estradiol doses used in transfeminine people are also not arbitrary, as they are needed to achieve adequate testosterone suppression in transfeminine people. This is critical for achieving maximal demasculinization and feminization, and will be discussed in the next section.

Progesterone and Testosterone Suppression

Progesterone suppresses [luteinizing hormone (LH)] and [testosterone (T)] in men (17), […]

Progesterone feeds back to the hypothalamus slowing the pulsatility of LH and lowering average LH levels (25), thus decreasing gonadal T production. Again, this is an action of P4/progesterone to assist antiandrogen therapy in achieving a feminine shape and secondary sexual characteristics.

For metabolic and antiandrogen effects [to suppress LH and gonadal testosterone (T) and inhibit the conversion of T to dihydro-T (DHT)], I suggest that transgender women’s progesterone be given daily rather than cyclically, […]

Prior says that progesterone suppresses luteinizing hormone and testosterone levels in cisgender men and cites a study to support this claim. But checking her source (“(17)”—Grecu, Weinshelbaum, & Simmons (1990)), the study employed medroxyprogesterone acetate, not progesterone. Prior advocates for the use of oral micronized progesterone (rather than non-oral progesterone or a progestin), yet oral micronized progesterone has been shown to have no effect on testosterone levels in cisgender men even at high doses (400 mg/day) (Goletiani, Keith, & Gorsky, 2007; Tollan et al., 1993; Wiki). Conversely, non-oral routes of progesterone, for instance rectal progesterone and injectable progesterone, produce marked testosterone suppression (Wiki; Aly, 2018). Progestogens alone in general can maximally suppress testosterone levels by about 50 to 70% (Aly, 2019; Wiki). Hence, progesterone and other progestogens can be very useful for testosterone suppression. In the case of progesterone however, this is only if it is taken non-orally—oral progesterone is likely to be ineffective for such purposes.

Given the recent evidence that “low doses” of conjugated equine E (0.625 to 1.25 mg/d), with or without cyproterone acetate, lowered androgen, LH, and follicle-stimulating hormone levels into ciswoman ranges (22), it is not clear why higher E/E2 doses are commonly used for transgender women’s cross-sex hormone therapy (CHT).

The findings of Cunha and colleagues (Cunha et al., 2018) are very surprising and warrant skepticism. The study is contradicted by many other studies on the antigonadotropic effectiveness of estrogens (Wiki). Studies have found that estradiol levels of at least 200 pg/mL (734 pmol/L) on average are typically needed to suppress testosterone levels to 50 ng/dL or less (Wiki). Cunha and colleagues found that 0.625 to 1.25 mg/day oral conjugated estrogens suppressed testosterone levels by 98% (from 732 ng/dL [25.4 nmol/L] to 18 ng/dL [0.62 nmol/L]), while estradiol levels were, surprisingly, unchanged (went from 45 pg/mL [170 pmol/L] to 38 pg/mL [140 pmol/L]) (Cunha et al., 2018):

The estrogen levels before and after cross-sex hormone treatment were not significantly different (p=0.6) (Table 1). […] In our cohort, the estrogen levels before and after cross-sex hormone treatment were not significantly different. The conversion of male levels of T to estrogen before treatment was similar to that achieved by the low-dose estrogen treatment (30).

Other studies have found that a dosage of 7.5 mg/day oral conjugated estrogens is needed to consistently suppress testosterone levels into the castrate range (<50 ng/dL [<1.7 nmol/L]) in cisgender men with prostate cancer (Shearer et al., 1973; Graph; Scott, Menon, & Walsh, 1980). Moreover, oral estradiol at up to 8 mg/day, with or without spironolactone, fails to suppress testosterone levels into the female range in many transfeminine people (Leinung, 2014; Liang et al., 2018; Leinung, Feustel, & Joseph, 2018; Cheung et al., 2018). Estradiol levels with oral estradiol across a dose range of 2 to 8 mg/day are expected to range from about 50 to 200 pg/mL ((184–734 pmol/L)) on average (Aly, 2020). As such, we should be quite skeptical of the findings of Cunha and colleagues. Their results were probably due to flawed blood tests or some other methodological problem—particularly considering the lack of increase in estradiol levels. Ada Cheung and colleagues in a review article that cited the study noted its small sample size (n=8 for oral conjugated estrogens alone) (Angus et al., 2021).

Prior made no mention of the various other recent studies, which clearly show that even high doses of oral estradiol are often insufficient for suppressing testosterone levels into the female range. Moreover, Prior herself found in the 1980s that high doses of oral conjugated estrogens alone were unable to adequately suppress testosterone levels in transfeminine people (Prior et al., 1986; Prior et al., 1989). This difficulty of achieving adequate testosterone suppression with estrogens alone was in fact the reason for Prior’s advocacy of the use of spironolactone in transfeminine people (Prior et al., 1986; Prior et al., 1989) and is why spironolactone and other antiandrogens ultimately became widely adopted for use in transfeminine hormone therapy.

Progesterone and 5α-Reductase Inhibition

[Progesterone] inhibits conversion of T to DHT in men (18), […]

Progesterone competes for the 5-alpha reductase enzyme that converts T into DHT (18), the hormone that masculinizes skin and hair follicles. Thus, progesterone decreases the masculinizing effects of DHT on unwanted male-pattern hair.

It is true that progesterone has been found to act as a 5α-reductase inhibitor in vitro in various studies. However, this action is of very low potency, and is almost certainly clinically insignificant even in the case of pregnancy (i.e., very high) levels of progesterone (Wiki). Only topical progesterone applied to the skin, which achieves very high local concentrations of progesterone in the skin, is likely to have any meaningful inhibitory effects on 5α-reductase. Quality clinical evidence even for that is lacking however.

Progesterone and Health Risks

Progesterone and breast cancer risk. E (E or E2) with MPA increased the risks for breast cell proliferation and breast cancer, but there is increasing evidence that the opposite may occur with progesterone (15, 46). The large French E3N Prospective Cohort Study of menopausal therapy in ciswomen by its component characteristics showed no increased risk for breast cancer in women on E/E2 with progesterone, although the same study showed a significantly elevated risk with ET or EPT (14). The combined evidence suggested that progesterone would protect against the rare risk of breast cancer in transgender women treated with E.

Progesterone and cardiovascular effects. The assumption that progesterone causes adverse cardiovascular effects is primarily because of CVD related to androgenic progestins. However, there are no long-term RCT data on progesterone and cardiovascular effects and no progesterone therapy studies in which the primary outcomes are acute myocardial infarction, stroke, VTE, or heart failure. In part, at least, this is because oral micronized progesterone has only been available for a couple of decades. However, progesterone shows no signal for increased coagulation (21, 24). Progesterone has substantial random-ordered, positive endothelial effects compared with vehicle and E2 (20), but similar results did not reach significance in a 3-month RCT in menopausal ciswomen for which the endothelial function data were underpowered (42). In that same 3-month RCT, progesterone caused no changes in weight, waist circumference, blood pressure, inflammation, coagulation, or lipids (except a substantial but clinically unimportant lowering of high-density lipoprotein cholesterol) (42).

Decades ago, many researchers thought that progestogens might protect against breast cancer similarly to how they protect against estrogen-induced endometrial hyperplasia and endometrial cancer. However, observational studies and the Women’s Health Initiative clinical trials have since shown that progestins are associated with significantly increased risk of breast cancer, as well as with increased risk of blood clots and cardiovascular problems. Conversely, oral progesterone has been associated with no change in the risk of breast cancer and blood clots relative to estrogens alone in observational studies. As a result, many researchers assumed that, for some reason, oral progesterone was different from progestins.

However, there is a problem in that this perception has come from studies that have used oral progesterone. As described above, oral progesterone has major bioavailability issues and weak progestogenic effects (Aly, 2018). Researchers were originally not aware of this. There have been no sufficiently powered studies using non-oral progesterone (e.g., vaginal, injectable) that have shown that progesterone does not in fact have a risk of breast cancer, blood clots, or cardiovascular problems. As a result, assuming that progesterone does not have such risks is premature and non-oral progesterone may actually share similar risks as progestins (Aly, 2018). This notion makes sense considering that both progesterone and progestins share the common action of progesterone receptor agonism and that this action is thought to underly much of the said risks (though not all; androgenic and/or glucocorticoid activities of certain progestins may contribute some to certain risks as well). With that said however, similarly to the case of oral estradiol, the risks are not marked, and apply largely to those with specific risk factors (e.g., old age). Progestins have been widely used in transfeminine people in the form of cyproterone acetate and medroxyprogesterone acetate and are reasonably safe.

Indeed, a large observational study found that long-term (10-year) treatment with oral progesterone was associated with a significantly increased risk of breast cancer, which has been said to be consistent with the low levels of progesterone achieved with oral progesterone having a weak proliferative effect on the breasts that requires a longer period of exposure to manifest as an increase in breast cancer risk (Kuhl & Schneider, 2013; Davey, 2018). Moreover, Prior’s claim that progesterone could decrease breast cancer risk is unfounded based on available clinical research (Aly, 2020).

Language About Transfeminine People

There is also clinical evidence that breast maturation occurs on progesterone in men (7).

The cited source (“(7)”—Prior et al. (1989)), which was Prior’s own study, indicates that the “men” she refers to here were in fact transgender women.

[…] we need to prescribe oral micronized progesterone (referred to in this article as progesterone) as an at least cyclic component of treatment of all transgender women (gender dysphoric men to women).

Gonadal steroids have sex-specific actions (16); thus, the application of data from progesterone actions in women to the care of those who were biological men before they became transgender women requires evidence.

The terminology used by Prior here, such as transgender women having been “gender dysphoric men” or “biological men” before they “became” transgender women, is outdated by modern standards and is likely to be insensitive and even offensive to many transfeminine people. Moreover, an argument cannot be made that transfeminine children who started transition before becoming adults were ever “men”.

Terminology of the sort used by Prior is rarely seen in the literature on transgender health nowadays. I think that clinicians and researchers, including old-fashioned ones like Prior, should discard the terminology of the past and become fully competent in more modern and appropriate language. Much as how Prior previously referred to us as “male-to-female transsexuals” or “men” regardless of our transition status (Prior et al., 1986; Prior et al., 1989; Basson & Prior, 1998)—but now no longer does so and instead (usually) refers to us as “transgender women”—she should adapt here as well.

Additional Comments

The letter to the editor in response to Prior’s paper also challenged her claims that progesterone has beneficial effects on breast development, bone mineral density, breast cancer risk, and cardiovascular risk (see below). They criticized Prior’s extrapolation from clinical experience, preclinical research, and findings in cisgender women, calling instead for evidence-based recommendations based on rigorous and well-designed clinical studies in transfeminine people. They described Prior’s conclusions as “premature and potentially dangerous”. In her response, Prior claimed that they were conflating progesterone with progestins. This certainly may be true. But, as I described above, it may for the most part actually not be inappropriate to treat progesterone and progestins as a combined group, at least when the form of progesterone is not oral progesterone.

I should note that I am not opposed to the use of progesterone in transfeminine people. Non-oral progesterone and progestins are very useful for suppressing testosterone levels in transfeminine people (Aly, 2018; Aly, 2019; Wiki). And, as pointed out by Maddie Deutsch—the editor of the University of California, San Francisco transgender health guidelines—the risks of progestogens are likely to be small in transfeminine people (Deutsch, 2016). While there are no certain benefits of progestogens aside from testosterone suppression, I think that if people want to, they should be able to try progesterone and other progestogens. Cisgender women have progesterone in their bodies, so it’s hard to make a case that transfeminine people absolutely should never have it in theirs. This is especially true considering that progestogens are widely used in transfeminine people—and notably at very high doses—in the form of the antiandrogen cyproterone acetate, which is a strong progestogen (Aly, 2018).

On the issue of Prior and her review, I am simply interested in scientific accuracy and rigor, which I feel that her review falls quite short on. Moreover, I want to mention that my critique here is not comprehensive; I’ve largely only spoken on the issues that I’m familiar with and that particularly stood out to me. As touched on by the letter to the editor, there are also other problems with her review.

The following excerpt, from the letter to the editor, was also notable:

We await the World Professional Association for Transgender Health’s commissioned systematic review on progesterone use for the upcoming Standards of Care, 8th Version. We propose that RCTs, as advocated in the 2017 Endocrine Society Clinical Practice Guidelines(8), investigate the addition of P4 to current GAHT regimens and the risks/benefits of GAHT in older trans women.

In September 2022, the World Professional Association for Transgender Health (WPATH) Standards of Care for the Health of Transgender and Gender Diverse People Version 8 (SOC8) were finally published after many years of work (Coleman et al., 2022). They found that there is no reliable evidence at present to support the use or benefits of progesterone in transfeminine people:

GAHT with feminine embodiment goals typically consists of estrogen and an androgen-lowering medication (Hembree et al., 2017). Although there are anecdotal reports of progesterone use for breast development and mood management, there is currently insufficient evidence the potential benefits of progesterone administration outweigh the potential risks (Iwamoto, T’Sjoen et al., 2019).

With the exception of cyproterone acetate (note this is not approved for use in the US because of concerns of potential hepatotoxicity), the use of progestins in hormone therapy regimens remains controversial. To date, there have been no quality studies evaluating the role of progesterones in hormone therapy for transgender patients.

We are aware some practitioners who prescribe progestins, including micronized progesterone, are under the impression there may be improvements in breast and/or areolar development, mood, libido, and overall shape for those seeking it along with other benefits yet to be demonstrated (Deutsch, 2016a; Wierckx, van Caenegem et al., 2014). However, these improvements remain anecdotal, and there are no quality data to support such progestin use. An attempted systematic review we commissioned for this version of the SOC failed to identify enough data to make a recommendation in favor of any progestins. Instead, existing data suggest harm is associated with extended progestin exposure (Safer, 2021).

For cisgender women who have a uterus, progestins in combination with estrogens are necessary to avoid the endometrial cancer risk associated with the administration of unopposed estrogen. For cisgender women who do not have a uterus, progestins are not used. The best data for the concerns related to progestin use come from comparisons between the above two cisgender populations, which we acknowledge is not necessarily generalizable to this population. Although not definitive of a class effect for all progestins, medroxyprogesterone added to combined equine estrogens is associated with greater breast cancer and cardiac risks (Chlebowski 2020; Manson, 2013). It is important to note data from the Women’s Health Initiative (WHI) studies may not be generalizable to transgender populations. Compared with the cisgender women in the studies, transgender populations seeking hormone therapy tend to be younger, do not use equine estrogen, and hormone therapy in these cases address current mental health and quality of life and not solely risk prevention (Deutsch, 2016a).

Potential adverse effects of progestins include weight gain, depression, and lipid changes. Micronized progesterone may be better tolerated and may have a more favorable impact on the lipid profile than medroxyprogesterone (Fitzpatrick et al., 2000). When paired with estrogens for transgender women, the progestin cyproterone acetate is associated with elevated prolactin, decreased HDL cholesterol, and rare meningiomas—none of which are seen when estrogens are paired with GnRH agonists or spironolactone (Bisson, 2018; Borghei-Razavi, 2014; Defreyne, Nota et al., 2017; Sofer et al., 2020).

Thus, data to date do not include quality evidence supporting a benefit of progestin therapy for transgender women. However, the literature does suggest a potential harm of some progestins, at least in the setting of multi-year exposure. If, after a discussion of the risks and benefits of progesterone treatment, there is a collaborative decision to begin a trial of progesterone therapy, the prescriber should evaluate the patient within a year to review the patient’s response to this treatment.

The systematic review of progestogens in transfeminine people was subsequently published as follows:

  • Patel, K. T., Adeel, S., Miragaya, J. R., & Tangpricha, V. (2022). Progestogen Use in Gender Affirming Hormone Therapy: A Systematic Review. Endocrine Practice, advance online publication. [DOI:10.1016/j.eprac.2022.08.012]

Letter to the Editor and Response

Here is the letter to the editor in opposition to Prior’s review on progesterone for transfeminine people:

  • Iwamoto, S. J., T’Sjoen, G., Safer, J. D., Davidge-Pitts, C. J., Wierman, M. E., Glodowski, M. B., & Rothman, M. S. (2019). Letter to the Editor: “Progesterone is Important for Transwomen’s Therapy—Applying Evidence for the Benefits of Progesterone in Ciswomen”, The Journal of Clinical Endocrinology & Metabolism, 104(8), 3127–3128. [DOI:10.1210/jc.2019-00249]

Prior replied to the letter to the editor in the following response:

  • Prior, J. C. (2019). Response to Letter to the Editor: “Progesterone is Important for Transwomen’s Therapy—Applying Evidence for the Benefits of Progesterone in Ciswomen”, The Journal of Clinical Endocrinology & Metabolism, 104(8), 3129–3130. [DOI:10.1210/jc.2019-00524]

Background of Dr. Jerilynn Prior

Some biography on Dr. Jerilynn C. Prior can be found here at her center’s website and here on Wikipedia. She is a professor of endocrinology and metabolism at the University of British Columbia in Vancouver, British Columbia, Canada. She has studied and published in the field of reproductive endocrinology, especially in the area of progesterone, since the 1980s.

Prior worked at the Vancouver Gender Clinic in the 1980s and was responsible for the 1986 and 1989 publications that led to the use of spironolactone in transfeminine people. Before that, cyproterone acetate was not available in Canada or the United States and antiandrogens in general were not yet commonly used in transfeminine people. Instead, high-dose estrogen therapy with oral estrogens like conjugated estrogens and ethinylestradiol, alone or in combination with progestogens like medroxyprogesterone acetate and hydroxyprogesterone caproate, was mainly used in transfeminine people. Prior’s publications reported that spironolactone could decrease testosterone levels in transfeminine people and reduce needed doses of estrogens (Prior et al., 1986; Prior et al., 1989).

However, as other researchers have since pointed out (Leinung, Feustel, & Joseph, 2018), Prior’s study was confounded because of the concomitant use of medroxyprogesterone acetate, which has antigonadotropic effects and reduces testosterone levels all on its own (Aly, 2018). In actuality, on the basis of dozens of studies, spironolactone does not appear to consistently decrease testosterone levels in cisgender men or transfeminine people (Aly, 2018), nor does it do so in cisgender women (Aly, 2020). In any case, owing to its activity as a direct antagonist of the androgen receptor, spironolactone is still an effective antiandrogen regardless of whether or not it lowers testosterone levels.

Publications

Books

Prior co-wrote the following notable book (as well as a few others which can be browsed here or here):

Papers and Book Chapters

Prior has written the following notable papers and book chapters, among many others (Google Scholar):

  • Basson, R., & Prior, J. C. (1998). Hormonal Therapy of Gender Dysphoria: The Male-to-Female Transsexual. In Denny, D. (Ed.). Concepts in Transgender Identity (Garland Gay and Lesbian Studies, Volume 11) (pp. 277–296). New York: Garland Publishing Inc. [Google Scholar] [Google Books] [PDF]
  • Prior, J. C., & Elliott, S. (1998). Hormonal Therapy of Gender Dysphoria: The Female-to-Male Transsexual. In Denny, D. (Ed.). Concepts in Transgender Identity (Garland Gay and Lesbian Studies, Volume 11) (pp. 297–313). New York: Garland Publishing Inc. [Google Scholar] [Google Books] [PDF]
  • Prior, J. C. (2008–2010). Preventive Powers of Ovulation and Progesterone. Centre for Menstrual Cycle and Ovulation Research (CeMCOR). [Google Scholar] [PDF]
  • Prior, J. C. (2011). Progesterone for Symptomatic Perimenopause Treatment—Progesterone Politics, Physiology and Potential for Perimenopause. Facts, Views & Vision in ObGyn, 3(2), 109–120. [PubMed] [PubMed Central]
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