Progesterone for Feminising Hormone Therapy

Summary

  • What is Progesterone? Progesterone is a hormone that everyone’s body makes. It plays a part in periods, pregnancy, and breast growth. It can also help transgender women in their transition, especially for breast growth and lowering testosterone.
  • Benefits: Progesterone can help transgender women get better breast growth, lower testosterone, and improve overall health. Recent studies show it’s helpful when added to estrogen therapy.
  • Types of Progesterone: There are two kinds – synthetic (made in labs) and bioidentical (more like what the body makes naturally). The natural type is safer.
  • Blood Clot Risk: There’s a worry about blood clots, especially with synthetic types. But the natural type seems safer and doesn’t seem to increase this risk. Trans women should still watch out for other clot risks like smoking or high blood pressure.
  • Breast Cancer Risk: Synthetic hormone mixes can raise breast cancer risk, but the natural progesterone seems safer. Trans women have a slightly different breast cancer risk compared to other groups, so regular check-ups are good.
  • How Much to Take: More than 100mg a day might be needed for good results. Studies are trying to find the best dose.
  • In Short: Adding natural progesterone to hormone therapy seems to help and doesn’t add much risk. It’s part of a safe treatment plan for transgender women who want it.

What is progesterone?

Progesterone is a hormone that is produced by the gonads and the adrenal glands. Although progesterone is sometimes assumed to be a “female” hormone, it is actually produced by people of all sexes in varying amounts.

In people who have ovaries and uteruses, progesterone is involved in maintaining the womb lining in the second half of the menstrual cycle, so that it can support implantation of an embryo if fertilisation has occurred. During pregnancy, progesterone is produced by the placenta to support the development of the foetus. Progesterone also has a role in breast development in late puberty.

It has been suggested that progesterone could have a role in feminising hormone treatment for trans women and transfeminine people, because it could theoretically promote breast development, suppress testosterone production, and support other aspects of general health (Prior, 2019). Exogenous progesterone comes in two main forms, which are synthetic progestin (medroxyprogesterone acetate) and bioidentical progesterone (Utrogestan® and Cyclogest®). As discussed below, bioidentical progesterone tends to be associated with fewer health risks than synthetic progestin.

A Sex Hormone for Routine Consideration in Transfeminine Therapy

Progesterone is a sex hormone produced by the body, plays a crucial role in various physiological processes, including menstrual cycles, pregnancy, and breast development. Its significance extends to the realm of feminizing hormone therapy, particularly for transgender women and transfeminine individuals.

Recent medical insights suggest that incorporating progesterone as a routine component of hormone therapy for transfeminine people of all ages could offer substantial benefits. This approach is grounded in the hormone’s natural presence in the body and its integral role in developmental processes. For transfeminine individuals, progesterone can be particularly effective in enhancing breast development and contributing to more comprehensive feminization.

The suggestion to standardise the inclusion of progesterone in feminizing hormone regimens aligns with a broader understanding of gender-affirming care. It recognises the diversity of needs among the transfeminine population and emphasises the importance of tailored treatments that reflect the natural hormonal balance of the body. By considering progesterone as a routine element of therapy, healthcare providers can offer a more holistic and effective approach to transgender healthcare, one that respects and responds to the complexities of each individual’s transition journey.

In summary, the role of progesterone in feminising hormone therapy is increasingly acknowledged as essential, not just for its physical effects but also for its alignment with the body’s natural hormonal processes. As research and clinical experience in this area continue to evolve, the inclusion of progesterone is likely to become a standard recommendation, offering transfeminine individuals of all ages a more effective and natural pathway in their transition.

What are the benefits of progesterone?

Based on the knowledge of the effects of progesterone in cis women, it has been proposed that progesterone could theoretically benefit trans women by promoting breast development, suppressing testosterone production, supporting bone health, supporting cardiovascular health, and improving sleep (Prior, 2019). Studies on postmenopausal cis women have shown that progesterone decreases hot flashes and night sweats (Hitchcock et al., 2012).

Until recently, the empirical evidence for the benefits of progesterone for trans women was largely anecdotal, as no clinical studies had been undertaken on the use of progesterone as part of feminising hormone treatment. However, this is changing, as clinical studies are now being undertaken to test the benefits of progesterone in the trans population.

A recent cohort study compared 29 trans women who were taking progesterone in addition to oestrogen with 59 trans women who were taking oestrogen on its own (Bahr et al., 2023). In the study, the trans women who were taking progesterone reported significantly greater improvements with breast development, testosterone suppression, and mental health at six and nine months after the initiation of treatment.

At present, a randomised controlled trial is being undertaken to further examine the effects of adding progesterone to feminising hormone treatment (Dijkman et al., 2023).

Does progesterone influence the risk of thromboembolic disease?

Thromboembolic disease refers to blood clots in the arteries or veins and includes cardiovascular disease, stroke, deep vein thrombosis, and pulmonary embolism. Traditionally, a personal history of thromboembolic disease was considered a relative contraindication to the addition of progesterone to feminising hormone treatment. Research suggests that trans women who are receiving feminising hormone treatment have a higher lifetime risk of thromboembolic disease than the general population (Getahun et al., 2018; Streed et al., 2017). Research also suggests that cis women who are taking combined oral contraceptives that contain synthetic progestin have an increased lifetime risk of thromboembolic disease (Vinogradova et al., 2015).

However, such a risk may not be associated with bioidentical progesterone. Evidence on the effect of bioidentical progesterone in trans women is scarce. However, research on cis women who were receiving hormone replacement therapy has shown that while synthetic progestin was associated with an increased risk of thromboembolic disease, bioidentical progesterone was not associated with any increased risk of thromboembolic disease (Scarabin, 2018). Furthermore, there is evidence that progesterone exposure in cis women does not induce the mechanisms associated with thromboembolic disease.

In summary, while feminising hormone treatment with oestrogen is associated with an increased lifetime risk of thromboembolic disease, there is no evidence that the addition of bioidentical progesterone increases this risk of thromboembolic disease any further. The recommendations for the use of progesterone in feminising hormone treatment are: (1) to use bioidentical progesterone and not synthetic progestin; and (2) to recommend that people who are taking feminising hormones undertake measures to address other risk factors for thromboembolic disease, such as smoking, high cholesterol, hypertension, diabetes, and inactivity.

Does progesterone influence the risk of breast cancer?

While synthetic progestin and oestrogen have been associated with an increased lifetime risk of breast cancer, there is no evidence that bioidentical progesterone in combination with oestrogen is associated with increased breast cancer risk compared to oestrogen on its own.

A recent cohort study showed that trans women who are receiving feminising hormone treatment have a lifetime risk of breast cancer that is higher than the lifetime risk for cis men but lower than the lifetime risk for cis women (de Blok et al., 2019). For reference, the lifetime risk for cis women is approximately 12%, while the lifetime risk for cis men is approximately 0.1% (Sonnenblick et al., 2018). However, the study did not establish whether progesterone specifically influences this risk.

Several prospective studies on postmenopausal cis women have suggested that hormone replacement therapy is associated with an increased risk of breast cancer, especially in women who are taking progestin in addition to oestrogen (Beral, 2003; Colditz et al., 1995; Rossouw et al., 2002). However, the applicability of these results to gender affirming healthcare may be limited for the following two reasons.

First, the aforementioned studies were conducted on postmenopausal cis women who were receiving hormone replacement therapy, not on trans women who are receiving feminising hormone treatment. Hence, the results from these studies on the cis population may not be straightforwardly generalisable to the trans population.

Second, the aforementioned studies found that synthetic progestin, such as medroxyprogesterone acetate, was associated with an increased risk of breast cancer when combined with oestrogen. However, there is no evidence that bioidentical progesterone is associated with such a risk. Some studies on hormone replacement therapy in postmenopausal cis women have shown that bioidentical progesterone is associated with a significantly lower risk of breast cancer than synthetic progestin (Asi et al., 2016; Fournier et al., 2008).

Some research on trans women who developed breast cancer has shown that most of the tumours were positive for oestrogen and progesterone receptors (de Blok et al., 2019). Therefore, it is recommended that oestrogen and progesterone are not prescribed for people with active breast cancer, as there is a likelihood that the cancer will be sensitive to oestrogen and progesterone.

In summary, while feminising hormone treatment with oestrogen is associated with an increased lifetime risk of breast cancer, there is no evidence that bioidentical progesterone increases this risk of breast cancer any further. The recommendations for the use of progesterone in feminising hormone treatment are: (1) to use bioidentical progesterone and not synthetic progestin; (2) to recommend that people who are taking feminising hormones attend a routine breast cancer screening programme; and (3) to avoid the use of oestrogen and progesterone in people with active breast cancer.

What forms of progesterone are available?

Bioidentical progesterone is available as an oral tablet, an anal suppository, or a vaginal pessary. A common brand of progesterone that is available as an oral tablet is Utrogestan®. A common brand of progesterone that is available as an anal suppository or vaginal pessary is Cyclogest®. As noted above, bioidentical progesterone is recommended over synthetic progestin in feminising hormone treatment, because it has fewer medical risks.

Medroxyprogesterone acetate is a synthetic progestin, which is available as an oral tablet (Provera®) or as a depot injection (Depo-Provera®). It is commonly used as a contraceptive in people with ovaries and uteruses. As noted above, it is not usually recommended in feminising hormone treatment, because it has greater medical risks associated with it than bioidentical progesterone.

What dose of progesterone is effective?

In postmenopausal cis women, a progesterone dose of 300mg at night was effective at improving sleep and decreasing hot flashes (Hitchcock et al., 2012). However, this may not be straightforwardly applicable to the use of progesterone in trans women for the purpose of gender affirming hormone treatment.

A recent case-control study on trans women who were receiving feminising hormone treatment found that progesterone at a dose of 100mg daily was not associated with increased breast development after three months of treatment (Nolan et al., 2022). However, other research has contradicted this finding. A cohort study which assessed participants over a longer period of time found that taking progesterone at a dose of 100mg daily was associated with improved satisfaction with breast development after six and nine months of treatment (Bahr et al., 2003). This suggests that doses of 100mg daily and higher may be sufficient to produce beneficial effects, but that the effects may take at least six months to become apparent.

In clinical practice, doses of progesterone in gender affirming medical treatment usually do not exceed 200mg daily and there is little data on the safety or effectiveness of doses beyond 200mg daily. A current randomised controlled trial is testing progesterone doses of 200mg to 400mg daily (Dijkman et al., 2023). However, until the results of that trial become available, it would be prudent not to exceed 200mg daily due to a lack of sufficient evidence of the effects of doses beyond that.

Should I cycle my progesterone?

In people with ovaries who produce endogenous progesterone, progesterone levels tend to be low in the first half of the menstrual cycle (the follicular phase) and tend to be high in the second half of the menstrual cycle (the luteal phase). Some trans women cycle their progesterone doses so that the levels in the blood resemble the levels seen throughout the menstrual cycle. For example, they may take progesterone for two weeks, stop for two weeks, take it again for two weeks, and so on.

However, at present, there is no evidence that cycling progesterone doses has any benefits for feminising hormone treatment compared to taking progesterone continuously. Hence, there are no general recommendations for whether you ought to cycle progesterone or whether you ought to take progesterone continuously. It is a matter of finding what works best for you.

How long should I take progesterone for?

Progesterone is used in transgender hormone therapy to help promote breast development and achieve other feminizing effects, and the duration of progesterone therapy as part of feminization varies depending on individual medical needs and goals. Some people use it for a short time and others as a routine, long-term part of their hormone replacement. However, as noted above, evidence suggests that the benefits of progesterone for breast development may take six months or more to become apparent (Bahr et al., 2003).

Can I take progesterone if I have liver disease?

It is generally not recommended to use synthetic progesterone in people with impaired hepatic function or liver disease. However, using bioidentical progesterone as a replacement therapy, meaning that the hormones in these products have the same molecular structure as those in the human body, theoretically giving the same risk as a cisgender woman. Therefore, the progesterone’s impact on the liver is minimal. Progesterone pessaries avoid liver metabolisation and may be a better option if you are concerned.

Conclusion

There is increasing evidence that adding progesterone has benefits for trans women with regards to the outcomes of their feminising hormone treatment. While feminising hormone treatment with oestrogen is associated with increased lifetime risks of thromboembolic disease and breast cancer, there is no evidence that adding bioidentical progesterone increases these risks any further. Also, the health risks that are associated with synthetic progestin do not appear to be associated with bioidentical progesterone. Doses of 100mg to 200mg daily may be recommended in order to achieve the beneficial effects of bioidentical progesterone.

Given the benefits associated with progesterone and the relatively low risk associated with bioidentical progesterone, the above supports the addition of bioidentical progesterone to feminising hormone treatment for trans women and transfeminine people who request it.

References

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Updated on April 24, 2024

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