Anecdotal and proven uses for Progesterone for Transfeminine HRT

Enbyous Analog

Recently I started Progesterone, specifically 100mg “bio identical” Oral Micronized taken as suppository (hole poked in the capsule with a safety pin, run under water for a second to soften, then insert with a little lubricant for priming).

Without doing a lot of research I noticed some things simply based on the effects I felt immediately and the next day:

  • Within 30 minutes I felt kind of dizzy, fuzzy, and tired
  • While feeling the effects I noticed my muscles became more relaxed and I arched my back without feeling the usual pain from tension
  • I did not have great sleep and only slept around 5 hours; it was mildly stimulating in spite of also feeling tired, my brain felt awake
  • The next day I woke up with my breasts very swollen and tender
  • Strangely I could feel my scalp more and in particular some areas with less terminal hair felt kind of tingly near the front of my scalp
  • I felt fuzzy for half of the next day and it took a while to sharpen up and be productive
  • Overall I felt less passive tension in my muscles
  • I felt hornier than usual and masturbated twice the day after first dose; however, longer term it’s possible my libido has decreased
  • I felt a little more positive in the morning; though this largely faded by afternoon

At the time of this writing I have taken Progesterone for about a week. The effects have been similar each time, but I noted not feeling as dizzy/fuzzy the longer I have consistently taken it. I have also experienced an increase in dysphoria, but it’s hard to say if it’s from using Testosterone cream on my genitals a couple weeks ago, life events, or from the Progesterone specifically.

Other effects I have noticed within a short time – fuller thighs – possibly due to water retention; and more hip pain than usual while trying to sleep – possibly from relaxation of muscle or connective tissues? Also I may be experiencing some edginess more than usual.

My personal choice for dosage and timing

I started with 100mg oral micronized progesterone because I don’t want to potentially stunt breast development, but had a nagging feeling that my breasts needed some progesterone for roundness and some enhanced ductal branching. I have no reference for this other than cis women can have progesterone effects around breast tanner stage 3. My breasts may or may not have been stunted, but to me they feel stunted. Ultimately the nuance of timing is up to you (or your doctor if they are not open to your feedback); since no one really knows the answer as to the “absolute” effects of progesterone on breast development.

Progesterone essentially doesn’t appear during puberty until ovulatory menstrual cycles begin. Menarche, the onset of menstruation and hence menstrual cycling, occurs on average at Tanner breast stage 4, although it occurs at Tanner breast stage 3 or Tanner breast stage 5 (complete breast development) in significant subsets of girls (Marshall & Tanner, 1969; Hillard, 2007). Tanner breast stage 4 is on average about 2.5 years into breast development, while breast development as a whole takes on average about 3.5 years. Hence, the appearance of progesterone in normal female puberty is a relatively late event

https://doi.org/10.1007/978-1-4684-2622-9_6

Since I am still only about a week into progesterone therapy (at the time of this writing), I am unwilling to draw any conclusions about my treatment goals, cycling, or dosage changes. In my experience, many people seem to have difficulty reading their own hormone levels, fluctuations, and physiological changes. I tend to be very sensitive to the effects of drugs and generally isolate those effects and titrate dosage based upon the effects from mental and physical observations and tracking changes; as well as feedback from others about mood changes, etc. Additionally because I have ADHD, I often have paradoxical reactions to drugs; for example stimulants make me tired and depressants keep me awake.

I would always recommend anyone keep a log of changes they notice from medication, and maintain awareness about how they feel during and after the effects of medications. Most of the time your doctor will prescribe you whatever the manufacturer recommends. Those recommendations are based on some clinical trials; however, the reality is that the information from clinical trials can be guided and p-hacking can occur; additionally there can be bias and conflicts of interest between pharmaceutical stake holders and approval committees. The hard reality is that doctors mostly do what they are told and their liability is dependent on that fact; they have your best interest in mind, but ultimately you need to listen to your own body about the response to medication and whether or not that response is acceptable to you.

I am not advocating that you stop listening to your doctor or the dosage recommendations from manufacturers; but rather that you listen to your body – you are the only one who can.

The following citations are intended to loosely guide you through the known effects of progesterone, as well as anecdotes from real people, and some loose dosage guides. This article is not intended to be authoritative, but rather informative. Your authoritative guide for dosage and application is going to be your doctor, lab results, or your own best judgement if you are a DIYer (do it yourselfer).

1) In particular the tingly feeling on my scalp made me wonder if Progesterone has an effect on hair terminalization… as it turns out it does:

3.2.2. Progesterone
Progesterone can influence hair follicle growth through central and local action. Central action is referred to as the inhibitory effect on LH secretion, which in turn causes a decrease in ovarian theca cell stimulation (androgen synthesis). At the level of the hair follicle, progesterone decreases the conversion of testosterone to dihydrotestosterone (through the inhibition of 5-alpha reductase activity) [13].

4.2. Pregnancy

During pregnancy, the teloptosis phase is delayed and the number of shedding hairs is reduced. Moreover, the diameter of scalp hair increases during pregnancy [62]. This phenomenon is usually attributed to the effect of high levels of estrogen during gestation [62]. However, the complex changes seen in pregnancy (including increases in human chorionic gonadotropin, progesterone, prolactin, numerous growth factors, and cytokines) may well contribute to the increase in the rate of hair growth, in the hair diameter, and in the anagen/telogen ratio observed in pregnant women [63,64,65]. Hormonal changes due to gestation may cause some new terminal hair growth mainly at the abdomen, the lower back, and the thighs [66]. Sudden and severe hirsutism and/or acne during pregnancy may be a symptom of malignant ovarian or adrenal conditions, such as luteomas or Cushing’s syndrome [67,68,69].

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432488/#:~:text=2.-,Progesterone,cell%20stimulation%20(androgen%20synthesis).

2) Progesterone bone and cardiovascular effects

Evidence Synthesis
It is important to add progesterone to estradiol and an antiandrogen in transgender women’s CHT. Progesterone may add the following: (i) more rapid feminization, (ii) decreased endogenous testosterone production, (iii) optimal breast maturation to Tanner stages 4/5, (iv) increased bone formation, (v) improved sleep and vasomotor symptom control, and (vi) cardiovascular health benefits.

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. In general, that evidence is available, although sometimes from data using MPA, which usually acts through the P4 receptor (PR). Progesterone suppresses LH and T in men (17), it inhibits conversion of T to DHT in men (18), it has bone formation-stimulating effects and increases areal bone mineral density (BMD) in men (17), and it also improves sleep based on a randomized controlled trial (RCT) in men (19). There is also clinical evidence that breast maturation occurs on progesterone in men (7). As the fundamental endothelial system appears similar in men and women, progesterone likely will improve the cardiovascular system as well (20).

https://academic.oup.com/jcem/article/104/4/1181/5270376

3) Progesterone and breast development

Progesterone definitely makes my breasts swell significantly… within a few days I have gone up perhaps 1/2 cup size or more. The question is whether these changes are temporary and what exactly is the definition of temporary? For example, Estradiol will “temporarily” make breasts swell and cause breast tissue development while taking it… Testosterone will suppress breast development and reduce size, etc. if you add or remove these, breasts are affected dramatically – does this mean they are “temporary”? If you take progesterone for years and then stop, your breasts will perhaps reduce in size – is this temporary if the time scale is in years?

Regardless the same article cited above has more information about the topic of breast effects.

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 E/E2 plus antiandrogen therapy means the areola stays small (≤2.5 cm, ≤1 inch) and masculine, and breasts remain Tanner stage 3 (27). 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 areolar size changes in puberty and during development of ovulatory menstrual cycles, as well as in transgender women on CHT, require further study.

https://academic.oup.com/jcem/article/104/4/1181/5270376

4) Progesterone effects on the nervous system

Some progesterone is synthesized within both the central and the peripheral nervous systems, where it regulates neurotransmission and important glial functions, such as the formation of myelin. Progesterone can thus be designated a “neurosteroid.” 2. Steroids act not only on the brain, but also on peripheral nerves, which offer many advantages to study the biological significance of locally produced neurosteroids: their remarkable plasticity and regenerative capacity and their relatively simple structure. 3. By using the regenerating mouse sciatic nerve as a model, we have shown that progesterone synthesized by rat Schwann cells promotes the formation of new myelin sheaths. Progesterone also increases the number of myelinated axons when added at a low concentration to cocultures of Schwann cells and sensory neurons. 4. These findings show a function on myelination for locally produced progesterone and suggest a new pharmacological approach of myelin repair.

https://pubmed.ncbi.nlm.nih.gov/8743966/#:~:text=Progesterone%20can%20thus%20be%20designated,and%20their%20relatively%20simple%20structure.

5) Progesterone effects on the brain

Emerging data indicate that progesterone has multiple non-reproductive functions in the central nervous system to regulate cognition, mood, inflammation, mitochondrial function, neurogenesis and regeneration, myelination and recovery from traumatic brain injury. Progesterone-regulated neural responses are mediated by an array of progesterone receptors (PR) that include the classic nuclear PRA and PRB receptors and splice variants of each, the seven transmembrane domain 7TMPRbeta and the membrane-associated 25-Dx PR (PGRMC1). These PRs induce classic regulation of gene expression while also transducing signaling cascades that originate at the cell membrane and ultimately activate transcription factors. Remarkably, PRs are broadly expressed throughout the brain and can be detected in every neural cell type. The distribution of PRs beyond hypothalamic borders, suggests a much broader role of progesterone in regulating neural function. Despite the large body of evidence regarding progesterone regulation of reproductive behaviors and estrogen-inducible responses as well as effects of progesterone metabolite neurosteroids, much remains to be discovered regarding the functional outcomes resulting from activation of the complex array of PRs in brain by gonadally and/or glial derived progesterone. Moreover, the impact of clinically used progestogens and developing selective PR modulators for targeted outcomes in brain is a critical avenue of investigation as the non-reproductive functions of PRs have far-reaching implications for hormone therapy to maintain neurological health and function throughout menopausal aging.

https://pubmed.ncbi.nlm.nih.gov/18374402/#:~:text=Emerging%20data%20indicate%20that%20progesterone,recovery%20from%20traumatic%20brain%20injury.

6) Progesterone effects on sexual desire

Most studies indicate a decrease in sexual desire when progesterone is applied; however, due to effects on the brain in the context of reduced stress and anxiety, sexual desire can increase for some people. This becomes largely anecdotal because it varies person to person.

Taken together, there appears to be little or no evidence that progesterone or other progestogens improve sexual desire or function in humans. Instead, the available evidence suggests that progestogens are likely to result in either unchanged or decreased sexual desire and function. Decreased sexual desire/function may be especially likely at high doses. In any case, more research on progestogens and sexual desire, particularly with non-oral progesterone, is warranted.

https://transfemscience.org/articles/progestogens-sexual-desire/

7) Progesterone effects on mood

Compared with studies performed in the 1800s and to some extent the 1940s and 1950s, recent trials of reproductive endocrine therapies in mood disorders in women have employed more selective pharmacologic compounds, more rigorous study designs, and in some studies more homogeneous patient samples. Despite improved methodologies, the effects of gonadal steroids on mood regulation remain inconsistently demonstrated. However, there are compelling data supporting a role for gonadal steroids (and reproductive endocrine modulators) in the treatment of depression in women. Future studies should be directed to better identify both the clinical predictors and the physiological mechanisms of the psychotropic efficacy of reproductive therapies.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3181679/

8) Scientific evidence that Progesterone is not a requirement of Transfeminine HRT

I want to clarify why I think the “science” of Progesterone not being a requirement for HRT is short sighted.

a) Cis women run on Progesterone and the goal of transfeminine people is to have a feminine physiological experience. It’s a poor argument to say you can’t see a significant effect externally and claim that invalidates a hormone that women naturally run on.

b) “Women with androgen insensitivity have full breasts, so trans women don’t need progesterone” is missing an obvious fact: trans feminine/women are not androgen insensitive. This is not an apples to apples comparison.

c) Anecdotally some people with certain genetic aptitudes find important and crucial benefits from progesterone. Just like with Estradiol, different people respond differently. This doesn’t mean that people who don’t respond substantially automatically invalidate the people who do respond sunstantially.

d) Science, especially in minority/intersectional problem spaces without sufficient resources for long term/high population studies; often overlooks basic logic when making comparisons. If something works for 1 person, then it works for 1 person. You can say it doesn’t work for 99 people out of 100 and that means the 1 person who benefited is invalid as a data point – what works is what works. People are different, and different things work for different people. There’s a reason personalized medicine is a growing interest: people need personalized medicine to have optimum results, because the nuance of genetic and developmental expression is complex in terms of physiological efficacy of treatment.

There are findings suggesting that progesterone is dispensable for pubertal breast development. One is that women with complete androgen insensitivity syndrome, who have no progesterone, have excellent and full breast development (Aly W., 2020). Another is that, as mentioned above, a significant portion of girls reach Tanner breast stage 5 (complete breast development) before experiencing menarche. There is some more discussion on this topic, including other relevant findings, here on Wikipedia. We don’t know for certain whether progesterone is involved in pubertal breast development or not due to a lack of studies, but what we do know isn’t promising in terms of a potential role of progesterone. There is also theoretical concern that premature introduction of progestogens might have an adverse effect on final breast development, although more research is needed to confirm this possibility (Aly W., 2019). Moreover, it may only apply to high doses of progestogens (Aly W., 2019).

https://transfemscience.org/articles/p4-breast-dev-puberty/

9) Anecdotal findings of the effects of Progesterone therapy

I already listed my own limited experience from using Progesterone for about a week. I wanted to list some things people have reported on Reddit:

10) Why progesterone taken as a suppository is ideal (up your butt)

A lot of people don’t understand why “boofing” is a thing. Pretty much your entire GI tract is a closed system of blood separate from your regular bloodstream. This is a good design, because if you eat some poison, your liver gets at least one crack at it before it makes it to your heart lungs and brain.

However, the very end of the rectum, the distal 1/3 drains to systemic circulation. So stuff absorbed into the membranes there gets sucked right out onto the regular highway.

https://www.reddit.com/r/DrWillPowers/comments/gsc1cv/just_throwing_out_there_some_anecdotes_about/

Oral progesterone achieves very low progesterone levels and produces only weak progestogenic effects due to bioavailability problems related to the oral first pass. Hence, non-oral progesterone, which bypasses the first pass and has much better bioavailability, is preferable. Most non-oral progesterone routes have problems such as unavailability and inconvenience however. Rectal progesterone is the most practical non-oral route, but progesterone suppositories are not available in most of the world. Oral progesterone capsules have been administered vaginally with success in cisgender women and theoretically could be useful via rectal administration similarly. Based on unpublished anecdotal clinical experience, this indeed may be the case—oral progesterone capsules administered rectally in transfeminine people have been reported to achieve much higher progesterone levels than oral administration and to allow for robust suppression of testosterone levels in combination with estradiol.

https://transfemscience.org/articles/oral-p4-rectally/

11) When is the best time to take progesterone for breast development?

a) the rule of thumb is at least 12 months HRT for most HRT doctors. I have no citation for this off hand, but it is a common standard.

b) breast tanner stage 3 or higher: https://www.reddit.com/r/DrWillPowers/comments/ij2ej3/the_best_time_to_start_taking_progesterone/

c) once breast development has stalled at least 4 months while on estradiol injections (Dr. Powers v7 info, circa 2021): https://www.reddit.com/r/DrWillPowers/comments/nylg31/entering_tanner_3_is_it_too_early_to_start/

12) Stunted breast development if progesterone is taken too early

There have been suggestions in the literature that early exposure to progestogens may result in suboptimal breast development. An animal study using progesterone found that this was the case for mammary gland development in rabbits with high though not lower doses (Lyons & McGinty, 1941). It’s unknown whether or not this phenomenon actually occurs in humans however. And if it does occur in humans, it’s unknown what level of progestogen exposure would be required to produce it. In any case, this page is a collection of literature excerpts on the subject.

https://transfemscience.org/articles/progestogens-suboptimal-breast-dev-excerpts/

13) Oral micronized bio identical Progesterone not covered by insurance

Progesterone is not particularly expensive (in the USA), even if insurance doesn’t cover it. Check out GoodRx.com for coupons you can use at your pharmacy: https://www.goodrx.com/progesterone

14) Tools to insert progesterone as a suppository

  • finger condoms
  • gloves
  • lubricant
  • pin/tack to poke a hole

https://www.reddit.com/r/DrWillPowers/comments/l5i4z2/what_tool_to_take_progesterone_as_a_suppository/

If you find progesterone undissolved the next morning, try poking a hole in the capsule, running under warm water for a second, then inserting; to help it dissolve and absorb more completely.

15) How to insert progesterone as a suppository

Run under warm water, then I apply one drop of water based lube and spread it over the capsule with my fingers, then push it into the hole with my finger.

It’s pretty easy

https://www.reddit.com/r/DrWillPowers/comments/m0ngss/how_to_use_bio_identical_progesterone_pills_in/

16) Differences between types of progesterone

P numbers designate different versions of Progesterone and Progestins. Some are synthetic, some bio-identical such as P4.

Synthetics have been shown to increase clotting and cancer risks. Check your brand and search for its chemical make up. Then search for that Ingredient on Wikipedia to see what you have been prescribed.

https://www.reddit.com/r/DrWillPowers/comments/kqnqim/different_between_p1_and_p3_progesterone/

17) If your doctor is against the use of progesterone

a) Pro progesterone: https://academic.oup.com/jcem/article/104/4/1181/5270376

b) Critical analysis of the pro progesterone article: https://academic.oup.com/jcem/article/104/8/3127/5372732

c) A Reddit discussion: https://www.reddit.com/r/DrWillPowers/comments/ms3umh/if_your_doctor_is_against_progesterone/

18) Dosages and timing for progesterone as a suppository

19) Interactions between Dutasteride, Finasteride, and Progesterone

Dutasteride/Finasteride have interactions with Progesterone. Below are some citations about this topic. The simple answer as to whether you can mix these medications and have good physiological efficacy of both is: it depends on your goals. I personally am mixing progesterone (suppository) and dutasteride (oral) at the time of this writing. Since I have no control reference regarding how this makes me feel or how it is impacting progesterone effects, I cannot comment further.

Dutasteride (10(-6)M) inhibited progesterone conversion to 5alpha-pregnanes by >95% and increased 4-pregnene production. The results indicated that effects of dutasteride on the progesterone metabolizing enzymes are due to direct inhibition of 5alpha-reductase activity and to altered levels of expression of 5alpha-reductase and HSO mRNAs. Treatment of cells with progesterone without medium change for 72 h resulted in significant conversion to 5alpha-pregnanes and increases in cell proliferation and detachment. The increases in proliferation and detachment were blocked by dutasteride and were reinstated by concomitant treatment with 5alphaP, providing proof-of-principle that the effects were due not to progesterone but to the 5alpha-reduced metabolites. This study provides the first evidence that dutasteride is a potent progesterone 5alpha-reductase inhibitor and that such inhibition may be beneficial in breast cancer.

https://pubmed.ncbi.nlm.nih.gov/16806904/#:~:text=Dutasteride%20(10(%2D6)M,and%20increased%204%2Dpregnene%20production.&text=This%20study%20provides%20the%20first,be%20beneficial%20in%20breast%20cancer.

Despite any conclusive research studies, it is thought that 5α-reductase inhibitors like dutasteride may prevent the formation of neurosteroid metabolites like allopregnanolone from progesterone and hence may mitigate the psycho-cognitive effects of progesterone, particularly if it is administered orally.[36][37][38][39][40]

https://en.wikipedia.org/wiki/Dutasteride

Observations performed in a subset of patients treated for male pattern hair loss indicate that persistent sexual side effects as well as anxious/depressive symptomatology have been reported even after discontinuation of finasteride treatment. Due to the capability of finasteride to block the metabolism of progesterone (PROG) and/or testosterone (T) we have evaluated, by liquid chromatography-tandem mass spectrometry, the levels of several neuroactive steroids in paired plasma and cerebrospinal fluid (CSF) samples obtained from post-finasteride patients and in healthy controls. At the examination, post-finasteride patients reported muscular stiffness, cramps, tremors and chronic fatigue in the absence of clinical evidence of any muscular disorder or strength reduction. 

https://pubmed.ncbi.nlm.nih.gov/24717976/

Neurosteroids like 3α-androstanediol (derived from DHT) and allopregnanolone (derived from progesterone) activate the GABAA receptor in the brain; because finasteride prevents the formation of neurosteroids, it functions as a neurosteroidogenesis inhibitor and may contribute to a reduction of GABAA activity. Reduction of GABAA receptor activation by these neurosteroids has been implicated in depression, anxiety, and sexual dysfunction.[75][76][77]

https://en.wikipedia.org/wiki/Finasteride

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