Human males have a simple way of regulating their body’s testosterone. A small amount of the body’s testosterone is always converting to estrogens. (Note: the opposite does NOT happen.) So, a male body watches for this testosterone breakdown product — estradiol — to estimate how much testosterone is present. If you are a male, and your body sees a lot of estradiol, it thinks “I must have enough testosterone, so I will stop making more.” This is how estradiol acts to stop testosterone being made. (Ref’s 12,13,14,15) But, the human body cannot tell the difference between estradiol from its own breakdown of testosterone, and any external estradiol you add by taking hormones. If you take estradiol, and you have enough estradiol in your body, and you have testicles, your testicles will stop making testosterone, in a totally natural way. This is called androgen down-regulation and is the key to doing a male-to-female hormonal transition using estradiol ONLY. Trans women tend to report that it is the smoothest, most pleasant, healthiest, most natural, and most emotionally stable method of transitioning. Why isn’t it done for all MTF transsexuals? That’s a good question.
In the 90’s, studies of menopausal women receiving horse estrogens and synthetic progestins showed they suffered cardiovascular and cancer risks. This was a major blow to drug companies producing the horse estrogens (Premarin) and synthetic progestins (Provera or Medroxyprogesterone) — and drug companies, in order to prevent replacing their patented products with generic natural hormones, convinced the FDA that the proper and prudent caution required the FDA to put the caution on ALL forms of estrogen as well as natural forms of progesterone, even though there was no evidence to support it, until studies were done proving that some forms of estrogen were safe. (11)
But, the studies never happened — because the major drug companies had no motive to spend money to prove that generic natural hormones were superior to their patented synthetic substitutes.
So doctors, whose professional standing required them to be as conservative as possible, began limiting the estradiol they prescribed to trans women, to keep their levels at about 100-150pg/ml, which for most is not enough to trigger the “shutdown” of testosterone. Doctors saw that a type of transition was still possible by adding antiandrogens, especially Spironolactone, which reduced testosterone and/or blocked androgen receptors, without actually achieving a natural female hormone balance. Doctors judged this was justified because the low levels of estradiol were safe. Their patients did not know that for the right types of estradiol, especially estradiol by injection, gel, or patch, levels of 300-400 are entirely sufficient (for more than half of patients not previously treated with antiandrogens) to suppress testosterone with no antiandrogens (1, 2), and without the dangers of thrombosis or cancer (6) as feared in the tests of horse estrogens. [A few doctors are known to have even given their patients the false information that “too much estrogen will turn into testosterone in the body” as a way to discourage the patients from requesting higher treatment levels.] Meantime, antiandrogens which were never intended for transsexual use became popular, and their side effects became the dominant ones, possibly contributing to some of the self harm, addictive behavior, and suicide of trans women on HRT. This kind of Androgen Deprivation Therapy added to effects of low, starvation levels of estradiol, which had their own negative brain and emotional side effects. (3, 4, 5) All this, because of inappropriate balancing of risk in transsexual HRT, and doctor ignorance of how easy it is to use pure estradiol to down regulate testosterone.
Today, rising patient knowledge and the existence of small studies which confirm the safety of parenteral estradiol treatment is changing the nature of MTF HRT, from an anti-androgen dominated treatment, to a simpler estradiol-based treatment, which leads safely to a natural female hormone balance, with improved emotional benefits and superior physical feminization results. New recommendations for estradiol injection are being prepared for inclusion in WPATH standards. (10)
Once the patient has achieved an estradiol level at the threshold, which for most MTFs is in the range of 300-500pg/ml approx, testosterone begins declining. Testosterone levels slide gradually due to the parenteral estradiol, reaching female normal levels in as little as 1 month, (1) and the transitioner usually reports a pleasant and gradual change. (Time required to reach female normal levels varies per individual, and is shorter for higher levels of estradiol.) At that point, their hormonal balance is entirely female (instead of the “crippled male” balance caused by anti-androgen use.) Testicular atrophy begins a few months later. As atrophy begins, the E2 level required to maintain testosterone at female levels tends to drop, and an alert physician can ease the levels down further if they wish. (6)
Transdermal administration, at a high enough level, may also be sufficient. Ockrim et al. treated 20 men for eight weeks with 0.6 mg/24 hours of 17b-estradiol, reduced the number of patches to maintain castrate levels of testosterone, and ultimately found that an average of two patches per day was sufficient to maintain castrate levels. [Note that these patches are high dosages compared to commercially available estradiol patches meant for post menopausal symptoms.] (2)
Fears of high estradiol levels, when administered parenterally, have not proven to be justified. Studies do not show significant increased mortality (6) and with only a small remaining thrombosis risk. The remaining patients requesting anti-androgens for “hair regrowth” can be assured that estradiol down-regulation of testosterone is sufficient for scalp hair restoration in most cases. (7) New research suggests that the final remaining risk, minor thrombotic events, may be reduced or avoided entirely by patient use of Rutin as a supplement. (8,16)
It is unfortunate that, in the zeal to protect patients from the dangers of estradiol, transitioning MTF’s have instead been exposed to mental and emotional dangers (3, 5) which have almost certainly contributed to their experiences of anxiety, depression, and inability to handle the high stress levels associated with such a monumental change as male to female transition. We are optimistic as more and more endocrinologists see a more realistic risk assessment, based on a better balance between the risks of anti-androgens and estradiol, in which best patient outcome depends on reserving anti-androgen use for special cases, instead of routine use.
(1) “Emerging potential of parenteral estrogen as androgen deprivation therapy for prostate cancer”, Shah S, South Asian J Cancer. 2015 Apr-Jun; 4(2): 95–97.
(2) “Transdermal estradiol therapy for advanced prostate cancer–forward to the past?”, Ockrim JL, J Urol. 2003 May;169(5):1735-7.
(3) “Androgen deprivation therapy complications.”, Allan CA, Endocr Relat Cancer. 2014 Aug;21(4):T119-29
(4) “Drug-induced diseases: prevention, detection, and management”, Tisdale J, American Society of Health-System Pharmacists, 2005.
(5) “Anxiety and mood disorders associated with gonadotropin-releasing hormone agonist therapy.” Warnock JK, Psychopharmacol Bull. 1997;33(2):311-6.
(6) “Parenteral estrogen versus combined androgen deprivation in the treatment of metastatic prostatic cancer: part 2. Final evaluation of the Scandinavian Prostatic Cancer Group (SPCG) Study No. 5.”, Hedlund PO, Scand J Urol Nephrol. 2008;42(3):220-9.
(7) “Scalp Hair Regrowth in Hormone-Treated Transgender Women”, Stevenson MO, Transgender Health V 1.1, 2016
(8) “Protein disulfide isomerase inhibitors constitute a new class of antithrombotic agents”, Jasuja R, J Clinical Invest. 5-8-2012
(9) “Androgen Deprivation Therapy and the Re-emergence of Parenteral Estrogen in Prostate Cancer” Phillips et al, Oncology & Hematology Review, 2014;10(1):42–7
(10) “An example of a reasonable accommodation is the use of injectable cross-sex hormones, if not medically contraindicated… There is some evidence that parenteral estrogen treatments may be safer than oral preparations especially in people over 35 years of age.” https://www.researchgate.net/publication/247510691_Recommended_Revisions_to_the_World_Professional_Association_for_Transgender_Health%27s_Standards_of_Care_Section_on_Medical_Care_for_Incarcerated_Persons_with_Gender_Identity_Disorder
(11) “The Haunting of Medical Journals: How Ghostwriting Sold ‘HRT’”, PLoS Med. 2010 Sep; 7(9): e1000335, Published online 2010 Sep 7. doi: 10.1371/journal.pmed.1000335, PMCID: PMC2935455.
(12) “ Direct inhibition of Leydig cell function by estradiol.”, Jones TM, J Clin Endocrinol Metab. 1978 Dec;47(6):1368-73.
(13) “ The effect of oestrogen administration on plasma testosterone, FSH and LH levels in patients with Klinefelter’s syndrome and normal men.” Smals AG, Acta Endocrinol (Copenh). 1974 Dec;77(4):765-83.
(14) “In men, peripheral estradiol levels directly reflect the action of estrogens at the hypothalamo-pituitary level to inhibit gonadotropin secretion.”, Raven G, J Clin Endocrinol Metab. 2006 Sep;91(9):3324-8. Epub 2006 Jun 20.
(15) “Sex steroid control of gonadotropin secretion in the human male. II. Effects of estradiol administration in normal and gonadotropin-releasing hormone-deficient men.”, Finkelstein JS, J Clin Endocrinol Metab. 1991 Sep;73(3):621-8.
(16) “Rutin for Prevention of Thrombosis in MTF Transsexual Hormone Therapy“, Beverly Cosgrove, 2017.