by Beverly Cosgrove, Revision 18, 5-28-2018
Transgender health care is still often based on weak evidence, inappropriate assumptions, and outright inexperience. This is a summary article which spells out some mistakes and substandard choices being made right now by some doctors, including fine, experienced doctors who believe they are adhering to established standards or best practices, and who honestly believe they are acting in good faith for their patients best interests. I’m not a medical professional — I’m a lay expert only, but with 35 years experience as a peer coach, independent researcher, and HRT writer/journalist/group leader. Writing an article like this may be viewed by a few as audacious and perhaps, in some way, expressing ingratitude towards valuable and trusted medical providers, and that’s not what I intend. My goal here is to present information which may help bring prescribing doctors up to speed with the latest in formal research and clinical experience, plus some group knowledge derived from case histories in a 10000-member international online HRT discussion group (Ref 20).
 Antiandrogen-based treatment may cause symptoms of depression and anxiety. GNRH agonists are one of the most depression-causing medications known — (Refs. 1,2) — including among women, which may be the better test. (Ref. 21) The transition process is fraught with emotional stress – but the Spironolactone, Finasteride, or Dutasteride frequently prescribed is linked to depression, “brain fog” cognitive impairment, and anxiety, both in substantial online community reports and formal studies. We fear that this could be one of the factors causing the MTF suicide rate to remain high or go higher after beginning HRT. The possibility that harm is being done to the patient cannot be dismissed. See my article on Spironolactone in particular.
The irony of widespread antiandrogen use for trans people is that a safe, effective transition is possible based on Estradiol by injection, pellet, gel, or other parenteral methods — using no antiandrogen of any kind. (Refs 3,4) This is not a theoretical method, but one proven by large groups of trans women, including myself, and large populations of men undergoing prostate cancer treatment. The majority (nearly 100% of Assigned-Male-at-Birth (AMAB) patients never previously treated with antiandrogens) can eventually achieve testosterone suppression to female levels using a combination of parenteral estradiol (Ref 8) and (optionally, added later) progesterone. (Ref 7) In many or most patients, the levels required of E2 cannot be reached easily or safely by oral estrogens, and so injectables, gels, multiple patches or pellet implants are required. Group experience shows that E2 levels (“Total Estradiol”) giving this result are somewhere between 200 and 700 pg/ml when administered by injection. Testosterone levels decline over a period of about 6 months to reach the high end of female levels, where they continue a slower decline towards testicular atrophy beginning at about the 12 month mark and continuing indefinitely. Group experience shows that the time required to castrate levels of testosterone is inversely proportional to parenteral estradiol dose, and can be as short as 3-4 weeks — indeed, the drop can be dramatically fast. (Refs 9,10) Studies exist in the ADT regimens showing safety and efficacy (Ref 8), and AMAB transgender patients report a smooth, pleasant transition without the typical psychiatric symptoms.
 Experience and theory implies that the best feminization experience is not just a factor of estradiol level alone, but also maximizing estradiol compared to total estrogens. Ideal feminization regimens require this percentage to be as high as possible, to mimimize the antagonist action of estriol & estrone in the presence of estradiol.(Ref 5) The highest sustained percentage E2/Etotal aka E2/(E1+E2+E3) is achieved by parenteral methods injection or pellet implant — after those, gels and patches. (Ref 6) For the same reason, pills cannot be effectively combined with patches or injections — patients on injections should be warned not to attempt to “boost” their effects by adding pills on the side, as this may only cause a portion of the estradiol binding to degrade. To avoid antagonist effects, one leading-edge provider has developed a treatment decision algorithm based on measured E1 and E2 levels to optimize effective feminization by insuring that the E2/(E1+E2+E3) ratio remains high, regardless of administration method. (Ref 7)
 New studies show that parenteral administration of Estradiol (by transdermal or by injection) have minimal association with Thromboembolism. (Ref 12) It’s particularly important to start patients over age 40 on parenteral estradiol instead of oral estrogens. “After the age of 40, transdermal formulations are recommended as they bypass first pass metabolism and seem to be associated with better metabolic profiles.” (22) The days of fearing all forms of Estradiol lead to high risks of thromboembolism are ending. Higher doses of estradiol delivered parenterally (transdermal, injection, etc) have insignificant levels of thrombotic variables which have previously been related to risks of ischemic heart disease and/or venous thromboembolism. (23) The previous dosing data was inappropriately extrapolated from studies on Premarin/Provera combinations. (Ref 11) We are also pointing out the new research supporting Rutin as an anti-Thrombotic agent, and suggesting that all AMAB transgender patients consider taking it while receiving estrogens. (Ref 13)
 Replacing medroxyprogesterone (Provera) in AMAB transgender HRT with Progesterone, if it follows patterns observed in non-transgender women, may reduce associated cardiovascular risks by over 65%. A substantial reduction in cancer risk has also been demonstrated. (Ref 15) Non-progesterone Progestins in group settings are associated with negative side effects. One therapist reported high rates of depressive or even psychotic symptoms associated with Provera use in trans women. (Ref 16) Progestins such as MPA are noted for their ability to bind to glucocorticoid, androgen, and mineralocorticoid receptors — possibly explaining the wide range of side effects experienced from progestins which are not evident when progesterone is taken instead. (Ref 14)
 Because of the reduced risk of Deep Vein Thrombosis (DVT) and Coronary Heart Disease (CHD) discussed above, we believe there is no longer a general rationale for reducing the estrogen levels of post-GRS MTF patient in good health to postmenopausal female ones if the patient has never experienced an extended period (>10 years) of youthful levels, assuming that parenteral estradiol is used instead of oral methods. However, at the time of surgical removal of testicles, the need for Estradiol-based suppression of Testosterone ends, and suggested doses may be cut back. A chart showing some typical pre- and post-castration Estrogen doses is here.
 Patients who balk at self injection in the upper, outer quadrant of the buttocks can be offered the option to do their own injection subcutaneously. A recent Mexican clinical study showed that the uptake rate and blood level profile of the two methods for Estradiol Cypionate is remarkably similar. (Ref 17) Because it is so easy and painless, and the chance of self injury is so low, it could be a valuable option. Some community experience indicates that the dose may need slight adjustment, depending on the location on the body the SubCut injection is given. Patients are using shallow fat layer injection in the abdomen or above the hips with success. At this time, Subcutaneous is becoming a common option for AFAB transgender patients. (Ref 19) This method is widely used at some locations in the Canadian Health system, and this year became the preferred method for both AMAB and AFAB transgender patients at The Mayo Clinic. (Ref 18) Group experience with subcutaneous is good. A recent poll in our 10000-member online group among those using injections, showed that 61% were using gluteus injections, 28% using thigh, and 11% using subcutaneous. See our article for more details on the preferred equipment and the patient experience. Group experience reports an extremely high rate of inappropriate equipment recommendations (Syringe, needle) being given to patients by physicians, nurses, and pharmacists, which implies that these professionals are not familiar with the hydraulic issues of injecting viscous hormones through small needles.
In our group experience, patients report seeing the following clinical mistakes occurring more and more:
 Fourteen day injections cycles are being prescribed for estradiol valerate and cypionate. The estradiol blood levels are essentially zero by the 14th day, causing an uncomfortable mood swing, often accompanied by hot flashes or unwelcome testosterone flares. Not only does this make it impossible to suppress testosterone by estradiol alone in many cases, it adds to the burden of psychiatric symptoms of the patient. Suggested maximum injection intervals are: Estradiol Valerate in the gluteus: 7 days; Estradiol Cypionate in the gluteus: 9 days; Estradiol Valerate in the thigh: 5 days; Estradiol Cypionate in the thigh: 5 days. Maximum intervals for subcutaneous injection are at least as long as for thigh injection, perhaps longer.
 Some physicians, switching their patients from estradiol valerate injection to estradiol cypionate, are assuming the dosage is identical. However, we observe that in some patients the EC seems to have about 2-3.5 times the effective bioavailability by weight, and requires a proportionately smaller dose (despite having identical theoretical bioavailability). The other error is to make decisions based on blood tests which are too early — because of the long lasting depot sites, accurate E2 levels are not really available for Estradiol Valerate until week 4, and perhaps even longer for Estradiol Cypionate, because of the very slow rise of the baseline.
 Patients are being instructed to use thigh injection on a long schedule (7 days or more) or at doses equivalent to gluteal dosing. With EC and EV both, bioavailability is reduced by about 60% in the thigh, compared to the gluteus, and the halflife proportionately. We see thigh-injecting patients often experience low, irregularly varying blood levels compared to those who inject into the gluteus (recommended by the manufacturer). With thigh injecting patients, there is a high report rate of mood swings and emotional instability. Patients who switch to gluteal injection frequently achieve remission of symptoms. There is little or no published studies on the different uptake of oil-based hormones injected by gluteus and quadriceps. This may be new knowledge and needs to be confirmed, but is backed up by many patient reports and lab records.
In addition, even though formal research is still lacking, we believe we see evidence supporting the following:
 Allowing patients to add progesterone (NOT progestins), in oral forms, to their HRT often has a number of beneficial effects, especially for skin, hair, and the development of structures in the nipple and breast. Progesterone in injected forms or taken by rectal suppository typically makes it easier to eliminate antiandrogens from treatment regimens entirely. This alone is a strong argument for the inclusion of progesterone, or to replace an initial course of antiandrogens with progesterone after a few months to a year. Low amounts of injected progesterone on a frequent schedule (2x weekly) may be associated with slow but very long term breast development. There is anecdotal evidence that progesterone in oil applied directly to scalp follicles stimulates some regrowth of hair.
REFERENCES and LINKS
(1) “Drug-induced diseases: prevention, detection, and management”, Tisdale J, American Society of Health-System Pharmacists, 2005.
(2) “Androgen deprivation therapy complications.”, Allan CA, Endocr Relat Cancer. 2014 Aug;21(4):T119-29
(3) “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.
(4) “Transdermal estradiol therapy for advanced prostate cancer–forward to the past?”, Ockrim JL, J Urol. 2003 May;169(5):1735-7.
(5) “Molecular and kinetic basis for the mixed agonist/antagonist activity of estriol.”, Mol Endocrinol. 1997 Nov;11(12):1868-78.
(6) “Pharmacology of Estrogens and Progestogens — Influence of Different Methods of Administration” by Kuhl, from Climacteric, 2005;8 Suppl 1:3-63
(7) “Healthcare of the Transgender Patient V. 3“, Powers W. MD, Oct 2017.
(8) “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.
(9) “ Direct inhibition of Leydig cell function by estradiol.”, Jones TM, J Clin Endocrinol Metab. 1978 Dec;47(6):1368-73.
(10) “ 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.
(11) “What Went Wrong With MTF Hormonal Therapy?“, Cosgrove, B.
(12) “Oral vs Transdermal Estrogen Therapy and Vascular Events: A Systematic Review and Meta-Analysis.”, Mohammed K. J Clin Endocrinol Metab. 2015 Nov;100(11):4012-20. doi: 10.1210/jc.2015-2237.
(13) “Rutin for Prevention of Thrombosis in MTF Transsexual Hormone Therapy“, Cosgrove B, Nov 2017.
(14) “Differential signal transduction of progesterone and medroxyprogesterone acetate in human endothelial cells.”,Simoncini T, Mannella P, Fornari L, et al., Endocrinology. 2004 Dec;145(12):5745-56. Epub 2004 Sep 9
(15) “Safety and benefit considerations for menopausal hormone therapy”, Pickar JH, Expert Opin Drug Saf. 2017 Aug;16(8):941-954. doi: 10.1080/14740338.2017.1343298. Epub 2017 Jun 30.
(16) Mildred Brown Ph.D., personal communication, 1997.
(17) “Comparative pharmacokinetics and pharmacodynamics after subcutaneous and intramuscular administration of medroxyprogesterone acetate (25 mg) and estradiol cypionate (5 mg).” Contraception. 2011 Dec;84(6):565-70. doi: 10.1016/j.contraception.2011.03.014. Epub 2011 May 11.
(18) Callie Amber Foxx, private communication, Nov. 2, 2017.
(19) “Subcutaneous Injection of Testosterone Is an Effective and Preferred Alternative to Intramuscular Injection: Demonstration in Female-to-Male Transgender Patients”, Spratt, The Journal of Clinical Endocrinology & Metabolism, Volume 102, Issue 7, 1 July 2017, Pages 2349–2355, https://doi.org/10.1210/jc.2017-00359
(20) Online Facebook Group, “The MTF Trans HRT Hormone Forum“, founded Dec. 2014, membership approx 9800.
(21) “Preliminary results of a prospective, double-blind placebo-controlled study and an open label trial indicates that depressive mood symptoms increase in women treated with GnRH agonist therapy for endometriosis.”, “Depressive symptoms associated with gonadotropin-releasing hormone agonists.”, Warnock JK, Depress Anxiety. 1998;7(4):171-7.. https://www.ncbi.nlm.nih.gov/pubmed/9706454
(22) “Hormone therapy for transgender patients”, Unger C, doi: 10.21037/tau.2016.09.04
(23) “Effects of high dose oestrogen therapy on circulating inflammatory markers”, Wilson R, Maturitas 62 (2009) 281–286.