( Archives of Sexual Behavior, Vol. 18, No. 1, 1989. )
Jerilynn C. Prior, M.D., FRCP(C), (1),(3), Yvette M. Vigna, R.N., B.A., (1) and Dianne Watson, M.D., FRCP(C), (2)
The clinical and hormonal response to 12-month therapy with the anitandrogen,
spironolactone, in conjunction with near- physiological doses of female gonadal steroids
in 50 transsexual males, is presented. An unselected referred series of 61 men with the
psychiatric diagnosis of transsexualism was treated; 10 subjects who had received previous
gonadal surgery and 1 man with Klinefelter's syndrome were excluded. Twenty-seven
conventionally treated (CT; high-dose estrogen) age 34.4 +/- 10.5 years. mean +/- SD, and
23 untreated patients (SPS), age 30.7 +/- 6.2 years, were studied. Following the initial
visit, all 50 were begun on spironolactone and low dose female estrogen therapy. Despite
high- dose treatment for more than two years, the mean testosterone (T) level for the CT
group was not in the female range (169 +/- 193 ng/dl; normal 20-80). Spironolactone, in
doses of 200-600 mg/day, lowered T to the female range in both groups after 12 months (CT
87 +/- 111 and SPS 49 +/- 41 ng/dl). This was achieved in the CT group despite decreases
in estrogen dose and discontinuation of parenteral therapy. SPS subjects experienced
significant decreases in plasm T (642 +/- 236 to 49 +/- 41 ng/dl, p <0.001). Systolic blood pressure dropped (128 +/- 14 to 121 +/- 14mm Hg, p < 0.05). The clinical response, including decreased male pattern hair, breast development, feminization, and lack of erections was excellent in most subjects.
Keywords: transsexualism; antiandrogen; estrogen; progesterone; spironolactone.
(1) Department of Medicine (Endocrinology), University of British Columbia, and Vancouver General Hospital, Vancouver, British Columbia, Canada.
(2) Department of Psychiatry, University of British Columbia and Vancouver General Hospital, Vancouver, British Columbia, Canada.
(3) To whom correspondence should be addressed at 910 West 10th Avenue, Vancouver, British Columbia V5Z 1M9 Canada.
Conventional treatment for male-to-female transexuals relies on pharmacological doses of estrogenic compounds (Benjamin, 1964; Hamberger, 1969; Futterweit et al., 1984; Cooper, 1984). Oral and parenteral estrogen is prescribed in doses 2 to 15 times the normal physiological female replacement range. Contraindictions to high- dose therapy are rarely mentioned (Flutterweit, 1980). However, life threatening complications have occurred as noted in five case reports (Bell et al., 1977; de Marinis and Arnett, 1978; Fortin et al., 1984; Lehrman, 1976; Goodwin and Cummings, 1984). A conservative approach, without documented efficacy, is treatment with moderate-dose oral contraceptive agents (Steiner, 1985).
The goals of endocrine therapy for the male-to-female transsexual are to provide feminization of body shape and subcutaneous tissue, to decrease or eliminate male pattern hair and sebaceous gland production, and to decrease male sexual response. An essential aim of therapy is to achieve the above without causing complications or decreasing survival.
The antihypertensive medication, spironolactone, is an effective therapy for androgen excess in women (Cummings et al., 1982; Shapiro and Evron, 1980; Messina et al., 1983). Although it was created as a mineralocorticoid antigonist, it is a true antiandrogen since it interferes with dihydrotestosterone action in the pilosebaceous unit. Spironolactone has multiple other actions including lowering testosterone (T) production by reduction of cytochrome P450, decreasing sex hormone binding thereby increasing free T clearance, and lowering gonadotrophins (Givens, 1985).
This study reports three changes to conventional therapy for transsexual men: (i) near-physiologocal doses of cyclic oral conjugated estrogen, (ii) cyclic or continuous medroxyprogesterone, and (iii) spironolactone. Following 12 months of this combined therapy, normal female levels of androgen, marked feminization of skin, decrease in beard hair and acne, and increased breast size were produced. Preliminary data on lupids, blood pressure, prolactin, and glucose-intolerance suggest there will be less risk of long term complications.
Method and Subjects
The study population comprised 61 men referred between 1980 and 1985 with the diagnosis of transexualism (confirmed by two psychiatrists). Ten patients with previous gonadal surgery and one with Klinefelter's syndrome were excluded. Fifty men fell into two groups: (i) 27 Conventionally treated (CT) subjects on high-dose estrogen therapy at the time of referral, (ii) 23 subjects on no prior hormonal therapy (SPS). Both groups started treatment with spironolactone and physiological female steriods after the initial visit.
Spironolactone was initially given in doses of 100 to 200mg/day and gradually increased to achieve adequate T reduction. Conjugated estrogen (Premarin(R)) was prescribed in doses of 0.625mg/day, increasing to 2.5 mg twice/day for 3 out of 4 weeks. A higher dose was prescribed when the individuals stopped smoking, if weight, blood pressure, and lipids were normal, and if other risks were absent. Medrodroxyprogesterone (Provera(R)), 10mg/day, was taken during weeks 3 and 4 of a 4 week cycle. Provera was given continuously if gonadotrophins increased, or to aid in T reduction or breast development (Gordon et al., 1970).
Endocrine evaluation included confirmation by history of normal adolescence and physical maturation, and assessment of current health by history and physical examination. Documentation of risk factors for estrogen therapy and measurement of gonadal steroids, gonadotrophins, lipids, and glycosylated hemoglobin were also done. Laboratory methods included standard procedures and radioimmunoassays (Whitaker et al., 1985).