Transsexual Hormone Therapy

Transsexual Hormone Therapy

• No change in free cortisol with testosterone 60mg/week T given to women (Azziz 1991)

Asscheman H, Giltay EJ, Megens JA, de Ronde WP, van Trotsenburg MA, Gooren LJ. A long-term follow-up study of mortality in transsexuals receiving treatment with cross-sex hormones. Eur J Endocrinol. 2011 Apr;164(4):635-42.

OBJECTIVE: Adverse effects of long-term cross-sex hormone administration to transsexuals are not well documented. We assessed mortality rates in transsexual subjects receiving long-term cross-sex hormones. DESIGN: A cohort study with a median follow-up of 18.5 years at a university gender clinic. Methods Mortality data and the standardized mortality rate were compared with the general population in 966 male-to-female (MtF) and 365 female-to-male (FtM) transsexuals, who started cross-sex hormones before July 1, 1997. Follow-up was at least 1 year. MtF transsexuals received treatment with different high-dose estrogen regimens and cyproterone acetate 100 mg/day. FtM transsexuals received parenteral/oral testosterone esters or testosterone gel. After surgical sex reassignment, hormonal treatment was continued with lower doses. RESULTS: In the MtF group, total mortality was 51% higher than in the general population, mainly from increased mortality rates due to suicide, acquired immunodeficiency syndrome, cardiovascular disease, drug abuse, and unknown cause. No increase was observed in total cancer mortality, but lung and hematological cancer mortality rates were elevated. Current, but not past ethinyl estradiol use was associated with an independent threefold increased risk of cardiovascular death. In FtM transsexuals, total mortality and cause-specific mortality were not significantly different from those of the general population. CONCLUSIONS: The increased mortality in hormone-treated MtF transsexuals was mainly due to non-hormone-related causes, but ethinyl estradiol may increase the risk of cardiovascular death. In the FtM transsexuals, use of testosterone in doses used for hypogonadal men seemed safe. PMID: 21266549

Azziz R, Gay FL, Potter SR, Bradley E Jr, Boots LR. The effects of prolonged hypertestosteronemia on adrenocortical biosynthesis in oophorectomized women. J Clin Endocrinol Metab. 1991 May;72(5):1025-30.

Adrenal androgen production and adrenocortical biosynthesis are frequently abnormal in women with hyperandrogenism. It is possible that these abnormalities result from hypertestosteronemia of ovarian origin. We prospectively studied the effect of prolonged testosterone (T) administration on adrenocortical biosynthesis and basal hormone levels in seven oophorectomized euandrogenic volunteers, who received 20 mg T in oil (USP), im, three times weekly for 3 weeks. Blood was sampled before T administration (week 0), during therapy (weeks 1, 2, and 3), and 1 week after discontinuation of the medication (week 4). Acute adrenal stimulation using 250 micrograms ACTH-(1-24), iv, was performed on weeks 0, 2, and 3. Circulating T rose from an average of 1.53 nmol/L (44ng/dL)to 27.9 nmol/L (804ng/dL)by the end of week 3. Both LH and FSH decreased with T administration, while PRL rose slightly during the initial weeks of T therapy. Little change was observed in the basal levels of 17-hydroxyprogesterone, 11-deoxycortisol, 17-hydroxypregnenolone, estrone, and estradiol. Androstenedione (A) rose concurrent with T administration and normalized after therapy discontinuation. Dehydroepiandrosterone (DHA) decreased significantly with T administration, while DHA sulfate (DHS) increased, leading to an increased DHS/DHA ratio.Total cortisol (F) decreased during T therapy; however, corticosteroid-binding globulin levels also decreased, and the unbound F level remained unchanged. No significant change in adrenocortical response (measured by either the absolute poststimulation level or the net increment in steroid levels) for any steroid was noted after T administration. Although the absolute poststimulation level of A was higher during T administration, this change reflected the increased basal A levels, since the increment in A from 0-60 min was not different. In conclusion, raising endogenous T levels in oophorectomized healthy women 10- to 15-fold for a period of 3 weeks produced a decrease in circulating total F and corticosteroid-binding globulin levels, while maintaining normal levels of unbound F. Although the very high T levels produced in this study resulted in an increased DHS/DHA serum ratio, it remains to be proven that the lesser degree of hypertestosteronemia usually observed in hyperandrogenic patients is sufficient to alter DHS metabolism. With this exception, the adrenocortical biosynthetic abnormalities frequently noted in hyperandrogenism do not appear to result from the elevated circulating T levels. PMID: 1850751

Gooren LJ, Giltay EJ. Review of studies of androgen treatment of female-to-male transsexuals: effects and risks of administration of androgens to females. J Sex Med. 2008 Apr;5(4):765-76.

INTRODUCTION: Testosterone supplementation in ovariectomized or elderly women may improve their sense of well-being and libido, muscle mass and strength, and bone mineral density. Naturally, androgens may have virilizing effects in women. It is often believed that androgens have deleterious effects on cardiovascular risks. AIM: To obtain an inventory of the effects of administration of testosterone on female biological functions. METHODS: We reviewed here our publications on the effects of high-dose androgen administration to female-to-male transsexuals treated between 1975 and 2004 (N = 712). Annual accrual was at a steady rate of 22-30 persons. Dosages administered were far above those suited for women. MAIN OUTCOME MEASURES: There was special focus on the potential negative effects on cardiovascular risk markers. RESULTS: The standard treatment was administration of testosterone esters, 250 mg/2-3 weeks, parenterally). With this dose, virilizing effects on the skin and clitoris were prominent. Spatial ability improved, while verbal fluency deteriorated. The ovaries developed polycystic characteristics. Adequate dosages of testosterone preserved bone mass in females. Androgens increased kallikreins, such as prostate-specific antigen, in female reproductive tissues. High-dose testosterone administration appeared to increase weight, visceral fat, and hematocrit, decrease high-density lipoprotein cholesterol, increase endothelin-1, increase C-reactive protein, and increase total homocysteine. But blood pressure, insulin sensitivity, fibrinolytic markers, arterial stiffness, and levels of von Willebrand factor, fibrinogen, and interleukin-6 remained largely unchanged. CONCLUSIONS: Our studies demonstrated that, while some markers of cardiovascular risk factors showed a shift to a more negative risk profile, others were not affected. Androgen effects on cardiovascular risk markers are therefore not universally negative, and it is reasonable to assume that the latter effects will not be negative with the much lower doses suited for administration to women. PMID: 17971101

Grynberg M, Fanchin R, Dubost G, Colau JC, Brémont-Weil C, Frydman R, Ayoubi JM. Histology of genital tract and breast tissue after long-term testosterone administration in a female-to-male transsexual population.Reprod Biomed Online. 2010 Apr;20(4):553-8.

Growing evidence indicates that androgens play a positive role in follicle proliferation and growth. Hence, many authors have assumed that androgen supplementation in women with poor ovarian reserve might improve the number of antral follicles available for ovarian stimulation. As androgen administration may become more frequently used in reproductive medicine, this study aimed at describing the histological changes observed in the genital tract and the breast of female-to-male (FTM) transsexuals. A pathological analysis of the genital tract of 112 FTM subjects who were given androgen for at least 6 months before hystero-salpingo-oophorectomy was performed. In addition, 100 bilateral mastectomies were performed, allowing a study of the breast tissue. Mean ovarian volume was increased, with histological characteristics of polycystic ovaries (PCO), defined as >12 antral follicles per ovary, observed in 89 patients (79.5%). Endometrial atrophy was observed in 45%. Breast examination revealed marked reduction of glandular tissue and increase of fibrous connective tissue in 93%, without atypical hyperplasia or carcinoma. The present data confirms and expands the putative associations between long-term androgen administration and abnormalities in ovarian architecture with macroscopic and microscopic characteristics of PCO, increased risk of endometrial atrophy and fibrotic breast tissue with marked glandular reduction. PMID: 20122869

Mueller A, Binder H, Cupisti S, Hoffmann I, Beckmann MW, Dittrich R. Effects on the male endocrine system of long-term treatment with gonadotropin-releasing hormone agonists and estrogens in male-to-female transsexuals. Horm Metab Res. 2006 Mar;38(3):183-7.

We studied hormonal changes resulting from long-term treatment with gonadotropin-releasing hormone agonist and 17beta estradiol valerate in 40 healthy middle-aged male-to-female transsexuals over a period of two years. All of the participants received injections of 3.8 mg goserelin acetate every four weeks in combination with 6 mg oral 17beta estradiol valerate per day for cross-sex hormone treatment for male-to-female transsexuals. There was a significant reduction in the levels of serum luteinizing hormone and follicle-stimulating hormone to the hypogonadal stage. Mean testosterone levels decreased by 97% to 0.52 and 0.59 nmol/l after 12 months and 24 months, respectively. There was a significant reduction in dehydroepiandrosterone sulfate by 37% after 12 months and 43% after 24 months, and androstendione by 29% after 12 months and 27% after 24 months, respectively. Cortisol levels were reduced by 43% and 50%, respectively. Estrogen levels were significantly increased from 77.51 to 677 after 12 months and 661 pmol/l after 24 months. Sex hormone-binding globulin and corticoid-binding globulin levels were significantly increased after 12 and 24 months. There was a significant decrease in all measured androgen fractions and cortisol during long-term treatment with gonadotropin-releasing hormone agonist and 17beta estradiol valerate. Apart from suppression of testicular hormone production, one possible interpretation is that treatment with long-term gonadotropin-releasing hormone agonist and 17beta estradiol valerate influences adrenal hormone levels in healthy middle-aged male-to-female transsexuals. Cortisol serum levels may be decreased due to estrogen-induced increase in corticoid-binding globulin. PMID: 16673210(Actually the higher CBG levels would cause a higher total serum cortisol, but total cortisol was reduced meaning that free cortisol level must have been greatly reduced. I would be amazed if they did not begin to suffer from the lack of cortisol!—HHL)

RudenkoL.V., Ramazanova Y.I., KalinchenkoS.Y. Estimation of prolonged androgen therapy safety in patients with female-male transexualism. The Aging Male, March 2006; 9(1): 1–70

Background: Observation of the prolonged androgen therapy safety in patients with female-male type of transsexualism being treated with prolonged androgenic testosterone ether drugs. Materials and Methods: Fifty-two patients with female male transsexualism were included into the trial. They were administered substitution hormonotherapy (Sustanon-250, Omnadren-250—esterified testosterone depot preparations) once per 1–3 weeks with individually adjusted doses. To evaluate cardio-vascular system safety we applied instrumental examination algorithm, which included ECG and Holter monitoring. To evaluate hepatic function in all patients, blood biochemical analysis, including AST and ALT estimation was performed. Venous blood glucose level and immunoreactive insulin level were defined to evaluate carbohydrate metabolism. Besides, 13 patients underwent echocardiography with ultrasonic multifunctional scanner VIVID-7 GI US with multifrequency transducer (3.5 MHz), with main hemodynamic values estimation and evaluation of blood lipids (levels of total cholesterol, triglycerides, HDL, LDL). Statistical analysis were performed with non-parametric methods usage. Results: Median age was 28 [23;34] years, therapy length was 4 [2;7] years. Cardio-vascular status of all patients was appropriate to the age standard in the socially Abstracts of The 5th World Congress on the Aging Male 21 adapted age population. There were no significant arrhythmias and segment ST fluctuations. Carbohydrate metabolism was normal in all examined patients glucose and immunoreactive insulin levels (n¼9) were in normal values limits. None of patients had increased levels of AST or ALT. Eleven of 12 examined patients total cholesterol and LDL were 5.4 [5.3;5.8] and 3,7 [3.6;3.9] mmol\l, respectively and exceeded levels of normal values, whilst levels of HDL and triglyceride were 1.30 [0.99;1.47] and 1.3 [0.8;1.5] mmol\l, respectively, and were in levels of normal values. Found data are unable to indicate hyperlipidemic effect of androgentherapy, as increased levels of total cholesterol and LDL were not significant (p440.05). Conclusions: Results showed safety of the extended androgentherapy regarding cardio-vascular system, carbohydrate metabolism and impact on hepatic function. (and this is with MALE doses of testosterone given to females!—HHL)

Slagter MH, Gooren LJ, Scorilas A, Petraki CD, Diamandis EP. Effects of long-term androgen administration on breast tissue of female-to-male transsexuals. J Histochem Cytochem. 2006 Aug;54(8):905-10. Epub 2006 Apr 17.

Our aim was to examine the effects of androgen administration on breast tissue histology of female-to-male transsexuals and to study the immunohistochemical expression of three human tissue kallikreins, hK3 (PSA), hK6, and hK10. We studied 23 female-to-male transsexuals who were treated with injectable testosterone for 18-24 months. We also used 10 control female breast tissues. All tissues were fixed in buffered formalin, embedded in paraffin, and examined by hematoxylin-eosin staining and immunohistochemical staining for PSA, hK6, and hK10. Females treated with androgens exhibited similar involutionary changes as those seen in breast of menopausal women, such as marked reduction of glandular tissue, involution of the lobuloalveolar structures, and prominence of fibrous connective tissue, but presence of only small amounts of fat tissue. Fibrocystic lesions were generally not observed. In immunohistochemistry, in control breast tissues, we found moderate to strong cytoplasmic immunoexpression of hK6 and hK10 in the epithelial ductal and lobuloalveolar structures, but myoepithelial cells were negative. Luminal secretions were also positive. In menopausal breast, the immunoexpression of hK6 and hK10 was weaker and focal. No control case showed immunoexpression for PSA. In female-to-male transsexuals, one case showed focal PSA cytoplasmic immunoexpression in the epithelium of moderately involuting lobules. Long-term administration of androgens in female-to-male transsexuals causes marked reduction of glandular tissue and prominence of fibrous connective tissue. These changes are similar to those observed at the end-stage of menopausal mammary involution. (Therefore, testosterone supplementation would not be expected to promote breast cancer in women-HHL)

Spinder T, Spijkstra JJ, Gooren LJ, Hompes PG, van Kessel H. Effects of long-term testosterone administration on gonadotropin secretion in agonadal female to male transsexuals compared with hypogonadal and normal women. J Clin Endocrinol Metab. 1989 Jan;68(1):200-7.

We investigated the effects of long term testosterone (T) administration on pulsatile gonadotropin secretion in agonadal women and the effects of estradiol (E2) on gonadotropin secretion in eugonadal women in the follicular phase of the menstrual cycle. We studied 4 groups: A) 28 eugonadal women in the early follicular phase of the menstrual cycle, B) 11 hypogonadal women, C) 13 agonadal female to male (f-t-m) transsexuals treated for at least 3 months with 120-160 mg T undecanoate (TU)/day, orally, and D) 5 agonadal f-to-m transsexuals treated for at least 6 months with 250 mg of a mixture of testosterone esters, im (im T-esters), every 2 weeks. The eugonadal women in the early follicular phase had a mean serum E2 level of 193 ± 94 (±sd) pmol/L, significantly higher (P < 0.01) than that in the hypogonadal women (60 ± 24 pmol/L), whereas there was no difference in the mean serum T levels (1.8 ± 0.7 vs. 2.3 ± 1.5 nmol/L). The higher serum E2 level in the eugonadal women was associated with a significantly lower mean serum LH level (6.9 ± 2.6 vs. 44.6 ± 17.6 U/L; P < 0.01) and LH pulse amplitude (2.8 ± 1.0 vs. 12.6 ± 4.8 U/L; P < 0.01), whereas the mean nadir LH interval did not differ between the two groups (75 ± 29 vs. 81 ± 49 min). The mean serum T level in the agonadal f-to-m transsexuals treated with oral TU was significantly higher (P < 0.01) than that in the hypogonadal women (9.7 ± 4.7 vs. 2.3 ± 1.5 nmol/L). In spite of this elevated T level there was no difference in the mean serum LH level (38.4 ± 14.7 vs. 44.6 ± 17.6 U/L), LH pulse amplitude (14.3 ± 5.7 vs. 12.6 ± 4.8 U/L), or nadir LH interval (72 ± 27 vs. 81 ± 49 min) in these groups. Also, the mean serum E2 (64 ± 16 vs. 60 ± 24 pmol/L and FSH levels (62 ± 17 vs. 64 ± 28 U/L) did not differ between these groups. Treatment of the agonadal f-to-m transsexuals with im T-esters resulted in mean serum T and E2 levels of 34.4 ± 27.0 nmol/L and 121 ± 54 pmol/L,(32pg/ml) respectively, both significantly higher (P < 0.01) than those in groups B and C. Their mean serum LH (19.3 ± 6.4 U/L) and FSH (32 ± 10 U/L) levels were significantly lower (P < 0.01) than those in groups B and C; the mean nadir LH interval was significantly longer (131 ± 55 min; P < 0.01), whereas the LH pulse amplitude (8.8 ± 1.7 U/L) was similar.From these results we conclude that 1) the serum T levels in the agonadal f-to-m transsexuals treated with oral TU (9.7 ± 4.7 nmol/L) did not have an effect on gonadotropin secretion, whereas those in the agonadal f-to-m transsexuals treated with im T-esters (34.4 ± 27.0 nmol/L) decreased the mean serum LH level, LH pulse frequency, and FSH level; 2) the E2 levels attained in the early follicular phase did not have a suppressive effect on the LHRH pulse generator, since the LH pulse frequency did not differ between the hypogonadal women and the eugonadal women in the early follicular phase, despite the significantly higher mean E2 level in the latter group; 3) the suppressive effects of high T levels on LH pulse frequency were attributable to androgen action rather than to androgen-derived estrogen action, since serum E2 values were similar to those in the eugonadal women; 4) androgen levels in these experiments in T-treated agonadal female subjects were comparable to or exceeded those in women with polycystic ovarian disease, yet the agonadal females did not have abnormalities in gonadotropin secretion characteristic of polycystic ovarian disease. PMID: 2491861

Traish AM, Gooren LJ. Safety of physiological testosterone therapy in women: lessons from female-to-male transsexuals (FMT) treated with pharmacological testosterone therapy. J Sex Med. 2010 Nov;7(11):3758-64.

INTRODUCTION: The safety of long-term physiological doses of testosterone (T) therapy in women with sexual dysfunction is a contentious issue, in part, because of fear of adverse effects, such as breast cancer, vascular disease, and excessive virilization. This unsubstantiated fear has hampered progress in treating women with sexual dysfunction using T therapy in physiological doses to achieve circulating levels in the normal range. AIM: To examine evidence derived from studies in female-to-male transsexuals (FMT) treated with supraphysiological (pharmacological) doses of T for long periods of time with no apparent major adverse effects. METHODS: A comprehensive literature search of relevant articles published between 1980 and 2010 pertaining to the topic of T in FMTs was performed using PubMed. The following key words were used: female-to-male transsexuals; testosterone; virilization; gender re-assignment; and androgen therapy in women. Relevant articles were retrieved, reviewed, and the information was analyzed and evaluated for study methodology and major findings. MAIN OUTCOME MEASURES: Data from peer-reviewed publications were critically analyzed and the information was summarized. RESULTS: The data from the studies reported in the literature to date strongly suggest that treatment of FMTs with supra-physiological doses of T had minimal adverse effects. No increase in mortality, breast cancer, vascular disease, or other major health problems were reported. CONCLUSIONS: No significant serious adverse effects were reported in FMTs treated with pharmacological doses of T. In light of the findings with supraphysiological doses of T, we suggest that treatment with T at doses producing physiological levels in women with sexual dysfunction are expected to produce limited and minimal adverse effects. PMID: 20722789