Abdulmaged M. Traish, PhD,* and Louis J. Gooren, MD, PhD†

*Departments of Biochemistry & Urology, Boston University School of Medicine, Boston, MA, USA; †VU medical center- Endocrinology, Amsterdam, the Netherlands.

Abdulmaged Traish, PhD, Laboratory for Sexual Medicine Research, Boston University, 700 Albany Street, W-607, Boston, MA 02118, USA. Tel: +1 617 638 4578; Fax: +1 617 638 5412; E-mail: [email protected].

Abstract

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 supraphysi- ological (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.

Traish AM, and 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;7:3758-3764.

Key Words. Testosterone; Female to Male Transsexual; Adverse Effects; Breast Cancer; Sexual Dysfunction; Safety of Testosterone.

Introduction

The long-term safety of testosterone (T) therapy in women with sexual dysfunction remains a contentious issue in the field of women’s sexual health [1-4]. More recently the International Consensus on Sexual Medicine Committees (#23) (ICSM Committees #23) [5,6] on “Endocrine Aspects of Women’s Sexual Dysfunction,” which convened as part of the 3rd International Consultation on Sexual Medicine, held in Paris, July 10-13, 2009 and sponsored by the World Health Organization, also made recommendations on T therapy in women, discouraged diagnosis and treatment of women with sexual dysfunction with T therapy, citing lack of long-term safety [5,6]. A serious concern regarding the utility of such rec-ommendations is that neither the Endocrine Society Guidelines Panel [7] nor the ICSM Committees (#23) [5,6] comprehensively assessed the evidence available in literature on use and safety of T in women. The safety of long-term use of T in female-to-male transsexuals (FMT) [8-12] was not discussed in the aforementioned reports [5-7]. Given that no serious adverse events were reported with pharmacological doses of T administered for prolonged time periods [8-12], such findings strongly suggest that physiological T treatment in women with sexual dysfunction is expected to be safe and, at best, produces minimal adverse events. Here we provide a summary of discussions from various clinical and research settings on use of supraphysiological T doses in FMT with no serious adverse effects.

Safety Concerns Regarding Physiological T Therapy in Women

Clinical studies on the efficacy and safety of physi-ological T therapy in women with androgen insuf-ficiency and sexual dysfunction have demonstrated significant improvement in the various domains of sexual function with minimal side effects [13-18]. Van Staa and Sprafka [19] discussed the safety out-comes in women using T therapy in the clinical setting in which 2,103 women were treated with T with 6,309 control subjects. There were no major differences in the rate of Ischemic Heart Disease or Breast Cancer in women using T compared with controls. Further, no differences were noted in outcomes with or without hormone replacement therapy. There were no significant cases of clitorimegaly. However, there was an increase in acne and hirsutism, which were noted in many prior studies discussed herein.

Recently, Braunstein [20] and Shufelt and Braunstein [21,22] suggested that the major adverse reactions of physiological T administration in women were hirsutism and acne. Within the physiological doses of T, there do not appear to be increased cardiovascular risk factors and most of the data available to date support a neutral or beneficial effect of T. No increased risks in breast cancer, hepatotoxicity, neurobehavioral abnormalities or sleep apnea have been reported with use of physiological doses of T. Clitoris growth increases with T administration, but this growth is limited in adult mature women. In young women, however, the potential growth of the clitoris is more marked. Physiological levels of T have been shown to have minimal effects on clitoral enlargement in some women [19,23]. In a study by Davis et al. [13] more than 520 women were treated with T with only four women ( < 1%) experiencing clitoral enlargement, albeit mild, and none withdrew from the study because of clitoral growth.

The therapeutic administration of T in physiologic doses was deemed safe for up to several years [20-22]. Several recent reports have addressed the safety of T therapy women and concluded that T therapy improved sexual function with minimal adverse effects on women’s health [19,24,25].

Studies of Pharmacological T therapy in FMTs

To shed more light on the safety of physiological T use in women with androgen insufficiency, we reviewed data from studies investigating the effects of pharmacological T administration in FMT for periods ranging from 18 to 36 months. The effects of T on laboratory variables (Table 1) and clinical endpoints, such as cardiovascular morbidity and mortality, over a longer period were assessed. The findings from such studies are summarized in Tables 1-3. In FMT, T therapy produced small changes in lipid profiles and did not produce significant changes in liver enzymes. Further, hemoglobin and hematocrit rose upon T administration but remained within the physiological range. The most prominent effects of administration of high- doses of T in FMT were on skin and clitoris [8,9]. The ovaries exhibited some signs of polycystic characteristics (Table 2). T treatment also caused preservation of bone mass, increased weight, visceral fat, and hematocrit, and decreased high- density lipoprotein cholesterol, albeit nonsignifi- cantly (Tables 1 and 3). No significant changes were noted in blood pressure, insulin sensitivity, fibrinolytic markers, arterial stiffness, and levels of von Willebrand factor, fibrinogen, and interleukin-6 [8,9,39]. These data suggest that although some markers of cardiovascular risk factors showed a shift to a negative risk profile, others were not affected, indicating that androgen effects on cardiovascular risk markers in women are not universally negative [8,9]. It should be emphasized that as the T doses used in treatment of FMT are supra-physiological, it is reasonable to speculate that relative to the supra-physiological doses reported in various studies, the adverse effects of physiological doses of T on cardiovascular function in women will be markedly reduced [8-11,26].

Table 1. Effects of pharmacological testosterone on total T levels, lipids, hemoglobin, and hematocrit in female-to-male transsexuals.

Table 2. Effects of T administration on ovaries, endometrium, and breast tissue in female-to-male transsexuals.

Jacobeit etal. [12,26] examined the effects of long-acting T in FMT over a period of 36 months. No serious side effects were observed over the study period. T caused a small yet significant decrease in plasma total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) but exerted no changes in high-density lipoprotein cholesterol (HDL-C), triglycerides (TGs), or liver enzymes. Modest increases in hemoglobin and hematocrit were noted, but the values remained within the physiological range (Table 1). Breasts and gonads/internal genitalia did not show pathological changes over the observation period (Table 2). These data suggest that T use in FMT produced no significant side effects over a long time period. In contrast to the aforementioned studies, Goh et al. [40] showed significantly higher levels of TGs, TC, LDL-C, and apolipoprotein-B (Apo B) and a significantly lower level of HDL-C in T-treated women. These observations indicate that T at supra-physiological doses may promote atherogenicity in women. Also, a potential cardiovascular risk of high dose of T was reported by Emi et al. [41] who noted that long-term and high- dose administration of T may cause increased arterial stiffness in FMT transsexuals and suggested a periodic checkup and pharmacological therapies for hypertension to be tailored on an individual basis to prevent atherosclerosis and cardiovascular events. In successive clinical studies of side effects of cross-sex hormone administration of the same population, no evidence was found in support of longer term T administration causing increased cardiovascular morbidity and mortality [39,42,43]. A recent review pertaining to the potential adverse effects of T on breast tissue suggested that there is no substantiated association between T levels and increased risk of breast cancer [44].

Several other studies have suggested that T increased cortical bone thickness and bone mineral density in FMT and that T treatment did not result in significant adverse effects [28,37,38,45]. Some of the effects of long-term T administration in young, non-obese, female subjects include increased visceral fat [35]. T treatment also significantly reduced adiponectin serum levels in FMT [30] but this treatment did not significantly alter lipid profiles or adrenal steroidogenesis [46]. Furthermore, Perrone et al. [31] showed that exogenous T administration did not stimulate endometrial proliferation in FMT and may even exert atrophic effects on the endometrium. T treatment in FMT also caused marked reduction of glandular mammary gland tissue and prominence of fibrous connective tissue. Recently, several studies have focused on the potential adverse effects of T on breast tissue [10,27,33,34,47-49]. Most of these studies reported no serious adverse events with long-acting T with the exception of a single case of breast carcinoma [48] and several cases of ovarian cancer. These changes are similar to those observed at the end-stage of menopausal mammary involution [34,39,42,47].

The information derived from observational and uncontrolled studies in FMTs carry inherent limitation because of varying study designs, sample sizes, durations of therapy, formulations of T, and route of administration, as well as the clinical end points measured [50]. Further, lack of randomized, placebo control clinical trials in FMTs, for obvious reasons, contributes to the limitations of such studies. These methodological shortcomings contribute to the perceived low quality of evidence in such studies. Nevertheless, information gathered from these studies over the past three decades have contributed immensely to the advancement of management of gender reassignment with considerable success and with limited serious side effects [8,9,39]. Further the limited adverse effects observed with the pharmacological doses of T in FMT suggest that adverse effects of physiological T doses would be much less serious and limited in scope and scale.

Table 3. Effectc of T administration on body composition and bone density in female-to-male transsexual.

Summary and Discussion

T is an endogenous sex steroid hormone produced by the ovaries and the adrenal in women and plays an important physiological role in women’s health [51]. T insufficiency in women impacts women’s sexual health [52]. It is logical to speculate that in women with androgen insufficiency, physiological T replacement therapy restores or improves some domains of sexual function, especially in surgically or naturally postmenopausal women. Clinical studies have documented positive effects of T therapy on women sexual function [ 13—18,24,53— 57]. Nevertheless, fear of adverse effects of T in women has been used as an argument to halt or prevent diagnosis of androgen deficiency in women and to halt use of T in treatment of women’s sexual dysfunction [1,5-7]. Unfortunately, the purported fear of T replacement therapy in women remains unsubstantiated, at best. Considerable knowledge was gained from treatment of FMT with supra- physiological doses of T with no serious adverse events reported [6,8,9,39,43]. These findings strongly suggest that physiological doses of T needed to treat women with androgen insufficiency and sexual dysfunction are significantly far lower than those pharmacological doses of T needed to treat sex reassignment and would produce minimal adverse effects. This conclusion is corroborated by a host of studies that examined use of physiological T in women treated for sexual dysfunction for periods ranging from 6 months to 4 years [13-18,24,53-57].

Conflict of Interest

None.

Statement of Authorship

Category I

• (a) Conception and Design: Abdulmaged M. Traish; Louis J. Gooren
• (b)Acquisition of Data: Louis J. Gooren; Abdulmaged M. Traish
• (c)Analysis and Interpretation of Data: Abdulmaged M. Traish; Louis J. Gooren

Category 2

• (a)Drafting the Article: Abdulmaged M. Traish; Louis J. Gooren
• (b)Revising It for Intellectual Content: Abdulmaged M, Traish; Louis J. Gooren

Category 3

• (a) Final Approval of the Completed Article: Abdulmaged M. Traish; Louis J. Gooren

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