From Nature Clinical Practice Endocrinology & Metabolism

Henry Burger

Background: Hypopituitarism in women can cause adrenal and ovarian dysfunction, resulting in severe androgen deficiency. Although testosterone replacement therapy has been shown to be beneficial in androgen-deficient men, its effects in women are unclear. Objective: To assess the efficacy of low-dose testosterone replacement therapy in androgen-deficient premenopausal women with hypopituitarism. Design and Intervention: This 12-month, randomized, double-blind, placebo-controlled trial enrolled women aged 19-50 years with hypopituitarism leading to hypogonadism and/or adrenal insufficiency. Eligible participants had a serum free testosterone level <10.75 pmol/l, were estrogen replete, and were either growth-hormone-naive or else had been receiving a stable dose of growth hormone for >2 years. Exclusion criteria included androgen therapy or treatment with agents known to affect BMD within 1 year before enrollment. Participants received a total of 300µg transdermal testosterone, given as two 150µg patches, or two placebo patches. Free testosterone levels were monitored and the dose reduced to 150µg if necessary; however, increases in dose were not made. Study visits were carried out at baseline and at 3-month intervals thereafter, and included measurement of testosterone levels, BMD, and body composition. The Beck Depression Inventory was used to assess mood and the Derogatis Interview for Sexual Functioning was used to determine sexual function; in addition, general health, quality of life, and cognition were also measured. Outcome Measures: The primary outcome measures were BMD, body composition, and behavioral function. Results: A total of 24 women received testosterone and 27 received placebo. Baseline characteristics were similar, with pituitary adenomas being the most common cause of hypopituitarism. Overall, 59% of participants were depressed and 68% had reduced sexual functioning. Mean free testosterone levels were below the normal range for women of reproductive age at baseline, but increased with testosterone treatment. Testosterone significantly increased BMD at the hip (P = 0.023) and radius (P = 0.007), but not the posteroanterior spine. Compared with placebo, testosterone increased fat-free mass (P = 0.040) and muscle area at the mid-femur (P = 0.038); however, total, intra-abdominal, and subcutaneous fat cross-sectional area and body weight were not affected. Beneficial effects of testosterone on mood (P = 0.029) and sexual functioning (P = 0.044) were observed. There was also a marked improvement in the general health and quality of life of patients receiving testosterone, although changes in cognition were limited. Women receiving testosterone had a 6% mean increase in total cholesterol levels when compared with those receiving placebo. Acne was reported by 8 women receiving testosterone, compared with only one woman in the placebo group (P = 0.004). The most common adverse effect in both groups was skin irritation at the patch application site. Conclusion: Low-dose testosterone was well tolerated and associated with improvements in BMD, body composition, mood, sexual function, and quality of life.

Fertil Steril. 2006 May 31; [Epub ahead of print]

Zang H, Carlstrom K, Arner P, Linden Hirschberg A.

Department of Obstetrics and Gynecology, Karolinska University Hospital.

OBJECTIVE: Little is known about metabolic effects of testosterone treatment in postmenopausal women. The aim of the study was to compare the treatment effects of testosterone, estrogen, and testosterone plus estrogen on insulin sensitivities, body compositions, and lipid profiles in healthy postmenopausal women. DESIGN: An open, randomized clinical study with parallel group comparison. SETTING: Women's health clinical research unit at a university hospital. PATIENT(S): Sixty-three naturally postmenopausal women participated in the study. INTERVENTION(S): The participants were randomly assigned to 3 months of treatment with testosterone undecanoate (40 mg every second day), estradiol valerate (2 mg daily), or the combination of both. MAIN OUTCOME MEASURE(S): Insulin sensitivity assessed by euglycemic hyperinsulinemic clamp, body composition, and serum lipids. RESULT(S): Insulin-induced glucose disposal was reduced by approximately 20% after treatment with testosterone alone, and after the combined treatment, but not by estrogen alone. Body weight, but not total body fat, increased significantly by about 1 kg in all groups. Lean body mass was significantly increased in the group of combined treatment and tended to be increased by testosterone alone. High-density lipoprotein (HDL)-cholesterol decreased significantly by testosterone treatment. In contrast, HDL-cholesterol increased, whereas low-density lipoprotein (LDL)-cholesterol and lipoprotein-(a) [Lp(a)] decreased with estradiol treatment. CONCLUSION(S): We conclude that 3 months of treatment with testosterone undecanoate in postmenopausal women induces insulin resistance and an adverse serum lipid profile but may increase lean body mass.

Menopause. 2006 Jan-Feb;13(1):65-71.

Bell RJ, Donath S, Davison SL, Davis SR.

The Jean Hailes Foundation, Monash University, Clayton Victoria, Australia.

OBJECTIVE: We investigated whether there is a relationship between androgens levels and well-being in pre- and postmenopausal women. DESIGN: We randomly recruited 1423 women aged 18 to 75 years from the community via the electoral roll. Each provided a morning blood sample and completed the Psychological General Well Being Index questionnaire on the same day. Women were excluded if they took medication for any psychiatric illness, had abnormal thyroid function, or had documented polycystic ovarian syndrome. Analysis was by linear regression for well-being, including demographic and lifestyle variables as well as serum levels of androgens. RESULTS: We included 1224 women in the analysis. Being partnered was positively associated with well-being in premenopausal women. In postmenopausal women, well-being was positively related to age and exercising, whereas smoking, obesity, and postmenopausal hormone therapy use were each negatively associated with well-being. None of the measured androgens (total and free testosterone, dehydroepiandrosterone sulfate, and androstenedione) made an independent contribution to well-being in postmenopausal women (n = 603). However, for premenopausal women (n = 621), levels of dehydroepiandrosterone sulfate were independently and positively associated with the domain score for vitality. CONCLUSIONS: Our findings do not support an important independent role for androgens as determinants of well-being in postmenopausal women. That dehydroepiandrosterone sulfate alone is associated with greater vitality in premenopausal women is of interest but requires further evaluation as an a priori hypothesis in another study.

Menopause. 2006 Jan-Feb;13(1):46-56

Leiblum SR, Koochaki PE, Rodenberg CA, Barton IP, Rosen RC.

University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, USA.

OBJECTIVE: To determine the prevalence of hypoactive sexual desire disorder (HSDD) among US women by reproductive status and age and to explore the correlates of sexually related distress. DESIGN: The Women's International Study on Health and Sexuality questionnaire was mailed to a national sample of US women in 2000. The survey included validated questionnaires: the Short Form-36, which measures overall health status; the Profile of Female Sexual Function, which assesses sexual desire; and the Personal Distress Scale, which measures distress caused by low desire. Four groups of women were studied: surgically postmenopausal, aged 20 to 49 years and 50 to 70 years; premenopausal, aged 20 to 49 years; and naturally postmenopausal, aged 50 to 70 years. Clinically derived cutoff Profile of Female Sexual Function and Personal Distress Scale scores were used to classify women with HSDD and determine its prevalence. The relations between sexual desire and frequency of sexual activity or relationship satisfaction were assessed. Overall health status of HSDD women and women with normal desire were compared. RESULTS: The prevalence of HSDD ranged from 9% in naturally postmenopausal women to 26% in younger surgically postmenopausal women. The prevalence of HSDD was significantly greater among surgically postmenopausal women, aged 20 to 49 years, than premenopausal women of similar age, whereas there were no significant differences in the prevalence between surgically postmenopausal women, aged 50 to 70 years, and naturally postmenopausal women. For many women, HSDD was associated with emotional and psychological distress as well as significantly lower sexual and partner satisfaction. HSDD was also associated with significant decrements in general health status, including aspects of mental and physical health. CONCLUSIONS: HSDD is prevalent among women at all reproductive stages, with younger surgically postmenopausal women at greater risk, and is associated with a less active sex life and decreased sexual and relationship satisfaction.

Eur J Endocrinol. 2006 Jan;154(1):131-9

Leao LM, Duarte MP, Silva DM, Bahia PR, Coeli CM, de Farias ML.

Disciplinas de Endocrinologia dos Hospitais Universitários: Clementino Fraga Filho (HUCFF), Universidade Federal do Rio de Janeiro e Pedro Ernesto (HUPE), Universidade do Estado do Rio de Janeiro, RJ. Brazil.

BACKGROUND: There has been a growing interest in treating postmenopausal women with androgens. However, hyperandrogenemia in females has been associated with increased risk of cardiovascular disease. OBJECTIVE: We aimed to assess the effects of androgen replacement on cardiovascular risk factors. DESIGN: Thirty-seven postmenopausal women aged 42-62 years that had undergone hysterectomy were prospectively enrolled in a double-blind protocol to receive, for 12 months, percutaneous estradiol (E(2)) (1 mg/day) combined with either methyltestosterone (MT) (1.25 mg/day) or placebo. METHODS: Along with treatment, we evaluated serum E(2), testosterone, sex hormone-binding globulin (SHBG), free androgen index, lipids, fibrinogen, and C-reactive protein; glucose tolerance; insulin resistance; blood pressure; body-mass index; and visceral and subcutaneous abdominal fat mass as assessed by computed tomography. RESULTS: A significant reduction in SHBG (P < 0.001) and increase in free testosterone index (P < 0.05; Repeated measures analysis of variance) were seen in the MT group. Total cholesterol, triglycerides, fibrinogen, and systolic and diastolic blood pressure were significantly lowered to a similar extent by both regimens, but high-density lipoprotein cholesterol decreased only in the androgen group. MT-treated women showed a modest rise in body weight and gained visceral fat mass relative to the other group (P < 0.05), but there were no significant detrimental effects on fasting insulin levels and insulin resistance. CONCLUSION: This study suggests that the combination of low-dose oral MT and percutaneous E(2), for 1 year, does not result in expressive increase of cardiovascular risk factors. This regimen can be recommended for symptomatic postmenopausal women, although it seems prudent to perform baseline and follow-up lipid profile and assessment of body composition, especially in those at high risk of cardiovascular disease.

Eur J Endocrinol. 2006 Jan;154(1):1-11

Arlt W.

Division of Medical Sciences, Institute of Biomedical Research, Endocrinology, Room 233, University of Birmingham, Birmingham, B15 2TT, UK.

Androgens in women either derive from direct ovarian production or from peripheral conversion of the adrenal sex steroid precursor, dehydroepiandrosterone, towards active androgens. Therefore, loss of adrenal or ovarian function, caused by Addison's disease or consequent to bilateral oophorectomy, results in severe androgen deficiency, clinically often associated with a loss of libido and energy. Importantly, physiological menopause does not necessarily lead to androgen deficiency, as androgen synthesis in the ovaries may persist despite the decline in estrogen production. However, the definition of female androgen deficiency, as recently provided by the Princeton consensus statement, is not precise enough and may lead to over-diagnosis due to the high prevalence of its diagnostic criteria: androgen levels below or within the lower quartile of the normal range and concurrent sexual dysfunction. Importantly, physiological menopause is not necessarily associated with androgen deficiency and therefore does not routinely require androgen therapy. Current replacement options include transdermal testosterone administration or dehydroepiandrosterone treatment, both of which have been shown to result in significant improvements, in particular in libido and mood, while effects on body composition and muscular function are not well documented. It is important to keep in mind that the number of randomized controlled trials is still limited and that currently none of the available preparations is officially approved for use in women. Currently, androgen replacement should be reserved for women with severe androgen deficiency due to an established cause and matching clinical signs and symptoms.

J Clin Endocrinol Metab. 2006 May 23; [Epub ahead of print]

Testosterone use in men and its effects on bone health. A systematic review and meta-analysis of randomized placebo-controlled trials.

Tracz MJ, Sideras K, Bolona ER, Haddad RM, Kennedy CC, Uraga MV, Caples SM, Erwin PJ, Montori VM.

Knowledge and Encounter Research Unit, Department of Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota, USA; Mayo Library, Mayo Clinic College of Medicine, Rochester, Minnesota, USA; Division of Endocrinology, Department of Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.

Context: Androgen-deficient men are at increased risk of osteoporosis. The extent to which testosterone can prevent and treat osteoporosis in men remains unclear. Objective and Design: We performed a systematic review and meta-analysis of randomized placebo-controlled trials in men to estimate the effect of testosterone use on bone health outcomes. Data sources: Librarian-designed search strategies using MEDLINE (1966 to March 2005), EMBASE (1988 to March 2005), and Cochrane CENTRAL (inception to March 2005); review of reference lists from included studies; and content expert files. Data Collection: Independently and in duplicate, we assessed the methodological quality of the eligible trials and collected data on bone mineral density and bone fractures at the longest point of complete follow-up. Data Synthesis: We included 8 trials enrolling 365 patients. Two trials followed patients for more than 1 yr. Meta-analysis of these trials showed that, compared with placebo, intramuscular testosterone was associated with an 8% (CI 4%, 13%) gain in lumbar bone mineral density and transdermal testosterone had no significant impact. Testosterone use was associated with a non-significant 4% (CI -2%, 9%) gain in femoral neck bone mineral density with unexplained differences in results across trials (26% of these differences were not explained by chance alone). No trials measured or reported the effect of testosterone on fractures. Conclusions: Intramuscular testosterone moderately increased lumbar bone density in men; the results on femoral neck bone density are inconclusive. Without bone fracture data, the available trials offer weak and indirect inferences about the clinical efficacy of testosterone on osteoporosis prevention and treatment in men.