Methodology and challenges to recruitment to a randomized, double-blind, placebo-controlled trial of oral DHEA in postmenopausal women.

OBJECTIVE: To report on the issues encountered in the recruitment of healthy naturally menopausal women in the community to a randomized placebo-controlled trial of dehydroepiandrosterone (DHEA) therapy for treatment of loss of sexual desire. METHODS: Recruitment of women was achieved by advertising and media publicity. We have reported on the method by which women initially contacted us and the reasons for nonparticipation. RESULTS: Nine hundred and eighteen women contacted us about participating in the study; 706 of these were telephoned screened, and 93 of these (10%) women were randomized to therapy. The main determinants for nonparticipation included ineligibility on phone screening (58%), withdrawal of interest either before or after screening (55%), and preexisting pathology after attending for screening (8%). CONCLUSIONS: Despite ongoing interest by women to participate in research for therapies to treat low libido, concerns about the use of any hormonal treatment and the time poverty experienced by many women at midlife present new barriers to recruitment and need to be considered in assessing the feasibility of studies in this field.

Effects of the route of estrogen administration on insulinlike growth factor-I, IGF binding protein-3, and insulin resistance in healthy postmenopausal women: results from a randomized, controlled study.

OBJECTIVE: Oral estrogen therapy suppresses insulin like growth factor I (IGF-I) levels, whereas conventional dose transdermal estradiol (E2) does not. However, it has been proposed that if sufficiently high serum E2 levels are achieved, nonoral E2 will also suppress serum IGF-I. The aim of the study was to investigate the effects of intranasal E2 with norethisterone (E2/NET) versus oral E2/NET acetate on IGF-I, IGF binding protein 3, and insulin resistance in postmenopausal women. DESIGN: This was a randomized, multicenter, double-blind, double-dummy trial. Postmenopausal women were randomized to receive either daily intranasal E2/NET (175 microg/275 microg) as a spray and a placebo tablet (n = 41) or oral E2/NET acetate (1 mg/0.5 mg) plus placebo intranasal spray (n = 41) for 1 year. Fasting plasma concentrations of IGF-I, IGF binding protein 3, glucose and insulin, glucose and insulin at 120 minutes post-glucose challenge, and the homeostasis model assessment for insulin resistance were assessed at baseline and after 52 weeks of treatment. RESULTS: The two groups were well matched for all clinical and biochemical parameters at baseline. There were no significant between-group differences for fasting and 120-minute glucose, insulin, homeostasis model assessment for insulin resistance, and IGF binding protein 3. The mean IGF-I level at week 52 was significantly lower for women treated with oral versus intranasal therapy (116 +/- 21 [SD] versus 134 +/- 33 [SD], P = 0.005) and the mean difference in change over 52 weeks in IGF-I was significantly different between groups (-19, 95% CI:-37 to -1, P = 0.04). CONCLUSIONS: In healthy postmenopausal women, intranasal E2 at a dose that results in serum levels that exceed the proposed threshold for growth hormone and IGF-I effects, does not alter IGF-I levels. This suggests that the effect of exogenous estrogen on IGF-I is a function of the method of administration rather than being dose related.

Safety and efficacy of a testosterone metered-dose transdermal spray for treating decreased sexual satisfaction in premenopausal women: a randomized trial.

BACKGROUND: It is not known whether premenopausal women who report low sexual satisfaction and have low circulating testosterone levels will benefit from testosterone therapy. OBJECTIVE: To evaluate the effects of exogenous testosterone in premenopausal women reporting diminished sexual function. DESIGN: Randomized, double-blind, placebo-controlled, dose-ranging trial. SETTING: 6 Australian medical centers. PATIENTS: 261 women age 35 to 46 years who reported a decrease in satisfying sexual activity relative to their younger years and had a morning serum free testosterone level less than 3.8 pmol/L (<1.1 pg/mL). INTERVENTION: 3 different doses of testosterone administered by a metered-dose transdermal spray for 16 weeks or placebo. MEASUREMENTS: The primary outcome was the mean number of self-reported satisfactory sexual events (SSEs) over 28 days at week 16. The frequency of SSEs, total number of sexual events (every 4 weeks), scores from the modified Sabbatsberg Sexual Self-Rating Scale and the Psychological General Well-Being Index, and safety variables were also measured. RESULTS: The number of SSEs increased during the treatment period in the active treatment groups and the placebo group. The mean number of SSEs over 28 days at week 16 was statistically significantly greater for women treated with the intermediate dose of testosterone therapy (one 90-microL spray) than for women treated with placebo. The least-squares mean was 2.48 versus 1.70 SSEs, respectively (event rate ratio, 1.49 [95% CI, 1.01 to 2.18]; P = 0.04). The frequency of SSEs in women treated with low and high doses of testosterone did not differ from that in women who took placebo. The rate ratios based on the least-squares mean rates of SSEs during weeks 4 to 16 for each treatment group showed statistically significant or borderline significant increases in all testosterone groups compared with the placebo group. The rate ratios for the one 56-microL spray, one 90-microL spray, and two 90-microL sprays treatment groups were 1.34 (CI, 0.97 to 1.85; P = 0.081), 1.48 (CI, 1.07 to 2.06; P = 0.018), and 1.38 (CI, 1.00 to 1.92; P = 0.052), respectively. At week 16, 95% of women treated with the one 90-microL dose had a free testosterone level less than the upper limit of the reference range for women. The most frequently reported adverse event was hypertrichosis, which was dose-related and mostly confined to the application site. No clinically relevant changes in blood test values, serum biochemical variables, or vital signs occurred. LIMITATION: The study duration was short, and the placebo effect was strong. CONCLUSION: A daily 90-microL dose of transdermal testosterone improves self-reported sexual satisfaction for premenopausal women with reduced libido and low serum-free testosterone levels by a mean of 0.8 SSE per month. The rate of SSEs with higher and lower testosterone doses did not differ from that with placebo.

Endogenous androgen levels and cardiovascular risk profile in women across the adult life span.

OBJECTIVE: Whether endogenous androgen levels contribute to the cardiovascular disease (CVD) risk profile in women is controversial. The purpose of this study was to investigate systematically the relationships between serum levels of endogenous androgens and sex hormone-binding globulin (SHBG) and biochemical CVD risk profile, taking other known risk factors into account. DESIGN: This community-based cross-sectional study included 587 non-healthcare-seeking-women, aged 18 to 75 years, who were randomly recruited from the community via the electoral roll from April 2002 to August 2003. Participants were euthyroid; had no usage of exogenous steroids; had no history of tubal ligation, hysterectomy, or bilateral oophorectomy; and did not have hyperprolactinemia or polycystic ovarian syndrome. The relationships between total testosterone, SHBG, free testosterone, dehydroepiandrosterone sulfate, and androstenedione and high-sensitivity C-reactive protein (CRP) and lipids were explored using linear regression with natural logarithm (ln) -or square root-transformed data as indicated. Issues of nonlinearity and interaction were addressed by the inclusion of extra regression terms where appropriate. We determined the change in the proportion of variation for each marker of the CVD risk profile explained by the addition of each hormone term to the models, having adjusted for age, body mass index, smoking, alcohol, and exercise. RESULTS: Menopausal status did not influence the statistical models for high-sensitivity CRP and high-density lipoprotein cholesterol, but for both low-density lipoprotein cholesterol and triglycerides, the proportion of variation explained by the models was substantially less in postmenopausal than in premenopausal women. Almost all of the highly statistically significant findings were related to the addition of the SHBG terms to the models. The changes in r2 values were highly statistically significant for the addition of the SHBG terms to the models for ln CRP and ln high-density lipoprotein for both pre- and postmenopausal women (P <= 0.01 and < 0.001, respectively) and for ln triglycerides in postmenopausal (P < 0.001) and premenopausal women (P < 0.01). CONCLUSIONS: Endogenous testosterone and the adrenal preandrogens per se are not significant independent determinants of circulating high-sensitivity CRP or lipoprotein lipids. Our analyses provide further support for the independent predictive value of low SHBG levels for CVD risk profile and an independent contribution of the menopausal transition to the determination of low-density lipoprotein cholesterol and triglycerides.

Testosterone aromatization and cognition in women: a randomized, placebo-controlled trial.

OBJECTIVE: To explore whether inhibition of the conversion of testosterone to estradiol modifies the effects of testosterone on cognition in 61 healthy, estrogen-treated postmenopausal women. DESIGN: Seventy-six postmenopausal women using transdermal estrogen for at least 8 weeks, with a serum total testosterone less than 1.2 nmol/L participated in a single-center, double-blind, randomized, placebo-controlled study. All participants received transdermal testosterone, 400 muL of a 0.5% testosterone gel, daily and were randomized to receive either letrozole 2.5 mg/day or an identical placebo tablet. The main outcome measure was cognition, evaluated using a comprehensive battery of standardized neuropsychological tests, at baseline and week 16. RESULTS: Thirty women in each group completed the study. Free testosterone increased from baseline in both groups, with no difference between groups. Free testosterone levels achieved were below the 90th centile for young women in 80% of the participants at week 16. Serum estradiol and sex hormone-binding globulin levels did not differ from baseline or between groups during the study. No clinically significant effects of testosterone treatment were seen for attention and working memory, psychomotor speed, or executive function. Significant improvements were seen for immediate and delayed visual and verbal memory and for simple concentration with testosterone therapy, all of which were unaffected by the aromatase inhibitor. CONCLUSIONS: We did not observe any effects of aromatase inhibition on cognition in healthy, estrogen-treated postmenopausal women treated with testosterone. This may be due to insufficient study power or a true lack of effect. However, our findings highlight that the detection of subtle changes in cognition in well women require the development of sensitive instruments and large randomized, controlled trials.

A clinical update on female androgen insufficiency--testosterone testing and treatment in women presenting with low sexual desire.

The diagnosis of female androgen deficiency syndrome is suggested by complaints of a diminished sense of well being, persistent unexplained fatigue and decreased sexual desire, sexual receptivity and pleasure in a woman who is oestrogen-replete and in whom no other significant contributing factors can be identified. The diagnosis is supported by the finding of low circulating concentrations of free testosterone. Barriers to its recognition include the non-specificity of the symptoms and methodological problems due to insensitive testosterone assays. Barriers to its treatment include the unavailability of satisfactory forms of testosterone for administration to women and lack of data regarding long-term safety. Although several conditions lead to clear-cut androgen deficiency, such as hypopituitarism, adrenal and ovarian insufficiency, glucocorticoid therapy and use of oral contraceptives and oral oestrogens, it is important for clinicians to recognise that in normal women, androgen levels decline by 50% from the early 20s to the mid 40s, and hence age-related androgen insufficiency may occur in women in their late 30s and 40s, as well as postmenopausally. Satisfactory measurements of free testosterone requires a sensitive and reliable assay for total testosterone, and quantitation of sex hormone binding globulin, from which free testosterone is readily calculated. Adverse effects of testosterone treatment are few if replacement is monitored to achieve physiological circulating testosterone concentrations. Currently, available methods include testosterone implants and testosterone creams, and transdermal patches and sprays are in development.

Effects of aromatase inhibition on sexual function and well-being in postmenopausal women treated with testosterone: a randomized, placebo-controlled trial.

OBJECTIVE: The extent to which aromatization of testosterone (T) to estradiol is required for the observed effects of testosterone therapy on sexual function and well-being are not known. Therefore, the authors investigated the effects of aromatase enzyme inhibition on sexual function, well-being, and mood in estrogen- and T-replete postmenopausal women in a double-blind, randomized, placebo-controlled study. DESIGN: Postmenopausal women using transdermal estrogen therapy for at least 8 weeks and reporting low sexual satisfaction (score <42 for the Sabbatsberg Sexual Self-rating Scale [SSS]) with a total T value of less than 1.2 nmol/L were treated with 400 muL of a 0.5% T gel (total dose 2 mg) and were randomly assigned to receive treatment with either 2.5 mg/day of letrozole or an identical placebo tablet. Women were assessed at baseline (week -2) and at 0, 4, 8, and 16 weeks. Sexual function was assessed with the SSS, well-being was assessed with the Psychological General Well-being Index, and mood was assessed with the Beck Depression Inventory at 0 and 16 weeks. Eighty-one women were screened, 76 were randomly assigned to a treatment group, and 30 in each group completed the study. Because this was a mechanistic study, only the 60 women who completed the study per protocol were included in the final analysis. RESULTS: Total T and calculated free T increased from baseline in both groups, with no difference between groups. At 16 weeks, estradiol, sex hormone-binding globulin, fasting lipids, lipoprotein(a), and C-reactive protein did not differ from baseline or between groups. Significant increases in total Sabbatsberg Sexual Self-rating Scale scores, total Psychological General Well-being Index scores, and a reduction in Beck Depression Inventory scores from baseline to 16 weeks was seen for both treatment groups, with no effect of treatment allocation. No adverse treatment effects were reported. CONCLUSIONS: Increases in total and free T in the physiologic range in postmenopausal women were associated with improved sexual satisfaction, well-being, and mood. In this study, aromatase inhibition did not influence any of these outcomes. Short-term transdermal T therapy did not modify fasting lipids, lipoprotein(a), or C-reactive protein.

Clinical evaluation of women presenting with low libido and determination of whether androgen therapy might be appropriate.

The assessment of female sexual dysfunction (FSD) is often challenging in the clinical setting. Although androgen deficiency is regarded as a major cause for FSD, the causes of this condition are multifactorial. Women presenting with FSD require thorough clinical evaluation to determine the cause of FSD. Androgen therapy should be used in women only when clinical and biochemical parameters indicate that FSD stems from androgen deficiency. This review outlines the various causes of FSD, clinical and biochemical investigations required to diagnose androgen deficiency, and options for treatment of the woman found to have androgen deficiency as a cause of FSD.

What is the rationale for androgen therapy for women?

To date, no formal definition of female androgen insufficiency (FAI) based on strong epidemiological data exists. However the proposed key symptoms of FAI, being reduced libido, diminished well-being, and lowered mood, have been reported to respond well to testosterone replacement, generally without significant adverse effects. Androgens are quantitatively the predominant sex steroid in women, circulating in the micro- and nanomolar concentration range, compared with picomolar levels of estrogens. Androgens have important physiological roles in women, acting both as precursors for estrogen biosynthesis and directly via the androgen receptor. The most significant biologically active androgen is testosterone, which circulates bound tightly to sex hormone binding globulin and loosely to albumin. Circulating androgen levels decline in the years preceding menopause. This may be attributed to the gradual reduction in adrenal androgen production with age and to the loss of cyclical ovarian androgen production in the late reproductive years. Those who experience surgical menopause, have adrenal insufficiency or pituitary insufficiency, or those who experience premature ovarian failure, also have reduced androgen production. Androgen replacement therapy in the form of either dehydroepiandrosterone or testosterone is becoming increasingly widespread for the treatment of FAI. Evidence exists for the benefits of such therapy in relieving both the physical and psychological symptoms thought to be due to FAI in clinically affected women. However, clear guidelines regarding the diagnosis of androgen insufficiency, optimal therapeutic doses, and long-term safety remain lacking.