Role of testosterone in the treatment of hypoactive sexual desire disorder

Hypoactive sexual desire disorder (HSDD) is a common clinical problem that may have a very negative impact on a woman's quality of life. Diagnosis and treatment is challenging, as one must keep in mind the complex web of factors influencing sexual functioning alone or in concert. Data suggest that androgens are significant independent factors affecting sexual desire, sexual activity and satisfaction, as well as other components of women's health such as mood and energy. For decades, physicians used various androgen preparations to improve sexual function in women, based on the results of smaller clinical trials and personal clinical observations when taking care of patients. Today, there is substantial body of evidence from randomized placebo-controlled trials that low-dose testosterone treatment is efficacious in women with HSDD who have an established cause of androgen deficiency such as surgical menopause. Recent data support the hypotheses that androgens may also be beneficial in naturally menopausal women or in premenopausal women with low circulating testosterone levels and a decrease in satisfying sexual activity. No single testosterone level has been found to be predictive for low female sexual function, even though women suffering from HSDD commonly have low testosterone levels. The most frequently reported side effects of testosterone treatment are mild hirsutism or acne. Long-term safety is not yet established. Several clinical trials are in progress to further investigate potential benefits and risks of androgen treatment in women with sexual dysfunction.     

Hormones and sexuality: current complexities and future directions

Complex correlations between women's sexual function and psychosexual variables confound the identification of any etiological role for estrogen and androgen deficiencies in sexual dysfunction. Although serum levels of androgens show minimal correlation with women's sexual function, the intracellular production of testosterone from adrenal and ovarian precursors may be relevant. Current research involves the detailed assessment of mid aged and older women, with and without sexual dysfunction, assessing medical and multiple psychosexual parameters, estrogen status, serum testosterone levels by mass spectrometry methods plus total androgen activity by means of androgen metabolites. Identification of any correlation between androgen activity and sexual function is one priority. A second is to confirm safety and efficacy of supplemental systemic estrogen and androgen from early menopause in sexually symptomatic women. Although local estrogen supplementation is effective therapy for loss of genital sexual sensitivity and vaginal elasticity, and reduced potential for lubrication, any systemic testosterone therapy requires concomitant systemic estrogen therapy. In the future, augmentation of estrogen and androgen sexual effects may be possible using certain selective estrogen and androgen receptor modulators.     

Benefits and risks of testosterone treatment for hypoactive sexual desire disorder in women: a critical review of studies published in the decades preceding and succeeding the advent of phosphodiesterase type 5 inhibitors

With advancing age, there is an increase in the complaints of a lack of a libido in women and erectile dysfunction in men. The efficacy of phosphodiesterase type 5 inhibitors, together with their minimal side effects and ease of administration, revolutionized the treatment of erectile dysfunction. For women, testosterone administration is the principal treatment for hypoactive sexual desire disorder. We sought to evaluate the use of androgens in the treatment of a lack of libido in women, comparing two periods, i.e., before and after the advent of the phosphodiesterase type 5 inhibitors. We also analyzed the risks and benefits of androgen administration. We searched the Latin-American and Caribbean Health Sciences Literature, Cochrane Library, Excerpta Medica, Scientific Electronic Library Online, and Medline (PubMed) databases using the search terms disfunção sexual feminina/female sexual dysfunction, desejo sexual hipoativo/female hypoactive sexual desire disorder, testosterona/testosterone, terapia androgênica em mulheres/androgen therapy in women, and sexualidade/sexuality as well as combinations thereof. We selected articles written in English, Portuguese, or Spanish.After the advent of phosphodiesterase type 5 inhibitors, there was a significant increase in the number of studies aimed at evaluating the use of testosterone in women with hypoactive sexual desire disorder. However, the risks and benefits of testosterone administration have yet to be clarified.     

Changes in sexual behavior as a function of plasma sex steroid levels in post-menopausal women

Eight women who had been maintained on a combined estrogen-androgen drug since hysterectomy and bilateral oophorectomy 2 yr previously were investigated for changes in sexual behavior during the course of 1 treatment cycle. Following intramuscular injection of both sex steroids, plasma estradiol levels were within the normal range of young, cycling women but plasma testosterone exceeded the upper limit of normal female values. Sexual motivational behaviors (desire, fantasies and arousal) covaried with plasma steroid levels. Rates of coitus and orgasm, however, were unrelated to the changing levels of circulating hormones. A differential effect of the sex steroids on various aspects of sexual functioning was thus confirmed.     

Decreased androgen concentrations and diminished general and sexual well-being in women with premature ovarian failure

OBJECTIVE: To describe general and sexual well-being in women with premature ovarian failure (POF) and to investigate whether there is a relationship between androgen levels and sexual functioning. DESIGN: Women with POF and healthy volunteers with regular menstrual cycles participated. Participants completed a written questionnaire and underwent hormonal screening. The questionnaire included standardized measures: the Questionnaire for Screening Sexual Dysfunctions, the Shortened Fatigue Questionnaire, and the Symptom Check List-90. Serum hormone measurements included estradiol, total testosterone, bioavailable testosterone, androstenedione, dehydroepiandrosterone, and dehydroepiandrosterone sulfate. RESULTS: Eighty-one women with POF and 68 control women participated in the study. Compared with control women, women with POF reported more complaints of anxiety, depression, somatization, sensitivity, hostility, and psychological distress. Overall women with POF were less satisfied with their sexual life. They had fewer sexual fantasies and masturbated less frequently. Sexual contact was associated with less sexual arousal, reduced lubrication, and increased genital pain. However, the frequency of desire to have sexual contact and the frequency of actual sexual contact with the partner did not differ between women with POF and control women. Women with POF had lower levels of estradiol, total testosterone, and androstenedione. Multiple regression analysis revealed that androgen levels had only a weak influence on sexual functioning; higher total testosterone levels were associated with increased frequency of desire for sexual contact, and higher androstenedione levels were associated with elevated frequency of sexual contact. CONCLUSIONS: Women with POF have diminished general and sexual well-being and are less satisfied with their sexual lives than control women. Although women with POF had lower androgen levels, we did not find an important independent role for androgens in various aspects of sexual functioning.     

The role of androgen in the maintenance of sexual functioning in oophorectomized women

Five aspects of sexual behavior were monitored daily in three groups of women who had undergone total abdominal hysterectomy and bilateral salpingo-oophorectomy approximately 4 years ago for benign disease. One group had been receiving an estrogen-androgen preparation intramuscularly once a month since their surgery (E-A). The second group had been receiving estrogen alone (E) and the third group of women had remained untreated. Plasma estradiol and testosterone were measured at an established baseline and again on days 2, 4, 8, 15, 21, and 28 postinjection. Women who received both sex steroids reported higher rates of sexual desire (p less than 0.01), sexual arousal (p less than 0.01), and numbers of fantasies (p less than 0.01) than those who were either given E or who were untreated. Moreover, changes in these behaviors covaried with plasma testosterone but not with plasma estradiol levels during the treatment month as the drug was being metabolized. Rates of coitus and orgasm were also higher in the E-A group during the first two postinjection weeks (p less than 0.01) coincident with their higher testosterone levels. These findings imply that androgen may be critical for the maintenance of optimal levels of sexual functioning in postmenopausal women.     

Safety of testosterone use in women

Female sexual desire appears to be in part androgen dependent, which has lead to the use of testosterone in women for low libido. Despite this benefit, the long-term safety of testosterone as a hormone replacement or therapy has not been well established. Side effects of testosterone therapy include mild and reversible acne and hirsuitism, as well as changes to the lipid profile with oral, but not transdermal testosterone. Short-term studies, up to 2 years, have shown that for serum plasma testosterone levels at the upper portion or slightly above the reference range for reproductive-aged women, testosterone does not increase the risk of hepatotoxicity, endometrial hyperplasia, or behavioral hostility. No adverse cardiovascular effects including changes in blood pressure, blood viscosity, arterial vascular reactivity, hypercoagulable states, and polycythemia have been shown. Data is mixed with outcomes of breast cancer risk, with some experimental studies suggesting a decrease in estrogen-induced breast epithelial proliferation with low dose testosterone. Additionally, models of superphysiologic testosterone levels, such as polycystic ovarian disease, have not shown an increased risk of breast cancer. As with all hormone therapy in postmenopausal women, testosterone therapy should be individualized and requires that each woman weigh the risk and benefits. Nevertheless, only long-term safety studies will provide conclusive evidence as to testosterone safety in women.     

Androgen enhances sexual motivation in females: a prospective, crossover study of sex steroid administration in the surgical menopause

Various parameters of sexual functioning were assessed in a prospective, crossover investigation of 53 surgically menopausal women. Patients randomly received either an estrogen-androgen combined preparation, an estrogen-alone drug, an androgen-alone drug, or a placebo. Also included were a group of women who had undergone hysterectomy and whose ovaries had been left intact. Two treatment phases, each of 3 months' duration, were separated by an intervening placebo month. Additionally, plasma levels of total estrogens and testosterone were assayed four times during the study concurrent with monitoring of sexual behaviors. It was clear that exogenous androgen enhanced the intensity of sexual desire and arousal and the frequency of sexual fantasies in hysterectomized and oophorectomized women. However, there was no evidence that testosterone affected physiologic response or interpersonal aspects of sexual behavior. These findings suggest that the major impact of androgen in women is on sexual motivation and not on sexual activity per se.     

Sexuality in the climacteric years

Menopause is a time of anatomic, physiological and psychological changes that often influence in the sexuality of aging female. Being sexual functioning an important aspect of health and well-being, doctors should have an holistic approach reassuring about the possibility of treating the various symptoms. The central nervous system is an important target for sex steroid hormone; estrogen, progestagens and androgens are able to modulate several brain functions, and receptors for gonadal steroids have been identified in several brain areas. Because there is no test that physicians can make to assess sexual function, taking a sexual history is probably the most important aspect in the diagnostic and treatment of sexual problems. Hormonal transition with decreasing levels of estrogen and testosterone produces clinical effects, so women need to make adjustments for this period of life. Testosterone is an important component of female sexuality, and alterations in its circulating levels play an important role in psychological and sexual changes that occur after menopause. This is the reason why the research in identifying women who have a decrease androgen active should be aimed. Treatment may include education about sexuality and medical management of symptoms or problems interfering with sexual activity. Also treatment implications and the diverse aspects that may influence on sexuality in the climacteric years are discussed.     

Altered striatal vulnerability to 3-nitropropionic acid in rats due to sex hormone levels during late phase of brain development

Systemic administration of 3-nitropropionic acid (3-NPA) leads to a shortage of cellular ATP and induces striatum-specific lesions that resemble Huntington's disease. Gender differences, in terms of vulnerability of striatum to 3-NPA, have been shown in male rats. The goal of the present study was to determine whether changes in sex hormone levels during the critical period of sexual differentiation (E17-P4) influence striatal vulnerability to 3-NPA. An androgen receptor antagonist, flutamide, or an aromatase-inhibitor, fadrozole hydrochloride, which block conversion of testosterone to estradiol, were administered to embryonic rats during E17-E20 or E18-E20, respectively, with subsequent 3-NPA (20mg/(kg day) for 2 days) treatment during adulthood (8-9 weeks old). Motor behavior and histological changes (IgG exudation due to blood-brain barrier dysfunction and glial fibrillary acidic protein immunoreactivity) were assessed. Treatment with flutamide significantly decreased the 3-NPA-induced motor behavior in male rats, while administration of fadrozole hydrochloride increased atypical motor behavior in female rats. IgG exudation, as well as decreased glial fibrillary acidic protein reactivity, was observed in animals with motor defects. Flutamide decreased testosterone levels in male rats, while fadrozole hydrochloride increased testosterone levels in female rats. These results suggest that prenatal modulation of sexual hormonal levels greatly influences vulnerability to 3-NPA during adulthood and directly correlates to serum testosterone levels.     

WNT4 deficiency--a clinical phenotype distinct from the classic Mayer-Rokitansky-Kuster-Hauser syndrome: a case report

The pathways leading to female sexual determination in mammals are incompletely defined. Loss-of-function mutations in the WNT4 gene appear to cause developmental abnormalities of sexual differentiation in women and mice. We recruited six patients with different degrees of Müllerian abnormalities, with or without renal aberrations and a normal female 46,XX karyotype. A clear androgen excess was found only in one patient. This 19-year-old woman was affected by primary amenorrhoea, absence of Müllerian ducts derivatives, clinical (acne and hirsutism) and biochemical (repeatedly high levels of testosterone) signs of androgen excess. Direct sequencing of her WNT4 gene followed by functional studies in human ovarian cells (OVCAR3) was performed. This patient carried the novel R83C loss-of-function dominant negative mutation in her WNT4, confirming the role of WNT4 in the development and maintenance of the female phenotype in women. Our study can also help refine the phenotype of WNT4 deficiency in humans. In fact, it appears that at least in this limited casuistic small group of patients, the absence of a uterus (and not other Müllerian abnormalities) and the androgen excess are the pathognomonic signs of WNT4 defects, suggesting that this might be a clinical entity distinct from the classic Mayer-Rokitansky-Kuster-Hauser syndrome.     

Androgen insufficiency in women: diagnostic and therapeutic implications

The proposed key symptoms of the female androgen insufficiency syndrome (FAIS) include reduced libido, diminished well being and lowered mood. The diagnosis of FAIS is made on the basis of these symptoms in the setting of a low serum free testosterone level. However, there is currently no readily available inexpensive assay which reliably measures free testosterone levels in the female range. The diagnosis of FAIS is further complicated by the lack of data demonstrating a minimum serum free testosterone level which, if below this, correlates with the symptoms of FAIS. Despite the complexities involved with defining FAIS, the symptoms have been reported to respond well to testosterone replacement. There is a need for formulations of testosterone therapy specifically designed for use in women, along with clear guidelines regarding optimal therapeutic doses and long-term safety data.     

Are androgen steroids acting as pheromones in humans?

In animals, chemosensory communication is successfully used to transmit behaviourally relevant information, e.g. information about sexual status, danger and social organisation. In many instances pheromones might have evolved from hormone-like substances. Consequently, a large number of studies have been carried out in humans, in order to investigate possible pheromonal properties of androgen steroids. Besides discussing the production and perception of androgen steroids, it will primarily be questioned whether their perception can alter mood and behaviour in humans. Therefore, a study has been carried out to investigate whether local preferences can be altered through androstenone exposure. It is shown that heterosexual women and homosexual men prefer seats sprayed with androstenone. However, as this effect is positively correlated with the sensitivity to androstenone, the effect might be due to a general olfactory attraction of low androstenone concentrations. In regard to the conflicting results of studies on putative human pheromones, it will finally be discussed whether the perceptual context and the individual learning history of the perceiver contribute significantly to a successful communication of pheromonal information.     

Sexuality in sexagenarian women

Sexual behavior was examined in 59 healthy, post-menopausal women between 60 and 70 years of age. Subjects were interviewed by a psychologist, completed medical and sexual questionnaires and had a gynecologic exam and blood drawn for determination of estradiol, luteinizing hormone and total and free testosterone. Partners filled out a mail-back sexual questionnaire. Thirty-nine (66%) of the group were coitally active and twenty (34%) were abstinent. The coitally active group reported higher levels of sexual desire (P less than 0.03), greater sexual satisfaction (P less than 0.007), more comfort in expressing sexual preferences (P less than 0.009) and greater pre-menopausal sexual satisfaction (P less than 0.01) and on pelvic examination were noted to have less genital atrophy (P less than 0.0005) than the abstinent group. For the entire sample sexual complaints such as decreased desire and vaginal lubrication in the female and erectile difficulties in the male were reported frequently. Of the hormones studied, higher serum levels of free testosterone were associated with reports of increased sexual desire.     

The relationship between Vitamin D deficiency and polycystic ovary syndrome

BackgroundVitamin D deficiency is frequently seen in patients with polycystic ovary syndrome (PCOS) and has been shown to exhibit multiple effects on the disease process. The purpose of this study was to investigate the role of vitamin D deficiency in complex PCOS pathophysiological pathways.MethodsTwo hundred sixty-seven patients with PCOS were divided into two groups Group 1 with 25(OH)D3 deficiency, and Group 2 with normal 25(OH)D3. Biochemical and hormonal parameters (androgen hormones, gonadotropins, and thyroid function tests) were compared between the two groups.ResultsEighty-six percent of the patients (n=231) were in Group 1 and 14% (n=36) in Group 2. Statistically significantly higher concentrations of serum testosterone, dehydroepiandrosterone-sulfate and LH were determined in Group 1 (p<0.05). 25(OH)D3 concentrations were negatively correlated with body mass index (r=−0.459), serum testosterone (r =−0.374) and dehydroepiandrosterone-sulfate levels (r=−0.418); (all; p< 0.05).ConclusionThe study findings show that low 25(OH)D3 levels are associated with high androgen levels in women with PCOS. Vitamin D deficiency should be considered as an additional risk factor in the development of PCOS. We think that providing vitamin D supplementation for women from identified deficiency areas can reduce the risk of PCOS development.     

Sex and gonadotropic hormones in arteriopathy with lesions of the brain and skin (Sneddon's syndrome)

Changed levels of sex and gonadotropic hormones in the follicular and lutein phases of the menstrual cycle have been revealed in 12 women with Sneddon's syndrome. The detected disorders contribute to the genesis of obstetrical and gynecological abnormalities and of arteriopathy, which are characteristic of this syndrome. Reduced testosterone levels in 3 female and 4 male patients correlate with disordered sexual function.     

Androgene für Frauen?

In women androgens are secreted by both the ovaries and the adrenal glands. Causes of androgen deficiency are ovarian or adrenal failure or therapy with estrogens or glucocorticosteroids. Women with androgen deficiency complain of fatigue and loss of well-being and libido. Replacement with DHEA or testosterone relieves the symptoms and, in the case of testosterone, increases bone density. Long-term effects on the cardiovascular system remain uncertain, as does any influence on breast cancer development. Masculinization and contraindications have to be considered. Widespread use of androgens in women is limited by the lack of data and the lack of suitable androgen preparations that result in physiological serum levels.     

Senile hypogonadism in man and hormone replacement therapy

Aging is accompanied by a progressive decline of testicular function. Whereas fertility persists until a very old age, endocrine function declines progressively and at age 70 yrs, more than 25% of men have hypogonadal testosterone levels. This decline in testosterone plays an important role in a series of signs and symptoms that accompany the aging process such as a decline in virility, in libido and sexual activity, muscle mass and strength, decline in bone mass (osteoporosis), an increase in abdominal fat mass and a decrease in the feeling of general well being. Most of these signs and symptoms have a multifactorial origin, nevertheless, androgen substitution generally improves most of these symptoms, increasing muscle mass and strength, improving libido and sexual activity, decreasing abdominal fat and improving insulin sensitivity as well as the sense of well being, effects which suggest a role of androgen deficiency in their genesis. Side effects of this substitutive therapy, mainly at the level of the prostate, with possible stimulation of a prostatic carcinoma, should be carefully looked for. Before starting any androgen therapy, the presence of a prostatic carcinoma should be excluded by rectal examination and PSA measurement, eventually, in case of doubt, complemented by transrectal echography. Presence of a prostatic carcinoma is an absolute contraindication for androgen therapy. During treatment, development of side effects should be traced by a six monthly rectal examination and PSA determination as well by monitoring of hematocrit and lipid profile.     

Sexual dysfunction in the peri- and postmenopause. Status of incidence, pharmacological treatment and possible risks. A secondary publication

The frequency of female sexual dysfunction increases with age, and the menopausal transition has a negative effect on the sexuality. Pharmacological treatment options for female sexual dysfunction during the peri- and post-menopause include hormone therapy or sildenafil. A limited number of randomized, controlled trials have been conducted and evidence suggests that systemic hormone therapy with estrogen, estrogen/progesterone, estrogen/testosterone and tibolone have a positive impact on sexual dysfunction during the peri- and postmenopause. Further, there is evidence that treatment with local estrogen relieves vaginal dryness and dyspareunia. Recent knowledge on side effects related to hormone therapy necessitates careful evaluation of the indication for hormone therapy and the duration of postmenopausal hormone therapy should be as short as possible. Long-term side effects of testosterone have not yet been fully investigated. A positive effect of sildenafil has been observed in a limited group of women; those with arousal problems but with no desire problems. The results suggest an intensified focus on new pharmaceutical products for the treatment of female sexual dysfunction in the postmenopause. For the time being the effect of testosterone therapy and tibolone on female sexual dysfunction is being investigated. Sexual dysfunction in women (Female Sexual Dysfunction, FSD) is multi-factorial and influenced by physiological, psychological, social and emotional factors. FSD is defined in four diagnostic groups: desire-, arousal-, orgasm- and pain problems. Recently, it has been suggested that the woman herself should assess the dysfunction as distressful to be diagnosed as having a sexual dysfunction [1]. There are only a limited number of well-conducted population surveys on the prevalence of FSD. Further, relatively few randomized, controlled trials of pharmacological treatment of FSD have been carried out.     

Serum androgen levels and insulin resistance in postmenopausal women: association with hormone therapy, tibolone and raloxifene

OBJECTIVE: To assess endogenous androgen and insulin resistance status in postmenopausal women receiving continuous combined hormone therapy (HT), tibolone, raloxifene or no therapy. METHODS: A total of 427 postmenopausal women aged 42-71 years were studied in a cross-sectional design. Among them 84 were taking HT (46 women conjugated equine estrogens 0.625 mg; medroxyprogesterone acetate, 5 mg, CEE/MPA; and 38 women 17beta-estradiol 2 mg; norethisterone acetate 1 mg, E2/NETA); 83 were taking tibolone 2.5 mg; 50 were taking raloxifene HCl 60 mg; and 210 women were not receiving any therapy. Main outcome measures were FSH, LH, estradiol, total testosterone, SHBG, free androgen index (FAI), Delta4-Androstendione (Delta4-A), Dehydroepiandrosterone sulphate (DHEAS) and HOMA insulin resistance index (HOMA-IR). RESULTS: In women not on hormone therapy smoking and older age was associated with lower DHEAS levels. FAI values increased linearly with increasing BMI. Age and BMI were positive determinants of HOMA-IR, while no association was identified between endogenous sex steroids and insulin resistance. CEE/MPA therapy was associated with higher SHBG, lower FAI and lower HOMA-IR values compared to women not on therapy (age and BMI-adjusted SHBG: CEE/MPA 148.8 nmol/l, controls 58.7 nmol/l, p < 0.01; age-adjusted FAI: CEE/MPA 0.8, controls 3.2, p < 0.05; age-adjusted HOMA-IR: CEE/MPA 1.3, controls 2.6, p < 0.05). On the contrary, E2/NETA treatment had no effect on these parameters. Women on tibolone had lower SHBG, higher FAI and similar HOMA-IR values compared to controls (age and BMI-adjusted SHBG: 24.1 nmol/l, p < 0.01; FAI: 6.0, p < 0.05; HOMA-IR: 2.3, p = NS). Raloxifene users did not exhibit any difference with respect to sex steroids and HOMA-IR levels. CONCLUSIONS: CEE/MPA users had lower free testosterone and improved insulin sensitivity. Tibolone on the other hand associated with higher free testosterone, while raloxifene did not relate to any of these parameters.