Womens Sexual Health Update on Testosterone Therapy

• Healthcare, including sexual healthcare, is a fundamental human right.¹
• Multiple population-based studies reveal a high prevalence of sexual-health concerns in women of all ages.²
• A woman’s sexual problems can cause significant personal distress, including a diminution of selfworth and self-esteem, a reduction in life satisfaction and a decline in the quality of her relationship with her partner.³
• Many investigations have shown that a satisfying sex life is important to most women throughout most of their lives.⁴
• Women with sexual-health concerns are becoming more empowered to seek medical consultations for assistance.
• Increasing numbers of pharmaceutical agents will become indicated as safe and effective for the treatment of women with sexual-health problems, such as the topical testosterone patch for surgically menopausal women with hypoactive sexual desire disorder.⁵
• A woman’s sexual problems can also cause sexual problems in her partner.

For all of these reasons, healthcare professionals will be increasingly engaged in the sexual healthcare of women. Among many international sexual-medicine societies, the existence of the International Society for the Study of Women’s Sexual Health (ISSWSH)—an international, multidisciplinary, academic, clinical, and scientific organization—should be noted.The purposes of ISSWSH are unique and focus exclusively on providing opportunities for communication about women’s sexual health, supporting the highest standards of ethics and professionalism relative to women’s sexual health and providing the public with accurate information about women’s sexual health.⁶

Healthcare professionals need to be holistic and consider biopsychosocial aspects when managing patients with sexual dysfunction.Although it is not within the realm of this article to thoroughly discuss all aspects of women’s sexual-health management, because of the recent approval of the testosterone patch by the European Medicines Agency for treatment of hypoactive sexual desire disorder in surgically menopausal women,⁵ it will focus on the management of sexual dysfunction in women with relation to androgen insufficiency. Physiology and Pathophysiology— Changes in the Female Genitalia with Aging
The structure and function of a woman’s genitalia are highly dependent on the estrogen and androgen sex steroid hormonal milieu. While it is well appreciated that estrogens are critical for women’s genital structure and function, it is now being understood that androgens and androgen precursors also modulate the structure and function of genital and other tissues in women.⁷ Preclinical studies of ovariectomized animals show that androgen treatment enhanced androgen receptor in the vaginal muscularis, facilitated vaginal smooth-muscle relaxation in response to electricalfield stimulation, enhanced nitric-oxide-synthase activity and protein in the vagina and increased vaginal mucification. Diminished estrogen and androgen levels render women’s genital tissues susceptible to atrophy. The urogenital area—the ‘vestibule’—contains multiple organs that are very important in female sexual function.Various vestibular organs rich in androgen receptors include glands of Littre or minor vestibular glands, clitoris, prepuce and vaginal muscularis. Physical examination of the genitalia of a woman with low levels of androgen sex steroids may reveal clitoral atrophy and phimosis. Other signs and symptoms of a decline in estrogen and androgen sex hormones in women include vaginal dryness, decreased secretions or lubrication, epithelial/mucosal thinning, organ prolapse, changes in external genitalia and decreased tissue elasticity. Sex steroid hormone changes may lead to such clinical complaints as dyspareunia, diminished sexual interest, diminished orgasm, vaginal and/or urinary tract infections, vaginal pH-level imbalance, and overactive bladder or incontinence.

Laboratory Testing
There are no generally agreed-on, recommended routine laboratory tests for the evaluation of women with sexual-health concerns.8 Blood testing should be dictated by clinical suspicion, especially the results of the history and physical examination. If appropriate, the healthcare clinician may assess multiple androgen and estrogen values such as: dehydroepiandrosterone sulphate (DHEAS); total testosterone; free testosterone; sex-hormone-binding globulin (SHBG); dihydrotestosterone (DHT); estradiol; and progesterone. Pituitary function may be measured by obtaining luteinising hormone, follicle-stimulating hormone, and prolactin. Thyroid-stimulating hormone should be measured to exclude thyroid disorders.

There are numerous problems with the determination of serum-hormone levels.⁹ The normal ranges of testosterone-concentration values for women of different age groups without sexual dysfunction are not well-defined.Testosterone levels reach a nadir during the early follicular phase, with small but less-significant variation across the rest of the cycle.Testosterone assays are not uniformly sensitive or reliable enough to accurately measure testosterone at the low-serum concentrations typically found in women. Unbound testosterone is clinically more important than total testosterone in sexual function because the vast majority of testosterone is bound to SHBG and only a small amount of total testosterone is biologically available.The measurement of SHBG is relatively simple to perform with good reproducibility. Equilibrium dialysis is a highly sensitive assay for free testosterone; however, this method is not feasible for clinical practice. Measurement of free testosterone by analog assays is unreliable. Free androgen may be calculated using the free-androgen index, defined as total testosterone in nanomoles per litre (nmol/L), divided by SHBG (nmol/L). Calculated free testosterone is based on total testosterone, SHBG, and albumin.¹⁰ DHEAS is commonly measured because the half-life is much longer than that of dehydroepiandrosterone (DHEA), resulting in more stable levels. The immunoassay for DHEAS is relatively robust and simple to perform. DHEAS does not vary in concentration within the various phases of the menstrual cycle. Multiple investigators have shown consistent decline curves for DHEAS with aging.¹¹

A common controversy concerns the ‘normal range’ for sex steroid blood-test values in women with sexual-health problems. Androgen values in women ‘without sexual dysfunction’, as determined by a validated sexual function questionnaire, were examined. It was found that androgen concentrations were highest in the women aged 20 to 29 years, decreased at approximately age 30 and remained relatively constant thereafter. The free-androgen index in women without sexual dysfunction was approximately 3.7 for women aged 20 to 29 years and 2.0 for women between the ages of 30 and 39.^12,13

Serum levels of sex steroids can only measure deficiency or excess. Sex steroid hormone actions are quite complex and involve critical enzymes and critical hormone receptors that also determine tissue exposure, tissue sensitivity and tissue responsiveness. For example, the amount and activity of critical enzymes such as 5-alpha-reductase and aromatase vary by individual. In addition, there are variations in individual sex steroid hormone-receptor sequencing. Thus, independent of the values of sex steroid hormones, the unique variations in critical enzymes and sex steroid hormone receptors result in individual differences in tissue exposure, tissue sensitivity and tissue responsiveness. Further research is needed in the blood testing of sex steroid hormones in women with sexual-health concerns.¹¹

Hormonal Treatment
Studies have consistently reported that androgen sex steroid hormone values decline gradually and estradiol values decline abruptly in menopausal women. Ovarian androgens decline with aging. Testosterone levels decline from the mid-reproductive years such that, relative to women in their 20s,women in their 40s have an approximately 50% reduction in plasma testosterone.¹¹ In a study of 160 Swedish women longitudinally through the menopausal transition, small but significant decreases in testosterone were observed.¹⁴ DHEAS also decreased over time. The Massachusetts Women’s Health Study—derived from a population-based sample of largely Caucasian women, reported results in 88 women sampled at four- to sixmonth intervals over a 10-year period. A significant decline in DHT and DHEAS was observed.¹⁵ Hormone-insufficiency states may also be caused by a number of clinical conditions and medications, including the use of oral contraceptive therapy.16Women who seek treatment may have symptoms of sexualhealth problems due, in part, to the onset of natural menopause or menopause induced by chemotherapy or surgery. They may be younger women whose labia minora have begun to atrophy because of the adverse effects of oral contraceptives on the sex steroid hormonal milieu. Infertility or endometriosis treatments may also disturb the sex steroid hormone milieu.¹¹

Since there is a lack of clinical consensus as to the value, specificity and sensitivity of individual hormone blood tests, it is especially important that a woman with troublesome sexual-health concerns who is considering testosterone treatment has the clinical symptoms of androgen insufficiency, including hypoactive sexual desire disorder.⁹

It is of note that, of all the therapies available to women with sexual dysfunction—including sex therapy, physical therapy, lifestyle modification, use of vibrators and/or lubrication agents and change in medications— the one therapy with the most evidence supporting efficacy is hormonal therapy, in particular testosterone therapy. There are multiple evidence-based, placebocontrolled, double-blind data supporting the efficacy of exogenous testosterone treatment in women with sexual-health concerns.^17–25 These studies have demonstrated that hormone therapy using systemic testosterone, systemic and/or local estrogen with or without systemic progesterone improves sexual desire, arousal, orgasm and frequency of sexual activity in women.^17–25 Transdermal patches or gels, which are more consistently absorbed and avoid first passing through the liver. are currently being studied.

Transdermal testosterone patches were compared with placebo in estrogenized women (conjugated equine estrogen) who had undergone oophorectomy and hysterectomy.After 24 weeks of transdermal testosteronepatch therapy, there were significant correlations observed among changes in serum total, bioavailable and free testosterone, and the frequency of satisfying sexual activity.One study was dose-ranging and data suggested a dose-response relationship. In one trial—in which all women used transdermal estradiol patches—serum total and free testosterone and DHT correlated with desire, arousal, orgasm, pleasure responsiveness and the number of satisfying sexual events. There were significant correlations between testosterone levels and multiple aspects of sexual response in the study of naturally menopausal women.Approximately one more episode of satisfying sexual activity per month compared with controls resulted.The benefit over placebo was observed with the 300-microgram patch administered biweekly. There is no single hormonal intervention that will be effective in all women, with desire, arousal, and orgasm sexual-health concerns secondary, in part, to sex steroid hormone-deficiency states.Treatment for women with sexual dysfunction is holistic and is based on the history, physical examination and laboratory tests. Hormonal therapy is one component of overall sexual-health management.¹¹ It should be noted that testosterone has been used to treat women with sexual dysfunction for more than 50 years.²⁶

Based on blood-test results, systemic androgen treatment may be achieved with DHEA alone or systemic testosterone alone or a combination of both. Based on the history and physical examination, local estrogen treatment may be achieved with vestibular estradiol alone or intravaginal estradiol alone or a combination of both. Systemic estradiol and progesterone may be used as needed.

Systemic administration of the androgen precursor (DHEA) has been shown to improve mood, energy, stimulation, sensation, arousal and orgasm.^27,28 Limited clinical trials have examined the effects of DHEA therapy on sexual function in women. In a 2000 study, DHEA (50 milligrams) or placebo was administered to 140 women between the ages of 60 and 79 years for 12 months. DHEA treatment produced approximately a doubling of serum total testosterone concentration and significantly increased skin hydration and bone density. Libidinal interest was increased after six months of treatment, and sexual activity and sexual satisfaction were increased after 12 months.²⁸

Concerning androgens and the risk of endometrial carcinoma, it is widely believed that androgens—acting through classical androgen-receptor mechanisms—are anti-proliferative in the human endometrium.29 Endometrial adenocarcinoma growth is prevented by androgens, and the presence of androgen receptors appears to be associated with reduced proliferation. Endometrial hyperplasia is not observed in women taking exogenous androgens. Studies using doses of testosterone that result in free testosterone in or near the normal range for women report no increase in hirsutism, acne, or virilising side effects with short-term administration.^17–25With regard to androgens and breast cancer, androgens—acting through the androgen receptor—oppose estradiolinduced proliferation of human breast-cancer cell lines. Clinically,women with elevated androgen levels, either endogenous or exogenous, experience breast atrophy, consistent with the notion that androgens are anti-proliferative for the breast.^29–32 If one considers polycystic ovarian syndrome as a model of androgen excess, the risk of breast cancer is not increased despite hyperandrogenism and long-term exposure to unopposed estrogens.³² Women with sexual dysfunction who are placed on androgen treatment need to undergo surveillance blood tests after three months of therapy to monitor the patient’s levels of estradiol, progesterone, DHEA, testosterone, androstenedione, dihydrotestosterone, follicle-stimulating hormone, luteinizing hormone, prolactin and thyroid-stimulating hormone as indicated.

Conclusions
Physicians face a challenge in finding the time and opportunity to discuss sexual-health concerns with their female patients.There are increasing and growing demands for other preventive care issues for our aging population. There are especially significant financial pressures on providing ‘managed care’. Of importance, many physicians have limited training in the diagnosis and treatment of women with sexual-health concerns. Many medical schools devote only limited time in the curriculum to sexual-medicine issues and, currently, approximately two-thirds of US medical schools devote less than 10 hours over four years to sexualmedicine education. Physicians may be hesitant to introduce patient issues that are not within with their comfort level or knowledge background. Patients, additionally, are often unwilling or too uncomfortable to inform the physician or initiate a discussion about their own sexual problems, even if they cause distress. In a US telephone survey of adults, approximately seven out of 10 respond
nts said they would be very or somewhat concerned that their physician would dismiss any sexual problem they might mention. Approximately two out of three respondents said they would be concerned that their physician would be uncomfortable talking about sexual problems, and approximately three out of four said they would be concerned that no medical treatment exists for their problem. There are other issues. Sexual medicine is complex and it is often difficult to separate psychological issues from interpersonal relationship concerns from biological disorders. There are only limited evidence-based data available.

The basic premise of biologically focused management of women’s desire, arousal, and orgasm sexual-health concerns is that physiological processes can be altered by pathology. How specific medical conditions modulate woman’s sexual health requires much investment in basic science investigation. From the perspective of biology-focused clinicians, the essential principle guiding their medical decision-making is the identification of the underlying pathophysiology of the sexual dysfunction. If the biological basis of the desire, arousal and orgasm dysfunction can be diagnosed, management outcome may be successfully directed to the source of the pathophysiology.