11 May, 2015:

There is a biological plausibility for the association between sexual desire and androgens. Indeed, according to epidemiological and clinical studies, they both decline with age. However, any attempt to link directly low sexual desire with circulating low androgens (total testosterone, free testosterone) or androgen precursors (androstenedione, dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS)) has failed to identify a lower limit that can be used to diagnose women with sexual dysfunction related to androgen deficiency [1]. A Danish cross-sectional study by Wåhlin-Jacobsen and colleagues [2] has recently reported that sexual desire, measured by the total score in the sexual desire domain of the Female Sexual Function Index (FSFI), correlated overall with free testosterone and androstenedione in a cohort of 560 healthy women aged 19–65 years. Moreover, the androstenedione : total testosterone ratio, an indirect marker of the activity of 17β-hydroxysteroid dehydrogenase, was overall correlated with women's sexual desire in women not using systemic hormonal contraception (HC) or postmenopausal hormone therapy (HT), indicating that the speed of transformation of androstenedione to testosterone is important. When the study population was stratified into three age groups depending on the intake of HC and HT, the authors demonstrated that, in women aged 25–44 years with no use of HC, sexual desire correlated with total testosterone, free testosterone, androstenedione, and DHEAS, whereas, in women aged 45–65 years, only androstenedione correlated with sexual desire. The primary androgen metabolite androsterone glucuronide did not show a correlation with sexual desire.

Comment

The unique nature of the intrinsic and extrinsic factors influencing women's sexuality across the lifespan limits our ability to discriminate between biological/organic components and psychological and contextual determinants of sexual response and behavior and to find effective pharmacotherapy for sexual symptoms [3]. The evidence that testosterone treatment of postmenopausal women with sexual dysfunction due to hypoactive sexual desire disorder is effective and safe in the short term [4] supports the notion that the sex steroid milieu is crucial for human sexuality and that hormonal perturbation may impact domains of sexual response. Longitudinal studies [5,6] suggested that significant changes of sexual responsivity may be observed across the menopausal transition, and both age and menopause cooperate differentially over time to decrease sexual desire and to increase vaginal dryness. However, the challenge of linking endogenous sex steroids with sexual motivation and performance capability continues to fascinate investigators who have to take into account individual variability in biosynthesis, enzymatic intracrine conversion, receptor binding, absorption rate, bioavailability, elimination, etc., when attempting to document the 'hormonal factor' by determination of circulating levels [7].

That being so, the Endocrine Society Clinical Practice Guideline confirms the recommendations against making a clinical diagnosis of androgen deficiency in women because data correlating measurements of androgens and specific signs and symptoms are inconsistent and monitoring plasma levels during testosterone treatment with available testosterone assays may be unreliable [1]. The recommendations presented at the 3rd International Consultation on Sexual Medicine [8] have already underlined the importance of using accurate methods based on mass spectrometry (MS) to measure testosterone levels at baseline or under therapy in women with sexual symptoms, but an agreed-upon standard is still lacking. The new instructions to authors for the reporting of steroid hormone measurements give hope to optimize measurement of steroid hormones in research publications in order to obtain reproducible data for standard of care [9].

Research data obtained with MS-based methods in a large and ethnically diverse longitudinal study (SWAN) have demonstrated a modest significant association between endogenous reproductive hormones and sexual function in midlife women across the menopausal transition. Testosterone was positively associated with masturbation (the sexual function domain least dependent on partner status), desire, and arousal, whereas FSH was negatively associated with masturbation, arousal, and the ability to climax in the absence of any association with estradiol [10]. Whether such a subtle link is clinically relevant in the psycho-relational context remains to be fully established, given the evidence that, in spite of low desire, most of the women in the SWAN cohort reported to be moderately or extremely sexually satisfied [6]. It is interesting to observe that, by using both a validated questionnaire and a highly sensitive methodology (MS) to measure androgens, the Danish data [2] seem to support a stronger role of androgens in women's sexual desire in adult women aged 25–44 years who are more likely to be in a stable sexual relationship, whereas, in younger or in older women, the role of androgen was less evident due to a stronger potential influence of other factors such as body image, self-esteem, partner status (new, absent, sexually dysfunctional), general health, co-morbidity with sexual pain disorders, etc. On the other hand, the strong associations between the pro-androgen androstenedione and the androstenedione°:°total testosterone ratio and sexual desire in women aged 45–65 years indicate that enzyme activity may play a more important role in women with lower production of androgen precursors of ovarian origin. Indeed, no statistically significant correlations were established between androsterone glucuronide and sexual desire, a finding explained by the fact that the level of androsterone glucuronide primarily represents the level of DHEAS, which reflects more the adrenal androgen reservoir. However, the cross-sectional nature of the study, the absence of a documented ovulation in premenopausal women and the lack of a significant decline of androgens with age, apart from DHEAS, are likely due to the insufficient number of postmenopausal women, and limit comments on causation.

Sexual symptoms are very common in clinical practice and health-care providers have difficulties in evaluating the wide variety of bio-psychosocial determinants that may influence the level of distress associated with low desire. It is mandatory to expand this field of research in sexual medicine, taking into account the bio-psychosocial model, which combines an optimal assessment of endocrine aspects of the sexual response in women with the intrapersonal and interpersonal clues during the lifespan, in order to establish a multidimensional, tailored treatment plan.

Rossella E. Nappi
Research Center for Reproductive Medicine, Gynecological Endocrinology and Menopause, IRCCS S. Matteo Foundation, Department of Clinical, Surgical, Diagnostic and Paediatric Sciences, University of Pavia, Pavia, Italy

References

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