CLIMACTERIC 2015;18:1–3

Invited Editorial

To be or not to be in sexual desire: the androgen dilemma R. E. Nappi Research Center for Reproductive Medicine, Gynecological Endocrinology and Menopause, IRCCS S. Matteo Foundation, Department of Clinical, Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy

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ABSTRACT The androgen milieu and sexual desire in women seem to be tightly linked because they both decline with age. However, we are still missing a cut-off plasma level for androgens (total testosterone, free testosterone) or androgen precursors (androstenedione, dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS)) to diagnose androgen deficiency in clinical practice. Apart from the complex multidimensional nature of sexual desire across the reproductive lifespan, the correlation between measurements of testosterone and specific signs and symptoms has been difficult because, according to guidelines, most available assays are unreliable at baseline and under hormonal treatments. Recent data obtained with accurate methods based on mass spectrometry to measure total testosterone levels found a significant positive association with sexual desire, arousal and masturbation in midlife US women across the menopausal transition. Even in a European cohort of healthy women aged 19–65 years, sexual desire, measured with a validated questionnaire, correlated overall with free testosterone and androstenedione measured with mass spectrometry. Collectively, these data support the therapeutic use of testosterone for low desire and sexual dysfunction in those clinical conditions in which androgen deficiency may be accurately diagnosed.

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 deficiency1. A Danish crosssectional study by Wåhlin-Jacobsen and colleagues2 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 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 hormonal contraception and HT, the authors demonstrated that, in women aged 25–44 years with no use of hormonal contraception, 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. 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

Correspondence: Professor R. E. Nappi, Research Center for Reproductive Medicine, Gynecological Endocrinology and Menopause, IRCCS S. Matteo Foundation, Department of Clinical, Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy; E-mail: [email protected]

INVITED EDITORIAL © 2015 International Menopause Society DOI: 10.3109/13697137.2015.1064268

Received 27-04-2015 Accepted 28-04-2015

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Androgens and sexual desire for sexual symptoms3. The evidence that testosterone treatment of postmenopausal women with sexual dysfunction due to hypoactive sexual desire disorder is effective and safe in the short term4 supports the notion that the sex steroid milieu is crucial for human sexuality and that hormonal perturbation may affect domains of sexual response. Androgens and androgen precursors are produced both by the ovaries and by the adrenals and circulating levels progressively decline across the reproductive lifespan. The postmenopausal ovary is still an androgen-secreting organ and it has been calculated that ovariectomy reduces circulating androgen concentrations by approximately 50% in both premenopausal and postmenopausal women. Therefore, surgical menopause has been considered the best clinical paradigm to investigate the role of androgen deficiency in women’s sexual desire5. Other endocrine causes of androgen deficiency, including hypopituitarism, adrenal insufficiency, ovarian failure, and some drugs, including hormonal contraception, corticosteroids, antiandrogenic agents and oral estrogen replacement therapies, have been also documented. Androgen deficiency may be related not only to an impairment of sexual functioning, but also to a broad range of symptoms and conditions, such as diminished well-being and quality of life, low mood, loss of energy, cognitive disturbances, declining muscle mass and strength and lowering of bone density6. Longitudinal studies7,8 have 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. In addition, in middle-aged women, several intrapersonal and interpersonal factors, namely mood disorders and relationship conflicts, are implicated in sexual behavior. That being so, the challenge of linking endogenous sex steroids with sexual motivation and performance capability continues to fascinate investigators, both from a biological and a psychosocial standpoint. Indeed, the attempt to document the ‘hormonal factor’ by measuring circulating levels should take into account individual variability in biosynthesis, enzymatic intracrine conversion, receptor binding, absorption rate, bioavailability, elimination, etc.9. On the other hand, it is very difficult to establish a clinically useful conceptualization of women’s sexual problems because sexual desire is a rather complex construct that is only partially androgendependent. It has been hypothesized that different phenotypes of women endorse different models of sexual response, and the testosterone-dependent component of female sexuality may be more important for some women than others. Alternatively, it is conceivable that age and reproductive status may influence women’s attitudes to attribute a higher importance to emotional and relationship cues as sexual incentives rather than to endocrine stimuli10. This concept is relevant to the understanding of the wide range of distribution for each of the circulating androgens (total and free testosterone, androstenedione, DHEAS) measured in an homogeneous group of women with normal sexual function11. Moreover, it explains the lack of agreement on the role of androgen deficiency induced by hormonal contraception in the modulation of


Nappi mood and sexual side-effects12. Indeed, in a recent systematic review and meta-analysis, hormonal contraception reduces free testosterone by 61%, exerting a ‘class effect’ independently from the estrogen dose and the type of progestins13, but not all women experience a reduction of sexual desire, arousal and orgasm and some hormonal contraception may even improve sexual function14. In early menopausal women, variable combinations of estrogens and progestogens with different chemical nature (e.g. synthetic versus natural estrogens, progestogens with high versus low androgenicity) affecting androgen bioavailability seem to exert peculiar effects on sexual response, but a recent analysis of randomized clinical trials comparing HT to either placebo or no intervention reported that HT treatment with estrogens alone or in combination with progestogens was associated with a small to moderate improvement in sexual function, particularly in sexual pain, with a poor effect on sexual desire15. That notwithstanding, 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 unreliable1. The recommendations presented at the 3rd International Consultation on Sexual Medicine16 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 care17. 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. Total testosterone was positively associated with masturbation (the sexual function domain least dependent on partner status), desire, and arousal, whereas follicle stimulating hormone was negatively associated with masturbation, arousal, and the ability to climax in the absence of any association with estradiol18. Whether such a subtle link is clinically relevant in the psychorelational 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 satisfied8. It is interesting to observe that, by using both a validated questionnaire and a highly sensitive methodology (MS) to measure androgens, the Danish data2 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


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Androgens and sexual desire 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. This finding is in line with the evidence that, in spite a potential link between low DHEA levels and impaired sexual function, well-being, and cognitive performance in postmenopausal women which has been hypothesized, placebo-controlled, randomized, controlled trials did not show benefits of oral DHEA for any of these outcomes19. However, the cross-sectional nature of the Danish 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.

Nappi 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. In addition, inter-individual differences and intra-individual changes in sexual desire are variable and unpredictable and the use of objective measures of sexual response does not reflect the subjective experience of women. It is, then, 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 plan20. Conflict of interest The author reports no confl ict of interest. The author alone is responsible for the content and writing of this paper. Source of funding


References 1. Wierman ME, Arlt W, Basson R, et al. Androgen therapy in women: a reappraisal: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2014;99:3489–510 2. Wåhlin-Jacobsen S, Pedersen AT, Kristensen E, et al. Is there a correlation between androgens and sexual desire in women? J Sex Med 2015;12:358–73 3. Nappi RE, Cucinella L. Advances in pharmacotherapy for treating female sexual dysfunction. Expert Opin Pharmacother 2015;16:875–87 4. Davis SR, Worsley R. Androgen treatment of postmenopausal women. J Steroid Biochem Mol Biol 2014;142:107–14 5. Nappi RE, Wawra K, Schmitt S. Hypoactive sexual desire disorder in postmenopausal women. Gynecol Endocrinol 2006;22: 318–23 6. Bachmann G, Bancroft J, Braunstein G, et al. Female androgen insufficiency: the Princeton consensus statement on definition, classification, and assessment. Fertil Steril 2002;77(Suppl 4): 660–5 7. Dennerstein L, Dudley E, Burger H. Are changes in sexual functioning during midlife due to aging or menopause? Fertil Steril 2001;76:456–60 8. Avis NE, Brockwell S, Randolph JF, et al. Longitudinal changes in sexual functioning as women transition through menopause: results from the Study of Women’s Health Across the Nation. Menopause 2009;16:442–52 9. Nappi RE, Domoney C. Pharmacogenomics and sexuality: a vision. Climacteric 2013;16(Suppl 1):25–30 10. Bancroft J, Graham CA. The varied nature of women’s sexuality: unresolved issues and a theoretical approach. Horm Behav 2011;59:717–29 11. Salonia A, Pontillo M, Nappi RE, et al. Menstrual cycle-related changes in circulating androgens in healthy women with self-reported normal sexual function. J Sex Med 2008;5:854–63


12. Graham CA, Bancroft J, Doll HA, Greco T, Tanner A. Does oral contraceptive-induced reduction in free testosterone adversely affect the sexuality or mood of women? Psychoneuroendocrinology 2007;32:246–55 13. Zimmerman Y, Eijkemans MJ, Coelingh Bennink HJ, Blankenstein MA, Fauser BC. The effect of combined oral contraception on testosterone levels in healthy women: a systematic review and meta-analysis. Hum Reprod Update 2014;20: 76–105 14. Davis SR, Bitzer J, Giraldi A, et al. Change to either a nonandrogenic or androgenic progestin-containing oral contraceptive preparation is associated with improved sexual function in women with oral contraceptive-associated sexual dysfunction. J Sex Med 2013;10:3069–79 15. Martins WP, Lara LA, Ferriani RA, Rosa-E-Silva AC, Figueiredo JB, Nastri CO. Hormone therapy for female sexual function during perimenopause and postmenopause: a Cochrane review. Climacteric 2014;17:133–5 16. Wierman ME, Nappi RE, Avis N, et al. Endocrine aspects of women’s sexual function. J Sex Med 2010;7:561–85 17. Wierman ME, Auchus RJ, Haisenleder DJ, et al. Editorial: The new instructions to authors for the reporting of steroid hormone measurements. J Clin Endocrinol Metab 2014;99:4375 18. Randolph JF Jr, Zheng H, Avis NE, Greendale GA, Harlow SD. Masturbation frequency and sexual function domains are associated with serum reproductive hormone levels across the menopausal transition. J Clin Endocrinol Metab 2015;100:258–66 19. Davis SR, Panjari M, Stanczyk FZ. Clinical review: DHEA replacement for postmenopausal women. J Clin Endocrinol Metab 2011;96:1642–53 20. Bitzer J, Giraldi A, Pfaus J. A standardized diagnostic interview for hypoactive sexual desire disorder in women: standard operating procedure (SOP Part 2). J Sex Med 2013;10:50–7


To be or not to be in sexual desire: the androgen dilemma.

The androgen milieu and sexual desire in women seem to be tightly linked because they both decline with age. However, we are still missing a cut-off p...
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