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SPECIAL FEATURE

Testosterone — It’s Not the Magic Bullet

March 1, 2013
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By Catherine Leclair, MD, Associate Professor, Department of OB/GYN, Oregon Health & Science University, Portland, is Associate Editor for OB/GYN Clinical Alert.

Dr. Leclair reports no financial relationships relevant to this field of study.

1998 was a landmark year for men’s sexuality. the FDA approved sildenafil (Viagra®), a medication that now has household name familiarity. Viagra and its longer-acting cousins not only revolutionized the treatment of erectile dysfunction (ED) for men, but the PDE5 inhibitors are now used recreationally to enhance the sexual encounters for many couples without ED. Although Viagra proved to be a major advancement for the common and troublesome male sexual symptom of ED, no comparable breakthrough has been achieved in women’s sexuality. Despite initial curiosity by some providers to try Viagra in women, in most cases, the problem doesn’t match the solution. That’s because the PDE5 inhibitors primarily address sexual arousal. Although epidemiologic studies reveal that up to 42%1,2 of women have concerns about their sexuality, the most common complaint is low libido. The clinician who treats female sexual dysfunction simplistically as a category rather than a spectrum of disorders rarely will achieve therapeutic success.

Female sexual function has a major influence on quality of life. When problems arise, the multidimensional and multifactorial determinants do not facilitate a quick fix in a 15-minute office encounter. In 2000, a consensus team of experts in the field of women’s sexuality convened to define women’s sexual dysfunction as an initial step to improve clinical care and research in the field of women’s sexuality.3 The definitions give credence to both the psychological and physiological influences on these common problems with diagnoses included in four categories: 1) sexual desire disorders (hypoactive sexual desire disorder [HSDD] and sexual aversion disorder); 2) sexual arousal disorder (AD), 3) orgasmic disorder, and 4) sexual pain disorders (dyspareunia, vaginismus, and noncoital sexual pain disorder). New to these diagnoses was the element of “personal distress,” which accounts for the vital role of the human psyche in sexual expression. Viagra, as a PDE5 inhibitor, is indicated for arousal dysfunction by inducing vasodilation of the genital tissue. Unfortunately, arousal disorder as a pure abnormality is rare in women, and it is challenging to distinguish AD from HSDD — a more complex problem rooted in the psychosocial dynamic. It’s no wonder Viagra doesn’t work in the majority of women.

In an effort to find that magic bullet for HSDD, the spotlight continues to focus on testosterone. Testosterone is a potent androgen produced in the adrenal gland, the ovary, and through peripheral conversion of steroid precursors from both glands. Testosterone is almost exclusively bound to either sex hormone binding globulin (SHBG) or albumin and peaks mid-cycle in premenopausal women. Therefore, any product (e.g., oral contraceptive pills) that impacts the concentration of SHBG will affect the amount of bound testosterone. Over a woman’s lifetime, testosterone levels wane, but unlike the rapid drop in estrogen seen at menopause, the decline in testosterone production is modest. Testosterone normograms are challenging to interpret since many have been modeled after scales for men and vary based on age and menstrual phase and fail to provide guidance on free hormone levels — factors that contribute to the confusion and misunderstanding generated by obtaining testosterone levels. However, since the decreased sexual desire and impaired sexual response exhibited by hypogonadal men improve with physiologic levels of testosterone replacement, many investigators have presumed that testosterone plays a central role in female sexuality and sexual behavior.

To date, studies in women suggest a complex relationship between testosterone and sexual function and support that supplementation may have a limited role in select populations of women. Although several routes of supplementation — e.g., oral, transdermal (patch), subcutaneously injected (pellet), and topical (gel or cream) — have been studied, the route most associated with significant results in postmenopausal (PMP) women has been the patch. Mind you, doses studied induced levels considered supra-physiologic for women. On the plus side, the transdermal testosterone patch has been shown to improve the number of “sexually satisfying events” (SSE) in PMP women, as well as several other secondary sexual outcome measures. The most robust data come from several randomized trials comparing a 300 mcg or 150 mcg transdermal testosterone patch to a sham patch over 12-24 weeks.4-9 One important caveat is all participants in these studies received concomitant estrogen therapy. There is a strong role for estrogen alone in sexuality, as it treats symptoms of vaginal dryness, vulvovaginal atrophy, and vasomotor symptoms — all of which are important in normal sexual function in the PMP woman.10,11 In a population of surgically menopausal (hysterectomy/oophorectomy) women, Shifren showed that use of a 300 mcg testosterone patch was associated with a significant increase in SSE, pleasure-orgasm, well-being, masturbation, and sexual fantasies compared to a 150 mcg testosterone or placebo patch over 12 weeks.4 The number of sexually satisfying events increased from a baseline of one time per month to two to three times per month. In the INTIMATE Surgically Menopause-1 study published in 2005, Simon corroborated these findings in a larger group of PMP estrogen-replete women over 24 weeks.5 The follow-up INTIMATE Naturally Menopausal-1 study published in 2006 also supported the use of a 300 mcg patch in women taking a stable dose of estrogen-progesterone replacement.6 Women reported less sexual distress while enjoying more sexual desire and SSE. In the last patch study, Braustein demonstrated that increasing the dose of the testosterone patch to 450 mcg did not result in additional benefit.7 To tease out the effect estrogen may play in healthy sexuality in PMP women, Davis evaluated the transdermal testosterone patch in PMP women who were not replaced with estrogen.8 Again, a number of important sexual outcomes including the number of SSE, sexual desire, and frequency improved in women using the 300 mcg patch. As the primary outcome, the number of SSE increased from a baseline of 0.7/4 weeks to 2.1/4 weeks in women using the higher dosed patch. These changes were not seen in the group receiving the 150 mcg or control patch. However, breast cancer was diagnosed in four women receiving the testosterone patch (compared to none in the placebo group) — all of whom had a normal screening mammogram within 12 months of enrollment (recall that androgens are aromatized to estrogens in many tissues). This is the major reason why the patch has not received FDA approval.

The role of testosterone in premenopausal women has been less well studied and is more controversial. Theoretically, this population should have normal testosterone levels since ovarian function has not ceased. Still, many women seeking a medical explanation for low libido insist on having a level checked (often ordered by a naturopath or primary care doctor, but brought to you to “fix”). Since testosterone levels are subject to menstrual phase changes, defining a true low can be challenging. Additionally, sexual outcomes have not consistently been correlated with testosterone levels so the prognostic implication of any level is questionable. There is one well-designed, randomized, placebo-controlled trial in premenopausal women worth mentioning. In this study, Davis randomized 261 otherwise healthy women aged 35-46 years to one of four doses (0 [placebo], 45, 90, and 180 microL) of metered nasal-sprayed testosterone daily for 16 weeks.9 Interestingly, the middle dose of 90 microL was associated with more sexually satisfying events compared to all other doses and placebo. Unfortunately, a pregnancy was diagnosed at 20 weeks gestation in a single participant in one of the testosterone groups — a sober realization that testosterone use in a fertile population has potential risks for what may be considered a modest benefit.

So how should we view testosterone’s role in female sexuality? Although modest improvements in some sexual outcomes are seen in PMP women, long-term benefit and safety has not been proven. Additionally, each of the trials was relatively short when you consider that sexuality is experienced over a lifetime. Finally, is one extra SSE over a 4-week period meaningful for most couples? It is naïve to think that a patch or spray will be a simple answer to all female sexual issues, particularly the ubiquitous problem of HSDD. The best approach is to sit down and talk to your patient about her concerns. Through discussion, you’ll help her identify what she really wants out of her sexual relationship — not only for herself but also for her partner relationship.

Since the role of hormones and female sexual function is complicated, it’s not surprising that testosterone levels and sexual outcomes are not correlated. Testosterone supplementation is not the easy answer to the epidemic of disappointment women feel about their sexual relationships. It’s understandable that women and clinicians look for a magic bullet as the mass media distorts women’s sexuality into something perverse, intangible, and marketable. It’s not surprising that women feel confused and dissatisfied since there is very little healthy exposure to mature, monogamous love. Emerging data on the complexity of female sexuality emphasizes a multidimensional model that includes biologic, psychologic, sociocultural, and interpersonal dynamics to replace the antiquated Master’s & Johnson’s linear sexual response model (spontaneous desire leads to arousal that then allows orgasm followed by resolution). Basson’s updated model of the female sexual response cycle stresses the role of emotional intimacy in a “sexually receptive” woman.12 Openness to sexual cues in a thoughtful, safe environment governs a woman’s arousability. Desire and arousal are often interchangeable and “lust” is usually not the force that motivates women to participate in a sexual exchange. In fact, 42% of women in the SWAN study reported never or rarely “sensing” desire but were “moderately or extremely satisfied with their sexual relationship.”13 As we learn more about female sexuality, we have come to understand that women are indeed different than men. So while we continue to try to focus on identifying the magic bullet of desire for women, we’re missing the opportunity to encourage our patients to find ways to enhance intimacy. Positive sexual experiences and feelings for her partner are strongly correlated with sexual satisfaction and likely protect against dysfunction. It is through a fulfilling sexual encounter that a meaningful love relationship is sustained for both him and her.

References

  1. Laumann EO, et al. Sexual dysfunction in the United States: Prevalence and predictors. JAMA 1999;281:537-544.
  2. Shifren JL, et al. Sexual problems and distress in United States women: Prevalence and correlates. Obstet Gynecol 2008;112:970-978.
  3. Basson R, et al. Report of the international consensus development conference on female sexual dysfunction: Definitions and classifications. J Urol 2000;163:888-893.
  4. Shifren JL, et al. Transdermal testosterone treatment in women with impaired sexual function after oophorectomty. N Engl J Med 2000:343:682-688.
  5. Simon J, et al. Testosterone patch increases sexual activity and desire in surgically menopausal women with hypoactive sexual desire disorder. J Clin Endocrinol Metab 2005;90:5226-5233.
  6. Shifren JL, et al. Testosterone patch for the treatment of hypoactive sexual desire disorder in naturally menopausal women: Results from the INTIMATE NM1 Study. Menopause 2006;13:770-779.
  7. Braunstein GD, et al. Safety and efficacy of a testosterone patch for the treatment of hypoactive sexual desire disorder in surgically menopausal women: A randomized, placebo-controlled trial. Arch Intern Med 2005;165:1582-1589.
  8. Davis SR, et al. Testosterone for low libido in postmenopausal women not taking estrogen. N Engl J Med 2008;359:2005-2017.
  9. Davis S, et al. Safety and efficacy of a testosterone metered-dose transdermal spray for treating decreased sexual satisfaction in premenopausal women: A randomized trial. Ann Intern Med 2008;148:569-577.
  10. Wierman ME, et al. Endocrine aspects of women’s sexual function. J Sex Med 2010;7(1 Pt 2):561-585.
  11. Huang A, et al. The effect of ultralow-dose transdermal estradiol on sexual function in postmenopausal women. Am J Obstet Gynecol 2008;198:265.e1-7.
  12. Basson R. Female sexual response: The role of drugs in the management of sexual dysfunction. Obstet Gynecol 2001;98:350-353.
  13. Caine VS, et al. Sexual functioning and practices in a multi-ethnic study of midlife women: Baseline results from SWAN. J Sex Res 2003;40:266-276.