Female Sexual Function at Midlife and Beyond

INTRODUCTION

Sexual function is an important aspect of life for many women, regardless of age. Sexual function is closely correlated with overall well-being and relationship satisfaction.^1–3 Most women continue to consider sexual function important as they age.^4–6 However, 45% of midlife women have sexual problems,^2,7 and 15% have a sexual problem that causes significant personal distress.⁷ Female sexual dysfunction remains under-recognized and undertreated by healthcare providers. In this article, we will review definition of female sexual dysfunction, examine how sexual function changes during the midlife transition, define factors that are associated with sexual dysfunction at midlife, and discuss new and emerging treatments.

DEFINITIONS

Sexual dysfunction, as defined in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), is a heterogeneous group of disorders characterized by clinically significant disturbances in sexual response or the experience of sexual pleasure.^,8 A key element of the DSM-5 definition is significant personal distress. Revision of the DSM between versions 4 and 5 included substantive changes to female sexual dysfunction terminology (Figure 1). Notably, Hypoactive Sexual Desire Disorder and Female Sexual Arousal Disorder were combined into a single diagnosis, Female Sexual Interest and Arousal Disorder⁸ as there is considerable overlap between the disorders, and the concepts of desire and arousal are virtually indistinguishable for many women.^9,10 These changes were controversial,^11–13 and some experts still favor the older terminology. It is also essential to consider overall sexual satisfaction. For many women, the end-goal of sex is not “functional” sex where all the parts are working well, but emotional and physical satisfaction and increased intimacy with one’s partner.

Figure 1.

Female Sexual Dysfunction Terminology. From American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Washington, DC: American Psychiatric Publishing; 2000; and American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Washington, DC: American Psychiatric Publishing; 2013; with permission.

CHANGES IN SEXUAL FUNCTION DURING MIDLIFE

Sexual function declines during midlife. The Study of Women’s Health Across the Nation (SWAN) and others found that this decline corresponds with the menopausal transition, including in women who have hysterectomies.^14,15 While symptoms such as vaginal dryness increase over the same period, changes in sexual function are independent of other symptoms associated with the menopausal transition. Declines in sexual activity during midlife are multi-factorial (discussed below). One prominent reason that women do not engage in sexual activity is lack of a partner.¹⁶

Women who are sexually active prior to menopause appear to continue to engage in sexual activities during midlife, despite poor “functional sex.”⁵ Lifestyle factors, including sufficient sleep and physical activity, contribute to more positive sexual functioning during midlife.¹⁶ Alternative models of sexual function may provide more insight into the impact of these changes during menopause. In contrast to the traditional linear model posited by Masters and Johnson,¹⁷ Basson suggests that the sexual response, particularly in women, is more circular and dependent on emotional connection and fulfillment.¹⁸ This model offers an explanation for the dichotomy of decline in sexual function, with endurance of sexual activities as a means to express and maintain connected partnerships.

FACTORS THAT AFFECT FEMALE SEXUAL FUNCTION AT MIDLIFE

Biologic factors - hormones, menopausal symptoms

The menopause is characterized by ovarian follicular exhaustion and hypogonadism. Reduced ovarian steroidogenesis leads to the development of genitourinary syndrome of menopause (GSM),¹⁹ which adversely affects the genital system and lower urinary tract in menopausal women and significantly contributes to sexual dysfunction.²⁰ More than half of menopausal women experience GSM, which is responsive to local estradiolUnlike vasomotor symptoms, which often decrease over time, GSM does not resolve and recurs after discontinuation of estrogen.^21,22

Vulvovaginal atrophy (VVA), also known as vulvovaginitis, is a key component of GSM, and can result in post coital vaginal bleeding, vaginal burning, irritation, and pain and discomfort with sex. Symptomatic GSM is often accompanied by diminished secretions from vulvar sebaceous glands and reduced vaginal lubrication during sexual stimulation. Hypoestrogenic menopausal women often experience a shift of the vaginal microbiome from lactic acid producing lactobacilli to gram negative and positive bacteria.²³ This shift in the vaginal microbiome results in increased vaginal pH, local immune changes and increased cytokine synthesis which worsens symptoms of vaginal dryness and burning²³ and contributes to sexual dysfunction. These external genital changes are covered in detail in Chapter 12-Waetjen.

Pelvic organ prolapse (POP) involves descent of one or more female genital organs (anterior and/or posterior vaginal wall, the uterus or the apex of the vagina). The incidence of pelvic floor relaxation increases with aging and is hypothesized to result from a combination of connective tissue degradation, pelvic denervation, and devascularization, all of which predispose to prolapse.²⁴ Dyspareunia, chronic pelvic pain, and reduced self-image are associated with POP. Any one of these adverse anatomical changes can devastate sexual interest and function.²⁵ Estrogen treatment may reduce the risk for POP, especially in postmenopausal women who have undergone hysterectomy and require transvaginal reconstructive surgery.²⁶

Medical problems and medications

Multiple medical problems, including diabetes, hypertension, and breast cancer, have been associated with female sexual dysfunction (Box 1). These conditions become more common as women move through midlife.

Box 1. Medical and psychiatric conditions that are associated with female sexual dysfunction.

Cardiovascular disease 108

Diabetes mellitus 109

Neurologic disease (stroke, multiple sclerosis, spinal cord injury) 110

Hypertension 28

Substance use disorders 111

Genitourinary syndrome of menopause 57,112

Breast, ovarian, uterine, and cervical cancer 113–115

History of gynecologic surgery 116,117

Chronic renal failure 118,119

Urinary incontinence 120,121

Both type 1 and 2 diabetes are associated with a 2–3 times higher rate of female sexual dysfunction.²⁷ Biologically, diabetes imparts chronic microvascular damage that could affect small nerves and blood vessels in the clitoris and associated structures, leading to impaired arousal and lubrication. Through similar mechanisms, hypertension has a 3-fold higher risk of sexual dysfunction in women,²⁸ with the strongest effects on the domain of lubrication.²⁹ While early studies suggested that certain antihypertensives, especially beta blockers, may negatively affect sexual function in women,³⁰ newer studies have found no association between antihypertensives and female sexual dysfunction.^31–33 In fact, antihypertensive medications that work on the renin-angiotensin system may be associated with better sexual function.^31,34

Breast cancer can negatively effect sexual function in both short and long terms.^35–37 Around 50% of women with a history of breast cancer report sexual problems,³⁷ and the prevalence rises to 70% among women with invasive cancer.³⁸ The causes are multifactorial. Receipt of chemotherapy is one of the strongest risk factors,³⁹ particularly if it results in premature menopause.⁴⁰ Aromatase inhibitors are associated with vaginal dryness and sexual pain^38,41 while tamoxifen does not have strong effects on sexual function.³⁸ Mastectomy can negatively affect body image³⁹ and in turn sexual function.^37–39,42 Among women with diabetes, hypertension, or breast cancer, depression is highly correlated with sexual dysfunction.^35,37,43,44 This highlights the importance of screening for and treating mood disorders in these populations.

Other medications have been associated with female sexual dysfunction (Box 2). Among the most common offenders are antidepressants, including selective-serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and tricyclic antidepressants.⁴⁵ While depression itself is associated with sexual dysfunction, odds of sexual dysfunction are 4–6 times higher for women taking a medication.⁴⁶ Sexual side effects are less common with bupropion^46,47 and mirtazapine.^47,48 Providers should counsel women about the potential for sexual side effects when starting these medications. Small studies have shown sildenafil and bupropion to be effective antidotes for antidepressant-associated sexual dysfunction.^49,50

Box 2. Medications that are associated with female sexual dysfunction.

Antidepressants (selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, tricyclic antidepressants) 46,47,122,123

Opiates 111

Cancer therapies, especially for breast and gynecologic cancer 113,124–126

Antihypertensives (mixed evidence), particularly beta-blockers 30– 127

Antiepileptics 128,129

Benzodiazepines 130,131

Psychosocial

Several psychosocial factors that are common during midlife are associated with sexual dysfunction:

• Mood symptoms, such as depression and anxiety

• Life stressors such as career and family demands

• A history of trauma, particularly sexual trauma

The development of depression and anxiety symptoms during the menopausal transition is common.^51–53 Mood disorders and sexual dysfunction are highly comorbid,⁵⁴ with 25–75% of depressed women reporting sexual problems⁵⁵ even when controlling for other factors.^56–58 It is important for providers to screen women with sexual complaints for depression and anxiety symptoms and recognize that not all women with sexual dysfunction have a mood disorder. Everyday life stressors also have a negative impact.^59–61 Midlife women may be caring for children of their own, having adult children return home, and/or be caring for aging parents.⁵⁹ Job-related stress and financial concerns are also common.⁵⁹ Providers should be attuned to the effects of life stressors and work with women to develop stress reduction strategies, such as mindfulness meditation.

Women who are victims of violence are at increased risk for sexual dysfunction in women,⁶² with those who have experienced sexual trauma—up to 44% of women over their lifetime⁶³—at particularly high risk.⁶⁴ The relationship between trauma history and sexual dysfunction is not entirely explained by mental health disorders, such as depression, anxiety, and post-traumatic stress disorder. It is important to use evidence- based, trauma-informed care techniques to screen for these events when providing care for women with sexual dysfunction.^65,66

Interpersonal factors

Most midlife women are sexually active with a partner,⁵ and partner-associated issues can affect the woman’s sexual function:

• Positive relationship aspects - Higher relationship satisfaction and intimacy are associated with better sexual function,^67,68 and the ability to openly communicate with one’s partner is of key importance.⁵⁹

• Loss or gain of a partner - Many women experience the loss of a partner (to death, divorce, or separation) at midlife, and some gain a new partner, both of which can affect sexual function.^57,69 Gain of a new partner is associated with increased desire, arousal, and emotional satisfaction with sex.⁵⁷

• Issues affecting aging partners - Partners may develop medical problems, medications, or sexual dysfunction that can affect the woman’s sexual function. In particular, erectile dysfunction in male partners is associated with decreased sexual function and satisfaction in female partners.^59,70

NEW AND EMERGING TREATMENTS

Female sexual interest and arousal disorder

There is only one Food and Drug Administration (FDA) approved medication for the treatment of hypoactive sexual desire disorder: flibanserin. While only approved for use in premenopausal women, it is efficacious in postmenopausal women.⁷¹ Flibanserin increases satisfying sexual events by about 0.5 per month compared to placebo, with statistically significant improvements in desire, overall sexual function, and sexually- related distress.^72–75 Some have questioned whether these improvements are clinically significant.⁷⁵ Providers should be aware:

• Common adverse effects include somnolence, dizziness, and nausea^73,75

• Flibanserin interacts with some common medications (macrolide antibiotics, azole antifungals, and calcium channel blockers)

• Women cannot drink alcohol while using flibanserin

• Healthcare providers must be certified to prescribe flibanserin

Testosterone has been studied for the treatment of hypoactive sexual desire disorder, but is not FDA approved for this purpose. Most testosterone studies were conducted among surgically menopausal women,^76–78 although there a few studies included naturally menopausal women.^79,80 All but two studies^79,81 paired testosterone with estrogen therapy. Consistent positive effects were seen on sexual desire, overall sexual function, and sexual distress.^{76–80,82–84} Common adverse effects were acne and hirsutism, occurring in 5–20% of women.^76–82 Negative effects on lipid parameters were not observed.^77,84 However, randomized trial data beyond 24 weeks is sparse, and a recent analysis suggests only women who achieve supraphysiologic testosterone levels have a significant response⁸⁵ Observational studies have suggested there may be an increased risk of cardiovascular disease⁸⁶ and invasive breast cancer^81,87 when testosterone is added to traditional hormone therapy, but findings are inconsistent^.88,89

Behavioral interventions, most notably mindfulness-based therapies, have shown positive effects on sexual desire, sexual distress, and overall sexual function.^90–92 These methods may improve sexual function by increasing bodily awareness⁹³ and improving concordance between physiologic and psychological arousal.⁹⁴ However, these studies are relatively small, limited by use of wait-list controls or no control group, and lack comparison to pharmaceutical interventions.

Genitourinary syndrome of menopause and sexual pain

Many women have been dissatisfied with prior treatment for GSM and sexual pain.^95,96 These symptoms remain underrecognized and undertreated by healthcare providers.^95,97,98 Newer options include ospemifene, prasterone, estradiol softfels, and carbon dioxide laser therapy.

Ospemifene is an FDA-approved selective estrogen receptor modifier that results in significant improvements in vaginal symptoms and dyspareunia.^99,100 Adverse effects include hot flashes (7–10%)^101,102 and endometrial proliferation (2–12%), although no cases of hyperplasia or endometrial cancer are reported.¹⁰¹ Prasterone, intravaginal dehydroepiandrosterone (DHEAS), was recently approved for the treatment of dyspareunia due to GSM, with the only adverse effect being vaginal discharge (6%).¹⁰³ A new formulation of vaginal estradiol, a softgel tablet, has shown promising results in early trials.^104,105 Finally, carbon dioxide laser use is emerging as another potential treatment;^106,107 however, trials have lacked adequate control groups and further research is necessary. Data beyond 52 weeks are not available for any of these newer treatments, and it is unclear how they compare to older treatments in terms of efficacy or safety.

FUTURE DIRECTIONS

Much progress has been made in the field of women’s sexual function. However, much work remains. Sexual health education for providers in training needs to be better developed and tested. Easy-to-use, efficient screening methods for sexual problems in primary care settings are needed. Research should seek to define protective factors— ways that women adapt to the changes that occur with the midlife transition, and how they are able to maintain sexual function and satisfaction. Data on how sexual function changes with aging is needed among sexual minority groups. Research should explore how the traditional and newer treatment options for GSM compare to one another, not just placebo, and define which treatments are safest and most effective for specific patient groups. Treatments for desire and arousal difficulties remain lacking; behavioral interventions hold promise, and ongoing research should explore which aspects of these interventions are most powerful, and how they can be scaled up to reach the women in need. Helping women preserve healthy sexual function with aging is an essential component of maintaining quality of life into older adulthood.

Key Points:

• A sizeable minority of women report sexual dysfunction during the perimenopause and menopausal years; about 15% endorse personal distress as a result.

• Genitourinary syndrome of menopause (GSM), vulvovaginal atrophy (VVA), and pelvic organ prolapse (POP) can cause vaginal and sexual pain and remain under-recognized and under-treated.

• Relationship and social factors, as well as sexual trauma, are important predictors of midlife sexual function.

• A variety of pharmacologic treatments are available with varying efficacy; more information is needed to help clinicians target treatments effectively.

Synopsis:

Sexual function is an important component of quality of life for women. Midlife poses a number of challenges to optimal sexual function and intimacy for women. In addition to anatomical factors related to estrogen deficiency, such as GSM, VVA, and POP, psychosocial factors, including prior sexual trauma, play an important role in sexual function in women. A number of treatments have emerged for female sexual dysfunction; long-term studies and head-to-head comparisons are lacking.