Women's Sexual Function and Dysfunction. Irwin Goldstein MD

Sexual function in the menopause and perimenopause

Manjari Patel, Candace S Brown, Gloria Bachmann

Introduction

Just as pain syndromes or cancers have many etiologies, so do female sexual dysfunctions that women report during the peri- and postmenopausal years (see Chapters 13.1-13.3 in this volume). That is, not all of the sexual complaints that a woman in this stage of her life cycle reports to her clinician are due to gonadal hormone insufficiency. Rather, sexual function depends on an intact neurologic and vascular system in addition to endocrinologic integrity. Any deviation in one of these systems will cause dysfunction affecting sexual health1 (see Chapters 3.1—3.4 and 6.1-6.5). In addition, nonmedical factors also affect the sexual health of the menopausal patient, which may either act by themselves (care of an elderly parent living in the home) or exacerbate the condition already caused by the hormonal changes (sleep deprivation from night sweats caused by diminished estrogen) or disease (diabetes mellitus). Family structure [children leaving home, financial difficulties, dysfunctional partner (see Chapters 8.1 and 8.2)], social environment (stigma of menopause associated with aging and loss of feminine allure), religious beliefs (sexual activity solely for the purpose of reproduc tion), previous personal sexual experience (never having had a rewarding sexual life and onset of menopause the excuse to stop engaging in coital activity), and a history of past or current sexual abuse and domestic violence (from an alcoholic or unemployed partner; see Chapter 3.4) are all important contributors to female sexual dysfunction.

Although the hormonal changes from the menopause transition itself can be overwhelming and have a markedly negative effect on sexual health, the sexual distress that these changes trigger in the menopausal woman may not have as great an impact on her quality of life compared with the younger woman. A woman during the menopausal years may be married to a partner with declining sexual health, and so a premium may not be placed on optimal sexual function. Moreover, at this point in the life cycle, most women have completed the pregnancies they desire and therefore fertility is no longer an issue. In comparison, the reproductive-aged woman with a sexual problem who has a functional partner and who has not yet fulfilled childbearing desires will experience a greater decline in quality of life than the older woman. Nonetheless, although the impact may not be as great on personal and interpersonal relationships, female sexual dysfunctions that occur with the menopausal transition frequently lead to a deterioration in the relationship between the partners, a loss of the woman’s self-esteem, and a diminution in her quality of life. For affected menopausal women, female sexual dysfunction can be physically disconcerting, emotionally distressing, and socially disruptive.1 Another negative aspect of female sexual dysfunction in the menopausal woman is that the sexual problem is usually progressive. The lactating woman who experiences vaginal dryness and dyspare- unia after childbirth has a reversible condition. The menopausal women who experiences vaginal dryness and dys- pareunia from urogenital atrophy due to loss of estrogen has neither a reversible etiology nor one that decreases in intensity over time. On the contrary, vaginal dryness and pain symptoms will become more severe over time.2 Since female sexual dysfunctions increase dramatically with menopause, offering early intervention to affected women should be the goal of all clinicians who treat this cohort of women.

Definition

Female sexual dysfunction is a multidimensional and multifactorial problem, and often all contributors to the complaint may not be obvious at the first visit in which they are addressed (see Chapter 9.1). However, for many climacteric women, having their sexual concerns addressed by the physician and being offered education and counseling is often an effective first step, regardless of whether the woman consents to pharmacologic therapy, such as estrogen or androgen treatment, or sexual counseling. The World Health Organization’s International Statistical Classification of Diseases and Related Health Problems (ICD-10) defines sexual dysfunction as “the various ways in which an individual is unable to participate in a sexual relationship as he or she would wish”.3 Today, there are no upper limits of age at which sexual health issues should not be addressed. However, for all women, especially menopausal woman, the key to offering intervention rests with whether the sexual complaint causes personal distress. According to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV), sexual dysfunctions are “disturbances in sexual desire and in the psychophysiologic changes that characterize the sexual response cycle and cause marked distress and interpersonal difficulty”4 (Table 7.2.1). It bears repeating that all of the sexual complaints seen in the reproductive-aged female also occur (but with greater frequency) in the menopausal woman. Each of these diagnoses is subtyped as (i) lifelong versus acquired type, (ii) generalized versus situational type, and (iii) etiologic origin (organic, psychogenic, mixed, and unknown).For menopausal women, sexual complaints that begin at the time of ovarian decline are more amenable to treatment with hormones and/or counseling than sexual complaints that commence premenopausally. In fact, menopausal women reporting sexual complaints that began long before the menopausal transition should be offered referral to a sex therapist in addition to hormonal and or pharmacologic intervention.

Many women may have more than one female sexual dysfunction (such as loss of sexual desire and pain with vaginal intercourse) and more than one etiology that contributes to the complaint(s). This aspect of multiple etiologies is often overlooked in the menopausal patient when defining successful intervention. That is, when a full response is not seen with estrogen or estrogen/androgen therapy, it is often assumed that the intervention was not effective. However, since female sexual dysfunction is multifactorial, and, frequently, an overlap of the disorders can be observed, the estrogen therapy intervention may have treated only one of the etiologies (the urogenital atrophy), but not the relationship issues.2

Table 7.2.1. American Psychiatric Association4 classification of sexual dysfunctions

Epidemiology

Female sexual disorders affect 20—50% of women in the USA, affecting not only midlife and older women, but also the younger population (see Chapters 2.1—2.4). Data clearly show that sexual dysfunction affects men and women throughout the adult life cycle, but becomes more prevalent with menopause in the female and with aging in both men and women.5,6 For example, hypoac- tive sexual desire disorder, more commonly reported in females than men (with a female to male ratio of approximately 2—3:1), becomes more prevalent at age 60 years and older in both sexes.Moreover, according to the National Health and Social Life Survey studies, approximately 20% of women aged 18—59 years report having difficulty in lubrication during sexual stimulation,whereas this number jumps to 44.2% for postmenopausal women.8 This same pattern is seen with orgasmic dysfunction. According to the National Health and Social Life Survey studies, although there is no relationship between orgasmic dysfunction and race, socioeconomic status, and educational or religious background,5,9 there seems to be a higher prevalence of anor- gasmia in single women than married women,5 and in postmenopausal women than reproductive-aged ones.10 Dyspareunia is the sexual dysfunction associated most closely with menopausal status and is the most frequent sexual complaint that aging women report to their gynecologist.5,8 With anticipation of vaginal pain, many women with dyspareunia will develop vaginismus over time, although in the general population other etiologies such as previous sexual abuse and trauma may lead to this sexual dysfunction. Up to 17% of women with vaginismus may ultimately present for intervention.11

Physiology

Masters and Johnson, who first detailed the female sexual response cycle, depicted a linear pattern of sexual response for both premenopausal and postmenopausal subjects. Although the four successive phases, starting with excitement and then progressing from plateau to orgasm and finally to resolution, do not change with aging, there are marked alterations that occur with loss of gonadal stimulation in each of these phases.12 For example, the excitement phase is dependent on both the activation of central nervous system and an environment of adequate ovarian hormones to achieve genital vasocongestion, increased blood flow, smooth muscle relaxation, and ultimately transudation of vaginal wall secretions. The labia increase in size, the clitoris engorges, the vagina expands, and the uterus elevates. With inadequate estrogen, the excitement phase is prolonged, and vasocongestion may be inadequate to produce the anatomic changes and the vaginal secretions necessary for comfortable coital activity. During the plateau phase, there is further engorgement of the labia, retraction of the clitoris, increased bartholin gland secretion, congestion of the outer third of the vagina, and expansion of the upper two-thirds of the vagina. Plateau is also attenuated in an environment of estrogen insufficiency. With orgasm, the intensity and number of vaginal and uterine contractions may also decrease in the menopausal woman. The final phase of resolution, characterized by gradual, pleasant diminishment of sexual tension and response, is similar in pre- and post-menopausal women.

In 1979, Kaplan proposed a three-phase model consisting of desire, arousal, and orgasm, with the same adverse changes described in the menopausal woman as with the Masters and Johnson model. It was also noted that desire for sexual exchange may be more adversely affected in the surgically menopausal patient than the naturally menopausal one because of the complete cessation of gonadal androgens.13 This three-phase model of sexual response is the basis for DSM-IV definitions of female sexual dysfunction. The reclassification system proposed by the American Foundation of Urologic Disease Consensus Panel in October 1998 is also based on this three-phase model.14 Another sexual function model, described as a circuit with four main domains of libido, arousal, orgasm, and satisfaction, may more accurately describe the female sexual response cycle. In this model, sexual response is thought of as a circular rather than a linear response, such that each of the four domains may overlap with each other, and each domain can give positive or negative feedback on the remaining three domains. This model explains modification of sexual response under many circumstances (situational loss of sex desire due to a teenage child studying with friends in the next room) and with many inputs affecting ultimate sexual satisfaction.

Because of the complexity of the female sexual response and the hormonal changes that occur in the aging woman with the onset of menopause, the many biologic, physiologic, psychologic, and sociocultural factors that influence sexual response are often exacerbated. Therefore, it is necessary to evaluate all contributors to sexual health in addition to hormonal ones before making treatment recommendations.15 Use of pharmacotherapy after evaluation of only biologic or physiologic components of the dysfunction may not achieve satisfactory treatment outcomes: that is, treating vaginal atrophy with vaginal estrogen may not correct the dyspareunia if the woman is living in a household in which there is ongoing domestic violence.

Etiology - factors affecting normal sexual function

Hormonal changes

Estrogen

In otherwise healthy women, estrogen levels are well maintained until the perimenopause. Estrogen deficiency causes cellular dysfunction in the urogenital tissue, leading to vaginal atrophy. The hypoestrogenic vaginal vault shifts from an acidic pH to an alkaline pH, which contributes not only to a shift in the vaginal flora, but also to more infections, leading to discharge and odor.16 With chronic lack of estrogen over time, vascular, muscular, and connective tissues also atrophy, and the vaginal vault becomes pale in appearance with loss of rugation and tissue friability. When coital exchange is attempted after years of estrogen loss and abstinence, the marked shortening and narrowing of the vaginal vault may make this type of sexual exchange extremely painful or impossible to achieve. Estrogen loss also affects the bladder, and complaints of urinary frequency, urgency, nocturia, dysuria, incontinence, and postcoital infection are common. The clitoris may also get fibrosed over time with loss of estrogen and decreased blood flow. Although not anatomically visible, lack of estrogen has also been shown to decrease touch perception, diminish vibratory sensation, and slow nerve impulses, causing delays in reaction time17 (see Chapters 9.2—9.5).

The correlation of low estradiol levels with vaginal atrophy and dyspareunia is very high. Significantly more women with an estradiol level of less than 50 pg/ml report vaginal dryness, dys- pareunia, and pain than women with an estradiol level of more than 50 pg/ml, and women with an estradiol level of less than 35 pg/ml report reduced coital activity.18 Estradiol has been reported to have a stronger relationship than testosterone with declining female sexual function across the menopausal transition.19

Androgens

Data from both men and women show that testosterone is very important in maintaining sexual integrity as well as for maintaining libido and orgasm. Androgens also contribute to other nonsexual physiologic functions, including bone metabolism, cognition, and feeling of well-being. Total testosterone and androstenedione start to decline in the young reproductive years, and circulating levels continue to decrease with advancing age20 (Table 7.2.2). Androgen levels peak around age 25 years and begin their gradual age-related decline during the mid-30s21 (see Chapter 6.3).

However, surgical menopause appears to be a major contributor not only to decreased libido and impaired sexual functioning, but also to muscle wasting, osteoporosis, loss of energy, changes in mood, and depression. Before menopause, most of the decline is from the adrenals, but after menopause, the decline has contributors in both the adrenal cortex and the ovaries. Dehydroepiandrosterone, dehydroepiandrosterone sulfate, androstenedione, and testosterone22—26 diminish in quantity. In addition, sex hormone-binding globulin, which binds with testosterone, may increase in postmenopausal women who are treated with oral estrogen therapy, thus reducing the amount of free testosterone. A major difficulty in androgen evaluation is the lack of sensitive assays to assess the low testosterone levels founds in women, as discussed in detail elsewhere.27

Table 7.2.2. Mean steroid levels in women (converted to pg/ml)

Hormone

Reproductive age

Natural menopause

Surgical menopause

Estradiol

’00-150

10-15

’0

Testosterone

400

290

’’0

Androstenedione

’900

1000

700

DHEA

5000

2000

1000

DHEA-S

3,000,000

1,000,000

1,000,000

DHEA = dihydroepiandrosterone; DHEA-S = dihydroepiandrosterone sulfate. From Lobo.20

Psychosocial factors

Along with obvious hormonal factors, psychologic and social factors also play a role in a woman’s sexual health. Unfortunately, most of the changes in these factors at the time of menopause adversely affect sexual function. Not only do these changes in the female affect sexual function, but, for heterosexual women, changes in the male partner also contribute to the woman’s sexual problems. Sexual changes in the male, the most common being erectile dysfunction and a prolonged preorgasmic plateau phase leading to delayed arousal and delayed orgasm, occur in the 50s and 60s. These occur at a time when religious and cultural beliefs frequently dictate that the woman’s feminine role is over since she can no longer get pregnant. Considering that women usually marry men older than they are, sexual problems in both partners often surface at the same point in the relationship. Moreover, the greater longevity of women leads to a shortage of male partners later in life, which also contributes to abstinence in many older women. Adverse changes in mental health, such as depression, mood disorders, and other psychologic disorders, also have a significant impact on sexual health during the menopausal years.5

Medical issues

Medical conditions, although they can occur at any point in a person’s life, are more prevalent at the time of the menopause. Acute and chronic illness may have both reversible and nonreversible effects on female sexual dysfunction. Medical illnesses that often commence at the time of the menopause are coronary artery disease and arthritis, which may affect arousal and orgasm capability. Neurologic diseases, such as multiple sclerosis, Parkinson’s disease, or diabetes with progressive microvascular disease, also play a role, but usually a decade or so after menopause.5

Medications

Medications affect female sexual dysfunction in many ways, such as altering blood flow (e.g., antihypertensive medications), or affecting the central nervous system (e.g., psychotropic drugs) (Table 7.2.3)28 Moreover, the drug effects may not be as detrimental in the younger woman as they are in the menopausal woman. For example, drying of the mucus membranes by antihistaminics may not be very troublesome to a reproductive-aged woman. However, the additive drying effect of the drug on the already atrophied vaginal vault will be very detrimental to the older woman. One major class of drugs that has a serious impact on sexuality in the menopausal woman, since women in this age category often use them, are the selective serotonin reuptake inhibitors. In fact, selective serotonin reuptake inhibitors are frequently prescribed for perimenopausal depression. Of the antidepressant class of drugs, bupropion has been shown to have the most favorable profile in sexual function.29

Table 7.2.3. Common classes of medications causing sexual dysfunction

Class Examples

Antihypertensive drugs

a1- and a2-adrenergic antagonists (clonidine, reserpine, prazosin) b-adrenergic antagonists (metoprolol, propranolol)

Calcium channel antagonists (diltiazem, nifedipine)

Diuretics (hydrochlorothiazide)

Chemotherapeutic drugs

Alklylating agents (busulfan, chorambucil, cyclophosphamide)

CNS drugs

Acetycholine receptor antagonists (diphenhydramine) Antiepileptic drugs (carbamazepine, phenobarbital, phenytoin) Antidepressants (MAOIs, TCAs, SSRIs)

Antipsychotics (phenothiazines, butyrophenones)

Opioids (oxycodone)

Sedatives/anxiolytics (benzodiazepines)

Drugs affecting hormones

Antiandrogens (cimetidine, spironolactone) Antiestrogens (tamoxifen, raloxifene)

Oral contraceptives

MAOIs = monoamine oxidase inhibitors; TCA = tricyclic antidepressants; SSRI = selective serotonin reuptake inhibitors. From Walsh and Berman.20

Surgical issues

As women progress through the menopause, the likelihood increases they will need a surgical procedure that affects their sexual self. Breast and genital tract procedures have the greatest negative influence on sexuality, but not in all cases. For example, after simple hysterectomy without excision of the ovaries for the treatment of pelvic prolapse or chronic bleeding, women usually report an improvement in sexual function (see Chapter 16.7). When hysterectomy is accompanied by oophorectomy, there is a high probability that sexual dysfunction will result, especially hypoactive sexual desire disorder.30 Data show that adverse changes in libido and orgasmic response are more likely in women who have had an oophorectomy than in those who retain their ovaries, and they are less likely to report improvements than women who have had hysterectomy without oophorectomy (55% compared with 74%).31 They are also more likely to experience decreased positive psychologic well-being. Compared with an age-matched normative population of partnered women, the surgically menopausal woman has significantly reduced sexual thoughts and desire, arousal, frequency of activity, receptivity and initiation, pleasure and orgasm, and relationship satisfaction.32 Preservation of the cervix may help to avoid adverse changes in sexual response when hysterectomy is needed, but data are not conclusive. The woman and her partner should be offered preoperative counseling for potential sexual changes, better or worse, that might follow the surgery.

Nonpelvic surgery, such as coronary bypass for a woman or her partner, also may lead to physical and emotional decline.

Clinical evaluation: assessment and diagnosis

Clinicians caring for menopausal women should introduce the topic of sexual dysfunction during both the medical history and the pelvic examination, especially if urogenital atrophy is noted. Menopausal women may not discuss the topic of sexual problems themselves without direct questioning, since many come from an era when these concerns were not openly talked about. Moreover, even though a gonadal hormonal profile may be ordered in some cases, there is no consensus on this practice for all cases, and for most women sexual history alone is sufficient to uncover hormonal insufficiency etiologies and to commence treatment with estrogens and androgens.

Sexual history should evaluate sexual interest, arousal, orgasm, and pain (Table 7.2.4)33 (see Chapter 9.4). Treatment is offered if the woman is distressed because of the sexual change or problem. As part of the sexual history, medication use, including over-the-counter, prescription, and street drugs, should be recorded, as menopausal women are often on more medications than younger ones and there is a higher probability of their being on a drug that will affect sexual function.

Physical evaluation

A pelvic examination is essential in the menopausal woman to assess vaginal atrophy, dryness, trauma, infection, muscle tone, and pain-triggering spots (see Chapter 9.5). An important measurement is vaginal pH. A pH of more than 5 indicates atrophy, even in the younger perimenopausal women, if no other infective agent is responsible for the basic environment. The clinician should also perform a complete physical examination to rule out other comorbid conditions that might be causing sexual dysfunction.

An endocrine evaluation with measurement of the serum follicle-stimulating hormone, leuteinizing hormone, serum estradiol, dehydroepiandrosterone, total testosterone, free testosterone, sex hormone-binding globulin, and prolactin levels may be indicated in women with sexual dysfunction.2

Table 7.2.4. Guidelines for taking a general sexual history General sexual history

Psychosocial/psychosexual assessment

Psychosocial factors have great impact on female sexual dysfunction for both younger and older women (see Chapter 9.3). Social issues, past sexual beliefs, and emotional aspects and other psychiatric disorders should always be ruled out.34

Many subjective and objective measures have been used in clinical trials in an attempt to standardize definitions and outcomes. The clinical assessment of female sexual dysfunction in the menopausal patient does not include many objective measures except obvious changes on pelvic examination and vaginal pH. Objective research measures include (1) genital blood flow (measuring clitoral, labial, urethral, and vaginal peak systolic velocities and end-diastolic velocities by duplex Doppler ultrasonography); (2) vaginal lubrication measurements and vaginal pH; (3) vaginal compliance and elasticity (pressure volume changes); and (4) genital sensation (vibration and temperature perception thresholds).35

Subjective measures are primarily used in research and include self-rated questionnaires, daily diaries, and event logs. Self-report measures have been developed that are reliable, well-standardized, validated, inexpensive, and easy to administer and score, and have normative values for both clinical and nonclinical populations. The most common self-rated questionnaires measure desire, arousal, orgasm, and sexual pain; they include the Brief Sexual Function Index for Women,36 the Female Sexual Function,37 and the Derogatis Interview for Sexual Functioning.38 Daily diaries and event logs quantify the frequency of sexual activity, attempts at intercourse, and other forms of sexual activity.35

Management

Accurate assessment of the menopausal patient leads to an optimal management plan. Treatment plans should always include all facets affecting sexual dysfunction, including proper education about normal anatomy and physiology, as well as endocrine factors, such as changes in androgen and estrogen levels. Women should be asked to avoid medications that may have influence on sexual function, and encouraged to avoid alcohol and to stop smoking. Maintaining optimal health and correcting reversible medical problems are important steps to optimize sexual function.2

Nonpharmacologic therapy

Lifestyle changes such as drinking more water, smoking cessation, and aerobic exercises all have positive impacts on sexuality by maintaining the stamina to perform sex, increase libido, decrease depression, enhance body image, and increase testosterone levels. Communicating sexual likes and dislikes between partners, and reviewing sex videos and erotic literature can broaden sexual techniques. Increased tactile stimulation can increase arousal and desire, while communication and spending time together improves intimacy. Specific treatment strategies are illustrated in Table 7.2.5.

Pharmacologic therapy

Even though there are many suggested treatment options available, there is no single intervention that will be effective in all peri- and post-menopausal women.

Estrogen therapy

Decreased sexual function in postmenopausal women is due in part to estrogen depletion after menopause. The estrogen decline associated with menopause is a major cause of climacteric signs and symptoms, such as vaginal atrophy, hot flashes, dyspareunia, and nocturnal awakening. One controlled and two open-label trials have shown reduced vaginal symptoms after estrogen therapy (Table 7.2.6). Lower doses of conjugated equine estrogen (0.45 and 0.3 mg) with and without medroxyprogesterone acetate (2.5 mg, 1.5 g) reduced vaginal atrophy compared with placebo in 2673 healthy menopausal women.39 A 12-week, randomized clinical trial found that among 194 postmenopausal women with urogenital atrophy, a continuous, low-dose, estradiol-releasing vaginal ring provided relief comparable to conjugated equine estrogen vaginal cream, but was more acceptable than the cream.40 Similarly, a 24-week comparative study of 159 menopausal women found that 25-pg 17-P estradiol vaginal tablets and 1.25 mg conjugated equine estrogen vaginal cream were equally efficacious in relieving atrophic vaginitis, but the vaginal tablets produced less endometrial proliferation or hyperplasia, and were more favorable than the cream.41

Several clinical trials have reported improved sexual desire in healthy postmenopausal women receiving estrogen therapy42-46 (Table 7.2.6), but only one placebo-controlled trial has been conducted in postmenopausal women with sexual dysfunction.47,48 In this 12-month trial, a significant improvement in mood, sexual desire, enjoyment, and orgasmic frequency, apart from vaginal symptoms, was reported in 49 ovariectomized women receiving ethinyl estradiol (50 pg) compared with levonorgestrol (250pg/day), a combination of these two substances, or placebo.47,48 No differences were found between groups in coital rate. Thus, while the literature shows that estrogen is effective in postmenopausal women with vaginal atrophy, which may impede sexual function, there are few data to suggest that estrogen improves sexual desire, enjoyment, and orgasmic frequency.

Testosterone therapy

Studies of testosterone use have been conducted in postmenopausal women for over half a century. The studies are difficult to compare because of different methodologies, pooling of diverse cohorts (oophorectomized and nonoophorectomized women), varied definitions of sexual dysfunction, and a nonoverlapping range of inclusion criteria.

The first androgen studies combined estrogen with testosterone pellets of 5049,50 or 100 mg,51 or intramuscular injections (150 mg).52,53 Both unblinded50'52,53 and blinded49,51 studies showed improvement in mood and sexual functioning. However, supra- physiologic doses were often used, and intramuscular injections showed erratic absorption. Two blinded studies found that oral methyltestosterone (2.5 mg) with estrogen (Estratest)54,55 improved sexual functioning at physiologic doses.

Transdermal patches or gels, which are more consistently absorbed and avoid first pass through the liver, are being studied for safety and efficacy in reducing sexual symptoms associated with testosterone insufficiency. Recently, transdermal testosterone patches (150 pg and 300 pg) were compared with placebo in 75 estrogenized women who had undergone oophorectomy and hysterectomy.56 The study results showed that the 300-pg testosterone patch was significantly more effective than the 150-pg patch or placebo in improving frequency of sexual activity, pleasure, and fantasy during a 12-week period. There are no safety or efficacy data available on topical preparations in women, so their effects on sexual function are not known.

Possible adverse effects of testosterone include weight gain, clitoral enlargement, increased facial hair, voice deepening, and decreases in high-density lipoprotein cholesterol, which are dose dependent. The risks and benefits of androgen therapy are described in Table 7.2.7.57 Testosterone dosage formulations that have been used but are not US Food and Drug Administration approved are listed in Table 7.2.8.57,58 Safety and efficacy data are not available on off-label uses. Table 7.2.8 also provides information on how they are prescribed. There is no consensus on the value of androgen levels to predict which women will respond to androgens and at what level a response occurs.

Dehydroepiandrosterone

Dehydroepiandrosterone, which is both an ovarian and adrenal androgen precursor hormone, provides hormonal substrate for conversion to testosterone and dehydrotestosterone, which then interacts with androgen receptors.59 Because dehydro- epiandrosterone is classified as a “dietary supplement” rather than a drug, it is not under the control of the Food and Drug Administration, and thus there is no standardization of potency.

Table 7.2.6. Trials of pharmacologic agents in treating sexual dysfunction

Drug

Ref.

Design

N

Regimen

Measure

Outcome

Estrogen

39

OL

194

Vag Ring; Vag Crm

Vaginal atrophy

Vag Ring = Vag Crm

 

40

OL

159

E2 Vag Tab; CEE Vag Crm

Vaginal atrophy

Vag Tab = Vag Crm

 

41

RCT

2,673

CEE/MPA; PB

Vaginal atrophy

All CEE/MPA > PB

 

44, 45

RCT

49

EE (50 pg); LVN (250 pg); PB

Sexual activity

EE >EE + LVN = PB

Estrogen-androgen

46

RCT

20

E2 (40 pg) + T (50 mg) PT; PB

Sexual activity

E2/T > PB

combinations

47

OL

34

E2 (50 pg) + T (50 mg) PT

Sexual activity

E2/T50 > PB

 

48

RCT

17

E2 (40 pg) + T (100 mg) PT; PB

Sexual activity

E2/T > PB

 

49

OL

44

E2 (8.5-10 pg) + T (150 mg) IM; PB

Sexual activity

E2/T > PB

 

50

OL

53

E2 (8.5 pg) + T (150 mg) IM

Sexual activity

E2/T > PB

   

RCT

75

CEE + TT (150 or 300 pg); PB

Sexual activity

CEE/TT > PB

 

51

RCT

218

EE (0.625 mg) + MT (2.5 mg); PB

Sexual activity

EE/MT > PB

 

52

RCT

20

EE (1.25 mg) + MT (2.5 mg); PB

Sexual activity

EE/MT > PB

Sildenafil

58

RCT

781

S (10-100 mg); PB

Sexual activity

All S = PB

 

59

RCT

34

S (50 mg); PB

Erotic video;

S > PB (erotic video);

         

sexual activity

S = PB (sexual activity)

 

60

OL

33

S (50 mg)

Sexual activity

Effective

Tibilone

63

RCT

38

T (2.5 mg); PB

Sexual activity

T > PB

 

64

RCT

28

T (2.5 mg); PB

Sexual activity

T > PB

 

65

COMP

437

T (2.5 mg), E2 (2 mg) + NE

Sexual activity

T > E2/NE

DHEA

57

RCT

60

DHEA (50 mg); PB

Sexual activity

DHEA = PB

Arginine-Yohimbine

66

RCT

24

AG/Y; Y; PB

Erotic video

AG/Y > Y = PB

Phentolamine

67

RCT

6

PH (40 mg); PB

Erotic video

PH > PB

Alprostadil

68

RCT

79

A (100 pg); PB

Sexual activity

A > PB

AG = arginine; CEE = conjugated equine estrogen; COMP = comparative study; CRM = cream; DHEA, dehydroepiandrosterone; E2 = estradiol; EE = ethinyl estradiol, IM = intramuscular; LVN = levonorgestrel; OL = open label; MPA = medroxyprogesterone; MT = methyltestosterone; NE = norethindrone; P = patch;

PH = phentolamine; PT = pellet; PB = placebo, RCT = randomized placebo-controlled trial, Ref = reference; S = sildenafil; T = testosterone; Vag = vaginal;

Y = yohimbine.

One 3-month, placebo-controlled study of dehydroepiandrosterone (50mg/day) in 60 perimenopausal women with complaints of altered mood and well-being, found that the active treatment produced changes in hormone levels (242% increase in dehydroepiandrosterone, 95% increase in testosterone, and 13% decline in cortisol compared with baseline), but was no more effective than placebo in improving perimenopausal symptoms, mood, dysphoria, libido, cognition, memory, or well- being.60

Table 7.2.7. Androgen therapy: risks versus benefits

Benefits

Risks

Development or maintenance of

Fluid retention

secondary sex characteristics

Acne/oily skin

Improves libido and sexual function

Clitoromegaly

Increases muscle mass and strength

Male-pattern baldness

Increases bone mineral density

Lowered voice

Decreases body and visceral fat

Increases hematocrit

Increases hematocrit

Decreases HDL-cholesterol

Improves mood

Sleep apnea

Positive effect on cognition (?)

Aggressive behavior

Positive effect on quality of life (?)

 

Assertive behavior

 

HDL, high-density lipoprotein. Adapted from Swerdloff and Wang.57

Selective phosphodiesterase type 5 inhibitors

Selective phosphodiesterase type 5 inhibitors are used for the treatment of male erectile dysfunction. They work by decreasing the catabolism of the cyclic nucleotide, cyclic guanosine monophosphate, the second messenger in the nitric oxide- mediated pathway, thus promoting smooth muscle relaxation and vascular engorgement. Theoretically, selective phosphodiesterase type 5 inhibitors should also enhance the vaginal engorgement and lubrication response in women, especially menopausal ones, through smooth muscle relaxation.28

Research on the use of selective phosphodiesterase type 5 inhibitors in postmenopausal women with sexual arousal disorder has shown mixed results. In a large randomized, placebo-controlled trial, 577 estrogenized and 204 estrogen- deficient women receiving a selective phosphodiesterase type 5 inhibitor (10-100 mg/day) showed no overall improvement in sexual response.61 Selective phosphodiesterase type 5 inhibitors (50 mg/day) improved subjective arousal during visualization of an erotic video in 34 estrogenized postmenopausal women with acquired genital disorder and impaired orgasm, but it was no more effective than placebo in improving sexual arousal or orgasm.62 Changes in vaginal lubrication and clitoral sensitivity were reported in an open-label study of selective phosphodiesterase type 5 inhibitor (50 mg) in 33 postmenopausal women with sexual dysfunction, but there was no overall improvement in sexual function.63 Other selective phosphodiesterase type 5 inhibitors have not undergone clinical trails in postmenopausal women with sexual complaints.28

Table 7.2.8. Testosterone therapy regimens currently used for treatment of disorders of desire1

Tibolone

Tibolone is a synthetic steroid that is available in Europe and Asia for the management of climacteric symptoms and the prevention of osteoporosis. Recent evidence suggests that tibolone may improve mood and libido in postmenopausal women because it has androgenic as well as progestogenic and estrogenic effects.

It is thought to bind to androgen receptors, increase circulating free testosterone, and lower sex hormone-binding globulin levels.64,65 There are a few small clinical trials that have shown an improvement in sexual desire and arousability in tilolone (2.5 mg/day) as compared with placebo and to estradiol;66,67 tibolone (2.5 mg/day) was reported more efficacious than estradiol (2 mg) plus norethisterone acetate in increasing sexual frequency, sexual satisfaction, and enjoyment in 437 postmenopausal women in a 48-week multicenter trial.68 More data are needed to evaluate fully tibolone’s effect on postmenopausal women with low sexual desire.

Arginine and yohimbine

Arginine is an amino acid precursor to the formation of nitric oxide, and promotes relaxation of smooth muscle. Sold as a component in many herbal supplements, preliminary studies have found it to be promising in erectile disorder.28 Yohimbine is an a2-adrenoceptor antagonist that acts as a vasodilator.28 One randomized, double-blind study found that the combination of arginine and yohimbine increased vaginal and subject response to an erotic film compared with yohimbine alone or placebo in 24 postmenopausal women.69

Phentolamine

Phentolamine is a nonspecific adrenoceptor antagonist causing vascular smooth muscle relaxation and subsequent vasodilation. It has been previously studied in men for the treatment of erectile dysfunction.28 One study found oral phentolamine (40 mg) more effective than placebo in improving subjective arousal and vaginal blood flow in six postmenopausal women with poor arousal and lack of lubrication.70

Alprostadil

Alprostadil is a naturally occurring form of the hormone prostaglandin E1 and a potent vasodilator. It was approved by the Food and Drug Administration in 1995 for the treatment of erectile dysfunction in men and is available in both injection and intraurethral suppository forms.28 One study found topical alprostadil (400 pg) to be more effective than alprostadil (100pg) or placebo in improving level of sexual arousal and satisfaction in 79 postmenopausal women with a sexual arousal disorder.71

Other products

Androgenic dietary supplements, dopamine receptor antagonists (apomorphine), a-melanocyte stimulating hormone analogs, and vasoactive intestinal peptide have been studied in erectile disorder, but have not been studied in postmenopausal women.72

Summary

In summary, many new and promising interventions are on the horizon for the pharmacologic treatment of sexual problems. The role of over-the-counter and herbal products used in the treatment of postmenopausal women with sexual dysfunction is based on a few, small, short-term trials, so that there is a lack of efficacy and safety data. Hormonal therapies with estrogens and androgens have been more thoroughly studied, with efficacy observed in the treatment of dyspareunia (estrogen) and hypoactive sexual desire disorder (androgen). Both systemic and topical estrogens - which is the preferred route of administration - are effective for postmenopausal women with vaginal dryness or atrophic changes causing dyspareunia, but do not appear to improve sexual desire, enjoyment, and orgasmic frequency. The use of androgens to improve sexual desire in postmenopausal women is supported by placebo-controlled studies of combined oral estrogen-testosterone, combined estrogen- testosterone pellets, combined estrogen-testosterone intramuscular injection, and transdermal testosterone in estrogenized women. All studies showed improvement in sexual desire with the active compared with placebo groups. Further research on gonadal hormone preparations, as well as other pharmacologic and herbal interventions, is necessary for the treatment of postmenopausal sexual dysfunction.

Conclusion

Sexuality is an integral part of healthy human life and does not abruptly come to an end with the onset of menopause. The first step in treating older women is taking a comprehensive medical and sexual history to learn whether the sexual problems began before or after the onset of declining gonadal hormone levels. With menopausal women, proper knowledge of different cultural beliefs and social structure helps to understand what role menopause plays in the woman’s overall sexual health and function. Newer definitions and classifications, and inclusion of the psychosocial aspect have led to important changes in approach to female sexual dysfunction in all women, including the menopausal woman. Female sexual dysfunction is complex with varied etiologies, and comprehensive history is important to reach appropriate etiologies. Researchers have developed multiple types of questionnaires that help to explore different domains of female sexual dysfunction. Many modalities of treatment options have been suggested for menopausal female sexual dysfunction, including nonpharmacologic measures, psychosocial therapies, and behavioral modifications. Many drugs are under clinical trial to help treat female sexual dysfunction with sound safety profiles and efficacy. Even though extensive work has been done to understand the impact of menopause on female sexual dysfunction, many research questions still remain, and as further clinical trials are undertaken, expanded pharmacologic therapies will be added to the interventions clinicians can use for their menopausal patients with female sexual dysfunction.

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