Alan M Altman, Dina M Deldon-Saltin
The menopause, or last menstrual period, and the perimenopause, the transition leading up to and encompassing the last menstrual period, are not diseases. They are part of the natural transition from the reproductive years to postreproductive life. All women will experience this transition, with or without symptoms of hormonal change, if they live long enough. While the mean age of the menopause has remained around 51 years, the time women will live beyond their menopause has increased due to the extension of life expectancy to the mid-80s. Many women will now spend approximately one-third of their lives or more after the cessation of estradiol production by the ovaries. This leads to a change in the spectrum of diseases that women will suffer from as they age. Coronary heart disease, dementia, and osteoporotic fractures increase as women live further beyond the menopause.
Along with this life extension, there is an expectation of continuing sexual function beyond the menopause. This has been more pronounced of late due to three sociologic phenomena: the arrival of a more openly sexual generation to the perimenopausal years, the sexual emphasis in the media and entertainment industries, and the growing equality in the bedroom with women asking, “What about me?” While the sexual changes during the perimenopausal transition and after the menopause have been covered in earlier chapters, the endocrine therapies available for women with sexual dysfunction will be reviewed in this chapter. The postmenopausal period will be covered first. The perimenopausal transition, characterized by erratic ovarian function of almost certain unpredictability due to wide variations in estrogen levels, will then be discussed.
While 50% of men over 50, 60% of men over 60, and 70% of men over 70 have some degree of erectile dysfunction, 100% of women have some degree of genital atrophy at some point after the menopause due to the cessation of ovarian estradiol production. Estrogen production continues in postmenopausal women, however, through peripheral conversion of androstenedione to estrone. This conversion increases with increasing body weight due to the ability of adipose tissue to aromatize androgens into estrogens1 (see Chapters 5.5 and 6.1—6.3 of this book).
Urogenital changes contributing to altered sexual function
Estrogen is required for normal blood flow to the tissues of the reproductive organs. It also acts on estrogen receptors in these organs, allowing successful intercourse by maintaining the vaginal epithelium, thereby supporting elasticity and lubrication capabilities. High concentrations of estrogen receptors in the vagina, vulva, and urethra suggest that these tissues require estrogen for maintenance of function and make these tissues highly susceptible to atrophy due to the diminished estrogen production that occurs after the menopause. Low estrogen levels cause thinning of vaginal mucosal epithelium, atrophy of vaginal smooth muscles, and vaginal dryness, which in turn can lead to dyspareunia. Atrophic changes in the genitourinary system can be detected within 6-8 weeks in an estrogen-reduced environment.2,3 Sarrel found that vaginal dryness, burning, and dyspareunia were reported more often in women with levels of estradiol under 50 pg/ml than in those with higher levels4 (see Chapter 7.2).
The vaginal lining is highly rugated or folded. Its epithelium has a unique microscopic structure, which is responsive to estrogen. The cells respond cyclically to monthly variations in hormone levels. The vaginal epithelium contains no glands. Lubrication is produced by fluid transudation from blood vessels with some contribution from endocervical and Bartholin’s glands. Before menopause, the vaginal environment has a pH of 3.5—4.5. This low pH environment is maintained by breakdown of the glycogen provided by sloughed cells in the vaginal lumen. Glycogen is hydrolyzed into glucose, and the latter is metabolized to lactic acid by normal vaginal flora. This acidic environment discourages growth of pathogenic bacteria5 (see Chapters 4.1—4.4).
Urogenital atrophy, also referred to as vaginal dryness or atrophic vaginitis, is common, affecting nearly 15% of peri- menopausal and 10—40% of postmenopausal women. Atrophy begins in the perimenopausal period and continues over many years. Aging also contributes to thinning of the hair of the mons and shrinkage of the labia minora. The labia majora flatten as the subcutaneous fat and elasticity of the structures diminish. It is common for women to experience pruritis at the onset of atrophy, as tissues are shrinking. With estrogen loss, the vagina becomes pale and its epithelium thins, resulting in diminished distensibility and reduced secretions. The estrogen-deficient vagina is easily traumatized and can bleed. The estrogen deficiency also changes the vaginal environment into an alkaline one, predisposing the vagina to colonization by pathogenic bacteria. By the postmenopausal period, the endocervical glandular tissue produces less mucin, contributing to the overall vaginal dryness that is often the presenting complaint of the patient6 (see Chapters 6.1—6.4).
These physiologic, vascular, and hormonal changes can cause dyspareunia. Women begin avoiding sexual relations with their partner secondary to the fear of painful intercourse. Dyspareunia can lead to avoidance, and avoidance can lead to further vaginal atrophy, which can cause worsening dyspareu- nia. Hence, the vicious cycle can ultimately lead to performance anxiety and loss of any sexual desire.
Treatment of urogenital atrophy
Nonpharmacologically, vaginal lubricants and moisturizers applied on a regular basis can be used to treat urogenital symptoms such as vaginal itching, irritation, and dyspareunia. Local use of vaginal lubricants to ease penetration and allow successful and pain-free intercourse can help treat symptoms and also allow some increase in blood flow, but has diminished ability to treat the source of the problem, namely, estrogen insufficiency. However, they can be offered to women as a first- line therapy, especially for those who wish to avoid the use of hormones. Lubricants should be pH neutral so as to not alter the vaginal environment and flora. Many varieties are available over-the-counter at local pharmacies or specialty stores. Water- based lubricants are easily absorbed, but silicone-based lubricants can leave the skin with an oily texture. It should be noted that some lubricants can decrease condom integrity, especially petroleum-based products and oils.
Vaginal moisturizers are promoted as providing long-term relief of vaginal dryness rather than being just sexual lubricants. Moisturizers are claimed to provide more than transient lubrication. A bioadhesive, polycarbophil-based polymer works by attaching to mucin and epithelial cells on the vaginal wall through anionic binding. The polycarbophil portion carries up to 60 times its weight in water and holds water in place against the vaginal epithelial surface until it is sloughed off, typically after 24 h. One such moisturizer was compared with a lubricant in a double-blind, randomized, crossover trial in 93 perimeno- pausal and postmenopausal women with vaginal dryness. After 5 days of daily use, the polycarbophil-based polymer produced a longer duration of lubrication and a significantly lower vaginal pH than the lubricant (baseline pH 5.6 ± 1.1, moisturizer 4.9 ± 1.1, lubricant 5.7 ± 1.0). More women reported product residue with the polycarbophil-based polymer (8%), but, overall, side effects were similar between the two groups.5
While the process of intercourse itself or, for that matter, masturbation can increase vaginal blood flow and help maintain vaginal health, it often takes the use of estrogen therapy to return function that can again lead to successful intercourse. The replenishment of estrogen results in increased vaginal compliance, decreased vaginal pH, increased vaginal blood flow and lubrication, and restored clitoral and vaginal vibration and pressure thresholds. In a recent study, 15% of women on hormone therapy reported vaginal dryness after a 5-year follow-up, compared to 30—40% of their non-hormone-therapy counterparts. Consequently, the degree of dyspareunia was also less among the hormone therapy than the non-hormone-therapy users.7 With estrogen use, women report less vaginal irritation, pain, dryness, or burning during intercourse. Relief from these symptoms often leads to increased sexual desire and arousal.2
Oral versus nonoral estrogen use
Local estrogen therapy can be as effective as systemic estrogen for restoring vaginal epithelium and relieving atrophy.2,8 Recent studies on local estrogen therapy have shown restoration of vaginal epithelium to its normal state within several months. Local therapy in the past has meant the use of vaginal estrogen creams. Conjugated equine estrogen, estradiol, and estriol creams administered intravaginally can partly or completely restore vaginal cytology to premenopausal levels, and improve or cure urogenital atrophy and dryness.5 Creams, however, can be absorbed into the systemic circulation, higher dosages resulting in higher systemic estrogen concentrations. The cream form of estrogen is also more subject to irregular application intervals, bolus absorption, and low absorption capacity of the fat-based vehicle, as well as the overall messiness of the product.9
More recently, other forms of local estrogen vehicles have been developed, such as rings and tablets, which may have better efficacy as well as more convenience. An opaque vaginal ring containing 2 mg estradiol is now available. The ring is placed in the vagina for 3 months, during which time it slowly releases the hormone. Comparisons between estradiol released from a ring and estradiol in cream form have shown equivalent efficacy in studies. A randomized, open-label, crossover study of 165 postmenopausal women with atrophic vaginitis compared continuous low-dose estradiol released from a ring with estriol vaginal cream. Both treatments were shown to be equally effective in alleviating the feeling of vaginal dryness as well as improving vaginal atrophy. They were also both efficient in restoring the vaginal mucosa to an estrogen-rich state. Quantitative analysis of the vaginal smears showed no difference between the two treatments in the number of parabasal, intermediate, and superficial cells in the mucosal wall. In relation to preference, 106 (64%) of 165 women preferred treatment with the ring. No preference was shown in 8 women (5%), while 29 (18%) preferred cream. The estradiol ring was welltolerated by patients and did not cause more severe local adverse events than other, existing treatments. Systemic effects were minimal, as very little estradiol reaches the systemic circulation.9 However, the ring must fit the individual’s vagina; otherwise, it is impractical to use, as too much atrophy does not allow enough room for the ring.
Local estrogen in the form of a tablet is also available for symptoms associated with vaginal dryness. A 17-beta-estradiol tablet in a 25-pg, single vaginal dose applicator is administered daily for the first 2 weeks of treatment, and then decreased to one vaginal tablet twice weekly as maintenance therapy. This product works locally and is not designed to help systemic symptoms of menopause.10
With respect to systemic use, estrogens can be divided into three groups: 17-beta-estradiol, conjugated equine estrogen, and estrone derivatives, which include the synthetic conjugated estrogens, esterified estrogens, and other estrogen derivatives. 17-beta-estradiol is the estrogen that is made in abundance by the ovaries prior to menopause. Estrone is the estrogen most abundant after menopause because its primary source is peripheral conversion of androstenedione in adipose and other tissue. Estradiol and estrone are interconverted, conversion of estradiol to estrone predominating. Estradiol can also be con verted to estriol.5,11 Conjugated equine estrogen is manufactured from pregnant mare’s urine.
Oral administration has been the most common route of estrogen therapy. Oral estrogens have been available for many years. They are usually well tolerated and cost-effective, especially the older generic brands. Oral estrogens undergo first-pass metabolism in the liver. The most notable benefit of first-pass metabolism is improvement in lipid values, such as high-density lipoprotein and low-density lipoprotein cholesterol.
There are several drawbacks to the oral administration of estrogen, however. First-pass metabolism reduces the systemic availability of estradiol, after oral administration, to less than 20%, because most of the oral estradiol is metabolized to estrone and conjugates, resulting in a high estrone to estradiol ratio that does not reflect physiologic levels.8,12 Oral estrogens also increase sex hormone-binding globulin, which binds free testosterone, thereby reducing the amount of biologically active testosterone. It is thought that this reduction in biologically active testosterone is one cause of decreased libido in postmenopausal women on oral estrogen therapy.
Oral estrogen is also associated with prothrombotic changes in hemostatic factors and an increase in inflammatory markers, such as C-reactive protein. The difference in C-reactive protein level may be due to the first-pass effect and a resultant stimulation of C-reactive protein synthesis in the liver.13 In addition, there is an increased risk of having a venous thromboembolic event with oral estrogen therapy. The Estrogen and ThromboEmbolism Risk Study, an observational study, documented a 3.5-fold greater risk of venous thromoboembolism in women using oral estrogen than in those using placebo (95% CI, 1.8—6.8).14
Transdermal hormone therapy provides more consistent blood hormone levels, and this translates into prevention of withdrawal symptoms. In addition to effectiveness at lower doses compared with oral administration, products administered by the nonoral route avoid first-pass hepatic effects.12 This decreases some of the adverse events associated with oral estrogen use. The Estrogen and ThromboEmbolism Risk Study showed that the risk of venous thromboembolic events is not associated with transdermal estrogen use, finding no significant difference in venous thromboembolic event rates between the transdermal and the placebo groups.14
Systemic estrogen is also available in the form of a vaginal ring. The estradiol acetate vaginal ring is an off-white, soft, flexible ring with central core, which contains either 0.05 or 0.10 mg/day of estradiol acetate. It is placed intravaginally, where it remains for 90 days, steadily releasing hormone over that time. This ring has the added benefit of increasing local, as well as systemic, estradiol levels. In a 13-week, double-blind, placebo- controlled trial conducted to evaluate the efficacy of the two doses of the estradiol acetate ring, vaginal superficial cells were noted to increase by a mean of 16.0% for the 0.05 mg/day dose and 18.9% forthe 0.10 mg/day dose, as compared to 1.11% for placebo.15
Heart and Estrogen/Progestin Replacement Study and Women’s Health Initiative
There has been a decline of systemic hormone therapy use since the premature discontinuation and publication of the estrogen- progestin arm of the Women’s Health Initiative Study in July 2002. In 1995, approximately 38% of postmenopausal women in the USA were taking hormone therapy. In 1997, hormone therapy was at its highest use in the USA with the rate of increase in use of 1% per quarter. After publication of the Heart and Estrogen/Progestin Replacement Study in 1998, the first decrease in hormone use occurred, with a decline of 1% per quarter.16
The Heart and Estrogen/Progestin Replacement Study was initiated in 1993 as a randomized, blinded, placebo-controlled, secondary prevention trial in which 2763 women with established coronary artery disease were randomly assigned to receive either 0.625 mg conjugated equine estrogen with 2.5 mg medroxyprogesterone acetate or placebo.17 The women had a mean age of 66.7 years, were postmenopausal with an intact uterus, and were followed for an average of 4.1 years. Although there was no net difference in myocardial infarction rate between the two groups, a significant time trend was observed for the outcomes. There were more cardiovascular events in the hormone-treated group than the placebo group during year 1, and fewer in years 4 and 5, but no overall net benefit or detriment. Other findings included a statistically significant net decrease in low-density lipoprotein cholesterol and net increase in high-density lipoprotein cholesterol among hormone therapy users. There were also significantly more venous thromboembolic events and gallbladder disease in the active treatment group.
The Women’s Health Initiative was designed as a primary prevention study, the primary outcome measuring the rate of nonfatal myocardial infarction or death due to myocardial infarction.18,19 The study was a two-arm, randomized, doubleblind, placebo-controlled study. It included healthy postmenopausal women aged 50—70 years, with a mean of 64 years. Women were an average of 12 years postmenopausal. They were divided into two groups, an estrogen-progesterone arm for those with intact uterus and an estrogen-only arm for women with prior hysterectomy. The estrogen-progesterone arm studied the use of conjugated equine estrogen plus medroxyprogesterone acetate versus placebo, while the estrogen arm studied only conjugated equine estrogen versus placebo.
The Women’s Health Initiative was terminated after an average of 5.2 years of follow-up, as the stopping statistic for a greater risk of breast cancer in one of the treatment groups had been reached.18 The estrogen-only arm of the Women’s Health Initiative was terminated in March 2004 because of a slight increase in stroke risk among women in the conjugated equine estrogen treatment group.
The data obtained from the Women’s Health Initiative inform us of the risks and benefits of the use of oral systemic hormone therapy (conjugated equine estrogen with or without medroxyprogesterone acetate) in North American women that were, on average, 12 years postmenopausal. Women treated with conjugated equine estrogen and medroxyprogesterone acetate had a possible risk of coronary heart disease that was 29% higher than women in the placebo group (OR = 1.29; 95% CI, 1.02—1.63). The absolute rate of coronary heart disease events was 7 more cases per 10,000 person-years for the hormone-treated group than for the placebo group. There was an increased risk of coronary heart disease apparent at year 1, as seen with the Heart and Estrogen/Progestin Replacement Study, and a longitudinal trend toward overall benefit (p = 0.02).18 In contrast, the estrogen-only arm demonstrated no increased or decreased risk of coronary heart disease in women treated with conjugated equine estrogen without medroxyprogesterone acetate (OR = 0.91; adjusted 95% CI, 0.72—1.15).19
Although the primary outcome measure of the Women’s Health Initiative was the rate of nonfatal myocardial infarction or death due to myocardial infarction, several other outcomes measures were analyzed. The outcome measure of breast cancer was especially noted, as it was the outcome measure that stopped the estrogen/progestin arm of the study. However, this was a secondary endpoint and, in the final analysis, did not achieve statistical significance when correctly analyzed as such. There was no significant difference between the groups in the rate of in situ breast carcinoma, raising the question as to whether these excess tumors were promoted, as opposed to initiated. In addition, the invasive breast cancers were larger and more advanced at diagnosis in the active treatment arm (p = 0.04 for both).18 In the estrogen-only arm, there was an opposite trend with a nonsignificant reduction in risk of breast cancer among women treated with conjugated equine estrogen (OR 0.77; adjusted 95% CI, 0.57—1.06).19
The risk of venous thromboembolic events was increased among women in the estrogen/progestin group of the Women’s Health Initiative compared with the placebo group. The absolute risk attributable to treatment with estrogen/progestin was 8 additional cases of pulmonary embolism per 10,000 person- years.18 The estrogen/progestin arm also showed an increased rate of ischemic stroke (OR = 1.44; 95% CI, 1.09—1.90), among women treated with hormone therapy, compared with those who received placebo. There was no increased risk of hemorrhagic stroke.20 In the estrogen-only arm, the incidence of venous thromboembolic events, including both deep vein thrombosis and pulmonary embolism, was increased in women treated with estrogen compared with women who received placebo.19 There was a slightly increased risk of stroke, equivalent to 12 additional events per 10,000 person-years among women treated in the estrogen-only arm of the Women’s Health Initiative compared with women who received placebo.20
Both arms ofWomen’s Health Initiative showed that hormone therapy significantly reduces the risk of spine, hip, and other fragility fracture in women not selected for increased fracture risk.
The results of the Women’s Health Initiative Memory Study, a study within the Women’s Health Initiative, showed that more women in the treatment group had smaller average increases in the Mini-Mental Status Examination scores than in the placebo group (p = 0.008).21 This study had some methodological limitations, and the findings are not surprising, given that the women were aged over 65 years, a group in whom hormone therapy is not routinely commenced. When the data from this Women’s Health Initiative subgroup were segmented by 5-year age groups, the only active treatment group with an increased risk of dementia was the one of women 75—79 years of age.22 In the estrogen-only arm of the Women’s Health Initiative an adverse effect of treatment was not demonstrated.
Because only one-third of women were younger than 60 years old, only 13% were 50—54 years old, and most importantly, only 16% were within five years of their final menstrual period, the WHI does not provide strong evidence about younger postmenopausal women who are closer to menopause; the women who are most likely to initiate hormone therapy for treatment of menopausal symptoms. Evaluating the subgroup of women in the WHI who were 50—54 years of age is risky, because the study was not designed to provide reliable data on these women. Thus, the WHI does not provide information on the benefits and risks of beginning hormone therapy at the time of the menopause. The WHI trials also only tested one drug regimen CEE 0.625 mg/day (plus MPA 2.5 mg/day in women with intact uterus). It does not provide information about the use of other doses, formulations, regimens, routes of administration or doses and duration of hormone therapy.
Lobo reported on results from two large, prospective, randomized control trials of over 4000 women with a mean age of 53.6 years and averaging 4.9 years from the final menstrual period, a good ten years younger than in the WHI study, in order to look at CHD risk in young, healthy postmenopausal women.23 Several regimens of combined CEE and MPA were assessed. Results were reported for year one of the trials, as this was the event time for early harm demonstrated in both the HERS and WHI studies. The rates for CHD related death or MI were 0/1000 vs 3.01/1000 in the treatment and placebo groups respectively. He concluded that the results of early CHD risk observed in the WHI study may not be applicable to healthy postmenopausal women closer to their menopause, even with the use of CEE/MPA.
In response to the discontinuation of the estrogen/progestin arm of the Women’s Health Initiative, professional societies and governmental agencies released statements or revised practice guidelines for hormone therapy. The American College of Obstetricians and Gynecologists published a response to the Women’s Health Initiative on their website on 3 June 2003. In this response, the college stated that “the decision about use of hormone therapy requires evaluation of the risks and benefits for each individual woman. For women currently using hormone therapy, it is important to assess their reasons for use and to evaluate potential risks, benefits, and alternatives. Women who take hormone therapy for the management of vasomotor symptoms should be encouraged to take it for as short a time as needed, and to use the lowest effective dose.”24 Other societies, such as the National Association of Nurse Practitioners in
Women’s Health and the North American Menopause Society, and the US Food and Drug Administration have also recommended that the lowest dose and shortest duration of hormone therapy be used. However, there are no randomized, controlled clinical data showing that lower dose and shorter duration are as effective or safer. In fact, while the Women’s Health Initiative and the Heart and Estrogen/Progestin Replacement Study showed a greater risk of coronary heart disease in year 1, longer- term use actually showed increased protection against coronary heart disease over time.16,18,19
It is obvious that since the publication of the Heart and Estrogen/Progestin Replacement Study and the Women’s Health Initiative trials, hormone therapy usage has declined to a significant extent. It is, however, unclear how to weigh the menopausal symptom relief provided by hormone therapy and the significantly reduced fracture risk against the risks of coronary heart disease, venous thromboembolic events, stroke, and possible breast cancer with combined therapy.25 Using a Markov decision-analysis model, a group of researchers designed a study which compared the quality-adjusted life expectancy with and without combination hormonal replacement therapy in three cohorts of women over a 20-year period. The women were at either high or low risk of breast cancer and coronary heart disease or at high risk of osteoporosis. The results of this study revealed that hormone therapy decreased life expectancy slightly compared with no hormone therapy if menopausal symptoms are not considered. However, if relief from menopausal symptoms is considered and the usefulness of life with symptoms is worth under 0.996 compared with life without symptoms, then 5 years of hormone therapy provides equivalent quality-adjusted life-years.25 In essence, if the benefit of hormone therapy exceeds the risks, that is, if vaginal dyspareunia is improved, women should continue their hormone usage.
The use of estrogen must be individualized to each patient’s needs and expectations. There is no “one-size-fits-all” recipe. What holds for women 10—20 years postmenopausal cannot be extrapolated to women recently postmenopausal, the largest population drawn to the health-care provider with questions and pending decisions about hormone therapy. What holds for oral estrogen therapy, and its thrombogenic potential, cannot be extrapolated to nonoral systemic estrogen or to use of vaginal estrogen for local therapy.
Systemic estrogen has been shown to improve vasomotor symptoms significantly, including hot flushes, night sweats, and sleep disturbance, all of which can affect a women’s body image, mood, and sexual desire. Alleviation of such symptoms can often go a long way toward increasing both quality of life and, indirectly, the drive for intimate contact and sexual activity.
In a woman with an intact uterus, the addition of progestogen to estrogen therapy is necessary to prevent endometrial hyperplasia and carcinoma. Progestogens are steroid compounds that help prevent endometrial hyperplasia and cancer in women on estrogen with an intact uterus, by downregulating estrogen receptors in the endometrium. There are two types of progesto- gens, natural and synthetic. Progesterone is the only natural progestogen, and it is poorly absorbed. However, a microniza- tion process, breaking down the progesterone into minute particles, improves its absorption by increasing the surface area of the hormone, making it more likely to be dissolved in the intestine. The bioavailability of micronized progesterone, however, continues to be limited because of extensive hepatic metabolism. Thus, large doses or twice daily dosing is often required to achieve therapeutic levels.11
Synthetic progestogens are divided into those related to progesterone, and those related to testosterone.11 The progesto- gens related to progesterone can be divided into two major groups: the pregnane group and the 19-non-pregnane group. Both can be further divided into acetylated and nonacetylated derivatives. The most widely used (in the USA) progestogen in this group is medroxyprogesterone acetate, which is an acety- lated pregnane derivative. In the circulation, medroxyprogesterone acetate is bound nonspecifically to albumin and undergoes extensive metabolism by hydroxylation and conjugation. The half-life of the drug is approximately 24 h. The other major group of progestogens is related to testosterone. This group can be divided into two major subgroups: the ethinylated and nonethinylated groups. The ethinylated group can be subdivided into two additional groups. One is the estranes group, which includes nonethindrone (USA) or norethisterone (Europe). In the other subgroup, 13-ethylgonanes, levonor- gestrel is one of the most potent and orally active progestogens. Other compounds belonging to this group are desogestrel, norgestimate, and gestodene.11
The addition of a progestogen to estrogen therapy is necessary in women with an intact uterus to eliminate the risk of endometrial cancer associated with unopposed estrogen. However, the addition of a progestogen can decrease both mood and libido.26 It does this by downregulating the estrogen receptor, a desired result in the endometrium, but potentially undesirable in the brain, heart, bone, and genitalia. It is this decrease in mood and libido that may lead to poor compliance among women who would benefit from estrogen therapy. In a recent, double-blind, crossover study, the side effects of medroxyprogesterone acetate and norethindrone acetate were compared in women using postmenopausal hormone therapy. The women showed cyclic changes, with negative mood and physical symptoms culminating during the late progestogen phase, and positive mood during the estrogen-only phase. Symptoms declined with time but remained after 5 months. Women with a history of premenstrual syndrome responded more strongly than those without a history of premenstrual syndrome.27
Several studies in the literature have reported negative effects of progestogens on sexual function. The effects of estrogen alone or with medroxyprogesterone acetate on psychologic function and sexual behavior were evaluated in a study of 48 healthy, naturally menopausal women. The benefits of estrogen were diminished by medroxyprogesterone acetate coadministration.28 Another report, comparing the use of estradiol alone or in combination with lynestrenol, a 19-norsteriod, revealed that women who used the combination therapy reported more negative mood symptoms than the estrogen-only group.29 In a third study, women who were intolerant of a conjugated equine estrogen/medroxyprogesterone acetate regimen were switched to conjugated equine estrogen plus progesterone and reported better vasomotor, somatic, psychologic, cognitive, and sexual function.30
In a recent animal study, the potential for medroxyprogesterone acetate to antagonize the estradiol effects of the female social sexual behavior of ovariectomized pigtail macaques was examined. Six ovariectomized pigtail macaques were tested under the following conditions: (1) placebo; (2) 17-beta- estradiol alone; (3) estradiol plus progesterone; (4) estradiol plus medroxyprogesterone acetate. Each hormone treatment was administered for 1 week and was separated by a minimum 3-week washout period. Female sexual initiation rates varied significantly across the treatment conditions (p < 0.001). The estradiol-only treatment induced a rise in female sexual initiation rates relative to the placebo condition (p = 0.016). The addition of progesterone failed significantly to attenuate the effect of estradiol on female sexual initiations (p = 0.276). Although rates of behavior during the estradiol plus progesterone condition also failed to rise above those observed under the placebo condition (p = 0.181), the medroxyprogesterone acetate plus estradiol treatment significantly attenuated rates of female sexual behavior, both in comparison with the estradiol-only (p = 0.001) and the estradiol plus progesterone condition (p = 0.038).31
Progestogens, however, appear to produce a wide range of patient responsiveness and tolerability, suggesting that women who do not tolerate one regimen might be effectively switched to another and experience improvement. Bjorn et al. showed that medroxyprogesterone acetate induced more physical symptoms than norethindrone when compared in a doubleblind, crossover study of postmenopausal women on hormone therapy.27
When added to estrogen for endometrial protection, progestogens can be administered in a variety of regimens. In a continuous combined regimen, patients receive daily doses of both estrogen and progesterone. There are also several different cyclic regimens in which progesterone is taken during only a portion of the cycle, such as the last 10—14 days of the hormone therapy cycle. In some instances, progesterone is given for only 10—14 days every 3—6 months, depending on the progestogen used and the bleeding response. If this regimen is chosen, a potent progestogen should be used to ensure sufficient endometrial shedding. A meta-analysis of the relative risk of endometrial cancer with hormone therapy found no difference between continuous and intermittent regimens.32 In the Postmenopausal Estrogen/Progestin Interventions Study, the risk of endometrial hyperplasia was lower among women who received progesto- gens than those who took estrogen alone, whether these were administered in a continuous or sequential regimen.33
Androgens (see Chapter 13.1)
The question as to whether estrogen has a direct impact on sexual desire is complex. However, the question of whether androgens have a direct impact on sexual desire has been studied extensively. Historically, androgens have been identified with male sexual function. However, androgens not only are necessary for the development of reproductive function and hormonal homeostasis within a woman, but also represent the immediate precursors to the biosynthesis of estrogens.34 A normal ovary produces relatively large amounts of androgen compared with estrogen across the female life span. The three main naturally occurring steroids responsible for androgen action are testosterone and dihydrotestosterone, formed from the precursors dehy- droepiandrosterone and its sulfate (dehydroepiandrosterone-S), as well as androstenedione. In women, peripheral tissues convert androgen precursors into more potent androgens, and may also convert androgens to estrogens via aromatase activity.35
The extent to which the postmenopausal ovary produces androgens remains controversial. In the early postmenopausal time period, elevated gonadotropins (follicle-stimulating hormone, luteinizing hormone) drive the remaining stromal tissue of the ovary to produce testosterone. Despite this drive by the postmenopausal ovary to produce androgens, testosterone levels are still lower than they were premenopausally due to the significant age-related decline in testosterone and adrenal androgen production beginning in the mid-20s. Circulating testosterone falls by approximately 50% after bilateral oophorectomy.36 Oral estrogen therapy increases the production of sex hormonebinding globulin by its first-pass effect through the liver. Sex hormone-binding globulin preferentially binds testosterone, but also binds estrogen, thereby reducing the amount of both bioavailable hormones. Hence, the use of oral estrogen postmenopausally (as well as its use premenopausally in oral contraceptive therapy) can diminish bioavailable testosterone and may affect sexual desire and arousal, as well as diminish bioavailable estrogen and allow relapse of vasomotor symptoms. Therefore, some have suggested that testosterone therapy, as an adjunct to estrogen therapy, is useful in the treatment of female sexual dysfunction and relapse of estrogen-withdrawal symptoms.
In a study of postmenopausal women by Laughlin et al.,36 androstenedione levels in hysterectomized women were approximately 10% lower than nonhysterectomized women (p = 0.039), regardless of ovarian status. In women with an intact uterus, androstenedione levels declined with age and were 20% lower in women who were greater than 30 years postmenopausal. In addition, total and bioavailable testosterone levels were reduced 29% (p < 0.001) in hysterectomized women with ovarian conservation and 40% (p < 0.001) in women with bilateral oophorectomy, compared to women with an intact uterus. Interestingly, total, but not bioavailable, testosterone levels increased with chronologic age, most of the increase occurring during the fifth decade with stable levels thereafter. Both total and bioavailable testosterone levels were 40—50% lower in oophorectomized than in intact women. Plasma sex hormone-binding globulin adjusted for body mass index reportedly increased with age in women with an intact uterus, but did not vary, in regard to age or years since surgery, in oophorectomized women.36
Among the studies demonstrating the impact of testosterone on sexual function, Sarrel et al. showed significant improvement in sexual desire (p < 0.05) and in frequency of sexual intercourse (p < 0.01) in healthy, postmenopausal women receiving 1.25 mg estrogen plus 2.5 mg methyltestosterone versus estrogen alone and placebo.37 Other studies have shown similar results with estrogen/testosterone combinations. Shifren et al. showed improvement in scores for the frequency of sexual activity and pleasure orgasm on the Brief Index of Sexual Functioning for Women for surgically postmenopausal women receiving conjugated equine estrogen 0.625 mg and transdermal testosterone 300 pg/day versus placebo (p = 0.07).38,39
Esterified estrogen and methyltestosterone 1.25 mg/2.5 mg is a combination estrogen and androgen pill approved for and utilized in the management of moderate to severe vasomotor symptoms associated with menopause in patients who do not respond to estrogen alone. This formulation also comes in a half-strength dose of esterified estrogen/methyltestosterone 0.625 mg/1.25 mg.40 Although this formulation has not been approved for treatment of female sexual dysfunction, many researchers have shown success in the treatment of sexual dysfunction in postmenopausal women with these formulations.
Lobo et al. conducted a double-blind, randomized, controlled study of 218 women, measuring change in level of sexual interest or desire in women receiving esterified estrogen 0.625 mg versus those receiving esterified estrogen/methyltestosterone 0.625 mg/1.25 mg. The target population was healthy, postmenopausal women aged 40—65 years with hypoactive sexual desire associated with the onset of menopause. Women were required to be currently taking estrogen and to have had adequate sexual interest before the onset of menopause. Results showed that the mean serum concentration of bioavailable testosterone almost doubled in patients receiving esterified estrogen and methyltestosterone (p < 0.010). A significant decrease in sex hormone-binding globulin was also observed in this group (p < 0.010). Both treatments produced increases in the Sexual Intimacy Quotient sexual interest/desire score, the combination group showing consistently greater improvement and reaching significance at week 16.41
Because of the short half-life and ability of testosterone to permeate readily the layers of skin to become absorbed, transdermal administration of testosterone in women has a compelling biopharmaceutic rationale. In addition, nongenital skin contains low levels of 5a-reductase and aromatase, thereby decreasing the degree of metabolism into dihydrotestosterone and estradiol that occurs with oral administration.42 Data obtained from surgically menopausal women receiving treatment with a testosterone matrix patch of 300 pg a day and either transdermal estradiol (0.05—0.10 mg daily) or oral conjugated equine estrogen (0.625 mg/day) indicated that women on conjugated equine estrogen had higher sex hormone-binding globulin levels. In addition, the calculated increments in total testosterone for a 300 pg/day patch would be 51.4 ng/dl with transdermal estradiol versus 69.2 ng/dl for oral conjugated equine estrogen. However, the calculated increments, for free testosterone, were 4.6 pg/ml for transdermal estradiol versus 3.0 pg/ml for oral conjugated equine estrogen. This indicates that for women who require treatment with both testosterone and estrogen, the use of transdermal estradiol results in greater levels of free (bioavailable) testosterone.42
Topical gels containing micronized testosterone are compounded and sold in specialized pharmacies in the USA. The big disadvantage of compounded pharmaceuticals is that there is no way to regulate the dose and purity of the product. Therefore, not all batches are equivalent, and the compounded formula may not be uniform throughout. Experimental testosterone transdermal patches are currently being developed for use in women. They are not yet approved by the Food and Drug Administration for treatment of low sexual desire, but researchers are getting promising results. They have been designed to deliver testosterone at rates of 150 and 300 pg/day, which are approximately 50% and 100%, respectively, of daily testosterone production in premenopausal women.42
Although a large body of data suggests that testosterone replacement can be effective in the treatment of female sexual dysfunction and the rush by pharmaceutic companies to develop the best testosterone delivery system, there is, as yet, no Food and Drug Administration approval for such use of androgens in women. Clinicians also have limited ability to test adequately for testosterone insufficiency due to the use of assays based on higher levels in males with reduced sensitivity at the lower levels where female levels lie. Furthermore, there is no evidence that any specific lower limit of measured free or total testosterone is diagnostic of a deficiency state. Presently, most off-label use of androgen therapy in the USA for sexual dysfunction in women is via empiric trial of therapy based on the patient’s clinical history and presenting complaints, with or without verification by testing of blood levels.
As no androgen products are approved for use in women, off-label products from the male side have been utilized. However, testosterone is available in many forms. There are several varieties of oral androgens available from pharmacies currently. However, they require cautious use, as their 17-alkyl substitutions can lead to liver toxicity. Oral testosterone unde- conate is generally thought to be safe, but it requires at least twice daily dosing, taken with food to enhance absorption.43 Testosterone has also been administered as intramuscular injections of either testosterone enanthate or testosterone cypionate in doses of 200—250 mg every 2 weeks.43 A testosterone implant is also currently available. The implant is inserted under the skin into the lower abdominal wall or buttock. The implant slowly releases testosterone over 4—5 months.44 Recently, two transdermal gels have reached the market.45,46 The gels are rubbed onto the skin daily. Both have proven effective and well tolerated, but are expensive. Skin patches have also been effective, but the adhesive can cause irritation.43 The latest devel oped preparation, buccal tablets, has reached the market. The buccal system produces a steady-state testosterone level comparable to the gels.47
Dehydroepiandrosterone, a weak androgen, is available in the USA without prescription. Dehydroepiandrosterone is produced by both the adrenal glands and ovaries. Like other androgens, its production is decreased after the menopause. In the postmenopausal woman, production of dehydroepiandros- terone and dehydroepiandrosterone sulfate (the sulfated form) by the adrenals is the major source of serum testosterone.48
In 1994, a small, randomized, placebo-controlled, crossover trial of nightly oral dehydroepiandrosterone administered to 13 men and 17 women aged 40—70 over a 6-month period was conducted. In response to dehydroepiandrosterone administration, serum levels of dehydroepiandrosterone and dehydroepiandros- terone sulfate were elevated from placebo values (7.19 ± 0.5—16.13 ± 1.3 nmol/l; 1.78 ± 0.17—9.27 ± 0.76 pmol/l; p <0.001). Between baseline and 12 weeks of dehydroepiandros- terone administration in women, serum androstenedione increased from 1.33 ± 0.13 to 3.0 ± 0.19 nmol/l (p < 0.001), serum testosterone from 0.72 ± 0.07 to 1.46 ± 0.14 nmol/l (p<0.001), and serum dihydrotestosterone from 0.32 ± 0.03 to 0.9±0.1 nmol/l (p < 0.001). Serum sex hormone-binding globulin concentrations exhibited a tendency to decline (105.5 ± 12.3 to 81.2 ± 10.6 nmol/l) that was not statistically significant. Serum levels of estrone and estradiol were not significantly altered (estrone, 256.2 ± 58.5 vs 268.2 ± 58.8 pmol/l; estradiol, 144.7 ± 35.2 vs 107.3 ± 20.6 pmol/l). Specific statements of well-being ranged from improved quality of sleep, more relaxed, increased energy to better ability to handle stress. No difference was noted in libido while subjects were receiving dehydroepiandrosterone compared to the placebo group.49
A more recent, retrospective, open-label study by Munarriz et al. showed that after a mean duration of 4 ± 2 months of dehydroepiandrosterone 50 mg (two subjects used 25 mg), serum values for dehydroepiandrosterone and dehydroepiandrosterone sulfate increased. The mean score for the sexual distress scale decreased from 35.7/48 to 19.6/48. The mean score for the Female Sexual Function Index increased from 41.3 ± 18.9 to 67.7 ± 16.1. The individual domain scores for desire increased from 3.3/10 to 5.9/10; arousal, 6.9/20 to 14.3/20; lubrication, 10.0/20 to 14.6/20; orgasm, 5.7/15 to 11.5/15; and satisfaction, 6.2/15 to 12.2/15.50
Data pertaining to the use of dehydroepiandrosterone remain inconclusive, and safety data for dehydroepiandros- terone therapy are clearly lacking.
Now used in Europe, Asia, and Australasia, tibolone is a synthetic steroid with therapeutic indications for the treatment of estrogen deficiency symptoms in postmenopausal women more than 1 year after menopause, as well as the prevention of osteoporosis in estrogen-deficiency states.51 Tibolone has tissue-specific estrogenic, progestogenic, and androgenic properties. Treatment with tibolone does not require a separate progestogen to offset the risk of endometrial hyperplasia that is present with estrogens, because of its own progestogenic actions on the endometrium.
Upon oral administration, tibolone is metabolized into 3a-OH tibolone and 3P-OH tibolone. These metabolites bind to estrogen receptors. The 3P-OH tibolone metabolite and tibolone itself may be further metabolized to a Д-4 isomer of tibolone, which has affinity for progesterone and androgen receptors. Furthermore, tibolone lowers sex hormone-binding globulin, such that the effects of tibolone with respect to sexual function may be due to lowering of sex hormone-binding globulin and direct effects of the Д-4 isomer.52
The effects of tibolone 2.5 mg have been compared with both placebo and oral estrogen-progestin therapy. However, none of these studies distinguish whether any benefit of tibolone is due to a direct action or sex hormone-binding globulin lowering effect. In a study of tibolone versus 17-beta- estradiol 2 mg plus norethisterone acetate 1 mg on sexual life when tibolone was compared to estradiol/norethisterone acetate, higher scores were found regarding all items in favor of tibolone at 24 weeks as well as at 48 weeks. These differences reached significance for the items frequency, satisfaction and enjoyment. Unfortunately, there was no placebo group in this study with which to compare drug effect.53
The effects of tibolone versus conjugated equine estrogen 0.625 mg plus medroxyprogesterone acetate 2.5 mg on sexual performance in postmenopausal women was also studied.54 Approximately 25 women were randomized to each group and treated for 1 year. At the end of the year, it was found that treatment with either preparation significantly improved subjective well-being, vasomotor symptoms, and vaginal dryness. Tibolone therapy increased sexual desire and coital frequency (p = 0.001, p = 0.014). The rates of side effects in both groups were not statistically significant (p = 0.84).55
A pilot study investigating the effect of a continuous combination of norethisterone acetate (1 mg) and estradiol valerate (2 mg) versus tibolone on memory, sexuality, and mood was performed by Albertozzi et al. in 2000. Both groups had improvements in sexuality, which was achieved mainly by an improvement of sexual desire (p < 0.05). Both drugs also showed an increase in semantic memory and no effect on mood.54
A randomized, double-blind, crossover study was conducted to compare the effects of tibolone versus placebo on sexual function and climacteric symptoms in postmenopausal women in 2001. Each of the 38 subjects that completed the study was randomized to receive oral tibolone 2.5 mg a day for 3 months followed by placebo for 3 months, or the reverse. Vaginal blood flow during erotic stimulation by fantasy and film was measured by vaginal photoplethysmograph. Subjective sexual satisfaction data were also collected from participants by sexual function questionnaires and daily diaries. The results showed that baseline phasic changes in vaginal pulse amplitude levels were significantly higher on tibolone than on placebo (p < 0.001), indicating that tibolone enhanced vaginal blood flow independently of sexual stimulation. After exposure to two periods of sexual fantasy, a significantly greater increase in vaginal pulse amplitude was noted with tibolone than with placebo (p < 0.05). Subjective assessment of vaginal lubrication after erotic stimulation showed significantly more lubrication with tibolone than with placebo (p < 0.001). Analysis of sexual function based on subjects’ daily diaries revealed that the mean frequency of sexual fantasies, the mean frequency of arousability, and mean frequency of desire for sex were higher with tibolone than with placebo, with p values of < 0.03, < 0.01, and 0.08 respectively. Significantly more vaginal lubrication during sexual intercourse was reported with tibolone than with placebo (p < 0.01), and there was also a trend in favor of tibolone for less dyspareunia (p = 0.08). According to the Greene climacteric scale, vasomotor symptoms were significantly reduced with tibolone treatment compared with placebo (p < 0.0005).56
Other over-the-counter therapies
The recent fear of hormones has led many women to pursue herbal therapies because they are “natural” and therefore assumed to be safer. In the USA, this is a totally unregulated, multibillion-dollar industry. What is on the label is not necessarily in the jar, and what is in the jar is not necessarily on the label. All sorts of claims are made for these products, especially when it comes to sexual improvement effects. Health-care providers should caution patients about use of such products and to be wary of the claims of effect on sexual function.
The years prior to menopause that encompass the change from normal ovulatory cycles to cessation of menses are known as the perimenopausal transition years.57 The perimenopausal transition period is characterized by erratic production of estradiol by the ovaries. Estrogen levels in women during this transition can be high, normal, or low at any given time. This fluctuation in blood levels of estrogen can persist until full ovarian failure occurs. Menstrual cycle length is determined by the rate and quality of follicular growth and development, and it is normal for the cycle to vary in individual women. In perimenopausal women, cycles can become progressively shorter, primarily because of the shortening of the follicular phase. A decrease in the production of inhibin B by the ovarian granulosa cells leads to an increase in production of follicle-stimulating hormone by the pituitary, leading to accelerated development of the predominant ovarian follicle, a shorter follicular phase, and increased levels of estradiol.
These fluctuating levels of hormones may cause perimeno- pausal women to experience insomnia, hot flushes, and changes in mood. They also begin experiencing dyspareunia from a reduction in vaginal lubrication and elasticity. Both the changes in sleep patterns and mood, and increases in dyspareu- nia can lead to an overall loss of libido.
While education is the first-line therapy for perimenopausal women, some may ultimately require hormonal therapy of some kind. Unlike their postmenopausal counterparts, however, traditional hormone replacement therapy is not the best option for these women. The low doses of estrogen utilized in hormone replacement do not suppress the ovary and the fluctuating levels of estrogen continue. The addition of hormonal therapy can augment or exaggerate problems instead of modifying them. Appropriate hormone therapy should first suppress the erratically functioning ovaries and then provide a stable level avoiding the fluctuations and hence symptoms. The use of oral contraceptive therapy has remained the reference standard for perimenopausal hormone therapy when it is needed due to the suppression provided. While perimenopausal decreases in sexual desire can stem from diminishing levels of testosterone, low-dose oral contraceptive therapy is more frequently the culprit. Such therapy can increase sex hormone-binding globulin levels, decrease bioavailable testosterone by decreased ovarian production as well as increased binding by sex hormone-binding globulin, and delete the midcycle surge of testosterone involved in increased sexual drive at the time of ovulation. Other perimenopausal therapeutic interventions, such as the use of antidepressant therapies, can have a negative impact on sexual function, including decreased desire and arousal capabilities.
Thus, while the treatment of sexual dysfunction in peri- menopausal women is not very different from its treatment in premenopausal women, the variables presented by the unique pathophysiology of this transition and the kinds of therapies available for perimenopausal symptoms can have a negative impact on sexual function. Any therapeutic intervention must take into account these variables, and adjustments of such therapies may be necessary.
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