Tuesday, September 30, 2008

Androgen production and therapy in women

Androgen production and therapy in women

Author
Laurence Udoff, MD
Section Editor
Robert L Barbieri, MD
William F Crowley, Jr, MD
Deputy Editor
Kathryn A Martin, MD



Last literature review version 16.2: May 2008 | This topic last updated: May 28, 2008 (More)


INTRODUCTION — All women produce some androgens, which may contribute to maintaining normal ovarian function, bone metabolism, cognition and sexual behavior. This topic will review androgen production in pre- and postmenopausal women and the effects of androgen therapy in postmenopausal women. Female sexual dysfunction, including hypoactive sexual desire disorder, is discussed elsewhere. (See "Etiology and diagnosis of sexual dysfunction in women" and see "Treatment of sexual dysfunction in women").

ANDROGEN PRODUCTION

Premenopausal women — The major androgens in the serum of normal cycling women are dehydroepiandrosterone sulfate (DHEA-S), dehydroepiandrosterone (DHEA), androstenedione (A), testosterone (T), and dihydrotestosterone (DHT) in descending order of serum concentrations [1] .

Though abundant in the circulation, DHEA-S, DHEA, and A may be considered pro-hormones requiring conversion to T or DHT to express their androgenic effects. Androgens are mainly produced in the adrenal gland, the ovary and from the peripheral conversion of pro-hormones.

• DHEA-S is produced solely by the adrenal gland at a rate of 3.5 to 20 mg per day [2] . Circulating levels are in the range of 1 to 4 mcg/mL.
• DHEA is also produced in the adrenal gland (50 percent), the ovary (20 percent) and from peripheral conversion of DHEA-S (30 percent) with total production rates of 6 to 8 mg per day [3] . Circulating levels are in the range of 1 to 10 ng/mL.
• A production is split equally between the adrenal gland and the ovary. Daily rates of production are 1.4 to 6.2 mg/day and circulating levels are in the range of 0.5 to 2 ng/mL [4,5] .
• T is synthesized in the adrenal gland (25 percent), the ovary (25 percent) and from the peripheral conversion of A (50 percent). Daily production rates are in the range of 0.1 to 0.4 mg/day and circulating levels are between 0.2 and 0.7 ng/mL with the lowest levels found during the early follicular phase followed by a 20 percent increase at midcycle [3] . Nearly all (99 percent) of circulating T is protein-bound (mainly to sex-hormone binding globulin [SHBG]) [6] . Therefore, any impact on SHBG concentration (eg, oral estrogen-mediated increase in SHBG) affects the concentration of the free/active androgen.
• Lastly, DHT is mainly a peripheral product of T conversion and has very low circulating levels [7] .

All the major androgens are metabolized and excreted into the urine almost exclusively as 17-ketosteroids.

Natural history — In a report of normal women ages 18-75 years, serum androgen concentrations (total and free testosterone, DHEA-S, and androstenedione) gradually declined in women of reproductive age [8,9] , with no further decrease after clinical menopause [10] .

Putative roles for androgens — Androgens are essential precursors for estrogen synthesis. They also play an important role in follicular development. Maintenance of a precise balance of estrogens and androgens within ovarian follicles is a requirement for successful follicular maturation [11-13] . In addition, many tissues have androgen receptors, including the central nervous system [14] and bone [15] , which has led to speculation that androgens affect their function.

It has also been proposed that androgens play a role in sexual behavior. A woman's libido is dependent upon many factors, including psychological factors [16] . As an example, in a study of 341 peri- and postmenopausal women, common menopausal symptoms, including depression, sleep disturbances, and night sweats, were associated with diminished libido [17] .

A balance of estrogen and androgen also may be necessary for normal sexual desire and responsiveness, but the results of studies on the role of androgens in sexuality in normal premenopausal women are inconclusive [9,16] . As an example, a cross-sectional study of a population-based cohort of women ages 48 to 58 years suggested that most aspects of female sexual function were not affected by age, menopausal functioning, or serum sex hormone concentrations [9] . Additionally, a study comparing women with premature ovarian failure with normal premenopausal controls did not find an important role for circulating androgens in sexual functioning [18] .

The special case of adrenal insufficiency may be an exception, as data suggests that young women with this condition may show improvement in sexuality with the addition of DHEA to their replacement regimen. (See "Dehydroepiandrosterone and its sulfate", section on Adrenal insufficiency).

Androgens may also be important for the maintenance of normal affect, cognitive functioning and of skeletal homeostasis. (See "Cognitive function" below and see "Bone metabolism" below). Regarding the latter, a significant body of evidence exists implicating a role for androgens in the maintenance of bone health. Androgens may impact bone homeostasis directly (eg, all bone cells including osteoblasts, osteoclasts, and osteocytes have androgen receptors), or indirectly by conversion to estrogen, or by their effect on local and systemic factors that control the bone cells' microenvironment [15] .

Low serum androgen concentrations may be associated with lower bone density and fracture risk:

• Serum free androgen concentrations and bone mineral density have been positively correlated in several studies [19-21] .
• In another study, postmenopausal women with a history of vertebral crush fractures had lower serum free androgen concentrations (and similar serum estrogen values) when compared to women with no fractures [19] .
• Women with hypopituitarism (who are androgen deficiency) have low bone density [22] .


Postmenopausal women — The production rate and serum concentrations of androstenedione fall by 50 percent after the menopause (show figure 1) [23,24] . This change appears to result from decreased ovarian production of the hormone with the adrenal glands becoming the major site of androstenedione production. This hypothesis is based upon the following findings in postmenopausal women:

• Administration of corticotropin (ACTH), but not human chorionic gonadotropin (hCG), raises serum androstenedione concentrations.
• Serum androstenedione concentrations fall little after oophorectomy, but markedly after the administration of dexamethasone, which suppresses the release of ACTH.
• There is a diurnal variation in serum androstenedione concentrations that parallels the diurnal variation in serum cortisol concentrations.
• The ratio of androstenedione in ovarian venous blood to peripheral venous blood is decreased [24] .


The rate of testosterone production also falls in postmenopausal women (show figure 2) [25,26] , mostly because of a decline in the peripheral production of testosterone from androstenedione [27] . Ovarian testosterone production remains relatively constant, thereby increasing the relative ovarian contribution to overall testosterone production [27] . These observations are substantiated by the larger ovarian-to-peripheral serum gradient of testosterone in postmenopausal than in premenopausal women [24] , and by the 40 to 50 percent decrease in serum testosterone concentration seen after oophorectomy in postmenopausal women [28] , a change that persists over time [29] .

In addition to this decline in ovarian androgen secretion, there is an age-related decline in the adrenal androgens dehydroepiandrosterone (DHEA) and its sulfate ester (DHEA-S). As an example, in women ages 40 to 50, serum DHEA concentrations are approximately 50 percent of the peak concentrations seen in younger women [30] . (See "Dehydroepiandrosterone and its sulfate").

Serum androstenedione and testosterone concentrations fall little with advancing age after the menopause, despite a progressive fall in serum DHEA concentrations [31] . This difference suggests that little androstenedione and testosterone are derived from DHEA in older women, and that ovarian androstenedione and testosterone production increases or their clearance decreases with age [32] .

The decline in ovarian androgen production in postmenopausal women is much less than the decline in estrogen production; as a result, the ovaries become primarily androgen-producing glands. The relatively high rate of androgen production is due to the increase in gonadotropin secretion, which stimulates steroidogenesis in ovarian hilar cells or luteinized stromal cells [32] . Ovarian stromal tissue has receptors for both follicle-stimulating hormone and luteinizing hormone [30,33] , and chorionic gonadotropin (hCG) stimulates androstenedione, estradiol and progesterone secretion by isolated ovarian cortical stromal and hilar cells [34,35] . In addition, postmenopausal women given hCG have a small increase in serum testosterone concentrations [36] and hyperplasia of their ovarian hilar cells [37] ; in comparison, their serum estrogen concentrations do not increase [38] .

The vast majority of evidence suggests that the postmenopausal ovary is a major androgen-producing gland [27-38] , with the exception of one study [39] . In 10 postmenopausal women with adrenal insufficiency, women with natural and surgical menopause had undetectable serum androgen concentrations. In addition, ovarian stimulation with hCG did not increase circulating levels of androgens in the women with intact ovaries. Negligible levels of T and A were found in ovarian homogenates, and ovarian immunocytochemistry did not detect the presence of enzymes for androgen synthesis. These data have not been confirmed by other investigators.

ANDROGEN DEFICIENCY
— Women with low levels of circulating androgens are said to have androgen deficiency or androgen insufficiency syndrome. However, there are no clear biochemical criteria for this syndrome; measurement of serum androgen concentrations, in particular, free testosterone, is problematic because of a lack of validated assays in the female range (much lower than the male range); there are no age-based normative data; and serum androgen concentrations do not appear to be an independent predictor of sexual function in women [40-44] .

An Endocrine Society Clinical Practice Guideline recommended against making a diagnosis of androgen deficiency because of the lack of both a well-defined clinical syndrome and age-based normative data for serum testosterone and free testosterone concentrations That said, there are a number of conditions that may represent androgen deficiency syndromes:

• Bilateral oophorectomy
• Primary adrenal insufficiency
• Hypopituitarism, particularly women with both ACTH and gonadotropin deficiency [45]


Medications including oral contraceptives and glucocorticoids may cause a relative androgen deficiency due to ovarian and adrenal androgen suppression, respectively. Oral estrogens, even at low doses (menopausal replacement) reduce serum free testosterone concentrations by increasing serum SHBG levels.

Women with anorexia nervosa have lower serum concentrations of total and free testosterone, but not DHEAS concentrations when compared to normal-weight women with hypothalamic amenorrhea or healthy controls [46] . In this report, women with anorexia nervosa who were taking oral contraceptives had the lowest concentrations of free testosterone and DHEAS.

EFFECTS OF EXOGENOUS ANDROGENS — Androgen replacement therapy has been advocated by some for postmenopausal women with decreased sexual desire associated with personal distress and with no other identifiable cause [47,48] . However, given the lack of a well-defined clinical syndrome, age-based normative data for serum testosterone concentrations, and long-term safety data for testosterone preparations, we agree with the Endocrine Society guidelines and currently do not suggest the routine use of androgen therapy in women [42] .

Exceptions to this may include women with hypopituitarism (ACTH and gonadotropin deficiency), bilateral oophorectomy and premature ovarian failure (POF). However, our ability to treat these women is limited by the lack of an approved testosterone preparation. Women with primary and secondary adrenal insufficiency are candidates for DHEA therapy. (See "Dehydroepiandrosterone and its sulfate").

Sexual function — Testosterone therapy in postmenopausal women may have a beneficial effect on sexual function in select women, but data are variable.

Replacement vs. supraphysiologic therapy — Studies of androgen therapy in women with androgen deficiency (eg, hypopituitarism, bilateral oophorectomy) should be considered separately from studies in women with sexual desire disorders who are not androgen deficient, as the former would be considered to be replacement therapy, and the latter, supraphysiologic therapy. However, in almost all trials reporting a beneficial effect of testosterone, including those considered to be "replacement" trials, serum testosterone concentrations are higher than the upper limit of normal for premenopausal women.

• Studies in heterogeneous populations - Many testosterone trials have been performed in heterogeneous populations of women (natural or surgical menopause, with normal or low libido) receiving variable types, doses, and routes of administration of estrogen and testosterone. One of these trials reported no effect of testosterone on sexual arousal [49] , while others reported an improvement in sexual function in women with normal [50,51] or low [52] libido at baseline.

A trial in naturally menopausal women diagnosed with hypoactive sexual desire disorder who were taking estrogen reported improved sexual function with the transdermal testosterone patch (dose 300 mcg/day) [53] .

• Women post-oophorectomy — The main evidence that testosterone has an effect on sexual function comes from trials that have examined a transdermal testosterone preparation combined with exogenous estrogen in women who have undergone bilateral oophorectomy and subsequently developed hypoactive sexual desire disorder (HSDD). Although there is a modest improvement in sexual function with testosterone in these trials, serum testosterone concentrations are typically in the high normal or supranormal range for younger premenopausal women.

In one study, 300 mcg/day of transdermal testosterone improved sexual function and psychological well-being, but mean serum free testosterone concentration increased to approximately twice the mean of premenopausal women [54] . A dose of testosterone (150 mcg/day) that increased the mean serum testosterone to a value similar to that of the mean in premenopausal women did not increase sexual function or psychological well-being.

In a second, larger, multicenter trial, 532 women with hypoactive sexual desire who had undergone hysterectomy with bilateral oophorectomy received either testosterone (300 mcg/day) or placebo patch twice per week (in addition to estrogen) for 24 weeks [55] . Sexual desire and frequency of sexual activity increased more in the testosterone group compared to placebo, but only by one additional episode per 2.5 week interval in the testosterone group versus one additional episode per 5.5 week interval with placebo. Serum testosterone levels and androgenic side effects increased with transdermal therapy; however, the side effects were considered mild. Although promising, the results of this trial do not address the safety of long-term testosterone administration.

Additional, phase-III trials reported similar results on sexual desire and sexual activity [56,57] . In one study, no additional benefits were observed with a testosterone patch delivering 400 mcg/day when compared to 300 mcg/day [56] .

• Hypopituitarism — Women with hypopituitarism, in particular those with both ACTH and gonadotropin deficiency, may also benefit from testosterone therapy. In a trial of women with androgen deficiency due to hypopituitarism, treatment with 150 to 300 mcg of testosterone transdermally daily for one year improved overall sexual function, as judged by a questionnaire, by a small but statistically significant amount [58] .
• Use of testosterone without estrogen — Preliminary data from a trial in postmenopausal women (both natural and surgical) with hypoactive sexual desire disorder receiving transdermal testosterone 300 mcg (without estrogen) suggest that sexual function may also be improved in this group of patients [59] .
• Meta-analysis — In a systematic review of 23 clinical trials (with 1957 participants) of testosterone plus hormone therapy versus hormone therapy alone in peri- or postmenopausal women, a significant decrease in serum HDL concentrations was observed, there was insufficient evidence of a treatment effect in perimenopausal women, and there appeared to be an improvement in sexual function scores in postmenopausal women [60] . However, only three trials were included in the sexual function analysis. In addition, this review was not limited to women who would be considered to be truly androgen-deficient (ie post-oophorectomy). (See "Androgen deficiency" above).


Other effects

Vasomotor symptoms — Testosterone therapy may be effective for postmenopausal women who remain symptomatic (eg, hot flashes) despite estrogen or estrogen-progestin treatment [61-63] . Because androgen production declines after the menopause, it is reasonable to assume that some postmenopausal symptoms could at least in part be due to androgen deficiency. However, we do not consider persistent vasomotor flushes to be an indication for routine androgen replacement.

Cognitive function — Some data from uncontrolled studies in which postmenopausal women were treated with estrogen alone or with androgen have suggested that androgen may improve affect and cognitive functioning. This issue was also addressed in a randomized double-blind, placebo-controlled trial in which postmenopausal women were treated for two months with either estrogen, estrogen plus testosterone, or placebo [64] . Both hormone treatments were associated with better scores on a self-rating scale of anxiety and depression than placebo, and there was a trend towards better scores in the estrogen plus testosterone group as compared with the estrogen group.

In another study of the effect of hormone treatment on energy, well-being and appetite, estrogen plus testosterone was superior to estrogen alone [65] . Androgen therapy has also resulted in increased well-being, improved energy levels, and less dysphoric mood in oophorectomized women [66] .

A common criticism of these studies is that the testosterone given is metabolized into estrogen and therefore that the results are mainly due to an estrogen effect. However, in the last report, there was no difference in the incidence of hot flashes between the treatment and placebo groups, suggesting a mode of action for testosterone distinct from aromatization to estrogen [66] .

Bone metabolism — A direct correlation between bone density and serum androgens has been noted in postmenopausal women [20,21] . The effects of androgen therapy on bone in postmenopausal women have been examined in studies of androgen alone and androgen in combination with estrogen; numerous observations are compatible with a beneficial effect of androgen in this setting [49,67-74] :

• In a study of biochemical markers of bone resorption and formation, women receiving either estrogen or estrogen plus androgen had evidence of increased bone formation, whereas bone resorption decreased only in the women receiving estrogen alone [67] . In another report, androgen monotherapy in postmenopausal women with osteoporosis reduced markers of bone turnover (serum alkaline phosphate concentrations and urinary calcium excretion) to the same extent as estrogen [75] .
• A number of reports have shown that nandrolone increased bone mineral density at the spine and radius when compared with no treatment [68-70] .
• In studies of the effect of androgen plus estrogen, the addition of androgen to a regimen of estrogen with or without progestin had a more beneficial effect on bone density [72-74] .
• In a study of women with clear androgen deficiency due to hypopituitarism, who were taking estrogen and had normal baseline bone density, physiologic testosterone replacement (150 to 300 mcg/day transdermally) increased serum testosterone into the normal range, and increased mean hip and radius, but not spine, bone mineral density [58] .

Taken together, these results suggest that androgen alone or in combination with estrogen may protect against osteoporosis. The putative mechanisms involve a decrease in bone resorption by either direct androgenic action or conversion of androgen to estrogen, or an increase in bone formation. However, there is no strong evidence that the addition of androgen to estrogen in postmenopausal women is more beneficial than estrogen alone.

Adrenal androgen replacement — DHEA replacement therapy appears to be effective in women with adrenal androgen deficiency, including those with primary adrenal insufficiency, hypopituitarism (ACTH deficiency), and chronic glucocorticoid use (for example, women with systemic lupus erythematosus). (See "Dehydroepiandrosterone and its sulfate", section on Adrenal insufficiency and see "Overview of the therapy and prognosis of systemic lupus erythematosus in adults", section on Dehydroepiandrosterone (DHEA)).

DHEA supplementation has also been proposed as adjunctive hormone replacement therapy for aging men and women. While there is a well-known decline in serum DHEA and DHEA-S concentrations with age, the role of adrenal androgen replacement in peri- and postmenopausal women is unclear. However, DHEA supplementation in otherwise healthy peri- or postmenopausal women does not appear to have clinical benefits. (See "Dehydroepiandrosterone and its sulfate").

Risks and side effects — One concern regarding androgen replacement therapy in postmenopausal women is the possible adverse effect on cardiovascular disease risk, because androgens have been thought to be atherogenic. This supposition is based mainly on the higher rates of cardiovascular disease in men as compared with women and the higher risk in women with androgen excess (eg, polycystic ovary syndrome) [76,77] . (See "Postmenopausal hormone therapy and cardiovascular risk").

One proposed mechanism by which androgens may adversely affect the risk of cardiovascular disease is through a decline in serum high-density lipoprotein (HDL) cholesterol concentrations. As compared with normal women, women with hyperandrogenism have lower serum HDL cholesterol concentrations [78] . In postmenopausal women, however, the results are less clear. One report found no strong correlation between serum androgen and HDL cholesterol concentrations [79] , but another study found that serum testosterone concentrations were inversely correlated with serum HDL cholesterol concentrations [80] . Confounding variables that could explain the disparity in the results include the effects of diet, body weight, exercise, and heredity, as well as methodological differences such as problems associated with the standardization of methods to measure serum lipids.

The more androgenic progestins (eg, norethindrone, levonorgestrel), when given as the progestin component of estrogen-progestin replacement therapy in postmenopausal women, tend to blunt the estrogen-related rise or even produce a treatment-related decline in serum HDL cholesterol concentrations [81] . However, the addition of testosterone to estrogen replacement therapy has produced conflicting results: it caused a decline in serum HDL cholesterol concentrations in studies using oral estrogen [52,74,82,83] , but not in others using non-oral routes of administration [54,62,84,85] .

One study suggests that testosterone administration might decrease cardiovascular risk in postmenopausal women on hormone replacement therapy (HRT) [86] . In 33 postmenopausal women on HRT compared with 15 controls, both endothelial-dependent and -independent brachial artery vasodilatation was improved by the addition of a testosterone implant (50 mg) for six weeks. Additionally, it has been shown in a group of sixty postmenopausal women that endogenous testosterone levels are positively correlated with brachial artery vasodilation [87] .

Other potential side effects of adding androgen to estrogen in postmenopausal women are acne, hirsutism, deepening of the voice, and clitoromegaly. Among women given testosterone implants, 15 to 20 percent had slight increase in downy facial hair after several years, but acne, voice changes and clitoromegaly were very rare [88] . Women given oral methyltestosterone doses (2.5 mg daily) may become mildly hirsute [74] . Androgen replacement therapy does not affect body weight or blood pressure [63,89] .

A possible association between testosterone administration and breast cancer risk has been reported. However, data are limited. (See "Postmenopausal hormone therapy and the risk of breast cancer", section on Effect of testosterone).

In a review of available testosterone clinical trials, hirsutism and acne appeared to be the major adverse reactions (both were dose- and duration-related and generally reversible). Virilization was rare, and oral, but not parental or transdermal, testosterone was associated with a decrease in serum HDL concentrations, which could have a negative impact on cardiovascular risk. However, there were no adverse effects on blood pressure, vascular reactivity, blood viscosity, hemoglogin concentration, coagulation factors or insulin sensitivity. All available trials are limited by their short duration (≤ two years) and the co-administration of estrogen or estrogen-progestin therapy [90] .

INFORMATION FOR PATIENTS — Educational materials on this topic are available for patients. (See "Patient information: Sexual problems in women" and see "Patient information: Postmenopausal hormone therapy" and see "Patient information: Alternatives to postmenopausal hormone therapy"). We encourage you to print or e-mail these topic reviews, or to refer patients to our public web site, www.uptodate.com/patients, which includes these and other topics.

SUMMARY — The use of androgens as an addition to estrogen or estrogen-progestin therapy for postmenopausal women is controversial.

• The clearest indication for androgen replacement therapy is in patients with symptomatic androgen insufficiency in association with hypopituitarism, adrenal insufficiency, premature ovarian failure, or in women who have undergone bilateral oophorectomy.
• Androgens may significantly improve sexual functioning in select postmenopausal women. (See "Sexual function" above).
• The data that androgens significantly improve cognitive function and affect are not compelling. (See "Cognitive function" above).
• Androgen may have a beneficial effect on bone, which may simply be due to the additional estrogen formed from the administered androgen; studies with nonaromatizable androgens could resolve this question. (See "Bone metabolism" above).
• Serum HDL cholesterol concentrations decline slightly in postmenopausal women receiving oral testosterone therapy, but it is not known if the change substantially affects overall cardiovascular risk. (See "Risks and side effects" above).
• Cosmetic side effects such as hirsutism and acne are usually mild and are well tolerated and irreversible virilizing changes are rare.

In conclusion, for highly selected postmenopausal women, especially those who have undergone bilateral oophorectomy, estrogen replacement alone may not be adequate therapy. Based upon the finding that endogenous androgen production declines after spontaneous menopause as well as oophorectomy, it may be logical to offer some women androgen therapy in conjunction with estrogen therapy. The practitioner and patient should realize, however that many questions remain to be answered regarding the efficacy and safety of this therapy. Most androgen preparations that have been used for this indication are not approved the United States Food and Drug Administration. (See "Treatment of sexual dysfunction in women").

Treatment of sexual dysfunction in women

Treatment of sexual dysfunction in women

Author
Alan Altman, MD
Section Editor
Robert L Barbieri, MD
Deputy Editor
Kathryn A Martin, MD



Last literature review version 16.2: May 2008 | This topic last updated: June 11, 2007 (More)


INTRODUCTION — A number of nonpharmacologic and pharmacologic therapies are available to treat sexual dysfunction in women. Prior to initiating treatment, however, it is important to emphasize that sexual activity or frequency is not necessarily correlated with sexual satisfaction. Sexual dysfunction only becomes a problem when the patient or her partner finds it to be a problem.

The management of sexual dysfunction in women is reviewed here. The etiology and diagnosis are discussed separately. (See "Etiology and diagnosis of sexual dysfunction in women").

NONPHARMACOLOGIC THERAPY — Treatment of sexual dysfunction can begin with any of a number of nonpharmacologic measures. Blood flow increases during sexual activity; thus, sexual activity begets better sexual function. Masters and Johnson demonstrated this in their early work; sexual activity maintained vaginal pH, pO2, and mucosal health and allowed successful function to continue. The same beneficial effects could be achieved with sexual activity of any kind, partnered or unpartnered, including masturbation or sexual fantasy alone.

A number of other nonpharmacologic interventions also may be helpful.

Communication — Communicating sexual likes and dislikes, in a nonthreatening manner, can reignite novelty and intensify satisfaction. This may be difficult if techniques of communication were never the couple's forte. Sex videos or erotic literature can assist in seeking out new directions. Communication also means giving attention to a partner's presence, discussions, and ideas, which can help validate their importance and self image.

Lifestyle changes — Changes in lifestyle such as smoking cessation, strength training exercises, and aerobic training, can all have positive impacts on sexuality. Strength training, with weights or resistance machines may enhance body image and therefore, indirectly enhance libido.

Vaginal weights — Vaginal weights can be used to strengthen the pelvic floor muscles. In some women with orgasmic disorders, this can improve awareness of sexual response and also potentially correct urine leakage, which might cause a problem during sexual activity [1] .

Vaginal weights are usually available in sets of five weights. The patient inserts the lightest weight and remains upright for 15 minutes, twice a day. With the weight in place, she should feel the urge to hold it in. After a number of days, she will no longer feel the urge to hold in the weight, because an improvement in muscle tone has occurred. She then moves up to the next weight in the progression. Once she no longer feels the urge to hold in the heaviest weight, a significant increase in muscle tone has taken place. Maintenance with the fifth weight should be carried out each month for five to seven consecutive days to preserve muscle tone.

Use of vaginal lubricants — Genitourinary atrophy symptoms, in particular vaginal dryness and dyspareunia, develop in a high percentage of postmenopausal women who are not taking estrogen. Vaginal estroggen is highly effective for treating these symptoms, but water soluble vaginal lubricants are also helpful for continued sexual activity. This topic is reviewed in detail separately. (See "Diagnosis and treatment of vaginal atrophy").

Increased tactile stimulation of partner — Decreased vasocongestion during arousal can create the need for increased manual and/or oral stimulation in the male to help achieve or maintain an erection, and in the female to achieve adequate clitoral, labial, and vaginal response. Just providing an explanation of the need for more stimulation in both partners can have a positive effect, not only on sexual response, but also on the relationship.

Sexual frequency — How frequent is enough? Everyone has a different answer and that answer depends on multiple variables. Surveys are notoriously inaccurate due to their questionable ability to collect honest data. The bottom line has to remain what is comfortable for each individual pair of partners [2] .

PHARMACOLOGIC THERAPY — When education, lifestyle, communication, and behavioral changes do not achieve the desired level of success, pharmacological therapy can be utilized to treat sexual dysfunction in women. Treatment options focus on providing hormonal support and increasing genital blood flow. However, there are few randomized, placebo controlled trials of pharmacologic therapy in postmenopausal women upon which to base recommendations [3] .

Estrogen — Estrogen may positively affect sexual function in a number of ways. Estrogens rapidly restore the superficial cell layer of the vaginal epithelium, reestablish elasticity, restore the balance in vaginal pH, improve mood, and increase vaginal blood flow to enhance lubrication. (See "Postmenopausal hormone therapy: Benefits and risks"). In addition, their positive effect on neuronal growth and nerve transmission could help restore tactile perception and sensation, although treatment with estrogen alone is associated with inconsistent results with respect to sexual desire and arousal.

Short-term studies of estrogen replacement therapy (ERT) have confirmed a benefit in some postmenopausal women with sexual dysfunction:

• In a report of 93 women, 68 percent reported problems with sex, specifically vaginal dryness of at least moderate degree (58 percent); dyspareunia (39 percent); decrease in clitoral sensitivity (36 percent), decrease in orgasmic frequency (29 percent), decrease in orgasm intensity (35 percent), decrease in sexual desire (77 percent), and intercourse once a month or less (50 percent) [4] . Women reported vaginal dryness, pain with penetration, and burning sensation when the serum estradiol concentration dropped below 50 pg/mL. Symptoms decreased markedly when the estradiol concentration was above 50 pg/mL. Overall, oral estrogen therapy resulted in an improvement in clitoral sensitivity. Orgasm rates also improved. The most dramatic response was seen in the women who reported a lack of desire; after three to six months of treatment, 90 percent of these women had an increase in level of desire and increase in sexual activity with ERT.
• In a study of 242 women ages 45 to 65 requiring ERT for climacteric symptoms, women were randomly assigned to blinded treatment with transdermal estrogen or placebo for 12 weeks [5] . Answers to a questionnaire regarding satisfaction with frequency of sexual activity, sexual fantasies, degree of enjoyment, vaginal lubrication, and pain during intercourse were positively influenced by estrogen compared with placebo therapy, while the frequency of orgasm and sexual arousal were not affected.


However, not all studies have demonstrated positive results [6] , possibly because women most likely to respond are those with symptoms of hypoestrogenism. Furthermore, any short term positive effects of oral estrogen may diminish in the long term because of increasing sex hormone binding globulin (SHBG) levels, which lead to reduced estrogen and androgen bioavailability, and consequent decreased desire and activity [7] . The increase in SHBG appeared to be less significant in women who use nonoral delivery systems for ERT, suggesting improved bioavailability of estrogens and androgens [8] . (See "Etiology and diagnosis of sexual dysfunction in women", for a more complete discussion of the effects of SHBG.)

Progestins — Progestational agents down-regulate the estrogen receptor, a desired result in the endometrium, but potentially undesirable in the brain, heart, bone, and genitalia. They generally have an overall negative effect in the CNS with respect to depression and mood, and have been shown to decrease sexual desire and diminish vaginal blood flow [9,10] . Medroxyprogesterone acetate (MPA) is the most potent progestin available, therefore its ability to down-regulate the estrogen receptor and diminish estrogen effects may be particularly intense. Other available options include micronized progesterone (MP) and the 19 nortestosterone derivatives, norethindrone acetate (NA) and norgestimate (NGM). (See "Preparations for postmenopausal hormone therapy"). NA, the more androgenic progestin, has been shown to decrease SHBG and increase bone density.

A number of studies have evaluated the effect of progestins on sexual function:

• The effects of estrogen alone or with MPA on psychological functioning and sexual behavior were evaluated in a study of 48 healthy, naturally menopausal women [9] . The benefits of estrogen were diminished by MPA co-administration [9] .
• A second 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 [11] .
• In a single-arm, unblinded study, women who were intolerant of a conjugated equine estrogen (CEE)/MPA regimen were switched to CEE plus progesterone and reported better vasomotor, somatic, psychologic, cognitive, and sexual functioning [10] .


Progestins 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. When estrogen is given with a progestin, the effect on SHBG depends upon the type of progestin used; 19-nortestosterone derived progestins, such as NA, decrease SHBG levels, a potential benefit while derivatives of C-21 progesterone, such as MPA, do not significantly influence them [12] . Newer studies in progress with more modern combinations of progestins with estrogens and androgens will provide better insight into the progestational effects on sexuality.

Androgens — Androgens play an important role in physiologic aspects of the female sexual response. (See "Etiology and diagnosis of sexual dysfunction in women"). However, the effect of androgen therapy on sexual function in women is controversial. Androgen replacement therapy for women with androgen deficiency (eg, bilateral oophorectomy) must be distinguished from pharmacologic androgen treatment of women with low libido who are not androgen deficient. (See "Androgen production and therapy in women").

Some studies have reported improvements in libido, sexual arousal, and the frequency of sexual fantasies with testosterone therapy in a variety of forms [4,13-15] , while others have been unable to detect a significant benefit from androgen therapy [6,7] . The observation that testosterone therapy may result in improvements in mood and well being [16] is felt by some researchers to be most important; the central sex steroid effect on mood may be what underlies sexual function in both women and men. (See "Androgen production and therapy in women")

Side effects — Potential adverse effects of androgens include a decline in serum high density lipoprotein (HDL) cholesterol with oral preparations, and mild cosmetic side effects such as hirsutism and acne; irreversible virilizing changes are rare. (See "Androgen production and therapy in women", section on Risks and side effects.) Hepatocellular damage is rare at the prescribed doses. The effect of testosterone on breast cancer risk is discussed separately. (See "Postmenopausal hormone therapy and the risk of breast cancer", section on Effect of testosterone).

Preparations — Most early papers demonstrating a benefit of androgens on sexual function utilized injections or pellets. Since that time, compounding pharmacists have formulated testosterone creams, gels, and tablets that can be taken orally or used sublingually, but their production is not uniform, they are not approved by the United States Food and Drug Administration (FDA), and efficacy studies are lacking. Many clinicians have tried creams used for vulvar dystrophies made up with 2 percent testosterone propionate. Others tapered down the potency using micronized testosterone 0.5 percent up to 1 percent, and rarely 2 percent.

Creams were applied first on the inside of the forearms or thighs, while later paraclitoral use became common. Mixed results were common, and the effect of rubbing the cream into the clitoris prior to intercourse may have been nothing more than masturbatory prestimulation. Anecdotally, the creams seemed to work better paraclitorally in patients with sexual arousal disorder than in those with hypoactive sexual desire disorder (HSDD).

A transdermal testosterone preparation has also been studied in clinical trials of postmenopausal women (primarily women who are post-oophorectomy). These trials are discussed in detail elsewhere. (See "Androgen production and therapy in women").

Studies on the use of dehydroepiandrosterone (DHEA), which is available over-the-counter in the United States, have shown an increase in energy level, well-being, sexual satisfaction, and sexual function only in women with primary and secondary adrenal insufficiency [17,18] . There are no receptors for DHEA; side effects occur due to conversion to testosterone and then to estrogens [18] . (See "Dehydroepiandrosterone and its sulfate").

Combination therapy with oral estrogen and methyltestosterone also improved sexual interest/desire in postmenopausal women already taking estrogen who were experiencing hypoactive sexual desire. A double-blind trial randomly assigned such women to four months of therapy with 0.625 mg esterified estrogens alone (n = 111) or with 1.25 mg methyltestosterone (n = 107). Improvements in self-reported sexual desire were seen in the combined therapy group, which correlated with changes in bioavailable testosterone concentrations [19] . However, acne was more common and significant decreases in HDL cholesterol were seen with combined treatment. (See "Androgen production and therapy in women").

Thus, the data that androgen therapy significantly improves sexual functioning are suggestive but not conclusive. Many of the positive studies have been in women who had surgical menopause or who achieved supraphysiologic levels of testosterone with therapy [20] , suggesting that the clinical application may be limited. No guidelines for androgen therapy for female sexual dysfunction are available, and no androgen preparations have been approved for the treatment of sexual desire disorders, although the combination oral estrogen/methyltestosterone preparation described above is approved for management of persistent vasomotor symptoms not relieved by estrogen alone.

Women most likely to benefit from androgen therapy are probably those who have undergone bilateral oophorectomy with hysterectomy.

For any woman considering androgen therapy, the risks and benefits should be discussed prior to initiating treatment. Women with hepatic disease, a history of breast cancer, uncontrolled hyperlipidemia, acne, or hirsutism should not be treated.

Although there are no FDA-approved testosterone products for women presently available in the US, specialists utilize the following products off-label or compounded for women with sexual dysfunction after extensive history and counseling:

• Combination estrogen/methyltestosterone (Estratest or Estratest HS)
• Testim 1 percent testosterone Gel (one to two drops/day)
• Methyltestosterone (1.22 to 2.5 mg/day)
• Micronized oral testosterone (5 mg BID)
• Testosterone injectables/pellets
• Testosterone propionate 2 percent in petroleum applied QOD
• DHEA 50 mg per day

Non-oral estrogen should be administered in conjunction with testosterone therapy to avoid increasing SHBG and to negate any potential negative effects of either on lipoproteins. Baseline free and total testosterone levels, liver function tests, and a lipid profile should be obtained prior to initiating therapy, and women should be current on cervical and breast cancer screening. The lipid profile and liver function tests should be reevaluated along with a clinical evaluation for symptoms in three to four months, and the androgen tapered to the lowest dose possible. Some authors recommend that the serum testosterone concentration remain in the normal range for premenopausal women, but this is not universal. Liver function tests and lipids should be monitored every six months during therapy [1] .

Herbal therapies — The literature on herbal therapies for the treatment of sexual dysfunction in women is sparse. In general, St John's wort, ginseng, dong quai do not appear to be more effective than placebo for sexual dysfunction. Herbal products such as yohimbine have been reported to enhance desire, arousal, and orgasm in women with sexual dysfunction secondary to SSRIs, but results are inconsistent [21,22] .

L-arginine, an amino acid, has been touted as the natural Viagra due to the claimed ability to release nitric oxide, causing increased vasocongestion in the genitalia of both sexes [21,23] . More studies are necessary before conclusions can be drawn regarding any of these products.

Future therapies — A number of products are undergoing research and development for use in women with sexual dysfunction:

Tibolone — Tibolone, currently available in Europe and Australia, has not yet gained FDA approval in the United States. Taken orally, its metabolites have estrogenic, androgenic, and progestational effects. The level of androgenic activity and its potential use for sexual dysfunction is under evaluation. A small placebo controlled trial in postmenopausal women found tibolone increased vaginal lubrication, arousability, and sexual desire, but did not change frequency of sexual intercourse or orgasm compared to placebo [24] . Tibolone is effective for the management of osteoporosis, but may be associated with an increased risk of breast and endometrial cancer. Tibolone is discussed in more detail elsewhere. (See "Overview of the management of osteoporosis in postmenopausal women").

Sildenafil — Preliminary findings on use of sildenafil demonstrated positive effects in the areas of sexual arousal and orgasm in appropriately selected women [25-28] . However, several large scale, placebo controlled studies including about 3000 women with female sexual arousal disorder yielded inconclusive results [29] . For this reason, the manufacturer has decided not to seek regulatory approval to use the drug for female sexual arousal disorder.

Other — Now available in the United States is a clitoral suction device modeled after a pump used before the advent of penile injections and sildenafil to produce and maintain erection in males, uses suction or negative pressure to increase vasocongestion and engorge the clitoris and paraclitoral tissues for enhanced arousal and orgasm [30] .

One placebo-controlled randomized study of daily apomorphine SL administered to premenopausal women suggested this drug may improve sexual desire and function in women with hypoactive sexual desire [31] . Apomorphine SL is not FDA approved for this indication and requires further investigation.

This growing pharmacopoeia should not overshadow the psychosocial, intimacy, and relationship issues that are equally, if not more involved in problems with midlife sexuality.

INFORMATION FOR PATIENTS — Educational materials on this topic are available for patients. (See "Patient information: Sexual problems in women"). We encourage you to print or e-mail this topic review, or to refer patients to our public web site, www.uptodate.com/patients, which includes this and other topics.

Etiology and diagnosis of sexual dysfunction in women

Etiology and diagnosis of sexual dysfunction in women

Author
Alan Altman, MD
Section Editor
Robert L Barbieri, MD
Deputy Editor
Kathryn A Martin, MD



Last literature review version 16.2: May 2008 | This topic last updated: October 24, 2007 (More)


INTRODUCTION — Female sexual dysfunction refers to persistent or recurring reduction in sex drive, aversion to sexual activity, difficulty becoming aroused, inability to achieve orgasm, or dyspareunia that causes distress. According to the National Health and Social Life Survey, a study of sexual behavior in a demographically representative cohort of American men and women, sexual dysfunction is more prevalent among women than men (43 versus 31 percent) [1] .

Sexual dysfunction can occur at any age in women, but "midlife" is a particularly common time for changes to occur. The transition to menopause impacts the lives of women in different ways. Many will notice little change, some may experience an improvement, while others will complain of diminished sexual function. These variations are understandable considering the multiple factors that may affect midlife sexuality:

• Erratic ovarian function and fluctuating hormone levels that define perimenopause and the more definite decline that follows the menopause
• Alterations in anatomical structure, neurologic function, vascular responsiveness, and psychosocial function that accompany the normal aging process
• Relationship dynamics and each individual's foundation of sexual beliefs, expectations, and prior sexual experiences


Caring for women at this stage of life presents a unique opportunity for the clinician to ask the appropriate questions, bring the problem out into the open, and offer counsel and guidance. This requires the ability to communicate comfortably with patients plus an understanding of the physiology of human sexual response, the normal effects of aging on sexuality, relationship dynamics, and the healthcare provider's own limitations.

The etiology and diagnosis of sexual dysfunction are discussed here, with a focus upon changes that occur in midlife. The treatment of sexual dysfunction in women and an overview of the approach to sexual dysfunction in both men and women are discussed separately. (See "Treatment of sexual dysfunction in women" and see "The sexual history and approach to the patient with sexual dysfunction").


MIDLIFE
— The concept of "midlife" must be redefined as life expectancy grows longer. Women today experience "two midlives:" one is reproductive, the other chronological, and they do not necessarily coincide. In the past, with a life expectancy of 50 to 60 years, menopause generally appeared near the end of a woman's life, and midlife, chronologically, coincided with the reproductive changes in ovarian function beginning in the mid 30s.

Today life expectancy has increased and chronological midlife has been redefined as the 50s and 60s, while age at menopause remains unchanged. This discrepancy between a woman's reproductive midlife and her chronological midlife presents some problems. It is difficult for women in their 30s to think of themselves as entering midlife, even though decline in reproductive function begins at that age. In addition, when midlife occurs it will impact the kind of sexual changes that are experienced. The older midlife woman will tend to have more physiologic and anatomic problems compared with the younger midlife woman, in whom psychosocial problems might predominate. Women and men expect sexual interest and function to continue for decades beyond the point where women lose their natural reproductive capabilities. Fortunately, the clinician can do much to help patients in reproductive midlife maintain sexual function well into and beyond chronological midlife.

Midlife sexuality — While the host of hormonal and other changes that begin prior to the menopausal transition and continue beyond the menopause affect sexuality, the desire for an active sex life remains important for many men and women throughout midlife, as illustrated by the following surveys:

• One survey of 1879 women ages 45 to 55 (most of whom had partners) was designed to identify changes in sexual interest over the previous year [2] . Of the respondents, 62 percent noted no change, 31 percent reported a decline in interest, and 7 percent indicated an increase in interest; most of the last group had new partners.
• A 1999 survey asked responders ages 45 and older if they were more or equally satisfied with their current sex life when compared with their past levels of sexual activity [3] . Fifty-six percent of men and 51 percent of women were more or equally satisfied. In addition, 54 percent of the men and 38 percent of the women considered themselves "a better lover now than in the past."


Seventy percent of males and females with partners in this study had intercourse one or two times per week. Of those without regular partners, 6 percent of males had intercourse one or two times per week; women had considerably less. Women ages 45 to 59 years were more likely than men to approve of sex outside of marriage, oral sex, masturbation, and sex, as a normal part of aging. Age became a factor when the participants were asked, "What would improve your sex life?" Men and women age 45 to 59 cited less stress and more free time; men over 60, better health; women 60 to 74, better health for their partner; and women over 75 responded that just having a partner would improve their sex life.

Midlife can be a time of sexual freedom for many women; freedom from menstrual cycles, interruptions by small children, and unwanted pregnancy. These factors may enhance midlife sexuality, especially if sex was a positive experience earlier in life. On the other hand, some women see midlife as a loss of youth, femininity, and childbearing capacity, leading to a negative impact upon sexuality. Still others see midlife as a time when they can finally use these changes as a long anticipated excuse to avoid sex that was never enjoyable for them before. Absence of sexual activity is, in itself, not a problem; it should be viewed and treated as a problem only when a woman or her partner are bothered by it.

PHYSIOLOGY OF THE NORMAL HUMAN SEXUAL RESPONSE — Knowledge of the physiology of the normal sexual response can facilitate an understanding of what may go wrong. Two basic models have been proposed to illustrate the physiology of human sexual response: the Masters and Johnson model and the biopsychosocial model (see below). While they differ in many ways, both acknowledge that neurologic and vascular responses are essential to produce a sexual response.

The brain is the most important sex organ in the human body. Neurologic changes initiate the process as the brain reacts to an image, idea, fantasy, smell, or anything else that stimulates a response or triggers desire. This leads to changes in vascular blood flow. Sex hormones play key roles here. There are estrogen, androgen, and progesterone receptors in the brain [4,5] . Estrogen and androgen receptors are particularly dense in the hypothalamus, which controls sexual function and mood.

Testosterone is the primary precursor for estradiol biosynthesis in the brain; the testosterone concentration in the brain is 7 to 10 times higher than the estrogen concentration. Thus, the free circulating concentration of estrogen and testosterone does not necessarily correlate with what is occurring in the brain.

Estrogen increases blood flow to the brain. Estrogens also increase vibratory sensation peripherally and have a positive effect on neuronal growth and nerve transmission. Other hormones, including oxytocin and endorphins, influence sexuality in the brain as well, while prolactin may have a negative effect on sexual response.

Increased blood flow to the genitalia occurs with sexual stimulation. This marks the arousal phase, in which the additional blood flow produces peripheral responses that define the sexual response. Estrogens affect how blood flows: increased estrogen increases vaginal blood flow (VBF) while a decreased concentration diminishes VBF [6] . The mechanism by which this occurs is related to estrogen stimulation of the release of vasoactive substances such as nitric oxide by endothelial cells, which induces vasodilatation [7] .

Addition of androgens to estrogen increases VBF further. Testosterone may work directly in the artery or indirectly by increasing the availability of estrogen [8] . Progesterone, on the other hand, can diminish blood flow by down-regulating the estrogen receptor [9] . Blood flow can also be increased through any mechanism that provides the neurovascular stimulus, be it sexual activity, the use of sexual aids, masturbation, or fantasy.

Masters and Johnson — Masters and Johnson first detailed the phases of human sexual response as a linear progression from excitement to plateau to orgasm, followed by resolution [10] .

Excitement — Activation of the central nervous system (CNS) causes specific changes in blood flow. Ovarian hormones also play essential roles in this process, encouraging vasodilation and increased blood flow. Uterine and internal mammary arteries contain some of the highest density of estrogen receptors, hence their responsiveness in the excitement phase.

Genital vasocongestion occurs because of this increase in blood flow and smooth muscle relaxation. The vaginal wall becomes lubricated. The labia increase in size and spread open. The clitoris increases in size and the vagina expands while the uterus elevates. Other areas of the skin, including the face and breasts, demonstrate this increase in blood flow with the "sex flush."

Following Masters and Johnson, Kaplan replaced the excitement phase with two phases: desire, in which the neurologic stimulus occurs; followed by arousal, in which blood flow produces the peripheral response leading up to orgasm [11] .

Plateau — Masters and Johnson presented this as a separate phase, while Kaplan later blended it into the arousal phase. Actions associated with this phase include retraction of the clitoris and engorgement of the labia. Bartholin gland secretion occurs, as well as congestion of the outer third of the vagina and further expansion of the upper two thirds of the vagina. Muscle tension builds.

Orgasm — In the orgasm phase, 8 to 12 muscular contractions of the levator ani muscles occur at precise intervals. Vaginal and uterine contractions occur followed by massive release of muscle tension. Regularly orgasmic women will achieve orgasm 50 to 70 percent of the time and a satisfying prolonged plateau phase other times.

Resolution — The final phase, or culmination, is often characterized as a gradual, pleasant diminishment of sexual tension and response, differing in the time it lasts among individuals.

The biopsychosocial sexual response — An alternative model has also been proposed to describe the female sexual response. Proponents believe that a large component of women's sexual desire is responsive rather than spontaneous. They maintain the biopsychosocial nature of the female sexual response cycle is a result of the dynamic and mutable interaction of four components [12,13] :

• Biology
• Psychology
• Sociocultural influences
• Interpersonal relationships


If only the biological or physiological component is addressed, as with the use of pharmacotherapy, successful treatment will frequently not be achieved. In this model, emotional intimacy of some kind motivates the woman to seek out or become responsive to sexual stimuli, which in turn leads to arousal. Once arousal is achieved, sexual desire is then accessed, allowing continuation of the experience for sexual reasons. Hence, sexual desire can be responsive to arousal instead of preceding it. While spontaneous drive can occur, it is not essential. Thus, lack of spontaneous desire is not necessarily a dysfunction. In addition, satisfaction is the goal, which may or may not include orgasm.

SEXUAL CHANGES WITH AGING — Sexuality and sexual capacity evolve over a lifetime of development and change, based on personal experience, interest, cultural attitudes, interpersonal relationships, desires, behaviors, physiology, and other factors.

Epidemiology — Although many older adults remain sexually active, sexual problems become more common, and these problems are infrequently discussed with their health care providers. This was illustrated in a national probability sample study of 3005 men and women ages 57 to 85 years [14] . The prevalence of sexual activity decreased with age in both men and women, but women at all ages were less likely than men to be sexually active (62, 40, and 17 percent among women who were ages 57 to 64, 65 to 74, and 75 to 85 years, respectively). The most common sexual problems in women were low desire, vaginal dryness, and inability to achieve orgasm (43, 39, and 34 percent, respectively). Only 38 percent of men and 2 percent of women reported having discussed their sexual concerns with a health care provider since the age of 50.

Estrogen — Estrogen deficiency develops gradually as women near menopause. A more abrupt decline is seen with surgical menopause. This decline in estrogen can cause several changes that may affect sexual function.

Urogenital function — Estrogen sustains the structure and function of the cells of the vagina. Every woman with estrogen deficiency for a prolonged period of time will develop some degree of vaginal and genital atrophy. Epithelial changes in the vagina occur first within weeks to months of estrogen loss. This leads to a decrease in superficial cells, an increase in parabasal cells, and a progressive loss of elasticity and integrity of the epithelium. Along with this change comes an increase in vaginal pH, which promotes the growth of organisms and leads to more frequent vaginal infections [15] .

Later changes, over years, affect the deeper structures such as the underlying vascular, muscle, and connective tissue, leading to a decrease in vaginal blood flow, and both foreshortening and narrowing of the vagina. There is actual loss of blood vessels in the layers beneath the epithelium. This constellation of changes can lead to vaginal dryness, decreased or absent lubrication and, dyspareunia. (See "Clinical manifestations and diagnosis of menopause" and see "Approach to the woman with dyspareunia").

The bladder tissues also suffer from estrogen loss with mucosal changes that can lead to urinary frequency, urgency, nocturia, dysuria, and incontinence. Clitoral changes can occur, including a 50 percent decrease in perfusion and shrinkage of the structure [16] . Neurologic changes include decreased touch perception, a decline in vibratory sensation, and slowing of nerve impulses leading to a delay in reaction time [17] . Decreased androgen levels also affect some of these changes (see below).

Effect on sexual response — Changes in the vaginal and clitoral tissues due to estrogen deficiency can have a profound effect on sexual response. The decrease in genital blood flow will affect vasocongestion. Sexual arousal will be delayed or altered. More time and stimulation may be necessary to achieve lubrication, which may be significantly reduced or absent. The outer third of the vagina, including the labia and G-spot, demonstrate decreased or absent congestion, as does the clitoris. Vaginal expansion in length and transcervical width decreases. Elsewhere, there is a reduced incidence of skin flush, a lack of increase in breast and nipple size during stimulation, decreased tactile sensation, or worse, aversion to skin touch due to pain perception instead of pleasure in the clitoris, skin, and nipples, and a general decrease in muscle tension [18] .

Taken together, these changes can result in delayed arousal, delayed or absent orgasm, or diminished peak of orgasm. Fewer uterine contractions occur with orgasm and, in older women, particularly age 70 and older, painful uterine contractions can be associated with orgasm because of vasoconstriction that produces a reaction similar to ischemia [16] .

Androgens — All women produce some androgens, which may contribute to maintaining normal ovarian function, bone metabolism, cognition, and sexual behavior [19] . However, serum testosterone concentrations are not a good predictor of libido in women. Studies evaluating vaginal blood flow and vasocongestion of the clitoris and labia suggest that normal testosterone levels are necessary for arousal and orgasm to occur [20] . In women who undergo bilateral oophorectomy and subsequently develop hypoactive sexual desire disorder, exogenous testosterone therapy may be moderately effective for libido and sexual activity. (See "Androgen production and therapy in women").

Total testosterone and androstenedione (the major androgen in the serum of cycling women) gradually decline with increasing age in normal women. Androgen levels peak around age 25 and begin a gradual, age-related decline in the early to mid 30s, much earlier than the decline in estrogen levels [21] . There is also a midcycle testosterone surge that declines with age [22] . Some have argued that the sexual effects of reduced androgen levels can occur well before menopause and the onset of estrogen deprivation [23] .

Other suggested causes of androgen deficiency include:

• Oophorectomy (producing sudden 50 percent fall in levels within 24 hours of surgery)
• Premature ovarian failure
• GnRH agonist therapy
• Corticosteroid therapy suppressing ACTH secretion
• Adrenal insufficiency


Additional important causes include exogenous oral estrogens, such as oral contraceptives (OCs) and hormone replacement therapy (HRT), both of which increase sex hormone binding globulin (SHBG), resulting in reduced bioavailability of androgens as well as estrogens. Non-oral contraceptives, ie ring and patch, also increase SHBG, while non-oral postmenopausal therapy does not.

The menopausal transition (ie, perimenopause) results in a somewhat unique hormonal profile. Erratic ovarian function leads to estrogen levels that can be normal, elevated, or decreased at any given time, but in general, estrogen secretion is preserved. (See "Clinical manifestations and diagnosis of menopause"). Ultimately, lower estrogen levels predominate. The postmenopausal ovary is an androgen-producing organ. Ovaries continue to produce androgens well into the postmenopausal years [24] . (See "Androgen production and therapy in women").

Serum androgen concentrations — It has been proposed that serum androgen concentrations are an independent predictor of sexual desire and function in women. In a community-based, cross-sectional study of 1021 women aged 18 to 75 years, low serum concentrations of testosterone, free testosterone, or androstenedione were not significantly associated with a low score on the Profile of Female Sexual Dysfunction instrument [25] . Women with low sexual function were more likely to have a low DHEAS level, however, the majority of women with a low DHEAS level did not report low sexual function. This suggests that the measurement of serum androgens in women presenting with sexual dysfunction is not clinically useful.

Impact of male sexuality — One of the major factors that impacts female midlife sexuality is the spectrum of midlife sexual changes in men. It has been reported that 50 percent of men over 50, 60 percent of men over 60, and 70 percent of men over 70 have some degree of erectile dysfunction [26] . (See "Overview of male sexual dysfunction"). Other changes include a prolonged preorgasmic or plateau phase during which it can take considerably longer to achieve orgasm after arousal, and, as with women, orgasm may not always be achieved [27] . Finally, the ejaculate itself can be decreased or absent during sexual encounters.

Many couples adjust to these changes with more manual or oral stimulation to compensate for waning maintenance of erection and carry on normal sex lives. Sexual dysfunction occurs when either partner is bothered by the changes and the lack of successful activity. In men, however, these changes often lead to performance anxiety, one of the most significant psychosocial sexual problems. When the man experiences performance anxiety, he will frequently withdraw from intimacy at all levels of the relationship for fear of stimulating his partner to expect sexual activity that he believes he cannot provide. This withdrawal from other areas of intimacy has a most profound impact on the woman because of the major importance of intimacy to female desire and sexual response.

Decreased libido or sexual desire — Decreased libido or sexual desire, termed hypoactive sexual desire disorder (HSDD), has increasingly become one of the more common complaints of women in the menopausal transition and in midlife in general [28] . Sexual desire includes sexual appetite, drive, and fantasy. While sexual arousal leading to orgasm is predominantly a physiological event dependent upon neurovascular responses to stimuli within the appropriate hormonal milieu, libido or sexual desire is more psychosocial and behavioral, impacted by a multitude of factors in daily life and relationships.

The desire for sexual intimacy can be diminished in spite of normal levels of testosterone and estrogen. Many factors affect sexual drive and its expression in midlife and should be evaluated when patients present with decreased libido.

A number of instruments exist for the measurement of female sexual function, but only one has been validated for use in evaluation of treatment response (Profile of Female Sexual Function [PFSF]) in women with HSDD in international clinical trials [29] . Of note, androgen deficiency is not one of the criterion for the diagnosis of HSDD. Revised definitions of female sexual disorders have been proposed that reflect the importance of subjective sexual arousal and the concept of a circular sex-response cycle rather than a linear model (Masters and Johnson) [30] . In this model, a woman may access desire only after she becomes aroused by her partner, in which case lack of spontaneous desire is not a sexual dysfunction.

Partner availability — Women tend to live longer than men, resulting in a natural shortage of males ages 50 and older. At the same time, many men seek out younger partners, further affecting the availability of partners for women in midlife and beyond.

Personal well-being — A woman's sense of personal well-being is important to sexual interest and activity. Low perceived levels of physical and emotional satisfaction and a sense of unhappiness correlate with low sexual desire, resistance to arousal, and pain during sex [1] . Women who experience premenopausal physical or emotional problems, particularly disorders of sexual desire, sexual response, and sexual behavior, tend to experience a worsening of these conditions after menopause [16] .

Overall health and socioeconomic circumstances — Analysis of data from the National Health and Social Life Survey of 1749 women and 1410 men indicated that sexual dysfunction is highest in women with poor health, low income, and a history of infrequent sexual interest. Sexual dysfunction is also more common among women and men with poor physical and emotional health [1] .

Other — Other predictors of decreased libido have been described in women in their late reproductive years. In a four-year prospective cohort study of 326 women ages 35 to 47 (27 percent of whom reported a decreased libido), depression, vaginal dryness, and children living at home were associated with an increased risk of low libido [31] . Mean serum testosterone concentrations (measured every eight months in the early follicular phase) were not associated with libido. However, women with the greatest variability in serum testosterone concentrations reported the greatest declines in libido.

In a second report of 341 peri- and postmenopausal women, common menopausal symptoms, including depression, sleep disturbances, and night sweats, were associated with diminished libido [32] .

Medical issues — Chronological midlife may be associated with medical issues that impact sexuality in either the woman or her partner. These problems can diminish the physical ability to perform sexually, such as with coronary artery disease or arthritis (the most prevalent cause of sexual inactivity in the United States), or can affect arousal and orgasm capability as with neurologic disorders such as multiple sclerosis, Parkinson's disease, or sequelae of diabetes [1] . Alcohol and substance abuse may have a disabling affect on performance by altering erectile capability in the male and arousal in the female. Psychiatric or emotional problems can impact sexual function due to the particular disorder or to the treatment.

Medications — Both prescription and over-the-counter medications have the capability to alter desire, arousal, and orgasm. Any medication that alters blood flow (eg, antihypertensives), affects the CNS (eg, psychotropics), or dries the skin or mucous membranes (eg, antihistamines), may disrupt normal sexual function. As previously mentioned, both oral estrogens in HRT and oral asl well as non-oral contraceptives can adversely affect levels of bioavailable androgens. Non-oral estrogens, however, used peri or postmenopausally, do not diminish bioavailable androgens.

One of the major classes of medications that impacts sexuality is the selective serotonin reuptake inhibitors (SSRIs), frequently used to treat depression in the perimenopausal woman. (See "Antidepressant medication in adults: SSRIs and SNRIs"). The risk/benefit ratio with use of these agents is based on individual need and response. When depression is severe, SSRI's may allow for increase in sexual activity by treating the underlying process. However, in many patients, therapy can diminish sexual desire and alter or eliminate arousal and orgasm. Changing to a different antidepressant may help; the addition of bupropion to ongoing therapy also has been shown to improve sexual function [33] . (See "Sexual dysfunction associated with selective serotonin reuptake inhibitor (SSRI) antidepressants").

Surgery
— Surgery related to cancers of the breast or female genital tract can have a profound effect on sexuality in midlife, as can prostate surgery in men. This occurs as a result of the extensive surgery affecting body image and function, as well as the psychological sequelae of the cancer diagnosis and prognosis on patient and partner. Many of these malignancies preclude the use of hormonal therapies, leading to even further problems involving genital function. Referral for counseling is critical in these patients.

Contrary to public perception, sexual function often improves with hysterectomy. Seriousness of pathology along with level of annoyance of bleeding, pain, or pressure preoperatively, affect satisfaction with sexual activity postoperatively. A two year prospective study assessed measures of sexual functioning in over 1000 women prior to hysterectomy and at 6, 12, 18, and 24 months, after the procedure [34] . The percentage of women who engaged in sexual relations increased from approximately 71 percent before hysterectomy to 77 percent at 12 and 24 months after hysterectomy; the rate of frequent dyspareunia dropped from 19 to 4 percent; the rate of experiencing orgasms increased from 92 to 95 percent; and libido increased. Overall, the frequency of sexual activity increased and problems with sexual functioning decreased postoperatively.

There remain, however, women who note a decrease or total absence of orgasm after hysterectomy. Preoperative counseling can help to prepare and assist the patient and partner by reviewing the risks of surgery, as well as the risks of not having the surgery, and potential sexual changes, better or worse, that might follow. Preservation of the ovaries and cervix, if not contraindicated and surgically possible, may help to avoid major changes in sexual response. (See "Abdominal hysterectomy", section on Outcome).

DIAGNOSIS OF SEXUAL DYSFUNCTION — The diagnosis of sexual dysfunction should begin with use of the non-threatening question, "Are you sexually active?" If the answer is affirmative, the second question can be, "Do you have any questions, problems, or concerns about your sexual activity that you would like to discuss?" If, instead, the patient indicates that she is not sexually active, the next and most important question should be, "Does that bother you or your partner?"

There are two common reasons that these questions are not asked. First, because the clinician may feel uncomfortable with the questions or with his or her level of knowledge of the subject and, second, the amount of time needed for discussion once the patient senses sincere interest and feels comfortable beginning a dialogue with the provider. After initiating the discussion, a separate consultation can be scheduled at a later date so that more uninterrupted time can be spent, and also to allow the patient to gather all her thoughts on the topic she now knows is open for discussion. Presence of the partner may also be useful later, once the patient has covered her own concerns. (See "The sexual history and approach to the patient with sexual dysfunction").

A teaching session should occur during the second consultation, in which the clinician describes normal sexual response as well as the physiological changes in sexuality that are common in midlife. Frequently little or no therapy is needed once patients realize so many of these changes are a normal part of the aging process and learn how to cope with them effectively.

The point at which the physiologic changes of aging become sexual dysfunction is best defined within the context of each individual relationship, based on the effect these changes have on the couple. The need for referral to a specialized counselor, therapist, or sexologist, should be made when more detailed consultation is necessary or when the clinician is unable to provide the service.

A detailed gynecologic examination is an important component of the evaluation. Careful assessment of the vulva, clitoris, introitus, and vagina, for atrophic changes, loss of elasticity, inflammation, scarring, infection, or genital prolapse, is paramount. Any tenderness to palpation, superficial or deep, must be evaluated. The pelvic structures, including the bladder, should be evaluated for pathology that might interfere with successful sexual activity, such as masses, endometriosis, or urinary incontinence. Routine breast and cervical cancer screening should be updated.

Laboratory testing is guided by the history and physical examination. No specific tests are universally recommended in all women. Assessment of the serum free and total testosterone concentrations are often done in women considering androgen therapy. However, many currently available methods for measurement of total and free testosterone lack the sensitivity and accuracy necessary for determining androgen deficiency in women [35] .

It is also important to note that the type and dose of androgen replacement therapy for women has not been well established. (See "Androgen production and therapy in women").

INFORMATION FOR PATIENTS — Educational materials on this topic are available for patients. (See "Patient information: Sexual problems in women"). We encourage you to print or e-mail this topic review, or to refer patients to our public web site, www.uptodate.com/patients, which includes this and other topics.

Monday, September 22, 2008

Patient information: Painful bladder syndrome and interstitial cystitis

Patient information: Painful bladder syndrome and interstitial cystitis

Author
Mary P Fitzgerald, MD
Section Editor
Linda Brubaker, MD, FACS, FACOG
Deputy Editor
Leah K Moynihan, RNC, MSN
Sandy J Falk, MD



Last literature review version 16.2: May 2008 | This topic last updated: July 12, 2007 (More)


INTRODUCTION — Painful bladder syndrome/interstitial cystitis (PBS/IC) is a group of disorders with symptoms of mild to severe bladder pain and an urgent and/or frequent need to urinate. The disorder can affect women and men, but is more common in women. It can be difficult to diagnose and treat because the underlying cause is not well understood.

The symptoms and diagnosis of PBS/IC will be discussed here. Treatment of this disorder is reviewed separately. (See "Patient information: Treatment of painful bladder syndrome and interstitial cystitis").


DEFINITION
— The definitions of painful bladder syndrome and interstitial cystitis have evolved over the years, and will probably continue to change as the cause is better understood.

Painful bladder syndrome — PBS is defined as a group of symptoms that include bladder pain and a frequent and/or urgent need to urinate during the day and/or night.

Interstitial cystitis — IC is the diagnosis used to describe people who have symptoms of PBS as well as changes in the bladder lining (seen during cystoscopy, see "Cystoscopy" below).

It is difficult to know for sure how many people are affected by PBS/IC; estimates range from 0.01 to 11 percent of women and 0.04 to 5 percent of men.

CAUSES — Little is known about the cause of PBS/IC. Many studies have shown that patients with IC have abnormalities in the lining of the bladder. However, it is not known if these bladder abnormalities are the cause of symptoms or develop as a result of some unknown underlying disorder that also causes painful bladder symptoms.

It is likely that the nerves in the bladder become highly sensitive to pain and pressure as PBS/IC develops. Nerves outside the bladder, including nerves of the abdomen, pelvis, and hips, and legs, may also become more sensitive.

One or more events may lead to the symptoms of PBS/IC, including:

Urinary tract infection
• An episode of vaginitis or prostatitis (eg, a yeast infection of the vagina or a bacterial infection of the prostate)
• Bladder, pelvic, back or other type of surgery
• Trauma (eg, fall onto the tailbone [coccyx] or car accident)

However, in many people, there is no clear explanation for why or how the symptoms of PBS/IC first began.


SYMPTOMS — The symptoms of PBS/IC can vary from one person to another and from time to time for each person. All patients with PBS/IC have bladder pain that is relieved at least partially by urinating. Symptoms usually include a frequent and urgent need to urinate during the day and/or night. Most, although not all, people with PBS/IC do not have urinary leakage (incontinence). Most people describe pain in the suprapubic area (in the lower abdomen, above the pubic bone) or urethral area (show figure 1). Some people describe one-sided lower abdominal pain or low back pain. The severity of pain ranges from mild burning to severe and debilitating pelvic pain.

Most people describe symptoms that begin gradually, with worsening discomfort, urgency and frequency over a period of months. A smaller subset of patients describes symptoms that are severe from the beginning. When symptoms of PBS/IC begin suddenly, some patients are able to name the exact date on which symptoms began (see "Causes" above).

Some people have chronic pelvic pain that is distinct from bladder pain, sometimes with other pain symptoms. Some people have several pain-related diagnoses, such as irritable bowel syndrome, painful menstrual periods, endometriosis, vulvar pain (vulvodynia), or fibromyalgia. PBS/IC symptoms are sometimes at their worst during times when other pain symptoms are also at their worst. (See "Patient information: Irritable bowel syndrome" and see "Patient information: Endometriosis" and see "Patient information: Fibromyalgia").

Symptoms may vary from one day to the next. Worsening of PBS/IC symptoms may occur after consuming certain foods or drinks (eg, strawberries, oranges, beer, coffee), or during the luteal phase of the menstrual cycle (14 to 28 days after the first day of the last period), during stressful times, or after activities such as exercise, sexual intercourse, or being seated for long periods of time (eg, during a plane trip).

A person with severe disease may have to urinate several times per hour, which can seriously disrupt daily activities and sleep. As a result of these symptoms, home and work life are often disrupted, interest in sex may be minimal, and difficulty coping with chronic pain and fatigue can occur. In surveys, 50 percent of patients reported being unable to work full-time, 75 percent described pain with intercourse, 70 percent reported sleep disturbance, and 90 percent reported that PBS/IC affected their daily activities [1] .

EVALUATION — The diagnosis of PBS/IC is based upon a person's symptoms and examination. A careful medical history, physical examination, and sometimes laboratory testing are needed to confirm the diagnosis and also to be sure that another condition (eg, bladder infection or kidney stone) is not the cause of symptoms. There is no single test that can definitively diagnose PBS/IC. (See "Patient information: Urinary tract infections in adolescents and adults" and see "Patient information: Kidney stones in adults").

Physical examination — The physical examination usually includes a complete pelvic examination with a brief rectal exam. Often, patients with PBS/IC have tenderness in the lower abdomen, hips, and buttocks. Women often have tenderness in the vagina and around the bladder, and men may have tenderness in the scrotum and penis. For this reason, being examined can be uncomfortable. In some individuals, it may be necessary to use ultrasound to ensure that the pelvic organs have no evidence of abnormalities.

If an examination or ultrasound is too uncomfortable, some healthcare providers will recommend that the patient begin a course of treatment for PBS/IC without further testing. If improvement is not seen, it may be necessary to perform more testing to confirm the diagnosis.

Some providers will measure the amount of urine remaining in the bladder after the patient urinates; this is called a post-void residual. This measurement can be done by inserting a small catheter into the bladder or by using ultrasound. While it is normal to have some urine in the bladder after voiding, having a large amount of urine is not normal. Urinary retention is the medical term for retaining urine in the bladder, and is not typical of PBS/IC.

Laboratory tests — Most clinicians will perform a urine test to confirm the diagnosis of PBS/IC and ensure that a person's symptoms are not related to another condition, such as a kidney stone or bladder infection. If a urinary tract infection is discovered, the person will be treated with antibiotics. If blood is detected in the urine, further urine and/or diagnostic testing (eg, cystoscopy) may be recommended. (See "Patient information: Urinary tract infections in adolescents and adults" and see "Patient information: Blood in the urine (hematuria)").


Recurrent urinary tract infection
— PBS/IC is sometimes misdiagnosed as a chronic or recurrent urinary tract infection. Some people are given antibiotics to treat the pain, urgency, and frequency of PBS/IC, although there is no benefit of antibiotics unless an infection is present. The best way to determine if a urinary tract infection is present is to have a urine culture and sensitivity. (See "Patient information: Urinary tract infections in adolescents and adults").

Cystoscopy — Cystoscopy is a test that allows a doctor to examine the inside of the bladder. Cystoscopy is not required to diagnose PBS/IC, but may be recommended in certain situations. Cystoscopy can be done in the office, after a numbing gel is applied inside the urethra. It can also be done in an operating room while a patient is under anesthesia, sometimes in combination with other procedures (see "Hydrodistension" below).

To perform cystoscopy, a physician inserts a thin telescope with a camera through the urethra and into the bladder. The physician examines the inside (lining) of the bladder to determine if there are any abnormalities. A person with PBS/IC may have either a normal or abnormal-appearing bladder. If an abnormality is seen, further testing may be recommended.

Hydrodistension — Hydrodistension is a procedure that is sometimes recommended to diagnose interstitial cystitis. The procedure is done while a person is under anesthesia, after cystoscopy. The physician fills the patient's bladder with water to stretch the walls of the bladder. The water is released after a few minutes, and then filled again with a smaller amount of water. The lining of the bladder is then examined with a cystoscope to determine if there are signs of IC. Signs of IC can include glomerulations (small reddened areas) and Hunner's patches (larger red areas). Some patients with painful bladder symptoms can have a completely normal appearance during cystoscopy, however. A biopsy (small tissue sample) may be taken from any abnormal areas and later examined with a microscope.

There are conflicting opinions about the need for hydrodistension in the diagnosis of IC. Although some clinicians still perform hydrodistension, most clinicians believe is not necessary or helpful to see such evidence of IC before treating it.

TREATMENT — A topic review that discusses the treatment of painful bladder syndrome/interstitial cystitis is available separately. (See "Patient information: Treatment of painful bladder syndrome and interstitial cystitis").

WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.

This discussion will be updated as needed every four months on our web site (www.uptodate.com/patients). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.

A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable.

National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)


National Institute of Diabetes and Digestive and Kidney Diseases
(http://kidney.niddk.nih.gov/kudiseases/pubs/interstitialcystitis/)


Interstitial Cystitis Association
(www.ichelp.org)


Interstitial Cystitis Network
(www.ic-network.com)


European Society for the Study of Interstitial Cystitis
(www.essic.eu)


United States Department of Health and Human Services
(www.4woman.gov/faq/intcyst.htm)

Treatment of painful bladder syndrome/interstitial cystitis

Treatment of painful bladder syndrome/interstitial cystitis

Author
Mary P Fitzgerald, MD
Section Editor
Linda Brubaker, MD, FACS, FACOG
Deputy Editor
Sandy J Falk, MD



Last literature review version 16.2: May 2008 | This topic last updated: May 16, 2008 (More)


INTRODUCTION — Although painful bladder syndrome/interstitial cystitis (PBS/IC) can cause major deterioration in quality of life, there is no consensus surrounding the optimal approach to its treatment. This is due, in part, to our lack of a clear understanding of the etiology of the disorder, which precludes development of therapies targeted at the underlying pathophysiology. In addition, there have been few randomized, controlled treatment trials of PBS/IC, instead the great majority of therapeutic studies have been retrospective and/or uncontrolled. Lastly, varying definitions of the condition and outcome have been an impediment to interpretation of results and their application to clinical care [1] .

The symptoms of PBS/IC can be somewhat nonspecific; these patients probably suffer from one or more unrecognized disorders. Therefore, it is not surprising that clinically popular treatment algorithms for PBS/IC usually involve several treatment modalities or cycling through various therapies when initial treatments are unsuccessful. This was illustrated by the Interstitial Cystitis Data Base study, which recorded data on 581 women with a diagnosis of IC [2] . These women underwent 183 different types of therapy over several years follow-up. No one therapy was successful in a majority of patients.

In practice, physicians who treat patients with PBS/IC choose a model of the disease that seems to fit their clinical experience, and treat according to that model. Clinicians tend to favor one theory over others, and initiate treatment(s) in line with their favored theory. Therefore, treatment algorithms are highly empiric and vary considerably from site to site. Since treatments tend to have a low success rate, most patients try more than one therapy before finding relief. In this clinical setting, it cannot be determined whether the relief that patients experience is simply due to the passage of time and natural remission of symptoms, or whether the treatment was responsible for the improvement.

NONSPECIFIC THERAPIES — Common sense dictates that the following components are part of all treatment programs:

Psychosocial support — Psychosocial support is an integral part of treatment of any chronic pain disorder. Patients may benefit from identification of a support person within the clinical practice whom they may contact, as needed. They may wish to be in touch with local pain support groups, or with national support groups, such as the Interstitial Cystitis Society (www.ichelp.org) or the Interstitial Cystitis Network (www.ic-network.com). Some centers may have resources to refer patients for formal counseling by a psychologist with expertise in support of patients with chronic illness.

Depression is common in patients with chronic pain, and may impede treatment success. Referral for mental health evaluation may be useful when there is any suspicion that depression is present. (See "Depression: Clinical manifestations and diagnosis").

Referral to pain management specialists — Referral to specialists in pain management should be considered if the full range of pain management options is not available within the practice.

Treatment of comorbid conditions — Acute genitourinary disorders (eg, urinary tract infection, vulvovaginitis) can exacerbate PBS/IC symptoms, thus they should be addressed promptly. Other disorders associated with visceral pain should also be treated since sensitization of any viscera probably results in increased bladder sensitivity. Therefore, it is critically important to treat concomitant inflammatory bowel disease (Crohn's disease, ulcerative colitis, diverticulitis), irritable bowel syndrome, dysmenorrhea or endometriosis. Since PBS/IC patients often carry more than one of these diagnoses, treatment decisions can be complex, and collaboration with other medical professionals is usually necessary. (See "Clinical features and diagnosis of painful bladder syndrome/interstitial cystitis").

Avoidance of activities associated with flares — Patients frequently note that some exercises or recreational activities, sexual activities, or body positions seem to worsen bladder symptoms. Others note that some foods or beverages are troublesome. Common sense suggests that these factors be avoided until symptoms are resolved, at which time they may be reintroduced. Some practitioners strongly recommend the highly restrictive interstitial cystitis diet [3] , but its benefit has never been studied, and in practice, most patients with food sensitivities are already aware of them and have already excluded them from their diet.

Behavioral therapy — Behavioral therapy forms the cornerstone of all treatment packages. It includes avoidance of exacerbating activities, and also some form of a timed voiding protocol to expand functional bladder capacity. Such protocols are critical because frequent voiding leads to diminished functional bladder capacity (possibly due to shrinkage of smooth muscle, similar to diminished stomach capacity after fasting or after chronic intake of smaller amounts of food).

A typical bladder reeducation protocol involves teaching patients to "void by the clock" rather than voiding when they feel an urge to do so. As an example, a patient who is currently voiding every half an hour is asked to void only on the hour during the daytime (drills are not typically continued through the night), whether they feel the need to void or not, and not to void more frequently than the prescribed interval. This voiding interval is continued for a full week, and if patients are successful at that voiding interval, it is increased by an appropriate amount. This might result in the prescription of a voiding interval of 90 minutes for the second week, of two hours for the third week, 2.5 hours for the fourth week, and three hours for the fifth week. Other similar bladder retraining therapies are widely used since they are cheap, without side effects, and universally available.

The only study of timed voiding in IC patients reported 15 of 21 patients experienced a 50 percent decrease in their IC symptoms [4] .

SPECIFIC THERAPIES

Correction of uroepithelial abnormalities — Proponents of the theory that urothelial abnormalities are responsible for symptoms favor use of therapies directed at the urothelium. These include:

Pentosan polysulfate sodium — Pentosan polysulfate sodium (PPS) is the only oral medication approved by the United States Food and Drug Administration (FDA) for treatment of IC. The approved dose is 100 mg three times daily, although off-label treatment using 200 mg twice daily is clinically common. The medication is a protein that is supposed to be filtered by the kidneys and appear in the urine so that it can reconstitute the deficient glycosaminoglycan (GAG) layer over the urothelium. In fact, only a tiny proportion of the drug is absorbed by the gastrointestinal tract and excreted in the urine. Urinary levels in patients who respond to treatment are not significantly different from the levels in nonresponders [5] .

A systematic review of randomized trials assessing pharmacologic treatments of PBS/IC found that PPS was more effective than placebo in overall improvement of patient-reported symptoms (pain, urgency, frequency) (RR 1.78, 95% CI 1.34-2.35), but the magnitude of effect was modest [6] . There was considerable heterogeneity in the studies that addressed this question.

Intravesical heparin and lidocaine — Some practitioners recommend intravesical instillations of heparin and/or lidocaine, PPS, and sodium bicarbonate in various nonstandardized drug cocktails. No controlled studies of these therapies exist. As an example, use of a solution consisting of 40,000 units of heparin, 8 mL of 2 percent lidocaine, and 3 mL of 8.4 percent of sodium bicarbonate to reach a total fluid volume of 15 mL instilled into the bladder has been described as effective, with over 80 percent of patients experiencing good remissions after two weeks of three treatments per week [7] . Similar solutions have been recommended for use in patients with severe symptoms as a "rescue" intervention. Patients can be taught to perform the instillations themselves at home.

Intravesical dimethyl sulfoxide (DMSO) — Dimethyl sulfoxide (DMSO) was approved by the FDA for use in IC in 1997 on the basis of data from one uncontrolled clinical trial. Its action is thought to be nonspecific, including antiinflammatory, analgesic, smooth muscle relaxing, and mast cell inhibiting effects [8] . Treatment involves bladder catheterization with instillation of 50 mL DMSO weekly for six to eight weeks, followed by 50 mL every two weeks for 3 to 12 months. Small randomized trials initially suggested benefit [9,10] , but adverse effects, including pain and significant exacerbation of symptoms, limited its use. DMSO is currently less commonly used than in the past, as other, less painful treatments have become available.

Hydrodistension — Hydrodistension is usually used as a diagnostic aid for PBS/IC. (See "Clinical features and diagnosis of painful bladder syndrome/interstitial cystitis" section on Hydrodistension). It has also been used as a treatment because some patients report prolonged relief of symptoms after the procedure, possibly due to disruption of sensory nerves within the bladder wall [11] . An uncontrolled study reported a positive effect in 35 of 50 patients who underwent 30 minutes of hydrodistension [8] , but others have reported lower success rates [12] . Even when there is benefit, it is usually short-lived, and many patients experience worsening of their symptoms; thus, many clinicians feel that the risk-benefit ratio of hydrodistension therapy is not appropriate for their patients. It may be appropriate to reserve use of repetitive therapeutic hydrodistension for patients who generally obtain significant and prolonged relief. Risks of hydrodistension include bleeding (from ruptured vessels) and, rarely, rupture of the bladder wall.

Neuromodulating therapies — Proponents of the theory that PBS/IC represents a neurological hypersensitivity disorder tend to favor use of neuromodulating treatments. These include:

Amitriptyline — Medications used to treat other pain syndromes are commonly utilized for IC patients, as well. Amitriptyline is commonly prescribed for relief of PBS/IC symptoms. In Germany, one trial randomly assigned 50 subjects with IC to amitriptyline or placebo (IC was defined according to National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) criteria) (show table 1) [13] . Subjects were treated for four months with a self-titration protocol that allowed them to escalate drug dosage by 25 mg increments weekly to a maximum of 100 mg. Amitriptyline use resulted in greater improvement in symptom scores than placebo. In addition, significantly more subjects prescribed amitriptyline rated their satisfaction with treatment as being "good" or "excellent" than those given placebo, 63 and 4 percent, respectively. However, only 42 percent of patients in the amitriptyline group experienced greater than 30 percent decrease in symptom score, suggesting that benefits are modest.

An open-label study of the long-term use of amitriptyline in 94 patients followed for a mean of 19 months reported similar results [14] . Almost one-half of patients rated satisfaction with treatment as "good" or "excellent" and designated themselves as being "moderately" or "markedly" improved. However, about one-third dropped out of the study after a mean treatment period of six weeks, with nonresponse to treatment being the primary reason for dropout. Side effects of amitriptyline include sedation, dry mouth and weight gain.

A National Institutes of Health-sponsored randomized trial comparing behavioral therapy to amitriptyline-plus-behavioral therapy for treatment of PBS is ongoing [15] .

Side effects of amitriptyline include anticholinergic effects, sedation, weight gain, orthostatic hypotension, and conduction abnormalities. (See "Antidepressant medication in adults: Tricyclics and tetracyclics", section on Heterocyclic antidepressants).

Gabapentin — In an uncontrolled study, 21 patients with refractory genitourinary pain were treated with gabapentin at a dose of 300 to 1200 mg/day [16] . About one-half of the patients reported improvement in pain, including five of eight patients who had a diagnosis of IC. Anecdotal reports also suggest that pregabalin can be effective for pain relief in PBS/IC, but no formal studies support its use. (See "Antiepileptic drugs in the treatment of neuropathic pain").

Electrical stimulation therapy — Several reports support treatment of PBS/IC symptoms with implanted sacral neuromodulation (eg, InterStim device, Medtronic Inc, Minneapolis, MN). This device is FDA approved for treatment of urinary urgency and frequency, but not specifically for treatment of PBS/IC. The device consists of an implanted lead that lies along a sacral nerve root (usually at S3 level) and is attached to an implanted pulse generator. An uncontrolled study from a single center described 17 patients diagnosed with IC according to NIDDK criteria (show table 1) who received InterStim implants and were followed for an average of 14 months [17] . Mean daytime and nighttime voiding frequencies decreased from 17 and 9 to 4 and 1, respectively. Average pain rating decreased from 5.8/10 at baseline to 1.6/10 [17] . Another case series documented "moderate" or "marked" improvement in pain in 20 of 21 IC patients (NIDDK criteria) during one year of follow-up [18] .

InterStim is a costly procedure, and surgical revisions are relatively common. Adverse events include surgical site infections and pain, and reoperation for revisions at the lead or pulse generator site(s) is not uncommon.

Somatic therapy — Proponents of the theory that bladder symptoms are caused or maintained by somatic (body wall) abnormalities favor somatic therapies. At present, physical therapy is the only somatic therapy in routine use.

Physical therapy — Treatment of the somatic abnormalities in PBS/IC patients is not within the scope of training of most physical therapists, even those who are skilled in treatment of urinary incontinence. Resolution of the tender points, trigger points, connective tissue restrictions, and muscular abnormalities of the soft tissues requires specialized training in pelvic soft tissue manual manipulation and rehabilitation. The therapist may also suggest that manual therapy treatments be supplemented by heat or ice treatments.

Several case series have described symptom relief from manual physical therapies. As an example, one study reported that 70 percent of IC patients who were treated with manual physical therapy to the pelvic floor tissues for 12 to 15 visits experienced moderate to marked improvement [19] . Another study of 21 women with IC and associated pelvic floor hypertonicity demonstrated decreased symptom scores after five weeks of pelvic floor massage [20] . A randomized trial of physical therapies for treatment of PBS/IC is currently ongoing [15] .

Therapies directed at mast cells — Proponents of the theory that mast cells play a critical role in the development and/or maintenance of IC symptoms favor therapies directed at mast cells and allergic phenomena. These include:

Hydroxyzine and cimetidine — Until recently, the antihistamine hydroxyzine was a mainstay of IC treatment, with initial dosing of 10 mg in the evening [21] , increasing to 50 to 100 mg daily as needed. However, a randomized controlled trial found hydroxyzine had no benefit over placebo [22] .

Two small studies suggested benefit of treatment with cimetidine, an H2-receptor blocker, but clinical experience has not generally supported these smaller studies and cimetidine is not commonly used [23,24] .

Montelukast — The presence of leukotriene D4 receptors in human detrusor myocytes and increased urinary leukotriene E4 in patients with interstitial cystitis and detrusor mastocytosis suggest cysteinyl containing leukotrienes may have a role as proinflammatory mediators in this disease [25] . One small study of 10 women with interstitial cystitis (NIDDK criteria) and detrusor mastocytosis received a single dose of montelukast daily for three months [25] . After one month of montelukast treatment, there was a statistically significant decrease in 24-hour urinary frequency, nocturia and pain which persisted during the three months of treatment. After three months, 24-hour urinary frequency decreased from 17.4 to 12 voidings, nocturia decreased from 4.5 to 2.8 voidings, and pain decreased from 46.8 to 19.6 mm on a visual analog scale. No side effects were observed during treatment. Further investigation of this modality is required.

Dimethyl sulfoxide — (see "Intravesical dimethyl sulfoxide (DMSO)" above)

Immunomodulatory treatments — There is some current interest in exploration of immunomodulatory treatments for PBS/IC. In one trial, 64 patients were randomized in a 1:1 ratio to 1.5 mg/kg cyclosporine A twice daily or 100 mg PPS three times daily for six months [26] . Cyclosporine A was superior to PPS in all clinical outcome parameters measured: micturition frequency in 24 hours was significantly reduced (-6.7 +/- 4.7 versus -2.0 +/- 5.1 times) and the clinical response rate (according to global response assessment) was significantly higher for cyclosporine than PPS (75 versus 19 percent). Adverse effects of cyclosporine A include hair growth, gingival hyperplasia, paresthesias, abdominal pain, flushing and muscle pain.

Although intravesical instillation of bacillus Calmette-Guerin (BCG) triggers a variety of local immune responses and has an acceptable safety profile, it has not provided significantly greater relief of IC symptoms than placebo in randomized trials [27,28] .

INFORMATION FOR PATIENTS — Educational materials on this topic are available for patients. (See "Patient information: Painful bladder syndrome and interstitial cystitis" and see "Patient information: Treatment of painful bladder syndrome and interstitial cystitis"). We encourage you to print or e-mail these topics, or to refer patients to our public web site www.uptodate.com/patients, which includes these and other topics.

SUMMARY AND RECOMMENDATIONS — Painful bladder syndrome/Interstitial cystitis (PBS/IC) causes significant deterioration in quality of life, and there is no consensus on the optimal treatment. Several etiologies have been proposed, and clinicians tend to treat according to their belief about the pathophysiology of the disorder. Significant advances in treatment success are likely to depend on major advances in our understanding of the etiology of these disorders, and refinements in diagnosis. (See "Clinical features and diagnosis of painful bladder syndrome/interstitial cystitis").

Pentosan polysulfate sodium is the only oral treatment for IC approved by the FDA. Uncontrolled studies suggest modest benefit, in a minority of patients, but a randomized controlled trial suggested no benefit over placebo. (See "Pentosan polysulfate sodium" above).

Intravesical therapy with dimethyl sulfoxide is approved by the FDA, but is not in common clinical use due to associated pain and uneven clinical benefit. Intravesical therapy with heparin, lidocaine and/or pentosan polysulfate sodium is also used clinically, without strong evidence to support its use. (See "Intravesical heparin and lidocaine" above and see "Intravesical dimethyl sulfoxide (DMSO)" above).
Hydrodistension is primarily a diagnostic test, but may be considered for patients who obtain significant relief of symptoms after the procedure. (See "Hydrodistension" above).

Amitriptyline has clinical utility, probably acting as a nonspecific neuromodulatory agent that decreases the sensitivity of bladder sensory pathways. (See "Amitriptyline" above).

Sacral neuromodulation with implanted electrodes that lie along a sacral nerve root has shown significant benefit in uncontrolled studies, but is expensive and is not approved by the FDA for this indication. (See "Electrical stimulation therapy" above).

Physical therapy is directed at resolution of the tender points, trigger points, connective tissue restrictions, and muscular abnormalities of the soft tissues, but requires specialized training. (See "Physical therapy" above).

There is no good evidence showing that one treatment regimen is clearly superior to another. We suggest physical therapy for initial treatment of patients with PBS/IC (Grade 2C). We also suggest a trial of amitriptyline (Grade 2B). We start with 10 mg nightly and increase to 25 mg nightly as tolerated, in accordance with side effects and symptom relief. In our experience, it is only those women with the most severe symptoms who are willing to tolerate the side effects (eg, sedation and weight gain) that can be associated with amitriptyline use. When symptoms improve on this dual therapy, patients can usually discontinue amitriptyline while maintaining physical therapy, which is continued until their symptoms have resolved. We suggest sacral neuromodulation to patients who do not respond to physical therapy and/or amitriptyline (Grade 2C).