Journal of Clinical Endocrinology & Metabolism
, doi:10.1210/jc.2006-0740
The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 12 4743-4752
Copyright © 2006 by The Endocrine Society
Controversies Regarding Transdermal Androgen Therapy in Postmenopausal Women
Shehzad Basaria and
Adrian S. Dobs
Department of Medicine, Division of Endocrinology and Metabolism, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287
Address all correspondence and requests for reprints to: Adrian Dobs, M.D., M.H.S., 1830 East Monument Street, Suite 328, Baltimore, Maryland 21287. E-mail: adobs{at}jhmi.edu.
 |
Abstract
|
|---|
Context: Recently, the field of androgen therapy in postmenopausal women has received much attention and press. Although the ovary ceases to produce follicles and estrogen at menopause, it continues to produce androgens. Hence, many oophorectomized women complain of sexual dysfunction (despite adequate estrogenization). Previous studies of nontransdermal testosterone replacement have shown an improvement in libido and sexual frequency, although at the cost of supraphysiological testosterone levels. Transdermal testosterone patch (Intrinsa) was developed to deliver a physiological amount of testosterone. In 2004, the Food and Drug Administration voted not to approve Intrinsa until long-term safety data are available.
Evidence Acquisition: Recent trials of Intrinsa in postmenopausal women were included. A MEDLINE search was conducted for articles published over the last 40 yr based on the key words androgen therapy/replacement and postmenopausal women. Relevant placebo-controlled trials of nontransdermal androgen therapy in postmenopausal women were also reviewed.
Evidence Synthesis: Early results from industry-funded trials show that transdermal testosterone therapy results in only moderate (although statistically significant) improvement in libido in surgically menopausal women (on estrogen). However, the published data are of short duration (24 wk). Hence, long-term safety in these women remains unclear.
Conclusion: We recommend a short-term trial (not to exceed 24 wk) of transdermal testosterone therapy (once approved) in surgically menopausal (estrogenized) women with distressful sexual dysfunction. Until the patch gets approval, a short trial of oral methyltestosterone in deserving estrogenized women may be justified.
|
Introduction
|
|---|
IN DECEMBER 2004, the Advisory Board of the Food and Drug Administration (FDA) met to review the data from the clinical trials of transdermal testosterone replacement in postmenopausal women (oophorectomized and estrogenized) with decreased libido. The transdermal patch was manufactured by Procter & Gamble and was named Intrinsa. The data submitted were to evaluate the safety and efficacy of Intrinsa used over 18 months. Although the panel voted 14 to 3 in favor of its efficacy in the treatment of female hypoactive sexual desire, the panel did not approve the application based on inadequate long-term safety data. This decision by the FDA may have been influenced by two recent events. First, the recent results from the Heart Estrogen Replacement Study (1) and the Women’s Health Initiative study (2) have taught us humbling lessons regarding the cardiovascular complications of estrogen replacement in postmenopausal women (which is now essentially limited to the treatment of hot flashes and vulvo-vaginal atrophy). Because androgens are aromatized to estradiol, the FDA is obviously concerned about the long-term effects of androgen replacement in these women. Furthermore, there remain unsolved issues regarding the association of androgens and breast cancer (3, 4). Second, the FDA has recently come under the limelight after the cardiovascular complications of cyclooxygenase-2 inhibitors became apparent. Hence, the FDA demands long-term safety data before a new treatment, such as Intrinsa, can be approved.
In this review, we have attempted to provide an evidence-based summary regarding the role of androgen replacement in postmenopausal women. We have also tried to clarify some misconceptions regarding the physiology of androgen secretion in postmenopausal women and the factors contributing to sexual dysfunction. We also briefly review the safety concerns of androgen therapy. This article does not discuss the role of androgen therapy in premenopausal women and in women with hypogonadism due to premature ovarian failure, pituitary disease, HIV, and eating disorders.
|
Sexual Dysfunction in Women: Epidemiology
|
|---|
Because significant human and financial resources have been employed in the trials of androgen replacement in women with sexual dysfunction, it is important to review the magnitude of prevalence of these problems. A recent analysis of data from the National Health and Social Life Survey on 1749 women aged 18–59 yr showed the prevalence of sexual dysfunction to be 43% in the United States (5). This prevalence is much higher than in American men (31%). Although the androgen levels decline with aging, surprisingly, the results showed a decrease in the prevalence of sexual problems with advancing age (except vaginal dryness). A status of being separated, widowed, and divorced had a negative impact on sexual function. The survey also showed that black women are more likely to suffer from decreased libido than white or hispanic women.
It is known that aging and length of relationship adversely effect sexual function, with coital rate declining by 50% during the first year of marriage (6). To determine the influence of age and menopausal status on sexual function, an observational study evaluated menstruating premenopausal women and followed them into natural menopause (7). The authors found that both advancing age and menopausal status independently decreased sexual responsiveness. Indeed, menopausal transition itself increases the prevalence of sexual dysfunction from 42 to 88% (8). However, this dysfunction was more related to a decline in estradiol levels rather than androgen levels.
Another etiology of sexual dysfunction is hysterectomy (9), with 32–37% of women experiencing decreased sexual response even with intact ovaries. Some have suggested the surgical absence of a cervix as the reason for lack of pleasure because many women describe cervical pressure as the trigger mechanism for arousal. Furthermore, strong rhythmic, contractile movement of the uterus and cervix during intercourse (especially when the penis is in contact with the cervix), results in pleasure and orgasm. Because the vaginal walls are generally insensitive, the absence of cervix may explain the lack of arousal in hysterectomized women. Not all studies are in agreement. A study of 678 women, who had either undergone hysterectomy or oophorectomy, showed that women with preserved ovaries experienced less deterioration of overall sexual life (coital frequency and sexual intercourse) compared with oophorectomized women (10). This response was not influenced by age.
These observations suggest that the prevalence of sexual dysfunction is common among women and is influenced by age, race, menopausal status, hysterectomy, and status of relationship.
|
Androgen Physiology in Premenopausal Women
|
|---|
In women, there are two main sources of androgen production: the ovaries and the adrenal glands. The ovary is a highly complex endocrine organ. In premenopausal women, it is responsible for the production of ova, synthesis of estradiol in the granulosa cells (rich in enzyme aromatase, which converts testosterone and androstenedione to estradiol and estrone, respectively) and production of androgens (testosterone and androstenedione) from theca and hilar cells (11, 12). The LH stimulates theca cells resulting in production of testosterone and androstenedione, whereas the FSH stimulates aromatase in the granulosa cells, resulting in aromatization of androgens into estrogens. The serum estradiol levels in premenopausal women range between 50 and 260 pg/ml during the menstrual cycle. The adrenals produce dehydroepiandrosterone (DHEA) and its sulfated ester (DHEAS) from zona reticularis. Although these are most abundant steroids in the human circulation, they are weak androgens. They mainly act as a precursor of sex steroids with DHEA (not DHEAS) being converted in the periphery to testosterone [and dihydrotestosterone (DHT)] and estradiol. Approximately 80% of DHEA and 90% of DHEAS is produced by the adrenals (13). In premenopausal women, the production rate of total testosterone is 250 µg/24 h, with 25% coming directly from the ovaries and 75% from nonovarian sources (the adrenals and extraglandular conversion) (Fig. 1
). Similarly, 50% of androstenedione is contributed by the ovaries and the remaining by the adrenals, each accounting for 1.5 mg/24 h (total secretion, 3 mg/24 h) (14, 15).
View larger version (25K):
[in this window]
[in a new window]
|
FIG. 1. The contribution of the ovaries and the adrenals to serum androgen levels in pre- and postmenopausal women (adapted from Ref. 11 ). In premenopausal women, the direct adrenal contribution of testosterone is 50%, whereas the remaining 25% is derived from precursor androgens.
|
|
|
Androgen Physiology in Postmenopausal Women
|
|---|
Menopause changes sex hormone dynamics. The most important change is the sudden, complete, and permanent cessation of ovarian follicle formation, rendering a woman infertile. In addition, there is a definitive loss of estrogen synthesis, and serum estradiol levels fall to less than 30 pg/ml. After menopause, estrone becomes the dominant estrogen, mostly derived via aromatization of androstenedione (16). Although the postmenopausal ovary is an atrophic, wrinkled structure that loses its capacity to synthesize follicles and estradiol, the climacteric ovary continues to secrete a substantial amount of androgens. It has been known for three decades that the climacteric ovary contributes 50% of testosterone and 30% of androstenedione to the circulation (17). Indeed, the concentration of testosterone and androstenedione in ovarian veins of postmenopausal women is 15- and 4-fold higher, respectively, compared with peripheral vein concentration (18), and oophorectomy results in a significant decrease in these steroids (19). To the contrary, estradiol and estrone concentrations in the ovarian veins are only 2-fold higher, suggesting that estrogens in postmenopausal women are mainly synthesized in the periphery via aromatization. The production rate of testosterone in postmenopausal women is 180 µg/24 h, 50% of which comes from the ovary (Fig. 1
). Similarly, of the daily production of 1.5 mg/24 h of androstenedione, 20% comes from the ovary. Similar to premenopausal women, the adrenal glands remain the main source of DHEA and DHEAS production. This is confirmed by the fact that DHEA levels rise after ACTH stimulation and are suppressed with dexamethasone (17).
|
The Climacteric Ovary
|
|---|
As discussed above, the postmenopausal ovary continues to be a significant source of androgens. These androgens are synthesized in theca and hilar cells under the stimulation of LH, which is elevated in the postmenopausal state (12, 20, 21). Indeed, there is a significant decrease in testosterone levels when these women are treated with GnRH agonists (22, 23, 24). Although the data presented above are strong, some do not consider climacteric ovary to be a major source of androgen production and attribute most of the androgen production to the adrenals (25).
|
Androgens in Women: Influence of Aging and Natural vs. Surgical Menopause
|
|---|
Aging
Similar to men (26), women also experience an age-related decline in androgen production. A recent study evaluating 33 cycling women (age 21–51 yr) showed a steep decline in testosterone levels with age (27). In fact, women in their 40s had levels that were half the concentration seen in women in their 20s. Older premenopausal women (43–47 yr) also have a lesser midcycle rise in testosterone and androstenedione compared with younger women (19–37 yr) (28). Studies suggest no significant change in the metabolic clearance rate of testosterone with aging in women (29). Similarly, both DHEA and DHEAS levels decline with aging, without any influence of menopause (30).
Natural menopause
Many population-based studies have evaluated changes in sex hormones through menopausal transition. One study showed no changes in testosterone or DHEAS levels as a function of menopause, however, age was associated with a decline in both hormones (31, 32). Because SHBG levels decreased with age, there was a significant rise in free androgen index (FAI) (32). Interestingly, a cross-sectional study showed that in the seventh decade of life, an increase in testosterone level was seen that reached premenopausal levels (33). These findings were confirmed by a recent study showing the steepest decline in testosterone occurring in the early reproductive years followed by a plateau in midlife and then a minor rise (34). This shows that natural menopause is not associated with a decline in testosterone levels and that ovaries remain a major source of androgen production in postmenopausal women.
Surgical menopause
In contrast to natural menopause, surgical menopause does result in a significant decrease in androgen levels. Earlier studies evaluated pre- and postmenopausal women undergoing oophorectomy for endometrial cancer (19). In premenopausal women, serum androstenedione and testosterone declined by 50 and 57%, respectively. In the postmenopausal women, the decline was 21 and 54%. These observations are confirmed in recent epidemiological studies that report significant reduction in testosterone levels in women undergoing bilateral oophorectomy (33, 34).
The above observations suggest that the decline in androgen levels in women is a function of age rather than menopause. In other words, women achieve andropause and adrenopause before reaching menopause. In fact, FAI may even increase in the latter years. Hence, oophorectomized women may be the ideal candidates for androgen replacement.
|
Circulating Androgens and Its Correlates: Population Studies
|
|---|
Before reviewing the interventional trials of androgen replacement in postmenopausal women, it is important to evaluate the correlation between androgen levels and symptomatology in women. An earlier study in 100 surgically menopausal women (only four patients on estrogen) reported the following symptoms: depression (62%), insomnia (48%), low libido (46%), dyspareunia (38%), and hot flashes (28%) (35). Interestingly, the authors found no significant correlation between testosterone levels and vasomotor symptoms or depression. A recent cross-sectional study measured androgen levels in 1423 women (age 18–75 yr) reporting low libido and satisfaction (36). Total and free testosterone, androstenedione, and DHEAS were measured, and sexual function was evaluated by the Profile of Female Sexual Function (PFSF) questionnaire. No significant association was found between serum total testosterone, free testosterone, and androstenedione levels with any domain of sexual function (desire, arousal, orgasm, pleasure, concerns, responsiveness, or self-image) (36). Furthermore, the majority of women with low DHEAS did not have low sexual function. The authors concluded that there is no absolute cutoff level for androgens that defines female androgen insufficiency syndrome, and hence the levels do not aid in its diagnosis. Another study of 2961 young menstruating women (age 42–52 yr) also showed either weak or no association between androgens and sexual desire, arousal, or well-being after adjustment for age, ethnicity, abdominal obesity, physical activity, smoking, and mood (37).
Recently, it has been shown that circulating levels of testosterone and DHT may not reflect the true androgen status in women. Labrie et al. (38) have shown that administration of DHEA to postmenopausal women does not result in a significant increase in serum levels of testosterone or DHT, although there is a significant rise in their metabolites. This suggests that many target tissues possess enzymes that convert precursor androgens to active androgens and then into their metabolites (with active androgens never leaving the tissue). This phenomenon has been termed intracrinology. This suggests that DHEA and other precursor androgens may have an important role in sexual function in postmenopausal women, and serum testosterone concentration may not be a good correlate of sexual function.
These studies indicate that female sexual dysfunction is a complex, heterogeneous, and multifactorial condition that does not always correlate with serum testosterone levels. Hence, simply establishing thresholds of androgen level would not be adequate in diagnosing this syndrome.
|
Female Androgen Deficiency Syndrome: Diagnostic Criteria and Pitfalls
|
|---|
For decades, hypoandrogenism in women lacked clear definition or diagnostic criteria. Even in the recent past, this condition was loosely termed as female androgen deficiency syndrome (FADS) or hypoactive sexual desire disorder based on the criteria in Diagnostic and Statistical Manual IV (DSM-IV). On June 28 and 29, 2001, an international panel of experts from various fields (endocrinology, epidemiology, urology, obstetrics and gynecology, psychology, psychiatry, and women’s health) met in Princeton, NJ, to brainstorm and come up with diagnostic criteria for FADS. At the conclusion of the Princeton Consensus Conference, the group published three diagnostic criteria (39).
1) Clinical symptoms of androgen deficiency
The presence of symptoms is a prerequisite for the diagnosis of FADS. These include diminished well-being or dysphoric mood, persistent unexplained fatigue, and sexual dysfunction (decreased libido, responsivity, or pleasure). The committee also entertained vasomotor instability and decreased vaginal lubrication as additional symptoms of FADS. The experts, however, admitted that some of these symptoms are nonspecific and may be present in other common conditions (e.g. depression). Hence, clinical symptoms alone were deemed insufficient for the diagnosis.
2) Adequate estrogenization
Because the above-mentioned symptoms are not specific to FADS and may be seen with just estrogen deficiency, the panel decided that the diagnosis of FADS should be entertained only in estrogenized women (normally menstruating premenopausal women or postmenopausal women on estrogen).
3) Free testosterone
The free testosterone levels should be at or below the lowest quartile of the normal range for the reproductive age (20–40 yr) in conjunction with the other two criteria. The panel’s inability to establish precise quantitative cutoffs for free testosterone level was influenced by the lack of sensitive assays to measure free testosterone in women and lack of correlation between symptoms and androgen levels (discussed previously).
Pitfalls
Despite the Princeton criteria, pitfalls remain that create obstacles in the diagnosis of FADS. First, there is a paucity of normative data for free testosterone in women; hence, there are no well established quartiles available to which a symptomatic woman can be assigned. Most of these ranges are either established by commercial laboratories or based on smaller studies. Second, in most of the laboratories, free testosterone is measured by the tracer analog method. Although convenient and inexpensive, they remain inaccurate because they are influenced by SHBG concentrations (40). Hence, free testosterone should be measured by the more accurate equilibrium dialysis method. Furthermore, normative data should be established for equally accurate bioavailable testosterone (measured by the ammonium sulfate precipitation technique). These methods are cumbersome; however, if encouraged, they will be adopted by commercial laboratories. Third, although the committee recommended that the diagnosis of FADS be made in an estrogenized woman, ironically, oral estrogen administration causes a reduction in free testosterone levels by elevating SHBG concentration. Hence, some suggest switching the patient to transdermal estrogen or decreasing the dose of oral estrogen (and monitor symptoms) rather than initiating testosterone replacement. Similarly, in women with an intact uterus who are on a combined estrogen/progestin pill, one must ensure that the progestin is not an antiandrogen (e.g. drospirenone or cyproterone acetate). Antiandrogens like cimetidine, digitalis, and spironolactone should also be discontinued or substituted. Finally, if we consider testosterone replacement in all women who have sexual dysfunction or decreased well-being and happen to have free testosterone in the lowest quartile, a significant number will end up on androgen therapy (41). Hence, there is a tremendous need to use reliable testosterone assays and develop novel biological markers of androgen action in women. Furthermore, more focus should be directed toward specific patient populations that have a higher likelihood of androgen deficiency (Table 1).
|
Role of Estrogen Replacement on Sexual Life
|
|---|
Before discussing the efficacy of testosterone replacement on sexual function in menopausal women (natural or surgical), we briefly review some data on the role of estrogen replacement in these women. It has been known for sometime that although estrogen replacement in oophorectomized women improves vaginal dryness, vaginal atrophy and hot flashes, it does not restore libido (42). Nathorst-Boos and colleagues (43) studied three groups of hysterectomized women, 1) oophorectomized not receiving estrogen (n = 33), 2) oophorectomized receiving estrogen (n = 33), and 3) women with preserved ovaries (n = 35), and measured their sexual satisfaction and well-being. The total and free testosterone levels were higher in women with preserved ovaries than the other groups. The sexual life in oophorectomized women, irrespective of estrogen replacement, was worse than women with intact ovaries. These women experienced decreased libido and pleasure from coitus despite being estrogenized. However, these women did experience less anxiety and depression and improved well being than women not receiving estrogen (their scores comparable to women with intact ovaries). Another 12-wk study randomized 242 women with climacteric symptoms due to natural menopause to transdermal estradiol patch (twice a week) or placebo (44). After 12 wk, women in the estradiol group experienced improvement in sexual fantasies, degree of enjoyment, dysparunia, and vaginal lubrication; however, no improvement was seen in sexual desire, arousal, or orgasm. To determine the relative role of estrogen and testosterone on climacteric symptoms, Myers et al. (45) enrolled 40 naturally menopausal women (mean age, 58 yr) in a 10-wk study and randomized them to four treatment groups: conjugated equine estrogen (CEE) 0.625 mg/d, CEE 0.625 mg/d plus medroxyprogesterone acetate 5 mg/d, CEE 0.625 mg/d plus methyltestosterone 5 mg/d, and placebo. Although the improvement in hot flashes was significantly higher in the CEE only and CEE plus progesterone group (compared with testosterone and placebo groups), the increase in sexual frequency, pleasure and orgasm during masturbation was only seen in the estrogen plus testosterone group.
These results suggest that estrogen therapy alone does have beneficial effects on hot flashes, vaginal atrophy, dysparunia, lubrication, anxiety, depression, and sense of well-being. However, it does not improve libido and sexual enjoyment. Hence, it appears that androgens are necessary for libido and sexual pleasure. However, testosterone replacement should be initiated only in adequately estrogenized women. These data also raise questions regarding routine oophorectomy performed in women undergoing hysterectomy. This practice is based on an earlier survey showing a 10% reduction in annual ovarian cancer rate if all women over 40 yr of age underwent oophorectomy while undergoing pelvic surgery (46). This notion needs to be revisited in light of sexual dysfunction experienced by ovariectomized women.
|
Efficacy of Nontransdermal Testosterone on Sexual Health
|
|---|
The main impetus to the development of the transdermal testosterone patch was provided by earlier studies showing efficacy of testosterone replacement (nontransdermal) on female sexual health. These studies used various modalities of testosterone replacement including oral tablets, im injections and intraabdominal pellets. Although these studies showed significant improvement in sexual function in women on testosterone compared with those on estrogen and placebo, these modalities resulted in supraphysiological and unpredictable levels of testosterone (injections and pellets), whereas oral preparations resulted in an adverse lipid profile and were potentially hepatotoxic (methyltestosterone). Hence, these modalities are not ideal forms of androgen replacement. However, these trials opened the door for the manufacturing of transdermal agents. Some of these trials are listed in Table 2.
|
Transdermal Testosterone Patch: Rationale and Pharmacokinetics
|
|---|
Because prior studies of testosterone replacement were plagued by suboptimal modalities, there was a tremendous need for designing a delivery mode that was easy to use and achieved physiological levels. Hence, came an alcohol-free transdermal testosterone matrix patch that is applied twice weekly to the abdomen. Because serum half-life of testosterone is short, the patch provides a sustained delivery of testosterone. Because of the lipophilic nature of testosterone, it easily crosses the epidermis and reaches dermal capillaries, from where it is absorbed. The abdomen was chosen to be the site of application because the nongenital skin has less 5
-reductase activity (56), hence resulting in decreased production of DHT.
Patches were developed by Watson Laboratories (Salt Lake City, UT) in two doses, 150 µg (14-cm2 patch) and 300 µg (28-cm2 patch), to be applied twice a week. These doses correspond to 50 and 100% of the daily testosterone production rate in premenopausal women. The patches are translucent and contain testosterone, sorbitan monooleate (permeation enhancer), and a hypoallergenic acrylic adhesive in an alcohol-free matrix patch. The average testosterone content in the 150- and 300-µg patch is 4.1 and 8.2 mg, respectively. After application of the patch, the levels peak in 24 h and remain constant for about 96 h (delivering 150 and 300 µg, respectively, over 3–4 d) (57). Upon removal of the patch, the levels return to baseline within 12–24 h. A 150-µg patch results in an average increase in total testosterone and free testosterone of 27.6 ng/dl and 2.7 pg/ml, respectively. A 300-µg patch results in an increase in total and free testosterone levels of 51.4 ng/dl and 4.6 pg/ml, respectively. It is important to appreciate that concomitant use of oral estrogen replacement increases total testosterone levels while decreasing free testosterone levels (because of a rise in SHBG). Such effects are not seen with transdermal estrogen replacement.
|
The First Study with Transdermal Testosterone Patch
|
|---|
The first randomized, double-blind, placebo-controlled trial was published in September 2000 (58). The study was supported by Procter & Gamble Pharmaceuticals. This 12-wk study randomly assigned 75 surgically menopausal women (31–56 yr old) on 0.625 mg oral estrogen (for at least 2 months) to the 150- and 300-µg testosterone patch. All women had total testosterone less than 30 ng/dl and free testosterone less than 3.5 pg/ml (lower than the median values for premenopausal women). The majority of the women were Caucasian, and all women were in a heterosexual monogamous relationship for at least 1 yr. The mean total testosterone level increased from a baseline of 21 to 64 ng/dl and 102 ng/dl in the 150- and 300-µg groups, respectively. The corresponding increase in free testosterone (baseline, 1.1 pg/ml) was 3.9 and 5.9 pg/ml, respectively (normal range, 1.3–6.8 pg/ml). Sexual function (measured by the Brief Index of Sexual Functioning for Women) improved only in the 300-µg group, showing an increase in the scores of sexual thoughts, desire, frequency of activity, and pleasure-orgasm (compared with placebo). The results of various components of sexual function are summarized in Table 3. As for the Psychological General Well-Being Index, women in the 300-µg testosterone group also experienced significant improvement in scores for positive well-being and depressed mood compared with placebo. There were no differences in acne and hirsutism scores, lipid profile, complete blood counts, liver function tests, or fasting insulin and glucose concentration between the groups. However, the facial depilation rates increased in the 300-µg group.
Although the study was well conducted and the patches resulted in normal free testosterone levels, there were several limitations. First, the majority of women in this study were Caucasians. Hence, these data cannot be extrapolated to women of other ethnicities. Second, although the 300-µg dose resulted in improvement in sexual function, significant placebo effects were seen. Third, the improvement in sexual function, although statistically significant, was small in magnitude. Finally, although the overall side-effect profile was acceptable, four women withdrew from the study because of adverse effects (two developed anxiety and agitation, one application-site reaction, and one pink nipple discharge). These rates are significant considering there were only 75 women, and these small numbers could translate into large numbers if androgen replacement is approved for all such women.
|
Follow-Up Studies of Androgen Replacement with Testosterone Patch
|
|---|
After the initial study, three studies followed evaluating various doses of testosterone patch in a larger number of patients. All these studies were also supported by Procter & Gamble Pharmaceuticals. A phase-III multicenter, double-blind, placebo-controlled 24-wk trial of 533 surgically menopausal women on estrogen therapy soon followed to further judge the safety and efficacy of the 300-µg patch (59). Only the 300-µg patch was used because the original study showed the 150-µg patch not to be different from placebo (58). Women were recruited from 53 sites in Australia, Canada, and the United States. After randomization, 266 and 267 women were assigned to placebo and active group, respectively (206 and 211 women completed the study). The mean free testosterone level was 3.1 pg/ml (normal range, 0.9–7.3 pg/ml). Women receiving the testosterone patch had a mean increase of 1.56 satisfying episodes per month compared with 0.73 for placebo (P = 0.001). The median change from baseline was one satisfying episode per month compared with no increase in placebo. All domains of PFSF (desire, pleasure, arousal, orgasm, concerns, responsiveness, and self-image) showed significant improvement in the testosterone group. For the personal distress scores, measured by the Personal Distress Scale, although improved in both groups, the improvement in the testosterone group was significantly greater than placebo (P < 0.05). There were no significant differences between the groups in terms of hirsutism or acne scores, metabolic profile, hepatic profile, or blood counts. Although this study had a larger sample size and longer duration of therapy, the improvement in sexual activity, although again statistically significant, translated into one additional sexual event per month compared with baseline.
A recent double-blind, randomized, placebo-controlled, 24-wk parallel group trial evaluated three doses of testosterone patch (150, 300, and 450 µg) in 447 healthy women (age 24–70 yr) who were surgically menopausal for at least 1 yr and complained of distressful low sexual desire since surgery (60). This multicenter trial recruited women from 39 sites within the United States. Randomization was done to receive placebo (n = 119; completed = 81), 150-µg patch (n = 107; completed = 71), 300-µg patch (n = 110; completed = 81), or 450-µg patch (n = 111; completed = 85) twice a week. All women had a mean free testosterone level below the lower limit of the normal range of 0.9 pg/ml. At the end of the study, mean free testosterone increased to 2.15, 3.7, and 5.9 pg/ml in the 150-, 300-, and 450-µg groups, respectively. Overall, there was no significant linear dose-response relationship with sexual desire (P = 0.06) or sexual activity (P = 0.06). When evaluating scores for various domains in the PFSF scale, there was significant improvement in sexual desire and arousal only in the 300-µg group (no improvement in orgasm, pleasure, concerns, responsiveness, and sexual self-image). There was no significant improvement seen in any of the domains in the 150- or 450-µg group. The absolute frequency of satisfying sexual activity per week increased in all four groups compared with baseline, although statistical significance was achieved only in women in the 300-µg group. Although significant, this increase in the 300-µg group translated into an increase of 2.32 satisfying sexual episodes per month. There was no significant reduction in personal distress score in any of the testosterone groups compared with placebo. The adverse-effect profile was similar between the four groups. This study again confirmed a substantial placebo response, whereas the benefits, although statistically significant, resulted in minor improvement in sexual function (although it may still hold significance for these women). There was a significant placebo response, probably as a result of a psychological impetus to increase sexual activity because of wearing a patch. This trial confirmed that the 150-µg dose is subtherapeutic and no different from placebo. Interestingly, the 450-µg dose was not different from the 300-µg dose, probably suggesting that a 300-µg dose may be at the top of the dose-response curve for women. Finally, the trial confirmed that testosterone replacement in these doses is relatively safe for at least 24 wk. However, the authors correctly pointed out that long-term studies are needed to judge the safety of androgen replacement.
The final study of transdermal testosterone was published in late 2005. In this multicenter study (52 centers in Australia, Canada, and the United States), the investigators recruited 562 surgically menopausal women (age 26–70 yr) on estrogen and randomized them to placebo (n = 279) and 300-µg testosterone patch (n = 283) (61). The purpose of this 24-wk-long study was to compare the efficacy of the optimal dose of testosterone (300 µg) over placebo in terms of sexual function. The primary end point of the study was the change in the frequency of total satisfying sexual activity (a composite end point of a variety of sexual activities, e.g. intercourse, masturbation, etc.) at 24 wk. The women applied the patch twice weekly on the abdomen. In the testosterone group, there was a significant increase in free testosterone from 0.8 to 4 pg/ml (normal range, 0.9–7.3 pg/ml). Total testosterone and DHT levels also increased, whereas there was no change in estradiol or estrone levels. At the end of 24 wk, the total number of episodes of satisfying sexual activity per month significantly increased in the testosterone group compared with placebo (P = 0.0003). The women in the testosterone group experienced an increase of 2.10 episodes of total satisfying sexual activity per month compared with 0.98 episodes in the placebo group. A significant increase in sexual desire was also seen in the testosterone group (P = 0.0006). Furthermore, significant improvements were seen in all domains of PFSF in the testosterone group. Women in the active group also showed a decrease in personal distress scores (P = 0.0006). There were no significant differences in the side-effect profile among the groups. This study further confirmed that women in the testosterone group do experience improvement in sexual life (despite a placebo response) and do not develop significant side effects over a treatment period of 6 months; however, the efficacy and safety of these products over a long-term period remains a question.
|
Safety and Adverse Effects
|
|---|
The main concern of long-term testosterone replacement therapy in women is its safety. Although the detailed overview of known and potential adverse effects of androgen therapy in women is beyond the scope of this review, they have been recently reviewed elsewhere (3, 4) and are summarized in Table 4. Although the duration of testosterone therapy in clinical trials now extends to 18 months, long-term studies are needed to ensure safety of these women. There remain some contraindications to any form of androgen therapy in women (Table 5).
View this table:
[in this window]
[in a new window]
|
TABLE 4. Potential adverse effects of testosterone therapy in women (most of these occur with nontransdermal modalities)
|
|
|
Conclusions
|
|---|
Review of the data suggests that the decline in testosterone levels in women is a function of aging rather than natural menopause. In fact, postmenopausal women with intact ovaries may even experience an increase in FAI in the seventh decade of life. Hence, these women do not strictly qualify as being androgen deficient. Epidemiological studies show little correlation between symptoms of sexual dysfunction and androgen levels. Furthermore, the syndrome of FAD is still not objectively defined, and there is a tremendous need for using reliable testosterone assays (equilibrium dialysis) and novel biological markers of androgen deficiency in women. One thing, however, is clear: women undergoing surgical menopause do experience a significant decline in androgen levels. However, these women should be treated with estrogen first because many symptoms related to sexual dysfunction may improve (except libido) and result in overall improvement in quality of life.
Review of the data on transdermal testosterone therapy shows that the published studies are of short duration (maximum 24 wk), are sponsored by industry, and show statistically significant but modest benefits. Although in absolute terms the sexual benefits may appear modest, it should be emphasized that these small changes may make a substantial impact in the sexual life of these women. If an increase of one satisfying sexual event a month (although appears modest) improves the quality of life of a woman with androgen deficiency, then it should be accepted. It is the patients, not the physicians, industry, statisticians, or governmental organizations that decide what is significant. However, one thing is certain: these short-term studies fail to satisfy the scientific community regarding the potential side effects of long-term therapy. We have recently been humbled by the estrogen story in women. The current short-term studies of transdermal testosterone therapy show side effects of mild hirsutism and acne, although this does not address the potential effect of androgens on breast and endometrial tissue in long-term studies (62, 63). The same could be said about the possible role of androgens in the development of metabolic syndrome in women (64).
Based on the current evidence, we recommend only a short-term trial (not to exceed 24 wk) of transdermal testosterone therapy (once approved by the FDA) in only those surgically menopausal and estrogenized women who have distressful sexual dysfunction (until the patch is approved, a short trial of methyltestosterone in deserving patients may be justified). If there is no benefit after 24 wk of therapy, the treatment should be discontinued. We do not recommend generalized or long-term use of testosterone therapy in women until long-term data on safety and efficacy are available. Currently, there is extensive off-label use of testosterone gel in women. The difficulty in standardizing the dose to achieve, but not exceed, physiological testosterone levels is challenging and susceptible to abuse or accidental overuse. Hence, we do not support this practice. We hope that future trials of transdermal testosterone treatment in women would be funded by Federal sources and other organizations.
|
Footnotes
|
|---|
The authors declare no conflict of interest.
First Published Online September 19, 2006
Abbreviations: CEE, Conjugated equine estrogen; DHEA, dehydroepiandrosterone; DHEAS, dehydroepiandrosterone sulfate; DHT, dihydrotestosterone; FADS, female androgen deficiency syndrome; FAI, free androgen index; PFSF, Profile of Female Sexual Function.
Received April 5, 2006.
Accepted September 8, 2006.
|
References
|
|---|
- Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E 1998 Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/Progestin Replacement Study (HERS) Research Group. JAMA 280:605–613[Abstract/Free Full Text]
- Rossouw JE, Anderson GL, Prentice RL, La Croix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, Kotchen JM, Ockene J, 2002 Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 288:321–333[Abstract/Free Full Text]
- Basaria S, Dobs AS 2004 Safety and adverse effects of androgens: how to counsel patients. Mayo Clin Proc 79(Suppl 4):S25–S32
- Somboonporn W, Davis SR 2004 Testosterone effects on the breast: implications for testosterone therapy for women. Endocr Rev 25:374–388[Abstract/Free Full Text]
- Laumann EO, Paik A, Rosen RC 1999 Sexual dysfunction in the United States: prevalence and predictors. JAMA 281:537–544[Abstract/Free Full Text]
- James WH 1983 Decline in coital rates with spouses’ ages and duration of marriage. J Biosoc Sci 15:83–87[Medline]
- Dennerstein L, Dudley E, Burger H 2001 Are changes in sexual functioning during midlife due to aging or menopause? Fertil Steril 76:456–460[CrossRef][Medline]
- Dennerstein L, Randolph J, Taffe J, Dudley E, Burger H 2002 Hormones, mood, sexuality, and the menopausal transition. Fertil Steril 77(Suppl 4):S42–S48
- Zussman L, Zussman S, Sunley R, Bjornson E 1981 Sexual response after hysterectomy-oophorectomy: recent studies and reconsideration of psychogenesis. Am J Obstet Gynecol 140:725–729[Medline]
- Nathorst-Boos J, von Shoultz B 1992 Psychological reactions and sexual life after hysterectomy with and without oophorectomy. Gynecol Obstet Invest 34:97–101[Medline]
- Adashi EY 1994 The climacteric ovary as a functional gonadotropin-driven androgen-producing gland. Fertil Steril 62:20–27[Medline]
- Rinaudo P, Strauss 3rd JF 2004 Endocrine function of the postmenopausal ovary. Endocrinol Metab Clin North Am 33:661–674[CrossRef][Medline]
- Abraham GE 1974 Ovarian and adrenal contribution to peripheral androgens during the menstrual cycle. J Clin Endocrinol Metab 39:340–346[Abstract/Free Full Text]
- Adashi EY, Jones PB, Hsueh AJ 1981 Synergistic effect of glucocorticoids on the stimulation of progesterone production by follicle-stimulating hormone in cultured rat granulosa cells. Endocrinology 109:1888–1894[Abstract/Free Full Text]
- Arlt W, Justl HG, Callies F, Reincke M, Hubler D, Oettel M, Ernst M, Schulte HM, Allolio B 1998 Oral dehydroepiandrosterone for adrenal androgen replacement: pharmacokinetics and peripheral conversion to androgens and estrogens in young healthy females after dexamethasone suppression. J Clin Endocrinol Metab 83:1928–1934[Abstract/Free Full Text]
- Rannevik G, Jeppsson S, Johnell O, Bjerre B, Laurell-Borulf Y, Svanberg L 1995 A longitudinal study of the perimenopausal transition: altered profiles of steroid and pituitary hormones, SHBG and bone mineral density. Maturitas 21:103–113[CrossRef][Medline]
- Vermeulen A 1976 The hormonal activity of the postmenopausal ovary. J Clin Endocrinol Metab 42:247–253[Abstract/Free Full Text]
- Judd HL, Judd GE, Lucas WE, Yen SS 1974 Endocrine function of the postmenopausal ovary: concentration of androgens and estrogens in ovarian and peripheral vein blood. J Clin Endocrinol Metab 39:1020–1024[Abstract/Free Full Text]
- Judd HL, Lucas WE, Yen SS 1974 Effect of oophorectomy on circulating testosterone and androstenedione levels in patients with endometrial cancer. Am J Obstet Gynecol 118:793–798[Medline]
- Peluso JJ, Steger RW, Jaszczak S, Hafez ES 1976 Gonadotropin binding sites in human postmenopausal ovaries. Fertil Steril 27:789–795[Medline]
- Nakano R, Shima K, Yamoto M, Kobayashi M, Nishimori K, Hiraoka J 1989 Binding sites for gonadotropins in human postmenopausal ovaries. Obstet Gynecol 73:196–200[Medline]
- Sluijimer AV, Heineman MJ, De Jong FH, Evers JL 1995 Endocrine activity of the postmenopausal ovary: the effects of pituitary down-regulation and oophorectomy. J Clin Endocrinol Metab 80:2163–2167[Abstract]
- Crighton IL, Dowsett M, Lal A, Man A, Smith IE 1989 Use of luteinising hormone-releasing hormone agonist (leuprorelin) in advanced post-menopausal breast cancer: clinical and endocrine effects. Br J Cancer 60:644–648[Medline]
- Dowsett M, Cantwell B, Lal A, Jeffcoate SL, Harris AL 1988 Suppression of postmenopausal ovarian steroidogenesis with the luteinizing hormone-releasing hormone agonist goserelin. J Clin Endocrinol Metab 66:672–677[Abstract/Free Full Text]
- Couzinet B, Meduri G, Lecce MJ, Young J, Brailly S, Loosfelt H, Milgrom E, Schaison G 2001 The postmenopausal ovary is not a major androgen-producing gland. J Clin Endocrinol Metab 86:5060–5066[Abstract/Free Full Text]
- Kaufman JM, Vermeulen A 2005 The decline of androgen levels in elderly men and its clinical and therapeutic implications. Endocr Rev 26:833–876[Abstract/Free Full Text]
- Zumoff B, Strain GW, Miller LK, Rosner W 1995 Twenty-four-hour mean plasma testosterone concentration declines with age in normal premenopausal women. J Clin Endocrinol Metab 80:1429–1430[Abstract]
- Mushayandebvu T, Castracane VD, Gimpel T, Adel T, Santoro N 1996 Evidence for diminished midcycle ovarian androgen production in older reproductive aged women. Fertil Steril 65:721–723[Medline]
- Longcope C 1998 Androgen metabolism and the menopause. Semin Reprod Endocrinol 16:111–115[Medline]
- Zumoff B, Rosenfeld RS, Strain GW, Levin J, Fukushima DK 1980 Sex differences in the twenty-four-hour mean plasma concentrations of dehydroisoandrosterone (DHA) and dehydroisoandrosterone sulfate (DHAS) and the DHA to DHAS ratio in normal adults. J Clin Endocrinol Metab 51:330–333[Abstract/Free Full Text]
- Burger HG, Dudley EC, Hopper JL, Shelley JM, Green A, Smith A, Dennerstein L, Morse C 1995 The endocrinology of the menopausal transition: a cross-sectional study of a population-based sample. J Clin Endocrinol Metab 80:3537–3545[Abstract]
- Burger HG, Dudley EC, Cui J, Dennerstein L, Hopper JL 2000 A prospective longitudinal study of serum testosterone, dehydroepiandrosterone sulfate, and sex hormone-binding globulin levels through the menopause transition. J Clin Endocrinol Metab 85:2832–2838[Abstract/Free Full Text]
- Laughlin GA, Barrett-Connor E, Kritz-Silverstein D, von Muhlen D 2000 Hysterectomy, oophorectomy, and endogenous sex hormone levels in older women: the Rancho Bernardo Study. J Clin Endocrinol Metab 85:645–651[Abstract/Free Full Text]
- Davison SL, Bell R, Donath S, Montalto JG, Davis SR 2005 Androgen levels in adult females: changes with age, menopause, and oophorectomy. J Clin Endocrinol Metab 90:3847–3853[Abstract/Free Full Text]
- Chakravarti S, Collins WP, Newton JR, Oram DH, Studd JW 1977 Endocrine changes and symptomatology after oophorectomy in premenopausal women. Br J Obstet Gynaecol 84:769–775[Medline]
- Davis SR, Davison SL, Donath S, Bell RJ 2005 Circulating androgen levels and self-reported sexual function in women. JAMA 294:91–96[Abstract/Free Full Text]
- Santoro N, Torrens J, Crawford S, Allsworth JE, Finkelstein JS, Gold EB, Korenman S, Lasley WL, Luborsky JL, McConnell D, Sowers MF, Weiss G 2005 Correlates of circulating androgens in mid-life women: the study of women’s health across the nation. J Clin Endocrinol Metab 90:4836–4845[Abstract/Free Full Text]
- Labrie F, Belanger A, Cusan L, Candas B 1997 Physiological changes in dehydroepiandrosterone are not reflected by serum levels of active androgens and estrogens but of their metabolites: intracrinology. J Clin Endocrinol Metab 82:2403–2409[Abstract/Free Full Text]
- Bachmann G, Bancroft J, Braunstein G, Burger H, Davis S, Dennerstein L, Goldstein I, Guay A, Leiblum S, Lobo R, Notelovitz M, Rosen R, Sarrel P, Sherwin B, Simon J, Simpson E, Shifren J, Spark R, Traish A 2002 Female androgen insufficiency: the Princeton consensus statement on definition, classification, and assessment. Fertil Steril 77:660–665[CrossRef][Medline]
- Winters SJ, Kelley DE, Goodpaster B 1998 The analog free testosterone assay: are the results in men clinically useful? Clin Chem 44:2178–2182[Abstract/Free Full Text]
- Geiss IM, Umek WH, Dungl A, Sam C, Riss P, Hanzal E 2003 Prevalence of female sexual dysfunction in gynecologic and urogynecologic patients according to the international consensus classification. Urology 62:514–518[CrossRef][Medline]
- Utian WH 1975 Effect of hysterectomy, oophorectomy and estrogen therapy on libido. Int J Gynaecol Obstet 13:97–100[Medline]
- Nathorst-Boos J, von Schoultz B, Carlstrom K 1993 Elective ovarian removal and estrogen replacement therapy: effects on sexual life, psychological well-being and androgen status. J Psychosom Obstet Gynaecol 14:283–293[Medline]
- Nathorst-Boos J, Wiklund I, Mattsson LA, Sandin K, von Schoultz B 1993 Is sexual life influenced by transdermal estrogen therapy? A double blind placebo controlled study in postmenopausal women. Acta Obstet Gynecol Scand 72:656–660[Medline]
- Myers LS, Dixen J, Morrissette D, Carmichael M, Davidson JM 1990 Effects of estrogen, androgen, and progestin on sexual psychophysiology and behavior in postmenopausal women. J Clin Endocrinol Metab 70:1124–1131[Abstract/Free Full Text]
- Grundsell H, Ekman G, Gullberg B, Johnsson JE, Larsson G, Lindahl B, Moller T, Trope C 1981 Some aspects of prophylactic oophorectomy and ovarian carcinoma. Ann Chir Gynaecol 70:36–42[Medline]
- Dow MG, Hart DM, Forrest CA 1983 Hormonal treatments of sexual unresponsiveness in postmenopausal women: a comparative study. Br J Obstet Gynaecol 90:361–366[Medline]
- Burger HG, Hailes J, Menelaus M, Nelson J, Hudson B, Balazs N 1984 The management of persistent menopausal symptoms with oestradiol-testosterone implants: clinical, lipid and hormonal results. Maturitas 6:351–358[CrossRef][Medline]
- Sherwin BB, Gelfand MM 1985 Differential symptom response to parenteral estrogen and/or androgen administration in the surgical menopause. Am J Obstet Gynecol 151:153–160[Medline]
- Sherwin BB, Gelfand MM 1987 The role of androgen in the maintenance of sexual functioning in oophorectomized women. Psychosom Med 49:397–409[Abstract/Free Full Text]
- Davis SR, McCloud P, Strauss BJ, Burger H 1995 Testosterone enhances estradiol’s effects on postmenopausal bone density and sexuality. Maturitas 21:227–236[CrossRef][Medline]
- Sarrel P, Dobay B, Wiita B 1998 Estrogen and estrogen-androgen replacement in postmenopausal women dissatisfied with estrogen-only therapy. Sexual behavior and neuroendocrine responses. J Reprod Med 43:847–856[Medline]
- Dobs AS, Nguyen T, Pace C, Roberts CP 2002 Differential effects of oral estrogen versus oral estrogen-androgen replacement therapy on body composition in postmenopausal women. J Clin Endocrinol Metab 87:1509–1516[Abstract/Free Full Text]
- Floter A, Nathorst-Boos J, Carlstrom K, von Schoultz B 2002 Addition of testosterone to estrogen replacement therapy in oophorectomized women: effects on sexuality and well-being. Climacteric 5:357–365[Medline]
- Lobo RA, Rosen RC, Yang HM, Block B, Van Der Hoop RG 2003 Comparative effects of oral esterified estrogens with and without methyltestosterone on endocrine profiles and dimensions of sexual function in postmenopausal women with hypoactive sexual desire. Fertil Steril 79:1341–1352[CrossRef][Medline]
- Griffin JE, Allman DR, Durrant JL, Wilson JD 1981 Variation in steroid 5-reductase activity in cloned human skin fibroblasts. Shift in phenotypic expression from high to low activity upon subcloning. J Biol Chem 256:3662–3666[Abstract/Free Full Text]
- Mazer NA, Shifren JL 2003 Transdermal testosterone for women: a new physiological approach for androgen therapy. Obstet Gynecol Surv 58:489–500[CrossRef][Medline]
- Shifren JL, Braunstein GD, Simon JA, Casson PR, Buster JE, Redmond GP, Burki RE, Ginsburg ES, Rosen RC, Leiblum SR, Caramelli KE, Mazer NA 2000 Transdermal testosterone treatment in women with impaired sexual function after oophorectomy. N Engl J Med 343:682–688[Abstract/Free Full Text]
- Buster JE, Kingsberg SA, Aguirre O, Brown C, Breaux JG, Buch A, Rodenberg CA, Wekselman K, Casson P 2005 Testosterone patch for low sexual desire in surgically menopausal women: a randomized trial. Obstet Gynecol 105:944–952[Medline]
- Braunstein GD, Sundwall DA, Katz M, Shifren JL, Buster JE, Simon JA, Bachman G, Aguirre OA, Lucas JD, Rodenberg C, Buch A, Watts NB 2005 Safety and efficacy of a testosterone patch for the treatment of hypoactive sexual desire disorder in surgically menopausal women: a randomized, placebo-controlled trial. Arch Intern Med 165:1582–1589[Abstract/Free Full Text]
- Simon J, Braunstein G, Nachtigall L, Utian W, Katz M, Miller S, Waldbaum A, Bouchard C, Derzko C, Buch A, Rodenberg C, Lucas J, Davis S 2005 Testosterone patch increases sexual activity and desire in surgically menopausal women with hypoactive sexual desire disorder. J Clin Endocrinol Metab 90:5226–5233[Abstract/Free Full Text]
- Secreto G, Toniolo P, Berrino F, Recchione C, Cavalleri A, Pisani P, Totis A, Fariselli G, Di Pietro S 1991 Serum and urinary androgens and risk of breast cancer in postmenopausal women. Cancer Res 51:2572–2576[Abstract/Free Full Text]
- Bryan RM, Mercer RJ, Bennett RC, Rennie GC, Lie TH, Morgan FJ 1984 Androgen receptors in breast cancer. Cancer 54:2436–2440[CrossRef][Medline]
- Golden SH, Ding J, Szklo M, Schmidt MI, Duncan BB, Dobs A 2004 Glucose and insulin components of the metabolic syndrome are associated with hyperandrogenism in postmenopausal women: the atherosclerosis risk in communities study. Am J Epidemiol 160:540–548[Abstract/Free Full Text]
This article has been cited by other articles:
|
|
|
|
 
M. L. Walker and J. G. Herndon
Menopause in Nonhuman Primates?
Biol Reprod,
September 1, 2008;
79(3):
398 - 406.
[Abstract]
[Full Text]
[PDF]
|
|
|
Top
Abstract
Introduction
