- Email: [email protected]
Androgen therapy for low female libido
MOHAMAD S. MAHMOUD MD, et al.
Androgen therapy for low female libido © 2006 VIRGINIA FERRANTE
Libido—or sexual desire—can be affected by several factors. Sexual motivation, emotional intimacy and sexual skills of the couple, psychological and biological factors and sex hormones— including estrogens and androgens—all play roles. Decreased levels of androgens in late reproductive years contribute to the decline in sexual interest/desire in older women. Several investigators agree that androgens influence libido and behavior but not activity or response—such as lubrication and orgasm.
✒ KEY POINTS ■
Human sexual response doesn’t follow a linear model as once thought, rather the phases overlap and are complex.
■
Motivation to have sex (including increasing emotional intimacy, self-image and well-being) leads to subjective arousal, which triggers desire, leading to a responsive sexual arousal and orgasm and/or satisfaction.
■
Low libido is associated with the conditions that decrease the physiologic levels of androgens, such as oophorectomy, adrenal gland dysfunction or hypopituitarism.
■
Decreased testosterone levels are associated with loss of libido, fatigue and decreased feelings of well-being.
■
Androgen formulations are available—alone or in combination with estrogen—for treatment of low libido in women.
■
It is important to take a thorough sexual and general psychiatric history to exclude mental illness associated with sexual dysfunction, preoccupation with a life crisis, and/or core relationship problems and to find out whether the patient’s psychological profile is fairly intact.
Mohamad S. Mahmoud, MD Resident, Department of Obstetrics and Gynecology Oakwood Hospital and Medical Center Dearborn, MI
Michael P. Diamond, MD Professor, Department of Obstetrics and Gynecology Wayne State University Kamran S. Moghissi Professor Associate Chair, Department of Obstetrics and Gynecology Wayne State University Detroit, MI
Richard Balon, MD Professor, Dept Psychiatry Wayne State University Associate Director, Residency Training Detroit, MI © 2006 American Society for Reproductive Medicine Published by Elsevier Inc.
52 Sexuality, Reproduction & Menopause
T
he World Health Organization defineas sexual dysfunction as “the various ways in which an individual is unable to participate in a sexual relationship as he or she would wish.” In 1988, the Sexual Function Health Council of the American Foundation for Urologic Disease (AFUD) provided the first consensus–based definition of female sexual dysfunction (FSD). This classification divides FSD into 5 categories: hypoactive sexual desire disorder (HSDD), sexual aversion disorder, sexual arousal disorder (FSAD), female orgasmic disorder (FOD) and sexual pain disorder.1 This classification is based on the linear model of sexual response described by the work of Masters and Johnson and revised by Kaplan.2 In this model, Masters and Johnson assumed a linear progression from desire to arousal, meaning genital swelling and lubrication, to orgasm and resolution. Current data has in fact proven that human sexual response doesn’t follow such a linear model; the phases described rather overlap and are more complex.3 In the new model of the sex response cycle, motivation to have sex (including increasing emotional intimacy, self image and well being) leads to subjective arousal, which triggers desire, leading to a responsive sexual arousal and orgasm and/or satisfaction. There are two types of desire: innate desire, or desire preceded by some form of motivation.2 VOL. 4, NO. 2, OCTOBER 2006
Androgen therapy for low female libido Based on this new model, the new classification encompasses a wide spectrum of pathologies related to sexual function (see Table 1).3 The largest study done on FSD showed it affects 43% of women in the United States. This study based on the U.S. National Health and Social Life Survey of 1992 also found that among women with FSD, 51% had low libido. This makes it the most prevalent female disorder (22% of all women), followed by arousal problem (33%) and pain disorders (16%).4 Unfortunately, prevalence of the recently defined categories is largely unknown. The 51% of women with low libido in this survey are those with lack of initial spontaneous desire, which doesn’t constitute a sexual disorder by itself in the new definition. The role of estrogen deficiency in FSD has always been controversial: in fact some studies have found that estrogen deficiency was responsible for delayed or absent vaginal lubrication, decreased congestion of the vagina and reduced contractions with orgasm.2 Estrogen improved libido and orgasm in postmenopausal women,5 and systemic estrogen replacement improved vaginal lubrication, blood flow and vaginal compliance in menopausal women.6,7 However, others found that systemic estrogen alone was insufficient to cure symptoms of sexual dysfunction.8,9 Since oral estrogen can increase the level of sex hormone-binding globulins, the use of oral contraceptives containing estrogen, or oral estrogen alone, for menopausal symptoms can result in decreasing free testosterone levels.10
Androgen physiology, pharmacology and role in sexuality Androgens in women are made by the ovaries and the adrenal glands, and are partially regulated by the pituitary gland. The major androgens in women include: dehydroepiandrosterone–sulfate (DHEAS), androstenedione (A), testosterone (T), and dihydrotestosterone (DHT). Some would also include dehydroepiandrosterone (DHEA) as an androgen precursor. An anatomical presentation of the pathways of these androgens is given in Figure 1. Dehydroepiandrosterone–sulfate, DHEA and A are considered pro-androgens, because they need to be converted to T, the most potent androgen, to express their effect. The adrenal zona fasciculata produces 25% of circulating T and is regulated by adrenocorticoVOL. 4, NO. 2, OCTOBER 2006
T
he largest study on FSD showed it affects 43% of women in the United States.
tropic hormone (ACTH). The ovarian stroma, under the effect of leuteinizing hormone (LH), produces 25% of circulating T. The rest is produced by peripheral tissue conversion of circulating A.11 Testosterone in the plasma exists in three forms: free testosterone (FT), testosterone nonspecifically bound to albumin (AT), and testosterone specifically bound to sex hormone binding globulin (SHBG). The sum of FT and AT is referred to bioavailable testosterone. It is estimated that 66% of T is bound to SHBG and 1%–2% is estimated to be free or biologically available.12 There is enough evidence that the bioavailable fraction rather than total testosterone reflects the clinical miTABLE 1
Categories of female sexual dysfunction (FSD)* Type
Common symptoms
Sexual desire/ interest disorder
Feeling of sexual interest or desire, sexual thoughts or fantasies, and responsive desire are absent or diminished. Motivating reasons or incentives for attempting to become sexually aroused are scarce or absent. The lack of interest is beyond the normative lessening that may occur with life cycle and relationship duration.
Combined sexual arousal disorder
Absent or markedly reduced subjective sexual arousal (feelings of excitement, pleasure) from any type of stimulation, and absent or impaired genital sexual arousal (vulvar swelling, lubrication).
Subjective sexual arousal disorder
Absent or markedly reduced subjective sexual arousal (feelings of excitement, pleasure) from any type of stimulation. Vaginal lubrication and other signs of physical response still occur.
Genital arousal disorder
Absent or impaired genital sexual arousal: minimal vulvar swelling or vaginal lubrication from any type of sexual stimulation, and reduced sexual sensation from caresses of the genitalia. Subjective sexual excitement still occurs from non-genital sexual stimuli.
Persistent sexual arousal disorder
Spontaneous, intrusive and unwanted genital arousal (tingling, throbbing) when sexual interest or desire is absent. Any awareness of subjective arousal is typically but not invariably unpleasant. The arousal is unrelieved by orgasm, and the feelings persist for hours or days.
Orgasmic disorder
Despite self-report of high sexual arousal, orgasm from any kind of stimulation is lacking, markedly diminished in intensity or considerably delayed.
Vaginismus
Persistent or recurrent difficulties in allowing vaginal entry of a penis, finger or any object, despite the woman’s expressed wish to do so. There is often (phobic) avoidance; anticipation, fear of experience of pain; and variable involuntary contraction of pelvic muscles. Structural or other physical abnormalities must be ruled out.
Dyspareunia
Persistent or recurrent pain with attempted or complete vaginal entry or penile-vaginal intercourse.
*Adapted from reference 2.
Sexuality, Reproduction & Menopause 53
Androgen therapy for low female libido Pituitary regulation ACTH
LH
Adrenal zona fasciculata
T25%
T25%
A DHEAS
A
Ovarian stroma
Systemic circulation T50% T A T + 5α-reductase = DHT Target tissue
A T Peripheral tissue
© 2006 VIRGINIA FERRANTE
Figure 1. An anatomical presentation of the pathways of androgens in a woman’s body. ACTH = adrenocorticotropic hormone, LH = leuteinizing hormone, T = testosterone, A = androgen, DHEAS = dehydroepiandrosterone, DHT = dihydrotestosterone.
lieu. Moreover, the total testosterone level does not accurately reflect the bioavailable T, because the latter is dependent upon the concentration of binding globulins. Several methods can be used to measure bioavailable testosterone: FT can be measured using equilibrium dialysis to measure the apparent FT concentration (AFTC), which is the gold standard. Alternatively it can be measured by precipitation of SHBG with ammonium sulfate. Both methods are considered time consuming. Faster but less reliable methods are usually used: free androgen index (FAI), which is 100 T/SHBG, and immunoassay using an analog ligand (aFT).13 Plasma levels of total testosterone in women are 0.2–0.7 ng/mL (0.6–2.5 nmol/L). The level fluctuates with the phase of men-
54 Sexuality, Reproduction & Menopause
strual cycle, being highest at ovulation and lowest during the early follicular phase. It also has circadian variations with a peak in the early morning hours. Testosterone is converted to DHT in target tissues via the enzyme, 5α-reductase. Dihydrotestosterone is the principal ligand of testosterone to the androgen receptors (AR). Those receptors occur in the proximal and distal vagina and the clitoris. Androgens and estrogens regulate their expression. Testosterone can also be aromatized to estradiol (E2) in the central nervous system14 and, along with estrogen modulates cortical centers involved in the interpretation of sexual sensations. Both affect, via the release of neurotransmitters and neuromodulators, the sensitivity of genital organs and the hypothalamic-limbic structures.15 VOL. 4, NO. 2, OCTOBER 2006
Androgen therapy for low female libido In mice, there is evidence of an indirect effect of androgens on the brain via aromatization to estrogens, whereas in women, even though it is known that androgen and estrogen receptors are present throughout the brain, it is not yet clear whether androgens have a direct effect on the brain or whether the effects occur after the aromatization of androgen to estrogen.16 It has been suggested that free T relates to sexual desire and masturbation in young women.17 In women reporting low libido following menopause, 5αreductase activity is significantly impaired.18 Serum androgens decline in women for several reasons. Advancing age promotes a decline of the level of circulating androgens (free testosterone, total testosterone, DHEA, and DHEAS). This is caused by the decrease in adrenal and ovarian production of androgen in older women.19 Physiologic menopause
leads to decreased ovarian A synthesis, which leads to decreased levels of testosterone produced by peripheral conversion of A.14 Surgical or chemical ovariectomy (by GnRH antagonists, radiotherapy and exogenous estrogens administration) can reduce both testosterone and androstenedione by 50%. Oral contraceptive pills and oral estrogen can also decrease androgen levels by suppressing LH secretion and increasing the level of sex hormone binding globulins (SHBG).20,21 Glucocorticosteroids can also reduce adrenal androgen production by suppressing ACTH production.22 It is well known that low libido is associated with the conditions that decrease the physiologic levels of androgens such as oophorectomy,23 adrenal gland dysfunction or hypopituitarism.24 Decreased testosterone levels are associated with loss of libido, fatigue
Androgen formulations Androgens are available in the following forms: oral methyltestosterone, micronized testosterone, DHEA, topical testosterone ointment, intramuscular testosterone injections, testosterone implants and testosterone patches. All—alone or in combination with estrogen—can used for treatment of low libido in women. However none of these preparations has been approved by the FDA for female hypoactive sexual disorder and thus their use is considered off-label. Unique characteristics of these individual agents follow. Methyltestosterone Methyltestosterone is available in doses of 1.25 or 2.5 mg/day. It is well-absorbed orally and is available in a fixed-dose combination product with esterified estrogens (0.625 mg/day or 1.25 mg/day).9 Its use for FSD have been associated with a significant decrease in high density lipoprotein (HDL) cholesterol level, increased ratio of total cholesterol to HDL cholesterol, but significant decrease in triglyceride levels.10,35,36 Although there exist health concerns regarding high dose methyltestosterone on hepatic enzymes and blood pressure, there are little data to support convincingly the detrimental effects of low-dose methyltestosterone on these endpoints.36 Injectable testosterone Injectable testosterone is available as testosterone esters (cypionate, propionate, and enanthate) and are administered 25–50 mg intramuscularly every 2–4 weeks.
VOL. 4, NO. 2, OCTOBER 2006
The injections can be painful and the formulations may result in extreme fluctuations in androgen levels.11 Testosterone implants Testosterone implants are available in a 50-mg pellet, which are placed alone or in a pair every 3 months, requiring a minor surgical procedure. Depending on the number of implants inserted, they can result in supraphysiological dosing.37 Topical testosterone Topical testosterone can be compounded to any strength in an absorbent medium and is applied to the inner thigh and inner arm. Despite its popularity, there are few good studies of this application.38 Testosterone patch Testosterone is available in 300-µg patches for men applied once daily. It achieves supraphysiologic plasma levels and, as of this writing, haven’t lead to significant changes in the mean levels of lipids, lipoproteins, and other metabolic markers.27,30 A lower dosage patch is under development for women. DHEA Dehydroepiandrosterone, a popular over-the-counter supplement, is available in 25-mg and 50-mg tablets and can be used in women with Addison’s disease. This treatment produces a physiologic serum level of androgens and no significant side effects at these doses.31,33,34,39,40
Sexuality, Reproduction & Menopause 55
Androgen therapy for low female libido
T
here are two types of desire: innate desire, or desire preceded by some form of motivation. and decreased feelings of well-being.25 In a cross-sectional study, six hundred eighty-four women, ages 50–89 years, were surveyed for hysterectomy and oophorectomy status and had plasma obtained between 1984–1987. They found that total and bioavailable (nonSHBG-bound) testosterone levels were 4050% reduced in bilaterally oophorectomized postmenopausal women compared to those in intact women26 leading to decreased libido in 30% to 50% of those patients.14,26,27 Since our ability to measure free testosterone accurately in the range normally found in women is limited, it is generally considered inappropriate to treat a woman with low level of testosterone unless she complains of low libido.13,28
T
he androgen regimens currently used in postmenopausal women haven’t been shown to possess high risk in most women, and are felt by many to provide significant benefit encompassing sexual health. Testosterone and low libido The role of androgens in female sexuality has been addressed since the 1940s by Greenblatt et al.29 Many studies have been published since the Greenblatt study with mostly inconclusive results. Most of those reports were retrospective, uncontrolled and used unsystematic methods of data collection. Several new, more methodologically sophisticated studies have been recently published and our review focuses mostly on those. The majority of those studies have been done on postmenopausal women (surgically or naturally) receiving or not concomitant estrogen replacement therapy. The sudden and uniform decrease of plasma levels of androgen and estrogen provided in fact a unique opportunity for studying the effect of those steroids on sex behavior. Sherwin et al found that surgically menopausal women who received supraphysiologic doses of testosterone enanthate adminis-
56 Sexuality, Reproduction & Menopause
tered intramuscularly alone or with estrogen had significantly higher scores for sexual desire, fantasies and arousal compared to women who received estrogen alone. The effect on the frequency of coitus and orgasm was not significant.10 Lobo et al found that in healthy postmenopausal women (natural or surgical > 6 months) methyltestosterone treatment results in improvement in sexual interest or desire partially by decreasing the levels of SHBG, leading to increased bioavailable testosterone, and possibly by a direct effect of methyltestosterone acting as androgen. They also concluded that the combined treatment wasn’t associated with a clinically significant change in acne and hirsutism.9 Shifren et al found that the 300-µg testosterone patch significantly increased the scores for thoughts, i.e., desire; frequency of sexual activity, and orgasm compared to placebo in surgically menopausal women.8 SR Davis et al found that the addition of testosterone to estradiol in postmenopausal women resulted in significantly greater improvement compared to estradiol alone for sexual activity (p < 0.03), satisfaction (p < 0.03), pleasure (p < 0.01), orgasm (p < 0.035) and relevancy (p < 0.05). They concluded that the addition of testosterone has therapeutic effect for dimished libido in postmenopausal women.28 S Davis et al found a statistically significant increase in the sexual desire score of the profile of female sexual function (PFSF) compared with the placebo group (p < 0.05) as well as change in other domains of the PFSF including orgasm, sexual arousal, sexual responsiveness, sexual self image and sexual concerns, and significant reduction in personal distress in surgically menopausal women using 300-µg/day testosterone transdermal patch.30 Buster et al found a significant improvement of all seven domains of sexual function, including sexual desire, pleasure, arousal, orgasm, concerns, responsiveness and self image, in surgically menopausal women using 300-mg testosterone.27 Their data agree with other clinical findings that high physiologic/ low supraphysiologic doses of testosterone improve several aspects of sexual function in postmenopausal women with FSD—precisely low libido. The majority of the aforementioned studVOL. 4, NO. 2, OCTOBER 2006
Androgen therapy for low female libido
TABLE 2
Testosterone studies Duration of study
Scale used to measure sexual function
Monthly testosterone enanthate injection
8 months
Daily menopausal rating scale (DMRS)
Crossover
218
1.25 mg of methyltestosterone
16 weeks
Sexual interest questionnaire (SIQ)
Double-blind randomized clinical trial
Shifren et al8
75
150-mg/300-µg testosterone patches
12 weeks
Brief index of sexual functioning for women (BISF-W)
Randomized clinical trial
SR Davis et al28
34
50-µg testosterone implant
2 years
Sabbatsberg sexual self-rating scale
Single-blind randomized clinical trial
S Davis et al30
77
300-µg testosterone transdermal patch
24 weeks
Profile of female sexual function (PFSF)
Double-blind randomized clinical trial
Buster et al27
533
300-µg testosterone transdermal patch
24 weeks
PFSF and the personal distress scale
Double-blind randomized clinical trial
Investigator
N
Testosterone form
Sherwin et al10
43
Lobo et al9
ies used different validated and nonvalidated instruments and scales to measure the effect of androgen on sexual function. The effectiveness and value of those scales to measure low libido, even though used by several studies, is questionable. Also the measurement of the different serum testosterone fraction varied from one study to another, which makes it even harder to compare those studies (see Table 2).
Dehydroepiandrosterone and low libido Patients with Addison’s disease usually have a chronic deficiency in DHEA, because their treatment focuses on glucocorticoides and mineralocorticoides and neglects the androgen deficiency. Dehydroepiandrosterone is transformed into potent androgens in various tissues; therefore its replacement may be important in women suffering from Addison’s disease.31 In this randomized crossover study, nine women with normal baseline DHEA underwent adrenal suppression of DHEA with dexamethasone to levels found in Addison’s disease and were randomly assigned to receive 50 mg or 100 mg oral capsules of DHEA. The administration of 50 mg of DHEA was sufficient to restore the serum concentration of DHT and ADG to nonsupressed baseline levels, whereas 100 mg DHEA was required to fully restore A and T concentrations to baseline. A dose of 100 mg/day induces supraphysiological levels of DHEA in these women. The investigators concluded that a daily dose of 50 mg DHEA is a suitable replacement therapy in females with adrenal androgen deficiency.31 VOL. 4, NO. 2, OCTOBER 2006
Type of study
In the randomized clinical trial conducted by Lovas et al, 39 women aged between 18 and 70 years with confirmed primary or secondary adrenal failure were randomized to receive 25 mg of oral DHEA versus placebo for 9 months. They found that 25 mg DHEA was enough to produce physiologic serum levels of androgen in patients with Addison’s disease but did not have any significant effect on sexual function.32 The same result was found in the randomized crossover clinical trial done by Hunt et al using a daily 50 mg dose of DHEA for 12 weeks. The treatment corrected the deficiency of DHEA and DHEAS, achieving normal range of those hormones, with T levels at the lower end of the normal range. However, there was no significant difference in any of the indices for sexual interest compared to placebo.33 In contrast, Arlt et al conducted a doubleblind, placebo-controlled, crossover study on 24 women with adrenal insufficiency. Women received in a random order 50 mg of oral DHEA daily for 4 months versus placebo. The investigators concluded that replacing DHEA in women with adrenal insufficiency improves sexual desire as a direct effect of DHEA on the nervous system, an increase of peripheral androgen synthesis or both.34
Side effects and safety of androgen therapy Side effects of androgen therapy can be divided into two categories: early reversible side effects that encompass acne, skin oiliness, hirsutism and menstrual irregularities; and late Sexuality, Reproduction & Menopause 57
Androgen therapy for low female libido irreversible side effects of virilisation including male-pattern baldness, hirsutism, voice changes and hypertrophy of the clitoris. These late side effects have been reported primarily in supraphysilogical doses of androgen, especially those doses used in men. However, the androgen regimens currently used in postmenopausal women haven’t been shown to possess high risk in most women, and are felt by many to provide significant benefit, encompassing sexual health.8,9,27,41 However, all patients should be aware of the possibility of side effects whenever androgen replacement is administered. They should be aware that prolonged use of high doses of certain androgens (17α-alkyl androgens like methyltestosterone) have been associated with serious hepatic adverse effects: peliosis hepatis, hepatic neoplasms, cholestatic hepatitis and jaundice. Peliosis hepatis can be
P
rolonged use of high doses of certain androgens (17α-alkyl androgens like methyltestosterone) have been associated with serious hepatic adverse effects: peliosis hepatis, hepatic neoplasms, cholestatic hepatitis, and jaundice. a life-threatening or fatal complication. Longterm therapy with testosterone enanthate, which elevates blood levels for prolonged periods, has produced multiple hepatic adenomas. Testosterone is not known to produce these adverse effects. Edema with or without congestive heart failure may be a serious complication in patients with preexisting cardiac, renal or hepatic disease. Diuretic therapy may be required in addition to discontinuation of the drug. In patients with breast cancer, androgen therapy may cause hypercalcemia by stimulating osteolysis. In this case, the drug should be discontinued. Although there are rare reports of hepatocellular carcinoma in patients receiving long-term therapy with androgens in high doses, withdrawal of the drugs did not lead to regression of the tumors in all studied cases. Hemoglobin and hematocrit levels should be checked periodically in patients on long-term androgen therapy to de-
58 Sexuality, Reproduction & Menopause
tect the possible side effect of polycythemia. Also liver function, cholesterol and high-density lipoprotein should be checked periodically to rule out any hepatic disorder.42 Finally, further studies need to be done in order to evaluate the long-term side effects of androgen replacement therapy in women.
Conclusion Evidence agrees that supraphysiologic doses of testosterone improve the desire/interest and pleasure of sexual experience in surgically postmenopausal women. However, sexual function is complex and depends on more than hormones. It is very possible for postmenopausal women with low androgen levels to have fulfilling sexual lives. The reverse, that is women with healthy levels of hormones having unsatisfactory sexual lives, is also true. Before embarking on any treatment for low libido, it is important to take a thorough sexual and general psychiatric history to exclude mental illness associated with sexual dysfunction, preoccupation with a life crisis and/or core relationship problems and to find out whether the patient’s psychological profile is fairly intact. As Levine suggested, it may be useful to conceptualize libido/sexual desire as consisting of drive (biological, mostly hormones), motive (individual and relationship psychology), and wish (cultural) components.43 Further variables affecting libido include age, social situation, and health.43 Thus, though hormones play an important role in sexual desire, they are only part of the entire story. Nevertheless, assessing the effect of testosterone and other androgens in premenopausal women could help improve our understanding of the role of androgens in female sexuality and sexual desire. The ideal androgen preparation to be used in treating low sexual desire in women would be the one that combines safety and efficacy and would maintain androgen levels reliably within the female normal range. The most effective therapeutic formulation remains to be defined. Sensitive instruments designed specifically to assess sexual function in postmenopausal women are lacking, and the aspects of sexual function measured by the interventions have been unspecified. Few data have been published concerning the longterm effects of androgen substitution in women; therefore the long-term safety of this treatment is still unknown. ■ VOL. 4, NO. 2, OCTOBER 2006
Androgen therapy for low female libido REFERENCES 1. Basson R, Berman J, Burnett A, et al. Report of the international consensus development conference on female sexual dysfunction: definitions and classifications. J Urol 2000;183:888-893. 2. Masters EH, Johnson VE. Human sexual response. Boston: Little, Brown; 1966. 3. Basson R. Women’s sexual dysfunction: revised and expended definition. CMAJ 2005;172(10):1327-1333. 4. Laumann EO, Paik A, Rosen RC. Sexual dysfunction in the United States: prevalence and predictors. JAMA 1999;281:537-544. 5. Sarrel PM. Sexuality and menopause. Obstet Gyneol 1990;7(5):26S-30S. 6. Semimons JP, Wagner G. Estrogen deprivation and vaginal function in postmenopausal women. JAMA 1982;248:445-448. 7. Berman JR, Berman LA, Werbin TJ, et al. Clinical evaluation of female sexual function: effects of age and estrogen status on subjective and physiologic sexual responses. Int J Impotence Res 1999;11:S31-S38. 8. Shifrin JL, Braunstein GD, Simon JA, et al. Transdermal testosterone treatment in women with impaired sexual function after oophorectomy. N Engl J Med 2000;343:682-688. 9. Lobo RA, Rosen C, Yang HM, Block B, van der Hoopp RG. 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 2003; 79(6):1341-1352. 10. Sherwin BB, Gelfand MM, Brender W. Androgen enhances sexual motivation in females: a prospective, crossover study of sex steroid administration in the surgical menopause. Psychosom Med 1985;47: 339-351. 11. Langcope C. Adrenal and gonadal androgen secretion in normal females. Clin Endocrinol Metab 1986;15:213-227. 12. Davison SL, Davis SR. Androgens in women. Journal of steroid biochemistry and molecular biology 2003;85(2003):363-366. 13. Vermeulen A, Verdonck L, Kaufman JM. A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab 1999;83(10):3666-3672. 14. Abraham GE. Ovarian and adrenal contribution to peripheral androgens during the menstrual cycle. J Clin Endocrinol Metab 1975;39: 340-346. 15. Nappi RE. Meanopause e sessualita. CIC, Roma, 2002. 16. Apperloo MJ, Van Der Stege JG, Hoek A, Weijmar Schultz WCM. In the mood for sex: the value of androgens. Journal of sex and marital therapy 2003;29(2):87-102. 17. Vermeulen A. Plasma androgens in women. J Reprod Med 1998;43: 725-33. 18. Kennedy RG, Davies T, Al-azzawi F.sexual interest in postmenopausal women is related to 5-alpha-reductase activity. Hum Reprod 1997;12:209-13. 19. Mushayandebvu T, Castracane DV, Gimbel T, Adel T, Santoro N. Evidence for diminished mid-cycle ovarian androgen production in older reproductive aged women. Fertil Steril 1996;65:721-723. 20. Mathur RS, Landgreve SC, Moody LO, Semmens JP, Williamson HO. The effect of estrogen treatment on plasma concentrations of steroid hormones, gonadotropins, prolactin and sex hormone-binding globulin in post-menopausal women. Maturitas 1985;7:129-133. 21. Krug R, Psych D, Petrowsky R, Fehm HL, Born J. Selective influence of menstrual cycle on perception of stimuli with reproductive significance. Psychom Med 1994;56:410-417. 22. Abraham GE. Ovarian and adrenal contribution to peripheral androgens during the menstrual cycle. J Clin Endocrinol Metab 1974;39: 340-346. 23. Shifren JL. Androgen deficiency in the oophorectomized woman. Fertil Steril 2002;77(S4):S60-S62. 24. Rannevik G, Jeppsson S, Johnell O, Bjerre B, Laurell-Borulf Y, Svanberg L.A Longitudinal study of the perimenopausal transition: altered
profiles of steroid and pituitary hormones, SHBG and bone mineral density. Maturitas 1995;21:103-113. 25. Sherwin BB. Changes in sexual behavior as a function of plasma sex steroid levels in post-menopausal women. Maturitas 1985;7:225-233. 26. Laughlin GA, Barrett-Connor E, Kritz-Silverstein D, von Muhlen D. Hysterectomy, oophorectomy, and endogenous sex hormone levels in older women: the Rancho Bernardo Study. J Clin Endocrinol Metab 2000;85:645-51. 27. Buster JE, Kingsberg SA , Aguirre O, Brown C, Breaux JG, Buch A, Rodenberg CA, Wekselman K, Casson P. Testosterone Patch for Low Sexual Desire in Surgically Menopausal Women: A Randomized Trial. Obstet Gynecol 2005;105:944-952. 28. Davis S. Androgen replacement in women: a commentary. J Clin Endocrinol Metab 1999;84:1886-1891. 29.Greenblatt RB. Androgenic therapy in women. J Clin Endocrinol Metab 1942;2:665-666. 30. Davis S, Rees M, Ribot C, Moufarege A, Rodenberg C, Purdie D. Efficacy and safety of testosterone patches for the treatment of low sexual desire in surgically menopausal women. Fertil Steril 2003;80(suppl 3):S76. Abstract O-199. 31.Wiebke Arlt, Hans-georg justl, Frank Callies, Martin reincke, Doris Hubler, Michael Ottel, et al. 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 1998;8(6):1928-1934. 32. Lovas K, Gebre-Medhin G, Trovic TS, et al. Replacement of dehydtroepiandrosterone in adrenal failure: no benefit for subjective health status and sexuality in a 9 month, randomized, parallel group clinical trial. J Clin Endocrinol Metab 2003;88(3)1112-1118. 33. Hunt PJ, Gurnell EM, Huppert FA, et al. Improvement in mood and fatigue after Dehydroepiandrosterone replacement in Addison’s disease in a randomized, double blind trial. J Clin Endocrinol Metab 2000;85 (12):4650-4656. 34. Arlt W, Callies F, Van vlijmen JC, et al. Dehydroepiandrosterone replacement in women with adrenal insufficiency. N Engl J Med 1999;342: 1013-1020. 35. Barrett-Connor E, Young R, Notelovitz M, Sullivan J, Wiita B, Yang HM, Nolan J. A two-year, double blind comparison of estrogen-androgen and conjugated estrogens in surgically menopausal women. Effects on bone density, symptoms and lipid profiles. J Reprod Med 1999;44: 1012-1020. 36. Gitlin N, Korner P, Yang HM. Liver function in postmenopausal women on estrogen-androgen hormone replacement therapy: A metaanalysis of eight clinical trials. Menopause 1999;6:216-224. 37. Davis SR, McCloud P, Strauss BJ, Burger H. Testosterone enhances estradiol’s effects on postmenopausal bone density and sexuality. Maturitas 1995;21:227-236. 38. Rust J, Gomlombok S. The GRISS: a psychometric instrument for the assessment of sexual dysfunction. Arch Sex Behav 1986;15:157-165 39. Casson PR, Anderson RN, Herrod HG, et al. Oral dehydroepiandrosterone in physiologic doses modulates immune function in postmenopausal women. Am J Obstet Gynecol 1993;169:1536-1539. 40. Young J, Couzinet B, Nahoul K, et al. Panhypopituitarism as a model to study the metabolism of dehydroepiandrosterone (DHEA) in humans. J Clin Endocrin Metab 1997;82:2578-2585. 41. Casson PR, Faquin LC, Stentz FB, et al. Replacement of dehydroepiandrosterone enhances T-lymphocyte insulinebinding in postmenopausal women. Fertil Steril 1995;63:1027-1031. 42. Simon JA. Safety of estrogen/androgen regimens. J Reprod Med 2001;46(3 Suppl):281-390. 43. PDR 2005. 44. Levine SB. The nature of sexual desire: a clinician’s perspective. Archives of Sexual Behavior 2003;32:279-285.
Mohamad S. Mahmoud, MD Resident, Department of Obstetrics and Gynecology Oakwood Hospital and Medical Center Dearborn, MI 48123 mohamadmahmoud @yahoo.com
Michael P. Diamond, MD Professor, Department of Obstetrics and Gynecology Wayne State University Kamran S. Moghissi Professor Associate Chair, Department of Obstetrics and Gynecology Wayne State University Detroit, MI 48201 [email protected]
Richard Balon, MD Professor, Dept Psychiatry Wayne State University Associate Director, Residency Training Detroit, MI 48207 [email protected]
Disclosures Dr Diamond has disclosed the following contractual support relationships: Serono, TAP, GSK, Wyeth, Merck, and Pfizer; and the following consulting relationships: Serono, Genzyme, and Kytogenics. Dr. Balon has disclosed the following relationships: lecturer, GSK; Consultant, Shire Pharmaceuticals. VOL. 4, NO. 2, OCTOBER 2006
Sexuality, Reproduction & Menopause 59
Androgen therapy for low female libido © 2006 VIRGINIA FERRANTE
Libido—or sexual desire—can be affected by several factors. Sexual motivation, emotional intimacy and sexual skills of the couple, psychological and biological factors and sex hormones— including estrogens and androgens—all play roles. Decreased levels of androgens in late reproductive years contribute to the decline in sexual interest/desire in older women. Several investigators agree that androgens influence libido and behavior but not activity or response—such as lubrication and orgasm.
✒ KEY POINTS ■
Human sexual response doesn’t follow a linear model as once thought, rather the phases overlap and are complex.
■
Motivation to have sex (including increasing emotional intimacy, self-image and well-being) leads to subjective arousal, which triggers desire, leading to a responsive sexual arousal and orgasm and/or satisfaction.
■
Low libido is associated with the conditions that decrease the physiologic levels of androgens, such as oophorectomy, adrenal gland dysfunction or hypopituitarism.
■
Decreased testosterone levels are associated with loss of libido, fatigue and decreased feelings of well-being.
■
Androgen formulations are available—alone or in combination with estrogen—for treatment of low libido in women.
■
It is important to take a thorough sexual and general psychiatric history to exclude mental illness associated with sexual dysfunction, preoccupation with a life crisis, and/or core relationship problems and to find out whether the patient’s psychological profile is fairly intact.
Mohamad S. Mahmoud, MD Resident, Department of Obstetrics and Gynecology Oakwood Hospital and Medical Center Dearborn, MI
Michael P. Diamond, MD Professor, Department of Obstetrics and Gynecology Wayne State University Kamran S. Moghissi Professor Associate Chair, Department of Obstetrics and Gynecology Wayne State University Detroit, MI
Richard Balon, MD Professor, Dept Psychiatry Wayne State University Associate Director, Residency Training Detroit, MI © 2006 American Society for Reproductive Medicine Published by Elsevier Inc.
52 Sexuality, Reproduction & Menopause
T
he World Health Organization defineas sexual dysfunction as “the various ways in which an individual is unable to participate in a sexual relationship as he or she would wish.” In 1988, the Sexual Function Health Council of the American Foundation for Urologic Disease (AFUD) provided the first consensus–based definition of female sexual dysfunction (FSD). This classification divides FSD into 5 categories: hypoactive sexual desire disorder (HSDD), sexual aversion disorder, sexual arousal disorder (FSAD), female orgasmic disorder (FOD) and sexual pain disorder.1 This classification is based on the linear model of sexual response described by the work of Masters and Johnson and revised by Kaplan.2 In this model, Masters and Johnson assumed a linear progression from desire to arousal, meaning genital swelling and lubrication, to orgasm and resolution. Current data has in fact proven that human sexual response doesn’t follow such a linear model; the phases described rather overlap and are more complex.3 In the new model of the sex response cycle, motivation to have sex (including increasing emotional intimacy, self image and well being) leads to subjective arousal, which triggers desire, leading to a responsive sexual arousal and orgasm and/or satisfaction. There are two types of desire: innate desire, or desire preceded by some form of motivation.2 VOL. 4, NO. 2, OCTOBER 2006
Androgen therapy for low female libido Based on this new model, the new classification encompasses a wide spectrum of pathologies related to sexual function (see Table 1).3 The largest study done on FSD showed it affects 43% of women in the United States. This study based on the U.S. National Health and Social Life Survey of 1992 also found that among women with FSD, 51% had low libido. This makes it the most prevalent female disorder (22% of all women), followed by arousal problem (33%) and pain disorders (16%).4 Unfortunately, prevalence of the recently defined categories is largely unknown. The 51% of women with low libido in this survey are those with lack of initial spontaneous desire, which doesn’t constitute a sexual disorder by itself in the new definition. The role of estrogen deficiency in FSD has always been controversial: in fact some studies have found that estrogen deficiency was responsible for delayed or absent vaginal lubrication, decreased congestion of the vagina and reduced contractions with orgasm.2 Estrogen improved libido and orgasm in postmenopausal women,5 and systemic estrogen replacement improved vaginal lubrication, blood flow and vaginal compliance in menopausal women.6,7 However, others found that systemic estrogen alone was insufficient to cure symptoms of sexual dysfunction.8,9 Since oral estrogen can increase the level of sex hormone-binding globulins, the use of oral contraceptives containing estrogen, or oral estrogen alone, for menopausal symptoms can result in decreasing free testosterone levels.10
Androgen physiology, pharmacology and role in sexuality Androgens in women are made by the ovaries and the adrenal glands, and are partially regulated by the pituitary gland. The major androgens in women include: dehydroepiandrosterone–sulfate (DHEAS), androstenedione (A), testosterone (T), and dihydrotestosterone (DHT). Some would also include dehydroepiandrosterone (DHEA) as an androgen precursor. An anatomical presentation of the pathways of these androgens is given in Figure 1. Dehydroepiandrosterone–sulfate, DHEA and A are considered pro-androgens, because they need to be converted to T, the most potent androgen, to express their effect. The adrenal zona fasciculata produces 25% of circulating T and is regulated by adrenocorticoVOL. 4, NO. 2, OCTOBER 2006
T
he largest study on FSD showed it affects 43% of women in the United States.
tropic hormone (ACTH). The ovarian stroma, under the effect of leuteinizing hormone (LH), produces 25% of circulating T. The rest is produced by peripheral tissue conversion of circulating A.11 Testosterone in the plasma exists in three forms: free testosterone (FT), testosterone nonspecifically bound to albumin (AT), and testosterone specifically bound to sex hormone binding globulin (SHBG). The sum of FT and AT is referred to bioavailable testosterone. It is estimated that 66% of T is bound to SHBG and 1%–2% is estimated to be free or biologically available.12 There is enough evidence that the bioavailable fraction rather than total testosterone reflects the clinical miTABLE 1
Categories of female sexual dysfunction (FSD)* Type
Common symptoms
Sexual desire/ interest disorder
Feeling of sexual interest or desire, sexual thoughts or fantasies, and responsive desire are absent or diminished. Motivating reasons or incentives for attempting to become sexually aroused are scarce or absent. The lack of interest is beyond the normative lessening that may occur with life cycle and relationship duration.
Combined sexual arousal disorder
Absent or markedly reduced subjective sexual arousal (feelings of excitement, pleasure) from any type of stimulation, and absent or impaired genital sexual arousal (vulvar swelling, lubrication).
Subjective sexual arousal disorder
Absent or markedly reduced subjective sexual arousal (feelings of excitement, pleasure) from any type of stimulation. Vaginal lubrication and other signs of physical response still occur.
Genital arousal disorder
Absent or impaired genital sexual arousal: minimal vulvar swelling or vaginal lubrication from any type of sexual stimulation, and reduced sexual sensation from caresses of the genitalia. Subjective sexual excitement still occurs from non-genital sexual stimuli.
Persistent sexual arousal disorder
Spontaneous, intrusive and unwanted genital arousal (tingling, throbbing) when sexual interest or desire is absent. Any awareness of subjective arousal is typically but not invariably unpleasant. The arousal is unrelieved by orgasm, and the feelings persist for hours or days.
Orgasmic disorder
Despite self-report of high sexual arousal, orgasm from any kind of stimulation is lacking, markedly diminished in intensity or considerably delayed.
Vaginismus
Persistent or recurrent difficulties in allowing vaginal entry of a penis, finger or any object, despite the woman’s expressed wish to do so. There is often (phobic) avoidance; anticipation, fear of experience of pain; and variable involuntary contraction of pelvic muscles. Structural or other physical abnormalities must be ruled out.
Dyspareunia
Persistent or recurrent pain with attempted or complete vaginal entry or penile-vaginal intercourse.
*Adapted from reference 2.
Sexuality, Reproduction & Menopause 53
Androgen therapy for low female libido Pituitary regulation ACTH
LH
Adrenal zona fasciculata
T25%
T25%
A DHEAS
A
Ovarian stroma
Systemic circulation T50% T A T + 5α-reductase = DHT Target tissue
A T Peripheral tissue
© 2006 VIRGINIA FERRANTE
Figure 1. An anatomical presentation of the pathways of androgens in a woman’s body. ACTH = adrenocorticotropic hormone, LH = leuteinizing hormone, T = testosterone, A = androgen, DHEAS = dehydroepiandrosterone, DHT = dihydrotestosterone.
lieu. Moreover, the total testosterone level does not accurately reflect the bioavailable T, because the latter is dependent upon the concentration of binding globulins. Several methods can be used to measure bioavailable testosterone: FT can be measured using equilibrium dialysis to measure the apparent FT concentration (AFTC), which is the gold standard. Alternatively it can be measured by precipitation of SHBG with ammonium sulfate. Both methods are considered time consuming. Faster but less reliable methods are usually used: free androgen index (FAI), which is 100 T/SHBG, and immunoassay using an analog ligand (aFT).13 Plasma levels of total testosterone in women are 0.2–0.7 ng/mL (0.6–2.5 nmol/L). The level fluctuates with the phase of men-
54 Sexuality, Reproduction & Menopause
strual cycle, being highest at ovulation and lowest during the early follicular phase. It also has circadian variations with a peak in the early morning hours. Testosterone is converted to DHT in target tissues via the enzyme, 5α-reductase. Dihydrotestosterone is the principal ligand of testosterone to the androgen receptors (AR). Those receptors occur in the proximal and distal vagina and the clitoris. Androgens and estrogens regulate their expression. Testosterone can also be aromatized to estradiol (E2) in the central nervous system14 and, along with estrogen modulates cortical centers involved in the interpretation of sexual sensations. Both affect, via the release of neurotransmitters and neuromodulators, the sensitivity of genital organs and the hypothalamic-limbic structures.15 VOL. 4, NO. 2, OCTOBER 2006
Androgen therapy for low female libido In mice, there is evidence of an indirect effect of androgens on the brain via aromatization to estrogens, whereas in women, even though it is known that androgen and estrogen receptors are present throughout the brain, it is not yet clear whether androgens have a direct effect on the brain or whether the effects occur after the aromatization of androgen to estrogen.16 It has been suggested that free T relates to sexual desire and masturbation in young women.17 In women reporting low libido following menopause, 5αreductase activity is significantly impaired.18 Serum androgens decline in women for several reasons. Advancing age promotes a decline of the level of circulating androgens (free testosterone, total testosterone, DHEA, and DHEAS). This is caused by the decrease in adrenal and ovarian production of androgen in older women.19 Physiologic menopause
leads to decreased ovarian A synthesis, which leads to decreased levels of testosterone produced by peripheral conversion of A.14 Surgical or chemical ovariectomy (by GnRH antagonists, radiotherapy and exogenous estrogens administration) can reduce both testosterone and androstenedione by 50%. Oral contraceptive pills and oral estrogen can also decrease androgen levels by suppressing LH secretion and increasing the level of sex hormone binding globulins (SHBG).20,21 Glucocorticosteroids can also reduce adrenal androgen production by suppressing ACTH production.22 It is well known that low libido is associated with the conditions that decrease the physiologic levels of androgens such as oophorectomy,23 adrenal gland dysfunction or hypopituitarism.24 Decreased testosterone levels are associated with loss of libido, fatigue
Androgen formulations Androgens are available in the following forms: oral methyltestosterone, micronized testosterone, DHEA, topical testosterone ointment, intramuscular testosterone injections, testosterone implants and testosterone patches. All—alone or in combination with estrogen—can used for treatment of low libido in women. However none of these preparations has been approved by the FDA for female hypoactive sexual disorder and thus their use is considered off-label. Unique characteristics of these individual agents follow. Methyltestosterone Methyltestosterone is available in doses of 1.25 or 2.5 mg/day. It is well-absorbed orally and is available in a fixed-dose combination product with esterified estrogens (0.625 mg/day or 1.25 mg/day).9 Its use for FSD have been associated with a significant decrease in high density lipoprotein (HDL) cholesterol level, increased ratio of total cholesterol to HDL cholesterol, but significant decrease in triglyceride levels.10,35,36 Although there exist health concerns regarding high dose methyltestosterone on hepatic enzymes and blood pressure, there are little data to support convincingly the detrimental effects of low-dose methyltestosterone on these endpoints.36 Injectable testosterone Injectable testosterone is available as testosterone esters (cypionate, propionate, and enanthate) and are administered 25–50 mg intramuscularly every 2–4 weeks.
VOL. 4, NO. 2, OCTOBER 2006
The injections can be painful and the formulations may result in extreme fluctuations in androgen levels.11 Testosterone implants Testosterone implants are available in a 50-mg pellet, which are placed alone or in a pair every 3 months, requiring a minor surgical procedure. Depending on the number of implants inserted, they can result in supraphysiological dosing.37 Topical testosterone Topical testosterone can be compounded to any strength in an absorbent medium and is applied to the inner thigh and inner arm. Despite its popularity, there are few good studies of this application.38 Testosterone patch Testosterone is available in 300-µg patches for men applied once daily. It achieves supraphysiologic plasma levels and, as of this writing, haven’t lead to significant changes in the mean levels of lipids, lipoproteins, and other metabolic markers.27,30 A lower dosage patch is under development for women. DHEA Dehydroepiandrosterone, a popular over-the-counter supplement, is available in 25-mg and 50-mg tablets and can be used in women with Addison’s disease. This treatment produces a physiologic serum level of androgens and no significant side effects at these doses.31,33,34,39,40
Sexuality, Reproduction & Menopause 55
Androgen therapy for low female libido
T
here are two types of desire: innate desire, or desire preceded by some form of motivation. and decreased feelings of well-being.25 In a cross-sectional study, six hundred eighty-four women, ages 50–89 years, were surveyed for hysterectomy and oophorectomy status and had plasma obtained between 1984–1987. They found that total and bioavailable (nonSHBG-bound) testosterone levels were 4050% reduced in bilaterally oophorectomized postmenopausal women compared to those in intact women26 leading to decreased libido in 30% to 50% of those patients.14,26,27 Since our ability to measure free testosterone accurately in the range normally found in women is limited, it is generally considered inappropriate to treat a woman with low level of testosterone unless she complains of low libido.13,28
T
he androgen regimens currently used in postmenopausal women haven’t been shown to possess high risk in most women, and are felt by many to provide significant benefit encompassing sexual health. Testosterone and low libido The role of androgens in female sexuality has been addressed since the 1940s by Greenblatt et al.29 Many studies have been published since the Greenblatt study with mostly inconclusive results. Most of those reports were retrospective, uncontrolled and used unsystematic methods of data collection. Several new, more methodologically sophisticated studies have been recently published and our review focuses mostly on those. The majority of those studies have been done on postmenopausal women (surgically or naturally) receiving or not concomitant estrogen replacement therapy. The sudden and uniform decrease of plasma levels of androgen and estrogen provided in fact a unique opportunity for studying the effect of those steroids on sex behavior. Sherwin et al found that surgically menopausal women who received supraphysiologic doses of testosterone enanthate adminis-
56 Sexuality, Reproduction & Menopause
tered intramuscularly alone or with estrogen had significantly higher scores for sexual desire, fantasies and arousal compared to women who received estrogen alone. The effect on the frequency of coitus and orgasm was not significant.10 Lobo et al found that in healthy postmenopausal women (natural or surgical > 6 months) methyltestosterone treatment results in improvement in sexual interest or desire partially by decreasing the levels of SHBG, leading to increased bioavailable testosterone, and possibly by a direct effect of methyltestosterone acting as androgen. They also concluded that the combined treatment wasn’t associated with a clinically significant change in acne and hirsutism.9 Shifren et al found that the 300-µg testosterone patch significantly increased the scores for thoughts, i.e., desire; frequency of sexual activity, and orgasm compared to placebo in surgically menopausal women.8 SR Davis et al found that the addition of testosterone to estradiol in postmenopausal women resulted in significantly greater improvement compared to estradiol alone for sexual activity (p < 0.03), satisfaction (p < 0.03), pleasure (p < 0.01), orgasm (p < 0.035) and relevancy (p < 0.05). They concluded that the addition of testosterone has therapeutic effect for dimished libido in postmenopausal women.28 S Davis et al found a statistically significant increase in the sexual desire score of the profile of female sexual function (PFSF) compared with the placebo group (p < 0.05) as well as change in other domains of the PFSF including orgasm, sexual arousal, sexual responsiveness, sexual self image and sexual concerns, and significant reduction in personal distress in surgically menopausal women using 300-µg/day testosterone transdermal patch.30 Buster et al found a significant improvement of all seven domains of sexual function, including sexual desire, pleasure, arousal, orgasm, concerns, responsiveness and self image, in surgically menopausal women using 300-mg testosterone.27 Their data agree with other clinical findings that high physiologic/ low supraphysiologic doses of testosterone improve several aspects of sexual function in postmenopausal women with FSD—precisely low libido. The majority of the aforementioned studVOL. 4, NO. 2, OCTOBER 2006
Androgen therapy for low female libido
TABLE 2
Testosterone studies Duration of study
Scale used to measure sexual function
Monthly testosterone enanthate injection
8 months
Daily menopausal rating scale (DMRS)
Crossover
218
1.25 mg of methyltestosterone
16 weeks
Sexual interest questionnaire (SIQ)
Double-blind randomized clinical trial
Shifren et al8
75
150-mg/300-µg testosterone patches
12 weeks
Brief index of sexual functioning for women (BISF-W)
Randomized clinical trial
SR Davis et al28
34
50-µg testosterone implant
2 years
Sabbatsberg sexual self-rating scale
Single-blind randomized clinical trial
S Davis et al30
77
300-µg testosterone transdermal patch
24 weeks
Profile of female sexual function (PFSF)
Double-blind randomized clinical trial
Buster et al27
533
300-µg testosterone transdermal patch
24 weeks
PFSF and the personal distress scale
Double-blind randomized clinical trial
Investigator
N
Testosterone form
Sherwin et al10
43
Lobo et al9
ies used different validated and nonvalidated instruments and scales to measure the effect of androgen on sexual function. The effectiveness and value of those scales to measure low libido, even though used by several studies, is questionable. Also the measurement of the different serum testosterone fraction varied from one study to another, which makes it even harder to compare those studies (see Table 2).
Dehydroepiandrosterone and low libido Patients with Addison’s disease usually have a chronic deficiency in DHEA, because their treatment focuses on glucocorticoides and mineralocorticoides and neglects the androgen deficiency. Dehydroepiandrosterone is transformed into potent androgens in various tissues; therefore its replacement may be important in women suffering from Addison’s disease.31 In this randomized crossover study, nine women with normal baseline DHEA underwent adrenal suppression of DHEA with dexamethasone to levels found in Addison’s disease and were randomly assigned to receive 50 mg or 100 mg oral capsules of DHEA. The administration of 50 mg of DHEA was sufficient to restore the serum concentration of DHT and ADG to nonsupressed baseline levels, whereas 100 mg DHEA was required to fully restore A and T concentrations to baseline. A dose of 100 mg/day induces supraphysiological levels of DHEA in these women. The investigators concluded that a daily dose of 50 mg DHEA is a suitable replacement therapy in females with adrenal androgen deficiency.31 VOL. 4, NO. 2, OCTOBER 2006
Type of study
In the randomized clinical trial conducted by Lovas et al, 39 women aged between 18 and 70 years with confirmed primary or secondary adrenal failure were randomized to receive 25 mg of oral DHEA versus placebo for 9 months. They found that 25 mg DHEA was enough to produce physiologic serum levels of androgen in patients with Addison’s disease but did not have any significant effect on sexual function.32 The same result was found in the randomized crossover clinical trial done by Hunt et al using a daily 50 mg dose of DHEA for 12 weeks. The treatment corrected the deficiency of DHEA and DHEAS, achieving normal range of those hormones, with T levels at the lower end of the normal range. However, there was no significant difference in any of the indices for sexual interest compared to placebo.33 In contrast, Arlt et al conducted a doubleblind, placebo-controlled, crossover study on 24 women with adrenal insufficiency. Women received in a random order 50 mg of oral DHEA daily for 4 months versus placebo. The investigators concluded that replacing DHEA in women with adrenal insufficiency improves sexual desire as a direct effect of DHEA on the nervous system, an increase of peripheral androgen synthesis or both.34
Side effects and safety of androgen therapy Side effects of androgen therapy can be divided into two categories: early reversible side effects that encompass acne, skin oiliness, hirsutism and menstrual irregularities; and late Sexuality, Reproduction & Menopause 57
Androgen therapy for low female libido irreversible side effects of virilisation including male-pattern baldness, hirsutism, voice changes and hypertrophy of the clitoris. These late side effects have been reported primarily in supraphysilogical doses of androgen, especially those doses used in men. However, the androgen regimens currently used in postmenopausal women haven’t been shown to possess high risk in most women, and are felt by many to provide significant benefit, encompassing sexual health.8,9,27,41 However, all patients should be aware of the possibility of side effects whenever androgen replacement is administered. They should be aware that prolonged use of high doses of certain androgens (17α-alkyl androgens like methyltestosterone) have been associated with serious hepatic adverse effects: peliosis hepatis, hepatic neoplasms, cholestatic hepatitis and jaundice. Peliosis hepatis can be
P
rolonged use of high doses of certain androgens (17α-alkyl androgens like methyltestosterone) have been associated with serious hepatic adverse effects: peliosis hepatis, hepatic neoplasms, cholestatic hepatitis, and jaundice. a life-threatening or fatal complication. Longterm therapy with testosterone enanthate, which elevates blood levels for prolonged periods, has produced multiple hepatic adenomas. Testosterone is not known to produce these adverse effects. Edema with or without congestive heart failure may be a serious complication in patients with preexisting cardiac, renal or hepatic disease. Diuretic therapy may be required in addition to discontinuation of the drug. In patients with breast cancer, androgen therapy may cause hypercalcemia by stimulating osteolysis. In this case, the drug should be discontinued. Although there are rare reports of hepatocellular carcinoma in patients receiving long-term therapy with androgens in high doses, withdrawal of the drugs did not lead to regression of the tumors in all studied cases. Hemoglobin and hematocrit levels should be checked periodically in patients on long-term androgen therapy to de-
58 Sexuality, Reproduction & Menopause
tect the possible side effect of polycythemia. Also liver function, cholesterol and high-density lipoprotein should be checked periodically to rule out any hepatic disorder.42 Finally, further studies need to be done in order to evaluate the long-term side effects of androgen replacement therapy in women.
Conclusion Evidence agrees that supraphysiologic doses of testosterone improve the desire/interest and pleasure of sexual experience in surgically postmenopausal women. However, sexual function is complex and depends on more than hormones. It is very possible for postmenopausal women with low androgen levels to have fulfilling sexual lives. The reverse, that is women with healthy levels of hormones having unsatisfactory sexual lives, is also true. Before embarking on any treatment for low libido, it is important to take a thorough sexual and general psychiatric history to exclude mental illness associated with sexual dysfunction, preoccupation with a life crisis and/or core relationship problems and to find out whether the patient’s psychological profile is fairly intact. As Levine suggested, it may be useful to conceptualize libido/sexual desire as consisting of drive (biological, mostly hormones), motive (individual and relationship psychology), and wish (cultural) components.43 Further variables affecting libido include age, social situation, and health.43 Thus, though hormones play an important role in sexual desire, they are only part of the entire story. Nevertheless, assessing the effect of testosterone and other androgens in premenopausal women could help improve our understanding of the role of androgens in female sexuality and sexual desire. The ideal androgen preparation to be used in treating low sexual desire in women would be the one that combines safety and efficacy and would maintain androgen levels reliably within the female normal range. The most effective therapeutic formulation remains to be defined. Sensitive instruments designed specifically to assess sexual function in postmenopausal women are lacking, and the aspects of sexual function measured by the interventions have been unspecified. Few data have been published concerning the longterm effects of androgen substitution in women; therefore the long-term safety of this treatment is still unknown. ■ VOL. 4, NO. 2, OCTOBER 2006
Androgen therapy for low female libido REFERENCES 1. Basson R, Berman J, Burnett A, et al. Report of the international consensus development conference on female sexual dysfunction: definitions and classifications. J Urol 2000;183:888-893. 2. Masters EH, Johnson VE. Human sexual response. Boston: Little, Brown; 1966. 3. Basson R. Women’s sexual dysfunction: revised and expended definition. CMAJ 2005;172(10):1327-1333. 4. Laumann EO, Paik A, Rosen RC. Sexual dysfunction in the United States: prevalence and predictors. JAMA 1999;281:537-544. 5. Sarrel PM. Sexuality and menopause. Obstet Gyneol 1990;7(5):26S-30S. 6. Semimons JP, Wagner G. Estrogen deprivation and vaginal function in postmenopausal women. JAMA 1982;248:445-448. 7. Berman JR, Berman LA, Werbin TJ, et al. Clinical evaluation of female sexual function: effects of age and estrogen status on subjective and physiologic sexual responses. Int J Impotence Res 1999;11:S31-S38. 8. Shifrin JL, Braunstein GD, Simon JA, et al. Transdermal testosterone treatment in women with impaired sexual function after oophorectomy. N Engl J Med 2000;343:682-688. 9. Lobo RA, Rosen C, Yang HM, Block B, van der Hoopp RG. 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 2003; 79(6):1341-1352. 10. Sherwin BB, Gelfand MM, Brender W. Androgen enhances sexual motivation in females: a prospective, crossover study of sex steroid administration in the surgical menopause. Psychosom Med 1985;47: 339-351. 11. Langcope C. Adrenal and gonadal androgen secretion in normal females. Clin Endocrinol Metab 1986;15:213-227. 12. Davison SL, Davis SR. Androgens in women. Journal of steroid biochemistry and molecular biology 2003;85(2003):363-366. 13. Vermeulen A, Verdonck L, Kaufman JM. A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab 1999;83(10):3666-3672. 14. Abraham GE. Ovarian and adrenal contribution to peripheral androgens during the menstrual cycle. J Clin Endocrinol Metab 1975;39: 340-346. 15. Nappi RE. Meanopause e sessualita. CIC, Roma, 2002. 16. Apperloo MJ, Van Der Stege JG, Hoek A, Weijmar Schultz WCM. In the mood for sex: the value of androgens. Journal of sex and marital therapy 2003;29(2):87-102. 17. Vermeulen A. Plasma androgens in women. J Reprod Med 1998;43: 725-33. 18. Kennedy RG, Davies T, Al-azzawi F.sexual interest in postmenopausal women is related to 5-alpha-reductase activity. Hum Reprod 1997;12:209-13. 19. Mushayandebvu T, Castracane DV, Gimbel T, Adel T, Santoro N. Evidence for diminished mid-cycle ovarian androgen production in older reproductive aged women. Fertil Steril 1996;65:721-723. 20. Mathur RS, Landgreve SC, Moody LO, Semmens JP, Williamson HO. The effect of estrogen treatment on plasma concentrations of steroid hormones, gonadotropins, prolactin and sex hormone-binding globulin in post-menopausal women. Maturitas 1985;7:129-133. 21. Krug R, Psych D, Petrowsky R, Fehm HL, Born J. Selective influence of menstrual cycle on perception of stimuli with reproductive significance. Psychom Med 1994;56:410-417. 22. Abraham GE. Ovarian and adrenal contribution to peripheral androgens during the menstrual cycle. J Clin Endocrinol Metab 1974;39: 340-346. 23. Shifren JL. Androgen deficiency in the oophorectomized woman. Fertil Steril 2002;77(S4):S60-S62. 24. Rannevik G, Jeppsson S, Johnell O, Bjerre B, Laurell-Borulf Y, Svanberg L.A Longitudinal study of the perimenopausal transition: altered
profiles of steroid and pituitary hormones, SHBG and bone mineral density. Maturitas 1995;21:103-113. 25. Sherwin BB. Changes in sexual behavior as a function of plasma sex steroid levels in post-menopausal women. Maturitas 1985;7:225-233. 26. Laughlin GA, Barrett-Connor E, Kritz-Silverstein D, von Muhlen D. Hysterectomy, oophorectomy, and endogenous sex hormone levels in older women: the Rancho Bernardo Study. J Clin Endocrinol Metab 2000;85:645-51. 27. Buster JE, Kingsberg SA , Aguirre O, Brown C, Breaux JG, Buch A, Rodenberg CA, Wekselman K, Casson P. Testosterone Patch for Low Sexual Desire in Surgically Menopausal Women: A Randomized Trial. Obstet Gynecol 2005;105:944-952. 28. Davis S. Androgen replacement in women: a commentary. J Clin Endocrinol Metab 1999;84:1886-1891. 29.Greenblatt RB. Androgenic therapy in women. J Clin Endocrinol Metab 1942;2:665-666. 30. Davis S, Rees M, Ribot C, Moufarege A, Rodenberg C, Purdie D. Efficacy and safety of testosterone patches for the treatment of low sexual desire in surgically menopausal women. Fertil Steril 2003;80(suppl 3):S76. Abstract O-199. 31.Wiebke Arlt, Hans-georg justl, Frank Callies, Martin reincke, Doris Hubler, Michael Ottel, et al. 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 1998;8(6):1928-1934. 32. Lovas K, Gebre-Medhin G, Trovic TS, et al. Replacement of dehydtroepiandrosterone in adrenal failure: no benefit for subjective health status and sexuality in a 9 month, randomized, parallel group clinical trial. J Clin Endocrinol Metab 2003;88(3)1112-1118. 33. Hunt PJ, Gurnell EM, Huppert FA, et al. Improvement in mood and fatigue after Dehydroepiandrosterone replacement in Addison’s disease in a randomized, double blind trial. J Clin Endocrinol Metab 2000;85 (12):4650-4656. 34. Arlt W, Callies F, Van vlijmen JC, et al. Dehydroepiandrosterone replacement in women with adrenal insufficiency. N Engl J Med 1999;342: 1013-1020. 35. Barrett-Connor E, Young R, Notelovitz M, Sullivan J, Wiita B, Yang HM, Nolan J. A two-year, double blind comparison of estrogen-androgen and conjugated estrogens in surgically menopausal women. Effects on bone density, symptoms and lipid profiles. J Reprod Med 1999;44: 1012-1020. 36. Gitlin N, Korner P, Yang HM. Liver function in postmenopausal women on estrogen-androgen hormone replacement therapy: A metaanalysis of eight clinical trials. Menopause 1999;6:216-224. 37. Davis SR, McCloud P, Strauss BJ, Burger H. Testosterone enhances estradiol’s effects on postmenopausal bone density and sexuality. Maturitas 1995;21:227-236. 38. Rust J, Gomlombok S. The GRISS: a psychometric instrument for the assessment of sexual dysfunction. Arch Sex Behav 1986;15:157-165 39. Casson PR, Anderson RN, Herrod HG, et al. Oral dehydroepiandrosterone in physiologic doses modulates immune function in postmenopausal women. Am J Obstet Gynecol 1993;169:1536-1539. 40. Young J, Couzinet B, Nahoul K, et al. Panhypopituitarism as a model to study the metabolism of dehydroepiandrosterone (DHEA) in humans. J Clin Endocrin Metab 1997;82:2578-2585. 41. Casson PR, Faquin LC, Stentz FB, et al. Replacement of dehydroepiandrosterone enhances T-lymphocyte insulinebinding in postmenopausal women. Fertil Steril 1995;63:1027-1031. 42. Simon JA. Safety of estrogen/androgen regimens. J Reprod Med 2001;46(3 Suppl):281-390. 43. PDR 2005. 44. Levine SB. The nature of sexual desire: a clinician’s perspective. Archives of Sexual Behavior 2003;32:279-285.
Mohamad S. Mahmoud, MD Resident, Department of Obstetrics and Gynecology Oakwood Hospital and Medical Center Dearborn, MI 48123 mohamadmahmoud @yahoo.com
Michael P. Diamond, MD Professor, Department of Obstetrics and Gynecology Wayne State University Kamran S. Moghissi Professor Associate Chair, Department of Obstetrics and Gynecology Wayne State University Detroit, MI 48201 [email protected]
Richard Balon, MD Professor, Dept Psychiatry Wayne State University Associate Director, Residency Training Detroit, MI 48207 [email protected]
Disclosures Dr Diamond has disclosed the following contractual support relationships: Serono, TAP, GSK, Wyeth, Merck, and Pfizer; and the following consulting relationships: Serono, Genzyme, and Kytogenics. Dr. Balon has disclosed the following relationships: lecturer, GSK; Consultant, Shire Pharmaceuticals. VOL. 4, NO. 2, OCTOBER 2006
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