Susan R Davis
Sexual activity in women is complex, involving biochemical, neurophysiologic, and cognitive processes. Psychologic functioning, past sexual history, the availability and presence of a partner, body image, life issues, and the culture and the society of a particular birth cohort contribute significantly to the multivariate nature of female sexuality (see Chapters 2.1—2.4 of this book). This chapter specifically focuses on the endocrine treatment of female sexual dysfunction in premenopausal women, with the assumption that the psychosocial aspects discussed in Chapters 3.1—3.4 and 9.3 are always addressed when any woman presenting with female sexual dysfunction is assessed.
The endogenous hormones that potentially influence female sexuality include estrogens, androgens, progesterone, prolactin, oxytocin, and glucocorticosteroids. These each interact with numerous neurochemicals within the central and peripheral nervous system. The latter include serotonin, catecholamines, dopamine, other neurotransmitters, and other hormones. The factors that determine the outcome of these complex interactions include the absolute levels of each hormone, their absolute receptor content, and the presence and levels of specific coactivator and corepressor proteins that modify the transcriptional response and the up- or down-regulation of receptor levels by other hormones (see Chapters 4.3, 5.3—5.5, and 6.1—6.3). Estrogens and androgens also influence vascular function by both endothelium-dependent and -independent mechanisms,1 and thus have a vital role in maintenance of the health of the female genital tract as well as in arousal and orgasm. Research on female sexual dysfunction in premenopausal women has relied primarily on observational data, and in vitro and in vivo animal models (see Chapter 5.6), and few randomized, placebo-controlled trials have been published. Thus, insufficient data are available to support specific endocrine therapy for otherwise well, premenopausal women with female sexual dysfunction.
Endocrine and intracrine sources of sex steroids in women
Phylogenetic analysis of steroid receptors (see Chapter 5.5) indicates that the first steroid receptor was an estrogen receptor, followed by a progesterone receptor.2 Specific regulation of physiologic processes by androgens and corticoids is a relatively recent innovation that emerged after these duplications.2 Thus, in humans, androgens in ovaries are obligatory precursors of the biosynthesis of estrogens by the aromatase cytochrome P450 enzyme. Estrone is formed by the aromatization of androstene- dione and estradiol by the aromatization of testosterone.
Throughout the reproductive years, the ovaries are a primary source of estradiol for action on peripheral target tissues under the control of follicle-stimulating hormone and inhibin. However, synthesis of estrogens from adrenal and ovarian androgen precursors within extragonadal compartments occurs throughout reproductive life.3
The primary source of circulating progesterone in premenopausal women is cyclic production by the ovaries. Serum progesterone concentrations are significantly correlated with brain tissue concentrations, suggesting that serum levels are a primary source for brain uptake,4,5 although progesterone can also be synthesized within the brain.6
Androgens are 19-carbon steroid hormones that are associated with the induction of male secondary sexual characteristics. In women, androgens circulate in the concentration range nanomolar to micromolar, in contrast to the estrogens whose circulating concentrations are in the picomolar range. In descending order of their serum concentrations, the major androgens found in women include dehydroepiandrosterone sulfate, dehydroepiandrosterone, androstenedione testosterone, and dihydrotestosterone. Giving testosterone a reference potency of 100, the relative androgenic activities of the other members of the class are: dihydrotestosterone, 300; androstene- dione, 10; and dehydroepiandrosterone and dehydroepiandros- terone sulfate, 5. Biosynthesis of the androgens takes place both in the adrenal and in the ovary. Dehydroepiandrosterone secretion is acutely stimulated by adrenocorticotropic hormone;7,8 however, dehydroepiandrosterone sulfate, which has a long plasma half-life, may not acutely increase after adrenocorticotropic hormone administration.9
Changes in sex steroids during the menstrual cycle and with age
In premenopausal women with regular menstrual cycles, there is a rise in estradiol, testosterone, and androstenedione in the late follicular phase of the menstrual cycle and in the luteal phase.10,11 There is also a diurnal variation in testosterone in women with the peak in the morning.12 The luteal phase is characterized by the rise in progesterone. Estradiol and progesterone levels fall when ovulation ceases, as at menopause. In contrast, total and free testosterone levels fall from the third to the fifth decade in premenopausal women, such that women in their 40s have about half the circulating levels of women in their 20s.13,14 Furthermore, in the late reproductive years, there is failure of the midcycle rise in free testosterone which characterizes the menstrual cycle in young ovulating women.15
The levels of dehydroepiandrosterone sulfate and dehydro- epiandrosterone also fall with increasing age.16 This may contribute significantly to the decline in total and free testosterone level with age, as dehydroepiandrosterone sulfate serves as a prehormone for about half of ovarian testosterone production17 (see Chapter 6.3).
Metabolism and action of sex steroids
Traditionally, hormonal action has been understood as endocrine and paracrine, and measurement of circulating hormone levels has been used as a determinant of tissue exposure. However, more recently, the complexity of steroid action has been appreciated.18 Labrie et al. defined intracrinology:
“Intracrine activity describes the formation of active hormones that exert their action in the same cells in which synthesis took place without release into the pericellular compartment.”19 Tissue sensitivity to androgens varies according to the amount and activity of the enzymes 5a-reductase and aromatase, which may vary considerably between individuals. Tissue responses may also vary with subtle differences in individual receptors. For example, the number of repeat sequences of cytosine, adenine, and guanine nucleotides, CAG repeats, in the deoxyribonucleic acid (DNA) molecule coding for the androgen receptor may vary in individuals. Thus, even with highly sensitive assays for sex steroids, the measurement of any sex steroid will provide only an indication of deficiency or excess, but not an absolute measure of tissue exposure or tissue sensitivity and responsiveness, and the clinical features will be the mainstay of diagnosis. This, unfortunately, limits much of the data pertaining to sex steroids and female sexual function.
Importance of sex hormone-binding globulin
Many steroids circulate tightly bound to sex hormone-binding globulin, which is a pivotal determinant of their bioavailability.20 In normal, reproductive-aged women, 82% of the binding sites of sex hormone-binding globulin are unoccupied. For the occupied binding sites, androstendiol is the major sex hormonebinding globulin ligand, followed by dehydroepiandrosterone, testosterone, cortisol, cortisone, dihydrotestosterone, and androstenedione. Conversely, the binding affinity for steroids bound by sex hormone-binding globulin is dihydrotestosterone > testosterone > androstenediol > estradiol > estrone. Sex hormone-binding globulin also weakly binds dehydroepiandros- terone, but not dehydroepiandrosterone sulfate.20 Because of its high affinity for sex hormone-binding globulin, only 1-2% of total circulating testosterone is free or biologically available under normal physiologic conditions in women.20 Elevations in estradiol (as occurs during pregnancy), hyperthyroidism, and liver disease cause a marked increase in sex hormone-binding globulin levels, whereas hypothyroidism, obesity, and hyperin- sulinemia are associated with decreased sex hormone-binding globulin levels. In addition, oral administration of steroid hormones and their analogs can alter sex hormone-binding globulin levels, whereas parenteral administration of these compounds typically has a much weaker influence. The standard dose of oral estrogen used in the oral contraceptive pill will increase sex hormone-binding globulin. Lower sex hormone-binding globulin levels enable increased clearance of testosterone, whereas higher sex hormone-binding globulin levels are associated with a decrease in clearance. Thus, women with high sex hormone-binding globulin, such as women on the oral contraceptive pill, have a greater total testosterone, and women with low sex hormone-binding globulin have little change in their total testosterone level with exogenous therapy. As total testosterone is a poor indicator of androgen exposure, the concentration of free testosterone or non-sex hormone-binding globulin-bound testosterone, so-called bioavailable testosterone, should be measured after testosterone therapy. Such assays may not always be reliable or available. As sex hormone-binding globulin levels may fall somewhat with increased circulating testosterone, baseline sex hormone-binding globulin may be a useful predictor of risk of excess androgenization with testosterone treatment, and should be measured in all women prior to such therapy. Sex hormone-binding globulin levels do not vary with age in premenopausal women.14,21
Hormones and hypoactive sexual desire disorder
As sexuality is multifactorial and mechanistic studies in humans cannot clearly elucidate the role of hormones in sexual function, rodent models of sexually receptive behaviors have been used to gain insight into some of the actions of sex steroids. There is, however, no animal model for female arousal or orgasm, and the influence of cognitive factors, such as fantasy, cannot be studied in animals. Vaginal plethysmography (see Chapter 10.1) has been used in human studies; however, the correlation between blood flow measures and verbal reports of arousal is poor.22-24
The central role of estrogens in sexual function
Estradiol and testosterone are both present in the human female brain, with the highest concentrations of estradiol measured in the hypothalamus and the preoptic area, and of testosterone, in the substantia nigra, hypothalamus, and preoptic area25 (see Chapter 5.3). The concentration of testosterone is several times higher than estradiol in each of these regions, with the highest ratio of testosterone to estradiol demonstrated in the hypothalamus and preoptic area. This distribution corresponds with the high aromatase activity found in these regions in animals.26 It is biologically plausible that within these regions testosterone is aromatized to estradiol, resulting in high estradiol concentrations that then modify sexual behavior.
Animal studies of hormones and female sexual function
Both estrogen receptors (estrogen receptors a and P) are expressed in the primate brain.27 Estrogen exhibits widespread actions throughout the brain, both via its receptors, and non- genomically, with interactions with many neurotransmitter systems, including catecholaminergic, serotoninergic, cholinergic, and Y-aminobutyric acidergic systems.28,29 Oophorectomized rats and mice exhibit no lordotic behavior, but they have no estrogens or androgens because their adrenals do not make C19 steroids. Estrogen therapy alone has little or no effect on restoration of lordosis in oophorectomized mice, but after estrogen priming, progesterone restores lordosis.30
To clarify the possible role of each of the estrogen receptors and estrogen action in sexual behaviors, mice in which each or both estrogen receptors have been knocked out, or in which the aromatase enzyme has been mutated (aromatase knockout), have been studied. In each of these models, serum testosterone is normal or elevated. Behavioral changes evaluated have included female sexual receptivity (lordosis posturing), aggression, and pup-caring behavior. Mice in which the estrogen receptor a has been knocked out (estrogen receptor knockout mice) exhibit no lordosis behavior, reduced pup caring, and increased aggression.31 In contrast, the mice in which the estrogen receptor P has been knocked out (beta estrogen receptor knockout mice) exhibit normal sexual function.31 In female aromatase knockout mice, which are completely estrogen deficient, there is marked loss of lordosis.32 Residual lordotic behavior in the aromatase knockout mice indicates that neuronal pathways may be activated in a ligand-independent manner by the intact estrogen receptor. When both estrogen receptors a and P are knocked out, there is complete loss of sexual function in the animals despite the presence of normal testosterone levels.31 Taken together, these data indicate that, in the mouse model, estrogen receptor a is crucial for lordotic behavior, and that, despite lack of a relationship between circulating estradiol levels and sexual parameters, estradiol and the estrogen receptors have an essential role in the neurobiology of sexual behavior in animal models.
There no evidence from randomized clinical trials that treatment of premenopausal women with estradiol improves sexual function.
Central effects of progesterone
The progesterone receptor exists in two different molecular forms, progesterone receptor-A and progesterone receptor-B. Progesterone receptors are also present in the brain.33 The function and role of the two different isoforms in the brain have not been defined, and pharmacologic approaches using ligand antagonists and knockout models do not distinguish between the two isoforms. Progesterone, like estrogen, modulates gene expression in the rodent hypothalamus and thus regulates neuronal networks that control female sexual behavior. Estradiol increases the expression of progesterone receptor, which in turn functions as a critical coordinator of key regulator events associated with the sexual response.33 The results of various studies using the progesterone antagonist RU 486, intracerebral administration of antisense nucleotides, and progesterone receptor knockout mice confirm that facilitation of sexual behavior of rodents by progesterone is mediated both by estradiol-induced genomic activation of neural progesterone receptor and by a process involving ligand-independent action of the progesterone receptor via the cell membrane dopamine1 receptor (D1).33 It is believed that activation of cell membrane receptors results in a signal transduction cascade that leads to phosphorylation of the progesterone receptor or a specific coactivator, and hence neuronal effects. In animal models, progesterone facilitation of lordosis is also influenced by the cannabinoids.34 There is no evidence from randomized clinical trials that treatment of premenopausal women with progesterone improves sexual function.
Dehydroepiandrosterone is converted to both testosterone and estradiol; therefore, any positive effects of dehydroepiandros- terone on sexual function cannot distinguish between the role of dehydroepiandrosterone alone or as a precursor of testosterone and/or estradiol. The effects of oral dehydroepiandrosterone on the sexual function of women have been evaluated in a few placebo-controlled, randomized, clinical trials with inconsistent findings. In a crossover study of 24 women with adrenal insufficiency, sexual thoughts, interest, and satisfaction (mental and physical) increased significantly after 4 months of active treatment (50 mg/day).35 In this study, serum testosterone was increased from below normal to the lower part of the normal range by the therapy. Two other studies of women with Addison’s disease found no effect of the same dose of dehydroepiandrosterone on cognitive or sexual function.36,37 Significant improvements in self-esteem, mood, and fatigue were observed.36,37 In perimenopausal women without adrenal deficiency, a parallel-group, placebo-controlled, randomized, clinical trial did not show improvements in libido in 66 peri- menopausal women treated with 50 mg/day dehydroepiandros- terone for 4 months.38 However, an open-label study of dehydroepiandrosterone treatment (50 mg/day) in 113 healthy women with diminished desire, arousal, and orgasmic capacity showed improvement in desire, arousal, lubrication, orgasm, and satisfaction (p < 0.05).39
In summary, there are no strong data to show beneficial effects of exogenous dehydroepiandrosterone on sexual function in health or in adrenal insufficiency.
Role of testosterone in premenopausal women
Evidence from basic research and physiology Androgen receptor message ribonucleic acid (mRNA)- containing neurons are widely distributed in the female rat brain, with the greatest densities in neurons in the hypothalamus, and in regions of the telencephalon that provide strong inputs in the medial preoptic and ventromedial nuclei, each of which is thought to play a key role in mediating the hormonal control of sexual behavior, as well as in the lateral septal nucleus, the medial and cortical nuclei of the amygdala, the amygdalohippocampal area, and the bed nucleus of the stria terminalis.40 In the adult, male, cynomolgus monkey, high densities of P450 aromatase and androgen receptor mRNA-containing neurons were observed in discrete hypothalamic areas involved in the regulation of gonadotropin secretion and reproductive behavior.41 All areas that contained P450 aromatase mRNA-expressing cells also contained androgen receptor mRNA-expressing cells. However, there were areas in which androgen receptor mRNA was expressed, but not P450 aromatase mRNA, suggesting that testosterone acts via different signaling mechanisms in specific brain regions.41 No equivalent data are available for humans or female primates. In rodent models, as reviewed above, testosterone does not maintain normal sexual behavior in the absence of estrogen action.
Evidence from studies in humans
Studies examining the relationships between circulating endogenous testosterone levels and sexual activity in premenopausal women have produced varying results. In several small studies, low sexual desire had been associated with lower testosterone and dehydroepiandrosterone sulfate levels.42-44 In contrast, other researchers have reported that decreased libido is associated with greater fluctuations in testosterone in the late reproductive years.45 Cawood and Bancroft reported no relationship between androgens and sexual parameters in 141 volunteer non-hormone-therapy users aged 40-60 years.46
As young women who undergo bilateral oophorectomy experience an approximately 50% reduction in circulating testosterone concentrations,47 the study of young women after oophorectomy has provided one approach to evaluate the effects of low testosterone levels on sexual function. However, there are several confounders in such studies, including the benefit of treating the problem that required the surgery in the first place and possible adverse effects of the surgery. Overall, observational studies of oophorectomized women suggest that decreased testosterone levels may affect sexual function in some women, although many women report improved sexual wellbeing after bilateral oophorectomy.48,49
Only one randomized, clinical trial of testosterone therapy has been reported in premenopausal women.50 This crossover study involved 45 premenopausal women presenting with low libido. Transdermal testosterone, administered as a cream, was reported to improve significantly sexual motivation, fantasy, frequency of sexual activity, pleasure, orgasm, and satisfaction.50 In addition to the positive effects on sexual function, testosterone significantly improved the total score and all subscale scores of the Personal General Well-Being Index in premenopausal women.50 The mean free androgen index was just above the proposed upper limit for young women, although no true range has been formally established for this estimate of free testosterone.
Hormones and sexual arousal
It is becoming clear that inadequate sexual arousal may in part be due to decreased blood flow to the sexually responsive organs. While atherosclerosis may be implicated in older women with vascular risk factors, it seems that hormonal changes may play a part in younger women.
Estrogen influences vascular function via genomic and nongenomic mechanisms.1 Estrogen has direct effects on genital anatomy, enhancing peripheral blood flow and peripheral nerve function, and improving vaginal lubrication.51
Testosterone appears to be important for its vasomotor effects,52 enhancing vaginal blood flow and lubrication.53,54
These effects may be due to direct androgen actions or partly to estradiol biosynthesis from testosterone in the vascular bed.55 Cellular research indicates that vaginal tissue may express a specific nuclear receptor for the very powerful androgen, Д5-Р androstenediol.56
In a randomized, clinical trial with a crossover design, acute testosterone administration at pharmacologic levels was found to increase vaginal pulse amplitude in eugonadal women, with a strong statistical correlation between vaginal pulse amplitude and self-reporting of genital sensations.53 In a single-blind study, acute dehydroepiandrosterone had no significant effect on either vaginal pulse amplitude responses or subjective responses to erotic films 30 min postdose in 12 healthy, premenopausal women.57 As sublingual testosterone did not have an effect until 1.5 h,53 it is possible that evaluation of vaginal pulse amplitude may have been performed at too early a time point for a true effect to be measured, resulting in a type 1 error.
Hormones and dyspareunia
Dyspareunia has a number of causes, but lack of estrogenization is a common cause in women experiencing estrogen deficiency due to a variety of causes. Significant negative associations between androstenedione and testosterone levels and vaginal atrophy have also been reported.54 Androgen receptors have been reported in the vagina, and these may play a role in vaginal health (see Chapter 12.4). Local estrogen therapy can be effectively used to treat vaginal atrophy. Although this is usually a treatment reserved for postmenopausal women, low-dose vaginal estrogen is worth considering when this is the presenting problem for premenopausal women.
Situations resulting in sex-steroid deficiency in premenopausal women
As long as women continue to ovulate regularly, estrogen and progesterone levels are maintained until the time of menopause. However, as described above, androgen levels decline with age from the young reproductive years. Thus, aging contributes to decline in androgens. Factors that interfere with cyclic sex steroid production will therefore interfere with sex-steroid levels. Such factors include rapid weight loss and anorexia nervosa, in which estrogen and progesterone levels fall, but testosterone levels are often maintained.
Hyperprolactinemia, when pathophysiologic or iatrogenic, results in hypogonadotropic hypogonadism, loss of libido, and distress.58 These adverse effects have been attributed to loss of ovarian function. Lundberg and Hulter reported that 53 (84.1%) out of the 63 women with hypothalamic pituitary disorders who had hyperprolactinemia had diminished sexual desire, but only 15 (32.6%) out of the 46 women with normal serum prolactin had this symptom (p < 0.001).59
Adrenal insufficiency is associated with reductions in dehydroepiandrosterone sulfate and free and total testos- terone.60 Similarly, glucocorticosteroid excess, either endogenous or exogenous, leads to adrenal suppression and androgen insufficiency, and thus may indirectly inhibit sexual function.61 However, no clinical data indicate that this is an effect independent of the disease process for which glucocorticosteroid therapy is being used.
Use of the oral contraceptive pill results in suppressed ovarian function, and hence suppressed estradiol and progesterone levels, suppressed ovarian testosterone production, and low pituitary gonadotropins (see Chapter 7.6). In addition, the oral estrogen in the oral contraceptive pill increases sex hormone-binding globulin and thus reduces free testosterone. It is often said that use of the oral contraceptive pill adversely affects libido, but evidence to support this hypothesis is lacking.
Other hormones influencing sexual behavior
Circulating levels of the neuropeptide oxytocin have been reported to be increased during sexual arousal and orgasm in humans, and its receptor may have a role in sexual behavior. When oxytocin had been infused into the brains of estrogen- treated, female rats (which are not very sexually receptive), their sexual activity was considerably stimulated.62 Estradiol increases the expression of oxytocin and its receptor in the ventromedial hypothalamus of the rat.63 The author is unaware of any correlates to this finding in humans.
Apomorphine is a dopaminergic agonist with affinity for dopamine D1, but mostly dopamine D2, receptors within the brain that are believed to be involved in sexual function.64 It has been hypothesized that apomorphine may improve sexual interest and arousal by a central mechanism.
A single, randomized, clinical trial of apomorphine, administered sublingually to premenopausal women with normal testosterone levels, presenting with arousal disorder with hypoactive sexual desire disorder, has been conducted. Apomorphine treatment improved sexual desire and arousal versus placebo.65 The extent to which these effects are due to central versus peripheral drug action requires further research.
Hormonal evaluation of the premenopausal woman presenting with low libido
Evaluation of loss of libido requires a sensitive, multisystem approach, including both physical and psychosocial factors.
History and examination
It is critical to establish whether the woman has ever experienced satisfactory sexual activity, how long she has felt sexual well-being to be a problem, and the extent to which this is causing her distress. The quality of the current relationship should be discussed, and other psychosocial stressors considered. All women need to be screened for depression as a primary cause of their female sexual dysfunction.
A complete gynecologic history should be taken, and the possibility of iron deficiency, thyroid disease, or hyperprolactinemia addressed. In the presence of regular cycles (periods every 21-35 days), dysfunction of the hypothalamic-pituitary- ovarian axis is unlikely, excluding estrogen deficiency and hyperprolactinemia. Amenorrhea before age 40 years requires full assessment.
A general physical examination should include assessment of thyroid status, and presence of anemia or galactorrhea. Gynecologic examination should include a pelvic examination with attention to signs of vaginal atrophy; size of the introitus; presence of discharge; and evidence of infection, vulvodynia, and deep tenderness (see Chapters 9.2-9.5).
Laboratory assessment (see Chapter 6.3)
In women presenting with low libido and fatigue, one should routinely measure iron stores (which might be low despite normal hemoglobin) and thyroid-stimulating hormone, to exclude subclinical thyroid disease; on clinical suspicion, other investigations should be conducted for chronic fatigue. Measurement of estradiol and follicle-stimulating hormone is indicated only to diagnose premature ovarian failure in amenorrheic women. Prolactin should be measured in the setting of oligomenorrhea, amenorrhea, and/or galactorrhea.
Free or bioavailable (non-sex hormone-binding globulin- bound) testosterone measures are the most reliable indicators of tissue testosterone exposure. High levels do not predict higher libido; however, a level above average probably rules out androgen insufficiency as a cause of the problem. Timing of measurement to prevent misdiagnosis of low testosterone is critical. Blood should be drawn between 8 and 10 am because of the diurnal variation of testosterone, which has higher levels at this time.12 Testosterone levels reach their nadir during the early follicular phase, with small but less significant variation across the rest of the cycle.10,66 Thus, blood should be drawn after day 8 of the cycle, and preferably before day 20. A serum sample is preferred to plasma.
The reference standard method to measure free testosterone is considered by many investigators to be equilibrium dialysis. However, this method is labor-intensive and expensive, and not feasible in clinical practice. The Sodergard equation can be reliably used to calculate free testosterone if total testosterone, albumin, and sex hormone-binding globulin are known.67,68 Measurement of free testosterone by analog assays is unreliable and should not be used in clinical practice.69 The free androgen index (nmol/l total testosterone x 100/nmol/l sex hormonebinding globulin) has been used as a surrogate for free testosterone, but it is unreliable when sex hormone-binding globulin levels are low.70
The measurement of sex hormone-binding globulin is not controversial, is relatively simple to perform, and has good reproducibility.
Dehydroepiandrosterone is usually measured in the sulfated form, dehydroepiandrosterone sulfate, because the half-life is much longer, resulting in more stable levels. The immunoassay for dehydroepiandrosterone sulfate is relatively robust and simple to perform. Dehydroepiandrosterone sulfate does not vary in concentration within the various phases of the menstrual cycle, and is not bound to dehydroepiandrosterone. It also does not seem to be affected by estrogen therapy at standard doses. A number of authors have shown normal, age-related decline curves for dehydroepiandrosterone sulfate, which are all quite compatible. If low levels are found, a morning cortisol level should be drawn to rule out adrenal insufficiency.
Table 13.1.2. Causes of low bioavailable testosterone in women
Table 13.1.3. Basic biochemical investigations for women presenting with low libido
It is inappropriate to treat premenopausal women with ovulatory cycles with estrogen therapy for female sexual dysfunction. Women found to be amenorrheic should have their underlying problem managed and, when indicated, receive estrogen- progestin therapy. There is no evidence that use of the oral contraceptive pill adversely affects sexual function in otherwise well women, or in women using the oral contraceptive pill to manage dysmenorrhea or menorrhagia. However, oral contraceptive pills containing antiandrogenic progestins may result in lowering of libido in some women.
Although testosterone levels clearly fall with age, and testosterone may prove to be a useful therapy for hypoactive sexual desire disorder in premenopausal women, at present, the use of testosterone therapy in premenopausal women remains highly controversial, as evidence for its efficacy is limited.
Potential adverse effects of testosterone therapy need to be considered, including hirsutism and acne, balding, voice deep ening, and cliteromegaly. Other symptoms associated with exogenous androgen excess may include menstrual disturbances and polycythemia. In the polycystic ovarian syndrome, androgen excess is also associated with abnormal carbohydrate metabolism. However insulin resistance may underlie the etiology of this disorder, such that it is inappropriate to extrapolate the metabolic consequences of polycystic ovarian syndrome to that of simple androgen excess. There is evidence that some women with adrenal androgen excess, as in congenital adrenal hyperplasia, have insulin resistance. Although oral testosterone therapy as methyltestosterone results in lowering of high- density lipoprotein cholesterol,71 there is no evidence that parenteral testosterone therapy has adverse cardiovascular effects.52,72-74 High doses of orally administered androgens, such as methyltestosterone and, to a lesser extent, testosterone undecanoate, may be associated with hepatoxicity (peliosis hepatis, hepatic neoplasms, and cholestatic jaundice), but this has not been a problem for lower-dose therapy.71
It is known that androgens may exert an effect on the endometrium via aromatization to estrogen locally within the endometrium. There is no evidence that exogenous testosterone increases the risk of endometrial cancer or endometriosis.
The greatest concern pertaining to the administration of testosterone to reproductive-aged women is the potential for harm to either the mother or fetus should pregnancy occur during therapy. Wolf et al. studied the effects of a range of doses of testosterone propionate administered subcutaneously to pregnant Sprague-Dawley rats.75 Androgenic effects were seen at a dose of 0.5 mg, which elevated maternal levels of testosterone 10-fold but had no effect on fetal levels. Viability of the offspring was unaffected at any dose. Adverse fetal effects included increased anogenital distance, reduced number of areolas and nipples, cleft phallus, small vaginal orifice, and presence of prostatic tissue. The 0.1-mg dose, which would be estimated to have increased female serum levels about twofold, did not cause any adverse effects.
Many cases of virilization during pregnancy have been reported, usually associated with luteoma of pregnancy or hyperreactio luteinalis. Fuller et al. reported a case of adrenal androgen-producing adenoma causing virilization of a 33-year- old woman, who delivered a virilized, healthy, female fetus. Postpartum, the mother had 2-5-fold excess circulating testosterone, dehydroepiandrosterone sulfate, and androstenedione.76 In contrast, other reports of significant maternal virilization due to a variety of causes have not been associated with fetal virilization.77-79 That virilization of the fetus does not commonly occur and that high levels are required for maternal virilization to occur is consistent with the fact that normal pregnancy is a hyperandrogenic state.79 Testosterone levels begin to rise in the first trimester, free testosterone peaking in the third trimester of normal pregnancy.79 It is believed that high circulating sex hormone-binding globulin and progesterone (which binds the androgen receptor) may protect the mother and fetus from virilization unless androgens are massively elevated.79-81
In the USA, oral formulations of the androgen precursors dehydroepiandrosterone and A-dione are available without prescription as “dietary supplements”. Vaginal and topical administration of dehydroepiandrosterone to women has also been shown to increase testosterone levels appreciably.81,82 In comparison, 100 mg androstenedione administered orally to women raised testosterone levels by approximately 3.5 nmol/l (100 ng/dl) in one study83 and by more than 25 nmol/l (720 ng/dl) in another,84 the latter corresponding to the upper normal range for men. The disparity in results could reflect differences in the purity and formulation of the androstenedione products used in the studies. Safety issues for oral dehydroepiandrosterone include acne, hirsutism, possible hepatotoxicity, and a reduction in high-density lipoprotein-cholesterol and other hepatic proteins (including sex hormone-binding globulin).35,38 In view of the markedly supraphysiologic testosterone levels attained with androstenedione, the risk of virilization during chronic use in women is considerable.84
Androgen precursors are also estrogen precursors and thus may raise both testosterone and estradiol/estrone levels. There are insufficient data to support their use for the purpose of managing female sexual dysfunction.
Any premenopausal woman treated with androgen therapy needs thorough counseling regarding contraception and risk of adverse effects on a fetus. Monitoring should include assessment for signs of androgen excess, regular breast and pelvic examination, monitoring of serum androgen levels, and, in the presence of abnormal bleeding, endometrial biopsy. When testosterone is administered, continuation for longer than 6 months should be contingent on a clear improvement in sexual function and satisfaction. Although no adverse effects on lipids have been found with short-term parenteral therapies, a lipid profile, and, in the presence of a family history of diabetes or significant obesity, fasting insulin and glucose levels should be considered. Additional biochemical investigations, such as liver function tests, should be based on clinical judgment.
Conclusions and recommendations
Although hormones have an important role in the maintenance of female sexual function, there is currently insufficient evidence to support the use of hormonal therapy in the general management of otherwise well premenopausal women with female sexual dysfunction. As testosterone levels decline prior to the menopause and do not vary with natural menopause, it is tempting to extrapolate from the increasing data from studies in postmenopausal women that support the use of testosterone therapy for female sexual dysfunction. However, before such therapy can be broadly recommended, further studies are needed. Such studies may support the preliminary evidence for the effectiveness of testosterone in increasing libido, arousal, and orgasm in premenopausal women. However, safety data for testosterone therapy for premenopausal women are lacking, and the long-term safety of exogenous testosterone in women requires study before long-term use can be recommended. The current evidence for the effectiveness of dehydroepiandros-terone and androstenedione is also inconclusive.
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