Androgens in Women before and after the Menopause and Post Bilateral Oophorectomy: Clinical Effects and Indications for Testosterone Therapy

Abstract

In postmenopausal women, the ovaries produce significant amounts of androgens for many years after the menopause. Bilateral oophorectomy markedly reduces circulating testosterone (T) in both pre- and postmenopausal women. Oral estrogen therapy in postmenopausal women increases sex hormone-binding globulin and decreases T bioavailablity. Circulating androgens decrease with increasing age. The occurrence of an androgen deficiency syndrome associated with loss of libido and sense of well-being is disputed, but in several randomized controlled trials, transdermal T patches produced a significant improvement in hypoactive sexual desire disorder in postmenopausal women who had bilateral oophorectomy and in some women who had a natural menopause. T therapy is legitimate and is clinically indicated in such women. T therapy may have other benefits in postmenopausal women including an increase in lean body mass and bone mineral density. T therapy should become an integral part of hormone therapy in selected postmenopausal women in the future.

Keywords

androgens HRT hypoactive sexual desire disorder libido menopause oophorectomy testosterone transdermal therapy women

Androgens are quantitatively the predominant sex steroid in women. Plasma levels are measured in micromolar and nanomolar levels compared with picomolar levels of estrogens. The major circulating androgens in descending order of concentration are; dehydroepiandrosterone sulfate (DHEAS), dehydroepiandrosterone (DHEA), androstenedione (ANDR), testosterone (T) and dihydrotestosterone (DHT). DHT is primarily a peripheral product of T metabolism and only T and DHT bind to androgen receptors. The other androgens are pro-androgens and act as precursors for the synthesis of T and estrogens. DHEAS and DHEA are primarily adrenal products and are regulated by adrenocorticotrophic hormone. ANDR and T are produced by both the adrenal gland and the ovary and the ovarian production is regulated by luteinizing hormone (LH) [1]. The most significant biologically active androgen is T, which is tightly bound in the plasma to sex hormone-binding globulin (SHBG) and loosely to albumin. The amount of free T is only 1–3% of the total T. Between 65 and 75% of T is bound to SHBG and the remaining 25–35% of T is bound to albumin [2]. The amount of free T plus the fraction of T bound to albumin is regarded as the ‘bioavailable T’.

Measurement of plasma T in women

The low concentrations of T in women and the presence of other closely related steroids make the direct measurement of T very difficult. The widely used radioimmunoassay-based measurements of total T have limited precision and specificity. The very low concentrations of free T make its measurements especially difficult and requires the use of the technically difficult equilibrium dialysis. A ‘Free Androgen Index’ (FAI), 100 × total T/SHBG, using radioimmunoassay measurement of total T, has been shown to correlate well with free T measured by equilibrium dialysis (r = 0.99; p < 0.0001) [3]. FAI measurements have been widely used in clinical practice. Some laboratories measure ‘bioavailable T’ (free T + not T estradiol-binding globulin – bound T) by differential precipitation of plasma proteins with ammonium sulfate and the method produces good agreement with T measured by equilibrium dialysis [4]. More recently liquid chromatography–tandem mass spectrometry (LC-MS) has been used to measure total T and the free T calculated according to a mass action equation using total T and SHBG [5,6]. Normal reference ranges in 10-year age groups for total and free T measured by LC-MS have been established. The levels of total and free T measured by LC-MS in women using oral contraceptives or HRT have also been reported. The changes in T, DHT, estradiol (E2) and estrone measured by LC-MS in the menstrual cycle in premenopausal women have been described [7]. Poor agreement has been found between total and free T measured by LC-MS and total T measured by four different immmunoassay methods [8]. The application of LC-MS should enable the very low levels of T in women with true androgen deficiency disorders to be measured and should facilitate the diagnosis of androgen deficiency in women [9].

Effects of age, menopause, bilateral oophorectomy, body mass & estrogen & corticosteroid use

Age

In normal healthy women with intact ovaries, all androgens, including DHEAS, DHEA, ANDR and total and free T decline with age. The decline is steepest in the early reproductive years and levels out in midlife [10]. T levels decline by an average of 50% from the early 20s to the mid 40s and, compared with younger women, women aged in the late 40s may be regarded as being relatively androgen insufficient [11].

In the Cardiovascular Health Study (CHS) of women aged over 65 years, total T declined with increasing age until the age of 80 years but free T, as measured by equilibrium dialysis, did not vary with age, possibly due to a concomitant increase in body mass and consequent decrease in SHBG with increasing age [12].

Normal ranges of free T measured by LC-MS for different age groups have been published and show a decline with increasing age [5].

Menopause

In the Melbourne Women's Midlife Project of women aged 45–54 years with intact ovaries, the androgen levels were not influenced by the occurrence of the menopause. The serum SHBG, however, decreased by 43% and the FAI increased by 68–80% from 4 years before the final menstrual period to 2 years after the final menstrual period. The SHBG levels were on average 5% lower for each halving of plasma E2 level and 4% lower for each increase in kg/m² of BMI. The FAI was not related to age or E2 levels but was on average 4% higher for each increase in kg/m² of BMI (p = 0.0001) [13].

In a study of serum collected from the ovarian veins in 13 women undergoing hysterectomy and bilateral oophorectomy there were significant gradients between the ovarian venous blood and peripheral venous blood samples for DHEA, ANDR, T and E2. A gradient for T between the ovarian venous and peripheral blood was present in four out of five women who were more than 10 years postmenopause [14]. The T levels in the peripheral venous blood post-oophorectomy were significantly lower than the preoperative T levels. The ovaries in postmenopausal women are hormonally active and, in women with intact ovaries, contribute significantly to the circulating androgens for at least 10 years after the menopause.

Bilateral oophorectomy

In a study of 100 premenopausal women who were 1–31 years after hysterectomy and bilateral oophorectomy, plasma E2 and total T were, respectively, 78 and 27% lower than the mean values of day 1–10 of the menstrual cycle in women of the same age with intact ovaries [15].

In the Rancho Bernado Study of 684 women aged 50–89 years, both total and bioavailable T levels, after adjusting for age and BMI, were reduced by 40–50% in postmenopausal women who had a hysterectomy with bilateral oophorectomy compared with postmenopausal women with intact ovaries (p < 0.001) [16]. Total T, but not bio available T, levels increased with age in women with intact ovaries reaching premenopausal levels at the age of 70–79 years but did not increase with age in oophorectomized women. The T levels in oophorectomized women were 40–50% lower than those in women with intact ovaries (p = 0.015). SHBG levels increased by 30% with increasing age in women with intact ovaries but were unchanged with increasing age in oophorectomized women (p < 0.001). In women with intact ovaries the increase in SHBG levels with increasing age reduced the levels of bioavailable T [16].

In the Melbourne Study in the age group of 55–64 years in oophorectomized women compared with women with intact ovaries, the mean total T levels were significantly reduced (0.38 vs 0.66 nmol/1; p = 0.02) and the mean free T levels were significantly reduced (5.54 vs 10.81 pmol/1; p = 0.04). Similar results were found in the 65–75 year age group. The mean total and free T levels were on average reduced by approximately half in oophorectomized postmenopausal women compared with postmenopausal women of the same age with intact ovaries [13].

In the CHS of women over the age of 65 years, those with bilateral oophorectomy had 16% lower mean free T as measured by equilibrium dialysis and 23% lower mean total T compared with women who had at least one ovary intact [12].

In cynomolgus macaques, ovariectomy was associated with a significant decrease in ANDR and T irrespective of whether the numbers of primordial follicles was low, intermediate or high, indicating that the ovarian stroma is a main source of androgens after the menopause [17]. Bilateral oophorectomy by removal of the ovarian stroma results in a significant loss of ovarian androgens both before and after the natural menopause.

Body mass

In the CHS study of women over the age of 65 years, overweight women had a 24% higher total T and a 14% higher free T and obese women had a 47% higher total T and a 20% higher free T than normal weight women [12]. In a reanalysis of 13 studies of circulating sex hormones, the levels of androgen were significantly higher in obese women (BMI >30 kg/m²) than in thin women (BMI <22.5 kg/m²). In the obese women, the mean total T was increased by 17% and the mean bioavailable T was increased by 72% compared with the mean levels in the thin women. Estrogen levels were significantly higher (E2 by 47%) and SHBG levels were significantly lower (46%) in obese compared with thin women [18]. In the Study of Women's Health Across the Nation in the USA, T levels were strongly correlated with BMI in both peri- and postmenopausal women [19].

Estrogen use

In the CHS, current oral estrogen users had 47% lower mean total and free T than never users. Estrogens had no effect on T levels in the women who had bilateral oophorectomy suggesting that the increase in SHBG did not entirely explain the fall in free T levels, and that estrogens may have an additional effect via negative feedback on LH production by the pituitary gland in postmenopausal women [12].

Oral contraceptive estrogen–progestin combinations suppress both total and free T levels in women with polycystic ovary syndrome to that in eumenorrheic women, and in normal women to below normal levels. The effects of oral contraceptive estrogen–progestin combinations, however, may not only be due to the exogenous estrogens, but to the androgenicity of the progestins [20,21].

In a review of the literature from 1966 to 2001 it was concluded that:

Circulating androgens decrease with age due to reduced production of androgens by the adrenal gland and by the ovary;

Aromatization (i.e., androgens are converted peripherally to estrogens) increases with age and with increasing body mass;

Estrogens downregulate androgen receptors and androgens downregulate estrogen receptors;

Oral estrogens increase SHBG and reduce endogenous androgen bioavailability due to both the increased binding with increased SHBG and the reduced production of androgens by the ovary, probably due to decreased secretion of LH by the pituitary gland;

The combination of oral estrogens and aging dramatically reduces the endogenous bioavailable androgen milieu [22].

Corticosteroid use

In the CHS, the factor with the greatest impact on T levels was corticosteroid use. Mean total T levels were 75% lower and mean free T levels were 43% lower in women taking oral corticosteroids compared with noncorticosteroid users [12]. Corticosteroids decrease both adrenal and ovarian androgen production. Women treated with corticosteroids are the ones that are most likely to experience the effects of low T levels and androgen deficiency.

Combination of age, oophorectomy, body mass & other factors

In the reanalysis of 13 studies of circulating sex hormones in postmenopausal women, the concentrations of all hormones were lower in older than younger women, the largest difference being in DHEAS, but SHBG was higher in older women. All androgens were significantly lower in women with bilateral oophorectomy than in women with a natural menopause, with a 30% difference in total and bioavailable T. All hormones were higher in obese women compared with thin women, the largest differences being in free E2 and in bioavailable T. SHBG was lower in obese women compared with thin women. Smokers had higher levels of all hormones but lower levels of SHBG than non-smokers. Drinkers of alcohol had higher levels of all hormones and lower levels of SHBG than nondrinkers [18]. Bilateral oophorectomy, body mass, estrogen, corticosteroid and alcohol use and smoking all have significant effects on total and free T levels in postmenopausal women.

Effects of androgens on the breast, endometrium, cardiovascular system, body composition, bone & cerebral function

Endogenous and exogenous androgens have significant effects on the breast, endometrium, cardiovascular system, body composition, bone and cognition.

Breast

The effect of androgens on the breast and on the development of breast cancer has not been fully elucidated [23]. Androgens have been demonstrated to have an inhibitory effect on the proliferation of the mammary epithelium both in vitro and in vivo. By contrast, epidemiological studies have shown a positive association with androgen levels and the incidence of breast cancer [24]. Epidemiological studies of T administered orally have, in general, reported an increased risk of breast cancer whereas studies based on parenteral and transdermal routes of administration of T apparently have not done so [25]. Expression of androgen receptors has been associated with better outcomes in estrogen receptor-positive breast cancers [26]. The addition of T to HRT with estrogen and progestin in postmenopausal women did not increase the incidence of breast cancer and possibly reduced the incidence to that of non-HRT users [27].

Endometrium

The effects of T on the endometrium have been studied by Ki67 immunolabeling in postmenopausal women given oral estradiol valerate 2-mg daily alone and with T undecanoate 40-mg daily. Endometrial proliferation was significantly increased with E2 alone but there was a lesser, nonsignificant increase with T and E2 combined, and no change with T alone [28]. Similar changes were found from Ki67 immunolabeling in cynomolgus monkeys treated with E2 1 mg/day and subcutaneous T pellets [29]. T does not appear to entirely prevent endometrial proliferation induced by estrogens, but does not cause endometrial proliferation or hyperplasia.

Body composition, plasma lipids & cardiovascular disease

In the Study of Women's Health Across the Nation in the USA, total T levels in pre- and perimenopausal women were strongly correlated with BMI, insulin resistance and metabolic syndrome [19]. In the CHS of women aged 67–94 years, after excluding estrogen users and adjusting for estradiol levels, free T but not total T levels were positively related to lean body mass and to total body fat and the correlation was both statistically and clinically significant [30].

In postmenopausal women randomized to E2 implants or E2 plus T implants, women who received E2 alone but not those who received E2 plus T had reduced hip and abdominal circumferences and fat mass/fat-free mass ratio. E2 plus T but not E2 alone resulted in an increase of fat-free mass. Both E2 and E2 plus T were associated with significant reductions in total and low-density lipoprotein cholesterol [31].

T administered by routes that avoid the first-pass effects on liver metabolism including implants and transdermal preparations do not appear to attenuate the positive effects of estrogens on lipids and lipopropteins [31 –33].

There have been concerns that administration of androgens may have deleterious effects on the cardiovascular system and increase cardiovascular risk. Investigations of the relationship between endogenous androgens and atherosclerosis and ischemic heart disease have yielded conflicting results. In the Multi-Ethnic Study of Atherosclerosis, total and bioavailable T were positively associated with increased carotid artery intimal-medial thickness [34]. Lower bioavailable T and higher SHBG levels, however, were associated with increased coronary artery calcium [34]. In the Women's Ischemia Syndrome Evaluation study, there was a significant association between total and free T and the presence of coronary heart disease [35]. In the Coronary Artery Risk Development in Young Adult Women's Study, SHBG, but not total or free T, was inversely associated with subclinical cardiovascular disease [36].

In a population-based prospective study of 651 postmenopausal women not taking estrogens who were followed for 19 years, the age-adjusted concentrations of total and bioavailable T did not differ significantly in women with or without cardiovascular disease and did not predict cardiovascular death [37].

The interpretation of the effects of administration of T on the cardiovascular system and on plasma lipids and lipoproteins in postmenopausal women is difficult because androgens are the main source of estrogens by aromatization, mainly in body fat, postmenopausally. There is no evidence that administration of T by nonoral routes increases cardiovascular risk and T therapy may be of benefit by increasing lean body mass, reducing sarcopenia and increasing muscle mass and strength.

Bone

Bone mineral density (BMD) measurements of the lumbar spine and hip have been shown to correlate with total and free T in pre-, peri- and postmenopausal women [38 –40]. In the CHS study of women aged 67–94 years total T was significantly associated with BMD of the lumbar spine and hip and free T was positively associated with hip BMD [30]. In a comparison of E2 implants with E2 plus T implants administered every 3 months for 2 years in 34 postmenopausal women, BMD of the spine increased by 3.5% with E2 alone and by 8.8% with E2 plus T [41]. In a 2-year double blind study of 311 surgically postmenopausal women treated with esterified estrogen plus methyl testosterone compared with those treated with conjugated equine estrogen in two different dosage regimes, the higher dose of esterified estrogen plus methyltestosterone increased the BMD of the spine and hip more than other regimes [42]. In a 12-month, randomized double-blind, placebo-controlled trial of T in androgen-deficient women with hypopituitarism, the use of T patches delivering 300 μg daily resulted in a significant increase in mean BMD of the hip and forearm [32]. T levels are positively associated with BMD and administration of T may have significant beneficial effects on the bone, particularly in androgen-deficient postmenopausal women.

Cognition

The cognitive consequences of the natural menopause transition are small [43]. In the Melbourne Women's Midlife Project, endogenous estradiol and T levels were significantly associated with semantic memory and verbal episodic memory [44]. In a population-based study in Sweden of 1276 women and 1107 men aged 35–90 years, free T was positively associated with better cognitive functions in men but negatively associated with verbal fluency and possibly other cognitive functions in women [45]. The cognitive scores in surgically menopausal women have been reported to be significantly improved by estrogen and/or T replacement [46]. The relationship to T levels and the effects of oophorectomy and administration of T on cognition in postmenopausal women requires further investigation.

Androgen deficiency

The concept of androgen deficiency in women as a cause of sexual disorders is not new [47]. The symptoms and changes associated with androgen deficiency in women include loss of libido, impaired response to sexual stimulation, persistent unexplained fatigue and a diminished sense of well-being, and constitute an ‘androgen deficiency syndrome’. These symptoms, however, are not specific and have many causes, physical and psychological, apart from androgen deficiency. No studies have linked these symptoms directly with low circulating T levels, but the assays used in many of the studies were not sensitive enough to measure the very low levels of free T in women [9]. A recent study using LC-MS to measure androgen levels in women with hypoactive sexual desire disorder (HSDD) compared with sexually healthy controls demonstrated lower levels of DHEAS and ANDR but no significant difference in the levels of T and a metabolite, androsterone glucuronide, in women with HSDD [48]. There is disagreement on the criteria to be used to define various sexual disorders [49]. HSDD has been defined as low sexual desire, leading to marked distress and the exclusion of other medical, psychological and drug-related causes [50]. In a survey of western European women aged 20–70 years, HSDD was significantly more common in surgically menopausal women than in those who had a natural menopause and in premenopausal women of the same age. The presence of HSDD in postmenopausal women was also highly correlated with other measures of sexual response [51].

The Princeton Consensus Panel in 2002 proposed, as a working definition, that ‘female androgen insufficiency syndrome’ could be diagnosed in women with HSDD symptoms and normal estrogen status in whom the bioavailable T was within the lowest quartile for women of reproductive age [52].

The North American Menopause Society (NAMS), in a 2005 position statement, proposed that the possibility of androgen deficiency should only be considered in women who are estrogen replete and in whom no other contributing factors can be identified. NAMS cautioned that T levels should not be used to diagnose androgen insufficiency. NAMS advised that “postmenopausal women with decreased sexual desire associated with personal distress and with no other identifiable cause may be candidates for T therapy after ensuring that there is a physiological cause for reduced T levels” [53].

In a 2011 update, the International Menopause Society noted that “postmenopausal women with intact ovaries do not usually suffer from androgen insufficiency” and recommended that “androgen replacement should be reserved for women with clinical signs and symptoms of androgen insufficiency” [54].

The Endocrine Society in the USA in 2006 recommended against making a diagnosis of androgen deficiency in women at the present time because “there is neither a well-defined clinical syndrome nor normative data on T or free T in women across their life spans” [55].

Bilateral oophorectomy in both pre- and postmenopausal women is associated with a substantial decrease in the mean levels of total and free T levels (on average approximately 50%) and a significant proportion of postmenopausal women with HSDD following bilateral oophorectomy may reasonably be regarded as being androgen deficient.

T therapy

T therapy has been used in the management of postmenopausal women for over 60 years. One of the first reports of T use in menopausal women was by Robert Greenblatt in the USA who used combined E2 and T implants [56]. Since then, a number of studies have used implants or intramuscular injections of combined E2 and T in postmenopausal women. Most have claimed that women receiving T showed significant improvements in sexual activity, satisfaction, pleasure and frequency of orgasms [41]. Three double-blind trials of oral T therapy, including those using T undecanoate, were carried out between 1998 and 2003 and a Cochrane review of the trials in 2004 concluded that oral T significantly improved libido, sexual function and sexual activity [57]. The effects of T administration by injection or implant may have been due to supraphysiological levels of T and there was concern about the possible adverse effect of oral T on liver function [58].

Because of these concerns, transdermal T patches were introduced with the aim of providing consistent physiological levels of T and avoiding first-pass effects on the liver. Shifren and collaborators carried out the first double-blind, placebo-controlled trial of trans dermal T patches in women aged 31–56 years taking oral estrogens with self-reported impaired sexual function after bilateral oophorectomy [33]. The participants were randomized to one of three 12-week treatments; 150 μg/day T patch, 300 μg/day T patch or placebo. Women who received the 300 μg/day patch reported significantly higher scores of sexual activity, sexual fantasies and orgasms. They also reported significant improvement in well-being and depressed mood. There were no significant side effects and the patches did not negate the beneficial effects of the oral estrogen therapy on vasomotor symptoms. In a Phase II 24-week trial, 318 surgically induced postmenopausal women with HSDD receiving oral estrogen were randomized to receive T patches of 150, 300 or 450 μg/day. Significant increases in sexual desire and sexual activity were found in the 300 μg/day group, but not in the groups treated with 150 and 450 μg/day patches [59]. In a later similar 24-week trial (INTIMATE NM1) of 483 naturally menopausal women with HSDD treated with 300 mg/day transdermal T, the treated women had a significantly increased frequency of satisfying sexual activity, sexual desire and decreased distress [60].

To further investigate the efficacy and safety of transdermal T, two concurrent large, randomized double-blind, multicentre Phase III trials were conducted in the USA, Canada and Australia (INTIMATE SM1 and SM2) on surgically postmenopausal women using 300 μg/day patches or placebo with oral or transdermal estrogens. In the INTIMATE SMI 24-week trial of 562 women with HSDD following bilateral oophorectomy, sexual function increased by 74% in women treated with T compared with 33% in the placebo group, distress decreased by 65% in the T treated group compared with 40% in the placebo group [61]. In the INTIMATE SM2 24-week trial of T patches 300 μg/day in 532 women with HSDD following bilateral oophorectomy on concomitant estrogen therapy, the treated group had significantly increased sexual activity and desire and decreased personal distress [62].

In a 24-week randomized, double-blind, controlled study of 61 women with HSDD following oophorectomy and treated with transdermal E2 and with transdermal T or placebo patches, the T-treated group experienced a significantly increased sexual desire compared with the placebo group [63]. The 52-week APHRODITE study of 814 postmenopausal women with HSDD not taking estrogens compared those using 150 or 300 μg/day T patches or placebo. The treated women in the 300 μg/day group, but not in the 150 μg/day group, experienced modest but meaningful increases in desire and decreases in distress. The rate of adverse events, mainly unwanted hair, was higher in the 300 μg/day group than in the placebo group(30 vs 23%) [64].

In the 6-month randomized, placebo controlled, double-blind ADORE study of 272 naturally menopausal women, predominantly not using hormone therapy, were treated with 300 μg/day T or placebo patches. The T-treated women, with or without concurrent hormone therapy, had significant improvements in sexual function and reduced personal distress compared with the placebo group. Similar numbers of women in the treated and placebo groups reported adverse events, most commonly skin reactions to the patches and similar numbers withdrew from the study. No clinically relevant changes were noted in laboratory parameters. Total serum and free T increased from baseline to within the physiological range at week 24. The increases in geometric means were a total T level of 67.8 ng/dl and free T level of 5.65 pg/ml [65].

A safety and tolerability study of 300 μg/day T patches in 1094 surgically menopausal women with HSDD followed for up to 4 years has recently been reported [66]. There was no increase in adverse effects with time, the most common being skin reactions to the patches and unwanted hair growth. No clinically meaningful changes were seen in a large number of laboratory measurements. The three cases of breast cancer were within the expected rate for age [66].

In 2004, the US FDA reviewed the data on the use of transdermal T patches for HSDD in postmenopausal women and accepted their efficacy, but did not approve the patches because of insufficient long-term safety data. T patches are currently available in Europe and off-label in the USA.

There is now sufficient evidence in at least nine randomized controlled studies for the use of transdermal T patches in women with HSDD, particularly following bilateral oophorectomy. It is sometimes assumed, tacitly, that HSDD only affects an individual woman's feelings and responses. Problems such as loss of sexual desire, inability to respond to sexual stimulation and aversion to intercourse, however, can cause great unhappiness and distress in a family and can lead to the break up of marriages and partnerships and affect a woman's whole life and future. Transdermal T therapy is legitimate and clinically indicated in such women. Postmenopausal women receiving estrogen replacement therapy and premenopausal women on oral contraceptives or selective serotonin uptake inhibitors may also experience HSDD. A case can be made for the addition of T therapy in these women. In the future, T therapy should become an integral part of menopausal hormone therapy in women with problems in sexual function particularly after bilateral oophorectomy.

Future perspective

Androgens play a major role in the physiology, health and well-being of women of all ages. The occurrence, diagnosis and significance of androgen deficiency in women, both clinically and biochemically, needs to be further clarified. The availability of T therapy is uncertain. T implants were withdrawn from the market throughout the world in 2011 causing great distress to many women and their doctors and there is no sign of reintroduction. T patches are not available in some countries and are only available off-label in the USA. T creams have been marketed but their composition, absorption and efficacy have not been scientifically investigated. There are a considerable number of postmenopausal women with HSDD whose well-being is seriously affected by androgen deficiency and whose lives would be greatly benefited by T therapy. T therapy may also be of benefit in preventing bone loss and sarcopenia and preventing fractures. In the years to come, T therapy will have an important place in the care of postmenopausal women, particularly those who have had a bilateral oophorectomy, and possibly other women with evidence of androgen deficiency.

Executive summary

Androgens & testosterone in women

Androgens produced by the adrenal cortex and ovaries are the predominant sex hormones in women. Testosterone (T) is the biologically active androgen.

T is tightly bound to sex hormone-binding globulin (SHBG; 65–75%), loosely to albumin (25–35%) and only 1–3% of T is free. The low concentrations of both total and particularly free T make their measurement difficult.

A ‘Free Androgen Index’ (100 × total T/SHBG) is closely correlated with free T as measured by the technically difficult equilibrium dialysis. Total and free T are now measured by liquid chromatography–tandem mass spectrometry.

Effects of age, menopause & bilateral oophorectomy

The ovaries continue to produce significant amounts of androgens and T for many years after the menopause.

Bilateral oophorectomy markedly reduces total and free T in pre- and postmenopausal women.

Oral administration of estrogens increases SHBG and decreases bioavailable T.

Effects of T on breast, endometrium & the cardiovascular system

These actions of T remain to be clarified but administration of T in postmenopausal women does not appear to produce any harmful effects.

Androgen deficiency syndrome

An ‘androgen deficiency syndrome’ with loss of libido and sense of well-being is well recognized but these symptoms have many other causes.

Hypoactive sexual desire disorder (HSDD) is defined as a loss of sexual desire causing distress without any other cause.

T therapy

Administration of T by implant, intramuscular injection and orally has been used for over 60 years in postmenopausal women. T levels produced by injection or implant of T may be supraphysiological and oral T may have adverse effects on liver function.

Transdermal T patches produce physiological levels of T and avoid first-pass effects on the liver.

Transdermal T patches significantly improved HSDD in postmenopausal women following bilateral oophorectomy in nine randomized controlled trials.

T therapy is clinically indicated in postmenopausal women with HSDD after bilateral oophorectomy and should become an integral part of menopausal hormone therapy in selected postmenopausal women in the future.

Footnotes

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

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