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Special Articles: Hormones and Reproductive Health |
Neuroendocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114
Address all correspondence and requests for reprints to: Karen K. Miller, M.D., Neuroendocrine Unit, Bulfinch 457B, Massachusetts General Hospital, Boston, Massachusetts 02114. E-mail: kkmiller{at}partners.org
Abstract
Physiological and pathological processes as well as iatrogenic interventions may result in androgen deficiency compared with levels in young healthy women. Whether relative androgen deficiency results in a clinical syndrome similar to that reported in men, including osteopenia, increased fat mass, decreased libido, and diminished quality of life, has not been definitively established. However, preliminary data in postmenopausal women suggest that physiological androgen replacement therapy, which involves substantially lower doses than those used in men, may result in increased bone mineral density, increased libido, and improved quality of life. The safety of androgen preparations that result in supraphysiological levels has not been established in women and would be expected to result in hirsutism, acne, and virilization with chronic use. Androgen preparations that avoid liver metabolism and result in physiological serum androgen levels in women with androgen deficiency are not currently available, but are in development. Therefore, although widespread screening and hormone replacement for androgen deficiency cannot be recommended yet, increasing interest in this topic makes consideration of the available data important.
THE CONSEQUENCES of androgen deficiency in men are well established and include severe osteopenia (1, 2, 3, 4, 5), alterations in body composition (5), and diminished libido (6). Although circulating androgen levels in women are substantially lower than those in men, recent attention has focused on whether a syndrome of androgen deficiency, with similar deleterious clinical consequences, exists in women and whether there are benefits of androgen replacement therapy (7, 8). A number of pathological disorders result in significantly reduced androgen levels compared with those in healthy women of reproductive age (9, 10, 11, 12). In addition, decreased androgen production may be observed with normal aging in women (13, 14, 15, 16, 17, 18). Some studies investigating the effects of androgen deficiency and androgen replacement therapy on bone density, quality of life, and libido in women have demonstrated significant benefits (9, 12, 19, 20). It will be important to determine to what extent androgen replacement within the physiologically normal range for young premenopausal women will result in clinically significant improvements. The clinical utility of pursuing a diagnosis of relative androgen deficiency in female patients in the United States is currently limited by the lack of an FDA-approved androgen preparation proven safe and effective for women.
Androgen production in healthy women
Testosterone is a potent androgen in women, 10-fold more potent than androstenedione and 20-fold more potent than dehydroepiandrosterone (DHEA) or DHEA sulfate (DHEAS) (21). Serum testosterone levels in women are approximately 1/10th those in men and increase 20–30% at midcycle due to higher ovarian production (11, 24, 25, 26, 27). Investigation of patients before and after bilateral oophorectomy provides a paradigm for evaluating the relative contributions of the ovaries and adrenal glands to testosterone production in women. Judd et al. reported a 50% decrease in circulating testosterone levels after oophorectomy in postmenopausal women (10). Oophorectomy in younger, premenopausal women resulted in an even greater reduction in testosterone levels than in postmenopausal women (10). This suggests that the ovaries account for at least half of the circulating testosterone levels in postmenopausal women and an even greater proportion in women of reproductive age.
The reduction in testosterone levels after oophorectomy results in large part from cessation of ovarian production of androstenedione, which is the predominant androgen secreted by the ovaries and adrenals and an important precursor of testosterone in women (28). Androstenedione levels are similar in young women and men (22, 23) and, as with testosterone, are reduced approximately 50% after oophorectomy (10), suggesting that half of circulating androstenedione is of ovarian origin in premenopausal women. In contrast, there is only a 20% decrease in androstenedione levels after oophorectomy in postmenopausal women, reflecting the fact that the ovaries are a less important contributor to circulating androstenedione levels in postmenopausal women (10). A 15% increase in androstenedione is present at midcycle, reflecting higher ovarian secretion of the hormone at that time of the menstrual cycle (24, 25).
DHEAS levels are similar in men and women less than 50 yr old. In older men, DHEAS levels surpass those of women because the slope of the decline in DHEAS vs. age curve is steeper in women than in men (14). In contrast to testosterone and androstenedione, more than 90% of circulating DHEAS is derived from the adrenal glands (25).
Causes of androgen deficiency in women
Aging results in a reduction of DHEAS and androstenedione levels, but the effects of age on testosterone are controversial. DHEAS levels decline linearly with age (14, 15, 16, 17, 29), resulting in serum levels in women in their 70’s that are approximately 20–25% of those in 20- to 30-yr-old women (14, 15, 16). Unlike the abrupt reduction in estrogen levels seen with menopause, the slope of declining serum DHEAS levels vs. age remains constant over time. Likewise, most studies demonstrate an age-related decline in androstenedione (18, 30, 31), with a reduction in levels after menopause to half those present in women of reproductive age (30, 32, 33). The effects of age on testosterone and free testosterone levels in women, however, are more controversial (31, 34, 35). Zumoff et al. demonstrated an age-related decrease in serum total and free testosterone levels in 33 premenopausal women, aged 21–51 yr, studied in the follicular phase of the menstrual cycle over 24 h with blood sampling every 20 min (13). However, most studies of testosterone and free testosterone levels after menopause have not demonstrated a persistent decline with advancing age (30, 31), with the possible exception of a transient decrease around the time of the menopause (18). None of these studies compared free testosterone levels in menopausal women to premenopausal levels at midcycle, which are known to be 20–30% higher than during the follicular phase (11, 26, 27). It is unknown whether comparison of free testosterone levels in postmenopausal women with midcycle premenopausal levels would have produced different results.
Pathological processes and iatrogenic interventions that affect adrenal
and/or ovarian function may also result in reductions in circulating
androgen levels compared with those of young healthy women. We have
recently demonstrated that women with hypopituitarism and secondary
hypogonadism and/or hypoadrenalism have markedly reduced serum androgen
levels compared with healthy controls. These women, regardless of age
and whether taking estrogen replacement therapy or not, were all
severely affected compared with controls of similar age and estrogen
therapy status. Moreover, serum testosterone, free testosterone (Fig. 1
), androstenedione, and DHEAS were all
decreased. Women with both hypoadrenalism and hypogonadism were more
severely affected than women with hypoadrenalism or hypogonadism alone.
Finally, women with hypopituitarism lacked the midcycle increase in
serum testosterone, free testosterone (Fig. 1), and androstenedione
seen in healthy eumenorrheic women (11).
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Given the effects of organic pituitary, adrenal, and ovarian disease on circulating androgen levels, stress-induced disturbances of hormonal function might similarly be expected to result in hypoandrogenemia. Spratt et al. studied 20 postmenopausal women in intensive care units with hypercortisolemia secondary to acute critical illness and found reduced serum testosterone and DHEA levels in these women compared with 110 healthy postmenopausal controls (36). Limited supportive evidence of hypoandrogenemia in women with hypothalamic amenorrhea can be found in a small study in which total testosterone levels in 8 women with functional hypothalamic amenorrhea were lower than those in 8 healthy eumenorrheic women (37). We have shown that women with acquired immune deficiency syndrome wasting, a chronically ill population with a high prevalence of amenorrhea, have reduced serum free testosterone and DHEAS levels (38). Moreover, our preliminary data suggest that testosterone therapy may result in beneficial effects on weight and quality of life in this population (39).
Medications that suppress ovarian and/or adrenal function may also result in reduction of circulating androgen levels. Estrogen (40, 41), GnRH agonist (42), and glucocorticoid administration (25, 43) are all associated with hypoandrogenemia in women.
Diagnosis
Because of the lack of safe and effective androgen replacement preparations for women, widespread screening for androgen deficiency cannot be recommended at this time. If an evaluation is undertaken, there are a number of gender-specific considerations when approaching the diagnosis of androgen deficiency in women. It is important to note that measurement of total testosterone levels is usually inadequate for the diagnosis of hypoandrogenemia in women. Approximately 66% of testosterone in women is bound to SHBG, a significantly larger proportion than in men (44). Therefore, medications and diseases that influence SHBG levels are particularly likely to affect free testosterone levels. Many factors are known to affect serum SHBG levels. Increases in serum estrogen and thyroid hormone levels result in increased SHBG levels. In contrast, obesity, as well as increases in insulin, GH, glucocorticoid and androgen levels, result in reduced SHBG levels (45). In conditions associated with abnormalities of SHBG, measurement of free testosterone is necessary. The effect of serum estradiol levels on SHBG is particularly important. Because estrogen concentrations vary widely in women, due to both physiological and pharmacological factors, total testosterone levels may not accurately reflect biologically active testosterone levels. Therefore, measurement of free testosterone levels is more important when evaluating hypoandrogenemia in women than it typically is in the evaluation of male hypogonadism. Unfortunately, however, limitations of the currently available free testosterone assays complicate measurement of serum free testosterone levels. Analog assays are widely available, but are at variance with values obtained by dialysis (46). Although dialysis is considered to be the gold standard for measuring free testosterone, it is time consuming, costly, and technically difficult. Calculation of free testosterone levels from serum total testosterone values and SHBG levels may be useful, but has not been adequately studied in women (46). Moreover, available androgen assays lack sensitivity at the lower ranges present in women and especially at the levels observed in women with androgen deficiency. Therefore, the diagnosis of hypoandrogenemia in women, particularly when considering states of relative deficiency, may be difficult.
Effects of androgen deficiency on bone
Hypoandrogenemia is clearly associated with decreased bone density in men (1, 2, 3, 4, 5), but definitive evidence is lacking to establish causality between osteopenia and deficiency of androgens in women. However, there are data to suggest that androgens may play a similar role in maintaining bone mass in women as in men. Abu et al. identified androgen receptors in bone samples obtained from tibial growth plates resected during corrective osteotomies and from osteophytes obtained during shoulder replacement surgeries. The pattern and number of cells expressing androgen receptors were similar in women and men. At sites of bone modeling and remodeling, androgen receptors were expressed in the majority of osteoblasts (47). Studies demonstrate significant correlations between bone density and serum testosterone and free testosterone concentrations in healthy pre-, peri-, and postmenopausal women (48, 49, 50), between DHEAS levels and bone density in healthy postmenopausal women (51), and between testosterone levels and changes in bone mass in perimenopausal women over a 3-yr period (52). Baseline and changes in spinal bone density have been reported to correlate strongly with both free testosterone and DHEAS levels in women with hyperprolactinemic amenorrhea and hypothalamic amenorrhea (53, 54, 55).
The effects of androgen replacement therapy on bone formation and bone
density provide indirect evidence that androgen deficiency is
potentially an important contributory factor to the development of
osteopenia in women. In an open label, randomized trial, Raisz et
al. demonstrated an increase in markers of bone formation in
postmenopausal women taking replacement doses of estrogen plus
methyltestosterone compared with that in women taking
estrogen alone (56). In addition, three randomized studies
of the effects of testosterone administration on bone mineral density
in postmenopausal women have been reported. Davis et al.
randomized 34 postmenopausal women to receive both sc testosterone and
estradiol or estradiol alone, administered as implants every 3 months
for 2 yr. Women receiving the combination treatment demonstrated higher
L1–L4 and trochanter bone densities at 24 months than those receiving
estradiol alone (Fig. 2). Spinal bone
density increased 8.8% over 2 yr in women receiving testosterone and
estradiol supplementation compared with 3.5% in women receiving
estradiol alone. The difference in bone density between groups might
have been even greater if there had been a comparison placebo group, in
which loss of bone mass might have been expected. Mean testosterone
levels for the group remained well within the normal range throughout
the study, but 13 testosterone implants were withheld because of
supraphysiological serum testosterone levels (19). In a
randomized, placebo-controlled trial involving 311 surgically
menopausal women, Barrett-Connor et al. demonstrated that
esterified estrogen (1.25 mg/day) plus methyltestosterone
(2.5 mg/day) resulted in an increase in spine and hip bone mineral
density compared with that produced by conjugated equine estrogen
(0.625 or 1.25 mg/day) alone. A lower dose of esterified estrogen plus
methyltestosterone was not effective (20). In
a smaller study Watts et al. randomized 66 oophorectomized
women to receive oral esterified estrogens (1.25 mg) or oral esterified
estrogens (1.25 mg) plus methyltestosterone (2.5 mg) daily
for 2 yr. Differences in bone density between the two groups did not
reach statistical significance (57). Therefore, some, but
not all, prospective controlled trials have shown that long-term
testosterone replacement added to estrogen therapy may confer
additional benefits on bone density compared with estrogen alone.
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Androgen deficiency in men is associated with an increase in percent body fat (5), and androgen administration results in a diminution in total and visceral fat, an increase in lean mass, and a reduction in total cholesterol and low density lipoprotein (LDL) in men (5, 58). Whether low doses of testosterone, which result in serum levels in the physiological range for women, will reduce visceral fat and alter cardiovascular risk remains unknown. Preliminary data suggest that low dose androgen replacement therapy may exert different effects on body composition in women than those reported in men receiving higher doses. Lovejoy et al. demonstrated that the oral androgen, nandrolone decanoate, at a dose of 30 mg every 2 weeks increased lean body mass and decreased fat mass in postmenopausal women on caloric restriction, findings similar to those observed in men. However, there was an unexpected finding that, in contrast to the pattern of fat reduction seen in men receiving higher doses of androgens, these women experienced an increase in visceral fat, with the reduction in total fat mass attributable to a decrease in sc fat only (59). Davis et al. demonstrated an increase in fat-free mass in 33 postmenopausal women randomized to estradiol (50 mg) plus testosterone (50 mg) implants compared with those given estradiol (50 mg) alone. The women who received estradiol alone demonstrated a reduction in centralized body fat, calculated as fat mass divided by fat-free mass in the abdominal area as measured by dual x-ray absorptiometry. However, the women who received testosterone in addition to estradiol demonstrated no reduction in centralized body fat (60). Because visceral fat is associated with an increase in cardiovascular risk (61, 62), this possible differential gender effect of androgen administration on body composition could be clinically important if confirmed.
There have been concerns that androgens might exert deleterious effects on cardiovascular risk in women. However, testosterone therapy administered by routes that avoid first pass liver metabolism, including sc implants and transdermal preparations, does not appear to attenuate the positive effects of estrogen therapy on lipids or lipoproteins (39, 60, 63). Moreover, a recent pilot study by Worboys et al. suggests that the addition of testosterone to estradiol implant therapy may improve endothelial-dependent and -independent brachial artery vasodilation in postmenopausal women (64). Oral androgens, in contrast, result in deleterious effects on cardiovascular risk factors. Nandrolone decanoate has been shown to increase LDL and decrease high density lipoprotein (HDL) cholesterol. The addition of oral methyltestosterone to estrogen replacement therapy in postmenopausal women has been demonstrated to result in a decrease in HDL levels in standard doses administered to women (56). Similarly, oral DHEA therapy resulted in reductions in HDL levels in one study (9). Therefore, the method and dose of androgen delivery are probably critical factors in determining the overall physiological effects of androgen replacement in women.
Effects of androgen deficiency on libido and quality of life
The effects of androgens on the brain are mediated by androgen
receptors as well as by aromatization of testosterone to estradiol
(65, 66). Androgen deficiency in men is clearly associated
with diminished libido and quality of life (67). Studies
suggest that androgen administration may lead to improvements in these
parameters in women with relative androgen deficiency. Beneficial
effects on libido and quality of life, including mood, have been
demonstrated in postmenopausal women administered short-term
supraphysiological testosterone at doses routinely used to treat
hypogonadal men (68, 69). However, the safety of
administering such high androgen doses has not been established in
women and cannot be recommended. The results of a few randomized,
placebo-controlled, double blind studies of physiological androgen
replacement have recently been reported and demonstrate improvements in
sexuality and quality of life. In an important study of physiological
DHEA replacement (50 mg/day) in women with primary or
secondary adrenal insufficiency, Arlt et al. demonstrated
significant increases in the frequency of sexual thoughts, interest,
and satisfaction compared with placebo (Table 1) (9). In addition,
DHEA therapy significantly improved overall well-being,
depression, and anxiety (9). Hunt et al.
demonstrated a significant improvement in evening mood and fatigue in a
group of 44 men and women with Addison’s disease after administration
of this same dose of DHEA (12). In both of
these studies, posttreatment androgen levels were within normal limits
for women. Davis et al. conducted a 2-yr prospective,
placebo-controlled trial of the effects of testosterone implants plus
estrogen vs. estrogen alone in 34 postmenopausal women. The
testosterone-treated women reported higher scores on sexual activity,
satisfaction, pleasure, and orgasm scales than women who received
estrogen alone (19). Mean testosterone levels remained in
the normal range, although a number of women experienced
supraphysiological testosterone levels, necessitating the withholding
of a subsequent testosterone implant (19). In a recent
report by Shifren et al., 75 oophorectomized women receiving
estrogen were randomized to receive 150 or 300 µg testosterone daily
or placebo using an investigational transdermal delivery system for 12
weeks. The 300-µg dose, which resulted in mean free testosterone
levels at the upper limit of normal, was associated with significant
improvements in sexual frequency, pleasure, and mood. The percentage of
women who had positive sexual experiences increased 2- to 3-fold from
baseline. The effect of the 150-µg dose, which resulted in free
testosterone levels in the physiologically normal range, was not
different from that of placebo (63). To date, there is
only one small study investigating the effects of androgen
administration on libido in women with hypogonadism of central origin.
In this study testosterone undecanoate was administered to 8 women with
hypothalamic amenorrhea. An improvement was demonstrated in physical
parameters associated with sexual functioning compared with placebo.
However, testosterone administration resulted in mean total
testosterone levels 1.5 times the upper limit of normal for women
(37). Therefore, studies to date in women with natural or
surgical menopause suggest that androgen replacement may improve libido
and sexual function, although physiological levels were exceeded in
some studies. Further studies are necessary to determine the effects of
androgen therapy on libido in women with hypothalamic and pituitary
causes of amenorrhea.
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The clinical utility of androgen replacement therapy for women is currently limited by the lack of available safe and effective androgen preparations that reliably result in serum androgen levels in the normal range for women. Subcutaneous testosterone implants are approved for use in the United Kingdom and Australia, but not in the United States, and result in variable serum testosterone levels in individual women, necessitating careful monitoring. Oral testosterone undecanoate is available in Europe, but not in the United States, and results in supraphysiological testosterone levels even at the lowest available doses (70). Similarly, im testosterone administration results in peak serum levels above the normal range for women. Oral methyltestosterone is available in combination with esterified estradiol (Estratest; Solvay Pharmaceuticals, Inc., Marietta, GA). However, in contrast to parenterally administered androgens, oral androgens can result in unfavorable lipid and lipoprotein effects, as previously discussed. In addition, methyltestosterone, in higher doses than marketed for use in women, has been associated with liver abnormalities, including tumors and cholestatic jaundice (71). DHEA is also metabolized by the liver. Therefore, transaminases, lipid, and lipoprotein levels should be followed in women who receive oral androgens.
Side effects reflective of hyperandrogenism have been reported in women receiving methyltestosterone, DHEA, testosterone, and nandrolone therapy. One study provides a statistical analysis of the incidence of side-effects in women treated with androgens. In that study a significantly higher incidence of facial hair growth and acne was demonstrated in patients who received daily methyltestosterone (2.5 mg) plus esterified estrogens (1.25 mg) compared with those receiving the estrogen preparation alone. The most frequent side-effects reported in this and other studies of androgen therapy in women were an increase in facial hair and acne (9, 12, 39, 57, 59, 63, 72). Alteration of voice range has been reported with sc testosterone implant use (72). Testosterone therapy designed to result in serum levels within the normal range for women might not be expected to result in androgenic side-effects. Two small studies using an investigational transdermal preparation seem to support this hypothesis (39, 63). The studies demonstrated no change in hirsutism or acne scores with the lower dose (150 µg daily), which resulted in free testosterone levels well within the normal range. Likewise, the higher dose (300 µg daily), which resulted in mean free testosterone levels at the upper limit of normal, did not result in increases in androgenic side-effects based on physician observation and rating on a hirsutism scale. However, it was associated with a small number of subjective complaints related to increased facial hair (39). Of importance, studies suggest that physiological DHEA replacement therapy (50 mg daily) results in androgenic side-effects in more than 20% of the patients treated despite serum DHEA and DHEAS levels that fall well within the normal range for women (9, 12). These side-effects include hair loss, which resolved when the dose of DHEA was reduced (9). Not all studies in which supraphysiological doses of androgens were administered to women reported whether subjects experienced side-effects (68, 69). Given the fact that evidence of hyperandrogenism was observed in some women receiving doses of androgens resulting in serum levels within or slightly above the normal range for women, the administration of supraphysiological doses of androgens cannot be recommended. Moreover, even women receiving lower, physiological androgen replacement therapy should be monitored for signs of hyperandrogenism, including hirsutism, acne, and virilization.
DHEA is available without a prescription in the United States and is not FDA regulated. The quantity and quality of DHEA contained in available preparations are not routinely monitored or tested for contaminants. FDA investigators recently determined DHEA levels in 45 commercial products labeled as containing DHEA and found them to contain 0–109.5% of the declared amount (73). In addition, as previously noted, androgenic side-effects have been reported in women receiving a dose of 50 mg daily, designed to result in DHEAS levels within the normal range (9, 12). Therefore, monitoring of serum DHEA levels and side-effects is essential in any patient taking the hormone.
The ideal androgen preparation for women would be FDA approved, avoid liver metabolism, thereby avoiding adverse effects on lipids and lipoproteins, and result reliably in serum levels within the normal range for women. Although no such preparation is currently FDA approved in the United States, transdermal preparations are currently in development and may provide the ideal mode for achievement of physiological androgen levels in women. It should be noted that patches available for use in hypogonadal men deliver testosterone doses that are greatly supraphysiological for women and when manually reduced in size by cutting do not result in proportionally reduced serum testosterone levels. Likewise, testosterone gels, as currently packaged, cannot be reliably parceled by patients to deliver appropriate doses for female administration and are not FDA approved for use in women. Once androgen preparations become available that avoid liver metabolism and reliably result in androgen levels within the normal range for women, it may become appropriate to screen women for androgen deficiency. In those women found to be deficient and to have clinical signs or symptoms that may be attributable to androgen deficiency, a therapeutic trial might then be considered. It is important to note, however, that contraindications to androgen therapy include pregnancy, lactation, signs of hyperandrogenemia, and androgen-dependent tumors. Women with reproductive potential should be counseled about the possible risks to a female fetus of androgen exposure, and androgens should not be prescribed unless a patient is using a reliable method of birth control. Regular pregnancy testing is also important in these women.
Conclusions
Physiological and pathological processes as well as iatrogenic interventions that affect the sources of androgen production in women result in androgen deficiency relative to levels in young healthy women. Whether relative androgen deficiency results in a clinical syndrome similar to that reported in men, including osteopenia, increased fat mass, decreased libido, and diminished quality of life, has not been definitively established. However, preliminary data in postmenopausal women suggest that physiological androgen replacement therapy for women, which involves substantially lower doses than those used in men, may result in increased bone mineral density, increased libido, and improved quality of life. Future studies are needed to confirm these findings and explore further the effects of androgen replacement on body composition in women. The safety of androgen preparations that produce supraphysiological levels has not been established in women and may result in hirsutism, acne, and virilization with chronic use. Androgen preparations that avoid liver metabolism and result in physiological serum androgen levels in women with absolute or relative androgen deficiency are not currently available, but are in development. Therefore, although widespread screening for androgen deficiency and initiation of androgen replacement therapy in women cannot be recommended at this time, future controlled studies of new preparations will be of great interest.
Acknowledgments
The author thanks Anne Klibanski and Joel Finkelstein for their helpful comments in the preparation of this manuscript.
Footnotes
1 This work was supported in part by NIH Grant
M01-RR-01066-24S2. 
Received February 16, 2001.
Revised March 21, 2001.
Accepted March 21, 2001.
References
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, Women with
hypopituitarism; 
, healthy controls. EF, Early follicular phase; MC,
midcycle; ML, midluteal phase. P < 0.03 for all
comparisons between women with hypopituitarism and controls
(
, Estradiol;