American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the Diagnosis and Treatment of Menopause

Androgen Deficiency in Postmenopausal Women

Androgen therapy has been proposed as a component of treatment for postmenopausal women. In this section, the rationale and evidence for this proposal will be reviewed and evaluated.

All women produce some androgens, which may contribute to the maintenance of normal ovarian function, bone metabolism, cognition, and sexual behavior. Testosterone has direct effects by the stimulation of androgen receptors and also serves as a prohormone in its conversion to estradiol. The adrenal androgens— androstenedione, DHEA, and DHEAS—are very weak androgens but may be converted to testosterone and estrogen. Moreover, symptoms ascribed to androgen deficiency, such as low libido, decreased sexual response, decreased sense of well-being, poor concentration, and fatigue, may also be symptoms of estrogen deficiency. Therefore, it is possible that symptoms ascribed to androgen deficiency may be a result of either androgen deficiency itself or a deficiency of estradiol.

The following questions may be asked: Does an androgen deficiency state exist in postmenopausal women? In fact, does an androgen deficiency state exist in premenopausal women? In premenopausal women, the only therapy directed at androgens is intervention to reduce rather than increase androgen levels.

The addition of androgen supplements to hormone replacement therapy in the menopausal woman dates from the 1940s. The efficacy of such therapy continues to be debated at this time. Two recent publications have summarized much of what is known or has been speculated about the future of androgen therapy for menopausal women. A 2001 Princeton consensus conference^[93] proposed a conservative definition of androgen deficiency in menopausal women (LOE 3). Three components were necessary for this diagnosis:

1. Clinical symptoms of androgen insufficiency must be present. Symptoms of androgen deficiency include loss of libido and decreased sexual motivation, arousal, fantasy, and enjoyment. Other nonsexual symptoms include loss of motivation, insomnia, depression, headache, loss of sense of well-being, fatigue, poor concentration, and decreased lean body mass in conjunction with osteopenia or osteoporosis^[94].
   
   

2. Androgen deficiency should be diagnosed only in women with adequate estrogen status.
   
   

3. Free testosterone levels should be at or below the lowest quartile of the reference range found in reproductive-age women (20 to 40 years old).

Further discussion of androgen therapy for post-menopausal women was provided in a 2004 Mayo Clinic Proceedings supplement.^[95] This publication emphasized that the FDA has never approved any use of androgens in women and that any such therapy must be considered an off-label application. At this time, the FDA has postponed approval of a testosterone skin patch for use in menopausal women. Most investigators recommend that androgen therapy should be offered only when the patient continues to have problems while receiving adequate estrogen replacement therapy.

A diagnosis of androgen deficiency in post-menopausal women is challenging, not only in the definition of androgen-deficiency symptoms but also because of technical difficulty in the laboratory measurement of testosterone and unrealistic "normal ranges" for post-menopausal women. Many commercial laboratories list normal serum testosterone levels up to 70 to 80 ng/dL; however, research publications have found levels between 30 and 40 ng/dL in premenopausal^[96] and between 20 and 30 ng/dL in postmenopausal^[97,98,99] normal female subjects. In women, high-performance liquid chromatography/tandem mass spectrometry is a more accurate method for measurement of serum testosterone levels.^[100,101] An even greater variation exists in the normal ranges for DHEA, DHEAS, and androstenedione.

Some investigators have suggested that it is more accurate to measure free testosterone or to calculate a free androgen index through measurement of total testosterone and sex hormone-binding globulin. Even these measurements provide considerable variation in what can be considered normal.^[102]

In normal postmenopausal women, the ovarian production of androstenedione declines, the adrenal gland becomes the primary source of this precursor, and an overall 50% reduction occurs in the serum androstenedione concentration. Consequently, there is a decrease in the rate of production of testosterone from the peripheral conversion of androstenedione to testosterone.^{[96,97,98,103,104]} Ovarian production of testosterone remains relatively stable; in fact, the relative contribution of the ovarian testosterone to total testosterone increases, as evidenced by a testosterone decline of about 40% to 50% after oophorectomy in postmenopausal women.^[98,103] The adrenal androgens DHEA and DHEAS also decline with aging, independent of menopause; accordingly, by 40 to 50 years of age, their values are about half those in younger women.^[94,105] The decline of serum testosterone concentrations is small after menopause despite the decrease in adrenal androgens,^[94,104] an indication that DHEA is a minor source of androstenedione and testosterone in older women.^[106] In contrast to the sharp decline in production of estrogen at menopause, the modest decline in ovarian production of testosterone is maintained with gonadotropins.^[96,97,105]

Loss of sexual function, diminished libido, decreased bone mass, decreased muscle mass, increased fat mass, and depression have all been ascribed, at least in part, to deficiency of androgen in postmenopausal women.^[102] Clinical trials have been conducted to assess the efficacy of androgen replacement therapy in addressing these problems and its safety in this setting.

Cameron and Braunstein,^[107] after a MEDLINE search, reviewed 14 reports of double-blind, randomized, placebo- or estrogen-controlled evaluations of androgen therapy in menopausal women with low libido. In 8 of the 14 studies, serum testosterone levels increased as much as 5 times above baseline levels, resulting in hyperandrogenemia. Androgen levels were not measured in 4 studies, and in the remaining 2 studies, one reported a physiologic level of free testosterone and the other described a physiologic level of total testosterone but a supraphysiologic free androgen index. These data suggest that, to be effective, androgen levels must be increased above normal (LOE 2a).

Estrogen therapy in postmenopausal women does not affect the serum pharmacokinetics of transdermally administered physiologic testosterone.^[108] It is interesting that no published clinical trials have included a third group treated with estrogen plus estrogen to compare with the estrogen only and estrogen plus testosterone groups. If one considers that testosterone serves as a prohormone to be converted to estradiol, it is possible that some seemingly androgen-induced effects could actually be estrogen effects. Most, if not all, symptoms of androgen deficiency might also be considered symptoms of estrogen deficiency. Consequently, it might be informative for each study of androgen therapy in menopausal women to include a group given a higher dose of estrogen that could be compared with groups receiving estrogen only and those receiving the same dose of estrogen plus an androgen.

Sexual Function. Reports of the effects of androgen replacement therapy on sexual function in menopausal women are conflicting. Administration of testosterone by injections,^[109] pellet implants,^[93,102,110] or methyltestosterone orally^[111,112] at supraphysiologic doses improves libido, sexual arousal, frequency of sexual fantasies, sexual function, body composition, muscle strength, and quality of life in comparison with administration of estrogen alone. Physiologic replacement testosterone therapy seems to have an inconclusive effect on sexual function.^[113] Adverse effects, however, were also reported when the androgen replacement therapy resulted in supraphysiologic levels. Acne, hirsutism, and a significant reduction in serum HDL cholesterol levels have been described^[102] (LOE 2b).

Bone Metabolism. A direct correlation between bone density and serum androgens has been noted in postmenopausal women.^[114] The effect of androgen therapy on bone in post-menopausal women has been examined in studies of androgen alone and of androgen in combination with estrogen. Numerous observations are compatible with androgen-induced improvement in bone variables, particularly with use of androgen doses that exceed the normal range.^{[93,115,116,117,118,119]} Biochemical markers of bone reabsorption and formation in women receiving estrogen or estrogen plus androgen showed evidence of increased bone formation, whereas bone reabsorption decreased only in women receiving estrogen alone.^[115] In another report,^[116] androgen monotherapy in postmenopausal women with osteoporosis reduced markers of bone turnover (serum alkaline phosphatase concentrations and urinary calcium excretion) to the same extent as did estrogen (LOE 2c).

Adrenal Androgen Replacements. Serum concentrations of DHEA and DHEAS decline with aging in both men and women. DHEA replacement therapy for aging men and women has been proposed to boost immune function and alleviate postmenopausal and perimenopausal symptoms (for example, hot flashes, insomnia, irritability, loss of libido), improve memory, and promote a sense of well-being^[98,120] (LOE 3). A dose of 50 mg of DHEA daily in comparison with placebo in 60 perimenopausal women significantly increased serum DHEAS and testosterone concentrations.^[121] Symptomatic improvement was not documented. Thus, although DHEA can improve testosterone levels in women, it does not appear to offer relief of symptoms or improvement in cognitive function.^[119,122]

The use of androgens other than testosterone (such as DHEA, DHEAS, or androstenedione) cannot be recommended. These substances are available as over-the-counter drugs and are not controlled relative to the amount of medication that is actually present in each tablet. A recent report evaluating amounts of DHEA in over-the-counter tablets found that three brands had no DHEA at all, one had 149% of the labeled amount, and most had 59% to 82% of the labeled amount^[121] (grade D).

At the current time, the following preparations might be considered for androgen therapy in menopausal women (grade C):

• or oral administration: Methyltestosterone
  
  

• For injection: Testosterone enanthate, testosterone cypionate
  
  

• For topical application: Androderm, AndoGel, Testim
  
  

• Not available in the United States: Testosterone undecanoate, testosterone pellets

All these preparations except methyltestosterone are designed for use in men with testosterone deficiencies and would not be appropriate in women. Other therapeutic options are being investigated. A testosterone skin patch is undergoing clinical trials. Over-the-counter preparations cannot be recommended until their consistent quality can be documented. Therapeutically, caution must be exercised if the most common androgen, methyltestosterone, is used. This weak androgen cross-reacts with the measurement of serum testosterone in most laboratory kits. Consequently, one might see a considerable elevation of the serum testosterone level that is a result of cross-reactivity of this weak androgen. In fact, when testosterone levels are measured after chromatographic separation from methyltestosterone, the administration of methyl-testosterone results in a reduction in the serum testosterone concentration.^[123] The potential side effects of androgen replacement therapy in women are dependent on the dose and include acne, hirsutism, deepening of the voice, and clitorimegaly. Lowering of the HDL cholesterol level is a concern, and long-term studies are needed to assess the cardiovascular benefits or risks of androgen therapy.^{[93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109]} A recent study by Sturgeon et al^[124] suggested that higher serum concentrations of testosterone or estradiol are risk factors for breast cancer in pre-menopausal women.

Overall, in selected, symptomatic, postmenopausal women, or women who have undergone bilateral oophorectomy, estrogen replacement alone may not be adequate therapy but should be implemented first (grade C). Combined estrogen-androgen therapy may be used in those patients who continue to have symptoms of androgen deficiency while receiving estrogen therapy (grade C). Because endogenous androgen production declines after spontaneous menopause as well as after oophorectomy, symptomatic women may benefit from androgen therapy in conjunction with estrogen therapy. The data on androgen therapy in postmenopausal women are suggestive of benefits, but further long-term safety studies are needed. Our recommendations are against the general use of androgen therapy at menopause, except in women with continuing symptoms during adequate estrogen therapy (grade C).

Endocr Pract. 2006;12(3):315-337. © 2006  American Association of Clinical Endocrinologists

Cite this: American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the Diagnosis and Treatment of Menopause - Medscape - May 01, 2006.