Androgen Replacement in Hypogonadal Women

Premenopausal circulating testosterone levels in women are approximately 10-fold lower than those seen in healthy men (22). They are maintained by the

Table 1

Who to Screen for Testosterone Deficiency

Adult women (receiving estrogen therapy or not)

With a history of premenopausal pituitary, adrenal, or ovarian failure With postmenopausal complaints of reduced libido Adult men (presenting with)

Incomplete/absent secondary sexual development (for example, scanty beard development or reduced testicular size) Complaints of fatigue, reduced libido, and/or sexual dysfunction, especially those With chronic illness and complaints of fatigue, sexual dysfunction and/or reduced libido

Receiving chronic supraphysiologic glucocorticoid treatment Over age 60 A positive ADAM questionnaire response score indirect production of testosterone from adrenal dehydroepiandrosterone (DHEA) and androstenedione and by the direct secretion of testosterone from the ovary. Adrenal DHEA secretion begins to decline in most women after the age of 30. This has been referred to as "adrenopause" and occurs at differing rates between individuals. Ovarian testosterone secretion declines by approximately 30% at menopause and then disappears almost entirely within the next decade. Although few studies have investigated the biologic effects of testosterone in women, several reports indicate that testosterone supplementation in ovariecto-mized women and some late menopausal patients results in a significant improvement in libido and sexual fantasy. More recent reports suggest, in addition, that testosterone supplementation may improve energy and depression (23) (Table 1).

Suspected testosterone deficiency is confirmed by a serum bioavailable or free testosterone value below the normal range for a premenopausal adult woman. As discussed later, these tests are more sensitive than the more commonly available total testosterone assay. Low-dose testosterone supplementation can be carried out using oral preparations containing methyl testosterone, sublingual testosterone, intramuscular long-acting testosterone esters, or compounded transdermal preparations. The most commonly used oral preparation is Estratest™, a combination of conjugated estrogens and methyl testosterone.

When administered alone, oral androgens have been shown to impact significantly on hepatic lipid metabolism by decreasing high-density lipoprotein (HDL) and increasing low-density (LDL). In contrast, estrogens alone both raise HDL and lower LDL. Lipid studies before and after the daily oral administration of 1.25 mg esterified estrogens and 2.5 mg of methyl testosterone (doses similar to those found in Estratest) showed significant decreases in total and HDL choles terol and a decline in triglycerides (24). This finding suggests that the conjugated estrogens in this preparation were not able to offset the deleterious HDL effects of the oral androgen.

Sublingual testosterone is rapidly absorbed into the systemic circulation but has a very short half-life. Thus repeated doses throughout the day would be required to maintain circulating levels of testosterone in a consistent physiologic range. A recent publication utilizing transdermal testosterone in hypoandrogenic women demonstrated effective restoration of high-normal serum free and bioavailable testosterone levels and midnormal premenopausal circulating testosterone levels, with improvements in libido, sexual function, and depression symptomatology. At this writing, however, neither the preparation used in that study nor other low-dose transdermal preparations have been approved for use by the Food and Drug Administration. Some clinicians have utilized compounding pharmacies to prepare reduced-strength topical testosterone creams or gels. However, there are no published studies regarding the efficacies or safety of these preparations.

I currently prefer to use intramuscular testosterone esters for female testosterone replacement. Intramuscular testosterone enanthate (Deletestryl™) or cypionate (Depotestosterone™) in doses of20-50 mg intramuscularly every 1014 d appears to reverse most sexual complaints, with only an approximate 10% incidence of mild hirsutism, which is usually reversed by lowering or discontinuing the medication. The much higher doses of testosterone supplementation used in men have occasionally been associated with increased fluid retention as well as increases in blood pressure and/or hemoglobin concentration. To date, however, these adverse long-term side effects have not been reported with low-dose testosterone supplementation in women.

recognition and treatment of hypogonadism in adult men

Somewhere between 4 and 5 million adult men in this country are believed to suffer from testosterone (T) deficiency. However, since these estimates are largely based on data using measurements of total testosterone (tT) values in blood, this incidence may be a significant underestimate (see the following discussion). Furthermore, only approximately 5% of recognized hypogonadal patients are currently receiving treatment, suggesting that T deficiency in adult men is both significantly underrecognized and undertreated.

The lack of T in men, like estrogen deficiency in women, has not been clearly linked to long-term increased mortality, but a number of metabolic derangements resulting from this condition are likely to have significant impact on quality of life (Table 1). These include loss of lean body and bone mass, increased fat mass, infertility, fatigue, depression, and loss of libido.

The appearance of primary gonadal failure in healthy mature men prior to their eighth decade is relatively uncommon and is usually linked to direct testicular damage resulting from gonadal radiation exposure, systemic chemotherapy, adult mumps orchitis, or castration. In contrast, secondary gonadal failure is relatively common. Hypothalamic or pituitary lesions (i.e., tumors or infiltrative diseases such as sarcoidosis or hemochromatosis) are relatively infrequent, whereas selective hypogonadotrophic hypogonadism appears to be a relatively common result of head trauma (25). Physical stress owing to injury or illness has been linked to transient hypotestosteronemia. Emotional stress can also be a presumably reversible cause of secondary hypogonadism. Unquestionably, however, the most common cause of T deficiency in otherwise healthy men appears to be a physiologic process that accompanies aging. Gradual declines in T production have been shown to begin at about 40 yr of age in most healthy men. This stems from an apparent decrease in hypothalamic/pituitary feedback sensitivity to circulating T, which results in a gradual decline in T production in the face of normal serum LH and FSH concentrations. This secondary hypogonadism is often subtle, and it progresses until about age 70. Thereafter T levels continue to decline but are associated with increasing levels of LH, suggesting the appearance of an additional primary gonadal failure component in this age group. This phenomenon has been given several names, the most prevalent of which is andropause.

The gradual declines in T secretion observed in men aged 40-70 is often obscured clinically because it usually is not associated with major declines in circulating tT values. This occurs for two reasons. First, the normal range of tT is rather large, often spanning 250-1000 ng/mL. Small to moderate changes within this range, which, as noted above, occur without increases in gonadotro-pins, are easily missed or, if detected, considered to be clinically insignificant. A second reason is that the fractional conversion of T to estradiol increases with age in men. The resulting increases in circulating estrogen stimulate increased hepatic sex hormone binding globulin (SHBG) production. This results in an increase in tightly bound circulating T with reciprocal declines in free and loosely bound T. The blunted pituitary gonadotropins response to this gives rise to stable or slightly lower T production rates. This sequence of events results in fairly constant tT values despite continually declining circulating fractions of biologically active T.

Using longitudinal cross-sectional data from the Massachusetts Male Aging Study, a recent publication by Feldman et al. (25) has reported that tT drops by 0.8%/yr in men 40-70 yr old and that free testosterone (fT) and bioavailable testosterone (bvT; the sum of free and loosely bound hormone) decline by about 2% annually during the same period. However, data following the same subjects over time revealed a more pronounced drop in tT and fT or bvT of 1.6 and 2-3%/yr, respectively (26). The extent to which these decreases in biologi-

Table 2

Androgen Deficiency in Aging Males (ADAM) Questionnaire^

1. Do you have a decrease in sex drive?

2. Do you have a lack of energy?

3. Do you have a decrease in strength and/or endurance?

4. Have you lost height?

5. Have you noticed a decreased enjoyment of life?

6. Are you sad and/or grumpy?

7. Are your erections less strong?

8. Has it been more difficult to maintain your erection throughout sexual intercourse?

9. Are you falling asleep after dinner?

10. Has your work performance deteriorated recently?

"Screening questionnaire for male hypogonadism. A positive response to questions 1 or 7, alone, or any three other questions, is considered preliminary evidence of hypogonadism. Data from ref. 26.

cally active T result in reduced physiologic function remains ill defined and probably varies between individuals. Nevertheless, most authors agree that serum fT or bvT values in symptomatic patients, which fall below those seen in normal young men, are consistent with a diagnosis of hypogonadism.

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From PMS To PPD

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