Androgens in Health and Disease.pdf - E Library

Chapter 19/Treating Hypoandrogenism in Women 367
not only in the ovaries but also in extragonadal tissues, including bone, adipose, and
brain. Therefore, maintenance of physiological circulating androgen levels in women
ensures adequate supply of substrate for estrogen biosynthesis in extragonadal sites,
such as bone, in which high tissue estrogen concentrations may be required physiologically.
The preovulatory phase of the menstrual cycle is associated with a rise in
intrafollicular and circulating androgen levels, such that peripheral A and testosterone
increase 15–20% at midcycle, followed by a secondary rise in A in the late luteal phase
(2). The mean daily production rate of testosterone in young healthy women is 0.04–
0.144 mg/d when measured in the follicular phase, with a diurnal variation, the highest
rate of production occurring between 4 AM and midday (8). The mean circulating level
of testosterone declines gradually with increasing age rather than a precipitous fall at the
menopause transition (9) such that the levels in women aged 40 are approximately half
that of women in their early twenties (10). Because the percent of free testosterone does
not vary with age, there is an absolute decline in free testosterone with age. Longcope
et al. noted the mean concentration of testosterone in women transiting the menopause
to be significantly less than that of premenopausal women sampled between d 5 and 7
of their regular cycles (9). Women approaching the menopause have loss of the midcycle
surge of free testosterone and A despite apparently regular menstrual cycle (3). Acutely
following bilateral oophorectomy, levels of both testosterone and A decrease by about
50% (11) with a lesser reduction following unilateral oophorectomy (12). Following
menopause, peripheral conversion of A becomes the major source of circulating testosterone,
although there are varying degrees of ongoing ovarian production (13).
Dehydroepiandrosterone and DHEA-S levels fall linearly with age, and this further
contributes to the decline in testosterone (14). Little is known of absolute testosterone
levels beyond menopause, as published studies have either included few women or have
been extensively statistically manipulated (12). Other iatrogenic causes of low testosterone
include nonsurgical oophorectomy—for example, the use of gonadotropin-releasing
hormone (GnRH) antagonists, chemotherapy or radiotherapy, and the use of
exogenous oral estrogens or glucocorticosteroids (15). The oral contraceptive pill or oral
estrogen-replacement therapy (ERT) significantly lowers circulating free-testosterone
levels (16) by increasing SHBG and suppressing pituitary LH secretion and, thus, may
render a woman hypoandrogenic.
Miller et al. have elegantly demonstrated profound androgen deficiency in women
with hypopituitism (17). Similarly, women with premature ovarian failure have reduced
circulating androgens (18).
ANDROGENS AND MOOD
Following surgical menopause, the addition of intramuscular testosterone therapy to
estrogen replacement results in women feeling more composed, elated, and energetic
than with estrogen alone (19). Other studies have demonstrated positive effects of testosterone
in perimenopausal and naturally postmenopausal women (20,21).
Transdermal testosterone replacement in surgically menopausal women significantly
improves the Psychological General Well-being Index score over placebo, with the
greatest change being in improved general well-being and less depressed mood (22). We
have recently demonstrated improvements in all the parameters of the Psychological
Well-being Index in premenopausal women presenting with low libido treated with