Summary and future directions

Holistic Hormone Balance

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Androgens circulate in appreciable amounts in women. Female serum testosterone levels rely on a complex interplay of hormonal secretion and bioconversion of peripheral prehormones. Testosterone levels are proportional to ovarian and adrenal secretion and peripheral bioconversion of the adrenal androgens DHEAS and DHEA, the predominant circulating androgens. Adrenal androgen secretion attenuates with age in a cortisol-independent fashion due to involution of the reticularis zone of the adrenal cortex. As a result, as women age, less testosterone is produced from peripheral bioconversion of DHEAS and DHEA. With the onset of menopause, while ovarian folliculogenesis ceases, the remaining theca and stroma respond to the elevated, menopausal levels of LH by greatly increasing ovarian testosterone secretion. This compensatory mechanism attenuates the age decline in serum testosterone levels from declining adrenal androgens. The combined effects create a subtle decline in serum testosterone levels with age, with no abrupt decline seen with natural menopause. Indeed, there is a plateauing of testosterone levels because of increased postmenopausal ovarian contribution. When the menopausal estrogen deficiency-related decrease in levels of SHBG are taken into account, there is actually an increase in circulating free testosterone in a woman's post reproductive years.

Most all androgen deficiency in women is not natural, but is iatrogenic. It is secondary to exogenous estrogen supplementation either in the form of oral contraceptives or HRT, particularly if the estrogens are orally administered. With both these therapies, there is a several-fold increase in hepatic production of SHBG, and a subsequent decrease in free testosterone, as well as suppression of pituitary LH secretion, resulting in decreased ovarian drive to produce testosterone. Other causes of testosterone deficiency in women include either adrenal failure or adrenal suppression with corticosteroids. These conditions greatly decrease circulating DHEAS levels and thus remove substrate for a large percentage of circulating testosterone production.

The commonly held axiom that androgens in women are simply steroid byproducts is gradually fading. There is no reason to believe that androgens do not play a physiologic role in women as evidenced by the widespread distribution of androgen receptors in both male and female reproductive and non-reproductive tissues. Careful assessment of the limited evidence available indicates that female androgens, and the replacement thereof, play a role in female sexual function, maintenance of bone mass, maintenance of favorable body morphometric indices, possibly insulin resistance, and cardioprotection.

It must be noted that these studies are limited by the fact that they are small, and involve multiple routes of administration of generally supraphysiologic levels of testosterone. However, modalities of testosterone replacement in women are rapidly evolving towards non-oral, physiologic replacement with the native steroid. With these new, much more appropriate modalities of replacement, more clinical studies need to be performed to assess efficacy in a wide range of end-point parameters. The future in this area is clearly promising.

17.7 Key messages

• Because of the compensatory postmenopausal production of ovarian testosterone, a testosterone deficiency in naturally menopausal women is very uncommon. The vast majority of testosterone deficiency in females is secondary to iatrogenic causes: hormonal replacement, prophylactic oophorectomy, hysterectomy, oral contraceptive use, or corticosteroid replacement.

• A clearly defined constellation of signs and symptoms defining testosterone deficiency in women remains elusive. Biochemical criteria based on testosterone, DHEAS, and SHBG levels are arbitrary at best.

• Testosterone replacement in women, while rapidly evolving, is still several generations behind that of men. Modalities of treatment are hampered by excessive androgenization, use of the non-native steroid, and oral administration with adverse lipoprotein effects. Recent development of a low-dose transdermal testosterone delivery system for women, mimicking physiology, heralds promise for the future.

• The data surrounding efficacy of testosterone replacement in women is hampered by poor study designs, multiple modalities of the testosterone replacement, most of which are supraphysiologic in nature, and lack of a clearly defined deficiency state. However, reasonable data suggests that testosterone replacement at a low dose may enhance sexual function, indices of general well-being, and bone mineral density. Its effects on exercise, muscle mass, lean body mass, insulin sensitivity and cardiovascular risk factors remain to be determined.


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