Androgen Replacement Therapy in Women

Marie Lebbe; David Hughes; Nicole Reisch; Wiebke Arlt

Disclosures

Expert Rev Endocrinol Metab. 2012;7(5):515-529. 

In This Article

Physiology

Androgen Production in Women

In women, the main source of circulating androgens are the adrenal glands and ovaries.[1] The adrenal zona reticularis is the principal source of production of dehydroepiandrosterone (DHEA) and its sulfated ester (DHEAS). DHEAS is the most abundant steroid hormone in the human circulation; nonconjugated DHEA crucially acts as a precursor of sex steroids, whereas DHEAS represents its inactive form.[2] In the adrenal, ovary and peripheral target cells, DHEA is converted to androstenedione and testosterone; both of which can be aromatized into estrogens, with the most commonly secreted estrogen being estrone (E1).[3] Therefore, a rise in testosterone levels will also lead to an increase in estrogens. Testosterone can also be converted to the much more potent androgen 5α-dihydrotestosterone (DHT) (Figure 1).[4] Testosterone and DHT are the only two hormones that bind and activate the androgen receptor in the physiological situation. As opposed to hydrophilic DHEAS, nonconjugated DHEA is lipophilic and therefore can readily enter peripheral target cells of sex steroid action,[2,5] where DHEA is converted to active sex steroids. The intracellular availability and activity of the involved steroidogenic enzymes determine the tissue-specific conversion rate of DHEA to downstream sex steroids (Figure 1).[6] This means that circulating levels of sex steroids and their precursors only partially reflect target cell concentrations.

Figure 1.

Androgen generation in adrenal, ovary and peripheral target cells from the universal sex steroid precursor dehydroepiandrosterone. 3β-HSD: 3β-hydroxysteroid dehydrogenases; 5α-red: 5α-reductases; 17β-HSD: 17β-hydroxysteroid dehydrogenases; DHEA: Dehydroepiandrosterone; DHEAS: Dehydroepiandrosterone sulphate; P450-aro: P450 aromatase; STS: Steroid sulfatase; SULT: DHEA sulfotransferase.

During the reproductive years, the ovary, and to some extent also the adrenal gland, are responsible for the synthesis of testosterone and estradiol.[7] Menopause signifies a permanent cessation of the ovarian contribution to estradiol synthesis and consequently estrone becomes the dominant female hormone, mostly derived via peripheral aromatization of androstenedione.[8] Interestingly, the postmenopausal ovary continues to secrete a substantial amount of androgens. This is due to the increase in luteinizing hormone secretion after the menopause, which stimulates steroidogenesis in ovarian hilar and stromal cells.[9] Indeed, the concentration of testosterone in ovarian veins of postmenopausal women has been shown to be approximately 15-fold higher compared with peripheral vein concentration.[10]

Androgen Levels Throughout the Female Lifespan

Increased production of DHEA, starting around the age of 8 years, with peripheral conversion to testosterone and DHT results in the first appearances of pubic hair, a phenomenon referred to as adrenarche. This process is independent of the onset of menarche and its regulation still remains elusive.[11] A cross-sectional study of 1423 healthy women aged 18–75 years with examination of serum levels of testosterone, DHEAS and androstenedione showed peak levels in the early reproductive years, followed by a steep decline with age. No independent effect of menopausal transition on androgen levels was observed.[12] The age-associated decline in DHEAS is more pronounced compared with the decrease in testosterone[13] and also shows high interindividual variability,[14] reflecting a genetic component. At age 70–80 years, serum DHEAS concentrations have decreased to 10–20% of those found in young adults. This age-associated decline occurs in both sexes and has been termed 'adrenopause',[15] which is slightly imprecise as adrenal glucocorticoid and mineralocorticoid production do not change with age.

Role of Androgens in Women

The androgen receptor, a member of the nuclear receptor family, plays a central role in androgen signaling. However, many effects of androgens depend on more complex signaling pathways, including nongenomic effects and paracrine and autocrine action. Androgen receptors in women are identified in the ovary, breast, brain, muscle, fat, bone, liver and skin.[16] Androgens are essential precursors of estrogen synthesis, mainly occurring in the ovary and a number of peripheral tissues.[2] Androgens also play an important role in the regulation of ovarian follicular growth and development and consequently oocyte maturation, although the exact mechanisms still warrant further investigation.[17] Testosterone is an important driver of female sexuality, enhancing interest in initiating sexual activity and response to sexual stimulation.[18] Androgens are known to have anabolic effects and are, at least in part, responsible for the marked sexual dimorphism in the development and function of muscle, fat and bone.[16] Androgen receptors activation in the brain is associated with greater well-being and with reduced anxiety and depression.[19,20] Furthermore, DHEA itself has well-described neurosteroidal properties, and by exerting anti-γ aminobutyric acid-ergic action, it may have antidepressive potential.[15]

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