madman
Super Moderator
ABSTRACT
Androgens in women, as well as in men, are intrinsic to maintenance of (i) reproductive competency, (ii) cardiac health, (iii) appropriate bone remodeling and mass retention, (iii) muscle tone and mass, and (iv) brain function, in part, through their mitigation of neurodegenerative disease effects. In recognition of the pluripotency of endogenous androgens, exogenous androgens, and selected congeners, have been prescribed off-label for several decades to treat low libido and sexual dysfunction in menopausal women, as well as, to improve physical performance. However, the long-term safety and efficacy of androgen administration have yet to be fully elucidated. Side effects often observed include (i) hirsutism, (ii) acne, (iii) deepening of the voice, and (iv) weight gain but are associated most frequently with supra-physiological doses. By contrast, short-term clinical trials suggest that the use of low-dose testosterone therapy in women appears to be effective, safe, and economical. There are, however, few clinical studies, which have focused on the effects of androgen therapy on pre-and post-menopausal women; moreover, androgen mechanisms of action have not yet been thoroughly explained in these subjects. This review considers the clinical effects of androgens on women's health in order to prevent chronic diseases and reduce cancer risk in gynecological issues.
1. Introduction
In men, and in women, endogenous androgens which include testosterone, dihydrotestosterone (DHT), androstenedione (A), dehydroepiandrosterone (DHEA), and dehydroepiandrosterone sulfate (DHEAS) are synthesized in various tissues including the (i) adrenal glands, (ii) ovaries, (iii) testis, (iv) placenta, (v) brain, and (vi) skin [1].
In women, circulating testosterone is derived in part from ovarian and adrenal gland secretion; by comparison, similar amounts are derived from the enzymatic conversion of A and DHEAS [2]. In the ovary, testosterone production increases during follicular phases and achieves maximal levels at ovulation and the luteal phase [3–15]; the adrenal glands, by comparison, produce only small amounts of testosterone [2]. The bulk of circulating testosterone is reversibly bound to plasma proteins including (i) sex hormone-binding globulin (SHBG) (50 to 60%), and (ii) albumin (40 to 50%). Only 1 to 2% of plasma testosterone is free, and bioavailable [16]; moreover, this free fraction may be further reduced by increased levels of SHBG induced by estrogen replacement therapy [4].
Half of the circulating levels of testosterone and DHT are derived from the enzymatic conversion of circulating adrenal pre-androgens (DHEAS, DHEA, and A) and estradiol [11, 17]. Testosterone conversion to DHT is mediated by 5α-reductase (type I and II Isoforms). Of these androgens, DHT has the greatest affinity for the androgen receptor (AR) and is the most biologically potent of the endogenous androgens. DHT cannot be further aromatized to estrogen [2], thereby enhancing its half-life.
Plasma DHEA is derived from (i) secretion from zona reticularis cells of the adrenal cortex (50 %), (ii) ovarian secretion (20 %), and (iii) peripheral DHEAS metabolism (30 %) [2]. DHEA itself is fragile and may be converted to A by 3β-hydroxysteroid dehydrogenase (3βHSD); subsequently, A may be converted to testosterone by 17β-hydroxysteroid dehydrogenase (17βHSD), as well as to DHT by 5α-reductases in endometrial tissue [8, 9].
In women, approximately one-half of circulating DHEA is derived from pre-androgens [11]; in particular, the zona reticularis accounts for 80% of the DHEAS in females' circulation, [5] with the balance arising from the ovaries [6]. The principal pre-androgen is DHEAS, which is converted into DHEA, DHT, and estrogens [7]. Plasma DHEAS, which exists in substantial concentrations, serves as a large substrate reservoir for conversion to DHEA, androgens, and/or estrogens in peripheral tissues. Substantial plasma concentrations of DHEAS are, in part, a consequence of its avid binding by albumin which prolongs its half-life [18,19]; consequently, plasma DHEAS concentrations are reflective of adrenal androgen production [2]. DHEAS secretion is mainly under hypothalamic/pituitary control, being stimulated by ACTH [2]; however, its secretion is modulated by other hormones such as estradiol, prolactin, and IGF-1.
To a great extent, testosterone is derived from A metabolism by 17βHSD (Type 5) (Figure 1) [10].
2. Androgen receptors in women
3. Androgens and ovarian function
4. Effects of Androgens on the endometrium
5. Effects of Androgens on vulvovaginal tissue and on sexual activity
6. Androgens and breast cancer
7. Androgens and cardiovascular diseases
8. Androgens and metabolic regulation
9. Androgens and neurodegenerative diseases
10. Effect of Androgens on bone metabolism
11. Effect of androgens on muscle mass and performance
12. Future perspective
Although androgen therapy in women is relevant from a clinical point of view, there are many limiting factors. First, gynecologists and internists do not know precisely the benefit of androgen therapy in women. The Endocrine Society “Guidelines” are extremely limitative in the prescription of androgens in women. Furthermore, clinical studies on the therapeutic effects of androgens in women are few. Studies conducted on large populations are necessary to evaluate specific correlations between androgen deficiencies and clinical signs.
13. Conclusions
Diagnosis of androgen deficiency in women is of clinical relevance because restoring physiological levels of androgens is essential in the prevention and treatment of many chronic diseases. However, based on experimental and clinical studies, androgen administration in women under specific clinical conditions, such as loss of sexual desire, loss of muscle mass and sarcopenia, osteoporosis, mental disorders, cardiovascular disease, and memory loss is therapeutically relevant. Androgens are useful in young women for the prevention of diseases and for fertility improvement, by regulating uterine and ovarian function. Androgen therapy in women at physiological doses and with cyclic treatment appears to be safe and well-tolerated. Adverse side effects are typically associated with supraphysiological doses and excessive treatment duration. Testosterone therapy in women can give clinically relevant benefits at low doses [257]. The rational prescription of androgen in women must take into account plasma hormonal levels achieved with the therapy and the clinical benefits. The premature decline in plasma androgen levels in women should be considered a risk factor for health.
The global consensus of the Endocrine Society about the use of androgen therapy in women [258] recommends against the routine prescription of testosterone; the only indication, based on clinical evidence is for the treatment of HSDD. The long-term safety for treatments with testosterone remains to be evaluated, and the panel highlighted the need for more research in this area
Androgens in women, as well as in men, are intrinsic to maintenance of (i) reproductive competency, (ii) cardiac health, (iii) appropriate bone remodeling and mass retention, (iii) muscle tone and mass, and (iv) brain function, in part, through their mitigation of neurodegenerative disease effects. In recognition of the pluripotency of endogenous androgens, exogenous androgens, and selected congeners, have been prescribed off-label for several decades to treat low libido and sexual dysfunction in menopausal women, as well as, to improve physical performance. However, the long-term safety and efficacy of androgen administration have yet to be fully elucidated. Side effects often observed include (i) hirsutism, (ii) acne, (iii) deepening of the voice, and (iv) weight gain but are associated most frequently with supra-physiological doses. By contrast, short-term clinical trials suggest that the use of low-dose testosterone therapy in women appears to be effective, safe, and economical. There are, however, few clinical studies, which have focused on the effects of androgen therapy on pre-and post-menopausal women; moreover, androgen mechanisms of action have not yet been thoroughly explained in these subjects. This review considers the clinical effects of androgens on women's health in order to prevent chronic diseases and reduce cancer risk in gynecological issues.
1. Introduction
In men, and in women, endogenous androgens which include testosterone, dihydrotestosterone (DHT), androstenedione (A), dehydroepiandrosterone (DHEA), and dehydroepiandrosterone sulfate (DHEAS) are synthesized in various tissues including the (i) adrenal glands, (ii) ovaries, (iii) testis, (iv) placenta, (v) brain, and (vi) skin [1].
In women, circulating testosterone is derived in part from ovarian and adrenal gland secretion; by comparison, similar amounts are derived from the enzymatic conversion of A and DHEAS [2]. In the ovary, testosterone production increases during follicular phases and achieves maximal levels at ovulation and the luteal phase [3–15]; the adrenal glands, by comparison, produce only small amounts of testosterone [2]. The bulk of circulating testosterone is reversibly bound to plasma proteins including (i) sex hormone-binding globulin (SHBG) (50 to 60%), and (ii) albumin (40 to 50%). Only 1 to 2% of plasma testosterone is free, and bioavailable [16]; moreover, this free fraction may be further reduced by increased levels of SHBG induced by estrogen replacement therapy [4].
Half of the circulating levels of testosterone and DHT are derived from the enzymatic conversion of circulating adrenal pre-androgens (DHEAS, DHEA, and A) and estradiol [11, 17]. Testosterone conversion to DHT is mediated by 5α-reductase (type I and II Isoforms). Of these androgens, DHT has the greatest affinity for the androgen receptor (AR) and is the most biologically potent of the endogenous androgens. DHT cannot be further aromatized to estrogen [2], thereby enhancing its half-life.
Plasma DHEA is derived from (i) secretion from zona reticularis cells of the adrenal cortex (50 %), (ii) ovarian secretion (20 %), and (iii) peripheral DHEAS metabolism (30 %) [2]. DHEA itself is fragile and may be converted to A by 3β-hydroxysteroid dehydrogenase (3βHSD); subsequently, A may be converted to testosterone by 17β-hydroxysteroid dehydrogenase (17βHSD), as well as to DHT by 5α-reductases in endometrial tissue [8, 9].
In women, approximately one-half of circulating DHEA is derived from pre-androgens [11]; in particular, the zona reticularis accounts for 80% of the DHEAS in females' circulation, [5] with the balance arising from the ovaries [6]. The principal pre-androgen is DHEAS, which is converted into DHEA, DHT, and estrogens [7]. Plasma DHEAS, which exists in substantial concentrations, serves as a large substrate reservoir for conversion to DHEA, androgens, and/or estrogens in peripheral tissues. Substantial plasma concentrations of DHEAS are, in part, a consequence of its avid binding by albumin which prolongs its half-life [18,19]; consequently, plasma DHEAS concentrations are reflective of adrenal androgen production [2]. DHEAS secretion is mainly under hypothalamic/pituitary control, being stimulated by ACTH [2]; however, its secretion is modulated by other hormones such as estradiol, prolactin, and IGF-1.
To a great extent, testosterone is derived from A metabolism by 17βHSD (Type 5) (Figure 1) [10].
2. Androgen receptors in women
3. Androgens and ovarian function
4. Effects of Androgens on the endometrium
5. Effects of Androgens on vulvovaginal tissue and on sexual activity
6. Androgens and breast cancer
7. Androgens and cardiovascular diseases
8. Androgens and metabolic regulation
9. Androgens and neurodegenerative diseases
10. Effect of Androgens on bone metabolism
11. Effect of androgens on muscle mass and performance
12. Future perspective
Although androgen therapy in women is relevant from a clinical point of view, there are many limiting factors. First, gynecologists and internists do not know precisely the benefit of androgen therapy in women. The Endocrine Society “Guidelines” are extremely limitative in the prescription of androgens in women. Furthermore, clinical studies on the therapeutic effects of androgens in women are few. Studies conducted on large populations are necessary to evaluate specific correlations between androgen deficiencies and clinical signs.
13. Conclusions
Diagnosis of androgen deficiency in women is of clinical relevance because restoring physiological levels of androgens is essential in the prevention and treatment of many chronic diseases. However, based on experimental and clinical studies, androgen administration in women under specific clinical conditions, such as loss of sexual desire, loss of muscle mass and sarcopenia, osteoporosis, mental disorders, cardiovascular disease, and memory loss is therapeutically relevant. Androgens are useful in young women for the prevention of diseases and for fertility improvement, by regulating uterine and ovarian function. Androgen therapy in women at physiological doses and with cyclic treatment appears to be safe and well-tolerated. Adverse side effects are typically associated with supraphysiological doses and excessive treatment duration. Testosterone therapy in women can give clinically relevant benefits at low doses [257]. The rational prescription of androgen in women must take into account plasma hormonal levels achieved with the therapy and the clinical benefits. The premature decline in plasma androgen levels in women should be considered a risk factor for health.
The global consensus of the Endocrine Society about the use of androgen therapy in women [258] recommends against the routine prescription of testosterone; the only indication, based on clinical evidence is for the treatment of HSDD. The long-term safety for treatments with testosterone remains to be evaluated, and the panel highlighted the need for more research in this area
