Androgen Replacement Therapy in Women

Marie Lebbe; David Hughes; Nicole Reisch; Wiebke Arlt

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

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.

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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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Table 1. Randomized controlled studies on testosterone treatment in postmenopausal women.
Study (year)	Patients	Design	Duration	Testosterone administration	Effect of testosterone	Ref.
Barrett-Connor et al. (1999)	n = 311; surgical menopause	Double-blind	2 years	CEE, 0.625 mg/day CEE, 1.25 mg/day CEE, 0.625 mg, + MT, 1.25 mg/day CEE, 1.25, + MT 2.5 mg/day	↓ menopausal symptoms ↑ HDL and TG in CEE alone ↑ BMD in CEE + MT	[44]
Braunstein et al. (2005)	n = 447; surgical postmenopausal women on ERT; 24–70 years	Double-blind, placebo-controlled, parallel-group	24 weeks	Placebo 150 µg/day TTP 300 µg/day TTP 450 µg/day TTP	↑ sexual desire and satisfying sexual activity in 300 and 450 µg/day group	[45]
Basaria et al. (2002)	n = 40; >1 year menopause; natural and surgical; >3 m ERT; >21 years	Double-blind, parallel-group	16 weeks	1.25 mg CEE 1.25 mg CEE +2.5 mg MT ↓ TG	↓ plasma viscosity ↑ fibrogen	[46]
Buster et al. (2005)	n = 533; HSDD, surgical menopause, on RT	Double-blind, placebo-controlled	24 weeks	Placebo TTP 300 µg/day	↑ satisfying sexual activity ↑ sexual desire ↓ personal distress	[38]
Chiuve et al. (2004)	n = 40; surgical menopause on ERT	Double-blind, parallel-group	10 weeks	1.25 mg CEE 1.25 mg CEE +2.5 mg MT	↓ apoC I,II,III ↓ apoE ↓ TG, ↓ HDL	[47]
Davis et al. (1995)	n = 34; menopause natural/surgical	Single-blind	2 years	E 50 mg/3M implant E 50 mg + T 50 mg/3M implant	More ↑ in BMD, in all sites of the body More ↑ sexual energy ↓ LDL in both group ↓ total body fat-free mass	[48]
Davis et al. (2000)	n = 34; menopause natural/surgical	Single-blind	2 years	E 50 mg/3M implant E 50 mg + T 50 mg/3M implant	↓ total chol ↓ LDL ↓ total body fat-free mass ↓ fat-free mass (FM:FFM) ratio	[49]
Davis et al. (2006)	n = 61; HSDD, surgical menopause on ERT	Double-blind, placebo-controlled	24 weeks	Placebo TTP 300 µg/day	↑ sexual desire ↓ personal distress	[50]
Davis et al. (2008)	n = 814; surgical and natural menopause 20–70 years	Double-blind placebo-controlled	52 weeks	150 µg/day TTP 300 µg/day TTP Placebo	↑ sexual desire, higher in 300-µg group	[41]
Davis et al. (2009)	n = 279; surgical and natural menopause	Double-blind, placebo-controlled, parallel-group	52 weeks	150 µg/day TTP 300 µg/day TTP Placebo	No difference from placebo for total dense or nondense area on digital mammograms from baseline to week 52	[51]
De Paula et al. (2007)	n = 85; HSDD, postmenopausal, on HRT	Double-blind, placebo-controlled and crossover	16 weeks	Placebo 16 week MT 2.5 mg 16 week Placebo 8 week + MT 2.5 mg 8 week MT 2.5 mg 8 week + placebo 8 week	No change in liver enzymes and lipids ↑ sexual satisfaction ↑ sexual desire	[52]
Dobs et al. (2002)	n = 36; natural menopause	Double-blind, placebo-controlled, parallel	16 weeks	EE 1.25 mg/day EE + MT 2.5 mg/day	↑ sexual activity ↑ lean body mass ↓ % body fat ↑ body weight	[53]
El-Hage et al. (2007)	n = 36; HSDD, surgical menopause	Double-blind, placebo-controlled, cross-over	12 weeks	T cream 10 mg/day	↑ sexual desire ↑ frequency of sex No change in lipids, blood pressure or weight	[54]
Flöter et al. (2005)	n = 50; surgical menopause, on ERT, 45–60 years	Double-blind, placebo-controlled, cross-over	24 weeks	(1) estradiol 2 mg + TU 40 mg (2) estradiol 2 mg + placebo	↓ IGF-I ↓ propeptide of type I procollagen ↑ total lean body mass No change in fat mass, BMI, BMD and blood pressure	[55]
Nathorst-Böös et al. (2006)	n = 53; HSDD, postmenopausal, on ERT	Double blind, crossover	24 weeks	(1) ERT + T gel 10 mg/day (2) ERT + placebo	↑ sex quality parameters No change in liver enzymes, lipids, endometrium and blood velocity	[56]
Hofling M et al. (2007)	n = 99; postmenopausal, on ERT (2 mg estradiol and 1 mg norethisterone acetate)	Prospective, double-blind, placebo-controlled	24 weeks	(1) ERT + TTP 300 µg/day (2) ERT + placebo	↑ mammographic density in 1830% of women, no differences between the two groups	[57]
Hofling M et al. (2007)	n = 99; postmenopausal, on ERT (2 mg estradiol and 1 mg norethisterone	Prospective, double-blind, placebo-controlled	24 weeks	(1) ERT + TTP 300 µg/day (2) ERT + placebo	Placebo group: fivefold ↑ (p < 0.001) in breast cell proliferation (fine needle biopsy). T group: no ↑	[58]
Panay et al. (2010)	n = 272; HSDD, natural menopause	Double-blind, placebo-controlled	24 weeks	(1) TTP 300 µg/day (2) placebo	↑ satisfying sexual episodes ↑ desire ↓ distress	[42]
Penotti et al. (2001)	n = 40; postmenopausal, on HRT since 1–5 years (E2 50 µg/day + MPA 10 mg/day for 12 days every other month)	Double-blind, placebo-controlled	32 weeks	(1) HRT + TU 40 mg/day (2) HRT + placebo	↑ pulsatility index of Doppler cerebral artery ↓ HDL ↑ sexual desire	[59]
Penteado et al. (2008)	n = 60; HSDD, postmenopausal, on HRT (CEE 0.625 mg + MPA 2.5 mg)	Double-blind, placebo-controlled	52 weeks	(1) HRT + MT 2.0 mg/day (2) HRT + placebo	↑ sexual energy No change in orgasmic capacity	[43]
Raisz et al. (1996)	n = 28; natural, menopause	Double-blind, placebo-controlled, parallel	9 weeks	(1) CEE 1.25 mg (2) CEE + MT 2.5 mg/day	↑ bone formation ↓ HDL, ↓ TG	[60]
Sherwin & Gelfand et al. (1985)	n = 53, surgical menopause	Double-blind, placebo-controlled, crossover	12 weeks	(1) EE (2) TE 150 mg (3) EE + TE 150 mg (4) placebo	↑ sexual desire, arousal, fantasies	[61,62]
Shifren et al. (2000)	n = 75, surgical menopause, on ERT (CEE 0.625 mg), 31–56 years	Double-blind, placebo-controlled	12 weeks	(1) ERT + TTP 150 µg/day (2) ERT + TTP 300 µg/day (3) ERT + placebo	↑ frequency of sexual activity, pleasure-orgasm, well-being at 300 µg/day	[37]
Shifren et al. (2006)	n = 549; HSDD, natural menopause, on ERT	Double-blind, placebo-controlled, parallel group	24 weeks	(1) 0.625 mg CEE (2) 0.625 mg CEE + TTP 300 µg/day	↑ total satisfying sexual episodes ↑ sexual desire ↓ personal distress	[63]
Simon et al. (2005)	n = 562; HSDD, surgical menopause, on ERT, 26–70 years	Double-blind, placebo-controlled	24 weeks	(1) ERT + TTP 300 µg/day (2) ERT + placebo	↑ total satisfying sexual activity ↑ sexual desire ↓ distress	[39]
Warnock et al (2005)	n = 102; HSDD, surgical menopause, on ERT (CEE 1.25 mg), 33–62 years	Double-blind	8 weeks	(1) ERT + MT 2.5mg (2) ERT + placebo	No changes in sexual desire/interest	[64]
Watts et al. (1995)	n = 66; surgical, menopause	Double-blind, placebo-controlled, parallel	24 months	(1) CEE 0.625 mg/day (2) CEE + MT 2.5 mg/day	↑ BMD (lumbar spine) ↓ HDL ↓↓ TG	[65]
Zang et al. (2006)	n = 63; natural menopause	Open, parallel group	12 weeks	(1) 40 mg TU/2 days (2) 2 mg estradiol valerate/day (3) both	(1) and (3): ↓ insulin-induced glucose disposal, ↑ lean body mass, ↓ HDL	[66]

BMD: Bone mineral density; CEE: Combined esterifi ed estrogens; Chol: Cholesterol; ERT: Estrogen replacement therapy; HDL: High-density lipoprotein; HRT: Hormonal replacement therapy; HSDD: Hypoactive sexual desire disorder; LDL: Low-density lipoprotein; MPA: Medroxyprogesterone acetate; MT: Methyltestosterone; T: Testosterone; TE: Testosterone enanthate; TG: Triglycerides; TTP: Transdermal testosterone patch; TU: Testosterone undecanoate.

Table 2. Randomized controlled trials on dehydroepiandrosterone replacement in women with adrenal insufficiency.
Study (year)	Patients	Design	Dose/duration	Effect of DHEA	Ref.
Arlt et al. (1999), Callies et al. (2001)	Primary (n = 14) and secondary adrenal insufficiency (n = 10; 23–59 years)	Double-blind, placebo-controlled, crossover	DHEA 50 mg/day versus placebo for 4 months	↑ well-being and mood ↓ anxiety and depression ↑ sexual interest and satisfaction ↓ HDL	[74,75]
Bilger et al. (2005)	Secondary adrenal insufficiency (n = 5; (15–23 years)	Double-blind, placebo-controlled, crossover	DHEA 50 mg/day versus placebo for 12 months	↑ psychological function	[76]
Brooke et al. (2006)	Secondary adrenal insufficiency (n = 26)	Double-blind, placebo-controlled, crossover	DHEA 50 mg/day versus placebo for 12 months	↓ dose growth hormone replacement	[77]
Hunt et al. (2000)	Primary adrenal insufficiency (n = 24; 26–59 years)	Double-blind, placebo-controlled, crossover	DHEA 50 mg/day versus placebo for 3 months	↑ self-esteem ↑ mood ↓ fatigue no change in sexual function; in BMD or in HDL	[78]
Johannsson et al. (2002)	Secondary adrenal insufficiency due to hypopituitarism (n = 38; 25–65 years)	Double-blind, placebo-controlled, crossover	DHEA 20–30 mg/day versus placebo for 6 months	↑ alertness ↑ sexual relations no change in BMD ↓ HDL	[79]
Libe et al. (2004)	Primary and secondary adrenal insufficiency (n = 7)	Double-blind, placebo-controlled	DHEA 50 mg/day versus placebo for 4 months	↓ LDL in Addison ↓ fat mass No change in sexuality and well-being, no change in glucose-metabolism	[80]
Lovas et al. (2003)	Primary adrenal insufficiency (n = 39)	Doubleblind, placebo-controlled, parallel	DHEA 25 mg/day versus placebo for 9 months	No change in subjective health status, fatigue and sexuality; ↑ sweat odor ↑ scalp itching	[81]
Dhatariya et al. (2005)	Adrenal insufficiency (n = 28)	Double-blind, placebo-controlled, crossover	DHEA 50 mg/day versus placebo for 12 weeks	↑ insulin sensitivity ↓ HDL ↓ LDL ↓ TG	[82]
Dhatariya et al. (2008)	Adrenal insufficiency (n = 28)	Double-blind, placebo-controlled, crossover	DHEA 50 mg/day versus placebo for 12 weeks	No effect on physical performance, body composition, protein metabolism	[83]
Gurnell et al. (2008)	Primary adrenal insufficiency (n = 106)	Double-blind, placebo-controlled	DHEA 50 mg/day versus placebo for 12 months	↑ BMD at femoral neck ↑ total body lean mass, no change in fat mass No benefit on fatigue, cognitive or sexual function	[84]
Van Thiel et al. (2005)	Secondary adrenal and somatotropic insufficiency (n = 16; 61 ± 2 years)	Double-blind, placebo-controlled, crossover	DHEA 50 mg/day versus placebo for 16 weeks	No substantial benefit on quality-of-life parameters	[85]

BMD: Bone mineral density; DHEA: Dehydroepiandrosterone; HDL: High-density lipoprotein; LDL: Low-density lipoprotein; TG: Triglycerides.

Table 3. Randomized controlled trials on dehydroepiandrosterone treatment in women with normal adrenal function.
Study (year)	Patients	Design	Dose/duration	Effect of DHEA	Ref.
Labrie et al. (1997)	Postmenopausal, 60–70 year (n = 14)	Placebo-controlled, crossover	12 months; 10% DHEA cream	↑ vaginal epithelium maturation, no effect on endometrium, ↑ hip BMD	[86]
Panjari et al. (2009)	Postmenopausal (n = 93)	Randomized, double-blind, placebo-controlled	52 weeks; oral DHEA, 50 mg/day	No effect on endometrium nor blood lipids nor insulin resistance	[87]
Morales et al. (1995)	40–70 years (n = 17)	Randomized, double-blind, placebo-controlled	6 months; oral DHEA, 50 mg/day	↑ circulating androgen levels, = estrogen/SHBG, ↓ HDL, = insulin sensitivity, ↑ IGF-1, ↑ well-being	[90]
Baulieu et al. (2000)	60–79 year (n = 140)	Double-blind, placebo-controlled	12 months; oral DHEA, 50 mg/day	↑ circulating testosterone and estradiol, ↑ BMD, ↑ libido, ↑ skin hydratation	[92]
Nair et al. (2006)	>60 year (n = 57)	Randomized, double-blind, placebo-controlled	2 years; oral DHEA, 50 mg/day	No effect on body composition, physical performance, insulin sensitivity or quality of life	[93]
Wiser et al. (2010)	Low ovarian reserve (n = 33)	Randomized, placebo-controlled	4–5 months; oral DHEA, 75 mg/day	↑ embryo quality, ↑ live birth rate	[100]

DHEA: Dehydroepiandrosterone.

Sidebar

Key Issues

The definition of female androgen deficiency syndrome, as provided by the Princeton consensus statement in 2002, has been criticized because of its broad interpretation and the lack of routinely available sensitive and specific testosterone assays. The diagnosis of hypoactive sexual desire disorder is unspecific and does not automatically lead to justification of androgen replacement.
Physiological menopause is not associated with a sudden loss of androgen synthesis, and therefore, postmenopausal women do not routinely require androgen replacement.
The physiological, age-associated decline in androgen production does not represent an indication for androgen replacement.
In established cases of severe androgen deficiency, including surgical menopause and adrenal insufficiency, and concomitant symptoms of impaired mood and libido, the use of testosterone replacement appears feasible with probable beneficial effects on health-related quality of life and sexuality. The use of dehydroepiandrosterone as an androgen replacement tool is recommended in case of adrenal insufficiency, where it has shown similar significant benefits. However, we do not recommend dehydroepiandrosterone supplementation in women with normal adrenal function with the aim of restoring sexual function and impaired mood.
Minimal androgenic side effects have been recorded, but evidence of metabolic, cardiovascular and oncologic safety in long-term studies are lacking.
Current direct immunoassay methods are unable to accurately measure testosterone levels in women and tandem mass spectrometry represents the emerging state-of-the-art method.
Current guidelines advise against widespread use of androgen therapy, highlighting the need for caution. Although transdermal testosterone is licensed for use in Europe, the US FDA still refuses approval of female androgen replacement therapy.
In the meantime, the physiological role of androgens in women needs to be further elucidated in order to clarify the definition of androgen deficiency. Standardized normative data on serum androgen levels throughout a women's lifespan are required. Further cohort studies into the long-term potential beneficial and adverse effects of androgen replacement are urgently needed.
While it is recognized that more research is needed, we should not forget that the last decade has seen significant progress being made in the field of androgen research in women, providing us with new and reassuring information on androgen physiology and treatment in women.