Androgen Replacement Therapy in Women

Marie Lebbe; David Hughes; Nicole Reisch; Wiebke Arlt

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

Studies on DHEA Replacement in Women

Women with adrenal insufficiency usually present with significant androgen deficiency due to the pathological loss in adrenal DHEA synthesis. Evidence exists that despite adequate replacement in glucocorticoids and mineralocorticoids, patients with adrenal insufficiency suffer from decreased well-being, increased fatigue, depression and loss of libido.^[71–73] Arlt et al. were the first to report that daily oral administration of 50 mg of DHEA in women with adrenal insufficiency normalized serum androgen levels and improved overall well-being and sexual function.^[74,75] It has been suggested that the beneficial effects of DHEA on mood and well-being may be centrally mediated as DHEA may have direct effects in the brain acting as a neurotransmitter rather than only through indirect action via downstream conversion to androgens. However, libido and sexual satisfaction are most likely a consequence of increased androgen activity derived from efficient conversion of exogenously administered DHEA to active androgens by peripheral bioconversion.^[1]Table 2 shows the randomized controlled trials studying the role of DHEA replacement in primary and secondary hypoadrenal women, and the observed effects.^[74–85] Several trials reported an improvement in subjective health status, anxiety, depression and sexuality,^[74–79] but other studies concluded to no psychological beneficial effects of DHEA.^{[80,81,83–85]} Again, the lack of comparable and appropriately validated sexual questionnaires challenges these results. Very few conclusive metabolic effects are reported, with the exception of a moderate HDL cholesterol-lowering effect^[75,79,82] and no change in insulin sensitivity and body composition.^[80,83] Reported androgenic skin effects are frequent and include acne and hirsutism and mainly occur in previously severely androgen-deprived women; however, they are usually mild and transient.

DHEA treatment has also been studied in women with normal adrenal function, in different settings, and randomized controlled trials are summarized in Table 3. It has been proposed that treatment of postmenopausal women with DHEA will result in androgenic effects and hence improve libido and well-being via its conversion to testosterone and estrogenic effects resulting in improvements in menopausal vasomotor symptoms. Two placebo-controlled double-blind trials were recently conducted with DHEA 50-mg daily for 12 months in 115 and 93 postmenopausal women, respectively, who all had intact adrenal function.^[86,87] Both studies showed no improvement of sexual function and well-being, no change in menopause-related quality-of-life scores^[86] and no benefit of DHEA in cognitive performance.^[87] This has been confirmed by two recent reviews summarizing the available evidence on randomized controlled trials on DHEA replacement in postmenopausal women that has demonstrated no benefit with regard to sexual function, well-being and cognitive performance.^[88,89] The age-related decline in circulating DHEA(S) has led to a number of randomized trials to assess the effect of oral DHEA in otherwise healthy elderly subjects.^[90–93] The trial by Nair et al. investigated the effect of DHEA and testosterone on quality of life, body composition, physical performance and metabolism in elderly subjects during a period of 2 years.^[93] The authors found no significant effects of DHEA in these healthy elderly individuals with low baseline DHEA levels on quality of life, body composition, physical performance or insulin sensitivity. One has to keep in mind that the decline in DHEA and active androgens observed over a woman's lifetime may represent a physiological, protective mechanism, for example, preventing increased sex steroid action in breast tissue.^[94]

In patients with systemic lupus erythematosus, which in the overwhelming majority are female, supraphysiological doses has been shown to reduce disease activity and has a glucocorticoid-sparing effect.^[95] DHEA has also been suggested as a steroid with immune-regulatory activity and this effect is more likely to be detected in patients with altered immune system at baseline.^[96]

Over the last decade, a number of controlled studies have shown that adjuvant DHEA and testosterone treatment can enhance fertility in women with low ovarian reserve.^[97–102] Low ovarian reserve is characterized by an impaired quantity and quality of the ovarian follicles, with advancing age as an important determinant. In a randomized open trial in 33 women with low ovarian reserve DHEA (75 mg/day) was associated with a higher oocyte yield and a significantly increased birth rate.^[100] Despite the still weak overall evidence due to the current lack of rigorous randomized trials of sufficient size,^[103] it is estimated that approximately one third of all IVF centers today use DHEA supplementation in women with low ovarian reserve.^[104]

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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.