Androgens and Testosterone

J Sex Marital Ther. 1998; 24(3):153-63 (ISSN: 0092-623X)

Davis SR
Jean Hailes Foundation, Clayton, Victoria, Australia.

Sexual health is an important component of overall health and well being. Multiple factors clearly influence an individual's sexuality; however, there is a general trend in Western societies to blame psychosocial factors for diminished sexuality in women. Sex steroid hormones are important determinants of sexual function in women and men, and there is increasing agreement that androgens play a key role in female sexuality. Androgen levels in women decline substantially during the reproductive years, with little change subsequent to spontaneous menopause. The most common complaint of women experiencing androgen deficiency is loss of sexual desire, and several studies have now shown improvements in a number of parameters of sexuality in postmenopausal women treated with exogenous testosterone.

Maturitas. 2007; 56(1):69-77 (ISSN: 0378-5122)

de Paula FJ; Soares JM; Haidar MA; de Lima GR; Baracat EC
jsoares415@hotmail.com

OBJECTIVE: To evaluate the benefits and risks of hormone replacement therapy (HRT) combined with methyltestosterone (MT) in postmenopausal women with sexual dysfunction.

DESIGN: This study was a randomized, double-blind, placebo-controlled and crossover trial. Eighty-five women using HRT were divided into four treatment groups: GI-HRT plus placebo for 4 months; GII-HRT plus MT 2.5mg/day for 4 months; GIII-HRT plus placebo for 2 months and then replaced with HRT plus MT 2.5mg/day for 2 months; GIV-HRT plus MT 2.5mg/day and then replaced with HRT plus placebo for 2 months. Blood was collected at baseline, after 2 months (T1) and 4 months (T2) of treatment for hormone determinations of estradiol, FSH, total and free testosterone, GOT, GPT, glucose, total and fractions of cholesterol and triglycerides. All participants answered clinical questions and a validated questionnaire of modified McCoy's sex scale.

RESULTS: The association of HRT with MT 2.5mg/day did not significantly change liver enzymes or increase cardiovascular risk factors. The patients of GII, GIIII and GIV when using MT presented amelioration of sex symptoms, mainly satisfaction and desire (p<0.01); however, GIII at T1 (1.3+/-0.3) presented similar problem score results as compared to GIII at T2 (1.5+/-0.6).

CONCLUSION: All data suggest that combined HRT-androgen therapy may be beneficial for postmenopausal women receiving HRT who continue to complain of sexual difficulties or for postmenopausal women with sexual complaints who are not undergoing estrogen therapy.

N Engl J Med. 2000; 343(10):682-8 (ISSN: 0028-4793)

Shifren JL; Braunstein GD; Simon JA; Casson PR; Buster JE; Redmond GP; Burki RE; Ginsburg ES; Rosen RC; Leiblum SR; Caramelli KE; Mazer NA
Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston 02114, USA. janshifren@hotmail.com

BACKGROUND: The ovaries provide approximately half the circulating testosterone in premenopausal women. After bilateral oophorectomy, many women report impaired sexual functioning despite estrogen replacement. We evaluated the effects of transdermal testosterone in women who had impaired sexual function after surgically induced menopause.

METHODS: Seventy-five women, 31 to 56 years old, who had undergone oophorectomy and hysterectomy received conjugated equine estrogens (at least 0.625 mg per day orally) and, in random order, placebo, 150 microg of testosterone, and 300 microg of testosterone per day transdermally for 12 weeks each. Outcome measures included scores on the Brief Index of Sexual Functioning for Women, the Psychological General Well-Being Index, and a sexual-function diary completed over the telephone.

RESULTS: The mean (+/-SD) serum free testosterone concentration increased from 1.2+/-0.8 pg per milliliter (4.2+/-2.8 pmol per liter) during placebo treatment to 3.9+/-2.4 pg per milliliter (13.5+/-8.3 pmol per liter) and 5.9+/-4.8 pg per milliliter (20.5+/-16.6 pmol per liter) during treatment with 150 and 300 microg of testosterone per day, respectively (normal range, 1.3 to 6.8 pg per milliliter [4.5 to 23.6 pmol per liter]). Despite an appreciable placebo response, the higher testosterone dose resulted in further increases in scores for frequency of sexual activity and pleasure-orgasm in the Brief index of Sexual Functioning for Women (P=0.03 for both comparisons with placebo). At the higher dose the percentages of women who had sexual fantasies, masturbated, or engaged in sexual intercourse at least once a week increased two to three times from base line. The positive-well-being, depressed-mood, and composite scores of the Psychological General Well-Being Index also improved at the higher dose (P=0.04, P=0.03, and P=0.04, respectively, for the comparison with placebo), but the scores on the telephone-based diary did not increase significantly.

CONCLUSIONS: In women who have undergone oophorectomy and hysterectomy, transdermal testosterone improves sexual function and psychological well-being.

Obstet Gynecol. 1995; 85(4):529-37 (ISSN: 0029-7844)
Watts NB; Notelovitz M; Timmons MC; Addison WA; Wiita B; Downey LJ
Emory University School of Medicine, Atlanta, Georgia.

OBJECTIVE: To compare an oral estrogen-androgen combination with estrogens alone on bone, menopausal symptoms, and lipoprotein profiles in postmenopausal women.

METHODS: Surgically menopausal women received oral esterified estrogens (1.25 mg), or esterified estrogens (1.25 mg) and methyltestosterone (2.5 mg) daily, for 2 years. Bone mineral density of the lumbar spine and hip, menopausal symptoms, lipoprotein profiles, and biochemical and hematologic indices were evaluated.

RESULTS: Sixty-six patients were enrolled in the study. Both treatment regimens prevented bone loss at the spine and hip; combined estrogen-androgen therapy was associated with a significant increase in spinal bone mineral density compared with baseline (n = 24; mean score +/- standard error 3.4 +/- 1.2%, P < .01). In the estrogen group, high-density lipoprotein (HDL) cholesterol increased significantly and low-density lipoprotein cholesterol decreased significantly. Cholesterol, HDL cholesterol, and triglycerides decreased significantly in the estrogen-androgen group. Menopausal symptoms of somatic origin (hot flashes, vaginal dryness, and insomnia) were improved significantly by both treatments. Neither adverse hepatic effects nor significant safety or tolerance problems were reported in either group.

CONCLUSION: Oral estrogen-androgen increased vertebral bone mineral density compared with pre-treatment values and relieved somatic symptoms. Safety indices, including lipoprotein levels, indicated that the combination was well tolerated over the 2 years of treatment.

J Clin Endocrinol Metab. 1998; 83(8):2717-25 (ISSN: 0021-972X)
Miller K; Corcoran C; Armstrong C; Caramelli K; Anderson E; Cotton D; Basgoz N; Hirschhorn L; Tuomala R; Schoenfeld D; Daugherty C; Mazer N; Grinspoon S
Neuroendocrine Department, Massachusetts General Hospital and Harvard Medical School, Boston 02114, USA.

Although human immunodeficiency virus (HIV) disease is increasing rapidly among women, no prior studies have investigated gender-based therapeutic strategies for the treatment of acquired immunodeficiency syndrome (AIDS) and its complications in this population. Markedly decreased serum androgen levels have been demonstrated in women with AIDS and may be a contributing factor to the wasting syndrome in this population. To assess the effects of androgen replacement therapy in women with AIDS wasting, we conducted a randomized, placebo-controlled, pilot study of transdermal testosterone administration. The primary aim of the study was to determine efficacy in terms of the change in serum testosterone levels, safety parameters and tolerability. A secondary aim of the study was to investigate testosterone effects on weight, body composition, quality of life, and functional indexes. Fifty-three ambulatory women with the AIDS wasting syndrome defined as weight less than 90% of ideal body weight or weight loss of more than 10% of the preillness maximum, free of new opportunistic infection within 6 weeks of study initiation, and with screening serum levels of free testosterone less than the mean of the normal reference range (< 3 pg/mL) were enrolled in the study. Subjects were age 37 +/- 1 yr old (mean +/- SEM), weighed 92 +/- 2% of ideal body weight, and had lost 17 +/- 1% of their maximum weight. CD4 count was 324 +/- 36 cells/mm3, and viral burden was 102,382 +/- 28,580 copies. Subjects were randomized into three treatment groups, in which two placebo patches (PP), one active/one placebo patch (AP group), or two active patches (AA group) were applied twice weekly to the abdomen for 12 weeks. The expected nominal delivery rates of testosterone were 150 and 300 microg/day, respectively, for the AP and AA groups. Forty-five subjects completed the study (PP group, n = 13; AP group, n = 14; AA group, n = 18). Two additional subjects from the PP group and two from the AP group were included in the intent to treat analysis. Serum free testosterone levels increased significantly from 1.2 +/- 0.2 to 5.9 +/- 0.8 pg/mL (AP) and from 1.9 +/- 0.4 to 12.4 +/- 1.6 pg/mL (AA) in response to testosterone administration (P < 0.0001 for comparison of AA vs. PP and AP vs. PP; normal range, 1.3-6.8 pg/mL). Testosterone administration was generally well tolerated locally and systemically, with no adverse trends in hirsutism scores, lipid profiles, or liver function tests. Weight increased significantly in the AP group (1.9 +/- 0.7 kg) vs. the PP group (0.6 +/- 0.8 kg; P = 0.043), but did not increase significantly in the AA group (0.9 +/- 0.4 kg; P = 0.263 vs. PP, by mixed effects model assessing the interaction of time and treatment on all available data, one-tailed test). Improved social functioning (P = 0.024, by one-tailed test) and a trend toward improved pain score (P = 0.059) were observed in the AP vs. the PP-treated patients (RAND 36-Item Health Survey questionnaire). Five of six previously amenorrheic patients in the AP group had spontaneous resumption of menses compared to only one of four amenorrheic patients in the AA group (P = 0.045 for comparison of actual number of periods during the study). This study is the first investigation of testosterone administration in women with AIDS wasting. We demonstrate a novel method to augment testosterone levels in such patients that is safe and well tolerated during short term administration. At the lower of the two doses administered in this study, testosterone therapy was associated with positive trends in weight gain and quality of life. Higher, more supraphysiological, dosing was not associated with positive trends in weight or overall well-being. These data suggest that testosterone administration may improve the status of women with AIDS wasting. Further studies are needed to assess the effects of testosterone on weight in HIV-infected women and to define the optimal therapeutic window for test

Maturitas. 1995; 21(3):227-36 (ISSN: 0378-5122)
Davis SR; McCloud P; Strauss BJ; Burger H
Prince Henry's Institute of Medical Research, Clayton, Victoria, Australia.

To investigate the role of androgens in increasing bone density and improving low libido in postmenopausal women, we have studied the long-term effects of estradiol and testosterone implants on bone mineral density and sexuality in a prospective, 2 year, single-blind randomised trial. Thirty-four postmenopausal volunteers were randomised to treatment with either estradiol implants 50 mg alone (E) or estradiol 50 mg plus testosterone 50 mg (E&T), administered 3-monthly for 2 years. Cyclical oral progestins were taken by those women with an intact uterus. Thirty-two women completed the study. BMD (DEXA) of total body, lumbar vertebrae (L1-L4) and hip area increased significantly in both treatment groups. BMD increased more rapidly in the testosterone treated group at all sites. A substantially greater increase in BMD occurred in the E&T group for total body (P < 0.008), vertebral L1-L4 (P < 0.001) and trochanteric (P < 0.005) measurements. All sexual parameters (Sabbatsberg sexual self-rating scale) improved significantly in both groups. Addition of testosterone resulted in a significantly greater improvement compared to E for sexual activity (P < 0.03), satisfaction (P < 0.03), pleasure (P < 0.01), orgasm (P < 0.035) and relevancy (P < 0.05). Total cholesterol and LDL-cholesterol fell in both groups as did total body fat. Total body fat-free mass (DEXA, anthropometry, impedance) increased in the E&T group only. We concluded that in postmenopausal women, treatment with combined estradiol and testosterone implants was more effective in increasing bone mineral density in the hip and lumbar spine than estradiol implants alone. Significantly greater improvement in sexuality was observed with combined therapy, verifying the therapeutic value of testosterone implants for diminished libido in postmenopausal women. The favourable estrogenic effects on lipids were preserved in women treated with T, in association with beneficial changes in body composition.

Summary and Introduction

Summary

Hypogonadism may play a significant role in the pathophysiology of erectile dysfunction (ED). A threshold level of testosterone may be necessary for normal erectile function. Testosterone replacement therapy is indicated in hypogonadal patients and is beneficial in patients with ED and hypogonadism. Monotherapy with testosterone for ED is of limited effectiveness and may be most promising in young patients with hypogonadism and without vascular risk factors for ED. A number of laboratory and human studies have shown the combination of testosterone and other ED treatments, such as phosphodiesterase type 5 (PDE5) inhibitors, to be beneficial in patients with ED and hypogonadism, who fail PDE5 inhibitor therapy alone. There is increasing evidence that combination therapy is effective in treating the symptoms of ED in patients for whom treatment failed with testosterone or PDE5 inhibitors alone. Testosterone replacement therapy has potentially evolved from a monotherapy for ED in cases of low testosterone, to a combination therapy with PDE5 inhibitors. Screening for hypogonadism may be useful in men with ED who fail prior PDE5 inhibitors, especially in populations at risk for hypogonadism such as type 2 diabetes and the metabolic syndrome.

Introduction

The pathophysiology of erectile dysfunction (ED) is multifactorial, involving vascular, neurologic, hormonal and/or psychological causes. The prevalence of hypogonadism in men with ED varies depending on the study populations, comorbidities and diagnosis methods. Approximately 12% of patients with ED may have hypogonadism. Hypogonadism is defined as a state of deficiency in gonadal function manifested by deficient secretion of gonadal hormones and/or gametogenesis. For the purpose of this paper, review and discussion will be limited to hypogonadism as testosterone deficiency. Reduced production of testosterone may increase the risk of osteoporosis, sexual dysfunction, fatigue, cardiovascular disease and mood disturbances, and may decrease muscle mass. Hypogonadism may be classified as hypergonadotrophic in cases of testicular failure or hypogonadotrophic in cases of hypothalamic/pituitary failure. Ageing is associated with gradually declining levels of testosterone (late-onset hypogonadism or androgen decline in the ageing male). In addition, chronic medical disorders are also frequently associated with hypogonadism, such as type 2 diabetes, the metabolic syndrome, chronic renal failure and chronic hepatic failure. The International Consultation on Sexual and Erectile Dysfunction recommended that adult-onset hypogonadism be defined as a clinical and biochemical syndrome.

Testosterone plays a key role in the central and peripheral modulation of erectile function New research in the laboratory and in humans is shaping a refinement of the role of testosterone replacement therapy in ED. This paper will address the evolving role of testosterone in the treatment of ED, both as a monotherapy and in combination with phosphodiesterase type 5 (PDE5) inhibitors.

Abstract and Introduction

Abstract

The ageing process in men is marked by changes in body composition (loss of fat-free mass (FFM) and skeletal muscle, and gain in fat mass (FM)) and is associated with a decline in serum testosterone. Correlations between these aspects of ageing and the acknowledged role of exogenous testosterone in reversing the loss of FFM and gain in FM seen in adult men with congenital or acquired hypoandrogenism have led to the hypothesis that testosterone therapy in ageing men will result in favourable changes in body composition and may improve metabolic status and/or cardiovascular risk. Data from randomized controlled trials of testosterone therapy in ageing men addressing the endpoints of body composition and components of the metabolic syndrome and cardiovascular risk factors are reviewed, and the impact of the increasing prevalence of obesity on these relationships is considered.

Introduction

As men age beyond 40 years, they experience a decline in serum testosterone. The rate of fall in testosterone has been well documented in cross-sectional and longitudinal studies and is estimated to be 1–2% per annum, excluding the further impact of other variables such as ill health or concomitant medications, and possibly environmental factors. The age-related fall in testosterone may impact the physical, sexual and/or psychological domains of a man's health; however, the relationship between ageing, declining sex steroids and symptomatology is complex. In particular, symptoms related to well being are often of a nonspecific nature. As androgens are known to be important determinants of body composition, this provides an objective parameter by which to examine the impact of declining testosterone levels in ageing men.

Serum testosterone levels correlate positively with fat-free mass (FFM) and negatively with fat mass (FM), and hypoandrogenism in young men is associated with a decline in FFM and skeletal muscle. Testosterone replacement therapy increases FFM and decreases FM in men with acquired hypogonadism and hypoandrogenism due to ageing. Furthermore, muscle mass has been shown to correlate with strength (as measured by dynamometry) in healthy older men, and in turn strength has been shown to positively correlate with bioavailable testosterone. This has led to interest in the hypothesis that testosterone supplementation may attenuate or even reverse age-associated sarcopaenia and enhance the physical strength and well being of older males. Also, because of the integral nature of the relationship between body composition, and visceral fat in particular, and metabolic health, change in FM is an important outcome measure when considering the role of testosterone therapy in this cohort. In this context, there is growing recognition of the need to define the role played by testosterone in the metabolic status of men as they age.

Body Composition and Ageing

In western populations body mass index (BMI) increases with age throughout adult life until approximately 65 years, after which time it plateaus and then decreases. The ageing process is associated with a decline in lean body mass and an increase in FM. Total body potassium studies show that between 25 and 65 years of age, a man will lose 12 kg of lean body mass, at a rate of 0.4 kg per year beyond the fifth decade, with a similar increase in FM and no appreciable change in overall weight. The loss of lean body mass represents a 20% decline between 25 and 65 years of age, with skeletal muscle lost more rapidly than non-skeletal muscle mass. This degree of change has been confirmed in other healthy cohorts. Skeletal muscle mass is preserved until the fifth decade, and thereafter the age-associated loss is greater in men than in women. The increase in FM represents a 60–85% increase over the same time period; the overall percentage of body fat increases from 19 to 35%. The distribution of the FM also changes, with a more central accumulation in men after puberty, and therefore this gain in FM is predominantly reflected by increasing abdominal adiposity. Furthermore, it appears that it is the visceral adipose tissue component (measured by computerized tomography (CT) scan) that continues to increase as a function of age, while the abdominal subcutaneous FM plateaus after the age of 30 years. The strongest anthropometric correlation with this intra-abdominal fat is waist circumference.

The decrease in BMI after the age of 65 years reflects loss of both lean and FM, with further central redistribution of adipose tissue. Others have described an accelerated loss of lean body mass after the age of 60 years, while FM continued to increase for another decade before it began to decline. There is marked inter-individual variability in these changes which in turn are influenced by alterations in total body weight.

The relationship of endogenous testosterone to body composition and the ability to intervene with the administration of exogenous testosterone is discussed below.

Testosterone and Body Composition

Skeletal Muscle, Fat-free Mass and Lean Body Mass

The term lean body mass is often used synonymously with fat free mass. Lean body mass measurements were originally derived from total body potassium measurements based on the assumption that potassium was distributed only in non-fat tissues. The subsequent development of more precise methods of estimating FM directly, for example, dual X-ray absorptiometry (DEXA), has allowed the determination of FM and therefore FFM. In practice, lean body mass and FFM measurements give similar results. Skeletal muscle mass can then be calculated from FFM measurements. Studies in established androgen deficiency states. Congenital or acquired (as a result of disease states or induced experimentally) hypoandrogenism is associated with a decline in FFM and skeletal muscle. Adult men with acquired hypogonadism, but otherwise in good health, have lower FFM than age-matched eugonadal controls, and young men subjected to short-term hypoandrogenism induced by the administration of a gonadotrophin releasing hormone (GnRH) analogue demonstrate a decrease in FFM and a reduction in the rate of protein synthesis. Older men undergoing androgen deprivation for treatment of prostate cancer also experience a decrease in lean body mass and muscle size. Testosterone replacement in hypogonadal men increases lean muscle mass (as defined by CT) and muscle size (quantified by magnetic resonance imaging (MRI)). Muscle strength is also increased significantly with testosterone replacement. In a further study of hypogonadal men (who had not received testosterone therapy for at least 2 years before enrollment in the trial), 6 months of testosterone treatment was associated with a 15% increase in FFM and a 20% increase in muscle mass. The effects of testosterone administration on FFM in hypogonadal men have been summarized by Bhasin, with increases of 1–5 kg being evident, dependent upon baseline serum testosterone and the dose and duration of the testosterone treatment regimen. The importance of testosterone dose on the magnitude of increase in skeletal muscle was clearly demonstrated in a study of healthy young men with experimentally induced hypogonadism in whom increases in FFM and muscle volume were directly proportional to the dose of testosterone administered and serum testosterone concentration. In this study, the doses of intramuscular testosterone ranged from sub-physiological to clearly supra-physiological, and despite achieving serum total testosterone (TT) levels >80 nM, no plateau effect on increasing FFM was identified. Furthermore, supra-physiological doses of testosterone administered to eugonadal men have been shown to significantly increase FFM, muscle size and strength.

The effects of testosterone supplementation in the ageing male. The description of age-related sarcopaenia in the setting of the decline in serum testosterone in older men, and the knowledge that testosterone replacement increases FFM and muscle volume in young hypogonadal men, has led to the hypothesis that testosterone therapy in older men will increase FFM and skeletal muscle and may subsequently improve quality of life by increasing strength and stability. The largest placebo-controlled trial to test the hypothesis that testosterone supplementation in the older male will improve muscle mass and/or strength found that over 36 months of treatment, an increase in mean serum testosterone from 12.7 to 21.7 nM led to a 1.9 kg (3.5%) increase in lean mass; linear regression analysis showed an inverse relationship to pretreatment testosterone levels. There was no demonstrable effect on dynamometric measures of muscle strength, although subjects with the lowest baseline testosterone levels reported that they perceived their physical performance to be improved. Other placebo-controlled trials have documented increases in lean body mass of 1.5–4.0 kg ( Table 1 ). In the majority of these studies, baseline testosterone levels have been in the low normal young adult range and increased to within the upper part of the reference range. Duration of therapy may be important in predicting the magnitude of demonstrable effect, and greater increases in lean body mass are seen in those studies employing supra-physiological androgen treatment regimens. This is consistent with a recent study of graded doses of testosterone administered to healthy older men (rendered hypogonadal with a long-acting GnRH agonist) who, akin to the younger cohort previously studied, demonstrated a dose-dependent increase in FFM, with no evidence of a plateau effect; the observed magnitude of increase in FFM was comparable for the young and older men (+7 to 8 kg or 12% increase from baseline). Of note, older men had a greater increase in serum testosterone than young men at set doses of testosterone, suggesting that older men have reduced testosterone clearance and may therefore potentially experience an enhanced tissue effect at a given testosterone dose. The increase in lean body mass has been linked to a decrease in muscle protein breakdown and an increase in muscle protein synthesis. Functional correlates of this increase in muscle mass are uncertain, although measures of muscle strength assessed in short-term studies do suggest benefits with treatment. Dihydrotestosterone and human chorionic gonadotrophin (hCG) over a 3-month period have also demonstrated improvement in selected aspects of muscle strength. While the favourable changes in FFM consistently demonstrated in short-term controlled studies may have important sequelae with regard to physical functioning, to date only surrogate predictors (strength, activity) of the desired end effects (for example, independent living, prevention of falls) have been studied.

Fat Mass and Regional Adipose Tissue Distribution

Studies in established androgen deficiency states. In parallel with the decrease in FFM seen in hypogonadal men, there is also an increase in FM. In a study of men aged 22–69 years (mean age 53 years), hypogonadal subjects had 26% body fat compared to 19% in eugonadal men. Similarly, induced hypogonadism (with a GnRH analogue) in young men resulted in a 1 kg increase in body fat over 10 weeks (body fat increased from 19 to 22%). In older men with prostate cancer (and 22% body fat at baseline), the induction of profound hypogonadism resulted in a 9% increase in body fat after 48 weeks. With respect to the role of testosterone replacement in otherwise healthy but hypoandrogenic men, the effects on FM were less marked than for the corresponding increase in lean body mass or FFM. Some studies have shown 10–15% decreases in FM with testosterone, with the decreases in FM correlated to the changes in serum testosterone. Others however have failed to find a significant decline in FM even with high-percentage body fat at baseline and an equivalent or longer treatment duration. Those studies failing to find a decrease in FM did not address the issue of regional fat distribution.

Quantitative CT analysis of hypogonadal men (mean age 52 years) has shown that they have a greater subcutaneous fat area and a trend towards an increased visceral fat area when compared to age-matched eugonadal men. Testosterone replacement, in addition to decreasing FM (as above), decreased subcutaneous fat by 12% and visceral fat by 6%. Young men downregulated with GnRH and administered increasing doses of intramuscular testosterone had a 20–40% increase in FM at sub-physiological testosterone replacement doses and a significant 10% decrease in FM at the highest (supra-physiological) testosterone dose. Abdominal subcutaneous fat volume (as quantified by MRI) increased at the lowest testosterone doses and the change in both subcutaneous and intra-abdominal (visceral) fat was negatively correlated with testosterone dose and serum testosterone concentration. Changes in fat distribution with both lowering and elevating serum testosterone were evenly distributed between the trunk and the appendices.

The effects of testosterone supplementation in the ageing male. Ageing is associated with increase in FM; the pattern of distribution of adipose tissue is also altered, with more marked increases in visceral as compared to subcutaneous FM. Furthermore, middle-aged men with visceral adiposity have lower serum total and free testosterone and sex hormone binding globulin (SHBG) levels than their peers without excess abdominal adipose tissue (as determined by CT).

Placebo-controlled trials of testosterone therapy in ageing men have shown decreases in FM ranging from 1 to 4.5 kg in studies of 3–36 months duration ( Table 2 ). In studies of 36 months duration, the magnitude of fat loss was greatest within the first 6 months of treatment, but unlike the increase in lean body mass, which plateaued after this time, the decrease in FM continued, albeit at a reduced rate. In these studies, a 70% or greater increase in mean serum testosterone from baseline readings of 12.7 nM and 9.9 nM led to 2.9 kg (12%) and 4.5 kg (16%) decreases in FM, respectively. A positive correlation between the change in FM and serum testosterone was seen in the Page et al. study. Smaller decreases in FM are seen after 6–12 months of testosterone supplementation in older eugonadal men and following 90 days of treatment in overweight/obese hypogonadal older men. Synthetic androgens (oxandrolone, oxymetholone) are associated with greater loss of FM than is native testosterone in short-term studies.

In each of the studies in Table 2 , the mean baseline BMI of enrolled subjects was in the overweight range, thus making it likely that they included men with BMIs ranging from normal to obese. There are no studies, however, that have reported the observed change in FM as a function of baseline BMI. The magnitude of the decrease in FM identified in these studies may also be influenced by baseline serum testosterone, as noted in the 12-week study of oxandrolone therapy, wherein men with baseline serum testosterone <10.4 nM had a significantly greater loss of FM than subjects with baseline serum testosterone >10.4 nM (-2.5 vs -1.5 kg; P=0.04).

Further to the reduction in total FM that has been consistently demonstrated, several studies have examined the effects of androgen supplementation on regional fat loss. Testosterone supplementation (oral for 8 months, transdermal for 9 months) of middle-aged men with mean BMI 29 kg/m2 and abdominal obesity (and serum testosterone levels within the normal range) decreased visceral adiposity by 5–10% (0.4–0.6 kg), as assessed by CT, although total body fat (by total body potassium calculations) and subcutaneous adipose tissue mass (by CT) did not change. These findings were not able to be replicated with dihydrotestosterone (DHT), and a further study of similar duration using intramuscular testosterone could not reproduce these results despite selecting for obese subjects.

Regional DEXA examinations in one study of older men showing significant loss of FM with testosterone treatment suggested that this loss was significant only in the appendices and not within the trunk. More detailed analyses of regional adipose tissue distribution have yielded conflicting reports of the effects of androgens. Older eugonadal (baseline serum testosterone 15.3 nM) men with a mean BMI 26 kg/m2 treated with intramuscular testosterone for 6 months had a non-significant 10% decrease in subcutaneous abdominal fat area, with no change in visceral or total intra-abdominal fat (at the level of L4–L5 on MRI); similarly, transdermal testosterone administered for 24 months to men with median BMI 28 kg/m2 did not decrease visceral fat on CT examination. Studies of 17-alkylated androgens (oxymetholone and oxandrolone) have shown both preferential loss of truncal FM[34] and an equivalent loss in both the trunk and the appendices. Within the abdomen, both subcutaneous and visceral fat areas were decreased (as determined by a single MRI slice at the level of L4–L5), although neither change was significant when compared to change within the placebo group. The change in subcutaneous fat area was greater in those men with lower baseline testosterone levels (<10.4 nM). Finally, dehydroepiandrosterone (DHEA) administered for 6 months to eugonadal, ageing overweight men resulted in a decrease in both visceral and subcutaneous abdominal fat, as analysed by cross-sectional MRI scans;[58] treatment resulted in an 8% increase in serum testosterone levels.

A major deficiency in the literature is that there have been no studies of androgen replacement in older men that have examined the effects of treatment on visceral or subcutaneous fat area as a function of baseline adiposity and none has examined abdominal fat (visceral, subcutaneous) volumes.

One of the most important considerations when assessing the influence of testosterone on FM and visceral fat, in particular, is the potential to modify lipid metabolism and insulin sensitivity. These data are reviewed below.

Although there remains debate about the existence and definition of the term metabolic syndrome, it has found wide usage in describing that cluster of cardiovascular risk factors comprising abdominal adiposity, atherogenic dyslipidaemia, elevated blood pressure and elevated glucose (as an indicator of insulin resistance). The two most accepted criteria for the diagnosis are those of the United States Adult Treatment Panel III of the National Cholesterol Education Program (ATP III) and the International Diabetes Federation (IDF). A major difference between these criteria is the necessity of an elevated waist circumference (set according to ethnicity) by the IDF, underscoring the integral role played by visceral adiposity in the metabolic syndrome. The impact of testosterone therapy in modifying abdominal adiposity has been discussed above and its role in modifying other cardiovascular risk factors is reviewed in the following sections.

Relationship of Endogenous Testosterone to Markers of Cardiovascular Risk in Ageing Men

When considering the association between serum testosterone and cardiovascular risk factors, it is important to be aware that the precise nature of the relationship between testosterone and individual cardiovascular risk factors may be obscured by failure to control for other related variables, for example, not controlling for BMI when investigating the relationships between testosterone and glycaemia and hyperlipidaemia. A study of middle-aged men classified by TT levels (10 vs 20 nM) found that systolic blood pressure, fasting glucose and total and low-density lipoprotein (LDL) cholesterol levels were inversely related to testosterone, but after adjusting for measures of adiposity and insulin resistance, only insulin levels and triglycerides remained significantly correlated with testosterone. Negative correlations between testosterone and hypertension, fasting plasma glucose, hyperinsulinaemia and visceral adiposity are documented, and there is an uncertain association with high-density lipoprotein (HDL) cholesterol. Overall, the observational evidence suggests a neutral or beneficial effect of endogenous testosterone on cardiovascular risk factors in middle-aged and older men.

The effects of testosterone therapy on markers of cardiovascular risk in ageing men

Hypertension. Testosterone therapy does not influence systolic or diastolic blood pressure readings in placebo-controlled trials. More detailed information about blood vessel function, specifically endothelial dysfunction, can be obtained by the technique of flow-mediated dilatation (FMD). FMD measured in the brachial artery has a 95% positive predictive value for coronary artery endothelial dysfunction. It declines with age in men, although the relationship to serum testosterone is uncertain. In eugonadal middle-aged men with coronary artery disease, supraphysiological doses of testosterone, administered intravenously, increased coronary blood flow. Three randomized controlled trials (RCTs) in older men with low-normal serum testosterone have examined the effect of physiological androgen replacement on vascular reactivity. No change in FMD was seen with 3 months of DHT or hCG or with 12 months of transdermal testosterone. FMD was increased with short-term physiological and acute supraphysiological testosterone treatments in middle-aged men with underlying coronary artery disease. In contradiction to the above data suggesting that testosterone has either a neutral or beneficial effect on vascular reactivity, men undergoing androgen deprivation for prostate cancer show increased FMD and hypogonadal men exhibit increased FMD compared to their eugonadal peers; this is reversed by testosterone replacement. More work is needed to clarify the relationship between testosterone and vascular reactivity.

Lipids. Many of the studies in ageing men have shown limited effects of testosterone treatment on lipid profiles, with falls of approximately 10% in total and LDL cholesterol, although accompanied by falls of approximately 10% in HDL cholesterol. A meta-analysis of intramuscular testosterone treatment of hypogonadal men of all ages (mean TT 1.7 nM at baseline) suggested a dose-dependent fall not only in total and LDL cholesterol but also in HDL cholesterol; the decline in HDL cholesterol became less prominent with age and with prolonged treatment. Placebo-controlled studies in which serum testosterone was increased within the healthy young adult male normal range showed minimal effects on total and LDL cholesterol and triglycerides, although the decline in HDL cholesterol levels was significant in two of four studies of 12 months or longer ( Table 3 ). Oxandrolone was associated with unfavourable lipid changes. There are insufficient data from randomized controlled trials to conclude whether the route of administration of testosterone is a significant determinant of the observed changes in lipid profiles.

Insulin resistance. An inverse association has been reported between endogenous testosterone levels and either hyperinsulinaemia or an increased likelihood of developing type II diabetes mellitus. Furthermore, clinical trial data documenting a decrease in FM, in particular a reduction in visceral adipose tissue, with testosterone therapy have led to the hypothesis that testosterone therapy may improve insulin sensitivity. Results from studies of testosterone therapy addressing this matter have recently been reviewed. Young, lean subjects did not demonstrate any change in insulin sensitivity across a wide range of serum testosterone levels in a dose–response study, despite a dose-related reduction in FM. Centrally obese middle-aged men receiving testosterone showed an improvement in insulin sensitivity (by hyperinsulinaemic/euglycaemic clamp studies) and a lowering of serum insulin levels; however, these results were not seen with DHT or oxandrolone (when administered to a similarly obese cohort). In ageing men, hCG administered for 3 months did not affect insulin sensitivity (as measured by euglycaemic clamp). It is unclear as to whether changes in serum testosterone mediate insulin sensitivity independent of their effect on FM (specifically visceral fat). Comparison of data sets is difficult as those middle-aged men showing improved insulin sensitivity had higher FM and greater waist circumference at baseline than the ageing men treated with hCG. Furthermore, the middle-aged cohort had significant visceral fat loss with treatment, and although total FM declined in the older men, there are no data regarding regional adipose tissue changes; it is also possible that the duration of hCG treatment was insufficient. Although anabolic steroids (oxandrolone) demonstrate a significant reduction in abdominal fat, they have been associated with insulin resistance, thought to be mediated through hepatotoxicity.

Conclusion: The Role of Testosterone Therapy in Ageing Men?

Evidence from randomized controlled trials of testosterone therapy in ageing men suggests that with respect to body composition and specifically FM, those men most likely to benefit from therapy are those with low baseline testosterone levels who receive therapy for in excess of 12 months. While there are little data examining the effect of therapy as a function of baseline FM, it is plausible to hypothesize that those men with the greatest amount of body fat may receive the greatest benefit from testosterone therapy in this regard. Indeed it may be that ageing males with a high proportion of body fat and those with age-related hypoandrogenism represent overlapping cohorts. In the Massachusetts Male Aging Study, obese men (with no other comorbidities) had TT levels 25% lower than their non-obese peers and increasing BMI was as important as age in influencing the decline in serum testosterone experienced by older men. In a cohort of ageing Australian men with symptoms suggestive of hypoandrogenism, 12.1% of obese men but only 0.8% of non-obese men had TT level <8 nM. As the worldwide prevalence of obesity increases, in the United States, 36% of men aged 60–74 years are obese (an increase of 12% between 1988 to 1994 and 1999 to 2000), it is likely that the number of men considered to have age-related hypoandrogenism will increase in parallel. Given the strong association of obesity with metabolic syndrome and excess cardiovascular morbidity and mortality, the question as to whether testosterone therapy in older men with low testosterone levels (and likely accompanying obesity) will modify metabolic and cardiovascular risk is a timely and pertinent one.

J Dtsch Dermatol Ges. 2008; 6(4):273-9 (ISSN: 1610-0387)

Schreiber G; Ziemer M
Department of Dermatology and Allergology, University Clinic of Jena, Friedrich Schiller University, Jena, Germany. gerhard.schreiber@derma.uni-jena.de

Managing the clinical features of hormone insufficiency in aging men is an important field of activity for dermatologists and in particular for dermatologists specialized in andrology. Potential consequences of age-associated decrease in plasma testosterone levels include long-term changes in diverse organ systems including changes of bone architecture, body composition, muscular strength, cognitive functions, and mood as well as negative effects on skin and hair. Indications and contraindications for a hormone replacement therapy as well as therapy monitoring are well-defined. Replacement of testosterone in the case of late-onset hypogonadism is not a standardized therapy. Previous studies suggest that testosterone replacement therapy has positive clinical effects. Dermatologic effects of testosterone replacement therapy have not yet been investigated. Further research is required to identify potential benefits and risks of hormone replacement therapy in aging men.