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For decades the widespread belief that low Testosterone contributes to decreased lean body mass, increased fat mass and sexual dysfunction resulted in treatment using androgens such as Testosterone gels, patches, pellets or injections. It has been proven that increasing Testosterone levels increases fat free mass, muscle strength, muscle power, muscle volume, hemoglobin and IGF-1. Most male users of Testosterone also report an increase in sexual function such as an increase in libido and frequency of erections. A recent study published in the New England Journal of Medicine has set out to determine exactly what role estrogen plays in body composition and sexual function. This is a significant study since many users employ aromatase inhibitors alongside their Testosterone treatment.

The vast majority of estrogen in the male is derived from aromatization of Testosterone. Therefore when serum Testosterone levels decline there is also an associated decline in estrogen levels. However many doctors focus on the role of Testosterone as treatment for hypogonadism and place less emphasis on the role of declining estrogen. The one exception may be bone loss as it is common knowledge that very low levels of estrogen contribute to bone loss. However estrogens role on body composition and sexual function is not entirely known. Information on the role of estrogens in male hypogonadism may help identify men at risk for specific manifestations of the condition and may provide a rationale for novel approaches to its management. The study “sought to determine the relative degree of testosterone deficiency, estradiol deficiency, or both at which undesirable changes in body composition, strength, and sexual function begin to occur and whether those changes are due to androgen deficiency, estrogen deficiency, or both.”

From a practical perspective, men suffering from hypogonadism need to know if very low levels of estrogen may be detrimental to sexual function and if those low levels may also be negatively effecting body composition. In addition, steroid users need to know if using aromatase inhibitors can contribute to sexual dysfunction and a higher percentage of body fat. It is the aim of this paper to answer those questions. I have removed some of the studies detailed data to make this more readable ~heavyiron

Gonadal Steroids and Body Composition, Strength, and Sexual Function in Men

Joel S. Finkelstein, M.D., Hang Lee, Ph.D., Sherri-Ann M. Burnett-Bowie, M.D., M.P.H., J. Carl Pallais, M.D., M.P.H., Elaine W. Yu, M.D., Lawrence F. Borges, M.D., Brent F. Jones, M.D., Christopher V. Barry, M.P.H., Kendra E. Wulczyn, B.A., Bijoy J. Thomas, M.D., and Benjamin Z. Leder, M.D.
N Engl J Med 2013; 369:1011-1022September 12, 2013DOI: 10.1056/NEJMoa1206168

Two groups of healthy men ages 20-50 were recruited and received goserelin acetate to suppress endogenous gonadal steroids. The 400 men were randomly assigned to receive 0 g (placebo), 1.25 g, 2.5 g, 5 g, or 10 g of a topical 1% testosterone gel (AndroGel, Abbott Laboratories) daily for 16 weeks. Participants in group 2 also received anastrozole (Arimidex, AstraZeneca) at a dose of 1 mg daily to block the aromatization of testosterone to estrogen. Primary analysis focused on comparisons of the group receiving the 5-g AndroGel dose with the other dose groups, because this dose produced testosterone levels that were similar to baseline levels. 5-g dose produced 470±201 ng per deciliter T levels. The 5-g dose plus Arimidex produced 485±240 ng per deciliter T levels.

Participants were seen every 4 weeks. At each visit, fasting blood samples were obtained to measure gonadal steroid levels, and questionnaires were administered to assess physical function, health status, vitality, and sexual function. At baseline and week 16, body fat and lean mass were assessed by means of dual-energy x-ray absorptiometry (DXA); subcutaneous- and intraabdominal-fat areas and thigh-muscle area were measured by means of computed tomography (CT); and lower-extremity strength was determined by means of a leg press.

1

Mean Serum Testosterone and Estradiol Levels from Weeks 4 to 16, According to Testosterone Dose and Cohort. Left blue columns above are the Testosterone only group and the right red columns the Testosterone and Arimidex group.

Hormone Levels

In men receiving goserelin acetate and 0 g (placebo), 1.25 g, 2.5 g, 5 g, or 10 g of testosterone gel daily (cohort 1), the mean testosterone levels were 44±13 ng per deciliter, 191±78 ng per deciliter, 337±173 ng per deciliter, 470±201 ng per deciliter, and 805±355 ng per deciliter, respectively (Figure 2A). The corresponding mean estradiol levels were 3.6±1.4 pg per milliliter, 7.9±2.9 pg per milliliter, 11.9±5.7 pg per milliliter, 18.2±10.2 pg per milliliter, and 33.3±15.3 pg per milliliter (Figure 2B). In men who also received anastrozole (cohort 2), the corresponding mean testosterone levels were 41±13 ng per deciliter, 231±171 ng per deciliter, 367±248 ng per deciliter, 485±240 ng per deciliter, and 924±521 ng per deciliter (Figure 2A), and the corresponding mean estradiol levels were 1.0±0.4 pg per milliliter, 1.2±0.4 pg per milliliter, 2.0±2.3 pg per milliliter, 2.1±1.9 pg per milliliter, and 2.8±1.8 pg per milliliter (Figure 2B).

2

Mean Percent Change from Baseline in Percentage of Body Fat, Lean Body Mass, Subcutaneous- and Intraabdominal-Fat Area, Thigh-Muscle Area, and Leg-Press Strength, According to Testosterone Dose and Cohort. T bars indicate standard errors. Within each cohort, bars with the same number indicate no significant difference between dose groups. For example, the change in the percentage of body fat (Panel A) did not differ significantly among the groups that received 0 g, 1.25 g, or 2.5 g of testosterone daily in cohort 1 (all labeled “1”). The change in each of those three groups differed significantly from the change in the group that received 5 g per day (labeled “2”) and the change in the group that received 10 g per day (labeled “3”), and the change also differed significantly between these latter two groups. P values are for the cohort–testosterone dose interaction terms in analyses of variance comparing changes in each outcome measure between cohorts 1 and 2.

3

Mean Absolute Change from Baseline in Sexual Desire and Erectile Function, According to Testosterone Dose and Cohort. Sexual desire (Panel A) was assessed at each visit by asking participants to rate their sex drive as compared with their sex drive before the study began (?2 indicates much less, ?1 somewhat less, 0 the same, 1 somewhat more, and 2 much more). Erectile function (Panel B) was evaluated by asking each man to consider the prior month and rate the degree to which each of the following three statements most closely applied to himself: “I had difficulty becoming sexually aroused,” “I had difficulty getting or maintaining an erection,” and “I had difficulty reaching orgasm,” with 1 indicating not at all, 2 a little, 3 some, 4 quite a bit, and 5 a great deal. For each man, the mean value at the final visit was then subtracted from the mean value at the baseline visit. T bars indicate standard errors. Within each cohort, bars with the same number indicate no significant difference between dose groups. P values are for the cohort–testosterone dose interaction terms in analyses of variance comparing changes in each outcome measure between cohorts 1 and 2.

In this study, we found that the dose of testosterone required to prevent adverse changes in a variety of measures varies considerably. When aromatization was intact, fat accumulation began with mild gonadal steroid deficiency (a testosterone level of approximately 300 to 350 ng per deciliter), whereas lean mass, thigh-muscle area, and muscle strength were preserved until gonadal steroid deficiency was more marked (a testosterone level ?200 ng per deciliter). Sexual desire and erectile function, the two major domains of sexual function, showed distinct patterns of change as serum testosterone levels were reduced.

Observational studies have shown that lean mass and strength are reduced and fat mass is increased in men with low testosterone levels. Men with hypogonadism report less sexual activity, fewer sexual thoughts, and fewer spontaneous erections than men with normal testosterone levels. Moreover, testosterone replacement increases lean mass, decreases fat mass, and can improve sexual function in men with hypogonadism. These observations have led to the widespread belief that undesirable changes in body composition and sexual dysfunction in men with hypogonadism are due to androgen deficiency. However, because estradiol is a metabolite of testosterone, it is difficult to distinguish the effects of androgens from those of estrogens in observational studies, or even in randomized, controlled trials if aromatizable androgens are used without the administration of an aromatase inhibitor.

By administering a variety of testosterone doses with and without concomitant aromatase inhibition, we found that changes in lean mass, thigh-muscle area, and leg-press strength were attributable to changes in testosterone levels, whereas changes in fat measures were primarily related to changes in estradiol levels. Both androgens and estrogens contributed to the maintenance of normal libido and erectile function. Although these results may be surprising, they are consistent with studies showing that body fat is increased in humans and male mice with null mutations of the aromatase gene or the estrogen-receptor ? gene and that sexual function is markedly impaired in mice and humans with these genetic defects.

Our observations may have important clinical implications. First, they provide a physiological basis for interpreting testosterone levels in young and middle-aged men and identifying the adverse consequences that are most likely to occur at various gonadal steroid levels. Second, because increases in visceral fat reduce insulin sensitivity and are associated with diabetes and the metabolic syndrome, the marked increase in intraabdominal fat with aromatase inhibition could portend an increase in cardiovascular disease with long-term estrogen deficiency. Finally, because lean mass, thigh-muscle area, and erectile function were reduced at a testosterone dose (1.25 g per day) that elicited a mean serum level of approximately 200 ng per deciliter, testosterone supplementation seems justified in men with testosterone levels in this range. However, some men have alterations in these functional outcomes at lower or higher testosterone levels, and other consequences of hypogonadism, such as increases in body fat and loss of sexual desire, routinely develop at higher mean testosterone levels. Thus, each person’s specific clinical scenario should be considered when interpreting the clinical significance of the circulating testosterone level.

These findings may also have implications for older men. Serum testosterone levels decline modestly as men age, such that 20% of men older than 60 years of age and 50% of men older than 80 years of age have testosterone levels at least 2 SD below the mean level in young men. Aging in men is also accompanied by declines in bone mineral density, lean mass, muscle strength, energy, and sexual function and by increases in fat mass — features that collectively are reminiscent of organic hypogonadism in young men. Decreases in muscle mass and strength are strong predictors of falls, fractures, and loss of the ability to live independently. Thus, if young and old men have similar responses to a decline in testosterone levels, as they do to an increase in testosterone levels, these findings suggest that some of the changes observed in aging men may be related to age-associated changes in gonadal steroids and may be preventable with appropriate replacement. A direct determination of the relationships between gonadal steroid levels and clinical measures in elderly men is needed to confirm this hypothesis.

Our finding that estrogens have a fundamental role in the regulation of body fat and sexual function, coupled with evidence from prior studies of the crucial role of estrogen in bone metabolism, indicates that estrogen deficiency is largely responsible for some of the key consequences of male hypogonadism and suggests that measuring estradiol might be helpful in assessing the risk of sexual dysfunction, bone loss, or fat accumulation in men with hypogonadism. For example, in men with serum testosterone levels of 200 to 400 ng per deciliter, sexual-desire scores decreased by 13% if estradiol levels were 10 pg per milliliter or more and by 31% if estradiol levels were below 10 pg per milliliter. Our findings also suggest that treatment with aromatizable androgens would be preferable to treatment with nonaromatizable androgens in most men with hypogonadism.

In summary, we conducted a dose-ranging study to determine the relative testosterone doses and associated serum levels at which body composition, strength, and sexual function initially decline. By examining these relationships with and without suppression of estrogen synthesis, we found that lean mass, muscle size, and strength are regulated by androgens; fat accumulation is primarily a consequence of estrogen deficiency; and sexual function is regulated by both androgens and estrogens. Delineation of the degrees of hypogonadism at which undesirable consequences develop and of the relative roles of androgens and estrogens in each outcome should facilitate the development of more rational approaches to the diagnosis and treatment of hypogonadism in men.

A novel compound heterozygous mutation of the aromatase gene in an adult man: reinforced evidence on the relationship between congenital oestrogen deficiency, adiposity and the metabolic syndrome.

Maffei L, Rochira V, Zirilli L, Antunez P, Aranda C, Fabre B, Simone ML, Pignatti E, Simpson ER, Houssami S, Clyne CD, Carani C.
Source Consultorios Asociados de Endocrinologia Buenos Aires, Argentina.

Abstract

BACKGROUND: Descriptions of new cases of human aromatase deficiency are useful for a better understanding of male oestrogen pathophysiology, as some aspects remain controversial.

OBJECTIVE: To present a new case of an adult man affected by aromatase deficiency, along with a description of clinical phenotype, and hormonal and genetic analysis.

DESIGN: Case report study.

PATIENT: A 25-year-old man with continuing linear growth, eunuchoid body habitus and diffuse bone pain.

MEASUREMENTS: Amplification and sequencing of all coding exons with their flanking intronic sequences of the CYP19A1 gene. Aromatase expression of the mutant human cDNAs was compared with wild type. Serum LH, FSH, testosterone, oestradiol, insulin, glucose, glycosylated haemoglobin (HbA1c), serum lipids and liver enzymes were measured. Histological analysis of liver and testis biopsies was performed.

RESULTS: Two novel heterozygous compound inactivating mutations of the CYP19A1 gene were disclosed. The first mutation is at bp380 (T–>G) in exon IV and the second one at bp 1124 (G–>A) in exon IX. LH and testosterone were normal, FSH was slightly elevated, and serum oestradiol undetectable. The subject showed a metabolic syndrome characterized by abdominal obesity, hyperinsulinaemia, acanthosis nigricans and nonalcoholic fatty liver disease.

CONCLUSIONS: These novel mutations improve our knowledge on genetics of the CYP19A1 gene. This new case of aromatase deficiency sheds new light on the heterogeneity of mutations in the CYP19A1 gene causing loss of function of the aromatase enzyme. The evidence of metabolic syndrome and of obesity associated with congenital oestrogen deprivation emphasizes the role of oestrogens in , a role that has long been partially overlooked in these patients.

PMID: 17547681 [PubMed - indexed for MEDLINE]

Differential regulation of bone and body composition in male mice with combined inactivation of androgen and estrogen receptor-alpha.

Callewaert F, Venken K, Ophoff J, De Gendt K, Torcasio A, van Lenthe GH, Van Oosterwyck H, Boonen S, Bouillon R, Verhoeven G, Vanderschueren D.

Source

Laboratory for Experimental Medicine and Endocrinology, Department of Experimental Medicine, Katholieke Universiteit Leuven, Leuven, Belgium.

Abstract

Osteoporosis and muscle frailty are important health problems in elderly men and may be partly related to biological androgen activity. This androgen action can be mediated directly through stimulation of the androgen receptor (AR) or indirectly through stimulation of estrogen receptor-alpha (ERalpha) following aromatization of androgens into estrogens. To assess the differential action of AR and ERalpha pathways on bone and body composition, AR-ERalpha double-knockout mice were generated and characterized. AR disruption decreased trabecular bone mass, whereas ERalpha disruption had no additional effect on the AR-dependent trabecular bone loss. In contrast, combined AR and ERalpha inactivation additionally reduced cortical bone and muscle mass compared with either AR or ERalpha disruption alone. ERalpha inactivation–in the presence or absence of AR–increased fat mass. We demonstrate that AR activation is solely responsible for the development and maintenance of male trabecular bone mass. Both AR and ERalpha activation, however, are needed to optimize the acquisition of cortical bone and muscle mass. ERalpha activation alone is sufficient for the regulation of fat mass. Our findings clearly define the relative importance of AR and ERalpha signaling on trabecular and cortical bone mass as well as body composition in male mice.

PMID: 18809737 [PubMed - indexed for MEDLINE]

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