Jon F.R. Barrett, M online drugs .B., B.Ch., M.D., Mary E. Hannah, M.D.C.M., Eileen K. Hutton, Ph.D., Andrew R. Willan, Ph.D., Alexander C. Allen, M.D.C.M., B. Anthony Armson, M.D., Amiram Gafni, D.Sc., K.S. Joseph, M.D., Ph.D., Dalah Mason, M.P.H., Arne Ohlsson, M.D., Susan Ross, Ph.D., J. Johanna Sanchez, M.I.P.H., and Elizabeth V. Asztalos, M.D. For the Twin Birth Study Collaborative Group: A Randomized Trial of Planned Cesarean or Vaginal Delivery for Twin Pregnancy.
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.: Gonadal Body and Steroids Composition, Power, and Sexual Function in Men Testosterone therapy is definitely prescribed for millions of men each year, and the quantity rapidly is increasing. Prescription product sales of testosterone elevated by 500 percent in the United States between 1993 and 2000.1 Most testosterone prescriptions are created to treat nonspecific symptoms, such as fatigue or sexual dysfunction, when accompanied by testosterone levels below the laboratory reference vary. Currently, testosterone levels that are at least 2 SD below the mean value for healthy young adults are categorized as low.1,2 Although convenient, this classification does not consider the physiological effects of specific testosterone levels. A lot more than 80 percent of circulating estradiol in men comes from the aromatization of testosterone.3 Thus, as serum testosterone amounts decline, there is a concomitant decline in serum estradiol levels.4,5 Nevertheless, the consequences of male hypogonadism are attributed solely to androgen deficiency routinely; the potential function of the concomitant decline in estrogens is normally ignored. It is becoming clear, however, that estrogen deficiency may be important in the pathogenesis of some consequences of man hypogonadism, such as bone loss.6-8 The potential role of estrogen deficiency in the pathogenesis of other effects of hypogonadism, such as for example alterations in body composition or sexual function, is unknown largely. Information on the function of estrogens in man hypogonadism may help identify men at risk for particular manifestations of the condition and may provide a rationale for novel approaches to its administration. We sought to determine the relative amount of testosterone insufficiency, estradiol deficiency, or both at which undesirable adjustments in body composition, power, and sexual function start to occur and whether those apparent changes are due to androgen deficiency, estrogen insufficiency, or both. Methods Study Participants We recruited two cohorts of men who were 20 to 50 years of age and healthy. All of the men had normal serum testosterone levels. Details of the eligibility requirements and study completion are given in the Supplementary Appendix, available with the full text of this article at NEJM.org. Study Protocol and Design All individuals received goserelin acetate , at a dosage of 3.6 mg subcutaneously at weeks 0, 4, 8, and 12, to suppress endogenous gonadal steroids. Participants were after that randomly assigned to receive 0 g , 1.25 g, 2.5 g, 5 g, or 10 g of a topical 1 percent testosterone gel daily for 16 weeks. Participants in cohort 2 also received anastrozole at a dose of 1 1 mg daily to block the aromatization of testosterone to estrogen. Individuals were unacquainted with the study-group assignments. Individuals were seen every four weeks. At each go to, fasting blood samples were obtained to measure gonadal steroid levels, and questionnaires were administered to assess physical function, health position, vitality, and sexual function. At baseline and week 16, surplus fat and lean mass were assessed by way of dual-energy x-ray absorptiometry ; subcutaneous – and intraabdominal-unwanted fat areas and thigh-muscle region were measured through computed tomography ; and lower-extremity strength was dependant on means of a leg press. Data on bone homeostasis , risk elements for cardiovascular disease , and degrees of leptin and prostate-particular antigen were also gathered but are not contained in the present report. The scholarly study was approved by the institutional review board of Companions HealthCare. All participants provided written educated consent. All authors attest to the completeness and precision of the data and analyses and the fidelity of the study to the protocol . All authors made the decision to post the manuscript for publication. Abbott Laboratories provided partial monetary support and provided the testosterone gel at no charge but had no part in the study design, data evaluation, data interpretation, or manuscript preparation. AstraZeneca offered Zoladex and Arimidex at no cost but had no role in the scholarly study design, data evaluation, data interpretation, or manuscript preparation. Testosterone and Estradiol Measurements The serum level of total testosterone was measured through a solid-phase chemiluminescent immunoassay by using an automated analyzer . The assay sensitivity was 20 ng per deciliter.9 The correlation between the testosterone assays was 0.93, and the assays had very similar results .25 pg per milliliter.9 Outcomes and Assessments The principal outcome variables were changes in the DXA-based measures of body fat and lean mass. The %age of surplus fat and the total-body lean mass had been determined by method of DXA .10 Subcutaneous – and intraabdominal-body fat areas were dependant on means of CT at the L4 vertebral level with a LightSpeed Pro 16 scanner .11 Cross-sectional thigh-muscle area was determined at the midpoint of the femur.12 Lower-extremity power was assessed as the maximum weight lifted for one repetition with the use of a leg press .13 Sexual function, physical function, vitality, and general health status were assessed at each visit by using a self-administered questionnaire in health-related standard of living that was previously validated in individuals with prostate cancer who were undergoing androgen-deprivation therapy.14 Sexual function was divided into domains of libido and erectile function. The principal analysis was a modified intention-to-treat analysis. Because we were assessing adjustments in outcome variables, individuals who completed just the baseline visit could not be contained in any longitudinal analyses. Because adjustments in body composition are unlikely that occurs within the first several weeks of hormonal manipulation, the protocol required that participants complete the first three visits in order to avoid exposing individuals to additional radiation from do it again body-composition scans when it made an appearance unlikely that the results would be informative. In addition, the protocol required that participants miss only 20 percent of their research medication doses to be contained in the analyses. Participants who discontinued the study medication after week 8 but before week 16 had been asked to undergo follow-up body-composition and strength assessments at their final visit. Statistical Analysis The study was made to have 80 percent power at an alpha level of 0.025, by using a one-way analysis of variance to detect mean changes from baseline to 16 weeks of at least 0.3 times the common regular deviation for body-composition measures on DXA and subcutaneous-fat region and thigh-muscle area on CT. These calculations were based on an example of 40 individuals per dose group, with the assumption that 80 percent of individuals would have data that could be assessed. To look for the testosterone dose needed to maintain body composition, strength, and sexual function, we compared changes in each result among dose groups by using Duncan’s multiple-range check. To control further for type I error, we followed a significance level of 0.025, using the Bonferroni solution to adjust for the two primary outcomes. Our major analysis centered on comparisons of the mixed group receiving the 5-g dose with the other dose groups, because this dosage produced testosterone levels which were similar to baseline amounts. To determine if the noticeable adjustments in each outcome were related to testosterone, estradiol, or both, we used the following approaches. To assess testosterone-related results, we compared changes in each final result among all dose groupings in cohort 2 with the use of Duncan’s multiple-range test. Because anastrozole suppresses estradiol creation dramatically, differences between groupings within cohort 2 should reflect the effect of testosterone on each outcome. The conversation compares the slopes of regression of the testosterone dosage with the outcome values in cohort 1 and cohort 2. The consequences of estradiol on each outcome were also inferred by using independent t-exams to compare the mean modify in each outcome for all organizations that received testosterone in cohort 1 with the mean alter in all groups that received testosterone plus an aromatase inhibitor in cohort 2. Because testosterone doses were similar in both cohorts and estradiol synthesis was selectively inhibited in cohort 2, variations in outcomes between cohorts by using this approach should also reflect the consequences of estradiol. All reported P values are two-sided. P ideals of significantly less than 0.025 were considered to indicate statistical significance, with the exception that for interaction tests, P values of significantly less than 0.05 were thought to indicate statistical significance. Results Baseline Characteristics and Study Completion We enrolled 198 men in cohort 1 and 202 guys in cohort 2 . There were no significant differences in baseline testosterone amounts among dose organizations or between cohorts . Ten males in cohort 1 and 27 in cohort 2 discontinued the analysis before week 8 and were included in analyses of baseline data just. We conducted a altered intention-to-treat evaluation of the rest of the data. In cohort 1, a complete of 24 males discontinued participation between weeks 8 and 16, of whom 16 underwent follow-up body-composition and power testing. Four additional participants were excluded for protocol violations later. In cohort 2, a complete of 17 guys discontinued participation between weeks 8 and 16, of whom 13 underwent follow-up body-composition and power testing. One participant in cohort 2 was excluded for a process violation. Paired DXA, CT, or strength tests could not be completed in an additional 3, 5, and 10 guys, respectively, in cohort 1 and in 1, 1, and 12 men, respectively, in cohort 2. Thus, the respective numbers of participants included in the analyses of libido, body composition as measured by DXA, body composition as measured by CT, and strength were 184, 173, 171, and 166 for cohort 1 and 174, 169, 169, and 158 for cohort 2. Hormone Levels In men receiving goserelin acetate and 0 g , 1.25 g, 2.). The corresponding suggest estradiol levels had been 3.4 pg per milliliter, 7.9 pg per milliliter, 11.7 pg per milliliter, 18.2 pg per milliliter, and 33.3 pg per milliliter .4 pg per milliliter, 1.4 pg per milliliter, 2.3 pg per milliliter, 2.9 pg per milliliter, and 2.8 pg per milliliter . Effects of Testosterone without Aromatase Inhibition on Body Composition In cohort 1, the %age of surplus fat increased in men who received 0 g significantly, 1.25 g, or 2.5 g of testosterone daily, in comparison with men who received 5 g daily, and it decreased in men who received 10 g of testosterone daily significantly, as compared with each of the other groups . Lean mass decreased in men who received placebo or 1 significantly.25 g of testosterone daily, as compared with men who received 2.5 g, 5 g, or 10 g of testosterone daily . Subcutaneous-fat area increased by a factor of 2-3 3 in males receiving 0 g, 1.25 g, or 2.5 g of testosterone daily, in comparison with men receiving 5 g or 10 g daily, though only the comparisons with the 10-g dose group were significant . Intraabdominal-fat area did not change significantly in virtually any group . Thigh-muscle region decreased in men who received placebo or 1 significantly.25 g of testosterone daily, as compared with men who received 5 g of testosterone daily, and it increased in men who received 10 g of testosterone daily significantly, in comparison with all the other groups . Leg-press power decreased in males who received placebo considerably, as compared with men receiving 2.5 g, 5 g, or 10 g of testosterone daily . Effects of Testosterone with Aromatase Inhibition on Body Composition In cohort 2, the %age of surplus fat increased in all groups when the aromatization of testosterone to estradiol was inhibited. The magnitudes of these increases were comparable with doses of 0 g, 1.25 g, 2.5 g, and 5 g of testosterone daily, a finding that suggests a predominantly estrogenic impact . Total-body lean mass decreased significantly in men who received placebo, as compared with those who received 1.25 g, 2.5 g, or 10 g of testosterone daily, a finding that implies an independent aftereffect of testosterone . Subcutaneous-fat area increased in every combined groupings in cohort 2, though only the comparison of changes between the 1.25-g and 10-g dose groups was significant . The increases in intraabdominal-fat region did not differ significantly among the dose organizations . Thigh-muscle region decreased in males who received placebo significantly, as compared with guys who received any of the four testosterone doses . As in cohort 1, leg-press power declined significantly in males who received placebo, as compared with guys who received the three highest testosterone doses . Ramifications of Testosterone with and without Aromatase Inhibition on Sexual Function In cohort 1, libido decreased with declining testosterone doses progressively, from 10 g to 0 g of testosterone daily, and all dose groups differed significantly from one another except for the 2 2.5-g and 5-g dose groups . Erectile function worsened considerably in men who received placebo, as compared with men who received testosterone, and declined even more in men who received 1.25 g of testosterone daily than in men in the three highest dose groups . In cohort 2, sexual desire declined in men who received placebo significantly, in comparison with men in the three highest dosage organizations, and declined more in men who received 1.25 g of testosterone daily than in men in the two highest dose groups . Erectile function decreased more in males who received placebo than in guys who received testosterone . Results for other self-reported measures can be found in the Supplementary Appendix.001), intraabdominal-fat area , subcutaneous-fat area , libido , and erectile function ; these findings reveal that estradiol exerted an independent effect on these variables . In the combined groupings that received testosterone, inhibition of estrogen synthesis , as compared with intact estrogen synthesis , was connected with significant raises in the %age of body fat , subcutaneous-fat region , and intraabdominal-fat area and with significant decreases in sexual desire and erectile function ; these findings provide additional evidence of an independent aftereffect of estradiol on these steps.22), thigh-muscle area , or leg-press strength ; among the males who received testosterone, there have been no significant distinctions between cohorts in adjustments from baseline for total-body lean mass , thigh-muscle region , or leg-press strength . Discussion Although the sensitivity of various androgen target tissues may vary,15 the diagnosis of androgen deficiency is normally based on a single laboratory criterion: a testosterone level at least 2 SD below the mean value in normal young men. In this scholarly study, we discovered that the dose of testosterone required to prevent adverse adjustments in a variety of measures varies significantly. Sexual desire and erectile function, both major domains of sexual function, showed specific patterns of switch as serum testosterone levels were reduced. The variation in tissue sensitivity to androgens could be due to polymorphisms affecting polyglutamine repeat length in the androgen-receptor gene, tissue-specific distinctions in androgen-receptor expression or regional hormone metabolism, or, as demonstrated in today’s study, variation in the roles of androgens and estrogens in the regulation of target-tissue responses. Observational studies have shown that lean mass and strength are decreased and fat mass is definitely increased in men with low testosterone levels.5,10,11 Men with hypogonadism report less sex, fewer sexual thoughts, and fewer spontaneous erections than men with normal testosterone levels. Moreover, testosterone replacement boosts lean mass, decreases fats mass, and will improve sexual function in guys with hypogonadism.11,16-22 These observations possess led to the widespread belief that undesirable changes in body composition and sexual dysfunction in men with hypogonadism are because of androgen deficiency. Nevertheless, because estradiol is definitely a metabolite of testosterone, it really is hard to distinguish the effects of androgens from those of estrogens in observational research, or in randomized even, managed trials if aromatizable androgens are utilised without the administration of an aromatase inhibitor. By administering a variety of testosterone dosages with and without concomitant aromatase inhibition, we discovered that adjustments in lean mass, thigh-muscle mass area, and leg-press power were attributable to changes in testosterone levels, whereas changes in fat steps were related to adjustments in estradiol levels primarily. Both androgens and estrogens contributed to the maintenance of regular libido and erectile function.23-26 Our observations might have important clinical implications. First, they provide a physiological basis for interpreting testosterone amounts in youthful and middle-aged men and determining the adverse outcomes that are most likely to occur at numerous gonadal steroid levels. Second, because increases in visceral fat reduce insulin sensitivity and so are associated with diabetes and the metabolic syndrome,27 the marked upsurge in intraabdominal fat with aromatase inhibition could portend a rise in coronary disease with long-term estrogen deficiency. Finally, because lean mass, thigh-muscle area, and erectile function were reduced at a testosterone dosage 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 guys have alterations in these useful outcomes at lower or more testosterone levels, and additional implications of hypogonadism, such as increases in surplus fat and reduction of sexual desire, develop at higher mean testosterone levels routinely. Thus, each person’s specific clinical scenario should be considered when interpreting the scientific need for the circulating testosterone level. These findings may also have implications for older men. Serum testosterone amounts decline modestly as males age, in a way that 20 percent of guys older than 60 years and 50 percent of men older than 80 years of age have testosterone amounts at least 2 SD below the mean level in young men.33 Decreases in muscle mass and strength are strong predictors of falls, fractures, and lack of the capability to live independently.36 Thus, if old and young men have got similar responses to a decline in testosterone amounts, because they do to an increase in testosterone levels,37,38 these findings suggest that a few of the changes seen in aging men may be linked to age-associated changes in gonadal steroids and could be preventable with right replacement. A direct determination of the interactions between gonadal steroid amounts and clinical methods in elderly men is needed to confirm this hypothesis. Our finding that estrogens have a simple role in the regulation of body sexual and fat function, coupled with proof from prior research of the crucial role of estrogen in bone rate of metabolism,6-8 indicates that estrogen deficiency is largely responsible for a few of the key outcomes of male hypogonadism and shows that measuring estradiol might be helpful in assessing the chance of sexual dysfunction, bone loss, or fat accumulation in men with hypogonadism. For example, in males with serum testosterone degrees of 200 to 400 ng per deciliter, sexual-desire scores reduced by 13 percent if estradiol levels had been 10 pg per milliliter or more and by 31 percent if estradiol levels had been below 10 pg per milliliter. Our findings also suggest that treatment with aromatizable androgens would be better treatment with nonaromatizable androgens generally in most men with hypogonadism. Our study has limitations. First, in order to avoid significant adjustments in healthy males clinically, such as for example bone loss, the study was limited by 16 weeks.39,40 Because shifts in body composition may progress over time, greater changes may have been seen at higher testosterone and estradiol amounts if gonadal steroids have been suppressed over a longer time. Second, although most circulating estradiol is derived from the aromatization of circulating testosterone, a small portion is straight secreted by the testes in normal men and may not be restored with exogenous testosterone administration.41 Third, changes induced by aromatase inhibition could reflect the consequences on local aromatase activity primarily; therefore, circulating estradiol amounts might not reflect estrogen effects reliably. Changes observed in our model of severe gonadal steroid deprivation could also differ from those seen when gonadal steroids decline gradually over a period of years. Finally, it appears likely that the relationship between declining gonadal steroid amounts and the risk of adverse implications is even more accurately represented as a continuum than as a rigid threshold above which scientific measures are regular and below which adverse changes occur. However, clinicians eventually must decide how to treat each patient based on his individual data, of which the testosterone level may be the principal component generally. In summary, we conducted a dose-ranging study to determine the relative testosterone doses and associated serum amounts of which body composition, strength, and sexual function initially decline. By examining these associations with and without suppression of estrogen synthesis, we discovered that lean mass, muscle tissue size, and power are regulated by androgens; fat accumulation is usually a rsulting consequence estrogen deficiency primarily; and sexual function is definitely regulated by both androgens and estrogens. Delineation of the examples of hypogonadism at which undesirable effects develop and of the relative roles of androgens and estrogens in each result should facilitate the advancement of more rational methods to the diagnosis and treatment of hypogonadism in males.