男性勃起障碍和性冷淡与睾酮和雌激素下降相关

《新英格兰医学杂志》9月11在线发表的一项研究报告显示，男性睾酮水平下降可导致肌肉质量和力量减少，雌激素水平下降可导致脂肪质量和腹部脂肪增多，而上述两种激素水平均下降可使性欲和勃起功能下降(N. Engl. J. Med. 2013 Sept. 11 [doi:10.1056/NEJMoa1206168])。

波士顿麻省总医院内分泌科的Joel S. Finkelstein医生及其同事称，这项旨在探索雄激素缺乏患者睾酮和雌激素复杂作用的多剂量研究结果表明，单纯的睾酮水平下降并不能解释性功能低下男性所出现的身体成分、力量以及性因素等方面各种各样的变化。这也进而表明，目前仅凭1次血清睾酮水平检测便认定为“低水平”，并仅采取简单的内源性睾酮补充的评估和治疗方法过于笼统，应转而采用更加合理细致的方法。

研究者通过皮下注射戈舍瑞林暂时抑制正常内源性性腺类固醇激素，分析了20~50岁健康男性不同水平睾酮的不良反应。其中198例男性随机每日接受安慰剂、1.25、 2.5 、5 或10 g局部睾酮凝胶治疗，共计16周；另外202例男性随机接受同样剂量的局部睾酮凝胶和每日1 mg的阿那曲唑以阻断睾酮通过芳构化反应转变为雌激素。

所有受试者均不知道其治疗分组，治疗期间每4周接受1次性腺类固醇激素水平、身体功能、健康状况、活力和性功能检查，并应用双能x 线吸收仪(DXA)测定身体脂肪和肌肉质量，应用CT测定皮下脂肪、腹内脂肪和大腿肌肉，应用腿部推蹬机评估大腿肌肉力度。

结果显示，肌肉质量、大腿肌肉面积以及腿部推蹬力量等变化与睾酮水平变化相关，脂肪测量指标的变化主要与雌激素水平变化相关，而正常性欲和勃起功能的维持则与睾酮和雌激素两种激素水平相关。

同样重要的是，受试者维持肌肉质量、脂肪质量、力量和性功能所需睾酮水平差异很大。

当平均血清睾酮水平为200 ng/dl时，大多数男性出现肌肉质量、肌肉面积和性功能下降，因此，此时开始睾酮补充治疗似乎是合理的。但许多男性在较低或较高睾酮水平时出现上述指标的下降。此外，出现身体脂肪增加和性欲下降的睾酮水平也差异很大。“因此，对血清睾酮水平临床意义的解读应考虑每例患者的具体临床情况。”

另外一项重要结果是，男性性功能减退症的某些关键后果主要是由于雌激素缺乏，而非睾酮缺乏，这表明测定男性雌激素水平或有助于评估性功能障碍、骨丢失或脂肪堆积风险。

该研究的局限性在于研究时间仅为16周。研究者指出，之所以如此，是为避免健康受试者出现有临床意义的变化。“因为身体成分的变化随着时间的推移而进展，如果长时间抑制性腺类固醇激素，较高水平的睾酮和雌激素可能会导致身体成分变化程度较大。”

该研究由美国国立卫生研究院(NIH)和雅培制药公司资助。雅培公司还免费提供睾酮凝胶，阿斯利康免费提供戈舍瑞林和阿那曲唑，但这两家公司均未参与研究设计、数据分析、数据解读或报告撰写工作。

随刊述评：研究出色，凸显了问题的复杂性

悉尼大学协和医院澳大利亚与新西兰军团(ANZAC)研究所的David J. Handelsman博士在随刊评述中指出，Finkelstein医生及其同事的这项研究回答了一些重要问题，但也引发了一些新的疑问(N. Engl. J. Med. 2013 Sept. 11 [doi:10.1056/NEJMe1305307])。

研究结果明确，有助于进一步了解睾酮复杂的作用机理。但有必要开展更长时间的研究以评估睾酮对一些重要临床终点指标的影响，如骨密度、骨折、前列腺增生、代谢、心血管功能以及脑功能(包括情绪、行为和认知)。

Handelsman博士报告接受了欧加农、先灵等多家公司的研究经费资助。

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By: MARY ANN MOON, Internal Medicine News Digital Network

Declines in testosterone regulate decreases in men's muscle mass and strength, declines in estrogen regulate increases in men’s fat mass and abdominal fat, and declines in both hormones regulate decreases in men’s libido and erectile function, according to a report published online Sept. 11 in the New England Journal of Medicine.

These are the key findings from a dose-ranging study designed to tease out the complex roles played by both testosterone and estrogen in so-called androgen deficiency. They indicate that a simple, straightforward decline in testosterone doesn’t account for the myriad changes in body composition, strength, and sexual factors experienced by men with "low T."

This in turn suggests that the current approach to assessing and managing the condition – a one-time measurement of serum testosterone only, an across-the-board designation of a "low" level, and simple replenishment with endogenous testosterone only – should be replaced by more rational, nuanced approaches, said Dr. Joel S. Finkelstein of the endocrine unit and his associates at Massachusetts General Hospital, Boston.

They examined a wide spectrum of testosterone levels, and the adverse effects of different levels, by temporarily suppressing the normal endogenous gonadal steroids of healthy men aged 20-50 years using subcutaneous goserelin. In one cohort, 198 men then were randomly assigned to receive placebo, 1.25 g, 2.5 g, 5 g, or 10 g of a topical testosterone gel daily for 16 weeks. In another cohort, 202 men were randomly assigned to receive these same doses of topical testosterone plus 1 mg daily of anastrozole to block the aromatization of testosterone to estrogen.

All the study subjects, who were blinded to their medication assignments, were assessed every 4 weeks for the duration of the study for gonadal steroid levels, physical function, health status, vitality, and sexual function. Dual-energy -ray absorptiometry (DXA) was used to measure body fat and lean mass, and CT was used to measure the areas of subcutaneous fat, intra-abdominal fat, and thigh muscle. Thigh-muscle strength was assessed using leg presses.

"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," Dr. Finkelstein and his associates said (N. Engl. J. Med. 2013 Sept. 11 [doi:10.1056/NEJMoa1206168]).

As important, the level of testosterone needed to maintain lean mass, fat mass, strength, and sexual function was found to vary considerably among these study subjects.

Most men showed reduced lean mass, muscle area, and erectile function at a mean serum testosterone level of 200 ng/dL, so testosterone supplementation appears to be justified at this level. However, many men showed impairment in these outcomes at lower or higher testosterone levels. In addition, the testosterone levels at which body fat increased and sexual desire decreased varied widely.

"Thus, each person’s specific clinical scenario should be considered when interpreting the clinical significance of the circulating testosterone level," Dr. Finkelstein and his colleagues said.

Also important was the finding that deficiency of estrogen, not testosterone, "is largely responsible for some of the key consequences of male hypogonadism." This indicates that measuring men’s estradiol levels may help in assessing their risk for sexual dysfunction, bone loss, or fat accumulation, the researchers added.

This study was limited in that the duration was restricted to 16 weeks, so as to avoid inducing clinically significant changes in the healthy men who participated. "Because changes in body composition may progress over time, greater changes might have been seen at higher testosterone and estradiol levels if gonadal steroids had been suppressed over a longer period," the investigators noted.

This study was supported by the National Institutes of Health and Abbott Laboratories. Abbott also supplied the testosterone gel at no cost, and Astra Zeneca provided goserelin and anastrozole at no cost, but neither company played a role in study design, data analysis, data interpretation, or manuscript preparation.

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Excellent study highlights complexities

The study by Dr. Finkelstein and his colleagues answers important questions but raises new questions as well, said Dr. David J. Handelsman.

The findings are unequivocal, and "this excellent study contributes to our expanding appreciation of the complex mechanisms of action of testosterone." However, longer studies are necessary to elucidate the hormone’s effects on important clinical end points such as bone density, fractures, prostate growth and diseases, metabolism, cardiovascular function, and cerebral function (including mood, behavior, and cognition), he said.

Dr. Handelsman is at the Australia and New Zealand Army Corps (ANZAC) Research Institute, Concord Hospital, University of Sydney. He reported having received research support from Organon, Schering, Ascend/Besins, Lilly, Pharmacia, Serono, and Lawley. These remarks were taken from his editorial accompanying Dr. Finkelstein’s report (N. Engl. J. Med. 2013 Sept. 11 [doi:10.1056/NEJMe1305307]).