It is the scourge of many a middle-aged man: He starts getting a pot belly, using lighter weights at the gym and doesn't have the sexual desire of his younger years.
The obvious culprit is testosterone, since men gradually make less of the male sex hormone as years go by. But a surprising new answer is emerging, one doctors say could reinvigorate the study of how men's bodies age.
Estrogen, the female sex hormone, turns out to play a much bigger role in men's bodies than thought, and falling levels contribute to expanding waistlines, as they do in women's.
The discovery of estrogen's role in men is "a major advance," said University of Pennsylvania medical professor Peter J. Snyder, who is leading a big new research project on hormone therapy for men 65 and over. Until recently, testosterone deficiency was considered nearly the sole reason that men undergo the familiar physical complaints of midlife.
The new frontier of research involves figuring out which hormone does what in men, and how body functions are affected at different hormone levels.
While dwindling testosterone levels are to blame for middle-aged men's smaller muscles, falling estrogen levels regulate fat accumulation, says a study published Wednesday in the New England Journal of Medicine, which provided the most conclusive evidence to date that estrogen is a major culprit in male midlife woes. And both hormones are needed for libido.
"Some of the symptoms routinely attributed to testosterone deficiency are actually partially or almost exclusively caused by the decline in estrogens," Harvard Medical School endocrinologist Joel Finkelstein, the study's lead author, said in a news release Wednesday.
His study is only the start of what many hope will be a new understanding of testosterone and estrogen in men.
Dr. Snyder is leading another study, the Testosterone Trial, which measures levels of both hormones and asks whether testosterone treatment can make older men with low testosterone levels more youthful -- by letting them walk more quickly, feel more vigorous, improve sexual functioning and memories, and strengthen bones.
Both men and women make estrogen out of testosterone, and men make so much that they end up with at least twice as much estrogen as postmenopausal women. As both hormones' levels decline with age, the body changes. But until now, researchers focused almost exclusively on how estrogen affects women and how testosterone affects men.
Dr. Finkelstein's study provides a new map of each hormone's function and behavior at various levels. It suggests different symptoms kick in at different testosterone deficiency levels.
Testosterone, he found, is the chief regulator of muscle tone and lean body mass, but it takes less than was thought to maintain muscle. For a young man, 550 nanograms of testosterone per deciliter of serum is the average level. Doctors have considered levels below 300 nanograms so low they may require treatment, typically with testosterone gels.
But Dr. Finkelstein's study found that muscle strength and size turn out to be unaffected until testosterone levels drop below 200 nanograms. Yet fat accumulation kicks in at higher testosterone levels: At 300 to 350 nanograms of testosterone, estrogen levels sink low enough that middle-aged spread begins.
Both sexual desire and performance require estrogen and testosterone, and increase steadily as those hormone levels rise.
Although doctors often prescribe testosterone gels for men whose levels fall below 300 nanograms, that cutoff point is arbitrary, with no clinical rationale for it, Dr. Finkelstein said. Often men take the hormone to treat complaints such as fatigue, depression or loss of sexual desire, which may or may not be from low testosterone.