Edited by: Thomas W. Durso
'MAJOR IMPORTANCE': Eric Smith evaluated a man shown to be estrogen-resistant.
Comments by Eric P. Smith, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, and Kenneth S. Korach, National Institute of Environmental Health Sciences, Research Triangle Park, N.C.
Estrogen is generally thought to have important effects only on women. But with the publication of this paper, describing the first reported case of estrogen resistance in a human male, researchers demonstrated the importance of the hormone in men.
The subject of this paper, a 28-year-old man who stood at 6 feet, 8 inches, was experiencing secondary-to-continued growth well into his third decade, and displayed delayed bone-age maturation comparable to a 15- year-old boy. Ultimately, the man was evaluated by pediatric endocrinologist Eric P. Smith, an associate professor of pediatrics at Cincinnati Children's Hospital Medical Center, which is affiliated with the University of Cincinnati College of Medicine.
Despite the man's age and height, further testing revealed that he had a bone-mineral mass similar to a "severely osteoporotic elderly woman," according to Smith. Levels of testosterone and androgen, a pair of male hormones, were normal, but estrogen levels were elevated, which suggested resistance to estrogen.
To test the hypothesis of estrogen resistance, Smith treated the man with estrogen skin patches, raising the hormone level tenfold, for six months. "There was no measurable response to the treatment," Smith recalls. "A normal individual would develop substantial breast enlargement, among many other physical and biomedical changes. We were quite surprised, because his lack of response suggested severe estrogen resistance, a condition that was thought to be embryonically lethal. Indeed, this was considered to be the explanation for why no cases of loss-of-function estrogen receptor mutations had been reported in the medical literature."
FIRST REPORT: Estrogen is now revealed to be important to men, says Kenneth Korach.
The implications of the case are significant, say the researchers. "Here's the first reported mutation of this gene resulting in a living individual who is hormonally insensitive to estrogen," Korach states.
The paper demonstrated, "dramatically and unequivocally," according to Korach, that estrogen is the principal hormone involved in the final fusion of the epiphyses, the plates at the end of bones whose closure is necessary for bones to stop lengthening. In addition, the researchers say, estrogen must now be considered important in males for normal accretion of bone-mineral mass, with major implications for the common clinical condition of osteoporosis.
"Whether you have patients who don't make estrogen or make estrogen but can't use it through the receptors," Korach declares, "you still have the same effect on the skeleton."
Smith points to estrogen's involvement in many different processes, such as growth and bone density, and the implications for males as the reasons the paper has been highly cited.
"From my point of view as a pediatric endocrinologist, the major importance is on growth implications," he says. "We see a lot of children who have growth disorders, and their degree of bone maturation is a major component of their evaluation. Any advance in the understanding of the primary determinants of how growth plates mature and fuse will be useful in the evaluation of childhood growth disorders. Potentially, final height could be augmented by manipulating the androgen/estrogen milieu."
Korach also attributes interest in the paper to "the uniqueness and novelty of the findings." He notes that it was the first clinical description of this gene mutation, which debunked the long-held notion that it was a lethal mutation. "Now it turns out you can have mutation in this gene and it does not result in lethality, but produces significant phenotype."
In addition, Korach points out correlations between the man's case and the male mice. For example, the estrogen-receptor gene mutation in the mice resulted in male infertility, and Korach speculates that human males may evolve similar impairments related to decreased estrogen action. The man profiled in this paper had a low-normal sperm count with decreased movement at the time of the initial analysis, and Korach explains that the condition in the mice appears progressive.
"It told us for the first time there's a critical role for estrogen in male fertility, and effects on the male reproductive tract were a real surprise," he adds. "From the past we thought it was something that was androgen- or testosterone-related. Now we see the lack of a functional estrogen receptor and lack of estrogen action has been associated with male infertility. It ties estrogen exposure to the male, and it's as important there as it is to the female. We hope it will allow us to make people aware that this mutation can exist in the human population."