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| Archive : Fall
2006 |
FROM BACH TO BEDOUINS, MANY STONES WERE TURNED IN SEARCH OF CLUES TO HOW PUBERTY BEGINS:
An eighteenth-century choir // A gene that “kisses” // Harry Potter // Saudi cousins // Songbirds //
And, of course,
pimply faced adolescents.
To Grow Hairy [page 2]
 By Stephen S. Hall |
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It isn’t as if estradiol and testosterone have been in hiding throughout a child’s life. To the contrary, since early infancy, they’ve been sleeping in late like many adolescents, in a kind of molecular hibernation. LH and FSH are present in fairly substantial amounts during fetal development and in infants during their first half-year. “Three-month-old boys have as much testosterone as you and I,” Crowley says. “And then, at around six months, it shuts down.” Boys enter “a mysterious period of dormancy during childhood,” Crowley and his colleagues have written, until being aroused at the beginning of puberty.
In the early 1980s, many physicians hoped that the discovery of GnRH would lead to better diagnosis of several rare disorders of sexual maturation, which can take the form of very early development (central precocious puberty) or, conversely, no puberty at all. Crowley, then a young doctor at the Massachusetts General Hospital (he now heads the reproductive endocrinology unit there), believed the hormone could be used therapeutically, and he had an astonishing case with which to make the point. It was that of a two-year-old girl who had already entered puberty, with rapid growth, vaginal bleeding, and breast and pubic-hair development.
A researcher at the University of Pittsburgh, Ernst Knobil, had shown that puberty could be triggered in primates by the administration of GnRH in pulses and then shut down again by the continuous administration of the same amount of hormone. In other words, the onset of puberty depended not only on the presence of the hormone but also on the way in which the body delivered it. So Crowley’s team treated the girl with constant low doses of a synthetic agonist, or stimulant, of GnRH. That continuous stimulation actually fatigued the pituitary, which then stopped sending hormone messages to the sexual organs. After two months of treatment, the girl’s development normalized, and she went back to being a toddler.
Next, Crowley tackled the opposite situation—inducing puberty in men who otherwise couldn’t achieve it. He and colleague Andrew R. Hoffman began treating patients with GnRH. But to be effective, they discovered, the drug had to be given in pulses, just as the hypothalamus releases it, so they customized a portable infusion pump to release a dose of hormone every two hours. These pulses induced all the clinical and biochemical changes of normal puberty within three months, and the patients achieved normal sexual development.
By then the researchers had a keen interest in identifying the genes that controlled the timed release of this crucial hormone, but they would have to wait more than a decade for the genetic tools—and the good fortune—that would allow them to make real progress in that search. The tools came as a by-product of the Human Genome Project (the federally funded effort to decipher the 3 billion biochemical letters of human DNA), and the good fortune happened when a researcher in Crowley’s lab, Yousef Bo-Abbas, returned to his native Kuwait during the late 1990s.
Crowley had sent Bo-Abbas there on an unusual assignment. “I told him to find me a good Bedouin family,” Crowley recalls, knowing that the group’s frequent practice of intermarriage increases the odds of finding significant gene mutations. “He went on TV with one of those portable IV pumps we had rigged up, and asked if anyone knew families suffering from infertility. Remarkably, Bo-Abbas found some.”
In one large Saudi Arabian extended family in particular, in which there were three marriages between first cousins, six of 17 children had failed to achieve puberty (the technical term is idiopathic hypogonadotropic hypogonadism, meaning that the chemical that triggers puberty is essentially undetectable). To a geneticist searching for a gene related to puberty, this increased the number of needles while dramatically diminishing the size of the haystack. |
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Photo by H. Armstrong Roberts/ ClassicStock |
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