What causes puberty to begin?

Puberty, that awkward phase when boys and girls are primed for their sexual reproductive years as men and women, appears to be triggered by the brain's own version of "It takes two to tango," whereby a signal literally gets turned on by a molecule that is produced by a gene aptly named KiSS-1.

The couple – a biochemical equivalent to Adam and Eve – makes its sudden appearance in a region of the brain called the hypothalamus just as puberty begins, according to a study published in this week's online edition of the Proceedings of the National Academy of Sciences (PNAS).

Until now, little had been known about what instigates the cascade of hormone secretions that, over time, produces puberty's tell-tale physical changes, including the development of breasts in girls and voice change in boys. As such, this research begins to answer one of the most vexing questions about human development: What causes puberty to begin? How is it that the full repertoire of reproductive hormones can exist at birth, go into hiding at about four to six months of age, then reemerge in full force some 10 to 12 years later?

"Puberty is critical to human development. And while there is a fairly good understanding of how the endocrine system regulates the hormones involved, just how and when the brain activates this process has been a great mystery. An appreciation of puberty's deep-seated neurobiological mechanisms could, for instance, help prevent precocious or delayed puberty from occurring in some children," noted the study's lead author, Tony Plant, Ph.D., a professor in the departments of cell biology and physiology and obstetrics, gynecology and reproductive sciences, as well as director of the Center for Research in Reproductive Physiology at the University of Pittsburgh School of Medicine.

The research, performed in collaboration with teams at Harvard University's Massachusetts General Hospital and the Oregon National Primate Research Center, builds on the discovery made independently by both Harvard and French researchers that a gene called GPR54 is defective in children with a rare disorder that inhibits puberty's onset. To better understand what role GPR54 plays in the initiation of puberty, as well as learn about KiSS-1, which in earlier rodent studies had been identified as a molecule that activates a signal receptor of GPR54, the researchers looked to the nonhuman primate, the only animal with a reproductive system in common with the human's.

The onset of puberty becomes official when gonadotropin-releasing hormone (GnRH) is secreted and sets off a chain reaction of chemical messages. Inside the hypothalamus, nerve cells release GnRH in a 'round-the-clock,' pulsatile fashion. With each secretion, the pituitary gland is stimulated to secrete its own messengers, lutenizing hormone (LH) and follicle-stimulating hormone (FSH), directly into the circulation. In turn, these rising levels of LH and FSH cause the testes and ovaries to produce the sex hormones testosterone and estradiol, the culprits responsible for the physical changes and emotional baggage of male and female puberty, respectively.

"We now have very good evidence that the GPR54 gene and its switch, the kisspeptin protein molecule produced by KiSS-1, are key to the initiation of puberty, when GnRH is released," Dr. Plant said. "However, it's unlikely that they act alone. Other signaling systems, some of which have probably yet to be identified in humans, help control GnRH release in primates."

Besides learning that GPR54 and KiSS-1 are expressed inside the hypothalamus of primates at the time of puberty, the researchers also found that by giving animals kisspeptin they could, essentially wake up the reproductive hormones from their childhood hibernation. Within 30 minutes of kisspeptin being administered to male monkeys, LH, one of the hormones stimulated by GnRH secretion, was no longer dormant, with levels 25-times higher than its baseline of zero.

In addition to Dr. Plant, other authors of the PNAS paper are Muhammad Shahab, Ph.D., formerly a fellow working with Dr. Plant and now with the department of biological sciences at Quaidi-i-Azam University in Islamabad, Pakistan; Claudio Mastronardi, Ph.D., and Sergio R. Ojeda, D.V.M., both from the division of neuroscience at the Oregon National Primate Research Center; and Stephanie B. Seminara, M.D., and William F. Crowley, Jr., M.D., of the reproductive endocrine unit at Harvard's Massachusetts General Hospital. Dr. Crowley was a senior author of a 2003 New England Journal of Medicine article that described the mutant GPR54 gene.