New understanding of how hormones kick-start puberty

A collaborative project between groups based at the University of Cambridge, UK, and the University of Cukurova, Turkey, has unveiled a link between a hormone and the onset of puberty. Eight Turkish children with a rare genetic disorder, in which puberty does not reach completion, were found to harbour mutations that impair the hormone's function. Last week's paper, accepted for print by Nature Genetics, adds to our comprehension of puberty - a fine-tuned, hormone-regulated process.

The story focuses on the pituitary gland. This pea-size organ, seated at the base of the brain, releases regulative hormones that act at far-off locations in the body. One role is to regulate sexual maturation. Yet the pituitary gland needs controlling itself, and receives signals from the nearby hypothalamus. One of these signals is called gonadotropin-releasing hormone (GnRH). Quite how GnRH secretion is modulated at the onset of puberty remains an enigma, as only a few of the factors that regulate its release have been identified. In this report, Kemal Topaloglu and colleagues make the novel proposal that the hormone neurokinin B is a key player.

The disorder studied by Ali Kemal Topaloglu and colleagues is termed normosmic idiopathic hypogonadotropic hypogonadism (nIHH). It results in a failure to progress through puberty, whereby girls fail to begin menstruation and boys do not undergo the common physical altercations associated with teens. The problem derives from an imbalance in the normal pattern of GnRH release.

By analysing DNA from both affected and unaffected siblings, the scientists identified two loss-of-function mutations in either one of the TAC3 or TACR3 genes, which code for neurokinin B or its receptor, respectively. Afflicted children carried two copies of the mutant versions. A critical experiment in the investigation was to introduce the hormone receptor, or in parallel its mutated variant, into cultured cells, and observe an influx of calcium ions only when 'wild-type' and not the mutated receptor was expressed. Such calcium ion movement is a common mechanism employed by cells to say 'we're ready for action'.

Whilst nIHH is rare, complications with premature or late-onset puberty are common, affecting as many as one in 10,000 children. Interestingly, the TACR3 receptor structurally resembles many of those that have been successfully targeted by drugs in the past.

'The neurokinin B/neurokinin 3 receptor system is highly amenable in principle to targeting as a treatment', said Dr Robert Semple, a researcher in the Cambridge group, 'and I expect that this genetic discovery will lead to intense efforts to understand neurokinin B's role in puberty in more detail, and to try to develop clinically valuable drugs'. By dampening-down or firing-up the GnRN-release pathway, both contraceptives and fertility drugs can be envisaged.