Cecilia Martin, Ph.D.

Research

A small and scattered population of hypothalamic neurons plays a critical role in the sexual maturation and fertility through the release the gonadotropin-releasing hormone (GnRH) and therefore modulating the hypothalamus-pituitary-gonads axis. They are several GnRH deficiency syndromes in humans including normosmic Idiopathic Hypogonadotropic Hypogonadism (nIHH), Kallmann Syndrome (KS), and Hypothalamic amenorrhea (HA). The HA is a reversible form of GnRH deficiency triggered by diverse stressors such as exercise, weight reduction or psychological stress. However, individuals show variable susceptibility to stress-induced inhibition of the reproductive axis. We hypothesized that defects in genes involved in GnRH neuronal development and function might confer susceptibility to HA. We have identified one heterozygous FGFR1 mutation (p.R756H) and a heterozygous Prokinectin 2 (PROKR2) mutation (p.R85H) in two out of 43 unrelated women with HA. Both patients demonstrated abnormal LH secretion patterns with absent and predominantly nocturnal LH pulses, respectively. The mutants exhibit reduced signaling in a transcription reporter assay and the R756H mutant had decreased cell membrane receptor expression, consistent with loss-of-function. Gene defects that affect GnRH ontogeny occur in women with HA, which may explain in part the variable susceptibility of women to suppression of the reproductive axis in response to stressors.