Hypogonadotophic Hypogonadisms: Lessons to understand development, to improve fertility treatment

For the past 40 years the rogress made in the field of reproductive physiology has been dramatic. Among key discoveries the understanding of the hormonal control of the Hypothalamic Pituitary Gonadal axis has been flabbergasting. Following the pioneer work of Cushing and Crowe, Geoffrey Harris and others, in the late 40s, demonstrated the existence of a blood born signal on the pituitary gonadotroph cells. The final step followed a huge biochemical and chemical endeavour to elucidate the structure of GnRH by Schally and Guillemin. This was achieved in 1971 after a dramatic competition to demonstrate the molecular basis of the brain control of reproduction. The competition ended in the imperial ballroom of the San Francisco Hilton with the presentation of the 10 amino acid sequence of GnRH by Schally on June 24, 1971.

Indeed, 40 years later, we are now able to understand the mechanisms of brain development and the diseases that are associated with the migration of GnRH neurons, the mechanisms of action of GnRH, but also we are, at last, able to understand after a very long period of hesitations, and hallucinations, the mechanisms of puberty and of nutritional amenorrhea, a frequent abnormality linked to the change of body image carried over by our society. More recently, genetic analysis of familial and individual cases where subtle mechanisms are impaired, have allowed us to discover new genes such as gpr 54 and its ligand Kisspeptin 1, the gateway of puberty, neurokinin B (NKB) and its receptor (NK3R), a controlling pathway of gpr 54, as well as the molecular abnormalities behind hypothalamic hypogonadisms associating malformation and hypogonadisms such as Kallmann Syndrome (genes Kal 1-4), the Charge syndrome, and other complex diseases such as Prader and Willi syndrome, Bardet Biedl syndrome…

Amazingly, it is only now , in 2009, 38 years after the discover y of GnRH structure, that the first patients with GnRH mutations (so called GnRH 1) have been identified, thus paying a tribute to the pivotal role of GnRH and its discoverers.

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Reprinted with permission of the International Society of Gynecological Endocrinology

References

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