Philippe Bouchard

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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.

International Society of Gynecological Endocrinology

1.AC Latronico the Neurokinin B pathway in human reproduction Nature genetics 41 : 269-270, 2009

2.Bouligand J, et al. Isolated familialhypogonadotropic hypogonadisms and a GnRH1 mutation. N Engl J Med 360: 2742-8, 2009

3.Chan YM et al GnRH1 mutations in patients with idiopathic hypogonadotropic hypogonadisms. Proc Natl Acad Sci USA 106 : 11703-8, 2009

4.Crowley WF Jr, Pitteloud N, Seminara S. New genes controlling human reproduction and how you find them. Trans Am Clin Climatol Assoc 119: 29-37, 2008

5.Pitteloud N et al Digenic mutations account for variable phenotypes in idiopathic hypogonadotrophic hypogonadisms. J Clin Invest 117: 457-463, 2207.

6.De Roux N et al Hypogonadotropic hypogonadisms due to loss of dunction of the Kiss1- derived peptide receptor GP 54. Proc Natl Acad Sci USA 52: 1178-81, 2003.

8.Hardelin JP, DodÃ© C The complex genetics of Kallmann syndrome : KAL, FGFR1, FHF8, PROKR2, PROK2 et al. Sex Dev 2: 181-93, 2008.

9.De Roux N et al, A family with hypogonatropic hypogonadism and mutations in the GnRH receptor. N Engl J Med 337: 1597-602, 1997.

Articles

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.

Author | Philippe Bouchard

Articles

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