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EDITORIAL |
Institute of Reproductive and Developmental Biology, Hammersmith Campus, Imperial College London, Du Cane Road, London W12 0NN, UK
Correspondence should be addressed to I Huhtaniemi; Email: ilpo.huhtaniemi{at}imperial.ac.uk
The crucial role of gonadotrophins in the regulation of reproductive functions has been known for a long time, and recent research has concentrated to a great extent on novel endocrine, paracrine and autocrine regulatory factors. The place of gonadotrophins in the treatment of infertility and hypogonadism is also well established, and their measurement is pivotal in the diagnostics of various reproductive disorders. Despite this established position and somewhat conservative image, novel information on the actions of gonadotrophins is constantly emerging. The developments of the last 10–15 years have brought the recombinant gonadotrophin preparations to clinical practice. Another development has been the discovery of mutations and polymorphisms in gonadotrophin subunit and receptor genes, which have unravelled totally new details in the physiology and pathophysiology of gonadotrophin synthesis, secretion and action (Themmen & Huhtaniemi 2000). Other novel findings of great importance have been the crystallization of gonadotrophin molecules; the latest development has been the crystallization of the extracellular FSH-receptor ligand-receptor complex (Fan & Hendrickson 2005), depicted on the cover of this issue of Reproduction. Finally, a number of transgenic mice with amplified gonadotrophin secretion and action, as well as knockout models for the gonadotrophin subunits and receptors have been produced. Besides providing the expected phenocopies of activating and inactivating mutations of the cognate human genes, these mouse models have presented us with novel and unexpected phenotypes caused by either defective or amplified gonadotrophin action.
The four focus articles in this issue of Reproduction summarise the most important recent developments in our knowledge on the physiology and pathophysiology of gonadotrophin function, based on human mutations and relevant genetically modified mouse models. The first review (Themmen 2005) summarises the current knowledge about the mutations and polymorphisms detected in the human gonadotrophin subunit and receptor genes. Although the phenotypes of most of the possible activating and inactivating mutations of these genes are reasonably well known by now, gaps still exist in our knowledge. For instance, we do not understand why activating LH receptor mutations have no phenotype in women, and there is still only one report (Gromoll et al. 1996) on an activating FSH receptor mutation. The influence of several common polymorphisms of these genes on reproductive functions is currently being investigated, but we still do not understand the real importance of this genetic variability in human reproduction. Another unsolved question is the importance of the apparently wide extragonadal expression of gonadotrophin receptors, especially those of LH (Filicori et al. 2005). The second review (Costagliola et al. 2005) deals with some very intriguing spontaneous mutations in gonadotrophin receptors that affect the ligand-specificity of the hormone-receptor interaction. They also alude to the possibility that gonadotrophin homo- or heterodimerization would play a role in the diversification of gonadotrophin actions.
The two reviews on genetically modified mice summarise the current knowledge about the phenotypes brought about by transgenic mice overproducing FSH, LH or hCG (Rulli & Huhtaniemi 2005) and by knockout mice for the gonadotrophin subunits and receptors (Kumar 2005). These models are relevant phenocopies of the respective pathologies in human gonadotrophin secretion and action, which may help us in designing new diagnostic and therapeutic strategies for the human conditions. Of particular interest is the clear tumorigenic effects found in several mouse models that overproduce gonadotrophins. It is therefore relevant to address the same possibility in humans. The knockout models have brought valuable information about the molecular pathogenesis of hypogonadism and offer useful models for testing novel treatment modalities. As expected, all the phenotypic features of mice and men do not match. This should not be a real concern, because understanding the molecular basis for the species differences will advance our knowledge about reproductive biology in general, and help us to identify the clinically relevant special features of human reproduction.
As the four brief reviews on gonadotrophin action reveal, lots of new information is currently emerging both from clinical observation and genetically modified animal models. Not everything is yet known about these seemingly ‘old’ hormones, and the final picture on the multitude of the physiological and pathophysiolgical actions of gonadotrophins may turn out to be very different from the current dogmas.
References
Costagliola S, Urizar E, Mendive F & Vasart G 2005 Specificity and promiscuity of gonadotropin receptors. Reproduction 130 275–281.
Fan QR & Hendrickson WA 2005 Structure of human follicle-stimulating hormone in complex with its receptor. Nature 433 269–277.[CrossRef][Medline]
Filicori M, Fazleabas AT, Huhtaniemi I, Licht P, Rao ChV, Tesarik J & Zygmunt M 2005 Novel concepts of human chorionic gonadotropin; reproductive system interactions and potentials in the management of infertility. Fertility and Sterility [in press].
Gromoll J, Simoni M & Nieschlag E 1996 An activating mutation of the follicle-stimulating hormone receptor autonomously sustains spermatogenesis in a hypophysectomized man. Journal of Clinical Endocrinology and Metabolism 81 1367–1370.[Abstract]
Kumar TR 2005 What have we learned about gonadotrophin function from gonadotrophin subunit and receptor knockout mice? Reproduction 130 293–302.
Rulli SB & Huhtaniemi IT 2005 What have gonadotrophin over-expressing transgenic mice taught us about gonadal function? Reproduction 130 283–291.
Themmen APN & Huhtaniemi IT 2000 Mutations of gonadotropins and gonadotropin receptors: Elucidating the physiology and patho-physiology of pituitary-gonadal function. Endocrine Reviews 21 551–583.
Themmen APN 2005 An update of the pathophysiology of human gonadotropin subunit and receptor mutations and polymorphisms. Reproduction 130 263–274.
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