Perspective: Male Reproduction

0013-7227/01/$03.00/0 Endocrinology Copyright © 2001 by The Endocrine Society Vol. 142, No. 6 Printed in U.S.A. Perspective: Male Reproduction Human mutations and genetically modified animal models The specific role of a gene product can be resolved by overexpressing or disrupting its gene in genetically modified animals, usually mice. Novel functions for specific genes have been found, and useful models for the study of molecular pathogenesis of human diseases are available. Also male reproductive endocrinology has greatly benefited from this in vivo application of molecular biology. The hypothalamic-pituitary-testicular (HPT) axis Mutations of gonadotropin receptors have recently been discovered in human patients. Although very rare, these findings have clarified the molecular pathogenesis of some disturbances in the reproductive function (1). An activating mutation of the LH receptor (R) gene causes the male-limited, early-onset, gonadotropin-independent precocious puberty (testotoxoicosis) but, interestingly, women with a similar mutation seem to have no alterations of the phenotype. If the activating LHR mutation activates the inositol trisphosphate cycle, as was found with one particular mutation, the patient presented with testicular Leydig cell adenomas (2). This finding emphasizes the potential role of gonadotropins as tumor promoters, thus supporting a theory that has been put forward on the basis of some clinical finding on gonadal maReceived February 28, 2001. Address all correspondence and requests for reprints to: Prof. Ilpo Huhtaniemi, Department of Obstetrics and Gynaecology, University of Aberdeen, Aberdeen AB24 2ZD, Scotland, United Kingdom. E-mail: . lignancies. Similar findings have been made on the role of gonadotropins in gonadal tumorigenesis of gene-modified mice, e.g. inhibin-␣ knockout (KO) mice with high FSH levels (3), LH overexpressing mice (4, 5), and those expressing the viral oncogene SV40 T-antigen (6). Such models offer good opportunities for further exploration of this potentially important but poorly characterized action of gonadotropins. Inactivating mutations of the human LHR disrupt male sex differentiation (1), which ranges, depending on severity of the receptor inactivation, from mild undervirilization to total lack of genital masculinization. The phenotype in females is milder, characterized only by anovulatory infertility. The phenotype of a single male with inactivating mutation of the LH␤ gene differs from the respective receptor mutation: the subject was normally masculinized at birth, but failed to undergo sexual maturation (7). This difference can be explained by the stimulatory role of human CG (hCG) on his testicular testosterone in utero, which naturally is not possible if the receptor is defective. The very recently developed mouse KO model for the LHR (LuRKO mouse) allows interesting comparison between LH/hCG effect on sexual differentiation in mice and men (8, 9). As in the male patient with inactivated LH␤, the male LuRKO mice were normally masculinized at birth but failed to show postnatal sexual maturation. Unlike in humans, functional LHR is thus not necessary in the mouse fetus for sufficient testicular androgen production to induce masculinization. Other bloodborne or paracrine factors can apparently maintain sufficient androgen production in the absence of LH action. It is intriguing that such a profound difference prevails in the hormonal regulation of masculinization between man and rodents. Inactivating FSH␤ subunit and FSHR mutations have been detected in humans (1), and the respective KO mouse models have been developed (3, 10, 11). There is good agreement between the mouse and human phenotypes of the inactivating FSH ligand and receptor mutations in females; all are infertile because of arrested follicular development. A discrepancy prevails in males; while men with FSHR inactivation (11a), as well as FRH␤ and FSHR KO mice (4, 10, 11) present with suppressed testicular size in the face of qualitatively normal spermatogenesis, and are fertile or subfertile, the two men so far described with inactivating FSH␤ mutation are azoospermic (12, 13). The small number of these cases in comparison to the other models shifts the balance toward the contention that FSH action per se is not necessary for spermatogenesis. This finding is of practical importance, indicating that a male contraceptive strategy based on elimination of FSH action may not be feasible. Interestingly, no clear activating mutations of the human FSHR have been discovered in either sex, although large numbers of patients with the expected phenotypes (e.g. premature ovarian failure or macro-orchia) have been screened. It is possible that our educated guesses of phenotypes of such cases are incorrect, 2178 Besides unraveling the basic mechanisms underlying male reproductive functions, studies of testicular function are clinically important for the specialty called andrology. Andrology covers all physiological and pathophysiological functions specific for the male gender, ranging from conception until senescence. The main challenges of clinical andrology entail improvement of diagnostics and treatment of male infertility, development of male-specific methods of fertility control, combating sexually transmitted diseases, and improving quality of life of aging males. Better basic understanding of male reproductive endocrinology is essential for improving our chances to tackle these challenges. As in all fields of biomedical research, the major recent advances have been made using the versatile methodology of molecular biology. This short review describes some of the recently emerged concepts of testicular endocrine regulation and function, as well as the approaches that have enabled this progress. The topics selected represent the subjective views of the authors. We admit that the scope chosen by someone else could have been different, and apologize to those whose findings and concepts were not included, mainly because of space limitations. For the same reason, the main emphasis of this review will be in testicular function. PERSPECTIVES or the mutations in the candidate syndromes have to be looked for in genes participating in the postreceptor cascade of FSH signal transduction. Therefore, genetically modified animal models for activating gonadotropin receptor mutations would be of great help in predicting the human phenotypes. All in all, the severity of the phenotypes of human mutations and genetically modified mice emphasize the sexual dichotomy between LH and FSH; the former is critically the male gonadotropin, and the latter the female one. There is considerable evidence that the somatotropic axis, GH, and IGF-I, as well as PRL, are involved in control of the HPT axis, and that locally produced IGF-I participates in paracrine interactions between different cell types in the testis. Targeted gene disruption and transgenic technolog (...truncated)