Role Of Gonadotropins Research Articles

Seasonal changes in gonadal expression of gonadotropin receptors, steroidogenic acute regulatory protein and steroidogenic enzymes in the European sea bass

The endocrine regulation of gametogenesis, and particularly the roles of gonadotropins, is still poorly understood in teleost fish. This study aimed to investigate transcript levels of both gonadotropin receptors ( FSHR and LHR) during an entire reproductive cycle in male and female sea bass ( Dicentrarchus labrax). To have a more comprehensive understanding of how different key factors interact to control sea bass gonadal function, changes in the transcript abundance of two important steroidogenic enzymes, P450 11β-hydroxylase ( CYP11B1) and P450 aromatase ( CYP19A1), and the steroidogenic acute regulatory protein ( StAR), were also studied. These expression profiles were analysed in relation to changes in the plasma levels of important reproductive hormones and histological data. Expression of the FSHR was connected with early stages of gonadal development, but also with the spermiation/maturation–ovulation periods. The expression profile of the LHR seen in both sexes supports the involvement of LH in the regulation of the final stages of gamete maturation and spermiation/ovulation. In both sexes StAR expression was strongly correlated with LHR expression. In females high magnitude increments of StAR expression levels were observed during the maturation–ovulation stage. In males, gonadotropin receptors and CYP11B1 mRNA levels were found to be correlated. In females, the expression profiles of FSHR and CYP19A1 and the changes in plasma estradiol (E2) indicate that the follicular production of E2 could be under control of FSH through the regulation of aromatase expression. This study supports the idea that FSH and LH may have different roles in the control of sea bass gonadal function.

Growth hormone in the management of female infertility

Ovulation is a complex process which is controlled by multiple hormonal systems. While the role of gonadotrophins in the regulation of ovulation is well understood and characterized, growth hormone has been studied less vigorously as far as its effect on female reproduction is concerned. This review discusses the physiologic basis of growth hormone in the regulation of induction of ovulation in women. It also reviews clinical studies done using growth hormone as co-therapy in women with infertility

Bone phenotypes in response to gonadotropin misexpression: the role for gonadotropins in postmenopausal osteoporosis.

Scant attention has been paid to the potential role of gonadotropins in bone tissue homeostasis. The focus on estrogen and estrogen replacement therapy for osteoporosis as far back as the 1940's may account for the paucity of gonadotropin studies in bone biology. It is conceivable that prevailing dogma may have subconsciously steered us away from addressing whether gonadotropins have a place in skeletal physiology. However an examination of bone tissue catabolism in ovariectomized (OVX) and luteinizing hormone-releasing hormone (LHRH) agonist (Zoladex((R)))-treated rats generated some interesting and conflicting data; Zoladex-treated rats, unlike the OVX group, failed to exhibit increased bone collagen catabolism despite clear evidence for estrogen deficiency. The findings, although controversial, supported the possibility that elevated gonadotropins in the OVX model were in some way accountable for increased bone catabolism. In response to these initial findings further studies were performed to determine if altered LH status may in some way impact on the skeleton To this end an investigation of bone mass and histomorphometry were conducted in LH receptor nullizygous mice and human chorionic gonadotropin (hCG) overexpressing mice. There were clear phenotypic differences; the LH receptor knockout mice displayed reduced bone mass whereas the hCG overexpressing animals had stark increases in bone mass. Much more recently the team of the Mount Sinai Bone Program have made a significant discovery that bone-resorbing osteoclasts express receptors for follicle-stimulating hormone (FSH) and that mice nullizygous for FSH receptor are resistant to bone loss despite severe estrogen deficiency. Details of these fascinating models will be presented together with additional findings that give credence for exploring gonadotropin action on the skeleton as we enter the twilight of this Decade of the Bone and Joint.

Spaying‐induced coat changes: the role of gonadotropins, GnRH and GnRH treatment on the hair cycle of female dogs

Although spaying can result in qualitative hair coat changes in dogs, the influence of spaying on the hair growth cycle has never been described. The study aims were to examine the effect of spaying and gonadotropin-releasing hormone (GnRH) treatment on canine hair coat, cycle stages of hair follicles, plasma gonadotropin concentrations and mRNA transcription of luteinizing hormone (LH) and GnRH receptors in hair follicles. Fifteen female dogs were examined before and 1 year after spaying and 24 spayed dogs before and after GnRH treatment. Spaying resulted in increased plasma gonadotropin concentrations and increased anagen : telogen ratio of hair follicles, but only 20% of the dogs developed coat changes. No differences were found in mRNA transcription of LH and GnRH receptors. GnRH treatment resulted in reduced plasma gonadotropin concentrations and improvement of coat changes in 79% of patients. This was associated with an increase in catagen hair follicles without changes in the anagen : telogen ratio. The present study demonstrated that spaying had an effect on the anagen : telogen ratio of hair follicles. Spaying-induced coat changes did not correlate with the anagen : telogen ratio. GnRH treatment reduced gonadotropin concentrations and reversed coat changes in some dogs, but had no effect on the hair growth cycle other than increasing the number of catagen hair follicles. A weak positive correlation between the plasma LH concentration and the anagen : telogen ratio was noted; however, our data did not suggest a direct receptor-mediated hormonal effect on the hair follicle. The present study did not identify the pathomechanism of spaying-induced coat changes.

Changes in the immunostaining intensities of follicle-stimulating hormone and luteinizing hormone during ovarian maturation in the female Japanese flounder

The role of gonadotropin (GTH) in the reproduction of the Japanese flounder, Paralichthys olivaceus, was studied by assessing the changes in the apparent activity of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in the pituitary gland during gonadal maturation by immunohistochemical analyses. Corresponding changes in plasma levels of testosterone (T), estradiol-17beta (E(2)), and 17alpha,20beta-dihydroxy-4-pregnen-3-one (DHP) were also studied. Reared fish at the early spawning to termination stages were sampled from May to August and wild fish at the previtellogenic to termination stages were caught at 3- to 4-week intervals between April and September offshore from the northern mainland of Japan by gill nets. The gonadosomatic index of the reared fish decreased from the early spawning stage to the termination stage, while that of the wild fish increased significantly from the previtellogenic stage to the early spawning stage and decreased thereafter. In the reared fish, the immunostaining intensities of FSH and LH were high during the spawning period, accompanied by high plasma levels of T, E(2), and DHP. In the wild fish, the immunostaining intensities of FSH and LH were low during the previtellogenic stage but increased during the maturing and spawning stages. These results indicate that both FSH and LH are likely associated with oocyte maturation in the Japanese flounder.

Role of gonadotropin and Leydig cell-secreted factors in the control of testicular macrophage activities in the wall lizard Hemidactylus flaviviridis

The present in vitro study for the first time demonstrates the endocrine and paracrine control of testicular macrophage activities in ectodermic vertebrates. Follicle-stimulating hormone (FSH) increased phagocytosis and superoxide production by macrophages. In regard to paracrine control, non-activated Leydig cell-conditioned medium (LCCM) decreased both the activities, whereas FSH-preactivated LCCM had differential effects: inhibitory on phagocytosis and stimulatory on superoxide production. However, FSH-activated LCCM, in addition to superoxide production, also enhanced phagocytosis. After heat inactivation, FSH-activated LCCM inhibited both the activities. Addition of FSH resulted in stimulation of phagocytosis, while partially restored the superoxide production. It can be speculated that androgen in heat-inactivated FSH-activated LCCM, in the presence of FSH, instead of inhibitory had stimulatory effect on phagocytosis, but remained inhibitory to superoxide production. Further, FSH-induced Leydig cell-secreted non-steroidal heat-labile factors appear to have stimulatory effect on superoxide production. This was corroborated by experiments with dihydrotestosterone in presence/absence of FSH.

The Role of Gonadotropins in Alzheimer's Disease: Potential Neurodegenerative Mechanisms

In addition to the classical role of gonadotropins as a modulator of sex hormone production, it is now becoming apparent that the gonadotropins may have actions within the central nervous system. Evidence is also mounting that age-related increases in levels of the gonadotropin, luteinizing hormone (LH), may exert neurodegenerative effects such as those seen in Alzheimer's disease (AD). LH has been implicated in key cellular and biochemical processes that contribute to the pathogenesis of AD. These processes include the altered metabolism of key proteins in AD pathology, beta amyloid (Abeta), and its parent molecule, the amyloid precursor protein (APP). Evidence in the literature suggests that gonadotropins may be involved in processes that contribute to the etiology/pathogenesis of AD such as inflammation, cholesterol homeostasis, and insulin status. Here we examine the potential mechanisms by which gonadotropins could influence neurodegenerative processes. The role of gonadotropins in the brain and potential direct neuropathological effects of elevated gonadotropin levels is an exciting new topic in neuroendocrinology that in turn will lead to the development of novel therapeutic approaches for AD.

What have gonadotrophin overexpressing transgenic mice taught us about gonadal function?

The two gonadotrophins, follicle-stimulating hormone and luteinising hormone, are pivotal regulators of the development and maintenance of normal fertility by maintaining testicular and ovarian endocrine function and gametogenesis. Too low gonadotrophin secretion, i.e. hypogonadotrophic hypogonadism, is a common cause of infertility. But there are also physiological and pathophysiological conditions where gonadotrophin secretion and/or action are either transiently or chronically elevated, such as pregnancy, pituitary tumours, polycystic ovarian syndrome, activating gonadotrophin receptor mutations, perimenopause and menopause. These situations can be either the primary or secondary cause of infertility and gonadal pathologies in both sexes. Also the role of gonadotrophins as tumour promoters is possible. Recently, the possibility to combine information from genetically modified mice and human phenotypes in connection with mutations of gonadotrophin or gonadotrophin receptor genes has elucidated many less well known mechanisms involved in dysregulation of gonadotrophin function. Among the genetically modified mouse models, transgenic mice with gonadotrophin hypersecretion have been developed during the last few years. In this review, we describe the key findings on transgenic mouse models overexpressing gonadotrophins and present their possible implications in related human pathologies. In addition, we provide examples of genetic mouse models with secondary effects on gonadotrophin production and, consequently, on gonadal function.

Estrogen Bows to a New Master: The Role of Gonadotropins in Alzheimer Pathogenesis

Epidemiological data showing a predisposition of women to develop Alzheimer disease (AD) led many researchers to investigate the role of sex steroids, namely estrogen, in disease pathogenesis. Although there is circumstantial support for the role of estrogen, the unexpected results of the Women's Health Initiative (WHI) Memory Study, which reported an increase in the risk for probable dementia and impaired cognitive performance in postmenopausal women treated with a combination of estrogen and progestin, have raised serious questions regarding the protective effects of estrogen. Although explanations for these surprising results vary greatly, the WHI Memory Study cannot be correctly interpreted without a complete investigation of the effects of the other hormones of the hypothalamic-pituitary-gonadal (HPG) axis on the aging brain. Certain hormones of the HPG axis, namely, the gonadotropins (luteinizing hormone and follicle-stimulating hormone), are not only involved in regulating reproductive function via a complex feedback loop but are also known to cross the blood-brain barrier. We propose that the increase in gonadotropin concentrations, and not the decrease in steroid hormone (e.g., estrogen) production following menopause/andropause, is a potentially primary causative factor for the development of AD. In this review, we examine how the gonadotropins may play a central and determining role in modulating the susceptibility to, and progression of, AD. On this basis, we suggest that the results of the WHI Memory Study are not only predictable but also avoidable by therapeutically targeting the gonadotropins instead of the sex steroids.

Effects of GnRH antagonist treatment on follicular development and angiogenesis in the primate ovary

Angiogenesis is required for normal follicular development but the role of gonadotrophins in the control of follicular angiogenesis remains to be elucidated. This study investigated the effects of treatment with GnRH antagonist in vivo on follicular development and angiogenesis in the marmoset. GnRH antagonist was administered on either follicular day 0 or day 5 of the 10-day follicular phase with ovaries collected on day 10. Ovaries from control marmosets were studied at day 5 (mid follicular phase) and day 10 (periovulatory period). Ovaries were fixed, serial sectioned and subjected to morphological analysis and immunocytochemistry to determine cell proliferation and follicular endothelial cell area and in situ hybridization to assess changes in expression of vascular endothelial growth factor (VEGF). Treatment with GnRH antagonist from day 0-10 resulted in an absence of dominant preovulatory follicles seen in controls. In the remaining tertiary follicles granulosa, theca and endothelial cell proliferation was reduced, resulting in a minor reduction in vascular density. However, VEGF mRNA expression was unaffected by treatment. Treatment from day 5-10 did not prevent development of ovulatory size follicles, but they were atretic and lacked VEGF mRNA. These results suggest that while VEGF expression in the preovulatory follicle is under gonadotrophic control it is not dependent on normal gonadotrophin secretion in tertiary follicles, indicating that there are other paracrine factors regulating VEGF expression in the developing ovarian follicle.

Gonadotropins and Alzheimer's disease: the link between estrogen replacement therapy and neuroprotection

The search for a definitive gender bias in Alzheimer's disease has resulted in a multitude of epidemiological findings that point to a higher prevalence and incidence of Alzheimer's disease in women. Due to this reported predisposition of women to Alzheimer's disease, the sex steroid estrogen has become the primary focus of research in this field, however, inconclusive data regarding estrogen replacement therapy has lead some researchers to further investigate the role of the other hormones of the hypothalamic-pituitary-gonadal (HPG) axis that have been, for the most, part overlooked. The hormones of the HPG axis, such as the gonadotropin, (luteinizing hormone and follicle-stimulating hormone), are involved in regulating reproductive function via a complex feedback loop. We propose that it is in fact the increase in gonadotropin concentrations and not the decrease in steroid hormone (e.g., estrogen) production following menopause/andropause that results in an increased risk of Alzheimer's disease. Furthermore, when the role of gonadotropins is taken into account, the data obtained from recent epidemiological studies and randomized trials suggesting the ineffectiveness estrogen may indeed be misinterpreted. In this review, we examine how hormones of the hypothalamic-pituitary-gonadal axis, in particular the gonadotropins, play a central and determining role in modulating the susceptibility to and progression of Alzheimer's disease. Based on this, we suggest that therapeutic interventions targeted at gonadotropins could both prevent disease in those patients currently asymptomatic or halt, and even reverse, disease in those currently afflicted.

Roles of gonadotropins and meiosis-activating sterols in meiotic resumption of cultured follicle-enclosed mouse oocytes

This study describes a model for short-term culture of intact mouse follicles under serum-free conditions. Follicles were either obtained from immature mice receiving no ovarian stimulation (i.e. no eCG-primed protocol, group I) or from mice undergoing ovarian stimulation (i.e. eCG-primed protocol, group II). Follicles were grouped according to size (100–170, 180–200, 210–250, 260–350 and 360–400 μm, respectively) and cultured for 24 h (group I) or for only 6 h (group II). Induced meiotic resumption of follicle-enclosed oocytes were evaluated following stimulation with gonadotropins (i.e. FSH and hCG), AY9944-A-7, an inhibitor of Δ14-reductase, and RS-21745, an inhibitor of lanosterol 14α-demethylase; both enzymes affect synthesis of the meiosis activating sterols (MAS) that induce oocyte maturation. The frequency of oocyte degeneration was also recorded. In group I, FSH (10–200 IU l −1) and AY9944-A-7 (5, 25 and 50 μM) separately induced resumption of meiosis in oocytes derived from follicles with a diameter of 180–400 μm. hCG (1.0 and 10 IU ml −1) exhibited a similar but weaker effect on oocytes present in follicles with a diameter of 260–400 μm. Irrespective of follicular diameter oocytes obtained from follicles in group II responded to hCG and FSH by resuming meiosis. FSH (50 IU l −1) alone or hCG (10 IU ml −1) alone both increased the GVBD percentage of oocytes enclosed in follicles with a diameter 260–400 μm, but the response to hCG was not significant compared to control. FSH (50 IU l −1) combination with hCG (10 IU ml −1) showed an additive effect raising the rate of GVBD after 6 h culture. Addition of 50 or 100 μM RS-21745 was able to attenuate gonadotropins-induced resumption of meiosis to below background levels. In conclusion, the ability of FSH to induce meiotic resumption of follicle-enclosed mouse oocytes is correlated to follicle size, being most pronounced in larger follicles. hCG caused a similar but less pronounced effect. The ability of RS-21745 to inhibit and the ability of AY9944-A-7 to enhance oocyte maturation of follicle-enclosed oocytes support the concept of FSH employing MAS as a downstream signal transduction molecule for initiation of oocyte maturation in mice.

Cloning and sequencing of FSH-β and LH-β subunits and changes in their expression during the reproductive cycle in the three-spined stickleback, Gasterosteus aculeatus

To achieve a better understanding of the role of gonadotropins (GTHs) in the stickleback we have cloned the full-length cDNAs of the β-subunits of follicle stimulating hormone (FSH) and luteinizing hormone (LH), and analysed the expression during the seasonal cycle. In females, LH-β levels were low during winter and early spring, increased to a peak in late May and declined to low levels again in July. FSH-β expression peaked earlier, in January and declined spring. In males, LH-β expression peaked in May. During June–September, when spermatogenesis occurs, LH-β levels were very low. FSH-β expression peaked earlier, in January, and reached the lowest levels in July. Thus, when spermatogenesis starts, the expression of both GTH-β mRNAs display their lowest levels.

Role of gonadotrophins in regulating numbers of Leydig and Sertoli cells during fetal and postnatal development in mice

The role of the gonadotrophins in regulating numbers of Leydig and Sertoli cells during fetal and postnatal development was examined using normal mice and hypogonadal (hpg) mice, which lack circulating gonadotrophins. The disector method was used to determine the number of cells from day 16 of gestation until adulthood. The numbers of Leydig cells did not change significantly between day 16 of gestation and day 5 after parturition in normal mice and were not significantly different from numbers in hpg mice at any age up to day 5 after parturition. There was a 16-fold increase in the number of Leydig cells in normal mice between day 5 and day 20 after parturition, followed by a further doubling of number of cells between day 20 and adulthood. The number of Leydig cells in hpg testes did not change between day 5 and day 20 after parturition but doubled between day 20 and adulthood so that the number of cells was about 10% of normal values from day 20 onwards. Leydig cell volume was constant in normal animals from birth up to day 20 and then showed a 2.5-fold increase in adult animals. Leydig cell volume was normal in hpg testes at birth but decreased thereafter and was about 20% of normal volume in adult mice. The number of Sertoli cells increased continuously from day 16 of gestation to day 20 after gestation in normal mice and then remained static until adulthood. The number of Sertoli cells in hpg testes was normal throughout fetal life but was reduced by about 30% on day 1 (day of parturition). Thereafter, Sertoli cells proliferated at a slower rate but over a longer period in the hpg testis so that on day 20 after parturition the number of Sertoli cells was about 50% of normal values, whereas in adult mice the number was 65% of normal. The number of gonocytes did not change between day 16 of gestation and day 1 and did not differ between normal and hpg testes. The number of gonocytes increased nine-fold in normal testes but only three-fold in hpg testes between day 1 and day 5 after parturition. Gonocytes differentiated into spermatogonia in both normal and hpg testes between day 5 and day 20 after parturition. These results show: (i) that fetal development of both Sertoli and Leydig cells is independent of gonadotrophins; (ii) that normal differentiation and proliferation of the adult Leydig cell population (starting about day 10 after parturition) is dependent on the presence of gonadotrophins; and (iii) that the number of Sertoli cells after birth is regulated by gonadotrophins, although proliferation will continue, at a lower rate and for longer, in the absence of gonadotrophins.

Role of gonadotrophins in regulating numbers of Leydig and Sertoli cells during fetal and postnatal development in mice.

The role of the gonadotrophins in regulating numbers of Leydig and Sertoli cells during fetal and postnatal development was examined using normal mice and hypogonadal (hpg) mice, which lack circulating gonadotrophins. The disector method was used to determine the number of cells from day 16 of gestation until adulthood. The numbers of Leydig cells did not change significantly between day 16 of gestation and day 5 after parturition in normal mice and were not significantly different from numbers in hpg mice at any age up to day 5 after parturition. There was a 16-fold increase in the number of Leydig cells in normal mice between day 5 and day 20 after parturition, followed by a further doubling of number of cells between day 20 and adulthood. The number of Leydig cells in hpg testes did not change between day 5 and day 20 after parturition but doubled between day 20 and adulthood so that the number of cells was about 10% of normal values from day 20 onwards. Leydig cell volume was constant in normal animals from birth up to day 20 and then showed a 2.5-fold increase in adult animals. Leydig cell volume was normal in hpg testes at birth but decreased thereafter and was about 20% of normal volume in adult mice. The number of Sertoli cells increased continuously from day 16 of gestation to day 20 after gestation in normal mice and then remained static until adulthood. The number of Sertoli cells in hpg testes was normal throughout fetal life but was reduced by about 30% on day 1 (day of parturition). Thereafter, Sertoli cells proliferated at a slower rate but over a longer period in the hpg testis so that on day 20 after parturition the number of Sertoli cells was about 50% of normal values, whereas in adult mice the number was 65% of normal. The number of gonocytes did not change between day 16 of gestation and day 1 and did not differ between normal and hpg testes. The number of gonocytes increased nine-fold in normal testes but only three-fold in hpg testes between day 1 and day 5 after parturition. Gonocytes differentiated into spermatogonia in both normal and hpg testes between day 5 and day 20 after parturition. These results show: (i) that fetal development of both Sertoli and Leydig cells is independent of gonadotrophins; (ii) that normal differentiation and proliferation of the adult Leydig cell population (starting about day 10 after parturition) is dependent on the presence of gonadotrophins; and (iii) that the number of Sertoli cells after birth is regulated by gonadotrophins, although proliferation will continue, at a lower rate and for longer, in the absence of gonadotrophins.

Role of gonadotropins in malignant progression of sex cord stromal tumors produced by sequential auto- and isogenic transplantation of ovarian tissue in ovariectomized rats.

In this study the effect of continuous stimulation of gonadotropins on sex cord stromal tumors in the rat was examined. Sex cord stromal tumors were induced by transplantation of ovaries under the splenic capsule of ovariectomized rats. Beginning 180 days after transplantation, these tumors were taken out and cut into several pieces, which were then retransplanted (by isotransplantation) under the splenic capsule of 80 either intact or ovariectomized rats. Most of the tumor grafts grew up to a median size of 0.7 cm in ovariectomized rats. However, some of the tumors recovered from recipient rats that were retransplanted with donor tumors differed significantly from the others. Characterized by a high mitotic rate, nuclear atypia, size (up to 3.8 cm) as well as growth in intact animals, these tumors were defined as malignant. They could be kept in culture and always led to the development of metastases after retransplantation into other rats. Benign sex cord stromal tumors can show malignant growth after transplantation. This study for the first time demonstrates that gonadotropins are involved in the induction of ovarian malignancies.

Mechanism of Delayed Ovulation in a Vespertilionid Bat, Scotophilus heathi: Role of Gonadotropin, Insulin, and Insulin-Like Growth Factor-1.

Previous articleNext article No AccessErratumMechanism of Delayed Ovulation in a Vespertilionid Bat, Scotophilus heathi: Role of Gonadotropin, Insulin, and Insulin‐Like Growth Factor‐1Amitabh Krishna and AbhilashaAmitabh KrishnaPhysiological and Biochemical Zoology 73:523–529 (2000) Search for more articles by this author and AbhilashaPhysiological and Biochemical Zoology 73:523–529 (2000) Search for more articles by this author Physiological and Biochemical Zoology 73:523–529 (2000)Original articleMechanism of Delayed Ovulation in a Vespertilionid Bat, Scotophilus heathi: Role of Gonadotropin, Insulin, and Insulin‐Like Growth Factor‐1PDFPDF PLUSFull Text Add to favoritesDownload CitationTrack CitationsPermissionsReprints Share onFacebookTwitterLinkedInRedditEmail SectionsMoreDetailsFiguresReferencesCited by Physiological and Biochemical Zoology Volume 74, Number 1January/February 2001 Sponsored by Division of Comparative Physiology and Biochemistry, Society for Integrative and Comparative Biology Article DOIhttps://doi.org/10.1086/319299 Views: 13Total views on this site PDF download Crossref reports no articles citing this article.Related articlesMechanism of Delayed Ovulation in a Vespertilionid Bat, Scotophilus heathi: Role of Gonadotropin, Insulin, and Insulin‐Like Growth Factor‐119 Jul 2015Physiological and Biochemical Zoology

Normal Prenatal but Arrested Postnatal Sexual Development of Luteinizing Hormone Receptor Knockout (LuRKO) Mice

To study further the role of gonadotropins in reproductive functions, we generated mice with LH receptor (LHR) knockout (LuRKO) by inactivating, through homologous recombination, exon 11 on the LHR gene. LuRKO males and females were born phenotypically normal, with testes, ovaries, and genital structures indistinguishable from their wild-type (WT) littermates. Postnatally, testicular growth and descent, and external genital and accessory sex organ maturation, were blocked in LuRKO males, and their spermatogenesis was arrested at the round spermatid stage. The number and size of Leydig cells were dramatically reduced. LuRKO females also displayed underdeveloped external genitalia and uteri postnatally, and their age of vaginal opening was delayed by 5-7 days. The (-/-) ovaries were smaller, and histological analysis revealed follicles up to the early antral stage, but no preovulatory follicles or corpora lutea. Reduced gonadal sex hormone production was found in each sex, as was also reflected by the suppressed accessory sex organ weights and elevated gonadotropin levels. Completion of meiosis of testicular germ cells in the LuRKO males differs from other hypogonadotropic/cryptorchid mouse models, suggesting a role for FSH in this process. In females, FSH appears to stimulate developing follicles from the preantral to early antral stage, and LH is the stimulus beyond this stage. Hence, in each sex, the intrauterine sex differentiation is independent of LH action, but it has a crucial role postnatally for attaining sexual maturity. The LuRKO mouse is a close phenocopy of recently characterized human patients with inactivating LHR mutations, although the lack of pseudohermaphroditism in LuRKO males suggests that the intrauterine sex differentiation in this species is not dependent on LH action.

Role of gonadotrophins and progesterone in the regulation of morphological remodelling and atresia in the monkey peri-ovulatory follicle.

Peri-ovulatory progesterone plays an indispensable role in ovulation and luteinization, possibly by controlling tissue remodelling of the ovulatory follicle. This study was designed to evaluate gonadotrophin- versus progestin-mediated changes to the morphology of the follicle wall during luteinization. Ovaries were obtained from macaques undergoing ovarian stimulation either before (0 h) or up to 36 h following administration of an ovulatory human chorionic gonadotrophin (HCG) bolus with or without a 3beta-hydroxysteroid dehydrogenase inhibitor and a non-metabolisable progestin. Morphological changes occurred within 12 h of HCG in the theca, and around 24 h in the granulosa layer and basement membrane. Steroid depletion resulted in follicles that did not luteinize during the 36 h interval, or alternatively, those that exhibited premature luteinization by 12 h post-HCG. Progestin replacement restored normal morphology, although the presence of antral blood suggested acceleration of normal tissue remodelling. A proportion of pre-ovulatory follicles became atretic after the HCG bolus, although progestin treatment reduced the percentage of atretic follicles. Ovarian stimulation resulted in the development of multiple pre-ovulatory follicles which are heterogeneous in their response to the HCG bolus and local progestin action. Nevertheless, this model supports both anti-atretic and pro-differentiative actions of progesterone in promoting follicular health and remodelling during the development of the corpus luteum.

The Parkes lecture. Mutations of gonadotrophin and gonadotrophin receptor genes: what do they teach us about reproductive physiology?

Although mutations in human gonadotrophin and gonadotrophin receptor genes are rare, they have greatly elucidated the physiology and pathophysiology of gonadotrophin action. These 'nature's transgenics' have been corroborated by mouse transgenic and knock-out models. An inactivating mutation of the human LHbeta chain and knock-out of the mouse common alpha-chain show that pituitary LH is not needed to stimulate fetal testicular steroidogenesis and male sexual differentiation. In mice, early testicular steroidogenesis is apparently gonadotrophin-independent and, in humans, it is regulated by placental hCG. Pituitary LH becomes necessary only after birth. Inactivating LH receptor mutations block prenatal hCG action, thus inhibiting male-type sexual differentiation. In females, this process is autonomous, and LH becomes important only at puberty; inactivation of LH receptor causes anovulatory infertility. Activating LH receptor mutations cause male-limited gonadotrophin-independent precocious puberty in males, but no apparent phenotype in females. Animal models for LH or LH receptor inactivation are not yet available. Inactivating FSH ligand and receptor mutations cause infertility because of a lack of follicular maturation in women. Findings in men are controversial, since FSHbeta inactivation is related to azoospermia, whereas the cognate receptor inactivation only suppresses spermatogenesis without causing absolute infertility. The FSHbeta and FSH receptor knock-out mice display phenocopies of the human FSH receptor mutation. Information about activating FSH receptor mutations is still insufficient. Hence, the above human mutations have brought important new information about the role of gonadotrophins in reproductive functions. The genetically modified animal models provide useful tools to explore the pathogenesis and new treatment modalities of infertility, and to develop new contraceptive strategies.