I. Introduction II. Development A. Embryonic adrenal development B. Fetal adrenal development C. Neonatal adrenal development D. Growth E. Functional development 1. Ontogeny of steroidogenic activity 2. Functional zonation and ontogeny of steroidogenic enzyme expression 3. Responsiveness to ACTH III. Regulation A. The fetal pituitary and ACTH B. Growth factors 1. Basic fibroblast growth factor (bFGF) 2. Epidermal growth factor (EGF) 3. Insulin-like growth factors I and II (IGF-I and IGF-II) 4. Activin/inhibins 5. TGFβ C. Nuclear receptors/transcription factors D. Placental factors 1. Human CG (hCG) 2. Placental CRH and ACTH 3. Indirect effect of placental glucocorticoid metabolism 4. Placental estrogens IV. Physiology A. Placental estrogen formation B. Timing of parturition and fetal maturation V. Summary

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Developmental and functional biology of the primate fetal adrenal cortex.

Both major and incremental advances in the past decade have provided important insights into the structure, function, and regulation of the luteinizing hormone receptor (LHR) and its gene. The availability of the crystal structure of the extracellular domain of the follicular stimulating hormone receptor-hormone complex, and its applicability to other members of the gonadotropin receptor family, has facilitated prediction of the localized areas of specific interaction between the LHR and its cognate hormone. This has been supported by the incorporation of information derived from mutational and chimeric studies. The nature of the structural and molecular changes involved in the initiation and propagation of signaling is beginning to be revealed by the various models. It is likely that components of each domain of the LHR, the hinge region of the extracellular domain, and the LH/human chorionic gonadotrophin α-1,3 loops participate in the receptor activation. Naturally occurring and created mutations have provided fertile ground for modeling, leading to plausible proposals for the regions of the receptor that participate in receptor coupling functions. The knockout mouse model has demonstrated the lack of participation of the hormone/receptor in fetal gonadal development, in contrast with the situation in the human, where the essentiality of the LHR is exemplified by Leydig cell hypoplasia. The association of an LHR polymorphism with breast cancer age of onset and severity has been documented. Significant advances have been achieved in studies on LHR gene structure and regulation of transcription. Two independent mechanism of repression/derepression have been identified. Studies on the epigenetic control of LHR transcription have revealed the combined importance of promoter methylation status; and changes in histone acetylation/methylation in the association/release of inhibitory complexes from the promoter, and recruitment of the preinitiation complex and polymerase II. Furthermore, major advances await elucidation of the participation and molecular mechanisms of signaling pathways involved in the transcription of the LHR.

The luteinizing hormone receptor.

I. Introduction II. Neurohormones/Neuropeptides A. GH-releasing hormone (GHRH) B. Pituitary adenylate cyclase-activating peptide (PACAP) C. GnRH D. CRH E. Oxytocin (OT) F. Arginine vasopressin (AVP) G. TRH H. Somatostatin (SRIF) I. Opioids J. Substance-P (SP) K. Neuropeptide Y (NPY) III. Peptides Originally Identified in the Male Gonad A. Inhibin (INH) and activin (ACT) B. PModS IV. Growth Factors A. Insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBs) B. Transforming growth factor-β (TGFβ) C. TGFα/EGF D. Fibroblast growth factor (FGF) E. Platelet-derived growth factor (PDGF) F. Nerve growth factor (NGF) G. Steel factor (SLF) H. Gastrin-releasing peptide (GRP) V. Immune Derived Cytokines A. Interleukins (ILs) B. Tumor necrosis factor-α (TNFα) VI. Vasoactive Peptides A. Endothelin (ET) B. Angiotensin-II (AT-II) C. Atrial natriuretic peptide (ANP) VII. Conclusions and Perspectives

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Gonadal Peptides as Mediators of Development and Functional Control of the Testis: An Integrated System with Hormones and Local Environment

Strong overexpression of anti-Mullerian hormone (AMH) in transgenic mice leads to incomplete fetal virilization and decreased serum testosterone in the adult. Conversely, AMH-deficient mice exhibit Leydig cell hyperplasia. To probe the mechanism of action of AMH on Leydig cell steroidogenesis, we have studied the expression of mRNA for steroidogenic proteins in vivo and in vitro and performed a morphometric analysis of testicular tissue in mice overexpressing the hormone. We show that overexpression of AMH in male transgenic mice blocks the differentiation of Leydig cell precursors. Expression of steroidogenic protein mRNAs, mainly cytochrome P450 17α-hydroxylase/C17–20 lyase (P450c17), is decreased in transgenic mice overexpressing AMH and in AMH-treated purified Leydig cells. In contrast, transgenic mice in whom the AMH locus has been disrupted show increased expression of P450c17. In vitro, but not in vivo, AMH also decreases the expression of the luteinizing hormone receptor. The effect of AMH is explained by the presence of its receptor on Leydig cells. Our results provide insight into the action of AMH as a negative modulator of Leydig cell differentiation and function.

https://www.pnas.org/content/pnas/95/2/594.full.pdf

Receptors for anti-Müllerian hormone on Leydig cells are responsible for its effects on steroidogenesis and cell differentiation

We have used immunohistochemistry to localize GH receptor/binding protein (BP) in the male and female reproductive systems of adult rats. Testes and ovaries from neonatal animals were also examined to determine if GH receptor/ BP expression in these tissues is developmentally regulated. Two monoclonal antibodies (MAb 43 and 263) were immunoreactive in identical locations whereas no immunoreactivity was evident when control monoclonal antibodies 7 and 50.8 were used. Localization of the receptor/BP was observed in both the nucleus and cytoplasm of immunopositive cells confirming our recent report of a nuclear GH receptor. Intense GH receptor/BP immunoreactivity in the male reproductive system was evident in the epithelium of the vas deferens and coagulating gland, the prostatic epithelium during the secretory phase, and the ductular epithelium of the coagulating and bulbourethral glands, respectively. Strong immunoreactivity was detectable in the Leydig and Sertoli cells, the epithelium of the ductus epidi...

Cellular localization of the growth hormone receptor/binding protein in the male and female reproductive systems.

We have investigated the effects of insulin and somatomedin-C/insulinlike growth factor I(Sm-C) in purified porcine Leydig cells in vitro on gonadotrophins (hCG) receptor number, hCG responsiveness (cAMP and testosterone production), and thymidine incorporation into DNA. Leydig cells cultured in a serum-free medium containing transferrin, vitamin E, and insulin (5 micrograms/ml) maintained fairly constant both hCG receptors and hCG responsiveness. When they were cultured for 3 days in the same medium without insulin, there was a dramatic decline (more than 80%) in both hCG receptor number and hCG responsiveness. However the cAMP but not the testosterone response to forskolin was normal. Both insulin and Sm-C at nanomolar concentrations prevent the decline of both hCG receptors and hCG-induced cAMP production. This effect of both peptides was dose dependent with an ED50 of about 1 ng/ml and 5 ng/ml for SM-C and insulin, respectively. Insulin and Sm-C had no additive effect on these parameters. At nanomolar concentrations, Sm-C and insulin enhanced hCG-induced testosterone production but the effect of Sm-C was significantly higher than that of insulin. However, the effect of insulin at higher concentrations (5 micrograms/ml) was significantly higher than that of Sm-C at 50 ng/ml. In contrast, at nanomolar concentrations only Sm-C stimulated [3H]-thymidine incorporation into DNA and cell multiplication, the stimulatory effect of insulin on these parameters, was seen only at micromolar concentrations. These results indicate that both Sm-C and insulin acting through their own receptors increase Leydig cell steroidogenic responsiveness to hCG by increasing hCG receptor number and improving some step beyond cAMP formation. In contrast, the mitogenic effects of insulin are mediated only through Sm-C receptors.

Regulation of gonadotropin receptors, gonadotropin responsiveness, and cell multiplication by somatomedin-C and insulin in cultured pig Leydig cells.

Porcine cultured Leydig cells (LC) lose hCG receptors and hCG responsiveness (cAMP and testosterone) when they are cultured for three days in a defined medium without insulin or somatomedin C (Sm-C) (Insulin-like growth factor I). In the presence of insulin (50 ng/ml) or of Sm-C (10 ng/ml) the loss of the hCG receptor number and the decreased cAMP response to hCG were prevented, but the steroidogenic response to hCG was only partially prevented. This parameter became normal when cells were pretreated with either Sm-C (10 ng/ml) plus insulin (50 ng/ml) or with insulin alone at high concentrations (5 micrograms/ml). These results indicate that both Sm-C and insulin acting through their own receptors increase Leydig cell steroidogenic capacity by increasing hCG receptor number and improving some step beyond cAMP formation.

P. Chatelain

Papers

Regulation of gonadotropin receptors, gonadotropin responsiveness, and cell multiplication by somatomedin-C and insulin in cultured pig Leydig cells.

Effects of insulin and somatomedin C on the function of cultured Leydig cells