Philip S. Lapolt

The type I BMP receptor BmprIB is essential for female reproductive function

Maintenance of female reproductive competence depends on the actions of several hormones and signaling factors. Recent reports suggest roles for bone morphogenetic proteins (BMPs) in early stages of folliculogenesis. A role for the type I BMP receptor BmprIB as a regulator of ovulation rates in sheep has been described recently, but little is known about the roles of BMP signaling pathways in other aspects of reproductive function. We report here that BMPRIB is essential for multiple aspects of female fertility. Mice deficient in BmprIB exhibit irregular estrous cycles and an impaired pseudopregnancy response. BmprIB mutants produce oocytes that can be fertilized in vitro, but defects in cumulus expansion prevent fertilization in vivo. This defect is associated with decreased levels of aromatase production in granulosa cells. Unexpectedly, levels of mRNA for cyclooxygenase 2, an enzyme required for cumulus expansion, are increased. BmprIB mutants also exhibit a failure in endometrial gland formation. The expression of BmprIB in uterine linings suggests that these defects are a direct consequence of loss of BMP signaling in this tissue. In summary, these studies demonstrate the importance of BMP signaling pathways for estrus cyclicity, estradiol biosynthesis, and cumulus cell expansion in vivo and reveal sites of action for BMP signaling pathways in reproductive tissues.

Molecular basis of gonadotropin receptor regulation

The anterior pituitary hormones, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), act upon the ovary and testis via occupancy of specific cell membrane receptors, resulting in increased cAMP production, steroidogenesis, and expression of differentiation-related genes. Recent cloning of the cDNAs for LH and FSH receptors allows the analysis of mRNA levels for these receptors in gonadal tissues. This review summarizes progress in elucidating the molecular basis of LH and FSH receptor gene regulation in the ovary and testis during different physiologic states.

Gonadotropin requirements of the developing follicle.

OBJECTIVE To evaluate follicular FSH and LH requirements during suppression of endogenous gonadotropins with the GnRH antagonist Nal-Glu and whether LH-like activity could be supplied by administering subcutaneous hCG. DESIGN Randomized clinical trial. PARTICIPANTS Thirty-two normally cycling females in the late follicular phase (dominant follicle mean diameter > or = 14 mm). INTERVENTION Twelve normal women were randomized to receive 150 IU IM FSH with or without 75 IU SC hCG; 11 subjects were randomized to receive 225 IU FSH with or without 50 IU SC hCG; 9 women received 150 or 225 IU IM hMG. Subjects returned the next day for repeat blood sample and ultrasound. RESULTS Continued follicular maturation, as evidenced by rising E2 levels, correlated with serum immunoactive and bioactive FSH levels and was unrelated to bioactive LH-hCG. Two hundred twenty-five international units of exogenous FSH consistently supported follicular maturation. There was a similar increase in mean follicular diameter in women with an E2 rise versus those with a plateau or fall. In subjects receiving SC mini-dose hCG, serum bioactive LH-hCG levels were increased significantly and were similar to levels before Nal-Glu. CONCLUSIONS During administration of a GnRH-a, the maturing follicle appears to require only FSH support. In markedly hypogonadotropic women, mini-dose hCG may be a more practical alternative to recombinant LH to promote normal follicle maturation.

Factors Influencing the Onset of Female Reproductive Senescence

Striking similarities exist between the mechanisms governing neuroendocrine and ovarian functions in the rat and in the human. Furthermore, age-related declines in reproductive cyclicity and fertility are also similar between the two species. Thus, the middle-aged female rat provides a relevant and practical model for studying the mechanisms controlling reproductive functions. Researchers have utilized aging rodent models to examine how advanced age affects the interactions between ovarian function and the neuroendocrine control of gonadotropin secretion. In young female rats, increased estradiol secretion by maturing follicles elicits a surge of luteinizing hormone on proestrus, which stimulates progesterone secretion by preovulatory follicles and induces ovulation the next morning. As the female rat ages, the magnitudes of the preovulatory surge of luteinizing hormone and associated progesterone secretion gradually decrease, serving as an early marker of the imminent loss of regular ovulatory cycles. The decline in the neuroendocrine regulation of luteinizing hormone secretion is associated with alterations in hypothalamic functions, involving both stimulatory and inhibitory pathways regulating gonadotropin-releasing hormone release. In addition, clear changes in the number and function of ovarian follicles occurs during aging, associated with declines in oocyte quality. Interestingly, the temporal onset of reproductive declines during aging can be modulated by factors such as exposure to ovarian steroid hormones, caloric intake, parity, and genetic influences. This chapter reviews previous and recent studies demonstrating that such extrinsic factors can significantly delay or advance the effects of aging on neuroendocrine and reproductive functions.

Recombinant FSH and Regulation of Ovulation

The pituitary glycoprotein hormone FSH consists of two dissimilar, noncovalently linked polypeptide chains. The α-subunit is common to all three pituitary glycoprotein hormones (FSH, LH, and TSH) and the placental-derived chorionic gonadotropin (CG). The unique β-subunit confers each molecule with its biological specificity. Although all subunits of the gonadotropins are believed to be derived from a common ancestral gene, each subunit is encoded for by a separate gene. The gene structure of the α- and β-subunits is well conserved, with the FSHβ subunit gene structure identified in 3 exons separated by 2 introns. The FSHβ gene is unique among the glycoprotein hormones in possessing a 3′-untranslated region of approximately 1 kb. The importance of this long 3′ tract is unknown, but is potentially involved in mRNA stability.

Regulation of LH and FSH Receptor Gene Expression in the Ovary and Testis

The action of gonadotropins is mediated through binding of these glycoprotein hormones to specific receptors on gonadal cells. In the testis, follicle stimulating hormone receptors (FSH-R) are located in Sertoli cells, while luteinizing hormone receptors (LH-R) are found exclusively in Leydig cells (reviewed in 1). In the ovary, granulosa cells contain the receptor for FSH, while granulosa, theca, and luteal cells contain LH-R (reviewed in 2). The binding of the respective ligand to the specific cell surface receptor initiates the transduction of the signal from the extracellular space into the cells, with resultant activation of specific genes (reviewed in 3).