Follicular Growth Arrest Research Articles

Growth Differentiation Factor 9 Promotes Rat Preantral Follicle Growth by Up-Regulating Follicular Androgen Biosynthesis

The transition from preantral to early antral stage is the penultimate stage of ovarian follicular development in terms of gonadotropin dependence and follicle destiny. Although oocyte-somatic cell communication is important in early follicular development, our knowledge of the precise role of the oocyte-derived growth differentiation factor (GDF)-9 during preantral follicle growth is incomplete. We examined whether and by what means oocyte-derived GDF-9 controls follicular development and steroidogenesis during the preantral to early antral transition, by a combination of in vitro gene manipulation (i.e. intraoocyte injection of GDF-9 antisense oligos) and preantral follicle culture. Intraoocyte injection of GDF-9 antisense suppressed rat preantral follicle growth in vitro, whereas GDF-9 enhanced follicular development. GDF-9 augmented testosterone production in preantral follicles. GDF-9 antisense suppressed androgen production and CYP17A1 mRNA expression in cultured follicles, a response attenuated by exogenous GDF-9. The nonaromatizable androgen 5alpha-dihydrotestosterone rescued the follicular growth arrest caused by GDF-9 down-regulation. The specific androgen receptor antagonist flutamide suppressed GDF-9-induced preantral follicle growth in vitro. The data suggest that GDF-9 plays an important role in promoting preantral follicle growth by up-regulating follicular androgen biosynthesis. GDF-9 is essential for CYP17A1 expression during follicular development from the preantral to the early antral stage.

Atrial natriuretic peptide inhibits ovarian functions in female mice

Objective: To investigate the effects of atrial natriuretic peptide (ANP) on ovarian regulation in mice through intraperitoneal administration. Study design: Forty-two ICR strain female mice were divided into seven groups, including one control. Each mouse received ovarian hyperstimulation. ANP was prepared with saline at concentrations of 0 (as control), 2, 4, 8, 10, 20, and 30 ng/g of body weight. The solution was intraperitoneally applied to each referred group ( n = 6) 1 h before the hMG and hCG injections. The mice were sacrificed next morning and blood samples were collected for analysis. Results: A significant reduction in both ovarian weight and the number of oocytes was found as the ANP dosage increased. ANP treatment decreased both serum estradiol and progesterone levels. The pituitary FSH and LH contents elevated significantly by ANP at a dosage larger than 4 ng/g of body weight; however, both serum FSH and LH levels remained unchanged. Histologically, there were remarkable ovarian inhibitory features, i.e. reduction in size and number of follicles, arrest of follicular growth and diminution of ovulation. Conclusion: Intraperitoneal administration of ANP inhibits the follicular growth, ovulation and steroidogenesis in female mice. These effects are attributed to the direct action of ANP on ovaries.

Reply: What is the ceiling level for follicular growth arrest in late follicular phase

Reply: What is the ceiling level for follicular growth arrest in late follicular phase

Clinical evidence for an LH 'ceiling' effect induced by administration of recombinant human LH during the late follicular phase of stimulated cycles in World Health Organization type I and type II anovulation

The objective of these studies was to test the hypothesis that over-dosing with recombinant human LH (rLH) during the late follicular phase would suppress the development of follicles. Two double-blind studies were conducted. In study A, WHO I anovulatory patients received treatment with rFSH and rLH. When at least one follicle reached a mean diameter of 10-13 mm, patients were randomized using a computer-generated randomization list (stratified by centre) to rFSH and rLH (225 IU/day) (n = 8) or rLH alone (n = 6) or rFSH alone (n = 6). In study B, WHO II anovulatory patients with a hyper-responsive FSH were randomized to rLH (225 IU/day) (n = 4) or rLH 450 IU/day (n = 8) or placebo (n = 5). Study A: the mean number of follicles >/=11 mm was 4.2 +/- 0.3 in the rFSH group, 1.5 +/- 0.7 in the rLH group and 6.0 +/- 2.3 in the rFSH/rLH group (P = 0.07). 0/8 patients presented follicular growth arrest in the rFSH group, but 4/6 in the rLH group and 1/6 in the rFSH/rLH did. Study B: 5/12 patients presented follicular growth arrest in the rLH groups, but none in the placebo group. The mean number of follicles >/=11 mm was 4.6 +/- 1.8 for the placebo group, 2.5 +/- 1.9 for the rLH 225 IU group and 4.2 +/- 1.4 in the rLH 450 IU group (not significant). Results of this pilot study suggest that rLH alone can trigger follicular growth arrest in a significant number of patients, suggesting the existence of an 'LH ceiling' during late follicular maturation.

Syndrome des ovaires polykystiques : apports récents de la génétique

Polycystic ovary syndrome is the most common endocrine disorder in women of reproductive age. It is characterized by hyperandrogenism, chronic anovulation and it is often associated with hyperinsulinaemia, insulin resistance and dyslipidaemia. The pathophysiology of polycystic ovary syndrome seems to implicate primary defects in ovarian steroidogenesis, influenced by environment, insulin action and obesity. Polycystic ovary syndrome is probably both a multigenetic and environmental disease. Knowing the genes of polycystic ovary syndrome would be helpful to develop therapeutics and prevention. Genes of gonadotrophins, steroid hormone synthesis and insulin resistance seem not to be directly involved, except perhaps the CYP 11a gene. On the other hand, identification of the signal transduction pathways involved in these genes may provide valuable information that can be applied to other clinical manifestations of polycystic ovary syndrome (follicular growth arrest, insulin resistance, obesity and endometrial cancer…).

A novel growth differentiation factor-9 (GDF-9) related factor is co-expressed with GDF-9 in mouse oocytes during folliculogenesis

Growth differentiation factor-9 (GDF-9) is a transforming growth factor-β (TGF-β) family member which is expressed in the oocytes in mouse ovaries (McGrath, S.A., Esquela, A.F., Lee, S.J., 1995. Oocyte-specific expression of growth/differentiation factor-9. Mol. Endocrinol. 9, 131–136). GDF-9 is indispensable for normal folliculogenesis since female mice deficient for the GDF-9 gene are infertile due to an arrest of follicular growth at the primary follicle stage (Dong, J., Albertini, D.F., Nishimori, K., Kumar, T.R., Lu, N., Matzuk, M.M., 1996. Growth differentiation factor-9 is required during early ovarian folliculogenesis. Nature 383, 531–535). We searched the GenBank Expressed Sequence Tag (EST) database with the mouse GDF-9 cDNA sequence, and identified from a mouse 2-cell embryo library an EST cDNA that encodes a putative member of the TGF-β superfamily, and named it as GDF-9B. Northern blot hybridization analyses of mouse ovaries revealed a single transcript of approximately 4.0 kilobases (kb) for GDF-9B and of 2.0 kb for GDF-9. We cloned by reverse transcription-polymerase chain reaction from mouse ovarian RNA a partial 821-base pair GDF-9B cDNA that spans the sequence encoding the putative mature region of GDF-9B. The COOH-terminal region of GDF-9B appears to be 53% homologous to GDF-9. Moreover, like GDF-9, GDF-9B lacks the cysteine residue needed for the covalent dimerization of several TGF-β family members. Using in situ hybridization analysis, we demonstrate that GDF-9B and GDF-9 mRNAs are co-localized in the oocyte. We also show that GDF-9B and GDF-9 genes are co-ordinately expressed during follicular development.