Cortisol/glucocorticoid receptor: a critical mediator of the ovulatory process and luteinization in human periovulatory follicles.

STUDY QUESTION: Do cortisol/glucocorticoid receptors play an active role in the human ovary during ovulation and early luteinization? SUMMARY ANSWER: The ovulatory hCG stimulation-induced glucocorticoid receptor signaling plays a crucial role in regulating steroidogenesis and ovulatory cascade in human periovulatory follicles. WHAT IS KNOWN ALREADY: Previous studies reported an increase in cortisol levels in the human follicular fluid after the LH surge or ovulatory hCG administration. However, little is known about the role of cortisol/glucocorticoid receptors in the ovulatory process and luteinization in humans. STUDY DESIGN, SIZE, DURATION: This study was an experimental prospective clinical and laboratory-based study. An in vivo experimental study was accomplished utilizing the dominant ovarian follicles from 38 premenopausal women undergoing laparoscopic sterilization. An in vitro experimental study was completed using the primary human granulosa/lutein cells (hGLC) from 26 premenopausal women undergoing IVF. PARTICIPANTS/MATERIALS, SETTING, METHODS: This study was conducted in a private fertility clinic and academic medical centers. Dominant ovarian follicles were collected before the LH surge and at defined times after hCG administration from women undergoing laparoscopic sterilization. Primary hGLC were collected from women undergoing IVF. hGLC were treated without or with hCG in the absence or presence of RU486 (20 µM; dual antagonist for progesterone receptor and glucocorticoid receptor) or CORT125281 (50 µM; selective glucocorticoid receptor antagonist) for 12 or 36 h. The expression of genes involved in glucocorticoid receptor signaling, steroidogenesis, and ovulatory cascade was studied with RT-quantitative PCR and western blotting. The production of cortisol, corticosterone, and progesterone was assessed by hormone assay kits. MAIN RESULTS AND THE ROLE OF CHANCE: hCG administration upregulated the expression of hydroxysteroid 11-beta dehydrogenase 1 (HSD11B1), nuclear receptor subfamily 3 group C member 1 (NR3C1), FKBP prolyl isomerase 5 (FKBP5), and FKBP prolyl isomerase 4 (FKBP4) in human ovulatory follicles and in hGLC (P < 0.05). RU486 and CORT125281 reduced hCG-induced increases in progesterone and cortisol production in hGLC. The expression of genes involved in glucocorticoid receptor signaling, steroidogenesis, and the key ovulatory process was reduced by RU486 and/or CORT125281 in hGLC. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: The role of cortisol/glucocorticoid receptors demonstrated using the hGLC model may not fully reflect their physiological roles in vivo. WIDER IMPLICATIONS OF THE FINDINGS: Successful ovulation and luteinization are essential for female fertility. Women with dysregulated cortisol levels often suffer from anovulatory infertility. Deciphering the functional role of glucocorticoid receptor signaling in human periovulatory follicles enhances our knowledge of basic ovarian physiology and may provide therapeutic insights into treating infertility in women. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by P01HD71875 (to M.J., T.E.C., and M.B.) and R01HD096077 (to M.J.) from the Foundation for the National Institutes of Health and the BTPSRF of the University of Kentucky Markey Cancer Center (P30CA177558). The authors report no competing interests. TRIAL REGISTRATION NUMBER: N/A.

The use of clomiphene citrate in the treatment of azoospermia secondary to incomplete androgen resistance.

An infertile male with a deletion within the AR gene is discussed. The patient presented with azoospermia and, after daily CC treatment, was found to have sperm within his ejaculate. However, the ultimate goal of pregnancy was not achieved, nor were there enough sperm present to warrant an IVF attempt.

The effects of baseline ovarian cysts on cycle fecundity in controlled ovarian hyperstimulation.

Patients undergoing COH were prospectively studied in 174 cycles for the presence of baseline ovarian cysts. In 37.4% of all cycles, a baseline cyst > 10 mm mean diameter was found, but a cyst was more common in subsequent cycles than on the first (41.5% versus 15.8%). Cycle fecundity as determined by life table analysis was significantly higher if no baseline cyst were present (0.25 versus 0.06, P > 0.01). These findings suggest that baseline ovarian cysts may adversely affect the chances for pregnancy in COH not associated with IVF or GIFT.

The effects of spontaneous luteinizing hormone surges on superovulatory cycles.

OBJECTIVE: To determine the effect of a spontaneous luteinizing hormone (LH) surge on the cycle fecundity during superovulation induction. DESIGN: Superovulatory cycles of patients with various diagnoses are retrospectively compared. SETTING: Reproductive Endocrinology Outpatient Clinic. PATIENTS: A total of 1,185 superovulatory cycles from July 1, 1982 until November 1, 1991 are compared. MAIN OUTCOME MEASURE: The probability of achieving a pregnancy per treatment cycle. RESULTS: Patients with unexplained infertility and hyperprolactinemia were more likely to have a spontaneous LH surge during superovulation than patients with either endometriosis or polycystic ovarian disease. However, the cycle fecundity rate did not differ whether or not an LH surge occurred, regardless of the diagnosis. CONCLUSIONS: Spontaneous onset of an LH surge during superovulation induction does not influence the chances for pregnancy.

Increasing quantity of maternal immunoglobulin G in trophoblastic tissue before the onset of normal labor.

While levels of maternal immunoglobulin G (IgG) increase in the fetal circulation during the third trimester, actual trophoblastic concentrations have not been extensively studied. To investigate this process, placentas from 71 patients with gestational ages between 26 and 42 weeks were examined by means of a peroxidase-antiperoxidase immunostaining technique specific for IgG. Linear regression revealed a significant increase in antibody with advancing gestational age (r = 0.36, p less than 0.01). In addition, placentas from patients in spontaneous term labor revealed a significantly higher antibody level when compared with those of patients at term delivered electively before the onset of labor (mean +/- SEM 2.6 +/- 0.2 vs 1.7 +/- 0.3, p less than 0.02). Patients in premature labor failed to demonstrate this increase in antibody staining. One possible explanation for these findings is an enhanced recognition of the fetal trophoblastic tissue by the maternal immune system at term. It also suggests immunologic factors may play an important role in the initiation of normal labor.

Evidence for a partial deletion in the androgen receptor gene in a phenotypic male with azoospermia.

Androgen resistance is thought to vary phenotypically from a normal female to an infertile male. Previous evaluation of infertile males has been limited to androgen receptor-binding affinity. The androgen receptor gene has been isolated, cloned, and studied extensively in patients with complete androgen insensitivity syndrome, but no comparative data are available on infertile males. To address this matter, the androgen receptor gene was studied in seven azoospermic males by use of the polymerase chain reaction and Southern blot hybridization. A partial gene deletion was found in one patient. This study provides the first molecular evidence of an abnormality in the androgen receptor gene in a phenotypic male with azoospermia.