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Background: Epithelial ovarian cancer (EOC) risk correlates strongly with the number of ovulations that a woman experiences. The primary source of EOC in women is the ovarian surface epithelium (OSE). Mechanistic studies on the etiology of OSE transformation to EOC cannot be realistically performed in women. Selecting a suitable animal model to investigate the normal OSE in the context of ovulation should be guided by the model's reproductive similarities to women in natural features that are thought to contribute to EOC risk.Methods: We selected the non-human primate, rhesus macaque, as a surrogate to study the normal OSE during the natural menstrual cycle. We investigated OSE morphology and marker expression, plus cell proliferation and death in relation to menstrual cycle stage and ovulation.Results: OSE cells displayed a morphological range from squamous to columnar. Cycle-independent parameters and cycle-dependent changes were observed for OSE histology, steroid receptor expression, cell death, DNA repair and cell adhesion. Contrary to findings in non-primates, primate OSE cells were not manifestly cleared from the site of ovulation, nor were proliferation rates affected by ovulation or stage of the menstrual cycle. DNA repair proteins were more highly expressed in OSE than in other ovarian cells.Conclusions: This study identifies significant differences between primate and non-primate OSE. In contrast to established views, ovulation-induced death and proliferation are not indicated as prominent contributors to EOC risk, but disruption of OSE cadherin-mediated adhesion may be, as could the loss of ovary-mediated chronic suppression of proliferation and elevation of DNA repair potential. [ABSTRACT FROM AUTHOR]

Objective: To compare LH, FSH, P, and E(2) levels obtained from blood spot vs. plasma (single-visit study) and to determine whether blood spots can document circulating hormone levels during ovulatory cycles (menstrual-cycle study).Design: Cross-sectional study.Setting: Academic center.Patient(s): Women 18-35 years of age with regular menstrual cycles and no recent use of hormonal contraception.Intervention(s): Women contributed both a blood spot sample from a finger-stick and a plasma sample through venipuncture on a random day within their menstrual cycle (n = 100, single study visit). Five additional women were followed for an entire menstrual cycle with biweekly venipuncture and daily self-collected blood spot sampling. Samples were analyzed for FSH, LH, P, and E(2).Main Outcome Measure(s): Correlation between blood spot and plasma levels.Result(s): Significant positive correlations were found between the blood spot and plasma samples in the single-visit study (r(2): FSH, 0.91; LH, 0.93; P, 0.83; and E(2,) 0.70). Two of the 5 menstrual-cycle study women had ovulatory cycles based on P levels (>3 ng/mL) and an LH surge. Daily blood spot sampling was better able to document hormonal changes than biweekly venipuncture.Conclusion(s): Blood spot monitoring of FSH, LH, P, and, to a lesser extent, E(2), appears to be as valid as traditional plasma assays for clinical research and care. [ABSTRACT FROM AUTHOR]

Background: Prostaglandins (PG), produced by the follicle just before ovulation, appear to act locally to promote follicle rupture and oocyte release.Methods: To determine whether administration of PG synthesis inhibitor directly into the primate follicle would prevent ovulatory events, serum estradiol was used to predict the day of the ovulatory LH surge in rhesus monkeys. On the day before or the day of the LH surge, vehicle (n = 9), the PG synthesis inhibitor indomethacin (10(-6) or 10(-5) mol/l final concentration; n = 8), or 10(-5) mol/l indomethacin + 1 micro g/ml PGE(2) (n = 3) was injected into the follicular fluid of the pre-ovulatory follicle. In some animals, luteal phase estrogen and progesterone were measured in daily serum samples. Other animals were ovariectomized 3 days after follicle injection; ovaries were examined for verification of follicle rupture and oocyte release.Results: Follicle injection of indomethacin [10(-6) mol/l (n = 4) or 10(-5) (n = 4) mol/l final concentration] or vehicle (n = 6) did not alter luteal function. Examination of serial sections of removed ovaries confirmed follicle rupture and the absence of oocytes in vehicle-injected follicles (n = 3). Trapped oocytes were observed in 4/8 indomethacin-injected follicles, though several ovaries with trapped oocytes had experienced follicle rupture. Oocytes were not detected in the ruptured, luteinizing follicles from indomethacin + PGE(2)-injected monkeys (n = 3).Conclusions: Follicular administration of indomethacin can prevent oocyte release without inhibition of follicle rupture or disruption of subsequent luteal function. The ability of PGE(2) to prevent indomethacin-induced ovulatory failure suggests a critical role for locally produced PGE(2) in the process of oocyte release in primates. [ABSTRACT FROM AUTHOR]

Pituitary gonadotrophins, notably LH, and ovarian steroids, such as progesterone, play essential roles in the events leading to ovulation of the mature follicle and development of the subsequent corpus luteum. Rhesus monkeys (Macaca mulatta) undergoing controlled ovarian stimulation cycles comparable to those in clinical IVF/assisted reproduction treatment protocols provide a non-human primate model for studying peri-ovulatory events. The ability to manipulate the intrafollicular steroid milieu, via oral administration of a steroid synthesis inhibitor, with or without steroid replacement, allows one to distinguish between gonadotrophin-initiated, steroid-dependent versus steroid-independent processes. The length of the periovulatory interval (onset of the LH surge to follicle rupture) is long (36-40 h) in primates and can be considered in terms of early (<12 h) versus later (>24 h) events. Granulosa cells lose their proliferative activity and differentiate into progesteron e-secreting cells during the early peri-ovulatory interval. The rapid increase in progesterone synthetic capacity and expression of progesterone receptors suggests that this steroid has early actions, e.g. in controlling cell cycle machinery or differentiation. However, it is not until later that morphological luteinization is evident. By this stage, progesterone may serve as a potent anti-apoptotic factor and regulator of tissue remodelling through control of protease expression and activity, angiogenesis, or other events. Application of modern techniques to study LH- and progesterone-responsive gene expression will further unravel ovulatory and luteinization processes in specific compartments of the primate follicle. [ABSTRACT FROM AUTHOR]

Abstract: To determine if anti-angiogenic agents disrupt primate ovarian function, vehicle or a general angiostatic compound (TNP-470), specific antagonists of vascular endothelial growth factor (soluble VEGF receptor-1, sVEGFR-1; anti-VEGF monoclonal antibody, VEGF Ab) and/or an angiopoietin antagonist (Ang-2) were administered to rhesus monkeys: (1) locally via injection into the preovulatory follicle at midcycle or the developing corpus luteum at the midluteal phase; or (2) systemically via subcutaneous injection in the early follicular phase or at midcycle during the natural menstrual cycle. Compared to controls, intrafollicular injection of TNP-470 or sVEGFR-1 decreased circulating progesterone (P) levels in the subsequent luteal phase. Treatment with sVEGFR-1, but not TNP-470, also decreased the incidence of ovulation. Intrafollicular injection of Ang-2 also prevented ovulation, as well as any functional luteal phase. In the absence of elevated P, serum estradiol levels rose to peak levels 11–12 days post-Ang-2 treatment, at which time another large antral follicle was observed on the contralateral (noninjected) ovary. Intraluteal and systemic injection of VEGF antagonists alone or with Ang-2 had minimal effects. Thus, anti-angiogenic factors can act locally in the primate follicle to disrupt the gametogenic (oocyte release) and endocrine (steroid) functions of the ovary. However, further studies are needed to optimize delivery of angiogenic agents before they can be meaningfully evaluated as possible contraceptive agents. [Copyright &y& Elsevier]

To determine the practicality of controlled ovulation of the dominant follicle as a technique to study meiotic maturation of oocytes during contraceptive research, we developed a technique for aspiration of the single dominant follicle using a dual-needle continuous irrigation technique 27 hours after an ovulatory stimulus. All of the oocytes (3/3) recovered from control animals, but only 1/6 (17%) of oocytes from animals treated with the meiotic inhibitor ORG 9935 exhibited germinal vesicle breakdown, indicating resumption of meiosis. [ABSTRACT FROM AUTHOR]