Concentration-dependent mechanisms of ovulation inhibition by the progestin ST-1435

We summarize the hormonal profiles of women at different stages of inhibition of ovarian function during sustained-release subcutaneous treatment with a progestin, ST-1435. In the highest release group of ST-1435, a decrease in the luteinizing hormone (LH)follicle-stimulating hormone (FSH) ratio was found; and in spite of follicular phase levels of plasma FSH, inhibition of folliculogenesis, as judged by plasma estradiol (E2) concentrations below 60 pg/ml, occurred during the entire treatment period of 230 days. This may be indicative of a direct action of ST-1435 on the ovaries. When the average plasma concentration of ST-1435 decreased below 100 pg/ml, follicle development had started in most of the study subjects. At that time, the LH/FSH ratio had normalized to that found during the follicular phase of the normal menstrual cycle. In spite of the E2 rise during follicular development, no midcycle gonadotropin surges or subsequent elevations in plasma progesterone concentrations were found, thus indicating that the positive feedback action of E2 on gonadotropins was blocked by this progestin. We infer that the mechanism of inhibition of ovulation by sustained parenteral treatment with the progestin ST-1435 is concentration dependent, in such a manner that lower plasma concentrations of ST-1435 act on the hypothalamus and/or pituitary, whereas at higher plasma concentrations of ST-1435, a direct effect on the ovaries is also achieved.     

Use of the novel combined contraceptive vaginal ring NuvaRing for ovulation inhibition

OBJECTIVE: To assess the effects of the combined contraceptive vaginal ring NuvaRing on ovarian function. DESIGN: Randomized, open-label, crossover study. SETTING: Clinical pharmacology unit. PARTICIPANT(S): Sixteen healthy female volunteers. INTERVENTION(S): Group 1: one cycle of combined oral contraceptive containing desogestrel (150 microg) and ethinyl estradiol (30 microg) (desogestrel/EE COC), followed by a NuvaRing treatment period. Group 2: NuvaRing treatment period followed by a cycle of desogestrel/EE COC. MAIN OUTCOME MEASURE(S): Follicular diameter, serum hormone concentrations (follicle-stimulating hormone, 17beta estradiol, luteinizing hormone, and progesterone), and endometrial thickness. RESULT(S): NuvaRing use for the recommended period of 3 weeks resulted in complete inhibition of ovulation, as assessed by vaginal ultrasound (follicular diameter) and by serum luteinizing hormone and progesterone concentrations. Inhibition of ovulation was maintained for an additional 2 weeks of NuvaRing use. Ovarian suppression between the groups was comparable. Furthermore, ovarian suppression after 3 weeks of NuvaRing use was comparable to that on day 21 of DGS/EE COC intake. NuvaRing was well tolerated. CONCLUSION(S): NuvaRing completely inhibited ovulation throughout the normal 3-week period and the extended period of use. Ovarian suppression was comparable to that with desogestrel/EE COC.     

Arrest of folliculogenesis and inhibition of ovulation in the monkey following weekly administration of progestins

Studies were undertaken in the rhesus monkey to determine whether development of a dominant ovarian follicle could be repeatedly arrested by the administration of a progestin on day 7 of the menstrual cycle, and then every 7 days thereafter regardless of menstrual bleeding history. Progesterone (7.5 mg), norethisterone (1.5 mg), and 17 alpha-ethinyl-17 beta-methoxy-7 alpha-methyl-4-estren-3-one (1.0 or 1.5 mg) effectively inhibited ovulation when injected intramuscularly once a week for 8 weeks. Orally administered STS 557 (17 alpha-cyanomethyl-17 beta-hydroxy-4,9-estradien-3-one, 1.0 mg) also inhibited ovulation. Two structurally related steroids (17 beta-methoxy-4-estren-3-one, 1.0 mg; and 17 beta-methoxy-7 alpha-methyl-4-estren-3-one, 1.5 mg) did not inhibit ovulation when given intramuscularly at the indicated doses. Although weekly administration of certain progestins effectively arrested follicular development and inhibited ovulation in the primate, the treatment was accompanied by disturbances in menstrual bleeding patterns.     

Anti-macrophage inhibitory factor antibody inhibits PMSG-hCG-induced follicular growth and ovulation in mice

Purpose : To investigate the effect of an anti-MIF antibody on PMSG-hCG-induced murine follicular growth and ovulation and to determine whether MIF plays an essential role in this process. Methods : Mice were primed with an intraperitoneal injection of pregnant mare serum gonadotropin (PMSG) and were treated with an anti-rat MIF antibody and human chorionic gonadotropin (hCG) to induce ovulation. After that, the ovulated ova were counted. The ovaries were studied using standard histological procedures. Results : Ovaries treated with the anti-MIF antibody showed reduced numbers of growing follicles surrounded by granulosa cells and theca cells with a little proliferation compared with the control. The average numbers of ova collected from mice treated with the anti-MIF antibody were reduced compared with those collected from control mice. Conclusions : Anti-MIF antibody inhibits the follicular growth and ovulation in mice, and MIF may play an important role in the inflammatory reactions during follicle growth and ovulation.     

Inducible and endothelial nitric oxide synthase: genetic background affects ovulation in mice.

OBJECTIVE: Inducible nitric oxide synthase (NOS) and endothelial NOS are involved in female reproductive physiology. We sought to investigate the influence of the inducible (Nos2) and endothelial (Nos3) NOS genes as a function of genetic background on ovulatory capacity and early embryonic development in a mouse model. DESIGN: Observational study of genetically altered mice and their response to a superovulation protocol. SETTING: Academic research institution. ANIMALS: Wild-type mice and mice deficient for Nos2 or Nos3 were bred to C57BL/6J and 129/Sv genetic backgrounds. INTERVENTION(S): Superovulation protocol, oocyte culture. MAIN OUTCOME MEASURE(S): Number of oocytes harvested, early embryonic development of zygotes, evaluation of ovarian histology. RESULT(S): The mean number of oocytes was significantly reduced in Nos3 deficient mice on a C57BL/6J background compared with controls. Oocytes deficient for Nos3 on a C57BL/6J background also showed reduced progression to two-cell stage embryos after 24 hours, two-cell stage embryos to blastocyst stage embryos, and survival to 48 hours. Those effects were distinctly absent in mice deficient for Nos3 on a 129/Sv background and in mice deficient for Nos2 on either genetic background. CONCLUSION(S): Our data show that disruption of Nos2 had no effect on ovulation in our mice. The negative effect of Nos3 deficiency on ovulatory capacity and early embryonic development is modulated by genetic background. This suggests a role for strain-specific modifier genes in these processes.     

Effect of vitrification method on survivability, follicular growth and ovulation of preantral follicles in mice

AIM: This study was designed to compare the survival rates, follicular growth rates, and ovulation rates of vitrified preantral follicles (PF) from ovaries with those isolated from a vitrified ovarian cortical strip. METHODS: Mouse ovaries were divided into three groups: those not treated by vitrification of the PF (control), those treated by vitrification of the PF isolated from the ovaries (group I), and those treated by vitrification of ovarian tissue followed by PF isolation (group II). The group I samples were exposed to equilibration solution (EG-20) for 5.0 min plus vitrification solution (EFS-40) for 0.5 min, while the group II samples were exposed to EG-20 for 10.0 min plus EFS-40 for 2.0 min, before vitrification. They were subsequently placed on an electron microscope grid, and submerged immediately in liquid nitrogen. After thawing, the survival rate and the growth rate of the follicles were evaluated every 2 days. RESULTS: In the in vitro condition, the follicles grew and developed into antral follicles in groups I and II. The survival rate of the group I samples was higher than that of the group II samples during the in vitro culture (P<0.05). The growth rates of the follicles in group I were higher than those in group II after day 6 (P<0.05). The ovulation rate of the samples in group I was higher than that of group II (P<0.05). CONCLUSION: These results demonstrated that direct PF vitrification appeared to be better than vitrification of the PF isolated from ovarian tissue.     

Significance of fibrinolysis in ovulation

To elucidate the significance of fibrinolytic enzymes in ovulation, the changes in the levels of plasminogen activator, plasminogen and plasmin activity were examined using prepubertal rats and sows treated with PMS and hCG. The following results were obtained. 1) The superovulation in rats was blocked with antifibrinolytic agents. 2) Plasminogen and plasminogen activator in the supernatant of rat ovarian homogenates increased toward ovulation. But plasmin activity did not show the significant change. 3) When the superovulation of the rats was blocked with indomethacin, plasminogen remained constant, but plasminogen activator was almost affected. 4) In the supernatant of follicle wall homogenates and the follicular fluid of sows, plasminogen decreased, but plasmin activity increased toward ovulation. 5) Plasminogen activator was produced by rat ovarian granulosa cells, but hCG, gonadotropins, prostaglandins and indomethacin did not activate the production of plasminogen activator in the granulosa cells.     

Induction of ovulation

Anovulatory infertility comprises about one-quarter of patients attending an infertility clinic. Management should be directed at determining the diagnosis, excluding other fertility problems and initiating ovulation induction therapies. Once the cause of anovulation has been corrected, good cumulative conception rates may be achieved, whether with pulsatile gonadotrophin-releasing hormone for hypogonadotrophic hypogonadism, dopamine agonists for hyperprolactinaemia or anti-oestrogen therapy for polycystic ovary syndrome. Polycystic ovary syndrome is the hardest condition to manage because of the additional metabolic problems, frequent obesity and sensitivity of the ovaries to stimulation, all of which increase risks of ovarian hyperstimulation syndrome and multiple pregnancy. Clomiphene-resistant cases of polycystic ovary syndrome can be managed with gonadotrophin therapy or laparoscopic ovarian diathermy. Treatment should be in specialist reproductive medicine clinics with adequate access to ultrasound monitoring of therapy in order to minimize the risks.     

Prediction of ovulation

The purpose of this investigation was to evaluate all available ovulatory diagnostics with respect to sensitivity, specificity, diagnostic specificity (predictive value of a positive test, PVP) and diagnostic sensitivity (predictive value of a negative test, PVN). Twenty-one ovulatory women with more than 3 years of infertility problems were included in the study. PVP and PVN were highest for detection of urinary luteinizing hormone (LH) peak at ovulation (PVP = 90%, PVN = 95%) and for serum-estradiol peak 1 day before ovulation (PVP = 83%, PVN = 97%). The predictive values were lower for all other tests. The PVP (54%) and PVN (90%) were rather low for detection of ovulation with vaginal electric impedance. However, all ovulations were predicted when urinary LH peak and vaginal impedance were combined. Two women were stimulated with human chorionic gonadotropin to investigate a possible connection between the LH peak and the preovulatory vaginal electric impedance. No close connection between them could be demonstrated. Basal body temperature should not be used for the prediction of ovulation (PVP = 25%). We suggest that ovulation should primarily be predicted from the identification of the urinary LH peak and that other methods be supplementary.