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PubMed1975

The effect of abrupt lengthening of the photoperiod on the onset of ovulation in gonadotrophin-treated immature rats.

Immature female rats exposed daily to a-14 h photoperiod were induced to ovulate precociously by administering pregnant mares' serum gonadotrophin (PMS) at 30 days of age (day 30). In these rats ovulation occurs on day 33 between 0130 and 0330 (midpoint of photoperiod equals 1200). The acute effect on the timing of ovulation of abruptly lengthening the photoperiod by 6 h was investigated in this preparation. When compared with controls kept on a 14-h photoperiod, adding 6 h of light to the beginning of the daily photoperiod (i.e., AM light) advanced ovulation by 2 h; adding 6 h of light to the end of the photoperiod (i.e., PM light) delayed ovulation by 5.5 h; adding 3 h of light to the beginning and to the end of the photoperiod delayed ovulation by 2 h. These results suggest that the time of release of an ovulatory quota of pituitary gonadotrophin may be advanced by exposure to AM light and delayed by exposure to PM light, but the PM light appears to have a stronger effect on the time of gonadotrophin secretion.

Animals↗

PubMed1995

Immunization against the N-terminal peptide of the inhibin alpha 43-subunit (alpha N) disrupts tissue remodeling and the increase in matrix metalloproteinase-2 during ovulation.

Immunization of ewes against the N-terminal peptide of inhibin alpha 43 (alpha N) reduces fertility; this is thought to be due to impaired oocyte release at ovulation. This study further investigates the effect of alpha N immunoneutralization on the ovulatory process. Light microscopy was used to examine the effects of alpha N immunization of the tissue-remodeling process during ovulation and formation of the corpus luteum (CL) structure. Changes in follicular levels of matrix metalloproteinase-2 (MMP-2) with approaching ovulation were also investigated in normal and alpha N-immunized ewes. Differences in structure of 2-day-old CL were observed between control and alpha N-immunized ewes. Control CL had confluent luteal tissue throughout the internal structure and invaginations of theca and vasculature were common and penetrated deep into the luteal tissue. Immunized ewe CL had large fluid-filled antra, giving them a cystic appearance; luteal tissue remained a thin 10- to 15-cell layer lining the wall surrounding the antrum. Infolding of the surrounding tissue was incomplete, and thecal/vascular invaginations were rare and failed to penetrate into the luteal tissue. Morphologically normal rupture stigma were seen at the apex of both control and alpha N-immunized CL. Gelatin-digesting activity in follicular fluid collected 0, 12, and 24 h after hCG administration in control ewes increased significantly as the time of ovulation approached (827 +/- 182, 842 +/- 159, and 1230 +/- 89 mU/ml, respectively, in Exp 1; 743 +/- 32, 1182 +/- 98, and 1306 +/- 91 mU/ml at the same times in Exp 2). alpha N immunization reduced follicular gelatinase activity at each time in Exp 1 (533 +/- 132, 740 +/- 67, and 809 +/- 147 mU/ml) and Exp 2 (587 +/- 21, 768 +/- 27, and 891 +/- 53 mU/ml); the reduction was significant at 24 h in Exp 1 and at all times in Exp 2. Gelatin zymography of follicular fluid revealed bands of gelatinase of 72/67 kilodaltons, consistent with latent and active MMP-2. The area digested by both latent and active MMP-2 increased with approaching time of ovulation and was reduced by alpha N immunization. These data suggest that MMP-2 has a role in the tissue-remodeling processes of ovulation and CL formation in the ewe and that immunization against alpha N, which impairs fertility, effects the preovulatory cascade of intrafollicular proteolytic activity, reducing MMP-2 levels and disrupting normal CL formation.

Animals↗

PubMed1996

Coordinated and cell-specific induction of both physiological plasminogen activators creates functionally redundant mechanisms for plasmin formation during ovulation.

Several lines of indirect evidence indicate that plasmin-mediated proteolysis plays a role in the breakdown of the follicle wall during ovulation. Consistent with this, the ovulation efficiency of mice lacking the two known physiological plasminogen activators (PAs), tissue-type PA (tPA) and urokinase-type PA (uPA), is reduced by 26%. Surprisingly, mice with a single deficiency of either tPA or uPA gene function were normal in their capacity to ovulate. In this study we used in situ hybridization and casein in situ zymography to localize the expression of messenger RNAs (mRNAs) encoding PAs and PA inhibitors and to examine the net PA activity in the mouse ovary at the time of ovulation. Although uPA mRNA expressed by granulosa cells is the most abundant and dramatically up-regulated PA before ovulation, a previously unnoticed coordinated induction oftPA mRNA was found in thecal-interstitial tissue. The existence of redundant mechanisms for plasmin production in the ovary may be the cause of the normal ovulation efficiency in single deficient mice lacking tPA or uPA. The expression of mRNAs for PA inhibitors, types 1 and 2, was low in the ovary, with minor inductions at restricted time points. In contrast, expression of protease nexin-1 (PN-1) by granulosa cells was high during the entire periovulatory period. Among subpopulations of granulosa cells, the expression of PN-1 and uPA was heterogeneous and complementary. Cumulus cells expressed high levels of PN-1 mRNA and low levels of uPA mRNA, thereby providing an inhibitory activity that may protect the mucified matrix of the cumulus oocyte complex from proteolytic degradation.

Amyloid beta-Protein Precursor↗

PubMed2001

Sensitization to insulin induces ovulation in nonobese adolescents with anovulatory hyperandrogenism.

In nonobese girls with an adolescent variant of polycystic ovary syndrome, insulin-sensitizing treatment reduces hyperinsulinism, dyslipidemia, and hyperandrogenism and restores eumenorrhea; however, the effect on anovulation is unknown. We assessed whether metformin treatment is capable of inducing ovulation in nonobese adolescents with anovulatory hyperandrogenism after precocious pubarche. The study population consisted of 18 adolescents (mean age, 16 yr; body mass index, 21.4 kg/m2; 3-7 yr beyond menarche) with hyperinsulinemic hyperandrogenism. All girls received metformin for 6 months in a daily dose of 1275 mg. Before inclusion, persistent anovulation was documented by weekly serum progesterone measurements less than 4 ng/ml (months -3 and -1); the ovulation rate was assessed similarly after 2, 4 and 6 months on metformin; a premenstrual progesterone level greater than 8 ng/ml was used as ovulation marker. Regular menses were reported by 16 of 18 girls within 4 months on metformin, and all girls were eumenorrheic after 6 months on metformin. Of the 18 girls, 1 (6%) ovulated after 2 months on metformin, 7 (39%) after 4 months, and 14 (78%) after 6 months; ovulation induction failed in the girls with the lowest birth weight or most severe hyperandrogenism. Metformin treatment was well tolerated. In conclusion, sensitization to insulin was found to be an effective approach to induce ovulation in nonobese adolescents with anovulatory hyperandrogenism.

Adolescent↗

PubMed2002

Reduced ovulation rate in adolescent girls born small for gestational age.

FSH and insulin are key hormones involved in spontaneous ovulation. Adolescent girls born small for gestational age (SGA) are at risk for FSH and insulin resistance. We have assessed whether ovulation rate is reduced in SGA girls. Ovulatory function was assessed by weekly filter paper progesterone measurements, obtained by finger-stick auto-sampling for 3 consecutive months in matched populations of asymptomatic, nonobese girls (mean age, 15.5 yr; > or =3 yr postmenarche) who were either born with an appropriate weight for gestational age (AGA; n = 24; mean birthweight, 3.3 kg) or born small for gestational age (SGA; n = 25; mean birthweight, 2.3 kg). The prevalence of anovulation was higher among SGA than AGA girls (40% vs. 4%; P = 0.002). Moreover, in the relatively small fraction of ovulating SGA girls, the ovulation rate was lower than in AGA adolescents (average number of ovulations during the study, 1.4 vs. 1.9; P < 0.01). In conclusion, the endocrine correlates of prenatal growth restraint are herewith extended to include oligo-ovulation and anovulation in adolescence. It remains to be verified whether this SGA-related phenomenon persists into the reproductive age range. If it does, then fetal growth restraint may prove to be one of the enigmatic components underpinning hitherto unexplained female subfertility.

Adolescent↗

PubMed2005

Knockout of luteinizing hormone receptor abolishes the effects of follicle-stimulating hormone on preovulatory maturation and ovulation of mouse graafian follicles.

It is considered a dogma that a secretory peak of LH is indispensable as the trigger of ovulation. However, earlier studies on hypophysectomized rodents have shown that stimulation with recombinant FSH, devoid of any LH activity, is able to boost the final stages of follicular maturation and trigger ovulation. As the expression of ovarian LH receptors (LHRs) still persists after hypophysectomy, such studies cannot totally exclude the possibility that LHR activation is involved in the apparently pure FSH effects. To revisit this question, we analyzed in LHR knockout (LuRKO) mice the progression of folliculogenesis and induction of ovulation by human chorionic gonadotropin and human recombinant FSH treatments. The results provide clear evidence that follicular development and ovulation could not be induced by high doses of FSH in the absence of LHR expression. Ovarian histology and oocyte analyses indicated that follicular maturation did not advance in LuRKO mice beyond the antral follicle stage. Neither were ovulations detected in LuRKO ovaries after any of the gonadotropin treatments. The ovarian resistance to FSH treatment in the absence of LHR was confirmed by real-time RT-PCR and immunohistochemical analyses of a number of gonadotropin-dependent genes, which only responded to the treatments in wild-type control mice. Negative findings were not altered by estradiol priming preceding the gonadotropin stimulations. Hence, the present study shows that, in addition to ovulation, the expression of LHR is essential for follicular maturation in the progression from antral to preovulatory stage.

Animals↗

PubMed2006

A novel pathway involving progesterone receptor, endothelin-2, and endothelin receptor B controls ovulation in mice.

The steroid hormone progesterone (P) plays a pivotal role during ovulation. Mice lacking P receptor (Pgr) gene fail to ovulate due to a defect in follicular rupture. The P receptor (PGR)-regulated pathways that modulate ovulation, however, remain poorly understood. To identify these pathways, we performed gene expression profiling using ovaries from mice subjected to gonadotropin-induced superovulation in the presence and in the absence of CDB-2914, a synthetic PGR antagonist. Prominent among the genes that were down-regulated in response to CDB-2914 was endothelin (ET)-2, a potent vasoactive molecule. ET-2 mRNA was transiently induced in mural granulosa cells of the preovulatory follicles immediately preceding ovulation. This induction was absent in the ovaries of PGR null mice, indicating a critical role of this receptor in ET-2 expression. To investigate the functional role of ET-2 during ovulation, we employed selective antagonists of endothelin receptors, ETR-A and ETR-B. Mice treated with an ETR-B antagonist exhibited a dramatic (>85%) decline in the number of released oocytes. Strong expression of ETR-B was observed in the mural and cumulus granulosa cells of the preovulatory follicles as well as in the capillaries lining the inner border of the theca interna. We also identified cGMP-dependent protein kinase II, a previously reported PGR-regulated gene, as a downstream target of ET-2 during ovulation. Collectively, our studies uncovered a unique pathway in which ET-2, produced by PGR in mural granulosa cells, acts in a paracrine or autocrine manner on multiple cell types within the preovulatory follicle to control the final events leading to its rupture.

Animals↗

PubMed1985

[The mechanism of induction of ovulation by bromocriptine in euprolactinemic anovulation--the role of occult hyperprolactinemia in anovulation].

It has been well documented that ovulation was induced by Bromocriptine treatment in euprolactinemic anovulation. The present study has been carried out to clarify the underlying mechanism. 28 patients with euprolactinemia (PRL less than 25 ng/ml) were treated with a 5 mg daily administration of Bromocriptine. Ovulation was induced in 13 cases, which were determined by their BBT charts. In the ovulated cases, PRL secreting capacities were increased, determined by TRH administration. On the other hand, PRL secreting capacities were normal in the anovulated cases. The studies of the circadian secretion of PRL revealed that a nocturnal hyperprolactinemic state occurred for several hours in the ovulated cases, which was not seen in the anovulated cases. From these results, the mechanism of induction of ovulation by Bromocriptine in euprolactinemic anovulation exists on the suppression of the increased PRL secreting capacity, which may be related to the occulted hyperprolactinemia at night. Ovulated cases by Bromocriptine are seemingly euprolactinemia, but in truth they may be a kind of hyperprolactinemia.

Adult↗

PubMed1978

Conditions for establishment of reflex ovulation in light estrous rats.

Continual anovulatory state associating with persistent vaginal cornification (light estrus) was induced by placing 4-day cycling rats under continuous lighting (LL). Uterine cervical stimulation was applied at arbitrary solar hours to light estrous rats showing continual vaginal estrus for more than 2 weeks. The ovulation was induced between 14 and 16 hr after the stimulation dissociating entirely with solar hours. Injection of anti-LHRH serum 5 min after the stimulation but not later than 20 min blocked this ovulation. Ovulation thus induced was always followed by pseudopregnancy with continual leucocytic vaginal smear lasting 10.70 days. The change in concentrations of peripheral serum progesterone during this period was almost similar to that of normal pseudopregnancy except extremely low levels observed at the start and end. Effectiveness of the cervical stimulation for induction of ovulation in light estrous rats was related to not only the duration of light estrus but also the time after transfer to LL, suggesting that the neural mechanism of ovulation in light estrous rats shifted from that of the spontaneous to reflex ovulators due to the extinction of environmental photic cue.

20-alpha-Dihydroprogesterone↗

PubMed1983

Follicular development and a single ovulation induced with pulsatile administration of Gn-RH in anovulatory women: studies of hormonal analysis and follicular sonometry.

The method of pulsatile administration of gonadotropin-releasing hormone (Gn-RH) has been proven as a useful means for induction of ovulation in anovulatory women. In our series of clinical trials, 23 out of 29 anovulatory patients ovulated with pulsatile administration of Gn-RH. Seven patients who ovulated volunteered for the present study with daily hormonal analysis and follicular sonometory . Two patients have oligomenorrhea, 3 patients secondary amenorrhea-1st grade (the sole administration of gestagen required for withdrawal bleeding) and the remaining 2 patients secondary amenorrhea-2nd grade (the combined administration of estrogen and gestagen required for withdrawal bleeding). A diagnosis of hyperprolactinemia was made for one patient with secondary amenorrhea-1st grade. Pulsatile administration of Gn-RH was performed by the use of a self-administered infuser . The infuser was connected to an i.v. indwelling catheter via a specially designed blood backflow eliminater . Five micrograms or less of Gn-RH was given every 2 hr from 07:00 to 23:00 hr daily. Five patients received HCG during the preovulatory period. In one patient, a short term treatment of HMG was added to Gn-RH treatment. Follicular sonometry revealed the development of a single dominant follicle which reached between 20 and 28 mm (23.7 +/- 0.12 mm, mean +/- S.E.) in diameter at the preovulatory period. Disappearance of a dominant follicle was recognized in the early luteal phase. Characteristic increases in estradiol were recognized concomitantly with the development of a dominant follicle. Progesterone levels after ovulation were within the limits of its normal "luteal phase" rise. The present data suggest that pulsatile administration of low dose Gn-RH with nocturnal interruption of treatment is effective for normal progress of follicular development in various types of anovulatory patients, culminating in single ovulation. This paper includes the discussion on our method which may be responsible for a high success rate of ovulation induction.

Adult↗

PubMed1982

Ovulation in the rabbit following intraventricular and intravenous administration of synthetic Gn-RH.

A comparison was made of the efficacy of intravenously (iv) and intraventricularly administered synthetic Gn-RH in inducing ovulation in conscious and urethane anaesthetized rabbits. Via the iv route of administration, the minimum dose of Gn-RH required to induce ovulation in all animals of the conscious group was 300 ng/kg body weight. This is in contrast to the larger systemic dose (400 ng/kg body weight) of Gn-RH required to achieve the same results in urethane anesthetized but otherwise identically treated rabbits. This suggests that although ovulation is no blocked by an anaesthetic dose of urethane (1.25 g/kg), the ovulatory response is altered in some way by the anaesthetic. When administered intraventricularly, the minimum dose of Gn-RH required to induce ovulation in anaesthetized animals was only 100 ng/kg body weight or 25% of the equivalent systemic dose. Systemically ineffective doses of Gn-RH (less than or equal to 200 ng/kg body weight) also induced ovulation in the anaesthetized group when administered via the third cerebral ventricle. All animals that ovulated did so between 13 and 16 h following Gn-RH administration and the number of ova recovered paralleled the number of ruptured follicles. A graded increase in the number of ova released with dosage of Gn-RH was not observed. In this study, the smaller defective dose requirement for intraventricularly administered decapeptide supports the view that Gn-RH in the CSF circumvents the general circulation and reaches the portal vasculature directly via the median eminence.

Animals↗

PubMed1986

Initiation and control of ovulation in the mouse luteal phases. Effects of gonadotropins and gonadotropin releasing hormone.

The aim of the present study was to examine the induction of ovulation during pregnancy, pseudopregnancy, and suckling-delayed pregnancy in mice using exogenous gonadotropins. The present results demonstrate that there are mature follicles in the ovary which can be induced to ovulate with administration of either exogenous human chorionic gonadotropin (hCG) or luteinizing hormone (LH) during pregnancy (Days 1-12) and pseudopregnancy (Days 4-8) in the mouse. hCG was relatively ineffective in initiating ovulation during suckling-delayed pregnancy, and hCG could not induce ovulation on Days 3-6 in any animals, suggesting that follicular growth is not continuous during suckling-delayed pregnancy in the mouse. Ovulation occurred in pregnant and pseudopregnant mice following injection of gonadotropin releasing hormone (GnRH) in a gelatin delay vehicle. Injection of GnRH in saline did not initiate ovulation in pregnant or pseudopregnant mice. A large release of LH was shown to occur following injection of GnRH in gelatin, but no release occurred after the same dose of GnRH in saline. In conclusion, the experiments demonstrate the existence of mature follicles during murine pregnancy and pseudopregnancy, and the lack of inductable follicles during suckling-delayed pregnancy.

Animals↗

PubMed1986

Initiation and control of ovulation in the mouse luteal phases. Effects of oestrogen, progesterone and prolactin.

The aim of the present study was to examine the effect of exogenous oestrogen and progesterone on ovulation in early pregnant mice and at the end of pseudopregnancy. The results demonstrate that there are mature follicles during early pregnancy which were induced to ovulate by administration of large doses of oestrogen (greater than or equal to 10 micrograms) on day 4 of pregnancy. Ovulation was also induced by inhibition of progesterone secretion with bromocriptine. If progesterone or prolactin was given in conjunction with bromocriptine, the ovulation effect was abolished. At the end of pseudopregnancy, the spontaneous ovulation was inhibited by injections of progesterone (1.0 mg). Oestrogen given by itself at the end of pseudopregnancy caused the animals to mate earlier than the control animals. This confirms the presence of mature follicles in mice during pregnancy and suggests that the LH peak needed for ovulation can either be provoked by administration of oestrogen or by blocking of progesterone.

Animals↗

PubMed1992

Patterns of ovulation, conception and pre-implantation embryo development during the breeding season in rhesus monkeys kept under semi-natural conditions.

The occurrence of ovulation and conception in the female rhesus monkey (Macaca mulatta) under natural conditions is seasonal and maximum during the months of October to March. Such seasonality in reproduction suggests dependence on environmental factors like photoperiod, temperature and rainfall. There occur significant fluctuations in these environmental factors also during the breeding season itself. Whether there occur any discernible changes in the occurrence of ovulation and conception, and in the incidence of abnormality in pre-implantation stage embryo development in the rhesus monkey, associated with changes in environmental factors within the breeding season has not been known and was investigated in the present study using a total of 304 menstrual cycles over a period of five years. No preferential sidedness for any ovary to ovulate more was evident, the frequency ratio of ovulations in left ovary to right ovary being 1.02. Despite the absence of any pattern in the side selection of ovulations in successive cycles, the chance of ovulations in alternate ovaries for successive cycles appeared more likely (67% cases). An average of 21% of menstrual cycles were found to be non-ovulatory with significantly higher menstrual cycle lengths (p less than 0.03) compared with that of ovulatory cycles. An additional 28% of the mated, conception cycles yielded degenerated or desynchronized pre-implantation stage embryos. Furthermore, the number of non-ovulatory cycles (p less than 0.05) and the incidence of abnormality in pre-implantation stage embryos (p less than 0.02) were higher during the months of transition in (October) and out (March) of the breeding season.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1975

Progesterone: sites of action in inhibiting ovulation in hamsters.

A single subcutaneous injection of progesterone (0.5 mg/animal at 17.00 hours) on Day 3 of the cycle (Day 1 = day of vaginal discharge) interfered with ovulation and external vaginal discharge in all the animals. Lower doses were only partly active. Intravenous administration of LH, FSH or their combination at 14.00 hours on Day 4 failed to restore ovulation in such animals, implying a direct action of the administered progesterone on the ovary. A large dose of oestradiol benzoate (400 mug/animal) also proved inactive suggesting that progesterone did not interfere with ovulation solely through antioestrogenic action. Depletion of the pituitary LH stores normally found in association with ovulation and ovulatory peak of LH in plasma seen in control animals were not observed in the progesterone-treated hamsters suggesting a further action of progesterone at the pituitary-hypothalamic level in inhibiting ovulation. Administration of synthetic LRF (100 ng/animal, i.v.) on Day 4 to hamsters treated with progesterone caused an increase in plasma LH 15 min later which was comparable to the rise observed in control animals given a similar injection of LH-RF, implying lack of action of progesterone at the pituitary level. It is concluded that progesterone acts centrally, principally on the hypothalamus, and peripherally on the ovary to interfere with ovulation in hamsters. It is possible that the anovulatory state accompanying pregnancy results from these actions.

Animals↗

PubMed1979

Total follicular populations in ewes of high and low ovulation rates.

The total ovarian follicular populations were studied in two breeds of ewes which differed greatly in their ovulation rates. Thus 8 Romanov (mean ovulation rate 3.1) and 12 Ile-de-France ewes (mean ovulation rate 1.4) were ovariectomized at oestrus during the breeding season. Each right ovary and 3 left ovaries were sectioned at 7 micron and examined microscopically. The number of small follicles, i.e. with 2 or less layers of granulosa cells, was estimated by a tested sampling procedure whilst all larger follicles were measured and arranged into classes. There were half as many small follicles but 1.5--2 times more large follicles in the ovaries of the Romanov ewes compared to those of the Ile-de-France ewes. The number of atretic follicles was approximately the same in both breeds and does not explain the difference observed in ovulation rate. It is concluded that the higher ovulation rate in the Romanov ewe is due to the greater number of large follicles available to be stimulated for ovulation.

Animals↗

PubMed1980

Ovulation from rat and hamster ovaries in vitro.

The ovaries of pro-oestrous rats (pubertal and adult) and hamsters were explanted in toto at various times after the preovulatory gonadotrophin surge to obtain endogenously stimulated ovaries. Subnormal numbers of ovulations from pubertal and adult rat ovaries were found when incubation was started during the period from 17:00 to 24:00 h on the day of pro-oestrus. Normal numbers of ovulations only occurred from rat ovaries in vitro when incubation was started at 01:00 h, i.e. when ovulation had already begun in vivo. In contrast, full ovulation from hamster ovaries was observed in vitro after incubation at 22:00 h and later, although the ovulatory process had not started in vivo. This difference in the ability of rat and hamster follicles to ovulate in vitro could be due to a different role of the accumulation of tissue fluid for the mechanism of ovulation.

Animals↗

PubMed1982

Proteolytic enzymes and gonadal hormones of the ovarian follicle wall during ovulation in the domestic fowl (Gallus domesticus).

There were no significant changes in the activities of collagenase, acid and neutral protease up to ovulation. Neutral protease activity increased significantly in the post-ovulatory follicle obtained immediately after ovulation. Acid protease and collagenase showed an increasing activity with time after ovulation. The progesterone concentration of the follicle wall rose 3 h before ovulation, peaked 1 h before ovulation and remained high until ovulation. Plasma progesterone values were high but decreased before those in the follicle. Follicular progesterone concentrations decreased markedly soon after rupture, but oestradiol values then increased.

Animals↗