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PubMed1996

Prognostic indicators for intrauterine insemination (IUI): statistical model for IUI success.

A retrospective analysis of 260 completed intrauterine insemination (IUI) cycles was used in an attempt to identify significant variables predictive of treatment success. Couples received a maximum of three IUI cycles for the treatment of anovulation, cervical factors or unexplained infertility. Male factor problems were largely excluded by pretreatment screening. The overall pregnancy rate was 19.6% per completed cycle, the miscarriage rate 15.6%, the multiple pregnancy rate 23.5% and the cancellation rate 19%. Logistic regression identified four significant IUI variables [follicle number (P < 0.005), endometrial thickness (P < 0.005), duration of infertility (P < 0.01) and progressive motility (P < 0.05)] which were the most predictive of IUI success. The chance of conceiving when only one follicle was produced was only 7.6%, whereas with two follicles this chance increased to 26%. These variables were incorporated into a statistical model to allow the prediction of the chance of success in subsequent cycles. We conclude that careful patient selection criteria coupled with successful ovarian stimulation is the model for IUI success.

Adult↗
PubMed1995

Adjuvant growth hormone for induction of ovulation with gonadotrophin-releasing hormone agonist and gonadotrophins in polycystic ovary syndrome: a randomized, double-blind, placebo controlled trial.

The objective of this study was to explore the effect of cotreatment with recombinant human growth hormone (GH), gonadotrophin-releasing hormone agonist (GnRHa) and human menopausal gonadotrophin (HMG) for induction of ovulation in women with clomiphene resistant polycystic ovary syndrome (PCOS). It was designed as a randomized, double-blind, placebo controlled trial in which 30 women with anovulation associated with PCOS who were resistant to clomiphene all received DTRP6-LHRH (Decapeptyl microcapsules, 3.75 mg, i.m.) and, 2 weeks later, HMG in a standard, conventional, individually adjusted dose regimen until human chorionic gonadotrophin (HCG) and then luteal phase support could be given. From day 1 of HMG therapy, patients were randomized to receive either human GH (Norditropin, 12 IU/day, i.m., for 7 days) or placebo. The number of ampoules, duration of treatment and daily effective dose of HMG required to achieve ovulation, serum oestradiol concentrations and number of follicles induced, ovulation and pregnancy rates, serum insulin and insulin-like growth factor-I (IGF-I) concentrations were measured. There were no significant differences between growth hormone and placebo groups in any of the outcomes measured, other than a growth hormone induced increase in serum insulin and IGF-I levels. We conclude that although GH kinetics are abnormal and GH pituitary reserves generally low in women with PCOS, adjuvant GH treatment to GnRHa/HMG does not influence follicular development or sensitivity in response to gonadotrophins and that it does not seem likely to be of any potential clinical benefit for the treatment of PCOS.

Adult↗
PubMed1995

Treatment of varicocele: counselling as effective as occlusion of the vena spermatica.

Occlusion of the spermatic vein by surgical or angiographic techniques is generally accepted as the treatment of choice in infertile patients with varicocele. We have recently demonstrated that surgical ligation and radiological embolization are equally effective in terms of pregnancies following treatment. Since, however, it remains unclear whether any treatment is more effective than no treatment, we initiated a controlled, randomized prospective study to address this question. Infertile patients with varicocele were investigated twice using Doppler sonography, ultrasonography of the scrotal contents, semen analysis according to World Health Organization guidelines and serum follicle stimulating hormone, luteinizing hormone and testosterone measurements. Other causes of male infertility were excluded. The patients' wives were free of obvious causes of infertility such as anovulation or tubal blockage. Subjects fulfilling the admission criteria were randomly allocated to groups receiving ligation, embolization or no treatment. Thereafter, all patients were investigated and counselled every 3 months for a period of 1 year. In all, 47 couples in the treatment group (23 ligations and 24 embolizations) and 48 in the non-treatment group concluded the study. When entering the study, there were no significant differences in semen analysis and hormonal parameters between the two groups, nor between the subgroups undergoing treatment. While no significant changes in semen parameters occurred in the non-treatment group, the sperm concentration increased significantly (P = 0.008) in the treated patients from 16.5 +/- 2.5 x 10(6)/ml (mean +/- SE) before to 25.1 +/- 4.1 x 10(6)/ml at the end of the study.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Gonadotrophin induction of ovulation using a step-down dose regimen: single-centre clinical experience in 82 patients.

A total of 82 normogonadotrophic clomiphene-resistant anovulatory patients were treated with exogenous gonadotrophins according to a step-down dose regimen during 234 cycles. In 43 (18%) cycles co-treatment with gonadotrophin-releasing hormone analogues was applied. The initial dose was between 1.5 and 2.5 ampoules (75 IU follicle-stimulating hormone each) per day (dependent on body weight), and decreasing steps of 0.5 ampoules/day were based on sonographic findings. The overall ovulation rate was 91% (213 cycles). The median treatment period was 11 days and a total of 14 ampoules of gonadotrophin were needed. In 131 (62%) of the ovulatory cycles not more than one, and in 208 (98%) cycles not more than two, follicles > or = 16 mm were present on the day human chorionic gonadotrophin was given. A total of 37 pregnancies occurred of which two were twins and one was a triplet (multiple pregnancy rate 8%). The pregnancy rate per cycle was 17% and the cumulative pregnancy rate after 7 months was 47%. The abortion rate was 19%. There were four (1.7%) cases of mild ovarian hyperstimulation, of which none became pregnant. In conclusion, this study shows that the applied step-down regimen for gonadotrophin induction of ovulation can be a safe and effective treatment alternative for patients with clomiphene-resistant anovulation. The duration of ovarian stimulation and the amount of exogenous gonadotrophin required is limited. Pregnancy rates are comparable with those reported for step-up regimens, and a low incidence of complications (i.e. multiple gestation and ovarian hyperstimulation) was noted.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

The role of pre-ovulatory progesterone in the midcycle gonadotrophin surge, ovulation and subsequent luteal phase: studies with RU486 in rhesus monkeys.

Conflicting evidence exists on the possible physiological role of progesterone in the regulation of the midcycle surge of gonadotrophins during the normal primate menstrual cycle. We designed the present study based on the availability of a potent antiprogesterone, RU486, that acts by binding to the progesterone receptor without inducing progestational activity. Regularly cycling rhesus monkeys received daily administration of RU486, 10 mg orally (n = 8) or vehicle (n = 5) from the day of the menstrual cycle in which serum oestradiol was 130 pg/ml or more, and a laparoscopy revealed the presence of a dominant follicle. While vehicle administration did not affect the normal ovulatory pattern nor the hormonal milieu of the menstrual cycles, RU486 induced marked aberrations during the treated cycles. Delay of ovulation with a normal subsequent luteal phase was observed in three animals. Three animals remained anovulatory until the following cycle and two animals that ovulated on days 14 and 16 of the treated cycles had short luteal phases. Analysis of daily FSH, LH, oestradiol and progesterone revealed that the administration of RU486 disrupted the midcycle pattern of gonadotrophins by disrupting them after the surge was initiated. Oestradiol surges were not different from controls and in all animals the ascendant levels of progesterone were interrupted by the administration of the antiprogesterone. This study clearly shows that the pre-ovulatory administration of RU486, a potent antiprogesterone, alters pre-ovulatory gonadotrophin secretion, inducing different degrees of menstrual irregularities such as anovulation, delayed ovulations and short luteal phases.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Low multiple pregnancy rate in combined clomiphene citrate--human menopausal gonadotrophin treatment for ovulation induction or enhancement.

Sixty-five infertile women, 37 with anovulation, eight with ovulatory disturbances and 20 with unexplained infertility were treated by a combination of clomiphene citrate (CC) from cycle day 5 (or 3) and human menopausal gonadotrophin (HMG) begun 3 days later for induction or enhancement of ovulation. Monitoring was carried out by measuring preovulatory 17-beta-oestradiol (E2) and progesterone (P) concentrations in blood samples and by follicle measurements using ultrasound. Forty-seven pregnancies resulted with a multiple pregnancy rate of 7.7% for those completed. This incidence is very low and within the range found for CC induction and might result from the later commencement of stimulation compared with many other protocols. These results were achieved with a low incidence of ovarian hyperstimulation syndrome (2.6% per cycle). The HMG doses given were low in comparison with those found in other forms of induction. The deleterious effects of this combined mode of induction on cervical mucus and the occurrence of premature spontaneous ovulation were much less than in the sequential mode of treatment. These results suggest that combined induction treatment by CC and HMG as described offers a means of achieving low rates of multiple pregnancies a known complication in the induction of ovulation.

Adult↗
PubMed1990

Combined luteinizing hormone releasing hormone analogue and exogenous gonadotrophins for the treatment of infertility associated with polycystic ovaries.

This study was designed to compare the results of treatment with, firstly, exogenous gonadotrophins, with (57 cycles) and without (65 cycles) pretreatment with a superactive analogue of luteinizing hormone releasing hormone (LHRH) and, secondly, pure follicle stimulating hormone (FSH) (50 cycles) with those of human menopausal gonadotrophin (HMG) (72 cycles) in 46 women with clomiphene-citrate-resistant anovulation associated with polycystic ovaries. Patients randomly allocated to the analogue group received buserelin (Suprefact, Hoechst, UK, Ltd, Hounslow, Middlesex), 800 micrograms/day by nasal insufflation and when hypogonadism was achieved, patients were again randomly allocated for ovarian stimulation with either FSH or HMG. Controls received FSH or HMG alone. Patients pretreated with the analogue had similar pregnancy and ovulation rates, needed larger doses and more days of gonadotrophin therapy and had more ovarian overstimulation than those receiving no pretreatment. The role of superactive LHRH analogues for induction of a single ovulation for in-vivo fertilization is thus uncertain. Pure FSH had no advantages over HMG, the LH content of HMG having no deleterious effect on the ovary.

Adult↗
PubMed1991

Multiple pregnancies: risk factors and prognostic variables during induction of ovulation with human menopausal gonadotrophins.

Multiple pregnancies still constitute a major and relatively frequent complication of induction of ovulation by human menopausal gonadotrophins (HMG) despite the increasing sophistication of monitoring techniques. In order to define specific variables which may be associated with multiple pregnancies, we have compared 51 multiple pregnancy cycles to 51 consecutive control singleton pregnancy cycles, following HMG induction of ovulation. The aetiology and classification of anovulation, duration of infertility, total amount of HMG utilized per cycle and the duration of stimulation were not associated with an increase in the rate of multiple pregnancy. Basal serum oestradiol levels and its periovulatory pattern were remarkably similar in the singleton and multiple pregnancy groups. The mean age of the multiple pregnancy group (29.4 +/- 4.4 years) was significantly lower than the mean age of the singleton pregnancy group (31.6 +/- 5.3 years) (P less than 0.05). In the multiple pregnancy group, there were significantly more cycles with intermediate sized (15-17 mm). (P less than 0.002), small sized (12-14 mm). (P less than 0.02) and immature follicles (less than 12 mm) (P less than 0.03), at the time of human chorionic gonadotrophin (HCG) administration, as compared with the singleton pregnancy group. Furthermore, a direct linear correlation was observed between the number of intermediate sized follicles and number of implanted embryos. The presence of intermediate sized follicles at the time of HCG administration after HMG induction of follicular maturation is predictive of, and independently associated with, a higher incidence of multiple pregnancy.

Estradiol↗
PubMed1992

Endocrinological environment with regard to the number of microcysts in patients with polycystic ovary syndrome.

Androgen, oestrogen and gonadotrophin levels in patients with the polycystic ovary syndrome (PCOS) were compared with those in normal ovulatory women (controls), and were correlated with the number of microcysts in the polycystic ovaries studied. The androgen levels (testosterone, delta 4-androstenedione and dehydroepiandrosterone-sulphate), oestrogen levels (oestrone and oestrone/oestradiol-17 ratio) and gonadotrophin levels [luteinizing hormone (LH) and LH/follicle stimulating hormone (FSH) ratio] of PCOS patients were significantly higher than those of controls. The number of microcysts in polycystic ovaries was significantly correlated with androstenedione, which in turn was also significantly correlated with LH and LH/FSH ratio. These correlations may play a part in the maintenance of chronic anovulation in PCOS.

Adult↗
PubMed1993

Triggering of ovulation using a gonadotrophin-releasing hormone agonist does not prevent ovarian hyperstimulation syndrome.

A total of 24 women with primary or secondary infertility due to oligo- or anovulation, were treated with human menopausal gonadotrophin (HMG). In 48 cycles, we used a gonadotrophin-releasing hormone agonist (GnRHa) nasal spray (buserelin) to induce a pre-ovulatory endogenous luteinizing hormone (LH) surge. In 44 cycles, there was a rapid rise of the serum LH concentration within 8 h from the first administration of GnRHa. One patient with pituitary hypogonadotrophic amenorrhoea showed a weak or no response in four treatment cycles. Conception occurred in 10 cycles (pregnancy/cycle (P/C) index = 22.7%), four of which ended in a spontaneous abortion and six of which are ongoing pregnancies. In 27 cycles, there was an increased risk for ovarian hyperstimulation syndrome (OHSS), defined as more than three follicles > or = 18 mm in diameter and/or serum oestradiol > 1200 pg/ml. Three of these treatment cycles gave rise to the development of moderate OHSS in the absence of exogenously administered human chorionic gonadotrophin, two being conception cycles.

Administration, Intranasal↗
PubMed1993

The combination of gonadotrophin-releasing hormone (GnRH) antagonist and pulsatile GnRH normalizes luteinizing hormone secretion in polycystic ovarian disease but fails to induce follicular maturation.

To evaluate the role of altered luteinizing hormone (LH) release in the mechanism of polycystic ovarian disease (PCOD) anovulation, we have co-administered a gonadotrophin-releasing hormone (GnRH) antagonist and pulsatile GnRH therapy to two clomiphene citrate-resistant PCOD patients. The aim was to correct their inappropriate gonadotrophin secretion. Nal-Glu was administered s.c. every 72 h to both subjects for 3 weeks. On day 7 after commencing the study, intravenous pulsatile GnRH therapy was initiated (10 micrograms/pulse) every 90 min for 15 days to both subjects. In one subject, Nal-Glu treatment was continued and the GnRH dose was increased to 20 micrograms/pulse for 10 additional days. Prior to Nal-Glu, mean serum LH levels were 10.4 +/- 1.6 and 9.3 +/- 1.3 mIU/ml (mean +/- SEM) and mean interpulse intervals were 67.1 and 60 min in patients 1 and 2, respectively. Mean serum FSH levels were 4.9 +/- 0.4 and 4.2 +/- 0.2 mIU/ml for patients 1 and 2, respectively. LH pulsatility was abolished following Nal-Glu, mean serum LH decreased to 1.1 +/- 0.1 and 1.3 +/- 0.5 mIU/ml and mean FSH to 1.8 +/- 0.1 and 2 +/- 0.1 mIU/ml in the two subjects. On the 4th day of the combined therapy, mean serum LH increased to 5.4 +/- 1.3 and 3.9 +/- 0.9 mIU/ml with a mean interpulse interval of 72 and 80 min, respectively. Mean FSH levels increased to 3 +/- 0.1 and 2.8 +/- 0.1 mIU/ml, respectively and to 5.5 +/- 0.2 mIU/ml after the GnRH dose was increased in patient 2.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Ultrasonic monitoring during replacement of frozen/thawed embryos in natural and hormone replacement cycles.

We evaluated the results of cryopreserved/thawed embryo replacement (FER) to determine if the outcome following transfer in a natural cycle in a defined group was different to that from a hormone replacement cycle, and also to assess vaginal ultrasonographic features that assist in predicting the timing of the transfer. At the London Fertility Centre, 149 consecutive FER cycles were studied retrospectively. Women with proven ovulation and regular cycles were included during natural cycles (n = 77). The hormone replacement cycle group included women with anovulation, irregular cycles and older women (n = 72). In the natural cycle group, transfer was performed following positive urinary luteinizing hormone (LH) surge and confirmation of ovulation by ultrasonography. With the hormone replacement therapy group, gonadotrophin-releasing hormone analogue was used to induce pituitary down-regulation, oestradiol valerate was supplemented followed by regular ultrasound monitoring, and FER 2 days following the initiation of progesterone, which was started once adequate endometrial development was noticed on ultrasonography. The pregnancy and ongoing/delivery rates were analysed in relation to the treatment cycle, age, number and quality of embryos transferred. Ultrasonographic features were examined to evaluate their relationship with the outcome of treatment. The results showed that no difference existed between natural and hormone replacement cycles in pregnancy rates per cycle (26 and 25%), ongoing/delivery rate (20.8% in both groups), and implantation rate (10.3 and 10.6%). Pregnancy rates were not influenced by the number of embryos transferred, stage at which the embryos were cryopreserved, or whether they were extra embryos from in-vitro fertilization/embryo transfer, or gamete intra-Fallopian transfer.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

The effect of three anti-oestrogen drugs on cervical mucus quality and in-vitro sperm-cervical mucus interaction in ovulatory women.

The anti-oestrogens, clomiphene citrate, tamoxifen and cyclofenil are commonly used in the treatment of female infertility. Their role in the management of anovulation is well established but there is continuing controversy about their relevance to other areas of management. We have studied the effects of each of these drugs on cervical mucus and sperm-cervical mucus interaction among 23 patients with unexplained infertility. Each patient received all three drugs in an alternative month treatment regime and in addition acted as her own control. The starting point in each patient was randomized. Luteinizing hormone (LH) and oestradiol were measured daily from day 10, and follicle scanning was also undertaken. Cervical mucus quality and sperm-cervical mucus interaction were studied on the day of onset of the LH surge. The use of clomiphene and tamoxifen resulted in a significant reduction in cervical mucus score and sperm-cervical mucus interaction as judged by the distance travelled by the vanguard spermatozoa. Cyclofenil had no effect on these parameters.

Adult↗
PubMed1993

The ovarian hyperstimulation syndrome in in-vitro fertilization: a Belgian multicentric study. I. Clinical and biological features.

The multicentric study regroups 128 cases of the ovarian hyperstimulation syndrome (OHSS) in in-vitro fertilization (IVF) and 256 selected controls. Values of serum oestradiol obtained from different laboratories were found to be normally distributed after logarithmic transformation. Comparative study of clinical and biological characteristics indicates that among OHSS patients (i) mean age was lower; (ii) tubal indications for IVF were less frequent; (iii) polycystic ovary-like conditions (i.e. hyperandrogenism, anovulation, luteinizing hormone/follicle stimulating hormone ratio > 2) were more frequent. OHSS patients displayed ovarian hypersensitivity reflected by higher oestradiol peak concentrations in response to lower dosage of human menopausal gonadotrophin and by a steeper slope of oestradiol increment during stimulation. In these patients, the collection of greater numbers of fertilizable oocytes allowed replacement of more embryos with a good vitality score. Ongoing pregnancy rate was found to be higher among the OHSS patients. The following complications were recorded among OHSS cases: abdominal fluid at echographic examination or clinical ascites (86.7 and 71.1%, respectively); pleural and pericardial effusion (21 and 3%, respectively); haemoconcentration (71.1%); electrolytic disorders (6.2%). Although significantly different between groups, clinical and biological parameters under study showed considerable overlap of their distributions in control and OHSS cases. Therefore, these data must be submitted to discriminant analysis in order to derive a formula predictive of the risk of OHSS.

Adult↗
PubMed1994

First established pregnancy and birth after induction of ovulation with recombinant human follicle-stimulating hormone in polycystic ovary syndrome.

This case report describes the first established pregnancy and birth after induction of ovulation with recombinant human follicle-stimulating hormone (FSH) in a woman suffering from chronic clomiphene-resistant anovulation due to polycystic ovary syndrome (elevated serum luteinizing hormone and testosterone concentrations together with polycystic ovaries). Starting on day 3 of a progestagen withdrawal bleeding, 75 IU of rFSH was administered i.m. daily until a single preovulatory follicle was seen upon transvaginal ultrasound examination at day 13. Ovulation was induced by a single i.m. administration of 10,000 IU of human chorionic gonadotrophin, after which a viable singleton pregnancy was revealed at a gestational age of 6 weeks. The course of pregnancy and labour was uneventful and no abnormalities were found upon a paediatric examination.

Female↗
PubMed2002

Effects of prenatal testosterone propionate on the sexual development of male and female rats: a dose-response study.

Testosterone plays a major role in male sexual development. Exposure of females to testosterone in utero can induce masculine characteristics such as anovulation, increased anogenital distance (AGD), absence of nipples, retention of male-like tissues, and agenesis of the lower vagina. In addition, high levels of androgens during fetal development can lead to toxic effects such as reduced litter size and viability. The study of the effects of testosterone administration during sexual differentiation provides a foundation for understanding the effects of environmental androgens on fetuses, a sensitive subpopulation. In the current study, we investigated the ability of a range of concentrations of testosterone propionate (TP) administered prenatally to masculinize female and alter male offspring, and measured maternal and fetal T levels. Pregnant Sprague-Dawley rats were dosed by sc injection on gestational day (GD) 14-19 (GD 1= day of plug) with either corn oil (vehicle; 0.1 ml/rat) or with 0.1 ml of TP solution at 0.1, 0.5, 1, 2, 5, or 10 mg/0.1 ml. Parturition was delayed at 2, 5, and 10 mg TP, litter size was reduced at 5 and 10 mg TP, and pup weight was significantly reduced in both sexes at 0.5 mg TP and higher doses. Viability of offspring was unaffected at any dosage level. Androgenic effects seen at 0.5 mg TP in females included increased AGD at weaning and adulthood, reduced number of areolas and nipples, cleft phallus, small vaginal orifice, and presence of prostate tissue. This dose of TP elevated maternal T levels 10x but had no effect on fetal T levels. At 1 mg TP and above, female AGD on postnatal day (PND) 2 (or postcoital day 24 [gestation length = 22(1/2)]) was increased; areolas and nipples were virtually eliminated; levator ani muscle, bulbourethral glands, and seminal vesicles (2 mg TP and above) were present; none of the females developed a vaginal orifice and many females in the 1 and 2 mg TP dose groups developed a greatly distended, fluid-filled uterus after puberty. Maternal T levels at 1 mg TP were elevated 30x, and female fetal T levels showed an 80% increase. Male offspring displayed a reduced AGD and body weight on PND 2 at 0.5 mg TP and higher doses. These effects were not evident by weaning and male offspring displayed no malformations. We conclude that gestational administration of 0.5 and 1 mg TP masculinizes female offspring without greatly affecting pup viability or pregnancy of the dam. This study provides a useful model for in utero testing of environmental androgens for their potential to induce developmental abnormalities.

Abnormalities, Drug-Induced↗
PubMed2002

Growth differentiation factor 9 and bone morphogenetic protein 15 are essential for ovarian follicular development in sheep.

The aim of this study was to test the hypothesis that both growth differential factor 9 (GDF9) and bone morphogenetic protein (BMP15; also known as GDF9B) are essential for normal ovarian follicular development in mammals with a low ovulation rate phenotype. Sheep (9-10 per group) were immunized with keyhole limpet hemocyanin (KLH; control), a GDF9-specific peptide conjugated to KLH (GDF9 peptide), a BMP15-specific peptide conjugated to KLH (BMP15 peptide), or the mature region of oBMP15 conjugated to KLH (oBMP15 mature protein) for a period of 7 mo and the effects of these treatments on various ovarian parameters such as ovarian follicular development, ovulation rate, and plasma progesterone concentrations evaluated. Also in the present study, we examined, by immunohistochemistry, the cellular localizations of GDF9 and BMP15 proteins in the ovaries of lambs. Both GDF9 and BMP15 proteins were localized specifically within ovarian follicles to the oocyte, thereby establishing for the sheep that the oocyte is the only intraovarian source of these growth factors. Immunization with either GDF9 peptide or BMP15 peptide caused anovulation in 7 of 10 and 9 of 10 ewes, respectively, when assessed at ovarian collection. Most ewes (7 of 10) immunized with oBMP15 mature protein had a least one observable estrus during the experimental period, and ovulation rate at this estrus was higher in these ewes compared with those immunized with KLH alone. In both the KLH-GDF9 peptide- and KLH-BMP15 peptide-treated ewes, histological examination of the ovaries at recovery (i.e., approximately 7 mo after the primary immunization) showed that most animals had few, if any, normal follicles beyond the primary (i.e., type 2) stage of development. In addition, abnormalities such as enlarged oocytes surrounded by a single layer of flattened and/or cuboidal granulosa cells or oocyte-free nodules of granulosa cells were often observed, especially in the anovulatory ewes. Passive immunization of ewes, each given 100 ml of a pool of plasma from the GDF9 peptide- or BMP15 peptide-immunized ewes at 4 days before induction of luteal regression also disrupted ovarian function. The ewes given the plasma against the GDF9 peptide formed 1-2 corpora lutea but 3 of 5 animals did not display normal luteal phase patterns of progesterone concentrations. The effect of plasma against the BMP15 peptide was more dramatic, with 4 of 5 animals failing to ovulate and 3 of 5 ewes lacking surface-visible antral follicles at laparoscopy. By contrast, administration of plasma against KLH did not affect ovulation rate or luteal function in any animal. In conclusion, these findings support the hypothesis that, in mammals with a low ovulation rate phenotype, both oocyte-derived GDF9 and BMP15 proteins are essential for normal follicular development, including both the early and later stages of growth.

Animals↗
PubMed2006

Metformin-induced stimulation of adenosine 5' monophosphate-activated protein kinase (PRKA) impairs progesterone secretion in rat granulosa cells.

Metformin is an anti-diabetic drug commonly used to treat cycle disorders and anovulation in women with polycystic ovary syndrome. However, the effects and molecular mechanism of metformin in the ovary are not entirely understood. We investigated the effects of this drug on steroidogenesis and proliferation in rat granulosa cells. Metformin (10 mM) treatment for 48 h reduced progesterone and estradiol (E2) production in both basal conditions and under FSH stimulation. It also decreased the levels of the HSD3B, CYP11A1, STAR, and CYP19A1 proteins in response to FSH (10(-8) M) and of HSD3B in the basal state only. Metformin treatment (10 mM, 24 h) also reduced cell proliferation and the levels of CCND2 and CCNE proteins without affecting cell viability, both in the basal state and in response to FSH. Furthermore, metformin treatment for 1 h simultaneously increased the Thr172 phosphorylation of PRKAA (adenosine 5' monophosphate-activated protein kinase alpha) and the Ser79 phosphorylation of ACACA (acetyl-Coenzyme A carboxylase alpha). The adenovirus-mediated production of dominant-negative PRKAA totally abolished the effects of metformin on progesterone secretion, HSD3B and STAR protein production, and MAPK3/1 phosphorylation. Conversely, total inhibition of PRKAA Thr172 phosphorylation with the dominant-negative PRKAA adenovirus did not restore the decrease in E2 production and cell proliferation induced by metformin. Our results therefore strongly suggest that metformin reduces progesterone production via a PRKAA-dependent mechanism, whereas PRKAA activation is not essential for the decrease in E2 production and cell growth induced by metformin in rat granulosa cells.

Acetyl-CoA Carboxylase↗