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PubMed1993

The significance of elevated FSH for reproductive function.

1. Women aged 40 or more with favourable hormone profiles can do well in assisted reproduction, while women of any age with basal FSH levels greater than 20 IU/litre will be poor responders to ovarian stimulation. 2. Basal FSH is an important predictor of ovarian reserve--levels over 25 IU/litre are rarely associated with ongoing pregnancy, and the best chance for pregnancy is an FSH between 10 and 20 IU/litre. 3. A basal E2 over about 50 pg/ml predicts poor ovarian reserve. 4. Age remains an important factor even when the FSH and E2 levels are known. 5. Optimal prediction involves simultaneous consideration of age, FSH, LH and E2. 6. Provocative tests of ovarian reserve are probably superior but are not as simple as static tests. 7. Defined risks of multiple pregnancy can be controlled by adjusting the number of pre-embryos transferred according to age and FSH levels. 8. Cases of otherwise unexplained infertility may be uncovered by evaluating basal FSH and E2 levels.

Adult↗
PubMed2006

Basal FSH concentration as a predictor of IVF outcome in older women undergoing stimulation with GnRH antagonist.

The aim of this study was to determine the value of basal FSH as a predictor of assisted reproduction outcome in women >or=35 years undergoing ovarian stimulation with gonadotrophin-releasing hormone (GnRH) antagonist. A retrospective clinical study was carried out on 83 infertile women, 35-45 years old, divided into three groups according to their day 3 FSH concentration (group A = FSH 10 and <15 mIU/ml, group C = FSH >15 mIU/ml). Patients underwent ovarian stimulation with a GnRH-antagonist protocol. Group A women had significantly higher basal inhibin B concentrations (P < 0.001), lower cancellation rate (P < 0.001), required a significantly lower dosage of recombinant FSH (P < 0.0001) and had significantly higher oestradiol concentration under stimulation compared with the other groups (P < 0.0001). Oocyte and embryo numbers were comparable in all groups, although groups B and C had more low quality embryos compared with group A. The number of metaphase II oocytes and embryos was related to patients' ovarian reserve markers only in group C. Pregnancy and delivery rates were 35 and 22.5% in group A, 22.2 and 16.6% in group B and 5 and 0% in group C. It is concluded that a basal FSH cut-off of 10 mIU/ml seems predictive of ovarian reserve, while basal FSH cut-off of 15 mIU/ml seems predictive of pregnancy potential and probably of oocyte quality.

Adult↗
PubMed2006

The importance of consistent FSH delivery in infertility treatment.

The use of gonadotrophins for the treatment of infertility began in the 1930s following early work on the pituitary-ovarian axis and the discovery of FSH and LH. The technological development of pharmaceutical gonadotrophins over the last 60 years has shown improvements in specific activity, purity, degradation and detection of impurities. Throughout these pharmaceutical developments the gonadotrophin content of both urinary and recombinant preparations has been assessed using an animal in-vivo bioassay. This paper reviews the manufacturing history of recombinant human FSH (r-FSH) and follitropin-alfa filled-by-mass (FbM), and evaluates the impact of introducing a pharmaceutical product that is formulated and assayed by a physicochemical method for r-FSH protein content. This consistent gonadotrophin preparation offers the opportunity to reconsider protocols of induction in a new light, deciding the daily amount of r-FSH in relation to specific clinical parameters such as the mean ovarian volume (MOV), basal FSH concentration and body mass index (BMI). Preliminary data on the application of the formula 'basal FSH x BMI/MOV x (5.5/75)' gave interesting results as a new method to standardize the induction therapy. A formula is proposed for deciding the first 5 days of drug administration.

Animals↗
PubMed2000

The in vitro inhibitory action of antiprogestin RU486 on LH and FSH secretion in the absence of progesterone in rats is estrogen-dependent.

Previous in vivo findings show that in the virtual absence of progesterone (P), the antiprogestin RU486 reduces LH and FSH secretion in proestrous rats, indicating that activation of P receptor (PR) can occur in the absence of the cognate ligand. The present study investigates, in vitro, whether or not the inhibitory effect of antiprogestin RU486 on gonadotropin secretion in the absence of P is estrous cycle dependent, and whether its specific expression in proestrus mirrors the high estrogen (E2) background. In the first experiment we investigated the effect of RU486 (10 nM) and/or LHRH (10 nM) on LH and FSH secretion in incubated pituitaries collected on each day of the estrous cycle of the rat. In the second experiment, we determined the effect of RU486 and/or LHRH on preovulatory LH and FSH release by pituitaries from female rats that were ovariectomized (OVX), treated with the antiestrogen LY117018-HCL (Eli Lilly & Co.), or injected with 20 micrograms of estradiol benzoate (EB). The third experiment investigated the effect of RU486 and/or LHRH on LH and FSH release by pituitaries collected from intact or EB-treated (0.1 mg/kg over three consecutive days) male rats. RU486 reduced both basal and LHRH-stimulated LH and FSH secretion in proestrous pituitaries from normal 4-day cyclic rats. By contrast, in diestrous pituitaries, RU486 increased both parameters of LH secretion but was without effect on FSH release. RU486 was also without effect in pituitaries collected from rats in estrus or metestrus, or from OVX or antiestrogen-treated rats. Moreover, EB injection or treatment induced the full inhibitory effect of RU486 in pituitaries from female and male rats, respectively. The above results suggested that P occupancy of the receptor is not required for the formation or function of the active receptor and hence for preovulatory LH and FSH secretion, and that this form of PR activation at pituitary level is E2-dependent and not genetically determined.

Animals↗
PubMed2002

Induction of transferrin secretion in murine Sertoli cells by FSH and IL-1: the possibility of different mechanism(s) of regulation.

In the present study we examined the capacity of interleukin-1 (IL-1) alpha, beta, interleukin-1 receptor antagonist (IL-1ra) and follicle stimulating hormone (FSH) to induce transferrin secretion by Sertoli cells under in vitro conditions. Primary Sertoli cell (SC) cultures from immature mice secreted constitutively transferrin. Stimulation of these cultures with IL-1alpha, IL-1beta significantly increas\d their capacity to secrete transferrin. Addition of IL-1ra to unstimulated SC cultures did not affect their capacity to secrete transferrin. Stimulation of SC cultures with a combination of both IL-1alpha and FSH or IL-1beta and FSH showed additive effect between IL-1 and FSH in their capacity to induce transferrin secretion by these cells. However, stimulation of Sertoli cells with a combination of both IL-1ra and FSH did not affect their capacity to secrete transferrin compared with FSH-stimulated cultures. Our results may suggest the involvement of testicular paracrine/autocrine factors (IL-1) and endocrine (FSH) factors in the regulation of transferrin secretion by SC. This capacity seems to be differently regulated by these factors. Thus, IL-1alpha and beta may directly affect physiological functions of the testis; which may suggest their involvement in the regulation of spermatogenesis and spermiogenesis processes and male fertility.

Animals↗
PubMedDate not supplied

Pituitary FSH is released by a heterodimer of the beta-subunits from the two forms of inhibin.

Inhibin is a gonadal protein that specifically inhibits the secretion of pituitary follicle-stimulating hormone (FSH). Two forms of inhibin (A and B) have been purified from porcine follicular fluid and characterized as heterodimers of relative molecular mass (Mr) 32,000 (ref. 2). Each inhibin is comprised of an identical alpha-subunit of Mr 18,000 and a distinct but related beta-subunit of Mr 13,800-14,700 linked by interchain disulphide bond(s). Throughout the purification of inhibins, we consistently observed two fractions which stimulated the secretion of pituitary FSH. We report here the isolation of one of the FSH-releasing proteins; it has a Mr of 24,000 and its N-terminal sequences up to residue 32 are identical to those of each beta-subunit of inhibins A and B. In the presence of reducing agents, SDS-polyacrylamide gel electrophoresis resolves the FSH-releasing substance into two subunits which are identical in their migration behaviour to the reduced beta-subunits of inhibins A and B. Based on the N-terminal sequence data and Mr of the intact and reduced molecules, we propose that the FSH-releasing substance, which is active in picomolar concentrations, is a heterodimeric protein composed of the two beta-subunits of inhibins A and B linked by interchain disulphide bond(s). The structural organization of the FSH-releasing substance is homologous to that of transforming growth factor-beta (TGF-beta), which also possesses FSH-releasing activity in the same bioassay. We suggest that the substance be called activin to signify the fact that it has opposite biological effects to inhibin.

Amino Acid Sequence↗
PubMed2001

In vitro secretion of FSH by cultured clinically nonfunctioning and gonadotroph pituitary adenomas is directly correlated with locally produced levels of activin A.

OBJECTIVE: Expression of mRNAs encoding activin and its antagonists inhibin and follistatin has been described in human pituitary adenomas, including clinically nonfunctioning adenomas (NFAs) and gonadotroph adenomas (Gn-omas). Since many of the NFAs and Gn-omas secrete FSH in vitro, we hypothesized that locally produced activin may stimulate secretion of FSH in these pituitary adenomas. PATIENTS AND METHODS: Pituitary adenoma tissue was obtained from 38 patients diagnosed preoperatively as having NFAs (n = 17), Gn-omas (n = 5), prolactinomas (n = 6) or growth hormone (GH)-producing adenomas (n = 10). Actual protein levels of activin, inhibin, follistatin, FSH and LH were measured in media of these 38 cultured pituitary adenomas. In addition, we investigated correlations between concentrations of these growth factors and hormones in NFAs and Gn-omas. RESULTS: Gn-omas were found to secrete significantly more activin A in their culture medium than PRL- and GH-producing adenomas (P < 0.05). Inhibin A and inhibin B protein levels in culture media were very low. A positive correlation between levels of activin A and FSH (r = 0.56, P < 0.005) was found, while no correlation between activin A and LH could be detected. Furthermore, levels of follistatin were positively correlated with activin A levels (r = 0.73, P < 0.0005). Comparison of the activin A:follistatin ratio with the measured FSH protein levels showed an even stronger relationship (r = 0.79, P < 0.0005). CONCLUSIONS: It is concluded that levels of activin A, follistatin and FSH in media of cultured nonfunctioning adenomas and gonadotroph adenomas are positively correlated. This suggests that these adenomas secrete FSH in response to the relatively high locally produced levels of activin A.

Activins↗
PubMed1996

Effect of CRH on the preovulatory LH and FSH surge in the cyclic rat: a role for arginine vasopressin?

The effect of intracerebroventricular (i.c.v.) injection or infusion of various doses of corticotropin-releasing hormone (CRH) on the LH and FSH surge was studied in pro-oestrous rats supplied with a jugular vein and an i.c.v. cannula. Additionally, we investigated if arginine vasopressin (AVP) was involved in the CRH-induced alterations to the surge of gonadotropins. I.c.v. injection of 10 micrograms CRH given 5 min before the presumed onset of the LH surge caused a strong inhibition of the LH surge and a slight inhibition of the FSH surge. Three to four h after CRH injection, its inhibitory effect diminished. A 6'h i.c.v. infusion of CRH started 1 h before the presumed onset of the LH surge, caused a dose-related inhibition of the LH and FSH surge. Infusion of 1 micrograms/h CRH did not suppress the surge of both hormones while infusion of 5 or 10 micrograms/h CRH inhibited the LH surge. Infusion of 10 micrograms/h CRH caused a strong suppression of plasma LH during the first 3 h of the LH surge. Despite continuation of CRH infusion, the inhibitory effect disappeared and plasma LH increased to similar levels as in controls at corresponding points of time of the LH surge. The FSH surge was also suppressed by infusion of 10 micrograms/h CRH. The surge of LH and FSH was not affected by a 9-h infusion of 10 micrograms/h CRH started 4 h before the presumed onset of the LH surge. This observation also indicates that the inhibitory effect of CRH may last for only 3-4 h. The surge of LH and FSH was not affected by i.c.v. injections of AVP-antiserum. However, pretreatment with AVP-antiserum prolonged the inhibitory effect of CRH on the LH surge. In conclusion, CRH can inhibit the pro-oestrous LH and to a lesser extent the FSH rise for only 3-4 h after the beginning of CRH administration. AVP may play a role in limiting the inhibitory effect of CRH on LH to 3-4 h.

Animals↗
PubMed2007

[Does FSH signaling have a gender?].

FSH is the main endocrine control of mammalian reproduction. FSH triggers somatic cells of the gonads which support germ cells metabolically, i.e. Sertoli cells of the seminiferous tubules, and granulosa cells harboring the oocyte, within the ovarian follicle. FSH leads to similar biological responses in both cell types since it stimulates proliferation and differentiation, according to the developmental stage. However, FSH receptor knock-out female mice are infertile, unlike male mice. Hence, FSH is not equally important in both sexes. Nevertheless, does FSH induce distinct signalling mechanisms in its target cells ? Here, we compare the signalling mechanisms induced by FSH in ovarian and testicular physiology.

Amino Acid Substitution↗
PubMed1989

Concentrations of FSH are elevated in new-born ewe lambs carrying the Booroola F gene but not in lambs from a prolific Romney strain.

Concentrations of FSH were measured in new-born lambs in Booroola Merino x Romney and Booroola Merino flocks where the Booroola F gene was segregating, and in progeny from sires of a prolific strain of Romney sheep. FSH concentrations increased with age and liveweight in Booroola Merino x Romney ewe lambs to reach peak concentrations at 4-6 weeks of age. Significantly higher mean concentrations were recorded in ewe lambs homozygous for the Booroola gene (FF) compared with non-carrier (+ +) ewe lambs. Concentrations in heterozygous (F+) ewe lambs were intermediate. Maximum differences between the genotypes were recorded at 6 weeks of age. Significantly higher FSH concentrations were also recorded in F-gene-carrier female lambs when compared to non-carriers in two other flocks. FSH concentrations remained low in ram lambs up to 12 weeks of age, and there were no differences between Booroola genotypes. The progeny of one ram from the prolific Romney family had high ovulation rates at 18 months of age. The progeny of other related rams showed no increase in ovulation rates at 18 months of age. Concentrations of FSH in the high-ovulation-rate progeny at 3 and 5 weeks of age did not differ from those in the low-ovulation-rate progeny, but were lower than those in the progeny of an FF Booroola Merino x Romney ram. These results support the hypothesis that neonatal concentrations of FSH are higher in lambs carrying the Booroola F gene, but not in all prolific strains since high FSH concentrations were not recorded in daughters from a prolific Romney flock.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2004

Induction of cyclin D2 in rat granulosa cells requires FSH-dependent relief from FOXO1 repression coupled with positive signals from Smad.

Ovarian follicles undergo exponential growth in response to follicle-stimulating hormone (FSH), largely as a result of the proliferation of granulosa cells (GCs). In vitro under serum-free conditions, rat GCs differentiate in response to FSH but do not proliferate unless activin is also present. In the presence of FSH plus activin, GCs exhibit enhanced expression of cyclin D2 as well as inhibin-alpha, aromatase, steroidogenic factor-1 (SF-1), cholesterol side chain (SCC), and epiregulin. In this report we sought to identify the signaling pathways by which FSH and activin promote GC proliferation and differentiation. Our results show that these responses are associated with prolonged Akt phosphorylation relative to time-matched controls and are dependent on phosphatidylinositol 3-kinase (PI 3-kinase) and Smad2/3 signaling, based on the ability of the PI 3-kinase inhibitor LY294002 or infection with adenoviral dominant negative Smad3 (DN-Smad3) mutant to attenuate induction of cyclin D2, inhibin-alpha, aromatase, SCC, SF-1, and epiregulin. The DN-Smad3 mutant also abolished prolonged Akt phosphorylation stimulated by FSH plus activin 24 h post-treatment. Infection with the adenoviral constitutively active forkhead box-containing protein, O subfamily (FOXO)1 mutant suppressed induction of cyclin D2, aromatase, inhibin-alpha, SF-1, and epiregulin. Transient transfections of GCs with constitutively active FOXO1 mutant also suppressed cyclin D2, inhibin-alpha, and epiregulin promoter-reporter activities. Chromatin immunoprecipitation results demonstrate in vivo the association of FOXO1 with the cyclin D2 promoter in untreated GCs and release of FOXO1 from the cyclin D2 promoter upon addition of FSH plus activin. These results suggest that proliferation and differentiation of GCs in response to FSH plus activin requires both removal of FOXO1-dependent repression and positive signaling from Smad2/3.

Activins↗
PubMed2000

Ovarian antibodies, FSH and inhibin B: independent markers associated with unexplained infertility.

Premature menopause and unexplained infertility are associated with ovarian antibodies, a marker of ovarian autoimmunity. In premature menopause, FSH is also elevated while in unexplained infertility FSH concentrations are often normal. The relationship of ovarian antibodies and FSH and inhibin B, as markers of follicle function, was investigated in unexplained infertility. Ovarian antibodies were determined by immunoassay in comparison to normal controls (n = 12); 51.9% were positive at two SD (P < 0.05) and 38.5% were positive at three SD above the control mean (P < 0.01). In this study three SD above the control mean was considered positive. In unexplained infertility, three out of 10 (30%) had elevated day 3 FSH (>10 mIU/ml) and ovarian antibodies, while 17/42 (40%) had normal FSH (<10 mIU/ml) and ovarian antibodies. In women with normal FSH, two out of seven (29%) had low inhibin B concentrations (<33 pg/ml) and ovarian antibodies, and 15/35 (43%) had normal inhibin B concentrations (> 33 pg/ml) and ovarian antibodies. Similarly, when women with and without ovarian antibodies were compared there was no difference in mean FSH or mean inhibin B concentrations. Thus, unlike other endocrine autoimmune disorders, hormone concentrations are not predictors of potential ovarian autoimmunity. This suggests that in unexplained infertility ovarian antibodies are an independent marker of potential ovarian failure, and may precede changes in regulatory hormones.

Adult↗
PubMed2001

Low-dose exogenous FSH initiated during the early, mid or late follicular phase can induce multiple dominant follicle development.

This prospective, randomized trial in normo-ovulatory women was designed to test whether administration of low-dose exogenous FSH initiated during the early, mid to late follicular phase can induce multiple dominant follicle development. Forty normal weight women (age 19-35 years, cycle length 25-32 days) participated. A fixed dose (75 IU/day) of recombinant FSH was started on either cycle day 3 (n = 13), 5 (n = 13) or 7 (n = 14) until the induction of ovulation with human chorionic gonadotrophin. Frequent transvaginal ultrasound scans and blood sampling were performed. Multifollicular growth occurred in all groups (overall in 60%), although day 7 starters showed less multifollicular growth. Age, cycle length and initial FSH and inhibin B concentrations were similar between subjects with single or multiple follicle development. However, for all women the lower the body mass index (BMI), the more follicles emerged (r = -0.44, P = 0.007). If multifollicular growth occurred, the length of the luteal phase was reduced (P = 0.002) and midluteal serum concentrations of LH (P = 0.03) and FSH (P = 0.004) were decreased and oestradiol (P = 0.002) and inhibin A (P = 0.01) were increased. In conclusion, interference with decremental serum FSH concentrations by administration of low dose FSH starting on cycle day 3, 5 or as late as day 7, is capable of disrupting single dominant follicle selection. The role of BMI in determining ovarian response suggests that differences in pharmacokinetics of exogenous FSH are involved. Multifollicular growth per se has a distinct effect on luteal phase characteristics. These observations may be relevant for the design of mild ovarian stimulation protocols.

Adult↗
PubMed2002

A moderately elevated day 3 FSH concentration has limited predictive value, especially in younger women.

BACKGROUND: A cycle day 3 FSH concentration is a popular screening tool for predicting success in achieving pregnancy after IVF. Difficulties interpreting this test have resulted from lack of consensus in defining an elevated FSH concentration, a change in the assays, and lack of controlling for factors which may confound the association between FSH concentration and pregnancy. METHODS: Assessment was made of the ability of a moderately elevated (10-11.4 mIU/ml, World Health Organization 2nd International Standard (IRP 78/549) and elevated FSH (>11.4 mIU/ml, conversion factor to SI units, 1.00) in predicting ability to achieve pregnancy through IVF and embryo transfer, both independently, and after controlling for confounding variables such as age, diagnosis, and response to gonadotrophins. RESULTS: A total of 293 IVF cycles were retrospectively reviewed. An FSH (>11.4) was strongly associated with inability to achieve pregnancy after IVF both independently (P < 0.01) and after multivariate analysis (P < 0.01), and had a strong predictive value (100%). A moderately elevated FSH (10-11.4) was not statistically associated with pregnancy outcome either independently or after multivariate analysis, and had a low predictive value (71%). CONCLUSIONS: Much of the predictive value of an elevated FSH is confounded by poor response to gonadotrophin stimulation, which may be overcome in younger women.

Adult↗
PubMed2002

Biological versus chronological ageing of oocytes, distinguishable by raised FSH levels in relation to the success of IVF treatment.

BACKGROUND: The present study addresses the issue of biological ageing of the oocyte (as indicated by basal serum FSH levels) versus chronological ageing. METHODS: 1019 infertile but ovulating women were studied in their first cycle of IVF treatment. A series of logistic regression models were developed to assess statistical significance of effects of age and FSH on implantation rates and live babies born. RESULTS: The number of oocytes retrieved and embryos available for transfer declined with increasing age and basal serum FSH concentrations. Fertilizing ability of oocytes increased with advancing age but was not affected by FSH concentrations. Although the number of oocytes or embryos available for transfer had no independent effect on implantation rates, the implanting ability of fertilized oocytes (embryos) was inversely related to increasing age and independently to FSH. The chance of a baby being born, however, was determined more by age than by serum FSH. CONCLUSIONS: Ovarian ageing affecting oocyte quality and fecundity can occur independently of chronological age. This has important practical implications whereby serum basal FSH measurement may be a valuable prognostic index, though chronological age remains important.

Adult↗
PubMed2003

Poor response to ovulation induction is a stronger predictor of early menopause than elevated basal FSH: a life table analysis.

BACKGROUND: During the course of assisted reproduction treatment, a number of women exhibit a "poor response" to ovulation induction, or demonstrate an elevated basal FSH level (> or =10 IU/l) at a young age. We sought to determine whether these women are at increased risk of early menopause and poor reproductive performance. METHODS: A retrospective cohort study included 118 "poor responders" with normal basal FSH level (<10 IU/l), 164 women with raised basal FSH (> or =10 IU/l), and 265 controls, who underwent assisted reproduction treatment between 1987 and 1998. All women were < 40 years of age at the time of treatment and had normal menstrual cycles. Participants were sent a postal questionnaire in 2000-2001, seeking information on ovarian function and reproductive performance following cessation of treatment. RESULTS: After adjusting for age and smoking habits, women with poor response and raised basal FSH levels were more likely to experience symptoms of the peri-menopause [hazard ratios 2.4, 95% confidence interval (CI) 1.52-3.78, and 2.76, 95% CI 1.78-4.29 respectively, P = 0.0001]. Poor responders were six times and 23 times more likely to experience the menopause within 10 years of treatment than those with raised basal FSH levels and controls respectively (hazard ratio 5.97 and 23.9, P = 0.015 and 0.002 respectively). Poor responders and those with raised basal FSH levels have half the chance of spontaneous conception after discontinuation of treatment compared with controls (P < 0.007). CONCLUSIONS: Both poor response to ovarian stimulation and raised basal FSH are markers of reduced ovarian reserve and predict an increased risk of early menopause.

Adult↗
PubMed2004

Sex differences in FSH-regulatory peptides in pubertal age boys and girls and effects of sex steroid treatment.

BACKGROUND: FSH concentrations are higher in girls than in boys before puberty. We hypothesized that steroid-mediated changes in FSH-regulatory proteins underlie the sex differences in FSH secretion and pubertal timing. METHODS: FSH-regulatory proteins, LH, FSH and sex steroids were measured in five boys, 10 girls, and five girls with Turner syndrome before and during sex steroid treatment (girls, 0.05 mg/day estradiol; boys, 5 mg/day testosterone) for up to 4 weeks. Blood was obtained every 15 min from 20.00 to 08.00 h before and during sex steroid treatment. RESULTS: The mean FSH concentration was higher in girls than in boys (P = 0.0044). Activin-A concentrations were greater (P < 0.0001) and inhibin-B concentrations lower (P < 0.0001) in girls compared with boys. Steroid treatment (i) suppressed LH/FSH concentrations in all subjects; (ii) increased the mean activin-A concentration in all but the Turner girls (P = 0.001); and (iii) decreased inhibin-B concentrations in boys (P = 0.005) but not in girls. Total follistatin and follistatin 288 concentrations did not differ by sex. CONCLUSIONS: Sex steroids regulate circulating activin-A and inhibin-B concentrations in children. The lower inhibin-B and higher activin-A concentrations may explain the higher FSH and earlier onset of puberty in girls.

Activins↗
PubMed2004

Mouse oocyte meiotic resumption and polar body extrusion in vitro are differentially influenced by FSH, epidermal growth factor and meiosis-activating sterol.

BACKGROUND: In this study, we compared the relative ability of FSH (100 mIU/ml), epidermal growth factor (EGF) (10 ng/ml), and follicular-fluid meiosis-activating sterol (FF-MAS, 10 micromol/l) to induce meiotic resumption and polar body I (PBI) extrusion in mouse oocytes. METHODS: Cumulus-enclosed oocytes (CEO) were co-incubated with meiosis-arresting agents, including 4 mmol/l hypoxanthine (Hx), 0.3 mmol/l dibutyryl cAMP (dbcAMP), and 8.5 micromol/l cilostamide, a selective inhibitor of the oocyte-specific phosphodiesterase 3 (PDE 3). RESULTS: In Hx-treated oocytes, FSH, EGF and FF-MAS induced meiosis resumption at very high rates, but only FSH and EGF also promoted PBI extrusion with high frequency. In experiments conducted in the presence of dbcAMP, FF-MAS was unable to promote an increase in germinal vesicle breakdown (GVBD) rate, whereas FSH and EGF generated a response similar to the Hx groups. Neither FSH, EGF nor FF-MAS caused any change in the meiotic status of CEO when meiotic arrest at the germinal vesicle (GV) stage was maintained by cilostamide. In the presence of Hx, naked oocytes (NkO) co-cultured with their cumulus cells were able to respond to the GVBD-inducing effect of FSH and EGF by resuming meiosis at high rate. CONCLUSIONS: Collectively, these results indicate that: (i) a signal triggered in cumulus cells by either FSH or EGF, but not necessarily coincident with FF-MAS, may contribute to meiotic maturation, supporting GVBD and extrusion of PBI; (ii) the transmission of this signal can occur in a paracrine fashion, at least with reference to the breakdown of the GV. It also appears that concomitant regulation of intra-oocyte cAMP degradation is a prerequisite for meiosis resumption.

Animals↗