Administration Of Follicle-stimulating Hormone Research Articles

Transcriptomic signature of the follicular somatic compartment surrounding an oocyte with high developmental competence

During antral folliculogenesis, developmental competence of prospective oocytes is regulated in large part by the follicular somatic component to prepare the oocyte for the final stage of maturation and subsequent embryo development. The underlying molecular mechanisms are poorly understood. Oocytes reaching the advanced stage of follicular growth by administration of exogenous follicle-stimulating hormone (FSH) possess higher developmental competence than oocytes in FSH-untreated smaller follicles. In this study, the transcriptomic profile of the cumulus cells from cows receiving FSH administration (FSH-priming) was compared, as a model of high oocyte competence, with that from untreated donor cows (control). Ingenuity Pathway Analysis showed that cumulus cells receiving FSH-priming were rich in down-regulated transcripts associated with cell movement and migration, including the extracellular matrix-related transcripts, probably preventing the disruption of cell-to-cell contacts. Interestingly, the transcriptomic profile of up-regulated genes in the control group was similar to that of granulosa cells from atretic follicles. Interferon regulatory factor 7 was activated as the key upstream regulator of FSH-priming. Thus, acquisition of developmental competence by oocytes can be ensured by the integrity of cumulus cells involved in cell-to-cell communication and cell survival, which may help achieve enhanced oocyte-somatic cell coupling.

Efficacy of Follicle-Stimulating Hormone (FSH) Alone, FSH + Luteinizing Hormone, Human Menopausal Gonadotropin or FSH + Human Chorionic Gonadotropin on Assisted Reproductive Technology Outcomes in the "Personalized" Medicine Era: A Meta-analysis.

Luteinizing hormone (LH) and human chorionic gonadotropin (hCG) act on the same receptor, activating different signal transduction pathways. The role of LH or hCG addition to follicle-stimulating hormone (FSH) as well as menopausal gonadotropins (human menopausal gonadotropin; hMG) in controlled ovarian stimulation (COS) is debated. To compare FSH + LH, or FSH + hCG or hMG vs. FSH alone on COS outcomes. A meta-analysis according to PRISMA statement and Cochrane Collaboration was performed, including prospective, controlled clinical trials published until July 2016, enrolling women treated with FSH alone or combined with other gonadotropins. Trials enrolling women with polycystic ovarian syndrome were excluded (PROSPERO registration no. CRD42016048404). Considering 70 studies, the administration of FSH alone resulted in higher number of oocytes retrieved than FSH + LH or hMG. The MII oocytes number did not change when FSH alone was compared to FSH + LH, FSH + hCG, or hMG. Embryo number and implantation rate were higher when hMG was used instead of FSH alone. Pregnancy rate was significantly higher in FSH + LH-treated group vs. others. Only 12 studies reported live birth rate, not providing protocol-dependent differences. Patients' stratification by GnRH agonist/antagonist identified patient subgroups benefiting from specific drug combinations. In COS, FSH alone results in higher oocyte number. HMG improves the collection of mature oocytes, embryos, and increases implantation rate. On the other hand, LH addition leads to higher pregnancy rate. This study supports the concept of a different clinical action of gonadotropins in COS, reflecting previous in vitro data.

Coasting (withholding gonadotrophins) for preventing ovarian hyperstimulation syndrome.

Coasting (withholding gonadotrophins) for preventing ovarian hyperstimulation syndrome.

Impacts of incorporation of follicle stimulating hormone into an estrous synchronization protocol for timed artificial insemination of crossbred beef cattle

One-hundred-eighty crossbred beef cows and 66 crossbred beef heifers across three locations were stratified by body weight (BW), body condition score (BCS), and age (within location) to evaluate administration of follicle stimulating hormone (FSH) on Day 2 using a modified 7-day CO-Synch plus CIDR® protocol (Day 0=CIDR insertion) with timed-artificial insemination (TAI) at 72h (cows) or 54h (heifers) following CIDR removal. Estrous response following CIDR removal was determined using an Estrotect patch and TAI and final pregnancy rates were determined by transrectal ultrasonography 42–45days following TAI and ≥45days following removal of clean-up bulls. Estrous response rate, TAI and final pregnancy rates for cows were not affected (P≥0.65) by treatment. Cows that exhibited estrus had greater (P<0.01) TAI pregnancy rate (66%) than cows not exhibiting estrus (38%). There was an estrous response by postpartum length interaction (P=0.02) where cows exhibiting estrus and ≥55days postpartum had greater TAI pregnancy rates (75%) compared to cows not exhibiting estrus and <55days postpartum (39%) or ≥55days postpartum (28%). For heifers, timed AI (P=0.46) and final pregnancy rates (P=0.45) were similar across treatments and estrous response had no effect (P=0.30) on TAI pregnancy rates. In conclusion, the addition of FSH to the CO-Synch plus CIDR estrous synchronization protocol did not increase TAI pregnancy rates in beef cows or heifers. However, a positive estrous response to the synchronization protocol was associated with increased TAI pregnancy rates in cows.

Successful Vitrification of In vivo Embryos Collected from Superovulated Japanese Black Cattle (Wagyu).

The aim of this study was to determine whether vitrification is an effective method when used for Japanese Black Cattle (Wagyu) in vivo-derived embryos, collected following a superovulation treatment and embryo transfer (MOET) programme. In vivo-derived morula and blastocysts collected on day 7 after artificial insemination, were vitrified using a modified droplet vitrification (MDV) procedure and subsequently warmed for transfer (ET) into synchronized recipients. Fresh embryos, and embryos cryopreserved using a standardized slow freezing procedure (direct thaw/direct transfer, DT) served as ET controls. Two different follicle-stimulating hormone (FSH) sources, Folltropin(®) Canada (FSH BAH, 24 donors) and a brand prepared by the Chinese Academy of Science (FSH CAS, 16 donors), were compared in a series of superovulation outcomes following well-established FSH administration protocols. Following data analysis, the total number of ovulations recorded at the time of embryo flushing (10.5 vs 8.5; p = 0.28) and the total number of transferable embryos (6.2 vs 5.1; p = 0.52) were similar between the two FSH sources. ET for MDV (39.7%, n = 78), DT (35.2%, n = 71) and fresh controls (47.1%, n = 34) resulted in similar pregnancy rates (p > 0.05). When MDV was used, a higher pregnancy rate (42.6%) resulted from the transfer of vitrified morulae, when compared to the DT counterparts (24.3%), (p = 0.05). Transfer of vitrified morulae resulted also in higher pregnancy rate, when compared to the transfer of vitrified blastocysts (42.6% vs. 29.4%; p < 0.05). Transfer of DT blastocysts resulted in higher pregnancy rate than morulae, similarly cryopreserved (47.1% vs. 24.3%, p < 0.05). In conclusion, MDV is an effective alternative methodology for cryopreservation of in vivo-derived embryos. This study gives also indication that, compared to vitrified blastocysts, MDV of morula stage embryos results in higher pregnancy rates following warming and transfer into synchronized recipients.

Effect of oral administration of low-dose follicle stimulating hormone on hyperandrogenized mice as a model of polycystic ovary syndrome.

BackgroundPolycystic Ovary Syndrome (PCOS) is a widespread reproductive disorder characterized by a disruption of follicular growth and anovulatory infertility. In women with PCOS, follicular growth and ovulation can be induced by subcutaneous injections of low doses of follicle stimulating hormone (FSH). The aim of this study was to determine the effect of oral administration of recombinant human FSH (rhFSH) on follicle development in a PCOS murine model. Moreover, since it is unlikely that intact rhFSH is present into the circulation after oral administration, the biological activity of a peptide fragment, derived from the predicted enzymatic cleavage sites with the FSH molecule, was investigated in vitro on cumulus-enclosed oocytes (COCs).MethodsFemale peripubertal mice were injected with dehydroepiandrosterone (DHEA) diluted in sesame oil for 20 consecutive days and orally treated with a saline solution of rhFSH. A control group received only sesame oil and saline solution. At the end of treatments, blood was analyzed for hormone concentrations and ovaries were processed for morphological analysis. The presumptive bioactive peptide was added during in vitro maturation of bovine COCs and the effects on cumulus expansion and on maturation rate were evaluated.ResultsDHEA treatment increased serum levels of testosterone, estradiol and progesterone as well as the percentage of cystic follicles. Orally administered rhFSH restored estradiol level and reduced the percentage of cystic follicles. Despite these results indicating a reduction of the severity of PCOS in the mouse model, the presumptive bioactive peptide did not mimic the effect of rhFSH and failed to induce bovine cumulus expansion and oocyte maturation in vitro.ConclusionsAlthough further studies are needed, the present data supports the concept that orally administrated FSH could attenuate some of the characteristic of PCOS in the mouse model.Electronic supplementary materialThe online version of this article (doi:10.1186/s13048-015-0192-9) contains supplementary material, which is available to authorized users.

The long-term effects of FSH and triiodothyronine administration during the pubertal period on Connexin 43 expression and spermatogenesis efficiency in adult rats.

Follicle-stimulating hormone (FSH) and triiodothyronine (T3) are known regulatory factors of spermatogenesis initiation. Hyperstimulation of both hormones evokes regressional changes in connexin 43 expression and the seminiferous epithelium in young rats during testicular maturation. However, separate treatments with T3 reduce Sertoli cell number, which seems to be closely connected with the maturation of connexin 43 gap junctions. FSH elevates Sertoli cell number and function, but this effect may take place regardless of the presence of connexin 43-dependent intercellular communication. The aim of the study was to evaluate the later effects of such treatments. Newborn, male Wistar rats were divided randomly into experimental groups receiving daily subcutaneous injections of either 7.5 IU/animal FSH, or 100 mg/kg b.w. T3, or both substances or the same volume of vehicle (control group) until day 15 of life. The animals were sacrificed on day 50. Morphometric analysis and immunohistochemical reactions were performed using antibodies against Vimentin, Proliferating Cell Nuclear Antigen and Connexin 43 in the testis. Sertoli cell count, efficiency of spermatogenesis, and hormonal pattern were examined. Disturbances in the connexin 43 expression reduced the number of Sertoli cells, the efficiency of spermatogenesis and impaired endocrine function of testes in adult rats treated with FSH and T3 during puberty. Stimulation with FSH alone increased Sertoli cell number, but was associated with a negative effect on cell-to-cell connexin 43-dependent communication, with a consequential reduction of spermatogenesis efficiency. J. Exp. Zool. 323A: 256-265, 2015. © 2015 Wiley Periodicals, Inc.

183 ULTRASONOGRAPHIC MONITORING OF CANINE OVARIES CLAMPED AT SUBCUTANEOUS SITE AFTER FOLLICLE-STIMULATING HORMONE TREATMENT

Follicle-stimulating hormone (FSH) alone can induce oestrus in bitches, but few reports describe oestrous induction by FSH because pregnant mare serum gonadotrophin (PMSG) has been more successful than FSH for oestrus induction. Real-time ultrasonography can show canine ovarian follicle development, but no method can determine or predict ovulation accurately. Moreover, the ovary location and size complicate imaging. Using ultrasonography, we investigated FSH treatment stimulation of canine ovary follicles, with clamping of the ovaries at a subcutaneous site. Bilateral malacotomy of four 5-year-old Beagle bitches (mean weight 10.3 ± 2.0 kg) with normal oestrous cycles was done using a ventral flank abdominal approach with routine techniques and materials. Each ovary that maintained blood circulation from the suspensory ligament was clamped at a subcutaneous site through muscles of the abdomen. After about six months of bilateral malacotomy, four bitches at the anestrous (two bitches) and diestrous (two bitches) stages of the oestrous cycle were given 0.5 Armour units of FSH twice daily for 5 days. Examinations with ovarian ultrasonography with 7.5 MHz sector transducer, vaginal cytology, and serum concentrations of progesterone and oestradiol were performed daily from the day before the start of FSH treatment through 7 days after FSH treatment. After 15 days of ovarian examination, each bitch received the same FSH treatment twice continually at 15-day intervals. No serosanguineous vaginal discharge was observed during the ovarian examination. The concentrations of progesterone (&lt;0.045–9.6 ng mL–1) and oestradiol (&lt;9.7–81.4 pg mL–1) varied through all treatments. Comparison of the concentrations of progesterone (&lt;0.045–7.6 ng mL–1) and oestradiol (&lt;9.7–30.3 pg mL–1) at the start of FSH administration in each trial revealed that elevated concentrations of both progesterone and oestradiol were observed in the first treatment in 3 bitches. Regarding the second and third treatments, no elevation of concentration was found for progesterone or oestradiol. A new follicular growth was observed in 1 animal after the third FSH treatment, but no follicular growth was found for the other animals. No correlation was found between follicular development and the profile of either progesterone or oestradiol. Ultrasonography proved that FSH stimulation alone cannot induce follicular growth by a single treatment, but it might increase the levels of progesterone and oestradiol, which are not correlated with follicular development and oestrous cycles at the start of FSH treatment.

Induction of oviposition by the administration of oxytocin in hawksbill turtles.

We set out to develop an oviposition induction technique for captive female hawksbill turtles Eretmochelys imbricata. The infertile eggs of nine females were induced to develop by the administration of follicle-stimulating hormone, after which we investigated the effects of administering oxytocin on oviposition. Seven of the turtles were held in a stationary horizontal position on a retention stand, and then oxytocin was administrated (0.6-0.8 units/kg of body weight; 5 mL). The seven turtles were retained for a mandatory 2 h period after oxytocin administration, and were then returned to the holding tanks. As the control, normal saline (5 mL) was administered to the other two turtles, followed by the administration of oxytocin after 24 h. The eggs in oviducts of all nine turtles were observed by ultrasonography at 24 h after oxytocin administration. The control experiment validated that stationary retention and normal saline administration had no effect on egg oviposition. Eight of the turtles began ovipositing eggs at 17-43 min after oxytocin administration, while one began ovipositing in the holding tank immediately after retention. All turtles finished ovipositing eggs within 24 h of oxytocin administration. This report is the first to demonstrate successful induced oviposition in sea turtles. We suggest that the muscles in the oviducts of hawksbill turtles may respond to relatively lower doses of oxytocin (inducing contractions) compared to land and freshwater turtles (4-40 units/kg) based on existing studies.

Involvement of FoxO1 in the effects of follicle-stimulating hormone on inhibition of apoptosis in mouse granulosa cells.

In mammalian ovaries, follicular atresia occurs periodically and destroys almost all the follicles in the ovary. Follicle-stimulating hormone (FSH) acts as the primary survival factor during follicular atresia by preventing apoptosis in granulosa cells. FoxO1 is a critical factor in promoting follicular atresia and granulosa cell apoptosis. FSH inhibits the induction of FoxO1. In this report, we investigated the role of FSH-FoxO1 pathway in mouse follicular atresia. FSH dampened stress-induced apoptosis and the expression of FoxO1 and pro-apoptosis genes in mouse granulosa cells (MGCs). In contrast, overexpression of FoxO1 inhibited the viability of MGCs and induced the expression of endogenous FoxO1. The signaling cascades involved in regulating FoxO1 activity upon FSH treatment were identified using FSH signaling antagonists. Blocking protein kinase A (PKA), phosphatidylinositol-3 kinase (PI3K) or protein kinase B (AKT) restored the upregulation of FoxO1 and apoptotic signals, which was suppressed by FSH. Moreover, inhibition of PKA or PI3K impaired FSH-induced AKT activity, but inactivation of PI3K or AKT had little effect on PKA activity in the presence of FSH. Correspondingly, constitutive activation of FoxO1 (all three AKT sites were replaced by alanines) also promoted MGC apoptosis despite FSH administration. Furthermore, both luciferase reporter assays and chromatin immunoprecipitation assays showed that FoxO1 directly bound to a FoxO-recognized element site within the FoxO1 promoter and contributed to the regulation of FoxO1 expression in response to FSH. Taken together, we propose a novel model in which FSH downregulates FoxO1-dependent apoptosis in MGCs by coordinating the PKA–PI3K–AKT–FoxO1 axis and FoxO1–FoxO1 positive feedback.

Follicle stimulating hormone (FSH) differentially regulates gene expression through AKT and ERK1/2 activation in human granulosa cells

FSH administration is routine for in vitro fertilization (IVF) patients to promote ovarian follicle development; however, the mechanisms by which FSH promotes follicle development, including granulosa cell differentiation, are not clearly defined. The objective of the study was to gain an understanding of signaling pathways activated by FSH to elicit human granulosa cell differentiation.

Ovulation Induction with Follicle-Stimulating Hormone Administration in Hawksbill TurtlesEretmochelys imbricata

Abstract: To develop ovulation induction techniques, we investigated the effects of follicle- stimulating hormone (FSH) administration on ovulation in captive hawksbill turtles Eretmochelys imbricata. Porcine FSH preparation was administered by intramuscular injection to four hawksbill turtles with fully-developed follicles (21.6–23.8 mm, measured using ultrasonography) in July or August 2009. Blood samples were obtained and subjected to plasma progesterone measurement, and ovaries and oviducts were observed by ultrasonography just before, and 1–6 days after, FSH administration. One day after the administraion, the plasma progesterone concentration significantly increased from the basal level (<0.01–0.3 ng/mL) to 0.8– 5.1 ng/mL and then dropped to nearly the basal level within 2–4 days. The formation of eggshells was observed two days after FSH administration. These data collectively indicate that in hawksbill turtles FSH administration effectively induces ovulation, progesterone secretion, and egg formation.

The effect of exogenous follicle stimulating hormone (FSH) and endogenous plasma leptin concentrations on the pregnancy rate of beef heifers subjected to fixed-timed artificial insemination (FTAI)

In this study, 53 crossbred beef heifers were used to test the hypotheses that administration of exogenous FSH 2 days following CIDR insertion and administration of estradiol would increase the pregnancy rate in heifers synchronized for FTAI and that plasma leptin concentrations in beef heifers would be higher for heifers that became pregnant to FTAI. The heifers used in this study had a median age of 440 days, an average weight of 324kg, an average body condition score of 5.1 and a mean reproductive tract score of 3.1. Heifers were stratified by weight and BCS into two groups and then treatments were randomly allotted to each group: (1) control (n=28) or (2) FSH (n=27). Both groups were administered 200mg estradiol benzoate (EB) and received an intravaginal controlled internal drug-releasing device (CIDR) on day 0. On day 2, females in the FSH treatment group were administered 20mg of FSH, while the control group received 1ml of saline. On day 7 all females were administered 25μg PGF2α and the CIDR was removed. Then 24h following CIDR removal all females were administered 1mg EB and 24h later were subjected to FTAI. Pregnancy diagnosis was performed via transrectal ultrasonography 43 days following insemination. Blood samples were collected via jugular venipuncture on days 2, 6–10, 13 and 52 and plasma leptin concentrations were determined by radioimmunoassay. Pregnancy rates were higher (P=0.01) for FSH-treated females (60%) compared with females not receiving FSH (25%). Circulating plasma leptin concentrations were higher (P=0.0051) for pregnant females compared with females that did not become pregnant following FTAI during the experiment. Mean plasma leptin concentration was also higher (P=0.04) from day 2 to day 9 during the synchronization protocol in heifers that became pregnant compared with heifers that did not become pregnant from FTAI. There was no difference (P=0.38) in reproductive tract scores for heifers that became pregnant compared with heifers that did not become pregnant from FTAI. Circulating leptin concentrations were not different (P=0.11) for females receiving FSH compared with females in the non FSH-treated group. Circulating leptin concentrations were affected by sampling day (P<0.0001). However, there was no interaction between sampling day and pregnancy status (P=0.80), treatment and pregnancy status (P=0.14) or treatment and sampling day (P=0.12). These results indicate that the administration of FSH on day 2 of the synchronization protocol may increase pregnancy rates in beef heifers and that increased circulating concentrations of plasma leptin during the synchronization protocol may be indicative of subsequent pregnancy outcome.

Improvement of Superovulatory Response and Pregnancy Rate after Transfer of Embryos Recovered from Japanese Black Cows Fed Rumen Bypass Polyunsaturated Fatty Acids

ABSTRACTFeeding rumen bypass polyunsaturated fatty acids (PUFA) affects to Japanese Black cows affects their reproduction, though its influence on superovulatory response in donor cows and conception in recipient cattle has not been well studied. Here, we investigated the effects of feeding PUFA to Japanese Black cows on blood biochemistry, the numbers of ova and embryos or transferable embryos and pregnancy rate following embryo transfer (ET) to recipient Holstein heifers. PUFA (40% linoleic acid) was fed at 300 g/day in the experimental group from the last day of estrus until the day of artificial insemination for superovulatory treatment. Blood was collected on the first day of follicle-stimulating hormone administration. Total cholesterol level was significantly higher in the 15- to 19-day feeding group (117.4 mg/dl) than in the control group (95.0 mg/dl). The numbers of ova and embryos or transferable embryos were significantly higher in the 15- to 19-day feeding group than in the control group. The numbers of transferable embryos in the 15- to 19-day feeding group were significantly higher than in the 10- to 14-day feeding group. The pregnancy rate at day 60 was significantly higher in the experimental group (66.7 and 57.1%) than in the control group (51.1 and 44.0%) after transfer of fresh and frozen-thawed embryos, respectively. In conclusion, the numbers of ova and embryos or transferable embryos after superovulatory treatment increased, and the pregnancy rate after ET was higher in Japanese Black cows fed PUFA than in the control group.

Superstimulation of follicular growth in Thai native heifers by a single administration of follicle stimulating hormone dissolved in polyvinylpyrrolidone.

This study was undertaken to determine whether a single i.m. injection of FSH dissolved in 10 ml of 30% (wt/vol) polyvinylpyrrolidone (PVP; MW=40,000) to form FSHp would induce follicular growth in Thai native heifers and to determine its optimal dose. In Group 1, heifers (n=4) were given multiple i.m. injections of FSHp every 12 h for 3 days at decreasing doses, for a total of 100 mg (control). In Groups 2, 3 and 4, heifers (n=4 in each group) were given single i.m. injections of FSHp at 50, 100 and 150 mg. All heifers received a single injection of 750 µg PGF2α 48 h after the initiation of exogenous FSH treatment. Ovaries of treated heifers were examined by transrectal ultrasonography every day until they showed estrus. Group 3 showed significantly higher numbers of ovulation follicles, significantly higher growth rates of follicles per day and significantly larger diameters of follicles and corpora lutea than groups 1 and 2 but not Group 4 (P<0.05). Group 4 showed significantly higher numbers of large follicles (≥5 mm in diameter), unovulated follicles and ovulations, a significantly higher growth rate of follicles per day, and significantly larger diameters of follicles and corpora lutea (P<0.05) than those of the other groups. This indicates a state of overstimulation of ovaries in this group. Besides, the plasma levels of FSH in Group 4 were significantly higher (P<0.05) than in the other group and were maintained in the range of 2.2–0.7 ng/ml over a period of 6 to 66 h after the FSHp injection. Meanwhile, the plasma levels of P4 and E2 did not differ in any of the groups in the period of 0 to 96 h during the superstimulation program. In conclusion, it was demonstrated that a single i.m. injection of 100 mg FSHp was the most effective dose for superstimulation of follicular growth in Thai native heifers under the experimental conditions in this study.

Follicle-stimulating hormone treatment in normogonadotropic infertile men

Several empirical treatments have been proposed to treat idiopathic infertility in men, including follicle-stimulating hormone (FSH). FSH administration is effective in patients with hypogonadotropic hypogonadism, which suggests it might be useful in patients with oligozoospermia who have normal FSH levels. Indeed, many studies have evaluated the efficacy of FSH administration in these patients, several of which have shown improvements in sperm parameters. By contrast, other studies have not reported any significant effect of FSH administration on conventional sperm parameters, although some of have reported the normalization of spermatozoon ultrastructural morphology, as well as reductions in DNA fragmentation, production of reactive oxygen species and aneuploidy. Contemporary studies suggest that the response to FSH treatment in oligozoospermic patients might, at least partially, reflect polymorphisms of the FSH receptor gene. Thus, FSH administration in oligozoospermic men with normal serum FSH levels might be efficacious only in selected patients. For this reason, additional studies are needed to determine the predictive factors and clinical conditions that can be used to identify patients who could benefit from FSH treatment.

The pattern of cervical penetration and the effect of topical treatment with prostaglandin and/or FSH and oxytocin on the depth of cervical penetration in the ewe during the peri-ovulatory period

Artificial insemination in sheep has two major limiting factors: the poor quality of frozen-thawed ram semen and the convoluted anatomy of the sheep cervix that does not allow transcervical passage of an inseminating catheter. It has been demonstrated that in the ewe during estrus, there is a degree of cervical relaxation mediated by ovarian and possibly gonadotrohic hormones, and we set out to investigate factors that might enhance cervical relaxation. Five experiments were conducted on ewes of different breeds to determine: 1) the pattern of cervical penetration during the periovulatory period in ewes of several breeds (Welsh Mountain, Île-de-France, Vendéenne, Romanov and Sarda); 2) the effect of the “ram effect” a socio-sexual stimulus, on cervical penetration; and 3) the effects of the intracervical administration of follicle-stimulating hormone (FSH), oxytocin and a prostaglandin E agonist (misoprostol) on the depth of cervical penetration during the periovulatory period. The results showed that during the periovulatory period in all breeds examined, there was increased penetration of the cervical canal (P < 0.05) by an inseminating catheter. Cervical penetration increased to a maximum 54 h after the removal of progestagen sponges and then gradually declined. Furthermore, the depth of cervical penetration but not its pattern, was affected (P < 0.05) by the breed of ewe. The maximum depth of cervical penetration was lower (P < 0.05) in the Vendéenne breed compared to the Île-de-France and Romanov breeds, which did not differ from one another. In the presence of rams, the depth of cervical penetration was increased at 48 and 54 h after removal of sponges (P < 0.05) and reduced at 72 h (P < 0.05). The local administration of hormones FSH, misoprostol (a PGE agonist) and oxytocin alone and in various combinations did not have any significant effect on the depth of cervical penetration during the periovulatory period. In conclusion, the natural relaxation of the cervix observed in ewes of several breeds occurs at a time during estrus, 54 h after the removal of progestagen sponges, which is the most suitable for artificial insemination. The effect was enhanced by the presence of a ram but not by the local intracervical administration of FSH, misoprostol and oxytocin even though oxytocin and PGE2 are involved in cervical function. The time of maximum cervical penetration in the preovulatory period (54 h) coincides with high LH and estradiol concentrations suggesting they might be responsible for the relaxation of the cervix probably through an oxytocin-PGE mediated pathway.

Frequent polymorphisms of FSH receptor do not influence antral follicle responsiveness to follicle-stimulating hormone administration as assessed by the Follicular Output RaTe (FORT)

To verify whether carriers of common single-nucleotide polymorphisms (SNPs) of the FSH receptor (FSHR) show reduced responsiveness of antral follicles to FSH administration as assessed by the FORT. We performed a prospective study in a university hospital. Study population consisted of 124 Caucasian IVF-ET candidates. FSHR 307Ala and 680Ser variants were analyzed in haplotypes and as separated genes. Serum FSH, estradiol (E(2)), and anti-Müllerian hormone (AMH) were measured on cycle-day 3. Antral follicle (3-8 mm) count (AFC) and preovulatory follicle (16-22 mm) count (PFC) were performed, respectively, at the achievement of pituitary suppression (before FSH administration) and on the day of hCG administration. Antral follicle responsiveness to FSH administration assessed by the FORT (PFCx100/AFC). Data concerning baseline and IVF-ET parameters were similar between SNPs carriers and controls. Moreover, FORT was similar for different haplotypes Thr307-Asn680 (45.9%) and Ala307-Ser680 (39.4%) and 307Thr/Ala-Ala/Ala (41.1%; 5.0-91.6%) versus 307Thr/Thr (44.4%; 17.3-83.3%) and in 680Asn/Ser-Ser/Ser (40.0%; 5.0-91.6%) versus 680Asn/Asn (42.2%; 8.3-90.0%) carriers. Antral follicle responsiveness to FSH, as far as measured by the FORT, is not influenced by the presence of SNPs of FSHR 307Ala and 680Ser.

Modeling Follicle Stimulating Hormone Levels in Serum for Controlled Ovarian Hyperstimulation III: Improved Gonadotropin Administration

A numerical model with two pharmacokinetic parameters (the rate of diffusion into the blood (τin) and the rate of disappearance from the blood (τout)) mimicks the slow changes of follicle stimulating hormone (FSH) seen in serum. It is often desired to change serum FSH levels more rapidly. Since the pharmacokinetic parameters cannot be changed in patients, we used the model to investigate changing the amount and timing of gonadotropin administration to change FSH levels in serum more rapidly. Parameters defining the model were obtained as described previously [1]. The doses administered, and the timing of administration were individually specified. The rise of serum FSH was made more rapid by administering an initial injection larger than the subsequent injections. When a rapid decrease of serum FSH was desired, administration of the new, lower dose was delayed. Use of a model that simulates the serum levels of FSH during gonadotropin administration provided a framework for learning how to achieve the desired serum FSH levels more rapidly in patients. With knowledge of a particular patient's τin and τout, optimal FSH administration for that patient can be determined through modeling.

Modeling Follicle Stimulating Hormone Levels in Serum for Controlled Ovarian Hyperstimulation I: Comparing Gonadotropin Products

Despite the dangers of gonadotropin administration, our understanding of serum levels of gonadotropins in our patients is poor. We created a mathematical model of gonadotropin administration in order to learn about the temporal profiles of Follicle Stimulating Hormone (FSH) levels in patients related to the doses of different gonadotropin products administered. Model parameters for each product were determined from published pharmacokinetic information available from the manufacturers. For each product, serum levels of FSH rose then fell following a single injection of FSH. When a gonadotropin dose was injected repeatedly (daily), each injection resulted in a peak level of FSH that was higher than the level attained from the previous injection. Daily FSH peaks rose asymptotically, requiring 3-10 days to approach the maximum. The maximum averaged 3.5 times the peak of the first injection. Decline of FSH following the final injection required 3-10 days to approach the baseline. Time courses and peak values of FSH using different gonadotropin preparations varied widely. Knowledge of the slow changes of FSH that occur during modeled FSH administration will provide a framework for understanding the gonadotropin profiles that occur in patients during controlled ovarian hyperstimulation.