Body Mass Index,Follicle-Stimulating Hormone and Their Predictive Value in In Vitro Fertilization

Purpose: The objective was to explore whether body mass and day 3 follicle-stimulating hormone have predictive value on odds of pregnancy after in vitro fertilisation. Few studies show that obesity produces a variety of alterations in the reproductive system, and that women with an elevation of day 3 FSH have declining ovarian function.Methods: The data of one-hundred-seventy-one women who underwent a standard regime of controlled ovarian hyperstimulation was analyzed with particular reference to variations in body mass and hormone levels.Results: By raising BMI and FSH (mIU/mL) by one unit, the odds for pregnancy were decreased by the respective factors 0.84 (95% confidence interval 0.73–0.97) and 0.77 (95% confidence interval 0.59–1.00).Conclusions: The results demonstrate that for the purpose of raising the odds of pregnancy BMI should be reduced. A low FSH value may cause the same effect. Nontheless, obesity and hormonal function may be independent risk factors for failure in assisted reproduction.     

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.     

Is there a future for ovulation induction in the current era of assisted reproduction?

The clinical use of medical induction of ovulation in normogonadotrophic anovulatory women (WHO II), including polycystic ovary syndrome, is increasingly questioned. However, we believe that this treatment modality still represents a highly effective means of fertility treatment in women with low pregnancy chances without intervention. A conventional treatment algorithm involving clomiphene citrate (CC) followed by FSH induction of ovulation may result in a 71% cumulative singleton live birth rate. In attempts to improve treatment outcome further and reduce complication rates, new compounds such as insulin-sensitizing agents or aromatase inhibitors are currently used increasingly. Approaches such as patient selection for different treatment modalities on the basis of initial screening characteristics and alternative protocols for FSH ovulation induction may also be proposed to render treatment algorithms more patient tailored and therefore improve overall outcomes. More research is needed in this area, rather than referring these patients to assisted reproduction prematurely. This may lead to a more individually tailored approach for ovulation induction in a given patient, resulting in a further improvement of the balance between chances for success versus complications.     

Meta-analysis of recombinant versus urinary-derived FSH: an update

BACKGROUND: The study aim was to analyse the results of randomized controlled trials (RCTs) comparing recombinant FSH and urinary-derived FSH gonadotrophins [hMG, urinary purified FSH (FSH-P) and highly purified FSH (FSH-HP)] in an IVF/ICSI programme. METHODS: All published truly RCTs using a long protocol of GnRH agonists for down-regulation, were reviewed. Data of pregnancy rate per started cycle were extracted, and odds ratios (OR) calculated using a fixed effect model. Subgroup analysis was carried out to compare recombinant FSH (rFSH) with each product (hMG alone, FSH-P alone and FSH-HP alone). RESULTS: There was no statistically significant difference in the pregnancy rate per started cycle between rFSH and urinary-derived FSH gonadotrophins (OR 1.07; 95% CI 0.94-1.22). Subgroup analysis showed no statistically significant difference in the pregnancy rate per started cycle between rFSH versus hMG (OR 0.81; 95% CI 0.63-1.05), rFSH versus FSH-P (OR 1.24; 95% CI 0.98-1.58) and rFSH versus FSH-HP (OR 1.14; 95% CI 0.94-1.40). There was no significant heterogeneity of treatment effect across the trials. CONCLUSIONS: There is no evidence of clinical superiority in clinical pregnancy rate for rFSH over different urinary-derived FSH gonadotrophins. Additional factors should be considered when choosing a gonadotrophin regimen, including the cost, patient acceptability, safety and drug availability.     

Premature luteinization during gonadotropin-releasing hormone antagonist cycles and its relationship with in vitro fertilization outcome

OBJECTIVE: To determine the prevalence and the effect of premature luteinization in GnRH antagonist IVF-ET cycles. DESIGN: Prospective observational study. SETTING: In vitro fertilization-embryo transfer (IVF-ET) program at the Instituto Valenciano de Infertilidad. PATIENT(S): Eighty-one infertile patients undergoing controlled ovarian hyperstimulation with gonadotropins and GnRH antagonist for IVF-ET. INTERVENTION(S): Gonadotropin-releasing hormone (GnRH) antagonist was administered from stimulation day 6. Serum P, E(2), and LH were determined on the day of hCG administration. MAIN OUTCOME MEASURE(S): Cycles were grouped according to serum P level on the day of hCG administration (<1.2 ng/mL or > or =1.2 ng/mL). Clinical pregnancy and implantation rates were determined. RESULT(S): The incidence of premature luteinization was 38.3%. Total recombinant FSH dose and stimulation days differed significantly between the groups. Pregnancy rate (25.8% vs. 54.0%) and implantation rate (13.8% vs. 32.0%) were significantly lower in the premature luteinization group. CONCLUSION(S): Premature luteinization during GnRH antagonist IVF-ET cycles is a frequent event that is associated with lower pregnancy and implantation rates. Progesterone elevations are not related to serum LH levels and may reflect the mature granulosa cell response to high FSH exposure.     

Coordination of early antral follicles by luteal estradiol administration provides a basis for alternative controlled ovarian hyperstimulation regimens

OBJECTIVE: To investigate whether luteal E(2) administration reduces size discrepancies of early antral follicles. DESIGN: Prospective, crossover study. SETTING: ART unit, Clamart, France. PATIENT(S): Sixty women and 120 cycles. INTERVENTION(S): On cycle day 3 (baseline day 3), all women underwent measurements of early antral follicles by ultrasound and serum FSH and ovarian hormones. From day 20 until the next cycle day 2, 30 of them received oral 17beta-E(2), whereas the remaining women served as controls. The day after E(2) discontinuation (E(2) day 3) or on subsequent cycle day 3 (control day 3), participants were reevaluated as on baseline day 3. MAIN OUTCOME MEASURE(S): Magnitude of follicular size discrepancies. RESULT(S): Follicular size discrepancies and follicular diameters were significantly attenuated on E(2) day 3 (3.7 +/- 0.5 mm) as compared with baseline day 3 (4.9 +/- 1.0 mm), but not in controls (5.0 +/- 0.8 vs. 4.9 +/- 0.8 mm). FSH (4.3 +/- 1.9 vs. 7.3 +/- 3.3 mIU/mL) and inhibin B (34 +/- 28 vs. 71 +/- 32 pg/mL) levels were consistently lower on E(2) day 3 than on baseline day 3 but remained unchanged in controls. CONCLUSION(S): Luteal E(2) administration reduces the size and improves the homogeneity of early antral follicles on day 3. This approach may be instrumental in synchronizing follicular development during controlled ovarian hyperstimulation.     

Effect of obesity on recombinant follicle-stimulating hormone absorption: subcutaneous versus intramuscular administration

OBJECTIVE: To determine whether recombinant follicle-stimulating hormone (rFSH) should be administered intramuscularly (i.m.) or subcutaneously (s.c.) to obese women. DESIGN: Randomized, single-center, two-way crossover study. SETTING: Academic clinical research center. SUBJECT(S): Nineteen healthy women of reproductive age with body mass indices of 19.9 kg/m(2)-42.8 kg/m(2). INTERVENTION(S): Leuprolide acetate 3.75 mg i.m. to achieve pituitary down-regulation as determined by serum E(2) levels. Subjects were then given a single dose of 300 IU rFSH either i.m. or s.c.. Multiple blood sampling was performed over the next two weeks, and after retreatment with leuprolide, a second 300 IU rFSH dose was given via the other administration route. MAIN OUTCOME MEASURE(S): Serum samples were analyzed in duplicate for follicle-stimulating hormone (FSH) using a standard radioimmunoassay in a single run. Maximum concentrations (C(max)), times to C(max) (T(max)), and extent of absorption (area under curve [AUC]) with i.m. vs. s.c. administration were compared using paired analysis. RESULT(S): Maximal concentrations were achieved within 24 hours with both s.c. and i.m. routes. No significant differences were found in C(max), T(max), or AUC with s.c. vs. i.m. administration. A decline of AUC occurred among subjects of higher body mass index (BMI) with rFSH given either s.c. or i.m.. Subcutaneous administration achieved AUCs comparable to i.m. administration in both normal-weight and obese subjects. CONCLUSION(S): Our data indicate that the s.c. administration of rFSH is appropriate for women regardless of body mass.     

Role of follicle-stimulating hormone receptor Ser680Asn polymorphism in the efficacy of follicle-stimulating hormone

OBJECTIVE: To evaluate the association between FSH efficacy and FSHR alleles. DESIGN: Retrospective study. SETTING: University-based fertility unit and a private center for biomedical research. PATIENT(S): One hundred two women with ovarian function who were undergoing controlled ovarian stimulation (COS). Women were categorized as poor responders (< or =3 ovarian follicles at the end of the cycle) or normal responders (>3 follicles). INTERVENTION(S): Daily administration of exogenous FSH. MAIN OUTCOME MEASURE(S): Number of good or poor responders. RESULT(S): The allele frequency and genotype distribution of the Ser680Asn marker differed significantly between groups. Cycle cancellations were increased (21%) among women who were homozygous for Ser680 compared with Ser/Asn and Asn/Asn patients, and 36% of poor-responders were homozygous for Ser680. CONCLUSION(S): The results support a role for FSHR gene in COS outcome. However, the weight of this factor is probably low. The Ser680 allele may act in concert with other environmental and genetic factors that contribute to FSH efficacy.     

Pharmacokinetics and pharmacodynamics of single-chain recombinant human follicle-stimulating hormone containing the human chorionic gonadotropin carboxyterminal peptide in the rhesus monkey

Objective: To compare the pharmacokinetics of a long-acting FSH analog containing the hCG-β carboxyterminal peptide (recombinant hFSH–CTP) with native recombinant hFSH and describe the pharmacodynamics of recombinant hFSH–CTP after SC injection in female rhesus monkeys.

Design: Rhesus monkey study.

Setting: Academic research environment.

Animal(s): Ten female rhesus monkeys.

Intervention(s): Recombinant hFSH and recombinant hFSH–CTP were administered via a single SC or IV dose to rhesus monkeys, and serial phlebotomy was performed (n = 2 and N = 4 for SC recombinant hFSH and recombinant hFSH–CTP, respectively; for IV dosing, N = 1 in each group). An additional two monkeys were pretreated with SC ganirelix and received SC recombinant hFSH–CTP after confirmation of pituitary suppression.

Main Outcome Measure(s): Plasma disappearance rate of recombinant hFSH and recombinant hFSH–CTP and serum estradiol levels.

Result(s): The elimination half-life of recombinant hFSH–CTP was twofold and fourfold longer than that for recombinant hFSH after SC and IV dosing, respectively. The absorption half-life was approximately threefold longer for recombinant hFSH–CTP than for recombinant hFSH after SC administration. Recombinant hFSH–CTP stimulates estradiol secretion for 5–7 days after an isolated SC dose.

Conclusion(s): Addition of the hCG-β carboxyterminal peptide to hFSH-β results in an FSH analog with longer absorption and elimination half-lives compared with native hormone. This analog is capable of prolonged ovarian stimulation in rhesus monkeys after an isolated SC injection.