Dose adjustment of follicle-stimulating hormone (FSH) during ovarian stimulation as part of medically-assisted reproduction in clinical studies: a systematic review covering 10 years (2007-2017).

BACKGROUND: Individualization of the follicle-stimulating hormone (FSH) starting dose is considered standard clinical practice during controlled ovarian stimulation (COS) in patients undergoing assisted reproductive technology (ART) treatment. Furthermore, the gonadotropin dose is regularly adjusted during COS to avoid hyper- or hypo-ovarian response, but limited data are currently available to characterize such adjustments. This review describes the frequency and direction (increase/decrease) of recombinant-human FSH (r-hFSH) dose adjustment reported in clinical trials. METHODS: We evaluated the proportion of patients undergoing ART treatment who received ≥ 1 r-hFSH dose adjustments. The inclusion criteria included studies (published Sept 2007 to Sept 2017) in women receiving ART treatment that allowed dose adjustment within the study protocol and that reported ≥ 1 dose adjustments of r-hFSH; studies not allowing/reporting dose adjustment were excluded. Data on study design, dose adjustment and patient characteristics were extracted. Point-incidence estimates were calculated per study and overall based on pooled number of cycles with dose adjustment across studies. The Clopper-Pearson method was used to calculate 95% confidence intervals (CI) for incidence where adjustment occurred in < 10% of patients; otherwise, a normal approximation method was used. RESULTS: Initially, 1409 publications were identified, of which 318 were excluded during initial screening and 1073 were excluded after full text review for not meeting the inclusion criteria. Eighteen studies (6630 cycles) reported dose adjustment: 5/18 studies (1359 cycles) reported data for an unspecified dose adjustment (direction not defined), in 10/18 studies (3952 cycles) dose increases were reported, and in 11/18 studies (5123 cycles) dose decreases were reported. The studies were performed in women with poor, normal and high response, with one study reporting in oocyte donors and one in obese women. The median day that dose adjustment was permitted was Day 6 after the start of treatment. The point estimates for incidence (95% CI) for unspecified dose adjustment, dose increases, and dose decreases were 45.3% (42.7, 48.0), 19.2% (18.0, 20.5), and 9.5% (8.7, 10.3), respectively. CONCLUSIONS: This systematic review highlights that, in studies in which dose adjustment was allowed and reported, the estimated incidence of r-hFSH dose adjustments during ovarian stimulation was up to 45%.

A predictive formula for selecting individual FSH starting dose based on ovarian reserve markers in IVF/ICSI cycles.

BACKGROUND: Although exogenous follicle-stimulating hormone (FSH) has been used for decades and millions of cycles have been performed worldwide until now, criteria for selecting the proper FSH starting dose have not been clearly identified. The aim of this study was to elaborate a formula based on markers of ovarian reserve for the calculation of the appropriate starting dose of FSH. METHODS: A total of 931 patients underwent in vitro fertilization (IVF) treatment using long GnRH agonist protocol was retrospectively identified and reviewed. 673 cases of them with a normal ovarian response (4-14 retrieved oocytes) were used to analysis the predictive formula. All follicles 4-7 mm in diameter were counted in the same day of blood sample in both ovaries using transvaginal ultrasound scan. The modified protocol of each patient was recorded and analyzed in the same center. In another center were the numbers of retrieved oocytes of 750 validated patients recorded and analyzed. RESULTS: A formula model based on age, AMH, and antral follicle count (AFC) was able to accurately predict the ovarian sensitivity and accounted for 57.2% of the variability of ovarian response to FSH. When tested in the same total population used to elaborate the model it predicts a high 46.88% rate of step-down protocol in higher-starting FSH dose group and about 57.92% of patients had their dose step-up modified in lower-starting FSH dose group during their treatment, respectively. And when tested in different population from another center used to elaborate the model it predicts a high 64.40% rate of ≥ 15 retrieved oocytes in higher-starting FSH dose group and about 22.50% of patients had ≤ 7 retrieved oocytes in lower-starting FSH dose group during their treatment, respectively. CONCLUSIONS: In the present study we demonstrated that the individualized FSH starting dose may be calculated on the basis of a woman's age, AMH and AFC. The formula model might be a useful, immediate, and easily applicable tool for clinicians to predict the tailored starting dose of FSH during their daily clinical practice.

Finding a place for corifollitropin within the PIVET FSH dosing algorithms.

PIVET recombinant FSH (rFSH) dosing algorithms have been designed for rFSH injection pens, providing optimal pregnancy and live birth productivity rates whilst minimizing risk and occurrence of ovarian hyperstimulation syndrome (OHSS). Recently, long-acting recombinant gonadotrophin corifollitropin (Elonva) was approved for use in assisted reproduction, and welcomed by patients as the single injection allowed ovarian stimulation over 7 days without need for multiple injections. Consequently, another rFSH dosing algorithm was devised to incorporate Elonva, and these cycles were compared to standard rFSH agents, Gonal-f and Puregon. Initiated Elonva cycles (n = 165) were compared with 972 cycles initiated with standard rFSH. Elonva replaced standard rFSH dosages across the 200-400 IU range, but provided equivalent oocyte retrieval numbers and live birth outcomes. Elonva is considered risky for women whose antral follicle count is ≥20 follicles, and was inadvertently administered contra-protocol in 19 cycles with ≥20 follicles. However, while oocyte retrieval numbers were higher, raising risk for OHSS, no actual cases ensued. Taken together, this indicated that Elonva was equivalent to standard rFSH stimulation, and consequently has been added to the rFSH algorithms for medium to lower antral follicle counts and represented by green colour coding in the existing PIVET algorithmic charts.

High initial FSH dosage reduces the number of available cleavage-stage embryos in a GnRH-antagonist protocol: Real-world data of 8,772 IVF cycles from China.

To evaluate the relationship between the initial follicle stimulating hormone (FSH) dose and the number of available cleavage-stage embryos in in vitro fertilization (IVF) cycles.We included 8772 fresh IVF cycles using a GnRH antagonist protocol at the Genetic and Reproductive Institution of Chongqing, P. R. China, from January 2016 to June 2021.Univariate linear regression was used to evaluate the associations between the initial FSH dosage (≤ 150, 187.5-200, 225, 250, or 300 IU) with the number of available cleavage-stage embryos on day 3. A two-factor linear regression model was applied to calculate the threshold effect of the initial FSH dosage on the number of available cleavage-stage embryos based on a smoothing plot. The initial FSH dose was negatively correlated with the number of available cleavage-stage embryos, independent of female age, body mass index, infertility factors, duration of infertility, anti-Müllerian hormone and basal FSH levels, antral follicle count and the proportions of patients with poor ovarian response or polycystic ovarian syndrome. Using a two-factor linear regression model, we calculated the inflection point to be 200 IU of FSH. The relationship between the initial FSH dose and the number of available cleavage-stage embryos was nonlinear. The initial FSH dose was negatively associated with the number of available cleavage-stage embryos when the initial FSH dose was > 200 IU. Therefore, clinicians should try to avoid unnecessarily increasing the initial FSH dose.

Predictive factors for biochemical pregnancy in intracytoplasmic sperm injection cycles.

The aim of this study was to investigate which factors contribute to the incidence of biochemical pregnancy (BP) in intracytoplasmic sperm injection (ICSI) cycles. This cohort study included cycles performed from June 2010 to September 2016 in a private, university-affiliated IVF centre. Cycles were split into four groups, depending on the pregnancy outcomes: Clinical Pregnancy (CP, n = 903), Biochemical Pregnancy (BP, n = 55), Miscarriage (MI, n = 142) and Negative Pregnancy (NP, n = 2034). The effects of ovarian stimulation, laboratory data and seminal parameters on pregnancy outcomes were evaluated using adjusted general linear models. Discriminant analyses were conducted to construct a model for pregnancy prediction and to establish cut-offs for BP. The total sperm count (p = 0.035), total and progressive sperm motility (p = 0.001 and p = 0.023, respectively), total motile sperm count (TMSC, p = 0.029) and the endometrial thickness (p < 0.001) were lower among BP group cycles. Lower rates of high-quality cleavage-stage embryos were observed in the BP group compared to CP and MI groups (p < 0.001). In discriminant analyses, cut-offs for BP prediction were established for the following factors: endometrial thickness < 11 mm, sperm motility < 55.5% and total dose of follicle-stimulating hormone (FSH)> 2400 IU. The incidence of biochemical pregnancy was four times higher when the aforementioned factors did not meet the defined cut-offs. The combination of suboptimal endometrial development and poor seminal and embryo quality contribute to an increased incidence of biochemical pregnancy in ICSI cycles.