Exogenous human follicle-stimulating hormone (hFSH), either derived from extraction and purification from the urine or obtained by recombinant technology in the form of follitropin α, β and δ (rFSH), has been used for decades in the treatment of infertility. The main applications of FSH treatment in the woman have been, and still are, ovulation induction in oligo-anovulatory subjects, and stimulation of the development of a cohort of follicles in patients undergoing controlled ovarian stimulation (COS) for in vitro fertilization (IVF). In the last years, two biosimilars of follitropin alfa, rFSH compounds structurally and functionally similar to the originator, have been approved and marketed for clinical use in Europe. Moreover, some other rFSH biosimilars are currently under investigation. The objective of this article is to review the available evidences comparing the efficacy, safety, and cost-effectiveness of rFSH follitropin alpha originator with its biosimilars, discussing the clinical trials that allowed biosimilars to get registration and marketing authorization.

The association of recombinant FSH (rFSH) plus recombinant LH (rLH) is currently used for Controlled Ovarian Stimulation (COS) in human IVF, but its efficacy has, to date, not yet been compared to that of human Menopausal Gonadotropin (hMG), the FSH + LH activity-containing urinary drug. Eight hundred forty-eight (848) IVF patients classified as expected “poor” or “normal” responders according to antral follicle count (AFC) and basal (day 3) FSH were treated with rFSH + rLH (2:1 ratio, n = 398, Group A) or hMG (n = 450, Group B). Data were collected under real-life practice circumstances and the pregnancy rate with fresh embryos was calculated by stratifying patients according to the number of retrieved oocytes (1–2, 3–4, 5–6, 7–8, >8). Overall, the pregnancy rate in both groups progressively improved according to the number of oocytes retrieved. When comparing patients within the same subgroup of oocyte yield, Group A and B showed a comparable outcome up to the reported highest yield (>8). When more than 8 oocytes were available, Group A had a significantly better pregnancy rate outcome. Patients’ characteristics did not significantly differ between the two groups and the better outcome in the best responding patients in Group A was confirmed by a multivariable logistic regression analysis, that showed that both the use of rFSH + rLH and the total number of retrieved oocytes increased the probability of pregnancy with odd ratio (OR) of 1.628 and 1.083, respectively. When comparing patients with the same number of retrieved oocytes under real-life circumstances, the association of rFSH + rLH results in a significantly higher pregnancy rate than hMG when more than 8 oocytes are retrieved. The reason(s) for this are unknown, but a more favorable effect on oocyte quality and/or endometrial receptivity could be involved.

Do the mRNA expression levels of zona pellucida (ZP) genes, ZP1, 2, 3 and 4 in oocyte and cumulus cells (CC) reveal relevant information on the oocyte? The ZP mRNA expression in human oocytes is related to oocyte maturity, zona inner layer (IL) retardance and fertilization capacity. ZP structure and birefringence provide useful information on oocyte cytoplasmic maturation, developmental competence for embryonic growth, blastocyst formation and pregnancy. In order to understand the molecular basis of morphological changes in the ZP, in the current study, the polarized light microscopy (PLM) approach was combined with analysis of the expression of the genes encoding ZP1, 2, 3 and 4, both in the oocytes and in the surrounding CC. This is a retrospective study comprising 98 supernumerary human cumulus oocyte complexes (COC) [80 Metaphase II (MII), 10 Metaphase I (MI) and 8 germinal vesicle (GV)] obtained from 39 patients (median age 33.4 years, range 22–42) after controlled ovarian stimulation. Single oocytes and their corresponding CC were analysed. Oocytes were examined using PLM, and quantitative RT-PCR was performed for ZP1, 2, 3 and 4 in these individual oocytes and their CC. Ephrin-B2 (EFNB2) mRNA was measured in CC as a control. Presence of ZP3 protein in CC and oocytes was investigated using immunocytochemistry. Data were analysed using one-parametric and multivariate analysis and were corrected for the potential impact of patient and cycle characteristics. Oocytes contained ZP1/2/3 and 4 mRNA while in CC only ZP3 was quantifiable. Also ZP3 protein was detected in human CC. When comparing mature (MII) and immature oocytes (MI/GV) or their corresponding CC, ZP1/2 and 4 expression was lower in mature oocytes compared to the expression in immature oocytes (all P < 0.05) and ZP3 expression was lower in the CC of mature oocytes compared to the expression in CC of immature oocytes (P < 0.05). This coincided with a significantly smaller IL-ZP area and thickness in mature oocytes than in immature oocytes (all P < 0.05). In mature oocytes, IL-ZP retardance was significantly correlated with the expression of all four ZP mRNAs (all P < 0.05). The oocyte ZP3 expression was the main predictor of the fertilization capacity, next to IL-retardance and IL-thickness. Using stepwise regression analysis, IL-thickness combined with EFNB2 expression in CC and the patient's ovarian response resulted in a noninvasive oocyte fertilization prediction model. Not applicable. This is a retrospective study and the relation of oocyte mRNA levels to fertilization capacity is indirect as oocyte gene expression analysis required lysis of the oocyte. Overall relations between PLM observations, mRNA expression changes and intrinsic oocyte competence were successfully documented. As such PLM and CC gene expression are confirmed as valuable noninvasive techniques to evaluate oocyte competence. This study was funded by University of Torino, Italy, WFWG UZ-Brussel and Agentschap voor Innovatie door Wetenschap en Technologie IWT 110680, Belgium. All authors declare that their participation in the study did not involve actual or potential conflicts of interests.

(1) Background: Several researchers have investigated alternative markers related to ovarian responsiveness in order to better predict IVF outcomes, particularly in advanced reproductive-aged women. The follicular output rate (FORT), the follicle-oocyte index (FOI) and the ovarian sensitivity index (OSI) are among the most promising. However, these three metrics have not been investigated as independent predictors of live birth in women of advanced reproductive age; neither have they been compared to the two ‘component’ characteristics that are used to calculate them. (2) Methods: A logistic regression model containing all relevant predictors of ovarian reserve or response was used to evaluate the potential of FORT, FOI and OSI as predictors of live birth. After, the non-linear associations between FORT, FOI and OSI and the probability of live birth were evaluated. Finally, we fitted multiple logistic regression models to compare whether FORT, FOI and OSI were more informative predictors than their components. (3) Results: 590 couples received a total of 740 IVF cycles, after which, 127 (17.5%) obtained a live birth. None of FORT, FOI and OSI showed a strength of association or a p-value even close to female age (odds ratio for live birth (95% confidence interval) 1.00 (0.99–1.01), 1.00 (0.99–1.01), 0.98 (0.88–1.11) and 0.58 (0.48–0.72), respectively). The three models comparing FORT, FOI and OSI with the number of oocytes retrieved, the AFC, the number of preovulatory follicles and the FSH total dose were not more informative. (4) Conclusions: In a population of women of advanced age with unexplained infertility, none of FORT, FOI and OSI were predictive of live birth or more predictive than the two ‘component’ characteristics that were used to calculate them. We suggest clinicians and researchers still use female age as the most reliable predictor of an IVF treatment.