Objective. This study aims to investigate the effect of combining calcium and vitamin D supplements with metformin on menstrual cycle abnormalities, gonadotropins, and IGF-1 system in vitamin D-deficient/insufficient PCOS women. Study Design. This is a randomized, placebo-controlled clinical trial. Setting. This study was performed in Damascus University of Obstetrics and Gynecology Hospital and Orient Hospital, in Damascus, Syria. Materials and Methods. Forty PCOS women with 25-OH-vitamin D < 30 ng/ml were randomly assigned to take either metformin (1500 mg/daily) plus placebo or metformin (1500 mg/daily) plus calcium (1000 mg/daily) and vitamin D3 (6000 IU/daily) orally for 8 weeks. Serum levels of gonadotropins (luteinizing hormone (LH) and follicle-stimulating hormone (FSH)), insulin-like growth factor-1 (IGF-1), and insulin-like growth factor binding protein-1 (IGFBP-1) were detected at the baseline during the early follicular phase of a spontaneous or induced menstrual cycle and after 8 weeks of intervention (except for the final gonadotropins levels which were assayed from samples obtained during the early follicular phase of a spontaneous menstrual cycle). Results. Thirty-four patients (85%) completed the study. After 8 weeks of intervention, calcium and vitamin D co-supplementation led to a significant increase in 25-OH-vitamin D levels and calcium levels in the supplementation group compared to the other group (change in 25-OH-vitamin D levels: +19.38 ± 7.78 vs +0.11 ± 4.79 ng/ml, respectively; p value=0.0001) (change in calcium levels: +0.83 ± 0.82 vs +0.01 ± 0.86 mg/dl, respectively; p value=0.014). An improvement in menstrual cycle irregularity was detected in 38.5% and 58.8% of patients in metformin-placebo group and metformin-calcium-vitamin D group, respectively; but the change was statistically significant only in the supplementation group (p value=0.002). Nevertheless, the means of changes from baseline in gonadotropins levels (serum levels of LH, FSH, and LH to FSH ratio) and the studied parameters of IGF-1 system (serum levels of IGF-1, IGFBP-1, and IGF-1 to IGFBP-I ratio) did not differ significantly between the two groups. Conclusions. Calcium and vitamin D supplements can support metformin effect on regulation of menstrual cycle irregularity in vitamin D-deficient/insufficient PCOS patients, but this effect is not associated with any significant changes in gonadotropins or IGF-1 system. These results suggest a possible role of calcium and vitamin D supplements in managing PCOS. However, further studies are needed to identify the underlying mechanisms. The Clinical Trial Registration Number is NCT03792984.

Gonadotropin-releasing hormone (GnRH) analogues are commonly used in clinical practice to prevent premature luteinizing hormone (LH) surge during In-Vitro Fertilization/ Intra-Cytoplasmic Sperm Injection (IVF/ICSI) cycles. This review aimed to summarize the available evidence comparing the effects of conventional GnRH antagonist protocols, the most commonly used GnRH antagonist protocols, and GnRH agonist protocols on IVF/ICSI outcomes in women with polycystic ovary syndrome (PCOS). A comprehensive electronic search was carried out in Pubmed, Cochrane CENTRAL, Scopus, Web of Science, CINAHL, TRIP, ClinicalTrials.gov and ISRCTN registry from inception until 24 November 2020 without any language or date restrictions. In addition, reference lists of eligible studies and previous meta-analyses were hand-searched to identify relevant studies. Eligible randomized controlled trials were those designed to compare the effects of conventional GnRH antagonist protocols and GnRH agonist protocols on IVF/ICSI outcomes in PCOS subjects. The Cochrane ROB 2.0 tool was used to assess the risk of bias of each study, and the GRADE assessment was used to evaluate the overall quality of evidence. Data synthesis and analyses were done using Review Manager 5.3 with the assistance of Revman Web. A random-effects model was used for all meta-analysis. Dichotomous outcomes were reported as Relative Risk (RR) and continuous outcomes as Weighted Mean Difference (WMD), both with 95% CIs. The primary outcomes were Live birth rate, Ongoing pregnancy rate, and Ovarian hyperstimulation syndrome (OHSS) rate. Other IVF outcomes were considered secondary outcomes. We included ten studies with 1214 randomized PCOS women. Using GnRH antagonist protocols led to a significantly lower OHSS rate (RR = 0.58; 95% CI: [0.44 to 0.77], P = 0.0002), shorter stimulation duration (WMD = − 0.91; 95% CI: [-1.45 to − 0.37] day, P = 0.0009), lower gonadotropin consumption (WMD = − 221.36; 95% CI: [− 332.28 to − 110.45] IU, P < 0.0001), lower E2 levels on hCG day (WMD = − 259.21; 95% CI: [− 485.81 to − 32.60] pg/ml, P = 0.02), thinner endometrial thickness on hCG day (WMD = − 0.73; 95% CI: [− 1.17 to − 0.29] mm, P = 0.001), and lower number of retrieved oocytes (WMD = − 1.82; 95% CI: [− 3.48 to − 0.15] oocytes, P = 0.03). However, no significant differences in live birth rate, ongoing pregnancy rate, clinical pregnancy rate, multiple pregnancy rate, miscarriage rate and cycle cancellation rate were seen between the GnRH antagonist protocols and the long GnRH agonist one. Although more cycles were cancelled due to poor ovarian response in the GnRH antagonist protocol (RR = 4.63; 95% CI: [1.49 to 14.41], P = 0.008), similar rates of cancellation due to risk of OHSS were noticed in both groups. The differences in IVF/ICSI outcomes may arise from the different patterns of gonadotropins suppression that the GnRH analogues exhibit during the early follicular phase of IVF/ICSI cycles and the divergent direct impacts of these analogues on ovaries and endometrial receptivity. The main evidence limitation was Imprecision. Conventional GnRH antagonist protocols represent a safer and more cost-effective treatment choice for PCOS women undergoing IVF/ICSI cycles than the standard long GnRH agonist protocol without compromising the IVF/ICSI clinical outcomes. The study had no sources of financial support and was prospectively registered at PROSPERO (International Prospective Register of Systematic Reviews) under registration number (CRD42021242476).

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Background Gonadotropin-releasing hormone (GnRH) analogues are commonly used to prevent premature luteinizing hormone (LH) surge during In-Vitro Fertilization/ Intra-Cytoplasmic Sperm Injection (IVF/ICSI) cycles in routine practice. However, it is still unclear whether they have different effects on the follicular microenvironment in normo-ovulatory women. Settings: This study was performed at Orient Hospital, Damascus, Syrian Arab Republic, from December 2019 to August 2021. Methods In this interventional, prospective, parallel, non-randomized, open-label controlled clinical trial, a total of 83 normo-ovulatory women were allocated to take either the long GnRH agonist protocol (n = 50) or the flexible GnRH antagonist protocol (n = 33). The trial was originally designed to be a randomized control trial. However, due to a lack in the drug supply during a certain point of the study duration, we used a non-random study design. Follicular fluid (FF) samples were collected on the retrieval day, and the FF levels of Placental growth factor (PlGF) and Anti-Müllerian hormone (AMH) were measured using ELISA Kits. Before being subjected to ICSI, the mature oocytes from both groups were morphologically assessed under an inverted microscope at 400x magnification. In addition, the embryological and clinical IVF/ICSI outcomes were detected. Results The two groups did not differ significantly in any of the baseline characteristics. The FF PlGF levels were significantly lower, while FFAMH levels were insignificantly higher in the GnRH antagonist group (FF PlGF; GnRH agonist = 140.46 ± 42.46 pg/ml vs. GnRH antagonist = 120.49 ± 35.07 pg/ml; P value = 0.029). (FF AMH; GnRH agonist = 7.40 ± 5.69 ng/ml vs. GnRH antagonist = 8.51 ± 7.93 ng/ml; P value = 0.440). The stimulation duration was significantly shorter in the GnRH antagonist group compared to the long-agonist one (GnRH agonist = 8.28 ± 1.09 days vs. GnRH antagonist = 7.26 ± 0.89 days; P value < 0.001). On the other hand, although the consumed dose of gonadotropin was lower in the antagonist group, the difference between the two groups was not statistically significant (GnRH agonist = 2523.00 ± 1034.11 IUs vs. GnRH antagonist = 2468.18 ± 879.53 IUs; P value = 0.952). However, there were not any significant differences between the two groups in embryological or clinical IVF/ICSI outcomes except for the endometrial thickness, which was thinner in the GnRH antagonist group, and the result almost reached significance level (GnRH agonist = 9.66 ± 1.39 mm vs. GnRH antagonist = 9.03 ± 1.51 mm; P value = 0.058). In addition, the morphological assessment of MII oocytes showed comparable oocytes morphology in both groups. Conclusions Flexible GnRH antagonist protocol and the long GnRH agonist protocol regulate the follicular microenvironment and angiogenesis differently in normo-ovulatory women. However, these differences have no influence on the oocyte’s morphology or the IVF/ICSI outcomes. In addition, although both protocols provide acceptable endometrial thickness, caution should be taken when designing the plans therapy for cases that are considered high risk of developing thin endometrial when stimulated with the flexible GnRH antagonist protocol. Study registration: This trial was prospectively registered at clinicaltrials.gov site under registration number (NCT04724343).