Is the Co-administration of Metformin and Clomiphene Superior to Induce Ovulation in Infertile Patients With Poly Cystic Ovary Syndrome and Confirmed Insulin-Resistance: A Double Blind Randomized Clinical Trial.

Objective: This study aimed to compare the effects of clomiphene citrate (CC) combined with metformin or placebo on infertile patients with poly cystic ovary syndrome (PCOS) and insulin resistance (IR). Materials and methods: We included 151 infertile women with PCOS and IR in a university hospital from November 2015 to April 2022 in this prospective, double-blind, randomized, placebo-controlled trial. Patients were randomized into two groups; group A: received CC plus metformin (n = 76) and group B: received CC plus placebo (n = 75). The ovulation rate was the main outcome measure. Clinical pregnancy, ongoing pregnancy, live birth and abortion rates were secondary outcome measures. Results: There was no remarkable difference in ovulation rate in two groups. Moreover, no significant changes were observed in clinical pregnancy, ongoing pregnancy, live birth and abortion rates between two groups. A larger proportion of women in group A suffered from side effects of metformin (9.3% versus 1.4%; p=0.064), although this was not significant. Conclusion: In IR infertile women with PCOS, metformin pre-treatment did not increase the ovulation, clinical pregnancy and live birth rates in patients on clomiphene citrate.

Luteal Phase Support in Intrauterine Insemination Cycles: A Randomized Clinical Trial of Vaginal Versus Intramuscular Progesterone Administration.

Background: Different progesterone doses and routes are used for luteal phase support in stimulated intrauterine insemination (IUI) cycles, but the optimal supplementation scheme has not yet been determined. Therefore, our aim was to compare the administration of two different doses of vaginal progesterone with two doses of intramuscular (IM) progesterone for luteal phase support in patients undergoing IUI cycles. Methods: In this randomized clinical trial, 312 women with unexplained or malefactor infertility intending to start IUI cycles between April 2015 and January 2018 were included. They were randomized into four groups (n=78/each) including group 1 who received IM progesterone in oil (25 mg daily), group 2 who received IM progesterone in oil (50 mg daily), group 3 who received progesterone suppository (400 mg daily), and group 4 who received progesterone suppository (800 mg daily; 400 mg twice daily). The primary outcome was the clinical pregnancy rate. The ongoing pregnancy rate, abortion rate, and patients' satisfaction, and convenience the secondary outcomes. Results: In our study, the overall clinical and ongoing pregnancy rates per cycle with COS and IUI were 16.02% and 12.8%, respectively. There were no significant differences in clinical pregnancy, ongoing pregnancy, and abortion rates among groups (p=0.84). The overall patients' satisfaction and convenience was significantly higher in the vaginal progesterone suppository groups than the IM progesterone groups (p=0.001). Conclusion: The results of this study showed that vaginal progesterone administration provides a more easy-to-use and convenient method than IM progesterone administration for luteal phase support in IUI cycles with comparable pregnancy rates.

A Novel De Novo Chromosomal Insertion, 46 XX, ins(7:13)(p14; q14.2q21.1) is Related to the Embryo Development Arrest Following Assisted Reproductive Technique.

BACKGROUND: Infertility is a problem affecting a large number of couples in the world. One of the causes of infertility can be chromosomal rearrangements such as insertions. In this case report study, the outcome of two intra-cytoplasmic sperm injection (ICSI) cycles of an infertile woman with de novo chromosomal insertion is explained. CASE PRESENTATION: A couple with a 10-year history of infertility referred to our infertility clinic. The husband had a daughter in his first previous marriage. The wife had a 7 and a 10 year history of infertility in the first and second marriages, respectively. In the first marriage, she reported a history of 2 failed intra-uterine insemination (IUI) cycles. In the second marriage, she had a history of 1 spontaneous abortion at 12 weeks of pregnancy, 4 failed IUI cycles, and 1 failed ICSI cycle. The couple was subjected to ICSI cycles twice and failed due to embryo development arrest. The couple referred for karyotyping. The husband showed a normal male karyotype. In comparison, the wife revealed an abnormal female karyotype with two rearrangements: chromosome 13 with an interstitial deletion between bands q14.2 and q21.1, and a derivative chromosome 7 containing this segment of chromosome 7 as an insertion onto short arm at the p14 position. CONCLUSION: To the best of our knowledge, this is the first report of insertion 46 XX, ins(7:13)(p14; q14.2q21.1) which is associated with the embryo development arrest following assisted reproductive technique.

The State of Peripheral Blood Natural Killer Cells and Cytotoxicity in Women with Recurrent Pregnancy Loss and Unexplained Infertility.

BACKGROUND: The prognostic value of peripheral natural killer (pNK) cells, as a screening test in women with recurrent pregnancy loss (RPL) and unexplained infertility, is still a matter for discussion. The purpose of this study was to compare the percentage of circulating CD56+NK cells, CD69 and perforin markers between women with unexplained infertility and RPL with the healthy control group. MATERIALS AND METHODS: In this case-control study, the percentage of CD56+NK cells and activation markers (CD69 and perforin levels) in the peripheral blood were measured in 25 women with unexplained infertility, 24 women with idiopathic RPL and 26 women from the healthy control group, using specific monoclonal antibodies by flow cytometry. RESULTS: The percentage of CD56+NK cells was significantly higher in patients with infertility in comparison with the healthy control group (P=0.007). There were not significant differences either in the total number of CD56+ cells between the RPL group and the control group (P=0.2) or between the RPL group and the infertile group (P=0.36). The percentage of CD69+ lymphocytes in RPL group was significantly higher than in the infertility group (P=0.004). There was a statistically significant difference in Perforin levels between RLP and control (P=0.001) as well as RPL and infertile (P=0.002) groups. CONCLUSION: An increased percentage of CD56+NK cells in patients with unexplained infertility, an elevated expression of CD69 on NK cells in patients with RPL and infertility and a high level of perforin on CD56+ cells in the RPL group might be considered as immunological risk factors in these women.

Vaginal progesterone on the prevention of preterm birth and neonatal complications in high risk women: A randomized placebo-controlled double-blind study.

BACKGROUND: Preterm birth is the major cause of neonatal mortality and morbidity. OBJECTIVE: The aim of this study was to evaluate the effect of prophylactic vaginal progesterone on decreasing preterm birth rate and neonatal complications in a high-risk population. MATERIALS AND METHODS: A randomized, double-blind, placebo-controlled study was performed on 100 high-risk singleton pregnancies. Vaginal suppository progesterone (400 mg) or placebo was administered daily between 16-22 wks to 36 wks of gestation. Progesterone (n=50) and placebo (n=50) groups were compared for incidence of preterm delivery and neonatal complications. RESULTS: The preterm birth rate was 52%. Preterm birth rate before the 37 wks of gestation (68% vs. 36%: RR=1.89, 95% CI: 1.25-2.86) and also before the 34 wks of gestation (42% vs. 18%: RR=2.33, 95% CI: 1.19-4.58) in placebo group was significantly higher than progesterone group. Our study also showed that the administration of vaginal progesterone was associated with a significant reduction in the risk of birth weight ≤2500 gr, the rates of respiratory distress syndrome (RDS) and admission to the Neonatal Intensive Care Unit (NICU) in the progesterone group when compared with the placebo group. However, there was no significant difference between the two groups in terms of neonatal death, days of admission in NICU, intraventricular hemorrhage and necrotizing enterocolitis. CONCLUSION: Prophylactic vaginal progesterone reduced the rate of preterm delivery, the risk of a birth weight ≤2500 gr, the rates of RDS and admission to NICU in women who were at risk of preterm delivery.

Effects of simvastatin pretreatment on clomiphene response in clomiphene - resistant women with polycystic ovary syndrome.

OBJECTIVE: The aim of this study is to determine if simvastatin pretreatment would change clomiphene response in clomiphene citrate-resistant (CC-R)women with (PCOS). MATERIALS AND METHODS: This quasi experimental study included twenty five clomiphene resistant women with PCOS. All patients received cyclic oral contraceptives pills (OCP) (30µg of ethinyl estradiol and 150µg of desogestrol) from the 5th day of their spontaneous or progesterone (P) induced menstrual cycle; in addition, they received simvastatin (20mg/day) from the first day of cycle for two consecutive months. Then, patients were given 100 mg clomiphene citrate (CC) (Iran Hormone, Iran) for five days starting from day three of their menstrual cycles. The primary outcome measures were ovulation and pregnancy rates. The change in body mass index (BMI), the mean number of follicles ≥ 18 mm, the mean of follicular size and endometrial thickness on the day of human chorionic gonadotropin (HCG) administration were secondary outcome measures. RESULTS: Ovulation occurred in 5 out of 25 (20%) patients, but none of the patients conceived in this study. No important change in BMI was observed after using simvastatin (0.28 + 1.13; p = 0.228). In all patients with ovulation, the number of follicles ≥ 18mm was one. The mean follicular size and endometrial thickness on the day of HCG administration were 19.67 ± 2.04 and 7.00 ± 1.34, respectively. CONCLUSION: In this study, we did not observe the favorable effect on ovulation and pregnancy rates with CC following of simvastatin pretreatment in CC-resistant PCOS women. So, further studies with a larger number of patients, higher doses of CC and more cycles are necessary to make this obvious.

Comparing clomiphen citrate plus HMG with clomiphen citrate plus rFSH in IUI cycles in couples with unexplained or male factor infertility: A prospective randomized study.

BACKGROUND: Different protocols are used for controlled ovarian hyper stimulation (COH), but the optimal method has not yet been determined. OBJECTIVE: The aim of this study was to compare the outcome of controlled ovarian stimulation (COS) using clomiphen citrate (CC) plus HMG versus CC plus rFSH in intra uterine insemination cycles (IUI). MATERIALS AND METHODS: 144 women with unexplained or male factor infertility undergoing IUI cycles were randomized (72 patients in CC plus rFSH group and 72 patients in CC plus HMG group) and included in this single blind study from October 2006 to June 2010. The primary outcomes were clinical and ongoing pregnancy rates. The number of dominant follicles, mean of follicular size, endometrial thickness on the day of HCG administration, total dose of gonadotropins and duration of stimulation with gonadotropins were secondary outcomes. RESULTS: Clinical and ongoing pregnancy rates were not significantly different in the two groups .There was a significant higher multiple pregnancy rate in CC plus rFSH group (33.3%) versus CC plus HMG group (12.5%; p<0.005). There were no statistically significant differences in the secondary outcomes between the two groups. CONCLUSION: According to our results it seems that CC plus HMG is a more suitable and cost-effective regimen than CC plus rFSH in IUI cycles in patients with unexplained or male factor infertility.

Pregnancies following the use of sequential treatment of metformin and incremental doses of letrozole in clomiphen-resistant women with polycystic ovary syndrome.

BACKGROUND: Clomiphen citrate (CC) is the first line therapy for women with infertility and poly cystic ovary syndrome( PCOS). However, 20-25% of women are resistant to CC and do not ovulate. OBJECTIVE: The objective of this study was to evaluate the efficacy of sequential treatment of metformin and incremental doses of letrozole in induction of ovulation in cases of CC-resistant PCOS patients. MATERIALS AND METHODS: In this prospective before-after study, we enrolled 106 anovulatory PCOS women who failed to ovulate with CC alone from Amir-Almomenin University Hospital in Semnan, Iran. After an initial 6-8 weeks of metformin treatment, they received 2.5 mg letrozole daily on days 3-7 after menes. If they did not ovulate with 2.5 mg letrozole, the doses were increased to 5 to 7.5 mg daily in subsequent cycles. The main outcomes were ovulatory rate, pregnancy rate and cumulative pregnancy rate. RESULTS: 13.33% of patients conceived with metformin alone. Ovulation occurred in 83 out of remaining 91 patients (91.2%). 78.02% of patients responded to lower doses of letrozole. Cumulative pregnancy rate was 60/ 105 (57.14%). CONCLUSION: We suggest that treatment in CC-resistant PCOS patients should begin at first with lower doses of letrozole and could increase to the higher dose depending on the patient response before considering more aggressive therapeutic alternatives such as gonadotropins.

A comparison of the efficacy, tolerability, and convenience of two formulations of follitropin-alpha in Iranian woman undergoing intracytoplasmic sperm injection cycles.

OBJECTIVE: To compare the efficacy, tolerability, and convenience of two formulations of the follitropin-alpha (Gonal-f) pen device versus the conventional form in Iranian women undergoing ovarian stimulation for intracytoplasmic sperm injection. DESIGN: Randomized, single-center trial, parallel-group, single blind. SETTING: Tertiary referral center, University Hospital. PATIENT(S): A total of 100 patients undergoing intracytoplasmic sperm injection. INTERVENTION(S): After down-regulation with busereline acetate, patients were randomized to receive the pen device or the conventional syringe of follitropin-alpha. A computer-generated randomization list was used to allocate the patients to one of these two groups. MAIN OUTCOME MEASURE(S): The primary outcomes were patients' satisfaction, convenience, occurrence of local tolerance symptoms, and pain. Total dose of follitropin-alpha, duration of follitropin-alpha treatment, number of oocyte retrieved, number of viable embryos, and clinical pregnancies were secondary outcome measures. Data collection was performed by means of a questionnaire designed for the purpose of this study. The pain scored according to the Visual Analogue Scale. RESULT(S): Self-administration and patients' satisfaction were significantly higher in the pen device group than the conventional syringe group. Local reactions at injection sites and pain were significantly higher in the conventional syringe group than in the pen device group. There were no statistically differences in secondary outcome measures and convenience between two groups. CONCLUSION(S): Among the Iranian patients that we studied, the pen device of Gonal-f is safe, convenient, and less painful, with more patients' satisfaction than the conventional syringe form, but both forms have equal efficacy in intracytoplasmic sperm injection cycles.

Association of bacterial vaginosis, trichomonas vaginalis, and vaginal acidity with outcome of pregnancy.

BACKGROUND: Bacterial vaginosis and Trichomons vaginalis are believed to be the risk factors for preterm labor birth and preterm prelabor rupture of membranes. The objective of this study was to investigate the association between bacterial vaginosis, T.vaginalis, and vaginal pH with preterm labor birth and preterm prelabor rupture of membranes after excluding other known risk factors. METHODS: In this cohort study, we enrolled 1223 pregnant women with gestational age of 16 - 36 weeks from Amir-Almomenin General Hospital in Semnan, Iran, who had no known medical risk factors for preterm labor birth. Bacterial vaginosis and T.vaginalis were determined on the basis of vaginal pH, saline wet mount, and Amsel tests. The principal outcome was delivery before 37 weeks of gestation and preterm prelabor rupture of membranes. RESULTS: Bacterial vaginosis and T.vaginalis were detected in 16.0% and 5.5% of these women, respectively. Bacterial vaginosis was positive in 65 (33.1%) patients at 16 - 20 weeks of gestation and in 134 (66.9%) patients at 36 weeks of gestation or during labor (developing preterm labor birth or preterm prelabor rupture of membranes). The frequencies for T.vaginalis were 20 (29.9%) and 47 (70.1%) patients, respectively. All patients with bacterial vaginosis and T.vaginalis had a vaginal pH > or = 5. There was a significant correlation between bacterial vaginosis and vaginal pH > or = 5, with preterm labor birth (OR: 5.99; CI: 3.79 - 9.49) and preterm prelabor rupture of membranes (OR: 2.34; CI: 1.07 - 4.99). Moreover, a significant correlation was found between vaginal pH > or = 5 with preterm labor birth (OR: 5.82; CI: 2.96 - 11.39) and preterm prelabor rupture of membranes (OR: 4.11; CI: 1.62 - 10.12). There was no significant correlation between T.vaginalis with preterm labor birth (OR: 0.73; CI: 0.22 - 2.17) and preterm prelabor rupture of membranes (OR: 1.22; CI: 0.29 - 5.05). CONCLUSION: The presence of bacterial vaginosis or vaginal pH > or = 5 at 16 - 36 weeks of gestation is associated with an increased risk of preterm labor birth and preterm prelabor rupture of membranes.