Competence of Combined Low Dose of Human Chorionic Gonadotropin (HCG) and Clomiphene Citrate (CC) Versus Continued CC during Ovulation Induction in Women with CC-Resistant Polycystic Ovarian Syndrome: A Randomized Controlled Trial.

Background and Objectives: Polycystic ovarian syndrome (PCOS) is a widespread endocrine disorder affecting 5-18% of females in their childbearing age. The aim of this study is to assess the efficacy of combining a low dosage of human chorionic gonadotropin (HCG) along with clomiphene citrate (CC) for stimulating ovulation in infertile women diagnosed with CC-resistant PCOS. Materials and Methods: A randomized controlled trial was carried out on 300 infertile CC-resistant PCOS women. All participants were assigned to two groups: the CC-HCG group and the CC-Placebo group. Subjects in the CC-HCG group were given CC (150 mg/day for 5 days starting on the 2nd day of the cycle) and HCG (200 IU/day SC starting on the 7th day of the cycle). Subjects in the CC-Placebo group were given CC and a placebo. The number of ovarian follicles > 18 mm, cycle cancellation rate, endometrial thickness, ovulation rate, clinical pregnancy rate, and occurrence of early ovarian hyper-stimulation syndrome were all outcome variables in the primary research. Results: Data from 138 individuals in the CC-HCG group and 131 participants in the CC-Placebo group were subjected to final analysis. In comparison to the CC-Placebo group, the cycle cancellation rate in the CC-HCG group was considerably lower. The CC-HCG group exhibited a substantial increase in ovarian follicles reaching > 18 mm, endometrial thickness, and ovulation rate. The clinical pregnancy rate was higher in the CC-HCG group (7.2% vs. 2.3%; CC-HCG vs. CC-Placebo). Upon adjusting for BMI and age, the findings of our study revealed that individuals in the CC-HCG group who had serum prolactin levels below 20 (ng/mL), secondary infertility, infertility duration less than 4 years, baseline LH/FSH ratios below 1.5, and serum AMH levels more than 4 (ng/mL) had a higher likelihood of achieving pregnancy. In the CC-Placebo group, there was a greater prediction of clinical pregnancy for those with serum AMH (<4), primary infertility, serum prolactin ≤ 20 (ng/mL), baseline LH/FSH < 1.5, and infertility duration < 4 years. Conclusions: The use of a small dose of HCG along with CC appeared to be an effective treatment in reducing cycle cancelation, improving the clinical pregnancy rate and ovulation rate in CC-resistant PCOS patients. The trial was registered with Clinical Trials.gov, identifier NCT02436226.

[Optimal Ovulation Induction in Polycystic Ovary Syndrome Resistant to Clomiphene Citrate or Letrozole.]

OBJECTIVES: To investigate the optimal ovulation induction with the combination of combining letrozole(LE),clomiphene citrate (CC),and human menopausal gonadotropin (HMG) in polycystic ovary syndrome(PCOS) patients resistant to CC or LE. METHODS: Two hundreds nine PCOS patients (209 cycles) resistant to CC or LE were randomly divided into three groups: CC+HMG group (59 cycles),LE+HMG group (72 cycles) and LE+CC group (78 cycles).The patients in LE+CC group unable to form the dominant follicle after 54 cycles were enrolled into LE+CC+HMG group.Maximum follicle diameter (MFD),endometrial thickness,number of follicles (diameter>1.4 cm),the level of serum estradiol (E2) were measured on the day of HMG administration.Also these results were observed and compared including the duration of treatment,dosage of HMG,number of ovulated follicles,clinical pregnancy rate,biochemical pregnancy rate,early abortion rate,twinning rate,and ectopic pregnancy rate. RESULTS: The ovulation rate was significantly lower in LE+CC group (30.77%) (P<0.05),but similar in the other three groups.The number of >1.4 cm follicles and ovulated follicles,ovulation duration and E2 concentration in LE+CC group were also at a lower level (P<0.05).The patients in LE+CC+HMG group showed higher E2 level and more HMG consumption (P<0.05).There was no statistical difference in endometrial thickness,MFD,clinical pregnancy rate,biochemical pregnancy rate,early abortion rate and twinning rate among these groups (P>0.05).No severe ovarian hyperstimulation syndrome (OHSS) or luteinized unruptured follicle (LUF) occurred. CONCLUSIONS: Combintion of LE with CC could achieve 1/3 ovulation induction in PCOS resistant to CC or LE alone.When both combined with HMG,the induction of ovulation could be significantly higher than LE+HMG and CC+HMG,while the risk of multiple pregnancy and OHSS was reduced.

Correlation of serum leptin and ghrelin levels with endocrine and reproductive parameters in women with clomiphene citrate resistant polycystic ovary syndrome.

Objective: To investigate the changes in serum ghrelin and leptin levels in patients with clomiphene-resistant polycystic ovary syndrome (PCOS). Materials and Methods: Thirty-five patients who could not achieve ovulation or pregnancy despite using 150 mg/day of clomiphene citrate (CC) participated in the study. Thirty-five patients who were compatible with the study group in terms of age and body mass index (BMI) but did not have clinical and laboratory findings of PCOS constituted the control group. On the third day of the cycle, in addition to the basal hormone profile, ghrelin and leptin levels were also measured. Patients in both groups went to IVF/ICSI. Basal hormone values, leptin, ghrelin, metabolic, demographic parameters, and clinical pregnancy rates were correlated. Results: Patients in both groups were recorded to be similar in terms of age (29.4±0.11 vs 28.5±7.30), BMI (24.3±3.07 vs 23.8±1.55), and infertility time (6.14±4.30 vs 6.03±1.28). Serum ghrelin levels of the PCOS group were significantly lower than the control group (0.48±2.21 vs 1.19±4.02) Serum leptin levels of the PCOS group were significantly higher than the control patients (45.6±304 vs 16.5±0.32). Serum leptin levels and BMI (r=0.65, p<0.01) A positive correlation was found between luteinizing hormone (LH) (r=0.53, p<0.02), and insulin resistance (r=0.74, p<0.03). There was a negative (r=-0.76, p<0.03) correlation between serum ghrelin and LH. A positive and significant correlation was found between serum ghrelin, testosterone, mature oocyte, and implantation rates. Conclusion: Serum ghrelin correlates with fertility outcomes in women with CC-resistant PCOS undergoing IVF/ICSI.

A comparison between a combination of letrozole and clomiphene citrate versus gonadotropins for ovulation induction in infertile patients with clomiphene citrateresistant polycystic ovary syndrome - a retrospective study.

OBJECTIVES: The aim of this study was to compare a combination treatment with CC plus letrozole versus gonadotropins in CC-resistant polycystic ovary syndrome (PCOS) patients with regard to ovulation and clinical pregnancy rate. MATERIAL AND METHODS: One hundred sixteen CC-resistant infertile PCOS patients were evaluated retrospectively. The patients were divided into two groups. Group 1 (n = 73) received CC plus letrozole, and Group 2 (n = 43) received gonadotropins. RESULTS: The ovulation rate in Group 1 was 65/73 (89%), the pregnancy rate was 13/73 (18%), the twin foetuses rate was 1/73 (1.3%) and the miscarriage rate was 2/73 (2.7%). In Group 2, the ovulation rate was 41/43 (95%), and the pregnancy rate was 8/43 (19%) the rate of the twin foetuses was 1/43 (2.3%) and the miscarriage rate was 1/43 (2.3%). There was no statistically significant difference in the ovulation (p = 0.25), pregnancy (p = 0.91), twin foetuses (p = 0.89) and miscarriage p = 0.89) rates between two groups. CONCLUSIONS: This new drug combination suggests that it may be a lower cost, lower risk alternative treatment that increases the rate of ovulation. Larger randomized clinical trials are needed to provide information on live birth rates of this combination.

Clinical observation of letrozole combined with methylprednisolone in the treatment of infertile patients with polycystic ovary syndrome resistant to clomiphene / 中国药房

OBJECTIVE To explore the effects of letrozole combined with methylprednisolone on clinical outcomes， ovarian reserve function， serum sex hormones， and safety in infertile patients with polycystic ovary syndrome resistant to clomiphene. METHODS The clinical data of 78 infertile patients with polycystic ovary syndrome resistant to clomiphene in the Department of Gynecology of Qingdao Central Hospital from February 2021 to January 2022 was analyzed retrospectively， and all patients were divided into control group （42 cases） and observation group （36 cases） based on the treatment methods. The control group took letrozole 5 mg/d orally on the 5th to 9th day of the menstrual cycle. Vaginal ultrasound was used to monitor the development of the endometrium and follicles； estradiol valerate was used to correct endometrial thickness， and measures such as inducing ovulation with follicle-stimulating hormone were taken to promote pregnancy. On the basis of treatment in the control group， the observation group began taking methylprednisolone orally at a dose of 4 mg/d starting from the third day of natural menstruation or withdrawal bleeding. Both groups were treated for 6 menstrual cycles. The ovulation and pregnancy within one year， serum levels of sex hormones [estradiol （E2）， luteinizing hormone （LH）， follicle-stimulating hormone （FSH）， testosterone] and anti-Müllerian hormone （AMH）， ovulation indicators （follicle growth time， the number of ovulations， and the number of dominant follicles）， and the occurrence of adverse drug reactions were compared between the two groups. RESULTS After treatment， the biochemical pregnancy rate （72.22%） and clinical pregnancy rate （47.22%） of the observation group were significantly higher than those of control group （47.62%， 19.05%）； the serum levels of E2， LH， FSH， testosterone and AMH were significantly lower than the control group； the follicle growth time was significantly shorter than the control group； the number of ovulation and dominant follicles were significantly higher than the control group （P＜0.05）. There was no statistically significant difference in ovulation rate （94.44% vs. 83.33%） and total incidence of adverse drug reactions （8.33% vs. 9.52%） between the observation group and the control group （P＞0.05）. CONCLUSIONS Compared with letrozole alone， the combination of letrozole and methylprednisolone can significantly improve the pregnancy rate， the sex hormone levels and ovarian reserve function in infertile patients with polycystic ovary syndrome resistant to clomiphene， with high safety profiles.

Ovarian granulosa cell tumor and clomiphene citrate resistance. A case report and review of the literature.

Granulosa cell tumors (GCTs) account for less than 5% of all ovarian malignancies, occur in younger ages, are usually diagnosed in their early stages, and have a good prognosis. GCTs usually present with features of hyperestrogenism. This paper reports the unusual case of an adult with a GCT with manifestations including amenorrhea, mild hirsutism, infertility, clomiphene citrate (CC) resistance (CC), mildly elevated testosterone, high anti-Müllerian hormone (AMH) and normal estrogen levels. The patient was initially diagnosed with polycystic ovarian syndrome (PCOS), and after four attempts at ovarian stimulation she was diagnosed with CC resistance. The patient later underwent laparoscopic evaluation on account of a solid mass on her left ovary. The pathology report described it as a borderline adult type GCT and four weeks after surgery she had a positive pregnancy test. Twelve months after delivery, the patient had no obvious symptoms of disease and her menstrual cycle was normal. Serial measurements of serum inhibin B, AMH, estrogen, and testosterone levels were within normal range. In conclusion, the resistance to clomiphene manifested by the patient might be explained by a potential mechanism implicating inhibin B and AMH due to the presence of a GCT. Further studies are required to evaluate the role of AMH and Inhibin B in the mechanism of CC resistance in women with PCOS.

Comparison of metformin and N-acetyl cysteine, as an adjuvant to clomiphene citrate, in clomiphene-resistant women with polycystic ovary syndrome.

OBJECTIVE: To evaluate the effects of short- and long-term treatment with metformin and NAC, in an adjuvant to clomiphene citrate (CC), on the improvement of hormonal profile (SHBG, total testosterone, FBS, and fasting insulin) and fertility status in CC-resistant women with PCOS. MATERIALS AND METHODS: One hundred and eight CC-resistant PCOS patients participated in the study and received either metformin (1500mg/day) or NAC (1800mg/day) with 100mg/day of CC for 8 and 12 weeks. Mean BMI, hirsutism score, LH/FSH ratio, endometrial thickness, mature follicle number, and serum concentrations of LH, FSH, E2, fasting insulin, total testosterone and FBS were evaluated before and after short- and long-term treatment. Furthermore, ovulation and pregnancy rates in the first and second cycles were also determined in treated patients. RESULTS: There was no significant difference in all variables before and 8 weeks after treatment with metformin and NAC. The BMI- and insulin-lowering effects of metformin were significantly higher than NAC after long-term treatment. However, the reducing-effect of NAC on hirsutism score and FBS levels was significantly more than metformin after 12 weeks. Treatment with metformin and NAC significantly increased ovulation and pregnancy rates in CC-resistant PCOS patients. In the first and second cycles, ovulation and pregnancy rates in patients treated with NAC were slightly higher than those received metformin. CONCLUSIONS: Compared with metformin, administration of NAC in an adjuvant to CC is recommended for improving of hormonal profile and treatment of anovulatory infertility in hyperinsulinemic patients especially women with PCOS who are CC-resistant.

Comparison of letrozole versus tamoxifen effects in clomiphen citrate resistant women with polycystic ovarian syndrome.

BACKGROUND: The objective of this prospective randomized study was to make a comparison between the effects of letrozole and tamoxifen (TMX) in ovulation induction in clomiphene (CC)-resistant women with polycystic ovarian syndrome (PCOS). METHODS: The study comprised a total of 60 infertile women (180 cycles) with CCresistant PCOS selected from the clinics affiliated to the Department of Obstetrics and Gynecology of Tanta University. Patients were randomized to treatment with 2.5 mg of letrozole daily (30 patients, 90 cycles) or 20 mg of TMX daily (30 patients, 90 cycles) for 5 days from day 5 of menses and 10000 IU hCG when mature follicles become =18 mm in diameter. The chi-square and t-test were used for comparing two groups and p < 0.05 was considered significant. RESULTS: The total number of follicles (=18 mm) in the letrozole group was more than TMX group. The endometrial thickness at the time of hCG administration was significantly higher (p < 0.05, at 95% CI) in the letrozole group than that of TMX group (10.2±0.7 vs. 9.1±0.2 mm). Ovulation occurred in 23.33% of cycles in the letrozole group and in 8.89% in the TMX group, whereas pregnancy occurred in 5.56% of the letrozole group and 2.22% of the TMX group. CONCLUSION: Both letrozole and TMX should be considered as optional therapies for CC-resistant women. In addition, letrozole was superior to TMX in achieving a higher pregnancy and ovulation rate and also lesser side effects in comparison to tamoxifen.