Double-blind randomized controlled trial of letrozole versus clomiphene citrate in subfertile women with polycystic ovarian syndrome

STUDY QUESTION: Would letrozole as a primary ovulation induction agent generate better pregnancy rates than clomiphene citrate (CC) in subfertile women with anovulatory polycystic ovarian syndrome (PCOS)? SUMMARY ANSWER: Participants receiving letrozole as a primary treatment achieved a significantly (P = 0.022) higher clinical pregnancy rate per patient (61.2%) compared to CC (43.0%). WHAT IS KNOWN ALREADY: According to a recent Cochrane systematic review (2014), letrozole appears to improve live-birth (LB) and pregnancy rates in anovulatory women with PCOS, compared to CC. However, the review concluded that the quality of evidence was low due to poor reporting of study methods and possible publication bias. STUDY DESIGN, SIZE, DURATION: This double-blind randomized controlled trial (RCT) included 159 participants between April 2007 and June 2014. Subjects were randomly allocated to either CC (n = 79) or letrozole (n = 80) in a 1:1 ratio. Both drugs were encapsulated to look identical. Randomization was performed in mixed blocks and stratified by patients’ BMI (<30 and 30–35 kg/m2). PARTICIPANTS/MATERIALS, SETTING, METHODS: The trial included subfertile women diagnosed with PCOS. Treatment started with one tablet (CC 50 mg, letrozole 2.5 mg) increasing to two in non-responders and continuing until pregnancy or for up to six ovulatory cycles. Non-responders were crossed over to the other treatment after a 6-week break. Cycles were initially monitored with ultrasound follicle tracking then mid-luteal serum progesterone measurement in subsequent cycles. MAIN RESULTS AND THE ROLE OF CHANCE: Amongst the 159 participants included in the intention-to-treat analysis, four women conceived before treatment and six were lost-to-follow-up. The remaining 149 participants (74 on CC and 75 on letrozole) completed at least the first treatment. Women receiving letrozole achieved a significantly (P = 0.022; absolute difference [95% confidence interval] 18% [3–33%]) higher pregnancy rate (61.%) than those on CC (43%). The median number of treatment cycles received until pregnancy was significantly (log rank P = 0.038) smaller with letrozole (4[3–5] cycles) compared to CC (6[4–7] cycles). LB rates were not statistically (P = 0.089) different between the two groups, although there was a trend towards higher rates on letrozole (48.8%) compared to CC (35.4%). After the crossover, pregnancy and LB rates on letrozole (n = 45; 28.9 and 24.4%, respectively) were not statistically (P = 0.539 and P = 0.601) different from CC (n = 31; 22.6 and 19.4%). LIMITATIONS, REASONS FOR CAUTION: One possible limitation of this trial may be the exclusion of PCOS women with BMI > 35 kg/m2, which would limit the applicability of the results in this subgroup of PCOS. However, this group of women are generally excluded from treatment in the majority of fertility centres, especially in Europe, due to the associated challenges and risks. WIDER IMPLICATIONS OF THE FINDINGS: The results of this trial are consistent with the recent Cochrane systematic review. However, with its robust design, the current RCT provides more valid and compelling evidence for the superiority of letrozole over CC as a primary ovulation induction agent in PCOS women with 40% increase in pregnancy rates and with a shorter time-to-pregnancy. Furthermore, the participants in this RCT are a good representation of subfertile PCOS population receiving fertility treatment in Europe and worldwide. The results are therefore globally generalizable for clinical practice. STUDY FUNDING/COMPETING INTEREST(S): This RCT was mainly funded by the R&D Funding Scheme of Derby Hospitals NHS Foundation Trust. The study also received funds from School of Medicine, University of Nottingham. The Trust R&D department was involved in the development of the protocol and the running of the trial. The trial was sponsored and monitored by the University of Nottingham. The authors have no conflicts of interest. TRIAL REGISTRATION NUMBER: www.Clinicaltrials.gov: NCT00478504. TRIAL REGISTRATION DATE: Registration was verified on 23/05/2007. DATE OF FIRST PATIENT’S ENROLMENT: 25/04/2007

Long-term reproductive performance after surgery for ovarian endometrioma

ObjectiveTo determine the long-term impact of different types of endometrioma surgery on reproductive performance and on age of menopause.Study designThis was a longitudinal observational cohort study of 68 women with previous endometrioma surgery and 68 age- and weight-matched healthy controls. All participants’ hospital records were reviewed and each woman completed a questionnaire and attended an interview. Pregnancy rates were compared between the study and control groups. In the study group, pregnancy rates were compared before and after surgery.ResultsAmongst the 38 women desiring pregnancy after endometrioma surgery, 19 (50%) achieved a spontaneous pregnancy during the follow-up period. This was not significantly different from a pre-operative pregnancy rate of 48% (22/46). Of these 19 patients, four achieved another pregnancy with fertility treatment. An additional eight patients conceived only with the help of fertility treatment, giving an overall long-term post-operative pregnancy rate of 71% (27/38). These results were significantly lower (p = 0.0001) than the 98% (57/58) long-term natural pregnancy rate in the control group. Pregnancy rates in patients receiving fertility treatment significantly (p = 0.001) increased from 7% (1/15) before surgery to 63% (12/19) post-operatively. In post-menopausal women, the median (quartile) age at menopause was similar in the study (n = 9) and control groups (n = 6) [48 (45–52) versus 49 (44–52) years, respectively].ConclusionEndometriomas per se appear to be the main cause of the reduced long-term reproductive performance of the affected patients, with little or no contribution from surgery. Furthermore, endometrioma surgery seems to improve the success rates of fertility treatment

Gene expression of inflammatory markers in adipose tissue between obese women with polycystic ovary and normal obese women

OBJECTIVE: The pathogenesis of polycystic ovary syndrome (PCOS), a common endocrine disease and metabolic disturbance, is still unknown. The aim of the study was to investigate whether patients with PCOS display increased expression of inflammatory markers in adipose tissue. PATIENTS AND METHODS: Two groups of women were investigated, those diagnosed with PCOS (n = 8) and age and BMI-matched normal women (n = 12). Their age was between 20-45 years and all subjects were apparently healthy and did not take any medications. Adipose tissue levels of mRNA of inflammatory markers were determined by use of real-time PCR. RESULTS: There were no differences between obese patients and obese PCOS in levels of adipocytokines. CONCLUSIONS: There were no effects of PCOS on the expression of any of the adipocytokines genes measured in subcutaneous adipose tissue

Excess androgen production in subcutaneous adipose tissue of women with polycystic ovarian syndrome

© 2019 Society for Endocrinology Published by Bioscientifica Ltd. The purpose of this study was to investigate androgen production and the role of insulin and LH in its regulation in subcutaneous adipose tissue (SAT) of women with polycystic ovarian syndrome (PCOS). Protein and mRNA expression of androgen synthesis enzymes (cytochrome P450 17A1 (CYP17A1) and aldo-keto reductase 1C3 (AKR1C3)) were measured in SAT biopsies from women with PCOS, diagnosed according to the Rotterdam criteria (n = 15) and healthy controls (n = 15). Cultured mature adipocytes (differentiated from SAT biopsies) were treated with insulin ± phosphoinositol-3-kinase inhibitor (LY294002) or LH ± insulin. CYP17A1 and AKR1C3 mRNA expression and testosterone concentrations were measured in treated and untreated adipocyte cultures. AKR1C3 mRNA was significantly (P < 0.001) greater in PCOS vs non-PCOS SAT, but CYP17A1 was not significantly different between the two groups. AKR1C3 and CYP17A1 protein expression was not significantly different in PCOS vs non-PCOS SAT. In untreated adipocyte cultures, CYP17A1, AKR1C3 and testosterone levels were significantly higher in the PCOS vs the non-PCOS groups. Addition of insulin increased AKR1C3 mRNA and testosterone levels, but not CYP17A1 mRNA in non-PCOS with no effect on PCOS adipocytes. The stimulatory effects of insulin were not inhibited by LY294002. Addition of LH increased CYP17A1, AKR1C3 and testosterone in non-PCOS adipocytes with no effect in PCOS adipocytes. In conclusion, SAT of women with PCOS produces excess androgen, which may contribute to PCOS-related hyperandrogenaemia. This SAT androgen excess is independent of obesity and is not directly stimulated by inulin or LH

The role of oxidative stress in antipsychotics induced ovarian toxicity

This study tested the hypothesis that oxidative stress could be an underlying mechanism for APs-induced ovarian cytotoxicity and reproductive dysfunction. Rat ovarian theca interstitial cells (TICs) were isolated and treated with four APs [chlorpromazine (CPZ), haloperidol (HAL), risperidone (RIS) and clozapine (CLZ)]. MTT assay was used to test the effects of these antipsychotics on TICs viability and to estimate their 50% inhibitory concentrations (IC50s). The effects of APs (IC50s and 1 μM concentrations) on the activities of caspases-3, -8 and -9, reactive oxygen species (ROS) production, total intracellular glutathione and lipid peroxidation (LPO) in TICs were assessed. The effect of antioxidants (reduced glutathione (GSH) and quercetin) on the APs-induced cytotoxicity on TICs was investigated. MTT assay showed all APs to reduce TICs viability. CPZ, HAL and CLZ significantly increased the activity of caspases-3, -8 and -9 (P < 0.0001, < 0.0001 and < 0.01, respectively). All APs at IC50s significantly (P < 0.0001) increased ROS production, decreased total intracellular glutathione and increased LPO. MTT assay in the presence of antioxidants (reduced GSH (5 mM) or quercetin (50 mM)) showed each antioxidant to significantly inhibit the effects of APs at their IC50s on TICs viability. In conclusion, oxidative stress seems to be a possible mechanism for APs-induced ovarian and reproductive toxicity

The influence of circulating anti-Müllerian hormone on ovarian responsiveness to ovulation induction with gonadotrophins in women with polycystic ovarian syndrome: a pilot study

Background Women with polycystic ovarian syndrome (PCOS) are known to have elevated circulating Anti-Müllerian hormone (AMH), which has been found to desensitize ovarian follicles to follicle stimulating hormone (FSH). The purpose of this study was to investigate the impact of high circulating AMH on ovarian responsiveness to ovulation induction with gonadotrophins in PCOS women. Methods This prospective observational pilot study was conducted in two collaborating Fertility Centres in the UK and Egypt. The study included 20 consecutive anovulatory women with PCOS who underwent 34 cycles of human menopausal gonadotrophin (hMG) ovarian stimulation using chronic low-dose step up protocol. Blood samples were collected for the measurement of serum AMH concentrations in the early follicular (day 2-3) phase in all cycles of hMG treatment. The serum levels of AMH were compared between cycles with good vs. poor response. The good response rates and the total dose and duration of hMG treatment were compared between cycles with high vs. low serum AMH concentrations. Results Cycles with poor response (no or delayed ovulation requiring >20 days of hMG treatment) had significantly (p = .007) higher median{range} serum AMH concentration (6.5{3.2-13.4}ng/ml) compared to that (4.0{2.2-10.2}ng/ml) of cycles with good response (ovulation within 20 days of hMG treatment). ROC curve showed AMH to be a useful predictor of poor response to hMG stimulation (AUC, 0.772; P = 0.007). Using a cut-off level of 4.7 ng/ml, AMH had a sensitivity of 100% and specificity of 58% in predicting poor response. The good response rate was significantly (p  = 4.7 ng/ml (100% vs. 35%, respectively). All cycles with markedly raised serum AMH levels (> 10.2 ng/ml) were associated with poor response. Cycles with high AMH (> = 4.7 ng/ml) required significantly (p < .001) greater amounts (median {range}, 1087{450-1650}IU) and longer duration (20 {12-30}days) of hMG stimulation than cycles with lower AMH (525 {225-900}IU and 8{6-14}days). Conclusions PCOS women with markedly raised circulating AMH seem to be resistant to hMG ovulation induction and may require a higher starting dose

Impact of Aspiration in the Assessing Process of Pediatric Lung Disease

This study aimed at analyzing the impact of Aspiration in the assessing process of pediatric lung disease, as the affected children will frequently encounter a situation where swallowing is insecure and aspiration is likely. Besides analyzing the Aspiration of foreign matter into the airways and lungs that can cause a wide spectrum of pulmonary disorders with various presentations. And discussing the type of syndrome resulting from aspiration depends on the quantity and nature of the aspirated material, the chronicity, and the host responses. Considering that Aspiration is most likely to occur in subjects with a decreased level of consciousness, compromised airway defense mechanisms, dysphagia, gastroesophageal reflux, and recurrent vomiting

The role of oxidative stress in ovarian toxicity induced by haloperidol and clozapine—a histological and biochemical study in albino rats

Oxidative stress has been implicated in reproductive toxicity induced by antipsychotics (APs). This study aims to further investigate the role of AP-induced oxidative stress in reproductive dysfunction. Thirty adult female albino rats were divided into three groups including a control group (n = 10) receiving distilled water, HAL group (n = 10) receiving haloperidol (HAL) (2 mg/kg/day), and CLZ group (n = 10) receiving clozapine (CLZ) (20 mg/kg/day). After 28 days, the rats were anesthetized, blood was withdrawn from their hearts, and ovaries were removed before they were sacrificed. Serum prolactin concentrations were measured. For each rat, one ovary was used for biochemical studies including mitochondrial complexes I and III activities and oxidative stress markers (lipid peroxidation, super oxide dismutase [SOD], catalase [CAT], and reduced glutathione [GSH]). The other ovary was used for histopathological examination and immunohistochemistry staining for p53 and Ki-67. HAL-treated rats showed significantly (p ≤0.001) higher serum prolactin concentrations compared with other groups. HAL significantly inhibited complexes I (p ≤ 0.001) and III activities (p ≤ 0.05), while CLZ inhibited only complex I (p ≤ 0.001). Lipid peroxidation was increased by HAL (p ≤ 0.001) and CLZ (p ≤ 0.01). HAL caused significant (p ≤ 0.001) reductions in SOD, CAT, and GSH. CLZ caused a significant decrease in SOD (p ≤ 0.001) and GSH (p ≤ 0.01) with no effect on CAT. Histopathological studies of CLZ- and HAL-treated ovaries showed features suggestive of hyperprolactinemia and oxidative stress. Ki-67- and P53-immunostained sections were suggestive of disruption of cellular proliferation. These findings support the hypothesis that HAL and CLZ induce reproductive dysfunction through mechanisms involving ovarian mitochondrial dysfunction and oxidative stress

The impact of laparoscopic ovarian drilling on AMH and ovarian reserve: a meta-analysis

Laparoscopic ovarian drilling (LOD) has been widely used as an effective treatment of anovulatory women with polycystic ovarian syndrome (PCOS). However, there has been a growing concern over a possible damaging effect of this procedure on ovarian reserve. The objective of this study was to investigate the hypothesis that LOD compromises ovarian reserve as measured by post-operative changes in circulating anti-Müllerian hormone (AMH). This meta-analysis included all cohort studies as well as randomised controlled trials (RCTs) investigating serum AMH concentrations and other ovarian reserve markers in women with PCOS undergoing LOD. Various databases were searched including MEDLINE, EMBASE, Dynamed Plus, ScienceDirect, TRIP database, ClinicalTrials.gov and Cochrane Library from January 2000 to December 2016. Sixty studies were identified, of which seven were deemed eligible for this review. AMH data were extracted from each study and entered into the RevMan software to calculate the weighted mean difference (WMD) between pre- and post-operative values. Pooled analysis of all studies (n = 442) revealed a statistically significant decline in serum AMH concentration after LOD (WMD −2.13 ng/mL; 95% confidence interval (CI) −2.97 to −1.30). Subgroup analysis based on duration of follow-up, AMH kit, laterality of surgery and amount of energy applied during LOD consistently showed a statistically significant fall in serum AMH concentration. In conclusion, although LOD seems to markedly reduce circulating AMH, it remains uncertain whether this reflects a real damage to ovarian reserve or normalisation of the high pre-operative serum AMH levels. Further long-term studies on ovarian reserve after LOD are required to address this uncertainty

The impact of excision of benign nonendometriotic ovarian cysts on ovarian reserve: a systematic review

Background Benign nonendometriotic ovarian cysts are very common and often require surgical excision. However, there has been a growing concern over the possible damaging effect of this surgery on ovarian reserve. Objective The aim of this metaanalysis was to investigate the impact of excision of benign nonendometriotic ovarian cysts on ovarian reserve as determined by serum anti-Müllerian hormone level. Data Sources MEDLINE, Scopus, ScienceDirect, and Embase were searched electronically. Study Design All prospective and retrospective cohort studies as well as randomized trials that analyzed changes of serum anti-Müllerian hormone concentrations after excision of benign nonendometriotic cysts were eligible. Twenty-five studies were identified, of which 10 were included in this analysis. Data Extraction Two reviewers performed the data extraction independently. Results A pooled analysis of 367 patients showed a statistically significant decline in serum anti-Müllerian hormone concentration after ovarian cystectomy (weighted mean difference, –1.14 ng/mL; 95% confidence interval, –1.36 to –0.92; I2 = 43%). Subgroup analysis including studies with a 3-month follow-up, studies using Gen II anti-Müllerian hormone assay and studies using IOT anti-Müllerian hormone assay improved heterogeneity and still showed significant postoperative decline of circulating anti-Müllerian hormone (weighted mean difference, –1.44 [95% confidence interval, –1.71 to –1.1; I2 = 0%], –0.88 [95% confidence interval, –1.71 to –0.04; I2 = 0%], and –1.56 [95% confidence interval, –2.44 to –0.69; I2 = 22%], respectively). Sensitivity analysis including studies with low risk of bias and excluding studies with possible confounding factors still showed a significant decline in circulating anti-Müllerian hormone. Conclusion Excision of benign nonendometriotic ovarian cyst(s) seems to result in a marked reduction of circulating anti-Müllerian hormone. It remains to be established whether this reflects a real compromise to ovarian reserve