Interim analysis in clinical trials

To the Editor:
Mansour et al. (1) report a positive effect of intrauterine injections of human chorionic gonadotropin (hCG) on implantation and clinical pregnancy rates (CPR) after in vitro fertilization with intracytoplasmic sperm injection (1). We congratulate the authors for exploring this intervention in considerable detail. We wish to comment on the interim analyses conducted in this randomized controlled trial and the completeness of their registration at clinicaltrials.gov.

Two doses of the intervention (injection of 40 ul of tissue culture media with 100 IU or 200 IU of hCG) were initially tested against the control (no injection of tissue culture media). With 80% power and a type I error rate of 5% for each comparison, the stated 10% absolute difference (effect size) in CPR that the authors wished to test would require 1161 participants with complete information on the outcome of interest (387 per arm). When the effect size is a change from a high baseline success rate (here 50%), and the study has three arms, a very large sample size is to be expected. After the first 280 participants, an interim analysis was conducted, no difference was found between 100IU or 200 IU and the controls, and the study testing these two interventions was terminated. It was not specified if this interim analysis was pre-planned, whether it was done to check for harm, and if the trial was stopped for lack of any trend toward benefit. We can readily understand when the previous human study was done with injection of 500 IU in 1,000 ul that they may have chosen the lower doses and done an early interim analysis to mitigate against harm. We can also sympathize with terminating the study when there was no trend toward benefit.

Re: Use of laptop computers connected to internet through Wi-Fi decreases human sperm motility and increases sperm DNA fragmentation

To the Editor:

We read with interest the article “Use of laptop computers connected to internet through Wi-Fi decreases human sperm motility and increases sperm DNA fragmentation” by Avendano et al.(1). However, we do actually think that the evidence presented in this paper cannot support the claim that the observed effects are nonthermal and caused by exposure to a Wi-Fi radiofrequency electromagnetic field.

Keeping constant the temperature under the computer by an air conditioning system is not sufficient to ensure homogeneity of the temperatures within the experimental area, since the heat source from the laptop is not homogenous itself, and to exclude that there is no local variation in the samples temperatures.

Comment on Increase of success rate for women undergoing embryo transfer by transcutaneous electrical acupoint stimulation: a prospective randomized placebo-controlled study

To the Editor:

It is widely known that embryo quality affects pregnancy and live birth rates. Nevertheless, in their article, “Increase of success rate for women undergoing embryo transfer by transcutaneous electrical acupoint stimulation: a prospective randomized placebo-controlled study,” Zhang et al. do not mention the quality of transferred embryos at all (1). In addition, there is no information about ovarian stimulation protocols (GnRH agonist? GnRH antagonist? Recombinant or urinary FSH?), length of stimulation, endometrial thickness or day of embryo transfer. One might expect day-5 cycles to be different, for better or worse, considering that the interval between intervention [transcutaneous electrical acupoint stimulation (TEAS)] and embryo implantation would have been shorter.

Defining exercise prescription in lifestyle modification programs for overweight/obese polycystic ovary syndrome women

To the Editor:

We reviewed the manuscript by Nybacka et al. (1) with great interest. The authors randomized overweight/obese women with polycystic ovary syndrome (PCOS) to investigate the effects of different lifestyle modification approaches on ovarian function and endocrine/metabolic parameters. The patients were assigned to diet, exercise or diet plus exercise for 4 months, and at least 1-year after the termination of the programs were invited to participate in a follow-up visit. A total of 14, 17 and 12 women completed, respectively, the diet, exercise and diet plus exercise intervention after 4 months, and 7 of each group completed the follow-up visit. At the end of the study the authors’ conclusion was that “properly managed diet and exercise, alone or in combination, are equally effective in improving reproductive function in overweight/obese women with PCOS, despite the minor weight loss associated with exercise.”

Re: Full-sibling embryos created by anonymous gamete donation in unrelated recipients

To the Editor:

The otherwise informative paper “Full-sibling embryos created by anonymous gamete donation in unrelated recipients” by Dicken et al. (1) was marred by use of limited evidence to support the claim that “most parents conceiving with the assistance of donor gametes do not disclose the nature of their conception to their resulting offspring.” A more thorough review of available literature than the two cited sources (2,3) reveals a more nuanced picture, as indicated by several European studies.

Comment on: “Should the myometrial free margin still be considered a limiting factor for hysteroscopic resection of submucous fibroids? A possible answer to an old question.”

To the Editor:

Paolo Casadio et al. recently published an interesting paper focusing on the dynamic changes of the myometrial free margin separating type II submucous fibroids from the serosa during hysteroscopic resection (1). Although the number of patients of this prospective observational study is limited (n = 13), the authors interestingly concluded that “myometrial free margin increases progressively with each step of the procedure probably leading to an increasing margin of safety.” This study updates and reinforces the previous observation by Yang et al., which first demonstrated that the myometrial free margin is not a static parameter but it “increased gradually after each step of the resection, reaching its maximum after the completion of the procedure” (2). They observed the progressive thickening of myometrium at transabdominal sonography while the myoma is progressively enucleated, suggesting two possible mechanism for this phenomenon: the reshaping of the distended uterine myometrial fibers and the contractions induced by electrosurgery and the myoma grasping by forceps.

It’s time to pay attention to the endometrium, including the nucleolar channel system

To the Editor:

In the context of the excellent Views and Reviews devoted to the endometrium (1), Dr. Bruce A. Lessey offers a thorough analysis of 186 publications that are of significance to the window of implantation (WOI) (2). We feel this already exhaustive effort needs to be expanded further. Although one histological hallmark of midluteal endometrium – pinopodes (whose significance as markers of endometrial receptivity has been questioned) – is reviewed in detail, another, the nucleolar channel system (NCS), went unmentioned. The presence of NCSs distinctly marks the midluteal phase of human endometrium overlapping with the WOI.

Should there be a/ny limit to IVF cycles? A rejoinder to Stewart et al.

In a recent paper, Stewart et al. (1) report the probability of a live delivery over real time in a population-based cohort of women undergoing in vitro fertilization (IVF) treatment at clinics in Western Australia. They suggested that women should persevere in IVF treatment. However, they did not mention any limit on IVF cycles. Moreover, in the report by Stewart et al., the success rate of live deliveries reaches a plateau (meaning zero new deliveries) long before the 180 months and the number of cycles for which they had data. This means that women may continue with IVF treatment even when the probability of a successful outcome is “zero,” which begs the question of whether there should be any limit on IVF cycles. Undoubtedly, IVF has been a milestone in reproductive medicine, as millions of babies (five million up to 2006) have already been born with the aid of IVF. However, many questions about IVF still remain (2). One of these questions is the effect/s of long-term IVF treatment on women (3).

Proficiency in oocyte retrieval: plausible steps before perfection

To the Editor:

We read with interest the retrospective analysis by Goldman et al (1). The authors attempt to determine the minimum number of procedures required for proficiency in oocyte retrieval (OR). Assessing and classifying the technical competence of a trainee objectively is quite difficult for two reasons: first, there is no clear definition of “competence,” as operative skill is a combination of knowledge, judgment, and technical ability (2). Second, the success of an OR depends on additional parameters, such as patient, nurse and embryologist compliance. We would like to share our thoughts on their work.

Letter regarding “Circulating inflammatory markers in polycystic ovary syndrome: a systematic review and metaanalysis”

To the Editor:

We read with great interest the article of Escobar-Morreale et al., in which the authors report that women with polycystic ovary syndrome (PCOS) exhibit an elevation in circulating C-reactive protein (CRP) that was independent of obesity. We agree with their conclusion that this finding confirms the existing molecular evidence of a chronic low-grade inflammation possibly being involved in the pathogenesis of PCOS (1).

A possible autoimmune etiology of at least some cases of PCOS was mentioned in the early 1990s (2). Gleicher et al. have hypothesized that functional autoantibodies could contribute to its development, which represents hyperfunction of follicular recruitment in the ovaries (3). Moreover, the incidence of autoimmune thyroid diseases such as Hashimoto’s thyroiditis has been reported to be three-fold higher in women with PCOS than in the general female population (4).

Comment on GnRH analogue cotreatment with chemotherapy for preservation of ovarian function

To the Editor:

With great interest we have read the systematic review and meta-analysis by Bedaiwy et al. (1). The outcomes of the meta-analysis suggest a potential benefit of GnRH analogs as a cotreatment with chemotherapy in preserving future fertility, with higher rates of spontaneous resumption of menstruation and ovulation.

Six randomized controlled trials (RCTs) met the inclusion criteria. One of the largest studies was published in 2009 (2). After publication, this study was criticized for significant methodological weaknesses invalidating any conclusion based on this study (3). Additional criticisms were that the study group consisted of very young women compared to European and American women with breast cancer, had an unlikely low resumption of menstruation (in particular, only 33% of the controls), and had a short follow-up time (maximum 8 months after the last dose of chemotherapy) (4). Based on these criticisms we doubt the wisdom of including this controversial study.

Melatonin protects human spermatozoa from apoptosis via melatonin receptor– and extracellular signal–regulated kinase-mediated pathways

To the Editor:

The paper of Espino et al. (1) addressed a very interesting issue about the anti-apoptotic activity of the pineal hormone melatonin in human semen. Employing 1 mM doses of melatonin in vitro and the MT1/MT2 receptor antagonists luzindole and 4-phenyl-2-propionamidotetralin (4P-PDOT), the authors claim to have demonstrated that “…melatonin prevention of H2O2-induced DNA fragmentation is dependent on …MT1 receptor ….”. We find that above statement may be arguable and there is need of further exploration and clarification of the mechanisms involved.

Gestational Sac Aspiration and Instillation for Treatment of Early Ectopic Pregnancy

To the Editor:

We thank Cepni et al. for sharing their recent case series, “An alternative treatment option in tubal ectopic pregnancies with fetal heartbeat: aspiration of the embryo followed by single-dose methotrexate administration” (1). This was of great interest to us, as we have used a similar aspiration and instillation technique using hyperosmolar glucose to treat a heterotopic pregnancy created after in vitro fertilization (IVF).