Alexander M. Quaas

Effect of isoflavone soy protein supplementation on endometrial thickness, hyperplasia, and endometrial cancer risk in postmenopausal women: a randomized controlled trial.

Objective This study aims to determine whether long-term isoflavone soy protein (ISP) supplementation affects endometrial thickness and rates of endometrial hyperplasia and cancer in postmenopausal women. Methods In this randomized, double-blind, placebo-controlled trial, 350 postmenopausal women aged 45 to 92 years were randomized to a total daily dose of 154 mg of ISP or a milk protein–matched placebo for a 3-year period. Women with a surgically absent uterus were excluded from the analysis (final study population, N = 224). The main outcome measures were as follows: mean change in endometrial thickness on transvaginal ultrasound from baseline until up to 36 months of follow-up and the incidence of endometrial sampling, endometrial hyperplasia, and endometrial cancer. Results A total of 666 visits among 224 participants were evaluated. Treatment groups did not significantly differ on the mean baseline or on-trial changes in endometrial thickness. Of the 103 placebo-treated participants, 7 (6.8%) underwent endometrial biopsy; 6 (85.7%) of these biopsies were benign. One woman in the placebo group was diagnosed with complex endometrial hyperplasia with atypia and underwent hysterectomy. The pathology result from this surgical operation was stage IB endometrial cancer. Of the 121 participants in the soy group, 9 (7.4%) underwent endometrial biopsy. The results were benign in all nine cases (100%). Although the rate of hyperplasia/malignancy was higher in the placebo group (14.3% vs 0%), the difference was not statistically significant. Conclusions Three-year ISP supplementation has no effect on endometrial thickness or on the rates of endometrial hyperplasia and cancer in postmenopausal women.

The role of steroid hormone supplementation in non–assisted reproductive technology treatments for unexplained infertility

Fertility treatment strategies are evolving, with a more rapid transition to assisted reproductive technology (ART) treatments after unsuccessful non-ART treatments. This trend increases the potential importance of adjuvant treatments in non-ART cycles, such as steroid hormone supplementation. It has been established that success rates of ART treatments are increased with the use of luteal support with progesterone. In the setting of non-ART cycles, however, the evidence is less clear, and clinical practices vary widely between providers and clinics. In this review, we aimed to provide an overview of the current evidence for the use of steroid hormone supplementation, including progesterone for luteal support, estrogens, androgens, and mineralocorticoids, in the setting of non-ART treatments for ovulatory women.

Time to “cool off”? Examining indications for “elective deferred frozen embryo transfer”

The first birth from in vitro fertilization (IVF) in 1978 occurred for the indication of tubal factor infertility [1, 2]. The goal was to unite the male and female gametes outside the body and transfer the resulting embryo into the uterus to bypass the obstruction that prevented fertilization and implantation. Since that time, the indications for the use of assisted reproductive technology (ART) including IVF have expanded to include virtually all causes of infertility as well as non-infertility indications such as preimplantation genetic diagnosis for the prevention of genetic disease. Over the past decades, the IVF process has evolved through improvements in stimulation protocols and laboratory techniques. Often, adaptation of new technologies occurred prior to, in parallel with, or in the absence of rigorous scientific evidence to support effectiveness and safety. Advances in the field of ART seldom (arguably never) occur in isolation and temporally separated. The last decade in the evolution of our field has witnessed a dramatic expansion in technologies of cryopreservation, genetic analysis, and non-invasive embryo assessment. In the early days of ART, providers sought to overcome low implantation rates with the transfer of multiple embryos, under the assumption that success rates of frozen embryo transfers (FETs) would be lower, especially prior to the advent of vitrification. However, as embryo cryopreservation became more commonplace, observational studies started to suggest that the perinatal outcomes of FETs compared to fresh transfers were Bsimilar or even better, particularly regarding fetal growth^ [3] [4]. Pregnancy and live births rates with FETs were approaching those of fresh cycles, likely through increasing use of vitrification [5]. These developments gave rise to the concept of universal cryopreservation of entire embryo cohorts in lieu of fresh transfer [6]. In this issue, Basile and Garcia-Velasco examine the topic of Bfrozen fever^ in their review article [7]. Specifically, they pose the question as to when the Belective deferred embryo transfer^ concept should be used, which involves segmentation of treatment via cryopreservation of oocytes or embryos and subsequent frozen embryo transfer (FET). For specific indications? Universally? Does segmentation of treatment Bimprove the soil^ or Bharm the seed^? In order to provide the background to this question, the authors review the relevant laboratory and clinical developments that led the field of ART to this point. A succinct history of embryo and oocyte cryopreservation, including the move from Bslow-freezing^ techniques towards vitrification, is followed by an overview of recent trends in stimulation protocols, with the goal of ovarian hyperstimulation syndrome (OHSS)–free clinics. The advent and increasing use of preimplantation genetic screening (PGS) is mentioned prior to a review of the literature on perinatal and obstetric outcomes with cryopreserved versus fresh embryo transfers. The evidence for the central question BWho benefits from a freeze-all strategy?^ is then presented. The authors agree that a freeze-all approach is useful for specific indications, such as the prevention of OHSS in high responders and the timely indication of reduction in Zika-related morbidity in affected areas (Table 2, [8]). However, when it comes to a universal freeze-all strategy, the authors are more cautious. A recent meta-analysis, which CapsuleAdvances in cryopreservation techniques and scientific evidence demonstrating benefits of frozen embryo transfers have led to an increased use of a Bfreeze-all^ strategy in ART. This commentary examines this trend and introduces the review article by Basile and Garcia-Velasco on the topic.

Lifestyle factors associated with histologically derived human ovarian non-growing follicle count in reproductive age women

STUDY QUESTION Are lifestyle factors (smoking, BMI, alcohol use and oral contraceptive pill use) associated with the human ovarian reserve as determined by the total ovarian non-growing follicle number? SUMMARY ANSWER Light to moderate alcohol use was significantly associated with greater ovarian non-growing follicle (NGF) count, whereas other lifestyle factors were not significantly related. WHAT IS KNOWN ALREADY A single previous investigation has suggested that smoking and alcohol use are associated with lower ovarian follicle density. However, this investigation utilized follicle density as the outcome of interest rather than the estimated total ovarian NGF count. STUDY DESIGN, SIZE, DURATION This cross-sectional investigation included a convenience sample of premenopausal women from two different academic sites, the University of Washington (n = 37, from 1999-2004) and the University of Oklahoma (n = 73, from 2004-2013), undergoing incidental oophorectomy at the time of hysterectomy (total n = 110, age range 21-52 years). PARTICIPANTS/MATERIALS, SETTING, METHODS Prior to undergoing oophorectomy, participants completed detailed questionnaires regarding lifestyle exposures. Following surgery, total ovarian NGF counts were determined with systematic random sampling rules and a validated fractionator/optical dissector technique. Associations between lifestyle factors and log-transformed ovarian follicle counts were determined using multivariable linear regression. MAIN RESULTS AND THE ROLE OF CHANCE After controlling for age, BMI, oral contraceptive pill (OCP) use, tobacco use and site of collection, cumulative alcohol use (measured in alcoholic drinks per day multiplied by years of drinking) was associated with ovarian NGF count. Women reporting light (>0 to <1 drink-years) and moderate (1-3 drink-years) alcohol use had greater NGF counts (β = 0.75, P = 0.04, and β = 1.00, P = 0.03; light and moderate use, respectively) as compared with non-users. Neither heavier alcohol use (>3 drink-years), BMI, OCP use, nor tobacco use were significantly associated with the ovarian NGF count. Similar patterns of association with moderate cumulative alcohol use were observed when evaluating associations with pre-antral follicles and total follicle counts. LIMITATIONS, REASONS FOR CAUTION All participants in this convenience sample had a benign indication for hysterectomy, and therefore may not be broadly representative of the population without such an indication. Additionally, lifestyle factors were self-reported, and the sample size of the present investigation limits our ability to detect associations of smaller magnitude. WIDER IMPLICATIONS OF THE FINDINGS While our findings are in disagreement with a single investigation that utilized human follicle density as the outcome of interest, they are consistent with many studies investigating the relationship between lifestyle factors and the age of spontaneous menopause. Furthermore, they suggest a mechanism that does not involve accelerated follicular atresia to explain the association between smoking and an earlier age of menopause. STUDY FUNDING/COMPETING INTERESTS This investigation was funded by NIA R29-HD37360-04 (N.A.K.) and OCAST HR04-115 (K.R.H.) and by the National Institute of General Medical Sciences, Grant 1 U54GM104938 (J.D.P.). There is no conflict of interest.