Edward J. Nejat

Predictors of chronic disease at midlife and beyond - the health risks of obesity

A burgeoning pandemic of obesity is well characterized. 41% of U.S. adults are projected to be obese by 2015 and obesity, a potentially modifiable risk, is emerging as a leading predictor of lifetime health. The wide spectrum of morbidities related to excess body mass includes risks for diabetes, hypertension, coronary artery disease, dyslipidemia, malignancy, venous thrombosis, degenerative joint disease, pulmonary compromise, sleep apnea, cholelithiasis, depression and overall reduced quality of life. Beyond the myriad major and minor morbidities linked to obesity, increased all-cause mortality and cardiovascular mortality is recognized in the obese. Bariatric surgery literature suggests that, in the morbidly obese, increase in the lifespan is achievable with reversal of obesity, reinforcing the realization that sequelae therein are by no means inevitable. Aggressive efforts must be targeted towards population-based strategies to educate and sensitize all generations on contributors to and sequelae of excess body mass as obesity represents one of the few modifiable factors that impact on the quantity and quality of lifespan.

The neuroendocrine physiology of female reproductive aging: An update

The transition into menopause is a complex process that affects fertility and increases the risk for a number of health problems in aging women that include, but are not limited to osteoporosis, heart disease, diabetes mellitus and cognitive dysfunction. Improved nutrition and enhanced access to medical care have increased the average lifespan for women in developed countries, and many will spend more than one-third of their life in a post-menopausal state. Epidemiological studies indicate that a delayed natural menopause confers longevity and decelerates the appearance of much age-related morbidity, suggesting that developing treatments to delay menopause would significantly improve quality of life for women. Although menopause is ultimately defined by ovarian follicular exhaustion, several lines of scientific evidence in humans and animals now suggest that dysregulation of estradiol feedback mechanisms and hypothalamic-pituitary dysfunction contributes to the onset and progression of reproductive senescence, independent of ovarian failure. This article provides a brief update on our current understanding of the role of the hypothalamic-pituitary axis in the onset of and transition into female reproductive senescence.

Implications of blood type for ovarian reserve

BACKGROUND We explored the relevance of blood type to ovarian reserve, as reflected by early follicular phase FSH levels. METHODS For this cross-sectional observational study, early follicular phase serum levels of FSH (mIU/ml) and estradiol (E2, pg/ml), and information on blood type (A, B, AB and O) and patient age were procured for female patients, ≤ 45 years age (n= 544), who were undergoing fertility evaluation at one of two tertiary care facilities. Serum FSH > 10 mIU/ml was taken to reflect diminished ovarian reserve (DOR). Data distribution for FSH and age was analyzed and non-parametric tests used for comparisons across blood groups. Multivariable logistic regression analyses determined the relationship between elevated FSH and respective blood types after adjusting for age and study site. RESULTS Prevalence of blood types according to order of frequency was: O (45%), A (35%), B (16%) and AB (5%). After adjusting for age and study site, patients with blood type O were twice as likely to exhibit FSH > 10 mIU/ml compared with those with A or AB blood types [odds ratio (OR) 2.36; 95% confidence interval (CI) 1.27-4.41; P= 0.007], and three times as likely to manifest FSH > 12 m IU/ml (OR 3.48, 95% CI 1.46-7.32, P= 0.004). The B blood group antigen failed to exhibit any relationship with ovarian reserve as reflected by baseline FSH (P> 0.05). CONCLUSIONS The A blood group antigen appears to be protective for ovarian reserve, whereas blood type O appears to be associated with DOR, in a relationship that is independent of advancing age. Further studies are needed to establish causality and identify the underlying mechanisms for the association.

The continuum of ovarian aging and clinicopathologies associated with the menopausal transition

The increased length of time that women live after the menopause has provided the impetus for the scientific and public communities to better understand the relationship between ovarian aging and pathologic conditions that present later in life. The maximal size of the ovarian germ cell pool occurs at midgestation and is followed by a continuous decline in oogonia through birth, puberty, the reproductive years, and finally, the menopause. The association between the relative hypoestrogenemia that occurs in the menopausal transition and the symptomatology of that stage of life has been widely studied. Similarly, the disease processes associated with prolonged lack of exposure to gonadal steroids has received a great deal of scientific inquiry. Although much progress has been made regarding our understanding of the clinicopathologies that occur later in the life of women, firm conclusions of associations and causality continue to elude physicians and scientists, prompting the need for additional research on this patient population.

Progesterone Threshold Determines Nucleolar Channel System Formation in Human Endometrium

Nucleolar channel systems (NCSs), micron-sized organelles specific to nuclei of human endometrial epithelial cells (EECs), are robust markers of the midluteal phase under the apparent control of progesterone. To gain further insight into the role of progesterone in NCS formation, we quantitatively assessed their sensitivity to oral contraceptive pills (OCPs) using immunofluorescence-based detection of NCSs. Comparison of endometrial biopsies and serum progesterone levels on cycle day (CD) 10 and 20 (LH +6/7) of 6 naturally cycling women and 6 OCP users demonstrated that OCPs interfered with NCS formation on CD20, their natural peak presence. Although this confirmed prior observation based on electron microscopic sampling, OCPs unexpectedly induced limited but distinct amounts of NCSs already on CD10, when they are never present in natural cycles. Thus, OCPs can cause secretory changes in the endometrium during the proliferative phase. In a novel finding, robust NCS formation on CD20 was dependent on a 4 ng/mL progesterone threshold but did not correlate linearly with serum progesterone levels. Given the threshold being close to that serving as evidence for ovulation, NCSs can serve as ovulation markers.

Determinants of female reproductive senescence: Differential roles for the ovary and the neuroendocrine axis

Aging in women is a complex process that begins with the transition into reproductive senescence and evolves to impact not just womens procreative potential but also multiple health-related parameters including longevity. Although somatic aging is an equal opportunity nemesis, certain disease states correlate highly with ovarian failure and the menopause, such as osteoporosis, diabetes, cardiovascular disease, and compromised cognitive function. Epidemiological studies suggest that a delayed natural menopause confers longevity and decelerates the appearance of many of the debilitating morbidities associated with the menopause. However, recent randomized clinical trials assessing the benefits of menopausal hormone therapy during the postmenopause clearly suggest that attenuation of the negative consequences of reproductive aging involves much more than a simple add back of ovarian steroids in the postmenopause. Conflicts between observations in epidemiological studies and in randomized clinical trials give good reason for continued innovative research focused on identifying the mechanisms that bring about the transition from peak reproductive potential to female reproductive quiescence. This article provides a brief update on our current understanding of the physiological and cellular mechanisms that precipitate and/or commit women to transit into reproductive senescence.

Timing the window of implantation by nucleolar channel system prevalence matches the accuracy of the endometrial receptivity array

OBJECTIVE To test if nucleolar channel system (NCS) prevalence matches the accuracy of the endometrial receptivity array (ERA) for identification of the window of endometrial receptivity. DESIGN Comparative retrospective study, May 2008-May 2012. SETTING University-affiliated infertility clinic. PATIENT(S) Forty-nine healthy oocyte donors, regularly cycling, aged 20-34 years with a body mass index of 19-25 kg/m2. INTERVENTION(S) Endometrial biopsies were collected throughout the menstrual cycle. All samples underwent transcriptomic signature identification by ERA testing (performed in a prior study) and quantification of NCS prevalence by using indirect immunofluorescence (performed in the present study). MAIN OUTCOME MEASURE(S) Concordance of ERA results determining the window of implantation with NCS prevalence was statistically analyzed using the kappa index. Based on dating according to the luteinizing hormone surge, specimens were dichotomized into receptive (n=24) and nonreceptive (n=25). The NCS prevalence was expressed as percentage of NCSs per endometrial epithelial cells in each endometrial biopsy. RESULT(S) Concordance of ERA and NCS dating vs. luteinizing hormone yielded comparable kappa indices of 0.878 and 0.836, respectively. Direct comparison of ERA and NCS dating resulted in a kappa index of 0.796. CONCLUSION(S) Prevalence of NCS identifies the window of endometrial receptivity previously identified by their transcriptomic signature using the ERA.

Quantification of nucleolar channel systems: uniform presence throughout the upper endometrial cavity

OBJECTIVE To determine the prevalence of nucleolar channel systems (NCSs) by uterine region, applying continuous quantification. DESIGN Prospective clinical study. SETTING Tertiary care academic medical center. PATIENT(S) Forty-two naturally cycling women who underwent hysterectomy for benign indications. INTERVENTION(S) NCS presence was quantified by a novel method in six uterine regions-fundus, left cornu, right cornu, anterior body, posterior body, and lower uterine segment (LUS)-with the use of indirect immunofluorescence. MAIN OUTCOME MEASURE(S) Percentage of endometrial epithelial cells (EECs) with NCSs per uterine region. RESULT(S) NCS quantification was observer independent (intraclass correlation coefficient 0.96) and its intrasample variability low (coefficient of variation 0.06). Eleven of 42 hysterectomy specimens were midluteal, ten of which were analyzable with nine containing >5% EECs with NCSs in at least one region. The percentage of EECs with NCSs varied significantly between the LUS (6.1%; interquartile range [IQR] 3.0-9.9) and the upper five regions (16.9%; IQR 12.7-23.4), with fewer NCSs in the basal layer of the endometrium (17 ± 6%) versus the middle (46 ± 9%) and luminal layers (38 ± 9%) of all six regions. CONCLUSION(S) NCS quantification during the midluteal phase demonstrates uniform presence throughout the endometrial cavity, excluding the LUS, with a preference for the functional luminal layers. Our quantitative NCS evaluation provides a benchmark for future studies and further supports NCS presence as a potential marker for the window of implantation.

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

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.

How many eggs should I freeze

TO THE EDITOR: We read with great interest the recent publication by Franasiak et al. (1). They retrospectively report the largest published series to date of blastocysts screened for aneuploidy. It brings to mind a question that often is presented to the infertility specialist with regard to elective oocyte cryopreservation to defer childbearing. Howmany oocytes should be frozen at a given age to obtain one live birth? Using data from the Franasiak et al. article, additional data from the same subjects, and some arithmetic extrapolation, perhaps we can make an informed estimate of this number as follows: