Gregory Zapantis

The menopausal transition: characteristics and management

The menopausal transition is a complex period in a womans life, reflecting ovarian ageing and concomitant hormonal changes, in addition to social and metabolic changes. These changes, in turn, influence the signs and symptoms common to this period. Symptoms which are influenced by the hormonal fluctuations occurring during the menopausal transition include vasomotor symptoms and vaginal dryness; others are breast tenderness, poor sleep and pre-menstrual dysphoria. Hormonal therapy has been shown to be first-line therapy for many of these symptoms. Other types of pharmacotherapies may be helpful, including selective serotonergic uptake inhibitors for vasomotor symptoms. Characteristic signs of the menopausal transition include abnormal uterine bleeding, best managed with hormonal pharmacotherapy; diminishing bone mineral density, which may warrant diagnostic intervention, and may benefit from dietary and lifestyle modifications; and increased body-mass index and worsening lipid profile, which also may benefit from dietary and lifestyle modifications.

Premature formation of nucleolar channel systems indicates advanced endometrial maturation following controlled ovarian hyperstimulation

STUDY QUESTION Is there a shift in the timing of nucleolar channel system (NCS) formation following controlled ovarian hyperstimulation (COH)? SUMMARY ANSWER NCSs appear prematurely following COH compared with natural cycles. WHAT IS KNOWN ALREADY During natural cycles, NCSs of endometrial epithelial cell (EEC) nuclei are exclusively present during the window of implantation and are uniformly distributed throughout the upper endometrial cavity. STUDY DESIGN, SIZE, DURATION Prospective two-cohort study. Cohorts I and II each consisted of seven volunteers for the duration of three menstrual study cycles that were separated by at least one wash-out or rest cycle, between December 2008 and May 2012. PARTICIPANTS/MATERIALS, SETTING, METHODS Participants were recruited from a pool of healthy oocyte donors. Consecutive endometrial biopsies were obtained during the same luteal phase on cycle days (CD) 16, 20 and 26 for Cohort I, and on CD14, 22 and 24 for Cohort II, following random assignment to a natural cycle group, a COH cycle group (using a GnRH antagonist), or a COH cycle group receiving luteal phase hormonal supplementation (COH + S). The day of oocyte retrieval was designated CD14 in COH cycles and the day of the LH surge was designated CD13 in natural cycles. Prevalence of NCSs in the nuclei of EECs was quantified using indirect immunofluorescence with an antibody directed against a subset of related nuclear pore complex proteins that are major constituents of NCSs. Progesterone and estradiol levels were measured on the day of each endometrial biopsy. MAIN RESULTS AND THE ROLE OF CHANCE The natural cycle group exhibited peak NCS prevalence on CD20 [53.3%; interquartile range (IQR) 28.5-55.8], which rapidly declined on CD22 (11.8%; IQR 6.3-17.6), CD24 (2.5%; IQR 0.0-9.2) and CD26 (0.3%; IQR 0.0-3.5), and no NCSs on CD14 and 16 defining a short NCS window around CD20. In contrast, in COH and COH + S cycles, NCS prevalence was high already on CD16 (40.4%; IQR 22.6-53.4 and 35.6%; IQR 26.4-44.5, respectively; P = 0.001 compared with CD16 of the natural cycle group, Mann-Whitney), whereas no significant difference in NCS prevalence was detected on any of the other five CDs between the three groups (P > 0.05). LIMITATIONS, REASONS FOR CAUTION The cohort size was small (n = 7) but was offset by the all-or-none presence of NCSs on CD16 in natural versus COH and COH + S cycles and the fact that each subject served as her own control. WIDER IMPLICATIONS OF THE FINDINGS Premature appearance of NCSs and hence maturation of the endometrium following COH is consistent with previous studies based on histological dating but contradicts studies based on mRNA expression profiling, which reported a lag in endometrial maturation. However, this is the first study of this kind that is based on consecutive endometrial biopsies within the same cycle and that reports such clear-cut differences: no versus robust NCS presence on CD16. Our observation of advanced endometrial maturation following COH may contribute to the reduced implantation rates seen in fresh compared with frozen and donor IVF-embryo transfer cycles. Therefore, the NCS window could serve as a sensitive guide for timing of embryo transfer in frozen and donor cycles. STUDY FUNDING/COMPETING INTEREST(S) The study was supported by the March of Dimes Birth Defects foundation (1-FY09-363 to U.T.M.); Ferring Pharmaceuticals, Parsippany, NJ; East Coast Fertility, Plainview, NY and the CMBG Training Program (T32 GM007491 to M.J.S.). We report no competing interests.

The nucleolar channel system reliably marks the midluteal endometrium regardless of fertility status: a fresh look at an old organelle

OBJECTIVE To determine whether nucleolar channel systems (NCSs) in the midluteal endometrium are associated with overall fertility status and/or with unexplained infertility. DESIGN Retrospective and prospective clinical studies. SETTING Repository of stored specimens from prior multicenter study and private infertility center. PATIENT(S) Retrospective study that included 97 women (49 fertile couples, 48 infertile couples) who had been randomized for endometrial biopsy during the midluteal or late luteal phase. The prospective study included 78 women with a variety of infertility diagnoses. INTERVENTION(S) Endometrial biopsies were obtained and assessed for the presence of NCSs by indirect immunofluorescence. MAIN OUTCOME MEASURE(S) The presence of NCS was graded semiquantitatively and dichotomized as normal versus low or absent. RESULT(S) Normal presence of NCS was significantly associated with the midluteal phase compared with the late luteal phase (80% vs. 29%). However, there was no association between presence of NCS and fertility status or between presence of NCS and unexplained infertility. CONCLUSION(S) Midluteal phase endometrium consistently forms NCSs regardless of fertility status, including unexplained infertility. This indicates a possible role for the NCS in initiating the window of endometrial receptivity. However, the consistent presence of NCSs across several different types of infertility challenges the likelihood that inadequate secretory transformation is a cause of infertility.

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.

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.

Status of nucleolar channel systems in uterine secretions accurately reflects their prevalence—a marker for the window of implantation—in simultaneously obtained endometrial biopsies

OBJECTIVE To assess whether nucleolar channel systems (NCSs) can be detected in exfoliated endometrial epithelial cells (EECs) of uterine secretions and whether such noninvasively determined NCS status is associated with significant NCS prevalence in simultaneously obtained endometrial biopsies. DESIGN Prospective study (December 2015-February 2017). SETTING University-affiliated and private fertility clinics. PATIENT(S) Luteal-phase patients of reproductive age requiring endometrial biopsy for medical indications. INTERVENTION(S) Uterine secretion aspiration before endometrial biopsy. Cells in uterine secretions were spun onto slides and fixed. NCSs were identified and quantified in cells and paraffin-embedded tissue sections by indirect immunofluorescence. MAIN OUTCOME MEASURE(S) Comparison of NCS status of uterine secretions with NCS prevalence in biopsies. Based on NCS detection, uterine secretions were assigned a status of NCS-positive (n = 15) or NCS-negative (n = 7). NCS prevalence in biopsies was expressed as a percentage of NCSs per EECs. RESULT(S) NCSs can be detected in exfoliated EECs of uterine secretions. Median NCS prevalence in endometrial biopsies from patients with NCS-positive secretions was 41.9% (interquartile range [IQR], 21.1-53.9) versus 2.0% (IQR, 0-6.9) when secretions were NCS-negative. The NCS status of secretions identified a significant difference in NCS prevalence of simultaneously obtained biopsies. CONCLUSION(S) NCS status of secretions accurately reflects NCS prevalence of biopsies, a marker for the implantation window. As secretion aspiration is compatible with same-day ET, our study provides proof of principle for a minimally invasive approach to determine endometrial receptivity for timing frozen ET.