Serum Progesterone Profile Across the Mid and Late Luteal Phase in Artificial Cycles Is Associated With Pregnancy Outcome

IntroductionRecent studies have shown that low serum progesterone levels on the day of embryo transfer (ET) are associated with poorer pregnancy outcome in hormonal replacement therapy cycles. It is of interest to know if serum progesterone levels during late luteal phase (following days after ET) are also related with the chances of ongoing pregnancy.ObjectiveTo evaluate the luteal phase endocrine profile through measurements of serum progesterone and estradiol on days ET+4, ET+7 and ET+11, to test their predictive value in relation to pregnancy outcome.SettingPrivate infertility center, Valencia, Spain.Materials and MethodsProspective cohort study performed between June 2017 and August 2018. Eligible patients were aged between 18-42 years, with a normal uterus, and being transferred 1-2 good quality blastocysts in a frozen ET cycle after an artificial endometrial preparation with estradiol valerate and vaginal micronized progesterone (400 mg/12 hours).ResultsA total of 127 patients were included. Mean age = 38.0 ± 3.9 years; BMI = 23.6 ± 3.6 kg/m2; endometrial thickness = 9.1 ± 1.6mm. Overall ongoing pregnancy rate = 47.2% (95%CI:38.3-56.3). Significantly higher levels of serum progesterone were observed on ET+4 (13.6 ± 6.0 vs. 11.1 ± 4.6ng/ml, p = 0.03) and ET+11 (15.7 ± 1.2 vs. 10.3 ± 0.6ng/ml, respectively; p = 0.000) in ongoing pregnancies versus negative β-hCG (β-human chorionic gonadotrophin) cases. On ET+7, ongoing pregnancies also had higher serum progesterone levels (14.2 ± 0.9 vs. 11.7 ± 0.8ng/ml, but did not reach statistical significance (p = 0.07). Serum estradiol levels were not related with pregnancy outcome at any moment of the luteal phase (p > 0.05). On days ET+4, +7 and +11, the ROC analysis showed that serum progesterone levels were predictive of ongoing pregnancy, and Pearson’s coefficient showed a significant association (p<0.05) of serum β-hCG levels with serum progesterone.ConclusionsIn hormonal replacement therapy cycles, serum progesterone levels across luteal phase days are associated with pregnancy outcome. Ongoing pregnancies were associated with a higher exposure to progesterone in comparison with pregnancy losses or negative β-hCG. Therefore, serum progesterone might be playing an important role not only during implantation, but also in pregnancy maintenance. It remains unknown if the variability in serum progesterone levels among patients, after receiving the exact same progesterone dose for luteal phase support, is the cause or just a consequence of pregnancy results.

Insomnia, Inattention and Fatigue Symptoms of Women with Premenstrual Dysphoric Disorder

Aim: Premenstrual dysphoric disorder (PMDD) has predictable, cyclic, psychological, and somatic symptoms, such as sleep problems. They result in functional impairment, are aggravated in the late luteal phase of the menstrual cycle, and are resolved by menstruation. The present study evaluated the insomnia, inattention, and fatigue symptoms of PMDD and their fluctuations during the menstrual cycle. Methods: A total of 100 women were diagnosed as having PMDD based on psychiatric interviews and a prospective investigation of three menstrual cycles. A total of 96 individuals without PMDD were recruited as controls. Their symptoms, namely insomnia, inattention, and fatigue as well as functional impairment were assessed by using the premenstrual symptoms screening tool, the Pittsburgh insomnia rating scale, the attention and performance self-assessment scale, and the fatigue-assessment scale during both premenstrual and follicular phases. Results: In both the premenstrual and follicular phases, women with PMDD experienced more severe insomnia, inattentiveness, and fatigue than did women in the control group. A paired t-test demonstrated that women with PMDD had more severe severity insomnia, inattentiveness, and fatigue in the luteal phase than in the follicular phase. A repeated-measures analysis of variance demonstrated that the interaction period of PMDD and a menstrual cycle was significantly associated with insomnia, inattentiveness, and fatigue. A further correlation analysis demonstrated that all three symptoms were positively associated with self-reported functional impairment due to PMDD. Conclusions: Our results demonstrated that women with PMDD experienced an exacerbation of insomnia, memory problems, difficulty maintaining focus, and fatigue in the premenstrual phase. These symptoms are correlated with PMDD symptoms severity and functional impairment, and as such, they should be evaluated, and interventions should be employed in the late luteal phase of women with PMDD.

Serum Concentrations of GDF9 and BMP15 Across the Menstrual Cycle

Growth differentiation factor-9 (GDF9) and bone morphogenetic protein-15 (BMP15) are TGF-β proteins that regulate key processes throughout folliculogenesis and are determinants of mammalian fecundity (1). They are uniquely produced predominantly by the oocyte and have potential clinical application as markers of oocyte quality and quantity (2). However, no studies have been conducted to assess whether serum concentrations alter across the different phases of the menstrual cycle, and thus if assessment should be confined to specific cycle stages. The aim of this study was to measure serum concentrations of these proteins during the menstrual cycle in women at different stages of reproductive life. Serum was collected every 1-3 days throughout the menstrual cycle from 41 healthy ovulatory women from three cohorts: menses to late luteal phase (21-29 years of age; n=16; University of Otago) and across one interovulatory interval (18-35 years of age; n=10; and 45-50 years of age; n=15; University of Saskatchewan), with simultaneous ultrasound scans confirming ovulation. Serum concentrations of GDF9, BMP15, estradiol, FSH, LH, progesterone, inhibin A and B and AMH were measured. GDF9 and BMP15 were detectable in 54% and 73% of women and varied 236- and 52-fold between women, respectively. To detect changes, mean concentrations and variances across the cycle were statistically modelled using a generalized additive model of location, shape and scale (GAMLSS). Across the menstrual cycle, there were minimal changes in serum GDF9 or BMP15 within a woman for all cohorts, with no significant differences detected in modelled mean concentrations. However, modelled variances were highest in the luteal phases of all women for BMP15 immediately following ovulation, regardless of age, suggesting a possible underlying cyclic pattern. These results suggest that serum BMP15 and GDF9 are not overtly affected by menstrual cycle dynamics but may be more stable in the follicular phase. Larger studies with more frequent sampling should establish if BMP15 and presumably GDF9 demonstrate clinically relevant cyclic variation. References: (1) Gilchrist RB et al., HRU 2008; 14:159-77. (2) Riepsamen AH et al., Endocrinol 2019; 160:2298-313.

Increased Incidence of Premenstrual Syndrome in Females with Palmar Hyperhidrosis

Background: Premenstrual syndrome (PMS) is a common disorder affecting the quality of life of women of reproductive age. In a previous study, sex hormone imbalances and alterations in autonomic function were present in PMS, with parasympathetic dysfunction and sympathetic overactivity during the late luteal phase. Palmar hyperhidrosis (PH) presents with oversweating, heat and emotional stimulation, sympathetic hyperactivity and parasympathetic hypofunction. We hypothesized that the incidence of PMS is increased in females with PH. Methods: Data were retrieved from the Taiwanese National Health Insurance Database. The patients with PH were identified by the International Classification of Disease, 9th Revision, Clinical Modification (ICD-9-CM) disease code 780.8. Female patients matched by age and index day were used as the control group. The incidence of PMS was considered an outcome by the ICD-9-CM disease code 625.4. The factors related to PMS were analyzed by Cox regression. Results: The adjusted hazard ratio for the incidence of PMS was 1.276 (95% confidence interval: 1.05–1.488) in females with PH. Conclusions: This study found a positive correlation between PMS and female PH patients. Patients and physicians must understand the relationship of PMS with autonomic function alterations and other risk factors to prevent this problematic disorder.

Changes in Aquaporin 1, 5 and 9 Gene Expression in the Porcine Oviduct According to Estrous Cycle and Early Pregnancy

Aquaporins (AQPs) are a group of small, integral membrane proteins which play an important role in fluid homeostasis in the reproductive system. In our previous study, we demonstrated AQP1, 5 and 9 protein expression and localization in the porcine oviduct. The presence of these isoforms could suggest their role in the transport of the ovum to the uterus by influencing the epithelial cells’ production of oviductal fluid. The aim of this study was to evaluate the expression of AQP1, AQP5 and AQP9 in the infundibulum, ampulla and isthmus in the porcine oviduct during the estrous cycle (early luteal phase, days 2–4, medium luteal phase, days 10–12, late luteal phase days 14–16, follicular phase days 18–20) and pregnancy (period before implantation, days 14–16 and after the implantation, days 30–32) using the Real-Time PCR technique. As clearly demonstrated for the first time, AQP1, 5, and 9 gene expression is influenced by the estrus cycle and pregnancy. Furthermore, expression of AQPs in the porcine oviduct may provide the physiological medium that sustains and enhances fertilization and early cleavage-stage embryonic development. Overall, our study provides a characterization of oviduct AQPs, increasing our understanding of fluid homeostasis in the porcine oviduct to successfully establish and maintain pregnancy.

Hormonal Profiles of Menstrual Bleeding Patterns During the Luteal-Follicular Transition

Context Menstrual cycle function is determined by a complex endocrine axis that controls the ovaries and endometrium. While the late luteal phase is characterized by declining progesterone and estrogen, how these hormonal profiles relate to menstrual bleeding patterns is not well understood. Objective Characterize associations between luteal phase hormonal profiles and subsequent menstrual bleeding patterns, specifically spotting before bleeding. Design, Setting, and Participants We examined creatinine-adjusted urinary estrone 3-glucuronide (E13G) and pregnanediol 3-glucuronide (Pd3G) levels in relation to spotting in 116 premenopausal women (ages 20–47) who kept daily menstrual diaries and collected first morning urine samples for ≥ 2 consecutive cycles or 1 luteal-follicular transition (n = 283 transitions). We used linear mixed models to estimate associations between luteal phase hormone levels and spotting before bleeding. Main Outcome Measure(s) and Results Transitions with ≥ 1 days of spotting before menstrual bleeding (n = 118) had greater luteal phase Pd3G levels vs nonspotting transitions (n = 165). Differences in Pd3G between spotting and nonspotting transitions were largest at menses onset (34.8%, 95% confidence interval, 18.9%, 52.7%). Pd3G levels for spotting transitions dropped to similar levels as nonspotting transitions an average of 1 day later, which aligned with the first day of bleeding for transitions with contiguous spotting. Spotting transitions were preceded by slower rates of Pd3G decline than nonspotting transitions, whereas E13G declines were similar. Conclusions Self-reported bleeding patterns may provide insight into luteal phase Pd3G levels. First bleed appears to be the best choice for defining the end of the luteal phase and achieving hormonal consistency across transitions.

Metabolomic Profile of Oviductal Extracellular Vesicles across the Estrous Cycle in Cattle

Oviductal extracellular vesicles (oEVs) have been proposed as key modulators of gamete/embryo maternal interactions. The aim of this study was to examine the metabolite content of oEVs and its regulation across the estrous cycle in cattle. Oviductal EVs were isolated from bovine oviducts ipsilateral and contralateral to ovulation at four stages of the estrous cycle (post-ovulatory stage, early and late luteal phases, and pre-ovulatory stage). The metabolomic profiling of EVs was performed by proton nuclear magnetic resonance spectroscopy (NMR). NMR identified 22 metabolites in oEVs, among which 15 were quantified. Lactate, myoinositol, and glycine were the most abundant metabolites throughout the estrous cycle. The side relative to ovulation had no effect on the oEVs’ metabolite concentrations. However, levels of glucose-1-phosphate and maltose were greatly affected by the cycle stage, showing up to 100-fold higher levels at the luteal phase than at the peri-ovulatory phases. In contrast, levels of methionine were significantly higher at peri-ovulatory phases than at the late-luteal phase. Quantitative enrichment analyses of oEV-metabolites across the cycle evidenced several significantly regulated metabolic pathways related to sucrose, glucose, and lactose metabolism. This study provides the first metabolomic characterization of oEVs, increasing our understanding of the potential role of oEVs in promoting fertilization and early embryo development.

Women Have Reduced Ability to Discriminate Body Odors During the Withdrawal Period of Oral Contraception

Introduction Women’s olfactory perception varies across the menstrual cycle. The influence of oral contraceptives on this variability remains unclear. Methods To further estimate this, we assessed discrimination performance for both body odors and ordinary odorants in 36 women, 18 naturally ovulating, and 18 using oral contraceptives. Each participant was tested once a week over the course of a month, and data was then parsed into menstrual phases. Results In naturally ovulating women, at the transition from follicular to luteal phases, there was a decline of 19% (p = 0.003) in olfactory discrimination of body odors but not ordinary odorants. In turn, in women using oral contraceptives, only at a later time of the month, at a point corresponding to the late luteal phase and shift from post-ovulation to pre-menstruation, was there a decline of 20% (p = 0.002) in olfactory discrimination performance. Moreover, when we reorganized the data from women using oral contraceptives in order to separately assess the contraceptive withdrawal period (the few days off pills), we observed a 23% reduction (p = 0.01) in discrimination accuracy of body odors but not ordinary odorants during this time alone. Conclusions Women have reduced ability to discriminate body odors during the withdrawal period of oral contraception. Implications If women indeed consider men’s body odor in their mate selections, then the oral contraception withdrawal period may not be the best time to make such decisions.

Early- and Late-Luteal-Phase Estrogen and Progesterone Levels of Women with Premenstrual Dysphoric Disorder

: Objective/introduction: The dynamics of ovarian hormone fluctuations during the luteal phase of the menstruation cycle were previously suggested to contribute to the development of premenstrual dysphoric disorder (PMDD) symptoms, but adequate empirical evidence has not been obtained from hormone concentration studies. We prospectively evaluated estrogen and progesterone levels in the early luteal (EL) and late luteal (LL) phases in women with PMDD and the association of these levels with PMDD symptom severity. Methods: 63 women with PMDD and 53 controls without such severe symptoms were evaluated for the estrogen and progesterone levels, and PMDD severity in the EL and LL phases. Results: The results demonstrated that the women with PMDD had a lower EL-phase estrogen level than the controls. Covariant analysis demonstrated that the interaction term between EL-phase estrogen and EL-phase progesterone level was associated with PMDD severity. Among women with lower EL estrogen levels, higher EL-phase progesterone was observed among the women with PMDD versus controls. These results suggest that low EL-phase estrogen level could moderate the provoking effect of EL progesterone in women with PMDD. Overall, these data suggest a possible role of estrogen and progesterone in the development of PMDD symptoms.