Midfollicular Phase Research Articles

Steroid profile of porcine follicular fluid and blood serum: Relation with follicular development.

The aim of this study was to identify follicular fluid (FF) steroids which reflect follicular development in the early stages of the follicular phase and to establish whether the levels of these FF steroids correspond to their levels in serum. If these relations are established, serum steroid profiles may be used to monitor follicular development already in this early stage of the follicular phase. We used samples of two experiments, one with multiparous sows at the onset of the follicular phase (weaning) and one with primiparous sows at the midfollicular phase (48 hr after weaning). Complete steroid profiles were measured in pooled FF of the 15 largest follicles and serum using high‐performance liquid chromatography‐tandem mass spectrometry. In experiment 1, pooled FF volume, as a measure for average follicle size, tended to be positively related to higher FF 17β‐estradiol levels (β = 0.56, p = .08). In experiment 2, a larger FF volume was related not only to FF higher 17β‐estradiol levels (β = 2.11, p < .001) but also to higher levels of β‐nortestosterone (β = 1.15, p < .0001) and its metabolite 19‐norandrostenedione (β = 1.27, p < .01). In addition, FF volume was related to higher FF 17α‐OH‐pregnenolone (β = 1.63, p = .03) and 17α‐OH‐progesterone (β = 1.83, p < .001), which could indicate that CYP17,20‐lyase activity is limiting for 17β‐estradiol production in larger follicles at the beginning of the follicular phase. In serum, most of the steroids were present at lower levels compared to FF, except for the corticosteroids. Serum progestins and androgens were never related to follicle pool volume and steroid levels did not differ in the midfollicular phase compared to the onset of the follicular phase in the second experiment. Serum steroid levels therefore poorly reflect the developmental stage of the follicle pool in the first half of the follicular phase of the estrous cycle in sows.

Visual Vignette

Case Presentation: A 25-year-old woman presented with galactorrhea to the endocrinology clinic. She had regular menstrual cycles until she began depot medroxyprogesterone a few years prior. She denied headaches or visual changes. She had no significant past medical or surgical history. On exam, she had a normal visual field on confrontation test. She did not have appreciably delayed reflexes or dry skin. Lab evaluations revealed a prolactin of 69 ng/mL (normal, 3.0 to 30.0 ng/mL). Prolactin dilution ruled out a hook effect. Other hormones levels were: TSH >150 mIU/L (normal, 0.40 to 4.50 mIU/L), free T4 0.4 ng/dL (normal, 0.8 to 1.8 ng/dL), and AM cortisol 13.4 mcg/dL (normal, 4.0 to 22 mcg/dL). Thyroid peroxidase antibody was 394 IU/mL (normal, <9 IU/mL) and thyroglobulin antibody was 2 IU/mL (normal, ≤1 IU/mL). LH was <0.2 mIU/mL (normal in midfolicular phase, 2.12 to 10.89 mIU/mL) and FSH was 4.6 mIU/mL (normal in midfollicular phase, 3.85 to 8.78 mIU/mL). Visual field testing revealed mild field cut bilaterally. Magnetic resonance imaging (MRI) of the brain revealed a 2 × 1.5 × 1 cm pituitary mass impinging on the optic chiasm (Fig. 1). The patient was initiated on levothyroxine which resulted in resolution of galactorrhea and hyperprolactinemia. It also led to a significant reduction of the size of the pituitary mass (Fig. 2) and resolution of the visual field defect within one year. What is the diagnosis? Fig. 2 View Large Image Figure Viewer

OR25-6 Higher Ovarian Androgen Responses to Ambient Luteinizing Hormone and to Recombinant Human Chorionic Gonadotropin Stimulation in Late Pubertal Girls with Obesity

Our studies suggest that 60% of obese peripubertal girls have androgen excess, a precursor to polycystic ovary syndrome. Since the ovary is a major source of androgens in women, we studied steroid levels after dexamethasone (DEX) and after recombinant human chorionic gonadotropin (r-hCG) in girls to assess how obesity affects ovarian androgens during puberty. We studied 41 peripubertal girls in the mid-follicular phase (if relevant, 11 were pre-menarcheal): age 13.2 ± 3.0 (7.3-18.8) y (mean ± SD [range]); BMI Z-score 1.2 ± 1.1 (-1.08 to +2.64); Tanner breast 4.0 ± 1.3 (1-5); bone age 14.2 ± 2.9 (7.8-18) y. In early pubertal girls (Tanner 1-3), 5 were normal weight (NW, BMI%-for-age [BMI%] 5-84) and 6 overweight (OW, BMI% ≥ 85). In late pubertal girls (Tanner 4-5), 12 were NW and 18 OW. DEX (1 mg po) was given at 10 pm. At 7 am the next day, progesterone (P4), 17-OH progesterone (OHP), 17-OH pregnenolone, androstenedione (A4), dehydroepiandrosterone (DHEA), testosterone (T), estradiol (E2), and anti-mullerian hormone were measured immediately before r-hCG (25 mcg IV) was given. DEX was again given at 10 pm; hormone levels were repeated 24h after r-hCG. Free T was calculated using SHBG. Forty girls also had frequent (q 10 min) LH sampling from 7 pm-7 am. Comparisons were made using Student’s t-tests. In early pubertal girls, NW girls had higher DHEA levels after r-hCG compared to OW girls (2.46 ± 1.07 vs. 1.23 ± 0.68 ng/dL, p=0.04). In late puberty, OW girls had higher free T after DEX (19.3 ± 15.6 vs. 8.6 ± 4.1 pmol/L, p=0.03) and after r-hCG (27.2 ± 22.3 vs. 10.7 ±4.5 pmol/L, p=0.02) versus NW girls. OW girls also had higher total T levels after DEX (21.7 ± 15.2 vs. 16.7 ± 7.4 ng/dL, p=0.3) and after r-hCG (30.0 ± 20.4 vs. 21.1 ± 10.2 ng/dL, p=0.2), but did not achieve significance. SHBG was lower in OW versus NW girls in late puberty only (20.7 ± 13.4 vs. 48.0 ± 21.8 nmol/L, p=0.0002). No other hormone levels were different. Overnight mean LH was not different for NW and OW groups, for either early or late puberty. However, in late pubertal girls, 33% in OW group had mean LH values ≥ 5 (5.3-9.3) mIU/mL compared to 17% in NW group. Compared to OW girls with mean LH < 5, OW girls with mean LH ≥ 5 had higher OHP, A4, free T, and total T after DEX and after r-hCG (p ≤ 0.05 for all, except A4 after r-hCG [p=0.06]). Results suggest that OW late pubertal girls had higher free T levels after DEX, which may reflect steady-state ovarian androgen production related to ambient LH milieu. OW late pubertal girls had higher free T levels after r-hCG, which may suggest increased capacity to produce ovarian androgens in response to stimulation. In a subgroup of OW girls, obesity during late puberty was associated with higher mean LH values and higher androgen levels after DEX and r-hCG, in keeping with our earlier reports that LH levels predict free T levels in girls with obesity.

Effects of menstrual cycle phase on associations between the error-related negativity and checking symptoms in women

The menstrual cycle is known to impact mood and cognitive function and has been shown to lead to variability in symptoms of obsessive-compulsive disorders and anxiety. Using a within-subject design, the present study examined ovarian hormones, the error-related negativity (ERN), and self-reported checking symptoms in both the mid-follicular and mid-luteal phases of the menstrual cycle. ERN amplitude and checking symptom severity did not vary between the follicular and luteal phases. However, a more negative ERN was associated with greater checking symptoms in the luteal phase of the menstrual cycle, even when controlling for ERN amplitude in the follicular phase. Moreover, changes in checking symptoms between phases were associated with phase-related changes in the ERN. Finally, a significant mediation model was found such that the ERN measured in the luteal phase mediated the association between progesterone in the luteal phase and checking symptoms in the luteal phase. Collectively, the present findings suggest that levels of progesterone in the luteal phase could impact checking symptoms by modulating response monitoring and sensitivity to errors, and that fluctuation in the ERN between menstrual cycle phases may play an important role in the expression of anxious and obsessive-compulsive symptoms.

Female sex hormones and the recovery from exercise: Menstrual cycle phase affects responses.

Evidence supports female sex hormones have an influencing effect on a multitude of physiological and psychological systems related to exercise. Little is known, however, whether is effect persist into the recovery from exercise. Our objective was to examine aspects of muscle damage/inflammation process during recovery in healthy, exercise-trained women following endurance activity at the mid-follicular (MF; low sex hormone level) and mid-luteal (ML; elevated sex hormone levels) phases of their menstrual cycle. The MF and ML exercise sessions consisted of running for 90 minutes at 70% VO2max on a treadmill in a controlled laboratory environment. Menstrual cycle phase was hormonally confirmed, diet and physical activity was control throughout the study. Outcome measures were: blood creatine kinase (CK) and interleukin-6 (IL-6) assessed at immediate-post exercise (IP), 24-hour and 72-hour into recovery. Statistics involved ANOVA procedures. At 24-hours and 72-hour into recovery CK activity was greater in MF than ML (p < 0.05) while for IL-6 at IP, 24-hour and 72-hour responses were significantly greater at MF than at ML (p < 0.05). A more robust recovery CK and IL-6 response occur in the MF of the menstrual cycle when female sex hormones are reduced. This finding suggests female sex hormone changes due to menstrual cycle phase affect the physiologic responses during the extended recovery period from intensive exercise in eumenorrheic women.

Endogenous Oxytocin Levels in Relation to Food Intake, Menstrual Phase, and Age in Females.

Oxytocin regulates a range of physiological processes including eating behavior and oxytocin administration reduces caloric intake in males. There are few data on oxytocin and eating behavior in healthy females or on the response of endogenous oxytocin to food intake and its relationship to appetite in humans. To determine the postprandial pattern of oxytocin levels, the relationship between oxytocin and appetite, and the impact of menstrual cycle phase and age on oxytocin levels in females. Cross-sectional. Clinical research center. Fifty-five healthy females (age 10 to 45 years). A standardized mixed meal was administered. Blood sampling for oxytocin occurred at fasting and at 30, 60, and 120 minutes postmeal. Appetite was assessed using Visual Analogue Scales pre- and postmeal. Mean fasting oxytocin levels were 1011.2 ± 52.3 pg/mL (SEM) and decreased at 30 and 60 minutes postmeal (P = 0.001 and P = 0.003, respectively). Mean oxytocin levels decreased19.6% ± 3.0% from baseline to nadir. Oxytocin area under the curve was lower in the early to midfollicular menstrual cycle phase (P = 0.0003) and higher in younger females (P = 0.002). The percent change in oxytocin (baseline to nadir) was associated with postprandial hunger (rs = -0.291, P = 0.03) and fullness (rs = 0.345, P = 0.009). These relations remained significant after controlling for calories consumed, menstrual cycle status, and age (P = 0.023 and P = 0.0001, respectively). Peripheral oxytocin levels in females decrease after a mixed meal and are associated with appetite independent of menstrual phase, age, and caloric intake, suggesting that endogenous oxytocin levels may play a role in perceived hunger and satiety.

Sex differences during emotion processing are dependent on the menstrual cycle phase

Sex differences in the neural processing of emotion are of special interest considering that mood and anxiety disorders predominant in females. However, these sex-related differences were typically studied without considering the hormonal status of female subjects, although emotion processing in the brain was shown to differ between phases of the menstrual cycle. In this functional MRI study, we demonstrated the influence of the menstrual cycle phase on sex differences in brain activity and functional connectivity during negative and positive emotions, using two different paradigms: emotion perception and emotion experience. Twenty naturally cycling healthy women without premenstrual symptoms were scanned twice: during the mid-follicular and late-luteal menstrual phases, and compared to a matched group of twenty healthy men. During negative emotion perception, men showed increased neural activity in the right hippocampal formation relative to women in the mid-follicular phase, and increased activity in the right cerebellum relative to women in the late-luteal phase. During experience of amusement, reduced putamen-ventrolateral prefrontal cortex and putamen-dorsomedial prefrontal cortex functional connectivity were observed for women in the late-luteal phase relative to men and associated with levels of sex hormones. These neural and hormonal findings were complemented by behavioral reports of reduced amusement and increased sadness in late-luteal women. Our results demonstrate menstrual phase-dependent sex differences in emotion perception and experience and may suggest a biological tendency for a deficient experience of pleasure and reward during the late-luteal phase. These findings may further shed light on the underlying pathophysiology of premenstrual dysphoric disorder.

Alternation of ten-eleven translocation 1, 2, and 3 expression in eutopic endometrium of women with endometriosis-associated infertility

Little is known about the differences in ten-eleven translocation 1, 2, and 3 (TET1-3) expression in the endometrial phases in eutopic endometrium from infertile women with endometriosis (IWE) and fertile women without endometriosis (FW). Using RT-qPCR and western blot analysis, we assessed the TET expression in the mid-follicular and mid-luteal phases in eutopic endometrium from IWE (n = 38) and FW (n = 18). Both IWE and FW underwent laparoscopic and histological examinations for endometriosis. In the mid-luteal eutopic endometrium in IWE, compared to that of FW, we found significantly reduced levels of TET1 transcripts and proteins (p = .001 and p = .003, respectively) at the severity stage of I/II (p = .029 and p = .003, respectively) and transcripts only at the severity stage of III/IV (p = .003). In the mid-follicular eutopic endometrium of IWE, compared to that of FW, there was a statistically significant reduction in TET2 transcript levels at the severity stage of III/IV (p = .037). Compared to the mid-follicular endometrium, we found a statistically significant increase in TET3 transcript levels during the mid-luteal phase in the eutopic endometrium of all IWE (p = .034) and in the severity stage of III/IV (p = .025). We observed a change in the expression levels of TET1-3 in the eutopic endometrium of IWE.

Analysis of the Effect of Menstrual Cycle Phases on Aerobic-Anaerobic Capacity and Muscle Strength

The objective of this study is to examine the effect of menstrual cycle phases on aerobic-anaerobic capacity and muscle strength. 10 female kickboxing athletes with an average age of 21.40±2.01 years; average height of 169.60±6.14 cm; average weight of 63.90±5.76 kg and average training age of 7.41±2.10 participated in the study. On the first day, maximal strength (1RM), strength endurance, wingate anaerobic power and capacity test (WAnT) were conducted and aerobic measurements were taken the next day. The measurements were conducted in follicular phase on the days 2-3rd of menstrual bleeding, in mid-follicular phase on 8-9th days and in luteal phase on 22-23th days. The data were analyzed with Friedman repeated measurements variance analysis. According to the results of the study, it was found that kickboxing athletes’ aerobic-anaerobic capacity, 1RM, strength endurance and heart rate (HR) were not affected by follicular phase, mid-follicular phase and luteal phase (p&gt;0.005). As a conclusion, it can be said that menstrual cycle does not influence performance parameters such as muscle strength, muscle endurance and aerobic-anaerobic capacity.

Effectiveness of Fish Oil Supplementation in Attenuating Exercise-Induced Muscle Damage in Women During Midfollicular and Midluteal Menstrual Phases.

McKinley-Barnard, SK, Andre, TL, Gann, JJ, Hwang, PS, and Willoughby, DS. Effectiveness of fish oil supplementation in attenuating exercise-induced muscle damage in females during midfollicular and midluteal menstrual phases. J Strength Cond Res 32(6): 1601-1612, 2018-The purpose of this study was to determine whether the differences in estrogen levels during the female menstrual cycle and fish oil supplementation would attenuate eccentric exercise-induced muscle damage and delayed-onset muscle soreness (DOMS). In a double-blind fashion, 22 physically active females (20.9 ± 1.4 years, 63.5 ± 9.0 kg, 165.2 ± 7.5 cm) were randomly assigned to ingest either 6 g of fish oil (n = 11) or placebo (n = 11) daily for 21 days. Participants underwent an eccentric exercise bout of the knee extensors on 2 occasions during the midfollicular (MF) and midluteal (ML) phases of the 28-day menstrual cycle. Before (PRE), at 6 (6HRPOST), and at 24 hours postexercise (24HRPOST) for each session, participants underwent assessments of DOMS, muscle strength, and had venous blood samples and muscle biopsies obtained. Data were analyzed using a 2 × 2 × 3 repeated-measures multivariate analysis of variance for each criterion variable (p ≤ 0.05). Further analysis of the main effects for the test was performed using separate 1-way analyses of variance. Delayed-onset muscle soreness was significantly greater at the 6HRPOST and 24HRPOST timepoints compared with PRE (p < 0.001). Superoxide dismutase and tumor necrosis factor-alpha (TNF-α) concentrations were significantly higher at the MF phase compared with the ML phase (p < 0.001 and p = 0.05, respectively). There were no statistically significant differences observed for muscle strength, myoglobin, NF-Kβ p50, or NF-Kβ p65. This study demonstrates that higher levels of estrogen may exert a cytoprotective effect on the sarcolemma.

Brachial artery endothelial function is unchanged after acute sprint interval exercise in sedentary men and women.

What is the central question of this study? What is the acute brachial artery endothelial function response to sprint interval exercise and are there sex-based differences? What is the main finding and its importance? Brachial artery endothelial function did not change in either men or women following an acute session of SIT consisting of 3×20s 'all-out' cycling sprints. Our findings suggest this low-volume protocol may not be sufficient to induce functional changes in the brachial artery of sedentary, but otherwise healthy adults. Sprint interval training (SIT) is a potent metabolic stimulus, but studies examining its acute effects on brachial artery endothelial function are limited. The influence of oestradiol on the acute arterial response to this type of exercise is also unknown. We investigated the brachial artery endothelial function response to a single session of SIT in sedentary healthy men (n=8; 22±4years) and premenopausal women tested in the mid-follicular phase of the menstrual cycle (n=8; 21±3years). Participants performed 3×20s 'all-out' cycling sprints interspersed with 2min of active recovery. Brachial artery flow-mediated dilatation (FMD) and haemodynamic parameters were measured before and 1 and 24h post-exercise. Despite attenuations in some haemodynamic parameters at 1 h post-exercise, there were no changes in absolute (P=0.23), relative (P=0.23) or allometrically scaled FMD (P=0.38) following a single session of SIT. Resting and peak dilatory diameters did not change in men or women (P>0.05 for all) and there were no interactions between time and sex for any measure (P>0.05). Oestradiol was not correlated with relative FMD at baseline (r=-0.22, P=0.42) or with the change in relative FMD from baseline to 1h post-exercise (r=0.24, P=0.40). Overall, brachial artery FMD appears to be unchanged in men and women following an acute session of SIT, and the higher oestradiol concentrations in women do not augment the baseline or post-exercise FMD response. The 3×20s model of low-volume sprint interval exercise may not be sufficient to alter brachial artery endothelial function in healthy men and women.

Brachial artery endothelial function is stable across a menstrual and oral contraceptive pill cycle but lower in premenopausal women than in age-matched men.

Sex hormone concentrations differ between men, premenopausal women with natural menstrual cycles (NAT), and premenopausal women using oral contraceptive pills (OCP), as well as across menstrual or OCP phases. This study sought to investigate how differences in sex hormones, particularly estradiol, between men and women and across cycle phases might influence brachial artery endothelial function. Fifty-three healthy adults (22 ± 3 yr, 20 men, 15 NAT women, and 18 second-, third-, or fourth-generation OCP women) underwent assessments of sex hormones and endothelial [flow-mediated dilation (FMD) test] and smooth muscle [nitroglycerin (NTG) test] function. Men were tested three times at 1-wk intervals, and women were tested three times throughout a single menstrual or OCP cycle (NAT: menstrual, midfollicular, and luteal phases and OCP: placebo/no pill, "early", and "late" active pill phases). Endogenous estradiol concentration was comparable between men and women in their NAT menstrual or OCP placebo phase ( P = 0.36) but increased throughout a NAT cycle ( P < 0.001). Allometrically scaled FMD did not change across a NAT or OCP cycle but was lower in both groups of women than in men ( P = 0.005), whereas scaled NTG was lower only in NAT women ( P = 0.001). Changes in estradiol across a NAT cycle were not associated with changes in relative FMD ( r2 = 0.01, P = 0.62) or NTG ( r2 = 0.09, P = 0.13). Duration of OCP use was negatively associated with the average relative FMD for second-generation OCP users only ( r = -0.65, P = 0.04). Our findings suggest that brachial endothelial function is unaffected by cyclic hormonal changes in premenopausal women but may be negatively impacted by longer-term use of second-generation OCPs. NEW & NOTEWORTHY We demonstrate that brachial artery flow-mediated dilation does not change across a menstrual or oral contraceptive pill cycle in premenopausal women but is lower in women than in men. Although unaffected by within-cycle changes in estradiol, brachial flow-mediated dilation is negatively correlated with duration of oral contraceptive pill use for second-generation pills.

Menstrual Cycle Influence on Hepcidin Secretion and Inflammatory Reponses in Female Athletes. IronFEMME Pilot Study

Deficient iron absorption may be conditioned by an increase in inflammatory markers and hepcidin levels after exercise. The interaction between inflammatory markers and hepcidin along menstrual cycle is still unknown. PURPOSE: To elucidate the effect of hormonal fluctuations during menstrual cycle on inflammatory and hepcidin responses after endurance exercise METHODS: Thirteen healthy eumenorrheic endurance-trained women (34.9± 4.2 years; 163.9±6.1 cm; 58.4±5.5 kg; peak oxygen consumption (VO2peak) 49.7±3.1 ml·min-1·kg-1) participated in the study. Subjects performed 40 min running on a treadmill at the speed corresponding to the 75% of VO2peak. Exercise was performed in three different moments: during early follicular (EFP), mid-follicular (MFP) and luteal phase (LP). Blood samples were obtained at baseline and immediately (Post0h) and 3 hours (Post3h) after exercise and were analyzed for interleukin-6 (IL-6), C-reactive protein (CRP) and hepcidin. Mixed linear models were conducted to analyze the data. RESULTS: Hepcidin (ng/ml) was not different across menstrual cycle phases (EFP: 76.5±25.3; MFP: 78.4±19.5; LP: 78.0±23.0; p=0.762). Time was significant (p=0.001) on Hepcidin with higher values at Post0h (81.9±21.5) compared to Baseline (74.2±24.1) and Post3h (76.8±21.9). IL-6 (pg/ml) levels were not different over menstrual cycle (EFP: 3.5±3.0; MFP: 3.0±1.5; LP: 5.4±6.6; p=0.079); however time (p<0.001) at Post3h (5.4±6.3) showed significant higher values compared to Baseline (2.6±2.1) and Post0h (3.9±3.2). We found an interaction between menstrual cycle phases and time (p=0.038) with greater values at Post3h during LP (8.7±9.9) compared to EFP (3.7±2.90) and MFP (3.7±1.9). Increased CRP (mg/dl) levels were reported (p=0.033) during EFP (2.0±3.3) related to MFP (1.0±1.1) and LP (0.8±1.4). Time had no significant effect on CRP (Baseline: 1.3±2.4; Post0h: 1.3±2.3; Post3h: 1.2±2.0; p=0.707). CONCLUSION: According to our preliminary results, inflammatory responses seem to be influenced by menstrual cycle even though hepcidin levels may not be affected by hormonal fluctuations. Hepcidin and IL-6 peak levels were found Post0h and Post3h after exercise respectively. CRP levels did not show an increase after exercise at any phase. Funding: DEP2016-75387-P (Spanish National Plan 2013-2016)

Effect of sex, menstrual cycle phase, and monophasic oral contraceptive pill use on local and central arterial stiffness in young adults.

Arterial stiffness is associated with increased cardiovascular disease risk. Previous sex-based investigations of local and central stiffness report inconsistent findings and have not controlled for menstrual cycle phase in women. There is also evidence that sex hormones influence the vasculature, but their impact on arterial stiffness across a natural menstrual (NAT) or oral contraceptive pill (OCP) cycle has been understudied. This study sought to 1) examine potential sex differences in local and central stiffness, 2) compare stiffness profiles between NAT and OCP cycles, and 3) investigate the relationship between duration of OCP use and arterial stiffness. Sex hormone concentrations, β-stiffness index (local stiffness), and carotid-femoral pulse wave velocity [cfPWV (central stiffness)] were assessed in 53 healthy adults (22 ± 3 yr old, 20 men, 15 NAT women, and 18 OCP women). All participants were tested three times: men on the same day and time 1 wk apart, NAT women in menstrual, midfollicular and luteal phases of the menstrual cycle, and OCP women in placebo, early active and late active pill phases. β-Stiffness was higher in men than NAT and OCP women ( P < 0.001), whereas cfPWV was similar between groups ( P = 0.09). β-Stiffness and cfPWV did not differ across or between NAT and OCP cycles ( P > 0.05 for both) and were not associated with duration of OCP use (β-stiffness: r = 0.003, P = 0.99; cfPWV: r = -0.26, P = 0.30). The apparent sex differences in local, but not central, stiffness highlight the importance of assessing both indexes in comparisons between men and women. Furthermore, fluctuating sex hormone levels do not appear to influence β-stiffness or cfPWV. Therefore, these stiffness indexes may need to be assessed during only one cycle phase in women in future investigations. NEW & NOTEWORTHY We observed higher local, but not central, arterial stiffness in men than women. We also demonstrated that there are no differences in arterial stiffness between naturally cycling women and women who use monophasic oral contraceptive pills, and that the duration of oral contraceptive pill use does not influence arterial stiffness.

Progesterone administration does not acutely alter LH pulse secretion in the mid-follicular phase in women.

It remains unclear how rapidly progesterone suppresses luteinizing hormone (LH) pulse frequency in women. Previous studies suggested that progesterone markedly increases LH pulse amplitude but does not slow LH pulse frequency within 10 h in estradiol‐pretreated women studied during the late follicular phase. However, this experimental paradigm may be a model of preovulatory physiology, and progesterone may have different effects at other times of the cycle. We studied regularly cycling, nonobese women without hyperandrogenism to assess the acute effect of progesterone during the midfollicular phase and in the absence of estradiol pretreatment. The study involved two admissions in separate cycles (cycle days 5–9). For each admission, either oral micronized progesterone (100 mg) or placebo was administered at 0900 h in a randomized, double‐blind fashion. Frequent blood sampling was performed between 0900 and 1900 h to define 10‐h LH pulsatility. Treatment crossover (placebo exchanged for progesterone and vice versa) occurred in a subsequent cycle. After an interim futility analysis, the study was halted after 7 women completed study. Mean progesterone concentrations after placebo and progesterone administration were 0.5 ± 0.1 (mean ± SD) and 6.7 ± 1.6 ng/mL, respectively. Compared to placebo, progesterone was not associated with a significant difference in 10‐h LH pulse frequency (0.79 ± 0.35 vs. 0.77 ± 0.28 pulses/h, P = 1.0) or amplitude (3.6 ± 2.8 vs. 4.3 ± 2.8 IU/L, P = 0.30). This study suggests that LH pulse frequency is not rapidly influenced by progesterone administration during the midfollicular phase.

Brain Structure and Function in Women with Comorbid Bipolar and Premenstrual Dysphoric Disorder.

Hormonal fluctuations associated with female reproductive life events may precipitate or worsen affective episodes in women with bipolar disorder (BD). Previous studies have shown that women with BD report higher rates of premenstrual dysphoric disorder (PMDD) than controls. Further, bipolar women who report premenstrual worsening of mood display a worse course of their bipolar illness. Despite this, the neural correlates of comorbid BD and PMDD have not been investigated. Eighty-five [CTRL, n = 25; PMDD, n = 20; BD, n = 21; BD with comorbid PMDD (BDPMDD), n = 19], regularly cycling women, not on hormonal contraception, underwent two MRI scans: during their mid-follicular and late luteal menstrual phases. We investigated resting-state functional connectivity (Rs-FC), cortical thickness, and subcortical volumes of brain regions associated with the pathophysiology of BD and PMDD between groups, in the mid-follicular and late luteal phases of the menstrual cycle. All BD subjects were euthymic for at least 2 months prior to study entry. Women in the BDPMDD group displayed greater disruption in biological rhythms and more subthreshold depressive and anxious symptoms through the menstrual cycle compared to other groups. Rs-FC was increased between the L-hippocampus and R-frontal cortex and decreased between the R-hippocampus and R-premotor cortex in BDPMDD vs. BD (FDR-corrected, p < 0.05). Cortical thickness analysis revealed decreased cortical thickness of the L-pericalcarine, L-superior parietal, R-middle temporal, R-rostral middle frontal, and L-superior frontal, as well as increased cortical thickness of the L-superior temporal gyri in BDPMDD compared to BD. We also found increased left-caudate volume in BDPMDD vs. BD (pCORR < 0.05). Women with BD and comorbid PMDD display a distinct clinical and neurobiological phenotype of BD, which suggests differential sensitivity to endogenous hormones.

Substrate oxidation in female adults during endurance exercise throughout menstrual cycle phases: IronFEMME pilot study

The main aim of the study was to investigate the effect of menstrual cycle phases on substrate oxidation during steady state intensity exercise in adult females with regular menstrual cycle and on oral contraceptive (OC). Twenty-four healthy endurance and strength trained females, with regular menstrual cycle phases (n= 15; Age 35.6±4.2; height 163.9±5.9 cm; body mass 58.1±5.2 kg; VO2peak 50.3±3.6 ml·min-1·kg-1) or on oral contraceptives (n=9; Age 30.4±4.5; height 163.9±9.0 cm; body mass 58.1±6.7 kg; VO2peak 52.4±4.2 ml·min-1·kg-1) participated in the study. All participants performed a graded maximal exercise test to determine their peak oxygen consumption (VO2peak). Participants then exercised at the speed corresponding to 75% of VO2peak for 40 minutes on a treadmill in each menstrual cycle phase: regular menstrual cycle group (early follicular phase, mid-follicular phase and luteal phase) and OC group (hormonal phase and non-hormonal phase). There were no differences in the respiratory exchange ratio of each phase, in regular menstrual cycle phase group (mean±SEM): early-follicular phase 0.89±0.01, mid-follicular phase 0.87±0.01 and luteal phase 0.88±0.01 (p>0.05). There were also no differences in respiratory exchange ratio for the participants using oral contraceptive: hormonal phase 0.89±0.01 and non-hormonal phase 0.91±0.01 (p>0.05). However, we found that OC may influence fat oxidation (p=0.018) during the hormonal phase. Our preliminary results suggest that menstrual cycle and oral contraceptive do not influence substrate oxidation in females with regular menstrual cycle phases. Regarding the few disparities, more research is needed to understand how sexual hormones influence substrate oxidation in female.

Gonadotropin Surge-Attenuating Factor: A Nonsteroidal Ovarian Hormone Controlling GnRH-Induced LH Secretion in the Normal Menstrual Cycle.

Gonadotropin surge-attenuating factor (GnSAF) is a nonsteroidal ovarian substance, which attenuates the endogenous LH surge in superovulated women. Different molecular sequences have been found, but only one of them has shown substantial homology to a known substance of the human genome. A molecular mass of 12.5kDa showing identity to the carboxyl-terminal fragment of human serum albumin and expressing GnSAF bioactivity in vitro has been identified. It has been suggested that in the normal menstrual cycle the in vivo bioactivity of GnSAF increases under the influence of the intercycle rise of FSH. GnSAF is considered the "missing link" between the ovaries and the hypothalamo-pituitary system, maintaining the pituitary in a state of low responsiveness to GnRH in the early- to midfollicular phase of the cycle. A marked decline in GnSAF bioactivity in the late follicular phase facilitates the onset and the full expression of the midcycle LH surge.

Structural and functional changes in the somatosensory cortex in euthymic females with bipolar disorder.

Current evidence from neuroimaging data suggests possible dysfunction of the fronto-striatal-limbic circuits in individuals with bipolar disorder. Somatosensory cortical function has been implicated in emotional recognition, risk-taking and affective responses through sensory modalities. This study investigates anatomy and function of the somatosensory cortex in euthymic bipolar women. In total, 68 right-handed euthymic women (bipolar disorder = 32 and healthy controls = 36) between 16 and 45 years of age underwent high-resolution anatomical and functional magnetic resonance imaging during the mid-follicular menstrual phase. The somatosensory cortex was used as a seed region for resting-state functional connectivity analysis. Voxel-based morphometry was used to evaluate somatosensory cortical gray matter volume between groups. We found increased resting-state functional connectivity between the somatosensory cortex and insular cortex, inferior prefrontal gyrus and frontal orbital cortex in euthymic bipolar disorder subjects compared to healthy controls. Voxel-based morphometry analysis showed decreased gray matter in the left somatosensory cortex in the bipolar disorder group. Whole-brain voxel-based morphometry analysis controlled by age did not reveal any additional significant difference between groups. This study is the first to date to evaluate anatomy and function of the somatosensory cortex in a well-characterized sample of euthymic bipolar disorder females. Anatomical and functional changes in the somatosensory cortex in this population might contribute to the pathophysiology of bipolar disorder.

Theca Cell INSL3 and Steroids Together Orchestrate the Growing Bovine Antral Follicle.

Insulin-like peptide 3 (INSL3) and its specific receptor RXFP2 are both expressed by theca interna cells of the growing antral follicle where they form an essential regulatory element in the production of the steroid precursor androstenedione. Using primary cultures of bovine theca cells from the mid follicular phase together with steroid agonists and antagonists we have examined how ovarian steroids modulate INSL3 expression. Transcript analysis shows that these cells express estrogen receptors α and β, androgen and progesterone receptors, besides the orphan nuclear receptors SF1 and nur77. Whereas, exogenous androgens have little or no effect, the androgen antagonist bicalutamide stimulates INSL3 production. In contrast, estrogen receptor agonists, as also progesterone, are stimulatory. Importantly, estrogen receptor signaling is convergent with the protein kinase A signaling pathway activated by LH, such that the estrogen receptor antagonist can inhibit the mild stimulatory effect of LH, and vice versa the PKA antagonist H89 blocks stimulation by estradiol. A significant finding is that the major steroid metabolite androstenedione appears to act predominantly as an estrogen and not an androgen in this system. Transfection of INSL3 gene promoter-reporter constructs together with various steroid receptor expression plasmids supports these findings and shows that steroid action uses non-classical pathways not requiring canonical steroid-responsive elements in the proximal promoter region. Together, the results indicate that increasing estrogens in the follicular phase stimulate a feedforward loop driving INSL3 signaling and thereby promoting steroidogenesis in the growing antral follicle until the LH surge which effectively switches off INSL3 expression.