Fluctuations In Ovarian Hormones Research Articles

Differential effects of the menstrual cycle on reactive and proactive aggression in borderline personality disorder.

Borderline personality disorder (BPD) is characterized by rapidly shifting symptoms, including intense anger and aggressive behavior. Understanding how fluctuations in ovarian hormones across the menstrual cycle may contribute to symptom instability is key for accurate assessment of BPD symptoms and effective interventions. Reactive and proactive aggression, as well as anger-in and anger-out, were assessed daily in 15 physically healthy, unmedicated naturally cycling female individuals meeting criteria for BPD across 35 days. Urine luteinizing hormone surge and salivary progesterone were used to confirm ovulation and verify the cycle phase. Multilevel models evaluated cyclical differences of symptoms between cycle phases. Both forms of aggressive behavior demonstrated marked cycle effects, with reactive aggression highest during the midluteal cycle phase, co-occurring with initial increases in anger and irritability and followed by perimenstrual peaks in anger and anger-in. In contrast, highest levels of proactive aggression were observed during the follicular and ovulatory phases, when emotional symptoms and anger were otherwise at lowest levels. These findings highlight the importance of identifying the function of aggression when considering potential psychological and biological influences. Naturally cycling individuals with BPD may be at elevated risk for luteal worsening of a range of interpersonally reactive symptoms, including reactive aggression, whereas proactive aggression may occur more in phases characterized by less emotional and cognitive vulnerability and greater reward sensitivity. Research on aggression in this population should consider cycle effects. Cycling individuals with BPD attempting to reduce aggressive behavior may benefit from cycle-tracking to increase awareness of these effects and to develop appropriate strategies.

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.

Stress, sex hormones, inflammation, and major depressive disorder: Extending Social Signal Transduction Theory of Depression to account for sex differences in mood disorders.

Social Signal Transduction Theory of Depression is a biologically plausible, multi-level theory that describes neural, physiologic, molecular, and genomic mechanisms that link experiences of social-environmental adversity with internal biological processes that drive depression pathogenesis, maintenance, and recurrence. Central to this theory is the hypothesis that interpersonal stressors involving social threat (e.g., social conflict, evaluation, rejection, isolation, and exclusion) upregulate inflammatory processes that can induce several depressive symptoms, including sad mood, anhedonia, fatigue, psychomotor retardation, and social-behavioral withdrawal. The original article describing this formulation (Psychol Bull 140:774-815, 2014) addressed critical questions involving depression onset and recurrence, as well as why depression is strongly predicted by early life stress and comorbid with anxiety disorders and certain physical disease conditions, such as asthma, rheumatoid arthritis, chronic pain, and cardiovascular disease. Here, we extend the theory to help explain sex differences in depression prevalence, which is a defining feature of this disorder. Central to this extension is research demonstrating that ovarian hormone fluctuations modulate women's susceptibility to stress, brain structure and function, and inflammatory activity and reactivity. These effects are evident at multiple levels and are highly context-dependent, varying as a function of several factors including sex, age, reproductive state, endogenous versus exogenous hormones, and hormone administration mode and dose. Together, these effects help explain why women are at greater risk for developing inflammation-related depressed mood and other neuropsychiatric, neurodevelopmental, and neurodegenerative disorders during the reproductive years, especially for those already at heightened risk for depression or in the midst of a hormonal transition period.

Preliminary Evidence for a Window of Increased Vulnerability to Sustain a Concussion in Females: A Brief Report.

A difference exists between sexes for the incidence of concussion injuries and severity of post-injury outcomes with females having a higher incidence rate (in comparable sports) and experience more robust symptoms than males. The basis for this disparity has remained largely unresolved. Recent findings point to a potential biological mechanism that may be related to the menstrual cycle as an arbiter of post-injury outcomes. What has not been addressed, is whether the phase of menstrual cycle (inferred fluctuations of ovarian hormones) contributes to an increased vulnerability to sustain a concussion injury. This prospective, observational study sought to determine if concussions occurred at different frequencies throughout the phase of the menstrual cycle. Female athletes who sustained a concussion injury were queried three times over the 7-day study (e.g., within 48 h of injury, and 4 and 7 days after injury) to recall the number of days that have elapsed since the beginning of their most recent menstruation. Twenty female athletes enrolled after sustaining a concussion; 18 were eumenorrheic and 2 amenorrheic. Among eumenorrheic participants at the time of injury, 2 were in the follicular phase, 4 were in the early luteal phase and 9 were in the late luteal phase. Two athletes were injured on the first and 1 was injured on the second day of menstruation. The greatest number of concussions were sustained during the late luteal phase and during the first 2 days of menstruation. This 9-day window accounted for 2/3rd of the sustained concussions in our study.

Sex Differences in Local Nucleus Accumbens Circuitry and Motivated Behavior

Drug addiction is a chronic, relapsing brain disease characterized by compulsive drug seeking, high levels of drug intake, and repeated cycles of abstinence and relapse. Historically, preclinical addiction research has focused almost entirely on male subjects; however, in humans, women take and use drugs in larger quantities, transition to addiction faster, and are more likely to relapse, thus representing a particularly vulnerable population. There are a variety of factors that could contribute to these sex differences – including estrous cycle dependent ovarian hormone fluctuations ‐ however the precise neural circuits and neurobiological mechanisms that underlie these differences in reward, motivation, and addiction vulnerability is largely unknown. The mesolimbic dopamine pathway, which connects the ventral tegmental area (VTA) to the nucleus accumbens (NAc), is an essential component of this process as it controls motivation and reward‐seeking behavior. To understand how these phenotypic differences in addiction vulnerability could be driven by estrous cycle‐dependent neurochemical mechanisms we took a multipronged approach to outlining sex‐differences in local circuit regulation of VTA dopamine terminals in the NAc. Using fast‐scan cyclic voltammetry (FSCV) paired with site‐specific pharmacology we measured subsecond dopamine kinetics in male and female mice in either diestrus (low circulating hormones) or estrus (high circulating hormones) and defined sex‐differences in local circuit regulation of dopamine release in the NAc. We found an enhanced dynamic range of calcium and presynaptic D2 autoreceptor control of dopamine release in females compared to males. During estrus, D2 autoreceptors were less effective at inhibiting dopamine release. Further, the relationship between calcium and dopamine release was enhanced in estrus. Finally, cholinergic regulation of dopamine signaling in the NAc was altered in a way that promotes and enhances dopamine release in estrus females. Together, these factors converge to increase the responsivity of dopamine terminals in the NAc to incoming stimuli and likely act to drive enhanced motivation and drug effects on this system. Moving forward it will be critical to directly link these sex‐differences to addiction vulnerability.Support or Funding InformationFunding was provided by startup funds from Vanderbilt University School of Medicine Department of Pharmacology (E.S.C, L.J.B.), as well as funding from the National Institutes of Health (NIH). Funds from the National Institute of Drug Abuse (NIDA) DA042111(E.S.C), National Institute of Mental Health (NIMH) MH065215 (A.R.J), the Brain and Behavior Research Foundation (to E.S.C), Whitehall Foundation (to E.S.C), Edward J Mallinckrodt Jr. Foundation (to E.S.C) also supported this work.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Stress as a potential moderator of ovarian hormone influences on binge eating in women.

Previous research has demonstrated significant associations between increased levels of ovarian hormones and increased rates of binge eating (BE) in women. However, whereas all women experience fluctuations in ovarian hormones across the menstrual cycle, not all women binge eat in response to these fluctuations, suggesting that other factors must contribute. Stress is one potential contributing factor. Specifically, it may be that hormone-BE associations are stronger in women who experience high levels of stress, particularly as stress has been shown to be a precipitant to BE episodes in women. To date, no studies have directly examined stress as a moderator of hormone-BE associations, but indirect data (that is, associations between BE and stress and between ovarian hormones and stress) could provide initial clues about moderating effects. Given the above, the purpose of this narrative review was to evaluate these indirect data and their promise for understanding the role of stress in hormone-BE associations. Studies examining associations between all three phenotypes (that is, ovarian hormones, stress, and BE) in animals and humans were reviewed to provide the most thorough and up-to-date review of the literature on the potential moderating effects of stress on ovarian hormone–BE associations. Overall, current evidence suggests that associations between hormones and BE may be stronger in women with high stress levels, possibly via altered hypothalamic–pituitary–adrenal axis response to stress and increased sensitivity to and altered effects of ovarian hormones during stress. Additional studies are necessary to directly examine stress as a moderator of ovarian hormone–BE associations and identify the mechanisms underlying these effects.

Estrogen, Stress, and Depression: Cognitive and Biological Interactions

This article reviews the interactions of estrogen changes and psychosocial stress in contributing to vulnerability to major depressive disorder (MDD) in women. Estrogen modulates brain networks and processes related to changes in stress response, cognition, and emotional dysregulation that are core characteristics of MDD. Synergistic effects of estrogen on cognitive and emotional function, particularly during psychosocial stress, may underlie the association of ovarian hormone fluctuation and depression in women. We propose a model of estrogen effects on multiple brain systems that interface with stress-related emotional and cognitive processes implicated in MDD and discuss possible mechanisms through which reproductive events and changes in estrogen may contribute to MDD risk in women with other concurrent risk factors.

Both Val158Met Polymorphism of Catechol-O-Methyltransferase Gene and Menstrual Cycle Affect Prepulse Inhibition but Not Attentional Modulation of Prepulse Inhibition in Younger-Adult Females

Prepulse inhibition (PPI) can be modulated by both the Val158Met (rs4680) polymorphism of the Catechol-O-Methyltransferase (COMT) gene and the menstrual-cycle-related hormone fluctuations, each of which affects the subcortical/cortical dopamine metabolism. PPI can also be modulated by attention. The attentional modulation of PPI (AMPPI) is sensitive to psychoses. Whether the Val158Met polymorphism affects the AMPPI in female adults at different menstrual-cycle phases is unknown. This study examined whether AMPPI and/or PPI are affected by the Val158Met polymorphism in 177 younger-adult females whose menstrual cycles were mutually different across the menstruation, proliferative, or secretory phases. The AMPPI was evaluated by comparing PPI under the condition of the auditory precedence-effect-induced perceptual spatial separation between the prepulse stimulus and a masking noise (PPIPSS) against that under the condition of the precedence-effect-induced perceptual spatial co-location (PPIPSC). The results showed that both the menstrual cycle and the COMT Val158Met polymorphism affected both PPIPSC and PPIPSS, but not the AMPPI (difference between PPIPSS and PPIPSC). Moreover, throughout the menstrual cycle, both PPIPSC and PPIPSS decreased monotonously in Val/Val-carrier participants. However, the decreasing pattern was not overserved in either Met/Met-carrier or Met/Val-carrier participants. Thus, in healthy younger-adult females, PPIPSC and PPIPSS, but not the AMPPI, is vulnerable to changes of ovarian hormones, and the COMT Val158Met polymorphism also has a modulating effect on this menstrual-cycle-dependent PPI variation. In contrast, the AMPPI seems to be more steadily trait-based, less vulnerable to ovarian hormone fluctuations, and may be useful in assisting the diagnosis of schizophrenia in female adults.

Lack of sexual dimorphism on the inhibitory effect of alcohol on muscle protein synthesis in rats under basal conditions and after anabolic stimulation.

Previous studies indicate women have a higher blood alcohol (i.e., ethanol) and acetaldehyde concentration after consuming an equivalent amount of alcohol, and that women are more susceptible to the long‐term negative health effects of alcohol. However, there is a paucity of data pertaining to whether there is a sexual dimorphic response in skeletal muscle to alcohol. Adult male and female Sprague–Dawley rats were used and the primary endpoint was in vivo determined muscle (gastrocnemius) protein synthesis (MPS). The initial study indicated MPS did not differ in female rats during proestrus, estrus, metestrus, or diestrus; hence, subsequent studies used female rats irrespective of estrus cycle phase. There was no difference in MPS between male and female rats under basal fasted conditions, and the time‐ and dose‐responsiveness of both groups to the inhibitory effect of acute alcohol did not differ. The ability of alcohol to suppress MPS was comparable in male and female rats pretreated with alcohol dehydrogenase inhibitor 4‐methylpyrazol. Chronic alcohol feeding for 6 weeks decreased MPS in male but not in female rats; however, MPS was reduced in both sexes at 14 weeks. Finally, oral gavage of leucine increased MPS similarly in male and female rats and chronic alcohol feeding for 14 weeks prevented the anabolic effect in both sexes. These data suggest normal fluctuations in ovarian hormones do not significantly alter MPS in female rats, and that there is no sexual dimorphic response to the effects of acute alcohol intoxication on MPS. While chronic alcohol consumption appeared to decrease MPS at an early time point in male compared to female rats, there was no sex difference in the suppressive effect of alcohol at a later time point. Overall, these data do not support the prevailing belief that females are more susceptible than males to alcohol's catabolic effect on MPS.

Ovarian hormones modulate endothelin-1 receptor responses in young women.

We recently demonstrated ETBR mediate vasodilation in young but not postmenopausal women; it is unclear if this is related to age or a decline in ovarian hormones. The purpose of this study was to test the hypothesis that ETBR responses are modulated by ovarian hormones. We measured cutaneous vasodilatory responses in 12 young women (22±1years, 23±1kg/m2 ) during the ML (days 20-25) and EF (days 2-5) phases of the menstrual cycle. Cutaneous microdialysis perfusions of lactated Ringer (control), ETBR antagonist (BQ-788, 300nmol/L), and ETAR antagonist (BQ-123, 500nmol/L) were performed, followed by local heating to 42°C. Serum estradiol (ML: 118±16 vs EF: 44±9pg/mL, P<0.05) and progesterone (ML: 8.3±1.0 vs EF: 0.7±0.2ng/mL, P<0.05) were higher during ML vs EF phase. ETBR blockade decreased vasodilation during ML (control: 91±2 vs BQ-788: 83±2%CVCmax, P<0.05) but not EF (control: 89±2 vs BQ-788: 89±1%CVCmax). ETAR blockade also decreased vasodilation during ML (control: 91±2 vs BQ-123: 87±2%CVCmax, P<0.05) but not EF (control: 89±2 vs BQ-123: 92±2%CVCmax). These data suggest that fluctuations in ovarian hormones modulate ETBR and ETAR responses in young women.

Effects of menstrual cycle phase on electrocortical response to reward and depressive symptoms in women

The menstrual cycle impacts mood and neural response to reward-phenomena that may be related to natural fluctuations in ovarian hormones. Using a within-subject design, the present study examined ovarian hormones (i.e., estradiol and progesterone) and ERPs in response to feedback indicating gains and losses in both the follicular and luteal phases of the menstrual cycle. We examined whether hormone levels and variation in neural response to reward and loss across menstrual cycle phases were associated with depressive symptoms. Participants high in depressive symptoms showed a reduced reward positivity (RewP) to monetary gains during the luteal phase of the menstrual cycle as compared to the follicular phase, while those low in depressive symptoms showed no change in the RewP to monetary gains between phases. Thus, increased fluctuation in the neural response to gains (but not losses) across menstrual cycle phases was associated with greater depression symptoms. Overall, findings indicate that hormonal fluctuations associated with the menstrual cycle may relate to depressive symptoms by altering reward sensitivity. Furthermore, fluctuation in the neural response to rewards over the menstrual cycle may play an important role in the expression of depressive symptoms.

Effects of estrus cycle stage on defensive behavior in female Long-Evans hooded rats

This study investigated the influence of the estrus cycle in mediating cat odor-induced unconditioned and conditioned defensive behaviors in female Long-Evans hooded rats. Unconditioned defensive behaviors were assessed during predatory cue exposure; conditioned defensive behaviors were examined 24 h after threat exposure. Estrus phases were determined by microscopic examination of vaginal smears within 10 min of completing the behavioral tests. Compared to no-odor controls, female rats exposed to cat odor exhibited both unconditioned and conditioned defensive behaviors, including elevated levels of freezing, risk assessment and avoidance. Rats in proestrus and estrus exhibited reduced levels of defensive behavior during the unconditioned test trial compared to subjects in diestrus and metestrus. Specifically, estrus stages characterized by high levels of circulating estrogens and progesterone were associated with reduced immobility (i.e. freezing) and enhanced active defense (i.e. risk assessment), profiles that may enable mate seeking and subsequent reproduction in potentially dangerous or novel environments. These results suggest a specific role for ovarian hormone fluctuations in mediating unconditioned fear- and anxiety-like defensive behaviors during exposure to predatory odors.

Ovarian hormones, age and pubertal development and their association with days of headache onset in girls with migraine: An observational cohort study.

Background Fifty-three percent of adolescent girls report headaches at the onset of menses, suggesting fluctuations of ovarian hormones trigger migraine during puberty. Aims To determine if urinary metabolites of estrogen and progesterone are associated with days of headache onset (HO) or severity in girls with migraine. Methods This was a pilot study and included 34 girls with migraine balanced across three age strata (pre-pubertal (8-11), pubertal (12-15), and post-pubertal (16-17) years of age). They collected daily urine samples and recorded the occurrence and severity of headache in a daily diary. Urine samples were assayed for estrone glucuronide (E1G) and pregnandiol glucuronide (PdG) and the daily change was calculated (ΔE1G, ΔPdG). Pubertal development was assessed by age, pubertal development score (PDS), and menstrual cycle variance. The primary outcome measures were HO days and headache severity. Generalized linear mixed models were used, and included the hormonal variables and three different representations of pubertal development as covariates. Results Models of HO days demonstrate a significant age*PdG interaction (OR 0.85 [95% CI 0.75, 0.97]) for a 1 standard deviation increase in PdG and three-year increase in age. A separate model showed a significant PDS*PdG interaction (OR -0.85 [95% CI; 0.76, 0.95]). ΔPDG was associated with headache severity in unadjusted models ( p < 0.017). Conclusion Age and pubertal development could moderate the effect of ovarian hormones on days of headache onset in girls with migraine.

Ovarian hormones and obesity.

Obesity is caused by an imbalance between energy intake, i.e. eating and energy expenditure (EE). Severe obesity is more prevalent in women than men worldwide, and obesity pathophysiology and the resultant obesity-related disease risks differ in women and men. The underlying mechanisms are largely unknown. Pre-clinical and clinical research indicate that ovarian hormones may play a major role. We systematically reviewed the clinical and pre-clinical literature on the effects of ovarian hormones on the physiology of adipose tissue (AT) and the regulation of AT mass by energy intake and EE. Articles in English indexed in PubMed through January 2016 were searched using keywords related to: (i) reproductive hormones, (ii) weight regulation and (iii) central nervous system. We sought to identify emerging research foci with clinical translational potential rather than to provide a comprehensive review. We find that estrogens play a leading role in the causes and consequences of female obesity. With respect to adiposity, estrogens synergize with AT genes to increase gluteofemoral subcutaneous AT mass and decrease central AT mass in reproductive-age women, which leads to protective cardiometabolic effects. Loss of estrogens after menopause, independent of aging, increases total AT mass and decreases lean body mass, so that there is little net effect on body weight. Menopause also partially reverses women's protective AT distribution. These effects can be counteracted by estrogen treatment. With respect to eating, increasing estrogen levels progressively decrease eating during the follicular and peri-ovulatory phases of the menstrual cycle. Progestin levels are associated with eating during the luteal phase, but there does not appear to be a causal relationship. Progestins may increase binge eating and eating stimulated by negative emotional states during the luteal phase. Pre-clinical research indicates that one mechanism for the pre-ovulatory decrease in eating is a central action of estrogens to increase the satiating potency of the gastrointestinal hormone cholecystokinin. Another mechanism involves a decrease in the preference for sweet foods during the follicular phase. Genetic defects in brain α-melanocycte-stimulating hormone-melanocortin receptor (melanocortin 4 receptor, MC4R) signaling lead to a syndrome of overeating and obesity that is particularly pronounced in women and in female animals. The syndrome appears around puberty in mice with genetic deletions of MC4R, suggesting a role of ovarian hormones. Emerging functional brain-imaging data indicates that fluctuations in ovarian hormones affect eating by influencing striatal dopaminergic processing of flavor hedonics and lateral prefrontal cortex processing of cognitive inhibitory controls of eating. There is a dearth of research on the neuroendocrine control of eating after menopause. There is also comparatively little research on the effects of ovarian hormones on EE, although changes in ovarian hormone levels during the menstrual cycle do affect resting EE. The markedly greater obesity burden in women makes understanding the diverse effects of ovarian hormones on eating, EE and body adiposity urgent research challenges. A variety of research modalities can be used to investigate these effects in women, and most of the mechanisms reviewed are accessible in animal models. Therefore, human and translational research on the roles of ovarian hormones in women's obesity and its causes should be intensified to gain further mechanistic insights that may ultimately be translated into novel anti-obesity therapies and thereby improve women's health.

Ovarian hormone fluctuations predict within-cycle shifts in women's food intake

What role do ovarian hormones play in modulating day-to-day shifts in women's motivational priorities? In many nonhuman mammals, estradiol causes drops in feeding and foraging, progesterone reverses this effect, and the two hormones in combination produce cycle phase shifts characterized by lower food intake near ovulation when sexual receptivity is at its peak. Hormonal predictors of within-cycle shifts in women's total food intake have not been previously tested. Here, in a study with both daily hormone measures and self-reported food intake, we found that within-cycle fluctuations in estradiol negatively predicted shifts in food intake, progesterone fluctuations positively predicted them, and the two hormones together statistically mediated a significant peri-ovulatory drop in eating. These patterns are precisely opposite to those previously reported for sexual desire from this same sample (i.e. positive and negative effects of estradiol and progesterone, respectively, on desire). To more precisely test endocrine regulation of tradeoffs between sexual and eating motivation, a difference score for the daily standardized values of the sexual desire and food intake variables was created. Fluctuations in estradiol and progesterone were oppositely associated with shifts in this difference score, supporting hormone modulation of tradeoffs between alternative motivational priorities. These tradeoffs were especially pronounced during the fertile window of the menstrual cycle on days when conception was possible, consistent with the hormone effects functioning to shift motivational salience between feeding and mating depending on within-cycle changes in fecundity. The findings provide direct evidence that phylogenetically conserved endocrine signals regulate daily shifts in human motivational priorities.

Sexually Dimorphic Risk Mitigation Strategies in Rats.

The scientific understanding of fear and anxiety—in both normal and pathological forms—is presently limited by a predominance of studies that use male animals and Pavlovian fear conditioning-centered paradigms that restrict and assess specific behaviors (e.g., freezing) over brief sampling periods and overlook the broader contributions of the spatiotemporal context to an animal’s behavioral responses to threats. Here, we use a risky “closed economy” system, in which the need to acquire food and water and the need to avoid threats are simultaneously integrated into the lives of rats, to examine sex differences in mitigating threat risk while foraging. Rats lived for an extended period (∼2 months) in enlarged chambers that consisted of a safe, bedded nest and a risky foraging area where footshocks could be delivered unpredictably. We observed that male and female rats used different strategies for responding to the threat of footshock. Whereas male rats increased the size of meals consumed to reduce the overall time spent foraging, female rats sacrificed their metabolic needs in order to avoid shocks. Ovarian hormone fluctuations were shown to exert slight but reliable rhythmic effects on risky decision-making in gonadally intact female rats. However, this did not produce significant differences in approach–avoidance trade-offs between ovariectomized and intact female groups, suggesting that male–female sex differences are not due to the activational effects of gonadal hormones but, rather, are likely to be organized during early development.

Особливості експресії ядерних стероїдних рецепторів в ендометрії у жінок з невдалими спробами запліднення in vitro в анамнезі

Structural and functional maturity of the endometrium is formed in a condition of dynamic fluctuations of ovarian steroid hormones – estrogens and progesterone during the menstrual cycle. The objective: of the research was to determine the reactivity of estrogene core receptors-б and progesterone core receptors in endometrial stroma and glands. Patients and methods. Endometrial samples were obtained during hysteroscopy in 42 patients with infertility on day LH + 6 – LH + 11 of the menstrual cycle. The control group (CG) consisted of 18 healthy women who had at least one physiological pregnancy that resulted in the birth of a healthy child. Receptivity of the endometrium to the hormones was studied by immunoperoxidase method using mouse MAbs for estrogen receptors-a (ER-a) (clone ID5, «DAKO», Denmark) and progesteron receptor (RP) (clone A6, «DAKO», Denmark). The color intensity was assessed by tree-point system. The expression levelі of ER-a and RP were set by calculating semiquantitative index: IRS = SI ґ PP, where IRS – immunoreactivity index; SI – optical intensity staining; PP – the percentage of positively stained nuclei. Results. Normal ER-a and RP immunoreactivity was observed in 8 (19.05%) women with failed in vitro fertilization attempts in history, total reduction of ER-a and RP immunoreactivity (medium and severe) in glands and stroma was observed in 6 (14.29%) of infertile patients. Normal levels of ER-a and RP immunoreactivity were observed among KG women. Noteworthy is the presence of comorbidity. So in 4 of the six cases of endometrial polyp appeared on the background of chronic endometritis. In 4 women diagnosed with simple hyperplasia without atypia the defective rejection of the endometrium from the previous cycle and the incompatibility of endometrium structure to the day of cycle were found. In the group of infertile women high reactivity of receptors was observed only in 8 (19.05%) biopsies. Deviation of the morphological structure of the endometrium in this subgroup was observed significantly more often than in KG: incompatibility of morphological endometrial structure to the day of menstrual cycle was found in 12.50% of cases, simple hyperplasia without atypia – of 55.00%, endometrial polyp – 12.50%, chronic endometritis – 25.00%. Conclusions. The change of immunoreactivity of estrogen receptor-б and progesterone plays an important role in the formation of implantation failure in women with unsuccessful in vitro fertilization attempts. The obtained data confirm the hypothesis of multiple factors of development regulation of the endometrium in natural cycles and in IVF cycles. High frequency of structural and functional inferiority of the endometrium is the indication for in-depth study. Correction of the endometrial condition need to be done before pregnancy. Key words: infertility, failed in vitro fertilization attemp, immunoreactivity, receptors estrogen-a, progesterone receptors.

Pharmacologically Induced Sex Hormone Fluctuation Effects on Resting-State Functional Connectivity in a Risk Model for Depression: A Randomized Trial.

Women are at relatively greater lifetime risk for depression than men. This elevated risk in women is partly due to heightened risk during time periods characterized by marked fluctuations in sex hormones, including postpartum and perimenopausal periods. How sex hormone fluctuations contribute to heightened risk is not fully understood but may involve intrinsic functional connectivity. We induced a biphasic ovarian sex hormone fluctuation using the gonadotropin-releasing hormone agonist (GnRHa) goserelin to determine, with a randomized placebo-controlled design, intervention effects on or GnRHa-provoked depressive symptoms associations with change in resting-state functional connectivity (rs-FC) in 58 healthy women for six seeds (amygdala, hippocampus, anterior cingulate cortex, dorsal raphe, median raphe, and posterior cingulate cortex). GnRHa intervention did not significantly affect rs-FC in any seeds. Considering the GnRHa group only, the emergence of depressive symptoms following intervention was positively associated with amygdala-right temporal cortex and negatively associated with hippocampus-cingulate rs-FC. A test for mediation suggested that rs-FC changes in these networks marginally mediated the association between decrease in estradiol and increase in depressive symptoms in the GnRHa group (p=0.07). Our findings provide novel evidence-linking changes in rs-FC networks, the emergence of depressive symptoms and sex hormone fluctuations. Notably, we observed evidence that changes in rs-FC may represent a key neurobiological intermediary between molecular changes induced by hormone fluctuations and the emergence of depressive symptoms. Taken together, our findings indicate that sex hormone fluctuations may contribute to heightened risk for developing depressive symptoms by affecting intrinsic functional connectivity of key limbic brain structures.

Influence of menstrual cycle phase on resting-state functional connectivity in naturally cycling, cigarette-dependent women.

BackgroundSex differences in tobacco-related morbidity and mortality exist, with women experiencing more severe health consequences and greater difficulty with smoking cessation than men. One factor that likely contributes to these sex differences is menstrual cycle phase and associated neural and cognitive changes associated with ovarian hormone fluctuations across the menstrual cycle. Previously, we showed that naturally cycling, cigarette-dependent women in the follicular phase of their menstrual cycle showed greater reward-related neural activity and greater craving during smoking cue exposure. To better understand our results and the observed sex differences in smoking behavior and relapse, we explored potential menstrual cycle phase differences in resting-state functional connectivity (rsFC) in naturally cycling, cigarette-dependent women. Understanding how menstrual cycle phase affects neural processes, cognition, and behavior is a critical step in developing more efficacious treatments and in selecting the best treatment option based on a patient’s needs.MethodsResting-state functional connectivity analyses were used to examine connectivity strength differences between naturally cycling, premenopausal, cigarette-dependent women who were in the follicular phase (FPs; n = 22) and those in the luteal phase (LPs, n = 16) of their menstrual cycle. We also explored associations between connectivity strength and attentional bias to smoking cues.ResultsCompared with LPs, FPs showed decreased rsFC between the dorsal anterior cingulate cortex (dACC) and the subgenual anterior cingulate cortex, medial orbitofrontal cortex (mOFC), and ventral striatum. Among FPs, rsFC strength between the dACC and the bilateral dorsolateral prefrontal cortex (DLPFC), the bilateral dorsal striatum, and the left temporal gyrus was inversely correlated with attentional bias to smoking cues.ConclusionsThis is the first study to explore menstrual cycle phase differences in rsFC among cigarette-dependent women, and results suggest that FPs show differences in rsFC underlying cognitive control, which could place them at greater risk for continued smoking and relapse. These findings provide new insights toward individualized treatment strategies.Electronic supplementary materialThe online version of this article (doi:10.1186/s13293-016-0078-6) contains supplementary material, which is available to authorized users.

Food restriction-induced augmentation of heroin seeking in female rats: manipulations of ovarian hormones.

Food restriction augments heroin seeking in chronically food-restricted male rats under withdrawal, an effect not yet examined in female rats. Importantly, women and female rats possess an increased vulnerability to drugs of abuse, which may be mediated by fluctuations in ovarian hormones. We investigated the role of estradiol and progesterone in augmented heroin seeking in chronically food-restricted female rats, under withdrawal. Female rats self-administered heroin for 10-12 days and were then allowed unrestricted (sated) or restricted access to food (FDR; ∼10 % reduction in body weight) for 14 days. On day 14, rats underwent a heroin-seeking test. Exp. 1: Rats underwent ovariectomy or sham surgery and were treated with a low dose of estradiol (5.0 % in cholesterol; subcutaneous capsule). Exp. 2: Rats underwent ovariectomy and were administered with a high dose of estradiol (0.5 mg/kg; subcutaneous) for 8 days before testing. Exp. 3: Progesterone injections (2.0 mg/kg; subcutaneous) were administered 24 h and 2 h before testing. Food restriction resulted in augmented heroin seeking, compared to sated controls. While ovariectomy had no effect, estradiol replacement attenuated the food restriction effect. Injections of progesterone had no effect on heroin seeking in either the sated or FDR groups. The effect of food restriction on heroin seeking in female rats under withdrawal is as robust as previously found in males. Interestingly, estradiol replacement, but not progesterone, attenuates the food restriction effect in the ovariectomized rats, possibly due to its anorexic properties.