Increased cerebrospinal fluid levels of GABA, testosterone and estradiol in women with polycystic ovary syndrome.

STUDY QUESTION: Do cerebrospinal fluid (CSF) concentrations of gamma-aminobutyric acid (GABA), testosterone (T) and estradiol (E2) differ in women with polycystic ovary syndrome (PCOS) as compared to eumenorrheic, ovulatory women (EW)? SUMMARY ANSWER: Women with PCOS displayed higher CSF levels of GABA and E2, and possibly T, than EW. WHAT IS KNOWN ALREADY: The chronic anovulation characteristic of PCOS has been attributed to increased central GnRH drive and resulting gonadotropin aberrations. Androgens are thought to regulate GABA, which in turn regulates the neural cascade that modulates GnRH drive. STUDY DESIGN, SIZE, DURATION: This cross-sectional observational study included 15 EW and 12 non-obese women with PCOS who consented to a lumbar puncture in addition to 24 h of serum blood collection at 15-min intervals. PARTICIPANTS/MATERIALS, SETTING, METHODS: In total, 27 women were studied at a the General Clinical Research Center (GCRC) at the University of Pittsburgh. Serum analytes included T, E2 and androstenedione. CSF analytes included GABA, glutamate, glucose, T and E2. MAIN RESULTS AND THE ROLE OF CHANCE: Women with PCOS had higher CSF GABA as compared to EW (9.04 versus 7.04 µmol/L, P < 0.05). CSF glucose and glutamate concentrations were similar between the two groups. CSF T was 52% higher (P = 0.1) and CSF E2 was 30% higher (P < 0.01) in women with PCOS compared to EW. Circulating T was 122% higher (P < 0.01) and circulating E2 was 75% higher (P < 0.01) in women with PCOS than in EW. LIMITATIONS REASONS FOR CAUTION: The study is limited by its small sample size and the technical limitations of measuring CSF analytes that are pulsatile and have short half-lives. WIDER IMPLICATIONS OF THE FINDINGS: Women with PCOS displayed significantly higher circulating levels of T and E2, significantly higher CSF levels of E2, and higher levels of CSF testosterone, although the latter was not statistically significant. A better understanding of the central milieu informs our understanding of the mechanisms mediating increased the GnRH drive in PCOS and lends a new perspective for understanding the presentation, pathogenesis and potential health consequences of PCOS, including gender identity issues. STUDY FUNDING/COMPETING INTEREST(S): No conflicts of interest. The study was funded by NIH grants to SLB (RO1-MH50748, U54-HD08610) and NIH RR-00056 to the General Clinical Research Center of the University of Pittsburgh. TRIAL REGISTRATION NUMBER: NCT01674426.

Apical Suspension at the Time of Hysterectomy for Uterovaginal Prolapse: A Comparative Analysis of 2001 and 2011.

OBJECTIVES: The primary aim of this study was to compare the proportion of concomitant apical procedures in women undergoing hysterectomy for uterovaginal prolapse in 2001 and 2011. The secondary aim was to identify factors associated with receiving concomitant apical procedures in 2001 and 2011. METHODS: The Nationwide Inpatient Sample database was queried for women with a primary diagnosis of uterovaginal prolapse who underwent hysterectomy in 2001 and 2011. The study cohort was analyzed for demographics, clinical factors, and concomitant procedures. Factors potentially associated with receiving concomitant apical procedure were evaluated using univariable analysis and multivariate logistic regression. RESULTS: A total of 14,647 women were identified (5867 in 2001 and 8780 in 2011). In 2001, 26.9% women received a concomitant apical procedure, and this proportion increased to 48.2% in 2011 (odds ratio, 2.53; 95% confidence interval, 2.36-2.72; P < 0.0001). In 2001, the mean (SD) age was 53.8 (14.1) years compared with 56.8 (13.3) years in 2011. Although vaginal hysterectomy was most common in both years, a concomitant apical procedure was more likely to be performed with abdominal hysterectomy (P < 0.001). On multivariate analysis, age older than 50 years (P = 0.0001), abdominal route of hysterectomy (P < 0.0001), and undergoing hysterectomy at an academic teaching hospital (P < 0.0001) were independently associated with concomitant apical procedures in both 2001 and 2011. CONCLUSIONS: Although the proportion of concomitant apical repair was higher in 2011 compared with 2001, it is still low given the existing data demonstrating the importance of a concomitant apical procedure at the time of hysterectomy for uterovaginal prolapse.

Neuroendocrine recovery initiated by cognitive behavioral therapy in women with functional hypothalamic amenorrhea: a randomized, controlled trial.

OBJECTIVE: To determine whether cognitive behavior therapy (CBT), which we had shown in a previous study to restore ovarian function in women with functional hypothalamic amenorrhea (FHA), could also ameliorate hypercortisolemia and improve other neuroendocrine and metabolic concomitants of in FHA. DESIGN: Randomized controlled trial. SETTING: Clinical research center at an academic medical university. PATIENT(S): Seventeen women with FHA were randomized either to CBT or observation. INTERVENTION(S): CBT versus observation. MAIN OUTCOME MEASURE(S): Circulatory concentrations of cortisol, leptin, thyroid-stimulating hormone (TSH), total and free thyronine (T(3)), and total and free thyroxine (T(4)) before and immediately after completion of CBT or observation. (Each woman served as her own control.) RESULT(S): Cognitive behavior therapy but not observation reduced cortisol levels in women with FHA. There were no changes in cortisol, leptin, TSH, T(3), or T(4) levels in women randomized to observation. Women treated with CBT showed increased levels of leptin and TSH, but their levels of T(3) and T(4) remained unchanged. CONCLUSION(S): In women with FHA, CBT ameliorated hypercortisolism and improved the neuroendocrine and metabolic concomitants of FHA while observation did not. We conclude that a cognitive, nonpharmacologic approach aimed at alleviating problematic attitudes not only can restore ovarian activity but also improve neuroendocrine and metabolic function in women with FHA. CLINICAL TRIAL REGISTRATION NUMBER: NCT01674426.

Persistent hypogonadism influences estradiol synthesis, cognition and outcome in males after severe TBI.

OBJECTIVE: Acute hypogonadotropic hypogonadism (AHH) occurs frequently after TBI, as does chronic hypogonadotropic hypogonadism. However, AHH and persistent hypogonadotropic hypogonadism (PHH) after TBI are not well studied. The objective of this study was to characterize longitudinal hormone profiles and the impact of AHH and PHH on outcome. METHODS: In this prospective cohort study, men with severe TBI (n = 38) had serum gonadal and gonadotropic hormones measured during weeks 1-52 post-injury. AHH, PHH and/or early resolving hypogonadotropic hypogonadism (ERHH) were based on temporal hormone assessments. PHH and hormone profiles were then compared to multiple outcome measures 6-12 months post-TBI. RESULTS: AHH affected 100% of the population, while 37% subsequently developed PHH. Acute testosterone (TEST) and estradiol/testosterone (E2/TEST) ratios were associated with PHH and outcome. Over time, post-acute TEST and E2 levels for the ERHH group approached normal range, while levels for the PHH group remained low. Post-acute gonadotrophin levels were within the normal range for both groups. PHH, along with lower post-acute TEST and E2 profiles, was associated with worse functional and cognitive outcomes at 6 and 12 months post-injury. CONCLUSIONS: These results support screening for post-acute secondary hypogonadism and further research to assess the mechanisms underlying PHH and associated functional and cognitive deficits.

Does postmenopausal estrogen use confer neuroprotection?

Sex steroids modulate brain function at all developmental stages of life. This article focuses on the role of sex steroids after menopause with the intent of addressing the question whether or to what extent sex steroids, particularly estrogenic agents, are neuroprotective for the aging brain of women. The rationale for delving into this complicated topic is that the information and perspective so acquired will aid physicians in counseling surgically and naturally menopausal women about their therapeutic options. Whereas we review and synthesize relevant data from monkey, other animal, cellular, and molecular studies, the emphasis is on human studies and reconciling the disparate evidence. Although the knowledge gaps are considerable, available evidence suggests that extended use of non-oral estradiol is a reasonable course of action if the woman to be treated has a relatively low risk for cardiovascular disease and venous thromboembolism or a high concern about developing dementia. It is important to emphasize that estradiol may negatively impact an already unhealthy individual and yet synergize other health-promoting behaviors such as good nutrition, exercise, and stress reduction in a relatively healthy individual.

Serotonin 1A receptor reductions in postpartum depression: a positron emission tomography study.

OBJECTIVE: To measure brain serotonin-1A (5HT1A) receptor binding potential (BP) in healthy and depressed postpartum women. DESIGN: 5HT1A receptor BP was measured with positron emission tomography by using [(11)C]WAY100635 a single time. Multivariate analysis of variance was used to determine depression effects on 5HT1A receptor BP in relevant brain regions. SETTING: An academic research environment. PATIENT(S): Seven postpartum healthy controls and nine postpartum depressed (PD) subjects with perinatal (antepartum or postpartum) depression onset. Of the nine PD subjects, five had unipolar depression, and four had bipolar disorder. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): 5HT1A receptor BP. RESULT(S): Age, time since delivery, and reproductive hormones did not differ between groups. Postsynaptic 5HT1A receptor binding in postpartum depression was reduced 20%-28% relative to controls, with most significant reductions in anterior cingulate and mesiotemporal cortices. CONCLUSION(S): Postsynaptic 5HT1A receptor binding is reduced in PD women by a similar magnitude as has been shown in other depression samples. The postpartum hormonal milieu and the large proportion of bipolar spectrum subjects in the PD group may have accentuated this finding in this small sample. Recognition of this neurobiological deficit in postpartum depression may be useful in the development of treatments and prevention strategies for this disabling disorder.

Neuromuscular and biomechanical characteristics do not vary across the menstrual cycle.

Research examining the menstrual cycle and its relationship to ACL injury has focused on determining the incidence of ACL injury during the different phases of the menstrual cycle and assessing the changes in neuromuscular and biomechanical characteristics between these phases. Conflicting results warrant further investigation to determine if neuromuscular and biomechanical characteristics respond in a similar pattern to the fluctuating estradiol and progesterone. The purpose of this study was to determine if changes in the levels of estradiol and progesterone significantly altered fine motor coordination, postural stability, knee strength, and knee joint kinematics and kinetics between the menses, post-ovulatory, and mid-luteal phases of the menstrual cycle. Ten healthy and physically active females (Age: 21.4 +/- 1.4 years, Height: 1.67 +/- 0.06 m, Mass: 59.9 +/- 7.4 kg), who did not use oral contraceptives, were recruited from the local university population. Single-leg postural stability, fine motor coordination, knee strength, knee biomechanics, and serum estradiol and progesterone were assessed at the menses, post-ovulatory, and mid-luteal phases of the menstrual cycle. Levels of estradiol were significantly higher during the post-ovulatory (P = 0.016) and mid-luteal phases (P < 0.001) compared to the menses phase. Levels of progesterone were significantly lower during the menses (P < 0.001) and post-ovulatory phases (P < 0.001) compared to the mid-luteal phase. No significant differences existed between phases of the menstrual cycle for fine motor coordination (P = 0.474), postural stability (P = 0.707), hamstring - quadriceps strength ratio at 60 degrees s(-1) (P = 0.748) or 180 degrees s(-1) (P = 0.789), knee flexion excursion (P = 0.6), knee valgus excursion (P = 0.899), peak proximal tibial anterior shear force (P = 0.797), flexion moment at peak proximal tibial anterior shear force (P = 0.698), or valgus moment at peak proximal tibial anterior shear force (P = 0.924). The results of the current study suggest neuromuscular and biomechanical characteristics are not influenced by estradiol and progesterone fluctuations. All neuromuscular and biomechanical characteristics remained invariable between testing sessions despite concentration changes in estradiol and progesterone.

Increased cortisol in the cerebrospinal fluid of women with functional hypothalamic amenorrhea.

CONTEXT: The proximate cause of functional hypothalamic amenorrhea (FHA) is reduced GnRH drive. The concomitant increase in circulating cortisol suggests that psychogenic stress plays an etiologic role, but others have argued for a strictly metabolic cause, such as undernutrition or excessive exercise. Indeed, our finding that the cerebrospinal fluid (CSF) concentration of CRH was not elevated in FHA cast doubt about the extent of hypothalamic-pituitary-adrenal activation in FHA and, therefore, we wondered whether central cortisol levels were elevated. OBJECTIVE: We tested the null hypothesis that CSF cortisol levels would be comparable in FHA and eumenorrheic women (EW). DESIGN: The study is a cross-sectional comparison. SETTING: The study was set in a general clinical research center at an academic medical center. PARTICIPANTS: Fifteen women with FHA who were of normal body weight and 14 EW participated. INTERVENTION: Blood samples were collected at 15-min intervals for 24 h, followed by procurement of 25 ml CSF. MAIN OUTCOME MEASURES: Cortisol, cortisol-binding globulin (CBG), and SHBG levels in blood and CSF were the main outcome measures. RESULTS: CSF cortisol concentrations were 30% greater when serum cortisol was 16% higher in FHA compared with EW. Circulating CBG, but not SHBG, was increased in FHA and, thus, the circulating free cortisol index was similar in FHA and EW. Because CBG and SHBG were nil in CSF, the increase in CSF cortisol in FHA was unbound. CONCLUSIONS: The hypothalamic-pituitary-adrenal axis is activated in FHA. The maintenance of CRH drive despite increased CSF cortisol indicates resistance to cortisol feedback inhibition. The mechanisms mediating feedback resistance likely involve altered hippocampal corticosteroid reception and serotonergic and GABAergic neuromodulation.

Use of cognitive behavior therapy for functional hypothalamic amenorrhea.

Behaviors that chronically activate the hypothalamic-pituitary-adrenal (HPA) axis and/or suppress the hypothalamic-pituitary-thyroidal (HPT) axis disrupt the hypothalamic-pituitary-gonadal axis in women and men. Individuals with functional hypothalamic hypogonadism typically engage in a combination of behaviors that concomitantly heighten psychogenic stress and increase energy demand. Although it is not widely recognized clinically, functional forms of hypothalamic hypogonadism are more than an isolated disruption of gonadotropin-releasing hormone (GnRH) drive and reproductive compromise. Indeed, women with functional hypothalamic amenorrhea display a constellation of neuroendocrine aberrations that reflect allostatic adjustments to chronic stress. Given these considerations, we have suggested that complete neuroendocrine recovery would involve more than reproductive recovery. Hormone replacement strategies have limited benefit because they do not ameliorate allostatic endocrine adjustments, particularly the activation of the adrenal and the suppression of the thyroidal axes. Indeed, the rationale for the use of sex steroid replacement is based on the erroneous assumption that functional forms of hypothalamic hypogonadism represent only or primarily an alteration in the hypothalamic-pituitary-gonadal axis. Potential health consequences of functional hypothalamic amenorrhea, often termed stress-induced anovulation, may include an increased risk of cardiovascular disease, osteoporosis, depression, other psychiatric conditions, and dementia. Although fertility can be restored with exogenous administration of gonadotropins or pulsatile GnRH, fertility management alone will not permit recovery of the adrenal and thyroidal axes. Initiating pregnancy with exogenous means without reversing the hormonal milieu induced by chronic stress may increase the likelihood of poor obstetrical, fetal, or neonatal outcomes. In contrast, behavioral and psychological interventions that address problematic behaviors and attitudes, such as cognitive behavior therapy (CBT), have the potential to permit resumption of full ovarian function along with recovery of the adrenal, thyroidal, and other neuroendocrine aberrations. Full endocrine recovery potentially offers better individual, maternal, and child health.

Recovery of ovarian activity in women with functional hypothalamic amenorrhea who were treated with cognitive behavior therapy.

OBJECTIVE: To determine whether cognitive behavior therapy (CBT) targeted to problematic attitudes common among women with functional hypothalamic amenorrhea would restore ovarian function. DESIGN: Randomized, prospective, controlled intervention. SETTING: Clinical research center in an academic medical institution. PATIENT(S): Sixteen women participated who had functional hypothalamic amenorrhea; were of normal body weight; and did not report psychiatric conditions, eating disorders, or excessive exercise. INTERVENTION(S): Subjects were randomized to CBT or observation for 20 weeks. MAIN OUTCOME MEASURE(S): Serum levels of E(2) and P and vaginal bleeding were monitored. RESULT(S): Of eight women treated with CBT, six resumed ovulating, one had partial recovery of ovarian function without evidence of ovulation, and one did not display return of ovarian function. Of those randomized to observation, one resumed ovulating, one had partial return of ovarian function, and six did not recover. Thus, CBT resulted in a higher rate of ovarian activity (87.5%) than did observation (25.0%), chi(2) = 7.14. CONCLUSION(S): A cognitive behavioral intervention designed to minimize problematic attitudes linked to hypothalamic allostasis was more likely to result in resumption of ovarian activity than observation. The prompt ovarian response to CBT suggests that a tailored behavioral intervention offers an efficacious treatment option that also avoids the pitfalls of pharmacological modalities.