Publications by authors named "Sarah L Berga"

97 Publications

Cabergoline Stimulates Human Endometrial Stromal Cell Decidualization and Reverses Effects of Interleukin-1β In Vitro.

J Clin Endocrinol Metab 2021 Nov;106(12):3591-3604

Department of Obstetrics and Gynecology, Wake Forest School of Medicine, Winston-Salem, NC, USA.

Context: Human embryonic implantation is regulated by neuroendocrine hormones, ovarian steroids, growth factors, and cytokines. Sympathetic innervation of the uterus also may play a role.

Objective: We tested the hypothesis that cabergoline (Cb), an agonist of type 2 dopamine receptors (DRD2), could influence endometrial decidualization in vitro.

Methods: Immunohistochemistry confirmed the presence of catecholaminergic neurons in human uterine tissue. DRD2 mRNA and protein expression in endometrial tissue and cells were validated by quantitative RT-PCR, cDNA microarrays, RNA sequencing, and Western blotting. Isolated human endometrial stromal cells (ESC) were subjected to dose-response and time-course experiments in the absence or presence of decidualizing hormones (10 nM estradiol, 100 nM progesterone, and 0.5 mM dibutyryl cAMP). In some cases, interleukin (IL)-1β (0.1 nM) was used as an inflammatory stimulus. Well-characterized in vitro biomarkers were quantified.

Results: DRD2 were maximally expressed in vivo in the mid-secretory phase of the cycle and upregulated in ESC in response to decidualizing hormones, as were classical (eg, prolactin) and emerging (eg, VEGF and connexin 43) differentiation biomarkers. Cabergoline treatment more than doubled decidual biomarker expression, whereas risperidone, a dopamine receptor antagonist, inhibited ESC differentiation by >50%. Cabergoline induced characteristic decidual morphology changes and blocked detrimental effects of IL-1β on decidual cytology.

Conclusion: Our results support the hypothesis that dopaminergic neurons modulate decidualization in situ. We postulate that dopamine agonists, like Cb, could be developed as therapeutic agents to enhance implantation in couples with inflammation-associated infertility.
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http://dx.doi.org/10.1210/clinem/dgab511DOI Listing
November 2021

Prior Oral Contraceptive Use and Longer Term Mortality Outcomes in Women with Suspected Ischemic Heart Disease.

J Womens Health (Larchmt) 2021 03 21;30(3):377-384. Epub 2021 Jan 21.

Barbra Streisand Women's Heart Center, Cedars-Sinai Smidt Heart Institute, Los Angeles, California, USA.

Previous Women's Ischemia Syndrome Evaluation (WISE) work demonstrated prior oral contraceptive (OC) use was associated with lower coronary artery disease (CAD) in women with suspected ischemia. The association of prior OC use with longer term all-cause and cardiovascular disease (CVD) mortality is unclear. WISE women undergoing coronary angiography for suspected ischemia (enrolled 1996-2001) with prior OC use history and 10-year follow-up data were analyzed. A blinded core laboratory assessed atherosclerotic CAD severity. Kaplan-Meier analyses evaluated prior OC use relative to all-cause and CVD mortality. Cox regression analyses adjusted for baseline differences. Mediation, interaction, and multicollinearity were analyzed. Our 686 women had a mean age 62.5 ± 9.6 years, multiple cardiac risk factors, and 39% previously used OC. Prior OC users were younger, with less lipid-lowering medication use and lower atherosclerotic CAD severity scores (all  < 0.05). Prior OC use was associated with lower 10-year all-cause ( = 0.007) and CVD mortality ( = 0.019). After adjustment, this was no longer significant ( = 0.77 and  = 0.90, respectively). Atherosclerotic CAD severity score mediated one-third of the observed association. Prior OC use was associated with increased CVD mortality among women with very elevated menopausal systolic blood pressure (SBP). Unadjusted prior OC use was associated with lower longer-term all-cause and CVD mortality. One-third of this observed effect appears mediated by the atherosclerotic CAD severity score. Prior OC was adversely associated with CVD mortality in women with very elevated menopausal SBP. Additional investigation is needed to understand the potential benefits and harms of prior OC use. Clinical Trial Number: NCT00000554, or https://www.clinicaltrials.gov/ct2/show/NCT00000554.
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http://dx.doi.org/10.1089/jwh.2020.8743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8098756PMC
March 2021

Foreword: What the Generalist Should Know About REI.

Authors:
Sarah L Berga

Clin Obstet Gynecol 2020 12;63(4):685-686

Department of Obstetrics and Gynecology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York.

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http://dx.doi.org/10.1097/GRF.0000000000000571DOI Listing
December 2020

What Every Gynecologist Should Know About Perimenopause.

Clin Obstet Gynecol 2020 12;63(4):720-734

Department of Obstetrics and Gynecology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York.

Perimenopause often represents a physiologically challenging phase in women's lives. The clinical presentation of the perimenopause includes infertility, irregular menstrual cycles, menorrhagia, and new onset of or worsening of mood disorders. Unlike menopause, which is characterized by low levels of estradiol and progesterone, the hallmark of perimenopause is highly variable levels of estradiol and progesterone with abrupt increases and decreases that are often described as a hormonal roller coaster. This chapter invites general gynecologists to understand the hormonal basis of the common complaints of perimenopause and offers information about the physiology of these issues and helpful treatment options.
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http://dx.doi.org/10.1097/GRF.0000000000000578DOI Listing
December 2020

A Clinician's Guide to Functional Hypothalamic Amenorrhea.

Clin Obstet Gynecol 2020 12;63(4):706-719

Department of Obstetrics and Gynecology, University of Buffalo Jacobs School of Medicine and Biomedical Sciences, Buffalo, New York.

Patients and clinicians alike want to know if stress causes infertility. Stress could impair with reproductive function by a variety of mechanisms, including compromise of ovarian function, spermatogenesis, fertilization, endometrial development, implantation, and placentation. Herein we focus on the pathogenesis and treatment of stress-induced anovulation, which is often termed functional hypothalamic amenorrhea (FHA), with the objective of summarizing the actual knowledge as a clinical guide. FHA is a reversible form of anovulation due to slowing of gonadotropin-releasing hormone pulse frequency that results in insufficient pituitary secretion of gonadotropins to support full folliculogenesis. Importantly, FHA heralds a constellation of neuroendocrine alterations with health concomitants. The activity of the hypothalamic-pituitary-adrenal axis is increased in women with FHA and this observation supports the notion that stress is the cause. The extent of reproductive suppression relates to individual endocrinological and physiological sensitivity to stressors, both metabolic and psychogenic, and chronicity.
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http://dx.doi.org/10.1097/GRF.0000000000000573DOI Listing
December 2020

Neuroendocrine mechanisms of reproduction.

Handb Clin Neurol 2020 ;171:3-23

Department of Obstetrics and Gynecology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, United States. Electronic address:

The neuroendocrinology of reproduction focuses on the neuromodulation of gonadotropin-releasing hormone (GnRH), the ontogeny of the hypothalamic-pituitary-gonadal axis, and common reproductive events and conditions, namely, puberty, the menstrual cycle, and disorders of reproductive function. The core concept underpinning the neuroendocrinology of reproduction is neuroregulation of hypothalamic GnRH drive. In both men and women, reproductive function requires that GnRH input elicit appropriate secretion of follicle-stimulating hormone and luteinizing hormone from the anterior pituitary and that the gonads respond to such input appropriately. Moreover, insufficient GnRH drive causes hypothalamic hypogonadism and secondary insufficiency of gonadal sex steroid hormone synthesis and release in both sexes. Alterations in GnRH drive also reflect gonadal conditions such as dysgenesis, hyperandrogenism, gonadotropin mutations, and aging and loss or absence of oocytes or Sertoli cells. The most common cause of insufficient GnRH drive is functional, that is, due to the endocrine effects of psychologic or behavioral variables. Rarely does reduced GnRH drive reflect organic or congenital causes such as developmental defects, brain tumors, or celiac disease. Despite a common neuropathogenesis the heterogeneity of behavioral variables associated with reduced GnRH drive has resulted in a variety of names, including functional hypothalamic amenorrhea, stress-induced anovulation, and psychogenic amenorrhea.
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http://dx.doi.org/10.1016/B978-0-444-64239-4.00001-1DOI Listing
July 2021

Human Endometrial Stromal Cell Differentiation is Stimulated by PPARβ/δ Activation: New Targets for Infertility?

J Clin Endocrinol Metab 2020 09;105(9)

Department of Obstetrics and Gynecology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.

Context: Implantation is a reproductive bottleneck in women, regulated by fluctuations in ovarian steroid hormone concentrations. However, other nuclear receptor ligands are modifiers of endometrial differentiation leading to successful pregnancy. In the present study we analyzed the effects of peroxisome-proliferator-activated receptor β/δ (PPARβ/δ) activation on established cellular biomarkers of human endometrial differentiation (decidualization).

Objective: The objective of this work is to test the effects of PPARβ/δ ligation on human endometrial cell differentiation.

Design: Isolated primary human endometrial stromal cells (ESCs) were treated with synthetic (GW0742) or natural (all trans-retinoic acid, RA) ligands of PPARβ/δ, and also with receptor antagonists (GSK0660, PT-S58, and ST247) in the absence or presence of decidualizing hormones (10 nM estradiol, 100 nM progesterone, and 0.5 mM dibutyryl cAMP [3',5'-cyclic adenosine 5'-monophosphate]). In some cases interleukin (IL)-1β was used as an inflammatory stimulus. Time course and dose-response relationships were evaluated to determine effects on panels of well characterized in vitro biomarkers of decidualization.

Results: PPARβ/δ, along with estrogen receptor α (ERα) and PR-A and PR-B, were expressed in human endometrial tissue and isolated ESCs. GW0742 treatment enhanced hormone-mediated ESC decidualization in vitro as manifested by upregulation of prolactin, insulin-like growth factor-binding protein 1, IL-11, and vascular endothelial growth factor (VEGF) secretion and also increased expression of ERα, PR-A and PR-B, and connexin 43 (Cx43). RA treatment also increased VEGF, ERα, PR-A, and PR-B and an active, nonphosphorylated isoform of Cx43. IL-1β and PPARβ/δ antagonists inhibited biomarkers of endometrial differentiation.

Conclusion: Ligands that activate PPARβ/δ augment the in vitro expression of biomarkers of ESC decidualization. By contrast, PPARβ/δ antagonists impaired decidualization markers. Drugs activating these receptors may have therapeutic benefits for embryonic implantation.
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http://dx.doi.org/10.1210/clinem/dgaa413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373326PMC
September 2020

Temporal Acute Serum Estradiol and Tumor Necrosis Factor-α Associations and Risk of Death after Severe Traumatic Brain Injury.

J Neurotrauma 2020 10 24;37(20):2198-2210. Epub 2020 Jun 24.

Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, Pennsylvania.

Severe traumatic brain injury (TBI) activates a robust systemic response that involves inflammatory and other factors, including estradiol (E2), associated with increased deaths. Tumor necrosis factor-alpha (TNFα) is a significant mediator of systemic shock, and it is an extra-gonadal transcription factor for E2 production. The study objectives were to test the hypotheses: (1) a positive feedback relationship exists between acute serum TNFα and E2; and (2) acute concentrations of E2 and TNFα are prognostic indicators of death after severe TBI. This prospective cohort study included N = 157 adults with severe TBI. Serum samples were collected for the first five days post-injury. The TNFα and E2 levels were averaged into two time epochs: first 72 h (T1) and second 72 h post-injury (T2). A cross-lag panel analysis conducted between T1 and T2 TNFα and E2 levels showed significant cross-lag effects: T1 TNFα and T1 E2 were related to T2 E2 and T2 TNFα, respectively. Cox proportional hazards multi variable regression models determined that increases in T1 E2 (hazard ratio [HR] = 1.79, 95% confidence interval [CI]: 1.15, 2.81), but not T2 E2 (HR = 0.91, 95% CI: 0.56, 1.47), were associated with increased risk of death. Increased T2 TNFα (HR = 2.47, 95% CI: 1.35, 4.53), and T1 TNFα (HR = 1.47, 95% CI: 0.99, 2.19), to a lesser degree, were associated with increased risk of death. Relationships of death with T2 TNFα and T1 E2 were mediated partially by cardiovascular, hepatic, and renal dysfunction. Both E2 and TNFα are systemic, reciprocally related biomarkers that may be indicative of systemic compromise and increased risk of death after severe TBI.
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http://dx.doi.org/10.1089/neu.2019.6577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7580589PMC
October 2020

Anti-Pituitary and Anti-Hypothalamus Autoantibody Associations with Inflammation and Persistent Hypogonadotropic Hypogonadism in Men with Traumatic Brain Injury.

J Neurotrauma 2020 07 13;37(14):1609-1626. Epub 2020 Apr 13.

Department of Physical Medicine & Rehabilitation, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

Traumatic brain injury (TBI) and can lead to persistent hypogonadotropic hypogonadism (PHH) and poor outcomes. We hypothesized that autoimmune and inflammatory mechanisms contribute to PHH pathogenesis. Men with moderate-to-severe TBI ( = 143) were compared with healthy men ( = 39). The TBI group provided blood samples 1-12 months post-injury ( = 1225). TBI and healthy control ( = 39) samples were assayed for testosterone (T) and luteinizing hormone (LH) to adjudicate PHH status. TBI samples 1-6 months post-injury and control samples were assayed for immunoglobulin M (IgM)/immunoglobulin G (IgG) anti-pituitary autoantibodies (APA) and anti-hypothalamus autoantibodies (AHA). Tissue antigen specificity for APA and AHA was confirmed via immunohistochemistry (IHC). IgM and IgG autoantibodies for glial fibrillary acid protein (GFAP) (AGA) were evaluated to gauge APA and AHA production as a generalized autoimmune response to TBI and to evaluate the specificity of APA and AHA to PHH status. An inflammatory marker panel was used to assess relationships to autoantibody profiles and PHH status. Fifty-one men with TBI (36%) had PHH. An age-related decline in T levels by both TBI and PHH status were observed. Injured men had higher APA IgM, APA IgG, AHA IgM, AHA IgG, AGA IgM, and AGA IgG than controls ( < 0.0001 all comparisons). However, only APA IgM ( = 0.03) and AHA IgM ( = 0.03) levels were lower in the PHH than in the non-PHH group in multivariate analysis. There were no differences in IgG levels by PHH status. Multiple inflammatory markers were positively correlated with IgM autoantibody production. PHH was associated with higher soluble tumor-necrosis-factor receptors I/II, (sTNFRI, sTNFRII), regulated on activation, normal T-cell expressed and secreted (RANTES) and soluble interleukin-2-receptor-alpha (sIL-2Rα) levels. Higher IgM APA, and AHA, but not AGA, in the absence of PHH may suggest a beneficial or reparative role for neuroendocrine tissue-specific IgM autoantibody production against PHH development post-TBI.
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http://dx.doi.org/10.1089/neu.2019.6780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7336882PMC
July 2020

Interleukin-1β inhibits estrogen receptor-α, progesterone receptors A and B and biomarkers of human endometrial stromal cell differentiation: implications for endometriosis.

Mol Hum Reprod 2019 10;25(10):625-637

Department of Obstetrics and Gynecology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.

Human blastocyst nidation in the uterus and successful pregnancy require coordinated endometrial expression of estrogen receptor (ER)-α, progesterone receptors (PR)-A and -B and the gap junction protein, connexin (Cx)43. Our prior work established that inflammation associated with conditions of reduced fecundity, particularly endometriosis, can perturb eutopic decidual function. In the current studies, we have modeled endometrial decidualization in primary human endometrial stromal cell cultures derived from normal controls (NESC) and from the eutopic endometria of women with endometriosis (EESC) to test the hypothesis that a proinflammatory cytokine, interleukin (IL)-1β, can disrupt stromal cell differentiation. The cells were grown under a standard protocol with hormones (10 nM 17β-estradiol, 100 nM progesterone and 0.5 mM dibutyryl cAMP) for up to 7 days in the absence or presence of IL-1β. Time-course experiments showed that IL-1β compromised decidual function in both NESC and EESC, which was accompanied by rapid phosphorylation of ER-α, PR and Cx43 and their cellular depletion. Inhibition of the extracellular signal-regulated kinase (ERK)1/2 pathway by a selective pharmacological blocker (PD98059) or siRNA interference, or the addition of hormones themselves, blocked the phosphorylation of ERK mediators; increased the production of steroid receptors, Cx43, prolactin, insulin-like growth factor binding protein-1 (IGFBP)-1 and vascular endothelial growth factor (VEGF) and accelerated the differentiation. The results indicate that inhibition of IL-1β can enhance decidualization in NESC and EESC in vitro. Strategies to interfere with this pathway might be implemented as an in vivo approach to enhance fertility in women with endometriosis and, potentially, other inflammatory pathologies.
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http://dx.doi.org/10.1093/molehr/gaz045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821275PMC
October 2019

Age at Menarche and Risk of Cardiovascular Disease Outcomes: Findings From the National Heart Lung and Blood Institute-Sponsored Women's Ischemia Syndrome Evaluation.

J Am Heart Assoc 2019 06 5;8(12):e012406. Epub 2019 Jun 5.

8 Barbra Streisand Women's Heart Center Cedars-Sinai Smidt Heart Institute Los Angeles CA.

Background Previous studies have reported an association between the timing of menarche and cardiovascular disease ( CVD ). However, emerging studies have not examined the timing of menarche in relation to role of estrogen over a lifetime and major adverse cardiac events ( MACE ). Methods and Results A total of 648 women without surgical menopause undergoing coronary angiography for suspected ischemia in the WISE (Women's Ischemia Syndrome Evaluation) study were evaluated at baseline and followed for 6 years (median) to assess major adverse CVD outcomes. MACE was defined as the first occurrence of all-cause death, nonfatal myocardial infarction, nonfatal stroke, or heart failure hospitalization. Age at menarche was self-reported and categorized (≤10, 11, 12, 13, 14, ≥15 years) with age 12 as reference. Total estrogen time and supra-total estrogen time were calculated. Cox regression analysis was performed adjusting for CVD risk factors. Baseline age was 57.9 ± 12 years (mean ± SD ), body mass index was 29.5 ± 6.5 kg/m, total estrogen time was 32.2 ± 8.9 years, and supra-total estrogen time was 41.4 ± 8.8 years. MACE occurred in 172 (27%), and its adjusted regression model was J-shaped. Compared with women with menarche at age 12 years, the adjusted MACE hazard ratio for menarche at ≤10 years was 4.53 (95% CI 2.13-9.63); and at ≥15 years risk for MACE was 2.58 (95% CI , 1.28-5.21). Conclusions History of early or late menarche was associated with a higher risk for adverse CVD outcomes. These findings highlight age at menarche as a potential screening tool for women at risk of adverse CVD events. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT00000554.
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http://dx.doi.org/10.1161/JAHA.119.012406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6645646PMC
June 2019

In pursuit of middle ground: understanding the bone benefits of hormonal contraception in women with anorexia nervosa.

Authors:
Sarah L Berga

Fertil Steril 2019 05 8;111(5):892-893. Epub 2019 Apr 8.

Department of Obstetrics and Gynecology, University of Utah School of Medicine, Salt Lake City, Utah.

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http://dx.doi.org/10.1016/j.fertnstert.2019.02.016DOI Listing
May 2019

Barriers to the Care of Menopausal Women.

Mayo Clin Proc 2019 02;94(2):191-193

Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN.

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http://dx.doi.org/10.1016/j.mayocp.2018.12.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6597249PMC
February 2019

IL-1β Stimulates Brain-Derived Neurotrophic Factor Production in Eutopic Endometriosis Stromal Cell Cultures: A Model for Cytokine Regulation of Neuroangiogenesis.

Am J Pathol 2018 10 20;188(10):2281-2292. Epub 2018 Jul 20.

Department of Obstetrics and Gynecology, Wake Forest School of Medicine, Winston-Salem, North Carolina; Molecular Medicine and Translational Sciences Program, Wake Forest School of Medicine, Winston-Salem, North Carolina; Clinical and Translational Science Institute, Wake Forest School of Medicine, Winston-Salem, North Carolina. Electronic address:

Endometriosis implants are comprised of glandular and stromal elements, macrophages, nerves, and blood vessels and are commonly accompanied by pelvic pain. We propose that activated macrophages are recruited to and infiltrate nascent lesions, where they secrete proinflammatory cytokines, promoting the production of chemokines, neurotrophins, and angiogenic growth factors that sustain an inflammatory microenvironment. Immunohistochemical evaluation of endometriosis lesions reveals in situ colocalization of concentrated macrophages, brain-derived neurotrophic factor (BDNF), and nerve fibers. These observations were coupled with biochemical analyses of primary eutopic endometriosis stromal cell (EESC) cultures, which allowed defining potential pathways leading to the neuroangiogenic phenotype of these lesions. Our findings indicate that IL-1β potently (EC = 7 ± 2 ng/mL) stimulates production of EESC BDNF at the mRNA and protein levels in an IL-1 receptor-dependent fashion. Selective kinase inhibitors demonstrate that this IL-1β effect is mediated by c-Jun N-terminal kinase (JNK), NF-κB, and mechanistic target of rapamycin signal transduction pathways. IL-1β regulation of regulated on activation normal T cell expressed and secreted (RANTES), a prominent EESC chemokine, also relies on JNK and NF-κB. An important clinical implication of the study is that interference with BDNF and RANTES production, by selectively targeting the JNK and NF-κB cascades, may offer a tractable therapeutic strategy to mitigate the pain and inflammation associated with endometriosis.
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http://dx.doi.org/10.1016/j.ajpath.2018.06.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6169127PMC
October 2018

Estradiol to Androstenedione Ratios Moderate the Relationship between Neurological Injury Severity and Mortality Risk after Severe Traumatic Brain Injury.

J Neurotrauma 2019 02 11;36(4):538-547. Epub 2018 Sep 11.

1 Department of Physical Medicine and Rehabilitation, University of Pittsburgh , Pittsburgh, Pennslvania.

Early declines in gonadotropin production, despite elevated serum estradiol, among some individuals with severe traumatic brain injury (TBI) suggests amplified systemic aromatization occurs post-injury. Our previous work identifies estradiol (E2) as a potent mortality marker. Androstenedione (A), a metabolic precursor to E2, estrone (E1), and testosterone (T), is a steroid hormone substrate for aromatization that has not been explored previously as a biomarker in TBI. Here, we evaluated serum A, E1, T, and E2 values for 82 subjects with severe TBI. Daily hormone values were calculated, and E2:A and E1:T ratios were generated and then averaged for days 0-3 post-injury. After data inspection, mean E2:A values were categorized as above (high aromatization) and below (low aromatization) the 50th percentile for 30-day mortality assessment using Kaplan-Meier survival analysis and a multivariable Cox proportional hazard model adjusting for age, and Glasgow Coma Scale (GCS) to predict 30-day mortality status. Daily serum T, E1, and E2 were graphed by E2:A category. Serum E1 and E2 significantly differed over time (p < 0.05); the high aromatization group had elevated levels and a significantly lower probability of survival within the first 30 days (p = 0.0274). Multivariable Cox regression showed a significant E2:A*GCS interaction (p = 0.0129), wherein GCS predicted mortality only among those in the low aromatization group. E2:A may be a useful mortality biomarker representing enhanced aromatization after TBI. E2:A ratios may represent non-neurological organ dysfunction after TBI and may be useful in defining injury subgroups in which GCS has variable capacity to serve as an accurate early prognostic marker.
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http://dx.doi.org/10.1089/neu.2018.5677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354608PMC
February 2019

Systemic Estrone Production and Injury-Induced Sex Hormone Steroidogenesis after Severe Traumatic Brain Injury: A Prognostic Indicator of Traumatic Brain Injury-Related Mortality.

J Neurotrauma 2019 04 24;36(7):1156-1167. Epub 2018 Aug 24.

1 Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh Pennsylvania.

Extensive pre-clinical studies suggest that sex steroids are neuroprotective in experimental traumatic brain injury (TBI). However, clinical trials involving sex hormone administration have not shown beneficial results, and our observational cohort studies show systemic estradiol (E2) production to be associated with adverse outcomes. Systemic E2 is produced via aromatization of testosterone (T) or reduction of estrone (E1). E1, also produced via aromatization of androstenedione (Andro) and is a marker of T-independent E2 production. We hypothesized that E1 would be (1) associated with TBI-related mortality, (2) the primary intermediate for E2 production, and (3) associated with adipose tissue-specific aromatase transcription. We assessed 100 subjects with severe TBI and 8 healthy controls. Serum levels were measured on days 0-3 post-TBI for key steroidogenic precursors (progesterone), aromatase pathway intermediates (E1, E2, T, Andro), and the adipose tissue-specific aromatase transcription factors cortisol, tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6). E1 was elevated after TBI versus controls. High E1 was associated with higher progesterone, cortisol, and IL-6 (p < 0.05). Multivariable logistic regression demonstrated that those in the highest E1 tertile had increased odds for mortality (adjusted OR = 5.656, 95% CI = 1.102-29.045, p = 0.038). Structural equation models show that early serum E2 production is largely T independent, occurring predominantly through E1 metabolism. Acute serum E1 functions as a mortality marker for TBI through aromatase-dependent E1 production and T-independent E2 production. Further work should evaluate risk factors for high E2 production and how systemic E2 and its key intermediate E1 contribute to the extracerebral consequences of severe TBI.
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http://dx.doi.org/10.1089/neu.2018.5782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6445057PMC
April 2019

Heightened cortisol response to exercise challenge in women with functional hypothalamic amenorrhea.

Am J Obstet Gynecol 2018 02 21;218(2):230.e1-230.e6. Epub 2017 Nov 21.

Section of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Wake Forest Baptist Medical Center, Winston-Salem, NC. Electronic address:

Background: Functional hypothalamic amenorrhea is characterized by anovulation caused by reduced gonadotropin-releasing hormone drive and is associated with hypercortisolemia that has been linked to heightened hypothalamic-pituitary-adrenal reactivity to common psychological and metabolic challenges.

Objective: We hypothesized that women with functional hypothalamic amenorrhea would display greater cortisol responses to exercise challenge than ovulatory women with eumenorrhea.

Study Design: We completed a cross-sectional comparison of 9 women with functional hypothalamic amenorrhea and 11 women with eumenorrhea who were of reproductive age, who weighed 90-110% ideal body weight, who did not exercise excessively, and who had no formal psychiatric diagnosis. Subjects completed a 20-minute submaximal exercise challenge using a cycle ergometer in a research exercise laboratory. Heart rate and circulatory cortisol, glucose, and lactate were measured at 10-minute intervals before, during, and after the exercise challenge.

Results: Baseline (t= -10 minutes) cortisol, glucose, lactate, and heart rate were comparable between groups. Glucose levels rose modestly during exercise by 2.9% in women with eumenorrhea (P=.4) but declined by 10.6% in functional hypothalamic amenorrhea (P<.03). The nadir in glucose levels in functional hypothalamic amenorrhea occurred at the end of the 20-minute exercise challenge (t= +20 min). Lactate levels rose comparably in both groups (P<.01). Heart rate increased significantly with exercise in both groups (P<.01), but the increase was smaller in subjects with functional hypothalamic amenorrhea (P<.01). Cortisol levels increased during the exercise challenge in both groups (P<.01) and peaked 10 minutes after the exercise ended (t= +30 min). At peak, subjects with functional hypothalamic amenorrhea displayed higher cortisol levels (147±22 [standard error of the mean] ng/mL) than women with eumenorrhea (96±12 ng/mL; P=.05). The mean percent increase over baseline was 62% in women with eumenorrhea and 92% in functional hypothalamic amenorrhea.

Conclusion: The heightened cortisol response to exercise in women with functional hypothalamic amenorrhea was associated with a decline in blood glucose level that was not observed in women with eumenorrhea. Women with functional hypothalamic amenorrhea appear to be more reactive at the endocrine level to the metabolic demand of exercise. Submaximal challenge unmasks underlying stress sensitivity in women with functional hypothalamic amenorrhea and highlights the importance of the use of psychological interventions for stress reduction in this population.
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http://dx.doi.org/10.1016/j.ajog.2017.11.579DOI Listing
February 2018

Examining the Validity of Self-reported Primary and Secondary Exposure to Cigarette Smoke in Adolescent Girls: The Utility of Salivary Cotinine as a Biomarker.

Subst Use Misuse 2018 04 23;53(5):792-799. Epub 2017 Oct 23.

c Department of Obstetrics and Gynecology , Wake Forest School of Medicine , Winston-Salem , North Carolina , USA.

Background: Studies of cigarette use and exposure often rely on either self-report or cotinine assay. In adolescence it is not clear how well assays and self-report correspond, or what effect estrogen exposure has on cotinine.

Objectives: This study sought to identify optimal cut-points for salivary cotinine thresholds for girls with primary, secondary, and no smoke exposure, and whether menarche and hormone contraceptive use are important for interpreting salivary cotinine.

Methods: This longitudinal prospective study recruited 262 healthy adolescent girls who participated in three annual interviews across 24 months. Salivary cotinine assays and self-report of primary and secondary smoke exposure, menarcheal status, and hormone contraceptive use were collected.

Results: No adolescents reported primary smoke exposure without secondary exposure. Optimal cut-points for distinguishing primary smoke exposure from secondary-only and no smoke exposure were 1.05 and 3.01 ng/ml, respectively based on receiver operator curves (ROC); no reliable cut-point for secondary-only versus no smoke exposure was identified. The ideal salivary cotinine cut-point to distinguish primary smoke exposure varied by hormone contraceptive use and was 2.14 ng/ml for those using progesterone contraceptives, higher than that of girls using estrogen contraceptives and those not using hormone contraceptives.

Conclusions: This study is the first to examine variance in salivary cotinine cut-points based on hormone exposure for adolescent girls, with findings indicating that hormone contraceptive use in particular may be a key consideration when identifying adolescent smoking. The use of previously recommended salivary cotinine cut-points of 3.85 ng/ml or higher may overestimate nonsmokers.
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http://dx.doi.org/10.1080/10826084.2017.1365904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6087668PMC
April 2018

IL-1β Inhibits Connexin 43 and Disrupts Decidualization of Human Endometrial Stromal Cells Through ERK1/2 and p38 MAP Kinase.

Endocrinology 2017 12;158(12):4270-4285

Department of Obstetrics and Gynecology, Wake Forest School of Medicine.

Inflammation can interfere with endometrial receptivity. We examined how interleukin 1β (IL-1β) affects expression of the uterine gap junction protein connexin 43 (Cx43), which is known to be critical for embryonic implantation. We used an in vitro model of human endometrial stromal cells (ESCs), Western blotting, and a combination of validated, selective kinase inhibitors to evaluate five canonical IL-1β signaling pathways. Cx43 and two other markers of ESC differentiation (prolactin and VEGF) were inhibited predominantly via IL-1β-activated ERK1/2 and p38 MAP kinase cascades. The findings were corroborated using small interfering RNA to silence critical genes in either pathway. By contrast, upregulation of endogenous pro-IL-1α and pro-IL-1β following recombinant IL-1β treatment was mediated via the Jun N-terminal kinase pathway. The clinicopharmacological significance of our findings is that multiple signaling cascades may need to be neutralized to reverse deleterious effects of IL-1β on human endometrial function.
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http://dx.doi.org/10.1210/en.2017-00495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5711380PMC
December 2017

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

Hum Reprod 2017 07;32(7):1450-1456

Section of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Wake Forest School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157.

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.
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http://dx.doi.org/10.1093/humrep/dex086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6251519PMC
July 2017

Functional Hypothalamic Amenorrhea: An Endocrine Society Clinical Practice Guideline.

J Clin Endocrinol Metab 2017 05;102(5):1413-1439

Center for Menopause, Hormonal Disorders, and Women's Health, Columbia University Medical Center, New York, New York 10021.

Cosponsoring Associations: The American Society for Reproductive Medicine, the European Society of Endocrinology, and the Pediatric Endocrine Society. This guideline was funded by the Endocrine Society.

Objective: To formulate clinical practice guidelines for the diagnosis and treatment of functional hypothalamic amenorrhea (FHA).

Participants: The participants include an Endocrine Society-appointed task force of eight experts, a methodologist, and a medical writer.

Evidence: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation approach to describe the strength of recommendations and the quality of evidence. The task force commissioned two systematic reviews and used the best available evidence from other published systematic reviews and individual studies.

Consensus Process: One group meeting, several conference calls, and e-mail communications enabled consensus. Endocrine Society committees and members and cosponsoring organizations reviewed and commented on preliminary drafts of this guideline.

Conclusions: FHA is a form of chronic anovulation, not due to identifiable organic causes, but often associated with stress, weight loss, excessive exercise, or a combination thereof. Investigations should include assessment of systemic and endocrinologic etiologies, as FHA is a diagnosis of exclusion. A multidisciplinary treatment approach is necessary, including medical, dietary, and mental health support. Medical complications include, among others, bone loss and infertility, and appropriate therapies are under debate and investigation.
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http://dx.doi.org/10.1210/jc.2017-00131DOI Listing
May 2017

Neuroprotection via Reduction in Stress: Altered Menstrual Patterns as a Marker for Stress and Implications for Long-Term Neurologic Health in Women.

Int J Mol Sci 2016 Dec 20;17(12). Epub 2016 Dec 20.

Department of Obstetrics and Gynecology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.

Individuals under chronic psychological stress can be difficult to identify clinically. There is often no outwardly visible phenotype. Chronic stress of sufficient magnitude not only impacts reproductive function, but also concomitantly elicits a constellation of neuroendocrine changes that may accelerate aging in general and brain aging in particular. Functional hypothalamic amenorrhea, a phenotypically recognizable form of stress, is due to stress-induced suppression of endogenous gonadotropin-releasing hormone secretion. Reversal of functional hypothalamic amenorrhea includes restoration of ovulatory ovarian function and fertility and amelioration of hypercortisolism and hypothyroidism. Taken together, recovery from functional hypothalamic amenorrhea putatively offers neuroprotection and ameliorates stress-induced premature brain aging and possibly syndromic Alzheimer's disease. Amenorrhea may be viewed as a sentinel indicator of stress. Hypothalamic hypogonadism is less clinically evident in men and the diagnosis is difficult to establish. Whether there are other sex differences in the impact of stress on brain aging remains to be better investigated, but it is likely that both low estradiol from stress-induced anovulation and low testosterone from stress-induced hypogonadism compromise brain health.
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http://dx.doi.org/10.3390/ijms17122147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5187947PMC
December 2016

Menopausal symptoms and cardiovascular disease mortality in the Women's Ischemia Syndrome Evaluation (WISE).

Menopause 2017 02;24(2):126-132

1Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 2Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA 3Barbra Streisand Women's Heart Center, Cedars-Sinai Heart Institute, Los Angeles, CA 4Section of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Wake Forest School of Medicine, Winston-Salem, NC 5Department of Obstetrics and Gynecology, Keck School of Medicine of University of Southern California, Los Angeles, CA 6Division of Cardiology, Department of Medicine, University of Florida, Gainesville, FL 7Division of Cardiovascular Disease, Department of Medicine, University of Alabama Birmingham, AL 8Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 9Division of Cardiology, Department of Medicine, Allegheny General Hospital, Pittsburgh, PA 10Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.

Objective: Studies have linked vasomotor symptoms (VMS) to markers of cardiovascular disease (CVD) risk, yet few have considered clinical cardiovascular events. Data suggest that associations may depend upon the age that symptoms occur. We examined associations between VMS and cardiovascular events and endothelial function, considering age of symptom onset.

Methods: The Women's Ischemia Syndrome Evaluation enrolled women referred for coronary angiography for suspected myocardial ischemia. A total of 254 women aged more than 50 years, postmenopausal, with both ovaries, not taking hormone therapy underwent a baseline evaluation, were followed annually (median = 6.0 y), and the National Death Index was searched to ascertain CVD mortality (median = 9.3 y). A subset of participants underwent brachial artery ultrasound for flow-mediated dilation (FMD). Receiver-operating curve analysis was used to determine vasomotor symptom groups (symptoms beginning < age 42 [early onset], beginning ≥42 [later onset], never) which were examined in relation to cardiovascular events and FMD in Cox proportional hazard and linear regression models.

Results: Women reporting early onset VMS (HR = 3.35, 95% CI = 1.23-7.86, P = 0.005) and women who never had VMS (HR = 2.17, 95% CI = 1.02-4.62, P = 0.05) had higher CVD mortality than women with later onset symptoms (multivariable models). Women with early onset VMS had lower FMD than women with later onset symptoms (b = -4.31, SE = 2.10, P = 0.04, multivariable).

Conclusions: Women with signs and symptoms of ischemia who had VMS beginning early in midlife had higher CVD mortality and reduced endothelial function relative to women with later onset symptoms. Future research should evaluate the vascular phenotype of women with early midlife VMS.
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http://dx.doi.org/10.1097/GME.0000000000000731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5266637PMC
February 2017

Social determinants of infertility: beyond the obvious.

Authors:
Sarah L Berga

Fertil Steril 2016 06 13;105(6):1459-60. Epub 2016 Apr 13.

Department of Obstetrics & Gynecology, Wake Forest School of Medicine, Winston-Salem, North Carolina.

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http://dx.doi.org/10.1016/j.fertnstert.2016.03.046DOI Listing
June 2016

Endometrial Stromal Decidualization Responds Reversibly to Hormone Stimulation and Withdrawal.

Endocrinology 2016 06 1;157(6):2432-46. Epub 2016 Apr 1.

Department of Obstetrics and Gynecology (J.Y., S.L.B., E.B.J.-M., R.N.T.), Clinical and Translational Science Institute (J.Y., R.N.T.), and Molecular Medicine and Translational Sciences Program (R.N.T.), Wake Forest School of Medicine, Winston-Salem, North Carolina 27157; Department of Gynecology and Obstetrics (N.S.), Emory University School of Medicine, Atlanta, Georgia 30322; and Departments of Comparative Biosciences (I.C.B.) and Molecular and Integrative Physiology (M.K.B.), University of Illinois Urbana/Champaign, Illinois 61801.

Human endometrial stromal decidualization is required for embryo receptivity, angiogenesis, and placentation. Previous studies from our laboratories established that connexin (Cx)-43 critically regulates endometrial stromal cell (ESC) differentiation, whereas gap junction blockade prevents it. The current study evaluated the plasticity of ESC morphology and Cx43 expression, as well as other biochemical markers of cell differentiation, in response to decidualizing hormones. Primary human ESC cultures were exposed to 10 nM estradiol, 100 nM progesterone, and 0.5 mM cAMP for up to 14 days, followed by hormone withdrawal for 14 days, mimicking a biphasic ovulatory cycle. Reversible differentiation was documented by characteristic changes in cell shape. Cx43 was reversibly up- and down-regulated after the estradiol, progesterone, and cAMP treatment and withdrawal, respectively, paralleled by fluctuations in prolactin, vascular endothelial growth factor, IL-11, and glycodelin secretion. Markers of mesenchymal-epithelial transition (MET), and its counterpart epithelial-mesenchymal transition, followed reciprocal patterns corresponding to the morphological changes. Incubation in the presence of 18α-glycyrrhetinic acid, an inhibitor of gap junctions, partially reversed the expression of decidualization and MET markers. In the absence of hormones, Cx43 overexpression promoted increases in vascular endothelial growth factor and IL-11 secretion, up-regulated MET markers, and reduced N-cadherin, an epithelial-mesenchymal transition marker. The combined results support the hypothesis that Cx43-containing gap junctions and endocrine factors cooperate to regulate selected biomarkers of stromal decidualization and MET and suggest roles for both phenomena in endometrial preparation for embryonic receptivity.
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http://dx.doi.org/10.1210/en.2015-1942DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4891781PMC
June 2016

Strategies and methods to study female-specific cardiovascular health and disease: a guide for clinical scientists.

Biol Sex Differ 2016 31;7:19. Epub 2016 Mar 31.

Barbra Streisand Women's Heart Center, Cedars-Sinai Heart Institute, Los Angeles, CA USA.

Background: In 2001, the Institute of Medicine's (IOM) report, "Exploring the Biological Contributions to Human Health: Does Sex Matter?" advocated for better understanding of the differences in human diseases between the sexes, with translation of these differences into clinical practice. Sex differences are well documented in the prevalence of cardiovascular (CV) risk factors, the clinical manifestation and incidence of cardiovascular disease (CVD), and the impact of risk factors on outcomes. There are also physiologic and psychosocial factors unique to women that may affect CVD risk, such as issues related to reproduction.

Methods: The Society for Women's Health Research (SWHR) CV Network compiled an inventory of sex-specific strategies and methods for the study of women and CV health and disease across the lifespan. References for methods and strategy details are provided to gather and evaluate this information. Some items comprise robust measures; others are in development.

Results: To address female-specific CV health and disease in population, physiology, and clinical trial research, data should be collected on reproductive history, psychosocial variables, and other factors that disproportionately affect CVD in women. Variables related to reproductive health include the following: age of menarche, menstrual cycle regularity, hormone levels, oral contraceptive use, pregnancy history/complications, polycystic ovary syndrome (PCOS) components, menopause age, and use and type of menopausal hormone therapy. Other factors that differentially affect women's CV risk include diabetes mellitus, autoimmune inflammatory disease, and autonomic vasomotor control. Sex differences in aging as well as psychosocial variables such as depression and stress should also be considered. Women are frequently not included/enrolled in mixed-sex CVD studies; when they are included, information on these variables is generally not collected. These omissions limit the ability to determine the role of sex-specific contributors to CV health and disease. Lack of sex-specific knowledge contributes to the CVD health disparities that women face.

Conclusions: The purpose of this review is to encourage investigators to consider ways to increase the usefulness of physiological and psychosocial data obtained from clinical populations, in an effort to improve the understanding of sex differences in clinical CVD research and health-care delivery for women and men.
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http://dx.doi.org/10.1186/s13293-016-0073-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4815158PMC
April 2016

Longitudinal sex and stress hormone profiles among reproductive age and post-menopausal women after severe TBI: A case series analysis.

Brain Inj 2016 10;30(4):452-461. Epub 2016 Mar 10.

a Department of Physical Medicine and Rehabilitation , University of Pittsburgh , Pittsburgh , PA , USA.

Primary Objectives: To describe hormone profiles for pre-/post-menopausal women, to monitor time to resumption of menstruation among pre-menopausal women and to describe cortisol associated LH suppression and phasic variation in other sex hormones over timeMethods and procedures: This study determined amenorrhea duration and characterized acute (days 0-7) and chronic (months 1-6) gonadotropins [luteinizing hormone and follicle stimulating hormone (LH, FSH)], sex hormones (progesterone, estradiol) and stress hormone (cortisol) profiles. Women were pre-menopausal (n = 3) or post-menopausal (n = 3). Among pre-menopausal women, menstrual cycle resolution and phase association (luteal/follicular) was monitored using self-report monthly reproductive history questionnaires. This study compared post-TBI hormone profiles, stratified by menopausal status, to hormone levels from seven controls and described 6- and 12-month outcomes for these women.

Main Outcomes And Results: Consistent with functional hypothalamic amenorrhea (FHA), menstruation resumption among pre-menopausal women occurred when serum cortisol normalized to luteal phase control levels. For post-menopausal women, serum cortisol reductions corresponded with resolution of suppressed LH levels.

Conclusions: The stress of TBI results in anovulation and central hypothalamic-pituitary-ovarian (HPG) axis suppression. Future work will examine acute/chronic consequences of post-TBI hypercortisolemia and associated HPG suppression, the temporal association of HPG suppression with other neuroendocrine adaptations and how HPG suppression impacts multidimensional recovery for women with TBI.
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http://dx.doi.org/10.3109/02699052.2016.1144081DOI Listing
January 2018

Persistent Hypogonadotropic Hypogonadism in Men After Severe Traumatic Brain Injury: Temporal Hormone Profiles and Outcome Prediction.

J Head Trauma Rehabil 2016 Jul-Aug;31(4):277-87

Department of Physical Medicine and Rehabilitation, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania (Messrs Barton and Kumar, Ms McCullough, and Drs Galang, Arenth, and Wagner); Department of Obstetrics and Gynecology, Wake Forest School of Medicine, Winston-Salem, North Carolina (Dr Berga); and Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, Pennsylvania (Dr Wagner).

Objective: To (1) examine relationships between persistent hypogonadotropic hypogonadism (PHH) and long-term outcomes after severe traumatic brain injury (TBI); and (2) determine whether subacute testosterone levels can predict PHH.

Setting: Level 1 trauma center at a university hospital.

Participants: Consecutive sample of men with severe TBI between 2004 and 2009.

Design: Prospective cohort study.

Main Measures: Post-TBI blood samples were collected during week 1, every 2 weeks until 26 weeks, and at 52 weeks. Serum hormone levels were measured, and individuals were designated as having PHH if 50% or more of samples met criteria for hypogonadotropic hypogonadism. At 6 and 12 months postinjury, we assessed global outcome, disability, functional cognition, depression, and quality of life.

Results: We recruited 78 men; median (interquartile range) age was 28.5 (22-42) years. Thirty-four patients (44%) had PHH during the first year postinjury. Multivariable regression, controlling for age, demonstrated PHH status predicted worse global outcome scores, more disability, and reduced functional cognition at 6 and 12 months post-TBI. Two-step testosterone screening for PHH at 12 to 16 weeks postinjury yielded a sensitivity of 79% and specificity of 100%.

Conclusion: PHH status in men predicts poor outcome after severe TBI, and PHH can accurately be predicted at 12 to 16 weeks.
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http://dx.doi.org/10.1097/HTR.0000000000000188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4786474PMC
March 2018

Patterns of change in cognitive function with anastrozole therapy.

Cancer 2015 Aug 23;121(15):2627-36. Epub 2015 Apr 23.

University of Pittsburgh, Pittsburgh, Pennsylvania.

Background: The purpose of this study was to examine and compare the effects of the first 18 months of anastrozole therapy on cognitive function in women with breast cancer.

Methods: This large, longitudinal cohort study was composed of postmenopausal women with early-stage breast cancer who received chemotherapy plus anastrozole (n = 114) or anastrozole alone (n = 173) and a control group (n = 110). Cognitive function was assessed before systemic therapy and 6, 12, and 18 months after therapy initiation and at comparable time points in controls.

Results: The chemotherapy-anastrozole and anastrozole-alone groups had poorer executive function than the controls at nearly all time points (P < .0001 to P = .09). A pattern of deterioration in working memory and concentration was observed during the first 6 months of anastrozole therapy for the chemotherapy-anastrozole group (P < .0001 and P < .0009, respectively) and the anastrozole-alone group (P = .0008 and P = .0002, respectively). This was followed by improved working memory and concentration from 6 to 12 months in both groups. The anastrozole-alone group had a second decline in working memory and concentration from 12 to 18 months after the initiation of therapy (P < .0001 and P = .02, respectively).

Conclusions: Women with breast cancer had poorer executive functioning from the period before therapy through the entire first 18 months of therapy. A pattern of decline in working memory and concentration with initial exposure to anastrozole was observed. Women receiving anastrozole alone had a second deterioration in working memory and concentration from 12 to 18 months after therapy initiation. The longer term effects (>18 months) of anastrozole on cognitive function remain to be determined.
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http://dx.doi.org/10.1002/cncr.29393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4512875PMC
August 2015

Gap junction blockade induces apoptosis in human endometrial stromal cells.

Mol Reprod Dev 2014 Jul 14;81(7):666-75. Epub 2014 May 14.

Department of Obstetrics and Gynecology, Wake Forest School of Medicine, Winston-Salem, North California.

One of the most dynamic adult human tissues is the endometrium. Through coordinated, cyclical proliferation, differentiation, leukocyte recruitment, apoptosis, and desquamation, the uterine lining is expanded and shed monthly, unless pregnancy is established. Errors in these steps potentially cause endometrial dysfunction, abnormal uterine bleeding, failed embryonic implantation, infertility, or endometrial carcinoma. Our prior studies showed that gap junctions comprised of Gap junction alpha-1 (GJA1) protein, also known as connexin 43 (CX43), subunits are critical to endometrial stromal cell differentiation. The current studies were undertaken to explore the mechanism of endometrial dysfunction when gap junction intercellular communication (GJIC) is disrupted. Gap junction blockade by two distinct GJIC inhibitors, 18α-glycyrrhetinic acid (AGA) and octanol (OcOH), suppressed proliferation and induced apoptosis in endometrial stromal cells, as manifested by reduced biomarkers of cell viability, increased TUNEL staining, caspase-3 activation, sub-G1 chromosomal DNA complement, as well as shortened telomere length. Unexpectedly, we also observed that the chemical inhibitors blocked CX43 gene expression. Moreover, when endometrial stromal cells were induced to undergo hormonal decidualization, following a 7-day exposure to 10 nM 17β-estradiol + 100 nM progesterone + 0.5 mM dibutyryl cAMP, characteristic epithelioid changes in cell shape and secretion of prolactin were blunted in the presence of AGA or OcOH, recapitulating effects of RNA interference of CX43. Our findings indicate that endometrial stromal cell proliferation and maintenance of decidualized endometrial function are GJIC-dependent, and that disruption of gap junctions induces endometrial stromal cell apoptosis. These observations may have important implications for several common clinical endometrial pathologies.
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http://dx.doi.org/10.1002/mrd.22334DOI Listing
July 2014
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