Article:Neuroprotection via Reduction in Stress: Altered Menstrual Patterns as a Marker for Stress and Implications for Long-Term Neurologic Health in Women (5187947)

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This page is the ScienceSource HTML version of the scholarly article described at https://www.wikidata.org/wiki/Q28072386. Its title is Neuroprotection via Reduction in Stress: Altered Menstrual Patterns as a Marker for Stress and Implications for Long-Term Neurologic Health in Women and the publication date was 2016-12-20. The initial author is David Prokai.

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Journal Information

Title: International Journal of Molecular Sciences

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

  • David Prokai
  • Sarah L. Berga
  • Katalin Prokai-Tatrai (Academic Editor)
  • Xiaofeng Jia (Academic Editor)

Department of Obstetrics and Gynecology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA; dprokai@wakehealth.edu

Publication date (epub): 12/2016

Publication date (collection): 12/2016

Abstract

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.

Paper

1. Introduction

Stress has many adverse health effects [[1]]. Unfortunately, individuals under chronic stress are often difficult to clinically identify, as there are few objective measures to define those that are chronically stressed. In women, phenotypic markers of chronic stress include menstrual irregularities, amenorrhea, and/or infertility due to hypothalamic hypogonadism. The endocrine signature of stress may be more likely to be reported as menstrual cycle changes rather than as complaints of stress per se. Herein, we focus on the pathobiological mechanisms mediating the link between chronic stress and reproductive compromise and show how stress-induced alterations in neuroendocrine secretory patterns may impact brain health and accelerate the onset of aging syndromes such as osteoporosis, vaginal atrophy, and dementia. Functional hypothalamic amenorrhea (FHA) is the most clinically evident example of the psychoneuroendocrinological condition, often termed functional hypothalamic hypogonadism. Our research has not only revealed the mechanisms mediating the link between chronic stress and FHA but has also established that stress reduction results in restoration of ovulation and amelioration of other neuroendocrine concomitants [[2]]. FHA is caused by chronic stress. While the stressors are often viewed as either metabolic or psychological, from a neuroendocrine perspective, this is a false dichotomy [[2]]. Regardless of the category, the final common pathway is activation of the limbic–hypothalamic–pituitary–adrenal axis [[3]] that then reduces central gonadotropin-releasing hormone (GnRH) drive [[4],[5]]. The term “functional” is used to distinguish organic from behavioral causes and implies that, once the salient stressors are identified and their impact reduced, cortisol levels will normalize, GnRH drive will increase, and ovulatory ovarian function will resume [[6]]. FHA may well be the most common cause of amenorrhea in reproductive-age women [[7]].

2. Role of Stress in Functional Hypothalamic Amenorrhea (FHA)

There is evidence that stress is the proximate cause of FHA [[6]]. The combination of metabolic and psychological stressors causes a multitude of physiologic changes; the initiating signal that elicits and maintains the other neuroendocrine concomitants is a subtle, mostly nocturnal, increase in circulating cortisol [[8]]. Women with FHA have higher cortisol levels relative to eumenorrheic women and women with other forms of ovulatory dysfunction [[6],[9]]. Notably, this hypercortisolism is also observed in the cerebrospinal fluid (CSF) of women with FHA [[10]]. Not only is the proportional rise greater in the CSF than in the circulation, the cortisol in the CSF is also unbound and thus more bioavailable. Therefore, the brunt of activated stress signaling may impact the brain more than peripheral tissues. Chronic hypoestrogenism from anovulation also compromises neural health and prevents age-appropriate bone accretion. Hypogonadism is due to stress-induced reduction in GnRH input leading to decreasing levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) [[2],[6],[11]] to the extent that folliculogenesis is not supported and anovulation and secondary amenorrhea occur [[2],[6]]. However, the suppression of GnRH occurs on a spectrum and lesser or intermittent “bouts” of reduced GnRH drive may manifest as luteal insufficiency and/or anovulatory cycles [[12]]. Therefore, the patient’s presenting symptoms to clinicians may be oligomenorrhea or infertility rather than amenorrhea [[4],[5]]. Clinicians need to recognize that FHA is a diagnosis of exclusion and establishing the diagnosis requires a thorough evaluation of the patient.

Of note, stress and its resulting hormonal changes could trigger either undernutrition or overnutrition, depending on fuel availability, attitudes about food, and dietary behaviors such as bingeing, purging, overeating, or restricting. While the classic description of FHA is a thin woman who undereats and overexercises as a means of stress management, the new age profile may well be a high-achieving individual with overeating behaviors. Thus, chronic stress leads to a range of problematic eating patterns that could eventuate in either thinness or obesity. Obesity alone can suppress GnRH drive [[13]]. It is important to realize that not all anovulatory women who are obese have polycystic ovary syndrome and that some, possibly the majority, have “heavy” as opposed to “thin” FHA. From a systemic perspective, stress and obesity can act synergistically to increase inflammation [[14]]. This increased systemic inflammation over time has been associated with increased brain aging and an increased propensity towards neurodegeneration, such as syndromic Alzheimer’s disease (AD) [[15]].

3. Glucocorticoid Effects upon Reproductive Tissues

The health impact of chronic hypothalamic hypercortisolism and its concomitants remain to be fully characterized; however, it is clear that the impact extends beyond perturbations in menstrual cyclicity [[16]]. Of particular interest to health care providers for women is that stress and increased glucocorticoids have been shown to have profound effects on pregnancy and fetal development [[17]]. An association between maternal socioeconomic status, stress levels, and increased risks of preterm labor has also been described [[18]]. Stress increases expression of corticotrophin-releasing hormone (CRH), which in turn stimulates myometrial contractions via cytokine release [[19],[20],[21]], thereby potentiating labor [[22],[23],[24]]. Additionally, elevated maternal serum levels of CRH are seen in the second trimester of pregnancy in women who eventually deliver prematurely [[25],[26]]. Stress reduction (e.g., group pregnancy care) has been shown to reduce rates of preterm labor [[27],[28],[29],[30]]. In essence, both the magnitude and type of stressor elicit a constellation of neurohormonal alterations and accelerate molecular aging via regulation of telomerase [[31]].

Exogenous glucocorticoids (betamethasone and dexamethasone) are given for pregnancies at risk of preterm delivery, as these steroids accelerate fetal lung surfactant expression and release, thereby decreasing respiratory compromise due to atelectasis encountered by the premature newborns [[32],[33]]. While synthetic glucocorticoids provide immediate fetal/neonatal benefit, repeated exposure not only negatively impact fetal outcomes, but emerging data suggest that glucocorticoid exposure in utero carries risks for diseases that will manifest in adulthood. Specifically, epidemiologic studies have shown that those exposed to excess glucocorticoids in utero display long-term health consequences due to accelerated aging [[34],[35],[36],[37]]. Animal models have also shown persistent changes at the level of the glomeruli following betamethasone exposure, further demonstrating that the long-lasting effect of antenatal steroid exposure [[38],[39],[40]] is at least in part mediated via epigenetic mechanisms and consequences of accelerated aging at critical stages of fetal development [[41]].

4. Neuroprotection via Reduction in Stress

Stress management falls into two main categories: pharmacologic and nonpharmacologic, which can be employed concomitantly. Nonpharmacologic approaches such as cognitive behavioral therapy (CBT) should be considered as first line therapy because most behaviors that are stressful to self and others are initiated in response to cognitions [[42]]. CBT improves coping mechanisms and has been shown to restore ovarian function, including ovulation, in women who were previously amenorrheic due to reduced central GnRH drive [[43]]. The goal of CBT is to reduce allostatic load [[44]] by recognizing the stressful attitudes and behavior that cause excess activation of the adrenal axis and secondarily other alterations in neuroendocrine function. We have previously shown that CBT-induced restoration of ovarian function was accompanied by reductions in cortisol, particularly during the nocturnal phase, and other metabolic variables, including increased leptin and thyroid-stimulating hormone (TSH) independent of weight gain [[45]]. In this study, sixteen women with FHA were randomized to CBT or observation for twenty weeks [[45],[46]]. Of the eight women treated with CBT, six resumed ovulating, one had partial recovery of ovarian function without evidence of ovulation, and only one did not display return of ovarian function. Two of the eight individuals not treated with CBT showed only partial return of ovarian function. In summary, stress causes more than an isolated disruption of reproduction function and stress management restores the panoply of neuroendocrine patterns. To the extent that chronic stress impairs brain function, then stress reduction will afford neuroprotection. Improvements in stress reduction and coping mechanisms may have both acute and chronic benefits to the individual and her offspring.

5. Molecular Consequences of Stress

An insidious consequence of the elevated cortisol that accompanies chronic stress is that the cellular machinery that estrogen would otherwise access is hijacked by the elevated glucocorticoids [[47]]. Using molecular expression, Bolt et al. showed that cortisol and estradiol utilized the same co-activators to “fine-tune” transcriptional responses [[48]].

Molecular analysis has shown that glucocorticoid and estrogen receptors have binding sites within the promotor elements of similar genes [[49]], and that glucocorticoid and estrogen receptor binding sites antagonistically regulate the promoters of many genes. Pathway analysis has shown significant overlap between the networks controlled by glucocorticoids and estrogen [[50]]. In addition to direct transcriptional regulation, antagonism of estradiol signaling by glucocorticoid may occur through regulation of chaperone proteins [[51]]. These molecular findings speak to the importance of lowering stress and cortisol. Therefore, not only do patients with FHA have lower levels of estrogen, but exogenous estrogen replacement may not reverse consequences of hypoestrogenism due to the antagonism of estrogen action by elevated glucocorticoids.

Hypercortisolism induces a state termed catabolism and women with FHA are catabolic rather than anabolic [[52]]. Catabolism is conferred and signaled by reduced thyroid hormone and growth hormone secretion [[6]]. The elevated cortisol that is central to FHA directly reduces TSH, thyroxine (T4), and thyronine (T3) levels. Cortisol suppresses the TSH response to thyrotropin-releasing hormone (TRH) [[53]].

A central theme is that chronic stress accelerates aging and, once an organism’s energy balance shifts toward survival, cellular upkeep suffers through switching from an anabolic to a catabolic state with suppression of the hypothalamic–pituitary–thyroidal (HPT) axis [[52]]. This metabolic reprioritization leads to diminished cellular repair and upkeep, which may contribute to the development of neurodegeneration and associated dementia. In Table 1, we summarize the metabolic patterns contributing to diminished brain health in women with FHA.

6. Stress and Neurodegenerative Diseases

Stress enhances sympathetic activity and activates the Hypothalamus–pituitary–adrenal (HPA) axis [[54]]. While such activation may foster acute survival, frequent and prolonged stimulation can have many deleterious consequences. The work of McEwen has focused on the “double edged” nature of stress in relation to the organism. When exposed to an acute stress, stress hormones released by the body seek to restore homeostasis in the face of a challenge. This is referred to as “allostasis” [[55]]. If the stress response is too frequent or the stress hormone response system is operating in an inefficient manner, there is a cost that must be paid by the organism. The price for maintaining equilibrium is referred to as the “allostatic load” [[44],[55]]. We surmise that, in women with FHA, the systems that protect and foster neurologic health suffer as a consequence of chronic stress.

The resultant inflammation owing to chronic stress extends far beyond the reproductive axis and most certainly extends to the central nervous system (CNS) [[7]]. Microglia play a critical role [[56]]. As the principal immune cells of the CNS, they are vital to protecting the brain against stressful stimuli. Microglia are rich in steroid hormone receptors and estrogen has been shown to be a potent regulator of microglial activity [[56],[57]]. Estrogen has been shown to limit the pro-inflammatory state of microglia in response to bacteria, viruses, and hypoxia [[58],[59],[60]]. Women with FHA, with hypoestrogenism, hypothyroidism, and hypercortisolism, are at risk for being in a pro-inflammatory state. If so, the brains of women with FHA may be more susceptible to routine physiologic or psychological stressors. Williams et al. have shown that stressors interact synergistically to amplify other stressors [[61]].

Unchecked neuroinflammation has been identified as one of the primary causes for impaired neurogenesis and the loss of neuronal stem cells [[62]]. In addition to impairing neurogenesis, persistent inflammation impairs neuronal stem cell survival and differentiation and promotes their age-related decline and neurodegenerative diseases [[63],[64],[65]].

For example, neuroinflammation is known to be involved in the pathology of AD and to accelerate the processing of amyloid precursor protein into neurotoxic amyloid-β peptides and their relocalization/deposition to plaques and to promote tau-protein hyperphosphorylation [[66]]. Neuroinflammation is also thought to be one of the central mechanisms that predisposes towards AD [[67]]. By restoring glucocorticoid exposure to physiological patterns, stress reduction may foster better acute and chronic neural health [[68]]. Thus, managing stress has benefits beyond fertility and may reduce brain aging.

7. Conclusions

While direct evidence may be lacking, FHA is likely to compromise brain health via several mechanisms. In particular, estradiol plays a critical role in maintaining brain architecture and metabolism, and chronically low levels associated with anovulation may impair brain health. The high systemic and CSF levels of cortisol due to stress likely cause direct neuronal and glial toxicity and potentiate early apoptosis in vulnerable regions of the brain. Alterations in the thyroid axis of women with FHA likely impair neurogenesis and synaptic connectivity. Finally, prolonged stress and its concomitant hormonal effect produce a catabolic state that may render the individual more susceptible on subsequent stressors including infection.

The development of amenorrhea and oligoamenorrhea afford the clinician an early warning sign and allow identification of patients who would benefit from interventions to reduce the burden of stress and treat FHA. Decreases in stress are predicted to not only restore fertility but also to reduce neuroinflammation and protect against premature brain aging and possibly even against neurodegenerative diseases. With a reduction of psychological stress, and a concomitant reduction in glucocorticoids, one can go beyond neuroprotection and eventually achieve “neuroprevention”.

References

  1. N. SchneidermanG.S. IronsonS.D. SiegelStress and health: Psychological, behavioral, and biological determinantsAnnu. Rev. Clin. Psychol.2005160762810.1146/annurev.clinpsy.1.102803.14414117716101
  2. S.L. BergaFunctional hypothalamic chronic anovulationReproductive Endocrinology, Surgery, and TechnologyE.Y. AdashiJ.A. RockZ. RosenwaksLippincott–RavenPhiladelphia, PA, USA199610611075
  3. S.L. BergaStress and reprodution: A tale of false dichotomy?Endocrinology200814986786810.1210/en.2008-000418292197
  4. N.E. ReameS.E. SauderG.D. CaseR.P. KelchJ.C. MarshallPulsatile gonadotropin secretion in women with hypothalamic amenorrhea: Evidence that reduced frequency of gonadotropin-releasing hormone secretion is the mechanism of persistent anovulationJ. Clin. Endocrinol. Metab.19856185185810.1210/jcem-61-5-8513900122
  5. W.F. Crowley Jr.M. FilicoriD.I. SprattN. SantoroThe physiology of gonadotropin-releasing hormone (GnRH) secretion in men and womenRecent Prog. Horm. Res.1985414735263931190
  6. S.L. BergaJ.F. MortolaL. GirtonB. SuhG. LaughlinP. PhamS.S.C. YenNeuroendocrine aberrations in women with hypothalamic amenorrheaJ. Clin. Endocrinol. Metab.19896830130810.1210/jcem-68-2-3012493024
  7. R.H. ReindollarM. NovakS.P. ThoP.G. McDonoughAdult-onset amenorrhea: A study of 262 patientsAm. J. Obstet. Gynecol.198615553154310.1016/0002-9378(86)90274-73529965
  8. B.S. McEwenThe neurobiology of stress: From serendipity to clinical relevanceBrain Res.200088617218910.1016/S0006-8993(00)02950-411119695
  9. S.L. BergaT.L. DanielsD.E. GilesWomen with functional hypothalamic amenorrhea but not other forms of anovulation display amplified cortisol concentrationsFertil. Steril.1997671024103010.1016/S0015-0282(97)81434-39176439
  10. B. BrunduT.L. LoucksL.J. AdlerJ.L. CameronS.L. BergaIncreased cortisol in the cerebrospinal fluid of women with functional hypothalamic amenorrheaJ. Clin. Endocrinol. Metab.2006911561156510.1210/jc.2005-242216464944
  11. M.D. MarcusT.L. LoucksS.L. BergaPsychological correlates of functional hypothalamic amenorrheaFertil. Steril.20017631031610.1016/S0015-0282(01)01921-511476778
  12. W. WuttkeL. PitzelD. Seidlova-WuttkeB. HinneyLH pulses and the corpus luteum: The luteal phase deficiency (LPD)Vitam. Horm.20016313115811358113
  13. A. JainA.J. PolotskyD. RochesterS.L. BergaT. LoucksG. ZeitlianK. GibbsH.N. PolotskyS. FengB. IsaacPulsatile luteinizing hormone amplitude and progesterone metabolite excretion are reduced in obese womenJ. Clin. Endocrinol. Metab.2007922468247310.1210/jc.2006-227417440019
  14. E.S. EpelPsychological and metabolic stress: A recipe for accelerated cellular aging?Hormones2009882210.14310/horm.2002.1217
  15. C.E. HanzelA. Pichet-BinetteL.S. PimentelM.F. IulitaS. AllardA. DucatenzeilerS. do CarmoaA.C. CuelloaNeuronal driven pre-plaque inflammation in a transgenic rat model of Alzheimer’s diseaseNeurobiol. Aging2014352249226210.1016/j.neurobiolaging.2014.03.02624831823
  16. S.M. HawkinsM.M. MatzukThe menstrual cycle—Basic biologyAnn. N. Y. Acad. Sci.20081135101810.1196/annals.1429.01818574203
  17. R.C. PainterT.J. RoseboomS.R. de RooijLong-term effects of prenatal stress and glucocorticoid exposureBirth Defects Res. Part C Embryo Today20129631532410.1002/bdrc.2102124203920
  18. C. Dunkel SchetterL.M. GlynnStress in pregnancy: Empirical evidence and theoretical issues to guide interdisciplinary researchersHandbook of StressR. ContradaA. BaumSpringerNew York, NY, USA2011321343
  19. S.A. JonesJ.R. ChallisSteroid, corticotrophin-releasing hormone, ACTH and prostaglandin interactions in the amnion and placenta of early pregnancy in manJ. Endocrinol.199012515315910.1677/joe.0.12501532159970
  20. M. McLeanD. ThompsonH.P. ZhangM. BrinsmeadR. SmithCorticotrophin-releasing hormone and β-endorphin in labourEur. J. Endocrinol.199413116717210.1530/eje.0.13101678075786
  21. S.A. JonesJ.R. ChallismLocal stimulation of prostaglandin production by corticotropin-releasing hormone in human fetal membranes and placentaBiochem. Biophys. Res. Commun.198915919219910.1016/0006-291X(89)92422-42784314
  22. C.J. LockwoodStress-associated preterm delivery: The role of corticotropin-releasing hormoneAm. J. Obstet. Gynecol.1999180S264S26610.1016/S0002-9378(99)70713-19914630
  23. M. McLeanA. BisitsJ. DaviesW. WaltresA. HackshawK. de VossR. SmithPredicting risk of preterm delivery by second-trimester measurement of maternal plasma corticotropin-releasing hormone and α-fetoprotein concentrationsAm. J. Obstet. Gynecol.199918120721510.1016/S0002-9378(99)70461-810411821
  24. P.D. WadhwaM. PortoT.J. GariteA. Chicz-DeMetC.A. SandmanMaternal corticotropin-releasing hormone levels in the early third trimester predict length of gestation in human pregnancyAm. J. Obstet. Gynecol.19981791079108510.1016/S0002-9378(98)70219-49790402
  25. C.J. HobelC. Dunkel-SchetterS.C. RoeschL.C. CastroP.A. ChanderMaternal plasma corticotropin-releasing hormone associated with stress at 20 weeks’ gestation in pregnancies ending in preterm deliveryAm. J. Obstet. Gynecol.1999180S257S26310.1016/S0002-9378(99)70712-X9914629
  26. C. KorebritsM.M. RamirezL. WatsonE. BrinkmanA.D. BockingJ.R.G. ChallisMaternal corticotropin-releasing hormone is increased with impending preterm birthJ. Clin. Endocrinol. Metab.1998831585159110.1210/jcem.83.5.48049589660
  27. C.S. KlimaCentering pregnancy: A model for pregnant adolescentsJ. Midwifery Women’s Health20034822022510.1016/S1526-9523(03)00062-X12764308
  28. A.H. PicklesimerD. BillingsN. HaleD. BlackhurstS. Covington-KolbThe effect of Centering Pregnancy group prenatal care on preterm birth in a low-income populationAm. J. Obstet. Gynecol.2012206e1e710.1097/OGX.0b013e318268feec
  29. S. TandonL. ColonP. VegaJ. MurphyA. AlonsoBirth outcomes associated with receipt of group prenatal care among low-income Hispanic womenJ. Midwifery Women’s Health20125747648110.1111/j.1542-2011.2012.00184.x22954078
  30. J.R. IckovicsT.S. KershawC. WestdahlS.S. RisingC. KlimaH. ReynoldsU. MagriplesGroup prenatal care and preterm birth weight: Results from a matched cohort study at public clinicsObstet. Gynecol.20031021051105710.1097/00006250-200311000-0003014672486
  31. R. MenonJ. YuP. Basanta-HenryL. BrouS.L. BergaS.J. FortunatoR. TaylorShort fetal leukocyte telomere length and preterm prelabor rupture of the membranesPLoS ONE201271610.1371/journal.pone.003113622348044
  32. P.L. BallardR.A. BallardScientific basis and therapeutic regimens for use of antenatal glucocorticoidsAm. J. Obstet. Gynecol.199517325426210.1016/0002-9378(95)90210-47631700
  33. S. PaganelliE. SonciniG. GarganoF. CapodannoC. VezzaniG.B. La SalaRetrospective analysis on the efficacy of corticosteroid prophylaxis prior to elective caesarean section to reduce neonatal respiratory complications at term of pregnancy: Review of literatureArch. Gynecol. Obstet.20132881223122910.1007/s00404-013-3035-124071819
  34. A. HarrisJ. SecklGlucocorticoids, prenatal stress and the programming of diseaseHorm. Behav.20115927928910.1016/j.yhbeh.2010.06.00720591431
  35. J.R. SecklM.J. MeaneyGlucocorticoid “programming” and PTSD riskAnn. N. Y. Acad. Sci.2006107135137810.1196/annals.1364.02716891583
  36. J.R. SecklGlucocorticoids, developmental “programming” and the risk of affective dysfunctionProg. Brain Res.2008167173418037004
  37. J.R. SecklM.C. HolmesMechanisms of disease: Glucocorticoids, their placental metabolism and fetal “programming” of adult pathophysiologyNat. Clin. Pract. Endocrinol. Metab.2007347948810.1038/ncpendmet051517515892
  38. J.P. FigueroaG. AcunaJ.C. RoseG.A. MassmannMaternal antenatal steroid administration at 0.55 gestation increases arterial blood pressure in young adult sheep offspringJ. Soc. Gynecol. Investig.200411358A
  39. S.A. ContagJ. BiM.C. ChappellJ.C. RoseDevelopmental effect of antenatal exposure to betamethasone on renal angiotensin II activity in the young adult sheepAm. J. Physiol. Ren. Physiol.2010298F847F85610.1152/ajprenal.00497.200920071463
  40. H.A. ShaltoutJ.C. RoseM.C. ChappellD.I. DizAngiotensin-(1–7) deficiency and baroreflex impairment precede the antenatal β-methasone exposure-induced elevation in blood pressureHypertension20125945345810.1161/HYPERTENSIONAHA.111.18587622215705
  41. C.J. PeñaC. MonkF.A. ChampagneEpigenetic effects of prenatal stress on 11β-hydroxysteroid dehydrogenase-2 in the placenta and fetal brainPLoS ONE20127e3979122761903
  42. S.G. HofmannA. AsnaaniI.J.J. VonkA.T. SawyerA. FangThe efficacy of cognitive behavioral therapy: A review of meta-analysesCogn. Ther. Res.20123642744010.1007/s10608-012-9476-123459093
  43. S.L. BergaT.L. LoucksUse of cognitive behavior therapy for functional hypothalamic amenorrheaAnn. N. Y. Acad. Sci.2006109211412910.1196/annals.1365.01017308138
  44. P. SterlingJ. EyerAllostasis: A new paradigm to explain arousal pathologyHandbook of Life Stress, Cognition and HealthS. FisherJ. ReasonJohn Wiley & SonsNew York, NY, USA1988629649
  45. S.L. BergaM.D. MarcusT.L. LoucksS. HlastalaR. RinghamM.A. KrohnRecovery of ovarian activity in women with functional hypothalamic amenorrhea who were treated with cognitive behavior therapyFertil. Steril.20038097698110.1016/S0015-0282(03)01124-514556820
  46. V. MichopoulosF. ManciniT.L. LoucksS.L. BergaNeuroendocrine recovery initiated by cognitive behavioral therapy in women with functional hypothalamic amenorrhea: A randomized, controlled trialFertil. Steril.2013992084209110.1016/j.fertnstert.2013.02.03623507474
  47. R. MohammadkhaniN. DarbandiA.A. VafaeiA. AhmadalipourA. Rashidy-PourGlucocorticoid-induced impairment of long-term memory retrieval in female rats: Influences of estrous cycle and estrogenNeurobiol. Learn. Mem.201511820921510.1016/j.nlm.2014.12.01125576134
  48. M.J. BoltF. StossiJ.Y. NewbergA. OrjaloH.E. JohanssonM.A. ManciniCoactivators enable glucocorticoid receptor recruitment to fine-tune estrogen receptor transcriptional responsesNucleic Acids Res.2013414036404810.1093/nar/gkt10023444138
  49. S. WhirledgeJ.A. CidlowskiEstradiol antagonism of glucocorticoid-induced GILZ expression in human uterine epithelial cells and murine uterusEndocrinology201315449951010.1210/en.2012-174823183181
  50. S. WhirledgeX. XiaojiangJ.A. CidlowskiGlobal gene expression analysis in human uterine epithelial cells defines new targets of glucocorticoid and estradiol antagonismBiol. Reprod.20138911710.1095/biolreprod.113.11105423843231
  51. S. WhirledgeJ.A. CidlowskiA role for glucocorticoids in stress-impaired reproduction: Beyond the hypothalamus and pituitaryEndocrinology20131544450446810.1210/en.2013-165224064362
  52. R.M. SapolskyL.C. KreyB.S. McEwenThe neuroendocrinology of stress and aging: The glucocorticoid cascade hypothesisEndocr. Rev.1986728430110.1210/edrv-7-3-2843527687
  53. M.H. SamuelsM. LutherP. HenryE.C. RidgwayEffects of hydrocortisone on pulsatile pituitary glycoprotein secretionJ. Clin. Endocrinol. Metab.1994782112158288706
  54. A. RozanskiL.D. KubzanskyPsychologic functioning and physical health: A paradigm of flexibilityPsychosom. Med.200567S47S5310.1097/01.psy.0000164253.69550.4915953801
  55. B.S. McEwenProtective and damaging effects of stress mediatorsN. Engl. J. Med.19983381711799428819
  56. A. VillaE. VegetoA. PolettiA. MaggiEstrogens, neuroinflammation, and neurodegenerationEndocr. Rev.20163737240210.1210/er.2016-100727196727
  57. A. SierraA. Gottfried-BlackmoreT.A. MilnerB.S. McEwenK. BullochSteroid hormone receptor expression and function in microgliaGlia20085665967410.1002/glia.2064418286612
  58. E. VegetoG. PollioP. CianaA. MaggiEstrogen blocks inducible nitric oxide synthase accumulation in LPS-activated microglia cellsExp. Gerontol.2000351309131610.1016/S0531-5565(00)00161-311113609
  59. G. SoucyG. BoivinF. LabrieS. RivestEstradiol is required for a proper immune response to bacterial and viral pathogens in the female brainJ. Immunol.20051746391639810.4049/jimmunol.174.10.639115879140
  60. L. ZhangA. NairK. KradyC. CorpeR.H. BonneauI.A. SimpsonS.J. VannucciEstrogen stimulates microglia and brain recovery from hypoxia-ischemia in normoglycemic but not diabetic female miceJ. Clin. Investig.2004113859510.1172/JCI20041833614702112
  61. N.I. WilliamsS.L. BergaJ.L. CameronSynergism between psychosocial and metabolic stressors: Impact on reproductive function in cynomolgus monkeysAm. J. Physiol. Endocrinol. Metab.2007293E270E27610.1152/ajpendo.00108.200717405827
  62. C.T. EkdahlJ.H. ClaasenS. BondeZ. KokaiaO. LindvallInflammation is detrimental for neurogenesis in adult brainProc. Natl. Acad. Sci. USA2003100136321363710.1073/pnas.223403110014581618
  63. P. TaupinAdult neurogenesis, neuroinflammation and therapeutic potential of adult neural stem cellsInt. J. Med. Sci.2008512713210.7150/ijms.5.12718566676
  64. L. MinghettiRole of inflammation in neurodegenerative diseasesCurr. Opin. Neurol.20051831532110.1097/01.wco.0000169752.54191.9715891419
  65. P. EikelenboomR. VeerhuisW. ScheperA.J. RozemullerW.A. van GoolJ.J. HoozemansThe significance of neuroinflammation in understanding Alzheimer’s diseaseJ. Neural Transm.20061131685169510.1007/s00702-006-0575-617036175
  66. C.H. LattaH.M. BrothersD.M. WilcockNeuroinflammation in Alzheimer’s disease; a source of heterogeneity and target for personalized therapyNeuroscience201530210311110.1016/j.neuroscience.2014.09.06125286385
  67. S. VastoG. CandoreG. DuroD. LioM.P. GrimaldiC. CarusoAlzheimer’s disease and genetics of inflammation: A pharmacogenomic visionPharmacogenomics200781735174510.2217/14622416.8.12.173518086003
  68. G. Van DijkS. van HeijningenA.C. ReijneC. NyakasE.A. van der ZeeU.L. EiselIntegrative neurobiology of metabolic diseases, neuroinflammation, and neurodegenerationFront. Neurosci.201510.3389/fnins.2015.0017326041981
The underlying source XML for this text is taken from https://www.ebi.ac.uk/europepmc/webservices/rest/PMC5187947/fullTextXML. The license for the article is Creative Commons Attribution. The main subject has been identified as hypogonadism.