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Perinatal hormones, mood, and cognition - 2007

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Relationships among perinatal hormones, mood and cognitive abilities.

Publicada em: Saúde e medicina
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Perinatal hormones, mood, and cognition - 2007

  1. 1. Dr. Chandler Marrs Hormones and Mood
  2. 2. Women’s Mental Health • Women have a 2-fold greater lifetime risk for MDD than men • Anxiety disorders • Somatic disorders • Associated with female-specific reproductive events • Puberty • Pregnancy/postpartum • Menopause 2
  3. 3. Why & How • What exactly is depression? • Can’t measure it, if you can’t define it-specifically • Are women more/less likely to experience certain clusters of symptoms? • If associated with reproductive events which hormones are involved with which symptoms? • Need to know how specific hormones interact with specific neurotransmitters in the CNS • How those neurotransmitters affect psychological behavior • Not good enough to say women are more susceptible to depression because of hormone changes 3
  4. 4. What is MDD? •Five or more for >2 weeks • Depressed mood • Diminished interest or pleasure in life (anhedonia) • Weight change (+/-) • Sleeping change (+/-) • Psychomotor retardation or agitation • Excessive feelings of worthlessness or guilt • Poor concentration • Recurrent thoughts of death 4
  5. 5. MDD, three syndromes in one • Melancholic depression • Sadness, loss of pleasure, hypersomnia, psychomotor retardation, lack of motivation, cognitive disturbances • Anxious depression • Psychomotor agitation, insomnia, phobic anxiety and/or OCD symptoms (obsessive fretting), plus anhedonia • Somatic depression • Physiological disturbances such as GI issues, chronic, unexplained illness, chronic pain, plus anhedonia 5
  6. 6. Reproduction and Mental Health • Puberty • Onset of menstruation • Increased incidence of MDD, OCD, bipolar • Cyclical disorders PMS, PMDD, cyclic psychosis • Pregnancy/Postpartum • Increased incidence of MDD, OCD and other anxiety disorders, bipolar, psychotic disorders • Identified as postpartum depression and psychosis • Menopause • Increased incidence of MDD, decreased incidence and severity of psychotic and bipolar disorders 6
  7. 7. Reproductive Cycle Hormone Changes • Puberty • Increase in DHEA/S • Increase & cyclical variation in PROG, estrogens (E1, E2, E3) • Changes in androgen concentrations • Pregnancy • HUGE increase in PROG, E1, E2, E3 • Increase in DHEA/DHEAS, testosterone & other androgens • Postpartum • HUGE decrease in PROG, E1, E2, E3 • HUGE increase in DHEAS • Menopause • Large and continued decrease in DHEA/S • Decline of testosterone, estrogens and progesterone 7
  8. 8. DHEAS across the Lifespan 8 When we speak of DHEAS linked to mood in the elderly, it is a completely different proposition then DHEAS in puberty, pregnancy or postpartum
  9. 9. Reproductive Hormone Patterns: Culprits for Mood Changes • DHEA/S • Precursor for androgens & estrogens synthesized in the adrenals • Non-pregnant: ~50% androgens, estrogens produced in adrenals • Pregnant: precursor for estriol, major pregnancy hormone • Postpartum: suspected of decreasing, but no real data • Until my study • Menopausal: 75-90% of androgens, estrogens produced by adrenals • Progesterone & Estrogens • Cyclic variations • HUGE Increase pregnancy, decrease immediately following delivery • Decrease across lifespan 9
  10. 10. Hormones & the Brain • The brain is major target for & source of steroid hormones • Intranuclear receptors located in the • Hippocampus, amygdala, cerebellum, basal forebrain, locus ceruleus, raphe nucleus, hypothalamus, pituitary, glial cells • Membrane receptors located all over • Co-localized on • GABA (inhibition) • DA (reward and motivation) • 5HT (alertness and mood) • NE (vigilance, attention and mood) • Glutamate (excitation) • Opioids (pain and pleasure) • And thus, are suspected of regulating mood & behavior in some fairly significant ways 10
  11. 11. GABA • Progesterone & metabolites are potent GABAA agonist • GABA is the primary inhibitory neurotransmitter • Drugs that increase GABA include • Benzodiazepines, barbiturates, alcohol • GABA agonists used acutely are • Sedative/hypnotic/anesthetic • Too much-respiratory depression & death • Chronic use • Anxiogenic b/c of changes to the GABAA receptor • Withdrawal symptoms include CNS instability, irritability, anxiety 11
  12. 12. The Estrogens • Estradiol (E2): excitatory • Mediates hippocampal dendritic growth & retraction across menstrual cycle • Elicits DA hypersensitivity (chronic high E2) • Less endogenous DA needed to get reward, reinforcement • Increases NE, 5HT, endorphin concentrations • Elevates mood & decreases pain • Enhances NMDA activation • Presumed mechanism of learn • Reduces cell death caused by stroke • Estrone & estriol • No research 12 McEwen et al. E2 mediated dendritic growth, rodent estrous cycle
  13. 13. Androgens •DHEA/DHEAS: excitatory • GABAA antagonist • DHEA acute & higher doses • DHEAS chronic, lower doses • Enhance NMDA, prolongs LTP • Increase NE, DA •Testosterone: inhibitory • Blocks Ca2+ channels • Increase K+ channel opening 13
  14. 14. How/When to study hormones & mood… • Pregnancy and Postpartum • Huge changes in maternal hormones • Huge increase in mood disorders • 80% experience postpartum mood lability • 15% develop “postpartum depression” • 8-50% develop “postpartum anxiety disorder” • 3-5% OCD during pregnancy • .1-.2% postpartum psychosis • 20X greater risk of psychosis & suicide • 4% risk of infanticide • Across a relatively short period of time • Temporally related to onset of psychiatric disturbances • 60-70% of cases develop within 3 weeks postpartum 14
  15. 15. Pregnancy Hormone changes 15 Harris et al., 1994 Pregnancy-Postpartum Changes in Progesterone, Estradiol & Cortisol
  16. 16. Postpartum Mental Illness •Definition, Diagnosis & Onset • DSM-IV • Time course specifier, mood disorders • <30 days of childbirth • Popular nomenclature • Baby blues • <2 weeks postpartum • Postpartum depression • <1 year postpartum • Postpartum Psychosis • Accepted as rapid 16
  17. 17. Etiology • Psychosocial Factors • Life stressors • Previous History • Ovarian Hormone Theory • Change from pre- to postpartum results in PPD • Lots of studies-inconsistent results • Methodological problems • Increased vulnerability hypothesis • “abnormal response to otherwise normal hormone levels.” Bloch et al., 2003 17 Harris et al., 1994 Pregnancy-Postpartum Changes in Progesterone, Estradiol & Cortisol
  18. 18. Design • Hypotheses • Anxiety type symptoms • Pre-morbid psychiatric symptoms (late pregnancy) – early warning • Hormone mediated • Assessed 9 psychiatric symptoms • Anxiety, hostility, phobia, paranoia, psychoticism, somatization, obsessive-compulsive behavior, interpersonal sensitivity, depression & a global severity index of distress • Measured salivary progesterone, DHEAS, testosterone, estrone, estradiol & estriol • Test times • T1: 37 weeks of pregnancy (n=32) • T2: <10 days postpartum (n=28) • T3: 4 months postpartum (n=9) • T4: 8 months postpartum (n=9) • T5: 12 months post (n=9) • Healthy, primigravids • Mean age: 29 yrs; education: 15.7 yrs; eFSIQ: 112; eVIQ: 114 18
  19. 19. Pregnancy to Postpartum T1-T2 Results
  20. 20. First Major Finding: Individual Variance in Hormone Change • PROG & Estriol decreased in all participants by 93% & 98% respectively • Confirms current literature • DHEAS increased 34% postpartum (21 of 27) participants • Challenges current literature • Testosterone decreased 49% (increased in 5) • Challenges current literature • Estradiol decreased 65% (increased in 3) • Might challenge-could be artifactual • Estrone decreased 91% (increased in 1) • Might challenge-could be artifactual 20
  21. 21. Second Major Finding: Increased Prevalence & Severity • Published rates • 10-15% PPD • 1-2 p/1000 psychosis • This study found • 50% >4 psychiatric symptoms • ~18% displayed mild- moderate psychotic symptoms absent paranoia • Thought insertion & broadcasting • Auditory hallucinations 21 >60 (1 SD above normative mean & 84th percentile)
  22. 22. Third Major Finding: Diversity of Symptoms •Perinatal psychiatric disturbances • Depression is part of syndrome, but not the only factor • Anxiety, phobia, psychoticism, OCD & somatization showed highest T-scores • Somatization scores-autonomic dysregulation •Symptoms in late pregnancy •Spike w/in 10 days of delivery 22
  23. 23. Fourth Major Finding: Symptoms may be Hormonally Mediated •Progesterone NOT correlated with psychiatric symptoms • But may still mediate severity •E2 only sporadically associated w/ symptoms •Unique pattern of adrenal androgens associated w/ all psychiatric symptoms • Low late pregnancy testosterone • High puerperal DHEAS • Correlated with all negative symptoms 23
  24. 24. 24 Pregnancy Testosterone pg/mL PostpartumSCL-90-RT-scores SCL-90-R score >60 = 84th percentile, symptomatic Lower Pregnancy Testosterone, More Pregnancy/Postpartum Symptoms Postpartum DHEAS pg/mL PostpartumSCL-90-RT-scores Higher Postpartum DHEAS, More Postpartum Symptoms
  25. 25. Testosterone A Possible Early Biomarker 25 14/14 women with low late pregnancy testosterone (<60 pg/mL) developed postpartum psychiatric disturbances (p=.002). Lower late pregnancy testosterone significantly correlated with postpartum ANX, HOS, PSY, SOM, OC, IS, DEP, GSI & DHEAS concentrations Asymptomatic Symptomatic PregnancyTestosterone
  26. 26. DHEAS • Postpartum DHEAS associated with • ANX, PHOB, PAR, PSY, SOM, GSI • 4/4 women with postpartum DHEAS > 2500 pg/mL psychiatric distress (p=.028). • 4/4 women with both low late pregnancy testosterone and high DHEAS psychiatric distress (p=.012). • DHEAS is a GABAA antagonist similar to picrotoxin 26 10.008.006.004.002.000.00 Total Number of Postpartum SCL Symptoms > 60 5000.00 4000.00 3000.00 2000.00 1000.00 0.00 PostpartumDHEAS(pg/mL)
  27. 27. Why Testosterone & DHEAS might be Important • With high DHEAS should have high testosterone • Along with high DHEA, but we didn’t measure DHEA • Testosterone is inhibitory at the cell level • Blocks Ca2+ channels • Neurally linked to AVP stress related inhibition of cortisol • Low testosterone = CNS excitability & increased cortisol • Low testosterone + high DHEAS may compound CNS excitability • May mark some sort of steroidogenic dysfunction • Need to measure other hormones along the pathway 27
  28. 28. Postpartum: The Perfect Storm • Radical change in internal chemistry with potentially • Excessive reductions in GABA activity mediated by • Simultaneous withdrawal of PROG & increase in DHEAS • CNS hyper-excitability, instability • Compounded by psychosocial changes associated with the birth • Relationship changes • Sleep deprivation • Career changes 28
  29. 29. Longitudinal Trends across the Postpartum Year Phase Two: T3, T4, T5
  30. 30. Hypothesis • As hormone values “normalize” symptoms of distress will abate • Chronic supra-physiological DHEAS concentrations will negatively impact mental health & other hormones 30
  31. 31. Hormones Changes across Time Hormone reference ranges for non- pregnant, non-postpartum, non- lactating women: *Progesterone: 10-600 pg/mL DHEAS: 220-2500 pg/mL Testosterone: 3-49 pg/mL *Estradiol: .5-25 pg/mL Estriol: .5-16 pg/mL * Cycle-phase dependent 31 Progesterone, DHEAS and Estriol 0 500 1000 1500 2000 2500 37 Weeks Pregnant <10 Days Postpartum 4-Months Postpartum 8-Months Postpartum 12-Months Postpartum Test Time HormoneValuespg/mL Progesterone DHEAS Estriol Testosterone and Estradiol 0 5 10 15 20 25 30 37 Weeks Pregnant <10 Days Postpartum 4-Months Postpartum 8-Months Postpartum 12-Months Postpartum Test Time HormoneValuespg/mL Testotsterone Estradiol
  32. 32. Symptoms across Time 32 Anxiety and Depressive Symptoms 0 20 40 60 80 100 37 Weeks Pregnant <10 Days Postpartum 4-Months Postpartum 8-Months Postpartum 12-Months Postpartum Test Time PercentageofSymptomatic Women ANX PHOB OC DEP Psychotic Symptoms 0 20 40 60 80 100 37 Weeks Pregnant <10 Days Postpartum 4-Months Postpartum 8-Months Postpartum 12-Months Postpartum Test Time PercentageofSymptomatic Women PSY PAR Symptomatic: SCL-90-R T-score >60 or 84th percentile.
  33. 33. Severity of Symptoms Severity of Symptoms 0 20 40 60 80 100 37 Weeks Pregnant <10 Days Postpartum 4-Months Postpartum 8-Months Postpartum 12-Months Postpartum Test Time PercentageofSymptomatic Women GSI 33 Symptomatic: SCL-90-R T-score >60 or 84th percentile.
  34. 34. Hormone-Symptom Associations •Elevated DHEAS significantly associated with • Symptoms @ T2, T3 & T4 • Other hormones • Progesterone • Testosterone • Estriol • Other hormones associated with symptoms • Progesterone • Testosterone • Estriol 34
  35. 35. Longitudinal Trends • DHEAS • Continues to increase across postpartum year • Associated with multiple symptoms & hormones (progesterone, testosterone & estriol) • Testosterone • Positively associated with symptoms • NOT correlated with estradiol • Puerperal psychiatric symptoms • Not limited to depression • Spike following parturition • Abate by 4 months (in all but most serious cases) • Linked to elevated DHEAS & perhaps other hormones • Chronically elevated DHEAS associated with irregularities in other hormone values 35
  36. 36. Future Research • Replicate w/ larger sample • More prenatal & postpartum test times • Include entire aromatase pathway • Measure enzymes in symptomatic women • Genetic testing in symptomatic women/sisters/mothers • Develop • Pregnancy & postpartum reference ranges for salivary hormones • Biomarker test (salivary assessment kit for late-pregnancy low testosterone) • Perinatal psychological assessment tool (underway) • Treatment options • Education programs • Counseling programs • Pharmacological options 36
  37. 37. Future Research Hormones & Mood • Define the symptoms • MDD probably a cluster of disorders • Some symptoms more common at different reproductive points • Understand breadth & scope of presumed hormone changes • HUGE inter-individual differences in hormones (can’t do between subjects research) • HUGE lack of research on potential the cyclical & reproductive related changes of most steroid hormones • Most focused on PROG & E2 • Know next to nothing about cyclic changes in other estrogens, androgens, gluccocorticoids and mineralocorticoid • Understand the presumed neural mechanisms action • Not sufficient to investigate the most obvious hormones if the presumed neuroactive mechanisms are not capable of eliciting the observed symptoms 37

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