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Perinatal hormones, mood, and cognition - 2007
1) The document discusses hormones and their relationship to mood disorders in women, specifically during reproductive stages like puberty, pregnancy, postpartum, and menopause. 2) It presents research showing elevated levels of the adrenal androgen DHEAS are associated with psychiatric symptoms in the postpartum period, while lower levels of pregnancy testosterone may be an early warning sign. 3) The research found that as hormone levels like DHEAS and progesterone normalized in the year following childbirth, psychiatric symptoms tended to abate, though chronically elevated DHEAS was linked to ongoing issues.
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Perinatal hormones, mood, and cognition - 2007
- 1. Dr. Chandler Marrs Hormonesand Mood
- 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. 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. What is MDD? •Fiveor 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. MDD, three syndromesin 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. Reproduction and MentalHealth • 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. 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. DHEAS across theLifespan 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. Reproductive Hormone Patterns: Culpritsfor 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. Hormones & theBrain • 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. 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. 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. Androgens •DHEA/DHEAS: excitatory • GABAAantagonist • 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. 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. Pregnancy Hormone changes 15 Harris et al.,1994 Pregnancy-Postpartum Changes in Progesterone, Estradiol & Cortisol
- 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. 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. Design • Hypotheses • Anxietytype 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.
- 20. First Major Finding: IndividualVariance 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. Second Major Finding: IncreasedPrevalence & 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. Third Major Finding: Diversityof 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. Fourth Major Finding: Symptomsmay 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 Pregnancy Testosterone pg/mL PostpartumSCL-90-RT-scores SCL-90-Rscore >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. Testosterone A Possible EarlyBiomarker 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. DHEAS • Postpartum DHEAS associatedwith • 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. 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. Postpartum: The PerfectStorm • 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. Longitudinal Trends across thePostpartum Year Phase Two: T3, T4, T5
- 30. Hypothesis • As hormonevalues “normalize” symptoms of distress will abate • Chronic supra-physiological DHEAS concentrations will negatively impact mental health & other hormones 30
- 31. Hormones Changes acrossTime 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. Symptoms across Time 32 Anxietyand 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. Severity of Symptoms Severityof 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. Hormone-Symptom Associations •Elevated DHEAS significantlyassociated with • Symptoms @ T2, T3 & T4 • Other hormones • Progesterone • Testosterone • Estriol • Other hormones associated with symptoms • Progesterone • Testosterone • Estriol 34
- 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. Future Research • Replicatew/ 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. 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