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.

1. Dr. Chandler Marrs
Hormones and
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?
•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. 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. 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. 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 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. 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. 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. 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
• 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. 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
• 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. Pregnancy to
Postpartum
T1-T2 Results

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. 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. 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. 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
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. 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. 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. 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 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. Longitudinal Trends
across the Postpartum
Year
Phase Two: T3, T4, T5

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. 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. 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. 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. 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. 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
• 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. 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