Hormones And Mood In PMDD And Pregnancy - Faina Novosolov, MD

Hormones and Mood
in PMDD and
Pregnancy
Faina Novosolov, M.D.
Women’s Mood and Hormone Clinic
UCSF/ LPPI
415-771-7711 www.fainamd.com
No other financial disclosures.

Educational Objectives
• Diagnosis/treatment of PMDD vs PMS
vs PME
• Better understanding of the menstrual
cycle in relation to mood symptoms
• Understanding the second mechanism
of SSRI’s
• How to treat depression in pregnancy
and risk factors to review with women
during pregnancy/delivery

Menstrual Cycle
Estrogen / E2
Testosterone
Follicular
Phase
Luteal
Phase

Brain Variability Controlled by
Ovarian Hormones
Depending on where a woman is in her cycle,
there is variability in the following:
• Mood
• Verbal performance
• Sexual interest
• Visual-spatial performance
-Sherwin, “Estrogenic effects on memory in women.” Ann N Y Acad Sci., Nov 1994
-Goldstein et al., “Sex Differences in Stress Response Circuitry Activation Dependent on Female Hormonal Cycle.” J
Neurosci. 2010 January 13.
-L. Brizendine, The Female Brain, 2006

Menstrual Cycle
Mood/verbal
Highest
Sex Drive
Visual-spatial

Best
Worst
week 1 2 3 4
-Stanicić A et al., “Psychophysical characteristics of the premenstrual period.” Coll Antropol. 2010 Dec;34(4):1421-5.

PMDD vs Normal PMS
Normal PMS (Premenstrual Syndrome):
• 80% of women
• Mild to moderate emotional fluctuations
PMDD (Premenstrual Dysphoric Disorder):
• 8-10% of women
• Severe moods swings, depressed mood,
irritability, or anxiety and 4 other symptoms
(occurring exclusively during the luteal phase
(weeks 3-4) and remitting within a few days of the
onset of menses

DSM-IV Research Criteria For PMDD
-It is considered “Depression NOS”
A. In most menstrual cycles during the past year, five (or more) of the following symptoms
were present for most of the time during the last week of the luteal phase, began to remit
within a few days after the onset of the follicular phase, and were absent in the week
postmenses, with at least one of the symptoms being either (1), (2), (3), or (4):
1. Markedly depressed mood, feelings of hopelessness, or self-deprecating thoughts
2. Marked anxiety, tension, feelings of being "keyed up" or "on edge"
3. Marked affective lability (e.g., feeling suddenly sad or tearful )
4. Persistent and marked anger or irritability or increased interpersonal conflicts
5. Decreased interest in usual activities (e.g., work, school, friends, hobbies)
6. Subjective sense of difficulty in concentrating
7. Lethargy, easy fatigability, or marked lack of energy
8. Marked change in appetite, overeating, or specific food cravings
9. Hypersomnia or insomnia
10. A subjective sense of being overwhelmed or out of control
11. Other physical symptoms, such as breast tenderness or swelling, headaches, joint or
muscle pain, a sensation of "bloating," or weight gain
B. The disturbance markedly interferes with work or school or with usual social activities and
relationships with others
C. The disturbance is not merely an exacerbation of the symptoms of another disorder
(although it may be superimposed on any of these disorders).
D. Criteria A, B, and C must be confirmed by prospective daily ratings during at least two
consecutive symptomatic cycles.

Daily Record of Symptoms

Menstrual Cycle Week and
All Psychiatric Admissions
• If random,
admissions of
women to
psychiatric hospitals
for all psychiatric
diagnoses would be
25% on each week
of the menstrual
cycle
70
60
50
40
30
20
10
0
1st 2nd 3rd 4th
Week of Menstrual Cycle
Hospital
Admits
-Luggin et al. “Acute psychiatric admission related to the menstrual cycle.” Acta Psychiatrica Scandinavica, Vol 69, Issue 6, pp 461–465,
June 1984.
-Targum et al. “Menstrual cycle phase and psychiatric admissions.” , J Affect Disord. 22(1-2):49-53, May-Jun 1991.

Menstrual Cycle
Estrogen / E2
Progesterone
Testosterone
Follicular
Phase
Luteal
Phase

PMDD
Progesterone → Allopregnanolone (ALLO)
soothing, like Valium
• ALLO= a neuroactive metabolite of progesterone
and works on GABA (gamma-aminobutyric acid)
receptors in the brain
• Hence, ALLO is a powerful anxiolytic,
anticonvulsant, and anesthetic agent which
decreases anxiety and depression.
• Barbituates, benzodiazepines and alcohol also
work at this receptor
-Lisa Griffin, 1999

PMDD
Progesterone → Allopregnanolone (ALLO)
soothing, like Valium
-Prozac, Paxil and Zoloft were found not only to increase
Serotonin, but also to increase ALLO production by
activating the enzyme that converts progesterone to ALLO
(by decreasing the enzyme’s K m 10- to 30-fold)
-Imipramine (Tofranil) had no effect on ALLO production
-Works almost immediately
Journal:
-Lisa Griffin, MD, PhD and Synthia Mellon, PhD.
Selective serotonin reuptake inhibitors directly alter activity of
neurosteroidogenic enzymes.
Proc Natl Acad Sci U S A. 1999 Nov 9;96(23):13512-7.

2 Main Treatments
• SSRI’s:
PMDD
– Either 7-10 days before menses to help boost ALLO, or
daily if also depressed
– Or, you can increase SSRI dose in luteal phase
• Hormones:
– Start an OCP, or change to one with a progesterone
good for mood
– Take OCP continuously
• Women are sensitive to hormones in different ways – some to
the hormone fluctuation, some to the amount, and some to the
progestin type

All Possible PMDD Treatments
Antidepressants
-SSRI*
-SNRI*
-Clomipramine**
Ovulation Suppression
-OCP’s*
-GnRH Agonists (Lupron)**
-Danazol (inhibits LH/FSH)
-Oophorectomy
Anxiolytics
-BZD**
-Buspar**
Other
-Exercise
-Calcium**
-CBT*
-Vit B6
-NSAIDS
-Diet
-Chasteberry
(may reduce FSH or Prolactin)
*Efficacy in double-blind studies of PMDD
**Efficacy in double-blind studies of PMS
-Teri Pearlstein, M.D. Warren Alpert Medical School of Brown University, APA Conference 2008

Advantages of SSRI’s
• Fluoxetine, Sertraline and Paroxetine CR are FDA
approved for PMDD
• Both continuous and intermittent dosing effective
• Intermittent Fluoxetine is effective for mood symptoms
at both 10 and 20 mg. 20 mg is more effective for
physical symptoms than 10 mg.*
• No discontinuation symptoms with intermittent dosing
• Dosing strategies can be tailored to a woman’s
preferences
*Cohen LS, et al. Obstet Gynecol. 2002; 100: 435-444.
-Teri Pearlstein, M.D. Warren Alpert Medical School of Brown University, APA Conference 2008

Intermittent Fluoxetine in PMDD
0
-2
DRSP Mood
Cluster
DRSP Physical
Cluster
DRSP Social
And Functional
Impairment Cluster
Mean change
from
baseline
-4
-6
-8
-10
-12
-14
-16
Placebo
Fluoxetine 10 mg
Fluoxetine 20 mg
DRSP = Daily Record of Severity of Problems
Cohen LS, et al. Obstet Gynecol. 2002; 100: 435-444.

Concerns With SSRI’s
• Potential long-term effects: weight gain, sexual SEs
• Lower doses are less effective for physical
symptoms than for mood/ anxiety symptoms
• Tolerance to dose over time
• Symptom recurrence after dose discontinuation
• Pregnancy during treatment (may not want to
choose Paroxetine CR if pregnancy is a possibility)
-Teri Pearlstein, M.D. Warren Alpert Medical School of Brown University, APA Conference 2008
-Cohen LS, et al.” Obstet Gynecol. 2002; 100: 435-444.

Other Luteal Phase Treatments
• Alprazolam up to 0.25 mg tid prn (taper at
menses), or Ativan 0.5 mg prn
• Spironolactone 50 mg bid for edema
• Bromocriptine 2.5 mg for breast pain/
tenderness (mastalgia)
• NSAIDS for cramps/ leg pain
-Teri Pearlstein, M.D. Warren Alpert Medical School of Brown University, APA
Conference 2008

Which birth control pill is good for mood
• Lower progestin potency:
Ortho Evra patch
Ovcon 35
Ortho-TriCyclen
Othro-Cyclen
Brevicon
Modicon
Necon 1/35
Alesse
Levlite
Tri-Levlen
Triphasil
Trivora
-Rohr, UD. “The impact of testosterone imbalance on depression and women's health.” Maturitas. 2002 Apr 15;41
Suppl 1:S25-46.
-Jelovsek, FR. (2003). “Accurate Answers to Questions About Birth Control Pills. “ [e-book].

Which OCP is good for mood
• Women are sensitive to hormones in different
ways – some to the progestin, some to the
amount and some to the hormonal fluctuation
• Seasonale or any monophasic OCP taken
continuously can stabilize mood
• Women who are sensitive to hormonal
fluctuation should avoid triphasic OCP’s
• It takes about 2 cycles to see if a certain OCP
will work

YAZ®
• Contains:
– Drospirenone 3 mg
– Ethinyl estradiol 20 µg (Yasmine has 30 µg)
• Shortened hormone-free interval:
– 24 active pills, 4 inactive pills (Yasmine has 21
active/ 7 inactive pills)
• Efficacy was expected for physical symptoms.
But, surprisingly, efficacy in mood and irritability
was also seen with YAZ
-Yonkers KA, Brown C, Pearlstein TB, et al. “Efficacy of a new low-dose oral contraceptive with
drospirenone in premenstrual dysphoric disorder.” Obstet Gynecol. 2005;106:492-501.

Drospirenone
• Derived from 17 alpha spirolactone
• Analogue of spironolactone
• Has antimineralocorticoid activity (leads
to water diuresis)
• Increases K+ retention, Na+ and water
excretion
• Has antiandrogenic activity

All OCPs (with estrogen)
Can Lower Libido
• The oral estrogen in OCPs increases SHBG (Sex
Hormone Binding Globulin)
• Increased SHBG → lower free testosterone
• Oral estrogen and thyroid increase SHBG
– Oral estrogen passes through the liver (vs
some patches or endogenous estrogen) and
binds up SHBG, increasing production of
SHBG. Progesterone is bound by transcortin.
-Rosner W. “Plasma steroid-binding proteins.” Endocrinology and Metabolism Clinics of North Am [1991, 20(4):697-720].
-Goodman MP. “Are all estrogens created equal A review of oral vs. transdermal therapy.” J Wom Health (Larchmt). 2012 Feb;21(2):161-9. Epub 2011 Oct 19.
-Pakarinen P et al. “The effect of intrauterine and oral levonorgestrel administration on serum concentrations of SHBG, insulin and insulin-like growth factor
binding protein-1.” Acta Obstet Gynecol Scand. 1999 May;78(5):423-8.

PMDD In Summary
• PMDD: 8-10% of women
• The current hypothesis: women who
experience PMDD are sensitive to the change
in estrogen and progesterone
• SSRIs are effective treatments with daily or
luteal phase dosing—higher doses are more
effective for physical symptoms
• YAZ® has similar efficacy to SSRI’s, both for
physical and mood symptoms
• The big question: should women with PMDD
be treated with OCP’s or SSRI’s first

Disorders with
Premenstrual Exacerbation
(PME)
• Affective disorders
• Anxiety disorders
• Psychotic disorders
• Eating disorders
• Substance abuse
• Migraine
• Allergies
• Asthma
• Seizures
• Personality
disorders

Sample Question:
Premenstrual dysphoric disorder (PMDD):
A. is associated with hormonally abnormal
menstrual cycles
B. is associated with abnormal levels of hormones
C. is associated with changing levels of sex steroids
that accompany ovulatory menstrual cycles
D. is seen in approximately 50% of women
E. is not treated with SSRI’s
F. all of the above

Sample Question:
Premenstrual dysphoric disorder (PMDD):
A. is associated with hormonally abnormal
menstrual cycles
B. is associated with abnormal levels of hormones
C. is associated with changing levels of sex steroids
that accompany ovulatory menstrual cycles
D. is seen in approximately 50% of women
E. is not treated with SSRI’s
F. all of the above

Sample Case: “Help my PMDD”
• 27 y/o married woman
• “I have a serious case of
PMDD. I get low energy,
irritable and depressed. I start
fights with my husband and
often have to skip work. Then,
when my period comes, I feel
fine.”
• “I have been using YAZ OCP
and Effexor XR. It kinda helps,
but not 100%.”

Things to Consider
• PMS charting
• Check labs: TSH, cbc to r/o anemia
• Meds: educate about SSRIs being 1 st
choice for PMDD (and safety in
pregnancy since she’s a young, married
woman)
• Effexor not ideal: SSRIs are 1 st line
(though some data that Effexor and
Clomipramine also help with PMDD)
• Since Effexor not working great
anyway, consider Zoloft 25 mg or
Prozac 10 mg
• Discuss her future plans for pregnancy
• Therapy

Things to Consider
• Ask about libido: She’s on YAZ, which
can lower her libido (via 2 mechanisms!!!)
• If unsure, you can also check libido labs:
– Free and total testosterone
– SHBG
– TSH
– Prolactin
– DHEA-S
• May want to switch to another OCP or the
Mirena or Copper IUD.

The Mommy Brain:
Hormones, Pregnancy and Mood
• The smell of a newborn baby stimulates the
woman to produce oxytocin – a love potion
creating baby lust
– Oxytocin is also released when talking to friends,
or creating a connection
– “A feel good” hormone – released in bonding and
during orgasm
• Throughout pregnancy, a woman is
marinated in neurohormones manufactured
by the fetus and placenta
-L. Brizendine, The Female Brain, 2006

The Mommy Brain:
Hormones, Pregnancy and Mood
• Progesterone: Spikes from 10-100x normal!
• Thirst and hunger centers on full blast
• Women become sensitive to smells,
especially of foods—to avoid eating
something that could harm the fragile fetus
-L. Brizendine, The Female Brain, 2006

The Mommy Brain:
Hormones, Pregnancy and Mood
• The size and structure of a woman’s brain change
• Between 6 months to the end of pregnancy, fMRI
scans show that her brain is shrinking!
– Restructuring and building new maternal circuits
• This state gradually returns to normal 6 months
after giving birth
-Oatridge et al. “Change in brain size during and after pregnancy: study in healthy women and women with
preeclampsia.” AJNR Am J Neuroradiol. 2002 Jan;23(1):19-26.

Depression and Pregnancy
• 1-2 out of every every 10 pregnant women
have symptoms of major depression
• Women who have been depressed before are
at higher risk
• Range of treatments:
– Support groups, light therapy, medications and ECT
– Individual therapy is highly recommended
-Dobie SA, Walker EA. “Depression after childbirth.” J Am Board Fam Pract. 1992 May-Jun;5(3):
303-11.

Depression and Pregnancy
• Depression carries serious risks:
– poor nutrition
– poor self-care
– substance abuse
– SI
• Can lead to premature birth, low birth weight
and developmental problems
• Depressed mothers are often less able to care
for themselves and/ or their children, or to bond
with their children

What are the symptoms of PPD
• MDE symptoms 1 month to 1 year
postpartum
• Things other than depression can
cause some of these symptoms
– Changes in appetite and trouble sleeping are
common in pregnancy
– Medical conditions, such as anemia and
hypothyroidism, can cause low energy

Depression and Pregnancy
• What I tell women: the risks….
– During pregnancy
– During delivery
– After delivery

During Pregnancy
• 2006 study—pregnant women with MDD are very
likely to become ill again if they stop taking their
medication
• Many studies have found no link between
antidepressants and serious malformations in
newborns
• 2005—FDA issued a warning about Paxil: taking
the drug during the first three months of
pregnancy may increase the risk of birth defects,
particularly heart defects
-Lee S. Cohen et al. “Relapse of Major Depression During Pregnancy in Women Who Maintain or Discontinue
Antidepressant Treatment.” JAMA. 2006;295(5):499-507.
-Levinson-Castiel R et al. “Neonatal abstinence syndrome after in utero exposure to SSRIs in term infants.”
Arch Pediatr Adolesc Med. 2006 Feb;160(2):173-6.

During Pregnancy
• SSRI’s have been linked to small increased risks of:
– heart defects (0.9% for 1 SSRI, 2.1% >1 SSRI, vs 0.5%)
– hydronephronsis (kidney defects)
– cleft palate (5% vs 2-4%)
• 2012 study—found
– Untreated maternal depression was associated with
slower rates of fetal body and head growth
– Fetuses from mothers treated with SSRIs had no delay
in body growth but did have delayed head growth and
were at increased risk for preterm birth
-Pedersen LH et al. “SSRIs in pregnancy and congenital malformations: population based cohort study.” BMJ. 2009 Sep 23;339:b3569.
doi: 10.1136/bmj.b3569.
-El Marroun H et al. “Maternal Use of SSRIs, Fetal Growth, and Risk of Adverse Birth Outcomes.” Arch Gen Psychiatry. 2012 Mar 5.
[Epub ahead of print]

During Pregnancy: Autism Risk
• 2011 study—examined fetal SSRI exposure in 298
children with autism spectrum disorders (ASDs) and
1507 control children
• Possible association between SSRI exposure and
childhood ASD
• Things to consider
– Rx use not confirmed
– dx from records not interview
– factors not controlled for (tobacco, alcohol, drug use)
– mothers of ASD kids were much older
– need to distinguish role of meds vs underlying dz
-Croen LA et al. “Antidepressant use during pregnancy and childhood autism spectrum disorders.” Arch Gen Psychiatry.
2011 Nov;68(11):1104-12. doi: 10.1001/archgenpsychiatry.2011.73. Epub 2011 Jul 4.

During Pregnancy (cont)
• "Clinicians and patients need to balance the small risks
associated with SSRIs against those associated with
undertreatment or no treatment.”
-Sept 2009, Pederson et al., British Medical Journal (BMJ)
• Although relative risks for certain anomalies are elevated
with SSRI use, absolute risks are low. For example,
excess risk for a major cardiovascular anomaly
attributable to SSRI use is 37 additional cases per
10,000 women.
-July 2011, Malm et al., Obstetrics and Gynecology

During Delivery
Neonatal Abstinence Syndrome (NAS):
– Baby “withdrawal” from SSRIs
• breathing or feeding problems, jerky movements, seizures,
irritability, abnormal crying, tremor
• Sx usually subside from 48 hours to a few days
Persistent Pulmonary Hypertension of the Newborn (PPHN):
– 2006 study—babies exposed to SSRIs in late pregnancy (after 20
weeks) may be more likely to have PPHN
– Since then, we have 7 studies total: 3 showed no link between PPHN
and SSRI’s, the other 4 showed some increased risk
– FDA will update their SSRI drug label to reflect the conflicting results
– Key point: Factors associated with depression itself (vs. SSRI
exposure) can increase PPHN risk (obesity, smoking, premature birth,
cesarean section)
-Chambers CD et al. “SSRIsand risk of persistent pulmonary hypertension of the newborn”. New Engl J Med 2006; 354(6):579-87.
-Ruta Nonacs. “SSRI’s and PPHN: the FDA revises its warning.” MGH Center for Women’s Health website, Jan 17, 2012.
-Jordan AE et al. “SSRI use in pregnancy and the neonatal behavioral syndrome..” J Matern Fetal Neonatal Med. 2008 Oct;21(10):745-51.

During Delivery (cont)
• Both untreated depression/ anxiety and SSRI
exposure have been correlated with early or
preterm birth
• 2009 study—SSRI use in late pregnancy
correlated with an elevated risk of gestational
hypertension and preeclampsia in the mother
-Catov JM et al. “Anxiety and optimism associated with gestational age at birth and fetal growth.” Matern Child Health J.
2010 Sep;14(5):758-64.
-Rita Suri et al. “Effects of Antenatal Depression and Antidepressant Treatment on Gestational Age at Birth and Risk of
Preterm Birth.” The American Journal of Psychiatry. 2007 August ; 8(164):1206-1213.
-Li, D. Liu L., Odouli R. “Presence of depressive symptoms during early pregnancy and the risk of preterm delivery: a
prospective cohort study.” Human Reproduction 2008 Oct 23 (E-published ahead of print).
-Toh et al. “SSRI use and risk of gestational hypertension.” Am J Psychiatry. 2009 Mar;166(3):320-8. Epub 2009 Jan 2.

After Delivery
• No link to serious problems with language,
behavior or intelligence
• There has been no data reported on long
term effects of antidepressants on the baby’s
well being
-
Nulman I, et al. “Child development following exposure to tricyclic antidepressants or fluoxetine throughout fetals
life: a prospective, controlled study.” Am J Psychiatry 2002; 159: 1889-1895.
-Nulman I, et al. “Neurodevelopment of children exposed to antidepressant and antipsychotic medications during
pregnancy.” In Clinics in Developmental Med No. 188. London, Mac Kieth Press, 2011.

Choosing an Antidepressant
• We don't know all the answers. No drug is entirely safe. A
woman and her health care team must look at her case and
carefully weigh risks/ benefits of:
– The drug
– Other treatments
– The risk of untreated depression
• If a woman has been or is currently stable on a certain
SSRI, that medication is usually continued (unless it is
Paxil, which is generally contraindicated)
• Zoloft and Prozac are often chosen b/c Zoloft has the
lowest levels in breast milk and Prozac’s long half-life

Important Points
• Pt should be followed closely by psychiatrist and ob/gyn
• Prenatal vitamins and folic acid
• Check thyroid, CBC and other lab work
• Deliver the baby in a hospital to adequately monitor and
assess any possible delivery complications
• Stress reduction techniques and individual therapy
• Be on the lowest number of meds and the lowest dose
necessary
• Start low and go slow

Within the first month after giving
birth: 10% of women will have had
‘Postpartum Depression’
• Huge ‘crash’ in hormones after
pregnancy
• Postpartum: the brain and ovaries
experience the re-establishment of
menstrual cycle hormone pulses just as
during the onset of puberty

Psychiatric Admissions in 2 Years
70
Before and After Delivery
Admissions/month*
60
50
40
30
20
10
Pregnancy
0
–2 Years – 1 Year Childbirth +1 Year +2 Years
*Rate of psychiatric admissions in the 2 years before and after delivery in a population of
470,000 people with 54,087 births in a 12-year period
Kendell RE, et al. Br J Psychiatry. 1987;150:662.

Postpartum Depression
• Postpartum Depression:
– Technically, onset is within 4 weeks after childbirth, but
can be seen up to 1 yr later (in DSM, it’s a specifier:
“With Postpartum Onset”)
– 10-15% of women will experience postpartum depression
within the 1 st month after giving birth
• ‘Baby blues’:
– Affect up to 80% of women during the 10 days
postpartum (usually lasts 2 weeks)
– These are transient, do not impair function, and don’t
meet MDD criteria

Sample Question:
Which antidepressant is found to be
transmitted in the lowest amounts in breast
milk
A. Prozac
B. Celexa
C. Zoloft
D. Lexapro
E. Klonopin

Sample Question:
Which antidepressant is found to be
transmitted in the lowest amounts in breast
milk
A. Prozac
B. Celexa
C. Zoloft
D. Lexapro
E. Klonopin

Sample Case: “I want to stop my meds”
• 33-year-old married
woman
• Had a MDE 1 yr ago
• She responded well to
Zoloft 100 mg and has
been symptom free for
9 months.
• She wants to stop her
Zoloft so she can get
pregnant.
• What do you do

Consider a Trial off Meds If:
• There was only one previous MDE
• It occurred more than 9 months ago
• It resolved quickly with medication
• She has been functioning well for
more than 6 months
• No family history
• No current stressors
• Good financial and emotional
supports
• Good insight into her illness so she
can recognize early signs
• She is cooperative with treatment
and willing to restart meds if needed
• At it’s worst, there was no significant
decompensation or SI

Educational Objectives
• Diagnosis/treatment of PMDD vs PMS
vs PME.
• Better understanding of the menstrual
cycle in relation to mood symptoms.
• Understanding the second mechanism
of SSRI’s.
• How to treat depression in pregnancy
and risk factors to review with women
during pregnancy/delivery.

The End
Thank You!
A special thank you to Dr. Louann Brizendine