The Effects of Estrogen Withdrawal on Mood Symptoms in Women

Conditions:Depression, Healthy Studies, Women's Studies
Therapuetic Areas:Psychiatry / Psychology, Other, Reproductive
Age Range:45 - 65
Start Date:May 5, 2003
End Date:April 27, 2016

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The Effects of Acute Withdrawal of Estradiol on Mood Symptoms in Women With Perimenopausal Depression

This study evaluates the effects on mood when stopping estrogen replacement therapy.

The purpose of this study is to investigate the effects of estrogen levels on perimenopausal
depression. This study will examine short-term withdrawal of estrogen in women whose mood had
improved with estrogen therapy.

Perimenopause-related mood disorders cause significant distress in a large number of women.
Evidence suggests that estradiol may have beneficial effects in women with perimenopausal
depression. However, the effect of declining estradiol secretion during perimenopause has not
been fully examined.

Peri- and post-menopausal women who experience a remission of perimenopause-related
depression symptoms while on estrogen therapy and a control group of healthy volunteers on
hormone replacement therapy (HRT) will be switched from their current form of HRT to
estradiol for a 3-week period; volunteers will also complete symptom ratings to confirm the
absence of mood symptoms. Participants will then be randomly assigned to either continue
estradiol or take a placebo (an inactive pill) for an additional 3 weeks. Mood ratings will
be used to determine response to estradiol withdrawal.

Perimenopause-related mood disorders cause significant distress to a large number of women.
Recent studies have reported the therapeutic benefits of estradiol in women with these mood
disorders; however, a relevant pathophysiologic role of declining estradiol secretion during
the perimenopause has not been demonstrated. In this protocol we wish to investigate the
effects of acute withdrawal of estradiol on mood under placebo controlled conditions. Thus,
mood and behavior symptoms may be precipitated by the experimental conditions of this
protocol. This protocol will address the following hypothesis: women with a past history of
perimenopause-related depression but not women without such a history will experience a
recurrence of mood and behavioral symptoms during acute estradiol withdrawal but not during
continued estradiol administration. The nature of the relationship between the declining
secretion of estradiol and mood in perimenopausal depressed women will be examined as
follows: Peri- and postmenopausal women reporting the onset of depression during the
perimenopause and who report remission of depressive symptoms on estrogen therapy (ET) will
be withdrawn from ET under blinded and placebo-controlled conditions. We will recruit as a
comparison group asymptomatic women on hormone replacement and without a history of
perimenopause-related depression. During a three week baseline phase, all women will be
switched from their current form of hormone replacement therapy to estradiol and will
complete symptom ratings to confirm the absence of mood symptoms prior to entry into the
study. After the screening, all women will be randomized to receive either estradiol or
placebo for an additional three weeks. Comparison of mood ratings during these contrasting
treatment conditions will allow us to examine the specific role of estrogen withdrawal in
depression that is responsive to ET.


All subjects for this protocol will be either self-referred in response to newspaper
advertisements or referred by their personal physician. The women participating in this
protocol will have previously completed the screening protocol # 88-M-0131 and, therefore,
will have had the presence or absence of perimenopausal or menopausal reproductive status
evaluated and documented.

1. Women with a past perimenopause-related depression (within 12 years) and whose
depression responded to ET will be recruited to participate in this randomized,
parallel-design, double-blind, placebo-controlled study. Women with histories of
either perimenopausal depression that was not responsive to ET or hormone replacement
therapy-induced dysphoria due to either the estrogen or the progesterone components of
their hormone replacement will be excluded. The diagnosis of perimenopause-related
depression will be based on a history of a past depressive episode (major or minor
depression confirmed by Structured Clinical Interview for DSM-IV (SCID) or Schedule of
Affective Disorders and Schizophrenia-Lifetime Version (SADS-L), respectively) at
midlife in association with menstrual cycle irregularity and the history of remission
(also confirmed by SCID or SADS-L) of this depression after ET. Additionally, all
women will report that they were placed on HRT for the treatment of perimenopausal
symptoms, including depression.

2. Age 45 to 65

3. In good medical health

Women without past perimenopausal depression -

To control for the effects of the hormonal manipulations in this protocol, we will also
recruit a group of asymptomatic controls who are either currently on ET or were prescribed
ET previously and with no previous history of perimenopause-related depression or
HRT-induced dysphoria. Women who participate in this study as the asymptomatic comparison
group will meet the following criteria:

1. Women who received hormone therapy (HT) with no previous history of
perimenopause-related depression or HT-induced dysphoria

2. No current mood or behavioral problems

3. Age 45 to 65

4. In good medical health


1. past history of severe major depression with suicidal ideation

2. current treatment with antidepressant medications

3. history of ischemic cardiac disease, pulmonary embolism, or thrombophlebitis

4. renal disease

5. hepatic dysfunction

6. women with a history of carcinoma of the breast

7. women with a history of uterine cancer, ill-defined pelvic lesions, particularly
undiagnosed ovarian enlargement, undiagnosed vaginal bleeding

8. pregnant women

9. cerebrovascular disease (stroke)

10. recurrent migraine headaches
We found this trial at
9000 Rockville Pike
Bethesda, Maryland 20892
Bethesda, MD
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