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Medications to Manage Mood Changes on Oral Micronized Progesterone: First-Line and Beyond

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Published Updated Last reviewed
7 linked public sourcesEditorial, sourcing, and corrections policy

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Key numbers

  • 19%Depression with cyclic 200 mg Prometrium plus conjugated estrogens vs placebo over three yearsSource: accessdata.fda.gov, as cited Nov 7, 2026
  • 15%Dizziness reported by 15% vs 9% in the three-year label trial with conjugated estrogensSource: accessdata.fda.gov, as cited Nov 7, 2026
  • 8%Irritability with 400 mg daily Prometrium vs 4% placebo in women with secondary amenorrheaSource: accessdata.fda.gov, as cited Nov 7, 2026
  • 200 mgLabeled bedtime dose for 12 days per 28-day cycle with conjugated estrogensSource: dailymed.nlm.nih.gov, as cited Nov 7, 2026

From the public record

FDA adverse event reports naming mood changes and progesterone

Through 2026-10-28, FDA had received 159 adverse event reports for progesterone that name mood changes, out of 21,732 reports for the drug in all. 142 of these reports concerned female patients and 2 male patients.

FDA adverse event reports naming mood changes and progesterone: the figures
MeasureValueNote
Reports naming mood changes159
All reports for progesterone21,732
Share of this drug's reports naming it0.7%share of reports received, not of people taking the drug
Of those: female patients142reflects who takes the drug and who files reports
Of those: male patients2
Of those: sex not recorded15

Source: FDA Adverse Event Reporting System (FAERS) via openFDA, data as of Oct 28, 2026

Scope: Reports where FDA recorded progesterone as a single-ingredient active substance (any brand), MedDRA terms mood swings, mood altered

FAERS reports are unverified and do not prove the drug caused the event. Reporting rises with use, publicity and lawsuits, so these counts cannot give rates or risks and cannot be compared between drugs.

How this was calculated

Counted FAERS reports listing this active substance and at least one of these reaction terms: mood swings, mood altered. A report can name several reactions and several drugs. Counts by year use the date FDA received the report.

Download the data (CSV)

From the public record

Most reported events in FDA adverse event reports for progesterone

Through 2026-10-28, FDA had received 21,732 adverse event reports for progesterone, 12,201 of them marked serious by the reporter. The symptom terms named most often were headache (2,044), fatigue (1,773) and pain (1,395).

Most reported events in FDA adverse event reports for progesterone: the figures
MeasureValueNote
All reports received21,732
Reports the reporter marked serious12,201death, hospitalisation, disability or similar outcome
Headache2,044 reports
Fatigue1,773 reports
Pain1,395 reports
Nausea1,354 reports
Rash953 reports

Source: FDA Adverse Event Reporting System (FAERS) via openFDA, data as of Oct 28, 2026

Scope: Reports where FDA recorded progesterone as a single-ingredient active substance (any brand), all years to 2026-10-28

FAERS reports are unverified and do not prove the drug caused the event. Reporting rises with use, publicity and lawsuits, so these counts cannot give rates or risks and cannot be compared between drugs.

How this was calculated

Counted FAERS reports listing this active substance, then the reaction terms named most often. A report can name several reactions, and a term can describe the illness being treated and not an effect of the drug. Terms about product use or complaints rather than symptoms (for example off label use) were left out of the list.

Download the data (CSV)

From the public record

FDA label facts for progesterone

The FDA label read for progesterone (ENDOMETRIN, application NDA022057) was last revised on 2026-07-29. It carries no boxed warning. Of the 4 population sections checked, 4 are present: pregnancy, lactation, pediatric use, geriatric use.

FDA label facts for progesterone: the figures
MeasureValueNote
Label revision date2026-07-29
Label readENDOMETRINNDA022057, brand-name application
Boxed warningNo
Pregnancy sectionPresent
Lactation sectionPresent
Pediatric use sectionPresent
Geriatric use sectionPresent

Source: FDA drug label via openFDA, viewable on NIH DailyMed, data as of Nov 11, 2026

Scope: One label: the newest prescription label for single-ingredient progesterone from an original manufacturer

Read from one label. Labels for other brands, strengths or forms of the same ingredient can differ. A missing section heading does not mean there is no guidance. Read the full label before relying on it.

How this was calculated

Selected the most recently revised prescription label for this single ingredient from an original manufacturer, preferring a brand-name application. Checked which sections exist and quoted headings and sentences exactly as printed.

Download the data (CSV)

At a glance

  • Depression, label Table 7 / 19% with Prometrium 200 mg plus conjugated estrogens vs 12% placebo over 3 years [1]
  • Irritability, label Table 8 / 8% with Prometrium 400 mg vs 4% placebo [1]
  • Dizziness, label Table 8 / 24% vs 4% placebo [1]
  • Mood-related postmarketing reports / Include suicidal ideation and aggression, frequency unknown [2]
  • Labeled dosing / Single daily dose at bedtime [2]
  • Labeled indications / Endometrial hyperplasia prevention with conjugated estrogens tablets; secondary amenorrhea [2]
  • Interaction information / In-vitro ketoconazole note only, clinical relevance unknown [1]

What does the Prometrium label record about mood?

In a three-year placebo-controlled trial described in the label, 200 mg of Prometrium for 12 days per 28-day cycle plus conjugated estrogens 0.625 mg daily (n=178) was compared with placebo and no hormones (n=174). Depression was reported by 19% versus 12%, dizziness by 15% versus 9%, and headache by 31% versus 27% [1]. That 19% belongs to the combination arm, which took estrogen as well as progesterone, so it cannot be assigned to progesterone alone [1].

A second label trial compared 400 mg daily with placebo in estrogen-primed postmenopausal women with secondary amenorrhea, 25 versus 24 women, and reported irritability in 8% versus 4% [1]. That is 2 women versus 1, and each woman in groups this size moves the percentage by about 4 points.

The label's postmarketing list, built from voluntary reports of unknown frequency, includes suicidal ideation, aggression, depersonalization, sedation, disorientation and depressed consciousness [2]. The label also describes an open-label study of 220 premenopausal women with secondary amenorrhea who received daily conjugated estrogens plus Prometrium 300 mg or 400 mg for 10 days of each cycle; mood swing was among the reactions reported by at least 5% of participants overall [2].

Did a large trial find more mood symptoms on micronized progesterone?

Not in the PEPI cohort. Among 875 postmenopausal women followed for three years, anxiety, cognitive and affective symptoms did not differ by treatment assignment, while every active hormone regimen reduced vasomotor symptoms at one year (odds ratio 0.17 to 0.28) [3]. Breast discomfort was higher only in the progestin-containing regimens (odds ratio 1.92 to 2.27) [3]. PEPI used conjugated equine estrogen, not estradiol, and its placebo group received no hormones [4].

What does the label say about timing and drowsiness?

Both labeled regimens are bedtime doses: 200 mg at bedtime for 12 days per 28-day cycle with conjugated estrogens, and 400 mg at bedtime for 10 days in secondary amenorrhea [2]. The patient leaflet gives the reason for the timing: some women become very drowsy or dizzy [1]. The label states that Prometrium may cause transient dizziness and drowsiness and should be used with caution when driving or operating machinery. It also says that during initial therapy a few women had extreme dizziness or drowsiness, blurred vision, slurred speech, difficulty walking, loss of consciousness, vertigo, confusion, disorientation, feeling drunk and shortness of breath [2][1].

Is there a medication that treats it?

We found no published study that tested an antidepressant, an anxiolytic or another prescription drug in women whose mood symptoms appeared on oral micronized progesterone. The label has no separate drug-interactions section; its only interaction statement is an in-vitro finding that ketoconazole inhibited progesterone metabolism in human liver microsomes, with the clinical relevance unknown [1]. The label does not name any CYP3A4 inducer [1].

Check what you know

Think you have it? Try these 5 quick questions and see what the article says.

1. According to the Prometrium label, what was the depression rate in women taking 200 mg cyclic Prometrium with conjugated estrogens?
2. In the PEPI cohort, how many postmenopausal women were followed for three years?
3. According to the label, when are the labeled Prometrium regimens taken?
4. What is the only interaction statement in the Prometrium label, according to the article?
5. What precaution does the label give about transient dizziness and drowsiness on Prometrium?

Score: 0 right, 0 of 5 answered

What people on Reddit report

Accounts from people who had mood changes on oral progesterone and changed how they took it, by route, schedule or dose, with mixed results.

mediumpace07 · Perimenopause

You can take it vaginally and it bypasses the liver (which converts it into neuro metabolites if taken orally). I got the clear from my obgyn and immediately felt better the next day.

Reports depression on oral progesterone, then switched to the vaginal route with her gynecologist's approval and felt better quickly.

Read the source discussion

violetgothdolls · Perimenopause

It gave me rage.....I had to stop taking it. I probably should go back to my GP to talk about adjusting the dose.

Reports rage on oral progesterone, stopped it, and is considering a dose discussion with the doctor.

Read the source discussion

mapspearson · Menopause

I noticed the return of anxiety when I would stop after day 12, as I initially was doing cyclical. Reached out to my doctor, told her my observations and asked if I could take it daily, she said yes.

Reports anxiety returning at the end of a cyclical course and says a daily schedule agreed with the doctor helped.

Read the source discussion

Questions worth asking

Choose the questions you want to keep

Frequently asked questions

Does the Prometrium label list depression as a side effect?
Yes. Depression was reported by 19% of women taking 200 mg cyclic Prometrium plus conjugated estrogens versus 12% on placebo over three years; the active arm also took estrogen, so the figure is not progesterone alone [1].
What does the label say about combining Prometrium with an SSRI?
The label has no separate drug-interactions section and gives no information on combining Prometrium with SSRIs. Its only interaction note is the in-vitro ketoconazole finding of unknown clinical relevance [1].
Does the 19% depression figure prove progesterone causes low mood?
No. That figure compares women taking progesterone plus conjugated estrogens with women taking no hormones at all, so it cannot separate progesterone from estrogen [1]. In the 875-woman PEPI cohort, affective and anxiety symptoms did not differ by treatment assignment [3].
Does the label give a different dose for mood symptoms?
The label's dosing section gives only the oral bedtime regimens: 200 mg for 12 days per cycle with conjugated estrogens, or 400 mg for 10 days for secondary amenorrhea. It gives no separate dosing instruction for mood symptoms [2].

Reader questions

What people actually ask

Short answers drawn from the sources this article cites.

Do progesterone pills make you moody?

The label records mood reactions, but the evidence does not show that progesterone alone causes them. Depression was reported by 19% of women on 200 mg Prometrium plus conjugated estrogens versus 12% on placebo over three years, and that arm also took estrogen. In the PEPI cohort of 875 women, anxiety and affective symptoms did not differ by treatment assignment.

When to take progesterone?

Both labeled regimens are taken at bedtime. The label gives 200 mg at bedtime for 12 days per 28-day cycle with conjugated estrogens, or 400 mg at bedtime for 10 days in secondary amenorrhea. The timing reflects that some women become very drowsy or dizzy, and the label advises caution when driving or operating machinery.

Why am I so angry on progesterone?

The label lists irritability, but the evidence is thin. In a trial of 25 women given 400 mg daily versus 24 on placebo, irritability was reported by 8% versus 4%, which is 2 women versus 1. Each woman in a group this size moves the percentage by about 4 points, so the difference is not established.

References

Show all 7 referencesHide references
  1. U.S. Food and Drug Administration. Prometrium (progesterone) capsules prescribing information, Revision 02/2026. Prometrium prescribing information
  2. U.S. National Library of Medicine, DailyMed. Prometrium progesterone capsules, Rev. 02/2026 prescribing information. Prometrium progesterone capsules, Rev. 02/2026 label
  3. Greendale GA, Reboussin BA, Hogan P, Barnabei VM, Shumaker S, Johnson S, et al. Symptom relief and side effects of postmenopausal hormones: results from the Postmenopausal Estrogen/Progestin Interventions Trial. Obstet Gynecol. 1998;92(6):982-8.
  4. The Writing Group for the PEPI Trial. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA. 1995;273(3):199-208.
  5. Thys-Jacobs S, Starkey P, Bernstein D, Tian J. Calcium carbonate and the premenstrual syndrome: effects on premenstrual and menstrual symptoms. Premenstrual Syndrome Study Group. Am J Obstet Gynecol. 1998;179(2):444-52.
  6. Reddit participants. I think progesterone is causing me rage and sadness. (r/Perimenopause). Accessed 2026-11-11.
  7. Reddit participants. Progesterone: is it the PMS hormone or the happy hormone? (r/Menopause). Accessed 2026-11-11.
Evidence overview for Medications to Manage Mood Changes on Oral Micronized Progesterone: First-Line and Beyond