What role does progesterone (a hormone) play in hormone therapy (HT) for regulating mood?

Role of Progesterone in Hormone Therapy for Mood Regulation

Progesterone has limited evidence supporting its use for mood regulation in hormone therapy, and may actually worsen mood symptoms in some women when used continuously.

Mechanisms of Progesterone and Mood

Progesterone has traditionally been thought to have anxiolytic and anesthetic properties that could potentially help with mood regulation 1. It modulates serotonergic receptors 1, which theoretically could provide mood benefits. However, the clinical evidence for these proposed benefits is inconsistent and often contradictory.

Key Physiological Effects:

• Progesterone undergoes a 10-fold increase during pregnancy and rapidly returns to baseline within 1-2 weeks postpartum 1
• Sudden withdrawal of progesterone has been hypothesized to contribute to postpartum mood disorders 1
• Progesterone can affect serotonergic receptor function, which is involved in mood regulation 1

Evidence on Progesterone and Mood

The evidence regarding progesterone's effects on mood is mixed and generally does not support its use specifically for mood regulation:

• Postpartum Depression: Despite theoretical justification, there is no robust primary research supporting progesterone use in treating postnatal mood disorders 2

• Menopausal Symptoms: A systematic review found no studies reporting improvement in mood symptoms with progestin-only therapy for menopausal symptoms 3

• Continuous vs. Cyclical Administration: Continuous progesterone administration may contribute to depressive symptoms in some women, while cyclical administration (12-14 days every 28 days) is associated with fewer mood disturbances 4

• Dose-Dependent Effects: Higher doses of estrogen combined with progestins can actually worsen mood symptoms during the progestin phase of sequential hormone therapy 5

Clinical Recommendations for Progesterone Use in HT

When Considering Progesterone for Mood:

1. Administration Pattern:

   • Use cyclical rather than continuous progesterone when possible (200mg for 12-14 days every 28 days) 4
   • Continuous administration is more likely to cause mood disturbances

2. Formulation Choice:

   • Natural micronized progesterone may have fewer side effects than synthetic progestins like medroxyprogesterone acetate (MPA) 1, 6
   • Micronized progesterone shows a better safety profile for cardiovascular risk and blood pressure 1

3. Monitoring:

   • Assess mood symptoms after 4-6 weeks of hormone therapy adjustments 4
   • Be alert for symptoms of depression that may emerge during progesterone administration

Potential Risks and Side Effects

Progesterone therapy carries several risks that must be weighed against potential benefits:

• Common side effects include headache (31%), breast tenderness (27%), and depression (19%) 7
• May cause dizziness and drowsiness, affecting ability to drive or operate machinery 7
• Can cause fluid retention, which may be problematic for women with cardiac or renal dysfunction 7

Alternative Approaches

If mood symptoms are a primary concern:

• Consider estrogen therapy alone for women who have had a hysterectomy 1
• Focus on optimizing estrogen therapy, as low estrogen levels are associated with increased risk of depression 4
• Consider transdermal estrogen administration as first-line approach for mood symptoms 4

Special Populations

Transgender Care:

• Progestins are often sought by transgender women for feminization effects, but are not recommended by the Endocrine Society due to risk factors 1
• No clear evidence of mood benefits in this population, with some patients discontinuing use due to poor mood effects 1

Conclusion

The evidence does not strongly support using progesterone specifically for mood regulation in hormone therapy. When progesterone is required as part of HT (such as for endometrial protection), using natural micronized progesterone in a cyclical rather than continuous pattern may minimize negative mood effects.