What is the role of progesterone in perimenopause?

Role of Progesterone in Perimenopause

Progesterone plays a crucial role in perimenopause primarily by providing endometrial protection when used with estrogen therapy, preventing the increased risk of endometrial hyperplasia and cancer associated with unopposed estrogen. 1

Physiological Changes in Perimenopause

• During perimenopause, progesterone levels decline as ovulation becomes irregular
• This decline leads to:
  • Menstrual irregularities (secondary amenorrhea)
  • Anovulatory cycles
  • Estrogen dominance relative to progesterone
  • Increased risk of endometrial hyperplasia when using estrogen therapy

Primary Functions of Progesterone in Perimenopause

1. Endometrial Protection

• The most important role of progesterone during perimenopause is protecting the endometrium from estrogen-induced hyperplasia 1, 2
• When used in hormone therapy, progesterone counteracts the proliferative effects of estrogen on the uterine lining 3
• All FDA-approved progesterone formulations provide endometrial protection when used at adequate doses and duration 2

2. Management of Menstrual Irregularities

• Progesterone can be prescribed to treat secondary amenorrhea due to decreased progesterone production 4
• The recommended dosage for secondary amenorrhea is 400 mg taken at bedtime for 10 days 4

Progesterone Formulations and Administration

Oral Progesterone

• Micronized progesterone (200 mg/day) is recommended for women with an intact uterus who are taking estrogen 1
• For endometrial protection: 200 mg daily at bedtime for 12 continuous days per 28-day cycle 4

Other Delivery Methods

• Transdermal progesterone has been studied but shows variable efficacy for symptom management 5
• Levonorgestrel intrauterine devices (LNG-IUD) provide effective endometrial protection with fewer systemic effects 6

Benefits of Progesterone vs. Synthetic Progestins

• Natural micronized progesterone appears to have a better safety profile than synthetic progestins, particularly regarding breast cancer risk 7
• The E3N Study showed that transdermal estrogen with progesterone did not significantly increase breast cancer rates (RR: 1.08) 7
• Progesterone has minimal impact on:
  • HDL/LDL cholesterol ratio
  • Carbohydrate metabolism
  • Blood pressure
  • Thrombogenicity
  • Body weight 7

Potential Side Effects and Cautions

• Common side effects include drowsiness and dizziness, which is why progesterone is typically taken at bedtime 4
• More serious but less common side effects include:
  • Abnormal blood clotting
  • Stroke
  • Heart attack
  • Pulmonary embolism 4
• Progestogens may diminish some beneficial effects of estrogen on cardiovascular risk factors 2
• Some women experience negative mood effects with progesterone supplementation 2

Clinical Recommendations

• For perimenopausal women with an intact uterus using estrogen therapy, progesterone must be added to prevent endometrial hyperplasia 1, 2
• The American College of Obstetricians and Gynecologists recommends starting with the lowest effective dose to control symptoms 1
• Micronized progesterone (200 mg orally for 12-14 days per month) is preferred over synthetic progestins due to its better safety profile 1, 7
• Annual clinical review is necessary to monitor compliance, bleeding patterns, and potential adverse effects 1

Important Caveats

• Hormone therapy should not be used for the primary or secondary prevention of cardiovascular disease 2
• Adding progesterone to estrogen therapy does not decrease breast cancer risk 2
• Progesterone can increase mammographic density, which reverses after discontinuation 2
• Progesterone should be used for the shortest possible time at the lowest effective dose 1