What are the differences between types of progesterone, including natural progesterone and synthetic progestins like norethindrone acetate and medroxyprogesterone acetate?

Differences Between Types of Progesterone

Natural micronized progesterone is preferable to synthetic progestins due to its more favorable cardiovascular, metabolic, and safety profile, with fewer side effects on blood pressure, thrombotic risk, and mood compared to synthetic alternatives like medroxyprogesterone acetate (MPA) and norethindrone acetate (NA). 1, 2

Natural Progesterone vs. Synthetic Progestins

Natural Micronized Progesterone

• Bioidentical to endogenous progesterone produced by the corpus luteum
• Minimizes hormone-related cardiovascular risks compared to synthetic progestogens 1
• Neutral or beneficial effect on blood pressure 1
• Better safety profile regarding thrombotic risk 1, 3
• Fewer psychological side effects 4
• Associated with lower risk of breast cancer compared to synthetic progestins 3
• Available in oral micronized form with improved bioavailability over non-micronized natural progesterone 2

Synthetic Progestins

Medroxyprogesterone Acetate (MPA)

• Most extensively studied progestin with proven endometrial efficacy 1
• Negatively impacts cardiovascular risk through effects on:
  • Lipid profiles
  • Vasomotion
  • Carbohydrate metabolism 1
• Associated with more physical symptoms than norethindrone 5
• May cause fatigue, fluid retention, lipid alterations, and dysphoria 2
• Linked to higher breast cancer risk compared to natural progesterone 3

Norethindrone Acetate (NA)

• First generation synthetic progestin 1
• Twice as potent as norethindrone on a weight basis 6
• Rapidly deacetylated to norethindrone after oral administration 6
• Associated with worse profile regarding blood pressure and renal function 1
• Induces more negative mood symptoms than MPA in women without history of premenstrual syndrome 5
• Can have potent off-target effects on androgen and glucocorticoid receptors 1
• May contribute to acne and adverse metabolic effects 1

Clinical Implications and Recommendations

For Hormone Replacement Therapy

• The European Society for Human Reproduction and Embryology (ESHRE) recommends natural micronized progesterone among the preferred progestogens for hormone replacement therapy in women with ovarian insufficiency 1
• For non-hysterectomized women requiring estrogen therapy, progesterone should be added to prevent endometrial hyperplasia 1
• Transdermal administration routes are preferred for estrogen when combined with progesterone to minimize cardiovascular risks 7

For Contraception

• Combined hormonal contraceptives typically contain synthetic progestins rather than natural progesterone 1
• Newer generation progestins (third and fourth generation) have been designed to reduce unwanted side effects 1
• Fourth generation progestins like drospirenone have anti-androgenic and anti-mineralocorticoid properties 1

For Preterm Birth Prevention

• In singleton pregnancies with prior preterm birth, 17-alpha-hydroxy-progesterone caproate is recommended (250 mg IM weekly) 1
• For singleton pregnancies with short cervical length but no prior preterm birth, vaginal progesterone (90-mg gel or 200-mg suppository) is recommended 1

Administration Routes and Considerations

Natural Progesterone

• Oral micronized: Better bioavailability than non-micronized forms 2
• Vaginal: Provides direct vagina-to-uterus transport with preferential uterine uptake despite lower systemic levels 4
• Rectal, intranasal, and transdermal routes are also available but with varying absorption rates 2

Synthetic Progestins

• Primarily administered orally
• Designed to resist enzymatic degradation and remain active after oral administration 4
• Some formulations (like norethindrone acetate) can be administered transdermally but may retain undesirable hepatic effects 4

Potential Adverse Effects

Natural Progesterone

• Milder side effect profile overall 2
• Oral micronized progesterone may cause drowsiness and dizziness due to metabolites reduced at the 5-alpha position 4
• Generally lower impact on mood and physical symptoms 5

Synthetic Progestins

• More significant side effects including:
  • Fatigue and fluid retention
  • Lipid level alterations
  • Dysphoria
  • Hypercoagulant states
  • Increased androgenicity 2
• May cause more severe psychological side effects 4
• Higher risk of breast cancer compared to natural progesterone 3

Clinical Decision-Making Algorithm

1. For women requiring hormone therapy with intact uterus:

   • First choice: Natural micronized progesterone (if cardiovascular risk factors present)
   • Alternative: Lower-dose synthetic progestins if micronized progesterone not tolerated

2. For women with history of mood disorders or PMS:

   • Strongly prefer natural micronized progesterone over synthetic progestins 5

3. For women with cardiovascular risk factors:

   • Natural micronized progesterone is preferred due to neutral effect on blood pressure and lower thrombotic risk 1

4. For preterm birth prevention:

   • Follow specific protocols based on risk factors (prior preterm birth or short cervical length) 1

The evidence clearly demonstrates that natural micronized progesterone offers significant advantages over synthetic progestins in terms of safety profile and side effects, particularly regarding cardiovascular health, thrombotic risk, and psychological well-being.