What are the different types of progesterone (Progesterone) supplementation, such as oral (e.g. Prometrium (Micronized Progesterone)), vaginal (e.g. Crinone (Progesterone) 8% gel or Endometrin (Progesterone)), and injectable (e.g. 17-hydroxyprogesterone caproate) forms?

Different Types of Progesterone Supplementation

Micronized progesterone (MP) is the preferred first-line progestin formulation due to its superior cardiovascular and thrombotic safety profile compared to synthetic progestins, available in oral, vaginal, and transdermal routes. 1, 2

Primary Progesterone Formulations

Natural Micronized Progesterone (Preferred)

• Oral micronized progesterone is the first-choice progestin, demonstrating lower cardiovascular disease and venous thromboembolism risk compared to synthetic alternatives 1, 2
• Standard dosing: 200 mg daily for 12-14 days every 28 days in sequential regimens 1, 2
• Vaginal micronized progesterone at 200 mg daily provides equivalent endometrial protection and is an effective alternative route 1, 2
• Oral micronized progesterone exhibits anti-estrogenic, anti-androgenic, and anti-mineralocorticoid effects without adverse impacts on lipid profiles, coagulation factors, or blood pressure 3
• Micronized formulations have superior bioavailability and milder adverse effects compared to non-micronized natural progesterone 4

Synthetic Progestins (Alternative Options)

Medroxyprogesterone Acetate (MPA)

• The only progestin with demonstrated full effectiveness in inducing secretory endometrium when combined with replacement-dose estrogen 1
• Sequential regimen: 10 mg daily for 12-14 days per month 1, 2
• Continuous regimen: minimum 2.5 mg daily 1, 2
• Important caveat: MPA negatively impacts cardiovascular risk through effects on lipid profiles, vasomotion, and carbohydrate metabolism more than alternative options 1

Dydrogesterone

• A synthetic progesterone with enhanced oral bioavailability 1
• Sequential regimen: 10 mg daily for 12-14 days per month 1, 2
• Continuous regimen: minimum 5 mg daily 1, 2
• Listed among recommended progestins by ESHRE guidelines, though endometrial effects in POI populations require further study 1

Norethisterone/Norethisterone Acetate

• Continuous regimen: minimum 1 mg daily 1, 2
• Critical warning: Associated with worse blood pressure profile, impaired renal function, and activation of renin-angiotensin system compared to micronized progesterone 1

Injectable Progesterone

17-Alpha Hydroxyprogesterone Caproate (17-OHPC)

• A synthetic form of natural 17-α hydroxyprogesterone, FDA-approved specifically for prevention of recurrent spontaneous preterm birth 5
• Specific indication: Women with history of prior singleton spontaneous preterm birth between 20-36+6 weeks gestation 5, 6
• Reduces recurrent preterm birth risk by more than 30% 5
• Administration: Weekly intramuscular injections begun early in second trimester, continued until 36 weeks 6, 7
• Not indicated for multiple gestation, short cervix, or as tocolytic therapy for active preterm labor 6

Transdermal Progestin Delivery

Combined Estrogen-Progestin Patches

• First-choice for compliance: Combined 17β-estradiol + levonorgestrel patches 1
• Sequential combined: 50 μg estradiol for 2 weeks, then 50 μg estradiol + 10 μg levonorgestrel for 2 weeks 1, 8
• Continuous combined: 50 μg estradiol + 7 μg levonorgestrel daily without interruption (avoids withdrawal bleeding) 1, 8

Route Selection Algorithm

When combined patches are available:

• Use sequential combined patches if withdrawal bleeding is acceptable 1
• Use continuous combined patches if avoiding withdrawal bleeding is required 1

When combined patches are unavailable:

• Administer transdermal estradiol continuously 1
• Add oral micronized progesterone 200 mg or vaginal micronized progesterone 200 mg for 12-14 days every 28 days 1
• Alternative: MPA 10 mg for 12-14 days per month 1

Special consideration for pregnancy detection:

• Cyclic administration allows earlier pregnancy recognition, as women with POI may spontaneously ovulate 1
• Absence of withdrawal bleeding should prompt pregnancy testing 1

Critical Safety Distinctions

Avoid synthetic progestins (Provera, PremPro, Cycrin) when possible due to significant side effects including fatigue, fluid retention, lipid alterations, dysphoria, hypercoagulant states, and increased androgenicity 4

Do not use progestins with anti-androgenic effects in women with low testosterone or sexual dysfunction 8

The evidence strongly supports micronized progesterone as the safest option across multiple cardiovascular and metabolic parameters, with synthetic progestins reserved for situations where natural progesterone is unavailable or contraindicated 1, 2, 4