When is progesterone therapy indicated in women?

When is Progesterone Therapy Indicated in Women

Progesterone therapy is indicated in three primary clinical scenarios: endometrial protection in postmenopausal women receiving estrogen therapy, prevention of recurrent preterm birth in women with prior spontaneous preterm birth, and fertility-sparing treatment for select early-stage endometrial cancer patients.

Endometrial Protection in Hormone Replacement Therapy

Postmenopausal Women with Intact Uterus

All postmenopausal women with an intact uterus who receive estrogen therapy must receive concurrent progestogen therapy to prevent endometrial hyperplasia and adenocarcinoma. 1, 2

• Unopposed estrogen increases endometrial hyperplasia risk dramatically, with odds ratios ranging from 5.4 at 6 months to 15.0 at 36 months of treatment 3
• In the PEPI trial, 62% of women taking moderate-dose unopposed estrogen developed hyperplasia at 36 months compared to 2% on placebo 3
• Adding appropriate dose and duration of progestogen reduces hyperplasia risk to levels seen in never-users of estrogen 2

Dosing Regimens for Endometrial Protection

Micronized progesterone should be prescribed at 200 mg daily for 12-14 days per month in sequential regimens, or 100 mg daily for 25 days per month in continuous regimens. 4, 5

• Sequential therapy: 200 mg daily for 12-14 days every 28 days provides adequate endometrial protection 6, 4
• Continuous therapy: 100 mg daily for 25 days per month for women preferring amenorrhea 5
• Progestogen must be given for at least 10-14 days per month to prevent hyperplasia 3, 2
• Continuous combined therapy is more protective than sequential therapy at longer treatment durations 3

Micronized progesterone is preferred over synthetic progestins due to superior safety profile regarding cardiovascular disease, venous thromboembolism, and breast tissue effects. 4, 7

Women Who Do NOT Need Progestogen

• Hysterectomized women receiving estrogen therapy should receive estrogen-only therapy, as there is no therapeutic advantage to adding progestogen 6
• Exception: Women with residual intra-peritoneal endometriosis after hysterectomy may benefit from combined estrogen-progestogen therapy 6

Prevention of Recurrent Preterm Birth

Women with Prior Spontaneous Preterm Birth

17-alpha hydroxyprogesterone caproate (17OHP-C) 250 mg intramuscularly weekly from 16-20 weeks until 36 weeks of gestation is indicated for all women with singleton pregnancy and prior spontaneous preterm birth. 6

• 17OHP-C reduces recurrent preterm birth at <37 weeks by 34% (from 54.9% to 36.3%) 6
• Significant reductions also seen in preterm birth at <32 and <35 weeks 6
• Reduces infant complications including intraventricular hemorrhage, necrotizing enterocolitis, and need for supplemental oxygen 6

Women Without Prior Preterm Birth but Short Cervix

Vaginal progesterone (90 mg gel or 200 mg suppository daily) from diagnosis until 36 weeks is indicated for singleton pregnancies without prior preterm birth but with cervical length ≤20 mm at 16-24 weeks. 6

Important Limitations

• Progesterone is NOT indicated for multiple gestations (twins, triplets) as trials show no benefit 6
• Progesterone is NOT indicated for symptomatic preterm labor or preterm premature rupture of membranes 6
• If cervix shortens to <25 mm despite 17OHP-C therapy in women with prior preterm birth, continue 17OHP-C rather than switching to vaginal progesterone 6

Fertility-Sparing Therapy for Endometrial Cancer

Highly Selected Early-Stage Disease

Continuous progestin-based therapy may be considered for highly selected patients with biopsy-proven grade 1, stage IA endometrioid adenocarcinoma who wish to preserve fertility. 6

Strict eligibility criteria must ALL be met: 6

• Grade 1 endometrioid adenocarcinoma only
• Stage IA disease (no myometrial invasion)
• No metastatic disease on imaging
• Patient counseled this is not standard of care

Dosing options include megestrol acetate 400-600 mg/day, high-dose medroxyprogesterone acetate, or levonorgestrel intrauterine device. 6, 8

Monitoring and Outcomes

• Endometrial sampling (biopsy or D&C) every 3-6 months is mandatory 6
• Durable complete response occurs in approximately 50% of patients 6
• Total hysterectomy with bilateral salpingo-oophorectomy recommended after childbearing complete, if progression occurs, or if cancer persists after 6 months of therapy 6
• Ultimate recurrence rate is high (35%) even in responders 6

This approach is NOT recommended for high-risk histologies including high-grade endometrioid, serous, clear cell adenocarcinoma, carcinosarcoma, or leiomyosarcoma. 6

Premature Ovarian Insufficiency

Adolescents and Young Women

Hormone therapy is indicated for all post-pubertal girls and women with premature ovarian insufficiency to replace physiologic hormone levels. 6

• Transdermal 17β-estradiol 50-100 mcg daily is preferred over oral formulations due to better safety profile 6
• Progestogen must be added after 2 years of estrogen therapy or when breakthrough bleeding occurs 6
• Micronized progesterone 100-200 mg daily for 12-14 days every 28 days is first choice 6

Pubertal Induction

For prepubertal girls with premature ovarian insufficiency requiring pubertal induction: 6

• Start low-dose transdermal estradiol at age 12-13 years if no spontaneous development and FSH elevated
• Gradually increase dose over 2-3 years to adult levels
• Add cyclic progestogen after 2 years of estrogen or when breakthrough bleeding occurs

Medically Inoperable Endometrial Cancer

Hormonal therapy may be considered in selected medically inoperable patients with endometrioid histology who are estrogen receptor-positive and progesterone receptor-positive, if not candidates for radiation or surgery. 6

• Progesterone-based therapy provides benefit with low toxicity in low-grade tumors 6
• Close monitoring with endometrial biopsies every 3-6 months required 6

Secondary Amenorrhea

Progesterone is indicated for diagnostic evaluation and treatment of secondary amenorrhea. 1

• Progesterone challenge test: medroxyprogesterone acetate 10 mg daily for 10 days 8
• Withdrawal bleeding within 2-7 days indicates adequate estrogen priming and patent outflow tract 8
• No bleeding suggests inadequate estrogen levels or anatomic obstruction 8

Common Pitfalls to Avoid

• Never prescribe unopposed estrogen to women with intact uterus - this dramatically increases endometrial cancer risk 3, 2
• Inadequate progestogen duration (less than 12 days per month in sequential regimens) fails to provide endometrial protection 4, 3
• Do not use progesterone for multiple gestations to prevent preterm birth - evidence shows no benefit 6
• Do not confuse diagnostic progesterone challenge test dosing (10 mg daily for 10 days) with therapeutic fertility-sparing dosing (400-600 mg daily) 8
• Assess contraindications carefully including breast cancer, stroke, myocardial infarction, pulmonary embolism, deep vein thrombosis, and smoking before prescribing progestin-based therapy 6