Progesterone Treatment for Secondary Amenorrhea

For secondary amenorrhea, prescribe oral progesterone 400 mg as a single daily dose at bedtime for 10 days to induce withdrawal bleeding. 1

Diagnostic Prerequisites Before Prescribing

Before initiating progesterone therapy, you must complete the following workup:

Rule out pregnancy first with a urine or serum pregnancy test—this is mandatory before any hormonal evaluation or treatment 2, 3, 4
Measure FSH, LH, prolactin, and TSH to identify the underlying cause of amenorrhea 2, 3, 4
Assess for hypoestrogenism by checking estradiol levels or performing pelvic ultrasound to evaluate endometrial thickness 2, 3

Progesterone withdrawal testing is indicated when:

The patient has adequate estrogen levels (estradiol >50 pg/mL or endometrial thickness >5 mm on ultrasound), suggesting chronic anovulation rather than ovarian failure 2, 3
FSH is normal or low (<40 mIU/mL), ruling out primary ovarian insufficiency 2, 3, 4
Prolactin and TSH are normal, excluding hyperprolactinemia and thyroid dysfunction 3, 4
The patient likely has PCOS or functional hypothalamic amenorrhea with preserved estrogen production 2, 3

Dosing regimen:

Progesterone 400 mg orally once daily at bedtime for 10 days 1
In clinical trials, this dosing induced withdrawal bleeding in 76.8% of women with secondary amenorrhea within 7 days of the last dose 1
Alternative dosing of 300 mg daily for 10 days is also effective (73.8% withdrawal bleeding rate) but 400 mg is preferred 1

Administration instructions:

Take with a full glass of water while standing to prevent difficulty swallowing the capsules 1
Bedtime dosing minimizes side effects such as dizziness and sedation 1

Withdrawal bleeding should occur within 7 days after completing the 10-day course 1
If bleeding occurs, this confirms adequate estrogen levels and suggests anovulation (PCOS or functional hypothalamic amenorrhea) 2, 3
If no bleeding occurs, this suggests hypoestrogenism (functional hypothalamic amenorrhea with low estrogen or primary ovarian insufficiency), requiring further evaluation with estradiol measurement and pelvic ultrasound 2, 3

Never prescribe progesterone without first ruling out pregnancy—this is the most common and dangerous error 2, 3, 4
Do not assume amenorrhea is benign without hormonal evaluation—prolonged hypoestrogenism increases risks of osteoporosis and cardiovascular disease 3, 4
If prolactin is elevated, order pituitary MRI immediately before prescribing progesterone, as prolactinomas require specific treatment and can cause visual field defects 3, 4
If FSH is elevated (>40 mIU/mL), do not use progesterone withdrawal testing—the patient has primary ovarian insufficiency and requires estrogen replacement therapy, not progesterone alone 2, 3, 4
If endometrial thickness is >8 mm on ultrasound, the patient has chronic anovulation with unopposed estrogen and is at increased risk for endometrial hyperplasia or cancer—progesterone is appropriate but requires ongoing cyclical therapy, not just a single course 3

If withdrawal bleeding occurs, indicating adequate estrogen:

For cycle regulation without contraception needs: Prescribe cyclical progesterone 200 mg daily for 12 days per month to prevent endometrial hyperplasia from unopposed estrogen 1
For contraception: Consider combined oral contraceptives, which also regulate cycles and reduce hyperandrogenism in PCOS 5, 6
For fertility: Refer to reproductive endocrinology for ovulation induction with clomiphene, letrozole, or gonadotropins 6, 7

If no withdrawal bleeding occurs, indicating hypoestrogenism:

Initiate estrogen-progesterone hormone replacement therapy to prevent bone loss and cardiovascular disease 3, 8, 7
Evaluate for eating disorders, excessive exercise, or stress in functional hypothalamic amenorrhea 2, 8, 7
Order DXA scan for bone mineral density if amenorrhea has persisted >6 months 3