Combined hormonal contraceptives (CHC), including combined oral contraceptives (COC), inhibit ovulation through hypothalamic-pituitary inhibition of gonadotropin secretion. While no casual relationship has been established between CHC and subsequent amenorrhea, historically, it was believed that this suppression could persist for months after discontinuation of COC, leading to “post-pill amenorrhea.” The name implies pill use, but it could apply after cessation of other combined hormonal methods such as the contraceptive patch or ring. This syndrome has been described as amenorrhea for more than one year after cessation of CHC, with an approximately 1% frequency, (similar to amenorrhea rates in those not using CHCs). When stopping cyclic CHCs, median duration from withdrawal bleeding to first menses is 32 days (range 15-82 days), and 98.9% of uses have clinical evidence of normal hypothalamic-pituitary function within 90 days. Return to fertility after the completion of CHC is generally similar to that observed with other common contraceptive methods (excluding the medroxyprogesterone acetate injectable), including non-hormonal contraceptive methods. Furthermore, the median time to pregnancy is 2.5 to 3 cycles, with a pregnancy rate of nearly 95% after one year.
Patients with post-pill amenorrhea should undergo the same evaluation as any patients with secondary amenorrhea, defined as no menses for 3 months in patients with previously regular menstrual cycles or 6 months in patients with irregular menstrual cycles. The differential diagnosis for secondary amenorrhea is broad, including hypothalamic dysfunction (e.g. weight loss/anorexia), chronic anovulation (e.g. PCOS), hypothyroidism, pituitary abnormalities (e.g. tumor, empty sella), hyperprolactinemia, and ovarian insufficiency. Less common causes include Asherman’s syndrome, ovarian tumors, and non-classical congenital adrenal hyperplasia (CAH).
The evaluation of secondary amenorrhea should begin with a thorough history and physical examination. After excluding pregnancy, the most useful diagnostic tests are TSH, prolactin, and FSH. An abnormal TSH should prompt further testing for thyroid disease. An elevated prolactin level with normal TSH is generally followed up with an MRI to assess for pituitary tumor. Elevated FSH in patients younger than 40 should prompt an investigation for ovarian insufficiency, including karyotype if younger than 30. Low or normal FSH levels would suggest further evaluation for conditions causing chronic anovulation. Testing androgens (e.g. testosterone and 17-hydroxyprogesterone) for patients with chronic anovulation and androgenic symptoms can reveal ovarian tumor or non-classical CAH. History will generally identify potential risk factors for Asherman’s syndrome that would prompt imaging such as hysterosalpingogram.
The management of secondary amenorrhea can include medical or surgical treatments, depending on the etiology. Thyroid disease requires either medical or surgical treatment, with the needs for thyroxine replacement determined by treatment. Pituitary microadenoma can be managed medically, but surgery or radiation therapy may be indicated for larger tumors or those refractory to medical management. Ovarian insufficiency can be treated with either CHC or replacement-dose therapy depending on the patient’s need for contraception. In patients with chronic anovulation, cyclic hormonal contraception can restore menstrual bleeding any progestin therapy can reduce the long term risks of unopposed estrogen, and clomiphene citrate can help with ovulation for patients desiring fertility. Hysteroscopic resection for the treatment of Asherman’s syndrome can restore the menstrual cycle.
- Practice Committee of American Society for Reproductive Medicine. Current evaluation of amenorrhea. Fertil Steril. 2008 Nov;90(5 Suppl):S219-25. doi: 10.1016/j.fertnstert.2008.08.038.
- American College of Obstetricians and Gynecologists. Guidelines for Women’s Health Care: A resource manual. Fourth Edition. Available through ACOG Pages 567-573. 2014.
- Eunice Kennedy Shriver National Institute of Child Health and Human Development. Amenorrhea: Treatment. Available at https://www.nichd.nih.gov/health/topics/amenorrhea/conditioninfo/treatments Retrieved January 2022
Initial approval 2/2015; Revised 5/2017; Reaffirmed November 2018; Reaffirmed July 2020; Revised January 2022
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