2/1/2016 A. Nyuyen, MD

Mentor: Gavin Jacobson, MD

Editor: Paul Hillard, MD.  Approved 11/3/15

Combined hormonal contraceptives (CHC) including combined oral contraceptives (COC) inhibit ovulation through hypothalamic-pituitary inhibition of gonadotropin secretion.  Historically, it was believed that this suppression could persist for months after discontinuation of COC, leading to the syndrome of “post-pill amenorrhea.” While the name implies pill use, the issues are the same after cessation of other combined hormonal methods (contraceptive patch and ring). This syndrome was described as amenorrhea for more than one year after cessation of COC, with an approximately 1% frequency, similar to women not taking COC. When stopping cyclic COC, median duration from withdrawal bleeding to first menses is 32 days (range 15-82 days), and 98.9% have clinical evidence of normal hypothalamic-pituitary function within 90 days. Return to fertility after the completion of COC is generally similar to that observed with other common contraceptive methods, 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.

Given the lack of evidence supporting a cause-and-effect relationship between CHC and subsequent amenorrhea, women with post-pill amenorrhea should undergo the same evaluation as any woman with secondary amenorrhea, which is 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 (weight loss/anorexia); chronic anovulation (e.g. PCOS); hypothyroidism; pituitary (tumor, empty sella); hyperprolactinemia; and gonadal failure. Less common causes include anatomic

(Asherman’s syndrome), ovarian tumors, and non-classical 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 women younger than 40 years of age should prompt an investigation for gonadal failure, including karyotype if younger than 30 years of age. Low or normal FSH levels would suggest further evaluation for conditions causing chronic anovulation. Laboratory evaluations (e.g. testosterone and 17-Hydroxyprogesterone) for chronic anovulation can reveal ovarian tumor or non-classic CAH. History will generally identify potential risk factors for Asherman’s that would prompt further imaging such as hysteroscopy.

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 after treatment. Pituitary tumor can be managed medically first and if that does not work, surgery or radiation therapy are indicated. Gonadal failure can be treated with either CHC or hormone therapy. CHC is the standard treatment for chronic anovulation while clomiphene citrate can help with ovulation for patients desiring fertility. Hysteroscopic resection for the treatment of Asherman’s syndrome can restore the menstrual cycle.

Further Reading:

Current evaluation of amenorrhea. The Practice Committee of the American Society for

Reproductive Medicine. Fertil Steril 2008;90:S219-25.

Guidelines for Women’s Health Care: A resource manual. Fourth Edition. American College of Obstetricians and Gynecologists. Pages 567-573. 2014.

Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Amenorrhea: Treatment. Available at http://www.nichd.nih.gov/health/topics/amenorrhea/conditioninfo/Pages/treatments.aspx.

Retrieved August 21, 2015

Robert A. Hatcher MD, MPH

Emeritus Professor of Gynecology and Obstetrics

Emory University School of Medicine

Atlanta, GA