Secondary Amenorrhea

Secondary amenorrhea is a symptomatic condition of an underlying etiology defined as the absence of menses for ≥3 cycle lengths in a person with previously regular menstrual cycles or the absence of menses for ≥6 months in a person with any previously established but irregular menses. Secondary amenorrhea occurs due to abnormalities at various points in the "menstrual pathway," including the hypothalamus, pituitary, ovaries, endometrium, cervix, and vagina. Thinking through the pathway systematically will provide clinicians with an effective framework in which to evaluate the patient with secondary amenorrhea. The menstrual cycle is orchestrated by the hypothalamic-pituitary-ovarian (HPO) axis. The cycle begins in the hypothalamus with the pulsatile secretion of gonadotropin-releasing hormone (GnRH). A specific pulsatile pattern of GnRH stimulates the anterior pituitary gland to secrete follicle-stimulating hormone (FSH). The FSH then stimulates the development of a cohort of follicles within the ovaries. Each developing follicle grows to contain several layers of stromal cells surrounding a single oocyte. Under the stimulation of FSH, these follicles mature, and the stromal cells begin secreting estrogen. Estrogen stimulates the endometrium (ie, the inner lining of the uterus) to grow and thicken. Estrogen also provides feedback inhibition at the pituitary level, reducing FSH secretion. As the FSH levels decline, most developing follicles undergo atresia, leaving (usually) a single dominant follicle that can increase its number of FSH receptors, allowing it alone to continue its maturation process. As this dominant follicle nears the time of ovulation, estrogen (briefly and for poorly understood reasons) develops a stimulatory effect on the pituitary gland, resulting in a surge of luteinizing hormone (LH) from the anterior pituitary. This LH surge triggers ovulation in which the oocyte is released from the follicle, and the now-empty follicle transforms into a structure called the corpus luteum.  In the cycle's luteal phase, the corpus luteum secretes progesterone, which causes maturation and stabilization of the endometrium. Progesterone, the "pro-gestational hormone," is necessary for maintaining the endometrium throughout gestation. Without fertilization, the corpus luteum undergoes involution approximately 2 weeks after ovulation. Involution results in a rapid decline in progesterone and estrogen levels, and this hormonal withdrawal leads to endometrial shedding. The menstrual fluid then flows out of the uterus through the cervix and vagina. Low levels of gonadal hormones (ie, estrogen and progesterone) release the hypothalamus and pituitary from feedback inhibition and allow the GnRH pulse to restart, triggering a new cycle. The best way to approach secondary amenorrhea is first to consider the 3 physiologic causes of secondary amenorrhea (ie, pregnancy, lactation, and menopause) and then consider abnormalities that may affect each of the points in the primary menstrual pathway (eg, the hypothalamus, pituitary gland, ovary, endometrium, cervix, and vagina. Generally, this includes diseases and hormonal disturbances affecting HPO axis function, primary ovarian dysfunction, and anatomic or structural abnormalities involving the endometrium and outflow tract. By definition, though, patients with secondary amenorrhea have menstruated previously, indicating that ovarian tissue and a uterus were at least present and connected to a patent outflow tract at menarche. This knowledge eliminates some congenital structural causes of amenorrhea (eg, Müllerian agenesis) that present only with primary amenorrhea (ie, patients who have never menstruated).  Despite the numerous potential etiologies discussed in more detail below, nonphysiologic secondary amenorrhea is primarily caused by 1 of 5 conditions: 1. Functional hypothalamic amenorrhea . 2. Polycystic ovary syndrome . 3. Hyperprolactinemia. 4. Primary ovarian insufficiency . 5. Intrauterine adhesions . Therefore, in addition to always ruling out pregnancy, the initial history, exam, and laboratory assessment should focus on identifying these conditions while looking for signs and symptoms of less common etiologies. Management and prognosis are dependent on the etiology.