Secondary amenorrhea is defined as the absence of periods for a length of time equivalent to a total of at least three of the previous cycle intervals or 6 months of amenorrhea. The initial work up of secondary amenorrhea after excluding a pregnancy begins with a prolactin level, thyroid stimulating hormone (TSH) level and a progesterone challenge test. Additionally, FSH, LH, estradiol levels are generally measured at the time of initial blood draw and progesterone challenge test may not be needed. Secondary amenorrhea can be investigated under four categories: Uterine factors, ovarian failure, pituitary disorders and hypothalamic causes.
Compartment I: Uterus
Cessation of menses can be secondary to adhesion formation (scarring) in the endometrial cavity (Intrauterine Adhesions [IUA] or formerly known as Asherman’s syndrome). This is most commonly observed in patients with a history of postpartum bleeding who underwent a curettage procedure. It can also present following any type of uterine surgery such as a termination of pregnancy or D&C, cesarean section, myomectomy (removal of myomas/fibroids) and uterine corrective surgery (metroplasty). Rare causes include tuberculosis of the pelvis, uterine infections and pelvic inflammatory disease. The treatment is hysteroscopic lysis of adhesions. If the adhesions are severe, the procedure may need to be repeated to achieve a normal uterine cavity.
Compartment II: Ovary
Premature ovarian failure (POF) typically would present with secondary amenorrhea and can be diagnosed by the presence of low estradiol and high FSH levels. The exact cause is unknown but resumption of ovarian function can occur in up to 10% of patients. Birth control pills are commonly used in patients with POF to prevent bone loss, maintain estrogenic state in the body and allow the possibility of spontaneous recovery. Most patients do not resume ovarian function and can choose to utilize donor eggs to become pregnant.
A chromosome analysis is recommended in POF patients under age 30. This is due to the fact that an abnormality in the chromosome structure might cause premature cessation of menses in this group of patients.
Compartment III: Pituitary Gland
The pituitary gland secretes hormones such as prolactin, TSH, FSH, LH, growth hormone and some others. Pituitary tumors can secrete excessive hormones, occupy space and disrupt physiological balance of the reproductive hormones. This disruption can cause cessation of menses and require evaluation. Extrapituitary tumors (craniopharyngiomas, meningiomas) can also result in a similar clinical picture and additionally affect vision. Non-neoplastic masses such as cysts, tuberculosis, sarcoidosis, arterial aneurysms and autoimmune diseases can cause similar symptoms. The treatment of pituitary tumors can be medical or surgical.
The most common pituitary tumor is a prolactin hormone-secreting tumor; elevated prolactin levels may inhibit ovulation. This is due to the inhibition of gonadotropin releasing hormone (GnRH), secondary to elevated levels of prolactin in the circulation. Decreased levels of GnRH translate into low levels of FSH and LH as well as estradiol and anovulation, which presents as secondary amenorrhea. Treatment of hyperprolactinemia can be done using one of these two drugs available today: bromocriptine or cabergoline.
Another condition that can result in cessation of menses is called Sheehan’s syndrome. This is a result of infarction of the gland and can be secondary to excessive bleeding postpartum. Patients usually present with lactational failure and loss of pubic/axillary hair. Most commonly, there is a deficiency in growth hormone and gonadotropins (FSH, LH). These patients require hormone replacement for maintenance of estrogenic state and gonadotropin injections to become pregnant.
Polycystic ovary syndrome (PCOS) is generally considered a pituitary cause of anovulation and secondary amenorrhea. Whereas the symptoms may be complex and quite variable among individuals, the presence of polycystic appearing ovaries, anovulation and evidence of increased hair growth or high androgen levels in the blood are the most common findings. Ovulation induction is the treatment in PCOS patients if fertility is desired. Birth control pills, monthly progesterone and/or metformin can be considered in patients who do not desire fertility and need to regulate menstrual or metabolic abnormalities. In cases of hirsutism (excessive hair growth), anti-androgenic medications can be utilized. Metformin can be used for ovulation induction alone or in combination with Clomid or injectible gonadotropins (FSH and LH).
Compartment IV: Hypothalamus
a. Hypothalamic amenorrhea:
Hypothalamic amenorrhea is generally due to a deficiency in the pulsatile secretion of the GnRH hormone. It’s commonly diagnosed by exclusion of a pituitary cause or lesion. It is frequently associated with stress and a high proportion of women who are underweight have a hypothalamic component. The degree of suppression of GnRH determines the severity (Mild → inadequate luteal phase; Moderate → anovulation and menstrual irregularities; Profound → hypothalamic amenorrhea).
Clinical characteristics include low or normal gonadotropins, normal prolactin and thyroid levels, normal imaging of the pituitary area and failure to have withdrawal bleeding with progesterone. Spontaneous recovery has been reported in a good proportion of patients with hypothalamic amenorrhea and return of menstrual function can be observed in patients with eating disorders. Ovulation induction with gonadotropins is an excellent option for patients who desire fertility, but does not stimulate the return of normal menstrual function.
b. Weight loss, anorexia and bulimia:
Although obesity is associated with amenorrhea, it is not associated with hypothalamic type of amenorrhea. On the other hand, weight loss can be associated with amenorrhea and is related to hypothalamic factors.
Anorexia nervosa is characterized by relentless dieting in an obsessive pursuit of thinness often leading to marked emaciation, cold intolerance and death. It can be present in 1% of women and the age of onset is 10-30. The special attitudes are denial, distorted body image, unusual hoarding and handling of food. Weight loss of 25% or weight 15% below the normal for age and height is diagnostic, and mortality from this disorder can be between 5-15%.
Symptoms and findings include lanugo, bradycardia (slow heart beat), low blood pressure (hypotension), overactivity, episodes of overeating and vomiting, amenorrhea and constipation. It’s typically observed in an individual who has been under undue stress and perceives a need to be “perfect”. Pubertal weight gain can initiate true anorexia and excessive physical activity often is the earliest sign. The abuse of diuretics and laxatives can occur and cause low potassium levels in the blood, which can have serious cardiac effects and complications.
Bulimia nervosa is also present in 1-2% of women in the general population and in half of anorexia nervosa patients. The eating disorder bulimia nervosa is characterized by binge eating, self-induced vomiting, and intermittent episodes of calorie restriction, but these patients do not lose weight to the point of emaciation. There is a high incidence of depressive symptoms and a significant dysfunction of the hypothalamic system with abnormal patterns of appetite, thirst, water conservation, sleep and temperature. When FSH and LH hormone levels are low, cortisol is elevated and prolactin and thyroid hormone levels are normal.
The treatment of these disorders includes psychoanalysis, psychotherapy, family therapy, force-feeding, behavioral modification, anti-depressant therapy and generally a combination of these approaches. Hypothalamic function may return back to normal with weight gain and therapy, and resumption of menses can be expected.
A strong correlation between exercise and amenorrhea exists because as many as two-thirds of runners have menstrual cycles with short luteal phases or that are anovulatory. Intense athletic training can delay menses by 3 years and cause primary amenorrhea as well. The two major influences are the critical level of body fat and the effect of stress itself. Changes with acute exercise include low FSH, LH, thyroid hormone levels and elevated levels of prolactin, growth hormone and testosterone. Patients can respond to criticism with regard to body image, and progression to true anorexia nervosa can occur. Simple weight gain can reverse amenorrhea but hormone therapy is generally recommended with dietary changes to restore normal bone density.
Dr. Bayrak recommends a multi-disciplinary approach in cases of eating disorders and a detailed evaluation before fertility treatment is initiated. In most cases, a healthy pregnancy can be accomplished with treatment.