Approach Considerations
Treatment is determined by the etiology of the amenorrhea and the desires of the patient. Ideally, treatment should be directed at correcting the underlying pathology. In the case of outflow tract abnormalities (eg, imperforate hymen), surgery may be indicated. In other cases, correcting the underlying pathology should restore normal ovarian endocrine function and prevent the development of osteoporosis.
Dopamine agonists are effective in treating hyperprolactinemia. In most cases, this treatment restores normal ovarian endocrine function and ovulation.
Hormone replacement therapy is required to achieve peak bone density in patients whose underlying pathology cannot be reversed to restore normal endocrine function. In conditions leading to estrogen deficiency, hormone replacement therapy is required to maintain bone density, and it may have other possible health benefits in patients whose underlying pathology cannot be reversed to restore normal endocrine function.
Women with evidence of hyperandrogenism and disordered menses have many other medical issues that must be addressed (eg, PCOS with associated diabetes and hypertension).
Gonadotropin therapy or the use of pulsatile gonadotropin-releasing hormone (GnRH) therapy may be required to induce ovulation in patients with infertility whose underlying pathology cannot be reversed. As of 2014, medicinal GnRH for pulsatile SQ pump administration was not available in the United States.
Other than pregnancy, constitutional delay, anovulation, and chronic illness, most other disorders that cause amenorrhea may require referral to a subspecialist for treatment. Many of the treatment methods require surgery or specific therapies. For the adolescent with constitutional delay and anovulation, the goal should be the restoration of ovulatory cycles. If ovulatory cycles are not spontaneously restored, estrogen-progestin therapy is indicated.
Osteoporosis prevention
Evidence is mounting that loss of menstrual regularity, especially if related to hypogonadotropic hypogonadism, is a risk factor for later development of osteoporosis and hip fractures. Patients and clinicians need to view the ovary as an important endocrine organ that helps to maintain healthy bones. Excessive delay in the evaluation and treatment of disordered menses can contribute to osteoporosis. At some point, failure to promptly evaluate for the presence of ovarian insufficiency could become a medicolegal pitfall.
Many patients are deficient in their body stores of vitamin D, reflected by a serum 25-hydroxy vitamin D level less than 30 nmol/L. If this is the case, patients should be treated for 8-12 weeks with high-dose vitamin D, 50,000 IU/week, for repletion. Once the 25-OH-D level is greater than 30 nmol/L, 1000 IU/d of vitamin D may be instituted.
Emotional health concerns
Primary amenorrhea and the potential for impaired fertility affect the emotional health of the adolescent and her family. Adolescence encompasses a broad spectrum of emotional maturity, which needs to be considered in assessment and treatment. For the adolescent girl, a reproductive disorder impacts her developing sense of self, body-image, and sexuality, which, in turn, can affect her self-esteem and relationships with others.
Because of the sexual nature of a reproductive disorder, feelings of embarrassment, inadequacy, or protectiveness can make it difficult for families. Families should be encouraged to be open and honest regarding the condition and discouraged from keeping the diagnosis a secret.
The family is an emotional unit and a family systems approach to deal with health issues is most appropriate. Parents must first deal with their own feelings about the condition before they can help their child. They must also be provided with tools to build an ongoing conversation with their child. Physicians need to be culturally sensitive because in some cultures a woman's identity in adulthood as a mother could play a crucial role in her life. The objective is to help the adolescent girl formulate positive self-esteem and body image, despite impaired fertility.
Treatment of Common Causes
In the overall management of females with amenorrhea, remembering the most likely causes that may present in an outpatient setting is helpful. The following information is a guide to managing the most common causes.
Although the differential diagnosis for amenorrhea is broad, most patients who present in an outpatient setting with primary or secondary amenorrhea have 1 of 5 common medical problems: PCOS, hypothalamic amenorrhea, hyperprolactinemia, ovarian failure, or thyroid dysfunction.
For women with strictly primary amenorrhea, müllerian abnormalities are second to premature ovarian failure as the most likely diagnosis. The management options of the most common causative processes are below. Unusual and uncommon causative factors of amenorrhea, such as sarcoidosis, require referral and evaluation by a specialist and are not reviewed below.
Polycystic ovarian syndrome
PCOS is characterized by oligomenorrhea or amenorrhea, an excess androgen hormone environment (either clinically or biochemically detected), and polycystic-appearing ovaries on ultrasonography. [58] A high body mass index (BMI) and insulin resistance also play an important role in the pathogenesis of PCO syndrome. Women with PCO syndrome have lifelong increased risks of developing adult-onset diabetes mellitus, hypertension, lipid disorders, hypothyroidism, and endometrial cancer. [59]
If pregnancy is not desired, monthly withdrawal bleeding should be induced. Both cyclic progesterone (10-12 days per month) and oral contraceptives can accomplish monthly withdrawal bleeding; however, oral contraceptives use different mechanisms to control other aspects of PCOS. Oral contraceptives decrease LH secretion, leading to lower androgen production and improvement in acne and hirsutism. Oral contraceptives atrophy the endometrial lining, decreasing the risk of endometrial hyperplasia and endometrial cancer.
Metformin is presently offered to improve ovulation. [60] There is no evidence that metformin improves live birth rates, although some studies have shown it to be associated with improved clinical pregnancy. [61] Further research is needed to determine whether metformin should be used for the prevention of the long-term development of adult-onset diabetes mellitus, cardiovascular disease, and lipid disorders. [62] Patients should be strongly encouraged to maintain a weight-to-height ratio within the reference range and to regularly exercise because both are first-line therapies used to control PCO syndrome. [63]
Hypothalamic amenorrhea
Hypothalamic amenorrhea is most common in patients who exercise to excess and/or have eating disorders, caloric restriction, and psychogenic stress. Hypothalamic amenorrhea is best treated using behavioral modification and a multidisciplinary team approach, depending on the root cause.
An interdisciplinary team approach that involves nutritionists, clinicians, counselors, and family members is most effective. [64] After correcting the behavior that leads to hypothalamic amenorrhea, most women resume normal pulsatile release of GnRH and subsequent normal menstrual cycling. [64]
Women with severe anorexia nervosa may not resume normal menstrual cycling after weight gain. [65, 66] A BMI of less than 15 kg/m2 requires immediate intervention by an eating disorder specialist. Hospitalization may be indicated. This group of women may need hormone replacement and monitoring of bone density. [67] Weight gain may be the most important factor in bone recovery. [68] Gonadotropin therapy may be needed for conception.
Patients with hypothalamic amenorrhea caused by excessive exercise may refuse to correct or change their behavior. This is especially true for professional, competitive college, or elite athletes participating in "leanness" sports. Although controversial, consideration should be given to correcting their low estradiol (E2) level by prescribing oral contraceptives. [69, 70] Many athletes may request to use oral contraceptives continuously to limit or avoid menses. [71]
Functional hypothalamic amenorrhea due to stress is a diagnosis of exclusion. An occult eating disorder and caloric restriction must be ruled out as a compounding factor. [72] Behavioral modification is the first-line treatment. Although controversial, consideration should be given to correcting the low E2 by prescribing oral contraceptives. [69, 70] If oral contraceptive therapy is initiated, it can be intermittently stopped to determine if the GnRH pump has regained pulsatile function. An increase in BMI is associated with the best long-term recovery. [73]
Hyperprolactinemia
Hyperprolactinemia with a normal TSH level requires an MRI to determine the presence of a tumor, microadenomas or macroadenomas, and other organic CNS lesions. Microadenomas and prolactinomas less than 1 cm in diameter are slow growing and are mostly found in the premenopausal population. Treatment should be considered to reverse hypoestrogenemic symptomatology, improve fertility, and/or eliminate bothersome galactorrhea.
Symptomatic hyperprolactinemia from a pituitary disorder should first be treated by dopamine agonists such as bromocriptine (Parlodel) and cabergoline (Dostinex). Pergolide has been associated with heart value abnormalities; it should not be used and was withdrawn from the US market in March, 2007.
Macroadenomas may also be treated with dopamine agonists initially. Occasionally, larger lesions fail to respond to medical therapy or present with acute vision changes. Referral with subsequent surgery or radiation is indicated. The recurrence rate after surgery can be as high as 50%. Patients with hyperprolactinemia associated with medications (eg, antipsychotics, metoclopramide) should consider discontinuation or switching of the causative medication if medically possible.
Some pituitary and hypothalamic tumors may require surgery and, in some cases, radiation therapy.
Hypergonadotropic hypogonadism
In a patient who fails to enter puberty, hypergonadotropic hypogonadism (gonadal failure) is most often associated with Turner syndrome or other gonadal dysgenesis disorders, such as Swyer syndrome. An X chromosome deletion (Turner syndrome), ring formation, partial deletion, or translocation is the most common diagnosis in this setting. A karyotype is required to detect any Y-containing chromatin.
Patients who have a Y chromosome have a 25% chance of developing a gonadal tumor. The gonads should immediately be removed. [74] These gonads are nonfunctioning; therefore adult height and bone mass are not affected by their presence. Hormone replacement therapy (HRT) should be offered to allow completion of puberty in a controlled fashion, similar to her peers, and should facilitate maximum bone density development. [75] Turner syndrome is associated with ear and renal disease; evaluation of these organ systems is indicated.
Premature ovarian failure after puberty occurs in 1% of adult women. Treatment should be decided on an individual basis. Some patients may require estrogen replacement therapy (ERT) for hot flashes and other symptomatic menopausal issues. Long-term E2 use should be individualized. [76] A small number of women with repetitively elevated FSH levels may have a resumption of cycles for a short period before proceeding to complete menopause. No medications or therapies have been found to induce normal cycling; its occurrence is sporadic, spontaneous, and not inducible.
Ovarian failure that occurs in patients younger than 30 years requires a karyotype to detect any Y chromatin and an evaluation of the fragile X area of the X chromosome. A strong family history of premature ovarian failure may require a referral for evaluation of GALT and autoimmune regulatory gene (AIRE) mutations and other autosomal disorders. [77] Documentation of a fragile X area requires other family members to receive genetic counseling. With a normal karyotype, evaluation of other autoimmune disease should be considered, including antithyroid and antiadrenal antibody titers. [78] Bone density should be monitored and treated appropriately using hormonal or nonhormonal therapy.
Thyroid dysfunction
Patients with hypothyroidism and hyperthyroidism should undergo a standard work-up and therapy. Treatment in most cases is straightforward.
Diet and Activity
Women with findings suggestive of an eating disorder should be evaluated by a multidisciplinary team with special expertise in these disorders. Nutritional counseling alone is inadequate therapy for these women.
In some cases, nutritional deficiencies induced by dieting and exercise can cause amenorrhea even in the absence of a psychiatric disorder. Strict fat restriction often plays a role. Frequently, simply explaining the need to balance energy expenditure with energy intake resolves the problem. In this situation, nutritional counseling may be all that is required.
More than 8 hours of vigorous exercise a week may cause amenorrhea. As noted above, in some cases this resolves with appropriate adjustment of the diet.
A study by Ackerman et al that included 121 athletes with oligo-amenorrhea reported greater improvement over 12 months in bone mineral density with transdermal estradiol when compared to combined oral contraceptives. [79]
Consultations
The causes of menstrual cycle disturbance leading to the development of amenorrhea are so diverse that in some complex cases, the situation is best addressed by a multidisciplinary team. For example, a patient with complete androgen resistance would benefit from the involvement of experts in endocrinology, human genetics, psychiatry, and reproductive surgery.
With hereditary causes of amenorrhea, such as Kallmann syndrome, a geneticist's expertise can be helpful in counseling patients and their families regarding the disorder
In cases of pituitary/hypothalamic tumor, other endocrine disorders (eg, central hypothyroidism, central adrenal insufficiency) may be involved. Generally, the expertise of a medical endocrinologist is required to assist in the treatment of patients who require neurosurgery to treat the underlying condition. In cases of hyperthyroidism or Cushing syndrome, the expertise of a medical endocrinologist is required to treat the underlying pathology.
Cases of major depression, anorexia nervosa, bulimia nervosa, or other major psychiatric disorders warrant consultation with a psychiatrist.
In some unusual cases, such as with vaginal agenesis, consult with a reproductive surgeon with extensive experience in the specific disorder.
In many cases, exercise-induced amenorrhea is due to an imbalance in energy intake and expenditure. Nutritional counseling to increase energy intake without reducing exercise is a means of reversing the underlying pathology. Women who are underweight or who appear to have nutritional deficiencies should receive nutritional counseling and can be referred to a multidisciplinary team specializing in eating disorders.
In certain cases in which an underlying chronic disease process is present, the insights of an internist may be needed.
Long-Term Monitoring
The need for ongoing care is defined by the mechanism disrupting the menstrual cycle and the patient's desires.
See patients with primary ovarian insufficiency annually to monitor their ovarian hormone replacement and to detect the development of associated conditions that may be related to the original pathogenic mechanism that led to the disruption of the menstrual cycle.
See patient every 3-6 months for the first 2 years to monitor ovarian hormone replacement and to detect the development of associated conditions that may be related to the original pathogenic mechanism that led to the disruption of the menstrual cycle.
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Hypothalamus, pituitary and ovaries form a functional endocrine axis, known as HPO axis with hormonal regulations and feedback loops.
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Primary amenorrhea flowchart.
