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Introduction
Amenorrhea is the absence of menstruation. It can be the result of transient, intermittent, or permanent conditions. Further classification divides amenorrhea into two distinct subsets, primary and secondary amenorrhea. Primary amenorrhea is used to describe the absence of menses by age fifteen in the presence of secondary sexual characteristics. It can also be used to describe those patients who exhibit the absence of both menses and secondary sexual characteristics by age 12–13.[1] Secondary amenorrhea refers to the cessation of menses for more than three cycles or six months in women who have undergone menarche. The goal of treatment in primary amenorrhea is restoration of normal growth and development. In secondary amenorrhea, the goal may be focused on restoring fertility.
Approximately 3%–4% of reproductive aged women, not including those who are pregnant or breastfeeding, are diagnosed with amenorrhea. Of the cases of primary amenorrhea, 40% are the result of endocrine factors and the remaining 60% are attributed to abnormalities of development.[2] The most common cause of secondary amenorrhea is pregnancy.
For the purpose of diagnosing and treating amenorrhea, attempting to distinguish between the historical definition of primary and secondary amenorrhea may be misleading. Practically, the workup of amenorrhea should be approached by level of menstrual cycle control. The basic levels of control are the hypothalamic-pituitary axis, ovary, uterus, and vagina. Workup of the patient with primary amenorrhea includes all the causes linked to secondary amenorrhea; diagnoses lined mainly with primary amenorrhea are listed in Table 15-1.
Normal menstrual cycle
In order to completely understand amenorrhea along with its causes and treatments, knowledge of the normal menstrual cycle is essential. There are many levels of control of the menstrual cycle and a problem at any level can lead to amenorrhea. The cascade of regulation of menstrual function begins with environmental stimuli that act on the central nervous system (CNS). In turn, the hypothalamus secretes gonadotropin-releasing hormone (GnRH) in a pulsatile manner. The GnRH released by the hypothalamus then exerts an effect on the anterior pituitary to cause release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). FSH and LH exert end organ effect on ovarian follicular development and regulation of estrogen and progesterone production. The uterine lining changes in response to ovarian estrogen and progesterone production. This ultimately results in menses.
Causes of amenorrhea
Hypothalamic
Dysfunction of the hypothalamus is a common cause of secondary amenorrhea but can also cause primary amenorrhea. Menstrual abnormalities resulting from hypothalamic causes can be mild leading to luteal phase dysfunction, moderate resulting in disorders of follicle development and anovulation or severe resulting in hypothalamic amenorrhea. Hypothalamic amenorrhea is commonly associated with excessive physical activity, nutritional disturbances, or emotional and mental stressors.
Other causes of hypothalamic dysfunction leading to abnormalities of the menstrual cycle include eating disorders such as anorexia and bulimia, excessive exercise, congenital GnRH deficiency (Kallmann’s syndrome), and rarely, mutations in the GnRH receptor.
Hypothalmic amenorrhea is a diagnosis made by the exclusion of other causes of hypogonadotrophic-hypogonadaism (diminished function of gonads due to suboptimal secretion of the gonadotropins FSH and LH). Hypothalamic amenorrhea is characterized by low to normal serum FSH levels in the setting of low estrogen levels. These findings occur in the absence of any pituitary causes. Most women with hypothalamic amenorrhea have abnormal patterns of GnRH secretion that cause abnormalities in pituitary gonadotropin release and subsequent menstrual disturbances.[2]
Treatment of amenorrhea associated with hypothalamic dysfunction is often multifactorial and dependent upon the cause. Those who suffer from an eating disorder frequently require intense multidisciplinary treatment with a dietician, physician, and mental health-care provider in order to address issues with nutrition, electrolyte abnormalities, osteoporosis, and intensive cognitive behavioral therapy.[3] Oral contraceptives are seldom useful in the treatment of patients with amenorrhea resulting from an eating disorder. Physiologic hormone supplementation or oral contraceptives are an option for those with exercise-induced amenorrhea and can play a role in preserving bone health and the prevention of osteoporosis. Ovulation induction may ultimately be required to help these patients achieve pregnancy.[4] All patients with hypothalamic amenorrhea should be on calcium supplementation for bone health. Finally, patients with congenital GnRH deficiency can be treated with exogenous gonadotropins.
Pituitary
Many conditions of the anterior pituitary can result in amenorrhea. Tumors are the most common pituitary cause and of these, benign pituitary adenomas account for approximately 90% of all pituitary tumors. There are multiple different types of benign pituitary adenomas, each named for their cell type. The most common of these is prolactinoma. Among the other less common types of adenomas are thyrotroph, somatotroph, corticotroph, and gonadotroph. Malignant tumors of the pituitary are rare. Other non-hormone-secreting tumors that can affect the anterior pituitary and subsequently lead to amenorrhea include meningiomas, craniopharyngiomas, gliomas, chordomas, and metastatic tumors. In addition to neoplasms, other systemic and localized entities can cause pituitary dysfunction. These include, tuberculosis, sarcoidosis, cyts, and fatty deposits. These can all lead to compressive damage of the pituitary. Finally, infiltration of the pituitary by lymphocytes, (hemochromatosis), radiation, surgical damage, or infarction (Sheehan’s syndrome) can compromise pituitary function.[2]
Diagnosis of pituitary abnormalities is typically made with a combination of lab work and imaging studies such as MRI. For the purpose of this chapter, the discussion of diagnosis and treatment will focus primarily on prolactinoma. Patients with prolactin-secreting adenoma can present with a variety of complaints including headache, amenorrhea, visual changes, and galactorrhea.[5] Functional adenomas cause elevated prolactin levels. Patients with significantly elevated prolactin levels, greater than 100 ng/mL, should undergo an MRI to assess for macro or microadenoma.[6] It should be noted that modest elevations in prolactin levels also occur as the result of stress, nipple stimulation, sex, and sleep. MRI should also be obtained in patients who are amenorrheic with normal prolactin levels if they have headaches, visual disturbances, or any other CNS symptoms suggestive of mass lesion.
Prolactin causes amenorrhea by suppressing GnRH secretion. Negative feedback from hypothalamic dopamine controls prolactin release. Therefore, first line medical treatment of amenorrhea caused by prolactin-secreting adenoma is often by administration of a dopamine agonist.[8] The two most commonly used are bromocriptine and cabergoline. Nonfunctional adenomas can result in amenorrhea by mass effect and compression on the pituitary stalk. In these patients, transphenoidal resection is the treatment of choice. Resection is also used in functional adenomas that failure conservative medical therapy. Radiation therapy can be used in cases that are refractory to medical and surgical therapy.
Ovarian disorders
Among the most common causes of amenorrhea are disorders of the ovary. They are responsible for many cases of both primary and secondary amenorrhea. Ovarian dysfunction can have many causes including polycystic ovary syndrome (PCOS), obesity, thyroid disease, chronic anovulation, and prolactin-driven processes. In addition, disorders that result in ovarian failure also cause amenorrhea and will be the primary focus of the discussion of ovarian disorders presented in this chapter.
Ovarian failure results when scant or no follicles are present that can produce estradiol in response to pituitary stimulation with gonadotropins. The occurrence of amenorrhea will be determined by the time in one’s life when ovarian follicles are depleted. This can occur at any point in an individual’s life, from embryonic development to menopause.
Gonadal dysgenesis
Gonadal dysgenesis is one of the most common causes of primary amenorrhea, accounting for approximately 30%–40% of cases.[2] It is characterized by incomplete or defective gonad formation. The cause can either arise from problems with the structure or number of chromosomes. The most common cause of gonadal dysgenesis is Turner’s syndrome.
Turner’s syndrome
Turner’s syndrome is usually the result of a 45, XO karyotype.[7] Other causes may include structural problems with the X chromosome. Turner’s syndrome may also be expressed through varying degrees when only some of the body’s cells are affected. This is known as mosaicism.[8] The typical Turner’s syndrome phenotype is that of short stature, webbed neck, absence of sexual development, low set ears, widely spaced nipples, short fourth metacarpels, posterior hairline, and increased carrying angle at the elbow. In addition to their specific phenotypical appearance, patients with Turner’s syndrome present clinically with primary amenorrhea and absent secondary sex characteristics. They also exhibit poor growth during childhood. Once the diagnosis of Turner’s syndrome is made, the patient should be routinely monitored for the development of cardiac conditions, thyroid abnormalities, renal abnormalities, and other disorders including celiac disease and diabetes.[2]
Other forms of gonadal dysgenesis exist and include Swyer syndrome 46, XY and 46, XX gonadal dysgenesis.
Premature ovarian failure
Premature ovarian failure usually refers to amenorrhea that occurs before the age of 40. It has many causes and the patients exhibit a variety of phenotypes. These patients usually experience a hypergonadotrophic-hypogonadal state. Typically, premature ovarian failure occurs after onset of menarche but it can also occur before menarche as well. Patients with ovarian failure may have episodes of intermittent ovarian function.[9] Ovarian failure can have multiple causes including chromosomal abnormalities, fragile X mutations, radiation therapy, chemotherapy, autoimmune disorders, and galactosemia. Premature ovarian failure results from accelerated follicular atresia or disorders in follicular development. In most patients, a single cause is never identified.[10]
The diagnosis of premature ovarian failure can be made by demonstration of a low estradiol level in the setting of consistently elevated FSH levels.
Treatment of ovarian failure should include appropriate psychological and emotional support in addition to management of any associated autoimmune disease, hormone therapy, and fertility issues. Patients affected by premature ovarian failure are at significant risk for depression and often describe feeling a sense of loss. Counseling and support groups should be offered.[11, 12] Hormone replacement with estrogen and progestin or oral contraceptive pills (OCPs) is important to promote bone health and prevent vasomotor symptoms in addition to vaginal atrophy and should continue until approximately age 50, when most women begin to experience a decline in ovarian function.[10, 13] Calcium and vitamin supplementation are also important for bone health.[14] Those patients interested in fertility can explore the option of in vitro fertilization (IVF) with donor oocytes.
Uterine and genital outflow tract disorders
Disorders of the genital outflow track are the result of failure of vertical fusion or failure of müllerian duct development during embryonic development. They most often present during the time of puberty with primary amenorrhea. There is a group of outflow tract disorders where the patients usually present with secondary amenorrhea as the result of damage to the cervix or endometrium with subsequent scar tissue formation from trauma or infection. These patients usually have developmentally normal genital tract structures.
Imperforate hymen
Imperforate hymen is a congenital condition that causes obstruction of the vaginal opening. It occurs when there is failure of the hymen to perforate during development in utero. This happens when the sinovaginal bulbs fail to canalize along with the rest of the vagina.[2] Patients usually present during adolescence with complaints of primary amenorrhea and cyclic pelvic and abdominal pain sometimes with accompanying urinary complaints secondary to accumulation of obstructed menstrual flow. On physical exam, these patients exhibit normal secondary sexual development. The vagina may be distended, and there is no obvious vaginal opening. Instead, a blue, bulging perineal membrane, caused by hematocolpos, is usually noted.
Treatment consists of surgical resection of the hymen to relieve the obstruction and allow for the menstrual fluid to drain. This should be done as soon as possible after diagnosis to decrease the chance of infertility related to reproductive tract scar tissue formation from inflammation caused by accumulated menstrual fluid. Surgical treatment is accomplished by making a cruciate incision in the hymen and subsequent excision of the central portion of tissue. Topical estrogen cream is often applied for a brief period of time to promote adequate healing of the vaginal tissue.
Imperforate hymen most often occurs as a sporadic event but can rarely be found in multiple members of the same family.[2]
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