Amenorrhea

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Chapter 16 Amenorrhea

DEFINITIONS

In common medical usage, amenorrhea refers to the abnormal cessation of menses.1 Physiologic amenorrhea exists before puberty, during pregnancy and lactation, and after menopause. However, these physiologic causes are not included in the standard amenorrhea classifications.

Amenorrhea can be divided into two major groups based on presentation: primary or secondary amenorrhea (Table 16-1).2,3 Although many of the causes of primary and secondary amenorrhea are similar, the most likely causes, and thus the diagnostic approach, are distinct.

Table 16-1 Definitions of Primary and Secondary Amenorrhea

Secondary Amenorrhea

Secondary amenorrhea refers to cessation of menses after establishment of menstruation for reasons other than pregnancy, lactation, or menopause. By convention, the diagnosis is applied after menses have been absent for a length of time equivalent to at least 3 of the previous menstrual cycle intervals or 6 months.

The incidence of secondary amenorrhea not due to pregnancy, lactation, or menopause is approximately 4%.5,6 Although the list of causes for amenorrhea is quite extensive (Table 16-2), it appears that this list will continue to grow or be modified as more sophisticated genetic testing becomes available and the genetic understanding of human disease expands. The majority of patients with amenorrhea will have premature ovarian failure, hyperprolactinemia, hypothalamic amenorrhea, or polycystic ovary syndrome (PCOS).

Table 16-2 Classification of Amenorrhea, Both Primary and Secondary3

Classification

The most widely accepted classification of amenorrhea was published by the World Health Organization (WHO) and divides amenorrhea into three groups (Table 16-3).3 This WHO amenorrhea classification is designed to help the practicing clinician summarize the causes of amenorrhea to assist in evaluating the condition. Group I include individuals who lack endogenous estrogen production, in association with normal or low follicle-stimulating hormone (FSH) levels, and no evidence of hypothalamic-pituitary pathology or elevated prolactin levels. Group II is associated with evidence of estrogen production and normal levels of prolactin and FSH. Finally, Group III involves elevated serum FSH levels that indicate gonadal failure.7 Although amenorrhea can occur among patients with sexual ambiguity or virilization, it is rarely the cause for initial consultation.8

PRIMARY AMENORRHEA

The etiologies of primary amenorrhea are multiple and diverse (Tables 16-4 and 16-5). The four most common causes of primary amenorrhea have been reported to be the following:4

Table 16-4 Common Causes of Primary Amenorrhea

Category Frequency
Normal Secondary Sexual Development (∼1/3 of total)
Müllerian agenesis 10%
Androgen insensitivity 9%
Constitutional delay 8%
Outlet obstruction (e.g., vaginal septum, imperforate hymen) 3%
Absent Secondary Sexual Development (∼2/3 of total)
High FSH (gonadal dysgenesis)  
Abnormal karyotype (e.g., 46,XO, mosaic) 20%
46,XX 15%
46,XY 5%
Low FSH  
Hypothalamic disorders 8%
Constitutional delay 10%
Hyperandrogenic conditions (e.g., PCOS, CAH) 6%
Pituitary adenomas 5%

Adapted from Practice Committee of ASRM: Current evaluation of amenorrhea. Fertil Steril 82(Suppl 1):33-S39, 2004.

Other causes of primary amenorrhea, while less common, include outflow obstructions (e.g., imperforate hymen, transverse vaginal septum), androgen insensitivity syndrome, and inborn defects in gonadotropin secretion or response. Several of these are examined in this chapter; others are discussed in separate chapters.

Gonadal Dysgenesis

The term gonadal dysgenesis is used globally to refer to all forms of abnormal gonads, which can occur in individuals with normal karyotypes (46,XX; 46,XY) as well as a variety of abnormal or mosaic states, most commonly Turner’s syndrome (45,XO). The gonads are usually streaks of fibrous tissue.

General Principles of X Chromosome Genetic Disorders

Short stature is the result of a mutation of the SHOX gene (short stature homeobox-containing gene). The gene is located on the pseudoautosomal region of the X chromosome, and two normal copies are required for the development of normal stature.

Isolated deletions of portions of the X chromosome have also been reported. Deletions affecting Xp11 result in ovarian failure in about half of women. Deletions involving the q arm of the X chromosome also usually result in ovarian failure. Even in those who achieve normal menstruation, fertility is rare.

When the deletion on the X chromosome is more distal (Xp21 region), the phenotype is generally milder. However, secondary amenorrhea or infertility is common. Most women with Xp deletions are short, regardless of their ovarian function, and present with a Turner’s syndrome-like phenotype. The molecular mechanism responsible for ovarian failure in these cases is due to loss of a putative ovarian determinant gene necessary for ovarian development, increasing follicular atresia, but not to the extent of that observed in patients with Turner’s syndrome.

Translocations of the X chromosome, although extremely rare, may cause amenorrhea depending on the location of breakpoints. In a balanced X translocation one X chromosome is normal, and the other is an X autosome translocation chromosome. X inactivation is not usually random so that the normal X is usually inactivated. If the translocated chromosome were inactivated, the autosome would also be inactivated, making the karyotype lethal. Nearly all males and half of the females with X autosome translocations are sterile.10

Turner’s Syndrome

It is known that specific genes in the X chromosome are essential for normal functioning of the ovaries.11 It appears that both X chromosomes with normally functioning genes need to be present in the oocytes to prevent the formation of a streak gonad.

Turner’s syndrome (45,XO) is the most common cause of gonadal dysgenesis. It is usually caused by nondisjunction of the sex chromosomes and occurs in approximately 1 out of 2500 live births. In some cases, Turner’s syndrome occurs in patients with normal karyotypes (46,XX) when a genetic abnormality results in one of the X chromosomes not being fully functional.

The characteristic physical features common to females with Turner’s syndrome include short stature, somatic abnormalities (webbed neck, shield chest, increased angle at the elbow known as cubitus valgus, cardiovascular abnormalities), and prepubertal status associated with elevated gonadotropins.12 Patients with Turner’s syndrome require special attention to the autoimmune disorders and renal anomalies that are frequently found with the condition. All patients with Turner’s syndrome should seek expert cardiology consultation and screening, including chest X-ray and echocardiography, at the time of diagnosis. Annual cardiac examinations, including evaluation of blood pressure, and repeated screening at 3- to 5-year intervals if the initial screening reveals no abnormalities. When the cardiac echo is abnormal or the ascending aorta cannot be visualized, magnetic resonance imaging (MRI) of the chest should be performed in all patients.12

Due to the absence of one of the X chromosomes, these patients have streak gonads with complete lack of ovarian follicle development. The absence of sex hormone production from the ovary in early adolescence results in the absence of puberty and primary amenorrhea.

Patients with variations of the syndrome can present with some clinical features but not all of the characteristic physical findings. For this reason, Turner’s syndrome should be suspected in every adolescent with primary amenorrhea, sexual infantilism, and poor growth during the teenage years. If the serum FSH is elevated in such a patient, a karyotype should be obtained. Even if the FSH is normal, a karyotype should be obtained to rule out mosaicism in adolescents with poor growth after puberty (i.e., <5 feet tall).

Management of Gonadal Dysgenesis

Adolescents with gonadal dysgenesis will require hormone therapy to induce puberty and stimulate increased growth. Low-dose estrogen (0.25 to 0.3 mg/day) is used for the first year to reproduce normal pubertal development and to minimize the effect on epiphysis closure and therefore try to achieve a more acceptable final height. In some cases growth hormone is used as well to increase final adult height. After about 1 year of estrogen therapy, progesterone (medroxyprogesterone acetate, 5 mg/day, or other forms of progesterone) can be added during the last half of the month. The dose of estrogen is increased gradually so as to complete pubertal development over 2 or 3 years.

The final maintenance dose is usually 2 mg of estradiol valerate or 1.25 mg conjugated estrogens daily. The estrogen can be started earlier if growth hormone is used. If not, estrogen initiation can be delayed for a short time but no later than age 14 or 15. The use of ethinyl estradiol has been shown to increase hypertensive risk in Turner’s syndrome patients. Patients with Y chromosomes will require gonadectomy to avoid the risk of developing a malignancy.

Oocyte donation offers women with Turner’s syndrome the opportunity to achieve pregnancy. However, the increased cardiovascular demands of pregnancy also may pose unique and serious risk given their high rate of cardiovascular malformations (25% to 50% prevalence). A recent Practice Committee position from the American Society for Reproductive Medicine (ASRM) has stated that because the risk for aortic dissection or rupture during pregnancy may be 2% or higher, the risk of death during pregnancy is increased as much as 100-fold.12 Any significant cardiac abnormality should be regarded as a contraindication to oocyte donation. Even those having a normal evaluation should be thoroughly counseled regarding the high risk of cardiac complications during pregnancy because aortic dissection may still occur.12

Disorders of the Genital Tract

Disorders of the genital tract encompass both abnormalities of the müllerian system (uterus, fallopian tubes, and vagina) and abnormalities of the external genitalia. In adolescents with normal pubertal development and primary amenorrhea, a genital tract disorder will be found on physical examination in 15% of cases. Common disorders include müllerian agenesis, imperforate hymen, and transverse vaginal septum.

Müllerian Agenesis

Mullerian agenesis, also referred to as Mayer-Rokitansky-Küster-Hauser syndrome, is a condition in which all or part of the uterus and vagina are absent in the presence of otherwise normal female sexual characteristics. This diagnosis accounts for approximately 10% of cases associated with primary amenorrhea.15 In Finland, the incidence was calculated to be approximately 1 of every 5000 newborn girls.16 In müllerian agenesis, the ovaries are not affected and thus ovarian function is normal. Secondary sexual development and height are in a normal range.

The differential diagnosis of patients who present with primary amenorrhea and have a genital tract anomaly is summarized in Table 16-4. Partial development of the müllerian structures can lead to obstructed menses and painful distention of a hematocolpos, hematometra, or hematoperitoneum. It is important to separate müllerian agenesis from complete androgen insensitivity syndrome, because the vagina may be absent or short in both disorders.17

It is currently unknown why müllerian agenesis occurs, but likely causes are mutations of genes that are responsible for müllerian tract maintenance. Thus far, no mutations have been reported.18 It appears that the mode of inheritance is not autosomal dominant.19

Approximately 30% of patients will have urinary tract anomalies, such as pelvic kidney, horseshoe kidney, unilateral renal agenesis, hydronephrosis, and ureteral duplication. Another 10% to 12% will have skeletal anomalies mostly associated with the spine. There are also reports of absent digits and webbing or fusion of fingers or toes (syndactyly).

Although ultrasound could be an important aid in confirming the presence or absence of uterine structures, MRI is usually more definitive. Occasionally laparoscopic visualization is needed, because there is disagreement between MRI and laparoscopic findings.20 If persistent chronic pelvic pain and symptoms associated with endometriosis are present, laparoscopy can usually aid in determining the location and potential removal of incompletely formed müllerian structures.

Evaluation of Androgen Insensitivity Syndrome

These patients usually present with a family history of scant pubic hair and the presence of inguinal masses. Other female family members should be evaluated for the same diagnosis.

Patients with the condition may have a eunuchoid habitus with long arms and large hands and feet. Although the breasts develop for the most part normally, they lack glandular tissue and the nipples are small with a pale areola.

On pelvic examination, the patients will have scant or absent pubic hair and a blind vagina that is no more than a few centimeters long. More than 50% of patients have inguinal hernias and underdeveloped labia minora. Laboratory evaluation will demonstrate a 46,XY karyotype and elevated total testosterone (in the normal male range).22 This distinguishes patients with androgen insensitivity syndrome from those with müllerian agenesis, who will have an XX karyotype and total testosterone in the normal female range.

Gonadal malignancies have been reported in the 20% range, but are rarely seen before age 20. Therefore, a typical plan of action for these patients is to wait, allowing them to reach their normal adult stature and full breast development, then perform bilateral laparoscopic gonadectomy after puberty has been reached.

Patients with lack of 17β-hydroxysteroid dehydrogenase activity also have impaired testosterone production and present clinically as incomplete androgen insensitivity. The treatment for both conditions is essentially the same.

Rare Causes of Primary Amenorrhea

LH Receptor Abnormalities

Abnormalities of the LH receptor in 46,XX females will result in normal female sexual development and primary amenorrhea.26 Serum LH may be normal to increased, FSH is normal, follicular phase estradiol levels are normal, and progesterone is low. The uterus is small and the ovaries are consistent with anovulation.

Diagnostic Approach for Primary Amenorrhea

What Age?

An evaluation of primary amenorrhea is indicated when an adolescent fails to menstruate by age 15 in the presence of normal secondary sexual development (two standard deviations above the mean of 13 years), or within 5 years after breast development, if that occurred before age 10.2 This age has recently been adjusted to a younger age, because girls are menstruating at a younger age. If there is a failure to initiate breast development by age 13 (two standard deviations above the mean of 10 years), an investigation should also be initiated.2 These criteria are not absolute, and complete evaluation should be initiated if the patient presents with amenorrhea and obvious associated pathology such as cyclic pain or a blind vaginal pouch.

History and Physical Examination

A careful history is a key component to the evaluation and planning for the treatment of amenorrhea (Fig. 16-1). Special emphasis should be focused on physical or emotional stress, nutritional status, and history of genetic inherited disorders. The family should be questioned about familial disorders such as diabetes mellitus, previous medical disorders that may have been treated with gonadotoxic agents, and surgical disorders that involve the genital tract, including abnormal sexual differentiation. The functional inquiry should include secondary sexual development, galactorrhea, and the presence of hyperandrogenic symptoms.

A detailed physical examination includes gynecologic examination, body mass index, pubertal status, signs of hyperandrogenism or other skin manifestations of endocrine disorders, and genital tract evaluation. Milestones of sexual development and growth should be documented. The most important single feature on history and physical examination is the presence or absence of breast development, which is a clear indication of the initiation of puberty.

The presence of galactorrhea either described by the patient or observed by a careful breast examination is of great clinical significance. Specific clinical features of the galactorrhea, such as whether it is unilateral or bilateral, constant or intermittent, will determine the potential endocrine nature of the symptom. Galactorrhea of hormonal origin comes from multiple duct openings on the breast. This is in contrast to secretions occurring from a single duct, which are usually related to a local problem.

Gynecologic examination will usually reveal the presence of any genital abnormities, including obstructive processes.

Laboratory Evaluation

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