The term “gonadal dysgenesis ” refers to a number of disorders in which the gonads have not formed normally. This condition can occur in individuals with normal karyotypes as well as in a variety of abnormal or mosaic states. Gonadal dysgenesis accounts for almost half of all cases of primary amenorrhea. Gonadal dysgenesis with the stigmata of Turner syndrome is the most common variation, which has a wide spectrum of genotypes (most commonly 45,X but including individuals who may have a portion of a Y chromosome as well) and phenotypes. Individuals with gonadal dysgenesis may develop hypothyroidism and also commonly develop hypertension and glucose intolerance. Swyer syndrome (46,XY) is also associated with gonadal dysgenesis, and 46,XX gonadal dysgenesis may occur as well; in both cases, the individual presents as a normal appearing but sexually immature female.

Müllerian agenesis (Mayer–Rokitansky–Kuster–Hauser syndrome) is a condition in which all or part of the uterus and vagina are absent with blind vaginal pouch in the presence of otherwise normal female sexual characteristics and a normal 46,XX karyotype (which generally need not be assessed because the diagnosis is evident on examination). This condition accounts for approximately 10% of cases associated with primary amenorrhea and occurs in 1 in 4000–5000 births; it is autosomal dominant with incomplete penetrance and variable expressivity [5, 6]. A karyotype can be performed to rule out androgen insensitivity, but individuals with Müllerian agenesis have completely developed secondary sexual characteristics whereas those with androgen insensitivity generally have only Tanner stage 3 breast development and very little, if any, pubic and axillary hair. Serum FSH , LH, estradiol, TSH , prolactin, and testosterone will be within normal limits barring iatrogenic effects of hormonal therapy. Pelvic ultrasound shows variable absence of Müllerian structures, and follow-up MRI of the abdomen and pelvis can reveal associated renal abnormalities, found in 30% of patients [1]. Other associated findings include skeletal abnormalities of the spine, syndactyly, and auditory deafness.

Hypothalamic disorders that may cause amenorrhea include emotional/physical stress, intense exercise, malnutrition or a chronic disease state, as well as primary or secondary gonadotropin deficiency, and a wide variety of rare tumors and diseases (◘     Table 6.1). Patients with hypothalamic amenorrhea may present with the absence of secondary sexual characteristics or following normal puberty. Circulating levels of FSH , LH, and estradiol levels are all low. In a patient with a history concerning for emotional or physical stress, malnutrition, or a chronic disease state, growth charts can be very illustrative when combined with low to normal FSH and low estradiol concentrations. Dual energy X-ray absorptiometry (DEXA) scan will reveal low bone density when compared to age-matched controls.

Gonadotropin-releasing hormone deficiency presents with the delayed development of secondary sexual characteristics, but most commonly with associated anosmia and sometimes color blindness due to an absent olfactory bulb in 50% of cases, in which case it is termed Kallmann syndrome . Kallmann syndrome can be difficult to distinguish from both constitutional delay (discussed subsequently) and other forms of hypothalamic amenorrhea in which there is an environmental stressor. Other forms of isolated hypogonadotropic hypogonadism are associated with GnRHR (GnRH receptor ) inactivating mutations [7, 8]. There actually is a whole spectrum of midline abnormalities associated with GnRH deficiency and hypothalamic amenorrhea, with absence of the septum pellucidum representing the most extreme example.

Isolated gonadotropin deficiency is characterized by decreased or absent endogenous gonadotropin-releasing hormone (GnRH) secretion, resulting in very low to undetectable levels of LH and FSH , along with incomplete development of secondary sexual characteristics and primary amenorrhea. These characteristics may be accompanied by eunuchoid features, anosmia, and, more rarely, color blindness (and again is termed Kallmann syndrome ). Abnormalities of GnRH receptors have also been found, but are difficult to distinguish from isolated gonadotropic deficiency. Abnormalities of the LH receptor in 46,XX females result in normal female sexual development and primary amenorrhea [9]. Serum LH may be normal or increased, and FSH will be normal, as will follicular phase estradiol levels. Progesterone will be low. The uterus in patients with LH receptor abnormalities is small, and the ovaries are consistent with the absence of ovulation.

Constitutional delay is the single most common cause of delayed puberty in both genders and is defined as the onset of otherwise normal puberty 2.5 standard deviations later than the mean age of pubertal onset (breast development by 13 years in girls and testicular development by 14 years in boys). Patients with constitutional delay frequently experience concomitant delay in adrenarche and pubarche. Fifty to 75% of patients have a family history of delayed puberty followed by normal pubertal development, as well as short stature [10]. This is a diagnosis of exclusion.

Although an abnormality of sexual differentiation, androgen insensitivity syndrome is identified in as many as 5% of all patients presenting with primary amenorrhea [11]. The disorder is due to the inability of biologically active testosterone to act normally in cells, generally because of the absence of the androgen receptor but sometimes because of a defect in the post-receptor action of androgens. Patients with androgen insensitivity commonly present with distinctive physical characteristics, including a blind vagina, eunuchoid habitus, breasts that have matured only to Tanner stage 3, and small nipples with pale areolae. Pubic and axillary hair is generally scant or absent. There may be fullness in the inguinal area if the normal testicles are located there rather than intra-abdominally. The diagnosis can be confirmed by determining that serum testosterone levels are within or above the range normally found in males and by the presence of a 46,XY karyotype. The gonads, which are histologically normal testes, should be removed after the age of sexual maturity to eliminate the 30% risk of gonadal tumors later in life [1]; estrogen should be provided exogenously. Such individuals first may be identified after straddle injuries in childhood associated with intense pain due to trauma to the sometimes present inguinal testes.

Disorders of the genital tract encompass abnormalities of the Müllerian system as well as abnormalities of the external genitalia. Genital tract disorders will be found in 15% of adolescents who present with normal adolescent development and primary amenorrhea. Common disorders of the genital tract include Müllerian agenesis (see above), imperforate hymen , and transverse vaginal septum . Imperforate hymen is the most frequent obstructive female genital tract anomaly, with an estimated frequency of approximately 0.1%. Transverse vaginal septum is less common, occurring in fewer than one in 20,000 females. Patients with these abnormalities often present with adult secondary sexual characteristics, cyclic pelvic pain, and lack of menses. A bulging hymen with hematocolpos, evidence of an imperforate hymen, may be detected on pelvic exam. MRI of the pelvis may be used to detect transverse vaginal septum and is also more sensitive than ultrasound when excluding other structural abnormalities [1, 12]. If a normal uterus and fallopian tubes are present, these individuals will develop endometriosis as well because of the obstructed outflow tract.

Hypothalamic forms of amenorrhea result from diminished GnRH input to the pituitary gland and commonly occur in women stressed mentally, emotionally, or physically as well as in those who are nutritionally deficient. Often a combination of these stressors is present, resulting in anovulation. Menstrual cycle disturbances are common among competitive athletes, especially in those sports that encourage a low body weight. Menstrual irregularities appear to be greatest in ballet dancers (6–43%) and middle- and long-distance runners (24–26%). Hypothalamic amenorrhea is also common in women who have experienced a profound stress, such as rape, incest, or loss of someone particularly close. Severe eating disorders such as bulimia and anorexia nervosa can disrupt menstrual function in a similar manner. Clinicians should screen for stressors by reviewing the patient’s lifestyle, including diet, exercise, and drug use [8, 15].