Hypogonadotropic Hypogonadism

GnRH and gonadotropin deficiency can be caused by various genetic or developmental defects of the hypothalamus or by destructive lesions, such as tumors, inflammatory processes, vascular lesion, or trauma. Patients with isolated gonadotropin deficiency are generally of normal height for age in the prepubertal period and contrast with boys with constitutional delay who are shorter. In patients with hypogonadotropic hypogonadism, gonadotropin responses to GnRH stimulation may be subnormal, but because of the functional hypogonadotropism in constitutional delay, the differential diagnosis between these two conditions may be difficult (54,55).

Temporary Gonadotropin Deficiencies

Anorexia Nervosa. Anorexia nervosa, which results from a distorted body image, an obsessive fear of obesity, and avoidance of food, can be associated with severe, even fatal, weight loss. For unknown reasons, this disorder is much more common in girls than in boys. The boys' functional hypogonadotropic hypogonadism at least partly results from severe weight loss. The underlying pathophysiology of delayed puberty is GnRH deficiency, because the LH secretory pattern in adolescents with anorexia is similar to that of normal prepuberty: low or absent LH pulses and a blunted LH response to stimulation by exogenous GnRH (56). Pulsatile administration of GnRH restores a pubertal pattern of LH secretion, confirming the hypothalamic location of the defect. The mechanism for GnRH deficiency may relate to the effects of stress (57). Corticotropin-releasing factor (CRF) levels increase in stress, and CRF, in turn, stimulates P-endorphin levels, which then directly inhibit GnRH release. Recovery to normal weight will normalize most of the endocrine and metabolic disturbances, but in girls, amenorrhea may persist for years.

Athletic Training. Intensive exercise may inhibit GnRH secretion and arrest puber-tal development. Although participation in sports in which weight control does not occur does not affect pubertal development, in some sports, such as long-distance running and weight lifting, the energy deficit may be sufficient to delay puberty (58). Hypogonadotropic hypogonadism may occur even when the athletes are of normal weight but have less fat and more muscle mass than nonathletic boys (57). The mechanism of delayed puberty is unclear, but interruption of intensive training advances puberty before any change in body composition or weight, suggesting a direct effect of physical activity on GnRH secretion, possibly through stress effects (57) (see also Chapter 16).

Malnutrition and Chronic Diseases. In malnutrition and chronic diseases, weight loss to below 80% of ideal body weight can delay or arrest pubertal development. Nutrition plays an important, but poorly understood, role in the control GnRH secretion, e.g., in regional enteritis gonadotropin secretion remains normal if nutrition is optimally balanced, whereas suboptimal nutrition will result in a hypogonadotropic state and arrested pubertal maturation. More than 50% of patients with regional enteritis have subnormal height velocity, and approx 25% will have short stature. The endocrine status is characterized by normal GH secretion and a slightly subnormal serum insulin-like growth factor (IGF)-1 levels, which is related to nutritional status (59).

Chronic renal insufficiency delays pubertal development, but after successful renal transplantation, gonadotropin secretion is usually restored. GnRH secretion is disrupted in these patients as well.

Central Nervous System Tumors

Tumors causing delayed puberty most commonly interfere with GnRH synthesis or secretion. Deficiency of other anterior pituitary hormones, diabetes insipidus, and visual disturbance is common.

Craniopharyngioma. The most common neoplasm causing hypothalamic-pitu-itary dysfunction and hypogonadotropic hypogonadism is craniopharyngioma. It is a congenital tumor, which most commonly becomes symptomatic between the ages of 6 and 14 yr. At presentation, the most common symptoms are headache, visual disturbances, short stature, delayed puberty, polyuria, and polydipsia. Skull radiographs may show suprasellar or intrasellar calcification or an abnormality of the sella turcica. Computed tomography (CT) or magnetic resonance imaging (MRI) scans may reveal fine calcifications that are not apparent on routine skull radiographs. The structure of the tumor varies from solid to cystic. Treatment consists of surgery and radiotherapy, but the recurrence rate is high, even when complete surgical removal is attempted.

Langerhans Cell Histiocytosis. Langerhans cell histiocytosis, also called Hand-Schuller-Christian disease or Histiocytosis X, is characterized by infiltration of lipid-containing histiocytic cells in the skin, bone, and viscera. Cyst-like areas can be found by X-ray in the flat bones of the skull, pelvis, dorsolumbar spine, scapula, and long bones of the arms and legs. CNS involvement and, in particular, hypothalamic-pituitary involvement are well-described features of Langerhans cell histiocytosis. The precise incidence of CNS-Langerhans cell histiocytosis disease is unknown, and the natural history is poorly understood. Diabetes insipidus is reported to be the most common and well-described manifestation of hypothalamic-pituitary involvement (up to 50%). Anterior pituitary dysfunction occurs in up to 20% of patients with Langerhans cell histiocytosis and almost exclusively together with diabetes insipidus. Although histiocytosis is not a tumor, it can be treated with chemotherapeutic agents, especially vinblastine. The natural course of the disease fluctuates, which makes it difficult to evaluate treatment efficacy. Endocrine function does not improve after medical treatment of Langerhans cell histiocytosis with chemotherapy and glucocorticoids. All Langerhans cell histiocytosis with patients should undergo a thorough endocrine evaluation periodically.

Germinomas. Germinomas are uncommon extrasellar tumors that often cause delayed puberty. Polydipsia, polyuria, and visual disturbances are the most common presenting symptoms, followed by arrested growth and delayed puberty. Germinomas are located in the pituitary stalk, in the suprasellar region of the hypothalamus, or close to the pineal gland. Seeding of the tumor into the cerebrospinal fluid is common and can be used in diagnosis, i.e., examination of tumor markers (human chorionic gonadotropin [hCG]-P, or a-fetoprotein) or germ cells (with positive placental alkaline phosphatase staining). These laboratory findings, together with typical clinical features, and an excellent response to radiation therapy are so characteristic of this condition that surgery is rarely indicated, except for biopsy to establish a histological diagnosis (60,61).

Other Central Nervous System Disorders

Defects in Development. Various malformations affecting the development of the prosencephalon may cause hypogonadotropic hypogonadism together with deficiency of any, or all, other pituitary hormones. Midline malformations are often associated with optic dysplasia, and an absent septum pellucidum is often found by imaging techniques (septo-optic dysplasia). Other congenital midline defects, ranging from holoprosencephaly to cleft lip and palate, may also be associated with variable hypothalamic-pituitary dysfunction.

Genetic defects in the development of the anterior pituitary cause hypopituitarism, including hypogonadotropic hypogonadism. During fetal development of the anterior pituitary gland, several sequential processes occur that affect cell differentiation and proliferation. Recent advances in molecular biology have revealed several steps that are required for pituitary cell line specification, and several genes have been identified to play a role in the control of these steps. Mutations in DAX1 gene cause X-linked adrenal hypoplasia congenita and mutations in the DAXl-related orphan nuclear receptor, steroidogenic factor-1; leptin and prohormone convertase-1 may influence GnRH release and processing of the GnRH receptor. The pituitary transcription factors, HESX-1, LHX3, and PROP-1, are important for gonadotroph development. Depending on the condition, different approaches for family counseling are needed. Despite recent advances, the pathophysiological basis of hypogonadotropic hypogonadism in the majority of individuals remains unclear.

Recently, compound heterozygous mutations in the GnRH receptor gene were described in males and females, and GnRH resistance was confirmed in vitro (62,63). Because of various mutations, there is a wide spectrum of phenotypes, ranging from complete hypogonadotropic hypogonadism with lack of pubertal development to partial hypogonadism with pubertal arrest. In complete GnRH resistance, endogenous LH secretory patterns are abnormal: they are either apulsatile, or characterized by a low-normal pulse frequency with small pulses, or erratic pulses of low amplitude. In patients with partial resistance, basal LH plasma concentration are low, but FSH levels are in the normal range (62).

Kallmann Syndrome. Kallmann syndrome is the most common form of isolated hypogonadotropic hypogonadism (see Chapter 5). Hypogonadism in these subjects results from GnRH deficiency. The other components of this syndrome include anosmia or hyposmia, resulting from hypoplasia of the olfactory lobes, and occasionally cleft lip and palate, unilateral renal agenesis, short metacarpals, sensory-neural hearing loss, and color blindness. Nearly 50% of Kallmann syndrome patients have mutations in the KAL gene on chromosome Xp22.3. This gene encodes an extracellular matrix protein that regulates axonal path-finding and cellular adhesion (64). Defects in this gene cause failure of fetal GnRH neurons to migrate from the olfactory palacode to the mediobasal hypothalamus, resulting in hypoplasia of the olfactory sulci. Autosomal disorders (dominant or recessive) may also cause Kallmann syndrome, but those gene defects have not yet been characterized. Because approximately half of the patients have the X-linked disorder, the syndrome is more common in boys than in girls.

Iatrogenic Gonadotropin Deficiencies

Treatment of CNS tumors, leukemia, or metastatic neoplasms with cranial irradiation may result in the gradual development of hypothalamic-pituitary failure. GH

Delayed or Absent Pubertal Development

Family history of delayed puberty

_ Extreme weight loss

Competitive athletics Chronic illness

LH/FSH levels

Low values 4-GnRH analog testing -► High values-

Height velocity

Normal

Anosmia & other midline defects i

Temporary,

Congenital

Hypopituitarism

Primary Testicular Failure

Secondary or

Hypogonadotropic

Constitutional

Hypogonadism

Delay

(Klinefelter syndrome)

Karyotype

(Klinefelter syndrome)

Fig. 5. Differential diagnosis of delayed puberty.

deficiency is the most common component of the radiation induced hormone disorder, but gonadotropin deficiency also occurs after sufficiently high radiation doses. Development of radiation-induced hypothalamic-pituitary failure usually develops over 1 to several years.

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