Current Medical Diagnosis & Treatment 2015
Paul A. Fitzgerald, MD
DISEASES OF THE HYPOTHALAMUS & PITUITARY GLAND
ESSENTIALS OF DIAGNOSIS
Partial or complete deficiency of one or any combination of anterior pituitary hormones.
Adrenocorticotropic hormone deficiency: reduced adrenal secretion of cortisol and epinephrine; aldosterone secretion remains intact.
Growth hormone (GH) deficiency: short stature in children; asthenia, obesity, and increased cardiovascular risk in adults.
Prolactin deficiency: postpartum lactation failure.
Thyroid-stimulating hormone (TSH) deficiency: secondary hypothyroidism.
Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) deficiency: hypogonadism and infertility in men and women.
Hypopituitarism can be caused by either hypothalamic or pituitary dysfunction. Patients with hypopituitarism may have single or multiple hormonal deficiencies (Table 26–1). When one hormonal deficiency is discovered, others may be present.
Table 26–1. Pituitary hormones.
- Hypopituitarism with mass lesions—Lesions in the hypothalamus, pituitary stalk, or pituitary can cause hypopituitarism. Pituitary adenomas can cause anterior hypopituitarism but rarely cause diabetes insipidus. Pituitary adenomas are usually sporadic but sometimes arise as part of multiple endocrine neoplasia (MEN) types 1 or 4. Other types of mass lesions include granulomas, such as granulomatosis with polyangiitis (formerly Wegener granulomatosis), tuberculosis, cholesterol granuloma; Rathke cleft cysts; pituitary apoplexy; metastatic carcinomas or hematologic malignancies; aneurysms; and brain tumors (craniopharyngioma, meningioma, dysgerminoma, glioma, chondrosarcoma, chordoma of the clivus). Rare causes include postpartum pituitary necrosis (Sheehan syndrome), African trypanosomiasis, and Langerhans cell histiocytosis.
Pituitary autoimmune disease is characterized by an infiltration of the pituitary by lymphocytes, macrophages, and plasma cells. Lymphocytic hypophysitis is an autoimmune disorder that most typically affects women during pregnancy or postpartum. Affected individuals may present with headache or visual field impairment. The appearance of hypophysitis on MRI scanning is variable, but it often appears as a homogeneous sellar mass that mimics a tumor and can extend above the sella. It usually results in ACTH deficiency but can cause deficiencies in any pituitary hormone. The serum prolactin may be elevated if the lesion damages the pituitary stalk. About 25% of cases are associated with other autoimmune conditions, such as systemic lupus erythematosus. Hypophysitis can also be caused by chemotherapy with ipilimumab, an anti-CTLA4 monoclonal antibody that activates T-lymphocytes and enhances immunity.
- Hypopituitarism without mass lesions—Congenital panhypopituitarism occurs in syndromes such as septo-optic dysplasia (de Morsier syndrome) and in patients with various gene mutations, such asPROP1mutations, resulting in the gradual development of several pituitary hormone deficiencies.Congenital isolated hypogonadotropic hypogonadism can be caused by mutations in any of the many genes that control the production or release of gonadotropin-releasing hormone (GnRH), LH, or FSH; it also occurs with the syndrome of congenital adrenal hypoplasia. Prader-Willi syndrome is a genetic disorder where genes on the paternal chromosome 15 are deleted or unexpressed. The incidence of this disorder is 1:15,000; both sexes are affected equally. Kallmann syndrome is caused by various gene mutations that impair the development or migration of GnRH-synthesizing neurons from the olfactory bulb to the hypothalamus. Congenital GH deficiency occurs as an isolated pituitary hormone deficiency in about one-third of cases.
Acquired hypopituitarism without mass lesions can result from closed-head brain injury, cranial radiation therapy, pituitary surgery, encephalitis, hemochromatosis, autoimmunity, or coronary artery bypass grafting (CABG). At least one pituitary hormone deficiency develops in about 25–30% of survivors of moderate to severe traumatic brain injury and in about 55% of survivors of aneurysmal subarachnoid hemorrhage. Some degree of hypopituitarism, most commonly GH deficiency and hypogonadotropic hypogonadism, occurs in one-third of ischemic stroke patients. Mitotane, given for adrenal cortical carcinoma, can suppress TSH secretion and cause reversible secondary hypothyroidism. Therapy with exogenous corticosteroids (parenteral, oral, inhaled, or topical) can suppress adrenocorticotropic hormone (ACTH) secretion and causes functional isolated secondary adrenal insufficiency.
Functional hypopituitarism can occur with normal aging because of variable degrees of GH deficiency. Similarly, aging men develop variable degrees of hypogonadotropic hypogonadism, with serum free testosterone levels that are slightly low or near the lower end of normal reference ranges, while serum FSH and LH levels remain in the normal range. Obesity also causes variable degrees of GH deficiency and male hypogonadotropic hypogonadism that are typically reversible with sufficient weight loss. Hypothalamic amenorrhea commonly occurs in women during severe emotional or physical stress, caloric restriction or eating disorders, or very high levels of exercise. Hypogonadotropic hypogonadism also occurs with severe illness, alcoholism, opioid analgesics, anabolic steroids; Cushing syndrome due to corticosteroid medication or excessive endogenous cortisol; hyperprolactinemia (drug-induced or spontaneous); anorexia nervosa; and malnutrition.
- Symptoms and Signs
- GH deficiency—Congenital GH deficiencytypically presents with hypoglycemia in infancy and short stature in childhood.
Acquired GH deficiency is quite common. The pituitary somatotroph cell is particularly sensitive to damage from radiation therapy, compression, or trauma. Therefore, GH deficiency often heralds other pituitary hormone deficiencies that may occur simultaneously or years later. Also, when other more recognizable pituitary hormone deficits are present, there is a high likelihood of concurrent GH deficiency.
GH deficiency varies in severity from mild to severe, resulting in a variable spectrum of nonspecific symptoms that include mild to moderate central obesity, reduced physical and mental energy, impaired concentration and memory, and depression. Patients may also have variably reduced muscle and bone mass, increased low-density lipoprotein (LDL) cholesterol, and reduced cardiac output with exercise.
Laron syndrome is an autosomal recessive disorder that is mainly caused by mutations in the gene that encodes the GH receptor, resulting in GH-resistance. This causes a severe deficiency in serum IGF-I, resulting in short stature (dwarfism). Affected individuals have a prominent forehead, depressed nasal bridge, small mandible, and central obesity. They may have recurrent hypoglycemic seizures. Partial resistance to GH may cause some cases of idiopathic short stature without features of Laron syndrome.
- Gonadotropin deficiency—Also known as hypogonadotropic hypogonadism, gonadotropin deficiency is caused by insufficiencies in LH and FSH, which cause hypogonadism and infertility.
Congenital gonadotropin deficiency is characterized by partial or complete lack of pubertal development. It can be one deficit in congenital panhypopituitarism. Isolated hypogonadotropic hypogonadism occurs with an estimated prevalence between 1 in 4000 and 1 in 10,000 males; it is less common in females. In affected patients, the sense of olfaction (smell) is entirely normal in 58% (normosmic isolated hypogonadotropic hypogonadism), or hypoosmic or anosmic in 42% (Kallmann syndrome). Regardless of their olfaction status, patients with isolated hypogonadotropic hypogonadism frequently have abnormal genitalia (25%), including small phallus, cryptorchidism; renal anomalies (28%); midline craniofacial defects (50%), including cleft lip, high-arched or cleft palate, absent nasal cartilage, dental agenesis, hypertelorism; neurologic deficits (42%), including cognitive problems, bimanual synkinesis, cerebellar ataxia, oculomotor dysfunction, color blindness, or neurosensory hearing loss; musculoskeletal malformations, including pectus excavatum, syndactyly, clinodactaly, camptodactyly. Some affected women have menarche followed by secondary amenorrhea. Some patients with isolated hypogonadotropic hypogonadism also have congenital adrenal hypoplasia with X-linked inheritance. Most such boys with isolated hypogonadotropic hypogonadism who survive beyond childhood are diagnosed when they fail to enter puberty. However, isolated hypogonadotropic hypogonadism and subtle signs of adrenal failure can present in adulthood in males.
Patients with Prader-Willi syndrome have variable features of both gonadotropin deficiency and primary gonadal dysfunction; boys have cryptorchidism. Other features of Prader-Willi syndrome can include mental retardation, short stature, hyp