Pituitary and Hypothalamus

Oriba Dan Langoya

Disorders of the Anterior Pituitary and Hypothalamus• Ant pit often is referred to as

the "master gland“• Produces 6 major hormones:1. Prolactin (PRL)2. Growth hormone (GH), 3. Adrenocorticotropic

hormone (ACTH)4. Luteinizing hormone (LH)5. Follicle-stimulating hormone

(FSH)6. Thyroid-stimulating

hormone (TSH)

Anatomy and Development

• Pit gland weighs 600mg located in sellar turcica• Pit dev’t from Rathke's pouch involves a cplx

interplay of lineage-specific transcription factors • Transcription factor Prop-1 induces pit dev’t of Pit-

1-specific lineages as well as gonadotropes• Pit-1 determines cell-specific expression of GH, PRL,

and TSH in somatotropes, lactotropes, and thyrotropes.• High levels of ER in cells that contain Pit-1 favors

PRL expression, whereas thyrotrope embryonic factor (TEF) induces TSH expression

Hypothalamic & Ant Pit Insufficiency

• Development/structural • Transcription factor • Pituitary dysplasia/aplasia • Congenital CNS mass,

encephalocele • Primary empty sella • Congenital hypothalamic

disorders (septo-optic dysplasia,

• Prader-Willi synd • Kallmann syndrome)

Etiology of Hypopituitarism

• Traumatic • Surgical resection • Radiation damage • Head injuries • Infections • Fungal (histoplasmosis) • Parasitic (toxoplasmosis) • Tuberculosis • Pneumocystis carinii

Etiology of Hypopituitarism

• Neoplastic • Pituitary adenoma • Parasellar mass

(germinoma, ependymoma, glioma)

• Rathke's cyst • Craniopharyngioma • Pituitary metastases (breast,

lung, colon carcinoma) • Lymphoma and leukemia • Meningioma

• Infiltrative/inflammatory • Lymphocytic hypophysitis • Hemochromatosis • Sarcoidosis • Histiocytosis X • Granulomatous hypophysitis • Vascular • Pituitary apoplexy • Infarction with diabetes;

postpartum necrosis) • Sickle cell disease • Arteritis

Dev’tal and Genetic Causes of Hypopituitarism

Pituitary Dysplasia Result in aplastic, hypoplastic, or

ectopic pituitary gland dev’t

Septo-Optic Dysplasia Pit dysfunction leads to diabetes

insipidus, GH def and short stature, and, TSH def.

Mutations in the HESX1 gene

Tissue-Specific Factor Mutations

Pit-1 mutations cause combined GH, PRL, and TSH deficiencies

Prop-1 is appears to be required for Pit-1 function

PROP1 mutations result in combined GH, PRL, TSH, and gonadotropin deficiency

Over 80% of these patients have growth retardation

Developmental Hypothalamic Dysfunction

Kallmann Syndrome Defective hypothalamic GnRH syn & is assoc with anosmia or hyposmia due to olfactory bulb agenesis

Xterized by low LH and FSH levels and low conc of sex steroids

(testosterone or estradiol)

Repetitive GnRH admin restores normal pit gonadotropin responses,

pointing to a hypothalamic defect

Bardet-Biedl Syndrome Rare genetical disorder xterized

by mental retardation, renal abnormalities, obesity, and

polydactle. Central diabetes insipidus may or may not be

associated.

• GnRH deficiency occurs, Retinal degeneration begins in early childhood, and most patients are blind by age 30

Developmental Hypothalamic Dysfunction

Leptin and Leptin Receptor Mutations Lack causes broad spectrum of hypothalamic abnormalities,

• Including hyperphagia, obesity, and central hypogonadism.

• Decreased GnRH prodn in these patients results in attenuated pituitary FSH and LH synthesis and release.

Prader-Willi Syndrome Deletion of genes on chromosome 15q.

• Xterised by hypogonadotropic

hypogonadism, hyperphagia-obesity, chronic muscle

hypotonia, mental retardation, and adult-onset diabetes mellitus

Acquired Hypopituitarism

Caused by • Accidental or neurosurgical

trauma• Vascular events such as

apoplexy • Pituitary or hypothalamic

neoplasms, • Craniopharyngioma,

lymphoma, or metastatic tumors.

• Inflammatory disease such as lymphocytic hypophysitis

• Infiltrative disorders such as sarcoidosis, hemochromatosis

• Tuberculosis; or irradiation.

Acquired Hypopituitarism

• Inflammatory Lesions commonly infections by

• Tuberculosis

• Opportunistic Fungal infection assoc with HIV

• Tertiary syphilis

• Other inflammatory processes, such as granulomas and sarcoidosis

• Lymphocytic Hypophysitis• Often in postpartum

women; it usually presents with hyperprolactinemia,• Mildly elevated PRL levels.• patients manifest syms of

progressive mass effects with headache and visual disturbance. ESR often is elevated

Pituitary Apoplexy

• Acute intrapituitary hemorrhagic vascular events

• May occur spontaneously in a preexisting

• Adenoma;

• Postpartum (sheehan's syndrome); or in assoc with diabetes

• Hypertension, sickle cell anemia, or acute shock

• Apoplexy is an endocrine emergency

• May result in severe hypoglycemia, hypotension and shock, central nervous system (CNS) hemorrhage, and death.

• Acute symps include severe headache with signs of meningeal irritation, bilateral visual changes, ophthalmoplegia, and, in severe cases.

• Cardiovascular collapse and loss of consciousness

Presentation and Diagnosis• Clinical manifestations of

depend on which hormones and the extent of hormone deficiency• GH def causes growth

disorders in children & abnormal body composit in adults• Gonadotropin def causes

menstrual disorders and infertility and decreased sexual function, infertility, and loss of secondary sexual Xteristics in men.

• TSH def causes growth retardation in children and features of hypothyroidism in children and adults.• ACTH def leads to

hypocortisolism• PRL def causes failure of

lactation.• When lesions involve the

posterior pituitary, polyuria and polydipsia reflect loss of vasopressin secretion

Laboratory Investigation

• Biochemical diagnosis of pituitary insufficiency is made by demonstrating low levels of trophic hormones in the setting of low levels of target hormones• Test for• ACTH• TSH• FSH/LH• GH• Vasopressin

Treatment: Hypopituitarism

ACTH, Hormone Replacement• Hydrocortisone (10–20

mg A.M.; 5–10 mg P.M.)

• Cortisone acetate (25 mg A.M.; 12.5 mg P.M.)

• Prednisone (5 mg A.M.)

FSH/LH• Males• Testosterone enanthate (200 mg IM

every 2 weeks)• Testosterone skin patch (5 mg/d)• Females• Conjugated estrogen (0.65–1.25 mg

qd for 25 days)• Progesterone (5–10 mg qd) on days

16–25• Estradiol skin patch (0.5 mg, every

other day)• For fertility: Menopausal gonadotropins,

human chorionic gonadotropins

Treatment: Hypopituitarism

TSH L-Thyroxine (0.075–0.15 mg daily)

• Generally hormone replacement therapy, including glucocorticoids, thyroid hormone, sex steroids, growth hormone, and vasopressin

GH• Adults: Somatotropin (0.1–

1.25 mg SC qd)• Children: Somatotropin [0.02–

0.05 (mg/kg per day)]• Vasopressin • Intranasal desmopressin (5–

20 g twice daily)

• Oral 300–600 g qd