Hypothalamus/Pituitary PDF

Hypothalamus/Pituitary Airani Sathananthan MD Distribution of slides not permitted Disclosures Conflict of Interest Disclosure The speaker is or has been a clinical investigator for Novo Nordisk, Sanofi, Lilly, Abbvie, and Mylan. Objectives Diagram the...

Hypothalamus/Pituitary Airani Sathananthan MD Distribution of slides not permitted Disclosures Conflict of Interest Disclosure The speaker is or has been a clinical investigator for Novo Nordisk, Sanofi, Lilly, Abbvie, and Mylan. Objectives Diagram the feedback mechanisms governing the hypothalamus and pituitary gland. Summarize the normal function and hormonal secretion of the anterior and posterior pituitary gland from a clinician’s perspective. Compare and contrast clinical syndromes associated with hormone deficiencies of the pituitary gland (hypopituitarism) and those associated with hormone excess (with special focus on hyperprolactinemia, acromegaly) Outline the most appropriate management and approach to hypothalamic pituitary disorders based on clinical features, laboratory testing, and radio- imaging of the hypothalamic pituitary axis. Decide on the most appropriate medical and surgical treatment of a patient with a hypothalamic-pituitary disorder. Discuss the clinical features, diagnosis and management of diabetes insipidus, prolactinoma, acromegaly, hypopituitarism Endocrine Axes  Approach to Endocrine Clinical Case: Too Little End Hormone Too Much End Hormone Classification of Endocrine Disorders Tertiary HYPOTHALAMUS Secondary PITUITARY Primary TARGET ORGAN Hypopituitarism , Hypothalamic/Anterior Pituitary Insufficiency Hypopituitarism results from impaired production of one or more of the anterior pituitary trophic hormones.  Etiology o Development/Structural ▪ Transcription factor defect, pituitary dysplasia/aplasia, congenital CNS mass, encephalocele, primary empty sella (atrophy or compression of pituitary, often idiopathic) ▪ Congenital hypothalamic disorders (septo-optic dysplasia, Prader-Willi syndrome, Laurence-Moon-Biedl syndrome, Kallmann syndrome (Leads to defective hypothalamic gonadotropin-releasing hormone (GnRH) synthesis and is associated with anosmia or hyposmia due to olfactory bulb agenesis or hypoplasia in addition to hypogonadism) o Traumatic: surgical resection, radiation damage, head injuries o Neoplastic: ▪ Pituitary adenoma ▪ Parasellar mass (germinoma, ependymoma, glioma) ▪ Rathke's cyst ▪ Craniopharyngioma ▪ Hypothalamic hamartoma, gangliocytoma ▪ Pituitary metastases (breast, lung, colon carcinoma) ▪ Lymphoma and leukemia ▪ Meningioma o Infiltrative/inflammatory: Lymphocytic hypophysitis, Hemochromatosis, Sarcoidosis, Histiocytosis X, Granulomatous hypophysitis o Vascular: Pituitary apoplexy, Pregnancy-related Sheehan’s Syndrome , Sickle cell disease, Arteritis, o Infections:Fungal (histoplasmosis), Parasitic (toxoplasmosis), Tuberculosis, Pneumocystis carinii  Hypopituitarism: Presentation and Diagnosis o The clinical manifestations of hypopituitarism depend on which hormones are lost and the extent of the hormone deficiency. o Growth Hormone (GH) deficiency causes growth disorders in children and leads to abnormal body composition in adults. o Gonadotropin deficiency causes menstrual disorders and infertility in women and decreased sexual function, infertility, and loss of secondary sexual characteristics in men.  Hypopituitarism: Presentation and Diagnosis o TSH and ACTH deficiency usually develop later in the course of pituitary failure. ▪ TSH deficiency causes growth retardation in children and features of hypothyroidism in children and in adults. ▪ The secondary form of adrenal insufficiency caused by ACTH deficiency leads to hypocortisolism with relative preservation of mineralocorticoid production. o PRL deficiency causes failure of lactation. o When lesions involve the posterior pituitary, polyuria and polydipsia reflect loss of vasopressin secretion.  Hypopituitarism: Laboratory Investigation o Biochemical diagnosis of pituitary insufficiency is made by demonstrating low levels of trophic hormones in the setting of low target hormone levels. ▪ For example, low free thyroxine in the setting of a low or inappropriately normal TSH level suggests secondary hypothyroidism. ▪ Similarly, a low testosterone level without elevation of gonadotropins suggests hypogonadotropic hypogonadism. o Provocative tests may be required to assess pituitary reserve Hypopituitarism: Treatment o Hormone replacement therapy, including glucocorticoids, thyroid hormone, sex steroids, growth hormone and vasopressin is usually safe and free of complications. o Treatment regimens that mimic physiologic hormone production allow for maintenance of satisfactory clinical homeostasis. o Patients in need of glucocorticoid replacement require careful dose adjustments during stressful events such as acute illness, dental procedures, trauma, and acute hospitalization  Pituitary Apoplexy oAcute intrapituitary hemorrhagic vascular events can cause substantial damage to the pituitary and surrounding sellar structures. oPituitary apoplexy may occur spontaneously in a preexisting adenoma; postpartum or in association with diabetes, hypertension, sickle cell anemia, or acute shock. oApoplexy is an endocrine emergency that may result in severe hypoglycemia, hypotension and shock, central nervous system (CNS) hemorrhage, and death. oAcute symptoms may include severe headache with signs of meningeal irritation, bilateral visual changes, ophthalmoplegia, and, in severe cases, cardiovascular collapse and loss of consciousness.  Pituitary Apoplexy o Pituitary CT or MRI may reveal signs of intratumoral or sellar hemorrhage, with deviation of the pituitary stalk and compression of pituitary tissue. o Patients with no evident visual loss or impaired consciousness can be observed and managed conservatively with high-dose glucocorticoids. o Those with significant or progressive visual loss or loss of consciousness require urgent surgical decompression. o Visual recovery after sellar surgery is inversely correlated with the length of time after the acute event. Therefore, severe ophthalmoplegia or visual deficits are indications for early surgery. o Hypopituitarism is very common after apoplexy. Sheehan’s Syndrome o Pituitary infarct post partum, can result in Hypopituitarism o Can present with lactation problems. Pituitary Adenomas Pituitary Adenomas oThey can be divided into functioning and nonfunctioning tumors. oFunctioning tumors are usually microadenomas (1 cm) that produce symptoms by mass effect, giving rise to headaches, visual impairment (such as bitemporal hemianopia), and hypopituitarism. Pituitary Adenomas oPituitary adenomas are benign neoplasms that arise from one of the five anterior Pituitary cell types. oThe clinical and biochemical phenotype of Pituitary adenomas depend on the cell type from which they are derived. Thus, tumors arising from lactotrope (PRL), somatotrope (GH), corticotrope (ACTH), thyrotrope (TSH), or gonadotrope (LH, FSH) cells hypersecrete their respective hormones. oBased on immunohistochemistry, most clinically nonfunctioning adenomas can be shown to originate from gonadotrope cells. oHormonally active or functional tumors are characterized by autonomous hormone secretion with diminished responsiveness to physiologic inhibitory pathways. Adenoma Cell Hormone Clinical Syndrome Origin Lactotrope PRL Hypogonadsim, galactorrhea Gonadotrope FSH, LH Silent or hypogonadism subunits Somatotrope GH Acromegaly/gigantism Thyrotrope TSH Thyrotoxicosis Coticotrope ACTH Cushing’s Disease Sellar Mass Lesions Mass effect due to compression of surrounding structures OR hypofunction leading to hormone deficiencies due to compression of normal pituiocytes Imaging: o Sagittal and coronal T1-weighted MRI imaging before and after administration of gadolinium allows precise visualization of the pituitary gland with clear delineation of the hypothalamus, pituitary stalk, pituitary tissue and surrounding suprasellar cisterns, cavernous sinuses, sphenoid sinus, and optic chiasm. o Anterior pituitary gland soft tissue consistency is slightly heterogeneous on MRI, and signal intensity resembles that of brain matter on T1-weighted imaging. o Adenoma density is usually lower than that of surrounding normal tissue on T1- weighted imaging, and the signal intensity increases with T2-weighted images. The high phospholipid content of the posterior pituitary results in a "pituitary bright spot." (B) T1 sagittal brain MRI without contrast in a normal patient, showing the normal bright spot of the posterior pituitary. MRI, magnetic resonance imaging. Citation: Endocrinology, Diabetes & Metabolism Case Reports 2020, 1; 10.1530/EDM-19-0070 Williams Textbook of Endocrinology 2016 Williams Textbook of Endocrinology 2016 Management: (Depends on size and clinical presentation) o Asymptomatic small nonfunctioning microadenomas adenomas with no threat to vision may be followed with regular MRI and visual field testing without immediate intervention. o However, for macroadenomas, transsphenoidal surgery is indicated to reduce tumor size and relieve mass effects o Although it is not usually possible to remove all adenoma tissue surgically, vision improves in 70% of patients with preoperative visual field defects. Preexisting hypopituitarism that results from tumor mass effects may improve or resolve completely. o Beginning about 6 months postoperatively, MRI scans should be performed yearly to detect tumor regrowth. Within 5–6 years after successful surgical resection, ~15% of nonfunctioning tumors recur. When substantial tumor remains after transsphenoidal surgery, adjuvant radiotherapy may be indicated to prevent tumor regrowth Laboratory Testing: Visual Field Testing: o Because optic tracts may be contiguous to an expanding pituitary mass, reproducible visual field assessment using perimetry techniques should be performed on all patients with sellar mass lesions that abut the optic chiasm o Bitemporal hemianopia or superior bitemporal defects are classically observed, reflecting the location of these tracts within the inferior and posterior part of the chiasm Williams Textbook of Endocrinology 2016 Treatment: Medical, Surgical , Radiation o Surgery: Transsphenoidal rather than transfrontal resection is the desired surgical approach for pituitary tumors, except for the rare invasive suprasellar mass. ▪ COMPLICATIONS OF SURGERY: ▪ Operative mortality rate is about 1%. ▪ Transient diabetes insipidus and hypopituitarism occur in up to 20% of patients. ▪ Permanent diabetes insipidus, cranial nerve damage, nasal septal perforation, or visual disturbances may be encountered in up to 10% of patients. ▪ CSF leaks occur in 4% of patients. ▪ Less common complications include carotid artery injury, loss of vision, hypothalamic damage, and meningitis. Permanent side effects are rare after surgery for microadenomas.  Treatment: Medical, Surgical , Radiation o Pituitary Radiation: ▪ Because of its relatively slow onset of action, radiation therapy is usually reserved for postsurgical management. ▪ As an adjuvant to surgery, radiation is used to treat residual tumor and in an attempt to prevent regrowth o Medical Management: ▪ Medical therapy for pituitary tumors is highly specific and depends on tumor type. ▪ For prolactinomas, dopamine agonists are the treatment of choice. ▪ For acromegaly, somatostatin analogues and GH receptor antagonists are indicated. ▪ For TSH-secreting tumors, somatostatin analogues and occasionally dopamine agonists are indicated. ▪ ACTH-secreting tumors and nonfunctioning tumors are generally not responsive to medications and require surgery and/or irradiation. Diabetes Insipidus Diabetes Insipidus: o A primary deficiency of AVP secretion usually results from agenesis or irreversible destruction of the neurohypophysis. It is referred to variously as neurohypophyseal DI, neurogenic DI, pituitary DI, cranial DI, or central DI. o Primary deficiencies in the antidiuretic action of AVP result in nephrogenic DI. The causes can be genetic, acquired, or drug induced Diabetes Insipidus: o In pituitary/nephrogenic DI, the polyuria results in a small (1–2%) decrease in body water and a commensurate increase in plasma osmolarity and sodium that stimulates thirst and a compensatory increase in water intake. o As a result, hypernatremia and other overt physical or laboratory signs of dehydration do not develop unless the patient also has a defect in thirst or fails to increase fluid intake for some other reason. o In pituitary and nephrogenic DI, the severity of the defect in AVP secretion or action varies significantly from patient to patient. Clinical Features: oDI usually presents as severe polyuria, nocturia and polydipsia. oGenerally may go undetected unless in a situation where there is no access to free water. oIn severe cases may present with life threatening dehydration, hypernatremia mental obtundation, seizures, coma and death. Water deprivation can test can be used in diagnosis as well. Central DI Treatment: o The signs and symptoms of uncomplicated pituitary/central DI can be eliminated completely by treatment with desmopressin (DDAVP), a synthetic analogue of AVP. o It acts selectively at V2 receptors to increase urine concentration and decrease urine flow in a dose-dependent manner. o DDAVP can be given by IV or SC injection, nasal inhalation, or oral tablet. o Doses : Usually range from 1–2 µg once or twice daily by injection, 10–20 µg two or three times daily by nasal spray, or 100–400 µg two or three times orally. The onset of action is rapid, ranging from as little as 15 min after injection to 60 min after oral administration. Hyperprolactinemia Hyperprolactinemia o Hyperprolactinemia is the most common pituitary hormone hypersecretion syndrome in both men and women. o PRL-secreting pituitary adenomas (prolactinomas) are the most common cause of PRL levels >200 μg/L o Less pronounced PRL elevation can also be seen with microprolactinomas but is more commonly caused by drugs, pituitary stalk compression, hypothyroidism, or renal failure.  Etiologies of Hyperprolactinoma o Pregnancy and lactation are the important physiologic causes of hyperprolactinemia. o Sleep-associated hyperprolactinemia reverts to normal within an hour of awakening. o Nipple stimulation and sexual orgasm also may increase PRL. o Chest wall stimulation or trauma (including chest surgery and herpes zoster) invoke the reflex suckling arc with resultant hyperprolactinemia. o Chronic renal failure elevates PRL by decreasing peripheral clearance. o Primary hypothyroidism is associated with mild hyperprolactinemia, probably because of compensatory TRH secretion. o Pituitary stalk damage: due to interference with normal dopaminergic inhibition known as “stalk effect” (see examples below) ▪ Trauma- pituitary stalk section, suprasellar surgery ▪ Tumors, ie craniopharyngioma, suprasellar pituitary mass, ▪ Rathke’s cyst ▪ Infiltrative disorders, lymphocytic hypophysitis o Pharmacologic agents ▪ Dopamine receptor blockers (atypical antipsychotics), Cimetedine, etc. o Pituitary Hypersecretion (Prolactinoma) Diagnosis-Hyperprolactinemia oClinical Features as well as lab tests oProlactin Level: normal for most Laboratories is 1cm or symptoms  Treatment-Hyperprolactinemia: o Treat the underlying disorder:eg hypothyroidism, o Switch/Discontinue offending medications i.e. Dopamine receptor blockers o Prolactinoma: ▪ Generally medical with dopamine agonists such as Bromocriptine or Cabergoline. ▪ Cabergoline use has been reported to be associated with valvular heart disease ▪ Surgery: Only for impending neurological damage (ie compromised vision) and usually try drug treatment first. Acromegaly Somatotroph Adenomas Pathogenesis: o GH hypersecretion is usually the result of a somatotrope adenoma but may rarely be caused by extrapituitary lesions o In addition to the more common GH-secreting somatotrope adenomas, mixed mammosomatotrope tumors and acidophilic stem- cell adenomas secrete both GH and PRL. o In patients with acidophilic stem-cell adenomas, features of hyperprolactinemia (hypogonadism and galactorrhea) predominate over the less clinically evident signs of acromegaly.  Acromegaly Clinical Features: o Manifestations of GH and IGF-I hypersecretion are indolent and often are not clinically diagnosed for 10 years or more. ▪ Acral bony overgrowth results in frontal bossing, increased hand and foot size, mandibular enlargement with prognathism, and widened space between the lower incisor teeth. ▪ In children and adolescents, initiation of GH hypersecretion before epiphyseal long bone closure is associated with development of pituitary gigantism (vs acromegaly after closure) ▪ Soft tissue swelling results in increased heel pad thickness, increased shoe or glove size, ring tightening, characteristic coarse facial features, and a large fleshy nose. ▪ Other commonly encountered clinical features include hyperhidrosis, a deep and hollow-sounding voice, oily skin, arthropathy, kyphosis, carpal tunnel syndrome, proximal muscle weakness and fatigue, acanthosis nigricans, and skin tags. ▪ Generalized visceromegaly occurs, including cardiomegaly, macroglossia, and thyroid gland enlargement. Acromegaly Diagnosis: o Age- and sex-matched serum IGF-I levels are elevated in acromegaly. o Consequently, an IGF-I level provides a useful laboratory screening measure when clinical features raise the possibility of acromegaly. o Due to the pulsatility of GH secretion, measurement of a single random GH level is not useful for the diagnosis or exclusion of acromegaly and does not correlate with disease severity. o The diagnosis of acromegaly is confirmed by demonstrating the failure of GH suppression to