Pituitary Disease

Amy Toscano-Zukor, MD

Based upon a presentation prepared byAnne Marie Van Hoven, MD

UMDNJ – Robert Wood Johnson Medical School

Anatomy of the Pituitary Gland

Pituitary Hormones Anterior Pituitary

Thyroid Stimulating Hormone (TSH) Adrenocorcticotropic Hormone (ACTH) Growth Hormone (GH) Follicle Stimulating Hormone (FSH) Luteinizing Hormone (LH) Prolactin (Prl)

Posterior Pituitary

Arginine Vasopressin (AVP) Oxytocin

Hypothalamic Hormones

Thyrotropin Releasing Hormone (TRH)

Corticotropin Releasing Hormone (CRH)

Growth Hormone-Releasing Hormone (GHRH)

Growth Hormone Release Inhibiting Hormone (Somatostatin)

Gonadotropin Releasing Hormone (GnRH)

Prolactin Release Inhibiting Hormone (Dopamine)

The Hypothalamic- Pituitary Axes

Lesions of Hypothalamic Pituitary Axis

Hypothalamic (hypothalamic or pituitary stalk disease) vs. Primary Pituitary Disease

Acquired Defects: Tumors (inc. Pit. Adenomas), Trauma, Irradiation, Inflammatory/Infiltrative d/s, Vascular d/s (inc. Apoplexy), Empty Sella, Primary Neoplastic d/s, Metastatic d/s, Metabolic d/s and Functional d/s.

Congenital Embryopathic Defects: Kallman’s syndrome, Pituitary Aplasia, Anencephaly, Midline defects.

Genetic Defects: Hypothalamic / Pituitary Hormone Gene Defects and Hormone Receptor Gene Defects.

Clinical Manifestations of Lesions of Hypothalamic Pituitary Axis

Mass effects: Headaches, Visual Field and CN III-VI Defects, Obstructive Hydrocephalus, CSF Rhinorrhea, Hypothalamic Syndromes (DI, SIADH, thirst/ appetite/ satiety/ sleep/ temperature regulation), Frontal/ Temporal Lobe Dysfunction

Endocrine Effects: Hypopituitarism: TSH/ ACTH/ GH/ LH-FSH/ Prolactin Hyperpituitarism: TSH/ ACTH/ GH/ LH-FSH/ Prolactin

Mass Effects of Pituitary Lesions

Organization of visual fibers at the Optic Chiasm

Pituitary Adenoma With Involvement Of Left

Oculomotor Nerve

Pituitary Tumor

Pituitary Apoplexy

Pituitary Apoplexy w/ OC compression

Clinical Manifestations of Lesions of Hypothalamic Pituitary Axis

Mass effects: Headaches, Visual Field and CN III-VI Defects, Obstructive Hydrocephalus, CSF Rhinorrhea, Hypothalamic Syndromes (DI, SIADH, thirst/ appetite/ satiety/ sleep/ temperature regulation), Frontal/ Temporal Lobe Dysfunction

Endocrine Effects: Hypopituitarism: TSH/ ACTH/ GH/ LH-FSH/ Prolactin Hyperpituitarism: TSH/ ACTH/ GH/ LH-FSH/ Prolactin

Syndrome of Panhypopituitarism

Progressive loss of Anterior Pituitary function: FSH/LH and GH; TSH; ACTH.

Hypopituitarism with DI is suggestive of Hypothalamic etiology.

Syndrome of Panhypopituitarism

Control of Gonadotropin Secretion

Syndrome of Panhypopituitarism

FSH / LH deficiency:

In women: Oligo-amenorrhea, Infertility, “Post-menopausal” symptomatology, Bone loss.

In Men: Decreased Libido, ED, Gynecomastia with loss of secondary sexual characteristics, Bone loss.

Labs: Gonadotropins inappropriately low for E2 in women and T in men.

Syndrome of Panhypopituitarism

GH deficiency in Adults:

Symptoms: Reduced muscle mass and decreased exercise performance, Increased abdominal adiposity, Decreased psychosocial well being.

Signs: Central adiposity, thin dry skin, Decreased muscle strength.

Labs: Hyperinsulinemia, Dyslipidemia, “Low-normal” IGF-1 with inadequate response on Insulin tolerance test/ L-Dopa test/ L-Arginine test.

Syndrome of Panhypopituitarism

GH deficiency in Children:

GH deficiency (especially prior to onset of puberty) leads to growth retardation/ short stature.

Thyroid and Corticosteroid replacement are necessary for GH action in patients with panhypopituitarism.

Syndrome of Panhypopituitarism

TSH deficiency:

Symptoms: Fatigue, Cold intolerance, Lethargy, Constipation, Diminished appetite, Weight gain, Hoarseness of voice, Menorrhagia.

Signs: Bradycardia, Hypothermia, Pale/ cool/ dry skin, dry hair, “hung up” DTRs, stupor/ coma in severe cases.

Labs: “Low-normal” TSH with low Free T4, Abnormal TRH Stimulation test, Hyponatremia in severe cases.

Syndrome of Panhypopituitarism

ACTH deficiency:

Symptoms: Weakness, Fatigue, Nausea/ Vomiting, Weight loss

Signs: Pale skin with inability to tan, Postural Hypotension.

Labs: Mineralocorticoid function is preserved, Low AM cortisol, +/- ACTH Stimulation test, Poor pituitary ACTH reserve on Insulin tolerance test/ CRH stimulation test/ Metyrapone test.

Maintenance Medications for Hypopituitarism

Empty Sella Syndrome

Defects in diaphragma sella allowing herniation of arachnoid membrane into the hypophyseal fossa thereby leading to transmission of ICP and compressing the pituitary against the walls of the sella.

Primary vs. Acquired (Surgery, Radiation therapy, Infarction)

Pituitary function is usually normal +/- mild elevations of Prolactin.

Empty Sella Syndrome

Clinical Manifestations of Lesions of Hypothalamic Pituitary Axis

Mass effects: Headaches, Visual Field and CN III-VI Defects, Obstructive Hydrocephalus, CSF Rhinorrhea, Hypothalamic Syndromes (DI, SIADH, thirst/ appetite/ satiety/ sleep/ temperature regulation), Frontal/ Temporal Lobe Dysfunction

Endocrine Effects:

Hypopituitarism: TSH/ ACTH/ GH/ LH-FSH/ Prolactin Hyperpituitarism: TSH/ ACTH/ GH/ LH-FSH/ Prolactin

Pituitary Adenoma

Microadenomas are < 10mm.

Macroadenomas are ≥ 10mm.

Majority are monoclonal and not malignant.

May or may not be functional.

Mass effects and hypopituitarism may be present irrespective of functional status.

Functioning (secretes hormones) vs. non-functioning

Prevalence of Pituitary Tumors

TSH tumors<3%

FSH / LH tumors10-15%

ACTH tumors10-15%

GH tumors10-15%

Non-functioning tumors10-25%

Prolactin tumors25-40%

The Thyroid Axis

TSH secreting Pituitary Adenoma TSH molecule may be biologically inactive or may cause

clinical hyperthyroidism resembling Graves’ disease. TSH levels are variable, from normal to as high as 500s. Diagnosis: Inappropriately elevated TSH in presence of

high T3/T4 is highly suggestive. Alpha Subunit levels may be significantly elevated.

Treatment: Pituitary Surgery, Radiation therapy, Octreotide.

FSH/LH secreting Pituitary Adenoma

No characteristic syndrome of hormone excess is seen. Occasionally- In Men: +/- testicular enlargement, hypogonadal

symptoms. In Women: +/- hypogonadal signs and symptoms. Treatment: Pituitary surgery, Radiation therapy.

Neuroendocrine regulation of the HPA axis

ACTH secreting Pituitary Adenoma(Cushing’s Disease)

Accounts for about 60-70% of cases of Cushing’s syndrome.

Symptoms: Fatigue, Weight gain, Easy bruising, Headaches, Irregular menses, Psychiatric symptoms from depression to frank psychosis.

Signs: Plethoric “Moon facies”, ”Buffalo hump”, Central adiposity with thin extremities, Hyperpigmentation, Hypertension, Hirsuitism, Acne, Purple striae, Proximal myopathy.

ACTH secreting Pituitary Adenoma(Cushing’s Disease)

Labs: IFG/IGT, Hypokalemia and Alkalosis, Leukocytosis, Lymphopenia, Bone loss on DXA.

Diagnosis : Elevated 24 hour urinary free cortisol and/or lack of suppression by low dose dexamethasone, Elevated ACTH levels, Ectopic ACTH syndrome ruled out.

Treatment: Pituitary surgery, Medical therapy as temporizing measure, Radiation therapy

GH secreting Pituitary Adenoma(Acromegaly)

“Acral” and “facial” growth in Adults (once the epiphyses of long bones are fused).

40% may co-secrete Prolactin.

Symptoms: Headaches, Arthralgias, Fatigue, Hyperhidrosis, entrapment neuropathies, Sleep Apnea, Deepening of voice, Impotence in men, irregular menses in women.

GH secreting Pituitary Adenoma(Acromegaly and Gigantism)

Signs: “Coarsening” of facial features, enlarged hands and feet secondary to soft tissue hypertrophy, oral malocclusion and increased spacing between teeth, Moist “doughy” skin, increased heel pad thickness, Hypertension, Goiter.

Labs: IFG/IGT, +/- elevated Prolactin, Hypogonadism.

Diagnosis: Elevated IGF-1, Abnormal GTT. In children, gigantism occurs because of accelerated

linear growth (growth plates haven’t fused yet)

Diseases associated with Acromegaly

DM Arthritis and carpal tunnel syndrome

secondary to hypertrophy of joint cartilage Hypogonadism Sleep Apnea HTN, LVH Colon Polyps

Management of Acromegaly

Causes of Hyperprolactinemia

Prolactin secreting Pituitary Adenoma

Most common Pituitary lesion. Majority are microprolactinomas, few are

macroprolactinomas. E2 stimulates lactotroph proliferation. Note: Physiologic elevation of Prolactin is seen

in pregnancy. Idiopathic Prolactinoma: When the etiology is

unclear. A subset of these patients may have macroprolactinemia.

Prolactin secreting Pituitary Adenoma

Prolactin >200ng/ml is consistent with Prolactinoma

Prolactin <50ng/ml is often secondary to physiologic causes.

Prolactin 20-100ng/ml may be secondary to pituitary stalk compression by tumors not actively secreting Prolactin.

Prolactin secreting Pituitary Adenoma

Clinical Presentation: Signs and Symptoms of hypogonadism (especially amenorrhea and infertility in pre-menopausal women) +/- galactorrhea (especially in women) and gynecomastia (in men) +/- tumor mass effects.

Diagnosis: Elevated Prolactin levels in the presence of Pituitary lesion on imaging and other causes of Hyperprolactinemia ruled out.

Management of Prolactinoma

Transsphenoidal Surgical Approach

Morbidity and Mortality in Transsphenoidal

Surgery

Posterior Pituitary and AVP Secretion

Variables influencing Plasma AVP

Osmotic: Plasma Osmolality (Water balance)

Hemodynamic: Volume and Pressure sensing

Others: Emesis, Hypoglycemia

Diabetes Insipidus

Excretion of a “large” volume (usually >4 L/d) of hypotonic urine in absence of glycosuria.

Differential Diagnosis: Hypothalamic/ Central DI Nephrogenic DI Primary Polydipsia

Serum Sodium is usually maintained in the normal range. Diagnosis is suggested by inappropriately low Urine Osmolality in relation to the Serum Osmolality.

Causes of Diabetes Insipidus

Diabetes Insipidus

Clinical Features:

Central DI: Relatively abrupt onset of symptoms, Preference for cold liquids, Polyuria and Thirst persisting through the night.

Nephrogenic DI: Lithium, Demeclocycline use, Hypokalemia, Hypercalcemia.

“Psychogenic” Polydipsia: Erratic course, Symptoms exacerbated during stress, Minimal disruption of sleep (lack of nocturia), Underlying psychiatric disease.

Treatment of DI

Adequate water replacement is essential to avoid metabolic complications.

Central DI: DDAVP (Selective action on antidiuretic V2 receptors, minimal on pressor V1 receptors)

Nephrogenic DI: Thiazide leading to greater proximal tubular reabsorption of glomerular filtrate.

SIADH

Hyponatremia with low plasma osm Urine less than maximally dilute Increased urine sodium Euvolemia Normal thyroid and adrenal fxn No drugs that increase ADH

Thyroid Disease

Sheri Gillis Funderburk, MD

Thyroid

Physiology Hypothyroidism Thyroiditis Hyperthyroidism Thyroid Nodules Thyroid Cancer

Thyroid Physiology

Under regulation of the hypothalamus (TRH) and pituitary (TSH)

Thyroid gland synthesizes and releases thyroid hormone

Thyroid consists of thyroid follicles containing colloid material that contains thyroglobulin

Thyroglobulin is a glycoprotein involved in thyroid hormone synthesis

Thyroid Hormone

T4 and to lesser extent T3 is released from thyroid gland Majority T3 is produced peripherally by deiodination of

T4 Majority T4 and T3 is bound to thyroid binding globulin

(TBG) and albumin T4 is bound more tightly than T3 to TBG

Only the free hormone is active

T3 has higher affinity for thyroid receptor T3 is the more active thyroid hormone

Thyroid Hormone

Thyroid

T3 uptake

Indirect measurement of free T4 Constant x T3 resin Uptake x Total T4

Inverse relationship with TBG (in situations whn TBG is high (pregnancy, OCP use), then T3U will be low.

T3U is inversely proportional to the percentage of total T4 that is protein-bound

Thyroid

TBG Increased

Congenital Estrogen

Contraceptive, replacement, pregnancy

Hypothyroidism*

Decreased Congenital Androgens Liver failure Nephrotic syndrome Malnutrition Hyperthyroidism* Sick patients glucocorticoids

Lab values in different scenarios

↑ ↓↓↓Protein binding

↓↓↓Hypothyroidism

↓↑↑↑ Protein binding

↑↑↑Hyperthryoidism

T3RUTotal T3Total T4

Hypothyroidism

Primary Secondary

Pituitary disease follow free T4, TSH unreliable

Tertiary Hypothalamic disease

Sarcoidosis, tumor, radiation Resistance to thyroid hormone

Rare Abnormal binding of thyroid hormone to receptor High TSH and T3/T4 +/- signs hypothyroidism

Hypothyroidism

Symptoms Nonspecific Modest weight gain Cold intolerance Constipation Dry skin Fatigue Constipation Menstrual irregularities Muscle aches

Signs Dry skin/hair Nonpitting edema Thick lips or tongue Slow relaxation phase

of DTR (“hung up reflex”)

Thinning lateral aspect of eyebrows

Primary Hypothyroidism

Hashimoto’s Most common cause hypothyroidism Women>men Incidence increases with age Autoimmune destruction of thyroid gland Associated with positive anti-TPO and/or anti-

thyroglobulin antibody Slowly progressive May coexist with other autoimmune diseases

Hashimoto’s

Labs High TSH, low Total T4, total T3, T3 resin Uptake,

and free T4; positive thyroid peroxidase and/or anti thyroglobulin antibodies

We don’t usually measure free T3 Treatment

Thyroxine replacement T4 vs T3

Subclinical hypothyroidism Modestly elevated TSH with normal T4/T3

Indications for treatment Hypercholesterolemia Symptoms consistent with hypothyroidism

Post Partum Hypothyroidism

Recovery phase

Self limiting

Can reoccur with future pregnancies

Positive Thyroid Peroxidase antibodies associated with increase risk of later developing permanent hypothyroidism

Primary Hypothyroidism (other)

Iatrogenic/Drugs Thyroidectomy Radioablation Anti-thyroid medications Lithium, Amiodarone, Interferon

Frequently underlying autoimmune process Iodine deficiency

Rare in well-developed countries Dyshormonogenesis

Rare Enzymatic defect in biosynthesis

Leads to hypothyroidism and goiter

Myxedema Coma

End stage severe longstanding hypothyroidism

Endocrinology emergency Elderly Hypothermia, bradycardia, hypotension Predisposing condition

Cold, infection, trauma, CNS depressants

Myxedema Coma

Treatment Supportive care

correction hypothermia, treat underlying illness, IV fluids with glucose

IV thyroid replacement

Corticosteroids

Hypothyroidism

Miscellaneous Dosing T4

Elderly vs young Start at 25ug and titrate up 1.5ug/kg body weight

Treat TSH within normal range Exception secondary/tertiary hypothyroidism-free T4 upper

end of normal

Consider R/O adrenal insufficiency Primary vs secondary hypothyroidism

Hypothyroidism in Pregnancy

Thyroid Binding Globulin (TBG) increases with pregnancy

Pregnant women with underlying thyroid disease often unable to increase thyroid hormone production

Patient given instruction as soon as pregnancy confirmed increase dose by 30%

Some evidence hypothyroidism in 1st trimester associated with mental disability in offspring

Goal TSH in pregnancy is less than in non-pregnant patients (< 2)

Differential for thyroiditis: low uptake on scan

Infectious Acute (suppurative)-

fungal, parasite, bacterial, PCP, rare

Subacute: usually viral in origin (granulomatous: de Quervain’s)--tender gland

Painless (non post-partum)

Amiodarone-Induced

Radiation Induced Traumatic

Autoimmune: painless Chronic Lymphocytic

(Hashimotos) Postpartum

Subacute Thyroiditis

Often history viral illness Neck tenderness During recovery phase transient period hypothyroidism

lasting weeks to several months Usually transient Positive antibodies associated with increased risk of

developing primary hypothyroidism

Stages of subacute and postpartum thyroiditis

Hyperthyroid phase occurs first, usually in first 3 months after the viral illness or pregnancy and thyroid pain

Followed by several weeks of a transitory phase when euthyroidism occurs

Followed by a hypothyroid phase for several months

Followed by a Recovery phase when the patient returns to euthyroidism

Subacute Thyroiditis

Labs TSH, Total T4 and T3 resin Uptake or free T4,

total T3, and thyroid antibodies ESR: high Serum thyroglobulin: high in all forms

thyroiditis Imaging

Uptake and Scan: low uptake

Subacute Thyroiditis

Treatment Depending on stage

Beta blockers Anti inflammatory High dose PTU (decrease peripheral conversion

T4 T3) Steroids Thyroid hormone

Hyperthyroidism

Thyrotoxicosis Excess thyroid hormone from any cause

Low TSH +/- elevated T4/T3

Radioactive Iodine uptake and scan helps to differentiate various forms

Hyperthyroidism

Grave’s Disease Subacute Thyroiditis Post-Partum Thyroiditis Lymphocytic thyroiditis Acute Thyroiditis Toxic Adenoma Toxic Multinodular Goiter Iodine induced

IV contrast, iodine containing supplements

Factitious Excess Beta HCG from

molar pregnancy or choriocarcinoma

Struma ovarii TSH producing pituitary

adenoma Medications

Amiodarone, lithium, interferon

Hyperthyroidism

Symptoms Palpitations Anxiety Weight loss/gain Polyphagia Heat intolerance Increased frequency BM Tremulous Difficulty concentrating Menstrual irregularities

Signs Goiter Thyroid bruit* Resting tremor Lid lag Proptosis* Tachycardia/atrial fibrillation Widened pulse pressure Proximal myopathy Neck tenderness Dermopathy* Warm/moist skin

RAIU: most useful test in the differentiatal dx of thyrotoxicosis

High uptake Graves: diffuse pattern Toxic Multinodular

Goiter: irregular patern Solitary Toxic

Adenoma: increased in one area of thyroid

Low Uptake Factitious: low

thyroglobulin levels Iodine-Induced Thyroiditis: have high

thyroglobulin levels; may have high ESR or antibodies, depending on cause

Grave’s Disease

Most common cause hyperthyroidism (60-70%) Autoimmune activation TSH receptor

Thyroid Stimulating Immunoglobulin Familial Women > Men Associated with other autoimmune diseases

Vitiligo, Pernicious Anemia, Myasthenia Gravis, Addison’s disease, TIDM

Anti-TPO and Anti-Thyroglobulin antibodies may also be present

May have positive Thyroid stimulating immunoglobulins and/or positive Thyroid receptor antibodies

Grave’s Disease

Triad Thyroid bruit, dermopathy, proptosis are all

pathognomonic Labs

Suppressed TSH, elevated T4 and/or T3, increased T3 uptake

Imaging Uptake and scan

Increased, diffuse uptake

Grave’s Disease: Treatment

Anti-thyroid medications PTU

Inhibits synthesis thyroid hormone Decreases peripheral conversion T4 T3 Does not block release preformed thyroid hormone Side effects

Agranulocytosis, hepatitis, urticaria 18-24 months treatment to decrease chance of relapse Preferred pretreatment in surgery

Grave’s Disease: Treatment

Anti-thyroid medication Methimazole

Inhibits synthesis only Preferred treatment prior to RAI Same side effects as PTU

Cross reactivity

Beta Blocker Symptomatic relief Decrease peripheral conversion T4T3

Grave’s Disease

Treatment Radioactive iodine

Exacerbation of hyperthyroidism and eye disease Pretreatment drug of choice is methimazole (hold 5-7 days prior to

RAI) Hypothyroidism wanted/potential side effect

Iodine: used in severe thyrotoxicosis or storm Blocks release thyroid hormone Wolf Chaikoff Effect (Escape)

Surgery Rarely used Pretreatment indicated with PTU/Iodine Major complications are hypothyroidism, hypoparathyroidism,

damage to recurrent laryngeal nerve

Toxic Multinodular Goiter

Accounts for 20-30% cases hyperthyroidism Nodular goiter on exam Milder increase in T4/T3 RAI uptake and Scan

Normal to high patchy uptake RAI treatment of choice Large doses of iodine may precipitate

thyrotoxicosis in Non-Toxic MNG

Toxic Adenoma

AKA Plummer’s Disease 3-5% toxic adenoma Caused by solitary hyperfunctioning nodule Nodule may be palpable on exam Low TSH with elevated T4 and/or T3 RAI uptake and scan

Normal to high uptake Solitary hot nodule Remainder glands suppressed

RAI treatment of choice

Hyperthyroidism due to Iodine

Iodine Induced Jod Basedow Underlying thyroid pathology Self limiting History IV contrast obtained within several weeks of

onset or pt is on Amiodarone Low TSH, elevated T4, typically normal T3 Low RAI uptake Pretreatment Symptomatic relief

Hyperthyroidism due to Meds

Medications Lithium Amiodarone

Type I vs Type II Increased thyroid hormone production vs destructive

thyroiditis Often difficult to differentiate Treatment (depending on Type I vs II)

Discontinue amiodarone Anti-thyroid medications (Type 1), steroids (type II), beta-

blocker, surgery

Hyperthyroidism: other causes

Factitious Low TSH Low RAI uptake Decreased thyroglobulin

Elevated in thyroiditis Molar Pregnancy and Choriocarcinoma

Stimulatory effect of hCG, which structurally resembles TSH Struma Ovarii

Ectopic thyroid tissue RAI uptake and scan

Uptake in pelvis and no uptake in neck TSH producing pituitary adenomas

Extremely rare Suspect with elevated T4/T3 and normal/high TSH

Apathetic Hyperthyroidism

Seen in the elderly Thyrotoxicosis without the adrenergic

manifestations Appear depressed, often diagnosed with

mxyedema Weight loss, atrial fibrillation, CHF, muscle

weakness Often Toxic MNG underlying disorder

Hyperthyroidism Emergency

Thyroid Storm Decompensated form of severe thyrotoxicosis Uncommon, life threatening condition Precipitating event

ex. Infection, trauma, surgery, DKA

Fever, tachycardia, neurological abnormalities, hypertension followed by cardiovascular collapse

Treatment Anti-thyroid medications, iodine, steroids, B-blockers, control

hyperthermia

Sick Euthyroid Syndrome

Seen in critically ill patients

Low TSH, free T4, and T3

Elevated Reverse T3*

No treatment

Thyroid Nodule

Extremely common Approximately 50% patients over 65 will

have at least 1 thyroid nodule on US Incidentaloma

Thyroid Nodules

Benign Non toxic Goiter

Not associated with inflammation or neoplastic process Causes

Majority unknown Iodine deficiency Iodine excess Dyshormonogenesis Radiation

Cyst Adenoma Thyroiditis

Thyroid Nodule

Carcinoma Papillary Follicular Anaplastic Medullary Lymphoma Metastatic

Thyroid Cancer

Treatment Surgery Radioactive iodine to ablate any remnant thyroid

tissue Thyroid replacement after surgery and RAI

Suppression of TSH without overt hyperthyroidism

Follow Up Physical Exam TFTs including Thyroglobulin Thyrogen whole body scan Ultrasound