Disorders of the Anterior Pituitary

Erna Sulistyowati

Anterior Pituitary
often referred to as the "master gland" because, together with the hypothalamus The anterior pituitary gland produces six major hormones: (1) prolactin (PRL), (2) growth hormone (GH), (3) adrenocorticotropin hormone (ACTH), (4) luteinizing hormone (LH), (5) folliclestimulating hormone (FSH), and (6) thyroidstimulating hormone (TSH) See Table

Diagram of pituitary axes

a:Hormone secretion integrated over 24 h. M: male; F: female.

Anterior Pituitary
(Tropic, Adenohypophyseal) Hormones

They are Classified into:

Somatotropic Hormones:
1- Growth Hormone (GH). 2- Prolactin (Prl). 3- Placental Lactogen (PL).

Glycoprotein Hormones:
1- Luteinizing Hormone (LH). 2- Follicle-Stimulating Hormone (FSH). 3- Chrionic Gonadotropin (CG). 4- Thyroid-Stimulating Hormone (TSH).

Pro-Opiomelanocortin (POMC) derived Hormones:

1- Corticotropin: ACTH. 2- Melanocyte-Stimulating Hormones: -MSH, -MSH. 3- Lipotropins: -LPH, -LPH

Anatomy

Diagram of hypothalamic-pituitary vasculature

Anterior Pituitary
weighs ~600 mg Loc. sella turcica ventral to the diaphragma sella The sella contiguous to vascular and neurologic structures, including the cavernous sinuses, cranial nerves, and optic chiasm expanding intrasellar pathologic processes may have significant central mass effects in addition to their endocrinologic impact. Pituitary Development from Rathke's pouch involves a complex interplay of lineage-specific transcription factors expressed in pluripotent stem cells and gradients of locally produced growth factors (see Table 333-1) Abnormalities of pituitary development caused by mutations of Pit-1, Prop-1, SF-1, DAX-1, and T-Pit result in a series of rare, selective or combined, pituitary hormone deficits

Growth Hormone (GH)

Structure: It is a single polypeptide chain composed
of 191 amino acid residues. It has two disulfide bonds.

GH
Secretion: Somatotropes of the Anterior Pituitary. Level: High in children. Maximal during adolescence. Lowest during adulthood. Measurments: During 24 hours. After stimulation. Regulation: Stimulation: By Growth Hormone Releasing Hormone (GHRH). Inhibition: By Somatostatin.

Physiological Effects:
Direct Effects:

GH

1- Stimulation of Lipolyses (Hydrolyses of Triglycerides). 2- Stimulation of Hepatic glucose output. 3- Production of Insulin-like growth factors (IGFs, Somatomedins)

Indirect Effects:
Mediated by IGF-1:
1- Increase cell numbers. 2- Positive Nitrogen balance. 3- Increase Protein synthesis.

Disease Conditions Related to GH:

Deficiency: * Dwarfism. Excessive Secretion: * Gigantism:
Due to tumor in somatotrpes in young children or adolescents.

* Acromegaly: Rare disease (3/Million). Causes: 1. Benign tumor of Pituitary gland (90%). 2. Tumors of pancreas, lung or adrenal gland. Symptoms: Enlargements of extremities.

Treatment of Acromegaly:
Transsphenoidal surgery to remove tumor. Radiation therapy usually follow the surgery. Drug Therapy: 1- Dopaminergic Agonists: Bromocriptine (Parlodel). 2- Synthetic Somatostatin analogs: Octeroide (Sandostatin).

Treatment of Acromegaly:
Uses of Growth Hormone:
* Replacement therapy for children with GH deficiency. * Administered by intramuscular or subcutaneous.

Sources:
* Recombinant DNA technology.

Growth Hormone Releasing Hormone (GHRH)

Structure: Single polypeptide chain composed of 108 amino acid residues. Function: Stimulate the secretion of GH. Uses: Treatment of children with GH deficiency due to hypothalamic defects. Diagnoses of the cause of GH deficiency.

Prolactin (Prl)
Structure: It is a single polypeptide chain composed of 199 amino acid residues. It has three disulfide bonds. Secretion: Lactotropes of the Anterior Pituitary. Level: Starts early in the fetal stages. Decline shortly after birth and remain low in males. In female increase with pregnancy reach maximum level at term and remains high during lactation. Regulation: Inhibited by Dopamine. No hypothalamic stimulation. Stimulated by TRH but this is of pathological importance.

 Physiological Effects: Breast developments and initiation of lactation. Prolactin imbalance: Hyperprolactinemia: Causes: Tumors in the lactotropes. Dopamine antagonists. Hypothyroidism associated with high level of TRH. Hypothalamus or Anterior Pituitary disorders. Renal failure. Clin manifest: In females: Galactorrhea, Amenorrhea, Infertility. In males: Galactorrhea, Impotence, Infertility.

Hyperprolactinemia, Treatment:
Dopamine agonists: Bromocriptine (Parlodel)

Gonadotropic Hormones:
They were given this name due to their effect on Gonads. They includes:
1- Luteinizing Hormone (LH). 2- Follicle-Stimulating Hormone (FSH). 3- Chrionic Gonadotropin (CG).

Structures:

They are glycoproteins. All glycoproteins are composed of two subunits and . The -subunit is similar in all hormones and contain two N-linked oligosaccharide chains. The -subunit is specific for each hormone. In LH, TSH it contains one N-linked oligosaccharide chain, while in CG and FSH it contain two N-linked oligosaccharide chains.

 Secretion:
LH and FSH are secreted from the Gonadotropes of the Anterior Pituitary. CG secreted by the placenta.

Regulation:
Stimulation: Gonadotropin-Releasing Hormone from the hypothalamus (Gn RH). Inhibition: Feed back mechanism by sex hormones. CG produced by placenta after fertilization.

Physiological effects:
In Males: LH: Stimulate production of androgens by Leydig cells. FSH: Enhance normal sperm production by Sertoli cells. In Females: LH: Induce Ovulation and stimulate Progesterone production. FSH: Enhance production of Estrogen and development of follicles.

 Uses:
Diagnostic uses: Diagnosis of Pregnancy: CG in Urine or Blood. Prediction of Ovulation: LH 36 hr before Ovulation. Reproductive system disorder in males and females. Therapeutic uses: Male infertility. Female infertility. Cryptorchidism. Antagonists: Used as contraceptives.

Gonadotropin-Releasing Hormone
(GnRH, LHRH)
Structure: Polypeptide composed of 10 amino acid residues
Secretion: Hypothalamic neurones with onset of puberty

Uses: Stimulation of Gonadotropin Secretion:

Long-term pulsatile administration in cases of deficiency. Suppresion of Gonadotropin Secretion: Long-acting GnRH in a continuous fashion. This is required in: Prostate cancer Estrogen dependent breast cancers. Endometriossis. Gonadotropin-dependent precocious puberty

Analogs: Gonadorelin HCl (Synthetic Human GnRH)

Adrenocorticotropic Hormone (ACTH)

Structure:
Peptide hormone composed of 39 amino acid residues.

Function:
Stimulate the secretion of Corticosteroids. Necessary for the adrenal gland otherwise atrophy of the gland takes place.

Control:
Feed-back inhibition by corticosteroids.

Uses:
Diagnoses of Adrenal insufficiency.

Steroidal Hormones
(Adrenocorticosteroids, Adrenocorticoids, Corticosteroids, Corticoids) Secretion:
Adrenal cortex of the adrenal gland.

Regulation:
Stimulation: ACTH. Inhibition: Feed back Mechanism.

Classification of corticosteroids
They are all C21 hormones.

Corticosteroids

Glucocorticoids
Regulate carbohydrates, lipids and proteins metabolism

Mineralocorticois
Control electrolytes and water balance

e.g. Hydrocortisone

e.g. Aldosterone.

Numbering System of Steroidal ring:

21 12 11 1 2 19 10 3 4 5 6 9 8 18 13 14 7 15 20 17 16 27 22 23 24 25

26

HO

Biosynthesis of Adrenocorticosteroids
O O

HO

HO

Cholestrol

Pregnenolone

Progesterone

HO

O OH

21-Hydroxyprogesterone

17-Hydroxyprogesterone

HO HO

HO

O OH

Corticosterone

11-Deoxycortisol

HO HO CHO

HO O HO

O OH

Aldosterone

Cortisol Hydrocortisone

Physiological Functions and Pharmacological Effects: Carbohydrates and Proteins Metabolism:

Stimulate glucose formation in the brain. Decrease peripheral utilization of glucose. Promote storage of glucose in the liver. Promote gluconeogenesis.

Lipids Metabolism:
Redistribution of body fat (Buffalo hump, Moon face). Enhance lipolyses of Triglycerides.

Electrolyte and Water balance:

Enhance reabsorption of sodium and water into plasma. Increase urinary excretion of potassium.

 Blood Picture:
Increase hemoglobin and Red blood cells. Decrease white blood cells.

Anti-inflammatory effects:
Suppress inflammations regardless to their cause.

Immunosuppressive Effects:
Decrease immunity as a result of decrease the WBCs.

Cell Growth:
Retardation of cell division and cell growth.

Disease States:
Addisons disease:
Rare syndrome 1/100,000 due to Hypoadrenalism. Causes:
Atrophy of adrenal gland. Tuberculoses. Low level of ACTH.

Symptoms:
Weakness, fatigue, apathy, depression and irritability. Anemia and low blood pressure. Loss of sodium and dehydration. Hypersensitivity to Insulin. Hyper pigmentation. Nausea and vomiting.

 Cushings disease:
Rare syndrome 2- 5/Million due to Hyperadrenalism. Causes:
Tumor of the Adrenal Cortex. Tumor of the Pituitary gland.

Symptoms:
Alteration of fat distribution. Hypertension. Osteoporosis. Growth retardation. Decrease Immunity.

Conns syndrom:
Causes:
Inability of adrenal cortex to carry out 17 -hydroxylation of pregnenolone. That leads to low level of Cortisol and high level of Aldosterone.

Symptoms:
Hypertension. Alkalosis. Polyuria. Edema.

Pharmacokinetics:
Absorption:
Well absorbed from all sites of administration.

Plasma Protein binding:

90% to albumin or globulin.

Half life (t1/2):

1- 1.5 hr.

Metabolism and Excretion:

Excreted in urine after glycosylation with glucuronic acid.

Structure-Activity Relationship
Halogen & halomethylene greatly increase Topical antiinflammatory activity Essential for activity 12-F increase all activities if no OH at C-17 12-F with 16,17dihydroxy--inactive compounds

HO
18 12

21

O
Essential for antiinflammatory activity & carbohydrate regulatory activity

Ether & esters increase antiinflammatory & glucocorticoid activities

HO
11 19 9

1, 2 Double bond improve carbohydrate metabolism to Na+ retention 1 2 10

13

17

OH
Essential for antiinflammatory activity 16 CH3 or OH eleminate Na+ retention activity

C
14

-CH3 increase glucocorticoid activity

A
5

B
6 9-Fluoro increase all activities F Br Cl

O
Essential for activity

-CH3 in Cortisol increase all activities -CH3 in Prednisolone increase antiinflammatory activity &Decrease Na retaining activity
+

Classification of Endocrine Diseases

q Hyperfunction (Excess) q Hypofunction Impaired synthesis or release (deficiency) Abnormal target tissue interaction (resistance) Abnormal target tissue response (resistance) q Mass Lesions (Neoplasia) Non-functioning (No hormone) Functioning (Hormone)

Hypopituitarism (Anterior Pituitary-AP)

Loss or Absence of > 75% of AP Most Common Causes: Nonsecretory Pituitary Adenomas Ischemic Necrosis (Sheehan's Syndrome) Ablation by Surgery or Radiation

Hypopituitarism (Anterior Pituitary-AP)

Loss or Absence of > 75% of AP Less Common Causes: Hypothalamic Tumors Empty Sella Syndrome Inflammation Trauma Metastatic Disease

AP - Hypofunction - Clinical
Usually slow in onset Growth hormone Pallor ( MSH) LH & FSH (Gonadal Atrophy) TSH - life threatening ACTH - life threatening Prolactin

Etiology of Endocrine Deficiency & Resistance Syndromes Hormone Deficiency

Autoimmune Hypothyroidism (Hashimotos) Type I Diabetes Mellitus Post Surgical Hypoparathyroidism Hypothyroidism Inflammation, Neoplasia Granulomatous Non-Functioning Adenoma Receptor Defect/Resistance Type II Diabetes Mellitus

Anterior Pituitary Insufficiency, Etiology

Anterior Pituitary Insufficiency, Etiology,cont

Developmental and Genetic Causes of Hypopituitarism

Pituitary Dysplasia Tissue-Specific Factor Mutations Developmental Hypothalamic Dysfunction

Kallmann Syndrome Bardet-Biedl Syndrome Leptin and Leptin Receptor Mutations

Prader-Willi Syndrome

Acquired Hypopituitarism
caused by
accidental or neurosurgical trauma vascular events apoplexy pituitary or hypothalamic neoplasms pituitary adenomas, craniopharyngiomas, lymphoma, or metastatic tumors inflammatory disease lymphocytic hypophysitis, infiltrative disorders such as sarcoidosis, hemochromatosis and tuberculosis irradiation brain injury trauma, subarachnoid hemorrhage, and irradiation transient hypopituitarism and require intermittent long-term endocrine follow-up 2540% permanent hypothalamic or pituitary dysfunction

Sheehan's Syndrome
Most Common Cause of Ischemic Necrosis Normal in AP in Pregnancy Ischemia During Delivery (Hypotension) Posterior Pituitary Spared

Presentation and Diagnosis of Anterior Pituitary Insufficiency

Depend on which hormones are lost and the extent of the hormone deficiency
GH deficiency growth disorders (children) and abnormal body composition (adults) Gonadotropin deficiency menstrual disorders and infertility (women) and decreased sexual function, infertility, and loss of secondary sexual characteristics (men). TSH deficiency growth retardation in children and features of hypothyroidism in children and in adults. PRL deficiency failure of lactation.

Polyuria and polydipsia (reflect loss of vasopressin secretion) if lesions involve the posterior pituitary increased cardiovascular and cerebrovascular disease increased mortality rate in patients with longstanding pituitary damage

Laboratory Investigation of Anterior Pituitary Insufficiency

Biochemical diagnosis of pituitary insufficiency is made by demonstrating low levels of trophic hormones in the setting of low target hormone levels

Laboratory Investigation of Anterior Pituitary Insufficiency

Laboratory Investigation of Anterior Pituitary Insufficiency

Hypopituitarism: Treatment
Hormone replacement therapy, including glucocorticoids, thyroid hormone, sex steroids, growth hormone, and vasopressin, is usually safe and free of complications

Pituitary Diseases
Hyperpituitarism Adenoma Sella Turcica Visual Field 's IC Pressure Hypopituitarism Destructive Processes Ischemic Injury Radiation Inflammation

Pituitary Adenomas Associations & Tendencies

In General: 10% of Cranial Neoplasms 4th - 6th Decade Functioning 3% of MEA-I Microadenomas (<1cm) Early Sxs Non-Functioning* Macroadenomas (>1cm) Late Sxs
* Null Cell (~20%)

Pituitary Adenomas Associations & Tendencies

Hormone Effect Prolactin (~25%) Growth Hormone (~15%) ACTH (~15%) Can Have Mass Effect Mass Effect* Visual Field Changes Increased Cranial Pressure Headache, N&V Hypopituitarism can Occur
* Null Cell (20%)

Pituitary Adenomas - Clinical

Hormone Effect Prolactin, ACTH,GH, TSH, etc Mass Effect Sella Turcica Erosion Visual Field Defects Intracranial Pressure

Pituitary Adenomas & Hormonal Syndromes

Hormone Secreted
Growth Hormone Gigantism & Acromegaly Prolactin Galactorrhea & Amenorrhea ACTH Cushing's Syndrome, Nelson's Syndrome

Prolactinomas
Most Common Hyperfunctioning Pituitary Adenoma F (microadenomas) > M (macroadenomas) Microscopically - Chromophobe or Weakly Acidophilic Hyperprolactinemia (>200 ug/L) Detection Depends on Clinical Status

Prolactin Effects
Prolactin
Amenorrhea Galactorrhea Libido Loss Infertility

Other Causes of Hyperprolactinemia Pregnancy Hypothyroidism Hypothalamic Supracellular Mass

Prolactinoma - Rx
1. Treated with bromocriptine (dopamine receptor agonist) 2. Surgery 3. Radiation

Growth Hormone (Somatotroph) Adenoma

Second (2nd) most common functioning adenoma Macroscopically - May be larger when detected Microscopically: +/- granulated acidophilic/chromophobic cells Immunoreactive for GH and +/- PRL

GH - Secreting Adenoma
Before Epiphyseal Closure (Prepubertal) After Epiphyseal Closure (Adults) Gigantism Body Size Long Legs/Arms Acromegaly Prognathism Enlarged Hands/Feet

Acromegaly - Other Clinical Findings

Abnormal GIT risk of cancer Diabetes Mellitus Hypertension Arthritis Osteoporosis Congestive Heart Failure (CHF)

Corticotroph Cell Adenomas

Microadenomas (<1cm) Microscopically: Basophilic or Chromophobic PAS Positive Immunochemically (+) for ACTH

Basophilic or Chromophobic

Corticotroph Adenomas - Clinically

ACTH Cortisol
Cushing's Disease Weight Gain BP Truncal Obesity Muscle Mass Diabetes Mellitus

Nelson's Syndrome
Pre-Existing Corticotroph Adenoma Adrenalectomy Removes Feed Back, hipercortosolism does not develop. Aggressive Enlargement of Adenoma, produces Mass Effect and Invasion ACTH precursor molecule on melanocyte hyperpigmentation

Pituitary Adenomas - The "Others"

Null Cell (~20%) Gonadotroph (~10%-15%) "Mass Effect" "Mass Effect" Libido Rare (<1%)

Thyrotroph (~1%)