Medicine Marrow Pg No 945-954 (Endocrinology)

Growth Hormone Pathway

• Growth hormone receptor mutation (GHR) leads to elevated GH levels but impaired receptor function, resulting in low IGF-1 levels.
• Growth Hormone (GH) Stimulation Tests are used to measure GH levels and its response to different stimuli.
• Measuring IGF-1 levels is an indirect way to evaluate GH activity.

Acromegaly Causes

• Acromegaly is caused by excessive growth hormone secretion.
• Somatotropin adenoma is the most common cause of acromegaly, accounting for 98% of cases.
• Ectopic tumors, like those in the pancreatic islets (a classical finding) or the hypothalamus, can also lead to acromegaly.
• Other ectopic tumors include bronchial carcinoid, small cell lung cancer, and medullary carcinoma of the thyroid.

Acquired Hypopituitarism

• Loss of energy/loss of libido, bone and muscle wasting are common features of FSH/LH deficiency.
• Central obesity, hypertriglyceridemia, and endothelial dysfunction are common features of GH deficiency in adults.
• Diabetes Insipidus may be masked by other hormonal deficiencies.
• Hypocortisolemia is exacerbated by thyroxine in acquired hypopituitarism.

Pituitary Apoplexy

• Pituitary apoplexy is an acute condition caused by intra-pituitary hemorrhage.
• Clinical features include progressive headache, possible meningeal signs, ophthalmoplegia, decreased blood pressure, and hypoglycemia.

GH Secreting Adenoma

• GH secreting adenomas are macroadenomas affecting individuals between 35 - 50 years old.
• They are more common in males than females.
• Prolactinomas are microadenomas affecting individuals between 25 - 40 years old and are more common in females.
• Actions of GH secreting adenomas include increased GH levels, hypopituitarism and hyperprolactinemia (stack effect), and headache, visual impairment, and cavernous sinus thrombosis (mass effect).
• Organ manifestation includes acral enlargement (peripheral enlargement without affecting brain or internal organs), and classical coarse facies.
• Histology findings distinguish between a sparsely granulated adenoma (bad prognosis) and a densely granulated adenoma (good prognosis).
• Clinical Features include thick lips/nose, macroglossia, jaw malocclusion, prominent supraorbital ridge, frontal bossing, prognathism, and coarse facies.

Acquired Hypopituitarism - Causes

• Stalk effect (most common) causing both hypopituitarism and hyperprolactinemia.
• Sheehan's syndrome (most common).
• Viper bite (third most common).
• Secondary empty sella syndrome (fourth most common).
• Lymphocytic hypophysitis.
• Pituitary apoplexy.
• Infections: TB, Histoplasmosis, HIV, Toxoplasmosis
• Infiltration: Sarcoidosis, LCH (Langerhans' cell histiocytosis).
• Trauma/Surgery, Radiation (>18 Gy), Hemochromatosis.

Acquired Hypopituitarism - Presentation

• TSH deficiency (least prominent): Cold intolerance, bradycardia, constipation.
• ACTH deficiency (most prominent): Fatigue, asthenia, weight loss, loss of appetite, hypotension, postural hypotension, hypoglycemia, hyponatremia, no aldosterone effects, eosinophilia.
• Aldosterone deficiency (RAS deficiency): Salt craving, dehydration, hyperkalemia.

Endocrinology

• Investigations include MRI.
• Treatment involves 100 mg IV hydrocortisone and decompressive surgery.

Sheehan's Syndrome and Empty Sella Syndrome

• Sheehan's Syndrome is postpartum pituitary necrosis due to vascular insufficiency predisposing to pituitary apoplexy.
• Precipitating factors include postpartum hemorrhage (PPH), hypotension, and disseminated intravascular coagulation (DIC).
• Pathophysiology involves increased pituitary gland size during pregnancy with increased demand for blood flow which is disrupted by precipitating factors. This leads to pituitary necrosis, hypopituitarism, and hypoprolactinemia.

Growth Hormone

• Growth hormone (GH) is secreted by somatotroph cells in the anterior pituitary gland.
• It contains 191 amino acids and is secreted during stages 2 and 4 of non-rapid eye movement (NREM) sleep.

GH Signaling Pathway

• GH signaling is mediated by the JAK-STAT pathway.

Estimation and Factors Affecting GH

• GH cannot be estimated directly due to its pulsatile nature.
• Indirect estimation involves measuring IGF-1 and IGFBP-3.
• Stimulators of GH secretion include hypoglycemia, GHRH, Ghrelin, acromegaly, and TRH administration.
• Inhibitors of GH secretion include somatostatin, aging, obesity, and hypocaloric state/malnutrition.

Direct and Indirect Actions of GH

• GH has a direct action on receptors and an indirect action mediated by Insulin-like growth factor 1 (IGF-1).
• Direct actions are on target tissues.
• Indirect actions are through stimulation of IGF-1 production in the liver, which acts on bones, muscles, and other tissues.

Factors that affect Growth in Obesity

• Growth is increased in obesity due to increased IGF-1 levels, even with low GH levels.
• This is partially due to increased insulin levels in obesity.

Classical Signs in Brain Lesions

• Ring enhancing lesion: Abscess.
• Notochordal remnant with clivus destruction: Chordoma.
• Calcification, bony hyperostosis, pneumosinus dilatations: Meningioma.
• Large lobulated suprasellar mass within 3rd ventricle causing obstructive hydrocephalus: Germinoma.
• Claw sign, posterior ledge sign, nodule inside, dot sign: Rathke's cleft cyst.

Surgical Resection

• After surgery, GH level is evaluated.
• An undetectable GH level indicates good success rate.
• A detectable GH level indicates low success rate, requiring medication to prevent relapse.
• MRI is performed after 3-6 months.
• Transsphenoidal Hypophysectomy is the preferred surgical approach.
• Gamma Knife Stereotactic radiotherapy is used when surgery is not feasible.

Medication

• Somatostatin Analogs target SST2 to SST5 receptors, including Octreotide, Lanreotide, and Pasireotide.
• Dopaminergic agonists like Bromocriptine and Cabergoline are used.
• GH Receptor Antagonist: Pegvisomant
• Microadenomas have an 80% success rate, while macroadenomas have a 50% success rate.

Actions of GH, IGF and GH Measurement

• GH and IGF-1 have similar actions on bone growth, epiphyseal growth, muscle anabolism, and protein anabolism.
• Non-similar actions include:
  • Carbohydrate metabolism: GH is diabetogenic while IGF-1 is anti-diabetogenic.
  • Lipid metabolism: GH is lipolytic while IGF-1 is anti-lipolytic.
• GH actions independent of IGF-1:
  • BEAMS: Bone growth, epiphyseal growth, adipose tissue (lipolysis), muscle anabolism, salt and water retention.

Actions of IGF-1

• Wonder molecule: Genetic stability, stress resistance, telomere shortening.
• Effects: Thymus development, hematopoiesis, immune cell function, glomerular development, fetal growth, ovarian function, testicular function, neural development, amyloid-β clearance, anti-inflammatory, cardiovascular development, vasodilator, musculoskeletal development.

IGF-2

• Effects: Multiplication stimulation activity (MSA), diverse tissue, intrauterine growth development.

Somatostatin

• Effects not fully known.

Craniopharyngioma

• Characteristics:
  • Childhood (5-15): 90% of cases, suprasellar + sellar location, M>F, Adamantinomatous appearance (usually solid), wet keratin nodule, calcification ++.
  • Adults (50-74): 10% of cases, suprasellar location, M=F, Papillary appearance (solid), no calcification.
• MRI Findings: Vivid hyperintense T1 signal without contrast.
• CT Findings: Suprasellar mass with calcification.
• Central Diabetes Insipidus: Can be associated with Craniopharyngioma.
• Contrast Enhancement: Margins will only take contrast (claw sign).

Rathke's Cleft Cyst

• Characteristics: Unilocular sellar mass, typically seen in the 4th to 6th decade.

Management of Acromegaly

• Investigations:
  • Screening: Elevated IGF-1 levels.
  • Diagnostic: Oral glucose suppression test (75 gm Glucose) to check GH levels.
  • Imaging: Gadolinium enhanced MRI.
  • Pituitary Function Test: To check for other hormone dysfunction.
• Poor Prognosis: Associated with 24-hr GH >40 ng/ml.

Features of GH-secreting adenoma

• Ophthalmic features: Angle closure glaucoma.
• Nerve involvement: Carpal tunnel syndrome.
• Muscle: Myopathy (hypertrophy of type-1 and atrophy type-2).
• Cardiovascular: Increased risk of asymmetrical CVH, CAD, HF with preserved ejection fraction.
• Respiratory: Obstructive sleep apnea syndrome (OSAS).
• Gastrointestinal: Non-malignant colonic polyposis.
• Skin: Seborrhea and hyperhydrosis, warm hands.
• Gonads: Oligomenorrhea.

Metabolic Manifestations

• Diabetes Mellitus (DM): Insulin resistance, acanthosis nigricans, hirsutism.
• Elevated triglycerides.
• Elevated Calcium: Hypercalcemia leading to stones.
• Elevated Phosphate: Hyperphosphatemia.
• Fluid and Electrolyte Imbalance: Salt and water retention (due to aldosterone), decreased sodium.

Features of High Activity and Poor Prognosis

• Diabetes Mellitus (DM): Insulin resistance.
• Obstructive Sleep Apnea Syndrome (OSAS):
• Seborrhea.
• Arthritis.

Macroadenomas

• Functional Tumor:
  • GH Secreting Adenoma: Acromegaly, prolactinoma.
• Non-Functional Tumor:
  • Craniopharyngioma: (Bimodal age distribution), mass effect & stalk effect, apoplexy (bleeding), Rathke's cleft cyst.

Mc Cune Albright Syndrome

• Asymmetry of face: Polyostotic fibrous dysplasia (PDF).
• Features of Acromegaly: Classical features, precocious puberty, café-au-lait spots.

Imaging Findings:

• Heterogeneously enhancing GH secreting adenoma (all macroadenoma).
• Cystic component: Will not enhance.

Pituitary Gland Imaging:

• Pituitary gland enhanced (with contrast):
• Cystic part (without contrast): Not enhanced.