Pathophysiology

Pathophysiology

I-23. Overproduction of growth hormone and prolactin

成長ホルモン・プロラクチン過剰分泌

Growth Hormone Regulation & Effects

  • GHRH (hypothalamus, pulsatile) → somatotrophs → GH; somatostatin inhibits GH.
  • GH acts on nearly all organs (many effects via hepatic IGF-1):
    • Liver: ↑protein synthesis, ↑gluconeogenesis, ↑IGF-1.
    • Muscle: ↓glucose uptake, ↑AA uptake → ↑protein synthesis/muscle mass.
    • Adipose: ↓glucose uptake, ↑lipolysis → ↓body fat.
    • Most organs: ↑size/function; cartilage: ↑longitudinal bone growth.

Acromegaly / Gigantism

  • Usually a pituitary GH adenoma (may compress optic fibers → visual field loss).
  • Before epiphyseal closure → gigantism; after → acromegaly.
  • Symptoms (4 groups):
    1. Diabetes mellitus: GH ↑blood glucose (↓muscle/adipose uptake, ↑hepatic gluconeogenesis) → insulin resistance → T2DM; glucosuria, polyuria, polydipsia, dyslipidemia.
    2. Bone/cartilage: continued bone growth → neuropathy, arthrosis, hand-foot-face deformities, large nose/jaw, separated teeth, carpal tunnel syndrome.
    3. Visceral growth: macroglossia, cardiomegaly (hypertension, arrhythmia), sweat/sebaceous gland hypertrophy, colon polyps.
    4. Prolactin-like effect: GH shares a precursor with prolactin → GH binds prolactin receptors and/or co-secretion → ↓GnRH → galactorrhea (women), gynecomastia (men).

Prolactin Regulation

  • Inhibition: hypothalamic dopamine (main brake); prolactin induces dopamine → self-inhibition.
  • Stimulation: TRH, estrogen, breast stimulation (inhibits dopamine).
  • Effect: breast enlargement + milk production; inhibits GnRH (↓FSH/LH).

Hyperprolactinemia

Causes

  1. ↓Dopamine effect: breast stimulation; pituitary stalk injury/compression (↑prolactin, ↓other hormones).
  2. ↑TRH: primary/secondary hypothyroidism (no negative feedback → ↑TRH).
  3. Iatrogenic: dopamine-receptor-blocking drugs (antipsychotics, antihypertensives, anti-ulcer).
  4. Insufficient clearance: renal failure; macroprolactinemia (anti-prolactin antibodies → large prolactins, longer half-life; severe cases → functional hypo-prolactinemia).
  5. Prolactinoma (or prolactin + GH co-secreting adenoma).

Most common causes

  • Physiological (pregnancy/breastfeeding), pituitary adenoma, iatrogenic.

Clinical presentation

  • Most common pituitary disease.
  • Early: galactorrhea (women), gynecomastia (men); ↓GnRH → hypogonadism (both sexes).
  • Late: osteoporosis (from hypogonadism), inflammatory/autoimmune disease (prolactin’s cytokine-like effects), cognitive dysfunction.
  • Treatment: dopamine agonist (BBB-crossing); surgery/irradiation/gamma knife for adenoma.

一問一答

▶What determines whether GH excess causes gigantism or acromegaly?

Timing relative to epiphyseal closure: before closure → gigantism; after closure → acromegaly.

▶What is the usual cause of acromegaly/gigantism?

A pituitary GH-producing adenoma, which may also compress optic fibers → visual field loss.

▶How is growth hormone secretion regulated?

GHRH (hypothalamus, pulsatile) stimulates somatotrophs to release GH; somatostatin inhibits GH release.

▶How does GH exert most of its growth effects?

Largely via hepatic IGF-1; GH itself acts on most organs while IGF-1 mediates growth-promoting actions.

▶What are GH's metabolic effects on liver, muscle, and adipose tissue?

Liver: ↑protein synthesis, ↑gluconeogenesis, ↑IGF-1. Muscle: ↓glucose uptake, ↑amino-acid uptake → ↑protein/muscle mass. Adipose: ↓glucose uptake, ↑lipolysis → ↓body fat.

▶Why does GH excess cause diabetes mellitus?

GH raises blood glucose (↓muscle/adipose uptake, ↑hepatic gluconeogenesis) → insulin resistance → type 2 DM with glucosuria, polyuria, polydipsia, and dyslipidemia.

▶What bone and cartilage features occur in acromegaly?

Continued bone/cartilage growth → hand-foot-face deformities, large nose/jaw, separated teeth, arthrosis, neuropathy, and carpal tunnel syndrome.

▶What visceral changes occur in acromegaly?

Macroglossia, cardiomegaly (with hypertension and arrhythmia), sweat/sebaceous gland hypertrophy, and colon polyps.

▶Why can GH excess cause galactorrhea/gynecomastia?

GH shares a precursor with prolactin, so it can bind prolactin receptors (and/or be co-secreted) → ↓GnRH → galactorrhea in women and gynecomastia in men.

▶How is prolactin secretion regulated?

Hypothalamic dopamine is the main inhibitor (and prolactin induces dopamine → self-inhibition); TRH, estrogen, and breast stimulation increase prolactin.

▶What are the physiological effects of prolactin?

Breast enlargement and milk production, plus inhibition of GnRH (↓FSH/LH).

▶How does a pituitary stalk lesion cause hyperprolactinemia?

It interrupts dopamine delivery from the hypothalamus, releasing prolactin from inhibition (↑prolactin) while other pituitary hormones fall.

▶Why does primary hypothyroidism cause hyperprolactinemia?

Loss of negative feedback raises TRH, which stimulates prolactin secretion.

▶Which drugs cause iatrogenic hyperprolactinemia?

Dopamine-receptor-blocking drugs — antipsychotics, some antihypertensives, and anti-ulcer agents.

▶What is macroprolactinemia?

Anti-prolactin antibodies bind prolactin into large complexes with a longer half-life; severe cases reduce biologically active prolactin (functional hypoprolactinemia).

▶What are the most common causes of hyperprolactinemia?

Physiological (pregnancy/breastfeeding), a pituitary adenoma (prolactinoma), and iatrogenic (drugs).

▶What are the early clinical features of hyperprolactinemia?

Galactorrhea (women), gynecomastia (men), and hypogonadism in both sexes from ↓GnRH.

▶What are the late consequences of chronic hyperprolactinemia?

Osteoporosis (from hypogonadism), inflammatory/autoimmune disease (prolactin's cytokine-like effects), and cognitive dysfunction.

▶What is the treatment of hyperprolactinemia/prolactinoma?

A BBB-crossing dopamine agonist; surgery, irradiation, or gamma knife for an adenoma.

▶Why can a pituitary adenoma cause visual field defects?

An expanding adenoma compresses the optic chiasm/fibers, producing visual field loss (classically bitemporal).