Adrenal hormones and insulin

Adrenal cortex and medulla

• Cortisol is not stored: steroids are lipid-soluble and diffuse out of the cell as soon as they are made, so secretion equals synthesis and depends on ACTH-driven cholesterol supply. Peptide glands store hormone in granules; the thyroid stores hormone outside cells in colloid.
• Cortisol peaks in the early morning around waking and is lowest near midnight; loss of this rhythm suggests Cushing syndrome.
• Cortex-to-medulla portal blood carries high cortisol, which induces PNMT to make adrenaline. Cortisol is permissive for catecholamine actions.
• Aldosterone acts mainly on principal cells of the late distal tubule and collecting duct: more ENaC and Na/K-ATPase, so sodium is reabsorbed and potassium and hydrogen ions are secreted. Secondary hyperaldosteronism in heart failure follows low renal perfusion and high renin.
• Exogenous steroids or a cortisol-secreting adenoma suppress ACTH: fasciculata and reticularis atrophy, but glomerulosa is preserved. After removal of an adenoma the other gland needs months to recover, so steroid cover is given.
• Primary adrenal failure: low cortisol and aldosterone, high ACTH and renin; hyponatraemia, hyperkalaemia, hypoglycaemia, pigmentation. Bilateral adrenal haemorrhage in meningococcal septicaemia (Waterhouse–Friderichsen) is a classic acute cause. In labour a woman on replacement needs stress-dose hydrocortisone.

Adrenal changes in pregnancy

• Cortisol: oestrogen raises CBG, so total cortisol rises; free cortisol also rises because placental CRH stimulates ACTH. The daily rhythm persists.
• Placental 11-beta-HSD2 converts cortisol to inactive cortisone, protecting the fetus. Prednisolone is largely inactivated this way; betamethasone and dexamethasone escape it (used to mature fetal lungs).
• Renin–angiotensin–aldosterone is strongly activated, yet potassium stays normal because progesterone antagonises the mineralocorticoid receptor.
• Blood pressure falls in the second trimester despite high angiotensin II because vessels show reduced sensitivity (refractoriness) to angiotensin II, mediated by prostacyclin and NO. Women who develop pre-eclampsia regain sensitivity weeks before hypertension appears.
• Fetal adrenal: the large fetal zone makes DHEA sulphate, the main fetal adrenal steroid; fetal liver 16-hydroxylates it and the placenta converts it to oestriol. Low oestriol: anencephaly or placental sulphatase deficiency.
• Phaeochromocytoma in pregnancy causes paroxysms when lying supine or with fetal movement; urinary metanephrines or VMA are raised.

Cushing syndrome and hypopituitarism in women

• Amenorrhoea in Cushing syndrome: excess cortisol suppresses hypothalamic GnRH pulses, so LH and FSH are low-normal; the cause is central, not ovarian.
• Cushing syndrome in pregnancy is rare (anovulation) and risks hypertension, diabetes and pre-eclampsia. While surgery waits for the second trimester, metyrapone (11-beta-hydroxylase inhibitor) is the usual drug; ketoconazole is avoided because its anti-androgen action can undervirilise a male fetus.
• Sheehan syndrome after massive PPH: failure to lactate (no prolactin) and later fasting hypoglycaemia with suppressed insulin, because cortisol and GH counter-regulation are lost. Hypotension, dry skin and fatigue reflect ACTH and TSH loss.

Congenital adrenal hyperplasia

• 21-hydroxylase deficiency: low cortisol removes feedback, so ACTH rises and the glands enlarge; precursors are shunted to androgens (virilised 46,XX girl). Aldosterone deficiency gives a salt-wasting crisis at 1–2 weeks: low sodium, high potassium.
• Non-classical form: hirsutism and irregular periods. Glucocorticoid treatment suppresses ACTH and androgen excess.

Insulin and glucagon

• Insulin release: glucose enters beta cells via GLUT2, glucokinase raises ATP, ATP closes K-ATP channels, depolarisation opens calcium channels, granules fuse. C-peptide is secreted equimolar.
• Inhibited by adrenaline and noradrenaline (alpha-2), somatostatin and fasting; stimulated by glucose, amino acids, GLP-1 and vagal (M3) input.

• GLUT4 in skeletal muscle and adipose tissue is the insulin-dependent transporter. Brain (GLUT1, GLUT3), liver and beta cells (GLUT2) and red cells (GLUT1) are insulin-independent. Exercise moves GLUT4 without insulin.
• Glucagon acts mainly on liver via Gs and cAMP: glycogenolysis (main action), gluconeogenesis and ketogenesis; it decreases glycogen synthesis and fatty acid synthesis. Glucagon and adrenaline share the cAMP pathway and both raise blood glucose by glycogenolysis. Cortisol's main metabolic action is gluconeogenesis.
• Defence against falling glucose: insulin falls first, then glucagon and adrenaline; cortisol and GH later.
• Factitious hypoglycaemia: high insulin with low C-peptide means injected insulin (commercial insulin has no C-peptide); high insulin with high C-peptide means insulinoma or sulphonylurea.

Metabolism in pregnancy

• The fasting glucose is low mainly because the fetus and placenta draw glucose continuously, by facilitated diffusion (GLUT1), whether or not the mother eats; plasma volume expansion adds a little dilution. It is not a sign of better insulin sensitivity.
• Insulin does not cross the placenta; glucose does.
• DKA occurs at lower glucose in pregnancy. Glycosuria reflects raised GFR. Betamethasone and beta-2 agonists raise glucose in diabetic women. Gestational diabetes predicts later type 2 diabetes.

Fetal effects of maternal hyperglycaemia

• In PCOS, high insulin stimulates theca androgen production and lowers SHBG.

Remember Placenta: blocks insulin, lets glucose through, inactivates cortisol but not betamethasone.

Exam trap hPL, not hCG, is the main cause of insulin resistance in late pregnancy.

Exam trap Hypoglycaemia with suppressed insulin is counter-regulatory failure (cortisol, GH), not insulinoma.

How FCPS asks about this

• Cortisol peaks: early morning around waking.
• Why steroids are not stored: lipid-soluble, they diffuse out as made.
• High insulin, low C-peptide: exogenous insulin injection.
• Insulin-dependent glucose transporter: GLUT4 in muscle and fat.
• Low fasting glucose in pregnancy: continuous glucose transfer to the fetus.
• Pregnancy protection against angiotensin II: reduced vascular sensitivity; lost before pre-eclampsia.
• Main steroid of the fetal adrenal: DHEA sulphate, made into oestriol by the placenta.