L15 Clinical Pharmacology Endocrine Pharmacology

Overview

Endocrine pharmacology treats disorders caused by deficiency or hypersecretion of a hormone anywhere along a hypothalamus to pituitary to target-gland axis. The lecture sets out the general logic (hormones act through cascades with negative feedback, so any single intervention feeds back through the whole system, and drugs can be used diagnostically to locate the level at which the imbalance sits), then works through two axes in detail: the thyroid axis, with carbimazole for hypersecretion and levothyroxine for deficiency, and the adrenal glucocorticoid axis, with ketoconazole or metyrapone for hypersecretion and hydrocortisone plus fludrocortisone for deficiency. Levothyroxine and prednisone are the 13th and 14th most dispensed medicines in New Zealand (740,000 and 710,000 dispensings in 2024), which is why the material is high-yield.

Principles of endocrine control

The endocrine system co-ordinates physiological systems and homeostasis on a large scale: whole body metabolism, fluid and electrolyte balance, growth and development, and reproductive and sexual function. Endocrine glands secrete messages into the bloodstream to direct cell, tissue and organ responses.

Key properties of hormones:

• Secreted in small amounts, often in a pulsatile fashion.
• They induce the secretion of other hormones, giving a cascade: gland 1 releases hormone 1, which acts on gland 2, which releases hormone 2, which acts on gland 3, which releases hormone 3 onto target cells.
• They reach all parts of the body but act only at receptors on certain cell types.
• They provide negative feedback that turns off secretion of their stimulating hormones.

Hypothalamic releasing hormones, produced in response to changes in homeostasis and acting on the anterior pituitary: PRF (prolactin-releasing factor/hormone), TRH (thyrotropin-releasing hormone), CRH (corticotropin-releasing hormone), GnRH (gonadotropin-releasing hormone), GH-RH (growth hormone-releasing hormone).

Pituitary hormones, which target other endocrine glands to produce a biological effect or to secrete further hormones: prolactin and oxytocin (breast), GH (bone, driving IGF-1, and muscle), ADH/vasopressin (kidney), TSH (thyroid, driving T3 and T4), ACTH (adrenal cortex, driving glucocorticoids), MSH (skin), and the gonadotrophins FSH and LH (ovary and testis, driving testosterone, estrogen and progesterone).

The logic of endocrine drug treatment

• Endocrine disorders can result from either deficiency or hypersecretion of any hormone at any step in the axis.
• Goals of treatment: restore correct physiological levels of hormones and treat symptoms associated with the hormone imbalance.
• Because the system has multiple feedback loops, interventions feed through the whole system. A drug given to replace a deficient upstream hormone restores downstream signalling, and a single intervention changes the whole axis.
• Drugs also have diagnostic utility: they identify the physiological level at which an imbalance occurs, and they let you monitor the effect of drugs on hormone levels. Giving drug A or drug B at different levels of the cascade shows where a missing hormone signal lies.
• Treatment tends to target downstream of the hypothalamus, at the pituitary or other endocrine glands.
• What you need to know for each drug: name and class, how it works, indications, safety, contraindications and drug interactions, and any factors that influence dosage.

Thyroid axis: physiology

The cascade is TRH (hypothalamus) to TSH (anterior pituitary) to the thyroid, which releases thyroxine T4 (the pro-hormone) and triiodothyronine T3 (the active hormone) to most tissues, with negative feedback from thyroid to pituitary and pituitary to hypothalamus. Release is pulsatile and higher in the morning.

Actions of thyroid hormones:

• Growth and development in many tissues.
• Metabolic: basal metabolic rate, glycolysis, gluconeogenesis, lipolysis.
• Cardiovascular: heart rate, systolic pressure, cardiac output.
• Neurological: alertness, memory, reflexes, emotion.

Target organs illustrated: muscle, heart, liver and kidney. On the “thyroid hormone levels” balance, Hashimoto’s thyroiditis sits at the low end, good health in the middle, and Graves’ disease at the high end.

Thyroid hormone hypersecretion

Graves’ disease is an autoimmune disease:

• Around 1% of the population, more in females, in teens and 30s to 40s, and in people with other autoimmune diseases.
• Biochemistry: no TSH, high T3/T4.
• Antibodies: TSH receptor activating antibodies and thyroid peroxidase antibodies.
• Mechanism: stimulating TSHR antibodies (TSAb) bind the TSH receptor alongside TSH and over-activate it, driving GαS to adenylyl cyclase to a large rise in cAMP (greater than with normal TSH activation) and then PKA.

Other causes of hypersecretion:

• Thyroid nodules: common, usually benign but overactive; older adults; low TSH, raised T3/T4, no antibodies.
• Thyroiditis: inflammation causes leakage of hormones, then thyroid damage; triggered by infection, after childbirth, or too much iodine; TSH and T3/T4 vary, thyroid peroxidase antibodies present but not receptor antibodies.

Features of hypersecretion: weight loss, increased metabolic rate, tachycardia, diarrhoea, overheating and sweating, infertility, anxiety, difficulty sleeping, gaunt face, goitre, exophthalmos (bulging eyes).

Treating thyroid hormone hypersecretion

Carbimazole

• Class and mechanism: inhibitor of an enzyme in T3/T4 synthesis. It prevents thyroid peroxidase from iodinating thyroglobulin, so T4 production and secretion fall. In the follicular cell, iodide transported in is normally combined with thyroglobulin by peroxidase (MIT, DIT, T3, T4) and released by proteolysis; thioamides such as carbimazole inhibit this pathway.
• Lipid soluble, so given orally.
• Starting dose: 5 to 40 mg/day for 4 to 8 weeks.
• Further dosing: titrate according to thyroid function, 5 to 15 mg/day.
• Side effects: bone marrow suppression and granulocytopenia with risk of bleeding, infection and fever (withdraw treatment immediately if WBC counts fall); risk of jaundice and liver toxicity; use in pregnancy can cause neonatal hypothyroidism, with a 2% risk of birth defects.
• Interactions and contraindications: the antipsychotic clozapine exacerbates granulocytopenia; blood disorders; liver disease, hepatitis or alcohol abuse.

Definitive treatment

• Surgery or iodine-131 (radioactive) removes or destroys the overactive thyroid gland. Surgery is more common in New Zealand.

Beta blockers (for example metoprolol)

• T3 increases beta-adrenergic receptors in the heart, raising rate and contractility, so beta blockade gives symptomatic relief by reducing the cardiac effects. Covered in other pharmacology lectures.

Thyroid hormone deficiency

Hashimoto’s thyroiditis is an autoimmune disease:

• 2 to 5% of the population, more in females, in older people, and with other autoimmune diseases.
• Biochemistry: high TSH, low T3/T4.
• Antibodies: TSH receptor blocking antibodies, which prevent TSH activating the thyroid to produce T3/T4.
• Mechanism: blocking TSHR antibodies (TBAb) occupy the TSH receptor and prevent GαS to adenylyl cyclase to cAMP to PKA signalling, so cAMP rise is reduced compared with normal TSH activation.

Features of deficiency: weight gain, fatigue, bradycardia, hair loss, intolerance for cold, heavy menstruation, poor concentration, depression, puffy face and diffuse goitre.

Iodine deficiency causes endemic goitre. Global urinary iodine concentration bands: moderate deficiency 20 to 49 µg/L, mild deficiency 50 to 99 µg/L, adequate nutrition 100 to 299 µg/L, excess intake 300 µg/L or more. Deficiency is concentrated in parts of Europe and Russia, Africa and South America.

Treating thyroid hormone deficiency

Iodinated salt treats iodine deficiency.

Levothyroxine

• Recombinant human T4.
• Lipid soluble, so given orally.
• Starting dose: 8 to 12 microgram/kg/day.
• Further dosing: titrate according to thyroid function, 8 to 15 microgram/kg/day.
• Effects: increases free T4 levels to allow uptake into cells; conversion to T3 allows nuclear translocation; it is a full agonist of thyroid hormone receptors; it reverses the effects of hypothyroidism. At cell level, T4 and T3 cross the membrane via transporters, deiodinases (D1/D2, and D3) convert T4 to T3, T3 translocates to the nucleus and binds the thyroid hormone receptor with RXR and coregulators on DNA, driving mRNA transcription and protein synthesis.
• Safety: regular TSH tests to keep levels in the normal range; low therapeutic index, so it can cause hyperthyroidism; a lower dose is needed for age over 50 or cardiac disease.
• Contraindications: suppressed TSH levels; acute myocardial infarction or adrenal insufficiency; diabetes mellitus and diabetes insipidus; and it must not be used to treat obesity or for weight loss.

Important

On the thyroid axis the two drugs act at opposite points: carbimazole blocks the thyroid’s output, while levothyroxine feeds into the T3/T4 pathway to tissues. Levothyroxine treats deficiency in hypothyroidism; carbimazole treats hypersecretion in hyperthyroidism.

Adrenal glucocorticoid axis: physiology

The cascade is CRH (hypothalamus, from the paraventricular nuclei via the median eminence) to ACTH (anterior pituitary, via the hypophyseal veins) to the adrenal gland, which releases cortisol (glucocorticoid) and aldosterone (mineralocorticoid) to many tissues and the kidney, with negative feedback back to the hypothalamus. Cortisol peaks in the morning.

Actions of glucocorticoids:

• Metabolic: gluconeogenesis, lipolysis, protein catabolism, fat mobilisation, effects on muscle and bone.
• Cardiovascular: heart rate, vascular tension.
• Immune: white cell circulation, inflammation.
• Neural: mood.
• Stress: blood glucose.

Target tissues illustrated: heart, vasculature, adipose tissue and muscle. On the “glucocorticoid levels” balance, Addison’s disease sits at the low end, good health in the middle, and Cushing’s syndrome at the high end.

Corticoid hypersecretion

Cushing’s syndrome

• Rare; caused by pituitary or adrenal tumours; 30s to 40s; higher in females; associated with type 2 diabetes.
• Can be caused by prolonged, high dose, systemic glucocorticoid therapy.
• Biochemistry: high cortisol that remains high after low dose dexamethasone suppression. ACTH levels indicate the site of the tumour.
• Features: body fat redistribution to the core and around the face, neck and shoulders; fatigue; osteoporosis; increased risk of bruising; stretch marks; infection and impaired healing; mood and personality changes.

Treatment

• Surgery, radiation or chemotherapy to remove pituitary or adrenal tumours.
• Glucocorticoid withdrawal: slow and gradual reduction in therapy.
• Ketoconazole or metyrapone: CYP450 enzyme inhibitors; lipid soluble, so given orally; dosing 0.4 to 1.2 g daily in divided doses.
  • Ketoconazole inhibits CYP11B1 and CYP11A1.
  • Metyrapone inhibits CYP11B1 and CYP11B2.
  • These sit on the steroid biosynthesis pathway running from cholesterol through pregnenolone and progesterone (and 17-hydroxy pregnenolone/progesterone, dehydroepiandrosterone, androstenedione, deoxycorticosterone, 11-deoxycortisol, corticosterone) to cortisol and aldosterone, with the gonadal branches to estrone, testosterone and estradiol. Blocking these enzymes blocks cortisol synthesis.
  • Safety: should not be used in pregnancy or with QTc prolongation; monitor liver and adrenal function; many drug interactions.

Corticoid deficiency

Addison’s disease (adrenal insufficiency)

• Rare; 30s to 50s; more in females; concurrent autoimmune disease.
• Causes: autoimmune antibodies, infection, tumours, or abruptly stopping long term glucocorticoid therapy.
• Biochemistry: varied ACTH, low cortisol and aldosterone, levels non-responsive to ACTH challenge, and 21-hydroxylase autoantibodies (21-hydroxylase produces cortisol and aldosterone).
• Features: fatigue, aching, dizziness, weight loss, hypoglycaemia.
• Adrenal crisis: pain, vomiting, diarrhoea, high K+, low Na+, loss of consciousness, death.

Treating corticoid deficiency

Glucocorticoid replacement uses synthetic corticosteroids, which are lipid soluble and given orally.

Effects:

• Agonist of the intracellular glucocorticoid receptor.
• Induces anti-inflammatory and metabolic gene expression (trans-activation at GREs: Annexin-1, SLPI, MKP-1, IκB-α, GILZ).
• Represses inflammatory gene expression (trans-repression of NF-κB/CBP, reducing cytokines, chemokines, adhesion molecules and inflammatory enzymes, receptors and proteins). Cis-repression at negative GREs affects the side-effect genes POMC, CRF-1, osteocalcin and keratin.
• Reduces hypotension and fatigue; improves energy intake, so causes weight gain.

Regimen: 20 to 30 mg daily of hydrocortisone (or a longer lasting glucocorticoid) plus or minus 50 to 300 mg daily of fludrocortisone.

Relative potencies (glucocorticoid / topical / mineralocorticoid):

• Short acting, 8 to 12 hours: hydrocortisone (cortisol) 1 / 1 / 1; cortisone 0.8 / 0 / 0.8.
• Intermediate acting, 12 to 36 hours: fludrocortisone 10 / 0 / 250 (a potent mineralocorticoid); prednisone 4 / 0 / 0.3; prednisolone 5 / 4 / 0.3; triamcinolone 5 / 4 / 0.
• Long acting, 36 to 72 hours: dexamethasone 30 / 10 / 0 (a potent glucocorticoid with no mineralocorticoid activity); betamethasone 30 / 10 / 0.

Side effects, contraindications and interactions

• Side effects and cautions: diabetics, cardiovascular disease, infections, autoimmune disease. Increase the dose during stress, infection and inflammation. Use the IV route if the patient is vomiting.
• Contraindications: immune suppression increases fungal infections; vaccine responses are compromised.
• Interactions: increased excretion of K+, with hypokalaemia when combined with amphotericin B or frusemide; CYP3A4 inhibitors such as clarithromycin and antivirals; CYP3A4 inducers such as anticonvulsants, St John’s wort and rifampicin.

Important

Prolonged high dose oral corticosteroids can cause Cushing’s syndrome with adrenal atrophy or suppression, and abrupt withdrawal leads to Addison’s disease symptoms and a flare-up of inflammatory diseases. Dose and duration are not predictive of which patients will be affected. Assess by monitoring early morning cortisol. Manage by gradual reduction: taper by 2.5 to 5 mg every 3 to 7 days until the physiological level (5 to 7.5 mg) is reached. The HPA axis may take 6 to 12 months to recover.

Overall summary

• Imbalance of endocrine hormones affects a range of physiological systems.
• The aim of treatment is to restore the typical physiological level of the hormone.
• Treatment tends to target downstream of the hypothalamus, at the pituitary or other endocrine glands, using antagonists to block a gland’s output or agonists to supply the missing hormone.
• A single intervention feeds back through the whole system, so careful monitoring of endocrine function is needed for accurate dosing.
• Be aware of risks for patients with underlying metabolic, cardiovascular or immune disease, and of food and drug interactions.
• Take care when adjusting or stopping endocrine therapies.

Self-test

1. List the four broad functions the endocrine system co-ordinates.
2. Describe the four key properties of hormones given in the lecture.
3. List the five hypothalamic releasing hormones and state which gland they act on.
4. Match each of these pituitary hormones to its target: ACTH, TSH, MSH, ADH, GH, gonadotrophins.
5. Explain why a single drug intervention in an endocrine axis affects the whole system.
6. Describe two diagnostic uses of endocrine drugs.
7. Describe the four categories of thyroid hormone action, with an example effect in each.
8. Describe the mechanism by which Graves’ disease causes thyroid hormone hypersecretion, from antibody to second messenger.
9. Distinguish Graves’ disease, thyroid nodules and thyroiditis by their TSH, T3/T4 and antibody findings.
10. List six features of thyroid hormone hypersecretion.
11. Describe how carbimazole reduces thyroid hormone production.
12. State the starting and maintenance dose ranges for carbimazole and what maintenance dosing is titrated against.
13. A patient on carbimazole develops fever and a sore throat. Explain the concern and what should happen to the drug.
14. Why is clozapine a problem in a patient taking carbimazole?
15. Explain why a beta blocker such as metoprolol helps in hyperthyroidism.
16. Describe the antibody mechanism of Hashimoto’s thyroiditis and predict the resulting TSH and T3/T4 levels.
17. List six features of thyroid hormone deficiency.
18. What urinary iodine concentration range counts as adequate iodine nutrition, and what does deficiency cause?
19. Describe the steps by which levothyroxine produces its cellular effect.
20. Explain why levothyroxine dosing needs regular TSH monitoring, and name two groups needing a lower dose.
21. List four contraindications to levothyroxine.
22. Describe the five categories of glucocorticoid action.
23. Describe the biochemical findings that support a diagnosis of Cushing’s syndrome, and what ACTH adds.
24. Distinguish ketoconazole from metyrapone by the enzymes they inhibit.
25. Predict what happens to cortisol synthesis if CYP11B1 is inhibited, and why that is therapeutically useful in Cushing’s syndrome.
26. List the biochemical findings in Addison’s disease, including the response to ACTH challenge and the autoantibody.
27. Describe the features of adrenal crisis.
28. Describe the three transcriptional mechanisms by which a glucocorticoid acts at its receptor.
29. State the replacement regimen for corticoid deficiency, including both drugs and their dose ranges.
30. Why is fludrocortisone chosen when mineralocorticoid replacement is needed, and dexamethasone when it is not? Use the relative potency figures.
31. List the three classes of drug interaction that affect glucocorticoid therapy.
32. A patient has been on high dose oral prednisone for months. Describe how you would withdraw the therapy and why, including the taper and the recovery time.
33. Explain how the same axis can produce both Cushing’s syndrome and Addison’s disease as consequences of glucocorticoid therapy.

Answers

Reveal answers

1. Whole body metabolism; fluid and electrolyte balance; growth and development; reproductive and sexual function.
2. Secreted in small amounts, often pulsatile; they induce secretion of other hormones; they reach all parts of the body but act only at receptors on certain cell types; they provide negative feedback that turns off secretion of their stimulating hormones.
3. PRF (prolactin-releasing factor), TRH, CRH, GnRH and GH-RH. They stimulate the anterior pituitary to release more hormones.
4. ACTH to the adrenal cortex (glucocorticoids); TSH to the thyroid (T3 and T4); MSH to the skin; ADH to the kidney; GH to bone (IGF-1) and muscle; gonadotrophins (FSH, LH) to the ovary and testis (testosterone, estrogen, progesterone).
5. Because the endocrine system contains multiple feedback loops, so a change at one level feeds back up and down the cascade rather than staying local. Careful monitoring is therefore needed for accurate dosing.
6. Identifying the physiological level at which an imbalance occurs (by giving drugs acting at different points in the cascade and seeing where the hormone signal fails), and monitoring the effect of drugs on hormone levels.
7. Growth and development in many tissues; metabolic (basal metabolic rate, glycolysis, gluconeogenesis, lipolysis); cardiovascular (heart rate, systolic pressure, output); neurological (alertness, memory, reflexes, emotion).
8. Stimulating TSH receptor antibodies (TSAb) bind the TSH receptor and over-activate it, coupling through GαS to adenylyl cyclase, giving a larger cAMP rise than normal TSH activation, and then PKA activation, so thyroid hormone output rises.
9. Graves’: no TSH, high T3/T4, TSH receptor activating antibodies plus thyroid peroxidase antibodies. Thyroid nodules: low TSH, raised T3/T4, no antibodies. Thyroiditis: TSH and T3/T4 vary, thyroid peroxidase antibodies present but not receptor antibodies.
10. Any six of: weight loss, increased metabolic rate, tachycardia, diarrhoea, overheating and sweating, infertility, anxiety, difficulty sleeping, gaunt face, goitre, exophthalmos.
11. It prevents the thyroid peroxidase enzyme from iodinating thyroglobulin in the follicular cell, so the MIT/DIT/T3/T4 pathway is blocked and T4 production and secretion decrease.
12. Starting dose 5 to 40 mg/day for 4 to 8 weeks; then titrate to 5 to 15 mg/day according to thyroid function.
13. Carbimazole causes bone marrow suppression and granulocytopenia, so fever and infection suggest a falling white cell count; treatment should be withdrawn immediately if WBC counts are reduced.
14. Clozapine exacerbates granulocytopenia, compounding carbimazole’s marrow toxicity.
15. T3 increases beta-adrenergic receptors in the heart, raising rate and contractility; a beta blocker gives symptomatic relief by reducing these cardiac effects.
16. Blocking TSH receptor antibodies (TBAb) occupy the TSH receptor and prevent TSH activating it, so GαS to adenylyl cyclase to cAMP to PKA signalling is reduced and thyroid hormone production falls. Result: high TSH, low T3/T4.
17. Any six of: weight gain, fatigue, bradycardia, hair loss, cold intolerance, heavy menstruation, poor concentration, depression, puffy face, diffuse goitre.
18. Adequate iodine nutrition is a urinary iodine concentration of 100 to 299 µg/L. Iodine deficiency causes endemic goitre.
19. It raises free T4 levels so T4 is taken up into cells via membrane transporters; deiodinases (D1/D2) convert T4 to T3; T3 translocates to the nucleus and binds the thyroid hormone receptor with RXR and coregulators on DNA as a full agonist, driving mRNA transcription and protein synthesis, reversing the effects of hypothyroidism.
20. It has a low therapeutic index and can cause hyperthyroidism, so TSH is tested regularly to keep it in the normal range. Lower doses are needed for patients over 50 and those with cardiac disease.
21. Suppressed TSH levels; acute myocardial infarction; adrenal insufficiency; diabetes mellitus and diabetes insipidus. It must also never be used for obesity or weight loss.
22. Metabolic (gluconeogenesis, lipolysis, protein catabolism, fat mobilisation, muscle and bone); cardiovascular (heart rate, vascular tension); immune (white cell circulation, inflammation); neural (mood); stress (blood glucose).
23. High cortisol that remains high after low dose dexamethasone suppression. ACTH levels indicate the site of the tumour (pituitary versus adrenal).
24. Ketoconazole inhibits CYP11B1 and CYP11A1; metyrapone inhibits CYP11B1 and CYP11B2. Both are CYP450 inhibitors given orally at 0.4 to 1.2 g daily in divided doses.
25. CYP11B1 catalyses the conversion of 11-deoxycortisol to cortisol in the steroid biosynthesis pathway, so inhibiting it blocks cortisol production; this lowers the excess cortisol that causes Cushing’s syndrome.
26. Varied ACTH, low cortisol and low aldosterone, levels non-responsive to ACTH challenge, and 21-hydroxylase autoantibodies (21-hydroxylase produces cortisol and aldosterone).
27. Pain, vomiting, diarrhoea, high K+, low Na+, loss of consciousness and death.
28. Trans-activation at glucocorticoid response elements, inducing anti-inflammatory genes (Annexin-1, SLPI, MKP-1, IκB-α, GILZ); cis-repression at negative GREs affecting side-effect genes (POMC, CRF-1, osteocalcin, keratin); and trans-repression of NF-κB/CBP, reducing cytokines, chemokines, adhesion molecules and inflammatory enzymes, receptors and proteins.
29. 20 to 30 mg daily of hydrocortisone (or a longer lasting glucocorticoid), plus or minus 50 to 300 mg daily of fludrocortisone.
30. Fludrocortisone has a mineralocorticoid potency of 250 against a glucocorticoid potency of 10, so it delivers mineralocorticoid replacement; dexamethasone has a glucocorticoid potency of 30 with zero mineralocorticoid activity, so it gives glucocorticoid effect alone.
31. Increased K+ excretion causing hypokalaemia with amphotericin B or frusemide; CYP3A4 inhibitors (clarithromycin, antivirals); CYP3A4 inducers (anticonvulsants, St John’s wort, rifampicin).
32. Withdraw gradually, because abrupt withdrawal leads to Addison’s disease symptoms and a flare-up of inflammatory disease after adrenal atrophy or suppression. Taper by 2.5 to 5 mg every 3 to 7 days until the physiological level of 5 to 7.5 mg is reached, monitoring early morning cortisol. Dose and duration do not predict who will be affected, and the HPA axis may take 6 to 12 months to recover.
33. Prolonged high dose systemic glucocorticoid therapy raises glucocorticoid levels above physiological and produces Cushing’s syndrome with adrenal atrophy or suppression; then abruptly stopping that therapy leaves the suppressed adrenal unable to produce cortisol, giving Addison’s disease symptoms. The same axis therefore swings from one end of the glucocorticoid balance to the other.