Thyroid and Hormone Disorders

TL;DR. Hormones are chemical messages released into the blood by one organ to control another, and the endocrine system is built almost entirely out of feedback loops: a gland senses too little of something, releases a stimulating signal, the target organ responds, and the rising level shuts the signal off. Understanding the loop means you can predict every lab result. Too little thyroid hormone means a high stimulating signal (TSH) and a low hormone level; too much means the reverse. The thyroid sets the body's metabolic pace, so its failure slows everything and its excess speeds everything, which is why both are misdiagnosed as depression, anxiety, ageing, or heart disease. Thyroid disease is extremely common, easy to test for with one blood test, and, in the case of underactivity, treated with a cheap tablet that works.

Key takeaways

• Hypothyroidism affects roughly 5 percent of people and is far more common in women. One blood test finds it, and one daily tablet treats it completely.
• Iodine deficiency remains the leading preventable cause of intellectual disability worldwide, and salt iodisation is one of the great cheap public health victories.
• TSH moves in the opposite direction to thyroid hormone. A high TSH means an underactive gland. This single fact explains most thyroid test interpretation.
• Thyroid nodules are extremely common and cancer in them is rare, which is why aggressive ultrasound screening produced an epidemic of overdiagnosis in South Korea with no change in mortality.
• Adrenal insufficiency is rare and lethal if missed. Anyone on long-term steroids has a suppressed adrenal axis and needs extra steroid during illness or surgery.
• PCOS affects roughly 1 in 10 women of reproductive age and is a metabolic condition as much as a gynaecological one.

How the system works

In short: Three levels with feedback, which means two numbers tell you which level has failed.

An endocrine axis has three levels: the hypothalamus in the brain releases a releasing hormone, the pituitary below it releases a stimulating hormone into the blood, and the target gland releases the final hormone, which feeds back to switch off both levels above.

The feedback structure lets you locate a problem from two numbers. If the final hormone is low and the stimulating hormone is high, the target gland has failed (primary disease). If both are low, the pituitary or hypothalamus has failed (secondary or tertiary). That logic runs through everything below.

Hypothyroidism

In short: Everything slows, it mimics depression and dementia, one blood test finds it, and one cheap daily tablet fixes it completely.

What it is. Insufficient thyroid hormone. The thyroid, a butterfly-shaped gland in the neck, produces thyroxine (T4), largely a prohormone, which is converted in tissues to the active T3. Thyroid hormone sets the basal metabolic rate of nearly every cell, regulating how fast they use oxygen and produce heat, and it is essential for brain development in the fetus and infant.

Causes. In iodine-sufficient countries, the commonest cause is Hashimoto's thyroiditis, an autoimmune destruction of the gland (Chapter 47). Also: treatment of previous hyperthyroidism (radioiodine or surgery), certain drugs (amiodarone, lithium, checkpoint inhibitors), congenital absence or malfunction, and, globally, iodine deficiency.

What it does. Everything slows:

• General: fatigue, weight gain (usually modest, 2 to 5 kg, mostly fluid rather than fat), intolerance of cold, hoarse voice.
• Neurological and psychiatric: slowed thinking, poor memory and concentration, depression. Hypothyroidism is a treatable mimic of both depression and dementia, and testing for it is routine in both work-ups for that reason.
• Cardiovascular: slow heart rate, raised cholesterol, raised diastolic blood pressure, eventually pericardial effusion.
• Skin and hair: dry coarse skin, hair loss including the outer third of the eyebrows, brittle nails.
• Gut: constipation.
• Reproductive: heavy or irregular periods, subfertility, and, in pregnancy, increased miscarriage and adverse outcomes.
• Severe untreated: myxoedema coma, a rare emergency with hypothermia, hyponatraemia, reduced consciousness, and high mortality.

In infancy, untreated congenital hypothyroidism causes irreversible intellectual disability and growth failure. This is why it is on every newborn screening panel: found in the first days and treated immediately, development is normal, and the entire disaster is averted with a cheap test and a cheap tablet. It is one of the strongest arguments for newborn screening in existence.

Diagnosis: TSH first. A raised TSH with low free T4 confirms primary hypothyroidism. A raised TSH with normal T4 is subclinical hypothyroidism, which is common, often transient, and where the decision to treat depends on the TSH level, symptoms, antibody status, pregnancy, and age. Treating mild subclinical hypothyroidism in older people has not shown benefit in trials, which has changed practice toward more watching and less prescribing.

Treatment: levothyroxine, synthetic T4, taken once daily on an empty stomach (calcium, iron, coffee, and soy interfere with absorption), with the dose titrated by TSH after 6 to 8 weeks. It is one of the most-prescribed drugs in the world and one of the most satisfying to prescribe: physiological replacement of a missing molecule, with complete resolution of symptoms in genuine deficiency.

Two honest caveats. A minority of adequately treated patients report persistent symptoms despite a normal TSH; whether this reflects inadequate tissue T3, another diagnosis, or the non-specificity of the symptoms is unresolved, and combination T4/T3 therapy has not shown consistent benefit in trials. And levothyroxine is widely prescribed to people with borderline results and non-specific tiredness who do not benefit from it, which is a genuine overtreatment problem alongside genuine undertreatment elsewhere.

Hyperthyroidism

In short: Everything accelerates, it is a treatable cause of atrial fibrillation, and in older people it can present as apathy rather than agitation.

What it is. Excess thyroid hormone, so everything accelerates.

Causes: Graves' disease (autoimmune antibodies that stimulate the TSH receptor, the commonest cause, and a rare and instructive example of an activating autoantibody), toxic multinodular goitre, a single toxic adenoma, thyroiditis (a transient release of stored hormone from an inflamed gland, often after viral illness or after pregnancy), and excess thyroid hormone intake.

What it does: weight loss despite increased appetite, heat intolerance and sweating, tremor, anxiety and irritability, palpitations, atrial fibrillation (an important and treatable cause, and one that should prompt a thyroid test in every new case), insomnia, frequent bowel movements, muscle weakness particularly in the thighs, and menstrual disturbance. In older adults it can present paradoxically as apathy, weight loss, and atrial fibrillation without the classic agitation, which is why it is missed.

Graves' disease adds two distinctive features: a diffusely enlarged gland, and thyroid eye disease, in which the same immune process inflames and expands the tissue behind the eyes, causing them to protrude, with grittiness, double vision, and, rarely, sight-threatening optic nerve compression. Smoking substantially worsens eye disease, which makes stopping smoking a specific treatment recommendation here.

Thyroid storm is the emergency: fever, tachycardia, agitation or confusion, and cardiovascular collapse, usually precipitated by infection or surgery in untreated hyperthyroidism. Mortality is substantial even with treatment.

Treatment:

• Antithyroid drugs (carbimazole, methimazole, propylthiouracil) block thyroid peroxidase, the enzyme that attaches iodine to make hormone. Typically given for 12 to 18 months in Graves' disease, after which about half remain in remission. Agranulocytosis occurs in roughly 0.2 to 0.5 percent, and every patient must be told to stop the drug and get an urgent blood count if they develop a sore throat or fever.
• Beta blockers for symptom control while waiting for the above to work.
• Radioactive iodine, taken orally and concentrated by the thyroid, which irradiates and destroys it from within. Definitive, simple, and it usually results in permanent hypothyroidism requiring lifelong levothyroxine, which is an acceptable trade. It can worsen thyroid eye disease and is avoided in pregnancy.
• Surgery for large goitres, suspicion of cancer, or where other treatments are unsuitable.

Iodine, goitre, and a public health success

In short: Salt iodisation cost a few cents per person and removed the leading preventable cause of intellectual disability from most of the world.

Thyroid hormone contains iodine, and the body cannot make it. Where soil and therefore food is iodine-poor, characteristically inland and mountainous regions, the thyroid enlarges as it strains to capture what little there is, producing a goitre.

The consequences of deficiency, in ascending severity: goitre, hypothyroidism, and, in pregnancy, impaired fetal brain development. Severe deficiency causes cretinism, a syndrome of profound intellectual disability, deafness, and stunting, and moderate deficiency causes measurable losses in IQ across whole populations without any individually obvious disease.

Universal salt iodisation, adopted progressively since the 1920s and pushed globally from the 1990s, has reduced the number of iodine-deficient countries from over 110 to a small number. It costs a few cents per person per year. It is one of the largest and cheapest gains in global cognitive health ever achieved, and it is invisible precisely because it worked.

Deficiency is re-emerging in some high-income countries as people shift to non-iodised salt, reduce dairy intake, and eat more processed food made with non-iodised salt, with mild deficiency documented in pregnant women in several European countries.

Thyroid nodules and thyroid cancer

In short: South Korea diagnosed fifteen times more thyroid cancer after mass screening and mortality did not change, which is overdiagnosis in its purest form.

Thyroid nodules are extremely common: palpable in perhaps 5 percent of adults, and found on ultrasound in up to half of people over 50. The overwhelming majority are benign.

Thyroid cancer, mostly papillary, is usually indolent, with a 20-year survival above 95 percent for the common types. Which sets up one of the clearest overdiagnosis stories in medicine.

South Korea introduced widespread thyroid ultrasound screening in the late 1990s, often as a cheap add-on to general health checks. Thyroid cancer diagnoses rose roughly fifteen-fold over two decades, making it the country's most commonly diagnosed cancer. Tens of thousands of thyroids were removed. Mortality from thyroid cancer did not change at all. Autopsy studies had long shown that a substantial proportion of people who die of other causes have small papillary thyroid cancers that never troubled them.

The response has been better nodule risk stratification, higher thresholds for biopsy, and active surveillance for small low-risk papillary cancers, which Japanese centres have shown is safe over long follow-up. This is Chapter 17's overdiagnosis section made concrete: a test that finds real cancers, and finding them does not help.

Adrenal disorders

In short: Too little cortisol is rare and lethal if missed, and the commonest cause is not a disease but long-term steroid treatment.

The adrenal glands sit on top of the kidneys and produce cortisol (the stress hormone regulating glucose, blood pressure, and immune function), aldosterone (salt and water balance), and adrenal androgens.

Adrenal insufficiency (Addison's disease): too little cortisol. Primary disease is usually autoimmune destruction in high-income countries and tuberculosis globally. Symptoms are vague and progressive: fatigue, weight loss, nausea, dizziness on standing, salt craving, and, in primary disease, darkening of the skin and gums (because the pituitary's ACTH signal, produced in excess, also stimulates pigment cells).

Adrenal crisis is the emergency: vomiting, abdominal pain, profound hypotension, low sodium, high potassium, and collapse, precipitated by infection, injury, or surgery in someone who cannot mount a cortisol response. It kills people, and it is preventable with prompt injectable hydrocortisone.

The commonest cause of adrenal insufficiency in practice is not Addison's disease: it is suppression from long-term corticosteroid treatment. Exogenous steroids switch off the pituitary's ACTH output, the adrenal glands atrophy, and the axis takes weeks to months to recover. Anyone taking steroids for more than a few weeks must not stop abruptly and needs extra steroid cover during illness, injury, and surgery: sick day rules that every such patient should be taught and given in writing, along with a steroid emergency card.

Cushing's syndrome: too much cortisol. Again most commonly from prescribed steroids; endogenous causes are a pituitary adenoma secreting ACTH (Cushing's disease), an adrenal tumour, or ectopic ACTH from a cancer. It produces central obesity with thin limbs, a round face, purple stretch marks, thin bruisable skin, muscle weakness, diabetes, hypertension, osteoporosis, and mood disturbance.

Primary aldosteronism: excess aldosterone causing hypertension and often low potassium. Once considered rare, it is now recognised as a cause of perhaps 5 to 10 percent of hypertension and considerably more of resistant hypertension (Chapter 20). It is worth finding because it can be cured surgically if one gland is responsible, or treated specifically with spironolactone, and because it causes more cardiovascular damage than equivalent essential hypertension.

Phaeochromocytoma: a rare adrenaline-secreting tumour producing episodic severe hypertension, headache, palpitations, and sweating.

Reproductive and metabolic hormone disorders

In short: PCOS is a metabolic condition with reproductive consequences, and menopause treatment is still recovering from how one trial was reported in 2002.

Polycystic ovary syndrome (PCOS) affects roughly 8 to 13 percent of women of reproductive age and is the commonest cause of anovulatory infertility. Diagnosis requires two of three: irregular or absent ovulation, clinical or biochemical excess androgens (acne, excess hair growth, hair thinning), and polycystic ovarian morphology on ultrasound.

The core mechanism is insulin resistance plus excess androgen production, which interact: insulin resistance raises insulin, insulin stimulates ovarian androgen production and lowers the binding protein that keeps testosterone inactive, and the resulting hormonal environment disrupts ovulation. So PCOS is a metabolic condition with reproductive consequences, and women with it have substantially raised risks of type 2 diabetes, gestational diabetes, metabolic syndrome, and endometrial cancer (from unopposed oestrogen when periods are absent).

Management follows the mechanism: weight management where relevant (5 to 10 percent loss often restores ovulation), metformin, combined hormonal contraception to regulate cycles and reduce androgen effects, letrozole for ovulation induction (now first-line, ahead of clomifene), and specific treatment of hirsutism and acne. GLP-1 receptor agonists are increasingly used where obesity is prominent.

Menopause: the permanent cessation of ovarian function, on average around age 51. The fall in oestrogen causes hot flushes and night sweats (in up to 80 percent), sleep disruption, mood change, vaginal dryness and urinary symptoms, and accelerated bone loss. Hormone replacement therapy is the most effective treatment for symptoms, and its story is a cautionary tale about evidence communication: the 2002 Women's Health Initiative results were reported in a way that produced a collapse in prescribing worldwide, and subsequent analysis showed the risk profile depends heavily on age at initiation, formulation, and route, with the balance generally favourable for symptomatic women starting within about ten years of menopause. Millions of women went untreated in the interim.

Male hypogonadism: reduced testosterone from testicular failure or pituitary disease, causing fatigue, low libido, erectile dysfunction, reduced muscle mass, and bone loss. Genuine deficiency should be confirmed on repeated morning samples and investigated for cause. This is distinct from the large commercial market in testosterone for age-related decline, where benefits are modest and the long-term cardiovascular and prostate safety data are limited.

Vitamin D, which is a hormone rather than a vitamin, deserves a sentence: genuine deficiency causes rickets in children and osteomalacia in adults, and supplementation in deficiency is clearly worthwhile, while large trials of supplementation in unselected populations have failed to show the benefits for cancer, cardiovascular disease, and infection that observational studies had suggested. Low vitamin D is often a marker of poor health rather than a cause of it.

Is any of this contagious?

No. Endocrine disorders cannot be transmitted between people. The autoimmune ones cluster in families through shared genetic susceptibility, and iodine deficiency clusters geographically because it is a property of the soil, not of contagion.

What the person can do

In short: Ask for a TSH test for unexplained fatigue or mood change, use iodised salt, and never stop long-term steroids abruptly.

• Ask for a TSH test if you have unexplained fatigue, weight change, cold or heat intolerance, new depression or anxiety, new atrial fibrillation, or unexplained high cholesterol. It is cheap, and the conditions it finds are eminently treatable.
• Take levothyroxine consistently, on an empty stomach, away from calcium, iron, and coffee, and have the dose rechecked in pregnancy, when requirements rise substantially and early.
• Use iodised salt, and if pregnant or planning pregnancy, check that your intake is adequate, since fetal brain development depends on it.
• If you are on long-term steroids: never stop abruptly, carry a steroid card, learn the sick day rules, and have injectable hydrocortisone at home if you have adrenal insufficiency.
• On antithyroid drugs: stop and seek an urgent blood count for sore throat or fever.
• In PCOS, treat it as a metabolic condition: address insulin resistance, screen for diabetes, and ensure you have at least a few withdrawal bleeds a year to protect the endometrium.
• Do not accept a thyroid nodule scan as automatically requiring action. Ask about the risk stratification and whether surveillance is reasonable.
• Be sceptical of hormone testing outside conventional care. Saliva hormone panels, "adrenal fatigue," and compounded bioidentical hormones are marketed heavily and are not supported by evidence; genuine adrenal insufficiency is a specific, diagnosable, dangerous condition and is not what those products are describing.

What's next

• Better hyperthyroidism treatment: antibody-targeted therapies for Graves' disease, and teprotumumab, an IGF-1 receptor antibody that produced substantial improvement in thyroid eye disease, the first effective drug for a condition previously managed with steroids and surgery.
• De-escalating thyroid cancer care, extending active surveillance and reducing unnecessary thyroidectomy.
• Understanding persistent hypothyroid symptoms despite normal TSH, which affects a real minority and currently has no accepted explanation or treatment.
• PCOS as a metabolic target, with GLP-1 drugs likely to change management substantially.
• Reassessing menopause hormone therapy on the basis of the full evidence rather than the 2002 headlines, which is now underway in guidelines.

Sources and notes

Hypothyroidism prevalence and thyroid physiology follow standard endocrinology references (Williams Textbook of Endocrinology). Iodine deficiency and salt iodisation: WHO and the Iodine Global Network; the reduction in iodine-deficient countries since the 1990s is documented in their periodic reports. Congenital hypothyroidism newborn screening outcomes: long-standing programme data. South Korean thyroid cancer overdiagnosis: Ahn, Kim, and Welch, NEJM, 2014. Active surveillance of low-risk papillary thyroid cancer: Ito et al., Kuma Hospital cohort. Subclinical hypothyroidism treatment in older adults: TRUST trial, NEJM, 2017. Combination T4/T3 therapy: systematic reviews finding no consistent benefit. Primary aldosteronism prevalence in hypertension: Monticone et al. and Brown et al. analyses. PCOS prevalence and diagnostic criteria: International Evidence-Based Guideline, 2023. Women's Health Initiative: JAMA, 2002, and subsequent age-stratified reanalyses. Teprotumumab: Douglas et al., NEJM, 2020. Vitamin D supplementation trials: VITAL, NEJM, 2019, and D-Health.

Open questions. Why some treated hypothyroid patients remain symptomatic is unresolved. The optimal threshold for treating subclinical thyroid dysfunction is contested. The long-term safety of testosterone therapy in age-related decline is not established.

Next: the tube that runs through you, and everything that goes wrong with it. 👉