The Hypothalamus and the Pituitary

Hormones are chemical messengers produced by specialised cells and sent via the blood. Each hormone has a different purpose, a different effect and a different set of cells to target. This entry looks at two of the most important hormone-producing organs in the body: the hypothalamus and the pituitary.

Function

The hypothalamus is situated at the centre of the base of the brain, behind and slightly above the nasal passage. The hypothalamus is responsible for many functions such as temperature, hunger, thirst and sleep, and maintains a daily cycle so that different hormones are released in different amounts, depending on the time of day. From it hangs the pituitary, the body of which is connected to the hypothalamus by a thin stalk¹. The hypothalamus sends hormones down the stalk to the pituitary via two different systems, with different results:

• Hormones are sent to the anterior pituitary (the front-most part) via a portal blood supply (one that runs between organs instead of back to the heart). Each hormone sent from the hypothalamus will cause the anterior pituitary to release more or less of one of its own hormones. These hormones travel to other parts of the body and cause further hormones to be released. For example, growth hormone-releasing hormone is produced by the hypothalamus and released into the portal blood supply, then travels to the anterior pituitary and causes it to release more growth hormone. The growth hormone then travels to the liver and causes it to release Insulin-like Growth Factor-1, which is responsible for the final effects on the body (see below).

• Hormones are sent to the posterior pituitary (the rear-most part) via nerves that run within the stalk. The posterior pituitary then stores and releases the hormones from the hypothalamus without making any hormones itself. For example, anti-diuretic hormone is produced by the hypothalamus, travels down through the nerves in the stalk, and is then released into the blood by the posterior pituitary.

If you had to guess which part of the pituitary was merely an extension of the hypothalamus, you'd probably pick the posterior part. And you'd be right.

The system described above is responsible for the release of a number of hormones into the main blood supply. The following sections detail each hormone released by the hypothalamus, the hormone it causes the anterior pituitary to release, and the effects that the hormone released by the pituitary has on the body, along with a brief description of associated diseases.

The Thyroid Axis

TRH →⁺ TSH →⁺ T4 and T3 →⁺ Increase in cell activity

• Thyrotropin-releasing hormone (TRH) is produced by the hypothalamus.
• TRH causes the anterior pituitary to release more thyroid-stimulating hormone (TSH).
• TSH causes the thyroid to produce more T4 (thyroxine) and T3 (triiodothyronine)² from iodine.
• T4 and T3 cause cells to increase their activity.

Hyperthyroidism is the name given to an excess of T4 and T3, and is almost always caused by a malfunctioning thyroid (TSH-secreting pituitary tumours are vanishingly rare). The increase in cellular activity causes increased appetite, weight loss, irritability, heat intolerance, sweating, fast heart rates, tremors and hypertension. One of the most important signs in hyperthyroidism is the 'stare' caused by eyelid retraction, which along with the thin, flushed face and the enlarged thyroid (goitre) produce the characteristic appearance seen in those with the disease. Common causes include Graves' disease, in which antibodies are produced by the immune system which then bind to receptors on the thyroid and cause it to increase production, and solitary and multiple 'hot' nodules of thyroid tissue which overproduce T4 and T3. Treatment is with the anti-thyroid drug carbimazole, or with destruction of the thyroid through surgery or radioablation with radioactive iodine.

Hypothyroidism is the opposite - a lack of T4 and T3 - and may be due to a number of causes including iodine deficiency, destruction by the immune system (Hashimoto's disease), a tumour, or due to a lack of TSH production by the pituitary. If the disease is thyroid-related it is described as primary hypothyroidism, whereas hypothyroidism due to a lack of TSH is termed secondary hypothyroidism. It is also possible for cells to be resistant to the effects of T4 and T3. The decrease in cellular activity in hypothyroidism causes tiredness, weight gain, slow heart rate, dry skin and hair, and cold intolerance. The thyroid can swell up just as it does in hyperthyroidism, though in this case it is due to compensation for the underactivity of the thyroid tissue. Treatment of hypothyroidism is with T4 (thyroxine) replacement therapy.

The Growth Hormone Axis

GHRH →⁺ GH →⁺ IGF-1 →⁺ Promotion of protein synthesis and growth

• Growth hormone-releasing hormone (GHRH) is produced by the hypothalamus.
• GHRH causes the anterior pituitary to release more growth hormone (GH).
• GH causes the liver to release more Insulin-like Growth Factor 1 (IGF-1).
• IGF-1 causes an increase in protein and collagen synthesis³, promotes growth of bones, and causes the body to retain the nitrogen, calcium and phosphorus vital for growth and repair.

Somatostatin (GHRIH) →^- GH and TSH

• Somatostatin, aka Growth Hormone Release Inhibitory Hormone (GHRIH), is produced by the hypothalamus.
• Somatostatin causes the anterior pituitary to release less growth hormone and less thyroid-stimulating hormone.

Growth hormone deficiency can be caused by tumours, infection, head injury or irradiation of the pituitary. In adults, it leads to reduced exercise capability, increased fat deposition, cold hands and feet, intolerance of the cold, and an impairment in psychological wellbeing. In children, the deficiency may also be due to an inborn defect, and leads to stunted growth in addition to the above. In all cases, the treatment is with replacement growth hormone.

An excess of growth hormone causes overgrowth of bones known as acromegaly in adults and rarely leads to gigantism, a disease characterised by growth to an excessive height, when excessive GH production begins prior to puberty. The overwhelming majority of cases are due to a benign GH-secreting tumour of the pituitary. However, one percent are due to excessive GHRH production by the hypothalamus that causes the pituitary to overproduce GH and is associated with an increased risk of malignant pituitary tumours.

Individuals with acromegaly slowly develop a characteristic face similar to that of the character Jaws in the Bond films The Spy Who Loved Me and Moonraker. Other symptoms include arthritis, backache, thickened skin, excessive sweating, deepened voice, headaches, impaired vision, weakness, menstrual cycle disruption and erectile dysfunction. However, the real risks associated with acromegaly come from the high blood pressure, greater risk of heart disease, sleep apnoea (obstruction of the airways during sleep), and type 2 diabetes that it causes.

Treatment of growth hormone excess is by radiotherapy or surgical removal of the tumour, although somatostatin-like drugs can be used to reduce growth hormone levels⁴, and growth hormone receptor blockers can be used to reduce its effect on the liver. Treatment of symptoms and prophylaxis against heart disease are also important.

The Cortisol Axis

CRH (and ADH)→⁺ ACTH →⁺ Cortisol →⁺ Various effects

• Cortiocotrophin-releasing hormone (CRH) and anti-diuretic hormone (ADH) are produced by the hypothalamus.
• CRH and ADH cause the anterior pituitary to release more adrenocorticotrophic hormone (ACTH).
• ACTH causes the adrenal glands to release more cortisol.
• Cortisol causes increased protein breakdown, fat and carbohydrate storage, fluid loss, salt retention, potassium loss and uric acid production, and causes a reduction on the body's immune response.

Cushing's syndrome, caused by excessive levels of cortisol, is best discussed in an entry covering the adrenal glands⁵. The same applies to hypoadrenalism, a lack of cortisol production by the adrenals which is known as Addison's when caused by a defect in the adrenal glands, and secondary hypoadrenalism if it is due to a pituitary defect.

The Sex Hormone Axes

Males: GnRH →⁺ LH and FSH →⁺ Testicular function and testosterone release

Females: GnRH →⁺ LH and FSH →⁺ Ovarian function and oestrogen and progesterone release

• Gonadotrophin-releasing hormone (GnRH) is produced by the hypothalamus.
• GnRH causes the pituitary to release more luteinising hormone (LH) and follicle-stimulating hormone (FSH).
• In males, LH causes the testis to produce testosterone and FSH stimulates sperm production. Testosterone produces male secondary sexual characteristics.
• In females, LH causes the ovaries to produce androgens and FSH stimulates development of egg follicles and causes conversion of the androgens into oestrogen. The follicle responsible for producing an egg during that cycle will later produce progesterone as part of the cycle. Oestrogen is responsible for female secondary sexual characteristics, and oestrogen and progesterone are responsible for building the lining of the uterus.

A lack of LH and FSH is known as gonadotrophin deficiency and can be caused by disease of the hypothalamus or stalk, and by hyperprolactinaemia (see below), anorexia nervosa, secondary hypoadrenalism (see above) and secondary hypothyroidism (see above). Gonadotrophin deficiency leads to a reduction in sex hormone production and can disrupt puberty in adolescents, whereas in adults it produces the predictable decrease in libido, fertility, potency, testicular volume in men, and breast size and period regularity in women. Long term lack of oestrogen also leads to a loss of bone mineralisation. Treatment is with correction of the underlying hyperprolactinaemia, or with replacement therapy.

Prolactin

Dopamine →^- Prolactin →⁺ Milk production

• Dopamine is produced by the hypothalamus.
• Dopamine causes the anterior pituitary to release less prolactin.
• Prolactin increases milk production, but is also responsible for depression of GnRH and LH.

Prolactin is responsible for the production of milk in response to breastfeeding, but only functions after the rise and then sudden fall of oestrogen and progesterone following pregnancy. An excessive level of prolactin in the blood is known as hyperprolactinaemia, and can be caused by pituitary tumours, damage to the stalk, inhibition of dopamine by drugs, polycystic ovary disease, hypothyroidism as well as many rarer causes.

Quite predictably, hyperprolactinaemia causes production of milk, but also depresses GnRH and LH to the point that there is decreased fertility and libido along with disrupted periods in women and decreased potency in men. In children, hyperprolactinaemia can disrupt puberty. Pituitary tumours can also cause headaches and visual field defects due to pressure on the nerves from the eyes. Treatment of hyperprolactinaemia involves the removal of the underlying cause, the use of dopamine-like drugs to inhibit prolactin release, and occasionally surgery or radiotherapy if the cause is a pituitary tumour.

Oxytocin

Oxytocin →⁺ Milk ejection and uterine contraction

• Oxytocin is produced by the hypothalamus, then secreted by the posterior pituitary.
• Oxytocin causes uterine contraction and causes milk ejection in breastfeeding mothers.

Production of oxytocin is triggered by dilation of the uterus, cervix and vagina as the foetus enters the birth canal, and in this case it causes contraction of the uterine muscles. It is also secreted as a response to breastfeeding, in which case it causes ejection of milk. Deficiency of oxytocin is rare and is only produced by damage to the hypothalamus, for instance by a hypothalamic tumour. Excess, on the other hand, might one day be deliberately induced in individuals in order to win their trust, as it has been shown that oxytocin has a role in mother-child bonding as well as in more general social relationships.

Vasopressin

Anti-Diuretic Hormone (ADH) →⁺ Retention of water and salt

• Anti-Diuretic Hormone (ADH), aka vasopressin, is produced by the hypothalamus, then secreted by the posterior pituitary.
• ADH causes the kidneys to retain water.

ADH is released in response to a drop in blood pressure or blood volume, and acts in the kidneys to cause more water to be salvaged from the urine to be retained in the blood, thus leading to production of more concentrated urine. The part of the hypothalamus responsible for ADH production is also responsible for the regulation of thirst, though the two systems are thought to be separate.

Diabetes insipidus⁶ is a disease in which the salvaging of water and salt from the urine fails, leading to a need to drink large amounts of fluid in order to maintain production of large amounts of dilute urine. Diabetes insipidus can be caused either by a defect of the pituitary leading to ADH insufficiency (cranial DI), or by a lack of response to ADH by the kidneys (nephrogenic DI). Cranial DI is treated using desmopressin, a drug that effectively replaces ADH. Nephrogenic DI may be due to high calcium levels or the use of lithium, in which case treatment is removal of the cause. Inherited causes of nephrogenic DI are more difficult to treat, and the focus is usually on treating symptoms.

The opposite of diabetes insipidus is SIADH, which stands for Syndrome of Inappropriate Anti-Diuretic Hormone secretion. In this disease, ADH is secreted persistently or inappropriately by the posterior pituitary or by a tumour, thus leading to a reduction in water lost in the urine. However, the amount of sodium lost in the urine increases, eventually leading to loss of appetite and nausea, drowsiness, confusion, and cramps, with a greater lack of sodium eventually causing convulsions, a coma and then death. There are many underlying causes of SIADH, including cancers, brain infection or injury and lung diseases. Treatment is of the underlying cause along with restriction of fluid intake and injection of sodium in order to carefully raise sodium levels in the blood.

Mix and Match

Diseases of the pituitary can cause derangement of more than one axis at a time, leading to a more complicated picture. Failure of the anterior pituitary can occur one hormone at a time, and several or the entire set of hormone deficiencies can be produced by damage to the pituitary either through natural causes or through pituitary surgery and radiotherapy. Combinations of excesses are less common as pituitary tumours tend to produce one hormone, which is most commonly prolactin.

Pituitary Surgery

Pituitary surgery usually follows the trans-sphenoidal route via the nose and through the bony roof of the nasal passages. Surgery is used to remove hormone-secreting tumours, referred to as 'functioning' tumours, in order to correct excesses which were otherwise unresponsive to treatment, but is also used to remove 'non-functioning' pituitary tumours that are pressing on surrounding structures, thus leading to defects in the individual's vision as the nerves from the eye are compressed⁷. These tumours may also press on the lining of the brain just above the pituitary and thus cause a headache, and they can even put pressure on the nerves controlling eye movement that run past either side of the pituitary on the way from the brain stem to the eyes. Surgery is especially called for in cases where a sudden loss of blood supply to the pituitary, known as pituitary apoplexy, leads to headache and sudden vision loss followed by a life-threatening coma. Radiotherapy can be used as an alternative to surgery, and is also used following some surgery to ensure clearance of the tumour.

Pituitary surgery can be successful in both restoring normal hormone levels and in rectifying vision loss. However, in a small minority of cases the surgery is unsuccessful, and in some successful cases the invasiveness of the tumour will have necessitated removal of a large part of the pituitary, thus leading to a lack of hormone production.

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¹ The pituitary weighs around 0.1 grams in the average male and up to 1 gram in pregnant females, and is around 13 millimetres across at its widest point.
² T4 is less active than T3, but is converted by the target cells into T3.
³ Collagen is an important constituent of the connective tissues of the body and is also a key part of bones and cartilage.
⁴ While somatostatin has a limited negative effect on the release of TSH, the use of a somatostatin-like drug fortunately does not produce hypothryoidism.
⁵ NB - 'Cushing's disease' refers to an excess of ACTH production by the pituitary, but this is just one of several forms of the more generalised term 'Cushing's syndrome'.
⁶ Not to be confused with diabetes mellitus, a disease relating to insulin and blood glucose levels. Both diseases cause excessive production of urine (diabetes comes from the Greek for 'siphon'), but while that of diabetes mellitus is sweet-tasting due to the sugar in it (mellitus from the Latin for 'honey'), that of diabetes insipidus is, well, insipid.
⁷ The compression occurs at the optic chiasm, a point just above the pituitary where the nerves from the nasal half of each eye cross over and head to the opposite sides of the brain. The lower part of the chiasm is affected first, but as everything seen by the eye is upside-down and the wrong way round, it is the upper, outer parts of each eye's vision that are lost first.