The hypothalamus is the region in the ventral brain which coordinates the endocrine system. It receives many signals from various regions of the brain and in return, releases both releasing and inhibiting hormones, which then act on the pituitary gland to direct the functions of the thyroid gland, adrenal glands, and reproductive organs and to influence growth, fluid balance, and milk production. It is also involved in the non-endocrine functions of temperature regulation, regulation of the autonomic nervous system, and the control of appetite.
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The hypothalamus is located in the ventral brain above the pituitary gland and below the third ventricle. The afferent pathways to the hypothalamic nuclei, the majority of which are located in the anterior hypothalamus, arise from the brainstem, thalamus, basal ganglia, cerebral cortex, and olfactory areas.
One of the major efferent pathways from the hypothalamus is the hypothalamic-neurohypophysial tract, which connects the para-ventricular and supraoptic nuclei of the hypothalamus to the nerve terminals in the median eminence, towards the anterior pituitary gland, and the posterior pituitary gland. The para-ventricular nucleus releases mostly oxytocin and some ADH, and the supraoptic nucleus releases mostly ADH and some oxytocin directly into the bloodstream. The pituitary gland is comprised of the adenohypophysis, also known as the anterior pituitary, and the neurohypophysis, also known as the posterior pituitary.
The hypothalamus forms during the first trimester, specifically at week 8, and is derived from the diencephalon.
The hypothalamus ultimately affects the functions of the pituitary gland, thyroid gland, adrenal glands, kidneys, musculoskeletal system, and reproductive organs.
The hypothalamus functions in conjunction with the pituitary gland through the hypothalamic-pituitary axis. The hypothalamus itself contains several types of neurons that release different hormones. The thyrotropin-releasing hormone (TRH), gonadotropin-releasing hormone (GnRH), growth hormone-releasing hormone (GHRH), corticotropin-releasing hormone (CRH), somatostatin, and dopamine are released from the hypothalamus into the blood and travel to the anterior pituitary.
The thyrotropin-releasing hormone is a tripeptide that stimulates the release of thyroid-stimulating hormone and prolactin from the anterior pituitary gland. The gonadotropin-releasing hormone triggers sexual development at the onset of puberty and maintains female and male physiology after that by controlling the release of follicle-stimulating hormone and luteinizing hormone. The growth hormone-releasing hormone stimulates the secretion of growth hormone by the anterior pituitary. The corticotropin-releasing hormone stimulates the release of adrenocorticotropic hormone from the anterior pituitary. Somatostatin inhibits the release of both growth hormone and thyroid-stimulating hormone, and various intestinal hormones. Dopamine inhibits the release of prolactin from the anterior pituitary, modulates motor-control centers, and activates the reward centers of the brain. Prolactin functions mainly to promote lactation but also helps regulate reproduction, metabolism, and the immune system.
Vasopressin and oxytocin are 2 hormones made in the hypothalamus itself which travel in hypothalamic neurons directly to the posterior pituitary. Vasopressin, also known as the anti-diuretic hormone or ADH, acts on the collecting ducts in the kidneys to facilitate reabsorption of water. Oxytocin stimulates contractions of the uterus at birth and release of milk when an infant begins to breastfeed. Orexin and ghrelin are known to increase appetite. So these hormones enhance the action of the lateral hypothalamic nucleus while leptin does the reverse. However, leptin promotes the function of the ventromedial nucleus by decreasing appetite; orexin and ghrelin antagonize its actions. 
Impairment or damage to any of the hypothalamic nuclei causes a deficit in its function. The following abnormalities can be seen in the impairment of each hypothalamic nuclei:
- Anterior nucleus: Poor heat dissipation
- Posterior nucleus: Excessive heat dissipation
- Ventromedial nucleus: Increase in appetite
- Lateral nucleus: Decrease in appetite
- Arcuate nucleus: Dysfunction of the tuberoinfundibular pathway
- Supraoptic nucleus: Central diabetes insipidus due to loss of ADH production
- Paraventricular nucleus: Decrease in the secretion of oxytocin
- Suprachiasmatic nucleus: Circadian rhythm dysfunction
Disorders of the hypothalamic-pituitary axis can manifest in various clinical syndromes.
Acromegaly and Pituitary Gigantism
Both acromegaly and pituitary gigantism are rare disorders of growth, occurring in anywhere between 40 to 125 per million people, that occur due to persistent secretion of growth hormone from the pituitary gland. Pituitary gigantism occurs in adolescents and children who have growth hormone excess before the fusion of their epiphyseal growth plates whereas acromegaly occurs in adults who have growth hormone excess after the fusion of their epiphyseal growth plates.
Excess growth hormone can originate from excess hypothalamic growth hormone-releasing hormone, excess growth hormone production by the pituitary somatotroph cells, and rarely due to an ectopic source of either growth hormone or growth hormone-releasing hormone. Excess growth hormone leads to excess secretion of insulin-like growth factor from the liver, which then mediates growth-promoting effects in skeletal muscle, cartilage, bone, liver, kidneys, nerves, skin, and lung cells and regulates cellular DNA synthesis.
Adolescents and children with pituitary gigantism present most often with a rapid abnormal increase in height concurrent with rapid weight gain. Other less common features include large hands and feet, macrocephaly, coarsening of the facial features, and excessive sweating. Adults with acromegaly present with soft tissue overgrowth and skin thickening, with the characteristic features of macrognathia, macroglossia, and enlarged hands and feet, hypertrophy of the knees, ankles, hips, and spine, visceral enlargement of the thyroid and heart, insulin resistance, and diabetes. In particular, adults with growth hormone excess do not present with an increase in height due to the growth hormone excess occurring after the fusion of the epiphyseal growth plates.
Central Diabetes Insipidus
Central diabetes insipidus is an uncommon condition, occurring in 1 per 25,000 people, that occurs due to a decrease in anti-diuretic hormone production. The most common cause of central diabetes insipidus is idiopathic and is associated with the destruction of the ADH secreting supraoptic and para-ventricular hypothalamic nuclei, most likely due to an autoimmune process.
Individuals with central diabetes insipidus present with polyuria, polydipsia, and nocturia. These individuals can maintain their serum sodium in the high-normal range due to the ongoing stimulation of thirst. If their thirst is impaired or cannot be expressed, such as in children and patients with central nervous system (CNS) lesions, they will also present with hypernatremia.
Syndrome of Inappropriate Anti-diuretic Hormone
The anti-diuretic hormone, or vasopressin, maintains our serum osmolality by controlling water reabsorption in the collecting ducts of the kidneys. The syndrome of inappropriate anti-diuretic hormone, also known as SIADH, occurs due to an inappropriately high serum ADH concentration in relation to serum osmolality. The most common causes of SIADH include central nervous system disorders, including stroke, hemorrhage, infection, and trauma, malignancies such as small cell carcinoma of the lung, and medications such as chlorpropamide, carbamazepine, cyclophosphamide, and selective serotonin reuptake inhibitors.
Individuals with SIADH present with hyponatremia and its associated symptoms including nausea, vomiting, headaches, trouble thinking clearly, weakness, restlessness and muscle weakness. One study attributed up to one-third of cases of hyponatremia in hospitalized patients to SIADH. Treatment of chronic hyponatremia due to SIADH should be done slowly and limit correction of serum sodium to a maximum of 8 mEq/L in the first 24 hours due to the risk of osmotic demyelination syndrome.
Most cases of hypothyroidism are due to primary thyroid disease. Central hypothyroidism is a rare disorder, occurring in anywhere between 1 in 20,000 to 1 in 80,000 people, and can occur due to both hypothalamic and pituitary disorders. The major hypothalamic causes of central hypothyroidism are mass lesions such as craniopharyngiomas and metastatic cancers, infiltrative lesions such as sarcoidosis and Langerhans cell histiocytosis, infections such as tuberculosis, radiation, stroke, and traumatic brain injury.
The most common cause of central hypothyroidism is a pituitary mass lesion such as a pituitary adenoma. These tumors can cause disease by either compressing pituitary thyrotroph cells by disrupting the hypothalamic-pituitary portal blood flow, or by causing acute infarction. Ultimately, a diminished release of either thyrotropin-releasing hormone or thyroid-stimulating hormone can cause central hypothyroidism.
The clinical symptoms of hypothyroidism include lethargy, slow growth in children, sensitivity to cold, hair loss, dry skin, constipation, sexual dysfunction, and weight gain. Individuals with central hypothyroidism may present with either masked or additional symptoms due to a possible concurrent dysregulation of other hormones.
Functional Hypothalamic Amenorrhea
Secondary amenorrhea is the absence of menses for more than 3 months in women who previously had regular menses or more than 6 months in women who have irregular menses. The most common cause of secondary amenorrhea is hypothalamic and can be attributed to 35% of cases. The most common risk factors for developing functional hypothalamic amenorrhea include low body weight disorders, such as anorexia nervosa, excessive exercise, and inadequate caloric intake, and emotional stress.
In these individuals, a decrease in gonadotropin-releasing hormone secretion by the hypothalamus leads to a decreased pulsatile release of gonadotropins, absent mid-cycle surges of luteinizing hormone, an absence of normal follicular development, and anovulation. The energy deficiency due to lack of adequate caloric intake in relation to exercise levels causes decreased levels of insulin-like growth factor-1, and the high-stress state leads to increased levels of cortisol. The low energy availability suppresses the hypothalamic-pituitary-ovarian axis and diverts energy towards more vital systems.
Women with functional hypothalamic amenorrhea are estrogen deficient and therefore present with the symptoms of low bone density, anovulatory infertility, breast and vaginal atrophy, dyspareunia, sexual dysfunction, and mood disorders.
Prolactin release is inhibited by the release of dopamine from the hypothalamus. Therefore, any condition that decreases the release of dopamine leads to an uninhibited excess of prolactin secretion by the lactotroph cells of the pituitary gland. Some common causes of hyperprolactinemia include lactotroph adenomas, damage to the dopaminergic neurons of the hypothalamus, and dopaminergic antagonist medications such as antipsychotics.
Individuals with hyperprolactinemia present with differing symptoms depending on whether they are men, pre-menopausal women, or post-menopausal women. Pre-menopausal women most commonly present with infertility, headaches, oligomenorrhea, and galactorrhea. Post-menopausal women are already hypogonadal and hypoestrogenic; therefore, they rarely present with these symptoms and are only diagnosed incidentally on head imaging or if a lactotroph adenoma grows large enough to cause a mass effect on the optic chiasm causing visual field defects. Men with hyperprolactinemia have hypogonadotropic hypogonadism, causing decreased libido, impotence, infertility, gynecomastia, and rarely galactorrhea.
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