The Hypothalamus Gland

The hypothalamus is part of the brain lying under the thalamus. The stalk of the pituitary gland is attached to the hypothalamus.

The main function of the hypothalamus is homeostasis, or maintaining the body’s status quo. Factors such as blood pressure, body temperature, fluid and electrolyte balance, and body weight are held to a precise value called the set-point. Although this set-point can migrate over time, from day to day it is remarkably fixed.

The general functions of the hypothalamus are of extreme importance for the body

    • pituitary gland regulation
    • blood pressure regulation
    • hunger and salt cravings
    • feeding
    • reflexes
    • thirst
    • body temperature regulation
    • hydration
    • heart rate
    • bladder function
    • water preservation
    • ovarian function
    • hormonal/neurotransmitter regulation
    • testicular function
    • wakefulness
    • mood & behavioral functions
    • metabolism
    • sleep cycles
    • energy levels

The hypothalamus controls and integrates the overlapping functions of the endocrine system and the autonomic nervous system.  The hypothalamus links the brain to the hormonal system and plays a vital role in powerful basic drives for survival such as hunger, thirst, sex and the strong emotions such as rage or ecstatic joy,  that may accompany them.

The hypothalamus sends out nerve signals to various muscles, often through the autonomic nervous system.  For example, in response to a sudden scare, the hypothalamus takes control and tells the adrenal glands to release adrenaline which tells the heart to beat faster, and the skeletal muscles to tense in readiness for sudden action: the fight or flight response.

The hypothalamus functions as a type of thermostat for the body.   It sets a desired body temperature, and stimulates either heat production and retention to raise the blood temperature to a higher setting, or sweating and vasodilation to cool the blood to a lower temperature. Rarely, direct damage to the hypothalamus, such as from a stroke, will cause a fever; this is sometimes called a hypothalamic fever. However, it is more common for such damage to cause abnormally low body temperatures.

The feeling of hunger, which motivates us to eat, is generated by the brain’s hypothalamus in response to a range of signals received from the body, including those delivered by various hormones. For example, the hormone ghrelin, released by an empty stomach, activates parts of the hypothalamus that make people feel hungry. The hormone leptin, released by the body’s fat stores after eating, causes the hypothalamus to inhibit hunger and create a sense of fullness.

The hypothalamus initiates the hormonal surges that occur in puberty which are responsible for some of the most dramatic changes that occur in the human body. The hypothalamus secretes gonadotropic-releasing hormone (GnRH). This triggers the pituitary gland to release luteinizing hormone (LH) and follicle stimulating hormone (FSH), which act on the testes or ovaries. In males, LH stimulates Leydig cells to produce testosterone and FSH prompts Sertoli cells to support developing spermatozoa. In females, LH triggers ovulation and FSH stimulates the growth of ovarian follicles and eggs.  FSH and LH,  travel through the bloodstream to trigger the production of the sex hormones:  estrogen and progesterone from the ovaries in girls, and testosterone from the testes in boys. These hormones are responsible for all of the developments underlying puberty in both sexes. The feedback loop reduces GnRH secretion in response to rising levels of testosterone or estrogen.

The In-depth physiology of the Hypothalamus

The hypothalamus coordinates many hormonal and behavioral circadian rhythms, complex patterns of neuroendocrine outputs, complex homeostatic mechanisms, and important behaviors. The hypothalamus must therefore be able to respond to many different signals, some of which are generated externally and some internally. The hypothalamus is richly connected with many parts of the central nervous system including the brainstem reticular formation and autonomic zones, and the limbic forebrain, particularly the amygdala, septum, diagonal band of Broca, the olfactory bulbs and the cerebral cortex.

The hypothalamus is responsive to:

    • Light and dark or daylight and nighttime.
    • Olfactory stimuli, or smells, including pheromones
    • Steroids, including gonad steroids and corticosteroids
    • Neurally transmitted information particulary from the heart, stomach, and reproductive tract
    • Autonomic inputs
    • Blood-borne stimuli, including leptin, ghrelin, angiotensin,insulin, pituitary hormones, cytokines, plasma concentrations of glucose and osmolarity
    • Stress
    • Invading microorganisms

Peptide hormones have important influences upon the hypothalamus, and to do so they must evade the blood-brain barrier. The hypothalamus is bounded in part by specialized brain regions that lack an effective blood-brain barrier; the capillary endothelium at these sites has openings, to allow free passage of even large proteins and other molecules. There are also sites at which the brain samples the composition of the blood. Two of these sites, the SFO (subfornical organ) and the OVLT (organum vasculosum of the lamina terminalis) are so-called circumventricular organs, where neurons are in intimate contact with both blood and cerebrospinal fluid. These structures are densely vascularized, and contain osmoreceptive and sodium-receptive neurons which control drinking, vasopressin release, sodium excretion, and sodium appetite. They also contain neurons with receptors for angiotensin, atrial natriuretic factor, endothelin and relaxin, each of which is important in the regulation of fluid and electrolyte balance. .

It is not clear how all peptides that influence hypothalamic activity gain the necessary access. In the case of prolactin and leptin, there is evidence of active uptake from blood into central spinal fluid at the choroid plexus, a structure found in the brain’s ventricles. Some pituitary hormones have a negative feedback influence upon hypothalamic secretion; for example, growth hormone feeds back on the hypothalamus, but how it enters the brain is not clear. There is also evidence for central actions of prolactin and TSH.

The hypothalamus contains neurons that react strongly to steroids and glucocorticoids (the steroid hormones of the adrenal gland, released in response to ACTH). It also contains specialized glucose-sensitive neurons (in the arcuate nucleus and ventromedial hypothalamus), which are important for appetite. The preoptic area of the hypothalamus contains thermo-sensitive neurons; these are important for TRH (thyrotropin releasing hormone) secretion.

The hypothalamus receives many inputs from the brainstem; notably from the nucleus of the solitary tract, the locus coeruleus, and the ventrolateral medulla. Oxytocin secretion in response to suckling or vaginal-cervical stimulation is mediated by some of these pathways; vasopressin secretion in response to cardiovascular stimuli arising from chemoreceptors in the carotid body and aortic arch, and from low-pressure atrial volume receptors, is mediated by others.

In the rat, stimulation of the vagina also causes prolactin secretion, which results in pseudo-pregnancy following an infertile mating. In the rabbit, coitus elicits reflex ovulation. In the sheep, cervical stimulation in the presence of high levels of estrogen can induce maternal instincts in a virgin ewe. These effects are all mediated by the hypothalamus, and the information is carried mainly by spinal pathways that relay in the brainstem.

Stimulation of the nipples stimulates release of oxytocin and prolactin and suppresses the release of LH and FSH. Cardiovascular stimuli are carried by the vagus nerve, but the vagus also conveys a variety of visceral information, including signals arising from gastric distension to suppress feeding.  Again this information reaches the hypothalamus via relays in the brainstem.

In addition, hypothalamic function is responsive to, and regulated by, levels of all three classic monoamine neurotransmitters,  noradrenaline, dopamine and 5-hydroxytryptamine (serotonin), in those tracts from which it receives innervation. For example, noradrenergic inputs arising from the locus coeruleus have important regulatory effects upon CRH (corticotropin releasing hormone) levels.

The outputs of the hypothalamus can be divided into two categories: neural projections, and endocrine hormones.

Neural projections

Most fiber systems of the hypothalamus run in two ways (bidirectional).

    • Projections to areas caudal to the hypothalamus go through the medial forebrain bundle, the mammillotegmental tract and the dorsal longitudinal fasciculus.
    • Projections to areas rostral to the hypothalamus are carried by the mammillothalamic tract, the fornix and terminal stria.
    • Projections to areas of the sympathetic motor system (lateral horn spinal segments T1-L2/L3) are carried by the hypothalamospinal tract and they activate the sympathetic motor pathway.

Endocrine hormones

The hypothalamus affects the endocrine system and governs emotional behavior, such as anger and sexual activity. Most of the hypothalamic hormones generated are distributed to the pituitary via the hypophyseal portal system.  The hypothalamus maintains homeostasis; this includes a regulation of blood pressure, heart rate, and temperature.

The hypothalamus releases the following hormones:

    • Thyrotropin-releasing hormone (TRH, TRF) – stimulates thyroid stimulating hormone (TSH) release from the pituitary
    • Prolactin-releasing hormone (PRH) – stimulates prolactin release from the pituitary
    • Dopamine (DA) – inhibits prolactin release from the pituitary
    • Growth hormone releasing hormone (GHRH) – stimulates growth hormone (GH) release from the pituitary
    • Somatostatin (SS) growth hormone inhibiting hormone (GHIH) (SRIF) – inhibits growth hormone (GH) release from the pituitary and inhibits thyroid stimulating hormone release from the pituitary
    • Gonadotropin-releasing hormone (GnRH or LHRH) – stimulates follicle-stimulating hormone (FSH) and luteinizing hormone (LH) release from the pituitary
    • Corticotropin-releasing hormone (CRH or CRF) – stimulates adrenocortisotropic hormone (ACTH) release from the pituitary
    • Oxytocin – causes uterine contractions and lactation
    • Vasopressin (ADH or AVP) – increases the permeability to water of the cells of distal tubule and collecting duct in the kidney and thus allows water reabsorption and excretion of concentrated urine

The extreme lateral part of the ventromedial nucleus of the hypothalamus is responsible for the control of food intake. Stimulation of this area causes increased food intake. Bilateral lesion of this area cause complete cessation of food intake. Medial parts of the nucleus have a controlling effect on the lateral part. Bilateral lesion of the medial part of the ventromedial nucleus causes hyperphagia and obesity of the animal. Further lesion of the lateral part of the ventromedial nucleus in the same animal produces complete cessation of food intake.

There are different hypotheses related to this regulation:

Lipostatic hypothesis – this hypothesis holds that adipose tissue produces a humoral signal that is proportionate to the amount of fat and acts on the hypothalamus to decrease food intake and increase energy output. It has been evident that the hormone leptin acts on the hypothalamus to decrease food intake and increase energy output.

Gutpeptide hypothesis – gastrointestinal hormones like Grp, glucagons, CCK and others are claimed to inhibit food intake. The food entering the gastrointestinal tract triggers the release of these hormones which acts on the brain to produce satiety. The brain contains both CCK-A and CCK-B receptors.

Glucostatic hypothesis – the activity of the satiety center in the ventromedial nuclei is probably governed by the glucose utilization in the neurons. It has been postulated that when their glucose utilization is low and consequently when the arteriovenous blood glucose difference across them is low, the activity across the neurons decrease. Under these conditions, the activity of the feeding center is unchecked and the individual feels hungry. Food intake is rapidly increased by intraventricular administration of 2-deoxyglucose therefore decreasing glucose utilization in cells.

Thermostatic hypothesis – according to this hypothesis, a decrease in body temperature below a given set point stimulates appetite, while an increase above the set point inhibits appetite. Several hypothalamic nuclei are sexually dimorphic, i.e. there are clear differences in both structure and function between males and females.  Some differences are apparent even in gross neuroanatomy: most notable is the sexually dimorphic nucleus within the preoptic area, which is present only in males. However most of the differences are subtle changes in the connectivity and chemical sensitivity of particular sets of neurons.

The importance of these changes can be recognized by functional differences between males and females. For instance, males of most species prefer the odor and appearance of females over males, which is instrumental in stimulating male sexual behavior. If the sexually dimorphic nucleus is lesioned, this preference for females by males diminishes.

Also, the pattern of secretion of growth hormone is sexually dimorphic, and this is one reason why in many species, adult males are much larger than females.

Responses to ovarian hormones

Other striking functional dimorphisms are in the behavioral responses to ovarian hormones of the adult. Males and females respond differently to ovarian steroids, partly because the expression of estrogen-sensitive neurons in the hypothalamus is sexually dimorphic, i.e. estrogen receptors are expressed in different sets of neurons.

Estrogen and progesterone can influence gene expression in particular neurons or induce changes in cell membrane potential and kinase activation, leading to diverse non-genomic cellular functions. Estrogen and progesterone bind to their cognate nuclear hormone receptors, which translocate to the cell nucleus and interact with regions of DNA known as hormone response elements (HREs) or get tethered to another transcription factor’s binding site.

Estrogen receptor (ER) has been shown to transactivate other transcription factors in this manner, despite the absence of an estrogen response element (ERE) in the proximal promoter region of the gene. ERs and progesterone receptors (PRs) are generally gene activators, with increased mRNA and subsequent protein synthesis following hormone exposure.

Male and female brains differ in the distribution of estrogen receptors, and this difference is an irreversible consequence of neonatal steroid exposure. Estrogen receptors (and progesterone receptors) are found mainly in neurons in the anterior and mediobasal hypothalamus, notably:

    • the preoptic area (where LHRH neurons are located)
    • the periventricular nucleus (where somatostatin neurons are located)
    • the ventromedial hypothalamus (which is important for sexual behavior).


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Kallmann syndrome

Kallmann syndrome is a condition characterized by delayed or absent puberty and an impaired sense of smell.

Kallmann syndrome is a hypogonadism (decreased functioning of the glands that produce sex hormones) caused by a deficiency of gonadotropin-releasing hormone (GnRH), which is created by the hypothalamus. Kallmann syndrome is also called hypothalamic hypogonadism, familial hypogonadism with anosmia, and hypogonadotropic hypogonadism, reflecting its disease mechanism.

Kallmann syndrome is a form of tertiary hypogonadism, reflecting that the primary cause of the defect in sex-hormone production lies within the hypothalamus rather than a defect of the pituitary (secondary hypogonadism), testes or ovaries (primary hypogonadism).

Males with hypogonadotropic hypogonadism are often born with an unusually small penis (micropenis) and undescended testes (cryptorchidism). At puberty, most affected males do not develop secondary sex characteristics, such as the growth of facial hair and deepening of the voice. Affected females usually do not begin menstruating at puberty and have little or no breast development. In some people, puberty is incomplete or delayed.

The features of Kallmann syndrome vary, even among affected people in the same family. Additional signs and symptoms can include a failure of one kidney to develop (unilateral renal agenesis), a cleft lip with or without an opening in the roof of the mouth (a cleft palate), abnormal eye movements, hearing loss, and abnormalities of tooth development. Some affected individuals have a condition called bimanual synkinesis, in which the movements of one hand are mirrored by the other hand. Bimanual synkinesis can make it difficult to do tasks that require the hands to move separately, such as playing a musical instrument.

Under normal conditions, GnRH travels from the hypothalamus to the pituitary gland, where it triggers production and release of LH and FSH. When GnRH is low, the pituitary does not create the normal amount of LH and FSH. The LH and FSH normally increase the production of gonadal steroids; so, when they are low, these steroids will be low as well.

Kallmann syndrome is estimated to affect 1 in 10,000 to 86,000 people and occurs more often in males than in females. Kallmann syndrome 1 is the most common form of the disorder

Researchers have identified four forms of Kallmann syndrome, designated types 1 through 4, which are distinguished by their genetic cause. The four types are each characterized by hypogonadotropic hypogonadism and an impaired sense of smell. Additional features, such as a cleft palate, seem to occur only in types 1 and 2.

Treatment is directed at restoring the deficient hormones. Hormone replacement therapy (HRT)

Males are administered human chorionic gonadotropin (hCG) or testosterone.

Females are treated with estrogen and progestin.

There are a range of different methods for the delivery of HRT, especially for men. The short acting monthly injection is now less widely used in favor of the longer lasting injection, Nebido, which can last from three to six months depending on the individual. Daily application gels and patches are also available as are implants inserted every six months.

Tablets are not thought to be effective for the treatment of Kallmann syndrome due to their low bio-availability once processed by the liver, though this can be overcome by using oil filled capsules which allows the testosterone to reach the blood stream in effective doses.

To induce fertility in males or females, GnRH (aka LHRH) is administered by an infusion pump, or hCG/hMG/FSH/LH combinations are administered through regular injections. Fertility is maintained only during treatment with these hormones. Once fertility treatment stops, it is necessary to revert to the normal hormone-replacement therapy (HRT) of testosterone for men and estrogen and progestin for women.

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