hypopituitarism hypopituitarism hypopituitarism is the decreased (hypo) secretion of one or more of the eight hormones normally produced by the pituitary gland at the base of the brain. if there is decreased secretion of one specific pituitary hormone, the condition is known as selective hypopituitarism. if there is decreased secretion of most or all pituitary hormones, the term panhypopituitarism (pan meaning "all") is used. not to be confused with hyperpituitarism. hypopituitarismthe pituitary gland on a plate from gray's anatomy (1918). the anterior lobe is on the left, and the posterior lobe on the right, both in red.specialtyendocrinology the signs and symptoms of hypopituitarism vary, depending on which hormones are undersecreted and on the underlying cause of the abnormality. the diagnosis of hypopituitarism is made by blood tests, but often specific scans and other investigations are needed to find the underlying cause, such as tumors of the pituitary, and the ideal treatment. most hormones controlled by the secretions of the pituitary can be replaced by tablets or injections. hypopituitarism is a rare disease, but may be significantly underdiagnosed in people with previous traumatic brain injury. the first description of the condition was made in 1914 by the german physician dr morris simmonds. signs and symptoms the hormones of the pituitary have different actions in the body, and the symptoms of hypopituitarism therefore depend on which hormone is deficient. the symptoms may be subtle and are often initially attributed to other causes. in most of the cases, three or more hormones are deficient. the most common problem is insufficiency of follicle-stimulating hormone (fsh) and/or luteinizing hormone (lh) leading to sex hormone abnormalities. growth hormone deficiency is more common in people with an underlying tumor than those with other causes. sometimes, there are additional symptoms that arise from the underlying cause; for instance, if the hypopituitarism is due to a growth hormone-producing tumor, there may be symptoms of acromegaly (enlargement of the hands and feet, coarse facial features), and if the tumor extends to the optic nerve or optic chiasm, there may be visual field defects. headaches may also accompany pituitary tumors, as well as pituitary apoplexy (infarction or haemorrhage of a pituitary tumor) and lymphocytic hypophysitis (autoimmune inflammation of the pituitary). apoplexy, in addition to sudden headaches and rapidly worsening visual loss, may also be associated with double vision that results from compression of the nerves in the adjacent cavernous sinus that control the eye muscles. pituitary failure results in many changes in the skin, hair and nails as a result of the absence of pituitary hormone action on these sites. complications several hormone deficiencies associated with hypopituitarism may lead to secondary diseases. for instance, growth hormone deficiency is associated with obesity, raised cholesterol and the metabolic syndrome, and estradiol deficiency may lead to osteoporosis. while effective treatment of the underlying hormone deficiencies may improve these risks, it is often necessary to treat them directly. anterior pituitary the major endocrine glands of the body. pituitary hormones control the function of the adrenal gland, thyroid gland and the gonads (testes and ovaries). deficiency of all anterior pituitary hormones is more common than individual hormone deficiency. deficiency of luteinizing hormone (lh) and follicle-stimulating hormone (fsh), together referred to as the gonadotropins, leads to different symptoms in men and women. women experience oligo- or amenorrhea (infrequent/light or absent menstrual periods respectively) and infertility. men lose facial, scrotal and trunk hair, as well as have decreased muscle mass and anemia. both sexes may experience a decrease in libido and loss of sexual function, and have an increased risk of osteoporosis (bone fragility). lack of lh/fsh in children is associated with delayed puberty. growth hormone (gh) deficiency leads to a decrease in muscle mass, central obesity (increase in body fat around the waist) and impaired attention and memory. children experience growth retardation and short stature. adrenocorticotropic hormone (acth) deficiency leads to adrenal insufficiency, a lack of production of glucocorticoids such as cortisol by the adrenal gland. if the problem is chronic, symptoms consist of fatigue, weight loss, failure to thrive (in children), delayed puberty (in adolescents), hypoglycemia (low blood sugar levels), anemia and hyponatremia (low sodium levels). if the onset is abrupt, collapse, shock and vomiting may occur. acth deficiency is highly similar to primary addison's disease, which is cortisol deficiency as the result of direct damage to the adrenal glands; the latter form, however, often leads to hyperpigmentation of the skin, which does not occur in acth deficiency. thyroid-stimulating hormone (tsh) deficiency leads to hypothyroidism (lack of production of thyroxine (t4) and triiodothyronine (t3) in the thyroid). typical symptoms are tiredness, intolerance to cold, constipation, weight gain, hair loss and slowed thinking, as well as a slowed heart rate and low blood pressure. in children, hypothyroidism leads to delayed growth and in extreme inborn forms to a syndrome called cretinism. prolactin (prl) plays a role in breastfeeding, and inability to breastfeed may point at abnormally low prolactin levels. posterior pituitary antidiuretic hormone (adh) deficiency leads to the syndrome of diabetes insipidus (unrelated to diabetes mellitus): inability to concentrate the urine, leading to polyuria (production of large amounts of clear urine) that is low in solutes, dehydration and—in compensation—extreme thirst and constant need to drink (polydipsia), as well as hypernatremia (high sodium levels in the blood). adh deficiency may be masked if there is acth deficiency, with symptoms only appearing when cortisol has been replaced. oxytocin (oxt) deficiency generally causes few symptoms, however may lead to abnormal social developments due to its complex role as a social neuropeptide. causes type causes tumors most cases of hypopituitarism are due to pituitary adenomas compressing the normal tissue in the gland, and rarely other brain tumors outside the gland—craniopharyngioma, meningioma, chordoma, ependymoma, glioma or metastasis from cancer elsewhere in the body. infection,inflammation andinfiltration the pituitary may also be affected by infections of the brain (brain abscess, meningitis, encephalitis) or of the gland itself, or it may be infiltrated by abnormal cells (neurosarcoidosis, histiocytosis) or excessive iron (hemochromatosis). empty sella syndrome is unexplained disappearance of pituitary tissue, probably due to outside pressure. autoimmune or lymphocytic hypophysitis occurs when the immune system directly attacks the pituitary. vascular as a pregnancy comes to term, a pregnant woman's pituitary gland is vulnerable to low blood pressure, such as may result from hemorrhage; pituitary damage due to bleeding after childbirth is called sheehan's syndrome. pituitary apoplexy is hemorrhage or infarction (loss of blood supply) of the pituitary. other forms of stroke are increasingly recognized as a cause for hypopituitarism. radiation radiation-induced hypopituitarism mainly affects growth hormone and gonadal hormones. in contrast, adrenocorticotrophic hormone (acth) and thyroid stimulating hormone (tsh) deficiencies are the least common among people with radiation-induced hypopituitarism. changes in prolactin-secretion is usually mild, and vasopressin deficiency appears to be very rare as a consequence of radiation. other physical external physical causes for hypopituitarism include traumatic brain injury, subarachnoid hemorrhage, neurosurgery and ionizing radiation (e.g. radiation therapy for a previous brain tumor). bites from russell's vipers have also been known to cause hypopituitarism in approx 29% of cases. congenital congenital hypopituitarism (present at birth) may be the result of complications around delivery, or may be the result of insufficient development (hypoplasia) of the gland, sometimes in the context of specific genetic abnormalities. mutations may cause either insufficient development of the gland or decreased function. forms of combined pituitary hormone deficiency ("cphd") include: type omim gene cphd1 613038 pou1f1 cphd2 262600 prop1 cphd3 600577 lhx3 cphd4 602146 lhx4 cphd5 (septo-optic dysplasia) 182230 hesx1 kallmann syndrome causes deficiency of the gonadotropins only. bardet–biedl syndrome and prader–willi syndrome have been associated with pituitary hormone deficiencies. pathophysiology the pituitary gland is located at the base of the brain, and intimately connected with the hypothalamus. it consists of two lobes: the posterior pituitary, which consists of nervous tissue branching out of the hypothalamus, and the anterior pituitary, which consists of hormone-producing epithelium. the posterior pituitary secretes antidiuretic hormone, which regulates osmolarity of the blood, and oxytocin, which causes contractions of the uterus in childbirth and participates in breastfeeding. the pituitary develops in the third week of embryogenesis from interactions between the diencephalon part of the brain and the nasal cavity. the brain cells secrete fgf-8, wnt5a and bmp-4, and the oral cavity bmp-2. together, these cellular signals stimulate a group of cells from the oral cavity to form rathke's pouch, which becomes independent of the nasal cavity and develops into the anterior pituitary; this process includes the suppression of production of a protein called sonic hedgehog by the cells of rathke's pouch. the cells then differentiate further into the various hormone-producing cells of the pituitary. this requires particular transcription factors that induce the expression of particular genes. some of these transcription factors have been found to be deficient in some forms of rare combined pituitary hormone deficiencies (cphd) in childhood. these are hesx1, prop1, pou1f1, lhx3, lhx4, tbx19, sox2 and sox3. each transcription factor acts in particular groups of cells. therefore, various genetic mutations are associated with specific hormone deficiencies. for instance, pou1f1 (also known as pit-1) mutations cause specific deficiencies in growth hormone, prolactin and tsh. in addition to the pituitary, some of the transcription factors are also required for the development of other organs; some of these mutations are therefore also associated with specific birth defects. hypothalamic-pituitary-end organ axis thyroidadrenalgonadsgrowthmammary releasing hormonetrhcrhgnrhghrhdopamine (inhibitor) pituitary cellsthyrotropecorticotropegonadotropesomatotropelactotrope pituitary hormonetshacthlh and fshghprolactin end organthyroidadrenaltestes or ovarieslivermammary gland productthyroxinecortisoltestosterone, estradioligf-1milk (no feedback) most of the hormones in the anterior pituitary are each part of an axis that is regulated by the hypothalamus. the hypothalamus secretes a number of releasing hormones, often according to a circadian rhythm, into blood vessels that supply the anterior pituitary; most of these are stimulatory (thyrotropin-releasing hormone, corticotropin-releasing hormone, gonadotropin-releasing hormone and growth hormone-releasing hormone), apart from dopamine, which suppresses prolactin production. in response to the releasing hormone rate, the anterior pituitary produces its hormones (tsh, acth, lh, fsh, gh) which in turn stimulate effector hormone glands in the body, while prolactin (prl) acts directly on the breast gland. once the effector glands produce sufficient hormones (thyroxine, cortisol, estradiol or testosterone and igf-1), both the hypothalamus and the pituitary cells sense their abundance and reduce their secretion of stimulating hormones. the hormones of the posterior pituitary are produced in the hypothalamus and are carried by nerve endings to the posterior lobe; their feedback system is therefore located in the hypothalamus, but damage to the nerve endings would still lead to a deficiency in hormone release. unless the pituitary damage is being caused by a tumor that overproduces a particular hormone, it is the lack of pituitary hormones that leads to the symptoms described above, and an excess of a particular hormone would indicate the presence of a tumor. the exception to this rule is prolactin: if a tumor compresses the pituitary stalk, a decreased blood supply means that the lactotrope cells, which produce prolactin, are not receiving dopamine and therefore produce excess prolactin. hence, mild elevations in prolactin are attributed to stalk compression. very high prolactin levels, though, point more strongly towards a prolactinoma (prolactin-secreting tumor). diagnosis ct scan of the brain showing a craniopharyngioma (white structure in the center of the image). this tumor may cause hypopituitarism and requires surgical removal. the diagnosis of hypopituitarism is made on blood tests. two types of blood tests are used to confirm the presence of a hormone deficiency: basal levels, where blood samples are taken–usually in the morning–without any form of stimulation, and dynamic tests, where blood tests are taken after the injection of a stimulating substance. measurement of acth and growth hormone usually requires dynamic testing, whereas the other hormones (lh/fsh, prolactin, tsh) can typically be tested with basal levels. there is no adequate direct test for adh levels, but adh deficiency can be confirmed indirectly; oxytocin levels are not routinely measured. generally, the finding of a combination of a low pituitary hormone together with a low hormone from the effector gland is indicative of hypopituitarism. occasionally, the pituitary hormone may be normal but the effector gland hormone decreased; in this case, the pituitary is not responding appropriately to effector hormone changes, and the combination of findings is still suggestive of hypopituitarism. basal tests levels of lh/fsh may be suppressed by a raised prolactin level, and