are therefore not interpretable unless prolactin is low or normal. in men, the combination of low lh and fsh in combination with a low testosterone confirms lh/fsh deficiency; a high testosterone would indicate a source elsewhere in the body (such as a testosterone-secreting tumor). in women, the diagnosis of lh/fsh deficiency depends on whether the woman has been through the menopause. before the menopause, abnormal menstrual periods together with low estradiol and lh/fsh levels confirm a pituitary problem; after the menopause (when lh/fsh levels are normally elevated and the ovaries produce less estradiol), inappropriately low lh/fsh alone is sufficient. stimulation tests with gnrh are possible, but their use is not encouraged. for tsh, basal measurements are usually sufficient, as well as measurements of thyroxine to ensure that the pituitary is not simply suppressing tsh production in response to hyperthyroidism (an overactive thyroid gland). a stimulation test with thyrotropin-releasing hormone (trh) is not regarded as useful. prolactin can be measured by basal level, and is required for the interpretation of lh and fsh results in addition to the confirmation of hypopituitarism or diagnosis of a prolactin-secreting tumor. stimulation tests growth hormone deficiency is almost certain if all other pituitary tests are also abnormal, and insulin-like growth factor 1 (igf-1) levels are decreased. if this is not the case, igf-1 levels are poorly predictive of the presence of gh deficiency; stimulation testing with the insulin tolerance test is then required. this is performed by administering insulin to lower the blood sugar to a level below 2.2 mmol/l. once this occurs, growth hormone levels are measured. if they are low despite the stimulatory effect of the low blood sugars, growth hormone deficiency is confirmed. the test is not without risks, especially in those prone to seizures or are known to have heart disease, and causes the unpleasant symptoms of hypoglycemia. alternative tests (such as the growth hormone releasing hormone stimulation test) are less useful, although a stimulation test with arginine may be used for diagnosis, especially in situations where an insulin tolerance test is thought to be too dangerous. if gh deficiency is suspected, and all other pituitary hormones are normal, two different stimulation tests are needed for confirmation. if morning cortisol levels are over 500 nmol/l, acth deficiency is unlikely, whereas a level less than 100 is indicative. levels between 100 and 500 require a stimulation test. this, too, is done with the insulin tolerance test. a cortisol level above 500 after achieving a low blood sugar rules out acth deficiency, while lower levels confirm the diagnosis. a similar stimulation test using corticotropin-releasing hormone (crh) is not sensitive enough for the purposes of the investigation. if the insulin tolerance test yields an abnormal result, a further test measuring the response of the adrenal glands to synthetic acth (the acth stimulation test) can be performed to confirm the diagnosis. stimulation testing with metyrapone is an alternative. some suggest that an acth stimulation test is sufficient as first-line investigation, and that an insulin tolerance test is only needed if the acth test is equivocal. the insulin tolerance test is discouraged in children. none of the tests for acth deficiency are perfect, and further tests after a period of time may be needed if initial results are not conclusive. symptoms of diabetes insipidus should prompt a formal fluid deprivation test to assess the body's response to dehydration, which normally causes concentration of the urine and increasing osmolarity of the blood. if these parameters are unchanged, desmopressin (an adh analogue) is administered. if the urine then becomes concentrated and the blood osmolarity falls, there is a lack of adh due to lack of pituitary function ("cranial diabetes insipidus"). in contrast, there is no change if the kidneys are unresponsive to adh due to a different problem ("nephrogenic diabetes insipidus"). further investigations if one of these tests shows a deficiency of hormones produced by the pituitary, magnetic resonance imaging (mri) scan of the pituitary is the first step in identifying an underlying cause. mri may show various tumors and may assist in delineating other causes. tumors smaller than 1 cm are referred to as microadenomas, and larger lesions are called macroadenomas. computed tomography with radiocontrast may be used if mri is not available. formal visual field testing by perimetry is recommended, as this would show evidence of optic nerve compression by a tumor. other tests that may assist in the diagnosis of hypopituitarism, especially if no tumor is found on the mri scan, are ferritin (elevated in hemochromatosis), angiotensin converting enzyme (ace) levels (often elevated in sarcoidosis), and human chorionic gonadotropin (often elevated in tumor of germ cell origin). if a genetic cause is suspected, genetic testing may be performed. treatment treatment of hypopituitarism is threefold: removing the underlying cause, treating the hormone deficiencies, and addressing any other repercussions that arise from the hormone deficiencies. underlying cause main article: treatment of pituitary adenomas pituitary tumors require treatment when they are causing specific symptoms, such as headaches, visual field defects or excessive hormone secretion. transsphenoidal surgery (removal of the tumor by an operation through the nose and the sphenoidal sinuses) may, apart from addressing symptoms related to the tumor, also improve pituitary function, although the gland is sometimes damaged further as a result of the surgery. when the tumor is removed by craniotomy (opening the skull), recovery is less likely–but sometimes this is the only suitable way to approach the tumor. after surgery, it may take some time for hormone levels to change significantly. retesting the pituitary hormone levels is therefore performed 2 to 3 months later. prolactinomas may respond to dopamine agonist treatment–medication that mimics the action of dopamine on the lactrotrope cells, usually bromocriptine or cabergoline. this approach may improve pituitary hormone secretion in more than half the cases, and make supplementary treatment unnecessary. other specific underlying causes are treated as normally. for example, hemochromatosis is treated by venesection, the regular removal of a fixed amount of blood. eventually, this decreases the iron levels in the body and improves the function of the organs in which iron has accumulated. hormone replacement most pituitary hormones can be replaced indirectly by administering the products of the effector glands: hydrocortisone (cortisol) for adrenal insufficiency, levothyroxine for hypothyroidism, testosterone for male hypogonadism, and estradiol for female hypogonadism (usually with a progestogen to inhibit unwanted effects on the uterus). growth hormone is available in synthetic form, but needs to be administered parenterally (by injection). antidiuretic hormone can be replaced by desmopressin (ddavp) tablets or nose spray. generally, the lowest dose of the replacement medication is used to restore wellbeing and correct the deranged results, as excessive doses would cause side-effects or complications. those requiring hydrocortisone are usually instructed to increase their dose in physically stressful events such as injury, hospitalization and dental work as these are times when the normal supplementary dose may be inadequate, putting the patient at risk of adrenal crisis. long-term follow up by specialists in endocrinology is generally needed for people with known hypopituitarism. apart from ensuring the right treatment is being used and at the right doses, this also provides an opportunity to deal with new symptoms and to address complications of treatment. difficult situations arise in deficiencies of the hypothalamus-pituitary-gonadal axis in people (both men and women) who experience infertility; infertility in hypopituitarism may be treated with subcutaneous infusions of fsh, human chorionic gonadotropin–which mimics the action of lh–and occasionally gnrh. prognosis several studies have shown that hypopituitarism is associated with an increased risk of cardiovascular disease and some also an increased risk of death of about 50% to 150% the normal population. it has been difficult to establish which hormone deficiency is responsible for this risk, as almost all patients studied had growth hormone deficiency. the studies also do not answer the question as to whether the hypopituitarism itself causes the increased mortality, or whether some of the risk is to be attributed to the treatments, some of which (such as sex hormone supplementation) have a recognized adverse effect on cardiovascular risk. the largest study to date followed over a thousand people for eight years; it showed an 87% increased risk of death compared to the normal population. predictors of higher risk were: female sex, absence of treatment for sex hormone deficiency, younger age at the time of diagnosis, and a diagnosis of craniopharyngioma. apart from cardiovascular disease, this study also showed an increased risk of death from lung disease. quality of life may be significantly reduced, even in those people on optimum medical therapy. many report both physical and psychological problems. it is likely that the commonly used replacement therapies do not completely mimic the natural hormone levels in the body. health costs remain about double those of the normal population. hypopituitarism is usually permanent. it requires lifelong treatment with one or more medicines. epidemiology there is only one study that has measured the prevalence (total number of cases in a population) and incidence (annual number of new cases) of hypopituitarism. this study was conducted in northern spain and used hospital records in a well-defined population. the study showed that 45.5 people out of 100,000 had been diagnosed with hypopituitarism, with 4.2 new cases per year. 61% were due to tumors of the pituitary gland, 9% due to other types of lesions, and 19% due to other causes; in 11% no cause could be identified. recent studies have shown that people with a previous traumatic brain injury, spontaneous subarachnoid hemorrhage (a type of stroke) or radiation therapy involving the head have a higher risk of hypopituitarism. after traumatic brain injury, as much as a quarter have persistent pituitary hormone deficiencies. many of these people may have subtle or non-specific symptoms that are not linked to pituitary problems but attributed to their previous condition. it is therefore possible that many cases of hypopituitarism remain undiagnosed, and that the annual incidence would rise to 31 per 100,000 annually if people from these risk groups were to be tested. history the pituitary was known to the ancients, such as galen, and various theories were proposed about its role in the body, but major clues as to the actual function of the gland were not advanced until the late 19th century, when acromegaly due to pituitary tumors was described. the first known report of hypopituitarism was made by the german physician and pathologist dr morris simmonds. he described the condition on autopsy in a 46-year-old woman who had had severe puerperal fever eleven years earlier, and subsequently had amenorrhea, weakness, signs of rapid aging, and anemia. the pituitary gland was very small and there were few remnants of both the anterior and the posterior pituitary. the eponym simmonds' syndrome is used infrequently for acquired hypopituitarism, especially when cachexia (general ill health and malnutrition) predominates. most of the classic causes of hypopituitarism were described in the 20th century; the early 21st century saw the recognition of how common hypopituitarism could be in previous head injury victims. until the 1950s, the diagnosis of pituitary disease remained based on clinical features and visual field examination, sometimes aided by pneumoencephalography and x-ray tomography. nevertheless, the field of pituitary surgery developed during this time. the major breakthrough in diagnosis came with the discovery of radioimmunoassay by rosalyn yalow and solomon berson in the late 1950s. this allowed the direct measurement of the hormones of the pituitary, which as a result of their low concentrations in blood had previously been hard to measure. stimulation tests were developed in the 1960s, and in 1973 the triple bolus test was introduced, a test that combined stimulation testing with insulin, gnrh and trh. imaging of the pituitary, and therefore identification of tumors and other structural causes, improved radically with the introduction of computed tomography in the late 1970s and magnetic resonance imaging in the 1980s. popular culture the scenario of the movie orphan by jaume collet-serra in 2009, is entirely based on the antagonist, a 33-year-old estonian serial killer named leena klammer; who has a form of hypopituitarism that also causes her to have proportional dwarfism, making her look like a 9-year-old child named esther. in 2014, into the french tv show "profilage", the storyline of the episode "poupée russe" (season 5, episode 2) is also based on the theme of a similar illness.