Hypopituitarism: Difference between revisions

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 defect]]s. [[Headache]]s may also accompany pituitary tumors,<ref name=Schneider/> as well as [[pituitary apoplexy]] (infarction or haemorrhage of a pituitary tumor) and [[autoimmune hypophysitis|lymphocytic hypophysitis]] ([[autoimmune]] inflammation of the pituitary).<ref name=Prabhakar>{{cite journal |vauthors=Prabhakar VK, Shalet SM |title=Aetiology, diagnosis, and management of hypopituitarism in adult life |journal=Postgrad Med J |volume=82 |issue=966 |pages=259–66 |date=April 2006 |pmid=16597813 |doi=10.1136/pgmj.2005.039768 |pmc=2585697}}</ref> Apoplexy, in addition to sudden headaches and rapidly worsening visual loss, may also be associated with [[diplopia|double vision]] that results from compression of the nerves in the adjacent [[cavernous sinus]] that control the [[Muscles of orbit|eye muscles]].<ref>{{cite journal |vauthors=Rajasekaran S, Vanderpump M, Baldeweg S, etal | title=UK guidelines for the management of pituitary apoplexy | journal=Clin Endocrinol |date=Jan 2011 | volume=74 | issue=1 | pages=9–20 | pmid=21044119 | doi=10.1111/j.1365-2265.2010.03913.x| s2cid=52867017 | doi-access=free }}</ref>

[[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 [[osmolarity|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).<ref>{{cite journal |author=Maghnie M |title=Diabetes insipidus |journal=Horm. Res. |volume=59 Suppl 1 |pages=42–54 |year=2003 |issue=Suppl 1 |pmid=12566720 |doi=10.1159/000067844|s2cid=24638358 }}</ref> ADH deficiency may be masked if there is ACTH deficiency, with symptoms only appearing when cortisol has been replaced.<ref name=Prabhakar/>

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 [[FGF8|FGF-8]], [[WNT5A|Wnt5a]] and [[Bone morphogenetic protein 4|BMP-4]], and the oral cavity [[Bone morphogenetic protein 2|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.<ref name=CohenRadovick>{{cite journal |vauthors=Cohen LE, Radovick S |title=Molecular basis of combined pituitary hormone deficiencies |journal=Endocr. Rev. |volume=23 |issue=4 |pages=431–42 |date=August 2002 |pmid=12202459 |doi=10.1210/er.2001-0030 |doi-access=free }}</ref> The cells then [[cellular differentiation|differentiate]] further into the various hormone-producing cells of the pituitary. This requires particular [[transcription factor]]s 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]]'', ''[[Pituitary-specific positive transcription factor 1|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.<ref name=CohenRadovick/><ref name=KelbermanDattani>{{cite journal |vauthors=Kelberman D, Dattani MT |title=Hypothalamic and pituitary development: novel insights into the aetiology |journal=Eur. J. Endocrinol. |volume=157 Suppl 1 |pages=S3–14 |date=August 2007 |issue=Suppl 1 |pmid=17785694 |doi=10.1530/EJE-07-0156 |doi-access=free }}</ref> For instance, ''POU1F1'' (also known as Pit-1) mutations cause specific deficiencies in growth hormone, prolactin and TSH.<ref name=MelmedJameson/><ref name=CohenRadovick/><ref name=KelbermanDattani/> 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.<ref name=CohenRadovick/><ref name=KelbermanDattani/>

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 [[hypoglycemia|a level below 2.2&nbsp;mmol/lL]]. 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 [[seizure]]s or are known to have [[ischemic heart disease|heart disease]], and causes the unpleasant symptoms of [[hypoglycemia]].<ref name=Schneider/><ref name=VanAken/> 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.<ref>{{cite journal |vauthors=Kaushal K, Shalet SM |title=Defining growth hormone status in adults with hypopituitarism |journal=Horm. Res. |volume=68 |issue=4 |pages=185–94 |year=2007 |pmid=17389809 |doi=10.1159/000101286|doi-access=free }}</ref> If GH deficiency is suspected, and all other pituitary hormones are normal, two different stimulation tests are needed for confirmation.<ref name=Prabhakar/>

If morning [[cortisol]] levels are over 500&nbsp;[[Mole (unit)|nmol/lL]], ACTH deficiency is unlikely, whereas a level less than 100 is indicative. Levels between 100 and 500 require a stimulation test.<ref name=VanAken/> 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.<ref name=Dorin>{{cite journal |vauthors=Dorin RI, Qualls CR, Crapo LM |title=Diagnosis of adrenal insufficiency |journal=Ann. Intern. Med. |volume=139 |issue=3 |pages=194–204 |year=2003 |pmid=12899587 |doi=10.7326/0003-4819-139-3-200308050-00017|doi-access=free }}</ref> Stimulation testing with [[metyrapone]] is an alternative.<ref name=Dorin/> 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.<ref name=VanAken/><ref name=Prabhakar/> The insulin tolerance test is discouraged in children.<ref name=VanAken/> 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.<ref name=Schneider/>

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.<ref>{{cite journal |vauthors=Schneider HJ, Kreitschmann-Andermahr I, Ghigo E, Stalla GK, Agha A |title=Hypothalamopituitary dysfunction following traumatic brain injury and aneurysmal subarachnoid hemorrhage: a systematic review |journal=Journal of the American Medical Association |volume=298 |issue=12 |pages=1429–38 |date=September 2007 |pmid=17895459 |doi=10.1001/jama.298.12.1429 |doi-access=free }}</ref> After traumatic brain injury, as much as a quarter have persistent pituitary hormone deficiencies.<ref>{{cite journal |vauthors=Behan LA, Phillips J, Thompson CJ, Agha A |title=Neuroendocrine disorders after traumatic brain injury |journal=J. Neurol. Neurosurg. Psychiatry |volume=79 |issue=7 |pages=753–59 |date=July 2008 |pmid=18559460 |doi=10.1136/jnnp.2007.132837|s2cid=12153361 |doi-access= }}</ref> Many of these people may have subtle or [[non-specific symptom]]s 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.<ref name=Schneider/>

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.<ref name=Sellwood>{{cite book |vauthors=Sellwood RA, Welbourn RB, Friesen SR |title=The History of Endocrine Surgery |publisher=Praeger Publishers |location=New York |year=1990 |isbn=978-0-275-92586-4}}{{page needed|date=August 2015}}</ref> The first known report of hypopituitarism was made by the [[Germany|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.<ref name=Schneider/><ref name=Simmonds1914>{{cite journal |last1=Simmonds |first1=M. |title=Ueber Hypophysisschwund mit tödlichem Ausgang |trans-title=About hypophysis with fatal outcome |language=de |journal=Deutsche Medizinische Wochenschrift |date=February 1914 |volume=40 |issue=7 |pages=322–323 |doi=10.1055/s-0029-1190185 |s2cid=76080976 |url=https://zenodo.org/record/1429826 }}</ref> The eponym ''Simmonds' syndrome'' is used infrequently for acquired hypopituitarism, especially when [[cachexia]] (general ill health and malnutrition) predominates.<ref>{{WhoNamedIt|synd|2008}}</ref><ref>{{DorlandsDict|nine/000956983|Simmonds disease}}</ref> 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.<ref name=Schneider/>

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