{"paper_id":"0ab043b5-d237-4ad8-b5e4-60df29451918","body_text":"DOI: 10.1530/JOE-16-0653\nhttp://joe.endocrinology-journals.org © 2017 Society for Endocrinology\nPrinted in Great Britain\nPublished by Bioscientifica Ltd.\nJournal of Endocrinology\nR53–R65h -c lee and s-j tsai Hypoxia and endocrine disorder\nReview\n234:1\n10.1530/JOE-16-0653\nEndocrine targets of hypoxia-inducible \nfactors\nHsiu-Chi Lee1 and Shaw-Jenq Tsai1,2\n1Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, \nTainan, Taiwan\n2Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, Taiwan\nAbstract\nEndocrine is an important and tightly regulated system for maintaining body \nhomeostasis. Endocrine glands produce hormones, which are released into blood stream \nto guide the target cells responding to all sorts of stimulations. For maintaining body \nhomeostasis, the secretion and activity of a particular hormone needs to be adjusted \nin responding to environmental challenges such as changes in nutritional status or \nchronic stress. Hypoxia, a status caused by reduced oxygen availability or imbalance of \noxygen consumption/supply in an organ or within a cell, is a stress that affects many \nphysiological and pathological processes. Hypoxic stress in endocrine organs is especially \ncritical because endocrine glands control body homeostasis. Local hypoxia affects not \nonly the particular gland but also the downstream cells/organs regulated by hormones \nsecreted from this gland. Hypoxia-inducible factors (HIFs) are transcription factors \nthat function as master regulators of oxygen homeostasis. Recent studies report that \naberrant expression of HIFs in endocrine organs may result in the development and/or \nprogression of diseases including diabetes, endometriosis, infertility and cancers. In this \narticle, we will review recent findings in HIF-mediated endocrine organ dysfunction and \nthe systemic syndromes caused by these disorders.\nIntroduction\nOxygen is an important substrate/co-factor for energy \nproduction and many cellular biochemical reactions. Low \noxygen condition (hypoxia) is considered a physiological \nand also a pathological situation, which involves in many \nbiological processes such as organ development, stem cell \nmaintenance, inflammation, aging, pulmonary disorder, \ncardiovascular disease, neuronal degeneration and cancer \n(Semenza 2007). Hypoxic effects can be accounted for by \ntwo distinct pathways: hypoxia-inducible factor (HIF)-\ndependent and HIF-independent pathways. The HIF-\nindependent pathway is mainly mediated by changing \nprotein phosphorylation status (acute) and global \ntranscription/translation efficiency (chronic), whereas \nthe HIF-dependent pathway is regulated by altering \nspecific target genes expression by HIF (chronic). HIF is \nthe master transcriptional regulator, which modulates \nmany cellular responses to enable cells to adapt to lower \noxygen concentration. Besides the adaptive function \nof hypoxic stress and environmental changes, HIF is \nreported to play an important role in many diseases, such \nas circulatory disorder, metabolic disorder, inflammatory \ndisease and cancer ( Lin  et  al. 2014 , Semenza 2014 , \nCummins et al. 2016).\nThe endocrine system consists of endocrine glands \nand circulatory system. The major endocrine glands \ninclude the pineal gland, pituitary gland, pancreas, \n234\n1\nCorrespondence \nshould be addressed \nto S-J Tsai \nEmail \nseantsai@mail.ncku.edu.tw\nKey Words\n f hypoxia\n f endocrine\n f reproduction\n f cancer\n f metabolism\nJournal of Endocrinology  \n(2017) 234, R53–R65\nDownloaded from Bioscientifica.com at 06/09/2026 07:32:42PM\nvia free access\n\n\nReview R54\nHypoxia and endocrine disorder\nDOI: 10.1530/JOE-16-0653\nJournal of Endocrinology\nh -c lee and s-j tsai\nhttp://joe.endocrinology-journals.org © 2017 Society for Endocrinology\nPrinted in Great Britain\nPublished by Bioscientifica Ltd.\n234:1\novaries, testes, thyroid glands, parathyroid glands, \nmammary glands, hypothalamus and adrenal glands. \nSince the discovery of leptin and other adipocytokines, \nadipose tissue is also considered as a nonclassical \nendocrine organ ( Prins 2002). These glands produce and \nsecrete hormones into the blood stream. Hormones act \non target cells of specific organs via paracrine, autocrine \nor intracrine manners to modulate physiological \nfunctions. Hormone’s effects are slow to initiate but \nprolonged in their response, lasting from a few hours up \nto weeks. In addition, as the hormonal effects usually \ninvolve different feedback mechanisms, the picture of \nendocrine disorders are quite complex. The disorders \nwithin the endocrine system may vary considerably \nin terms of symptoms. In general, endocrine disorders \ncan be categorized as hypersecretion, hyposecretion, \nhyperresponsiveness and hyporesponsiveness. \nMolecular mechanisms responsible for endocrine \ndisorder are complicated and remain largely unknown. \nRecent studies indicate that hypoxia is involved in \nhormone regulation, endocrine organ development and \nendocrine disorders. In this review, we summarize the \ncurrent understanding about the pathological effects of \nhypoxia in endocrine organ with an emphasis on HIF-\ndependent pathway.\nHypoxia and HIF regulation\nHIF is a heterodimeric protein that includes a stable \nβ subunit, also known as aryl hydrocarbon receptor \nnuclear translocator and an oxygen-sensitive α subunit. \nThere are three members of HIF- α in mammal ( Fig.  1). \nHIF-1α and HIF-2 α proteins are critical for mediating \nthe adaptive response of hypoxia, whereas HIF-3 α is \nusually considered as a negative regulator of HIF. HIF- α \nproteins form heterodimer with HIF-1 β and then bind to \nhypoxia response element (HRE) of DNA to transactivate \ndownstream target genes, which consist of at least 1000 \ngenes (Manalo et al. 2005, Xia et al. 2009, Schodel et al. \n2011). Both the α and β subunits contain basic helix-\nloop-helix (bHLH) domain for DNA binding, Per-Arnt-\nSim (PAS) domain for dimerization and transactivation \ndomains (TADs) (Semenza 2000, Wu et al. 2015). Besides \nthe common domains, the α subunit has a unique \ndomain called oxygen-dependent degradation domain \n(ODDD), which contains two proline residues (Pro402 \nand Pro564 in HIF-1 α and Pro405 and Pro531 in HIF-2 α) \nas target sites for hydroxylation by prolyl hydroxylase \n(Fig.  1). This specific modification generates a binding \nsite for von Hippel–Lindau (VHL) protein, a component \nof the protein complex that possesses E3 ubiquitin ligase \nFigure 1\nSchematic drawings show domain structure and regulation of HIFs. (A) Protein domain structures of HIF family members. Basic helix-loop-helix (H) \ndomain is for DNA binding and Per-Arnt-Sim (PAS) domain is for dimerization. HIF-α contains oxygen-dependent degradation domain (O), which \nregulates HIF-α stability through the hydroxylation of proline (P) residues. HIF-1α and HIF-2α contain two transactivation domains (T), N-TAD and C-TAD. \nThe asparagine (N) residue is another amino acid that can be hydroxylated. The total length of each subunit is marked at the end of the domain \nstructure. (B) Under normal oxygen tension, HIF-α subunit is hydroxylated by PHD, the hydroxylated proline residues is recognized and ubiquitylated by \nVHL and its associated ubiquitin ligase complex. Polyubiquitylated HIF-α subunit causes the protein degradation. HIF-α subunit binding with \ntranscriptional co-activator p300/CBP complex is also inhibited by hydroxylation of asparagine residue by FIH. Under hypoxia, the enzymatic activity of \nPHDs and FIH are decreased. Therefore, HIF-α subunit escapes the degradation and associates with HIF-β and the transcriptional co-activator in the \nnucleus. The heterodimer of HIF binds to consensus sequence HRE at the promoter region of HIF-responsive genes, such as VEGF and EPO, and initiates \nthe gene transcription.\nDownloaded from Bioscientifica.com at 06/09/2026 07:32:42PM\nvia free access\n\n\nR55Review\nh -c lee and s-j tsai Hypoxia and endocrine disorder\nDOI: 10.1530/JOE-16-0653\nJournal of Endocrinology\nhttp://joe.endocrinology-journals.org © 2017 Society for Endocrinology\nPrinted in Great Britain\nPublished by Bioscientifica Ltd.\n234:1\nactivity. Thus, HIF- α will be polyubiquitylated by VHL \nand then degraded by the 26S proteasome (Maxwell et al. \n1999). Prolyl hydroxylase requires oxygen molecule, \nferric ion and α-ketoglutarate as cofactors to complete the \nenzymatic reaction. Thus, under hypoxic condition, the \nα-subunit of HIF cannot be hydroxylated and the protein \naccumulates in the cytosol and translocates to nucleus.\nBesides hydroxylation at the proline residues, HIF-\nα also undergoes another major modification by factor \ninhibiting HIF-1 (FIH), which hydroxylates an asparagine \nresidue (Asp803 in HIF-1 α and Asp847 in HIF-2 α) in \nC-terminal TAD of HIF- α. This modification prevents the \ninteraction of TAD and transcriptional activator, p300 \nand CBP ( Lando  et  al. 2002 a,b, Ruas  et  al. 2002 ), and \nthus, attenuates the transcriptional activity of HIF. The \nenzymatic reaction catalyzed by FIH also requires oxygen \nmolecule; therefore, FIH activity is decreased and the \nhydroxylation is reduced under hypoxia. As a result, the \ntranscriptional activity of HIF is enhanced. Further, FIH \nalso interacts with VHL and binds to the TAD of HIF-1 α. \nThe binding of FIH, VHL and HIF-1α does not require the \nenzymatic activities of FIH or VHL. Instead, they form \na ternary complex and recruits histone deacetylases to \ninhibit the transactivation activity of HIF-1α (Mahon et al. \n2001). It is suggested that this interaction may serve as \na safeguarding system to prevent improper activation \nof HIF-1 α activity under normoxia. However, detailed \nmechanism regarding how histone deacetylase causes \ntranscriptional repression needs further investigation.\nHIF signaling in endocrine disorders\nDiabetes\nType II diabetes mellitus (T2DM) is a global health \nproblem, which is characterized by hyperglycemia and \nvariable degrees of insulin deficiency and resistance. A \ngrowing body of evidences indicate that dysfunction of \nHIF signaling is involved in pathogenesis of T2DM. It \nhas been found that HIF-1 β expression is decreased in \nT2DM patients compared to normal controls and that β \ncell-specific Hif-1β-knockout mice displayed abnormal \nglucose metabolism and insulin secretion ( Gunton et al. \n2005). Similarly, β cell-specific Hif-1α-knockout mice \nalso exhibited glucose intolerance and β cell dysfunction \nand developed severe glucose intolerance on a high-fat \ndiet (Cheng et al. 2010). These data indicate that HIF is \ncritical for maintaining normal function of β cell and \nwhole body glucose homeostasis ( Fig.  2). Interestingly,  \nβ cell-specific or pancreas-specific Vhl-knockout mice \ndeveloped glucose intolerance with impaired insulin \nsecretion. The impairment of insulin secretion in Vhl-\nknockout mice is mediated by aberrant elevation of Hif-1α \nas deletion of Hif-1α in Vhl-deficient β cells restored glucose \nhomeostasis (Cantley et al. 2009). Therefore, results from \nanimal studies demonstrate that loss of function and \naberrant gain of function of HIF signaling both result \nin reduced insulin secretion and glucose intolerance. \nThese contradictory results provide a good example to \nillustrate the importance and complexity of HIF signaling \nin regulating insulin secretion and glucose homeostasis. \nFurther studies are warranted to dissect the regulatory \ngene network downstream of HIF in contributing to the \nphysiological and pathological functions of β cell.\nAdipose tissue is an endocrine organ, which synthe-\nsizes and releases adipocyte-derived polypeptides known \nas adipocytokines including pro-inflammatory cytokines \n(TNF-α, IL-6, resistin, etc.), leptin and adiponectin to the \ncirculation to regulate energy homeostasis. Dysfunction \nof adipose tissue due to obesity-induced hypoxia \nconsequently leads to glucose intolerance and metabolic \nsyndrome ( Fig.  2). A handful of studies implicate that  \nHIF-1α and HIF-2α are upregulated in obese adipose tissue \nand play critical roles in energy homeostasis. Inflammation, \nglucose intolerance and decreased liver sensitivity were \nobserved in mice overexpressing constitutively active  \nHIF-1α in white adipose tissue ( Halberg  et  al. 2009 ). In \ncontrast, mice with adipocyte-specific Hif-1α or Hif-1β \nknockout are more resistant to high-fat diet-induced \nweight gain, glucose intolerance and insulin insensitivity \n(Jiang et al. 2011, Krishnan et al. 2012). Hypoxic adipose \ntissue elicits hypersecretion of pro-inflammatory \ncytokines and hyposecretion of adiponectin, which \nresults in increased infiltration of immune cells and \ndecreased insulin sensitivity, respectively ( Hosogai  et  al. \n2007, Ye et al. 2007, Rausch et al. 2008, Halberg et al. 2009, \nSun et al. 2013, Lee et al. 2014). Interestingly, recent finding \nreveals that HIF-2 α plays a protective role by promoting \nangiogenesis in adipose tissue (Garcia-Martin et al. 2016), \na result similar to what was observed in pancreatic β cells. \nCollectively, these studies provide the concept that the \nadipose tissue plays critical roles in maintaining body \nenergy balance and is a druggable target for treating \ninsulin resistance and metabolic diseases.\nLiver is the major organ regulating not only glucose \nbut also lipid metabolism. Hepatic glucose production \nand fatty acid β-oxidation are two important processes to \ngenerate ATP for brain, heart and adrenal medulla during \nDownloaded from Bioscientifica.com at 06/09/2026 07:32:42PM\nvia free access\n\n\nReview R56\nHypoxia and endocrine disorder\nDOI: 10.1530/JOE-16-0653\nJournal of Endocrinology\nh -c lee and s-j tsai\nhttp://joe.endocrinology-journals.org © 2017 Society for Endocrinology\nPrinted in Great Britain\nPublished by Bioscientifica Ltd.\n234:1\nfasting ( Postic  et  al. 2004 ). In contrast, liver uptakes \nlarge amounts of blood glucose to store as glycogen or \nlipid (triacylglycerol) in the fed state. Oxygen tension \nis an important factor that controls hepatic glucose and \nlipid metabolism ( Fig.  2). The flow of blood through \nthe liver generates gradients of oxygen tension, which \ncauses hepatocytes to become functionally different \ndepending on their location along the portocentral axis \n(Hijmans et al. 2014). It is known that gluconeogenesis \nand β-oxidation take place in periportal hepatocytes \n(exposed to higher oxygen level), whereas glycolysis \nand lipogenesis occur in pericentral hepatocytes \n(exposed to lower oxygen level) (Guzman & Castro 1989, \nJungermann & Thurman 1992 ). The distinct zonation of \nglucose/lipid metabolism indicates that the imbalance \nor inequality of oxygen concentrations may markedly \ninfluence energy homeostasis and disease development. \nIt has been reported that expression of HIF-1 β is \ndecreased in liver of T2DM patients ( Wang et al. 2009). \nBy using liver-specific Hif-1β-knockout mouse model, \nWang and coworkers demonstrated that loss of H IF-1β \nfunction results in increased hepatic gluconeogenesis, \nincreased lipogenic gene expression and low serum \nβ-hydroxybutyrate, the characteristics of T2DM \n(Wang et al. 2009 ). Ochiai and coworkers reported that \nmice with hepatocyte-specific Hif-1α knockout exhibited \nmore severe impairment of glucose tolerance and insulin \nresistance than control littermates when fed with  \nFigure 2\nRegulation and function of HIF in endocrine organs associated with type 2 diabetes mellitus. (A) The effects of HIF signaling on glucose and lipid \nmetabolism are more ambiguous, but there appears some link between hypoxia and T2DM development. The process of glucose metabolism consumes \nrobust oxygen; thus, β-cells encounter cellular hypoxia condition that activates HIF-1/2α. Mice with β-cell-specific knockout Hif-1α, Hif-1β, or Vhl knockout \nshow the impaired glucose metabolism features. (B) Adipose tissue expansion in obesity causes the hypoxic microenvironment. Hypoxia activates the \nHIF-1α and HIF-2α cascades. HIF-1α increases adipose tissue fibrosis by upregulating collagen expression and promoting the crosslinking of collagens, \nwhich ultimately results in inflammation and insulin resistance. Conversely, HIF-2α has protective effect through opposing the HIF-1α pathway. Besides, \nHIF-2α induces angiogenesis, which improves the oxygen level of adipose. (C) Hepatic lipid metabolism is a component of T2DM. Hypoxic hepatocytes, \nsuch as those in pericentral zone, are more involved in lipogenesis and repression of β-oxidation. In experimental obesity models, intermittent hypoxia \nexposure worsens the insulin intolerance and hepatic steatosis. Hepatocyte-specific Hif-1α knockout mice fed with high-fat diet exhibit glucose \nintolerance. Hepatic ablation of Hif-1β in mice increases the hepatic glucose production and impairs the glucose tolerance.\nDownloaded from Bioscientifica.com at 06/09/2026 07:32:42PM\nvia free access\n\n\nR57Review\nh -c lee and s-j tsai Hypoxia and endocrine disorder\nDOI: 10.1530/JOE-16-0653\nJournal of Endocrinology\nhttp://joe.endocrinology-journals.org © 2017 Society for Endocrinology\nPrinted in Great Britain\nPublished by Bioscientifica Ltd.\n234:1\nhigh-fat diet (Ochiai et al. 2011). These data demonstrate \nthat HIFs exert a protective role in preventing high-\nfat diet-induced liver steatosis. On the other hand, \nconditional knockout of Vhl or overexpression of Hif-1α in \nhepatocytes cause hepatic lipid accumulation (Haase et al. \n2001, Kim et al. 2006 ), suggesting H IF as a detrimental \nfactor for liver disease and metabolic syndrome. The \ndiscrepancies between these distinct phenotypes are not \nknown and warrant further investigation.\nTaken together ( Fig.  2), it is clear that HIFs, \nincluding HIF-1 α, HIF-2 α and HIF-1 β are necessary \nfor maintaining whole body glucose homeostasis \nvia regulating functions of β-cell, hepatocyte and \nadipocyte. Deficiency in either gene in any of these \nthree endocrine tissues causes metabolic syndrome \nand ultimately results in T2DM. Equally importantly, \naberrant overexpression of HIF- α, especially HIF-1 α, also \nresults in glucose intolerance and metabolic syndrome. \nThus, avoiding high-fat diet- or obesity-induced \nchronic inflammation to maintain HIF plasticity may \nbe beneficial for glucose homeostasis.\nThyroid disorder\nThyroid hormone is another important mediator in \nregulating energy metabolism. The main hormone \nsecreted by thyroid gland is the prohormone, thyroxine \n(T4). Once in the target tissue, T4 can be converted to \n3,5,3′-triiodothyronine (T3, active form) or reverse T3 \n(rT3, inactive form). This action is modulated by different \niodothyronine deiodinases. The activating deiodinase \n(D2) and inactivating deiodinase (D3) have been reported \nto regulate thyroid hormone during different conditions. \nTherefore, the regulation of D2 and D3 within target \ntissues dictates the function of thyroid hormone. The \nexpression of D3 in the hypoxic tissues of human fetus \nand the ischemic tissues of critically ill patients suggests \nthat hypoxia induces D3 expression ( Richard et al. 1998, \nHuang et al. 2003, Peeters et al. 2003). The D3 expression \nis regulated through HIF-dependent pathway in hypoxic–\nischemic heart disease using a rat model. Consequently, \nthe elevated D3 decreases the level of T3 and impairs \nmitochondrial energy homeostasis, which might result \nin cell death ( Simonides  et  al. 2008 ). Nevertheless, the \nstudy of hypoxia and thyroid hormone actions is still \nin its infancy, more investigations are needed in order \nto advance our understandings in how hypoxia/HIF \nregulates energy homeostasis through the metabolic \neffects of thyroid hormones.\nMale infertility\nIn male reproduction, testosterone is responsible for \nspermatogenesis and the development of secondary sexual \ncharacteristics. Chronic hypobaric hypoxia decreases \nthe luteinizing hormone and testosterone levels in men \n(Sawhney  et  al. 1985 ). Male rats exposed to chronic \nhypoxia and intermittent hypoxia result in changes in \ntesticular morphology and loss of spermatogenic cells in \nall stages of the spermatogenic cycle ( Farias et al. 2005). \nBy monitoring the time course of endocrine change, it is \nsuggested that the spermatogenic effect of chronic hypoxia \nmay partially involve in changes of hypothalamus–\npituitary–gonad axis (Farias et al. 2008).\nLocal hypoxia in testis, mainly caused by varicocele \nand testicular torsion, also markedly reduces male \nfertility. Testicular torsion is caused by twisting of the \nspermatic cord, which reduces blood supply to the testicle \nand might lead to total loss of the testis. Varicocele is \ncharacterized by deficiency of the valves in the testicular \nvenous system. The deficient valves cause exceeded \nblood pressure in venous system than that in the arterial \nsystem, which results in hypoxia in the seminiferous \ntubules of bilateral testes. In patients with varicocele, \nsperm production degenerates and then progresses to \nazoospermia (Gat et al. 2005), a phenomenon seen in up \nto 20% of male infertility situation. The levels of HIF-1 α \nand VEGF are elevated in the testis of male with varicocele \nand experimental varicocele rat model (Kilinc et al. 2004, \nShiraishi & Naito 2008 ). Interestingly, elevation of VEGF \nin testis is inversely correlated with total mobile sperm \ncounts (Shiraishi & Naito 2008), which suggests VEGF has \na harmful effect in spermatogenesis. Indeed, it has been \nshown that overexpression of VEGF in the testis inhibits \nthe proliferation of spermatogonia ( Nalbandian  et  al. \n2003) and causes infertility in transgenic mice \n(Korpelainen et al. 1998).\nTestosterone production is also under the control \nof oxygen tension. Experimental animals exposed to \nchronic hypoxia exhibits a reduction in plasma and \ntesticular testosterone concentrations ( Farias et al. 2008, \nMadrid et al. 2013). This effect of testosterone reduction \nwas also observed in patients suffering from obstructive \nsleep apnea ( Liu et al. 2007) and in humans with long-\nterm exposure to high altitude ( Benso et al. 2007). Study \nusing experimental animals reveals that the reduction \nin testosterone is likely due to a decrease in Leydig cell \npopulation (Farias et al. 2005). As testosterone is a potent \nparacrine factor for spermatogenesis, prolonged exposure \nto hypoxia may result in low sperm counts and infertility.\nDownloaded from Bioscientifica.com at 06/09/2026 07:32:42PM\nvia free access\n\n\nReview R58\nHypoxia and endocrine disorder\nDOI: 10.1530/JOE-16-0653\nJournal of Endocrinology\nh -c lee and s-j tsai\nhttp://joe.endocrinology-journals.org © 2017 Society for Endocrinology\nPrinted in Great Britain\nPublished by Bioscientifica Ltd.\n234:1\nFemale infertility\nOvarian function is critical for female reproduction. \nOocytes grow in the follicle surrounded by granulosa \ncells and thecal cells. The basement membrane forms a \ntight barrier between granulosa and thecal cells and thus \nblocks the blood vessel from infiltrating into the region \nwhere granulosa cells and oocyte reside. This structural \nbarrier creates a hypoxic microenvironment for granulosa \ncells and germ cell. HIF has been postulated to involve in \nfollicle development ( Neeman et  al. 1997 ) likely due to \nthe hypoxic microenvironment in the follicle. However, \nit has become clear that expression of HIF-1 α is regulated \nby pituitary hormones instead of hypoxia in follicles. It \nhas been shown that follicle-stimulating hormone (FSH) \nenhances HIF-1α transcriptional activity, which augments \nFSH-induced upregulation of luteinizing hormone \nreceptor, inhibin- α and VEGF to promote follicular \ndifferentiation to a preovulatory phenotype ( Alam et al. \n2004). HIF-1α mRNA or protein was absent in pre-antral \nand antral follicles ( Duncan  et  al. 2008 ) and become \nevident in the granulosa cells of preovulatory follicles in \nmonkey (Duncan et al. 2008), porcine (Boonyaprakob et al. \n2005) and mouse (Kim et al. 2009). In luteinized granulosa \ncells of human (van den Driesche et al. 2008) and bovine \n(Fadhillah  et  al. 2014 ), expression of HIF-1 α was also \ndetected. These observations indicate that expression of \nHIF-1α in granulosa cells is likely stimulated by luteinizing \nhormone (LH). Indeed, treatment of mouse granulosa cells \nwith human chorionic gonadotropin (a hormone that \nalso binds to LH receptor) but not hypoxia induces HIF-1α \nmRNA (Tam et al. 2010). It is now clear that upregulation \nof HIF-1α in the preovulatory granulosa cells is critical for \novulation as inhibition of HIF activity by echinomycin \nblocks ovulation in mice ( Kim et al. 2009). Several genes \ninvolved in ovulation such as endothelin-2 ( Na  et  al. \n2008, Wang  et  al. 2012 ), VEGF ( Duncan et  al. 2008 ), \ndisintegrin and metalloproteinase with thrombospondin-\nlike motifs-1 (Kim et al. 2009) are upregulated by HIF-1 in \nthe preovulatory granulosa cells.\nDuring ovulation, the basement membrane that \nseparates granulosa cells and thecal cells brakes down \nand blood vessels infiltrate to facilitate the luteinization \nprocess. HIF-induced VEGF expression certainly is \ncritical for this process. In addition, hypoxia also \npromotes progesterone production during luteinization \n(Fadhillah  et  al. 2014 ). In corpus luteum, HIF-1 α was \nhighly expressed in the early corpus luteum and gradually \ndeclined as the corpus luteum aged ( Boonyaprakob et al. \n2005, Duncan et  al. 2008 ). In early bovine luteal cells, \nhypoxia induces VEGF expression, which facilitates luteal \ndevelopment ( Nishimura & Okuda 2010 ). Interestingly, \nhypoxia inhibits progesterone production and promotes \nluteal cell apoptosis in mid-corpus luteum but not in the \nearly corpus luteum (Nishimura et al. 2008, Nishimura & \nOkuda 2010). These data indicate that hypoxia may exert \ndistinct functions in bovine corpus luteum to regulate \novarian cycle and fertility.\nEndometriosis\nEndometriosis is a common gynecological disease, \nwhich causes severe pain and infertility. The etiology \nof endometriosis remains elusive; however, recent \nfindings reveal that hypoxia plays critical roles in the \ndevelopment and progression of this disease ( Fig.  3). \nAberrant expression of HIF-1 α mRNA and protein has \nbeen found in endometriotic lesion, especially in the \nendometriotic stromal cells (Wu et al. 2007). Elevated level \nof HIF-1 α induces leptin production, which stimulates \nthe proliferation of endometrial stromal cells ( Wu et al. \n2007). Prostaglandin E 2 (PGE 2) is a major mediator in \nthe pathogenesis of endometriosis, which stimulates \nsteroidogenesis, angiogenesis and immune suppression \n(Wu et al. 2010 for review). Abnormal production of PGE2 \nis caused by overexpression of cyclooxygenase-2 (COX-2) \nin endometriotic stromal cells and peritoneal macrophages \nin women with endometriosis ( Wu  et  al. 2002 , 2005 ). \nOur studies demonstrate that hypoxia stimulates \nCOX-2 expression through repression of dual-specificity \nphosphatase-2 ( Wu  et  al. 2011 ) and induction of miR-\n20a (Lin et al. 2012). Besides regulating PGE 2-dependent \npathogenesis, recent studies also show that hypoxia \npromotes angiogenesis via interleukin 8 (Hsiao et al. 2014), \nincreases the migration ability of stromal cells via CD26/\ndipeptidyl peptidase IV ( Tan  et  al. 2014 ) and enhances \nautophagy via upregulating miR210 (Xu et al. 2016). These \nstudies indicate that hypoxia promotes the development \nof endometriosis through various mechanisms. More \nimportantly, a recent study demonstrates that hypoxia \ncauses epigenome reprogramming by stimulating the \ndegradation of DNA methyltransferase 1 mRNA, which \nresults in altering the expression profile of some critical \ngenes involved in the development/progression of \nendometriosis ( Hsiao  et  al. 2015 ). This suggests that \nhypoxia may contribute to endometriosis by means of \nanother layer of gene regulation. It would be interesting to \ninvestigate whether hypoxia also regulates RNA or histone \nmodification to modulate gene expression epigenetically \nin endometriosis.\nDownloaded from Bioscientifica.com at 06/09/2026 07:32:42PM\nvia free access\n\n\nR59Review\nh -c lee and s-j tsai Hypoxia and endocrine disorder\nDOI: 10.1530/JOE-16-0653\nJournal of Endocrinology\nhttp://joe.endocrinology-journals.org © 2017 Society for Endocrinology\nPrinted in Great Britain\nPublished by Bioscientifica Ltd.\n234:1\nHIF signaling in endocrine tumors\nEndocrine gland tumor, in contrast to other solid cancers \nthat normally only affect specific tissue or organ, always \nresults in altering the physiological functions of whole \nbody due to the complex feedback mechanisms of \nhormone. Hypoxia is known as a primary consequence \nof rapid cell proliferation in solid tumors because the \noxygen molecule can only diffuse for 100–150 μm. \nTumor hypoxia is strongly associated with tumor cell \nproliferation, malignancy and the resistance of therapy \n(Hockel & Vaupel 2001 ). Considering the pathological \nfunctions of hypoxia in cancer have been reviewed in \nmany articles, we will only discuss the unique effects of \nHIF in endocrine gland tumors-related systemic disorders \nin this section (Fig. 4).\nPituitary tumor\nPituitary adenomas are the most common intracranial \nneoplasms with the preference rate of one in ten \nthousand per year ( Melmed 2008 ). Pituitary adenomas \nalways accompany with some hormone disorder \nsyndromes, such as acromegaly, Cushing’s syndrome, \nhyperpituitarism and central diabetes insipidus. Although \nthe genetic and molecular mechanisms responsible for \nthe development and progression of pituitary adenomas \nremain largely unknown, recent studies reveal that \nhypoxia does play some critical roles in pituitary tumor \nmalignancy. Like in any solid tumor, HIF-1 α is also \nelevated in pituitary adenoma. Overexpression of HIF-\n1α promotes hemorrhagic transformation in pituitary \nadenomas (Xiao et al. 2011), which usually causes sudden \nonset of headache, visual impairments, mental disorder \nand hormonal dysfunction, a disease known as pituitary \napoplexy. The secretion of adrenocorticotropic hormone \nis reduced in patients with pituitary apoplexy, which \nresults in lack of cortisol production (by adrenal gland). \nA decrease in cortisol may cause low blood pressure and \nlow blood sugars, which is life-threatening and needs \nimmediate medical attention. Elevation of HIF-1 α also \nreduces the sensitivity of temozolomide treatment by \nincreasing autophagy process ( Kun  et  al. 2015 ); thus, \nHIF-1α knockdown or treatment with HIF-1 α inhibitor \nconfers the temozolomide treatment sensitization in \nhuman adenomas through downregulation of O-6-\nmethylguanine-DNA methyltransferase expression \n(Chen et al. 2013). Taken together, these data suggest that \nHIF-1 may be a potential therapeutic target of pituitary \nadenomas and the related hormone disorder syndromes.\nThyroid cancer\nThyroid cancer is the most common malignancy of \nendocrine glands, which can be divided into papillary \ncarcinomas (80%), follicular carcinomas (10%), medullary \nthyroid carcinomas (5–10%), anaplastic carcinomas \n(1–2%), primary thyroid lymphomas (rare) and primary \nFigure 3\nHypoxia is involved in pathological processes of \nendometriosis. Retrograded endometrial \nfragments suffer from hypoxia before the \nvascular growth. Hypoxic condition stimulates \nprostaglandin-E2 (PGE2) production in ectopic cell \nby repression of dual-specificity phosphatase-2 \n(DUSP2) and induction of miR20-a. Activation of \nERK further promotes angiogenesis by induction \nof angiogenic factors, such as, Cysteine-rich \nangiogenic inducer 61 (CYR61), osteopontin \n(OPN) and interleukin-8 (IL-8). Hypoxia induces \nleptin (LEP) and miR210 expression and thus \npromotes ectopic cell proliferation and \nautophagy/cell viability. In addition, hypoxia \ninhibits the migration inhibitor CD26/dipeptidyl \npeptidase IV (CD26/DPPIV) expression that \nincreases the ability of cell migration.\nDownloaded from Bioscientifica.com at 06/09/2026 07:32:42PM\nvia free access\n\n\nReview R60\nHypoxia and endocrine disorder\nDOI: 10.1530/JOE-16-0653\nJournal of Endocrinology\nh -c lee and s-j tsai\nhttp://joe.endocrinology-journals.org © 2017 Society for Endocrinology\nPrinted in Great Britain\nPublished by Bioscientifica Ltd.\n234:1\nthyroid sarcomas (rare) ( Kondo  et  al. 2006 ). HIF-1 α is \nexpressed in both differentiated and dedifferentiated \nprimary thyroid carcinomas and is positively associated \nwith an aggressive disease phenotype ( Burrows  et  al. \n2010). Papillary carcinoma is a less malignant type of \nthyroid cancer with good prognosis; however, a small \npercentage of patients with papillary carcinoma still \nsuffer from local invasion and metastasis. Animal study \nreveals that the invasive phenotype is accompanied \nwith elevated level of HIF-1 α, which can be blocked by  \nHIF-1α siRNA or inhibitor treatment ( Mo  et  al. 2012 ). \nOther studies demonstrate that HIF-1 α and HIF-2 α \nexpression is correlated with the lymph node metastasis \n(Wang et al. 2013, 2014). In medullary thyroid carcinoma, \nHIF-1 cooperates with mutant form proto-oncogene, \nrearranged during transfection (RET), to affect the \nexpression of carbonic anhydrase 9 (CA9). The increased \nexpression of CA9 in medullary thyroid carcinoma \nprovides a highlight for targeting the RET oncoprotein \nand HIF-1 signaling pathway ( Takacova  et  al. 2014 ). \nAnaplastic thyroid carcinoma is the most aggressive \nmalignant thyroid tumors, which also exert highest level \nof HIF-1 α. Recently, it was found that HIF-1 α induces \nthe expression of IL-11, which then induces epithelial–\nmesenchymal transition in anaplastic thyroid cancer \ncells via the PI3K/AKT/GSK3 β pathway ( Zhong  et  al. \n2016). Take together, these findings suggest that both \nHIF-1α and HIF-2 α promote thyroid cancer progression \nand metastasis even in the less malignant papillary \ncarcinomas.\nAdrenal cancer\nAdrenal tumor is a benign or malignant neoplasm of  \nadrenal gland. Malignant adrenal tumor includes \nneuroblastoma, adrenocortical carcinoma and some \nadrenal pheochromocytoma. Most adrenal pheochromo-\ncytomas and adrenocortical adenomas do not metastasize \nor invade nearby tissues, but cause health problems such \nas elevated blood pressure, anxiety, diaphoresis, elevated \nblood glucose level and arterial hypertension due to \nunbalancing hormones secretion or sympathetic nervous \nsystem hyperactivation. It has been reported that HIF-\n2α is overexpressed in pheochromocytoma and results \nin vascular growth (Favier et al. 2002). Overexpression of \nHIF-2α is relatively common in VHL deficiency-related \npheochromocytoma, whereas HIF-1α is more frequent in \nsuccinate dehydrogenase-deficient pheochromocytoma \n(Pollard et al. 2006). Interestingly, it was reported that HIF-\n1α and HIF-2α exert opposite effect in pheochromocytoma, \nsuggesting the signaling pathways may be similar but the \ndownstream effects are divergent ( Qin  et  al. 2014 ). The \ndistinct effects of HIF-1 α and HIF-2 α were also observed \nin adrenal neuroblastoma. Adrenal neuroblastoma is one \nof the common cancers in infant, which is an aggressive \ncancer of immature neuroblastic cells. HIF-1α is negatively \ncorrelated with advanced clinical stage and tumor \nvascularization (Noguera  et  al. 2009). In contrast, HIF-2 α  \nexpression is well correlated with vascularized areas \n(Holmquist-Mengelbier  et  al. 2006 ) and poor prognosis \n(Pietras et al. 2009). Downregulation of miR-145 was found \nFigure 4\nHIF expression levels and systemic effects of endocrine gland tumor. (A) A summary of disorders caused by endocrine tumors. The imbalance of hormone \nsecretion due to endocrine glands tumors usually leads to alteration of physiological functions due to the complex feedback mechanisms of hormone. \nAs a result, whole body homeostasis is disturbed and symptoms occur. (B) The levels of HIFs are correlated with the clinical observation in different types \nof endocrine tumors. PET, pancreatic endocrine tumor.\nDownloaded from Bioscientifica.com at 06/09/2026 07:32:42PM\nvia free access\n\n\nR61Review\nh -c lee and s-j tsai Hypoxia and endocrine disorder\nDOI: 10.1530/JOE-16-0653\nJournal of Endocrinology\nhttp://joe.endocrinology-journals.org © 2017 Society for Endocrinology\nPrinted in Great Britain\nPublished by Bioscientifica Ltd.\n234:1\nto be an upstream cause for the overexpression of HIF-2 α \nin adrenal neuroblastoma as forced expression of miR-145 \nreduces HIF-2α protein level and suppresses tumor growth, \ninvasion, angiogenesis and metastasis (Zhang et al. 2014). \nCollectively, these findings indicate that HIF-2 α but not \nHIF-1α contributes to the pathogenesis of neuroblastoma \nand related endocrine disorder syndromes.\nPancreatic endocrine tumor\nPancreatic cancers can arise from the exocrine (~95%) \nand endocrine (< 5%) portions of the pancreas. Pancreatic \nendocrine tumors (PETs) are quite distinct from the usual \nform of pancreatic cancer. Pancreatic endocrine tumors \ncan be divided into two general groups: functional and \nnonfunctional. Functional PETs ectopically secrete \nhormones to cause clinical symptoms such as Zollinger–\nEllison syndrome (caused by aberrant secretion of gastrin-\ninduced peptic ulcer), hypoglycemia (caused by aberrant \nsecretion of insulin), severe secretory diarrhea (caused by \naberrant secretion of vasoactive intestinal peptide) and \nhyperglycemia/diabetes (caused by aberrant secretion of \nglucagon). In contrast, nonfunctional PETs do not secrete \nor secrete products that do not cause a clinical syndrome \n(Jensen  et  al. 2008 ). PETs are highly vascularized and \nexhibits distinct HIF expression pattern from other tumor \n(Marion-Audibert et al. 2003, Couvelard et al. 2005). The \ncytoplasmic HIF-1α and 2 α are expressed in normal islet \ncell, which is progressively lost with tumor progression \n(Couvelard et al. 2005). In contrast, the highly expressed \nHIF regulatory proteins, PHD and FIH are positively \ncorrelated with tumor metastases, tumor recurrence and \nprognosis (Couvelard et al. 2008). Furthermore, RSUME, \na RWD-containing protein that stabilizes and enhances \nHIF-1α expression is reduced in pancreatic endocrine \ntumors. In vivo  orthotopic mice show that knockdown \nof RSUME enhances pancreatic endocrine tumor growth \nand liver metastasis ( Wu et al. 2016). Collectively, these \nstudies show that HIF expression and microvessel density \nare increased in well-differentiated pancreatic endocrine \ntumors and are positively correlated with overall survival \nrate. It also demonstrates that effect of HIF is significantly \ndifferent in pancreatic endocrine tumor compared to \nother cancers.\nConclusion and perspective\nA large body of evidence demonstrates that HIF-mediated \nsignaling pathway involves in pathological progression \nof endocrine disorders and endocrine tumors. Different \ntissues have specific HIF expressions and downstream \nimpacts. Some of the data suggest that HIF-1 α and  \nHIF-2α have synergistic effect, whereas some indicate \nthe antagonistic effect. This should be taken into \nconsideration when developing inhibitors targeting the \nHIF isoforms as the therapeutic drugs.\nThe other critical point that deserves attention is that \nalthough most of the cells in our body need oxygen to \nfunction normally, some tissues/cells are under ‘normal’ \nhypoxic condition (examples like pericentral hepatocytes, \nbone marrow, Sertoli cells of testis, granulosa and germ \ncells of ovarian follicles and islet cells of pancreas). \nThese normal hypoxic tissues/cells are adaptive to \nhypoxic condition through specific HIF-mediated \npathway. Therefore, inhibiting HIF activity would result \nin detrimental effect for these tissues. Therefore, it is \ngenerally accepted that HIF is not druggable and recent \nfocus is shifted to target HIF downstream effectors to \ndesign more specific and less adverse compound as \ntherapeutic approach. With the availability of large \nquantity of omics and metabolomics data and CRISPR/\nCas9 gene editing technique ( Wiedenheft  et  al. 2012 ), \nit is now applicable to pinpoint the function of critical \ngene downstream of HIF in regulating specific biological \nprocess and manipulate it to alter or rectify the diseases \ncaused by aberrant expression of this gene. One could \nexpect that by employing these new techniques, diseases \nwith complicated mechanisms such as hypoxia-mediated \nendocrine gland disorder can be manageable in the \nnear future.\nDeclaration of interest\nThe authors declare that there is no conflict of interest that could be \nperceived as prejudicing the impartiality of this review.\nFunding\nThis work was supported by grants from Ministry of Science and \nTechnology, Taiwan (MOST 104-2320-B-006-036-MY3) and Top University \ngrant of National Cheng Kung University (D105-35B03).\nAuthor contribution statement\nH C Lee drafted the manuscript. S J Tsai conceived this project and edited \nthe manuscript.\nAcknowledgments\nThe authors would like to thank all the contributing scientists to make this \nreview article possible and to apologize to those whose works were not \ncited due to space limitation.\nDownloaded from Bioscientifica.com at 06/09/2026 07:32:42PM\nvia free access\n\n\nReview R62\nHypoxia and endocrine disorder\nDOI: 10.1530/JOE-16-0653\nJournal of Endocrinology\nh -c lee and s-j tsai\nhttp://joe.endocrinology-journals.org © 2017 Society for Endocrinology\nPrinted in Great Britain\nPublished by Bioscientifica Ltd.\n234:1\nReferences\nAlam H, Maizels ET, Park Y, Ghaey S, Feiger ZJ, Chandel NS & Hunzicker-\nDunn M 2004 Follicle-stimulating hormone activation of hypoxia-\ninducible factor-1 by the phosphatidylinositol 3-kinase/AKT/Ras \nhomolog enriched in brain (Rheb)/mammalian target of rapamycin \n(mTOR) pathway is necessary for induction of select protein markers \nof follicular differentiation. 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(doi:10.1152/\najpendo.00435.2007)\nZhang H, Pu J, Qi T, Qi M, Yang C, Li S, Huang K, Zheng L & Tong Q \n2014 MicroRNA-145 inhibits the growth, invasion, metastasis and \nangiogenesis of neuroblastoma cells through targeting hypoxia-\ninducible factor 2 alpha. Oncogene 33 387–397. (doi:10.1038/\nonc.2012.574)\nZhong Z, Hu Z, Jiang Y, Sun R, Chen X, Chu H, Zeng M & Sun C 2016 \nInterleukin-11 promotes epithelial–mesenchymal transition in \nanaplastic thyroid carcinoma cells through PI3K/Akt/GSK3beta \nsignaling pathway activation. Oncotarget 7 59652–59663.\nReceived in final form 18 April 2017\nAccepted 28 April 2017\nAccepted Preprint published online 28 April 2017\nDownloaded from Bioscientifica.com at 06/09/2026 07:32:42PM\nvia free access","source_license":"public-domain-us","license_restricted":false}