Tenapanor , sold under the brand name  Ibsrela  among others, is a  medication  used for the treatment of adults with a disease of the gut called  irritable bowel syndrome  with  constipation  commonly referred to as IBS-C. [ 3 ] [ 5 ]  It is used in form of tenapanor hydrochloride. [ 3 ]  It is also used in the treatment of hyperphosphatemia associated with  chronic kidney disease . [ 4 ]  Tenapanor is a sodium hydrogen exchanger 3 (NHE3) inhibitor. [ 4 ]


Tenapanor is a drug developed by Ardelyx, which acts as an inhibitor of the  sodium-proton exchanger NHE3 . This  antiporter  protein is found in the kidney and intestines, and normally acts to regulate the levels of  sodium  absorbed and secreted by the body. When administered orally, tenapanor selectively inhibits sodium uptake in the intestines, limiting the amount absorbed from food, and thereby reduces levels of sodium in the body. [ 6 ]  This may make it useful in the treatment of chronic kidney disease and  hypertension , both of which are exacerbated by excess sodium in the diet. [ 7 ]


It was approved for medical use in the United States in September 2019. [ 3 ] [ 8 ] [ 5 ] [ 9 ]  The U.S.  Food and Drug Administration  (FDA) considers it to be a  first-in-class medication . [ 10 ]  In October 2023, tenapanor was approved by the FDA for the treatment of  hyperphosphatemia . [ 11 ]


Teprenone  (or  geranylgeranylacetone ), sold under the brand name  Selbex , [ 1 ]  is a  medication  used for the treatment of  gastric ulcers . [ 2 ]


Testosterone  is a  medication  and naturally occurring  steroid hormone . [ 9 ]  It is used to treat  male hypogonadism ,  gender dysphoria , and certain types of  breast cancer . [ 9 ] [ 10 ]  It may also be used to increase  athletic ability  in the form of  doping . [ 9 ]  It is unclear if the use of testosterone for  low levels due to aging  is beneficial or harmful. [ 11 ]  Testosterone can be administered through several different routes, including  topical   gels  or  patches ,  nasal sprays,  subdermal implants, or  tablets dissolved inside the mouth . [ 9 ]


Common  side effects  of testosterone include  acne ,  swelling , and  breast enlargement in men . [ 9 ]  Serious side effects may include  liver toxicity ,  heart disease , and behavioral changes. [ 9 ]  Women and children who are exposed may develop  masculinization . [ 9 ]  It is recommended that individuals with  prostate cancer  should not use the medication. [ 9 ]  It can cause harm to the baby if used during  pregnancy  or  breastfeeding . [ 9 ]  Testosterone is in the  androgen  family of medications. [ 9 ]


Testosterone was first isolated in 1935, and approved for medical use in 1939. [ 12 ] [ 13 ]  Rates of use have increased three times in the United States between 2001 and 2011. [ 14 ]  It is on the  World Health Organization's List of Essential Medicines . [ 15 ]  It is available as a  generic medication . [ 9 ]  In 2022, it was the 118th most commonly prescribed medication in the United States, with more than 5   million prescriptions. [ 16 ] [ 17 ]


The primary use of testosterone is the treatment of males with too little or no natural testosterone production, also termed  male hypogonadism  or  hypoandrogenism  (androgen deficiency). [ 18 ]  This treatment is referred to as  hormone replacement therapy  (HRT), or alternatively, and more specifically, as testosterone replacement therapy (TRT) or  androgen replacement therapy  (ART). It is used to maintain serum testosterone levels in the normal male range. Decline of testosterone production with age has led to interest in testosterone supplementation. [ 19 ]


A 2020 guideline from the  American College of Physicians  supports the discussion of testosterone in adult men with age-related  low levels of testosterone  who have  sexual dysfunction . They recommend yearly evaluation regarding possible improvement and, if none, to discontinue testosterone; physicians should consider intramuscular treatments, rather than transdermal treatments, due to costs and since the effectiveness and harm of either method is similar. Testosterone treatment for reasons other than possible improvement of sexual dysfunction may not be recommended. [ 20 ] [ 21 ]


Testosterone deficiency (also termed hypotestosteronism or hypotestosteronemia) is an abnormally low testosterone production. It may occur because of testicular dysfunction ( primary hypogonadism ) or hypothalamic–pituitary dysfunction ( secondary hypogonadism ) and may be  congenital  or acquired. [ 22 ]


Testosterone levels may decline gradually with age. [ 23 ] [ 24 ]  The United States  Food and Drug Administration  (FDA) stated in 2015 that neither the benefits nor the safety of testosterone supplement have been established for low testosterone levels due to aging. [ 11 ]  The FDA has required that labels on testosterone include warnings about increased risk of heart attacks and stroke. [ 11 ]


To take advantage of its  virilizing  effects, testosterone is administered to  transgender men  and other  transmasculine individuals  as part of  masculinizing hormone therapy , [ 25 ]  titrated to clinical effect with a "target level" of the average male's testosterone level. [ 26 ]


Testosterone therapy is effective in the short-term for the treatment of  hypoactive sexual desire disorder  (HSDD) in women. [ 37 ]  However, its long-term  safety  is unclear. [ 37 ]  Because of a lack data to support its efficacy and safety, the  Endocrine Society  recommends against the routine use of testosterone in women to treat  low androgen levels  due to  hypopituitarism ,  adrenal insufficiency ,  surgical removal of the ovaries , high-dose  corticosteroid  therapy, or other causes. [ 37 ]  Similarly, because of a lack of data to support its efficacy and safety, the Endocrine Society recommends against the use of testosterone in women to improve general  well-being , to treat  infertility ,  sexual dysfunction  due to causes other than HSDD, or to improve  cognitive ,  cardiovascular ,  metabolic , and/or  bone  health. [ 37 ]


A 2014 systematic review and meta-analysis of 35 studies consisting of over 5,000  postmenopausal  women with normal  adrenal gland  function found that testosterone therapy was associated with significant improvement in a variety of domains of sexual function. [ 38 ]  These domains included frequency of  sexual activity ,  orgasm ,  arousal , and sexual satisfaction, among others. [ 38 ]  Women who were menopausal due to  ovariectomy  showed significantly greater improvement in sexual function with testosterone relative to those who had normal menopause. [ 38 ]  In addition to beneficial effects on sexual function, testosterone was associated with unfavorable changes in  blood lipids . [ 38 ]  These included decreased levels of total  cholesterol ,  triglycerides , and  high-density lipoprotein  (HDL) cholesterol, and increased levels of  low-density lipoprotein  (LDL) cholesterol. [ 38 ]  However, the changes were small in magnitude, and the long-term significance in relation to  cardiovascular  outcomes is uncertain. [ 38 ]  The changes were more pronounced with oral  testosterone undecanoate  than with  parenteral  routes, such as  transdermal  testosterone. [ 38 ]  Testosterone showed no significant effect on  depressed   mood   anxiety ,  bone mineral density  (BMD), or  anthropomorphic measures  like  body weight  or  body mass index . [ 38 ]  Conversely, it was associated with a significant incidence of androgenic side effects, including  acne  and  hirsutism  (excessive facial/body hair growth). [ 38 ]  Other androgenic side effects, such as  weight gain ,  pattern hair loss , and  voice deepening , were also reported in some trials, but were excluded from analyses due to insufficient data. [ 38 ]  The overall quality of the evidence was rated as low and was considered to be inconclusive in certain areas, for instance on long-term safety. [ 38 ]


A subsequent 2017 systematic review and meta-analysis of studies including over 3,000 postmenopausal women with HSDD similarly found that short-term transdermal testosterone therapy was effective in improving multiple domains of sexual function. [ 39 ]  Androgenic adverse effects such as acne and hirsutism were significantly greater in incidence with testosterone therapy, whereas no significant differences in "increase in facial hair, alopecia, voice deepening, urinary symptoms, breast pain, headache, site reaction to the patch, total adverse events, serious adverse events, reasons for withdrawal from the study, and the number of women who completed the study" were seen relative to controls. [ 39 ]


Although testosterone has been found to be effective at improving sexual function in postmenopausal women, the doses employed have been supraphysiological. [ 40 ] [ 41 ]  In contrast to these high doses, there is little support for the notion that testosterone is a critical hormone for sexual desire and function in women under normal physiological circumstances. [ 40 ] [ 41 ]  Low doses of testosterone resulting in physiological levels of testosterone (<50 ng/dL) have not been found to significantly increase sexual desire or function in women in most studies. [ 40 ]  Similarly, there appears to be little or no relationship between total or free testosterone levels in the normal physiological range and sexual desire in premenopausal women. [ 41 ] [ 40 ]  Only high doses of testosterone resulting in supraphysiological levels of testosterone (>50 ng/dL) significantly increase sexual desire in women, with levels of testosterone of 80 to 150 ng/dL "slightly" increasing sex drive. [ 40 ] [ 41 ]  In accordance, men experience  sexual dysfunction  at testosterone levels of below 300 ng/dL, and men that have levels of testosterone of approximately 200 ng/dL frequently experience such problems. [ 41 ]  The high doses of testosterone required to increase sexual desire in women may have a significant risk of masculinization with long-term therapy. [ 41 ] [ 40 ]  For this reason, and due to the unknown health effects and safety of testosterone therapy, its use may be inappropriate. [ 41 ] [ 40 ]  In 2003, the FDA rejected Intrinsa, a 300 μg/day  testosterone patch  for the treatment of sexual dysfunction in postmenopausal women. [ 40 ] [ 41 ]  The reasons cited were limited efficacy (about one additional sexually satisfying event per month), concerns about safety and potential adverse effects with long-term therapy, and concerns about inappropriate  off-label use . [ 40 ] [ 41 ]  It appears that in women, rather than testosterone,  estradiol  may be the most important hormone involved in sexual desire, although data on the clinical use of  estradiol  to increase sexual desire in women is limited. [ 40 ] [ 42 ] [ 43 ]


There are no testosterone products approved for use in women in the United States and many other countries. [ 44 ]  There are approved testosterone products for women in Australia, where it is considered a drug of dependence, medicines that are subject to misuse and trafficking,  [ 45 ]  and some European countries. [ 44 ]  Testosterone pellet implants are approved for use in postmenopausal women in the United Kingdom. [ 46 ] [ 47 ]  Testosterone products for men can be used  off-label  in women in the United States. [ 44 ]  Alternatively, testosterone products for women are available from  compounding pharmacies  in the United States, although such products are unregulated and manufacturing quality is not ensured. [ 48 ]


Testosterone has been marketed for use by  oral ,  sublingual ,  buccal ,  intranasal ,  transdermal  ( patches ),  topical  ( gels ),  intramuscular  ( injection ), and  subcutaneous  ( implant )  administration . [ 49 ] [ 50 ] [ 51 ] [ 52 ]  It is provided unmodified and as a  testosterone ester  such as  testosterone cypionate ,  testosterone enanthate ,  testosterone propionate , or  testosterone undecanoate , which act as  prodrugs  of testosterone. [ 49 ] [ 50 ] [ 51 ]  The most common  route of administration  for testosterone is by intramuscular injection. [ 49 ]  However, it has been reported that AndroGel, a transdermal gel formulation of testosterone, has become the most popular form of testosterone in androgen replacement therapy for hypogonadism in the United States. [ 50 ]


Testosterone is used as a form of  doping  among  athletes  in order to improve performance. [ 65 ]  Testosterone is classified as an  anabolic  agent and is on the  World Anti-Doping Agency  (WADA) List of Prohibited Substances and Methods. [ 65 ]  Hormone supplements cause the endocrine system to adjust its production and lower the natural production of the hormone, so when supplements are discontinued, natural hormone production is lower than it was originally. [ citation needed ]


Anabolic–androgenic steroids  (AAS), including testosterone and its esters, have also been taken to enhance muscle development, strength, or endurance. They do so directly by increasing the muscles' protein synthesis. As a result, muscle fibers become larger and repair faster than the average person's. [ citation needed ]


After a series of scandals and publicity in the 1980s (such as  Ben Johnson's  improved performance at the  1988 Summer Olympics ),  prohibitions  of AAS use were renewed or strengthened by many sports organizations. Testosterone and other AAS were designated a " controlled substance " by the  United States Congress  in 1990, with the  Anabolic Steroid Control Act . [ 66 ]  Their use is seen as an issue in modern sport, particularly given the lengths to which athletes and professional laboratories go to in trying to conceal such use from sports regulators. Steroid use once again came into the spotlight as a result of Canadian  professional wrestler   Chris Benoit 's double murder-suicide in 2007; however, there is no evidence implicating steroid use as a factor in the incident. [ citation needed ]


Some female athletes may have naturally higher levels of testosterone than others, and may be asked to consent to  sex verification  and either surgery or drugs to decrease testosterone levels. [ 67 ]  This has proven contentious, with the  Court of Arbitration for Sport  suspending the IAAF policy due to insufficient evidence of a link between high androgen levels and improved athletic performance. [ 68 ] [ 69 ]


A number of methods for detecting testosterone use by athletes have been employed, most based on a  urine test . These include the testosterone/ epitestosterone  ratio (normally less than 6), the testosterone/luteinizing hormone ratio and the  carbon-13 / carbon-12  ratio (pharmaceutical testosterone contains less carbon-13 than endogenous testosterone). In some testing programs, an individual's own historical results may serve as a reference interval for interpretation of a suspicious finding. Another approach being investigated is the detection of the administered form of testosterone, usually an ester, in hair. [ 70 ] [ 71 ] [ 72 ] [ 73 ]


Absolute  contraindications  of testosterone include  prostate cancer ,  elevated hematocrit  (>54%), uncontrolled  congestive heart failure , various other  cardiovascular diseases , and uncontrolled  obstructive sleep apnea . [ 74 ]   Breast cancer  is said by some sources to be an absolute contraindication of testosterone therapy, [ 74 ]  but androgens including testosterone have also actually been used to treat breast cancer. [ 75 ]  Relative contraindications of testosterone include elevated  prostate-specific antigen  (PSA) in men with a high risk of prostate cancer due to  ethnicity  or family history, severe  lower urinary tract symptoms , and elevated hematocrit (>50%). [ 74 ]


Adverse effects may also include minor side effects such as oily skin, acne, and seborrhea, as well as loss of scalp hair, which may be prevented or reduced with  5α-reductase inhibitors . In women, testosterone can produce  hirsutism  (excessive facial/body hair growth),  deepening of the voice , and other signs of  virilization . Exogenous testosterone may cause suppression of  spermatogenesis  in men, leading to, in some cases, reversible  infertility . [ 76 ]   Gynecomastia  and  breast tenderness  may occur with high dosages of testosterone due to peripheral conversion of testosterone by  aromatase  into excessive amounts of the  estrogen   estradiol . [ 77 ]  Testosterone treatment, particularly in high dosages, can also be associated with  mood changes , increased  aggression , increased  sex drive ,  spontaneous erections , and  nocturnal emissions . [ 78 ] [ 79 ] [ 80 ] [ 81 ]


Other side effects include increased  hematocrit , which can require  venipuncture  in order to treat, and exacerbation of  sleep apnea . [ 82 ]


The FDA stated in 2015 that neither the benefits nor the safety of testosterone have been established for low testosterone levels due to aging. [ 11 ]  The FDA has required that testosterone pharmaceutical labels include warning information about the possibility of an increased risk of heart attacks and stroke. [ 11 ]  They have also required the label include concerns about abuse and dependence. [ 83 ]


Injectable forms of testosterone can cause a lung problem called pulmonary oil microembolism (POME).  Symptoms of POME include cough, shortness of breath, tightening of the throat, chest pain, sweating, dizziness, and fainting. [ 84 ] [ 85 ]  A postmarketing analysis by the manufacturer of Aveed (testosterone undeconate injection) found that POME occurred at a rate of less than 1% per injection per year for Aveed. [ 86 ]


Adverse effects of testosterone supplementation may include increased cardiovascular events (including  strokes  and  heart attacks ) and  deaths  based on three peer-reviewed studies involving men taking testosterone replacement. [ 87 ]  In addition, an increase of 30% in deaths and heart attacks in older men has been reported. [ 88 ]  Due to an increased incidence of adverse cardiovascular events compared to a  placebo group , a Testosterone in Older Men with Mobility Limitations (TOM) trial (a  National Institute of Aging  randomized trial) was halted early by the  Data Safety and Monitoring Committee . [ 89 ]  On January 31, 2014, reports of  strokes ,  heart attacks , and  deaths  in men taking FDA-approved testosterone-replacement led the FDA to announce that it would be investigating the issue. [ 90 ]  Later, in September 2014, the FDA announced, as a result of the "potential for adverse cardiovascular outcomes", a review of the appropriateness and safety of Testosterone Replacement Therapy (TRT). [ 91 ] [ 92 ] [ 93 ]  The FDA now requires warnings in the drug labeling of all approved testosterone products regarding  deep vein thrombosis  and  pulmonary embolism . [ 94 ]


Up to the year 2010, studies had not shown any effect on the risk of death,  prostate cancer  or  cardiovascular disease ; [ 95 ] [ 96 ]  more recent [ when? ]  studies, however, do raise concerns. [ 97 ]  A 2013 study, published in the Journal of the American Medical Association, reported "the use of testosterone therapy was significantly associated with increased risk of adverse outcomes." The study began after a previous, randomized, clinical trial of testosterone therapy in men was stopped prematurely "due to adverse cardiovascular events raising concerns about testosterone therapy safety." [ 88 ]


However, when given to men with hypogonadism in the short- and medium-term, testosterone replacement therapy does not increase the risk of cardiovascular events (including strokes and heart attacks and other heart diseases). The long-term safety of the therapy is not known yet. [ 98 ] [ 99 ]


Testosterone therapy for patients with late-onset hypogonadism, in addition to increasing risk of cardiovascular disease and prostate cancer, may exacerbate the risk factors associated with  benign prostatic hyperplasia , a condition that involves the noncancerous enlargement of the prostate gland, which can lead to urinary symptoms. [ 100 ]


Testosterone in the presence of a slow-growing prostate cancer is assumed to increase its growth rate. However, the association between testosterone supplementation and the development of prostate cancer is unproven. [ 101 ]  Nevertheless, physicians are cautioned about the cancer risk associated with testosterone supplementation. [ 102 ]


Testosterone may accelerate pre-existing  prostate cancer  growth in individuals who have undergone androgen deprivation. [ 82 ]  It is recommended that physicians screen for prostate cancer with a digital rectal exam and  prostate-specific antigen  (PSA) level before starting therapy, and monitor PSA and hematocrit levels closely during therapy. [ 23 ]


Ethnic groups have different rates of prostate cancer. [ 103 ]  Differences in sex hormones, including testosterone, have been suggested as an explanation for these differences. [ 103 ]  This apparent paradox can be resolved by noting that prostate cancer is very common. In autopsies, 80% of 80-year-old men have prostate cancer. [ 104 ]


Testosterone is  contraindicated  in  pregnancy  and not recommended during  breastfeeding . [ 105 ]  Androgens like testosterone are  teratogens  and are known to cause  fetal  harm, such as producing  virilization  and  ambiguous genitalia .


5α-Reductase inhibitors  like  finasteride  and  dutasteride  can slightly increase circulating levels of testosterone by inhibiting its  metabolism . [ 106 ]  However, these drugs do this via prevention of the conversion of testosterone into its more potent  metabolite   dihydrotestosterone  (DHT), and this results in dramatically reduced circulating levels of DHT (which circulates at much lower relative concentrations). [ 106 ] [ 107 ]  In addition, local levels of DHT in so-called androgenic (5α-reductase-expressing) tissues are also markedly reduced, [ 106 ] [ 107 ]  and this can have a strong impact on certain effects of testosterone. [ 51 ] [ 108 ]  For instance, growth of body and facial hair and  penile growth  induced by testosterone may be inhibited by 5α-reductase inhibitors, and this could be considered undesirable in the context of, for instance,  puberty induction . [ 108 ] [ 109 ]  On the other hand, 5α-reductase inhibitors may prevent or reduce adverse androgenic side effects of testosterone like  scalp hair loss ,  oily skin ,  acne , and  seborrhea . [ 51 ]  In addition to the prevention of testosterone conversion into DHT, 5α-reductase inhibitors also prevent the formation of  neurosteroids  like  3α-androstanediol  from testosterone, and this may have neuropsychiatric consequences in some men. [ 110 ]


Aromatase inhibitors  like  anastrozole  prevent the conversion of testosterone into  estradiol  by  aromatase . [ 51 ]  As only a very small fraction of testosterone is converted into estradiol, this does not affect testosterone levels, but it can prevent  estrogenic  side effects like gynecomastia that can occur when testosterone is administered at relatively high dosages. [ 51 ]  However, estradiol exerts  negative feedback  on the  hypothalamic–pituitary–gonadal axis  and, for this reason, prevention of its formation can reduce this feedback and disinhibit gonadal production of testosterone, which in turn can increase levels of endogenous testosterone. [ 111 ]  Testosterone therapy is sometimes combined with an aromatase inhibitor for men with secondary hypogonadism who wish to conceive children with their partners. [ 112 ]


Inhibitors  and  inducers  of  cytochrome P450   enzymes  like  CYP3A4  have been associated with little or no effect on circulating testosterone levels. [ citation needed ]


Antiandrogens  like  cyproterone acetate ,  spironolactone , and  bicalutamide  can block the androgenic and anabolic effects of testosterone. [ 113 ] [ 59 ]   Estrogens  can reduce the effects of testosterone by increasing the hepatic production and in turn circulating levels of  sex hormone-binding globulin  (SHBG), a  carrier protein  that binds to and occupies androgens like testosterone and DHT, and thereby reducing free concentrations of these androgens. [ 59 ] [ 114 ]


Testosterone is a high  affinity   ligand  for and  agonist  of the  nuclear   androgen receptor  (AR). In addition, testosterone binds to and activates  membrane androgen receptors  (mARs) such as  GPRC6A  and  ZIP9 . Testosterone is also potentiated via  transformation  by  5α-reductase  into the more  potent  androgen DHT in so-called androgenic  tissues  such as the  prostate gland ,  seminal vesicles ,  skin , and  hair follicles . In contrast to the case of testosterone, such potentiation occurs to a reduced extent or not at all with most  synthetic  AAS (as well as with DHT), and this is primarily responsible for the dissociation of  anabolic  and androgenic effects with these agents. [ 115 ]  In addition to DHT, testosterone is converted at a rate of approximately 0.3% into the  estrogen   estradiol  via  aromatase . [ 116 ]  This occurs in many tissues, especially  adipose tissue , the  liver , and the  brain , but primarily in adipose tissue. [ 116 ]  Testosterone, after conversion into DHT, is also metabolized into 3α-androstanediol, a  neurosteroid  and potent  positive allosteric modulator  of the  GABA A  receptor , and  3β-androstanediol , a potent and preferential agonist of the  ERβ . [ 117 ]  These metabolites, along with estradiol, may be involved in a number of the effects of testosterone in the brain, including its  antidepressant ,  anxiolytic ,  stress -relieving,  rewarding , and  pro-sexual  effects. [ 117 ]  Whereas testosterone produced both anabolic and androgenic effects, despite the lack of clear boundaries between these effects, as there is a great deal of mutual overlap between them, [ 118 ]  the relative potency of these effects exerted by testosterone can depend on various factors and is a topic of ongoing research. [ 119 ] [ 120 ]


The ARs are expressed widely throughout the body, including in the  penis ,  testicles ,  epididymides ,  prostate gland ,  seminal vesicles ,  fat ,  skin ,  bone ,  bone marrow ,  muscle ,  larynx ,  heart ,  liver ,  kidneys ,  pituitary gland ,  hypothalamus , and elsewhere throughout the  brain . [ 121 ] [ 122 ]  Through activation of the ARs (as well as the mARs), testosterone has many effects, including the following: [ 121 ] [ 49 ] [ additional citation(s) needed ]


Testosterone can be taken by a variety of different  routes of administration . [ 123 ]  These include  oral ,  buccal ,  sublingual ,  intranasal ,  transdermal  ( gels ,  creams ,  patches ),  rectal   suppositories ), by  intramuscular  or  subcutaneous   injection  (in  oil  or  aqueous ), and as a  subcutaneous implant . [ 123 ]  The  pharmacokinetics  of testosterone, including its  bioavailability , circulating testosterone levels,  metabolism ,  biological half-life , and other parameters, differ by route of administration. [ 123 ]


Testosterone is a  naturally occurring   androstane   steroid  and is also known by the chemical name androst-4-en-17β-ol-3-one. [ 124 ]  It has a  double bond  between the C4 and C5 positions (making it an  androstene ), a  ketone   group  at the C3 position, and a  hydroxyl  ( alcohol ) group at the C17β position. [ 124 ]


Testosterone esters are  substituted  at the C17β position with a  lipophilic   fatty acid   ester   moiety  of varying  chain  length. [ 125 ]  Major testosterone esters include  testosterone cypionate ,  testosterone enanthate ,  testosterone propionate , and  testosterone undecanoate . [ 59 ] [ 124 ] [ 126 ]  A C17β  ether   prodrug  of testosterone,  cloxotestosterone acetate , has also been marketed, although it is little known and is used very rarely or no longer. [ 124 ]  Another C17β ether prodrug of testosterone,  silandrone , also exists but was never marketed, and is notable in that it is orally active. [ 124 ]  In addition to ester and ether prodrugs,  androgen prohormones  or  precursors  of testosterone, such as  dehydroepiandrosterone  (DHEA),  androstenediol , and  androstenedione , exist as well, and convert into testosterone to variable extents upon oral ingestion. [ 127 ]  Unlike testosterone ester and ether prodrugs however, these prohormones are only weakly androgenic/anabolic. [ 127 ]


All synthetic AAS are  derivatives  of testosterone. [ 127 ]  Prominent examples include  nandrolone  (19-nortestosterone),  metandienone  (17α-methyl-δ 1 -testosterone), and  stanozolol  (a 17α-alkylated derivative of DHT). Unlike testosterone, AAS that are  17α-alkylated , like metandienone and stanozolol, are orally active. This is due to  steric hindrance  of C17β-position metabolism during the first-pass through the liver. In contrast, most AAS that are not 17α-alkylated, like nandrolone, are not active orally, and must instead be administered via intramuscular injection. This is almost always in ester form; for instance, in the case of nandrolone, as  nandrolone decanoate  or  nandrolone phenylpropionate .


Testosterone was first isolated and  synthesized  in 1935. [ 128 ]  Shortly thereafter, in 1937, testosterone first became commercially available as a  pharmaceutical drug  in the form of  pellets  and then in ester form for intramuscular injection as the relatively short-acting testosterone propionate. [ 51 ] [ 49 ] [ 129 ]   Methyltestosterone , one of the first synthetic AAS and orally active androgens, was introduced in 1935, but was associated with hepatotoxicity and eventually became largely medically obsolete. [ 129 ]  In the mid-1950s, the longer-acting testosterone esters  testosterone enanthate  and  testosterone cypionate  were introduced. [ 129 ]  They largely superseded testosterone propionate and became the major testosterone esters used medically for over half a century. [ 129 ]  In the 1970s,  testosterone undecanoate  was introduced for oral use in Europe, [ 129 ]  although intramuscular testosterone undecanoate had already been in use in China for several years. [ 130 ]  Intramuscular testosterone undecanoate was not introduced in Europe and the United States until much later (in the early to mid 2000s and 2014, respectively). [ 8 ] [ 131 ]


The history of testosterone as a medication has been reviewed. [ 132 ] [ 133 ] [ 134 ] [ 135 ]


In the US in the 2000s, companies and figures in the popular media have heavily marketed notions of "andropause" as something parallel to  menopause ; these notions have been rejected by the medical community. [ 136 ] [ 137 ]  Additionally, advertising from drug companies selling testosterone and human growth hormone, as well as  dietary supplement  companies selling all kinds of "boosters" for aging men, have emphasized the "need" of middle-aged or ageing men for testosterone. [ 138 ]  There is a medical condition called  late-onset hypogonadism ; according to Thomas Perls and David J. Handelsman, writing in a 2015 editorial in the  Journal of the American Geriatrics Society , it appears that this condition is  overdiagnosed  and  overtreated . [ 138 ]  Perls and Handelsman note that in the US, "sales of testosterone increased from $324 million in 2002 to $2 billion in 2012, and the number of testosterone doses prescribed climbed from 100 million in 2007 to half a billion in 2012, not including the additional contributions from compounding pharmacies, Internet, and direct-to-patient clinic sales." [ 138 ]


Testosterone  is the  generic name  of testosterone in English and Italian and the  INN Tooltip International Nonproprietary Name ,  USAN Tooltip United States Adopted Name ,  USP Tooltip United States Pharmacopeia ,  BAN Tooltip BAN , and  DCIT Tooltip Denominazione Comune Italiana  of the drug, while  testostérone  is its French name and the  DCF Tooltip Dénomination Commune Française . [ 124 ] [ 139 ] [ 140 ]  It is also referred to in  Latin  as  testosteronum , in Spanish and Portuguese as  testosterona , and in German,  Dutch , and Russian and other  Slavic languages  as  testosteron . [ 139 ] [ 140 ]  The  Cyrillic script  of testosterone is  тестостерон . [ 141 ]


Testosterone is marketed under a large number of brand names throughout the world. [ 139 ]  Major brand names of testosterone and/or its esters include Andriol, Androderm, AndroGel, Axiron, Delatestryl, Depo-Testosterone,  Intrinsa , Nebido,  Omnadren , Primoteston,  Sustanon , Testim, TestoGel, TestoPatch, Testoviron, and Tostran. [ 59 ] [ 115 ] [ 139 ]


As of November 2016 [update] , unmodified (non-esterified) testosterone is available in the United States in the following formulations: [ 57 ]


And the following ester prodrugs of testosterone are available in the United States in oil solutions for intramuscular injection: [ 57 ]


Unmodified testosterone was also formerly available for intramuscular injection but was discontinued. [ 57 ]


Testosterone cypionate and testosterone enanthate were formerly available in combination with  estradiol cypionate  and  estradiol valerate , respectively, under the brand names Depo-Testadiol and Ditate-DS, respectively, as oil solutions for intramuscular injection, but these formulations have been discontinued. [ 57 ]


Unlike in Europe, Canada, and much of the rest of the world, oral testosterone undecanoate is not available in the United States. [ 57 ]


[ 142 ] [ 143 ]


As of November 2016 [update] , testosterone is available in Canada in the form of topical gels (AndroGel, Testim), topical solutions (Axiron), transdermal patches (Androderm), and intranasal gels (Natesto). [ 144 ]  Testosterone cypionate (Depo-Testosterone, Testosterone Cypionate (generic)), testosterone enanthate (Delatestryl, PMS-Testosterone Enanthate), and testosterone propionate (Testosterone Propionate (generic)) are available as oil solutions for intramuscular injection and testosterone undecanoate (Andriol, PMS-Testosterone, Taro-Testosterone) is available in the form of oral capsules. [ 144 ]  Testosterone buccal tablets and pellet implants do not appear to be available in Canada. [ 144 ]


Testosterone and/or its esters are widely available in countries throughout the world in a variety of formulations. [ 139 ]


Testosterone and its esters, along with other AAS, are  prescription-only   controlled substances  in many countries throughout the world. In the United States, they are  Schedule III  drugs under the  Controlled Substances Act , in Canada, they are  Schedule IV  drugs under the  Controlled Drugs and Substances Act , and in the United Kingdom, they are  Class C  drugs under the  Misuse of Drugs Act . [ 145 ] [ 146 ]


As of 2014 [update] , a number of lawsuits are underway against manufacturers of testosterone, alleging a significantly increased rate of stroke and heart attack in elderly men who use testosterone supplementation. [ 147 ] [ needs update ]


There are many known cases of  doping in sports  with testosterone and its esters by  professional   athletes .


Testosterone has been used to treat depression in men who are of middle age with low testosterone. However, a 2014 review showed no benefit on the mood of the men with normal levels of testosterone or on the mood of the older men with low testosterone. [ 148 ]  Conversely, a 2009 review found that testosterone had an antidepressant effect in men with depression, especially those with hypogonadism, HIV/AIDS, and in the elderly. [ 149 ]


Testosterone replacement can significantly improve  exercise capacity ,  muscle strength  and reduce  QT intervals  in men with  chronic heart failure  (CHF). Over the 3 to 6-month course of the studies reviewed, testosterone therapy appeared safe and generally effective, and (ruling out prostate cancer) the authors found no justification to absolutely restrict its use in men with CHF. [ 150 ]  A similar 2012 review also found increased exercise capacity and reasoned the benefits generlizable to women. [ 151 ]  However, both reviews advocate larger, longer term,  randomized controlled trials . [ 150 ] [ 151 ]


Testosterone, as esters such as testosterone undecanoate or testosterone buciclate, has been studied and promoted as a  male contraceptive  analogous to  estrogen-based contraceptives  in women. Otherwise considered an adverse effect of testosterone, reduced spermatogenesis can be further suppressed with the addition of a  progestin  such as  norethisterone enanthate  or  levonorgestrel butanoate , improving the contraceptive effect. [ 152 ] [ 153 ]


Testosterone is under development in a low-dose intranasal formulation for the treatment of  anorgasmia  in women. [ 154 ]


Testosterone therapy may improve the management of  type 2 diabetes . [ 155 ]  Low testosterone has been associated with the development of  Alzheimer's disease . [ 156 ] [ 157 ]


Topical androgens like testosterone have been used and studied in the treatment of  cellulite  in women. [ 158 ]


Tidiacic  is a  hepatoprotective  drug.  It is a component of  tidiacic arginine .


Tidiacic arginine (trade name  Tiadilon ) is a 1:1 combination of the  amino acid   arginine  and tidiacic (thiazolidine-2,4-dicarboxylic acid), which acts as a sulfur donor.


In France, its indications and use have been described as "identical to those of  silymarin ". [ 1 ]


Tiropramide  is the  International nonproprietary name  of an  antispasmodic  drug. [ 1 ]


The  acylation  of  racemic   tyrosine  (1) with  benzoyl chloride  gives N,O-dibenzoyl-tyrosine (2).  Amide  formation with  dipropylamine  (3) using the  mixed anhydride  method gives the intermediate (4).  Hydrolysis  of the  phenolic ester  with  sodium hydroxide  forms (5), which is  alkylated  with  ClCH 2 CH 2 N(CH 2 CH 3 ) 2  to produce the  ether  tiropramide. [ 2 ] [ 3 ]


Ulimorelin  ( INN ,  USAN ) (developmental code name  TZP-101 ) is a  drug  with a modified  cyclic   peptide   structure  which acts as a selective  agonist  of the  ghrelin/growth hormone secretagogue receptor  (GHSR-1a). [ 1 ]  Unlike many related drugs, ulimorelin has little or no effect on  growth hormone  (GH)  release  in rats. [ 2 ]   However, like ghrelin and other ghrelin agonists, ulimorelin does stimulate GH release with concomitant increases in insulin-like growth factor 1 (IGF-1) in humans. [ 3 ]  It has been researched for enhancing  gastrointestinal motility , especially in  gastroparesis [ 4 ]  and in aiding recovery of bowel function following  gastrointestinal surgery , where  opioid   analgesic  drugs used for post-operative pain relief may worsen existing  constipation . [ 5 ] [ 6 ] [ 7 ] [ 8 ]  While ulimorelin has been shown to increase both upper and lower gastrointestinal motility in rats, [ 8 ]  and showed promising results initially in humans, [ 4 ] [ 6 ]  it failed in pivotal clinical trials in post operative  ileus . [ 7 ]


A common  side effect  of ghrelin is  reduced blood pressure . Ulimorelin has been shown to inhibit  vasoconstriction  of rat arteries in vitro elicited by the   α 1 -adrenoceptors  agonists  phenylephrine  and  methoxamine , and to increase artery tension at high concentrations. [ 9 ]  Effects on blood pressure, however, were not observed in human clinical trials. [ 4 ] [ 7 ]


Ursodeoxycholic acid  ( UDCA ), also known as  ursodiol , is a secondary  bile acid , produced in humans and most other species from metabolism by intestinal bacteria. It is synthesized in the liver in some species, and was first identified in  bile of bears  of genus  Ursus , from which its name derived. [ 8 ]  In purified form, it has been used to treat or prevent several diseases of the  liver  or  bile ducts .


It is available as a  generic medication . [ 9 ] [ 10 ]


UDCA has been used as medical therapy in  gallstone  disease (cholelithiasis) and for  biliary sludge . [ 11 ] [ 12 ]   UDCA helps reduce the  cholesterol  saturation of bile and leads to gradual dissolution of cholesterol-rich gallstones. [ 11 ]


UDCA may be given after bariatric surgery to prevent cholelithiasis, which commonly occurs due to the rapid weight loss producing biliary cholesterol oversaturation and also biliary dyskinesia secondary to hormonal changes. [ 13 ]


UDCA is used as therapy in  primary biliary cholangitis  (PBC; previously known as primary biliary cirrhosis) where it can produce an improvement in biomarkers. [ 14 ]  Meta-analyses have borne out conflicting results on the mortality benefit. [ 15 ]   However analyses that exclude trials of short duration (i.e. < 2 years) have demonstrated a survival benefit and are generally considered more clinically relevant. [ 16 ]  A Cochrane systematic review in 2012 found no significant benefit in reducing mortality, the rate of liver transplantation,  pruritus  or fatigue. [ 17 ]  Ursodiol and  obeticholic acid  are FDA-approved for the treatment of primary biliary cholangitis. [ 18 ]


UDCA use is associated with improved serum liver tests that do not always correlate with improved liver disease status. [ 19 ]  WHO Drug Information advises against its use in primary sclerosing cholangitis in unapproved doses beyond 13–15 mg/kg/day. [ 20 ]


UDCA in a dose of 28–30 mg/kg/day increases risk of death and need for liver transplant by 2.3-fold among those with primary sclerosing cholangitis, despite decrease in liver enzymes. [ 21 ]


UDCA has been used for  intrahepatic cholestasis of pregnancy . UDCA lessens itching in the mother and may reduce the number of preterm births. Effects on fetal distress and other adverse outcomes are unlikely to be great. [ 22 ] [ 23 ]


UDCA use is not licensed in children, as its safety and effectiveness have not been established. Evidence is accumulating that ursodeoxycholic acid is ineffective, unsafe and its use is associated with significant risk of morbidity and mortality in neonatal hepatitis and neonatal cholestasis. [ 24 ] [ 25 ] [ 26 ] [ 27 ]


UDCA has been suggested to be an adequate treatment of bile reflux  gastritis . [ 28 ]


In  cystic fibrosis  there is insufficient evidence to justify routine use of UDCA, especially as there is a lack of available data for long-term outcomes such as death or need for liver transplantation. [ 29 ]


UDCA has also been in effective in  non-alcoholic fatty liver disease , in liver bile duct-paucity syndromes. It is contraindicated in obstruction of biliary tracts such as  biliary atresia . It is not effective in liver allograft rejection, and in  Graft-versus-host disease  involving the liver. [ medical citation needed ]


Diarrhea was the most frequent adverse event seen in trial of UDCA in gallstone dissolution, occurring in 2 to 9%, which is less frequent than with  chenodeoxycholic acid  therapy. Bacterial conversion of UDCA to chenodeoxycholic acid may be the mechanism for this side effect. Right upper quadrant abdominal pain and exacerbation of pruritus was occasionally reported in trials in patients with PBC. [ 30 ]   Additional symptoms may include bloating, weight gain, and occasionally, thinning of hair. [ 31 ]


Primary bile acids are produced by the  liver  and stored in the  gall bladder . When secreted into the intestine, primary bile acids can be metabolized into secondary bile acids by intestinal bacteria. Primary and secondary bile acids help the body  digest   fats . Ursodeoxycholic acid helps regulate  cholesterol  by reducing the rate at which the  intestine  absorbs cholesterol molecules while breaking up  micelles  containing cholesterol. The drug reduces cholesterol absorption and is used to dissolve (cholesterol)  gallstones  in  patients  who want an alternative to  surgery . [ 32 ]  There are multiple mechanisms involved in cholestatic liver diseases. [ 33 ]


Ursodeoxycholic acid has also been shown experimentally to suppress  immune response  such as immune cell  phagocytosis . Prolonged exposure and/or increased quantities of systemic (throughout the body, not just in the digestive system) ursodeoxycholic acid can be toxic. [ 34 ]


Ursodeoxycholic acid has been shown to exert anti-inflammatory and protective effects in human epithelial cells of the  gastrointestinal tract . It has been linked to regulation of immunoregulatory responses by regulation of  cytokines , [ 35 ]  antimicrobial peptides  defensins , [ 36 ]  and take an active part in increased restitution of wound in the colon. [ 37 ]  Moreover, UDCA's effects has been shown to have exert actions outside the epithelial cells. [ 38 ]


While some bile acids are known to be colon tumor promoters ( e.g.   deoxycholic acid ), others such as ursodeoxycholic acid are thought to be  chemopreventive , perhaps by inducing cellular differentiation and/or cellular senescence in colon epithelial cells. [ 39 ]


Ursodeoxycholic acid is an  epimer  of  chenodeoxycholic acid , which has similar choleretic effects and a wider species distribution. However, CDCA is not as well-tolerated in humans and it does not show immunomodulating or chemoprotective effects. Both are 7-hydroxyl derivatives of deoxycholic acid, but UDCA has the group in the beta instead of the alpha orientation. [ 40 ]


Among mammals, only bears ( Ursidae ; excluding  giant pandas ) produce UDCA at useful amounts [ 40 ]  (>30%). It is produced in the bear liver, but the pathway remains unknown. [ 8 ]


Other vertebrates produce UDCA in much smaller amounts by gut bacteria. CDCA is oxidized into 7-oxo-CDCA then reduced into UDCA. [ 41 ]


UDCA is most commonly produced from  cholic acid  (CA) derived from bovine bile, a by-product of the beef industry. The current yield of this  semisynthesis  is about 30%. [ 42 ]


The term is from the Latin noun  ursus  meaning bear, as  bear bile  contains the substance. [ 43 ]


Ursodeoxycholic acid can be chemically synthesized and is marketed under multiple trade names, including Ursetor, Udikast, Actibile, Actigall, Biliver, Deursil, Egyurso, Heptiza 300/150, Stener, Udcasid, Udiliv, Udinorm, Udoxyl, Urso, Urso Forte, Ursocol, Ursoliv, Ursofalk, [ 44 ]  Ursosan, Ursoserinox, Udimarin, and Ursonova. [ citation needed ]


Bear bile, a natural source of UDCA, is used in  traditional Chinese medicine  since the seventh century. Japanese scientists successfully synthesized UDCA chemically in 1955. [ 40 ]  The earliest reference to UDCA in  PubMed  dates to 1957 under an alternative spelling "ursodesoxycholic acid", in a small-scale clinical trial. [ 45 ]


Ursodeoxycholic acid (application filed by  Allergan ) was approved for use in the United States in December 1987, [ 46 ]  and was designated an  orphan drug . [ 47 ]


Volixibat  ( INN ; [ 1 ]  development code  SHP626 ) is a  medication  under  development  as a possible treatment for nonalcoholic steatohepatitis (NASH), the most severe form of  non-alcoholic fatty liver disease  (NAFLD). No other  pharmacotherapy  yet exists for NASH, so there is interest in whether volixibat can prove to be both safe and effective. To encourage development and testing, the U.S.  Food and Drug Administration  (FDA) has issued  fast track  status. [ 2 ]


Volixibat is an IBAT inhibitor, meaning that it blocks the function of the IBAT protein (ileal bile acid transporter), which is also called  SLC10A2  (solute carrier family 10 member 2) or ASBT (apical sodium–bile acid transporter). IBAT is  most highly expressed in the  ileum , where it is found on the  brush border  membrane of  enterocytes .  It is responsible for the initial uptake of  bile acids , particularly conjugated bile acids, from the intestine as part of their  enterohepatic circulation . [ 3 ]


Vonoprazan , sold under the brand name  Voquezna  among others, is a  first-in-class   potassium-competitive acid blocker  medication. [ 2 ] [ 1 ]  Vonoprazan is used in form of the  fumarate  for the treatment of  gastroduodenal ulcer  (including some drug-induced peptic ulcers) and reflux  esophagitis , and can be combined with antibiotics for the eradication of  Helicobacter pylori . [ 2 ]


It was approved in Japan in February 2015, [ 3 ] [ 4 ]  and in Russia in April 2021. [ 5 ]  Vonoprazan was approved for medical use in the United States in November 2023. [ 1 ] [ 6 ]  Co-packaged combinations of  vonoprazan with amoxicillin  and  vonoprazan with amoxicillin and clarithromycin  are available. [ 7 ] [ 8 ]


Vonoprazan  is  indicated  for healing of all grades of erosive esophagitis and relief of heartburn associated with erosive esophagitis in adults; to maintain healing of all grades of erosive esophagitis and relief of heartburn associated with erosive esophagitis in adults; in combination with amoxicillin and clarithromycin for the treatment of Helicobacter pylori (H. pylori) infection in adults; in combination with amoxicillin for the treatment of H. pylori infection in adults. [ 1 ] [ 7 ] [ 9 ]


In July 2024, the indication was expanded in the US to include non-erosive gastroesophageal reflux disease. [ 10 ]


The most common side effects are constipation, diarrhea,  enlarged feeling of abdomen , nausea, rash, and  edema . [ 1 ] [ 11 ]


Long-term use may lead to  vitamin B12 deficiency ,  hypomagnesemia , and  fundic gland polyps . [ 11 ]


Vonoprazan is the  international nonproprietary name  (INN). [ 12 ]


Vonoprazan/amoxicillin , sold under the brand name  Voquezna Dual Pak  among others, is a co-packaged medication used for the treatment of  Helicobacter pylori  ( H. pylori ) infection. [ 1 ]  It contains  vonoprazan  (as the fumarate), a  potassium-competitive acid blocker  and  amoxicillin , a  beta-lactam antibiotic . [ 1 ]  It is taken  by mouth . [ 1 ]


The co-packaged medication was approved for medical use in the United States in May 2022. [ 1 ] [ 2 ] [ 3 ] [ 4 ]


Vonoprazan/amoxicillin is  indicated  for the treatment of  H. pylori  infection in adults. [ 1 ] [ 5 ]


The dual therapy of using vonoprazan with amoxicillin has been investigated for the treatment of  H. pylori  infection [ 6 ]  and also compared with the  triple therapy  of using vonoprazan,  amoxicillin , and  clarithromycin  for the eradication of  H. pylori  infection. [ 7 ]  Both treatments have been found to be effective. [ 6 ] [ 7 ]  As of 2024, [update]  evidence indicates that vonoprazan/amoxicillin therapy has similar efficacy to  bismuth-containing quadruple therapies  in eliminating  H. pylori . [ 8 ]


Vonoprazan/amoxicillin/clarithromycin , sold under the brand name  Vonosap  among others, is a co-packaged medication used for the treatment of  Helicobacter pylori  ( H. pylori ) infection. [ 1 ] [ 4 ]  It contains  vonoprazan  (as the fumarate), a  potassium-competitive acid blocker ;  amoxicillin , a  beta-lactam antibiotic ; and  clarithromycin , a  macrolide antibiotic . [ 1 ] [ 4 ]


It was approved for medical use in Japan in 2016, [ 3 ]  and in the United States in May 2022. [ 1 ] [ 2 ] [ 5 ] [ 6 ]  The US  Food and Drug Administration  (FDA) considers it to be a  first-in-class medication . [ 7 ] [ 8 ]


Zastaprazan  (trade name  Jaqbo ) is a pharmaceutical drug for gastrointestinal disorders.  It is classified as a  potassium-competitive acid blocker . [ 1 ] [ 2 ]  In April 2024, it was approved for use in South Korea for the treatment of erosive  gastroesophageal reflux disease  (GERD). [ 3 ]   In addition, it is in Phase III clinical trials for  gastric ulcer  and  peptic ulcer . [ 4 ]


An  abdominal examination  is a portion of the  physical examination  which a physician or nurse uses to clinically observe the abdomen of a patient for signs of disease. The abdominal examination is conventionally split into four different stages: first,  inspection  of the patient and the visible characteristics of their abdomen.  Auscultation  (listening)  of the abdomen with a  stethoscope .  Palpation  of the patient's abdomen. Finally,  percussion  (tapping) of the patient's abdomen and abdominal organs. [ 1 ]  Depending on the need to test for specific diseases such as  ascites ,  special tests  may be performed as a part of the physical examination. [ 2 ]  An abdominal examination may be performed because the physician suspects a disease of the organs inside the  abdominal cavity  (including the liver, spleen, large or small intestines), or simply as a part of a complete physical examination for other conditions. In a complete physical examination, the abdominal exam classically follows the respiratory examination and cardiovascular examination. [ 3 ]


A suggested position is for the patient to be  supine  (on their back), with their arms to their sides. The patient should be placed in an environment with good lighting, and should be draped with towels or sheets to preserve privacy and warmth. [ 2 ]  The patient's hips and knees should be flexed (in a bent position) so that their abdominal muscles remain relaxed during the examination. [ 4 ]  Asking the patient to indicate areas that may be tender or painful is recommended to avoid exacerbating the pain during inspection and to increase the patient's comfort.  [ 3 ]


Although physicians have had concern that giving patients pain medications during acute abdominal pain may hinder diagnosis and treatment, separate  systematic reviews  by the  Cochrane Collaboration [ 5 ]  and the Rational Clinical Examination [ 6 ]  refute this.


The doctor will look at the movement of the abdomen checking specifically for waves or odd flexing. [ 7 ]


Auscultation refers to the use of a  stethoscope  by the examiner to listen to sounds from the abdomen.  [ 8 ]


Unlike other physical exams, auscultation is performed prior to percussion or palpation, as both of these could alter the regularity of bowel sounds. [ 3 ]


Some controversy exists as to the length of time required to confirm or exclude bowel sounds, with suggested durations up to seven minutes.  Bowel obstruction  may present with grumbling bowel sounds or high-pitched noises. Healthy persons can have no bowel sounds for several minutes  [ 9 ]  and intestinal contractions can be silent. [ 10 ]  Hyperactive bowel sounds may be caused by partial or complete bowel obstruction as the intestines initially try to clear the obstruction. [ 11 ]  Absence of sounds may be caused by peritonitis, paralytic ileus, late-stage bowel obstruction, intestinal ischemia or other causes. [ 12 ]  Some authors suggest that listening at a single location is enough as sounds can be transmitted throughout the abdomen. [ 13 ]


A prospective study published in 2014 where 41 physicians listened to the bowel sounds of 177 volunteers (19 of which had bowel obstructions and 15 with an ileus) found that "Auscultation of bowel sounds is not a useful clinical practice when differentiating patients with normal versus pathologic bowel sounds. The listener frequently arrives at an incorrect diagnosis. Agreement between raters was also low (54%).". [ 14 ]  This article suggests focusing on other indicators (flatus, pain, nausea) instead. There is no research evidence that reliably corroborates the assumed association between bowel sounds and gastro-intestinal motility status. [ 15 ]


The examiner also typically listens to the two  renal arteries  for abnormal blood flow  sounds  (bruits) by listening in each upper quadrant, adjacent to and above the  umbilicus . Bruits heard in the  epigastrium  that are confined to systole are considered normal. [ 3 ]


The examiner should first talk to the patient and explain what this part of the examination will involve. [ 4 ]  He or she will typically  palpate  all nine areas of the patient's abdomen, and being mindful of areas of discomfort, begin by palpating areas of no pain. This is typically performed twice, first with light pressure and then with deeper pressure to better exam the abdominal organs.


On light palpation, the examiner tests for any palpable mass, rigidity, or pain on the surface.


On deep palpation, the examiner is testing for any  organomegaly  (enlarged organs.) Typically, the clinician is looking for enlargement of the liver and spleen or abnormal masses in the intestines. Sometimes the physician looks for the kidney and uterus as well. [ 11 ]


Reactions that may indicate pathology include:


Percussion  can be performed in all four quadrants of the abdomen and may reveal a painful response by the patient. During the abdominal examination, percussion may allow the estimation of location and quantity of gas, hard or soft masses, and sizes of certain organs, such as the liver and the spleen. Abnormal findings may include  splenomegaly ,  hepatomegaly  and  urinary retention . [ citation needed ]


Organomegaly of the liver and the spleen can be appreciated by percussing in a particular manner:


Examination of the spleen may reveal  Castell's sign  or alternatively  Traube's space .


Dull sounds on the abdomen could suggest pregnancy, an  ovarian tumor , a distended bladder, hepatomegaly or splenomegaly. Dullness on either side of the abdomen could suggest  ascites . Some other areas of the abdomen may sound dull suggesting that there may be some fluid or  feces . The dullness of the liver can be appreciated by percussing at the edge of the lower chest right above the  costal margins . The resonant sounds of gastric air bubbles can be appreciated at the left side. In rare cases, when organs are reversed as is the case in  situs inversus , resonant (hollow) sounds would be expected on the right side and liver dullness on the left.  [ 3 ]


Special maneuvers may also be performed, to elicit signs of specific diseases. [ 16 ] [ 17 ]  These include


The  Alvarado score  is a clinical scoring system used in the diagnosis of  appendicitis . [ 1 ]   Alvarado scoring has largely been superseded as a clinical prediction tool by the  Appendicitis Inflammatory Response score . [ 2 ] [ 3 ] [ 4 ]


Also known by the  mnemonic  MANTRELS, the scale has 6 clinical items (3  signs  and 3  symptoms ) and 2 laboratory measurements, each given an additive point score, with a maximum of 10 points possible. [ 5 ]   It was introduced in 1986 by Dr. Alfredo Alvarado and although meant for pregnant females, it has been extensively validated in the non-pregnant population.  A known limitation of the score is that only 20% of elderly patients present with classic findings on which the score focuses. [ 5 ]  A modified Alvarado score is at present in use. [ 6 ]


Elements from the person's  history , the  physical examination  and from laboratory tests: [ 7 ]


The two most important factors, tenderness in the right lower quadrant and leukocytosis, are assigned two points, and the six other factors are assigned one point each, for a possible total score of ten points. [ 7 ]


A score of 5 or 6 is compatible with the diagnosis of acute appendicitis. A score of 7 or 8 indicates probable appendicitis, and a score of 9 or 10 indicates very probable acute appendicitis. [ 8 ]


The original Alvarado score describes a possible total of 10 points, but those medical facilities that are unable to perform a differential white blood cell count, are using a Modified Alvarado Score with a total of 9 points which could be not as accurate as the original score. The high diagnostic value of the score has been confirmed in a number of studies across the world. The consensus is that the Alvarado score is a noninvasive, safe, diagnostic method, which is simple, reliable, repeatable, and able to guide the clinician in the management of the case. However, a recent study demonstrated a sensitivity of only 72% of the Modified Alvarado Score for detection of appendicitis which has led to criticism of the usefulness of the score. Scores of less than five in children were useful for eliminating appendicitis from the differential diagnosis. [ 9 ]


It carries high significance in the diagnosis of acute appendicitis. [ 10 ]


Online calculator of the Alvarado Score


The  Appendicitis Inflammatory Response  ( AIR )  score  is a  diagnostic  scoring system used to assist with the identification of  appendicitis  in children and adults.


The scoring system was developed in 2008. [ 1 ]  The AIR score was developed to overcome some of the drawbacks of the  Alvarado score , another diagnostic scoring system for identifying appendicitis. [ 2 ]  The AIR score is one of the two scores (the other being the  Adult Appendicitis Score , AAS) recommended by the 2020 World Society of Emergency Surgery clinical practice guidelines for the diagnosis and treatment of acute appendicitis. [ 3 ]


The AIR score is calculated by tallying "points" ascribed to meeting its criteria, which are: [ 4 ]


A 2017 review found that the AIR score has a sensitivity of 92% and specificity of 63% if a score of 5 is used as a cut off for indicating a positive test, whereas the sensitivity is 20% and the specificity is 97% if a score of 8 is used. [ 5 ]


While the AIR score has better predictive power than certain other diagnostic tools for appendicitis (e.g. the  Alvarado score ), it has only been validated in a small number of studies as of 2017 [update] . [ 5 ]


Boas' point  is an area of tenderness to  palpation  to the left of the  12th thoracic vertebra  found in some patients with  gastric ulcer .


This  medical sign  is named after  Ismar Isidor Boas .


Boas' point  at  Who Named It?


The  bow and arrow sign  is an  endoscopic   sign  for determining the location of the  ileocecal valve  during  colonoscopy .  Identifying the ileocecal valve in a colonoscopy is important, as it indicates that the entire  colon  has been visualized.


The identifiable landmarks in the  cecum  are the  appendiceal orifice —which is a curvilinear indent indicating the location of the appendix from the lumen of the bowel—and the ileocecal valve, which appears as a puckering in the most distal fold of the cecum.


The bow and arrow sign uses the curve of the appendiceal orifice to point toward the direction of the ileocecal valve, as if it were a  bow  guiding an  arrow . The  colonoscope  can be passed in this direction in order to enter the  terminal ileum . [ 1 ]   This is used as one of two identifiable landmarks of the colon (the other being the  anus ), and signifies that the entire colon has been visualized.


The  Bristol stool scale  is a diagnostic  medical  tool designed to classify the form of  human faeces  into seven categories. [ 4 ]  It is used in both clinical and  experimental  fields. [ 5 ] [ 6 ] [ 7 ]


It was developed at the  Bristol Royal Infirmary  as a clinical assessment tool in 1997, by Stephen Lewis and Ken Heaton [ 8 ]  and is widely used as a research tool to evaluate the effectiveness of treatments for various diseases of the bowel, as well as a clinical communication aid; [ 9 ] [ 10 ]  including being part of the diagnostic triad for  irritable bowel syndrome . [ 11 ]


The seven types of stool are: [ 12 ]


Types 1 and 2 indicate  constipation , with 3 and 4 being the ideal stools as they are easy to  defecate  while not containing excess liquid, and 6 and 7 indicate diarrhea. [ 13 ]


In the initial study, in the population examined in this scale, the type 1 and 2 stools were more prevalent in females, while the type 5 and 6 stools were more prevalent in males; furthermore, 80% of subjects who reported  rectal tenesmus  (sensation of incomplete defecation) had type 7. These and other data have allowed the scale to be validated. [ 12 ]  The initial research did not include a pictorial chart with this being developed at a later point. [ 8 ]


The Bristol stool scale is also very sensitive to changes in intestinal transit time caused by medications, such as  antidiarrhoeal   loperamide ,  senna , or  anthraquinone  with  laxative  effect. [ 14 ]


People with irritable bowel syndrome (IBS) typically report that they suffer with abdominal  cramps  and  constipation .
In some patients, chronic constipation is interspersed with brief episodes of  diarrhoea ; while a minority of patients with IBS have only diarrhoea.
The presentation of symptoms is usually months or years and commonly patients consult different doctors, without great success, and doing various specialized investigations.
It notices a strong correlation of the reported symptoms with  stress ; indeed diarrhoeal discharges are associated with  emotional phenomena .
IBS blood is present only if the disease is associated with  haemorrhoids . [ 15 ]


Research conducted on irritable bowel syndrome in the 2000s, [ 16 ] [ 17 ]   faecal incontinence [ 18 ] [ 19 ] [ 20 ] [ 21 ]  and the gastrointestinal complications of  HIV [ 22 ]  have used the Bristol scale as a diagnostic tool easy to use, even in research which lasted for 77 months. [ 23 ]


Historically, this scale of assessment of the faeces has been recommended by the  consensus group  of  Kaiser Permanente  Medical Care Program ( San Diego , California, US) for the collection of data on functional bowel disease (FBD). [ 15 ]


More recently, according to the latest revision of the  Rome III Criteria , six clinical manifestations of IBS can be identified: [ 24 ] [ 25 ] [ 26 ] [ 27 ] [ 28 ]


These four identified subtypes correlate with the consistency of the stool, which can be determined by the Bristol stool scale. [ 15 ]


In 2007, the  Mayo Clinic College of Medicine  in  Rochester, Minnesota , United States, reported a piece of  epidemiological research  conducted on a population of 4,196 people living in  Olmsted County   Minnesota , in which participants were asked to complete a questionnaire based on the  Bristol stool scale . [ 30 ]


The research results (see table) indicate that about 1 in 5 people have a slow transit (type 1 and 2 stools), while 1 in 12 has an accelerated transit (type 5 and 6 stools). Moreover, the nature of the stool is affected by age, sex,  body mass index , whether or not they had  cholecystectomy  and possible  psychosomatic  components ( somatisation ); there were no effects from factors such as  smoking ,  alcohol , the level of education, a history of  appendectomy  or familiarity with gastrointestinal diseases, civil state, or the use of  oral contraceptives .


Several investigations correlate the Bristol stool scale in response to medications or therapies, in fact, in one study was also used to titrate the dose more finely than one drug ( colestyramine ) in subjects with  diarrhoea  and faecal incontinence. [ 31 ]


In a  randomised controlled study , [ 32 ]  the scale is used to study the response to two laxatives:  Macrogol  ( polyethylene glycol ) and  psyllium  ( Plantago psyllium  and other  species  of the same  genus ) of 126 male and female patients for a period of 2 weeks of treatment; failing to show the most rapid response and increased efficiency of the former over the latter. In the study, they were measured as primary  outcomes : the number weekly bowel movements, stool consistency according to the types of the  Bristol stool scale , time to defecation, the overall effectiveness, the difficulty in defecating and stool consistency. [ 32 ]


From 2010, several studies have used the scale as a diagnostic tool validated for recognition and evaluation of response to various treatments, such as  probiotics , [ 33 ] [ 34 ]   moxicombustion , [ 35 ]  laxatives in the elderly, [ 36 ]  preparing  Ayurvedic  poly-phytotherapy filed TLPL/AY, [ 37 ]  psyllium, [ 38 ]   mesalazine , [ 39 ]   methylnaltrexone , [ 40 ]  and  oxycodone / naloxone , [ 41 ]  or to assess the response to physical activity in athletes. [ 42 ]


Developed and proposed for the first time in  England  by Stephen Lewis and  Ken Heaton  at the University Department of Medicine,  Bristol Royal Infirmary , it was suggested by the authors as a clinical assessment tool in 1997 in the  Scandinavian Journal of Gastroenterology [ 14 ]  after a previous  prospective study , conducted in 1992 on a  sample  of the population (838 men and 1,059 women), had shown an unexpected  prevalence  of  defecation  disorders related to the shape and type of stool. [ 43 ]  The authors of the former paper concluded that the form of the stool is a useful surrogate measure of  colon  transit time. That conclusion has since been challenged as having limited validity for Types 1 and 2; [ 44 ]  however, it remains in use as a research tool to evaluate the effectiveness of treatments for various diseases of the bowel, as well as a clinical communication aid. [ 9 ] [ 10 ]


The same scale has been validated in  Spanish , [ 45 ] [ 20 ]   Brazilian Portuguese , [ 46 ]  and  Polish  versions. [ 47 ]  A version has also been designed and validated for children. [ 48 ] [ 49 ]  More recently, in September 2011, a modified version of the scale was validated using a criterion of self-assessment for ages six–eight years of age. [ 50 ]


A version of the scale was developed into a chart suitable for use on US television by Gary Kahan of  NewYork–Presbyterian Hospital . [ 51 ]


Capsule endoscopy  is a medical procedure used to record internal images of the  gastrointestinal tract  for use in  disease diagnosis . Newer developments are also able to take  biopsies  and release medication at specific locations of the entire gastrointestinal tract. [ 1 ]  Unlike the more widely used  endoscope , capsule endoscopy provides the ability to see the middle portion of the  small intestine . It can be applied to the detection of various  gastrointestinal cancers ,  digestive diseases , ulcers, unexplained bleedings, and general abdominal pains. After a patient swallows the capsule, it passes along the gastrointestinal tract, taking a number of images per second which are transmitted wirelessly to an array of receivers connected to a portable recording device carried by the patient. General advantages of capsule endoscopy over standard  endoscopy  include the minimally invasive procedure setup, ability to visualize more of the gastrointestinal tract, and lower cost of the procedure. [ 2 ] [ medical citation needed ]


Capsule endoscopy was first conceptualized by Israeli engineer  Gavrial Iddan  and Israeli gastroenterologist Eitan Scapa in Boston, Massachusetts in the early 1980s. The two partners first developed a CCD ( charged coupled device ) camera-based imaging system using a fiber-optic tether. This initial design suffered from high power consumption and slow transmission times of image data of at best 10 minutes. In 1993 Iddan had the idea to split the system into three components, the camera and transmitter, the recorder attached to a  sensor array  on the patient's abdomen, and a software package that processes the stored data at leisure by a physician at a later time. This new setup was made possible by the replacement of the CCD camera with a CMOS ( complementary metal–oxide–semiconductor ) camera. These cameras consume just one percent of the energy of their CCD counterparts. The more efficient power system allowed for the removal of the fiber optic cable for a stand-alone imaging system. This three-component imaging system remains popular today. [ 3 ]


In 2001 the FDA ( Food and Drug Administration ) approved the first capsule endoscope developed by  Given Imaging  for use in patients. Many new models such as the PillCam SB and DBE for obscure gastrointestinal bleeding, the Olympus CE for the small bowel, the PillCam ESO for investigation of esophageal diseases, and the PillCam COLON for detection of colonic neoplasias have been created. [ 4 ]


As research into capsule endoscopy has increased and technology has advanced better wireless and more energy-efficient systems have allowed for the creation of more compact capsules and image processing systems, with many in development today.


Capsule endoscopy uses a small vitamin-sized wireless camera to capture images of a patient's digestive tract. The capsule is generally composed of a camera, antenna, and light array. [ 5 ]  Due to the small nature of the device images can not be stored within it. As a result, a sensor array with a storage unit is placed on the abdomen of the patient for the imaging period. This storage unit can then be connected to a computer at a later time so that a medical professional can analyze the images. [ 6 ]


Newer models of the capsule endoscope have looked to add camera systems on both ends of the pill or even store images within the pill itself to minimize the amount of medical equipment carried while using the device. [ 6 ]  For systems that store images directly within the pill, the pill must be collected after excretion for extraction of the images by a secondary device. [ 7 ]


The main shortcoming of capsule endoscopy is the  field of view . Depending on the placement of the camera system within the device images may become obstructed by folds in the digestive tract. Due to the passive nature of image capture and lack of control in maneuvering the device through the digestive tract novel solutions are being developed by various companies and research labs. For systems that utilize the setup with the camera system at the end of the capsule, the field of view ranges from 140 to 170 degrees. [ 8 ]


There are several advantages to choosing to use capsule endoscopy over standard  endoscopy . Standard endoscopy can be more uncomfortable for a patient, can be more prone to puncturing the digestive tract walls, and is not able to access the middle portion of the small intestine. Endoscopes must enter either through the mouth/nasal cavities or the rectum. Due to restrictions in length, extremely important regions for diagnosis in the small intestine are not able to be accessed. Currently, [ when? ]  within the United States, capsule endoscopy can not be used as a primary imaging method over standard endoscopy first. [ citation needed ]  As a result, many patients must first undergo standard endoscopy to then be referred for capsule endoscopy. Further innovation will be required to make capsule endoscopy comparable to the current standard of care, but extensive work is being performed to achieve this. [ 9 ]


Esophagogastroduodenoscopy  (EGD), employs a camera attached to a long flexible tube to view the upper portion of the gastrointestinal tract, namely the  esophagus , the  stomach , and the beginning of the first part of the  small intestine  called the  duodenum . A  colonoscope , inserted through the  rectum , can view the  colon  and the distal portion of the small intestine, the terminal  ileum . These two types of endoscopy however cannot visualize the majority of the middle portion of the small intestine.


Capsule endoscopy is therefore used to examine parts of the gastrointestinal tract that cannot be seen by standard endoscopy. It is useful when the disease is suspected in the small intestine, and can sometimes be used to find the site of  gastrointestinal bleeding  or the cause of unexplained abdominal pain, such as  Crohn's disease . However, unlike EGD or colonoscopy, it cannot be used to treat pathology that may be discovered. Common reasons for using capsule endoscopy include diagnosis of unexplained bleeding, iron deficiency, or abdominal pain, searching for polyps, ulcers, and tumors of the small intestine, and diagnosis of  inflammatory bowel disease . [ 10 ]


The images collected by the miniature camera during a session are transferred wirelessly to an external receiver worn by the patient, using any one of a band of appropriate frequencies. The collected images are then transferred to a computer for display, review, and diagnosis. [ 11 ]  A transmitted radio-frequency signal emitted by some capsules can be used to accurately estimate the location of the capsule and to track it in real-time inside the body and gastrointestinal tract. [ 12 ]  Capsule endoscopy can still not yet replace standard endoscopy for various diseases, as is the case for those with  cirrhosis . [ 13 ]


As of 2014, research was targeting additional sensing mechanisms and localization and motion control systems to enable new applications for the technology, for example, drug delivery. Wireless energy transmission was also being investigated as a way of providing a continuous energy source for the capsule. [ 14 ]


Capsule endoscopy requires a number of different preparatory procedures to ensure clear images are taken of a patient's gastrointestinal tract for an accurate diagnosis of disease. [ 15 ]  There are various types of capsule endoscopes, but for a generalized description, one can assume the most common setup requires the capsule, sensor array, storage unit, and computer system being used. First, a patient will need to have the sensor array placed on their abdomen with a recording unit worn as a belt. The patient may be asked to stay at the hospital or return home depending on the start time. Next, the pill must be swallowed by the patient. After approximately 8 hours the sensor array can be removed and returned to a physician. The capsule will be excreted through regular bowel movements. [ 16 ]


During the procedure, there are a number of different policies to follow. A patient should only drink clear liquids for the first two hours after swallowing the pill and may eat after 4 hours. MRI studies, ham radios, metal detectors, and strenuous physical activity should all be avoided. Additionally, all external equipment must be kept dry. [ 16 ]


As of 2022, there are a number of manufacturers who produce capsule endoscopes. [ 17 ]  The technology was originally developed by Israeli scientists,  Gavriel Iddan  and Eitan Scapa, with the first pill swallowed in 1997; [ 18 ]  Iddan founded  Given Imaging  in Israel which received FDA approval in 2001. [ 18 ]   Medtronic  today (2024) produces one of the more widely used capsule endoscope systems called the PillCam having sold over 4 million units. [ 19 ]  Medtronic purchased the PillCam system from Given Imaging in 2014. [ 20 ]


Capsule endoscopy is considered to be a very safe method for gastrointestinal tract examination. The capsule is usually excreted with a patient's  feces  within 24–48 hours after ingestion. There has been a single report of retention of the capsule lasting almost four and a half years although the patient was asymptomatic. However, the risk of bowel obstruction may be countered by an abdominal X-ray to locate the device for removal by endoscopy or surgery. [ 21 ]


In a review of 22,840 cases, the capsule was retained 1.4% of the time, with  Crohn's disease  a common cause; most were surgically removed. [ 22 ]  The rate of capsule retention varies by the indication for the procedure, with the highest rate seen with known Crohn's disease (5-13%), followed by obscure gastrointestinal bleeding (1.5%), suspected Crohn's disease (1.4%), and healthy volunteers (0%). [ 23 ]  Risk factors for capsule retention include Crohn's disease, NSAID use, and abdominal radiation. [ 23 ]


Charcot's cholangitis triad  is the combination of  jaundice ;  fever , usually with  rigors ; and  right upper quadrant   abdominal pain . It occurs as a result of  ascending cholangitis  (an infection of the  bile duct  in the liver). When the presentation also includes  low blood pressure  and  mental status changes , it is known as  Reynolds' pentad . [ 1 ]  It is named after  Jean-Martin Charcot . [ 2 ]


In  medicine , specifically  gastroenterology , the  Child–Pugh score  (or the  Child–Turcotte–Pugh  ( CTP )  score  or  Child Criteria ) is used to assess the prognosis of chronic liver disease, mainly  cirrhosis . Although it was originally used to predict mortality during surgery, it is now used to determine the prognosis, as well as the required strength of treatment and the necessity of  liver transplantation . [ citation needed ]


The score employs five clinical measures of liver disease. Each measure is scored 1–3, with 3 indicating most severe derangement. [ 1 ]


Either the prothrombin time or INR should be used to calculate the Child–Pugh score, not both.


In  primary sclerosing cholangitis  (PSC) and  primary biliary cholangitis  (PBC), some use a modified Child–Pugh score where the bilirubin references are changed to reflect the fact that these diseases feature high  conjugated bilirubin  levels. The upper limit for 1 point is 68 μmol/L (4 mg/dL) and the upper limit for 2 points is 170 μmol/L (10 mg/dL). [ 2 ]


Chronic liver disease is classified into Child–Pugh class A to C, employing the added score from above. [ 1 ]


The surgeon and portal hypertension expert Charles Gardner Child (1908–1991) (with Turcotte) of the  University of Michigan  first proposed the scoring system in 1964 in a textbook on liver disease. [ 3 ]  It was modified by Pugh et al. in 1972 in a report on surgical treatment of bleeding from  esophageal varices . [ 4 ]  They replaced Child's criterion of nutritional status with the  prothrombin time  or INR, and assigned scores of 1–3 to each variable. [ 1 ]


Colonoscopy  ( / ˌ k ɒ l ə ˈ n ɒ s k ə p i / ) or  coloscopy  ( / k ə ˈ l ɒ s k ə p i / ) [ 1 ]  is a medical procedure involving the  endoscopic  examination of the  large bowel  (colon) and the  distal  portion of the small bowel. This examination is performed using either a  CCD camera  or a  fiber optic camera , which is mounted on a flexible tube and passed through the anus. [ 2 ] [ 3 ]


The purpose of a colonoscopy is to provide a visual diagnosis via inspection of the internal lining of the colon wall, which may include identifying issues such as ulceration or  precancerous  polyps, and to enable the opportunity for  biopsy  or the removal of suspected  colorectal cancer  lesions. [ 4 ] [ 5 ]


Colonoscopy is similar in principle to  sigmoidoscopy , with the primary distinction being the specific parts of the colon that each procedure can examine. The same instrument used for sigmoidoscopy performs the colonoscopy. A colonoscopy permits a comprehensive examination of the entire colon, which is typically around 1,200 to 1,500 millimeters in length. [ 6 ]


In contrast, a sigmoidoscopy allows for the examination of only the distal portion of the colon, which spans approximately 600 millimeters. [ 7 ]  This distinction is medically significant because the benefits of colonoscopy in terms of improving cancer survival have primarily been associated with the detection of lesions in the distal portion of the colon. [ 8 ]


Routine use of colonoscopy screening varies globally. In the US, colonoscopy is a commonly recommended and widely utilized screening method for colorectal cancer, often beginning at age 45 or 50, depending on risk factors and guidelines from organizations like the American Cancer Society. [ 9 ]  However, screening practices differ worldwide. For example, in the European Union, several countries primarily employ fecal occult blood testing (FOBT) or sigmoidoscopy for population-based screening. [ 10 ]  These variations stem from differences in healthcare systems, policies, and cultural factors. Recent studies [ 11 ]  have stressed the need for screening strategies and awareness campaigns to combat colorectal cancer - on a global scale. [ 12 ] [ 13 ]


Conditions that call for colonoscopies include  gastrointestinal hemorrhage , unexplained changes in bowel habit and suspicion of  malignancy . [ 14 ]  Colonoscopies are often used to diagnose  colon polyp  and  colon cancer , [ 15 ]  but are also frequently used to diagnose  inflammatory bowel disease . [ 16 ] [ 17 ]


Another common indication for colonoscopy is the investigation of iron deficiency with or without  anaemia . The examination of the colon, to rule out a lesion contributing to blood loss, along with an upper gastrointestinal endoscopy (gastroscopy) to rule out oesophageal, stomach, and proximal duodenal sources of blood loss.


Fecal occult blood  is a quick test which can be done to test for microscopic traces of blood in the stool. A positive test is almost always an indication to do a colonoscopy. In most cases the positive result is just due to  hemorrhoids ; however, it can also be due to  diverticulosis , inflammatory bowel disease ( Crohn's disease ,  ulcerative colitis ), colon cancer, or  polyps .  Colonic polypectomy  has become a routine part of colonoscopy, allowing quick and simple removal of polyps during the procedure, without invasive surgery. [ 18 ]


With regard to blood in the stool either visible or occult, it is worthy of note, that occasional rectal bleeding may have multiple non-serious potential causes. [ 19 ]


Colonoscopy is one of the colorectal cancer screening tests available to people in the US who are 45 years of age and older. The other screening tests include  flexible sigmoidoscopy ,  double-contrast barium enema ,  computed tomographic (CT) colonography  (virtual colonoscopy),  guaiac-based fecal occult blood test  (gFOBT),  fecal immunochemical test  (FIT), and  multitarget stool DNA screening test  (Cologuard). [ 20 ]


Subsequent rescreenings are then scheduled based on the initial results found, with a five- or ten-year recall being common for colonoscopies that produce normal results. [ 21 ] [ 22 ]  People with a family history of colon cancer are often first screened during their teenage years.
Among people who have had an initial colonoscopy that found no polyps, the risk of developing colorectal cancer within five years is extremely low. Therefore, there is no need for those people to have another colonoscopy sooner than five years after the first screening. [ 23 ] [ 24 ]


Some medical societies in the US recommend a screening colonoscopy every 10 years beginning at age 50 for adults without increased risk for colorectal cancer. [ 25 ]  Research shows that the risk of cancer is low for 10 years if a high-quality colonoscopy does not detect cancer, so tests for this purpose are indicated every ten years. [ 25 ] [ 26 ]


Colonoscopy screening is associated with approximately two-thirds fewer deaths due to colorectal cancers on the left side of the colon, and is not associated with a significant reduction in deaths from right-sided disease. It is speculated that colonoscopy might reduce rates of death from colon cancer by detecting some colon polyps and cancers on the left side of the colon early enough that they may be treated, and a smaller number on the right side. [ 27 ]


Since polyps often take 10 to 15 years to transform into cancer in someone at average risk of colorectal cancer, guidelines recommend 10 years after a normal screening colonoscopy before the next colonoscopy. (This interval does not apply to people at high risk of colorectal cancer or those who experience symptoms of the disease.) [ 28 ] [ 29 ]


The large  randomized   pragmatic clinical trial  NordICC was the first published trial on the use of colonoscopy as a screening test to prevent colorectal cancer, related death, and death from any cause. It included 84,585 healthy men and women aged 55 to 64 years in Poland, Norway, and Sweden, who were randomized to either receive an invitation to undergo a single screening colonoscopy (invited group) or to receive no invitation or screening (usual-care group). Of the 28,220 people in the invited group, 11,843 (42.0%) underwent screening. A total of 15 people who underwent colonoscopy (0.13%) had major bleeding after polyp removal.


None of the participants experienced a  colon perforation  due to colonoscopy. After 10 years, an  intention-to-screen analysis  showed a significant  relative risk reduction  of 18% in the risk of colorectal cancer (0.98% in the invited group vs. 1.20% in the usual-care group). The analysis showed no significant change in the risk of death from colorectal cancer (0.28% vs. 0.31%) or in the risk of death from any cause (11.03% vs. 11.04%). To prevent one case of colorectal cancer, 455 invitations to colonoscopy were required. [ 30 ] [ 31 ]


As of 2023, the CONFIRM trial, a randomized trial evaluating colonoscopy vs. FIT is currently ongoing. [ 32 ]


In 2021, the US spent $43 billion on cancer screening to prevent five cancers, with colonoscopies accounting for 55% of the total. [ 33 ]  The death rate from colon cancer has been on a linear decline for 40 years, falling by nearly 50 percent from the 1980s (when few were screened) to 2024; however, the increase in screening did not accelerate the decline. [ 34 ]  Therefore, resources devoted to cancer screening would be better directed toward ensuring widespread access to effective cancer treatment. [ 35 ]


The  American Cancer Society  issues recommendations on colorectal cancer screening guidelines. These guidelines often change and are updated as new studies and technologies have become available [ 9 ]


Many other national organizations also issue such guidance, such as the UK's  NHS [ 36 ]  and various European agencies, [ 37 ]  guidance can vary between such agencies.


In the United States,  Medicare  insurance covers a number of colorectal-cancer screening tests. [ 38 ]


The American Society for Gastrointestinal Endoscopy estimates around three in 1,000 colonoscopies lead to serious complications. [ 39 ]


The most serious complication is generally  gastrointestinal perforation , which is life-threatening and requires immediate surgical intervention. [ 40 ]


The key to managing a colonoscopic perforation is diagnosis at the time. Typically, the reasons are that the bowel prep done to facilitate the examination acts to reduce the potential for contamination, resulting in a higher likelihood of conservative management. In addition, detection at the time allows the physician to deploy strategies to seal the colon, or mark it should the patient require surgery.


As with any procedure involving  anaesthesia , complications can occur, such as: [ 41 ] [ 42 ]


Electrolyte imbalance caused by bowel preparation solutions is possible, but current bowel cleansing laxatives are formulated to account for electrolyte balance, making this a very rare event. [ 43 ]


During colonoscopies, when a  polyp  is removed (a polypectomy), the risk of complication increases. [ 44 ] [ 45 ]  One of the most serious complications is  postpolypectomy coagulation syndrome , occurring in 1 in  1000  procedures. [ 46 ]  It results from a burn injury to the wall of the colon causing abdominal pain, fever, elevated white blood cell count and elevated serum  C-reactive protein . Treatment consists of intravenous fluids, antibiotics, and avoiding oral intake of food, water, etc. until symptoms improve. Risk factors include right colon polypectomy, large polyp size (>2 cm), non-polypoid lesions (laterally spreading lesions), and hypertension. [ 47 ]


Although rare, infections of the colon are a potential colonoscopy risk. The colon is not a  sterile  environment, and infections can occur during biopsies from what is essentially a 'small shallow cut', enabling bacterial intrusion into lower parts of the colon wall. In cases where the lining of the colon is perforated, bacteria can infiltrate the  abdominal cavity . [ 48 ]   Infection may also be introduced if the endoscope is not cleaned and sterilized appropriately between procedures.


Minor colonoscopy risks may include  nausea ,  vomiting  or  allergies  to the  sedatives  that may have been used. If medication is given intravenously, the  vein  may become irritated, or mild  phlebitis  may occur. [ 49 ]


The colon must be free of solid matter for the test to be performed properly. [ 50 ]  For one to three days, the patient is required to follow a  low fiber  or clear-liquid-only diet. Examples of clear fluids are  apple juice , chicken and/or beef broth or  bouillon ,  lemon-lime   soda , lemonade,  sports drink , and  water . It is important that the patient remains hydrated. Sports drinks contain  electrolytes  which are depleted during the purging of the bowel. Drinks containing fiber such as  prune  and  orange juice   should not be consumed, nor should liquids  dyed  red, purple, orange, or sometimes brown; however, cola is allowed. In most cases,  tea  or  coffee  taken without milk are allowed. [ 51 ] [ 52 ]


The day before the colonoscopy (or  colorectal surgery ), the patient is either given a  laxative  preparation (such as  bisacodyl ,  phospho soda ,  sodium picosulfate , or  sodium phosphate  and/or  magnesium citrate ) and large quantities of fluid, or  whole bowel irrigation  is performed using a solution of  polyethylene glycol  and  electrolytes . [ 53 ] [ 54 ]  The procedure may involve both a pill-form laxative and a bowel irrigation preparation with the polyethylene glycol powder dissolved into any clear liquid, such as a sports drink that contains electrolytes.


The patient may be asked not to take aspirin or similar products such as  salicylate ,  ibuprofen , etc. for up to ten days before the procedure to avoid the risk of bleeding if a polypectomy is performed during the procedure. A blood test may be performed before the procedure. [ 55 ]


During the procedure, the patient is often given  sedation  intravenously, employing agents such as  fentanyl  or  midazolam . Although meperidine (Demerol) may be used as an alternative to fentanyl, the concern of seizures has relegated this agent to second choice for sedation behind the combination of fentanyl and midazolam. The average person will receive a combination of these two drugs, usually between 25 and 100   μg IV fentanyl and 1–4   mg IV midazolam. Sedation practices vary between practitioners and nations; in some clinics in Norway, sedation is rarely administered. [ 56 ] [ 57 ]


The first step is usually a  digital rectal examination  (DRE), to examine the tone of the anal  sphincter  and to determine if preparation has been adequate. A DRE is also useful in detecting anal  neoplasms  and the clinician may note issues with the prostate gland in men undergoing this procedure. [ 58 ]  The  endoscope  is then passed through the  anus  up the  rectum , the  colon  (sigmoid, descending, transverse and ascending colon, the cecum), and ultimately the  terminal ileum . The endoscope has a movable tip and multiple channels for instrumentation, air, suction and light. The bowel is occasionally insufflated with air to maximize visibility (a procedure that gives the patient the false sensation of needing to take a  bowel movement ). Biopsies are frequently taken for  histology . Additionally in a procedure known as  chromoendoscopy , a contrast-dye (such as  indigo carmine ) may be sprayed through the endoscope onto the bowel wall to help visualize any abnormalities in the mucosal morphology. A  Cochrane review  updated in 2016 found strong evidence that chromoscopy enhances the detection of cancerous tumors in the colon and rectum. [ 59 ]


In most experienced hands, the endoscope is advanced to the junction of where the colon and small bowel join up ( cecum ) in under 10 minutes in 95% of cases. Due to tight turns and redundancy in areas of the colon that are not "fixed", loops may form in which advancement of the endoscope creates a "bowing" effect that causes the tip to actually retract. These loops often result in discomfort due to stretching of the colon and its associated  mesentery . Manoeuvres to "reduce" or remove the loop include pulling the endoscope backwards while twisting it. Alternatively, body position changes and abdominal support from external hand pressure can often "straighten" the endoscope to allow the scope to move forward. In a minority of patients, looping is often cited as a cause for an incomplete examination. Usage of alternative instruments leading to completion of the examination has been investigated, including use of pediatric colonoscope, push enteroscope and upper GI endoscope variants. [ 60 ]


Lawsuits over missed cancerous lesions have recently prompted some institutions to better document endoscope examination times, as rapid examination times may be a source of potential medical legal liability. [ 61 ]  This is often a real concern in clinical settings where high caseloads could provide financial incentive to complete colonoscopies as quickly as possible.


The pain associated with the procedure is not caused by the insertion of the scope but rather by the inflation of the colon in order to do the inspection. The scope itself is essentially a long, flexible tube about a centimeter in diameter — that is, as big around as the little finger, which is less than the diameter of an average stool. [ 62 ]


The colon is wrinkled and corrugated, somewhat like an accordion or a clothes-dryer exhaust tube, which gives it the large surface area needed for nutrition and water absorption. In order to inspect this surface thoroughly, the physician blows it up like a balloon, using air from a compressor or  carbon dioxide  from a gas bottle (CO 2  is absorbed into the bloodstream through the mucosal lining of the colon much faster than air and then exhaled through the lungs which is associated with less post procedural pain), in order to get the creases out.


The colon has sensors that can tell when there is unexpected gas pushing the colon walls out—which may cause mild discomfort. Usually, total anesthesia or a partial  twilight sedative  are used to reduce the patient's awareness of pain or discomfort, or just the unusual sensations of the procedure. Once the colon has been inflated, the doctor inspects it with the scope as it is slowly pulled backward. If any polyps are found they are then cut out for later biopsy. [ 63 ]


Colonoscopy can be carried out without any sedation and a number of studies have been performed evaluating colonoscopy outcomes without sedation. [ 64 ]  Though in the US and EU the procedure is usually carried out with some form of sedation. [1]


Researchers have found that older patients with three or more significant health problems (i.e., dementia or heart failure) had higher rates of repeat colonoscopies without medical indications. These patients are less likely to live long enough to develop colon cancer. [ 65 ]


In the 1960s, Niwa and Yamagata at Tokyo University developed the  fibre-optic endoscopy device. [ 66 ]  After 1968, William Wolff and Hiromi Shinya pioneered the development of the colonoscope. [ 67 ]  Their invention, in 1969 in Japan, was a significant advance over the barium enema and the flexible sigmoidoscope because it allowed for the visualization and removal of polyps from the entire colon. Wolff and Shinya advocated for their invention and published much of the early evidence needed to overcome skepticism about the device's safety and efficacy. [ 68 ]


Some of the leading medical device companies in the colonoscopy market as of 2023 include:  Fujifilm ,  Karl Storz SE , Pro Scope Systems,  Olympus Corporation ,  Medtronic Plc ,  Steris  and  Pentax  Medical. [ 69 ] [ better source needed ]


The terms  colonoscopy [ 70 ] [ 71 ] [ 72 ]  or  coloscopy [ 71 ]  are derived from [ 71 ]  the ancient Greek noun κόλον, same as English  colon , [ 73 ]  and the verb σκοπεῖν,  look (in)to ,  examine . [ 73 ]  The term  colonoscopy  is however ill-constructed, [ 74 ]  as this form supposes that the first part of the compound consists of a possible root κολων- or κολον-, with the connecting vowel -o, instead of the root κόλ- of κόλον. [ 74 ]  A compound such as κολωνοειδής,  like a hill , [ 73 ]  (with the additional -on-) is derived from the ancient Greek word κολώνη or κολωνός,  hill . [ 73 ]  Similarly, colonoscopy (with the additional -on-) can literally be translated as  examination of the hill , [ 74 ]  instead of the  examination of the colon .


In English, multiple words exist that are derived from κόλον, such as  colectomy , [ 71 ] [ 75 ]   colocentesis , [ 71 ]   colopathy , [ 71 ]  and  colostomy [ 71 ]  among many others, that actually lack the incorrect additional -on-. A few compound words such as  colonopathy  have doublets with -on- inserted. [ 71 ] [ 72 ]