Inclusion and exclusion characteristics of patients with ischemic stroke who could be treated with IV rtPA within 3 hours from symptom onset.
\r\n\t
",isbn:"978-1-78984-671-3",printIsbn:"978-1-78984-670-6",pdfIsbn:"978-1-78985-657-6",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,hash:"d5feb836870aef4d30893f10898e7791",bookSignature:"Dr. Gokul Sridharan",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10791.jpg",keywords:"HPV, Inflammation and Immunity, Cancer Stem Cells, Genomics and Epigenomics, Transcriptomics, Proteomics, Targeted Therapy, Immunotherapy, Surgery, Next-Gen Sequencing, Bioinformatics, Pharmacogenomics",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"February 10th 2021",dateEndSecondStepPublish:"April 19th 2021",dateEndThirdStepPublish:"June 18th 2021",dateEndFourthStepPublish:"September 6th 2021",dateEndFifthStepPublish:"November 5th 2021",remainingDaysToSecondStep:"7 days",secondStepPassed:!1,currentStepOfPublishingProcess:2,editedByType:null,kuFlag:!1,biosketch:"A pioneering researcher and academician with an interest in oral pre-cancer and oral cancer with special emphasis on salivary diagnostics.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"82453",title:"Dr.",name:"Gokul",middleName:null,surname:"Sridharan",slug:"gokul-sridharan",fullName:"Gokul Sridharan",profilePictureURL:"https://mts.intechopen.com/storage/users/82453/images/system/82453.jpeg",biography:"Dr. Gokul Sridharan is currently an associate professor in the Department of Oral Pathology and Microbiology at Y.M.T. Dental College and Hospital, Navi Mumbai. He obtained his Ph.D. for the work titled “Salivary and serum metabolomics in oral leukoplakia and oral squamous cell carcinoma.” His fields of interest include oral pre-cancer, oral cancer, salivary diagnostics, oral and maxillofacial diseases, and advanced diagnostic aids with an emphasis on bioinformatics and metabolomics. He has several scientific publications to his credit and actively contributes as a peer reviewer to numerous journals. He is an active member of the editorial boards of several journals of repute. 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From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. 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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"314",title:"Regenerative Medicine and Tissue Engineering",subtitle:"Cells and Biomaterials",isOpenForSubmission:!1,hash:"bb67e80e480c86bb8315458012d65686",slug:"regenerative-medicine-and-tissue-engineering-cells-and-biomaterials",bookSignature:"Daniel Eberli",coverURL:"https://cdn.intechopen.com/books/images_new/314.jpg",editedByType:"Edited by",editors:[{id:"6495",title:"Dr.",name:"Daniel",surname:"Eberli",slug:"daniel-eberli",fullName:"Daniel Eberli"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"60116",title:"Emergency Management of Acute Ischaemic Stroke",doi:"10.5772/intechopen.75305",slug:"emergency-management-of-acute-ischaemic-stroke",body:'\nStroke has been defined by the World Health Organization as “rapidly developing clinical signs of focal (at times global) disturbance of cerebral function, lasting more than 24hours or leading to death with no apparent cause other than of vascular origin” [1].
\nStroke is a neurologic emergency with poorer prognosis in blacks [2, 3]. It represents one of the major causes of morbidity and mortality globally and ranks third as the most common cause of mortality in developed countries resulting in long term disability and accounting for 4.4 million deaths in the world [4, 5]. The severity of stroke varies widely, ranging from full recovery on one hand to both fatal and non-fatal events with neurological deficits and functional disabilities on the other hand [5, 6, 7].
\nRisk factors for stroke have been classified as modifiable and non-modifiable. The non-modifiable factors include sex, age, race, family history, genetic and low birth weight while the modifiable risk factors include hypertension, diabetes mellitus, hyperlipidaemia, atrial fibrillation, smoking, obesity, carotid artery disease, hyperhomocysteinemia, hypercoagulable states and select biomarkers [8].
\nStroke increases sharply with age and the incidence of a first time stroke is about 200 per 100,000 annually with a prevalence of 5–12 per 1000 population. Stroke mortality rate is different among countries ranging from 20 to 250 per 100,000 populations annually [9]. In the UK about 90,000 females and 60,000 males die from stroke yearly with the approximate cost of stroke to NHS and social services being £2.3bn annually [10]. The risk of a recurrent stroke is very high among survivors. About 14% of patients who survive a stroke or TIA will have a recurrence in the first year; 22% of males and 25% of females will have mortality in the first year of an initial stroke and more than half of all stroke patients experience mortality within 8 years [5].
\nStroke is classified into two major types: Ischaemic and haemorrhagic. Ischaemic stroke is by far the commonest, accounting for 85% of all strokes while haemorrhagic stroke accounts for 15% of strokes - intracerebral 10%, subarachnoid 5% [5].
\nIschaemic stroke is the leading worldwide cause of morbidity and mortality in the developed world. About 8–12% of patients die within 30 days of their first stroke and those that survive the first attack are at increased risk of a recurrence [11]. Ischaemic stroke is caused by atherosclerotic vascular disease leading to occlusion and stenosis of major intracranial or extracranial arteries and constriction of small penetrating arteries of the brain. Cardioembolic stroke due to myocardial infarction is usually due to atherosclerosis of the coronary arteries. The resulting ischaemia leads to direct brain insult because of inadequacy of flow, hypoxia and metabolic substrate and institutes a cascade of neurochemical processes causing continuous damage within hours. Treatment of ischaemic stroke has been with the use of drugs such as fibrinolytic agents, anticoagulants and antiplatelets to improve blood supply to the brain. Prevention of stroke both at the primary and secondary levels is now possible because of availability of various safe and successful interventions directed at high risk individuals [5, 12].
\nPatients present with abrupt onset of focal neurological deficit such as facial paresis, arm drift, leg weakness and abnormal speech [13]. Although patients with acute ischaemic stroke do present with headache, vomiting, seizures, depressed level of consciousness; these symptoms are commoner in patients with haemorrhagic stroke. It is difficult, on the basis of clinical presentation, to distinguish intracerebral haemorrhage from ischaemic stroke as they may look alike [14]. The duration of stroke onset should be noted as this is crucial in defining treatment options. Past medical and drug history (e.g heroin, amphetamines, and cocaine) should be obtained. History of vascular risk factors such as obesity, hypertension, hyperlipidaemia, diabetes mellitus, and smoking should also be obtained. The initial neurological assessment of the patient should be brief but detailed. Different stroke scales such as National Institutes of Health Stroke Scale (NIHSS) can be employed as this helps in determining the severity of the stroke [15]. Assessment of airway, breathing and circulation may precede a thorough evaluation of the stroke patient. A comprehensive physical examination is carried out by the attending physician or the stroke team. This may reveal an irregular pulse, bradycardia, cardiomegaly or heart murmurs. The blood pressure should also be checked [16].
\nBesides doing basic investigations such as carotid Doppler, pregnancy test, full blood count, fasting lipid profile, blood sugar, serum homocysteine, serum electrolyte, urea and creatinine, coagulation studies (PT/INR/PTT), liver function tests, Haemoglobin AIc, electrocardiography (ECG), electroencephalopathy (EEG), toxicology screen, cardiac enzymes (CK,CK-MB, TROPONIN I and T) a brain Computed Tomography/Magnetic Resonance Imaging (CT/MRI) Scan is also required as this is the single most important investigation to help exclude a cerebral haemorrhage and stroke mimics. It confirms the diagnosis of ischaemic stroke allowing for prompt treatment of the condition. Increase in both cardiac Troponin T and Troponin I have been found to be associated with stroke severity and poor clinical outcomes [17, 18].
\nIssues to be focused on include: Airway management, hydration, increased intracranial pressure (ICP), Blood pressure control, Blood sugar control, Temperature.
\nComa is uncommon with ischaemic stroke patients. Patients who have neurological decline with reduced level of consciousness have challenges in maintaining their airway due to loss of protective reflexes [19]. This can result in aspiration, hypoxaemia or hypercapnia that may increase intracranial pressure by causing cerebral vasodilatation. The role of oxygen therapy in ischaemic stroke has been controversial due to failure of three clinical trials of hyperbaric oxygen to demonstrate efficacy. Supplemental oxygen can be administered at a dose of 10-15 L/min if there is evidence of hypoxia by pulse oximetry. This was shown to slow down the process of ischaemia and extend the therapeutic time window for thrombolysis [20, 21]. Patients with depressed level of consciousness should be intubated to avoid the risk of aspiration [22].
\nPatients with ischaemic stroke should be routinely hydrated with isotonic saline. This helps ensure adequate perfusion to the ischaemic penumbra and may prevent infarct extension. Hypotonic solutions should be avoided as this may lead to increased cerebral oedema.
\nThe head of the bed should be elevated at 30 degrees. Other measures to reducing ICP include administration of 0.5-1 g/kg of 20% mannitol as a bolus. Infusion of hypertonic saline solution (23.4%) can also be administered at a dose of 0.5–2.0 ml/kg as an alternative to mannitol especially in the setting of hypotension. Hyperventilation to a pCO2 of 28-35 mmHg has also been employed as a measure in reducing ICP.
\nHigh blood pressure is a frequent occurrence in acute ischaemic stroke. Although blood pressure declines spontaneously within 90 mins after stroke onset [23], about one third of the patients continue to have hypertension with an increased risk of poor outcome [24, 25]. The mechanisms implicated for the increase in blood pressure are multifactorial and include a previous history of hypertension, release of endogenous catecholamines, raised intracranial pressure (Cushing’s reflex), infection, “White coat hypertension effect”, prior alcohol intake, pain from urinary retention, impaired baroreceptor sensitivity and stress relating to hospitalization [25, 26, 27, 28, 29].
\nHypotension, though uncommon in acute stroke, correlates with a poor clinical outcome. Causes implicated include infection, cardiac failure, arrhythmias, hypovolaemia and aortic dissection [30].
\nRapid blood pressure reduction in acute ischaemic stroke reduces the cerebral blood flow thereby increasing the area of cerebral infarction and worsening neurological outcome [31]. For over three decades, there has been a controversy regarding the treatment of high blood pressure in the setting of acute ischaemic stroke [32, 33]. Some studies have observed a U-shaped relationship between the admission blood pressure and good clinical outcomes, with an optimal systolic blood pressure ranging from 121 to 200 mm Hg and diastolic blood pressure ranging from 81 to 110 mm Hg [34]. High blood pressure should not be treated in the first 24 hours after ischaemic stroke unless the systolic blood pressure is greater than 220, the diastolic blood pressure is greater than 120, the mean arterial blood pressure is greater than 130 mmHg or there are associated complications such as presence of myocardial infarction, aortic dissection or heart failure. At such times, the goal would be to reduce the blood pressure by 15%.
\nRecommendations for blood pressure control have been established regarding patients undergoing fibrinolytic therapy. The recommendations include a gradual approach to reducing the pressure below 185/110 mm Hg to qualify for fibrinolytic therapy with intravenous recombinant tissue plasminogen activator (rt-PA). Once intravenous (rt-PA) is given, the blood pressure must be maintained below 180/105 mm Hg to reduce the risk of intracerebral haemorrhage [16].
\nAntihypertensives given when considering re-perfusion therapy include IV Labetalol 10–20 mg over 1–2 minutes, may be repeated once, IV Nicardipine 5 mg/h, titrating up by 2.5 mg/h every 5–15 minutes, maximum 15 mg/h; when desired BP is reached, adjust to maintain proper BP levels. Other drugs such as hydralazine, enalaprilat, etc. may be considered where necessary. Do not administer rt-PA if the blood pressure is not maintained at or below 185/110 mm Hg. Blood pressure should be monitored every 15 minutes for 2 hours from the start of rt-PA therapy, then every 30 minutes for 6 hours, and then every hour for 16 hours. If the blood pressure still remains uncontrolled or diastolic BP >140 mm Hg, consider IV sodium nitroprusside [16].
\nHyperglycaemia occurs in about 20–40% of acute stroke patients with no previous diagnosis of diabetes mellitus [35]. There is overwhelming clinical evidence that correlates hyperglycaemia at the onset of acute ischaemic stroke with a negative outcome [36]. Hyperglycaemia influences neuronal damage by encouraging anaerobic metabolism and lactic acidosis within the ischaemic tissue, thus worsening outcome and heightening the risk of haemorrhagic transformation after thrombolysis [37]. Hyperglycaemia should be treated with insulin to achieve a blood sugar control between 7.7 and 10.0 mmol/l with close monitoring to avoid hypoglycaemia [16]. Insulin is indicated in the treatment of hyperglycaemia in acute ischaemic stroke because of its ability to reduce neuronal necrosis regardless of its effect on glucose levels [38].
\nAbout one third of patients presenting with stroke develop fever in the first few hours after stroke onset [39]. Increased body temperature of 37.5°C is associated with poor neurological outcome secondary to increased free radical production, increased metabolic demands and increased release of neurotransmitters [39, 40].
\nThe source of the fever should be determined. Some of the possible causes of the fever include aspiration pneumonia and other respiratory infections, urinary tract infections or line infections, infective endocarditis, deep vein thrombosis/pulmonary embolism and cocaine intoxication. The guideline for the early management of acute ischaemic stroke recommends the lowering of temperature during the acute stroke period. Fever is managed strictly with antipyretics and appropriate antibiotics given if infection is suspected. The most frequently used antipyretic is acetaminophen. Aspirin, ibuprofen and indomethacin have also been considered in patients with reduced risk of bleeding [41].
\nThe commonly used antiplatelets include aspirin, clopidogrel and dipyridamole. The use of aspirin in acute ischaemic stroke was examined in CAST (the Chinese Acute Stroke Trial) and IST (the International Stroke Trial). In IST study, aspirin at a dose of 300 mg/day was found to reduce stroke recurrence within the first 14 days with no effect on early mortality. In the CAST study, aspirin 160 mg/day reduced the risk of recurrence and mortality in the first 28 days. Clopidogrel at a dose of 75 mg was found to have a risk reduction of 8.7% in the prevention of cerebrovascular and cardiovascular events [42]. Various studies have shown that the combination of dipyridamole and aspirin is superior to aspirin alone as an antithrombotic therapy after cerebral ischemia of arterial origin [43, 44].
\nHeparin is not indicated for routine use in the treatment of acute ischaemic stroke. Some of the indications for its use include cerebral venous thrombosis, acute infarct with high grade carotid stenosis, cardiogenic emboli with high risk of recurrence, hypercoagulable states such as protein C deficiency, protein S deficiency, antithrombin III deficiency and antiphospholipid antibody syndrome. Other anticoagulants include warfarin which is useful in the prevention of stroke recurrence in atrial fibrillation patients [45]. Dabigatran has also been found to reduce the occurrence of stroke among non-valvular atrial fibrillation patients [46].
\nStatins have been observed to be efficacious in both primary and secondary prevention of stroke independent of cholesterol levels. This might be due to other beneficial effects of statins such as stabilization of atherosclerotic plaques, improvement of endothelial function, antioxidant properties, increased nitric oxide bioavailability, inhibition of inflammatory responses and immunomodulatory actions [47, 48]. The use of Statin early in stroke patients has been found to be strongly associated with improved post stroke survival, and discontinuation of statin, even for a brief period, has been associated with worsened survival [49].
\nThe goal of reperfusion therapy for acute ischaemic stroke is prompt restoration of blood flow to regions of brain that are ischemic but not yet infarcted. This reduces the volume of brain damage, reduces oedema and improves outcome. The use of intravenous recombinant tissue plasminogen activator was approved by the US FDA in 1996 for use in acute ischaemic stroke patients presenting within 3 hours of stroke onset [50]. Its use is associated with favourable outcomes although increased risk of intracranial haemorrhage has been observed [16].
\nIntravenous recombinant tissue plasminogen activator (IV rt-PA) is administered when an acute stroke patient meets all of the inclusion criteria and none of the absolute exclusion criteria. The dose of the IV rt-PA is 0.9 mg/kg (maximum dose 90 mg). Infuse 0.9 mg/kg over 60 minutes, with 10% of the dose given as a bolus over one minute. Patient should be admitted into the intensive care unit or stroke unit for close monitoring. The infusion should be discontinued if the patient develops severe headache, acute hypertension, nausea, or vomiting or has a worsening neurological examination. An emergent CT scan should be requested for. Blood pressure monitoring and neurological assessment are carried out every 15mins during and after the administration of the IV rt-PA infusion for 2 hours, then every 30 minutes for 6 hours, then hourly until 24 hours after IV rt-PA treatment [16].
\nPlacement of nasogastric tubes, indwelling bladder catheters, or intra-arterial pressure catheters should be delayed if the patient can be safely managed without them. A follow-up CT or MRI scan should be obtained at 24 hours after IV rt-PA before commencing anticoagulants or antiplatelets (Tables 1 and 2).
\nDiagnosis of ischemic stroke causing measurable neurological deficit | \n
Onset of symptoms <3 hours before beginning treatment | \n
Aged ≥18 years | \n
Significant head trauma or prior stroke in previous 3 months | \n
Symptoms suggest subarachnoid haemorrhage | \n
Arterial puncture at non-compressible site in previous 7 days | \n
History of previous intracranial haemorrhage | \n
Intracranial neoplasm, arteriovenous malformation, or aneurysm | \n
Recent intracranial or intraspinal surgery | \n
Elevated blood pressure (systolic >185 mm Hg or diastolic >110 mm Hg) | \n
Active internal bleeding | \n
Acute bleeding diathesis, including but not limited to | \n
Platelet count <100,000/mm3 | \n
Heparin received within 48 hours, resulting in abnormally elevated aPTT greater than the upper limit of normal | \n
Recent experience suggests that under some circumstances—with careful consideration and weighting of risk to benefit—patients may receive fibrinolytic therapy despite 1 or more relative contraindications. Consider risk to benefit of IV rt-PA administration carefully if any of these relative contraindications are present: | \n
Only minor or rapidly improving stroke symptoms (clearing spontaneously) | \n
Pregnancy | \n
Seizure at onset with postictal residual neurological impairments | \n
Major surgery or serious trauma within previous 14 days | \n
Recent gastrointestinal or urinary tract haemorrhage (within previous 21 days) | \n
Recent acute myocardial infarction (within previous 3 months) | \n
Inclusion and exclusion characteristics of patients with ischemic stroke who could be treated with IV rtPA within 3 hours from symptom onset.
Adapted from Guidelines for the early management of patients with acute ischaemic stroke. Stroke 2013.
The checklist includes some FDA-approved indications and contraindications for administration of IV rt-PA for acute ischemic stroke. Recent guideline revisions have modified the original FDA-approved indications. A physician with expertise in acute stroke care may modify this list.
Onset time is defined as either the witnessed onset of symptoms or the time last known normal if symptom onset was not witnessed.
In patients without recent use of oral anticoagulants or heparin, treatment with IV rt-PA can be initiated before availability of coagulation test results but should be discontinued if INR is >1.7 or PT is abnormally elevated by local laboratory standards.
In patients without history of thrombocytopenia, treatment with IV rt-PA can be initiated before availability of platelet count but should be discontinued if platelet count is <100,000/mm3.
aPTT indicates activated partial thromboplastin time; CT, computed tomography; ECT, ecarin clotting time; FDA, Food and Drug Administration; INR, international normalized ratio; IV, intravenous; PT, partial thromboplastin time; rt-PA, recombinant tissue plasminogen activator; and TT, thrombin time.
Diagnosis of ischemic stroke causing measurable neurological deficit | \n
Onset of symptoms within 3 to 4.5 hours before beginning treatment | \n
Aged >80 years | \n
Severe stroke (NIHSS>25) | \n
Taking an oral anticoagulant regardless of INR | \n
History of both diabetes and prior ischemic stroke | \n
Additional inclusion and exclusion characteristics of patients with acute ischemic stroke who could be treated with IV rt-PA within 3 to 4.5 hours from symptom onset.
INR indicates international normalized ratio; IV, intravenous; NIHSS, National Institutes of Health Stroke Scale; and rt-PA, recombinant tissue plasminogen activator.
This modality of treatment for acute ischaemic stroke is fast emerging. Mechanical clot retrieval with MERCI device (Mechanical Embolus Removal in Cerebral Ischaemia) has been employed. Other interventions have included mechanical clot aspiration with the Penumbra system. The Penumbra System (PS) is a new embolectomy device specifically designed to remove the thrombus in acute ischemic stroke secondary to large vessel thromboembolism. The device removes the thrombus through two mechanisms: aspiration and extraction [16]. Earlier trials, Trevo versus Merci Retrievers for Thrombectomy Revascularization of Large Vessel Occlusions in Acute Ischaemic Stroke (TREVO 2) and SWIFT, showed significantly higher recanalization rates associated with stent retriever devices compared to the first generation Merci Retriever [51, 52].
\nPatients who have sustained a stroke are prone to developing complications. About 30–60% of patients after acute ischaemic stroke develop these complications. The most frequent complications include respiratory and urinary tract infections, deep vein thrombosis (DVT) and pulmonary embolism (PE) [53]. Pulmonary embolism occurs in about 10% of patients post stroke. Deep vein thrombosis and pulmonary embolism tend to occur in the first three months post stroke with an incidence of 2.5% and 1.2% respectively [54]. The risk of DVT/PE is increased in immobile and elderly patients with severe stroke [55]. Pressure sores are also common and have been attributed to poor nursing care. Stroke patients should therefore be turned frequently at 2-hourly interval to prevent this complication. Water bed can also be used.
\nIschaemic stroke remains the commonest type of stroke worldwide. Its successful treatment is dependent on prompt restoration of blood flow to the penumbral tissue. Other supportive therapies have also been helpful in ensuring a favourable outcome. This was an overview of the management of the condition.
\nThis refers to bleeding into the brain parenchyma. Intracerebral haemorrhage is a devastating disease with increased morbidity and mortality constituting 15% of all stroke types [56, 57]. Factors associated with increased mortality include large clots, low Glasgow Coma Scale score, intraventricular haemorrhage and haematoma expansion. The causes of haematoma growth include a past history of stroke, liver disease, hyperglycaemia and hypertension [58]. The common sites for ICH include the basal ganglia, thalamus, brain stem and the cerebellum.
\nCauses of ICH have been classified into primary and secondary. Hypertension remains the most common modifiable risk factor for the development of ICH [59, 60] while cerebral amyloid angiopathy is the second most frequent risk factor in ICH leading to lobar haemorrhages . Other risk factors include increasing age, anticoagulation therapy, AV malformations, and aneurysms [61].
\nThe symptoms are usually sudden in onset; most times occurring during exercise or emotional stress although it can also occur during routine activity [61, 62]. It is difficult, on the basis of clinical presentation, to distinguish ICH from ischaemic stroke as they may look similar.
\nPresentation of ICH differs depending on the size and location of the ICH. Symptoms that may suggest ICH include severe headache, vomiting, seizures, reduced level of consciousness. Headache is more frequent in patients with large haematomas and has been attributed to raised intracranial pressure and traction on the meningeal pain fibres. Small, deep haematomas rarely present with headache. [61]. About 15–23% of patients tend to have haematoma expansion and neurological deterioration in the first few hours of the event [63, 64].
\nAccording to the guideline on the emergency diagnosis and assessment of an ICH patient, the following should be done:
\nA baseline severity score should be performed as part of the initial evaluation of patients with ICH (Class 1; level of evidence B); rapid neuroimaging with CT or MRI is recommended to distinguish ischaemic stroke from ICH (Class 1, level of evidence A); Computed Tomography Angiography (CTA) and contrast-enhanced CT may be considered to help identify patients at risk for hematoma expansion (Class 11b, level of evidence B) and CTA, CT venography, contrast-enhanced CT, contrast-enhanced MRI, MR angiography and magnetic resonance venography, and catheter angiography can be useful to evaluate for underlying structural lesions including vascular malformations and tumours when there is clinical or radiological suspicion (Class 11a, level of evidence B).
\nRapid diagnosis is essential in the management of the condition. Deterioration in the first few hours after onset has been reported due to haematoma expansion [64].
\nInitial assessment will include stabilization of patient by maintaining the airway. General physical examination and quick neurological examination should be performed on all patients. Vital signs should be measured. Baseline severity scale score like ICH score, Glasgow coma scale (GCS), NIHSS should be employed. The ICH score is a simple clinical grading scale, reliable and validated for rapid evaluation of ICH severity [63].
\nBrain non- contrast CT Scan (NCCT) - this is the goal standard in diagnosing ICH. It is convenient and highly sensitive in the detection of ICH [65]. Other useful information that can be extracted from NCCT includes the location of ICH, intraventricular bleed, hydrocephalus, early signs of herniation, lesional oedema, and midline shift. ICH volume, a strong predictor of outcome can also be estimated. Brain MRI can help in identifying the exact neuroanatomic site as well as the aetiology [66]. Other investigations are same as for ischaemic stroke.
\nAirway management is similar to that of acute ischaemic stroke.
\nThis occurs in the first few days after intracerebral haemorrhage. It is significantly associated with hematoma expansion, increased intracranial pressure, mass effect, midline shift and brain herniation leading to poor functional outcome of ICH [67, 68, 69]. Agents that can reduce peri-haematomal oedema process provide protective effects for ICH. These include the use of osmotic diuretics such as Mannitol. Hypertonic saline can also be used. An earlier retrospective study had reported rapid reversal of transtentorial herniation and decreased intracranial pressure with the use of 23.4% of hypertonic saline [70]. Another study had observed the superiority of hypertonic saline over mannitol in the treatment of increased intracranial pressure [71]. The routine use of mannitol in small ICH and asymptomatic peri-haematoma oedema should be discouraged.
\nThese are common in ICH occurring in up to 16% of the cases in the first week with most occurring at onset [72]. Lobar haematomas carry an increased risk of seizures than deep ICH [73]. A recent AHA/ASA guideline for management of spontaneous ICH recommend the use of antiepileptic drugs only in patients with clinical seizures and those with depressed mental status found to have electrographic seizures on EEG [74]. Drugs that have been used include intravenous Lorazepam (0.05–0.1 mg/kg), fosphenytoin (or Phenytoin 15-20 mg/kg), and valproic acid (15-45 mg/kg).
\nHyperglycaemia at presentation portends a worse outcome. This is independent of diabetes mellitus [75]. Treatment involves the use of Insulin. Hypoglycaemia should be avoided.
\nSymptomatic deep vein thrombosis occurs in 1–5% of patients with ICH with pulmonary embolism occurring in about 0.5–2% of such cases. It is therefore crucial to prevent both DVT and PE [76]. Prophylaxis for DVT includes the use of intermittent pneumatic compression devices (IPC) or compression stockings if IPC devices are not available. Subcutaneous low-dose unfractionated heparin can be used when the intracranial bleeding has been controlled within 48 hours of the admission [74].
\nLowering of blood pressure in the setting of ICH has been frequently practiced to reduce haematoma growth. However, the association between elevated BP and hematoma expansion remains controversial. An increasing blood pressure has been associated with haematoma expansion. The AHA/ASA guidelines recommend mean arterial Pressure of 130 mmHg. Titratable antihypertensive drugs such as Intravenous Labetalol (10–20 mg IV bolus, can be repeated up to max of 60 mg) and Nicardipine (5 mg/h up to 15 mg/h) are often used in acute ICH. Nitroprusside should be avoided because of its tendency to increase ICP.
\nThis is a frequent occurrence in patients with ICH especially in those with intraventricular extension. Patients with persistent fever after ICH tend to have a worse prognosis [77].
\nThe outcome of ICH is made worse by coagulopathy as this causes expansion of haematoma. Coagulopathy should therefore be reversed. Intravenous Vitamin K 10 mg and fresh frozen plasma 20 ml/kg can be given to patients with Warfarin related ICH. Alternatives to fresh frozen plasma include prothrombin complex concentrate and activated factor VII (Novoseven) [78]. Although recombinant factor VIIa was shown to be efficacious in reducing haematoma growth in phase II trial, it failed to demonstrate consistency in efficacy in subsequent trials. It is often used in patients with ICH associated haemophilia.
\nAbout 45% of patients with intracerebral haemorrhage (ICH) develop intraventricular haemorrhage (IVH). ICH often predicts a poor outcome. There are two types of IVH; the primary –confined to the ventricles and secondary due to extension of an ICH. Secondary IVH is the commonest and is related to haemorrhages from hypertension involving the basal ganglia and the thalamus [79]. Treatment involves the use of intraventricular administration of rt-PA or urokinase. This was found to reduce mortality and morbidity by increasing blood clearance and clot lysis [80]. Unfortunately, the procedure was not without the risk of intracranial bleeding [81]. Other treatment options included an endoscopic surgical evacuation and ventriculostomy, ventriculoperitoneal shunting or lumbar drainage for hydrocephalus [82, 83, 84].
\nControversies exist over the role of surgical haematoma evacuation. The International Surgical Trial in Intracerebral haemorrhage (ISTICH) and subsequent STICH 11 demonstrated no improvement for early haematoma evacuation in patients with supratentorial ICH [85, 86]. However in subgroup analysis, patients with superficial haematomas were more prone to a favourable outcome when managed surgically compared to deep ICH. In contrast to supratentorial haematomas, cerebellar ICH is a neurosurgical emergency requiring urgent evacuation as rapid deterioration can occur in the first 24 hours of onset. Indications for surgical intervention include haemorrhages greater than 3 cm and those with brainstem compression or hydrocephalus [87].
\nAdvancement in the treatment of acute stroke and the establishment of dedicated stroke units has led to an increase in the survival of stroke patients. Many of the survivors experience persistent difficulty in their activities of daily living. Moderate functional impairment has been observed in 40% of stroke patients with about 15–30% having severe disability [88]. Early initiation of effective rehabilitation post stroke has been found to enhance recovery process and minimize functional disability. Stroke rehabilitation is therefore crucial for recovery post stroke.
\nThe services of rehabilitation involve a multidisciplinary approach comprising healthcare providers with training in neurology, rehabilitation nursing, physical therapy, occupational therapy and speech and language therapy. Other health professionals who play key roles in rehabilitation include social workers, psychologists, psychiatrists and counselors [89].
\nStroke rehabilitation usually commences during the acute hospitalization when the patient has been stabilized medically and neurologically. The major concern in the acute phase are prevention of a recurrent stroke, prevention of complications, mobilizing the patient, promoting resumption of activities of daily living as well as providing emotional support to the patient and family. Thereafter the focus shifts to evaluation and recovery of any residual physical and cognitive deficits [90].
\nA patient with stroke is at risk of developing joint and muscle contractures. The reasons for this are multifactorial and include hemiparesis, impaired sensation, reduced level of consciousness, older age, incontinence and pressures sores. Early rehabilitation can reduce the contractures.
\nRecent advances in neuroimaging, organized stroke care, dedicated Neuro-ICUs, medical and surgical management have changed the management of ICH. Early airway protection, blood pressure control, rapid reversal of coagulopathy and surgical intervention may increase the chance of survival for patients with severe ICH.
\nThere is much evidence that significant changes in the body and fat weight in men with metabolic disorders, such as severe obesity and type 2 diabetes mellitus (DM2), and with long-term fasting can lead to the alteration in the hypothalamic-pituitary-gonadal (HPG) axis, as illustrated by the changed secretion of gonadotropin-releasing hormone (GnRH) and gonadotropins, the reduced testosterone (T) production by Leydig cells and the impaired spermatogenesis. The alterations in the HPG axis, as a result, lead to infertility [1, 2, 3]. The relationship between the fat content and androgens level has been demonstrated in animals with obesity and DM2, as well as in fasting conditions [4, 5, 6]. All this indicates that adipocyte-produced factors can play an important role in controlling the HPG axis and in regulating the steroidogenesis in Leydig cells. Among these factors, the most interesting are adipokines, such as leptin, adiponectin, resistin and visfatin [3, 7, 8]. It is well known that in metabolic disorders, the plasma levels of these adipokines and the functional activity of adipokines-regulated signaling systems in the target tissues undergo significant changes, which can be considered to be one of the key causes of abnormalities in the HPG axis and androgen deficiency [9, 10, 11].
\nThe regulatory effects of the plasma, pituitary and testicular leptin on the male HPG axis and the testosterone synthesis in the testes in the norm and in the metabolic disorders. Abbreviations: p-Lep and t-Lep, the pituitary and testicular leptin; LepR, leptin receptor; GnRH, gonadotropin-releasing hormone; GnRH-R, receptor of GnRH; LH, luteinizing hormone; T, testosterone; AMPK, AMP-activated protein kinase; CREB, cAMP response element-binding protein; Nur77, c-Jun, c-Fos and Sf1, transcription factors Nur77, c-Jun, c-Fos and Sf1; SREBP1, sterol regulatory element-binding protein-1; cAMP-PDE, cAMP-specific phosphodiesterase; StAR, steroidogenic acute regulatory protein; P450scc and P450c17, cytochromes P450scc (P450 cholesterol side chain cleavage enzyme) and P450c17; 3β-HSD, 3β-hydroxysteroid dehydrogenase; α-MSH, α-melanocyte-stimulating hormone; AgRP, agouti-related peptide; NPY, neuropeptide Y; BBB, blood-brain barrier; BTB, blood-testicular barrier.
The regulatory effects of adiponectin circulating in the blood and adiponectin synthesized in the pituitary and testes on the activity of the male HPG axis and the testosterone production. Abbreviations: AdipoR1 and AdipoR2, adiponectin receptors of the types 1 and 2; ERK1/2, extracellular signal-regulated kinases 1/2; Sp1, transcription factor Sp1. The other abbreviations are the same as in
There is evidence that adipokines affect the different components of the male HPG axis. Transferred to the brain through the blood-brain barrier (BBB), adipokines act on the activity of hypothalamic GnRH-expressing neurons, thus changing the GnRH-stimulated production of luteinizing hormone (LH), the main regulator of T synthesis, by pituitary gonadotrophs [12, 13]. The adipokines can directly affect the gonadotrophs producing LH, and in this regulation both the adipokines circulating in the bloodstream and the adipokines synthesized within the pituitary can be involved [14, 15]. Some adipokines can also directly affect the functions of Leydig cells, as indicated by a high level of adipokines expression in the testes, as well as detection of the main components of the adipokine signaling, including adipokine-specific receptors, in testicular cells, including Leydig cells [16, 17, 18, 19]. The study of the effects of leptin, adiponectin and other adipokines on the male HPG axis and their role in the regulation of steroidogenesis is a major problem of clinical endocrinology and reproductive medicine. The solution of this problem will allow developing the new approaches for restoring the reproductive functions and androgen status in men with endocrine and metabolic disorders, which is based on the normalization of the adipokine signaling in the CNS and at the periphery.
\nThis review presents the comprehensive analysis of the involvement of leptin, adiponectin, resistin and visfatin in the regulation of the male HPG axis and steroidogenesis, as well as of the possible mechanisms of this regulation. The role of adipokines in the dysregulation of the male reproductive system and the impaired steroidogenic activity in the testes in obesity and DM2 are also discussed.
\nLeptin, a 167-amino acid polypeptide hormone encoded by the
The regulatory effects of leptin are realized due to its specific interaction with leptin receptors (Ob-R) that are generated by alternative splicing and include at least six isoforms [26]. The full-length isoform Ob-Rb is active and expressed in the hypothalamus with high intensity [27, 28]. The truncated isoforms, Ob-Ra, Ob-Rc, Ob-Rd and Ob-Rf are inactive, but retain the ability to bind to leptin at its excess. It is assumed that they carry out the receptor-mediated transport of leptin through the BBB and, possibly, through other tissue barriers [29, 30]. In the arcuate nuclei (ARC) of hypothalamus, leptin binds to Ob-Rb receptor, which leads to the phosphorylation of JAK2, a non-receptor tyrosine kinase, that phosphorylates the Tyr985, Tyr1077 and Tyr1138 residues located within the intracellular domain of Ob-Rb, each responsible for the activation of certain signaling cascade [23]. It has been shown that the phospho-Tyr985 is responsible for activation of Src Homology 2 domain-containing protein tyrosine phosphatase 2 (SHP-2) and the mitogen-activated protein kinases (MAPK), such as extracellular signal-related kinases-1/2 (ERK1/2), c-Jun amino-terminal kinases (JNK) and p38-MAPK, which are involved in the regulation of cell growth and differentiation. The targets of MAPK are different transcription factors, including c-Fos, c-Jun and cAMP response element-binding protein (CREB), which control the expression of a large number of genes [3, 31]. The phospho-Tyr1138 is responsible for activation of the transcription factor STAT3 (signal transducer and activator of transcription-3) regulating the expression of genes involved in metabolic and growth processes. In turn, phospho-Tyr1077 induces the activation of the transcription factor STAT5, responsible for the regulation of energy metabolism and endocrine system [23, 32].
\nAnother mechanism of leptin action is the activation of 3-phosphoinositide pathway, which involves phosphatidylinositol-3-kinase (PI3K) and Akt kinase controlling the activity of the multi-component kinase mTOR complex 1. Since Akt-mediated inhibition of this complex in the hypothalamic ARC leads to a decrease in the expression of the
In the recent years, the evidence has been obtained that leptin plays a very important role in the control of male reproductive functions and puberty, which is based on leptin-mediated regulation of the HPG axis [8, 37]. The
A survey of men from Slovenia, Macedonia and Serbia with three different mononucleotide mutations within the
The mutations within the
The effects of leptin on the male HPG axis can be carried out at the level of hypothalamic neurons, pituitary gonadotrophs and testicular cells. It is important to note that the response of the HPG axis to leptin depends on the dose of this adipokine and the duration of treatment, the metabolic and hormonal status, as well as the functional state of the leptin signaling system in the target tissues. This is well illustrated by the data on the influence of leptin on the hypothalamic structures. It is shown that a single i.c.v. administration of leptin to ovariectomized female rats under starvation conditions, when the leptin level was reduced, led to a rapid increase in the plasma LH level, which demonstrates leptin-mediated stimulation of secretory activity of the GnRH-neurons [12, 46]. At the same time, under conditions of prolonged administration of leptin, an increase in LH level [47] or lack of leptin effect on LH secretion [48] were detected, which may be assumed to be due to varying degrees of leptin resistance in the case of long-term action of leptin on hypothalamic neurons. This was supported by the fact that the action of low, nanomolar concentrations of leptin on the ARC and the ventromedial nuclei of the hypothalamus led to an increase in the GnRH secretion, while high, micromolar leptin concentrations did not cause this effect [5, 37]. The i.c.v. administration of leptin to fasting cows led to an increase of both basal and GnRH-stimulated LH secretion, while the administration of leptin to fed animals with the increased leptin level did not induce significant changes in LH level [49, 50]. Thus, the stimulating effect of leptin on the HPG axis at the hypothalamic level was largely dependent on eating behavior, and was the main mechanism that mediates the relationship between the satiety and metabolic status, on the one hand, and the gonadotropins levels and activity of the steroidogenesis system, on the other.
\nThe central effects of leptin on the HPG axis are mediated through its interaction with leptin receptors located on hypothalamic ARC neurons expressing either pro-opiomelanocortin (POMC) or agouti-related peptide (AgRP) and neuropeptide Y (NPY). Due to activation of these neurons by leptin, the positive (POMC-neurons) or negative (AgRP/NPY-neurons) regulation of GnRH-neurons occurs, especially since these neurons themselves do not contain the receptor Ob-Rb and, therefore, can not be target for leptin (Figure 1).
\nLeptin-induced activation of ObRb located on the POMC-neurons leads to an increase in the production of POMC-derived melanocortin peptides, primarily α-melanocyte-stimulating hormone (α-MSH), an agonist of types 3 and 4 melanocortin receptors (MC3R and MC4R) [51]. The α-MSH binds to MC3/4R located on GnRH-neurons, and stimulates the GnRH secretion by them. In favor of this mechanism, there is evidence that the administration of leptin to the preoptic area of the hypothalamus leads simultaneously to an increase in α-MSH level and a stimulation of GnRH secretion [52]. The MC3/4R agonists, such as α-MSH and its analogue melanotan-II are also effective, increasing GnRH release [53, 54]. It should be noted that at least 70% of GnRH-neurons are activated by α-MSH [53]. Both MC3R and MC4R are involved in the effects of melanocortin peptides on GnRH-neurons, since mice lacking only one type of MCR remain capable of reproduction [55, 56].
\nAnother mechanism for leptin regulation of GnRH secretion, in which the melanocortin peptides also participate, is more complex. In accordance with this, in the first stage the melanocortin peptides secreted by POMC-neurons interact with MCR located on the KNDy-neurons. Kisspeptin released from KNDy-neurons binds to the kisspeptin receptors located on GnRH-neurons and stimulates GnRH secretion [57]. In the hypothalamic ARC, the outgrowths of POMC-neurons form the contacts with the bodies of KNDy-neurons, and a release of α-MSH by POMC-neurons causes a rapid depolarization of KNDy-neurons. Pharmacological inhibition of MC3R and MC4R by the antagonist SHU9119 decreases the expression of kisspeptin by 45%. The stimulating effect of melanotan-II on LH production in mice lacking the kisspeptin receptor GPR54 was reduced significantly [57].
\nThe AgRP, the endogenous MC3/4R antagonist, and NPY, both produced by the AgRP/NPY-neurons, mediate the inhibitory effect of leptin on LH production by pituitary gonadotrophs. However, the degradation of AgRP/NPY-neurons and the knockout of the
Leptin can stimulate LH production, acting directly on gonadotrophs (Figure 1). Unlike the hypothalamus, where leptin is mainly transferred from the bloodstream, its source in gonadotrophs can be either the plasma leptin or pituitary leptin synthesized by gonadotrophs [67, 68]. There is a good reason to believe that pituitary leptin functions as a paracrine and autocrine regulator controlling the survival and functional activity of gonadotrophs, since the plasma leptin can not mediate the complex pattern of pituitary hormone secretion [69]. This assumption is supported by the data obtained in mice with tissue-specific knockout of the
The functions of the autonomous leptin system in the pituitary, its participation in gonadotropins production and the relationship between the activity of this system and the physiological state of the HPG axis are supported by the following facts. The
Currently, there is evidence that leptin not only indirectly affects the steroidogenesis in Leydig cells through the regulation of the HPG axis but is also capable of directly affecting the activity of steroidogenesis system [3, 8]. The following facts support this: (1) the transport of leptin circulating in the bloodstream through the blood-testicular barrier (BTB) and the synthesis of leptin in the testicular cells; (2) the expression of leptin receptors and the presence of effector components of the leptin signaling in Leydig cells and (3) the results of the
In 1999, Banks and coauthors showed that leptin circulating in the blood was transported through the BTB, and the permeability was higher than in the case of the BBB [75]. Based on high rate of leptin transport through the BTB and high permeability of this barrier to other proteins, it was concluded that the mechanisms of leptin transport through the BBB and BTB differ significantly. However, taking into account the high density of the truncated isoform Ob-Ra of leptin receptor on the surface of endothelial cells forming the BTB, there is reason to believe that, like the BBB, leptin transport through the BTB is also a receptor-dependent [37]. In this case, one should expect its dependence on the activity of the leptin signaling system at the periphery and its decrease in the conditions of leptin resistance. Another source of intratesticular leptin was its synthesis in the testes of adult men and animals. The highest level of the
The effectors, whose activity is regulated by leptin through the activated forms of Ob-Rb and JAK2, control the activity of the transcription factors regulating the expression of steroidogenesis genes in different ways [3]. Leptin-induced stimulation of Akt-kinase and MAPK results in the phosphorylation and activation of the transcription factor CREB that is also activated by gonadotropins via cAMP-dependent pathways [81]. The activation of p38-MAPK and JNK leads to the stimulation of the transcription factors Nur77 and c-Jun [82, 83]. The main targets for these factors are the genes encoding StAR protein responsible for transport of cholesterol into the mitochondria and P450 cholesterol side chain cleavage enzyme (cytochrome P450scc) converting cholesterol to pregnenolone [84] (Figure 1). Along with this, the activation of MAPK cascade results in an increase in the expression of Sf-1 factor, the coactivator of expression of the gene encoding StAR and the genes
Leptin activation of the STAT3 and STAT5, as well as leptin-induced ERK1/2-dependent activation of the factor c-Fos lead to the opposite effect and suppress steroidogenesis in Leydig cells. An increase in ERK1/2 activity may be due to the prolonged leptin effect on the system Ob-Rb/JAK2 and, as a result, the activation of SHP-2 phosphatase, which affects the activity of MAPK cascade [89]. A decrease in T production by Leydig cells can be the result of AMPK activation, which suppresses the activity of sterol regulatory element-binding protein-1 (SREBP1) [90]. As is well known, SREBP1 positively regulates the
In addition to direct leptin effect on the expression of steroidogenesis genes, this adipokine can modulate the gonadotropin signaling pathways in Leydig cells, inducing an increase in gonadotropin-stimulated T production. It is well known that LH and human chorionic gonadotropin (hCG) specifically bind to LH/hCG receptors located on Leydig cells and stimulate the activity of adenylyl cyclase catalyzing cAMP synthesis, which leads to the activation of protein kinase A and CREB. Further, the level of intracellular cAMP is reduced due to its hydrolysis by cAMP-specific phosphodiesterases (cAMP-PDE), which leads to the attenuation of signal transduction generated by gonadotropins and inhibits their stimulating effect on steroidogenesis. Leptin suppresses the cAMP-PDE activity, maintaining the increased level of intracellular cAMP and thereby potentiates steroidogenic effect of gonadotropins (Figure 1). This is supported by the data that leptin enhances the stimulating effect of hCG on the cAMP level in rat Leydig cells [77].
\nAlong with the regulation of T synthesis in Leydig cells, leptin controls the mass and size of the testes, diameter of the seminiferous tubules and spermatogenesis and affects the survival of Leydig cells and other testicular cells [26, 93]. Leptin also regulates steroidogenesis in the ovaries and adrenal glands, and the mechanisms of its regulatory effect are believed to be similar to those in Leydig cells [37, 94].
\nIn men with obesity, metabolic syndrome and DM2, the activity of the male HPG axis and the T production are decreased, which lead to androgen deficiency [95, 96, 97]. Along with this, in diabetic men the plasma level of estrogens and the ratio of estrogen/T are significantly increased, which due to the increased activity of aromatase and the altered production of sex hormone-binding globulin [98, 99, 100, 101]. The elevated concentrations of reactive oxygen species and inflammatory factors lead to the damage in Leydig cells and reduce their steroidogenic activity [97, 102].
\nIn obesity and DM2, the plasma leptin level is significantly increased [103, 104], which leads to leptin resistance. As a result, the receptor-mediated transport of leptin through the BBB is reduced, which leads to a decrease in the intrahypothalamic leptin level and to a weakening of the regulatory effects of leptin on hypothalamic neurons and GnRH secretion (Figure 1). It is also not possible to exclude the possibility of reducing leptin transport through the BTB, although such data have not yet been obtained.
\nThe detailed study of the relationships between the leptin signaling and androgen deficiency in men with obesity and DM2 are not currently available. In rats with diet-induced obesity, severe hyperleptinemia and leptin resistance was associated with a decrease in the number of Leydig cells by 30%. This can be caused by the reduced intratesticular levels of leptin or the decreased sensitivity of testicular cells to this adipokine that participates in the regulation of survival and proliferation of Leydig cells (Figure 1). Although the plasma T level in obese male rats did not change, in the testes of animals it decreased by 25%, which was associated with a decrease in the expression of the
The deterioration of reproductive functions was found in mice with a knockout of the gene encoding the catalytic p110α-subunit of PI3K in the adipose tissue [106]. In the testes of 30-day knockout mice with severe hyperleptinemia, the expression of the gene encoding leptin was increased, while the expression of the genes encoding StAR and P450scc was reduced. Adult knockout mice had a severe form of hyperleptinemia, obesity, hepatic steatosis and the impaired glucose tolerance, and were infertile. It was quite unexpected that in the testes of knockout animals the expression of the
Polypeptide hormone adiponectin is produced mainly by the adipose tissue [109, 110], but despite this, the plasma adiponectin level is negatively correlated with the body mass index and the reserves of adipose tissue [111]. The plasma level of adiponectin is characterized by gender specificity and significantly lowers in males, which is true for humans and rodents [112]. Adiponectin can be synthesized not only by the adipose tissue but also by the brain, pituitary, testes and others [17, 113]. Adiponectin is consists of a variable N-terminal domain, a large globular C-terminal domain and a collagenous domain located between them, containing 22 collagenous Gly-XY repeats [114, 115, 116]. Using the collagenous repeats, adiponectin molecules interact with each other to form the homotrimeric complexes that aggregate into the hexamers and high-molecular complexes similar to those in the case of tumor necrosis factor-α (TNF-α) [117]. To form the trimeric complex, hydroxylation of the proline and lysine residues in the collagenous repeats is necessary, since the lack of this modification does not allow the formation of such complex and leads to a loss in the adiponectin activity [118, 119]. High-molecular complexes of adiponectin are stabilized by disulfide bonds formed between the trimers [120]. The trimeric, hexameric and high-molecular complexes are present in the bloodstream, while the monomeric forms are found in trace amounts [115, 121, 122, 123]. Post-translational modifications of adiponectin and its oligomerization significantly affect the bioavailability, binding characteristics and pattern of specific activity of adiponectin [115, 120, 123, 124, 125].
\nThe tissues, the targets of adiponectin, express the adiponectin receptors AdipoR1 and AdipoR2, which bind specifically to various forms of adiponectin with different affinity [111, 125, 126, 127]. Despite the fact that both these receptors seven times penetrate the plasma membrane, like classical G protein-coupled receptors, they differ significantly from them in membrane topology, having the extracellular C-terminal domain and the intracellular N-terminal domain. In addition, the adiponectin receptors interact with APPL proteins (adaptor protein, phosphotyrosine interacting with plekstrin-homologous domain and leucine zipper), but not with heterotrimeric G-proteins. The AdipoR1 binds with a high affinity to the truncated globular form of adiponectin and with a low affinity with the oligomeric and high-molecular forms of full-length adiponectin, while AdipoR2 binds with an intermediate affinity to both the full-length and globular forms. The both receptors interact with two isoforms of the APPL proteins, APPL-1 and APPL-2 [128, 129]. The interaction of adiponectin-activated AdipoR1 with APPL-1 leads to the activation of AMPK and the 3-phosphoinositide and MAPK cascades. The APPL-2 forms a complex with APPL-1 and prevents APPL-1-mediated regulations. When adiponectin binds to AdipoR1, the APPL-1/APPL-2 complex dissociates, resulting in the release of APPL-1 to interact with the downstream effector proteins [116, 130].
\nAdiponectin is able to control steroidogenic function in the testes directly, acting on Leydig cells, and indirectly, acting on the HPG axis at the hypothalamic and pituitary levels. To interact with hypothalamic neurons, the main target of adiponectin in the CNS, it is necessary to transport adiponectin into the brain through the BBB. It is suggested that the receptor-mediated transport of adiponectin through the BBB can be carried out through the AdipoR1 and AdipoR2 receptors located on the endothelium of cerebral vessels (Figure 2). In addition, a large number of adiponectin receptors and the components of adiponectin-regulated signaling pathways have been identified in the ARC and paraventricular nuclei of the hypothalamus [131, 132, 133, 134] and in other brain areas [13]. Adiponectin is easily transferred from the bloodstream to the brain and cerebrospinal fluid (CSF), although its concentration in the CSF is low, being only 0.1% of that in the blood [132, 133, 134, 135]. In obesity, which was characterized by the reduced plasma level of adiponectin [134, 136, 137], its concentration in the brain areas was also decreased [134]. It should be noted that, as in the case of circulating adiponectin, a negative correlation was found between the adiponectin level in the CSF and the body mass [133, 134]. Thus, unlike leptin, intracerebral adiponectin deficiency in obesity is caused by a reduced level of this adipokine in the blood. Although there is evidence that adiponectin can be synthesized in the CNS [17, 113], the greatest, if not all, amount of this adipokine comes from the periphery, and the intracerebral level of adiponectin depends on the activity of adiponectin-transporting system of the brain.
\nUpon binding to adiponectin receptors in neurons of the paraventricular nuclei and the periventricular region of the hypothalamus, adiponectin activates AMPK [13, 138], decreases the activity of ERK1/2 [13], causes a weakening of the calcium-dependent signaling pathways and inhibits the hyperpolarization-activated cationic currents responsible for pacemaker activity of GnRH-neurons [139]. It is important to note that the inhibition of ERK1/2 activity is due to an increase in AMPK activity [13]. The main result of adiponectin action on GnRH-neurons is a decrease in the synthesis and secretion of GnRH and, as a consequence, a decreased LH production by gonadotrophs [13, 139] (Figure 2).
\nAdiponectin also interacts with the KNDy-neurons expressing kisspeptin. Adiponectin-induced increase in AMPK activity in these neurons results in the inhibition of AMPK-dependent transport of the transcription factor SP1 into the nucleus, which is illustrated by SP1 accumulation in the cytoplasm. As a result, the expression of the
The inhibitory effect of adiponectin on LH production can be carried out at the pituitary level, since both adiponectin receptors were detected in the LH-expressing gonadotrophs of human and rats [14, 142, 143]. In addition, the expression of the
As noted above, the expression of the
The main regulators of the
The AdipoR2 was located on the surface of Leydig cells, while AdipoR1 was found in the epithelium of the seminiferous tubules. In spermatozoa there are both types of the adiponectin receptors [17, 148, 149]. The
All of the above indicates that adiponectin positively regulates the T synthesis (Figure 2). Indeed, treatment of the MA-10 Leydig cells with adiponectin at the concentrations of 50–5000 ng/mL resulted in an increase in the production of progesterone, a precursor of T, which was associated with cAMP-dependent activation of StAR and cytochrome P450scc [151]. In the earlier studies, it was shown that adiponectin, acting on the testes, suppressed both the basal and hCG-stimulated T production, although the expression of the steroidogenesis enzymes, such as cytochrome P450scc and dehydrogenases 3β-HSD and 17β-HSD3, did not change [17, 148]. The mechanisms of adiponectin action on Leydig cells include the stimulation of PI3K and Akt kinase, which results in the changed expression of Akt-dependent genes, as well as the regulation of ERK1/2, whose activity decreases at low concentrations of adiponectin and increases at its high concentrations [148]. It can be assumed that the dependence of adiponectin effect on ERK1/2 on its concentration, as well as a set of the effector components of MAPK cascade regulated by adiponectin are responsible for the different mode of the regulation of steroidogenesis by this adipokine. The treatment of Leydig cells with adiponectin did not affect the expression of LH receptor, and this indicates the preservation of the sensitivity of these cells to gonadotropins [148].
\nVisfatin produced by the adipose tissue is a multifunctional protein that functions as a signal molecule and as a nicotinamide phosphoribosyltransferase (NAMPT) catalyzing the synthesis of nicotinamide adenine mononucleotide from nicotinamide and 5-phosphoribosyl-1-pyrophosphate [152, 153, 154]. In humans, visfatin includes 491 amino acids and forms a functionally active homodimer complex [10, 155, 156]. Paradoxically, the receptor for visfatin has not yet been found. It is known that the main targets of visfatin, as in the case of most other adipokines, are the MAPK and PI3K/Akt pathway, and the activation of Akt kinase occurs 5 min after treatment of cells with visfatin [156, 157, 158].
\nThe highest concentration of visfatin is detected in the white adipose tissue. In obesity and DM2, the plasma visfatin level is steadily increased, and the degree of this increase varies greatly, due to both the individual characteristics of patients and the various approaches to measure the visfatin concentration [2, 155]. The visfatin level is also increases in women with a polycystic ovary syndrome, for which obesity and insulin resistance are characteristic [155]. Despite an increase in the plasma level of visfatin, its concentration in the CSF decreases, and this is probably due to the impaired transport of visfatin through the BBB. These data suggest that, as in the case of leptin and insulin, the transport of visfatin into the brain can be receptor-mediated, and decreases in the conditions of visfatin resistance.
\nThe data on the involvement of visfatin in regulation of the reproductive system are mainly related to the female HPG axis, folliculogenesis and steroidogenesis in the ovaries [7]. There is a positive correlation between the visfatin level in follicular fluid and the quantity and quality of the follicles [159]. It is assumed that the effect of visfatin on the ovarian steroidogenesis system can be realized via the mechanisms that lead to an increase in the production of insulin-like growth factor-1 (IGF-1), a stimulator of steroidogenesis [138]. In this case, the effects of visfatin are characterized by species specificity. The introduction of recombinant human visfatin into chicken did not stimulate, but, on the contrary, suppressed the basal and IGF-1-stimulated expression of the
In the case of the male reproductive axis, the targets for visfatin may be all of its components. Information on the central mechanisms of action of visfatin is limited to its effect on the hypothalamic neurons responsible for control of glucose homeostasis [160]. However, the fact that visfatin, like leptin, affects the activity of 3-phosphoinositide pathway, supports its possible participation in the regulation of GnRH-neurons activity. The evidences were obtained in favor of the regulation of LH-expressing pituitary gonadotrophs by visfatin. Firstly, the mRNA for visfatin was detected in gonadotrophs, which indicates its synthesis in them and the role of visfatin in the autocrine and paracrine regulation of the anterior pituitary. Secondly, visfatin stimulates the AMPK activity in the cultured murine gonadotroph-like cells LβT2, resulting in a decrease in LH secretion [161].
\nThe ability of visfatin to influence the testicular functions and the T synthesis is supported by the following data. Visfatin is expressed in Leydig cells, spermatocytes and spermatozoa [19], and its level in the seminal fluid is much higher than in the blood [162]. When exposed to Leydig cells, visfatin increases the T production, and the maximal effect of visfatin is achieved at its concentration of 10−6 M [163]. The inhibitor of Raf-1 kinase reduces the stimulating effect of visfatin on steroidogenesis, while the inhibitors of the protein kinases A and C have a little influence on this effect. It is assumed that the effects of visfatin on steroidogenesis may be due to activation of insulin receptors [163], which are widely represented in Leydig cells, especially since previously it has been reported that insulin receptor can interact with visfatin [154, 164]. However, despite the similarity of regulatory effects of insulin and visfatin, in the recent years the ability of visfatin specifically binds to insulin receptor has been questioned [157].
\nResistin is a polypeptide with a molecular mass of 12.5 kDa, which forms a homodimer stabilized by disulfide bonds [138]. Although resistin is mainly secreted by adipocytes of the white and brown adipose tissues and macrophages [165, 166], its expression is also shown in the testes in the Sertoli and Leydig cells, which indicates the participation of resistin in the autocrine and paracrine regulation of testicular cells [16]. The expression of the
The level of resistin in the bloodstream, from which it is able to be transported to the testes, varies greatly depending on the metabolic status, gender and species. Fasting leads to a decrease in the plasma resistin level and the
Using the primary culture of pituitary cells of rhesus monkey it was shown that resistin activates a number of signaling pathways, including cAMP-dependent and 3-phosphoinositide cascades regulating the cell survival and secretory activity. Resistin affects the secretion of growth hormone and adrenocorticotropic hormone, although LH secretion remains unchanged. It should be noted, however, that the treatment of pituitary cells with leptin and adiponectin also did not affect LH secretion, which is probably due to the peculiarities of cultured cells used in the experiment [174].
\nResistin was found in the brain and CSF, and although its concentration was much lower than in the bloodstream, it can be assumed that resistin affects the activity of hypothalamic neurons controlling GnRH secretion [116, 133]. One of the mechanisms of this may be the influence of resistin on the adiponectin signaling in hypothalamic neurons. A prolonged i.c.v. administration of resistin into rats and mice results in a decrease in the expression of both types of adiponectin receptors, AdipoR1 and AdipoR2, and also reduces the functional activity of APPL-1 protein, thereby weakening the APPL-1-mediated adiponectin signaling. There is reason to believe that this effect of resistin is implemented through the receptor TLR4, since the inhibiting effect of resistin on the adiponectin signaling was not detected in mice lacking TLR4 [175].
\nThe
The regulation of the male gonadal axis by adipokines can be carried out both through the changes in the plasma level and bioavailability of adipokines produced (a systemic regulation) and through the changes in the expression and specific activity of adipokines in the target tissues, the components of the HPG axis, such as the hypothalamus, pituitary and testes (an autonomous regulation). In the case of systemic adipokines regulation, the changes in the plasma level of adipokines that are associated with feeding behavior, physiological conditions, and also with an imbalance of adipokines and a resistance to them in obesity, DM2 and other metabolic disorders directly affect the functional activity of the male HPG axis and T production. Of great importance is the activity of the adipokine-transporting system, which transfers the adipokines through the BBB into the brain, where they regulate the GnRH- and KNDy-neurons involved in GnRH secretion, and also through the BTB into the testes, where they control the steroidogenesis system and the synthesis of T, the main effector hormone of the male HPG axis. In the case of autonomous regulation, the adipokines synthesized in the pituitary and testes function as the autocrine and paracrine factors and to a large extent determine functional activity of the components of the HPG axis. On the one hand, they regulate proliferation and survival of gonadotrophs and testicular cells, primarily Leydig cells, and on the other, affect their ability to produce gonadotropins and steroid hormones. It is important to note that between the systemic and autonomous adipokine-mediated regulation of the male HPG axis there are the complex integrative relationships and interactions that are realized at different levels of this axis. As a consequence, the changes in the pattern and levels of adipokines in the bloodstream can be differently associated with activity of the hypothalamic, pituitary and testicular components of the HPG axis, since in this case it is necessary to take into account the functional state of autonomous adipokine systems. The ratio of different adipokines in the blood and in the tissues, the components of the HPG axis, contributes significantly to the resulting effects of adipokines on the reproductive system, since their effects on the male HPG axis, including the testicular steroidogenesis system, may be synergistic or antagonistic.
\nThe study of the role of adipokines in the regulation of the male HPG axis is of great interest, since it will allow in the future to develop the effective approaches for monitoring functional activity of the male reproductive system and correcting the dysfunctions in this system in metabolic and endocrine disorders, including obesity and DM2. The adipokines and their analogues, as well as regulators and modulators of their signaling cascades in the hypothalamic neurons and testes, can be used as potential drugs to improve the reproductive functions and to normalize the steroidogenesis in men. It is also important how the treatment of men with GnRH analogous, gonadotropins with LH-like activity and androgens will affect the systemic and autonomic regulation of the GPH axis by adipokines. This should be taken into account when developing the approaches to improve metabolic status in obese and diabetic patients and in elderly men with an androgen deficiency using the activators of the HPG axis and androgens. The study of the interaction between the male HPG axis and the adipokine system will allow us to decipher the fundamental mechanisms that determine the relationships between the eating behavior, hunger and satiety, on the one hand, and the sexual behavior and aggression, on the other.
\nThis work was supported by the Russian Foundation of Basic Investigations (project No 18-515-45004 IND-a).
\nConflicts of interest are absent.
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