Published results of randomized controlled trials of second-line therapy versus best supportive care or placebo.
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
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Interested readers will find in this book the topics of image compression, groundwater quality, establishing the downscaling and spatio-temporal scale conversion models of NDVI, modelling and optimization of 3T fractional nonlinear generalized magneto-thermoelastic multi-material, algebraic fractals in steganography, strain induced microstructures in metals and much more. The book will definitely be of interest to scientists dealing with fractal analysis, as well as biomedical engineers or IT engineers. I encourage you to view individual chapters.",isbn:"978-1-83962-483-4",printIsbn:"978-1-83962-482-7",pdfIsbn:"978-1-83962-484-1",doi:"10.5772/intechopen.87695",price:119,priceEur:129,priceUsd:155,slug:"fractal-analysis-selected-examples",numberOfPages:128,isOpenForSubmission:!1,hash:"f0c3d700a69d15b52ff8a59fe7e99062",bookSignature:"Robert Koprowski",publishedDate:"September 9th 2020",coverURL:"https://cdn.intechopen.com/books/images_new/9886.jpg",keywords:null,numberOfDownloads:1093,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"October 1st 2019",dateEndSecondStepPublish:"March 3rd 2020",dateEndThirdStepPublish:"May 2nd 2020",dateEndFourthStepPublish:"July 21st 2020",dateEndFifthStepPublish:"September 19th 2020",remainingDaysToSecondStep:"a year",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:"Edited by",kuFlag:!1,biosketch:null,coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"50150",title:"Prof.",name:"Robert",middleName:null,surname:"Koprowski",slug:"robert-koprowski",fullName:"Robert Koprowski",profilePictureURL:"https://mts.intechopen.com/storage/users/50150/images/system/50150.jpg",biography:"Robert Koprowski, MD (1997), PhD (2003), Habilitation (2015), is an employee of the University of Silesia in Poland, Institute of Computer Science, Department of Biomedical Computer Systems. For 20 years he has studied the analysis and processing of biomedical images with particular emphasis on the full automation of measurement for a large inter-individual variability of patients. He is the author of dozens of papers with the impact factor (IF) and more than a hundred other papers, as well as the author or co-author of six books. Additionally, he is the author of several national and international patents in the field of biomedical devices and imaging. 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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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Markovi?-Nikoli?",coverURL:"https://cdn.intechopen.com/books/images_new/7614.jpg",editedByType:"Edited by",editors:[{id:"23261",title:"Prof.",name:"Goran",surname:"Nikolic",slug:"goran-nikolic",fullName:"Goran Nikolic"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6230",title:"Topics in Splines and Applications",subtitle:null,isOpenForSubmission:!1,hash:"93059c7907be129c419e4f9960b4e9c3",slug:"topics-in-splines-and-applications",bookSignature:"Young Kinh-Nhue Truong and Muhammad Sarfraz",coverURL:"https://cdn.intechopen.com/books/images_new/6230.jpg",editedByType:"Edited by",editors:[{id:"207517",title:"Dr.",name:"Young Kinh-Nhue",surname:"Truong",slug:"young-kinh-nhue-truong",fullName:"Young Kinh-Nhue Truong"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10062",title:"Forecasting in Mathematics",subtitle:"Recent Advances, New Perspectives and Applications",isOpenForSubmission:!1,hash:"9a3ad05fef0502040d2a238ad22487c0",slug:"forecasting-in-mathematics-recent-advances-new-perspectives-and-applications",bookSignature:"Abdo Abou Jaoude",coverURL:"https://cdn.intechopen.com/books/images_new/10062.jpg",editedByType:"Edited by",editors:[{id:"248271",title:"Dr.",name:"Abdo",surname:"Abou Jaoude",slug:"abdo-abou-jaoude",fullName:"Abdo Abou Jaoude"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8655",title:"Advances in Complex Analysis and Applications",subtitle:null,isOpenForSubmission:!1,hash:"6abcaa5b5cf98a51a769d1bce7e5ebe5",slug:"advances-in-complex-analysis-and-applications",bookSignature:"Francisco Bulnes and Olga Hachay",coverURL:"https://cdn.intechopen.com/books/images_new/8655.jpg",editedByType:"Edited by",editors:[{id:"92918",title:"Dr.",name:"Francisco",surname:"Bulnes",slug:"francisco-bulnes",fullName:"Francisco Bulnes"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8600",title:"Recent Advances in Integral Equations",subtitle:null,isOpenForSubmission:!1,hash:"55d44e96dac2ef01fb52708933293c71",slug:"recent-advances-in-integral-equations",bookSignature:"Francisco Bulnes",coverURL:"https://cdn.intechopen.com/books/images_new/8600.jpg",editedByType:"Edited by",editors:[{id:"92918",title:"Dr.",name:"Francisco",surname:"Bulnes",slug:"francisco-bulnes",fullName:"Francisco Bulnes"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophanides",surname:"Theophile",slug:"theophanides-theophile",fullName:"Theophanides Theophile"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"48319",title:"Chemotherapy for Gastric Cancer — What Comes Next?",doi:"10.5772/60420",slug:"chemotherapy-for-gastric-cancer-what-comes-next-",body:'Gastric cancer (GC) is the fourth (in men) and fifth (in women) most commonly newly diagnosed cancer worldwide and the third (in men) and fifth (in women) leading cause of cancer death [1]. Radical resection remains the only way cure, but cure rates following surgery for resectable GC in the West lag behind those in Japan. In addition, many GC patients will suffer recurrence even after curative resection in approximately 50% of cases [2], which eventually results in a still poor 5-year survival rate of <30% both in the USA [3] and in Europe [4]. Although the 5-year survival rate in Japan is much better than that in the West, there is a global consensus that advanced GC patients need further anticancer therapy.
Currently, five classes of cytotoxic agents (fluoropyrimidines, platinums, taxanes, topoisomerase inhibitors, and anthracyclines) and new molecular targeting agents have been used in GC. Recent randomized controlled trials (RCTs) in the field of treatment for advanced GC have established first-line chemotherapy, although the approach and management for advanced GC varies from region to region so that there is no worldwide consensus on this matter. The most promising regimens are ECF (epirubicin, cisplatin, and 5-fluorouracil) in Europe [5], DCF (docetaxel, cisplatin, and 5-fluorouracil) in the USA (V325 trial) [6], and SP (S-1 and cisplatin) in Japan (SPIRITS trial) [7]. Strikingly, however, the global RCT conducted in the USA (FLAGS trial) failed to exhibit any survival advantage of the SP regimen over the FP (5-fluorouracil plus cisplatin) regimen [8]. Very recently, trastuzumab combined with cisplatin and fluoropyrimidines has been found to be active for human epidermal growth factor receptor-2 (HER2 or ERBB2)-positive GC (ToGA trial) [9]. Although these regimens are active, the treatment progress is painfully slow [4]. The median time to progression (TTP) or progression free survival (PFS) was 7.4 months by ECF [5], 5.6 months by DCF [6], 6.0 months by Japanese style SP [7], 4.8 months by global style SP [8], and 6.7 months even by adding trastuzumab [9], suggesting that many advanced GC patients experience failure after first-line chemotherapy.
Interestingly, the median TTP or PFS of these regimens are almost equivalent (5.6-7.4 months) [5-7] while median overall survival times (OS) differ between the studies (Figure 1). The 13 months of median OS by the Japanese SP regimen [7] was apparently longer than those (8.7-9.2 months) by ECF and DCF regimens [5,6] (Figure 1). In addition, even by the use of the SP regimen, the post-progression survival –the survival length difference between median PFS and median OS– differed considerably, being 7 months in the SPIRITS trial [7] and 3.8 months in the FLAGS trial [8] (Figure 1). Such inter-trial differences in post-progression survival are partly attributable to different proportions of subsequent second-line therapy after the failure of first-line chemotherapy, being over 70% in the SPIRITS trial while 30-45% in other trials [6,8,9]. In this regard, patients who retain good performance status at the time of first-line treatment failure are candidates for second-line therapy. Currently, however, no standard regimens for any second-line therapy hitherto determined suggest an urgent need for the establishment of second-line therapy. Reflecting this urgency, clinical research concerning second-line therapy has been recently commenced. In the era of post first-line chemotherapy, this chapter reviews the next research issues deserving of focus in the field of advanced GC treatment.
Median TTP or PFS (white bar) and post-progression free survivals (gray bar) of the previous first-line RCTs. The sum of the white and gray bars indicates median OS. Percentages indicate the proportion of patients receiving further therapy. The reference numbers are expressed in brackets. ECF; epirubicin, cisplatin, and 5-fluorouracil, DCF; docetaxel, cisplatin, and 5-fluorouracil, SP; S-1 and cisplatin. ND; not described.
The significance of second-line therapy after disease progression by first-line chemotherapy has been evaluated by several randomized comparisons of survival times between second-line therapy and best supportive care (BSC) or placebos. Various kinds of agents have been investigated in the RCTs of second-line therapy, such as chemotherapy drugs [10-12] and molecular targeting agents [13-15]. Some of these trials have demonstrated significantly improved survival times by second-line therapies as compared with BSC or a placebo (Table 1).
The AIO conducted a RCT to compare irinotecan (21 patients) with BSC (19 patients) [10]. Although this study was closed prematurely due to poor patient accrual, irinotecan could significantly (p=0.012) prolong median OS (4.0 months) as compared to those by BSC (2.4 months). The second RCT conducted in Korea [11] assigned patients in a ratio of 2:1 to chemotherapy (docetaxel or irinotecan) plus BSC (133 patients) or BSC alone (69 patients). Choice of chemotherapy drugs was left to the discretion of the investigators. Median OS of the chemotherapy arm (5.3 months) was significantly (p=0.007) longer than those of the BSC arm (3.8 months). This survival difference may be partly ascribed to the significantly (p=0.02) greater number of patients receiving further chemotherapy (third-line chemotherapy) in the chemotherapy arm (40%) than in the BSC arm (22%) because median OS was longer (8.0 months) for patients who received subsequent treatment than those who did not (3.76 months), regardless of treatment arm. Of note, the lack of any difference in median OS between docetaxel use (5.2 months) and irinotecan use (6.5 months) implies that both agents are equally active, although bias for patient allocation can not be denied. In the third RCT conducted in the UK [12], 168 patients were allocated to either docetaxel plus active symptom control or active symptom control alone (84 patients each). The median OS in the docetaxel group (5.2 months) was significantly longer (p=0.01) than that in the active symptom control alone group (3.6 months). Measurements of disease specific quality of life showed benefits for docetaxel in reducing dysphagia and abdominal pain.
The efficacy of molecular targeting agents as a second-line setting has been investigated by three other RCTs [13-15]. First, a GRANITE-1 trial [13] randomly assigned 656 patients at a 2:1 schedule either to everolimus (n=439) or a matching placebo (n=217). Significantly longer median PFS by everolimus (1.7 months, p<0.0001) than that by placebo (1.4 months) did not reflect a difference in median OS (5.4 months in the everolimus arm versus 4.3 months in the placebo arm, p=0.12). Such a discrepancy, namely a significant PFS difference and nonsignificant OS difference, could be ascribed to the fact of the similar or even longer median OS (4.3 months) in the placebo arm in this study as compared to those (2.4-3.8 months) of BSC arms in other second-line RCTs [10-12]. Therefore, one should remember that the longer survival length in the control arm might diminish any statistical significance even when the experimental regimen is effective. Subsequently, a global REGARD trial [14] was able for the first time to demonstrate that ramucirumab, a monoclonal antibody of vascular endothelial growth factor receptor (VEGFR)-2, was significantly superior to placebo with regard to median OS (5.2 months versus 3.8 months, p=0.047) and median PFS (2.1 months versus 1.3 months, p<0.0001), respectively. In addition, more patients receiving ramucirumab experienced stable or improved QOL than those in the placebo arm. Finally, apatinib, a tyrosine-inhibitor agent targeting VEGFR with an anticipated anti-angiogenesis effect, has been now tested in a clinical trial (NCT 01512745) [15]. This study aims to determine whether apatinib can improve PFS or OS compared to placebos.
Subsequently, a metaanalysis has very recently elucidated a 36% reduction in the risk of death (p<0.0001) by second-line therapy [16], suggesting that second-line therapy is effective and should be considered in some segments of GC patients refractory to first-line therapy.
Several randomized trials have been released to explore the optimal combination and doses for second-line therapy using the currently active agents or those deemed active. The agents investigated by these trials include chemotherapeutic drugs [17-20], a molecular targeting agent [21], and their combinations [22-26].
The efficacy of chemotherapy as a second-line setting has been investigated in several RCTs. In the TCOG GI-0801 trial [17], median PFS was significantly longer (3.8 months, n=64) by biweekly irinotecan plus cisplatin than by irinotecan alone (2.8 months, n=63), but median OS did not differ between the arms (10.7 months versus 10.1 months). Notably, the proportion of patients receiving third-line therapy was the same (75%) in both groups. The results of another randomized trial (ECRIN) have been reported in the abstract form [18], in which irinotecan plus cisplatin (n=84) was compared with irinotecan alone (n=84) in patients refractory to an S-1 containing regimen. WJOG 4007 [19] is a RCT comparing weekly paclitaxel (n=108) with biweekly irinotecan (n=111) in GC patients refractory to fluoropyrimidines plus cisplatin. Although there are no statistically significant differences between weekly paclitaxel and biweekly irinotecan for median OS (9.5 months vs 8.4 months, p=0.38), median PFS (3.6 months vs 2.3 months, p=0.33), or response rate (20.9% vs 13.6%, p=0.24), the median OS of both arms are equally longer than those of the previous second-line studies (Table 1, Figure 2). Several explanations are possible for the longer median OS in this study. One explanation is the lower proportion of patients with severe peritoneal metastasis in this study (25.6%) as compared with those in the AIO [10] (45%) and Kang [11] (45%) studies. Another explanation is that the proportion of patients receiving third-line therapy in this study was substantial, being 89.8% in the paclitaxel arm and 72.1% in the irinotecan arm. Interestingly, the third-line therapy was an irinotecan-containing regimen in 75% of patients of the paclitaxel arm and a taxane-containing regimen in 60% of the irinotecan arm. Including later lines, 81% patients in the paclitaxel arm received irinotecan and 68% of patients in the irinotecan arm received paclitaxel. The more prolonged median OS in both arms of the WJOG 4007 than those of the previous studies implies that both irinotecan and paclitaxel in second- and further-line settings could potentially contribute to prolonged survival. The ongoing fourth RCT (JACCRO GC05) [20] has been comparing irinotecan plus S-1 with irinotecan alone to GC patients refractory to S-1. Since the standard regimen in adjuvant and advanced settings in Japan is respectively S-1 and S-1 plus cisplatin, this study will provide one answer to the clinically important question of whether the prolonged use of S-1 is effective even to the S-1 resistant patients whom the clinicians face.
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t|||
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t|||
Thuss-Patience [10] | \n\t\t\tIriontecan | \n\t\t\t250-350mg/m2, q3w | \n\t\t\t21 | \n\t\t\t19 | \n\t\t\t4 | \n\t\t\t2.4 | \n\t\t\t2.5 | \n\t\t\tND | \n\t\t
\n\t\t\t | \n\t\t\t | \n\t\t\t | \n\t\t\t | \n\t\t\t | p=0.012 | \n\t\t\t\n\t\t\t | \n\t\t | |
Kang [11] | \n\t\t\tIriontecan or Docetaxel | \n\t\t\t150mg/m2, q2w or 60mg/m2, q3w | \n\t\t\t133 | \n\t\t\t69 | \n\t\t\t5.3 | \n\t\t\t3.8 | \n\t\t\tND | \n\t\t\tND | \n\t\t
\n\t\t\t | \n\t\t\t | \n\t\t\t | \n\t\t\t | \n\t\t\t | p=0.007 | \n\t\t\t\n\t\t\t | \n\t\t | |
COUGAR-02 [12] | \n\t\t\tDocetaxel | \n\t\t\t75mg/m2, q3w | \n\t\t\t84 | \n\t\t\t84 | \n\t\t\t5.2 | \n\t\t\t3.6 | \n\t\t\tND | \n\t\t\tND | \n\t\t
\n\t\t\t | \n\t\t\t | \n\t\t\t | \n\t\t\t | \n\t\t\t | p=0.01 | \n\t\t\t\n\t\t\t | \n\t\t | |
GRANITE-1 [13] | \n\t\t\tEvelorimus | \n\t\t\t10mg/day | \n\t\t\t439 | \n\t\t\t217 | \n\t\t\t5.4 | \n\t\t\t4.3 | \n\t\t\t1.7 | \n\t\t\t1.4 | \n\t\t
\n\t\t\t | \n\t\t\t | \n\t\t\t | \n\t\t\t | \n\t\t\t | p=0.12 | \n\t\t\tp<0.001 | \n\t\t||
REGARD [14] | \n\t\t\tRamucirumab | \n\t\t\t8mg/kg, q2w | \n\t\t\t238 | \n\t\t\t117 | \n\t\t\t5.2 | \n\t\t\t3.8 | \n\t\t\t2.1 | \n\t\t\t1.3 | \n\t\t
\n\t\t\t | \n\t\t\t | \n\t\t\t | \n\t\t\t | \n\t\t\t | p=0.047 | \n\t\t\tp<0.0001 | \n\t\t
Published results of randomized controlled trials of second-line therapy versus best supportive care or placebo.
OS; overall survival, PFS; progression free survival, ND; not described
Comparisons of median OS between the previous RCTs. The percentage indicates the proportion of patients receiving further therapy in each trial. The reference numbers are expressed in brackets. *; first-line trials, BSC; best supportive care, PBO; placebo, Cape; capecitabine, Ox; oxaliplatin, EOC; epirubicin, oxaliplatin, and capecitabine, ND; not described.
The RCT comparing a molecular targeting agent with a chemotherapeutic agent has been ongoing. HER2-positive advanced GC patients have been allocated to either trastuzumab emtansine or taxane (GATSBY, NCT01641939) [21].
A combination of molecular targeting agents and chemotherapy agents has been investigated in several RCTs. First, paclitaxel with or without lapatinib, which binds to the intracellular tyrosine kinase domains of ERBB1 and ERBB2 (HER2), was compared in HER2-positive advanced GC (TYTAN) [22]. Neither median OS nor median PFS were prolonged by lapatinib plus paclitaxel (n=132) as compared to paclitaxel alone (n=129). Second, the results of the RAINBOW trial [23,24], which compared ramucirumab plus paclitaxel with placebo plus paclitaxel, have been very recently reported in the abstract form. Sixty hundred and sixty-five GC patients, who were refractory to cisplatin and fluoropyrimidine-containing regimens, were randomized in a 1:1 ratio to receive paclitaxel plus ramucirumab or paclitaxel plus a placebo. The paclitaxel and ramucirumab arm showed a significant benefit in median OS (HR=0.807, p=0.0169) and median PFS (HR=0.635, p<0.0001). The subsequent geographical region-stratified analysis elucidated that the advantage of median PFS and median OS was more evident in Western patients than in Japanese patients (Figure 2). Such a regional difference could partly explained by a higher use of post-discontinuation treatment in Japan (75% of patients) than in Western countries (36-38% of patients), which may eventually mask any potential OS benefit of ramucirumab plus paclitaxel in Japan. Two other RCT trials [25,26] are now ongoing. Paclitaxel with or without everolimus has been compared in patients with advanced GC refractory to fluoropyrimidine containing regimens [25]. Patients will be randomized in a 1:1 ratio for a total of 240 patients per treatment arm. Nimotuzumab plus irinotecan versus irinotecan monotherapy as second-line therapy has been investigated in patients with ERBB1 overexpressed advanced GC [26]. This is a Japan and Korea collaborative RCT allocating patients at 1:1 ratio for a total of approximately 400 patients per arm.
The results of some trials have been published; however, at present, trials in which the primary endpoint has been met have been unfortunately very limited. The positive results hitherto obtained include a prolonged PFS by a combination of irinotecan and cisplatin after the failure of S-1 based first-line chemotherapy, and prolonged PFS and OS by ramucirumab in combination with weekly paclitaxel. The results of other studies, especially using molecular targeting agents, are awaited.
When considering second-line therapy, clinicians must be aware that, by definition, patients receiving second-line therapy are not chemonaive and experience treatment failure; thus, they are more likely to be resistant to therapy than first-line treatment. Furthermore, patient performance status is more likely to deteriorate due to a recurrent cancer burden and treatment against it. Indeed, widely ranging grades of gastrointestinal symptoms-related adverse events occurred in a substantial proportion of patients in the BSC arms of clinical trials, suggesting a poor quality of life even by the BSC. In addition, a more intensive regimen aiming at a prolonged OS may cause a higher likelihood of severe adverse events that may result in treatment discontinuation and limitation. For example, the DCF regimen caused 82% of grade 3-4 neutropenia and 29% of febrile neutropenia. Therefore, balancing efficacy and adverse events should be taken into account when developing second-line therapy. The development of more intensive while less toxic second-line regimens could be positioned as a breakthrough marker of GC treatment, which can then ultimately achieve further survival prolongation without treatment withdrawal.
In this context, another direction for research is to establish less toxic regimens with preserved anticancer activity. As described earlier, the conventional first-line treatment comprises 5-fluorouracil and emetogenic/nephrotoxic cisplatin. Therefore, the challenges for a less toxic regimen are the substitution of oxaliplatin for nephrotoxic cisplatin [27,28] or substitution of oral capecitabine for intravenous 5-fluorouracil [29]. Such substitutions aim to reduce toxicity and maintain organ function, thus avoiding treatment withdrawal and prolonged treatment duration.
Fluorouracil, leucovorin, and oxaliplatin (FLO) were associated with significantly less anemia, nausea, vomiting, fatigue, renal toxicity, and serious adverse events related to the treatment as compared with fluorouracil, leucovorin, and cisplatin (FLP) [27]. In addition, there was a better trend toward improved median PFS by FLO than FLP. Similarly, as compared to SP, S-1 plus oxaliplatin (SOX) resulted in a reduced risk of grade 3/4 neutropenia (41.5% vs 19.5%) and febrile neutropenia (6.9% vs 0.9%) while median PFS was similar between the two regimens (5.4 months versus 5.5 months) [28]. These findings further support the possibility that the substitution of oxaliplatin for cisplatin reduced toxicity while maintaining efficacy. Accordingly, length of hospital stay per cycle of SOX regimen (0.85 day) was significantly shorter than that for the SP regimen (6 days) [28]. Furthermore, capecitabine and cisplatin (XP) versus 5-fluorouracil and cisplatin (FP) proved similar median OS (10.5 months versus 9.3 months), suggesting that the inconvenience of infusional 5-fluorouracil could be replaced by oral capecitabine, thus realizing a more simplified dosing schedule [29]. Whether this concept can be applied to second-line therapy warrants further investigation.
With the development of a new generation of cytotoxic agents and molecular targeting agents, the research field of GC treatment appears to be transitioning into a new era with a focus on the targetable molecules in GC. Several molecular targeting agents are currently being evaluated both in first- and second-line settings. The pending results of ongoing clinical trials motivates researchers to continue the challenge of establishing the best second-line regimens or less toxic combinations for the treatment of advanced GC.
Clarifying the genetic alterations of targeted molecules and their interactions.
Unfortunately, in sharp contrast to colorectal cancer in which there has been a significant achievement in treatment by the use of molecular targeting agents, only one agent (ramucirumab) has been currently proved to be an agent for second-line therapy presumably due to the genetic complexity and molecular heterogeneity of the disease.
Recent findings have highlighted the mechanisms of the actions of molecular targeting agents or patterns of expression of targetable molecules in several tumors. For example, genetic alterations that are critical for cell growth occur with considerably different frequencies, being 60%, 33%, and 32% in cancers of the pancreas, biliary tract, and colon, respectively [30]. Furthermore, certain combinations of targets are expressed in a mutually exclusive or co-occurring manner in the same tumor. A mutually exclusive fashion would be a case being KRAS and BRAF in colorectal cancer, or ERBB1 and KRAS in lung cancer [31]. The co-occurring expression of targets is a case of being ERBB2 and PIK3CA in breast cancer [32]. With regard to GC, although KRAS mutations are initially recognized as an infrequent phenomenon in GC [33], the alterations and amplifications of other genes --both known or previously unreported-- have been subsequently found in a substantial number of GC patients in a mutually exclusive manner [34,35] or co-amplified manner [36]. These findings create a challenge in the treatment regimen with either a use of each blockade of each targetable molecule or a use of dual- or pan-inhibitors of kinases [37]. In addition, elucidation of the roles of each domain in ERBB2 that plays a role in resistance to anti-HER2 therapy further provides the theoretical basis to modify therapeutic strategies to circumvent this resistance [38]. These advances may expand therapeutic options, thereby making larger proportions of GC patients possible candidates for molecular targeting therapies than previously appreciated. Accordingly, there may be a desperate need for multiple gene profiling which could help establish rational molecular criteria for patient inclusion and exclusion in clinical trials. Patient selection by gene profiling may allow better patient recruitment for those most likely to respond to targeted therapies.
Positive and negative interactions between chemotherapy and molecular targeting therapies.
It should be noted that the recent clinical trials of first-line molecular targeting therapies regrettably resulted in some negative results [39-41] (Figure 2). The addition of cetuximab to cisplatin plus capecitabine had a similar median PFS (4.4 months) and median OS (9.4 months) compared to cisplatin plus capecitabine alone (5.6 months and 10.7 months, respectively) [39] (EXPAND). Surprisingly, the addition of panitumumab to epirubicin, oxaliplatin, and capecitabine (EOC) resulted in a significantly shorter (p=0.013) median OS (8.8 months) compared to EOC (11.3 months) (REAL-3) [40]. Furthermore, lapatinib in combination with capecitabine and oxaliplatin could not show any significant survival benefit (LoGiC) [41]. These negative results lead to speculation that there may be ideal combinations or compatibility between chemotherapy and molecular targeting therapy. In addition, even the addition of panitumumab to EOC achieved only similar median OS to those of the WCOG 4007 trial (Figure 2) [19,40]. Therefore, a certain combination, such as anti-EGFR antibody and capecitabine or oxaliplatin, may be ineffective or even interfere with the other. This speculation can be supported by the observation that addition of cetuximab to oxaliplatin plus fluoropyrimidine-based chemotherapy failed to demonstrate survival benefits for advanced colorectal cancer [42].
Need to evaluate the updated molecular profile.
Another obstacle for the progression of second-line treatment lies in the possibility that the molecular profile of GC is likely to change under the stress of treatment. Generally, lower response rates and shorter survival times in patients receiving second-line therapy than chemonaive patients may partly be explained by such molecular changes that lead to a resistance to therapy. Ideally, the on-demand tissue samples from tumor sites currently of interest are needed to assess the updated genetic and molecular patterns and to predict whether the planned second-line therapy is really effective. However, direct tumor tissue sampling and subsequent gene analysis are often hampered by virtually inaccesible tumor localization and by overly small sample volumes to perform gene analysis. It is necessary to discover novel markers which can be alternatives for those obtained only by direct tumor tissue sampling as well as to improvise new methods to assess them in order to select the right patients for the right second-line regimen.
Motivated by the first promising results of trastuzumab use in the ToGA trial, several molecular targeting therapies have been challenged in clinical trials. Continuous efforts should be necessary to clarify the mutation and amplification of targeted molecules, and novel methods for their genetic profiling should probably become part of clinical routines. Ultimately, GC patients harboring unique genetic profiles of targeted molecules should be allocated into specific, suitable trials. Targeted therapies tailored to individual genetic profiles maximize treatment efficacy because this allows the recruitment of selected, most suitable patients rather than unselected ones [43].
Against the background of survival advantages of second-line therapy over BSC in GC patients refractory to first-line treatment, efforts to establish the most effective regimens have been just begun. Parallel to the development of molecular targeting agents, the investigated regimens comprise doublet or triplet chemotherapeutic agents, molecular targeting agents, and their combinations. In addition, the minimization of adverse events should be taken into account to avoid treatment discontinuation. There is a desperate need to explore genetic mutations of targeted molecules and the interactions between them, to establish novel methods to assess them, to clarify the positive or negative interactions between chemotherapy and molecular targeting agents, and to find regimens in which adverse events are least likely to occur for avoiding treatment discontinuation. These could help determine rational molecular criteria for patient inclusion and exclusion in clinical trials, realize the most efficient patient recruitment for those most likely to respond to therapies, and accelerate the establishment of the most effective second-line therapy that could achieve greater survival prolongation.
There 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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