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.
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We 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!
IntechOpen is proud to announce that 179 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\n
Throughout the years, the list has named a total of 252 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\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\n
We 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!
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1. Background
Male circumcision is not a new practice in Africa. It has been practiced for thousands of years as a ritual and a rite of passage to manhood [1, 2]. Similarly, in Botswana, male circumcision has been practiced as far as 1875, marked by an initiation ceremony into manhood called “bogwera” [3]. During the bogwera ceremony, young adolescent males were taken through a month-long period of seclusion into the wilderness where they were taught survival skills, tribal laws, and customs [4]. The bogwera was not practiced by all tribes in Botswana; only the Balete and Bakgatla tribes were participating in this ceremony [5]. In 1917, the British High Commissioner to Botswana passed a law to abolish initiation ceremonies, indicating that they were unhygienic and cruel [6].
In 1985, Botswana had the first HIV/AIDS case. Ever since from that time, a series of response plans and programs have been devised to reduce HIV transmission. In the early 2000s, epidemiological studies observed a significant association between circumcision and low HIV/AIDS prevalence [7, 8, 9]. It was found that countries with high circumcision rates recorded the lowest HIV/AIDS prevalence rates, in West, East, and Southern Africa [1]. Most of the studies conducted in these regions found that circumcision reduced vulnerability to HIV [10, 11, 12]. In order to provide conclusive empirical evidence, three randomized clinical trials were conducted to assess the effects of safe male circumcision for the prevention of HIV infection through heterosexual contact in South Africa, Uganda, and Kenya [13, 14, 15]. These trials congruently showed that HIV transmission was reduced by over 60% among circumcised men.
Owing to the evidence of the protective effects of circumcision against HIV transmission, several studies were undertaken in Botswana. Initial studies assessed the acceptability of safe male circumcision (SMC) among men in Botswana [16]. Subsequently, a mathematical model was used to calculate the public health impact of large safe male circumcision for HIV prevention. It was found that male HIV prevalence reduced from 30 to 10% and female HIV prevalence was reduced from 40 to 20% [17]. In 2009 the government of Botswana through the Ministry of Health and Wellness adopted the voluntary safe male circumcision program [17]. A 5-year strategy was then developed, which aimed at reaching 80% circumcision coverage [17]. According to Dickson et al. [18], less than 20% of males in Botswana had access to male circumcision services in 2010. Although the SMC program has been running for about 10 years in Botswana, recent evidence indicates that the program has failed to achieve its intended coverage [3].
This chapter is therefore intended to provide the background and assess the patterns and correlates of safe male circumcision within the context of a high HIV/AIDS prevalence setting. The chapter starts by providing a brief background on male circumcision and the SMC program in Botswana. It goes on to assess the patterns and determinants of SMC since the introduction of the program in 2009. An understanding of the background, patterns, and correlates of safe male circumcision is essential for programming and assessment of the effectiveness of the program.
2. Theoretical framework
This chapter generally adopts a multifaceted approach that considers HIV/AIDS risk perception among circumcised men by assessing patterns of circumcision and factors associated with circumcision among men in Botswana. This is done with the assumption that circumcision can only be effective in the context where men consider its health benefits. Most public health studies have often used individual and social behavioral theories to explain why individuals are willing to undertake a certain action and why they behave the way they do [19, 20, 21, 22]. Individual behavior models focus on the role of individual characteristics in controlling individual behavior. Thus they focus on how individuals control their behaviors and make reasoned actions that impact those decisions [23]. On the other hand, social models include social pressures, peer influences, cultural expectations, economic factors affecting resource availability, legal and political structures, and political and religious ideologies that restrict individual’s options and the flow of information [23].
Among the various individual and social behavioral models, the theory of reasoned action (TRA) has been selected and used in this chapter to explain why men would or would not circumcise. The TRA was developed and revised numerous times by Ajzen and Fishbein [24, 25]. This theory proposes that behavioral intentions are a combined function of the attitude toward performing a particular behavior in a given situation and of the norms perceived to govern that behavior multiplied by the motivation to comply with those norms [26]. The assumption is that human beings are usually quite rational and make systematic use of the information available to them. People consider the implications of their actions before they decide to engage or not engage in a given behavior [25].
As circumcision is recommended for medical reasons (especially prevention of HIV acquisition), men who may choose circumcision must also believe that circumcision may reduce chances of HIV acquisition. This model was mainly chosen because, the constructs of this model are key in informing men’s decision to accept circumcision. The assumption of TRA is that most behaviors of social bearing are under voluntary control and that a person’s intention to perform or not do the behavior is the direct determinant of that action [25]. Consequently, men’s intention regarding SMC is determined by personal and social influences. One personal factor is the person’s evaluation of the outcome of circumcision, which can be either positive or negative.
Men who perceive that circumcision is necessary for reduction of HIV transmission may choose the procedure. Meanwhile men who believe otherwise may have negative evaluation of circumcision and may choose not to circumcise. Subjective norm is the other determinant of a person’s intention which is a person’s perception of the social pressures applied to perform the behavior [25]. As illustrated in Figure 1, an individual’s intentions and behaviors are influenced by certain background factors which include individual, social, and information factors.
Figure 1.
Theory of reason action [25].
3. Methodology
3.1 Data
Data used in this chapter was derived from the two Botswana AIDS Impact Surveys (BAIS III and IV). BAIS III was conducted in 2008 before the implementation of SMC program, while BAIS IV was conducted in 2013 after the implementation of the SMC program. The main objectives of the BAIS were to provide information to assess whether programs are operating as intended; assess performance of intervention programs; assess whether people are changing their sexual behavior; establish the proportion of people in need of care due to HIV infection; establish the proportion of people who are at risk of HIV infection; assess the impact of the pandemic at household level; and provide information on issues related to the impact of HIV/AIDS on households and communities [27]. BAIS III and IV are the two surveys which have asked the same questions on male circumcision that can be used to assess the patterns and determinants of SMC in Botswana. A sample consisting of 6290 and 3787 men in ages 10–64 years who had successfully completed BAIS III and IV individual questionnaires, respectively, were selected and included for analyses. Respondents who did not complete the individual questionnaire were excluded from the present analysis.
3.2 Response variable
The main variable of interest used in this paper is on “circumcision status.” This is based on the percentage of circumcised men between ages 10 and 64 years in the sample population. This variable is derived from self-reported responses to a question that sought to know whether the respondent was circumcised or not.
3.3 Explanatory variables
Sociodemographic variables such as age, sex, residence, education, and religion were used as control variables based on prior empirical research which has shown that conceptually these variables are associated with sexual risk behaviors [28, 29].
3.4 Statistical analysis
Analyses were conducted using SPSS version 25 program (IBM, SPSS, Chicago, IL, USA). In order to assess patterns of circumcision, adjusted prevalence ratios (APR) and their corresponding 95% confidence intervals were obtained using modified Poisson regression models. The associations between male circumcision and sociodemographic and behavioral factors were estimated for each of the surveys. In order to avoid cofounding effects between circumcision and covariates, sociodemographic variables were used as control variables. This ensured that the association between behavioral variables and circumcision becomes credible and discernible. In the adjusted analyses of sexual risk behaviors, sociodemographic characteristics were controlled for. In order to control for cluster effects, complex samples module in SPSS has been used since multistage probability sampling technique was used for both surveys.
4. Results
4.1 Patterns of safe male circumcision in Botswana (2008–2013)
Overall 785 (12.5%) and 956 (25.2%) men in the sample reported to have been circumcised in 2008 and 2013, respectively (Figure 2).
Figure 2.
Percentage of circumcised men in Botswana (2008 and 2013). Source: Analyzed from Botswana AIDS Impact Surveys III and IV (2008 and 2013).
Table 1 shows the sociodemographic characteristics of circumcised men in Botswana (2008 and 2013). The proportion of men who were circumcised decreased with age for both surveys. For instance, in both surveys the highest proportions of circumcised men were found in ages 10–24 (25 and 28.7% for 2008 and 2013, respectively) and lowest in ages 55–64 years (8.3 and 9.8% for 2008 and 2013, respectively). A high proportion of circumcised men in both surveys was found among those with secondary education in 2008 and 2013 (53.1 and 49.5%, respectively), cities and towns (38.4 and 44.1%, respectively), never married individuals (47.8 and 53.7%), and Christians (64.4 and 81.4%, respectively).
Variables
2008 BAIS
2013 BAIS
Circumcised, % (n)
N
Circumcised, % (n)
N
Age
10–24
25.0 (184)
2680
28.7 (274)
1490
25–34
31.8 (234)
1600
27.6 (264)
954
35–44
21.8 (160)
934
21.2 (203)
680
45–54
13.1 (96)
586
12.7 (121)
399
55–64
8.3 (61)
318
9.8 (94)
264
Education
Primary/less
13.7 (78)
841
18.8 (161)
930
Secondary
53.1 (302)
2558
49.5 (423)
1688
Tertiary/higher
33.2 (189)
894
31.7 (271)
724
Residence
Cities and towns
38.4 (282)
1739
44.1 (422)
1398
Urban villages
31.0 (228)
1901
25.9 (248)
948
Rural villages
30.6 (225)
2478
29.9 (286)
1441
Marital status
Never married
47.8 (351)
3866
53.7 (513)
2306
Married
24.4 (179)
874
21.9 (209)
635
Cohabiting
23.4 (172)
1251
22.2 (212)
787
Once married
4.5 (33)
127
2.3 (22)
59
Religion
Christian
64.4 (426)
3686
81.4 (778)
3089
Other non-Christian
35.6 (236)
2031
18.6 (178)
698
Total
12.5 (785)
25.2 (956)
Table 1.
Characteristics of circumcised men aged 10–64 years in Botswana (2008 and 2013).
Majority of men indicated that they were circumcised later in life for both surveys (56.1% in 2008 and 52.7% in 2013). However, the proportion of men who were circumcised in later life was highest in 2008. As for the place of circumcision, a high proportion of men reported that they were circumcised in a health facility, and this was high in 2013 (78.8%) than in 2008 (69%). Under one-tenth of men (9.3% in 2008 and 7.1% in 2013) reported that they experienced some complications during circumcision. The proportion of men who expressed willingness to be circumcised in was highest in 2008 (58.6%) than in 2013 (49.5%) (Table 2).
Variable
2008 BAIS III
2013 BAIS IV
%
N
%
N
Time of circumcision?
At birth
40.3
299
38.1
331
Later in life
56.1
416
52.7
537
Do not know
3.6
27
9.2
88
Place of circumcision?
Health facility
69
511
78.8
753
Traditional
21.9
162
16.2
155
Do not know
9.1
68
5
48
Experienced complications?
Yes
9.3
69
7.1
68
No
76.1
564
80.9
773
Do not know
14.6
108
12
115
Willingness to be circumcised in the next 12 months?
Yes
58.6
3694
49.5
1270
No
41.4
2608
50.5
1295
Table 2.
Selected key safe male circumcision variables.
4.2 Determinants of safe male circumcision in Botswana
Results in Table 3 present the adjusted odd ratios for the association between safe male circumcision and sociodemographic factors in 2008 and 2013. Age was observed to be a significant correlate of male circumcision in both 2008 and 2013. The odds of safe male circumcision increased with age for both survey periods, with men aged 55–64 years three times (APR = 3.40, CI = 2.00–5.76 in 2008 and APR = 3.63, CI = 2.36–5.57 in 2013) more likely to have been circumcised than men aged 10–24 years. Considering education level, men with primary or less and secondary education were less likely to have been circumcised than men with tertiary or higher education level for both survey periods.
Variable
2008
2013
Adjusted PR
95% CI
Adjusted PR
95% CI
Age
10–24
1.00
1.00
25–34
1.76
(1.35–2.30)
1.36
(1.09–1.69)
35–44
2.43
(1.73–3.41)
1.76
(1.35–2.29)
45–54
2.54
(1.65–3.91)
2.41
(1.72–3.38)
55–64
3.40
(2.00–5.76)
3.63
(2.36–5.57)
Education
Primary/less
0.32
(0.22–0.46)
0.36
(0.28–0.47)
Secondary
0.72
(0.57–0.91)
0.67
(0.55–0.82)
Tertiary/higher
1.00
1.00
Residence
Cities and towns
1.00
1.00
Urban villages
0.79
(0.63–1.00)
0.90
(0.74–1.10)
Rural villages
0.70
(0.54–0.89)
0.71
(0.58–0.86)
Marital status
Never married
0.43
(0.24–0.76)
1.10
(0.55–2.18)
Married
0.68
(0.39–1.18)
0.93
(0.47–1.82)
Cohabiting
0.45
(0.26–0.80)
1.05
(0.53–2.08)
Once married
1.00
1.00
Religion
Christian
0.81
(0.66–1.00)
0.95
(0.77–1.18)
Other non-Christian
1.00
1.00
Table 3.
Adjusted prevalence ratios for the association between safe male circumcision and sociodemographic factors (2008 and 2013).
Men in rural villages were less likely to have been circumcised than men who resided in cities and towns in 2008 (APR = 0.70, CI = 0.54–0.89) and 2013 (APR = 0.71, CI = 0.58–0.86). On the other hand, there were no significant variations observed for circumcision and residing in urban villages. The odds of circumcision were significantly low among never married (APR = 0.43, CI = 0.24–0.76) and cohabiting (APR = 0.45, CI = 0.26–0.80) men than once-married men in 2008, while for married men there was no significant variation. In 2013, the odds of circumcision were significantly low among married (APR = 0.93, CI = 0.47–1.82) than once-married men, while no significant association was found for cohabiting and never married men. When considering religious affiliation, there was no variation on whether a man was from a Christian or any other religious background and circumcision.
5. Discussion
Due to high HIV prevalence and incidence rates, inadequacy of the response programs such as PMTCT program, BCIC programs, HIV testing and counseling, blood safety program, and STI management and control gave way to safe male circumcision program. The SMC program was seen as essential in adding to the existing strategies in preventing the spread of HIV infection [17]. The combination of research findings in South Africa, Kenya, and Uganda and the WHO/UNAIDS recommendations that male circumcision is efficacious in reducing HIV infection prompted the government of Botswana to scale up this component of HIV prevention and develop national policies, strategies, and implementation plans. Although Botswana is not a traditionally circumcising society, evidence from this study indicates that male circumcision is highly acceptable in Botswana, corroborating the initial evidence [3, 5].
Majority of men who participated in the 2008 and 2013 surveys indicated that they were circumcised later in life and that they were circumcised in a health facility. A relatively low proportion of men reported that they experienced some complications during the procedure. This corroborates findings from other studies which show that when circumcision is done within hygienic clinical settings, there are minor chances of complications [1]. Common complications associated with circumcision in such settings include excessive loss of foreskin, skin bridges, amputation of the glans penis, and buried penis.
Evidence from this chapter indicates that between 2008 and 2013, the period before and after the implementation of the safe male circumcision program, the proportion of men who circumcised doubled. Although the program has not met its target [5], substantial gains have been made in getting high numbers of men to undergo circumcision. The scale-up of safe male circumcision program has benefited immensely from external funding which has supported biomedical marketing in the media including, billboard, radio, and TV advertising. Moreover, a renowned afro-pop artist was contracted as the campaign ambassador during the program in order to attract more men [5]. Additionally, specialized clinics have been set up in selected areas in addition to general public health facilities where SMC is conducted in hygienic, clinical conditions by medical practitioners [5].
On the other hand, the proportion of men who expressed willingness to undergo safe male circumcision had declined by about 10% in 2013. A plausible explanation for this decline is linked to several reasons. First, a review study on the SMC program by Katisi et al. [5] indicates that during the implementation of the program, cultural taboos such as the breaching of secrecy of the circumcision act by inclusion of women in performing circumcision procedure were introduced. Second, there are views that the traditional leadership has been left during the implementation of the program [3]. Lastly, elements of the minimum package for SMC that include counseling and voluntary HIV testing were repeatedly mentioned as other barriers that blocked men from circumcising [5]. HIV testing, in particular, seems to scare men away even if they would opt for circumcision.
Age was a significant predictor of male circumcision. For example, circumcision was found to increase with age, with highest proportions of circumcised men found in ages 55–64 years and lowest in ages 10–24 years. Similar observations were made in Uganda, where it was found that more than half of elderly men indicated that they have been circumcised compared to two-fifths of youth [30]. Although circumcision levels are lowest among young adolescents in Botswana, a study by Lane et al. [31] has shown that at the country level, deliberately prioritizing young adolescents is likely to achieve national coverage targets more quickly and cost-effectively than continuing to focus on older, harder-to-reach men. In Botswana, prioritization of younger men is critical to VMMC sustainability. As a result there is the school-going children circumcision initiative, whereby young boys are targeted to undergo circumcision through parental involvement. In this approach young boys consent to undergo circumcision through the involvement of parents. However, the decision to circumcise or not to circumcise lies with the children.
Considering education level, men with primary or less and secondary education were less likely to have been circumcised than men with tertiary or higher education level for both survey periods. This corroborates findings from other studies that men with high education and socioeconomic status have the propensity to undergo safe male circumcision compared to men with low education and poor socioeconomic status [32, 33, 34]. Educational attainment predisposes individuals to appreciate health programs better [35]. This is because men who have high education have better perception of the risk of HIV infection than men with low education. Consequently, there is need for more education and information for men with low education to take part in circumcision.
Men in rural villages were less likely to have been circumcised than men who resided in cities and towns in 2008. A plausible explanation for this scenario is that in 2008, the safe male program was not yet rolled out in the country. Moreover, men in rural areas are prone to lack of access to information and education. The odds of circumcision were significantly low among never married and cohabiting men than once-married men in 2008. This corroborates findings of a study by Mangombe and Kalule-Sabiti [36] which also found that in Zimbabwe never married and cohabiting men were less likely to circumcise. The main reason being that this cohort of men assumes that they at low risk of HIV infection. Meanwhile, other studies show the contrary that married men are at risk of infection compared to never married and cohabiting men [37].
In 2013, the odds of circumcision were significantly low among married than once-married men. Low prevalence of circumcision among married men can also be attributed to low risk of infection, especially where marital fidelity is practiced. There was no variation on whether a man was from a Christian or any other religious background and circumcision. Findings of the association between religion and circumcision are at best mixed. In some contexts, religion is a key predictor of circumcision among men [38], while in other contexts, as is the case in Botswana, it is not [39].
6. Conclusion
Safe male circumcision is as an effective additional strategy for HIV prevention. The medical benefits of SMC outweigh the risks. Age, education, residence, and marital status are significant determinants of male circumcision in Botswana. Consequently, more efforts should be geared toward educating men, especially those residing in rural areas and those in cohabiting relationships about the benefits of circumcision. Moreover, women need to be involved in understanding the benefits of male circumcision to ensure effectiveness of the SMC program.
\n',keywords:"voluntary, safe male circumcision, HIV/AIDS, prevention, Botswana",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/70967.pdf",chapterXML:"https://mts.intechopen.com/source/xml/70967.xml",downloadPdfUrl:"/chapter/pdf-download/70967",previewPdfUrl:"/chapter/pdf-preview/70967",totalDownloads:191,totalViews:0,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,dateSubmitted:"September 3rd 2019",dateReviewed:"December 19th 2019",datePrePublished:"May 7th 2020",datePublished:"May 20th 2020",dateFinished:null,readingETA:"0",abstract:"The safe male circumcision program has been running for about 10 years now, in Botswana. This chapter uses data derived from the two Botswana AIDS Impact Surveys (BAIS III and IV) conducted in 2008 and 2013, the period before and after the implementation of the SMC program to assess the background, patterns, and correlates of safe male circumcision. Data were analyzed using multivariate logistic regression models. Overall, 785 (12.5%) and 956 (25.2%) men reported to have been circumcised in 2008 and 2013, respectively. Elderly men aged 55–64 years were more likely to have been circumcised than men aged 10–24 years (APR = 3.40, CI = 2.00–5.76 in 2008 and APR = 3.63, CI = 2.36–5.57 in 2013). Men with primary or low and secondary education and those who reside in rural villages (APR = 0.70, CI = 0.54–0.89 in 2008; APR = 0.71, CI = 0.58–0.86 in 2013) were less likely to have been circumcised compared to men who resided in cities and towns. The odds of circumcision were also significantly low among never married (APR = 0.43, CI = 0.24–0.76) and cohabiting (APR = 0.45, CI = 0.26–0.80) men than once-married men in 2008. In 2013, the odds of circumcision were significantly low among married men (APR = 0.93, CI = 0.47–1.82). Understanding the background, patterns, and correlates of safe male circumcision is essential for programming and assessment of the effectiveness of the program.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/70967",risUrl:"/chapter/ris/70967",book:{slug:"circumcision-and-the-community"},signatures:"Mpho Keetile",authors:[{id:"237985",title:"Ph.D.",name:"Mpho",middleName:null,surname:"Keetile",fullName:"Mpho Keetile",slug:"mpho-keetile",email:"mphokeet@yahoo.com",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Background",level:"1"},{id:"sec_2",title:"2. Theoretical framework",level:"1"},{id:"sec_3",title:"3. Methodology",level:"1"},{id:"sec_3_2",title:"3.1 Data",level:"2"},{id:"sec_4_2",title:"3.2 Response variable",level:"2"},{id:"sec_5_2",title:"3.3 Explanatory variables",level:"2"},{id:"sec_6_2",title:"3.4 Statistical analysis",level:"2"},{id:"sec_8",title:"4. Results",level:"1"},{id:"sec_8_2",title:"4.1 Patterns of safe male circumcision in Botswana (2008–2013)",level:"2"},{id:"sec_9_2",title:"4.2 Determinants of safe male circumcision in Botswana",level:"2"},{id:"sec_11",title:"5. Discussion",level:"1"},{id:"sec_12",title:"6. Conclusion",level:"1"}],chapterReferences:[{id:"B1",body:'Lawal TA, Olapade-Olaopa EO. Circumcision and its effects in Africa. Translational Andrology and Urology. 2017;6(2):149-157. DOI: 10.21037/tau.2016.12.02'},{id:"B2",body:'Sovran S. Understanding culture and HIV/AIDS in sub-Saharan Africa. SAHARA-J: Journal of Social Aspects of HIV/AIDS Research Alliance. 2013;10(1):32-41. DOI: 10.1080/17290376.2013.807071'},{id:"B3",body:'Sabone M, Magowe M, Busang L, Moalosi J, Binagwa B, Mwambona J. Impediments for the uptake of the Botswana Government’s male circumcision initiative for HIV prevention. The Scientific World Journal. 2013:1-7. DOI: 10.1155/2013/38750'},{id:"B4",body:'Katide G. 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Attitudes, beliefs and predictors of male circumcision promotion among medical university students in a traditionally non-circumcising region. International Journal of Environmental Research and Public Health. 2017;14(10):1097. DOI: 10.3390/ijerph14101097'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Mpho Keetile",address:"mphokeet@yahoo.com",affiliation:'
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Clinton Weeb",slug:"r.-clinton-weeb"},{id:"134107",title:"Dr.",name:"Trevor",middleName:null,surname:"Hardigan",fullName:"Trevor Hardigan",slug:"trevor-hardigan"}]},{id:"30225",title:"The Assessment of Atherosclerosis in Erectile Dysfunction Subjects Using Photoplethysmography",slug:"the-assessment-of-atherosclerosis-in-erectile-dysfunction-subjects-using-photoplethysmography",signatures:"Yousef Kamel Qawqzeh, Mamun Ibne Reaz and Mohd Aluadin Mohd Ali",authors:[{id:"30522",title:"Prof.",name:"Mohd Alauddin",middleName:null,surname:"Mohd Ali",fullName:"Mohd Alauddin Mohd Ali",slug:"mohd-alauddin-mohd-ali"},{id:"80493",title:"Dr.",name:"Yousef",middleName:"Kamel",surname:"Qawqzeh",fullName:"Yousef Qawqzeh",slug:"yousef-qawqzeh"},{id:"129681",title:"Dr.",name:"Mamun Bin Ibne",middleName:null,surname:"Reaz",fullName:"Mamun Bin Ibne Reaz",slug:"mamun-bin-ibne-reaz"},{id:"129683",title:"Prof.",name:"Oteh",middleName:null,surname:"Maskon",fullName:"Oteh Maskon",slug:"oteh-maskon"}]}]}]},onlineFirst:{chapter:{type:"chapter",id:"59246",title:"Autoantibodies: Key Mediators of Autoimmune Infertility",doi:"10.5772/intechopen.73899",slug:"autoantibodies-key-mediators-of-autoimmune-infertility",body:'\n
\n
1. Introduction
\n
As per immunculus concept, natural antibodies (NAbs) are formed in response to gut microflora and environment in addition to self-antigens through feedback network to maintain homeostasis [1, 2, 3] bridging innate and adaptive immune response. Thus, any chronic inflammation combined with compromised central tolerance can culminate into autoimmune disease [4]. However, autoimmune diseases have gender bias with prevalence in females owing to ‘autoimmune X chromosome’ and autoimmune infertility (AI) is no exception [5]. Concomitantly, reproductive autoimmune failure could result from an activated immune system or by anti-ovarian antibodies (AOA) alone as described in endometriosis patients [6]. Other reproductive disorders such as POI, polycystic ovary syndrome (PCOS), unexplained infertility, and repeatedly unsuccessful IVF attempts may be responsible for the pathophysiology of preeclampsia or spontaneous abortions and may also have presence of multiple autoantibodies (AAbs) [7, 8, 9, 10, 11].
\n
Immune dysregulation is the cause of unexplained or idiopathic infertility in 20–30% of infertile couples [12]. AI is diagnosed when spontaneously synthesized antibodies bind or react with sperm/oocyte to prevent any one or several events: fertilization, acrosome reaction, capacitation or embryo implantation. Despite much research into organ specific biomarkers, no specific and sensitive biomarkers have been identified making detection of AI elusive. Organ-specific autoimmune disease gets treated using established protocols without sufficient consideration for fertility of women. Detection of AAbs mandates management of endometriosis, POI and other idiopathic infertility as an autoimmune disease with the treatment having adverse effects. This chapter will focus on AI, briefly in males but mainly in females, to include:
autoantigenic targets identified in female infertility with special emphasis on endometriosis and POI,
current understanding of effect of autoantibodies using animal models of disease,
including (AAbs) as diagnostic tools: current practices and
future research.
\n
\n
\n
2. Male autoimmune infertility: anti-sperm antibodies (ASA)
\n
Sperm are specialized haploid cells with autoantigenic and isoantigenic potential. Thus, ASA can be present in blood, semen, follicular fluid and cervicovaginal secretions affecting sperm movement, capacitation, fertilization and embryo implantation [13, 14]. ASA are far more frequent than oocyte antibodies.
\n
In testis, the Sertoli cells through tight junctions form the impervious blood-testis barrier of two compartments: basal and adluminal. Basal compartment, which houses spermatogonia and young spermatocytes, is connected to vasculature through phagocytic Sertoli cells, which in turn act as antigen presenting cells to induce tolerance. The adluminal surface housing sperm undergoing meiosis and spermiogenesis is segregated from vasculature. Thus leakage of autoantigens from basal compartment can potentially generate ASAs. However, the exact mechanism of ASA generation is still unclear [13]. In some cases, Human Leucocyte Antigen system is associated with ASA and AI [15]. In 0.9–4% of normal fertile adult males as well as pre-pubertal boys, ASA are found in blood serum, seminal plasma, or directly attached to sperm surface indicating these to be NAbs generating confusion on their role in human infertility [16, 17].
\n
Very few ASA are sperm specific [18] and never directed to multiple organs (except in animals). These can appear more frequently due to testicular failures: cryptorchidism, undescended testes, mobile testes and orchitis (especially due to infectious diseases such as mumps). Additionally, varicocele increases the risk of ASA production by two-fold [19]. The reduced testosterone levels due to altered Leydig cell function in undescended testes could theoretically result in reduced T regulatory cells and compromised central tolerance, however, exact mechanism is unclear. Elevated ASA could lead to low sperm count or low progressive motility. Hence, surgery at an early age, followed by steroid therapy to suppress immune reaction is recommended to prevent future infertility in cases with testicular failure.
\n
ASA could be against carbohydrate moieties and sperm antigens example integral membrane proteins (exposed due to undescended testes) mainly through molecular mimicry. Natural ASA are reported in rodents due to sperm antigenic ‘leak’ to ensure immune tolerance. ASA are generally associated with genital tract infections. Vasectomy induces AAbs to antigens of mature human sperm [20, 21] with HLABw22 and A28 having increased predisposition post vasectomy [22]. Incidence reported is 61% pre- and 73–80% post-vasectomy. Antigens could be of either testicular or epididymal origin (epididymal maturation) with Abs directed to acrosome, equatorial and postacrosomal regions, tail midpiece and sperm nucleus. This could be due to sperm leakage in either the vas or cauda epididymis [21]. AutoAbs to FA-1 antigen (44%) and protamine (28%) seen post vasectomy in sera (none in seminal plasma) with prevalence of reduced fertilization rate in vitro. These were either of IgG, M or A subclass [23]. Post vasectomy ASA are seen only in serum while in seminal plasma and ejaculate post vasovasostomy. Fertile men with no ASA before vasovasostomy will show ASA that can affect sperm count [24, 25]. Further, there is no overlap of ASA between infertile men, post vasectomy [26] and post vasovasostomy. However, there are conflicting reports on their influence on pregnancy rate [27, 28]. Table 1 enlists ASA in men with autoimmune infertility.
\n
\n
\n
\n
\n
\n\n
\n
Autoantigen
\n
Body fluid compartment
\n
Function
\n
Reference
\n
\n\n\n
\n
Nuclear autoantigenic sperm protein (NASP) histone binding
List of autoantigens in men with autoimmune infertility.
\n
High titers of IgA-ASA found in seminal plasma of infertile men bind sperm head and impair fertilizing ability, the IgG elicit opsonization, and IgM from vaginal washings of vaginitis cases reduce fertilization by 44% [13]. ASAs directed to surface antigens are clinically relevant since they affect semen quality (not morphology or count) by any one of: premature acrosome reaction making the sperm moribund, sperm agglutination leading to impairment in cervical mucus penetration, opsonization through female genital tract via complement pathway.
\n
ASA may aid sperm capacitation with no adverse effects on sperm-oocyte fusion. However, ASA binding outer acrosomal membrane proteins are washed away during procedure and do not affect IVF-intracytoplasmic sperm injection (IVF-ICSI) outcomes unlike those in females which are reported to reduce cleavage rate [47, 48, 49], with multiple autoantigenic targets necessary for AI [50].
\n
Typically in women, the mucosal immunity protects entire reproductive tract up to Fallopian tubes against incoming sperm or any microbes. Thus vaginal and cervical secretions may contain ASA due to multiple semen exposures causing autoantigenicity to seminal fluid proteins. In rare cases of Human Seminal Plasma Allergy, first exposure can elicit antibodies [51] though it is not always associated with infertility [52, 53].
\n
ASA in females are of IgG, IgA and IgE subtypes in blood, lymph and cervical-vaginal mucus [50]. IgA antibodies in the cervical secretions can bind and agglutinate sperm with eventual clearance by circulating macrophages while the predominant IgG [54] can lead to opsonization and local clearance of antibody-antigen complexes. The uterus and Fallopian tubes are also protected by circulating macrophages and NK cells that clear the incoming sperm. Thus sperm coated with IgA-ASA are unaffected unlike those by IgG which are opsonized and cleared via macrophages. Both subtypes in the mucus individually affect fertilization alone while a combination significantly affects fertilization rate [55, 56, 57, 58].
\n
IgA alloantibodies to FSH are seen in some normal fertile women and can be produced during tolerance to partner antigens (sperm proteins and shared maternal antigens) through semen [59, 60]. Patients with increased intestinal permeability in bowel inflammatory disease show higher production of ASA through molecular mimicry or epitope sharing between intestinal microbes and spermatozoa [61]. An upregulated normal mucosal immune response could lead to the elevated levels of anti-FSH IgA antibodies in IVF patients. Another possible explanation could be a deficit in producing antibodies that neutralize anti-FSH immunoglobulins, which has been noted in patients who produce ASA [62]. These results together suggest that the elevated values of anti-FSH IgA in IVF patients could represent a failure in mucosal tolerance in the genital tract, which could be genetically determined [12] (Table 2). Enlists ASA detected in sera of women.
List of autoantigenic targets against sera of women with ASA.
\n
\n
2.1. Diagnostic approaches and treatment modalities for couples with ASA
\n
Presence of ASA in serum of seminal fluid binding to sperm outer membrane antigens and thereby altering fertilization rate are relevant, is inversely correlated with pregnancy and not a good indicator of pregnancy outcome. Testing for ASA is indicated for men with genitourinary infections (e.g., Chlamydia) or acquired genital tract obstructions. Nevertheless, these ASA may not always hinder pregnancy.
\n
Sexually active homosexual individuals who have also undergone pelvic surgery should be advised to test for ASA [69]. Routine semen samples can be tested for sperm bound antibodies by IgG-mixed antiglobulin reaction (IgG-MAR [70]), immunobead test (IBT) [71] or sperm-MAR test [72]. However, none of the available diagnostic tests quantitate, are neither effective nor specific [73, 74]. Hence, instead of ineffective generalized immunosuppressive therapy IVF-ICSI should be considered [75, 76, 77, 78, 79].
\n
Post vasovasostomy couples are advised IVF for pregnancy depending on body mass index and age which affect serum testosterone levels as well as ASA in men. In these cases, IVF may be beneficial only after testing for hypogonadism and serum testosterone levels [80]. ASA post vasovasostomy can cause necrospermia and deteriorate sperm count hence IVF-ICSI using testicular sperm is an option [81].
\n
\n
\n
\n
3. Female autoimmune infertility
\n
Women are prone to autoimmune diseases due to hormonally dictated cytokine and chemokine milieu [82] often leading to other autoimmune dysfunctions [83] including reproductive autoimmune failure. Gleicher and co-workers [6] postulated that endometriosis could be an autoimmune disease and studies from our lab show 30% prevalence [84]. Commonly seen serum AAbs are anti-phospholipid, anti-nuclear, anti-thyroid, anti-annexin V, anti-prothrombin, anti-laminin, anti-ZP (Table 3 for entire list), with the high level of NK cells as the risk factors but not as those pathognomonic [85]. However, none of the AAb biomarkers tested were effective [86]. A recent study reported better sensitivity of 6 new biomarkers [87]. With detection of AAbs to steroid producing cells and thyroglobulin in cases with concomitant adrenal or thyroid disease in PCOS, it is now considered an autoimmune disease. However, anti-ovarian antibodies were reported in only one study [7, 88] with no clarity on their role in PCOS pathogenesis [89]. Organ-specific AAbs such as ovary, adrenal and thyroid (endocrine autoimmune) disease are reported to cause infertility due to premature ovarian insufficiency (POI) [90].
List of autoantigenic targets against sera of women with reproductive infertility.
\n
Both PCOS and endometriosis are also causative factors of POI. 40–60% women with endometriosis possess anti-ovarian Abs in addition to anti-endometrial Abs [103]. Several AAbs to non-organ specific targets are seen in women with unexplained infertility [104]. Further, 22% of patients with SLE show anti-corpus luteum antibodies and elevated FSH levels typical of POI [57] and 60% POI cases are of autoimmune origin [105, 106]. POI is typically detected late with both non-organ and organ-specific antibodies in conjunction with an autoimmune disease thus evading a specific and accurate biomarker for diagnosis and prognosis [107, 108]. Whether AAbs are causative of or a by-product of underlying disease is unclear.
\n
Nevertheless, elaborate animal models of the disease as well as case studies have provided relevant data. Day three neonatal thymectomy mouse model showed that multi-organ autoimmune disease prevails. Immunization with a single antigen causes oophoritis alone while those to multiple antigens completely compromises ovarian function. Additionally, concomitant presence of the autoantigens was mandatory [109].
\n
Efforts to identify target autoantigens based on discovery of an ovary specific autoantigen by ELISA, immunofluorescence or immunohistochemistry approach were unfruitful. This interference was due to non-specific reactivity of natural albumin antibodies [110]. Attempts to identify target autoantigens using sera and proteomics approach were fruitful enough to identify several somatic proteins: alpha actin, alpha actinin-4, heat shock proteins 70 and 90β in 30% of POI and 26% of IVF-ET failure cases [100, 111, 112]. Of these, 47% cases showed presence of AAbs to HSP90β. Reactivity of these antibodies was seen against several follicular components (Table 4). Note, besides oocyte the corpus luteum seems to be a major cellular target while HSP90β the molecular target contributing to early POI (bold and italics in Table 4) [111]. AAbs to MATER led to assuming it to be an ovary specific target [113] however, these AAbs were also seen in idiopathic hypoparathyroidism cases only in context of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome [114].
\n
\n
\n
\n
\n
\n\n
\n
Condition
\n
Age at detection
\n
Cellular target
\n
Molecular target
\n
\n\n\n
\n
POI
\n
22
\n
Oocyte, theca, corpus luteum
\n
90
\n
\n
\n
33
\n
Oocyte, corpus luteum
\n
30
\n
\n
\n
38
\n
45, 90
\n
\n
\n
24
\n
90, 97
\n
\n
\n
33
\n
Oocyte, theca, corpus luteum
\n
97
\n
\n
\n
90
\n
\n
\n
39
\n
Oocyte, theca
\n
\n
\n
33
\n
Theca
\n
120
\n
\n
\n
38
\n
Oocyte
\n
90
\n
\n
\n
33
\n
Ooplasm and nucleus of oocyte, theca
\n
\n
\n
35
\n
Oocyte
\n
55
\n
\n
\n
36
\n
97
\n
\n
\n
35
\n
Oocyte of primordial follicle
\n
70, 75
\n
\n
\n
32
\n
Oocyte
\n
70
\n
\n
\n
35
\n
Granulosa, corpus luteum
\n
30, 45
\n
\n
\n
IVF-ET
\n
29
\n
Oocyte, corpus luteum
\n
97
\n
\n
\n
28
\n
120
\n
\n
\n
39
\n
30, 90
\n
\n
\n
32
\n
Oocyte
\n
120
\n
\n
\n
34
\n
50, 75, 90
\n
\n
\n
30
\n
Oocyte, granulosa
\n
80, 97
\n
\n
\n
28
\n
Oocyte
\n
120
\n
\n
\n
31
\n
Theca
\n
45, 97
\n
\n
\n
29
\n
Oocyte
\n
90, 120
\n
\n
\n
32
\n
30, 50, 90
\n
\n
\n
90
\n
\n
\n
33
\n
Oocyte
\n
90, 97
\n
\n
\n
30
\n
Zona pellucida
\n
45
\n
\n\n
Table 4.
List of antigens and cellular targets detected using sera of women with premature ovarian insufficiency (POI) and in vitro fertilization-embryo transfer (IVF-ET); compiled from [97].
\n
Though a 75–90% accuracy was observed in ELISA assays using immunodominant epitopes from the identified targets, the AAbs were also present in normal population, highlighting the fact that these were NAbs. These were also validated to induce aPOI in a mouse model. The immunodominant epitopes tested were able to induce POI and alter ovarian cytoarchitecture. Folliculogenesis was severely affected at each developmental stage with gross lack of mature Graafian follicles and a persistent corpus luteum [101].
\n
AAbs to a single immunodominant epitope (EP6) HSP90β led to 9% dissociated oocyte-cumulus complexes, granulosa cells undergoing apoptosis, 48% empty follicles, and 12% degenerated follicles. These animals demonstrated significant pre- and post-implantation loss with concomitant decrease in fertility index along with an increased polymorphonuclear cell infiltration of the ovarian follicles. The infiltration may have contributed to generation of antibodies against the EP6 peptide [115, 116].
\n
In normal physiological inflammatory processes like ovulation, follicular atresia, corpus luteum regression and tissue remodeling, the ovarian leukocytes like T cells and macrophages play an important role [117, 118]. Interestingly, NAbs especially, IgM play a role in clearing apoptotic cells, maintaining B cell homeostasis, inflammation, atherosclerosis and autoimmunity. Any drop in IgM levels is associated with ineffective clearance of apoptotic cells culminating into autoimmune disease. Alternatively, strong and persistent recognition of apoptotic cells by such NAbs may overactivate the immune system and cause chronic inflammation [3]. Corticosteroid treatment resolves the ensuing infertility [119]. However, there are no randomized controlled trials (RCT) to date. Our animal studies showed high dose corticosteroid was better able to rescue fertility in mice immunized with immunodominant epitopes of HSPA5 (Table 5). An interesting finding was the epitope spreading observed: AAbs to HSPA5 cross-react with immunodominant epitope (EP6) of HSP90β at high titer [120]. Thus, autoreactivity to HSP90β could have diagnostic and prognostic value.
\n
\n
\n
\n
\n
\n
\n
\n
\n\n
\n
AutoAb target
\n
Cellular target
\n
Effect on estrus cycle
\n
Delay in vaginal plug
\n
Preimplantation loss
\n
Fertility reduction
\n
Effect of corticosteroid treatment
\n
\n\n\n
\n
Alpha actinin-4
\n
Ooplasm, theca and corpus luteum
\n
Not determined
\n
30%
\n
24%
\n
32%
\n
44%
\n
\n
\n
HSPA5
\n
Ooplasm, granulosa, theca and corpus luteum
\n
–
\n
44%
\n
\n
\n
Alpha actin
\n
Ooplasm, granulosa and theca,
\n
30%
\n
36.4%
\n
\n
\n
HSP90-beta (EP6)
\n
Granulosa cells, developing embryo
\n
Not significant
\n
Not determined
\n
\n
\n
\n
\n
\n
MATER/NALP5 (parathyroid autoantigen)
\n
oocytes of later-stage small follicles
\n
Not determined
\n
\n
\n
\n
\n\n
Table 5.
Effect of autoantibodies on fertility and extent of rescue with corticosteroid therapy.
\n
Thyroid autoimmunity is commonly found with other systemic autoimmune diseases [121, 122] and is associated with anti-phospholipid syndrome (APS) due to anti-phospholipid antibodies [123] which in turn mediate recurrent miscarriages common to APS [124]. Thus women with thyroid autoimmunity and APS have greater risk of recurrent miscarriages mandating screening for anti-phospholipid antibodies. AAbs to ANA (12%), ANCA (20%), AECA (24%), ACLA (8%), anti-dsDNA (0%), β2 microglobulin (14%), and anti-HLA antibodies (10%) have been reported among Indian RSA patients [125]. This indicates that women with thyroiditis, endometriosis, SLE, APS also run the risk of repeated miscarriages.
\n
At least 20–30% of POI cases have an additional autoimmune disorder [126] including several endocrinopathies, thyroid diseases, Addison’s disease, rheumatoid arthritis and polyglandular syndrome with greater prevalence of thyroid autoimmunity (14–27% at initial diagnosis) and thyroid peroxidase AAbs [127, 128]. At least 10% women with Addison’s disease manifest AAbs to 21- or 17-hydroxylase and autoimmune oophoritis [129]. Thyroid peroxidase antibodies (TPO Abs) are also prevalent in PCOS cases. Thus, these along with HSP90β could be included in an antibody detection panel.
\n
In women with endometriosis, use of biomarkers including CA-125 for diagnosis of endometriosis was prohibited [130, 131]. However as per recent guidelines, use of biomarkers has been recommended for both diagnosis and disease monitoring [132] and is still a researchable area. Anti-endometrial antibodies exist but their sensitivity and accuracy varies from 0 to 100% [131, 133, 134].
\n
\n
3.1. Treatment modalities and management of autoimmune infertility
\n
Endometriosis management guidelines are valid for women with mild to moderate disease and do not recommend hormonal therapy for managing ovulation to improve fertility rate [135]. Despite reduction in ovarian function, one time laparoscopic operation to remove endometriosis and improve pregnancy rates is often recommended [136, 137]. Adjunctive hormonal therapy is prohibited pre- or post-surgery to improve pregnancy rates [138]. Intra uterine insemination along with controlled ovarian stimulation is recommended 6 months post-surgery since it shows similar pregnancy rates as that of women with unexplained infertility [139]. ART can also be recommended especially in cases of tubal factor or male factor infertility as controlled ovarian stimulation does not increase chances of recurrence of endometriosis after IVF/ICSI [140, 141, 142, 143] however, it may not always be effective [144, 145].
\n
POI seems to be an end-stage disease in women with an autoimmune disorder since it is detected at a late stage when the ovary has been substantially ravaged with little scope for fertility management. Thus treatment options for fertility management of women with POI are limited. Counseling for early marriage and pregnancy to complete the family is applicable only in case of early diagnosis or known familial origin. Other options include egg donation and IVF-ICSI or surrogacy. The women are administered corticosteroids in case of known autoimmune disease diagnosis and advised IVF-ICSI when AAb titers fall. However, this is not an option since it entails risk of osteoporosis and iatrogenic Cushing’s syndrome [119]. In most cases, adoption is the only option along with psychological counseling and cardiovascular and bone health management of hypoestrogenism effects [146].
\n
Additionally, there should be efforts to increase awareness among reproductive endocrinologists to recommend testing for undiagnosed autoimmune disease to couples on a case basis before embarking on ART-IVF [147].
\n
\n
\n
\n
4. Future research
\n
Presence of AAbs is hallmark of autoimmune disease with no clarity on their role in disease pathogenesis and ensuing AI. With few exceptions these are not organ-specific indicating them to be NAbs [148, 149, 150, 151]. Obtaining clarity on role of AAbs will guide further treatment modalities for patients with AI [93, 101, 152]. Global high dose immunosuppressive therapy seems to be the only effective option for autoimmune reproductive failure despite its shortcomings [153, 154].
\n
Targeted interventional therapy by inducing antigen-specific tolerance is another option [155, 156]. Till such a time as a definitive therapy is available, pan autoimmune disease diagnostic panels can be designed using autoantigenic targets (recombinant proteins or peptides) such as β2-glycoprotein I and HSP90β (EP6) [151, 157, 158, 159] followed by management with corticosteroid therapy. A loss of reactivity to key autoantigens (predetermined to affect ovarian function) would serve as biomarkers to better manage immunosuppressant therapy.
\n
\n
\n
5. Conclusion
\n
The very lack of any organ-specific biomarker till date along with the preponderance of NAbs indicates that warped self-tolerance would lead to AI. AAbs in females alone appear to be significant in AI. Fertility studies need to be undertaken to gauge effect of such AAbs identified thus far and immunodominant epitopes gleaned could prove useful to design a pan autoimmune disease diagnostic peptide array to manage AI. Global immunosuppressant therapy and IVF-ICSI are the only current hope for such couples.
\n
\n
Acknowledgments
\n
The work was co-funded by Indian Council of Medical Research and Dept. of Biotechnology, Govt. of India.
\n
Conflict of interest
None.
\n',keywords:"autoantibodies, premature ovarian insufficiency, endometriosis, autoimmune infertility",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/59246.pdf",chapterXML:"https://mts.intechopen.com/source/xml/59246.xml",downloadPdfUrl:"/chapter/pdf-download/59246",previewPdfUrl:"/chapter/pdf-preview/59246",totalDownloads:599,totalViews:316,totalCrossrefCites:0,dateSubmitted:"July 13th 2017",dateReviewed:"January 12th 2018",datePrePublished:"March 2nd 2018",datePublished:null,dateFinished:null,readingETA:"0",abstract:"Autoimmune diseases have gender bias with predominance in females, autoimmune infertility (AI) being no exception. This chapter will focus on AI in females with brief reference to the same in males. Autoimmune diseases have established protocols for detection and management of ensuing infertility, however similar protocols for unexplained infertility [tubal blockage, endometriosis, premature ovarian insufficiency (POI), undiagnosed underlying autoimmune disease (Sjögren’s syndrome, IBS, celiac disease) and tubal blockage] are not established. Endometriosis and POI, in particular, have autoimmune etiology yet lack specific and sensitive biomarkers for accurate diagnosis. If autoantibodies are indeed diagnosed, then treatment regimen focuses on AI which has known adverse effects. The detection of natural antibodies as autoantibodies presents a viable alternative to organ specific biomarker panel for better management of AI.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/59246",risUrl:"/chapter/ris/59246",signatures:"Kaushiki M. Kadam, Purvi Mande and Asmita Choudhury",book:{id:"6243",title:"Autoantibodies and Cytokines",subtitle:null,fullTitle:"Autoantibodies and Cytokines",slug:"autoantibodies-and-cytokines",publishedDate:"April 24th 2019",bookSignature:"Wahid Ali Khan",coverURL:"https://cdn.intechopen.com/books/images_new/6243.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"64042",title:"Dr.",name:"Wahid Ali",middleName:null,surname:"Khan",slug:"wahid-ali-khan",fullName:"Wahid Ali Khan"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Male autoimmune infertility: anti-sperm antibodies (ASA)",level:"1"},{id:"sec_2_2",title:"2.1. Diagnostic approaches and treatment modalities for couples with ASA",level:"2"},{id:"sec_4",title:"3. Female autoimmune infertility",level:"1"},{id:"sec_4_2",title:"3.1. Treatment modalities and management of autoimmune infertility",level:"2"},{id:"sec_6",title:"4. Future research",level:"1"},{id:"sec_7",title:"5. Conclusion",level:"1"},{id:"sec_8",title:"Acknowledgments",level:"1"},{id:"sec_11",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'Poletaev A, Boura P. The immune system, natural autoantibodies and general homeostasis in health and disease. Hippokratia. 2011;15(4):295-298. PMCID: PMC3876841\n'},{id:"B2",body:'Siloşi I, Siloşi CA, Boldeanu MV, Cojocaru M, Biciuşcă V, Avrămescu CS, Cojocaru IM, Bogdan M, Folcuţi RM. The role of autoantibodies in health and disease. Romanian Journal of Morphology and Embryology. 2016;57(2):633-638. PMID: 27833954\n'},{id:"B3",body:'Panda S, Ding JL. Natural antibodies bridge innate and adaptive immunity. Journal of Immunology. 2015;194:13-20. DOI: https://doi.org/10.4049/jimmunol.1400844. PMID: 25527792\n'},{id:"B4",body:'Weiss G, Goldsmith LT, Taylor RN, Bellet D, Taylor HS. 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DOI: 10.1186/1471-2172-15-11\n'},{id:"B152",body:'Cline AM, Kutteh WH. Is there a role of autoimmunity in implantation failure after in-vitro fertilization? Current Opinion in Obstetrics & Gynecology. 2009;21(3):291-295. PMID: 19469047\n'},{id:"B153",body:'Boumpas DT, Chrousos GP, Wilder RL, Cupps TR, Balow JE. Glucocorticoid therapy for immune mediated diseases: Basic and clinical correlates. Annals of Internal Medicine. 1993;119:1198-1208. PMID: 8239251\n'},{id:"B154",body:'Boumpas DT, Austin HA 3rd, Vaughan EM, Yarboro CH, Klippel JH, Balow JE. Risk for sustained amenorrhea in patients with systemic lupus erythematosus receiving intermittent pulse cyclophosphamide therapy. Annals of Internal Medicine. 1993;119(5):366-369. PMID: 8338289\n'},{id:"B155",body:'Otsuka N, Tong Z-B, Vanevski K, Tu W, Cheng MH, Nelson LM. Autoimmune oophoritis with multiple molecular targets mitigated by transgenic expression of mater. Endocrinology. 2011;152(6):2465-2473. PMID: 21447630. DOI: 10.1210/en.2011-0022\n'},{id:"B156",body:'Zhang D, Tu E, Kasagi S, Zanvit P, Chen Q, Chen W. Manipulating regulatory T cells: A promising strategy to treat autoimmunity. Immunotherapy. 2015;7:1201, 11. PMID: 26568117-1211. DOI: 10.2217/imt.15.79\n'},{id:"B157",body:'Vojdani A. Antibodies as predictors of complex autoimmune diseases. International Journal of Immunopathology and Pharmacology. 2008;21:267-278. PMID: 18547471. DOI: 10.1177/039463200802100203\n'},{id:"B158",body:'Busnelli A, Paffoni A, Fedele L, Somigliana E. The impact of thyroid autoimmunity on IVF/ICSI outcome: A systematic review and meta-analysis. Human Reproduction Update. 2016;22(6):775-790. PMID: 27323769. DOI: 10.1093/humupd/dmw019\n'},{id:"B159",body:'Unuane D, Velkeniers B, Anckaert E, Schiettecatte J, Tournaye H, Haentjens P, Poppe K. Thyroglobulin autoantibodies: Is there any added value in the detection of thyroid autoimmunity in women consulting for fertility treatment? Thyroid. 2013;23(8):1022-1028. PMID: 23405888. DOI: 10.1089/thy.2012.0562\n'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Kaushiki M. Kadam",address:"kaushikikadam@gmail.com",affiliation:'
National Institute for Research in Reproductive Health, Indian Council of Medical Research, India
Department of Medicine, UMass Medical School, United States
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As a gold Open Access publisher, an Open Access Publishing Fee is payable on acceptance following peer review of the manuscript. In return, we provide high quality publishing services and exclusive benefits for all contributors. IntechOpen is the trusted publishing partner of over 118,000 international scientists and researchers.
\\n\\n
The Open Access Publishing Fee (OAPF) is payable only after your full chapter, monograph or Compacts monograph is accepted for publication.
\\n\\n
OAPF Publishing Options
\\n\\n
\\n\\t
1,400 GBP Chapter - Edited Volume
\\n\\t
10,000 GBP Monograph - Long Form
\\n\\t
4,000 GBP Compacts Monograph - Short Form
\\n
\\n\\n
*These prices do not include Value-Added Tax (VAT). Residents of European Union countries need to add VAT based on the specific rate in their country of residence. Institutions and companies registered as VAT taxable entities in their own EU member state will not pay VAT as long as provision of the VAT registration number is made during the application process. This is made possible by the EU reverse charge method.
\\n\\n
Services included are:
\\n\\n
\\n\\t
An online manuscript tracking system to facilitate your work
\\n\\t
Personal contact and support throughout the publishing process from your dedicated Author Service Manager
\\n\\t
Assurance that your manuscript meets the highest publishing standards
\\n\\t
English language copyediting and proofreading, including the correction of grammatical, spelling, and other common errors
\\n\\t
XML Typesetting and pagination - web (PDF, HTML) and print files preparation
\\n\\t
Discoverability - electronic citation and linking via DOI
\\n\\t
Permanent and unrestricted online access to your work
What isn't covered by the Open Access Publishing Fee?
\\n\\n
If your manuscript:
\\n\\n
\\n\\t
Exceeds 20 pages (for chapters in Edited Volumes), an additional fee of 40 GBP per page will be required
\\n\\t
If a manuscript requires Heavy Editing or Language Polishing, this will incur additional fees.
\\n
\\n\\n
Your Author Service Manager will inform you of any items not covered by the OAPF and provide exact information regarding those additional costs before proceeding.
\\n\\n
Open Access Funding
\\n\\n
To explore funding opportunities and learn more about how you can finance your IntechOpen publication, go to our Open Access Funding page. IntechOpen offers expert assistance to all of its Authors. We can support you in approaching funding bodies and institutions in relation to publishing fees by providing information about compliance with the Open Access policies of your funder or institution. We can also assist with communicating the benefits of Open Access in order to support and strengthen your funding request and provide personal guidance through your application process. You can contact us at oapf@intechopen.com for further details or assistance.
\\n\\n
For Authors who are still unable to obtain funding from their institutions or research funding bodies for individual projects, IntechOpen does offer the possibility of applying for a Waiver to offset some or all processing feed. Details regarding our Waiver Policy can be found here.
\\n\\n
Added Value of Publishing with IntechOpen
\\n\\n
Choosing to publish with IntechOpen ensures the following benefits:
\\n\\n
\\n\\t
Indexing and listing across major repositories, see details ...
\\n\\t
Long-term archiving
\\n\\t
Visibility on the world's strongest OA platform
\\n\\t
Live Performance Metrics to track readership and the impact of your chapter
\\n\\t
Dissemination and Promotion
\\n
\\n\\n
Benefits of Publishing with IntechOpen
\\n\\n
\\n\\t
Proven world leader in Open Access book publishing with over 10 years experience
\\n\\t
+4,800 OA books published
\\n\\t
Most competitive prices in the market
\\n\\t
Fully compliant with OA funding requirements
\\n\\t
Optimized processes, enabling publication between 8 and 12 months
\\n\\t
Personal support during every step of the publication process
\\n\\t
+108,170 citations in Web of Science databases
\\n\\t
Currently strongest OA platform with over 130 million downloads
As a gold Open Access publisher, an Open Access Publishing Fee is payable on acceptance following peer review of the manuscript. In return, we provide high quality publishing services and exclusive benefits for all contributors. IntechOpen is the trusted publishing partner of over 118,000 international scientists and researchers.
\n\n
The Open Access Publishing Fee (OAPF) is payable only after your full chapter, monograph or Compacts monograph is accepted for publication.
\n\n
OAPF Publishing Options
\n\n
\n\t
1,400 GBP Chapter - Edited Volume
\n\t
10,000 GBP Monograph - Long Form
\n\t
4,000 GBP Compacts Monograph - Short Form
\n
\n\n
*These prices do not include Value-Added Tax (VAT). Residents of European Union countries need to add VAT based on the specific rate in their country of residence. Institutions and companies registered as VAT taxable entities in their own EU member state will not pay VAT as long as provision of the VAT registration number is made during the application process. This is made possible by the EU reverse charge method.
\n\n
Services included are:
\n\n
\n\t
An online manuscript tracking system to facilitate your work
\n\t
Personal contact and support throughout the publishing process from your dedicated Author Service Manager
\n\t
Assurance that your manuscript meets the highest publishing standards
\n\t
English language copyediting and proofreading, including the correction of grammatical, spelling, and other common errors
\n\t
XML Typesetting and pagination - web (PDF, HTML) and print files preparation
\n\t
Discoverability - electronic citation and linking via DOI
\n\t
Permanent and unrestricted online access to your work
What isn't covered by the Open Access Publishing Fee?
\n\n
If your manuscript:
\n\n
\n\t
Exceeds 20 pages (for chapters in Edited Volumes), an additional fee of 40 GBP per page will be required
\n\t
If a manuscript requires Heavy Editing or Language Polishing, this will incur additional fees.
\n
\n\n
Your Author Service Manager will inform you of any items not covered by the OAPF and provide exact information regarding those additional costs before proceeding.
\n\n
Open Access Funding
\n\n
To explore funding opportunities and learn more about how you can finance your IntechOpen publication, go to our Open Access Funding page. IntechOpen offers expert assistance to all of its Authors. We can support you in approaching funding bodies and institutions in relation to publishing fees by providing information about compliance with the Open Access policies of your funder or institution. We can also assist with communicating the benefits of Open Access in order to support and strengthen your funding request and provide personal guidance through your application process. You can contact us at oapf@intechopen.com for further details or assistance.
\n\n
For Authors who are still unable to obtain funding from their institutions or research funding bodies for individual projects, IntechOpen does offer the possibility of applying for a Waiver to offset some or all processing feed. Details regarding our Waiver Policy can be found here.
\n\n
Added Value of Publishing with IntechOpen
\n\n
Choosing to publish with IntechOpen ensures the following benefits:
\n\n
\n\t
Indexing and listing across major repositories, see details ...
\n\t
Long-term archiving
\n\t
Visibility on the world's strongest OA platform
\n\t
Live Performance Metrics to track readership and the impact of your chapter
\n\t
Dissemination and Promotion
\n
\n\n
Benefits of Publishing with IntechOpen
\n\n
\n\t
Proven world leader in Open Access book publishing with over 10 years experience
\n\t
+4,800 OA books published
\n\t
Most competitive prices in the market
\n\t
Fully compliant with OA funding requirements
\n\t
Optimized processes, enabling publication between 8 and 12 months
\n\t
Personal support during every step of the publication process
\n\t
+108,170 citations in Web of Science databases
\n\t
Currently strongest OA platform with over 130 million downloads
\n
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