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      The diagnosis of male infertility: an analysis of the evidence to support the development of global WHO guidance—challenges and future research opportunities

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          Abstract

          BACKGROUND

          Herein, we describe the consensus guideline methodology, summarize the evidence-based recommendations we provided to the World Health Organization (WHO) for their consideration in the development of global guidance and present a narrative review of the diagnosis of male infertility as related to the eight prioritized (problem or population (P), intervention (I), comparison (C) and outcome(s) (O) (PICO)) questions. Additionally, we discuss the challenges and research gaps identified during the synthesis of this evidence.

          OBJECTIVE AND RATIONALE

          The aim of this paper is to present an evidence-based approach for the diagnosis of male infertility as related to the eight prioritized PICO questions.

          SEARCH METHODS

          Collating the evidence to support providing recommendations involved a collaborative process as developed by WHO, namely: identification of priority questions and critical outcomes; retrieval of up-to-date evidence and existing guidelines; assessment and synthesis of the evidence; and the formulation of draft recommendations to be used for reaching consensus with a wide range of global stakeholders. For each draft recommendation the quality of the supporting evidence was then graded and assessed for consideration during a WHO consensus.

          OUTCOMES

          Evidence was synthesized and recommendations were drafted to address the diagnosis of male infertility specifically encompassing the following: What is the prevalence of male infertility and what proportion of infertility is attributable to the male? Is it necessary for all infertile men to undergo a thorough evaluation? What is the clinical (ART/non ART) value of traditional semen parameters? What key male lifestyle factors impact on fertility (focusing on obesity, heat and tobacco smoking)? Do supplementary oral antioxidants or herbal therapies significantly influence fertility outcomes for infertile men? What are the evidence-based criteria for genetic screening of infertile men? How does a history of neoplasia and related treatments in the male impact on (his and his partner's) reproductive health and fertility options? And lastly, what is the impact of varicocele on male fertility and does correction of varicocele improve semen parameters and/or fertility?

          WIDER IMPLICATIONS

          This evidence synthesis analysis has been conducted in a manner to be considered for global applicability for the diagnosis of male infertility.

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          Most cited references107

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          Cancer, pregnancy and fertility: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.

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            Disruption of histone methylation in developing sperm impairs offspring health transgenerationally.

            A father's lifetime experiences can be transmitted to his offspring to affect health and development. However, the mechanisms underlying paternal epigenetic transmission are unclear. Unlike in somatic cells, there are few nucleosomes in sperm, and their function in epigenetic inheritance is unknown. We generated transgenic mice in which overexpression of the histone H3 lysine 4 (H3K4) demethylase KDM1A (also known as LSD1) during spermatogenesis reduced H3K4 dimethylation in sperm. KDM1A overexpression in one generation severely impaired development and survivability of offspring. These defects persisted transgenerationally in the absence of KDM1A germline expression and were associated with altered RNA profiles in sperm and offspring. We show that epigenetic inheritance of aberrant development can be initiated by histone demethylase activity in developing sperm, without changes to DNA methylation at CpG-rich regions.
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              Incidence and main causes of infertility in a resident population (1,850,000) of three French regions (1988-1989).

              To estimate the prevalence and main causes of infertility, a multicentre survey was conducted over 1 year (July 1988-June 1989) in three regions of France. All the 1686 couples in these regions, who consulted a practitioner for primary or secondary infertility during this period, were included in the investigation. The prevalence rate of infertility was found to be 14.1%, indicating that one woman out of seven in France will consult a doctor for an infertility problem during her reproductive life. The main causes of female infertility were ovulation disorders (32%) and tubal damage (26%), and of male infertility oligo-terato-asthenozoospermia (21%), asthenozoospermia (17%), teratozoospermia (10%) and azoospermia (9%). Infertility was also found to be caused by disorders in both the male and female partners together; thus in 39% of cases both the man and woman presented with disorders. The woman alone was responsible for infertility in one-third of cases and the man alone in one-fifth. Unexplained infertility was found in 8% of the couples surveyed.
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                Author and article information

                Journal
                Hum Reprod Update
                Hum. Reprod. Update
                humupd
                Human Reproduction Update
                Oxford University Press
                1355-4786
                1460-2369
                November 2017
                19 July 2017
                19 July 2017
                : 23
                : 6
                : 660-680
                Affiliations
                [1 ] Department of Reproductive and Developmental Biology, Medical School, Ninewells Hospital, University of Dundee , Dundee, DD1 9SY, Scotland
                [2 ] Karolinska University Hospital and Karolinska Institutet , Stockholm, Sweden
                [3 ] University of Minnesota , Minneapolis, MN, USA
                [4 ] Baylor College of Medicine, Houston, TX, USA
                [5 ] Clinica Alemana de Santiago, Santiago, Chile
                [6 ] Hudson Institute of Medical Research, Clayton, Australia
                [7 ] Boston University School of Medicine and Boston Medical Center , Boston, MA, USA
                [8 ] Department of Reproductive Health and Research, Human Reproduction Programme, (HRP, The UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction), WHO, Geneva, Switzerland
                [9 ]Population Council, New York, NY, USA
                [10 ] Hudson Institute of Medical Research, Clayton, Australia
                [11 ]Warren Alpert Medical School of Brown University, RI, USA
                [12 ]Department of Obstetrics and Gynaecology and Medicine, Keck School of Medicine, University of Southern California, CA, USA
                [13 ] Centre for Reproductive Medicine, Vrije Universiteit Brussel , Brussels, Belgium
                Author notes
                [* ]Correspondence address. Department of Reproductive and Developmental Biology, Medical School, Ninewells Hospital, University of Dundee, Dundee, Scotland. E-mail: c.barratt@ 123456dundee.ac.uk
                Article
                dmx021
                10.1093/humupd/dmx021
                5850791
                28981651
                d178336b-7c08-4f57-9ea8-b56baff812a6
                © The Author 2017. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited

                History
                : 02 September 2016
                : 12 April 2017
                : 12 July 2017
                Page count
                Pages: 21
                Funding
                Funded by: UK Medical Research Council 10.13039/501100000265
                Funded by: NHS Scotland
                Funded by: Principal Research
                Award ID: 1022327
                Categories
                Review

                Human biology
                male infertility,spermatozoa,genetics,y deletions,cystic fibrosis transmembrane conductance regulator,semen analysis,varicocele,evidence-based guideline,cancer

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