title: Male Reproductive Disorders and Fertility Trends: Influences of Environment and Genetic Susceptibility.
abstract: It is predicted that Japan and European Union will soon experience appreciable decreases in their populations due to persistently low total fertility rates (TFR) below replacement level (2.1 child per woman). In the United States, where TFR has also declined, there are ethnic differences. Caucasians have rates below replacement, while TFRs among African-Americans and Hispanics are higher. We review possible links between TFR and trends in a range of male reproductive problems, including testicular cancer, disorders of sex development, cryptorchidism, hypospadias, low testosterone levels, poor semen quality, childlessness, changed sex ratio, and increasing demand for assisted reproductive techniques. We present evidence that several adult male reproductive problems arise in utero and are signs of testicular dysgenesis syndrome (TDS). Although TDS might result from genetic mutations, recent evidence suggests that it most often is related to environmental exposures of the fetal testis. However, environmental factors can also affect the adult endocrine system. Based on our review of genetic and environmental factors, we conclude that environmental exposures arising from modern lifestyle, rather than genetics, are the most important factors in the observed trends. These environmental factors might act either directly or via epigenetic mechanisms. In the latter case, the effects of exposures might have an impact for several generations post-exposure. In conclusion, there is an urgent need to prioritize research in reproductive physiology and pathophysiology, particularly in highly industrialized countries facing decreasing populations. We highlight a number of topics that need attention by researchers in human physiology, pathophysiology, environmental health sciences, and demography.
authors.affiliation: Department of Growth & Reproduction and EDMaRC, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; Division of Epidemiology, Statistics and Prevention Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland; Department of Physiology & Pediatrics, University of Turku and Turku University Hospital, Turku, Finland; Male Reproductive Medicine & Surgery Program, Stanford University, Stanford, California; Icahn School of Medicine at Mount Sinai, New York, New York; and The Fertility Clinic, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Niels E
authors.initials: NE
authors.lastname: Skakkebaek
authors.affiliation: Department of Growth & Reproduction and EDMaRC, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; Division of Epidemiology, Statistics and Prevention Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland; Department of Physiology & Pediatrics, University of Turku and Turku University Hospital, Turku, Finland; Male Reproductive Medicine & Surgery Program, Stanford University, Stanford, California; Icahn School of Medicine at Mount Sinai, New York, New York; and The Fertility Clinic, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Ewa
authors.initials: E
authors.lastname: Rajpert-De Meyts
authors.affiliation: Department of Growth & Reproduction and EDMaRC, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; Division of Epidemiology, Statistics and Prevention Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland; Department of Physiology & Pediatrics, University of Turku and Turku University Hospital, Turku, Finland; Male Reproductive Medicine & Surgery Program, Stanford University, Stanford, California; Icahn School of Medicine at Mount Sinai, New York, New York; and The Fertility Clinic, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Germaine M
authors.initials: GM
authors.lastname: Buck Louis
authors.affiliation: Department of Growth & Reproduction and EDMaRC, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; Division of Epidemiology, Statistics and Prevention Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland; Department of Physiology & Pediatrics, University of Turku and Turku University Hospital, Turku, Finland; Male Reproductive Medicine & Surgery Program, Stanford University, Stanford, California; Icahn School of Medicine at Mount Sinai, New York, New York; and The Fertility Clinic, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Jorma
authors.initials: J
authors.lastname: Toppari
authors.affiliation: Department of Growth & Reproduction and EDMaRC, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; Division of Epidemiology, Statistics and Prevention Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland; Department of Physiology & Pediatrics, University of Turku and Turku University Hospital, Turku, Finland; Male Reproductive Medicine & Surgery Program, Stanford University, Stanford, California; Icahn School of Medicine at Mount Sinai, New York, New York; and The Fertility Clinic, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Anna-Maria
authors.initials: AM
authors.lastname: Andersson
authors.affiliation: Department of Growth & Reproduction and EDMaRC, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; Division of Epidemiology, Statistics and Prevention Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland; Department of Physiology & Pediatrics, University of Turku and Turku University Hospital, Turku, Finland; Male Reproductive Medicine & Surgery Program, Stanford University, Stanford, California; Icahn School of Medicine at Mount Sinai, New York, New York; and The Fertility Clinic, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Eisenberg
authors.affiliation: Department of Growth & Reproduction and EDMaRC, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; Division of Epidemiology, Statistics and Prevention Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland; Department of Physiology & Pediatrics, University of Turku and Turku University Hospital, Turku, Finland; Male Reproductive Medicine & Surgery Program, Stanford University, Stanford, California; Icahn School of Medicine at Mount Sinai, New York, New York; and The Fertility Clinic, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Tina Kold
authors.initials: TK
authors.lastname: Jensen
authors.affiliation: Department of Growth & Reproduction and EDMaRC, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; Division of Epidemiology, Statistics and Prevention Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland; Department of Physiology & Pediatrics, University of Turku and Turku University Hospital, Turku, Finland; Male Reproductive Medicine & Surgery Program, Stanford University, Stanford, California; Icahn School of Medicine at Mount Sinai, New York, New York; and The Fertility Clinic, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Jørgensen
authors.affiliation: Department of Growth & Reproduction and EDMaRC, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; Division of Epidemiology, Statistics and Prevention Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland; Department of Physiology & Pediatrics, University of Turku and Turku University Hospital, Turku, Finland; Male Reproductive Medicine & Surgery Program, Stanford University, Stanford, California; Icahn School of Medicine at Mount Sinai, New York, New York; and The Fertility Clinic, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Shanna H
authors.initials: SH
authors.lastname: Swan
authors.affiliation: Department of Growth & Reproduction and EDMaRC, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; Division of Epidemiology, Statistics and Prevention Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland; Department of Physiology & Pediatrics, University of Turku and Turku University Hospital, Turku, Finland; Male Reproductive Medicine & Surgery Program, Stanford University, Stanford, California; Icahn School of Medicine at Mount Sinai, New York, New York; and The Fertility Clinic, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Sapra
authors.affiliation: Department of Growth & Reproduction and EDMaRC, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; Division of Epidemiology, Statistics and Prevention Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland; Department of Physiology & Pediatrics, University of Turku and Turku University Hospital, Turku, Finland; Male Reproductive Medicine & Surgery Program, Stanford University, Stanford, California; Icahn School of Medicine at Mount Sinai, New York, New York; and The Fertility Clinic, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Søren
authors.initials: S
authors.lastname: Ziebe
authors.affiliation: Department of Growth & Reproduction and EDMaRC, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; Division of Epidemiology, Statistics and Prevention Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland; Department of Physiology & Pediatrics, University of Turku and Turku University Hospital, Turku, Finland; Male Reproductive Medicine & Surgery Program, Stanford University, Stanford, California; Icahn School of Medicine at Mount Sinai, New York, New York; and The Fertility Clinic, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Lærke
authors.initials: L
authors.lastname: Priskorn
authors.affiliation: Department of Growth & Reproduction and EDMaRC, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; Division of Epidemiology, Statistics and Prevention Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland; Department of Physiology & Pediatrics, University of Turku and Turku University Hospital, Turku, Finland; Male Reproductive Medicine & Surgery Program, Stanford University, Stanford, California; Icahn School of Medicine at Mount Sinai, New York, New York; and The Fertility Clinic, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Anders
authors.initials: A
authors.lastname: Juul
mesh_terms: D004781:Environmental Exposure; D005298:Fertility / Q000235:genetics*; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease; D006801:Humans; D015994:Incidence; D007248:Infertility, Male / Q000175:diagnosis / Q000453:epidemiology* / Q000235:genetics / Q000503:physiopathology; D008019:Life Style; D008297:Male; D010641:Phenotype; D011157:Population Dynamics; D012307:Risk Factors