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Review
. 2016 Jan;96(1):55-97.
doi: 10.1152/physrev.00017.2015.

Male Reproductive Disorders and Fertility Trends: Influences of Environment and Genetic Susceptibility

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Free PMC article
Review

Male Reproductive Disorders and Fertility Trends: Influences of Environment and Genetic Susceptibility

Niels E Skakkebaek et al. Physiol Rev. .
Free PMC article

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.

Figures

Figure 1.
Figure 1.
Total Fertility Rates (TFR), European Union, Japan and United States, 1960–2013. Dotted line represents a fertility rate of 2.1, below which a population cannot be sustained. From the World Bank: http://databank.worldbank.org/data/views/variableselection/selectvariables.aspx?source=world-development-indicators.
Figure 2.
Figure 2.
Total Fertility Rate (TFR), Denmark 1901–2014. From Statistics Denmark: http://www.statistikbanken.dk/statbank5a/default.asp?w=1600. Dotted line represents a fertility rate of 2.1. Note that a downwards trend in TFR started long before introduction of the contraceptive pill in the 1960s. Apparently the trend was interrupted by the First and Second World Wars.
Figure 3.
Figure 3.
The hypothesis of testicular dysgenesis syndrome (TDS) and signs that might be linked to it: poor spermatogenesis, testicular cancer, hypospadias, cryptorchidism, and short ano-genital distance (AGD). The single symptoms and combinations thereof are risk factors for reduced fecundity. [Updated from Skakkebaek et al. (387).]
Figure 4.
Figure 4.
Trends in testicular cancer; age-standardized (world) incidence (regional or national), all ages. [Modified from Znaor et al. (481). Courtesy of Dr. Arinana Znaor and statistician Mathieu Laversanne, M.Sc., WHO, International Agency for Research in Cancer (IARC), Lyon, France.]
Figure 6.
Figure 6.
Examples of testicular dysgenesis in biopsy materials from men with abnormal spermatogenesis. A: specimen showing dysgenetic seminiferous tubules (D) containing numerous undifferentiated Sertoli cells and several microliths (M), but no germ cells. Tubules containing all types of germ cells, including spermatocytes and spermatids, are seen to the right. Hematoxylin-eosin staining was used. B: i) Immunostaining with OCT4, an embryonic marker, of testicular biopsy specimen with a mixture of GCNIS and normal spermatogenesis. ii) Same, higher magnification showing details of tubules with GCNIS and normal spermatogenesis, respectively. Note that OCT4 is only expressed in the nuclei of the GCNIS cells.
Figure 5.
Figure 5.
Model for the pathogenesis of testicular germ cell tumors of young adults, which are derived from germ cell neoplasia in situ (GCNIS), previously known as carcinoma in situ testis (CIS). These tumors are an example of developmental cancer and are thought to be caused by a combination of adverse environmental and genetic factors (multifactorial and polygenic). The key pathogenetic event is insufficient masculinization and impaired function of the testicular somatic cell niche, which in fetal life is mainly composed of Sertoli and Leydig cells. The insufficient stimulation of developing germ cells causes arrest of gonocyte differentiation to spermatogonia and prolonged expression of pluripotency genes (depicted by red nuclei in all pluripotent cell types in the figure). The delayed gonocytes (pre-GCNIS cells) then gradually acquire secondary genomic aberrations (including polyploidization and gain of chromosome 12p), while adapting to the changing niche, especially during and after pubertal hormonal stimulation of the testis. Increased proliferation results in malignant transformation of GCNIS cells into an invasive tumor, either a seminoma or nonseminoma (the latter through the reprogrammed pluripotent stage of embryonal carcinoma, EC). Normal germ cell development is shown in the top part in the figure (PGC, primordial germ cells) on the green background which symbolizes a normal testicular somatic cell niche. [Updated and modified from Rajpert-De Meyts (344).]
Figure 7.
Figure 7.
Incidence of cryptorchidism at birth on the basis of prospective clinical studies from the 1950s to the 2000s in Denmark, Finland, and United Kingdom. The data points are marked on the year of the publication of the study which represents the preceding incidence rate (3, 47, 61, 184, 377).
Figure 8.
Figure 8.
Recent changes in male pubertal timing. Testicular volume was >3 ml. [From Mouritsen et al. (293).]
Figure 9.
Figure 9.
Average male serum testosterone levels by age (full drawn line) based on healthy men from the general population show only a moderate decline from the age of 20–60 years. Superimposed (dotted line) is an illustration of the consequence of applying the average rate of decline (−1.6%/year) observed in a longitudinal study of individual testosterone levels (115) from the age of 22 (year of peak testosterone levels in the cross-sectional material). [From Andersson et al. (15).]
Figure 10.
Figure 10.
Secular trends in mean total testosterone levels of normal men by age. A: stratified by time period of study. B: stratified by 5-yr birth cohort. Please note the different scales of the y-axes in A and B. [Modified from Travison et al. (427).]
Figure 11.
Figure 11.
Distributions of sperm counts in Danish men from the general population, examined from 1996 to 2010 and Danish men examined in an infertility clinic in the 1940s. All men had durations of ejaculation abstinence greater than 48 h. Sperm concentration (A) and total sperm counts (B) are shown. [From Jørgensen et al. (189).]
Figure 12.
Figure 12.
Sex ratio at birth and joinpoint segments, 1940–2002, all mothers. [From Mathews and Hamilton (264).]
Figure 13.
Figure 13.
Sex ratio at birth and joinpoint segments for births to white mothers, 1970–2002. [From Mathews and Hamilton (264).]
Figure 14.
Figure 14.
Roles of definitions, populations, numerators, and denominators of calculated prevalence of infertility.
Figure 15.
Figure 15.
Dynamic nature of fecundity and fertility.
Figure 16.
Figure 16.
Assisted reproduction (ART) in Denmark, 2001–2014. IUI-D, insemination with donor semen; IUI-H, husband semen; OD, oocyte donation; FER, frozen embryo replacement; IVF, in vitro fertilization; ICSI, intracytoplasmatic sperm injection. From The Danish Fertility Society: http://www.fertilitetsselskab.dk/images/2015_dok/dfs2014.pdf.
Figure 17.
Figure 17.
Fertility rates, 1960–2013, across North America, South America, Africa, Asia, and Europe. From the World Bank: http://databank.worldbank.org/data/views/variableselection/selectvariables.aspx?source=world-development-indicators.
Figure 18.
Figure 18.
Total pregnancy rate of the total Danish population according to year of birth (1960–1980) of the pregnant women. ART pregnancies not included. Note the declining pregnancy rate. [From Jensen et al. (177).]
Figure 19.
Figure 19.
Mean ages of Danish women delivering from 1901–2014. From Statistics Denmark: http://www.statistikbanken.dk/statbank5a/default.asp?w=1600.
Figure 20.
Figure 20.
Total number of births in Denmark, 1940–2012 (blue curve), and total number of births minus births after ART, 2003–2012 (red curve). Note that the numbers of births conceived without the use of ART in 2012 were similar to the low point reached in 1983, before ART was introduced. From Statistics Denmark and The Danish Fertility Society: http://www.statistikbanken.dk/statbank5a/default.asp?w=1600 and http://www.fertilitetsselskab.dk.
Figure 21.
Figure 21.
Examples of longitudinal changes in population sizes with different total fertility rates (TFR). A population is sustained if TFR is 2.1. However, a constant TFR of 1.5 (which is the current average in EU) will result in a 60% reduction of the population of young people over three generations, excluding immigration.

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