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tility, the percentage of men with a history of cryptorchidism is between 5% and 10% (Carizza et al, 1990; Mieusset et al, 1995). In this review, we will analyze the literature on the incidence and risk factors for cryptorchidism, as well as the arguments for and against a correlation between deleterious environmental conditions and the occurrence of cryptorchidism.
Over the past 10 years, a number of reports have increased concerns that exposure to certain types of chemicals in the environment, including in utero exposure to compounds with estrogenic or antiandrogenic activities, may be linked with recently observed deleterious effects on male reproductive health, especially a decrease in sperm production and an increased incidence of testicular cancer. In this broad debate concerning the reliability of the environmental hypothesis, numerous studies have been published on incidence trends, risk factors for cryptorchidism, and also the possible role of environmental conditions (Carlsen et al, 1992; Sharpe and Skakkebaek, 1993; Auger et al, 1995; Safe, 1995; Bergstrom et al, 1996; Cheek and McLachlan, 1998). Scorer (1964) has proposed the following denition of descent of the testis: the descent of the testis is the movement of the organ from the abdominal cavity to the bottom of a fully developed and fully relaxed scrotum. Cryptorchidism is the most frequent abnormality of male sexual differentiation. Cryptorchidism is the main risk factor for testicular cancer, which is currently the most frequent cancer in young men (Scorer, 1964; Chilvers et al, 1984; John Radcliffe Hospital Cryptorchidism Study Group, 1986, 1992). To date, only cryptorchidism persisting until the age of 1 year has been considered a risk factor for testicular cancer. Several authors now believe that any form of cryptorchidism at birth, regardless of the outcome, should be considered a risk factor for testicular cancer (Berkowitz et al, 1993). Cryptorchidism is also a major risk factor for male infertility. Among couples consulting for inferSupported by a grant from the UIPP (Union des Industries de la Protection des Plantes). Correspondence to: Dr P. F. Thonneau, Human Fertility Research Group, Urology and Andrology Department, La Grave Hospital, 31052 cedex Toulouse, France (e-mail: thonneau.p@chu-toulouse.fr). Received for publication July 23, 2002; accepted for publication October 9, 2002.
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Comparison of 3 cohort studies, with the follow-up of neonates diagnosed with a cryptorchidism at birth
United Kingdom (Oxfordshire Area) Period of Follow-up (n 3612)* (n Percentage with a cryptorchidism: At birth 4.20 At 3 mo 0.97 At 1 y 0.78 United States (New York City) 7400) (n 6935) 3.68 1.00 1.06
* From Scorer (1964). From the John Radcliffe Hospital Study Group (1992). From Berkowitz et al (1993).
of cryptorchidism of 5.01% at birth and 1.78% at 3 months (John Radcliffe Hospital Cryptorchidism Study Group, 1986, 1992). It is very interesting to note that several decades earlier, and in the same place (Oxfordshire), Scorer (1964) reported an incidence of 4.2% at birth, 0.97% at 3 months, and 0.78% at 1 year, by using a similar methodology for the diagnosis and follow-up of cryptorchidism. Comparison of the results of these studies therefore strongly suggests a marked and signicant increase in the incidence of cryptorchidism between the late 1950s and the 1980s, in this region of England. In the United States (Mount Sinai Hospital, New York), a prospective hospital-based cohort study was conducted in cryptorchidism by using the same examination technique and the same denition of undescended testis as previously described by Scorer and the John Radcliffe Hospital Cryptorchidism Study Group (Berkowitz et al, 1993). Between 1987 and 1990, 6935 consecutive male neonates were examined, and 255 cases of cryptorchidism were identied at birth, giving an incidence rate of 3.68% at birth, 1.00% at 3 months, and 1.06% at 1 year. As shown in the Table, comparison of the results reported in these 3 studies (based on the same methodology) indicates an increase in the cryptorchidism incidence rate at 3 months in 2 of the 3 studies and also at 1 year for the 2 studies in which results were available at this time. Finally, in a meta-analysis performed in 1999, Paulozzi (1999) used data collected by the International Clearing House of Birth Defect Monitoring Systems (a nongovernmental organization of the World Health Organization, based in Rome, Italy) to compare cryptorchidism incidence from several industrialized countries. In the United States, a continuous increase (from 1970 to 1994) was observed with discordances in the United StatesAtlanta system. In Canada, the incidence of cryptorchidism has globally increased, with an incidence rate growing from 14 per 1000 to 24 per 1000, in the 20 years from 1974 to 1994, although a slight decrease was observed after 1990. In European countries, the incidence of cryptor-
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small for gestational age with other well-identied risk factors for cryptorchidism (cesarean section, breach presentation, low parity, and twin) into a comprehensive model. These authors suggested that fetal growth retardation that causes children to be small for gestational age may be due to uteroplacental malfunction, resulting in inadequate androgen production. Although placental dysfunction cannot explain all cases of cryptorchidism, this hypothesis is sufciently attractive to be conrmed by ongoing studies.
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In Humans: The Dramatic Story of DESOne of the most documented deleterious actions of estrogens concerns the use of DES in pregnant women to prevent abortion complications (Brackbill and Berendes, 1978; Stillman, 1982). DES, a nonsteroidal estrogenic substance, is associated with undescended testes in male offspring (Gill et al, 1979; Driscoll and Taylor, 1980). In a follow-up study of DES exposure in males, Wilcox et al (1995) observed that genital abnormalities were more frequent in men exposed before the 11th week of gestation than in those exposed later. However, in a recent meta-analysis of fetal genital effects of rst-trimester sex hormone exposure, no association was observed between genital abnormalities and rst-trimester exposure to sex hormones other than DES (Raman-Wilms et al, 1995). In Humans: Results of Epidemiological Studies of Occupational and Environmental FactorsIn the province of Granada, in Spain, Garcia-Rodriguez et al (1996) carried out an ecology-based study to search for variations in the frequency of orchidopexy according to geographical differences in pesticide exposure (4-level classication). They observed that the frequency of orchidopexy tended to be higher in districts near the Mediterranean Coast, where the entire family, including the mother, is involved in intensive farming and pesticide spraying (in Murcia province, the adjoining province, high concentrations of endosulfan and lindane have been found in the adipose tissue of children). In Denmark, Skakkebaek and colleagues from the Department of Growth and Reproduction at the University of Copenhagen performed a register-based case-control study of parental occupation in agriculture and horticulture for 6177 cases of cryptorchidism and 23 273 controls, born alive from 1983 to 1992 (Weidner et al, 1998). They found that the risk of cryptorchidism was signicantly higher in sons of women working in horticulture (adjusted odds ratio 1.67; 1.142.47) but not in the sons of men working in horticulture. In Hungary, Czeizel et al (1999) reported congenital abnormalities in 46 326 infants born to mothers living in a region close to an acrylonitrile factory between 1980 and 1996. Cases with congenital abnormalities were identied from the data set of the Hungarian Congenital Abnormality Register, complemented with cases reviewed in pediatric and cytogenetic units. A higher frequency of undescended testes was observed in the newborns of mothers living in the town closest to the factory. This factory produced vinyl chloride monomer and acrylonitrile, which were used for the manufacture of stiffened plastic tubes and cartons for the packaging of margarine to be sold to local consumers. In Norway, 2 studies (Kristensen et al, 1997, 2000) were performed to investigate adverse reproductive outcomes, including cryptorchidism (using the Medical Birth
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antiandrogen effect is based on toxicology results for certain pesticide compounds (p,p -DDE, vinclozolin, and phthalates) that have been shown to have an antiandrogen activity (Goh et al, 1993; Kelce et al, 1995; McMahon et al, 1995; Kelce and Wilson, 1997; Mylchreest et al, 1999). The Role of Competition in BioavailabilitySeveral studies have also reported that sex hormone-binding globulin (hSHBG) may transport contaminating xenoestrogens in the plasma and modulate their bioavailability to cells and tissues. Certain chemical compounds (eg, pentachlorophenol, alkyl phenols, and biphenols) may therefore displace endogenous sex steroid hormones from hSHBG sites, disrupting the androgen-to-estrogen balance (Danzo, 1997; Dechaud et al, 1999). Similar conclusions have been already obtained by Bernstein et al (1998). In a case-control study to assess the role of hormonal factors, they found that cases had signicantly higher percentages of nonprotein-bound and albumin-bound estradiol than controls during the rst trimester of pregnancy: on average, cases had 16% more bioavailable estradiol than controls. In humans, the debate is still very open concerning the substances actually involved and the mechanisms by which they may cause cryptorchidism (Soto et al, 1994; Massad and Barouki, 1999; Douglas, 2000).
Conclusion
At the same time as a widespread increase in the incidence of testicular cancer (Huyghe et al, in press), a tendency toward an increase in the incidence of cryptorchidism has also been observed over recent decades in industrialized countries. The differences in incidence rates reported for cryptorchidism may result from biases due to the nonuniform denition of this condition. As stated by several authors, harmonization is required concerning the precise denition of this malformation and its diagnostic criteria. To date, the main risk factor identied for cryptorchidism is denitely low birth weight (for equal gestational age). Other malformations (hypospadias, epididymal anomalies, and inguinal hernia) are often observed in cases of cryptorchidism, and this may direct the search for potential similar risk factors (Fallon et al, 1982; Donnell et al, 1995; Barthold and Redman, 1996). Data concerning the effects of environmental exposure are more convincing in animals (especially under experimental conditions) than data concerning environmental or occupational exposure in humans. No formal conclusions can be drawn, at the present time, that industrial chemicals known to be potential endocrine disruptors are responsible for the recent increase in the number of cases of cryptorchidism (Safe, 2000; Joffe, 2001). The relatively high frequency of cryptorchidism and
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the short time between in utero exposure and the end point constitute strong arguments for the pursuit of research into this malformation (Siemiatycki et al, 1989). Nevertheless, from an epidemiological point of view, it would be useful to clearly distinguish between the various types of undescended testicles (abdominal position vs inguinoscrotal position) and to separate boys with late descending, primary persisting, and ascending testicles. Taking these factors into account, cryptorchidism has the potential to become an excellent indicator to follow possible deteriorations in male reproductive health (Paul, 1997).
References
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