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2, March/April 2003 American Society of Andrology Copyright
Cryptorchidism: Incidence, Risk Factors, and Potential Role of Environment; An Update
PATRICK F. THONNEAU,* PEGGY CANDIA,*† AND ROGER MIEUSSET*
From the *Human Fertility Research Group, Urology and Andrology Department, and the †Occupational Medicine Department, La Grave Hospital, Toulouse, France.
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 deﬁnition 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: email@example.com). Received for publication July 23, 2002; accepted for publication October 9, 2002.
Has the Incidence of Cryptorchidism Increased?
As pointed out by Toppari et al (1996), it is difﬁcult to compare the incidence rates of cryptorchidism reported in various publications. First of all, the deﬁnition of cryptorchidism varies according to the site of the testis: for example, some authors consider the testis ‘‘normal,’’ even when it is not located in the depth of the scrotum but in a high scrotal position. It is also often impossible to determine, in published studies, whether retractile testes (ie, testes that are not located in the bottom of the scrotum but that can be manually pushed into this position) are classiﬁed as ‘‘cryptorchidism’’ or as a ‘‘normal’’ testicular position. Another key point consists of clearly identifying, in published studies, the age of diagnosis of cryptorchidism, as it has been clearly established that the great majority of cases of cryptorchidism diagnosed at birth resolve spontaneously during the ﬁrst years of life (natural course of cryptorchid testes). This could explain the large range of incidence rates reported in the literature: from less than 1% to 10% in data from hospital-based or central registers (with diagnosis performed from birth to 1 year of age) and from 0.2% to 13% in surveys performed in schools and in the army (with diagnosis performed in adolescents and young adults) (Buemann et al, 1961; Campbell et al, 1987; Thorup and Cortes, 1990; Kaul and Roberts, 1992; Thong et al, 1998). Finally, very few studies have tried to analyze cryptorchidism incidence trends over recent decades based on the same diagnostic criteria and in the same areas. In the United Kingdom, by studying the Hospital Inpatient Enquiry data for England and Wales, Chilvers et al (1984) reported a doubling of the incidence of cryptorchidism at birth, from 1.4% in 1952 to 2.9% in 1977. In 1992, a prospective study was performed on 7441 boys born in the John Radcliffe Hospital (Oxford) between 1984 and 1988. The authors observed an incidence
boys with a low birth weight. 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. although a slight decrease was observed after 1990. New York). of cryptorchidism of 5.06 Journal of Andrology · March/April 2003 chidism has remained more or less stable. Italy) to compare cryptorchidism incidence from several industrialized countries. and infants small for gestational age.68 1. Between 1987 and 1990. In European countries. with about 15 cases per 1000 from 1974 to 1996 in Norway.156 Comparison of 3 cohort studies. In London. ‡ From Berkowitz et al (1993). * From Scorer (1964). a continuous increase (from 1970 to 1994) was observed with discordances in the United States–Atlanta system. In the United States. the incidence has increased slightly from 8 per 1000 in 1981 to 12 per 1000 in 1993 and is currently stable at this level. the great majority of published data are in favor of an increase in the incidence of cryptorchidism over recent decades in North America and Europe.. In England. A signiﬁcant increase in the risk of cryptorchidism was found to be associated with the ﬁrst birth. In France (Paris area).. In conclusion to this chapter on the incidence of cryptorchidism.00 1. the incidence of cryptor- What Are the Main Results of Epidemiological Studies on Risk Factors? A number of epidemiological studies (case-control studies and cohort surveys) were conducted in the 1980s and 1990s in order to identify the risk factors for cryptorchidism. 1986. a prospective hospital-based cohort study was conducted in cryptorchidism by using the same examination technique and the same deﬁnition of undescended testis as previously described by Scorer and the John Radcliffe Hospital Cryptorchidism Study Group (Berkowitz et al. and it is also difﬁcult to compare data derived from different countries because of the lack of precise methodology. Swerdlow et al (1983) compared 146 cases of orchidopexy and 146 matched controls (Oxford Record Linkage Study) and found that the risk of cryptorchidism was higher for boys delivered in a breech presentation.78% at 3 months (John Radcliffe Hospital Cryptorchidism Study Group. 6935 consecutive male neonates were examined. Depue (1984) studied the cohort of the Collaborative Perinatal Project of the National Institute of Neurological and Communicative Disorders and Stroke. 1. only a few reliable studies have been performed to evaluate trends in cryptorchidism incidence. and 0. In a prospective hospitalbased cohort study conducted in New York. 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. and the total number of diagnosed cases was not indicated. and 1. In the United States (Mount Sinai Hospital. by using a similar methodology for the diagnosis and follow-up of cryptorchidism. for example). 5. The risk of cryptorchidism was signiﬁcantly higher in boys with low birth weight and when estrogens (estradiol. 1993).2% at birth. and 255 cases of cryptorchidism were identiﬁed at birth. with an incidence rate growing from 14 per 1000 to 24 per 1000. Hjertkvist et al (1989) used the Swedish personal identiﬁcation code and the Medical Birth Registry to compare cryptorchid boys with the total population of male births during the same period. 1992). in this region of England. and estrone) had been administered during gestation. in the 20 years from 1974 to 1994. the incidence of cryptorchidism has globally increased.06% at 1 year. It is very interesting to note that several decades earlier. Scorer (1964) reported an incidence of 4. followed by a sudden drop linked to recent major changes in cryptorchidism coding.97 At 1 y 0. In the United States. Berkowitz et al (1995) examined 6699 singleton male neonates deliv- . † From the John Radcliffe Hospital Study Group (1992). giving an incidence rate of 3. similar trends toward a global increase in the incidence of cryptorchidism were observed until 1987. diethylstilbestrol [DES].00% at 3 months. the methodology used to assess cryptorchidism in these studies was not described.78% at 1 year. Unfortunately.78 United States (New York City) 7400)† (n 6935)‡ 3.97% at 3 months. This tendency certainly needs to be conﬁrmed by conducting new cohort studies with an adequate and standardized methodology (such as those described by Scorer . based in Rome. Nevertheless.68% at birth. In Sweden. As shown in the Table. In Canada.20 At 3 mo 0. and boys born to primiparous or young mothers ( 20 years).01% at birth and 1. Comparison of the results of these studies therefore strongly suggests a marked and signiﬁcant increase in the incidence of cryptorchidism between the late 1950s and the 1980s. and in the same place (Oxfordshire).00 1.78 . 0. cesarean section or toxemia. in a meta-analysis performed in 1999. making interpretation of incidence rates very difﬁcult and the comparison of trends impossible. Finally. Paulozzi (1999) used data collected by the International Clearing House of Birth Defect Monitoring Systems (a nongovernmental organization of the World Health Organization.
with low birth weight or born preterm. 1994. the essential problem is to integrate the risk of being born 157 small for gestational age with other well-identiﬁed risk factors for cryptorchidism (cesarean section. and chronic diseases in relatives. as stated by Moller and Weidner (1999). and twin) into a comprehensive model. researchers thought that inbreeding might account for the drastic reduction in Florida panther numbers and the observed reproductive disorders. gonadal abnormalities. they proposed another possible explanation: exposure to environmental xenoestrogens (Florida panthers eat raccoons. breech presentation. 1995) in Florida (which have smaller than normal penises. and sex steroid concentrations (estradiol 17 . the same authors found no relationship between phallus size and other body parameters. 1995). which evaluates the contribution of environmental pollutants to speciﬁc diseases observed in wildlife by distinguishing between genetic causes (for example. The risk of cryptorchidism was associated with birth weight: risks were highest for boys small for gestational age at birth and boys born before the 33rd week of gestation. 2000). including a very high frequency of cryptorchidism (ca 90%). and serum testosterone concentrations were lower in males from Lake Apopka and Orange Lake than in controls from the Lake Woodruff National Wildlife Refuge. Firstborn infants were at slightly higher risk than those of higher parity. Finally. The risk of cryptorchidism increased with decreasing birth weight. After a more complete investigation of the dietary habits of the Florida panther. In England. The risk of cryptorchidism was almost 4 times higher when an older brother had a history of the same condition. Florida panthers were found to display a large variety of endocrine and reproductive disorders. Jones et al (1998) conducted a case-control study to examine prenatal risk factors for cryptorchidism. In British Columbia. this hypothesis is sufﬁciently attractive to be conﬁrmed by ongoing studies. inbreeding in isolated subpopulations) and environmental conditions (Bowerman et al. and vomiting) and cryptorchidism. . nausea. These negative results were comparable to those observed by Beard et al (1984) with exposure to estrogens. breach presentation. independently of the duration of gestation. At ﬁrst. England. from invertebrates to mammals. The risk of cryptorchidism was found to be high for infants born to obese mothers. 1995. In Austria. Another example of possible environmental contamination (organochlorine pesticides) is provided by juvenile alligators of Lake Apopka (Guillette et al. In Sweden. The frequency of cryptorchidism was higher in the case of intrauterine growth retardation (low birth weights for equal gestational age). Denmark. The authors also observed that ﬁrst. The authors compared 2782 boys undergoing surgery for cryptorchidism with 13 916 random matched controls. The authors therefore suggested that the deleterious effects in juvenile alligators are not associated with current serum levels of environmental contaminants but could be due to exposure during embryonic development. Nevertheless. and low testosterone concentrations). 4 case-control studies based on large numbers of individuals have been conducted in Sweden. by using the Oxford Record Linkage Study. and preeclampsia. twins were found to have a lower risk of cryptorchidism than singletons in the same birth weight classes. More recently. Although placental dysfunction cannot explain all cases of cryptorchidism. Boys (n 1449) treated for cryptorchidism by orchidopexy were compared with random matched controls from all live births (n 10 811).testosterone). One interesting approach in this ﬁeld is the methodology of ecoepidemiology. in a recent study (Guillette et al. Moline et al. McBride et al (1991) found no signiﬁcant association between exogenous estrogen exposure (oral contraceptive use and female hormones) or indirect indicators of endogenous estrogen exposure (such as bleeding. 1999). organochlorine pesticides and PCBs were detected at all sites. serum contaminant levels (organochlorine pesticides—polychlorinated biphenyls [PCBs]). complicated deliveries. delivered by cesarean section. Mayr et al (1999) performed a retrospective hospital-based study in which 447 boys undergoing orchidopexy were compared with an equal number of otherwise healthy male age-matched trauma patients. Finally. and Austria.and secondborn boys were overrepresented in the case group.Thonneau et al · Cryptorchidism Incidence Rate ered between 1987 and 1990. low social class. The history of the Florida panther illustrates this approach (Facemire et al. which eat ﬁsh that have accumulated large amounts of endocrine-disrupting pesticides). These authors suggested that fetal growth retardation that causes children to be small for gestational age may be due to uteroplacental malfunction. Akre et al (1999) used record linkage between the Inpatient and Birth Registries to conduct a casecontrol study (nested in a nationwide cohort). in a case-control study with 244 cases and 488 controls. The risk of cryptorchidism was found to be higher for low birth weight and premature infants but also for low parity. However. low parity. What Evidence Is There for a Potential Impact of Environment in Cryptorchidism? In Animals—Environmental pollutants have been linked to adverse effects on male reproduction in various wildlife species. Weidner et al (1999) compared 6177 boys with cryptorchidism to 23 273 male controls born alive in Denmark from 1983 to 1992. resulting in inadequate androgen production.
Stillman. and 2) free estradiol concentration was not determined (free estradiol may be the only bioavailable form) in these newborns. PCBs.67. They found that the risk of cryptorchidism was signiﬁcantly higher in sons of women working in horticulture (adjusted odds ratio 1. taxophenes. prevalence depended on climatic conditions. chlorinated cyclodienes. 1995). complemented with cases reviewed in pediatric and cytogenetic units. 1997. 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. and chlorinated benzenes). This factory produced vinyl chloride monomer and acrylonitrile. where the entire family. A higher frequency of undescended testes was observed in the newborns of mothers living in the town closest to the factory. high concentrations of endosulfan and lindane have been found in the adipose tissue of children). Driscoll and Taylor. Hadziselimovic et al (2000) recently compared estradiol levels in the placenta between newborns with cryptorchidism and normal male newborns. including cryptorchidism (using the Medical Birth Journal of Andrology · March/April 2003 Register). the adjoining province. 1980). but within this group. In Humans: The Evidence for Bioaccumulation of Some Chemical Compounds—To determine whether some pesticides and synthetic chemicals known to act as hormonal disruptors accumulate and persist in adipose tissue. High levels of estradiol were found in the placentas of neonates with cryptorchidism. including the mother. 1998).158 In Humans: The Dramatic Story of DES—One of the most documented deleterious actions of estrogens concerns the use of DES in pregnant women to prevent abortion complications (Brackbill and Berendes. 2 studies (Kristensen et al. 2) DES has a well-documented impact on undescended testes in male offspring. 1979. 3) Results of ecoepidemiological and occupational studies in humans are not totally conclusive on a direct relationship between environmental exposure (for example. Hosie et al (2000) used high-resolution gas chromatography and mass spectrometry to examine fat samples from 48 German patients. 1994). The prevalence of cryptorchidism was not higher in the sons of grain farmers. with the prevalence higher under conditions associated with the issue of fungal warnings. DES. In Norway. but heptachloroepoxide and hexachlorobenzene were present in signiﬁcantly higher concentrations in patients with undescended testes. In a follow-up study of DES exposure in males. 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. 1982). Cases with congenital abnormalities were identiﬁed from the data set of the Hungarian Congenital Abnormality Register. What Kind of Hormonal Mechanisms Could Be Involved in Cryptorchidism? The testicles descend in 2 distinct.5 years). They observed that the frequency of orchidopexy tended to be higher in districts near the Mediterranean Coast. To conclude this chapter on the potential impact of the environment on cryptorchidism: 1) Ecoepidemiological studies performed in various animal species are in favor of an impact of environmental pollutants (especially organochlorine pesticides) on reproductive disorders and on the unexpected high incidence of cryptorchidism. 18 of whom had undescended testes (mean age of 3. The ﬁrst phase of relative transabdominal migration (10–15 weeks of gestation) may be controlled by Mullerian inhibiting substance and ¨ . born alive from 1983 to 1992 (Weidner et al. a nonsteroidal estrogenic substance. 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. is involved in intensive farming and pesticide spraying (in Murcia province. 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 classiﬁcation). 2000) were performed to investigate adverse reproductive outcomes. no association was observed between genital abnormalities and ﬁrst-trimester exposure to sex hormones other than DES (Raman-Wilms et al. pesticides) and a high cryptorchidism incidence rate. 1. All substances tested were detected in both cases and controls (DDT and metabolites. 1978. Two points must be made concerning this study: 1) there was no matching for parity (maternal free estradiol levels are higher during the ﬁrst pregnancy than in subsequent pregnancies). hexachlorocyclohexane. hormonally regulated phases (Hutson et al. in Spain.47) but not in the sons of men working in horticulture. in a recent meta-analysis of fetal genital effects of ﬁrst-trimester sex hormone exposure. is associated with undescended testes in male offspring (Gill et al. which were used for the manufacture of stiffened plastic tubes and cartons for the packaging of margarine to be sold to local consumers. In Humans: Results of Epidemiological Studies of Occupational and Environmental Factors—In the province of Granada. In Denmark. in various Norwegian farming families involved in the production of grain and nongrain crops (identiﬁed by means of agricultural census). In Hungary. suggesting that there may be a similar increase in estradiol concentration in the fetal plasma during gestation. However.14–2.
To date. 2000. that industrial chemicals known to be potential endocrine disruptors are responsible for the recent increase in the number of cases of cryptorchidism (Safe. In animals. Mylchreest et al. harmonization is required concerning the precise deﬁnition of this malformation and its diagnostic criteria. 1991. In humans. As stated by several authors. at the present time. The second inguinoscrotal phase occurs at 26 to 35 weeks of gestation and seems to be androgen-dependent and possibly indirectly mediated by the release of calcitonin gene-related peptide from the genitofemoral nerve (Hutson et al. alkyl phenols. 1999). van der Schoot. 1999. No formal conclusions can be drawn. Indeed. 2000). to prenatal rats during the early gubernaculum outgrowth phase partially or completely inhibits testicular descent in rodents (Husmann and McPhaul. 1990). Zimmermann et al. Marin et al. 2001). The Antiandrogen Hypothesis—Administration of a potent nonsteroidal antiandrogen. The differences in incidence rates reported for cryptorchidism may result from biases due to the nonuniform deﬁnition of this condition. 1991. 1997. among other effects. 2000. 2000. 1997. 1999. 1982. Kassim et al. 1994. The Role of Competition in Bioavailability—Several 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. 1993. Maternal exposure in mice to estrogens. exogenous estrogens induce a reduction of gubernaculum outgrowth. Recent data in rodents suggest that insulin-3 may be a potential target for endocrine disruptors with estrogenic activities. 1999). Baker et al. the debate is still very open concerning the substances actually involved and the mechanisms by which they may cause cryptorchidism (Soto et al. Walk¨ er et al. 1991). in press). Certain chemical compounds (eg. a gubernacular derivative (Donaldson et al. Conclusion At the same time as a widespread increase in the incidence of testicular cancer (Huyghe et al. Similar conclusions have been already obtained by Bernstein et al (1998). However. and phthalates) that have been shown to have an antiandrogen activity (Goh et al. 1999. 1999. recent studies failed to ﬁnd any association between Insl3 gene mutation and human cryptorchidism (Koskimies et al. 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. The Estrogen Hypothesis—Experimental models in pregnant rodents have demonstrated that in utero exposure to estrogens can induce cryptorchidism. In a case-control study to assess the role of hormonal factors. 1995. Donnell et al. Nef et al. Other malformations (hypospadias. Moreover. Kelce and Wilson. The relatively high frequency of cryptorchidism and . such as ﬂutamide. providing a possible mechanism for cryptorchidism (Zimmermann et al. Spencer et al. 1995. indicating an androgen-independent pathway (Nef and Parada. Dechaud et al. endogenous estrogens could interfere with testicular descent via development of the gubernaculum testis. Emmen et al.and postnatal period failed to inhibit testicular descent in rats (Husmann and McPhaul. 1991. 2001. 1997). was recently shown to speciﬁcally down-regulate insulin-3 production in embryonic Leydig cells (Nef and Parada. and this may direct the search for potential similar risk factors (Fallon et al. as 70% of sexually mature mice with an estrogen receptor–disrupted mutation presented with cryptorchidism due to excessive development of the cremaster muscle. they found that cases had signiﬁcantly higher percentages of nonprotein-bound and albumin-bound estradiol than controls during the ﬁrst trimester of pregnancy: on average. Krausz et al. epididymal anomalies. vinclozolin. 1996). 2000). McMahon et al. Zakaria et al. 1996). the use of androgen receptor blockade with ﬂutamide in the peri. 2000). 1995. the main risk factor identiﬁed for cryptorchidism is deﬁnitely low birth weight (for equal gestational age). Recently. 2000). Insl3 knockout mice presented bilateral intra-abdominal cryptorchidism but normal androgenization of the other internal and external genitalia. a tendency toward an increase in the incidence of cryptorchidism has also been observed over recent decades in industrialized countries. Shono et al. Kelce et al. 1988. Massad and Barouki. including 17 and -estradiol and DES. and a stabilization of the Mullerian ducts (Grocock et al. and biphenols) may therefore displace endogenous sex steroid hormones from hSHBG sites. 1999.p -DDE. an induction of estrogen receptors within the Wolfﬁan ducts. insulin-like growth factor 3 (Insl3) was identiﬁed as a protein manufactured by Leydig cells that may have a role in testicular descent by causing normal gubernacular proliferation. 2002). Emmen et al. 1994. and inguinal hernia) are often observed in cases of cryptorchidism. Spencer et al. 2000).Thonneau et al · Cryptorchidism Incidence Rate probably also by other hormones. Joffe. However. Barthold and Redman. 1997. disrupting the androgen-to-estrogen balance (Danzo. pentachlorophenol. cases had 16% more bioavailable estradiol than controls. 1992. These results indicate that androgen inhibition during a brief period of embryonic development can block testicular descent in the rat. Douglas. The hypothesis that cryptorchidism may result from an 159 antiandrogen effect is based on toxicology results for certain pesticide compounds (p. 1994.
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