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Review |
From the * Human Fertility Research Group, Urology
and Andrology Department, and the Occupational
Medicine Department, La Grave Hospital, Toulouse, France.
| 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{at}chu-toulouse.fr). |
| Received for publication July 23, 2002; accepted for publication October 9, 2002. |
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 infertility, 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.
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 of cryptorchidism of 5.01% at birth and 1.78% at 3 months (John
Radcliffe Hospital Cryptorchidism Study Group,
1986,
1992).
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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 significant 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 definition 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 identified 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 States–Atlanta 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 cryptorchidism has remained more or less stable, with about 15 cases per 1000 from 1974 to 1996 in Norway. In France (Paris area), the incidence has increased slightly from 8 per 1000 in 1981 to 12 per 1000 in 1993 and is currently stable at this level. In England, similar trends toward a global increase in the incidence of cryptorchidism were observed until 1987, followed by a sudden drop linked to recent major changes in cryptorchidism coding. Unfortunately, the methodology used to assess cryptorchidism in these studies was not described, and the total number of diagnosed cases was not indicated, making interpretation of incidence rates very difficult and the comparison of trends impossible.
In conclusion to this chapter on the incidence of cryptorchidism, only a few reliable studies have been performed to evaluate trends in cryptorchidism incidence, and it is also difficult to compare data derived from different countries because of the lack of precise methodology. Nevertheless, 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. This tendency certainly needs to be confirmed by conducting new cohort studies with an adequate and standardized methodology (such as those described by Scorer [1964], for example).
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.
In London, 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, boys with a low birth weight, and boys born to primiparous or young mothers (<20 years). In Sweden, 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. A significant increase in the risk of cryptorchidism was found to be associated with the first birth, cesarean section or toxemia, and infants small for gestational age.
In the United States, Depue (1984) studied the cohort of the Collaborative Perinatal Project of the National Institute of Neurological and Communicative Disorders and Stroke. The risk of cryptorchidism was significantly higher in boys with low birth weight and when estrogens (estradiol, diethylstilbestrol [DES], and estrone) had been administered during gestation. In a prospective hospital-based cohort study conducted in New York, Berkowitz et al (1995) examined 6699 singleton male neonates delivered between 1987 and 1990. The risk of cryptorchidism was found to be high for infants born to obese mothers, delivered by cesarean section, with low birth weight or born preterm. In British Columbia, in a case-control study with 244 cases and 488 controls, 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, nausea, and vomiting) and cryptorchidism. These negative results were comparable to those observed by Beard et al (1984) with exposure to estrogens.
More recently, 4 case-control studies based on large numbers of individuals have been conducted in Sweden, Denmark, England, and Austria. In England, by using the Oxford Record Linkage Study, Jones et al (1998) conducted a case-control study to examine prenatal risk factors for cryptorchidism. Boys (n = 1449) treated for cryptorchidism by orchidopexy were compared with random matched controls from all live births (n = 10811). The risk of cryptorchidism was found to be higher for low birth weight and premature infants but also for low parity, low social class, breech presentation, and preeclampsia.
Weidner et al (1999) compared 6177 boys with cryptorchidism to 23 273 male controls born alive in Denmark from 1983 to 1992. The risk of cryptorchidism increased with decreasing birth weight, independently of the duration of gestation. The risk of cryptorchidism was almost 4 times higher when an older brother had a history of the same condition. Firstborn infants were at slightly higher risk than those of higher parity. Finally, twins were found to have a lower risk of cryptorchidism than singletons in the same birth weight classes.
In Sweden, Akre et al (1999) used record linkage between the Inpatient and Birth Registries to conduct a case-control study (nested in a nationwide cohort). The authors compared 2782 boys undergoing surgery for cryptorchidism with 13 916 random matched controls. 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.
In Austria, 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. The frequency of cryptorchidism was higher in the case of intrauterine growth retardation (low birth weights for equal gestational age), complicated deliveries, and chronic diseases in relatives. The authors also observed that first- and secondborn boys were overrepresented in the case group.
Finally, as stated by Moller and Weidner (1999), the essential problem is to integrate the risk of being born small for gestational age with other well-identified 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 sufficiently attractive to be confirmed by ongoing studies.
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, from invertebrates to mammals. One
interesting approach in this field is the methodology of ecoepidemiology,
which evaluates the contribution of environmental pollutants to specific
diseases observed in wildlife by distinguishing between genetic causes (for
example, inbreeding in isolated subpopulations) and environmental conditions
(Bowerman et al, 1995; Moline et al, 2000).
The history of the Florida panther illustrates this approach (Facemire et al, 1995). Florida panthers were found to display a large variety of endocrine and reproductive disorders, including a very high frequency of cryptorchidism (ca 90%). At first, researchers thought that inbreeding might account for the drastic reduction in Florida panther numbers and the observed reproductive disorders. After a more complete investigation of the dietary habits of the Florida panther, they proposed another possible explanation: exposure to environmental xenoestrogens (Florida panthers eat raccoons, which eat fish that have accumulated large amounts of endocrine-disrupting pesticides).
Another example of possible environmental contamination (organochlorine pesticides) is provided by juvenile alligators of Lake Apopka (Guillette et al, 1994, 1995) in Florida (which have smaller than normal penises, gonadal abnormalities, and low testosterone concentrations). Nevertheless, in a recent study (Guillette et al, 1999), the same authors found no relationship between phallus size and other body parameters, serum contaminant levels (organochlorine pesticides—polychlorinated biphenyls [PCBs]), and sex steroid concentrations (estradiol 17ß,testosterone). However, organochlorine pesticides and PCBs were detected at all sites, and serum testosterone concentrations were lower in males from Lake Apopka and Orange Lake than in controls from the Lake Woodruff National Wildlife Refuge. 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.
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, 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 first-trimester sex hormone exposure, no association was observed between genital abnormalities and first-trimester exposure to sex hormones other than DES (Raman-Wilms et al, 1995).
In Humans: Results of Epidemiological Studies of Occupational and Environmental Factors— In 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 classification). 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 significantly higher in sons of women working in horticulture (adjusted odds ratio = 1.67; 1.14–2.47) 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 identified 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 Register), in various Norwegian farming families involved in the production of grain and nongrain crops (identified by means of agricultural census). The prevalence of cryptorchidism was not higher in the sons of grain farmers, but within this group, prevalence depended on climatic conditions, with the prevalence higher under conditions associated with the issue of fungal warnings.
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, Hosie et al (2000) used high-resolution gas chromatography and mass spectrometry to examine fat samples from 48 German patients, 18 of whom had undescended testes (mean age of 3.5 years). All substances tested were detected in both cases and controls (DDT and metabolites, PCBs, taxophenes, hexachlorocyclohexane, chlorinated cyclodienes, and chlorinated benzenes), but heptachloroepoxide and hexachlorobenzene were present in significantly higher concentrations in patients with undescended testes.
Hadziselimovic et al (2000) recently compared estradiol levels in the placenta between newborns with cryptorchidism and normal male newborns. High levels of estradiol were found in the placentas of neonates with cryptorchidism, suggesting that there may be a similar increase in estradiol concentration in the fetal plasma during gestation. 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), and 2) free estradiol concentration was not determined (free estradiol may be the only bioavailable form) in these newborns.
To conclude this chapter on the potential impact of the environment on cryptorchidism:
What Kind of Hormonal Mechanisms Could Be Involved in
Cryptorchidism?
The testicles descend in 2 distinct, hormonally regulated phases
(Hutson et al, 1994). The
first phase of relative transabdominal migration (10–15 weeks of
gestation) may be controlled by Müllerian inhibiting substance and
probably also by other hormones. Recently, 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.
Indeed, Insl3 knockout mice presented bilateral intra-abdominal cryptorchidism
but normal androgenization of the other internal and external genitalia,
indicating an androgen-independent pathway
(Nef and Parada, 1999;
Zimmermann et al, 1999; Emmen et al, 2000). However,
recent studies failed to find any association between Insl3 gene mutation and
human cryptorchidism (Koskimies et al,
2000; Krausz et al,
2000; Marin et al,
2001; Baker et al,
2002).
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, 1994, 1997).
The Estrogen Hypothesis— Experimental models in pregnant rodents have demonstrated that in utero exposure to estrogens can induce cryptorchidism. In animals, among other effects, exogenous estrogens induce a reduction of gubernaculum outgrowth, an induction of estrogen receptors within the Wolffian ducts, and a stabilization of the Müllerian ducts (Grocock et al, 1988; Walker et al, 1990).
Moreover, endogenous estrogens could interfere with testicular descent via development of the gubernaculum testis, as 70% of sexually mature mice with an estrogen receptor–disrupted mutation presented with cryptorchidism due to excessive development of the cremaster muscle, a gubernacular derivative (Donaldson et al, 1996).
Maternal exposure in mice to estrogens, including 17
- and
ß-estradiol and DES, was recently shown to specifically down-regulate
insulin-3 production in embryonic Leydig cells
(Nef and Parada, 1999;
Nef et al, 2000).
Recent data in rodents suggest that insulin-3 may be a potential target for endocrine disruptors with estrogenic activities, providing a possible mechanism for cryptorchidism (Zimmermann et al, 1999; Emmen et al, 2000).
The Antiandrogen Hypothesis— Administration of a potent nonsteroidal antiandrogen, such as flutamide, to prenatal rats during the early gubernaculum outgrowth phase partially or completely inhibits testicular descent in rodents (Husmann and McPhaul, 1991; Spencer et al, 1991; van der Schoot, 1992; Shono et al, 1994; Kassim et al, 1997; Zakaria et al, 2000). However, the use of androgen receptor blockade with flutamide in the peri- and postnatal period failed to inhibit testicular descent in rats (Husmann and McPhaul, 1991; Spencer et al, 1991). These results indicate that androgen inhibition during a brief period of embryonic development can block testicular descent in the rat.
The hypothesis that cryptorchidism may result from an 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 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. 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 significantly higher percentages of nonprotein-bound and albumin-bound estradiol than controls during the first 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 definition of this condition. As
stated by several authors, harmonization is required concerning the precise
definition of this malformation and its diagnostic criteria.
To date, the main risk factor identified for cryptorchidism is definitely 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 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).
Footnotes
Supported by a grant from the UIPP (Union des Industries de la Protection des Plantes).
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