Published 2014; Reviewed and Validity Confirmed 2018

Cryptorchidism or undescended testis (UDT) is one of the most common pediatric disorders of the male endocrine glands and the most common genital disorder identified at birth. This clinical guideline discusses diagnosis and treatment to prevent future risks, including impairment of fertility potential, testicular malignancy, torsion and/or associated inguinal hernia.

Unabridged version of this Guideline [pdf]
Algorithm associated with this Guideline [pdf]
Appendices associated with this Guideline [pdf]

Thomas F. Kolon, C. D. Anthony Herndon, Linda A. Baker, Laurence S. Baskin, Cheryl G. Baxter, Earl Y. Cheng, Mireya Diaz, Peter A. Lee, Carl J. Seashore, Gregory E. Tasian, Julia S. Barthold

Purpose 

Cryptorchidism or undescended testis (UDT) is one of the most common pediatric disorders of the male endocrine glands and the most common genital disorder identified at birth. The main reasons for treatment of cryptorchidism include increased risks of impairment of fertility potential, testicular malignancy, torsion and/or associated inguinal hernia. Cryptorchidism has evolved significantly over the past half century, with respect to both diagnosis and treatment. The current standard of therapy in the United States is orchidopexy (also referred to as orchiopexy in the literature), or surgical repositioning of the testis within the scrotal sac, while hormonal therapy has fewer advocates. Successful scrotal relocation of the testis, however, may reduce but does not prevent these potential long-term sequelae in susceptible individuals. The purpose of this guideline is to provide physicians and non-physician providers (primary care and specialists) with a consensus of principles and treatment plans for the management of cryptorchidism. The panel members are representative of various medical specialties (pediatric urology, pediatric endocrinology, general pediatrics).

Methods

The primary source of evidence for this guideline was the systematic review conducted as part of the Agency for Healthcare Research and Quality (AHRQ) Comparative Effectiveness Review titled Evaluation and Treatment of Cryptorchidism (2012). That report included rigorous searches of MEDLINE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and EMBASE for English-language studies published from January 1980 through February 2012 relevant to cryptorchidism. To capture more recently published manuscripts and expand the body of evidence provided in the original AHRQ report, the American Urological Association (AUA) conducted additional supplementary searches of PubMed and EMBASE for relevant articles published between January 1980 and March 2013 that were systematically reviewed using a methodology developed a priori. In total, these sources yielded 704 studies, after exclusions, that were used to inform the statements presented in the guideline as Standards, Recommendations or Options. When sufficient evidence existed, the body of evidence for a particular clinical action was assigned a strength rating of A (high), B (moderate) or C (low). In the absence of sufficient evidence, additional information is provided as Clinical Principles and Expert Opinions. In 2018, this guideline underwent its first update literature review (ULR) where new evidence using the same methodology developed a priori from the original guideline were evaluated. The search period for the ULR extended from March 2013 to October 2018. A total of 93 references were included in the ULR evidence base, with the ULR panel finding no sufficient new evidence to alter existing guideline statements or to develop new ones. Additional supporting data were however added to the bibliography of the present guideline to emphasize the importance of counseling expectant and new parents about the potential risk of cryptorchidism associated with certain maternal risk factors.

Guideline Statements

Diagnosis

1. Providers should obtain gestational history at initial evaluation of boys with suspected cryptorchidism. (Standard; Evidence Strength: Grade B)

2. Primary care providers should palpate testes for quality and position at each recommended well-child visit. (Standard; Evidence Strength: Grade B)

3. Providers should refer infants with a history of cryptorchidism (detected at birth) who do not have spontaneous testicular descent by six months (corrected for gestational age) to an appropriate surgical specialist for timely evaluation. (Standard; Evidence Strength: Grade B)

4. Providers should refer boys with the possibility of newly diagnosed (acquired) cryptorchidism after six months (corrected for gestational age) to an appropriate surgical specialist. (Standard; Evidence Strength: Grade B)

5. Providers must immediately consult an appropriate specialist for all phenotypic male newborns with bilateral, nonpalpable testes for evaluation of a possible disorder of sex development (DSD). (Standard; Evidence Strength: Grade A)

6. Providers should not perform ultrasound (US) or other imaging modalities in the evaluation of boys with cryptorchidism prior to referral as these studies rarely assist in decision making. (Standard; Evidence Strength: Grade B)

7. Providers should assess the possibility of a disorder of sex development (DSD) when there is increasing severity of hypospadias with cryptorchidism. (Recommendation; Evidence Strength: Grade C)

8. In boys with bilateral, nonpalpable testes who do not have congenital adrenal hyperplasia (CAH), providers should measure Müllerian Inhibiting Substance (MIS or Anti- Müllerian Hormone [AMH]) level), and consider additional hormone testing, to evaluate for anorchia. (Option; Evidence Strength: Grade C)

9. In boys with retractile testes, providers should assess the position of the testes at least annually to monitor for secondary ascent. (Standard; Evidence Strength: Grade B)

Treatment

10. Providers should not use hormonal therapy to induce testicular descent as evidence shows low response rates and lack of evidence for long-term efficacy. (Standard; Evidence Strength: Grade B)

11. In the absence of spontaneous testicular descent by six months (corrected for gestational age), specialists should perform surgery within the next year. (Standard; Evidence Strength: Grade B)

12. In prepubertal boys with palpable, cryptorchid testes, surgical specialists should perform scrotal or inguinal orchidopexy. (Standard; Evidence Strength: Grade B)

13. In prepubertal boys with nonpalpable testes, surgical specialists should perform examination under anesthesia to reassess for palpability of testes. If nonpalpable, surgical exploration and, if indicated, abdominal orchidopexy should be performed. (Standard; Evidence Strength: Grade B)

14. At the time of exploration for a nonpalpable testis in boys, surgical specialists should identify the status of the testicular vessels to help determine the next course of action. (Clinical Principle)

15. In boys with a normal contralateral testis, surgical specialists may perform an orchiectomy (removal of the undescended testis) if a boy has a normal contralateral testis and either very short testicular vessels and vas deferens, dysmorphic or very hypoplastic testis, or postpubertal age. (Clinical Principle)

16. Providers should counsel boys with a history of cryptorchidism and/or monorchidism and their parents regarding potential long-term risks and provide education on infertility and cancer risk. (Clinical Principle)

Purpose

Cryptorchidism or undescended testis (UDT) is one of the most common pediatric disorders of the male endocrine glands and the most common genital disorder identified at birth. The main reasons for treatment of cryptorchidism include reducing the risks of impairment of fertility potential, testicular malignancy, torsion and/or associated inguinal hernia. Cryptorchidism has evolved significantly over the past half century, with respect to both diagnosis and treatment. The current standard of therapy in the United States is orchidopexy (also referred to as orchiopexy in the literature), or surgical repositioning of the testis within the scrotal sac, while hormonal therapy has fewer advocates. Successful scrotal relocation of the testis, however, may reduce but does not prevent all of these potential long-term sequelae in susceptible individuals. The purpose of this guideline is to provide physicians and non-physician providers (primary care and specialists) with a consensus of principles and treatment plans for the management of cryptorchidism. The panel members are representative of various medical specialties (pediatric urology, pediatric endocrinology, general pediatrics).

Methodology

Quality of Studies and Determination of Evidence Strength. The primary source of evidence for this guideline was the systematic review conducted as part of the Agency for Healthcare Research and Quality (AHRQ) Comparative Effectiveness Review titled Evaluation and Treatment of Cryptorchidism (2012). That report included rigorous searches of MEDLINE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and EMBASE for English-language studies published from January 1980 through February 2012 relevant to cryptorchidism. To capture more recently published manuscripts and expand the body of evidence provided in the original AHRQ report, the American Urological Association (AUA) conducted additional supplementary searches of PubMed and EMBASE for relevant articles published between January 1980 and March 2013 that were systematically reviewed using a methodology developed a priori. In total, these sources yielded 704 studies, after exclusions, that were used to inform the statements presented in the guideline as Standards, Recommendations or Options. Quality of individual studies was rated as high, moderate, or low based on instruments tailored to specific study designs. Randomized controlled trials (RCTs) were assessed using the Cochrane Risk of Bias tool.¹ Conventional diagnostic cohort studies, diagnostic case-control studies, or diagnostic case series that presented data on diagnostic test characteristics were evaluated using the QUADAS-2 tool² that evaluates the quality of diagnostic accuracy studies. Cohort studies with a comparison of interest were evaluated with the Drug Effectiveness Review Project instrument.³ The categorization of evidence strength is conceptually distinct from the quality of individual studies. Evidence strength refers to the body of evidence available for a particular question and includes consideration of study design, individual study quality, consistency of findings across studies, adequacy of sample sizes, and generalizability of samples, settings and treatments for the purposes of the guideline. The AUA categorizes body of evidence strength as Grade A (well-conducted RCTs or exceptionally strong observational studies), Grade B (RCTs with some weaknesses of procedure or generalizability or generally strong observational studies) or Grade C (observational studies that are inconsistent, have small sample sizes or have other problems that potentially confound interpretation of data). The quality of the evidence was variable depending on the issue examined. For many epidemiological issues there was a combination of moderate to large sized population-based studies, some of them prospective, being the key issue, as well as the consistency of findings. When evidence was consistent it was graded B, otherwise C. For issues related to management, studies tend to be non-randomized cohorts of moderate size or randomized trials of small to moderate size. Again the key issue was consistency of findings and the same criterion indicated above was applied. Seventy percent of the graded statements were considered level B (many under the AUA's premise of moderate quality, moderate certainty).

AUA Nomenclature: Linking Statement Type to Evidence Strength. The AUA nomenclature system explicitly links statement type to body of evidence strength and the Panel's judgment regarding the balance between benefits and risks/burdens.⁴ Standards are directive statements that an action should (benefits outweigh risks/burdens) or should not (risks/burdens outweigh benefits) be undertaken based on Grade A or Grade B evidence. Recommendations are directive statements that an action should (benefits outweigh risks/burdens) or should not (risks/burdens outweigh benefits) be undertaken based on Grade C evidence. Options are non-directive statements that leave the decision to take an action up to the individual clinician and patient because the balance between benefits and risks/burdens appears relatively equal or appears unclear; the decision is based on full consideration of the patient's prior clinical history, current quality of life, preferences and values. Options may be supported by Grade A, B or C evidence.

In some instances, the review revealed insufficient publications to address certain questions from an evidence basis; therefore, some statements are provided as Clinical Principles or as Expert Opinions with consensus achieved using a modified Delphi technique if differences of opinion emerged.⁵ A Clinical Principle is a statement about a component of clinical care that is widely agreed upon by urologists or other clinicians for which there may or may not be evidence in the medical literature. Expert Opinion refers to a statement, achieved by consensus of the Panel that is based on members' clinical training, experience, knowledge and judgment for which there is no evidence.

Limitations of the Literature. Limitations of the literature identified by both the AHRQ and the AUA reviews include, (1) lack of studies assessing the value of hormonal stimulation testing, long-term fertility outcomes, as well as inconsistent reporting of age at diagnosis and/or at treatment; (2) scant information about imaging effectiveness for modalities other than ultrasound (US) and magnetic resonance imaging (MRI); (3) low level evidence for the effectiveness of surgical treatment other than primary orchidopexy, accompanied by a lack of a standardized definition of success, follow-up length, reporting of complications, and control of confounding variables by indication; (4) inconsistent control of confounding variables among studies evaluating the epidemiology of cryptorchidism. This could be the result of the remaining uncertainty with respect to the etiological factors strongly and consistently associated with cryptorchidism.

Peer review. The AUA conducted an extensive peer review process. The initial draft of this Guideline was distributed to 84 peer reviewers of varying backgrounds, including those who applied through open comment; 43 responded with comments. The panel reviewed and discussed all submitted comments and revised the draft as needed. Once finalized, the Guideline was submitted for approval to the Practice Guidelines Committee (PGC). It was then submitted to the AUA Board of Directors for final approval.

Update Literature Review. In 2018, this guideline underwent its first ULR where new evidence using the same methodology developed a priori from the original guideline were evaluated. The search period for the ULR extended from March 2013 to October 2018. A total of 93 references were included in the ULR evidence base, with the ULR panel finding no sufficient new evidence to alter existing guideline statements or to develop new ones. Additional supporting data were, however, added to the bibliography of the present guideline to emphasize the importance of counseling expectant and new parents about the potential risk of cryptorchidism associated with certain maternal risk factors.

Definitions

Cryptorchidism, or undescended testis (UDT), is defined as failure of a testis to descend into a scrotal position. This situation most commonly refers to a testis that is present but in an extrascrotal position, but may also lead to identification of an absent testis. In the latter situation, the testis is most commonly referred to as vanishing (or vanished); consistent with evidence suggesting that it was present initially but disappeared during development most likely due to spermatic cord torsion or vascular accident.

Congenital cryptorchidism refers to testes that are extrascrotal from the time of birth. Acquired cryptorchid testes are intrascrotal at birth but subsequently identified in an extrascrotal position. Cryptorchid testes may be prescrotal (above or at the scrotal inlet), in the superficial inguinal pouch (distal and lateral to the external inguinal ring, anterior to the rectus muscle), at the external ring (or prepubic), canalicular (within the inguinal canal), ectopic (most commonly perineal) or abdominal ("peeping" through or proximal to the internal inguinal ring, or near the bladder, iliac vessels or kidney).

Acquired cryptorchid testes are considered ascending, when apparent change from an intrascrotal to an extrascrotal position occurs spontaneously at some point after birth, or entrapped, when such change occurs after prior inguinal surgery. A retractile testis is one that is initially extrascrotal on examination or moves easily out of scrotal position, (often associated with a vigorous cremasteric reflex), but that can be manually replaced in stable, dependent scrotal position and remain there without tension at least temporarily. An atrophic testis is one that suffers significant volume loss after prior inguinal or testicular surgery, or due to prolonged location in an extrascrotal position or primary developmental failure.

Epidemiology

Prevalence/incidence of congenital v. acquired cryptorchidism. Although delayed diagnosis or treatment of cryptorchidism beyond the neonatal period is well-documented, the relative proportion of cases of true testicular ascent v. congenital cases that were not identified and/or referred early for care remains unclear. ^{6, 7, 8, 9} However, the preponderance of data strongly supports the existence of acquired cryptorchidism as a real phenomenon whose prevalence may be similar to that of congenital cryptorchidism. In a population-based health registry study, cryptorchidism was frequently diagnosed beyond the newborn period, and there were no age-specific differences in time between diagnosis and surgical correction.¹⁰ Similarly, in birth cohort studies,^{9, 11} suprascrotal testes were newly diagnosed in about 2% of boys examined longitudinally at intervals up to 10 years of age. Spontaneous descent of congenitally cryptorchid testes occurred in 35-43% of newborn boys followed longitudinally, usually prior to 3 months of age,^{9, 11, 12} but re-ascent (recurrent cryptorchidism) may occur, and was reported in 22% of boys in a recent prospective study.¹³ In a referral population, Wenzler et al.¹⁴ documented spontaneous descent in 24% of boys presenting prior to age 4 months and none presenting at or after 6 months, or a total of 6.9% of boys presenting in the first year of life. The overall rate of spontaneous descent in this latter study may be low because the referral population likely excluded cases of early postnatal spontaneous descent.

Sijstermans et al.¹⁵ compiled a systematic review estimating the prevalence of cryptorchidism by different ages and birth weights (Table 1). They identified 97 articles, but only 49 remained eligible. These studies were conducted between 1934 and 2006. Thirty-eight studies (83%) were prospective, and the other eleven were retrospective, totaling over 704,000 males. Fifty percent of the studies used a formal definition to identify and diagnose cryptorchidism, although these definitions varied widely. Ten percent of articles used the definition by Scorer¹⁶ that considers all testes at least 4 cm below the pubic crest in full term males (2.5 cm in preterm males) as descended; 41% included location in the definition, and 13% excluded high scrotal testes.

Table 1: Prevalence of cryptorchidism

*Adapted from Sijstermans K, Hack WW, Meijer RW et al: The frequency of undescended testis from birth to adulthood: a review. Int J Androl 2008; 31: 1.

It can be seen that for boys up to one year of age and of normal weight, the estimates are rather stable, while for the same age range but low birth weight they vary widely. This age group constitutes 57% of the studies with over 591,000 infants. It is important to highlight, as indicated by the authors of the compendium, that low birth weight and prematurity were often used synonymously. The prevalence for boys three years and older is again rather stable between null and 6.6%. In addition to birth weight and prematurity, the authors indicate that the lack of distinction between congenital (never descended from birth) and acquired (previously scrotal) cryptorchidism may explain the differences in rates. The distinction between congenital and acquired cryptorchidism could not be made for the majority of these studies as only 5 (11%) of the studies reviewed included data documenting prior testicular position.

In a large population-based study of 819,111 non-syndromic boys in Denmark, Jensen and colleagues analyzed associations between birth weight, prematurity and cryptorchidism, which occurred in 14.1 cases out of 1000 boys.¹⁷ When correcting birth weight for gestational age, only boys in the lowest quintile (<20^th percentile) were at increased risk for cryptorchidism (OR 1.4, 95% CI 1.3-1.5).

Barthold and González (2003)¹⁸ performed a review of epidemiological issues relevant to acquired cryptorchidism. One of the issues they addressed was the incidence of testicular ascent among boys with completely descended testes at birth. Eleven studies have reported these cases (see evidence table in Appendix A). The studies reviewed by these authors performed a lengthy follow-up in which a normal position was recorded prior to discovery of testicular ascent. The mean age at surgery in most series was seven years. They found that the ascended testis is generally unilateral and most likely located distal to the inguinal ring (prescrotal, superficial inguinal pouch or high scrotal).

Genetic susceptibility. In a large population-based twin study, Jensen et al. observed increasing concordance rates of treated cryptorchidism based on family relationships: 1.8% in unrelated males, 2.4-4.3% in half-brothers, 7.5% in full brothers, and 16.7% in dizygotic and 26.7% in monozygotic twins.¹⁹ These data suggest both unknown genetic and environmental factors contribute to cryptorchidism risk.

Animal models of cryptorchidism, mostly knockout mice, have identified insulin-like 3 (INSL3) and its receptor relaxin/insulin-like family peptide receptor 2 (RXFP2), also known as leucine-rich repeat-containing G protein-coupled receptor 8 (LGR8), as molecules involved in the genesis of cryptorchidism. However, despite a large number of studies comprising over 1,000 patients screened for mutations in the INSL3 and RXFP2 genes, few clear exonic variants have been identified that are likely functional mutations (see Table 2), and there is poor correlation between these variants and clinical phenotype.²⁰ While the T222P mutation of RXFP2 significantly reduces INSL3 signaling experimentally,²¹ it is also found in normal controls.^{22, 23}

Table 2: Summary of exonic variants in INSL3 and RXFP2 in cryptorchidism

Two other potential candidate genes, androgen receptor (AR), and estrogen receptor alpha (ESR1) are involved in sex hormone function. Exon 1 of the AR gene encodes highly polymorphic polyglutamine (CAG) and polyglycine (GGN) repeat sequences. In vitro assays have demonstrated that CAG repeat expansion or GGN deletion is associated with diminished transcriptional activity of the receptor.²⁴ Five different cohorts^24-28 have examined the potential association between AR exonic repeats and cryptorchidism by testing the difference in the mean number of repeats between cases and controls (see evidence table in Appendix B). Three of these studies identified no differences in repeat length between cases and controls, one reported increased CAG repeat length in two small subgroups of Portuguese males (six bilateral cryptorchidism and seven unilateral with contralateral patent processus vaginalis),²⁸ and the largest study reported reduced CAG repeats in Hispanic cryptorchid males from California.²⁵ GGN repeat length was higher in cryptorchid cases than controls in one study.²⁴

For the ESR1 gene, efforts have focused on the potential difference in the frequency distribution of alleles A and G between cases and controls for SNP12 (rs6932902). This SNP12 has been labeled as the tag SNP of the 5-SNP haplotype AGATA. Such allele frequency distributions have been assessed in three independent groups of cases and controls from three different ethnic backgrounds with disparate results (see evidence table in Appendix C). The A allele has been found to confer susceptibility to Japanese men,²⁹ (OR1.99, 95% CI 1.07, 3.67), seems protective among Caucasian men from Italy (OR 0.5, 95%CI 0.28, 0.90),³⁰ and showed lack of association among a multi-ethnic US cohort.³¹ For the latter, the allele frequency for G was significantly different between moderate and severe cases (OR 10.0, 95% CI 1.2, 78.2).

In summary, although there is some suggestion that the examined genomic loci may contribute to cryptorchidism susceptibility, the evidence is weak at this point and likely due to the multifactorial nature of the trait, the heterogeneous phenotypic manifestation of cryptorchidism as well as the lack of simultaneous assessment of potential gene-environment interactions.

Familial Aggregation

Two studies have explored the risk of UDT in an individual with a family history. Elert et al³² assessed the familial risk in a group of 374 cases and 374 controls in Germany. Cases were identified in boys and men who underwent surgery for UDT between 1989 and 2001. The mean age of these males at surgery was 6 years (range 1-39 years). They found that 85 cases (23%) v. 28 controls (7.5%) had one or more family members with UDT for an overall risk of 3.6 (95% CI 2.3, 5.7). The highest risk was present if the family member was a brother (95% CI 6.9 [2.7, 17.9]), followed by an uncle (95% CI 5.2 [1.8, 15.4]) and then by the father (95% CI 4.6 [2.0, 10.6]).

The second study was a large population-based study conducted in Denmark between 1977 and 2005.³³ Danish boys were identified from the Civil Registration Systems and their relatives from the Danish Family Relations Database. The cryptorchidism status was gathered from the Danish Hospital Discharge Register. Using these data sources, of 42,105 cases, 20,398 (48.5%) were confirmed surgically. The measure of risk the authors used is the recurrence risk ratio (RRR), the ratio between cryptorchidism prevalence for individuals with a proband (older affected relative) and the prevalence of cryptorchidism for individuals with known relatives of the same kind where none of them is a proband. For twin pairs, a weighted average contribution from dizygotic and monozygotic twins was applied. Given their almost equal distribution in this cohort, a weight of 0.5 was assigned for each. The RRR was 10.1 (95% CI: 7.78, 13.1) in twins, 3.52 (95% CI: 3.26, 3.79) in brothers, 2.31 (95% CI: 2.09, 2.54) in sons, 2.12 (95% CI: 1.74, 2.60) in maternal half-brothers and 1.28 (95% CI: 1.01, 1.61) in paternal half-brothers. This led the authors to conclude that the maternal contribution is greater than the paternal one, suggesting either an X-linked mode of inheritance or a combination of genetic factors and maternal environment. Elert et al.³² noted similar findings in a much smaller cohort study, but did not observe a difference in rates for maternal and paternal inheritance.

Environmental Exposure. The possibility that environmental chemicals alter normal reproductive tract development has been debated in the recent literature. There is significant potential concern that endocrine-disrupting chemicals may be linked to male reproductive tract anomalies that may have a common etiology, including cryptorchidism (sometimes termed 'testicular dysgenesis syndrome').^{34, 35} Concerns for a connection between endocrine-disrupting chemicals and cryptorchidism developed because of a reported higher risk related to early maternal exposure to diethylstilbestrol (DES).

Environmental Chemicals

A quantitative summary of the potential effect of exposure to pesticides and the risk of cryptorchidism is not possible because of the large variability on study designs, exposure and outcome assessment and measurement. Virtanen and Adamsson (2012)³⁶ qualitatively summarized 18 studies in 2012. Two large ecological studies with adequate power found different results based on the pesticide use in the area; one a significant positive association and the other a non-significant positive association. Ten studies assessing exposure in terms of parental occupation, primarily in agriculture and gardening also had sufficient power. Outcomes differed with four studies indicating a positive significant association, three a non-significant association, and three studies reporting a decreased risk. Six studies assessed the exposure in terms of pesticide levels in biological specimens, assessing the exposure in a more direct fashion, but were inconclusive because of small sample size.

There have been a number of case control studies assessing other chemicals such as polychlorinated biphenyls (PCBs), dioxins, flame retardants and phthalates. These studies have been of small sample size and have not demonstrated statistical significance.^36-41

Incidence seasonality

Mamoulakis et al.⁴² examined the significance of seasonal trends in cryptorchidism incidence among over 209,000 live-born boys in Greece between 1995 and 1999. The incidence of cases at birth was cyclic with a peak in March (61.0) and a trough in September (36.1). After exclusions, 583 isolated true cryptorchid cases were identified. The authors reported that maternal hCG levels at 26 weeks gestation were lower in winter months and suggest that low environmental temperature may influence maternal hCG profiles and hence the inguinoscrotal phase of testicular descent. However, this finding is of questionable relevance as the authors did not compare hCG in pregnancies with and without cryptorchid fetuses, and hCG levels are normally very low after the first trimester.

Three other studies were cited with a large number of cryptorchid cases conducted in European countries in which March is the month with peak incidence for cryptorchidism births. A fourth study in the United States of America found two peaks: one during September-November when a trough was observed in the other studies and a second smaller peak during March-May.

Maternal environment

Maternal Body Mass Index (BMI)

Adams et al.⁴³ conducted a population-based case-control study using birth record data from the state of Washington during the period 1992-2008. The authors discuss three potential mechanisms relating maternal obesity to the risk of cryptorchidism and hypospadias. These are, (1) levels of circulating hormones, (2) lower overall diet quality and blood concentrations of micronutrients, (3) impaired fasting glucose and glucose tolerance before and during pregnancy. Five randomly selected controls from the same birth year were assigned to each of the 3,946 cases of cryptorchidism. Maternal BMI was missing in 30% of cases and 28% of controls. Cryptorchidism and hypospadias may be more common in first pregnancies. Maternal weight was collected from the birth certificates, while height was collected from the driver's licenses prior to 2003, and from the birth certificates from 2003 onwards. BMI was categorized using the World Health Organization (WHO) thresholds. No association between BMI and the incidence of cryptorchidism was found based on odds ratios adjusted for year of birth, maternal age, education, parity, race, and cigarette smoking during pregnancy. Based on a reference group of mothers with normal weight, the adjusted odds ratio for underweight mothers was 1.14 (95% CI 0.93, 1.39); for overweight 1.03 (95% CI 0.93, 1.14) and for obese mothers 0.99 (95% CI 0.89, 1.11). Similarly, no effect was observed when weight was analyzed as a continuous variable with changes measured per each 5 kg/m2, OR=1.01 (95% CI 0.97, 1.05).

Maternal hypertension

Arendt et al. conducted a population-based cohort study evaluating boys born between 1978 and 2012 who, along with their mothers had a valid personal identification number to enable the linking of long-term follow-up data with the Danish Medical Birth Register.⁴⁴ By classifying their mothers into categories based on the presence of a hypertensive disorder in pregnancy identified using ICD-8, ICD-9 or ICD-10 codes, they were able to analyze the risk of cryptorchidism by types of hypertensive disorders in pregnancy, against a reference group of mothers who did not have any form of hypertension in pregnancy. A total of 5,098 boys were born to mothers who had pre-gestational hypertension, 9,283 boys were born to mothers who had gestational hypertension, 32,427 boys were born to mothers who had pre-eclampsia or eclampsia, including HELLP syndrome and 1,026,218 boys were born to mothers who had no hypertensive disorder in pregnancy. Pre-gestational hypertension (HR=1.3, 95% CI 1.1, 1.6), gestational hypertension (HR=1.2, 95% CI 1.1, 1.4), moderate pre-eclampsia (HR=1.2, 95% CI 1.1, 1.4), severe pre-eclampsia (HR=1.7, 95% CI 1.4, 2.0) and HELLP syndrome (HR=2.1, 95% CI 1.4, 3.2) were associated with a greater likelihood of cryptorchidism, after adjusting for maternal age at birth in years, parity, maternal years of education, maternal nationality, calendar year at birth and maternal diabetes, and accounting for clustering within families using robust standard errors. Further analysis was conducted to examine if timing of onset of pre-eclampsia/eclampsia influenced the risk of cryptorchidism. Pre-eclampsia or eclampsia occurring <34 weeks of gestation was found to be associated a greater likelihood of cryptorchidism compared to children born to mothers with no pre-eclampsia/eclampsia (HR=1.8, 95% CI 1.6, 2.1) while no significant difference was found between mothers who developed pre-eclampsia/eclampsia at ≥34 weeks of gestation and those who did not have pre-eclampsia/eclampsia (HR=1.1, 95% CI 1.0, 1.2) after controlling for the same confounders listed above. Through restricted cubic spline regression to analyze a possible non-linear association between the risk of cryptorchidism and gestational age at onset of moderate and severe pre-eclampsia, the authors found the strongest association between early onset severe pre-eclampsia and cryptorchidism, and weak associations between late-onset and moderate pre-eclampsia, overall supporting the hypothesis that placental dysfunction may be an underlying reason. By relying on registry data, the potential of misclassification of confounders, and the inability to obtain all possible confounders introduces limitations to the interpretation of the data. Furthermore, pre-eclampsia and eclampsia are often associated with preterm births, which may be an important element that mediates the observed association between earlier age at onset of pre-eclampsia or eclampsia, and cryptorchidism.

Maternal diabetes

Arendt et al. conducted another population-based cohort study using birth registry data from the Danish (1978-2012) and Swedish (1987-2012) population, whereby 7,526 singleton boys born to mothers with pre-gestational type 1 or 2 diabetes, 8,990 boys born to mothers with gestational diabetes and 1,026,218 boys born to mothers without diabetes, were examined.⁴⁵ Both pre-gestational (overall HR: 1.40, 95% CI 1.23, 1.59) and gestational diabetes (HR=1.21, 95% CI 1.07, 1.37) were found to be associated with an increased risk of cryptorchidism, with the preponderance increasing among mothers who developed diabetic complications associated with pre-gestational diabetes (HR=1.92, 95% CI 1.39, 2.65), after adjusting for maternal age, parity, maternal years of education, maternal nationality and calendar year of birth.

Maternal smoking

Hackshaw et al.⁴⁶ performed a systematic review of articles published in English between 1959 and February 2010 regarding the association between maternal smoking in pregnancy and birth defects, including cryptorchidism. Study designs included cohort, case-control, and surveys. Eighteen studies provided data for cryptorchidism (8,753 cases and 98,627 controls). Overall, mothers who reported smoking during pregnancy were 13% more likely to have a child with cryptorchidism (OR=1.13, 95% CI 1.02, 1.25); although this estimate includes moderate heterogeneity I²=39%; individual study estimates ranged between OR=0.41 and OR=1.69. A second estimate was calculated based on 15 studies that adjusted for potential confounders. These 15 studies assessed 8,258 boys with cryptorchidism and 72,224 controls. The overall estimate was not different to the unadjusted estimate (OR=1.16, 95% CI 1.08, 1.25).

A meta-analysis performed by Zhang et al.⁴⁷ in 2015 included 25 studies published between 1984 and 2014, sixteen of which had been analyzed in the Hackshaw 2011 systematic review⁴⁶ described earlier. A total of 11,897 cases and 63,380 controls were analyzed. This meta-analysis showed that mothers who reported smoking during pregnancy were 17% more likely to have a child with cryptorchidism (OR=1.17, 95% CI 1.11, 1.23) with low between-study heterogeneity (I2) of 28.3%. Additionally, Kjesgaard et al.⁴⁸ conducted a population-based study which evaluated 1,864 boys with a diagnosis of cryptorchidism (1,098 of whom were boys with cryptorchidism who underwent surgery) and 84,000+ healthy controls from the Danish National Birth Cohort and Aarhus Birth Cohort. The authors found that among mothers who stopped smoking during the first trimester of pregnancy (HR=1.19, 95% CI 1.03, 1.38) and among mothers who smoked between 10-14 cigarettes/day during pregnancy (HR=1.37, 95% CI 1.06, 1.76), the likelihood of having a child with cryptorchidism remained higher after adjusting for maternal years of education, maternal age at delivery, parity, calendar year, cohort, mothers’ caffeine intake and alcohol intake, maternal pre-pregnancy BMI and time to index pregnancy, compared to non-smokers. Among mothers who reported smoking 1-9 cigarettes/day or ≥15 cigarettes/day, the effect estimates after adjusting for confounders ranged between 1.11 and 1.18, but the authors found no statistical significance.

Maternal alcohol consumption

Three studies conducted in Denmark^10,49-51 and one in the United States⁵² examined the potential association between maternal alcohol consumption during pregnancy and the risk of cryptorchidism in a prospective fashion (see Appendix D). The disparity in outcome measure used (two used odds ratio, one risk ratio and the other hazard ratio) precludes quantitative aggregation but allows qualitative summarization. Alcohol consumption was found to be associated with transient cryptorchidism if the mother consumed five or more drinks per week, adjusted OR 3.10, 95% CI 1.05, 9.10).⁴⁹ This finding was not present among boys with persistent cryptorchidism, adjusted risk ratio 0.70 (95% CI 0.40, 1.30).⁴⁹ The third Danish study⁵⁰ aimed at assessing in more detail the association of binge drinking with persistent cryptorchidism rather than regular alcohol consumption did not find a statistical effect. The American study also failed to find an association.⁵²

Maternal analgesic consumption

Four cohort studies^53-56 reported the incidence/prevalence of cryptorchidism in infants and young boys born from mothers who reported on the use of mild analgesics (COX inhibitors) during pregnancy. The underlying hypothesis is that COX inhibitors may impede prostaglandin production by a mechanism not completely elucidated yet. Prostaglandins are necessary for male sexual differentiation. Three of the studies^53,54,56 show that the use of mild analgesic, mainly paracetamol, during the second trimester (end of the defined "programmatic window") increases the risk for cryptorchidism.

The way exposure information was collected does not allow us to determine whether consumption in both first and second trimester is necessary, and more precisely, when within these two periods the exposure increases the risk. This was the case in the study by Jensen et al.⁵³ where the risk of cryptorchidism did not increase if exposure to analgesic was in the first or second trimester alone, but when both combined the risk increased. The rate of exposure ranged between 47% and 81% and was by far most common for paracetamol.

The association between maternal analgesic consumption and cryptorchidism estimated from multivariable models ranged between a hazard ratio of 1.33 for paracetamol consumed in the first and second trimester,⁵³ to an odds ratio of 1.89 for paracetamol consumed in the second trimester (unknown whether also consumed during the first),⁵⁶ to an odds ratio of 2.30 for any mild analgesic consumed during the second trimester (again unknown whether consumed during the first).⁵⁴ Two of the studies (conducted in Denmark)^53,54 also showed that use of any mild analgesic for over two weeks increased the odds of cryptorchidism.⁵⁴ In another study,⁵³ the odds of cryptorchidism increased when the prolonged analgesic use was for more than four weeks during weeks 8-14 of gestation.

Maternal estrogen exposure

Vidaeff and Sever⁵⁷ performed a systematic review of articles published in English, French, Italian and Spanish between 1990 and 2003 dealing with prenatal exposure to endocrine disruptors, xenoestrogens and/or environmental estrogens. Articles were included if they reported the adverse effect of these exposures on cryptorchidism, hypospadias, or impaired sperm quality. Nine studies were identified, but heterogeneity of retrieved information precluded aggregation into meta-analysis. Three large studies report a positive association between pesticide exposure and cryptorchidism. The authors caution about the complex nature of both the components of the exposure and the pathogenic mechanisms involving multifactorial origin and potential trans-generation effects. Available data do not support with certainty the potential contribution of environmental estrogens to an increase in male reproductive disorders, but also do not provide sufficient information to totally reject such hypotheses.

Martin et al.⁵⁸ performed a meta-analysis aimed at assessing the role of estrogen in components of the testicular dysgenesis syndrome (TDS), namely hypospadias, cryptorchidism, and testicular cancer. It excluded exposure to suspected endocrine disruptors for which the mode of action was unspecified (e.g., pesticides), exposures to phytoestrogens, and maternal endogenous hormones. Only three studies examining DES exposure show an association with cryptorchidism based on a fixed effect model (OR 2.09, 95% CI 1.13, 3.86) but not if based on a random effects model (OR 1.80, 95% CI 0.83, 3.93).

Providers should obtain gestational history at initial evaluation of boys with suspected cryptorchidism. (Standard; Evidence Strength: Grade B)

Primary care providers should palpate testes for quality and position at each recommended well-child visit. (Standard; Evidence Strength: Grade B)

Providers should refer infants with a history of cryptorchidism (detected at birth) who do not have spontaneous testicular descent by six months (corrected for gestational age) to an appropriate surgical specialist for timely evaluation. (Standard; Evidence Strength: Grade B)

Providers should refer boys with the possibility of newly diagnosed (acquired) cryptorchidism after six months (corrected for gestational age) to an appropriate surgical specialist. (Standard; Evidence Strength: Grade B)

Providers must immediately consult an appropriate specialist for all phenotypic male newborns with bilateral, nonpalpable testes for evaluation of a possible disorder of sex development (DSD). (Standard; Evidence Strength: Grade A)

Providers should not perform ultrasound (US) or other imaging modalities in the evaluation of boys with cryptorchidism prior to referral, as these studies rarely assist in decision making. (Standard; Evidence Strength: Grade B)

Providers should assess the possibility of a disorder of sex development (DSD) when there is increasing severity of hypospadias with cryptorchidism. (Recommendation; Evidence Strength: Grade C)

In boys with bilateral, nonpalpable testes who do not have congenital adrenal hyperplasia (CAH), providers should measure Müllerian Inhibiting Substance (MIS or Anti- Müllerian Hormone [AMH]) and consider additional hormone testing to evaluate for anorchia. (Option; Evidence Strength: Grade C)

In boys with retractile testes, providers should assess the position of the testes at least annually to monitor for secondary ascent. (Standard; Evidence Strength: Grade B)

Providers should not use hormonal therapy to induce testicular descent as evidence shows low response rates and lack of evidence for long-term efficacy. (Standard; Evidence Strength: Grade B)

In the absence of spontaneous testicular descent by six months (corrected for gestational age), specialists should perform surgery within the next year. (Standard; Evidence Strength: Grade B)

In prepubertal boys with palpable, cryptorchid testes, surgical specialists should perform scrotal or inguinal orchidopexy. (Standard; Evidence Strength: Grade B)

In prepubertal boys with nonpalpable testes, surgical specialists should perform examination under anesthesia to reassess for palpability of testes. If nonpalpable, surgical exploration and, if indicated, abdominal orchidopexy should be performed. (Standard; Evidence Strength: Grade B)

At the time of exploration for a nonpalpable testis in boys, surgical specialists should identify the status of the testicular vessels to help determine the next course of action. (Clinical Principle)

In boys with a normal contralateral testis, surgical specialists may perform an orchiectomy (removal of the undescended testis) if a boy has a normal contralateral testis and either very short testicular vessels and vas deferens, dysmorphic or very hypoplastic testis, or postpubertal age. (Clinical Principle)

Providers should counsel boys with a history of cryptorchidism and/or monorchidism and their parents regarding potential long-term risks and provide education on infertility and cancer risk. (Clinical Principle)

More research is needed to address long-term follow-up of surgically treated ascending UDTs. These studies should compare fertility and testis cancer rates with UDTs identified and treated in infancy.

Additionally, a randomized control trial is needed to compare long-term testicular function after one-stage versus two-stage laparoscopic Fowler-Stephens abdominal orchidopexy. While a one-stage approach has a slightly lower success rate, the two-stage approach has added risks. A similar comparison of open versus laparoscopic abdominal orchidopexy could be employed.

Continued research should also investigate the effects of genetic susceptibility and environmental toxins on the risk of cryptorchidism and/or testicular maldevelopment.

Studies of paternity in patients surgically treated for cryptorchidism, and its correlation with semen analysis, androgen function, and testis histology data as available, are needed.

Long-term outcome data are needed in boys with monorchidism due to a vanishing testis and monorchidism; additional research should whether excision of the vanishing testis is indicated and the necessity for scrotal fixation of the contralateral testis.

Finally, further studies are needed to determine whether orchiopexy between six and eighteen months of age is superior to later surgical treatment in improving fertility potential in adulthood.

Patient Education Resources

Additional Educational Resources Available

Cryptorchidism – Clinical Problem Solving (CPS) Protocol

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This document was written by the Cryptorchidism Panel of the American Urological Association Education and Research, Inc., which was created in 2013. The Practice Guidelines Committee (PGC) of the AUA selected the committee chair. Panel members were selected by the chair. Membership of the committee included urologists and other clinicians with specific expertise on this disorder. The mission of the committee was to develop recommendations that are analysis-based or consensus -based, depending on Panel processes and available data, for optimal clinical practices in the treatment cryptorchidism. Funding of the committee was provided by the AUA. Committee members received no remuneration for their work. Each member of the committee provides an ongoing conflict of interest disclosure to the AUA. While these guidelines do not necessarily establish the standard of care, AUA seeks to recommend and to encourage compliance by practitioners with current best practices related to the condition being treated. As medical knowledge expands and technology advances, the guidelines will change. Today these evidence-based guidelines statements represent not absolute mandates but provisional proposals for treatment under the specific conditions described in each document. For all these reasons, the guidelines do not pre-empt physician judgment in individual cases. Treating physicians must take into account variations in resources, and patient tolerances, needs, and preferences. Conformance with any clinical guideline does not guarantee a successful outcome. The guideline text may include information or recommendations about certain drug uses ('off label') that are not approved by the Food and Drug Administration (FDA), or about medications or substances not subject to the FDA approval process. AUA urges strict compliance with all government regulations and protocols for prescription and use of these substances. The physician is encouraged to carefully follow all available prescribing information about indications, contraindications, precautions and warnings. These guidelines and best practice statements are not in-tended to provide legal advice about use and misuse of these substances. Although guidelines are intended to encourage best practices and potentially encompass available technologies with sufficient data as of close of the literature review, they are necessarily time-limited. Guidelines cannot include evaluation of all data on emerging technologies or management, including those that are FDA-approved, which may immediately come to represent accepted clinical practices. For this reason, the AUA does not regard technologies or management which are too new to be addressed by this guideline as necessarily experimental or investigational.

List of Abbreviations