Measurements of Serum Müllerian Inhibiting Substance in the Evaluation of Children with Nonpalpable Gonads
Mary M. Lee, M.D., Patricia K. Donahoe, M.D., Bernard L. Silverman, M.D., Tomonobu Hasegawa, M.D., Yukihiro Hasegawa, M.D., Michael L. Gustafson, M.D., YuChiao Chang, Ph.D., and David T. MacLaughlin, Ph.D.
Background Müllerian inhibiting substance, produced constitutivelyby the prepubertal testes, promotes involution of the müllerianducts during normal male sexual differentiation. In childrenwith virilization and nonpalpable gonads, only those with testiculartissue should have detectable serum concentrations of müllerianinhibiting substance.
Methods We measured serum müllerian inhibiting substancein 65 children with virilization at birth and nonpalpable gonads(age at diagnosis, 2 days to 11 years) and serum testosteronein 54 of them either after the administration of human chorionicgonadotropin or during the physiologic rise in testosteronethat occurs in normal infants.
Results The mean (±SD) serum müllerian inhibitingsubstance concentration in the 17 children with no testiculartissue was 0.7±0.5 ng per milliliter, as compared with37.5±39.6 ng per milliliter in the 48 children with testes(P<0.001). In the latter group, the mean values in the 14children with abnormal testes and the 34 with normal testeswere 11.5±11.8 and 48.2±42.1 ng per milliliter,respectively (P< 0.001). The sensitivity and specificityof the serum müllerian inhibiting substance assay for detectingthe absence of testicular tissue were 92 percent and 98 percent,respectively, as compared with 69 percent and 83 percent forthe measurement of serum testosterone. Furthermore, measurementof serum müllerian inhibiting substance was more sensitivethan serum testosterone measurement for the identification ofchildren with abnormal testes (67 percent vs. 25 percent), whereasthe specificity of the two tests was similar.
Conclusions Measurements of serum müllerian inhibitingsubstance can be used to determine testicular status in prepubertalchildren with nonpalpable gonads, thus differentiating anorchiafrom undescended testes in boys with bilateral cryptorchidismand serving as a measure of testicular integrity in childrenwith intersexual anomalies.
The accurate identification of abdominal gonads is essentialfor evaluating children with virilization and nonpalpable gonads.Gonadal biopsies provide definitive diagnoses, but the gonadsmay be difficult to find, and operative exploration is invasiveand may compromise the gonadal tissue. Radiologic imaging, thoughnoninvasive, may miss abdominal gonads.1,2 Measurement of serumgonadotropins is helpful in agonadal infants and peripubertalchildren but is often nondiagnostic in midchildhood.3,4 Therefore,the primary method of gonadal evaluation in prepubertal childrenhas been to determine the response of serum testosterone tothe administration of human chorionic gonadotropin.5,6,7,8,9,10The ability to detect a circulating hormone produced constitutivelyby prepubertal testes, but not ovaries, would obviate the needfor provocative testing.
Müllerian inhibiting substance,11 or anti-müllerianhormone,12 a gonadal hormone that promotes the involution ofthe müllerian ducts during normal male sexual differentiation,is secreted in such a sexually dimorphic pattern.13 The absenceof müllerian inhibiting substance in female embryos isnecessary for the müllerian ducts to differentiate intothe uterus, oviducts, and upper vagina.14 Testicular secretionof müllerian inhibiting substance commences by the eighthweek of gestation and persists postnatally, whereas ovarianproduction starts after birth.15 Serum concentrations of müllerianinhibiting substance are readily detectable in boys from birthto puberty, when the concentrations decline, but are negligiblein girls until puberty.13,16,17,18 We undertook this study todetermine whether measurements of serum müllerian inhibitingsubstance would help identify abdominal testes in boys withbilateral cryptorchidism and facilitate gonadal evaluation inchildren with intersexual disorders.
Methods
Study Subjects
We studied 65 children ranging in age from 2 days to 11 yearswho were referred to Massachusetts General Hospital (Boston),Children's Memorial Hospital (Chicago), or Kiyose Children'sHospital (Tokyo, Japan) for the evaluation of cryptorchidismor ambiguous genitalia. Blood samples for the measurement ofserum müllerian inhibiting substance were obtained in conjunctionwith the collection of samples for other laboratory studies,with oral parental consent, according to approved institutionalguidelines. All the children studied had no palpable gonadsand were virilized, with the phenotype ranging from clitoromegalywith otherwise normal appearing female genitalia to normallydeveloped male genitalia. All subsequently either underwentsurgical exploration or had spontaneous testicular descent.The assignment of sex was based on the diagnosis, the degreeof virilization, the karyotype, and potential fertility andsexual function. The 65 children were ultimately grouped diagnosticallyas those with anorchia, abnormal testes, normal testes, or ovaries(Table 1).
Table 1. Final Diagnosis in 65 Children with Virilization and Nonpalpable Gonads.
Serum Müllerian Inhibiting Substance Assay
Serum müllerian inhibiting substance was measured by anenzyme-linked immunosorbent assay as described previously.13,17,19The limit of sensitivity of the assay was 0.5 ng per milliliter,and the intraassay and interassay coefficients of variationwere 9 percent and 15 percent, respectively. Undetectable valueswere assigned a value of 0.5 ng per milliliter. The resultsin the 65 study subjects were compared with those in 438 normalchildren of similar ages (<1 month, >1 month to <24months, >2 years to <6 years, and >6 years to <12years).13 The respective mean (and lowest) values for boys ineach of the successive age groups were 22.6 (3.2), 84.0 (6.4),63.8 (7.0), and 43.0 (0.8) ng per milliliter, and the respectivemean values for girls were 0.6, 0.9, 1.4, and 2.7 ng per milliliter,with the majority of values being undetectable in girls.
Other Hormonal Assays
Serum testosterone was measured before and after the administrationof two to six injections of human chorionic gonadotropin ata dose of 1500 IU per square meter of body-surface area in 44of the children. The results were compared with published dataobtained with similar testing regimens.6,7,8,10 In 10 otherchildren, serum testosterone was measured basally during earlyinfancy, a period when the values in normal children are elevatedbecause the hypothalamic–pituitary–gonadal axisis transiently activated.20,21 In the remaining children, serumtestosterone was measured basally at ages when the values areindistinguishable between boys and girls and therefore nondiagnostic.Serum testosterone was measured by radioimmunoassay in the clinicallaboratories of the referring centers, as was serum follicle-stimulatinghormone.
Statistical Analysis
We used Kolmogorov–Smirnov statistics to compare the distributionof serum müllerian inhibiting substance values among thefour groups of children. The 95 percent confidence intervalsof the test characteristics (sensitivity, specificity, and positiveand negative predictive values) were obtained with exact intervalestimation.22,23
Serum müllerian inhibiting substance concentrations inthe children with anorchia, abnormal testes, normal testes,or ovaries are shown in Figure 1. The mean values differed significantlyamong the four groups (P<0.001), except between the childrenwith anorchia and those with ovaries.
Figure 1. Serum Müllerian Inhibiting Substance Concentrations in Children with Anorchia, Abnormal Testes, Normal Testes, and Ovaries.
The mean (±SD) serum müllerian inhibiting substance concentrations are listed below the graph for each group.
None of the 12 children with anorchia had identifiable gonadaltissue at surgery. Three had microphallus, but nine had normalphallic development. All had low or undetectable serum concentrationsof müllerian inhibiting substance. Ten of these childrenreceived stimulation with human chorionic gonadotropin, whichincreased serum testosterone concentrations slightly to 40 ngper deciliter (1.39 nmol per liter) in one but not in the othernine. Serum follicle-stimulating hormone concentrations wereelevated (for age) in nine and normal in three, but the valuesdid not correlate with those for either serum testosterone ormüllerian inhibiting substance.
Fourteen children had histologically abnormal testes and variousdegrees of genital virilization: 11 had gonadal dysmorphogenesisincluding testicular dysgenesis, streak gonads, ovotestes, andLeydig-cell hypoplasia, and 3 had bilateral intrauterine torsionwith gonadal atrophy. The mean (±SD) müllerian inhibitingsubstance concentration was 11.5±11.8 ng per milliliterin this group, and the values were at or below the fifth percentileof the values for normal children in 10 (71 percent) of thesechildren (Figure 2). In contrast, serum testosterone concentrationsincreased after the administration of human chorionic gonadotropinin all but one child. Eleven children in this group had elevatedbasal or stimulated serum testosterone concentrations of 59to 405 ng per deciliter (2.1 to 14.2 nmol per liter).
Figure 2. Serum Müllerian Inhibiting Substance Concentrations as a Function of Age in Children with Abnormal Testes and Those with Normal Testes.
The dotted line represents the fifth percentile of the values relative to age in normal boys.
Thirty-four children had normal testes verified by intraoperativeexamination, histologic assessment, or palpation after spontaneousdescent; 24 of these children had bilateral cryptorchidism,and 10 had male pseudohermaphroditism. Four boys with bilateralcryptorchidism had hypospadias or microphallus, and 20 had normalexternal male genitalia. The extent of virilization of the childrenwith male pseudohermaphroditism ranged from mild clitoromegalyto microphallus. The mean serum müllerian inhibiting substanceconcentration in these children was 48.2±42.1 ng permilliliter. The values were all within the normal range forboys, and only three were at or below the fifth percentile forage (Figure 2). Of the 27 boys in whom serum testosterone valueswere measured after the administration of human chorionic gonadotropin,19 (70 percent) had normal increases for age and 8 (30 percent)had subnormal increases. In two other boys with bilateral cryptorchidism,the basal serum testosterone values were elevated.
All five girls with female pseudohermaphroditism had undetectableserum müllerian inhibiting substance concentrations, whereasbasal serum testosterone concentrations were elevated in threeof the girls with a diagnosis of congenital adrenal hyperplasia.
Serum concentrations of müllerian inhibiting substanceand testosterone were discordant in other children besides thesegirls. In four boys with bilateral cryptorchidism, serum müllerianinhibiting substance values were normal although serum testosteronevalues failed to increase with stimulation, whereas in fourchildren with mixed gonadal dysgenesis and one with true hermaphroditism,serum müllerian inhibiting substance values were low butbasal or stimulated serum testosterone concentrations were elevated.
Determination of Testicular Status
The mean serum müllerian inhibiting substance concentrationin the 12 children with anorchia and the 5 children with ovarieswas significantly lower than that in the 48 children with abnormalor normal testes (0.7±0.5 vs. 37.5±39.6 ng permilliliter, P<0.001). The serum müllerian inhibitingsubstance concentration was both a sensitive and a specificindicator of the absence of testes (Table 2). The predictivevalue of a low concentration for the absence of testes was 89percent, and that of a normal value for the presence of testeswas 98 percent.
Table 2. Value of Serum Müllerian Inhibiting Substance Assay for the Identification of Testicular Tissue.
To compare the usefulness of serum müllerian inhibitingsubstance and testosterone determinations for identifying testiculartissue, a similar analysis was performed in 54 children in whomserum testosterone values were measured after stimulation withhuman chorionic gonadotropin in 44 and during the physiologictestosterone rise that occurs in normal infants in 10.20,21Serum testosterone values were classified as normal if theywere elevated above those present in females in the appropriateage group. The sensitivity and specificity of the müllerianinhibiting substance assay in this subgroup of children weresimilar to those in the entire group (Table 2). The sensitivityand specificity of the serum testosterone assay were 69 percentand 83 percent, respectively. Although the positive predictivevalue of a low serum testosterone value for the absence of testiculartissue was only 56 percent, normal serum müllerian inhibitingsubstance and testosterone values were both highly predictiveof the presence of testicular tissue. The sensitivity and specificityof the combination of both tests for detecting the absence oftestes were 62 percent and 100 percent, respectively.
Discriminating between Abnormal and Normal Testes
Among the 48 children with testicular tissue (14 with abnormaltestes and 34 with normal testes), the sensitivity and specificityof the serum müllerian inhibiting substance assay for identifyingabnormal testes were 71 percent and 91 percent, respectively(Table 3). For the presence of abnormal testes, the predictivevalue of a concentration below the fifth percentile for normalboys was 77 percent. For the presence of normal testes, thepredictive value of a concentration at or above the fifth percentilewas 89 percent.
Table 3. Value of Serum Müllerian Inhibiting Substance Assay for Distinguishing between Abnormal and Normal Testes.
Among the 41 children with testicular tissue in whom serum testosteronewas measured, the sensitivity and specificity of the müllerianinhibiting substance assay were similar to those in the largergroup of 48 children (Table 3). Serum testosterone values wereclassified as normal if basal values obtained during the physiologicpeak that occurs in normal infants or values measured afterstimulation with chorionic gonadotropin were in the normal rangefor boys.6,7,8,10 The serum testosterone assay was not sensitive(25 percent) in this group and was a poor predictor of abnormaltestes (27 percent). Using both tests together decreased theirsensitivity and increased their specificity. Therefore, thecombination of low serum müllerian inhibiting substanceand testosterone values was 100 percent predictive of abnormaltestes, but there was only one child in this category.
Discussion
These results demonstrate that measurement of serum müllerianinhibiting substance is a sensitive and specific test for thedetection of testes in prepubertal children. A measurable valuewithin the normal range for boys is predictive of testiculartissue, and an undetectable value is predictive of anorchiaor ovaries. Serum concentrations of müllerian inhibitingsubstance differ quantitatively in children with abnormal andnormal testes and, therefore, are also helpful for assessingthe structural integrity of the testes. As compared with testinginvolving the administration of human chorionic gonadotropin,the measurement of serum müllerian inhibiting substanceis more sensitive and equally specific, and its predictive valuefor the absence of testicular tissue is higher. Measurementof serum müllerian inhibiting substance is particularlyuseful in young children, because serum gonadotropin concentrationsin those who are agonadal are nondiagnostic in midchildhood4and serum testosterone concentrations may fail to increase withprovocative testing in children with abdominal testes, as foundin this study. Measurement of serum müllerian inhibitingsubstance is also simpler, requiring only a single blood sample,than testing with human chorionic gonadotropin.
The presence of müllerian inhibiting substance in serumis a highly specific marker of testicular tissue in infantsand prepubertal children.13,19,24,25 With pubertal maturation,testicular synthesis of this hormone declines, whereas ovariansynthesis increases, and serum concentrations overlap in menand women.13,26,27 Nevertheless, values above the normal rangefor women remain diagnostic of the presence of testicular tissueexcept in women with granulosa-cell tumors or sex-cord tumorsthat secrete müllerian inhibiting substance.28,29 Conversely,serum müllerian inhibiting substance concentrations maybe low in a subgroup of children with the rare syndrome of persistentmüllerian ducts despite the presence of structurally normaltestes.30
Müllerian inhibiting substance is produced and secretedby Sertoli cells, and testosterone is produced and secretedby Leydig cells. Thus, the discordant serum müllerian inhibitingsubstance and testosterone values in some of the children inthe study may reflect the disparate effects of abdominally positionedtestes or gonadal dysgenesis on Sertoli and Leydig cells. Testicularfunction has traditionally been assessed by examining the steroidogeniccapacity of Leydig cells and spermatogenesis. Assessment ofthe function of immature Sertoli cells may also be relevant,however, because Sertoli cells constitute the supporting cellularmatrix for spermatogenesis and an adequate complement in thedeveloping testes may be critical for the survival and maturationof germ cells.31 Long-term follow-up of the children with discordantresults may resolve whether functional assessment of Sertolicells or Leydig cells before puberty will be the better predictorof mature testicular function.
Several questions may arise during the evaluation of childrenwith virilization and nonpalpable gonads. Are gonads present,and if so, are they normal? What is the potential for sexualand reproductive function? Is surgical exploration necessary?In this study, we found that measurement of serum müllerianinhibiting substance is a clinically useful and convenient testthat can help answer these questions. We suggest that the testcan best be used as outlined in Figure 3. In boys with bilateralcryptorchidism, determination of serum müllerian inhibitingsubstance should distinguish those with anorchia from thosewith abdominal testes; a value in the normal range for boysis sufficient to confirm that testicular tissue is present.Consequently, surgical exploration is necessary if the testesfail to descend spontaneously during infancy. Conversely, ifthe serum müllerian inhibiting substance value is low,serum testosterone should be measured before and after the administrationof human chorionic gonadotropin to verify the absence of testiculartissue or identify other cases of cryptorchidism. In childrenwith intersexual disorders, the serum müllerian inhibitingsubstance value is a measure of the structural integrity ofthe gonads that helps delineate the cause of the disorder. Avalue in the normal range for boys indicates that morphologicallynormal testes are present and suggests that the child has adisorder of androgen action or biosynthesis.32 A low value suggeststhat the testes are dysgenetic, and an undetectable value suggeststhat the testes are absent, as would be the case in girls withfemale pseudohermaphroditism and pure gonadal dysgenesis. Inchildren with intersexual disorders, measurement of serum müllerianinhibiting substance offers an additional index of testicularfunction but should not preclude testing involving stimulationwith human chorionic gonadotropin, which is necessary for thedefinitive diagnosis of defects in the synthesis of testosterone.Moreover, as a highly specific test for the presence of testiculartissue, measurement of serum müllerian inhibiting substancewill effectively identify unwanted residual testicular tissuein girls with true hermaphroditism who have undergone partialgonadectomies.19
Figure 3. Interpretation of the Assay of Serum Müllerian Inhibiting Substance in the Evaluation of Boys with Bilateral Undescended Testes or Children with Intersexual Disorders.
Supported in part by grants from the Genentech Foundation forGrowth and Development and the National Institute of Diabetesand Digestive and Kidney Diseases (DK-02129) (to Dr. Lee), agrant from the National Cancer Institute (CA 17393) (to Dr.Donahoe), a grant from the Food and Drug Administration's OrphanDrug Program (FD-R-000669) (to Dr. MacLaughlin), and a grantfrom the National Institute of Child Health and Human Development(2F32HD07435) (to Dr. Gustafson).
We are indebted to Drs. Lynne L. Levitsky, Paul A. Boepple,Soja Park-Bennet, and John D. Crawford of the Pediatric EndocrineUnit and Drs. Daniel Ryan, Daniel Doody, and Samuel Kim of PediatricSurgery at Massachusetts General Hospital for their clinicalcare and identification of study children; to the followingphysicians for contributing patients' data and serum for thedetermination of müllerian inhibiting substance: SamirNajjar and Alan Retik (Boston), Curtis Sheldon and Eric Smith(Cincinnati), Carolyn Becker (Danbury, Conn.), Gary Freidenberg(Indianapolis), Martin Goldsmith (Fresno, Calif.), Jerome Grunt(Kansas City, Mo.), Stuart Howards (Charlottesville, Va.), RobertMcVie (Shreveport, La.), Sharon Oberfeld (New York), HaroldStarkman (Morristown, N.J.), A. Winthrop (Hamilton, Ont., Canada),and Stephen Wolf (Des Moines, Iowa); and to Ms. Laura Asmundsonand Ms. Gretchen B. Crist for technical assistance.
Source Information
From the Pediatric Surgical Research Laboratory (M.M.L., P.K.D., M.L.G., D.T.M.), Pediatric Endocrine Unit (M.M.L.), and Medical Practices Evaluation Center (Y.C.), Massachusetts General Hospital and Harvard Medical School, Boston; the Department of Pediatric Endocrinology and Diabetes, Children's Memorial Hospital and Northwestern Medical School, Chicago (B.L.S.); and the Division of Endocrinology and Metabolism, Tokyo Metropolitan Kiyose Children's Hospital, Tokyo, Japan (T.H., Y.H.). Presented at the 1996 Pediatric Academic Societies' Annual Meetings, Washington, D.C. (Pediatric Research 1996;39:92A).
Address reprint requests to Dr. Lee at the Pediatric Endocrine Unit, ACC 709, Massachusetts General Hospital, Boston, MA 02114.
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