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An intersexual or intersex person (or animal of any unisexual species) is one who is born with genitalia and/or secondary sex characteristics determined as neither exclusively male nor female, or which combine features of the male and female sexes. more...

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(The terms hermaphrodite and pseudohermaphrodite, which have been used in the past, are now considered pejorative and inaccurate and are no longer used to refer to an intersexual person.) Sometimes the phrase "ambiguous genitalia" is used.


According to the highest estimates (Fausto-Sterling et. al., 2000) perhaps 1 percent of live births exhibit some degree of sexual ambiguity , and that between 0.1% and 0.2% of live births are ambiguous enough to become the subject of specialist medical attention, including surgery to disguise their sexual ambiguity. Other sources (Leonard Sax, 2002) estimate the incidence of true intersexual conditions as far lower, at approximately 0.018%.

In typical fetal development, the presence of the SRY gene causes the fetal gonads to become testes; the absence of it allows the gonads to continue to develop into ovaries. Thereafter, the development of the internal reproductive organs and the external genitalia is determined by hormones produced by certain fetal gonads (ovaries or testes) and the cells' response to them. The initial appearance of the fetal genitalia (a few weeks after conception) is basically feminine: a pair of "urogenital folds" with a small protuberance in the middle, and the urethra behind the protuberance. If the fetus has testes, and if the testes produce testosterone, and if the cells of the genitals respond to the testosterone, the outer urogenital folds swell and fuse in the midline to produce the scrotum; the protuberance grows larger and straighter to form the penis; the inner urogenital swellings swell, wrap around the penis, and fuse in the midline to form the penile urethra.

Because there is variation in all of these processes, a child can be born with a sexual anatomy that is typically female, or feminine in appearance with a larger than average clitoris; or typically male, masculine in appearance with a smaller than average penis that is open along the underside. The appearance may be quite ambiguous, describable as female genitals with a very large clitoris and partially fused labia, or as male genitals with a very small penis, completely open along the midline ("hypospadic"), and empty scrotum.

There are dozens of named medical conditions that may lead to intersex anatomy. Fertility is variable. The distinctions "male pseudohermaphrodite", "female pseudohermaphrodite" and especially "true hermaphrodite" are vestiges of 19th century thinking that placed "true sex" in the histology (microscopic appearance) of the gonads.

The common habit in the 21st century of elevating the role of the sex chromosomes above all other factors when determining gender may be analogous to the older habit of finding "true" sex in the gonads. Though high school biology teaches that men have XY and women XX chromosomes, in fact there are quite a few other possible combinations such as Turner_syndrome XO, Triple-X syndrome XXX, Klinefelter's Syndrome XXY, XYY, XO/XY, XX male, Swyer syndrome XY female, and there are many individuals who do not follow the typical patterns (such as cases with four or even more sex chromosomes).


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Morphometry and histology of gonads from 13 children with dysgenetic male pseudohermaphroditism
From Archives of Pathology & Laboratory Medicine, 5/1/01 by Scolfaro, Marica Ribeiro

Background.-Dysgenetic male pseudohermaphroditism (DMP) is a sexual differentiation disorder characterized by bilateral dysgenetic testes, persistent mullerian structures, and cryptorchidism in individuals with a 46,XY karyotype. However, the histologic criteria for the diagnosis of DMP are poorly established.

Objective.-To determine gonadal histology in children with DMP.

Patients and Methods.-Between 1996 and 1998, 13 patients with DMP were evaluated on our service. The clinical diagnosis of DMP was based on a 46,XY karyotype, sex ambiguity, high levels of follicle-stimulating hormone and low levels of antimullerian hormone, a decreased testosterone response to human chorionic gonadotropin stimulation without accumulation of testosterone precursors, and the presence of mullerian structures. Molecular sequencing the HMGbox region of the SRY gene did not reveal any mutations. Biopsies were performed for 22 of 26 gonads (patient age at the time of biopsy, 16 months to 10 years). Conventional microscopy was used to evaluate mean tubular diameter, tubular fertility index, and number of Sertoli cells per tubular profile.

Results.-All 26 gonads were located outside of the labioscrotal folds. Their histologic features varied from only a reduction in tubular size to features of a streak gonad. Five of the 22 gonads grossly resembled a streak gonad. The mean tubular diameter was severely reduced (>30% reduction relative to the normal tubular diameter for the patient's age) in 4 gonads, markedly reduced (10%-30%) in 11 gonads, slightly reduced (

Conclusion.-The histologic findings confirmed the clinical diagnosis of DMP in every patient in the present series. However, gonadal histology was variable, and careful morphometric evaluation may be necessary to establish the diagnosis.

(Arch Pathol Lab Med. 2001;125:652-656)

Dysgenetic male pseudohermaphroditism (DMP) is a sexual differentiation disorder diagnosed on the basis of morphologic features in patients with evidence of gonadal dysgenesis. Typically, patients have ambiguous genitalia, low testosterone levels, persistence of mullerian structures, bilateral abnormal testes, and an increased risk for gonadal neoplastic transformation.1-4 Depending on the severity of testicular dysgenesis, the antimullerian hormone (AMH) level may be low or undetectable in patients with abnormal testicular determination.5,6 Typically, the gonadal histology is characterized by poorly developed seminiferous tubules surrounded by wavy ovarian stroma. However, gonadal development may range from apparently normal testicular differentiation to a streak gonad, and the criteria for the histologic diagnosis of DMP are not well established.

The most frequently observed karyotype in patients with DMP is 46,XY. However, multiple cell lines, including a monosomic X cell line, may be detected, and somatic features of Turner syndrome, such as short stature, webbed neck, cubitus valgus, and renal malformation, may be present.7

In fact, some authors consider DMP a variant of mixed gonadal dysgenesis,4,8-9 which is defined as the coexistence of a streak gonad and a dysgenetic testis in a patient with a 45,X/46,XY karyotype.1,8,10 In order to rule out the presence of Denys-Drash syndrome, which occurs as a consequence of mutations at the WT1 gene on chromosome 11, patients with DMP must be examined periodically for the presence of Wilms tumor and nephropathy with progressive renal failure.11

The objective of this study was to better define the histologic criteria for the diagnosis of DMP by determining the morphometric and histologic features of the gonads of 13 children with a strict clinical diagnosis of this entity.



The series consisted of 13 patients with a clinical diagnosis of DMP evaluated by the Interdisciplinary Group for the Study of Sex Determination and Differentiation at the University Hospital of the UNICAMP (Campinas, Sao Paulo, Brazil), between May, 1996, and May, 1998. The diagnosis of DMP was supported by the findings of ambiguous genitalia in patients with a 46,XY karyotype and bilateral cryptorchidism, low levels of testosterone and AMH, and evidence of mullerian duct derivatives. This study was approved by the Ethics Committee of the University Hospital.

The patients' mean age at first consultation was 3 years and 1 month (range, 15 days to 9 years), and the initial sex assignment was male in all cases. One patient (case 12) had a previous history of unilateral Wilms tumor and renal failure. No consanguinity was registered, and there was no family history of sex ambiguity. All individuals had hypospadias, bilateral cryptorchidism (Table 1), and evidence of mullerian duct derivatives, which was confirmed by laparoscopy.

Routine hormonal determination was performed by radioimmunoassay and included basal levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), androstenedione, and dehydroepiandrosterone. Total testosterone levels were determined before and 24 hours after the last of a series of 3 daily intramuscular injections of 2000 IU of human chorionic gonadotropin (hCG) (Profasi hp, Serono Lab, Sao Paulo, Brazil). An increase in testosterone level of more than 4.9 nmol/L (1.4 ng/mL) was considered normal. When testosterone levels did not increase, determination of serum beta-hCG was performed to confirm that it was really used. Serum AMH levels were measured by an enzyme-linked immunosorbent assay, using antibodies against human recombinant AMH,12 in the laboratory of the Unite de Recherches sur l'Endocrinologie du Developpement (INSERM), Montrouge, France. In one patient (patient 4), who was less than 6 months of age, testosterone levels were assayed only in baseline blood samples, because, at this age, testosterone values in normal children are elevated. All patients had low AM levels as compared with the normal values published by Rey et al.5 They also had decreased testosterone levels either at baseline or after hCG stimulation, with no accumulation of testosterone precursors. All patients had a predominance of FSH over LH, despite the fact that only 5 patients (patients 2, 4, 6, 7, and 8) had elevated gonadotropin levels (Table 1).

Genomic DNA samples from each patient and normal male and female controls were previously used as templates to amplify the HMGbox region of the SKY gene and no mutations were found after direct sequencing of polymerase chain reaction products.


The biopsies of gonads were fixed in Bouin solution, dehydrated in alcohol, and embedded in paraffin. Serial 4-(mu)m sections from each part of the gonads were stained with hematoxylineosin and examined under light microscopy. The mean tubular diameter, tubular fertility index (TFI), and Sertoli cell number per tubular profile were evaluated in 50 to 100 randomly selected seminiferous tubules of each section. Our findings were compared with the normal data for age published by Nistal and Paniagua (Figure 1).13

The mean tubular diameter of both the longitudinal and transverse sections was measured using a calibrated vernier ocular micrometer with a 40x objective, as described by Lennox et al.14 The reduction of diameter was classified according to Nistal and Paniagua13 into 3 degrees of severity: slight (30% reduction) tubular hypoplasia.

Germ cell number was evaluated by determining the TFI, which is the mean number of germ cells per tubular profile. This value was calculated by counting the number of germ cells in a single light microscope field and dividing that number by the number of tubular profiles in that given field. According to Nistal and Paniagua,13 3 levels of severity of germinal hypoplasia can be recognized: slight (TFI, >50%), marked (TFI, of 50%-30%) and severe (TFI,

The number of Sertoli cells per tubular profile was determined. The Leydig cell number was not evaluated because this number is low during infancy. Streak gonads were defined as those composed of an ovarian-type stroma with sclerohyaline nodules.


Biopsies were performed for 22 of the 26 gonads. The patients' ages at the time of biopsy ranged from 16 months to 10 years (Table 2). Biopsies were not performed for 4 gonads: the left gonad of patients 1 and 7, and the right gonad of patients 2 and 4. The left gonad of patient 7 was not found, but the ipsilateral absence of mullerian duct derivatives and the presence of wolffian duct derivatives suggested a unilateral vanishing testis. In the other 3 patients, the biopsy of one of the gonads was not suitable for histologic analysis.

There were 5 streak gonads (the left gonad of patients 2, 6, 9, 10, and 13), which were all in an abdominal position.

Table 2 shows values for the mean tubular diameter, TFI, and number of Sertoli cells per tubular profile observed in the 17 remaining gonads.

Eleven gonads showed marked tubular hypoplasia, 4 showed severe tubular hypoplasia, and one showed slight tubular hypoplasia (Figures 2 through 4). The mean tubular diameter was normal in only one gonad (the right gonad of patient 13).

The TFI was severely reduced in 9 gonads, markedly reduced in 2 gonads (Figures 2 through 4), and normal in 6 gonads.

The Sertoli cell number per tubular profile was elevated in 16 of 17 gonads analyzed (Figures 2 through 4). Only the right gonad of patient 13 showed a normal number of Sertoli cells.


Ambiguous development of the genital ducts, urogenital sinus, and external genitalia occurs in patients with dysgenetic gonads. These patients usually present with evidence of AMH deficiency as well as androgen deficiency, and therefore have mullerian duct derivatives and ambiguous external genitalia.8 Mutations and deletions in genes involved in the testes determination and differentiation cascade have been implicated in the etiology of DMP.15

Our 13 patients presented with some interesting findings: all had a male sex assignment before the first consultation, and there was a delay in the evaluation of the ambiguous genitalia (mean age at the time of evaluation, 3 years and 1 month). Although all patients had a predominance of FSH over LH, only 5 of them had high FSH levels for their age. Among these 5 patients, 3 were older than 6 years, 1 was 15 days old, and 1 was 1 year old, suggesting that gonadotropins may be useful in the diagnosis of DMP at the extremes of prepubertal age. Variable degrees of masculinization of the external genitalia were noted, and the gonads were located outside of the labioscrotal folds in all patients. One patient (patient 12) had features of Denys-Drash syndrome.

The diagnostic confirmation of DMP is based on the histologic finding of variable degrees of bilateral dysgenetic testes, which range from an almost "normal" testis to a testis that grossly resembles a streak gonad. Although the abnormalities observed in dysgenetic testes are well defined, pathologists usually have some difficulties establishing the diagnosis of dysgenetic testes, and the characteristics of dysgenetic gonads are not routinely evaluated.

Testicular biopsy is essential for the diagnosis in some patients with ambiguous genitalia, and the evaluation of biopsies of prepubertal testes should involve assessment of the mean tubular diameter and the number of germ cells, Sertoli cells, and Leydig cells (when evaluated) per tubular profile, per unit area, per unit volume, or per testis.

Mean tubular diameter is a very good indicator of the development of the seminiferous epithelium.13 In the prepubertal testis, this diameter depends mainly on the number of Sertoli cells, and thus indicates whether they are adequately stimulated by FSH and responsive to this stimulus. Testicular diameter varies throughout childhood; it is smallest in the fourth year of life, increases slowly until 9 years of are, and increases rapidly thereafter, up to 15 years of age (Figure 1).13 Our patients with DMP showed a variable mean tubular diameter, from normal to severely decreased, but with a predominance of marked and severe tubular hypoplasia (15/17 gonads). Even though there are technical pitfalls in evaluating the mean tubular diameter, our data indicate the need for this evaluation in all testicular biopsies when there is clinical suspicion of gonadal dysgenesis, independent of the gonadal location.

Germ cells may be counted by several methods. The most common method is calculating the TFI, which reflects the percentage of tubular profiles containing germ cells. In neonates, 68% of tubular profiles contain at least one germ cell. From birth to 3 years, this value decreases to 50%, followed by a progressive increase to 100% at puberty (Figure 1).13 A more complete determination of germ cell number can be obtained by calculating the total number of germ cell per testis, but this approach requires morphometric assessment of the intratubular volume and careful clinical measurement of the 3 axes of the testis.16 The TFI was altered in 11 of the 17 testes that we evaluated. Among the 6 patients with dysgenetic testes and normal TFIs, 5 had a decreased and 1 had a normal mean tubular diameter. Therefore, our data suggest that mean tubular diameter is a better indicator of testicular dysgenesis than TFI.

Another histologic parameter evaluated was the number of Sertoli cells per tubular profile, which varies during childhood as a result of low levels of Sertoli cell proliferation between the ages of 4 and 12 years.17 Hyperplasia of Sertoli cells is usually pronounced in patients with DMP, and it is a sign of tubular dysgenesis.18 The number of Sertoli cells was increased in all of the gonads of our patients with DMP, but in one patient, this increase was not marked (Figure 1). This finding probably reflects the fact that the ideal time for this evaluation is during the first year of life or at the onset of puberty.

Finally, it is important to emphasize that among the 22 evaluated gonads, only 5 grossly resembled streak gonads. It is interesting to point out that they were all found on the left side; among true hermaphrodites, there is also a predominance of ovaries and ovotestes on the left side.19,20

In conclusion, the histologic findings in our patients with DMP, although highly variable, confirmed the clinical diagnosis. A careful histologic and morphometric evaluation, particularly the measurement of mean tubular diameter, may help establish and improve the diagnosis of DMP.

We wish to express our sincere gratitude to Rodolfo Rey, MD, PhD, for his expert technical assistance and continuous support. We also thank the members of the Cytogenetics Laboratory of Medical Genetics Department and the Main Clinical Laboratory of the University Hospital (UNICAMP).


1. Robboy SJ, Miller T, Donahoe PK, et al. Dysgenesis of testicular and streak gonads in the syndrome of mixed gonadal dysgenesis: perspective derived from clinicopathologic analysis of twenty-one cases. Hum Pathol. 1982;13:700-716.

2. Troche V, Hernandez E. Neoplasia arising in dysgenetic gonads. Obstet Gynecol Surv. 1986;41:74-79.

3. Krasna IH, Lee ML, Smilow P, Sciorra L, Eierman L. Risk of malignancy in bilateral streak gonads: the role of the Y chromosome. J Pediatr Surg. 1992;27: 13 176-1380.

4. Rohatgi M, Gupta DK, Menon PS, Verma IC, Mathur M. Mixed gonadal dysgenesis and dysgenetic male pseudohermaphroditism-a critical analysis. Indian J Pediatr. 1992;59:487-500.

5. Rey RA, Belville C, Nhou-Fekete C, et al. Evaluation of gonadal function in 107 intersex patients by means of serum antimullerian hormone measurement. J Clin Endocrinol Metab. 1999;84:627-631.

6. Stuchi-Perez EG, Lukas-Croisier C, Castro M, et al. Evaluation of the tubular

and interstitial functions of the testis in 46,XY patients with ambiguous genitalia. J Pediatr Endocrinol Metab. 2000;13:605-612.

7. Chang HJ, Clark RD, Bachman H. The phenotype of 45,X/46,XY mosaicism: an analysis of 92 prenatally diagnosed cases. Am J Hum Genet. 1990;46:156167.

8. Rajfer J, Walsh PC. Mixed gonadal dysgenesis: dysgenetic male pseudohermaphroditism. In: Josso N, ed. The Intersex Child: Pediatric and Adolescent Endocrinology. Basel, Switzerland: S. Karger; 1981:105-115.

9. Borer JG, Nitti VW, Glassberg KI. Mixed gonadal dysgenesis and dysgenetic male pseudohermaphroditism. J Urol. 1995;153:1267-1273.

10. Donahoe PK, Crawford JD, Hendren WH. Mixed gonadal dysgenesis: pathogenesis and management. J Pediatr Surg. 1979;14:287-300.

11. Pelletier J, Bruening W, Kashtan CE, et al. Germline mutations in the Wilms' tumor supressor gene are associated with abnormal urogenital development in Denys-Drash syndrome. Cell. 1991;67:437-447.

12. Carre-Eusebe D, Imbeaud S, Harbison M, New MI, Josso N, Picard JY. Variants of the anti-Mullerian hormone gene in a compound heterozygote with the persistent Mullerian duct syndrome and his family. Hum Genet. 1992;90: 389-394.

13. Nistal M, Paniagua R. Non-neoplastic diseases of the testis. In: Bostiwick DG, Eble IN, eds. Urologic Surgical Pathology. St Louis, Mo: Mosby; 1996:458565.

14. Lennox B, Ahmad KN, Mack WS. A method for determining the relative total length of the tubules in the testis. J PathoL 1970;102:229-238.

15. Jimenez R, Sanchez A, Burgos M, Dias de la Guardia RC. Puzzling out the genetics of mammalian sex determination. Trends Genet. 1996;12:164-166.

16. Muller J, Skakkebaek NF. Quantification of germ cells and seminiferous tubules by stereological examination of testicles from 50 boys who suffered from sudden death. Intl Androl. 1983;6:143-156.

17. Cortes D, Muller J, Skakkebaek NE. Proliferation of Sertoli cells during development of the human testis assessed by stereological methods. Intl Androl. 1987;10:589-596.

18. Nistal M, Abaurrea MA, Paniagua R. Morphological and histometric study on the human Sertoli cell from birth to the onset of puberty. J Anat. 1982;14: 351-363.

19. Van Niekerk WA, Retief AE. The gonads of human true hermaphrodites. Hum Genet 1981;58:117-122.

20. Guerra G Jr, De Mello MP, Assumpcao JG, et al. True hermaphrodites in the southeastern region of Brazil: a different cytogenetic and gonadal profile. J Pediatr Endocrinol Metab. 1998;11:519-524.

21. Quigley CA, De Bellis A, Marschke KB, E-Awady MK, Wilson EM, French FS. Androgen receptor defects: historical, clinical and molecular perspectives. Endocr Rev. 1995;16:271-321.

Marcia Ribeiro Scolfaro, MD; Izilda Aparecida Cardinalli, MD, PhD; Eliana Gabas Stuchi-Perez, MD, MS; Maricilda Palandi de Mello, BSc, PhD; Juliana de Godoy Assumpcao, BSc, MS; Maria Tereza Matias Baptista, MD, PhD; Joaquim Murray Bustorff Silva, MD, PhD; Andrea Trevas Maciel-Guerra, MD, PhD; Gil Guerra Junior, MD, PhD

Accepted for publication January 3, 2001.

From the Interdisciplinary Group for the Study of Sex Determination and Differentiation, Faculty of Medical Science, State University of Campinas, Sao Paulo, Brazil.

This manuscript was presented at the 39th Annual Meeting of European Society for Pediatric Endocrinology (ESPE), Brussels, Belgium, September 17, 2000.

Reprints: Gil Guerra Junior, MD, PhD, Departamento de Pediatria, Faculdade de Ciencias Medicas, UNICAMP Campinas, Sao Paulo, Brazil CP 6111, CEP 13083-970 (e-mail:

Copyright College of American Pathologists May 2001
Provided by ProQuest Information and Learning Company. All rights Reserved

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