True Hermaphroditism Research Articles

Seudohermafroditismo masculino

Diagnosis of ambiguous genitalia in a newborn is an emergency that can be difficult to manage, not only because salt wasting entities must be ruled out, but also due to the importance of gender assignment before psychological gender is established. We report two cases of male pseudohermaphroditism, a true hermaphroditism and a 5-alfa-reductase deficiency. The physiology of sexual differentiation and diagnosis, as well as the management of these infants, are discussed.

Linkage to CFA29 Detected in a Genome-Wide Linkage Screen of a Canine Pedigree Segregating Sry-Negative XX Sex Reversal

Canine Sry-negative XX sex reversal is a disorder of gonadal development wherein individuals having a female karyotype develop testes or ovotestes. In this study, linkage mapping was undertaken in a pedigree derived from one proven carrier American cocker spaniel founder male and beagle females. All affected dogs in the analysis were XX true hermaphrodites and confirmed to be Sry negative by polymerase chain reaction. A genome-wide linkage screen conducted using 245 microsatellite markers revealed highest LOD score of 3.4 (marker CPH9) on CFA29. Fine mapping with additional microsatellites in the region containing CPH9 localized the Sry-negative XX sex reversal locus to a 5.4-Mb candidate region between markers CPH9 and FH3003 (LOD score 3.15). Insignificant LOD scores were found at genome-wide screen or fine mapping markers that were within 10 Mb of 45 potential candidate genes reported to have a role in mammalian sex determination or differentiation. Together, these results suggest that a novel locus on CFA29 may be responsible for sex reversal in this pedigree.

Ambiguous genitalia: an overview of 17 years' experience

Aim The newborn with abnormal genital development presents a difficult diagnostic and treatment challenge for the pediatric surgeon providing care. The purpose of this study was to evaluate the results of surgical treatment for children with ambiguous genitalia. Patients and Methods The records of 85 children managed surgically for ambiguous genitalia in our unit from 1988 to 2005 were reviewed retrospectively. Age at surgery, operative procedures, sex of rearing, and outcome were recorded. Results The intersex committee's decision concerning sex assignment was female for 62 children (75%) and male for 23 children (25%). The etiologies of children reared as female were congenital adrenal hyperplasia (n = 37), male pseudohermaphroditism (n = 12), mixed gonadal dysgenesis (n = 6), true hermaphroditism (n = 4), and Mayer-Rokitansky syndrome (n = 3). Fifteen children with male pseudohermaphroditism, 5 children with congenital adrenal hyperplasia, and 3 children with true hermaphroditism were reared as male. The mean age at surgery was 4.4 years and follow-up period averaged 7 years. Eighteen (29%) patients with feminization procedures and 8 (34%) of 23 patients with masculinization procedures experienced complications and required redo operations. Vaginal stenosis was the most common complication. Conclusion The surgical management of ambiguous genitalia has always been difficult, and it must be performed by skilled pediatric surgeon. Genital surgery in infancy needs to be reassessed in the light of literature findings revealing poor outcome. In patients who underwent feminizing genitoplasty, vaginal reconstruction should be delayed until adolescence to achieve better cosmetic and functional results.

Hermaphroditism in a Sprague-Dawley Rat

A spontaneous case of unilateral true hermaphroditism was observed during the routine necropsy of a 9-week-old presumed female Sprague-Dawley rat on a repeat-dose toxicity study. There were no drug-related effects observed. True hermaphroditism is rare in rats, and despite the large numbers of rats examined annually, few cases are reported in the literature.

Long-term follow-up of true hermaphroditism cases treated by conservative surgery

Long-term follow-up of true hermaphroditism cases treated by conservative surgery

Standardized Endoscopic/Laparoscopic Workup for Patients with Disorders of Sexual Differentiation

Purpose Treatment recommendations for patients with disorders of sexual differentiation (DSD) are rarely evidence based. This deficiency is due to the relative rarity of these disorders and the lack of standards of diagnostic workup. In particular, anatomic aspects of internal and external genital development may be very variable within a given disorder. The individual anatomy can not be predicted from genetic or endocrine data. To propose a standardized diagnostic workup for patients with DSD in order to establish a detailed knowledge of the associated anatomy. Material and methods We evaluated 19 patients with different types of DSD between 2002 and 2006. Patients were examined by laparoscopy of the retrovesical space and the inguinal region, cystoscopy and endoscopy of the vagina/urogenital sinus. Diagnosis were 46 XY gonadal dygenesis, 17 s-HSD-deficiency, 5 AR-deficiency, 450 SCC deficiency, true hermaphroditism and PAIS. Relevant findings were documented as videos. Results In 7 of the 19 patients we discovered anatomy that was not predicted on the basis of the preceding clinical, endocrine and molecular genetic characterization. These findings included (1) a 0,5 cm gonadoblastoma in a patient with gonadal dysgenesis, (2) a vagina in a patient with true hermaphroditism, (3) a complete separation of the urethra and vagina in a patient with 5 alpha-reductase type II deficiency and (4) a vas deferens in a patient with suspected 17sHSD type III deficiency without a detectable mutation. In this latter patient, a second run of the genetic examination disclosed the mutation. In the other patients information on size , location and eventually histology of the gonads was obtained. Conclusions Systematic laparoscopic and endoscopic examination produces clinically valuable information that cannot be obtained by other techniques, e.g., the presence of gonadoblastoma or the exact anatomy of external urogenital ducts. We propose that, if any examination under anaesthesia is scheduled for a patient with DSD, video documenting of the laparoscopic findings of the pelvis and cystoscopy/genitoscopy should be obtained.

Hermaphroditism in 3 Chimeric Mice

Hermaphroditism was diagnosed in three, 6-month-old, male, chimeric mice generated by microinjection of 129/Ola XY recombinant embryonic stem cells into unsexed C57BL/6 blastocysts. Grossly, mice Nos. 1 and 2 had perigenital masses and hydrometra. All mice had unilateral ovaries and cystic endometrial hyperplasia. Mice Nos. 1 and 3 also had contralateral testes and epididymides. Histologically, mice Nos. 1 and 3 were true hermaphrodites with unilateral ovotestes, while mouse No. 2 was a pseudohermaphrodite with ovarian tissue only. The presence of a uterus with cystic endometrial hyperplasia in these mice resembles XY pseudohermaphroditism in miniature schnauzers. The mice were determined to be 95 to 100% chimeric via haircoat color; however, the presence of both male and female sex organs in these phenotypically male mice suggests otherwise. Published reports note incidences for sex chimeras and hermaphroditism in genetically engineered mice of 50% and 20%, respectively. Hermaphroditism is expected to increase as the numbers of chimeric mice rise with technical advances in genetic engineering.

We used to call them hermaphrodites

We used to call them hermaphrodites

True hermaphroditism presenting as an inguinal hernia

A 21-year-old patient with cryptorchidism was found to have a left inguinal mass on physical examination. The patient was operated with a diagnosis of bilateral cryptorchidism and left inguinal hernia. Besides bilateral inguinal undescended testicles, female genital organs like fallopian tubes, uterus and ovary were found on the exploration.

The Long-Term Followup of 33 Cases of True Hermaphroditism: A 40-Year Experience With Conservative Gonadal Surgery

Little is known about long-term outcomes of conservative gonadal surgery in true hermaphroditism. We present our experience with evaluation and treatment of a large series of children with this rare form of ambiguous genitalia, focusing on gonadal structure and function before and after conservative gonadal surgery. We retrospectively reviewed 33 consecutive patients with histologically confirmed true hermaphroditism treated at the Hopital des Enfants-Malades between 1965 and 2005. The most common karyotype of true hermaphrodites was 46,XX, constituting 82% of our series. The frequency of finding the SRY gene in 46,XX cases was 35%. Ovotestis was the most frequent finding (65%) and testis the rarest (9%). Ovarian tissue was more often found on the left side, and testicular tissue on the right side (p <0.05). Proper gonadal tissue was preserved in 28 cases. No gonadal tumors were detected during followup. Ovarian tissue remained normal, while testicular tissue gradually developed signs of dysgenesis in all biopsied cases, confirmed by endocrinological studies. However, testosterone production remained satisfactory in the majority of cases during followup. Diagnosis of true hermaphroditism is well defined and the condition can be recognized even prenatally. Conservative gonadal surgery is the procedure of choice after a diagnosis of true hermaphroditism. Continued followup is necessary because of the multiple psychological, gynecological and urological problems encountered postpubertally by these patients.

Seminoma in a Male Phenotype 46XX True Hermaphrodite

Although true hermaphrodite is uncommon, it has been reported in more than 400 individuals. Tumours arising in the gonads of true hermaphrodite is a very rare finding and only very few cases have been reported in the literature. We report a case of a 35-year-old phenotype man with bilateral undescended testis with lump hypogastrium. On examination, he had an ovotestis on one side and pure seminoma arising in testis on the other side. The seminoma arising in the left undescended testis was successfully treated by excision and combination chemotherapy. Cytogenetic studies revealed that 46XX karyotype with primer specific for the sex-determining region of the Y chromosome was negative. The karyotypic abnormality noticed in the patient is also reviewed in the article.

Valor de la biopsia gonadal en el diagnóstico de los desórdenes del desarrollo sexual

The gonadal biopsy provides essential information for the identification, classification and early detection of neoplasias in patients with disorders of sex development. Histopathological findings in these cases must be analysed together with clinical, hormonal, genetic and molecular information before deciding a therapeutic option. Sexual differentiation is the result of multiple and complex genetic and endocrinal mechanisms; therefore, we first present the events taking place during gonadal embryonic development, focusing on the genetic mechanisms involved in sexual determination and the differentiation of the testis and the urogenital tract. In second place, we describe the different gonads in the intersexual states -in testicular regression syndrome, fibrous streak, testicular dysgenesis, streak testes, ovotestes and microscopically normal testes and ovaries-, highlighting the histological features and the differential findings that allow the pathologist to distinguish between these entities with the aid of clinical, genetic, hormonal and molecular information that are characteristic for each situation.In third place, we studied the incidence of neoplasias in gonadal dysgenesis, male pseudohermaphroditism and true hermaphroditism. Finally, we discuss the limitations of gonadal biopsy to achieve a correct diagnosis in the disorders of sex development.

Long-term outcome of vaginal reconstruction: Comparing techniques and timing

Objective In a retrospective review, to analyse the long-term outcomes of vaginal reconstruction, comparing techniques and timing. Patients and methods We identified 63 patients who underwent a total of 71 vaginoplasties in 1985–2000. The techniques used were posterior skin flap (42), intestinal replacement (21) and pull through (8). The majority of operations were performed before puberty (63%) and as primary procedures (79%). Presenting diagnoses were congenital adrenal hyperplasia (23), cloacal exstrophy (8), true persistent cloaca (12), androgen insensitivity (8), urogenital sinus anomaly (6), mixed gonadal dysgenesis (3), true hermaphroditism (2) and sacrococcygeal teratoma (1). Results The mean age at operation was 83.9 (2–235) and mean follow up was 116.8 (48–232) months. Strictures and discharge were the most common problems. Nine patients underwent revision surgery and a fistula repair was required in two patients. Mucosal prolapse was observed in one ileo- and one colovaginoplasty patient, and diversion colitis occurred after colovaginoplasty in one patient. More complications occurred in operations performed prior to than following puberty. Conclusion If vaginoplasty is the only indicated operation, delaying until puberty may minimize complications. When other genital surgery is indicated or in the presence of symptoms pre-pubertal vaginoplasty should be performed, since the second procedure usually involves simple dilatations and is associated with good results.

A case of true hermaphroditism reveals an unusual mechanism of twinning

Traditionally twins are classified as dizygous or fraternal and monozygous or identical (Hall Twinning, 362, 2003 and 735-743). We report a rare case of 46,XX/46,XY twins: Twin A presented with ambiguous genitalia and Twin B was a phenotypically normal male. These twins demonstrate a third, previously unreported mechanism for twinning. The twins underwent initial investigation with 17-hydroxyprogesterone and testosterone levels, pelvic ultrasound and diagnostic laparoscopy. Cytogenetic analysis was performed on peripheral blood cells and skin fibroblasts. Histological examination and Fluorescence in situ hybridization studies on touch imprints were performed on gonadal biopsies. DNA analysis using more than 6,000 DNA markers was performed on skin fibroblast samples from the twins and on peripheral blood samples from both parents. Twin A was determined to be a true hermaphrodite and Twin B an apparently normal male. Both twins had a 46,XX/46,XY chromosome complement in peripheral lymphocytes, skin fibroblasts, and gonadal biopsies. The proportion of XX to XY cells varied between the twins and the tissues evaluated. Most significantly the twins shared 100% of maternal alleles and approximately 50% of paternal alleles in DNA analysis of skin fibroblasts. The twins are chimeric and share a single genetic contribution from their mother but have two genetic contributions from their father thus supporting the existence of a third, previously unreported type of twinning.

Chimera and other fertilization errors

The finding of a mixture of 46,XX and 46,XY cells in an individual has been rarely reported in literature. It usually results in individuals with ambiguous genitalia. Approximately 10% of true human hermaphrodites show this type of karyotype. However, the underlying mechanisms are poorly understood. It may be the result of mosaicism or chimerism. By definition, a chimera is produced by the fusion of two different zygotes in a single embryo, while a mosaic contains genetically different cells issued from a single zygote. Several mechanisms are involved in the production of chimera. Stricto sensu, chimerism occurs from the post-zygotic fusion of two distinct embryos leading to a tetragametic chimera. In addition, there are other entities, which are also referred to as chimera: parthenogenetic chimera and chimera resulting from fertilization of the second polar body. Furthermore, a particular type of chimera called 'androgenetic chimera' recently described in fetuses with placental mesenchymal dysplasia and in rare patients with Beckwith-Wiedemann syndrome is discussed. Strategies to study mechanisms leading to the production of chimera and mosaics are also proposed.

The importance of preoperative radiological assessment in intersex patients

[1]. They performed laparoscopy in 14 patients among 80 intersex patients, in order to observe gonadal structures, obtain biopsy if necessary and remove them in selected cases. Out of these 14 patients, five cases with androgen insensitivity syndrome (AIS) underwent laparoscopic gonadectomy with subsequent estrogen replacement following gonadal biopsies. As authors emphasized, the procedure is minimally invasive with low morbidity, shorter postoperative recovery period and less formation of cutaneous scars. It also provides magnified and easy access to the pelvic and peritoneal cavity. However, precise radiological evaluation has to be accomplished for the establishment of additional congenital anomalies related with other organ systems, mainly the urinary system in intersex patients. Since the Mullerian ducts develop in association with the Wolffian ducts and derivatives, the clinician must expect renal abnormalities if maldevelopment or absence of Mullerian structures were noticed. For this purpose, use of magnetic resonance imaging (MRI) technique has some advantages over other imaging modalities. Particularly, good contrast resolution and soft tissue visualization allow exact localization of undescended testes or immature gonadal structures. It was reported that in up to 86% of cases with AIS or true hermaphroditism, gonadal structures were localized accurately with MRI [2]. We recently diagnosed a case of complete ASI with solitary pelvic kidney [3]. She was a 16-year-old female who was admitted initially with the chief complaint of amenorrhea. It was seen that her kidney was localized in bony pelvis between the dome of the bladder and sacrum on left side. In addition, gonadal structures were clearly demonstrated in pelvic sections of MRI. So, coexistence of other congenital anomalies in patients with intersex disorders must be kept in mind. Although detailed evaluation is sometimes regarded as unnecessary and time consuming, it gives the precise localization of pelvic organs to the surgeon, preoperatively. In conclusion, during surgical treatment of these patients, especially with minimally invasive techniques like laparoscopy, preoperative assessment with MRI allows the surgical anatomy to be handled easily. In addition, possible intraoperative injuries to other organ systems could be prevented, especially when experience in laparoscopic procedures is not excessive. Certainly, this is not the case for Dr. Chertin and associates, as they successfully operated more than 80 intersex patients, including 14 cases which were laparoscopically managed without any complication.

Intersex genetic anomalies with malignant potential

Mutations in genes contributing to sexual determination and differentiation can cause clinical syndromes with potential for the development of malignant tumors. This article focuses on intersex disorders requiring surveillance for and/or operation to prevent or treat malignancies. Classification of intersex disorders into risk groups gives guidance to physicians about children who are vulnerable to malignant degeneration of the gonads or kidneys. The gonads most at risk are both dysgenetic and intra-abdominal, and early gonadectomies are recommended as malignancies have been reported in infancy. Predominant risk groups include syndromes of gonadal dysgenesis and Ullrich-Turner syndrome. Partial gonadectomy is feasible in true hermaphrodites commensurate with sex of rearing. Histologically normal intra-abdominal gonads may be left through puberty (androgen insensitivity syndromes). A palpably normal descended gonad in a child with a Y chromosome can be observed if the child is reared as male. Certain intersex syndromes with splice variants of the WT1 gene are susceptible to Wilms' tumors (Frasier and Denys-Drash syndromes). Prevention or early recognition of malignancy in intersex disorders requires knowledge of the risk factors including dysgenetic gonads, a Y chromosome with intra-abdominal gonads and dysgenetic syndromes with WT1 gene splice variants. This paper describes the evolution toward laparoscopic gonadectomy in intersex patients, as a means to remove abnormal gonads and associated ductal structures as dictated by the disease or syndrome.

Long-Term Surgical Results and Patient Satisfaction With Male Pseudohermaphroditism or True Hermaphroditism: A Cohort of 63 Patients

To improve treatment policy, we retrospectively evaluated the results of early corrective genital surgery in 63 sexually ambiguous patients 14 to 38 years old. We analyzed all records classified under male pseudohermaphroditism and true hermaphroditism. Anatomical and functional results and data on self-reported satisfaction were recorded by the managing physician at the last routine followup visit. A total of 38 patients were raised female and 25 were raised male. Basal procedures for external genital reconstruction were initiated shortly after birth, when gender was assigned. Complementary surgical procedures were usually required later. In both sexes there was a significant negative correlation between the number of basal, but not complementary, procedures required and year of birth, due to the adoption of 1-stage procedures in the early 1980s. Most patients with gonadal dysgenesis were raised as females and menstruated under treatment but breast development was abnormal in 30%. Spontaneous puberty was observed in true hermaphrodites raised as either sex. In females with partial androgen insensitivity the main problem was shortness of the vagina. Amenorrhea and infertility often led to transient distress. In males results were poor due to intractable micropenis and minimal virilization. Results were good in 5alpha-reductase deficiency. Results of intersex surgery have clearly improved with time, and apart from a patient with 5alpha-reductase deficiency who underwent a successful sex change, no patient expressed dissatisfaction with sex of rearing. However, in the absence of an in-depth psychological survey, these optimistic conclusions are valid only in the settings of our study.

The use of laparoscopy in intersex patients

The management of intersex patients is a challenge. Although in the majority of patients the diagnosis may be made on the basis of cytogenetic and biochemical tests, there is a selective group of patients with difficulties in the establishment of final diagnosis and gender assignment. Since laparoscopy has been used in the management of impalpable gonads in the normal male population, it may be an alternative method for the diagnosis and surgical management of intersex patients. Thus we have evaluated our experience with laparoscopy in intersex population. Over the last 10 years (1995-2005) more than 80 intersex patients underwent surgical correction at our department. Out of those, 14 patients with a median age of 3 years (range 2-18 years) underwent laparoscopic surgery. Laparoscopic gonadectomy with subsequent estrogen replacement was performed following gonadal biopsy in five patients with androgen insensitivity syndrome (AIS). In three patients with mixed gonadal dysgenesis (MGD) gonadal biopsy was performed. In two of those the initial diagnosis was changed to true hermaphroditism, and they underwent removal of ovotestis from one side and orchidopexy of the normal testis on the other. In one patient with MGD, timed gonadectomy following laparoscopic biopsy was performed due to malignant potential of the streak gonads. In two patients with persistent müllerian duct syndrome (PMDS), laparoscopic orchidopexy was performed following gonadal biopsy. Three patients with total gonadal dysgenesis (TGD) underwent laparoscopic gonadectomy and one with true hermaphroditism underwent laparoscopic biopsy followed by bilateral inguinal orchiectomy with preservation of the ovarian tissue. Our data show that the laparoscopic gonadal biopsy remains the only way to obtain morphologic gonadal structure and to establish a final diagnosis in doubtful cases. Magnification and easy access to the pelvic cavity allow removal of gonads or ductal structures with the advantages of minimally invasive procedure.

Genetics, genomics, and molecular biology of sex determination in small animals

The genomic revolution is beginning to facilitate advances in canine and feline medicine, as illustrated in our research. Our studies are focused upon identifying the gene mutation that causes canine Sry-negative XX sex reversal, a disorder of sex determination in which chromosomal females (78,XX) develop testicular tissue, becoming either XX true hermaphrodites with ovotestes, or XX males with bilateral testes. A genome-wide screen, using mapped markers in our pedigree of Sry-negative XX sex reversed dogs founded upon the American cocker spaniel, identified five chromosomal regions in which the causative gene may be located. The canine genome was used to identify the canine homologue of goat Pisrt1 and so determine that canine and caprine Sry-negative XX sex reversal are genetically heterogeneous. A second goal of our research is to determine the molecular mechanism by which the mutation causes testis induction. Thus far, we have reported gonadal Sry and Sox9 expression patterns in normal embryos, which have temporal and spatial patterns similar to those reported in humans, sheep, and pigs. Once gene mutations causing such inherited disorders are identified, DNA tests will become a part of general veterinary practice, advancing both diagnostic techniques and preventative medicine.