Testicular Position in the Androgen Insensitivity Syndrome: Implications for the Role of Androgens in Testicular Descent

Barthold, Julia Spencer; KUMASI-RIVERS, KANDIS; Upadhyay, Jyoti; Shekarriz, Bijan; Imperato‐McGinley, Julianne

doi:10.1097/00005392-200008000-00072

Cited by 22 publications

(29 citation statements)

References 24 publications

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“…27 Differences in the effects of inguinal versus abdominal position of the gonads are difficult to assess because of an unequal age distribution of the study group, with inguinal gonads being more frequent in younger patients.…”

Section: Discussionmentioning

confidence: 99%

Complete androgen insensitivity syndrome: factors influencing gonadal histology including germ cell pathology

et al. 2014

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Patients with complete androgen insensitivity syndrome are at an increased risk for the development of gonadal germ cell cancer. Residual androgen receptor (AR) activity and abnormal gonadal location may influence the survival of atypical germ cells and the development of other histopathological features. To assess this, we evaluated 37 gonads from 19 patients with complete androgen insensitivity (ranging in age from 3 months to 18 years). Histological abnormalities were examined using hematoxylin and eosin-stained sections and sections stained for POU5F1 and KITLG, markers of early changes in germ cells at risk for malignant transformation. Hamartomatous nodules (HNs), Leydig cell hyperplasia (LCH), decreased germ cells, tubular atrophy and stromal fibrosis were more pronounced as age increased (Po0.001). Expected residual AR activity acted as a positive predictor only for non-malignant germ cell survival in (post)pubertal patients (Po0.05). Immunohistochemical studies indicated that delayed maturation of germ cells was present in three patients, whereas intermediate changes that occurred between delayed maturation and intratubular germ cell neoplasia, designated pre-intratubular germ cell neoplasia, were identified in four cases. Intratubular germ cell neoplasia was observed in one patient. Neither POU5F1 nor KITLG expression was dependent on expected residual AR activity. An independent effect of inguinal versus abdominal position of the gonads was difficult to assess because inguinal gonads were present primarily in the youngest individuals. In conclusion, many histological changes occur increasingly with age. Expected residual AR activity contributes to better survival of the general germ cell population in (post)pubertal age; however, it did not seem to have an important role in the survival of the germ cells at risk for malignant transformation (defined by POU5F1 positivity and KITLG overexpression) in complete androgen insensitivity. Comparison of the high percentage of patients in our study that were carrying germ cells with delayed maturation or pre-intratubular germ cell neoplasia with previously reported cumulative risk of tumor development in adult patients indicates that not all such precursor lesions in complete androgen insensitivity will progress to invasive germ cell cancer.

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Section: Discussionmentioning

confidence: 99%

Complete androgen insensitivity syndrome: factors influencing gonadal histology including germ cell pathology

et al. 2014

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“…On the other hand, Tfm mice, which lacked androgen action caused by mutation in androgen receptor gene, but have normal INSL3 secretion, also showed undescended testes near the kidneys. In humans, a correlation between testicular position and androgen insensitivity was reported (Barthold et al 2000). Therefore, whether undescended testes of mp/mp rats are caused by a lack of INSL3 secretion or as a defect of androgen action remains unclear.…”

Section: Discussionmentioning

confidence: 99%

A missense mutation of the Dhh gene is associated with male pseudohermaphroditic rats showing impaired Leydig cell development

Kawai¹,

Noguchi²,

Akiyama³

et al. 2011

Reproduction

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Development of the male gonads is a complex process with interaction of various cells in the gonads including germ, Sertoli, Leydig, and myoid cells. TF is a mutant rat strain showing male pseudohermaphroditism, with agenesis of Leydig cells and androgen deficiency controlled by an autosomal single recessive gene (mp). The mp locus was mapped on the distal region of rat chromosome 7 by linkage analysis, but the gene responsible for the mp mutation has not been identified. In this study, we performed fine linkage mapping and sequence analysis to determine the causative gene of the mp mutation, and performed an immunohistochemical study using a Leydig cell-specific marker to investigate detailed phenotypes of the mutant rats during the testicular development. As a result, we found a missense mutation of the gene encoding Desert hedgehog (Dhh) in the mutant rat, which could result in loss of function of the DHH signaling pathway. Histochemical examination revealed remarkably reduced number of fetal Leydig cells and lack of typical spindleshaped adult Leydig cell in the mp/mp rats. These phenotypes resembled those of the Dhh-null mice. Additionally, testosterone levels were significantly lower in the mp/mp fetus, indicating androgen deficiency during embryonic development. These results indicate that the mutation of the Dhh gene may be responsible for the pseudohermaphrodite phenotypes of the mutant rat, and that the Dhh gene is probably essential for the development of Leydig cells.

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“…Some papers noted that development of the gubernaculum and/or vaginal process was subnormal. In two compilations of humans with severe androgen insensitivity syndrome, 90% of 32 testes were below the internal inguinal ring (Hutson 1986) and 46% of 176 testes were outside the abdominal cavity (Barthold et al 2000). Thus, in mice exposed to flutamide or mice and humans not expressing normal androgen receptor, abdominal translocation is completed by the majority of testes.…”

Section: Role Of Testosteronementioning

confidence: 99%

“…Testosterone also targets the vaginal process to stimulate changes needed to constrict/close the inguinal canal (Barthold et al 2000; except in rodents and rabbits) and the cremaster muscles to stimulate their growth (at least in rodents or rabbits). The most important regressive effect of testosterone is to drive changes in molecular structure of the gubernacular bulb and the structure's virtual elimination leaving a short ligament (McMahon et al 1995, Barthold et al 2000.…”

Section: Role Of Testosteronementioning

confidence: 99%

Cryptorchidism in common eutherian mammals

2007

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Cryptorchidism is failure of one or both testes to descend into the scrotum. Primary fault lies in the testis. We provide a unifying cross-species interpretation of testis descent and urge the use of precise terminology. After differentiation, a testis is relocated to the scrotum in three sequential phases: abdominal translocation, holding a testis near the internal inguinal ring as the abdominal cavity expands away, along with slight downward migration; transinguinal migration, moving a cauda epididymidis and testis through the abdominal wall; and inguinoscrotal migration, moving a s.c. cauda epididymidis and testis to the bottom of the scrotum. The gubernaculum enlarges under stimulation of insulin-like peptide 3, to anchor the testis in place during gradual abdominal translocation. Concurrently, testosterone masculinizes the genitofemoral nerve. Cylindrical downward growth of the peritoneal lining into the gubernaculum forms the vaginal process, cremaster muscle(s) develop within the gubernaculum, and the cranial suspensory ligament regresses (testosterone not obligatory for latter). Transinguinal migration of a testis is rapid, apparently mediated by intra-abdominal pressure. Testosterone is not obligatory for correct inguinoscrotal migration of testes. However, normally testosterone stimulates growth of the vaginal process, secretion of calcitonin gene-related peptide by the genitofemoral nerve to provide directional guidance to the gubernaculum, and then regression of the gubernaculum and constriction of the inguinal canal. Cryptorchidism is more common in companion animals, pigs, or humans (2-12%) than in cattle or sheep (%1%). Laboratory animals rarely are cryptorchid. In respect to non-scrotal locations, abdominal testes predominate in cats, dogs, and horses. Inguinal testes predominate in rabbits, are common in horses, and occasionally are found in cats and dogs. S.c. testes are found in cattle, cats and dogs, but are most common in humans.

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Testicular Position in the Androgen Insensitivity Syndrome: Implications for the Role of Androgens in Testicular Descent

Cited by 22 publications

References 24 publications

Complete androgen insensitivity syndrome: factors influencing gonadal histology including germ cell pathology

Complete androgen insensitivity syndrome: factors influencing gonadal histology including germ cell pathology

A missense mutation of the Dhh gene is associated with male pseudohermaphroditic rats showing impaired Leydig cell development

Cryptorchidism in common eutherian mammals

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