睾丸源性生殖障碍综合征研究进展

睾丸源性生殖障碍综合征(TDS)是近10年来男性不育领域研究的热点。环境内分泌干扰因子作用于睾丸Leydig细胞和/或Sertoli细胞致使睾丸发育异常,从而导致TDS症状的出现是被广泛接受的发病机制。分子生物学研究提示类胰岛素样因子3(INSL-3)、雄激素受体(AR)、P27kip蛋白、WT-1基因及副中肾管抑制物(M IS)等可能与TDS的发病有关,本文对TDS的病因、机制及研究进展等进行了综述。     

A rare diagnosis： testicular dysgenesis with carcinoma in situ detected in a patient with ultrasonic microlithiasis

A rare case is presented where a dysgenetic testis with microinvasive carcinoma in situ （CIS, also known as intratubular germ cell neoplasm of unclassified type [IGCNU] and testicular intraepithelial neoplasia [TIN]） with microinvasion to rete testis and the interstitial tissue was found in a 32-year-old man presenting with mild scrotal pain and ultrasonic testicular microlithiasis. Knowledge of the association of ultrasound and CIS is important to diagnose patients at the stage prior to development of an overt germ cell tumor. The patient had three of four disorders considered symptoms of the testicular dysgenesis syndrome （TDS）： a dysgenetic left testicle with CIS, a mild left-sided cryptorchidism （high positioned scrotal hypotrophic testis） and a slightly reduced semen quality. Therefore, it should be kept in mind that a patient with one TDS symptom may harbour the other, even CIS or testicular cancer. Accordingly, patients with one TDS symptom ought to be examined for the presence of the others, and if more that one is present, extra concern is warranted.     

Removal of gonads in Y-chromosome-bearing gonadal dysgenesis and in androgen insensitivity syndrome by laparoscopic surgery

Background: This paper addresses the value of laparoscopic surgery for the removal of gonads in patients with Y-chromosome-bearing gonadal dysgenesis and androgen insensitivity syndrome, who are otherwise faced with a high rate of gonadal malignancy. Methods: Three patients with Y-chromosome-bearing gonadal dysgenesis and one patient with androgen insensitivity syndrome were operated upon laparoscopically. Removal of gonads was accomplished by their mobilization and dissection from the pelvic side walls, with ligation and transection of the utero-ovarian and infundibulopelvic ligaments. Results: Surgery was without complications. Histological examination of the gonads showed complete removal and absence of malignancy in each patient. Patients were discharged the day after surgery. Conclusions: The laparoscopic approach is a safe and effective alternative to laparotomy in the management of patients with Y-chromosome-bearing gonadal dysgenesis and with androgen insensitivity syndrome.     

Testicular dysgenesis syndrome and the origin of carcinoma in situ testis

Recent increases in male reproductive disorders have been linked to exposure to environmental factors leading to the testicular dysgenesis syndrome (TDS). Testicular cancer is the most severe condition in TDS and studies have shown a clear correlation between risk of testicular cancer and other components of TDS and that the geographical location of the mother during pregnancy can be a risk factor. This suggests that the dysgenesis has its origin in utero and that TDS is initiated by environmental factors, including possibly hormone-disrupting compounds that act on the mother and the developing foetus, but the genetic background may also play a role. The morphological similarity of carcinoma in situ (CIS) cells (the precursor of the majority of invasive testicular cancers) with primordial germ cells and gonocytes, and overlap in expression of protein markers suggests an origin of CIS from primordial germ cells or gonocytes. CIS cells and germ cell-derived cancers of the human type have so far not been described in any animal model of TDS, which could be caused by species differences in the development of the male gonad. Regardless of this, it is plausible that the dysgenesis, and hence the development of CIS cells, is a result of disturbed signalling between nurse cells and germ cells that allow embryonic germ cells to survive in the pre-pubertal and adult testis. The post-pubertal proliferation of CIS cells combined with aberrant signalling then leads to an accumulation of genetic changes in the CIS cells, which eventually results in the development of invasive testicular cancer in the adult.     

Is human fecundity declining?

Summary The decreasing trends in fertility rates in many industrialized countries are now so dramatic that they deserve much more scientific attention. Although social and behavioural factors undoubtedly play a major role for these trends, it seems premature, and not based on solid information, to conclude that these trends can be ascribed to social and behavioural changes alone. There is evidence to suspect that changing lifestyle and increasing environmental exposures, e.g. to endocrine disrupters, are behind the trends in occurrence of male reproductive health problems, including testis cancer, undescended testis and poor semen quality. These biological factors may also contribute to the extremely low fertility rates. However, the necessary research is complex and requires non-traditional collaboration between demographers, epidemiologists, clinicians, biologists, wild life researchers, geneticists and molecular biologists. This research effort can hardly be carried out without major support from governments and granting agencies making it possible to fund collaborative projects within novel research networks of scientists.     

Cellular origins of testicular dysgenesis in rats exposed in utero to di(n-butyl) phthalate

Foetal exposure of male rats to di(n-butyl) phthalate (DBP) induces testicular changes similar to testicular dysgenesis syndrome in humans, including the formation of focal 'dysgenetic areas' within post-natal testes, surrounded by otherwise normal tubules exhibiting complete spermatogenesis. We hypothesize that these dysgenetic areas form when Sertoli (and other) cells are 'trapped' during the abnormal formation of large Leydig cell (LC) clusters in foetal life and by post-natal day (d) 4 these groups of intermingled cells attempt to form seminiferous tubules. It is likely that the malformed tubules resulting correspond to the dysgenetic areas evident in later life. This also provides a plausible explanation for the occurrence of LCs within seminiferous cords/tubules in or bordering the dysgenetic areas. In our previous studies intratubular LCs (ITLCs) were identified by immunostaining for 3beta-hydroxysteroid dehydrogenase (3beta-HSD), the definitive LC cytoplasmic marker. However, the possibility remained that the 'presumptive' ITLCs were in fact Sertoli cells that had aberrantly gained the ability to express 3beta-HSD. Therefore, the aim of the present study was to fully characterize the ITLCs induced by in utero DBP exposure in d25 rats using a number of LC- (3beta-HSD, P450 side-chain cleavage enzyme, insulin-like factor 3, oestrogen receptor alpha) and Sertoli cell- (vimentin, Wilm's tumour-1) specific markers. Our results show that ITLCs express all four LC-specific markers but do not express either of the Sertoli cell markers. It is therefore concluded that the ITLCs are bona fide LCs that are abnormally located within the seminiferous tubules of DBP-exposed rats in post-natal life.     

XO/XY嵌合型性腺发育不全(附9例报告)

混合型性腺发育不全的定义:一侧性腺为发育不全的睾丸,一侧为条索状,染色体核型45,X/46,XY。本组9例嵌合体核型45,X/46,XY有多种表型与性腺病理。社会性别女8例,男1例;9例均有Turner综合征表现,5例合并阴蒂增大,2例有泌尿生殖窦。术中见双侧条索状性腺6例;一侧发育不全睾丸,一侧条索状性腺2例;与一侧为发育不全卵睾,一侧条索状性腺1例。病理检查一侧发育不全睾丸5例,对侧卵巢间质3例,Leydig与门细胞各1例;3例双侧为卵巢间质,其中1例一侧有原始卵泡,2例性腺染色体均为45,X;1例一侧性腺为卵睾,另一侧为卵巢间质。XO/XY嵌合型性腺发育不全从表型、性腺与病理表现均为多样化,唯有染色体核型一致为45,X/46,XY,因而采用XO/XY嵌合体性腺发育不全为此类患者的名称。本组3例已发生性腺母细胞与支持细胞肿瘤。全部行性腺与子宫切除术。     

Bilateral testicular tumors in androgen insensitivity syndrome

We report on a case of complete androgen insensitivity syndrome with bilateral testicular tumors and a point mutation in the androgen receptor gene. A bilateral gonadecotmy was performed and both of the resected tumors were histologically diagnosed as pure seminoma. Direct sequencing of amplified exons E-G of the androgen receptor gene from the resected tumor identified a CGA to CAA substitution in exon E, resulting in arginine to glutamine replacement at codon 752. To our knowledge, this is the first reported case of androgen insensitivity syndrome with bilateral testicular tumors.     

睾丸女性化综合症4例

目的：探讨睾丸女性化综合症的诊断和治疗。方法：回顾性分析1985-09/2001-10收治的4例睾丸女性化综合症患者的临床特征、影像学检查、治疗方法及随访资料。结果：术后随访0.5-1.5a，患者女性第二性征显著，有2例患者服用小剂量雌激素。结论：对睾丸女性化综合征患者应以预防未成熟睾丸发生恶变及维持女性特征为治疗原则。     

Adverse trends in male reproductive health: we may have reached a crucial 'tipping point'

Healthy men produce an enormous number of sperms, far more than necessary for conception. However, several studies suggest that semen samples where the concentration of sperms is below 40 mill/mL may be associated with longer time to pregnancy or even subfertility, and specimens where the concentration of sperms is below 15 mill/mL may carry a high risk of infertility. Historic data from the 1940s show that the bulk of young men at that time had sperm counts far above 40 mill/mL with averages higher than 100 mill/mL. However, recent surveillance studies of young men from the general populations of young men in Northern Europe show that semen quality is much poorer. In Denmark approximately 40 percent of the men have now sperm counts below 40 mill/mL. A simulation assuming that average sperm count had declined from 100 mill/mL in 'old times' to a current level close to 40 mill/mL indicated that the first decline in average sperm number of 20-40 mill/mL might not have had much effect on pregnancy rates, as the majority of men would still have had counts far above the threshold value. However, due to the assumed decline in semen quality, the sperm counts of the majority of 20 year old European men are now so low that we may be close to the crucial tipping point of 40 mill/mL spermatozoa. Consequently, we must face the possibility of more infertile couples and lower fertility rates in the future.     

Renal tubular dysgenesis in twins

In a fetal autopsy series, we have explored the occurrence of renal tubular dysgenesis in twins. Renal tubular dysgenesis was found exclusively among those monozygotic twins with evidence of twin transfusion syndrome, particularly in those donor twins with oligohydramnios and growth restriction. We infer that hypotension in the donor twin of the twin transfusion syndrome pair is responsible for the failure of proximal convoluted tubule differentiation, and the disturbance of renal function is manifested as oligohydramnios prenatally, and either oliguria or tubular dysfunction postnatally. Received February 7, 1997; received in revised form and accepted December 15, 1997     

DDT and urogenital malformations in newborn boys in a malarial area

Study Type – Symptom prevalence (retrospective cohort)
Level of Evidence 2b

OBJECTIVE

To determine the risk of external urogenital birth defects (UGBDs) in newborn boys from a malarial area currently sprayed with technical 1,1,1‐trichloro‐2,2‐bis(4‐chlorophenyl) ethane (DDT), as increased fetal oestrogenic or anti‐androgenic exposure might be involved in the pathogenesis of increased prevalence of human male reproductive tract anomalies, and DDT and metabolites interact with both these receptors.

SUBJECTS AND METHODS

We examined 3310 newborn baby boys and recorded external UGBDs.

RESULTS

Of the newborn boys 10.8% (357) had UGBDs; a multivariate logistic model showed that mothers who lived in villages sprayed with DDT between 1995 and 2003 had a significantly greater chance (33%) of having a baby with a UGBD than mothers whose homes were not sprayed (odds ratio 1.33, 95% confidence interval 1.04–1.72). Being a homemaker instead of being employed further significantly increased the risk of having a baby with a UGBD by 41% (odds ratio 1.41, 1.13–1.77).

CONCLUSIONS

Maternal exposure to DDT by living in a DDT‐sprayed village was associated to having male offspring with one or more UGBDs. Monitoring the impact of indoor residual spraying on human and environmental health is imperative if DDT is being used, especially as climate change raises concerns about the global spread of malaria. Integrating adequate indoor residual spraying measures by malarial vector control programmes, and increased public awareness to limit personal exposure, are crucial components that need to be addressed.     

Subtype-specific incidence of testicular cancer in Germany: a pooled analysis of nine population-based cancer registries

Comparisons of incidence estimates of testicular cancer subtypes beyond seminoma and non-seminoma are virtually missing in the epidemiologic literature. We analysed incidence data from population-based German cancer registries to provide subtype-specific incidences of testicular cancer. We pooled data from nine cancer registries from 1998 to 2003. We estimated incidence and mortality time trends of West and East Germany. Incidence and mortality were standardized by the European standard population. The annual percentage incidence change from 1961 through 1989 was 4.9% in East Germany and 3.0% from 1970 through 2004 in Saarland. Incidence increases were the most pronounced among adolescents and young men aged 15–49 years. In 1998–2003, the seminoma incidence rate was 5.1 per 100 000; among non-seminomas, the rates were the highest for malignant teratoma (1.6 per 100 000), followed by embryonal carcinoma (1.2 per 100 000). Testicular lymphomas were rare (0.1 per 100 000). The incidence of testicular cancer among children aged 0–14 years was nearly constant from 1987 through 2004. Majority of these cancers were yolk sac tumours (0.1 per 100 000). In East and West Germany, rates of embryonal carcinoma in the early periods were considerably lower than the rates of malignant teratoma. In the most recent periods, rates of embryonal carcinoma became quite similar to the rates of malignant teratoma. The mortality decline started in West Germany roughly 12 years earlier than in East Germany. The later start of the mortality decline in East Germany may be because of a later introduction of platinum-based chemotherapy compared to West Germany.     

Long-term survival and renal transplantation in a monozygotic twin with cloacal dysgenesis sequence

Cloacal dysgenesis sequence (CDS) is a severe hindgut malformation occurring in 1:50,000 to 250,000 live births (Qureshi et al. Prenatal diagnosis of cloacal dysgenesis sequence: differential diagnosis from other forms of fetal obstructive uropathy. Fetal Diagn Ther 1998;13:69-74; Bargaje et al. Cloacal dysgenesis sequence. Ann Diagn Pathol 2008;12:62-66). It is characterized by a smooth perineum with no urethral, vaginal, or anal openings, and lack of labioscrotal development. Typically, the bladder, vagina, and colon each end blindly, although persistent cloaca without perineal orifice can be seen. With no egress for urine, infants have renal insufficiency and pulmonary hypoplasia, usually making CDS lethal (Sahinoglu Z et al. The prenatal diagnosis of cloacal dysgenesis in six cases: can the termination of pregnancy always be the first choice? Prenat Diagn 2004;24:10-16). Reported survivors have had a persistent urachus or have been spared the effects of oligohydramnios by the presence of a twin (Liang X. Cloacal dysgenesis sequence: observations in four patients, including three fetuses of second trimester gestation. Pediatr Dev Pathol 1998;1:281-288). We report a case of long-term survival, currently to 25 months of age, and renal transplantation in a monochorionic, diamniotic twin girl with CDS.     

Renal tubular dysgenesis: the first case reported in Japan

Renal tubular dysgenesis (RTD) is a fatal congenital disease characterized by a defect in the differentiation of the proximal and distal convoluted tubules. This disorder is clinically associated with oligohydramnios, intrauterine growth retardation, and acute renal failure, and the diagnosis is made only at autopsy. We report a very low birth-weight infant with RTD. The infant was delivered at 32 weeks of gestation by cesarian section, because of fetal distress, and weighed 631 g. She had no micturition after birth and developed acute renal failure on day 3 of life. Because ultrasound scan did not show any abnormalities of the kidneys, she was treated aggressively with various blood purification procedures, but she died of sepsis and disseminated intravascular coagulation (DIC) on day 13 after birth. Postmortem examination of the kidneys showed glomerular crowding and undifferentiated tubules. Positive staining of tubular epithelial cells for epithelial membrane antigen supported a diagnosis of RTD. When renal failure occurs in a neonate without any gross morphological abnormalities of the kidneys on ultrasound imaging, RTD should be considered. A review of the literature showed that this is the first case of RTD reported in Japan. Received: June 4, 2001 / Accepted: June 25, 2001     

A novel E153X point mutation in the androgen receptor gene in a patient with complete androgen insensitivity syndrome

Aim: To study a 46, XY newborn patient with a phenotype suggestive of an androgen insensitivity syndrome toconfirn an anomaly in the AR gene. Methods: Genomic DNA from leukocytes was isolated in order to analyze SRYgene by PCR and sequencing of the eight exons of AR gene. Isolation of human Leydig cell mesenchymal precursorsfrom the testis was performed in order to study testosterone production and response to hCG stimulation in culture.Results: Surgical exploration disclosed two testes, no Wolffian structures and important Mullerian derivatives. TheSRY gene was present in peripheral blood leukocytes. Sequencing of the AR gene evidenced a previously unreported Gto T transversion in exon 1 that changed the normal glutamine 153 codon to a stop codon. Interstitial cell culturesproduced sizable amounts of testosterone and were responsive to hCG stimulation. Conclusion: This E153X nonsensepoint mutation has not been described previously in cases of AIS, and could lead to the synthesis of a short truncated(15     

Prevalence of carcinoma in situ in testicular biopsies of infertile Iranian men

Almost all testicular germ cell tumours are proved to originate from carcinoma in situ cells. Infertility is one of the factors that increase the risk of carcinoma in situ. The reported prevalence for carcinoma in situ from different parts of the world is 0–3.7% in infertile men. This retrospective study was performed to determine the prevalence of carcinoma in situ in Iranian infertile men. We reviewed the testicular biopsies of 1153 infertile men at the pathology department of Avicenna Infertility Center. One hundred and fifty‐one cases were suspicious of having carcinoma in situ. Immunohistochemical marker for placental alkaline phosphatase was employed to confirm the diagnosis of carcinoma in situ. Positive results were detected in 7 (0.6%) of 1153 cases (95% CI 0.24%–1.24%), 6 (0.94%) of which (95% CI 0.34%–2.04%) were under the age of 35 years (636 patients were in this age group). This study is the first study in Iran determining the prevalence of carcinoma in situ among the infertile Iranian men; the result is in the range of reports from other countries.     

LH/hCG Responsive Adenylyl cyclase in Rat Testis and Testes from Testicular Feminized Male (Tfm) Rats and Mice: Desensitization by Homologous Hormone

Testes of testicular feminized (tfm) rats and mice, as well as of normal male rats contain an LH/hCG responsive adenylyl cyclase. Basal, as well as hCG stimulated activities were higher in tfm rats and mice than in normal rats. The presence of an LH/hCG responsive adenylyl cyclase in the testis of tfm rats and mice shows that the greatly elevated LH levels present in males having this syndrome, giving 80–90% reduction in LH//hCG receptors, do not cause an uncoupling of the remaining receptors from the adenylyl cyclase. It also shows that androgens are not essential for coupling of the LH/hCG receptors to the adenylyl cyclase.
Injection of 200 IU of hCG into adult normal rats and tfm rats caused, after 48 h, a complete loss of LH/hCG stimulated adenylyl cyclase, whereas the FSH responsive adenylyl cyclase in both animal preparations was maintained. Desensitization of the LH responsive adenylyl cyclase by hCG in normal rats, confirms previous studies showing lack of hCG stimulated cyclic-AMP secretion after a comparable dose of hCG in vivo. Similarly, hCG (50 IU) caused a transient loss of LH/hCG responsive adenylyl cyclase in tfm mice, with a complete disappearance of response after 24 h. At 48 and 72 h after injection of hCG the response gradually returned to normal. The fact that hCG caused a complete desensitization of the LH/hCG responsive adenylyl cyclase in both tfm rats and mice, proves that androgen receptor mediated events are not involved in hCG desensitization of the adenylyl cyclase in Leydig cells.     

宫、腹腔镜联合诊治性腺发育不全6例报告

目的：探讨宫、腹腔镜联合诊治性腺发育不全的作用及性腺发育不全的镜下特点。方法：对6例性腺发育不全患者进行宫、腹腔镜检查及腹腔镜下切除的性腺病例资料进行分析。结果：6例均为女性外阴,含有Y染色体,性激素低,5例骨龄明显低于同龄,3例为xo/xy性腺发育不全,3例为xy单纯性性腺发育不全,性腺均位于腹腔内,5例宫腔镜下见有宫颈,2例合并腹股沟斜疝,1例因B超未见子宫外院诊为CAIS,1例xo/xy性腺发育不全者性腺合并性腺母细胞瘤（16.67%）。结论：宫、腹腔镜是鉴别性腺发育不全抑或性激素及功能异常较好的诊断手段,且腹腔镜下观察清晰,在镜下切除性腺组织简单易行,可防止性腺发生病变。