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PubMed2002

Sex with two SOX on: SRY and SOX9 in testis development.

Although gonads are not required for development or survival, defects in gonadal development undoubtedly have a profound influence on affected individuals. Recent complementary studies in the fields of cytology, biochemistry and molecular genetics have revealed that normal gonad development involves an exquisitely regulated network of gene expression and protein-protein interactions. The initial event of gonadogenesis, in both males and females, involves the formation of a bipotential primordium. A Y chromosome then activates the male-specific pathway. The demonstration that mutations in the SOX proteins, SRY and SOX9, are responsible for disorders associated with male-to-female sex reversal showed dramatically that SRY and SOX9 have an essential role in male sex differentiation. This was emphasized when it was shown that female mice carrying transgenes that encode these proteins developed as males. SRY and SOX9 proteins have been characterized extensively and aspects of their function and regulation are now known.

Active Transport, Cell Nucleus↗
PubMed2006

Phenotypic plasticity of reproductive traits in response to food availability and photoperiod in white-footed mice (Peromyscus leucopus).

Although most temperate-zone mammals are seasonal breeders, many populations display variation in winter reproductive phenotype. For most mammals, the primary environmental cues regulating reproductive status are food availability and photoperiod, and these two factors can interact in their effect. Low food availability is primarily thought to suppress reproduction by reducing body mass and thereby forcing energy allocations to survival alone. However, because most small mammals rely on an increase in food intake rather than stored nutrients for reproduction, we hypothesized that food availability could act as a signal for low resource availability and affect reproduction even when body condition was not affected. We tested the prediction that restricted food access, without reduced body mass, could alter reproductive responses to short photoperiod. We used genetically distinct lines of white-footed mice (Peromyscus leucopus) derived from a wild population with genetic variation in the neuroendocrine pathway that regulates reproduction in response to environmental cues. The lines were created by artificial selection on gonad size in short photoperiods. Individuals from one line strongly suppress gonadal development in response to short photoperiods, while individuals from the other line suppress gonadal development weakly or not at all. Unresponsive individuals from the selected and an unselected control line were exposed to an intermittent food access protocol that did not affect body mass and only slightly reduced total food intake. We found that restricting food access caused reproductive suppression in short photoperiods but not long photoperiods, with no decrease in body mass. These results provide evidence for an interaction between food and photoperiod that is not dependent upon body condition or energy balance. The results also demonstrate plasticity in the reproductive response to photoperiod of otherwise reproductively nonphotoperiodic white-footed mice.

Analysis of Variance↗
PubMed1985

Influence of testosterone on precocious sexual development in immature rainbow trout.

The influence of testosterone on plasma and pituitary levels of gonadotrophin (GTH) as well as on gonadal development was studied in immature rainbow trout. Among the animals receiving a testosterone-cocoa butter implant (200 micrograms) at the age of 5 months, gonadal puberty occurred 8 months later in half of the males (opposite to the controls which remained immature) and the beginning of oocyte maturation was observed in only one female. These animals were characterized by a higher pituitary GTH level. Owing to the multivariate statistical analyses made, it was possible to provide evidence for the presence of two populations with different reactions to the same steroid treatment. They also confirmed the existence of a positive testosterone feedback, in the male, leading to a precocious gonadal development. The pituitary GTH load obtained with 200 micrograms of testosterone seemed to be related to the age of first maturation. The secretion of an appropriate level of GTH resulting in the stimulation of gametogenesis required the availability of a relatively large pituitary GTH level and seemed to be possible because the animals were already in the pubertal period. The fact that the highest pituitary GTH level of the treated lot was found in the only female showing a beginning of sexual maturation suggests that testosterone may also act in females.

Animals↗
PubMed2003

Sry expression level and protein isoform differences play a role in abnormal testis development in C57BL/6J mice carrying certain Sry alleles.

Transfer of certain Mus domesticus-derived Y chromosomes (Sry(DOM) alleles, e.g., Sry(POS) and Sry(AKR)) onto the C57BL/6J (B6) mouse strain causes abnormal gonad development due to an aberrant interaction between the Sry(DOM) allele and the B6-derived autosomal (tda) genes. For example, B6 XY(POS) fetuses develop ovaries and ovotestes and B6 XY(AKR) fetuses have delayed testis cord development. To test whether abnormal testis development is caused by insufficient Sry(DOM) expression, two approaches were used. First, gonad development and relative Sry expression levels were examined in fetal gonads from two strains of B6 mice that contained a single M. domesticus-derived and a single M. musculus-derived Sry allele (B6-Y(POS,RIII) and B6-Y(AKR,RIII)). In both cases, presence of the M. musculus Sry(RIII) allele corrected abnormal testis development. On the B6 background, Sry(POS) was expressed at about half the level of Sry(RIII) whereas Sry(AKR) and Sry(RIII) were equally expressed. On an F(1) hybrid background, both Sry(POS) and Sry(RIII) expression increased, but Sry(POS) expression increased to a greater extent. Second, sexual development and Sry expression levels were determined in XX mice carrying a transgene expressing Sry(POS) controlled by POS-derived or MUS-derived regulatory regions. In both cases one B6 transgenic line was recovered in which XX transgenic mice developed only testicular tissue but cord development was delayed despite normal Sry transcriptional initiation and overexpression. For three transgenes where B6 XX transgenic mice developed as females, hermaphrodites, or males, the percentage of XX transgenic males increased on an F(1) background. For the one transgene examined, Sry expression increased on an F(1) background. These results support a model in which delayed testis development is caused by the presence of particular DOM SRY protein isoforms and this, combined with insufficient Sry expression, causes sex reversal. These results also indicate that at least one tda gene regulates Sry expression, possibly by directly binding to Sry regulatory regions.

Animals↗
PubMed2001

Ontogeny of steroidogenesis in the fetal sheep gonad.

The aim of this study was to determine 1) the time of onset and cellular localization of gene expression for steroidogenic factor-1 (SF-1), steroidogenic acute regulatory protein, 3beta-hydroxysteroid dehydrogenase/Delta(5),Delta(4) isomerase (3beta-HSD), and the cytochrome P450 enzymes for cholesterol side-chain cleavage (P450(scc)), 17alpha-hydroxylase (P450(17alphaOH)), and aromatase (P450(arom)) during gonadal development; and 2) the amount of progesterone, androstenedione, testosterone, and 17beta-estradiol present in the fetal sheep gonad. Fetuses were collected on Days 24, 26, 28, 30, 32, 35, 40, 55, and 75 of gestation, and gene expression was determined by in situ hybridization. The steroid content of gonads collected on Days 30, 35, 55, and 75 of gestation was determined by RIA. Developing gonads collected from both male and female fetuses were steroidogenically active around the time of morphological sexual differentiation. In the female, the steroidogenic cells were initially located at the boundary of the cortex and medulla but become increasingly restricted to the mesonephric-derived cell streams. In the male, once tubules were identifiable, steroidogenesis was restricted to the interstitial regions. Interestingly, expression of both SF-1 and 3beta-HSD was observed prior to morphological sexual differentiation. In addition, expression of both of these genes was more widespread than the other genes in both males and females.

3-Hydroxysteroid Dehydrogenases↗
PubMed2005

Seasonal ovarian cycle in freshwater teleost, Labeo rohita (Ham.) in Tarai region of Uttaranchal.

Seasonal ovarian cycle, based on histophysiological changes, and correlative variations in liver were studied in an Indian major carp, Labeo rohita reared in captivity under ambient environmental conditions in Tarai region of Uttaranchal. The oocyte features used for marking ovarian cycle included nuclear-ooplasmic ratio, yolk vesicle incorporation into ooplasm, number and size of nucleolus and differentiation of follicular layer. Based on these features the ovarian cycle in L. rohita was divided into five phases i.e. resting, preparatory, pre-spawning, spawning and post-spawning/regression. The resting and preparatory phases were characterized by the dominating presence of chromatin-nucleolar and yolk-vesicle stage oocytes. The pre-spawning phase ovary was marked by the prevalence of yolk globule stage oocytes having cortical alveoli and differentiating follicular wall. The oocytes containing densely packed yolk-granules and large masses of yolk vesicles and also exhibiting germinal vesicle movement (GVM) signified the ovary of spawning phase. The ovary in regression phase contained pre-ovulatory atretic oocytes and significant number of oogonia. The histophysiological changes in liver showing augmented biosynthetic activity during preparatory and pre-spawning phases seemed well correlated with the gonadal development. The increasing water temperature and day-length apparently was favourable for the gonadal development in L. rohita.

Animals↗
PubMed2006

Development of chronic tests for endocrine active chemicals. Part 1. An extended fish early-life stage test for oestrogenic active chemicals in the fathead minnow (Pimephales promelas).

An extended early-life stage test (based on OECD test guideline 210) was developed to allow the evaluation of a weak environmental oestrogen, 4-tert-pentyphenol (4TPP), on sexual differentiation and gonadal development. Fathead minnow (Pimephales promelas) embryos were exposed to three concentrations of 4TPP (56, 180 and 560 microg l(-1)) in a flow-through system, at 25+/-1 degrees C, for <107 days post-hatch (dph). In addition, some embryos were exposed to 180 microg 4TPPl(-1) until 30 or 60 dph, after which they were exposed to dilution water only until 107 dph. At 30, 60 and 107 dph fish were evaluated for growth and gonadal development (via histology), and at 107 dph fish were also evaluated for secondary sexual characteristics (SSC), gonadosomatic index (GSI) and plasma vitellogenin (VTG). There were no effects of 4TPP on hatching success or survival, however, there was a delay in the time taken for embryos to hatch (560 microg 4TPPl(-1)). No treatment-related effects were observed on fish growth, with the exception of at 107 dph when the condition factor in female fish was reduced in all 4TPP continuous exposure treatments. Plasma VTG was only elevated in female fish exposed to 180 microg 4TPPl(-1) and inhibition of gonadal growth (GSI) occurred only in females exposed to 560 microg 4TPPl(-1). Histological examination of the gonads revealed delays and disruption in male sexual differentiation and development (180 microg 4TPPl(-1)) and no testicular tissue was observed in any fish exposed to 560 microg 4TPPl(-1). Mixed gonads (predominately testes with a scattering of primary oocytes) were present in fish exposed to all doses of 180 microg 4TPPl(-1) at 107 dph. Feminisation of the reproductive ducts (formation of an ovarian like cavity) occurred in the testis of all males exposed to 180 microg l(-1), regardless of length of 4TPP exposure. Results indicate that the period of 30-60 dph appears to be the sensitive window for disruption of formation of the reproductive duct and this effect is not reversible when the fish are transferred to dilution water. The data also show that this integrative test is suitable for the detection of a weak environmental oestrogen and comparisons of these results with that of a fish full life-cycle, in medaka, indicate that this test could be a suitable surrogate for a fish full life-cycle.

Animals↗
PubMed2003

Cloning and gene expression of P450 17alpha-hydroxylase,17,20-lyase cDNA in the gonads and brain of the fathead minnow Pimephales promelas.

P450 17alpha-hydroxylase,17,20-lyase (P450c17) is a key steroidogenic enzyme in the production of androgens and, therefore, is also indispensable for the production of oestrogens (that are produced from the aromatisation of androgens). In this study, P450c17 cDNA was cloned from the ovary of the fathead minnow (FHM) and its gene expression was examined in the gonads and brains of male and female FHM at different stages of gonadal development with a view to developing an understanding of its involvement in the reproductive physiology in this species. The FHM-P450c17 cDNA sequence cloned was 1812 bp in length, with an open reading frame of 1554 nucleotides encoding a protein of 518 amino acids. Amino acid identity of FHM-P450c17 with P450c17s in other animals was up to 81.8% in other teleosts (channel catfish), 62% in elasmobranches (spiny dogfish), 64% in birds (chicken), and up to 48.8% in mammals (human). FHM-P450c17 gene expression occurred in the ovary, testis, and also in the brain (both male and female) at all stages of sexual development studied. Expression in the brain was at least 30-fold lower than in the gonads, but consistent in all fish life stages studied. In the testis, FHM-P450c17 gene expression was negatively correlated with gonadal development, but there was no obvious association between P450c17 gene expression and sexual development in the ovary, or brain (in both males and females). The results from this study demonstrate the expression of P450c17 in the brain for the first time in fish. Enzymatic studies are now needed to investigate the possible role of P450c17 in neurosteroid production in teleosts.

Amino Acid Sequence↗
PubMed1997

Correlation among thermosensitive period, estradiol response, and gonad differentiation in the sea turtle Lepidochelys olivacea.

Reptile embryos with temperature sex determination have a thermosensitive period (TSP). The finding that exogenous estradiol (E2) overcomes the effect of male-promoting temperature led to the idea that temperature may regulate estrogen concentration in the gonad during TSP. Since interspecific variations in TSP and in the effect of exogenous E2 exist, we undertook a study in the olive ridley Lepidochelys olivacea. Four parameters were correlated: the TSP (time dimension), the thermosensitive stages (rate of development), gonad development (histological aspect), and the estradiol response. Two kinds of experiments were performed: (1) Eggs were shifted once, at different stages of development, from a male-promoting temperature to a female-temperature (or vice versa) for the remainder of development. (2) Eggs at male-promoting temperature were treated once with 6 or 12 microg of estradiol (E2) at various times of incubation. Sex ratio was established around hatching in each experimental series. We found that the temporal dimension of the TSP was around 7 days (Days 20-27 of incubation) at a male-promoting or a female-promoting temperature. The rate of development of the whole embryo and gonadal growth was faster at female-promoting temperature than at male-promoting temperature. Formation of the genital ridge began at stage 21-22 and histological differentiation of the gonads occurred around stage 26-27. Although these stages coincided with the TSP, at male-promoting temperature the thermosensitive stages occurred earlier (from stages 20-21 to stages 23-24) than at female-promoting temperature (from stages 23-24 to stages 26-27). Thus, at male promoting-temperature, sex was determined in embryos with incipient or undifferentiated gonads. In contrast, E2 treatment continued to feminize the gonads of embryos at a male-promoting temperature beyond the TSP up to stage 25-26, but the E2-induced ovaries were significantly smaller than temperature-induced ovaries. It is suggested that the doses of E2 used were higher than the concentration of endogenous E2 required for normal sex determination. The lack of correlation between sex determination and gonad differentiation suggests that irreversible molecular processes underlying sex determination occur earlier at male- than at female-promoting temperature. Results suggest that the male sex may be the default state and that the female condition must be imposed upon it.

Animals↗
PubMed1997

The effects of photoperiod and food intake on reproductive development in male deer mice (Peromyscus maniculatus).

Seasonal breeding is a tactic that has evolved in rodents that limits reproduction to specific times of the year to increase reproductive success. In order to time breeding accurately, many animals respond to changes in daily photoperiod. Short day lengths inhibit breeding in many nontropical rodent species. Restricted food availability can also inhibit reproductive function among some individuals in these so-called "photoperiodic" populations. Rodents born at the end of the breeding season typically delay sexual maturation until the following spring. Prepubertal rodents exposed to day lengths that are < 12 h light/day will not undergo puberty for 4-7 months in the laboratory. Food restriction can also affect the timing of puberty onset. Reproductive function of food-restricted juvenile mice may remain inhibited until food availability improves. Alternatively, reproductive function of food-restricted juvenile mice might eventually develop despite restricted food intake. This study examined the effects of chronic food restriction and photoperiod on reproductive development in male deer mice (Peromyscus maniculatus bairdii). Short-day mice fed ad lib delayed gonadal development for 5-7 months, but eventually achieved reproductive maturity. The reproductive function of short-day mice fed ad lib was indistinguishable from long-day control animals when assessed at week 32. Long-day food-restricted mice exhibited an intermediate level of gonadal development and function. Short-day food-restricted deer mice also inhibited reproductive growth, but failed to demonstrate reproductive maturity by week 32 of the study. Taken together, these results suggest that retardation of reproductive development by food restriction is only superficially similar to the delay in reproductive maturation imposed by short day exposure. It does not appear that male deer mice escape from the inhibitory effects of food restriction to attain sexual development.

Animals↗
PubMed1991

NCAM in developing mouse gonads and ducts.

The expression of the Neural Cell Adhesion Molecule, NCAM, in mouse gonads and ducts was studied from fetal life to maturity. The methods used were immunocytochemical staining and Western blotting. The immunocytochemical studies showed that the only structures that remain NCAM-positive throughout life were the mesonephric-derived rete ovarii and rete testis. Also in the fetal gonads some somatic cell lining the groups of differentiating germ cells were stained. In the immature as well as in the mature ovary the granulosa cells and oocytes of growing and large follicles--but not of small follicles--were stained. A particularly strong staining of the cytoplasm of the oocyte, healthy as well as atretic, was seen. All cells of the testis remained negative except for weakly stained residual bodies and late spermatids. At all ages the male ducts showed only weak staining, whereas in the female Müllerian duct the epithelium became strongly positive at puberty. The stroma of the Müllerian duct was positive during a transitory period around day 16 of fetal life in both sexes. One-dimensional gel immunoblotting of total protein from gonads, rete and ducts from immature and mature mice showed that only the two largest isoforms of NCAM (NCAM-A and NCAM-B) were present. The gonads and the rete of both sexes and the adult uterus expressed only NCAM-B, whereas NCAM-A was also detected in the adult epididymis. The present findings suggest that NCAM may be involved in the normal development and formation of both the gonads and ducts.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Fine structural characteristics of testicular cord formation in the developing rabbit gonad.

This paper presents morphological (light- and electron-microscopical) evidence for the role of the mesonephros in contributing cells to the differentiating indifferent gonad and, after sexual differentiation, to the testis. A continuous process is revealed during which segregation of cells occurs from the developing and regressing mesonephros. Additionally, the complementary role of the coelomic epithelium in gonadal ridge and testis formation is demonstrated. The differentiation of testicular cords, their remodelling from a primary reticulum, and the composition and further change of the cellular content during the period after sexual differentiation is described using a computer-aided three-dimensional reconstruction system. Apart from these morphogenetic events, cytodifferentiation in the somatic cells of the indifferent gonad and of the early differentiated testis is demonstrated using indirect immunofluorescence in combination with monoclonal antibodies to the intermediate filament proteins keratin 8 and 18 and vimentin. The immunohistochemical results show that different forms of cytodifferentiation coexist among the somatic cells present in the indifferent gonad and in the testis early after sexual differentiation.

Animals↗
PubMed1994

[TGF beta (transforming growth factor beta) and its related peptides in the local control of the testicle].

Recent data on TGF beta (and related peptides) expression and action in the testis are briefly reviewed. At least, three isoforms of TGF beta are expressed during the male gonadal development. TGF betas are expressed in somatic and germ cells. The expression of the different isoforms varies during gonadal development and is cell specific. Both types I, II and III TGF beta receptors have been localized in somatic cells. TGF beta inhibits gonadotropin action both in Sertoli cells and Leydig cells as well as proliferation of germ cells and Leydig cells. Inhibins and activins (in terms of mRNA and proteins) are expressed in somatic cells and germ cells. Inhibin production in Sertoli cells is under the control of FSH, local factors (ex: EGF, insulin, opiods) and probably of germ cells. Activins and inhibins regulate Leydig and Sertoli cells activities and germ cells development. The existence of activin receptors in somatic and germ cells has been suggested by the presence of type II receptor mRNA (ActRII and ActRIIB).

Activins↗
PubMed2003

Molecular characterization of three gonad cell lines.

To facilitate the study of the regulation and downstream interactions of genes involved in gonad development it is important to have a suitable cell culture model. We therefore aimed to characterize molecularly three different mouse gonad cell lines. TM3 and TM4 cells were originally isolated from prepubertal mouse gonads and were tentatively identified as being of Leydig cell and Sertoli cell origin, respectively, based upon their morphology and hormonal responses. The third line is a conditionally immortalized cell line, derived from 10.5-11.5 days post-coitum (dpc) male gonads of transgenic embryos carrying a temperature-sensitive SV40 large T-antigen. We studied by reverse transcription-polymerase chain reaction (RT-PCR) the expression profiles of a number of genes known to be important for early gonad development. Moreover, we assessed these cell lines for their capacity to induce SOX9 transcription upon expression of SRY, a key molecular event occurring during sex determination. We found that all three cell lines were unable to upregulate SOX9 expression upon transfection of SRY-expression constructs, even though these cells express many of the studied embryonic gonad genes. These observations point to a requirement for SRY cofactors for direct or indirect upregulation of SOX9 expression during testis determination.

Animals↗
PubMed2001

Gonadal tumors of mice double transgenic for inhibin-alpha promoter-driven simian virus 40 T-antigen and herpes simplex virus thymidine kinase are sensitive to ganciclovir treatment.

We have previously produced transgenic (TG) mice expressing the mouse inhibin alpha-subunit promoter/Simian virus 40 T-antigen (Inhalpha/Tag) fusion gene. The mice develop gonadal somatic cell tumors at the age of 5-7 months; the ovarian tumors originate from granulosa cells, and those of the testes from Leydig cells. In the present study another TG mouse line was produced, expressing under the same inh-alpha promoter the herpes simplex virus thymidine kinase gene (Inhalpha/TK). Crossbreeding of the two TG mouse lines resulted in double TG mice (Inhalpha/TK-Inhalpha/Tag), which also developed gonadal tumors. The single (Inhalpha/Tag) and double TG (Inhalpha/TK-Inhalpha/Tag) mice, both bearing gonadal tumors, were treated at the age of 5.5-6.5 months with ganciclovir (GCV, 150 mg/kg body weight twice daily i.p.) for 14 days, or with aciclovir (ACV, 300-400 mg/kg body weight per day perorally) for 2 months. During GCV treatment, the total gonadal volume including the tumor, decreased in double TG mice by an average of 40% (P<0.05), while in single TG mice, there was a concomitant increase of 60% in gonadal size (P<0.05). GCV was also found to increase apoptosis in gonads of the double TG mice. Peroral treatment with ACV was less effective, it did not reduce significantly the gonadal volume. We also analyzed the in vitro efficacy of ACV and GCV treatments in transiently HSV-TK-transfected KK-1 murine granulosa tumor cells, originating from a single-positive Inhalpha/Tag mouse. GCV proved to be more effective and more specific than ACV in action. These results prove the principle that targeted expression of the HSV-TK gene in gonadal somatic cell tumors is potentially useful for tumor ablation by antiherpes treatment. The findings provide a lead for further development of somatic gene therapy for gonadal tumors.

Acyclovir↗
PubMed2003

Mutations in the SRY, DAX1, SF1 and WNT4 genes in Brazilian sex-reversed patients.

In most mammals, male development is triggered by the transient expression of the SRY gene, which initiates a cascade of gene interactions ultimately leading to the formation of a testis from the indifferent fetal gonad. Mutation studies have identified several genes essential for early gonadal development. We report here a molecular study of the SRY, DAX1, SF1 and WNT4 genes, mainly involved in sexual determination, in Brazilian 46,XX and 46,XY sex-reversed patients. The group of 46,XX sex-reversed patients consisted of thirteen 46,XX true hermaphrodites and four 46,XX males, and was examined for the presence of the SRY gene and for the loss of function (inactivating mutations and deletions) of DAX1 and WNT4 genes. In the second group consisting of thirty-three 46,XY sex-reversed patients we investigated the presence of inactivating mutations in the SRY and SF1 genes as well as the overexpression (duplication) of the DAX1 and WNT4 genes. The SRY gene was present in two 46,XX male patients and in none of the true hermaphrodites. Only one mutation, located outside homeobox domain of the 5' region of the HMG box of SRY (S18N), was identified in a patient with 46,XY sex reversal. A novel 8-bp microdeletion of the SF1 gene was identified in a 46,XY sex-reversed patient without adrenal insufficiency. The dosage of DAX1 and WNT4 was normal in the sex-reversed patients studied. We conclude that these genes are rarely involved in the etiology of male gonadal development in sex-reversed patients, a fact suggesting the presence of other genes in the sex determination cascade.

DAX-1 Orphan Nuclear Receptor↗
PubMed2003

Early manifestations of testicular dysgenesis in children: pathological phenotypes, karyotype correlations and precursor stages of tumour development.

Testicular dysgenesis derives from abnormal gonadal development caused by chromosome aberrations/mosaicisms or mutations/deletions in SRY or other genes responsible for testicular differentiation. Dysgenetic male pseudohaermaphroditism has bilateral dysgenetic testes characterized by a cortical network of anastomosing seminiferous cords that penetrate a thin albuginea. In asymmetric gonadal differentiation (or Mixed Gonadal Dysgenesis) a dysgenetic testis associates with a streak gonad with primitive sex cords embedded in an ovarian-like stroma. Uni- or bilateral ovotestes identify true haermaphroditism. Fluorescent in situ hybridisation studies demonstrate that the sex chromosomes of mosaic patients do not distribute homogeneously in asymmetric gonads. 45,X lines predominate over 46,XY in streak gonads, while the relationship between these two is more equivalent in dysgenetic testes, suggesting that testicular or streak differentiation is related to the balance between X0 and XY lines. Testicular dys-genesis is more severe when there is a frank predominance of X0 or XX cells. Higher percentages of XY cells coincide with lesser degrees of dysgenesis. DNA densitometry indicate a higher incidence of neoplastic transformation than previously anticipated. Various specimens showed clear aneuploid histograms but no clear indication of a cytological CIS phenotype. There was a wide cytological variation in aneuploid germ cells, ranging from normally looking big infantile spermatogonia to gonocyte/CIS cells. Aneuploidy probably precedes the full expression of the CIS phenotype. In case of doubt we recommend DNA densitometry to either confirm or discard their neoplastic nature. The earliest recognizable change in germ cell tumorigenesis is probably the polyploidisation of fetal germ cells, followed by the expression of the CIS phenotype in isolated germ cells scattered along infantile seminiferous tubules that later proliferate to give an adult type CIS pattern.

Child↗