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Biomedical subjects

R Rey

Publications and source records attributed to R Rey.

At least 19 recordsLinked to original sources
PubMed2001

Sertoli cell proliferations of the infantile testis: an intratubular form of Sertoli cell tumor?

We report on six boys with intratubular Sertoli cell proliferations (ISCPs), studied by routine histologic methods, electron microscopy, and immunohistochemistry of anti-müllerian hormone (AMH), inhibin alpha-subunit, 3beta-hydroxysteroid dehydrogenase (3beta-HSD), proliferative cellular nuclear antigen, and p53, and carefully followed for extended periods with periodic clinical examinations, testicular ultrasonographies, and determinations of serum levels of AMH and inhibin B. Peutz-Jeghers syndrome was found in four of six patients, and gynecomastia occurred in five of six patients. One boy had isosexual pseudoprecocity. ISCPs were observed as multiple foci of seminiferous tubules with large and proliferated Sertoli cells replacing germ cells and limited by the basement membrane. Mitotic figures, atypia, and/or interstitial invasion were not observed. Bilateral ISCPs were the only pathologic finding in three patients (patient nos. 1-3) and were associated with a microscopic tumor that resembled a large-cell calcifying Sertoli cell tumor (LCCSCT) in a fourth patient (patient no. 4). In the two remaining patients (patient nos. 5 and 6) ISCPs and LCCSCT were found in both testes. Ultrastructural examination showed large Sertoli cells, with round nuclei, sparse organelles, and some glycogen. Inhibin alpha-subunit immunolocalization was positive in the five patients in whom it was determined (patient nos. 2-6), AMH was positive in those ISCPs associated with tumors (patient nos. 4-6) and negative in isolated ISCPs (patient nos. 2 and 3); 3beta-HSD and PCNA were variable, and p53 was negative in all ISCPs. Patient nos. 1-4 have been followed for 2-19 years. One of them is currently entering puberty, the other two have already completed puberty and have testes of normal size, and the remaining one is an adult with clinically normal testes and sperm production. None of these patients had evidence of tumor development during follow-up as shown by serial ultrasonographies and serum levels of AMH and inhibin B. Patient nos. 5 and 6 who had bilateral ISCPs and LCCSCT were orchidectomized and evolved for 2-10 years after surgery without tumor recurrence. The prognostic significance of ISCPs, particularly when they are the only pathologic finding in a testicular biopsy, is a matter of controversy. Based on the long normal evolution, we recommend a conservative approach to therapy. The bilateral and multicentric character of ISCPs and their association with Sertoli tumors and Peutz-Jeghers syndrome suggest that they represent either proliferative lesions with tumorigenic potential or the intraepithelial stage in the evolution of some testicular Sertoli cell tumors.

3-Hydroxysteroid Dehydrogenases↗
PubMed2001

Ovarian granulosa cell tumors express a functional membrane receptor for anti-Müllerian hormone in transgenic mice.

Anti-Müllerian hormone inhibits granulosa cell growth and function. Both anti-Müllerian hormone and its type II receptor are expressed in normal granulosa cells. We show by histologic and molecular analyses that ovarian tumors developing in transgenic mice, obtained by targeted oncogenesis using an anti-Müllerian hormone promoter-SV40 oncogene construct, are of granulosa-cell origin. Because tissue-specific, cell-surface molecules are of particular interest for the analysis and treatment of tumors, we examined the expression of anti-Müllerian hormone type II receptor in the ovaries of these transgenic mice. We demonstrate that the anti-Müllerian hormone type II receptor is expressed not only in normal ovarian follicles, but also in granulosa cell tumors. Using a cell line derived from one of these tumors, we show that the anti-Müllerian hormone type II receptor protein is present on the surface of tumor cells and binds anti-Müllerian hormone. Furthermore, we show that the anti-Müllerian hormone receptor is functional in the granulosa tumor cell line, with anti-Müllerian hormone treatment inducing selective activation of Smad1. In conclusion, in this study we present a new murine transgenic model of granulosa cell tumors of the ovary and, using this model, we demonstrate for the first time cell-surface expression of a highly tissue-specific molecule, anti-Müllerian hormone type II receptor, as well as the selective activation of Smad proteins by anti-Müllerian hormone, in granulosa tumor cells.

Animals↗
PubMed2001

Macroorchidism due to autonomous hyperfunction of Sertoli cells and G(s)alpha gene mutation: an unusual expression of McCune-Albright syndrome in a prepubertal boy.

We report an unusual observation of a 3.8-yr-old boy with McCune-Albright syndrome (MAS) associated with abnormal prepubertal testis enlargement and no sexual precocity. Physical examination showed café-au-lait skin lesions, enlarged testes, prepubertal sized penis, and no pubic or axillary hair. Skeletal radiography disclosed fibrous dysplasia. The serum testosterone level was 0.58 nmol/L and remained below 1.4 nmol/L during the 4-yr follow-up. By contrast, serum inhibin B and anti-Mullerian hormone concentrations were abnormally increased up to 255 pg/mL (childhood range, 35--180) and 792 pmol/L (childhood range, 309--566), respectively. The LH response to a GnRH test was in the prepubertal range, whereas the FSH response was blunted. This abnormal hormone concentration profile indicates autonomous hyperfunction of Sertoli cells, with no evidence of Leydig cell activation. Testicular histology showed tubules with marked Sertoli cell hyperplasia and very rare germinal cells, and interstitial tissue containing mesenchymal cells but no mature Leydig cells. DNA sequence analysis from bone and testis tissues detected the known activating mutation in MAS that results in replacement of Arg by His at codon 201 of the G(s)alpha protein. Other endocrine tests showed excessive GH secretion and moderate adrenal androgen hypersecretion. These findings are consistent with the occurrence of an activating mutation of the G(s)alpha gene mainly expressed in Sertoli cells and weakly expressed or absent in Leydig cells. Abnormal prepubertal testicular enlargement extends the clinical spectrum of MAS, suggesting that determination of serum inhibin B and anti-Mullerian hormone should be considered in boys with this syndrome. This observation demonstrates the usefulness of detailed molecular and biological investigations in atypical cases of MAS.

Base Sequence↗
PubMed2000

Assessment of seminiferous tubule function (anti-müllerian hormone).

Anti-müllerian hormone (AMH) is specifically produced by Sertoli cells in the male. The testes express a high level of AMH from early fetal life, driven by the transcription factors SOX9, SF1, WT1 and GATA4, until puberty, when AMH is downregulated by testosterone and meiosis. When androgen negative effect is absent, follicle-stimulating hormone increases the secretion of AMH. Serum AMH determination is useful in the evaluation of children with non-palpable gonads, with or without ambiguous genitalia. It signals the existence of functional testicular tissue and allows a distinction to be made between gonadal dysgenesis and dissociated tubular-interstitial dysfunction. Serum AMH is a useful marker in the follow-up of male patients with precocious puberty or hypogonadotrophic hypogonadism, as well as of patients with sex cord stromal tumours of the gonads. Finally, AMH determination on the seminal plasma of men with non-obstructive azoospermia may be used as a marker of the existence of testicular spermatozoa when intracytoplasmic sperm injection is considered.

Anti-Mullerian Hormone↗
PubMed2000

Anti-Müllerian hormone is a specific marker of sertoli- and granulosa-cell origin in gonadal tumors.

Sex cord stromal tumors are gonadal neoplasms containing Sertoli, granulosa, Leydig, or thecal cells, which originate from cells derived from either the sex cords (Sertoli and granulosa cell tumors) or the specific mesenchymal stroma (Leydig and thecal cell tumors) of the embryonic gonad. Only granulosa and Sertoli cells produce anti-Müllerian hormone (AMH). Our purpose was to investigate whether AMH can be used as a specific marker of human granulosa or Sertoli cell origin in gonadal tumors, to distinguish them from other primary or metastatic neoplasms, using immunohistochemistry. We studied 7 juvenile and 6 adult-type granulosa cell tumors of ovarian localization and 3 extraovarian metastases, 20 other ovarian tumors, 6 testicular Sertoli cell tumors, 2 gonadoblastomas, and 13 extragonadal tumors. Granulosa cell tumors, both juvenile- and adult-type of either ovarian or metastatic localization, showed an heterogeneous pattern of AMH immunoreactivity: Areas containing intensely or weakly AMH-positive cells were intermingled with AMH-negative areas. Although in most cases AMH-positive areas represented a minor proportion of tumor cells, we found a positive reaction in all the cases examined. In testes, although normal prepubertal Sertoli cells were intensely positive, testicular Sertoli cell tumors showed large areas of negative reaction, with few positive cells scattered throughout the tumor. AMH was also reactive in most of the cells of sex-cord origin in gonadoblastomas. No AMH immunoreaction was observed in other gonadal and extragonadal tumors. We conclude that AMH expression is conserved in only a small proportion of tumor cells of granulosa or Sertoli cell origin; however, a positive reaction in a few cells helps to distinguish between granulosa or Sertoli cell tumors or gonadoblastomas and other gonadal tumors of different origin.

Adrenal Cortex Neoplasms↗
PubMed2000

Detection of minimal levels of serum anti-Müllerian hormone during follow-up of patients with ovarian granulosa cell tumor by means of a highly sensitive enzyme-linked immunosorbent assay.

Granulosa cell tumors (GCT) are ovarian neoplasms that tend to recur and spread in the pelvis and the abdomen several years after the initial treatment. Anti-Mülerian hormone (AMH) is a reliable serum marker of these tumors. To enhance the availability and the sensitivity of serum AMH determination, we developed an ultrasensitive enzyme-linked immunosorbent assay. In this work we compare the results of serum AMH levels, obtained using the ultrasensitive and the traditional assays, in 31 patients with ovarian GCT followed up for up to 7 yr. The ultrasensitive enzyme-linked immunosorbent assay has a significantly higher sensitivity than the traditional one. This resulted in the detection of low serum AMH levels, which were undetectable with the traditional assay, in several cases including one patient in whom a recurrence of a GCT had developed and two patients in whom the treatment had not been completely successful. These cases highlight the importance of the availability of a highly sensitive assay allowing evaluation with high precision of the results of treatment and to detect the recurrences of GCT at an early, preclinical stage.

Adolescent↗
PubMed2000

[Primary aortoenteric fistula].

Aortoenteric fistulas are a very unlikely cause of digestive bleeding. We present the case of a fifty six year old patient with a primary aortoduodenal fistula who consulted because of melena and a pulsating abdominal mass. He underwent three digestive endoscopies without arriving at any diagnosis. A computed axial tomography and an angiography showed an aneurysm of the abdominal aorta. With an exploring laparotomy a fistula was identified between the aneurysm and the fourth portion of the duodenum. An aortoaortic bypass was carried out followed by a surgical fix of the duodenum. The patient was released six days after the operation.

Aortic Aneurysm, Abdominal↗
PubMed2000

[Study on the anti-müllerian hormone served as a marker for granulosa cell tumor of ovary].

OBJECTIVE: To probe the experimental basis for anti-mullerian hormone(AMH) served as a specific tumor label in diagnosis of granulosa cell tumor(GCT) of ovary. METHODS: The expression of AMH and its receptor mRNA in early and late GCT of ovary in transgenic mice was studied by using immunohistochemistry, in stiu hybridization and Northern hybridization. Furthermore, the expression of AMH and its receptor mRNA in cultured GCT cells was also determined by using radioiodine labeling method and Northern hybridization. RESULTS: In the early ovary GCT of transgenic mice, immunohistochemistry showed that AMH was positively stained as brownish yellow granulars, which were located in the cell membrane of the tumor, in situ hybridization showed its receptor mRNA was positive as blue granulars, which were also located in the cell membrane. The positive rate of both AMH and its receptor mRNA was 100%. Results by northern hybridization also showed that the positive rate of AMH and its receptor mRNA in the early ovary GCT and GCT cells was 100%. Radioautography indicated that there was a radioactive bright point, the binding rate of 125I labeled AMH with tumor cells reached 100%. CONCLUSIONS: AMH can be served as a specific tumor marker in the diagnosis of difficult and complicated tumors of ovary, and in the diagnosis, treatment and follow-up survey of the early GCT.

Animals↗
PubMed1999

Presence of anti-Müllerian hormone correlates with absence of laminin alpha5 chain in differentiating rat testis and ovary.

The distribution of anti-Müllerian hormone (AMH) and laminin (Ln) alpha5 chain in differentiating rat testis and ovary were studied by immunohistochemistry. In the incipient embryonic male gonad a weak reaction for Ln alpha5 chain, but not for AMH, was detected. With further prenatal development, Ln alpha5 chain rapidly disappeared from the basement membrane (BM) of the incipient testicular cords in parallel with the appearance of AMH in the Sertoli cells. After birth, Ln alpha5 chain reappeared in the BMs of the cords with the decline and disappearance of AMH from the respective Sertoli cells. In the corresponding stages of the ovary, Ln alpha5 chain was present in the BM of the prenatal gonadal cords and in postnatal primordial follicles. The cells of those epithelia were negative for AMH. With the growth of the follicles, Ln alpha5 chain disappeared from the BM when AMH appeared in the epithelial follicular cells. The present results show that male and female gonadal epithelia negative for Ln alpha5 chain were positive for AMH, and that epithelia positive for Ln alpha5 chain were negative for AMH. Thus, epithelial Ln alpha5 chain and AMH as a product of the same cell seemed to exclude each other. The results require an explanation why Ln alpha5 chain has to be excluded from the BM of the epithelia during the secretion of AMH chain through the basal cell membrane to the surrounding tissues where it executes its important biological functions. These observations suggest a hypothesis that the production of both components is regulated by the same gene and factor system.

Animals↗
PubMed1999

Reversion of the differentiated phenotype and maturation block in Sertoli cells in pathological human testis.

To study the relationship between abnormal Sertoli cell differentiation and spermatogenic impairment, we examined the expression of Sertoli cell markers normally lost at puberty, cytokeratin 18 (CK18), anti-Müllerian hormone (AMH) and M2A antigen, in three children (aged 1-2 years), 50 adults (aged 19-45 years) with obstructive or non-obstructive azoospermia or oligozoospermia, and six patients (aged 1-18 years) with 5 alpha-reductase deficiency. There was CK18 and/or AMH expression, but never M2A antigen expression, associated with spermatogonial arrest or Sertoli cell-only (SCO) syndrome in infertile men. Loss of M2A antigen suggests the transition of Sertoli cells to an adult phenotype, while CK18 and/or AMH expression may be a manifestation of de-differentiation of Sertoli cells. In 5 alpha-reductase deficiency, there was a sequential loss of CK18, M2A antigen and AMH around puberty, associated with partial spermatogenesis. The persistence of immature Sertoli cells expressing M2A antigen was associated with prepubertal seminiferous cords and SCO syndrome. Therefore, 5 alpha-reductase deficiency may prevent the maturation of Sertoli cells, resulting in impairment of spermatogenesis, and loss of M2A antigen expression coincides with a critical step in the Sertoli cell maturation. High follicle stimulating hormone concentrations due to failure of normal Sertoli cell differentiation indicate a normal development pattern of the hypothalamic-pituitary-gonadal axis.

Adolescent↗
PubMed1999

Anti-Müllerian hormone as a seminal marker for spermatogenesis in non-obstructive azoospermia.

Anti-Müllerian hormone (AMH) also known as Müllerian inhibiting substance or factor, is a Sertoli cell-secreted glycoprotein responsible in male embryos for Müllerian duct regression. However, its role in adults remains unknown. AMH seminal concentrations have been evaluated using an enzyme-linked immunoassay in three groups of young men: group 1, fertile donors (n = 18); group 2, obstructive azoospermia (n = 9) after vasectomy or associated with deferent duct agenesia; and group 3, non-obstructive azoospermia with spermatogenesis deficiency and normal karyotype (n = 23). AMH was present in seminal plasma of most fertile donors at concentrations ranging from undetectable (<3.5 pmol/l) up to 543 pmol/l (geometric mean: 153 pmol/l), higher than the serum level (range <3.5 up to 67 pmol/l, geometric mean: 10.7 pmol/l, n = 13). Seminal AMH concentrations were undetectable in all obstructive azoospermic patients, confirming its testicular origin. In non-obstructive azoospermia (group 3), seminal AMH concentration was lower (range <3. 5-68.5 pmol/l, geometric mean: 17 pmol/l) than in fertile donors (P < 0.003) without correlation with plasma follicle stimulating hormone values. In group 3, comparison of seminal AMH concentration and the results of histological analysis of testicular biopsies revealed that undetectable AMH found in 14 cases was associated in 11 of them with lack of spermatozoa, while detectable concentrations of AMH (10-68.5 pmol/l) found in nine cases were associated in seven of them with persistent spermatogenesis. In the adult, AMH is secreted preferentially towards the seminiferous lumen. Although its relationship with spermatogenesis requires further investigation, our results suggest that seminal AMH may represent a non-invasive marker of persistent hypospermatogenesis in cases of non-obstructive azoospermia which may indicate the likely success of testicular spermatozoa recovery before intracytoplasmic sperm injection.

Adult↗
PubMed1999

Antimüllerian hormone in patients with hypogonadotropic hypogonadism.

Antimullerian hormone (AMH) is produced by immature Sertoli cells until pubertal maturation. At puberty, elevation of serum testosterone correlates with a decrease in serum AMH. To further investigate the hormonal control of AMH secretion, serum AMH levels were measured in 20 normal men (20-60 yr), in 12 patients (19-30 yr) with congenital hypogonadotropic hypogonadism (CHH), and in 18 patients (19-65 yr) with acquired hypogonadotropic hypogonadism (AHH) either untreated or during testosterone or human chorionic gonadotropin (hCG) therapy. Mean serum AMH levels in normal adult men were low (20+/-4.9 pmol/L). In untreated CHH patients, mean serum AMH levels were significantly higher than in normal men (292+/-86 pmol/L, P < 0.001) and were similar to those previously reported in prepubertal boys. In men with AHH, mean serum AMH levels were also significantly increased (107+/-50 pmol/L; P < 0.01) when compared with healthy men but were less than in men with CHH. In addition, in 10 patients treated for prostate cancer, a modest but significant increase of serum AMH (from 11.4 +/-5.7 pmol/L to 49+/-9.9 pmol/L; P < 0.01) was observed 12 months after suppression of the gonadal axis with the GnRH agonist Triptorelin (3.75 mg IM once a month). Plasma testosterone (T) and serum AMH levels were measured at baseline and at 3 and 6 months in 10 HH patients (6 CHH and 4 AHH) treated with hCG (1500 IU/twice weekly for 6 months) and in 8 HH (4 CHH and 4 AHH) patients treated with T (T enanthate 250 mg/3 weeks for 6 months). hCG treatment induced an increase of plasma T (from 1.0+/-0.7 to 11+/-2.4 and 19+/-4.8 nmol/L, at 3 and 6 months respectively) associated with a dramatic decrease of serum AMH (from 314+/-93 to 56+/-30 and 17+/-4.3 pmol/L). The similar increase in plasma T levels (from 1.4+/-1.0 to 15.6+/-4.2 and 23+/-6.2 ng/mL) obtained with exogenous T induced a lesser decrease of serum AMH (from 221+/-107 pmol/L to 114+/-50 and 66+/-17 pmol/L, at 3 and 6 months respectively). In conclusion, high plasma AMH levels in CHH patients are related to the absence of pubertal maturation of Sertoli cells. The high AMH levels in AHH and its increase after Triptorelin-induced gonadotropin deficiency suggest that the suppression of AMH is a reversible phenomenon. Finally, the inhibition of AMH production by Sertoli cells is induced by intratesticular T.

Adult↗
PubMed1999

The prepubertal testis: a quiescent or a silently active organ?

The development of the testis is characterised by dramatic changes between birth and adulthood. The most conspicuous changes take place during puberty, when the seminiferous tubule diameter increases significantly owing to an important proliferation of germ cells, giving rise to spermatozoa, and to the development of a tubular lumen; in the interstitial tissue characteristic Leydig cells appear and secrete high levels of testosterone. These pubertal changes of the testis can be detected clinically since they result in testicular volume and serum androgen level increments. The prepubertal testis has classically been defined as a quiescent organ. However, since adequate stereological methods for microscopic analysis are available, it has been shown that the male gonad triplicates its volume between birth and the onset of puberty. Sertoli cells and spermatogonia proliferate intensely; this is critical for the development of quantitatively normal adult spermatogenesis. Seminiferous tubule volume increases owing to an increment in tubular length, not diameter. Sertoli cells are also functionally active during childhood: they produce high amounts of anti-Müllerian hormone during the whole prepubertal period, and inhibin B until the age of 2-4 years. Anti-Müllerian hormone and inhibin seem to play a role as modulators of the proliferation and differentiation of Leydig cell precursors.

Adult↗
PubMed1998

The role of anti-Müllerian hormone in gonadal development.

Anti-Müllerian (AMH), a member of the transforming growth factor beta produced by immature Sertoli cells and, to a lesser degree, by granulosa cells from birth to the end of reproductive life, does not affect gonadal determination but has a negative effect upon gonadal development in both sexes. It blocks meiosis in fetal ovaries, leading to loss of germ cells and subsequent fibrous degeneration, and inhibits the transcription of aromatase and LH receptor. AMH also affects the development and function of the adult testis by blocking the differentiation of mesenchymal into Leydig cells and by independently decreasing the expression of steroidogenic enzymes.

Animals↗
PubMed1998

Receptors for anti-müllerian hormone on Leydig cells are responsible for its effects on steroidogenesis and cell differentiation.

Strong overexpression of anti-Müllerian hormone (AMH) in transgenic mice leads to incomplete fetal virilization and decreased serum testosterone in the adult. Conversely, AMH-deficient mice exhibit Leydig cell hyperplasia. To probe the mechanism of action of AMH on Leydig cell steroidogenesis, we have studied the expression of mRNA for steroidogenic proteins in vivo and in vitro and performed a morphometric analysis of testicular tissue in mice overexpressing the hormone. We show that overexpression of AMH in male transgenic mice blocks the differentiation of Leydig cell precursors. Expression of steroidogenic protein mRNAs, mainly cytochrome P450 17 alpha-hydroxylase/C17-20 lyase (P450c17), is decreased in transgenic mice overexpressing AMH and in AMH-treated purified Leydig cells. In contrast, transgenic mice in whom the AMH locus has been disrupted show increase expression of P450c17. In vitro, but not in vivo, AMH also decreases the expression of the luteinizing hormone receptor. The effect of AMH is explained by the presence of its receptor on Leydig cells. Our results provide insight into the action of AMH as a negative modulator of Leydig cell differentiation and function.

Animals↗
PubMed1998

Embryology and endocrinology of genital development.

In the human male fetus, testes develop by the 7th week and begin to secrete two hormones: anti-müllerian hormone (AMH) induces the regression of müllerian ducts, the anlagen of the uterus, fallopian tubes and upper vagina, upon binding to a specific membrane receptor, whereas testosterone induces the differentiation of the wolffian ducts into the epididymes, vasa deferentia and seminal vesicles. In some target tissues, testosterone is converted to dihydrotestosterone, which is responsible for masculinization of the urogenital sinus and external genitalia. Both androgens act upon binding to the same nuclear receptor. In the absence of AMH and androgen action, or example in the female or in abnormal male differentiation, the internal and external genital primordia differentiate following the female pathway, even in the absence of ovaries. In males, an impaired function of the AMH-dependent pathway results in the persistent müllerian duct syndrome, a disorder characterized by the presence of uterus and fallopian tubes in otherwise normally virilized boys. Several mutations found in the AMH and AMH-receptor genes explain the pathophysiology of this syndrome.

Anti-Mullerian Hormone↗