[Refractive anemia, preleukemic states and multiple enzymatic anomalies].
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Biomedical subjects
Publications and source records attributed to C Sultan.
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Virilization of the external genitalia in the male fetus requires testosterone and dihydrotestosterone (DHT), which is formed from testosterone by the action of the enzyme, 5alpha-reductase type 2 (5alphaR-2). Mediation of the effects of both testosterone and DHT requires a functional androgen receptor (AR) located in the cytoplasmic compartment of target cells. DHT (or testosterone) binding induces a conformational change which facilitates AR nuclear transport, phosphorylation and dimerization, ultimately regulating of the rate of transcription of androgen-dependent genes. Any event which impairs DHT formation (mutation within the 5alphaR-2 gene or 5alphaR-2 inhibitors) or normal function of the AR (mutation in the AR gene, antiandrogens) may result in insufficient androgen action in the male fetus and in subsequent undervirilization in the newborn. Hypospadias may be due to a defect in androgen action due to mutation of the 5alphaR-2 or of the AR gene. Mutation of unidentified genes is likely to underlie this displacement of the urethral meatus from the tip to the ventral side of the phallus. An aetiological role for environmental chemical products has been postulated, since ethnic as well as geographical differences in the incidence of hypospadias have been noted. Increasing evidence has been gathered indicating that widely used industrial and agricultural chemicals have deleterious effects on normal male sexual differentiation. Cryptorchidism and micropenis may represent an intersex phenotype, even if they are isolated. Aetiological factors include 5alphaR-2 gene mutation, AR gene mutation or environmental hormonal disruptors. In conclusion, several phenotypes have been attributed to insufficient androgen action during fetal life. Whereas mutations in the 5alphaR-2 gene and AR gene are natural, attention should be focused on environmental endocrine disruptors that are able to mimic steroid 5alpha-reductase deficiency or partial androgen insensitivity syndrome.
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Prostate cancer is an androgen-dependent tumor which presents an androgen-independent regrowth after clinical regression in response to antiandrogen treatment. Four hypotheses have been developed to understand how androgen signal transduction pathway mediate androgen-independent tumor progression: over expression of the wild-type androgen-receptor gene, androgen-receptor gene mutation, excessive recruitment of transcriptional co-activator ARA-70 and a cross-talk between the androgen-receptor and the growth factor receptor pathways. In this work, C. Sawyers's group elegantly demonstrates, in LAPC-4 androgen-independent prostate cancer sublines, that forced hyperexpression of HER-2/Neu receptor tyrosine kinase allowed androgen-independent growth, that HER-2/Neu activated the androgen-receptor pathway in the absence of androgens and synergized with low levels of androgen to superactivate the pathway. These important data could have therapeutic implications for the management of androgen-independent prostate cancer.
The technique of bone marrow cultures in vitro on semi solid agar medium has been applied to the study of 24 cases of chronic myeloid leukemia in chronic phase and/or in acute blastic crisis. At the chronic phase of the disease the colony forming capacity is normal or above the normal range. In blastic crisis the number of colonies is very low. In the same time clusters are prominent.
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Dydrogesterone, an orally effective progestational compound, frequently used in a large spectrum of endocrine and gynecologic problems was evaluated for possible peripheric androgenic or anti-androgenic activity. The drug was tested in vivo in the hamster flank organ test and in vitro in tests based on molecular mechanisms of androgen action. Dydrogesterone appeared to have neither androgenic nor anti-androgenic properties. This is important in view of the fact that dydrogesterone can also be indicated during pregnancy.
Male pseudohermaphroditism due to partial androgen insensitivity (PAI) may be suspected clinically in case of incomplete masculinization of external genitalia in spite of age related plasma androgen levels. In 25 children or adolescents in whom PAI was suspected, the 5 alpha-reductase activity of external genitalia fibroblasts, the number of androgen receptor sites (Bmax) and the affinity of receptors for dihydrotestosterone (Kd) were studied. Clinical expression of PAI is highly polymorphic (Prader's type I to type IV), when most children (18/25) were considered as males. In a single patient the very low 5 alpha-reductase activity permitted the diagnosis of 5 alpha-reductase deficiency. The number of receptor sites (fmoles/mg DNA) varied from 0 to 730. Mean Bmax of patients (282 +/- 187 fmoles/mg DNA) was statistically lower than that of normal subjects (642 +/- 220 fmoles/mg DNA), p less than 0.05. The 5 cases in whom receptor concentrations were normal may be related to a qualitative abnormality of the androgen receptor or to a "post-receptor" defect. On the contrary no significant differences in Kd values were found. Correlation between sexual ambiguity and the number of measured receptors was not possible. These results emphasize the clinical and biochemical heterogeneity of PAI. Nevertheless, the decrease in number of androgen receptor sites remains the major data for the biochemical diagnosis of PAI. Study of post-receptor "markers" (3 alpha-reductase activity, aromatase, collagen) might allow better analysis of cases with PAI in whom androgen receptor concentrations are normal.
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