RESUMEN
The effect and mechanism of action of basic fibroblast growth factor (bFGF) on testicular steroidogenesis were investigated using as a model primary cultures of purified porcine Leydig cells from immature intact animals. Basic FGF increased basal and human chorionic gonadotrophin (hCG)-induced testosterone accumulation (with an ED50 of 0.64 ng/ml bFGF, 35 pM) in the medium following a long-term treatment. The effects of bFGF (10 ng/ml, 72 h) were found at all hCG concentrations tested (0.001-1 ng/ml), the growth factor affecting the maximal steroidogenic capacity of the Leydig cells but not their sensitivity to the gonadotrophin. In this context, we have therefore investigated whether the stimulatory effect of bFGF on testosterone formation was related to an increase of the steroidogenic enzyme activities. The data obtained indicate that the growth factor did not affect the gonadotrophin action on the formation of delta 5-steroid hormone, namely dehydroepiandrosterone (DHEA) (evaluated in the presence of 10(-5) M WIN 24540, an inhibitor of 3 beta-hydroxysteroid dehydrogenase/isomerase). By contrast, bFGF (10 ng/ml, 72 h) was found to increase in a comparable manner the conversion of pregnenolone, DHEA and delta 4-androstenedione into testosterone, suggesting a stimulatory effect on 17 beta-hydroxysteroid dehydrogenase activity. Indeed, bFGF enhanced in a dose-dependent manner (ED50 = 39 pM) this enzyme activity evaluated through the conversion of delta 4-androstenedione to testosterone. These effects of bFGF on Leydig cell steroidogenic activity are probably exerted through specific membrane bFGF receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
17-Hidroxiesteroide Deshidrogenasas/metabolismo , Deshidroepiandrosterona/metabolismo , Factor 2 de Crecimiento de Fibroblastos/farmacología , Células Intersticiales del Testículo/efectos de los fármacos , Testosterona/metabolismo , Animales , Células Cultivadas , Gonadotropina Coriónica/farmacología , Activación Enzimática/efectos de los fármacos , Hormonas Esteroides Gonadales/metabolismo , Células Intersticiales del Testículo/metabolismo , Masculino , Receptores de Factores de Crecimiento de Fibroblastos/efectos de los fármacos , Receptores de Factores de Crecimiento de Fibroblastos/metabolismo , Estimulación Química , PorcinosRESUMEN
In the present study, we evaluated the effect of the homodimer activin A on immature porcine Leydig cell functions in primary culture. Activin A (0.5-100 ng/ml) reduced hCG-stimulated dehydroepiandrosterone (DHEA) accumulation in a dose- and time-dependent manner, with a maximal inhibitory effect (58% decrease) at 20 ng/ml (8 x 10(-10) M). Activin A was found not to control steroidogenesis, either through a modulation of the gonadotropin LH/hCG binding or low-density lipoprotein cholesterol binding and internalization. However, activin A significantly decreased pregnenolone (p less than 0.002) and DHEA (p less than 0.001) formation (evaluated in the presence of 10(-5) M of WIN 24540, an inhibitor of 3 beta-hydroxysteroid dehydrogenase/isomerase [3 beta-HSDI]activity) in Leydig cells maximally stimulated with hCG (3 ng/ml, 3 h) or incubated in the presence of 22R-hydroxycholesterol (5 micrograms/ml, 2 h). These findings indicate that activin A probably exerts a partial inhibitory effect on cholesterol side-chain cleavage cytochrome P450 (P450scc) activity. On the other hand, activin A significantly (p less than 0.001) enhanced the conversion of exogenous pregnenolone and DHEA (500 ng/ml) but not of progesterone and androstenedione (500 ng/ml) into testosterone, suggesting that activin A potentially enhances 3 beta-HSDI activity in Leydig cells. Activin A action on 3 beta-HSDI activity was found to be closely related to that of transforming growth factor-beta 1 (TGF beta 1), since both activin A (20 ng/ml) and TGF beta 1 (2 ng/ml) induced a comparable and non-additive increase in 3 beta-HSDI activity.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Deshidroepiandrosterona/metabolismo , Inhibinas/farmacología , Células Intersticiales del Testículo/metabolismo , Testosterona/metabolismo , 3-Hidroxiesteroide Deshidrogenasas/antagonistas & inhibidores , 3-Hidroxiesteroide Deshidrogenasas/metabolismo , Activinas , Animales , Células Cultivadas , Gonadotropina Coriónica/farmacología , Sistema Enzimático del Citocromo P-450/metabolismo , Dihidrotestosterona/análogos & derivados , Dihidrotestosterona/farmacología , Hidroxicolesteroles/farmacología , Células Intersticiales del Testículo/efectos de los fármacos , Masculino , Pregnenolona/metabolismo , PorcinosRESUMEN
The actions and the mechanisms of action of epidermal growth factor (EGF) in testicular steroidogenesis were investigated using a model of primary culture of purified porcine Leydig cells from immature intact animals. EGF decreased (1.7-fold) human CG (hCG)-induced dehydroepiandrosterone (DHEA) accumulation in the medium whereas it enhanced (2.5-fold) that of testosterone. The maximal and half-maximal effects on both DHEA and testosterone secretions were observed at similar concentrations which were, respectively, 3 (5 x 10(-10) M) and 0.7 (11 x 10(-11) M) ng/ml EGF, after 72-h treatment. EGF effect on DHEA and testosterone secretion was similarly observed whether the cells were acutely (3 h) stimulated with hCG (1 ng/ml) or with 8-bromo-cAMP (10(-3) M). To further localize the steroidogenic biochemical steps affected by EGF, the growth factor action on steroidogenic enzyme activities was investigated. EGF increased delta 5 steroid intermediate (i.e. pregnenolone and DHEA) formation [evaluated in the presence of 10(-5) M of WIN 24540, an inhibitor of 3 beta-hydroxysteroid dehydrogenase/iosomerase (3 beta-HSDI) activity]. However, this stimulation was observed in cells when acutely (3 h) stimulated with hCG (0.01-1 ng/ml) but not when incubated with 22R-hydroxycholesterol (0.01-10 micrograms/ml). Such findings indicate that EGF did not affect cholesterol side chain cleavage cytochrome P450 activity but probably increased cholesterol substrate availability for this enzyme in the inner mitochondria. Moreover, EGF significantly (P less than 0.001) increased delta 5 steroid intermediate (i.e. pregnenolone and DHEA) but not delta 4 steroid intermediate (i.e. progesterone and androstenedione) conversion into testosterone, indicating that EGF enhances 3 beta-HSDI activity. Such effects of EGF are directly exerted on Leydig cells since EGF receptors (Kd = 16 x 10(-11) M) are present in primary cultures of purified porcine Leydig cells. Together, the present findings show that in Leydig cells from intact animals, EGF enhances the gonadotropin action on testosterone formation through an increase in the availability of cholesterol substrate in the mitochondria as well as an increase in the activity of 3 beta-HSDI.
Asunto(s)
Andrógenos/biosíntesis , Factor de Crecimiento Epidérmico/farmacología , Células Intersticiales del Testículo/metabolismo , 3-Hidroxiesteroide Deshidrogenasas/antagonistas & inhibidores , 8-Bromo Monofosfato de Adenosina Cíclica/farmacología , Androstenodiona/metabolismo , Animales , Células Cultivadas , Gonadotropina Coriónica/farmacología , Deshidroepiandrosterona/biosíntesis , Dihidrotestosterona/análogos & derivados , Dihidrotestosterona/farmacología , Receptores ErbB/metabolismo , Células Intersticiales del Testículo/efectos de los fármacos , Masculino , Porcinos , Testosterona/biosíntesisRESUMEN
Testicular function is regulated not only by circulating hormones, among which the gonadotrophins play the main role, but also by local factors originating in multiple and complex interactions among cells. In this review, the example of gonadotrophins (LH and FSH) and Transforming Growth Factor beta (TGF beta) was chosen to illustrate the role of interactions between circulating hormones and gonadal growth factors in testicular function control; TGF beta-like activity has been found in the male gonad and we have used a model of cultured purified testicular cells to show that the action of TGF beta on testicular function mainly involves antagonism of the effect of gonadotrophins. Conversely, TGF beta promotes differentiated Leydig and Sertoli cell function. The example of interactions between TGF beta and gonadotrophins reported here shows that locally produced growth factors can regulate the response of testicular cells to gonadotrophins, a finding that extends our concept of reproductive endocrinology to cell-cell interactions.
Asunto(s)
Hormona Folículo Estimulante/fisiología , Hormona Luteinizante/fisiología , Testículo/fisiología , Factor de Crecimiento Transformador beta/fisiología , Interacciones Farmacológicas/fisiología , Sustancias de Crecimiento/fisiología , Humanos , Células Intersticiales del Testículo/fisiología , Masculino , Células de Sertoli/fisiologíaRESUMEN
By using immature porcine Leydig cells cultured in defined medium as a model, transforming growth factor-beta (TGF beta) was shown to exert a dramatic inhibitory effect on their basal and human chorionic gonadotropin (hCG) (or 8-bromo-cyclic AMP) stimulated dehydroepiandrosterone secretion, in the presence or absence of saturating concentrations of exogenous (low density lipoprotein) cholesterol substrate. In contrast, TGF beta exerted both a stimulating and inhibitory effect on testosterone secretion: while hCG-stimulated testosterone secretion was enhanced by low doses of TGF beta (0.06-0.4 ng/ml, 48 h), it was decreased with higher concentrations of TGF beta (2.5-10 ng/ml, 48 h). The data obtained show that the inhibitory action of TGF beta on testicular steroidogenesis was related to a decrease in pregnenolone formation by affecting a step(s) distal to cyclic AMP formation but before cholesterol association with cytochrome P-450 side-chain cleavage. As for the stimulatory effect of TGF beta on testosterone formation, this was mainly related to an increase (about 2-fold) in 3 beta-hydroxysteroid dehydrogenase/isomerase activity (ED50 0.05 ng/ml, 2 X 10(-13) M). The results indicate that the (short-term) steroidogenic stimulatory action of luteinizing hormone (LH)/hCG is antagonized by high concentrations of TGF beta by decreasing pregnenolone formation while it is enhanced by the stimulating action of low concentrations of TGF beta exerted on 3 beta-hydroxy steroid dehydrogenase/isomerase activity.
Asunto(s)
Andrógenos/biosíntesis , Células Intersticiales del Testículo/metabolismo , Factores de Crecimiento Transformadores/fisiología , Androstenodiona/biosíntesis , Animales , Deshidroepiandrosterona/biosíntesis , Técnicas In Vitro , Células Intersticiales del Testículo/citología , Masculino , Microscopía de Contraste de Fase , Pregnenolona/biosíntesis , Porcinos , Testosterona/biosíntesisRESUMEN
Thirteen plasma steroids as well as ACTH, LH and FSH were measured by specific RIAs under basal and dynamic conditions in a 16-year-old boy (normal external genitalia, 46, XY karyotype) who presented slowness and unachievement of pubertal development. On the delta 4-pathway: basal levels of testosterone and dihydrotestosterone were low- with a normal ratio-, delta 4-androstenedione and 11 beta-hydroxyandrostenedione were in the low normal range. Meanwhile, 17 alpha-hydroxyprogesterone and progesterone levels were markedly elevated. On the delta 5-pathway: dehydroepiandrosterone was extremely low while 17 alpha-hydroxypregnenolone and pregnenolone were almost normal; dehydroepiandrosterone sulfate was subnormal while pregnenolone sulfate was normal. Cortisol, aldosterone were normal while ACTH was moderately increased. Basal and responsive levels of LH and FSH were markedly increased. ACTH stimulation induced a subnormal rise of cortisol and 11 beta-hydroxyandrostenedione, a low or absent rise of dehydroepiandrosterone, 17 alpha-hydroxypregnenolone, androstenedione and 17 alpha-hydroxyprogesterone contrasting with a marked rise of pregnenolone and progesterone. After hCG stimulation, responses were low for testosterone, extremely high for 17 alpha-hydroxyprogesterone with a normalisation of the 17 alpha-hydroxyprogesterone/progesterone ratio. Fluoxymesterone dramatically reduced the pathologically high basal levels of progesterone and 17 alpha hydroxyprogesterone. Dexamethasone induced only a minute decrease in the delta 4-progestagens, a marked decrease in pregnenolone, with a more than 80% reduction of 17 alpha- hydroxypregnenolone, dehydroepiandrosterone, dehydroepiandrosterone sulfate and androstenedione. These data suggest a defect involving the cytochrome P450 common to both 17 alpha-hydroxylase and 17, 20-desmolase activities.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Hiperplasia Suprarrenal Congénita , Aldehído-Liasas/deficiencia , Sistema Enzimático del Citocromo P-450/deficiencia , Pubertad Tardía/enzimología , Esteroide Hidroxilasas/deficiencia , Adolescente , Glándulas Suprarrenales/fisiopatología , Dexametasona , Hormona Folículo Estimulante/sangre , Hormona Liberadora de Gonadotropina , Humanos , Hormona Luteinizante/sangre , Masculino , Pubertad Tardía/fisiopatología , Testículo/fisiopatologíaRESUMEN
17 alpha-hydroxylase deficiency is a rare form of congenital abnormality in steroid synthesis, usually associated with moderate arterial hypertension and suppression of the renin-angiotensin system in a young adult. We report on a 45 years old woman with malignant hypertension (220/135 mmHg, severe retinopathy with papilledema, progressive renal insufficiency with serum creatinine over 300 mumol/l) of recent onset. Biological exploration revealed a metabolic alkalosis, a moderate hypokalemia (3 mmol/l), with elevated urinary excretion of potassium. Plasma aldosterone concentration (33 ng/dl) and plasma renin activity (17 ng/ml/h) were elevated. Acute captopril administration was followed by a marked (-29 p. 100) decrease in mean arterial pressure. In this 46 XX patient, a primary amenorrhea had never been explored; clinical examination disclosed the absence of female secondary sex characteristics. Plasma cortisol was low (203 mmol/l) as were plasma androgens (testosterone 0.55, androstene dione 0.19, delta HEA less than 0.1 nmol/l respectively) and oestrogens (oestradiol 59 nmol/l). Elevated levels of progesterone and pregnenolone sulfate (12.1 and 2027 nmol/l respectively) contrasted with decreased levels of 17 OH progesterone (0.35 nmol/l). Computed tomography revealed a subnormal right adrenal gland and a pseudo-tumoral aspect on the left side. Treatment with dexamethasone and combined antihypertensive drugs (captopril, nifedipine and atenolol) resulted in normalisation of blood pressure and secretion of renin and aldosterone but renal function did not fully recovered. Thus, the hypertension of 17 alpha-hydroxylase deficiency can follow a malignant course in association with a marked activation of the renin-angiotensin system.
Asunto(s)
Hiperplasia Suprarrenal Congénita , Hiperplasia Suprarrenal Congénita/complicaciones , Hipertensión Maligna/etiología , Esteroide Hidroxilasas/deficiencia , Hiperplasia Suprarrenal Congénita/tratamiento farmacológico , Hiperplasia Suprarrenal Congénita/fisiopatología , Aldosterona/sangre , Andrógenos/sangre , Antihipertensivos/uso terapéutico , Dexametasona/uso terapéutico , Femenino , Humanos , Hidrocortisona/sangre , Persona de Mediana Edad , Progesterona/sangre , Renina/sangreRESUMEN
The effect of transforming growth factor beta on testicular steroidogenesis was studied by using a model of immature porcine Leydig cells cultured in a chemically defined medium. Leydig cells were cultured in the presence of human or porcine purified TGF beta and the following parameters were measured: cell proliferation, LH/hCG binding, and hCG-stimulated steroid hormone productions (DHEA, DHEAS and testosterone). Whereas TGF beta from the two sources had no effect on Leydig cell multiplication, it markedly inhibited LH/hCG-stimulated DHEA and DHEAS in a time- and dose-dependent manner. The maximal inhibitory effect of this peptide on LH/hCG binding (65% decrease), hCG-stimulated DHEA (77% decrease) and DHEAS (92% decrease) productions was observed with 2 ng/ml for 48 h of treatment. In contrast, TGF beta exerted a biphasic effect on hCG-stimulated testosterone production: stimulating (110% increase) until 2 ng/ml and inhibiting (35% decrease) for higher concentrations. [125I]TGF beta was cross-linked to Leydig cells using disuccinimidyl suberate; cells affinity labelled with [125I]TGF beta exhibit a major labelled band of approx 280 kDa, which has the properties expected from a TGF beta receptor. These data demonstrate that TGF beta is a direct potent regulator of Leydig cell steroidogenic function and its effects are probably mediated via a specific receptor.
Asunto(s)
Andrógenos/biosíntesis , Sustancias de Crecimiento/farmacología , Células Intersticiales del Testículo/metabolismo , Péptidos/farmacología , Animales , Células Cultivadas , Gonadotropina Coriónica/farmacología , Cinética , Células Intersticiales del Testículo/efectos de los fármacos , Masculino , Receptores de HL/metabolismo , Porcinos , Factores de Crecimiento TransformadoresRESUMEN
By using immature porcine Sertoli cells cultured in serum-free defined medium, we report that Sertoli cell-conditioned medium (SCCM) contains immunoreactive somatomedin C/insulin-like growth factor 1 (ir-SmC/IGF 1) which dilutes in parallel with purified human SmC/IGF 1. The release of ir-SmC/IGF 1 in the culture medium was dependent on the exposure time to Sertoli cells: no measurable ir-SmC/IGF 1 at 8 h, 12.1 +/- 1.2 ng/10(6) cells at 24 h and 33.9 +/- 5.3 ng/10(6) cells at 48 h of incubation. Moreover, ir-SmC/IGF 1 was also evidenced in SCCM following high performance liquid chromatography using a muC18 Bondapak column; ir-SmC/IGF 1 Sertoli cell-conditioned medium co-eluted with pure human SmC/IGF, suggesting a high homology between the two peptides. The effects of SmC/IGF 1 on testicular steroidogenesis were studied by incubating immature porcine Leydig cells with a biosynthetic human SmC/IGF 1. SmC/IGF 1 exerted a dose- and time-dependent stimulating effect on Leydig cell function with a maximal response at 50 ng/ml after 48 h of treatment. SmC/IGF 1 increased both LH/hCG binding (4.3-fold), basal testosterone (4-fold) and DHAS- and hCG-stimulated testosterone and DHAS (dehydroepiandrosterone sulfate) production (15.5- and 6.4-fold respectively). The slight effect of SmC/IGF 1 (100 ng for 48 h) on cell number (1.3-fold) and incorporation of [3H]thymidine into DNA (1.5-fold) in comparison with the high steroidogenic effect, supports the concept that SmC/IGF 1 acts as a cytodifferentiative factor rather than as a growth factor.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Factor I del Crecimiento Similar a la Insulina/fisiología , Células Intersticiales del Testículo/metabolismo , Somatomedinas/fisiología , Animales , Células Cultivadas , Gonadotropina Coriónica/metabolismo , Gonadotropina Coriónica/farmacología , Citarabina/farmacología , Deshidroepiandrosterona/análogos & derivados , Deshidroepiandrosterona/biosíntesis , Sulfato de Deshidroepiandrosterona , Insulina/farmacología , Factor I del Crecimiento Similar a la Insulina/farmacología , Hormona Luteinizante/metabolismo , Masculino , Células de Sertoli/fisiología , Porcinos , Testosterona/biosíntesisRESUMEN
By using immature porcine Sertoli cells cultured in serum-free defined medium, we report that medium conditioned by Sertoli cells contained immunoreactive somatomedin C/insulin-like growth factor 1 (SmC/IGF1) measured following acidic gel filtration. The release of this immunoreactive SmC/IGF1 was slightly increased following Sertoli cell treatment with fibroblast growth factor but not with follicle-stimulating hormone or growth hormone. On the other hand, human biosynthetic SmC/IGF1 exerts a potent stimulatory effect on Leydig cell differentiated functions such as LH/hCG-binding (greater than 4-fold) and hCG-stimulated testosterone secretion (greater than 15-fold). This effect was dose and time dependent and the maximal increase of Leydig cell function was observed following 48 h treatment with 50 ng/ml SmC/IGF1. The steroidogenic action of the peptide was not related to Leydig cell growth since both cell number and 3H-thymidine incorporation into DNA were not or slightly (approximately equal to 1.5-fold) increased in the optimal conditions with SmC/IGF1 treatment (100 ng/ml for 48 h). Moreover, the concomitant treatment of Leydig cells by both arabinoside C (10(-5) M), a DNA synthesis inhibitor, and SmC/IGF1 did not modify the stimulating effect of the peptide on LH/hCG-binding and hCG-stimulated testosterone production. Taken together, the present findings support the concept that Sertoli cell derived SmC/IGF1 could be a potent regulator of Leydig cell differentiated functions.
Asunto(s)
Factor I del Crecimiento Similar a la Insulina/fisiología , Células Intersticiales del Testículo/citología , Células de Sertoli/fisiología , Somatomedinas/fisiología , Animales , Diferenciación Celular , División Celular , Células Cultivadas , Gonadotropina Coriónica/metabolismo , Células Intersticiales del Testículo/metabolismo , Hormona Luteinizante/metabolismo , Masculino , Radioinmunoensayo , Células de Sertoli/metabolismo , Porcinos , Testosterona/biosíntesisRESUMEN
The aim of this study was to determine whether patients with homozygous familial hypercholesterolaemia (FH) have impaired adrenal cortical function. Plasma levels of cortisol, dehydroepiandrosterone (DHA), pregnenolone sulphate (PS) and DHA sulphate (DHAS) were measured during and 8 h ACTH infusion in six controls and two patients with homozygous FH. The basal PS levels of both patients and the basal DHA level of one were abnormally low for age and pubertal stage. During ACTH infusion we observed in both patients: (1) a mild impairment of control response after sustained stimulation (P less than 0.002); (2) a clear impairment of PS response (values less than 2 SD of those in controls); (3) a clear impairment of DHA response (values less than 2 SD) until 4 h in the boy who was at pubertal stage 4 and whose response could be compared to controls; no increase at all in the affected girl (pubertal stage 2) at a stage where normal subjects respond with significant increase. These results suggest that patients with FH lack cholesterol for corticosteroid biosynthesis under maximal ACTH stimulation and that mild chronic ACTH stimulation due to a deficit in the cholesterol supply to adrenal cells might increase the conversion of delta 5 to delta 4-steroids. They provide further evidence to support the primordial role of low density lipoprotein (LDL)-cholesterol in adrenal steroidogenesis in vivo.
Asunto(s)
Hormona Adrenocorticotrópica/farmacología , Deshidroepiandrosterona/sangre , Hidrocortisona/sangre , Hiperlipoproteinemia Tipo II/sangre , Pregnenolona/sangre , Corteza Suprarrenal/efectos de los fármacos , Corteza Suprarrenal/fisiopatología , Adulto , Deshidroepiandrosterona/análogos & derivados , Sulfato de Deshidroepiandrosterona , Femenino , Humanos , Hiperlipoproteinemia Tipo II/fisiopatología , MasculinoRESUMEN
In normal subjects, plasma pregnenolone sulfate (PS) levels high at birth, decreased during the first year of life in relation to the pattern of involution of the fetal adrenal zone. Thereafter, PS levels, in contrast with those of DHAS, did not show the abrupt rise characteristic of the adrenarche, but increased very progressively till adulthood. The response of PS to various provocative tests of adrenal and pituitary function (ACTH and Metyrapone stimulation, dexamethasone suppression), has been established in normal subjects. The measurement of plasma PS levels in basal conditions as well as in response to dynamic tests was very useful in the diagnosis of various adrenal and pituitary diseases in children.
Asunto(s)
Enfermedades de las Glándulas Suprarrenales/diagnóstico , Enfermedades de la Hipófisis/diagnóstico , Pregnenolona/sangre , Adolescente , Insuficiencia Suprarrenal/diagnóstico , Hormona Adrenocorticotrópica/sangre , Envejecimiento , Niño , Preescolar , Cortodoxona/sangre , Dexametasona , Femenino , Humanos , Hidrocortisona/sangre , Lactante , MetiraponaRESUMEN
An assay for urinary gonadotropins (UG) performed after acetone extraction is presented. This dosage was performed either on a sample of the 24 assay urine, or on the fractionated 12 hr/12 hr urines (night/day) in normal children whose ages ranged from 2 to 20 years and in children presenting with various endocrine diseases (on about 2,000 urine samples). Normal values were established according to sex and stage of puberty. In boys, the lack of overlap between values of LH (UI/24 hr) observed in stage I (prepubescent, 9-13 yrs) and those observed in stage II represents an obvious biological marker of the onset of puberty. The night/day ratio of LH also increases close to puberty, reflecting the onset of the well-known night secretion of LH, at the time of the first stages of puberty. In girls, the preferential increase in FSH is the best criterion for the onset of puberty. In children with endocrine diseases, assay for UG/24 hr is a valuable parameter of the gonadotropic function allowing 1. to separate delayed puberty from hypogonadotropic hypogonadism; 2. to confirm a diagnosis of precocious puberty and 3. to control a treatment with LHRH analogous.
Asunto(s)
Enfermedades del Sistema Endocrino/orina , Gonadotropinas Hipofisarias/orina , Pubertad , Adolescente , Niño , Preescolar , Femenino , Humanos , Hipogonadismo/orina , Masculino , Preservación Biológica , Pubertad Tardía/orina , Pubertad Precoz/orina , Valores de Referencia , Factores de TiempoRESUMEN
Among 59 children presenting with congenital adrenal hyperplasia due to 21-hydroxylase deficiency observed between 1976 and 1982, 12 (9 males, 3 females) aged 3 1/2 to 12 years, were treated with medroxyprogesterone acetate (MPA) associated with the usual glucocorticoid and eventually mineralo-corticoid treatment. There were two indications: precocious puberty after the onset of the gluco-mineralo-corticoid treatment; Unbalanced biological status with advancement of bone maturation. After the onset of MPA, a decrease in plasma 17-hydroxyprogesterone (17 OHP) and testosterone levels is observed, the bone maturation speed decreases when growth in height continues. MPA may be a contributive treatment for congenital adrenal hyperplasia due to 21-hydroxylase deficiency, permitting restoration of biological balance by restraining adrenal function and improving the final height prognosis.
Asunto(s)
Hiperplasia Suprarrenal Congénita , Hiperplasia Suprarrenal Congénita/tratamiento farmacológico , Medroxiprogesterona/análogos & derivados , Esteroide Hidroxilasas/deficiencia , Hiperplasia Suprarrenal Congénita/enzimología , Estatura/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Desarrollo Óseo/efectos de los fármacos , Preescolar , Quimioterapia Combinada , Femenino , Fludrocortisona/uso terapéutico , Estudios de Seguimiento , Humanos , Hidrocortisona/uso terapéutico , Masculino , Medroxiprogesterona/uso terapéutico , Acetato de Medroxiprogesterona , Factores de TiempoRESUMEN
The kinetics of the responses of plasma testosterone (T) its precursors and estrogens to a single injection of human chorionic gonadotropin (hCG) was studied in 9 46 XY subjects affected with one of 4 inborn errors of testicular biosynthesis. In the adults (n = 4), the kinetics and profile of the hormonal responses to hCG were qualitatively comparable to those previously described in normal adult men, and the profile of response characteristic of the hCG-induced steroidogenic desensitization was observed, suggesting that the 17,20 desmolase blockade induced by hCG is superimposed to the inborn enzymatic defect. In the prepubertal patients (n = 5), testicular desensitization was not observed, as in prepubertal controls. However, T precursors, each marker of a given enzymatic blockade, significantly rose several fold 2-5 days after the hCG injection, while they do not in normal children. The results also show that an hCG test is necessary for a clear-cut diagnosis of a given enzymatic block in children, but is not in adults. The single hCG injection protocol used in this study offers a sophisticated way of a qualitative analysis of the testicular secretory products, but is not a must.
Asunto(s)
Gonadotropina Coriónica/farmacología , Testículo/metabolismo , 17-Hidroxiesteroide Deshidrogenasas/deficiencia , 3-Hidroxiesteroide Deshidrogenasas/deficiencia , Adolescente , Hiperplasia Suprarrenal Congénita , Adulto , Aldehído-Liasas/deficiencia , Algestona/sangre , Androstenodiona/sangre , Niño , Preescolar , Dihidrotestosterona/sangre , Estradiol/sangre , Estrona/sangre , Humanos , Lactante , Cinética , Masculino , Oxidorreductasas/deficiencia , Testículo/enzimología , Testosterona/sangre , Testosterona/metabolismoRESUMEN
The patient was born with ambiguous genitalia (stade III of Prader). The karyotype revealed a normal female genotype. A defect in 21-hydroxylase, at first suspected, was denied by the hormonal studies. Indeed, extremely high levels of pregnenolone, pregnenolone sulfate, progesterone were found in association with low plasma levels of delta 4-androstenedione, testosterone, dehydroepiandrosterone and its sulfate, while cortisol 17OH-progesterone and ACTH levels and plasma renin activity were normal. The hormonal pattern was thus consistent with 17,20-desmolase deficiency. The dynamic studies further supported this contention: all the progestagens rose further after ACTH stimulation and were suppressed by dexamethasone. Meanwhile, all androgens failed to rise after ACTH: the responses of cortisol were normal. The in utero virilization of the female fetus was not understood until an history of virilization was allegedly found in the mother (luteoma of pregnancy). This is the first case of 17-20 desmolase defect recognized in a female newborn. This child, born with ambiguous genitalia had presented the concurrence of two very rare conditions. The in utero virilization of maternal origin enabled us to make the diagnosis of the 17-20 desmolase defect, which otherwise would have been ignored in a XX subject in the neonatal period because it would obviously be unsymptomatic at this age.
Asunto(s)
Aldehído-Liasas/deficiencia , Genitales Femeninos/anomalías , Intercambio Materno-Fetal , Hormona Adrenocorticotrópica , Dexametasona , Femenino , Hormonas Esteroides Gonadales/sangre , Humanos , Recién Nacido , Neoplasias Ováricas/complicaciones , Embarazo , Complicaciones Neoplásicas del Embarazo , Esteroide 17-alfa-Hidroxilasa , Neoplasia Tecoma/complicacionesRESUMEN
Plasma levels of pregnenolone sulfate (PS) were measured in 659 normal subjects whose age ranged from birth to adulthood. PS levels were similar in both sexes. At birth PS values (mean +/- 1 SD) were very high, 109.7 +/- 49 micrograms/dl in mixed cord plasma of 50 neonates, and they were 86 +/- 38.7 micrograms/dl in peripheral plasma during the first day of life in 52 babies. During the first month of life, PS levels decreased to mean values of 53.8 +/- 31.3 micrograms/dl in infants aged 2-30 days, 11.1 +/- 7.9 micrograms/dl between 4 and 6 months, and 3.7 +/- 2.8 micrograms/dl between 7 and 12 months of life. PS values were very low during the second year (1.7 +/- 1.6 micrograms/dl) and remained low through the ninth year of life. A progressive rise was then found until adulthood. The values in adults (5.3 +/0- 2.6 micrograms/dl) were 3 to 4 times higher than between 1 and 9 yr of life but 20 times lower than in cord plasma. This pattern of evolution is in contrast with that of DHAS which rose abruptly at the seventh year of life at the time of the adrenarche. PS therefore does not contribute to the adrenarche. The changes induced by adrenal stimulation and suppression and by testicular stimulation were also studied. Plasma PS levels rose after either acute or long term stimulation with ACTH and were suppressed by dexamethasone, as were cortisol levels in the same tests. A very close correlation was found between the rise of PS and ACTH levels at the end of metyrapone tests. In contrast gonadal participation in the production of PS was moderate. These results suggest that the measurement of PS could be a good index of ACTH production in children.
Asunto(s)
Envejecimiento , Pregnenolona/sangre , Adolescente , Hormona Adrenocorticotrópica , Adulto , Niño , Preescolar , Gonadotropina Coriónica , Ritmo Circadiano , Deshidroepiandrosterona/análogos & derivados , Deshidroepiandrosterona/sangre , Sulfato de Deshidroepiandrosterona , Dexametasona , Femenino , Sangre Fetal/metabolismo , Humanos , Lactante , Recién Nacido , Masculino , Metirapona , Persona de Mediana EdadRESUMEN
The temporal events of adrenarche (prepubertal shift in adrenal androgen biosynthesis) are described. The mechanisms responsible for the initiation and maintenance of the adrenal secretion of androgens are poorly understood. The hypotheses put forward to explain it are reviewed. The transectional or longitudinal study of the plasma levels of dehydroepiandrosterone, its sulfate (DHAS), delta 4-androstenedione, testosterone, and 170H-progesterone in 121 children with a variety of clinical disorders in which adrenarchal and gonadal maturations are dissociated (precocious adrenarche, precocious or delayed puberty, adrenal insufficiency, gonadal dysgenesis, hypogonadotropism hypogonadotrophic) is presented. Treatment of a group of 10 children, with delayed or absent adrenarche and growth failure, with DHAS at physiological dose, for a mean of two years, failed to induce any change in growth rate, bone maturation, growth of sexual hair, or genitalia, or to advance puberty. A physiological role for adrenal androgens remains to be discovered. The author's concept is that adrenarche represents a "marker of body maturation".
Asunto(s)
Enfermedades de la Corteza Suprarrenal/tratamiento farmacológico , Corteza Suprarrenal/metabolismo , Andrógenos/metabolismo , Deshidroepiandrosterona/análogos & derivados , Ovario/metabolismo , Pubertad , Testículo/metabolismo , Adolescente , Corteza Suprarrenal/efectos de los fármacos , Enfermedades de la Corteza Suprarrenal/fisiopatología , Niño , Deshidroepiandrosterona/sangre , Deshidroepiandrosterona/uso terapéutico , Sulfato de Deshidroepiandrosterona , Femenino , Disgenesia Gonadal/fisiopatología , Humanos , Hipogonadismo/fisiopatología , Masculino , Pubertad Tardía/fisiopatología , Pubertad Precoz/fisiopatología , Maduración Sexual/efectos de los fármacosRESUMEN
Fifteen patients with idiopathic hirsutism, who had no attenuated adrenal hyperplasia, obesity, enlarged ovaries, or amenorrhea, were studied. Excessive androgen secretion by adrenal tissue was suggested by the finding of increased levels of dehydroepiandrosterone sulfate, which decreased after dexamethasone administration but did not change after human chorionic gonadotropin (hCG) injection. Excessive androgen secretion by ovarian tissue was suggested by the finding that testosterone and androstenedione levels were elevated, correlated significantly with the levels of luteinizing hormone, decreased with administration of estrogen-progestagen, and increased after hCG injection. Notably, free testosterone levels, which were significantly increased, were only partially suppressed during dexamethasone or estrogen-progestagen administration. These results provide further evidence that both the adrenals and the ovaries secrete androgens excessively in patients with idiopathic hirsutism.
Asunto(s)
Glándulas Suprarrenales/metabolismo , Andrógenos/metabolismo , Hirsutismo/fisiopatología , Ovario/metabolismo , Adulto , Andrógenos/sangre , Gonadotropina Coriónica/farmacología , Dexametasona/farmacología , Estrógenos/farmacología , Femenino , Hormona Folículo Estimulante/sangre , Hirsutismo/sangre , Humanos , Hormona Luteinizante/sangre , Persona de Mediana Edad , Progestinas/farmacología , Globulina de Unión a Hormona Sexual/análisisRESUMEN
The plasma levels of 8 steroid hormones were studied longitudinally in 20 newborns affected with either 21-hydroxylase (21-OH), 11-hydroxylase (11-OH) or 3 beta-hydroxysteroid deshydrogenase (3 beta-ol) deficiencies during the first month of life. Comparison was also made between the patterns observed according to age at first examination (n = 13 before 8 days of age) and the type of the enzymatic block. The most striking findings were the variability in hormone levels and/or evolution with age and the difficulties in making a definite positive or etiological diagnosis at first examination. In some newborns with untreated 21-OH deficiency, 17 alpha-hydroxyprogesterone levels may start off within the normal range or not so far above it. Also, levels of unconjugated dehydroepiandrosterone and other delta 5 steroids may be so high during the first week of life in all 3 forms that an erroneous diagnosis of 3 beta-ol deficiency could easily be considered. In several cases the etiological diagnosis was only ascertained by multiple steroid determination and/or dynamic tests. These discrepancies were not found in infants studied later on in life. It thus appears that a peculiar steroid pattern is observed in the immediate postnatal period in babies with various enzyme defects, which might be related to the morphological changes occurring in the adrenal cortex at this age.