Pubertal development in girls with sexual precocity after discontinuation of treatment with cyproterone acetate.
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Twenty-four girls with sexual precocity who had been treated with cyproterone acetate were followed for periods from 1 to 8 1/2 years after the discontinuation of therapy. It was found that their further pubertal development and the resumption or appearance of menstruation followed a natural course within the wide limits of physiological variability. It is concluded that puberty resumes its natural course following cessation of treatment with cyproterone acetate, and it is assumed that the reproductive ability of these patients will not be affected.Keywords:
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Abstract. Cyproterone acetate (CPA), an anti-androgen and a gestagen, was administered to pregnant Wistar rats at very low doses (0.5 or 1.0 mg/day) between days 15 and 20 of pregnancy. No anatomical abnormalities were observed in external genitalia of their offspring, either immediately after birth or upon reaching maturity. However, when these animals were studied in adulthood, several endocrine abnormalities became apparent. While the pituitary content of Prl decreased in the CPA-exposed offspring, the amount of LH increased. Plasma Prl was lower and FSH was higher in treated females whereas plasma LH was higher in both sexes compared to controls. Treatment induced a Prl-responsiveness to TRH in both sexes and an enhanced LH- and FSH-response to GnRH in females. Testicular weights, LH/hCG receptors in testicular membrane preparations and testosterone response to in vivo hCG stimulation were identical in both the treated and control groups. Basal testosterone, however, was increased in the face of decreased ventral prostate weight and of decreased androgen receptors in prostate cytosol, indicating androgen resistance of the target organ. Females displayed normal oestrous cycles, but possessed enlarged ovaries and uteri. The decrease in oestrogen receptors (ER) in uterine cytosol during oestrus and the relative increase of ER in dioestrus were consistent with enhanced oestrogenic action, presumably by increased oestrogen secretion by the hyperstimulated ovaries.
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Corticosterone
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Antiandrogens
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Pituitary adrenal suppression has been assessed in twenty-two patients receiving cyproterone acetate (100 mg) and ethinyl oestradiol (30 micrograms) for the treatment of hirsutism. Cortisol responsiveness to ACTH and to insulin induced hypoglycaemia, and diurnal variations of plasma cortisol levels were measured before and after 6 months of treatment. There was no evidence that adrenal suppression is a significant problem in this group of patients.
hirsutism
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beta-Endorphin
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Central precocious puberty (CPP) is characterized by early activation of the pituitary-gonadal axis, which leads to increased growth velocity and development of secondary sexual characteristics. It is generally believed that gonadal sex steroids stimulate pulsatile GH secretion, which, in turn, stimulates insulin-like growth factor I (IGF-I) and IGF-binding protein 3 (IGFBP-3) production. However, little is known about GH, IGF-I, and IGFBP-3 serum levels in children with precocious puberty. Treatment of CPP by GnRH agonists has become the treatment of choice. However, the effect of long term treatment with GnRH in combination with an antiandrogen (cyproterone acetate) to block the possible effect of adrenal androgens has not previously been evaluated. We, therefore, studied 40 patients with idiopathic CPP that were treated for 24 months with either GnRH analog (Buserelin) in combination with cyproterone acetate (Androcur; n = 23) or with long acting GnRH analog (Decapeptyl Depot; n = 17). We found that serum IGF-I levels were increased before treatment in both groups (mean +/- SE, 446 +/- 35 and 391 +/- 35 micrograms/L; P < 0.0001, respectively) compared to those in normal age-matched prepubertal children. Similarly, IGFBP-3 levels were significantly elevated (4675 +/- 209 and 4305 +/- 162 micrograms/L, respectively; P < 0.0001) in the two groups. Treatment with GnRH analog in combination with cyproterone acetate significantly decreased height velocity and serum IGF-I and IGFBP-3 levels to normal levels after 2 yr of treatment (P < 0.0001). Serum IGF-I levels remained unchanged during monthly im treatment with long acting GnRH analog, whereas IGFBP-3 levels significantly increased during the first year of this treatment despite unmeasurable estradiol levels. Thus, in both groups, the molar ratio between IGF-I and IGFBP-3 (i.e. free biologically active IGF-I) declined concomitantly with a decrease in growth velocity. Serum levels of IGF-I and IGFBP-3 (expressed as the SD score for bone age), but not those of estradiol, correlated with height velocity before and during treatment (r = 0.34; P < 0.0001 and r = 0.24; P = 0.003, respectively). Six of the patients with a subnormal GH response to clonidine had similar IGF-I and IGFBP-3 serum levels and growth velocity compared to the other 34 girls with CPP and a normal GH response.(ABSTRACT TRUNCATED AT 400 WORDS)
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Polycystic ovary syndrome (PCOS) is associated with abnormalities of insulin action and insulin secretion. Ethinyl oestradiol/cyproterone acetate is a common agent used to treat the symptoms of PCOS, but its effects on insulin action and insulin pulsatility have not been examined. We investigated the relationship between insulin action and insulin secretion in 11 patients with PCOS, at diagnosis and after 3 months of treatment with ethinyl oestradiol/cyproterone acetate, and in 13 controls. Insulin action was assessed using the euglycaemic hyperinsulinaemic clamp (2 mU/kg/min for 2 h). Insulin pulsatility was examined over 90 min by 2 min sampling. Short‐term insulin pulses were identified using PULSAR. Treatment with ethinyl oestradiol/cyproterone acetate resulted in significant reductions in testosterone (3.3±0.7 vs. 1.9±0.2 nmol/l, p<0.05), free androgen index (10.2±0.7 vs. 1.2±0.2, p<0.05) and LH/FSH ratio (2.6±0.5 vs. 1.0±0.2, p<0.05). During hyperinsulinaemic clamps, the glucose infusion rate (GIR) required to maintain euglycaemia was lower in PCOS compared to controls (33.6±2.7 vs. 45.1±3.5 μmol/kg/min, p<0.05) but similar in PCOS before and after treatment (33.6±2.8 vs. 33.6±2.7 μmol/kg/min, p=0.9). Numbers of pulses identified in PCOS and controls were similar and unaltered by ethinyl oestradiol/cyproterone acetate. There was no correlation between GIR and frequency of insulin pulses in PCOS before or after treatment (r=0.2, p=0.6; post r=−0.5, p=0.1) unlike controls (r=−0.6, p=0.04). Despite considerable improvement in androgen profile, treatment with ethinyl oestradiol/cyproterone acetate did not alter insulin action in PCOS, and this insulin resistance does not appear to be determined by insulin pulse frequency.
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Abstract. The effect of cyproterone acetate (CA) on adrenal glucocorticoid secretion was studied in 35 women with hirsutism. Patients were treated for 9 months with 100 mg CA orally 10 days each month, administered in reverse sequence with 21 days of a combination oral contraceptive containing 50 μg ethinyloestradiol and 2 mg CA. During treatment one patient had a mildly impaired plasma cortisol response to insulin-induced hypoglycaemia and 2 patients showed slight reduction of the plasma cortisol response to ACTH. Responses to metyrapone were normal in all patients tested. Overall, the mean response to these tests was significantly greater during CA treatment compared with pre-treatment measurements, probably due to effects of oestrogen on cortisol-binding globulin. In all patients urinary cortisol excretion remained normal and no patient demonstrated any features of steroid insufficiency. Thus it appears that CA has no untoward effect upon glucocorticoid secretion when given in high dosage for prolonged periods to hirsute women.
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Twenty-four girls with sexual precocity who had been treated with cyproterone acetate were followed for periods from 1 to 8 1/2 years after the discontinuation of therapy. It was found that their further pubertal development and the resumption or appearance of menstruation followed a natural course within the wide limits of physiological variability. It is concluded that puberty resumes its natural course following cessation of treatment with cyproterone acetate, and it is assumed that the reproductive ability of these patients will not be affected.
Discontinuation
Cyproterone
Menstruation
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