Ethinylestradiol + cyproterone: back in France for acne and hirsutism, despite frequent off-label prescription.

Following a European review, products containing the ethinylestradiol + cyproterone combination are back on the French market for women with acne (as second-line treatment) or hirsutism. Yet experience has shown that frequent off-label prescription of this combination for contraceptive purposes exposes many women to an unjustified risk of thromboembolism.

Alteration of cardiovascular risk parameters in women with polycystic ovary syndrome who were prescribed to ethinyl estradiol-cyproterone acetate.

PURPOSE: We aimed to evaluate the alteration of cardiovascular and metabolic risk parameters of polycystic ovary syndrome (PCOS) patients after a 6-month treatment with an oral contraceptive (OC) containing cyproterone acetate (CPA). METHODS: Forty women with PCOS were evaluated at baseline and after treatment with an OC. Carotid intima-media thickness (CIMT), brachial artery flow-mediated dilatation (FMD), nitrate-mediated dilatation (NMD), high sensitive (hs)-CRP, lipid levels, index of glucose sensitivity, and homeostasis model assessment of insulin resistance index (HOMA) were assessed. RESULTS: Mean CIMT was significantly elevated (0.03 ± 0.01 mm) (p < 0.05). There was a tendency of reduction in FMD, which was significant among overweight patients (p < 0.05). Total cholesterol, low-density lipid (LDL), and triglyceride levels were significantly elevated (p < 0.05). CONCLUSION: CIMT as an indicator of early atherosclerosis and FMD as a finding of endothelial dysfunction seem to be deteriorated especially in overweight PCOS patients who were prescribed to OC containing cyproterone acetate for 6 months.

[Mediastinal lymph nodes during the course of a metastatic prostate cancer]. / Adenopatías mediastínicas en la evolución de un cancer de próstata metastásico.

Prostate carcinoma is one of the most frecuent cancers in men. Significant numbers of patients have regional lymph node and bone metastases during the course of the disease. Mediastinal lymphadenopathy and cutaneous metastases are uncommon and signify well-advanced disease. We report the case of a patient with prostate cancer who develops mediastinal lymphadenopathy, pulmonary nodules and cutaneous metastases 8 years after the diagnosis.

Induction of dorsolateral prostate adenocarcinomas and other accessory sex gland lesions in male Wistar rats by a single administration of N-methyl-N-nitrosourea, 7,12-dimethylbenz(a)anthracene, and 3,2'-dimethyl-4-aminobiphenyl after sequential treatment with cyproterone acetate and testosterone propionate.

Groups of 20-25 male Wistar rats (Cpb:WU), nine groups of 4-week-old rats, and nine groups of 8-week-old rats, were given cyproterone acetate (CA) s.c. or by gavage daily for 18 days at a dose of 50 mg/kg/day. Directly following CA treatment, the rats received 3 daily s.c. injections with testosterone propionate (TP) at a dose of 100 mg/kg/day. On the day after the last TP administration, a single dose of one of the following carcinogens was given to 3 groups: N-methyl-N-nitrosourea (MNU), 50 mg/kg i.v.; 7,12-dimethylbenz(a)anthracene, 30 mg/kg i.v.; 3,2'-dimethyl-4-aminobiphenyl, 250 mg/kg s.c. Three other groups received the same carcinogen treatments after 7 days of recovery from the CA administration. The last 3 groups received carcinogen without TP treatment, but immediately after CA pretreatment was stopped. A 25% incidence of invasively growing, metastasizing adenocarcinomas was found in the dorsolateral prostate region of 8-week-old rats that had received MNU after treatment with CA plus TP. In addition, this group had a 5% incidence of carcinoma in situ and a 5% incidence of atypical hyperplasia in the dorsolateral prostate. Lower incidences of adenocarcinoma of the dorsolateral prostate region and of carcinoma in situ and atypical hyperplasia of the dorsolateral prostate were found in other groups that were treated with MNU or 7,12-dimethylbenz(a)anthracene after pretreatment with CA, followed by TP or recovery, but never in rats that had been treated with CA only. In the groups treated with 3,2'-dimethyl-4-aminobiphenyl, which is slowly metabolized, these lesions were also found in groups that were pretreated with only CA. The carcinomas seemed to originate from the dorsolateral prostate and their average latency time was approximately 61 weeks. The 8-week-old rat given a MNU injection after sequential treatment with CA and TP may provide a relevant animal model for human prostatic cancer.

Rat prostatic weight regression in reaction to ketoconazole, cyproterone acetate, and RU 23908 as adjuncts to a depot formulation of gonadotropin-releasing hormone analogue.

The effects of the s.c. administration of a depot formulation of the luteinizing hormone-releasing hormone (LHRH) analogue Zoladex were studied in normal male rats, alone and in combination with three drugs with "antiandrogenic" action (ketoconazole, cyproterone acetate, and RU 23908) on prostatic weight and on circulating hormone levels in order to investigate whether these antiandrogens might prevent the LHRH-A-induced initial increase in these parameters. These effects were compared with those caused by surgical castration. In addition the effects of the antiandrogens on the activity of the hypothalamic-pituitary-adrenal axis were investigated. The depot LHRH analogue caused an initial increase in ventral prostatic weight after 4 days but suppressed the prostatic and testicular weights, the pituitary luteinizing hormone (LH) content, and plasma LH and testosterone levels after 10 and 17 days. All three antiandrogenic drugs used prevented the initial LHRH analogue-induced rise in prostatic weight, while RU 23908 suppressed its weight after only 4 days. After 10 and 17 days cyproterone acetate and RU 23908 had a similar significantly greater suppressive effect on prostatic and testicular weights than the LHRH analogue alone, while the additive inhibitory effect of ketoconazole was smaller. Surgical castration suppressed prostatic weight significantly more after 4 days, while its effects after 10 and 17 days were similar to that exerted by the combination of LHRH-A and RU 23908. The antigonadotropic effect of cyproterone acetate and the indirect gonadotropin-stimulating effects of ketoconazole and RU 23908 were not recognized in rats simultaneously treated with the LHRH analogue and did not interfere with the LHRH analogue-induced rapid depletion of the pituitary LH content and the decrease in circulating LH and testosterone levels. The LHRH analogue stimulated circulating progesterone and suppressed 17-hydroxyprogesterone levels. Ketoconazole and cyproterone acetate caused disorders in the pituitary-adrenal axis via different mechanisms: ketoconazole caused adrenal hypertrophy with normal circulating corticosterone levels caused by a compensatory increase in ACTH secretion; while cyproterone acetate exerted glucocorticoid-like effects causing a depletion of the pituitary adrenocorticotropic hormone content, adrenal atrophy, and lowered corticosterone levels. The addition of RU 23908 did not change the LHRH agonist-induced changes in adrenocortical activity.(ABSTRACT TRUNCATED AT 400 WORDS)

Local suppression of sebum secretion in rats by topical cyproterone acetate in ethanol.

Sebum production was measured on 2 symmetrically placed areas on the flanks of rats over alternating periods of 18 and 6 hr for 4 days, by absorbing the lipid on pads of cigarette paper held in place by a specially designed harness. Castrated rats receiving testosterone produced about twice as much sebum as untreated littermate controls. Once daily application of ethanol to one flank significantly reduced sebum production, in comparison with the other flank in testosterone-treated but not in untreated rats. Daily application of 5 mg cyproterone acetate in ethanol to one flank in a third group of rats significantly reduced sebum production in comparison with that of the other flank treated with vehicle only. The effects became significant within 24 hr. It seems likely that the sebaceous glands received the topically applied materials by way of the pilo-sebaceous orifices rather than by transepidermal absorption. The results demonstrate that one action of cyproterone acetate is at the target site and suggest that the anti-androgen may be effective when applied topically. The method could prove useful in assessing the local action on sebaceous activity of topically applied substances.

Serum lipids, lipoproteins, and apolipoproteins during postmenopausal estrogen replacement therapy combined with either 19-nortestosterone derivatives or 17-hydroxyprogesterone derivatives.

PURPOSE: To study the influence of combined hormone replacement therapy on levels of serum lipids, lipoproteins, and apolipoproteins. PATIENTS AND METHODS: One hundred thirty-nine healthy early postmenopausal women selected by means of a questionnaire, a medical examination, and a laboratory screening procedure to be a representative sample of postmenopausal Danish women aged 45 to 55 years old were randomized to four treatment and two placebo groups. The four groups receiving hormone replacement therapy were given 2 mg estradiol valerate equivalents (E), either sequentially combined with 75 micrograms levonorgestrel (E/LNG), 10 mg medroxyprogesterone acetate (E/MPA), or 150 micrograms desogestrel (E/DG), or continuously combined with 1 mg cyproterone acetate (E/CPA). Serum lipids, lipoproteins, and apolipoproteins were measured before institution of hormone replacement therapy and at nine well-defined times during the following 84 days. Total response and cyclical variations were calculated. RESULTS: All active treatment regimens reduced serum low-density lipoprotein cholesterol (LDL-C) significantly: E/CPA, 6% (95% confidence limits 0.3% to 11.3%); E/LNG, 10.9% (4.9% to 16.6%); E/MPA, 14.4% (7.4% to 20.9%); E/DG, 10.7% (3.3% to 17.6%). The changes in serum total cholesterol and apolipoprotein B were similar but smaller than those in LDL-C. None of these treatment regimens induced significant overall changes in serum high-density lipoprotein cholesterol (HDL-C) or apolipoprotein A1 (Apo A1). The sequentially combined hormone treatments induced significant cyclical variations in HDL-C, with an increase during estrogen therapy and a decrease during combined therapy: E/LNG, 13.3% (7.4% to 19.4%); E/MPA, 6.9% (1.6% to 12.6%); E/DG, 10.3% (5.8% to 14.9%). No cyclical changes in HDL-C were found in the group receiving continuously combined hormone replacement therapy (E/CPA). The changes in Apo A1 parallel those in HDL-C. CONCLUSION: All the treatment regimens produced changes in levels of serum lipids, lipoproteins, and apolipoproteins that may be considered favorable in terms of cardiovascular disease.

Clinical efficacy and safety of cyproterone acetate in severe hirsutism: results of a multicentered Canadian study.

We compared the efficacy and safety of cyproterone acetate (Shering AC, Berlin, FRG) at a low (Diane, 2 mg) or a high dose (Androcur, 100 mg) in the treatment of 158 patients with severe hirsutism. At baseline, no difference was observed in mean hirsutism total index (19.5 Diane versus 20.1 Androcur) or distribution (facial, bust, or abdomen). By the end of the study, patient loss in Diane and Androcur groups was 29.1% and 27.8%, respectively, and the mean percent difference in the scoring index was as follows: total, 24.6 Diane versus 30.8 Androcur, P less than 0.05; facial, 30.1 Diane versus 33.0 Androcur, P less than 0.10; bust, 12.1 Diane versus 31.2 Androcur, P less than 0.02; and abdomen, 20.1 Diane versus 31.2 Androcur, P less than 0.02. Except for breast tenderness (Diane greater than Androcur), amenorrhea, and weight gain, (Androcur greater than Diane), the incidence of side effects was comparable in both groups.

Treatment of hirsutism by an association of oral cyproterone acetate and transdermal 17 beta-estradiol.

Twenty-four hirsute women were treated with an inversal sequential scheme of cyproterone acetate, 50 mg/d by oral route from the 1st to the 15th day of the menstrual cycle, along with 100 micrograms/24 h of 17 beta-estradiol transdermally administered from days 1 to 21, for nine cycles at weekly intervals. The acne and seborrhea as well as hirsutism showed a significant improvement in all subjects studied. The plasma testosterone and dehydroepiandrosterone sulfate decrease from 1.5 +/- 1.3 ng/mL and 6.9 +/- 1.3 micrograms/mL to 0.5 +/- 0.03 ng/mL and 2.7 +/- 1.7 micrograms/mL, respectively. Similar values were observed in subjects with idiopathic hirsutism during the treatment. The metabolic parameters, as well as the plasma levels of sex hormone-binding globulin, appeared unaffected by the therapy. Furthermore, the luteinizing hormone and follicle-stimulating hormone secretion was strongly inhibited from the first cycle of treatment. In conclusion, considering the good clinical results and the avoidance of any hepatic effect, this association should be taken into account in the treatment of hirsutism, especially in case of oral estrogen intolerance.

Effect of short-term cyclic administration of cyproterone acetate on pituitary-ovarian function in the human.

Short courses of cyproterone acetate, a compound with progestational and antiandrogenic activities, were administered to normally menstruating women during different phases of the menstrual cycle to suppress growth and maturation of the follicles and corpus luteum function. Postovulatory administration of 20 mg of the drug daily for 8 days to two women delayed menstruation by 4 to 6 days, followed by prolonged bleeding and short post-treatment cycles. Plasma levels of progesterone were suppressed temporarily during therapy, but increased immediately after cessation of treatment. Administration of 10 mg of the drug for 8 days during the early follicular phase to two women resulted in irregular bleeding, short cycles, and decreased plasma levels of progesterone throughout the cycle. Reduction of the dose to 2.5 mg during the early follicular phase in two other women also resulted in irregular cycles. When the 2.5-mg dose was administered to three women from the 8th to the 15th days of the cycle, vaginal bleeding and cycle length were normal. Plasma levels of luteinizing hormone and progesterone were suppressed during therapy. In one subject, cervical mucus was found to be hostile to sperm penetration in all three treatment cycles. The results indicate that, with cyclic administration of low doses of cyproterone acetate to women during the late follicular phase, it may be possible to interrupt pituitary-ovarian function, as well as sperm transport through the cervical mucus.

PIP: The effect of short-term cyclic administration of cyproterone acetate (CPA) on pituitary-ovarian function was investigated in the human. Postovulatory administration of 20 mg CPA/day for 8 days to 2 normally menstrauting women delayed menstraution by 4-6 days, followed by prolonged bleeding and short posttreatment cycles. Plasma progesterone levels were suppressed temporarily during therapy but increased immediately after cessation of treatment. Administration of 10 mg CPA for 8 days during the early follicular phase to 2 women resulted in irregular bleeding, short cycles, and decreased progesterone levels throughout the cycle. A 2.5 mg dose of CPA during the early follicular phase in 2 other women also resulted in irregular cycles. When the 2.5 mg dose was administered to 3 women from the 8th to 15th days of the cycle, vaginal bleeding and cycle length were normal. Plasma progesterone and luteinizing hormone were suppressed during therapy. In 1 woman cervical mucus was found to be hostile to sperm penetration in all 3 treatment cycles. These data indicate that with cyclic administration of low doses of CPA to women during the late follicular phase, it may be possible to interrupt pituitary-ovarian function as well as sperm transport through the cervical mucus.

Antiandrogenic effects of topically applied spironolactone on the hamster flank organ.

The effects of topically applied spironolactone on the sebaceous glands of flank organs in adult male golden hamsters were investigated. Daily treatment with spironolactone (0.3 mg and 3 mg) on one side only significantly reduced the size of the treated flank organs, while the contralateral flank organs remained unchanged. Lower doses of spironolactone and the vehicle had no effect. Cyproterone acetate therapy resulted in the bilateral reduction of flank organ sizes. In vivo measurement of the palpable bulk of the flank organs correlated with flank organ volumes as determined by computer-assisted planimetry of serial histologic sections. Dry weights of seminal vesicles in animals treated with spironolactone did not differ significantly from those of the control group, while topically applied cyproterone acetate significantly reduced seminal vesicle weight. Topically administered spironolactone appears to have only local antiandrogenic effects, as indicated by the lack of changes in the untreated contralateral flank organs and in the weights of seminal vesicles.

Cyproterone. A review of its pharmacology and therapeutic efficacy in prostate cancer.

Cyproterone (cyproterone acetate) is a steroidal antiandrogenic agent that inhibits the action of adrenal and testicular androgens on prostatic cells. Additionally, its progestogenic activity causes a centrally mediated reduction in testicular secretion of androgens. Studies have demonstrated the effectiveness of cyproterone monotherapy in patients with prostate cancer, and for those in whom orchiectomy is not an acceptable option cyproterone may be a useful alternative. In addition, the drug may be administered in combination with surgical or gonadotrophin-releasing hormone (GnRH) agonist-mediated castration to ensure ablation of adrenal androgens. However, the effectiveness of cyproterone in combination with these forms of testicular androgen deprivation remains to be fully established. Trials to date have not demonstrated prolonged survival in patients receiving the combination therapy. Importantly, however, cyproterone does prevent acute exacerbation of disease during initial treatment with a GnRH agonist. Furthermore, combination therapy tends to be associated with a lower incidence of hot flushes than GnRH agonist-mediated or surgical castration alone. Thus, cyproterone 200 mg/day has proven efficacy in preventing acute flare of disease and reducing the incidence of hot flushes associated with GnRH agonist therapy or orchiectomy. It may also facilitate maximal androgen deprivation in patients receiving GnRH agonist therapy. If this drug is used as monotherapy, dosages of 250 mg/day or greater will probably be required.

Post-heparin plasma hepatic lipase activity as predictor of high-density lipoprotein response to progestogen therapy: studies with cyproterone acetate.

Cyproterone acetate (CPA) was administered to 13 menstruating women from day 14 to day 27 of the cycle at a dose of 5 mg/day. Serum lipoprotein lipid levels and postheparin plasma lipase activity were determined on day 27 of the cycle before treatment and during two treatment cycles. No significant changes were observed in hepatic lipase activity or in very-low-density (VLDL) or low density lipoprotein (LDL) concentrations. However, analysis of high-density-lipoprotein (HDL) subfractions by precipitation demonstrated a significant reduction in HDL2 cholesterol (-24%, P less than 0.05) during cyproterone acetate treatment. It is suggested that this change is related to oestrogen deficiency induced by inhibition of luteinizing hormone (LH) secretion.

Hormone replacement therapy: lipid responses to continuous combined oestrogen and progestogen versus oestrogen monotherapy.

Fifty-five postmenopausal women with climacteric complaints were randomly assigned to treatment with either 2 mg oestradiol valerate (E2V) (cyclic regimen: 21 days of treatment followed by a 7-day treatment-free interval), or 2 mg E2V combined with 1 mg cyproterone acetate (E2V+CPA) daily, over a 6-month period. Treatment was by the oral route in both cases. The aim was to compare the influence of these two hormone replacement therapy regimens on lipid metabolism. Blood samples were obtained before and after 1 and 6 months of treatment. Serum was analyzed for total cholesterol (TC), high-density lipoproteins (HDL), apolipoproteins A1 and B and triglycerides. The low-density lipoprotein (LDL) concentrations were derived by calculation. All parameters were evaluated in terms of mean +/- S.D. There was no significant difference in the response of the blood lipids to the two treatments, as assessed by analysis of variance (P greater than 0.05). Serum levels of TC were found to have fallen after month 1 and 6 by 5.3 and 5.6%, respectively, during E2V treatment and by 2.4 and 0.2% during E2V+CPA treatment. Serum HDL levels had increased after months 1 and 6 by 9.7 and 5.2%, respectively, in the E2V group and by 6.9 and 2% in the E2V+CPA group, which was also confirmed by the increase in apolipoprotein A1 levels. There was, however, a borderline increase in LDL and apolipoprotein B in the E2V+CPA group. Serum triglycerides were reduced and serum levels of SHBG increased during treatment in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Climacteric symptoms after oral and percutaneous hormone replacement therapy.

One hundred and ten (110) healthy early post-menopausal women with mild subjective vasomotor symptoms (mean Kupperman index score 11) participated in a long-term, double-blind, placebo-controlled therapeutic trial. The effects of 2 hormone regimens were evaluated. Group I received percutaneous oestrogen therapy for 2 yr, opposed by oral micronized progesterone (200 mg) during the second year, while Group II received oral 17 beta-oestradiol valerate together with cyproterone acetate (CPA). The serum oestrogen concentrations differed markedly in the 2 treatment groups. In Group I the serum/oestrone/oestradiol ratio was 1 (comparable to the pre-menopausal value), but in group II the ratio was greater than 5. Despite the difference in the serum oestradiol and oestrone concentrations, the mean symptom scores were rapidly and similarly reduced in both treatment groups (P less than 0.001). They remained low throughout the study and were not significantly different from pre-menopausal values.

Comparison of two hormone replacement regimens--influence on lipoproteins and bone mineral content.

Two hormone replacement therapy regimens were tested in a double-blind clinical trial involving 49 patients. In both cases the oestrogen component was 2 mg oestradiol valerate. This was administered for 21 days and sequentially combined for 10 days with either 0.5 mg norgestrel + (Cyclo-Progynova) or 1 mg cyproterone acetate (SH D 461 A). Each treatment cycle was followed by a 7-day tablet-free period. Both regimens proved to be equally effective in alleviating climacteric complaints. However, the low-density-lipoprotein cholesterol lowering effect of SH D 461 A was found to be superior to that of Cyclo-Progynova. There were no changes in bone mineral content during the one-year treatment period with either combination.

Secretory endometrial protein PP14 in serum from post-menopausal women receiving continuous combined oestradiol-cyproterone acetate: correlation with serum hormone concentrations and bleeding patterns.

The secretory endometrial protein PP14 was measured in serum from 49 healthy, early post-menopausal women receiving continuous combined oestradiol valerate/cyproterone acetate (2 mg E2V + 1 mg CPA daily) or placebo over a period of 2 years. In the hormone group, serum PP14 increased from 2.1 micrograms/l to a maximum of 8.1 micrograms/l after 1 month of treatment, then fell after 3 months to 3.8 micrograms/l and remained at that level for the rest of the 2-year period. After the first month, the occurrence of uterine bleeding was associated with significantly increased serum PP14 levels. Bleeding was not correlated with the serum concentration of 17 beta-oestradiol (E2) or CPA, or the CPA/E2 ratio. Serum PP14 was significantly dependent on the serum concentration of E2, but not on that of CPA. The present data confirm that serum PP14 levels reflect the secretory phase of the endometrium and that bleeding during continuous combined hormone replacement therapy is probably caused by a sub-optimal hormonal balance.

Progestogens: therapeutic and adverse effects in early post-menopausal women.

Progestogen treatment is associated with a number of subjective symptoms. In the present study, 148 healthy post-menopausal women suffering from mild climacteric symptoms were randomly allocated to 12 weeks of treatment with (a) 2 mg oestradiol valerate combined with cyproterone acetate, medroxyprogesterone acetate or levonorgestrel; (b) 1.5 mg 17 beta-oestradiol combined with desogestrel; or (c) placebo. Climacteric symptoms, Kupperman index scores and potential adverse progestogen effects were recorded before treatment and three times per month during therapy. All the hormone regimens had a rapid effect, reducing the severity of climacteric symptoms to about 30% of the baseline values (P less than 0.001) within one month. Hot flushes were reduced in severity and/or frequency by 76 100% within 3 months (P less than 0.001). The regimens which included hydroxyprogesterone derivatives produced a transient increase in breast tenderness. Other recorded potential adverse progestogen effects showed no significant changes during the study. We concluded that the addition of progestogens (whether 19-nortestosterone or hydroxyprogesterone derivatives) does not produce significant side effects during combined hormone replacement therapy.

Modification of serum IGF-I, IGFBPs and SHBG levels by different HRT regimens.

UNLABELLED: During the menopause, levels of SHBG, IGF-I and IGFBPs are significantly modified by the use of different HRT regimens. OBJECTIVE: The aim of this study is to evaluate the influence of three different HRT regimens on serum levels of SHBG, IGF-I, IGFBP-1 and IGFBP-3 in postmenopausal women. METHODS: 41 postmenopausal women requesting HRT were enrolled in the study. Subjects were divided in three groups according to the therapy assigned; Group A: estradiol 2 mg/day+cyproterone acetate 1 mg/day in a cyclic sequential regimen; Group B: estradiol hemihydrate 2 mg/day plus norethisterone acetate (NETA) 1 mg/day in a continuous combined regimen; Group C: estradiol hemihydrate 1 mg/day plus NETA 0.5 mg/day in a continuous combined regimen. Blood samples were drawn before the start of hormonal treatment and after 6 months of HRT. Levels of SHBG, IGF-I, IGFBP-1 and IGFBP-3 in the serum were measured by means of a specific immunoassay. RESULTS: In group A, a significant increase of SHBG, no change of IGFBPs and a significant decrease of IGF-I were observed; in group B and in group C, no significant variations for any of the parameters were recorded. CONCLUSIONS: The association of cyproterone acetate to oral estradiol determines a significant reduction of IGF-I levels and an increase of SHBG; nevertheless, it does not seem to influence the serum levels of the IGF-I binding proteins. The treatment with oral continuous combined estrogens plus androgenic progestins, at low doses, produces minor, not significant, changes in the circulating levels of IGF-I, SHBG and IGFBPs.