Cabiria Ricci

Treatment of hirsutism: comparisons between different antiandrogens with central and peripheral effects

OBJECTIVE To compare the clinical and endocrinologic effects of cyproterone acetate (CPA), an antiandrogen with progestational activity; flutamide, a nonsteroidal antiandrogen, and finasteride, an inhibitor of 5alpha-reductase. DESIGN Randomized, open, controlled clinical study. SETTING Department of Obstetrics and Gynecology, University of Pisa, Pisa, Italy. PATIENT(S) Forty-five hirsute women were enrolled in the study: 29 were hyperandrogenic and 16 had idiopathic hirsutism. Three women dropped out of the study. INTERVENTION(S) Women were randomly treated with finasteride (5 mg/d; n = 14), CPA (25 mg plus ethinyl E2 (EE); n = 13), or flutamide (500 mg/d; n = 15) for 1 year. MAIN OUTCOME MEASURE(S) Hirsutism was assessed using the Ferriman-Gallwey method. Levels of total and free T, androstenedione (A), DHEAS, sex hormone-binding globulin, dihydrotestosterone, and 3alpha-androstanediol glucuronide were evaluated at the beginning of the study and every 3 months. RESULT(S) Treatment with finasteride, flutamide, and CPA significantly decreased the Ferriman-Gallwey score. The percent decreases in the hirsutism score induced by the different treatments were similar. Treatment with CPA plus EE significantly decreased levels of total and free T, A, dihydrotestosterone, and 3alpha-androstanediol glucuronide. These parameters were unchanged with flutamide therapy. Finasteride significantly increased total T levels but reduced dihydrotestosterone and 3alpha-androstanediol glucuronide concentrations. CONCLUSION(S) Finasteride, CPA, and flutamide are equally effective in decreasing hirsutism, despite different mechanisms of action.

Clinical and endocrine effects of flutamide in hyperandrogenic women.

OBJECTIVE To investigate the clinical and endocrine effects of the antiandrogen flutamide in hirsute women. DESIGN Hirsutism was assessed before and after 3 months of treatment with flutamide 500 mg/d. Endocrine evaluations were performed before and during the 2nd month of treatment with flutamide 500 mg or 750 mg/d. SETTING Department of Obstetrics and Gynecology, Pisa, Italy. PARTICIPANTS Eighteen hirsute women were studied: nine women were hyperandrogenic, and the other 9 had an idiopathic hirsutism. INTERVENTIONS Women were randomly treated with flutamide 500 mg/d (9 patients) or 750 mg/d (9 patients) for 3 and 2 months, respectively. Six received placebo 1 month before flutamide treatment. MAIN OUTCOME MEASURES Hirsutism was assessed by measuring hair diameter. Follicle-stimulating hormone and LH responses to GnRH were evaluated. Basal plasma levels of T, androstenedione (A), 17-hydroxyprogesterone (17-OHP), DHEAS, cortisol (F), and sex hormone-binding globulin (SHBG) were evaluated. The same hormones were determined after a single dose of flutamide (250 or 500 mg) or placebo throughout a 12-hour period and in samples collected 60 and 120 minutes after ACTH intravenous injection. RESULTS Hair diameter was reduced by 30%. Both dosages of flutamide did not change basal and stimulated gonadotropin, T, A, 17-OHP, F, and SHBG levels. Both dosages reduced stimulated DHEAS levels. CONCLUSIONS Flutamide may have a beneficial effect on hirsutism. This effectiveness is mainly due to its peripheral antiandrogen action. However, an effect on the adrenal gland seems to be present.

Effect of long-term naltrexone treatment on endocrine profile, clinical features, and insulin sensitivity in obese women with polycystic ovary syndrome

OBJECTIVE Evaluation of clinical and endocrine effects of naltrexone administration in obese women with PCOS. DESIGN Open, controlled, clinical study. SETTING Department of Reproductive Medicine and Child Development, Section of Gynecology and Obstetrics, University of Pisa, Pisa, Italy. PATIENT(S) Ten PCOS women were studied. INTERVENTION(S) Women were treated with naltrexone (50 mg/day) for 6 months. MAIN OUTCOME MEASURE(S) Body mass index and the menstrual cyclicity during naltrexone treatment were assessed. Basal levels of LH, FSH, 17beta-estradiol (E(2)), 17-hydroxyprogesterone, total and free T, androstenedione, dehydroepiandrosterone sulfate, cortisol, sex hormone-binding globulin were evaluated before treatment and every 3 months. Progesterone levels were measured in the luteal phase during the sixth month. Gonadotropin response to GnRH administration (10 microg) and a 75-g oral glucose tolerance test were performed before and every 3 months. RESULT(S) Body mass index significantly decreased from 29.94 +/- 1.04 to 26.07 +/- 0.81 during treatment. The menstrual cyclicity improved in 80% of PCOS women: the mean cycle length was 40-360 days before treatment and ranged between 25 and 120 days and 28-120 days after 3 and 6 months of treatment. Plasma levels of free T, androstenedione, dehydroepiandrosterone sulfate, and cortisol significantly decreased. Fasting glucose-to-insulin ratio improved in women with insulin resistance. CONCLUSION(S) Naltrexone may have a beneficial effect on the clinical and endocrine-metabolic disturbances of obese PCOS women. Whether these effects are the consequences of weight loss or are due to changes in opioidergic tone is debatable.

A comparative study on the effects of a monophasic pill containing desogestrel plus 20 μg ethinylestradiol, a triphasic combination containing levonorgestrel and a monophasic combination containing gestodene on coagulatory factors

The changes in haemostasis during oral contraception are related to the ethinylestradiol dose present in the formulation taken by the patient. An open, randomized longitudinal study was performed to evaluate and compare the effects that low-dose oral contraceptives (OCs) containing different doses of ethinylestradiol exert on the haemostatic system. Eighty-nine healthy women, aged 18-45 years, were randomly assigned to treatment with 3 different OCs: a monophasic pill containing 30 micrograms of ethinylestradiol plus 75 micrograms of gestodene (GSD/30) (30 subjects), a triphasic pill containing levonorgestrel (TRI/LNG) (28 subjects), a monophasic pill containing 20 micrograms ethinylestradiol plus 150 micrograms of desogestrel (DOG/20) (31 subjects). From every woman, blood samples were collected before treatment and at the 3rd and 6th cycle of pill intake. The number of platelets significantly increased (p less than 0.01) during treatment with TRI/LNG. Fibrinogen plasma values were significantly increased (p less than 0.05) only in women treated with the preparation GSD/30. Fibrinopeptide A (FPA) plasma levels significantly increased (p less than 0.01) during treatment with the pills TRI/LNG and GSD/30, but the levels of FPA were unchanged in the group treated with DOG/20. The overall results of this study confirm that the effects of OCs on haemostasis are dependent on the ethinylestradiol dose. Moreover, they suggest that with reduction of the ethinylestradiol component to 20 micrograms, the effects of OCs on haemostasis seem to be virtually eliminated.

Haemostasis profile in smoking and nonsmoking women taking low-dose oral contraceptives

The effects of oral contraceptives on coagulation in 258 nonsmoking and in 190 smoking women were determined. In smokers and in nonsmokers taking oral contraceptives, fibrinogen and fibrinopeptide A concentrations were higher than in oral contraceptive nonusers. In nonsmokers, oral contraceptives increased antithrombin III activity. The effects on coagulation of oral contraceptives with a different ethinylestradiol content (from 35 mcg to 20 mcg) were then evaluated in 333 of these women. The biggest changes in coagulation were observed in smokers taking the preparation with the highest estrogen content. Reduction of the ethinylestradiol dose caused a decrease of the changes in coagulation induced by oral contraceptives both in smokers and nonsmokers. These results might suggest that during oral contraception the coagulation system is affected mainly in smokers and that the decrease of the estrogen dose might lower the effects of the association of smoking and oral contraception on coagulation.

METABOLIC EFFECTS OF THREE NEW LOW-DOSE PILLS : A SIX-MONTH EXPERIENCE

We evaluated the effects on glucose and lipid metabolism in 57 healthy volunteers randomly assigned to one of three low-dose oral contraceptives: two monophasic (desogestrel + ethinylestradiol, EE, and cyproterone acetate + EE) and one triphasic (gestodene + EE) contraceptives. Glucose and insulin responses during OGTT were slightly affected by the cyproterone pill. The insulin area/glucose area ratio and HbA1c level were unchanged in all women. No preparation affected total and LDL-cholesterol levels. Triglycerides rose in all groups, while HDL-CH did only in women taking the two monophasic pills. The three low-dose pills assessed in this study have negligible effects on glucose and lipid metabolism.

Ovarian influence on adrenal androgen secretion in polycystic ovary syndrome

OBJECTIVE To determine whether the ovary influences adrenal androgen secretion in polycystic ovary syndrome (PCOS). DESIGN The adrenal androgen secretion was evaluated before and during ovarian suppression with a long-acting GnRH agonist. SETTING Department of Obstetrics and Gynecology, Pisa, Italy. PARTICIPANTS Women with PCOS and high (10 subjects) and normal (12 subjects) DHEAS levels and 6 normal women. INTERVENTIONS After 1 mg dexamethasone, an ACTH-(1-24) stimulation test was performed in the early follicular phase of the menstrual cycle. The test was repeated after two injections of a long-acting GnRH analogue (GnRH-a). MAIN OUTCOME MEASURES Basal plasma levels of gonadotropins, E2, T, androstenedione (A), 17 alpha-hydroxyprogesterone (17-OHP), DHEAS, and cortisol (F) were evaluated before the evening administration of dexamethasone. Serum A, T, 17-OHP, DHEAS, and F were measured 9 hours after dexamethasone and in samples collected 60 and 120 minutes after ACTH IV injection. RESULTS In the high DHEAS group the maximum increases in T, A, 17-OHP, and DHEAS in response to ACTH were significantly higher than in normal DHEAS PCOS women and in normal women. The GnRH-a modified the A and T responses to ACTH in the high DHEAS group. CONCLUSIONS Ovarian steroids, or other extra-ovarian factors, seem to be responsible for the increased A and T responses to the corticotropin stimulation demonstrated in some PCOS women.

Clinical and metabolic effects of a pill containing 30 mcg ethinylestradiol plus 75 mcg gestodene

The clinical and metabolic effects of a short-term treatment with a combination contraceptive pill containing 30 mcg ethinylestradiol and 75 mcg gestodene were evaluated in a group of 31 healthy women. The pill exerted good cycle control and the incidence of irregular bleeding was low. Side effects rarely occurred, and an improvement in premenstrual symptoms was reported during pill intake. Among the different biochemical parameters tested to monitor the coagulatory system, the only modification observed was an increase of fibrinopeptide A plasma levels, confirming that low-dose pills have less effects on the haemostatic system than oral contraceptives with a higher estrogen content. No significant modification in plasma total cholesterol, triglycerides, high density lipoprotein-cholesterol (HDL-CH), HDL2-CH, nor low density lipoprotein-cholesterol were observed. HDL3-CH levels were significantly increased. Moreover, the pill did not significantly alter the fasting insulin and glucose levels nor their response to an oral glucose tolerance test. It may be suggested that this new formulation has high efficacy and clinical acceptability, primarily due to the total absence of any adverse metabolic effect.

A 12-month clinical investigation with a 24-day regimen containing 15 μg ethinylestradiol plus 60 μg gestodene with respect to hemostasis and cycle control

Abstract The effects of a 24-day regimen containing 15 μg ethinyl estradiol (EE) plus 60 μg gestodene on cycle control and on hemostasis, were evaluated in 58 healthy women (age 19–47 years). All women received the pill for 12 months. Withdrawal bleeding at every cycle during the tablet-free interval was experienced by 84.5% of the women. The overall incidence of irregular bleedings was 19.3%. Hemostasis was evaluated in 20 women. No changes in plasma fibrinogen concentrations, nor in prothrombin fragment F1+2 were observed. A slight increase in thrombin-antithrombin III complexes was observed after 6 and 12 months of oral contraceptive use. Antithrombin III activity significantly increased after one-year of pill intake. The concentrations of tissue plasminogen activator and plasminogen activator inhibitor, both antigen and activity, did not change. These results show that very low doses of EE, such as 15 μg, do not impair hemostasis in healthy females. However, the reduction for the EE dose is responsible of some of the effects on cycle control.

Oral contraceptives and venous thromboembolic disease: the effect of the oestrogen dose

Low-dose oral contraceptives when tested for vascular or thrombotic effects not only show no risk of venous thromboembolic disease, but this method could possibly reduce the chance of thromboembolic disease as compared with pills which have a higher estrogen dose. It has also been found that pills containing lower doses of estrogen have no effect on the coagulatory system. Concerns raised about the connection between oral contraceptive use and the risk of cardiovascular disease called for testing in the late 1960s. Epidemiological studies confirmed the risk of oral contraceptive use and cardiovascular disease especially venous thromboembolism. A further association was identified between the amount of estrogens contained in oral contraceptives and the risk of disease. Estrogens affect the hemostatic system; decreases in antithrombin III activity in addition to platelet adhesiveness and blood viscosity have been observed in oral contraceptive users. Although both a decreased influence on the hemostatic system and the risk of thromboembolic disease have been found in pills with lower doses of estrogen, further research on the effect of the clotting system by low-dose oral contraceptives is needed.