Franca Fruzzetti

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.

Adolescent girls with polycystic ovary syndrome showing different phenotypes have a different metabolic profile associated with increasing androgen levels

OBJECTIVE To evaluate the metabolic profiles of adolescents with different phenotypes of polycystic ovary syndrome (PCOS). DESIGN Observational study. SETTING University outpatient clinic. PATIENT(S) Adolescents with PCOS (n = 120) were divided into four groups: oligomenorrhea and hirsutism (O-H, n = 50), oligomenorrhea, hirsutism, and polycystic ovaries (PCO-O-H, n = 22), oligomenorrhea, hirsutism, and hyperandrogenemia (A-O-H, n = 28), oligomenorrhea, and hirsutism, hyperandrogenemia, and polycystic ovaries (PCO-A-O-H, n = 20). A control group of age-matched adolescents (n = 30) was included. INTERVENTION(S) Subjects underwent physical and ultrasound evaluations; fasting blood samples were taken for the measurement of endocrine and metabolic parameters. MAIN OUTCOME MEASURE(S) The endocrine and metabolic profiles were evaluated. RESULT(S) Adolescents with PCOS showed reduced insulin sensitivity and dyslipidemia. Triglycerides, and total and low-density lipoprotein cholesterol were higher in the phenotypes with hyperandrogenemia. Insulin resistance and body mass index were not significantly different between PCOS phenotypes. Triglyceride positively and high-density lipoportein cholesterol levels negatively correlated with free testosterone and free androgen index. CONCLUSION(S) The risk of metabolic alterations may vary in adolescent PCOS patients with different phenotypes. Hyperandrogenemia is a risk factor for dyslipidemia. This information may be of relevance in counseling adolescents with PCOS.

Hormone replacement therapy in perimenopausal women with a low dose oral contraceptive preparation: effects on bone mineral density and metabolism.

In a 2-year longitudinal, calcium-controlled study we evaluated bone density and metabolism in perimenopausal women with initial ovarian failure, and the effects of hormone replacement with a low dose oral contraceptive preparation (OC). In perimenopausal oligomenorrhoic women (n = 16) a significant (P < 0.01) increase in cycle length and plasma FSH levels as well as a parallel decrease in plasma estradiol levels (P < 0.01) were evident. In this group, despite the calcium supplementation (500 mg/day), a significant (P < 0.001) increase in the biochemical markers of bone remodelling paralleled a significant (P < 0.001) decrease (-3.4% after 24 months) in bone density. Conversely, in premenopausal oligomenorrhoic women treated with a low dose oral contraceptive (OC) formulation (30 mcg ethinyl estradiol plus 75 mcg gestodene, n = 16), bone markers showed a significant (P < 0.01) decrease, that paralleled a slight but significant (P < 0.01) increase (+1.71%) in bone density. These data suggest that premenopausal administration of OC can prevent the acceleration of bone turnover and reverse the decrease in bone density that follows the premenopausal impairment of ovarian function.

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.

Bone metabolism in young women taking a monophasic pill containing 20 mcg ethinylestradiol: A prospective study

The present one-year prospective study was performed to evaluate the effects of an oral contraceptive containing 20 mcg ethinylestradiol plus 0.150 mg desogestrel on bone metabolism in young women. Nineteen women aged 20 to 30 years completed the trial. Bone density was measured in the distal radius by dual photon absorptiometry before starting pill use and at the 3rd, 6th and 12th cycle. At the same time intervals, urinary hydroxyproline-to-creatinine ratio and serum alkaline phosphatase were evaluated. Bone density showed a slight, but not significant, increase at the end of the trial. Both urinary hydroxyproline-to-creatinine ratio and serum alkaline phosphatase showed a significant decrease. The results suggest that bone resorption is reduced, although bone density in the distal radius is not significantly increased in young women using an oral contraceptive containing only 20 mcg ethinylestradiol for one year.

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.

Comparison of effects of 3 mg drospirenone plus 20 μg ethinyl estradiol alone or combined with metformin or cyproterone acetate on classic metabolic cardiovascular risk factors in nonobese women with polycystic ovary syndrome

OBJECTIVE To evaluate the effects of a pill with drospirenone (3 mg) plus ethinyl E(2) (20 μg) (DRP/20EE) alone or associated with metformin or cyproterone acetate (CPA) on some metabolic cardiovascular risk factors in women with polycystic ovary syndrome (PCOS). DESIGN Randomized, open-label clinical trial. SETTING Academic medical clinic. PATIENT(S) Forty-eight hirsute women with PCOS. INTERVENTION(S) Patients were randomized to treatment with DRP/20EE or with DRP/20EE plus metformin (1,500 mg/d) or with DRP/20EE plus CPA (12.5 mg/d, 10 days per cycle) for 6 months. MAIN OUTCOME MEASURE(S) Blood pressure, lipid profile, and indexes of glucose tolerance and insulin sensitivity were assessed before and after 6 months of treatment. RESULT(S) Body mass index and blood pressure were not modified by any treatment. Treatment with DRP/EE20 did not change the lipid profile; DRP/EE20 plus metformin significantly increased high-density lipoprotein cholesterol concentrations; DRP/EE20 plus CPA significantly increased triglycerides and total cholesterol. The area under the curve for insulin was significantly decreased by DRP/EE20 and DRP/EE20 plus metformin, but it was significantly increased by DRP/EE20 plus CPA. Treatment with DRP/EE20 plus CPA significantly increased the homeostasis model assessment of insulin resistance index and significantly reduced the glucose to insulin ratio index. Treatment with DRP/EE20 significantly increased the glucose to insulin ratio index. CONCLUSION(S) Treatment with DRP/EE20 improved insulin sensitivity in hirsute women with PCOS, with no deterioration of lipid profile. This effect was not ameliorated by the addition of metformin. The positive metabolic effects of DRP are abolished by the concomitant use of CPA.

Serum thyrotropin by ultrasensitive immunoradiometric assay and serum free thyroid hormones in pregnancy

Variations of serum TSH, measured by an ultrasensitive immunoradiometric assay, of serum total and free thyroid hormones and of thyroxine-binding globulin (TBG) and sex hormone-binding globulin (SHBG) were investigated in a group of 18 normal women before and during pregnancy. A gradual increase of total thyroid hormones, TBG and SHBG was observed, while mean serum free thyroxine and free triiodothyronine progressively decreased. Serum TSH concentrations were comprised within the normal range throughout pregnancy, although a small but significant increase was found in the 2nd and 3rd trimester. These changes may represent a compensatory mechanism to meet the increased demand for thyroid hormones in pregnancy and must be taken into account for a correct evaluation of thyroid function during gestation.