Leopoldo Falsetti

Postsurgical medical treatment of advanced endometriosis: Results of a randomized clinical trial

OBJECTIVE Our purpose was to investigate the efficacy of postsurgical treatment with nafarelin in women with advanced endometriosis. STUDY DESIGN Eligible for trial were women < or = 38 years old with unexplained infertility with or without chronic pelvic pain and stage III or IV endometriosis according to the American Fertility Society, revised, classification who underwent laparotomy as first surgical treatment for debulking or radical surgery of endometriotic lesions. Patients were assigned according to a randomization list to nasal nafarelin, 400 micrograms/day (36 subjects) or placebo nasal spray (39 subjects) for 3 months. Pelvic pain was assessed before first surgery and at the 12-month follow-up visit in women with pelvic pain by means of a multidimensional score system and a 10-point linear pain scale. RESULTS No marked differences in pain scores emerged among women allocated to different treatments. The mean reduction of the multidimensional score was 3.6 and 4.0, respectively, in women allocated to nafarelin and placebo and of the 10-point linear scale scores was 7.0 and 6.9. These differences were not statistically significant. Within 1 year from randomization, of the 36 women allocated to nafarelin and the 39 allocated to placebo, seven (19%) and seven (18%), respectively, became pregnant. CONCLUSION This study suggests that medical treatment with nafarelin does not markedly improve pelvic pain and short-term reproductive prognosis in women with stages III and IV endometriosis.

Effects of long-term administration of an oral contraceptive containing ethinylestradiol and cyproterone acetate on lipid metabolism in women with polycystic ovary syndrome.

Background. The effects of an oral contraceptive pill containing cyproterone acetate on lipid metabolism in women with polycystic ovary syndrome (PCOS) was studied.

Treatment of moderate and severe hirsutism by gonadotropin-releasing hormone agonists in women with polycystic ovary syndrome and idiopathic hirsutism

OBJECTIVE To compare the therapeutic effects of a GnRH-agonist (GnRH-a), leuprolide acetate (LA) depot, versus LA plus and oral contraceptive (OC) containing cyproterone acetate in the treatment of hirsutism. DESIGN Randomized study. SETTING Women addressed to the Department of Gynecological Endocrinology, University of Brescia, Brescia, Italy. PATIENTS Thirty-two patients suffering from moderate and severe hirsutism secondary to polycystic ovary syndrome (PCOS) or idiopathic causes were selected. INTERVENTION Leuprolide acetate was injected IM every 28 days in all patients; 16 women, randomly allocated, received LA plus OC. At the beginning and at the end of treatment hirsutism score and hair diameters were evaluated. RESULTS Both treatment arms resulted in a decrease of hirsutism score and hair diameter, both in idiopathic hirsutism (16% to 31% versus 24% to 32%) and in hirsutism secondary to PCOS (23% to 33% versus 24% to 36%). CONCLUSIONS Gonadotropin-releasing hormone agonist can improve moderate and severe hirsutism effectively. It is necessary to add an OC.

Management of Hirsutism

This review reports our own experience with, and literature studies of, the pharmacological management of hirsutism in women with hyperandrogenism (polycystic ovary syndrome) or with normal serum androgen levels and regular ovulatory menstrual cycles (idiopathic hirsutism). Treatment consists of suppressing ovarian or adrenal androgen secretion, or blocking androgen actions in the skin. The major drugs used are gonadotropinreleasing hormone (GnRH) agonists, combined oral contraceptives (COCs), and steroidal (cyproterone acetate and spironolactone) or nonsteroidal (flutamide and finasteride) antiandrogens.GnRH agonists, suppressing the pituitary, decrease androgen and estradiol secretion and improve severe hirsutism. To avoid estrogen deficiency problems, ‘add back’ therapy with estrogen-progestogen or COCs is advisable. This method of treatment is complicated and expensive, limiting its use to severe forms of ovarian hyperandrogenism with hyperinsulinemia.The third-generation COCs, containing new progestogens or cyproterone, have very restricted effectiveness in the short term (6 cycles), but their long term use (>12 cycles) cures mild-to-moderate hirsutism and improves severe hirsutism. As well as suppressing gonadotropins and ovarian androgen steroidogenesis, these formulations decrease free testosterone levels and may also decrease adrenal androgen production. In women being treated with antiandrogens, COCs are important to provide control of the menstrual cycle and contraception.Cyproterone, a progestational agent, inhibits gonadotropin secretion and blocks androgen action. It is used in COCs or in a reverse sequential regimen. In the latter, it is very effective in the short term treatment of hirsutism.Spironolactone blocks androgen receptors. Its effectiveness in hirsutism is dosage-dependent: low dosages are less active than other antiandrogens, whereas high dosages (200 mg/day) are very effective at the cost of several adverse effects (particularly dysfunctional uterine bleeding), but the concomitant use of a COC may prevent these.Flutamide is a pure antiandrogen that blocks androgen receptors and inhibits hair growth. It is very effective in treating hirsutism within 6 to 12 months. Dry skin is very frequent during treatment with flutamide, and hepatotoxicity is possible at high dosages. Finasteride, a 5α-reductase type 2 inhibitor, is the least effective antiandrogen, but a dosage of 5 mg/day decreases hirsutism without adverse effects. Pregnancy must be avoided during therapy with antiandrogens because of the possible risk of abnormal development of a male fetus.Antiandrogens, especially flutamide (250 to 500 mg/day) and cyproterone (12.5 to 50 mg/day in a reverse sequential regimen), alone or in association with COCs, seem to be the most effective agents for the treatment of hirsutism.

Estroprogestin vs. gonadotrophin agonists plus estroprogestin in the treatment of endometriosis-related pelvic pain: a randomized trial

OBJECTIVE This is a randomized clinical trial comparing estroprogestin (E/P) pill given for 12 months vs. gonadotrophin releasing hormone agonist (GNRHa) given for 4 months followed by E/P pill treatment for 8 months in the relief of endometriosis-related pelvic pain. METHODS Eligible for the study were women with laparoscopically confirmed endometriosis and pelvic pain lasting 3-12 months after diagnosis. Eligible women were randomly assigned to treatment with E/P pill (gestroden 0.75 mg and ethynlestradiol 0.03 mg) for 12 months (47 patients) vs. tryptorelin 3.75 mg slow release every 28 days for 4 months followed by E/P pill for 8 months (55 patients). RESULTS At baseline, dysmenorrhea was reported in 46 women allocated to E/P pill only (97.9%), and in all the 55 women allocated to GNRHa+E/P pill. The corresponding value at the 12 months follow-up visit was 14 subjects (35.9%) and 16 subjects (34.8%). The baseline median values of the multidimensional and analog scale were for dysmenorrhea 4 and 6 in the EP only and 3 and 6 in the GNRHa+E/P group. The corresponding value at the 12 months follow-up visit were 2 and 6 and 0 and 5. Non-menstrual pain was reported, respectively, at baseline and 12 month visit by 46 (97.9%) and 15 (38.5%) subjects in the E/P pill group and 49 (89.1%) and 17 (37.0%) of the GNRHa+E/P pill one. The baseline median values of the multidimensional and analog scale were for non-menstrual pain 3 and 5 in the E/P only and 2 and 6 in the GNRHa+E/P group. The corresponding values at the 12 month follow-up visit were 0 and 4 and 0 and 4. These differences between the two groups were not statistically significant. CONCLUSIONS 1 year after randomization, the two treatment schedules show similar relief of pelvic pain in women with endometriosis.

Comparison of finasteride and flutamide in the treatment of idiopathic hirsutism

OBJECTIVE To compare the effectiveness of finasteride and flutamide in the treatment of idiopathic hirsutism. DESIGN Randomized study. SETTING Department of Gynecological Endocrinology, University of Brescia, Italy. PATIENT(S) Forty-six women with idiopathic hirsutism were selected. INTERVENTION(S) Patients were assigned randomly to receive 5 mg of finasteride once daily or 250 mg of flutamide twice daily for 12 consecutive months. MAIN OUTCOME MEASURE(S) Hirsutism was evaluated at 6 and 12 months of therapy by measuring the Ferriman-Gallwey score and the terminal-hair diameters (microm) taken from different body areas. Blood samples were taken and side effects were monitored during the treatment. RESULT(S) Both finasteride and flutamide induced a statistically significant decrease in hirsutism scores and hair diameters at the end of 12 months. Finasteride reduced the Ferriman-Gallwey score by 20.5% at 6 months and by 34.2% at 12 months, and hair diameter by 18.9%-23.6% at 6 months and by 29.6%-37.9% at 12 months. Flutamide reduced the Ferriman-Gallwey score by 26.6% at 6 months and by 50.9% at 12 months, and hair diameter by 22.3%-28.2% at 6 months and by 47.7%-56.5% at 12 months. Flutamide did not induce hormonal variations, whereas finasteride increased T levels by 60% and decreased 3alpha-androstanediol glucuronide by 69.5% at 12 months. CONCLUSION(S) Both drugs were effective in the treatment of idiopathic hirsutism, but flutamide was more effective than finasteride.

An Open Randomized Comparative Study of an Oral Contraceptive Containing Ethinyl Estradiol and Cyproterone Acetate with and without the GnRH Analogue Goserelin in the Long-Term Treatment of Hirsutism

A multicenter randomized study was carried out to compare the efficacy of combined therapy with a GnRH analog (goserelin) + an oral contraceptive (OC) containing ethinyl estradiol and cyproterone acetate and same OC alone in the treatment of severe hirsutism. The effect of these two therapies was assessed in a subjective and an objective evaluation of hair growth. According to the subjective evaluation, judged by physician and patient. 95% of patients obtained a partial response. The objective response was assessed by measuring the mean diameter of hair from 3 different areas and 1 control area. The decrease in hair diameter compared to pretreatment was statistically significant for both treatments, mainly for the abdomen and face. The difference between the two groups did not reach statistical significance. Therefore, we assume that OC alone remains the treatment of choice for hirsutism. However, the addition of the GnRH analog to OC needs further investigation and could be justified for patients with no response to standard monotherapy.

Long-term follow-up of functional hypothalamic amenorrhea and prognostic factors

Functional hypothalamic amenorrhea (FHA), caused by deficient output of gonadotropin-releasing hormone, may present with an inadequate luteal phase, anovulation with menstrual irregularity, or actual amenorrhea. The underlying mechanisms remain uncertain but there appear to be numerous neuroendocrine abnormalities in FHA, including hyperfunction of the hypothalamic-pituitary-adrenal axis, leading to increased secretion of corticoids and opioids as well as heightened dopaminergic tone and increased nocturnal melatonin secretion. The investigators followed 93 women with FHA over 7 to 9 years (average, 8.1 years), at which time 65 patients (70.7%) had recovered. The FHA diagnosis was based on amenorrhea for 6 months or longer, the hormonal findings, and a radiologically normal sella turcica. In no case did 5 days of oral medroxyprogesterone acetate induce menstrual bleeding. Patients underwent transabdominal or transvaginal pelvic ultrasonography, which excluded polycystic ovary syndrome. Depending on their wish to conceive, patients received either estrogen replacement therapy or oral contraception. Compared with control women, those with FHA had significantly lower levels of gonadotropins, prolactin, estradiol, and thyrotropin, and higher levels of cortisol. The major historical factors associated with FHA were psychological stress and competitive athletic activity, but these factors did not correlate with the likelihood of recovery. Recovered women had higher baseline body mass indices, but age and the duration of amenorrhea were not factors. The only significant hormonal differences were higher androstenedione and lower cortisol levels in recovered women. Recovery did correlate with an increased body mass index at follow-up, but not with the ultrasonographic appearance of the ovaries (whether multifollicular or not). Recovery rates were 74% in women given hormone replacement therapy, 42% in those receiving oral contraception, and 80% in untreated patients. The respective mean recovery times were 25, 34, and 16.5 months. Twelve recovering women had 14 spontaneous pregnancies during follow-up, all but one of which occurred in the setting of hormone replacement therapy. On multivariate logistic regression analysis, baseline body mass index as well as baseline plasma cortisol and A levels predicted recovery from FHA (Fig. 1). FHA is frequently a result of psychological or physical stress, which, along with an inappropriate diet, may alter energy balance and reduce the body mass index. The disorder is reversible, as was the case in more than two thirds of the present patients. The role of various treatments remains unclear, but a stable or increasing body mass index does seem to be a factor in recovery.