Antonio Cianci

Effects of metformin on gonadotropin-induced ovulation in women with polycystic ovary syndrome

OBJECTIVE To evaluate whether pretreatment with metformin improves FSH-induced ovulation in women with clomiphene-resistant polycystic ovary syndrome (PCOS). DESIGN Randomized prospective trial. SETTING Department of Obstetrics and Gynecology, University of Siena. PATIENT(S) Twenty women with clomiphene citrate-resistant PCOS. INTERVENTION(S) The women were divided randomly into groups A and B (10 subjects each). Group B received 1,500 mg of metformin for at least a month before a single cycle of FSH stimulation. Group A underwent two cycles of FSH stimulation and then received metformin for a month before undergoing a third cycle. MAIN OUTCOME MEASURE(S) The number of FSH ampules, days of treatment, E2 level on the day of hCG, number of follicles > 15 mm, number of hyperstimulation, and the number of cycles with hCG withheld. RESULT(S) The number of follicles > 15 mm in diameter on the day of hCG administration was significantly lower in cycles performed after metformin treatment. The percentage of cycles with hCG withheld because of excessive follicular development was significantly lower in cycles treated with metformin. Plasma levels of E2 were significantly higher in cycles treated with FSH alone than in those treated with FSH and metformin. CONCLUSION(S) By reducing hyperinsulinism, metformin determines a reduction in intraovarian androgens. This leads to a reduction in E2 levels and favors orderly follicular growth in response to exogenous gonadotropins.

Effects of metformin on adrenal steroidogenesis in women with polycystic ovary syndrome.

OBJECTIVE To determine whether the administration of metformin, an insulin-sensitizing agent, is followed by changes in adrenal steroidogenesis in women with polycystic ovary syndrome (PCOS). DESIGN Prospective trial. SETTING Department of Obstetrics and Gynecology, University of Siena, Siena, Italy. PATIENT(S) Fourteen women with PCOS. INTERVENTION(S) Blood samples were obtained before (-15 and 0 minutes) and after (15, 30, 45, and 60 minutes) the administration of ACTH (250 microg). Metformin then was given at a dosage of 500 mg three times a day for 30-32 days, at which time the pretreatment study was repeated. MAIN OUTCOME MEASURE(S) The adrenal androgen responses to ACTH before and after treatment with metformin. RESULT(S) Ovulation occurred in two women (14%) in response to metformin treatment. A significant reduction in basal concentrations of free testosterone and a significant increase in concentrations of sex hormone-binding globulin were observed. The administration of metformin was associated with a significant reduction in the response of 17alpha-hydroxyprogesterone, testosterone, free testosterone, and androstenedione to ACTH. The ratio of 17alpha-hydroxyprogesterone to progesterone, which indicates 17alpha-hydroxylase activity, and the ratio of androstenedione to 17alpha-hydroxyprogesterone, which indicates 17,20-lyase activity, were significantly lower after a month of metformin treatment, indicating a reduction in the activities of these enzymes. CONCLUSION(S) The administration of metformin to unselected women with PCOS led to a reduction in the adrenal steroidogenesis response to ACTH. This finding supports the hypothesis that high insulin levels associated with PCOS may cause an increase in plasma levels of adrenal androgens.

Clinical and endocrine effects of finasteride, a 5α-reductase inhibitor, in women with idiopathic hirsutism

OBJECTIVE To evaluate the effects of long-term administration of finasteride on hirsutism score, basal gonadotropin, and androgen secretion in women with idiopathic hirsutism. DESIGN Randomized single-blinded study. PATIENTS Eighteen patients with moderate-severe hirsutism were recruited for the study. INTERVENTIONS Nine hirsute patients received 7.5 mg/d oral finasteride for a period of 9 months whereas the other nine were treated with placebo. Hirsutism score, serum basal gonadotropin, androgens, estrogen, and sex hormone-binding globulin (SHBG) levels were evaluated in all patients before treatment and every 3 months during treatment. RESULTS After 6 and 9 months of treatment, the hirsutism score improved significantly in the patients receiving finasteride, whereas no significant modifications were observed in patients treated with placebo. The side effects observed were headache and depression of modest entity during the 1st month of treatments, whereas libido did not change. Serum levels of LH, FSH, androstenedione, unbound T, DHEAS, E2, 17 alpha-hydroxyprogesterone, and SHBG did not change during therapy. Hirsute patients treated with finasteride exhibited a marked decrease of dihydrotestosterone and a significant increase of T serum levels from the 3rd and 6th months of treatment, respectively. CONCLUSION Finasteride decreased the hirsutism score of patients affected by idiopathic hirsutism with few side effects during treatment. No modification of libido was observed.

Insulin-lowering treatment reduces aromatase activity in response to follicle-stimulating hormone in women with polycystic ovary syndrome

OBJECTIVE To investigate the effects of reduction of insulin resistance and hyperinsulinemia associated with the polycystic ovary syndrome (PCOS) on FSH-stimulated ovarian aromatase activity. DESIGN Prospective study. SETTING Academic health center, Siena, Italy. PATIENT(S) Twenty women 18 to 26 years of age in whom PCOS was diagnosed on the basis of oligomenorrhea or amenorrhea and hyperandrogenemia. INTERVENTION(S) Recombinant FSH was administered. The next day, therapy with metformin (500 mg t.i.d.) was begun. After 35 to 40 days of treatment, the pretreatment protocol was repeated. MAIN OUTCOME MEASURE(S) Plasma levels of estradiol (E(2)), androstenedione (A), and testosterone (T). The ratios of basal levels and areas under the curve (AUCs) of products and substrates were compared before and after metformin administration to detect differences in aromatase activity. RESULT(S) Metformin treatment was associated with significant reduction in basal free testosterone plasma levels, insulin plasma levels, and insulin response to oral glucose tolerance testing. Administration of FSH was followed by a significantly lesser E(2) response after metformin therapy than before this therapy. The ratios of AUC(E2) to AUC(A) and to AUC(T), indicative of aromatase activity in response to FSH, were significantly lower after metformin therapy than before. CONCLUSION(S) Metformin therapy in women with PCOS is associated with a reduction in aromatase activity in response to FSH. Insulin affects production of both androgen and estrogen. Insulin therefore plays a central role in regulating the activity of thecal and granulosa cells.

Effect of oral contraceptives on markers of hyperandrogenism and SHBG in women with polycystic ovary syndrome.

BACKGROUND This randomized studys aim was to compare the effect of four oral contraceptives (OCs) containing 30 mcg of ethinylestradiol (EE) and different progestogens [drospirenone, (DRSP), chlormadinone acetate (CMA), desogestrel (DSG), gestodene (GSD)] on biochemical and hormonal parameters of hyperandrogenism and sex hormone-binding globulin (SHBG) in women with polycystic ovary syndrome (PCOS). STUDY DESIGN Forty women with PCOS (age 16-35 years) were recruited and randomly assigned to one of four treatment groups of 10 women each, treated, respectively, with 3 mg DRSP/30 mcg EE (Yasmin, Bayer Shering), 2 mg CMA/30 mcg EE (Belara, Grunenthal), 75 mcg GSD/30 mcg EE (Minulet, Wyeth Lederle) and 150 mcg DSG/30 mcg EE (Practil 21, Organon Italia). Blood samples were obtained on day 6-8 of the control cycle and day 6-8 of the third treatment cycle for assay of the following hormones: androsteredione (A), total testosterone (T), free T, SHBG, dehydroepiandrosterone sulphate (DHEAS). RESULTS In all groups, mean concentrations of free T, total T and A dropped by 40-60%, and concentrations of DHEAS dropped by 20-50%. Formulations with DRSP and CMA caused a greater reduction of androgens and a progressive increase in serum concentrations of SHBG than those with DSG and GSD. CONCLUSIONS Clinical studies need to be performed to determine effects of these OCs upon clinical signs of hyperandrogenism.

Auditory brainstem response in postmenopausal women treated with hormone replacement therapy: a pilot study.

Objective: To research the nongenital audiological target for gonadal steroids in postmenopausal women who are treated with hormone replacement therapy. Design: Fifty postmenopausal volunteers were treated with hormone replacement therapy. Women with an intact uterus had sequential weekly transdermal estradiol plus nomegestrole acetate 5 mg orally for 12 days per month or a continuous daily oral dose of conjugated estrogen 0.625 mg and medroxyprogesterone acetate 5 mg tablet. Eighteen surgically postmenopausal women received a weekly transdermal estradiol system. Twenty‐five postmenopausal volunteers—5 with a natural menopause and 10 with a surgical menopause—and 20 premenopausal normally cycling women were used as a control group. Each woman performed auditory brainstem response by auditory‐evoked potentials for waves I, III, and V and for interpeak I‐III, I‐V, and III‐V intervals. Results: Women who were treated with hormone replacement therapy showed wave latencies and interpeak latencies shorter than those for postmenopausal women in the control group (p ≤ 0.05), overlapping those of the premenopausal women (p > 0.05). Women who were treated with estrogen replacement therapy showed shorter time latencies than those treated with combined hormone replacement therapy (p ≤ 0.05). Conclusions: Our data suggest that fluctuating hormone levels cause changes in auditory brainstem response waves, even if the exact mechanism of activity of the gonadal steroids is not clear. However, we believe that estrogen may influence the neuronal plasticity, the metabolic levels of neurotransmitters, and thus the neuronal conduction time into the audiological system. (Menopause 2000;7:178‐183.

Preliminary Study on the Effect of Four‐phasic Estradiol Valerate and Dienogest (E2V/DNG) Oral Contraceptive on the Quality of Sexual Life

INTRODUCTION A new oral contraceptive containing the natural estrogen estradiol and a 19-nortestosterone derivate dienogest (DNG) in a four-phasic 28-day regimen may be used by women. AIM To investigate the quality of sexual life of healthy women on estradiol valerate and DNG (E2V/DNG) oral contraceptive. METHODS Fifty-seven women (age range 18-48 years) were enrolled. The Short Form-36 (SF-36) questionnaire to assess quality of life (QoL) was administered at baseline and at the 26th day of both the 3rd and 6th cycles of oral contraceptive (OC) intake. The Short Personal Experience Questionnaire (SPEQ) to measure the change of sexual behavior was used at the 2nd, 7th, 14th, 21st, 26th, and 28th days of the baseline cycle, as well as at the same days of both the 3rd and 6th cycle of contraceptive intake. MAIN OUTCOME MEASURE The SF-36 and the SPEQ questionnaires. RESULTS Women reported QoL improvement at the 3rd (P < 0.05) and at the 6th cycles (P < 0.01). By SPEQ, improvement of sexuality during the 3rd and the 6th cycle with respect to baseline experience was observed (P < 0.05). The frequency of sexual activity remained basically unchanged (P = NS). Enjoyment and desire improved at the 6th cycle with respect to the 3rd cycle (P < 0.05). All women reported decreased dyspareunia at the 3rd and 6th cycles (P < 0.05). Interestingly, desire, arousal, orgasm, enjoyment, and sexual activity improved, reaching a peak around the 14th day of the menstrual cycle (P < 0.05). At the 3rd and 6th cycle, women on OCs were sexually cyclic, but the peak improvement of desire, arousal, orgasm, enjoyment, and sexual activity appeared around the 7th day of OC intake (P < 0.05). CONCLUSION Reduced hormone-free interval is a new concept in low-dose OC regimens. Moreover, the E2V/DNG multiphasic extended regimen has been found to positively modify the sexuality of users.

Conventional vs. extended-cycle oral contraceptives on the quality of sexual life: comparison between two regimens containing 3 mg drospirenone and 20 µg ethinyl estradiol.

INTRODUCTION Women may use new oral contraceptives (OC) having flexible extended-cycle regimens with a reduced hormone-free interval. AIM To study the changes of the quality of sexual life in users of the traditional 21/7 or extended-cycle 24/4 OC regimens both containing 3 mg drospirenone and 20 µg ethinyl estradiol. METHODS One hundred fifteen women (age range 18-37 years) were enrolled. Fifty-four women were randomly placed on traditional OC standard regimen, administered for 21 days, followed by a 7-day hormone-free interval (group A); and 61 women were placed on extended-cycle OC regimen covering 24 days of the cycle with a 4-day hormone-free interval (group B). The Short Form-36 (SF-36) validate questionnaire to assess quality of life (QoL) and the Short Personal Experience Questionnaire (SPEQ) to measure the changes of sexual behavior were administered before starting OC intake and at the 3rd and 6th cycle follow-ups. MAIN OUTCOME MEASURE The SF-36 and the SPEQ questionnaires. RESULTS Group A women reported QoL improvement during the 6th cycle on all the scales (P < 0.05). Group B women reported QoL improvement during the 3rd and 6th cycle (P < 0.05). Satisfaction with sexual activity, arousal, orgasm, and desire increased during the 3rd cycle in women on the group B (P < 0.05). Group A women did not report any change in all SPEQ items. At the 6th cycle, group B women reported better sexual experience than baseline in all SPEQ items (P < 0.05). All subjects who were affected by dyspareunia before OC intake reported decreased genital pain associated with intercourse at the 3rd and 6th cycle of both OC regimens (P < 0.05). CONCLUSION Women could use OCs in a subjective flexible modality. The extended-cycle OC might produce positive effects on the quality of sexual life, enforcing the concept of tailoring an OC to a woman.

Altered Transcriptional Regulation of Cytokines, Growth Factors, and Apoptotic Proteins in the Endometrium of Infertile Women with Chronic Endometritis

Chronic endometritis (CE) is a poorly investigated and probably underestimated pathology, which may cause abnormal uterine bleeding (AUB), pain, and reproductive failures. Due to undefined symptoms and the normal presence of leukocytes in the endometrial mucosa, diagnosis may be missed. Fluid hysteroscopy is a reliable technique for diagnosing this pathology. Few data exist on the biochemical and paracrine alterations that occur in the endometrium of women diagnosed with CE. The aim of the study was to find molecular modification in endometrium related to CE.

Treatment of hirsutism with flutamide and a low-dosage oral contraceptive in polycystic ovarian disease patients

OBJECTIVE To evaluate the clinical and hormonal response of the antiandrogen flutamide (Eulexin, Schering Plough, Milan, SA, Italy) associated with a low dosage oral contraceptive (OC) in a group of hirsute women who were unresponsive to OC treatment. DESIGN Twenty-two polycystic ovarian disease (PCOD) patients with hirsutism were treated with flutamide (250 mg twice/d) in association with ethinyl-E2 (0.030 mg/d) plus desogestrel (0.150 mg/d) (Practil 21; Organon, Rome, Italy) for 21 d/mo. SETTING Patients were recruited in the Institute of Obstetrical and Gynaecological Pathology, St. Bambino Hospital, University of Catania, Italy. Hormonal assays were performed in the Hormone Laboratories of St. Bambino Hospital, University of Catania, Catania, Italy. MAIN OUTCOME MEASURE Every 2 months the hirsutism score was evaluated using the Ferriman-Gallwey hair density index. Mean plasma concentrations of LH, FSH, E2, total T, dihydrotestosterone (DHT), androstenedione (A), sex hormone-binding globulin, DHEAS were determined. RESULTS After 8 months treatment with flutamide and low dosage OC, the Ferriman-Gallwey score improved in all patients, mean values decreasing from 25.4 +/- 3.96 to 14.6 +/- 1.92. Plasma levels of total T and E2 were unchanged, whereas LH, FSH, A, and DHT values decreased significantly. Sex hormone-binding globulin levels showed a marked increase. CONCLUSION Flutamide, associated with low dosage OC, favorably influence the hirsutism in PCOD women who are unresponsive to OC treatment alone.