Giuseppe Morgante

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.

Comparison of two malignancy risk indices based on serum CA125, ultrasound score and menopausal status in the diagnosis of ovarian masses

Objective To evaluate the ability of two malignancy risk indices (RMI 1 and Rh4I 2) incorporating menopausal status, serum CA125 level and ultrasound findings, to discriminate a benign from a malignant pelvic mass.

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.

Effects of dexamethasone and dexamethasone plus naltrexone on pituitary response to GnRH and TRH in normal women.

The hypothesis that glucocorticoids have a direct central inhibitory effect on the reproductive axis is sutained by the identification of glucocorticoid receptors on GnRH-secreting neurons and gonadotropic pituitary cells. It has been proposed that glucocorticoids and opioids interact centrally in the regulation of the GnRH-LH axis. The inhibitory effect of glucocorticoids may manifest not only directly through the hormone-receptor link, but also indirectly through an increase in opioid tone. The aim of this study was to evaluate the role of glucocorticoids and glucocorticoids combined with an opioid antagonist, in the regulation of basal and GnRH- and TRH-stimulated secretion of LH, FSH and Prl in 7 women with normal menstrual cycles. Blood samples were obtained every 10 min for an hour. GnRH (50 μg) and TRH (200 μg) were administered and blood sampling was continued every 15 min for 2 h (day 1). At 5 a.m. the next day, naltrexone (50 mg) was given and at 8 a.m. the GnRH-TRH test was repeated (day 2). At 5 a.m. on day 3, the patients took 2 mg oral dexamethasone and the test was repeated. At 5 a.m. on day 4, the patients took naltrexone and dexamethasone and at 8 a.m. the GnRH-TRH test was repeated. Administration of naltrexone did not cause significant changes in basal concentrations of LH and FSH and their response to GnRH. The area under the curve of the LH response to GnRH on day 3 was significantly less than on days 1, 2 and 4. Administration of naltrexone (day 2) did not cause any significant increase in basal and TRH-stimulated levels of Prl with respect to day 1. On day 3, dexamethasone caused a reduced response of Prl to TRH. Pretreatment with naltrexone (day 4) prevented this reduction. These results suggest that suppression of the response of LH to GnRH induced by dexamethasone may be partly mediated by endogenous opioids. Dexamethasone led to a reduction in the response of Prl to TRH, and naltrexone blocked this suppression. Hence the suppression of Prl and LH by dexamethasone must be partly mediated by endogenous opioids, which must therefore inhibit pituitary secretion of Prl.

Infertility and psychiatric morbidity

OBJECTIVE To assess the relationship between psychiatric disorders and infertility. DESIGN Case-control study. SETTING Fertile and infertile volunteer couples in an academic research setting. PATIENT(S) Eighty-one infertile couples recruited from an infertility center before fertility treatment and 70 fertile controls recruited from an obstetrics and gynecology clinic. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) The presence of Axis 1 psychiatric disorders. RESULT(S) The occurrence of current psychiatric disorders was significantly higher among infertile subjects than among fertile controls, especially for adjustment disorder with mixed anxiety and depressed mood (16% vs. 2%) and for binge eating disorder (8% vs. 0). CONCLUSION(S) Our data highlight that a percentage of infertile patients have already developed a psychiatric disorder at the time of their first contact with a specialized fertility service. Possible applications are discussed, including the recommendation that gynecologists screen for clinical or subclinical psychiatric disorders in infertility patients and offer treatment accordingly.

Bone mineral density and biochemical markers of bone turnover in peri- and postmenopausal women.

Abstract. Bone mineral density (BMD) measured by densitometry is the elective parameter for the diagnosis of osteopenia and osteoporosis. Biochemical markers have been proposed as sensitive indicators of high bone turnover and for monitoring response to antiresorptive treatment. We conducted a retrospective study to investigate the values of biochemical markers of bone metabolism with a view to early diagnosis of osteoporosis and monitoring of hormone replacement and calcitonin therapy. The subjects were 415 women, mean age 51 ± 8 years (43–62 years) in peri- and postmenopause, recruited at the Menopause Center of Obstetrics and Gynecology Department of Siena University and divided in five groups. Bone densitometry was performed in all subjects and blood samples were taken for assayed biochemical markers, that is, [osteocalcin (OC), parathyroid hormone (PTH), type 1 procollagen (PICP), and calcitonin (CT)].Three groups of women were divided into two subgroups: those with normal and those with low BMD (<1 SD). Basal concentrations of PCP1, OC, PTH, and CT were compared in the various groups. Two groups of postmenopausal women with BMD below the normal were treated with estrogen replacement therapy and unmodified eel calcitonin.We evaluated whether some of these biochemical markers of bone turnover could help identify women with low BMD and whether they could be useful for monitoring the results of antiresorptive therapies.Markers of bone formation (PICP and OC) make it possible to distinguish women with high turnover who are at risk for osteoporosis from women with low turnover in menopause. A good correlation was also found between changes in levels of these markers and changes in BMD during treatments, which suggests that the PICP and OC would be useful for monitoring response to antiresorptive therapy.

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.

Surgical treatment of ovarian dermoid cysts

OBJECTIVE To evaluate the efficacy of laparoscopic ovarian cystectomy and to compare the surgical course, post-surgical course and particularly post-surgical pain of the laparoscopic and laparotomic methods. STUDY DESIGN We conducted a surgical study on dermoid cysts at the Gynecology Department of Siena University between 1 January 1992 and 31 December 1996. The selected cases were randomized into two groups based on surgical approach: via laparotomy (n=22) or laparoscopy (n=22). Surgical times, estimated blood loss, post-surgical pain, time in hospital, speed of recovery and complications were compared. RESULTS Mean blood loss was significantly less for laparoscopy (58.64+/-30.17 ml versus 103.84+/-38.45 ml, P<0.05). Mean hospitalization was 6.32+/-1.09 days for laparotomy and 3.18+/-0.39 days for laparoscopy (P<0.05). Post-surgical pain was significantly less in laparoscopy patients (P<0.05). The laparoscopic technique had fewer post-surgical complications. CONCLUSIONS The laparoscopic approach had many advantages. Laparoscopy should be the elective treatment for women with dermoid cysts, because it has many advantages for the patient and lower costs for the national health system.

A benefit-risk assessment of medical treatment for uterine leiomyomas.

The growth of a uterine leiomyoma stops and regresses after the menopause suggesting that leiomyoma growth is dependent on ovarian steroids. Therefore, estrogen has received much attention as the major factor responsible for the development of uterine leiomyomas, but progesterone also plays an important role in development of this disease.Cytogenetic analyses of resected samples has revealed that about 40 to 50% of leiomyomas show karyotypically detectable chromosomal abnormalities.Gonadotrophin releasing hormone (GnRH) agonists exert their action through the suppression of endogenous gonadotrophins and gonadal steroid secretion. Significant reductions of uterine/leiomyoma volume under GnRH agonist therapy has been reported in several studies. However, the leiomyoma generally returns to its pretreatment volume within a few months after discontinuation of the GnRH agonist. To minimise the adverse effects of hypoestrogenism during GnRH agonist treatment, add back therapy can be used (estrogen-progestin, progestin alone and recently tibolone).Antiprogestins have a potential clinical utility in uterine leiomyomas. Mifepristone is a synthetic steroid with both antiprogesterone and antiglucocorticoid activities, that may have an inhibitory effect on growth of leiomyoma. Danazol is an isoxazole of 17β-ethinyl testosterone, a synthetic steroid, which has a suppressive effect on sex hormone binding globulin concentrations, resulting in efficacy in the short-term treatment of uterine leiomyomas. Gestrinone is a tri-enic steroid with antiestrogen and antiprogesterone properties and has been shown to reduce uterine volume and stop bleeding.Growth factors play a relevant role on the pathophysiology of uterine leiomyoma and probably the inhibition of the action of growth factors on the myometrium will be the basis for future therapy. A number of agents are under investigation for treating uterine leiomyoma. Agents developed from increasing genetic knowledge of this condition could represent, in the next few years, new trends in the medical treatment of uterine leiomyomas.