Maria Concetta Musacchio

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.

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.

The role of inositol supplementation in patients with polycystic ovary syndrome, with insulin resistance, undergoing the low-dose gonadotropin ovulation induction regimen

In an attempt to evaluate the role of inositol supplementation in insulin-resistant patients with polycystic ovary syndrome (PCOS), undergoing gonadotropin ovulation induction using the low-dose step-down regimen, we conducted a prospective longitudinal study comparing the stimulation characteristics of 15 patients treated with inositol, to a cohort, matched by age and body mass index (BMI), without inositol. Inositol nutritional supplementation produced very good clinical results with a significant reduction in cancellation rate (0 vs. 40%) and the consequent improvement in clinical pregnancy rate (PR) (33.3% vs. 13.3%).

Effect of a new oral contraceptive with estradiol valerate/dienogest on carbohydrate metabolism.

BACKGROUND Insulin resistance may be induced by both the estrogen and progestin component in hormonal contraception. When estrogen dose is reduced from 50 to 20 mcg, the extent of hyperinsulinemia decreases. Recently, the oral combination contraceptive (COC) containing estradiol valerate (E2V) in combination with dienogest (DNG) was developed in a new estrogen step-down, progesterone step-up dosing strategy (Qlaira, Bayer Healthcare Pharmaceuticals). This study was conducted to evaluate of the effect of a 3-month treatment with E2V/DNG on carbohydrate metabolism in women with polycystic ovarian syndrome (PCOS) and insulin resistance. STUDY DESIGN Study consisted of subjects attending the gynecological clinic of Siena or Pisa, with PCOS and insulin resistance, and without contraindications for the use of COCs. PCOS females (n=20) aged 18 to 33 years were treated with a contraceptive formulation containing E2V/DNG for 3 months. Before treatment and during the third month of therapy, body mass index (BMI) measurement and an oral glucose tolerance test (OGTT) were performed. RESULTS Median values of insulin after treatment were lower than median values before treatment. In particular, the median value of insulin at T0 was reduced by 54.6% (p<.001), and the mean difference between time 0 and 30 min was significantly reduced [42.96 (9.99) mU/mL vs 38.00 (15.10) mU/mL; p<.05]. Homeostasis model assessment of insulin resistance levels were significantly decreased following treatment. OGTT after treatment revealed median fasting glucose levels to be stable (p=.895) at T0. At T30, T60, T120 and T180 min, glucose median values were moderately reduced in comparison to median values before treatment. No significant difference was observed between median BMI values before [26 (4.8) kg/m(2)] and after treatment [26 (3.7) kg/m(2)]. CONCLUSIONS Median insulin levels at T0 and the mean difference between time 0 and 30 of insulin following OGTT were significantly reduced than values before treatment with E2V/DNG for 3 months. Median BMI and glucose levels were not significantly modified. Natural estradiol and nonandrogenic progestogen in the Qlaira formulation could be recommended as an oral contraceptive in women with PCOS who are insulin resistant or who are overweight.

Present and future of recombinant gonadotropins in reproductive medicine.

Pharmacological ovarian stimulation has a major role in reproductive medicine and has been used in anovulatory patients and in the induction of multifollicular development required for the procedures of assisted reproductive techniques (ART). Currently, gonadotropins are the most important tools to proceed with ovarian stimulation for all purposes, including ART and anovulation disorders, like hypogonadotropic hypogonadism and hypothalamic hypophyseal dysfunction. Gonadotropin preparations derived from human urine have been used clinically since the early 1960s and the first urine-derived preparation containing only FSH (urofollitropin) became available in 1983. More recently, the application of recombinant DNA technology has resulted in the development of recombinant FSH produced in mammalian cells. In the last period, LH became available by recombinant DNA technology and is now a new option for protocols of ovarian stimulation. Treatment with gonadotropins has been shown to be effective in males affected by hypogonadotropic hypogonadism. This success has resulted in attempts to utilize FSH therapy in oligozoospermic men, aimed at obtaining a quantitative increase in sperm count. The purpose of this review was to examine the pharmacological aspects and different clinical applications of recombinant gonadotropins (FSH, LH, hCG) in the treatment of female infertility in all its aspects and their use also in the treatment of male infertility. This review will trace these events, from the past through to the present, and conclude with a glance towards the future.

The safety of veralipride

The perimenopausal period, from 1 to 4 years, is characterised by vasomotor symptoms, or hot flushes, and other effects due a deficit of estrogens. Approximately 85% of women have hot flushes for 1 year and 25 – 50% continue for up to 5 years. The cause of hot flushes has been linked to dysfunction of the thermoregulatory centre caused by estrogen withdrawal. One proposal for the aetiology of hot flushes is that the thermoregulatory zone is shifted downward in patients who experience hot flushes. Estrogen withdrawal creates a change of the central opioid system and a thermoregulatory instability. Estrogen and/or progestin replacement is the treatment of choice for this distressing symptom. However, steroid replacement may be associated with risks and complications, and is limited in some subjects by well-known contraindications. Veralipride, a synthetic benzamide derivative with antidopaminergic action, is effective in reducing the frequency and severity of hot flushes associated with menopausal hypoestrogenism, gaining interest as a non-hormonal treatment for climacteric flushing. In recent years, extrapyramidal disorders associated with veralipride therapy have been reported and are often due to drug misuse. Adverse effects include acute dyskinesia or Parkinsonism, which may occur after many months of treatment. An association between adverse effects and mistake of administration has been described. This article discusses available data on the benefits and risks of veralipride therapy for menopausal symptoms.

New protocol of clomiphene citrate treatment in women with hypothalamic amenorrhea

Objective. To determine if a new protocol of administration of clomiphene citrate (CC) is effective in menstrual cycle recovery in women with hypothalamic secondary amenorrhea. Design. This was an open-label study. Patients. Patients comprised a group of eight women with secondary amenorrhea. Interventions. An oral preparation containing CC (50 mg/day) was administered for 5 days followed by a double dose (100 mg/day) for another 5 days, initiated on day 3 after estrogen/progestogen-induced withdrawal bleeding. If ovulation and vaginal bleeding occurred, treatment continued in the two next months with 100 mg/day from day 3 to day 7 day of the cycle. Main outcome measures. Cycle control was evaluated at each visit, when patients recorded bleeding patterns and tablet intake. Data on the intensity and duration of bleeding were collected. Results. Six patients responded to the first cycle of CC administration, resuming normal menstrual cycles. The other two patients failed to menstruate after the first 10 days of treatment with CC and repeated the same protocol. After the second administration, these two women also had normal menstrual bleeding. Conclusions. The present data show that this new protocol of CC treatment may be useful to restore normal menstrual cycles in young women with hypothalamic amenorrhea.

Effects of raloxifene therapy on plasma renin and aldosterone levels and blood pressure in postmenopausal women.

Objective. Blood pressure, which generally increases after menopause, is one of the best tools to characterize cardiovascular disease. The renin–aldosterone system plays a role in determining cardiovascular risk and the role of estrogen in the regulation of angiotensinogen gene expression and serum levels is well known. Raloxifene can induce endothelium-dependent vasodilation without affecting endothelium-independent vasorelaxation. The aim of the study was to investigate the effects of raloxifene on the renin–aldosterone system and blood pressure in postmenopausal women. Designs. Forty women, 54–59 years of age, in physiological menopause for 6 months to 4 years, were enrolled in the study and treated with raloxifene 60 mg/day for 6 months. All had blood pressure less than 130/85 mm Hg at the start of the study. The women were divided into two groups: the first (group A; 20 women) with normal blood pressure and the second (group B; 20 women) with previous high blood pressure treated with antihypertensive drugs, not angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Results. No significant changes in plasma renin activity (PRA) or plasma concentrations of aldosterone were observed between the two groups after 6 months of raloxifene use. There was a slight reduction in PRA (11±4% for group A and 13±5% for group B) and in plasma levels of aldosterone (3.6±0.5% and 4.6±0.5%, respectively) with respect to basal values, but neither change was statistically significant. Conclusions. The results of the present study show that raloxifene at 60 mg/day dose is well tolerated and has no clinical impact on blood pressure, PRA or aldosterone in postmenopausal women.

Comparison of biochemical markers of bone turnover and bone mineral density in different groups of climacteric women

In the present study we evaluated plasma levels of two markers of bone turnover (osteocalcin (OC) and urinary pyridinium cross-links) in association with bone mineral density (BMI) in different groups of climacteric women. We have investigated 158 women in pre- ,peri- and postmenopause. Blood and urine samples for assay of hormones and markers were collected and bone mineral density (BMD) was measured by DEXA densitometry in the distal tenth of the non-dominant forearm. There was a significant increase in mean absolute levels of both markers in perimenopause and women in natural and surgical menopause, with respect to women in premenopause. There was a significant correlation between OC and deoxypyridoline (DPYR) in peri- and postmenopause groups. In peri- and postmenopause groups ,BMD was correlated with an increase in the biochemical markers of bone remodeling. In the present study ,OC and DPYR were found to have good sensitivity for identifying perimenopausal women with pathological BMD. The present results reveal a positive and significant correlation between DPYR and OC ,inversely proportional to BMD ,during hormone replacement therapy. These markers therefore turn out to be sensitive not only for monitoring severe pathology of bone turnover ,but also for monitoring slight physiological deficits in bone equilibrium beginning in perimenopause.

Alterations in thyroid function among the different polycystic ovary syndrome phenotypes.

Abstract The study evaluates the prevalence of subclinical thyroid dysfunction in infertile PCOS patients, according to the different PCOS phenotypes and to examine whether insulin sensitizers in insulin resistant (IR) PCOS patients may improve thyroid function. The study population consisted of all PCOS patients, attending the infertility and IVF unit of Department of Pediatrics, Obstetrics and Reproductive Medicine of University of Siena, Italy, and compared them to regularly cycling, healthy, infertile controls. Upon admission, blood was drawn from all patients during the early follicular phase, for complete hormonal and metabolic profiles. In IR-PCOS patients treated with insulin sensitizers, blood was drawn again after 6 months. PCOS patients had a significantly higher prevalence of subclinical thyroid dysfunction compared to infertile controls. While no significant association was detected between TSH value and the presence of hyperandrogenism, overweight and obese PCOS patients, as well as IR PCOS patients showed significantly higher prevalence of subclinical thyroid dysfunction. Moreover, among IR PCOS patients, 6 months treatment with insulin sensitizers significantly reduces TSH levels. Infertile PCOS patients have a high prevalence of subclinical thyroid dysfunction, which may be successfully treated in IR PCOS patients by insulin sensitizers.