Simona Ambroggio

Effect of different doses of metformin on serum testosterone and insulin in non-diabetic women with breast cancer: a randomized study.

UNLABELLED This is a randomized controlled trial to test the effect of different doses of metformin in patients with breast cancer and without diabetes, with the aim of modifying the hormonal and metabolic parameters linked to breast cancer prognosis. Analysis of the results suggest that the dose of 1500 mg/d of metformin causes a significant reduction of insulin and testosterone serum levels. BACKGROUND Serum levels of insulin and testosterone may affect both breast cancer (BC) incidence and prognosis. Metformin reduces hyperglycemia and insulin levels in patients with diabetes. In women without diabetes and with polycystic ovary syndrome, metformin lowers both insulin and testosterone levels. Patients with diabetes who are treated with metformin showed a lower risk of cancer; a protective effect of metformin also was observed for BC. Recently, studies on metformin use for prevention or treatment of BC have been proposed in patients who are not diabetic. The aim of the present study was to test the effect of different doses of metformin on serum levels of insulin and testosterone in those postmenopausal patients with breast cancer and without diabetes who have basal testosterone levels ≥0.28 ng/mL (median value). PATIENTS AND METHODS A total of 125 eligible women were initially invited to take metformin 500 mg/d for 3 months. The 108 women who completed the first 3 months were invited to continue the study with metformin 1000 mg/d (500 mg twice a day [b.i.d.]) for 1 month. The women were then randomized into 2 groups, and, for the subsequent 5 months, 1 group increased the dose by taking metformin 1500 mg/d (500 mg 3 times a day [t.i.d.]), and the other group continued with metformin 1000 mg /d (500 [b.i.d.]). RESULTS A total of 96 women completed the study: 43 women received 1500 mg/d, and 53 women received 1000 mg/d. The women who took 1500 mg/d showed a significant reduction of insulin level, HOMA-IR index (homeostasis model assessment-insulin resistance index), testosterone level, and free androgen index compared with women treated with 1000 mg/d. After treatment with 1500 mg/d, the insulin level decreased by 25% and the testosterone level decreased by 23%. CONCLUSION Both these changes might have a prognostic importance.

Life-style and metformin for the prevention of endometrial pathology in postmenopausal women

In western women, the endometrium is frequently exposed, even after menopause, to the endogenous hormonal stimulation. Such a stimulation increases the risk of pathologic conditions such as endometrial hyperplasia and type I (endometrioid) endometrial adenocarcinoma. Metabolic syndrome, obesity, insulin resistance and type II diabetes promote the endometrial stimulation, and are recognized risk factors for endometrial cancer. Furthermore, chronic hyperinsulinemia linked both to obesity and metabolic syndrome influences endometrial proliferation through direct and indirect actions. Intentional weight loss, calorie restriction and physical activity are associated with a reduced risk of the endometrial pathology. Biological mechanisms include reduction in insulin and sex steroid hormone levels. In addition to life-style modifications, the antidiabetic metformin may be proposed as preventive agent. Metformin reduces the metabolic syndrome, lowers insulin and testosterone levels in postmenopausal women, and it is a potent inhibitor of endometrial cancer cell proliferation.

Modification of serum IGF-I, IGFBPs and SHBG levels by different HRT regimens

UNLABELLED During the menopause, levels of SHBG, IGF-I and IGFBPs are significantly modified by the use of different HRT regimens. OBJECTIVE The aim of this study is to evaluate the influence of three different HRT regimens on serum levels of SHBG, IGF-I, IGFBP-1 and IGFBP-3 in postmenopausal women. METHODS 41 postmenopausal women requesting HRT were enrolled in the study. Subjects were divided in three groups according to the therapy assigned; Group A: estradiol 2 mg/day+cyproterone acetate 1 mg/day in a cyclic sequential regimen; Group B: estradiol hemihydrate 2 mg/day plus norethisterone acetate (NETA) 1 mg/day in a continuous combined regimen; Group C: estradiol hemihydrate 1 mg/day plus NETA 0.5 mg/day in a continuous combined regimen. Blood samples were drawn before the start of hormonal treatment and after 6 months of HRT. Levels of SHBG, IGF-I, IGFBP-1 and IGFBP-3 in the serum were measured by means of a specific immunoassay. RESULTS In group A, a significant increase of SHBG, no change of IGFBPs and a significant decrease of IGF-I were observed; in group B and in group C, no significant variations for any of the parameters were recorded. CONCLUSIONS The association of cyproterone acetate to oral estradiol determines a significant reduction of IGF-I levels and an increase of SHBG; nevertheless, it does not seem to influence the serum levels of the IGF-I binding proteins. The treatment with oral continuous combined estrogens plus androgenic progestins, at low doses, produces minor, not significant, changes in the circulating levels of IGF-I, SHBG and IGFBPs.

Progestogen use in women approaching the menopause and breast cancer risk

OBJECTIVE Progestogens, particularly synthetic progestins, are widely used to contrast the clinical consequences of the relative hyperestrogenism that characterizes the years preceding the menopause. As a large body of data on postmenopausal hormone therapy (HT) demonstrates that the addition of synthetic progestins to estrogen increases the breast cancer risk compared to estrogen alone, it is important to evaluate if the use of progestogens in premenopausal years is associated with the risk of breast cancer. METHODS Main literature data on the association with breast cancer risk of progestogens, either used alone in premenopausal years or added to estrogen in postmenopausal HT, were reviewed. RESULTS Available data suggest that long-term current use of progestogens in premenopausal women after the age of 40 years can increase the risk of breast cancer. Consistently with the data on postmenopausal HT, the risk increase is higher for lobular cancer than for ductal cancer. CONCLUSIONS The most important and widely accepted indications to the use of progestogens in the years preceding the menopause are anovulatory menstrual disorders, for which a limited period of treatment is generally sufficient. Awaiting for further data, when using progestogens for longer periods to treat other problems (endometriosis, cyclical mastalgia, etc.), the possibility of increased breast cancer risk and clinical benefits have to be weighed. Anyway, as micronized progesterone and dydrogesterone, at least when they were used in postmenopausal HT, seem to have, according to a large observational study, a safer risk profile on the breast, the preferential use of these preparations could be suggested.

Breast cancer and hormone replacement therapy: putting the risk into perspective

Data on hormone replacement therapy and breast cancer risk come from a number of observational studies (mostly American studies). Those published up to 1995 were reanalyzed by the Collaborative Group on Hormonal Factors in Breast Cancer (CGHFBC). They involved populations where exceedingly high estrogen doses were used as first-line therapy, and a progestin was added in a minority of women. Overall, the CGHFBC reanalysis found that the relative risk increased by 0.023 for each year of use (with an absolute excess risk of two or six cases out of 1000 women treated for 5 or 10 years, respectively). Further American studies, published in 2000 and involving populations where lower doses were used, showed a risk increase of 0.01 per year of estrogen-only use. Both the CGHFBC reanalysis and the further studies did not find an increase of risk in treated overweight women. Possibly, overweight women already have a maximal estrogenic stimulus on the breast due to extraglandular estrogen production. An additional explanation could be that oral estrogens, through their hepatocellular effects, reverse some biological features of obesity (e.g. decreased sex hormone binding globulin level and increased insulin-like growth factor-I bioactivity) that potentially increase breast cancer risk, so balancing the estrogen stimulation. The CGHFBC reanalysis did not show a substantial difference in breast cancer risk between the majority using estrogen alone and the small minority using estrogen plus progestin. Conversely, Swedish studies and the recent American studies suggest that the risk increase could be higher with the addition of a progestin, compared with estrogen-only use. The biological effect of progesterone/progestins on the breast tissue is controversial. Even if the observed increase in risk could be partially ascribed to non-progesterone-like effects of some progestins (e.g. opposing the hepatocellular effects of oral estrogens) and also (in the American studies) to use-bias, a detrimental action due to progesterone-like effects cannot be excluded. However, the theoretical possibility exists that low doses of oral estrogens, plus a progestin providing progesterone-like effects only, will be shown to be associated with a limited breast cancer risk increase.

Insulin-like growth factor-l and risk of breast cancer

by Kitaoka and co-workers is straightforward, the complexity of neurohormones and their relation might be an obstacle to finding an answer. Natriuretic peptides are affected by atrial distension, left-ventricular filling, renal function, and renin-angiotensin activation. Furthermore, all neurohormones are inter-related, and natriuretic peptides are increased secondary to sympathetic or inotropic stimulation. Although high concentrations of neurohormones predict a poor prognosis in congestive heart failure, the effects of different therapies on neurohormones do not generally correlate with the effects on mortality. Moreover, whereas the improvement in cardiac function and a reduction in filling pressures would result in lower concentrations of natriuretic peptides, several studies have shown that 1-selective and nonselective -blockers might increase the concentration of natriuretic peptides. Natriuretic and vasodilating properties of the atrial peptides could be responsible for some of the positive effects of -blockers. A proposed mode of action is that -blockade induces a down-regulation of the natriuretic peptide-C clearance receptor, leading to increased peptide plasma concentrations. In this context, it should be emphasised that although most neurohormones exert negative longterm effects on heart failure pathophysiology, the effects of atrial peptide are beneficial in counterbalancing other neurohormones. Nevertheless, natriuretic peptides are probably better predictors of long-term prognosis than other neurohormones in congestive heart failure. A study on the ability of these peptides to predict -blocker effects would be of value.

How to manage the menopause following therapy for breast cancer. Is raloxifene a safe alternative

Raloxifene is a selective oestrogen receptor modulator (SERM) that has anti-oestrogenic effects on breast and endometrial tissue and oestrogenic actions on bone, lipid metabolism and blood clotting. In postmenopausal women raloxifene decreases bone turnover and increases bone mineral density, reducing the incidence of vertebral fractures. Unlike tamoxifen, raloxifene does not cause endometrial hyperplasia or cancer, as demonstrated by endometrial monitoring with ultrasonography and biopsy during treatment. Evidence suggests that raloxifene lowers total low-density lipoprotein cholesterol levels behaving like oestrogens, but does not increase high-density lipoprotein cholesterol levels. In randomised clinical trials on postmenopausal women with osteoporosis, raloxifene reduced the risk of newly diagnosed ER-positive invasive breast cancer by 76% during a median of 40 months of treatment. However, raloxifene does not alleviate early menopausal symptoms, such as hot flushes and urogenital atrophy, and may even exacerbate some of them. In conclusion, raloxifene may be an alternative for the prevention of long-term effects of oestrogen deficiency (osteoporosis and heart diseases) in women with previous breast cancer not having hot flushes. For symptomatic patients, the association of raloxifene with different drugs which have demonstrated efficacy in the control of vasomotor symptoms is now under evaluation.

The first case of breast cancer in thalassemic patient: case report and review of literature

Abstract Thalassemias are genetic disorders characterized by decreased synthesis of one of the globin chains. Beta-thalassemia is caused by impairment in the production of beta-globin chains leaving the excess alpha chains unstable. With better treatment approaches and improvement in chelation therapy, thalassemic patients are living longer. As a consequence, new complications and associations with other conditions including malignancy have emerged. The occurrence of malignancies in thalassemia has rarely been reported, and our review of the literature revealed only few cases. We report the first case of a thalassemic patient developing breast cancer and discuss the possibility of a link between the two disease entities. This case is intended to alert physicians of the possibility of a malignancy in thalassemia patients.

Differential effects of various progestogens on metabolic risk factors for breast cancer.

Biological and epidemiological findings suggest that metabolic factors – insulin, insulin-like growth factor-I (IGF-I) and sex hormone-binding globulin (SHBG) – are involved in the development and promotion of breast cancer. Estrogens, particularly if administered orally, counteract metabolic factors that increase breast cancer risk, i.e. they reduce insulin and IGF-I and increase SHBG. This could contribute toward explaining epidemiological data showing that unopposed oral estrogens do not increase breast cancer risk, or do so only modestly. In contrast to natural progesterone and progesterone-derived progestins, progestins endowed with androgenic (or glucocorticoid) activity negatively influence these metabolic factors, counteracting the favorable effects of estrogens. While most biological and epidemiological findings suggest that natural progesterone does not augment breast cancer risk, available data show an increased risk with synthetic progestins – with the possible exception of progesterone-derived dydrogesterone. Different mechanisms for different progestins could possibly be involved. Differences from progesterone with regard to pharmacokinetics and pharmacodynamics, potency, interaction with the two isoforms of the progesterone receptor, and binding to other steroid receptors could all be relevant. These remain theoretical speculations for the time being, but the possibility that some progestins increase breast cancer risk through their negative influence on metabolic factors cannot be rejected.

β-thalassemia patients and gynecological approach: review and clinical experience

Abstract Significant improvements in therapy and life expectancy of β-thalassemia patients in last decades result in the need of commitment for gynecologists and obstetricians as the complexity of organ impairment needs a specific multidisciplinary approach. After a review of clinical manifestations of β-thalassemia from a gynecologic point of view, we present the experience of a gynecologic center in treating β-thalassemia patients from more than 20 years.