Inositol Restores Appropriate Steroidogenesis in PCOS Ovaries Both In Vitro and In Vivo Experimental Mouse Models.

Androgen excess is a key feature of several clinical phenotypes of polycystic ovary syndrome (PCOS). However, the presence of FSH receptor (FSHR) and aromatase (CYP19A1) activity responses to physiological endocrine stimuli play a critical role in the pathogenesis of PCOS. Preliminary data suggest that myo-Inositol (myo-Ins) and D-Chiro-Inositol (D-Chiro-Ins) may reactivate CYP19A1 activity. We investigated the steroidogenic pathway of Theca (TCs) and Granulosa cells (GCs) in an experimental model of murine PCOS induced in CD1 mice exposed for 10 weeks to a continuous light regimen. The effect of treatment with different combinations of myo-Ins and D-Chiro-Ins on the expression of Fshr, androgenic, and estrogenic enzymes was analyzed by real-time PCR in isolated TCs and GCs and in ovaries isolated from healthy and PCOS mice. Myo-Ins and D-Chiro-Ins, at a ratio of 40:1 at pharmacological and physiological concentrations, positively modulate the steroidogenic activity of TCs and the expression of Cyp19a1 and Fshr in GCs. Moreover, in vivo, inositols (40:1 ratio) significantly increase Cyp19a1 and Fshr. These changes in gene expression are mirrored by modifications in hormone levels in the serum of treated animals. Myo-Ins and D-Chiro-Ins in the 40:1 formula efficiently rescued PCOS features by up-regulating aromatase and FSHR levels while down-regulating androgen excesses produced by TCs.

Prospective evaluation of estrogen receptor-beta in predicting response to neoadjuvant antiestrogen therapy in elderly breast cancer patients.

It has been proposed that knowledge of estrogen receptor beta (ER-beta) expression may refine estrogen receptor alpha (ER-alpha) predictivity of response to endocrine therapy. We challenged this hypothesis in ER-alpha-positive breast cancers subjected to preoperative antiestrogen treatment. Forty-seven elderly (> or =65 years old) women with nonmetastatic, ER-alpha-positive (by immunohistochemistry) primary breast cancers (> 2 cm in diameter) entered a neoadjuvant hormone therapy protocol (60 mg/day toremifene for 3 months). ER-alpha and ER-beta (ERs) mRNA was determined by semiquantitative RT-PCR, before (on core needle biopsy) and after (on surgical specimens) neoadjuvant treatment. Study end points included: (1) relation between treatment response and ER mRNA expression; and (2) changes in ER expression after treatment. The response was clinically assessed as tumor size change at the end of the preoperative treatment. ER mRNA expression was assessable before and after treatment in 38 and 20 cases respectively. ER-beta was co-expressed with ER-alpha at variable levels and significantly correlated only with progesterone receptor (P = 0.0285). Objective clinical response, including patients with minor change (> or =25-<50% tumor shrinkage after treatment), was documented in 68.4% of cases and was independent of ER-beta levels or changes. ER-alpha levels were higher in tumors from patients in complete remission than in those from women achieving partial response or minor change compared with non-responsive patients (median expression values: 801 versus 516 versus 320 arbitrary units) and were consistently down-regulated by preoperative treatment. We conclude that in this elderly patient population with ER-alpha-positive tumors, ER-beta mRNA was neither predictive of response to preoperative toremifene nor provided additional information to the knowledge of ER-alpha mRNA levels, which, conversely, were directly correlated with likelihood of response.

Is axillary lymph node dissection necessary in elderly patients with breast carcinoma who have a clinically uninvolved axilla?

BACKGROUND: Axillary dissection in elderly patients with early-stage breast carcinoma who do not have palpable axillary lymph nodes is controversial because of the associated morbidity of the surgery, reduced life expectancy of the patients, and efficacy of hormone therapy in preventing recurrences and axillary events. METHODS: The authors performed a retrospective analysis of 671 consecutive patients with breast carcinoma who were age >or= 70 years and who underwent conservative breast surgery with axillary dissection (172 patients) or without axillary dissection (499 patients). Tamoxifen always was given. The effects of axillary dissection compared with no axillary dissection on breast carcinoma mortality and distant metastasis were analyzed using multiple proportional-hazards regression models. Because the assignment to axillary treatment was nonrandom, covariate adjustments were made for baseline variables that influenced the decision to perform axillary dissection and for prognostic factors. RESULTS: The crude cumulative incidence curves for breast carcinoma mortality and distant metastasis did not appear to differ significantly between the two groups (P = 0.530 and P = 0.840, respectively). The crude cumulative incidences of axillary lymph node occurrence at 5 years and 10 years were 4.4% and 5.9%, respectively (3.1% and 4.1%, respectively, for patients with pT1 tumors). CONCLUSIONS: Elderly patients with breast carcinoma who have no evidence of axillary lymph node involvement may be treated effectively with conservative surgery and tamoxifen. Immediate axillary dissection is not necessary but should be performed in the small percentage of patients who later develop overt axillary lymph node involvement.