Femara

[JohnnyB]

The role of sex steroids in the regulation of insulin sensitivity and serum lipid concentrations during male puberty: a prospective study with a P450-aromatase inhibitor.

Wickman S, Saukkonen T, Dunkel L.

Hospital for Children and Adolescents, University of Helsinki, PL281, FIN-00029 HUS, Helsinki, Finland. sanna.wickman@helsinki.fi

OBJECTIVE: Our purpose was to study the sex steroid-mediated changes in serum insulin and lipid concentrations in boys during puberty.

DESIGN AND METHODS: We treated boys with constitutional delay of puberty either with testosterone plus placebo or with testosterone plus an aromatase inhibitor, letrozole, which inhibits the conversion of androgens to oestrogens. We demonstrated previously that during treatment with testosterone plus letrozole the increase in testosterone concentration was more than 5-fold higher than during treatment with testosterone plus placebo. The concentrations of 17beta-oestradiol, IGF-I and IGF-binding protein-3 increased during testosterone-plus-placebo treatment, but during testosterone-plus-letrozole treatment the concentrations remained unchanged. These divergent changes in the two groups enabled us to study the effects of sex steroids and GH on insulin sensitivity and lipid concentrations.

RESULTS: The insulin concentration in the testosterone-plus-placebo-treated group did not change. In contrast, in the testosterone-plus-letrozole-treated group, the concentration decreased during letrozole treatment, indicating improved insulin sensitivity. Changes in insulin and IGF-I concentrations within 12 and 18 months were correlated. In the testosterone-plus-placebo-treated group, the high-density lipoprotein cholesterol concentration did not change but in the testosterone-plus-letrozole-treated group the concentration decreased. The concentrations of low-density lipoprotein cholesterol (LDL-cholesterol) and triglycerides did not change in either of the groups.

CONCLUSIONS: The findings indicate that androgens do not directly alter insulin sensitivity in boys during puberty. In contrast, the observations suggest tight regulation of glucose--insulin homeostasis by GH in boys at this stage. Furthermore, our findings indicate that sex steroids do not significantly participate in the regulation of serum concentrations of LDL-cholesterol or triglycerides in boys during early and mid-puberty.

JohnnyB

[JohnnyB]

Femara and clomid

A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women.

Fisher SA, Reid RL, Van Vugt DA, Casper RF.

Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Queen's University, Kingston General Hospital, Ontario, Canada.

OBJECTIVE: To evaluate the ovarian follicular dynamics of cycle modification with the aromatase inhibitor letrozole compared with clomiphene citrate in normal ovulatory women.

DESIGN: Randomized double-blind controlled trial.

SETTING: Tertiary care hospital.

PATIENT(S): Nineteen ovulatory female volunteers, ages 18-35 years.

INTERVENTION(S): Subjects were monitored in one control cycle. Subjects then received either letrozole 2.5 mg daily or clomiphene citrate 50 mg daily on days 5-9 after menses.
MAIN OUTCOME MEASURE(S): Number of mature follicles, endometrial thickness and endometrial pattern at ovulation, and follicular profiles of LH, FSH, and E(2).

RESULT(S): The number of mature follicles at the LH surge in natural cycles was 1.0 with an exaggerated response seen for treatment both with clomiphene and letrozole. There was no difference in the endometrial thickness at midcycle during either the natural cycles or the medicated cycles. LH surges and spontaneous ovulation were documented in all natural and medicated cycles. When measured daily, follicular profiles of LH and FSH are similar between the groups in both the natural and medicated cycles. In the medicated cycles, clomiphene results in a significant increase in E(2) levels, while E(2) levels in letrozole-stimulated cycles appeared lower than in natural cycles.

CONCLUSION(S): Transient inhibition of aromatase activity in the early follicular phase with the aromatase inhibitor letrozole results in stimulation of ovarian folliculogenesis similar to that seen with clomiphene citrate with no apparent adverse effect on endometrial thickness or pattern at midcycle.

JohnnyB

[JohnnyB]

Femara raising IGF-1

The aromatase inhibitor letrozole in advanced breast cancer: effects on serum insulin-like growth factor (IGF)-I and IGF-binding protein-3 levels.

Bajetta E, Ferrari L, Celio L, Mariani L, Miceli R, Di Leo A, Zilembo N, Buzzoni R, Spagnoli I, Martinetti A, Bichisao E, Seregni E.

Medical Oncology B Division, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy.

Serum insulin-like growth factor (IGF)-I and IGF-binding protein-3 levels were measured in two groups of postmenopausal women with advanced breast cancer, who received the aromatase inhibitor letrozole 0.5 or 2.5 mg p.o. once daily. Blood samples were obtained from 15 patients in each dose group at baseline, and one and three months after starting therapy. Circulating IGF-I and IGFBP-3 concentrations were determined by means of radioimmunoassay. In both dosage groups a statistically significant increase in the IGF-I levels was observed during three months of letrozole treatment (P=0.003). In addition, the multiple testing procedure yielded in the whole patient population a significant result in the comparison between mean IGF-I values after three months of therapy and those observed at baseline (P=0.004), the estimated average increase being of 24%. No significant result was obtained in the analysis for the dose effect (P=0.077) and for the time x dose interaction (P=0.208). Circulating IGFBP-3 levels did not appear to be affected by letrozole treatment in either of the dose groups. This is the first report concerning the short-term effects of letrozole on components of the IGF system in breast cancer patients; further investigations are warranted in order to confirm these preliminary data.

JohnnyB

[JohnnyB]

Femara raising test in men

Femara raising test

Aromatase inhibitors in men

The effect of aromatase inhibition on male gonadotrophin and sex steroid concentrations is illustrated in the paper by Trunet et al. (1993): 2.5 mg letrozole suppressed plasma oestradiol concentrations to less than 50% of pretreatment after 2 days, with recovery to approximately pretreatment values after 6 days. These decreases were accompanied by increased gonadotrophin concentrations, with resultant increases of approximately 50% in plasma testosterone. These results, and those previously published (Bhatnagar et al. 1992) on the effects of fadrozole in men, indicate that the aromatization pathway is of major importance in the regulation of gonodotrophin secretion by aromatically androgens.

Full text of this article can be downloaded in PDF format.
http://journals.endocrinology.org/erc/006/...181/0060181.pdf

[JohnnyB]

Femara + Nolva

Impact of tamoxifen on the pharmacokinetics and endocrine effects of the aromatase inhibitor letrozole in postmenopausal women with breast cancer.

Dowsett M, Pfister C, Johnston SR, Miles DW, Houston SJ, Verbeek JA, Gundacker H, Sioufi A, Smith IE.

Department of Biochemistry, Royal Marsden Hospital, London, United Kingdom.

This study examined whether the addition of tamoxifen to the treatment regimen of patients with advanced breast cancer being treated with the aromatase inhibitor letrozole led to any pharmacokinetic or pharmacodynamic interaction. Twelve of 17 patients completed the core period of the trial in which 2.5 mg/day letrozole was administered alone for 6 weeks and in combination with 20 mg/day tamoxifen for the subsequent 6 weeks. Patients responding to treatment continued on the combination until progression of disease or any other reason for discontinuation. Plasma levels of letrozole were measured at the end of the 6-week periods of treatment with letrozole alone and the combination and once more between 4 and 8 months on combination therapy. No further measurements were done thereafter. Hormone levels were measured at 2-week intervals throughout the core period. Marked suppression of estradiol, estrone, and estrone sulfate occurred with letrozole treatment, and this was not significantly affected by the addition of tamoxifen. However, plasma levels of letrozole were reduced by a mean 37.6% during combination therapy (P<0.0001), and this reduction persisted after 4-8 months of combination therapy. Letrozole is the first drug to be described in which this pharmacokinetic interaction occurs with tamoxifen. The mechanism is likely to be a consequence of an induction of letrozole-metabolizing enzymes by tamoxifen but was not further addressed in this study. It is possible that the antitumor efficacy of letrozole may be affected. Thus, sequential therapy may be preferable with these two drugs. It is not known whether tamoxifen interacts with other members of this class of drugs or with other drugs in combination.

JohnnyB