afimoxifene and Body-Weight

Adult hypothalamic neurogenesis has recently been reported, but the cell of origin and the function of these newborn neurons are unknown. Using genetic fate mapping, we found that median eminence tanycytes generate newborn neurons. Blocking this neurogenesis altered the weight and metabolic activity of adult mice. These findings reveal a previously unreported neurogenic niche in the mammalian hypothalamus with important implications for metabolism.

Topics: Age Factors; Animals; Animals, Newborn; Bacterial Proteins; Body Weight; Bromodeoxyuridine; Cell Count; Cell Proliferation; Diet, High-Fat; ELAV Proteins; Female; Gene Expression Regulation, Developmental; Histones; Intermediate Filament Proteins; Luminescent Proteins; Magnetic Resonance Spectroscopy; Median Eminence; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nerve Tissue Proteins; Nestin; Neurogenesis; Pregnancy; Proteins; Radiation; Receptors, Estrogen; RNA, Untranslated; SOXB1 Transcription Factors; Stem Cell Niche; Tamoxifen

Tamoxifen, a nonsteroidal antiestrogen, is used widely in the treatment of breast cancer and is undergoing evaluation as a chemopreventive agent. In this study, we investigated several long-term effects of tamoxifen in intact adult female rats following acute treatment at various dosages. The effects of tamoxifen on somatic growth, growth hormone (GH) levels, thyroid hormone levels, and on hepatic cytochrome P450 (P450) expression were compared with those of fulvestrant (ICI 182,780), 17beta-estradiol-3-benzoate, and 4-hydroxytamoxifen under the same experimental conditions. Each compound was injected s.c. for two consecutive days, and rats were killed 37 days after treatment. Tamoxifen decreased body weight and serum triiodothyronine (T3) levels at dosages ranging from 0.5 to 200 mg/kg. Ovary weight, uterus weight, peak plasma GH concentration, and hepatic CYP2A1 content were decreased 37 days after treatment with tamoxifen at a dosage of 20 mg/kg, but expression of other P450 enzymes was not affected. However, tamoxifen and 4-hydroxytamoxifen could not be detected in plasma by high performance liquid chromatography analysis at this time, which suggests that the effects of tamoxifen were mediated indirectly. 4-Hydroxytamoxifen exhibited effects similar to those of tamoxifen, indicating that this metabolite contributes to the in vivo activity of tamoxifen. Estradiol benzoate decreased CYP2A1 and increased CYP3A hepatic levels, but had no effect on serum T3 concentration. In contrast, treatment with ICI 182,780 had little or no effect on the endpoints measured. In summary, 2-day tamoxifen treatment of intact adult female rats resulted in persistent suppression of somatic growth, serum T3 levels, and hepatic CYP2A1 expression.

Topics: Animals; Aryl Hydrocarbon Hydroxylases; Body Weight; Cytochrome P-450 Enzyme System; Dose-Response Relationship, Drug; Estradiol; Female; Gene Expression Regulation, Enzymologic; Liver; Organ Size; Ovary; Rats; Rats, Long-Evans; Steroid Hydroxylases; Tamoxifen; Testosterone; Thyroxine; Time Factors; Triiodothyronine; Uterus

Tamoxifen is widely used to treat oestrogen-dependent carcinoma of the breast. Previous long-term studies have shown that oral administration of tamoxifen induces hepatoproliferative lesions and hepatocellular tumours in rats. 4-hydroxytamoxifen is an active metabolite of tamoxifen undergoing clinical evaluation for the treatment of various non-malignant breast diseases by topical application. In the present study, 4-hydroxytamoxifen was administered daily by cutaneous application for 101 weeks to groups of 50 female Sprague-Dawley rats at 20, 140 or 1000 microg/kg/day. The product was applied with no occlusive bandage and oral ingestion was avoided by application of an Elizabethan collar for 6 h after administration. Treatment with 4-hydroxytamoxifen was clinically well tolerated and induced changes such as decreased food consumption and body weight gain, uterine and ovarian atrophy, mucification of vaginal epithelium and reduced mammary development, all of which were attributed to its pharmacological action. Mortality was significantly lower in the treated animals. The number of animals with palpable masses was similarly reduced. The incidence of mammary tumours and hypophyseal tumours was markedly lower in 4-hydroxytamoxifen-treated animals. The incidence of chronic tubulo-interstitial nephropathies, a common cause of mortality, was also lowered. There was no evidence of a carcinogenic action of 4-hydroxytamoxifen on the liver, genital organs or skin. Plasma levels of 4-hydroxytamoxifen were stable over the duration of the study and were proportional to the administered dose, exceeding clinical plasma levels by 60-fold at the high dose-level. In conclusion, 4-hydroxytamoxifen is not carcinogenic in the rat and reduces the incidence of spontaneous mammary and hypophyseal tumours.

Topics: Administration, Cutaneous; Adrenal Glands; Animals; Blood Cell Count; Body Weight; Carcinogens; Drug Evaluation; Eating; Estrogen Antagonists; Female; Genitalia, Female; Kidney; Liver; Lung; Mammary Glands, Animal; Mammary Neoplasms, Animal; Palpation; Rats; Rats, Sprague-Dawley; Survival Rate; Tamoxifen; Thymus Gland

Topics: Animals; Body Weight; Humans; Mammary Neoplasms, Experimental; Mice; Neoplasm Transplantation; Neoplasms, Hormone-Dependent; Organ Size; Receptors, Estrogen; Tamoxifen