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PubMed2006

Use of aromatase inhibitors to increase final height.

During puberty in both sexes, the mechanism involved in epiphyseal fusion is mediated by the action of estrogen through a cascade of events including proliferation, differentiation, and apoptosis of chondrocytes. The enzyme P450 aromatase catalyzes the aromatization of C19 androgens (androstenedione and testosterone) to C18 estrogens (estrone and estradiol). Inhibition of estrogen action by aromatase inhibitors (AIs) appears to decelerate the process of growth plate fusion, and thus AIs may be used therapeutically to increase adult height. The clinical experience with AIs in the pediatric setting is limited to testolactone, fadrozole, letrozole, and anastrozole. Testolactone, a nonselective steroidal AI, has been used successfully as an adjunct to antiandrogen and gonadotropin-releasing hormone analogue (GnRHa), therapy for children with familial male-limited precocious puberty (FMPP) and congenital adrenal hyperplasia (CAH), and with some success in girls with McCune-Albright syndrome. The limitations of testolactone include its relatively low potency and the need for frequent dosing. Results of a randomized placebo-controlled trial in boys with delayed puberty treated with letrozole, a selective nonsteroidal AI, found that boys treated with letrozole + testosterone experienced delayed bone maturation and good growth response and achieved an increase in predicted adult height. In this study, only minor differences in bone density were seen between the placebo and letrozole treatment groups, both of which were receiving concomitant testosterone therapy. No adverse effects on testis size or inhibin B concentration were noted. The therapeutic value of AIs in growth promotion now remains to be substantiated in future controlled clinical trials.

Aromatase Inhibitors↗
PubMed2005

Effect of catecholestrogen administration during adriamycin-induced cardiomyopathy in ovariectomized rat.

The therapeutical beneficial effect of estrogen-derived metabolites or catecholestrogens is controversial. These molecules are produced during estrogen therapy based on 17-beta-estradiol treatment. The metabolization of 17-beta-estradiol is carried out in brain, kidney or liver, and triggers different products such as 2- and 4- hydroxyestradiol (2OH and 4OH). These products have shown antioxidant properties against oxidative stress (OS) in several experimental models. Different noxious side effects related to those metabolites have also been observed upon estrogen therapy. In this sense, catecholestrogens seem to be implicated in tumoral and mutagenic process after long treatment with estrogens substitutive therapy. In our study, we have verified that 2OH and 4OH have antioxidant and cardioprotective effects against adriamycin (AD)-induced cardiomyopathy in ovariectomized (OVX) rats. Catecholestrogens diminished the lipid peroxides and carbonyl protein (CO) content, and different enzymes related to cell injury (creatinine kinase, lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase) in cardiac tissue from OVX-, AD-, and OVX+AD-treated rats. All these changes were correlated to a recovery on reduced glutathione (GSH), glutathione peroxidase (GPx), superoxide dismutase (SOD) and catalase (CAT) in heart tissue. The present study showed that 2OH and 4OH reduced all the parameters related to OS, antioxidant depletion and cardiac injury in OVX rats treated or not with AD.

Alanine Transaminase↗
PubMed1991

Cyproterone acetate for severe hirsutism: results of a double-blind dose-ranging study.

OBJECTIVE: The objective was to determine if cyproterone acetate (CPA) therapy for hirsute women demonstrated a dose response. DESIGN: A double-blind dose-ranging study of the effect of 3 doses of cyproterone acetate for a period of 12 months. PATIENTS: Twenty-one hirsute women received the Dianette contraceptive pill (35 micrograms ethinyl oestradiol + 2 mg CPA, Schering Healthcare, UK), 20 received Dianette plus 20 mg CPA and 19 received Dianette plus 100 mg CPA: supplementary CPA was administered on days 1-10 of the birth control pill cycle as described by Hammerstein. MEASUREMENTS: Hair growth was measured using the clinical scale of Ferriman and Gallwey and by direct measurement of hair shaft diameter and linear growth of hair on the face, forearm, abdomen and thigh. RESULTS: Thirty-eight women completed 12 months therapy, eight withdrew due to side-effects and 14 were lost to follow-up. All three dose schedules produced significant reductions in clinical hair growth scores. This reduction was seen after 6 months with Dianette alone (P less than 0.005) and after 3 months with both the higher doses (P less than 0.01). There were no significant differences between the effect of different doses at any of the three-monthly time points. Hair diameter measurements were reduced by all doses after 12 months: face by 27*, 37, 37%*, forearm 5, 10, 8%*, abdomen 22*, 39*, 33%*, thigh 12, 24*, 30%* (median reductions (*P less than 0.01) for Dianette, D + 20 mg CPA and D + 100 mg CPA respectively). There were no significant reductions in daily linear growth rates. A comparison of the percentage reduction in hair shaft diameter at each site demonstrated no significant difference between doses, although the reductions by the three doses on the forearm, abdomen and thigh suggested a trend towards a dose response. CONCLUSIONS: We conclude that cyproterone acetate 2 mg daily appears to be as effective as higher doses in the therapy of hirsute women.

Adolescent↗
PubMed2005

Endocrine biomarkers in ductal lavage samples from women at high risk for breast cancer.

BACKGROUND: Ductal lavage is a method of minimal epithelial sampling of the breast, with potential utility for repeat sampling and biomarker analysis in chemoprevention studies. We report here the baseline findings from a study designed to assess the utility of ductal lavage in this setting. METHODS: Tamoxifen-eligible, high-risk women underwent ductal lavage; epithelial cell number (ECN) and morphology were assessed on Papanicolaou-stained slides. Additional slides were immunostained for estrogen receptor (ER) alpha, Ki-67, and cyclooxygenase-2, and the labeling index (LI) was established by counting negative and positive cells. The ductal lavage supernatant (DLS) was assayed for estradiol, several of its precursors, progesterone, cathepsin D, interleukin-6, and epidermal growth factor (EGF). RESULTS: One hundred sixty-eight women have entered the study (mean age, 51 years; mean 5-year Gail score, 2.8). Ductal lavage was accomplished in 145 (86.3%) women. Data were analyzed by duct and by woman (averaging data across all ducts). Mild atypia was seen in 43 of 145 (29.6%), whereas severe atypia was seen in 2 (1.4%) of women. We observed significant positive correlations between ECN and cytologic atypia, ER LI, cyclooxygenase-2 LI, and Ki-67 LI. EGF levels in supernatant were significantly associated with estrogenic precursors, ER LI and ECN. A factor representing the DLS hormone and protein variables explained 36% of the variance; total ECN was highest when factor score and ER LI were high and was lowest when both were low (P for interaction = 0.001). CONCLUSIONS: Biomarker analyses in epithelial cells and DLS are feasible. The significant associations of EGF with other markers suggest a possible role in increasing epithelial cell mass.

Biomarkers, Tumor↗
PubMed1977

The effect of 7beta, 17alpha-dimethyltestosterone (calusteron) on testosterone metabolism in women with advanced breast cancer.

Calusterone (7beta, 17alpha-dimethyltestosterone) is a 17-alkylated, orally active androgenic steroid used in the treatment of breast cancer. The effect of this steroid on the metabolism of 14C-testosterone and the excretion of endogenous urinary androgen metabolites has been studied in four patients with breast cancer. Total glucuronide metabolites of the tracer decreased significantly, the andorsterone/etiocholanolone ratio rose by a factor of 2-4, and there was increased formation of uncharacterized polar metabolites. There was no significant change in either the sum of the excretion of endogenous androgen metabolites or the androsterone/etiocholanolone ratio. The changes resemble those we have seen in cirrhosis of the liver. It is concluded that the effects of Calusterone on testosterone metabolism, like its effects on cortisol or estradiol metabolism, represent nonspecific effects of an orally administered 17-alkylated steroid on hepatic structure and function, and probably bear no relationship to its therapeutic effect in breast cancer.

Androsterone↗
PubMed1986

[Does sex hormone balance modify the pathogenesis of laryngeal cancer?].

Although there are some pointers towards dependence of pathogenesis of laryngeal cancer on hormone metabolism, proof for this assumption is still missing. We studied hormone metabolism of 43 patients with laryngeal disease (testosterone, oestradiol, FSH, LH, prolactin). We subdivided the patients into two groups: 20 patients with squamous cell carcinoma and 23 patients with non-malignant diseases. No differences were seen between the two groups on statistical evaluation of the data. We could not prove any hormonal dependence, which might have had a therapeutical impact on the administration of antiandrogen drugs.

Carcinoma, Squamous Cell↗
PubMed1985

Chromatographic pattern of circulating prolactin in ovulatory hyperprolactinemia.

Hyperprolactinemia is a major cause of anovulation and female infertility. However, we found 22 hyperprolactinemic patients with preserved ovarian function as assessed by midluteal plasma progesterone levels greater than 7 ng/ml. We performed a gel chromatography on the plasma of six of those patients to study the circulating pattern of prolactin (PRL). In all six patients we found that the vast majority of circulating PRL corresponds to big,big and big PRL, with only a small proportion of monomeric biologically active PRL. This finding might explain the preserved luteal function in those women and might have therapeutic implications.

Adult↗
PubMed1994

Emergency contraception alters progesterone-associated endometrial protein in serum and uterine luminal fluid.

OBJECTIVE: To evaluate the effect of high-dose oral contraceptives on serum and uterine luminal fluid progesterone-associated endometrial protein in the luteal phase. METHODS: Five ovulatory women participated in the study. In a control cycle, serum and uterine lavage samples were collected on luteal day 11. In the next cycle, on luteal day 9, the participants were given two 50-micrograms ethinyl estradiol-norgestrel tablets, repeated 12 hours later. Serum and uterine lavage samples were collected 48 hours (luteal day 11) after the last dose and analyzed by two-dimensional polyacrylamide gel electrophoresis and radioimmunoassays of the serum. RESULTS: Progesterone-associated endometrial protein levels were lower in sera from treated compared with control cycles. Analysis of serum levels of this protein by two-dimensional polyacrylamide gel electrophoresis did not reveal bands corresponding to the known size and charge characteristics (27 kd and pI of 4.9) in either control or treatment samples. On the other hand, in uterine lavage samples, a complete suppression of the 27-kd, pI-4.9 species was evident after treatment. CONCLUSION: High-dose ethinyl estradiol-norgestrel emergency contraception effectively suppresses progesterone-associated endometrial protein in the midluteal uterus, potentially altering the endometrial environment unfavorably and affecting the survival of the early embryo.

Contraceptives, Oral, Hormonal↗
PubMed1983

Dehydrogesterone treatment of endometrial luteal phase deficiency after ovulation induced by clomiphene citrate and human chorionic gonadotropin.

Twenty infertile patients being treated with clomiphene citrate (CC) and human chorionic gonadotropin (hCG) for induction of ovulation, with a defective endometrial secretory pattern despite normal plasma levels of progesterone, estradiol, and prolactin, were entered into treatment plans on a random basis involving the following: CC-hCG plus dehydrogesterone (group 1), and CC-hCG (group 2). Success rates were similar in both groups (20% and 30%, respectively), based on a corrected endometrial defect during the second treated cycle. It is concluded that progestational agents are of low therapeutic value in endometrial luteal phase deficiency induced by CC.

Adult↗
PubMed2001

Natural killer cells express estrogen receptor-alpha and estrogen receptor-beta and can respond to estrogen via a non-estrogen receptor-alpha-mediated pathway.

Natural killer (NK) cells play a crucial role in host defense against pathogens and immune surveillance against cancer. Given that estrogens have been reported to suppress NK cell activity, we sought to elucidate the mechanisms by which estrogen mediates this effect. We demonstrate by immunocytochemical staining with estrogen receptor-alpha (ERalpha)- and estrogen receptor-beta (ERbeta)-specific antibodies that both ERalpha and ERbeta are expressed in murine NK cells. We also compared the ability of high doses of 17beta-estradiol ( approximately 800 pg/ml) to regulate NK cell activity in wild-type and estrogen receptor-alpha-deficient (ERalphaKO) mice. 17beta-estradiol elicited a significant decrease in NK cell activity in both wild-type and ERalphaKO mice (P < 0.001). These data suggest that ERbeta or possibly a novel receptor is involved in mediating estrogen action on NK cell activity and raise the potential for therapeutic modulation of NK cell activity with selective estrogen receptor modulators (SERMS).

Animals↗
PubMed2000

Comparison of the efficacy and endometrial safety of two estradiol valerate/dienogest combinations and Kliogest for continuous combined hormone replacement therapy in postmenopausal women.

OBJECTIVE: To compare the efficacy and endometrial safety of two estradiol valerate/dienogest combinations with Kliogest in the treatment of postmenopausal symptoms. DESIGN: This was a double-blind, randomized, multicenter study. METHODS: Patients were randomized to estradiol valerate 2.0 mg/dienogest 2.0 mg (Climodien), estradiol valerate 2.0 mg/dienogest 3.0 mg (E2Val 2/DNG 3); or estradiol 2.0 mg/estriol 1.0 mg/norethisterone acetate 1.0 mg (Kliogest) once daily for 1 year. The primary efficacy variable was the Kupperman index. Endometrial safety was determined primarily by biopsy. RESULTS AND CONCLUSIONS: Climodien and E2Val 2/DNG 3 were therapeutically equivalent to Kliogest (mean changes in Kupperman index -20.1, -19.0 and -18.3, respectively). No statistically significant differences existed between treatment groups in the severity of postmenopausal symptoms. The incidences of endometrial atrophy were similar in all groups. Climodien appeared to be superior to Kliogest in terms of vaginal bleeding pattern, whereas E2Val 2/DNG 3 was associated with a slightly higher incidence and greater intensity of vaginal bleeding. The incidences of adverse events were similar in all groups. A greater proportion of women in the Kliogest and E2Val 2/DNG 3 groups experienced vaginal bleeding, whereas breast problems were more common with Climodien. Climodien and E2Val 2/DNG 3 induced desirable changes in insulin-like growth factor I (decrease) and sex hormone binding globulin (increase) that were not seen with Kliogest.

Biopsy↗