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PubMedDate not supplied

Benefits of complete polyamine deprivation in hormone responsive and hormone resistant MCF-7 human breast adenocarcinoma in vivo.

Polyamines are ubiquitous cellular compounds which are required for estradiol induced proliferation in breast cancer. Complete polyamine deprivation, using 2 alpha-difluoromethyl-ornithine (DFMO, Eflornithine), a specific inactivator of ornithine decarboxylase (key-enzyme of the polyamine biosynthesis) combined with inhibition of the bacterial production of gastrointestinal polyamine and a polyamine free regimen, was demonstrated to exhibit a cytostatic effect and a decrease of the three tumoral polyamine concentrations in a MCF-7 tumor model. In this experiment, complete polyamine deprivation has been tested on a standard MCF-7 tumor and on a variant MCF-7 tumor (i.e. with a tamoxifen acquired resistance). Polyamine deprivation was effective on the tumor growth, both on standard and variant sub-types. The polyamine contents of two types of tumor were similar, and identically, polyamine deprivation has caused a decrease of putrescine, spermidine and also spermine tumoral concentrations measured by the HPLC method in standard and variant MCF-7 tumors. Acquired tamoxifen resistance is common in patients undergoing hormonal therapy for advanced breast cancer. It has been hypothesized that the direct stimulation of polyamine pathway without estradiol involvement could be one of the mechanisms responsible for the tamoxifen resistance. The ability of polyamine deprivation to inhibit the growth of tumors becoming tamoxifen resistant could offer a therapeutic advantage in case of tumor with acquired tamoxifen resistance and could be tested to prevent or delay the hormonal responsiveness to breast cancer.

Adenocarcinoma↗
PubMed2005

[Predominant effect of bushen ningxin decoction on postmenopausal osteoporosis in mice].

OBJECTIVE: To investigate the preventive and therapeutic effect of Bushen Ningxin decoction (BSNX) on postmenopausal osteoporosis. METHODS: The BALB/c female mice postmenopausal osteoporosis model was established. The model mice were treated by BSNX, with 17beta-estradiol (E2) and normal saline as positive and negative control, respectively. All mice were sacrificed after 12 weeks' treatment, the serum cytokines Th1/Th2, bone mineral density (BMD) of vertebrae (L3 - 4) and left femur were determined, and morphological quantitative analysis of bone tissue of right femurs was performed and osteoprotegerin (OPG) mRNA expression in tibia was detected by semi-quantitative RT-PCR. The ratio in weight of uterus to body was calculated, and uterine slice was gotten for histological observation. RESULTS: As compared with the negative control group, the level of interferon-gamma (IFN-gamma) was significantly increased (P < 0.01) and interleukin-4 (IL-4) decreased (P < 0.05) in the BSNX treated group. The BMD of mice were improved, area of bone trabecula and OPG mRNA expression were increased in the BSNX treated and E2 treated group (P < 0.01). But the uterus in the former was significantly smaller than that in the latter (P < 0.01), while it was not significantly different to that in the negative control group. CONCLUSION: BSNX can selectively prevent and cure the postmenopausal osteoporosis, it has no or slight stimulation on uterus. The mechanism may relate with its effects in regulating the deviation of Th1/Th2, enhancing the OPG expression and inhibiting the activity of osteoclasts.

Animals↗
PubMed1991

Ovulatory dysfunction.

Ovulation is the result of a perfectly balanced and coordinated function of endocrine, paracrine, and autocrine systems. Any disruption in the delicately coordinated interaction between the integrated components of the hypothalamic-pituitary-ovarian axis may lead to ovulatory dysfunction, a multifactorial entity. The widening scope of knowledge regarding physiology of the reproductive processes as well as rapid development of new diagnostic methods and therapeutic procedures necessitates the continued reassessment and identification of factors leading to ovulatory dysfunction and the design of safe therapy for this condition. The combined use of serial ultrasonography and estradiol measurements should be the standard method of ovulation induction monitoring. The identification of high-risk groups prior to the initiation of ovulation induction regimens must also be taken into consideration if we want to improve pregnancy rate and reduce the incidence of hyperstimulation to a minimal level.

Abnormalities, Drug-Induced↗
PubMed1997

[Principles of hormone replacement therapy in climacteric].

With age-specific diminished and excluded ovarian function and estrogen deficiency, 60% of females may develop various systemic disorders (the menopausal syndrome, urogenital and cardiovascular diseases, osteoporosis). In the past 10-15 years, hormone replacement treatment regimens have been developed for climacteric females. Numerous epidemiological surveys have indicated that hormone replacement therapy shows a 50% reduction in the incidence of stroke, myocardial infarction, bone fractures. Therefore, post-menopausal hormone therapy is indicated both for therapeutical and prophylactic purposes, which may increase female longevity.

Aged↗
PubMed1999

Estrogenic stimulation of hypothalamic-limbic system metabolism in ageing diabetic C57BL/KsJ mice.

The therapeutic influences of estrogen treatment on age- and diabetes-related declines in regional brain glucose utilization (RBGU) rates were evaluated in 8- to 20-week-old female C57BL/KsJ normal (+/?) and diabetic (db/db) mice. Following either oil vehicle (oil: 0.1 ml) or estradiol (E: 1 microgram/3.5 days) treatments starting at 3 weeks of age, RBGU rates were subsequently determined at 8, 12, 16 and 20 weeks of age. A gradual decline in the basal rate of brain glucose utilization was observed in all control (oil- and E-treated) groups between 8 and 20 weeks. Expression of the hyperglycemic-obese diabetes syndrome in db/db mice resulted in a significant reduction in RBGU rates between 8 and 20 weeks relative to control values. In estrogen-sensitive hypothalamic, septal and amygdaloid regions, E therapy modulated RBGU rates in db/db mice relative to oil-treated diabetics, but did not significantly alter utilization rates in +/? mice. In cortical samples, E therapy had no significant influence on glucose utilization rates in either control or diabetic groups. A noticeable pattern of maturation-associated decline in CNS glucose utilization rates in all brain regions resulted in comparable regional metabolic indices being exhibited by all groups at 20 weeks of age, with the exception of the diabetes-associated exacerbation of RBGU rates in the oil-treated db/db group. These data demonstrate that the normal development-related decline in regional brain carbohydrate metabolism is accelerated by the diabetes syndrome, and that E therapy can modulate the syndrome-associated suppression of glucose utilization in steroid-sensitive CNS loci. These data suggest that the depressive influences of the diabetes syndrome on brain carbohydrate utilization rates may be therapeutically modified in recognized CNS regions possessing steroid-sequestering, metabolically responsive neurons.

Aging↗
PubMed1982

Correlation between hormonal levels and ultrasound in patients with threatened abortion.

96 women with threatened abortion were monitored by repeated ultrasonic examinations. Simultaneously plasma HCG, progesterone, estradiol and estriol levels were measured. 12 patients with blighted ovum had hormonal levels in the low normal range before the 8th week and abnormal values after the 10th week. 31 patients had abnormal ultrasonic morphology and absence of fetal heart movements. In half of these patients, estradiol was low even before vaginal bleeding. When vaginal bleeding occurred, all subjects who aborted later, except 1, had at least one abnormal hormonal value. In 4 cases, fetal life signs were detected only after the 10th week; hormonal levels remained normal, confirming the presence of a viable fetus. 31 patients had normal ultrasounds despite vaginal bleeding and arrived to term. Hormonal profiles were also normal. 18 patients had normal ultrasounds and aborted in the second trimester of pregnancy. Some of them had low normal hormonal levels. Others had a secondary decrease in hormonal levels (most often estrogen levels) which, in some cases, preceded the abnormality of the ultrasounds. It is concluded that ultrasounds and hormonal measurements are complementary. Ultrasounds alone gave a correct prognosis in 78% of the cases after a single examination. Caution is advised when fetal life signs are absent and termination of pregnancy is contemplated. Hormonal measurements may then confirm or refute the unfavorable prognosis. Also, hormonal measurements may provide some insight as to the subsequent evolution of a threatened pregnancy, even in the presence of normal ultrasounds. The therapeutic prospect of this knowledge is, however, still to be defined.

Abortion, Spontaneous↗
PubMed2006

Inhibition of steroid sulfatase activity and cell proliferation in ZR-75-1 and BT-474 human breast cancer cells by KW-2581 in vitro and in vivo.

In the present study, we found that two hormone receptor-positive human breast cancer cell lines, ZR-75-1 and BT-474, naturally expressed steroid sulfatase (STS) protein and had catalytic activity to produce estrone from estrone sulfate (E1S) with a comparable level to those in human breast cancer tissues. E1S at physiological concentrations stimulated the growth of those cells. A novel steroidal STS inhibitor, KW-2581 inhibited the STS activity of ZR-75-1 cells with an IC(50) of 13 nM, a potency equal to or higher than that of the non-steroidal STS inhibitor, 667 COUMATE. The inhibitory effect of KW-2581 was enhanced by pre-incubation with STS enzyme, suggests being irreversible inhibition. KW-2581 inhibited the E1S-stimulated growth of ZR-75-1 cells with an IC(50) of 0.18 nM, but failed to inhibit the growth stimulated by 17beta-estradiol. Expression of E1S-induced progesterone receptors in ZR-75-1 cells was reduced by treatment of KW-2581 at concentrations as low as 0.1 nM. Oral administration of KW-2581 for 4 weeks caused tumor shrinkage in a mouse xenograft model. Tumor STS activity had been completely (>95%) eliminated by 24 hours after the last administration. These findings suggest that KW-2581 has considerable potential for therapeutic development as a novel anti-hormonal drug for treatment of breast cancer.

Animals↗
PubMed1990

The proliferative effect of "anti-androgens" on the androgen-sensitive human prostate tumor cell line LNCaP.

The effect of steroidal and nonsteroidal "anti-androgens" on the proliferative capacity of androgen-sensitive LNCaP-FGC human prostate tumor cells in culture was studied using charcoal-dextran stripped human serum-supplemented media. Cyproterone and medroxyprogesterone acetates, flutamide, hydroxyflutamide, and anandron (R23908) were administered alone at concentrations between 3 X 10(-12) and 3 X 10(-6) M. Results indicated that although medroxyprogesterone induced maximal proliferation at 3 X 10(-9) M, the other "anti-androgens" (with the exception of flutamide that was ineffective) were effective at 3 X 10(-8) M and higher concentrations; the amplitude of the proliferative response by these compounds was comparable to that elicited by estradiol-17 beta (3 to 5-fold over control). None of the anti-androgens tested triggered the shutoff effect characteristic of androgen action. When 3 X 10(-10) M DHT and the above mentioned anti-androgens were administered simultaneously, a synergistic pattern was seen; on the contrary, 3 X 10(-8) M DHT cancelled the proliferative effect of each of the anti-androgens when administered simultaneously. The relative binding affinity of these anti-androgens to androgen receptors present in LNCaP-FGC cells did not correlate well with their proliferative efficiency. The data collected were interpreted within the premises of the negative control hypotheses for the regulation of cell proliferation in metazoans. Within those premises, results became compatible with the notion that first, "anti-androgens" elicited the proliferation of androgen-sensitive cells by neutralizing the effect of a serum-borne inhibitor (androcolyone-I); this event seems not to be mediated by androgens receptors. Second, anti-androgens did not trigger a proliferative shutoff response like androgens do, i.e. the proliferative pattern induced by anti-androgens was comparable to that elicited by estrogens and progestins. Third, when administered simultaneously with 3 X 10(-10) M DHT, anti-androgens behaved synergistically. Fourth, the DHT-induced shutoff effect consistently overrode the proliferative effect generated by anti-androgens and estrogens when added alone. Finally, taken together these results raise important questions regarding the therapeutic role of anti-androgens in prostate cancer.

Androgens↗
PubMed2006

Volumetric BMD and vascular calcification in middle-aged women: the Study of Women's Health Across the Nation.

UNLABELLED: The association of spine vBMD with AC and CAC was studied in a biracial cohort of 490 middle-aged women in the Study of Women's Health Across the Nation. Lower vBMD was related to high AC, but not to CAC, independent of age and shared risk factors between osteoporosis and cardiovascular disease. INTRODUCTION: This analysis studied the association of spine volumetric BMD (vBMD) with aortic (AC) and coronary artery (CAC) calcification in middle-aged women and evaluated whether such associations were independent of age and shared risk factors between osteoporosis and cardiovascular disease (CVD) or explained by endogenous estradiol levels. MATERIALS AND METHODS: Vascular calcification and trabecular vBMD of the spine were measured using electron-beam CT in 490 women free from clinical CVD in the Study of Women's Health Across the Nation. Women were 45-58 years of age, 61% were white, and 64% were perimenopausal. Calcification scores were categorized into three levels (no AC, N = 146; moderate AC, scores = 1-74, N = 221; high AC, N = 123; no CAC, N = 256; moderate CAC, score = 1-7.54, N = 111; high CAC, N = 123). The highest categories were set at the 75th percentiles. Multinomial logistic regression was used to assess the association between vBMD (per SD) and the AC and CAC levels, with no calcification as the reference group. RESULTS: AC and CAC were detected in 70% and 48% of the population, respectively. Mean vBMD was 161.6 +/- 37.2 (SD) mg/ml. vBMD was associated with high AC in unadjusted, age-adjusted, and risk factor-adjusted analysis. Per 1 SD decrease in vBMD, the adjusted odds of high AC compared with no AC was significantly increased by 68% (95% CI, 1.06-2.68). Estradiol did not influence this association. vBMD was related to high CAC in unadjusted (OR = 1.35; 95% CI, 1.08-1.70) but not adjusted models. No associations of vBMD with moderate AC or CAC were observed. CONCLUSION: Lower vBMD was related to high AC, but not to CAC, in a biracial cohort of healthy middle-aged women independent of age and shared risk factors between osteoporosis and CVD. Further research should study possible pathophysiological links between the two conditions and the potential for common preventive and therapeutic interventions.

Bone Density↗
PubMedDate not supplied

[Short-term comparison of the treatment of precocious puberty with 2 different LHRH antagonists (buserelin and long-acting triptorelin). An endocrinologic and echographic study].

To compare the short term effects of a short (Buserelin, 1800 micrograms/day as nasal spray) and a long acting (Triptorelin Depot, 3.75 mg/every 4 weeks i.m.) LHRH agonist, LH and FSH (LHRH test and 2 hours spontaneous rhythm during the morning and during the evening), estradiol and pelvic ultrasonography were evaluated in 12 children (1 boy, mean age 8.24 +/- 1.39 years, mean bone age 9.39 +/- 1.76 years) with early puberty before and after 1 and 2 months of treatment. Informed consent was obtained in all the cases. 6 patients started with Buserelin and 6 with Triptorelin. The therapeutic regimen was crossed over after 2 months of treatment and 2 more months of treatment withdrawal. The results indicate that while in both groups FSH values decreased significantly already from the last month of treatment, patients treated with Triptorelin showed a later LH decrease (significant only after 2 months of treatment). A decrease of pelvic structures volume was however evident only in patients treated with Triptorelin. After 2 months of treatment estradiol levels lowered (but not significantly) in both group. In conclusion despite a later LH decrement, patients treated with the long acting analogue showed however a more evident reduction of pelvic organs volume.

Buserelin↗
PubMed2002

Review of estrone sulfatase and its inhibitors--an important new target against hormone dependent breast cancer.

A high proportion (approximately 40%) of breast cancers are hormone dependent. The female hormones estradiol and androstenediol are believed to play a key role in the initiation and promotion of this disease. In the fight against hormone dependent breast cancers, extensive research has been undertaken to produce compounds which are potent inhibitors against the cytochrome P-450 enzyme aromatase (AR), which converts the C19 androgens to the C18 estrogens. However, the administration of AR inhibitors alone has failed to produce the expected decrease in plasma levels of estrone. The major impetus to the development of steroid sulfatase inhibitors has therefore been the realisation that in order to improve therapeutic response for women with hormone-dependent breast cancer, not only must the AR enzyme be inhibited, but also the synthesis of estrogens via alternative routes. The steroid sulfatase enzyme regulates the formation of estrone (which can subsequently be converted to the potent estrogen estradiol) from estrone sulfate, a steroid conjugate present in high concentrations in tissue and blood in women with breast cancer. The sulfatase enzyme system also controls the formation of dehydroepiandrosterone (DHEA) from the DHEA-sulfate. This is important since DHEA can be converted to 5-androstene-3 beta,17 beta-diol, which possesses estrogenic properties capable of stimulating the growth of breast cancer cells in vitro and in vivo. Considerable progress has been made in recent years in the development of a number of potent steroid/estrone sulfatase inhibitors, as such both steroidal and non-steroidal compounds have been considered and a number of highly potent inhibitors have been produced and evaluated against what is now considered a crucial enzyme in the fight against hormone dependent breast cancer. The review therefore considers the work that has been undertaken to date, as well as possible future development with respect to dual inhibitors of both estrone sulfatase and AR.

Antineoplastic Agents↗
PubMed1997

[Comparative study of the acceptability of a new estradiol Tx 11323 (A) gel and a transdermal matrix system].

OBJECTIVE: to compare the acceptability of a new estradiol gel TX 11323 (A) and a transdermal matrix system. METHOD: this randomised open crossed study was conducted on 80 healthy menopausal female volunteers treated successively with 1.5 mg of estradiol per day in gel form (Estreva Gel, Theramex, Monaco) and by a transdermal matrix twice-weekly system delivering 50 micrograms/24 h of estradiol (Oesclim 50, Fournier, Dijon-France). The treatment was applied for 25 days with an interval of 6 days between the 2 administration cycles. Acceptability was evaluated and compared by a self-questionnaire given on D1 and D25 of each therapeutic cycle. RESULTS: the 2 treatments, after 25 days of use, were judged convenient, easy and fast to use by more than 90% of subjects. There was, nevertheless, a significant difference in favour of the gel in respect of the estimation of the "visual aspect" of the treatment, reported skin problems, problems with application technique, as well as discomfort during intimacy found in 11% of cases using the transdermal system. It is noted that 80% of the women consider the gel treatment more feminine (p < 0.001) and that 61.3% prefer this treatment compared to 32.5% preferring the transdermal system studied (p = 0.005). CONCLUSION: this study shows a better acceptability of the estradiol gel TX 11323 (A) compared to that of the transdermal matrix system studied.

Administration, Cutaneous↗
PubMed1987

Sensitivity differences in reproductive/endocrine organs to chronically administered LHRH agonists in female rats.

The acute and chronic effects of two LHRH agonists on reproductive endocrine target organs were examined in female rats. Animals were injected twice daily with [(ImBzl)-D-His6,Pro9-NEt]LHRH (histrelin) or [D-Trp6,Pro9-NEt]LHRH for 1, 3, 5, 7, 11 or 28 days at 1, 10, 100 or 1000 micrograms/kg/day beginning in the luteal phase. The responses observed with the two agonists were similar. An initial stimulatory phase was observed on the first day of treatment with substantial increases in serum LH and progesterone levels. A significant diminution of hormone response was seen by day 3. Only 1000 micrograms/kg abolished the pituitary LH response at later treatment periods. Estrous cyclicity, ovarian and uterine weight, and progesterone and estradiol levels were inhibited in a time and dose dependent manner. The results demonstrate target organ sensitivity differences. In contrast to the relatively high doses needed to inhibit the pituitary response and decrease ovarian weight, doses as low as 1 microgram/kg were sufficient to decrease uterine weight. If these findings extrapolate to humans, it may be that conditions in which the desired therapeutic action is suppression of uterine tissue, may be treated with lower doses of LHRH agonists than conditions requiring complete gonadal suppression.

Adrenal Glands↗