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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Progesterone is a major hormone controlling normal breast development and function. In breast cancer, progesterone may be involved in tumor growth regulation, and the concentration of the intracellular receptor proteins for progesterone are used to distinguish hormone dependent from autonomous tumors. We have been studying the cytoplasmic and nuclear distribution of progesterone receptors after progesterone treatment of cultured T47Dco human breast cancer cells. Anomalous behavior of the receptors, when progesterone was compared to synthetic progestins, suggested that progesterone was being rapidly metabolized by the cells. We have now studied this metabolism in detail. When progesterone is added to medium of proliferating cells, it disappears with a half life of 2-4 h. A single metabolite (P-metabolite) is quantitatively released into the medium, but its release is delayed 10-14 h. The quantitative conversion of progesterone to P-metabolite was confirmed using two independent methods: gas chromatography with internal standards, and 14C-radioisotope measurements. We have used gas chromatography, gas chromatography/mass spectrometry, thin layer chromatography and nuclear magnetic resonance to identify the final metabolic product released into the medium as 5 alpha-pregnan-3 beta,6 alpha-diol-20-one.
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PMID:Progesterone metabolism in T47Dco human breast cancer cells--I. 5 alpha-pregnan-3 beta,6 alpha-diol-20-one is the secreted product. 379 43

There is renewed interest in the use of progestins to treat advanced breast cancer because results with these agents are comparable to those obtained with antiestrogens. However, it is not known whether progestins inhibit the growth of breast tumor cells directly and independently of estradiol. To study this, we have used T47DCO human breast cancer cells. The progesterone receptors in these cells do not require estrogen induction, and this permits study of pure progestin effects without interference by estradiol. We report here that, in the absence of estradiol, physiological concentrations of progestins directly inhibit proliferation of these cells. At the same time, progestins increase the levels of the receptors for insulin, a common cell mitogen. Ten days of treatment with 1 or 10 nM of the synthetic progestin R5020 suppresses cell growth approximately 50 to 60%. This is consistent with the concentrations that either partially (approximately 10%) or more extensively (greater than 60%) translocate cytoplasmic progesterone receptors. Even a brief 1-hr pulse of R5020 has long-term growth-inhibitory effects. Progesterone is also antiproliferative, but its effects are attenuated because, unlike R5020, it is rapidly metabolized in the medium. Other synthetic progestins also inhibit cell growth, but unrelated steroids (estradiol, androgens, glucocorticoids, 1,25-dihydroxyvitamin D3) are ineffective. While growth is suppressed by R5020, insulin receptors increase rapidly and then fall to a new, elevated steady state as the cells slowly begin to proliferate. Only progestins have this effect on insulin receptors. We conclude that the hormonal regulation of breast tumor cell growth is complex and includes progestins among the regulating factors. Furthermore, since T47Dco cells are antiestrogen-resistant and estrogen receptor-negative, the antiproliferative effects of progestins must be mediated through mechanisms that differ from the cytotoxic effects of antiestrogens. We propose that, clinically, antiestrogens and progestins may have complementary uses in breast cancer treatment, and we outline two therapeutic strategies.
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PMID:Growth inhibition and increase of insulin receptors in antiestrogen-resistant T47DCO human breast cancer cells by progestins: implications for endocrine therapies. 383 85

Progestin, estrogen, androgen, glucocorticoid as well as mineralocorticoid receptors (PR, ER, AR, GR and MR, respectively) were all evaluated with specific synthetic radioligands (biochemical assays) in 25 meningiomas, 9 gliomas and 4 brain metastases. In meningiomas the main steroid hormone receptors appeared to be the progestin receptor, present in 24/25 cases (mean level: 7 105 fmol/gT) and the androgen receptor, present in 23/25 cases (mean level: 2 265 fmol/gT). Progestin receptor levels were found to be significantly lower in meningiomas of the fibroblastic subtype whereas none of the steroid hormone receptors were detected in the anaplastic case. On the other hand, glucocorticoid receptor levels were related to the preoperative glucocorticoid therapy. In gliomas only estrogen receptors (2/9 cases) and especially androgen receptors (8/9 cases) were noticeable: the latter seemed to be related to the histological types and to the sex of patients. No receptors were found in any of the four studied metastases, including one from breast cancer. The biochemical characterization of the receptors as well as their relevance to tumor biology and to the physiology of the normal tissues where tumors arise, were discussed, and biochemical data were compared with those previously reported.
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PMID:Steroid hormone receptors in human meningiomas, gliomas and brain metastases. 608 14

Twenty-three evaluable patients with advanced breast cancer were treated with MPA, 1,400 mg/m2 daily PO for the first 6 months, and 500 mg/m2 daily PO thereafter. The median total dose was 191,400 mg in 88 days, with the maximum dose given to date 522,600 mg in 282 days. Most patients tolerated high-dose MPA well. Side-effects were minimal and reversible. The commonest side-effects were tremor or edema. The CR plus PR rate was five of 23 (22%). All responding patients were over 50 years of age and had a good performance status. Hormone receptor status was known in four patients only, so that no correlation between receptor status and response could be drawn. MPA appears to be a useful hormone for use in the management of breast cancer. Optimal dosage remains to be determined.
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PMID:A phase II study of high-dose medroxyprogesterone acetate in advanced breast cancer. 622 3

Twenty-six patients with metastatic breast cancer were treated with high dose medroxyprogesterone acetate (MAP) p.o. according to currently available pharmacokinetic data (2000 mg/day b.i.d. for 30 days, 1000 mg/day for the following 60 days). Objective response (WHO criteria) was obtained in seven patients (CR + PR = 27%), with good results on visceral and soft tissue localizations; performance status improvement and/or pain relief was obtained in twenty-three (88%). Oral high dose MPA seems to be an effective and well tolerated palliative treatment in advanced breast cancer.
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PMID:Oral route administration of medroxyprogesterone acetate (MAP) at high doses in the treatment of advanced breast cancer: clinical results. 624 48

Estrogen and progesterone receptors were measured in cystosols prepared from 32 normal ovaries and 25 benign and 49 malignant ovarian tumors. In normal ovarian tissue, estrogen and progesterone receptors were detected in 22 and 75% of specimens, respectively. Estrogen receptors were present in low concentrations ranging from 2 to 9 fmol/mg cytosol protein. The estrogen receptor content and distribution were similar in benign tumors (20%), but progesterone receptors were significantly decreased in 16% of specimens (P less than 0.001). In malignant ovarian tissues, estrogen receptors were present in 57% of specimens in concentration ranging from 1 to 132 fmol/mg cytosol protein. Of these, 72% of tissues had estrogen-receptor concentrations greater than 10 fmol/mg cytosol protein. The presence of estrogen receptors in ovarian cancer was significantly different from normal ovaries and benign tumor tissues (P less than 0.01). Progesterone receptors were detectable in 29% of ovarian cancer specimens. Estrogen and progesterone receptors were present alone or in combination, in 65% of ovarian cancers. The similarity in sex steroid content between ovarian and breast cancer warrants prospective studies of sex steroid receptor content in ovarian malignancies as a possible predictive index of survival and response to hormone therapy.
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PMID:Estrogen and progesterone receptors in human ovarian tumors. 631 94

The effects of oral MPA, 300 mg t.i.d., on adrenal function in postmenopausal patients with disseminated breast cancer were evaluated. The levels of serum cortisol, ACTH, androstenedione, DHEA-S, LH, FSH, GH, and prolactin in 22 patients receiving MPA were compared with those in another group of 28 postmenopausal patients in whom levels were measured before treatment. The median morning cortisol level was 70, 10-465 nmol/l (controls 395, range 155-785 nmol/l), median androstenedione 1.09, range 0.55-3.10 nmol/l (controls 3.75, range 1.23-9.81 nmol/l), and median DHEA-S 555, range 55-1,300 nmol/l (controls 2,440, range 1,015-6,340 nmol/l). No appreciable change in ACTH levels was found. Gonadotropins were also markedly suppressed. The median LH level was 4.3 (range 0.8-18) U/l, as against 83 (range 19-116) U/l in controls. The median FSH level was 7.2 (range 0.5-27) U/l, as against 71 (range 12-262) U/l in controls. Prolactin and GH levels remained largely unchanged. The suppression of androstenedione synthesis, the main precursor of postmenopausal estrogens, may represent the major therapeutic effect of high-dose MPA in postmenopausal patients with breast cancer.
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PMID:Adrenal suppression by oral high-dose medroxyprogesterone acetate in breast cancer patients. 632 Oct 47

Blood clotting, platelet aggregation, complete blood count and lipid profile were evaluated in 12 postmenopausal patients with advanced breast cancer. Patients under treatment with high-dose MPA were considered not at risk for thomboembolic disease and were given MPA orally, 800 mg/day, for at least 3 months. Laboratory investigations were performed prior to treatment with MPA then once weekly during the first month and every 2 weeks during the following months. PTT, TEG, antithrombin III and platelet adhesiveness underwent statistically significant changes, tending towards hypercoagulability, although, on the average, they did not exceed the upper normal range. The authors conclude that a clinically relevant thrombotic activity cannot be attributed to MPA at the administered oral doses in the absence of additional risk factors.
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PMID:Hematologic parameters during treatment with high-dose medroxyprogesterone acetate. 645 98

In this discussion of Depo-Provera (DMPA) attention is directed to the following: pharmacology and mode of action; clinical considerations; cervical dysplasia; breast cancer; and endometrial carcinoma. DMPA, a microcrystalline suspension of medroxy-progesterone acetate, is used widely around the world as a contraceptive, particularly in developing countries. MPA (medroxy-progesterone acetate) is a synthetic progesterone which in its mycrocrystalline depot form can be delivered by simple intramuscular injection or jet injector to that depending on the dose administered plateau contraceptive blood levels will be maintained for 90-180 days when doses of 150 mg and 300 mg respectively are used. The effect of DMPA in suppressing ovulation is at the hypothalmic level where it inhibits the gonadotrophic release responsible for the midcycle surge in luteinizing hormone responsible for ovulation. When 150 mg is administered every 3 months pregnancy rates range from 0.0-1.2/100 women years. The pregnancy rates range from 0.0-3.8/100 women years when 300 mg is administered every 6 months. The drug is usually administered initially in the first 7 days of the menstrual cycle to avoid possible effects on an established pregnancy. Menstrual disturbances are the major reason for discontinuation of DMPA. The usual side effects are amenorrhea, irregular but infrequent bleeding, and a few instances of prolonged or heavy bleeding. There is no evidence to suggest that DMPA increases the risk of invasive cancer of the cervix, but the evidence regarding the incidence of cervical dysplasia is ambiguous. There have not been any cases of breast cancer that can be related to DMPA use, but DMPA toxicology studies on beagle bitches revealed an increased incidence of benign and malignant breast tumors. It is well established that in adenocarcinoma of the endometrium DMPA is effective in causing regression and preventing recurrence of this tumor.
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PMID:Depo provera in perspective. 646 84

4 kinds of progestin only oral contraceptives (OCs) and numerous combined OCs containing ethinyl estradiol (EE) or occasionally mestranol and either norgestrel or norethindrone are currently available in Australia. All progestins except norgestrel are effective in vivo after metabolism to norethindrone. Mestranol is effective in the human after demethylation to EE. The main side effects of OCs, including menstrual disturbances and changes in weight and mood, are primarily of nuisance value. Menstrual blood loss with OCs is almost invariably less than during spontaneous menses, but breakthrough bleeding and midcycle spotting may cause concern in patients. Amenorrhea and weight gain are rare with low dose pills. Approximately 6 in 1000 women remain anovulatory for 12 months or more after discontinuing OCs, but it is not yet know whether the amenorrhea is related to pill use and it is usually corrected by induction of ovulation. Cardiovascular side effects including venous thrombosis and pulmonary embolism are seen less frequently with new lower dose pills. The effects of OCs on the cardiovascular system are complex and depend on the interaction of estrogen and progestin. Amounts of estrogen and progestin should be the lowest possible to prevent ovulation, and routine monitoring should be provided for all women using pills. Older high dose formulations altered lipid metabolism in the direction of greater risk of coronary heart disease. Although research suggests the lowest dose triphasic pills have no significant effect, not enough large studies have been done with matched controls. Any effects on carbohydrate metabolism of the low dose pills are apparently minor and of little clinical significance. Insulin dependent diabetics with adequate supervision may safely use low dose pills. Combined OCs reduce the incidence of endometrial and ovarian malignancy. No relationship between OCs and the risk of breast cancer has been demonstrated except possibly in women under 35 when the cancer developed. The risk of intraepithelial neoplasia may be increased in women taking OCs for more than 8 years. Data on drug interactions are inconclusive, but women on rifampicin should use some other method. Absolute contraindications to OCs include breast cancer, history of deep venous thrombosis or pulmonary embolism, active liver disease, use of rifampicin, familial hyperlipidemia, previous arterial thrombosis, and pregnancy, while relative contraindications include smoking, age over 35, hypertension, breastfeeding, and irregular spontaneous menstruation. Progestin only OCs have a higher rate of failure and irregular bleeding than combined pills and their main use is for breastfeeding women and those with contraindications to estrogen. The pill of 1st choice should be a triphasic low-dose formulation.
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PMID:Oral contraceptives. 650 52


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