Mechanism of action and clinical effects of antiprogestins on the non-pregnant uterus.
(1/878)
Considerable progress has been made in elucidating the mechanism of action of antiprogestins. The biological response to a progesterone antagonist depends on many factors. The usual effect is that of an antagonist, but progesterone agnostic or even antioestrogenic or oestrogenic effects have also been observed. The present review focuses on the clinical applications of antiprogestins in the non-pregnant uterus. Whereas high doses of antiprogestins block ovulation, low doses impair endometrial development without affecting ovulation, hormonal levels or bleeding patterns Indeed, the endometrium is the tissue which is the most sensitive to antiprogestins. The effect of antiprogestins is to produce a delay in endometrial maturation and to postpone the appearance of the implantation window. This concept of 'endometrial contraception' requires further testing in humans, although the principle has been proven in monkeys. In contrast to the low doses of mifepristone which delay endometrial maturation, a minimum dose of 50 mg is required to produce endometrial bleeding. Late luteal phase antiprogestin administration does not disturb ovulation, hormonal levels or bleeding patterns. This has clinical application, and mifepristone has been used together with prostaglandins in women with delayed menses to successfully prevent implantation. Mifepristone has also been shown to be an effective post-coital agent. However, when used on a regular basis once monthly at the end of the cycle as a potential contraceptive, the results are disappointing. Because of their antiproliferative and anti-oestrogenic effects on the endometrium, antiprogestins are also used in the treatment of oestrogen-dependent conditions such as endometriosis and fibromyomas. In humans, chronic administration of high doses of antiprogestins has on rare occasions been associated with endometrial hyperplasia, presumably a consequence of unopposed oestrogen activity. This does not occur with low doses (1 mg daily for 5 months). (+info)
Progestins inhibit the growth of MDA-MB-231 cells transfected with progesterone receptor complementary DNA.
(2/878)
Because progesterone exerts its effects mainly via estrogen-dependent progesterone receptor (PgR), the expression of progesterone's effects may be overshadowed by the priming effect of estrogen. PgR expression vectors were transfected into estrogen receptor (ER)-alpha and PgR-negative breast cancer cells MDA-MB-231; thus the functions of progesterone could be studied independent of estrogens and ERs. Eight stable transfectant clones expressing both PgR isoform A and B were studied for their growth response to progesterone and its analogues. Although progesterone had no effect on growth in the control transfectant, the hormone markedly inhibited DNA synthesis and cell growth in all of the PgR-transfectants dose-dependently from 10(-12)-10(-6) M. This growth inhibition was associated with an arrest of cells in the G0/G1 phase of the cell cycle. Progestins medroxyprogesterone acetate, Org2058, and R5020 also strongly inhibited DNA synthesis, and their doses required for maximal inhibition of 60-70% were 10(-17) M, 10(-13) M, and 10(-7) M, respectively. Antiprogestin ZK98299 alone had no effect, but the compound was capable of counteracting the inhibitory effect of progesterone. In contrast, RU486 inhibited DNA synthesis, and it showed no further effects when it was used concurrently with progesterone. These results indicate that progestins are per se antiproliferative via a PgR-mediated mechanism in breast cancer cells. More importantly, we have shown that progestins may exert effective inhibitory control over the cell growth if the PgR expression is reactivated in ER- and PgR-negative breast cancer cells. (+info)
Health aspects of partially defatted flaxseed, including effects on serum lipids, oxidative measures, and ex vivo androgen and progestin activity: a controlled crossover trial.
(3/878)
BACKGROUND: Currently there is considerable interest in the potential health benefits of oil seeds, such as soy and flaxseed, especially in relation to cardiovascular disease and cancer. OBJECTIVE: We therefore evaluated health aspects of partially defatted flaxseed in relation to serum lipids, indicators of oxidative stress, and ex vivo sex hormone activities. DESIGN: Twenty-nine hyperlipidemic subjects (22 men and 7 postmenopausal women) completed two 3-wk treatment periods in a randomized, crossover trial. Subjects were given muffins that contributed approximately 20 g fiber/d from either flaxseed (approximately 50 g partially defatted flaxseed/d) or wheat bran (control) while they consumed self-selected National Cholesterol Education Program Step II diets. Both muffins had similar macronutrient profiles. Treatment phases were separated by > or = 2 wk. RESULTS: Partially defatted flaxseed reduced total cholesterol (4.6+/-1.2%; P = 0.001), LDL cholesterol (7.6+/-1.8%; P < 0.001), apolipoprotein B (5.4+/-1.4%; P = 0.001), and apolipoprotein A-I (5.8+/-1.9%; P = 0.005), but had no effect on serum lipoprotein ratios at week 3 compared with the control. There were no significant effects on serum HDL cholesterol, serum protein carbonyl content, or ex vivo androgen or progestin activity after either treatment. Unexpectedly, serum protein thiol groups were significantly lower (10.8+/-3.6%; P = 0.007) at week 3 after the flaxseed treatment than after the control, suggesting increased oxidation. CONCLUSIONS: These data indicate that partially defatted flaxseed is effective in lowering LDL cholesterol. No effects on lipoprotein ratios, ex vivo serum androgen or progestin activity, or protein carbonyl content were observed. The significance of increased oxidation of protein thiol groups with flaxseed consumption requires further investigation. (+info)
Hormone replacement therapy, inflammation, and hemostasis in elderly women.
(4/878)
Lipid-lowering by postmenopausal hormone therapy (HRT) explains only partly the assumed coronary risk reduction associated with therapy. To explore other possible mechanisms, we studied associations of HRT use with inflammation and hemostasis risk markers in women >/=65 years of age. Subjects were selected from 3393 participants in the fourth year examination of the Cardiovascular Health Study, an observational study of vascular disease risk factors. After excluding women with vascular disease, we compared levels of inflammation and hemostasis variables in the 230 women using unopposed estrogen and 60 using estrogen/progestin, with those of 196 nonusers selected as controls. Compared with nonusers, unopposed estrogen use was associated with 59% higher mean C-reactive protein (P<0.001), but with modestly lower levels of other inflammation indicators, fibrinogen, and alpha-1 acid glycoprotein (P<0.001). Factor VIIc was 16% higher among estrogen users (P<0.001), but this was not associated with higher thrombin production (prothrombin fragment 1-2), or increased fibrin breakdown (D-dimer). Concentration of plasminogen activator inhibitor-1 was 50% lower in both using groups (P<0.001) compared with nonusers, and this was associated with higher plasmin-antiplasmin complex: 8% higher in estrogen and 18% higher in estrogen/progestin users (P<0. 05). Relationships between the markers and hormone use were less pronounced in estrogen/progestin users, with no association for C-reactive protein except in women in upper 2 tertiles of body mass index (P for interaction, 0.02). The direction and strength of the associations of HRT use with inflammation markers differed depending on the protein, so it is not clear whether HRT confers coronary risk reduction through an inflammation-sensitive mechanism. Associations with hemostasis markers indicated no association with evidence of procoagulation and a possible association with increased fibrinolytic activity. (+info)
Low use of long-term hormone replacement therapy in Denmark.
(5/878)
AIMS: To examine individual use of hormone replacement therapy (HRT) in a defined population of Danish women during a 5-year period. HRT may reduce osteoporosis and cardiovascular disease in postmenopausal women, but may also have side-effects. Little is known about the use of HRT in most populations. METHODS: A Pharmacoepidemiological Prescription Database was used to identify all reimbursed prescriptions for HRT in the county during the period 1991 to 1995. The Danish retail pharmacies' drug subsidy system made it possible to identify prescriptions by individual use. RESULTS: We examined 255797 HRT prescriptions issued during the period in the County of North Jutland. Total sales reached 16.5 million defined daily doses (DDDs), purchased by 31653 women, which corresponds to 26.9% of the female population above the age of 39 years. The annual prevalence proportion of current users rose from 10.4% to 14.8% during the study period, and the therapeutic intensity (DDD/1000 women/day) increased from 20.6 to 32.0. The mean DDD sum of systemic HRT per user was 73.4 in 1991; it and the proportion of users who received less than 90 DDD per year (83.4% in 1991) remained almost constant during the study period. The amount of oestrogen unopposed by progestin was high, 28.1% of all prescriptions. CONCLUSIONS: Less than one-fifth of the study population used HRT for more than 3 months per year, and only 32.8% of the women who were new users of HRT in 1992 continued this therapy throughout the study period. (+info)
Combined oestrogen-progestogen replacement therapy does not inhibit low-density lipoprotein oxidation in postmenopausal women.
(6/878)
AIMS: The use of oestrogen containing hormone replacement therapy (HRT) is related to a significantly reduced atherosclerotic cardiovascular risk in postmenopausal women. Oestrogen is thought to be antioxidant and may inhibit low-density lipoprotein (LDL) oxidation in vitro. We investigated the effect of combined oestrogen and progestogen HRT on LDL oxidation in postmenopausal women. METHODS: Eighteen healthy women were given oestrogen/progestogen, and the susceptibility of LDL to oxidation was measured as the level of autoantibody to oxidative modified LDL and the production of conjugated dienes during copper-dependent oxidation after 3 and 6 months HRT. The levels of vitamin E, the major antioxidant in LDL, were also measured. RESULTS: After HRT, the anti-oxidatively modified LDL antibody level remained unchanged [1.58+/-0.16, 0.10 (-0.10, 0.26), and 0.08 (-0.09, 0.19), mean+/-s.d. at baseline, and mean change with 95% confidence intervals for differences at 3 and 6 months, respectively, P>0.05] as did the production of conjugated dienes when determined as lag phase [51.2+/-7.5, -0.3 (-3.9, 3.3), and 1.5 (-3.4, 6.4) min, P>0.05]. The LDL vitamin E content, measured as alpha-tocopherol, was also not altered [2.34+/-0.54, -0.07 (-0.27, 0.13), and -0.07 (-0.33, 0.16) nmol mg(-1) LDL, P>0.05] by treatment. CONCLUSIONS: Combined oestrogen and progestogen therapy for 6 months in postmenopausal women does not protect LDL against oxidation. (+info)
Non-transcriptional action of oestradiol and progestin triggers DNA synthesis.
(7/878)
The recent findings that oestradiol and progestins activate the Src/Ras/Erks signalling pathway raise the question of the role of this stimulation. Microinjection experiments of human mammary cancer-derived cells (MCF-7 and T47D) with cDNA of catalytically inactive Src or anti-Ras antibody prove that Src and Ras are required for oestradiol and progestin-dependent progression of cells through the cell cycle. The antitumoral ansamycin antibiotic, geldanamycin, disrupts the steroid-induced Ras-Raf-1 association and prevents Raf-1 activation and steroid-induced DNA synthesis. Furthermore, the selective MEK 1 inhibitor, PD 98059, inhibits oestradiol and progestin stimulation of Erk-2 and the steroid-dependent S-phase entry. The MDA-MB231 cells, which do not express oestradiol receptor, fail to respond to oestradiol in terms of Erk-2 activation and S-phase entry. Fibroblasts are made equally oestradiol-responsive in terms of DNA synthesis by transient transfection with either the wild-type or the transcriptionally inactive mutant oestradiol receptor (HE241G). Co-transfection of catalytically inactive Src as well as treatment with PD98059 inhibit the oestradiol-dependent S-phase entry of fibroblasts expressing either the wild-type oestrogen receptor or its transcriptionally inactive mutant. The data presented support the view that non-transcriptional action of the two steroids plays a major role in cell cycle progression. (+info)
Measuring endocrine profiles of women in field studies.
(8/878)
Improved methods are needed to evaluate the effects of occupational and environmental hazards on the reproductive health of human female populations. This communication describes highly specific, sensitive, and reliable time-resolved fluorescence immunoassays for measuring luteinizing hormone (LH) and follicle-stimulating hormone (FSH), estrone 3-glucuronide (E13G), and pregnanediol 3-glucuronide (Pd3G) in urine, a fluid that is convenient and painless to collect serially from large populations. Furthermore, some of the technical issues relevant to the successful application of these measurements to field studies are discussed. (+info)