Hormonal modulation of interleukin-6, tumor necrosis factor and associated receptor secretion in postmenopausal women

Hormone replacement therapy (HRT) reduces the risk for osteoporosis but transiently increases cardiovascular risk for some postmenopausal women. This study investigated the hypothesis that these risks are associated with HRT-induced changes in mononuclear cell secretion of interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), and associated soluble receptors. Compared to the untreated condition (n=8), estrogen therapy (n=7) and estrogen+progestin therapy (n=7) both caused 2-fold elevations in TNF-alpha secretion. IL-6 secretion was increased (48%, P=0.04) only by estrogen+progestin therapy. Although soluble receptor secretion was not different among groups, soluble TNF receptor type I and IL-6 receptor secretion were inversely related to plasma follicle stimulating hormone (P<0.05). Both therapies reduced plasma osteocalcin (a marker for osteoporosis) by approximately 50% (P<0.002). Plasma C-reactive protein (CRP, a marker for cardiovascular risk) was 3-fold higher in women receiving only estrogen, compared to untreated women (P=0.01), and twice as high as those receiving estrogen+ progestin (P=0.045). Simple linear relationships were not observed between cytokine secretion and these markers, but a significant HRT/TNF-alpha interaction with osteocalcin (P=0.022) and an HRT/IL-6 interaction with CRP (P =0.016) indicated more complex relationships between hormone replacement, cytokine activity, and health risks associated with menopause.     

Chronic hormone replacement therapy alters thermoregulatory and vasomotor function in postmenopausal women

Brooks, E. M., A. L. Morgan, J. M. Pierzga, S. L. Wladkowski, J. T. O'Gorman, J. A. Derr, and W. L. Kenney. Chronic hormone replacement therapy alters thermoregulatory and vasomotor function in postmenopausal women. J. Appl.Physiol. 83(2): 477-484, 1997.This investigationexamined effects of chronic (2 yr) hormone replacement therapy (HRT),both estrogen replacement therapy (ERT) and estrogen plus progesteronetherapy (E+P), on core temperature and skin blood flow responses ofpostmenopausal women. Twenty-five postmenopausal women [9 not onHRT (NO), 8 on ERT, 8 on E+P] exercised on a cycle ergometer for1 h at an ambient temperature of 36°C. Cutaneous vascularconductance (CVC) was monitored by laser-Doppler flowmetry, and forearmvascular conductance (FVC) was measured by using venous occlusionplethysmography. Iontophoresis of bretylium tosylate was performedbefore exercise to block local vasoconstrictor (VC) activity at oneskin site on the forearm. Rectal temperature (T_re) was ~0.5°C lower forthe ERT group (P < 0.01) comparedwith E+P and NO groups at rest and throughout exercise. FVC: mean body temperature (T_b) and CVC:T_b curves were shifted~0.5°C leftward for the ERT group(P < 0.0001). Baseline CVC wassignificantly higher in the ERT group(P < 0.05), but there was nointeraction between bretylium treatment and groups once exercise wasinitiated. These results suggest that1) chronic ERT likely acts centrally to decrease T_re,2) ERT lowers theT_re at which heat-loss effector mechanisms are initiated, primarily by actions on active cutaneous vasodilation, and 3) addition ofexogenous progestins in HRT effectively blocks these effects.

     

Adrenal and gonadal steroids inhibit IL-6 secretion by human marrow cells

Adrenal and gonadal steroids have protective effects on the skeleton that may be conferred partly by their ability to inhibit bone resorptive cytokines such as interleukin 6 (IL-6). We tested the hypothesis that IL-6 secretion by human marrow cells and a line of marrow stromal cells (KM101) is inhibited by dehydroepiandrosterone (DHEA), dihydrotestosterone (DHT) and 17beta-oestradiol (E(2)). We also examined whether the estrogen status of the donor influenced the steroids' effects on IL-6 secretion. Femoral bone marrow was obtained from 19 postmenopausal women undergoing hip arthroplasty, and from seven subjects receiving oestrogen replacement therapy (ERT) at the time of surgery. Low-density mononuclear cells were isolated and cultured in IL-1beta-supplemented media, with or without DHEA, DHT or E(2). DHEA suppressed IL-6 more consistently than DHT or E(2): DHEA significantly suppressed IL-6 in 84% of cultures, DHT suppressed IL-6 in 58%, and E(2)did so in 50%. The magnitude of IL-6 inhibition was also greater for DHEA (group mean, treated/control of 62%) compared to DHT (81%) and E(2)(76%). In cultures from subjects receiving ERT, DHEA and DHT suppressed IL-6 in some, whereas E(2)did not suppress IL-6 secretion. Each steroid also significantly inhibited IL-6 secretion by KM101 cells. In summary, in marrow cultured from postmenopausal women, DHEA suppressed IL-6 secretion more consistently and to a greater degree than did DHT and E(2). Second, the inhibitory effect of E(2)was abrogated in marrow from women receiving ERT.     

Thermoregulation in the cold after physical training at different ambient air temperatures

Since human thermoregulation at rest is altered by cold exposure, it was hypothesized that physical training under cold conditions would alter thermoregulation. Three groups (n = 8) of male subjects (mean age 24.3 +/- 0.9 years) were evaluated: group T (interval training at 21 degrees C), group CT (interval training at 1 degrees C), and group C (no training, equivalent exposure to 1 degrees C). Each group was submitted, before and after 4 weeks of interval training (5 d/week), to a cold air test at rest (SCAT) (dry bulb temperature (Tdb) = 1 degrees C) for a 2-h period for evaluation of the thermoregulatory responses. During SCAT, after the training/acclimation period, group T exhibited a higher rectal temperature (Tre) (P < 0.05) without significant change in mean skin temperature (Tsk) whereas metabolic heat production (M) was higher at the beginning of the SCAT (P < 0.05). For group CT, no thermoregulatory change was observed. Group C showed a lower Tre (P < 0.05) without significant change in either Tsk or in M, suggesting the development of a hypothermic general cold adaptation. This study showed, first, that the cold thermoregulatory responses induced by an interval training differed following the climatic conditions of the training and, second, that this training performed in the cold prevented the development of a general cold adaptation.     

Hormone replacement therapy and cardiovascular disease: lessons from a monkey model of postmenopausal women

Concerns exist about the cardiovascular effects of hormone replacement therapy (HRT) in postmenopausal women because results from the Women's Health Initiative (WHI) and the Heart and Estrogen/Progestin Replacement Study (HERS) are contradictory. In both of these studies, postmenopausal conjugated equine estrogens + medroxyprogesterone acetate did not reduce risk, and somewhat increased the risk of myocardial infarction in both primary (WHI) and secondary (HERS) prevention. These results appear to contradict numerous observational clinical trials and animal studies, which reported profound beneficial effects of HRT on cardiovascular disease risk. Results of both human and monkey studies indicate that estrogen replacement therapy (ERT)/HRT is effective in inhibiting progression of early stage (fatty streak) atherosclerosis but that ERT/HRT is much less effective in inhibiting progression of more advanced (established plaque) atherosclerosis. Results of these monkey studies are consistent with those of studies in women wherein ERT/HRT was initiated in postmenopausal women with different initial amounts of atherosclerosis. Based on these findings, it is speculated that ERT/HRT may be more cardioprotective in younger postmenopausal women with less coronary artery disease, and less effective in women with established coronary artery disease. Researchers are challenged to define the relative cardiovascular risk/benefit in different populations of postmenopausal women based on differences in age, amounts of pre-existing atherosclerosis, and risk factors.     

Effect of hormone replacement therapy on the production of bone-resorbing cytokines by peripheral blood cells in postmenopausal women.

We studied the effects of hormone replacement therapy (HRT) with estrogen on postmenopausal changes in the production of bone-resorbing cytokines interleukin 1 beta (IL-1beta) and tumor necrosis factor alpha (TNFalpha). Both cytokines were measured in the supernatants of lipopolysaccharide (LPS)-stimulated whole-blood cells from 72 untreated and 44 HRT-treated women by ELISA. The levels of IL-1beta were significantly higher in women in their 40s and 50s and in postmenopausal women than in women in their teens, 20s and 30s, while the levels of TNFalpha did not show any changes related to age. Both levels in HRT-treated women were significantly lower than those in untreated women at almost every postmenopausal stage. In a prospective study, HRT induced significant declines in both levels. These results show that estrogen decreases the accelerated production of IL-1beta and reduces the production of TNFalpha in postmenopausal women at each postmenopausal stage, even in late-postmenopausal women.     

Estrogen modifies the temperature effects of progesterone.

To test the hypothesis that progestin-mediated increases in resting core temperature and the core temperature threshold for sweating onset are counteracted by estrogen, we studied eight women (24 +/- 2 yr) at 27 degrees C rest, during 20 min of passive heating (35 degrees C), and during 40 min of exercise at 35 degrees C. Subjects were tested four times, during the early follicular and midluteal menstrual phases, after 4 wk of combined estradiol-norethindrone (progestin) oral contraceptive administration (OC E+P), and after 4 wk of progestin-only oral contraceptive administration (OC P). The order of the OC P and OC E+P were randomized. Baseline esophageal temperature (T(es)) at 27 degrees C was higher (P < 0.05) in the luteal phase (37.08 +/- 0.21 degrees C) and in OC P (37.60 +/- 0.31 degrees C) but not during OC E+P (37.04 +/- 0.23 degrees C) compared with the follicular phase (36.66 +/- 0.21 degrees C). T(es) remained above follicular phase levels throughout passive heating and exercise during OC P, whereas T(es) in the luteal phase was greater than in the follicular phase throughout exercise (P < 0.05). The T(es) threshold for sweating was also greater in the luteal phase (38.02 +/- 0.28 degrees C) and OC P (38.07 +/- 0.17 degrees C) compared with the follicular phase (37.32 +/- 0.11 degrees C) and OC E+P (37.46 +/- 0.18 degrees C). Progestin administration raised the T(es) threshold for sweating during OC P, but this effect was not present when estrogen was administered with progestin, suggesting that estrogen modifies progestin-related changes in temperature regulation. These data are also consistent with previous findings that estrogen lowers the thermoregulatory operating point.     

Catecholestrogens excretion in smoking and non-smoking postmenopausal women receiving estrogen replacement therapy

Estrogens are involved in the etiology of breast cancer. Their blastomogenic influence may be partly realized through their conversion into catecholestrogens, rate of which may be modified by smoking. The risk of having breast cancer diagnosed can increase in women using estrogen replacement therapy (ERT). The principal aim of this investigation was to compare the excretion of classical estrogens and catecholestrogens in smoking and non-smoking postmenopausal women receiving Progynova (estradiol valerate, 2 mg/day, 1 month). Total 16 women were studied before and after treatment. Urinary estrogen profile method based on isotope dilution capillary gas chromatography-mass spectrometry was used. Before ERT, significantly lower excretion of 16-epiestriol and 4-hydroxyestrone (4-OHE1) and lower ratio of 4-OHE1/E1 were revealed in smokers. After ERT, much higher excretion of 2-OHE1, and 4-hydroxyestradiol (4-OHE2), higher ratios of 2-OHE1/E1 and 4-OHE1/E1 and lower ratio of 2-methoxyestrone/2-OHE1 were discovered in smokers as compared to non-smoking women. In conclusion only combination of ERT + smoking and not smoking itself leads to the specific prevalence of catecholestrogens (2-OH- and carcinogenic and DNA-damaging 4-OH-metabolites) that may increase risk of genotoxic variant of hormone-induced breast carcinogenesis without influence on the total morbidity.     

Thermoregulation and the effect of body temperature on call temporal parameters in the cicada Diceroprocta olympusa (Homoptera: Cicadidae)

We investigated the thermoregulatory behavior, thermal responses (minimum flight, maximum voluntary tolerance and heat torpor temperatures) and the effect of body temperature (T(b)) on call parameters in the cicada Diceroprocta olympusa (Walker). Regression of T(b) as a function of ambient (T(a)) or perch temperatures (T(p)) suggests thermoregulation is occurring. Thermoregulation occurs through behavioral changes that alter the uptake of solar radiation. T(p) is a better predictor of T(b) than is T(a). Thermal responses (minimum flight temperature 20.4 degrees C, maximum voluntary tolerance temperature 37 degrees C, and heat torpor temperature 46.7 degrees C) may be related to the humid, grassland habitat of the species. In contrast to other acoustic insects, no significant relationship was found between the temporal parameters of the calling song and T(b) within the population of D. olympusa.     

Heterothermy in two mole-rat species subjected to interacting thermoregulatory challenges

Maintaining a high and constant body temperature (T(b) ) is often viewed as a fundamental benefit of endothermy, but variation in T(b) is likely the norm rather than an exception among endotherms. Thus, attempts to elucidate which factors cause T(b) of endotherms to deviate away from the T(b) that maximizes performance are becoming more common. One approach relies on an adaptive framework of thermoregulation, used for a long time to predict variation in T(b) of ectotherms, as a starting point to make predictions about the factors that should lead to thermoregulatory variation in endotherms. Here we test the predictions that when confronted with thermoregulatory challenges endotherms should (1) become more heterothermic, (2) lower their T(b) setpoint, and/or (3) increase behavioral thermoregulation (e.g., activity levels or social thermoregulation). We exposed two species of relatively homeothermic mole-rats to two such challenges: (a) ambient temperatures (T(a)) well below the thermoneutral zone and (b) increased heat loss caused by the removal of dorsal fur. In general, our results support the adaptive framework of endothermic thermoregulation with each species conforming to some of the predictions. For example, Mashona mole-rats (Fukomys darlingi) increased heterothermy as T(a) decreased, highveld mole-rats (Cryptomys hottentotus pretoriae) displayed lower T(b) 's after shaving, and both species increased behavioral thermoregulation as T(a) decreased. This suggests that there is some merit in extending the adaptive framework to endotherms. However, none of the three predictions we tested was supported under all experimental conditions, reiterating that attempts to determine universal factors causing variation in T(b) of endotherms may prove challenging.     

Thermoregulation by kangaroos from mesic and arid habitats: influence of temperature on routes of heat loss in eastern grey kangaroos (Macropus giganteus) and red kangaroos (Macropus rufus)

We examined thermoregulation in red kangaroos (Macropus rufus) from deserts and in eastern grey kangaroos (Macropus giganteus) from mesic forests/woodlands. Desert kangaroos have complex evaporative heat loss mechanisms, but the relative importance of these mechanisms is unclear. Little is known of the abilities of grey kangaroos. Our detailed study of these kangaroos' thermoregulatory responses at air temperatures (T(a)) from -5 degrees to 45 degrees C showed that, while some differences occur, their abilities are fundamentally similar. Both species show the basic marsupial characteristics of relatively low basal metabolism and body temperature (T(b)). Within the thermoneutral zone, T(b) was 36.3 degrees + or - 0.1 degrees C (X + or - SE) in both species, and except for a small rise at T(a) 45 degrees C, T(b) was stable over a wide range of T(a). Metabolic heat production was 25% higher in red kangaroos at T(a) -5 degrees C. At the highest T(a) (45 degrees C), both species relied on evaporative heat loss (EHL) to maintain T(b); both panting and licking were used. The eastern grey kangaroo utilised panting (76% of EHL) as the principal mode of EHL, and while this was so for red kangaroos, cutaneous evaporative heat loss (CEHL) was significant (40% of EHL). CEHL appeared to be mainly licking, as evidenced from surface temperatures. Both species utilised peripheral vascular adjustments to control heat flow, as indicated by changes in dry conductance (C(dry)). At lower temperatures, C(dry) was minimal, but it increased significantly at T(a) just below T(b) (33 degrees C); in these conditions, the C(dry) of red kangaroos was significantly higher than that of eastern grey kangaroos, indicating a greater reliance on dry heat loss. Under conditions where heat flows into the body from the environment (T(a) 45 degrees C), there was peripheral vasoconstriction to reduce this inflow; C(dry) decreased significantly from the values seen at 33 degrees C in both kangaroos. The results indicated that, while both species have excellent thermoregulatory abilities, the desert red kangaroos may cope better with more extreme temperatures, given that they respond to T(a) 45 degrees C with lower respiratory evaporation than do the eastern grey kangaroos.     

Estrogen replacement in middle-aged women: thermoregulatory responses to exercise in the heat.

Thermoregulatory, cardiovascular, and body fluid responses during exercise in the heat were tested in five middle-aged (48 +/- 2 yr) women before and after 14-23 days of estrogen replacement therapy (ERT). The heat and exercise challenge consisted of a 40-min rest period followed by semirecumbent cycle exercise (approximately 40% maximal O2 uptake) for 60 min. At rest, the ambient temperature was elevated from a thermoneutral (dry bulb temperature 25 degrees C; wet bulb temperature 17.5 degrees C) to a warm humid (dry bulb temperature 36 degrees C; wet bulb temperature 27.5 degrees C) environment. Esophageal (Tes) and rectal (Tre) temperatures were measured to estimate body core temperature while arm blood flow and sweating rate were measured to assess the heat loss response. Mean arterial pressure and heart rate were measured to evaluate the cardiovascular response. Blood samples were analyzed for hematocrit (Hct), hemoglobin ([Hb]), plasma 17 beta-estradiol (E2), progesterone (P4), protein, and electrolyte concentrations. Plasma [E2] was significantly (P < 0.05) elevated by ERT without affecting the plasma [P4] levels. After ERT, Tes and Tre were significantly (P < 0.05) depressed by approximately 0.5 degrees C, and the Tes threshold for the onset of arm blood flow and sweating rate was significantly (P < 0.05) lower during exercise. After ERT, heart rate during exercise was significantly lower (P < 0.05) without notable variation in mean arterial pressure. Isotonic hemodilution occurred with ERT evident by significant (P < 0.05) reductions in Hct and [Hb], whereas plasma tonicity remained unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)     

Estrogen and estrogen plus progestin act directly on the mammary gland to increase proliferation in a postmenopausal mouse model

Hormone replacement therapy (HRT) with ovarian hormones is an important therapeutic modality for postmenopausal women. However, a negative side effect of HRT is an increased risk of breast cancer. Surgical induction of menopause by ovariectomy (OVX) in mice is an experimental model that may provide insights into the effects of hormone replacement therapy on the human breast. We have developed a mouse model of early and late postmenopausal states to investigate the effects of HRT on the normal mammary gland. The purpose of this study was to determine if HRT-induced proliferation was due to the direct action of the hormones on the mammary gland, or mediated systemically by hormones or growth factors produced elsewhere in the body. Estrogen (E) or E plus the synthetic progestin, R5020, were implanted directly into the mammary glands of early (1 week post OVX) and late (5 week post OVX) postmenopausal mice instead of administration by injection. We report that responses of early and late postmenopausal mice to implanted hormones were the same as those observed previously with systemically administered hormones. Implanted E conferred an enhanced proliferative response in the late postmenopausal gland characterized morphologically by enlarged duct ends. E+R5020 implants induced similar degrees of cell proliferation in both postmenopausal states but the morphological responses differed. Ductal sidebranching was observed in early postmenopausal mice, whereas duct end enlargement was observed in late postmenopausal mice. The differences in morphological response to E+R5020 in 5 week post OVX were associated with an inability of E to induce progesterone receptors (PR) in the late postmenopausal gland. The responses of the late postmenopausal glands to E and E+P were very similar to that observed previously in immature pubertal glands in ovary-intact mice. In pubertal mice, PR cannot be induced by E unless the mammary gland is pre-treated with EGF-containing implants. Similarly, herein pre-treatment of the late postmenopausal mammary gland with EGF-containing implants restored PR induction by E. Thus, EGF may determine the sensitivity of the mammary gland to E and E+P in late postmenopause and at puberty.     

Hormone replacement therapy in rheumatoid arthritis is associated with lower serum levels of soluble IL-6 receptor and higher insulin-like growth factor 1

Hormone replacement therapy (HRT) modulates the imbalance in bone remodeling, thereby decreasing bone loss. Sex hormones are known to influence rheumatic diseases. The aim of this study was to investigate the effects of HRT on the serum levels of hormones and cytokines regulating bone turnover in 88 postmenopausal women with active rheumatoid arthritis (RA) randomly allocated to receive HRT plus calcium and vitamin D3 or calcium and vitamin D3 alone for 2 years. An increase in estradiol (E2) correlated strongly with improvement of bone mineral density in the hip (P < 0.001) and lumbar spine (P < 0.001). Both baseline levels and changes during the study of IL-6 and erythrocyte sedimentation rate were correlated positively (P < 0.001). HRT for 2 years resulted in an increase of the bone anabolic factor, insulin-like growth factor 1 (IGF-1) (P < 0.05) and a decrease of serum levels of soluble IL-6 receptor (sIL-6R) (P < 0.05), which is known to enhance the biological activity of IL-6, an osteoclast-stimulating and proinflammatory cytokine. Baseline levels of IL-6 and IGF-1 were inversely associated (P < 0.05), and elevation of IGF-1 was connected with decrease in erythrocyte sedimentation rate (P < 0.05) after 2 years. Interestingly, increase in serum levels of E2 was associated with reduction of sIL-6R (P < 0.05) and reduction of sIL-6R was correlated with improved bone mineral density in the lumbar spine (P < 0.05). The latter association was however not significant after adjusting for the effect of E2 (P = 0.075). The influences of IGF-1 and the IL-6/sIL-6R pathways suggest possible mechanisms whereby HRT may exert beneficial effects in RA. However, to confirm this hypothesis future and larger studies are needed.     

Hormone replacement therapy increases renal kallikrein excretion in healthy postmenopausal women

Hypertension and its related increase in cardiovascular morbidity in postmenopausal women is a major public health problem. The hypotensive property of urinary kallikrein has been described since 1909. Despite the controversy surrounding the effects of hormone replacement therapy on blood pressure regulation, its mechanisms remain incompletely understood, and no evidence has yet been provided for its effects on renal kallikrein excretion in postmenopausal women. In a double-blind, randomized study we examined the effects of hormone replacement therapy in the form of 2 mg 17-beta estradiol (ERT) or 2 mg 17-beta estradiol combined with continuous 5 mg medroxyprogesterone acetate (HRT) on urinary kallikrein excretion in postmenopausal women. Thirty-nine postmenopausal women collected their urine for 24 hours on two separate occasions 3 months apart. During the 3 month period women were randomized to placebo, ERT, or HRT. Urine samples were assayed for kallikrein activity, normalized to urine creatinine and expressed as mU/gm creatinine. Urinary kallikrein excretion increased significantly after 3 months in the ERT (p < 0.001) and HRT (p < 0.01) groups, and decreased non-significantly in the placebo group (p > 0.06). There were no significant blood pressure changes after 3 months of therapy. The findings demonstrate that hormone replacement therapy in the form of estrogen or estrogen combined with continuous medroxyprogesterone is effective in increasing urinary kallikrein excretion. Given that a decrease in kallikrein excretion may mark risk for development of hypertension, the findings of this study are of value in demonstrating a novel mechanism underlying cardioprotective properties of postmenopausal hormone replacement therapy in women without pre-existing coronary disease.     

Measurement of bone mineral density (BMD) with quantitative computed tomography (QCT) in postmenopausal osteoporosis: effect of estrogen.

To determine the efficacy of the estrogen replacement therapy (ERT) on the bone mineral density (BMD) measured with quantitative computed tomography (QCT) in postmenopausal osteoporosis 16 women aged 46-72 were examined. They were divided into two groups: 8 women treated with conjugated estrogens (Group I) and 8 who did not received ERT (Group II). In all 16 patients the serum hormonal concentrations (LH, FSH and estradiol) were measured with radioimmunological methods. The bone densitometry was performed in all of them using the single-energy computed tomography (QCT) with the computer Picker 1200. Bone mineral density was measured in three lumbar vertebra (L1-L3) and expressed in milligrams K2HPO4 per ml. The bone mineral density (BMD) was statistically significantly higher in the estrogen treated group (Group I) in every vertebra compared with that of controls (Group II). The serum FSH concentration was statistically significantly lower in the ERT group (Group I) and a statistically significant correlation between FSH level and average BMD (Lmean) was present. In conclusion: 1. the ERT is very efficacious in preventing bone loss in postmenopausal women; 2. measurement of BMD in lumbar vertebra L1 or L3 may be a sufficiently reliable and accurate, cost-effective and time-saving method of screening for osteoporosis; 3. the serum FSH determination seems to be useful in monitoring of the estrogen therapy for postmenopausal osteoporosis.