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PubMed2007

Insulin-like growth factor and mammographic density in postmenopausal Norwegian women.

Insulin-like growth factor-I (IGF-I) is associated with breast cancer risk among premenopausal women but rarely among postmenopausal women. Recent data from two European studies suggested an increased risk of breast cancer with increasing levels of IGF-I among women >50 years old or among postmenopausal hormone therapy users >or=55 years old. Mammographic density is one of the strongest risk factors, and possibly an intermediate marker, for breast cancer. We examined the relationship between IGF and mammographic density among postmenopausal women overall and according to hormone therapy use. Altogether, 977 postmenopausal participants in the Norwegian governmental mammographic screening program had IGF concentrations measured by ELISA. Mammograms were classified according to percent and absolute mammographic densities using a previously validated computer-assisted method. After adjustment for age, number of children, age at menopause, body mass index, and hormone therapy use, both plasma IGF-I concentration (P(trend) = 0.02) and IGF-I/IGF binding protein 3 ratio (P(trend) = 0.02) were positively associated with percent mammographic density. The magnitudes of differences in percent mammographic density between women in the lowest and highest quartiles of IGF-I concentrations were 1.5% absolute difference and 21% relative difference. These associations were similar with absolute mammographic density as the outcome variable. When the analyses were stratified according to hormone therapy use, the associations between IGF-I and mammographic density were significant among noncurrent users (P(trend) = 0.03). In conclusion, we found a positive but weak association between plasma IGF-I concentrations and both percent and absolute mammographic densities among postmenopausal women. These associations were found among noncurrent hormone therapy users but not among current users.

Aged↗

PubMed1998

Estrogen and progesterone receptors of adenomyosis in postmenopausal breast cancer patients treated with tamoxifen.

Adenomyosis is an ectopic endometrial tissue located in the myometrium. It has been reported to develop at a higher rate among postmenopausal breast cancer patients on tamoxifen (TAM) treatment than in untreated patients. It has also been reported to be stimulated by estrogen. Assessing receptor levels in adenomyotic tissue may indicate the adenomyotic cell's potential to interact with TAM. In the present study the estrogen receptor (ER) and progesterone receptor (PR) were analyzed by an immunohistochemical technique in adenomyotic and the corresponding endometrial tissues of 14 postmenopausal breast cancer patients treated with TAM and in 15 healthy postmenopausal patients who served as controls. All TAM-treated patients had normal postmenopausal serum estradiol levels. Overall the ER and PR contents in adenomyotic tissue (42.9 and 71.4%) and in the endometriotic tissue (64.3 and 78.6%) obtained from the study patients were similar to those obtained from the control group (adenomyosis, ER and PR = 46.7 and 86.7%; endometrium, ER and PR = 40 and 73.3%; p = NS). In the study group, the ER content was lower in the adenomyotic (42.9%) than in the endometriotic tissue (64.3%). No correlation was found between the duration of TAM therapy, the TAM dosage level or the ER or PR content in the adenomyotic or endometrial tissues. The finding of a relatively low ER content in the adenomyotic tissue than in the endometriotic tissue in postmenopausal TAM-treated patients without endogenous estrogens, similar to that observed in healthy premenopausal women, may be attributed to the estrogen-like effect of TAM.

Aged↗

PubMed1999

Psychological and endocrine responses to psychosocial stress and dexamethasone/corticotropin-releasing hormone in healthy postmenopausal women and young controls: the impact of age and a two-week estradiol treatment.

In this placebo-controlled double-blind study, psychological and endocrine stress responses were investigated in healthy postmenopausal placebo-treated women (n = 15; 60-75 years; placebo via transdermal patches), healthy postmenopausal estradiol-treated women (n = 13; 60-79 years; 0.1 mg 17beta-estradiol daily via transdermal patches) and young controls (n = 15; 20-31 years; untreated). The aged subjects received estradiol or placebo treatment for 14 days. All subjects were then exposed to the 'Trier Social Stress Test' (TSST) and the dexamethasone (Dex)-human corticotropin-releasing hormone (hCRH) test (100 microgram hCRH after premedication with 1.5 mg Dex). Psychological parameters including perceived stressfulness, mood and subjective well-being were measured by visual analog scales, a mood questionnaire and a mood diary, respectively. Results show that the TSST induced significant increases in adrenocorticotropin (ACTH), free salivary cortisol, total plasma cortisol and heart rates (all p < 0.0001). Regardless of age, comparable hormonal response patterns were observed in the TSST as indicated by similar peak levels and recovery phases. Visual analog scales confirmed that the same amount of stress was experienced by young and elderly subjects. In both age groups, hCRH injection after Dex premedication provoked significant increases in ACTH, free salivary cortisol and total plasma cortisol (all p < 0.0001). In contrast to the psychosocial stressor, elderly women were found to respond with a markedly enhanced cortisol response compared to young controls in the Dex-CRH test (p < 0.025). Additional investigation of morning cortisol profiles could not reveal any age-related differences in basal hypothalamus-pituitary-adrenal (HPA) axis activity. Following estradiol treatment, estradiol levels significantly increased only in substituted postmenopausal women (p < 0.001) reaching concentrations typically found in younger women during the follicular phase of the menstrual cycle. Corticosteroid-binding globulin levels did not differ significantly between groups. When confronted with the TSST, no response differences emerged between the three groups. However, estradiol treatment appeared to blunt the total plasma cortisol response in the Dex-CRH test, resulting in smaller increases in untreated premenopausal women and estradiol-treated postmenopausal women compared to placebo-treated postmenopausal women (p < 0.02). In sum, no response differences were observed after confrontation with a psychosocial stress test in our sample of healthy elderly subjects. As shown with the Dex-CRH test, our data suggest that the negative feedback of the HPA axis in elderly women is altered. Moreover, the current data suggest that estradiol replacement may modulate HPA feedback sensitivity in humans.

Adrenocorticotropic Hormone↗

PubMed2004

Is serum ferritin an additional cardiovascular risk factor for all postmenopausal women?

BACKGROUND: Most of the studies on cardiovascular disease (CVD) risk factors in menopause have focused on serum lipid(lipoprotein) abnormalities and were conducted in populations which were not well controlled for several important influential factors. METHODS: Two homogenous groups of 30 apparently healthy Caucasian premenopausal women and 3-5 years postmenopausal women who were nonobese, nonsmoking and not using estrogen were compared in a well-controlled cross-sectional design. Fasting serum ferritin and plasma total homocysteine (tHcy) were evaluated concomitantly to classical serum lipid(lipoprotein) risk factors. Relationships between risk factors and the influence of other contributing variables such as diet and body weight were also examined. RESULTS: Serum total cholesterol (p < 0.01), low-density lipoproteins (LDL; p < 0.05) and triglycerides (p < 0.05) of postmenopausal women were greater than that of their menstruating counterparts, even though they ate a CVD-preventive diet, had similar body weight and body fat distribution. Their serum ferritin was almost 3-fold greater (p < 0.0001) but was still within normal limits, except for the 38.5% of postmenopausal women who exhibited values above the 80 mug/l limit that has been associated with sharp increases in the rate of heart disease in either gender. Serum ferritin was low in one third of the postmenopausal group (as low as in the premenopausal control group, whose dietary iron intake was slightly below the nutritional recommendation). The mean plasma tHcy of the postmenopausal group was almost twice as elevated (p < 0.0001). Both ferritin and tHcy were found to be linked to serum cholesterol. The correlation between tHcy and triglycerides was also significant. CONCLUSION: Early menopause is not associated with blood iron overload and CVD risk factor in an important proportion of women.

Adult↗

PubMed2005

Hormone receptor expressions and proliferation markers in postmenopausal endometrial polyps.

BACKGROUND/AIMS: Endometrial polyps are quite common in the general population, they have a significant role in postmenopausal bleeding, and the pathogenesis is unclear. The aim of this study was to investigate proliferation markers and expression of estrogen and progesterone receptors in endometrial polyps in postmenopausal women. METHODS: Endometrial polyps were removed by hysteroscopy from 36 women who presented with postmenopausal bleeding. None were using hormonal therapy. The control group consisted of 16 inactive-atrophic postmenopausal endometrial specimens removed at hysterectomy. Immunohistochemistry was used to demonstrate expression of estrogen and progesterone receptors and the cell growth and apoptosis markers, Ki67, bcl-2, c-erbB-2. RESULTS: In both the glandular epithelium and stroma of endometrial polyps, estrogen and progesterone receptors, Ki67 and bcl-2 showed significantly more positive staining than the inactive endometrium from the control group. There was no difference in expression of c-erbB-2 between the two groups. CONCLUSIONS: Estrogen may have a role in the development of postmenopausal endometrial polyps, either by direct stimulation of localized proliferation or by stimulation of proliferation via other pathways, such as activation of Ki67 or through inhibition of apoptosis via bcl-2. c- erbB-2 is unlikely to play any role in development of these lesions.

Adult↗

PubMed1995

Total serum calcium reference intervals in postmenopausal outpatients.

The distribution of values of serum calcium has been studied in the following four outpatient populations: premenopausal (n = 411) and postmenopausal women (n = 399), men less than 50 years old (n = 365) and men over 55 years old (n = 361). Their respective average total serum calcium values (mg/dl) were 9.42, 9.56, 9.53, and 9.45. The reference intervals derived for total serum calcium (mg/dl) were 8.4-10.3 (premenopausal women), 8.4-10.7 (postmenopausal women), 8.6-10.5 (men less than 50 years old), and 8.4-10.4 (men over 55 years old). Increased total serum calcium levels were observed in the postmenopausal women as compared with both premenopausal women (p < 0.001) and with men over 55 years old (p < 0.003). Eight percent of the values obtained in postmenopausal women were above the current reference interval, as compared to 1.7% in premenopausal women, and 3.3% in men over 55 years old. In conclusion, the age-related increase in total serum calcium in postmenopausal female outpatients warrants a higher upper limit of the reference interval for this subpopulation.

Calcium↗

PubMed1997

Effects of oral and transdermal estrogen/progesterone regimens on blood coagulation and fibrinolysis in postmenopausal women. A randomized controlled trial.

Postmenopausal hormone replacement therapy is associated with a reduction in the incidence of coronary heart disease. However, inconclusive results have been reported with respect to the risk of stroke, and recent studies consistently showed an increased risk of venous thromboembolism in postmenopausal women using oral estrogen. There are surprisingly few interventional studies to assess the true effects of estrogen-progestin regimens on blood coagulation and fibrinolysis, and the impact of the route of estrogen administration on hemostasis has not been well documented. Therefore, we investigated the effects of oral and transdermal estradiol/progesterone replacement therapy on hemostatic variables. Forty-five healthy postmenopausal women, aged 45 to 64 years, were assigned randomly to one of the three following groups: cyclic oral or transdermal estradiol, both combined with progesterone, or no hormonal treatment. Hemostatic variables were assayed at baseline and after a 6-month period. Pairwise differences in the mean change between the three groups were compared using nonparametric tests. Oral but not transdermal estradiol regimen significantly increased the mean value of prothrombin activation peptide (F1 + 2) and decreased mean antithrombin activity compared with no treatment. Differences in fragment F1 + 2 levels between active treatments were significant. The oral estrogen group was associated with a significant decrease in both mean tissue-type plasminogen (t-PA) concentration and plasminogen activator inhibitor (PAI-1) activity and a significant rise in global fibrinolytic capacity (GFC) compared with the two other groups. A transdermal estrogen regimen had no significant effect on PAI-1, t-PA, and GFC levels. There were no significant changes in mean values of fibrinogen, factor VII, von Willebrand factor, protein C, fibrin D-dimer, and plasminogen between and within the three groups. We conclude that oral estrogen/progesterone replacement therapy may result in coagulation activation and increased fibrinolytic potential, whereas opposed transdermal estrogen appears without any substantial effects on hemostasis. Whereas these results may account for an increased risk of venous thromboembolism in users of oral postmenopausal estrogen, they emphasize the potential importance of the route of estrogen administration in prescribing hormone replacement therapy to postmenopausal women, especially to those at high risk of thrombotic disease.

Administration, Cutaneous↗

PubMed1994

Ethinyl estradiol acutely attenuates abnormal coronary vasomotor responses to acetylcholine in postmenopausal women.

BACKGROUND: Estrogen administration in postmenopausal women is associated with a 50% reduction in the clinical manifestations of coronary artery disease. The mechanisms are not known, although one potential explanation is estrogen-induced modulation of coronary vasoreactivity. Acetylcholine is an endothelium-dependent vasodilator that may be used to assess coronary vasoreactivity and elicits coronary responses that parallel those found with common daily vasomotor stimuli. Therefore, we tested whether estrogen attenuates abnormal coronary vasomotor responses to acetylcholine in postmenopausal women. METHODS AND RESULTS: Acetylcholine-induced changes in coronary flow, resistance, and cross-sectional area were determined before and 15 minutes after intravenous administration of ethinyl estradiol (EE, 35 micrograms) in 15 postmenopausal women. The influence of estrogen on basal coronary flow, resistance, and epicardial cross-sectional area was also assessed by measuring these parameters before and after EE or placebo administration in 33 women. Estrogen altered basal coronary vasomotor tone in 22 women as manifested by an EE-induced 23.3 +/- 4.5% (mean +/- SEM) increase (P < .01) in coronary flow, a 15.0 +/- 3.2% decrease (P < .01) in resistance, and a 20.0 +/- 6.5% increase (P = .02) in epicardial cross-sectional area. Placebo administration in 11 women did not change these parameters. Estrogen also attenuated abnormal coronary vasomotor responses to acetylcholine. Seven women who exhibited a paradoxical acetylcholine-induced decrease in coronary flow (-33.5 +/- 12.3%, P < .01) and increase in resistance (38.9 +/- 14.1%, P = .05) and seven who had an abnormal acetylcholine-induced decrease in epicardial cross-sectional area (-14.2 +/- 4.4%; P = .04) did not have acetylcholine-induced changes in these parameters after EE administration. Acetylcholine-induced flow, resistance, and cross-sectional area responses before and after EE were significantly different (P < .01, P = .02, and P = .02, respectively). Normal coronary responses to acetylcholine were not affected by EE administration. CONCLUSIONS: EE attenuates abnormal coronary vasomotor responses to acetylcholine in postmenopausal women. EE also decreases basal coronary vasomotor tone as manifested by increased coronary flow, decreased resistance, and increased epicardial cross-sectional area. These acute effects of estrogen on coronary vasoreactivity may explain, in part, the cardioprotective effects of estrogen in postmenopausal women.

Acetylcholine↗

PubMed1994

Effects of physiological levels of estrogen on coronary vasomotor function in postmenopausal women.

BACKGROUND: Estrogen replacement therapy has been associated with a reduction in cardiovascular events in postmenopausal women. One of the mechanisms responsible may be a beneficial effect of estrogen on coronary vascular function. We therefore studied the short-term effects of estrogen on coronary artery dimensions and microvascular resistance in postmenopausal women. METHODS AND RESULTS: Twenty postmenopausal women 61 +/- 7 years old participated in this study. Seven had angiographic evidence of atherosclerosis of the left coronary artery. Coronary artery diameters were measured by quantitative coronary angiography. Blood flow velocity was measured with a Doppler wire placed in a proximal left coronary artery segment. Left coronary artery infusions of acetylcholine (range, 10(-8) to 10(-5) mol/L estimated delivered concentrations) and of adenosine (n = 18) and sodium nitroprusside (n = 10) were performed before and during concomitant continuous intracoronary infusion of 17 beta-estradiol to test endothelium-dependent and independent vasodilation, respectively. Intracoronary infusion of estradiol increased coronary sinus estradiol levels from postmenopausal (16 +/- 11 pg/mL) to premenopausal (282 +/- 121 pg/mL) levels. Estradiol did not affect basal coronary artery diameter, blood flow, or resistance. Epicardial coronary artery constriction induced by acetylcholine infusion in the control study (maximum, 10 +/- 15% from baseline) was prevented during repeat acetylcholine infusion with concomitant estradiol administration (P < .001). Estradiol potentiated the vasodilator coronary microvascular response to acetylcholine as manifest by significantly greater coronary flow (P < .001) and lower coronary resistance (P < .02). The reduction in coronary resistance from baseline in response to acetylcholine was significantly potentiated by estradiol (P = .01), with a mean decrease in coronary vascular resistance during acetylcholine infusion of 20 +/- 38% before and 35 +/- 33% during concomitant estradiol administration. The effect of estradiol on coronary dynamics was similar in women with and women without angiographically apparent left coronary artery atherosclerosis and was most prominent in women with the most impaired responses to acetylcholine at both the epicardial (r = -.72, P < .001) and microvascular (r = -.59, P = .006) coronary artery levels. In contrast, estradiol did not affect the coronary epicardial or microvascular vasodilator responses to adenosine or sodium nitroprusside. CONCLUSIONS: Physiological levels of 17 beta-estradiol acutely and selectively potentiate endothelium-dependent vasodilation in both large coronary conductance arteries and coronary microvasuclar resistance arteries of postmenopausal women. This effect may contribute to the reduction in cardiovascular events observed with estrogen replacement therapy.

Acetylcholine↗

PubMed1994

Acute vascular effects of estrogen in postmenopausal women.

BACKGROUND: Although hormone replacement therapy has been associated with reduction of cardiovascular events in postmenopausal women, the mechanisms that mediate this apparent benefit are unclear. Because improvement in vasomotor function may represent one of the beneficial effects of estrogen administration, we investigated the acute effects of physiological levels of estrogen on the vascular responses of estrogen-deficient postmenopausal women. METHODS AND RESULTS: The study included 40 postmenopausal women 60 +/- 8 years old (mean +/- SD), 20 of whom had one or more conditions associated with vascular dysfunction (hypertension, hypercholesterolemia, diabetes, or coronary artery disease). The forearm vascular responses to the endothelium-dependent vasodilator acetylcholine were studied before and during infusion of 17 beta-estradiol into the ipsilateral brachial artery. In 31 subjects, the effect of estradiol on the responses to the endothelium-independent vasodilator sodium nitroprusside was also studied. Women with risk factors for vascular dysfunction had significantly reduced vasodilator responses to acetylcholine (P = .01) and to sodium nitroprusside (P < .001) compared with healthy subjects. Intra-arterial infusion of 17 beta-estradiol increased the forearm venous estradiol concentration from 16 +/- 10 to 318 +/- 188 pg/mL, levels typical of reproductive-age women at midcycle, but caused no vasodilation. However, estradiol potentiated the forearm vasodilation induced by acetylcholine by 18 +/- 30% (P < .001) in women with risk factors for vascular dysfunction and by 14 +/- 23% (P = .03) in healthy women. Estradiol also potentiated the forearm vasodilation induced by sodium nitroprusside in women with risk factors for vascular dysfunction by 14 +/- 21% (P < .001) but not in healthy women. CONCLUSIONS: Physiological levels of 17 beta-estradiol selectively potentiate endothelium-dependent vasodilation in healthy postmenopausal women and potentiate both endothelium-dependent and endothelium-independent vasodilation in post-menopausal women with risk factors for atherosclerosis and evidence of impaired vascular function. These vascular effects may be partly responsible for the long-term benefit of estrogen therapy on cardiovascular events in postmenopausal women.

Acetylcholine↗

PubMed2005

Estradiol induces discordant angiotensin and blood pressure responses to orthostasis in healthy postmenopausal women.

Postmenopausal estrogen replacement therapy (ERT) is reported to increase angiotensin II under resting conditions. To determine the implications of this increase for cardiovascular regulation during simulated orthostasis, blood pressure (BP), heart rate (HR), renin, angiotensinogen, angiotensin II, and aldosterone were measured at rest and during lower body negative pressure (LBNP; -10, -20, and -40 mm Hg). We studied 13 normotensive postmenopausal women (54+/-2 [mean+/-SE] years) before and after 1 month of oral estradiol 2 mg daily, and 14 premenopausal women. LBNP activated the renin-angiotensin system acutely in premenopausal but not postmenopausal women. Resting renin and aldosterone were unaffected by estradiol, whereas angiotensinogen (P<0.001) and angiotensin II (P<0.01) increased. Renin, aldosterone, and HR responses to LBNP (which tended to be less in postmenopausal women [P=0.06]) were not affected by estradiol. Importantly, angiotensin II was higher on estradiol during all stages of LBNP, and increased 70% above resting values at the end of this stimulus (P<0.05), yet BP was significantly lower, both at rest (P<0.05) and during LBNP (P<0.01). In summary, in normotensive postmenopausal women, estradiol increases angiotensin II, but not aldosterone, at rest and during orthostatic stress, yet lowers, rather than raises, BP under both conditions. Downregulation of vascular and adrenal responsiveness to angiotensin II may protect healthy women against this activation. Loss of such protection may elevate BP and have adverse implications for women with conditions that impair their capacity to counteract the pathological actions of angiotensin II. This may contribute to higher cardiovascular event rates reported in recent ERT trials.

Aldosterone↗

PubMed1995

Menopause, postmenopausal estrogen preparations, and the risk of adult-onset asthma. A prospective cohort study.

We prospectively evaluated the association of hormone replacement therapy and asthma incidence in a cohort of pre- and postmenopausal women 34 to 68 yr of age. During 582, 135 person-years of follow-up between 1980 and 1990, 726 new cases of asthma were documented. Postmenopausal women who were never users of replacement hormones had a significantly lower age-adjusted risk of asthma than premenopausal women (relative risk = 0.65; 95% confidence interval [CI] = 0.46 to 0.92). Among naturally menopausal women, the age-adjusted relative risk of asthma for ever use of postmenopausal hormones was 1.49 (95% CI = 1.10 to 2.00); for current use of hormones (conjugated estrogens with or without progesterone), 1.50 (95% CI = 0.98 to 2.30); and for past use, 1.52 (95% CI = 1.08 to 2.13), compared with never use of hormones. Ever users of 10 or more years' duration had twice the age-adjusted risk of asthma compared with women who never used postmenopausal hormones (95% CI = 1.39 to 2.87). Among current users of conjugated estrogens, there was a positive dose-response demonstrated between daily dose and asthma risk (p for trend = 0.007). While confirmatory studies are warranted, these data suggest that estrogen plays a role in the pathophysiology of asthma and that long-term use and/or high doses of postmenopausal hormone therapy increase subsequent risk of asthma.

Adult↗

PubMed2002

Differences in adipose tissue metabolism between postmenopausal and perimenopausal women.

Changes in adipose tissue metabolism may contribute to the changes in body fat distribution seen during the menopause transition. We compared in vitro abdominal and gluteal sc adipose tissue metabolism [basal and stimulated lipolysis and activity of adipose tissue lipoprotein lipase (AT-LPL)] in postmenopausal and perimenopausal women (n = 12/group), matched for race, body mass index (29.5 +/- 3.8 kg/m(2); mean +/- SD), and percentage body fat (42 +/- 6%). The postmenopausal women were older (54 +/- 3 vs. 48 +/- 3 yr; P < 0.01) and had higher FSH (55.5 +/- 26.4 vs. 16.6 +/- 22.5 IU/ml; P < 0.01) and lower estradiol (33.8 +/- 14.9 vs. 97.4 +/- 61.7 pmol/liter; P < 0.05) concentrations than the perimenopausal women. Despite similar fat cell size and beta-adrenergic receptor and postreceptor (dibutyryl-cAMP)-stimulated lipolysis, basal lipolysis was 77% lower in gluteal adipose cells from postmenopausal compared with perimenopausal women (P < 0.05). Within each group, AT-LPL activity in the gluteal region was significantly higher than in the abdominal region (P < 0.05). In addition, AT-LPL activity was significantly higher in the postmenopausal compared with perimenopausal women in both gluteal (4.9 +/- 3.6 vs. 2.0 +/- 1.4 nmol free fatty acid/g.min; P < 0.05) and abdominal (3.2 +/- 2.6 vs. 1.3 +/- 0.9 nmol free fatty acid/g.min; P < 0.05) adipose cells. The results of this study suggest that menopause status is associated with differences in adipose tissue metabolism in both the abdominal and gluteal fat depots. The lower lipolysis and higher AT-LPL activity in postmenopausal women may predispose them to gain body fat after menopause.

Abdomen↗

PubMed2003

Stromal cells of the human postmenopausal ovary display a distinctive biochemical and molecular phenotype.

The stroma of the human postmenopausal ovary is postulated to produce androgens, but evidence for and against this idea exits in the literature. The purpose of this study was to determine whether key steroidogenic enzymes involved in androgen synthesis are expressed in the postmenopausal ovarian stroma. Stromal cells were isolated from postmenopausal ovaries and expression for genes involved in steroidogenesis [steroidogenic acute regulatory protein (StAR), P450scc, 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) P450c17, and P450c27] as well as for several growth factor binding proteins [gremlin, IGF binding protein-4, follistatin, and secreted frizzled-related protein (sFRP)-1 and -4], were compared with cultured human theca cells and dermal fibroblasts. Production of steroids (pregnenolone, progesterone, and hydroxysterol metabolites) and the metabolism of [3H] pregnenolone by ovarian stromal cells were also assessed. Isolated ovarian stromal cells from different subjects had a uniform morphology within and across cultures. Quantitative real time RT-PCR revealed that StAR, P450scc, and 3 beta-HSD transcripts were, respectively 30, 25, and 45 times more abundant in theca cells than in stromal cells. Mean levels of P450scc and 3 beta-HSD transcripts in stromal cells were similar to those found in dermal fibroblasts, whereas StAR transcripts in stromal cells were 285-fold more abundant than in fibroblasts. There was no significant expression of P450c17 in ovarian stromal cells or fibroblasts ( approximately 2000-fold less than in theca cells). Western analysis demonstrated the presence of the 30-kDa StAR mature protein in the cultured stromal cells, whereas P450c17 protein was not detectable. Ovarian stromal cells did not metabolize [3H] pregnenolone in the presence or absence of 8-Br-cAMP. Furthermore, pregnenolone and progesterone secretion by stromal cells was also undetectable, even in the presence of 22-hydroxycholesterol. P450c27 protein was detected in ovarian stromal cells and its metabolic products (i.e. 27-hydroxycholesterol and cholestenoic acid) were found in the culture media, reflecting functional cholesterol 27-hydroxylase activity. Follistatin, gremlin, IGF binding protein-4, and sFRP-1 and -4 transcripts were detected in the stromal cells in relative amounts significantly higher than theca cells, but not significantly different from fibroblasts, except for sFRP-1, which was significantly higher in stromal cells. Our observations demonstrate that stromal cells of the postmenopausal ovary have a signature biochemical and molecular phenotype that can be distinguished from fibroblasts. These cells do not appear to have significant steroidogenic potential in vitro, but they do metabolize cholesterol into hydroxysterols. We conclude that the predominant stromal cells of the postmenopausal ovary are not a significant site of androgen biosynthesis.

Carrier Proteins↗

PubMed1992

Skeletal responsiveness to endogenous parathyroid hormone in postmenopausal osteoporosis.

To test the hypothesis that increased sensitivity of bone to PTH may be a major cause of bone loss in postmenopausal osteoporosis, we induced acute calcium deprivation and measured bone responsiveness to endogenous PTH under physiological conditions. Eighteen osteoporotic and 17 normal postmenopausal women with similar dietary calcium intakes were studied before and after 4 days of calcium deprivation (dietary calcium 230 mg/day and treatment with a calcium-binding agent). Despite decreased serum PTH values, the baseline indices of bone turnover (serum osteocalcin level and 24-h urinary excretions of total deoxypyridinoline/creatinine and pyridinoline/creatinine corrected for total body bone mineral content), were higher in the osteoporotic women. During calcium deprivation, the changes in bone markers from baseline were similar in both groups, except for serum osteocalcin and serum type I procollagen carboxy-terminal propeptide. Changes in the normal and the osteoporotic women were, respectively: serum ionized calcium concentration decreased 3.3% and 2.1%; serum intact PTH increased 65% and 56%; plasma 1,25-dihydroxyvitamin D3 increased 29% and 39%; pyridinoline/creatinine increased 12% and 11%; and deoxypyridinoline/creatinine increased 27% and 12%. Serum osteocalcin increased 2.3% and serum procollagen carboxy-terminal propeptide decreased 9.4% in the normal women but did not change in the osteoporotic women. We conclude that women with postmenopausal osteoporosis do not have increased skeletal responsiveness to PTH compared with age-comparable normal postmenopausal women. Therefore, the higher bone turnover in postmenopausal osteoporosis, despite lower serum intact PTH concentration, must be due to other factors. Assessment of acute changes in bone turnover during physiological alterations in endogenous PTH secretion is a useful test in metabolic bone diseases.

Bone Density↗

PubMed1999

Hormone replacement therapy with estrogen or estrogen plus medroxyprogesterone acetate is associated with increased epithelial proliferation in the normal postmenopausal breast.

The relative effects of postmenopausal hormone replacement therapy (HRT) with estrogen alone vs. estrogen+progestin on breast cell proliferation and on breast cancer risk are controversial. A cross-sectional observational study was carried out to examine the proliferative effects of HRT with estrogen or estrogen plus the progestin, medroxyprogesterone acetate, in breast tissue of postmenopausal women. Benign breast biopsies from 86 postmenopausal women were analyzed with antiproliferating cell nuclear antigen (anti-PCNA) and Ki67 antibodies to measure relative levels of cell proliferation. Epithelial density and estrogen and progesterone receptor status were also determined. The women were categorized either as users of: 1) estrogen (E) alone; 2) estrogen+medroxyprogesterone acetate (E+P); or 3) no HRT. Compared with no HRT, the breast epithelium of women who had received either E+P or E alone had significantly higher PCNA proliferation indices, and treatment with E+P had a significantly higher index (PCNA and Ki67) than treatment with E alone. Breast epithelial density was significantly greater in postmenopausal women treated with E and E+P, compared with no HRT. Thus, the present study shows that postmenopausal HRT with E+P was associated with greater breast epithelial cell proliferation and breast epithelial cell density than E alone or no HRT. Furthermore, with E+P, breast proliferation was localized to the terminal duct-lobular unit of the breast, which is the site of development of most breast cancers. Further studies are needed to assess the possible association between the mitogenic activity of progestins and breast cancer risk.

Adult↗

PubMed2005

Association of a -1997G-->T polymorphism of the collagen Ialpha1 gene with bone mineral density in postmenopausal Japanese women.

Genetic variants that affect collagen Ialpha1 metabolism may be important in the development of osteoporosis or osteoporotic fractures. A -1997G-->T polymorphism in the promoter of the collagen Ialpha1 gene (COL1A1) was shown to be associated with bone mineral density (BMD) for the lumbar spine in postmenopausal Spanish women. The relation of this polymorphism to BMD in Japanese women or men has now been examined in a population-based study. The subjects (1,110 women, 1,126 men) were 40 to 79 years of age and were randomly recruited for a population-based prospective cohort study of aging and age-related diseases. BMD for the lumbar spine, right femoral neck, right trochanter, and right Ward's triangle was measured using dual-energy x-ray absorptiometry. Genotypes for the -1997G-->T polymorphism of COL1A1 were determined with a fluorescence-based allele-specific DNA primer assay system. When all women were analyzed together, BMD for the lumbar spine and trochanter was significantly lower in subjects with the COL1A1 *G/*G genotype than in those in the combined group of COL1A1 *G/*T and COL1A1 *T/*T genotypes. When postmenopausal women were analyzed separately, BMD for the femoral neck and trochanter was also significantly lower in those with the COL1A1 *G/*G genotype than in those with the COL1A1 *G/*T genotype or those in the combined group of COL1A1*G/*T and COL1A1 *T/*T genotypes. BMD was not associated with -1997G-->T genotype in premenopausal women or in men. Multivariate regression analysis revealed that -1997G-->T genotype affected BMD at various sites with a variance of 0.46-0.62% for all women and 0.61-1.01% for postmenopausal women. The -1997G-->T genotype was not related to the serum concentration of osteocalcin, the serum activity of bone-specific alkaline phosphatase, or the urinary excretion of deoxypyridinoline or cross-linked N-telopeptides of type I collagen in men or in premenopausal or postmenopausal women. These results suggest that COL1A1 is a susceptibility locus for reduced BMD in postmenopausal Japanese women.

Absorptiometry, Photon↗

PubMed2005

Association of the OSCAR promoter polymorphism with BMD in postmenopausal women.

UNLABELLED: In an effort to identify genetic polymorphisms in potential candidate genes for osteoporosis, 10 variants were identified in the OSCAR gene using direct DNA sequencing, and 560 postmenopausal women were genotyped at five SNP loci, using the TaqMan method. The rare allele (G allele) of OSCAR-2322A>G (SNP in the 5' flanking region) showed significant association with lower BMD at various bone sites in postmenopausal women (n = 560). INTRODUCTION: BMD is the major factor for determining bone strength and osteoporotic fracture risk and is determined by both environmental and multiple genetic factors. The osteoclast-associated receptor (OSCAR) plays a critical role in osteoclast differentiation and thus is an important candidate gene for the modulation of BMD. MATERIALS AND METHODS: Through direct sequencing in 24 Korean individuals, 10 sequence variants were identified: 2 in the 5' flanking region, 7 in the exons (including 6 nonsynonymous single-nucleotide polymorphisms [SNPs]), and 1 in an intron. Five of these polymorphisms were selected for larger-scale genotyping in postmenopausal women (n = 560). Areal BMD (g/cm2) of the anterior-posterior lumbar spine and the nondominant proximal femur was measured using DXA (Lunar Expert XL and Hologic QDR 4500-A). Lateral thoracolumbar radiographs were obtained in all subjects. RESULTS: Using multiple regression analysis and controlling for age, years since menopause, height, weight, and evaluation machine as covariates, the rare allele (G allele) of OSCAR-2322A>G showed significant association with lower BMD at various bone sites in postmenopausal women. CONCLUSION: These findings suggest that the promoter variant in OSCAR gene (OSCAR-2322A>G) might be one of genetic determinants of BMD in postmenopausal women.

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