Changes in plasma LRH during the normal menstrual cycle in women

The plasma concentration of immunoreactive LRH, LS, FSH, oestradiol and progesterone were measured dialy by a sensitive double antibody radioimmunoassay during 12 cycles of 8 normal cyclic women. The mean (+/- SE) immunoreactive LRH levels in the follicular and luteal phase except the immunoreactive LRH peaks during normal cycles were 4.18 +/- 0.38 pg/ml and 4.50 +/- 0.45 mg/ml, respectively. The immunoreactive LRH peaks were observed in 11 of 12 cycles, appearing on day -4 to -1 from the LH surge in 9 cycles and on day +1 and +2 in 2 cycles. The mean value of immunoreactice LRH peaks was 42.0 +/- 11.4 pg/ml with range of 12 to 154 pg/ml. The immunoreactive LRH peak lasted for one day in 10 cycles and for 4 days in one cycle. The immunoreactive LRH peaks in different cycles of the same women did not occur on the same day relative to the LH peak. The plasma immunoreactive LRH levels measured every 10 min for 40 min periods every day in normal cyclic women during the ovulatory phase showed slight, but not significant fluctuations. Plasma oestradiol levels began to increase on day -6, reaching a peak on day -1, and were followed by peaks of LH and FSH. These data indicate that increase in serum oestradiol was followed by release of LRH from the hypothalamus and pre-ovulatory discharge of gonadotrophins from the pituitary.     

Haematocrit, type 2 diabetes, and endothelium-dependent vasodilatation of resistance vessels

Aims In conditions such as type 2 diabetes, hypertension, andsmoking, in which haematocrit (Hct) tends to be higher, endothelialfunction is impaired. In vitro, haemoglobin neutralizes nitricoxide very effectively. Whether red blood cells participatein the regulation of endothelial function in vivo has not beenestablished. Methods and results Clinical and haematological parameters andforearm blood flow responses to acetylcholine (ACh) and sodiumnitroprusside (SNP) were measured in 84 type 2 diabetic patientsand 19 control subjects. Diabetics showed blunted dose–responsecurves to both SNP and ACh. In diabetics, across quartiles ofHct, ACh blood flow responses were progressively lower (881±96,652±81, 513±54, 307±46%, P</0.0001),and maximal SNP responses tended to be lower (706±72,578±61, 607±69, 499±53%, P=0.06) despitesimilar age, body mass index, glycated haemoglobin (HbA_1c),blood pressure, serum total and HDL-cholesterol levels, indicesof insulin sensitivity, and markers of inflammation. After normalizingthe ACh response for the SNP response (ACh/SNP ratio), a progressivereduction across Hct quartiles (1.54±0.23, 1.22±0.15,0.93±0.09, 0.66±0.09, P<0.0001) was still observed,with patients in the III and IV quartile showing a blunted responsecompared with controls (1.44±0.08). Both in diabeticsand controls, the ACh/SNP ratio was reciprocally related toHct (r=–0.46 and r=–0.66, respectively, P<0.002for both). This association was independent of comorbidities,gender, metabolic control, plasma lipids, or concomitant treatments,was stronger in the subjects with preserved endothelium-dependentdilatation, and was unchanged when haemoglobin replaced Hct. Conclusion Both in diabetics and non-diabetics, haematocritis inversely related to small vessel endothelium-dependent dilatation.Thus, in addition to blood rheology, a direct negative effecton nitric oxide availability might explain the link betweenhigh Hct and cardiovascular disease.     

Platelet cyclic guanosine monophosphate production during menstrual cycle in healthy women

The incidence of cardiovascular disease among women during their reproductive years is considerably less than in men and this difference decreases after menopause. Since in cultured endothelial cells and in platelets E2 increases nitric oxide (NO) production, it is possible that their cardioprotective effect may be mediated by NO. The aim of this study was to evaluate platelet cyclic guanosine monophosphate (cGMP), as a marker of NO production, during menstrual cycle. Fifteen women aged 26-40 yr were studied to evaluate: LH, FSH, E2, P and cGMP on the 5th follicular and 22nd luteal day of the cycle and during the ovulatory period. Platelet cGMP was evaluated in basal condition (3-isobuthyl 1-methylxanthine-IBMX) and with ionomycine (IONO) and sodium nitroprusside (SNP). RESULTS: LH, FSH, E2 and P demonstrated the typical patterns of ovulatory cycle. During follicular and luteal IBMX, SNP and IONO phase were homogeneous while they increased during the ovulatory period. A correlation between IBMX cGMP and E2 (p<0.002, rs=0.456) was found. In conclusion the data show an increase in platelet cGMP during the ovulatory period and a correlation between E2 and cGMP suggesting that E2 modulates NO production. The cardioprotective effect of E2 may be, at least in part, mediated by the increase in NO production.     

Low-grade inflammation and estimates of insulin resistance during the menstrual cycle in lean and overweight women

BACKGROUND: Inflammatory markers and insulin resistance are independent cardiovascular risk factors and are thought to be influenced by sex steroids. We investigated changes of inflammatory markers and estimates of insulin resistance during the menstrual cycle, their variances, and their relationship to each other, sex steroids, and regional body fat distribution. METHODS: Eight normal weight (body mass index, 21.6 +/- 1.9 kg/m(2)) and nine overweight (body mass index, 30 +/- 2.4 kg/m(2)) young women with normal ovarian function were assessed 15 times throughout the menstrual cycle. Regional fat distribution was assessed using dual x-ray absorptiometry. RESULTS: Concentrations of highly sensitive C-reactive protein (hs-CRP) changed significantly during the menstrual cycle and were highest in the early follicular phase (P < 0.00001). SHBG concentrations were stable in the follicular phase but increased in the luteal phase (P < 0.00001). During the follicular phase, estimates of insulin resistance had a higher within-subject variance when determined by the homeostasis model assessment index (42%) than when estimated by SHBG concentrations (5%, P < 0.05). During the menstrual cycle, using repeated measurements, hs-CRP correlated inversely to estradiol (beta-coefficient, -0.23, P < 0.0001) and SHBG concentrations (beta-coefficient, -0.83, P = 0.004). Central accumulation of body fat correlated to the mean hs-CRP concentration (r = 0.63, P = 0.007) and the mean homeostasis model assessment index for insulin resistance (r = 0.75, P = 0.001). CONCLUSION: We demonstrate that serum concentrations of hs-CRP and SHBG significantly change during the menstrual cycle. We reveal a close link between sex steroids, subclinical inflammation, insulin resistance, and body fat distribution in regularly menstruating women.     

Changes in lipoprotein composition during the menstrual cycle.

Composition of major plasma lipoproteins was studied in 14 normal women during different phases of the menstrual cycle for three consecutive months. The results were compared to measurements in ten normal age-matched men for a comparable period, to delineate possible sex differences in lipoprotein metabolism in young adults. Blood samples were obtained every 3--5 days after a 14-hr overnight fast and processed for determinations of total plasma cholesterol, LDL- and HDL-cholesterol, and apoproteins B and A-1. In premenopausal women, a significant, 10%--25% cyclical suppression of total plasma cholesterol, LDL-Chol, and LDL-apoB occurred during the luteal phase, which was significantly lower than unchanging concentrations found in men at any time interval. HDL-Chol remained in a significantly higher fixed concentration range in the female subjects as compared to the men. These sex differences in lipoprotein metabolism may have relevance to the reduced susceptibility of premenopausal women to atherosclerosis.     

Growth hormone responses to dexamethasone in healthy females throughout the menstrual cycle

OBJECTIVE In health, acute administration of dexamethasone (DEX) leads to growth hormone release. As sex steroids have a profound Influence on the somatotrophic axis, we decided to investigate the effects of DEX on OH release throughout the menstrual cycle. DESIGN A within subjects, randomized double-blind counter-balanced design was employed. METHODOLOGY Baseline levels Of GH, oestradiol and progesterone were taken at three the points In two consecutive menstrual cycles, after which 4mg of oral DEX or placebo was administered. Plasma samples for OH estimation were taken at 60,180,240 and 300 minutes. Each woman was tested 6 times, 3 times with placebo and 3 times with DEX. SUBJECTS Six women with regular menstrual cycles were studied. MEASUREMENTS Plasma OH, oestradiol and Progesterone were measured by radioimmunoassay. RESULTS When expressed as maximum change from base line (AGH) mean OH responses to DEX Increased Incrementally from early (12·2 ± 2·5 μ/I), through mid (25·6 ± 33 μ/I) to late (37·2 ± 3·5 μ/I) cycle. This represents a significant effect of cycle phase on GH responses to DEX (P < 0.05). GH responses at both the mid-cycle and the luteal the points are different from those during the follicular phase (P < 0.05) and differences between mid-cycle and luteal phases just fall to reach significance (P < 015). Responses to placebo did not vary from baseline. Plasma oestradiol values were significantly correlated with GH responsivity to active drug throughout the cycle (P < 0.05); the same was not true of progesterone. CONCLUSION Our study has demonstrated that dexa-methasone-mediated GH release shows a stepwise Increase throughout the menstrual cycle.     

Insulin receptors during the menstrual cycle in normal women.

Specific binding of 125I-insulin to circulating monocytes from eight normal menstruating women, four postmenopausal women and four men were studied four times during a 28-day period (one sample at 7-day intervals). Data indicate the presence of a higher specific cell binding fraction in the follicular phase compared to the luteal phase due to changes in insulin receptor concentration. No changes were observed in men or postmenopausal women during the same period of time suggesting that sex hormones should be included among the factors influencing insulin receptors.     

Intact endothelium-dependent dilation and conducted responses in resistance vessels of hypercholesterolemic mice in vivo

Atherosclerosis and hyperlipidemia impair endothelium-dependent nitric oxide (NO)-mediated dilations in conducting arteries. In addition to NO, the endothelium releases an endothelium-derived hyperpolarizing factor (EDHF) in response to acetylcholine (ACh), which is particularly important in microvessels and initiates a dilation that conducts along the vessel through gap junctional communication. The expression of connexins is, however, altered by hypercholesterolemia. Therefore, we studied endothelium-dependent dilations and their conduction in murine hypercholesterolemic models. Dilations were assessed by intravital microscopy in arterioles with a diameter of approximately 35 microm in ApoE and LDL receptor (LDLR(-/-))-deficient mice after superfusion or locally confined application of ACh. ACh induced comparable concentration-dependent dilations in wild-type, LDLR(-/-), and ApoE(-/-) mice fed a normal or high-cholesterol diet, however EC(50) was slightly higher in ApoE(-/-) mice. Furthermore, the NO donor sodium-nitroprusside dilated arterioles to a similar extent (approximately 60%). Locally initiated ACh dilations (approximately 68%) conducted up to a distance of 1,100 microm without significant attenuation even under severe hypercholesterolemic conditions. Since ACh dilation in the arterioles of mice is mainly mediated via EDHF, we conclude that hypercholesterolemia does not alter EDHF release and efficacy. This conclusion is confirmed by an intact conducted response since EDHF is a prerequisite for this response. The intact conduction also suggests that gap-junctional communication is functionally preserved in these models.     

The influence of dieting on the menstrual cycle of healthy young women

Nine normal young women of normal weight, aged 20-29 yr, who had regular menstrual cycles, dieted for 6 weeks (approximately 800-1000 kcal/day) and lost between 6 and 8 kg body wt. Half-hourly blood samples were taken from 1800-0530 h on two occasions before and after 1, 2, 3, 4, 5, and 6 weeks of dieting. In three women with anovulatory cycles the LH secretion pattern was not altered by dieting, but plasma estradiol levels decreased and reached menopausal concentrations during the final 2 weeks of dieting. In two of these three women the menstrual cycles were disrupted and regular cycles occurred only 3 and 6 months after dieting. Six women had regular ovulatory cycles. High progesterone values (greater than 3 ng/ml) were recorded in two cycles before the dieting period. While dieting, three women maintained ovulatory cycles and three women had no periovulatory hormone secretion pattern and/or a pattern characteristic of the luteal phase. No significant alterations of average LH concentrations and LH peak frequency developed. It is concluded that mild dieting does not suppress LH secretion in the manner found in anorexia nervosa or during total fasting. Dieting may interfere with gonadal steroid production, thus causing disturbances of the menstrual cycle. The effect described here may be responsible for the early onset of amenorrhea in patients with beginning anorexia nervosa.     

Pulsatile growth hormone release in normal women during the menstrual cycle

OBJECTIVE: We sought to characterize pulsatile growth hormone (GH) release in normal women during the menstrual cycle and to document possible relationships between such characteristics and concentrations of 17 beta-oestradiol and progesterone. SUBJECTS: Fifteen women with ostensibly normal menstrual function were studied during the early follicular phase, 15 during the late follicular phase and 15 during the mid-luteal phase of the menstrual cycle. DESIGN: The phase of the menstrual cycle having been documented, blood samples were obtained from each woman every 10 minutes for 24 hours. MEASUREMENTS: Serum GH was measured in each sample by immunoradiometric assay. Pulsatile GH release was appraised utilizing the objective, statistically-based pulse detection algorithm Cluster. RESULTS: The mean (+/- SEM) integrated serum GH concentration (mU/l min) in late follicular phase women (5335 +/- 848) was higher than that observed in early follicular phase women (3156 +/- 322; P = 0.032). The integrated GH concentration calculated for mid-luteal phase women (3853 +/- 788) was intermediate between but not statistically different from that observed in early follicular (P = 0.48) and late follicular (P = 0.14) phase women. No differences in GH pulse frequency (pulses/24 hours) were found among early follicular (8.27 +/- 0.55), late follicular (7.93 +/- 0.91) or mid-luteal (8.47 +/- 0.66) phase women. Mean maximal GH pulse amplitude (mU/l) was higher in late follicular phase (8.93 +/- 1.00) than early follicular phase (5.74 +/- 0.67; P = 0.008) and mid-luteal phase (5.76 +/- 0.74; P = 0.008) women. Similarly, incremental GH pulse amplitude (mU/l) was higher in late follicular phase (7.33 +/- 0.83) than early follicular phase (4.68 +/- 0.58; P = 0.005) and mid-luteal phase (4.36 +/- 0.39; P = 0.002) women. No differences in mean pulse widths or in the interpeak valley mean GH concentrations were found among the groups. Multiple regression of each pulse parameter against serum concentrations of testosterone, 17 beta-oestradiol and progesterone revealed a significant (P = 0.045) positive correlation between maximum GH pulse amplitude and oestradiol and a significant (P = 0.04) negative correlation between maximal GH pulse amplitude and progesterone (r = 0.41). CONCLUSION: These results suggest that late follicular phase concentrations of oestradiol may enhance circulating GH via an amplitude-modulated rather than a frequency-modulated effect on the endogenous GH pulse. Progesterone may blunt this oestrogen-associated effect, thus resulting in the observed mid-luteal phase concentrations of GH. Whether these gonadal hormones act primarily at the hypothalamus and/or anterior pituitary gland remains to be clarified, but the present observations indicate that pulsatile GH release throughout the normal menstrual cycle is significantly amplitude regulated.     

Changes in biochemical markers of osteoblastic activity during the menstrual cycle

Serum levels of osteocalcin [OC; bone Gla protein (BGP)] and bone alkaline phosphatase (B-AP) are both correlated to osteoblastic activity, which may be regulated by several hormones, including estrogen, 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3], and PTH. Estrogen shows reproducible variations during the menstrual cycle, while available data on variations in serum 1,25-(OH)2D3 and serum immunoreactive PTH show midcyclic increases or no changes. In the present study we evaluated osteoblastic activity by measuring serum OC and B-AP during the menstrual cycle in eight healthy women, aged 20-47 yr. The cycles were synchronized by LH peaks, and follicular and luteal periods were normalized by lengths. Repeated measures analysis of variance showed that serum OC varied significantly (P less than 0.05), with highest levels during the luteal period. Although the same pattern was seen for serum B-AP, the variation just failed to reach significance (P less than 0.10), but the mean level was significantly higher during the luteal than during the follicular period (P less than 0.05). Gonadotropins and ovarian sex hormones showed significant variations. There were no significant changes in serum vitamin D-binding protein, serum total and free 1,25-(OH)2D3 index, or serum immunoreactive PTH-(1-84), but serum levels of somatomedin-C showed a significant variation, with the highest level during the luteal period (P less than 0.05). Blood levels and urinary excretion of minerals exhibited no significant variations. Cross-correlation studies between OC and estradiol showed the highest correlation coefficient, when OC was lagged about 7 days after estradiol (r = 0.69; P less than 0.05). Moreover, a high correlation was found between OC and somatomedin-C when matched at concurrent time points (r = 0.76; P less than 0.01). No significant correlations were found between the other calcium-regulating hormones and OC when matched at concurrent time points. In conclusion, we found a significant effect of the menstrual cycle on the serum levels of two osteoblastic bone markers, OC and B-AP. The changes indicated that osteoblastic activity is higher during the luteal period. However, whether the changes are caused by direct or indirect effects of the fluctuations in calciotropic hormones is still unresolved.     

Effects of menstrual cycle and race on peripheral vascular alpha-adrenergic responsiveness

Gender differences in the incidence of many cardiovascular diseases may be due to the effects of sex hormones. Both alpha(1)- and alpha(2)-adrenergic receptors produce vasoconstriction in peripheral blood vessels and have demonstrated gender effects in previous studies. In addition, race has been shown to influence the effects of some alpha-adrenergic stimuli. We therefore sought to determine the effects of the menstrual cycle and race on peripheral blood flow responses to the intra-arterial infusion of phenylephrine (alpha(1)-agonist) and clonidine (alpha(2)-agonist). Ten white and 8 black women were studied during the early luteal phase and the follicular phase; these phases were verified in each woman through measurements of plasma estradiol and progesterone. Plasma norepinephrine was measured with HPLC. During phenylephrine infusion, there was significantly greater vasoconstriction in the luteal phase versus the follicular phase (P<0.05). There were no differences (P>0.8) between white and black women. During clonidine infusion, white women showed significantly more vasoconstriction in the follicular phase than during the luteal phase (P<0.006). For black women, the responses for both phases did not differ (P>0.9). Blood pressures were significantly higher in the black women (diastolic P<0.005, systolic P<0.05). The luteal-phase elevation of alpha(1)-adrenergic responses may be due to elevated levels of estradiol, progesterone, or both. The lack of luteal-phase reduction in alpha(2)-adrenergic vasoconstriction in black women may contribute to their increased pressor responses to adrenergic stimuli.     

Effects of the menstrual cycle on excess postexercise oxygen consumption in healthy young women

The effects of the menstrual cycle on excess postexercise oxygen consumption (EPOC) were studied in seven healthy young women aged 18 to 20 years. EPOC, resting metabolic rate (RMR), and energy expenditure during exercise (EEDE) in the fasting state were measured in the follicular and luteal phases. On the experimental days, subjects exercised for 60 minutes on a bicycle ergometer at an intensity of 60% maximal oxygen consumption (VO2max) followed by rest for 6 hours. The EPOC and RMR were significantly higher (P < .05) and the postexercise respiratory exchange ratio (RER) was significantly lower (P < .05) in the luteal phase versus the follicular phase, whereas differences in the EEDE and basal and exercise RER were negligible in both phases. Fat oxidation during the experimental period was significantly greater in the luteal phase (P < .05). These results suggest that exercise in the luteal phase results in greater postexercise energy expenditure and fat utilization than in the follicular phase.     

Insulin action does not change during the menstrual cycle in normal women

Normal women have alterations in carbohydrate metabolism during pregnancy and when taking oral contraceptives, and clinical observations suggest that diabetic women need more insulin during menstruation. We, therefore, studied insulin action in normal women during the menstrual cycle in the follicular, luteal, and menstrual phases. Glucose tolerance was similar at all three times. Specific insulin receptor binding to monocytes did not change during the menstrual cycle. Euglycemic insulin clamp studies at four different insulin infusion rates (15, 40, 120, and 240 mU/M2 X min) showed no differences in insulin sensitivity or responsiveness throughout the menstrual cycle, and hepatic glucose output did not change. These studies suggest that if insulin action is impaired during menstruation in diabetic women it is because of factors that are not detected in normal women.