Physiological aspects of menopausal hot flush.

Eighteen hot flushes experimenced by eight menopausal women were studied and compared with the effects of warming in six premenopausal women. The hot flushes were associated with an acute rise in skin temperature, peripheral vasodilatation, a transient increase in heart rate, fluctuations in the electrocardiographic (ECG) baseline, and a pronounced decrease in skin resistence. Although premenopausal women had greater maximum increases in skin temperature and peripheral vasodilatation, they showed a much smaller decrease in skin resistance and no changes in heart rate or ECG baseline. These findings suggest that the onset of the hot flush is associated with a sudden and transient increase in sympathetic drive. Further investigations may lead to the development of a more specific alternative to oestrogen for relieving menopausal hot flushes.     

Effect of oral gamolenic acid from evening primrose oil on menopausal flushing.

OBJECTIVE--To evaluate the efficacy of gamolenic acid provided by evening primrose oil in treating hot flushes and sweating associated with the menopause. DESIGN--Randomised, double blind, placebo controlled study. SETTING--District general hospital and teaching hospital. SUBJECTS--56 menopausal women suffering hot flushes at least three times a day. INTERVENTION--Four capsules twice a day of 500 mg evening primrose oil with 10 mg natural vitamin E or 500 mg liquid paraffin for six months. MAIN OUTCOME MEASURES--Change in the number of hot flushes or sweating episodes a month. RESULTS--56 diaries were analysed, 28 from women taking gamolenic acid and 28 from those taking placebo. Only 18 women given gamolenic acid and 17 given placebo completed the trial. The mean (SE) improvement in the number of flushes in the last available treatment cycle compared with the control cycle was 1.9 (0.4) (P < 0.001) for daytime flushes and 0.7 (0.3) (P < 0.05) for night time flushes in women taking placebo; the corresponding values for women taking gamolenic acid were 0.5 (0.4) and 0.5 (0.3). In women taking gamolenic acid the only significant improvement was a reduction in the maximum number of night time flushes (1.4 (0.6); P < 0.05). CONCLUSION--Gamolenic acid offers no benefit over placebo in treating menopausal flushing.     

Effects of "natural oestrogen" replacement therapy on menopausal symptoms and blood clotting.

In a double-blind study on the value of equine ("natural") oestrogens 30 patients presenting with menopausal symptoms in a group practice were monitored for possible adverse effects on blood clotting, weight, and blood pressure. The women were randomly allocated to two groups and given either three months'' hormone treatment followed by three months'' placebo or vice versa. An appreciable amelioration of all symptoms on placebo made it difficult to asses the genuine value of oestrogen treatment during the period of study. Both groups made a dramatic clinical improvement during the first three months. Nevertheless, the symptoms of the 15 women who received oestrogen first returned after the cross-over to placebo without any suggestion of a placebo response. In contrast, the other group who took placebo first did not deteriorate after changing to oestrogen. The menopausal index and the karyopyknotic index were not reliable guides to the need for oestrogen treatment. Hot flushes, however, were proportionately reduced on oestrogen and they seemed to be more readily eliminated in individual cases by oestrogen. The results of blood clotting studies indicated that natural oestrogen administration raised the levels of the extrinsic clotting factors VII and X and accelerated the prothrombin time. The findings were similar to those observed after three months synthetic oestrogen administration with oral contraception. Long-term studies and epidemiological surveys of the clinical incidence of thrombotic and other sequelae are needed before large-scale oestrogen replacement treatment can be recommended.     

An examination of the relationship between sunlight exposure and hot flush in working women

ABSTRACT

We examined whether sunlight affects hot flushes in working menopausal women and explored effect modification by shift work and season. In this prospective cohort study, daily hot flush score (outcome) was measured by the 7-day North Central Cancer Treatment Group Daily Vasomotor Symptoms Diary. Daily duration of sunlight (≥2000 lux) was recorded by the HOBO MX2202 pendant. Both variables were measured in two 7-day data collection phases. T0 data were collected during the Australian Summer (December 2017, January and February 2018); and T1 data were collected in the Australian winter (June, July and August 2018). Linear mixed effects model was used. Shift work and season were both confounders and effect modifiers. To detect a median effect size of R² = 0.2, 34 women were required to achieve an effective sample size of 41. A total of 49 menopausal women were recruited, 11 shift and 38 day workers. Some 13 women had various missing observations. For shift workers, an hour increase in sunlight exposure was associated with a 1.4-point reduction in hot flush score (p = .016). This relationship was not significant for day workers (p = .185). The finding of this study suggests increased sunlight exposure might improve hot flushes in menopausal shift workers who are moderately bothered by hot flushes, but probably not in day workers. The possible role of shift-work associated circadian disruption on estrogen level in regard to elevated intensity and frequency of hot flush in menopausal women is discussed.     

Similarities between morphine withdrawal in the rat and the menopausal hot flush

Skin temperature, cardiovascular and neuroendocrine responses to morphine withdrawal in the rat were evaluated in an effort to develop a potential animal model for the menopausal hot flush in women. Morphine dependency was produced by s.c. implantation of pellets containing morphine alkaloid. In response to precipitous, naloxone-induced withdrawal, rats showed surges in tail skin temperature (TST) which were similar in magnitude (4.8 to 7.2 degrees C) and duration (60 to 90 min.) to peripheral skin temperature increases reported during menopausal hot flushes. Additionally, a brief period of accelerated heart rate (59%) and a 9-fold hypersecretion of luteinizing hormone (LH) preceded the TST response to morphine withdrawal. These cardiovascular and neuroendocrine responses are observed to precede or coincide with the menopausal hot flush. Additionally, protracted morphine withdrawal subsequent to abstention, resulted in TST instability characterized by spontaneous, high amplitude TST fluctuations. Thus, the alteration in skin temperature, heart rate and LH secretion during precipitated morphine withdrawal in the rat are similar in magnitude, duration and in their temporal relationship to those observed during the hot flush. These data suggest a possible opioid etiology in this vasomotor disturbance. Acute withdrawal in the morphine addicted rats may serve as an animal model by which to study the neural mechanism underlying the menopausal hot flush.     

Trifolium pratense isoflavones in the treatment of menopausal hot flushes: A systematic review and meta-analysis

OBJECTIVE: To critically assess the evidence of supplements containing Trifolium pratense (red clover) isoflavones in the reduction of hot flush frequency in menopausal women. DATA SOURCES: Systematic literature searches were performed in (Medline (1951 - April 2006), Embase (1974 - April 2006), CINAHL (1982 - April 2006), Amed (1985 - April 2006) and The Cochrane Library (Issue 2, 2006). Reference lists located were checked for further relevant publications. Experts in the field and manufacturers of identified products were contacted for unpublished material. No language restrictions were imposed. REVIEW METHODS: Studies were selected according to predefined inclusion and exclusion criteria. All randomized clinical trials of monopreparations containing T. pratense isoflavones for treating hot flushes were included. Study selection, data extraction and validation were performed by at least two reviewers with disagreements being settled by discussion. Weighted means and 95% confidence intervals were calculated and sensitivity analyses were performed. RESULTS: Seventeen potentially relevant articles were retrieved for further evaluation. Five were suitable for inclusion in the meta-analysis. The meta-analysis indicates a reduction in hot flush frequency in the active treatment group (40-82 mg daily) compared with the placebo group (weighted mean difference -1.5 hot flushes daily; 95% CI -2.94 to 0.03; p=0.05). CONCLUSION: There is evidence of a marginally significant effect of T. pratense isoflavones for treating hot flushes in menopausal women. Whether the size of this effect can be considered clinically relevant is unclear. Whereas there is no apparent evidence of adverse events during short-term use, there are no available data on the safety of long-term administration.     

Effect of oestrogen on the sleep,mood, and anxiety of menopausal women.

A double-blind controlled study of the effect of piperazine oestrone sulphate on sleep, depression, anxiety, and hot flushes was performed in 34 perimenopausal women. Half of the patients were given six weeks'' placebo followed by eight weeks'' oestrogen, and half remained on placebo throughout. Sleep was recorded electrophysiologically every week, and mood and anxiety were rated daily by means of visual analogue scales. Hot flushes were counted daily. Observer rating scales of anxiety and depression were complete at intervals. During the first month of active treatment the amount of intervening wakefulness in the first six hours of sleep decreased significantly more in the oestrone group than in those on placebo. Between the baseline period and the second treatment month the oestrone group showed a significantly greater decrease in the total amount of intervening wakefulness and in the frequency of awakenings. Their total amount of rapid eye movement sleep increased. Mood and anxiety improved and the number of hot flushes decreased to a similar degree in both groups. Although oestrogen did reduce the number of episodes of wakefulness in perimenopausal women complaining of insomnia, its effects on their psychological symptoms were little different to those of placebo.     

Local oestrogen therapy modulates extracellular matrix and immune response in the vaginal tissue of post‐menopausal women with severe pelvic organ prolapse

This study investigates the effect of local oestrogen therapy (LET) on the expression of proteins participating in collagen/elastin biogenesis and immune markers in vaginal tissues of post‐menopausal women with severe pelvic organ prolapse (POP). Vaginal biopsies were collected from the anterior vaginal wall of informed and consented 52 post‐menopausal women with severe POP undergoing total hysterectomy. Twenty‐nine of the 52 women were treated with LET (in the form of vaginal oestrogen cream or tablet), while the remaining 23 untreated patients served as the controls. This study was approved by Sinai Health System REB. Vaginal tissue specimens were analysed for gene and protein expression using real‐time RT‐PCR and Luminex assays, protein localization and immune cell infiltration were assessed by immunohistochemistry. Forty‐four cytokines were detected. We found that LET application: (a) significantly increased (P < 0.05) gene and protein expression levels of extracellular matrix (ECM) structural proteins, collagen and elastin, as well as the expression of ECM maturation enzyme BMP1; (b) decreased protein expression level of ECM degradation enzymes MMP1, MMP2 and MMP3 accompanied by an increase in their tissue inhibitors, TIMP1 and TIMP4; (c) significantly increased (P < 0.05) the gene and protein expression levels of 14 vaginal cytokines involved in leucocyte infiltration, which was confirmed by immunohistochemistry. Our results indicate that LET plays an important role in the activation of immune system within the local vaginal environment, limiting the undesirable ECM degradation, which supports the strengthening of vaginal ECM in post‐menopausal women, therefore resisting menopause/age‐related changes and inducing urogenital tract tissue regeneration.     

Efficacy and safety of a phytoestrogen preparation derived from Glycine max (L.) Merr in climacteric symptomatology: a multicentric, open, prospective and non-randomized trial.

A multicentric, open, prospective, observational and no-randomized clinical trial was carried out in Spain with 190 postmenopausal women receiving a soy preparation rich in isoflavones (PHYTO SOYA, capsules containing 17.5 mg isoflavones). The main object of the present study was to investigate its efficacy in alleviating the symptomatology derived from the lack of estrogen, mainly hot flushes, but also other symptoms such as sleep disorder, anxiety, depression, vaginal dryness, loss of libido and bone pain. Each patient received 35 mg isoflavones per day in two doses. During the four months' treatment, a statistically significant decrease in the number of hot flushes with PHYTO SOYA was experienced by 80.82% women; only 5,48% patients did not improve with the treatment. The average reduction was 47.8%, which is equivalent to 4 hot flushes. All the other studied parameters also showed a statistically significant decrease. No severe side-effects were reported and tolerance was excellent. Treatment with PHYTO SOYA resulted in a significant improvement of the symptomatology that accompanies the lack of estrogen during menopause.     

Topical KGF treatment as a therapeutic strategy for vaginal atrophy in a model of ovariectomized mice

One of the most frequent complaints for post‐menopausal women is vaginal atrophy, because of reduction in circulating oestrogens. Treatments based on local oestrogen administration have been questioned as topic oestrogens can reach the bloodstream, thus leading to consider their safety as controversial, especially for patients with a history of breast or endometrial cancers. Recently, growth factors have been shown to interact with the oestrogen pathway, but the mechanisms still need to be fully clarified. In this study, we investigated the effect of keratinocyte growth factor (KGF), a known mitogen for epithelial cells, on human vaginal mucosa cells, and its potential crosstalk with oestrogen pathways. We also tested the in vivo efficacy of KGF local administration on vaginal atrophy in a murine model. We demonstrated that KGF is able to induce proliferation of vaginal mucosa, and we gained insight on its mechanism of action by highlighting its contribution to switch ERα signalling towards non‐genomic pathway. Moreover, we demonstrated that KGF restores vaginal trophism in vivo similarly to intravaginal oestrogenic preparations, without systemic effects. Therefore, we suggest a possible alternative therapy for vaginal atrophy devoid of the risks related to oestrogen‐based treatments, and a patent (no. RM2012A000404) has been applied for this study.     

Metabolic,Hormonal, and Vascular Changes after Synthetic Oestrogen Therapy in Oophorectomized Women

Mestranol, the three-methyl ether form of ethinyloestradiol and one of the two oestrogens used in oral contraceptive steroids, was administered in a dose of 0·02 mg daily for 120 days to 25 oophorectomized women.Urinary oestriol and pregnanediol excretions were unaffected by the mestranol treatment but there was a shift of the maturation index of the vaginal smear to the right, indicating a correction of the pretreatment oestrogen deficiency. No significant change in the blood pressure or electrocardiograph recordings occurred during this relatively short period of administration. A significant rise in the serum protein-bound iodine, which might be regarded as an undesirable effect of mestranol on a long-term basis, occurred. Hepatic function as measured by bromsulphthalein was not impaired by the treatment. Mestranol had no effect on the total body water or on the total exchangeable potassium of the women. Its two most serious adverse effects were impairment of glucose tolerance and a high incidence (16%) of venous thrombo-embolic disease.The gravity of the adverse effects far outweighs any beneficial ones and precludes the use of mestranol alone for long-term hormone replacement therapy in postmenopausal women.     

The insulin-like growth factor I generation test in adults

The insulin-like growth factor I (IGF-I) generation test has the potential to assess the ability of an individual to respond to an acute bolus of growth hormone (GH), in terms of IGF-I, IGF-binding protein 3 and acid-labile subunit responses. This article will discuss something of the history of the IGF-I generation test, and review some of the major studies to date. The IGF-I generation test was first used in adults by Lieberman et al., who studied the effects of ageing and oestrogen administration, and suggested that decreased responsiveness to GH occurs with increasing age and oral oestrogen administration. Our results, however, show that, while activity of the GH/IGF-I axis declines with age, peripheral responsiveness to GH is not affected. As in the Lieberman study, we found that oral oestrogen replacement reduces responses of GH-dependent peptides to GH stimulation in healthy post-menopausal women. Transdermal oestrogen administration also reduced responsiveness to GH, although to a lesser degree than orally administered oestrogen. In addition, utilizing a non-weight-based dose of GH we have demonstrated that obese individuals produce greater increases in IGF-I following an acute bolus of GH. In GH deficiency (GHD), data suggesting enhanced peripheral responsiveness should be interpreted with caution, and with awareness of differences between these groups in terms of age and obesity. The IGF-I generation test may allow a fresh approach to unanswered questions in the field of GHD, but as the IGF-I response to GH is not strictly associated with protein anabolism or clinical benefit, the question remains whether this test will predict the effect of longer-term GH administration.     

Post-menopausal hormone replacement therapy, coronary heart disease and plasma lipoproteins

At least 20 million postmenopausal women worldwide now use some form of hormone replacement therapy. This figure is increasing because the resistance of the medical community to these therapies is diminishing and because of increasing acknowledgement of the benefits of such therapies on the cardiovascular system. This is a remarkable development for a medication originally used to relieve menopausal symptoms such as hot flushes and to prevent bone loss. Although several mechanisms are now accepted to be involved in this protection from cardiovascular disease, changes in plasma lipoproteins remain a major area of research interest. The main issue in this field, whether the addition of a progestogen to postmenopausal oestrogen ('combined therapy') will diminish the benefits on the cardiovascular system, remains unresolved, but combined therapies have now been formulated that minimize the potentially detrimental effects of progestogens on plasma lipoproteins. Recent findings of interest include the effects of these therapies on plasma lipoprotein (a) concentration and on LDL particle size. Studies of the mechanisms behind such changes are needed.     

Correlation of serum oestrogen with salivary calcium in post-menopausal women with and without oral dryness feeling

doi: 10.1111/j.1741‐2358.2011.00580.x
Correlation of serum oestrogen with salivary calcium in post‐menopausal women with and without oral dryness feeling Objective: The aim of this study was to verify the association between salivary calcium and serum oestrogen levels with oral dryness in post‐menopausal women. Also, the correlation between these variables was evaluated. Methods: A case‐control study was carried out on 60 selected menopausal women with and without oral dryness feeling (30 as case and 30 as control) conducted in the Department of Oral Medicine and Radiology, Maharishi Markandeshar University, Mullana, India. Paraffin‐stimulated saliva samples were obtained by expectoration. Salivary calcium concentrations were assessed colorimetrically using Arsenazo III reaction. The serum oestrogen concentration was measured using ELISA. Statistical analysis of Student’s t‐test and Pearson correlation was used. Results: There was significant difference in mean values of both salivary calcium concentration and serum oestrogen between case and control groups. The result obtained also showed that an inverse correlation was found between salivary calcium concentration and serum oestrogen levels in both the groups and in total sample size. Conclusion: Oral dryness in post‐menopausal women is associated with high levels of salivary calcium and low levels of serum oestrogen. The concentrations of salivary calcium and serum oestrogen are inversely correlated in post‐menopausal women, regardless of the presence or absence of oral dryness.     

Exercise hyperemia and vasoconstrictor responses in humans with cystic fibrosis.

ATP released from circulating erythrocytes is a potential signal regulating muscle blood flow during exercise (exercise hyperemia), and intravascular ATP appears to blunt sympathetic vasoconstriction during exercise. Erythrocytes from patients with cystic fibrosis (CF) do not release ATP. The goal of the present study was to determine whether increases in forearm blood flow during exercise are blunted in CF patients and whether CF patients exhibit greater vasoconstrictor responsiveness during exercise. Nine control subjects and 10 CF patients who were free of other disease complications (approximately 96% O2 saturation) performed incremental rhythmic forearm exercise at 5, 10, and 15% of maximum handgrip strength for 21 min (7 min at each workload). We used a cold pressor test to evoke sympathetic vasoconstriction under resting conditions and at each exercise workload. As a control, subjects performed a second exercise bout without the cold pressor test. Continuous brachial artery blood velocity was monitored beat-to-beat, and vessel diameter was assessed by Doppler ultrasound. Artery diameter, as well as blood pressure, heart rate, and O2 saturation, was measured at steady-state exercise and at 1 min into the cold pressor stimulus. Blood pressure and heart rate responses to the forearm exercise and each cold pressor test were similar in both groups (P > 0.05). Contrary to our hypothesis, forearm blood flow (P = 0.91) and forearm vascular conductance (P = 0.82) were similar at rest and at each level of exercise between CF patients and controls. Additionally, there was no difference in the degree of sympathetic vasoconstriction between groups at rest and at each level of exercise (P = 0.22). Our results suggest that ATP released from the deformation of erythrocytes is not an obligatory signal for exercise hyperemia in human skeletal muscle.     

Oestrone, oestradiol and oestriol glucosiduronates and sulphates in human puerperal plasma and milk

Conjugated and unconjugated oestrone, oestradiol and oestriol were measured in simultaneous milk and plasma samples obtained from 21 women in the early post-partum period. Conjugated oestrogens comprised more than 90% of the total oestrogen content of both milk and plasma. Oestrone glucosiduronate was the major oestrogen metabolite in milk (33%), the levels being significantly higher (P less than 0.01) than in plasma. Oestriol glucosiduronates were the predominant oestrogen metabolites (63%) in plasma.     

Mechanism of ethanol-induced vasodilation

The mechanism by which ethanol ingestion causes dermal vasodilation is unclear, but it may result from a direct action on central vascular control mechanisms. Forearm blood flow and peripheral skin temperatures were examined in five quadriplegics (lesions above T7) and five control subjects, before and after the ingestion of ethanol (0.75 ml/kg body wt). The lack of vasomotor efferent function was confirmed in the quadriplegics by the absence of vasodilation in response to radiant heating of the torso. There were no significant changes in peripheral temperatures or forearm blood flow after ethanol in the quadriplegics. The control subjects had a significant increase in forearm blood flow (1.12 +/- 0.2 ml.min-1.100 ml-1) and skin temperature (finger 2.4 +/- 0.4 degrees C, toe 3.4 +/- 0.3 degrees C) after ethanol. These data suggest that ethanol may induce peripheral vasodilation by modulation of central vasomotor control mechanisms.     

Forearm blood flow follows work rate during submaximal dynamic forearm exercise independent of sex.

To test the hypothesis that sex influences forearm blood flow (FBF) during exercise, 15 women and 16 men of similar age [women 24.3 +/- 4.0 (SD) vs. men 24.9 +/- 4.5 yr] but different forearm muscle strength (women 290.7 +/- 44.4 vs. men 509.6 +/- 97.8 N; P < 0.05) performed dynamic handgrip exercise as the same absolute workload was increased in a ramp function (0.25 W/min). Task failure was defined as the inability to maintain contraction rate. Blood pressure and FBF were measured on separate arms during exercise by auscultation and Doppler ultrasound, respectively. Muscle strength was positively correlated with endurance time (r = 0.72, P < 0.01) such that women had a shorter time to task failure than men (450.5 +/- 113.0 vs. 831.3 +/- 272.9 s; P < 0.05). However, the percentage of maximal handgrip strength achieved at task failure was similar between sexes (14% maximum voluntary contraction). FBF was similar between women and men throughout exercise and at task failure (women 13.6 +/- 5.3 vs. men 14.5 +/- 4.9 ml.min(-1).100 ml(-1)). Mean arterial pressure was lower in women at rest and during exercise; thus calculated forearm vascular conductance (FVC) was higher in women during exercise but similar between sexes at task failure (women 0.13 +/- 0.05 vs. men 0.11 +/- 0.04 ml.min(-1).100 ml(-1).mmHg(-1)). In conclusion, the similar FBF during exercise was achieved by a higher FVC in the presence of a lower MAP in women than men. Still, FBF remained coupled to work rate (and presumably metabolic demand) during exercise irrespective of sex.     

Hemodynamics and brain blood flow during posture change in younger women and postmenopausal women compared with age-matched men

Increased incidence of orthostatic hypotension and presyncopal symptoms in young women could be related to hormonal factors that might be isolated by comparing cardiovascular and cerebrovascular responses to postural change in young and older men and women. Seven young women, 11 young men, 10 older women (>1 yr postmenopausal, no hormone therapy), and 9 older men participated in a supine-to-sit-to-stand test while measuring systemic hemodynamics, end-tidal Pco(2), and blood flow velocity of the middle cerebral artery (MCA). Women had a greater reduction in stroke volume index compared with age-matched men (change from supine to standing: young women: -22.9 ± 1.6 ml/m(2); young men: -14.4 ± 2.4 ml/m(2); older women: -17.4 ± 3.3 ml/m(2); older men: -13.8 ± 2.2 ml/m(2)). This was accompanied by offsetting changes in heart rate, particularly in young women, resulting in no age or sex differences in cardiac output index. Mean arterial pressure (MAP) was higher in older subjects and increased with movement to upright postures. Younger men and women had higher forearm vascular resistance that increased progressively in the upright posture compared with older men and women. There was no difference between sexes or ages in total peripheral resistance index. Women had higher MCA velocity, but both sexes had reduced MCA velocity while upright, which was a function of reduced blood pressure at the MCA and a significant reduction in end-tidal Pco(2). The reductions in stroke volume index suggested impaired venous return in women, but augmented responses of heart rate and forearm vascular resistance protected MAP in younger women. Overall, these results showed significant sex and age-related differences, but compensatory mechanisms preserved MAP and MCA velocity in young women.     

Blood Flow Characteristics and Tissue Nutrition in Apparently Ischaemic Feet

Blood flow in the apparently ischaemic feet of patients with atherosclerotic peripheral vascular disease was only weakly pulsatile but the volume of the resting total foot blood flow was higher than normal. No biochemical evidence of overall regional ischaemia or tissue anoxia was found to explain the aetiology of chronic nutritional skin lesions in these clinically ischaemic feet. The physiological effectiveness of a regional blood flow ultimately depends on its ability to perfuse the tissues, and in this respect it is suggested that pulse and pressure are more important than mere volume. It is further suggested that ischaemic or anoxic nutritional skin lesions develop in the presence of localized tissue perfusion failure and not from any overall regional blood flow insufficiency.