Philip M. Sarrel

Cardiovascular protection by oestrogen-a calcium antagonist effect?

During their premenopausal years, women have a lower risk than men of getting cardiovascular disease. This protection continues after the menopause if women receive oestrogen replacement. Based on new experimental evidence we propose that some of the cardiovascular benefits of oestrogen replacement therapy may be due to a long-term calcium antagonist effect of oestrogen.

Effect of 17β‐oestradiol on contraction, Ca2+ current and intracellular free Ca2+ in guinea‐pig isolated cardiac myocytes

1 The effect of 17β‐oestradiol on cardiac cell contraction, inward Ca2+ current and intracellular free Ca2+ ([free Ca2+]i) was investigated in guinea‐pig single, isolated ventricular myocytes. The changes of cell length were measured by use of a photodiode array, the voltage‐clamp experiments were performed with a switch clamp system and [free Ca2+]i was measured with the Ca2+ indicator, Fura‐2. 2 17β‐Oestradiol (10, 30 μm) caused a decrease in cell shortening at both 22 and 35°C. This negative inotropic effect was accompanied by a decrease in action potential duration mainly brought about by a shortening of the plateau region of the action potential. 17β‐Oestradiol (10, 30 μm) induced a similar decrease in cell shortening in voltage‐clamped and current‐clamped cells. 3 In Fura‐2 loaded cells, 17β‐oestradiol (10 and 30 μm) decreased systolic Fura‐2 fluorescence to 72 ± 7% and 47 ± 4% (n = 6, P < 0.001) of control respectively. 17β‐Oestradiol (10 μm) had no significant effect on diastolic Fura‐2 fluorescence, but at higher concentration (30 μm) induced a slight decrease in resting Fura‐2 fluorescence. The effect of 17β‐oestradiol was reversible after 1–2 min of washout of the steroid. 4 17β‐Oestradiol (10 and 30 μm) decreased the peak inward Ca2+ current (ICa), which was sensitive to [Ca2+]o, dihydropyridines and isoprenaline, to 59 ± 3% and 39 ± 5% (n = 7∼9, P < 0.01) respectively, without producing any significant change in the shape of the current‐voltage relationship. 5 The recovery time of ICa from inactivation was delayed by 17β‐oestradiol (10 μm). The inhibitory effect of 17β‐oestradiol on ICa was less at a holding potential of −80 mV than at −40mV. 6 We conclude that 17β‐oestradiol has a negative inotropic effect on guinea‐pig single ventricular myocytes by inhibiting ICa and so reducing systolic [Ca2+]i. 17β‐Oestradiol may therefore have a Ca2+ channel blocking property in guinea‐pig isolated ventricular myocytes.

Sexual molestation of men by women

The belief that it is impossible for males to respond sexually when subjected to sexual molestation by women is contradicted. Previous research indicating that male sex response can occur in a variety of emotional states, including anger and terror, are corroborated. Eleven cases of male sexual molestation by females are classified and described. A post-trauma reaction occurs in which sexual function and psychological state are affected. The men were all personally interviewed. Recognition of this phenomenon should lead to increased identification of male victims as well as to better medical, psychological, and legal services for them.

Ovarian hormones and the circulation

Ovarian steroids have effects on blood circulation involving the mechanisms which control blood flow and the changes that occur in the pathogenesis of atherosclerosis. Estrogens appear to protect women from cardiovascular disease through their effects on lipid metabolism as well as more direct effects on arterial walls which appear to inhibit atherosclerotic plaque formation. There is increasing evidence that estrogen replacement after menopause can markedly reduce female mortality due to vascular disease. Effects of hormone imbalance and deficiency on vasomotor control are clinically significant and hormone treatment appears to be effective in the management of a variety of conditions due to abnormal blood flow including vasomotor instability, migraine, vaginal dryness and, perhaps, some forms of angina. Most review articles have focused on the effects of ovarian steroids and lipid metabolism as well as the findings of recent epidemiologic studies. This is understandable as those investigations have proved so valuable in understanding the protective effects of estrogens. The present discussion, in contrast, focuses on the effects of ovarian steroids, estrogens in particular, on circulatory mechanisms. At the present time there is increasing interest in these studies. Findings thus far appear to contribute to understanding estrogen cardioprotection and also raise awareness of a variety of clinical conditions in which estrogen treatment could be indicated because of its effects on circulation.

The Stroke Prognosis Instrument II (SPI-II) A Clinical Prediction Instrument for Patients With Transient Ischemia and Nondisabling Ischemic Stroke

BACKGROUND AND PURPOSE In 1991 we developed the Stroke Prognosis Instrument (SPI-I) to stratify patients with transient ischemic attack or ischemic stroke by prognosis for stroke or death in 2 years. In this article we validate and improve SPI-I (creating SPI-II). METHODS To validate SPI-I, we applied it to 4 test cohorts and calculated pooled outcome rates. To create SPI-II, we incorporated new predictive variables identified in 1 of the test cohorts and validated it in the other 3 cohorts. RESULTS For SPI-I, pooled rates (all 4 test cohorts) of stroke or death within 2 years in risk groups I, II, and III were 9%, 17%, and 24%, respectively (P<0.01, log-rank test). SPI-II was created by adding congestive heart failure and prior stroke to SPI-I. Each patients risk group was determined by the total score for 7 factors: congestive heart failure (3 points); diabetes (3 points); prior stroke (3 points); age >70 years (2 points); stroke for the index event (not transient ischemic attack) (2 points); hypertension (1 point); and coronary artery disease (1 point). Risk groups I, II, and III comprised patients with 0 to 3, 4 to 7, and 8 to 15 points, respectively. For SPI-I, pooled rates (3 cohorts excluding the SPI-II development cohort) of stroke or death within 2 years in risk groups I, II, and III were 9%, 17%, and 23%, respectively. For SPI-II, pooled rates were 10%, 19%, and 31%, respectively. In receiver operator characteristic analysis, the area under the curve was 0.59 (95% CI, 0.57 to 0.60) for SPI-I and 0.63 (95% CI, 0.62 to 0.65) for SPI-II, confirming the better performance of the latter. CONCLUSIONS Compared with SPI-I, SPI-II achieves greater discrimination in outcome rates among risk groups. SPI-II is ready for use in research design and may have a role in patient counseling.

Cyclical variation in paroxysmal supraventricular tachycardia in women

BACKGROUND Paroxysmal supraventricular tachycardia (SVT) in premenopausal women is often judged to be related to anxiety, and may be associated with the menstrual cycle. The aim of this study was to determine whether a cyclical variation of episodes of SVT exists and to correlate such variation with cyclical variation in plasma ovarian hormones. METHODS 26 women (mean age 36 [SD 8] years; with paroxysmal SVT were screened; those with regular menses who experienced at least three episodes of paroxysmal SVT in two consecutive 48-hour ambulatory ECG recordings were included. 13 patients (aged 32 [6] years) met these criteria. Patients underwent 48-hour ambulatory ECG monitoring and determination of plasma concentrations of oestradiol-17 beta and progesterone on day 7, 14, 21, and 28 of their menstrual cycle. FINDINGS An increase in the number and duration of episodes of paroxysmal SVT was observed on day 28 as compared to day 7 of the menstrual cycle. A significant positive correlation was found between plasma progesterone and number of episodes and duration of SVT (5.6 [2.2] ng/mL; r=0.83, p=0.0004; and r=0.82, p=0.0005), while a significant inverse correlation was found between plasma oestradiol-17 beta and number of episodes and duration of SVT (155 [22] pg/mL; r=0.89, p<0.0001; and r=0.81, p=0.0007). INTERPRETATION Women with paroxysmal SVT and normal menses exhibit a cyclical variation in the occurrence of the arrhythmia with their menstrual cycle. There is a close correlation between the episodes of paroxysmal SVT and the plasma concentrations of ovarian hormones. These data suggest that changes in plasma levels of ovarian hormones (and their interaction) may be of importance in determining episodes of arrhythmia in such patients. The mechanisms of these effects are unknown.

Sex and menopause: defining the issues

This is a study of 185 women attending a menopause clinic in London, England. Individual interviews carried out by a gynecologist trained in sex therapy found a variety of psychosexual problems affected the lives of a large majority of the women. Sex problems existing prior to menopause were exacerbated. For most of the women, however, problems developed during the years immediately preceding and following menopause. Problems included disorders of sexual desire, sexual response and sexual behavior. Menopause clinic staff should be alert to the presence of sex problems and should play a role in diagnosis, treatment and/or referral.

Effect of Estrogen Replacement Therapy on Heart Rate Variability and Heart Rate in HealthyPostmenopausal Women

Increased sympathetic drive in symptomatic menopausal women was reduced after estrogen replacement therapy for 4 months, which has a potentially beneficial effect on cardiovascular functions.

Skin changes in menopause

Skin signs and symptoms were examined in 46 menopausal women prior to estrogen replacement therapy. Several symptoms such as pruritus, bruising, dryness and thinning were seen more frequently in sun-exposed skin emphasizing the contribution of photoaging. At the end of a 6-mth treatment period, no significant difference was observed in the prevalence or severity of the cutaneous signs and symptoms when patients receiving transdermal 17 beta-estradiol (Estraderm) were compared with controls (the only exception was cutaneous flushing). Elastic fibers from sun-protected (buttock) skin of menopausal women were studied by light and electron microscopy. In 3 women (ages 30-37) with a history of premature menopause, the elastic fibers had several degenerative changes including coalescence of cystic spaces into lacunae, peripheral fragmentation, granular degeneration and splitting of the fibers into strands. Similar age-related ultrastructural changes are normally found in individuals that are at least 20 yrs older than these patients. These findings are suggestive of a relationship between premature aging of the dermal elastic fibers and estrogen deprivation.

Psychosexual effects of menopause: Role of androgens

Ovarian hormones-estrogens, androgens, and progesterone-produce a myriad of effects in the nervous system. The effects of androgens in the brain are mediated through androgen-specific receptors and by the aromatization of testosterone to estradiol. Alterations in the circulating levels of androgens play an important role in psychologic and sexual changes that occur after menopause. The effects of short-term estrogen therapy in improving psychologic symptoms, maintaining vaginal lubrication, decreasing vaginal atrophy, and increasing pelvic blood flow in postmenopausal women are well documented. However, some patients require more than estrogen alone to improve psychologic dysfunction, decreased sexual desire, or other sexual problems associated with menopause. Results from clinical studies show that hormone replacement therapy with estrogen plus androgens provides greater improvement in psychologic (eg, lack of concentration, depression, and fatigue) and sexual (eg, decreased libido and inability to have an orgasm) symptoms than does estrogen alone in naturally and surgically menopausal women.