Relationships of serum estradiol levels, menopausal duration, and mood during hormonal replacement therapy.

A study was undertaken in 38 menopausal women on-cyclic HRT (estropipate) and estropipate + nor-ethindrone). Serum estradiol levels during treatment were related to mood changes and platelet MAO activity. The relationship between serum estradiol levels and mood changes was found to be a function of the duration of menopause. Women with a short duration of menopause (12.9 months +/- 6.1) were compared to women with a long duration of menopause (76.6 months +/- 52.3). Women with a short duration of menopause had significantly lower mean serum estradiol levels during HRT compared to women with a long duration of menopause (216.9 +/- 62.3 vs. 291.13 +/- 118.12, respectively, p < .02). It had previously been reported that estrogen treatment in menopausal women had a positive effect on mood, whereas the combination of estrogen plus a progestin had a negative effect on mood. We found that the women with a long duration of menopause and higher treatment serum estradiol levels had significantly more dysphoria when receiving a combination of estrogen plus progestin than did the women with a short duration of menopause and lower serum estradiol levels. However, both short and long duration menopausal groups showed improvement in mood when estrogen was administered alone. Platelet MAO levels, a marker of adrenergic and serotonergic function thought to relate to mood, were negatively correlated with serum estradiol levels during HRT. We suggest that these paradoxical findings may be secondary to a prolonged estrogen deficiency state in women with a long duration of menopause.

Individual differences in changes in mood and platelet monoamine oxidase (MAO) activity during hormonal replacement therapy in menopausal women.

Estrogen replacement treatment in menopausal women has been reported to have a positive effect on mood states. However, the addition of a progestin partially negates this positive effect in some women. The opposite effects of estrogen and progestin on mood may relate to their opposite effects on adrenergic and serotonergic neural function. In a double-blind, placebo-controlled, crossover study, 38 nondepressed menopausal women were cyclically treated with estrogen and estrogen plus progestin, or with placebo, for five 28-day cycles. This paper identifies the pretreatment attributes of women who do and do not have negative mood responses to progestin, and examines the relationship of these adverse side-effects to platelet monoamine oxidase (MAO), a marker of adrenergic and serotonergic functioning. Adverse mood responses to progestin occur in women with a long duration of menopause, low pretreatment serum estradiol and testosterone levels, high pretreatment serum FSH levels, low pretreatment platelet MAO activity, and pretreatment mood abnormalities. We conclude that adverse mood response to the addition of a progestin occurs in menopausal women who have low pretreatment gonadal hormone levels secondary to a long duration of menopause. Impaired central nervous system adrenergic and serotonergic functioning also may be a factor predisposing to a negative mood response to progestin.

Dynamics of estradiol and testosterone and seminal fluid indexes in smokers and nonsmokers.

The serum levels of estradiol (E2) and testosterone (T), the metabolic clearance rates of estradiol (MCRE2) and testosterone (MCRT), and the production rates of estradiol and testosterone (PRE2) and (PRT) were examined in 22 male smokers and 21 male nonsmokers. Seminal fluid indexes (sperm count, % motility, grade of motility, and % of sperm with abnormal morphology) were also assessed. The mean E2 level and the mean PRE2 were significantly greater in smokers than in nonsmokers (P less than 0.001 and P less than 0.01, respectively); however, the means of MCRE2, MCRT, PRT, and T did not differ significantly in smokers compared to nonsmokers. No significant product-moment correlations were found between the various hormonal measures and the seminal fluid indexes in the overall sample. However, the smokers with sperm counts below the median sperm count of the sample had significantly higher mean levels of E2 and PRE2 than did the smokers with sperm counts above that median. Mechanisms that might mediate the greater PRE2 of smokers and a negative relationship between estradiol and sperm count are discussed.

PIP: Serum levels of estradiol (E2) and testosterone (T), the metabolic clearance rates of estradiol (MCRE2) and testosterone (MCRT), and the production rates of estradiol (PRE2) and testosterone (PRT) were examined in 22 male smokers and 21 male nonsmokers recruited from local colleges. Also assessed were seminal fluid indexes. The mean E2 level of smokers (36.7 + or - 14.3 pg/ml) was significantly higher than that of nonsmokers (24.6 + or - 7.0 pg/ml) (p0.001); the mean PRE2 was also significantly higher among smokers (48.3 + or - 18.5 mcg/24 hours) than nonsmokers (34.1 + or - 14.0 mcg/24 hours) (p0.01). Although smokers had a significantly higher mean MCRT than nonsmokers, this difference was no longer significant when corrections were made for body surface area. There were no significant differences between T, PRT, or MCRE2 of the smokers and nonsmokers. No significant product-moment correlations were found between the various hormonal measures and the seminal fluid indexes in the overall sample. However, smokers with sperm counts below the median of the sample had significantly higher mean levels of E2 and PRE2 than smokers with sperm counts above the mean. The number of cigarettes smoked or the duration of smoking did not relate significantly to the E2 levels, PRE2, or the seminal fluid indexes. The mechanism by which cigarette smoking induces an increased PRE2 is unknown. However, it is hypothesized that, by increasing blood catecholamine levels, smoking may increase the conversion of testosterone to estradiol, via aromatization in peripheral tissues, thereby increasing the production rate and, secondarily, the serum level of estradiol.

Interrelationships of cigarette smoking, testicular varicoceles, and seminal fluid indexes.

Data on cigarette smoking, testicular varicoceles, seminal fluid indexes, and oligospermia were examined in 160 young men without known disease and in 94 husbands in infertile couples. The combination of smoking and testicular varicoceles is strongly related to the incidence of oligospermia, defined as sperm count less than or equal to 20 X 10(6)/ml, in each sample. Smokers with testicular varicoceles, in each sample, had a disproportionately high incidence of oligospermia. In the combined sample of 254 men, the smokers with testicular varicoceles had an incidence of oligospermia approximately ten times greater than that in nonsmokers with testicular varicoceles and approximately five times greater than that in men who smoked but were without testicular varicoceles. This relationship of cigarette smoking and testicular varicoceles to oligospermia has not been previously reported. The pathophysiologic basis of the interaction between smoking and varicoceles was theorized to be due to an increased secretion of catecholamines from the adrenal medulla, induced by cigarette smoking. The elevated catecholamine concentrations in the renal vein would then reach the testes via retrograde flow down the internal spermatic vein in men with testicular varicoceles, resulting in seminiferous tubule damage.

Relation of blood estradiol levels to EEG photic driving in smoking vs. non-smoking normal males.

In normal young males, estradiol has effects which are opposite to those of testosterone on EEG driving responses to photic stimulation. Testosterone in males impairs the EEG driving response to photic stimulation, while estrogen enhances the EEG response to photic stimulation. Estrogen in males would appear to impair central adrenergic functioning.

A comparison of the antidepressant effects of a synthetic androgen (mesterolone) and amitriptyline in depressed men.

The antidepressant effects of amitriptyline and mesterolone, a synthetic androgen, were compared in a double-blind parallel treatment design. The drugs were equally effective in reducing depressive symptoms. Mesterolone produced significantly fewer adverse side effects than amitriptyline.

Serum estradiol levels in male cigarette smokers.

Serum estradiol levels were compared in smoking and nonsmoking men in two separate samples. Sample I consisted of 41 young adult male volunteers ranging in age from 18 to 24 years. Twenty-three men smoked an average of 24.5 +/- 6.9 cigarettes daily. The duration of smoking averaged 5.2 +/- 2.2 years. Sample II consisted of 35 husbands who had been evaluated for infertility; they ranged in age from 19 to 49 years. Eighteen men smoked an average of 21.6 +/- 7.9 cigarettes daily. The duration of smoking averaged 11.5 +/- 4.5 years. Age, height, and weight did not differ significantly between smokers and nonsmokers within either group. Serum estradiol levels were significantly elevated in smokers compared with nonsmokers in both groups (p less than 0.001 and p less than 0.0001 in Samples I and II, respectively). No significant correlations were found between serum estradiol levels and the number of cigarettes smoked daily, or with the duration of smoking in either sample. The differences in serum estradiol levels between smokers and nonsmokers could not be attributed to the differences in marijuana and alcohol use that existed between the smokers and nonsmokers in each sample. The recent reports of elevated serum estradiol levels as a possible risk factor in coronary heart disease are discussed in view of the known relationship of cigarette smoking to coronary heart disease.

Serum estrogen levels in men with acute myocardial infarction.

Serum estradiol and serum estrone levels were assessed in 29 men in 14 men in whom myocardial infarction was ruled out; in 12 men without apparent coronary heart disease but hospitalized in an intensive care unit; and in 28 men who were not hospitalized and who acted as control subjects. (The 12 men who were hospitalized but who did not have coronary heart disease were included to control for physical and emotional stress of a severe medical illness.) Ages ranged from 21 to 56 years. Age, height, and weight did not differ significantly among groups. Blood samples were obtained in the patient groups on each of the first three days of hospitalization. The serum estrone level was significantly elevated in all four patient groups when compared with that in the control group. Estrone level, then, did not differentiate patients with and without coronary heart disease. Serum estradiol levels were significantly elevated in the groups with myocardial infarction, unstable angina, and in the group in whom myocardial infarction was ruled out. However, estradiol levels were not significantly elevated in the group in the intensive care unit without coronary heart disease when compared to the level in the normal control group. Serum estradiol levels, then, were elevated in men with confirmed or suspected coronary heart disease but were not elevated in men without coronary heart disease even under the stressful conditions found in an intensive care unit. Serum estradiol levels were significantly and positively correlated (p less than 0.03) with serum total creatine phosphokinase levels in the patients with myocardial infarction. The five patients with myocardial infarction who died within 10 days of admission had markedly elevated serum estradiol levels. The potential significance of these serum estradiol elevations is discussed in terms of estradiol's ability to enhance adrenergic neural activity and the resultant increase in myocardial oxygen demand.

Effect of caffeine on performances of a perceptual-restructuring task at different stages of practice.

Caffeine, a sympathomimetic drug which stimulates the adrenergic nervous system, was hypothesized to exert opposite effects upon performances of a perceptual-restructuring task (the Embedded Figures Task) at different stages of practice. Specifically, caffeine was hypothesized to impair performances of perceptual-restructuring tasks when the task is still novel in early trials; and to facilitate practice induced gains in task performance as the task becomes less novel. Sixty male undergraduates were studied. Each subject was tested on the Embedded Figures Task twice, in one of the following three sequences: caffeine-placebo; placebo-caffeine; and placebo-placebo. Both hypotheses received statistically significant support.

Changes in cognitive task performance across the menstrual cycle.

Menstrual-cycle-related changes in estrogen were expected to differentially affect various cognitive tests. Specifically, the estrogen peak occurring at midcycle in ovulatory women was expected to facilitate performance of highly practiced "automatized" tasks and to impair performance of "perceptual-restructuring" tasks, compared with performance of these tasks in the postovulatory phase of the cycle when progesterone is thought to counteract the action of estrogen. Perceptual-restructuring tasks are defined as tasks in which the initial percepts to obvious stimulus attributes are wrong and must be set aside in favor of percepts to less obvious stimulus attributes. Eight-seven regularly menstruating undergraduate women were studied. Odd-numbered subjects were tested first on or about Day 10 of their cycle and then again on Day 20; even-numbered subjects, in the reverse sequence. Daily basal body temperature records were obtained. These temperature records suggested that 21, or 24%, of the subjects did not ovulate in the cycle(s) studied. No main effect of Day 10 versus Day 20 occurred for any task in the 66 women who did appear to ovulate. However, the magnitude of predicted shifts in performance was significantly correlated with proximity of the "Day 10" testing day to the thermal nadir of the basal body temperature record, the presumed preovulatory estrogen peak; and to the "Day 20" proximity to the basal body temperature thermal peak, the presumed progesterone peak. Subjects tested 3 or fewer days before the thermal nadir and on or after the thermal peak had the predicted significant changes on three of the four administered tasks. No other temporally defined group produced significant changes. The results of the study support the experimental hypotheses and also indicate that precise timing is essential to demonstrate the phenomena.

Estrogen therapy for severe persistent depressions in women.

Positive results are reported from a double-blind study of estrogen therapy administered to severely depressed, inpatient women who had failed to respond to various conventional treatments of depression. Large doses of oral conjugated estrogen were administered for a three-month period to 23 premenopausal and postmenopausal inpatient women. Placebos were administered for a comparable period to 17 similar patients. The posttreatment Hamilton ratings of depression were significantly reduced in the estrogen-treated group, but not in the placebo group. Possible physiological mechanisms are discussed. The risk-benefit ratio for estrogen therapy of depression in these patients was judged to be favorable. However, periodic endometrial biopsies are required to monitor the endometrial response of women receiving high doses of estrogens.

PIP: The effectiveness of estrogen therapy for alleviating severe depressions was investigated in a double blind study in which large doses of estrogen were administered to 15 premenopausal and 8 postmenopausal women and placebos were administered to 12 premenopausal and 5 postmenopausal women. The estrogens and placebos were administered over a three month period, and the women were blind rated each week by psychologists and psychiatrists using Hamilton rating scales for depression. There was a significant decline in the depression scores for the group treated with estrogens when compared to the placebo treated group. Considerable variation in the degree of improvement for the women in the estrogen treated group was observed. These variations were not related to age or to menstrual status but were significantly related to depression duration. Women with shorter histories of depression were more likely to show improvement than women with longer illness durations. Efforts were also made to understand the physiological mechanisms through which estrogen treatment contributed toward reducing depression. Previous studies revealed that decreased availability of norepinephrine at the central adrenegic receptor sites in the brain was related to the manifestation of depression while increased availability of norepinephrine at these sites was ralated to a manifestation of elation. Increased availability of norepinephrine has been shown to be related to an inhibition of monoamine oxidase activity (MAO), and estrogen, in turn, has been demonstrated to inhibit MAO activity. During the 3 month study period, 2 blood samples were obtained from the women every week and analyzed for MAO activity. All patients had elevated levels of plasma MAO activity prior to treatment. In estrogen treated patients, MAO levels declined significantly; MAO levels unexplicably increased for the placebo treated group. Reduced MAO activity was not, however, significantly correlated with lower depression ratings. In determining the risk/benefit ratio of estrogen therapy both the risk of developing endometrial cancer and the risks of life long disability and suicide stemming from severe depression should be considered. Tables show 1) mean depression ratings and average MAO activity levels before and after treatment for the estrogen and placebo treated groups and 2) degree of change in depression ratings before and after treatment for both groups of women.

Effect of ascorbic acid on the human electroencephalogram.

Controversy exists over whether ascorbic acid (vitamin C) in doses in excess of known physiological requirements has demonstrable biological effects. The present study reports that such megadoses of vitamin C do significantly effect an objective electrophysiological measure, i.e., electroencephalogram (EEG) driving responses to photic stimulation. Four thousand milligrams of vitamin C administered 27 and 3 hours prior to assessment produced an effect on the EEGs of 18 healthy adolescent human males that was significantly different from a placebo. Fifty milligrams of ascorbic acid administered in this manner did not produce an effect on the EEG significantly different from placebo administration.