Estrogen replacement therapy. Measuring benefit v cardiovascular risk.
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Cardiovascular Diseases↗
Biomedical subjects
D R Mishell
Publications and source records attributed to D R Mishell.
Management of the postmenopausal woman with hypertension. Case presentation and panel discussion.
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Antihypertensive Agents↗
Long-term reversible contraception with levonorgestrel-releasing Silastic rods.
Subcutaneously placed Silastic capsules containing levonorgestrel are effective for 5 years and have a higher continuation rate than other methods of reversible contraception. Six 3 cm capsules are required to achieve satisfactory circulating levels of levonorgestrel. Two 4 cm covered Silastic rods containing levonorgestrel, which are easier to manufacture, insert, and remove than the capsules, produce similar in vitro release rates. This study compared clinical and metabolic effects as well as bleeding patterns in 23 women using either six capsules (n = 11) or two covered rods (n = 12). Serum levels of levonorgestrel, lipids, and lipoproteins as well as frequency of elevated progesterone levels were compared in serum samples obtained before treatment and 1, 6, 12, 18, and 24 months after insertion with the two systems. While bleeding patterns were similar for users of the two systems, rod users had slightly higher serum levels of levonorgestrel and a lower incidence of cycles with elevated progesterone levels. Therefore, rods could replace capsules as a long-term, reversible contraceptive method.
Adolescent↗
The relation of physiological changes to subjective symptoms in postmenopausal women with and without hot flushes.
This study was designed to fully correlate the temporal relationship between augmented digital perfusion, (vasodilatation) and hot flushes, peripheral temperature, plasma luteinizing hormone, (LH) epinephrine and norepinephrine. Plasma samples were measured every 3 min for 2-4 h, in 5 symptomatic women before and after estrogen replacement and in 3 asymptomatic post-menopausal women. In all 5 symptomatic women the augmented digital perfusion occurred at a mean (+/- SEM) of 1.5 +/- 0.2 min before the initiation of the flush, at least 3 min before the initial rise in temperature and 9 min before the LH rise. There was a significant (P less than 0.05) rise in epinephrine but not norepinephrine at 3 and 6 min after the initiation of augmented digital perfusion. Although subjective improvement occurred in all 3 women receiving estrogen, all measured parameters disappeared in only 1 subject and the 2 others continued having augmented digital perfusion, flushes, and temperature vasomotor changes although the related LH increase was absent. Surprisingly, asymptomatic women who never received estrogens also demonstrated similar augmented digital perfusion and temperature changes, but failed to show the LH related rise, as observed in women with short-term estrogen treatment. In conclusion, these results demonstrate that augmented digital perfusion consistently precedes the hot flush, the rise in temperature and plasma LH in symptomatic post-menopausal women. The increase in epinephrine may be a homeostatic mechanism to compensate for the peripheral vasodilatation. The finding that augmented digital perfusion and temperature changes also occur in asymptomatic post-menopausal women indicates that objective changes are more specific and reliable indicators of vasomotor instability than the subjective sensation of hot flushes.
Adult↗
Effect of variable concentration of serum on mouse embryo development.
This study was undertaken to determine the optimal concentration of serum necessary for maximal embryo development. Mouse embryos were cultured in vitro with 0% to 30% concentrations of serum of 96 hours. After 72 and 96 hours of culture, embryo growth was improved with 5%, 10%, 20%, and 30% serum supplement when compared with Ham's F-10 medium alone. Embryos were then cultured with the same concentrations of serum for 29 hours, following which blastomere number, sister chromatid exchange (SCE), number of micronuclei, and chromosomal aberrations were observed. There was no difference in blastomere number with any concentration of serum supplement studied. All concentrations of serum decreased the number of SCE when compared with Ham's F-10 medium alone. The rate of SCE in embryos cultured with 10%, 20%, or 30% serum was also smaller than that of the embryos cultured with 5% serum. The results of these studies indicate that serum should be employed for culturing embryos, and at least 10% serum concentration is necessary to obtain optimal conditions for embryo development.
Animals↗
Hyperprolactinemia: comparison of thyrotropic-releasing hormone and tomography.
A group of 95 women with unexplained hyperprolactinemia (over 20 ng/mL) underwent radiologic examination of the sella turcica with hypocycloidal polytomography (N = 58), computed axial tomography (N = 8), or both (N = 29). All patients also underwent a thyrotropin-releasing hormone (TRH) stimulation test, with serum prolactin (PRL) measurement before and 20 and 30 minutes after a 500-micrograms intravenous bolus of TRH. Their PRL responses were compared with those of two control groups, nine normal women in the follicular phase of the menstrual cycle, and 13 women in the first five months of gestation with pregnancy-related hyperprolactinemia. Both control groups exhibited PRL increases with 95% confidence limits at least 200% above baseline levels. In all, 12 patients from the study group also had a normal PRL response (more than a 200% increase) to TRH, and none of these women had tomographic findings consistent with a pituitary tumor. The remaining 83 women all had diminished or absent PRL increases after TRH administration; 46 (55%) of these patients had radiographic evidence of an adenoma, whereas 37 (45%) had no clear signs of a tumor on either polytomography or computed axial tomography. No patient with a baseline PRL level in excess of 60 ng/mL had a normal PRL response to TRH. The results of the study indicate that 1) in patients with PRL between 20 and 60 ng/mL, a normal TRH test can be relied upon to avoid the expense and radiation of tomography (computed axial tomography or polytomography), 2) there is no benefit to be obtained in performing a TRH test in patients with a baseline PRL level over 60 ng/mL, and 3) about 45% of patients with hyperprolactinemia and an abnormal TRH test have a normal computed tomography or polytomography. These patients may have a small adenoma, and thus warrant closer follow-up than patients with a normal TRH test.
Adenoma↗
Intrauterine devices.
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Abortion, Septic↗
The effect of serum fractions on embryo growth.
In order to determine optimal culture conditions for embryos, human fetal cord serum (HCS) small- and large-molecular-weight fractions of HCS, and human serum albumin were employed as media supplements. In the first phase, embryos were cultured with the various protein supplements for 96 hours and observed morphologically every 24 hours. In the second phase, embryos were cultured with the various protein supplements and 5-bromo-2-deoxyuridine for 29 hours. Blastomere number, sister chromatid exchange (SCE), micronuclei, and chromosomal aberrations were observed. Morphologically, any protein supplement was better than no media supplement. Whole HCS and large-molecular-weight fraction provided the best conditions for embryo growth. Blastomere number was increased with whole serum when compared with no supplementation, small-molecular-weight fraction, or human serum albumin. In the analysis of SCE, all supplements had a lower SCE number than no serum supplement, and HCS supplement demonstrated a significantly lower SCE number than the other supplements. No difference in micronuclei or chromosomal aberration was observed in any of the supplements. In conclusion, whole HCS provides optimal conditions for culturing embryos, compared with the various serum fractions, and the beneficial components are primarily found in the large-molecular-weight fraction.
Animals↗
A modified technique of human in vitro fertilization and embryo transfer.
Forty-seven ovulatory women were treated with a modified technique of human in vitro fertilization and embryo transfer. All patients received clomiphene citrate, 150 mg per day, and follicle development was monitored by real-time ovarian ultrasound and serum estradiol measurement. In the 45 patients who underwent laparoscopy, eight patients were found to have a poor response to clomiphene citrate and were dropped from the treatment cycle. Four additional patients had an endogenous luteinizing hormone increase and did not undergo laparoscopy. Nine patients were found to have inaccessible ovaries at the time of laparoscopy. In patients with accessible ovaries, oocytes were recovered in all cases. Embryo transfers were performed in 72% of patients, and 19% of these transfers resulted in pregnancy. This technique of ovulation monitoring appears to increase oocyte recovery and fertilization rate and subsequent implantation success.
Adult↗
Clinical applications of techniques used in human in vitro fertilization research.
Human in vitro fertilization-embryo transfer not only provides an opportunity for pregnancy in women who were previously considered to be sterile, but also provides a unique method by means of which basic reproductive physiology can be investigated. From September, 1981, to September, 1982, 71 women with normal cycles who elected to attempt in vitro fertilization-embryo transfer underwent timed laparoscopy for recovery of oocytes. Oocytes were recovered in 60 patients, with embryo transfer resulting in 50 patients, and normal implantation occurred in nine patients. There was a significant correlation between ultrasound observation of follicle size and serum estradiol levels, thus making ultrasound monitoring of follicular growth during stimulation with clomiphene citrate or human menopausal gonadotropin in anovulatory women clinically useful. The technique of sperm washing employed for in vitro fertilization has now been used with good results for intrauterine insemination in patients with infertility due to a cervical factor or oligospermia. Therefore, the techniques used in human in vitro fertilization-embryo transfer are now clinically applicable for couples with infertility due to causes other than tubal disease.
Adult↗
Effects of two low-dose oral contraceptives on serum lipids and lipoproteins: differential changes in high-density lipoprotein subclasses.
Oral contraceptives containing DL-norgestrel or norethindrone with ethinyl estradiol were administered by random assignment to 21 menstruating women, matched for anthropometric measurements, age, diet, alcohol consumption, smoking, and exercise habits. Pretreatment and 7-week treatment blood samples were obtained and assayed for serum cholesterol, triglyceride high-density lipoprotein cholesterol (HDL-C), and total high-density lipoprotein (HDL), HDL2a, HDL2b, and HDL3 subclasses by analytic ultracentrifugation. Subjects using the norethindrone oral contraceptive had a significant increase in HDL-C: baseline, 46 mg/dl; 7 weeks, 51 mg/dl. Values for the subjects using the norgestrel oral contraceptive were not significantly changed: 46 and 44 mg/dl, respectively. Users of the norethindrone oral contraceptive had significant elevations of total HDL and HDL3, while norgestrel oral contraceptive users demonstrated no significant changes. HDL2b increased with the norethindrone oral contraceptive and declined with the norgestrel oral contraceptive. The changes in HDL2b from baseline to treatment were not significant (p greater than 0.05), but the change with the norethindrone oral contraceptive did differ significantly from that with the norgestrel oral contraceptive (p less than 0.02). These changes may indicate oral contraceptive-induced alterations in HDL structure and metabolism that could be related to the risk of development of atherosclerosis.
Adult↗
Psychological stress and increases in urinary norepinephrine metabolites, platelet serotonin, and adrenal androgens in women with polycystic ovary syndrome.
Twenty-three women with polycystic ovary syndrome, 10 women with hypothalamic-pituitary dysfunction, and 50 control subjects were studied in an attempt to investigate the prevalence of psychological stress and its possible relationship to various hormonal parameters. Norepinephrine (NE) excretion, as reflected by urinary 3-methoxy-4-hydroxyphenylglycol (MHPG), and urinary 3-methoxy-4-hydroxymandelic acid (VMA), platelet serotonin, plasma adrenocorticotrophic hormone (ACTH), urinary free cortisol, serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), androstenedione (Adione), dehydroepiandrosterone (DHEA), its sulfate (DHEA-S), delta 5-androstenediol (delta 5-Adiol), testosterone (T), and unbound estradiol (E2) were measured. In addition, psychological stress was assessed by means of questionnaires modified from the Schedule of Recent Experiences, in which a Life Events Inventory was scored between 1 and 100. Women with polycystic ovary syndrome had significantly elevated levels of serum LH, LH:FSH ratios, unbound E2, Adione, DHEA, delta 5-Adiol, T, and DHEA-S (p less than 0.01). The number of Major Life Events (events scored on the questionnaire above 60) was significantly higher in women with polycystic ovary syndrome than in control women and women with hypothalamic-pituitary dysfunction (p less than 0.05). Urinary MHPG and platelet serotonin levels were also significantly higher in women with polycystic ovary syndrome (p less than 0.05), whereas VMA was normal. Levels of plasma ACTH and urinary free cortisol were similar in all groups. There was a significant positive correlation between MHPG and DHEA-S, MHPG and LH, and LH and T levels in women with polycystic ovary syndrome and those with hypothalamic-pituitary dysfunction (p less than 0.01). VMA also correlated with DHEA-S (p less than 0.05). In conclusion, psychological stress may be more prevalent in women with polycystic ovary syndrome and may be associated with elevated levels of MHPG and platelet serotonin. Because we have found that MHPG, but not VMA, correlated with LH, and because both MHPG and VMA correlated with DHEA-S, we hypothesize here that psychological stress and neurotransmitter levels may be linked to some of the hormonal derangements, including inappropriate gonadotropin secretion and elevated adrenal androgen levels in women with polycystic ovary syndrome.
Adolescent↗
Methods to determine success of attempts to terminate early gestation pregnancies with prostaglandin vaginal suppositories.
One-hundred subjects received vaginal suppositories containing prostaglandin analogues in order to terminate their pregnancies of 49 days gestation or less. This non-surgical method was successful in 61 subjects, failed in 35 subjects and four subjects were lost to follow-up. Success of prostaglandin therapy cannot be predicted using pretreatment clinical parameters, pretreatment serum beta-hCG levels, or the passage of tissue from the vagina based upon history obtained from the subject. The passage of tissue histologically identified as of fetal origin is a definitive way to determine the success of pregnancy termination but the passage of tissue obtained by history is not. Of the 61 subjects in whom the prostaglandin suppositories were a success, 56 (92%) had a beta-hCG level day 7 +/- 2 following treatment which was 15% or less than the pretreatment value and 5 had beta-hCG levels which were more than 15% of the pretreatment value. All subjects with beta-hCG levels 5 to 9 days after the abortion that were less than 15% of the pretreatment concentrations had a successful termination. Of 35 subjects in whom the prostaglandin suppositories were unsuccessful, 26 had a beta-hCC level 7 +/- 2 days following treatment which was greater than the pretreatment level and 9 had beta-hCG levels less than the pretreatment value. The results of this study indicate that when prostaglandin vaginal suppositories are used to terminate early gestations, if there is no decline in beta-hCG levels 7 +/- 2 days following treatment, the pregnancy should be terminated by another method.
Abortion, Induced↗
Metabolic parameters and steroid levels in postmenopausal women receiving lower doses of natural estrogen replacement.
This study was carried out to determine whether some of the lowest doses of natural estrogens currently prescribed for postmenopausal women result in significant changes in plasma lipids, urinary calcium, urinary free cortisol, or level of androgens. Twenty-four postmenopausal women were studied and the estrogens ingested were either conjugated estrogens (0.3 or 0.6 mg), piperazine estrone sulfate (0.6 or 1.2 mg), or micronized estradiol (1 mg). Plasma lipids were unaltered, with the exception of a decrease in low-density lipoprotein cholesterol in women receiving conjugated estrogens, 0.625 mg, and micronized estradiol. The fasting calcium: creatinine ratio, which was significantly higher than that of premenopausal women, decreased significantly after treatment with all the prescribed doses. There was no correlation between the initial calcium: creatinine ratio and urinary free cortisol or androgen levels. Urinary free cortisol was in the premenopausal range and did not change with treatment; levels of dehydroepiandrosterone sulfate and testosterone were significantly lower than premenopausal levels but did not change with treatment. In conclusion, these natural estrogens have no effect on lipids, urinary free cortisol, and androgen levels, but they appear to reduce the urinary loss of calcium in the fasting state.
Androgens↗
Comparison of pharmacodynamic properties of various estrogen formulations.
A group of 23 healthy postmenopausal women received one or more 2-week courses of daily administration of the following estrogen preparations: piperazine estrone sulfate (Ogen), 0.3, 0.625, 1.25, 2.5, and 5.0 mg; micronized estradiol (Estrace), 1, 2, and 10 mg; conjugated estrogens (Premarin), 0.3, 0.625, 1.25, and 2.5 mg; ethinyl estradiol (Estinyl), 10 and 20 micrograms; and diethylstilbestrol, 0.1 and 0.5 mg. Each dosage of each formulation was ingested by three women. In those women who received more than one dosage, each course was separated by a drug-free interval of at least 4 weeks. Pretreatment and posttreatment levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), corticosteroid-binding globulin-binding capacity, sex hormone-binding globulin-binding capacity, angiotensinogen, estrone, and estradiol were determined. The relative potency of these five estrogen formulations was determined by parallel line analysis for each of these responses, except LH. On a weight basis, piperazine estrone sulfate and micronized estradiol were equipotent for all responses. Conjugated estrogens suppressed FSH in a fashion equipotent to that of the other nonsynthetic estrogens; however, for all three hepatic parameters, the response was exaggerated twofold to threefold. The synthetic estrogens, diethylstilbestrol and ethinyl estradiol, were relatively more potent on a weight basis for every response and produced the most marked response (fourfold to eighteenfold in excess of their FSH suppression) for the hepatic parameters.
Angiotensinogen↗
Correlation of ultrasonic measurement of ovarian follicle size and serum estradiol levels in ovulatory patients following clomiphene citrate for in vitro fertilization.
Ovarian follicle development was investigated in 38 normally cycling women who received clomiphene citrate, 150 mg per day for 5 days, to maximize follicular development. Ultrasonic determination of follicle growth was performed on a daily basis with a real-time sector scanner and correlated with daily concentrations of estradiol (E2) in the peripheral serum as measured by rapid radioimmunoassay. Human Chorionic gonadotropin was given to induce ovulation, and the day of injection was considered day 0. Mean concentrations of E2 reached a maximum of 1,150 +/- 65 pg/ml on day 0. Mean diameter of the dominant follicle increased to 22.1 +/- 0.4 on day 0. When peripheral concentrations of E2 were correlated with diameter and total follicular volume it was found that plasma E2 levels varied, depending on the number of follicles seen on ultrasound examination, with a mean E2 value of 459 +/- 18.9 pg/ml per follicle per day. Multiple growth of follicles occur with artificial induction of ovulation; therefore, the use of ultrasound is an important parameter to assess follicular maturation and the timing of ovulation more precisely.
Adult↗
Changes in unbound sex steroids and sex hormone binding globulin--binding capacity during oral and vaginal progestogen administration.
Four groups of five cycling women each received either a contraceptive vaginal ring containing a combination of either levonorgestrel or norethindrone with estradiol or oral contraceptives containing a combination of either dl-norgestrel or norethindrone with ethinyl estradiol. Pretreatment as well as 2- and 7-week treatment serum samples were assayed for sex hormone binding globulin-binding capacity (SHBG-BC), estradiol, non-SHBG-bound estradiol, testosterone, and non-SHBG-bound testosterone, d-norgestrel, non-SHBG-bound d-norgestrel, and norethindrone. SHBG-BC was significantly increased in the norethindrone oral contraceptive group, unchanged in the norgestrel oral contraceptive group, and significantly reduced in both contraceptive vaginal ring groups. These findings indicate that the positive effect of oral ethinyl estradiol on SHBG-BC offsets the suppressive effects of d-norgestrel on SHBG-BC, while the estradiol in the d-norgestrel or norethindrone contraceptive vaginal rings is insufficient to alter the suppressive effect of d-norgestrel or norethindrone on SHBG-BC. In contrast, the ethinyl estradiol in the norethindrone oral contraceptive overcame the suppressive effect of norethindrone on SHBG-BC, resulting in a significantly increased SHBG-BC level. Although total circulating estradiol was significantly decreased in the contraceptive vaginal ring groups, the percentage of unbound serum estradiol was significantly increased in both contraceptive vaginal ring groups and significantly reduced in the norethindrone oral contraceptive group. Although total circulating testosterone was significantly reduced only in the norgestrel oral contraceptive group, the percentage and mass of unbound testosterone were significantly decreased in the norethindrone oral contraceptive group, while the percentage of unbound testosterone was significantly reduced in the norgestrel oral contraceptive group and significantly increased in the norethindrone contraceptive vaginal ring group. As levels of unbound (biologically active) steroid differ markedly from levels of total steroid, it is essential to measure levels of non-SHBG-bound estradiol and testosterone in order to determine effects of steroidal contraceptives on physiologically active circulating endogenous steroids.
Adult↗