Biomedical subjects
J W Goldzieher
Publications and source records attributed to J W Goldzieher.
Media scan. Hormone replacement therapy and breast cancer risk. Commentary.
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Natural family planning: suitability of the CUE method for defining the time of ovulation.
The purpose of this study was to compare the CUE method for family planning with the Ovulation Detection Method for defining the fertile phase of the menstrual cycle. We evaluated 42 cycles from 10 women in Monterrey, Mexico, who were monitored by basal body temperatures, urinary LH, pelvic ultrasound, and the CUE monitor. The fertile phase of the cycle was adequately defined in all cycles using the CUE method, and in 35 cycles (83.3%) by the Ovulation Method. Using our protocol, the period of recommended abstinence with the CUE method is 9 days and with the Ovulation Method 11 days. The CUE method accurately defines the fertile phase of the menstrual cycle, thus improving the predictability of ovulation for women who use natural methods of birth control.
Diagnosis of menopause: ratios of FSH/LH?
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Oral contraceptive side effects: where's the beef?
The initial report is reviewed, as well as the results of subsequent investigations, and the current status of the following side effects attributed to the use of oral contraceptives: subjective symptoms such as mood and libido changes, also headache; melanoma; gallbladder disease; liver tumors, sickle cell disease exacerbation; teratogenesis; "post-Pill" amenorrhea; atherogenesis; and diminished carbohydrate tolerance. In many instances a cause-and-effect relationship appears to be incorrect or highly improbable. In other instances the side effects are clinically insignificant or so rare as to be of minimal importance. Yet they continue to be listed by various authorities as validated side effects or relative contraindications to oral contraceptive use. This, in turn, limits the access of many women to a highly effective form of contraception. This re-examination of past history is intended to modernize our concepts of the safety of this modality.
When is it safe to switch from oral contraceptives to hormonal replacement therapy?
Women may continue to use oral contraceptives (OCs) into their 40's and 50's, but to date no method has been evaluated to ascertain their ovarian status, i.e., whether fertility and estrogen production have diminished sufficiently so they could be safely switched to hormonal replacement therapy. A group of 12 postmenopausal women who had been, for long periods of time, on a regimen of 3 back-to-back packages (i.e., 63 days on, 7 days off) of low-dose oral contraceptives have been studied. Secondly, a group of 9 perimenopausal women aged 36 to 47 were examined in the same manner. The third group consisted of early reproductive age women (arbitrarily divided into subsets aged 17-25 and 26-35 using low-dose OCs in the customary regimen) as normal controls. Blood samples were obtained on the last day of a pill cycle and at 7 days off the pill. In some menopausal women, blood samples were obtained at both 7 and 14 days off OCs. Serum was assayed by RIA for estradiol, FSH and LH. As expected in the young reproductive age women, estradiol levels increase at one week off the pill, together with a rebound in FSH and LH to follicular phase levels. In the perimenopausal group, there was a sharp distinction based on age. The women over 40 showed a more marked rise in FSH while those aged 36-40 showed a distinctly lesser response. Estradiol levels were variable, but tended to show some age grouping. Little diagnostic separation was observed for LH. In postmenopausal women, FSH levels were not always elevated at one week post-pill, and even in a second trial with sampling at one and two weeks off the OC, not all postmenopausal women showed a "menopausal" increase in FSH. The more uniform feature was that estradiol levels never increased above basal values. The study found that serum estradiol levels increase after a week off the pill in controls, but are unchanged at one and two weeks in the menopausal group. FSH levels rebound normally in reproductive age women and usually, but not always, increase substantially in postmenopausal women. After two weeks off OCs, an increased FSH and/or no change in basal estradiol levels is strong evidence that it is now safe (contraceptively speaking) to switch from OCs to standard hormone replacement regimens.
Are low-dose oral contraceptives safer and better?
It is widely believed that the use of low-dose oral contraceptives decreases thrombotic risks, compared with higher-dose oral contraceptives. Two recent epidemiologic studies infer a lower risk with 30 to 35 mcg than with 50 mcg estrogen oral contraceptives. However, as with prior studies from which similar conclusions were drawn, these studies have major flaws, the worst being that all 50 mcg oral contraceptives are lumped together, whereas 50 mcg mestranol oral contraceptives are actually bioequivalent to 35 mcg ethinyl estradiol oral contraceptives, thus confounding all such studies. Moreover, while rare thrombotic events have received inordinate attention, the major protective effect against endometrial and ovarian cancer that has been shown in older studies among users of oral contraceptives containing > or = 50 mcg ethinyl estradiol or > or = 80 mcg mestranol are almost totally ignored. The theoretical benefits of using lower-dose oral contraceptives have not been demonstrated, whereas the protection against these types of reproductive cancer have been shown repeatedly with high-dose oral contraceptives but not, to date, with lower-dose oral contraceptives. Such protection may be diminished by lowering the oral contraceptive dosage. Should every woman of reproductive age use high-dose oral contraceptives for 2 years? Are we throwing out the baby with the bath water?
Cardiovascular disease in women.
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Sexual behavior, contraception and the risk of contracting HIV.
Recently, concern has been expressed on a possible association between the use of oral contraceptive pills (OCs) and an increased risk of contracting the HIV infection. As a consequence it has been postulated that a low prevalence of condom use due to widespread utilization of oral contraceptive pills would result in an acceleration of the spread of AIDS. The International Committee for Research in Reproduction (ICRR) a group of eleven experts in the field of gynecology, endocrinology and contraception, wishes to comment on the concerns raised about OC use and AIDS.
The history of steroidal contraceptive development: the estrogens.
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Selected aspects of polycystic ovarian disease.
Although there is general agreement about the polycystic ovary as an anatomic entity, a classic description of an associated syndrome remains elusive. This lack of definition, however, has not impeded clinical investigation. This article focuses on the diagnosis, pathogenesis, hypotheses, and treatment of polycystic ovarian disease.
Thirty years of hormonal contraception: an historical perspective.
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Pharmacokinetics of ethinyl estradiol and mestranol.
Pharmacokinetally, a 50 micrograms oral dose of mestranol (which itself is inactive) is bioequivalent to a 35 micrograms dose of ethinyl estradiol. Physiologically, mestranol ranges from 50% to 100% of the activity of ethinyl estradiol, depending on the endpoint chosen. Compounds such as these, which are metabolized with a first-pass effect and are enterohepatically recirculated, demonstrate large interindividual and intraindividual variability in their pharmacokinetics. Thus a given dose of ethinyl estradiol in one person may produce an effect equivalent to a substantially larger (or smaller) dose in another person. This wide variability confounds efforts to establish tight dose-response relationships, a point rarely considered in clinical or epidemiologic studies of these compounds. The circulating levels of ethinyl estradiol sulfates may be higher than those of free ethinyl estradiol itself. It has been thought that these sulfates represent a "reservoir" of ethinyl estradiol. Our studies show that this idea is untenable because the half-life of the sulfates is not long enough for such an effect. Differences in the pharmacokinetics of ethinyl estradiol and mestranol have been observed in studies of various populations. The reality of these group differences is affirmed by analyses of urinary metabolite patterns.
Selected aspects of the pharmacokinetics and metabolism of ethinyl estrogens and their clinical implications.
Careful studies in an adequate sample of subjects show a very marked degree of variability in the pharmacokinetics of ethinyl estradiol--specifically, in parameters such as area under the curve, half-life, and time to peak. This variability is seen in differences between different populations, as well as from one individual to another. These studies also show variability in area under the curve and other parameters in the same person from time to time. Such differences may equal or exceed the differences between low dose (35 micrograms) and high-dose (50 micrograms) formulations. The levels of plasma ethinyl estradiol produced by a 50 micrograms dose of mestranol are similar to those from 35 micrograms of ethinyl estradiol. Thus a high-dose pill may be no higher than a low-dose pill if the nature of the estrogen is not kept in mind. Qualitative differences in the oxidative metabolites of estrogens may be of significance with respect to oncogenic potential.
Management of menopause when estrogen cannot be used.
Estrogen deficiency, whether surgically induced or as a consequence of natural ovarian failure, has destructive effects on many organ systems. With current levels of life expectancy, untreated women may expect to spend a third of their lifetime in this state. Appropriate estrogen replacement therapy (ERT) can avert (if started promptly) or ameliorate these devastating consequences, some of which (osteoporotic fractures, increased cardiovascular morbidity) can be lethal. Nevertheless, from 10 to 20% of postmenopausal women may have significant contraindications to ERT. Treatment of symptoms and improving the quality of life is imperative, yet many physicians abjure intervention, for reasons which are not entirely clear. Recent studies of conventional intervention with sedatives or tranquilisers show results equivalent to placebo therapy. On the other hand, specific agents with demonstrated effectiveness are available for management of the major estrogen-deficiency effects, although none of them are truly adequate replacement for the effect of estrogen itself.
Comparison of immunoreactive gonadotropin-releasing hormone and human chorionic gonadotropin in term placentas from normal women and those with insulin-dependent and gestational diabetes.
We measured prohormone gonadotropin-releasing hormone (high-molecular-weight gonadotropin-releasing hormone), gonadotropin-releasing hormone and human chorionic gonadotropin concentrations in term placentas from normal women and those with insulin-dependent and gestational diabetes. The placental immunoreactive gonadotropin-releasing hormone levels were significantly higher in normal tissues than in tissues from insulin-dependent and gestational diabetes (p less than 0.01). When compared with diabetic placental extracts, normal tissue also had more stored prohormone immunoreactive gonadotropin-releasing hormone. Whereas there were no consistent differences in placental human chorionic gonadotropin concentrations in normal tissues and tissues from insulin-dependent and gestational diabetes, there was a significant correlation between gonadotropin-releasing hormone and human chorionic gonadotropin concentrations in normal samples (r = 0.57, p less than 0.05), which was abolished when the diabetic tissue was included in the analysis. These data suggest that differences in high-molecular-weight gonadotropin-releasing hormone and gonadotropin-releasing hormone concentrations in term placentas from normal versus diabetic mothers may be due to enhanced processing of the prohormone and increased release of the decapeptide in diabetic pregnancy.
Ovarian cysts and oral contraceptives.
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Pharmacokinetics of three bioequivalent norethindrone/mestranol-50 micrograms and three norethindrone/ethinyl estradiol-35 micrograms OC formulations: are "low-dose" pills really lower?
We have examined the pharmacokinetic parameters derived from the analysis of plasma ethinyl estradiol (EE) and norethindrone levels after administration of a single dose of three bioequivalent norethindrone-1mg/mestranol (ME)-50 micrograms formulations (Ortho-NovumR 1/50, NorinylR 1/50 and Norcept-MR 1/50) and three norethindrone-1mg/ethinyl estradiol-35 micrograms formulations (Ortho-Novum 1/35R, NorinylR 1/35, Norcept-ER 1/35) in a randomized crossover design involving 24 women for the 35 micrograms and 27 women for the 50 micrograms agents. Differences between the AUC-EE of pairs from the same manufacturer (1 + 35 and 1 + 50) were not significantly different, indicating that 50 micrograms of mestranol was equivalent to 35 micrograms ethinyl estradiol with respect to this pharmacokinetic parameter. The Cmax values were also similar. Inter-individual coefficients of variation (C.V.) for the AUC-EE were 47% and 57% for the 1 + 35 and 1 + 50 agents, respectively. Intra-individual C.V.s were 41% and 42%, respectively. For norethindrone, the AUC was larger with the 1 + 50 formulations than with the 1 + 35 group (87.9 vs. 72.8 pg hr/ml). Additionally, the Cmax values were larger for the 1/50 group (17.7 vs. 14.0). Since the amount of norethindrone in the two dosage groups was the same, this difference in the pharmacokinetics between the 35 micrograms EE and the 50 micrograms ME formulations remains unexplained. The inter-individual C.V. averaged 56% for both dosage groups. The intra-individual C.V.s were 17% and 46% for the 1 + 35 and 1 + 50 groups, respectively. The large variation in blood levels of ethinyl estradiol and norethindrone between and within individuals may overshadow clinical differences attributable to differences in dosage.