Oestrogen and pregnanediol excretion through childhood, menarche and first ovulation.
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Biomedical subjects
Publications and source records attributed to J B Brown.
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To examine the hypothesis that familial breast cancer risk is related to estrogen metabolism, we analyzed urines of daughters of breast cancer patients and their matched controls for estrone (E1), estradiol (E2), and estriol (E3). From this, we computed estriol proportions (E3/E1 + E2 + E3). "Patient-daughters" and the matched controls showed no differences in estriol proportions. Our results failed to support the hypothesis that high-risk women (those with a family history of breast cancer) have relatively lower estriol proportions, and we concluded that whatever family history contributes to breast cancer risk, that risk is not likely to be transmitted by the estrogen profile.
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From experience gained in the monitoring of ovarian responses to gonadotropin therapy, it has been possible to develop concepts concerning the mechanisms which operate during the normal menstrual cycle. It is shown that the ovarian requirement for FSH operates in a very narrow range, involving changes in concentration of only 10%; this range operates from a threshold level, through an intermediate level to a maximum level. After adequate stimulation, the follicle goes through a costing phase during which it is independent of further FSH stimulation and it acquires sensitivity to LH. Methods for determining optimum requirements for FSH and HCG for the induction of singleton pregnancies are presented. The relevance of the findings in providing hypotheses explaining some aspects of ovulatory and anovulatory cycles are discussed.
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Plasma and urinary levels of estrogens and progesterone were studied on days 11 and 22 of the menstrual cycle in 27 teenage daughters of breast cancer patients and 25 teenage daughters of controls. Plasma and urinary values correlated well, which implied that most previous findings based on urinary levels of these hormones were applicable to their plasma levels. The "estriol ratio" (urinary estriol:urinary estrone plus estradiol) hypothesis was not supported by this study, the ratio having been no lower in the daughters of breast cancer patients than in daughters of controls. The day-11 results showed elevated plasma prolactin-estrogen values in daughters of breast cancer patients; the day-22 results did not.
Basal serum levels of prolactin were measured in 37 infertile anovulatory patients who had failed to conceive on therapy with clomiphene citrate. Twenty of these patients, 16 of whom had galactorrhoea, had elevated basal serum prolactin values which were suppressed to normal or subnormal values during therapy with bromocriptine, the most commonly effective dose being 2.5 mg twice daily. Ovulation, as assessed by urinary oestrogen and pregnanediol measurements, was induced in 17 of these patients with pregnancy in 14. Ovarian responses short of defined criteria for ovulation were induced initially in eight patients, but these progressed to full ovulatory responses in five patients, either on the same or increased doses of bromocriptine. In all the patients who ovaulated, the prolactin levels had been reduced below the mean value for normal women (10.6 ng-ml). The three patients who failed to ovulate all had values higher than this at a dose of bromocriptine reaching 5.0 mg thrice daily. There seemed to be no value in increasing the dose of bromocriptine once ovulation had been achieved. Of the 17 patients with normal basal prolactin values, only one had an unequivocal response to bromocriptine with ovulation and conception, even though the prolactin values in the majority were suppressed to below normal.
Serum and prolactin levels and urinary oestrogen and pregnanediol excretion were measured during early pregnancy in 12 hyperprolactinaemic subjects who became pregnant during treatment with bromocriptine. Prolactin levels were suppressed below normal whilst taking the bromocriptine, but rose significantly when this drug was stopped and by eight weeks of gestation reached values significantly higher than those observed in normal pregnancy. Further increases in prolactin levels were, however, not observed. Urinary oestrogen and pregnanediol excretion was initially normal but, following cessation of bromocriptine, urinary pregnanediol excretion decreased and was significantly less than normal at 11 to 14 weeks gestation. These results suggest that elevated prolactin levels affect corpus luteum function of early pregnancy. Because the effect is maintained until at least 14 weeks gestation, prolactin may also affect progesterone production by the placenta.
Urinary oestrogen and pregnanediol excretion were measured before and after hysterectomy and bilateral salpingo-oophorectomy in 26 postmenopausal women with adenocarcinoma of the endometrium, 10 postmenopausal women with mixed adenosquamous carcinoma and 11 postmenopausal women with atypical hyperplasia (the patient groups). The results were compared with the values obtained in 22 active postmenopausal women, 20 hospitalized postmenopausal women and 18 women who had been subjected to hysterectomy and bilateral salpingo-oophorectomy for cancer of the cervix (the control groups). The ovaries and Fallopian tubes obtained at operation were examined for evidence of current or past excessive oestrogen production. Preoperative oestrogen values were higher in the patient groups than in the controls and the elevated values persisted after oophorectomy. The implications of these findings are discussed.
Twelve anovulatory patients with normal serum prolactin values and six with elevated values were treated with bromocriptine and the effects on serum prolactin, FSH and LH levels were recorded. Ovulation resulted in one patient who had normal prolactin values and in all six who had raised values. No patient with normal basal prolactin values showed an increase in serum FSH during therapy with bromocriptine, whereas 5 of the 6 patients with elevated values showed significant increases. Similar results were obtained for LH. Although these differences were highly significant (P less than 0-005) the majority of the serum FSH and LH values remained within the normal ranges. Five patients with normal basal prolactin values and one with elevated values were also treated with human pituitary gonadotrophin (HPG). An increase in ovarian responsiveness to HPG during therapy with bromocriptine was recorded in the one patient with initially elevated prolactin values. It was concluded that bromocriptine acts by allowing FSH to rise above threshold requirements for follicular stimulation.
Serum or plasma total unconjugated estriol and total estriol glucuronide fractions were measured in 14 patients with unaborted hydatidiform mole between 11 and 25 weeks of gestation and in 20 normal pregnant patients between 8 and 17 weeks of gestation. The estriol fractions were separated by solvent partition, and the estriol was measured by radioimmunoassay using antiserum against estriol-16-17-dihemisuccinate conjugated to bovine serum albumin. The values (means and ranges) found in normal pregnant patients were as follows: estriol 1.3 ng/ml (0.3-2.9); estriol glucuronide, 11.1 ng/ml (4.7-24.8). Wide ranges of values were found in patients with molar pregnancies compared to those with normal pregnancies of equivalent gestation, some values being within the upper range of normal and others being well below the normal range. Of the 14 molar pregnancies studied, 9 (64%) were associated with serum estriol values which were below the ranges for normal pregnancy, and 8 (57%) were associated with similarly low estriol glucuronide values. The incidences of low estriol and estriol glucuronide values were less than those reported for low urinary estriol excretion in hydatidiform moles. No correlation was found between any of the serum estriol fractions and the serum hCG values or with the presence of theca lutein cysts in the ovaries. It was suggested that the trophoblast was the principal source of estriol in these molar pregnancies.
Women who bear their first child at an early age have lower breast-cancer incidence-rates than do women who are older at first birth or who remain nulliparous. The urine "oestriol ratio", the concentration of oestriol relative to the sum of the concentrations of oestrone and oestradiol, is inversely related to a population's breast-cancer rate. To evaluate the relationship between these two breast-cancer risk indicators the urine oestriol ratio was determined for recently delivered uniparous women aged 19-23, 25-27, and 29-34 years and nulliparous women of comparable ages. In the follicular phase, the youngest parous women had an oestriol ratio 40% higher than, and significantly different from, the ratios of all other groups which were otherwise quite similar. In the luteal phase, the oestriol ratio of the youngest parous women was again distinctively raised and generally the oestriol ratios of parous women were higher than those of nulliparae. The results are not explained by differing frequencies of ovulation among the groups or by confounding from several breast-cancer risk indicators. These findings support the hypothesis that oestrogen metabolism, as reflected by the urine oestriol ratio, is a determinant of breast-cancer risk.
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Urinary oestrogen and pregnanediol excretion was measued daily ("daily monitoring") for a complete cycle in 20 normally menstruating women, in one patient with an anovulatory cycle and for 28 days in a patient with secondary amenorrhoea. The measurements were also performed on urine specimens collected at weekly intervals for 4 to 6 weeks ("weekly tracking") from 506 patients with evidence of abnormal ovarian function. These included 9 patients with primary amenorrhoea, 132 patients with secondary amenorrheoa, 138 patients with oligomenorrhoea and 227 patients with evidence of ovarian dysfunction and cycle lengths of 25 to 42 days. The results were subjected to statistical analysis. In the normal cycles, ovulation could be identified on the criteria of a rising pregnanediol value reaching or exceeding 2-0 mg. per 24 hours for a period of 7 days or more. Valid conclusions on the overall mean oestrogen and pregnanediol values for a complete cycle could be made from the results of weekly tracking, irrespective of which day the tracking commenced. Correlations were obtained by comparing the mean and maximum urinary oestrogen values and the variability of the values with the evidence of ovarian function indicated by the clinical classifications of the patients, the duration of the disorders and the subsequent occurrence of uterine bleeding. Mean oestrogen values of 10 mug. per 24 hours or less were associated with lack of ovarian function. For values higher than this a discriminant function based on both the mean oestrogen value and the variability of the oestrogen values was useful in predicting onset of spontaneous menstruation. A single urine specimen collected 4 to 8 days before onset of menstruation showing a raised pregnanediol value of 2-0 mg. per 24 hours or more provided a valid test for ovulation in women with regular cycles, and a single urine specimen giving an oestrogen value of 10 mug per 24 hours or less gave a valid indication of absent ovarian function in women with amenorrhoea for two years or more. In all other circumstances serial sampling at weekly intervals provided a valid assessment of ovarian activity. Application of these principles allows the greatest amount of information on ovarian function to be obtained with the greatest economy of effort.