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S. B. Fishel
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R. G. Edwards
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D. E. Walters
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Oocytes were collected by aspiration of preovulatory follicles from 55 women. The preovulatory rise in LH was monitored in urine using the Hi-Gonavis (Mochida Pharmaceuticals) technique. Patients were treated either during the natural cycle or after the induction of ovulation with clomiphene citrate. After collection and culture, the oocytes were inseminated with the spermatozoa of the husband. The levels of progesterone, oestradiol-17β and androstenedione in the clear follicular fluid were measured by radioimmunoassay. A multivariate analysis containing these three hormone levels together with two ratios of progesterone with each of the other hormones indicated reasonable discrimination between the oocytes which fertilized and those which remained unfertilized after insemination. The discriminant analysis suggested that the fertilization of the oocytes could have been predicted on the basis of these hormonal profiles with a success rate which exceeded 90%.

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R. E. FOWLER
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N. L. FOX
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R. G. EDWARDS
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D. E. WALTERS
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P. C. STEPTOE
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SUMMARY

Human granulosa cells from Graafian follicles aspirated 3–4 h before the expected time of ovulation were incubated with various steroid substrates, including pregnenolone, androstenedione, testosterone and dehydroepiandrosterone (DHA). Steroid production after 3 and 10 h of incubation was determined by radioimmunoassay.

Progesterone and 17α-hydroxyprogesterone were the major products of granulosa cells in control short-term cultures with endogenous substrates. The addition of pregnenolone increased the synthesis of progesterone and 17α-hydroxyprogesterone compared with the controls, although the response varied considerably between paired short-term cultures. Little or no oestradiol-17β was produced from endogenous precursors or short-term cultures to which pregnenolone had been added; one follicle, however, produced similar amounts of oestradiol-17β in the control cultures and after incubation with pregnenolone.

When granulosa cells were cultured with various amounts of androstenedione, DHA or testosterone, large amounts of oestradiol-17β were produced, especially in short-term cultures in which larger amounts of substrate were added. Progesterone production continued and progesterone was synthesized more rapidly or in greater amounts in some short-term test cultures than in the controls.

The results indicate that human granulosa cells are one source of oestradiol-17β during the preovulatory phase. The data support the two-cell theory for oestradiol synthesis, for granulosa cells do not appear to undertake steroid conversion via the 5-unsaturated pathway, but aromatize androgens known to be produced by thecal cells. It is also suggested that either androgens or oestradiol-17β stimulate progesterone production by granulosa cells, at least in vitro.

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R. W. H. EDWARDS
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G. J. A. I. SNODGRASS
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J. R. DALY
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1-Oxygenated steroids were recognized during preliminary characterization of substances isolated from the urine of two hypertensive infants (Edwards, Harvey & Knight-Jones, 1968; Edwards & Trafford, 1968) with raised values of the steroid 11-oxygenation index (Edwards, Makin & Barrett, 1964; B. E. Clayton, R. W. H. Edwards & H. L. J. Makin, in preparation). Shortly afterwards, Gower, Daly, Snodgrass & Stern (1970) described a 15-month-old female child with a virilizing adrenocortical carcinoma, who was excreting large quantities of dehydroepiandrosterone and monofunctional C1916-steroids together with increased quantities of testosterone, oestrogens and pregnanediol. Since this child was also hypertensive (blood pressure ranged from 160/85 to 180/115 mmHg) and had a urinary steroid 11-oxygenation index of 1·3 (upper limit of normal 0·7 at the 90% level) it was decided to look for 1-oxygenated steroids in her urine.

Examination of qualitative, two-dimensional paper chromatograms (Edwards, 1968) of urinary extracts with the

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J. R. Seckl
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R. C. Dow
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S. C. Low
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C. R. W. Edwards
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G. Fink
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ABSTRACT

Steroid-metabolizing enzymes modulate the effects of androgens on brain differentiation and function, but no similar enzymatic system has been demonstrated for adrenocorticosteroids which exert feedback control on the hypothalamus. 11β-Hydroxysteroid dehydrogenase (11β-OHSD) rapidly metabolizes physiological glucocorticoids (corticosterone, cortisol) to inactive products, thereby regulating glucocorticoid access to peripheral mineralocorticoid and glucocorticoid receptors in a site-specific manner. Using in-situ hybridization, we found expression of 11β-OHSD mRNA in neurones of the hypothalamic paraventricular nucleus (PVN) where corticotrophinreleasing factor-41 (CRF-41) is synthesized and from where it is released into hypophysial portal blood. Administration of glycyrrhetinic acid (GE), a potent 11β-OHSD inhibitor, decreased CRF-41 release into hypophysial portal blood in the presence of unchanged circulating glucocorticoid levels, suggesting that 11β-OHSD regulates the effective corticosterone feedback signal to CRF-41 neurones. These effects of GE were not observed in adrenalectomized animals, demonstrating dependence on adrenal products. In contrast, GE led to two- to threefold increases in arginine vasopressin and oxytocin release into portal blood, effects also dependent upon intact adrenal glands. These results suggest that 11β-OHSD in the PVN, and possibly other sites, may represent a novel and important control point of corticosteroid feedback on CRF-41 release in vivo.

Journal of Endocrinology (1993) 136, 471–477

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R. E. FOWLER
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R. G. EDWARDS
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D. E. WALTERS
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S. T. H. CHAN
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P. C. STEPTOE
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SUMMARY

The administration of human menopausal gonadotrophin (HMG) followed by human chorionic gonadotrophin (HCG) stimulated the development of various numbers of follicles in patients treated for infertility. Graafian follicles from these patients were aspirated 32–33 h after the injection of HCG and the levels of steroids in the follicular fluid and matching serum samples were measured by radioimmunoassay. The follicles could not be grouped into two distinct clusters as found in patients given HCG during the menstrual cycle but a broad classification of follicles into four groups was indicated from the dendrogram. Two of the groups were similar to the ovulatory and non-ovulatory groups found previously, whereas the other two groups of follicles were more intermediate in nature. The use of a discriminant analysis showed that these two groups had clearly been stimulated by the HMG and HCG, although they were not yet fully ovulatory.

Our data indicate that the number of developing follicles is considerably increased by treatment with HMG and HCG but there is asynchrony in follicular development because the pattern of steroid synthesis differs in many follicles. The effects of this asynchronous development on oocyte maturation and disorders of the luteal phase are discussed.

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R. E. FOWLER
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S. T. H. CHAN
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D. E. WALTERS
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R. G. EDWARDS
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P. C. STEPTOE
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SUMMARY

Human chorionic gonadotrophin (HCG) was given to patients at mid-cycle before the endogenous LH surge. Graafian follicles were aspirated 32–33 h later, before ovulation was expected, and the levels of several steroids in follicular fluid and in matching serum samples were measured by radioimmunoassay. Two types of Graafian follicle were identified at laparoscopy, based on the nature of the oocyte, granulosa cells and follicular fluid withdrawn from the follicles. Some were large, preovulatory and presumably becoming luteinized while others were generally smaller, non-ovulatory and still growing.

The concentrations of dehydroepiandrosterone (DHEA) and 17α-hydroxypregnenolone (Δ5 intermediates), androstenedione and testosterone were higher in non-ovulatory follicles, whereas large follicles usually contained high levels of progesterone, 17α-hydroxyprogesterone, pregnenolone and oestradiol-17β. A cluster analysis of these data grouped follicles into two distinct clusters, which accorded with their identification as ovulatory or non-ovulatory at laparoscopy.

Levels of progesterone, 17α-hydroxyprogesterone and oestradiol-17β in follicular fluid were high in preovulatory follicles in comparison with plasma. Results in two patients indicated that plasma levels of these steroids were determined by the preovulatory follicle. Levels of plasma Δ5 steroids were closer to follicular fluid concentrations, whereas DHEA was higher in plasma.

The role of the theca and granulosa is discussed in relation to the synthesis of progesterone and oestradiol-17β in follicles as ovulation approaches.

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M. A. KUMAR
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E. SLACK
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A. EDWARDS
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H. A. SOLIMAN
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A. BAGHDIANTZ
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G. V. FOSTER
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I. MacINTYRE
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SUMMARY

(1) Calcitonin preparations from acetone-dried thyroid were administered to rats by various routes.

(2) Intravenous administration, especially by infusion, produced a much greater fall in plasma calcium than s.c. or i.p. injection.

(3) The log dose-effect curves after i.v. injection or infusion showed no evidence of non-linearity over a 100-fold dose range and had highly significant slopes.

(4) The potency ratio of two preparations was estimated by means of a (2+2) assay design using both i.v. infusion and single i.v. injection. There was satisfactory agreement.

(5) The i.v. injection method is recommended for the routine assay of calcitonin. A simple assay schedule is given in the Appendix.

(6) A unit of calcitonin activity is defined in terms of a standard preparation.

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Ruijuan Gao Department of Structural and Cellular Biology, School of Basic Medicine, Department of Pathology and Laboratory Medicine, Department of Pediatrics and Adolescent Medicine, Department of Molecular and Cellular Biology, Department of Physiology, Department of Endocrinology and Diabetes Mellitus, Beijing Institute of Transfusion Medicine, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, Louisiana 70112, USA

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Lijuan Zhao Department of Structural and Cellular Biology, School of Basic Medicine, Department of Pathology and Laboratory Medicine, Department of Pediatrics and Adolescent Medicine, Department of Molecular and Cellular Biology, Department of Physiology, Department of Endocrinology and Diabetes Mellitus, Beijing Institute of Transfusion Medicine, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, Louisiana 70112, USA

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Xichun Liu Department of Structural and Cellular Biology, School of Basic Medicine, Department of Pathology and Laboratory Medicine, Department of Pediatrics and Adolescent Medicine, Department of Molecular and Cellular Biology, Department of Physiology, Department of Endocrinology and Diabetes Mellitus, Beijing Institute of Transfusion Medicine, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, Louisiana 70112, USA

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Brian G Rowan Department of Structural and Cellular Biology, School of Basic Medicine, Department of Pathology and Laboratory Medicine, Department of Pediatrics and Adolescent Medicine, Department of Molecular and Cellular Biology, Department of Physiology, Department of Endocrinology and Diabetes Mellitus, Beijing Institute of Transfusion Medicine, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, Louisiana 70112, USA

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Martin Wabitsch Department of Structural and Cellular Biology, School of Basic Medicine, Department of Pathology and Laboratory Medicine, Department of Pediatrics and Adolescent Medicine, Department of Molecular and Cellular Biology, Department of Physiology, Department of Endocrinology and Diabetes Mellitus, Beijing Institute of Transfusion Medicine, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, Louisiana 70112, USA

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Dean P Edwards Department of Structural and Cellular Biology, School of Basic Medicine, Department of Pathology and Laboratory Medicine, Department of Pediatrics and Adolescent Medicine, Department of Molecular and Cellular Biology, Department of Physiology, Department of Endocrinology and Diabetes Mellitus, Beijing Institute of Transfusion Medicine, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, Louisiana 70112, USA

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Yoshihiro Nishi Department of Structural and Cellular Biology, School of Basic Medicine, Department of Pathology and Laboratory Medicine, Department of Pediatrics and Adolescent Medicine, Department of Molecular and Cellular Biology, Department of Physiology, Department of Endocrinology and Diabetes Mellitus, Beijing Institute of Transfusion Medicine, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, Louisiana 70112, USA

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Toshihiko Yanase Department of Structural and Cellular Biology, School of Basic Medicine, Department of Pathology and Laboratory Medicine, Department of Pediatrics and Adolescent Medicine, Department of Molecular and Cellular Biology, Department of Physiology, Department of Endocrinology and Diabetes Mellitus, Beijing Institute of Transfusion Medicine, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, Louisiana 70112, USA

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Qun Yu Department of Structural and Cellular Biology, School of Basic Medicine, Department of Pathology and Laboratory Medicine, Department of Pediatrics and Adolescent Medicine, Department of Molecular and Cellular Biology, Department of Physiology, Department of Endocrinology and Diabetes Mellitus, Beijing Institute of Transfusion Medicine, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, Louisiana 70112, USA

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Yan Dong Department of Structural and Cellular Biology, School of Basic Medicine, Department of Pathology and Laboratory Medicine, Department of Pediatrics and Adolescent Medicine, Department of Molecular and Cellular Biology, Department of Physiology, Department of Endocrinology and Diabetes Mellitus, Beijing Institute of Transfusion Medicine, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, Louisiana 70112, USA
Department of Structural and Cellular Biology, School of Basic Medicine, Department of Pathology and Laboratory Medicine, Department of Pediatrics and Adolescent Medicine, Department of Molecular and Cellular Biology, Department of Physiology, Department of Endocrinology and Diabetes Mellitus, Beijing Institute of Transfusion Medicine, Tulane University School of Medicine, Tulane Cancer Center, New Orleans, Louisiana 70112, USA

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Elevated circulating estrogen levels, as a result of increased peripheral aromatization of androgens by aromatase, have been indicated to underlie the association between obesity and a higher risk of breast cancer in postmenopausal women. Although aromatase inhibitors have been used as a first-line therapy for estrogen receptor-positive breast cancer in postmenopausal women, their potential as breast cancer chemopreventive agents has been limited due to toxicities and high costs. It is therefore imperative to develop new aromatase-inhibiting/suppressing agents with lower toxicities and lower costs for breast cancer chemoprevention, especially in obese postmenopausal women. The expression of the aromatase gene, CYP19, is controlled in a tissue-specific manner by the alternate use of different promoters. In obese postmenopausal women, increased peripheral aromatase is primarily attributed to the activity of the glucocorticoid-stimulated promoter, PI.4, and the cAMP-stimulated promoter, PII. In the present study, we show that methylseleninic acid (MSA), a second-generation selenium compound, can effectively suppress aromatase activation by dexamethasone, a synthetic glucocorticoid, and forskolin, a specific activator of adenylate cyclase. Unlike the action of aromatase inhibitors, MSA suppression of aromatase activation is not mediated via direct inhibition of aromatase enzymatic activity. Rather, it is attributable to a marked downregulation of promoters PI.4- and PII-specific aromatase mRNA expression, and thereby a reduction of aromatase protein. Considering the low-cost and low-toxicity nature of MSA, our findings provide a strong rationale for the further development of MSA as a breast cancer chemopreventive agent for obese postmenopausal women.

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