Objective: To compare the bioavailability of oral and intramuscular (IM) dexamMethods: Oral and IM dexamethasone levels were compared in a randomized, parallel, crossover bioavailability study involving 11 gravid women in the third trimester of pregnancy. Subjects were randomized to receive either 6 mg of IM or 8 mg of oral dexamethasone. The following week, the alternative regimen was administered. Serial blood samples were obtained after drug administration. Dexamethasone concentrations were measured by radioimmunoassay. Total area under the curve was compared for the oral and IM groups using a paired t test.Results: Eight of the 11 women completed the study through 12 hours; all 11 women completed the study through 6 hours. Among the 11 women, peak levels of dexamethasone occurred 30 minutes after IM injection (mean +/- standard deviation, 101.7 +/- 19.2 ng/mL) and 120 minutes after oral administration (65.9 +/- 20.5 ng/mL). Area under the curve did not differ significantly between those receiving IM dexamethasone (258.3 +/- 50.0 ng/minute/mL) and those receiving oral dexamethasone (251.8 +/- 59.7 ng/minute/mL) when measured 6 hours after administration of the drug. Terminal half-lives were similar in the IM and oral groups. Similar findings were noted among the eight women who were studied through 12 hours. This study had a power of 87% to detect a 20% difference in area under the curve between the two groups.Conclusion: The bioavailability of 8 mg of oral dexamethasone is similar to that of a 6-mg IM dose, as determined by the area under the curve. Copyright (C) 1997 by The American College of Obstetricians and Gynecologists.

OBJECTIVES: This single-dose study compares three dehydroepiandrosterone delivery methods (oral crystalline steroid, micronized steroid, and vaginal administration) to ascertain whether physiologic levels of circulating dehydroepiandrosterone and dehydroepiandrosterone sulfate can be obtained while increases in testosterone are minimized.STUDY DESIGN: Two randomized, double-blind, placebo-controlled single-dose comparisons were made. For oral micronized versus crystalline dehydroepiandrosterone 300 mg doses of micronized or crystalline dehydroepiandrosterone were administered, followed by 6 hours of blood sampling (n = 7). Serum dehydroepiandrosterone, dehydroepiandrosterone sulfate, and testosterone levels were measured; areas under the curve and mean peak values were analyzed by Student-Newman-Keuls tests. For oral versus vaginal micronized dehydroepiandrosterone 150 mg oral or vaginal doses of micronized dehydroepiandrosterone were administered, followed by blood sampling over 12 hours (n = 5). Data analysis was as described.RESULTS: Oral micronized and unmicronized dehydroepiandrosterone resulted in increases in serum dehydroepiandrosterone, dehydroepiandrosterone sulfate, and testosterone. Micronization increased the area-under-the-curve ratios for dehydroepiandrosterone sulfate/dehydroepiandrosterone and dehydroepiandrosterone sulfate/testosterone. Vaginal administration provided equivalent serum dehydroepiandrosterone; however, it failed to increase dehydroepiandrosterone sulfate or testosterone over placebo.CONCLUSION: Micronization of oral dehydroepiandrosterone diminishes bioconversion to testosterone. Vaginal dehydroepiandrosterone delivers equivalent dehydroepiandrosterone but substantially diminishes dehydroepiandrosterone bioconversion.

Annals of the New York Academy of SciencesVolume 774, Issue 1 p. 291-293 Dehydroepiandrosterone Attenuates Study-Induced Declines in Insulin Sensitivity in Postmenopausal Womena G. WRIGHT BATES Jr., G. WRIGHT BATES Jr. bDepartment of Obstetrics and Gynecology University of Tennessee Memphis, Tennessee 38163Search for more papers by this authorROBERT S. EGERMAN, ROBERT S. EGERMAN bDepartment of Obstetrics and Gynecology University of Tennessee Memphis, Tennessee 38163Search for more papers by this authorEDWARD S. UMSTOT, EDWARD S. UMSTOT bDepartment of Obstetrics and Gynecology University of Tennessee Memphis, Tennessee 38163Search for more papers by this authorJOHN E. BUSTER, JOHN E. BUSTER cDepartment of Obstetrics and Gynecology Division of Reproductive Endocrinology Baylor College of Medicine Houston, Texas 77030Search for more papers by this authorPETER R. CASSON, PETER R. CASSON cDepartment of Obstetrics and Gynecology Division of Reproductive Endocrinology Baylor College of Medicine Houston, Texas 77030Search for more papers by this author G. WRIGHT BATES Jr., G. WRIGHT BATES Jr. bDepartment of Obstetrics and Gynecology University of Tennessee Memphis, Tennessee 38163Search for more papers by this authorROBERT S. EGERMAN, ROBERT S. EGERMAN bDepartment of Obstetrics and Gynecology University of Tennessee Memphis, Tennessee 38163Search for more papers by this authorEDWARD S. UMSTOT, EDWARD S. UMSTOT bDepartment of Obstetrics and Gynecology University of Tennessee Memphis, Tennessee 38163Search for more papers by this authorJOHN E. BUSTER, JOHN E. BUSTER cDepartment of Obstetrics and Gynecology Division of Reproductive Endocrinology Baylor College of Medicine Houston, Texas 77030Search for more papers by this authorPETER R. CASSON, PETER R. CASSON cDepartment of Obstetrics and Gynecology Division of Reproductive Endocrinology Baylor College of Medicine Houston, Texas 77030Search for more papers by this author First published: December 1995 https://doi.org/10.1111/j.1749-6632.1995.tb17389.x-i1Citations: 17 a This work was supported in part by the American College of Obstetricians and Gynecologists Ortho Academic Training Fellowship, of which Dr. Casson is the 1990–1991 recipient, and by United States Public Health Service Clinical Research Center grant No. RR00211–27. AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article.Citing Literature Volume774, Issue1Dehydroepiandrosterone (DHEA) and AgingDecember 1995Pages 291-293 RelatedInformation

OBJECTIVES: Because dehydroepiandrosterone may protect against neoplasia, osteoporosis, and cardiac disease, we investigated the bioavailability of oral micronized dehydroepiandrosterone, anticipating its adjunctive use in postmenopausal steroid replacement.STUDY DESIGN: Eight postmenopausal women randomly received either a placebo or 150 or 300 mg of oral micronized dehydroepiandrosterone in a lipid matrix. Serum dehydroepiandrosterone, dehydroepiandrosterone sulfate, testosterone, and estradiol were measured periodically over the 12 hours after each dose. All treatments, all doses, and mean serum dehydroepiandrosterone, dehydroepiandrosterone sulfate, and testosterone were compared with analysis of variance for repeated measures and Newman-Keuls a posteriori test of statistical significance.RESULTS: Mean peak steroid concentrations after 150 mg (300 mg) doses were dehydroepiandrosterone 1617 (2639) ng/dl, 7 (11.5)-fold above placebo; dehydroepiandrosterone S 1185 (1688) mu-g/dl, 14 (20)-fold above placebo; and testosterone 183 (311) ng/dl, 4 (7)-fold above placebo. Estradiol concentrations remained < 20 pg/ml, but androgen concentrations rose by 1 hour and remained elevated through the twelfth hour. Peak androgen concentrations and areas under the curves exhibited proportionality with both doses. A testosterone radioimmunoassay with celite chromatography revealed a 300% overestimation for testosterone in the direct-assay method used in this study. Thus after appropriate readjustment maximum testosterone concentrations were observed consistently within physiologic premenopausal ranges after the 150 mg dose.CONCLUSIONS: Micronized dehydroepiandrosterone may provide a steroidal postmenopausal replacement that is adjunctive to estrogens and worthy of further investigation.

A graphic method called close-pair-analysis is described for determining the high affinity binding parameters in a complex system. Assumptions are that the nonspecific binding is accurately measured, and that there are two specific binding classes in which the affinities (Ka) are a factor of 5 or greater apart. Using this method and equilibrium dialysis data of delta 5-Adiol and E2 binding in serum, an apparently new binding site class was found. The average Ka for both delta 5-Adiol and E2 was 8 X 10(7) L/M, with the number of binding sites ranging from 20 to 200 nM.

Given the same quantity of fatty acid, livers from male rats esterify less fatty acid and secrete less triacylglycerol in very-low-density lipoprotein than do livers from female animals. To elucidate the role of testosterone in maintenance of this male pattern, conversion of [1-14C]oleic acid into triacylglycerol was assessed in vitro by rat hepatocytes (male) following gonadectomy and replacement with testosterone. Following castration, incorporation of fatty acid into triacylglycerol was increased. In contrast, esterification of exogenous fatty acid into phospholipid, cholesteryl esters, and diacylglycerol was unchanged. Treatment with testosterone (75 μg/day) reduced incorporation of exogenous fatty acid into triacylglycerol. Higher doses of testosterone (200 or 100 μg/day) modified the effect, such that inhibition was observed only at low oleate (0.5 mM) concentrations. At higher substrate concentrations (1.0–2.0 mM) the inhibitory effect was no longer observed. Further, a similar dose-dependent effect of testosterone was observed following in vivo treatment of castrate females with testosterone. These data support the concept of a regulatory role of testosterone in hepatic triacylglycerol synthesis. These findings also demonstrate a biphasic effect of testosterone, an effect that is dependent not only upon the dose of testosterone administered, but also on the concentration of fatty acid to which the hepatocyte is exposed in vitro.

Several steroid hormones affect free testosterone (FT) levels in blood by competing with testosterone for binding sites on testosterone-binding globulin (TeBG). However, the effect of endogenous nonsteroidal substances in serum has not been reported. Some of these potential modifiers of FT were studied using equilibrium dialysis. Nonesterified fatty acids at 0.9 mM elevated FT approx 10% at pH 7.4. Investigation of the curvilinear relationship of percent FT (pFT) vs pH showed that pH-dependent changes of testosterone binding to albumin were responsible for a small linear increase in pFT with decreasing pH. The greater portion of the curvilinear increase of pFT with decreasing pH was due to fatty acids competing with testosterone for TeBG binding sites. Ketone bodies significantly affected FT (7.5% elevation) only at levels found in diabetic ketoacidosis. Sodium ions improved binding 11% when 7 mM was compared to 157 mM sodium, but physiological changes in sodium would result in only +/- 1% changes in FT. Very low levels (0.03 mM) of calcium may be essential for normal testosterone binding to TeBG since 1.0 mM EGTA raised FT by 75%. This study shows that dialysis at 37 degrees C should not be performed overnight, that thimerosol should not be used as a preservative, and that the dialysis buffer should contain physiological concentrations of sodium and calcium.

Free testosterone measured in serum equilibrated in vitro is considered a good index of biologically available testosterone even though a large part of free testosterone in vivo is derived locally from rapid dissociation of testosterone bound to albumin. The most accurate method for measuring free testosterone, however, is unsettled. The classical method--equilibrium dialysis--has been questioned because of the dilution of serum that it entails and the previous inability to achieve identical results with diluted and undiluted serum. Essentially identical measurements of free testosterone were achieved in diluted and undiluted charcoal-stripped serum by using the dialysis method and calculation reported here. The measured free testosterone in undiluted whole serum from women was only 4-6% lower than the estimated physiological values. These results were obtained using a validated calculation, controlling pH, using physiological bicarbonate buffer at 37 degrees C, maintaining a constant free ligand concentration for dilutions, measuring the water gain by the dialysis bag, and using highly purified labeled testosterone. The mean free testosterone for normal women was 0.17 ng/dl (0.11-0.23) and for hirsute women was 0.49 ng/dl (0.27-0.71). The testosterone not bound to testosterone-estradiol binding globulin, calculated from free testosterone and albumin concentrations, was close to the production rate/min of testosterone. The method should be adaptable to other ligands.

The first objective of this study was to determine which plasma androgen assay or combination of assays would be the most useful in documenting hyperandrogenism in women with hirsutism, acne, oligomenorrhea, or unexplained infertility. Plasma levels of androstenedione (A), total testosterone (T), and dehydroepiandrosterone sulfate (DHEAS) were measured and free T (FTc) was calculated from the measured total T and T-estradiol-binding globulin binding capacity (TeBG-BC) in 138 consecutive women referred to our clinic for hirsutism, acne, oligomenorrhea, and/or unexplained infertility. FTc was elevated in 82% and was most frequently elevated parameter. DHEAS was elevated in 59% of the women, and 93% were noted to have hyperandrogenemia on the basis of a combination of FTc and DHEAS levels. The second objective of this study was to determine whether there was significant correlation between the androgen parameters and any of the clinical features. Body weight was significantly negatively correlated with DHEAS and TeBG-BC in those women with a normal DHEAS level but not in those with an elevated level. A strong positive correlation (simple and partial) was noted between body weight and plasma T levels in the whole group of patients, as well as in those with a normal or an elevated DHEAS level. It is suggested that the relationship between T and body weight is multifaceted. Conceivably, T could influence body mass by effects on food intake or through alterations in intermediary metabolism.

Fifteen preovulatory hirsute woman were studied before and at the completionof one cycle (21 days) of an oral contraceptive that contained norethindrone (2 mg) and mestranol (0.1 mg; N + M). A 3-day protocol included a diurnal study, followed by overnight dexamethasone suppression and ACTH stimulation. Plasma A4-androstenedione (A), testosterone (T), and dehydroepiandrosterone sulfate (DHEAS) and plasma cortisol (F) were meDHEAS was reduced 28%, and F was increased 176% with therapy. A exhibiteda diurnal rhythm synchronouswith F across all of the time periods, but T and DHEAS did not. ACTH dependency of A was determined by measuring the magnitude of changein A between the timeof the F peak and the F nadir in the diurnal study. In the diurnal study, both themean concentration of A as wellas the net change in plasma A concentration from the time of theF peak to the F nadir correlated significantly with the mean DHEAS concentration during N+ M treatment. The responsiveness of A and F to 0.5 U ACTH iv was determined afterdexamethasone (mg)had beengiven the night before. On treatment, dexamethasone-suppressed mean F values wer higher and mean A levels were lower. The incremental increase above the dexamethasone-suppressedlevels was significantly decreased for A,but was significantly increased fo F during N + M treatment. The responsiveness of A and F to 0.5 U ACTH iv was determined after dexamethasone (1 mg) had been given the night before. On treatment, dexamethasone-suppressed mean F values were higher and mean A levels were lower. The incremental increase above the dexamethasone-suppressed levels was significantly decreased for A, but was significantly increased for F during N + M treatment. The response of A to ACTH correlated significantly with the mean concentration of DHEAS during but not before treatment. The significant reduction in plasma A and T by N + M noted in this study confirms the usefulness of this agent in reducing androgen levels in hirsute women. The data ofthis study document that N + M reducesadrenal androgen activity as evidenced by 1 a reduction of the magnitude of the diurnalchange in A synchronous with F, 2) a reductionof the A response to exogenous ACTH, and 3) a reduction in the circulating concentration of DHEAS. DHEAS correlated significantly with the mean and the difference in the peak to nadiaconcentration in the diurnal study and with the A response to ACTH during N + M. This suggests that this relatively simple assay can serve as an indicator of the magnitud ofadrenal androgen secretion in hirsute females.

The binding capacity of plasma testosterone-estradiol-binding globulin (TeBG) and testosterone (T) levels were measured in four women with proved polycystic ovaries and three women with a clinical diagnosis of polycystic ovarian disease before, during, and after administration of norethindrone, 2 mg., and mestranol, 0.1 mg. (N + M). TeBG was increased within four days after N + M treatment was begun. Mean TeBG was significantly elevated (P < 0.05) and mean T was significantly suppressed (p < 0.05) relative to pretreatment levels by 9 to 12 days after N + M treatment was started. Both TeBG and T remained significantly different from pretreatment levels during the posttreatment period of 12 days' duration. Although the dynamics of TeBG changes were different in two of the seven women, all seven women responded to N + M with a decrease in both total and free T.

The clinical features, ovarian pathology, and hormonal responses to dexamethasone (Dex), Dex + ethinyl estradiol (EE), and Dex + hCG were compared in 5 women with polycystic ovarian disease (PCOD) who have normal 24-hr urinary luteinizing hormone (LH levels to 5 who had elevated urinary LH levels. No differences were noted in the clinical features. There was no correlation between ovary size and LH levels. Three in the normal-LH group had hyperthecosis. Plasma androstenedione (A) was more frequently elevated in the high-LH group. Dex + EE markedly increased LH secretion in the high-LH group, suggesting increased responsiveness of the positive feedback control mechanism of LH secretion in the high-LH group. There was a greater response of A, testosterone (T), and 17-ketosteroids to Dex + hCG in the normal-LH group. Those with high-LH levels did not exhibit a significant increase in A, T, and 17-KS with hCG. The limitations and usefulness of the Dex + hCG test are discussed. The hypothesis is advanced that the increased LH secretion in the high-LH group is due at least in part to positive feedback resulting from the increased A levels. The amount of 17beta-oxidoreductase activity in the ovary may influence LH secretion in PCOD.

To assess the effects of d-norgestrel on pituitary-adrenal-ovarian function, basal levels and responses to metyrapone of urinary 17-ketogenic steroids (17-KGS) and 17-ketosteroids (17-KS), plasma cortisol (F), plasma delta4-androstenedione (A), plasma testosterone (T), plasma estrone (E1) and estradiol (E2), plasma and urinary LH and FSH were determined in 10 normal women before and while taking d-norgestrel 1 mg/day. Cortisol secretion rate (CSR) and binding capacities of cortisol binding globulin (CBG) and testosterone-estradiol binding globulin (TeBG) were also measured. Norgestrel did not significantly alter 17-KGS, 17-KS, F, LH, FSH, CSR, or the 17-KGS and 17-KS responses to metyrapone. Norgestrel reduced TeBG binding capacity but not CBG binding capacity. Norgestrel competitively inhibited the binding of dihydrotestosterone to TeBG under in vitro conditions. Levels of T, E2, and E1 were reduced by norgestrel. All measured hormone levels except FSH were increased following metyrapone prior to norgestrel administration. Norgestrel completely blocked the metyrapone-induced increases in LH and E2 and markedly reduced the E1 increase. Metyrapone reduced E2 during norgestrel treatment.

The effectiveness of two oral contraceptives in suppressing plasma androstenedione (A), testosterone (T), LH, and FSH and in stimulating testosterone-estradiol-binding globulin TeBG) was evaluated in 39 hirsute women. Twenty-seven hirsute women received norethindrone 2 mg.-mestranol 0.1 mg. (Group I) and 12 received norgestrel 0.5 mg.-ethinyl estradiol 0.05 mg. (Group II). Hormone assays were performed before treatment and at the end of 3 weeks of therapy. Ninety per cent of the women in both groups had an elevated plasma A and/or T. During treatment, plasma A, T, LH, and FSH were significantly reduced in both groups (p < 0.01). In Group II, 78 per cent of the women had a normal plasma A and T during treatment. In Group II, 83 per cent of the women had a normal A and T during treatment. There was a greater increase in TeBG in Group I (p < 0.01). It is concluded that these two oral contraceptives effectively suppressed the hyperandrogenism of most of the hirsute women.

ACTH dependency of plasma androstenedione (A) and testosterone (T) was determined in normal and hirsute women by measuring the magnitude of change of A and T between the time of the cortisol (F) peak and F nadir in a diurnal study. There was a significant diurnal rhythm of A synchronous with F in both normal and hirsute women (P less than 0.01). Five of 12 hirsute women had a greater than normal diurnal swing of A (P less than 0.05), but only 2 of the 12 had a greater than normal diurnal swing of T. Responsiveness of A and T to 1/2 unit of intravenous ACTH was determined after dexamethasone 1 mg was given the night before. Plasma A and T were elevated in most of the hirsute women during acute ACTH suppression by dexamethasone, indicating ACTH-independent hypersecretion of androgens. Nine of 17 hirsute women had a greater than normal A response to ACTH (P less than 0.05). Those who had an exaggerated diurnal swing of A also had hyper-responsiveness of A secretion to ACTH. Only 2 hirsute women had an exaggerated T response to ACTH. Some T levels were decreased by ACTH. Seven of the 9 hiruste women who had an exaggerated A response to ACTH had a normal maximum F response, but a greater than normal 17-hydroxy-progesterone (17-OHP) response to ACTH with a high 17-OHP to F ratio, suggesting they have a mild but compensated reduction in 21-hydroxylase or 11beta-hydroxylase activity. Two women with hyper-responsiveness of A secretion had low F and 17-OHP responses to ACTH suggesting reduced C21 but intact C19 3beta-hydroxysteroid dehydrogenase-delta-5,-4 isomerase activity. These apparent reduced enzyme activity may not be congenital, but induced by an altered hormonal milieu such as an abnormal androgen-estrogen ratio. It is concluded that ACTH uniformly stimulated A secretion but not T secretion and that approximately 50% of the hirsute women had ACTH-dependent hypersecretion of A, but most of these also had concurrent ACTH-independent hypersecretion of androgens.