Guy E. Abraham

Oral dehydroepiandrosterone in physiologic doses modulates immune function in postmenopausal women

OBJECTIVEnThis study tests the hypothesis that dehydroepiandrosterone or its metabolic products are immunomodulatory in postmenopausal women with relative adrenal androgen deficiency.nnnSTUDY DESIGNnA prospective, randomized, double-blind, crossover study of 11 subjects with 3-week treatment arms separated by a 2-week washout period was performed. Immunologic evaluation at the beginning and end of the treatment arms consisted of flow cytometry to delineate T-cell populations, in vitro T-cell mitogenic response and cytokine production, and natural killer cell cytotoxicity. Statistical analysis was based on a split-plot design with analysis of variance with repeated measures.nnnRESULTSnDehydroepiandrosterone supplementation decreased CD4+ (helper) T cells and increased CD8+/CD56+ (natural killer) cells. Although T-cell mitogenic and interleukin-6 responses were inhibited, natural killer cell cytotoxicity increased dramatically.nnnCONCLUSIONSnThese data provide the first in vivo evidence in human for an immunomodulatory effect of dehydroepiandrosterone. The salutary immune changes could account for clinical and experimental evidence of antioncogenic effects of this steroid. This study provides a strong rationale for further clinical studies on dehydroepiandrosterone supplementation in adrenal androgen-deficient states.

Postmenopausal dehydroepiandrosterone administration increases free insulin-like growth factor-I and decreases high-density lipoprotein: A six- month trial

OBJECTIVEnTo determine the effect of administering 6 months of oral postmenopausal DHEA therapy on serum DHEA, DHEAS, and T levels and on physiologic endpoints including lipoproteins and insulin-like growth factor-I (IGF-I).nnnDESIGNnRandomized, double-blind, parallel trial.nnnSETTINGnAcademic referral practice.nnnPATIENT(S)nThirteen normal-weight or overweight, healthy, nonsmoking, postmenopausal women.nnnINTERVENTION(S)nAdministration of oral micronized DHEA (25 mg/d).nnnMAIN OUTCOME MEASURE(S)nMonthly fasting 23 hours postdose levels of serum DHEA, DHEAS, T, lipoproteins, IGF-I, IGF binding protein-3 (IGFBP-3), and liver function tests. Morphometric indices by dual-energy x-ray absorptiometry scan (percent body fat; lean body mass), immune indices, and insulin sensitivity.nnnRESULT(S)nLevels of DHEA, DHEAS, and T all rose into premenopausal ranges, but after 6 months, levels of DHEA and T did not differ from baseline or placebo. At 3 months, the ratio of IGF-I to IGFBP-3 rose by 36.1% +/- 12.7%, but it fell to placebo values by 6 months. High-density lipoprotein and apolipoprotein A1 levels declined.nnnCONCLUSION(S)nPatients appeared to tolerate 6 months of DHEA therapy well. Given the small study size, no statistically significant differences in morphometric indices, immune indices, or insulin-sensitizing properties were observed, but significant attenuation of bioavailability occurred. Supplementation with DHEA increased IGF-I/IGFBP-3 levels at 3 months and decreased high-density lipoprotein and apolipoprotein A1 levels at 6 months.

Replacement of dehydroepiandrosterone enhances T-lymphocyte insulin binding in postmenopausal women * †

OBJECTIVEnTo demonstrate bioavailability of 3 weeks of oral micronized DHEA and to delineate changes induced on insulin sensitivity, morphometric indexes, and lipoprotein profiles.nnnDESIGNnOral micronized DHEa (50 mg/d) was administered in 3-week treatments to 11 postmenopausal women in a prospective, placebo-controlled, randomized, blinded, crossover trial with an interarm washout. After dose (23 hour) serum DHEA, DHEAS, T, and cortisol levels were measured, as were fasting lipoproteins, oral glucose tolerance tests (OGTT), T-lymphocyte insulin binding and degradation, and urine collagen cross-links. Morphometric changes were determined by hydrostatic weighing.nnnRESULTSnDehydroepiandrosterone sulfate, DHEA, T, and free T increased up to two times premenopausal levels with treatment. Fasting triglycerides declined; no change in collagen cross-links or morphometric indexes was noted. Oral glucose tolerance test parameters did not change, but both T-lymphocyte insulin binding and degradation increased with DHEA.nnnCONCLUSIONnFifty milligrams per day of oral DHEA gives suprahysiologic androgen levels; 25 mg/d may be more appropriate. Dehydroepiandrosterone enhanced tissue insulin sensitivity and lowered serum triglycerides. Rationale is provided for postmenopausal replacement therapy with this androgen.

Postmenopausal steroid replacement with micronized dehydroepiandrosterone: Preliminary oral bioavailability and dose proportionality studies

OBJECTIVESnBecause 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.nnnSTUDY DESIGNnEight 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.nnnRESULTSnMean 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) micrograms/dl, 14 (20)-fold above placebo; and testosterone 183 (311) ng/dl, 4 (7)-fold above placebo. Estradiol concentrations remained less than 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.nnnCONCLUSIONSnMicronized dehydroepiandrosterone may provide a steroidal postmenopausal replacement that is adjunctive to estrogens and worthy of further investigation.

Delivery of dehydroepiandrosterone to premenopausal women: effects of micronization and nonoral administration.

OBJECTIVESnThis 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.nnnSTUDY DESIGNnTwo 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.nnnRESULTSnOral 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.nnnCONCLUSIONnMicronization of oral dehydroepiandrosterone diminishes bioconversion to testosterone. Vaginal dehydroepiandrosterone delivers equivalent dehydroepiandrosterone but substantially diminishes dehydroepiandrosterone bioconversion.

Secondary Amenorrhea in Obesity: Etiologic Role of Weight-Related Androgen Excess*

A massively obese, amenorrheic young woman had elevated levels of plasma androgens which could be reduced either acutely by dexamethasone administration or chronically by weight loss. Normalization of plasma androgen levels in both instances led to resumption of ovulation, suggesting that weight-related hyperandrogenism is a cause of amenorrhea in obesity.

Bromocriptine in the Treatment of Premenstrual Tension Syndrome

Twenty-four women with regular cycles who reported moderate to severe premenstrual tension participated in a double-blind study to test the effectiveness of CB154 on the control of their symptoms. Symptoms were scored daily and were further evaluated objectively twice monthly by physical examination. Control cycle follicular/luteal δ weights were not different statistically from a 0 change (P > .10), despite long-standing symptoms of bloating, swelling, and reported weight gain. CB154 treatment resulted in statistically significant improvement in daily ratings of breast tenderness (P < .005), bloating (P < .02), and depression (P < .05). Significant placebo effects observed for several other symptoms emphasize the psychologic component of this condition as well as the need for caution in the interpretation of any uncontrolled trials for therapies thought effective in the treatment of this disorder. (Obstet Gynecol 56:723, 1980)

COMPARISON BETWEEN URINARY 17-KETOSTEROIDS AND SERUM ANDROGENS IN HIRSUTE PATIENTS

In order to ascertain the usefulness of urinary 17-ketosteroids (17-KS) in the evaluation of hirsutism, 28 paired determinations of 17-KS and serum androgens were performed in 26 hirsute women before (control) and after (post Dex) 7 days of dexamethasone (Dex) administration. Upper normal control and post Dex urinary 17-KS and serum steroid levels were as follows: 17-KS, 15 and 5 mg/24 hour urine collection; dehydroepiandrossterone sulfate (DHEA-S), 2500 and 400 ng/ml serum; testosterone (T), 0.5 and 0.3 ng/ml; dihydrotestosterone (DHT), 0.35 and 0.2 ng/ml; androstencdione (A), 2. and 1.6 ng/ml; androst- 5-ene-3β-17β-diol (?5-diol), 1.6 and 0.4 ng/ml; and cortisol (F), 140 and 40 ng/ml. In 5 of the 28 tests, control 17-KS levels were elevated. In these 5 tests, control scrum levels of one or more androgens were also elevated. DHEA-S was the only steroid of which the scrum levels were elevated in all these 5 patients. Control 17-KS were within normal limits in 23 tests. Of these, 19 had elevated serum androgens. Nine patients with elevated post Dex urinary 17-KS also had elevated post Dex levels of serum androgens. Of 19 patients with normal post Dex 17-KS, 14 had elevated post Dex serum androgen levels. These data indicate that 1) urinary 17-KS determinations do not reliably identify patients with elevated serum androgens; 2) Dex suppression of 17-KS does not correlate well with Dex suppression of serum androgens; and 3) for. the evaluation of hyperandrogenism, measurements of serum androgens give a better understanding of the type of androgens involved and the source of hyperandrogenism.

PERIPHERAL AND OVARIAN STEROIDS IN OVARIAN HYPERTHECOSIS

Scrum levels of cortisol (F), prcgncnolone (Δs-P), I7-hydroxypregncnolonc (17-Δs-P), progesterone (P), 17-h_vdroxyprogesterone (17-P), androslcncdionc (A), testosterone (T), 5αdihydrotcstoslerone (DHT), dchydroepiandrostcronc (DHEA), its sulfate (DHEA-S), cslrone (E1), and cstradiol-17β (E2) were measured in 2 virilizcd patients with ovarian hypcrlhccosis. Daily morning blood samples were obtained for 6 consecutive days. Dexamethasone (Dex) 2 mg/day was administered orally starting after vcnipuncture on the second day and continued for 5 days. Human chorionic gonadotropin (hCG) was administered intramuscularly on the afternoon of the fourth and fifth days. Following the suppression-stimulation test, both patients underwent abdominal hysterectomy and bilateral salpingo- oophorcctomy. At the time of surgery, samples of peripheral and ovarian vein blood were obtained for steroid measurements. Blood samples were also obtained postsurgcry to evaluate the effect of ovariectomy on the steroid levels. Of significance were the following observations: I) Although both patients were eumenorrhcic, no corpus luteum or corpus albicans was seen on histologic examination of the ovaries. 2) Of the androgens measured, only peripheral T and DHT were elevated and did not suppress on Dex treatment, but decreased to low levels following ovariectomy, pointing toward the ovary as the source of excess T and DHT. Both patients had elevated T and DHT in the ovarian vein samples. 3) In 1 patient the ovarian vein samples showed elevated F levels with a significant ovarian-peripheral venous gradient for this steroid, an indication of ovarian secretion of F in this patient. 4) The levels of 17-P were elevated in both patients, did not suppress on Dex, and increased markedly following hCG, suggesting the ovary as the source of excess 17-P. Since A levels were normal and did not increase concomitantly with 17-P levels following hCG, it is likely that the patients had a decreased activity of the ovarian C17-20 desmolase, the enzyme responsible for the conversion of 17-P to A.