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

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.

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

OBJECTIVE: To demonstrate bioavailability of 3 weeks of oral micronized DHEA and to delineate changes induced on insulin sensitivity, morphometric indexes, and lipoprotein profiles. DESIGN: Oral 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. RESULTS: Dehydroepiandrosterone 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. CONCLUSION: Fifty 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.

Treatment of fibromyalgia syndrome with Super Malic: a randomized, double blind, placebo controlled, crossover pilot study.

OBJECTIVE: To study the efficacy and safety of Super Malic, a proprietary tablet containing malic acid (200 mg) and magnesium (50 mg), in treatment of primary fibromyalgia syndrome (FM). METHODS: Twenty-four sequential patients with primary FM were randomized to a fixed dose (3 tablets bid), placebo controlled, 4-week/course, pilot trial followed by a 6-month, open label, dose escalation (up to 6 tablets bid) trial. A 2-week, medication free, washout period was required before receiving treatment, between blinded courses, and again before starting open label treatment. The 3 primary outcome variables were measures of pain and tenderness but functional and psychological measures were also assessed. RESULTS: No clear treatment effect attributable to Super Malic was seen in the blinded, fixed low dose trial. With dose escalation and a longer duration of treatment in the open label trial, significant reductions in the severity of all 3 primary pain/tenderness measures were obtained without limiting risks. CONCLUSIONS: These data suggest that Super Malic is safe and may be beneficial in the treatment of patients with FM. Future placebo-controlled studies should utilize up to 6 tablets of Super Malic bid and continue therapy for at least 2 months.

Oral dehydroepiandrosterone in physiologic doses modulates immune function in postmenopausal women.

OBJECTIVE: This study tests the hypothesis that dehydroepiandrosterone or its metabolic products are immunomodulatory in postmenopausal women with relative adrenal androgen deficiency. STUDY DESIGN: A 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. RESULTS: Dehydroepiandrosterone 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. CONCLUSIONS: These 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 steroid replacement with micronized dehydroepiandrosterone: preliminary oral bioavailability and dose proportionality studies.

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) 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. CONCLUSIONS: Micronized dehydroepiandrosterone may provide a steroidal postmenopausal replacement that is adjunctive to estrogens and worthy of further investigation.

A total dietary program emphasizing magnesium instead of calcium. Effect on the mineral density of calcaneous bone in postmenopausal women on hormonal therapy.

The use of calcium supplementation for the management of primary postmenopausal osteoporosis (PPMO) has increased significantly in the past few years. A review of the published data does not support calcium megadosing during postmenopause. Controlled studies showed no significant effect of calcium intake on mineral density of trabecular bone and a slight effect on cortical bone. Since PPMO is predominantly due to demineralization of trabecular bone, there is no justification for calcium megadosing in postmenopausal women. Soft tissue calcification is a serious risk factor during calcium megadosing under certain conditions. A total dietary program emphasizing magnesium instead of calcium for the management of PPMO takes into account the available data on the effects of magnesium, life-style and dietary habits on bone integrity and PPMO. When this dietary program was tested on 19 postmenopausal women on hormonal replacement therapy who were compared to 7 control postmenopausal women, a significant increase in mineral bone density of the calcaneous bone (BMD) was observed within one year. Fifteen of the 19 women had had BMD below the spine fracture threshold before treatment; within one year, only 7 of them still had BMD values below that threshold.

Role of nutrition in managing the premenstrual tension syndromes.

The clinical, biochemical and endocrine effects of a total dietary program were evaluated in patients with the premenstrual tension syndromes (PMTS). The program consisted of dietary guidelines and nutritional supplementation. Open trials suggested that an initial dosage of the supplement consisting of six tablets daily gave the best symptomatic relief during the first three to six months. Double-blind studies confirmed that a daily average of six tablets decreased PMTS symptom scores to significantly lower levels than did the placebo. A significantly higher percentage of PMTS patients reported feeling better on the dietary program than did those on the placebo. Although significant changes were observed in some liver function tests, the values were within the normal ranges. The dietary program, implemented for three to six months, decreased serum estradiol 17-beta and increased serum progesterone levels during the midluteal phase in PMTS patients. Nonresponders using the program should be reevaluated and treated according to the results of the reevaluation and the PMTS symptoms.

Effect of a nutritional supplement, optivite, on symptoms of premenstrual tension.

Using a menstrual symptom questionnaire (MSQ) to assess the presence and severity of premenstrual tension (PMT), we evaluated the effect of a nutritional supplement, Optivite, on PMT symptoms in 31 patients for the week after the period (F) and the week before it (L). The total MSQ scores decreased significantly in all patients after Optivite administration at a daily dose of 3-12 tablets for one to six menstrual cycles. The mean +/- S.E. total MSQ scores were F = 8.1 +/- 1.8 and L = 31.5 +/- 2.1 for control cycles and F = 2.3 +/- 0.72 and L = 10.3 +/- 1.4 for treated cycles. The best responses were observed in patients taking 6-12 tablets/day for three or more cycles. If these results can be confirmed by well-controlled studies, this simple and safe nutritional approach can be recommended in the initial management of PMT.

The ubiquitousness of premenstrual tension in gynecologic practice.

One hundred thirty-seven premenopausal women with premenstrual tension underwent laparoscopy for bleeding, pain and/or infertility. Endometriosis was the associated gynecologic disease observed most frequently (66 patients). Other associated disorders were primary dysmenorrhea (31), poststerilization syndrome (24), chronic pelvic inflammatory disease (8) and leiomyoma uteri (8). Screening for prolactin and thyroid-stimulating hormone in patients with galactorrhea (74) revealed one patient with pituitary microadenoma and two with primary hypothyroidism. The midluteal progesterone levels were significantly decreased, whereas the midluteal estradiol 17 beta levels were significantly elevated. Because of the frequent association of premenstrual tension with other gynecologic diseases, screening for premenstrual tension in all premenopausal women is recommended.

Nutritional factors in the etiology of the premenstrual tension syndromes.

The premenstrual symptom complex many women experience in a moderate to severe form can be divided into four subgroups. Because there is more than one syndrome and nervous tension is one of the most common symptoms, the term premenstrual tension syndromes (PMTS) is used. The most common subgroup, PMT-A, consists of premenstrual anxiety, irritability and nervous tension, sometimes expressed in behavior patterns detrimental to self, family and society. Elevated blood estrogen and low progesterone have been observed in this subgroup. Administration of vitamin B6 at doses of 200-800 mg/day reduces blood estrogen, increases progesterone and results in improved symptoms under double-blind conditions. Women in this subgroup consume an excessive amount of dairy products and refined sugar, and progesterone may be of value in them. The second-most-common subgroup, PMT-H, is associated with symptoms of water and salt retention, abdominal bloating, mastalgia and weight gain. The severe form of PMT-H is associated with elevated serum aldosterone. Vitamin B6 at high dosage suppresses aldosterone and results in diuresis and clinical improvement. Vitamin E helps the breast symptoms. Methylxanthines and nicotine should be curtailed and sodium limited to 3 gm/day. PMT-C is characterized by premenstrual craving for sweets, increased appetite and indulgence in eating refined sugar followed by palpitation, fatigue, fainting spells, headache and sometimes the shakes. PMT-C patients have increased carbohydrate tolerance and low red-cell magnesium. Adequate magnesium replacement results in improved glucose tolerance tests and decreased PMT-C symptoms. Deficiency of the prostaglandin PGE1 may also be involved in PMT-C. PMT-D is the least common but most dangerous because suicide is most frequent in this subgroup. The symptoms are depression, withdrawal, insomnia, forgetfulness and confusion. In ten PMT-D patients the mean blood estrogen was lower and the mean blood progesterone higher than normal during the midluteal phase. Elevated adrenal androgens are observed in some hirsute PMT-D patients. Two PMT-D patients with normal blood progesterone and estrogens had high lead levels in hair tissue and chronic lead intoxication. This subgroups needs careful medical attention when the symptoms are severe. Therapy should be individualized according to the results of the evaluation.