Arlene J. Morales

Replacement of DHEA in Aging Men and Women

DHEA in appropriate replacement doses appears to have remedial effects with respect to its ability to induce an anabolic growth factor, increase muscle strength and lean body mass, activate immune function, and enhance quality of life in aging men and women, with no significant adverse effects. Further studies are needed to confirm and extend our current results, particularly the gender differences.

Treatment of endometriosis with the antiprogesterone mifepristone (RU486)

OBJECTIVE To evaluate the safety and efficacy of an antiprogesterone (mifepristone, RU486; Roussel-Uclaf, Romaineville, France) on endometriosis. DESIGN An open, prospective clinical trial. SETTING The clinical practice of an academic faculty. PATIENTS Nine women with endometriosis were studied. INTERVENTIONS RU486 (50 mg/d) was administered for 6 months. MAIN OUTCOME MEASURES Daily symptom inventories and urinary steroid metabolites were assessed before, during, and after treatment. Blood for hormone analysis was obtained weekly for 4 weeks and monthly thereafter. The extent of endometriosis, bone mineral density, circadian rhythm of cortisol, and LH pulsatility were determined before and after treatment. Safety laboratory measurements were made before and at 1, 2, and 6 months of treatment. RESULTS Pelvic pain and uterine cramping improved in all patients. Endometriosis regressed by 55%. All patients exhibited endocrine features of anovulatory amenorrhea without hypoestrogenism. A rise in serum LH and T levels was observed during the first month of treatment and one patient developed an elevation of liver transaminases during the last month of treatment. All other measurements were unchanged. CONCLUSION RU486 appears to be effective in improving the symptoms and causing regression of endometriosis in the absence of significant side effects.

Regression of uterine leiomyomata to the antiprogesterone RU486: dose-response effect.

OBJECTIVE To study the response of uterine leiomyomata to three daily doses of RU486 (5, 25, and 50 mg). DESIGN Prospective nonrandomized trial of women with symptomatic leiomyomata. SETTING Patients from the clinical practice of the authors at the University of California, San Diego Medical Center. PATIENTS Ten patients with symptomatic leiomyomata previously reported after treatment with 50 mg of RU486 daily for 3 months. Eleven patients treated with 25 mg of RU486 daily and nine patients placed on 5 mg of RU486 daily for 12 weeks. MAIN OUTCOME MEASURES Changes in leiomyomata volume as measured with vaginal ultrasounds at baseline and monthly thereafter. Frequent blood samples for hematology, chemistry, and hormone levels were obtained. Twenty-four-hour urine collections for free cortisol and creatinine were obtained at baseline and at 12 weeks. RESULTS All three doses induce ovarian acyclicity. Administration of 50 mg of RU486 decreases leiomyomata volume to 78.1% +/- 4.8% of baseline at 4 weeks, 60.5% +/- 6.6% at 8 weeks, and 51.0% +/- 9.2% after 12 weeks of treatment. Regressive response in patients treated with 25 mg of RU486 daily was 76.3% +/- 5.0% of baseline at 4 weeks, 54.0% +/- 5.1% at 8 weeks, and 44.0% +/- 5.0% after 12 weeks. At 5 mg of RU486 leiomyomata volume was 80.6% +/- 8.3% of baseline after 4 weeks, 63.7% +/- 14.6% after 8 weeks, and 74.4% +/- 19.8% after 12 weeks of therapy. CONCLUSIONS Although acyclicity is seen at all three doses, an effective dose to cause a clinically significant (50%) decrease in leiomyomata volume appears to be 25 mg daily.

The effects of RU 486 and leuprolide acetate on uterine artery blood flow in the fibroid uterus: a prospective, randomized study.

OBJECTIVE Our purpose was to examine the effects of RU 486 and leuprolide acetate on uterine artery blood flow and uterine volume. STUDY DESIGN Patients were randomly assigned to group A (eight patients) receiving 25 mg of RU 486 daily for 3 months or group B (six patients) receiving 3.75 mg of leuprolide acetate monthly for 3 months. Uterine artery blood flow change was determined by resistive index by means of vaginal color Doppler ultrasonography. Uterine volume was measured before and during the study with abdominal ultrasonography. RESULTS Both groups showed an increase in resistive index. Patients receiving RU 486 had uterine artery blood flow decreased by 40%, and those receiving leuprolide acetate had a 21% decrease. We noted a significant decrease in uterine volume compared with pretreatment in both groups at 3 months. There was no significant decrease between groups. CONCLUSION Both RU 486 (25 mg daily) and leuprolide acetate (3.75 mg monthly) are effective in decreasing blood flow to the uterus (increasing resistive index) and decreasing uterine volume at 3 months. A significant decrease in uterine artery blood flow may provide a mechanism for the decrease in uterine size and the decrease in uterine blood loss at the time of surgery.

Rapid regression of uterine leiomyomas in response to daily administration of gonadotropin-releasing hormone antagonist * †

Objective The efficacy of acute and sustained pituitary gonadotropin down-regulation by the Nal-Glu GnRH antagonist (Nal-Glu) was evaluated in the treatment of uterine leiomyomas. Design Prospective, open clinical trial. Patients Seven normally cycling women with symptomatic leiomyomas. Interventions Nal-Glu (50 μ g/kg per day) was administered subcutaneously for 3 months. Main Outcome Measures Baseline ultrasound examinations were obtained and repeated monthly throughout treatment. Each leiomyoma was mapped and measured in three dimensions. Blood samples were drawn daily for 7 days, weekly for 4 weeks, and monthly for the remaining 2 months. Results Mean leiomyoma size decreased 52.8 ± 7.3% (means ± SD) after 1 month of therapy and remained unchanged for the remainder of the study. Serum levels of E 2 (35.9 ± 11.8 to 9.3 ± 0.8 pg/mL, 131.7 ± 43.3 to 34.0 ± 1.4 pmol/L), estrone (37.3 ± 7.5 to 13.0 ± 2.5 pg/mL, 138.1 ± 27.7 to 48.1 ±9.1 pmol/L), and P (1.6 ± 1.1 to 0.3 ± 0.01 ng/mL, 5.0 ± 3.6 to 0.9 ± 0.04 nmol/L) declined rapidly (within 48 hours) and remained suppressed throughout treatment. Serum LH, FSH, andro-stenedione, T, and DHEA levels did not change significantly. In two subjects who did not have surgical removal, leiomyomas grew to original size within the 1st month off drug. Six patients remained amenorrheic and the other subject spotted during the last 2 months of therapy. Conclusions Continuous treatment with Nal-Glu induces immediate and sustained pituitary-gonadal down-regulation that results in regression in leiomyoma size. By circumventing GnRH agonist-induced pituitary-ovarian up-regulation, GnRH antagonists may prove to be superior tools in the medical management of leiomyomas.

Evidence for Oxidatively Modified Lipid-Protein Complexes in Endometrium and Endometriosis

OBJECTIVE To evaluate for the presence of oxidatively modified lipid-protein complexes in endometriosis and endometrium of women with endometriosis and controls. DESIGN Controlled clinical study. SETTING Academic tertiary care center. PATIENT(S) Women undergoing surgery for pelvic pain, infertility, endometriosis, or tubal ligation controls. INTERVENTION(S) Biopsy of endometrium and endometriosis. MAIN OUTCOME MEASURE(S) Staining with antibodies to oxidatively modified lipid proteins (HNE-7, MDA2), macrophages (HAM-56), and muscle cell actin (HHF-35). RESULT(S) Both endometrium and endometriosis tissues contain stromal cells that immunostain with HAM-56 and show immunostaining (both intracellular and extracellular) with HNE-7 and MDA2. Some endometriotic implants show patchy staining with HHF-35. Endometrium was devoid of staining with HHF-35. Control staining with nonimmune sera in both tissues was also devoid of staining. CONCLUSION(S) These data strongly implicate the occurrence of oxidative stress in endometriosis tissue. These data also suggest that oxidative modification is a normal physiological process in endometrium.

Circulating levels of follistatin from puberty to menopause.

OBJECTIVE To determine the changes in circulating levels of follistatin, a binding protein for activin and inhibin, through the reproductive life cycle in women. DESIGN An open, prospective descriptive study. SETTING An academic endocrine research unit. PATIENTS Prepubertal (n = 10), midpubertal (n = 7), and postpubertal (n = 25) (early adolescent) girls, normal cycling adult women (n = 8), postmenopausal women (n = 17), and men (n = 13) were studied. INTERVENTIONS Normal cycling women were given Nal-Glu GnRH antagonist for 3 days in the follicular phase of the cycle. MAIN OUTCOME MEASURE Serum concentrations of follistatin determined in a heterologous RIA. RESULTS Mean follistatin levels did not change during puberty but were higher in adult and postmenopausal women. Levels of immunoreactive follistatin in men were lower than levels found in normal cycling women and postmenopausal women. Daily immunoreactive follistatin levels during the menstrual cycle remained constant and did not change significantly after ovarian suppression with GnRH antagonist. CONCLUSION Because dynamic changes of serum immunoreactive follistatin do not occur during ovarian activation (puberty), suppression, and age-related ovarian failure, the increase in immunoreactive follistatin levels in adult and postmenopausal women may implicate sources of follistatin other than the ovary.

Lack of insulin resistance in fibroblasts from subjects with polycystic ovary syndrome

Insulin resistance in polycystic ovary syndrome (PCOS) is characterized by a novel defect in insulin signal transduction expressed in isolated human adipocytes as impaired insulin sensitivity for glucose transport and antilipolysis. To determine whether this is a generalized defect of a potentially genetic basis, or possibly a tissue-specific one, fibroblast cultures were established from age- and weight-matched obese normal cycling (NC; n = 5) and PCOS (n = 6) subjects. Adipocytes from the current PCOS subjects displayed impaired sensitivity for glucose transport stimulation (half-maximal effective concentration [EC50], 317 +/- 58 pmol/L in PCOS v 130 +/- 40 in NC; P < .025). Specific insulin binding was similar in fibroblasts from NC (0.57% +/- 0.10%/10(6) cells) and PCOS (0.45% +/- 0.10%) subjects. Fibroblasts from NC (4.9- +/- 0.5-fold stimulation) and PCOS (4.6- +/- 0.3-fold) subjects were equally responsive to insulin for stimulation of glucose incorporation into glycogen. Insulin sensitivity for glycogen synthesis in fibroblasts did not differ between NC (EC50, 9.6 +/- 0.9 nmol/L) and PCOS (9.1 +/- 0.9) cells. For thymidine incorporation into DNA, relative insulin responsiveness was similar in NC (2.3- +/- 0.3-fold stimulation) and PCOS (2.1- +/- 0.1-fold) fibroblasts. Insulin sensitivity for DNA synthesis was similar in NC (EC50, 12.9 +/- 2.4 nmol/L) and PCOS (7.6 +/- 1.3) cells. In summary, (1) insulin receptor binding is normal in PCOS fibroblasts; and (2) PCOS fibroblasts have normal insulin sensitivity and responsiveness for metabolic and mitogenic responses. Impaired insulin signal transduction, while present in adipocytes from a group of PCOS subjects, is not found in fibroblasts from the same subjects. This defect is not generalized to all cell types, but may be limited to specific tissues and responses.

Regulation of Insulin-Like Growth Factor Binding Protein-I During the 24-Hour Metabolic Clock and in Response to Hypoinsulinemia Induced by Fasting and Sandostatin in Normal Women

Objective: To establish the relation of insulin-like growth factor-I (IGF-I) and IGF-binding protein-1 (IGFBP-1) with 24-hour metabolic excursions in normal healthy women and in response to acute interruption of metabolic homeostasis by hypoinsulinemia. Methods: Hourly blood samples during the 24-hour metabolic clock were obtained from seven normally cyclin women. Uniform dietary composition (50% carbohydrate, 35% fat, and 15% protein) and timing of meals (8 AM, 12 PM, and 6 PM) were prescribed. Daytime hypoinsulinemia was induced by omitting meals and by Sandostain (100 μg) administration. Changes in serum levels of glucose, insulin, cortisol, IGF-I, and IGFBP-1 were measured. Results: The diurnal pattern of serum IGFBP-1 levels during the 24-hour metabolic clock was characterized by a rapid fall during the feeding phase of the day and a progressive 3.5-fold rise during nocturnal fasting; IGF-I levels were unchanged. Changes in IGFBP-1 levels were in parallel to those of cortisol and were inversely related to increases in glucose (80%) and insulin (tenfold) levels after each meal and to their decline during nocturnal fasting. Daytime fasting and administration of Sandostatin were accompanied by rapid and sustained increases in IGFBP-1 when insulin levels declined to 54 ± 20 pmol/L. Conclusions: With constant levels of IGF-I, the diurnal rhythm of IGFBP-1 may subserve a physiologic function by coordinating insulin and IGF-I action with substrate availability. Fluctuations of insulin levels during the 24-hour metabolic clock in normal women appear to sere as a signal, with an inhibitory effect on IGFBP-1 production when levels are above 70 pmol/L and a stimulatory effect at levels below 70 pmol/L. These findings provide a basis for future investigations in woman with nutritionally related reproductive disorders.

Rapid Regression of Uterine Leiomyomas in Response to Daily Administration of Gonadotropin-Releasing Hormone Antagonist

OBJECTIVE The efficacy of acute and sustained pituitary gonadotropin down-regulation by the Nal-Glu GnRH antagonist (Nal-Glu) was evaluated in the treatment of uterine leiomyomas. DESIGN Prospective, open clinical trial. PATIENTS Seven normally cycling women with symptomatic leiomyomas. INTERVENTIONS Nal-Glu (50 micrograms/kg per day) was administered subcutaneously for 3 months. MAIN OUTCOME MEASURES Baseline ultrasound examinations were obtained and repeated monthly throughout treatment. Each leiomyoma was mapped and measured in three dimensions. Blood samples were drawn daily for 7 days, weekly for 4 weeks, and monthly for the remaining 2 months. RESULTS Mean leiomyoma size decreased 52.8 +/- 7.3% (means +/- SD) after 1 month of therapy and remained unchanged for the remainder of the study. Serum levels of E2 (35.9 +/- 11.8 to 9.3 +/- 0.8 pg/mL, 131.7 +/- 43.3 to 34.0 +/- 1.4 pmol/L), estrone (37.3 +/- 7.5 to 13.0 +/- 2.5 pg/mL, 138.1 +/- 27.7 to 48.1 +/- 9.1 pmol/L), and P (1.6 +/- 1.1 to 0.3 +/- 0.01 ng/mL, 5.0 +/- 3.6 to 0.9 +/- 0.04 nmol/L) declined rapidly (within 48 hours) and remained suppressed throughout treatment. Serum LH, FSH, androstenedione, T, and DHEA levels did not change significantly. In two subjects who did not have surgical removal, leiomyomas grew to original size within the 1st month off drug. Six patients remained amenorrheic and the other subject spotted during the last 2 months of therapy. CONCLUSIONS Continuous treatment with Nal-Glu induces immediate and sustained pituitary-gonadal down-regulation that results in regression in leiomyoma size. By circumventing GnRH agonist-induced pituitary-ovarian up-regulation, GnRH antagonists may prove to be superior tools in the medical management of leiomyomas.