Samuel S.C. Yen

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.

Idiopathic premature ovarian failure: clinical and endocrine characteristics

The characteristics of 26 patients with presumptive premature ovarian failure have been examined. The initial diagnosis was based on any single serum follicle-stimulating hormone (FSH) concentration of greater than 40 mIU/ml in karyotypically normal women under 35 years of age with irregular menses or amenorrhea. Clinical manifestations were heterogeneous: some failed to undergo pubertal maturation, and other developed hypergonadotropic amenorrhea following several years of regular menses. Almost 70% experienced hot flashes. Three had thyroiditis. Nine of 18 patients had hormonal evidence of functioning ovarian follicles, and 4 of 9 women had viable oocytes on biopsy. Evidence of ovulation was noted in five patients, and spontaneous pregnancy occurred in one. These data emphasize the fallacy of using elevated FSH levels to diagnose irreversible ovarian failure and indicate the possibility of ovulation and pregnancy in some affected individuals.

GnRH Release from the Mediobasal Hypothalamus: in vitro Inhibition by Corticotropin-Releasing Factor

The effects of corticotropin-releasing factor (CRF) on GnRH release from the adult male rat mediobasal hypothalamus (MBH) and median eminence (ME) were studied in an in vitro incubation system. CRF induced a dose-related inhibition of GnRH release from both the MBH and the isolated ME, and this inhibition was blocked by treatment with CRF receptor antagonist. Moreover, GHRF, a hypothalamic peptide similar in size to CRF, did not alter the ME release of GnRH. These results demonstrate that CRF can inhibit in vitro release of GnRH by a CRF receptor-mediated mechanism at the level of the neurosecretory terminals in the ME. Thus, increased hypothalamic CRF secretion associated with stress and adrenalectomy may inhibit hypothalamic GnRH release and produce the suppression of pituitary luteinizing hormone secretion which occurs under these conditions.

Endocrine responses to long-term administration of the antiprogesterone RU486 in patients with pelvic endometriosis

OBJECTIVE To examine endocrine and clinical responses to long-term administration of RU486 in patients with endometriosis. DESIGN Prospective open trial. SETTING Faculty practice of the authors. PATIENTS, PARTICIPANTS Six normally cycling women with endometriosis were recruited. INTERVENTIONS Subjects received RU486 100 mg/d for 3 months. MAIN OUTCOME MEASURE(S) Hormonal changes during RU486 were compared with control data obtained in the preceding cycle during the early follicular phase. Clinical responses were determined by patient assessment and second-look laparoscopy. RESULTS All women became amenorrheic, and daily urinary levels of ovarian steroid metabolites remained acyclic. Mean luteinizing hormone (LH) (P less than 0.02) and LH pulse amplitude (P less than 0.05) were increased without changes in LH pulse frequency. An antiglucocorticoid effect was demonstrated by an increase in serum cortisol (P less than 0.01) and adrenocorticotropic hormone (P less than 0.05) levels. Treatment resulted in an improvement in pelvic pain in all subjects without significant change in the extent of disease as evaluated by follow-up laparoscopy. CONCLUSIONS Daily administration of RU486 results in acyclic ovarian function and improvement in the subjective painful symptoms of endometriosis.

Clinical applications of gonadotropin-releasing hormone and gonadotropin-releasing hormone analogs *

Investigations have proved the clinical importance of hypothalmic gonadotropin-releasing hormone (GnRH) and its agonistic and antagonistic analogs. A pulsatile pattern of stimulation of specific receptors in the anterior pituitary gonadotrope has been shown to activate pituitary-gonadal function; continuous administration inhibits it. Clinical research has shown promising results in the induction of ovulation using the pulsatile pattern of GnRH administration in patients with hypogonadotropic amenorrhea. Attempts to use GnRH and its agonists to activate the pituitary-gonadal system in patients with idiopathic delayed puberty has proved logistically impractical because of the duration of treatment required to achieve sexual maturation. Treatment of cryptorchidism by intranasal administration 6 times daily for 4 weeks resulted in complete descent in 38% of the 48 boys and partial descent in 28%. For GnRH nonresponders, sequential treatment with human chorionic gonadotropin produced an 86.2% success rate. Because of the ability of GnRH agonists to reversibly suppress the pituitary-gonadal axis without side effects, it can be used in diseases mediated by gonadal steroids. Successful halting of precocious puberty through the administration of GnRH to suppress the nocturnal release of gonadotropin has been demonstrated. Unlike treatment with progestational agents, no side effects are discerned. Continuous administration of GnRH agonist in patients with endometriosis reduces ovarian estrogens and androgens to castration levels, mimicking an ovariectomy. This castration effect highlights the potential use of GnRH agonists in the treatment of metastatic breast cancer. The use of GnRH agonists for the treatment of androgen-dependent prostatic carcinoma has induced clinical improvement with nonmetastatic stage 3 disease and pain relief in metastic stage D disease. In polycystic ovary syndrome, administration of GnRH agonist shows promising results. As a potential contraceptive, GnRH agonists have not yet demonstrated practical advantages. The actions under study include: ovulation inhibition, luteolysis induction, induction of luteal phase defect and reduction of testosterone production. Numerous antagonistic analogs of GnRH have been synthesized and have shown some potential contraceptive effects in animal studies.

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.

Aging and the adrenal cortex

Aging in humans is accompanied by an increase in adrenal glucocorticoid secretion and a decline in adrenal androgen synthesis and secretion. The intense interest in adrenal function in aging individuals in recent years is in large measure related to the potential impact of cortisol excess in the development of cognitive impairment and hippocampal neuronal loss, and to the desire to provide hormone replacement and healthy aging. Although the preliminary data is tantalizing, solid scientific evidence are not at hand. It is apparent that both issues are extremely complex. Dehydroepiandrosterone (DHEA) and its 3 beta-sulfate are fascinating molecules, including their synthesis and actions in the brain. Recent studies have shown that DHEA-sulfate (DHEA-S), but not DHEA, activates peroxisome proliferator-activated receptor alpha (PPAR alpha) in the liver, an intracellular receptor belonging to the steroid receptor superfamily. Thus, DHEA-S may serve as a physiological modulator of liver fatty acid metabolism and peroxisomal enzyme expression, and thereby may contribute to the anticarcinogenic and chemoprotective properties of this intriguing class of endogenous steroids. The life-sustaining role of adrenal cortisol secretion and its regulation of metabolism via catabolic actions may be modulated by its partner DHEA and DHEA-S. During the anabolic growth period (childhood and early adulthood) the body is exposed to relatively high levels of DHEA/DHEA-S but to relatively or absolutely high levels of cortisol during infancy and the aging phase. The cortisol/DHEA-S ratio during the life span follows a U-shape curve, which may be telling us to explore these two critical adrenal steroids in tandem.

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.

The gonadotropin-releasing hormone antagonist (Nal-Glu) acutely blocks the luteinizing hormone surge but allows for resumption of folliculogenesis in normal women

The gonadotropin-releasing hormone antagonist offers several advantages over the use of the agonist and allows several physiologic questions to be addressed. In this study, we evaluated the ability of Nal-Glu to acutely inhibit the luteinizing hormone surge and prevent ovulation. We also assessed whether recovery of the follicle would be possible after several days of gonadotropin deprivation and estradiol decrement. Eight normal ovulatory women were randomized to control or Nal-Glu-treated cycles (50 micrograms/kg intramuscularly) for 3 to 4 days. Monitoring was carried out with daily vaginal ultrasonographic scans and serum estradiol levels and twice-daily serum luteinizing and follicle-stimulating hormone levels. Nal-Glu acutely inhibited the luteinizing hormone surge and ovulation, even when administered as late as the onset of the luteinizing hormone surge. Evidence was provided that spontaneous follicular rescue recurred in eight of 10 cycles after 3 to 4 days of Nal-Glu administration. Although an estradiol to follicular size dissociation occurred with Nal-Glu, subsequent ovulation occurred in 5.1 +/- 0.6 days after the last Nal-Glu dose. The decrement in estradiol after Nal-Glu administration correlated negatively with the days required for subsequent ovulation to occur (r = 0.77, p less than 0.05). The subsequent luteal phase also was normal in terms of length and progesterone levels. These data confirm the potency and efficacy of Nal-Glu in acutely inhibiting gonadotropins and extends our knowledge on the physiologic characteristics of the dominant follicle.