André Lemay

Reversible hypogonadism induced by a luteinizing hormone-releasing hormone (LH-RH) agonist (Buserelin) as a new therapeutic approach for endometriosis

Ten women with endometriosis (stages I to IV) were treated with twice-daily subcutaneous injections of 200 micrograms of (D-Ser[TBU]6-des-Gly-NH2(10] luteinizing hormone-releasing hormone ethylamide (Buserelin) for 5 days followed by 400 micrograms intranasally three times daily for 25 to 31 weeks. Serum follicle-stimulating hormone levels returned to basal values on the second day of treatment, and serum luteinizing hormone levels progressively decreased to normal within 4 weeks. Serum estradiol decreased below early follicular phase levels within 7 to 30 days and continued to decrease to castrate levels. Light to moderate estrogen withdrawal bleeding was followed by amenorrhea with occasional bleeding or spotting in four women. Abdominal pain and dyspareunia disappeared or were ameliorated after 2 months of treatment. Resorption of endometrial implants was demonstrated by laparoscopy, and endometrial biopsy revealed atrophy or weak proliferation. Ovulation returned within 45 days, and two of four sexually active women became pregnant during cycles 3 and 5. The treatment was well accepted in spite of the expected hot flushes and vaginal dryness. Safety laboratory tests during and after treatment did not reveal any abnormalities. Reversible down-regulation of pituitary/ovarian function using repetitive luteinizing hormone-releasing hormone agonist administration can be a worthwhile approach to medical treatment of endometriosis.

Inhibition of serum androgen levels by chronic intranasal and subcutaneous administration of a potent luteinizing hormone-releasing hormone (LH-RH) agonist in adult men

The effect of chronic treatment with the luteinizing hormone-releasing hormone (LH-RH) agonist Buserelin (Hoechst AG, Frankfurt/Main, West Germany) ([D-Ser(TBU)6,des-Gly-NH2(10)]LH-RH ethylamide) administrered by nasal spray (200 or 500 micrograms, twice daily) or subcutaneously (50 micrograms daily) for periods of 1 to 8 months was studied on serum sex steroids and LH levels in 18 patients with cancer of the prostate. Basal serum testosterone concentration decreases to 71.1 +/- 18.3 (NS) and 28.6 +/- 9.3%, (P less than 0.01) of control in patients receiving the 200-micrograms and 500-micrograms dose by nasal spray, respectively. In patients treated subcutaneously, a more rapid inhibition of serum testosterone levels to 19.6 +/- 6.4% of control (P less than 0.01) is observed. The finding of decreased levels of 17-OH-progesterone, testosterone, and dihydrotestosterone in the presence of unchanged pregnenolone concentration indicates that the decrease in androgen biosynthesis induced by Buserelin treatment is due to a blockage at the level of 17-hydroxylase and 17,20-desmolase activities. The present data indicate that chronic administration of Buserelin could be a safe and effective means of reducing serum androgens in patients with cancer of the prostate.

Elevated concentration and biologic activity of monocyte chemotactic protein-1 in the peritoneal fluid of patients with endometriosis * † ‡

OBJECTIVE To estimate the concentration and the biologic activity of monocyte chemotactic protein-1 (MCP-1) in the peritoneal fluid (PF) of women with and without endometriosis. DESIGN A case control study was conducted. SETTING Gynecology clinic and Laboratories of endocrinology of reproduction and immunology. PATIENTS Women presenting for infertility, pelvic pain, or tubal ligation in which endometriosis was diagnosed at laparoscopy (n = 36) and normal fertile controls presenting for tubal ligation (n = 21). INTERVENTIONS Collection of PF via laparoscopy. MAIN OUTCOME MEASURES Determination of PF concentrations of MCP-1 by an ELISA and evaluation of its monocyte chemotactic activity using a human hystiocytic cell line (U937). RESULTS. The concentration of MCP-1 (median, range of values) was increased in the PF of endometriosis patients (283, 0 to 1,930 pg/mL; conversion factor to SI unit, 0.155) compared with the control group (140, 0 to 435 pg/mL). The most significant elevation of MCP-1 levels was found in the stage II of the disease (371, 200 to 1,930 pg/mL). An increased chemotactic activity for monocytes (mean number of migrating cells/mm2 +/- SD) also was found in stages I (1,460 +/- 312) and II (1,541 +/- 336) of the disease when compared with fertile controls (393 +/- 56). Forty percent to 53% of this activity was inhibited in the presence of an antibody specific to MCP-1. CONCLUSIONS These observations are consistent with previous data indicating increased leukocyte chemotaxis in the PF of patients with endometriosis and suggest that MCP-1 may play a relevant role in the peritoneal inflammatory reaction associated with the disease.

Flaxseed dietary supplement versus hormone replacement therapy in hypercholesterolemic menopausal women

OBJECTIVE To assess serum lipid changes by a phytoestrogen dietary supplement compared with oral estrogen‐progesterone replacement in hypercholesterolemic menopausal women. METHODS Twenty‐five menopausal patients with total cholesterol greater than 6.2 mmol/L (240 mg/dL), a cholesterol/high‐density lipoprotein‐cholesterol ratio greater than 4.5 and triglycerides less than 3.5 mmol/L (310 mg/dL) after a 4‐month diet, were randomized to add 40 g/day of crushed flaxseed to their diet or to take daily 0.625 mg of conjugated equine estrogens alone (hysterectomy, n = 10) or combined with 100 mg of micronized progesterone (intact uterus, n = 15). After 2 months of treatment, both groups continued the diet alone during a 2‐month washout period before crossing over to the alternate treatment for 2 more months. RESULTS Differences were found between hormone replacement therapy and flaxseed respectively for decrease of low‐density lipoprotein cholesterol (3.8 ± 0.2 versus 4.4 ± 0.2 mmol/L) (148 ± 8 versus 170 ± 8 mg/dL) (P = .10), increase of high‐density lipoprotein cholesterol (1.6 ± 0.04 versus 1.3 ± 0.03 mmol/L) (62 ± 1 versus 50 ± 1 mg/dL) (P = .001), and increase of apolipoprotein A‐1 (1.71 ± 0.07 versus 1.42 ± 0.05 g/L) (P = .003). These changes were not related to modifications in diet, exercise, or anthropometric measurements evaluated in parallel. Both treatments produced similar decreases in menopausal symptoms and in glucose and insulin levels. Only hormone replacement therapy as compared with flaxseed induced an elevation of sex hormone binding globulin (P = .004), lowered fibrinogen (P = .08), and plasminogen activator inhibitor type 1 (P = .01). CONCLUSION Although 40 g of flaxseed is as effective as oral estrogen‐progesterone to improve mild menopausal symptoms and to lower glucose and insulin levels, only hormone replacement therapy significantly improves cholesterol profile in hypercholesterolemic women and favorably modifies markers related to cardiovascular health.

Luteinizing hormone-releasing hormone agonist and uterine leiomyoma: A pilot study☆

Ten women with 12 uterine leiomyomas ranging from 7.5 to 420 cc (mean, 112.6 +/- 39.4) were treated with subcutaneous injections of the luteinizing hormone-releasing hormone agonist buserelin, 200 micrograms three times daily for 1 week and then 500 micrograms daily for the rest of the 6-month treatment period. Following initial stimulation the pituitary ovarian axis was suppressed after 3 weeks of treatment with mean serum estradiol ranging between 17 and 36 pg/ml. Seven uterine leiomyomas had a marked regression in size following treatment with luteinizing hormone-releasing hormone agonist; two were undetectable and the volume of the other five diminished by an average of 80%. One tumor did not respond to treatment, two regressed by 25%, and two, following an initial reduction of 65% and 50%, reenlarged during the last 2 months of treatment to 75% and 100% respectively of their initial volume. Luteinizing hormone-releasing hormone agonist is the first medication demonstrated effective in reducing the size of uterine myomas.

Possible Luteolytic Effects of Luteinizing Hormone-Releasing Hormone in Normal Women

The administration of five subcutaneous 250-microgram doses of lutienizing hormone (LH)-releasing hormone (LHRH) at 4-hour intervals, the first injection being given at 8 A.M. on 1 or 2 consecutive days between days 1 and 9 following the LH surge in normal women, shortened the luteal phase from 1 to 4 days in 16 of 17 treatment cycles. There was a better efficiency of treatment when LHRH was administered on days 6 to 9 after the LH surge as compared with days 1 to 5. In fact, the luteal phase was shortened from 3.3 +/- 0.2 days versus 1.4 +/- 0.2 days (P less than 0.01) and the serum progesterone level was decreased to 44% +/- 6% versus 71% +/- 6% of control levels (P less than 0.01) when the neurohormone was injected late as compared with early in the luteal phase. The present data raise the possibility of a luteolytic effect of LHRH in normal women and indicate the interest of such a near-physiologic approach for the control of luteal function and time of appearance of menses.

Secretion of monocyte chemotactic protein-1 by cytokine-stimulated endometrial cells of women with endometriosis *

OBJECTIVE To evaluate in vitro the production of monocyte chemotactic protein-1 (MCP-1) by endometrial cells of patients with and without endometriosis. DESIGN Primary cultures of stromal and epithelial cells isolated from human endometrium were exposed during 24 hours to different cytokines. Monocyte chemotactic protein-1 secretion was analyzed in the culture medium. SETTING Gynecology clinic and laboratories of endocrinology of reproduction and immunology. PATIENTS Women presenting for infertility or pelvic pain in which endometriosis was diagnosed at laparoscopy (n = 6) and women presenting for tubal ligation without laparoscopic evidence of the disease (n = 6). INTERVENTIONS None. MAIN OUTCOME MEASURES De novo secretion of MCP-1 in the culture supernatant by immunoprecipitation and sodium dodecyl sulfate-polyacrylamide gel electrophoresis after metabolic labeling with 35S-cysteine. RESULTS The incubation of endometrial epithelial cells of endometriosis women with either interleukin-1 beta or tumor necrosis factor-alpha resulted in the appearance of at least two and sometimes three bands having approximately 15, 13, and 9 kd molecular weights. These bands were identified as three distinct species of MCP-1 as their immunoprecipitation was prevented effectively in presence of an excess of cold MCP-1. In contrast, the endometrial epithelial cells of only one of six normal women produce significant levels of MCP-1 under the same stimulation conditions. The stromal cells of both groups of subjects do not secrete appreciable amounts of MCP-1 or only small quantities in two cases of endometriosis. CONCLUSIONS Monocyte chemotactic protein-1 secretion is upregulated in cytokine-stimulated endometrial epithelial cells of women having endometriosis as compared with normal women without evidence of the disease. Such a difference at the level of eutopic endometrial cell may have a significance in the physiopathology of endometriosis.

Cytokine-induced secretion of monocyte chemotactic protein-1 by human endometriotic cells in culture

OBJECTIVE Local secretion of chemotactic factors could contribute to the attraction of macrophages into the peritoneal cavity of women with endometriosis. The purpose of this study was to investigate the ability of endometriotic cells to produce monocyte chemotactic and activating protein-1 in response to interleukin-1 beta and tumor necrosis factor-alpha, which are found in elevated levels in the peritoneal fluid of patients with endometriosis. STUDY DESIGN Cultures of fibroblast-like and epithelial cells isolated from endometriotic tissue were incubated with different concentrations of cytokines for varying periods of time. The de novo secretion of monocyte chemotactic protein-1 in the culture supernatants was analyzed by immunoprecipitation and electrophoresis after metabolic labeling with sulfur 35-labeled cysteine. RESULTS The incubation of endometriotic fibroblast-like cells with interleukin-1 beta and tumor necrosis factor-alpha resulted in a time- and dose-dependent release of monocyte chemotactic protein-1 into the culture supernatant. Coincubation of the cells with tumor necrosis factor-alpha and interferon gamma resulted in a synergistic and dose-dependent increase of the monocyte chemotactic protein-1 secretion, whereas interferon gamma alone had no significant effect. Preliminary results indicate that monocyte chemotactic protein-1 is also produced by endometriotic epithelial cells in response to the same cytokines. CONCLUSIONS Cytokine-stimulated endometriotic cells synthesize and secrete monocyte chemotactic protein-1 in culture, and they may play a relevant role in the recruitment of macrophages to the peritoneal cavity of patients by the local production of chemotactic factors.

Use of intranasal luteinizing hormone-releasing hormone agonist in uterine leiomyomas

Nine women harboring uterine leiomyomas have been treated with subcutaneous injections and then with intranasal insufflation of luteinizing hormone-releasing hormone agonist for a total treatment period of 6 months. After initial stimulation, mean serum estradiol progressively decreased and stabilized at 36.8 +/- 4.9 pg/ml for the rest of the treatment period. The volume of uterine leiomyomas has been reduced by an average of 71%. Side effects and hot flushes were less severe and better tolerated than reported after sole subcutaneous administration.

Potential new treatment of endometriosis: reversible inhibition of pituitary-ovarian function by chronic intranasal administration of a luteinizing hormone-releasing hormone (LH-RH) agonist

This paper reports on the case of a 30 year old woman suffering from pelvic endometriosis, dyspareunia, and postcoital bleeding. The patient was treated for 173 days, starting on the 7th day of the cycle, with intranasal administration of 300 mcg of Buserelin, a luteinizing hormone-releasing hormone (LH-RH) agonist, every 12 hours. During the treatment period basal luteinizing hormone (LH) and estradiol (E2) levels were measured at various time intervals. Buserelin caused a marked inhibition of pituitary and ovarian function 2 weeks after inception of treatment. Basal LH levels were low, and serum E2 levels were decreased below those usually found in the early follicular phase. The hormonal inhibition lasted for the entire treatment period, and the only side effects were hot flashes. After 2 months of treatment dyspareunia and postcoital bleeding had almost disappeared; laparoscopy at the end of treatment showed a marked regression of endometrial lesions. Ovulation returned spontaneously after only 43 days of treatment, and regular menstrual cycles appeared shortly after termination of treatment. This prompt return to normal ovarian function should be particularly advantageous for patients seeking pregnancy. This study shows that LH-RH treatment could be a valuable approach for the medical treatment of endometriosis; however, this is only a preliminary report, and further investigation is needed before it can be safely stated that LH-RH agonist is an effective drug for the longterm treatment of endometriosis.