[Hyperhomocysteinemia. A new coronary risk factor]. / Hiperhomocisteinemia. Un nuevo factor de riesgo coronario.

Cardiovascular disease is the leading cause of mortality in Mexico, as well as in other Western countries. Conventional risk factors for atherosclerosis, such as cigarette smoking, systemic hypertension, diabetes mellitus, and hypercholesterolemia, do not explain this association completely. Recently, it has been recognized that hyperhomocysteinemia contributes to the atherosclerotic process, promoting endothelial damage and oxidative stress in the vascular wall. Homocysteine, an amino acid generated under physiologic conditions after ingestion of protein-rich foods, is used in a variety of metabolic pathways. Elevated plasma levels of this amino acid (higher than 15 mmol/L or lower in the presence of other cardiovascular risk factors) promote the development of atherosclerosis. Folic acid and vitamin B6 and B12 supplements decrease plasma levels of homocysteine effectively and may play an important role in the prevention and treatment of atherosclerotic vascular disease.

[Effect of transdermal administration of 17-beta estradiol on the release of growth hormone by growth hormone liberating hormone (GH-RH-1-29) in climacteric women before and after treatment]. / Influencia de la administración transdérmica de 17-beta estradiol sobre la liberación de hormona de crecimiento mediante la hormona liberadora de la hormona de crecimiento (GH-RH-1-29) en mujeres climatéricas pre y postratamiento.

BACKGROUND: Great interest has sparked recently the role that plays the changes that the growth hormone undergoes in the menopausal woman, specially its involvement in the central nervous, cardiovascular, genitourinary, digestive and osteomuscular systems. OBJECTIVE: To evaluate the influence of transdermal administration of 17-beta estradiol on growth hormone secretion in menopausal women before and after treatment under the stimulus of growth-hormonereleasing hormone (GH-RH). MATERIAL AND METHODS: We studied 5 patients with a mean age of 51 +/- 4.1 yr. with clinical and biochemical evidence of menopause. Evolution time 5.4 +/- 4.61 (range: 1-13 yr.). We monitored the pulsatility of GH during the first 120 minutes and 3 hours after the administration of the GHRH-1-29-NH2, i.v. bolus (50 micrograms). There were obtained every 15 minutes for the determination of GH levels before and after the stimulus. Immediately thereafter hormone replacement therapy was initiated with transdermal beta-estradiol with 50 micrograms patches twice a week. Clinical evaluations and hormone dynamics with OHRH-1-29 were performed at baseline and at 1,3 and 6 months from the start of therapy as described previously. RESULTS: GH pulsatility before estrogen replacement therapy (ERT) in these 5 patients was: X: 0.48 +/- 0.22, 0.38 +/- 0.17, 0.45 +/- 0.25 and 0.29 (at baseline, 1, 3 and 6 months respectively) and 2.74 +/- o 1.21; 3.48 +/- 1.32 (p > 0.05) 4.91 +/- 1.57 (p < 0.05) and 6.04 +/- 1.69 (p < 0.05) (p in relation to baseline) post stimulus with GH-RH-1-29 at baseline 1, 3 and 6 months respectively after transdermal estrogen therapy. Gonadotrophins basal serum levels fall from X: 54.68 +/- 27 to 33.20 +/- 11.23 and 40.48 +/- 12 to 28.30 +/- 6.70 (FSH and LH respectively). Estradiol serum level were from 1.82 +/- 4.06 to 25.95 +/- 5.96 before and after treatment, respectively. COMMENTS AND CONCLUSIONS: These results demonstrate that transdermal estrogen therapy does not modify the pulsatility of growth hormone but it does increase the magnitude of response to the stimulus with GH-RH-1-29 proportional to the time of treatment. We consider that this tendency to increase the production of growth hormone could be explained by an endogenous deficit of growth hormone releasing hormone due to a number of factors including the lack of adequate estrogen serum levels in menopausal women. More investigations will be needed to support this hypothesis and to bring forth a new understanding of menopause and its treatment.

[Androgen-producing steroid cell ovarian tumor. Report of a case]. / Tumor ovárico de células esteroideas productor de andrógenos. Informe de caso.

UNLABELLED: Ovarian Tumors with Endocrine Repercussion make-up 5% of neoplasms in this gland, occupying the first place are the estrogen-producing tumors, in the second place are the androgen-producing tumors, progesterone, corticosteroids and renin are exceptional. In these tumors' nomenclature has existed a kind of synonyms that create confusion about their histogenesis and their difficult use in the literature. CASE REPORT: A 23 yr-old woman with opsomenorrhea of several years evolution, secondary amenorrhea, deep voice and progressive hirsutism. Weight: 98.500 kg. Height: 1.74 m. Body Mass Index (BMI): 32.61 (kg/m2). Vellus hair in the face (beard and moustache), android distribution in abdomen, forearms, thighs and legs (Ferriman score of 20), acne and bilateral breast involution. All paraclinic exams were negative. Human chorionic gonadotropin quantification in urine of 24 hours was negative. X-Ray: Right ovarian tumor was demonstrated with pelvic ultrasound and computerized axial tomography of abdomen. Cytogenetic study expressed 46 XX chromosomes. Presurgery endocrinologic studies were: total and free testosterone: 3.55 ng/mL and 14.30 pg/mL, respectively. Insulin: 43.3 microU/mL and C peptide: 5.7 ng/mL. The glucose tolerance test demonstrate intolerance to carbohydrates. During operation, the hormone levels in the right ovarian vein were: total and free testosterone of 2.70 ng/mL and 12.70 pg/mL respectively, which normalized after 12 hours of surgery. Other steroid hormones were normal. After six months of surgery the patient had Ferriman score of 10 and eumenorrhea. Weight: 98.100 kg, glucose tolerance test and basal hormone levels were normal. Electron Microscopy showed characteristic data of a steroid producing tumor without crystalloids of Reinke.

Treatment of uterine leiomyomas with luteinizing hormone-releasing hormone antagonist Cetrorelix.

The efficacy of the luteinizing hormone-releasing hormone antagonist Cetrorelix (SB-75) in the medical management of uterine leiomyomas (fibromas) was evaluated. Cetrorelix was administered to 18 pre-menopausal women with myomas with a mean age of 33.3 years, who had been candidates for hysterectomy. The initial dose of Cetrorelix was 5 mg twice daily s.c. for the first 2 days and thereafter 0.8 mg was given twice daily s.c. for at least 3 months. The mean duration of the treatment was 4.4 months. Before the therapy with Cetrorelix, the mean uterine volume, measured by ultrasonography, was 395.4 +/- 69.2 ml (range 89-1166). Sixteen patients showed a progressive reduction in uterine volume from 410.4 +/- 77.1 to a mean of 230.8 +/- 52.6 ml at 3 months. All patients became amenorrhoeic and had hot flushes. After treatment with Cetrorelix, a surgical myomectomy was performed in 12 women. One of the patients subjected to myomectomy after therapy with Cetrorelix became pregnant. These patients have been followed for up to 25 months and only in one case has the uterine volume increased after therapy. Three patients had good responses to therapy with Cetrorelix and it was decided to follow them only by observation. One patient became pregnant 2 months later. In the other patient, the uterine volume remained unchanged for the duration of the follow-up of 2 years and the third patient showed an increase after 21 months. In three patients, it was necessary to perform total hysterectomy. In 14 patients, serum concentrations of luteinizing hormone, follicle stimulating hormone and oestradiol decreased after the administration of the first dose of Cetrorelix and continued at subnormal values throughout therapy. In 15 patients who were not subjected to total hysterectomy, menstrual function returned at 1 month after cessation of treatment. Overall results support the use of Cetrorelix for the management of uterine leiomyomas.

Luteinizing hormone-releasing hormone antagonist cetrorelix as primary single therapy in patients with advanced prostatic cancer and paraplegia due to metastatic invasion of spinal cord.

OBJECTIVES: To assess the clinical response to luteinizing hormone-releasing hormone (LH-RH) antagonist cetrorelix (SB-75) in patients with advanced carcinoma of the prostate and paraplegia due to metastatic invasion of spinal cord. METHODS: Cetrorelix was given at two different dose regimens to 5 patients with prostatic cancer Stage D2 and paraplegia. Urologic and neurologic examinations, laboratory studies, radiography (myelography), and prostate ultrasonography were carried out. Prostate-specific antigen (PSA) and free testosterone were also measured. RESULTS: In all patients, the neurologic symptoms regressed. The recovery of the thermic and vibratory sensation and motility of the toes was observed. The neurologic improvement continued during the treatment and at 3 months all the patients were able to walk with the aid of a cane. In 1 patient, the myelography showed that the spinal cord compression had disappeared and prostate volume assessed by ultrasonography showed a significant decrease. The bladder function greatly improved in all 5 patients during the treatment with cetrorelix. Baseline levels of luteinizing hormone fell from 9.28 to 1.0 IU/L and those of follicle-stimulating hormone (FSH) fell from 18.28 to 12 IU/L (P < 0.05) after the first day of therapy with cetrorelix. Mean levels of free testosterone were reduced from 52.4 to 14.7 pmol/L (P < 0.005) at 12 hours and to 13.1 pmol/L (P < 0.005) 3 days after the first injection of cetrorelix. A persistent inhibition of gonadotropins and testosterone was maintained during the subsequent 3 months of therapy. The high levels of PSA gradually decreased. CONCLUSIONS: Our results show that LH-RH antagonist cetrorelix causes an immediate lowering of the serum testosterone levels in patients with prostate cancer and metastases in the spinal cord, in whom the LH-RH agonists cannot be used as single drugs because of the possibility of flare-up and appears to be appropriate for long-term therapy.

Inhibition of luteinizing hormone, follicle-stimulating hormone and sex-steroid levels in men and women with a potent antagonist analog of luteinizing hormone-releasing hormone, Cetrorelix (SB-75).

Cetrorelix (SB-75; [Ac-D-Nal(2)1, D-Phe(4Cl)2, D-Pal(3)3, D-Cit6, D-Ala10] luteinizing hormone-releasing hormone (LHRH)) is a new highly potent antagonist analog of LHRH containing the D-ureidoalkyl amino acid D-citrulline at position 6 and is free of allergenic effects. This study shows the inhibition of LH and follicle-stimulating hormone (FSH) release in normal men, postmenopausal women and patients with gonadal dysgenesis, using different doses and i.m., s.c. and i.v. routes of administration of SB-75. The mean serum levels of LH and FSH in normal men who received one single dose of 300 micrograms of SB-75 sc started to decline rapidly 1 h after its administration; the LH suppression was sustained for 14 h and that of FSH up to 24 h or longer as the samples were obtained only up to this time. The nadir for LH was reached at 14 h and that for FSH at 24 h or later after administration of the antagonist (p < 0.05). Serum levels of total and free testosterone decreased after the first hour and this inhibition was maintained for up to 14 h. The nadir for total testosterone was at 6 h and that for free testosterone was at 8 h (p < 0.001), corresponding to 56% and 60% of inhibition, respectively. In postmenopausal women, inhibition of the elevated basal serum LH and FSH levels occurred after a single injection of the antagonist analog SB-75 in doses of 75, 150, 300, 600 and 1200 micrograms using im, sc and iv routes of administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Responses to the antagonistic analog of LH-RH (SB-75, Cetrorelix) in patients with benign prostatic hyperplasia and prostatic cancer.

Among new highly potent antagonistic analogs of luteinizing hormone-releasing hormone (LH-RH), containing neutral hydrophilic D-ureidoalkyl amino acids such as D-Cit and D-Hci at position 6 and free of edematogenic and anaphylactoid reactions, Ac-D-Nal(2)1, D-Ph(4Cl)2, D-Pal(3)3, D-Cit6, D-Ala10 (LH-RH) (SB-75; Cetrorelix) was shown to be one of the most powerful. In this trial, we evaluated the response to 500 micrograms SB-75 given every 12 hr subcutaneously (sc) for 4 weeks in 11 patients with benign prostatic hyperplasia (BPH), and 6 weeks in 6 prostatic cancer patients (2 stage C, 4 stage D2). In patients with BPH presenting with prostatism and urinary outflow obstruction, there was a noticeable clinical improvement after the first week of SB-75 administration. This improvement continued during the course of treatment. Before therapy with SB-75, the serum levels of prostate-specific antigen (PSA) (6.73 +/- 1.46 ng/ml), acid phosphatases, total (12.67 +/- 1.15 U/l), and prostatic (2.27 +/- 0.34 U/l), were mildly elevated, but declined to normal values at 4 weeks: (2.13 +/- 0.59 ng/ml; P < 0.01), (7.68 +/- 0.89 U/l; P < 0.01), and (1.39 +/- 0.18 U/l; P < 0.01), respectively. Mean prostatic volume assessed by ultrasonography showed a significant decrease in all patients from 67.84 +/- 8.86 to 37.92 +/- 8.52 cm3; P < 0.01, which represents a reduction of 44%. In patients with prostate cancer, after the first week of therapy with SB-75, we observed a significant decrease in bone pain, relief in urinary outflow obstruction, and reversal of the signs of prostatism. Subjective improvement continued during the following weeks of treatment, so that the patients no longer needed analgesics. PSA, acid, and alkaline phosphatases gradually fell, achieving nearly normal values at 6 weeks. Initial serum testosterone levels in BPH and prostatic cancer patients were within normal limits, but during treatment with the antagonistic analog SB-75, fell to castration values. A major fall in free testosterone levels was observed after the first dose; the maximal inhibition was seen after 6-12 hr, with a simultaneous decrease in levels of both gonadotropins. Our results show that antagonist SB-75 can be safely administered for prolonged periods of time. The rapid shrinkage of the prostate and concomitant improvement in obstructive symptoms of prostatism obtained with antagonistic analog SB-75 in patients with BPH may decrease the morbidity of prostatic surgery and offer a therapeutic alternative in men who are considered poor surgical risks.(ABSTRACT TRUNCATED AT 400 WORDS)

Present status of agonistic and antagonistic analogs of LH-RH in the treatment of advanced prostate cancer.

The methods for treatment of advanced prostate cancer, based on the agonistic analogs of LH-RH were reviewed. New therapeutic approaches utilizing antagonistic analogs of LH-RH such as SB-75 (Cetrorelix) have been described. Analogs of LH-RH chemically linked to various cytotoxic radicals are also being developed. Combinations of LH-RH agonists or antagonists with superactive somatostatin analogues such as Octastatin (RC-160) or with bombesin/GRP antagonists are being investigated in order to delay or prevent the relapse and improve the therapy for prostate cancer.

Influence of D-Trp-6-LH-RH on the survival time in patients with advanced pancreatic cancer.

Carcinoma of the exocrine pancreas seems to be sex-hormone sensitive. Administration of agonistic analogs of luteinizing hormone--releasing hormone (LH-RH) creates a state of sex-hormone deficiency. Therapy with D-Trp-6-LH-RH was evaluated in 17 patients with unresectable and biopsy-proven adenocarcinoma of the pancreas (stage IV). Nine patients were male and 8 female, and the median age at diagnosis was 60 years. The majority of patients underwent a gastro-intestinal and biliary bypass. The therapy with D-Trp-6-LH-RH was started 3-31 days after bypass surgery. The analog was given at the dose of 1 mg/day subcutaneously for the first 7 days. Subsequently, the dose was reduced to 100 micrograms/day. One month after the start of the therapy the gonadotropin levels were in subnormal range. This therapy led to clinical improvement, better quality of life and an increase in survival time. The median survival time for all the groups was 7.2 months (men 7.4 months and women 6.9 months). LH-RH agonists appear to decrease pancreatic cancer growth by eliminating the stimulatory effect of sex steroids, and by direct effects on tumors. Further improvement in the clinical response in patients with inoperable pancreatic carcinoma might be possibly obtained by the combination of LH--RH agonists with modern somatostatin analogs.

Inhibition of the pituitary-gonadal axis by a single intramuscular administration of D-Trp-6-LH-RH (decapeptyl) in a sustained-release formulation in patients with prostatic carcinoma.

For the past 6 years we used daily injection of luteinizing hormone-releasing hormone (LH-RH) agonists to treat patients with advanced prostate carcinoma. In this study we determined the hormonal response of the pituitary-testicular axis over a 2-month period and evaluated the safety and tolerance of the single intramuscular administration of sustained-release formulations of D-Trp-6-LH-RH microcapsules designed to release 50, 100, or 200 micrograms/day for over 1 month. Serum levels of LH, testosterone, and D-Trp-6-LH-RH were measured by RIA for up to 60 days in 10 patients with advanced prostatic carcinoma who had not received any previous drug therapy. After the administration of the microcapsules there was a biphasic increase in D-Trp-6-LH-RH serum levels. The maximal peak was obtained between 1 and 3 hr, and a second peak occurred between weeks 4 and 6. LH levels increased initially, with a maximal peak at 60 min, and elevated serum LH values persisted for more than 24 hr. LH levels began to fall on the second day, reaching subnormal values after 1 week. Serum testosterone rose during the first week and fell subsequently to less than 100 ng/dl. A rebound in LH and testosterone was seen about the 50th day after the microcapsule administration. Following the first week of therapy, we observed in all patients a significant decrease in bone pain, improvement in urinary flow obstruction, and a reversal of the signs of prostatism. No side effects were observed, and acceptance of the microcapsules was very good. Our results show that a single dose of D-Trp-6-LH-RH microcapsules suppresses of the pituitary-testicular axis for at least 50 days. D-Trp-6-LH-RH microcapsules facilitate the treatment and should lead to an improvement in the therapeutic response.

Correlation study between prolactin and androgens in male patients with systemic lupus erythematosus.

The hypothalamic-pituitary-gonadal axis was studied in 8 male patients with systemic lupus erythematosus (SLE), both before and after intravenous administration of luteinizing hormone-releasing hormone (LH-RH). We provide evidence herein that resting serum levels of estrone are increased and that resting serum testosterone (T) and dihydrotestosterone (DHT) levels are decreased in male patients with SLE. The decreased serum T levels were observed even after the IV administration of 25 micrograms of LH-RH. The high basal serum prolactin (PRL) levels observed in these patients with SLE is a novel finding not previously reported that could explain why serum T and DHT levels are low in this syndrome. We observed a decrease in the pituitary response to LH-RH stimulation; this low response could also be a hormonal manifestation of hyperprolactinemia. Furthermore, it has been suggested that PRL plays a role in immunocompetence, and therefore it could have influence either directly or indirectly in the altered immunoregulation observed in SLE.

Persistent blockade of the pituitary-gonadal axis in patients with prostatic carcinoma during chronic administration of D-Trp-6-LH-RH.

Forty patients with stage D2 prostatic carcinoma were treated for up to 30 months with D-Trp-6-LH-RH. The analog was given s.c. once daily at a dose of 1 mg/day for the first 7 days. Subsequently, the dose was reduced to 100 micrograms/day. In follow-up studies, 30 men continued this therapy for up to 24 months. Blood samples were taken before the injection of the analog and 1, 2, 4, and 6 hours later. Serum LH, FSH, and testosterone levels were measured by RIA every month for 2 years. The initial administration of 1 mg D-Trp-6-LH-RH caused a marked elevation of LH and FSH, which lasted more than 24 hours. However, 1 month later and throughout the therapy, the basal values of LH and FSH were below the normal range and no increase in serum gonadotropins levels was obtained after administration of the analog. Initial plasma testosterone was within normal limits, but during treatment with D-Trp-6-LH-RH it fell to castration levels, and no increases were seen during the 6 hours following the injection of the analog. These results show that chronic administration of D-Trp-6-LH-RH, at the doses used, blocks the pituitary-gonadal axis and that the escape phenomenon from the effects of the LH-RH agonists-induced blockade does not occur under our conditions in contrast to observations of Kerle et al with the I.C.I. Analog 118630 (8). The accumulated results reinforce the view that long-term therapy with agonists of LH-RH is the preferred alternative to surgical castration or therapy with estrogens in men with metastatic prostate cancer.

Treatment of advanced prostatic carcinoma with D-Trp-6-LH-RH.

Twenty patients with stage D2 prostatic carcinoma were treated for up to 18 months with D-Trp-6-LH-RH. Results of more than 3 months of treatment on these 20 patients are reported. The analog was given SC once daily at a dose of 1,000 micrograms/day. All patients had bone pain and high levels of acid and alkaline phosphatase. After the first week of D-Trp-6-LH-RH administration, major decreases in bone pain and reversal of the signs of prostatism were observed. Acid phosphatase gradually fell, achieving normal values after 12 weeks. Initial plasma testosterone was within normal limits, but during treatment with D-Trp-6-LH-RH it fell to castration levels. Resting values of PRL, GH, TSH, and cortisol did not show significant changes. After TRH, TSH increased in five patients, but five did not respond. However, at 2 and 4 months, all patients released TSH in response to TRH. Two patients died during the treatment with D-Trp-6-LH-RH despite initial subjective responses and decreases in testosterone levels. The rise in acid phosphatase levels in these two patients was accompanied by a general deterioration, suggesting that they had androgen-independent cancer. One patient who developed progressive hepatic, bone, and pulmonary metastases in spite of previous orchiectomy was also treated with the analog. Three months later his acid phosphatase levels were within normal values, and partial regression of metastases was observed. These results demonstrate that D-Trp-6-LH-RH and other LH-RH agonists can be used as an effective endocrine therapy for advanced prostate carcinoma, thereby avoiding the side effects of estrogens or the psychological impact of surgical castration.

Gonadotropins pituitary secretion in systemic lupus erythematosus.

Hormonal abnormalities have been suggested to play a role in the pathogenesis of systemic lupus erythematosus (SLE). In order to define the regulatory mechanism involved, the pituitary reserve for gonadotropins secretion was investigated in eight untreated SLE patients with normal menstrual cycles. Serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were determined on the fifth day of the menstrual cycle before and after intravenous administration of 25 micrograms synthetic luteinizing hormone-releasing hormone (LH-RH). The pulsatile LH and FSH resting values in SLE were not significantly higher than those found in the controls; after LH-RH stimulation no difference was observed between the SLE group and controls. The LH and FSH response to exogenous LH-RH administration in SLE demonstrate the integrity of the hypothalamic-pituitary-ovary axis that explains normal menses and fertility in this disease.