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A patient is described who developed neurological signs of the left leg following transvaginal ultrasound-guided puncture. A hypodense lesion of the obturator space above the lumbosacral plexus was seen on ultrasound which could explain her signs, due to compression by a hematoma. She recovered completely.
The effect of treatment with D-Trp-6-LH-RH, an agonist of luteinizing hormone-releasing hormone (LHRH), and somatostatin analog RC-160 was studied in male Syrian hamsters with N-nitrosobis(2-oxopropyl)amine (BOP)-induced pancreatic carcinoma. The peptides were administered periodically in long-acting microcapsule formulations designed to release controlled doses and maintain continuous blood levels of these analogs. The treatment lasted 60 d. Eighteen wk after administration of BOP, 80% of the animals developed ductal pancreatic adenocarcinomas, typically in multinodular form. Treatment with D-Trp-6-LH-RH resulted in a significant decrease in the tumorous pancreatic weight, and, in 35% of the specimens, changes indicative of histological regression were seen. Similarly, regressive alterations in the tumorous epithelium could be observed in 28% of the tumors in the RC-160 treated group. This regression was not accompanied by accumulation of lymphoid cells and only the epithelial components of the tumors were involved. These data indicate that the analogs D-Trp-6-LH-RH and RC-160 exert antitumoral effects on the experimentally-induced pancreatic cancer. It is unlikely that immunological mechanisms are involved in this response. These inhibitory effects on tumor growth could be mediated by creating a state of sex hormone deprivation of D-Trp-6-LH-RH and by inhibition of the release and/or action of gastrointestinal hormones and growth factors by the somatostatin analog RC-160.
We studied endogenous phosphorylation in rat transplantable MT/W9A hormone-dependent mammary tumors of untreated rats and of animals treated with LH-RH analogs, the agonist D-Trp-6-LH-RH and the antagonist N-Ac-D-p-Cl-Phe1,2,D-Trp3,D-Arg6,D-Ala10-LH-RH. Incorporation of 32P from 32P-ATP was reduced significantly in tumors of rats treated with agonistic and antagonistic analogs of LH-RH or ovariectomized. The inhibition of protein phosphorylation may be related to tumor regression.
We have investigated the effects of chronic administration of D-Trp6-LH-RH on the growth of various hormone dependent tumors in rats and mice. Treatment of male Copenhagen F-1 rats bearing the Dunning R-3327H prostate adenocarcinoma with 25 micrograms of D-Trp6-LH-RH bid for 21 days significantly reduced tumor weight and volume as compared to controls. Serum LH, prolactin and testosterone levels in Copenhagen F-1 rats bearing Dunning tumors were significantly decreased after treatment with D-Trp6-LH-RH. Administration of D-Trp6-LH-RH in doses of 25 micrograms/day for 21 days to mice bearing the MXT mammary carcinoma significantly decreased tumor weight and volume. In rats bearing the MT/W9A mammary adenocarcinoma, D-Trp6-LH-RH, at a dose of 25 micrograms bid for 28 days significantly decreased tumor weight and volume. Administration of D-Trp6-LH-RH in a dose of 25 micrograms/day, 3-18 days after inoculation with the tumor, inhibited the growth of the prolactin (PRL) and ACTH-secreting pituitary tumor 7315a in female Buffalo rats. In three experiments D-Trp6-LH-RH (30-60 micrograms/day) decreased tumor weight and/or volume of the Swarm chondrosarcoma. Regression of these hormone-dependent tumors in rats and mice in response to chronic administration of D-Trp6-LH-RH suggests that this compound can be used for treatment of prostate cancer and breast cancer, and also considered for the development of a new endocrine therapy for chondrosarcomas, osteosarcomas, pituitary tumors and other hormone-dependent neoplasias. The demonstration of the successful use of LH-RH agonists for the palliative management of stage C and D prostate cancer has already shown that this treatment could be employed instead of surgical orchiectomy or estrogen therapy. Preliminary clinical trials suggest that agonists of LH-RH might also be of help in the treatment of breast cancer in premenopausal women.
An oriented phase II trial of D-Trp6-LH-RH was conducted according to Gehan's statistical method on 25 patients suffering from prostatic carcinoma. LH and testosterone serum levels decreased rapidly. Pain disappeared during the third month in 14 out of the 21 patients and markedly decreased in 5. Prostatism completely regressed in 10 out of the 22 subjects presenting it and markedly decreased in 9. Prostate hypertrophy regressed, as shown by ultrasonography, in 84% and by more than 50% in 37% of the patients. The overall regression rate of bone scintigraphy images was 43%; a regression of more than 50% was only registered in 12.5% of the patients; this may be explained by the long time which is necessary before bone image disappearance occurs. Prostatic acid phosphatase levels regressed in 75% and by more than 50% in 66.7% of the patients.
Analogs of luteinizing hormone-releasing hormone (LH-RH) and bombesin/gastrin-releasing peptide were previously shown to inhibit the growth of experimental pancreatic cancers. In the present study, in an attempt to increase the efficacy of therapy, female Syrian golden hamsters with N-nitrosobis(2-oxopropyl)amine-induced pancreatic cancers were treated for 2 mo with a combination of LH-RH agonist [D-Trp6]LH-RH or antagonist [Ac-D-Nal(2)1, D-Phe(4Cl)2, D-Pal(3)3, D-Cit6-Ala10]LH-RH (SB-75) and bombesin/GRP antagonist D-Tpi6, Leu13 psi(CH2NH)Leu14bombesin(6-14) (RC-3095). The results were compared to those obtained by treatment with same doses of single peptides. LH-RH analogs and bombesin antagonist given alone significantly reduced the number of tumorous animals and decreased weight of pancreata by 46-71% and weight of tumorous pancreas by 38-64%. Histology showed lower mitotic activity and a decreased number of AgNORs in tumor cells from treated animals. Enhanced apoptosis was also observed after treatment with the LH-RH analogs. Combination therapy had no superior inhibitory effect on tumors compared to single peptides, by practically all the parameters analyzed. The reasons for this lack of potentiation are not clear. The tumor inhibitory effect of bombesin antagonists appears to be mediated by interference with EGF-receptor mechanisms. In the present study, although a significant downregulation of EGF-receptors was found in tumors treated with combination, the decrease in binding capacity for EGF was maximal in the group treated with RC-3095 alone.(ABSTRACT TRUNCATED AT 250 WORDS)
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The intrafollicular levels of IGF-I and epidermal growth factor (EGF) were studied in women undergoing controlled ovarian hyperstimulation using the multidose GnRH-antagonist protocol or the long agonist protocol, in an attempt to elucidate whether GnRH-antagonists affect the levels of the two growth factors. The follicular fluid concentration of IGF-I, EGF, estradiol and progesterone were detected in 68 women undergoing ovarian hyperstimulation for intracytoplasmic sperm injection (ICSI) cycles. There were no differences in intrafollicular concentrations of EGF and IGF-I in the two studied groups. Additionally, we found no correlation between the intrafollicular levels of IGF-I or EGF and the ICSI outcome. The intrafollicular levels of IGF-I were positively correlated with those of progesterone. In conclusion, the intrafollicular levels of IGF-I and EGF do not seem to be influenced by the stimulation protocol. The intrafollicular levels of both growth factors can not serve as prognostic markers for the ICSI outcome.
Gonadal steroids drive the significant bone mineral increase that occurs at puberty, while estrogen deprivation in postmenopausal women results in bone mass reduction. We looked for bone mineralization in girls with true precocious puberty (TPP) before and after six months of LH-RH analogs treatment. Calcitonin secretion in these girls were studied too. Bone mineral content (BMC) and BMC/BW ratio (single photon absorptiometry) were measured in seven girls (aged 4.3 to 8.7 years) with TPP before LH-RH agonist therapy (long acting D-Trp6-LH-RH 60 micrograms/kg im every 28 days) was started; the patients were reevaluated after six months of therapy. Before therapy, BMC and BMC/BW were increased for chronological age but appropriate for bone age according to our mineralization normative data. After six months of LH-RH analog administration, 17 beta-estradiol and LH levels were suppressed and BMC and BMC/BW showed a small but significant decrease (respectively -5.4%, p less than 0.02 and -6.3%, p less than 0.02). Basal and calcium stimulated calcitonin levels (total and extractable) did not significantly change during the study period. We conclude that in girls with TPP bone mineralization was increased for chronological age but normal for bone age. The estrogen withdrawal secondary to LH-RH analog therapy caused a reduction in bone mass. Such a bone loss is not due to an impairment of calcitonin secretion.
Our aim was to investigate the effect of GnRH-agonist (GnRH-a) induced suppression of plasma sex steroids on serum GH, insulin like growth factor-I (IGF-I) and insulin levels after an oral glucose load (OGTT) in women with polycystic ovary syndrome (PCOS). Serum insulin, GH and IGF-I levels during a 75-g 4-h OGTT were measured in 3 nonobese and 7 obese hyperandrogenic women with PCOS and normal glucose tolerance before and after 10 weeks of treatment with the GnRH-a triptorelin (3,75 mg im every 28 days). Basal estrogen and androgen levels were also measured at time 0 of the first and the second OGTT. After the therapy serum estrogens and androgens were significantly suppressed. Body weight remained unchanged. Basal GH significantly increased after the treatment while fasting IGF-I and insulin levels decreased from (mean +/- SE) 349.3 +/- 31.8 to 278.7 +/- 33.2 ng/mL and from 22.4 +/- 4.1 to 18.8 +/- 4.4 microU/mL, respectively. The insulin response to OGTT (area under curve) was also reduced (from 16,017 +/- 2598 to 11,736 +/- 2317 microU/mL/240 min). Our results suggest that the GnRH-a induced suppression of ovary secretion may modify the serum GH and IGF-I levels and the insulin response to an OGTT in women with PCOS.
This work analyzes the effect of the pulse amplitude and frequency of a potent LHRH analog, D-Trp6-LHRH, in a perfusion system of isolated rat pituitary cells. To this purpose, we studied the LH and PRL secretion in different conditions: basal secretion, secretion after increasing concentrations of D-Trp6-LHRL (0.001, 0.01, 0.1 and 1 nM) secretion in function of the pulses frequency (2,3, and 4 pulses per h) and amplitude (0.1, 1 and 10 nM). The principal findings were: 1. The basal LH and PRL secretions was pulsatile; 2. The stimulation of LH by the analog was not dose-dependent; 3. When more than 2 pulses per h were administered, a rapid desensitization of gonadotroph to release LH (at 20-30 min) occurred; 4. There was a loss of pulsatility of PRL secretion with an increase in the pulse frequency and amplitude of the D-Trp6-LHRH, which was produced parallelly to the desensitization of the gonadotroph to release LH. In summary, these findings suggest that a rapid loss of pulsatility of the PRL when the D-Trp6-LHRH pulse frequency and amplitude is increased might be due to the early desensitization of the gonadotroph to the analog.
A case of hyperandrogenism and virilization is described in an elderly female. She had elevated testosterone levels, but normal DHEAS and 24-h urinary 17-oxosteroid excretion, suggesting an ovarian tumor. Stimulation and suppression tests, and radioisotopic and radiological scans proved unhelpful in the diagnosis although hyperthecosis of the ovary was later suggested by ultrasound. Testosterone and gonadotropin levels fell during therapy with cyproterone acetate and subsequently ethinyl estradiol. Because of side effects encountered on these drugs, she was treated with a synthetic, slow-release preparation of an LHRH agonist, D-TRP-6-LHRH (Decapeptyl), with symptomatic and biochemical improvement. Long term LHRH agonists might be a valuable treatment for hyperandrogenic states in elderly patients.
We report a case of a 66-yr-old woman with progressive hair balding, hirsutism and virilization. Gonadotropins and estradiol levels were in the postmenopausal range; total testosterone (TT), free testosterone (FT) and 17-hydroxyprogesterone (17-OHP) were elevated with dehydroepiandrosterone sulphate, androstendione and cortisol serum levels in the normal range, as 24-hr free urinary cortisol. TT, FT and 17-OHP were normalized, and FSH and LH fell to premenopausal levels on 18th day after a single i.m. injection of the GnRH analogue (GnRHa), triptorelin. Then, a diagnosis of hyperandrogenism of ovarian origin was made and bilateral ovariectomy was performed. Histological study of gonadal tissue revealed diffuse stromal hyperplasia of both ovaries with occasional nests of luteinized cells. With immunoperoxidase techniques these cells stained positively for testosterone and progesterone. One month after surgery, androgen levels were normalized together with regression of most of the clinical signs of virilization. In conclusion, our patient showed a severe virilization developed after menopause; hormonal investigations suggested a gonadotropin dependent ovarian hyperandrogenism, confirmed by histological examination; the presence of luteinized cells in the ovarian stroma was responsible for hyperandrogenism, as confirmed by the immunoperoxidase technique.
We report endometrial adenocarcinoma in two patients shortly after suspending GnRH-agonist treatment for menometrorrhagia and uterine fibromata.
The intramuscular (i.m.) administration of Decapeptyl Depot has been approved in Germany for the treatment of advanced hormone dependent prostate cancer since July 1990. In this study a reformulated Decapeptyl Depot, administered as a first-line endocrine therapy, was injected intramuscularly (i.m.) or subcutaneously (s.c.) every 28 days for 6 months. At 12 different hospitals, 52 prostate cancer patients were treated, whereby 25 patients received a s.c. injection and 27 patients a i.m. injection. Testosterone was measured as the main parameter: after 28 days, both the s.c. and the i.m. application form of Decapeptyl Depot successfully reduced initial testosterone levels of at least 2.3 ng/ml to steady-state castration levels below 1.2 ng/ml, maintaining this complete suppression for the entire length of the trial (168 days). Decapeptyl Depot was well tolerated and very acceptable to the patients in both groups. Side effects were few and predictable, being largely associated with decreased testosterone concentrations. No cumulation in triptorelin serum levels was observed within the 6 months of treatment. Decapeptyl Depot, administered subcutaneously or intramuscularly was effective and safe in the treatment of patients with advanced prostate cancer.
This prospective longitudinal study was undertaken to examine the short-term effects (6 months) of estrogen withdrawal on the circulating IGF system. A series of 40 patients suffering from endometriosis was studied before and after a 6-month treatment period with gonadotrophin releasing hormone (GnRH) agonist and calcium, with or without nasal salmon calcitonin. The plasma concentrations of insulin-like growth factor I (IGF-I) and insulin-like growth factor II (IGF-II) were measured by radioimmunoassay and radioreceptor assay respectively. Plasma IGF binding proteins (IGFBPs) were quantified and characterized by ligand blot and immunoblot. In all patients, a secondary hypoestrogenism was observed, including a 4% decrease in lumbar bone mineral density (L-BMD). The plasma IGF-I and IGF-II concentrations increased after treatment (24%, p < 0.0005 and 40%, p < 0.004 respectively), with no significant difference between the treatment groups. There was a positive correlation between plasma IGF-I (but not IGF-II) changes and changes in urinary deoxypyridinoline (r = 0.32, p < 0.05), urinary C telopeptide of type 1 collagen (r = 0.33, p < 0.04) and total plasma alkaline phosphatases (r = 0.33, p < 0.04). No correlation was found between IGF-I and L-BMD changes, while there was a positive correlation between the changes in plasma IGF-II and L-BMD (r = 0.32, p < 0.05). Ligand blot analysis revealed a significant increase in IGF-II binding to a 29-31 kilodalton region where positive staining with specific antibodies to IGFBP-3 or IGFBP-1 was observed. In conclusion, IGF-I and IGF-II plasma concentrations are both increased following a short period of treatment with a GnRH agonist. The changes in individual IGF peptides are differently correlated with changes in markers of bone remodelling and L-BMD.
To evaluate bone biochemical markers as predictors of the efficacy of a hormone replacement therapy (HRT), we studied the bone changes induced by the cessation and return of ovarian function in 28 patients treated for 6 months with a GnRH agonist. This model reproduced the effects observed in postmenopausal women with high bone turnover treated with HRT. At the end of the treatment, Z scores were 1.8 +/- 0.3 for Crosslaps (CTx) and deoxypyridinoline (D-Pyr), and 1.1 +/- 0.2 for bone alkaline phosphatase (B-ALP) and osteocalcin (OC). This indicated an imbalance in bone remodeling with a high bone resorption. Bone mineral density (BMD) fell by 4.2 +/- 2.5%. The changes in BMD between the 6th and 12th months were 0. 34 +/- 2.24 and -1.73 +/- 3.25% at the lumbar spine and the femoral neck, respectively. Biochemical markers except urinary calcium and hydroxyproline measured at 6 months were positively correlated with the BMD changes at the lumbar spine. After the resumption of menstruation, 13 of 28 women displayed positive spine BMD changes between the 6th and 12th months; in this group, bone biochemical markers measured at 6 months were significantly higher (P = 0.02). Stepwise regression analysis showed that the association of B-ALP and D-Pyr measured at 6 months explained 40% of BMD variance and the association of B-ALP, PTH, and estradiol 56%. We conclude that measuring individual biochemical bone markers can help to predict the bone effect of an increase in the circulating estradiol in women with ovarian deficiency.
We report a study in which our objective was to analyze the clinical response during IAD in patients with biochemical failure after RRP for clinically localized prostate cancer. Between February 1994 and May 1996, 34 patients who exhibited a primary postoperative decrease in PSA to below the detection limit after RRP and then showed PSA progression during follow-up were included as group 1 and 17 patients in whom PSA did not decrease after RRP were included as group 2. Patients were offered IAD when PSA progressed over 0.4 ng/ml in group 1 and over 4.0 ng/ml in group 2. Median follow-up is 184 weeks in group 1 and 206 weeks in group 2. The median time "off" therapy increased from 25% (1st cycle) to 68.7% (5th cycle) of the entire cycle in group 1 and from 33.3% to 58.3% in group 2. Nine out of 12 cases with Gleason score > or =8 failed to respond to IAD and all developed metastatic and/or local failure. No case with Gleason score <7 failed to respond to IAD. Our conclusions suggest that IAD may be effective in patients with biochemical progression after RRP. In our experience, Gleason score seems to be an important variable.