Administration Of Luteinizing Hormone-releasing Hormone Analog Research Articles

Change in Estradiol Levels among Premenopausal Patients with Breast Cancer Treated Using Leuprolide Acetate 11.25 Milligrams 3-Month Depot and Tamoxifen.

The combination of luteinizing hormone-releasing hormone analogs (LHRHa) with tamoxifen is used as a standard postoperative adjuvant therapy in patients with hormone receptor-positive/premenopausal breast cancer. Long-acting LHRHa formulations offer advantages in terms of patient convenience. However, data on the effectiveness of the 3-month (3M) acting formulation are still insufficient. This study was performed on patients who received the 3M LHRHa after surgery. The serum estradiol (E2) and follicle-stimulating hormone levels were measured before surgery, and periodically after surgery. In total, 318 patients were included in the study and analyzed. The mean E2 level before surgery was 63.7 pg/mL, while the mean E2 level during the administration of 3M LHRHa was 4.9 pg/mL. None of the patients were menstruating and had E2 values above 30.0 pg/mL. It is thought that the 3M LHRHa formulation can suppress the ovarian function effectively and be safely used to improve compliance.

Función cognitiva en pacientes tratados con supresión androgénica: estudio prospectivo y multicéntrico

ObjectiveTo assess the effect of androgen deprivation therapy (ADT) on cognitive performance (CP) in patients with prostate cancer (PCa) after 6 months of treatment with luteinizing hormone-releasing hormone (LHRH) analogues. Material and methodsProspective, observational, multicentre, open-label study of patients diagnosed with nonmetastatic or asymptomatic metastatic PCa scheduled to receive LHRH analogues for≥6 months. We assessed four CP domains at baseline and after 6 months of ADT: 1) Working memory: Wechsler Adult Intelligence Scale III (WAIS III) Digit Span Subtest (WAIS III-Digit); 2) Visual memory: ad hoc visual memory test; 3) Visuospatial ability: Judgement of Line Orientation (JLO) and Mental Rotation of Three-Dimensional Objects (3D-Rotation); and 4) Nonverbal analytical reasoning: WAIS III Matrix Reasoning Test (WAIS III-MRT). Changes outside the baseline 95% confidence intervals were considered significant. ResultsA total of 308 patients completed the study. Of these, 245 (79.6%) experienced no statistically significant changes on any test and 63 patients (20.4%) experienced significant changes in ≥1 test. Of these, most presented a change in only one test, distributed evenly between improvements (58 patients; 18.8%) and worsening (56 patients; 18.2%). For individual tests, most patients (87.8% to 91.8%) had no change from baseline; however, the significant changes (improvement vs. deterioration, respectively) were as follows: WAIS III-Digit (6.3% vs. 5.9%); visual memory (5.3% vs. 5.7%); JLO (5.3% vs. 4.5%); 3D-Rotation (4.1% vs. 4.1%); and WAIS III-MRT (4.8% vs. 5.8%). ConclusionsCP in patients with PCa does not appear to be adversely affected by 6 months of LHRH analogue administration.

Cognitive Function in Patients With Prostate Cancer Receiving Luteinizing Hormone-Releasing Hormone Analogues: A Prospective, Observational, Multicenter Study

The effect of androgen deprivation therapy (ADT) on cognitive performance (CP) in prostate cancer (PCa) patients is not well understood. We evaluated changes in CP after 6months of medical castration with luteinizing hormone-releasing hormone (LHRH) analogues. We performed a prospective, observational, multicenter, open-label study of PCa patients scheduled to receive LHRH analogues for ≥6months. We assessed 4 domains of CP at baseline and after 6months of ADT: (1) working memory, assessed with the Wechsler Adult Intelligence Scale III (WAIS III) Digit Span subtest; (2) visual memory, assessed with an ad hoc visual memory test; (3) visuospatial ability, assessed with the Judgment of Line Orientation test and Mental Rotation of Three-Dimensional Objects test; and (4) nonverbal analytical reasoning, assessed with the WAIS III Matrix Reasoning test. Changes outside the baseline 95% confidence intervals were considered significant. A total of 308 patients completed the study. Of these, 245 (79.6%) experienced no statistically significant changes on any test whereas 63 (20.4%) experienced significant changes on ≥1 test. Most of these patients showed a change on only 1 test, distributed evenly between improvement (58 patients, 18.8%) and worsening (56 patients, 18.2%). For individual tests, most patients (87.8%-91.8%) had no change from baseline; however, the significant changes (improvement vs deterioration) were as follows: WAIS III Digit Span subtest (6.3% vs 5.9%), visual memory (5.3% vs 5.7%), Judgment of Line Orientation test (5.3% vs 4.5%), Mental Rotation of Three-Dimensional Objects test (4.1% vs 4.1%), and WAIS III Matrix Reasoning test (4.8% vs 5.8%). CP in patients with PCa does not appear to be adversely affected by 6months of LHRH analogue administration.

Abstract CT109: Adjuvant ovarian suppression in high risk premenopausal breast cancer: ten-year follow-up of a phase I-II study

Abstract Background: Two randomized studies have shown the benefit of ovarian suppression in the adjuvant treatment of high risk premenopausal breast cancer, both with estrogen receptor positive (ER+) (Pagani et al. N Engl J Med 2014) and estrogen receptor negative (ER-) (Moore et al. N Engl J Med 2015). Nevertheless the median follow-up of these studies was limited to 68 and 49 months, respectively. Here we present the results of a large, phase I-II study, of adjuvant ovarian suppression in ER+ and in ER- patients, after a median follow-up of 123 months (range 93-223). Two hundred patients were enrolled between 06-1997 and 06-2007. The primary end point of the study was to find the best dose and schedule of a luteinizing hormone releasing hormone (LH-RH) analogue given to prevent ovarian failure in premenopausal patients treated with adjuvant chemotherapy. Secondary end points were disease free survival (DFS) and overall survival (OS). Methods: One week before chemotherapy, a LH-RH analogue was administered, 3.75 mg every 28 days for 1 year to the first cohort of 64 patients. The same monthly dose was given, for 2 years, to the second cohort of 36 patients. Because we had observed a decrease of 31% in the recurrence rate for the longer administration of LH-RH analogue, the 11.25 mg dose every 84 days, for 5 years, was chosen for the remaining 100 patients. The treatment consisted of: a- LH-RH analogue; b- Breast conserving (74%) and radical surgery (26%); c- Tailored systemic therapy concurrent with radiation therapy; d- Aromatase inhibitor in ER+ patients. Results: The median age was 43 years (range 26-45), the mean number of positive axillary nodes was 3.2 (range 1-25), including 20 patients with >10 positive nodes. 71% of patients were ER+ and/or progesterone receptor positive (PGR+), 29% were ER - and PGR-, 21% of patients were c-ErbB-2 positive. The median KI-67 was 30% (range 15% -100%). Ovarian failure rate was 10% in patients younger than 40 years and 44% in patients older than 40 years. The 15-year DFS and OS rate were 64% and 73%, respectively. 15-year DFS rate of ER+ and ER- patients were 74% and 44% respectively (P<0.005), while the 15-year OS rate were 74% and 75%, respectively (P>0.005). The usual pattern of toxicity of chemotherapy was observed. Hot flashes and G1 osteopenia occurring after LH-RH analogue administration were temporary and receded after the cessation of therapy. Conclusions: LH-RH administration, concurrent with chemotherapy is tolerable and useful. Five full term pregnancies were observed. The long-term recurrence and survival rate for ER+ and ER-patients were similar, with different patterns: ER+ patients had disease recurrences even after 13 years, while ER- patients had late new primaries, but no recurrence after 5 years. Citation Format: Francesco Recchia, Giampiero Candeloro, Massimo Bratta, Michele Rosselli, Silvio Rea. Adjuvant ovarian suppression in high risk premenopausal breast cancer: ten-year follow-up of a phase I-II study. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT109.

566 ANAMEM: Prospective and observational study to evaluate cognitive changes in prostate cancer patients undergoing luteinizing hormone-releasing hormone analogue treatment

INTRODUCTION AND OBJECTIVES: The effect of androgen suppression on cognitive performance (CP) in prostate cancer (PCa) patients is unclear. To date, only 6 small case reports and controlled studies plus 5 cohort studies have been conducted, with inconclusive results. Patient numbers for these studies ranged from 18 to 57 with follow up between 1 and 12 months. This study evaluates changes in cognitive function in a large cohort of PCa patients during their first 6 months of treatmentwith luteinizinghormone-releasinghormone (LHRH)analogues. METHODS: An observational, prospective, multicentre, openlabel study was designed, evaluating CP at baseline and after 6 months of treatment with LHRH analogues. All patients received bicalutamide 50 mg/d 2 weeks before and after the first LHRH analogue administration. CP was evaluated using 5 tests: Digit Subtest of the Wechsler Adult Intelligence Scale (WAIS III-1); Matrices (WAIS III-2); Visual memory test; Line orientation test (Woodward et al.; abridged version); Mental Rotation of tridimensional objects. Improvement (or worsening) of CP tests was statistically significant when corresponding change score was above (or below) the study population upper (or lower) 95% CI bounds. Number and percentage of patients with 1 CP test showing improvement were calculated (overall and subgroups). RESULTS: A cohort of 404 patients was initially screened, 384 received LHRH analogues and 308 completed the study. Median age of patients was 71 years. Overall, in the completer population, 245 patients (79.5%) were unchanged. Of the patients who had changes in CP, the majority were in one test only, for which 59 patients (19.2%) showed improvements and 57 patients (18.5%) showed worsening. Results for individual tests are summarised in the table. Correlations between baseline and 6 months measurements for each test were found to be moderate to strong and statistically significant. No differences in CP in the subgroups studied were observed. CONCLUSIONS: In the ANAMEM study, CP status of patients with PCa is not adversely affected by androgen suppression with LHRH analogues over a period of 6 months.

Abstract P6-09-06: Estrogen (E2) suppression following diagnosis of node positive (N+) breast cancer (BC) in premenopause. Long term follow-up of a phase II study

Abstract Background: E2 plays a key role in human reproduction and in premenopausal BC growth through the induction of vascular endothelial growth factor (VEGF) and the expansion of T-Regulatory cells (T-Regs). In addition, few clinical data exist on long-term outcome of high-risk N+ premenopausal BC treated with E2 deprivation, by luteinizing hormone releasing hormone (LH-RH). We hypothesized that E2 suppression, following diagnosis of N+ BC in young premenopausal patients, could decrease VEGF and T-Regs and, therefore, could reduce the recurrence rate. Primary endpoint of this study was the evaluation of T-Regs and VEGF of premenopausal patients with high-risk N+, estrogen receptor positive (ER+) and negative (ER-) early BC, treated with an LH-RH analogue. Secondary endpoints were the 10 and 15-year disease-free survival (DFS) and overall survival (OS) rates. Methods: Between 06-1997 and 06-2007, 200 premenopausal high risk early BC patients were entered into the study. Before starting chemotherapy, the LH-RH analogue was administered, 3.75 mg every 28 days for 1 year to the first 64 patients. The same monthly dose was given, for 2 years, to 36 patients. Having observed a decrease of 31% in the recurrence rate for the longer administration of LH-RH analogue, we gave the 11.25 mg dose every 84 days, for 5 years, to the remaining 100 patients. Breast conserving and radical surgery were performed in 74% and 26% of patients, respectively. Systemic therapy was tailored to the biological characteristics of each patient and followed by radiation therapy, and hormonal therapy in ER+ tumors. Results: Median patient's age was 43 years (range 26-45). Mean number of positive axillary nodes was 3.2 (range 1-25). 71% of patients were ER+ and/or progesterone receptor (PGR+), 29% were ER - and PGR-. Median KI-67 was 30% (range 15% -100%). 21% of patients were c-ErbB-2 positive and 11 of them were treated with trastuzumab for 1 year. After a median follow up of 102 months (range 60-180), a statistically significant decrease of VEGF and T-Regs was observed, both in ER+ (P<0.0001) and ER- patients (P<0.0001). Ten-year DFS and OS rate were 86% and 90%, respectively, while the 15-year DFS and OS rate were 62%, and 73%, respectively. Two c-ErbB-2 positive patients (4.7%), had disease recurrence. ER+ patients had a better DFS (P<0.05) and OS (P<0.0001) with respect to ER- patients. The standard pattern of toxicity of chemotherapy was observed, while hot flashes and G1 osteopenia occurred after LH-RH analogue administration. Conclusions: E2 deprivation with an LH-RH analogue is able to decrease plasma VEGF and T-Regs in premenopausal high risk ER+ and ER- BC patients, at the price of a mild toxicity. A favourable impact on DFS and OS was observed. ER- patients had late new primaries, but no recurrence after 5 years, while ER+ patients had disease recurrence even after 15 years. Long term therapy should have further evaluation in premenopausal patients with ER+ tumors. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-09-06.

Effects of cysteamine on mRNA levels of growth hormone and its receptors and growth in orange-spotted grouper (Epinephelus coioides)

Effects of cysteamine (CS) on growth hormone (GH) mRNA, two types of growth hormone receptor (GHR) mRNAs and growth rate in orange-spotted grouper (Epinephelus coioides) were investigated. CS could cause a modification in the structure of somatostatin, which is the most important neuroendocrine inhibitor of basal and stimulated growth hormone synthesis and release, and renders it nonimmunoreactive probably through interaction with the disulfide bonds. In the present study, cysteamine hydrochloride (CSH) enhanced the level of pituitary GH mRNA in a dose-dependent manner through attenuating or deleting the inhibiting action of somatostatin on GH mRNA expression. CSH at relatively low doses (from 1 to 3mg/g diet) enhanced the levels of two types of GHR mRNAs in dose-dependent manner, whereas the stimulation induced by CSH declined from the peak at higher dose of CSH (4mg/g diet). It might be attributed to the variation in GH-induced up-regulation of GHRs at different doses of GH. Feeding of CSH could induce remarkable enhancement of growth rate in orange-spotted grouper. In addition, the stimulatory effect of CSH could be potentiated by the additive effect of luteinizing hormone-releasing hormone analog (LHRH-A). Compared with individual treatments, combined feeding of CSH and LHRH-A caused more efficient elevation of growth rate after 8weeks of feeding. CSH and LHRH-A individually and in combination remarkably increased the levels of GH and GHR mRNAs compared with the control. The combined administration of CSH and LHRH-A in diet was most effective to enhance the level of GH and GHR1 mRNA. The morphological characteristics of the experimental fish were evaluated. Compared with control, the ratios of muscle RNA/DNA, condition factors (CF) and feed conversion efficiency (FCE) were significantly enhanced in the treated groups, while the highest values were observed in the combined treatment. All the results suggested that CSH (1-3mg/g diet) is an effective, economical and feasible feed additive in orange-spotted grouper culture.

Changes in serum levels of prostatic acid phosphatase and prostate specific antigen after luteinizing hormone-releasing hormone analogue administration in patients with metastatic prostatic cancer in relation to glandular differentiation.

Eighteen previously untreated patients with metastatic carcinoma of the prostate were treated with LHRH analogue. They were divided into 3 groups according to the degree of glandular differentiation. In all groups, a transient rise of PAP and PSA was observed after the LH and testosterone surge. However, relative values of LH, testosterone, PAP and PSA did not differ significantly among the 3 groups. These facts suggest that a transient rise of PAP and PSA is caused by testosterone surge independently from the degree of glandular differentiation after LHRH analogue administration in patients with advanced prostatic cancer.

Administration of LHRH analog can improve working memory in aged female rats

We had previously found that an age-related deficit in working memory appeared in middle-aged females, possibly related to their ageing reproductive system. This experiment investigates the effect of administering an analog of luteinizing hormone-releasing hormone (LHRH), D-Trp 6-LHRH, to 22-mo-old female rats submitted to successive trainings in a water-reinforced matching to sample task since the age of three months. Animals were injected SC with a long-lasting microcapsule formulation (800 μg/kg continuously releasing 5 μg D-Trp 6-LHRH per day for at least 28 days). The action of the analog on ovary weight and estradiol and progesterone levels was also studied. Administration of D-Trp 6-LHRH counteracted the deleterious effect of age on performance and inhibited ovary function. However, hormone plasma levels were not modified. These results suggest that the hypothalamo-ovarian axis might be implicated in memory deficits of middle-aged females.

Luteinizing Hormone - Releasing Hormone Analogs: Female Contraception

Exploration of the potential uses of luteinizing hormone-releasing hormone (LHRH) analogs in contraception has involved inhibition of ovulation of implantation and luteolysis. LHRH analogs when given chronically have the paradoxical effect of down-regulating or desensitizing LHRH receptors in the pituitary raising LH and FSH levels and producing a hypogonadal state. Studies in rhesus monkeys have documented that LHRH given in the early follicular phase block follicular growth and delay ovulation. In women the LHRH analog 4f-Antag given sc also prolonged follicular phase but had no effect on luteal phase. Several LHRH analogs have effectively inhibited ovulation in women: Buserelin Naferelin Leuprolide ad D-TRP. While ovulation is consistently blocked some women experience amenorrhea some oligomenorrhea and some menstruation-like bleeding. Estrogen levels resemble follicular phase levels but the degree of gonadotropin suppression varied from hypoestrogenic conditions of vasomotor symptoms and atrophic vagina to a potential for endometrial hyperplasia. Combined treatments with LHRH analogs and progestins norethisterone or medroxyprogesterone acetate have been tested to induce withdrawal bleeding and prevent endometrial build-up. Another problem with these experimental ovulation-inhibiting treatments is that the intranasal spray route produced variable absorption but the daily injections are not practical. Long-acting implants or injections are being formulated. Conflicting results have appeared in studies on the possible luteolytic effect of LHRH analogs. Work in rhesus monkeys and in women suggests that a narrow window of time is required to get a luteolytic effect. Multiple doses or chronic administration of LHRH analogs will terminate early pregnancy in small animals and nonhuman primates. No effect on implantation has been reported in the few small trials in women to date.

Stimulation of ovarian function with gonadotropins following suppression of endogenous gonadotropin secretion by long-term infusion of the LHRH analog buserelin

The treatment of infertile women by gonadotropins is more effective in hypogonadotropic than in normogonadotropic ovarian insufficiency. In order to induce a hypogonadotropic state the luteinizing hormone-releasing hormone analog (LHRHA) buserelin was administered in eight cycles of four infertile patients suffering from luteal phase defect. Buserelin was infused subcutaneously in a dosage of 400 micrograms/d for 26-44 days using a portable external osmotic minipump system. Following suppression of estradiol-17 beta below 35 pg/ml within 11 +/- 5 days, gonadotropins were injected intramuscularly to stimulate ovarian function. In all cycles treated, ovulation and formation of a functional corpus luteum were observed without signs of premature luteinization. Whereas constant administration of LHRHA by a slow release system seems very useful for long-term reversible suppression of follicular maturation, further studies should evaluate the clinical usefulness of combined LHRHA/gonadotropin treatment in cases of infertility.

Induced spawning of milkfish, Chanos chanos, by a single application of LHRH-analogue

Current procedures for induced spawning in milkfish, Chanos chanos, involve the injection of pituitary homogenate and human chorionic gonadotropin followed by hand stripping of the hydrated eggs. This procedure results in the loss of valuable broodstock, low fertilization rates and unpredictable time of spawning. A reliable method for inducing spawning is essential. In this study, luteinizing hormone-releasing hormone analogue (LHRH-a) was tested for its effectiveness as an ovulatory and spawning agent. A single administration of LHRH-a via pellet implantation or liquid injection induced spontaneous spawning approximately 48 or 24 h after application, respectively. The average dosage used was 41.7 ± 3.3 μg/kg body weight for pellet implant and 58.7 ± 9.3 μg/kg body weight for injection. The spontaneous release of eggs was achieved in all spawning attempts when the initial egg diameter was at least 800 μm on average and had a single mode distribution. Seven of 15 attempts with natural fertilized spawns were successful and resulted in an average of 83.8% fertilization.

Des lead-in to use of luteinizing hormone releasing hormone analogs in treatment of metastatic carcinoma of prostate

Luteinizing hormone releasing hormone (LHRH) analogs have been shown to be an effective alternative endocrine treatment of metastatic prostatic carcinoma. After a transient stimulation of testosterone (T) and dihydrotestosterone (DHT) during the first week of therapy, continued administration of LHRH analogs has reliably suppressed serum androgens to castrate levels. About 10 per cent of previously untreated patients begun on LHRH therapy will experience transient worsening of disease symptoms corresponding to the initial rise in androgen levels. In an attempt to eliminate the early rise of T and DHT, 9 patients with metastatic prostatic carcinoma were pretreated with diethylstilbestrol (DES), 3 mg/day, for one week prior to the initiation of LHRH therapy. Following this, both DES and LHRH were given concomitantly for a week, after which DES was discontinued. LHRH was then continued as long as patients experienced clinical benefit. T and DHT levels were performed pre-study and on days 4, 8–11, 13, 15, and 29 of study. Results indicate that pretreatment with DES did not completely prevent the rise in T and DHT seen during the first week of LHRH therapy, although T and DHT levels rose to only slightly above baseline during the first four days. T and DHT levels then markedly decreased, and castrate levels were achieved by day 29 of treatment.

Administration of luteinizing hormone-releasing hormone analogs delays ovulation without affecting the luteal function in rhesus monkeys

Regularly cycling rhesus monkeys received, from days 1 to 6 of the menstrual cycle (1) the potent luteinizing hormone-releasing hormone (LH-RH) agonist D-Trp6-LH-RH, 20 micrograms/day; (2) the potent LH-RH antagonist [N-Ac-D-Trp1,3,D-p-Cl-Phe2,D-Phe6-D-Ala10]-LH-RH, 1 mg/day; or (3) vehicle. Whereas control animals showed normal menstrual cycles, as determined by dates of ovulation, length of luteal phases, and hormonal profiles, animals treated with either analog of LH-RH exhibited disruption of the cycles. In animals from both groups, delayed ovulation was observed (LH-RH agonist, 22, 23, 17, 19, and 20 days of the cycle; LH-RH antagonist, 22, 22, 24, and 10 days of the cycle, and one animal remained anovulatory for 65 days). Monkeys treated with either LH-RH analog showed normal luteal phase lengths (15, 15, 16, 14, and 15 days, and 15, 16, 16, and 13 days, respectively) and serum progesterone concentrations. The results of this study suggest that, in the rhesus monkey, the administration of LH-RH analogs during the early follicular phase induces a temporary cessation of folliculogenesis demonstrated by a delay of ovulation, with subsequent normal luteal function.

Influence of testosterone and/or luteinizing hormone releasing hormone analogue on precocious sexual development in the juvenile rainbow trout.

The influence of testosterone, luteinizing hormone releasing hormone (LHRH) agonist and combinations of these hormones on gonadotropic hormone (GtH) levels in the sexually immature trout was investigated. Both the steroid and releasing hormone preparations, testosterone in Silastic capsules and cholesterol-pelleted LHRH-A, were formulated for sustained release and long-term biological action following a single hormone implantation. Marked increases in pituitary GtH followed testosterone and/or testosterone and LHRH analogue treatment combined, but the low pituitary GtH level in controls remained unchanged after LHRH analogue administration alone. Plasma GtH titers increased with time after testosterone treatment, indicating a positive steroid feedback effect by androgen on GtH in the juvenile rainbow trout. When combined with testosterone treatment, LHRH analogue augmented plasma GtH levels compared to fish receiving testosterone treatment alone. In males the elevated plasma GtH levels were associated with testes stimulation and onset of spermatogenesis; in females, however, no significant stimulation of the ovaries was observed. It can be concluded from these studies that the testosterone stimulus is sufficient to induce onset of sexual development in immature males but not females. Whereas LHRH analogue releases GtH from the testosterone-primed trout pituitary, LHRH treatment alone under these conditions fails to stimulate the juvenile trout reproductive system.