Use Of Luteinizing Hormone-Releasing Hormone Research Articles

Testosterone Recovery after Androgen Deprivation Therapy in Prostate Cancer: Building a Predictive Model.

To analyze the variability, associated actors, and the design of nomograms for individualized testosterone recovery after cessation of androgen deprivation therapy (ADT). A longitudinal study was carried out with 208 patients in the period 2003 to 2019. Castrated and normogonadic testosterone levels were defined as 0.5 and 3.5 ng/mL, respectively. The cumulative incidence curve described the recovery of testosterone. Univariate and multivariate analyzes were performed to predict testosterone recovery with candidate prognostic factors prostate-specific antigen at diagnosis, clinical stage, Gleason score from biopsy, age at cessation of ADT, duration of ADT, primary therapy and use of LHRH (luteinizing hormone-releasing hormone) agonists. The median follow-up duration in the study was 80 months (interquartile range, 49-99 mo). Twenty-five percent and 81% of patients did not recover the castrate and normogonadic levels, respectively. Duration of ADT and age at ADT cessation were significant predictors of testosterone recovery. We built two nomograms for testosterone recovery at 12, 24, 36, and 60 months. The castration recovery model had good calibration. The C-index was 0.677, with area under the receiver operating characteristic curve (AUC-ROC) of 0.736, 0.783, 0.782, and 0.780 at 12, 24, 36, and 60 months, respectively. The normogonadic recovery model overestimated the higher values of probability of recovery. The Cindex was 0.683, with AUC values of 0.812, 0.711, 0.708 and 0.693 at 12, 24, 36, and 60 months, respectively. Depending on the age of the patient and the length of treatment, clinicians may stop ADT and the castrated testosterone level will be maintained or, if the course of treatment has been short, we can estimate if it will return to normogonadic levels.

Luteinizing hormone-releasing hormone agonists for prostate cancer patients: routine clinical practice of Russian cancer urologists

Background. Despite the recent amendments to the guidelines for the treatment of metastatic hormone-sensitive prostate cancer (PCa) implying standard use of luteinizing hormone-releasing hormone (LHRH) agonists in combination with chemotherapy or androgen inhibitors, androgen deprivation therapy (ADT) remains an essential component of treatment for advanced PCa. Testosterone target castration level of 20 ng/dL implies routine measurement of testosterone levels along with prostate-specific antigen (PSA) levels during ADT. It is particularly interesting to evaluate the frequency of achieving castration testosterone level in routine clinical practice. Objective: to assess the frequency of achieving castration testosterone level (20 ng/dL) and maintaining it after 6 months of therapy in patients with hormone-sensitive PCa receiving an LHRH agonist for the first time. Materials and methods. In 2019-2020, Russian Society of Cancer Urologists conducted a non-interventional prospective multicenter study (observational program) aimed to evaluate the efficacy of LHRH agonist (including buserelin, goserelin, leuprorelin or triptorelin) in routine clinical practice in Russia. This study involved 39 cancer urologists and 479 patients aged 18 years and older diagnosed with hormone-sensitive PCa, who started their ADT with LHRH agonists for the first time regardless of the disease stage and previous treatment. Patients received hormone therapy with an LHRH agonist for at least 6 months, visiting their doctor every 3 months (visit 1; visit 2: after 3 months; visit 3: after 6 months). Results. Patients received one of the following drugs: leuprorelin (3.75 mg; 7.5 mg; 22.5 mg; 45 mg; n = 225; 47,0 %), goserelin (3.6 mg; 10.8 mg; n = 132; 27.5 %), buserelin (3.75 mg; n = 67; 14.0 %), and triptorelin (3.75 mg; 11.25 mg; n = 55; 11.5 %). Of 479 patients, 186 (38.8 %) received combination treatment with bicalutamide, 12 (2.5 %) with fluta-mide, 54 (11.3 %) with zoledronic acid, and 11 (2.3 %) with denosumab. Among 146 patients with metastatic PCa, a combination of ADT plus docetaxel was administered to 30 participants (20.6 %), ADT plus abiraterone to 8 participants (5.5 %), and ADT plus enzalutamide to 2 participants (1.4 %). After 6 months of therapy, mean PSA level decreased by 94.2 % (from baseline 118.12 ng/mL to 6.87 ng/mL). Mean testosterone level was 19.0 ng/dL (range: 0.029-100 ng/dL). Among 430 patients, the targeted testosterone level <20 ng/dL was achieved in 257 individuals (59.8 %); the level of 20-50 ng/dL was achieved in 158 individuals (36.7 %); and fifteen patients (3.5 %) had their testosterone level >50 ng/dL. The incidence of adverse events was low; most of them were mild. Conclusion. Our findings suggest that not all patients achieve targeted testosterone level of <20 ng/dL, which corroborates the need for routine monitoring of testosterone levels during therapy to ensure its timely correction. We observed frequent administration of ADT with maximum androgen blockade. In patients with metastatic PCa, the use of standards for combination treatment with docetaxel and androgen inhibitors is limited.

SERENA-4: A phase 3 comparison of AZD9833 (camizestrant) plus palbociclib, versus anastrozole plus palbociclib, for patients with ER-positive, HER2-negative advanced breast cancer who have not previously received systemic treatment for advanced disease.

TPS1101 Background: More than two thirds of patients with advanced breast cancer (ABC) have estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2−) tumors. Current standard-of-care first-line treatments include an aromatase inhibitor (AI) or fulvestrant, a selective ER degrader (SERD), combined with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. Concurrent use of luteinizing hormone-releasing hormone (LHRH) agonists is recommended for men and premenopausal women with ABC. Nevertheless, almost all ABCs eventually become resistant to endocrine therapy (ET) and the disease is incurable. New therapies are needed to combat ET resistance, maintain patient quality of life (QoL), and delay the need for chemotherapy. AZD9833 (camizestrant) is an orally bioavailable, highly potent, next-generation SERD that demonstrated anti-cancer properties across a range of preclinical models, including those with ER-activating mutations (Scott et al, 2020). A phase I study (SERENA-1) has demonstrated that AZD9833 is well tolerated and has a promising antitumor profile when administered alone or in combination with palbociclib, a CDK4/6 inhibitor (Baird et al, SABCS 2020). SERENA-4 (NCT04711252) is a randomized, multicenter, double-blind, phase III trial to evaluate the safety and efficacy of AZD9833 in combination with palbociclib for patients with ER+ HER2− ABC who have not received any systemic treatment in the advanced disease setting. Methods: SERENA-4 will enroll 1,342 patients with de novo or recurrent ER+ HER2– ABC who have not previously received systemic treatment for their locoregionally recurrent or metastatic disease. Patients with recurrent disease must have received adjuvant AI or tamoxifen therapy for at least 24 months without relapse. Patients will be randomized 1:1 to receive orally either (a) AZD9833 (75 mg, once daily), palbociclib (125 mg, once daily for 21 days followed by 7 days off treatment) and anastrozole-matching placebo (once daily) or (b) anastrozole (1 mg, once daily), palbociclib (same as active arm), and AZD9833-matching placebo (once daily). Premenopausal women and men will also receive LHRH agonists. The primary endpoint will be progression-free survival (PFS; up to 5 years). Secondary endpoints will include overall survival (up to 8 years), length of second PFS period, objective response, time to chemotherapy, and changes in QoL measures. Enrollment began in January 2021. Acknowledgments: We thank Rose Goodchild, PhD, of Oxford PharmaGenesis, UK, for providing medical writing assistance. Funding: The SERENA-4 trial is funded and overseen by AstraZeneca. Clinical trial information: NCT04711252 .

Effect of luteinizing hormone-releasing hormone agonists on the testosterone levels and quality of life in patients with locally advanced and generalized prostate cancer

Prostate cancer (PC) was 5% of all revealed male malignancies in the Russian Federation in 2009. Among 23845 detected patients with PC, 53.4% had its Stage III or IV. This paper gives the results of a follow-up of patients with locally advanced and generalized PC treated by different hormonal therapy regimens. The purpose of the study was to search for the optimal hormonal therapy regimen, by maintaining the quality of life, whose criteria were potency level, libido, and normal physical activity. The follow-up data may lead to the conclusion that the 6-month use of luteinizing hormone-releasing hormone (LHRH) agonists causes an irreversible reduction in potency and libido and a considerable decrease in testosterone levels. Sustained-release LHRH agonists decrease testosterone levels (below 20 ng/dl), are an easy-to-use and simple dosage form, and may be recommended for outpatient administration.

Ovarian ablation as adjuvant therapy for breast cancer

For more than 100 years ovarian ablation has been used as treatment for breast cancer. There are several methods of ovarian ablation including surgical oophorectomy, radiation-induced ablation, and chronic use of luteinizing hormone-releasing hormone (LHRH) analogs. In addition, there is some suggestion that cytotoxic chemotherapy may act in part by inducing ovarian ablation in premenopausal breast cancer patients. Of the numerous case series and clinical trials of ovarian ablation performed in the past century, many have been fraught with methodologic problems. The Early Breast Cancer Trialists' Collaborative Group (EBCTCG) meta-analysis of 12 properly randomized trials shows a significant improvement in disease-free survival (DFS) and overall survival for women who underwent ovarian ablation as adjuvant therapy compared with those who did not. However, a number of questions remain. The relative efficacy of chemotherapy and ovarian ablation and the value of combining ovarian ablation with chemotherapy or other endocrine therapy have not yet been determined. This articles reviews and compares the methods of ovarian ablation, and discusses the EBCTCG overview data, as well as the newer and ongoing trials, which may answer the remaining questions about the optimal use of this therapy in the adjuvant treatment of breast cancer.

Luteinizing hormone-releasing hormone agonists for ovarian stimulation in assisted reproduction

Although the use of luteinizing hormone-releasing hormone (LHRH) agonists and human menopausal gonadotropin (hMG) for ovarian stimulation in assisted reproduction has gained widespread popularity, a number of major issues regarding their use remain unresolved. Some of these issues are examined in the light of recent developments. The routine use of LHRH agonists produces significantly higher pregnancy and livebirth rates compared with conventional methods of ovarian stimulation. A number of prospective, randomized studies have shown that the long protocol of LHRH agonist administration is superior to the short and ultrashort protocols, and it appears that early follicular phase initiation of the long protocol may be particularly beneficial. Another major advantage of the long protocol of LHRH agonist administration is that, with its use, precise timing of human chorionic gonadotropin (hCG) administration is not important. It would, therefore, appear that the routine use of LHRH agonists has both medical as well as practical advantages.

Embryo Loss, Blastomere Development and Chromosome Constitution after Human Chorionic Gonadotropin-Induced Ovulation in Mice and Rats with Regular Cycles

A dose of 7 IU human chorionic gonadotropin (hCG) given 14 h before the expected LH peak on proestrus significantly increased embryonic mortality in Swiss random-bred female mice to 55% of the number of corpora lutea. The use of luteinizing hormone-releasing hormone in a similar injection protocol did not induce embryonic death. The effect found in Swiss random-bred mice resembles that of a dose of 20 IU hCG in the rat. Afternoon-day-4 mouse embryos contained 39.1 +/- 12.6 nuclei after hCG-induced ovulation compared to 46.2 +/- 16.6 nuclei after spontaneous ovulation. For early-day-5 embryos of the rat, these figures were 34.2 +/- 10.1 and 31.7 +/- 8.4, respectively (mating was early on day 1). Numerical chromosome errors were estimated in secondary oocytes of the mouse and early-day-5 embryos of the rat. Compared with data from the literature, hCG seems to induce some extra meiotic nondisjunction in the rat only. Combining all genetic and physiological data, the loss of fecundity after hCG-induced ovulation is a maternal effect.

A synthetic luteinizing hormone releasing hormone vaccine: I. Conjugation and specificity trials in BALB/c mice

The immunobiology of luteinizing hormone releasing hormone (LHRH) was explored, to provide a conceptual and practical basis for the use of LHRH in immunocastration. Cysteine substituted analogues of LHRH were synthesized including Cys 1-LHRH (C1-LHRH), Cys 6-LHRH (C6-LHRH) and Cys 10-LHRH (C10-LHRH). These were reacted to carrier molecules using the heterobifunctional cross-linking reagent m-maleimidobenzoylsulfosuccinimide ester (SMBS), producing peptide-carrier conjugates of known peptide content and conjugation orientation. This reaction regime was found to be rapid, efficient and allowed for easy control of peptide to carrier ratios. Conjugates were used in active immunization trials in BALB/c mice to characterize the murine immune response against LHRH. BALB/c mice were shown to have the capacity to recognise all three cysteine substituted LHRH analogues and to produce antibodies cross-reactive with native LHRH. The specificity of LHRH antisera generated was found to be dependent on the site of conjugation of the peptide to carrier molecule. C1-LHRH generated carboxy terminal directed antibodies, C10-LHRH generated amino terminal directed antibodies, while C6-LHRH could generate amino terminal directed or carboxy terminal directed antibodies, or both within a given animal. No intrinsically immunodominant epitopes were seen within the LHRH molecule.

Luteinizing hormone releasing hormone and human behavior.

Sir .—The effects of luteinizing hormone releasing hormone (LHRH) on the sexual behavior of rats are well documented. 1-3 The data on adult humans are limited, and the data on children are nonexistent. We report the sexual and aggressive responses of children and adults after administration of LHRH. Patient Reports.—Patients and Methods .—Three males and two females, 11, 15, 18, 26, and 28 years old, suffering from Kallman's syndrome (one patient), delayed puberty (one patient), prepuberty (one patient), and infertility of undetermined cause (two patients) were studied. None manifested pathologic personality problems. No organic or intracranial lesion was detected. Each subject received intramuscular injections of 100 μg/m 2 of LHRH daily as a diagnostic agent for three consecutive days. All subjects were informed of the use of LHRH as a diagnostic agent; we did not discuss whether LHRH affects thoughts or behavior. A Rorschach Test and Thematic Apperception Test

Use of Luteinizing Hormone-Releasing Hormone for Ovulation Induction

Use of Luteinizing Hormone-Releasing Hormone for Ovulation Induction

LHRH

<h3>To the Editor.—</h3> The recent MEDICAL NEWS story¹on the growing applications for clinical use of luteinizing hormone-releasing hormone (LHRH) provides important updates on the use of this category of drug in the treatment of a number of conditions. With regard to the use of such analogues in the treatment of prostate carcinoma, Ms Ziporyn alluded to recent data²that show a rise in serum luteinizing hormone (LH) and testosterone concentrations in patients who have been treated for a mean of 12.7 months with one LHRH analogue (ICI 118630), 250 μg daily. The authors of this article are quoted as stating that LHRH analogues should not be used "as a long-term treatment for carcinoma of the prostate." We have recently reported observations on 98 patients treated for a median of 72 weeks with an LHRH analogue, leuprolide (Lupron), given in 1-mg/day subcutaneous doses.³Response rates and duration

Antibody production against an agonist analogue of luteinizing hormone-releasing hormone: evaluation of immunochemical and physiological consequences.

Because of the widespread long-term clinical use of luteinizing hormone-releasing hormone (LRH) agonists, the possibility of antibody development to one of these, (D-Ser-(Butt)6) LRH (1-9) nonapeptide-ethylamide (buserelin), has been studied by examining sera from experimental animals and humans receiving long-term agonist-treatment for ability to bind 125I-labelled buserelin. None of the sera from monkeys, rabbits, dogs or rats receiving buserelin by sc injection or via minipump or from 81 patients receiving the agonist by sc injection or nasal spray had detectable antibodies. The immunochemistry of buserelin was investigated by actively immunizing male rabbits against the agonist. This also enabled us to determine the possibility of this stimulus to the immune response resulting in the generation of antibodies which could cross-react with endogenous LRH and neutralize its biological effect. All 41 rabbits immunized against unconjugated buserelin and all 23 immunized against buserelin conjugated to a protein carrier developed antibodies, those in the latter group producing highest titres. Serum from one of the animals immunized against unconjugated buserelin and from 9 of the animals immunized against conjugated buserelin had the capacity to bind 125I-labelled LRH. These LRH antibody titres were very low and were insufficient to cause suppression of serum testosterone concentrations or affect testicular weight except in one rabbit immunized against unconjugated agonist. The LRH antibody titre in this rabbit was always less than 1:100 which our other studies have indicated to be too low to produce a biological effect. It may be that the association of low LRH antibody titre with decreased testes weight in this animal was fortuitous. We conclude that the possibility of circulating antibodies being produced to buserelin or their interfering with the action of endogenous LRH is extremely low.

The use of luteinizing hormone-releasing hormone in pediatric patients.

Luteinizing hormone-releasing hormone (LH-RH), first synthetized in 1971; became soon available for clinical purposes and was immediately used as a diagnostic tool in children and adolescents as well as in adults. The first results of the LH-RH test in pediatrics were reported in 1972 and soon after discussed in meetings allowing comparison of the data from different groups. From this time, a great number of publications has been devoted to the diagnostic usefulness of LH-RH in the study of pubertal development and of pituitary-gonadal disorders in children and adolescents. Until recently, the theraeputic use of LH-RH has been restricted by the lack of availability of sufficient amounts, so that only few preliminary data have been reported in this field. Thus the scope of this review is mainly to present a critical survey of the data concerning LH-RH test in pediatric patients.

Diagnostic and therapeutic use of luteinizing hormone-releasing hormone (LH-RH)

For about 5 years has hypothalamic LH-RH been used to study the response of the pituitary gonadotropins and the gonadal steroids both in physiological conditions and in endocrine diseases. The significance of this clinical research shall be summarized with respect to the determination of the functional capacity of the hypothalamo-pituitary-gonadal system as well as its diagnostic and therapeutic consequences.

Therapeutic use of luteinizing hormone-releasing hormone in the human female.

A gonadotropin-releasing hormone became available for clinical studies in 1971, when Schally and associates isolated, determined the structure and synthesized LH releasing hormone (LH-RH). It was hoped that this new hypothalamic hormone, among other things, would prove to be useful in the diagnosis and therapy of disorders of the hypothalamo-pituitary axis. The diagnostic value of the LH-RH test has recently been questioned by Mortimer et al. (1973) who reported that it was not possible to distinguish between hypothalamic and pituitary causes of hypogonadotrophic hypogonadism. However, the possibility of using LH-RH in the treatment of infertility in men and women is of great interest and the potential therapeutic role of LH-RH has to be thoroughly explored.

The Use of Luteinizing Hormone-Releasing Hormone in Gynecologic Endocrinology

The discovery and characterization of luteinizing hormone-releasing hormone (LH-RH) and the subsequent production of a synthetic decapeptide are described. The physiologic actions of LH-RH include an increase in circulating LH and FSH in males and females following intravenous or intramuscular administration. Estrogen and progesterone can reduce pitu itary responsiveness to LH-RH; when estrogen levels are high (early luteal phase) pituitary sensitivity to LH is also high. LH-RH has been used in an attempt to learn about the etiology of secondary amenorrhea. Patients with pituitary tumors usually show a diminished response to LH-RH and functional pituitary disease is always accompanied by a low response to LH-RH. Severe malnutrition may also result in a low response to LH-RH. Most patients with secondary amenorrhea respond easily to synthetic LH-RH; LH-RH then is useful in distinguishing underlying pituitary disease from a disturbed interrelationship among pituitary hypothalamus and ovaries as a cause of secondary amenorrhea. 48 women with secondary amenorrhea (with proven diagnoses by conventional methods) were tested with an LH-RH stimulation test. Results suggested the correct diagnosis by the pattern of LH and FSH response. Reports on using LH-RH appears to be promising.