-
BMC Veterinary Research Apr 2022Buserelin is a luteinizing hormone releasing hormone (LHRH) agonist used for the treatment of hormone-dependent diseases in males and females. However, the...
BACKGROUND
Buserelin is a luteinizing hormone releasing hormone (LHRH) agonist used for the treatment of hormone-dependent diseases in males and females. However, the pharmacokinetics of buserelin in pigs and cows are not fully understood. This study was designed to develop a sensitive method to determine the concentration of buserelin in blood plasma and to investigate the pharmacokinetic parameters after intramuscular (i.m.) administration in pigs and cows.
RESULTS
A sensitive and rapid stability method based on ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was developed. The pharmacokinetic parameters of buserelin after i.m. administration were studied in five pigs and five cows at a single dose of 1 mg per pig and 3 mg per cow. The plasma kinetics were analyzed by WinNonlin 8.1.0 software using a non-compartmental model. The mean concentration area under the curve (AUC) was 25.02 ± 6.93 h × ng/mL for pigs and 5.63 ± 1.86 h × ng/mL for cows. The maximum plasma concentration (C) and time to reach the maximum concentration (t) were 10.99 ± 2.04 ng/mL and 0.57 ± 0.18 h for pigs and 2.68 ± 0.36 ng/mL and 1.05 ± 0.27 h for cows, respectively. The apparent volume of distribution (V) in pigs and cows was 80.49 ± 43.88 L and 839.88 ± 174.77 L, respectively. The elimination half-time (t), and clearance (CL) were 1.29 ± 0.40 h and 41.15 ± 11.18 L/h for pigs and 1.13 ± 0.3 h and 545.04 ± 166.40 L/h for cows, respectively. No adverse effects were observed in any of the animals.
CONCLUSION
This study extends previous studies describing the pharmacokinetics of buserelin following i.m. administration in pigs and cows. Further studies investigating other factors were needed to establish therapeutic protocol in pigs and cows and to extrapolate these parameters to others economic animals.
Topics: Animals; Area Under Curve; Biological Availability; Buserelin; Cattle; Chromatography, Liquid; Female; Male; Swine; Tandem Mass Spectrometry
PubMed: 35410205
DOI: 10.1186/s12917-022-03237-0 -
Human Reproduction Open 2023Is it possible to reduce the cost of GnRH agonist treatment for endometriosis by using non-standard dosing regimens? (Review)
Review
STUDY QUESTION
Is it possible to reduce the cost of GnRH agonist treatment for endometriosis by using non-standard dosing regimens?
SUMMARY ANSWER
An extended-interval dosing regimen of a 3.75 mg depot formulation of triptorelin injected every 6 weeks instead of every 4 weeks reduces the cost by one-third without compromising the effect on pain relief.
WHAT IS KNOWN ALREADY
Cost constitutes a limit to prolonged GnRH agonists use. Alternative modalities to reduce the economic burden of GnRH agonist treatment have been anecdotally attempted.
STUDY DESIGN SIZE DURATION
A systematic review was conducted to evaluate and compare the effect of three alternative modalities for GnRH use in women with endometriosis, i.e. intermittent oestrogen deprivation therapy, reduced drug dosage, and extended-interval dosing regimens of depot formulations. A PubMed and Embase search was initially conducted in October 2022 and updated in January 2023 using the following search strings: (endometriosis OR adenomyosis) AND (GnRH-agonists OR gonadotropin-releasing hormone agonists OR triptorelin OR leuprorelin OR goserelin OR buserelin OR nafarelin). Full-length articles published in English in peer-reviewed journals since 1 January 1980, and reporting original data on GnRH agonist treatment of pain symptoms associated with endometriosis were selected.
PARTICIPANTS/MATERIALS SETTING METHODS
Information was extracted on study design, GnRH-agonist used, dosage, total duration of therapy, side effects, treatment adherence, and pelvic pain relief. Reviews, commentaries, conference proceedings, case reports, and letters to the editor were excluded.
MAIN RESULTS AND THE ROLE OF CHANCE
Of the 1664 records screened, 14 studies regarding clinical outcomes associated with the 3 considered alternative modalities for GnRH agonist use were eventually included (intermittent oestrogen deprivation therapy, n = 2; low-dose or 'draw-back' therapy, n = 8; extended-interval dosing regimen, n = 4). Six studies were randomized controlled trials (RCTs) (double blind, n = 2) and eight adopted a prospective cohort design (non-comparative, n = 6; comparative, n = 2). A total of 776 women with endometriosis were recruited in the above studies (intermittent oestrogen deprivation therapy, n = 77; low-dose or 'draw-back' therapy, n = 528; extended-interval dosing regimen, n = 171). Robust data demonstrating cost saving without detrimental clinical consequences were available for the extended-interval dosing regimen only. In particular, the 3.75 mg triptorelin depot preparation inhibits ovarian function for a longer period compared with the 3.75 mg leuprorelin depot preparation, allowing injections every 6 instead of 4 weeks. Based on the cost indicated by the Italian Medicine Agency for the 3.75 mg triptorelin depot preparation, this would translate in a yearly saving of €744.60 (€2230.15-€1485.55; -33.4%).
LIMITATIONS REASONS FOR CAUTION
The quality of the evidence reported in the selected articles was not formally evaluated and a quantitative synthesis could not be performed. Some studies were old and the tested therapeutic approaches were apparently obsolete. Only cost containment associated with GnRH analogue use, and not cost-effectiveness, has been addressed.
WIDER IMPLICATIONS OF THE FINDINGS
Consuming less resources without negatively impacting on health outcomes carries ethical and practical implications for individuals and the community, as this approach may result in overall increased healthcare access.
STUDY FUNDING/COMPETING INTERESTS
This study was supported by the Italian Ministry of Health (Ricerca Corrente 2023, IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano). E.S. discloses payments from Ferring for research grants and honoraria from Merck-Serono for lectures. All other authors declare they have no conflict of interest.
REGISTRATION NUMBER
N/A.
PubMed: 37016694
DOI: 10.1093/hropen/hoad008 -
Indian Journal of Cancer Mar 2022Androgen deprivation therapy (ADT) using gonadotropin-releasing hormone agonist (s) (GnRH-A) remains the backbone of advanced prostate cancer treatment. In this review,... (Review)
Review
Androgen deprivation therapy (ADT) using gonadotropin-releasing hormone agonist (s) (GnRH-A) remains the backbone of advanced prostate cancer treatment. In this review, we assessed the efficacy, safety, and convenience of administration of various GnRH-A. All GnRH-A (goserelin, triptorelin, buserelin, histrelin, and leuprorelin) have comparable potential to suppress testosterone (T) levels (≤50 ng/dL in a month and ≤20 ng/dL in 3 months). However, goserelin has shown better efficacy in maintaining T levels ≤50 ng/dL compared with leuprolide. The incidences of T escape are lower with goserelin and leuprolide than buserelin. Goserelin also has maximum benefit in prostate-specific antigen suppression. In neoadjuvant setting, when only goserelin was used, the 10-year overall survival (OS) rate was 42.6% to 86%. When either goserelin or leuprolide was used, the 10-year OS rate was 62%. As an adjuvant to radical prostatectomy, goserelin had a 10-year survival rate of 87%, and triptorelin had an 8-year survival rate of 84.6%. Goserelin further showed an absolute survival rate of 49% when used as an adjuvant to radiotherapy. The survival rates further improved when GnRH-A are used as combined androgen blockade compared with monotherapy. The frequency and severity of adverse events (hot flushes, fatigue, sexual dysfunction) are comparable among the GnRH-A. Goserelin appears to be the most convenient of all the GnRH-A for administration. Lack of conclusive comparative evidence makes it imperative to have a holistic approach of considering the patient profile and the disease characteristics to select the appropriate GnRH-A for ADT in prostate cancer.
Topics: Androgen Antagonists; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Male; Prostatic Neoplasms
PubMed: 35343198
DOI: 10.4103/ijc.IJC_65_21 -
Frontiers in Endocrinology 2017Gonadotropin-releasing hormone (GnRH), follicle-stimulating hormone, and luteinizing hormone orchestrate the reproduction cycle and regulate the sex steroid secretion... (Review)
Review
Gonadotropin-releasing hormone (GnRH), follicle-stimulating hormone, and luteinizing hormone orchestrate the reproduction cycle and regulate the sex steroid secretion from the gonads. In mammals, GnRH1 is secreted as a hormone from the hypothalamus, whereas both GnRH1 and GnRH2 are present as neurotransmitters/peptides in various tissues, where the peptides exert many different effects. mRNA coding for GnRH1 and GnRH2 have been described in the human gastrointestinal tract, and GnRH has been found in both submucosal and myenteric neurons. mRNA coding for GnRH and the fully expressed peptide have been found in rat enteric neurons by some researchers but not by others. mRNA coding for GnRH receptors, but not the fully expressed receptor, has been found in one rat study. GnRH influences gastrointestinal motility and secretion. GnRH analogs are clinically used in the treatment of sex hormone-dependent diseases, i.e., endometriosis and malignancies, and as pretreatment for fertilization. Reduced numbers of enteric neurons and IgM antibodies against GnRH and progonadoliberin-2 (precursor of GnRH2) have been observed after such treatment, with the clinical picture of gastrointestinal dysmotility. Similarly, a rat model of enteric neurodegeneration has been developed after administration of the GnRH analog buserelin. Serum IgM antibodies against GnRH1, progonadoliberin-2, and GnRH receptors have been described in patients with signs and symptoms of gastrointestinal dysmotility and/or autonomic dysfunction, such as irritable bowel syndrome, enteric dysmotility, diabetes mellitus, and primary Sjögren's syndrome. Thus, apart from regulation of reproduction and sex hormone secretion, GnRH also constitutes a part of enteric nervous system (ENS) and its functions during physiological and pathological conditions. This review aimed to describe the role of GnRH in the ENS.
PubMed: 28638366
DOI: 10.3389/fendo.2017.00110 -
International Journal of Molecular... Mar 2019Male osteoporosis is a significant but undetermined healthcare problem. Men suffer from a higher mortality rate post-fracture than women and they are marginalized in... (Review)
Review
Male osteoporosis is a significant but undetermined healthcare problem. Men suffer from a higher mortality rate post-fracture than women and they are marginalized in osteoporosis treatment. The current prophylactic agents for osteoporosis are limited. Functional food components such as tocotrienol may be an alternative option for osteoporosis prevention in men. This paper aims to review the current evidence regarding the skeletal effects of tocotrienol in animal models of male osteoporosis and its potential antiosteoporotic mechanism. The efficacy of tocotrienol of various sources (single isoform, palm and annatto vitamin E mixture) had been tested in animal models of bone loss induced by testosterone deficiency (orchidectomy and buserelin), metabolic syndrome, nicotine, alcoholism, and glucocorticoid. The treated animals showed improvements ranging from bone microstructural indices, histomorphometric indices, calcium content, and mechanical strength. The bone-sparing effects of tocotrienol may be exerted through its antioxidant, anti-inflammatory, and mevalonate-suppressive pathways. However, information pertaining to its mechanism of actions is superficial and warrants further studies. As a conclusion, tocotrienol could serve as a functional food component to prevent male osteoporosis, but its application requires validation from a clinical trial in men.
Topics: Animals; Bone Development; Bone Resorption; Glucocorticoids; Humans; Male; Osteoporosis; Smoking; Tocotrienols
PubMed: 30889819
DOI: 10.3390/ijms20061355 -
European Surgical Research. Europaische... 2016Gonadotropin-releasing hormone (GnRH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) are involved in the reproductive cycle and regulate the secretion... (Review)
Review
BACKGROUND
Gonadotropin-releasing hormone (GnRH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) are involved in the reproductive cycle and regulate the secretion of sex steroids from the gonads. In mammals, GnRH1 is secreted as a hormone from the hypothalamus, whereas both GnRH1 and GnRH2 are present as neuropeptides in a variety of tissues. This review describes the role of GnRH in the gastrointestinal tract.
SUMMARY
GnRH1, GnRH2, and LH receptors in humans and rats, and GnRH receptors in rats, have been described in the gastrointestinal tract, where they affect motility, gastric and hormone secretion, and cell proliferation. GnRH analogs are clinically used in the treatment of sex hormone-dependent diseases, i.e., endometriosis and malignancies, and as pretreatments for in vitro fertilization. Severe gastrointestinal dysmotility has been shown to develop in some women after such treatment, along with a reduction in the number of enteric neurons and autoantibodies against GnRH. Consequently, a rat model of enteric neurodegeneration has been developed based on the administration of the GnRH analog buserelin. Serum IgM antibodies against GnRH1, the GnRH2 precursor progonadoliberin-2, and the GnRH receptor have also been described in patients with irritable bowel syndrome and dysmotility, as well as in patients with gastrointestinal disorders associated with diabetes mellitus, posterior laryngitis, and primary Sjögren's syndrome, although no treatments using GnRH analogs have been administered.
CONCLUSION
GnRH and receptors for GnRH and LH are present in the human and rat gastrointestinal tract. Treatment with GnRH analogs may induce severe dysmotility, and a rat model of enteric neurodegeneration has been developed based on stimulation by the GnRH analog buserelin. Autoantibodies against GnRH and its receptor are found in a subgroup of patients with functional bowel disorders and dysmotility, independent of treatment with GnRH analogs.
Topics: Animals; Antibody Formation; Buserelin; Gastrointestinal Microbiome; Gastrointestinal Motility; Gastrointestinal Tract; Gonadotropin-Releasing Hormone; Humans; Rats; Receptors, LHRH
PubMed: 27089503
DOI: 10.1159/000445717 -
Frontiers in Veterinary Science 2020This study aimed to investigate the effect of three different doses of estradiol-17β on ovulation and subsequent luteal development and function in llamas. Twenty-three...
This study aimed to investigate the effect of three different doses of estradiol-17β on ovulation and subsequent luteal development and function in llamas. Twenty-three llamas were examined daily by transrectal ultrasonography until the detection of an ovulatory follicle (≥8 mm). Thereafter, animals were divided into five groups: Control ( = 3; treated with 1.6 ml of saline solution), GnRH group ( = 6, treated with an intravenous injection of 8.4 μg Buserelin), and estradiol groups that received 0.6 mg (E1, = 4), 1 mg (E2, = 4), or 1.6 mg (E3, = 6) of estradiol-17β intravenously. Detection of ovulation was based on ultrasonographic visualization of disappearance of the largest follicle and subsequent presence of a newly formed corpus luteum (CL) and progesterone concentration exceeding 1 ng ml. Daily blood samples were collected to determine plasma progesterone concentration. Ovulation rate was 0% for control and E1 groups, 25% for E2 group, and 100% for GnRH and E3 groups. Differences in the mean CL diameter between GnRH and E3 groups were not statistically significant. Plasma progesterone concentration was similar between groups during the different days in ovulated animals. However, the day that the plasma progesterone concentration was above 1 ng ml and the day that the highest plasma progesterone concentration was achieved differed among E3 and GnRH groups, occurring later in females treated with estradiol. In conclusion, an injection of estradiol-17β is capable of inducing ovulation in llamas and the response depends on the dose used. Most of the animals required the highest tested dose (1.6 mg) to induce the ovulatory process. Although the CL diameter in females induced to ovulate with estradiol was similar to that in llamas induced to ovulate with a GnRH analog, the rise in plasma progesterone concentration above 1 ng ml and the peak progesterone concentration were attained 1 day later in the estradiol treated females.
PubMed: 33195576
DOI: 10.3389/fvets.2020.576204 -
Scientific Reports Apr 2021Multiple sclerosis (MS) is an autoimmune disease that usually occurs during the reproductive years in both sexes. Many male patients with MS show lower blood...
Multiple sclerosis (MS) is an autoimmune disease that usually occurs during the reproductive years in both sexes. Many male patients with MS show lower blood testosterone levels, which was also observed in male rats during experimental autoimmune encephalomyelitis (EAE), an animal model of MS. To better understand the causes of decreased testosterone production during EAE, we investigated the expression status of genes and proteins associated with steroidogenesis in the testes. No changes in the number of interstitial cells were observed in EAE animals, but the expression of the insulin-like 3 gene was reduced at the peak of the disease, implying that the Leydig cell functional capacity was affected. Consistent with this finding, the expression of most steroidogenic enzyme genes and proteins was reduced during EAE, including StAR, CYP11A1, CYP17A1 and HSD3B. No signs of testicular inflammation were observed. Recovery of steroidogenesis was observed after injection of hCG, the placental gonadotropin, or buserelin acetate, a gonadotropin-releasing hormone analogue, at the peak of EAE. Together, our results are consistent with the hypothesis that impaired testicular steroidogenesis originates upstream of the testes and that low serum LH is the main cause of decreased testosterone levels during EAE.
Topics: Animals; Cholesterol Side-Chain Cleavage Enzyme; Encephalomyelitis, Autoimmune, Experimental; Gene Expression Regulation, Enzymologic; Male; Multienzyme Complexes; Multiple Sclerosis; Progesterone Reductase; Rats; Steroid 17-alpha-Hydroxylase; Steroid Isomerases; Testis; Testosterone
PubMed: 33903635
DOI: 10.1038/s41598-021-88305-5 -
Frontiers in Veterinary Science 2017The current review summarizes progress in the field of and production of South American Camelid embryos. Both methods require ovarian superstimulation (with FSH and... (Review)
Review
The current review summarizes progress in the field of and production of South American Camelid embryos. Both methods require ovarian superstimulation (with FSH and eCG) to obtain multiple ovulations ( embryo production) or to induce follicle growth for oocyte collection ( embryo production). Moreover, superstimulation entails prior administration of hormones that inhibit follicular growth (progesterone, progestagens, and estrogens). Cumulus-oocyte complexes obtained must mature (buserelin administration) or to then be subjected to fertilization or intracytoplasmic sperm injection. All these techniques also require morphologically normal, motile spermatozoa to achieve fertilization. Methods used to decrease semen viscosity and to select the best spermatozoa (Percoll; Androcoll-E) are described. Additionally, nuclear transfer or cloning has been applied in llamas. Up to now, embryo deep-freezing and vitrification have progressed slowly but are at the height of development. Embryos that are obtained by any of these techniques, either or , need to be transferred to synchronized recipient females. The best results are achieved after transfer to the left uterine horn with an ipsilateral ovulation. No live offspring have been obtained after the transfer of cryopreserved embryos. Applying reproductive biotechnologies, such as those described, will permit the expansion of genetically selected animals in the population and also that of wild camelid species, vicunas, and guanacos, whose embryos could then be transferred to the uterus of domestic species.
PubMed: 29181380
DOI: 10.3389/fvets.2017.00190 -
Theriogenology Dec 2022In stallions temporarily not intended for breeding, reversible suppression of testicular function by vaccination against GnRH can be of interest. In the present study,...
In stallions temporarily not intended for breeding, reversible suppression of testicular function by vaccination against GnRH can be of interest. In the present study, effects of GnRH agonist treatment on the resumption of testicular function after GnRH vaccination were investigated. Testis size, testosterone release, semen characteristics and behavior were evaluated. We hypothesized that GnRH agonist treatment would restore testicular function. Shetland stallions were assigned to an experimental and a control group (n = 6 each). Experimental stallions were GnRH-immunized twice, four weeks apart. Ejaculates for semen analysis and blood for analysis of testosterone concentration and GnRH antibody titers were collected. Each experimental stallion was hemicastrated together with an age-matched control animal when testosterone concentration decreased below 0.3 ng/mL. Three weeks thereafter, daily treatment with the GnRH agonist buserelin was initiated (4 μg/day for 4 weeks followed by 8 μg/day). The remaining testicle was removed when testosterone concentration exceeded 0.5 ng/mL in vaccinated stallions. Time from exposure to a mare until mounting increased in GnRH-vaccinated stallions and decreased with buserelin treatment. Total sperm count decreased after vaccination but increased only slightly in response to buserelin. Sperm motility and percentage of membrane-intact spermatozoa decreased after vaccination and returned to pre-vaccination values with buserelin treatment. Testosterone concentration and testis volume decreased after GnRH vaccination and started to increase with buserelin treatment. In conclusion, the downregulation of testicular function by GnRH vaccination can be counteracted with buserelin. This approach may be useful in GnRH-vaccinated stallions with prolonged suppression of testicular function.
Topics: Horses; Male; Animals; Female; Sperm Motility; Semen; Buserelin; Testis; Testosterone
PubMed: 36193591
DOI: 10.1016/j.theriogenology.2022.09.011