ABSTRACT
Background: The first phase of the GAIL study ("Girls treated with an Aromatase Inhibitor and Leuprorelin," ISRCTN11469487) has shown that the combination of anastrozole and leuprorelin for 24 months is safe and effective in improving the predicted adult height (PAH) in girls with early puberty and compromised growth prediction by +1.21 standard deviation score (SDS; +7.51 cm) compared to inhibition of puberty alone, +0.31 SDS (+1.92 cm). Objectives and hypotheses: In the second phase of the GAIL study, we assessed the adult height (AH)/near-adult height (NAH) at the end of the first phase and, in addition, the efficacy of anastrozole monotherapy thereafter in further improving NAH. Methods: We measured the AH (age 16.5 years)/NAH [bone age (BA), 15 years] of the 40 girls included, divided into two matched groups: group A (20 girls on anastrozole + leuprorelin) and group B (20 girls on leuprorelin alone). Group A was further randomized into two subgroups: A1 and A2. Group A1 (n = 10), after completion of the combined therapy, received anastrozole 1 mg/day as monotherapy until BA 14 years, with a 6-month follow-up. Group A2 (n = 10) and group B (n = 20), who received only the combined treatment and leuprorelin alone, respectively, were recalled for evaluation of AH/NAH. Results: AH or NAH exceeded the PAH at the completion of the 2-year initial phase of the GAIL study in all groups, but the results were statistically significant only in group A1: NAH-PAH group A1, +3.85 cm (+0.62 SDS, p = 0.01); group A2, +1.6 cm (+0.26 SDS, p = 0.26); and group B, +1.7 cm (+0.3 SDS, p = 0.08). The gain in group A1 was significantly greater than that in group A2 (p = 0.04) and in group B (p = 0.03). Anastrozole was determined to be safe even as monotherapy in Group A1. Conclusions: In early-maturing girls with compromised growth potential, the combined treatment with leuprorelin and anastrozole for 2 years or until the age of 11 years resulted in a total gain in height of +9.7 cm when continuing anastrozole monotherapy until the attainment of NAH, as opposed to +7.4 cm if they do not continue with the anastrozole monotherapy and +3.6 cm when treated with leuprorelin alone. Thus, the combined intervention ends at the shortest distance from the target height if continued with anastrozole monotherapy until BA 14 years.
Subject(s)
Leuprolide , Puberty, Precocious , Female , Adult , Humans , Adolescent , Child , Anastrozole/pharmacology , Leuprolide/therapeutic use , Leuprolide/pharmacology , Aromatase Inhibitors/therapeutic use , Puberty, Precocious/drug therapy , Puberty , Body HeightABSTRACT
We examined the effect of the puberty blocker, leuprolide acetate, on sex differences in juvenile rough-and-tumble play behavior and anxiety-like behavior in adolescent male and female rats. We also evaluated leuprolide treatment on gonadal and pituitary hormone levels and activity-regulated cytoskeleton-protein messenger RNA levels within the adolescent amygdala, a region important both for rough-and-tumble play and anxiety-like behavior. Our findings suggest that leuprolide treatment lowered anxiety-like behavior during adolescent development, suggesting that the maturation of gonadotropin-releasing hormone systems may be linked to increased anxiety. These data provide a potential new model to understand the emergence of increased anxiety triggered around puberty. Leuprolide also reduced masculinized levels of rough-and-tumble play behavior, lowered follicle-stimulating hormone, and produced a consistent pattern of reducing or halting sex differences of hormone levels, including testosterone, growth hormone, thyrotropin, and corticosterone levels. Therefore, leuprolide treatment not only pauses sexual development of peripheral tissues, but also reduces sex differences in hormones, brain, and behavior, allowing for better harmonization of these systems following gender-affirming hormone treatment. These data contribute to the intended use of puberty blockers in stopping sex differences from developing further with the potential benefit of lowering anxiety-like behavior.
Subject(s)
Anxiety , Behavior, Animal , Leuprolide , Sexual Maturation , Animals , Leuprolide/pharmacology , Male , Female , Anxiety/drug therapy , Rats , Behavior, Animal/drug effects , Sexual Maturation/drug effects , Sex Characteristics , Amygdala/drug effects , Amygdala/metabolism , Corticosterone/blood , Rats, Sprague-Dawley , Testosterone/bloodABSTRACT
OBJECTIVE: The aim of the study is to show for the first time how aflibercept affects endometriosis lesions. MATERIAL AND METHODS: Surgically induced endometriosis in Wistar albino female rats. Rats with endometriosis were randomly divided into three groups: control (Co), aflibercept (Af), and leuprolide acetate (Le). Then, Af, aflibercept, and Le received leuprolide acetate. The control group was not treated. The weights and changes in intra-abdominal adhesions of the rats before and after treatment were recorded according to the Blauer adhesion score. Blood extracted for sacrifice was analyzed. Endometriotic lesions were evaluated for size, volume, histology, and immunohistochemistry (vascular endothelial growth factor [VEGF] and CD31). Significance level was accepted as p < 0.05. RESULTS: Aflibercept significantly reduced endometrial implant volume (p = 0.002). The explant epithelial histological score showed a significant difference between aflibercept and leuprolide acetate (p = 0.006) and between aflibercept and control groups (p = 0.002). Aflibercept decreased VEGF-H and CD31 expression (p = 0.001) more than leuprolide acetate. Aflibercept improved adhesions (p = 0.006). CONCLUSION: Aflibercept is more successful than leuprolide acetate in the treatment of endometriosis.
OBJETIVO: Mostrar por primera vez cómo afecta aflibercept a las lesiones de endometriosis. MATERIAL Y MÉTODOS: Endometriosis inducida quirúrgicamente en ratas hembras albinas Wistar. Las ratas con endometriosis se dividieron aleatoriamente en tres grupos: control (Co), aflibercept (Af) y acetato de leuprolida (Le). Luego, Af, aflibercept y Le recibieron acetato de leuprolida. El grupo de control no fue tratado. Los pesos y cambios en las adherencias intraabdominales de las ratas antes y después del tratamiento se registraron de acuerdo con la puntuación de adherencia de Blauer. La sangre extraída para el sacrificio fue analizada. Las lesiones endometriósicas se evaluaron en tamaño, volumen, histología e inmunohistoquímica (factor de crecimiento endotelial vascular [VEGF] y CD31). El nivel de significación se aceptó como p < 0.05. RESULTADOS: Aflibercept redujo significativamente el volumen del implante endometrial (p = 0.002). La puntuación histológica epitelial (EHS) del explante mostró una diferencia significativa entre aflibercept y acetato de leuprolida (p = 0.006) y entre los grupos de aflibercept y control (p = 0.002). Aflibercept disminuyó la expresión de VEGF-H y CD31 (p = 0.001) más que el acetato de leuprolida. Aflibercept mejoró las adherencias (p = 0.006). CONCLUSIÓN: Aflibercept tiene más éxito que el acetato de leuprolide en el tratamiento de la endometriosis.
Subject(s)
Endometriosis , Receptors, Vascular Endothelial Growth Factor , Recombinant Fusion Proteins , Female , Humans , Rats , Animals , Endometriosis/complications , Endometriosis/drug therapy , Leuprolide/pharmacology , Leuprolide/therapeutic use , Rats, Wistar , Angiogenesis Inhibitors/pharmacology , Angiogenesis Inhibitors/therapeutic use , Vascular Endothelial Growth Factor AABSTRACT
OBJECTIVE: This trial was to investigate the effect of different treatment methods on the clinical efficacy and fertility outcome of patients with adenomyosis. METHODS: In total, 140 patients with adenomyosis were evenly and randomly allocated into group A (laparoscopic surgery), group B (laparoscopic surgery combined with gonadotropin-releasing hormone analogs [GnRH-a]), group C (ultrasound-guided percutaneous radiofrequency ablation), and group D (ultrasound-guided percutaneous radiofrequency ablation combined with GnRH-a). On the 3rd day after surgery, patients in group B and group D were subcutaneously injected with GnRH-a (Leuprorelin Acetate SR for Injection) at 3.75 mg/time, once every 4 weeks, for a total of 3 months. The therapeutic effects of the 4 groups were compared, including menstrual volume, dysmenorrhea score, uterine volume, clinical efficacy, luteinizing hormone (LH), estradiol (E2), and follicle-stimulating hormone (FSH) levels, CA125 levels, recurrence, pregnancy status, and pregnancy outcomes. RESULTS: After treatment, the menstrual volume of 4 groups was lowered, dysmenorrhea, Visual Analog Scale (VAS) score, LH, FSH, E2, and CA125 levels were reduced, and uterine volume was decreased. The menstrual volume, VAS score, levels of LH, FSH, E2, and CA125, and uterine volume were reduced in groups B, C, and D compared with group A, and the decrease was more significant in group D. The total effective rate of group D was 100.00%, which was higher than that of group A (71.43%), group B (80.00%), and group C (82.86%). After one year of drug withdrawal, the recurrence of hypermenorrhea, dysmenorrhea, uterine enlargement, and excessive CA125 in group D was significantly lower than that in groups A, B and C, and the recurrence in groups B and C was significantly lower than that in group A (P < 0.05). Compared with groups A, B, and C, group D had a higher pregnancy rate, natural pregnancy rate, and lower in vitro fertilization-embryo transfer rate (P < 0.05), but showed no significant difference in pregnancy outcomes. CONCLUSION: Ultrasound-guided percutaneous radiofrequency ablation combined with Leuprorelin Acetate is effective in the treatment of adenomyosis, which can effectively relieve clinical symptoms, protect postoperative ovarian function, reduce recurrence rate, alleviate pain, and improve quality of life.
Subject(s)
Adenomyosis , Female , Pregnancy , Humans , Adenomyosis/drug therapy , Adenomyosis/surgery , Dysmenorrhea , Leuprolide/pharmacology , Leuprolide/therapeutic use , Quality of Life , Luteinizing Hormone , Treatment Outcome , Follicle Stimulating Hormone/therapeutic use , Fertility , Acetates/therapeutic use , Gonadotropin-Releasing Hormone/therapeutic useABSTRACT
More adolescents are coming out as transgender each year and are put on puberty blockers to suppress natal puberty, which is then followed by cross-hormone treatment to achieve puberty of the desired gender. Studies to examine the effects of puberty suppression and virilizing therapy on future reproductive potential among transgender males are lacking. This study used a translational murine in vitro fertilization model to examine the effects of female puberty suppression with depot leuprolide acetate (LA), followed by virilizing therapy with testosterone cypionate (T), on embryologic and pregnancy outcomes. LA effectively inhibited puberty when mice were treated beginning at 3 weeks of age. LA treatment was associated with higher mouse weight but lower ovarian weight. LA-treated mice ovulated developmentally competent eggs in response to gonadotropin administration, albeit at a higher dose than controls. Ovaries from mice treated with LA and T produced oocytes that had morphologically normal meiotic spindles after in vitro maturation and responded to gonadotropin stimulation. Eggs from mice treated with LA and T were fertilizable and produced developmentally competent embryos that led to births of fertile pups. These results suggest that fertility may not be impaired after puberty suppression and cross-hormone therapy for transgender males.
Subject(s)
Leuprolide , Sexual Maturation , Male , Female , Mice , Animals , Leuprolide/pharmacology , Leuprolide/therapeutic use , Testosterone/pharmacology , Gonadotropins , Ovary , Gonadotropin-Releasing HormoneABSTRACT
BACKGROUND: Mild hypoxic-ischemic encephalopathy (HIE) is a condition that predisposes to negative outcomes such as neuroanatomical injury, mood disorders, and motor or cognitive disabilities. The neuroinflammation plays an important role in the neurological damage; therefore, reducing it could provide neuroprotection. The leuprolide acetate (LA) has shown to have neuroregenerative and immunomodulator properties in other nervous system injuries. OBJECTIVE: The aim of this study was to evaluate the immunomodulatory effect of LA in the acute phase of mild HIE and its effects in motor activity and behavior in a subacute phase. METHOD: Forty-five Wistar rats on postnatal day 7 were divided into Sham, HIE treated with saline solution (HIE-SS), and HIE-LA. The HIE was performed cutting of the right carotid artery followed by 60 min of hypoxia. The expression of the inflammatory cytokines interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and the chemokine CXCL-1 were evaluated 72 h after HIE by RT-qPCR and the motor activity and behavior were evaluated by open field test at postnatal day 33. RESULTS: HIE-SS animals showed increased expression of IL-1ß, TNF-α, IFN-γ, and CXCL-1 genes in injured tissue. However, the HIE-LA group exhibited similar expression levels of IL-1ß and TNF-α to the Sham group, while IFN-γ and CXCL-1 mRNA expression were attenuated with LA treatment. LA treatment also prevented anxiety-like behavior in the open field test. CONCLUSION: Treatment with LA partially reverses HIE-induced neuroinflammation and prevents anxiety-like behavior in neonatal rats.
Subject(s)
Hypoxia-Ischemia, Brain , Animals , Rats , Hypoxia-Ischemia, Brain/drug therapy , Hypoxia-Ischemia, Brain/metabolism , Hypoxia-Ischemia, Brain/pathology , Animals, Newborn , Leuprolide/pharmacology , Leuprolide/therapeutic use , Tumor Necrosis Factor-alpha , Neuroinflammatory Diseases , Rats, Wistar , Immunologic Factors , Anxiety/drug therapy , Anxiety/etiologyABSTRACT
BACKGROUND: The hippocampus is highly vulnerable to damage in the brain ischemia-reperfusion injury model. Leuprolide acetate has been shown to promote neurological recovery after injury in various regions of the central nervous system. OBJECTIVE: The objective of this study was to assess the histology of the hippocampus and the expression of neuronal recovery markers, specifically the 200 kDa neurofilaments and the myelin basic protein, in rats with brain ischemia-reperfusion injury treated with leuprolide acetate. METHODS: The rats were divided into three groups: Sham, ischemia-reperfusion with saline solution, and ischemia-reperfusion treated with leuprolide acetate. Coronal brain slices were obtained and stained with hematoxylin-eosin. The histological analysis involved quantifying the number of neurons in the hippocampal regions CA1, CA3 and DG. The myelin basic protein and neurofilaments were quantified using western blot. RESULTS: The number of neurons in CA1 and DG was significantly higher in the leuprolide acetate group compared to the untreated group. Additionally, the expression of neurofilament and myelin basic protein markers was significantly increased in rats treated with leuprolide acetate compared to the untreated rats. CONCLUSIONS: Leuprolide acetate promotes the recovery of hippocampal neurons in an acute brain ischemia-reperfusion injury model. These findings suggest that leuprolide acetate could be a potential therapeutic intervention for reversing damage in hippocampal ischemic lesions.
Subject(s)
Brain Injuries , Brain Ischemia , Reperfusion Injury , Rats , Animals , Leuprolide/pharmacology , Leuprolide/therapeutic use , Leuprolide/metabolism , Myelin Basic Protein/metabolism , Hippocampus/pathology , Reperfusion Injury/drug therapy , Reperfusion Injury/metabolism , Ischemia/metabolism , Brain Ischemia/pathology , ReperfusionABSTRACT
Background: Leuprolide (LEU), a synthetic nonapeptide analog of naturally occurring gonadotropin-releasing hormone (GnRH), could exert a direct inhibitory activity on the proliferation of prostate cancer cells. However, the short half-life in blood and the biopharmaceutical problem of LEU limit this anticancer activity. Purpose: To improve its druggability for improving anticancer activity, the amine-group targeted LEU was conjugated with different chain lengths of saturated fatty acids (FAs). Methods: LEU-fatty acid conjugates (LFCs) were synthesized by exploiting N-hydroxysuccinimidyl (NHS) conjugation chemistry. The physicochemical properties and the self-assembled behaviors of the conjugates were extensively investigated. The in vitro anticancer activity of three LFCs was extensively studied in both 2D monolayer and 3D spheroid culture models of a prostate cancer cell line, PC3. Results: Three LFCs could be readily self-assembled into nanoparticles (LFNs) with a small size of around 100 nm, positive charges, and exhibited greater permeability rates compared to the same concentration of LEU, excluding LSN. The chain length of FA in conjugate was positively related to the selectivity index between cancer cells and non-cancerous cell lines. All LFCs showed a superior direct antiproliferative effect on cancer cells in the following order: LSC (98.9%) > LPC (86.7%) > LLC (75.0%) > LEU (8.9%) after repeat daily of the same dose strength of LEU for 4 days. In addition, the 3D spheroid model study indicates that all LFCs with a one-time treatment performed a long-acting inhibitory effect on tumor growth as compared to LEU after 7 days. Conclusion: The conjugation of LEU with different chain lengths of FAs could provide a novel strategy to improve peptide stability and exert an additional superior direct inhibitory effect for the treatment of several hormone-responsive tumor systems using therapeutic peptides.
Subject(s)
Biological Products , Prostatic Neoplasms , Male , Humans , Leuprolide/pharmacology , Fatty Acids , Gonadotropin-Releasing Hormone/metabolism , Gonadotropin-Releasing Hormone/pharmacology , Prostatic Neoplasms/drug therapy , Cell Line, TumorABSTRACT
Purpose: Treatment sequelae compromising reproductive health are highly prevalent in childhood cancer survivors, and a main determinant of health and quality of life. Follicular reserve determines ovarian function life span; thus, its preservation is important in the care of female survivors. Anti-Müllerian hormone (AMH) is a biomarker to measure functional ovarian reserve. We aimed to evaluate the effect of leuprolide during gonadotoxic therapy on pubertal females' post-treatment functional ovarian reserve using AMH levels. Methods: We conducted a single-center retrospective study including all pubertal females who had undergone gonadotoxic treatments between January 2010 and April 2020, and had an AMH level after completion of therapy. We used multivariable linear regressions to compare AMH-level beta coefficients in patients stratified by gonadotoxic risk, adjusting for leuprolide use. Results: Fifty-two females meeting study eligibility were included, of which 35 received leuprolide. The use of leuprolide was associated with higher post-treatment AMH levels in the lower gonadotoxic risk group (beta 2.74, 95% CI 0.97-4.51; p = 0.004). This association was lost in the higher gonadotoxic risk groups. Conclusions: Leuprolide may have a protective effect on the functional ovarian reserve. However, this is limited by increasing treatment gonadotoxicity. Larger, prospective studies are needed to elucidate the potential benefits of gonadotropin-releasing hormone agonist on preservation of ovarian reserve among children receiving gonadotoxic therapies, as cancer survivors.
Subject(s)
Leuprolide , Ovarian Reserve , Child , Female , Humans , Adolescent , Leuprolide/pharmacology , Leuprolide/therapeutic use , Retrospective Studies , Quality of Life , Survivors , Anti-Mullerian HormoneABSTRACT
Hypothalamic inflammation is a pathophysiological basis of polycystic ovarian syndrome (PCOS), while overactivated and/or excess M1 polarized microglia are considered to be the main reason for the occurrence of hypothalamic inflammation. Therefore, in vitro and in vivo experiments were performed to assess the relationships between microgliamediated inflammatory reactions and endocrine functions in the PCOS hypothalamus. The expression of gonadotropinreleasing hormone (GnRH) receptor (GnRHR) was demonstrated in hypothalamic microglia, and it was found that low concentration, GnRH agonist, leuprolide acetate accelerated the expression of M2 polarization marker CD206, while high concentration leuprolide acetate increased the expression of M1 polarization marker CD86 in vitro. Furthermore, aerobic exercise not only reduced the levels of serum testosterone, luteinizing hormone and GnRH and the amount of overactivated microglia, but also increased the number of M2 microglia in the hypothalamus of letrozoleinduced PCOS rats. In combination, these results not only demonstrated the expression of GnRHR in hypothalamic microglia, but also demonstrated that GnRH can induce microglial polarization, while aerobic exercise may improve the microgliamediated inflammatory reaction by reducing the expression of GnRHR in the hypothalamic microglia of PCOS rats.
Subject(s)
Polycystic Ovary Syndrome , Female , Humans , Rats , Animals , Polycystic Ovary Syndrome/metabolism , Receptors, LHRH/genetics , Leuprolide/pharmacology , Microglia/metabolism , Gonadotropin-Releasing Hormone/metabolismABSTRACT
BACKGROUND: GnRH agonists have been used to halt the development of puberty in children with precocious puberty since the 1980s. Recently, drugs like Lupron Depot® (leuprolide acetate), have been used to suppress pubertal progression in adolescents who are questioning their gender identity. However, few preclinical studies have been conducted to investigate potential effects of using GnRH agonists in this context. METHODS: The present study tested the effects of daily leuprolide treatment (50 µg/kg, postnatal day (PD) 25-50) on pubertal onset in female (i.e., vaginal opening) and male (i.e., preputial separation) Long-Evans rats. The first estrous cycle immediately after vaginal opening was also measured. Sexual behavior and sexual motivation were tested using the partner-preference paradigm. Female rats were tested during the first behavioral estrus after treatment ended (between PD 51-64). Male rats were tested weekly for four consecutive weeks starting three days after treatment ended (PD 53). RESULTS: Consistent with previous findings, leuprolide significantly delayed pubertal onset in both female and male rats. In addition, the first estrous cycle during the treatment period was disrupted by leuprolide, as indicated by a failure to cycle into estrus after vaginal opening until treatment ended. However, leuprolide affected neither sexual motivation nor fertility when female rats were tested within 14 days of leuprolide treatment ending. In contrast, the development of copulatory behavior and sexual motivation was significantly delayed by leuprolide in male rats; however, mature reproductive behavior was observed by the fourth week post-treatment. CONCLUSIONS: Taken together with previous findings, the present results indicate that male rats may be more sensitive to periadolescent leuprolide administration, taking longer to overcome the effects of leuprolide than female rats. Nevertheless, not long after leuprolide treatment is discontinued, sex-typical reproductive physiology and behavior emerge fully in female and male rats, indicating that the drug's effects are not permanent. If translatable to humans, leuprolide may be a reversible option to give adolescents more time to consider their gender identity with minimal long-term effects on sexual development.
Subject(s)
Leuprolide , Puberty, Precocious , Humans , Child , Rats , Female , Male , Animals , Adolescent , Leuprolide/pharmacology , Leuprolide/therapeutic use , Rats, Long-Evans , Gender Identity , Puberty, Precocious/drug therapy , EstrusABSTRACT
Relugolix (Orgovyx®), an orally active nonpeptide gonadotropin-releasing hormone (GnRH) receptor antagonist that provides rapid testosterone suppression, is indicated in the USA for the treatment of advanced prostate cancer and in the EU for advanced hormone-sensitive prostate cancer. In the pivotal phase III HERO trial in men with advanced prostate cancer, once-daily oral relugolix (with a loading dose on day 1) led to a sustained castration rate over 48 weeks of treatment of >â¯90%, a rate that was non-inferior to that provided by intramuscular leuprolide depot every 3 months (with an exploratory analysis further indicating the superiority of relugolix over leuprolide). Relugolix was generally well tolerated, having an adverse event profile that is consistent with testosterone suppression. Furthermore, there is evidence that relugolix may be associated with a lower risk of major adverse cardiac events compared with leuprolide. With the ability to provide the rapid testosterone suppression (with no initial surge in testosterone upon treatment initiation) combined with the benefits of oral administration and potentially improved cardiac safety, relugolix presents a valuable treatment option for men with advanced prostate cancer where androgen deprivation therapy is indicated.
Androgen deprivation therapy (ADT), a key component of prostate cancer treatment, reduces testosterone production to slow disease progression. Relugolix (Orgovyx®), from a class of drugs known as gonadotropin-releasing hormone (GnRH) receptor antagonists, is approved for the treatment of advanced prostate cancer. Whereas some ADT agents (i.e. GnRH agonists) produce an initial surge in testosterone levels (with the potential to cause a flare in disease symptoms), GnRH receptor antagonists, of which relugolix is the first available as an oral medication, provide rapid testosterone suppression with no initial surge. In a key clinical trial in men with advanced prostate cancer, once-daily relugolix provided sustained castration in >â¯90% of patients, with a sustained castration rate that was non-inferior to that of a comparator agent (leuprolide) administered by intramuscular injection every 3 months. Relugolix was generally well tolerated and may be associated with a lower risk of major adverse cardiac events than leuprolide. Providing rapid and sustained testosterone suppression, combined with the benefits of oral administration and potentially improved cardiac safety, relugolix presents a valuable treatment option for ADT in men with advanced prostate cancer.
Subject(s)
Prostatic Neoplasms , Male , Humans , Prostatic Neoplasms/drug therapy , Leuprolide/pharmacology , Leuprolide/therapeutic use , Gonadotropin-Releasing Hormone/therapeutic use , Androgen Antagonists/therapeutic use , TestosteroneABSTRACT
Adverse social experience during childhood and adolescence leads to developmental alterations in emotional and stress regulation and underlying neurocircuits. We examined the consequences of social subordination (low social rank) in juvenile female rhesus monkeys, as an ethologically valid model of chronic social stressor exposure, on brain structural and behavioral development through the pubertal transition. Adolescence is a developmental period of extensive brain remodeling and increased emotional and stress reactivity. Puberty-induced increases in gonadal hormones, particularly estradiol (E2), are likely involved due to its organizational effects on the brain and behavior. Thus, we also examined how experimentally delaying pubertal onset with Lupron (gonadotropin releasing hormone -GnRH- agonist used clinically to delay early puberty) interacted with social rank (dominant vs. subordinate) to affect brain and behavioral outcomes. Using a longitudinal experimental design, structural MRI (sMRI) scans were collected on socially housed juvenile female rhesus monkeys living in indoor-outdoor enclosures prior to the onset of puberty (18-25 months), defined as menarche or the initial occurrence of perineal swelling and coloration, and again at 29-36 months, when all control animals had reached puberty but none of the Lupron-treated had. We examined the effects of both social rank and pubertal delay on overall structural brain volume (i.e. intracranial, grey matter (GM) and white matter (WM) volumes), as well as on cortico-limbic regions involved in emotion and stress regulation: amygdala (AMYG), hippocampus (HC), and prefrontal cortex (PFC). Measures of stress physiology, social behavior, and emotional reactivity were collected to examine functional correlates of the brain structural effects. Apart from expected developmental effects, subordinates had bigger AMYG volumes than dominant animals, most notably in the right hemisphere, but pubertal delay with Lupron-treatment abolished those differences, suggesting a role of gonadal hormones potentiating the brain structural impact of social stress. Subordinates also had elevated baseline cortisol, indicating activation of stress systems. In general, Lupron-treated subjects had smaller AMYG and HC volume than controls, but larger total PFC (driven by bigger GM volumes), and different, region-specific, developmental patterns dependent on age and social rank. These findings highlight a region-specific effect of E2 on structural development during female adolescence, independent of those due to chronological age. Pubertal delay and AMYG volume, in turn, predicted differences in emotional reactivity and social behavior. These findings suggest that exposure to developmental increases in E2 modifies the consequences of adverse social experience on the volume of cortico-limbic regions involved in emotional and stress regulation during maturation. But, even more importantly, they indicate different brain structural effects of chronological age and pubertal developmental stage in females, which are very difficult to disentangle in human studies. These findings have additional relevance for young girls who experience prolonged pubertal delays or for those whose puberty is clinically arrested by pharmacological administration of Lupron.
Subject(s)
Leuprolide , Puberty, Delayed , Humans , Animals , Adolescent , Female , Macaca mulatta , Leuprolide/pharmacology , Brain , Emotions/physiology , Gray MatterABSTRACT
The thinlip gray mullet (Chelon ramada) belongs to the Mugilidae family, it is a low-trophic, euryhaline species adapted to a wide range of environmental conditions. As such, it represent a candidate to diversify aquaculture production toward more sustainable species. Nonetheless, several bottlenecks have to be overcome before production is undertaken at commercial scale. Indeed, C. ramada mature females do not spawn without hormonal treatments in captivity. This report describes the use of the gonadotropin releasing hormone analog (GnRHa), leuprorelin acetate as an effective single-dose inducer of spawning in this species. Wild mature females (n = 10; 29 ± 1 cm total length, TL and 199 ± 20 g body weight, BW) exhibiting protruded papilla and bulging abdomen, presenting vitellogenic oocytes (diameters higher than 657 µm) and fluent males (n = 21; 28 ± 1 cm TL and 181 ± 80 g BW) were treated with a single injection of leuprorelin acetate. Breeders spawned more than 500,000 eggs with a mean fertilization and hatching rate of 92 ± 3 and 91.4 ± 0.4 %, respectively. Larvae grew according to the equation y = 2.6841e0.044x, mean survival rate at 19 dph was 13.8 ± 1.5 %. Mean SGR% day-1 slightly decreased concomitantly with tail flexion, probably for a greater investment on ontogenic development rather than growth. Present results suggest that mature C. ramada presents easily recognizable reproductive traits, adapts without difficulty to captive conditions, and can be easily induced to spawn administrating a single dose of leuprorelin acetate. The protocol used in our study resulted in high fertilization and hatching rates, as well as promising larval survival minimizing broodstock stress.
Subject(s)
Leuprolide , Smegmamorpha , Male , Female , Animals , Leuprolide/pharmacology , Gonadotropin-Releasing Hormone/pharmacology , Larva , Oocytes , Acetates/pharmacologyABSTRACT
AIMS: To determine if a continuous administration of leuprolide acetate (LA), a synthetic agonist for the gonadotrophin-releasing hormone receptor, facilitates the recovery of urinary function in spinal cord injured male rats. MAIN METHODS: Male Wistar rats were randomized into spinal cord injury (SCI; n = 7), SCI with continuous administration of LA for two weeks via implantation of a subcutaneous osmotic pump (SCI + LA; n = 7), Sham SCI (SH-SCI; n = 6) or no surgery (Intact; n = 6) groups. Micturition, hind-limb nociception and locomotor behaviors were analyzed before and after surgical procedures on days 7, 14, 21 and 28. After behavioral studies, electromyography of the external urethral sphincter (EUS-EMG) and cystometric (CMG) studies were performed in all groups. KEY FINDINGS: SCI significantly decreased frequency of voids and CMG parameters (p < 0.001), abolished the bursting activity of the EUS during CMG, significantly increased hind limb sensory threshold and decreased locomotor performance in comparison to the other groups (p < 0.001). Continuous LA treatment significantly increased the frequency of voids and improved CMG parameters (p < 0.001), exhibiting bursting EUS activity during CMGs, and enhanced locomotor performance in comparison to SCI rats (p < 0.001). SIGNIFICANCE: SCI severely affected behavioral and functional micturition processes, including sensory and locomotor functions. Systemic and uninterrupted treatment with LA improves the recovery of micturition behavior and the synergistic function of the EUS. Furthermore, sensory and locomotor responses were also improved in SCI rats. This procedure may have a therapeutic potential to facilitate urinary function recovery in patients with SCI.
Subject(s)
Spinal Cord Injuries , Urination , Animals , Male , Rats , Leuprolide/pharmacology , Rats, Wistar , Spinal Cord , Spinal Cord Injuries/drug therapy , UrethraABSTRACT
This study aims to develop optimized leuprolide acetate (LA) nanoparticles (NPs) for intranasal delivery in the treatment of Alzheimer's disease. Box-Behnken Design was used to optimize LA polylactide-co-glycolic acid (PLGA) NPs. The independent variables chosen were PLGA concentration, surfactant concentration, and the ratio of water to oil phase, whereas the dependent variables were particle size and % entrapment efficiency. The optimized NPs were evaluated by in vitro drug release study, ex vivo diffusion study, histopathology study, hemolytic stability study, and stability in simulated nasal fluid (SNF). The optimized NPs had particle size of 182.6 ± 1.5 nm, polydispersity index (0.3), % entrapment efficiency (77.3 ± 0.6), and zeta potential (-5.6 mv ±0.2). The in vitro drug release indicated 96% of pure drug release in 6 h, whereas only 66.35% of the drug was released from the optimized formulation at 48 h. The ex vivo diffusion study indicated an apparent permeability coefficient of 5.0 + 0.3 × 104 for drug-containing NPs, which was higher than for plain drug solution (2.0 + 0.2 × 104). Sheep nasal toxicity and hemolytic study proved the safety of formulation. The optimized NPs were found to be stable in SNF. Thus, nanoparticulate formulation of LA was optimized by quality by design approach.
Subject(s)
Nanoparticles , Polyglycolic Acid , Animals , Drug Carriers , Lactic Acid , Leuprolide/pharmacology , Polylactic Acid-Polyglycolic Acid Copolymer , SheepABSTRACT
The present study examined the long-term effects of suppressing puberty with a GnRH agonist on reproductive physiology and behavior in female rats. We have recently reported that administration of the GnRH agonist leuprolide acetate (25 µg/kg) daily between postnatal day (PD) 25-50 delayed puberty and disrupted the development of copulatory behavior and sexual motivation in male rats. However, pilot data from our lab suggest that this low dose of leuprolide acetate (25 µg/kg) was not high enough to significantly delay puberty in female rats. Therefore, we injected female Long-Evans rats with leuprolide acetate at a higher dose (50 µg/kg) or 0.9% sterile saline, daily , starting on PD 25 and ending on PD 50. Vaginal opening was monitored daily starting on PD 30 for signs of pubertal onset and first estrous cycle. In addition, we measured estrous cyclicity starting approximately 2 weeks after the last injection of leuprolide (â¼PD 64). Immediately after monitoring estrous cyclicity, the female rats were mated on their first day in behavioral estrus using the partner-preference paradigm, with and without physical contact (PD 95-110). We found that this dose of leuprolide (50 µg/kg) significantly delayed puberty; however, neither estrous cyclicity nor sexual motivation was significantly affected by periadolescent exposure to leuprolide. Together with our findings in male rats, these results add to our understanding of the developmental effects of chemically suppressing puberty in rats.
Subject(s)
Estrous Cycle , Fertility Agents, Female , Leuprolide , Sexual Behavior, Animal , Sexual Maturation , Animals , Estrous Cycle/drug effects , Estrous Cycle/physiology , Estrus , Female , Fertility Agents, Female/pharmacology , Gonadotropin-Releasing Hormone/agonists , Leuprolide/pharmacology , Models, Animal , Periodicity , Rats , Rats, Long-Evans , Sexual Behavior, Animal/drug effects , Sexual Behavior, Animal/physiology , Sexual Maturation/drug effects , Sexual Maturation/physiologyABSTRACT
Importance: With a growing interest in the use of real-world evidence for regulatory decision-making, it is important to understand whether real-world data can be used to emulate the results of randomized clinical trials. Objective: To use electronic health record and administrative claims data to emulate the ongoing PRONOUNCE trial (A Trial Comparing Cardiovascular Safety of Degarelix Versus Leuprolide in Patients With Advanced Prostate Cancer and Cardiovascular Disease). Design, Setting, and Participants: This retrospective, propensity-matched cohort study included adult men with a diagnosis of prostate cancer and cardiovascular disease who initiated either degarelix or leuprolide between December 24, 2008, and June 30, 2019. Participants were commercially insured individuals and Medicare Advantage beneficiaries included in a large US administrative claims database. Exposures: Degarelix or leuprolide. Main Outcomes and Measures: The primary end point was time to first occurrence of a major adverse cardiovascular event (MACE), defined as death due to any cause, myocardial infarction, or stroke, analogous to the PRONOUNCE trial. Secondary end points were time to death due to any cause, myocardial infarction, stroke, and angina. Cox proportional hazards regression was used to evaluate primary and secondary end points. Results: A total of 32â¯172 men initiated degarelix or leuprolide for prostate cancer; of them, 9490 (29.5%) had cardiovascular disease, and 7800 (24.2%) met the PRONOUNCE trial eligibility criteria and were included in this study. Overall, 165 participants (2.1%) were Asian, 1390 (17.8%) were Black, 663 (8.5%) were Hispanic, and 5258 (67.4%) were White. The mean (SD) age was 74.4 (7.4) years. Among 2226 propensity score-matched patients, no significant difference was observed in the risk of MACE for patients taking degarelix vs those taking leuprolide (10.18 vs 8.60 events per 100 person-years; hazard ratio [HR], 1.18; 95% CI, 0.86-1.61). Degarelix was associated with a higher risk of death from any cause (HR, 1.48; 95% CI, 1.01-2.18) but not of myocardial infarction (HR, 1.16; 95% CI, 0.60-2.25), stroke (HR, 0.92; 95% CI, 0.45-1.85), or angina (HR, 1.36; 95% CI, 0.43-4.27). Conclusions and Relevance: In this emulation of a clinical trial of men with cardiovascular disease undergoing treatment for prostate cancer, degarelix was not associated with a lower risk of cardiovascular events than leuprolide. Comparison of these data with PRONOUNCE trial results, when published, will help enhance our understanding of the appropriate role of using real-world data to emulate clinical trials.
Subject(s)
Antineoplastic Agents, Hormonal/pharmacology , Antineoplastic Agents, Hormonal/therapeutic use , Leuprolide/pharmacology , Leuprolide/therapeutic use , Oligopeptides/pharmacology , Oligopeptides/therapeutic use , Prostatic Neoplasms/drug therapy , Aged , Aged, 80 and over , Cohort Studies , Humans , Male , Treatment Outcome , United StatesABSTRACT
BACKGROUND: GnRH analogs are widely used as neoadjuvant agents for radiotherapy in prostate cancer (PCa) patients, with well-documented effects in reducing tumor bulk and increasing progression-free survival. GnRH analogs act locally in the prostate by triggering apoptosis of PCa cells via activation of the GnRH receptor (GnRHR). During PCa progression, the distribution of GnRHR within the cell is altered, with reduced expression in the cell membrane and remaining sequestered in the endoplasmic reticulum. Pharmacoperone IN3 is able to relocalize GnRHR to the cell membrane. The aim of this study was to evaluate the effect of radiation on PCa cells pretreated with leuprolide, alone or in combination with IN3, as radiosensitizers. MATERIAL AND METHODS: PC3 and human PCa primary cell cultures were treated with IN3 for 24 h, followed by different doses of leuprolide for 48 h and, finally, single doses of radiation (3, 6, and 9 Gy). After radiation, cell survival, apoptosis, cell cycle distribution, and colony growth were evaluated. RESULTS: Radiation reduced cell survival and increased apoptosis in a dose-dependent manner. This effect was also directly related to leuprolide concentration. Pretreatment with IN3 enhanced apoptosis and decreased cell survival, also observing a higher proportion of cells arrested in G2. CONCLUSION: Neoadjuvant leuprolide increases radiation-mediated apoptosis of PCa cells. This effect was enhanced by pretreatment with pharmacoperone IN3. Clinical use of IN3 as a radiosensitizer combined with androgen deprivation therapy to improve survival of patients with PCa remains to be evaluated.
Subject(s)
Prostatic Neoplasms , Androgen Antagonists , Gonadotropin-Releasing Hormone , Humans , Leuprolide/pharmacology , Male , Prostate , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/radiotherapy , Radiation-Sensitizing Agents/pharmacology , Receptors, LHRHABSTRACT
BACKGROUND AND OBJECTIVES: Puberty onset and development contribute substantially to adolescents' bone mass and body composition. Our objective with this study was to examine the effects of gonadotropin-releasing hormone agonists (GnRHa) on these puberty-induced changes among youth with gender dysphoria (GD). METHODS: Medical records of the endocrine diversity clinic in an academic children's hospital were reviewed for youth with GD seen from January 2006 to April 2017 with at least 1 baseline dual-energy radiograph absorptiometry measurement. RESULTS: At baseline, transgender females had lower lumbar spine (LS) and left total hip (LTH) areal bone mineral density (aBMD) and LS bone mineral apparent density (BMAD) z scores. Only 44.7% of transgender youth were vitamin D sufficient. Baseline vitamin D status was associated with LS, LTH aBMD, and LS BMAD z scores. Post-GnRHa assessments revealed a significant drop in LS and LTH aBMD z scores (transgender males and transgender females) without fractures and LS BMAD (transgender males), an increase in gynoid (fat percentage), and android (fat percentage) (transgender males and transgender females), and no changes in BMI z score. CONCLUSIONS: GnRHa monotherapy negatively affected bone mineral density of youth with GD without evidence of fractures or changes in BMI z score. Transgender youth body fat redistribution (android versus gynoid) were in keeping with their affirmed gender. The majority of transgender youth had vitamin D insufficiency or deficiency with baseline status associated with bone mineral density. Vitamin D supplementation should be considered for all youth with GD.