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OBJECTIVES: To observe the therapeutic efficacy of high-intensity focused ultrasound (HIFU) combined with different pharmacological treatments for adenomyosis. MATERIALS AND METHODS: A total of 126 patients with adenomyosis who underwent HIFU combined with pharmacological treatment were retrospectively reviewed. Patients were treated with either dienogest (DNG) (Group A, N = 38) or GnRH-a (Group B, N = 88) for three months after HIFU, and received levonorgestrel-releasing intrauterine systems (LNG-IUS) at the end of the third month. Visual Analog Scale (VAS) and Pictorial Blood Loss Assessment Chart (PBAC) scores were used for evaluating symptom improvement. RESULTS: After propensity score matching (1:2), 38 patients were included in Group A and 76 in Group B. All patients showed significant improvement in VAS and PBAC scores after HIFU, but the PBAC score of Group A was significantly higher than that of patients in Group B at 18 months [11.50 (1.00, 29.50) vs. 0.00 (0.00, 16.50), p < 0.01] and 24 months [4.00 (0.25, 27.75) vs. 0.00 (0.00, 12.75), p = 0.04] after HIFU. Furthermore, patients in Group B had a greater uterine volume reduction at 24 months after HIFU than that of patients in Group A [51.00 (27.00, 62.00) vs. 30.00 (17.00, 42.75, p = 0.02)]. However, the adverse effects in Group A were lower than those in Group B [7 (15.79) vs. 35 (46.05), p < 0.01]. No significant difference was observed in the recurrence rate between the two groups. CONCLUSIONS: HIFU combined with DNG and LNG-IUS is a safe and effective treatment for patients with adenomyosis.
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Adenomiosis , Ultrasonido Enfocado de Alta Intensidad de Ablación , Humanos , Femenino , Adenomiosis/terapia , Adenomiosis/tratamiento farmacológico , Adenomiosis/cirugía , Ultrasonido Enfocado de Alta Intensidad de Ablación/métodos , Adulto , Persona de Mediana Edad , Hormona Liberadora de Gonadotropina/uso terapéutico , Estudios Retrospectivos , Nandrolona/análogos & derivados , Nandrolona/uso terapéutico , Nandrolona/farmacología , Terapia Combinada/métodos , Levonorgestrel/uso terapéutico , Levonorgestrel/administración & dosificación , Resultado del TratamientoRESUMEN
BACKGROUND: The hypothalamic-pituitary-gonadal (HPG) axis is pivotal in regulating reproductive functions, with gonadotropin-releasing hormone (GnRH) acting as a central regulator. Recently, polyamines have been shown to regulate the HPG axis, including GnRH expression and ovarian biology in old and adult rodents. The present study firstly highlights the age-specific variation in the polyamine and their corresponding biosynthetic enzymes in the ovary during aging, and further, the study focuses on the effect of polyamines, putrescine, and agmatine, in young female mice. METHOD AND RESULT: Immunofluorescence analysis revealed age-related differences in the expression of ornithine decarboxylase 1 (ODC1), spermine (SPM), and spermidine (SPD) in the ovaries, with adult mice exhibiting significantly higher expression levels compared to young and old mice. Likewise, qPCR analysis showed the mRNA levels of Odc1, Spermidine synthase (Srm), and Spermine synthase (Sms) show a significant increase in adult ovaries, which is then followed by a significant decline in old age. Histological examination demonstrated morphological alterations in the ovaries with age, including decreased follicle numbers and increased stromal cells in old mice. Furthermore, treatment with putrescine, a polyamine, in young mice resulted in larger ovaries and increased follicle numbers compared to controls. Additionally, serum levels of gonadotropin-releasing hormone (GnRH) and progesterone (P4) were measured, showing elevated levels in polyamine-treated mice. GnRH mRNA expression also increased significantly. Gene expression analysis revealed upregulation of genes associated with folliculogenesis such as Fshr, Bmp15, Gdf9, Amh, Star, Hsdb3, and Plaur in the ovaries and onset of puberty such as Tac2, and Kiss1, and a decrease in Mkrn3 in the hypothalamus of polyamine-treated mice. CONCLUSION: This study investigates the effect of polyamines in young immature female mice, shedding light on their role in upregulating GnRH, and enhancing folliculogenesis. Overall, these findings suggest that polyamines play a crucial role in ovarian aging and HPG axis regulation, offering potential therapeutics to reinstate fertility in reproductively challenged individuals.
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Hormona Liberadora de Gonadotropina , Maduración Sexual , Animales , Femenino , Hormona Liberadora de Gonadotropina/farmacología , Hormona Liberadora de Gonadotropina/metabolismo , Ratones , Maduración Sexual/efectos de los fármacos , Folículo Ovárico/efectos de los fármacos , Folículo Ovárico/metabolismo , Poliaminas/metabolismo , Envejecimiento , Ovario/efectos de los fármacos , Ovario/metabolismo , Regulación de la Expresión Génica/efectos de los fármacosRESUMEN
Context Understanding of central nervous system mechanisms related to age-related infertility remains limited. Fibril α-synuclein, distinct from its monomer form, is implicated in age-related diseases and propagates among neurons akin to prions. Aims We compared α-synuclein expression in gonadotropin-releasing hormone-expressing neurons (GnRH neurons) in the pre-optic area, arcuate nucleus, and median eminence of healthy heifers and aged cows to determine its role in age-related infertility. Methods We analysed mRNA and protein expression, along with fluorescent immunohistochemistry for GnRH and α-synuclein, followed by Congo red staining to detect amyloid deposits, and confocal microscopy. Key results Both mRNA and protein expressions of α-synuclein were confirmed by reverse transcription-polymerase chain reaction (RT-PCR) and western blots in bovine cortex, hippocampus, and anterior and posterior hypothalamus tissues. Significant differences in α-synuclein mRNA expression were observed in the cortex and hippocampus between young and old cows. Western blots showed five bands of α-synuclein, probably reflecting monomer, dimer, and oligomers, in the cortex, hippocampus, hypothalamus tissues, and there were significant differences in some bands between young and old cows. Bright-field and polarised light microscopy did not detect obvious amyloid deposition in aged hypothalami; however, higher-sensitive confocal microscopy unveiled strong positive signal of Congo red and α-synuclein in GnRH neurons in aged hypothalami. Additionally, α-synuclein expression was detected in immortalised GnRH neurons, GT1-7 cells. Conclusion Alpha-synuclein was expressed in GnRH neurons, and some differences were observed between young and old hypothalami. Implications Alpha-synuclein may play an important role in aging-related infertility.
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Envejecimiento , Hormona Liberadora de Gonadotropina , Hipotálamo , Neuronas , alfa-Sinucleína , Animales , Hormona Liberadora de Gonadotropina/metabolismo , Hormona Liberadora de Gonadotropina/genética , Bovinos , alfa-Sinucleína/metabolismo , alfa-Sinucleína/genética , Neuronas/metabolismo , Hipotálamo/metabolismo , Femenino , Envejecimiento/metabolismo , ARN Mensajero/metabolismoRESUMEN
BACKGROUND: Around 4% of women receive an endometrial cancer diagnosis before turning 40, mainly those without prior childbirth experience and a strong desire to preserve their ability to conceive. Consequently, for young patients diagnosed with atypical endometrial hyperplasia (AEH) or early endometrial carcinoma (EC), a fertility-preserving approach employing high-dose oral progesterone has been adopted. However, previous research has shown a notable relapse rate. Furthermore, the extended use of substantial oral progesterone doses may hinder ovarian function and raise the risk of weight gain, liver issues, blood clotting, and breast cancer. We previously assessed the clinical effectiveness and pregnancy outcomes of gonadotropin-releasing hormone agonist (GnRH-a) based re-treatment for women with EC and AEH who did not respond to oral progestin therapy but achieved favorable treatment results and reproductive outcomes. METHODS: This study will be an open-label, two-armed, randomized, investigator-initiated multicenter trial evaluating the combination of GnRH-a with the levonorgestrel-releasing intrauterine system or the combination of GnRH-a with an aromatase inhibitor (comprising a subcutaneous GnRH-a injection every 4 weeks and daily oral letrozole 2.5 mg). A total of 226 participants will be randomly allocated to one of the two treatment groups in a 1:1 ratio. The primary objective is to determine the effectiveness of GnRH-a-based re-treatment in achieving a complete response (CR) at 24 weeks for patients with AEH or EC. Secondary objectives include assessing the pregnancy rate 12 weeks after treatment, as well as post-treatment pregnancy outcomes and the rate of recurrence. ETHICS AND DISSEMINATION: The protocol received approval from the Institutional Review Board of Peking Union Medical College Hospital and from boards at five other institutions. The trial will adhere to the principles outlined in the World Medical Association's Declaration of Helsinki and follow Good Clinical Practice standards. The trial results will be disseminated through publication in a peer-reviewed journal. CONCLUSIONS: Prospective evidence supporting conservative treatment for EC and AEH is limited. There is a need for new approaches that can achieve higher CR rates with fewer side effects. This trial will assess the effectiveness of GnRH-a-based fertility-sparing treatment in obese women and recurrent patients, offering a promising alternative for patients with EC and AEH. TRIAL REGISTRATION NUMBER: Chinese Clinical Trial Registry ChiCTR2200067099. Registered on December 27, 2022.
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Hiperplasia Endometrial , Neoplasias Endometriales , Preservación de la Fertilidad , Hormona Liberadora de Gonadotropina , Levonorgestrel , Estudios Multicéntricos como Asunto , Ensayos Clínicos Controlados Aleatorios como Asunto , Humanos , Femenino , Hormona Liberadora de Gonadotropina/agonistas , Hiperplasia Endometrial/tratamiento farmacológico , Hiperplasia Endometrial/complicaciones , Neoplasias Endometriales/tratamiento farmacológico , Preservación de la Fertilidad/métodos , Embarazo , Levonorgestrel/administración & dosificación , Levonorgestrel/efectos adversos , Levonorgestrel/uso terapéutico , Inhibidores de la Aromatasa/uso terapéutico , Inhibidores de la Aromatasa/efectos adversos , Inhibidores de la Aromatasa/administración & dosificación , Dispositivos Intrauterinos Medicados , Resultado del Tratamiento , Adulto , Antineoplásicos Hormonales/uso terapéutico , Antineoplásicos Hormonales/efectos adversos , Antineoplásicos Hormonales/administración & dosificación , Letrozol/administración & dosificación , Letrozol/uso terapéutico , China , Índice de EmbarazoRESUMEN
Introduction: This study compared, in high responders undergoing IVF treatment, GnRH agonist-only trigger and dual trigger on oocyte retrieval rate and cumulative live birth rate (LBR). The aim was to determine if the GnRH agonist-only triggers had provided outcomes comparable to dual trigger, while minimizing the risk of ovarian hyperstimulation syndrome (OHSS). Materials and methods: A retrospective, matched case-control study was conducted at Taichung Veterans General Hospital, Taiwan, including women who underwent IVF/ICSI between January 1, 2014, and December 31, 2022. Inclusion criteria were: GnRH antagonist protocol and estrogen level >3,000 pg/ml on trigger day. Exclusion criteria were: immune/metabolic diseases, donated oocytes, and mixed stimulation cycles. Propensity score matching was applied to balance age, AMH level, and oocyte number between the GnRH agonist-only and dual trigger groups. Outcomes were analyzed for patients who had complete treatment cycles, focusing on oocyte retrieval rate and cumulative LBR. Results: We analyzed 116 cycles in the agonist-only group, and 232 cycles in the dual trigger group. No inter-group difference was found in their age, BMI, and AMH levels. The dual trigger group had a higher oocyte retrieval rate (93% vs. 80%; p <0.05), while fertilization rates, blastocyst formation rates, and cumulative LBR were comparable. Notably, no OHSS cases had been reported in the GnRH agonist-only group, compared with 7 cases in the dual trigger group. Conclusion: GnRH agonist-only triggers resulted in a lower oocyte retrieval rate compared to dual triggers but did not significantly affect cumulative LBR in high responders. This approach effectively reduces OHSS risk without compromising pregnancy outcomes, making it a preferable option in freeze-all strategies, despite a longer oocyte pick-up duration and a medium cost. GnRH agonist-only trigger, however, may not be suitable for fresh embryo transfers or patients with low serum LH levels on trigger day.
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Tasa de Natalidad , Fertilización In Vitro , Hormona Liberadora de Gonadotropina , Recuperación del Oocito , Síndrome de Hiperestimulación Ovárica , Inducción de la Ovulación , Humanos , Femenino , Hormona Liberadora de Gonadotropina/agonistas , Hormona Liberadora de Gonadotropina/antagonistas & inhibidores , Adulto , Recuperación del Oocito/métodos , Inducción de la Ovulación/métodos , Estudios Retrospectivos , Embarazo , Estudios de Casos y Controles , Fertilización In Vitro/métodos , Síndrome de Hiperestimulación Ovárica/prevención & control , Síndrome de Hiperestimulación Ovárica/epidemiología , Nacimiento Vivo/epidemiología , Índice de Embarazo , Fármacos para la Fertilidad Femenina/uso terapéutico , Fármacos para la Fertilidad Femenina/administración & dosificación , Taiwán/epidemiología , Inyecciones de Esperma Intracitoplasmáticas/métodosRESUMEN
The gonadotropin-releasing hormone (GnRH) receptor (GnRH-R) is highly expressed in ovarian cancer cells (OCC), and it is an important molecular target for cancer therapeutics. To develop a new class of drugs targeting OCC, we designed and synthesized Con-3 and Con-7 which are novel high-affinity GnRH-R agonists, covalently coupled through a disulfide bond to the DNA synthesis inhibitor mitoxantrone. We hypothesized that Con-3 and Con-7 binding to the GnRH-R of OCC would expose the conjugated mitoxantrone to the cellular thioredoxin, which reduces the disulfide bond of Con-3 and Con-7. The subsequent release of mitoxantrone leads to its intracellular accumulation, thus exerting its cytotoxic effects. To test this hypothesis, we determined the cytotoxic effects of Con-3 and Con-7 using the SKOV-3 human OCC. Treatment with Con-3 and Con-7, but not with their unconjugated GnRH counterparts, resulted in the accumulation of mitoxantrone within the SKOV-3 cells, increased their apoptosis, and reduced their proliferation, in a dose- and time-dependent manner, with half-maximal inhibitory concentrations of 0.6-0.9 µM. It is concluded that Con-3 and Con-7 act as cytotoxic "prodrugs" in which mitoxantrone is delivered in a GnRH-R-specific manner and constitute a new class of lead compounds for use as anticancer drugs targeting ovarian tumors.
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Apoptosis , Proliferación Celular , Hormona Liberadora de Gonadotropina , Mitoxantrona , Neoplasias Ováricas , Receptores LHRH , Humanos , Mitoxantrona/farmacología , Mitoxantrona/química , Femenino , Hormona Liberadora de Gonadotropina/farmacología , Hormona Liberadora de Gonadotropina/química , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Apoptosis/efectos de los fármacos , Receptores LHRH/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/química , Supervivencia Celular/efectos de los fármacosRESUMEN
There has been an alarming trend toward earlier puberty in girls, suggesting the influence of an environmental factor(s). As the reactivation of the reproductive axis during puberty is thought to be mediated by the hypothalamic neuropeptides kisspeptin and gonadotropin-releasing hormone (GnRH), we asked whether an environmental compound might activate the kisspeptin (KISS1R) or GnRH receptor (GnRHR). We used GnRHR or KISS1R-expressing HEK293 cells to screen the Tox21 10K compound library, a compendium of pharmaceuticals and environmental compounds, for GnRHR and KISS1R activation. Agonists were identified using Ca2+ flux and phosphorylated extracellularly regulated kinase (p-ERK) detection assays. Follow-up studies included measurement of genes known to be upregulated upon receptor activation using relevant murine or human cell lines and molecular docking simulation. Musk ambrette was identified as a KISS1R agonist, and treatment with musk ambrette led to increased expression of Gnrh1 in murine and human hypothalamic cells and expansion of GnRH neuronal area in developing zebrafish larvae. Molecular docking demonstrated that musk ambrette interacts with the His309, Gln122, and Gln123 residues of the KISS1R. A group of cholinergic agonists with structures similar to methacholine was identified as GnRHR agonists. When applied to murine gonadotrope cells, these agonists upregulated Fos, Jun, and/or Egr1. Molecular docking revealed a potential interaction between GnRHR and 5 agonists, with Asn305 constituting the most conservative GnRHR binding site. In summary, using a Tox21 10K compound library screen combined with cellular, molecular, and structural biology techniques, we have identified novel environmental agents that may activate the human KISS1R or GnRHR.
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Receptores de Kisspeptina-1 , Receptores LHRH , Humanos , Femenino , Animales , Receptores de Kisspeptina-1/metabolismo , Receptores de Kisspeptina-1/genética , Receptores LHRH/metabolismo , Receptores LHRH/genética , Ratones , Células HEK293 , Pez Cebra , Hormona Liberadora de Gonadotropina/metabolismo , Pubertad/efectos de los fármacos , Hipotálamo/metabolismo , Hipotálamo/efectos de los fármacos , Simulación del Acoplamiento Molecular , Maduración Sexual/efectos de los fármacos , Maduración Sexual/fisiología , Kisspeptinas/metabolismo , Kisspeptinas/genética , Contaminantes Ambientales/toxicidad , Contaminantes Ambientales/farmacologíaRESUMEN
This study hypothesized that SCFA, acetate impacts positively on hypothalamic pyroptosis and its related abnormalities in experimentally induced PCOS rat model, possibly through NrF2/HIF1-α modulation. Eight-week-old female Wister rats were divided into groups (n = 5), namely control, PCOS, acetate and PCOS + acetate groups. Induction of PCOS was performed by administering 1 mg/kg body weight of letrozole for 21 days. After PCOS confirmation, the animals were treated with 200 mg/kg of acetate for 6 weeks. Rats with PCOS were characterized with insulin resistance, leptin resistance, increased plasma testosterone as well as degenerated ovarian follicles. There was also a significant increase in hypothalamic triglyceride level, triglyceride-glucose index, inflammatory biomarkers (SDF-1 and NF-kB) and caspase-6 as well as plasma LH and triglyceride. A decrease was observed in plasma adiponectin, GnRH, FSH, and hypothalamic GABA with severe inflammasome expression in PCOS rats. These were accompanied by decreased level of NrF2/HIF1-α, and the alterations were reversed when treated with acetate. Collectively, the present results suggest the therapeutic impact of acetate on hypothalamic pyroptosis and its related comorbidity in PCOS, a beneficial effect that is accompanied by modulation of NrF2/HIF1-α.
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Hipotálamo , Subunidad alfa del Factor 1 Inducible por Hipoxia , Síndrome del Ovario Poliquístico , Piroptosis , Ratas Wistar , Síndrome del Ovario Poliquístico/inducido químicamente , Síndrome del Ovario Poliquístico/metabolismo , Síndrome del Ovario Poliquístico/tratamiento farmacológico , Síndrome del Ovario Poliquístico/patología , Femenino , Animales , Hipotálamo/metabolismo , Hipotálamo/efectos de los fármacos , Hipotálamo/patología , Piroptosis/efectos de los fármacos , Ratas , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Resistencia a la Insulina , Factor 2 Relacionado con NF-E2/metabolismo , Modelos Animales de Enfermedad , Letrozol/farmacología , Triglicéridos/sangre , Triglicéridos/metabolismo , Hormona Luteinizante/sangre , Hormona Folículo Estimulante/sangre , Adiponectina/metabolismo , Adiponectina/sangre , Testosterona/sangre , Leptina/sangre , Leptina/metabolismo , Hormona Liberadora de Gonadotropina/metabolismo , Ácido gamma-Aminobutírico/metabolismoRESUMEN
To investigate the effects of pretreatment with long-acting gonadotropin-releasing hormone agonist (GnRH-a) before frozen-thawed embryo transfer (FET) on pregnancy outcomes in patients after minimal-mild (stages I-II) peritoneal endometriosis surgery. A retrospective cohort study was performed from March 2018 to May 2019. Overall, 274 patients met inclusion criteria of undergoing FET after minimal/mild peritoneal endometriosis surgery. For the FET protocol, patients were divided into 2 groups: GnRH-a plus hormone replacement therapy (HRT) (group A, nâ =â 154) and HRT-only (group B, nâ =â 120), with the former divided into 2 subgroups receiving 1 (group A1, nâ =â 80) or 2 doses (group A2, nâ =â 74) of GnRH-a. Basic characteristics and pregnancy outcomes of groups A and B and groups A1 and A2 were compared. Clinical pregnancy rate (CPR) and live birth rate (LBR) were the primary outcomes and logistic regression was used to analyze independent correlation factors. The CPR and LBR in group A were 58.4% and 50.0%, respectively, and were not significantly higher than in group B (49.2% and 40.0%; respectively, χ2â =â 2.339, Pâ =â .126 and χ2â =â 2.719, Pâ =â .099, respectively). CPR and LBR in group A1 were not significantly lower than those in group A2 (52.5% and 45.0% vs 64.9% and 55.4%, respectively; χ2â =â 2.420, Pâ =â .120 and χ2â =â 1.665, Pâ =â .197, respectively). However, group A2's CPR and LBR were significantly higher than group B's (64.9% and 55.4% vs 49.2% and 40.0%, respectively; χ2â =â 4.560, Pâ =â .023 and χ2â =â 4.375, Pâ =â .026, respectively). Logistic regression analysis showed that GnRH-a pretreatment (1 or 2 doses) had no significant effect on CPR and LBR compared with the HRT-only group. Patients with minimal-mild (stages I-II) peritoneal endometriosis surgery may not require GnRH-a pretreatment before FET.
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Transferencia de Embrión , Endometriosis , Hormona Liberadora de Gonadotropina , Resultado del Embarazo , Humanos , Femenino , Endometriosis/tratamiento farmacológico , Endometriosis/cirugía , Embarazo , Estudios Retrospectivos , Adulto , Transferencia de Embrión/métodos , Hormona Liberadora de Gonadotropina/agonistas , Índice de Embarazo , Terapia de Reemplazo de Hormonas/métodos , Enfermedades PeritonealesRESUMEN
The objective of the study was to compare the effectiveness of CIDR vs. PRID-Delta devices for use in a 5-day Ovsynch protocol for TAI in lactating Holstein cows that were either not in estrus after the end of the voluntary waiting period or non-pregnant and not returning to estrus following the previous AI. Cows fitted with a collar-mounted automated activity monitoring system (Alta Cow Watch) were subjected to a standard 5-d Ovsynch protocol [100 µg of gonadorelin (GnRH) on Day 0 and 500 µg of cloprostenol on Days 5 and 6] and allocated randomly to receive either an intravaginal device containing 1.35 g (CIDR; n = 304) or 1.55 g (PRID ® DELTA; n = 304) of progesterone between Day 0 and 5. All cows received a second administration of GnRH at approximately 56 h and timed-AI (TAI) 72 h after intravaginal device removal. Inseminations were done using conventional frozen-thawed semen. Estrus events prior to TAI were recorded and transrectal ultrasonography was done on Day 0 to determine presence of a corpus luteum (CL) and 33 and 61 d post-TAI, respectively, to diagnose and confirm pregnancy. Cows had an average of 2.2 lactations, 124.3 days in milk, and a milk yield of 43.6 kg/d at enrollment. The overall percentage of cows with a CL at initiation of treatment was 68.8 % and did not differ between treatment groups. Cows with a CL had greater pregnancy per AI (P/AI) at 33 and 61 d post-TAI than cows without a CL (P < 0.01; 46.9 and 42.3 % vs. 32.1 and 27.4 %, respectively). The overall percentage of cows that expressed estrus prior to TAI was 24.8 % and did not differ between treatment groups; however, estrus expression prior to TAI affected P/AI at 33 and 61 d post-TAI (P < 0.01; 53.6 and 49.0 % vs. 38.5 and 33.9 % for those expressing or not expressing estrus, respectively). Pregnancy per AI at 33 d post-TAI tended to differ between treatment groups (P = 0.08; 46.1 vs. 38.5 % for PRID and CIDR groups, respectively) and P/AI at 61 d post-TAI was greater (P < 0.01) for PRID-treated cows (43.8 %) compared to CIDR-treated cows (31.6 %). Thus, PRID-treated cows had lower pregnancy loss than CIDR-treated cows (P < 0.01; 5.0 vs. 17.9 %). Also, treatment with a PRID tended (P = 0.08) to result in fewer twin pregnancies (7.9 vs. 14.5 % for PRID and CIDR treated cows, respectively). In conclusion, lactating dairy cows subjected to a 5-d Ovsynch TAI protocol plus a PRID-Delta had greater P/AI at 61 d post-TAI, lower pregnancy loss between 33 and 61 d post-TAI, and fewer twin pregnancies compared to cows subjected to a 5-d Ovsynch protocol plus a CIDR.
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Sincronización del Estro , Hormona Liberadora de Gonadotropina , Inseminación Artificial , Lactancia , Progesterona , Animales , Bovinos/fisiología , Femenino , Inseminación Artificial/veterinaria , Inseminación Artificial/métodos , Sincronización del Estro/métodos , Hormona Liberadora de Gonadotropina/farmacología , Hormona Liberadora de Gonadotropina/administración & dosificación , Progesterona/administración & dosificación , Progesterona/farmacología , Embarazo , Administración IntravaginalRESUMEN
PURPOSE: This study aimed to examine the correlation between different dominant follicle proportions (DFPs) and outcomes of in-vitro fertilization or intracytoplasmic sperm injection (IVF/ICSI) among patients classified under POSEIDON Groups 3 and 4, who underwent gonadotropin-releasing hormone antagonist (GnRH-ant) protocols. Additionally, it sought to determine the optimal DFP threshold for trigger timing. METHODS: A retrospective analysis was performed on patients classified under POSEIDON Groups 3 (n = 593) and 4 (n = 563) who underwent GnRH-ant protocols for controlled ovarian hyperstimulation (COH) between 2016 and 2022. These patients were categorized into two groups based on their DFPs, defined as the ratio of ≥ 18-mm dominant follicles to ≥ 12-mm follicles on the trigger day (DFP ≤ 40% and DFP ≥ 40%). Statistical analyses, including restricted cubic spline (RCS) and multivariate logistic regression, were employed to assess the relationship between DFP and IVF/ICSI outcomes. RESULTS: Demographic characteristics of patients were similar across groups. In POSEIDON Groups 3 and 4, DFP > 40 was associated with a significant decrease in the number (No.) of oocytes retrieved, cleaved embryos, and available embryos. Moreover, following the GnRH-ant cycle, the clinical pregnancy and live birth rates in fresh embryo transfer (ET) were notably reduced in the DFP > 40 group compared with the DFP ≤ 40 group, whereas no significant differences were observed in the pregnancy outcomes of the first frozen-thawed embryo transfer (FET) between the groups. In POSEIDON Group 3, the cumulative clinical pregnancy rate (CCPR) and cumulative live birth rate (CLRB) were significantly higher in the DFP ≤ 40 subgroup than in the DFP > 40 subgroup, with a notable decrease in CLRB observed with increasing DFP levels. However, in POSEIDON Group 4, no significant differences in CCPR and CLRB were found between the groups. Logistic regression analysis identified age and the No. of oocytes retrieved as pivotal factors influencing CLRB in Group 4. CONCLUSION: For patients in POSEIDON Group 3, maintaining a DFP ≤ 40 mm is crucial to achieve optimal laboratory and pregnancy outcomes by avoiding delayed triggering. However, for patients in POSEIDON Group 4, age remains a critical factor influencing CLRB regardless of DFP, although a higher No. of oocytes retrieved and available embryos with DFP ≤ 40 is beneficial.
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Fertilización In Vitro , Hormona Liberadora de Gonadotropina , Folículo Ovárico , Inducción de la Ovulación , Inyecciones de Esperma Intracitoplasmáticas , Humanos , Femenino , Hormona Liberadora de Gonadotropina/antagonistas & inhibidores , Estudios Retrospectivos , Adulto , Inyecciones de Esperma Intracitoplasmáticas/métodos , Embarazo , Fertilización In Vitro/métodos , Folículo Ovárico/efectos de los fármacos , Inducción de la Ovulación/métodos , Índice de Embarazo , Pronóstico , Antagonistas de Hormonas/uso terapéutico , Resultado del EmbarazoRESUMEN
Adenomyosis, endometriosis of the uterus, is associated with an increased likelihood of abnormal endometrial molecular expressions thought to impair implantation and early embryo development, resulting in disrupted fertility, including the local effects of sex steroid and pituitary hormones, immune responses, inflammatory factors, and neuroangiogenic mediators. In the recent literature, all of the proposed pathogenetic mechanisms of adenomyosis reduce endometrial receptivity and alter the adhesion molecule expression necessary for embryo implantation. The evidence so far has shown that adenomyosis causes lower pregnancy and live birth rates, higher miscarriage rates, as well as adverse obstetric and neonatal outcomes. Both pharmaceutical and surgical treatments for adenomyosis seem to have a positive impact on reproductive outcomes, leading to improved pregnancy and live birth rates. In addition, adenomyosis has negative impacts on reproductive outcomes in patients undergoing assisted reproductive technology. This association appears less significant after patients follow a long gonadotropin-releasing hormone agonist (GnRHa) protocol, which improves implantation rates. The pre-treatment of GnRHa can also be beneficial before engaging in natural conception attempts. This review aims to discover adenomyosis-associated infertility and to provide patient-specific treatment options.
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Adenomiosis , Infertilidad Femenina , Técnicas Reproductivas Asistidas , Humanos , Adenomiosis/metabolismo , Adenomiosis/complicaciones , Adenomiosis/tratamiento farmacológico , Femenino , Infertilidad Femenina/metabolismo , Infertilidad Femenina/etiología , Infertilidad Femenina/tratamiento farmacológico , Embarazo , Hormona Liberadora de Gonadotropina/metabolismo , Implantación del Embrión , Endometrio/metabolismo , Endometrio/patologíaRESUMEN
Normal reproductive function and fertility rely on the rhythmic secretion of gonadotropin-releasing hormone (GnRH), which is driven by the hypothalamic GnRH pulse generator. A key regulator of the GnRH pulse generator is the posterodorsal subnucleus of the medial amygdala (MePD), a brain region that is involved in processing external environmental cues, including the effect of stress. However, the neuronal pathways enabling the dynamic, stress-triggered modulation of GnRH secretion remain largely unknown. Here, we employ in silico modelling in order to explore the impact of dynamic inputs on GnRH pulse generator activity. We introduce and analyse a mathematical model representing MePD neuronal circuits composed of GABAergic and glutamatergic neuronal populations, integrating it with our GnRH pulse generator model. Our analysis dissects the influence of excitatory and inhibitory MePD projections' outputs on the GnRH pulse generator's activity and reveals a functionally relevant MePD glutamatergic projection to the GnRH pulse generator, which we probe with in vivo optogenetics. Our study sheds light on how MePD neuronal dynamics affect the GnRH pulse generator activity and offers insights into stress-related dysregulation.
Asunto(s)
Hormona Liberadora de Gonadotropina , Hormona Liberadora de Gonadotropina/metabolismo , Animales , Modelos Neurológicos , Amígdala del Cerebelo/fisiología , Amígdala del Cerebelo/metabolismo , Red Nerviosa/fisiología , Red Nerviosa/metabolismo , Neuronas/metabolismo , Neuronas/fisiología , Ratones , Neuronas GABAérgicas/fisiología , Neuronas GABAérgicas/metabolismoRESUMEN
Managing breast cancer in premenopausal women poses unique challenges due to its considerable effect on both morbidity and mortality. Goserelin, a gonadotropin-releasing hormone agonist, has emerged among the various modalities as a preferred option for ovarian function suppression, owing to its efficacy in reducing ovarian estrogen production in premenopausal women with hormone receptor-positive breast cancer. Recent studies have affirmed the efficacy and safety of long-acting (LA) goserelin 10.8 mg every 12 weeks, offering comparable outcomes to monthly injections. This flexibility enables personalized treatment approaches, potentially enhancing patient satisfaction. Off-label utilization of goserelin LA surged during the coronavirus disease pandemic, prompting initiatives to broaden its use for breast cancer treatment. Switching to goserelin LA can streamline treatment, boost adherence, and optimize resource utilization. With the recent approval of goserelin 10.8 mg LA by Health Canada on 6 May 2024, for use in breast cancer, Canada is the latest to join over 60 countries worldwide to expand the accepted indications for goserelin LA and ensure its availability to potentially enhance healthcare delivery, patient care, and breast cancer outcomes. Goserelin LA offers premenopausal patients a means to more effectively manage the constraints imposed by breast cancer treatment and its impact on survivorship.
Asunto(s)
Neoplasias de la Mama , Hormona Liberadora de Gonadotropina , Goserelina , Premenopausia , Humanos , Neoplasias de la Mama/tratamiento farmacológico , Femenino , Hormona Liberadora de Gonadotropina/agonistas , Hormona Liberadora de Gonadotropina/uso terapéutico , Goserelina/uso terapéutico , Antineoplásicos Hormonales/uso terapéutico , SupervivenciaRESUMEN
A 9.4 mg deslorelin slow-release implant was inserted into an adult, healthy billy goat to achieve temporary infertility and a reduction in sexual behavior. The implant was inserted in late autumn. No significant change in testis size was observed over the following 6 weeks. The endocrine function of the testis, which was examined by stimulation with human chorionic gonadotropin, was also unchanged after 6 weeks compared to the initial examination. Histological examination revealed a preserved spermatogenesis.In conclusion, the application of a GnRH analogue implant in the adult male goat has no influence on the investigated parameters - and thus probably also on its fertility.
Asunto(s)
Implantes de Medicamentos , Cabras , Hormona Liberadora de Gonadotropina , Pamoato de Triptorelina , Animales , Masculino , Pamoato de Triptorelina/administración & dosificación , Pamoato de Triptorelina/análogos & derivados , Pamoato de Triptorelina/farmacología , Hormona Liberadora de Gonadotropina/administración & dosificación , Testículo/efectos de los fármacos , Preparaciones de Acción Retardada , Espermatogénesis/efectos de los fármacosRESUMEN
PURPOSE OF REVIEW: While laparoscopic surgery plays a key role in the management of endometriosis, symptoms commonly recur, and repeat surgery comes with increased risk. Medical management, including hormonal and nonhormonal treatment, is vital in managing painful symptoms. This review summarizes recent evidence regarding various medical management options available to treat pelvic pain associated with endometriosis. RECENT FINDINGS: Efficacy of dienogest vs. combined oral contraceptive on pain associated with endometriosis: randomized clinical trial.Once daily oral relugolix combination therapy vs. placebo in patients with endometriosis-associated pain: two replicate phase 3, randomised, double-blind, studies (SPIRIT 1 and 2).A randomized, double-blind, placebo-controlled pilot study of the comparative effects of dienogest and the combined oral contraceptive pill in women with endometriosis.Two-year efficacy and safety of relugolix combination therapy in women with endometriosis-associated pain: SPIRIT open-label extension study. SUMMARY: All symptomatic women with suspected endometriosis who are not desiring immediate fertility can be offered suppressive treatment to control symptoms and slow the progression of disease. First-line treatments include the combined oral contraceptive pill and progestogens. Second-line treatments include gonadotropin-releasing hormone agonists and antagonists but current guidelines recommend that these should be reserved for people whose symptoms fail to be controlled by first-line agents. The use of complementary and alternative medicines is also increasing in both volume and number of agents used.
Asunto(s)
Anticonceptivos Orales Combinados , Endometriosis , Hormona Liberadora de Gonadotropina , Nandrolona , Dolor Pélvico , Humanos , Endometriosis/complicaciones , Endometriosis/tratamiento farmacológico , Endometriosis/terapia , Femenino , Dolor Pélvico/tratamiento farmacológico , Dolor Pélvico/etiología , Nandrolona/análogos & derivados , Nandrolona/uso terapéutico , Anticonceptivos Orales Combinados/uso terapéutico , Hormona Liberadora de Gonadotropina/agonistas , Ensayos Clínicos Controlados Aleatorios como Asunto , Progestinas/uso terapéuticoRESUMEN
PURPOSE: To provide a method for the differential diagnosis of Robert's uterus with adenomyosis, a rare uterine malformation, and determine the best course of treatment. METHODS: A patient who had Robert's uterus with adenomyosis was admitted to our hospital in December 2022. We analyzed and summarized her case . RESULTS: Our patient complained of progressively worsening primary dysmenorrhea over the course of 3 years and lower abdominal pain lasting for 2 days. Her carbohydrate antigen 125 (CA125) level was 372.10 U/mL. Examinations conducted by several hospitals indicated that she had a single-horned uterus and a residual horned uterus, and our hospital's examination identified Robert's uterus. This malformation was corrected by open abdominal surgery. For the procedure, pelvic adhesions were first isolated, after which the closed uterine cavity and adenomyosis were resected. Subsequently, the left ovarian endometriosis cyst was resected and right tubal ligation was performed. After surgery, three injections of gonadotropin-releasing hormone A (GnRH-A) were administered, which lowered the patient's CA125 level to 14 U/mL and normalized her condition. CONCLUSION: We pioneered a new therapeutic approach for the treatment of Robert's uterus with adenomyosis. Some valuable references are provided for clinical practice.
Asunto(s)
Adenomiosis , Útero , Humanos , Femenino , Adenomiosis/cirugía , Adenomiosis/complicaciones , Adenomiosis/diagnóstico , Útero/anomalías , Útero/cirugía , Adulto , Antígeno Ca-125/sangre , Anomalías Urogenitales/cirugía , Anomalías Urogenitales/diagnóstico , Anomalías Urogenitales/complicaciones , Hormona Liberadora de Gonadotropina/análogos & derivados , Hormona Liberadora de Gonadotropina/uso terapéutico , Dismenorrea/etiología , Endometriosis/cirugía , Endometriosis/complicaciones , Endometriosis/diagnósticoRESUMEN
This study evaluated the use of the GnRH agonist hormone, deslorelin, to control the follicular population before initiating multiple ovulation and embryo transfer (MOET) treatment. Twenty-four cross-bred Santa Inês ewes, aged between 2 and 4 years, were randomly assigned to either a control group (n = 11) or a treated group (n = 13). All ewes received an intravaginal device containing 60 mg of medroxyprogesterone acetate on day 0, and a new device on day 7, which remained in place until day 14. Additionally, the ewes were administered 125 µg of cloprostenol on day 7. The superovulatory treatment involved administering 200 mg of pFSH, divided into eight decreasing doses at 12-h intervals starting on day 12. On day 14, 300 IU of eCG was administered. In the deslorelin group, three doses of 100 µg of deslorelin were administered starting on day 3 after the insertion of the vaginal device, with subsequent doses given at 72-h and 144-h intervals. Natural mating was performed 36 h after the removal of the progesterone implant using males with proven fertility. Embryo collection took place on the 6th day after mating, and the recovered structures were quantified and evaluated for quality and developmental stage. Transrectal ultrasonography was conducted on days 12, 16 and 21 to evaluate the ovaries, specifically to assess the ovarian follicular population and the presence of the corpus luteum. Ewes in the control group had higher embryo recovery rates (p < .01) compared to the treated group (5.2 ± 0.8 vs. 1.1 ± 0.8), with differences observed primarily in the number of morulae. The number of corpus luteum observed during the laparotomy on day 21 was significantly higher (p < .01) in the control group (10.44 vs. 4.5 corpus luteum per ewe). Yet, the treated group had a significantly higher number of follicles (p < .05) on the first day of pFSH application (5.5 vs. 3.0 follicles per ewe). In conclusion, although the inclusion of deslorelin in the superovulation protocol resulted in increased synchronization of oestrus and follicle number, it did not lead to an increase in the number of corpus luteum or harvested embryos.
Asunto(s)
Transferencia de Embrión , Hormona Folículo Estimulante , Superovulación , Pamoato de Triptorelina , Animales , Femenino , Pamoato de Triptorelina/análogos & derivados , Pamoato de Triptorelina/farmacología , Pamoato de Triptorelina/administración & dosificación , Superovulación/efectos de los fármacos , Hormona Folículo Estimulante/farmacología , Hormona Folículo Estimulante/administración & dosificación , Transferencia de Embrión/veterinaria , Cloprostenol/farmacología , Cloprostenol/administración & dosificación , Embarazo , Ovario/efectos de los fármacos , Folículo Ovárico/efectos de los fármacos , Oveja Doméstica , Ovinos/fisiología , Hormona Liberadora de Gonadotropina/farmacología , Hormona Liberadora de Gonadotropina/administración & dosificación , Acetato de Medroxiprogesterona/farmacología , Acetato de Medroxiprogesterona/administración & dosificaciónRESUMEN
OBJECTIVES: Body esteem (BE) and quality of life (QOL) of girls aged 9-11 years may change depending on their puberty. We aimed to examine The Pediatric Quality of Life Inventory 4.0 (PedsQL 4.0) and the Body Esteem for Adolescents and Adults Scale (BESAA) for children. METHODS: The groups were determined as those whose puberty signs had not yet started (Group 1), those having with breast development stage 3 and/or larger (Group 2), and those who had received gonadotropin-releasing hormone agonist (GnRHa) treatment for at least 6 months (Group 3). RESULTS: A total of 145 girls (Group 1: 41, Group 2: 56, Group 3: 48), were included. The PedsQL scores of the Group 1 was higher than Group 2 (78.5 ± 10.3 vs. 70.1 ± 14.2; p=0.008). The PedsQL scores of the Group 1 was higher but not statistically different from Group 3 (78.5 ± 10.3 vs. 74.2 ± 14.3; p=0.401). The PedsQL scores of Group 2 was not statistically different from Group 3 (p=0.354). There was no statistical difference in BESAA scores between groups (p=0.291). Group 1's PedsQL Health and Activity subscale score was higher than Group 2 (p=0.002). CONCLUSION: The QOL of the girls with PP was found to be lower than their healthy peers. Health and Activity-related QOL scores were found to be lower in the untreated group, indicating that girls with PP were probably significantly disturbed by their puberty-related physical development at the onset of the disease.