Linzagolix: a new GnRH-antagonist under investigation for the treatment of endometriosis and uterine myomas

Dababou, Susan; Garzon, Simone; Laganà, Antonio Simone; Ferrero, Simone; Evangelisti, Giulio; Noventa, Marco; D’Alterio, Maurizio Nicola; Palomba, Stefano; Uccella, Stefano; Franchi, Massimo Piergiuseppe; Barra, Fabio

doi:10.1080/13543784.2021.1957830

Cited by 45 publications

(28 citation statements)

References 45 publications

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“…Although limited drugs, such as GnRH ( Dababou et al, 2021 ), mifepristone ( Bi et al, 2021 ), are widely used in the treatment of UF, they lack a well-defined target and always bring patients side-effects (for example, recidivation after drug withdrawal). Therefore, target drugs for UF urgently need to be discovered to avoid physical injury caused by hysterectomy.…”

Section: Discussionmentioning

confidence: 99%

Identification and Validation of miRNA-TF-mRNA Regulatory Networks in Uterine Fibroids

Peng

Liu

et al. 2022

Front. Bioeng. Biotechnol.

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Uterine fibroids (UF) are the most common benign gynecologic tumors and lead to heavy menstrual bleeding, severe anemia, abdominal pain, and infertility, which seriously harm a women’s health. Unfortunately, the regulatory mechanisms of UF have not been elucidated. Recent studies have demonstrated that miRNAs play a vital role in the development of uterine fibroids. As a high-throughput technology, microarray is utilized to identify differentially expressed genes (DEGs) and miRNAs (DEMs) between UF and myometrium. We identified 373 candidate DEGs and the top 100 DEMs. Function enrichment analysis showed that candidate DEGs were mainly enriched in biological adhesion, locomotion and cell migration, and collagen-containing extracellular matrix. Subsequently, protein-protein interaction (PPI) networks are constructed to analyze the functional interaction between DEGs and screen hub DEGs. Subsequently, the expression levels of hub DEGs were validated by real-time PCR of clinical UF samples. The DGIdb database was used to select candidate drugs for hub DEGs. Molecular docking was applied to test the affinity between proteins and drugs. Furthermore, target genes for 100 candidate DEMs were predicted by miRwalk3.0. After overlapping with 373 candidate DEGs, 28 differentially expressed target genes (DEGTs) were obtained. A miRNA-mRNA network was constructed to investigate the interactions between miRNA and mRNA. Additionally, two miRNAs (hsa-miR-381-3p and hsa-miR-181b-5p) were identified as hub DEMs and validated through RT-PCR. In order to better elucidate the pathogenesis of UF and the synergistic effect between miRNA and transcription factor (TF), we constructed a miRNA-TF-mRNA regulatory network. Meanwhile, in vitro results suggested that dysregulated hub DEMs were associated with the proliferation, migration, and apoptosis of UF cells. Our findings provided a novel horizon to reveal the internal mechanism and novel targets for the diagnosis and treatment of UF.

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Section: Discussionmentioning

confidence: 99%

Identification and Validation of miRNA-TF-mRNA Regulatory Networks in Uterine Fibroids

Peng

Liu

et al. 2022

Front. Bioeng. Biotechnol.

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“…In recent years, some literature has mentioned that Vilaprisan is used in the treatment of perimenopausal women. Compared with GnRH-a, Vilaprisan may have a better effect with lower side effects ( 43 , 44 ). However, this kind of drug is not widely used in China, so GnRH-a is still used in this study, which is also one of the shortcomings of this paper.…”

Section: Discussionmentioning

confidence: 99%

A Preliminary Study on the Effects of Black Cohosh Preparations on Bone Metabolism of Rat Models With GnRH-a-Induced Peri-Menopausal Symptoms

et al. 2022

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BackgroundEndometriosis (EMS) is a relapsing and estrogen-dependent disease. For endometriosis such as deep endometriosis and ovarian endometrioid cysts, surgery is the most effective treatment. Long-term follow-up showed that the recurrence rate of endometriosis after surgical treatment was high, so postoperative drugs were needed to reduce recurrence, and Gonadotropin-releasing hormone agonists (GnRH-a) were the most commonly used drug for postoperative management.GnRH-a may reduce the post-treatment endometriosis relapses by lowering the hormone levels in the body. However, the use of GnRH-a can give rise to perimenopausal symptoms, especially osteoporosis, bone loss, and bone pain, for which reason GnRH-a use is often limited. The add-back therapy is often used to alleviate the untoward effects caused by GnRH-a. However, long-term use of hormone drugs may lead to EMS recurrence, thrombosis, and breast cancer. Therefore, a safer and more effective drug is urgently needed to alleviate the untoward effects caused by GnRH-a. In recent years, scholars at home and abroad have found that isopropanolic Cimicifuga racemosa extract (ICR), as a plant extract, can better relieve the symptoms of perimenopausal women. At the same time, some studies have initially confirmed that black cohosh preparations can relieve the perimenopausal symptoms caused by GnRH-a treatment in EMS patients.ObjectiveTo investigate the effect of black cohosh preparations on the bone metabolism of rat models with GnRH-a-induced perimenopausal symptoms.MethodsThe rat models of perimenopausal symptoms were established by GnRH-a injection. and normal saline (NS injection) was used as the control. According to the modeling method and drug intervention, the rats were randomly divided into four groups: GnRH-a injection + saline intervention group (GnRH-a + NS), saline injection control + saline intervention group (NS + NS), GnRH-a injection + estradiol intervention group (GnRH-a + E2), and GnRH-a injection + black cohosh preparation intervention group (GnRH-a + ICR). The rat models were identified with the vaginal smear method, and then the corresponding drug intervention was administrated for 28 days. After the intervention, the rats were sacrificed. The rats’ bone mineral density (BMD) of the distal femur was detected by a dual-energy X-ray bone density scanner. Rat tibia bone tissues were decalcified and made into slices. The pathological and morphological changes of rat tibial bones in each group were observed through HE staining. Histomorphometry parameters of rat tibial bones in each group, such as trabecular bone volume (TBV), trabecular thickness (TbTh), trabecular number (TbN), and trabecular spacing (TbSp), were detected and analyzed by using an automatic image analysis system.Results(1) The BMD level of the distal femur in the GnRH-a + NS group was significantly lower than the NS + NS, GnRH-a + E2, and GnRH-a + ICR groups (P<0.01), the BMD levels in GnRH-a + E2 and GnRH-a + ICR groups were slightly lower than the NS + NS group, but there was no significant difference among the three groups (P>0.05). (2) The pathological changes of the tibia bones under the microscope in different groups were as follows: The tibia bone trabecular structure was normal in the NS + NS group, without trabecular thinning or fracture, and the arch structure was normal. In the GnRH-a + NS group, some trabecular structures tapered, the arch structure disappeared, but no obvious bone fracture was observed in the trabecula. In the GnRH-a + E2 and GnRH-a + ICR groups, the trabecular structures were normal, without trabecular bone thinning or fracture, and the arch structures were normal. (3) The TBV level of the GnRH-a + INS group was significantly lower than that of the NS + NS, GnRH-a + E2 and GnRH-a + ICR groups (P<0.01, P<0.05, P<0.01), while there was no significant difference among NS + NS, GnRH-a + E2 and GnRH-a + ICR groups (P>0.05). (4) The TbTh levels in the four groups had no significant difference (P>0.05). Compared with the NS + NS group, the TbTh levels in the GnRH-a + NS, GnRH-a + E2, and GnRH-a + ICR groups showed a descending tendency, while the TbTh levels in the GnRH-a + E2 and GnRH-a + ICR groups were slightly higher than that of the GnRH-a + NS group. However, such differences were not significant statistically (P>0.05). (5) Compared with the NS + NS group, the TbN levels in the GnRH-a + NS, GnRH-a + E2, and GnRH-a + ICR groups decreased remarkably (P<0.05). Compared with the GnRH-a + NS group, the TbN levels in the GnRH-a + E2 and GnRH-a + ICR groups showed a mild descending tendency, but such differences were not significant statistically (P>0.05). (6) The TbSp level of the GnRH-a + NS group was significantly higher than that of the NS + NS, GnRH-a + E2, and GnRH-a + ICR groups (P<0.01), while there was no significant difference among NS + NS, GnRH-a + E2 and GnRH-a + ICR groups (P>0.05).ConclusionThe GnRH-a injection could achieve the desired effect. GnRH-a injection may lead to the loss of bone mass in rats. Black cohosh preparations, like estrogen, may have a protective effect on bone mass loss caused by GnRH-a injection.

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“…In addition to the identification of susceptible individuals [ 7 , 18 , 20 , 21 ], insights into the molecular aspects of UL could assist in the development of targeted therapies. Several clinical management options for ULs are available and some are under investigation [ 33 , 34 ]. Current treatment options for UL could be improved by incorporating the molecular information on UL.…”

Section: Discussionmentioning

confidence: 99%

Risk of uterine leiomyoma based on BET1L rs2280543 single nucleotide polymorphism and vegetarian diet

et al. 2022

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Background Bet1 Golgi vesicular membrane trafficking protein-like (BET1L) rs2280543 single nucleotide polymorphism (SNP) and diet have been independently associated with uterine leiomyoma (UL). However, whether the SNP and diet could jointly influence the risk of UL is yet to be assessed. Therefore, we investigated the independent and interactive effects of vegetarian diet and BET1L rs2280543 on uterine fibroids in Taiwanese women. Methods We linked participants’ electronic data in the Taiwan Biobank (TWB) database to their medical records in the National Health Insurance Research Database (NHIRD). The TWB had genotypic, lifestyle, and biochemical data between 2008 and 2015 and the NHIRD had data on disease diagnoses between 1998 and 2015. In this study, we included 1997 premenopausal women with complete data. Results Compared to participants with the BET1L rs2280543 CC genotype (wildtype), those with CT/CC genotype had an odds ratio (OR) of 0.69 and a 95% confidence interval (CI) of 0.51–0.93. Vegetarian diet and UL were not significantly associated: OR = 1.09 and 95% CI = 0.77–1.55. However, the test for interaction between rs2280543 and vegetarian diet was significant (p = 0.046). Compared to individuals with the CC genotype, the risk of UL was lower among vegetarians with the CT/TT genotype: OR (95% CI) = 0.15 (0.05–0.47). Conclusion The BET1L rs2280543 CT/TT genotype was associated with a lower risk of UL especially among vegetarians.

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Linzagolix: a new GnRH-antagonist under investigation for the treatment of endometriosis and uterine myomas

Cited by 45 publications

References 45 publications

Identification and Validation of miRNA-TF-mRNA Regulatory Networks in Uterine Fibroids

Identification and Validation of miRNA-TF-mRNA Regulatory Networks in Uterine Fibroids

A Preliminary Study on the Effects of Black Cohosh Preparations on Bone Metabolism of Rat Models With GnRH-a-Induced Peri-Menopausal Symptoms

Risk of uterine leiomyoma based on BET1L rs2280543 single nucleotide polymorphism and vegetarian diet

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