A peek into the drug development scenario of endometriosis – A systematic review

Goenka, Luxitaa; George, Melvin; Sen, Maitrayee

doi:10.1016/j.biopha.2017.03.092

Cited by 30 publications

(18 citation statements)

References 68 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The findings of this Japanese study confirm the vast amount of published data concerning the appreciable degree of satisfaction with treatment that can be achieved with OCs in patients with the disease [3; Table 1]. However, Casper suggested that M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT Vercellini et al,7 progestogens should be preferred to OCs as a first-line treatment, based on the consideration that oestrogen and progesterone receptors would be, respectively, over-and under-expressed in ectopic endometrial implants [29]. Thus, administering OCs would be counterproductive, resulting in oestrogen dominance in the presence of progesterone resistance, with the potential risk of lesion progression.…”

Section: Pros and Cons Of Combined Oral Contraceptivessupporting

confidence: 82%

Medical treatment of endometriosis-related pain

Vercellini

Buggio

Frattaruolo

et al. 2018

Best Practice & Research Clinical Obstetrics & Gynaecol

115

101

View full text Add to dashboard Cite

Available medical treatments for symptomatic endometriosis act by inhibiting ovulation, reducing serum oestradiol levels, and suppressing uterine blood flows. For this, several drugs can be used with a similar magnitude of effect, in terms of pain relief, independently of the mechanism of action. Conversely, safety, tolerability, and cost differ. Medications for endometriosis can be categorized into low-cost drugs including oral contraceptives (OCs) and most progestogens, and high-cost drugs including dienogest and GnRH agonists. As the individual response to different drugs is variable, a stepwise approach is suggested, starting with OCs or low-cost progestogens, and stepping up to high-cost drugs only in case of inefficacy or intolerance. OCs may be used in women with dysmenorrhea as their main complaint, and when only superficial peritoneal implants or ovarian endometriomas <5 cm are present, while progestogens should be preferred in women with severe deep dyspareunia and when infiltrating lesions are identified.

show abstract

Section: Pros and Cons Of Combined Oral Contraceptivessupporting

confidence: 82%

Medical treatment of endometriosis-related pain

Vercellini

Buggio

Frattaruolo

et al. 2018

Best Practice & Research Clinical Obstetrics & Gynaecol

115

101

View full text Add to dashboard Cite

show abstract

“…Supporting this, a pharmacoperone restored sex hormone production in transgenic mice homozygous for the cLOF p.Glu90Lys mutant GnRH‐R and a pharmacoperone decreased symptoms of nephrogenic diabetes insipidus in patients with class II AVPR2 mutations (Tao & Conn, ). The clinical development of elagolix and other orally active small molecule GnRH‐R antagonists, for other applications (Goenka et al ., ), provides potential novel therapy for ncHH patients with class II (disrupted cell membrane trafficking) GnRH‐R mutants that can interact with endogenous GnRH, once expressed at the cell membrane. However, patients with class III or IV GnRH‐R mutants, such as our patient's variant, which cannot respond to endogenous GnRH concentrations, are less likely to benefit from these new drugs.…”

Section: Discussionmentioning

confidence: 99%

Genetics of ncHH: from a peculiar inheritance of a novel GNRHR mutation to a comprehensive review of the literature

et al. 2018

View full text Add to dashboard Cite

a First co-authors. b Last co-authors.ABSTRACT Background: Normosmic congenital hypogonadotropic hypogonadism (ncHH) is caused by the deficient production, secretion, or action of gonadotropin-releasing hormone (GnRH). Its typical clinical manifestation is delayed puberty and azoospermia. Homozygous and compound heterozygous mutations in the GNRHR gene (4q13.2) are the most frequent genetic causes of ncHH. Objectives: (i) Characterization at the molecular level (genetic origin and functional effect) of a unique homozygous mutation (p.Gly99Glu) in a ncHH man; (ii) to provide a comprehensive catalog of GNRHR mutations with genotype-phenotype correlation and comparison of in vitro studies vs. in silico prediction tools. Material and Methods: A ncHH man and his parents, in whom we performed the following: (i) Sanger sequencing, qPCR of the GNRHR gene; (ii) chromosome 4 SNP array; and (iii) competition binding assay and inositol phosphate signaling assay. PubMed and Human Genome Mutation Database (HGMD) search for GNRHR mutations. Bioinformatic analysis of 55 reported variants. Results: qPCR showed two GNRHR copies in the index case. SNP array revealed the inheritance of two homologous chromosomes 4 from the mother (maternal heterodisomy; hUPD) with two loss of heterozygosity regions, one of them containing the mutated gene (maternal isodisomy; iUPD). Functional studies for the p.Gly99Glu mutation demonstrated a right-shifted GnRH-stimulated signaling response. Bioinformatic tools show that commonly used in silico tools are poor predictors of the function of ncHH-associated GNRHR variants. Discussion: Functional analysis of the p.Gly99Glu mutation is consistent with severely decreased GnRH binding affinity (a severe partial loss-of-function mutation). Complete LOF variants are associated with severe and severe/moderate phenotype, whereas partial LOF variants show wide range of clinical manifestations. Conclusion: This is the first ncHH patient carrying a novel causative missense mutation of GNRHR with proven 'severe pLOF' due to maternal hUPD/iUPD of chromosome 4. Our literature review shows that functional studies remain essential both for diagnostic and potential therapeutic purposes.

show abstract

“…Endometriosis is common in premenopausal women, and coupled with its hyper-proliferative condition advocates that the disease may be mediated by high estrogen levels [48]. Proliferation of endometrial tissue outside the uterus resulting in pelvic pain and infertility are hallmarks of endometriosis [49]. Moreover, endometriosis can also result in menstrual disorders including menorrhagia [50].…”

Section: Endometriosismentioning

confidence: 99%

Estrogen–gut microbiome axis: Physiological and clinical implications

2017

View full text Add to dashboard Cite

Low levels of gonadal circulating estrogen observed in post-menopausal women can adversely impact a diverse range of physiological factors, with clinical implications for brain cognition, gut health, the female reproductive tract and other aspects of women's health. One of the principal regulators of circulating estrogens is the gut microbiome. This review aims to shed light on the role of the gut microbiota in estrogen-modulated disease. The gut microbiota regulates estrogens through secretion of β-glucuronidase, an enzyme that deconjugates estrogens into their active forms. When this process is impaired through dysbiosis of gut microbiota, characterized by lower microbial diversity, the decrease in deconjugation results in a reduction of circulating estrogens. The alteration in circulating estrogens may contribute to the development of conditions discussed herein: obesity, metabolic syndrome, cancer, endometrial hyperplasia, endometriosis, polycystic ovary syndrome, fertility, cardiovascular disease (CVD) and cognitive function. The bi-directional relationship between the metabolic profile (including estrogen levels) and gut microbiota in estrogen-driven disease will also be discussed. Promising therapeutic interventions manipulating the gut microbiome and the metabolic profile of estrogen-driven disease, such as bariatric surgery and metformin, will be detailed. Modulation of the microbiome composition subsequently impacts the metabolic profile, and vice versa, and has been shown to alleviate many of the estrogen-modulated disease states. Last, we highlight promising research interventions in the field, such as dietary therapeutics, and discuss areas that provide exciting unexplored topics of study.

show abstract

A peek into the drug development scenario of endometriosis – A systematic review

Cited by 30 publications

References 68 publications

Medical treatment of endometriosis-related pain

Medical treatment of endometriosis-related pain

Genetics of ncHH: from a peculiar inheritance of a novel GNRHR mutation to a comprehensive review of the literature

Estrogen–gut microbiome axis: Physiological and clinical implications

Contact Info

Product

Resources

About