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Expert Review of Clinical Pharmacology Sep 2022Endometriosis is a chronic, estrogen-dependent, inflammatory disease associated with pelvic pain, infertility, impaired sexual function, and psychological suffering.... (Review)
Review
INTRODUCTION
Endometriosis is a chronic, estrogen-dependent, inflammatory disease associated with pelvic pain, infertility, impaired sexual function, and psychological suffering. Therefore, tailored patient management appears of primary importance to address specific issues and identify the appropriate treatment for each woman. Over the years, abundant research has been carried out with the objective to find new therapeutic approaches for this multifaceted disease.
AREAS COVERED
This narrative review aims to present the latest advances in the pharmacological management of endometriosis. In particular, the potential role of GnRH antagonists, selective progesterone receptor modulators (SPRMs), and selective estrogen receptors modulators (SERMs) will be discussed. We performed a literature search in PubMed and Embase, and selected the best quality evidence, giving preference to the most recent and definitive original articles and reviews.
EXPERT OPINION
Medical therapy represents the cornerstone of endometriosis management, although few advances have been made in the last decade. Most studies have focused on the evaluation of the efficacy and safety of GnRH antagonists (plus add-back therapy in cases of prolonged treatment), which should be used as second-line treatment options in selected cases (i.e. non-responders to first-line treatments). Further studies are needed to identify the ideal treatment for women with endometriosis.
Topics: Endometriosis; Estrogens; Female; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Receptors, Estrogen; Receptors, Progesterone; Selective Estrogen Receptor Modulators
PubMed: 36000243
DOI: 10.1080/17512433.2022.2117155 -
Drugs Aug 2022Linzagolix (Yselty) is an orally administered, selective, non-peptide small molecule gonadotrophin releasing hormone (GnRH) receptor antagonist that is being developed... (Review)
Review
Linzagolix (Yselty) is an orally administered, selective, non-peptide small molecule gonadotrophin releasing hormone (GnRH) receptor antagonist that is being developed by Kissei Pharmaceutical for the treatment of uterine fibroids and endometriosis in women of reproductive age. Linzagolix binds to and blocks the GnRH receptor in the pituitary gland, modulating the hypothalamic pituitary-gonadal axis and dose-dependently reducing serum luteinising hormone and follicle-stimulating hormone production and serum estradiol levels. In June 2022, linzagolix was approved for the treatment of moderate to severe symptoms of uterine fibroids in adult women of reproductive age in the EU. Linzagolix is under regulatory review the USA for this indication and is in phase 3 clinical development in the treatment of pain associated with endometriosis. This article summarizes the milestones in the development of linzagolix leading to this first approval for the treatment of moderate to severe symptoms of uterine fibroids in adult women of reproductive age.
Topics: Adult; Carboxylic Acids; Endometriosis; Estradiol; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Leiomyoma; Luteinizing Hormone; Pharmaceutical Preparations; Pyrimidines; Receptors, LHRH
PubMed: 35997940
DOI: 10.1007/s40265-022-01753-9 -
Urologic Oncology May 2023Deep prostate-specific antigen (PSA) response, defined as a ≥90% decline in PSA (PSA90), is an important early response indicator for achieving radiographic...
Attainment of early, deep prostate-specific antigen response in metastatic castration-sensitive prostate cancer: A comparison of patients initiated on apalutamide or enzalutamide.
BACKGROUND
Deep prostate-specific antigen (PSA) response, defined as a ≥90% decline in PSA (PSA90), is an important early response indicator for achieving radiographic progression-free and overall survival in patients with metastatic castration-sensitive prostate cancer (mCSPC) treated with a next-generation androgen signaling inhibitor (ASI), such as apalutamide or enzalutamide. The objective of this study was to compare deep PSA response among patients with mCSPC newly initiated on apalutamide or enzalutamide.
METHODS
Clinical data from 69 community urology practices in the United States were evaluated. Patients with mCSPC were classified into cohorts based on their first dispensation (index date) for apalutamide or enzalutamide and were followed until the earliest of treatment discontinuation, initiation of a new next-generation androgen receptor signaling inhibitor, end of clinical activity (including death), or end of data availability (03/05/2021). Inverse probability of treatment weights (IPTW) were used to reduce baseline confounding. PSA90 was defined as the earliest ≥90% PSA decline relative to baseline PSA. The proportion of patients achieving PSA90 and time to PSA90 were reported using weighted Kaplan-Meier analysis and weighted Cox proportional hazards models, respectively.
RESULTS
The apalutamide and enzalutamide cohorts comprised 186 and 165 patients, respectively. Patient characteristics were generally well balanced after IPTW. By 6 months, patients initiated on apalutamide had a 56% greater likelihood of attaining PSA90 than those initiated on enzalutamide (P = 0.014). This result remained significant through the end of the observation period. The median time to achieving PSA90 was 3.1 months with apalutamide and 5.2 months with enzalutamide.
CONCLUSIONS
This real-world study demonstrated that apalutamide initiation is associated with a significantly higher likelihood of achieving ≥90% reduction in PSA as compared to initiation of enzalutamide. Moreover, this deep PSA response was observed to occur earlier with apalutamide treatment than with enzalutamide.
Topics: Humans; Male; Androgen Antagonists; Androgen Receptor Antagonists; Castration; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome
PubMed: 37061452
DOI: 10.1016/j.urolonc.2023.03.003 -
Current Medical Research and Opinion May 2020Endometriosis affects up to 10% of women of reproductive age, and the main goal of treatment is to relieve symptoms. Progestins have been the mainstay of endometriosis... (Review)
Review
Endometriosis affects up to 10% of women of reproductive age, and the main goal of treatment is to relieve symptoms. Progestins have been the mainstay of endometriosis suppression, of which dienogest has become an important option in many parts of the world. This is an expert literature review, with recommendations on the use of dienogest in the context of various clinical considerations when treating endometriosis. A search of PubMed was conducted for papers published between 2007 and 2019 on the use of dienogest in endometriosis. Experts reviewed these and included those they considered most relevant in clinical practice, according to their own clinical experience.: Evidence regarding the long-term use (>15 months) of dienogest for the management of endometriosis is presented, with experts concluding that the efficacy of dienogest should be assessed primarily on its impact on pain and quality of life. Fertility preservation, the option to avoid or delay surgery, and managing bleeding irregularities that can occur with this treatment are also considered. Counseling women on potential bleeding risks before starting treatment may be helpful, and evidence suggests that few women discontinue treatment for this reason, with the benefits of treatment outweighing any impact of bleeding irregularities. Overall, the evidence demonstrates that dienogest offers an effective and tolerable alternative or adjunct to surgery and provides many advantages over combined hormonal contraceptives for the treatment of endometriosis. It is important that treatment guidelines are followed and care is tailored to the woman's individual needs and desires.
Topics: Bone Density; Endometriosis; Female; Hormone Antagonists; Humans; Nandrolone
PubMed: 32175777
DOI: 10.1080/03007995.2020.1744120 -
Drugs Sep 2018Elagolix (ORILISSA™), an orally bioavailable, second-generation, non-peptide gonadotropin-releasing hormone (GnRH) receptor antagonist, is being developed AbbVie and... (Review)
Review
Elagolix (ORILISSA™), an orally bioavailable, second-generation, non-peptide gonadotropin-releasing hormone (GnRH) receptor antagonist, is being developed AbbVie and Neurocrine Biosciences for the treatment of reproductive hormone-dependent disorders in women. In July 2018, the US FDA approved elagolix tablets for the management of moderate to severe pain associated with endometriosis. This approval was based on positive results in two replicate phase III trials; additional phase III trials in the USA, Canada and Puerto Rico are currently evaluating elagolix as both monotherapy and in combination with low-dose hormone add-back therapy in the same indication. Elagolix with and without low-dose hormone add-back therapy is also undergoing phase III clinical development for heavy menstrual bleeding associated with uterine fibroids in the aforementioned locations. This article summarizes the milestones in the development of elagolix leading to its first approval for the management of moderate to severe pain associated with endometriosis.
Topics: Drug Approval; Drug Therapy, Combination; Endometriosis; Female; Hormone Antagonists; Humans; Hydrocarbons, Fluorinated; Pain; Pain Management; Pyrimidines; Receptors, LHRH; Treatment Outcome; United States; United States Food and Drug Administration
PubMed: 30194661
DOI: 10.1007/s40265-018-0977-4 -
Fertility and Sterility Jul 2020To study the effect of a new investigational oral gonadotropin-releasing hormone antagonist, linzagolix, on endometriosis-associated pain (EAP). (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To study the effect of a new investigational oral gonadotropin-releasing hormone antagonist, linzagolix, on endometriosis-associated pain (EAP).
DESIGN
A multinational, parallel group, randomized, placebo-controlled, double-blind, dose-ranging trial.
SETTING
Clinical centers.
PATIENT(S)
Women aged 18-45 years with surgically confirmed endometriosis and moderate-to-severe EAP.
INTERVENTION(S)
The interventions were 50, 75, 100, or 200 mg linzagolix (or matching placebo) administered once daily for 24 weeks.
MAIN OUTCOME MEASURE(S)
The primary endpoint was the number of responders (≥30% reduction in overall pelvic pain) after 12 weeks. Other endpoints included dysmenorrhea, non-menstrual pelvic pain, serum estradiol, amenorrhea, quality of life (QoL) measures, and bone mineral density (BMD).
RESULT(S)
Compared with placebo, doses ≥ 75 mg resulted in a significantly greater proportion of responders for overall pelvic pain at 12 weeks (34.5%, 61.5%, 56.4%, and 56.3% for placebo, 75, 100, and 200 mg, respectively). A similar pattern was seen for dysmenorrhea and non-menstrual pelvic pain. The effects were maintained or increased at 24 weeks. Serum estradiol was suppressed, QoL improved, and the rate of amenorrhea increased in a dose-dependent fashion. Mean BMD loss (spine) at 24 weeks was <1% at doses of 50 and 75 mg and increased in a dose-dependent fashion up to 2.6% for 200 mg. BMD of femoral neck and total hip showed a similar pattern.
CONCLUSION(S)
Linzagolix significantly reduced EAP and improved QoL at doses of 75-200 mg and decreased BMD dose-dependently.
CLINICAL TRIAL REGISTRATION NUMBER
NCT02778399.
Topics: Adolescent; Adult; Female; Humans; Middle Aged; Young Adult; Administration, Oral; Carboxylic Acids; Chronic Pain; Dose-Response Relationship, Drug; Double-Blind Method; Endometriosis; Gonadotropin-Releasing Hormone; Hormone Antagonists; Organic Chemicals; Pelvic Pain; Pyrimidines; Treatment Outcome; Uterine Diseases
PubMed: 32505383
DOI: 10.1016/j.fertnstert.2020.02.114 -
Fertility and Sterility Feb 2021
Topics: Endometriosis; Female; Hormone Antagonists; Humans; Progestins
PubMed: 33386111
DOI: 10.1016/j.fertnstert.2020.11.005 -
Pharmacology & Therapeutics May 2020Increasing evidence of interdependence between G protein-coupled receptors and receptor tyrosine kinase signaling pathways has prompted reevaluation of crosstalk between... (Review)
Review
Increasing evidence of interdependence between G protein-coupled receptors and receptor tyrosine kinase signaling pathways has prompted reevaluation of crosstalk between these receptors in disease and therapy. Investigations into thyroid-stimulating hormone (TSH) and insulin-like growth factor 1 (IGF1) receptor crosstalk, and its application to the clinic have in particular shown recent progress. In this review, we summarize current insights into the mechanism of TSH/IGF1 receptor crosstalk. We discuss evidence that crosstalk is one of the underlying causes of TSHR-based disease and the feasibility of using combinations of TSH receptor and IGF1 receptor antagonists to increase the therapeutic index for the treatment of Graves' hyperthyroidism and Graves' ophthalmopathy.
Topics: Animals; Autoantibodies; Graves Ophthalmopathy; Hormone Antagonists; Humans; Receptor Cross-Talk; Receptor, IGF Type 1; Receptors, Thyrotropin; Thyrotropin
PubMed: 32061922
DOI: 10.1016/j.pharmthera.2020.107502 -
Neuroendocrinology 2016Historically, medical treatment of acromegaly has mainly been used as an adjuvant therapy after surgery. In the last decades, an increased range of medical therapy... (Review)
Review
Historically, medical treatment of acromegaly has mainly been used as an adjuvant therapy after surgery. In the last decades, an increased range of medical therapy options has been available. Somatostatin analogues have become the cornerstones of medical treatment in acromegaly and are even seen as a primary treatment in a selected group of acromegaly patients. The most recent medical treatment available for acromegaly patients is pegvisomant, a growth hormone receptor antagonist. To date, it is the most effective medical treatment, but it is costly. Pegvisomant is used as monotherapy and combined with somatostatin analogues. In this article, we review clinical studies and cohorts that have documented the efficacy of pegvisomant monotherapy and combined therapy and give a concise overview of associated side effects.
Topics: Acromegaly; Drug Therapy, Combination; Hormone Antagonists; Human Growth Hormone; Humans; Octreotide; Somatostatin
PubMed: 25792221
DOI: 10.1159/000381644 -
Journal of Gynecology Obstetrics and... Nov 2023The French National College of Obstetricians and Gynecologists (CNGOF) published guidelines for managing endometriosis-associated pain in 2018. Given the development of...
The French National College of Obstetricians and Gynecologists (CNGOF) published guidelines for managing endometriosis-associated pain in 2018. Given the development of new pharmacological therapies and a review that was published in 2021, most national and international guidelines now suggest a new therapeutic approach. In addition, a novel validated screening method based on patient questionnaires and analysis of 109-miRNA saliva signatures, which combines biomarkers and artificial intelligence, opens up new avenues for overcoming diagnostic challenges in patients with pelvic pain and for avoiding laparoscopic surgery when sonography and MRI are not conclusive. Dienogest (DNG) 2 mg has been a reimbursable healthcare expense in France since 2020, and, according to recent studies, it is at least as effective as combined hormonal contraception (CHC) and can be used as an alternative to CHC for first-line treatment of endometriosis-associated pain. Since 2018, the literature concerning the use of DNG has grown considerably, and the French guidelines should be modified accordingly. The levonorgestrel intrauterine system (LNG IUS) and other available progestins per os, including DNG, or the subcutaneous implant, can be offered as first-line therapy, gonadotropin-releasing hormone (GnRH) agonists with add-back therapy (ABT) as second-line therapy. Oral GnRH antagonists are promising new medical treatments for women with endometriosis-associated pain. They competitively bind to GnRH receptors in the anterior pituitary, preventing native GnRH from binding to GnRH receptors and from stimulating the secretion of luteinizing hormone and follicle-stimulating hormone. Consequently, estradiol and progesterone production is reduced. Oral GnRH antagonists will soon be on the market in France. Given their mode of action, their efficacy is comparable to that of GnRH agonists, with the advantage of oral administration and rapid action with no flare-up effect. Combination therapy with ABT is likely to allow long-term treatment with minimal impact on bone mass. GnRH antagonists with ABT may thus be offered as second-line treatment as an alternative to GnRH agonists with ABT. This article presents an update on the management of endometriosis-associated pain in women who do not have an immediate desire for pregnancy.
Topics: Female; Humans; Endometriosis; Receptors, LHRH; Artificial Intelligence; Pelvic Pain; Gonadotropin-Releasing Hormone; Hormone Antagonists
PubMed: 37669732
DOI: 10.1016/j.jogoh.2023.102664