Review

Authors: Laura Buggio, Dhouha Dridi, Giussy Barbara...

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

Review

Authors: Susan J Keam

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

Meta-Analysis Review

Authors: Lingli Xin, Yinghao Ma, Mei Ye...

PURPOSE

The aim of this NMA is to comprehensively analyze evidence of oral GnRH antagonist in the treatment of moderate-to-severe endometriosis-associated pain.

METHODS

Literature searching was performed to select eligible studies published prior to April 2022 in PubMed, Cochrane, Embase and Web of Science. Randomized controlled trials involving patients who suffered from moderate-to-severe endometriosis-associated pain and treated with oral nonpeptide GnRH antagonists or placebo were included.

RESULTS

Elagolix 400 mg and ASP1707 15 mg were most efficient in reducing pelvic pain, dysmenorrhea and dyspareunia. Relugolix 40 mg was best in reducing the analgesics use. The rates of any TEAEs and TEAEs-related discontinuation were highest in relugolix 40 mg and elagolix 250 mg, respectively, while rates of hot flush and headache were highest in relugolix 40 mg and elagolix 150 mg. Significantly decreased spinal BMD was observed in elagolix 250 mg.

CONCLUSION

Oral GnRH antagonists were effective in endometriosis-associated pain in 12w, and most of the efficiency and safety outcomes were expressed in a dose-dependent manner, but linzagolix 75 mg was an exception.

Topics: Female; Humans; Endometriosis; Network Meta-Analysis; Gonadotropin-Releasing Hormone; Hormone Antagonists; Pelvic Pain

PubMed: 36656435
DOI: 10.1007/s00404-022-06862-0

Review

Authors: Ally Murji, Kutay Biberoğlu, Jinhua Leng...

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

Review

Authors: R Lemmens-Gruber, M Kamyar

Effects of vasopressin via V1a- and V2-receptors are closely implicated in a variety of water-retaining diseases and cardiovascular diseases, including heart failure, hyponatraemia, hypertension, renal diseases, syndrome of inappropriate antidiuretic hormone secretion, cirrhosis and ocular hypertension. As vasopressin receptors are found in many different tissues, vasopressin antagonists may benefit the treatment of disorders such as cerebral ischaemia and stroke, Raynaud's disease, dysmenorrhoea and tocolytic treatment. V1b selective vasopressin antagonists are discussed in terms of their usefulness in the treatment of emotional and psychiatric disorders. The vaptans are vasopressin receptor antagonists with V1a (relcovaptan) or V2 (tolvaptan, lixivaptan) selectivity or non-selective activity (conivaptan) which may be advantageous in some disorders. The V1a/V2 non-selective vasopressin antagonist conivaptan is the first vaptan which is approved by the FDA for the treatment of euvolaemic hyponatraemia.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Azepines; Benzamides; Benzazepines; Binding Sites; Cardiovascular Diseases; Clinical Trials as Topic; Hormone Antagonists; Humans; Indoles; Pyrroles; Pyrrolidines; Tolvaptan; Vasopressins; Water-Electrolyte Imbalance

PubMed: 16794787
DOI: 10.1007/s00018-006-6054-2

Review

Authors: Yvette N Lamb

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

Randomized Controlled Trial

Authors: Jacques Donnez, Hugh S Taylor, Robert N Taylor...

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

Authors: Hervé Fernandez, Aubert Agostini, Hortense Baffet...

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

Authors: Jah-Yao Liu, Bor-Ching Sheu, Cherry Yin-Yi Chang...

Dienogest has been proven effective as long-term therapeutic option for pelvic pain caused by endometriosis. However, in Taiwan, there is a lack of a well-tailored consensus on its long-term administration. To address this gap, Taiwanese experts in collaboration with the Taiwan Endometriosis Society (TES), convened to provide structured recommendations on dienogest treatment and monitoring strategies. Drawing from clinical evidence and collective expertise, the experts formulated individualized treatment strategies based on treatment objectives and the patient's demographics. The experts recommend long-term dienogest administration for endometriosis patients for appropriate symptom control while reducing the risk of disease recurrence. Specifically, they recommend regular ultrasound examinations and relevant blood tests to monitor disease progression and therapeutic response with additional breast screening for patients at high risk for breast cancer. These recommendations aim to provide physicians with comprehensive guidance on the long-term administration of dienogest for endometriosis, ensuring patient safety and optimizing treatment outcomes.

Topics: Female; Humans; Consensus; Endometriosis; Hormone Antagonists; Nandrolone; Pelvic Pain; Taiwan

PubMed: 39481987
DOI: 10.1016/j.tjog.2024.07.015

Authors: Hugh S Taylor

Topics: Endometriosis; Female; Hormone Antagonists; Humans; Progestins

PubMed: 33386111
DOI: 10.1016/j.fertnstert.2020.11.005