Abstract:
BACKGROUND:The drug research and development (R&D) for endometriosis/adenomyosis has been painfully slow. Most completed clinical trials on endometriosis did not publish their results, and presumably failed. While few published trials did report how they foundered, the reasons why they failed are often completely unclear. Surprisingly, there has been no open discussion on why these trials failed. If the causes for these failed trials remain unelucidated, mistakes made in these failed trials may be repeated in the future. Since failure can be infinitely more instructive and educational than success, elucidating the causes for failed clinical trials may yield a treasure trove for future drug R&D. Given our growing understanding of the natural history of ectopic endometrium, it is also important to make an inventory of biologicals/compounds that are currently under development to see where we stand and whether they would stand a better chance of gaining regulatory approval than their predecessors. OBJECTIVE AND RATIONALE:We provide an overview of all compounds under clinical investigation and in development in order to assess the evolution of R&D since the last inventory, reported in 2013. We also have attempted to analyse selected failed clinical trials in the context of published translational/preclinical research and our growing understanding of the natural history of endometriotic/adenomyotic lesions, in the hope that the lessons learned will steer investigators toward the right track in future drug R&D. SEARCH METHODS:We searched ClinicalTrials.gov and a database containing information on drugs gathered daily by Thomson Reuters from a wide range of sources (e.g. patent offices, biomedical literature, congresses, symposia, meetings, company information, regulatory information) for all therapeutic compounds that have undergone or are under clinical trials, or in the developmental stage, and then searched PubMed and Google to determine their publication status using trial identifiers. For trials that were completed at least 2 years ago and have, or have not, published their results, a PubMed search was performed using the name of the therapeutic that has been tested and 'endometriosis' or 'adenomyosis' to identify published preclinical studies prior to the launch of the trial. For those published trials, the cited preclinical studies were also retrieved and scrutinized. OUTCOMES:Despite repeated calls for more transparency, only a small fraction of completed trials on endometriosis has been published. A large number of 'novel' compounds under development are simply repurposed drugs, which seem to be ill-prepared to combat the fibroproliferative nature of endometriosis/adenomyosis. This sobering picture indicates an alarming innovation 'drought' in the drug R&D front, resulting in trickling drug pipelines. Some trials foundered owing to unanticipated serious side-effects, or because attempts were made to suppress a target that can be compensated for by redundant pathways, but many failed in efficacy, indicating that the translational value of the current models is seriously questionable. All existing animal models of endometriosis do not recapitulate the key features of human conditions. WIDER IMPLICATIONS:The glaring innovation drought in drug R&D for endometriosis/adenomyosis should sound alarms to all stake-holders. The failed clinical trials in endometriosis also indicate that some past research had serious deficiencies. In light of the recent understanding of the natural history of ectopic endometrium, it is perhaps time to shift the research paradigm and revamp our research focus and priorities.
journal_name
Hum Reprod Updatejournal_title
Human reproduction updateauthors
Guo SW,Groothuis PGdoi
10.1093/humupd/dmy020subject
Has Abstractpub_date
2018-09-01 00:00:00pages
577-598issue
5eissn
1355-4786issn
1460-2369pii
5035760journal_volume
24pub_type
杂志文章,评审abstract::There has been an improvement in the blastocyst rates achieved following in-vitro embryo production that can largely be attributed to improved embryo culture conditions based on an increased knowledge of the in-vivo environment, as well as the metabolic needs of the embryo. Despite this, in-vitro oocyte maturation (IV...
journal_title:Human reproduction update
pub_type: 杂志文章,评审
doi:10.1093/humupd/dmg009
更新日期:2003-01-01 00:00:00
abstract::Apoptosis is a selective process for deletion of cells in various biological systems. This event, similar to proliferation, is tightly regulated, with both processes playing essential roles in the homeostasis of renewable tissues. In human endometrium, proliferation and apoptosis occur at opposing poles of the menstru...
journal_title:Human reproduction update
pub_type: 杂志文章,评审
doi:10.1093/humupd/1.4.303
更新日期:1995-07-01 00:00:00
abstract:BACKGROUND:Despite great advances in assisted reproductive technology, poor ovarian response (POR) is still considered as one of the most challenging tasks in reproductive medicine. OBJECTIVE AND RATIONALE:The aim of this systemic review is to evaluate the role of different adjuvant treatment strategies on the probabi...
journal_title:Human reproduction update
pub_type: 杂志文章,meta分析
doi:10.1093/humupd/dmz046
更新日期:2020-02-28 00:00:00
abstract:BACKGROUND:A dynamic balance between pro- and anti-inflammatory factors contributes to regulating human female reproduction. Chronic low-grade inflammation has been detected in several female reproductive conditions, from anovulation to embryo implantation failure. C-reactive protein (CRP) is a reliable marker of infla...
journal_title:Human reproduction update
pub_type: 杂志文章
doi:10.1093/humupd/dmaa012
更新日期:2020-09-01 00:00:00
abstract::Relatively recent discoveries of the hormone disrupting properties of some pesticides have raised interest in how contemporary pesticide exposures, which primarily take the form of low level environmental or occupational exposures, impact spermatogenesis. The objective of the present review was to summarize results to...
journal_title:Human reproduction update
pub_type: 杂志文章,评审
doi:10.1093/humupd/dmm039
更新日期:2008-05-01 00:00:00
abstract::The long-term clinical effects of ethinyl estradiol and the impact on environmental safety of the alkylated estrogen components used in combined contraceptive pills remain the subject of debate. The development of improved methods for the use of progestogen-only contraception would represent a viable and desirable opt...
journal_title:Human reproduction update
pub_type: 共识发展会议,杂志文章,评审
doi:10.1093/humupd/dmb025
更新日期:2003-07-01 00:00:00
abstract::Varicocele is often cited as the most common cause of male factor infertility. Arguments in support of this statement include reports of increased prevalence of varicocele in populations of infertile men compared with fertile or otherwise unselected men, association of varicocele with abnormal semen parameters, and im...
journal_title:Human reproduction update
pub_type: 杂志文章,评审
doi:10.1093/humupd/8.1.53
更新日期:2002-01-01 00:00:00
abstract:BACKGROUND:It has been hypothesized that certain obstetrical populations, including women who conceive using assisted reproductive technologies (ART) and women with multiple births, may be at increased risk for postpartum depression. In this systematic literature review, we examine the published evidence for this hypot...
journal_title:Human reproduction update
pub_type: 杂志文章,评审
doi:10.1093/humupd/dmq025
更新日期:2011-01-01 00:00:00
abstract:BACKGROUND:Infertility affects ∼7% of all men. Despite much progress, mainly in genetics, its etiology remains obscure in ∼50% of cases. To fill this gap, imaging of the male genital tract (MGT) has progressively expanded, providing useful information in the assessment of MGT abnormalities. METHODS:A critical, systema...
journal_title:Human reproduction update
pub_type: 杂志文章,评审
doi:10.1093/humupd/dmu042
更新日期:2015-01-01 00:00:00
abstract:BACKGROUND:Anti-Müllerian hormone (AMH) is an established marker of ovarian reserve and a good predictor of poor or excessive ovarian response after controlled hyperstimulation. However, it is unclear whether it can predict the ultimate outcome of assisted conception, live birth. We undertook a systematic review and me...
journal_title:Human reproduction update
pub_type: 杂志文章,meta分析,评审
doi:10.1093/humupd/dmu003
更新日期:2014-07-01 00:00:00
abstract::Homocysteine, a product of the methionine cycle, is known to play an important role in cardiovascular diseases, neurological disorders and embryology, and in very important, fast growing fields concerning obstetrics and gynaecology. Therefore, we attempted an actual overview on possible obstetrical and gynaecological ...
journal_title:Human reproduction update
pub_type: 杂志文章,评审
doi:10.1093/humupd/5.1.64
更新日期:1999-01-01 00:00:00
abstract:BACKGROUND:Transfer of more than a single embryo in an IVF cycle comes with the finite possibility of a multiple gestation. Even a twin pregnancy confers significant risk to both mother and babies. The move to single-embryo transfer for all patients will be greatly facilitated by the ability to quantify embryo viabilit...
journal_title:Human reproduction update
pub_type: 杂志文章,评审
doi:10.1093/humupd/dmu064
更新日期:2015-11-01 00:00:00
abstract:UNLABELLED:BACKGROUND; Combined oral contraceptives (COCs) reduce levels of androgen, especially testosterone (T), by inhibiting ovarian and adrenal androgen synthesis and by increasing levels of sex hormone-binding globulin (SHBG). Although this suppressive effect has been investigated by numerous studies over many ye...
journal_title:Human reproduction update
pub_type: 杂志文章,meta分析,评审
doi:10.1093/humupd/dmt038
更新日期:2014-01-01 00:00:00
abstract::This review provides an overview of how women adjust emotionally to the various phases of IVF treatment in terms of anxiety, depression or general distress before, during and after different treatment cycles. A systematic scrutiny of the literature yielded 706 articles that paid attention to emotional aspects of IVF t...
journal_title:Human reproduction update
pub_type: 杂志文章,评审
doi:10.1093/humupd/dml040
更新日期:2007-01-01 00:00:00
abstract:BACKGROUND:The prevalence of congenital uterine anomalies in high-risk women is unclear, as several different diagnostic approaches have been applied to different groups of patients. This review aims to evaluate the prevalence of such anomalies in unselected populations and in women with infertility, including those un...
journal_title:Human reproduction update
pub_type: 杂志文章,评审
doi:10.1093/humupd/dmr028
更新日期:2011-11-01 00:00:00
abstract::The examination of fetal cells, specifically erythroblasts, and cell-free fetal DNA from the blood of pregnant women is currently the subject of intense research with the aim of developing new risk-free methods for prenatal diagnosis. An unexpected finding made during these studies was that the traffic of fetal erythr...
journal_title:Human reproduction update
pub_type: 杂志文章,评审
doi:10.1093/humupd/8.6.501
更新日期:2002-11-01 00:00:00
abstract::Uterine malformations consist of a group of miscellaneous congenital anomalies of the female genital system. Their mean prevalence in the general population and in the population of fertile women is approximately 4.3%, in infertile patients approximately 3.5% and in patients with recurrent pregnancy losses approximate...
journal_title:Human reproduction update
pub_type: 杂志文章,评审
doi:10.1093/humupd/7.2.161
更新日期:2001-03-01 00:00:00
abstract:BACKGROUND:Threatened miscarriage affects one in five women and is associated with significant emotional distress. The uncertainty around the prognosis of threatened miscarriage makes it equally challenging to the healthcare professionals. Various biochemical markers have been investigated in the past to predict the ou...
journal_title:Human reproduction update
pub_type: 杂志文章,meta分析,评审
doi:10.1093/humupd/dmv054
更新日期:2016-03-01 00:00:00
abstract::Amenorrhoea associated with reduced caloric intake and strenuous exercise leads to hypoestrogenism and is associated with clinical manifestations that include disordered eating, stress fractures, osteoporosis, and, as recently reported, a potential increase in the risk of premature cardiovascular disease. Disordered e...
journal_title:Human reproduction update
pub_type: 杂志文章,评审
doi:10.1093/humupd/dmh033
更新日期:2004-09-01 00:00:00
abstract::Polychlorinated dioxins, furans and polychlorinated benzene constitute a family of toxic persistent environmental pollutants. In Europe, environmental concentrations increased slowly throughout this century until the late 1980s. Dioxins have been shown to be carcinogenic in animals and humans. In humans, excess risks ...
journal_title:Human reproduction update
pub_type: 杂志文章,评审
doi:10.1093/humupd/7.3.331
更新日期:2001-05-01 00:00:00
abstract:BACKGROUND:Important roles for G-protein-coupled receptors (GPCRs) have been identified in the maternal physiological adaptations to pregnancy and in the pathogenesis of preeclampsia. On this basis, GPCRs are potential therapeutic targets for preeclampsia. OBJECTIVES AND RATIONALE:In this review, vasopressin and apeli...
journal_title:Human reproduction update
pub_type: 杂志文章,评审
doi:10.1093/humupd/dmw021
更新日期:2016-09-01 00:00:00
abstract::Nitric oxide (NO) is an important mediator of paracrine interactions, especially within the vascular system. It is a powerful inhibitor of platelet aggregation and a potent vasodilator. NO is also a neurotransmitter and it plays a role in cell-mediated cytotoxicity. NO-generating enzymes (nitric oxide synthases, NOS) ...
journal_title:Human reproduction update
pub_type: 杂志文章,评审
doi:10.1093/humupd/4.5.565
更新日期:1998-09-01 00:00:00
abstract:BACKGROUND:Reproductive disorders and infertility are associated with the risk of obstetric complications and have a negative impact on pregnancy outcome. Affected patients often require assisted reproductive technologies (ART) to conceive, and advanced maternal age is a further confounding factor. The challenge is to ...
journal_title:Human reproduction update
pub_type: 杂志文章,评审
doi:10.1093/humupd/dmv044
更新日期:2016-01-01 00:00:00
abstract::Mammalian oocytes begin meiosis in the fetal ovary, but only complete it when fertilized in the adult reproductive tract. This review examines the cell biology of this protracted process: from entry of primordial germ cells into meiosis to conception. The defining feature of meiosis is two consecutive cell divisions (...
journal_title:Human reproduction update
pub_type: 杂志文章,评审
doi:10.1093/humupd/dmm043
更新日期:2008-03-01 00:00:00
abstract::The wide use of assisted conception methods has risen dramatically. The greater proportion of singletons, twins and high order of multiplicity conceived by those methods have already focused the medical community to various obstetric complications. Recently, there have been suggestions that the levels of mid-gestation...
journal_title:Human reproduction update
pub_type: 杂志文章,评审
doi:10.1093/humupd/5.5.530
更新日期:1999-09-01 00:00:00
abstract::The signals and mechanisms that synchronize the timing of human parturition remain a mystery and a better understanding of these processes is essential to avert adverse pregnancy outcomes. Although our insights into human labor initiation have been informed by studies in animal models, the timing of parturition relati...
journal_title:Human reproduction update
pub_type: 杂志文章,评审
doi:10.1093/humupd/dmw022
更新日期:2016-09-01 00:00:00
abstract::Protamines are the major nuclear sperm proteins. The human sperm nucleus contains two types of protamine: protamine 1 (P1) encoded by a single-copy gene and the family of protamine 2 (P2) proteins (P2, P3 and P4), all also encoded by a single gene that is transcribed and translated into a precursor protein. The protam...
journal_title:Human reproduction update
pub_type: 杂志文章,评审
doi:10.1093/humupd/dml009
更新日期:2006-07-01 00:00:00
abstract::In 1987, Nigel Harris cautioned against over-diagnosing the antiphospholipid syndrome (APS). In what was a rather prophetic editorial titled 'The Syndrome of the Black Swan', he suggested that while patients with APS do indeed exist, they are probably much more unusual than many medical professionals might like to bel...
journal_title:Human reproduction update
pub_type: 社论
doi:10.1093/humupd/dms020
更新日期:2012-09-01 00:00:00
abstract::Significant association between endometriosis, including minor endometriosis, and infertility (or strictly subfertility) is shown by prevalence studies, but a causal relationship has not been established. This review focuses on evidence for pituitary-ovarian dysfunction as a cause for the subfertility. A methodologica...
journal_title:Human reproduction update
pub_type: 杂志文章,评审
doi:10.1093/humupd/6.1.56
更新日期:2000-01-01 00:00:00
abstract:BACKGROUND:Spermatogenesis culminates in production of one of the most highly differentiated cells in biology, the spermatozoon. The gametes that emerge from the testes are, however, functionally immature and only acquire full functionality once they have completed a process of post-testicular maturation in the epididy...
journal_title:Human reproduction update
pub_type: 杂志文章,评审
doi:10.1093/humupd/dms009
更新日期:2012-07-01 00:00:00