Comparing ART outcomes in women with endometriosis after GnRH agonist versus GnRH antagonist ovarian stimulation: a systematic review.

Background: Endometriosis is an oestrogen-dependent disease that can cause subfertility in women who may require assisted reproductive technology (ART) to achieve their pregnancy goals. Objectives: The aim of this study was to compare ART outcomes in women with endometriosis following the long GnRH-agonist controlled ovarian stimulation (COS) protocol with those taking the GnRH-antagonist COS protocol. Data Sources and Methods: MEDLINE, Embase and Web of Science were systematically searched in June 2022. Randomized controlled trials (RCTs) and observational studies comparing the long GnRH-agonist COS protocol and the GnRH-antagonist COS protocol in women with all stages/subtypes of endometriosis were included. Data were synthesized into comprehensive tables for systematic review. The Scottish Intercollegiate Guidelines Network (SIGN) checklists were used for the risk of bias assessment of non-randomized studies and randomized studies, and all the included studies were deemed to have acceptable quality. Main Results: Eight studies (one RCT and seven observational) with 2695 patients (2761 cycles) were included. Most studies generally reported non-significant differences in clinical pregnancy or live birth rates regardless of the COS protocol used. However, the GnRH-agonist protocol may yield a higher total number of oocytes retrieved, especially mature oocytes. Conversely, the GnRH-antagonist protocol required a shorter COS duration and lower gonadotrophin dose. Adverse outcomes, such as rates of cycle cancellation and miscarriage, were similar between both COS protocols. Conclusion: Both the long GnRH-agonist and GnRH-antagonist COS protocols generally yield similar pregnancy outcomes. However, the long GnRH-agonist protocol may be associated with a higher cumulative pregnancy rate due to the higher number of retrieved oocytes available for cryopreservation. The underlying mechanisms of the two COS protocols on the female reproductive tract remain unclear. Clinicians should consider treatment costs, stage/subtype of endometriosis and pregnancy goals of their patients when selecting a GnRH analogue for COS. A well-powered RCT is needed to minimize the risk of bias and compare the risk for ovarian hyperstimulation syndrome. Registration: This review was prospectively registered at PROSPERO under Registration No. CRD42022327604.

Female Reproductive Systems: Hormone Dependence and Receptor Expression.

The female reproductive system which consists of the ovaries, uterus (myometrium, endometrium), Fallopian tubes, cervix and vagina is exquisitely sensitive to the actions of steroid hormones. The ovaries play a key role in the synthesis of bioactive steroids (oestrogens, androgens, progestins) that act both within the tissue (intracrine/paracrine) as well as on other reproductive organs following release into the blood stream (endocrine action). Sex steroid receptors encoded by the oestrogen (ESR1, ESR2), progesterone (PR) and androgen (AR) receptor genes, which are members of the superfamily of ligand activated transcription factors are widely expressed within these tissues. These receptors play critical role(s) in regulation of cell proliferation, ovulation, endometrial receptivity, myometrial cell function and inflammatory cell infiltration. Our understanding of their importance has been informed by studies on human tissues and cells, which have employed immunohistochemistry as well as a wide range of molecular and genetic methods to identify which processes are dependent steroid ligand activation. The development of mice with targeted deletions of each of these receptors has provided complementary data that has extended our appreciation of cell-cell interactions in the fine tuning of reproductive tissue function. This large body of work has formed the basis of new and improved therapeutics to treat conditions such as infertility.

Menstruation Dysregulation and Endometriosis Development.

Endometriosis is a common gynecological condition characterized by the growth of endometrial-like tissue outside of the uterus which may cause symptoms such as chronic pelvic pain or subfertility. Several surgical and medical therapies are available to manage symptoms, but a cure has yet to be determined which can be attributed to the incomplete understanding of disease pathogenesis. Sampson's theory of retrograde menstruation is a widely accepted theory describing how shed endometrial tissue can enter the peritoneal cavity, but other factors are likely at play to facilitate the establishment of endometriosis lesions. This review summarizes literature that has explored how dysregulation of menstruation can contribute to the pathogenesis of endometriosis such as dysregulation of inflammatory mediators, aberrant endometrial matrix metalloproteinase expression, hypoxic stress, and reduced apoptosis. Overall, many of these factors have overlapping pathways which can prolong the survival of shed endometrial debris, increase tissue migration, and facilitate implantation of endometrial tissue at ectopic sites. Moreover, some of these changes are also implicated in abnormal uterine bleeding and endometrial diseases. More research is needed to better understand the underlying mechanisms driving dysregulation of menstruation in endometriosis specifically and identifying specific pathways could introduce new treatment targets. Analyzing menstrual fluid from women with endometriosis for inflammatory markers and other biomarkers may also be beneficial for earlier diagnosis and disease staging.

Rapid and automated production of [68Ga]gallium chloride and [68Ga]Ga-DOTA-TATE on a medical cyclotron.

INTRODUCTION: The demand for Gallium-68 (68Ga) for labelling PET radiopharmaceuticals has increased over the past few years. 68Ga is obtained through the decayed parent radionuclide 68Ge using commercial 68Ge/68Ga generators. The principal limitation of commercial 68Ge/68Ga generators is that only a limited and finite quantity of 68Ga (<1.85 GBq at start of synthesis) may be accessed. The focus of this study was to investigate the use of a low energy medical cyclotron for the production of greater quantities of 68Ga and to develop an automated and rapid procedure for processing the product. METHODS: Enriched ZnCl2 was electrodeposited on a platinum backing using a NH4Cl (pH 2-4) buffer. The Zn target was irradiated with GE PETtrace 880 at 35 µA and 14.5 and 12.0 MeV beam energy. The irradiated Zn target was purified using octanol resin on an automated system. RESULTS: Following the described procedure, 68Ga was obtained in 6.30 ±â€¯0.42 GBq after 8.5 min bombardment and with low radionuclidic impurities (66Ga (<0.005%) and 67Ga (<0.09%)). Purification on a single octanol resin gave 82% recovery with resulting [68Ga]GaCl3 obtained in 3.5 mL of 0.2 M HCl. [68Ga]GaCl3 production from irradiation to final product was <45 min. To highlight the utility of the automated procedure, [68Ga]Ga-DOTA-TATE labelling was incorporated to give 1.56 GBq at EOS of the labelled peptide with RCY of >70%. CONCLUSIONS: A straightforward procedure for producing 68Ga on a low energy medical cyclotron was described. Current efforts are focus on high activity production and radiolabelling using solid target produced 68Ga.

Biomimetic synthetic studies on meroterpenoids from the marine sponge Aka coralliphaga: Divergent total syntheses of siphonodictyal B, liphagal and corallidictyals A-D.

The marine sponge Aka coralliphaga is a rich source of biologically active and structurally interesting meroterpenoids. Inspired by these natural products, we have used biosynthetic speculation to devise biomimetic syntheses of siphonodictyal B, liphagal and corallidictyals A-D from sclareolide. This work resulted in the development of new cascade reactions in the synthesis of liphagal, the reassignment of the structure of siphonodictyal B, and the realisation that corallidictyals A and B are possibly isolation artefacts.

Total Synthesis and Structure Revision of (-)-Siphonodictyal B and Its Biomimetic Conversion into (+)-Liphagal.

The structure of siphonodictyal B has been reassigned on the basis of the total synthesis of both possible C-8 epimers. The revised structure of siphonodictyal B was converted into liphagal by acid catalyzed rearrangement of a proposed epoxide intermediate. This biomimetic cascade features a succession of four distinct reactions (epoxidation, o-quinone methide formation, ring expansion, and benzofuran formation) that occur in a one-pot operation under mild conditions. During these studies we also isolated a surprisingly stable o-quinone methide that supports our mechanistic proposal for liphagal biosynthesis.

Biomimetic total synthesis of (±)-yezo'otogirin A.

The total synthesis of yezo'otogirin A has been achieved via a biosynthetically-inspired strategy. Diastereoselective synthesis of pre-yezo'otogirin A, the proposed biosynthetic pre-cursor of yezo'otogirin A, was accomplished in eight steps from 3-ethoxy-2-cyclohexenone. A biomimetic oxidative radical cyclization was then used to construct the unique tricyclic ring system of yezo'otogirin A. The synthesis showcases the ability of biomimetic radical cyclizations to generate complex natural products from unprotected intermediates.

Total synthesis of (+)-aureol.

A total synthesis of the marine sponge meroterpenoid (+)-aureol has been achieved in 12 steps (6% overall yield) from (+)-sclareolide. Key steps of the synthesis include a biosynthetically inspired sequence of 1,2-hydride and methyl shifts, and a biomimetic cycloetherification reaction.

Synthesis of a liphagal-frondosin C hybrid and speculation on the biosynthesis of the frondosins.

A hypothesis for the biosynthesis of the frondosins A-E is presented. Synthesis of a liphagal-frondosin C hybrid molecule has been achieved, with the frondosin C 6-7-5-6 ring system being constructed by a photochemical process that follows an intramolecular Paternò-Büchi reaction/fragmentation pathway.