Does Gonadotropin-Releasing Hormone Agonist Administration Before Assisted Reproduction Techniques Improve Pregnancy Rates in Women With Endometriosis?

Importance: Axial downregulation with a 3- to 6-month administration of gonadotropin-releasing hormone agonists (GnRH-a) prior to assisted reproduction techniques has been proposed in order to improve clinical pregnancy rates in women with endometriosis. Although reduced inflammation, improved oocyte quality, and restored endometrial receptivity have been postulated, further investigation of their actual benefit and mechanism of action is considered essential. In that direction, well-designed clinical trials regarding the role of GnRH-a in IVF are necessary. Objective: The purpose of this review is to clarify whether GnRH-a administration prior to IVF-FET procedures improves pregnancy rates in women with endometriosis. Evidence Acquisition: A literature review was conducted in MEDLINE (PubMed), Cochrane, and Google Scholar and concluded on September 10, 2022. Results: Two Cochrane meta-analyses and 16 selected studies present various interesting data of assisted reproduction technique procedures on patients with endometriosis-related infertility with or without depot GnRH-a pretreatment. Conclusions: The regimen may have a positive clinical effect on cases of severe endometriosis (American Society for Reproductive Medicine stages III-IV), but their use is not routinely recommended in order to improve pregnancy rates. Relevance: Endometriosis and infertility are closely related through various pathogenetic mechanisms. Endometriosis has been traditionally considered to negatively affect fundamental aspects of the in vitro fertilization-frozen embryo transfer procedure. Numerous interventions, both medical and surgical, have been proposed in order to improve IVF success rates, and the optimal management of these cases poses an ever pressing challenge.

Placental mRNA Expression of Neurokinin B Is Increased in PCOS Pregnancies with Female Offspring.

Current research suggests that polycystic ovary syndrome (PCOS) might originate in utero and implicates the placenta in its pathogenesis. Kisspeptin (KISS1) and neurokinin B (NKB) are produced by the placenta in high amounts, and they have been implicated in several pregnancy complications associated with placental dysfunction. However, their placental expression has not been studied in PCOS. We isolated mRNA after delivery from the placentae of 31 PCOS and 37 control women with term, uncomplicated, singleton pregnancies. The expression of KISS1, NKB, and neurokinin receptors 1, 2, and 3 was analyzed with real-time polymerase chain reaction, using ß-actin as the reference gene. Maternal serum and umbilical cord levels of total testosterone, sex hormone-binding globulin (SHBG), free androgen index (FAI), androstenedione, dehydroepiandrosterone sulfate (DHEAS), Anti-Mullerian hormone (AMH), and estradiol were also assessed. NKB placental mRNA expression was higher in PCOS women versus controls in pregnancies with female offspring. NKB expression depended on fetal gender, being higher in pregnancies with male fetuses, regardless of PCOS. NKB was positively correlated with umbilical cord FAI and AMH, and KISS1 was positively correlated with cord testosterone and FAI; there was also a strong positive correlation between NKB and KISS1 expression. Women with PCOS had higher serum AMH and FAI and lower SHBG than controls. Our findings indicate that NKB might be involved in the PCOS-related placental dysfunction and warrant further investigation. Studies assessing the placental expression of NKB should take fetal gender into consideration.

The effect of GnRH-a on the angiogenesis of endometriosis.

PURPOSE: Neoangiogenesis is necessary for adhesion and invasiveness of endometriotic lesions in women affected by endometriosis. Vascular endothelial growth factor (VEGF) is one of the main components of angiogenesis and is part of the major pathway tissue factor (TF)-protease activated receptor-2 (PAR-2)-VEGF that leads to neoangiogenesis. Specificity protein 1 (SP1) is a transcriptional factor that has recently been studied for its crucial role in angiogenesis via a specific pathway. We hypothesize that by blocking angiogenetic pathways we can suppress endometriotic lesions. Gonadotrophin-releasing hormone-agonists (GnRH-a) are routinely used, especially preoperatively, in endometriosis. It would be of great interest to clarify which angiogenetic pathways are affected and, thereby, pave the way for further research into antiangiogenetic effects on endometriosis. METHODS: We used quantitative real-time polymerase chain reaction (qRT-PCR) to study mRNA expression levels of TF, PAR-2, VEGF, and SP1 in endometriotic tissues of women who underwent surgery for endometriosis and received GnRH-a (leuprolide acetate) preoperatively. RESULTS: VEGF, TF, and PAR-2 expression is significantly lower in patients who received treatment (p < 0,001) compared to those who did not, whereas SP1 expression is not altered (p = 0.779). CONCLUSIONS: GnRH-a administration does affect some pathways of angiogenesis in endometriotic lesions, but not all of them. Therefore, supplementary treatments that affect the SP1 pathway of angiogenesis should be developed to enhance the antiangiogenetic effect of GnRH-a in patients with endometriosis. TRIAL REGISTRATION: Clinicaltrial.gov ID: NCT06106932.