Using Letrozole Cotreatment With Progestin-Primed Ovarian Stimulation In Women With Polycystic Ovary Syndrome Treated For IVF

Background: Women with polycystic ovary syndrome (PCOS) often experience poor oocyte quality and a high risk of ovarian hyperstimulation syndrome (OHSS) when treated with controlled ovarian stimulation (COS) in vitro fertilization (IVF). Progestin-primed ovarian stimulation (PPOS) shows good potential to compete with conventional protocols in women with PCOS. However, it always accompanied by increased pituitary suppression and gonadotropin consumption. Letrozole (LE) has the ability to increase luteinizing hormone (LH) levels and appears to have the potential to alleviate pituitary inhibition during COS in women with PCOS. A retrospective cohort trial was performed to evaluate the efficacy of PPOS with or without letrozole in infertile women with PCOS.Methods: This retrospective cohort study included 448 women with PCOS who underwent COS with human menopausal gonadotropin (hMG) and medroxyprogesterone acetate (MPA) (n=224) or hMG and MPA cotreatment with LE (n=224) from January 2018 to March 2021. Baseline characteristics of the two groups were balanced with propensity score matching using the nearest neighbour random matching algorithm at a ratio of 1:1. The primary outcome measure was the implantation rate. The secondary outcomes were the endocrinological profiles, gonadotropin dose and duration, number of oocytes retrieved and viable embryos, clinical pregnancy rate, miscarriage rate and ectopic pregnancy rates.Result(s): The implantation rate was significantly higher in the study group than that in the control group (42.22% vs. 34.69%, P < 0.05). Compared with the control group，the study group had a higher LH concentration on the trigger day (3.85±3.6 mIU/ml vs. 2.44±1.71 mIU/ml, P < 0.01), but there was no case of premature LH surge or OHSS in both groups. The consumption of gonadotropin, the number of oocytes retrieved and viable embryos were similar between the two groups. Additionally, no difference was found in the clinical pregnancy rate, miscarriage rate or ectopic pregnancy rate.Conclusion(s): This study shows that LE administration in the PPOS protocol was feasible to improve the implantation rate and alleviate profound pituitary suppression from progestin administration without interfering with its premature LH surge blockade effect but with a non-significant reduction in gonadotropin consumption in women with PCOS undergoing IVF treatment.

Progestin-primed Ovarian Stimulation With Clomiphene Citrate Compared With the Standard Progestin-primed Ovarian Stimulation in Various Aged Women With Diminished Ovarian Reserve: a Retrospective Study

Background: Clomiphene citrate (CC) supplementation in the progestin-primed ovarian stimulation (PPOS) protocol effectively alleviated profound pituitary suppression from progestin administration and reduced the gonadotropin (Gn) dose in the population of women with normal-ovarian-reserve or polycystic ovarian syndrome. Limited data are available about the role of CC in PPOS for women with diminished ovarian reserve (DOR). This study aimed to compare the efficiency of the PPOS protocol with CC supplementation and the standard PPOS protocol for various aged women with DOR.Methods: A total of 364 patients with DOR were recruited for this retrospective cohort study. They were divided into subgroups based on female age, ≤35 years and ＞35 years. The clinical characteristics and outcome were compared between the groups in subgroups.Results: In all patients with DOR, the PPOS protocol with CC supplementation was associated with a lower percentage of women with profound pituitary suppression (0.0% vs 18.6%, P ＜0.001 and 1.3% vs 11.0%, P ＝0.002) and a higher mean luteinizing hormone (LH) level during controlled ovarian stimulation (COS) than the standard PPOS protocol (P ＜0.05＝. In young women with DOR, more number of high-quality cleavage-stage embryos (1.96 vs. 1.38, P ＝0.018) was achieved in the PPOS protocol with CC supplementation. In elderly women with DOR, PPOS protocol with CC supplementation led to an increase in the incidence of LH levels above 10 IU/L on the trigger day (12.7% vs. 4.9%, P ＝0.028) and decrease in the rate of oocyte maturation (84.7% vs. 89.9%, P ＝0.034) compared to the standard PPOS protocol. No significant differences were observed in the Gn duration, total dosage of Gn, and pregnancy outcomes between the groups. Conclusions: CC is an effective adjuvant to alleviate pituitary suppression in the PPOS protocol. For young women with DOR, CC supplementation has a positive impact on the number of high-quality embryos in PPOS protocol. However, elderly patients with DOR would be at risk of developing premature LH surge and poor oocyte maturation rate after the PPOS protocol with CC supplementation was applied.

Optimising Follicular Development, Pituitary Suppression, Triggering and Luteal Phase Support During Assisted Reproductive Technology: A Delphi Consensus

BackgroundA Delphi consensus was conducted to evaluate global expert opinions on key aspects of assisted reproductive technology (ART) treatment.MethodsTen experts plus the Scientific Coordinator discussed and amended statements plus supporting references proposed by the Scientific Coordinator. The statements were distributed via an online survey to 35 experts, who voted on their level of agreement or disagreement with each statement. Consensus was reached if the proportion of participants agreeing or disagreeing with a statement was &gt;66%.ResultsEighteen statements were developed. All statements reached consensus and the most relevant are summarised here. (1) Follicular development and stimulation with gonadotropins (n = 9 statements): Recombinant human follicle stimulating hormone (r-hFSH) alone is sufficient for follicular development in normogonadotropic patients aged &lt;35 years. Oocyte number and live birth rate are strongly correlated; there is a positive linear correlation with cumulative live birth rate. Different r-hFSH preparations have identical polypeptide chains but different glycosylation patterns, affecting the biospecific activity of r-hFSH. r-hFSH plus recombinant human LH (r-hFSH:r-hLH) demonstrates improved pregnancy rates and cost efficacy versus human menopausal gonadotropin (hMG) in patients with severe FSH and LH deficiency. (2) Pituitary suppression (n = 2 statements): Gonadotropin releasing hormone (GnRH) antagonists are associated with lower rates of any grade ovarian hyperstimulation syndrome (OHSS) and cycle cancellation versus GnRH agonists. (3) Final oocyte maturation triggering (n=4 statements): Human chorionic gonadotropin (hCG) represents the gold standard in fresh cycles. The efficacy of hCG triggering for frozen transfers in modified natural cycles is controversial compared with LH peak monitoring. Current evidence supports significantly higher pregnancy rates with hCG + GnRH agonist versus hCG alone, but further evidence is needed. GnRH agonist trigger, in GnRH antagonist protocol, is recommended for final oocyte maturation in women at risk of OHSS. (4) Luteal-phase support (n = 3 statements): Vaginal progesterone therapy represents the gold standard for luteal-phase support.ConclusionsThis Delphi consensus provides a real-world clinical perspective on the specific approaches during the key steps of ART treatment from a diverse group of international experts. Additional guidance from clinicians on ART strategies could complement guidelines and policies, and may help to further improve treatment outcomes.

A Review of the Occurrence and Mechanisms of Induction of Osteoporosis Following Spinal Cord Injury

Introduction: Spinal cord injury (SCI) causes devastating injuries in patients. The main mechanisms of the pathogenesis of secondary injury include nerve degeneration, gliosis, and inflammation. Spinal cord injury induces a disorder or failure in several organs due to the vital role of the spinal cord in regulating bodily functions. Osteoporosis is a consequence of spinal cord injury that occurs in the vast majority of patients with spinal cord injury. Articles on the related topic were searched in the following databases: Science Direct, Scopus, Springer Science, PubMed and Google scholar to have been used in writing from this review article. A total of 120 related research papers, including quantitatve and qualitative researches in English, from the last 57 years papers (1962- 2019) were included in this study. The review article is written according to 120 articles and the keywords “Spinal cord injury, Osteoporosis, Inflammation, Osteoblast and Osteoclast”. Conclusion: Although weight loss is an important factor in the development of osteoporosis following SCI, inflammation, nerve damage, and hormonal changes also contribute to this process. Hormonal changes mediated by SCI may contribute to postoperative osteoporosis with several mechanisms. These mechanisms included: increased renal excretion and decreased intestinal absorption of calcium, consequently, a negative balance of calcium ions; Vitamin D deficiency; impair the function of the gonads and inhibits the osteoanabolic (ossification) activity of sex steroids; elevated blood leptin; Pituitary suppression of parathyroid hormone, and bone loss following SCI may (at least in part) be caused directly by insulin resistance and insulin-like growth factor.

Ovarian hyperresponse following the sole administration of GnRH agonist

Background : The gonadotrophin-releasing hormone agonist (GnRHa) has gained widespread popularity of achieving pituitary suppression before ovarian stimulation with exogenous gonadotropins in assisted reproductive technology protocols. However, a very small part of patients may develop ovarian hyperresponse after the sole administration of GnRHa without gonadotropins. Case report: A 32-year-old female diagnosed with polycystic ovary syndrome presented for her second IVF cycle in our reproductive center. Twenty-eight days after 3.75mg triptorelin was administrated on day 2 of her menstrual cycle, bilateral ovaries were significantly enlarged and presented multiple cystic masses. The hormone profile was as follows: E2＞4870pg/ml, P 13.19ng/ml, FSH 14IU/L, and LH 10.77IU/L. The patient felt symptoms of mild ovarian hyperstimulation syndrome. In the subsequent IVF treatment cycle, antagonist protocol was performed. It showed that follicles developed slowly and exogenous gonadotropins were used for 13 days. Finally, seven oocytes were obtained and only one blastocyst graded 4BC formed. Conclusion: Ovarian hyperstimulation following the sole administration of GnRHa can be occurred, but the mechanism is still not yet clear. Antagonist protocol may be an alternative fertility strategy, but the risk of poor embryo quality and low pregnancy rate of transplantation should be warned.

Progestins for pituitary suppression during ovarian stimulation for ART: a comprehensive and systematic review including meta-analyses

BACKGROUND Progestins are capable of suppressing endogenous LH secretion from the pituitary. Progestins can be used orally and are less expensive than GnRH analogues. However, early endometrial exposure to progestin precludes a fresh embryo transfer (ET), but the advent of vitrification and increasing number of oocyte cryopreservation cycles allow more opportunities for using progestins for pituitary suppression. OBJECTIVE AND RATIONALE This review summarizes: the mechanism of pituitary suppression by progestins; the effectiveness of progestins when compared with GnRH analogues and with each other; the effect of progestins on oocyte and embryo developmental potential and euploidy status; and the cost-effectiveness aspects of progestin primed stimulation. Future research priorities are also identified. SEARCH METHODS The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE via PubMed, the Web of Science and Scopus were screened with a combination of keywords related to ART, progesterone, GnRH analogue and ovarian stimulation, in various combinations. The search period was from the date of inception of each database until 1 April 2020. Only full text papers published in English were included. OUTCOMES Overall, the duration of stimulation, gonadotrophin consumption and oocyte yield were similar with progestins and GnRH analogues. However, sensitivity analyses suggested that progestins were associated with significantly lower gonadotrophin consumption than the long GnRH agonist protocol (mean difference (MD) = −648, 95% CI = −746 to −550 IU) and significantly higher gonadotrophin consumption than the short GnRH agonist protocol (MD = 433, 95% CI = 311 to 555 IU). Overall, live birth, ongoing and clinical pregnancy rates per ET were similar with progestins and GnRH analogues. However, when progestins were compared with GnRH agonists, sensitivity analyses including women with polycystic ovary syndrome (risk ratio (RR) = 1.27, 95% CI = 1.06 to 1.53) and short GnRH agonist protocols (RR = 1.14, 95% CI = 1.02 to 1.28) showed significantly higher clinical pregnancy rates with progestins. However, the quality of evidence is low. Studies comparing medroxyprogesterone acetate, dydrogesterone and micronized progesterone suggested similar ovarian response and pregnancy outcomes. The euploidy status of embryos from progestin primed cycles was similar to that of embryos from conventional stimulation cycles. Available information is reassuring regarding obstetric and neonatal outcomes with the use of progestins. Despite the lower cost of progestins than GnRH analogues, the mandatory cryopreservation of all embryos followed by a deferred transfer may increase cost per live birth with progestins as compared to an ART cycle culminating in a fresh ET. WIDER IMPLICATIONS Progestins can present an effective option for women who do not contemplate a fresh ET, e.g. fertility preservation, anticipated hyper responders, preimplantation genetic testing, oocyte donors, double stimulation cycles.