Fixed Gonadotropin-Releasing Hormone Antagonist Protocol Versus Flexible Progestin-Primed Ovarian Stimulation Protocol in Patients With Asynchronous Follicular Development During Controlled Ovulation Stimulation: A Retrospective Study

Protocols utilizing gonadotropin-releasing hormone (GnRH) antagonists have emerged as mainstream procedures for ovarian stimulation; however, GnRH increases the risk for periodic cancellation of embryos. Therefore, this study aimed to compare the pregnancy outcomes of a fixed GnRH antagonist protocol and a flexible progestin-primed ovarian stimulation (fPPOS) protocol in patients with asynchronous follicular development during controlled ovulation stimulation and to explore the feasibility of converting patients undergoing a fixed GnRH antagonist protocol to an fPPOS protocol. This was the first retrospective study exploring the fPPOS protocol in patients with asynchronous follicular development, and it was conducted in a public reproductive medicine center from January to December 2020. We included infertile women. All participants were scheduled to undergo administration of a GnRH antagonist on the fifth day of controlled ovulation stimulation. The study group included 129 women who were converted from the fixed GnRH antagonist protocol to the fPPOS protocol for their asynchronous follicular development, while the antagonist group consisted of 258 women (ratio 1:2) who proceeded with a fixed GnRH antagonist protocol. On the second or third day of the menstrual period, 100–300 IU/day gonadotropin injections were administered. For patients who were converted to the fPPOS protocol, medroxyprogesterone acetate tablets at 10 mg/day were started on the fifth day of stimulation or when only one leading follicle reached 14 mm and the other follicles were ≤10 mm in diameter, whichever came first. The rates of embryo implantation, clinical pregnancy, and early pregnancy loss were obtained. The number of oocytes retrieved and the number of high-quality embryos in the antagonist group were significantly higher than those in the fPPOS group (P = 0.039 and P = 0.025, respectively). No significant differences in the rates of embryo implantation, clinical pregnancy, and early pregnancy loss were observed between the two groups. Our study found that in patients who were scheduled for administration of GnRH antagonists but presented with asynchronous follicular development on the fifth stimulation day, it was feasible to switch to the fPPOS protocol.

GnRH Antagonists with or without Add-Back Therapy: A New Alternative in the Management of Endometriosis?

To evaluate the effectiveness of a new class of medical drugs, namely oral gonadotropin-releasing hormone (GnRH) antagonists, in the management of premenopausal women with endometriosis-associated pelvic pain. We reviewed the most relevant papers (n = 27) on the efficacy of new medical alternatives (oral GnRH antagonists) as therapy for endometriosis. We first briefly summarized the concept of progesterone resistance and established that oral contraceptives and progestogens work well in two-thirds of women suffering from endometriosis. Since clinical evidence shows that estrogens play a critical role in the pathogenesis of the disease, lowering their levels with oral GnRH antagonists may well prove effective, especially in women who fail to respond to progestogens. There is a need for reliable long-term oral treatment capable of managing endometriosis symptoms, taking into consideration both the main symptoms and phenotype of the disease. Published studies reviewed and discussed here confirm the efficacy of GnRH antagonists. There is a place for GnRH antagonists in the management of symptomatic endometriosis. Novel algorithms that take into account the different phenotypes are proposed.

Comparison of Cumulative Live Birth Rates Per Aspiration IVF/ICSI Cycle Between GnRH Antagonist Protocol and Progesterone-Primed Ovarian Stimulation Protocol for Infertility With Normal Ovarian Reserve: A Randomised Controlled Trial

Background: Oral progestin has been used to prevent premature ovulation during follicle stimulation protocols performed in combination with a freeze-only strategy. However, no studies have determined how oral progestin clinically compares to gonadotropin-releasing hormone (GnRH) antagonists in women with normal ovulation. This study aimed to compare the efficacy and safety of controlled ovarian stimulation between progestin-primed ovarian stimulation (PPOS) protocol and GnRH antagonist (GnRH-ant) protocol.Methods: Young women with infertility and normal ovarian reserve who underwent in vitro fertilisation (IVF) treatments were screened and randomly allocated to the PPOS or GnRH-ant group. Women in the PPOS group underwent freeze-all and delayed embryo transfer, whilst fresh embryo transfer was preferred for those in the GnRH-ant group. The primary endpoint was the cumulative live birth rate (CLBR). Secondary endpoints included the incidence of premature luteinising hormone (LH) surge and the number of viable embryos.Results: CLBRs were similar in the PPOS and GnRH-ant group (55.75% vs. 52.87%, respectively, P > 0.05). No premature LH surge was observed during ovarian stimulation in the PPOS group, although six (3.45%) cases were observed in the GnRH-ant group. On the trigger day, LH level was lower in the PPOS group than in the GnRH-ant group (2.30 ± 1.78 mIU/ml vs. 3.66 ± 3.52 mIU/ml, P < 0.01). There were no differences in the number of retrieved oocytes, mature oocytes, or viable embryos between the two groups. Other clinical outcomes including implantation rates (37.27% vs. 36.77%), clinical pregnancy rates (55.75% vs. 55.89%), and miscarriage rates (12.28% vs. 13.76%) were comparable between the PPOS group and GnRH-ant group (P > 0.05). There was also no significant differences in newborn weights for singleton or twin births between the two groups (P > 0.05).Conclusion: Live birth outcomes are similar for PPOS and GnRH antagonist protocols in women with normal ovarian reserve. PPOS is likely to play a promising role in the freeze-only strategy given its simplicity and convenience for the patient. Trial registration: This trial was registered in the China Clinical Trial Registry on September 6, 2018 (number: ChiCTR1800018246).

Medical Treatment for Endometriosis: Tolerability, Quality of Life and Adherence

Endometriosis is associated with painful symptoms, infertility, sexological difficulties, and psychological suffering. All these symptoms have a negative impact on the overall quality of life of women with the disease, with significant personal, social and economic costs. Several medical options are available to manage symptomatic endometriosis. The pharmacological treatment for endometriosis-related pain may be necessary for decades, or at least until there is a desire for pregnancy or physiologic menopause occurs. In this perspective, clinicians should consider not only the efficacy, but also side effects, tolerability, and costs, along with women's preferences toward different treatments. In this mini-review, we analyzed the pros and cons of the available drugs for the medical therapy of endometriosis, such as estrogen-progestins, progestins, GnRH agonist and GnRH antagonists.

Conservative Management of Uterine Fibroid-Related Heavy Menstrual Bleeding and Infertility: Time for a Deeper Mechanistic Understanding and an Individualized Approach

(1) Background: Uterine fibroids are the most common form of benign uterine tumors, causing heavy menstrual bleeding (HMB), pelvic pain, infertility and pressure symptoms. Almost a third of women with uterine fibroids seek treatment. The objective of this review is to understand the mechanisms linking fibroids to these symptoms and evaluate different options for their management, particularly the place of gonadotropin-releasing hormone (GnRH) antagonist. (2) Methods: We gathered the most recent and relevant papers on the main fibroid-related symptoms and medical and surgical therapy for their treatment. Those reporting use of oral GnRH antagonists were investigated in detail. (3) Results: The mechanisms explaining myoma-related HMB and infertility were reviewed, as they are essential to a deeper mechanistic understanding and oriented approach. The choice of treatment depends on the number, size, and location of fibroids, and is guided by the patient’s age and desire to preserve her fertility. Economic impacts of myomas in terms of direct costs, lost workdays, and complications were found to be significant. Medical, surgical, and non-surgical strategies were analyzed in this context. Novel medical approaches with GnRH antagonist were explored and found to represent an effective new option. (4) Conclusion: The need for alternatives to surgical intervention is very real, especially for women seeking to preserve their fertility. New options now exist, with GnRH antagonists proven to treat fibroid symptoms effectively, opening the door to novel strategies for the management of myomas.

Uterine Adenomyosis: From Disease Pathogenesis to a New Medical Approach Using GnRH Antagonists

Uterine adenomyosis is a common chronic disorder frequently encountered in reproductive-age women, causing heavy menstrual bleeding, intense pelvic pain, and infertility. Despite its high prevalence, its etiopathogenesis is not yet fully understood, so there are currently no specific drugs to treat the disease. A number of dysregulated mechanisms are believed to contribute to adenomyosis development and symptoms, including sex steroid signaling, endometrial proliferation and invasiveness, and aberrant immune response. Abnormal sex steroid signaling, particularly hyperestrogenism and subsequent progesterone resistance, are known to play a pivotal role in its pathogenesis, which is why various antiestrogenic agents have been used to manage adenomyosis-related symptoms. Among them, gonadotropin-releasing hormone (GnRH) antagonists are swiftly gaining ground, with recent studies reporting efficient lesion regression and symptom alleviation. The aim of the present review is to compile available information on the pathogenesis of adenomyosis, explore the etiology and mechanisms of hyperestrogenism, and discuss the potential of antiestrogenic therapies for treating the disease and improving patient quality of life.

Cardiovascular Safety of Degarelix versus Leuprolide in Patients with Prostate Cancer: The Primary Results of the PRONOUNCE Randomized Trial

Background: The relative cardiovascular safety of gonadotropin-releasing hormone (GnRH) antagonists compared with GnRH agonists in men with prostate cancer and known atherosclerotic cardiovascular disease (ASCVD) remains controversial. Methods: In this international, multicenter, prospective, randomized, open-label trial, men with prostate cancer and concomitant ASCVD were randomized 1:1 to receive the GnRH antagonist degarelix or the GnRH agonist leuprolide for 12 months. The primary outcome was the time to first adjudicated major adverse cardiovascular event (MACE) (composite of death, myocardial infarction, or stroke) through 12 months. Results: Due to slower than projected enrollment and fewer than projected primary outcome events, enrollment was stopped before the 900 planned participants were accrued. From 3 May 2016 to 16 April 2020, a total of 545 patients from 113 sites across 12 countries were randomized. Baseline characteristics were balanced between study groups. The median age was 73 years, 49.8% had localized prostate cancer; 26.3% had locally advanced disease and 20.4% had metastatic disease. MACE occurred in 15 (5.5%) patients assigned to degarelix and 11 (4.1%) assigned to leuprolide (hazard ratio [HR] 1.28, 95% confidence interval [CI] 0.59-2.79; p=0.53). Conclusions: PRONOUNCE is the first, international, randomized clinical trial to prospectively compare the cardiovascular safety of a GnRH antagonist and a GnRH agonist in patients with prostate cancer. The study was terminated prematurely due to smaller than planned number of participants and events and no difference in MACE at 1 year between patients assigned to degarelix or leuprolide was observed. The relative cardiovascular safety of GnRH antagonists and agonists remains unresolved. Clinical Trial Registration: URL: https://clinicaltrials.gov Unique Identifier: NCT02663908

P–685 Luteinization after final oocyte maturation induction is not compromised in women that receive double dose of Gonadotrophin-releasing hormone antagonists during controlled ovarian hyperstimulation

Study question Does the use of double dose of GnRH antagonists during COH in women with risk of premature LH surge alter luteinization after final oocyte maturation induction? Summary answer The use of double dose of GnRH antagonist in women with risk of premature luteinizing hormone surge dosent affect luteinization after final oocyte maturation induction. What is known already GnRH antagonists are used to prevent a premature LH surge during controlled ovarian hyperstimulation. The antagonists directly inhibit gonadotrophin release within several hours through competitive binding to pituitary GnRH receptors, producing a rapid suppression of LH and FSH, with no initial flare effect. In women with diminished ovarian reserve (DOR) it is not uncommon that premature luteinization cannot be completely prevented using a daily dose GnRH antagonist. To date, no study has evaluated the effects of using a daily double dose of GnRH antagonists to prevent a premature LH surge and its effect on luteinization after final oocyte maturation induction. Study design, size, duration This monocentric retrospective analysis evaluated the effect on luteinization after final oocyte maturation induction in twenty women during COH who received a daily double dose of GnRH antagonists (Cetrotide 0.25 mg/mL, Merck) from January 2020 to December 2020. Participants/materials, setting, methods Women with severe DOR and history of premature luteinization during COH received a double dose of GnRH antagonist when the leading follicle reached 12–14 mm (am and pm). When two follicles reached ≥18 mm in diameter, final oocyte maturation was induced with dual trigger using Leuprolide acetate and hCG. Progesterone, estradiol, bHCG, and LH levels were measured the day after final oocyte maturation induction to assure adequate luteinization. Main results and the role of chance In total twenty women were included in the analysis. Mean age 36.8± 4.2, AMH 0.65± 0.32 ng/ml, baseline antral follicle count 4± 2.3, serum hormone levels the day of ovulation induction trigger: progesterone 0.89± 0.34 ng/ml, LH 1.6± 2.1 ng/ml, estradiol 1235 ± 1420 pg/ml. Post-surge serum hormone levels average reached adequate levels: estradiol 1645 ± 1116 pg/ml, progesterone 20.4 ±2.2 ng/ml, LH 62.66± 10.5 IU/ml and, bHCG 247±115 IU/ml. A total of 76 oocytes were retrieved (3.8± 0.8 oocytes per patient), 63.1% (48/76) MII, 22% (17/76) MI, 14% (11/76) GV. Limitations, reasons for caution The retrospective nature of the study, small sample size, and potential variability in the study center’s laboratory protocol(s) compared to other reproductive treatment centers may limit the external validity of our findings. Wider implications of the findings: The daily use of double dose of GnRH antagonists during COH offers the possibility of preventing a premature LH surge in women with DOR with high risk of early ovulation, without compromising luteinization after final oocyte maturation induction. Trial registration number NA

P–707 Does the dose or type of gonadotropin affect the reproductive outcomes of poor responders undergoing modified natural cycle IVF (MNC-IVF)?

Study question Does the dose or type of gonadotropin affect the reproductive outcomes of poor responders undergoing MNC-IVF? Summary answer Neither the type nor the dose of gonadotropins affects the reproductive outcomes of poor responders undergoing MNC-IVF. What is known already Poor ovarian response (POR) to ovarian stimulation remains a major therapeutic challenge in routine IVF practice, because of the association with low live birth rates and high cancellation rates. Although high doses of gonadotropins are traditionally used to stimulate the ovaries in women with predicted POR, MNC-IVF has been proposed as a mild-approach alternative in this population. Typically, the MNC protocol includes GnRH-antagonists to avoid premature ovulation and gonadotropin add-back stimulation at the late follicular phase. However, evidence is sparse, and there is no consensus regarding a specific dose or type of gonadotropins in this mild stimulation protocol. Study design, size, duration This is a retrospective cohort study including patients attending a tertiary referral University Hospital from 1st January 2017 until 1st March 2020. Participants/materials, setting, methods All women who underwent MNC-IVF in our center were included. Gonadotropins [recombinant FSH (rFSH), urinary FSH (uFSH) or highly purified human menopausal gonadotrophin (hp-hMG)] were started when a follicle with a mean diameter of 12–14 mm was observed on ultrasound scan, followed by GnRH antagonists (0.25mg/day) from the next day onwards. Mature oocytes were inseminated using ICSI. Main results and the role of chance In total, 484 patients undergoing 1398 cycles were included. Mean (SD) age and serum AMH were 38.2 (3.7) years and 0.46 (0.78) ng/ml, respectively. The daily dose of gonadotropins was either &lt;75 IU/d [11/1398 (0.8%)] or 75 to &lt; 100 IU/d [1303/1398 (93.2%)] or ≥ 100 IU/d [84/1398 (6%)]. Patients were stimulated with: rFSH [251/1398 (18%)], uFSH [45/1398 (3.2%)] or hp-hMG [1102/1398 (78.8%)]. Biochemical and clinical pregnancy rates were 142/1398 (10.1%) and 119/1398 (8.5%). Live birth was achieved in 80/1398 (5.7%) of cycles. Live birth rates (LBR) were similar between the different type and doses of gonadotropins (p-value 0.3 and 0.51, respectively). The GEE multivariate regression analysis adjusting for relevant confounders (age, BMI, number of MII oocytes) showed that the type of treatment strategy (rFSH/uFSH/hp-hMG) and the dose of gonadotropins were not significantly associated with LBR (coefficient 0.01 and –0.02, p value 0.09 and 0.3, respectively). Limitations, reasons for caution The main limitation is the retrospective design of our study, with an inherent risk of bias. Wider implications of the findings: This is the first and largest study evaluating MNC-IVF protocol modalities. Our data demonstrate that any type of gonadotropin can be used and there is no benefit from daily doses beyond 75IU. Trial registration number N/A