[IN VITRO FERTILIZATION (IVF) TREATMENTS IN MACCABI HEALTHCARE SERVICES 2015-2020].

BACKGROUND: Previously, we have summarized IVF treatment outcomes for the years 2007-2014. In 2014, the Ministry of Health (MOH) recommended that infertile patients above 39 years of age can be offered IVF as a first line treatment, given the natural age-related decrease in ovarian reserve. OBJECTIVES: The purpose of the current publication is to summarize IVF treatment outcomes for the years 2015-2020, and to explore possible changes in IVF treatments following the MOH statement. METHODS: IVF treatments and live birth data were collected from Maccabi Healthcare Services' fertility treatments registry. We have included only autologous fresh and frozen embryo transfer (FET) cycles. A successful treatment cycle was defined if a live birth was recorded between 6 to 10 months of its initiation. RESULTS: Mean patients' age increased from 36.2 years in 2011 to 37.5 years in the 6 years surveyed (2015-2020). While the number of fresh cycles was stable, the number of FET cycles increased from 4,507 in 2015 to 6,795 in 2020. The percentage of cycles performed in private hospitals increased gradually from 72% in 2015 to 77% in 2020. The number of patients over 40 years of age increased from 3,204 in 2011, to 3,648 in 2014, and to 3,915 in 2020. CONCLUSIONS: The total number of IVF cycles increased gradually from 2015 to 2020, mainly due to significant increase in FET cycles. The continued increase in mean patients' age may reflect the change in MOH recommendations.

LH supplementation in IVF: human nature, politics, and elephants in the room.

Luteinizing hormone (LH) is present throughout the natural follicular phase. However, the debate is still not settled on whether LH is needed during ovarian stimulation in IVF. This commentary looks at the evolution of this debate, mentioning three elephants in the room that were ignored by the Pharma industry, professional organizations, and clinicians alike: 1. The different endocrinology between the long agonist and the antagonist protocols. 2. The fixed dose of the two most widely commercially available antagonist preparations, namely cetrorelix and ganirelix. 3. The fact that most research in this area uses population-based criteria, ignoring endocrine parameters. Individual genetics of the LH receptor gene may also serve to individualize LH needs during stimulation; however, the jury is still out regarding this approach. CONCLUSIONS: Individual endocrine and genetics parameters may shed meaningful light on the question of LH supplemental during ovarian stimulation.

Ideal frozen embryo transfer regime.

PURPOSE OF REVIEW: This review aims to compare evidence on four criteria (embryo implantation, obstetric outcomes, patient convenience, and IVF-unit efficiency) by analyzing published research on different endometrial preparation methods for frozen embryo transfer (FET). RECENT FINDINGS: While the artificial-FET cycle provides advantages in scheduling and implantation, it falls short in ensuring optimal obstetric outcomes. In contrast, natural-FET ensures embryo implantation conditions if ovulation is correctly identified. Supplementing with exogenous progesterone shields against low corpus luteum progesterone secretion, crucial for positive obstetric outcomes. In mNC-FET, ovulation is hCG-triggered, closely resembling natural cycles and reducing monitoring visits for enhanced patient convenience.Letrozole is a recommended option for anovulatory patients, preserving endometrial thickness. It is cost-effective, less likely to induce multifollicular development than gonadotropins, and better tolerated.In a novel approach, the natural-proliferative-phase-FET initiates progesterone in an unmediated ovulatory cycle at 7 mm endometrial thickness, combining the benefits of a natural proliferative endometrium with the convenience of scheduled artificial cycles. SUMMARY: The artificial cycle offers scheduling advantages, but may compromise obstetric outcomes. Natural FET relies on accurate ovulation timing for successful implantation. mNC-FET simplifies the process using hCG induction, minimizing clinic visits for improved convenience. Letrozole is highlighted as a cost-effective and well tolerated option in anovulatory patients. A recent innovative approach combines elements of natural and artificial cycles, showing promise for FET procedures.

Time-sensitive assessment of luteal phase progesterone after HCG ovulation triggering: another brick off the wall?

In recent years, there has been growing interest in understanding the dynamics of progesterone levels during the luteal phase after HCG-triggered ovulation. Recent studies have provided data showing a deviation from the natural ovulatory cycle, with peak progesterone concentrations occurring earlier and declining steadily thereafter, demonstrating that a fall in progesterone concentration early in the luteal phase was associated with lower rates of ongoing pregnancy. These findings highlight the importance of changes in progesterone concentration, rather than absolute concentrations, in determining optimal endometrial conditions. The disadvantages of HCG triggering, including the lack of a natural FSH surge and asynchronization between embryo age and endometrium receptivity, can be addressed by using gonadotrophin-releasing hormone agonist (GnRHa) triggering. GnRHa triggering induces both LH and FSH surges, ensures appropriate progesterone concentrations and offers flexibility in manipulating the luteal phase. Transitioning to GnRHa triggering could improve infertility treatment.

Time, time, time: see what governs the luteal phase endocrinology.

Two modes of ovulation trigger are used in IVF: hCG, acting on ovarian LH receptors, and GnRH agonist, eliciting pituitary LH and FSH surges. These two modes are evaluated herein, focusing on how they serve specific time-sensitive events crucial for achieving embryo implantation and pregnancy. hCG trigger is associated with significant timing deviation from physiology. Peak progesterone is not synchronized with implantation window; progesterone level does not rise continuously to a mid-luteal peak, but rather drops from a too early peak. The luteal phase endocrinology post GnRH agonist trigger is characterized by a quick and irreversible luteolysis. Therefore, freeze all strategy is advised, if there is a risk of ovarian hyperstimulation syndrome. If fresh transfer is desired, numerous approaches for luteal phase support have been suggested. However, a thorough understanding of time-sensitive events suggests that a single 1,500 IU hCG dose, administered 48 h post oocyte retrieval, is all that is needed to fully support the luteal phase and secure best chances of achieving pregnancy.

The exogenous progesterone-free luteal phase: two pilot randomized controlled trials in IVF patients.

RESEARCH QUESTION: Is the reproductive outcome similar after gonadotrophin-releasing hormone agonist (GnRHa) trigger followed by luteal human chorionic gonadotrophin (HCG) boluses compared with HCG trigger and a standard luteal phase support (LPS)? DESIGN: Two open-label pilot randomized controlled trials (RCT) with 250 patients from 2014 to 2019, with a primary outcome of ongoing pregnancy per embryo transfer. Patients with ≤13 follicles on the trigger day were randomized (RCT 1) to: Group A (n = 65): GnRHa trigger followed by a bolus of 1500 IU HCG s.c. on the oocyte retrieval day (ORD) and 1000 IU HCG s.c. 4 days later, and no vaginal LPS; or Group B (n = 65): 6500 IU HCG trigger, followed by a standard vaginal progesterone LPS. Patients with 14-25 follicles on the trigger day were randomized (RCT 2) to Group C (n = 60): GnRHa trigger followed by 1000 IU HCG s.c. on ORD and 500 IU HCG s.c. 4 days later, and no vaginal LPS; or Group D (n = 60): 6500 IU HCG trigger and a standard vaginal LPS. RESULTS: In RCT 1, the ongoing pregnancy rate was 44% (22/50) in the GnRHa group versus 46% (25/54) in the HCG trigger group (RR 0.95, 95% CI 0.62-1.45). No ovarian hyperstimulation syndrome (OHSS) was seen in Groups A or B. In RCT 2, the ongoing pregnancy rate was 51% (25/49) in the GnRHa group versus 60% (31/52) in the HCG trigger group (RR 0.86, 95% CI 0.60-1.22). The OHSS rates were 3.3% and 6.7%, respectively. CONCLUSIONS: Although a larger-scale study is needed before standard clinical implementation, the present study supports that the exogenous progesterone-free LPS is efficacious, simple and patient-friendly.

Suboptimal response to GnRH agonist trigger: causes and practical management.

PURPOSE OF REVIEW: GnRH agonist products are used extensively worldwide to trigger ovulation and final oocyte maturation in in vitro fertilization cycles. The purpose of this article is to outline possible causes for a suboptimal response to the GnRH agonist trigger. RECENT FINDINGS: Risk factors for such a suboptimal response include prolonged hormonal contraceptive use, previous GnRHa-induced pituitary downregulation, a hypogonadotropic/hypogonadal condition, patient error, environmental conditions that may damage the GnRHa product used, GnRH and luteinizing hormone (LH) receptors polymorphisms, low baseline LH and low endogenous serum LH levels on trigger day as well as low BMI. The induction of an adequate LH surge can be ascertained by an LH urine test 12 h post trigger. SUMMARY: In most cases, GnRHa trigger elicits effective LH+follicle stimulating hormone surges, resulting in mature, fertilizable oocytes. Clinical awareness to conditions that may predispose to a suboptimal response to the GnRHa trigger may prevent failed oocyte retrial.

IVF and the exogenous progesterone-free luteal phase.

PURPOSE OF REVIEW: In a conventional IVF cycle, final oocyte maturation and ovulation is triggered with a bolus of hCG, followed by progesterone-based luteal support that spans several weeks if pregnancy is achieved. This article summarizes several approaches of the exogenous progesterone-free luteal support in IVF. RECENT FINDINGS: Triggering ovulation with GnRH agonist may serve as an alternative to hCG, with well established advantages. In addition, the luteal phase can be individualized in order to achieve a more physiologic hormonal milieu, and a more patient friendly treatment, alleviating the burden of a lengthy exogenous progesterone therapy. SUMMARY: GnRH agonist trigger followed by a 'freeze all' policy is undoubtedly the best approach towards the 'OHSS-free clinic'. If fresh embryo transfer is considered well tolerated after GnRH agonist trigger, rescue of the corpora lutea by LH activity supplementation is mandatory. Herein we discuss the different approaches of corpus luteum rescue.

GnRH agonist triggering followed by 1500 IU of HCG 48 h after oocyte retrieval for luteal phase support.

RESEARCH QUESTION: Gonadotrophin releasing hormone (GnRH) agonist trigger after GnRH antagonist-based ovarian stimulation protocol for IVF is gaining popularity, because it prevents ovarian hyperstimulation syndrome and allows for near physiological LH and FSH surges. A small dose of HCG (1500 IU) on the day of oocyte retrieval, followed by daily progesterone administration, is currently the preferred way to secure adequate luteal support after GnRH agonist trigger. In the present study, the possibility that a bolus of 1500 IU HCG, given 2 days after oocyte retrieval, may be sufficient to sustain adequate luteal support without additional progesterone treatment was questioned. DESIGN: A non-interventional retrospective cohort study between conducted between April 2017 and August 2018. A total of 154 consecutive patients treated with GnRH agonist trigger followed by day-2 HCG (1500 IU) support only (study group) were included. Data were compared with 155 consecutive patients who were treated with HCG (6500 IU) trigger followed by conventional progesterone luteal support (control group). RESULTS: Pregnancy, miscarriage and live birth rates were comparable between the study and control groups. In patients who became pregnant, mean oestradiol level 14 days after oocyte retrieval was 4719 pmol/l and 2672 pmol/l in the study and control group, respectively (P < 0.001), reflecting robust luteal activity in the study group. CONCLUSIONS: A bolus of 1500 IU HCG, administered 2 days after retrieval, can provide excellent luteal support, without the need for further progesterone supplementation.

LH Supplementation in Ovarian Stimulation for IVF: The Individual, LH Deficient, Patient Perspective.

The availability of recombinant follicle-stimulating hormone (FSH) and luteinizing hormone (LH) opens an opportunity to individualize ovarian stimulation. While the need for FSH in ovarian stimulation is universal, a question remains whether exogenous LH is beneficial. Previous population-based research showed that added LH is indicated in elderly and in profoundly LH depressed patients. This commentary explores potential individual patient parameters that may hint that this specific individual may prospectively need supplemented LH, irrespective of her age or experience from previous cycles. Specifically, it is suggested that in an antagonist protocol, the degree of LH recovery 24 h post first GnRH antagonist injection can identify those patients who may benefit from added LH. In addition, rising LH during the first 5 days of stimulation may predispose patients to a sharp LH drop following the first GnRH antagonist dose, and the need for added LH.

The Importance of Mid-Follicular Phase Luteinizing Hormone Rise in GnRH Antagonist-Based Ovarian Stimulation for IVF.

INTRODUCTION: Previous publications examined the endocrinology of follicular stimulation, focusing on luteinizing hormone (LH) levels changes. In selected, good prognosis IVF patients, a sharp drop in LH serum level was demonstrated between cycle days 2 and 6. OBJECTIVE: The purpose of this study was to examine if this finding holds true for unselected patients. METHODS: We retrospectively included 165 consecutive patients treated with a GnRH antagonist-based ovarian stimulation protocol during the year 2015. RESULTS AND CONCLUSIONS: In 33% of the patients an increase in LH, rather than the expected decrease, was demonstrated after 5 stimulation days. There was no difference in pregnancy outcome. Our results suggest that an increase in LH levels during ovarian stimulation occurs mainly in "high responders", or "low responders". LH rise in mid follicular phase may result in a sharp LH drop once a GnRH antagonist is given, and the possible need for LH supplementation.

Distinct and independent dielectrophoretic behavior of the head and tail of sperm and its potential for the safe sorting and isolation of rare spermatozoa.

Often, in semen samples with minute amounts of sperm, even the single spermatozoon required to fertilize an oocyte cannot be found in the ejaculate. This is primarily because currently, sperm is generally searched for manually under a microscope. In this study, dielectrophoresis (DEP) was investigated as an alternative automated technique for sorting sperm cells. Using a quadrupolar electrode array it was shown that the head and tail of the sperm had independent and unique crossover frequencies corresponding to the transition of the DEP force from repulsive (negative) to attractive (positive). These surprising results were further analyzed, showing that the head and tail have their own distinct electrical properties. This significant result allows for the sperm's head, which contains the DNA, to be distanced from potentially damaging high electric fields using negative DEP while simultaneously manipulating and sorting the sperm using the positive DEP response of the tail. A proof of concept sorting chip was designed and tested. The low crossover frequency of the tail also allows for the use of a higher conductivity, and thus more physiological, medium than the conventional DEP solutions. Although more research is required to design and optimize an efficient, user-friendly, and high-throughput device, this research is a proof of concept that DEP has the potential to automate and improve the processing of semen samples, especially those containing only rare spermatozoa.

A Rationale for Timing of Luteal Support Post Gonadotropin-Releasing Hormone Agonist Trigger.

Gonadotropin-releasing hormone (GnRH) antagonist-based ovarian stimulation protocol is gaining popularity. This protocol allows for the use of GnRH agonist as a trigger of final oocyte maturation, instead of the "gold standard" human chorionic gonadotropin (hCG) trigger. GnRH agonist trigger causes quick luteolysis, hence its widespread use in the context of ovarian hyperstimulation syndrome (OHSS) prevention. To secure pregnancy post GnRH agonist trigger, the luteal phase must be supplemented to counteract the luteolysis. Several luteal phase protocols post GnRH agonist trigger have been suggested, most notably based on increasing luteal luteinizing hormone (LH) activity (by adding LH or hCG). The current review aims at delineating a rationale for timing luteal support with a single hCG bolus post GnRH agonist trigger. The review also suggests a set of simple rules that must be followed when designing luteal phase support post GnRH agonist trigger.

GnRHa trigger and luteal coasting: a new approach for the ovarian hyperstimulation syndrome high-risk patient?

Final oocyte maturation using gonadotrophin-releasing hormone agonist (GnRHa) is increasingly common as it almost eliminates the risk of developing ovarian hyperstimulation syndrome (OHSS) in high-responder patients. The first studies using this approach showed a poor reproductive outcome when only vaginal progesterone was used as luteal phase support, due to the luteolysis that will develop as a result of LH withdrawal. Timely luteal administration of human chorionic gonadotrophin (HCG) will counterbalance the low LH concentrations and therefore maintain progesterone production from the corpora lutea, however, some patients with a high number of follicles will develop OHSS using this approach. The concept of 'luteal coasting' transfers the experience from follicular phase coasting for OHSS prevention to the early luteal phase for patients having fresh transfers. Daily monitoring of progesterone concentrations is required and a rescue HCG bolus can be administered, once progesterone concentrations drop below 30 nmol/l. This approach reduces the risk of OHSS development in high-responder patients undergoing fresh embryo transfer, without negatively impacting the reproductive outcome.

Day two post retrieval 1500 IUI hCG bolus, progesterone-free luteal support post GnRH agonist trigger - a proof of concept study.

Small dose of hCG (1500 IU) on the day of oocyte retrieval, followed by daily progesterone administration, is currently the preferred way to secure adequate luteal support following GnRH agonist trigger. In the current proof-of-concept study, we explored the possibility that a bolus of 1500 IU hCG, given two days after oocyte retrieval, may be sufficient to sustain adequate luteal support without additional progesterone treatment. From February 2015 to August 2016, we obtained 44 pregnancies following GnRHa trigger followed by day 2 hCG (1500 IU) support only (study group). Data from these 44 cycles were compared with the latest 44 pregnancies obtained following hCG (6500 IU) trigger followed by conventional progesterone luteal documented (control group). Mean progesterone levels (14 days postoocyte retrieval) in the study and control groups were 197 nmol/l and 173 nmol/l, respectively (NS). Mean E2 levels (14 days post oocyte retrieval) in the study group was 6937 pmol/l, significantly higher (p < .001) than in the control group (3.276 pmol/l). We conclude that bolus of 1500 IU hCG, administered 2 days after retrieval, can provide excellent support, without the need to further supplement with progesterone.

Anovulatory Patients Demonstrate a Sharp Decline in LH Levels upon GnRH Antagonist Administration during IVF Cycles.

To evaluate the decrease in luteinizing hormone (LH) levels following gonadotropin-releasing hormone (GnRH) antagonist administration in in vitro fertilization (IVF) cycles, data were retrospectively collected from 305 consecutive IVF or intracytoplasmic sperm injection (ICSI) cycles of patients who underwent ovarian stimulation with gonadotropins and were treated with GnRH antagonist for the prevention of premature luteinization. We compared the percent change in LH concentration from stimulation start to that observed before ovulation triggering in patients with or without anovulation. Anovulatory patients were younger, with higher body mass index (BMI), and demonstrated higher ovarian reserve parameters as compared to ovulatory patients. The decline in LH concentration was almost two-fold greater in anovulatory versus ovulatory patients. Numbers of oocytes, fertilizations, cleavage stage embryos, and transferred embryos were similar; however, implantation rates were higher in anovulatory versus ovulatory patients. Older patients (age ≥39) showed a smaller decline in LH levels as compared to younger ones (age <39) and exhibited poor IVF outcomes. There is a wide range of pituitary responses to GnRH antagonists. Anovulatory patients are more susceptible to GnRH antagonists and therefore demonstrate over-suppression of the pituitary. Older patients demonstrate a reduced pituitary response to GnRH antagonists than younger ones. Cycle scheduling with estradiol pretreatment did not influence LH decline, nor IVF treatment outcomes.

GnRH Agonist Triggering of Ovulation Replacing hCG: A 30-Year-Old Revolution in IVF Practice Led by Rambam Health Care Campus.

Final oocyte maturation is a crucial step in in vitro fertilization, traditionally achieved with a single bolus of human chorionic gonadotropin (hCG) given 36 hours before oocyte retrieval. This bolus exposes the patient to the risks of ovarian hyperstimulation syndrome (OHSS), particularly in the face of ovarian hyper-response to gonadotropins. Although multiple measures were developed to prevent OHSS, gonadotropin-releasing hormone (GnRH) agonist triggering is now globally recognized as the best approach to achieve this goal. The first report on the use of GnRH agonist as ovulation trigger in the context of OHSS prevention came from Rambam Health Care Campus, Haifa, Israel and appeared in 1988. This review details the events that culminated in worldwide acceptance of this measure and describes its benefit in the field of assisted reproductive technology.

GnRH-agonist triggering for final oocyte maturation in GnRH-antagonist IVF cycles induces decreased LH pulse rate and amplitude in early luteal phase: a possible luteolysis mechanism.

The use of GnRH agonist to trigger final oocyte maturation in GnRH-antagonist in vitro fertilization (IVF) cycles has been shown to significantly reduce or even eliminate the risk of ovarian hyperstimulation syndrome (OHSS) by inducing rapid luteolysis early in the luteal phase. The exact mechanism of this early luteolysis is still widely unknown. Since luteinizing hormone (LH) has a major role in corpus luteum support, we sought to explore the pattern of LH secretion early in the luteal phase. Ten high risk patients for developing OHSS and triggered with GnRH agonist were included. Frequent blood sampling (every 20 min for 6 h) to measure LH, estradiol and progesterone was done on the day of oocyte collection (n = 5, Group 1) and on the day of embryo transfer, 48 h after oocyte collection (n = 5, Group 2). We found that the mean LH concentration and its secretion rate decreased significantly in Group 2 compared to Group 1. Both groups had similar number of LH pulses characterized by very small amplitude. In Group 2, there was a steady significant decrease in estradiol and progesterone over time. The results of this study show that LH secretion deviates significantly from normal physiologic pattern, which can explain, at least in part, the post-GnRH-agonist trigger early luteolysis mechanism.