Double stimulation IVF (DuoStim)

Overview

Poor response to controlled ovarian stimulation (COS) is a significant concern in IVF, affecting 9-24% of infertile women. Such a large range is suggestive of a varied patient group.

Unlike typical IVF methods, which include a single round of ovarian stimulation with fertility medicines and egg retrieval during a single menstrual cycle, the DuoStim technique involves two rounds of ovarian stimulation and two egg retrievals during the same cycle (hence the name DuoStim).

 

What is Double stimulation?

Double stimulation in the same ovarian cycle (DuoStim) is a novel procedure for IVF patients that aims to optimize the number of oocytes recovered in the shortest amount of time.

For the first time in a clinical study, the results of double ovarian stimulation (DuoStim) were compared to those of two non-consecutive conventional stimulations. The study discovered significant disparities between these two treatment methods, notably in terms of the time required to create a healthy embryo. The study found that DuoStim cut the period between ovarian stimulation and generating a healthy (euploid) embryo by half.

When compared to typical stages of ovarian stimulation, this procedure is a very successful technique for accumulating both oocytes and embryos in a significantly shorter length of time for patients for whom time is a more essential component in their results.

The DuoStim procedure makes use of the fact that the ovaries recruit several (2-5) waves of follicles each month. In a normal ovulatory cycle, hormone cues from the brain choose just one follicle to hold one egg for ovulation, while several other follicles never mature, and the eggs within them perish due to atresia.

Fertility medicines are used during an IVF cycle to save some of the eggs that would otherwise perish, allowing the gathering of several mature eggs and the development of multiple embryos. A DuoStim procedure is an expansion of this concept in that, following the initial egg retrieval, the second session of stimulation with fertility medicines can begin during the luteal phase, allowing for a second egg harvest within the same menstrual cycle.

The primary benefit of a DuoStim treatment is that it enables the harvest of more eggs in the same length of time as a typical IVF stimulation strategy. This method is regarded to be useful in two therapeutic situations:

1. Women with a low ovarian reserve who produce relatively few eggs in a given cycle and
2. Women undergoing fertility preservation have limited time prior to starting chemotherapy for cancer.

 

Physiologic basis of DS/DuoStim

The physiologic processes underpinning the recruitment and selection of antral follicles in women remain unknown. There are three main hypotheses for follicular recruitment: 

• Continuous recruitment, 
• Single recruitment event, and 
• Follicular waves.

The cyclic recruitment notion includes theories such as single recruitment episodes and follicular waves. According to the continuous recruitment idea, tiny antral follicles 4-6 mm are recruited to develop constantly, independent of gonadotropins, at all phases of reproductive life.

The ovulating follicle is chosen at random from a constant supply of antral follicles by being at the proper level of maturity to respond to the spike in follicle-stimulating hormone (FSH) that happens after luteal regression. According to the single recruitment event idea, a cohort of 2-5 mm follicles is recruited once throughout each menstrual cycle from a constant supply of antral follicles.

An anovulatory wave appeared at the time of ovulation (i.e. early luteal phase), followed by the development of the ovulatory wave during the early follicular phase in women with two follicular waves. An anovulatory wave occurred at the moment of ovulation, a second anovulatory wave emerged during the mid to late luteal phase, and a third wave (the ovulatory wave) emerged during the early to mid-follicular phase in women with three waves. The wave hypothesis, which underpins DS/DuoStim, contradicts the traditional understanding of folliculogenesis. 

 

What is Poor ovarian response?

A poor ovarian response occurs when the number of oocytes retrieved during the In-vitro fertilization cycle is lower than predicted. Poor response in an in-vitro fertilization cycle is described by the European Society for Assisted Reproduction when two of the following criteria are met:

• Women over the age of 39.
• The previous cycle with less than 4 oocytes retrieved.
• Ovarian reserve test alteration (RFA <5-7 and AMH <0.5-1 ng / ml).

This slow reaction can be aggravating for both patients and clinicians. According to the series, the estimated incidence ranges between 5-24%. There are patients with a poor prognosis since the number of oocytes obtained in a cycle is closely proportional to the likelihood of conception.

Various treatments for improving outcomes in POR patients have been presented in recent years, but there is no obvious superiority of one over the other (use of androgens, aromatase inhibitors, selection of the most optimal cycle, accumulation of oocytes).

 

In what cases is DuoStim indicated? 

Cryopreservation of oocytes is a significant difficulty for oncological patients who require fertility preservation prior to undertaking chemotherapy and/or radiation. To boost the chances of future conception in these patients, it is critical to maximizing the number of cryopreserved oocytes following COS in a short time period (s). In this regard, an appropriate number of oocytes to cryopreserve is at least 10-15, mostly dependent on maternal age.

As a result, a random start strategy is employed to accelerate fertility preservation and, as a result, minimize the time to cancer treatment. Because ovarian-endometrial synchronization is not required, such a procedure is feasible. However, in many cases, not enough oocytes are harvested to guarantee a reasonable likelihood of conception. As a result, when time is limited and the oocytes recovered from a single stimulation are inadequate, DuoStim methods may be explored with the oncologist and the patients as a beneficial alternative for fertility preservation.

It is worth noting that, while aging decreases oocyte competence owing to insults such as mitochondrial and cohesion failure, telomere shortening, and spindle instability, 'young' oocytes also suffer from impairments that define the window of the woman's fertility. The prevalence of oocyte aneuploidy follows a U-shaped curve, with the The The maximum incidence occurs before menarche and shortly before menopause, and the lowest prevalence occurs at the age of 25.

In contrast, oocyte competence to grow as a blastocyst appears stable over the woman's age range until the age of 40, when it drastically falls. Both of these graphs show a rapid increase in the aneuploid blastocyst rate, which may range from 25-30% in women under the age of 35 to more than 90% in females over the age of 42.

These statistics also influence the selection of an effective COS approach based on the patient's age range (35 years, 35-40 years, or >40 years). Furthermore, in addition to causing lower fertility, aneuploidies increase the incidence of critical chromosomal abnormalities, miscarriage rates, and the prevalence of numerical chromosomal abnormalities in newborns. Nonetheless, no treatment is now available to mitigate the aforementioned age-related harm. The only viable method is to gather as many mature oocytes as feasible to compensate for the physiological loss in oocyte and embryonic competence.

Regardless of the quantity and morphological quality of the embryos acquired following the two stimulations, the DuoStim technique is always paired with PGT-A and a single vitrified-warmed euploid blastocyst transfer in our environment. The goal of this strategy is to lower both the frustrating repeated implantation failures and the miscarriage rate following IVF. These factors are especially important in reducing drop-out in poor-prognosis patients (such as those who meet the Bologna criteria) without jeopardizing overall treatment effectiveness.

 

What can we achieve with double ovarian stimulation?

The twofold ovarian stimulation approach allows for shorter durations to achieve pregnancy, which benefits the patient because the passage of time diminishes the odds of pregnancy in these individuals while simultaneously increasing the danger of abandonment.

If you have been diagnosed with Poor Ovarian Response or believe it may be your case, we encourage you to contact our team; we want to hear your story, listen to you, and determine whether the double ovarian stimulation treatment can increase your chances of success and help you achieve your dream of becoming a mother. 

 

How to perform double/dual stimulation?

DS/DuoStim, which is made of FPS and LPS, is conducted in a single menstrual cycle with the goal of increasing the number of recovered eggs. Although POR patients are the major focus, fertility preservation situations when time is of the essence may benefit from this strategy as well.

Recent research shows that, as compared to typical OS protocols, light OS regimens (low-dose gonadotropins with/without oral drugs) provide equivalent reproductive outcomes at a reduced cost in POR patients. Various OS methods for FPS and LPS have been documented in all published research on DS/DuoStim. In the case of FPS, luteal estrogen priming may be utilized to increase follicular development synchronization and coordination.

For FPS and LPS, either moderate or typical OS regimens can be used. Clomiphene citrate (CC) and letrozole (LE) with/without low-dose exogenous gonadotropins can be used to treat moderate OS. For FPS and LPS, conventional OS with a daily dosage of 225-450 IU of exogenous FSH with/without luteinizing hormone (LH)/LH-like activity can be employed.

GnRH-antagonist (GnRH-ant) usage, exogenous progestins, and/or Ibuprofen can all be used to minimize early LH surge during FPS and LPS. The most generally used technique is a flexible GnRH-ant plan, which begins when the leading follicle reaches a mean diameter of 12-14 mm and continues until and includes the day of triggering.

Exogenous progestins may also be utilized for this aim, particularly during LPS, not only to avoid early LH spike but also to avoid menstruation during egg extraction to reduce infection risk. Although ibuprofen has been utilized in certain trials, its specific effect in preventing early ovulation in this patient population requires additional research.

 

Does DuoStim have any associated risks?

The customization of COS has been a game changer in the care of poor prognosis IVF patients. DuoStim clearly fits within this scenario, and its advantages and disadvantages must be discussed. DuoStim still requires a cost-benefit analysis in comparison to sequential traditional FPS. More studies on its safety from a biological, clinical, and neonatal standpoint are still needed. The unavoidable requirement for a freeze-all technique illustrates an unavoidable constraint. Then, a consensus should be reached about the DuoStim protocol in terms of the time, kind, and dose of the drugs used in the LPS.

The luteal phase is distinguished by the presence of the CL, increased progesterone and oestrogen levels, and data suggesting that, following GnRH agonist stimulation in antagonist regimens, luteolysis varies widely across patients and is dependent on:

1. Levels of progesterone on the day of final oocyte maturation and oocyte retrieval; 
2. Duration of ovarian stimulation; 
3. Number of days of suppression; 
4. The total dosage of the medications used for ovarian suppression; and 
5. Number of oocytes retrieved  

As a result, the onset of menstruation following agonist triggering must be regarded as patient-specific. The use of gonadotropins a few days after an agonist trigger in the luteal phase of the ovarian cycle allows for the recovery of tiny antral follicles that would otherwise be lost due to recruitment from a physiologically anovulatory luteal wave. However, the drugs used in DuoStim therapy should be chosen based on their efficacy.

 

Latest Advances for Poor Ovarian Response

Because of the experience gained in the quick preservation of fertility in cancer patients, it has been discovered that stimulating during the luteal phase (after ovulation) and getting mature oocytes produces embryos appropriate for preservation.

A new method for improving poor ovarian response is double stimulation. Double stimulation in the same cycle, first in the follicular phase and then in the luteal phase, enables a higher number of oocytes to be obtained from the same cycle.

Childbirth rates increased from 7% to 15% in the twofold stimulation group, while the proportion of genetically normal embryos ready for transfer increased from 14% to 31%. Another notable finding in this trial was that 81% of patients in the single follicular phase stimulation group discontinued therapy due to the substantial psychological impact that the poor prognosis and past failures had on these individuals.

 

Conclusion 

DuoStim is a novel approach for increasing the number of oocytes recovered in a single menstrual cycle. Unlike typical IVF protocols, which include a single round of ovarian stimulation and egg extraction in a single menstrual cycle, the DuoStim technique involves two rounds of ovarian stimulation and two egg retrievals in the same cycle.