Infertility research priorities (Optimal Ovarian Stimulation) have been proposed for 2021. Healthcare professionals, people with fertility problems, and infertility researchers (healthcare funders, healthcare providers, healthcare regulators, research funding bodies, and researchers) were brought together in an open and transparent process resulting in an article that was published in Human Reproduction in November 2020 outlining the top future infertility-related research priorities. The initial survey was completed by 388 participants from 40 countries, and 423 potential research questions were submitted. Fourteen clinical practice guidelines and 162 Cochrane systematic reviews identified a further 236 potential research questions.
The top 10 infertility research priorities for the four areas of male infertility, female and unexplained infertility, medically assisted reproduction and ethics, access and organization of care for people with fertility problems were identified. These top ten research priorities in each topic area outline the most pressing clinical needs as perceived by healthcare professionals, people with fertility problems and others, to assist research funding organizations and researchers to develop their future research agenda.
In this post, we will discuss Research Priority #2, Optimal Ovarian Stimulation: What is the optimal treatment for women undergoing IVF who are poor responders to increase live birth rates?
Why is Optimizing Ovarian Stimulation a Research Priority?
Optimal Ovarian Stimulation is a research priority because, despite 40 years of research and clinical application, the average success rate of IVF today has been reported to be as low as 20-40%. Poor ovarian response in IVF cycles ranges from 10-20%.
An inadequate response to controlled ovarian stimulation leads to insufficient egg retrievals, poor quality and maturity oocytes, and reduced embryo quality
Appropriate cycle response can prevent cycle cancelation, empty follicle syndrome, miscarriage. The two main ovarian stimulation protocols are:
Common Steps In Ovarian Stimulation
Ovarian Stimulation Protocol Variables
For GnRH Agonists
In the so‐called ‘long protocol’, the GnRH agonist is started at least two weeks before stimulation and continued up until oocyte maturation is achieved.
Alternatively, a ‘short protocol’ is used in which the GnRH agonist is given simultaneously with stimulation and continued up until the day of oocyte maturation trigger.
For GnRH Antagonists
Yet another option is the use of GnRH antagonists. These involve a shorter duration of use compared with the agonist ‘long protocol’ and are started a few days after initiation of stimulation, continuing up until administration of a drug to trigger oocyte maturation.
At the end of the stimulation phase of an IVF cycle, a drug is used to trigger the final oocyte maturation, which is used to mimic the natural endogenous LH surge and initiate the process of ovulation before the mature eggs are collected from the woman and fertilized with sperm in the laboratory. Two drugs are currently used: human chorionic gonadotropin (HCG), which is the most common drug, or GnRH agonist in an antagonist protocol.
The Main clinical Decisions in Controlled Ovarian Stimulation
Ovarian Stimulation: Areas of Active Research
The FSH starting dose is usually chosen according to women’s age, clinical criteria, and markers of ovarian reserve. One of the best performing markers is the antral follicle count (AFC), which generally predicts ovarian response to FSH very well. However, we know in some cases that response can’t be predicted- we see either a “hyper” response or a poor response. Therefore, new ovarian response variables beyond; age, body mass index, day 3 serum FSH, AFC, ovarian volume, Doppler ovarian score, and smoking status are needed.
These could take the form of molecular biomarkers. For example, polymorphisms in genes involved in FSH signaling, estrogen biosynthesis, folliculogenesis, folate metabolism and others influence the response to exogenous gonadotropin administration are all good candidates. The promise of “precision medicine” i.e. Individualization of ovarian stimulation protocols could be realized through identifying these biomarkers, routinely testing infertility patients for them, and then incorporating them into clinical decision making.
Variations in FSH receptor (FSHR) gene have an essential influence on ovarian function and can account for several defects of female fertility. Normal functioning of the (FSHR) is crucial for follicular development and estradiol production in females and for the regulation of Sertoli cell function and spermatogenesis in males. In the last two decades, a number of inactivating and activating mutations, single nucleotide polymorphisms, and spliced variants of FSHR gene have been found, but the polymorphism FSHR Asn680Ser is practically the only genetic marker used clinically.
Growth characteristics and steroidogenic activities of antral cohorts exhibit considerable cycle to cycle variations, even in consecutive cycles using the same stimulation protocol, the type and dose of gonadotropin, and duration of stimulation. It is unclear why there are differences between two cohort of antral follicles of two different cycles exposed to FSH at the same dose and duration.
Antral follicles begin producing increasing levels of progestins, estrogens, and androgens. The mural granulosa cells and the adjacent theca cells surrounding the ovarian follicle are the sites of steroidogenesis. According to the “two cell theory” of steroidogenesis, the cells work cooperatively to produce estradiol. The theca cells express enzymes necessary for androgen synthesis, while the mural cells express aromatase, which converts androgens to estradiol.
Plausible explanations for cycle-to-cycle variation are; total steroid synthesis increase as a factor of increased number of growing follicles and their steroidogenic granulosa cell mass or increase in number or sensitivity of FSH and/or LH receptors on the granulosa cells in response to exogenous gonadotropin stimulation.
Follicle growth is so important for making clinical decisions related to optimal ovarian stimulation, yet ultrasound (the most common method to measure follicle growth) is an inaccurate, insensitive technology with large margins of error. Two-dimensional transvaginal ultrasound (2D), can only provide an approximate volume for follicles, it is not very accurate.
Research into new ovarian imaging technologies, such as 3D ultrasonography, ultrasound-based biomicroscopy, MRI and doppler imaging.
The ability to develop human oocytes from the earliest follicular stages through to maturation and fertilization in vitro would revolutionize fertility preservation practice. This is termed in vitro growth (IVG) or in vitro maturation (IVM) of human ovarian follicles. In vitro maturation of immature oocytes from an unstimulated cycle is an emerging technology. One of the safest ways to prevent OHSS is to not stimulate the ovaries. During an in vitro maturation of oocytes cycle, the immature eggs are retrieved from ovaries that are barely stimulated or completely unstimulated. The eggs are maturated in defined culture media for 24 to 48 hours and fertilized through IVF or ICSI. IVM is an experimental technique that consists of the in vitro conversion of oocytes at the GV stage to oocytes at the metaphase II stage.
This technology must include nuclear and cytoplasmic maturation of the oocyte and give rise to embryos that have a developmental potential that is similar to embryos obtained from standard IVF or from spontaneously in vivo matured oocytes. A few IVM practitioners have advocated for “rescue IVM” in IVF conventional settings to prevent severe OHSS. “Rescue IVM” is when the physician has come to the conclusion that a safe conventional IVF cycle cannot be done so they change the treatment direction to an IVM protocol to cycle instead. If the aspiration happens prior to the follicle selection, then OHSS risk can be eliminated.
Though IVM shows promising results, it is not mainstream for fertility treatment. Mainly because there are difficulties retrieving eggs from immature ovaries that are not stimulated, and a lower chance of live births compared to conventional IVF, and there is an increased rate of abnormalities in meiotic spindles and chromosomes from immature eggs. All of these are make compelling research case studies.