Top 10 Infertility Research Priorities: Optimal Ovarian Stimulation

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?

Blog Series

• An article was published in Human Reproduction in November 2020 outlining the top future infertility-related research priorities. The top ten ART research priorities are;
• What are the causes of implantation failure? 
• What is the optimal treatment for women undergoing IVF who are poor responders to increase live birth rates?
• What is the optimal method of sperm selection in IVF cycles?
• In couples with unexplained infertility, does IUI increase live birth rates when compared with other ARTs, including IVF?
• In couples with unexplained infertility, what is the optimal number of IUI cycles before moving to IVF?
• What is the optimal method of embryo selection in IVF cycles?
• What are the factors that affect cycle to cycle variability in the number and quality of oocytes produced in an IVF cycle?
• What is the optimal time interval between ovulation and IUI?
• What is the emotional and psychological impact on children born using donor gametes?
• What is the emotional and psychological impact of repeated fertility treatment failure?

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:

• GnRH agonists or antagonists, with a wide-variety of variations.
• An agonist is a drug that activates certain receptors, an antagonist is a drug that blocks receptors without activating them.

Common Steps In Ovarian Stimulation

• Exogenous gonadotrophins to stimulate multi‐follicular development.
• Cotreatment with either gonadotropin‐releasing hormone (GnRH) agonist or antagonists to suppress pituitary function and prevent premature ovulation.
• Triggering of final oocyte maturation 36 to 38 hours prior to oocyte retrieval.

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.

Final 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

• Stop stimulation
  • Trigger cycle
  • Continue stimulation
  • Number of days to follow-up, any dose adjustment needed

Ovarian Stimulation: Areas of Active Research

• How to determine the follicle-stimulating hormone (FSH) starting dose?

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.

• New predictive algorithms and artificial intelligence to predict response to optimal ovarian stimulation.
• What are the new technologies on the horizon for measuring follicle growth? 

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.

• 3D Ultrasonography allows for automated measurement of follicular size in three dimensions (3D) using a software program that identifies and quantifies hypoechoic regions within a 3D dataset to provide an objective, fast, valid and reliable standard for such follicle measurements. 
  • Magnetic resonance imaging (MRI) is emerging as a research tool in ovarian imaging. Typically, MRI can be extremely accurate in the diagnosis of benign lesions, such as mature cystic teratomas, endometriomas, and nondegenerative leiomyomas located on the ovaries. In fact, many studies have shown MRI to be superior to both US and CT scans in diagnosing malignancy in indeterminate ovarian masses. 
  • Ultrasound-based- biomicroscopy to image human ovaries allows precise characterization of the structural details of the follicle wall reflecting histology, and early antral ovarian follicles (< 2 mm) and cumulus-oocyte complexes, which are not visible with conventional ultrasonographic techniques.
  • Computer-assisted image analysis and mathematical modeling of the dynamic changes within the ovary
  • Spectral, color-flow, and power Doppler imaging can facilitate physiologic interpretations of vascular dynamics over time 
  • Synchrotron-based techniques each have the potential to enhance our real-time picture of ovarian function to the near-cellular level. The use of synchrotron light in medical imaging is an emerging field and has not been used previously to image ovarian tissue of any species. synchrotron light is tremendously bright (in the order of 10⁶ times brighter than the sun, at the surface of the sun) and therefore permits penetration and resolution not achievable with conventional radiography (e.g. angstroms to microns). It is particularly promising for soft tissue imaging because it provides exquisite contrast by using the X-ray bending properties of tissue, rather than the absorption properties.
  • The COVID pandemic has placed a particular urgency on developing remote home patient monitoring technologies, such as;
    • Home estrogen (E2) saliva testing
    • Home sonography of follicle development

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.