Novel Biomarker for monitoring ovarian reserve in patients undergoing chemotherapy
Protocol development- Full protocol, information sheets and consents available.
Ethics status – Multisite HREC approval and awaiting SSA approval which is scheduled for the 14th of April
Study Team – Dr Anazodo Anazodo, Prof William Ledger, Prof Robert Gilchrist, Prof Chris White, Prof David Robinson, Dr Angelique Riepsamen, Mrs Brigitte Gerstl, Miss Serena Chong.
Currently ovarian reserve is estimated by measuring serum levels of the hormones FSH, anti-Müllerian hormone (AMH) and/or obtaining an ovarian “antral follicle count” by vaginal ultrasound. These serum levels provide an indication of the number of growing/antral follicles in the ovaries and provide a crude estimate of ovarian reserve. Despite the limited accuracy of these measures, medical practitioners rely heavily on these tests for patient management. Currently, these tests measure oocyte (egg) quantity, however there are no tests available that directly measure oocyte quality, and therefore at this stage we are unable to accurately determine a female patient’s fertility.
In women, anti-Müllerian hormone (AMH) is exclusively produced by granulosa cells of ovarian follicles during the early stages of follicle development. AMH blood levels reflect the continuous non-cyclic growth of small follicles, thereby mirroring the size of the resting primordial follicle pool and thus acting as the best marker of ovarian reserve we currently have.
Oocyte-derived growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) are essential regulators of mammalian ovarian folliculogenesis, promoting early follicle growth, somatic cell differentiation and oocyte quality. Normally considered as homodimers, we recently established that individual subunits of GDF9 and BMP15 could form a heterodimer with dramatically (>1000-fold) enhanced activity towards granulosa/cumulus cells. We have called this new molecule Cumulin and demonstrated its presence in human follicular fluid. Our group has developed the capability to measure Cumulin and the subunits produced by the oocyte (egg) in blood.
The discovery of Cumulin is a major breakthrough in reproductive biology, and provides unique opportunities to improve female fertility. This project will advance understanding of the clinical potential for diagnosing and treating infertility. Specifically, the FUTuRE Fertility research team will test this world-first ELISA to measure Cumulin in blood and assess its utility to determine ovarian reserve, ovarian disease and as a biomarker of oocyte/embryo quality. Cumulin can be used to develop novel approaches in oncofertility, including oocyte in vitro maturation and the transplantation of ovarian tissue for cancer patients.
The measurement of a novel serum biomarker Cumulin provides a test of ovarian reserve and ovarian quality that has a high specificity and sensitivity, does not fluctuate with circadian rhythm and is not effected by temperature variability during processing and handling time.
- To validate the measurements of the new biomarker and correlate findings with AMH which is the
- current gold standard for assessment of ovarian reserve in AYA and adult patients.
- To determine the sensitivity and specificity of the new biomarker.
- To demonstrate that novel serum biomarker is a reliable marker for ovarian reserve, irrespective
- of time of testing and the circadian changes.
- To demonstrate that the novel serum biomarker will give more accurate measures of how the ovarian reserves and oocyte quality can be affected by cancer treatment and then recover following the completion of cancer treatment.
- To demonstrate the temperature stability of the serum biomarker.
Cancer patients will be recruited across Randwick Campus (Sydney Children’s Hospital, Prince of Wales Hospital and the Royal Hospital for Women) and will be given an age-specific patient information sheet and an age-appropriate consent form with outlines all details associated with this study. The consent process can occur anytime between date of diagnosis and the date of the start of chemotherapy treatment.
The research team will retrieve bloods at the following time periods:
- Diagnosis – prior to chemotherapy blood for Cumulin, AMH, FSH and estradiol will be taken.
- 3 months after cancer treatment starts blood for Cumulin, AMH, FSH and estradiol will be taken.
- At the end of treatment blood for Cumulin, AMH, FSH and estradiol will be taken.
- 12 months after cancer treatment finishes blood for Cumulin, AMH and FSH and estradiol will be taken but this part of the study will fall outside of the grant.
At diagnosis the research team will record MRN, DOB, cancer type and stage, gynaecological history and Tanner stage for patients older than 7 years of age. A study database will use the MRN and initials to record patient information and results but not record the name so all results will be de-identified.
Paediatric control patients will be recruited from non-cancer patients, who are not receiving treatment with cancer therapy, across Sydney Children’s Hospital and are having a blood test as part of their in-patient procedure. Consent will be taken for an extra 5mls of blood for Cumulin, AMH, FSH and estradiol. The research team will collect information on DOB, relevant gynaecological history and reason for blood test/diagnosis.Controls aged 18 years and over will be recruited from the general population with the use of advertorial flyers and posters. Bloods will be taken on-site at one of the participating hospitals and participants will be invited to discuss the findings of AMH, FSH and estradiol with a health professional at a clinic provided on site at the Royal Hospital for Women.