Ovarian Reserve Tests and Their Application to Infertility Management
Prasanna Raj Supramaniam1*, Monica Mittal2 and Lee Nai Lim MRCOG3
1Specialist Registrar in Obstetrics & Gynaecology, Oxford University Hospitals NHS Foundation Trust, UK
2Subspecia!ist Trainee in Reproductive Medicine and Surgery, Specialist Registrar in Obstetrics & Gynaecology, Oxford University Hospitals NHS Foundation Trust, UK
3Consu!tant in Reproductive Medicine and Surgery, Obstetrics and Gynaecology, Oxford University Hospitals NHS Foundation Trust, UK
Submission: August 19, 2017; Published: August 29, 2017
*Corresponding author: Prasanna Raj Supramaniam, Specialist Registrar in Obstetrics & Gynaecology, Oxford University Hospitals NHS Foundation Trust, UK, Email: email@example.com
How to cite this article: Prasanna Raj S. Monica M, Lee Nai Lim MR, Ovarian Reserve Tests and Their Application to Infertility Management. Curre Res Diabetes & Obes J. 2017; 3(5): 555625. DOI:10.19080/CRDOJ.2017.03.555625
As the diagnosis of male and female sub fertility is rising and the use of assisted reproductive technology (ART) increases, there is an increasing need to sub-select patients that would have a higher success rate of a pregnancy. There is still yet to be a single definitive test that is able to evaluate ovarian reserve and predict the outcome of ART. Multiple investigations are currently used as part of treatment protocols for sub-fertile couples. As under the NHS there is funding restrictions in particular to investigations that are yet to be proven to be effective, patients are not currently offered all of the tests discussed in this article. It is important to remember that this is mainly due to the limited evidence in any of these tests improving the eventual outcome for patients.
Follicle Stimulating Hormone (FSH) is an essential hormone in the menstrual cycle. It is synthesized and secreted by the anterior pituitary. The main role of this hormone is the development of graafian follicles from an immature to a mature follicle during the follicular phase of the cycle. Day 3 FSH is currently a routine test to evaluate ovarian response in patients seeking sub fertility treatment it is often used as a predictor for the success of ART . It has been said that age and Day 3 FSH used together has a better predictor for outcomes in patients undergoing ART . From a meta-analysis of 21 studies it has been showed that basal FSH is at best a moderate predictor of diminishing ovarian response. The recommendations from this meta-analysis was that in patients undergoing IVF basal FSH alone should not be used as a single indicator of ovarian reserve .
There is also a good body of evidence, which suggest that age compare to basal FSH is seen to be a better predictor of ovarian reserve. A study that looked at 1045 women who were undergoing their first IVF cycle revealed that basal FSH levels alone could not predict the pregnancy outcomes however; age was seen to be a much better predictor of this outcome . It was noted also that high FSH levels are more prevalent in women above 35 years of age. In another study of over 300 women looking at basal FSH levels and ongoing pregnancy rates, the study concluded that there was a general decline in pregnancy rate with an increase in FSH levels. The group of patients with an FSH level of less that 10IU/L had a 65% on going pregnancy rate compared to the group with a FSH level of more than 15IU/l that had a 28% on going pregnancy rate .
Antral follicles are commonly referred to as resting follicles. They are noted to be small in diameter mostly between 2 to 8mm and are normally measured via Tran's vaginal ultra sonography. It has been seen that the reproductive age could be predicted based on the total antral follicle count . As antral follicle count is assumed to reflect ovarian reserve. In a recent study comparing groups of women whom had unaffected ovaries, ovaries that were previously operated on for an endometrioma or un operated on but with an endometrioma showed some interesting results. This study of 83 women revealed that the antral follicle count did not defer in either of these group of women and the result was statistically significant with the area under the curve for the prediction of low response at 0.83 (95% CI, 0.68-0.99) and hyper response at 0.84 (95% CI, 0.70-0.97) .
A meta-analysis including 10 studies looking at ovarian volume and 17 studies looking at antral follicle count showed that due to significant heterogeneity the sensitivity and specificity of these studies were inaccurate. However, the authors concluded that the antral follicle count was a better predictor of ovarian reserve compared to the measurement of ovarian volume via ultrasound . One of the major challenges with ultra sonography is reproducibility. A study looking at 29 women revealed that three-dimensional ultrasonography and power Doppler angiography created excellent intra and inter observer reproducibility. In this study, the authors mainly evaluated the assessment of ovarian response and oocyte quality. The results revealed that the coefficients for both groups were close to unity in the ovarian volume category and 0.964 for intra observer and 0.978 for inter observer in reference to the antral follicle count measurements .
Anti-Mullerian hormone (AMH) is a glycoprotein that is secreted from the granulose cells of the pre-antral and small antral follicles of the ovary from 36 weeks gestation . The main function of AMH is to inhibit the primordial follicles from being recruited into the antral follicle pool . AMH also has a significant advantage over basal FSH wherein it is not altered by intra cycle or inter cycle variability . This allows AMH to be reliably measured at any point during the menstrual cycle. One of the challenges in interpreting AMH results in the general population is the variation in the assay. Evidence has been published highlighting differing outcomes with the use of different assays in the same population. This therefore limits the role of AMH and the context in which it is used. However, it is well established that the extremes of AMH results have a reliable prediction of fertility potential .
When compared to antral follicle count, AMH has been seen to be on par in the assessment of ovarian reserve  however, it is seen to be superior when compared to FSH and Inhibin B levels .
Serum Inhibin B is a polypeptide mainly found in the follicular phase of the menstrual cycle. It is secreted by the granulose cells of the antral follicles . The levels of Inhibin B are normally seen to peak during the early follicular phase . In a study that looked at the value of Inhibin B, demonstrated that women with an Inhibin B value above 45pg/ml had a better estrogenic response to stimulation, reduced cancellation rates, higher pregnancy rates, and increased oocyte retrial . When comparing ART success, a study looking at 120 women found that basal FSH was a better predictor of outcome compared to Inhibin B. These women had blood drawn at a 3-month interval following their IVF attempt to assess the levels of FSH and Inhibin B . However, it has been shown that serum and follicular Inhibin B levels have a strong correlation with the number of oocyte retrieved but sadly the same cannot be said for the prediction of pregnancy rates . When looking at dynamic testing the serum estradiol response to exogenous FSH administration has been seen to be an reliable predictor of implantation and pregnancy rates. Women who have had a estradiol level above 30pg/ml 24 hours following the administration of exogenous FSH have had higher implantation and pregnancy rates compared to patients with values below 30pg/ml . This test is called exogenous FSH ovarian reserve test (EFFORT).
In some local centers clinicians also use the clomiphene citrate challenge test. This involves performing a basal FSH level on Day 3 followed by the routine administration of clomiphene citrate for 5 days of the cycle starting on Day 5 up to Day 9. This is then completed with a repeat serum FSH level on Day 10. Patients who fall into the category of FSH level above 12.5 units are thought to be comparable to patients who have a normal basal FSH level in terms of predictability of pregnancy outcomes . It is clearly evident from the literature available and the significant variation in practice that there is still yet to be a single test to be hailed as a gold standard investigation for ovarian reserve testing. The test available to clinicians today when used with caution and generous counseling is able to produce a result that is in keeping with scientific needs. The difficulty therein lies in what a patients understanding of these needs would be and the clinicians ability to counsel the patients appropriately. There are also other limiting factors in this cohort of patients to consider.....such as age and body mass index, with the clinician needing to make a sound judgment with the available evidence. This is surely an art that is honed with experience, which is a trade built with time and effort.