Hormonal, functional and genetic biomarkers in controlled ovarian stimulation: tools for matching patients and protocols
© Alviggi et al; licensee BioMed Central Ltd. 2012
Received: 12 August 2011
Accepted: 6 February 2012
Published: 6 February 2012
Variability in the subfertile patient population excludes the possibility of a single approach to controlled ovarian stimulation (COS) covering all the requirements of a patient. Modern technology has led to the development of new drugs, treatment options and quantitative methods that can identify single patient characteristics. These could potentially be used to match patients with the right treatment options to optimise efficacy, safety and tolerability during COS. Currently, age and follicle-stimulating hormone (FSH) level remain the most commonly used single patient characteristics in clinical practice. These variables only provide a basic prognosis for success and indications for standard COS treatment based on gross patient categorisation. In contrast, the anti-Müllerian hormone level appears to be an accurate predictor of ovarian reserve and response to COS, and could be used successfully to guide COS. The antral follicle count is a functional biomarker that could be useful in determining the dose of FSH necessary during stimulation and the success of treatment. Finally, in the future, genetic screening may allow an individual patient's response to stimulation during COS to be predicted based on genotype. Unfortunately, despite the predictive power of these measures, no single biomarker can stand alone as a guide to determine the best treatment option. In the future, hormonal, functional and genetic biomarkers will be used together to personalise COS.
Keywordscontrolled ovarian stimulation biomarkers personalised genetic screening
Modern medical science has made great advances in the understanding and treatment of subfertility. This review is not an evidence-based meta-analysis, but rather provides our opinion on what we foresee as the future for controlled ovarian stimulation (COS) and how treatment protocols could be optimised to improve the outcome for individual patients. It is worth noting that some of the studies available in the literature and reported here have limited sample sizes and may not be adequately powered to show significance.
Novel technologies have created new ways to evaluate and treat patients and provide them with a prognosis for overcoming their subfertility. Basic and clinical research coupled with advances in technology have led to the development of a wide variety of new treatment options, particularly in the area of COS. Follicle-stimulating hormone (FSH [urinary or recombinant (u-FSH/r-FSH)]) levels can be used alone or associated with luteinising hormone (LH) activity, which in turn can be provided in the form of human menopausal gonadotrophin (hMG), recombinant human LH (r-hLH) or human chorionic gonadotrophin (hCG [urinary or recombinant (u-hCG/r-hCG)]). In addition, the optional use of steroid hormones such as progesterone, oestrogen, testosterone or dehydroepiandrosterone (DHEA), and even the possibility of growth hormone treatment, could be considered following further research. Taken together, all these options tend to increase the complexity of treatment decisions. The discussion around gonadotrophin-releasing hormone (GnRH) agonist versus antagonist protocols during COS is another example highlighting the expanding number of treatment options and the urgent need to develop a rationale for making the best choice of treatment for each single patient.
Currently, demographic and anthropomorphic data are the primary sources of information used to provide a prognosis and guide treatment. Along with basic medical and nutritional information, functional, hormonal and genetic biomarkers are tools that could provide more accurate diagnostic and prognostic information. Nonetheless, there is currently no consensus in the literature around the world as to how these newly available tools should be applied for a personalised treatment plan in order to improve the outcome of COS. Presently, general patient characteristics determine treatment, disregarding unique characteristics that might influence the needs of the individual patient, and thus, the chance of success. Empirical decision-making based on broad generalisations translates to similar patients receiving similar treatments. Thus, conventional factors like age and previous cycle data are used to make vital treatment decisions. Quantitative biomarkers are utilised mainly to predict prognosis and to inform patient counselling, but the strong potential of these indicators as tools to personalise COS is often underestimated .
Variables in the choice of COS protocol
Factors determining individual patients' response to ovarian stimulation
Treatments used in ovarian stimulation protocols
Demographics and anthropometrics (e.g., age, BMI and race)
GnRH agonist protocol (long, short and micro flare)
GnRH antagonist protocol (standard, mild and modified natural)
Cause of subfertility
Duration of subfertility
How can we predict ovarian response and personalise treatment?
Age versus biomarkers
Age is the most commonly used predictor of fertility; increasing age inevitably results in substantial germ cell loss by the age of 40 . Statistics for pregnancy, live birth and singleton live birth rate also decline rapidly from the mid-thirties on . However, even though age is clearly linked to declining fertility, it does not affect all women equally. On an individual basis, the chronological age of an individual may not be as valuable a predictor of fertility as their 'biological age', which is defined by the hormonal and functional profiles. Thus, biomarkers quantifying hormonal and functional profiles are more useful as prognostic factors than age alone when predicting response and choosing treatment strategy. Finally, genetic screening can provide specific information about a woman's reproductive system that would not be accurately predicted by age, hormonal or functional biomarkers. By considering hormonal (FSH and anti-Müllerian hormone [AMH]), functional (antral follicle count [AFC]), and genetic biomarkers in combination, a complete picture of an individual patient's overall reproductive status can be formulated to provide a basis of designing an optimal treatment plan.
Hormonal biomarkers: AMH
Inhibin-B, FSH and AMH are hormonal markers that can be used to predict ovarian response to COS and success with assisted reproductive technology (ART). Although FSH levels are more commonly used to evaluate a woman's probable response to COS, AMH (as a paracrine product of immature follicles) is a more direct measure of ovarian status compared with other endocrine reproductive hormones. AMH is primarily produced by the pre-antral and small antral follicles, and correlates with the number of primordial follicles at the gonadotrophin-independent stage of follicular development [4, 5].
A small study showing the potential use of AMH measurement in a routine in-vitro fertilisation (IVF) programme prospectively enrolled 316 patients and considered 132 oocyte retrievals in women undergoing a GnRH agonist long protocol. When the calculated optimal AMH cut-off of ≤1.26 ng/ml was used to predict responses to COS, it was found to have a 97% sensitivity for predicting poor responses (< 4 oocytes retrieved) and a 98% accuracy in predicting a normal COS response. These findings indicate that circulating AMH levels may be a good indicator of ovarian reserve, and are highly correlated with ovarian response to COS .
In the first study designed to evaluate the use of a hormonal biomarker to determine treatment strategy, Nelson and colleagues compared the safety, tolerability and success rates of different AMH-based COS strategies in two IVF centres. In this prospective cohort study, 538 women were stratified according to their AMH levels prior to COS (low: 1- < 5 pmol/l, medium: 5-15 pmol/l and high: > 15 pmol/l). In both centres, doses were similarly determined by each patient's AMH level; high, medium or low doses of FSH were given to women with low, medium and high AMH levels, respectively. However, in one centre, the choice between the GnRH agonist long protocol versus a milder GnRH antagonist protocol was also determined based on AMH levels. Specifically, most patients at the first centre (regardless of AMH level) were treated with a GnRH agonist long protocol, while in the second centre, those with high or low AMH levels were treated with a GnRH antagonist protocol.
Currently, a limiting factor in the use of AMH as a biomarker is the variability seen between commercial kits and variation in results reported from different laboratories . This variability may be one of the reasons for the lack of consensus on the cut off values of AMH when deciding whether or not to proceed with ART.
Functional biomarkers: AFC
The number of antral follicles detected by ovarian ultrasound has gained acceptance as an indicator of ovarian reserve, a COS response prognostic tool and predictor of IVF success [9, 10]. In a study including 149 treatment cycles, Chang and colleagues found that AFC declined with age and was negatively correlated to day 3 FSH and cancellation rate. In the same study, when patients were grouped by AFC (AFC < 4, 4-10 or > 10), the mean number of retrieved oocytes was 2.0, 6.3 and 14.0, and ongoing pregnancy rates were 0%, 13.2% and 26.3%, respectively .
Another study investigated 113 women undergoing their first ART cycle. In this group, AFC was found to be significantly associated with AMH levels and the number of retrieved oocytes, with the number of follicles between 5 and 6 mm having the highest correlation to both endpoints. AFC was also found to be predictive of poor responses to COS, with the number of follicles sized 2-4 mm, 2-5 mm, 2-8 mm and 2-10 mm being approximately equal in predicting response .
The basic clinical and technical requirements for assessment of the AFC in clinical practice (reproduced with permission from Broekmans et al.
Considerations for the assessment of the AFC in clinical practice
Select patients with regular menstrual cycles with no co-existing pathological condition that could technically affect the counting of follicles, such as ovarian endometriosis or previous ovarian surgery
A limited number of personnel, appropriately trained in transvaginal sonography should perform AFCs in each unit
Real-time, two-dimensional imaging is adequate
Count follicles between days 2 and 4 of a spontaneous menstrual or oral contraceptive cycle to avoid the effect of intra-cycle variation
Include all antral follicles of 2-10 mm in diameter
Use a transvaginal transducer
Use a probe with a minimum frequency of 7 MHz, which is maintained in an adequate condition and able to resolve a structure of 2 mm in diameter
Use a systematic process for counting antral follicles:
1. Identify the ovary
2. Explore the dimensions in two planes (perform a scout sweep)Decide on the direction of the sweep to measure and count follicles
3. Measure the largest follicle in two dimensions
A. If the largest follicle is ≤10 mm in diameter:
i. Start to count from outer ovarian margin of the sweep to the opposite margin
ii. Consider every round or oval transonic structure within the ovarian margins to be a follicle
iii. Repeat the procedure with the contralateral ovary
iv. Combine the number of follicles in each ovary to obtain the AFC
B. If the largest follicle is > 10 mm in diameter:
i. Further ascertain the size range of the follicles by measuring each sequentially smaller follicle, in turn, until a follicle with a diameter of ≤10 mm is found
ii. Perform a total count (as described) regardless of follicle diameter
iii. Subtract the number of follicles of > 10 mm from the total follicle count
The influence of genetic research continues to shape the scientific and medical landscape. Pharmacogenetics is the science of predicting drug effects based on the genotype of an individual. In the future, the treatment of a patient could be based on her individual DNA. Presently, even though the biological response to any given drug may be influenced by hundreds of genes, progress is being made in the identification of specific genetic variances, called single nucleotide polymorphisms (SNPs) that can predict the safety and effectiveness of certain drugs in individual patients. In the field of reproductive health, hormonal and functional biomarkers are more established as tools to predict ovarian response, but in the future, genetic biomarkers may well be the best predictive tool to guide individualised treatment.
Genetic traits that influence fertility may not have visible clinical signs or abnormalities. If a patient's genetic profile also diminishes her response to fertility treatment, the failure to consider the genotype when designing the treatment consequently leads to a suboptimal treatment strategy. For example, a subset of young, normogonadotrophic IVF patients may produce an adequate number of retrieved oocytes and normal oestrogen levels, but not respond to COS as anticipated. These women require high doses of FSH (> 2,500 IU) over long treatment periods and, despite good prognostic indicators, have low implantation and pregnancy rates [16–19]. One possible reason for this hyporesponder 'normal' population is that they may have a genetic predisposition to a reduced sensitivity to FSH.
FSH and LH synergistically regulate normal ovarian function and oocyte development, and the disruption of either hormonal signal could have an impact on normal ovarian function and stimulation response. Thus, the genetic variability that affects the innate activity of these hormones could provide valuable predictive information and help guide COS treatment choices. Mutations in the genes coding for LH [20–24], the LH receptor [25–27] and the FSH receptor [28–32] have been identified as possible causes of subfertility, as well as factors that may influence fertility treatment.
An additional study looked at FSH-induced oestradiol levels in women who were homozygous for the Ser680 variant compared with women with the wild-type (Asn/Asn). This represented the first attempt to develop a pharmacogenomical approach to COS. Ser680/Ser680 carriers were randomly allocated to two subgroups to receive a daily FSH dose of 150 IU or 225 IU, respectively. Age and BMI-matched Asn/Asn carriers, receiving a daily dose of 150 IU, constituted a third (control) group. Even though the treatment details, number of oocytes retrieved and fertilisation rates were similar, the wild-type group had higher oestradiol production after treatment with 150 IU/day of FSH compared with the Ser680 group given the same dose; conversely, when Ser680/Ser680 carriers were treated with 225 IU/day, this difference disappeared . These findings are consistent with carriers of the Ser680/Ser680 variant experiencing lower biological activity of both endogenous and exogenous FSH due to lower sensitivity of the FSH receptor to FSH. However, it should be noted that two further studies did not confirm that adjustment of the starting dose of FSH improved the hormonal response [43, 44]. Despite this, the findings of FSH starting dose modification studies raise an intriguing question about the interpretation of isolated markers, including AFC. In fact, the current literature suggests that AFC is effective in predicting ovarian response and choosing the right FSH dose; nevertheless, a pharmacogenomical approach to COS strongly indicates that, in at least one out of four patients with normal AFC (which reflects the frequency of Ser680/Ser680), the optimal FSH dose should be higher. This provides further support that AFC and genetic approaches should be integrated into determination of COS treatment protocols.
In addition to the two SNPs described above, there are also many genotypic SNPs found in the introns and untranslated regions of the FSH receptor gene; however, it is not currently known what physiological effects these mutations confer . Further mutations have been identified in young women (< 35 years) undergoing COS in the form of receptor splice variants . FSH receptor messenger RNA was isolated from the cumulus cells of women who demonstrated high or low response to FSH when treated with a GnRH agonist long protocol. Abnormal splicing products were identified that affected the ligand-binding extracellular domain. One variant was associated with a low response to FSH, and another variant was associated with a high FSH response .
Patient genetic profiles: interpretation of physiology and biomarker levels
Interpretation of genetic profile
Low AMH levels; low AFC
Suggests that even high doses of FSH would be ineffective and that LH would not improve results
Patient would benefit from counselling to better understand her limited chances of success
FSH receptor variant (eg. Ser680); good AMH levels; good AFC
Suggests a good prognosis, but it also predicts a genetic hyposensitivity to FSH that should be considered when formulating COS treatment
v-LH (variant in β subunit of LH receptor)
Suggest that a patient might benefit from LH supplementation during COS
In addition to using the patient's individual characteristics to determine which treatment protocols should be selected, this patient-specific approach could potentially be used to determine how treatment protocols are administered. The short, ultrashort, micro-flare and stop GnRH agonist protocols are all adaptations of the standard protocol for COS, generated by adjusting the timing and dose of GnRH agonist administration [45, 46]. Preparation of the endometrium is also a crucial step in the success of IVF. Further analysis of hormonal, functional and genetic biomarkers and their relationships with patient response to variations in treatment protocols could be used in the future, and additional clinical data are required to support this hypothesis.
Individual patient characteristics can be predictive of ovarian response, and these factors must be used to optimise the individual treatment regimen. AMH and AFC are good predictors of ovarian response to COS, and may be valuable in deciding which protocol and dose to use for COS. Additionally, initial data indicate that the use of AMH to determine protocol selection may reduce the incidence of OHSS, although further studies are required to confirm this. The hyposensitivity to FSH in a subset of women undergoing the GnRH agonist protocol despite other normal indicators was described by De Placido and colleagues . It is possible that this condition may be caused by genetic polymorphisms of LH, the FSH receptor or the LH receptor. Thus, genetic testing of normogonadotrophic women showing reduced sensitivity to FSH (e.g., a high FSH dose in previous cycles) may assist in tailoring subsequent treatment. Patients could be given higher doses of FSH if they are found to carry the Ser680 variant, or have LH added to their treatment if they are found to carry the v-LH polymorphism. As technology progresses and more powerful analytical tools are developed, predicting ovarian response using a single biomarker will not be sufficient to make the most accurate prognosis or to formulate a personalised treatment plan. In the future, the combination of hormonal, functional and genetic testing will be needed to ensure that the right treatment protocol is provided to the right patient. Finally, the patient's response to treatment should be monitored closely to determine if further tailoring of the personalised treatment plan is required.
List of abbreviations
antral follicle count
assisted reproductive technology
body mass index
Consolidated Standards of Reporting Trials
controlled ovarian stimulation
clinical pregnancy rate
human chorionic gonadotrophin
human menopausal gonadotrophin
ovarian hyperstimulation syndrome
polycystic ovary syndrome
recombinant follicle-stimulating hormone
recombinant human chorionic gonadotrophin
recombinant human luteinising hormone
single nucleotide polymorphism
urinary follicle-stimulating hormone
urinary human chorionic gonadotrophin
variant luteinising hormone
The authors would like to thank Dr Agnese Fiorentino for her helpful discussion of the manuscript. Medical writing assistance was provided by Michael Bankson and Kirsty Ratcliffe of Gardiner-Caldwell Communications, Macclesfield, UK. Funding for medical writing support was provided by Merck-Serono.
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