Managing poor ovarian response in the patient with diminished ovarian reserve

This month's Views and Reviews provides insights into one of the most difficult clinical care populations: individuals with low ovarian reserve and limited response to stimulation. After a discussion of available definitions of "poor ovarian response" and how new definitions are improving the characterization of the individual patient and our ability to offer prognosis, we review alternative strategies for management. The first chapter presents options for pretreatment, including hormonal manipulation and nutriceuticals. The second chapter discusses the potential benefit of more gentle stimulation in this population. Subsequent chapters address adjuvants during stimulation, alterations of final oocyte maturation and processes in the laboratory, and finally when and how to stop treatment. This month's Views and Reviews provides insights into one of the most difficult clinical care populations: individuals with low ovarian reserve and limited response to stimulation. After a discussion of available definitions of "poor ovarian response" and how new definitions are improving the characterization of the individual patient and our ability to offer prognosis, we review alternative strategies for management. The first chapter presents options for pretreatment, including hormonal manipulation and nutriceuticals. The second chapter discusses the potential benefit of more gentle stimulation in this population. Subsequent chapters address adjuvants during stimulation, alterations of final oocyte maturation and processes in the laboratory, and finally when and how to stop treatment. DIALOG: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/posts/34814 DIALOG: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/posts/34814 One of the most difficult problems in the current practice of assisted reproduction is how to best counsel and treat patients with a "poor ovarian response" (POR). Early publications assumed decreased "response" to exogenous gonadotropins. It is important to remember that the goal of exogenous gonadotropins was to maximize response in a single cycle and, importantly, there were no good markers of ovarian reserve. Thus, a "poor response" was considered a failure of stimulation and led to a search for modifications in the treatment protocol. The 2 more recent attempts to clarify and standardize definitions have different endpoints and goals. In the Bologna, European Society of Human Reproduction and Embryology, guidelines, the goal was the prediction of a low number of eggs retrieved—hence a "poor response" (1Ferraretti A.P. La Marca A. Fauser B.C.J.M. Tarlatzis B. Nargund G. Gianaroli L. ESHRE working group on Poor Ovarian Response Definition. ESHRE consensus on the definition of 'poor response' to ovarian stimulation for in vitro fertilization: the Bologna criteria.Hum Reprod. 2011; 26: 1616-1624Google Scholar). The Patient-Oriented Strategies Encompassing IndividualizeD Oocyte Number (POSEIDON) criteria (2Alviggi C. Andersen C.Y. Buehler K. Conforti A. De Placido G. Esteves S.C. et al.Poseidon Group (Patient-Oriented Strategies Encompassing IndividualizeD Oocyte Number). A new more detailed stratification of low responders to ovarian stimulation: from a poor ovarian response to a low prognosis concept.Fertil Steril. 2016; 105: 1452-1453Google Scholar) sought to develop criteria that better predict prognosis, rather than simply response. The European Society of Human Reproduction and Embryology criteria began with age. It is accepted that a woman is born with the full complement of oocytes, which then declines throughout her lifetime. Therefore, advancing age would be expected to be a risk factor for POR. As cited by the investigators, there is, however, intrinsic variability with age. In fact, as shown for the age of menopause itself (3van Asselt K.M. Kok H.S. Pearson P.L. Dubas J.S. Peeters P.H. Te Velde E.R. et al.Heritability of menopausal age in mothers and daughters.Fertil Steril. 2004; 82: 1348-1351Google Scholar), maternal menopause is a predictor of the daughters' antral follicle count (AFC) (4Rosen M.P. Johnstone E.B. Gillham S.J. Modan A.E. Lipshutz A.K. Reijo-Pera R. et al.Is antral follicle count a genetic trait?.Menopause. 2010; 17: 109-113Google Scholar) supporting the genetic contribution to ovarian aging. Additional criteria included other factors that lower the follicular pool, including other genetic factors (Turner syndrome and fragile X premutation) and acquired defects, such as endometriosis, pelvic inflammatory disease, and chemotherapy. As opposed to earlier definitions of POR, these diagnoses all result in a lowered "potential" for response and not an inadequate response to the stimulation dosing/protocol. The next criterion was ovarian reserve markers. Correctly suggesting that antimüllerian hormone and AFC are the most reliable, they still considered them only a "post hoc" test still requiring a prior stimulation for confirmation of an expected low response. The final criterion was a prior response (≤3 oocytes) with a conventional stimulation. The definition then requires 2 of the 3 criteria to be met. There are 2 main concerns with this definition: first, most clinicians—and patients—would like to have information before the first stimulation, and therefore, improved counseling and stimulation selection are possible; and second, the definition conflates appropriate but low response (the person with a low intrinsic capacity regardless of stimulation) and a true "poor response" where the ultimate capacity is not achieved but perhaps possible with a modification in stimulation. Additionally, this definition, with respect to predicting prognosis, disregards the impact of variable quantity and quality within the same woman. For the same number of eggs retrieved, the resultant pregnancy potential between a 32-year-old and a 42-year-old is quite different. The POSEIDON criteria (3van Asselt K.M. Kok H.S. Pearson P.L. Dubas J.S. Peeters P.H. Te Velde E.R. et al.Heritability of menopausal age in mothers and daughters.Fertil Steril. 2004; 82: 1348-1351Google Scholar, 5Humaidan P. Alviggi C. Fischer R. Esteves S.C. The novel POSEIDON stratification of 'low prognosis patients in assisted reproductive technology' and its proposed marker of successful outcome.F1000Res. 2016; 5: 2911Google Scholar), as described earlier, had as a goal recognizing this distinction and separating, based on age (quality) and quantity, probability for successful pregnancy. The marker for expected prognosis was based on chances to achieve a euploid embryo for transfer—thus including both oocyte number and female age. This classification allows better counseling of patients before stimulation as well as improving our ability to perform trials with homogeneous groups of patients improving interpretation of results. I would suggest 1 final distinction that is made in the POSEIDON criteria—but still not widely accepted. There are 2 reasons why a low number of oocytes may be collected: first, this is the patient's individual capacity ("diminished ovarian reserve"), and second, this is hyporesponse, that is, capacity is higher, but stimulation is not optimized ("poor ovarian response"). The approach to these 2 subsets of patients is different. For instance, the patient with an AFC of 3 should not have the cycle canceled if she only makes 3 mature-sized follicles; this could/should have been anticipated and discussed before the start of stimulation. Alternatively, the patient with an AFC of 15 who develops only 3–5 follicles may well be canceled as a "poor response" with a modification of the stimulation based on the anticipated source of hyporesponse. Therefore, while the POSEIDON criteria have improved counseling and prediction of successful treatment in an age-based manner, we still struggle with what to do once a patient likely to have a low response is identified. To help guide clinical care, we have gathered experts from around the world to review available literature and give their opinions on key areas of controversy. Orvieto will initiailly tackle the issue of pretreatment. Are there medications/manipulations of the cycle that enhance response? If so, how do these modifications work and to whom should they be applied? Does pretreatment actually increase the potential number for recruitment or optimize the response of available follicles/oocytes? If used, is there evidence to define dose and duration? Alviggi next discusses the issue of dose. Does dose variation impact response? If so, is this true for all cycles, or are there some individual patients for whom dose matters and others for whom the lowest effective dose should be used, or should the lowest possible dose be used for all patients? Hart will then address the available data regarding adjuvants to stimulation. Are there modifications in the stimulation protocol itself that optimize the recovery of available oocytes? Do the data inform us in selecting the optimal protocol for individual patients to help them achieve a live birth? Vuong will then examine the modifications of final oocyte maturation and laboratory techniques to enhance the usability of eggs retrieved. Are there modifications that can increase the competence and/or maturation of available oocytes? If the ultimate number of oocytes is limited, can we improve the quality of oocytes/embryos available for usage? Lastly, Cakmak will investigate the end of this journey for patients. What is the point at which we discuss stopping autologous stimulation? How do we have these discussions? Moreover, what treatments are on the horizon that may extend reproductive life for our patients? What is the biologic support for these now experimental options? Moreover, what is required before they enter into standard practice? How do we expand the treatment options? The identification of patients at risk for low oocyte recovery—either intrinsic or due to response—is becoming easier today. How to respond and improve expected outcome, perhaps less so. In this series of articles, from experts around the world, we will help to identify and define evidence-based treatment options. In addition, when evidence is not available, the investigators will speak to how we introduce new technologies into treatment. Patients are frequently desperate for the latest, newest treatment. How do we guide them with the best evidence possible for this challenging and growing patient group? DIALOG: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/posts/34814