LOW RESPONDERS. Poor Ovarian Response, Por

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1 LOW RESPONDERS Poor Ovarian Response, Por Patients with a low number of retrieved oocytes despite adequate ovarian stimulation during fertility treatment. Diagnosis Female About Low responders In patients defined low (poor) responders, the limited number of obtained eggs remains the main problem in optimizing the live birth rates. In fact, as a result of a lower number of oocytes retrieved, there are fewer embryos to select and transfer and subsequently these patients have lower pregnancy rates per transfer and lower cumulative pregnancy rates per started cycle compared with normal responders. At least two of the following three features must be present in a common definition of poor responder : advanced maternal age or any other risk factor for poor ovarian response (POR) a previous POR an abnormal ovarian reserve test The occurrence of poor response to ovarian stimulation is not infrequent; the prevalence of poor responders varies in the literature between 9 and 24%. This range is wide as it depends on the definition of a poor responder that individual in vitro fertilization (IVF) centers employ. In poor responders the mechanism of ovarian insufficiency is prematurely determined and not fully understood. Some causes of decrease in ovarian reserve have been identified: ovarian surgery especially in case of endometrioma, genetic defects, chemotherapy, radiotherapy, autoimmune disorders, single ovary, chronic smoking, and unexplained infertility.

2 Moreover, new risk factors of low ovarian response have been proposed: diabetes mellitus Type I, transfusion-dependent B-thalassemia, and uterine artery embolization for the treatment of uterine leiomyoma. Predicting ovarian response before starting hormonal stimulation is the only way to administer an efficient and safe treatment. There is still no consensus regarding the ideal protocol and so far no one treatment protocol has proven to be superior for poor responders. The majority of the strategies aim to recruit a higher number of follicles either by increasing the dose of gonadotropins, decreasing the dose of gonadotropin-releasing hormone (GnRH) analogs, suppressing an early rise in follicle-stimulating hormone (FSH) with estrogen priming, or optimizing the endogenous FSH flare effect. Associated diseases Endometriosis Endometriosis is classically defined as the presence of endometrial glands and stroma outside of the endometrial lining and uterine musculature. The abnormal growth of endometrial tissue with each female hormonal cycle causes adhesions and scars from forming in the organs where it is. This, in the case of the female reproductive organs can be fatal for the smooth passage of the ovum to the uterus. Premature ovarian failure Generally POF (or premature ovarian insufficiency) represents the clinical end stage of ovarian function in women less than 40 years old. Therefore, women at risk of POF who delay childbearing until after their 30s may experience problems conceiving and carrying a pregnancy to full term. This loss of fertility can be due to an accelerated loss of follicles, an inability of the remaining follicles to respond to ovulatory signals, an initially reduced ovarian reserve at the time of birth, or a combination of all. Complications It is not uncommon to have no oocytes retrieved in women undergoing IVF especially when there is very little follicular growth. In these situations, no oocytes are usually retrieved from apparently normally growing ovarian follicles with normal estradiol concentrations despite meticulous repeated follicular aspiration and flushing. Reasons for this include poor ovarian response, errors in human chorionic gonadotrophin (hcg) administration/timing for final oocyte maturation, underlying ovarian dysfunction, or premature ovulation. In spite of these reasons, obtaining no oocytes following oocyte retrieval represents a tremendous stress for the

3 patient. Luteal phase (Pic. 1) stimulation could potentially alleviate some of this stress since the patients do not have to wait for another menstrual cycle before undergoing ovarian stimulation. Pregnancy complications are not increased in poor responders when compared to their age matched counterparts. Risk factors women above 40 years of age pelvic infections previous ovarian surgery genetic defects chemotherapy radiotherapy autoimmune disorders Impact on fertility In most cases the mechanism involved in follicular depletion is still not clear. It has been suggested that the reduced number of oocytes could be correlated to a reduction of their quality, which is clinically translated into a reduction of the implantation rates and an increase of early pregnancy loss. Conversely, because of the lack of a clear correlation between quantity and quality, different authors have suggested that poor responders per se do not represent a lower chance of success in IVF, with the age of the woman being the most important predictor of live birth rate. However, very large studies have shown that this group of patients has reduced pregnancy rates compared with normal responders independently from the treatment protocol used and from the age of the patient. In this group of difficult patients it is thus clear that to optimize the clinical results in IVF it is not only important to predict the ovarian reserve but also, especially, to tailor the best stimulation protocol to exploit fully the ovarian reserve and optimize the number of oocytes to be retrieved. Only with recent advent of new reliable biomarkers of ovarian reserve better strategies for the management of these patients have been suggested. The number of developed follicles and the number of oocytes retrieved after a standard stimulation protocol are the most important criteria. The proposed quantity varies among authors and ranges from less than three to less than five dominant follicles on the day of hcg administration noted on ultrasound and/or less than three to less than five retrieved oocytes.

4 Prevention Despite being difficult, it is of extreme importance to predict who will be a poor responder, because stimulation protocols should be individualized according to the conditions of each case. However, several tests have been proposed to predict ovarian reserve, which can give an idea about the ovarian response. These include static and dynamic tests. Despite the extensive efforts made, a test that could reliably predict a poor ovarian response in all patients that undergo IVF is currently lacking. Therefore, a consistent identification of a poorresponder would comprise a previously demonstrated poor ovarian response to adequate ovarian stimulation. This means that entering the first cycle of IVF without any prior testing seems to be the most preferable strategy. Symptoms Poor respondres seek from failure to respond adequately to standard protocols and to recruit adequate follicles. This results in decreased oocyte production, cycle cancellation and, overall, it is associated with a significantly diminished probability of pregnancy. Therapies Self therapy Possible self/alternative approach to reduce the risk of being poor responder is to avoid known risk factors. Conventional medicine Several controlled ovarian hyper stimulation (COH) strategies have been described for treating poor responders, but at present, there are no clear guidelines for treating those patients. Currently, ovarian stimulation in women with diminished ovarian reserve has been individualized due to the development of a variety of ovarian

5 stimulation protocols. Many studies have evaluated the use of various ovarian stimulation regimens to improve the outcome of poor responders undergoing IVF treatment; some of these protocols involve minimal/mild ovarian stimulation. Additionally, patients with poor prognosis have high cancellation rates, along with lower pregnancy and live birth rates. Pharmacotherapy Gonadotropins When the standard dose of gonadotropins ( IU) fails to induce a proper multifollicular growth, the obvious clinical approach is to increase the dose. High doses of gonadotropins have been thus used for a couple of decades by the vast majority of the authors in poor responder patients. In the literature conflicting data are however reported on the outcomes of this approach - some but not all authors in prospective and retrospective studies did not report enhanced ovarian response and/or better pregnancy rates when the starting dose of gonadotropins was increased up to 450 IU. It is today clear that these patients have a reduced ovarian reserve; the recruitable follicles are fewer and the gonadotropins, independently of the dosage administered, can only support the cohort of follicles receptive to stimulation without manufacturing follicles de novo. GnRH Analogues This approach lowers cancellation rate and raises the number of preovulatory follicles and the number of oocytes retrieved and good quality embryos for transfer, leading to better pregnancy rates. However this protocol could have a detrimental effect in poor responders because it may induce an excessive ovarian suppression that could lead to a reduced or absent follicular response. However, although with the short flareup protocols significantly more oocytes can be retrieved compared with GnRH antagonist protocols; the number of the retrieved oocytes is still significantly lower when compared with long standard GnRH regimens. The rationale to lower or to stop (after pituitary suppression) the dose of GnRH agonists initiated during the luteal phase is to obtain a reduction of the inhibitory direct effect of the GnRH agonist on the gonads. GnRH Antagonist

6 On the other hand, the introduction of GnRH antagonists have presented a hope for the poor responders in view of its immediate suppression of luteinizing hormone (LH), the absence of flare-up effect, the reduction of the duration of stimulation and the dose of gonadotropins used. However, it seems that use of GnRH antagonists, in the general population, may lead to a nonstatistically significant reduction of the live birth rates compared to GnRH agonist protocols. The use of GnRH antagonist regimens could have some advantages over the GnRH agonist protocols: 1. First, it is possible to assess the ovarian reserve by ultrasound on days 2-3 of the cycle in which controlled ovarian stimulation is planned and decide whether to initiate gonadotropins in the cycle where the probability of a favourable response is optimal. 2. Second, with use of long acting gonadotropins could exploit fully the reduced ovarian reserve by the rapid increase in the serum FSH concentration that would result in a significantly higher exposure of the small antral follicles to constant high levels of FSH during the early follicular phase. Double ovarian stimulation Double ovarian stimulation (follicular and luteal phases) in the same menstrual cycle could provide an opportunity to retrieve more oocytes, potentially producing a pregnancy in poor responders in a shorter period of time. Although luteal phase ovarian stimulation does not seem to be better than follicular phase ovarian stimulation, it could produce a positive (good embryo) outcome in women with diminished ovarian reserve when no oocytes were retrieved in the same conventional IVF cycle. This, without doubt, alleviates some of the stress that poor responders have following a no egg results. Additionally, the resulting embryos from luteal phase ovarian stimulation protocols could have similar developmental potential and could produce clinically acceptable pregnancy rates when compared to embryos produced by follicular phase ovarian stimulation. Double stimulation thus represents a promising approach for patients with poor ovarian response especially when conventional IVF protocols have failed or when time is of the essence. It is unfortunate that studies to date included small sample sizes. Large cohort studies/randomized clinical trials with live-birth rates as outcomes are needed to better elucidate the benefit of luteal phase (and double) ovarian stimulation in the diminished ovarian reserve population. Surgical therapy

7 Poor responders are not treated with surgical intervention. Assisted reproduction Except individualized controlled ovarian hyper stimulation (COH) strategies, other possible approaches could be used in poor responders: Natural Cycles IVF Natural cycles IVF with or without minimal stimulation can be considered as an easy and cheap approach in the management of poor responders. In fact, some authors suggested that natural cycles IVF was a valid option for poor responder patients because it has the same chance in terms of pregnancy and implantation rates. Some critical issues have been highlighted: in only 50% of started cycles one embryo could be replaced into the uterine cavity (50% cancellation rate); the overall clinical pregnancy rate was 10% per started cycle and 18% per patient and per embryo transfer. The contradictory data can be very likely associated to the diversity of patients selected before the application of criteria. Oocyte Cryopreservation Oocyte vitrification (preservation using freeze) has resulted in the breakthrough in ART technologies, probably the most important one in our decade. Recent evidence indicates that this approach is a highly efficient procedure that can be applied in routine infertility programs. Different strategies are applicable for poor responder involving oocyte cryopreservation. Some authors have recently suggested obtaining a large cohort of oocytes in these patients by accumulating vitrified oocytes over several stimulation cycles creating a similar situation as in normal responder patients. According to the results presented in the study, it could be possible to obtain higher live birth rate per patient treated and potentially to reduce the dropout. Moreover, oocyte cryopreservation can also be used to preserve the fertility of all those women at risk to lose their ovarian potential over the time.

8 Find more about related issues Therapies Egg donation Process by which a woman donates eggs for purposes of assisted reproduction or biomedical research. Learn more at: ICSI A micromanipulative fertilization technique in which a single sperm is injected directly into an egg. Learn more at: Sperm donation The procedure in which a man (sperm donor) provides his sperm for fertility treatment. Learn more at: Standard IVF A process in which an egg is fertilised by sperm outside the body: in vitro. Own or donated gametes may be used. Learn more at: Gallery

9 Pic The ovarian cycle consists of the follicular phase, ovulation, and luteal phase whereas the uterine cycle is divided into menstruation, proliferative phase, and secretory phase. Sources Premature ovarian failure ( sourced from Fertilitypedia licensed under CC BY-SA 4.0 Management of Poor Responders in IVF: Is There Anything New? ( by Ubaldi et al. licensed under CC BY 3.0 Eendometriosis ( sourced from Fertilitypedia.org licensed under CC BY-SA 4.0 Premature Ovarian Failure of Autoimmune Causes ( by Carsote and Valea licensed under CC BY 4.0 Comparison of IVF Outcomes between Minimal Stimulation and High-Dose Stimulation for Patients with Poor Ovarian Reserve ( by Lazer et al. licensed under CC BY 3.0 Luteal phase ovarian stimulation following oocyte retrieval: is it helpful for poor responders? ( by Zhang licensed under CC BY 4.0

10 Comparative prospective study of 2 ovarian stimulation protocols in poor responders: effect on implantation rate and ongoing pregnancy ( by Merviel et al. licensed under CC BY 4.0 Strategies for Pituitary Down-regulation to Optimize IVF/ICSI Outcome in Poor Ovarian Responders ( by Badawy et al. licensed under CC BY-NC 3.0 Prediction and Diagnosis of Poor Ovarian Response: The dilemma ( by Badawy et al. licensed under CC BY-NC 3.0 MenstrualCycle en ( by Speck- Made licensed under CC BY-SA 3.0