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Individualized Luteal Phase Support CE: Alpana; GCO/310301; Total nos of Pages: 6; GCO 310301 REVIEW CURRENT OPINION Individualized luteal phase support Barbara Lawrenza,b, Carol Coughlanc, and Human M. Fatemia Purpose of review The aim of this review is to summarize the different aspects of luteal phase deficiency in IVF treatment and the possibilities of individualized luteal phase support. Recent findings 03/26/2019 on BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3iopPs8eUYypm2mXpsqYu+FTQQCfFlSo+95KUwgaSqwb665CtKO6gUQ== by https://journals.lww.com/co-obgyn from Downloaded Downloaded After the application of human chorionic gonadotrophin (hCG) for final oocyte maturation, the vaginal route for progesterone administration is sufficient to maintain an adequate luteal phase support. New data point toward the possibility of oral medication; however, those data have yet to be confirmed in larger from https://journals.lww.com/co-obgyn studies. Luteolysis after gonadotropinrealzing hormone (GnRH) agonist trigger is patient specific and not always severe. According to the progesterone level, individualized low dosages of hCG can be applied as luteal phase support without the risk of ovarian hyperstimulation syndrome (OHSS) development. Summary It is the task of the reproductive medicine specialist to individualize luteal phase support according to the by patient’s specific characteristics, needs and desires and the type of treatment performed. The greatest BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3iopPs8eUYypm2mXpsqYu+FTQQCfFlSo+95KUwgaSqwb665CtKO6gUQ== indication for individualization of the luteal phase is following GnRH agonist trigger in high responder patients in order to tailor luteal phase support to the patient-specific pattern of luteolysis and minimize the risk of causing OHSS with unnecessary high hCG dosages. Keywords individualized luteal phase support, luteolysis, progesterone INTRODUCTION is the uniformly applied administration of proges- In recent years, tailoring of ovarian stimulation terone, mainly via the vaginal route in the form of protocols for in-vitro fertilization (IVF) – treatments suppositories or intramuscular injections. The uni- according to the patient’s specific preconditions, formity of luteal phase support is not in keeping needs and requirements – is increasingly gaining with the diversity and developments of individual- importance and benefits the outcomes of assisted ized ovarian stimulation treatment. There is a need reproductive techniques (ARTs). However, individ- for individualization of the luteal phase support and ualization of luteal phase support has not been yet to achieve this, reproductive medicine specialists well implemented to date. need to be aware of the impact of ovarian stimula- Current developments in ART are characterized tion on the luteal phase and the available by a trend toward embryo vitrification and as a approaches for luteal phase support. result to subsequent frozen embryo transfer. This The aim of this review is to summarize the move toward frozen embryo transfer is the result of different aspects of luteal phase deficiency (LPD) an ongoing debate on the impact of supraphysio- and the possibilities of individualized luteal phase logical hormonal levels on endometrial receptivity, support. on 03/26/2019 particularly in the case of progesterone elevation. In addition, frozen embryo transfer facilitates preim- a b plantation genetic testing for aneuploidy at blasto- IVI Middle-East Fertility Clinic, Abu Dhabi, UAE, Obstetrical Depart- ment, Women’s University Hospital Tubingen, Tubingen, Germany and cyst stage, which prevents a timely transfer on day 5 cIVI Middle-East Fertility Clinic, Dubai, UAE after oocyte retrieval. Correspondence to Barbara Lawrenz, MD, PhD, IVIRMA Middle East A ‘freeze-all-strategy’ does not apply to all Fertility Clinic, Royal Marina Village, Villa B22-23, POB 60202, Abu patients and management of an adequate luteal Dhabi, UAE. Tel: +00971 2 6528000; phase support is crucial in order to achieve a preg- e-mail: [email protected] nancy after fresh embryo transfer. However, the Curr Opin Obstet Gynecol 2019, 31:000–000 most common approach for luteal phase support DOI:10.1097/GCO.0000000000000530 1040-872X Copyright ß 2019 Wolters Kluwer Health, Inc. All rights reserved. www.co-obgyn.com Copyright © 2019 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. CE: Alpana; GCO/310301; Total nos of Pages: 6; GCO 310301 Fertility, IVF and reproductive genetics To counterbalance the luteal phase insufficiency KEY POINTS after ovarian stimulation and to maintain the secre- After the administration of hCG for final oocyte tory endometrium, an adequate luteal phase sup- maturation, vaginal progesterone is sufficient to port is crucial and a must after ovarian stimulation. maintain an adequate luteal phase support. In a natural cycle, LPD was defined as having midluteal progesterone levels below 10 ng/ml Luteolysis after GnRH agonist for final oocyte (31.8 nmol/l) or a sum of three random serum P maturation is patient specific and not always severe. measurements less than 30 ng/ml (95.4 nmol/l) Individualization of luteal phase support after GnRH [13]. In IVF treatments, the lower limit of progester- agonist trigger can be performed with the use of low one levels to achieve and maintain a pregnancy is hCG dosages or even without any additional hCG, not defined yet. It seems that a progesterone level of according to the progesterone levels in the early and more than 30 ng/ml and an estradiol level of more mid-luteal phase. than 100 pg/ml at the day of implantation are more likely to have a viable and ongoing pregnancy com- pared to patients with hormone levels below these thresholds [14]. Other publications report successful LUTEAL PHASE IN NATURAL AND pregnancies with mid-luteal progesterone levels STIMULATED CYCLES above 17 ng/ml [15] or even as low as a progesterone In a natural cycle, the dominant follicle produces level above 15 ng/ml 2 days after gonadotropin- increasing amounts of estradiol, which will initiate releasing hormone (GnRH) agonist trigger [16], the luteinizing hormone surge. Even before the provided that adequate luteal phase support was luteinizing hormone surge, luteinizing hormone applied. pulse amplitude and frequency increase and finally As a consequence of the increasing knowledge lead to the surge which results in the resumption of on patient-specific characteristics, the old concept oocyte meiosis, luteinization of granulosa cells, ovu- of one type of luteal phase support for all IVF lation and the initial phase of corpus luteum devel- patients has to be abandoned and a personalized opment. Further on, granulosa cells and thecal cells approach, depending on the type of final oocyte produce up to 40 mg of progesterone per day accom- maturation and the ovarian response, should be panied by a significant amount of androgens and implemented into daily clinical routine. estradiol [1,2]. Progesterone induces the secretory transformation of the endometrium and lays the foundation for a receptive endometrium. Endome- STRATEGIES FOR LUTEAL PHASE trial receptivity is driven by the time of progesterone SUPPORT exposure after adequate estradiol exposure and is Worldwide, the preferred route of progesterone crucial for the trophoblast–endometrial interaction administration is the vaginal route (https://ivf- [3]. Although in a conception cycle corpus luteum worldwide.com/survey/an-updated-survey-on-the- function will be maintained by human chorionic use-of-progesterone-for-luteal-phase-support-in- gonadotrophin (hCG) production from the devel- stimulated-ivf-cycles/results-an-updated-survey-on- oping embryo, luteolysis will occur in a cycle with- the-use-of-progesterone-for-luteal-phase-support-in- out conception because of the lack of hCG support stimulated-ivf-cycles.html). Three to eight hours and the corpus luteum will undergo regression with after the application of vaginal suppositories or a loss of functional and structural integrity [4]. tablets, progesterone plasma concentrations reach In contrast to a natural cycle with normally one maximal serum levels and thereafter, they fall con- dominant follicle, the aim of ovarian stimulation for tinuously over the next 8 h. To achieve sufficient ART treatment is the development of multiple fol- luteal phase plasma levels, 300–600 mg of progester- licles to enhance the chance of pregnancy. Multiple one is administered daily, divided into two or three follicular growth can only be achieved by the dosages [17]. The absorption by the vaginal mucosa is administration of exogenous gonadotropins [5], influenced by the kind of formula preparation and resulting in supraphysiological levels of estradiol is enhanced after previous oestrogenization [18]. and progesterone not only in the follicular phase, Despite the fact that serum progesterone levels when but also lasting into the early luteal phase. Supra- measured using vaginal progesterone administration physiological hormonal levels will lead via the neg- are sometimes even lower than in a natural cycle, ative feedback mechanism to the inhibition of the adequate secretory endometrial transformation is luteinizing hormone secretion from the pituitary achieved. Obviously, the vaginally administered pro- gland [6–9] and therefore result in a defective luteal gesterone exerts a direct local effect on the endome- phase in almost all patients [10–12]. trium before it enters the systemic circulation. This
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