Individualized Luteal Phase Support

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Obstetrical Depart- b a www.co-obgyn.com 2019, 31:000–000 , and Human M. Fatemi c The aim of this review is to summarize the IVI Middle-East Fertility Clinic, Dubai, UAE IVI Middle-East Fertility Clinic, Abu Dhabi, UAE, Correspondence to Barbara Lawrenz,Fertility MD, Clinic, PhD, Royal IVIRMADhabi, Marina UAE. Middle Village, Tel: East +00971 Villa 2e-mail: B22-23, 6528000; [email protected] POB 60202,Curr Abu Opin Obstet Gynecol DOI:10.1097/GCO.0000000000000530 a c ment, Women’s University Hospital Tubingen, Tubingen, Germany and is the uniformly appliedterone, mainly administration via of the proges- suppositories vaginal or route intramuscular in the injections.formity form The of of uni- lutealwith phase the diversity support and isized developments ovarian not of stimulation individual- in treatment.for There keeping individualization is of a the luteal need phaseto support and achieve this,need to reproductive be medicine awaretion of specialists the impact on ofapproaches ovarian for stimula- the luteal phase support. lutealdifferent phase aspects of andand luteal the possibilities the phase ofsupport. deficiency individualized available (LPD) luteal phase , Carol Coughlan a,b GCO 310301 Barbara Lawrenz 2019 Wolters Kluwer Health, Inc. All rights reserved. ß Summary It is the taskpatient’s of specific the characteristics, reproductive needs medicineindication and specialist for desires to individualization and individualize of thepatients luteal the type in phase luteal of order support phase treatment to according isrisk performed. tailor to following of The luteal the GnRH causing greatest phase agonist OHSS support trigger with to in unnecessary theKeywords high high patient-specific responder hCG pattern dosages. ofindividualized luteolysis luteal and phase minimize support, the luteolysis, progesterone Purpose of review The aim of thisthe review possibilities is of to individualized summarize luteal the phase differentRecent support. aspects findings of lutealAfter phase the deficiency application in of IVFroute human treatment for chorionic and progesterone gonadotrophin administration (hCG)point is for toward sufficient final the to oocyte possibility maintainstudies. maturation, of an Luteolysis the oral adequate after vaginal medication; luteal gonadotropinrealzing however,always phase hormone those severe. support. (GnRH) data According New agonist have to data triggerluteal yet the is phase to progesterone patient support be level, specific without confirmed individualized and the in low not risk larger dosages of of ovarian hCG hyperstimulation can syndrome be (OHSS) applied development. as Individualized luteal phase support PINION A ‘freeze-all-strategy’ does not apply to all Current developments in ART are characterized URRENT O C nancy after freshmost embryo common approach transfer. for However, luteal the phase support plantation genetic testing forcyst aneuploidy stage, at which prevents blasto- a timelyafter transfer oocyte on retrieval. day 5 patients and managementphase support of is crucial an in adequate order to luteal achieve a preg- by a trendresult toward to subsequent embryomove frozen vitrification toward frozen embryo and embryo transfer. transferan as is ongoing This the a result debate of logical on hormonal the levels impact on endometrialparticularly of in receptivity, the supraphysio- case of progesteroneaddition, elevation. frozen In embryo transfer facilitates preim- needs and requirementsimportance – and is benefitsreproductive increasingly the techniques outcomes gaining (ARTs). of However,ualization assisted individ- of luteal phasewell support implemented has to not date. been yet INTRODUCTION In recent years,protocols for in-vitro tailoring fertilization (IVF) ofaccording – treatments to ovarian the stimulation patient’s specific preconditions, 1040-872X Copyright

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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 compared 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 is

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Individualized luteal phase support Lawrenz et al.

known as the ‘first uterine pass’ effect; hence The concept of hCG administration as luteal the underlying mechanism of which is not fully phase support mimics the physiology of corpus understood. Increased vaginal discharge and possible luteum maintenance by an implanting and devel- vaginal irritation are the most common side- oping embryo and was considered for a long time to effects. In case of severe side-effects with vaginal be the gold standard. Through the application of use, patients can be advised to administer progester- hCG, the corpora lutea will be stimulated continu- one rectally. ously and progesterone production will be sus- Theoretically, oral administration would offer a tained. The main disadvantage of this approach is convenient way of progesterone administration. the possible development of ovarian hyperstimula- However, natural progesterone is rapidly metabo- tion syndrome (OHSS), especially in the good lized after oral intake and ineffective in inducing a responder patients [25]. HCG administered for LPS sufficient secretory transformation. The side-effects is not identical to hyperglycosylated hCG (H-hCG), of synthetic progesterone derivatives on lipids and secreted by the developing embryo and to which an on the psyche [19] limit their use. Although micro- important role in implantation is contributed [26]. nisation of progesterone has improved the absorp- In addition to the risk of OHSS, it is not clear tion and bioavailability [20], even higher doses of whether exogenous applied hCG might disturb micronized progesterone have failed to induce suf- implantation because of interference with the spe- ficient secretory transformation. With the recently cific actions of H-hCG [27]. published data, confirming the efficacy of daily 30 mg dydrogesterone compared to daily 600 mg micronized vaginal progesterone as luteal phase LUTEAL PHASE SUPPORT AFTER THE support, the future possible use of oral progesterone INDUCTION OF FINAL OVULATION as an easy and convenient way of progesterone MATURATION WITH HCG administration may be reopened [21&]. HCG and luteinizing hormone activate the same Intramuscular progesterone administration rep- receptor and besides the capability of hCG to induce resents the most inconvenient Luteal phase support final oocyte maturation, hCG maintains corpora (LPS) approach, for the patients themselves as well lutea function in the early luteal phase for up to as for the treating IVF center, as it requires daily 5 days because of its half-life time of more than 24 h visits and injections. Progesterone is rapidly [28,29]. absorbed after i.m. injection and high progesterone Luteal phase support has to be initiated before plasma concentrations are reached after approxi- endogenous progesterone levels decrease or become mately 2 h with peak concentrations around 8 h too low; however, starting luteal phase support too after injection. A daily dosage of 25 mg progesterone early bears the risk of adversely affecting endome- is required to achieve progesterone levels, which are trial receptivity. Most commonly, progesterone is equivalent to those of the luteal phase in a natural started on the day of oocyte retrieval (https://ivf- cycle. It seems that the intramuscular injection site worldwide.com/survey/an-updated-survey-on-the- serves as a progesterone depot and sustains serum use-of-progesterone-for-luteal-phase-support-in- concentration of progesterone [22]. The disadvan- stimulated-ivf-cycles/results-an-updated-survey- tages of the i.m. application are undoubtedly pain on-the-use-of-progesterone-for-luteal-phase-support- experienced by the patient at injection time and the in-stimulated-ivf-cycles.html). Available evidence possible side-effects of swelling and redness and also suggests no significant difference in clinical preg- the possible danger of a sterile abscess formation nancy rates when commencing progesterone on the which should not be neglected. A rare but more day of oocyte retrieval as compared to starting severe and even life-threatening complication is progesterone on day 1–3 after oocyte retrieval. In the development of eosinophilic pneumonia after contrast, commencing progesterone on day 6 neg- progesterone i.m. injections for luteal phase support atively impacts the likelihood of pregnancy [30]. as an allergic reaction toward the oil vehicle, used as Repeatedly applied hCG in a dosage up to 2.500 excipient for the substance itself [23]. Subcutaneous IU, given during the luteal phase, is known to be progesterone injections could pose an alternative for efficient in sustaining corpora lutea function; how- women, who want to avoid i.m. injections as well as ever, this approach is accompanied by the risk of the vaginal route [24]. Finally, it seems that the OHSS development. Also, no significant favorable route of progesterone administration does not have effect of progesterone in combination with hCG an impact on ART outcome, therefore also the compared to exogenous progesterone alone was patients’ preference can be considered when choos- found in a Cochrane analysis [25]. ing the route of progesterone administration for Derived from the knowledge, gathered by pro- luteal phase support [25]. viding luteal phase support with low-dose hCG

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Fertility, IVF and reproductive genetics

administration after GnRH agonist trigger, Ander- low-dose hCG in dosages of 125 IU rec-hCG are sen et al. [27] designed a mathematical model in also sufficient to sustain progesterone levels, even order to calculate the daily applied hCG dosage, without the use of exogenous progesterone, yet still required to maintain sufficient hCG concentrations causing OHSS in some cases [36]. and therefore adequate progesterone levels in the Contrary to previous findings that GnRH ago- luteal phase. Preliminary results indicate that a nist trigger will practically always lead to severe daily-applied dosage of 100 IU hCG without addi- luteolysis, lately it was shown that luteolysis after tional exogenous progesterone seems to be suffi- GnRH agonist administration for final oocyte mat- cient to maintain the corpora lutea function until uration is patient specific and not always severe endogenous hCG from the developing embryo takes [37&]. In some cases, luteolysis is not present at all over. This approach may present a means of further and unprotected intercourse around the time of individualizing luteal phase support. Unfortunately, oocyte retrieval procedure might lead to spontane- the aforementioned small dosages of hCG are not ous pregnancies and also to ovarian hyperstimula- commercially available rendering it difficult to tion syndrome, despite GnRH agonist trigger and implement this as a clinical routine. ‘freeze-all’ strategy [38–40]. As a consequence of these findings, it is now recognized that not all patients after GnRH agonist LUTEAL PHASE SUPPORT AFTER THE trigger are in need of an intensive and aggressive INDUCTION OF FINAL OVULATION luteal phase support and should not be treated with MATURATION WITH a ‘one-size-fits-all’ approach. The concept of ‘luteal GONADOTROPINREALZING HORMONE coasting’ is based on the individual luteolysis pat- AGONIST tern by applying hCG based on the progesterone Through the use of GnRH agonist for final oocyte levels measured in the early and mid-luteal phase maturation, development of OHSS can be avoided and can be performed with or even without the almost completely. Hence, the natural luteinizing additional use of exogenous progesterone [41]. hormone surge is distinct from the luteinizing hor- Depending on the progesterone level 48 h post mone surge after GnRH administration, as the spon- oocyte retrieval, a single hCG dosage between 375 taneous luteinizing hormone surge is characterized and 1.500 IU, given in early luteal phase, can main- by an ascending phase of approximately 4 h, a peak tain adequate progesterone levels and this approach plateau of 20 h and a descending phase of 20 h, may well optimize the chance of pregnancy while whereas the GnRHa-induced luteinizing hormone/ reducing the risk of OHSS associated with higher follicle stimulating hormone surge has a signifi- doses of hCG supplementation in the luteal phase cantly shorter ascending phase. This remarkably [42&]. The necessity for repeat blood tests to measure shorter duration of the luteinizing hormone surge progesterone levels poses the most important disad- after GnRH agonist administration leads to a luteal vantage of this approach. phase which is mostly characterized by severe From day 7 of fertilization, the embryo will start luteolysis [30]. As a result of this severe luteal phase producing hCG [43], and from that point of time, insufficiency, the first studies which used this endogenous-produced hCG will compensate for the approach in combination with a standard luteal luteinizing hormone deficit caused by the supra- phase support reported a very poor reproductive physiologic steroid levels and avoid regression of outcome [31]. To counterbalance this luteal phase the corpora lutea. Progesterone production will shift defect, intensive luteal phase support is required, from the corpora lutea toward the placenta between either by hCG administration or by an aggressive 7 and 9 weeks of gestation and appear to be suffi- approach of luteal phase support, including i.m. cient at this point to maintain the pregnancy [44]. progesterone injections [32]. To revert GnRH ago- Table 1 summarizes the possibilities of luteal phase nist-induced luteolysis, hCG has to be given not support, depending on the medication used for final later than 72 h. Previously, it was shown that the oocyte maturation. rescue of the corpora lutea after up to 3 days of gonadotropin deprivation is hCG dose dependent and requires a minimum dose of 1500 IU hCG and CONCLUSION more [33]. Following this concept, a pilot study It is the task of the reproductive medicine specialist proved that 1.500 IU hCG, given 35 h after GnRH to individualize luteal phase support according to agonist administration, resulted in the same preg- the patient’s specific characteristics, needs and nancy rates as compared to triggering with 10.000 IU desires and the type of treatment performed. hCG [34]. However, this dosage may still lead to OHSS After the use of hCG for final oocyte maturation, in the high responder group [35]. Alternatively, daily exogenous progesterone administration in the form

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Individualized luteal phase support Lawrenz et al.

3. Simon C, Martın JC, Pellicer A. Paracrine regulators of implantation. Baillieres Table 1. Possibilities of luteal phase support, depending Best Pract Res Clin Obstet Gynaecol 2000; 14:815–826. on the medication used for final oocyte maturation 4. Stocco C, Tellerıas C, Gibori G. The molecular control of corpus luteum formation, function and regresion. Endocr Rev 2007; 28:117–149. 5. Type of medication used for final Macklon NS, Stouffer RL, Giudice LC, Fauser BC. The science behind 25 years of ovarian stimulation for in vitro fertilization. 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Fertility, IVF and reproductive genetics

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