© Springer India 2015
Surveen Ghumman (ed.)Principles and Practice of Controlled Ovarian Stimulation in ART10.1007/978-81-322-1686-5_2222. Luteal Support: What to Use When?
(1)
Department of Obstetrics and Gynaecology, Nova IVI Fertility Clinics, New Delhi, Delhi, India
Abstract
Supraphysiological hormonal profiles are the cause of luteal defect observed in stimulated IVF cycles. Hence it is essential to support the luteal phase in stimulated cycles for which different forms of support are available. Progesterone and human chorionic gonadotropins (hCGs) so far have been the ideal supports for pregnancy. HCG results in higher incidence of ovarian hyperstimulation. Luteal phase support with progesterone results in increase in implantation and pregnancy rates. For now, progesterone seems to be the best option as luteal phase support. Oral progesterone is associated with reduced bioavailablity. Vaginal progesterone is associated with increased at-site concentration.
Keywords
Luteal phaseProgesteronehCGLuteal support22.1 Introduction
The menstrual cycle starts with rise in level of FSH (follicle-stimulating hormone). Rise of FSH co-relates with the rise of oestrogen. Simultaneously there is first recruitment of follicles and then selection of the dominant follicle. In the middle of menstrual phase there is rise of LH (leutinizing hormone). This rise of LH causes ovulation. After ovulation the dominant follicle gets transformed into a corpus luteum. Corpus luteum secretes progesterone and oestrogen of which progesterone is the dominant hormone.
If conception takes place, then developing blastocyst secretes hCG (human chorionic gonadotropin). The role of hCG is to maintain the corpus luteum and support it. If conception does not take place, then corpus luteum regresses and the level of progesterone and oestrogen falls, which is then followed by onset of menstruation.
The luteal phase forms a bridge between the ovulatory phase and the beginning of the menstrual cycle.
Along with the hormonal changes there are changes in the endometrium, which starts growing after menstruation under the influence of rise of oestrogen. After ovulation, there is rise of progesterone, which transforms it into a secretory endometrium. Progesterone prepares the endometrium for pregnancy by stimulating proliferation in response to hCG, which is produced by the corpus luteum. This occurs in the luteal phase of the menstrual cycle. Progesterone also promotes local vasodilatation and uterine musculature quiescence by inducing nitric oxide synthesis in the decidua.
The length of the luteal phase varies, the average being 14 days. Corpus luteum and the hormones secreted by it support the ongoing pregnancy initially for 8–12 weeks. This function is then taken over by the placenta.
22.2 Effect of Luteal-Phase Support on Endometrial microRNA Expression Following Controlled Ovarian Stimulation
It has been suggested that during ovarian stimulation for IVF, the endometrium becomes receptive after oocyte retrieval. Prior to and during the implantation process, the expression of multiple endometrial genes and gene products is highly regulated. The role of mRNAs in regulating cellular processes during the endometrial transition has recently attracted a great deal of attention. Neo-angiogenesis is a pivotal process in reproductive function where it regulates endometrial regeneration, corpus luteum formation and finally placentation. The regulatory function of mRNAs in the process of neo-angiogenesis has been illustrated in several in vitro and in vivo models.
The array-based study has revealed that there is an expression of a unique set of mRNAs in the endometrium following controlled ovarian stimulation. The level of expression for these mRNAs undergoes significant changes during the peri-implantation period. This expression is influenced by ovarian steroids. Expression of mRNAs may be associated with target genes and gene pathways. The mRNAs found to have enriched or depleted transcript load during the luteal phase may have specific roles in the control of endometrial receptivity during the peri-implantation period through regulation of their target genes [1].
22.3 Aetiology of Luteal Phase Defect (LPD) in ART Cycles
Removal of large quantities of granulosa cells during oocyte retrieval leads to diminished production of progesterone by corpora lutea, resulting in defect in the luteal phase. HCG administration for final oocyte maturation in stimulated IVF cycle could cause LPD by suppressing LH production via short-loop feedback mechanism [2].
Supraphysiological levels of steroids secreted by number of corpora lutea directly inhibit LH release via negative feedback actions at the hypothalamo-pituitary level. Corpus luteum requires consistent LH stimulus to perform its physiological function. LH support during luteal phase is responsible for maintenance and normal steroidogenic activity of the corpus luteum. As a result, unnecessary withdrawal of LH causes premature luteolysis [3, 4]. LPD is also seen equally in stimulated cycles with use of GnRh antagonists [5]. Luteal phase support is thus an integral part of ART cycles.
22.4 Option for Luteal Support
Luteal support may be given as
1.
hCG: 1,500–2,000 I.U I/M starting from oocyte retrieval
2.
Progesterone: from day of oocyte retrieval to 7–10 weeks after pregnancy injectable progesterone in oil: 25–100 mg I/m, oral progesterone, vaginal progesterone 200 mg tds or q.i.d, gel: 90 mg once or twice daily
3.
Oestradiol valerate: 2 mg b.d. starting from oocyte retrieval to 7–10 weeks of pregnancy
4.
GnRha for luteal support
22.4.1 Progesterone
Progesterone is a naturally occurring hormone secreted by the corpus luteum. In the presence of oestrogen, it transforms a proliferative endometrium into a secretory endometrium for implantation of the embryo. Progesterone also promotes local vasodilatation and uterine musculature quiescence by inducing nitric oxide synthesis in the decidua [6]. Once the embryo is implanted it acts to maintain the pregnancy.
22.4.1.1 Route of Administration
Oral Ingestion
Oral progesterone is extensively metabolized and has systemic side effects. There is reduced bioavailability. Micronized progesterone formulations initially used orally are now used vaginally [7]. Dehydrogesterone (DG), an oral progesterone, is a retroprogesterone with good oral bioavailability. According to Chakravarty et al., comparing oral DG vs. vaginal micronized progesterone for luteal support, both are associated with similar rates of successful pregnancies [8].
Intramuscular Injection
It is the most reliable route to achieve desired concentration of progesterone. It is rapidly absorbed, and peak level is reached in 8 h. Serum progesterone levels remain sustained compared to other routes as it is administered in an oil vehicle. It has the disadvantage of inconvenience of daily injections and pain or abscess formation at injection site. Allergic reactions may be seen. However, results are similar with intramuscular and vaginal progesterone.
The doses of IM progesterone used for LPS vary between 50 and 100 mg/day without any significant difference concerning the outcome [9]. Despite the conclusion of Pritts and Atwood’s meta-analysis, vaginal administration of progesterone is a viable alternative to the IM injections of progesterone, as parenteral administration is associated with a high number of side effects [9]. On the basis of presented evidence, IM progesterone is not recommended as a first-choice LPS method in stimulated IVF cycles.
Rectal Administration
This route of progesterone administration is not widely accepted; there are minimal clinical trials on this method.
Vaginal Administration
Advantages of vaginal progesterone are patient comfort and effectiveness; there is high at-site concentration with low serum concentration. It does not cause drowsiness or sleepiness but is inconvenient because of vaginal discharge. Following intravaginal administration of progesterone, high uterine progesterone concentrations with low peripheral serum values are observed, due to counter-current exchange in progesterone transport between anatomically close blood vessels [10] and due to the uterine first-pass effect, where liver metabolization is absent [11]. It is a standard choice for luteal support. Vaginal and intramuscular progesterone have similar efficacy with comparable implantation and clinical pregnancy rates [12].
Vaginal delivery options are
Vaginal pessaries can be given in t.d.s or b.d dose. Patients have to lie flat for 30 min following insertion. Pessaries are messy and are associated with vaginal discharge. Occasionally the insertion can be associated with vaginal itching and perineal irritation.
Progesterone gel administration is delivered comfortably. There is no need to lie flat after insertion. The dose is 90 mg daily or B.D.
22.4.2 hCG
hCG is an indirect form of luteal support which acts by stimulating corpora lutea to produce progesterone. It is ineffective in the presence of inadequate number of LH receptors or a malfunctioning corpus luteum, which is hypo-responsive to hCG. hCG is effective if there is a specific defect in post-ovulatory LH secretion or in trophoblastic hCG production. It raises oestradiol and progesterone concentration, thus rescuing failing corpora lutea in stimulated IVF cycles. hCG administration increases concentration of placental protein [13], integrin and relaxin, which have been shown to increase at time of implantation [14]. The disadvantage of using hCG for luteal support stems from its potential for increasing rates of ovarian hyperstimulation syndrome (OHSS) when compared with other treatments or no treatment at all. With regard to OHSS, one should therefore be cautious with the administration of hCG for luteal supplementation in stimulated IVF cycles [13].
Luteal support with hCG should be avoided if E2 levels are >2,500–2,700 pg/ml on the day of hCG administration [15], or if the number of follicles is >10 [16]. According to the 2011 Cochrane database systematic review [17], luteal phase support with hCG provided significant benefit as compared to placebo or no treatment in terms of increased pregnancy rates and decreased miscarriage rates, but only when GnRha were used.
22.4.3 Oestradiol
The quality of endometrium on which implantation depends is affected by both progesterone and oestradiol. The role of progesterone for luteal support in stimulated cycles is clear. The role of oestradiol is not clear. There is a drop in oestrogen concentration in the luteal phase. There are some patients who could benefit from oestrogen addition during progesterone support. According to a meta-analysis by Kolibianakis et al. [18], the difference in pregnancy rates between two regimens, i.e. progesterone only and progesterone plus oestrogen, is very small.
According to a recent meta-analysis of 10 randomized controlled trials, 7 on GnRha and 3 on GnRh antagonists, the addition of oestrogen to progesterone for luteal phase support does not improve IVF outcomes [19].
|A study conducted and approved by the Johns Hopkins Hospital Institutional Review Board to evaluate the expression of miRNAs during the luteal phase following controlled ovarian stimulation for IVF and the influence of different luteal phase support protocols on miRNA profiles showed that after luteal phase support the miRNAs are up-regulated or down-regulated. Hence, luteal support following controlled ovarian stimulation has a profound influence on miRNA profiles. Up- or down-regulation of miRNAs after progesterone, or progesterone and oestrogen, suggests a role for luteal support in the peri-implantation uterus in IVF cycles through the regulation of associated target genes [20].
22.4.4 GnRh Agonist
GnRh agonist may support corpus luteum by stimulating secretion of LH by the pituitary, by acting on endometrium by locally expressed GnRh receptors, a direct effect on the embryos or by some combination of these possibilities. GnRh agonist also increased luteal phase hCG, E2 and progesterone in both stimulation regimens. It could be given as single dose or multiple dose.
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