Frontiers in Gynecological Endocrinology Volume 3: Ovarian Function and Reproduction - From Needs to Possibilities

2. Management of Luteal Phase in IVF Cycles

Pedro N. Barri¹ , Buenaventura Coroleu¹ and Francisca Martinez¹

(1)

Cátedra de Investigación en Obstetricia y Ginecología de la Universidad Autónoma de Barcelona, Gran Via Carlos III 71-77, Barcelona, 08024, Spain

Pedro N. Barri

Email: pbarri@dexeus.com

Email: Perbar@dexeus.com

2.1 Introduction

We will review in this chapter all the events that normally occur during the luteal phase of IVF cycles. Likewise, we will evaluate the different possibilities of luteal support that can be applied during the luteal phase of IVF cycles in which protocols of controlled ovarian hyperstimulation have been used.

In special circumstances, alternative protocols of luteal support have to be employed according to the type of ovulation triggering used. It will be also important to establish the length of this luteal support especially when a pregnancy has been obtained.

2.2 Physiopathology of the Luteal Phase in Stimulated Cycles

In normal conditions of a natural cycle, the slowing down of the GnRH pulse generator along with diminished LH pulse amplitude is responsible for the demise of the corpus luteum. In stimulated cycles, the luteal phase is abnormal with high follicular phase estrogen levels having a negative feedback effect which translates in reduced luteal phase length despite raised progesterone levels. Abnormally raised progesterone levels during the early luteal phase coincide with a premature luteolysis [3]. Supraphysiological steroid levels of estradiol and progesterone in early–mid-luteal phase exert a negative feedback on the hypothalamic-pituitary axis reducing LH secretion in early luteal phase [14].

LH plays a crucial role in the luteal phase for the following reasons:

· Is totally responsible for steroidogenic activity of the corpus luteum

· Stimulates LH receptors in the endometrium

· Induces upregulation of growth factors (VEGFA, FGF 2) as well as of different cytokines involved in implantation

Thus, in IVF cycles under pituitary suppression and HCG triggering, it is beneficial to supplement the luteal phase during the crucial period of 7 days between exogenous clearance and the effect of embryonic HCG. However, when a pregnancy is already established, progesterone support does not improve live birth rates.

Another important factor for implantation is the deleterious effect of severe periovulatory maturation advancement exceeding 3 days that can occur in stimulated cycles. The endometrium is very sensitive to suboptimal estradiol concentrations in mid-luteal phase, and too low estradiol levels can impair uterine receptivity [2].

2.3 Luteal Phase Support After HCG Triggering

It is well accepted that luteal support with HCG or with progesterone significantly improves IVF outcome and pregnancy rate. Hence, support of the corpus luteum remains mandatory after ovarian stimulation for IVF with GnRH antagonist cotreatment [1].

The need for luteal support between clearance of exogenous HCG and the start of embryonic HCG can be done with several protocols:

· HCG (potential OHSS risk)

· Progesterone

· Vaginal gel micronized P 90 mg/day

· Vaginal capsules micronized P 400–600 mg/day

· IM progesterone 50 mg/day

· SC progesterone 25 mg/day

· Oral dihydrogesterone

An international survey recently published [16] showed that vaginal progesterone was used in almost 80 % of IVF cycles carried out worldwide. Although there is no evidence favoring a specific route of progesterone administration [17], subcutaneous progesterone administration is well tolerated and without adverse events [10]. It seems that there is no need for estradiol cotreatment during the luteal phase because the best available evidence suggests that estradiol addition during the luteal phase does not improve IVF/ICSI outcomes even with different daily doses of estradiol oral administration [4].

2.4 Luteal Phase Support After GnRH Agonist Triggering

GnRH-a triggering leads to significantly reduced total amounts of gonadotropins released by the pituitary due to profile and duration of surge. GnRH-a triggering was associated to luteal phase defects responsible for the low implantation and clinical pregnancy rates [5, 13].

Several strategies have been proposed to rescue the luteal phase after GnRH triggering:

· Low periovulatory HCG doses + VE and P

· Low HCG doses (1000, 500, 250 IU) on days +1, +4, and +7

· Recombinant LH

· High doses of E + P IM

In these cycles under GnRH antagonists, some authors have suggested that two boluses of 1500 IU of HCG on the day of the oocyte pickup and 4 days later were enough to circumvent the problem and allowed to achieve normal pregnancy rates [7]. More recently, a modified luteal support has been proposed with a single bolus of 1500 IU at OPU and standard luteal support with oral estradiol and vaginal progesterone [6]. An alternative is to freeze all the embryos and the subsequent replacement in a later cycle (Table 2.1).

Table 2.1

IVF luteal phase after GnRH triggering

2.5 GnRH Cotreatment in the Luteal Phase

It has already been published that the administration of a GnRH agonist during the luteal phase could accidentally be involved with the establishment of a pregnancy [11]. Other studies have suggested that GnRH administration at the time of implantation enhances embryo potential by a direct effect on the embryo and improves implantation in oocyte recipients and in normal IVF patients [12, 15].

In a meta-analysis including six relevant RCTs with 2012 patients, it has been shown that GnRH addition during the luteal phase significantly increases the probability of clinical pregnancy and of live birth [8].

2.6 Cessation of Luteal Support

It has been classically said that luteal support should continue until the 8th gestation week. However, we have now enough evidence that confirms that luteal support could cease on the day of positive HCG, considering that embryonic HCG will rescue the corpus luteum and will protect the pregnancy. For this reason, we accept that progesterone supplementation can be safely withdrawn at 5 weeks of gestation, and ongoing pregnancy and miscarriage rates will not be affected by this discontinuation [9].

The currently available evidence clearly suggests that luteal phase support is mandatory given that if independently the ovarian stimulation protocol is used, the luteal phase will be altered.

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