Luteal phase support strategies in infertility

Infertility

Infertility refers to the failure to achieve pregnancy after 1 year of regular unprotected intercourse.¹   The condition has severe emotional and social repercussions, negatively impacts sexual health, and remarkably degrades the overall quality of life of the affected individuals. It is ranked highly in terms of burden of disease and prevalence, and exacts enormous costs to society.^2,3   A methodological study⁴   conducted on individuals in Western Siberia showed the overall infertility rate to be 16.7%. To delve further, Boivin and colleagues⁵   pooled data from population-based surveys and showed the prevalence of infertility to range from 3.5-16.7% and 6.9-9.3% in the developed and developing nations, respectively, with overall female infertility prevalence to be 72.4 million (figure 1).

As a consequence of the high prevalence rates, reproductive medicine is rapidly advancing, bringing in new possibilities to this burgeoning area of research.⁶   Techniques that aid in conception such as intrauterine insemination (IUI), in-vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) are gaining immense popularity at the global level and are now being applied to an expanding population of infertile individuals.^7-9

Assisted conception: Focus on IVF

The history of assisted reproductive technologies (ARTs) stretches back to the 19^th century-however, an abundance of breakthroughs in this field, in the successive decades, has allowed a large number of infertile couples the chance to have a baby. IVF is a type of ART that has drawn considerable public attention. Refinements in fertilization techniques and clinical practice, over the past few years have enabled IVF to evolve into an efficient, reliable, accessible, and relatively economical procedure. Outcomes obtained from IVF treatment surpass those of traditional ARTs and have served to widen its clinical scope and applicability. ^10,11       Notwithstanding this, evidences have surfaced suggesting that a large number of IVF cycles do not result in successful pregnancies. A study by Langen et al¹²   demonstrated low rates of implantation, clinical pregnancy and live birth in Asian women undergoing IVF procedures. Several other authors have also validated these findings and reported growing discontent among infertile couples due to disappointing results with IVF.^13,14

Good quality of evidence indicates that the largest percentage of unsuccessful IVF cycles is due to failure of implantation; an important cause attributable to this is endocrinal insufficiency during IVF. Researchers posit that deficiency of hormones such as progesterone and estrogen during the luteal phase of the IVF cycle may signal an increased risk of abnormal or unsuccessful implantation.¹⁵

Luteal phase insufficiency at a glance

Luteal phase is a period between ovulation and either establishment of pregnancy or onset of menses 2 weeks later. Following ovulation, the luteal phase of a physiological cycle is marked by the formation of corpus luteum, which releases sex steroid hormones, estrogen and mainly progesterone. The three major causes of LPD in unstimulated cycles-poor follicle production, premature demise of corpus luteum, and inability of the uterine lining to respond to normal levels of progesterone-are widely known. In contrast, the factors involved in LPD following stimulated cycles for IVF have been under speculation.

Formerly, researchers propounded that aspiration of granulosa cells during oocyte retrieval diminishes the most essential source of progesterone synthesis by the corpora lutea, giving rise to LPD. Besides, it was also proposed that the prolonged pituitary recovery that followed the GnRH agonist co-treatment to inhibit luteinizing hormone (LH) surge triggers changes that disrupt the luteal phase and lead to a hormone deficient environment. However, these hypotheses were disproved by researchers who later demonstrated the main cause of the LPD to be related to the multifollicular development achieved during ovarian stimulation, which significantly alters the hormone milieu. It was suggested that supra-physiological levels of steroids secreted by a high number of corpora lutea during the early luteal phase, which directly inhibit the LH release via negative feedback mechanism at the hypothalamic-pituitary axis level play the most critical role. It is an established fact that corpus luteum requires a consistent LH stimulus to perform its physiological function, and that its inhibition will inevitably lead to premature luteolysis. The events leading to luteal phase defect are summarized in figure 2.^15-17

Rationale for luteal support

Successful implantation during IVF requires good embryo quality, endometrial receptivity, and an efficient crosstalk between the two. There is persuasive evidence derived from studies that despite the transfer of good quality embryos, majority fail to get implanted; this makes the evaluation of endometrial receptivity essential. A myriad of researchers have suggested that deranged corpus luteum function resulting from the relatively short endogenous LH surge may be detrimental to endometrial receptivity and jeopardize the success of implantation or early pregnancy. The quality of endometrium is influenced by both progesterone and estrogen; thereby their deficiency during the luteal phase is a major contributory factor in infertility and IVF.^18-20

Studies in the past have made it reasonable to postulate that luteal phase defect is a clinical entity per se and a robust indicator of implantation failure in assisted conception. Aggressive luteal phase supplementation and monitoring is therefore mandatory in view of the overwhelming evidence indicative of deranged luteal sex steroid profile during IVF. The rationale of using luteal phase support is to recover the deficient endocrine secretion resulting from inhibition of LH release via the negative feedback mechanism at the hypothalamopitutary axis level caused by supraphysiological levels of steroids (secreted by a multiple corpora lutea) during the early luteal phase.^21,22

Luteal support strategies

The strategies for luteal support have been a focus of much debate, largely due to lack of a reliable diagnostic modality. Endometrial biopsy, though frequently employed is no longer the gold standard for assessment of endometrial maturation. Besides, single or random multiple serum progesterone measurements are difficult to interpret beyond documenting ovulation, and usually produce widely variable diagnoses.^15,23,24

A myriad of authors studying the management of luteal phase defect support the administration of progesterone, estrogen or human chorionic gonadotrophin (hCG) to overcome the suboptimal sex steroid environment in IVF cycles.^25,26       While a diverse range of preparations and dosages of these hormones are employed, there is lack of consensus regarding the best luteal support regime.²⁷

Progesterone

A considerable volume of information suggests that progesterone secretion by the corpus luteum is indispensable for the success of early human pregnancy. Researchers posit that progesterone not only augments endometrial growth but also improves vascularity and oxygen supply by facilitating nitric oxide production. Its utero-relaxing effect keeps the myometrium quiescent. In addition, its potential role in sustaining the survival of the embryo by shifting the immune system towards production of T-helper response is also well-recognized. In light of these effects, progesterone is considered a prerequisite for endometrial development and embryo implantation.^15,26

Several authors have shed light on the clinical benefits of luteal support with progesterone during IVF. A Cochrane review undertaken by Daya and coauthors²⁸   demonstrated an increase in conception rates following exogenous progesterone supplementation in ART cycles. The recent update of the Cochrane review²⁹   took this notion a step further and analyzed data extracted from 69 studies with a total of 16,327 women enrolled. The objective was to compare the effect of progesterone versus placebo or no treatment, and additionally investigate the efficacy of different progesterone regimens. The results revealed a significant benefit favoring progesterone supplement for clinical pregnancy and live birth rates. Besides, the main outcomes of the comparison between types of regimens did not show a significant difference. Ho et al³⁰   have also shown implantation and conception rates to be as high as 32.5% and 55.2% respectively with use of progesterone for luteal phase support during IVF cycles (figure 3). Besides, women with fibroids or difficult oocyte retrieval during IVF have also demonstrated desirable outcomes following progesterone supplementation.³¹

Multiple publications studying the benefits of progesterone supplementation have also underlined the widespread clinical potential of its micronized, sustained release (SR) form. It is posited that the oral SR natural micronized form enables consistent tissue concentrations for endometrial support allowing once daily dosage convenience, thereby enhancing patient compliance. The pharmacokinetic profile of SR preparation is reasonably good as it reduces drug exposure to hepatic metabolic enzymes at individual time points, thereby offering sustained activity with negligible central adverse effects. Investigators have evidenced the success of IUI procedure using oral SR natural micronized progesterone 400 mg administered once a day at bedtime with good tolerability and no significant undesirable effects such as drowsiness.^32,33

Based on the above-mentioned evidences, a strong case can be made for the administration of oral micronized SR formulation of progesterone during luteal phase in patients undergoing IVF.

Estrogen

As previously discussed, the implantation process, which is partly dictated by the quality of endometrium, is also affected by estrogen levels. Albeit the precise role of estrogen during the luteal phase of IVF cycles is incompletely deciphered, a fall in its midluteal concentrations is believed to adversely affect conception rates.¹⁵   Investigators have accumulated a large body of data suggesting estrogen monitoring to be an integral component of cycle monitoring in IVF programs and its luteal level to be a promising predictive marker for successful IVF.^34,35       Despite this, the use of estrogen supplementation in addition to progesterone remains debatable.

Evolving literature, however, has substantiated the evidences in favor of combined estradiol and progesterone therapy during luteal phases in patients undergoing IVF. A study³⁶   was conducted to evaluate the influence of luteal estrogen supplementation on implantation and pregnancy rates in women undergoing assisted conception. The patients were randomized to receive either progesterone alone (group A), progesterone and 2 mg of estrogen (group B), and progesterone and 6 mg estrogen (group C). The results revealed significantly higher conception rates in group B (32.8%) compared to group A (23.1%). However, the best implantation and pregnancy rates (PR) were found in group C (PR-51.3%) attesting to the benefits of adding a high dose of estrogen to progesterone therapy in IVF cycles. Gorkemli et al³⁷   validated these findings and showed a noteworthy increase in implantation and clinical pregnancy rates in IVF patients after administration of combined estrogen and progesterone compared to the latter alone.

Besides, previous meta analyses³⁸  , an update³⁹   and more recent randomized trials^40,41     reported beneficial effects of adding estradiol to luteal progesterone support. The meta-analysis by Pritts and coworkers³⁸   concluded that progesterone is favored for luteal phase supplementation in combination with estrogen in long and short agonist protocols.

Estradiol valerate is a widely available formulation that confers greater benefit compared to other estrogens (such as conjugated equine estrogens-CEE) without significant safety concerns. While CEE are known to increase LDL levels, estradiol valerate reduces LDL concentrations in the body thereby balancing the lipid profile of the patients. The latter is also known to decrease plasma endothelin-1 and improve endothelial function, while no such effect has been reported with the use of CEE. These data imply superior cardiovascular effects of estradiol valerate over CEE.^42-46

It is noteworthy to mention that the micronized form of estradiol offers several advantages (box 1). According to Martindale, micronized preparation of estradiol is the only natural unconjugated estrogen which is orally active.⁴⁷

Human chorionic gonadotropin

Human chorionic gonadotropin (hCG) acts as an indirect form of luteal support by stimulating the corpus luteum. It boosts the levels of estrogen and progesterone to rescue the failing corpora lutea. Administration of hCG has also been demonstrated to increase the concentration of placental proteins integrin and relaxin thereby aiding in implantation.¹⁵

Several researchers have advocated the use of hCG in addition to progesterone for luteal support during ART programs. Significant improvements in the luteal endocrine milieu have been noted following the use of combined hCG and progesterone in patients undergoing IVF.⁴⁸   Besides, women with low late-midluteal estrogen levels during IVF cycles have been shown to substantially benefit from use of hCG with concomitant progesterone. Fujimoto and coworkers⁴⁹   have demonstrated progesterone+hCG protocol to boost late-midluteal estrogen concentrations and produce a significantly higher pregnancy rate (31.7%) than progesterone alone (13.7%) (figure 4). However, it is noteworthy to mention that hCG supplementation was found to be associated with an increased risk of ovarian hyperstimulation syndrome (OHSS).

The above-mentioned evidences have strengthened the need for administering hCG for luteal support in IVF programs to improve pregnancy outcomes.

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