Preparation of Endometrium for Egg Donation

History of Oocyte Donation

The first successful pregnancy achieved using in-vitro fertilization (IVF) in the late 1970s led to an explosion of reproductive technologies, of which one is certainly gamete donation.¹   Historically, gamete donation was confined to sperm collection; however, oocyte donation techniques have now rapidly gained attention in IVF programs, and are being used to treat infertility due to various causes.^2-4   The history of the first reported live birth achieved with donated eggs stretches back to the mid-1980s. The subsequent decade witnessed live births after in vitro oocyte maturation (IVM), intracytoplasmic sperm injection (ICSI), and assisted hatching. Successful IVM and fertilization in non-stimulated cycles, and in non-ovulating women with polycystic ovary syndrome (PCOS) resulting in clinical pregnancies were also reported.⁵   Since then, oocyte donation has become more prevalent and a large fraction of fertile women are volunteering to help their infertile counterparts conceive with IVF.⁶   A research study suggested that donor IVF accounts for 11.6% of the ART programs undertaken in some of the developed countries.⁷   The technique is also rapidly gaining momentum in India. The period from 2007 to 2009 witnessed a more than two-fold increase in the number of donor egg cycles across Indian infertility clinics (figure 1).⁸

Indications for Oocyte Donation

Oocyte donation can be used as a treatment option in patients with premature ovarian failure, Turner syndrome, repeated IVF failure, ovarian failure following chemotherapy/radiotherapy, genetic disorders, and various other conditions (figure 2).²

Premature Ovarian Failure

Women aged below 40 years, who present with absent menses (primary amenorrhea) or premature depletion of ovarian follicles/arrested folliculogenesis (secondary amenorrhea) are said to have premature ovarian failure (POF).⁹   The etiology of POF is extremely heterogeneous and includes chromosomal, autoimmune, iatrogenic, infectious, and idiopathic causes.¹⁰   Specific causes deemed suitable for oocyte donation include surgical oophorectomy, irreversible gonadal damage after chemotherapy/radiotherapy, Turner syndrome and other chromosomal aberrations causing gonadal dysgenesis. In addition, oocyte donation may be used to prevent the transmission of a genetic disease in cases in which the carrier status of both partners is known.²   Overall, this technique provides women with POF or a diminished ovarian reserve (DOR), with a very realistic chance of pregnancy.¹¹

Turner Syndrome

Pregnancies among women with Turner syndrome are associated with a high probability of spontaneous abortion and a heavy risk of trisomy 21 in the child.²   About 40 50% patients with Turner syndrome show signs of some pubertal development, of which 10% may undergo menarche. The presence of ovarian follicles has been recorded in up to 40% of Turner girls. POF can occur at a future date in majority of these young women, and FSHstimulated oocyte retrieval and IVF can be undertaken before predicted POF. Appropriate counseling not to delay childbearing unnecessarily is recommended.¹²

A glance through the epidemiological data reveals that only 2% of the women experience natural conception, with a high incidence of miscarriages, stillbirths and malformed infants. Their pregnancy rate in oocyte donation cycles is 24-47%.¹³   A group of investigators¹⁴   reported a clinical pregnancy rate of 46% for fresh embryo transfer, and an implantation rate of 30% among women with Turner syndrome participating in an egg donation program.

In Vitro Fertilization Failure

For patients with recurrent IVF failure, especially those with poor oocyte quality, egg donation is a feasible option.²   De Brucker et al¹⁵   demonstrated a cumulative delivery rate of 46.5% in patients switching from failed IVF/ICSI treatment to oocyte donation (figure 3). Similar results were obtained in another study¹⁶   wherein oocyte donation by ICSI yielded pregnancy rates of 33.3% per started cycle and 38.4% per embryo transfer in women with previously failed IVF.

Ovarian Failure Following Chemotherapy or Radiotherapy

Anticancer treatment can cause ovarian failure resulting in a bleak fertility prognosis unless oocyte donation with IVF is used.²   Adjuvant chemotherapy, radiotherapy and endocrine therapies are notorious for causing ovarian insufficiency, sex steroid suppression, and premature menopause, particularly in women with a history of breast cancer. Estimates suggest that nearly 66% of premenopausal women become amenorrheic after initiation of chemotherapy treatment.^17,18       Exposure to higher doses of alkylating agents and radiation to the ovary augment the risk of ovarian failure in these women.¹⁹

All these cases are amenable to treatment with egg donation. Promising outcomes have been noted in women with a history of chemotherapy or radiotherapy exposure following donor IVF. Two live deliveries with embryos from donated oocytes were recorded in women (aged 36 years and 33 years) who had undergone bone marrow transplantation followed by total body irradiation for leukemia. Another successful live birth was reported with oocyte donation in a woman with ovarian carcinoma following radical surgery (with uterine conservation) and chemotherapy.²

Endometrial Parameters Predict Success of Oocyte Donation

The success of oocyte donation depends on several variables such as donor age, egg quality, number of embryos transferred, age and endometrial parameters of the recipient.²⁰   Among these, recipient’s midcycle endometrial thickness (ET) accounts for the most important predictive factor.²¹   ET is utilized as an indicator of endometrial receptivity and serves as a valuable prognostic parameter for successful pregnancy in all ARTs.²²

Endometrial Thickness

A myriad of investigators believe that an endometrial thickness less than a specific value is capable of reducing the likelihood of pregnancy to almost zero.²³   However, the optimal endometrial thickness has remained an area of controversy, and no conclusive cut-off value has been established till date.11 Some authors have suggested that a thickness of greater than 9 mm is associated with a more favorable prognosis for pregnancy in IVF while others have reported high conception rates above a minimum cut-off value of 10 mm.2^24,25   To further shed light on the optimal endometrial thickness during assisted reproduction, a prospective cross-sectional study²⁶   was conducted on 593 women undergoing IVF. The patients were divided into four groups according to endometrial thickness (ranging from 14mm) and implantation and pregnancy rates were evaluated. Although no threshold was observed above which pregnancy was unlikely to occur, both implantation and clinical conception rates were found to be remarkably lower in those with ET ²⁷

For assessing the clinical outcomes relative to ET specifically in oocyte donation, 270 recipients in a private tertiary care IVF clinic were enrolled. The results demonstrated the clinical pregnancy rates to be the highest in patients with ET >9mm (36%), followed by 34.09% and 30.7% in those with ET 8-9mm and <8mm, respectively. The implantation and ongoing pregnancy rates were also highest in the >9mm group (table 1).²⁰

Since endometrial thickness is an important biomarker of endometrial receptivity during the implantation window, it is logical to suggest that a thin endometrium would lead to compromised endometrial receptivity and consequently reduced implantation rates.²⁸

Endometrial Receptivity

Normally, the endometrium is non-receptive for an embryo. However, it becomes receptive for a particular period of time-called the implantation window-due to the influence of steroid hormones and paracrine signals from the developing embryo, allowing implantation.²⁹   The implantation window opens on day 19 or 20 of the cycle, and lasts 4-5 days.³⁰   Women receiving embryos after oocyte donation also exhibit a ‘window of embryo transfer’ which constitutes the pre-receptive phase and the receptive phase combined. If embryos transferred at a time other than this window, the chances of a positive pregnancy are bleak.³¹   Evidences suggest that poor endometrial receptivity is responsible for approximately two-thirds of implantation failures.³²   Furthermore, in women with unexplained implantation failure, despite optimal endometrial development, good-quality embryos, and absence of a clinical pathology, compromised endometrial receptivity appears to be a major factor in inhibiting embryo attachment.³³

Synchronization

In addition to ET and receptivity, the process of implantation of a fertilized oocyte is also greatly influenced by synchronization between embryonic and endometrial development. In the natural conception cycle, ovarian steroid production and the timely occurrence of ovulation are strongly linked with both receptivity and synchronization. Sex hormones released by the ovary ensure that endometrial preparation is synchronized with the presence of a mature blastocyst in the uterine lumen. Besides, in ovum donation cycles, that same careful synchronization must be initiated. To synchronize endometrial development with the embryos to be transferred, recipients with functioning ovaries are first down-regulated with GnRH agonists/antagonists that women with ovarian failure do not require. In either case, a programmed regimen of sequential estrogen and progesterone replacement is used to stimulate the natural cycle and to promote the normal endometrial growth and maturation. A wide variety of treatment regimens are being used successfully to achieve controlled endometrial development and maturation. A flexible protocol including estrogen and progesterone, for the endometrial preparation of recipients is vital in timing embryo transfer between days 17 and 19 of the cycle (‘window of receptivity’). In this regime estrogen administration is 8 mg/day, but its length varies prospectively from 6 to 27 days, followed by the addition of progesterone (100 mg daily i.m.) for 2-4 days according to the availability of good quality oocytes. The use of estrogen therapy can be oral, transdermal or transvaginal.

The duration of estrogen therapy is quite flexible and can range from as little as 7 days to a long as three weeks or more. Progesterone can be administered in doses designed to achieve serum concentrations approximating 20 ng/mL. In oocyte donation, the events of ovarian stimulation of the donor and the artificial preparation of the endometrium of the recipient are completely separated. Hence, the sufficient manipulation of the endometrial growth with the administration of hormones is prudent for making the endometrium receptive to implantation.^1,27,34,35

Thin Endometrium in IVF Cycles

Research suggests that endometrial growth depends on several factors including a woman’s age, infertility etiology, drug protocol, serum estradiol level and previous injuries to endometrium. In some older women, myomatous uterus or pelvic inflammatory disease (PID) can affect IVF results. While age is an indirect factor affecting the endometrium, ovarian anomalies and estrogen levels have direct effects. Reduced endometrial thickness in IVF cycles can also be ascribed to intrauterine adhesions and past surgical curettage procedures that can cause damage to the endometrium, leading to poor outcomes.

In addition to the above-mentioned factors, ET, receptivity and implantation also depend on the blood flow in the endometrium. In an endometrial line of ^36-40

Preparation of Endometrium for Oocyte Donation

Till date, the process of egg donation has invariably involved a complex steroid hormone replacement regimen given on a sequential and incremental basis for women with primary or secondary ovarian failure.⁴¹   Even advanced aged women (in their sixties) have given birth with donor oocytes, proving that the postmenopausal endometrium exhibits the capacity to allow pregnancies if provided appropriate hormonal support.7 Artificial preparation of endometrium with sex steroids is important as it seeks to mimic the natural cycle in preparation for embryo transfer (ET).⁴²   Several clinical egg donation studies have demonstrated that both physiologic and supraphysiologic levels of estrogen and progesterone enable good endometrial development.⁴³   This is because both these hormones play pivotal roles in not only regulating endometrial receptivity, but also blastocyst implantation, and sustenance of pregnancy. It is also apparent from assisted conception studies that the ratio of progesterone to estrogen in serum is important for the secretory maturation of the endometrial glands during the midluteal phase. Further, estrogen and progesterone regulate the cascade of growth factors and cytokines which are the prime paracrine mediators of embryo-endometrial dialogue.

As per recent research, in IVF-embryo transfer with egg donation, sequential administration of physiologic doses of estradiol valerate (an estrogen formulation available since the 1970s in oral and parenteral forms) and progesterone to women with dysfunctional ovaries has been demonstrated to restore endometrial receptivity and increase the chances of pregnancy.^29,44

Estradiol valerate and estradiol in a micronized form are the most popular estrogen formulations for steroid substitution therapy.¹   This is because the micronized preparation of estradiol is the only natural unconjugated estrogen which is orally active (as per the Martindale drug reference).45 The benefits of micronized preparation of estradiol are enlisted in box 1.^46,47

In oocyte donation cycles, 2 mg of oral micronized estradiol valerate is given on cycle days 1-5. The dose is titrated to 4 mg per day on days 10-13, followed by a decrease to 1 mg per day on cycle days 14-28.¹

Researchers have demonstrated that initiation of hormone replacement with estradiol valerate boosts the blood supply to the uterine layers, corrects the histologic features of the endometrium and increases its receptivity for embryo attachment.⁴⁸   A study⁴⁹   evaluated the effect of endometrial priming with estradiol valerate on pregnancy rates (PRs) in an egg donation program. The results revealed that sufficient endometrial preparation was achieved with continuous administration of estradiol valerate until the oocytes became available. It was further shown that the drug may be administered for up to 5 weeks with no negative impact on pregnancy rates. The latter finding was supported by a report²⁷   which suggested that the duration of estrogen therapy is quite flexible in egg donation cycles and can range from 7 days to as long as three weeks or more.

The effect of estrogen therapy on clinical outcomes was further evaluated in 29 women who underwent 51 cycles of egg donation. Endometrial preparation was carried out using a fixed dose of micronized estradiol administered for 5-35 days in accordance with oocyte availability. Oocytes were donated anonymously by patients undergoing routine IVF. The results showed 15 clinical pregnancies corresponding to a success rate of 29.4% (figure 5).⁵⁰   Notwithstanding these promising outcomes, a section of women may fail to attain adequate endometrial thickness in response to the standard replacement regimen. For these women, vaginal estrogen administration can help promote additional proliferation.²⁷

During the late 1980s, it was proposed that a fixed dose estrogen-progesterone regimen could be used in oocyte recipients regardless of the functional status of their ovaries. Following this protocol a research team administered oral estradiol valerate daily starting on day 2-6 of induced withdrawal bleeding, augmented with progesterone. All recipients underwent embryo transfer at the 2-pronuclei (2PN)-10-cell stage. A group of 21 patients underwent 26 treatment cycles, resulting in 16 pregnancies, yielding a success rate of 76.1%.⁵¹   While this study used progesterone via the i.m route, some authors⁴¹   have used 100 mg oral progesterone thrice daily, beginning on the day preceding the recovery of the donated oocytes. However, oral administration of progesterone has been shown to be associated with inefficient absorption due to hepatic hydroxylation and conjugation. This absorption becomes notably better when this compound is administered in the micronized form, just like in the case of estradiol valerate. Micronization leads to enhanced bioavailability of progesterone and increases its clinical potential.⁴⁷   Currently, oral micronized progesterone is employed during the preparatory cycles at the daily dose of 300 mg from days 16-26. For achieving adequate progesterone concentrations intravaginal progesterone pessaries are used.¹

In addition to the benefits of micronization, the clinical potential of the micronized, sustained release (SR) form of progesterone is also highlighted in the literature. It is suggested 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. Research papers confirm the success of ART procedures 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.^52,53

Luteal support in ovum donation cycles

Luteal phase disruption is a common occurrence in IVF cycles conducted with either gonadotropin-releasing hormone (GnRH) agonists or antagonists. It is one of the common reasons for implantation failure and has been responsible for miscarriages and unsuccessful assisted reproduction. Considering the failures related to insufficiency of luteal phase the supplementation with either exogenous progesterone or human chorionic gonadotropin (hCG) is thus necessary to optimize IVF cycle outcomes. Progesterone therapy is known to improve implantation in IVF.^54,55   However, addition of estradiol to progesterone is also thought to have additive benefits. Addition of estradiol valerate reduces the incidence of luteal vaginal bleeding (LVB) and increases the embryo implantation rate in patients undergoing IVF. This had been demonstrated in a prospective randomized study which evaluated the effect of the addition of estradiol to luteal progesterone supplementation in GnRH antagonist cycles for infertile patients undergoing IVF. A total number of 110 infertile patients who were enrolled into two groups (Gp1: progesterone + estradiol; Gp2: progesterone alone). The study results divulged that embryo implantation rate was significantly higher and LVB was lower in group 1, 22.1 and 7.4% respectively.

In view of the study results estradiol and progesterone is found to be efficacious in luteal phase of IVF. Moreover, the estradiol and progesterone treatment must be given for a minimum period of 7 weeks, or until approximately 10-12 weeks gestation, for added safety.⁵⁶

Conclusion

Egg donation has been used to treat human infertility for over 3 decades, and remains an integral part of ART setups. The technique is rapidly gaining popularity in developing countries including India. Specific causes amenable to oocyte donation include surgical oophorectomy, irreversible gonadal damage after chemotherapy/ radiotherapy, Turner syndrome and other chromosomal aberrations causing gonadal dysgenesis.

The success of oocyte donation depends on several variables such as donor age, egg quality, number of embryos transferred, age and endometrial parameters of the recipient. Among these, recipient’s mid-cycle endometrial thickness (ET) accounts for the most important predictive factor. Evidences suggest that poor endometrial receptivity is responsible for approximately two-thirds of implantation failures. Furthermore, in women with unexplained implantation failure, despite optimal endometrial development, goodquality embryos, and absence of a clinical pathology, compromised endometrial receptivity appears to be a major factor in inhibiting embryo attachment. Hence, sufficient manipulation of endometrial growth with the administration of hormones is prudent for making the endometrium receptive to implantation. Estradiol valerate in micronized form has gained attention as steroid substitution therapy. Oral micronized progesterone is also employed only during the preparatory cycles at a daily dose of 300 mg from days 16-26. These hormones play pivotal roles in not only regulating endometrial receptivity, but also blastocyst implantation, and sustenance of pregnancy.

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