DE (Donor Egg) IVF

Introduction

Since the first successful in vitro fertilization cycle was reported in 1978, efforts have been directed toward increasing the chance of success with the procedure. This first pregnancy was accomplished in a normal, unstimulated menstrual cycle. As time passed, it was recognized that stimulation of the ovaries in order to achieve the development of several mature follicles would increase the chance of retrieving one or more mature oocytes. Initially, clomiphene citrate was used, followed shortly thereafter by administration of gonadotropins. Reports were published showing that the chance of pregnancy could be enhanced by the transfer of more than one embryo, leading to higher pregnancy rates, but at the expense of higher multiple pregnancy rates. With the advent of GnRH agonists, pituitary down regulation permitted ovarian stimulation without the risk of an LH surge, a major reason for cycle cancellation in the early days of IVF.

As data accumulated, it became evident that the chance of pregnancy per embryo transferred was highly dependent upon the woman's age, and that a higher number of embryos could be transferred to the uterus of an older woman without increasing the risk of multiple pregnancy as much as in younger women. Despite this practice, however, the chance of successful pregnancy in older women remained low and the chance of live birth even lower. It was also recognized that many younger women had IVF cycles with characteristics similar to their older counterparts. These included poor response to ovarian stimulation, low number of oocytes retrieved, poor oocyte quality, poor embryo quality, poor implantation rates, and high spontaneous abortion rates. These findings were felt to be secondary to poor oocyte quality, as in the older women. Proof that an abnormality of oocyte quality rather than of uterine receptivity is the underlying cause for the poor results of IVF in older women came with the first reports of donor oocyte IVF, with the chance of successful pregnancy being related to the age of the donor and unrelated to the age of the recipient. This has been born out by many studies as well as the clinical experience of IVF programs throughout the world.

In many women undergoing IVF for reasons such as unexplained infertility, tubal occlusion, pelvic adhesions, endometriosis, and semen abnormalities, poor oocyte quality is suspected to be a significant problem, either before the cycle or because of the findings during the IVF cycle. In order to enhance the chance of success as well as to avoid performing an expensive IVF cycle for a woman in whom failure could be predicted, it would be optimal to be able to assess the quality of oocytes before committing resources to IVF. Unfortunately, that assessment is less than perfect and we often consider oocyte donation only after the failure of traditional IVF to result in a live birth.

When POF occurs, it has been shown that there may be some ovarian follicles remaining, menses may return, and pregnancies may occur. The two primary concerns of the woman and the clinician include the woman's fertility potential and the long-term consequences of hypoestrogenemia. This lecture will present the currently understood causes of POF, a reasonable diagnostic approach to the problem, the long-term health consequences of POF, and therapeutic considerations.

Selection Of Couples For Donor Oocyte IVF

Ovarian failure
Oophorectomy
Genetic disorders
Advanced age
Poor oocyte quality
Failed IVF

The Effect Of Advanced Age On The Success Of IVF

The chance of pregnancy per cycle decreased progressively with advancing age. In our practice over the last decade, the chance of pregnancy with donor insemination in women under age 35 has been 16% per cycle, while those between the ages of 35 and 40 have a 12% chance per cycle. In women between the ages of 40 and 45, the chance falls to 6% per cycle. In women in their late 30's, about one third have a fertility problem and about half of those over age 40 are infertile. This decline in reproductive function related to age is also seen in the population undergoing IVF.

Many studies have documented the effect of age on IVF outcome. Scott, et. al. showed in 1995 a progressive decline in the chance of pregnancy from 62.8% in women <30 to 5.6% in women >40. Roest, et. al., in 1996 showed a greater likelihood of poor response to stimulation with advancing age, as well as fewer oocytes retrieved, a lower pregnancy rate, a higher rate of spontaneous abortion, and a lower rate of multiple pregnancy. In 1997, Lim and Tsakok showed that the fertilization rate of oocytes from older women was no less than in those from younger women, despite fewer oocytes being retrieved. Pregnancy rates were substantially different, however, with 43% of women <34 years of age conceiving, compared to 14% of those >40 years old.
When intracytoplasmic sperm injection (ICSI) is performed, the age-related chance of success is still present. Alrayyes, et. al. reported in 1997 that younger patients had better implantation rates, clinical pregnancy rates, and ongoing pregnancy rates despite having ICSI performed.

The Predictive Value Of Failed IVF Cycles

It would be optimal to be able to accurately assess oocyte quality prior to performing IVF in order to estimate the prognosis. Because the ultimate assessment is achieved by direct microscopic examination of the oocyte and embryo, we are left with indirect means of assessment before oocyte retrieval is actually performed.

Early follicular phase FSH and estradiol levels
Scott et. al. showed in 1989 that women with early follicular phase serum FSH levels over 25 mIU/ml (in the assay performed at that time) did not conceive with IVF despite the fact that oocytes may have been retrieved and embryos transferred. The initial study included FSH levels drawn on cycle day 3. It was subsequently shown that there is no significant difference in levels drawn on cycle days 2, 3, or 4. This finding is independent of the woman's age, and appears to be more predictive of outcome than age alone. Elevated estradiol levels at this time of the cycle also appear to be related to poor IVF outcome.

Clomiphene challenge test
In 1987, Navot, et. al. reported the use of a clomiphene citrate challenge test (CCCT) to assess "ovarian reserve", a term which is now commonly used to refer to the processes of follicular depletion and diminished oocyte quality. After drawing blood samples for FSH and estradiol levels on cycle day 3, the patient is given 100 mg clomiphene citrate on cycle days 5-9, followed by FSH and estradiol determinations on cycle day 10. Typically, a normal result is considered to be a baseline FSH level under 10 to 12 mIU/ml and a cycle day 10 level no higher than 10 to 12 mIU/ml, and preferably lower than 10 mIU/ml. The estradiol level would be expected to be significantly elevated by day 10, but the normal range is debated. In fact, at least one author has suggested that the day 10 estradiol level is of no prognostic value. Women with an abnormal CCCT, regardless of age, can be expected to have a higher chance of cycle cancellation, a lower number of oocytes retrieved, and a lower pregnancy rate than women with a normal CCCT.

An abnormal CCCT is suggested to be a result of decreased follicular inhibin production. Inhibin is a glycoprotein produced by the follicle, which specifically inhibits the pituitary release of FSH. As inhibin production falls, possibly as a result of chronological age or "ovarian age", there is less inhibition of FSH release in the follicular phase, resulting in higher day 10 FSH levels during the CCCT.
Measurement of Inhibin
Because an elevated early follicular phase FSH and an abnormal CCCT are both felt to be a reflection of declining inhibin levels related to poor ovarian reserve, attempts have been made to find a relationship between serum inhibin levels and IVF success. This could provide a more direct prognostic assessment of ovarian reserve.

In the normal menstrual cycle, inhibin B levels are highest in the early to mid follicular phase and decrease in the late follicular phase. Several studies have shown higher levels of inhibin to be associated with a greater number of oocytes retrieved and a higher chance of pregnancy. Hofman, et. al. reported in 1998 that women with normal CCCT results had higher inhibin levels on both cycle days 3 and 10 as compared to women with poor CCCT results. Seifer, et. al. showed that women with an inhibin level of >45 pg/ml had a decreased response to gonadotropin stimulation, a lower number of oocytes retrieved, a higher cancellation rate, and a lower pregnancy rate. In contrast to these findings, Corson et. al. found in 1999 that serum inhibin levels did not correlate with CCCT results or the chance of pregnancy with IVF. Similar findings were reported by Creus, et. al. in 2000, who found cycle day 3 FSH levels to be more predictive of IVF success than inhibin levels.
Ultrasound evaluation of the ovaries
In 1997, Tomas, et. al. attempted to assess ovarian reserve by ultrasound measurement of ovarian volume and number of small follicles present. They found a correlation between the number of small follicles and the number of oocytes ultimately retrieved. Lass, et. al. reported an association between ovarian volume and ovarian reserve. The following year, Chang, et. al. showed a correlation between the number of small follicles on cycle day 1 and the number of oocytes retrieved as well as the pregnancy rate. Syrop, et. al., in 2000, also showed a relationship between ovarian volume and IVF outcome. This was confirmed by Sharara, Lim, and McClamrock.

Poor response to stimulation
It has been known for many years that a woman's response to gonadotropin stimulation relates to the number of oocytes retrieved and the chance of pregnancy. This response typically declines as age increases, but is often seen unexpectedly in younger women. Often these women have had sub optimal tests of ovarian reserve, however.

In the woman whose IVF stimulation has been cancelled due to poor response, or the poor responder who has completed the cycle but failed to conceive, several strategies have been offered to enhance the response to stimulation. The standard IVF stimulation includes initiating a GnRH agonist in the luteal phase of the preceding cycle, then starting gonadotropin stimulation in the early follicular phase while continuing the GnRH agonist.
Protocols which have been used with some success in poor responders include discontinuation of the GnRH agonist when the gonadotropin therapy is started, a "flare" or "microflare" protocol in which both the GnRH agonist and gonadotropin are started in the early follicular phase, and the use of a new GnRH antagonist rather than an agonist. Although some programs have used human growth hormone, most authorities feel there is no therapeutic benefit.
Favorable results have been reported with the use of each of these regimens, however they are less promising in the women with high early follicular phase FSH levels and in older women. In those groups, as well as those that fail to respond to a change in the stimulation protocol, oocyte donation should be considered.
Poor oocyte or embryo quality
The most direct assessment of oocyte quality occurs in the IVF laboratory after oocyte retrieval. Microscopic examination of the oocyte may detect abnormalities such as vacuolization, cytoplasmic inclusions, and clustering of organelles. These oocytes will have a poor likelihood of yielding embryos of normal potential. It is known that oocytes may have nuclear or cytoplasmic abnormalities that are not visible in the clinical setting by light microscopy. The most common genetic oocyte abnormality results from an error in chromatid segregation in the first meiotic division.

The only sign of poor oocyte quality that is apparent in the IVF laboratory may be seen in subsequent development of the embryo. An embryo that is developing slowly or is highly fragmented is likely to be the result of oocyte abnormalities. Advancing age has been associated with lower cytoplasmic levels of ATP and poor embryo development. Recent data has shown that oocytes have a fundamental polarization during development, continuing into embryonic development. Lack of normal polarization has been shown to be related to developmental potential of the embryo. The location of cellular fragmentation related to this polarization in the embryo is likely to be of critical prognostic significance.
Although oocyte and embryo abnormalities in one cohort may not be predictive of the quality of oocytes and embryos in a subsequent IVF cycle, they are often seen repetitively in the same woman, especially in older women, women with abnormal tests of ovarian reserve, and in couples with unexplained infertility. In those cases, strong consideration should be given to oocyte donation rather than a repeat standard IVF attempt.

Donor Oocyte IVF

Oocytes may be obtained from an anonymous donor or a designated donor. Anonymous donors are more commonly chosen because of availability, the option of keeping the procedure confidential, and security against a third person interfering with the parent-child relationship. A designated donor may be chosen in order for the couple to have more information about the donor and her characteristics or for genetic reasons, as in the case of a sister-to-sister donation. The donor should be young, fertile, and able to make a well-informed decision about the procedure. Her medical and family history should be carefully screened and her physical examination should be normal. Psychological screening and counseling should be mandatory.

Although some programs routinely perform karyotyping, it is not considered essential in a woman with no family or personal history suggestive of a familial disorder. The donor should be advised of the medical, legal, financial, and psychological risks of oocyte donation.
A hormone replacement evaluation ("sham") cycle is usually performed in which the donor is placed on a GnRH agonist to suppress the normal ovarian cycle, then given estrogen and progesterone in order to develop an appropriately secretory endometrium. Most centers perform an endometrial biopsy in this cycle to evaluate the endometrium in the mid luteal phase. If normal, this is the protocol that will be used in the IVF cycle.
A routine IVF stimulation protocol is used for the donor, with the recipient starting her estrogen replacement at the onset of the donor's cycle. At the time hCG is given to the donor, the recipient adds progesterone to her treatment regimen. The oocyte retrieval and embryo transfer are performed as usual.

Information Courtesy of: http://www.coloradofertility.com/