1

Historical Evolution of Oocyte

and Embryo Donation as a
Treatment for Intractable Infertility
JOHN E. BUSTER

Introduction
Within mammalian species, pregnancy is immunologically privileged. By
rules of this concept, a conceptus transferred into a host uterus can be
carried uneventfully to viability with a parturition time determined by the
genetics of the oocyte donor. 1,2 Clinical exploitation of this principle, long
established in laboratory animals and livestock breeding, produced the first,
reports of viable pregnancies to infertile women in 1983 and first births in
1984.3-5 During 1994, in the United States alone, more than 929 pregnancies
producing viable births from donated oocytes and embryos were cele-
brated. 6 With this number increasing steadily, oocyte and embryo donation
occupies a highly significant role in the practice of reproductive medicine.

Early Animal Experience

The first successful mammalian embryo transfer is attributed to W. Heape,
a reproductive physiologist at Cambridge University.? Heape's 1891 report
described the transfer of embryos from the uterus of donor rabbits to syn-
chronized recipients with subsequent birth of normal young.? Over the fol-
lowing 100 years, Heape's work was extended to other mammals. By the
early 1980s, the list totaled at least 14 different species: rodents, cattle,
sheep, horses, and two species of primates. 1.&-10 Today's longer list includes
exotic animals bred in surrogate carrier hosts of slightly different but closely
related species. 10
During the late 1970s, a multimillion-dollar industry developed around
successful commercialization of bovine embryo transfer. The first bovine
transfer and birth was reported by Willet et al. in 1951,8 Over the following
30 years, transfer efficiencies reached 60% to 70% live cattle per single
fresh embryo transferred. With increasing use of superovulated donors,
some 17,000 bovine embryo transfer pregnancies were reported in 1979

1
2 John E. Buster

alone.! By 1980 more than 40,000 calves had been birthed following embryo
transfer with no apparent excess of fetal anomalies.!

Initial Human Trials

By 1980 the arguments were compelling that sufficient animal research had
been reported for human investigation to begin. The births of the first chil-
dren from in vitro fertilization and embryo replacement in 1979 provided
a final technical impetus for human oocyte donation. ll Finally, by this time,
the ethical-legal experience accumulated with donor insemination was eas-
ily extended to oocyte and embryo donation.!2
The first human pregnancies from oocyte and embryo donations were
reported virtually simultaneously in 1983 by two groups, one at Monash
University in Melbourne and the other at the University of California, Los
Angeles. 3,13,14 Both groups reported the first births of normal children in
early 1984. 4 ,5 The approaches used by the groups differed in that the Mo-
nash group used oocyte aspiration and in vitro fertilization as a method of
oocyte acquisition and embryo donation, whereas the University of Cali-
fornia, Los Angeles, group utilized in vivo fertilization and uterine lavage,
adapted from work in the bovine industry, as a method to acquire blasto-
cysts for transfer.

Transfer of Human Embryos Fertilized In Vitro

The Monash research took place in the context of one of the busiest clinical
in vitro fertilization programs in the world at that time. Oocytes, obtained
by laparoscopic retrieval from other infertile patients, were donated when
an excess of embryos (more than two or three for transfer) was anticipated.
At the time, cryopreservation technology was not as established as it is
today.
Using this technique, the first human donor in vitro fertilization preg-
nancy was reported by Trounson et al. in 1983. 13 Synchronization of the
donor's and recipient's ovulatory cycles enabled fertilization and transfer
of the fresh embryo at the appropriate time of the recipient's cycle. Syn-
chronization was achieved by matching changes in urinary luteinizing hor-
mone (LH) excretion and plasma LH concentrations in the donor and the
recipient. Urine samples were collected hourly, three from the donor and
six from the recipient. Transfer of a single-cell embryo from the 42-year-
old donor to the 39-year-old recipient produced a pregnancy that aborted
spontaneously at 10 weeks gestational age. The abortus was found to be
trisomy 9.
The Monash group subsequently used alternative methods of bypassing
the highly serendipitous synchronization process utilized in the first preg-
nancy. In one case, a single eight-cell embryo transferred following cryo-
 1. Historical Evolution of Oocyte and Embryo Donation 3

preservation terminated in a spontaneous abortion at 24 weeks. 14 In another

case, the group cycled a premature ovarian failure patient with oral estra-
diol valerate tablets and intravaginal progesterone pessaries. Transfer of a
fresh two-cell embryo to this patient produced a term, viable pregnancy
reported in 1984-history's first birth following oocyte donation and in vitro
fertilization. 4
Oocyte aspiration and in vitro fertilization is the principal method in use
today as a source of donor oocytes. Efficiency and appeal of the process
has been considerably enhanced by the introduction of ultrasound-guided
transvaginal oocyte aspiration.

Transfer of Human Embryos Fertilized In Vivo

The University of California, Los Angeles, approach centered around uter-
ine lavage as a method of human embryo recovery.15-19 Uterine lavage in
humans was adapted from the technique developed in animal husbandry
and widely exploited in the cattle industry.l Uterine lavage and successful
recovery of human unfertilized oocytes and some unintentionally fertilized
embryos was first reported by Croxatto et al. in 1972. 20 Croxatto's studies
focused on the development of contraceptive strategies; thus, no attempt
was made to transfer these embryos. The first human recovery of a delib-
erately fertilized embryo was reported by Seed et al. in 1980; however,
again, no attempt was made to transfer this embryo.21
The group at the University of California, Los Angeles, assembled a
substantial pool of embryo donors who could be matched to a correspond-
ing pool of spontaneously ovulating infertility patients. 15 ,16 Synchronization
of recipients to regularly cycling donors was accomplished using oral con-
traceptives. The menstrual flows of matched recipients and donors were
manipulated to occur as closely as possible to one another. The subsequent
spontaneous ovulatory cycles were then monitored using serum LH mea-
surements. Donor insemination with sperm from the recipient's husband
was performed on the day of the LH surge, and uterine lavage for embryo
recovery was performed five days after the surge. The researchers had de-
signed a uterine catheter that could be inserted without anesthesia and
could produce high and consistent recovery of tissue culture fluid washed
through the uterus. 16-19 Using this strategy, the first human embryo transfer
utilizing an embryo conceived in vivo was reported by Buster et al. in 1983. 22
This 5-day-old, but only 14-cell, embryo did not produce a pregnancy in the
recipient. Over subsequent weeks, a total of 14 inseminations were per-
formed with recovery of five embryos, three of which were blastocysts. Two
ongoing pregnancies, the first donor pregnancies described to attain viabil-
ity, were produced in the recipients from the three blastocyst (Figure 1.1)
transfers and reported by Buster et al. in 1983.3 The delivery of the first of
these two pregnancies was reported by Bustillo et al. in 1984.5
Work with uterine lavage as a source of donated embryos continued
4 John E. Buster

FiGURE 1.1. Blastocyst recovered by uterine lavage and transferred into an infertile
recipient woman synchronized to the cycle of the donor. In 1983 this blastocyst
produced the first in vivo fertilized donor embryo pregnancy in history.5 l8 Reprinted
o

with permission from Bustillo et a1. 5

through 1986. The uterine catheter used in these studies is shown in Figure
1.2. A total of 35 ova were recovered from 84 spontaneous cycles. Of the
35 ova recovered, 8 were blastocysts, and of the 8 blastocysts transferred,
4 produced clinical pregnancies in recipients. 19 A very similar experience
was reported from the University of Pavia in Milan by Formigli et al.2 3- 25
Work with uterine lavage for transfer of donor embryos was discontinued
in 1987, not because of lack of promise, but because the specter of HIV
infection posed an unacceptable risk for donors. It also became clear that
lavage was a relatively inefficient method of embryo acquisition when used
with spontaneous cycles. 19 Methods to enhance its efficiency are under in-
vestigation again because of its application to preimplantation diagnosis. 26 ,27

Recent Developments
Over the decade that followed these initial reports, donor oocytes and em-
bryos became established, effective therapy for several forms of intractable
infertility. The technique has seen increasing use because of technical im-
provements in in vitro fertilization and because clinicians have applied it to
an increasing number of clinical problems.
 1. Historical Evolution of Oocyte and Embryo Donation 5
SUCTION--.

r.-J
SUPPLY

FIGURE 1.2. Uterine catheter utilized for recovery of embryos fertilized in vivo. The
supply (internal) line delivers tissue culture media into the uterine cavity where it
dislodges the embryo from the mucus in which it is floating. The media is recovered
through the outside line and delivered into a flask. The fluid is then scanned to
recover the embryo.19 Reprinted with permission from Sauer et aU 9

Sources of Embryos
For several reasons, donor in vitro fertilization evolved as the principal
source of oocytes and embryos during the latter 1980s. First, the oocyte
retrieval precludes the donor being exposed to any infectious diseases (e.g.,
HIV) that might be carried in sperm. Second, pregnancy rates with in vitro
fertilization improved considerably during recent years. A major objection
to donor in vitro fertilization during the initial years was the need for lap-
aroscopic oocyte retrieval. Because only extraordinarily compassionate oo-
cyte donors would likely submit to laparoscopic retrievals, there were ini-
tially severely limited sources of oocytes, namely, other infertility patients
and women undergoing tubal sterilization. 28 ,29 This problem was obviated
with the introduction of transvaginal oocyte aspiration. 28 ,29 The introduction
of ultrasound aspiration in the late 1980s made oocyte retrieval an office
procedure that is far more acceptable to anonymous oocyte donors than
laparoscopy would have been. Ultrasound-guided aspiration is the method
principally used today.
Synchronization of donors to recipients remains a challenge. Pivotal to
devising a successful strategy was appreciation of a window of endometrial
receptivity for embryo donation, initially cycle days 17 through 19, later
extended to include cycle days 15 through 20. 28 ,30,31 Synchronization is a
relatively simple matter in patients with ovarian failure but a far more dif-
ficult issue in recipients with intact ovarian function. Initially, natural cycles
6 John E. Buster

were synchronized with oral contraceptives. Natural ovulations were al-

lowed to occur in a pool of donors and recipients. 5 Inseminations and trans-
fers depended on good fortune. The scheme was simplified with the intro-
duction of gonadotropin-releasing hormone (GnRH) agonists. 32,33 Agonists
facilitated scheduling of donors and recipients, the latter being given
synthetic estrogen and progesterone replacement to compensate for the
agonist-induced quiescent ovaries. In this way, patients could be designated
for a specific donor.
Cryopreservation techniques have significantly improved in the past 15
years, and cryopreservation is now an alternative stategy for resolving the
problem of synchronization for patients with intact ovaries. Cryopreserved
embryos, however, do not produce the pregnancy rates observed with fresh
embryos.33.34 Improvements in cryopreservation would be highly desirable
in expanding the use of donor oocytes and embryos because large-scale
banking would become possible.

Indications
Compromised ovarian function from premature ovarian failure, gonadal
dysgenesis, sequelae of cancer chemotherapy, and oophorectomy were
seen initially as the principal applications for oocyte and embryo dona-
tionY>-lB,2B,29 Pregnancy rates were indeed gratifying. 16-18,28,29,35 Two addi-
tional indications later became evident. One is the application of oocyte
donation to women at high risk for transmission of genetic disease. This is
gratifying because it all bu_t eliminates that risk. 35 The second was the ap-
plication to older infertile women, even those beyond natural meno-
pause. 36-43 The magnitude of this application for infertility, though not ini-
tially envisaged, has been perhaps a most visible and sometimes
controversial venue. Sauer et al. have explored the application to older
women in a careful series of experiments. 36-39 This work, and that of others,
demonstrates that oocyte aging is the principal culprit in the decreased
reproductive efficiency in aging women and that the uterus and endome-
trium are secondary and probably play minor roles. 36-39

Ethical and Legal Issues

That human oocyte and embryo donation is ethically and legally acceptable
is argued today only by extremists. 44 The initial public discord, faced par-
ticularly by the Australian researchers, has subsided. 44 ,45 Details, however,
dealing with issues of donating surplus embryos, embryo ownership, and
archiving are increasingly occupying legislators and ethicists. 44 In the United
States, no federal laws govern disposition and care of human gametes; many
states, however, are instituting laws. Guidelines by professional societies do
exist and are adhered to by most physicians. 46,47 In Europe, practices are
 1. Historical Evolution of Oocyte and Embryo Donation 7

more highly regulated, as witnessed by recent statutory destruction of em-

bryos frozen for more than five years in the United Kingdom.

The Future
Oocyte and embryo donation is likely to playa major role in treating in-
tractable problems of diseased oocyte function. Donor oocytes should be-
come much more readily available as techniques for ovarian tissue culture,
in vitro maturation, in vitro fertilization of such oocytes, and cryopreser-
vation of oocytes are introduced. Continued laboratory research is needed
to reduce these methods to clinical practice. Even though women will prefer
to bear children with their own genetic characteristics, for many there is no
better choice. For families who benefit, each birth is an epoch event.

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