In 1954 and 1956, Deanesly [1] and Green, et al. [2] were one
of the first to experiment with the freezing and thawing of animal
ovarian tissue. In the first half of the 20th century, the art of tissue
cryopreservation was at its infancy with glycerol being the only
cryoprotectant available [3]. Glycerol is a poor cryoprotectant and,
therefore, early research showed very limited success [4]. Additional
cryoprotectants became available during the 1990s leading to
successful ovarian tissue cryopreservation, transplantation, and
resumption of fertility studies in animals and humans [3,5,6].
In 1983, Trounson and Mohr [7] reported what appeared to
be the first ever pregnancy in a human following preservation
and transfer of an [8] cell embryo. This was followed by the report
of the first human live birth after ovarian cryopreservation and
transfer with more cases to follow [8,9]. Sonmezer and Oktay [10]
performed a metanalysis, which included 21 studies on oocyte
cryopreservation. They found that the mean oocyte survival rate
after thaw, mean fertilization rate, and mean pregnancy rate
per cryopreserved/thawed oocyte was 47%, 52.5%, and 1.52%,
respectively.10 In a recent interview, Oktay, et al. [11] cited the
first report of resumption of ovarian endocrine function following
orthotopic transplantation of frozen banked ovarian tissue.
The preservation and autologous transplantation of endocrine
glandular tissue is not limited to the ovaries. In 1977, Wells, et
al. [12] introduced reimplantation of autologous cryopreserved
parathyroid tissue as a treatment modality of hypoparathyroidism.
Wagner, et al. [13] simplified the methods of parathyroid
gland cryopreservation and storage. For cryopreservation, the
parathyroid tissues were cut into cubes of 1 mm in length. The time
between parathyroidectomy and replantation of cryopreserved
tissue was 5 months on average (range, 0.5 to 15 months). Follow
up examinations in 25 patients were performed 6 months to 120
months (median: 40 months) postoperatively. In all patients, the
autografts functioned well and most of the patients did not require
any additional medication [13].
Despite technical difficulties with cryopreservation at that
time, pioneering research in parathyroid autotransplantation was
performed in the 70s by Alveryd, et al. [14] and Wells, et al. [15,16],
Alveryd, et al. [14] described six patients with primary parathyroid
hyperplasia who had parathyroid autografts. In 1976, Wells, et al.15
reported an additional four patients with primary parathyroid
hyperplasia who were treated by total parathyroidectomy and auto
transplantation of parathyroid tissue inserted into the forearm
muscle. All of these patients remained norm calcemic at 9 and 13
months, respectively. Good graft function was documented further
by detection of a higher concentration of parathyroid hormone
in the patients’ blood. Hormonal activity of auto transplants, if
excessive, can be adjusted by removing some transplanted tissue
[15]. Additional implantation can be carried out if the amount of
tissue initially implanted had been insufficient or if the transplanted
parathyroid tissue failed to survive. In the rat model, parathyroid
isografts functioned normally after cryopreservation for up to
9-12 months [16]. Wells, et al. [15] grafted autologous parathyroid
tissue, frozen for six weeks, into a patient who had had a total
parathyroidectomy for renal osteodystrophy. The graft was still
functioning 18 months after the procedure.
Research on oocyte and ovarian tissue cryopreservation has
gained momentum in recent years [17]. Oktay, et al. [18] reported
their experience with auto transplantation of ovarian tissue in
cancer patients to alleviate premature menopause and preserve
fertility.
Inspired by the success in parathyroid tissue auto
transplantation and recent advances in ovarian tissue
cryopreservation technology, we propose to apply this technique to
treat menopausal symptoms.19 We established an ovarian tissue
cryopreservation bank in 2000 in collaboration with Professor E.
Zharov (Russian Federation) with the goal to collect and preserve
ovarian tissue retrieved with the patient’s consent during indicated
obstetrical or gynecological procedures (cesarean section-15,
minilaparotomies and tubal ligation – 12, gynecological surgeries
for benign conditions – 22). Since our computer-assisted search
failed to find an ovarian tissue bank with similar goals, we used the
experience of the ovarian transplantation program in Denmark for
the purpose of preserving ovarian tissue to combat infertility. The
ovarian transplantation program started in Denmark in 2000 (800
women have had their ovarian tissue frozen) [19]. For this study,
the researchers studied the outcomes of women who had received
transplantation between 2003 and June 2014. The functional life
span of the grafts varied between one and ten years; grafted tissue
robustly restored ovarian function.
In 2000, we initiated a research protocol at Nassau University
Medical Center (Petrikovsky BM, Ansari AH, Beers PG, et al. which
stated as follows:
After obtaining approval from the Institutional Review Board,
patients, ages 40 and under, will be included in this study. Normal
ovarian function in these cases is to be established prior to ovarian
sampling, using such methods as; hormonal assay, pelvic ultrasonography
and endometrial sampling. Opportunistic ovarian
biopsy will be performed by means of laparoscopy or laparotomy.
Ovarian cortex will then be separated from its stroma and divided
into several pieces. Each piece will be placed in a special cryovial
container and filled with a special cryoprotectant solution
(dimethyl sulfoxide, human serum albumin factor V). The cryovials
are then transferred to a special aluminum case and lowered into
a liquid nitrogen tank where it is stored until such time that it is
used for autologous transplantation. To assess potential structural
alterations, it is the further aim of this study to examine a portion
of the ovarian tissue by means of TEM, prior to and after freeze
thawing. Whenever, clinically indicated, the specimen will be thawed
and reimplanted, subcutaneously, in a cosmetically acceptable
body site. The function of the transplanted ovarian tissue will be
assessed clinically by re-evaluation of symptomatology, as well as
such techniques as bone density analysis, ultrasonography, and
hormonal assay.”
None of the patients experienced complications directly related
to opportunistic ovarian sampling. Now, 20 years later, histological
assessment of preserved ovarian strips (15 samples) demonstrated
ovarian tissue adequate for reimplantation, 6 samples contained
visible icicles and were judged unfit for transplantation.
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