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Frontiers in Fertility — 87
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Preantral follicles (100 to 150 μm) are growing primary oocytes
surrounded by several (up to six) layers of cuboidal granulosa
cells. Theca cells are recruited from surrounding stroma around
the basement membrane of the follicle.[60]
Primordial follicles can be isolated by partial enzymatic disaggregation followed by mechanical dissection [61] or can be
kept in organ culture until they have grown to a stage where they
can be more easily isolated. After isolation, follicles can be grown
on collagen membrane, laminin, plastic culture plate, or under
mineral oil.[62] They can also be grown in three-dimensional
extracellular matrix environment.
Several culture systems were developed to support growth of
preantral and primordial follicles (for review [60]).
To date, live offspring were produced by in vitro growth of
primordial follicles only in the mouse [63], but this has not been
possible with human primordial or preantral follicles.
The factors that control primordial and preantral follicle
growth in vivo and in vitro are under extensive investigation at
this time.
OVARIAN TISSUE CRYOPRESERVATION
AND TRANSPLANTATION
History
The birth of a mammalian offspring after orthotopic transplantation of cryopreserved ovarian tissue was reported by Parrott in
1960 in mice.[63] Gosden in 1994 [64] reported on the delivery of two lambs after orthotopic transplantation of fresh and
frozen–thawed ovarian grafts. Oktay (2000) [65] reported the
first case of orthotopic transplantation of thawed ovarian cortical strips with return of ovarian function for a brief period.
The first human embryo produced from heterotopic transplant
of thawed ovarian cortical strips was reported by Oktay et al. in
2004. In the same year, delivery of a monkey after heterotopic
transplantation of fresh ovarian tissue was reported.[66] Donnez and coworkers in 2004 reported on the occurrence of pregnancy and delivery following orthotopic transplantation of ovarian cortical pieces [67]; however, questions were raised regarding the source of the oocyte that resulted in the pregnancy as
this patient still had occasional ovulation from her remaining
ovaries.
Fertility preservation involves a number of procedures other
than ovarian cryopreservation. Ouralgorithmicapproachissummarized below. The most common indication for ovarian tissue
freezing is amalignant disease requiring gonadotoxic chemotherapy.
The gonadotoxic effects of chemotherapeutic agents on steroid-producing cells as well as the oocytes are variable (Table
7.1.4). Alkylating agents are the most gonadotoxic. Cyclophosphamide-induced follicular damage is dose dependent. The
mechanism of gonadotoxicity is probably through interference
with cell cycle progression and induction of apoptosis. Older
women are more susceptible to premature ovarian failure because
of smaller primordial follicle pool size. Even after resumption of menses in younger patients, premature menopause may
develop later in their reproductive life.[68] The use of symptoms (e.g., menses, hot flashes, chronologic age) to assess ovarian reserve after chemotherapy is unreliable. There are several
established and developing means of ovarian reserve assess-
Table 7.1.4: Gonadotoxicity of Chemotherapeutic Agents
High risk
Cyclophosphamide
Chlorambucil
Melphalan
Procarbazine
Intermediate risk
Cisplatinum
Adriamycin
Paclitaxel?
Low risk
Methotrexat
5-Fluorouracil
Vincristine
Bleomycin
Actinomycin D
ment. These include biochemical markers (baseline and stimulated FSH, LH, estradiol, inhibin-B, antimullerian hormone),
biophysical markers (antral follicle count, ovarian volume, ovarian stromal blood flow), or dynamic testing (clomiphene citrate challenge test, gonadotropin-releasing hormone (GnRH)
agonist stimulation test, and exogenous FSH ovarian reserve
test).[69] Antimullerian hormone measurements appear to have
strong promise in assessing ovarian reserve as this hormone
is produced from very early-stage preantral follicles and the
expression of its protein can be found in as early as primordial
follicles.
Pharmacologic Ovarian Protection
Ovarian suppression by GnRH agonist does not seem to offer
gonadal protection in men or women. It may, however, be possible to protect ovarian reserve by pharmacologic treatments. For
example, rodent studies have shown that oocyte apoptosis can be
suppressed during chemotherapy and radiation by the disruption of acid sphingomyelinase gene and this apoptotic pathway
by sphingosine-1-phosphate treatment.[70,71]
IVF with Antiestrogen Compounds
Breast cancer is the most common malignant disease in
reproductive-age women. Although its incidence has increased
over the last several decades, the mortality of breast cancer has
declined. Fifteen percent of breast cancer cases occur in women
40 years or younger.
During treatment, a hiatus of up to 6 weeks exists between
surgery and chemotherapy. During that time, oocyte, embryo, or
ovarian tissue cryopreservation can be performed.[72] Because
controlled ovarian hyperstimulation using conventional regimens causes marked elevation in estrogen levels, alternative
ovarian stimulation agents such as tamoxifen and aromatase
inhibitors are used in combination with FSH.[72,73] When used
88 — Kutluk Oktay and Amr M.A. Azim
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Table 7.1.5: Major Reports of Ovarian Cortical Strip Transplantation in Humans
Study Age, years Indication Cryoprotectant Graft Site Results Onset, weeks
Heterotopic
Oktay (2001, 2003)
[75,76]
Oktay (2004) [77] 30 Breast cancer IIb
Kim (2004) [78] 37 Cervical cancer Ib
Wolner-Hanssen
(2005) [79]
Orthotopic
Oktay (2000, 2001)
[80,81]
Radford (2001) [82] 36 Hodgkin’s after
Donnez (2004) [67] 25 Hodgkin’s before
Meirow (2005) [83] 28 NHL, relapse after
35 Cervical cancer
IIIb before
chemoradiation
37 BSO for benign
disease
before
chemotherapy
at time of radical
hysterectomy
37 Sj¨ogren syndrome,
pure red cell
aplasia before
HSCT
29 BSO for benign
disease
third relapse,
before HSCT
chemotherapy
chemotherapy
DMSO Forearm Follicular growth,
oocyte retrieval
DMSO Forearm Follicular growth,
menses, ovulation
DMSO Abdominal wall Follicular growth,
oocyte retrieval,
IVM fertilization,
ET
DMSO Abdominal and
chest walls
PROH Forearm Follicular growth 18 8
PROH Pelvic
peritoneum
PROH ovary/
peritoneum
DMSO Pelvic
peritoneum
CS, small
pieces
Right ovary/left
ovary
Follicular growth,
ovulation
Follicular growth,
ovulation, menses
Menses (×1) 28 9
Follicular growth,
menses,
spontaneous
conception, live
∗
birth
Menses, follicular
growth, natural
cycle IVF, live
∗
birth
10 21
24 ≥24
12 ?
14 7
15 ≥10
20 ?
32 ≥9
†
Duration,
months
‡
BSO, bilateral salpingoophorectomy; CS, cortical strips; HSCT, hematopoietic stem cell transplantation; NHL, non-Hodgkin’s lymphoma.
∗
Source of oocyte leading to pregnancy could be the native ovary rather than transplanted tissue.
†Weeks between transplantation and hormonal and/or clinical activity of the graft.
‡Months of hormonal activity or ovulation after grafting.
for thispurpose, tamoxifen nearly doubles the number of oocytes
retrieved and is associated with less cyclecancellation when compared with natural cycles.[72]
A recent prospectivecomparisonbetweeninductionof ovulation with tamoxifen and letrozole in combination with low-dose
FSH stimulation indicated no significantincreaseintheincidence
of short-term cancer recurrence compared with non-IVF breast
cancer controls. The letrozole–FSH protocol resulted in lower
estradiol levels compared with tamoxifen–FSH and resulted in a
larger number of oocytes with a trend toward a higher number
of embryos.[73]
Letrozole, alone or in combination with FSH, may also be
used to cryopreserve oocytes and embryos in endometrial cancer
patients.[74]
Human Trials and Techniques
Main trials of ovarian tissue transplantation with or without cryopreservation are summarized in Table 7.1.5. This procedure has
the most potential when ovarian tissue is cryopreserved before
40 years of age.[68] Ovarian transplantation techniques may be
summarized as follows.
Orthotopic Ovarian Cortical Strip Transplantation
Oktay et al. 2001 [81]: Ovarian cortical pieces are strung
using 6-0 Vicryl sutures (Ethicon) under a microsurgical microscope. Those are then anchored to a triangular biodegradable
polycellulose membrane (Surgicel, Johnson & Johnson). The
membrane is tagged by a suture at its apex and laparoscopically
Frontiers in Fertility — 89
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Figure 7.1.1. Technique of orthotopic ovarian transplant. See text for more details. From Oktay et al. [76], with
permission from the American Society for Reproductive Medicine (ASRM).
inserted in a peritoneal pocket on the pelvic sidewall. The needle is passed through the peritoneum to wedge the graft in place.
The peritoneum isthen closed with laparoscopicsuturing (Figure
7.1.1).
Meirowet al.2005 [83]: Implantation of frozen-thawed ovar-
ian cortical pieces in the menopausal ovary was first proposed by
Oktay et al. In the Meirow group’s report, three pairs of 5-mm
transverse incisions were made in the ovary through the tunica
albuginea. With blunt dissection, cavities were formed beneath
the cortex for each of the three strips. Each piece of thawed ovarian tissue (1.5 × 0.5 cm in area and 0.1 to 0.2 cm in thickness)
was gently placed in each cavity, and the incisions were closed
with 4-0 Vicryl sutures (Figure 7.1.2).
Heterotopic Ovarian Cortical Strip Transplantation
Oktay et al. 2003 [76]: Each piece is tagged with 4-0 Vicryl by
passing the needlebetween stroma and cortexunder an operating
microscope.Theneedle is then cut. A 1.5-cm transverse incision is
made over the brachioradialis muscle, 5 to 10 cm below the antecubital fossa. Using blunt dissection, a pocket is created between
the fasciaand thesubcutaneous tissue. Attentionis given to avoid
injuring the largerveinsand arteries. Itisnot desirable toperform
extensivecauterization. Once the dissectionis completed, the free
end of the suture is threaded onto a reusable half-circle cutting
A
Proper
ovarian ligament
Figure 7.1.2. Technique of orthotopic ovarian transplantation. From
Meirow et al. 2005 [77], with permission from New England Journal of
Medicine and the author.
Thawed ovarian tissue
0.5 cm
1.5 cm
Left ovary
90 — Kutluk Oktay and Amr M.A. Azim
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A
B
C
Ty p e
Low risk (≤1%)
Breast cancer stage I–III
Hodgkin’s lymphoma
Non-Hodgkin’s lymphoma
Wilm’s tumor
Ewing sarcoma
Nongenital rhabdomyosarcoma
Osteosarcoma
Squamous cell carcinoma of the cervix
Moderate risk (1% to 10%)
Breast cancer stage IV
Adeno/adenosquamous carcinoma of the cervix
Colon cancer
High risk (≥10%)
Leukemia
Neuroblastoma
Burkitt lymphoma
Table 7.1.6: Risk of Ovarian Metastases According to Cancer
D
Figure 7.1.3. Technique of subcutaneous transplantation of ovarian
cortical strips. From Oktay et al. 2003 [76], with permission from
ASRM.
needle. This needle is inserted in the subcutaneous space as far
as possible and passed through the skin, and the cortical piece is
wedged into the subcutaneous pocket by pulling on the suture.
The transplanted strips are inserted with the cortical side facing
up. The needle is then removed, and the free end of the suture
is held with a mosquito clamp. The purpose of this suture pullthrough technique is to guide the tissue placement and to avoid
overlapping the strips, instead of anchoring them. The sutures
are cut and the skin is closed using an intradermal/subcuticular
suture. A nonpressure dressing is applied. The same technique
applies when the tissues are transplanted in the suprapubic subcutaneous location (Figure 7.1.3).
Transplantation of an Intact Human Ovary
with Its Vascular Pedicle
Although this technique had partial success in sheep, it has
not been possible to cryopreserve whole human ovaries. This is
mainly because of thelarger size ofhuman ovaries and the inability to efficiently cryopreserve both the oocytes and the vascular
pedicle. Nevertheless, this is an active research area in the cryopreservation field. [84]
Safety of Ovarian Transplantation; Transmission
of Cancer Cells
The risk of cancer metastases from various sites to the ovary
depends on type and stage of cancer (Table 7.1.6).[85]
Animal experiments involving mice (leukemia) and human
ovaries (Hodgkin’s lymphoma) yielded variable results. No case
of transmission of malignant cells after cure and transplantation
has been reported in human studies so far. Development of reliable methods for detection of malignant cells in ovarian grafts
is essential. Candidate methods, in addition to light microscopy,
include polymerase chain reaction assays and Northern blot and
immunohistochemistry for myeloperoxidase expression in acute
myeloid leukemia.
Other strategies include purging of tumor cells fromthe graft
using specific antibodies [86], in vitro growth and maturation of
preantral follicles [60], and xenografting (Figure 7.1.4).[87]
HUMAN EMBRYONIC STEM CELLS
AND REPRODUCTION
Embryonic stem cells (ESCs) are clonogenic immortal pluripotent cells capable of differentiation into all three germ layers and
germ cells. Adult stem cells (ASCs) are unipotent or multipotent mortal cells that form cells of lineage of tissue they originate from. Some ASCs may retain the plasticity to colonize a
variety of tissues under certain conditions; for example, bone
marrow–derived stem cells can demonstratemultiplicity of linear
differentiation (multipotent adult progenitor cells). The niche is
a microenvironment composed of support cells and associated
signals for controlling stem cell self-renewal and proliferation.
Female patient with cancer diagnosis
https://t.me/med1917
Frontiers in Fertility — 91
Low risk of ovarian metastasis
Ovarian
transposition
Embryo
cryopreservation
Estrogen
insensitive tumor
Conventional
COH
Figure 7.1.4. Proposed fertility preservation algorithm for a female cancer patient. COH, controlled ovarian hyperstimulation.
Chemotherapy
can be delayed
4–6w
Oocyte
cryopreservation±IVM
Estrogen sensitive
tumor
Ovarian stimulation
with Tamoxifen±FSH
Chemotherapy
cannot be delayed
Orthotopic graft Heterotopic graft
Ovarian stimulation
with letrozole±FSH
Totipotency of ESCs
Totipotent cells are capable of differentiating to extraembryonic
and embryonic tissue and are derived from early zygote. Pluripotent cells can differentiate to germ layers only and are generally
derived from inner cell mass (ICM) of blastocyst. Totipotential
differentiation of mouseESCs is supportedby their abilityto generate primordialgerm cells that can develop into maleand female
gametes and form a blastocyst-like structure that can give rise to
embryonic layers andtrophectoderm.[88–91] Moreover, haploid
male gametes derivedfromESCswerecapableoffertilizing mouse
oocytes with formation of blastocysts.
Derivation of Human ESCs
Human embryonic stem cells can be derived from:
1. Inner cell mass (ICM) of blastocyst.[92] Blastocysts can be
obtained by IVF or nuclear transfer to oocytes.
2. Morula.[93,94]
3. Single blastomere of eight-cell stage preimplantation embryo.[95]
The most common method is to derive ESC lines from ICM
obtained by immunosurgery. Blastocysts are typically donated
by women undergoing IVF. Zonae are removed. Blastocysts are
exposed to rabbit antisera then transferred to guinea pig complement to kill trophectoderm cells.[96] Cells are co-cultured on
meiotically inactivated embryonic feeder cells to form colonies.
Cultures are supplemented by leukemia inhibitory factor, other
growth factors, and protein source. Colonies are passaged weekly
until acell line is established.[97] Cellscan then attach or take the
High risk of ovarian metastasis
or ovary involved with cancer
Childhood/
adolescent
Ovarian
allograft??
Ovarian tissue
cryopreservation
Immature
oocyte
isolation+IVM
Forearm Abdominal wall
Xenografting?
Purging of tumor cells
from ovarian tissue?
form of hanging drop (embryoid bodies). These cells can differentiate spontaneously after prolonged culture to all three germ
layers and also to primordial germ cells (PGCs) as described by
Clark et al. [98] in 2004.
Formation of Primordial Germ Cells from ESCs
ESCs are capable of formation of male gametes in EB [88] and
female gametes in attached monolayer cultures.[90]
ESCs tagged by special reporter system (knock-in of green
fluorescent protein (GFP) or B-D-galactosidase (LacZ) genes in
octamer-4 homeodomain transcription factor of POU family or
mouse vasa homologue (mvh) loci) have been cultured without
feeder cells or growth factors. BMP4 (bone morphometric protein 4) or retinoic acid is added because of its mitogenic effect
on PGCs. Cultures are arranged to form colonies or EBs. Cells
develop in these culture systems within 7 days and express genes
specific for PGCs.
Detection of Primordial Germ Cell Formation In Vitro
Analysis of germ cell–specific markers can be used to detect
the differentiation of PGCs from ESCs (Figure 7.1.5). Because
of significant overlap between markers expressed in somatic
cells, ESCs, and PGCs, a combination approach includes sequential analysis of markers, morphologic studies, histochemical
methods, and analysis of steroidogenic enzyme gene expression.[90,98]
Generating Oocytes from ESCs
By days 8 to 12 in culture, aggregates of cells containing putative PGCs (mvh+) and somatic cells separate from the rest of
92 — Kutluk Oktay and Amr M.A. Azim
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Premeiotic Development
specification
ES cells
migration colonization mitosis meiosis differentiation
PGCs Gonocytes Gonia
Postmeiotic Development
Sperm
Mature
Spermatocytes
Oocytes
Oocyte
OCT4*
NANOG*
STELLAR*
GDF3
PUM1
PUM2
NANOS1
c-KIT
DAZL*
VASA*
SCP1*
SCP3*
MLH1
BOULE*
TEKT1*
GDF9*
Figure 7.1.5. Diagrammatic representation of the different stages of germ cell differentiation in fetal and adult development. Expected expression
patterns of genes used to predict each stage of germ cell development are shown by the name of the gene together with the black bars extending
to the right of each gene name. All genes shown are enriched in germ cells relative to somatic cells; those that are expressed only in germ cells
following gastrulation in vivo are indicated by an asterisk. Thus, genes known to be expressed in undifferentiated human embryonic stem cells
include OCT4, GDF3 (growth and differentiation factor 3), NANOG, STELLAR, PUM1, PUMILIO 1, PUM2, PUMILIO 2, and NANOS 1. Genes
known to be expressed in PGC development through to later stages of germ cell differentiation include DAZL (deleted in azoospermia-like),
c-kit, stella, and Nanos. Genes known to be expressed from gonocyte formation include VASA. Genes expressed during meiosis include SCP1
(synaptonemal complex protein 1 and 3), MLH1, Mut-L Homolog 1, and BOULE. Adult oocyte-specific marker: Gdf9. Adult spermatid-specific
marker: TEKT1, Tektin1.
the colonies. These are removed and cultured in a medium that
supports IVM. Overnight these cells expand and organize into
a follicle-like structure. By day 16 in culture, these structures
express markers of entry into meiosis (DMC1, SCPs) as well as
morphologic evidence of nuclear change (chromatin decondensation). On the other hand, surrounding somatic cells start to
express granulosa cell markers (GDF9, steroidogenic enzymes,
and estrogen production). Bydays 23 to25 in culture, oocyte-like
cells in these structures express markers of MII oocytes (zonapellucida proteins, polar body,spindle).On days 42 to 45, blastocystlike structures are found floating in culture. These expressed
markers of preimplantation embryos are probably formed by
parthenogenetic activation of oocytes.[90]
Similar experiments have confirmed the formationofhaploid
male gametes from ESCs inEBby20 days in culture. After transfer
to recipient testis, they were able to complete spermatogenesis
and the resultant spermatozoa were able to fertilize oocytes after
ICSI.[88,89]
Although the technology is in its infancy, the spontaneous
initiation of germ cell development from ESCs in vitro carries
profound implications for both reproductive biology and reproductive medicine.
CONCLUSIONS
This century holds great promise for excitingdevelopmentsin our
field. The advent of molecular and cryopreservation techniques
and stem cell technology is likely to change the way we look at
the limits of the reproductive life span. As geriatrics has become
one of the most prominent subspecialties of medicine because of
the aging population,fertility preservation willbecome one of the
most important aspects of our field given the increasing desire
to delay childbearing. The trend for delaying childbearing is not
only influenced by social reasons but also by increased life span
and improved odds of surviving malignant and other chronic
debilitating illnesses. An open-minded approach will facilitate
the progress and better enable us to help our patients improve
their quality of life.
Frontiers in Fertility — 93
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Section 7.2. Assessment of the Endometrial Cavity
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in the Patient with Infertility
Richard O. Burney and Amin A. Milki
The prevalence of uterine abnormalities in patients presenting
with infertility is as high as 50% [1–3], and these are believed
to play a major role among the 30% of couples who undergo
advanced reproductive treatment for multifactorial infertility.[4]
For patients undergoing in vitro fertilization, lower pregnancy
rates are observed in the setting of uterine cavity anomalies.[5–
7] The role of uterine pathology is a key factor in discordant
pregnancy outcomes among recipients of shared oocytes in an
ovum donation program.[8] Importantly, the correction of these
anomalies has beenassociatedwith improvedpregnancy rates.[3]
Therefore, the evaluation of the couple with infertility should
include an assessment oftheendometrial cavity.Traditionally, the
basic infertility work-up has included a hysterosalpingogram to
evaluate both the uterine cavity aswellasthepatency of the fallopian tubes. Other modalities to assess the endometrial cavity have
subsequently developed. These include transvaginal sonography
and sonohysterography and hysteroscopy. A variety of endometrial pathologies may prove deleterious to fertility. These include
endometrial polyps, leiomyomata,intrauterine adhesions, mullerian anomalies, and priorexposure to diethylstilbestrol (DES).In
this chapter,we review thevarious imagingmodalities. Additionally,we review the perturbations of normal endometrial anatomy
that these modalities can discern.
DIAGNOSTIC MODALITIES
Hysterosalpingography
Allowing assessment of both tubal and uterine pathology, hysterosalpingography (HSG) has become a basic component of the
initial infertility evaluation. HSG is reliable and well tolerated. In
addition to diagnostic yield,thestudyis potentially therapeutic. A
randomized controlled clinical trial comparing oil versus watersoluble contrast at HSG in infertile patients showed a 33% pregnancy rate with oil and a 17% pregnancy rate with water-based
contrast within nine ovulatory cycles after HSG.[9] Most pregnancies occurred within 7 months of the imaging study. These
substantial cumulative pregnancy rates may have been secondary
to the flushing of inspissated mucus and debris from the lumen
of the tube(s) to recreate patency. Inhibition of peritoneal fluid
immune cell function by oil-based contrast has been demonstrated in tissue culture studies, and this may explain the significantly higher pregnancy rates observed with oil versus watersoluble dye.[10]
The HSG study is ideally timed after the cessation of menses
and before ovulation. The dilatedperiuterine venous architecture
during the menses increases the incidence of vascular intravasation of contrast, and should be avoided. The risk of infectious
sequelae after HSG is 0.3% to 1.3%.[11] A potential prophylactic strategy is 100 mg of doxycycline taken twice daily for 5
days, starting 2 days before the procedure in patients testing positive for Chlamydia serum antibody or with a history of prior
pelvic inflammatory disease.[12] To ease cramping associated
with the procedure, the patient is asked to take a nonsteroidal
anti-inflammatory medication approximately 1 hour before the
study. The ability to appreciate subtle abnormalities of the reproductive tract is best garnered in real time, and this is the basis for
recommending the attendance of thegynecologist atfluoroscopy.
A reusable (Jarcho) cannula or disposable balloon–catheter systemattachedtoasyringe containing contrast is used for the procedure. Before insertion, the system should be adequately flushed
to minimize artifact associated with air bubbles. After a sterile
preparation of the cervix and vaginal vault, the instillation cannula or catheter is placed intracervically. Gentle pressure is used
to inject approximately 3 to5 mL of contrast. Theoptimal time to
appreciate abnormalities of the endometrial cavity is during the
early filling phase of the study, as these defects may be concealed
by overdistending the uterus with contrast agent. Lesions of the
endometrial cavity appearasareasof low contrast atHSGbecause
of the space-filling effect of the pathologic entity (Figure 7.2.1).
Within the cavity, polyps, fibroids, synechiae, mullerian anomalies, and the architectural sequelae of intrauterine DES exposure
can be appreciated. If a balloon–catheter system is used, it is
important to deflate the balloon at the conclusion of the study
to fully evaluate the lowermost portion of the endometrial cavity.
Complications associated with HSG are possible. In addition
to infection, vasovagal reaction and allergic reaction to contrast
have been reported. Vasovagal reaction is exemplified by nausea and/or lightheadedness and is transient. The radiation exposure, when radiation time islimitedand equipment properlycalibrated, is well within established margins of safety.[13]Calculated
at 3.7 milligrays, the radiation exposure during HSG is thought
to impart low teratogenic risk to an unsuspected pregnancy.[14]
Because very fewpregnanciesexposedtoHSGhavebeenreported,
conclusions regarding actual risks are difficult to make. Consequently, every precaution to exclude the possibility of pregnancy
should be taken before the study.
The sensitivity and specificity of HSG vary with the particular abnormality noted. Although HSG has 85% to 100% sensitivity for detecting tubal pathology [15,16], it is only 75% sensitive in documenting intrauterine adhesions.[17] HSG has a
sensitivity as low as 50% in the detection of intrauterine filling defects and cannot reliably differentiate polyps from submucosal leiomyomata.[17,18] As compared with subsequent hysteroscopy, HSG evidenced a 37% false-negative rate in patients
scheduled for IVF treatment.[5]
96
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