1.
Is there a role for GIFT and other tubal insemination
procedures?
This paper evaluated the most up to date information concerning
whether in vitro
fertilization (IVF) or gamete intrafallopian transfer
(GIFT) should be used in couples with infertility.
In in vitro fertilization, eggs and sperm
are fertilized outside the body and the resultant embryos
are transferred back into the uterus by means of a simple
office procedure like a Pap
smear. In the case of GIFT, eggs and sperm are laparoscopically
placed into the fallopian
tube, where fertilization occurs. The embryo then makes
its way down into the uterine cavity. Until the mid 1990s
GIFT was very popular because it had a higher pregnancy
rate than IVF. During the past several years, better culture
conditions and embryo transfer catheters have made in vitro
fertilization even more successful than GIFT. The petri
dish has become an even more nurturing environment for eggs,
sperm and embryos than the fallopian tube. For that reason,
GIFT has become a procedure with very few indications. Nationally,
and internationally, GIFT is now performed in a very small
minority of patients. Indications for GIFT include religious
preference or a blocked cervix (cervical stenosis). In our
own practice we use GIFT in only 2% of couples undergoing
assisted reproductive technologies. We utilize in vitro
fertilization in the other 98%.
2.Timing of the endometrial biopsy may be critical for
the accurate diagnosis of luteal
phase deficiency.
Luteal
phase defect has been defined as having two consecutive
endometrial biopsies showing delayed development of the
uterine lining during the second half of the menstrual cycle.
There is significant debate about the usefulness of endometrial
biopsies in evaluating women with infertility or recurrent
pregnancy loss. My personal opinion, is that luteal
phase defect rarely causes either condition. Among physicians
who still perform endometrial biopsies, considerable debate
exists about when is the best time in the menstrual cycle
to do the biopsy. In this study, we performed two endometrial
biopsies during the same menstrual cycle in over thirty
infertile women. The first biopsy was performed during the
time that the embryo actually comes in contact with the
uterine lining, the window of implantation. This occurs
between six and ten days after ovulation. The second endometrial
biopsy was performed ten to thirteen days after ovulation,
the time that physicians have traditionally
performed endometrial biopsies. This study suggests that
there is a of a higher detection rate of abnormal endometrial
biopsies if the procedure was performed during the window
of implantation. Interestingly, some women had abnormal
endometrial biopsies during the window of implantation that
subsequently returned to normal at the time of the traditional
later biopsy. My recommendation, after extensively evaluating
the literature, is that endometrial biopsies should be
performed eight to ten days after ovulation.
3.
Integrin adhesion molecules in the human endometrium:
Correlation with the normal and abnormal menstrual cycle.
This landmark publication demonstrated that markers of uterine
receptivity could be identified. We evaluated the uterine
lining of women throughout the menstrual cycle utilizing
antibodies to integrins. Integrins are glue-like substances
found on the surface of almost all cells in the human body.
We hypothesized that implantation, which requires the embryo
to attach to the uterine lining, could be mediated by integrins.
Our work was the first comprehensive study of many different
integrins throughout the menstrual cycle. We noted that
the b3 integrin sub-unit was present on the lining of the
uterus starting on cycle day nineteen or twenty. The uterine
lining is only receptive for an embryo to implant between
cycle days twenty and twenty-four. Therefore, the appearance
of this a v b3 integrin showed immense promise in being
able to identify women with normal uterine receptivity.
This study has subsequently been extended to include abnormalities
of av b3 expression, and therefore altered uterine receptivity
in women with blocked fallopian tubes (hydrosalpinges),
endometriosis,
recurrent pregnancy loss and unexplained infertility.
4. Further characterization of endometrial integrins
during the menstrual cycle and in pregnancy.
We
evaluated integrin expression in the uterine lining throughout
the menstrual cycle in one hundred and twelve women. This
exhaustive study showed that two integrins initially appeared
in the uterine lining six to ten days after ovulation.
This timing, called the "window of implantation",
is the only time during the menstrual cycle that the uterus
will allow an embryo to implant. The exciting finding
that both the avb3 and a4b1 integrins are expressed when
the uterus is receptive suggested that these two markers
of uterine receptivity used to investigate causes of uterine
receptivity defects including endometriosis, hydrosalpinges,
and unexplained infertility.
5. Endometrial integrin expression in women exposed
to diethylstilbestrol in utero.
Diethylstilbestrol (DES), a potent estrogen, was given
to pregnant women with a history of recurrent pregnancy
loss from the early 1940s until 1972. Unfortunately, DES
did not improve pregnancy outcome. Sadly many female fetuses
whose mother took DES had subsequent problems with recurrent
miscarriage, premature delivery, and precancerous and
cancerous changes of the vagina and cervix. In up to 80%
of women exposed to DES in utero, abnormalities of uterine
shape and size were noted. Our study hypothesized that
DES exposed women with abnormal uterine shape may have
abnormalities of the uterine lining making it more difficult
to conceive. We examined whether women exposed to DES
in utero had abnormal markers (integrins) of uterine receptivity.
This study compared many uterine integrins from women
exposed to DES in utero and compared them to normal fertile
women. Happily, integrin expression among women exposed
to DES in utero was comparable to that of normal fertile
women. The use of DES in pregnancy was banned by the United
States in 1972.
6. Aberrant integrin expression in the endometrium
of women with endometriosis.
Moderate and severe endometriosis accounts for 15% of women
with the disease because of endometriotic ovarian cysts
(endometriomas)
and pelvic adhesions. Most women suffering from endometriosis
have minimal and mild forms. Until the publication of this
paper, it was not clear why the presence of endometriosis
on the surface of pelvic organs such as the ovaries, pelvic
sidewalls, and rectum would cause reduced fertility. Women
with minimal and mild endometriosis do not have an apparent
physical reason for their inability to conceive. Our paper
investigated b3 integrin expression in the lining of the
uterus of women with minimal and mild endometriosis. The
b3 integrin is a marker of uterine receptivity. In this
study we evaluated over two hundred and fifty women with
endometrial biopsies. The findings of this landmark paper
suggest that women with minimal and mild endometriosis have
reduced fertility due to abnormal uterine receptivity. Four
years after the publication of our study, a beautifully
done Canadian study showed that surgical destruction of
minimal and mild endometriotic lesions doubled pregnancy
rates. Our practice's philosophy is to identify and completely
and safely destroy all endometriotic implants at the time
of laparoscopy.
7.
Hydrosalpinges adversely affect markers of endometrial
receptivity.
When
in vitro fertilization was first developed in the late
1970s, women with damaged fallopian tubes were the most
common patients. Beginning in the early 1990s, accumulating
evidence suggested that women with hydrosalpinges (blocked,
swollen fallopian tubes) actually had a lower pregnancy
rate with in vitro fertilization than women with other
diagnoses, like unexplained infertility . We hypothesized
that hydrosalpinges made the uterus less receptive to
an embryo being transferred into the uterus during an
in vitro fertilization cycle. receptivity in women with
hydrosalpinges. This landmark study demonstrated that
women with hydrosalpinges express significantly less b3
integrin compared to normal fertile women. Among twenty
women with abnormal uterine receptivity (diminished b3
integrin expression) 70% demonstrated increased b3 integrin
expression after the hydrosalpinges were removed. Overall,
women with blocked fallopian tubes have a 50% reduction
in pregnancy rate with in vitro fertilization, which returns
to normal once hydrosalpinges are removed. It is our practice's
philosophy that hydrosalpinges should be removed before
in vitro fertilization is performed to give each couple
the maximal chance for establishing a normal pregnancy
with in vitro fertilization.
8. Integrins as markers of uterine receptivity in women
with primary unexplained infertility.
Twenty percent of couples have no identifiable cause for
their difficulty in establishing a pregnancy. Over the past
decade better insight has been gained by using a day three
FSH
level or a clomiphene citrate challenge test in assessing
otherwise invisible defects in egg quality and number. Similarly,
many women with unexplained infertility are likely to have
abnormal uterine receptivity. This study used endometrial
integrins, markers of uterine receptivity, to evaluate the
uterine lining in women with otherwise unexplained infertility.
We found that abnormal endometrial integrin expression was
frequently noted in women with unexplained infertility.
Our data suggested that defective uterine receptivity may
be a frequently unrecognized cause of infertility.
9.
Characterization of integrin expression in a well-differentiated
endometrial cancer cell line.
No
good laboratory model exists to experimentally evaluate
the lining of the uterus to determine uterine receptivity.
The lining of the uterus (endometrium) is composed of
two types of cells, glands and stroma. One approach to
evaluate how endometrial glands change during the menstrual
cycle and during pregnancy is to use cancer cells that
can grow essentially forever in the test tube. We therefore
sought to test how good of a glandular model the well-described
Ishikawa cancer cell line was compared to normal human
endometrium. We therefore chose to evaluate it utilizing
markers of endometrial maturation and receptivity, namely
integrins. This hardcore science paper demonstrated that
the Ishikawa cell line is a reasonably good surrogate
for testing normal human endometrium.
10. Insights into the evaluation of the luteal phase.
Comprehensive
review of the literature regarding how to properly evaluate
the uterine lining for women with infertility. The use
of integrins for determining uterine receptivity is discussed
as well as more old fashioned techniques such as testing
for luteal phase defect.
11. Past, present, and future of steroid hormones.
This
article is a historical prospective on how far we have
come in understanding the hormones necessary for establishing
pregnancy. In the 1920s crude
experiments demonstrated that the dominant follicle
makes estrogen. Progesterone
was not identified until the 1930s. Since that time we have
also been able to identify many of the factors necessary
producing follicles and eggs, fertilize embryos outside
the body, and our subsequent outstanding pregnancy rates
utilizing in vitro fertilization.
12.
Endometrial Progesterone receptors and markers of uterine
receptivity in the window of implantation.
We
evaluated three hormonally regulated integrins from the
uterine lining of one hundred and seventy-five women.
This study demonstrated that normal endometrial receptivity
is tightly associated with the timely loss of glandular
progesterone receptors. One result of this abnormality
is luteal phase defect. However, occult uterine receptivity
defects (identified by the lack of the endometrial avb3
integrin) are regulated differently. This suggests that
avb3 is not only the marker of uterine receptivity, but
that its use could uncover otherwise occult defects in
normal implantation. This paper raises interesting insights
into how defects in uterine receptivity occur. Progesterone
can treat some, but not all receptivity defects. Our patients
frequently receive progesterone supplementation during
their infertility treatment.
13. Integrins in the human endometrium.
Detailed
review article with a 149 references that describes the
utility of looking at the uterine lining with integrins
to evaluate uterine receptivity and reproductive potential.
14.
Distribution of integrin cell adhesion molecules in endometrial
cancer.
We utilized integrins to evaluate women with cancer of
the uterine lining (adenocarcinoma). We demonstrated that
as the endometrial cancer became more aggressive, the
cancer cells lost integrins from their surface. The loss
of the alpha 2 beta 1 integrin was associated with the
presence of lymph node spread. The study suggests that
integrins could be used to give prognostic information
about the aggressiveness of endometrial adenocarcinoma.
15.
Characterization of a functional progesterone receptor
in a well-differentiated endometrial adenocarcinoma cell
line.
The
Ishikawa cancer cell line can be used as a model for evaluating
the uterine lining. We investigated whether the Ishikawa
cell line had progesterone receptors that worked with
the subsequent expression of the a1b3 integrin subunit.
These studies confirm that the Ishikawa cell line is an
excellent model for the study of hormonally regulated
events in the human uterine lining. Experiment performed
on Ishikawa cells give valuable insight into the events
controlling human implantation.
16. Intrapartum course of fetuses with isolated hypoplastic
left heart syndrome.
Hypoplastic
left heart syndrome is a severe congenital birth defect
in which the left side of the baby's heart does not develop.
This study reviewed the experience of babies with hypoplastic
left heart syndrome who delivered at the Hospital of the
University of Pennsylvania. We demonstrated that these babies
tolerate labor well, and do not need to have an elective
Cesarean delivery.
Dr. Castelbaum's and Dr. Freedman's findings have been
presented at the prestigious national and international
meetings listed below.
Abdela
SM, Berchuck A, Buck CA, Castlebaum A, Kohler M,
Lessey BA, Yeh I, Distribution of integrin cell adhesion
molecules in endometrial cancer. Am J Path 146: 717-26,
1995.
Lessey BA, Castelbaum AJ, Somkuti SG, Harris J, Sun
J, Young SL, Wolf L. Improvement in pregnancy rates with
GnRH agonist in women with infertility, minimal or mild
endometriosis and aberrant aVß3 expression.
Presented at the 52nd Annual Meeting of the American Society
for Reproductive Medicine, Boston, MA, 11/96. Abstract
#O-165.
Lessey BA, Castelbaum A, Bellardo L, Shell K, Sun
J, Somkuti SG. Defective endometrial receptivity: an under-appreciated
cause of idiopathic recurrent pregnancy loss. Presented
at the 51st Annual Meeting of the American Society for Reproductive
Medicine, Seattle, Washington, 10/95, Abstract#O-54
Castelbaum AJ, Sun J, Fritz M, Freedman MF,
Lessey BA. Decreased aVb3 integrin expression identifies
abnormal endometrial phenotype in luteal phase deficiency
(LPD). 42nd Annual Meeting of the Society for Gynecologic
Investigation, Chicago, Illinois, 3/95. Abstract #P-285.
Castelbaum AJ, Riben M, Howarth J, Tureck R, Lessey
BA. Minimal endometriosis impairs endometrial avb3 integrin
expression and cycle fecundity compared to tubal factor
patients in an IVF program. Presented
at the 50th Annual Meeting of the American Fertility Society,
San Antonio, Texas, 11/94. Abstract #P-7.
Lessey BA, Castelbaum AJ, Guzick D, Sun J, Fritz
M. The use of integrins as markers of uterine receptivity
to date the endometrial biopsy. Presented at 50th Annual
Meeting of the American Fertility Society, San Antonio,
Texas,11/94. Abstract #O-77.
Lessey BA, Castelbaum AJ, Riben M, Howarth J, Tureck
R, Meyers WR. Effect of hydrosalpinx on markers of uterine
receptivity and success in in vitro fertilization. Presented
at the 50th Annual Meeting of the American Fertility Society,
San Antonio, Texas, 11/94. Abstract #O-91.
Lei Y, Castelbaum AJ, Yowell CW, Somkuti S, Lessey
BA. Characterization of integrin subunits in a hormone-responsive
endometrial carcinoma cell line. Presented at the 76th Annual
Meeting of The Endocrine Society, Anaheim, California, 6/94.
Abstract #197.
Castelbaum A, Sawin S, Lessey BA. Endometrial integrin
expression of diethylstilbestrol exposed compared to normal
women. Presented at the
41st Annual Meeting of the Society of Gynecologic Investigation,
Chicago, Illinois, 3/94. Abstract #O-17.
Lessey BA, Ying L, Castelbaum A. Endometrial integrins
and the window of implantation. Presented at the 41st Annual
Meeting of the Society for Gynecologic Investigation, Chicago,
Illinois, 3/94. Abstract #O-2.
Castelbaum A, Wheeler J, Mastroianni L, Coutifaris
C, Lessey BA. Timing of the endometrial biopsy may affect
the incidence of out of phase (OOP) endometrium: Two biopsies
in a single menstrual cycle. Presented at the 49th Annual
Meeting of the American Fertility Society, Montreal, Canada,10/93.
Abstract #0-42.
Lessey BA and Castelbaum A. Characteristics of the
avb3 integrin in endometrium of patients with unexplained
infertility: A prospective controlled study. Presented at
the 40th Annual Meeting of the Society for Gynecologic Investigation,
Toronto, Canada, 4/93. Abstract #S-168.
Castelbaum A, Jackson GM, Ludmir J. Intrapartum course
of fetuses with left ventricular outflow tract obstruction.
Presented at the 11th Annual Meeting, Society of Perinatal
Obstetricians, San Francisco, CA, 1/91. Abstract #410.
Lessey BA, Castelbaum A, Ilesanmi AO. Luteal phase
deficiency: Immunohistochemical evaluation of endometrial
integrin receptor subunit a 1. Presented at the 47th Annual
Meeting of the American Fertility Society, Orlando, Florida,
1991. Abstract #P-163.
Lessey BA, Castelbaum A, Ilesanmi A, Yeh I. Immunohistochemical
diagnosis of luteal phase deficiency: Comparison between
endometrial
progesterone receptor distribution and TAG-72. The Endocrine
Society, Washington, DC, 1991. Abstract #1670.
