Uterine Receptivity ppt

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Uterine Receptivity

Peter A. W. Rogers

Centre for Women’s Health Research, Department of Obstetrics and Gynecology,

Monash University, Monash Medical Centre, Clayton, Victoria, Australia

INTRODUCTION

The aim of this chapter is to bring the reader up to date with current think￾ing about the role of uterine receptivity in in vitro fertilization (IVF).

The contents have been substantially revised and updated since the last

edition, including information on the wealth of new data currently emerging

on global gene expression profiling of human endometrium.

Although some progress in understanding of human uterine recep￾tivity has been made over the past 10 years, most workers in the field would

support the view that there have not been any paradigm shifts in our

understanding of this complex topic. The contribution that reduced uterine

receptivity makes to human infertility remains unclear. Unfortunately, a

number of issues prevent significant progress in understanding the role of

uterine receptivity in human reproduction, including first and foremost,

the ethical and practical constraints that limit mechanistic studies involving

embryo implantation in the human. Without successful embryo implan￾tation and pregnancy as an outcome measure, definitive studies investigating

uterine receptivity remain problematic. Despite this, the ready availability

of human endometrium from non-conception cycles under a wide range of

normal and manipulated situations provides huge scope for investigating

endometrial events that may characterize a ‘‘receptive state.’’

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The use of IVF as a routine clinical treatment for infertility provides

an important avenue for focusing basic and clinical research on the human

reproductive processes from gametogenesis to fertilization and implan￾tation. In particular, many of the research-oriented IVF programs are

now focusing attention on the role of the non-receptive uterus in reducing

embryo implantation rates following controlled ovarian hyperstimulation

(COH). There has been considerable speculation that implantation failure

due to reduced endometrial receptivity is one of the major remaining imped￾iments to higher IVF pregnancy rates.

ANIMAL STUDIES AND CURRENT CONCEPTS

ON UTERINE RECEPTIVITY

Although significant progress has been made over the past 10 years in under￾standing the basic mechanisms that control embryo implantation in a

number of mammalian species and in particular in the mouse (1), interpret￾ing these data in the context of human endometrial receptivity is difficult

because of the significant differences in mechanisms of implantation

between species (2).

It is important from the outset to appreciate that fundamental differ￾ences exist in how a receptive endometrium is achieved between the human

and commonly studied species, such as the mouse and rat. In human females,

an average non-conception reproductive cycle is approximately 28 days,

typically comprising four days of menstruation, 10 days of ovarian follicular

growth with rising circulating estrogen levels, and 14 days post-ovulation

with elevated progesterone levels. In a conception cycle, implantation com￾mences about 5–6 days post-ovulation, with the endometrium has been

exposed to 10 days of rising estrogen followed by 5–6 days of circulating

progesterone. There is no evidence yet to suggest that a receptive endo￾metrium in the human can be achieved by anything other than estrogen

exposure followed progesterone. In contrast, mice and rats have a 4-day

reproductive cycle, and it has been shown that the uterus becomes receptive

to the implanting blastocyst for a short period of time, a few days after the

commencement of continuous progesterone administration (3,4). Priming

estrogen prior to this progesterone as occurs in the human is not essential,

although a small amount of ‘‘nidatory’’ estrogen must be given at some time

after the commencement of progesterone for an implantation-receptive uterus

to be established. The length of time that the endometrium remains receptive

can be manipulated by altering the nidatory estrogen dose, with higher doses

resulting in shorter receptive periods (5). Nidatory estrogen is not a feature of

the human implantation process. In the mouse, implantation occurs five days

after ovulation, with stimulation of the uterine cervix during copulation

inducing a state of ‘‘pseudopregnancy’’ during which normal 4-day ovarian

cyclicity is halted for long enough to allow implantation to occur.

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Bearing in mind the major differences that have been found between

the different species studied, a number of general concepts have arisen from

animal studies which form the basis of our understanding of endometrial

receptivity in the human. First, it is generally believed that in the presence

of a healthy blastocyst, it is the uterus, appropriately conditioned by ovarian

hormones, that predominantly determines the success or otherwise of

implantation (6). The ‘‘implantation window’’ is defined as the period of

time when the uterus is receptive to the implanting blastocyst. In addition

to the receptive state, there is evidence in some species that the uterus goes

through ‘‘implantation neutral’’ and ‘‘implantation hostile’’ states (7). Dur￾ing the neutral phase, the embryo can survive in the uterus but will not

implant, whereas during the hostile phase the embryo is actively destroyed.

How the uterus affects these receptive, neutral, and hostile states remains

mostly unclear, although embryo toxic compounds have been demonstrated

in uterine flushing from rats and mice taken at times other than when

implantation normally occurs (7,8) and there is a suggestion that similar

embryo toxic compounds occur in the human (9). Another study has sug￾gested a major role for the uterine epithelium in preventing implantation

unless the correct hormonal priming had occurred (10). In this work, the

embryo was only able to implant in the unprimed mouse uterus once the epi￾thelium had been removed.

Further support for the hypothesis that the uterus is the major con￾trolling partner in the implantation process comes from numerous studies,

demonstrating that mammalian embryos can initiate implantation-type vas￾cular reactions in non-uterine tissues with a high degree of success regardless

of the sex or hormonal status of the host. Ectopic sites that have been stud￾ied in this way include the anterior chamber of the eye (11,12), the kidney

(13), the testis (14), and the spleen (15). Although tissues from ectopic sites

respond differently to the implanting embryo from those in uterine sites and

despite the fact that subsequent embryo development is often disorganized,

the study of ectopic implantation can provide valuable insights into normal

intra-uterine implantation (12,16). Indeed, normal development to term has

been reported in the human following ectopic implantation (17).

A number of mammalian species (including some of the marsupials)

utilize embryonic diapause or delayed implantation to maximize repro￾ductive efficiency (18). During diapause, blastocyst development has

arrested by the uterus until environmental or physiological conditions are

suitable for pregnancy to continue. That control over diapause is entirely

a uterine phenomenon and can easily be shown by removing the blastocyst

from the uterine environment, while normal development was re-commence

(19). Conversely, studies in cattle have shown that under certain conditions

the uterus can induce the preimplantation embryo to accelerate its devel￾opment in order to ‘‘catch up’’ the uterus and be ready to implant at the

optimal time in terms of uterine receptivity (20).

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