© Springer India 2015
Surveen Ghumman (ed.)Principles and Practice of Controlled Ovarian Stimulation in ART10.1007/978-81-322-1686-5_2121. Effect of Ovarian Stimulation on the Endometrium
(1)
Department of Reproductive Medicine, Nova IVI Fertility Clinics and Pulse Women’s Hospital, 108, Swastik Society, Navrangpura, Ahmedabad, Gujarat, 380009, India
Abstract
The endometrium is a dynamic endocrine organ. Its role in implantation is the single most vital step in the management of infertility, yet it is least understood.
In this chapter, we offer an insight into the endometrium. We discuss its physiology and functions, its molecular dynamics, the hormonal interplay involved in the menstrual cycle and its role in conception. We also discuss the factors regulating endometrial receptivity, how it is affected by various hormones, how the natural hormonal interplay affects the window of implantation and what effect different stimulation protocols have on its structure and functions.
Keywords
EndometriumImplantationReceptivityStimulation protocolsGnRH agonistsAntagonists21.1 Introduction
Implantation is the single most important step in the management of infertility and is also the most poorly understood part of reproduction. The endometrium is an active endocrine organ. It synthesizes and secretes lipids like prostaglandins and thromboxane, cytokines like interleukin and interferon and peptides like prolactin, growth factors, relaxin and renin. The interplay of all these substances is essential to create a receptive environment for the implanting blastocyst. This environment is labile and easily disturbed by exogenous as well as endogenous hormonal fluctuations. To understand these factors, we must first review the natural mechanisms of the endometrium and its functions.
21.2 Physiology of the Endometrium and Hormonal Interplay
The growth of the endometrium in every cycle is stimulated by the rising levels of oestrogen. There is increase in stromal thickness as well as increase in ciliated and micro-villous cells of the endometrium. Spiral arteries, the end arterial branches of the uterine arteries, are sensitive to hormonal changes. Glandular formation begins under the influence of oestrogen, in this phase. Glands become enlarged, filled with vacuoles and tortuous. Endometrial thickness increases. Oestrogen also stimulates VEGF synthesis, which helps in angiogenesis.
Epithelial proliferation stops 3 days after ovulation. This inhibition is brought about by the rising levels of progesterone that begin in the secretory phase. Tortuosity of glands increases, and there is intensive coiling of spiral arterioles in response to the progesterone. This heralds the beginning of the secretory phase. At the time of implantation, there is increased oedema of the endometrial stroma. Oestrogen and progesterone at this stage cause increase in production of prostaglandins, which leads to increased capillary permeability and thus increased stromal oedema.
Decidualization of the endometrium takes place around day 21–23 under the influence of progesterone. This decidualization helps to control the invasion of trophoblast after implantation. If there is no implantation, endometrial breakdown begins. Drop in the oestrogen and progesterone levels leads to withdrawal of support leading to vasomotor reactions that cause apoptosis, and subsequently tissue loss, which in turn leads to menstruation. At a cellular level, MMP (matrix metalloproteinase) secretion caused by progesterone withdrawal leads to cell membrane breakdown and dissolution of the cell membranes. MMP expression is suppressed post-menstrually by the rising oestradiol levels [1].
21.3 Role of Endometrium in Conception
The endometrium performs numerous functions to achieve conception [2]:
Sperm transport from cervix to oviducts
Nourishment of blastocyst
Removal of zona pellucida from fertilized ovum
Attachment and implantation of blastocyst
21.4 Endometrial Receptivity and Window of Implantation [WOI]
Endometrial receptivity is defined as a temporary unique sequence of factors that make the endometrium receptive to implantation of the embryo. The endometrium is normally a non-receptive environment for an embryo. The window of implantation is the window of time when the uterine environment is conducive to blastocyst acceptance and subsequent implantation. Embryo transfer data from assisted-conception cycles suggests a window lasting approximately 4 days, from days 20–24 of a 28-day normal cycle [3].
21.5 Markers of Endometrial Receptivity
21.5.1 Pinopodes
The beginning of the WOI is heralded by the progesterone-induced formation of pinopodes. Pinopodes are bleb-like short irregular surface projections found on the apical surface of the endometrial epithelium [4]. They are usually seen between the 19th and the 21st day of the menstrual cycle and persist for 24–48 h. They are considered transient markers of endometrial receptivity [5]. Their formation is stimulated by rising levels of progesterone seen in the luteal phase. Administration of oestradiol leads to their rapid loss, usually within 24 h. Thus, their detection during the mid-secretory phase is useful as a marker for endometrial receptivity. Blastocyst attachment has been shown to occur on top of pinopodes.
There are numerous other markers that help to define endometrial receptivity.
21.5.2 Biochemical Markers
Adhesion molecules: Mainly αvβ3 integrin appears in endometrial glands and luminal surface on cycle days 20 to 21 and is among the best-described markers of endometrial receptivity.
Anti-adhesion molecules: MUC-1 (mucin 1)
Cytokines: Leukaemia inhibitory factor (LIF)
Endometrial growth factors:
Heparin-binding epidermal growth factor (HB-EGF)
Insulin-like growth factor-binding protein-1(IGFBP-1)
Endometrial immune markers
21.5.3 Genetic Markers
Hoxa10 gene expression in the endometrium rises at the time of ovulation and has been shown to be essential for human implantation [6]. The uterine sensitization-associated gene-1 (USAG-1) is preferentially expressed in the maximal duration of endometrial receptivity [7]. Endometrial bleeding associated factor (EBAF) is found to be expressed in the late secretory and menstrual phase of the endometrium [8].
21.6 Hormonal Interplay
During stimulation, both gonadotropin (LH and FSH) and steroid hormone (oestrodiol and progesterone) levels vary. This may negatively or positively impact the endometrium according to the rise and timing of rise of these hormones.
21.6.1 Effect of Oestradiol on the Endometrium
A study by Basir et al. [9] in 2001 studied the effect of oestradiol in high and low responders in patients undergoing ovarian stimulation. They found that there was a much greater endometrial glandular volume in natural cycles as compared to stimulated cycles. The glands were more tortuous and numerous and occupied a greater area at the time of implantation.
In high responders, they observed a decline in glandular volume and an increase in the diameter of the glands, which was in direct proportion to the rise in oestradiol levels. This led to prolonged retention of glandular secretions and retarded emptying. This caused asynchronous secretory transformation of the endometrium due to reduced volume and insufficient secretions, leading to reduced endometrial receptivity. They also observed that stromal oedema was marked in such cases.
21.6.2 Effect of Progesterone
A study conducted by Bell et al. [10] has demonstrated the changes occurring in the endometrium due to the effects of progesterone. They divided the proteins that are secreted and synthesized by the endometrium into three groups, depending on their response to external stimulation.
