Reproductive Ecology and the Endometrium: Physiology, Variation, and New Directions Kathryn B.H. Clancy* Department of Anthropology, University of Illinois, Urbana-Champaign, Urbana, IL 61801 KEY WORDS reproductive ecology; endometrium; ecology; energetics; inflammation ABSTRACT Endometrial function is often overlooked in the study of fertility in reproductive ecology, but it is crucial to implantation and the support of a successful pregnancy. Human female reproductive physiology can handle substantial energy demands that include the pro- duction of fecund cycles, ovulation, fertilization, placen- tation, a 9-month gestation, and often several years of lactation. The particular morphology of the human endo- metrium as well as our relative copiousness of menstrua- tion and large neonatal size suggests that endometrial function has more resources allocated to it than many other primates. The human endometrium has a particu- larly invasive kind of hemochorial placentation and trophoblast that maximizes surface area and maternal– fetal contact, yet these processes are actually less effi- cient than the placentation of some of our primate rela- tives. The human endometrium and its associated proc- esses appear to prioritize maximizing the transmission of oxygen and glucose to the fetus over efficiency and protection of maternal resources. Ovarian function con- trols many aspects of endometrial function and thus var- iation in the endometrium is often a reflection of ecologi- cal factors that impact the ovaries. However, preliminary evidence and literature from populations of different reproductive states, ages and pathologies also suggests that ecological stress plays a role in endometrial varia- tion, different from or even independent of ovarian func- tion. Immune stress and psychosocial stress appear to play some role in the endometrium’s ability to carry a fetus through the mechanism of inflammation. Thus, within reproductive ecology we should move towards a model of women’s fecundity and fertility that includes many components of ecological stress and their effects not only on the ovaries, but on processes related to endo- metrial function. Greater attention on the endometrium may aid in unraveling several issues in hominoid and specifically human evolutionary biology: a low implanta- tion rate, high rates of early pregnancy loss, prenatal investment in singletons but postnatal support of several dependent offspring at once, and higher rate of reproduc- tive and pregnancy-related pathology compared to other primates, ranging from endometriosis to preeclampsia. The study of the endometrium may also complicate some of these issues, as it raises the question of why humans have a maximally invasive placentation method and yet slow fetal growth rates. In this review, I will describe en- dometrial physiology, methods of measurement, varia- tion, and some of the ecological variables that likely pro- duce variation and pregnancy losses to demonstrate the necessity of further study. I propose several basic ave- nues of study that leave room for testable hypotheses in the field of reproductive ecology. And finally, I describe the potential of this work not just in reproductive ecol- ogy, but in the resolution of broader women’s health issues. Yrbk Phys Anthropol 52:137–154, 2009. V V C 2009 Wiley-Liss, Inc. The uterus is the site of many physiological processes related to pregnancy, starting at implantation. It is the endometrium that is invaded by the trophoblast, and the endometrium that in part determines the degree of maternal–fetal contact. Human female reproductive physiology and behavior have evolved to handle substan- tial energy demands and determine not only the viability of conception, but also 9-month gestation and often sev- eral years of lactation, with babies that are larger and larger-brained than all other primates (Mace, 2000). Only humans have such invasive fetal burrowing to maximize the transfer of glucose and oxygen from mother to fetus that, in some cases of pathology, the placenta can breach the uterine wall (Bischof and Campana, 1996). The physiology and cyclic changes of the endome- trium and placentation vary broadly across the prima- tes (Martin, 2003). Where the strepsirhines have epitheliochorial placentation and relatively low mater- nal–fetal contact, haplorhines have hemochorial placen- tation with a high degree of maternal–fetal contact. Human hemochorial placentation and endometrial dif- ferentiation is characterized by the highest degree of maternal–fetal contact known, where the interhemal barrier (the cell layers separating maternal and fetal blood) narrow to a single-cell layer by the third trimester. This allocation of resources in humans to the fetus required a reorganization of endometrial tissue and a greater allocation of resources to endometrial function. Although the ovaries control much of the proliferation and secretary processes of endometrial function through the menstrual cycle and can thus be constructive in understanding variation in fecundity, variation in con- ception rates cannot be explained by ovulation alone (Lipson and Ellison, 1996; Kosmas et al., 2004; Ulug et al., 2006). This does not signal that ovarian function and endometrial function are not linked, but that ovar- *Correspondence to: Kathryn B. H. Clancy, Department of An- thropology, University of Illinois, Urbana-Champaign, 607 S. Math- ews Ave., 187 Davenport Hall, Urbana, IL 61801, USA. E-mail: kclancy@illinois.edu DOI 10.1002/ajpa.21188 Published online in Wiley InterScience (www.interscience.wiley.com). V V C 2009 WILEY-LISS, INC. YEARBOOK OF PHYSICAL ANTHROPOLOGY 52:137–154 (2009) ian hormone concentrations explain a portion of varia- tion in endometrial function rather than all of it. More direct studies of endometrial functioning are necessary to understand variation in reproductive function within and between human populations, especially if we are to understand reproductive processes that occur after ovu- lation. The lens of reproductive ecology is useful here, as the factors that produce variation in ovarian function are likely to exert some effect on the endometrium, indi- rectly via the ovaries if not also directly. Population var- iation in lifestyle, ecology, and developmental conditions produce significant variation in ovarian hormones (Ellison et al., 1993). As it is a target tissue of the ova- ries, but a tissue also responsive to inflammation and possibly insulin, age, energetic factors, and also immu- nological and psychosocial stress, ecological factors will be examined as possible sources of variation in endome- trial functioning. I will review the physiology of the endometrium from basic form to changes through the menstrual cycle, including some comparative review across the primates to provide the reader with basic information about endometrial processes and functioning. I will then describe some of the methods available for measuring endometrial function, and synthesize the current litera- ture on endometrial variation and its proximate determi- nants. This information will help to inform a set of topics in the context of reproductive ecology that I propose, which will create the framework for hypotheses for future testing. The central question of this review is to what extent does the endometrium mediate reproductive success due to its responsiveness to ovarian hormones that are themselves mediated by ecology, and how much of endo- metrial function is independent of the ovaries, that is, impacted directly by ecological factors? Ecology produces patterns of variation in ovarian function, which in turn affects endometrial function; this undoubtedly produces some effect. Inflammatory processes also exert significant effects on endometrial function (Sebire, 2001; Modugno et al., 2005; Agic et al., 2006; Puder et al., 2006). As the endometrium is largely engaged with processes of implantation and future gestation, energetic or more broadly ecological conditions may affect the ovaries and endometrium in different ways. This varia- tion could not be detected if only ovarian function were measured. This review will show how the study of the endome- trium will not only help answer current questions in reproductive ecology, but also lead to new questions about how adult and childhood energetic condition affect reproductive functioning, and discuss the possi- bility of more than one ecological pathway to lead to variation in endometrial function. An understanding of several important aspects of hominoid and human reproduction may be impacted by information regard- ing variation in endometrial function, including a low conception rate, high rates of early pregnancy loss, prenatal investment in singletons but postnatal sup- port of several dependent offspring at once, and higher rate of reproductive and pregnancy-related pathology compared to other primates, ranging from endometrio- sis to preeclampsia. Finally, the inclusion of the endo- metrium into the study of human reproductive ecology has implications not only for women’s health but also opens avenues for future research into nonhuman primates. ENDOMETRIAL PHYSIOLOGY Physiology and hormonal control of the endometrium The endometrium lines the corpus (body) of the uterus. It is one of the fastest-growing tissues in humans, composed of two layers: the functionalis and basalis. Although the basalis does not respond to the hormonal changes of the cycle, the basalis gives rise to the functionalis (Heller, 1994). The functionalis responds to hormonal action and proliferates, maintains, differen- tiates, or sheds its cells based on these signals (Heller, 1994). Not all mammalian endometria behave in this way: rodent endometria decidualizes only in the pres- ence of a blastocyst, where human endometria do it as a matter of course (Finn, 1974). Epithelial glands and cellular stroma compose the endometrium, both of which change morphologically across the menstrual cycle. Where increasingly coiled glands and vessels, increased gland complexity, and mitotic division of the stroma characterize the prolifera- tive (follicular) endometrium, the secretory (luteal) endo- metrium is characterized by subnuclear vacuoles lined up along the glands to maximize secretion, and stromal edema (swelling) at the time of the window of implanta- tion (Heller, 1994). The spiral arterioles are maximally coiled after this point (Heller, 1994), and towards the end of the cycle the entire stroma decidualizes (becomes a dense cellular matrix to control trophoblast invasion). If human chorionic gonadotropin (hCG) from an embryo had not signaled imminent implantation, the endome- trium would break down and hemorrhage from its differ- entiated state, which then leads to menstruation (Heller, 1994). The main hormones that act on the endometrium are ovarian sex steroids (estradiol and progesterone), insu- lin, hCG and luteinizing hormone (LH), prolactin, and oxytocin. Androgens and glucocorticoid receptors are also found in the endometrium (Jabbour et al., 2006). Cortisol may have a role in the endometrium, as it is often acti- vated as an anti-inflammatory response to the inflamma- tory mechanisms of menstruation and implantation (McDonald et al., 2006). Cortisol binds to the glucocorti- coid receptor and has a high affinity for the mineralocor- ticoid receptor in the endometrium; high cortisol concen- trations can interfere with mineralocorticoid signals and can cause disorders (McDonald et al., 2006). Further, cortisol is an important indicator of HPA activation and higher cortisol concentrations are correlated with preg- nancy loss (Nepomnaschy et al., 2006); chronic psychoso- cial stress is also associated with low birth weight babies in a sample of low income women (Borders et al., 2007). HPA activation can increase levels of matrix metallopro- teinases, which are involved in degrading the extracellu- lar matrix (ECM) in tissue remodeling (Yang et al., 2002). This is important to the creation of spiral arteries, decidualization of the endometrium, implantation, and early gestation (Curry and Osteen, 2003). Estradiol promotes the actions of the proliferative phase of the endometrium, and primes progesterone receptors for their role in the secretory phase; progester- one receptors cannot be expressed without first being primed by estradiol (de Ziegler et al., 1998). Progester- one, secreted by the corpus luteum, inhibits some of estradiol’s proliferative effects, and it maintains the endometrium through the implantation window in the mid-secretory phase (Brar et al., 1997). Whether the 138 K.B.H. CLANCY Yearbook of Physical Anthropology endometrium responds to ovarian hormones in a thresh- old (some minimum concentration is required for action) or dose–response model (the amount of action varies by hormonal concentration) is unclear. In vitro fertilization studies, where hormone concentrations are several times the physiological norm, sometimes demonstrate a dose– response model, where increased estradiol concentra- tions are associated with a thicker endometrium (Ran- dall et al., 1989; Milligan et al., 1995; Zhang et al., 2005); this relationship holds in some normal cycles as well (Randall et al., 1989; Bakos et al., 1994). Should the endometrium prove to operate in a threshold model simi- lar to testosterone and spermatogenesis, endometrial thickness and function may not be as functionally rele- vant as previously thought, or other factors could be im- portant to the production of variation other than ovarian hormones. And if the endometrium operates in a dose– response model, then greater inter and intrapopulational variation may be expected, as has been found in ovarian hormone concentrations. Hormone concentrations vary with energy expendi- ture, nutritional status, and other ecological factors, and thus ecology indirectly affects endometrial function (for a review see Ellison, 2001). But the presence of insulin, in- sulin-like growth factor-1 (IGF-1), and insulin-like growth factor-1 binding protein (IGF-1 BP) receptors in endometrial tissue (Strowitzki et al., 1993; Corleta et al., 2000) suggests that some energetic factors could directly affect the endometrium, because insulin is involved in energy storage and release. Insulin receptors are most present during the secretory phase, where IGF-1 recep- tors are present throughout the reproductive cycle and are modulated by IGF-1 BPs (Strowitzki et al., 1993). Estrogen receptors are necessary for IGF-1 to stimulate a proliferative response in the follicular phase (Klotz et al., 2002; Curtis Hewitt et al., 2005) and significant cross-talk occurs in this process; IGF-1 BP also modu- lates embryo implantation (Fluhr et al., 2006). Further, insulin resistance is associated with thick endometria in- dependent of reproductive pathology (Iatrakis et al., 2006), and insulin inhibits differentiation in the endome- trium in vitro (Giudice, 2006). Insulin and related hor- mones are most active, therefore, around the window of implantation, but insulin also plays some role in endo- metrial proliferation and the downregulation of decidual- izing mechanisms. These receptors and hormones are downstream mediators of ovarian function on the endo- metrium (Klotz et al., 2002), and so are not fully persua- sive evidence of direct ecological effects on the endome- trium; however, the relationship between inflammatory processes and insulin suggests, at the least, that inflammation in the body can disrupt some of these mechanisms (Pradhan et al., 2001). hCG and luteinizing hormone (LH) act on the same receptors; broadly, hCG signals the presence of an embryo to the endometrium, and LH triggers ovulation. Endometrial tissue contains HCG/LH receptors and mRNA (Licht et al., 2003). The expression of hCG/LH receptors is affected by cycle phase, in that mid-secretory phase endometria have full expression of their mRNA but downregulation of full-length hCG/LH receptor mRNA occurs in the late secretory phase and early preg- nancy (Licht et al., 2003). Where maternal processes may protect against late implantation through receptor downregulation, which would be in a suboptimal endo- metrial environment for successful pregnancy, fetal proc- esses appear to promote maintenance of decidualized endometrial tissue, as hCG both rescues the corpus luteum and affects prostaglandin synthesis. HCG exhib- its a dose-dependent inhibition of IGF-1 BP and prolac- tin (Fluhr et al., 2006), and prolactin affects endometrial function. Prolactin is present in the window of implanta- tion and beyond in the secretory phase of the endome- trium, and it is necessary for embryo implantation (Fluhr et al., 2006) through the maintenance of secretory phase estradiol receptors (Basuray et al., 1983; Frasor and Gibori, 2003). Finally, although oxytocin is best known for its dual roles as a major actor in parturition and as the ‘‘bonding hormone,’’ oxytocin is also present in the nonpregnant endometrium, most strongly at mid-cycle (Steinwall et al., 2004). Oxytocin, like its synthetic partner pitocin, stimulates muscle contractions. Steinwall et al. (2004) suggest that oxytocin production is upregulated by estra- diol and downregulated by progesterone, as this is the pattern seen for oxytocin production in the hypothala- mus. Locally produced oxytocin in the nonpregnant endometrium could produce myometrial contractions that support sperm and egg transport, menstruation, and implantation (Steinwall et al., 2004). It is neither the case that only estradiol and progester- one control the endometrium, nor that promotion of pro- liferation and decidualization are the only important actions on endometrial function. Other hormones act to promote sperm transport and implantation, as well as allow the possibility of other direct effects on endome- trial function such as those by insulin; some of these are regulated by ovarian hormones, but some may be regu- lated by other factors. This implies endometrial function is impacted not just by ovarian function but by several factors acting in concert to maximize chances for conception. Menstrual cycle behavior of the endometrium In addition to the broad proliferative and secretory shifts that occur in the endometrium across the men- strual cycle described earlier, the endometrium exhibits some specific behaviors at the periovulatory phase, the implantation phase, and the end of the cycle (menses). The periovulatory and menstrual phases are described next, and implantation receives its own separate discussion. Periovulatory phase. The endometrium responds to ec- ological and ovarian signals, but it also plays its own role in fertility. In natural and IVF cycles, the endome- trium produces periovulatory waves from cervix (the neck of the uterus that leads to the vagina) to fundus (the top of the uterus, at the other end of the corpus). These waves are quite literal; the muscles of the uterus contract in such a way that the endometrium moves in a wavelike, directional motion, that varies in frequency, direction, and intensity at different phases of the cycle (Bulletti and de Ziegler, 2005). Cervix to fundus waves predominate over other types of waves in conceptive cycles (IJland et al., 1997, 1999). IJland et al. (1997 1999) suggest that these ‘‘inward’’ waves encourage semen to travel towards the egg and increases the chan- ces of conception. In their examination of spontaneous, natural cycles, IJland et al. (1997) showed a greater ‘‘outward’’ (fundus to cervix) waves in nulliparous women in a nonconceptive cycle than parous women in a nonconceptive cycle or women in a conceptive cycle. 139REPRODUCTIVE ECOLOGY AND THE ENDOMETRIUM Yearbook of Physical Anthropology Tracking IVF patient cycles, significantly greater endo- metrial wavelike activity (91% vs. 71% of time observed) and wave frequency (8.29 waves/min vs. 3.99 waves/min) were observed compared to spontaneous cycles (IJland et al., 1999); other research teams also document this (Lesny et al., 1998). Seventy-three percent of these spon- taneous cycles had a wave direction switch from ‘‘outward’’ to ‘‘inward’’ at the time of ovum pickup (perio- vulatory period) (IJland et al., 1999). The earlier this wave direction switch occurred, the lower the chances of conception; the findings suggest that the persistence of ‘‘outward’’ waves until hCG administration (34 h before ovum pickup) is a frequent precursor to pregnancy (IJland et al., 1999). The endometrium may guide unwanted endometrial debris, pathogens or other sub- stances out of the uterus until the periovulatory period, when it switches to encourage sperm transport and pre- vent embryo expulsion. Therefore, endometrial behavior factors significantly in conception. Menstrual phase. Menstruation is a result of tissue remodeling, and also an inflammatory process. The men- strual phase may be susceptible to HPA activation because of the importance of matrix metalloproteinase action in the breakdown of the decidualized endome- trium (Yang et al., 2002). The end of the secretory phase of a nonconceptive cycle is associated with ‘‘secretory exhaustion,’’ that is, the endometrium has prepared for conception, and without an embryonic signal to maintain it, begins to break down (Heller, 1994). The withdrawal of ovarian steroids stimulates prostaglandin production, then prostaglandins aid in menstruation and stimulate contractions to remove endometrial debris and blood (Sugino et al., 2004); these prostaglandins are differen- tially transported away from the endometrium at other phases of the menstrual cycle (Kang et al., 2005). Luteal phase defects (defined by reduced corpus luteum func- tion and/or luteal phase shortening) are associated with energetic constraint (De Souza et al., 1998; Rosetta et al., 1998; Williams et al., 1999; Warren and Perlroth, 2001; De Souza, 2003) and affect progesterone levels, which may affect prostaglandin production. Thus, luteal maintenance of endometrial tissue is costly, and it is likely impacted by energetic and more broadly ecological variation (Strassmann, 1996b). The degree of withdrawal of ovarian steroids, where a higher degree of withdrawal is derived from having a higher concentration to begin with, may also prove to be important in future research on this topic. Implantation and invasion of the endometrium Should an embryo successfully implant and produce sufficient hCG to rescue the corpus luteum, ovarian ste- roid withdrawal, prostaglandin production, and other processes associated with menstruation do not occur (Baird et al., 2003), and the endometrium changes to prepare for implantation. Progesterone concentrations increase and are essential to the processes described next. In addition to corpus luteum rescue (Csapo and Pulkkinen, 1978; Baird et al., 2003), subepithelial capil- lary permeability increases to provide greater access to maternal blood flow (Tabibzadeh and Babaknia, 1995). Embryo implantation is then a tissue remodeling process of adhesion and implantation similar to that found in other processes of the body such as inflammation and tu- mor invasion (Bischof and Campana, 1996; Bulletti and de Ziegler, 2005). Implantation—paracrine cell-signaling and adhesion—is one of the oldest processes in multi- celled organisms and a critical step in their development is the ability for cells to communicate and adhere non- randomly. For embryonic implantation, the embryo moves to the uterus, orients itself so that the inner cell mass is facing the endometrial lining, and dissolves its zona pellucida. The embryo then apposes, adheres, and invades the endometrial epithelium. At this point, troph- oblast syncytia (cell-like structure containing many nuclei) proliferate to invade the ECM of the endome- trium; the embryo digests its way through the ECM to implant, which best occurs when the cells are quiescent (rather than experiencing frequent or intense wavelike activity) (Beier and Beier-Hellwig, 1998). Finally, cytotrophoblastic cells migrate within the forged syncy- tia pathway, leading placental villi formation (Fig. 1) (Bischof and Campana, 1996). In preparation for the receptive period or ‘‘implanta- tion window,’’ the endometrium changes its adhesion molecule, cytokine, and key endometrial protein expres- sion (Tabibzadeh and Babaknia, 1995). The cytokines present during endometrial receptivity are leukemia in- hibitory factor (LIF) and the interleukins, especially interleukin-1 (IL-1) (Lindhard et al., 2002). These cyto- kines coordinate implantation with the embryo under the influence of sex steroid hormones (Lindhard et al., 2002). LIF and IL-1 also are present during inflamma- tory processes generically in the body, suggesting that implantation and inflammation are evolutionarily linked. The apical plasma membrane of the surface epithelium is non-adhesive until it is specifically altered during receptivity; then, the plasma membrane acquires the ability to form reflexive gap junctions, or targets where cells can attach (Tabibzadeh and Babaknia, 1995). On its surface, the endometrial epithelium forms pinopodes, which are secretory membrane elements (Tabibzadeh and Babaknia, 1995; Beier and Beier-Hellwig, 1998), and are important to adhesion of the embryo during implan- tation (Norwitz et al., 2001). While described earlier as important during the perio- vulatory period, endometrial wave activity also plays a functional role in the implantation window. In spontane- ous cycles, a quiescent endometrium in the midluteal phase and conception are associated. While ‘‘outward’’ waves characterize the early to mid follicular and late luteal phases, and ‘‘inward’’ waves characterize the peri- ovulatory period, the implantation window tends to have the lowest wave activity (IJland et al., 1997). The picture is a bit more complicated when wavelike activity in dif- ferent regions of the uterus during an IVF cycle is meas- ured; there, the uterus tends to have ‘‘inward’’ waves in the isthmocervical region (neck of the uterus) and ran- dom or opposing (both ‘‘inward’’ and ‘‘outward’’) waves in the corpus (IJland et al., 1999). In artificial cycles of women with mostly female-origin subfertility (78%), where wave activity has a greater amplitude and higher frequency than in spontaneous cycles, there is some indi- cation that the endometrium guides the embryo to the main body of the uterus and uses ‘‘inward’’ waves close to the cervix to prevent embryo loss (IJland et al., 1999). The decidualization of the endometrium, its thickness, its wave activity, and its synthesis of a suite of cytokines and hormones together establish a specific, optimal envi- ronment for conception and implantation. Following ini- tial invasion, the trophoblast sends additional cells responsible for further remodeling of the endometrial environment during the first trimester. These cells 140 K.B.H. CLANCY Yearbook of Physical Anthropology promote arterial reorganization to increase access to the maternal blood supply, suppress immune function, and signal to the endometrial glands to create the required combinations of cytokines, nutrients and growth factors for fetal nourishment through at least 10 weeks (Burton et al., 2002; Hempstock et al., 2004). Beneath the implantation site, the once-thick endome- trium drastically thins to decrease the trophoblast’s sep- aration from maternal energy (Hempstock et al., 2004). Initially, the endometrium creates a hypoxic environ- ment most suitable to early fetal growth (Jauniaux et al., 2000, 2003a; James et al., 2006). As the first tri- mester ends, the placenta takes over the nourishment of the fetus and much of the endometrium’s activity ceases; however, the endometrial glands continue to communi- cate with the spaces between placental villi containing maternal blood, which suggests they could continue to provide additional nourishment or some other role (Jau- niaux et al., 2003b). The endometrium’s ability to provide a suitable environment for conception, implantation, and early ges- tation and placentation relates critically to pregnancy and fertility. Insufficient endovascular invasion can lead to hypertension, preeclampsia, and inadequate fetal growth, whereas unrestricted trophoblast invasion can lead to placenta accreta (when the placenta attaches itself too deeply to the uterus), hydatidiform moles (mass on the trophoblast that usually does not contain tropho- blast cells), and choriocarcinoma (cancer germ cell con- taining trophoblast cells) (Bischof and Campana, 1996). Pathological trophoblast invasion is increasingly thought to be a problem of the immune system and the regula- tion of inflammatory processes (Norwitz et al., 2001; Challis et al., 2009). These pathologies are not commonly found in other animals; literature searches on typical laboratory animals or nonhuman primates yielded no results. Next, I review the broad anatomical and physiological differences in the endometria of primates to highlight some of the adaptations particular to humans. Nonhuman primate endometria Long follicular phases characterize primate reproduc- tive cycles and differentiate them from nonprimate ani- mals; these follicular phases include estradiol priming of the endometrium and dominant follicle (or follicles in some cases) development (Barnett and Abbott, 2003). Most primates give birth to singletons, with exceptions in strepsirhines and, notably, the callitrichids within pla- tyrrhines (Harvey et al., 1987). After that, aspects of uterine and endometrial physiology diverge within the primates in at least four ways. First, uterine type diverges: strepsirhines and tarsiers have bicornuate uteri where the uterus has two ‘‘horns’’ but is fused in its lower two-thirds leading to one cervix and vagina, and the rest of the haplorhines have unicornuate uteri with one body, cervix, and vagina (Gelder, 1969). Second, the type of arteries formed to support a fetus varies: strepsirhines and platyrrhines have straight arteries, where the arteries of the catarrhines have spiral arteries (Hernandez-Lopez et al., 1998). Third, strepsirhines do not menstruate visibly but most haplorhines do (all catarrhines and most platyrrhines), and menstruation generally increases in copiousness as one moves through these categories (Hrdy and Whitten, 1987; Strassmann, 1996a,b). Forms of placentation are the fourth main way endo- metrial physiology of primates vary: while hemochorial placentation has been suggested as the ancestral form for eutherian mammals and for primates (Wildman et al., 2006), endotheliochorial placentation has also been suggested to be ancestral in primates (Martin, 2008). Strepsirhines and haplorhines diverged in their placen- tation types, where strepsirhines use epitheliochorial placentation and haplorhines use hemochorial (Martin, Fig. 1. The process of embryo implantation. 1, Transport; 2, orientation; 3, hatching of the zona pellucida; 4, apposition; 5, adhe- sion; 6, invasion; 7, syncytialization; 8, villous formation. Please see the section entitled Implantation and Invasion of the Endome- trium for a more detailed description. Reproduced from Bischoff P, Campana A. 1996. A model for implantation of the human blas- tocyst and early placentation. Human Reproduction Update 2(3):262–270, by permission of Oxford University Press. 141REPRODUCTIVE ECOLOGY AND THE ENDOMETRIUM Yearbook of Physical Anthropology 2008); strepsirhines have less maternal–fetal contact, with six cell layers dividing them, and haplorhines have more contact, with only two cell layers; humans lose one more cell layer by the third trimester of pregnancy (Abitbol, 1990). Several points need to be summarized here. First, the primate ancestral condition was likely invasive placenta- tion, but strepsirhines evolved less invasive means to grow fetuses. Second, primates that give birth to multi- ples have epitheliochorial placentation with the excep- tion of the callitrichids, and have straight arteries including the callitrichids. Thus, epitheliochorial placen- tation is in strepsirhines because it is more efficient for the carrying of multiple fetuses. Third, menstrual copi- ousness increases with placentation invasiveness. In haplorhines, however, placental invasion only increased, which suggests greater investment in their singletons. Primates have greater fetal brain growth than other mammals (Martin, 1996), which may explain the variety of attempts made to conserve maternal resources, increase maternal–fetal contact, or otherwise find an efficient means of negotiating the trade-offs between current and future reproduction, and reproduction and survival. More resources are then allocated to endometrial growth and function, and to fetal growth, than in other animals, with particular emphasis on the catarrhines and hominoids. The endometrium and its associated reproductive processes have transformed significantly across the primates, where more derived adaptations indicate increased secretory mechanisms and increased maternal–fetal contact. In particular, human endome- trial processes imply an increased embryonic and fetal role in directing maternal energy, and an increased need for maternal–fetal contact alongside the need for protec- tion from maternal immunological defenses. Martin (1996) has suggested that mammals have the largest brains they can in the context of maternal metabolic resources during gestation and lactation; further, Martin et al. (2005) demonstrate relationships between basal metabolic rate (BMR), gestation period, body mass, and brain mass that suggest a trade-off between BMR and gestation period in the development of relatively large brains. Thus, the close maternal–fetal contact found in the human placenta and endometrium may be a way for the fetus to take maximal advantage of maternal energy for brain growth. Measuring endometrial function Several methods exist to measure endometrial func- tion and morphology; these different methods generate different kinds of data that indicate different aspects of endometrial functioning. Asking women to record dura- tion of menstrual bleeding is the least invasive; asking them to rate their perceived menstrual copiousness is also possible, and a pencil-and-paper scale has been recently described (Mansfield et al., 2004). The difficulty in creating universal agreement across subjects for what constitutes menstrual copiousness impairs this method, as well as the difficulty in determining how many days one menstruates when the beginning and ending of cycles does not occur at the same time of day, and the ‘‘end’’ of menses can be difficult for a subject to interpret (for a review see Belsey and Farley, 1987). Further, sub- jects often have some difficulty recalling menstrual cycle dates, perhaps in part due to cultural discomfort with this biological process (Roberts et al., 2002; Andrist et al., 2004). The MVJ pencil-and-paper scale (Mansfield et al., 2004) correlated with menstrual blood loss meas- ured from used sanitary napkins at r 5 0.683 which, while a strong relationship, may not be sufficient for testing mechanistic, physiological hypotheses. Menstrual fluid can be more precisely measured through a few different methods of collection, from weighing used sanitary pads collected in sealed plastic bags (Mansfield et al., 2004), to performing an alkalin- hematin method to assess blood in used sanitary pads involving soaking the used pads in solution and using a photometer to determine heme (Hallberg and Nilsson, 1964; Newton et al., 1977), and to collecting menses in a menstrual cup (Morrison and Brown, 2008). All these methods miss the menstrual blood that is lost through sanitary practices and urination. Both the method of subject appraisal of menstrual blood loss and menstrual fluid collection assess the same thing: the amount of en- dometrial tissue and blood that was left at the end of a reproductive cycle; variation in this measurement could indicate the degree of endometrial proliferation, endome- trial maintenance after proliferation, or both. The most invasive method of assessing endometrial function is through an endometrial biopsy, which requires entry into the endometrium through the cervix and the collection of a small amount of endometrial tis- sue; this requires the most significant clinical support and can be uncomfortable for the participant. This tissue can be tested for various molecular and biomarkers of endometrial activation and receptivity including gene (Riesewijk et al., 2003), pinopode (Nardo et al., 2002), and integrin expression (Thomas et al., 2003). Transvaginal ultrasonography, which is ultrasound using an endovaginal probe, balances useful, quantita- tive information with comfort and invasiveness for sub- jects. Abdominal sonography does not yield consistent enough results in assessment of nonpregnant reproduc- tive organs in humans (though it is sufficient for smaller primates), so while transvaginal ultrasound may at first seem more daunting, it is the more reliable and compa- rable method, as it is used clinically for diagnostic and research purposes. Abdominal sonography also tends to require a full bladder to adequately view reproductive organs; this can be more time-consuming and uncomfort- able than transvaginal ultrasound. Transvaginal ultrasound can be measured multiple times, even daily, during a menstrual cycle, which allows observation of changes in endometrial thickness. In one survey of women, though they anticipated significant discomfort before experiencing transvaginal ultrasound, they found it significantly less uncomfortable than mammography and Pap smears (Kew et al., 2004). Transvaginal ultrasound makes possible the measure- ment of endometrial thickness, endometrial pattern, the functionalis/basalis ratio, and endometrial volume. Endo- metrial thickness is the double thickness measurement of the endometrium on the sagittal plane at its widest point. Endometrial pattern is an assessment of the degree of echogenicity of the endometrium, which is thought to reflect the degree of decidualization and receptivity of the tissue. Endometrial thickness and pattern in particular are useful assessments of morphology, both because of their frequency in the literature and the relationships that have been found between these measurements and pregnancy success; results are highly reproducible between sonographers (Epstein and Valentin, 2002). 142 K.B.H. CLANCY Yearbook of Physical Anthropology ENDOMETRIAL FUNCTION VARIATION In a fecund cycle, the endometrium proliferates in the follicular phase, and then is generally assumed to be maintained at about the same thickness while it differ- entiates through the luteal phase (Johnson and Everitt, 1988; Baerwald and Pierson, 2004). This means there are two main ways endometrial thickness can vary: in the degree of follicular proliferation, and in the degree of luteal maintenance. Most endometrial thickness studies are in assisted reproduction, when it is measured at the time of hCG injection or ovum pickup, which approxi- mates midcycle in a natural cycle; this means current literature only has information on potential variation in follicular endometrial proliferation. Any variation in the endometrium through the window of implantation is thus not assessed, when its functioning is most relevant to achieving pregnancy. What follows is a review of the recent literature. Most work was carried out in medical settings, and thus the populations are categorized clinically: normo-ovulatory women, women undergoing assisted reproductive treatment, postmenopausal women, and women with endometrial pathology. Normo-ovulatory women Menstrual bleeding duration was used as a biomarker for endometrial function in a study that examined ener- getic correlates to variation in reproductive functioning. Duration of menstrual bleeding was shorter in the pre- harvest hunger season than the harvest season in Lese women (Bentley et al., 1990). Cycle length, but not dura- tion of menstrual bleeding has been shown to vary with work-related physical activity in US workers (Sternfeld et al., 2002). And in a subcohort of women from that study who had participated in the Michigan Bone Health Study, recreational physical activity was negatively asso- ciated with duration of menstrual bleeding (Sternfeld et al., 2002). Other studies examined endometrial function using endometrial thickness as its proxy. Clancy (2007a,b) used a single luteal endometrial thickness measurement, and found that mean endometrial thickness did not dif- fer between urban US and rural agricultural Polish women sampled, and that endometrial thickness was dependent on luteal phase day in Polish women but not US women. Endometrial thickness was positively corre- lated with C-peptide concentrations (a biomarker for in- sulin) and negatively correlated with age in the Polish sample (P 5 0.05 and P 5 0.04, respectively); a negative trend was found with energy expenditure calculated in METs (kcal/min) (P 5 0.09) (Clancy et al., in press). Only one journal article addressed breastfeeding women, and it found that recently postpartum breastfeeding women have less endometrial activity as assessed by en- dometrial pattern than those women who bottle-feed their infants (Freedman et al., 1976). The richest data on endometrial function study nor- mal, spontaneous cycles, using transvaginal ultrasound to measure endometrial thickness repeatedly throughout the cycle. These data provide longitudinal information to determine population variation in endometrial prolifera- tion and maintenance across the cycle. Cycle-long stud- ies of endometrial thickness in natural menstrual cycles exist on populations in economically developed countries (Canada, Sweden, the UK), and they align their subjects’ data by ovulation day (Randall et al., 1989; Bakos et al., 1994; Baerwald and Pierson, 2004; Raine-Fenning et al., 2004). These data are briefly described below and illus- trated (Table 1 and Fig. 2). Ovarian development occurs in waves several times through the menstrual cycle, with waves defined as a group of follicles growing synchronously; most women have two or three waves per cycle (Baerwald et al., 2003). Baerwald and Pierson (2004) measured endome- trial thickness, area, volume, and pattern in Canadian women to test their hypothesis that women with differ- ent follicular wave patterns would exhibit different endo- metrial dynamics through the menstrual cycle. They found endometrial thickness increased earlier during the follicular phase in women with two over three waves, and within women with two waves increased earlier in women with major (a dominant follicle was selected) ver- sus minor (no dominant follicle selection detected) waves, and no differences were found in these groups during the luteal phase (Baerwald and Pierson, 2004). Follicular waves did not appear to impact luteal phase endometrial thickness, and these groups were pooled for the following analysis. They described a plateau in endo- metrial thickness during the luteal phase that lasts until just before menses, but their data demonstrate noticea- ble variation: while the first few days after ovulation do remain constant, there is a visual drop in endometrial thickness 4 days after ovulation and then a second pla- teau that lasts until day 12, with statistical analysis of this variation forthcoming (Clancy et al., in preparation). Bakos et al. (1994) described changes in the endome- trium through the menstrual cycle in 16 Swedish women to demonstrate the usefulness of sonography in sponta- neous and artificial cycles. They found a positive rela- tionship between estradiol and endometrial thickness when the entire follicular phase was analyzed, but not when analyzing the late follicular phase (Bakos et al., 1994). Endometrial thickness varied significantly between women and displayed a similar two-plateau effect found in the luteal phase of the Canadian sample, at a slightly higher overall thickness, though the quali- tative, rather than statistical, quality of this analysis must be stressed. In a sample of English women, endometrial thickness did not appear to change appreciably through the luteal phase (Raine-Fenning et al., 2004). These subjects were measured every 4 days, and the lower measurement fre- quency may account for the lack of variation found. Ran- dall et al. (1989) measured estradiol and endometrial thickness in three groups of Scottish women trying to conceive: women with unexplained infertility, normal women with male factor infertility, and women with tubal occlusion. The results from the normal women are described here. Estradiol and endometrial thickness pos- itively correlated, and endometrial thickness increased through the luteal phase; however, luteal measurement frequency was only every 5 days (Randall et al., 1989). Aligning cycles at ovulation rather than at the end of the cycle provides information about endometrial thick- ness in the follicular phase and early in the luteal phase, which supplies important evidence about the influence of estradiol on endometrial thickness. Through the luteal phase, endometrial thickness appears to vary more sig- nificantly, but the presentation of the data make quanti- tative assessment challenging: aligning at ovulation allows for comparisons around ovulation, but as women even in the same population experience wide variation in luteal phase length the decline in endometrial thick- 143REPRODUCTIVE ECOLOGY AND THE ENDOMETRIUM Yearbook of Physical Anthropology ness cannot be adequately assessed this way. Future work will assess the original data in a way that allows for better assessment of the late luteal phase, through the alignment via days before menses, an alignment typ- ical to the study of population variation in progesterone. The variation in mean endometrial thickness in these populations—from 6 to over 13 mm—suggests the capacity for significant variation in normal, premeno- pausal ovulatory cycles. Assisted reproductive treatments In vitro fertilization (IVF) studies demonstrate rela- tionships between the endometrium, hormone concentra- tions, and pregnancy, though the hormonal manipula- tions of these cycles can make it difficult to apply the findings to normal, spontaneous cycles. Endometrial thickness (ET) has been shown to positively correlate with implantation rate after IVF (Noyes et al., 1995; Kovacs et al., 2003; Zhang et al., 2005). In controlled ovarian hyperstimulation cycles where estradiol is often four times the physiologically normal concentration, estradiol and endometrial thickness have been positively correlated, though only 6% of the variation in endome- trial thickness could be explained by estradiol concentra- tions (Zhang et al., 2005). Through the exogenous hor- mones administered that prepare the endometrium for implantation, in vitro fertilization also affects endome- trial receptivity and maturation in the luteal phase (Kolb and Paulson, 1997; Tavaniotou et al., 2001), which confirms a link between hormone concentrations and en- dometrial function. However, these data suggest that the relationship between ovarian hormones and endometrial function, while certainly crucial, is not a strict dose– response model, meaning that incremental increases in hormones do not necessarily correlate to an equal increase in endometrial function. Assisted reproductive technologies research is a con- tradictory array of information: some studies say endo- metrial thickness bears no relationship to achieving a successful pregnancy (Bassil, 2001; Dietterich et al., 2002; Kolibianakis et al., 2004), another says increasing endometrial thickness decreases chances of pregnancy success (Weissman et al., 1999), and still other studies suggest that endometrial thickness is positively associ- ated with pregnancy success (Oliveira et al., 1993; Noyes et al., 1995; Kovacs et al., 2003; Zhang et al., 2005). A table is provided to demonstrate some of the main differ- ences in methods and results in a representative sample of the ART literature on endometrial thickness (Table 2). Three main issues explain these different results: 1) sta- tistical and grouping factors, 2) assisted reproductive method used, and 3) calculation of success of the ART method (i.e., successful implantation, chemical preg- nancy, gestational sac, fetal heartbeat, ongoing pregnancy, live birth). In terms of statistical methods, some articles com- pared endometrial thickness means between groups of pregnant and not pregnant women, while others com- pared pregnancy rates between groups of high and low endometrial thickness. This was often determined by the question the authors were asking; for instance, for those concerned that an artificially-induced thick endometrium (from hyperstimulation via exogenous hormone adminis- tration) could reduce pregnancy rates, the method was to group according to endometrial thickness, usually above or below 14 mm. Most of the articles that found that endometrial thickness had a positive relationship with pregnancy rates grouped subjects by their preg- nant/nonpregnant state rather than their endometrial thickness; thus, a threshold endometrial thickness prob- ably does not exist over or under which pregnancy is unlikely. Another factor that complicates interpretations of this literature are the different methods used to achieve pregnancy; for instance, clomiphene citrate stim- ulates ovulation but has been found to reduce endome- trial thickness (Randall and Templeton, 1991), whereas GnRh agonists are likely to impact endometrial thick- ness. Comparisons of these results are challenging because the degree of exogenous stimulation is so differ- ent. Finally, authors defined a successful outcome as chemical pregnancy (positive hCG test), clinical preg- nancy by ultrasound (gestational sac or heartbeat), or even ongoing pregnancy (pregnancy for at least 20 weeks). Sometimes subjects were in the pregnancy cate- gory even if they eventually miscarried, so long as they hit the milestone that study defined as successful (Richter et al., 2007), and sometimes the authors did not know the ultimate outcome of all the pregnancies of the included subjects (Kovacs et al., 2003). Despite these methodological differences, the ART lit- erature has a lot to offer reproductive ecologists. Because TABLE 1. Characteristics of natural cycle endometrial thickness studies from Clancy et al. (in press) Country Citation Alignment method Average subject age Number of subjects Canada (Baerwald and Pierson, 2004) USG confirmation of ovulation 28 50 Sweden (Bakos et al., 1994) LH surge 31.7 16 UK (England) (Raine-Fenning et al., 2004) USG confirmation of ovulation 31 27 UK (Scotland) (Randall et al., 1989) LH surge – 6–10 depending on measurement day Fig. 2. Results of four studies of natural luteal phase endo- metrium (Sweden: Bakos et al., 1994; Canada: Baerwald and Pierson, 2004; England: Raine-Fenning et al., 2004; Scotland: Randall et al., 1989). Studies were aligned by ovulation day, with the knowledge that ovulation (as confirmed by ultrasound) is 24 h after the LH surge. Error bars were omitted. Reproduced from Clancy KBH, Ellison PT, Jasienska G, Bribiescas RG. 2009. Endometrial thickness is not independent of luteal phase day in a rural Polish population. Anthropological Science. DOI: 10.1537/ase.090130. 144 K.B.H. CLANCY Yearbook of Physical Anthropology endometrial measurements are standard procedure for most ART, and the subjects have a stake in the outcome and tend not to miss appointments, many authors have successfully measured a large volume of cycles retrospec- tively and prospectively. So even though ART cycles are exogenously stimulated, relationships between endome- trial thickness and different calculations of implantation or pregnancy can still inform our understanding of vari- ation in endometrial function. Thus, what these articles together suggest is that a thicker endometrium largely improves the outcome for ART, but that those that are very weak or very strong responders to ART (with a very thin or thick endometrium) may have less success. Other factors documented in ART research important to pregnancy are differentiation of the endometrium, en- dometrial pattern (Coulam et al., 1994; Sharara et al., 1999), uterine contractility or endometrial waves (IJland et al., 1996, 1997, 1999), and molecular indicators of re- ceptivity (Paulson et al., 1990; Lessey et al., 1996; Beier and Beier-Hellwig, 1998; Lessey, 2000; Lindhard et al., 2002; Cavagna and Mantese, 2003). This body of research implies that endometrial thickness, waves, pat- tern, and receptivity are all relevant to achieving preg- nancy, at least in stimulated cycles. Endometrial thick- ness, waves, and pattern are measured with noninvasive transvaginal ultrasound; molecular indicators of recep- tivity require a more invasive endometrial biopsy. And while it is obvious that hormonal concentrations influ- ence endometrial proliferation and decidualization, these data do not resolve whether this relationship is one of a threshold model (where a threshold hormone concentra- tion produces an effect), a dose–response model (where increasing hormone concentrations produce increasing effects), or whether other factors additionally influence endometrial variation. Postmenopausal women While literature on natural and artificial cycles rarely includes lifestyle or energetic information, other data on postmenopausal women and other study populations indicate that endometrial thickness varies with energy availability in a dose–response model (Shu et al., 1992; Douchi et al., 1998; Iatrakis et al., 2006). The postmeno- pausal endometrium is no longer influenced by active ovaries, and yet it varies with energy status. Research- ers have found a positive relationship between BMI and endometrial thickness (Andolf and Aspenberg, 1996; Douchi et al., 1998), body weight and endometrial thick- ness (Andolf and Aspenberg, 1996), and obesity and endometrial thickness (Serin et al., 2003). A positive relationship between endometrial thickness and energy TABLE 2. Representative publications on endometrial thickness from the ART literature ART protocol Finding Number of subjects/cycles Age of subjects (years) Number of embryos transferred Citation Long GnRH, short GnRH, GnRH antagonist ET higher in conception cycles in women under 35 yrs; age negatively correlated with ET 2339 cycles 19-56, mean 33.5 – Amir et al., 2007 Long GnRH No difference in ET in conception vs non-conception cycles 153 cycles \38, mean 31.4 3 Bassil, 2001 Long GnRH, IVF, and ICSI High and low ET in nonconception cycles; not ss 606 subjects \41 3 Lamanna et al., 2008 GnRH ET higher in those that achieved pregnancy independent of age 1294 subjects Mean 33.7 – Richter et al., 2007 GnRH ET and pregnancy rate positively associated 897 cycles Mean 35.6, range 23-44 Mean 2.6 Zhang et al., 2005 Follicular LA with GnRH, luteal LA Women with ET over/under 14 mm had similar clinical pregnancy rates 570 cycles \40, range 21-39 – Dietterich et al., 2002 GnRH, CC Women with ET [9 mm had higher implantation, clinical pregnancy, and ongoing pregnancy rates 477 subjects, 516 cycles Mean 35.9 Mean 3.2 Noyes et al., 1995 CC, short GnRH ET higher in those that achieved pregnancy independent of age 1228 cycles Mean 32 in pregnant, 33.1 in not pregnant subjects Mean 2.9 in pregnant, 2.6 in not pregnant subjects Kovacs et al., 2003 CC with IUI No difference in ET in women with ongoing pregnancies or no pregnancies 168 subjects Kolibianakis et al., 2004 GnRH, gonadotropin releasing hormone; IVF, in vitro fertilization; ICSI, intracytoplasmic sperm injection; ss, statistically signifi- cant; ET, endometrial thickness; LA, leuprolide acetate; CC, clomiphene citrate; IUI, intrauterine insemination. 145REPRODUCTIVE ECOLOGY AND THE ENDOMETRIUM Yearbook of Physical Anthropology status in postmenopausal women could indicate aromati- zation of androgens to estrone by adipose tissue, insulin and IGF-1 action, or both, on the endometrium. Thus, both an indirect pathway via steroids (estrone action implicates this indirectly) or a direct pathway (via insu- lin) are possible. Endometrial pathology Obesity and postmenopausal endometrial cancer risk positively correlate (Shu et al., 1992; Gull et al., 2001; Kaaks et al., 2002; Lukanova et al., 2006; Setiawan et al., 2006; Xu et al., 2006). Further, endometrial thick- ness and BMI are positively correlated in recovering anorectics (Andolf et al., 1997). These data further sug- gest relationship between energy status and functioning. Women who experience multiple spontaneous miscar- riages have not had their endometrial function explicitly measured, but several aspects of this population imply an endometrial origin to pathology. Choriodecidual inflammatory syndrome is a main cause of early preterm delivery and second trimester miscarriage (Sebire, 2001), and this and other inflammatory syndromes are associ- ated with undiagnosed and untreated gluten intolerance (Rostami et al., 2001), which over time promotes sys- temic inflammation. As many endometrial processes are inflammatory, it may be important in future research to examine inflammation and immune function in the con- text of the endometrium, as another important aspect of ecology. Ovarian hormones, insulin and inflammation pull out as the most relevant factors that produce variation in endometrial function in the literature, with independent and interrelated actions documented. Ovarian hormones are often the bearers of ecological information, insulin can also inform on energy availability, and inflammation can be produced by immunological or psychosocial stress. This article focuses on these factors for its remainder. ENDOMETRIAL FUNCTION AND REPRODUCTIVE ECOLOGY Several hypotheses have been suggested in the last few decades to explain menstruation and endometrial cy- clicity. These hypotheses fall into three major categories: menstruation as a cleansing process, energetic explana- tions of menstruation, and physiological explanations for menstruation. Early researchers attempted to isolate an elusive compound they called the ‘‘menotoxin,’’ a toxic substance secreted in a menstruating woman’s sweat that could cause harm to male babies and cut flowers (Macht, 1924; Freeman et al., 1934; Macht and Davis, 1934; Davis, 1974; Reid, 1974; Bryant et al., 1977; Pickles, 1979). As problematic as that initial work was, the idea that menstruation cleanses the body persisted, perhaps because of the strength of widespread cultural beliefs in this purpose (Montgomery, 1974; Whelan, 1975): later work focused on the elimination of unwanted embryos (Clarke, 1994) and sperm-borne pathogens (Profet, 1993). Strassmann (1996a,b) and Finn (1996, 1998) offered alternatives to these ideas, with their hypotheses of energy economy and terminal differentia- tion, respectively. Strassmann (1996b) suggested that it was more costly to maintain the endometrium from cycle to cycle, and that menstruation evolved to reduce the energetic costs of fecundity. Finn (1998) argued that menstruation is a necessary consequence of the terminal differentiation of endometrial tissue that occurs after es- tradiol priming and progesterone action (de Ziegler et al., 1998); the endometrium must start over once the tis- sue has differentiated beyond a point at which it can proliferate for the next cycle. Finn’s hypothesis gains support in the light of the physiology and comparative primatology of the endome- trium: the variability in endometrial and placental archi- tecture, and the particular architecture of human placentation demonstrate the specialized tissue the endo- metrium becomes in preparation for implantation. Decidualization is a process that cannot be reversed, and so endometrial tissue must be removed if it is to prolifer- ate again. Further, the endometrium is maximally recep- tive through an implantation window in the luteal phase, after which implantation is unlikely regardless of embryo quality or stage. Strassmann’s hypothesis loses support because of this, but also from evidence sur- rounding ecological variation in endometrial function described in the previous section of this article. Terminal differentiation and menstruation’s other important pur- pose allows endometrium to respond to the ovaries and ecology from cycle to cycle; without this, the endome- trium could not respond to changing ecological conditions. Strassmann’s important contribution to reproductive ecology is attention on energetics and the endometrium, without which the ecology of the endome- trium and the primary topics of this review might never have been explored. Therefore, the following section will focus on ecology and endometrial function, synthesizing the existing literature, and describing new directions for research in reproductive ecology. While the relationship between ovarian function and reproductive success is obvious, the mechanisms that link them are not. Inter and intrapopulation variation in ovarian steroids has been consistently documented (i.e., Ellison and Lager, 1986; Bledsoe et al., 1990; Lager and Ellison, 1990; Bentley et al., 1998; Jasienska and Elli- son, 1998; Rosetta et al., 1998; Warren and Perlroth, 2001; Vitzthum et al., 2002; Nu ´ n ˜ ez-de la Mora et al., 2007). These data demonstrate relationships of energy expenditure (Ellison and Lager, 1986; Bledsoe et al., 1990; Rosetta et al., 1998; Warren and Perlroth, 2001), energy balance (Lager and Ellison, 1990), nutritional status (Bentley et al., 1998), and developmental condi- tions (Vitzthum et al., 2002; Nu ´ n ˜ ez-de la Mora et al., 2007) with ovarian hormones. Combine the data demonstrating a relationship between energy and immunity and the endometrium, energy and ovarian hormones, estradiol concentrations and rates of pregnancy in ovulatory cycles, and estradiol and endometrial function, and it becomes clear that ovarian and endometrial function are important compo- nents of fertility that must be studied together in repro- ductive ecology. Because the endometrium is a target tissue of ovarian steroids, it is the next place to look to better explain aspects of fecundity and fertility that remain unclear with ovarian function alone. In particu- lar, endometrial function plays a role in variation in fe- cundity and fertility via variation in endometrial thick- ness and pattern, as well as variation in implantation rates and early fetal loss. Ecology, ovarian function, and age are likely the prime determinants of endometrial and more general reproductive variation, though genetic variation is as yet largely unstudied and may also prove important. Because the endometrium has a strong role in implantation and early gestation, fetal loss is also of 146 K.B.H. CLANCY Yearbook of Physical Anthropology [...].. .REPRODUCTIVE ECOLOGY AND THE ENDOMETRIUM interest By articulating the relationship between ecology and reproductive functioning, and fetal loss and endometrial function, I will elucidate the relationships between lifestyle and fecundity, and more direct endometrial effects on fertility, that require more attention in reproductive ecology Ecology and reproductive function Several... conception, the endometrium, controlled in large part by hormones from the corpus luteum and then placenta, may be the guardians of pregnancy Future work in reproductive ecology and life history theory should incorporate endometrial function to provide a more complete picture of reproduction Fruitful areas of research include the study of ecology and endometrial physiology, comparative research into the primate... primate endometrium, and paracrine and endocrine signals to endometrial tissue Ultrasonography of the endometrium was established by clinicians working to understand the body in the context of understanding and treating disease, not the wide range of normal variation in response to ecology Thus, the opportunity that awaits us is in using these methods to understand variation more broadly: reproductive ecologists... glands provide the developing embryo with nourishment, when the pregnancy is so early that the embryo cannot receive it from the placenta (Burton et al., 2002; Hempstock et al., 2004; Jauniaux et al., 2005) Questions for reproductive ecology Once the basic physiology of the endometrium and some of the factors that tend to affect reproduction are understood, several issues in reproductive ecology can be... Thus, there are four main areas upon which we should focus our attention in reproductive ecology, to address broader questions of female fecundity and fertility: population variation, ecological variation, conception, and comparative primate physiology; further, the method for the first steps in this program should involve serial endometrial ultrasounds to measure thickness and echo pattern REPRODUCTIVE. .. loss The aforementioned areas of research measure fecundity, but the measurement of fertility and fetal loss are also crucial to an understanding of endometrial function The wealth of ART literature demonstrates the importance of this kind of study, but new work must diverge from their methods in the frequency of endometrial measurement Comparative primate physiology As described earlier, humans and other... Ecological variation In female reproductive physiology, ovarian hormones are the primary bearers of ecological information to the target tissues, and indirect signaling of ecology via ovaries to the endometrium may mean the endometrium processes this information differently There is also evidence to suggest the endometrium is able to receive ecological information independent of the ovaries (Corleta et al.,... energetic processes that directly impact the endometrium through action on insulin receptors The effects of inflammation, energetics, and stress could be measured in the context of ovarian and endometrial function Then, to better understand those factors that produce variation, causal modeling should be employed to parse out the mechanistic relationships between ecology, age and reproduction Causal modeling... However, the study of insulin receptors, inflammatory responses in tissue remodeling, and recent work on Type I and II GnRH receptors modulating embryo implantation and placentation in a paracrine and autocrine fashion (Wu et al., 2009), also suggest there may be direct ecological influences on the endometrium Mechanistic and population-based studies are still necessary to parse out these interactions and. .. affects the success of assisted reproductive technologies (Meldrum, 1993; Amir et al., 2007) Conception is not the only reproductive stage impacted by decreased endometrial function: troubles may arise in the ability of an embryo to attach to the endometrium and implant, or may affect an embryo’s ability to remain implanted and receive adequate maternal nourishment The endometrium’s secretory glands provide . Reproductive Ecology and the Endometrium: Physiology, Variation, and New Directions Kathryn B.H. Clancy* Department. cervix (the neck of the uterus that leads to the vagina) to fundus (the top of the uterus, at the other end of the corpus). These waves are quite literal; the