Placenta 36 (2015) 341e344
Contents lists available at ScienceDirect
Placenta journal homepage: www.elsevier.com/locate/placenta
Current opinion
The perinatal origins of major reproductive disorders in the adolescent: Research avenues I. Brosens a, *, A. Cur ci c b, T. Vejnovi c b, C.E. Gargett c, d, J.J. Brosens e, G. Benagiano f a
Leuven Institute for Fertility and Embryology, Tiensevest 168, B-3000 Leuven, Belgium Department of Gynecology and Obstetrics, Clinical Center of Vojvodina, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia c The Ritchie Centre, MIMR-PHI Institute of Medical Research, Clayton 3168, Australia d Department of Obstetrics and Gynecology, Monash University, Clayton 3168, Australia e The Division of Reproductive Health, Warwick Medical School, Coventry CV2 2DX, United Kingdom f Department of Gynecology, Obstetrics and Urology, Sapienza, University of Rome, Rome, Italy b
a r t i c l e i n f o
a b s t r a c t
Article history: Accepted 8 January 2015
The fetal endometrium becomes responsive to steroid hormones around the fourth month of pregnancy starting with an oestrogenic phase, which is followed late in pregnancy by a secretory phase. Based on post-mortem studies, the endometrium at birth is secretory in only one-third of neonates and proliferative in the remaining cases. Decidual or menstrual changes are rare in fetal endometrium despite high circulating steroid hormone levels, which drop rapidly after birth. Hence, acquisition of progesterone responsiveness appears to be dependent on endometrial maturation and relative immaturity may persist in a majority of girls until the menarche and early adolescence. Two major reproductive disorders have been linked with either advanced or delayed endometrial maturation. First, early-onset endometriosis may be caused by menstruation-like bleeding in the neonate, leading to tubal reflux and ectopic implantation of endometrial stem/progenitor cells. Second, persistence of partial progesterone resistance in adolescent girls may compromise deep placentation and account for the increased risk of major obstetrical syndromes, including preeclampsia, fetal growth retardation and preterm birth. The concept of neonatal origins of common reproductive disorders poses important research challenges but also subsumes potential new preventative strategies. © 2015 Elsevier Ltd. All rights reserved.
Keywords: Endometrium Neonatal uterine bleeding Progesterone resistance Endometriosis Obstetrical disorders
1. Introduction Recently, a dual hypothesis has been put forward on the role of the neonatal endometrium in the pathogenesis of reproductive disorders in adolescent women, more specifically early-onset endometriosis and the increased incidence of major obstetrical syndromes [1e4]. This hypothesis is based on two major studies: First, an autopsy study of 169 neonates published by Ober and Bernstein in 1955 [5], which describes in detail the histological appearance of endometrium and ovaries at birth. This study showed that in a majority of cases (58%), the endometrium exhibits only proliferative changes. Evidence of secretory changes in the glandular compartment was recorded in 27% of neonates but progesterone-dependent changes in the stromal compartment, such as decidualization or menstruation-like shedding, were rare
* Corresponding author. Tel.: þ32 16 270190; fax: þ32 16 270197. E-mail address: [email protected] (I. Brosens). http://dx.doi.org/10.1016/j.placenta.2015.01.003 0143-4004/© 2015 Elsevier Ltd. All rights reserved.
and found only in 5% of cases. The other remarkable study was performed at the University of Novi Sad, Serbia [6]. In this study, Beri c and colleagues examined all 2477 female babies born between 1st of January and 31st of December 1979 and documented evidence of neonatal uterine bleeding in 1 (0.8%) out of 126 preterm neonates, 85 (4.4%) out of 2241 term babies, and 10 (9.1%) out of 110 post-term infants (Table 1). The overall frequency of neonatal uterine bleeding was 3.87%. This incidence is very similar to that reported in two earlier clinical studies by Levy et al. [7] and Kaiser et al. [8]. Although the literature is scant, these carefully conducted observational studies suggest that the fetal endometrium is intrinsically progesterone resistant, but poised to transit soon after birth to a responsive state. In a small proportion of neonates, especially those born post-term, this transitional process is already under way, accounting for the increased incidence of menstruation-like neonatal uterine bleeding in response to the rapid fall in circulating placental progesterone levels after birth.
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I. Brosens et al. / Placenta 36 (2015) 341e344
Table 1 Data suggesting neonatal origins of adolescent endometriosis.
Table 2 Data suggesting neonatal origins of obstetrical syndromes in adolescents.
Date
Finding
Authors [reference]
Date
Finding
Reference
1955
The endometrium is decidual or menstruallike in 5% of the newborns. Functional cervical obstruction in the neonate favouring tubal reflux at the time of menstrual. Functional cervical obstruction in the neonate favouring tubal reflux at the time of menstrual shedding explains 3 days delay of neonatal bleeding. Uterine bleeding occurs in 0.1% of preterm newborns. ENDO study finds that for unknown reason endometriosis is rare in preterm born women Case report describes neonatal endometriosis. Case reports of premenarcheal endometriosis
Ober and Bernstein [5] Fluhmann [15]
1955
The hormonal response of the fetal endometrium starts after the 4th gestational month with proliferation. At birth the endometrium remains progesterone resistant in 68%. Endometrium in preterm is more immature than in term or post-term neonates. Association of young maternal age and adverse reproductive outcome Decidualisation precedes trophoblast invasion and impaired decidualisation affects deep placentation. Teenage pregnancy and adverse birth outcomes By imposing the need for cyclic renewal of the endometrium, spontaneous decidualization followed by menstruation bestows unique functions on the human endometrium that are essential for reproductive success
Rosa [9]
1960
1960
1985 2013
1996 2005
1955 Fluhmann [15]
1985 1995
Beri c et al. [6]
2011
Wolff et al. [19] 2007 2013 Arcellana et al. [16] Marsh and Laufer [20]
Initial insight into hormonal influences on the fetal uterus was provided in 1955 by Rosa [9] who, in an autopsy study of 47 human fetuses and infants, found that proliferative changes in the fetal endometrium start around the 4th month of pregnancy. This is followed from the 8th month onwards by secretory changes in the glandular compartment. The author suggested that the progression from proliferative to secretory changes in the fetal uterus during pregnancy mimics changes seen in a normal menstrual cycle. Yet none of the fetal ovaries showed signs of ovulation. As the secretion of steroid hormones by the placenta was at that time incompletely understood, an explanation for the uterine progesterone response was elusive. A subsequent study on 82 uteri from fetuses, infants and children confirmed that peak endometrial secretory activity is reached at birth [10]. Both studies reported evidence of regression and even sloughing off of the surface epithelium in term neonates, but not menstrual-like breakdown of the stromal compartment with associated bleeding. Notably, proliferative endometrium can exhibit interstitial bleeding, as is the case in anovulatory cycles, but this is distinct from menstruation following spontaneous decidualization of the stroma. A possible explanation for the absence of menstrual changes is the relative small number of term or postterm neonates in both studies. We recently summarized the circumstantial evidence that points towards a causal link between neonatal uterine bleeding and early-onset endometriosis, mediated by retrograde pelvic seeding and subsequent dormancy of endometrial stem cells [3] (Table 1). It is interesting to note that in 1948, Novak and De Lima strongly argued that “in the vast majority of cases (of endometriosis) the ectopic endometrium is of immature type, responding to growth effect of estrogen, but not to the differentiating effect of progesterone” [11]. In other words, there are similarities in the responsiveness of ectopic endometrial lesions and the eutopic fetal endometrium. We have also highlighted how an immature adolescent uterus, i.e. not fully responsive to progesterone, could predispose for obstetrical complications associated with impaired deep placentation, such as preeclampsia, fetal growth restriction, and preterm labour (Table 2). This hypothesis complements and extends an earlier theory suggesting that cyclic spontaneous decidualization and menstruation emerged in evolution to precondition the uterus for the intense tissue remodelling and hyper inflammation associated with deep haemochorial placentation [12]. These new theories, interesting as they may be, cannot be endorsed without more substantial supportive evidence; and this will not be easily obtained.
Ober [5] Beri c [6] Fraser [28] Brosens [23]
Chen [29] Lucas [26]
Hence, our intention here is to outline and evaluate possible research avenues that may support or rule out a role for the neonatal endometrium in early-onset endometriosis and major obstetrical syndromes during adolescence. 2. Perinatal uterine bleeding and early-onset endometriosis 2.1. Cellular or acellular vaginal bleeding An important first step would be to collect samples from neonates with signs of vaginal bleeding. This is worthwhile as there is no information on cellular constituents of the vaginal effluent. Our hypothesis infers that neonatal uterine bleeding should lead to active shedding of viable endometrial cells, including mesenchymal stem cells (MSCs), which could be purified, propagated and characterized in culture. Vaginal aspiration should be feasible using the technique of “catheter within a catheter” developed for obtaining vaginal secretions in pre-pubertal girls [13]. At the same time, it remains questionable whether this approach will yield meaningful €ssel [8] published results: indeed, a clinical study by Kaiser and Gra 40 years ago showed that neonatal bleeding can occur several days after the drop in circulating placental hormones. One explanation for this delay may lie in the anatomy of the lower female reproductive tract in the fetus and neonate [14]. At birth, the cervical canal is twice as long as the uterine corpus and filled with thick mucus, thereby favouring reflux rather than cervical outflow of the menstrual shedding [15]. Thus, the onset of overt bleeding may be intrinsically unpredictable and even obscured. Furthermore, a filtration process through the long cervical canal may render neonatal uterine bleeding predominantly acellular and stained with haemoglobin by the lysis of red blood cells [8]. 2.2. Cellular components of the tubal reflux Another critical step would be to demonstrate tubal reflux and ‘seeding’ of endometrial cells in the peritoneum during the perinatal period. At present there is only one case report that supports this conjecture. Arcellana et al. [16] carried out an autopsy on a baby with hydrometrocolpos and McKusickeKaufman syndrome who died on the day of birth. Spillage of genital tract secretions into the peritoneal cavity through the open ends of the Fallopian tubes was observed. A biopsy from a lesion on the serosa of the sigmoid colon demonstrated implantation of endometrial surface epithelium. In contrast to the pelvic findings, vaginal bleeding was not
I. Brosens et al. / Placenta 36 (2015) 341e344
observed at the time of bladder catheterization. This case-report also indicates that endometrial shedding can commence within hours of birth. 2.3. Endometrial stem/progenitor cells in refluxed endometrial shedding A difficult challenge is to isolate stem/progenitor cells presumably present in the retrograde menstrual effluent. Using a novel marker of human endometrial mesenchymal stem-like cells [17] Gargett et al. [18] recently reported significantly higher concentrations of W5C5þ endometrial MSCs in the peritoneal fluid of menstruating women with endometriosis compared to normal women. This preliminary report suggests that endometrial MSCs are preferentially shed by retrograde menstruation into the peritoneal cavity of women with endometriosis. While there is also evidence for retrograde shedding of endometrial epithelial progenitor cells, additional investigations are required to determine the significance of this finding. At any rate, these observations raise the possibility that endometrial stem/progenitor cells seeded during the neonatal period contribute to the pathogenesis of early onset endometriosis. However, this hypothesis also infers that endometrial stem/progenitor cells and their supporting niche cells must be able to survive in the pelvic cavity in the absence of steroid hormones for many years. Then, during telarche and subsequent menarche, ectopic endometrial MSCs are presumably activated in response to oestrogen actions on niche cells, leading to proliferation and formation of lesions characteristic of endometriosis [3]. 2.4. Preterm birth and the risk of endometriosis in the adolescent Another strand for further investigation is the relationship between the length of gestation and the subsequent risk of developing endometriosis. The epidemiological study of Wolff et al. [19] reported, for seemingly unknown reasons, that being born pretermly confers protection against endometriosis (Odds Ratio: 0.41; 95% Confidence Interval, 0.18e0.94). However, when placed in the context of the Novi Sad study [6], this epidemiological finding supports the notion that a lower incidence of neonatal uterine bleeding reduces the risk of endometriosis in adulthood. A study has started to trace and interview the women included in the original 1979 Novi Sad newborn study. While a major logistic challenge, it is hoped that the reproductive history of these women, now 35 years old, may reveal insights into the relationship between overt neonatal uterine bleeding and clinical or ultrasound evidence of pelvic endometriosis. Additional retrospective studies could be envisaged but, in the absence of a known cohort, these can only be based on the memory of mothers and thus subject to recollection bias. Clearly, time has come for maternity departments to systematically document the occurrence of uterine bleeding for future research.
343
incapable of establishing ectopic lesions due to their relative ageing compared to neonatal MSC. In this scenario, neonatal endometrial MSCs may be more potent than their adolescent and adult equivalents, in a manner similar to bone marrow MSC, which age dramatically after the neonatal period [22,23]. Studies examining molecular pathways involved in stem cell ageing in adult endometrial MSC populations may provide insight into the capabilities of adult endometrial MSC function. Even more powerful would be a comparison between neonatal and adult endometrial MSC, although the feasibility of obtaining neonatal endometrial MSC is very challenging. 3. Ontogenetic progesterone resistance and adverse pregnancy outcome 3.1. Uterine maturity and the risk of adverse pregnancy outcome The large majority of female babies do not experience overt neonatal bleeding and the first wave of endometrial regeneration will start after the onset of menarche. It has been argued that cyclic waves of endometrial regeneration may be needed to establish full responsiveness to ovarian hormones. Conversely, cyclic tissue destruction and menstrual bleeding may act as preconditioning events for pregnancy. The term “preconditioning” refers to the observation that a brief exposure to a harmful stimulus at a dose below the threshold for tissue injury provides robust protection, in any tissue, against the injurious effects of a subsequent more severe insult. In fact, the therapeutic potential of chemical or ischaemic preconditioning is intensively studied in a wide range of medical conditions, ranging from protection against perinatal brain injury to cardiac surgery [24,25]. The concepts of “ontogenetic progesterone resistance” and “menstrual preconditioning” infer that the human uterus starts out as an immature organ that acquires competence in response to dynamic remodelling events triggered by neonatal uterine bleeding, anovulatory bleeding, menstruation, miscarriage or parturition. In fact, the term “uterine plasticity” has been coined to describe the ability of this organ to constantly adapt throughout the reproductive years [26]. In case pregnancy occurs in the presence of residual uterine immaturity, placentation may well be affected. For example, a recent study provided evidence that the decidual response in the endometrium is spatially organized with differentiating perivascular cells establishing distinct cytokine and chemokine gradients that serve to direct trophoblast toward maternal vessels and govern local immune responses in pregnancy [27]. Thus, suboptimal responsiveness of perivascular niche cells to deciduogenic cues seems likely to lead to poor trophoblast invasion, inadequate remodelling of spiral arteries and defective deep placentation. This pathway may account for the findings from several large epidemiological studies showing that young maternal age confers an increased risk of adverse pregnancy outcomes, including preterm birth and small for gestation age, independently of possible confounding socio-demographic factors [28,29] (Table 2).
2.5. Perinatal origins of endometriosis 3.2. Research hurdles The interplay between perinatal versus postmenarcheal seeding of endometrial progenitor cells into the pelvic cavity should be considered. It is conceivable that postmenarcheal reactivation of dormant neonatal endometrial MSCs seeded in the pelvic cavity following overt neonatal menstruation initiates endometriosis [20]. Subsequent menstruations may seed additional adult endometrial MSCs into the pelvic cavity on a regular basis, contributing to the generation of more endometriosis lesions and rendering endometriosis a chronic disease [20,21]. An alternate hypothesis is that retrograde menstruation in postmenarcheal adolescents (and women) might contain endometrial stem/progenitor cells that are
Several obstacles make it difficult to establish an unequivocal link between uterine progesterone resistance or immaturity and subsequent adverse pregnancy outcome. Bar from the obvious logistic challenges, the precise relationship between stem cell populations, regenerative capacity and responsiveness of the endometrium to hormonal and placental cues has yet to be established. However, considerable progress is being made in identifying and analysing endometrial progenitor cells since their first successful isolation only 10 years ago [30]. Furthermore, stem cell deficiency or relative inactivity is predicted to lead to
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premature decidual senescence, which is increasingly recognized as a potentially important cause of preterm labour [31]. Regardless of the underlying mechanisms, defective placentation invariably involves inadequate transformation of the spiral arteries in the myometrial junctional zone [32,33]. Unfortunately, the technical challenge of obtaining targeted biopsies from the placental bed has prompted many to study the amorphous and less informative vascular channels in the basal plate of the placenta instead [34]. The use of the frontal and direct needle biopsy technique, as proposed by Cornelis et al. [35], may permit acquisition of full thickness placental bed tissue including inner myometrium, decidua, basal plate and placental villi. This tissue could be used for investigations aimed at defining deep placentation by molecular techniques, such as highthroughput immunohistochemistry or next-generation sequencing. From a full thickness biopsy, the decidua or the inner myometrium could be dissected out for functional analysis using in vitro models. This approach has been successfully employed to study the direct interactions between the invading trophoblast cells and microdissected spiral arteries [36]. Other useful models include in vitro explants of human spiral arteries from the decidua vera and cocultures of villous and decidual explants [37].
[8]
[9] [10]
[11]
[12]
[13] [14] [15] [16]
[17] [18]
4. Conclusions New research avenues have emerged from the hypothesis that major reproductive disorders in adolescents may have their roots in the progesterone effect on the endometrium at birth, which ranges from complete resistance to full responsiveness, the latter accounting for menstrual-like bleeding in the newborn. Sampson's theory [38] on menstrual reflux can be extended to include a role of neonatal uterine bleeding in early-onset endometriosis. On the other hand, residual progesterone resistance is associated with a blunted decidual response and may compromise deep placentation should pregnancy occur. While these hypotheses fit well with epidemiological findings, such as the decreased risk of endometriosis in women born preterm, but increased risk of pregnancy disorders in the adolescent primigravida, biological credence is as yet missing. For obvious reasons, this is a challenging area of research and animal models such as mice may not be informative. Nevertheless, we outlined avenues for investigations that are worthwhile pursuing as the dividend of this research could potentially be far-reaching; i.e. effective prevention and reduction in the burden of reproductive morbidity in young women. Conflicts of interest The authors report no conflict of interest, either direct or indirect.
[19]
[20] [21] [22] [23] [24]
[25]
[26] [27]
[28] [29]
[30] [31] [32]
References [1] Brosens I, Benagiano G. Is neonatal uterine bleeding involved in the pathogenesis of endometriosis as a source of stem cells? Fertil Steril 2013;100: 622e3. [2] Brosens I, Brosens J, Benagiano G. Neonatal uterine bleeding as antecedent of pelvic endometriosis. Hum Reprod 2013;28:2893e7. [3] Gargett CE, Schwab KE, Brosens JJ, Puttemans P, Benagiano G, Brosens I. Potential role of endometrial stem/progenitor cells in the pathogenesis of earlyonset endometriosis. Mol Hum Reprod 2014;20:591e8. [4] Brosens I, Benagiano G, Brosens JJ. Potential perinatal origin of major obstetric syndromes in the young primigravida. Am J Obstet Gynecol 01.2015. http:// dx.doi.org/10.1016/j.ajog.2015.01.013. W14-0962. [5] Ober WB, Bernstein J. Observations on the endometrium and ovary in the newborn. Pediatrics 1955;16:445e60. [6] Beri c BM, Prodanovi c Z, Mitrovi c M, Cur ci c O. Uterino krvavljenje u novoroCene dece [Uterine hemorrhage in newborn]. Jugosl ginekol perinatol 1985;25:89e91. nitale du nouveau[7] Levy JM, Rosenthal R, Dellenbach P, Pequenot JP. Crise ge . Re percussion de certains facteurs maternels ou gravidiques sur la ne
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quence des me trorragies ne onatales [Genital crisis in the newborn. reperfre cussion of certain maternal or pregnancy factors on the frequency of neonatal metrorrhagia]. Arch Fr Pediatr 1964;21:819e27. Kaiser R, Gr€ assel G. Frequenz und Starke der uterinen Neugeborenenblutung [Incidence and intensity of uterine bleeding in the neonate]. Geburtshilfe Frauenheilk 1974;34:644e8. Rosa P. Endocrinolgie sexuelle du foetus humain [Sexual endocrinology of the human fetus]. Paris: Masson & Cie; 1955. ^nderungen am fetalen und Huber A, Michael S, Feik K. Funktionelle Vera kindlichen endometrium [Functional changes in the fetal and infantile €k 1971;211:583e94. endometrium]. Arch Gyna Novak E, de Lima OA. A correlative study of adenomyosis and pelvic endometriosis, with special reference to the hormonal reaction of ectopic endometrium. Am J Obstet Gynecol 1948;56:634e44. Brosens JJ, Parker MG, McIndoe A, Pijnenborg R, Brosens IA. A role for menstruation in preconditioning the uterus for successful pregnancy. Am J Obstet Gynecol 2009;200:615.e1e6. Pokorny SF, Stormer J. Atraumatic removal of secretions from the pre-pubertal vagina. Am J Obstet Gynecol 1987;156:581e2. Terruhn V. A study of impression moulds of the genital tract of female fetuses. Arch Gynecol 1980;229:207e17. Fluhmann CF. The developmental anatomy of the cervix uteri. Obstet Gynecol 1960;15:62e9. Arcellana RC, Robinson TW, Tyson RW, Joyce MR. Neonatal fellowship. McKusick-Kaufman syndrome with legal complications of hydrometrocolpos and congenital endometriosis. J Perinatol 1997;17:220e3. Masuda H, Anwar S, Bühring HJ, Rao J, Gargett CE. A novel marker of human endometrial mesenchymal stem-like cells. Cell Transpl 2012;21:2201e14. Gargett CE, Masuda H, Schwab K, Tan C, Weston G. Retrograde menstruation of endometrial stem/progenitor cells in women with endometriosis 12th World Congress on Endometriosis, 30th Aprile3rd May 2014, M3-2. 22. Wolff EF, Sun L, Hediger ML, Sundaram R, Peterson CM, Chen Z, et al. In utero exposures and endometriosis: the endometriosis, natural history, disease, outcome (ENDO) study. Fertil Steril 2013;99:790e5. Marsh EE, Laufer MR. Endometriosis in premenarcheal girls who do not have an associated obstructive anomaly. Fertil Steril 2005;83:758e60. Gellersen B, Brosens JJ. Cyclic decidualization of the human endometrium in reproductive health and failure. Endocr Rev 2014;35:851e905. er20141045. Stolzing A, Scutt A. Age-related impairment of mesenchymal progenitor cell function. Aging Cell 2006;5:213e24. Oh J, Lee YD, Wagers AJ. Stem cell aging: mechanisms, regulators and therapeutic opportunities. Nat Med 2014;20:870e80. Healy DA, Clarke Moloney M, McHugh SM, Grace PA, Walsh SR. Remote ischaemic preconditioning as a method for perioperative cardioprotection: concepts, applications and future directions. Int J Surg 2014;12:1093e9. Sanders RD, Manning HJ, Robertson NJ, Ma D, Edwards AD, Hagberg H, et al. Preconditioning and postinsult therapies for perinatal hypoxic-ischemic injury at term. Anesthesiology 2010;113:233e49. Lucas ES, Salker MS, Brosens JJ. Uterine plasticity and reproductive fitness. Reprod Biomed Online 2013;27:506e14. Murakami K, Lee YH, Lucas ES, Chan YW, Durairaj RP, Takeda S, et al. Decidualization induces a secretome switch in perivascular niche cells of the human endometrium. Endocrinology 2014;155:4542e53. Fraser AM, Brockert JE, Ward RH. Association of young maternal age with adverse reproductive outcomes. N Engl J Med 1995;332:1113e7. Chen X-K, Wen SW, Fleming N, Demissie K, Rhoads GG, Walker M. Teenage pregnancy and adverse birth outcomes: a large population based retrospective cohort study. Int J Epidemiol 2007;36:368e73. Chan RW, Schwab KE, Gargett CE. Clonogenicity of human endometrial epithelial and stromal cells. Biol Reprod 2004;70:1738e50. Cha J, Hirota Y, Dey SK. Sensing senescence in preterm birth. Cell Cycle 2012;11:205e6. Brosens IA, Robertson WB, Dixon HG. The role of the spiral arteries in the pathogenesis of preeclampsia. Obstet Gynecol Annu 1972;1:177e91. Brosens I, Derwig I, Brosens J, Fusi L, Benagiano G, Pijnenborg R. The enigmatic uterine junctional zone: the missing link between reproductive disorders and major obstetrical disorders? Hum Reprod 2010;25:569e74. Langston C, Kaplan C, Macpherson T, Manci E, Peevy K, Clark B, et al. Practice guideline for examination of the placenta. Developed by the placental Pathology Practice guideline Development Task Force of the College of American Pathologists. Arch Pathol Lab Med 1997;121:449e76. Cornelis A, Verjans M, Van den Bosch T, Wouters K, Van Robaeys J, Janssens JP, Working Group on Hormone Dependent Cancers (European Cancer Prevention Organization). Efficacy and safety of direct and frontal macrobiopsies in breast cancer. Eur J Cancer Prev 2009;18:280e4. Cartwright JE, Kenny LC, Dash PR, Crocker IP, Aplin JD, Baker PN, et al. Trophoblast invasion of spiral arteries: a novel in vitro model. Placenta 2002;23:232e5. Dunk C, Petkovic L, Baczyk D, Rossant J, Winterhager E, Lye S. A novel in vitro model of trophoblast-mediated decidual blood vessel remodeling. Lab Invest 2003;83:1821e8. Sampson JA. Peritoneal endometriosis due to the menstrual dissemination of endometrial tissue into the peritoneal cavity. Am J Obstet Gynecol 1927;14: 422e69.
Contents lists available at ScienceDirect
Placenta journal homepage: www.elsevier.com/locate/placenta
Current opinion
The perinatal origins of major reproductive disorders in the adolescent: Research avenues I. Brosens a, *, A. Cur ci c b, T. Vejnovi c b, C.E. Gargett c, d, J.J. Brosens e, G. Benagiano f a
Leuven Institute for Fertility and Embryology, Tiensevest 168, B-3000 Leuven, Belgium Department of Gynecology and Obstetrics, Clinical Center of Vojvodina, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia c The Ritchie Centre, MIMR-PHI Institute of Medical Research, Clayton 3168, Australia d Department of Obstetrics and Gynecology, Monash University, Clayton 3168, Australia e The Division of Reproductive Health, Warwick Medical School, Coventry CV2 2DX, United Kingdom f Department of Gynecology, Obstetrics and Urology, Sapienza, University of Rome, Rome, Italy b
a r t i c l e i n f o
a b s t r a c t
Article history: Accepted 8 January 2015
The fetal endometrium becomes responsive to steroid hormones around the fourth month of pregnancy starting with an oestrogenic phase, which is followed late in pregnancy by a secretory phase. Based on post-mortem studies, the endometrium at birth is secretory in only one-third of neonates and proliferative in the remaining cases. Decidual or menstrual changes are rare in fetal endometrium despite high circulating steroid hormone levels, which drop rapidly after birth. Hence, acquisition of progesterone responsiveness appears to be dependent on endometrial maturation and relative immaturity may persist in a majority of girls until the menarche and early adolescence. Two major reproductive disorders have been linked with either advanced or delayed endometrial maturation. First, early-onset endometriosis may be caused by menstruation-like bleeding in the neonate, leading to tubal reflux and ectopic implantation of endometrial stem/progenitor cells. Second, persistence of partial progesterone resistance in adolescent girls may compromise deep placentation and account for the increased risk of major obstetrical syndromes, including preeclampsia, fetal growth retardation and preterm birth. The concept of neonatal origins of common reproductive disorders poses important research challenges but also subsumes potential new preventative strategies. © 2015 Elsevier Ltd. All rights reserved.
Keywords: Endometrium Neonatal uterine bleeding Progesterone resistance Endometriosis Obstetrical disorders
1. Introduction Recently, a dual hypothesis has been put forward on the role of the neonatal endometrium in the pathogenesis of reproductive disorders in adolescent women, more specifically early-onset endometriosis and the increased incidence of major obstetrical syndromes [1e4]. This hypothesis is based on two major studies: First, an autopsy study of 169 neonates published by Ober and Bernstein in 1955 [5], which describes in detail the histological appearance of endometrium and ovaries at birth. This study showed that in a majority of cases (58%), the endometrium exhibits only proliferative changes. Evidence of secretory changes in the glandular compartment was recorded in 27% of neonates but progesterone-dependent changes in the stromal compartment, such as decidualization or menstruation-like shedding, were rare
* Corresponding author. Tel.: þ32 16 270190; fax: þ32 16 270197. E-mail address: [email protected] (I. Brosens). http://dx.doi.org/10.1016/j.placenta.2015.01.003 0143-4004/© 2015 Elsevier Ltd. All rights reserved.
and found only in 5% of cases. The other remarkable study was performed at the University of Novi Sad, Serbia [6]. In this study, Beri c and colleagues examined all 2477 female babies born between 1st of January and 31st of December 1979 and documented evidence of neonatal uterine bleeding in 1 (0.8%) out of 126 preterm neonates, 85 (4.4%) out of 2241 term babies, and 10 (9.1%) out of 110 post-term infants (Table 1). The overall frequency of neonatal uterine bleeding was 3.87%. This incidence is very similar to that reported in two earlier clinical studies by Levy et al. [7] and Kaiser et al. [8]. Although the literature is scant, these carefully conducted observational studies suggest that the fetal endometrium is intrinsically progesterone resistant, but poised to transit soon after birth to a responsive state. In a small proportion of neonates, especially those born post-term, this transitional process is already under way, accounting for the increased incidence of menstruation-like neonatal uterine bleeding in response to the rapid fall in circulating placental progesterone levels after birth.
342
I. Brosens et al. / Placenta 36 (2015) 341e344
Table 1 Data suggesting neonatal origins of adolescent endometriosis.
Table 2 Data suggesting neonatal origins of obstetrical syndromes in adolescents.
Date
Finding
Authors [reference]
Date
Finding
Reference
1955
The endometrium is decidual or menstruallike in 5% of the newborns. Functional cervical obstruction in the neonate favouring tubal reflux at the time of menstrual. Functional cervical obstruction in the neonate favouring tubal reflux at the time of menstrual shedding explains 3 days delay of neonatal bleeding. Uterine bleeding occurs in 0.1% of preterm newborns. ENDO study finds that for unknown reason endometriosis is rare in preterm born women Case report describes neonatal endometriosis. Case reports of premenarcheal endometriosis
Ober and Bernstein [5] Fluhmann [15]
1955
The hormonal response of the fetal endometrium starts after the 4th gestational month with proliferation. At birth the endometrium remains progesterone resistant in 68%. Endometrium in preterm is more immature than in term or post-term neonates. Association of young maternal age and adverse reproductive outcome Decidualisation precedes trophoblast invasion and impaired decidualisation affects deep placentation. Teenage pregnancy and adverse birth outcomes By imposing the need for cyclic renewal of the endometrium, spontaneous decidualization followed by menstruation bestows unique functions on the human endometrium that are essential for reproductive success
Rosa [9]
1960
1960
1985 2013
1996 2005
1955 Fluhmann [15]
1985 1995
Beri c et al. [6]
2011
Wolff et al. [19] 2007 2013 Arcellana et al. [16] Marsh and Laufer [20]
Initial insight into hormonal influences on the fetal uterus was provided in 1955 by Rosa [9] who, in an autopsy study of 47 human fetuses and infants, found that proliferative changes in the fetal endometrium start around the 4th month of pregnancy. This is followed from the 8th month onwards by secretory changes in the glandular compartment. The author suggested that the progression from proliferative to secretory changes in the fetal uterus during pregnancy mimics changes seen in a normal menstrual cycle. Yet none of the fetal ovaries showed signs of ovulation. As the secretion of steroid hormones by the placenta was at that time incompletely understood, an explanation for the uterine progesterone response was elusive. A subsequent study on 82 uteri from fetuses, infants and children confirmed that peak endometrial secretory activity is reached at birth [10]. Both studies reported evidence of regression and even sloughing off of the surface epithelium in term neonates, but not menstrual-like breakdown of the stromal compartment with associated bleeding. Notably, proliferative endometrium can exhibit interstitial bleeding, as is the case in anovulatory cycles, but this is distinct from menstruation following spontaneous decidualization of the stroma. A possible explanation for the absence of menstrual changes is the relative small number of term or postterm neonates in both studies. We recently summarized the circumstantial evidence that points towards a causal link between neonatal uterine bleeding and early-onset endometriosis, mediated by retrograde pelvic seeding and subsequent dormancy of endometrial stem cells [3] (Table 1). It is interesting to note that in 1948, Novak and De Lima strongly argued that “in the vast majority of cases (of endometriosis) the ectopic endometrium is of immature type, responding to growth effect of estrogen, but not to the differentiating effect of progesterone” [11]. In other words, there are similarities in the responsiveness of ectopic endometrial lesions and the eutopic fetal endometrium. We have also highlighted how an immature adolescent uterus, i.e. not fully responsive to progesterone, could predispose for obstetrical complications associated with impaired deep placentation, such as preeclampsia, fetal growth restriction, and preterm labour (Table 2). This hypothesis complements and extends an earlier theory suggesting that cyclic spontaneous decidualization and menstruation emerged in evolution to precondition the uterus for the intense tissue remodelling and hyper inflammation associated with deep haemochorial placentation [12]. These new theories, interesting as they may be, cannot be endorsed without more substantial supportive evidence; and this will not be easily obtained.
Ober [5] Beri c [6] Fraser [28] Brosens [23]
Chen [29] Lucas [26]
Hence, our intention here is to outline and evaluate possible research avenues that may support or rule out a role for the neonatal endometrium in early-onset endometriosis and major obstetrical syndromes during adolescence. 2. Perinatal uterine bleeding and early-onset endometriosis 2.1. Cellular or acellular vaginal bleeding An important first step would be to collect samples from neonates with signs of vaginal bleeding. This is worthwhile as there is no information on cellular constituents of the vaginal effluent. Our hypothesis infers that neonatal uterine bleeding should lead to active shedding of viable endometrial cells, including mesenchymal stem cells (MSCs), which could be purified, propagated and characterized in culture. Vaginal aspiration should be feasible using the technique of “catheter within a catheter” developed for obtaining vaginal secretions in pre-pubertal girls [13]. At the same time, it remains questionable whether this approach will yield meaningful €ssel [8] published results: indeed, a clinical study by Kaiser and Gra 40 years ago showed that neonatal bleeding can occur several days after the drop in circulating placental hormones. One explanation for this delay may lie in the anatomy of the lower female reproductive tract in the fetus and neonate [14]. At birth, the cervical canal is twice as long as the uterine corpus and filled with thick mucus, thereby favouring reflux rather than cervical outflow of the menstrual shedding [15]. Thus, the onset of overt bleeding may be intrinsically unpredictable and even obscured. Furthermore, a filtration process through the long cervical canal may render neonatal uterine bleeding predominantly acellular and stained with haemoglobin by the lysis of red blood cells [8]. 2.2. Cellular components of the tubal reflux Another critical step would be to demonstrate tubal reflux and ‘seeding’ of endometrial cells in the peritoneum during the perinatal period. At present there is only one case report that supports this conjecture. Arcellana et al. [16] carried out an autopsy on a baby with hydrometrocolpos and McKusickeKaufman syndrome who died on the day of birth. Spillage of genital tract secretions into the peritoneal cavity through the open ends of the Fallopian tubes was observed. A biopsy from a lesion on the serosa of the sigmoid colon demonstrated implantation of endometrial surface epithelium. In contrast to the pelvic findings, vaginal bleeding was not
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observed at the time of bladder catheterization. This case-report also indicates that endometrial shedding can commence within hours of birth. 2.3. Endometrial stem/progenitor cells in refluxed endometrial shedding A difficult challenge is to isolate stem/progenitor cells presumably present in the retrograde menstrual effluent. Using a novel marker of human endometrial mesenchymal stem-like cells [17] Gargett et al. [18] recently reported significantly higher concentrations of W5C5þ endometrial MSCs in the peritoneal fluid of menstruating women with endometriosis compared to normal women. This preliminary report suggests that endometrial MSCs are preferentially shed by retrograde menstruation into the peritoneal cavity of women with endometriosis. While there is also evidence for retrograde shedding of endometrial epithelial progenitor cells, additional investigations are required to determine the significance of this finding. At any rate, these observations raise the possibility that endometrial stem/progenitor cells seeded during the neonatal period contribute to the pathogenesis of early onset endometriosis. However, this hypothesis also infers that endometrial stem/progenitor cells and their supporting niche cells must be able to survive in the pelvic cavity in the absence of steroid hormones for many years. Then, during telarche and subsequent menarche, ectopic endometrial MSCs are presumably activated in response to oestrogen actions on niche cells, leading to proliferation and formation of lesions characteristic of endometriosis [3]. 2.4. Preterm birth and the risk of endometriosis in the adolescent Another strand for further investigation is the relationship between the length of gestation and the subsequent risk of developing endometriosis. The epidemiological study of Wolff et al. [19] reported, for seemingly unknown reasons, that being born pretermly confers protection against endometriosis (Odds Ratio: 0.41; 95% Confidence Interval, 0.18e0.94). However, when placed in the context of the Novi Sad study [6], this epidemiological finding supports the notion that a lower incidence of neonatal uterine bleeding reduces the risk of endometriosis in adulthood. A study has started to trace and interview the women included in the original 1979 Novi Sad newborn study. While a major logistic challenge, it is hoped that the reproductive history of these women, now 35 years old, may reveal insights into the relationship between overt neonatal uterine bleeding and clinical or ultrasound evidence of pelvic endometriosis. Additional retrospective studies could be envisaged but, in the absence of a known cohort, these can only be based on the memory of mothers and thus subject to recollection bias. Clearly, time has come for maternity departments to systematically document the occurrence of uterine bleeding for future research.
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incapable of establishing ectopic lesions due to their relative ageing compared to neonatal MSC. In this scenario, neonatal endometrial MSCs may be more potent than their adolescent and adult equivalents, in a manner similar to bone marrow MSC, which age dramatically after the neonatal period [22,23]. Studies examining molecular pathways involved in stem cell ageing in adult endometrial MSC populations may provide insight into the capabilities of adult endometrial MSC function. Even more powerful would be a comparison between neonatal and adult endometrial MSC, although the feasibility of obtaining neonatal endometrial MSC is very challenging. 3. Ontogenetic progesterone resistance and adverse pregnancy outcome 3.1. Uterine maturity and the risk of adverse pregnancy outcome The large majority of female babies do not experience overt neonatal bleeding and the first wave of endometrial regeneration will start after the onset of menarche. It has been argued that cyclic waves of endometrial regeneration may be needed to establish full responsiveness to ovarian hormones. Conversely, cyclic tissue destruction and menstrual bleeding may act as preconditioning events for pregnancy. The term “preconditioning” refers to the observation that a brief exposure to a harmful stimulus at a dose below the threshold for tissue injury provides robust protection, in any tissue, against the injurious effects of a subsequent more severe insult. In fact, the therapeutic potential of chemical or ischaemic preconditioning is intensively studied in a wide range of medical conditions, ranging from protection against perinatal brain injury to cardiac surgery [24,25]. The concepts of “ontogenetic progesterone resistance” and “menstrual preconditioning” infer that the human uterus starts out as an immature organ that acquires competence in response to dynamic remodelling events triggered by neonatal uterine bleeding, anovulatory bleeding, menstruation, miscarriage or parturition. In fact, the term “uterine plasticity” has been coined to describe the ability of this organ to constantly adapt throughout the reproductive years [26]. In case pregnancy occurs in the presence of residual uterine immaturity, placentation may well be affected. For example, a recent study provided evidence that the decidual response in the endometrium is spatially organized with differentiating perivascular cells establishing distinct cytokine and chemokine gradients that serve to direct trophoblast toward maternal vessels and govern local immune responses in pregnancy [27]. Thus, suboptimal responsiveness of perivascular niche cells to deciduogenic cues seems likely to lead to poor trophoblast invasion, inadequate remodelling of spiral arteries and defective deep placentation. This pathway may account for the findings from several large epidemiological studies showing that young maternal age confers an increased risk of adverse pregnancy outcomes, including preterm birth and small for gestation age, independently of possible confounding socio-demographic factors [28,29] (Table 2).
2.5. Perinatal origins of endometriosis 3.2. Research hurdles The interplay between perinatal versus postmenarcheal seeding of endometrial progenitor cells into the pelvic cavity should be considered. It is conceivable that postmenarcheal reactivation of dormant neonatal endometrial MSCs seeded in the pelvic cavity following overt neonatal menstruation initiates endometriosis [20]. Subsequent menstruations may seed additional adult endometrial MSCs into the pelvic cavity on a regular basis, contributing to the generation of more endometriosis lesions and rendering endometriosis a chronic disease [20,21]. An alternate hypothesis is that retrograde menstruation in postmenarcheal adolescents (and women) might contain endometrial stem/progenitor cells that are
Several obstacles make it difficult to establish an unequivocal link between uterine progesterone resistance or immaturity and subsequent adverse pregnancy outcome. Bar from the obvious logistic challenges, the precise relationship between stem cell populations, regenerative capacity and responsiveness of the endometrium to hormonal and placental cues has yet to be established. However, considerable progress is being made in identifying and analysing endometrial progenitor cells since their first successful isolation only 10 years ago [30]. Furthermore, stem cell deficiency or relative inactivity is predicted to lead to
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premature decidual senescence, which is increasingly recognized as a potentially important cause of preterm labour [31]. Regardless of the underlying mechanisms, defective placentation invariably involves inadequate transformation of the spiral arteries in the myometrial junctional zone [32,33]. Unfortunately, the technical challenge of obtaining targeted biopsies from the placental bed has prompted many to study the amorphous and less informative vascular channels in the basal plate of the placenta instead [34]. The use of the frontal and direct needle biopsy technique, as proposed by Cornelis et al. [35], may permit acquisition of full thickness placental bed tissue including inner myometrium, decidua, basal plate and placental villi. This tissue could be used for investigations aimed at defining deep placentation by molecular techniques, such as highthroughput immunohistochemistry or next-generation sequencing. From a full thickness biopsy, the decidua or the inner myometrium could be dissected out for functional analysis using in vitro models. This approach has been successfully employed to study the direct interactions between the invading trophoblast cells and microdissected spiral arteries [36]. Other useful models include in vitro explants of human spiral arteries from the decidua vera and cocultures of villous and decidual explants [37].
[8]
[9] [10]
[11]
[12]
[13] [14] [15] [16]
[17] [18]
4. Conclusions New research avenues have emerged from the hypothesis that major reproductive disorders in adolescents may have their roots in the progesterone effect on the endometrium at birth, which ranges from complete resistance to full responsiveness, the latter accounting for menstrual-like bleeding in the newborn. Sampson's theory [38] on menstrual reflux can be extended to include a role of neonatal uterine bleeding in early-onset endometriosis. On the other hand, residual progesterone resistance is associated with a blunted decidual response and may compromise deep placentation should pregnancy occur. While these hypotheses fit well with epidemiological findings, such as the decreased risk of endometriosis in women born preterm, but increased risk of pregnancy disorders in the adolescent primigravida, biological credence is as yet missing. For obvious reasons, this is a challenging area of research and animal models such as mice may not be informative. Nevertheless, we outlined avenues for investigations that are worthwhile pursuing as the dividend of this research could potentially be far-reaching; i.e. effective prevention and reduction in the burden of reproductive morbidity in young women. Conflicts of interest The authors report no conflict of interest, either direct or indirect.
[19]
[20] [21] [22] [23] [24]
[25]
[26] [27]
[28] [29]
[30] [31] [32]
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