Acknowledgements
I would like to thank Wyndham Hackett Pain from Springer for asking me more than 4 years ago to revise this volume. I must confess that I did not respond to him initially but he gently persisted until I agreed. This volume would not have materialised had it not been for the amazing team of authors who have worked hard under very diffcult circumstances to write their chapters. A huge “thank-you” to all of you. I am delighted that we have managed to cover all the chapters in the previous edition and add several more chapters. I would like to give special thanks to David Chapel who was given limited time to deliver his chapter.
I would like to thank Angela Ralte who has provided me with missing illustrations for the Chap. 6
Huge thanks to the entire team at Springer in particular Naomi Portnoy, Melissa Morton and Nithya Sechin and latterly Anand Shanmugam who have worked really hard to bring the project to a conclusion.
Thank you to Naveena Singh for her positive feed-back regarding the second volume. Since writing this sentence in July 2023, I regret to acknowledge with huge sadness the passing of Dr naveena Singh 7th Dec1964- 5th Oct 2023. I know this series and the volume on the ovary was particularly dear to her heart. Her work on primary site assignment in ovarian tumours and its classifcation has had a huge positive impact on the staging of ovarian carcinoma and has led to far greater consistency in reporting site of origin of tumours. She contributed widely to all aspects of Gynaecological pathology and will be sorely missed. I am truly sorry that she did not get to see this book out in print.
It is with great sadness that I also acknowledge the contributions of two amazing authors, colleagues and friends who contributed to the previous volume but have since passed away. Dr. John Spencer (Leeds) and Dr. Judith Bulmer (Newcastle).
Finally, I would like to acknowledge the support and encouragement of my immediate family my husband Mark, son Christopher, my brother David and my sister-in-law Linda.
1 Anatomy, Development, Histology and Normal Function of the Ovary
Nicolas M. Orsi, N. Ellissa Baskind, and Michele Cummings
2 Nonneoplastic Disorders of the Ovary
Jaclyn C. Watkins and Robert H. Young
3 Ectopic Pregnancy: Diagnosis and Complications
Baljeet Kaur
4 Ovarian Cancer Screening in the General Population .
Aleksandra Gentry-Maharaj and Aarti Sharma
5 Overview of Ovarian Tumours: Pathogenesis and General Considerations 95 Katherine Vroobel
6 Integration of Imaging and Pathology in the Multidisciplinary Process
Sarah E. Swift, Michael J. Weston, Mahfooz Basha Mohamed, Andrew Scarsbrook, and Nafsa Wilkinson
7 An Approach to Ovarian Tumor Diagnosis .
Robert H. Young
8 Intraoperative Reporting in the Diagnosis of Ovarian Pathology 179
Paul A. Cross and Angela M. Ralte
9 The Role of Cytology in the Management of Ovarian Lesions
Sakinah A. Thiryayi, Nadira Narine, and Durgesh N. Rana
10 Surgical Management of Ovarian Cancer
Gemma L. Owens and Emma J. Crosbie
11 Gross Examination and Cut-Up of Surgical Specimens
Paul K. Wright, Rhona J. McVey, and Nafsa Wilkinson
13
14
Familial Ovarian Cancer Surveillance, Genetics, and Pathology 267
Malcolm Scott, Terri McVeigh, Rupali Arora, and Adam Rosenthal
The Molecular Classification of Ovarian Cancer and Implication for Treatment 285
Myriam Kossaï, Mathias Cavaille, and Frédérique
Penault-Llorca
An Overview of Immunohistochemistry of Ovarian Tumours to Include Both Epithelial and Non-epithelial Tumours 317
Mona El-Bahrawy
15 Advances in the Medical Management of Ovarian Cancer 345
Benjamin Pickwell-Smith, Mahaz Kayani, and Timothy Perren
16 Serous Tumours of the Ovary
Walia Saloni and Joseph Carlson
17 Mucinous Tumours of the Ovary .
Richard W. C. Wong, Philip P. C. Ip, and Annie N. Y. Cheung
18 Endometrioid Ovarian Tumours
Tiannan Wang, Lynn Hirschowitz, and Joseph W. Carlson
19 Clear Cell Carcinoma of the Ovary
David B. Chapel
397
417
439
457
20 Undifferentiated, Mixed and Other Tumours of the Ovary . . . . 479
David B. Chapel
21 Pathology of Malignancies Metastatic to the Ovary and of Synchronous Ovarian and Endometrial Carcinoma 515
Naveena Singh
22 Pathology of the Fallopian Tube 547
Richard W. C. Wong, Philip P. C. Ip, and Annie N. Y. Cheung
23 Pathology of the Peritoneum 575
Asma Zaman Faruqi
24 Dysgenetic Gonads 611
Melanie Joy Newbould
25 Germ Cell Tumors of the Ovary (and Maldeveloped Gonads)
Jaclyn C. Watkins and Robert H. Young
26 Sex Cord-Stromal Tumors
Ricardo R. Lastra and Raji Ganesan
625
655
27 Mesenchymal Tumors of the Ovary
Marisa Nucci and Nick Baniak
28 Lymphomas of the Ovary 717
Judith A. Ferry
29 Artificial Intelligence in Ovarian Digital Pathology 731
Katie E. Allen, Pratik Adusumilli, Jack Breen, Geoffrey Hall, and Nicolas M. Orsi
30 Staging of Ovarian, Fallopian tube and Primary Peritoneal Carcinoma .
Naveena Singh
1
1
ulating body growth, behaviour, appetite, immune function and the establishment of pregnancy. This range of functions is maintained by the dynamic role of the ovary in physiological homoeostasis, which, in turn, is governed by the structural arrangements and function of its follicles’ theca and granulosa cell compartments.
Ovarian Anatomy
Human ovaries are paired, fattened and ovoid bodies, which lie adjacent to the lateral pelvic wall just inferior to the pelvic inlet [1, 2]. These whitish structures are approximately 3–5 cm long, 2 cm wide and weigh 2–3.5 g. Based on age and ovarian cycle stage, they can have either a smooth or puckered/nodular, uneven surface. The ovaries feature both lateral and medial surfaces, superior (tubal) and inferior (uterine) poles, and anterior (mesovarian) and posterior (free) borders [3]. In nulliparous women, each is suspended in the ovarian fossae (a shallow depression on the lateral pelvic wall) by its own mesentery, the mesovarium, which runs bilaterally from the posterior aspect of the broad ligament of the uterus (posteriorly and inferiorly to the uterine (Fallopian) tubes to the lateral pelvic wall at the bifurcation point of the common iliac artery) [1–3]. In the erect posture, the long axes of the ovaries are vertical. This anatomical location is variable as the ovaries are frequently displaced outside the ovarian fossae during the frst pregnancy, a change believed to be permanent [3].
Ovaries are unusual in being the only pelvic structure that is extraperitoneal, as highlighted by the fact that their surface cuboidal/columnar germinal epithelium (of Waldeyer) is a modifed peritoneal covering continuous with the surrounding mesothelium of visceral peritoneum [1, 3]. The transition between the peritoneum’s squamous epithelium and that of the ovary is usually marked by a line around the anterior border of the gonad [3]. The germinal epithelium overlies a layer of connective tissue-based tunica albuginea
which, in turn, covers the cortical ovarian stroma and its resident follicles at various stages of development (Fig. 1.1). Surrounding these is a matrix containing various cell types, including fbroblasts, smooth muscle cells and vascular networks. By contrast, the medullary core is composed of irregular, dense connective tissue, which contains the gonad’s vascular, lymphatic and nerve supply and accounts for its original name of zona vasculosa of Waldeyer [1, 3]. This stroma also forms the hilar tissue, which provides the entry point for vessels and nerves as well as the ovary’s attachment [3].
The tubal pole lies near the external iliac vein, and over it are draped the fmbriae fringing the ostium of the Fallopian tube, whose role is to capture the oocyte at ovulation. This pole is also connected to the suspensory ligament, a fold of peritoneum directed upward over the iliac vessels, which runs to the lateral wall of the pelvis [1–3]. By contrast, the narrower uterine pole faces the pelvic foor and connects to the lateral angle of the uterus via the ligament of the ovary proper, which lies within the broad ligament. The position of the ovary within the pelvis varies considerably – testimony to this is the fact that it is frequently found prolapsed into the pouch of Douglas even in women with an otherwise normal anatomy [1].
The suspensory ligament of the ovary contains the gonad’s neurovascular and lymphatic supply [1, 2]. The principal arterial supply is via the ovarian artery, which traverses the mesovarium to enter the ovarian hilum. This vessel anastomoses extensively with the tubal branch of the uterine artery in the mesosalpinx, thereby also providing branches to the Fallopian tube. Venous drainage emerges from the hilum in the form of a pampiniform plexus akin to that of the testis. The ovarian vein is formed from this plexus within the broad ligament and leaves the pelvis following the course of its homonymous artery [3]. Although the right ovarian vein drains directly into the inferior vena cava, its left counterpart drains into it via the intermediary of the
Fig. 1.1 (a) Normal ovary from a non-pregnant, premenopausal woman (H&E, ×20). The ovary is encapsulated by a layer of fbrous connective tissue, the tunica albuginea (TA). The body of the ovary (ovarian stroma) consists of specialized spindle-shaped cells and a smaller amount of ordinary connective tissue. The core of the ovarian stroma (the medulla; M) contains the ovary’s main vessels, whereas the peripheral zone (the cortex; C) contains follicles (F) at various stages of development. Following ovulation, the ruptured follicle collapses to form the progesterone-secreting corpus luteum (CL). If fertilization or implantation does not occur, the CL degenerates to form the fbrous corpus albicans (CA). (b) Corpus luteum (×80). Granulosa (G) and theca (T) lutein layers form from the zona granulosa and the theca interna, respectively. Granulosa luteal cells are rich in lipid drop-
left renal vein. Lymphatic vessels meet their counterparts from the Fallopian tube and fundus to form the lumbar lymph plexus. The ovary also has sympathetic innervation, which runs alongside its vascular supply and connects to the pelvic plexus. A similar course is followed by parasympathetic fbres, which are derived from a pelvic splanchnic supply [2].
lets, which are used as substrates for steroidogenesis (progesterone biosynthesis principally). Theca luteal cells form a thin zone around the granulosa layer, into which they project. Theca luteal cells are smaller, stain more densely, have less vacuolated cytoplasm and are responsible for oestrogen biosynthesis. The CL is surrounded by a connective tissue zone (C), which arises from the theca externa. (c) Corpus albicans (×80). The corpus albicans is a steroidogenically inactive fbrous tissue mass resulting from the involution of the CL in the absence of pregnancy, whose secreting cells have been scavenged by macrophages and whose supporting vascular tissue has regressed and merged with that of the surrounding ovarian stroma. Corpora albicantes are abundant in the human ovary and their number increases with age
Embryological Origins of the Ovary
Ovarian development starts early during postimplantation development with the appearance of primordial germ cells (PGCs) during gastrulation. These are frst identifable in the posterior rim of the embryonic disk and, subsequently, in the intermediate mesoderm, visceral mesoderm,
yolk sac and allantois [4]. During the ffth week of development, PGCs start their migration from the yolk sac using amoeboid movement and travel caudally via the dorsal mesentery to populate the mesenchymal urogenital ridge of the posterior body wall near the 10th thoracic level, medial and ventral to the developing mesonephric kidney. Their arrival stimulates the surrounding coelomic epithelium and mesoderm to proliferate and thicken to form the genital ridges [4, 5]. These are the site of origin of the primary sex cords (composed of germinal epithelium growing into the underlying mesoderm), which develop into the weakly formed rete ovarii, which is succeeded by the secondary sex cords awaiting PGC colonization. During the sixth week of development, coelomic epithelial cells generate aggregates of somatic supporting cells, which progressively envelop the PGCs. In parallel, the paired Müllerian (paramesonephric) ducts form laterally to their mesonephric counterparts by the craniocaudal invagination of a ribbon of thickened coelomic epithelium to reach the posterior wall of the urogenital sinus caudally. These are completed by the end of the sixth week, at which stage both male and female presumptive gonads remain indistinguishable from each other. Initially, both the genital ridge and mesonephros share a common mesentery, but as development progresses, the former largely severs its contact, remaining connected by a peritoneal fold, the mesovarium [4].
Sexual differentiation becomes evident from the seventh week when the absence of the Y chromosome’s SRY gene expression enables the basic female developmental pathway to culminate in ovarian development [6]. While the PGCs will ultimately give rise to oogonia, somatic complement cells delaminating from the coelomic epithelium give rise to follicle pre-granulosa (GCs) and theca cells (TCs) (these two cell types are counterparts of the male Sertoli and Leydig cells, respectively). The allied defcient anti-Müllerian hormone and testosterone production allow the Müllerian ducts to persist (ultimately giving rise to the Fallopian tubes, uterus and upper vagina) while the male-pattern pathway mesonephric (Wolffan) ducts degenerate [4]. Throughout the
fourth month, the histoarchitecture of the gonadal cords is progressively disrupted. The mitotic division of germ cell nuclei with incomplete cytokinesis forms multinucleated syncytia known as germ cell nests. Through a combination of germ cell apoptosis and somatic cell migration, germ cell nuclei are packaged with their pregranulosa complement to form the initial primordial follicle pool [5]. The proliferation of these oogonia is tightly regulated by transforming growth factor (TGF)-β family mitogens, including activin, bone morphogenic proteins (BMPs) and TGF-β1, before these eventually enter their frst meiotic division to give rise to primary oocytes [7, 8]. This triggers adjacent gonadal cord cell-derived somatic support cells to differentiate into granulosa cells (GCs): as these form fattened monolayers surrounding individual oocytes, they form the frst primordial follicles, which, by the ffth month, are clearly visible in the cortical/perimedullary zone [8]. By contrast, the ovarian medulla becomes the focus of neoangiogenic, neural and supportive connective tissue development [4].
The development of oocytes that have completed the prophase of meiosis I (together with their follicle complement) then arrests until resumption is triggered by pubertal cyclical changes in pituitary gonadotropins. These primordial follicles constitute the entire female ovarian reserve, although recent fndings regarding the isolation of ovarian oogonial stem cells from women of reproductive age undermine this long-established notion [9]. Estimates of primordial follicle numbers vary, but attrition attributable to massive germ cell loss reduces oocyte numbers from circa six million in the foetal human ovary to 300,000–two million at birth [5, 10]. Of these, only around 40,000 will remain by the onset of puberty, of which 300–450 will mature throughout reproductive life, with the majority of later losses occurring through atresia [11, 12].
It is noteworthy that ovarian development starts in the posterior abdominal wall such that the ovaries have to descend into the pelvis in the late second to early third month [4, 13]. The ovaries are drawn down by their respective guber-
N.
nacula, bands of fbrous tissue derived from gonad-bound undifferentiated mesenchyme. Each of these runs from the inferior border of its developing ovary to the labioscrotal swellings [2, 13]. Unlike the descent of the testes, this process does not involve gubernacular shortening in females, such that the gubernacula develop in line with the rest of the body. As the gubernacula contact the uterine fundus at its junction with the Fallopian tube (as the developing Müllerian ducts) in the seventh week; however, this arrests the ovaries’ progress. Thus, they remain trapped in its peritoneal folds, while cranially, in the absence of androgens, the persistence of the cranial suspensory ligaments maintains the ovaries’ anchorage to the abdominal wall [4]. The gubernacular remnants between the ovaries and the uterus ultimately develop into the ovarian ligaments proper bilaterally. Analogously, the remnants between the uterus and the fascia of the labia majora form the round ligaments of the uterus. Each of the latter is accompanied anteriorly within the recently formed inguinal canal by a peritoneal pouch (the canal of Nuck), which later obliterates and completes the developmental sequence [2, 4].
Physiological Function of the Ovary
The ovary has a dual function in the endocrine regulation of reproductive function and the production of gametes, both of which are interdepen-
Fig. 1.2 The dynamics of GnRH (upper panel), gonadotropin (middle panel) and hormone (lower panel) profles throughout the human menstrual cycle. Key: E2 oestrogen and P progesterone. (Reprinted from Marshall and Eagleson [325], with permission from Elsevier)
dent. The modus operandi of the ovary is thus best understood in terms of cyclicity and by appreciating the details of follicular development.
Endocrine Function
Hypothalamic–Pituitary–Ovarian Control of the Ovarian
Cycle
Women’s reproductive lives are, without the intervention of hormonal contraception, characterized by a succession of menstrual cycles interspersed with pregnancies and lactation. The timing of each menstrual cycle (i.e. the interval between successive menses) is governed by the interlude between successive ovulations (each of which occurs approximately 14 days prior to the onset of menses) (Fig. 1.2). In humans, the ovarian cycle lasts 24–32 days and is traditionally divided into two phases characterized by follicular growth (the follicular phase) and that following ovulation (the luteal phase), wherein the latter is the more constant of the two. The control of both peptide and steroid hormones that regulate these functions depends on a complex and dynamic feedback system involving the hypothalamus with its production of gonadotropinreleasing hormone (GnRH), the anterior pituitary with its secretion of glycoprotein gonadotropins (follicle stimulating hormone, FSH and luteinizing hormone, LH) and the ovary itself with its production of steroid (e.g. androgens, oestrogen and progesterone) and peptide hormones (e.g.
inhibin)1. An assemblage of hypothalamic neurons makes up the GnRH pulse generator, which collectively coordinates the pulsatile secretion of GnRH into the hypophyseal portal system to reach its target pituitary gonadotropes. In response to stimulation, these produce both FSH and LH, although the frequency of GnRH pulsatility determines, which is preferentially produced: slower pulses favour FSH while rapid pulses favour LH, accounting for their differential predominance in the early and late follicular phase, respectively [16–18]. Gonadotropins act on ovarian follicles to promote oestrogen (FSH), progesterone and androgen (LH) biosynthesis, which can then feed back to the pituitary to regulate both GnRH pulsatility and gonadotropin production. Progesterone slows GnRH pulse frequency and therefore LH secretion, while oestradiol plays a permissive role in this regard, putatively through the upregulation of hypothalamic progesterone receptors [19–21]. In the absence of steroid feedback, such as after menopause or in premature ovarian failure, the GnRH pulse generator frequency returns to its baseline intrinsic fring frequency of circa one pulse per hour [22, 23].
The GnRH pulse generator is functional during intrauterine life but becomes relatively quiescent within 6–9 months of birth and maintains this hiatus until the prepubertal period. Childhood thus features a slow GnRH pulsatility, which is refected by low gonadotropin levels with a preponderance of FSH over LH [24, 25]. As this period draws to a close, nocturnal/sleep-related LH secretion becomes more prominent (i.e. as increased pulse amplitude/frequency), followed by an early diurnal production of oestrogen and testosterone [26–29]. This circadian pattern is progressively lost by late puberty, putatively through physiological changes relieving inhibi-
1 Note: GC-derived inhibins sensitize TCs to LH, enhancing androgen production/estrogen synthesis. Other protein systems are involved: activin orchestrates FSH/LH receptor levels, oestrogen synthesis and oocyte maturation; follistatin inhibits activin-induced responses – the discussion of the fner points of their actions falls out with the scope of this more generic chapter and the reader is referred to references [14, 15] for a more detailed account.
tion by higher central nervous system pathways on GnRH pulse frequency and/or a gradual, androgen-driven loss of sensitivity to oestrogenic feedback inhibition of LH secretion [30, 31].
The Follicular Phase
The follicular phase is dominated by growing follicle-derived oestrogen and lasts approximately 10–14 days. Synthesis and secretion of gonadotropins from the anterior pituitary are regulated by pulsatile (~1/h) hypothalamic GnRH release. GnRH is self-priming such that the secretory response to a second pulse of GnRH is larger than the frst [32]. In turn, FSH and LH secretion is modulated by both the amplitude and frequency of GnRH pulses. Through negative feedback, oestradiol normally suppresses FSH and LH secretion both directly, by acting on the hypothalamus and, indirectly, by altering the number of pituitary GnRH receptors [33].
At the time of menses, circulatory levels of oestrogen and progesterone are relatively low such that negative feedback is relaxed. This causes a rise in FSH and LH levels, which supports follicular development and growth that results in an increased production of oestrogens and inhibin. If oestradiol levels increase markedly (e.g. 200–400% more than in the early follicular phase) and remain high for ~48 h, then FSH and LH secretion is enhanced rather than being suppressed (i.e. generating a positive feedback loop) [34]. Thus, in the latter part of the follicular phase, the surge in oestradiol levels initiates positive feedback on the hypothalamus and pituitary and thus results in a rapid increase in gonadotropin levels. The theca interna solely expresses LH receptors; in response to LH, these cells convert cholesterol to androgens [35]. These steroids diffuse to the GCs below where they play a dual role: while they are substrates for aromatase, they also increase the activity of this enzyme, thereby increasing oestrogen production [36, 37]. Oestrogen production occurs in response to FSH, whose receptors are expressed by this cell type. In addition, oestrogen acts in a paracrine manner on GCs, stimulating both their proliferation and oestrogen biosynthesis, thereby establishing local positive feedback [38, 39].
A rise in both FSH and LH is a harbinger of the onset of the preovulatory phase, which is matched by a transient rise in androgens and oestrogens [40]. In particular, the LH surge induces terminal growth and maturation of both the dominant follicle, whose follicular fuid (FF) volume rapidly increases, and its oocyte, which resumes meiosis. The combination of oestrogen and FSH promotes LH receptor expression on GCs, which forfeit oestrogen production in favour of the LH-stimulated progesterone synthesis, which characterizes the luteal phase.
The Luteal Phase
The luteal phase that follows ovulation is characterized by a corpus luteum-derived progestogen dominance and lasts circa 12–15 days. Although signifcant quantities of ovarian oestrogens and androgens are still produced, high progesterone levels enhance the negative feedback effects of oestrogens on both the hypothalamus and pituitary such that FSH and LH production is dramatically reduced. Progesterone has a range of systemic effects such as immunomodulation and appetite/behavioural changes, although it is mostly recognized for its induction of endometrial gland secretion to favour blastocyst implantation in the oestrogen-primed uterus [41]. At the end of the luteal phase, if the corpus luteum regresses in the absence of an embryo, the accompanying decline in oestrogens and progesterone relieves feedback inhibition and enables FSH and LH levels to rise once again. In parallel, the withdrawal of ovarian steroid support triggers the onset of menses, and the endometrial lining is shed in preparation for a renewed oestrogendependent growth during the subsequent follicular phase [42].
Folliculogenesis and Ovarian Histology
Over the last two decades, the ovary has increasingly been appreciated to be a functional unit governed by the active and highly complex dialogue between oocytes, GCs, TCs, stromal cells and infltrating immune effector cells, both within and across follicles [43–45]. This hormonesensitive cross talk whose mediators are still being identifed is essential to support all stages
of oogenesis, folliculogenesis and ovulation [46–50].
Folliculogenesis occurs in the ovarian cortex and begins with the recruitment of a primordial follicle into the pool of growing follicles and ends with either ovulation or death by atresia. The entire process can take up to a year for women. Folliculogenesis is divided into two phases. The frst phase, termed the pre-antral or gonadotropin-independent phase, is characterized by the growth and differentiation of the oocyte and is principally controlled by locally produced growth factors through autocrine/paracrine mechanisms. This phase covers the transition of the primordial follicle to the primary pre-antral follicle. By contrast, although the second phase also features (continued) follicular growth, this occurs in response to pituitary gonadotropins (Fig. 1.3).
The Primordial Follicle
The oocyte in the primordial follicle measures 25 μm in diameter and is arrested in the dictyate stage of meiosis. It is surrounded by simple squamous epithelium composed of a single layer of fattened GCs and a basal lamina, which enables the oocyte and GCs to coexist within a microenvironment isolated from direct contact with other cells. Paracrine signalling and nutrition occur by diffusion since primordial follicles lack their own vascular supply and thus have limited access to endocrine support [51]. Follicular recruitment is marked by a change in GC morphology from squamous to cuboidal together with increased mitotic activity and oocyte growth. Follicular recruitment starts during foetal life and continues at a relatively constant rate during the frst three decades of life, with 20 or so primordial follicles being recruited during each ovarian cycle. This process is accompanied by the atresia of nongrowing follicles, which accelerates over time, resulting in an overall decrease in ovarian reserve and reduced fecundity by age 30 years and a more marked decrease by age 35 years [52].
Animal work suggests that the PI3K/Akt pathway participates in primordial follicle activation. In these models, phosphatase and tensin homolog (PTEN) normally suppresses the PI3k/Akt path-
Fig. 1.3 Schematic representation of the development of the primordial follicle to the pre-ovulatory Graafan follicle. Key: BL basement lamina, O oocyte, GC granulosa
way and maintains primordial follicle dormancy. However, removal of the inhibitory effect of PTEN (with consequent PI3K/Akt pathway activation) results in oocyte transcription factor fork head box O3 (FOXO3) phosphorylation, nuclear export and degradation, making this a potential switch for primordial follicle activation. Other transcription factors have also been implicated in this process, including the GC-specifc fork head box L2 (FOXL2), a GC-specifc transcription
cell, ZP zona pellucida, TC theca cell, FF follicular fuid, BV blood vessel/capillary and CT connective tissue (loose)
factor, which appears to be necessary for follicular development to the primary stage. Various intrafollicular cytokines also participate in regulating primordial follicle activation and transition to the primary follicle stage, including leukaemia inhibitory factor, basic fbroblast growth factor (bFGF), stem cell factor, stromal derived factor1, platelet-derived growth factor and BMP-4 [53–57] (Fig. 1.4). This growth factor network is supported by surrounding stromal cell-derived
N. M. Orsi
Fig. 1.4 Schematic representation of the predominant regulatory factors governing primordial follicle transition to the primary follicle in the ovary. The combined actions of primordial follicles themselves, surrounding stromal cells, follicles and endocrine factors are responsible for primordial follicle activation. The primordial follicle oocytes express PTEN and SDF-1, which inhibit their own activation, and secrete PDGF and b-FGF, which stimulate pre-granulosa cells to generate KL (SCF). KL then promotes oocyte growth and follicle activation, as well as stromal cell recruitment. Follicle activation is further stimulated by KGF, BMP-4 and BMP-7 secreted by adjacent stromal cells. Neighbouring follicles secrete AMH and SDF-1, which negatively regulate primordial follicle activation. Circulatory insulin contributes further to follicle activation. Once primary follicle status has been attained, the GCs continue to express KL, while the
mediators, such as keratinocyte growth factor, BMP-4 and BMP-7 [56, 58]. In addition, GC-derived anti-Müllerian hormone mediated dialogue also occurs in order to inhibit adjacent follicle activation [59–61].
The Primary Follicle
The primary follicle initially features a single layer of cuboidal GCs surrounding the oocyte, which proliferate rapidly to give rise to the stratifed zona granulosa (Fig. 1.5). This stage of development is characterized by an upregulation of FSH receptor expression and increased oocyte
oocytes secrete GDF-9 and BMP-15, which promote GC proliferation, KL secretion and theca formation to support the formation of the secondary follicle (whose structure has been simplifed for illustrative purposes). LIF, expressed by the GCs of the primordial and primary follicle, interacts with KL to promote primordial follicle transition and subsequent development of the primary. Progesterone inhibits follicle assembly, while TNF-α promotes apoptosis, which is key to follicle assembly. Key: TNF-α tumour necrosis factor, P progesterone, SDF-1 stromal derived factor-1, b-FGF basic fbroblast growth factor, KL kit ligand (stem cell factor (SCF)), LIF leukaemia inhibitory factor, KGF keratinocyte growth factor, BMPs bone morphogenic proteins, AMH anti-Müllerian hormone, PDGF platelet derived growth factor, PTEN phosphatase and tensin homologue, GDF-9 growth differentiation factor-9, GC granulosa cell and TC theca cell
growth [62]. Following genomic reactivation, the oocyte increases in size considerably and acquires the zona pellucida, a glycoprotein shell from which the blastocyst will ultimately hatch prior to implantation [57]. The oocyte nevertheless retains functional contact with its surrounding GCs through the development of intimate intercellular connections [47, 63]. Cytoplasmic projections and microvilli grow from both the oocyte and the GCs and interdigitate to create a large surface area for diffusion [64]. Gap junctions established in these areas of cell–cell contact facilitate the diffusion of ions, metabolites and
Fig. 1.5 (a) Primordial follicles in the ovarian cortex (×200), consisting of a single layer of fattened follicular cells surrounding an oocyte (O) (TA tunica albuginea). (b)
Primary follicle (×200): the oocyte (O) has greatly enlarged and a glycoprotein layer, the zona pellucida (ZP), develops between the oocyte and the surrounding follicular cells, which have now become cuboidal and proliferated to form a layer several cells thick (the zona granulosa, ZG). The connective tissue surrounding the follicle has begun to organize into a structure known as the theca folliculi (TF). (c) Late secondary/early tertiary (antral) follicle (×150). The follicle has continued to enlarge, and a fuid flled follicular antrum (FA) has almost entirely formed from the coalescence of individual vacuoles, such that the oocyte (O) is now positioned eccentrically. The granulosa layer sur-
rounding the oocyte is known as the cumulus oophorus (CO), and its cells have become more loosely attached to the mural zona granulosa cells (ZG). The TF has differentiated to form two layers, the theca interna (TI), a site of steroidogenesis, and the theca externa (TE), a layer of smooth muscle cells. (d) Mature (Graafan) follicle (×80); oocyte missing in this section. The cumulus oophorus (CO) layer can be distinguished from the mural zona granulosa (ZG), as a thicker layer with more loosely attached cells. (e) Late atretic follicle. The oocyte and granulosa cells have degenerated, and the basement membrane separating the granulosa (G) and theca interna (TI) layers has thickened to form the glassy membrane (GM). This follicle likely reached the antral stage of development without becoming a mature (Graafan) follicle
Fig. 1.6 Angiogenic growth factors acting at different stages in folliculogenesis. Key: b-FGF basic-fbroblast growth factor, VEGF vascular endothelial growth factor, ANG-2 angiopoietin-2 and IGF-1 insulin like growth factor-1 signalling molecules [65]. The stroma surrounding late primary follicles begins to organize into the theca folliculi, which is separated from the zona granulosa by a basement membrane. Subsequent development of primary follicles to fully grown secondary follicles results from an active autocrine/paracrine regulatory process dependent on oocyte-derived cytokines. Ovine and murine animal models suggest that growth differentiation factor (GDF)-9 and BMP-15 are crucial in this step; in the absence of these mediators, follicle growth and development arrest at the primary follicle stage [66].
The Secondary Follicle
Secondary follicles are typically located deeper in the ovarian cortex. As the follicular developmental continuum progresses, active GC proliferation results in the formation of a stratifed or pseudostratifed columnar epithelium surrounding the oocyte, which has by now almost reached its full size (120 μm). Within this, small fuidflled vacuoles appear, gradually causing the oocyte and its surrounding GCs to become eccen-
trically positioned. These eventually coalesce by the tertiary follicle stage. The surrounding TC layer – recruited from cortical stromal cells in bovine models—progressively differentiates into two primary layers: an inner theca interna comprising rounded interstitial cells and an outer theca externa that differentiates into spindleshaped smooth muscle cells [67].
Theca development is accompanied by neoangiogenesis, which promotes the development of a perifollicular vascular network within the layer that rapidly expands as the follicle increases in size (Fig. 1.6). Inter alia, this also sensitizes follicles to gonadotropins. In swine, this process has been noted to commence as the follicle diameter reaches 110 μm [68]. While angiogenesis is promoted by agents such as bFGF and vascular endothelial growth factor (VEGF) [69, 70, 71], overall vascular development is the product between the balance of these agents with inhibitory factors, including thrombospondin, angiostatin, endostatin, interleukin (IL)-8, 2-metoxiestradiol, hyaluronic acid, platelet factor-4, tumour necrosis factor
Fig. 1.7 Light sheet microscopy visualization and image reconstruction of murine perifollicular vascular networks (green, reconstructed in blue for a single follicle) surrounding the oocyte (zona pellucida, red, and reconstructed in yellow for a single follicle), highlighting their density and distribution. (Mappa, Cummings & Orsi, unpublished)
(TNF)-α, interferon (IFN)-α and IFN-γ [72–76].
Regardless, the follicular vascular networks that are established can be quite considerable (Fig. 1.7). Importantly, it is worth noting that angiogenesis is regulated independently across different follicles [77].
Follicular growth switches to become FSH dependent during the preantral to antral transition, a phenomenon essential for avoiding an atretic fate. The process is orchestrated by an array of mediators responsible for inducing the expression of GC FSH receptors (androgens, the IGF system) and F aromatase (IGF1), pituitary FSH production (activin) and follicular growth during the preantral to antral follicle transition. The oocyte also contributes to the process through the production of GDF-9 and BMP-15, wherein the former promotes TC androgen production which, in turn, induces FSH receptor expression, GC proliferation and FSHdependent growth.
Although the oocyte completes its growth during pre-antral folliculogenesis, it does not normally resume meiosis. This meiotic arrest is believed to be under the inhibitory control of cyclic AMP (cAMP) and/or cyclic GMP [78, 79]. In total, the development of a primordial follicle to a fully grown secondary follicle takes about 290 days.
The Antral Follicle
As outlined, the second, antral (Graafan) or gonadotropin-dependent phase of folliculogenesis is characterized not only by the further follicular growth regulated by FSH but also by LH and an extensive array of growth factors. Specifcally, LH receptors are expressed in theca and mural GCs only (induced by FSH, oestradiol and IGF1) as opposed to cumulus cells and oocytes (suppressed by oocyte-derived factors, including GDF-9).
A further 60 days are required for the Graafan follicle to develop. The most salient feature of these tertiary follicles is their evident cavity (antrum), which contains FF, a plasma transudate conditioned by secretory products from the oocyte, GCs and infltrating immune effector cells [80]. Although FF protein concentration is generally lower than that in the circulation (since the follicular wall acts as a coarse molecular sieve excluding proteins >850 kDa), amino acid concentrations are higher [81, 82]. The levels of various energy substrates and metabolites also differ markedly. Indeed, the energy metabolism of follicles is largely glycolytic, putatively in order to avoid oxygen being exhausted in the outer follicle layers in favour of supporting oocyte metabolism, which relies heavily on the oxidative phosphorylation of pyruvate [83, 84]. Together with the absence of a vascular supply in the zona granulosa, this explains the comparatively high lactate concentrations found in FF, which are also believed to inhibit meiotic resumption through a decrease in pH [85–87].
Antral follicles are heterogeneous in size, measuring 0.4–25 mm in diameter, as their overall size is largely determined by the size of the antrum which is, in turn, dictated by FF volume (0.02–7.0 mL) [88]. The relative abundance of antral follicles and their sizes vary as a function of age and menstrual cycle phase. Antral follicle counts can be determined by ultrasound and are used clinically in the early follicular phase as a marker of ovarian reserve [89]. In general terms, it is accepted that in natural cycles, the size of the Graafan follicle is directly correlated with oocyte maturity [90]. Bordering the antrum are distinct GC subtypes that exhibit individualized responses
N.
to FSH stimulation: the membrane, periantral area and cumulus oophorus. Their subtype appears to depend on the relative GC proximity to the oocyte and exposure to oocyte-derived GDF-9 and BMP-15 [44, 57, 88]. While GCs and TCs proliferate extensively in the dominant follicle concurrently with antrum growth, FF formation and somatic cell mitosis cease in atretic follicles, thereby limiting their size [57].
By now, the theca is fully differentiated. The theca externa smooth muscle cells are concentrically arranged and autonomically innervated; their precise role remains unclear although it has been suggested that they may play a role in subsequent ovulation. By contrast, the theca interna is dominated characteristically by large epithelioid cells whose cytoplasm is flled with lipid droplets, smooth endoplasmic reticulum and mitochondria with tubular cristae – the hallmark appearance of steroid-producing cells [67]. This refects their role, from the time of antrum formation, in the production of high concentrations of androgens (e.g. androstenedione in response to LH and insulin stimulation), oestrogen, and, in the preovulatory stage, progesterone, in addition to the FSH inhibitor inhibin F at the time of ovulation. The steroid hormones are responsible for promoting endometrial proliferation and secretion in preparation for subsequent blastocyst implantation. The theca thus becomes richly vascularized, with two independent capillary networks forming in the theca interna and externa, which collectively form the thecal vascular sheath [57, 91, 92]. The gradual increase in angiogenesis in the developing follicle peaks in the late pre-antral/antral stage, supported by continued endothelial cell proliferation [93]. The growth and development of the theca vascular network are understood to be regulated through the coordinated expression of pro- and antiangiogenic factors and their receptors [77, 94].
Interestingly, GCs predominantly synthesize these agents despite angiogenesis being confned to the thecal layer [77]. As outlined, GCs are separated from the theca by a basement membrane such that the metabolic requirements of GCs and oocytes must be met by either diffusion or active transport. The increase in vascularization, which
accompanies follicular growth, is believed to be driven by hypoxia (and the associated increase in transcriptional complex hypoxia inducible factor (HIF)-1α activity) and prevents GC and oocyte compromise [95, 96]. Moreover, VEGF secreted by TCs increases vascular permeability and contributes both to the accumulation of antral fuid in the growing follicle and the delivery of the lipid precursors required for steroid biosynthesis [97–100].
As oocytes near the end of their growth phase, they acquire competence to undergo two aspects of maturation: cytoplasmic and nuclear. The former encompasses the processes that prepare the germinal vesicle-stage oocyte for activation and preimplantation development, viz., the accumulation of mRNA, proteins, substrates and nutrients, which provide the oocyte with the capacity to complete nuclear maturation [101–103]. By contrast, the latter refers to the reversal of meiotic arrest and progress to metaphase II [104, 105].
Nuclear and cytoplasmic maturation is coordinated by the mixing of germinal vesicle contents with the cytoplasm during germinal vesicle (GV) breakdown as the oocyte is prepared for fertilization and activation [106]. While somatic cells in the follicle can provide developmental cues that regulate oocyte maturation and prevent parthenogenetic activation, data from animal models also suggest that oocytes can also regulate GC cell proliferation and progesterone production while enabling the cumulus oophorus to synthesize hyaluronic acid and undergo expansion in response to FSH stimulation [107–112].
The preovulatory LH surge allows the resumption of meiotic division and the progression of the oocyte from the dictyate stage to the metaphase of the second meiotic division, resulting in the extrusion of the frst polar body. This contains very little cytoplasm and remains within the confnes of the zona pellucida alongside the secondary oocyte. This response to LH in particular appears to relieve the inhibition exerted on the oocyte until then by follicular oocyte maturation inhibitor [113]. The cumulus oophorus regresses before ovulation, leaving the oocyte surrounded by a layer several cells thick, termed the corona radiata. Prior to ovulation, the remain-
ing attachment of the cumulus-oocyte complex connection to the now markedly thinned zona granulosa breaks down altogether. By this stage, the follicle bulges under the ovarian surface. The overlying surface epithelium cells become fattened and atrophic, and the thin intervening stroma becomes degenerate and avascular.
Follicle Selection and Atresia
In cycling women, the end of the luteal phase marks the selection of the dominant follicle from a cohort of early antral follicles. It appears that the selected follicle is the one that grows most rapidly in response to the intercycle rise in FSH and has differentiating GCs (i.e. the most FSH responsive in the cohort). This increased responsiveness is mirrored by enhanced FSH-induced aromatase activity [114]. In turn, GC-derived oestrogen and inhibin B reduce circulatory FSH levels, such that only those follicles most sensitive to FSH (refected by their higher GC FSH receptor expression profles) continue to develop and thus avoid atresia.
While FSH is key to follicular recruitment and growth, LH is essential for both further growth (typically >10 mm in diameter) and oestradiol production in the antral stage. According to the postulate that antral follicles become LH dependent, the frst follicle to express LH receptors in its mural GCs thus gains LH dependence in order to continue to mature as a dominant follicle. As such, antral follicle development features an initial FSH-dependent growth followed by LH-dependent maturation. Much of this process through to the point of ovulation is underpinned by oestrogen, which stimulates GC proliferation, FSH/LH receptor expression, aromatase synthesis and IGF1 production, while suppressing GC apoptosis.
Thus, while 5–15 antral follicles start FSHdependent development every monthly cycle, only a single dominant follicle prevails to ovulate. As the follicular phase proceeds, the dominant follicle grows rapidly in contrast to the remainder of its cohort and, in most species, acquires a greater blood supply [57, 115]. It is
still a matter of some debate whether the regression in thecal vasculature associated with follicular atresia identifed in animal models occurs as prominently in humans, although it has been proposed that this possible discrepancy may refect the longer time taken for atresia to occur in human follicles [116].
The vast majority (99.9%) of follicles undergo atresia, a process thought to be initiated by GC apoptosis controlled by both intrinsic and extrinsic pathways [117]. This process can occur in developing follicles after the secondary phase [57]. In the early stages, both theca and granulosa compartments remain largely intact. However, some loosened mural granulosa cells are found in the antrum, the cumulus oophorus may be disrupted, the oocyte starts to degenerate and the basement membrane appears to be thicker and folded. In the late stages, atretic follicles are shrunken, the basement membrane has further thickened and folded, and the stroma has broadly replaced the follicular cells. While extrinsic pathway cytokines such as members of the TNF family (TNF-α, Fas ligand and TNFrelated apoptosis-inducing ligand) are recognized activators of cell surface death receptors in atretic follicles, FSH appears to be key in inhibiting intrinsic cell death in the dominant follicle [118]. Further evidence from animal models implicates cytokines, such as GDF-9, BMP-6 and BMP-15, in the latter process through the inhibition of GC apoptosis and the promotion of cumulus cell survival, respectively [117, 119].
Ovulation
The dominant follicle is identifable by its larger size, and accompanying its enhanced growth and greater vascularity is an increased blood peak fow velocity relative to its cohort [120]. Key to ovulation is the proteolytic degradation of the basal lamina and the follicle’s apical connective tissue, which disrupts the follicular wall and allows oocyte release in response to the LH surge [121, 122]. This extensive remodelling of the extracellular N.
matrix is attributable to the concerted activity of an array of matrix metalloproteinases (MMPs) whose expression profles are decreased in the GC compartment in favour of its TC counterpart [123–125]. In turn, the activity of MMPs is controlled by their tissue inhibitors (TIMPs), whose production also increases in response to LH, albeit predominantly in the GC compartment [126–128]. While both MMPs and TIMPs are upregulated, MMP proteolytic activity is concentrated at the follicular apex, thus creating a weak point in the follicular wall, which facilitates ovulation [129]. The LH surge also promotes an increase in progesterone, various cytokines (e.g. macrophage chemotactic protein-1, IL-1, IL-8 and TNF- α ) and prostaglandins (e.g. PGF2α), lending support to the notion that ovulation has many of the features of an infammatory process [130–137]. Various animal models have implicated the action of additional mediators in increasing MMP expression, including relaxin and prolactin [138–141]. Through their control of localized MMP activity, TIMPs may have subsequent roles, such as stimulating cellular proliferation and/or promoting neoangiogenesis (which has until then been controlled by FF-dependent antiangiogenic factors) and steroidogenesis as the follicle luteinizes [129, 142–144]. They are likely to be assisted in this role via LH-induced immune effector cell infltration and alterations in the local cytokine microenvironment. As the weakened mature follicle wall ruptures at the stigma, the cumulus–oocyte complex is released near the entrance to the Fallopian tube where ciliary action at the fmbriae sweeps this into the ostium. The cumulus-oocyte complex progresses to the ampulla where the oocyte is fertilized, completes its meiotic division and extrudes the second polar body while the remaining cumulus cells maintain an active paracrine role [ 145 , 146 ]. Haemorrhage usually occurs in the follicle’s remnants, which becomes a transient corpus haemorrhagicum before completing its development into the highly vascularized, lipid/ lutein pigment-laden corpus luteum.
The Corpus Luteum
The onset of luteinization occurs in response to the preovulatory LH surge, which induces the terminal differentiation of follicular cells into steroidogenic lutein cells, whose activity primes the endometrium for embryo implantation [147–149]. Luteinization features the breakdown of the follicular basal membrane, which enables endothelial cells, fbroblasts, immune effector cells and TCs to penetrate the GC layer, although the degree of GC–TC mixing remains limited in primates [149]. Thus, two relatively distinct populations of steroidogenically active cell populations can be distinguished in the corpus luteum: large, hypertrophic and more centrally sited granulosalutein cells, which produce progesterone and oestrogen, and smaller, more peripherally located theca-lutein cells, which are largely responsible for androgen production [150, 151]. These changes are facilitated by extensive extracellular matrix remodelling via the action of an array of serine proteases, MMPs and TIMPs, whose expression levels are governed in response to the LH surge and prolactin levels [152–155]. In response to an array of angiogenic molecular cues (VEGF, endocrine gland-derived VEGF, bFGF and angiopoietins), thecal pericytes invade the developing luteal parenchyma and provide the starting point for the extensive endothelial development, which will ultimately allow each luteal cell cluster to be in direct contact with several capillaries, giving the corpus luteum one of the highest rates of blood fow and metabolic activities in the body [156–162]. This arrangement is essential in ensuring an adequate delivery of nutrients, hormones and lipoprotein-bound cholesterol as well as maximizing the effciency of progesterone export [162, 163].
The LH surge has widespread effects on ovarian endocrine signalling, which occurs within hours of its occurrence [164]. These include FSH receptor silencing, a transient LH receptor decline/desensitization, a brief progesterone receptor (which prolongs luteal lifespan by maintaining luteal paracrine progesterone signalling) and cyclooxygenase-2 upregulation, an increase
in the prolactin receptor (which acts to prevent the premature expression of 20α-hydroxysteroid dehydrogenase (HSD), the enzyme responsible for the catabolism of progesterone to its inactive 20α-dihydro metabolite) and alterations oestrogen receptor isoforms [165–168]. The hormonal control of luteal function is relatively complex and involves various key hormones. Firstly, in addition to its extraovarian roles, progesterone stimulates its own production, decreases its own catabolism and exerts antiluteolytic effects [169–171]. Pituitary-derived prolactin is also key to luteal function. In addition to preventing the catabolism of progesterone and increasing its production [172–177], it also enhances cholesterol uptake and maintains its stores [178–181]. Furthermore, prolactin enhances oestradiol/oestrogen receptor synthesis [182–184]. This latter role accounts for the angiogenic effects of prolactin, which are believed to be in part mediated through oestradiol [162, 185]. In turn, oestradiol stimulates progesterone biosynthesis, vascularization and hypertrophy of the corpus luteum, as well as enhancing cholesterol synthesis, circulatory uptake and intracellular mobilization [186–191]. The corpus luteum also produces androgens, principally androstenedione. In addition to being substrates for oestrogen synthesis, these can stimulate progesterone production, and thus also having antiapoptotic effects on luteal cells [162, 192–194]. There is additional evidence that LH is involved in luteal function, where it participates in the stimulation and maintenance of progesterone production by prolactin-primed luteal cells through the intermediary of oestradiol [162].
The subsequent lifespan of the corpus luteum is governed by whether fertilization and preimplantation development occur. If the released oocyte is fertilized, it will have completed its development into a late morula/early blastocyst by day 4 post-conception. By this stage, differentiation of the embryonic lineages will have commenced. Of these, the trophectoderm (which will ultimately give rise to the placenta and foetal membranes) actively secretes the LH-related peptide β-hCG by days 8–12 of pregnancy, which rescues the corpus luteum by providing a direct luteotrophic signal and prevents the onset of
PGF2α-induced luteolysis. In response to this, the corpus luteum persists and secretes progesterone until this role is later taken over by the fetoplacental unit in the second trimester of pregnancy [149]. However, in cases where fertilization does not occur or preimplantation development is unsuccessful, this signalling process fails: lutein cells shrink, their nuclei become pyknotic and luteal cells are progressively replaced by connective tissue as the corpus luteum degenerates to form a corpus albicans. There is an inbuilt safety mechanism to premature activation of this pathway: the oocyte produces BMP-15 and GDF-9, which prevent luteinization until after ovulation has occurred [195, 196]. These effects are additionally regulated by activin A, an autocrine GC factor that either promotes or inhibits follicular cell steroidogenesis depending upon their degree of differentiation and maturation [197].
The Corpus Albicans
Regression of the corpus luteum is associated with marked tissue remodelling and fbrosis, resulting in the formation of a scar, which is eventually reabsorbed into the surrounding ovarian stroma: the corpus albicans. The onset of these histological changes is heralded by the functional regression of the corpus luteum and an associated marked decrease in progesterone biosynthesis [149]. Much of the data available are drawn from rodent and ruminant studies and whether these fndings are broadly applicable to the human ovary is less clear. Nevertheless, both PGF2α and LH appear to be signifcant drivers in this process. In most species, PGF2α is largely produced by the uterus, although it has been proposed that its pulsatile release favours production by the corpus luteum itself, thereby amplifying luteolytic signalling [162, 198–200]. By contrast, luteolysis in primates is not mediated by uterine PGF2α and appears to depend entirely on luteal production [149, 201]. Rather than inhibiting progesterone biosynthesis per se, PGF2α appears instead to promote its metabolism to 20α-dihydroprogesterone through an increase in 20α-HSD levels [162]. In addition, PGF2α has N.
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Déclaration du Gouvernement lue le 20 novembre à la Chambre des Députés, par M. Georges Clemenceau, président du Conseil, ministre de la Guerre.
11 Décembre 1917.
Les Alliés occupent Jérusalem
Le général Allenby se propose d’entrer officiellement à Jérusalem demain, accompagné par les commandants des contingents français et italiens et par les chefs de la mission politique française.
Déclaration faite par M. Bonar Law, à la Chambre des Communes, le 10 décembre 1917.
..... A l’occasion de cet événement, un Te Deum sera chanté dimanche prochain 16 décembre, à 3 heures, en l’église métropolitaine Notre-Dame, pour remercier Dieu d’avoir délivré du joug turc la Ville Sainte, berceau du Christianisme.
Note communiquée à la Presse par l’archevêché de Paris.
Le Comité protestant français de propagande organise une manifestation interalliée pour célébrer l’entrée des forces anglaises, françaises et italiennes à Jérusalem.
Note communiquée par le Comité protestant français.
6 Mars 1918
Fin de l’état de guerre sur le front oriental
Le Gouvernement provisoire est déchu.
La cause pour laquelle luttait le peuple, c’est-à-dire la proposition de la paix démocratique et le contrôle des ouvriers sur la production et la constitution d’un gouvernement du Soviet, est assurée.
Appel du Comité révolutionnaire militaire de Petrograd aux citoyens de la Russie, publié le 10 novembre 1917.
..... Dans ces conditions, tout le traité de paix devenant un ultimatum, que l’Allemagne appuie immédiatement par la violence d’une action armée, la délégation russe a signé sans discussion les conditions de paix qui lui étaient dictées.
Radiotélégramme envoyé le 2 mars 1918 au soviet des Commissaires du peuple à Petrograd par les membres de la délégation russe aux seconds pourparlers de paix de Brest-Litovsk.
Un traité formel d’armistice a été signé de nouveau avec les Roumains. Les négociations de paix vont commencer sans délai.
Communiqué officiel allemand du 6 mars 1918.
21 Mars 1918
Offensive générale de l’armée allemande
Ce matin, vers 8 heures, à la suite d’un violent bombardement par obus explosifs et toxiques de nos lignes avant et zone arrière, l’ennemi a lancé une puissante attaque sur un front de plus de 80 kilomètres entre l’Oise (région de La Fère) et la Sensée (région de Croisilles).—Dans l’après-midi, de puissantes attaques effectuées par des masses considérables d’infanterie et d’artillerie ont rompu notre système défensif à l’ouest de Saint-Quentin.—L’ennemi a occupé Nesle et Bapaume.
Extraits des communiqués officiels britanniques des 21, 23 et 25 mars.
Nous sommes maintenant entrés dans le stade le plus critique de cette terrible guerre. Il y a un moment de calme dans la tempête, mais l’ouragan n’est pas encore terminé. Il rassemble sa force pour se déchaîner plus furieusement et avant son épuisement final il se déchaînera encore beaucoup de fois.
Discours prononcé à la Chambre des Communes, le 9 avril 1918, par M. Lloyd George.
21 Mars 1918
Offensive générale de l’armée allemande
L’ennemi a tiré sur Paris avec une pièce à longue portée.—Les troupes françaises ont commencé à intervenir, dès le 23 mars, dans la bataille en cours sur le front britannique. Elles ont relevé une partie des forces alliées et pris la lutte à leur compte sur ce secteur du front.—Noyon a été évacué pendant la nuit.—Nos régiments, luttant pied à pied et infligeant de lourdes pertes aux assaillants, n’ont faibli à aucun moment et se sont repliés en ordre sur les hauteurs immédiatement à l’ouest de Montdidier
Extraits des communiqués officiels français des 23, 25, 26 et 28 mars.
Je viens vous dire que le peuple américain tiendrait à grand honneur que nos troupes fussent engagées dans la bataille.
Déclaration du général Pershing, commandant en chef l’armée américaine, au général Foch, au cours d’une réunion tenue sur le front le 28 mars.
Le Gouvernement anglais et le Gouvernement français se sont mis d’accord pour donner au général Foch le titre de “commandant en chef des armées alliées opérant en France”.
Note communiquée à la Presse le 10 avril.
26 Avril 1918.
Arrêt de l’attaque allemande en direction de Rouen, tendant à séparer les armées anglaises des armées françaises
La bataille a repris ce matin avec une extrême violence. Sur une étendue d’environ 15 kilomètres, depuis Grivesnes jusqu’au nord de la route d’Amiens à Roye, les Allemands ont lancé des forces énormes, révélant une volonté ferme de rompre notre front à tout prix (C. O. F 4 avril).—Après une puissante préparation d’artillerie, l’ennemi a déclenché ce matin une forte attaque sur tout le front entre la Somme et l’Avre (C. O. B. 4 avril).—Après une série d’assauts furieux, l’ennemi a réussi à prendre pied dans le bois au nord de Hangard (C. O. F 24 avril).—L’ennemi a pu progresser à Villers-Bretonneux (C. O. B. 24 avril).—Notre ligne a été presque intégralement rétablie. Villers-Bretonneux est de nouveau entre nos mains (C. O. B. 25 avril).—Nous avons enlevé le monument au sud de Villers-Bretonneux, pénétré dans le bois de Hangard-en-Santerre et conquis la partie ouest du village (C. O. F 26 avril).
Extraits des communiqués officiels français et britanniques.
1er Mai 1918
Arrêt de l’attaque allemande en direction de Calais
Ce matin, après un intense bombardement depuis le canal de La Bassée jusqu’au voisinage d’Armentières, d’importantes forces ennemies ont attaqué les troupes britanniques et portugaises qui tenaient ce secteur de notre front (9 avril).—Nos troupes ont évacué Armentières, rendu intenable par les gaz (11 avril).—Bailleul est tombé entre les mains de l’ennemi (16 avril).—Nos troupes ont réussi à entrer dans les villages de Meteren et Wytschaete, mais les attaques renouvelées de l’ennemi ne leur ont pas permis de s’y maintenir (17 avril).—L’ennemi a pris pied sur la colline du Kemmel (26 avril).—Des postes tenus par l’ennemi dans le secteur de Meteren ont été enlevés par nos troupes. Les troupes françaises ont amélioré leurs positions dans le voisinage de Locre (1er mai).
Extraits des communiqués officiels britanniques.
10 Mai 1918
Embouteillage du port d’Ostende
Une brèche d’environ 60 pieds a été constatée à l’intérieur du môle de Zeebrugge, à l’extrémité de la côte. A Ostende, les navires coulés ont été vus à l’entrée de la jetée, obstruant la plus grande partie du chenal.—Le beau temps de ces derniers jours a rendu possible de constantes reconnaissances aériennes sur Bruges et le canal de Zeebrugge à Bruges et la prise de clichés photographiques. Le résultat montre qu’aucun changement ne s’est produit depuis le 23 avril et que la plus grande partie des sous-marins ennemis et torpilleurs qui ont leur base sur la côte des Flandres ont été immobilisés à Bruges depuis les opérations d’embouteillage à Zeebrugge.—L’opération ayant pour but de fermer les ports d’Ostende et de Zeebrugge a été complétée avec succès la nuit dernière: le vieux croiseur Vindictive a, en effet, été coulé entre les jetées et en travers de l’entrée du port d’Ostende.
Extraits des communiqués publiés par l’Amirauté britannique les 24 avril, 30 avril et 10 mai.
16 Juillet 1918.
Arrêt de l’attaque allemande en direction de Paris
Dans la deuxième partie de la nuit les Allemands ont déclenché un violent bombardement sur toute la région comprise entre la forêt de Pinon et Reims. Ce matin l’attaque ennemie s’est produite sur un très large front entre ces deux points (27 mai).—Dans la soirée du 27, les Allemands ont réussi à franchir l’Aisne entre Vailly et Berry-au-Bac (28 mai).—Sur la Marne, les Allemands ont atteint les hauteurs à l’ouest de Château-Thierry. Nous tenons la partie de la ville située sur la rive gauche (2 juin).—A 4h 30, l’infanterie ennemie s’est portée à l’attaque de nos positions entre Montdidier et Noyon (9 juin).—Les Allemands ont réussi à prendre pied dans Cœuvres et Saint-Pierre-Aigle (13 juin).—Les Allemands ont attaqué ce matin depuis Château-Thierry jusqu’à la Main de Massiges. Nos troupes soutiennent énergiquement le choc de l’ennemi sur un front d’environ 80 kilomètres (15 juillet).— Au sud de la Marne, les Allemands n’ont pu dépasser la ligne Saint-Agnan—La Chapelle-Monthodon (16 juillet).
Extraits des communiqués officiels français.
16 Juillet 1918
Contre-attaque et offensive de l’Aisne au sud de la Marne
Nous avons contre-attaqué l’ennemi sur le front Saint-Agnan-La ChapelleMonthodon. Nos troupes ont enlevé ces deux localités (C. O. F 16 juillet).—Nous avons attaqué ce matin les positions allemandes depuis la région de Fontenoy-surl’Aisne jusqu’à la région de Belleau (C. O. F. 18 juillet).—Après avoir brisé l’offensive allemande sur les fronts de Champagne et de la Montagne de Reims dans les journées des 15, 16 et 17 juillet, les troupes françaises, en liaison avec les forces américaines, se sont portées, le 18, à l’attaque des positions allemandes entre l’Aisne et la Marne sur une étendue de 45 kilomètres (C. O. F. 18 juillet).—Nous avons traversé l’Ourcq (C. O. A. 18 juillet).—Sur notre gauche nos troupes sont entrées dans Soissons (C. O. F. 2 août).—Les résultats de la victoire acquise par la contreoffensive entreprise si glorieusement par les troupes franco-américaines le 18 juillet ont été complètement obtenus aujourd’hui: l’ennemi, qui a subi sa seconde défaite sur la Marne, a été repoussé en désordre au delà de la ligne de la Vesle (C. O. A. 3 août).—Fismes est en notre possession (C. O. F. 4 août).
Extraits des communiqués officiels français et américains.
8 Août 1918
Offensive du nord de l’Oise à l’Ancre
A l’aube, ce matin, la 4e armée britannique et la 1re armée française sous le commandement du maréchal Sir Douglas Haig ont attaqué sur un large front à l’est et au sud-est d’Amiens (C. O. B. 8 août).—La ville de Montdidier est tombée aux mains des Français (C. O. B. 10 août).—Lassigny est tombé (C. O. F. 21 août).—Nos troupes ont repris Albert (C. O. B. 22 août).—Nous avons occupé Roye (C. O. F. 27 août).—Nous avons atteint Nesle (C. O. F 28 août).—Nous avons occupé Chaulnes (C. O. F. 28 août).—Nous avons enlevé Noyon de haute lutte (C. O. F. 29 août).—Les troupes néo-zélandaises se sont emparées de Bapaume (C. O. B. 29 août).—Les troupes australiennes tiennent Péronne (C. O. B. 1er septembre).—Nous tenons Ham et Chauny (C. O. F. 6 septembre).—L’ennemi a été complètement rejeté de SaintQuentin (C. O. F 2 octobre).—La 1re armée a battu complètement les six divisions qui lui faisaient face. Dès la première heure elle s’emparait de Guise (C. O. F. 5 novembre).—Hirson est entre nos mains (C. O. F. 9 novembre).
Extraits des communiqués officiels français et britanniques.
20 Août 1918
Offensive entre Oise et Aisne
A l’est de l’Oise, nos troupes ont attaqué les lignes allemandes sur un front de 25 kilomètres environ depuis la région de Bailly jusqu’à l’Aisne (20 août).—Nous occupons Coucy-le-Château et Coucy-la-Ville (5 septembre).—Nous avons pris le village d’Allemant et le moulin de Laffaux (14 septembre).—Nos troupes ont occupé le village et la lisière sud de la forêt de Pinon: Vaudesson, Chavignac et le fort de la Malmaison sont entre nos mains (28 septembre).—Nous sommes parvenus jusqu’à l’Ailette que nous bordons au nord de Craonne (12 octobre).—Nous avons pris La Fère. Les troupes de la 10e armée sont entrées à Laon (13 octobre).—Avec la coopération des troupes italiennes nous avons enlevé et dépassé Sissonne (14 octobre).—Entre Sissonne et Château-Porcien nous avons pénétré dans toutes les parties de la position Hunding où l’ennemi tenait encore (5 novembre).—Nous avons atteint la voie ferrée de Mézières à Hirson (9 novembre).—Les troupes italiennes sont entrées à Rocroi (11 novembre).
Extraits des communiqués officiels français.
