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Embryogenesis and sexual differentiation I and II Dr. sc. nat. Oliver Sterthaus University Hospital Basel Master Course in Toxicology Section: Reproductive Toxicology Swiss Center of Applied Human Toxicology 1 Embryogenesis and sexual differentiation I • Gametogenesis • Fertilization • Preimplantation Embryogenesis and sexual differentiation II • Implantation • Embryonic disk • Embryonic phase • Fetal phase Lecture from http://www.embryology.ch http://ivf-basel.ch/de/studenten/master-reproductive-toxicology/?L=0 2 Gametogenesis • • • • • The germline - origin of the germ cells Determining the gender Spermatogenesis Oogenesis Comparison of spermatogenesis with oogenesis 3 The germline - origin of the germ cells Emigration of the germ cells • In the third week, the primordial germ cells wander - in an amoeboid manner - from the primary ectoderm into the yolk sac wall and collect near the exit of the allantois. The primordial germ cells are now extraembryonal, lying in the endoderm and mesoderm of the yolk sac wall. Facilitated through the cranio-caudal curvature and the lateral folding of the embryo, the primordial germ cells wander back into the embryo again between the fourth and sixth week. They move along the yolk sac wall to the vitelline and into the wall of the rectum. After crossing the dorsal mesentery they colonize the gonadal ridge. During their journey, but also while still in the gonadal ridge, the primordial germ cells multiply by mitotic divisions. 1 Primordial germ cells 2 Allantois 3 Rectum 4 Ectoderm 5 Foregut 6 Primordial heart 7 Secondary yolk sac 8 Endoderm (yellow) 9 Mesoderm (red) 10 Amniotic cavity 1 Rectum 2 Vitelline 3 Allantois 4 Nephrogenic cord (pink) 5 Gonadal ridge (green) 6 Primordial germ cells (red dots) 7 Heart prominence 4 The germline - origin of the germ cells • • For both sexes the gonads arise in the gonadal ridges. These are bilateral, ridge-like protrusions that appear ventromedially to the nephrogenic cord. They are generated in the 5th week through the proliferation of the coelomic epithelium and the thickening of the underlying mesenchyma. At this point, the gonadal ridge represents the primitive gonadal primordium. In order for this to develop into the definitive and gender-specific gonads, the immigration of the primordial germ cells is necessary. In the 6th week, the primordial germ cells infiltrate into both gonadal ridges. The primordial germ cells become surrounded by the coelomic epithelial cells that have proliferated and advanced into the depths of the mesenchyma. These germinal cords are still connected with the surface of the coelomic epithelium. At this point, the male and female gonadal primordia cannot be distinguished and, for this reason, this condition is referred to as the indifferent gonadal primordium. 1 Proliferating coelomic epithelium 2 Thickening of the mesenchyma 3 Germinal cords 4 Primordial germ cells (red dots) 5 Mesenchyma 6 Allantois 7 Vitelline 8 Intestinal tube 9 Dorsal mesentery 10 Gonadal ridge 11 Nephrogenic cord 12 Mesonephric (Wolffian) duct 13 Mesonephric tubule 14 Aorta 5 The germline - origin of the germ cells 6 http://www.rci.rutgers.edu/~uzwiak/EndoSpring10/Endo08_Lect16.htm Determining the gender Male gonadal primordium • The key to sexual differentiation lies on the Y chromosome in the SRY (sex determining region of the Y chromosome). There the testis-determining factor (TDF) is found that induces male development. Among other substances, testosterone is formed beginning with the 7th week. If no Y chromosome - and thus no SRY - is present, a feminine phenotype is engendered. 7 Determining the gender Female gonadal primordium • The primary gonadal cords in the medullary region degenerate since no SRY-gene exists in the female body. In the cortex region, on the other hand, the proliferation of the coelomic epithelium remains preserved - its cells surround the multiplying germinal cells. These remain near the surface, however and, in contrast to the germinal cords, are called cortical cords. The cortical cords decay into isolated collections of cells and the epithelial cells surround one to two primordial germ cells, forming follicles. The primordial germ cells inside differentiate into oogonia and, with the first meiotic division, become primary oocytes. The interaction that then commences between primary oocytes with the surrounding epithelial cells stops the completion of the first meiotic division, which is then arrested until puberty begins. 8 Spermatogenesis 9 Spermatogenesis • Spermatogenesis is initiated in the male testis with the beginning of puberty. This comprises the entire development of the spermatogonia (former primordial germ cells) up to sperm cells. The gonadal cords that are solid up till then in the juvenile testis develop a lumen with the start of puberty. They then gradually transform themselves into spermatic canals that eventually reach a length of roughly 50-60 cm. They are termed convoluted seminiferous tubules (Tubuli seminiferi contorti) and are so numerous and thin that in an adult male testicle their collective length can be 300 to 350 meters. They are coated by a germinal epithelium that exhibits two differing cell populations: some are sustentacular cells (= Sertoli's cells) and the great majority are the germ cells in various stages of division and differentiation. 10 Spermatogenesis • • For an optimal sperm cell production a certain milieu is needed. By transferring the testicles into the scrotum a testicular temperature 2-3 ºC lower than body temperature is attained. In addition, a slightly elevated pressure from the surroundings is necessary. This is why when the taut tunica albuginea is slit open, the testicular parenchyma bulges out by itself. Evidently, both elevated pressure and lowered temperature are necessary for producing sperm cells. The development of the germ cells begins with the spermatogonia at the periphery of the seminal canal and advances towards the lumen over spermatocytes I (primary spermatocytes), spermatocytes II (secondary spermatocytes), spermatids and finally to mature sperm cells. 1 Basal lamina (membrane) (not recognizable) 2 Myofibroblast 3 Fibrocyte 4 Sertoli's cell 5 Spermatogonia 6 Various stages of the germ cells during spermatogenesis 7 Spermatozoon 8 Lumen 11 Spermatogenesis Developmental stages of spermatogenesis http://scientopia.org/blogs/scicurious/2010/03/10/basics-guest-post-2spermatogenesis 12 Spermatogenesis Spermiogenesis (spermatohistogenesis) and structure of the sperm cell 1 Axonemal structure, first flagellar primordium 2 Golgi complex 3 Acrosomal vesicle 4 Pair of centrioles (distal and proximal) 5 Mitochondrion 6 Nucleus 7 Flagellar primordium 8 Microtubules 9 Sperm cells tail 10 Acrosomal cap 13 Spermatogenesis 1 Plasma membrane 2 Outer acrosomal membrane 3 Acrosome 4 Inner acrosomal membrane 5 Nucleus 6 Proximal centriole 7 Rest of the distal centriole 8 Thick outer longitudinal fibers 9 Mitochondrion 10 Axoneme 11 Anulus 12 Ring fibers A Head B Neck C Mid piece D Principal piece E Endpiece 14 Spermatogenesis Leydig's interstitial cells and hormonal regulation Between the seminal canals lie Leydig's interstitial cells. These are endocrine cells that mainly produce testosterone, the male sexual hormone, and release it into the blood and into the neighboring tissues. An initial active stage of these cells occurs during the embryonic development of the testis. Later in juvenile life, due to the influence of the LH (luteinizing hormone) secreted by the anterior hypophysis (pituitary gland), Leydig's interstitial cells enter a second, long lasting stage of activity. Together with the hormones secreted by the adrenal cortex, testosterone initiates puberty and thus the maturation of the sperm cells. 1 Leydig's interstitial cells 2 Crystalloids of Reinke 15 Oogenesis Structure of the ovary 1 Primordial follicle 2 Primary follicle 3 Secondary follicle 4 Tertiary follicle 5 Antrum folliculi 6 Cumulus oophorus 16 Oogenesis The follicle stages from primordial follicle to tertiary follicle Primordial follicle Secondary follicle and Primary follicle A Primordial follicle B Primary follicle 1 Oocyte 2 Follicular epithelium Tertiary follicle 1 Oocyte 2 Pellucid zone 3 Stratum granulosum 4 Theca folliculi cells 1 Oocyte 2 Pellucid zone 3 Stratum granulosum 4 Theca interna 5 Theca externa 6 Antral follicle 17 7 Cumulus oophorus (Granulosa cells, together with the oocyte) 8 Basal lamina between theca and stratum granulosum Oogenesis Temporal course of the number of germ cells / follicles Phase A: Primordial germ cells grow, proliferate and become sheathed with coelomic epithelial cells. Gonadal cords arise; 6th to 8th week. Phase B: Spurt of growth: cellular clones of the oogonia are formed, whereby the cells remain connected with each other through cellular bridges; 9th to the 22nd week. Phase C: The oogonia become primary oocytes that enter the prophase of the first meiosis; 12th to the 25th week. Phase D: The primary oocytes become arrested in the dictyotene stage of the prophase: the primordial follicles are engendered; 16th to the 29th week. Phase E: At around the 14th week a quantitatively increased decline in the number of germ cells commences as well as atresia in all of the follicle stages. 18 Tabular comparison of spermatogenesis and oogenesis Spermatogenesis Oogenesis Number of gametes Principle: continuous production. Although from puberty to old age sperm cells are constantly being engendered, the production is subject to extreme fluctuations regarding both quantity and quality. Principle: Using up the oocytes generated before birth. Continual decrease of the oocytes, beginning with the fetal period. Exhaustion of the supply at menopause. Meiotic output Four functioning, small (head 4 µm), motile spermatozoids at the end of the meiosis One large, immotile oocyte (diameter 120 µm) and three shriveled polar bodies are left at the end of the meiosis Fetal period No meiotic divisions Entering into meiosis (arrested in the dictyotene stage) No germ cell production Production of the entire supply of germ 19 cells Fertilization • Ovulation • Getting the spermatozoa ready -The path of the sperm cells to the oocyte – capacitation -The sperm cells meet the oocyte - the acrosome reaction • The penetration of the spermatozoon into the oocyte • The fertilization is complete. The formation of the zygote 20 Ovulation The female genital tract 1 Ovary 2 Infundibulum 3 Fimbriae 4 Fallopian or uterine tube 5 Ampullary part of the tube 6 Uterine musculature 7 Uterine mucosa 8 Cervix 9 Portio 10 Vagina 11 Ligamentum ovarii proprium 12 Suspensory ligament of the ovary 13 Ovary cut open (follicles in various stages) 21 Ovulation In the center of this hormonal control is the hypothalamamics-hypophysial (pituitary gland) system with the two hypophysial gonadotropins FSH and LH. The pulsating liberation of GnRH by the hypothalamus is the fundamental precondition for a normal control of the cyclic ovarian function. This cyclic activity releases FSH and LH, both of which stimulate the maturation of the follicles in the ovary and trigger ovulation. During the ovarian cycle, estrogen is produced by the theca interna and follicular cells (in the socalled follicle phase) and progesterone by the corpus luteum (so-called luteal phase). http://commons.wikimedia.org/wiki/File:MenstrualCycle.png 22 Ovulation Maturation of the oocyte in the dominant follicle shortly before ovulation 1 Theca interna and externa 2 Basal membrane between theca and granulosa 3 Granulosa 4 Graafian follicle with follicle fluid 5 Primary oocyte 6 Cumulus oophorus 7 Ovarian tissue 8 Tunica albuginea of the ovary 9 Abdominal space 10 Pellucid zone 11 Nucleus in the diakinesis stage 12 Granulosa cells 13 Processes of the granulosa cells 14 Microvilli of the oocyte surface 23 Ovulation Termination of the first meiosis 1 Pellucid zone 2 Perivitelline space 3 Spindle apparatus in the anaphase of the first meiosis 4 Granulosa cells retract their cell processes 5 Microvilli of the oocyte surface 6 Granulosa cells 7 Polar body 24 Ovulation The follicle that is about to rupture 1 Peritoneal cavity 2 Follicle about to rupture with follicle fluid (containing lots of hyaluronic acid and progesterone) 3 Cloud of cumulus cells with oocyte 4 Loosened-up cumulus cells 5 Secondary oocyte 6 Corona radiata 7 Ovarian tissue 1 Spindle apparatus with chromosomes that form the metaphase plate 2 Arrested spindle apparatus in the polar body 3 Perivitelline space 25 Ovulation 1 Fallopian tube cut open with the tube mucosa that lies in folds 2 Closely apposed fimbriae 3 Follicle fluid that has flowed out 4 Secondary oocyte with corona radiata 5 Ovary with follicles in various stages of development and atresia 6 Pellucid zone 7 First polar body 8 Secondary oocyte 9 Cells of the corona radiata 10 Arrested spindle apparatus The oocyte now "waits" in the fallopian tube on fertilization by the sperm. The matrix of hyaluronic acid holds it "captive" there, so to speak. After a number of hours the matrix liquefies more and more and the oocyte is gradually transported towards the uterus by the ciliary beats of the tube's epithelium cells. Since after ovulation the oocyte can only be fertilized within a few hours, the fertilization must almost inevitably take place in the ampullary part of the fallopian tube. 26 Ovulation 27 27 Ovulation 28 Getting the spermatozoa ready 29 Getting the spermatozoa ready Spermatozoa maturation steps 1 Tail 2 Head 3 Acrosome The maturation and activation of the spermatozoa occur in the following four steps: Storage in the epididymis Ejaculation Ascension to the ovary Near the oocyte Maturation Activation Capacitation Acrosome reaction 30 The ejaculation and the ejaculate 1 Testicle 1a Efferent ductules of the testis 2 Ductus epididymidis 2a Cauda epididymidis 3 Deferent duct / vas deferens 4 Ampulla of the deferens duct 5 Glandula vesiculosa / Seminal gland 6 Ejaculatory duct 7 Prostate gland 8 excretory duct of the prostate 9 Bulbourethral gland (Cowper's gland) 10 Urethral gland (Littre's gland) 11 Urethra The ejaculation is brought about through rhythmic contractions of the deferent duct that come in waves and through supporting contractions of the pelvic musculature. The purpose of the coital ejaculation is to deposit spermatozoa, which are largely immobile having come from storage in the cauda of the epididymis, into the rear part of the vaginal cavity, i.e., near the external opening of the cervix, the entrance to the uterus. While the spermatozoa are pushed through the deferent duct and the urethra, a large volume of secretions of various glands are mixed in. This fluid part of the ejaculate is known as the seminal plasma. The ejaculate thus consists of up to 10% spermatozoa and 90% seminal plasma for a total volume of 2-6 ml. 31 Getting the spermatozoa ready The seminal plasma The seminal plasma mediates the chemical function of the ejaculate.The mixing together of the various glandular fractions leads to a coagulation of the fresh ejaculate in the rear vaginal cavity within a minute. In this way a deposit of spermatozoa is formed in the vagina. After about 15-20 minutes the coagulated ejaculate becomes a fluid again. Due to its slight alkalinity (light alkaline buffer) it is also responsible for creating a milieu beneficial for the spermatozoa in a vaginal surrounding that is normally maintained acidic. The seminal plasma has to fulfil the following tasks: Creation of an alkaline buffered milieu in the vagina Coagulation of the ejaculate and creating a sperm deposit in the vagina Coating the sperm cells with capacitation inhibitors Activation and augmenting the motility of the sperm cells Supplying nutrients for the sperm cells Fluidizing the ejaculate after 15-20 minutes 32 The path of the sperm cells to the oocyte - capacitation 33 The path of the sperm cells to the oocyte - capacitation 1 Rear part of the vaginal cavity 2 Portio / cervix 3 Cervix canal 4 Isthmus 5 Ampullary part of the fallopian tube (ampulla) 6 Ovary with attached Fimbriae 7 Endometrium 8 Myometrium 9 Cavum uteri 10 Meeting place of the sperm cells with the oocyte In order, though, that a sufficient number of sperm cells appear in the ampulla at the right time, a large number of sperm cells must be present in the ejaculate. Of the roughly 200 million ejaculated sperm cells only a few hundred are able to traverse the long way through the cervix, the uterus, and past the fallopian tube isthmus to the tube's ampullary region to there meet oocyte. Along the way whole groups of sperm cells can halt at certain places and enter a phase of reduced activity. That is why a portion of the sperm cells can retain their fertilizing capability for up to 4 days. 34 The path of the sperm cells to the oocyte - capacitation The cervical canal 1 Sperm cells 2 Mucus fibers (strongly meshed) 3 Crypt of a cervix gland 4 Mucus fibers (loosely meshed) 5 Portio entrance Before the ovulation the cervical canal is narrow and the cervix mucus is strongly meshed (it forms the so-called cervical barrier) that hinders the passage of sperm cells. At the time of ovulation the cervix wall becomes looser and the canal wide. The folds of the mucosa increase in number and let deeper and branched crypts come into being; there are then also more cervix glands. Under the influence of the estradiol that increases shortly before ovulation the cervix mucus is restructured and the mucus barrier becomes passable for sperm cells. 35 The path of the sperm cells to the oocyte - capacitation • Capacitation is a functional maturation of the spermatozoon. The changes take place via the sperm cell membrane in which it may be that receptors are made available through the removal of a glycoprotein layer. The area of the acrosomal cap is also so altered thereby that the acrosome reaction becomes possible. Through the membrane alterations, the motile properties of the spermatozoon also change. Discharging whipping movements of the tail together with larger sideways swinging movements of the head take place. This type of motility is designated as hyperactivity. One can therefore say that the visible consequences of capacitation consist in hyperactivity of the spermatozoon. • Since it cannot be determined ahead of time when the exact moment is that the oocyte and spermatozoon will meet, the maturation mechanisms are so configured that various groups of sperm cells are able to keep their chances of fertilization upright over a relatively long time after cohabitation. For this purpose the ejaculated sperm cells do not all end their capacitation at the same time, thus creating heterogenous groups of sperm cells. 36 The sperm cells meet the oocyte the acrosome reaction 37 The sperm cells meet the oocyte the acrosome reaction Penetrating the cumulus cells 1 Center of the oocyte 2 Corona radiata (surrounds and partly covers the oocyte) 3 Head of the spermatozoon Normally, the acrosome reaction of the spermatozoa takes place first when they encounter the pellucid zone. In a small percentage of the sperm cells, though, the acrosome reaction occurs spontaneously, just as when a small percentage of the cells experience capacitation immediately following ejaculation. This circumstance assures that a small amount of hyaluronidase is present from the very beginning and, when the wave of sperm cells meets the oocyte, a few of them are thus assisted in making their way to the pellucid zone. Upon arriving at the pellucid zone, these sperm cells themselves undergo an acrosome reaction and a further amount of hyaluronidase and other enzymes are released. In this way, the throng of cumulus cells is further loosened up and more and more sperm cells obtain the possibility38of undergoing the acrosome reaction themselves at the pellucid zone. The sperm cells meet the oocyte the acrosome reaction The contact with the pellucid zone 1 Pores 2 Emerging of the acrosomal contents 3 Inner acrosomal membrane 4 Acrosomal content (enzyme) 5 Outer acrosomal membrane 6 Cell membrane 7 Membrane residues dropping behind 8 Post-acrosomal membrane region A Head B Neck C Mid-piece A prerequisite for the success of the acrosome reaction is the previous binding of the spermatozoon to the pellucid zone. The enzymes that are released in the immediate vicinity of the pellucid zone by the acrosome reaction dissolve it locally and thus create a way through it for the sperm cells. A number of enzymes that have been released are involved. The best known are the already mentioned hyaluronidase and acrosin, whereby the acrosin makes it possible for the spermatozoa to get through the pellucid zone. 39 The penetration of the spermatozoon into the oocyte 40 The penetration of the spermatozoon into the oocyte The docking mechanism of the spermatozoon onto the oocyte (the key-lock principle) 1 Post-acrosomal region 2 Oolemma with microvilli 3 Perivitelline space 4 Pellucid zone 5 Cortical vesicle at the surface of the oocyte The docking triggers a cascade of events with the following goals: -Polyspermy block: The penetration of further sperm cells should be hindered -Hardening of the pellucid zone as a mechanical protection of the embryo -Entry of the spermatozoon into the oocyte Termination of the 2nd meiosis of the oocyte with expulsion of the 2nd polar body -Preparation at the molecular level of the oocyte for unpacking the paternal DNA 41 The penetration of the spermatozoon into the oocyte The polyspermy block 1 Pellucid zone 2 Perivitelline space 3 Cortical vesicle 4 Oolemma The docking triggers a rapid wave of depolarization in the oolemma, leading to changes in the membrane surface. The depolarization wave then also causes small cortical vesicles, found on the inside of the oolemma, to empty out their contents into the perivitelline space The entry of the spermatozoon into the oocyte (impregnation) 1 Oolemma 2 Cell membrane of the spermatozoon 3 Kinocilium 4 Nucleus (compact) of the spermatozoon 5 Centrosome of the spermatozoon The genetic material, lying in the nucleus and coming from the father, is unpacked and is used for building the paternal pronucleus. In what follows, the centrosome plays an important role in the convergence of the two pronuclei. Later - after the subsequent division - it will also be responsible for building the first division spindle of the new creature. All centrosomes in the bodily cells of a human originate from that of the father. Other sperm components transferred to the oocyte cytoplasm, like the kinocilium, are dissolved. Effective processes also exist for eliminating sperm mitochondria from the cytoplasm of the oocyte. Thus, all mitochondria in the bodily cells of an individual normally derive from the mother alone 42 The penetration of the spermatozoon into the oocyte The termination of the second meiosis of the oocyte 1 Mitotic spindle with chromatids 2 1rst polar body 3 Pellucid zone 4 Perivitelline space 5 Cell membrane of the spermatozoon (Remainder as appendage) 6 Kinocilium 7 Nucleus (compact) of the spermatozoon 8 Proximal centrosome of the spermatozoon 1 1rst polar body 2 Nucleus (slightly unpacked) of the spermatozoon 3 Proximal centrosome of the spermatozoon 4 2nd polar body (being formed) 5 Remainder of the mitotic spindle with maternal chromosomes 1n,1C The termination of the second meiosis implies the division of the secondary oocyte (1n,2C) into a mature oocyte (1n,1C) 43 by the expulsion of the 2nd polar body (1n,1C) into the perivitelline space. In vitro fertilisation 44 The fertilization is complete. The formation of the zygote 45 The fertilization is complete. The formation of the zygote Introduction into the creation and development of the pronuclei 1 Paternal pronucleus 2 Maternal pronucleus 3 Centrosome brought in by the spermatozoon 4 Group of polar bodies The maternal pronucleus is next to the polar bodies. The paternal one forms near where the sperm cell entered and is almost always some distance from the polar bodies. 46 The fertilization is complete. The formation of the zygote Approach of the pronuclei 1 Paternal pronucleus 2 Maternal pronucleus 3 Paternal centrosome 4 "Inner bodies" 5 Maternal astral microtubule 47 The fertilization is complete. The formation of the zygote The formation of the zygote 1 Nucleic membranes of the pronuclei, as they are dissolving 2 Microtubules of the mitotic spindle After the two pronuclei have come as close together as they can, no merging of them takes place, i.e., a fitting together of the chromosomes of the two pronuclei within a single nucleic membrane does not happen. It is much more accurate to say that the nucleic membranes of both pronuclei dissolve and the chromosomes of both align themselves on the spindle apparatus at the equator. 48 Preimplantation • The cleavage divisions and the migration of the embryo through the tube 49 Preimplantation The cleavage divisions and the migration of the embryo through the tube The cleavage divisions up to the morula stage 50 Preimplantation 51 Preimplantation How a blastocyst is engendered 1 Embryoblast 2 Pellucid zone 3 Trophoblast 4 Blastocyst cavity Around the end of the fifth day the embryo frees itself from the enveloping pellucid zone. Through a series of expansion-contraction cycles the embryo bursts the covering. This is supported by enzymes that dissolve the pellucid zone at the abembryonic pole. The rhythmic expansions and contractions result in the embryo bulging out of and emerging from the rigid envelope. This "first birth" is called hatching 52 Preimplantation 53 Preimplantation Blastocyst morphology Proposal for a universal minimum information convention for the reporting on the derivation of human embryonic stem cell lines. Stephenson EL, Braude PR, Mason C. Regen Med. 2006 Nov;1(6):739-50. 54 Preimplantation The emergence of the blastocyst (hatching) 1 Pellucid zone 2 Trophoblast (outer cell mass) 3 Hypoblast (part of the inner cell mass) 4 Blastocyst cavity 5 Epiblast (part of the inner cell mass) 55 Preimplantation The migration of the embryo through the fallopian tube 1 Ovary 2 Fallopian tube 3 Endometrium 4 Myometrium 5 Uterine cavity A Spermatozoon penetrates into the oocyte (conception), day 0 B Two-cell stage, day 1 C Four-cell stage, day 2 D Eight-cell stage, day 3 E Morula (16-32 cells), day 4 F Free blastocyst (following hatching), day 6 56 Embryogenesis and sexual differentiation II • Implantation • Embryonic disk • Embryonic phase • Fetal phase 57 Implantation • Role and functional anatomy of the endometrium • Implantation stages 58 Role and functional anatomy of the endometrium 1 Single-layered prismatic 2 epithelium 3 Basal lamina 4 Uterine glands (glandulae uterinae) 5 Connective tissue 6 Blood vessels A Superficial, functional layer B Basal layer C Myometrium Endometrial functions -Cyclic alterations of the uterine glands and blood vessels during the course of the menstruation, as preparation for the implantation -Location where the blastocyst is normally implanted -Location where the placenta develops 59 Role and functional anatomy of the endometrium Cyclic hormonal alterations of the endometrium The menstruation phase A Functional layer B Basal layer C Myometrium 1 Uterine cavity with epithelial cells, blood corpuscles and remainders of the expulsed mucosa 2 Intact and partially expulsed uterine glands 3 Intact epithelial cells 4 Basal membrane 5 Uterine stroma 6 Blood corpuscles 7 Free cells of the connective tissue The menstruation phase (1st to the 4th day) distinguishes the beginning of each menstruation cycle. When an implantation does not occur, the back-formation of the yellow body (corpus luteum) lowers the amounts of circulating estradiol and progesterone hormones, which leads to the expulsion of the functional layer of the 60 endometrium. Role and functional anatomy of the endometrium The follicular or proliferative phase 1 Glandular epithelium 2 Endometrium that is a little developed 3 Uterine glands 4 Myometrium 5 Stroma of the endometrium 6 Epithelial cells of the uterine glands 1 Glandular epithelium 2 Endometrium during the proliferation 3 Uterine glands 4 Myometrium 5 Stroma of the endometrium (mitosis) 6 Epithelial uterine gland cells with mitotic figures During the proliferative or follicular phase (4th to 14th day) the secretion of estrogen through the growing ovarian follicle is responsible for the proliferation of the endometrium (intensive mitosis in the glandular epithelium and in the stroma). The uterus epithelium clothes the surface again. In this stage a certain number of epithelial cells equipped with cilia can be recognized. The glands grow longer and the spiral arteries wind themselves lightly into the stroma. At the end of the proliferative phase the estradiol peak (released by the growing follicles) triggers a positive feedback mechanism at the level of the pituitary and the ovulation commences 35 to 44 hours after the initial LH increase (cyclic hormonal changes). 61 Role and functional anatomy of the endometrium The luteinizing or secretory phase 1 Glandular epithelium 2 Thickened endometrium 3 Uterine glands, curled 4 Myometrium 5 Stroma of the endometrium 6 Epithelial uterine gland cells with glycogen collections at the basal pole 1 Glandular epithelium 2a Stratum compactum 2b Stratum spongiosum 2c Stratum basale 3 Curled uterine glands 4 Myometrium 5 Stroma of the endometrium 6 Epithelial cells of the uterine glands with glycogen collections at the apical pole NB 2a + 2b = Stratum functionale During the secretory or luteinizing phase (14th to 28th day) the endometrium differentiates itself due to the influence of progesterone (from the corpus luteum) and attains its full maturity. The glands and arteries begin to entwine. The connective tissue stroma becomes the place of edematous changes. 62 The time period of the maximal reception ability for the blastocyst lies between the 20th and the 23rd day. This phase of the endometrium lasts 4 days and is usually termed the "implantation window" . Role and functional anatomy of the endometrium Normal implantation zone 1 Uterine cavity 2 Isthmus of the tube 3 Uterine tube (tuba uterina) 4 Uterine cervix (cervix uteri) In order that implantation can take its normal course, the blastocysts and the uterine mucosa must be able to interact. These two, independent structures must, therefore, undergo synchronous changes. The implantation normally takes place in the superior and posterior walls of the uterine body (corpus uteri) in the functional layer of the endometrium during the secretory phase of the cycle. extra-uterine pregnancy Placenta praevia 63 Role and functional anatomy of the endometrium Adhesion of the blastocyst to the endometrium A Menstruation B Proliferation C Secretion D Implantation window After the apposition of the free blastocyst at the uterine epithelium the microvilli on the surface of the outermost trophoblast cells interact with the epithelial cells of the uterus. In this stage the blastocyst can no longer be eliminated by a simple flushing out. The adhesion of the blastocyst on the endometrium arises through cell surface glycoproteins, the specific mechanisms of which, though, are not yet well understood. 64 Implantation stages 65 Implantation stages 1 Syncytiotrophoblast (ST) 2 Cytotrophoblast (CT) 3 Epiblast 4 Hypoblast 5 Blastocyst cavity 6 Maternal blood capillary 7 Amniotic cavity 8 Amnioblasts 9 Fibrin plug 10 Trophoblast lacunae 11 Multiplying hypoblast 1 Epithelium of the uterine mucosa 2 Hypoblast 3 Syncytiotrophoblast 4 Cytotrophoblast 5 Epiblast 6 Blastocyst cavity 1 Hypoblast growing ventrally 2 Eroded maternal capillaries 3 Extraembryonic reticulum 4 Heuser´s membrane 5 Amniotic cavity 6 Cytotrophoblast 7 Syncytiotrophoblast 8 Lacunae, filled with blood In the periphery the syncytiotrophoblast forms a syncytium, i.e., a multi-nucleic layer without cell boundaries that arises from the fusion of cytotrophoblast cells. The syncytiotrophoblast produces lytic enzymes and secretes factors that cause apoptosis of the endometrial epithelial cells. The syncytiotrophoblast also crosses the basal lamina and penetrates into the stroma. Numerous "implantation factors" are known: Interleukin 1 (IL-1), the inhibition factor for leukocytes (LIF), the colony-stimulating factor (CSF), as well as the epithelial growth factor (EGF) and its receptors (EGF-R). 66 Embryonic disk • The bilaminar germ disk (2nd week) • The trilaminar germ disk (3rd week) 67 Embryonic disk Development during the 2nd embryonic week 1 Extraembryonic mesoblast 2 Amniotic cavity 3 Primary umbilical vesicle In the bilaminar primordium of the embryo (hypoblast or primary endoderm and epiblast) one recognizes in the epithelium of the epiblast a fluid-filled space, the first primordium of the amniotic cavity. Ventrally, the roof of the still incompletely uncovered primary umbilical vesicle (previously the blastocyst cavity) is formed by the hypoblast. Schematically, amniotic cavity and primary umbilical vesicle together form two hemispheres with two layers (epi- and hypoblast) lying close to one another, thus representing the first embryonic primordium. However, only the epiblast is responsible for forming the embryo. The hypoblast develops into a part of the extraembryonic appendages. 68 Embryonic disk The trilaminar germ disk (3rd week) Formation of the primitive streak 1 Primitive groove 2 Primitive pit 3 Primitive node 4 Oropharyngeal membrane 5 Cardial plate 6 Sectional edge of amniotic membrane 7 Mesoderm 8 Endoderm 9 Future cloacal membrane 1+2+3 primitive streak Primitive groove 2 Epiblast 3 Extraembryonic mesoblast 4 Definitive endoblast 5 Invading epiblastic cells forming the intraembryonic mesoblast 6 Hypoblast The bilaminar germ disk differentiates itself further into a trilaminar embryo, in that the cells flow in over the primitive streak between the two already existing germinal layers and so form the third embryonic germinal layer (mesoblast/derm). This phenomenon is also termed epithelio-mesenchymal transition (gastrulation in lower vertebrates). During this period the embryo experiences profound alterations. Afterwards, one speaks of the dorsally lying ectoblast/derm (and no longer of an epiblast/derm), from intermediate mesoblast/derm, as well as from ventrally lying endoblast/derm, which replaces the hypoblast. In order to have a better overview, the developments of the third week should be divided into 69 several phases. One must keep in mind, though, that these do not always follow each other - they can just as easily take place concurrently. Embryonic disk Genesis of the notochord The chordal process at roughly the 19th-21st day (Stage 7) 1 Chordal process 2 Primitive node 3 Embryonic endoblast 4 Amniotic cavity 5 Body stalk 6 Extraembryonic mesoblast 7 Allantois 70 Embryonic disk The chordal process at roughly the 23rd day (Stage 8) 1 Fused chordal process 2 Prechordal plate 3 Pharyngeal membrane 4 Embryonic endoblast 5 Amniotic cavity 6 Neural groove 7 Canalis neurentericus 8 Intraembryonic mesoblast 9 Cloacal membrane 10 Umbilical vesicle 11 Allantois 71 Embryonic disk The chordal process at roughly the 25-28th day (Stage 9-10) 1 Chordal process 2 Embryonic endoderm 3 Amniotic cavity 4 Neural groove 5 Body stalk 6 Intraembryonic mesoblast 7 Prechordal plate 8 Pharyngeal membrane 9 Cloacal membrane 10 Aortae 11 Umbilical veins 12 Cardiogenic plate 13 Allantois Summary: the notochord determines the longitudinal axis of the embryo. It defines the future situation of the vertebral body and induces the ectoblast in its differentiation to 72 become the neural plate. Embryonic disk Location of the epiblast cell target and the development of the primitive streak Dorsal view of the primitive 1 Primitive streak streak at around the 17th day 2 Prechordal plate 3 Primitive node 4 Neural plate 5 Cloacal membrane 6 Chordal process 1 Primitive streak 2 Primitive node 3 Neural tube 4 Cloacal membrane 5 Prechordal plate 6 Chordal process 21st day 19th day 23rd day 73 Embryonic disk Induction of the neural plate - neurulation Neural plate: 19 – 23rd day Neural plate at roughly the 25th day 1 Neural plate 2 Primitive streak 3 Primitive nodes 4 Neural groove 5 Somites 6 Cut section of the amnion 7 Neural folds The neural tube at roughly The neural tube at roughly the 29th day the 28th day 1 Neural tube 2 Neural fold 3 Neural groove 4 Somites 5 Neural crest 6 Protrusion of the pericardium 7 Cranial neuropore 74 8 Caudal neuropore Embryonic disk The forming neural crest (neural plate stage) A Neural plate stage B Neural groove stage 1 Epiblast 2 Neural groove 3 Neural crest Migrating neural crest cells (neural groove stage) Neural crest after a completed detachment (neural tube stage) 1 Epiblast 2 Neural fold 3 Migrating neural crest cells 4 Neuroepithelium 5 Central canal 6 Neural tube 75 Development of the umbilical cord Body stalk at around the 3rd week Formation of the umbilical cord at around the 3.5th week A Body stalk B Stem of umbilical vesicle C Umbilical cord 1 Amniotic cavity 2 Umbilical vesicle 3 Chorionic cavity 4 Villous chorion 5 Allantois The body stalk and the yolk stalk are now united and form the umbilical cord. Through increasing secretion of amniotic fluid the chorionic cavity becomes obliterated. Here at around the 4.5th week: The chorionic cavity is reduced in size Flexing of the embryo at around the 8th week with expansion of the amnion that encircles the body stalk and the ductus omphalo-entericus, the umbilical coelom and the umbilical vessels 76 Embryonic phase • The Carnegie stages • Congenital abnormalities • Embryopathies 77 The Carnegie stages The embryo can be classified according to its age, its size or its morphologic characteristics. The correlation between these three criterias will allow identifying the embryonic Carnegie stages. This separation into stages was originally developed by Streeter (1942) who termed the various organizational stages "horizons". Later this scheme was completed by O'Rahilly and Müller (1987) who spoke more simply of embryonic stages or Carnegie stages. Taking into consideration various external and internal landmarks of embryonic development, it was decided to divide the 8 embryonic weeks (56 days) into 23 Carnegie stages. The fetal period that begins after the 8th week is characterized by the growth and maturation of the organs. The inner and outer morphologic alterations are less noticeable. For this reason 78 one no longer divides the fetal period into Carnegie stages. The Carnegie stages Stage 1 Approx. 1rst day 0.1 0.15 mm 1 Male pronucleus 2 Female pronucleus 3 Doubled paternal centrosome 4 "Inner bodies" Stage 11 Approx. 29th day 2.5 4.5 mm 1 Neural tube 2 Caudal neuropore 3 Rostral neuropore that is just closing 4 Somites 5 2. pharyngeal arch 6 1. pharyngeal arch Stage 22 Approx. 53rd day 23 28 mm 1 Umbilical cord with physiologic hernia 2 Nose 3 Subcutaneous vessel network of the head 4 Ear 5 Elbow 6 Pronation of the hands 7 Knee 8 Supination of the feet 9 Well-developed toes 10 Remainder of the embryonic tail 79 Inherited or congenital abnormalities Segment A represents the embryonic period in which the embryo is especially sensitive with respect to developmental abnormalities. Within the first eight weeks, the incidence of deformities (blue curve), which lead to miscarrieages, decreases from more than 10% to 1%. The frequency of neural tube defects decreases from 2.5% to 0.1% (green curve) by the end of the embryonic period. A Embryonic period B Fetal period 0-3 Death of the embryo is possible 3-8 Susceptibility to abnormalities is increased 8-38 Functional disorders are more likely 80 Classification of the congenital abnormalities •Primary abnormality: Defect (genetic anomaly) in the structure of an organ or a part of an organ that can be traced back to an anomaly in its development (spina bifida, cleft lip, congenital heart defect). •Secondary abnormality ("disruption"): Interruption of the normal development of an organ that can be traced back to outer influences. Either teratogenic agents (infection, chemical substance, ionizing radiation) or a trauma (amniotic bands, which led to an amputation) are involved. The most widespread infectious agents are the rubella virus, the cytomegaly virus and the toxoplasmosis parasite (toxoplasma gondii). To the chemical, teratogenic agents belong thalidomide, warfarin, chloroquine (malaria medicine) and lithium. It is important to understand that a congenital abnormality is not necessarily inherited. •Deformation: Anomalies that occur due to outer mechanical effects on existing normal organs or structures. •Dysplasia: Abnormal organization of the cells in a tissue (e.g., osteogenesis imperfecta). Numerous dysplasias are genetically caused (e.g., achondroplasia). •Agenesia: The absence of an organ due to a development that failed to happen during the embryonic period. •Sequence: When one, single factor results in numerous secondary effects, leading to several anomalies, one speaks of a sequence (e.g., Potter's sequence: not enough amniotic fluid because urine was not produced in large enough quantities. This leads to an oligoamnios. The fetus is crushed, the face is contused, the hips are shifted, and the lungs are smaller than normal [hypoplasia]). •Syndrome: A syndrome comprises a group of anomalies that can be traced to a common origin (Down syndrome occurs due to a trisomia of the 21rst chromosome and leads to a number of characteristic anomalies). 81 Primary abnormalities •Gene aberrations: Gene aberrations account for roughly 7.5% of congenital abnormalities. Either monogenetic mutations or polygenetic mutations are involved that can be further inherited in accordance with Mendel's laws. •Chromosomal aberrations: •One also distinguishes here two kinds: structural and quantity aberrations. They comprise roughly 0.5 % of the congenital abnormalities. •Multifactorial anomalies: They can be traced back to several genes and can be influenced by environmental factors (medications, chemical products). To this group belong all abnormalities of the neural tube, harelips and cleft palates, as well as cardiaccirculation-disorders, dysplasia of the hips, and cryptorchism. 82 Secondary abnormalities -They are due to the influence of teratogenic factors on an individual who was originally normal. Secondary abnormalities depend on the health of the mother, on the moment at which the violation occurred, on the nature of the responsible agent and on the genetic predisposition of the child. - There are numerous teratogenic factors that can be put into the following order: Infectious agents Medications, hormones and chemical products Physical agents (ionizing radiation) Other factors (metabolites, toxic substances) - Teratology (teras: monster) is concerned with congenital abnormalities. Teratogenesis is the area of embryology that studies the causes, the mechanisms and the models of developmental anomalies. One of the concepts of teratogenesis is that certain periods during the development are more susceptible to teratogenic agents than others. In order to examine a potentially teratogenic substance one has to pay attention to several points: The vulnerable phase of the forming organ The dose of the teratogenic substance and how it is applied The genotype of the embryo The environment - Studies of potentially teratogenic substances can be performed in two ways. In the first method epidemiologic criteria are involved. Here one examines the relationship between the frequency of the anomalies that occur and a prenatal exposure to an agent. As an alternative, based on animal experiments, substances can also be tested concerning their teratogenic potential. The results cannot, though, always be transferred to humans directly (e.g., thalidomide). The examination of the teratogenic potential of a substance is made more difficult by the fact that most congenital abnormalities are multifactorial. For the resulting pathology the genetic structure of the individual also plays an important role.This is why a teratogenic substance can have catastrophic consequences for one individual while for another there are no effects. 83 Viral pathogens • • • • • Rubella virus: The rubella virus (that causes German measles) is a typical example of a teratogenic pathogen. When the mother is infected the virus can pass through the placental barrier thereby infecting the embryo or the fetus. It is thus very important to vaccinate women during childbearing years. During the first trimester the danger of anomalies due to infection in the first month amounts to roughly 50%, but decreases in the second month to 25% and in the third month to 15%. Symptoms of this form of embryopathy include cardiac defects, cataracts and deafness. In addition microcephalia, mental deficiency, chorioretinitis, glaucoma, microphtalmia and dental abnormalities are also diagnosed. In the 2nd and 3rd trimesters the risk for the appearance of fetal abnormalities are smaller (roughly 10%). Cytomegalovirus: An infection with the cytomegalovirus (HHV-5, human herpes virus) is the most frequently occurring one during the fetal period and affects roughly 3% of pregnant women. One assumes that during the embryonic period this infection is lethal and leads to a spontaneous miscarriage in the first trimester. Children that are infected in the early part of the fetal period are asymptomatic and are detected thanks to special diagnostic techniques. From the 2nd trimester an infection with the virus leads to the following disease pictures: retarded growth, changes in the CNS (microcephalia, cerebral atrophy, hydrocephalia, cerebellary hypoplasia, chorioretinitis, atrophy of the eyes) and hepatosplenomegalia. Herpes simplex: As a rule, an infection by the herpes simplex virus (HSV) occurs only in the late phase of the pregnancy. A fetal infection leads to mental deficiency, microcephalia, myocardiopathy, spasticity, retinal dysplasis and characteristic dermal wounds. Often the baby gets infected during birth due to a genital herpes infection of the mother. Around 50% of the children of infected mothers get infected during the birth process and half of them die from it. Delivery via caesarian section can prevent this. Varicella virus: The varicella virus is responsible for congenital abnormalities that appear in the course of the first four months. To these belong scarring, muscle atrophy, hypoplasia of the limbs and fingers, abnormalities of the eyes and the brain (mental deficiency). The teratogenic risk has been established only up to the 20th week. HIV (Human Immunodeficiency Virus): The HIV is responsible for the acquired immunodeficiency syndrome (AIDS). In the past few years, HIV infection of pregnant women has grown into a huge problem (worldwide 33.4 million people now carry the virus). When the mother is seropositive, a third of the children that she gives birth to become infected. The infection of the child occurs in utero in 1/3 of the cases. In 2/3 of the cases the infection occurs during the delivery and one supposes that it occurs via the feto-maternal blood exchange shortly or during the delivery or via contact with cervico-vaginal secretions and maternal blood during the passage through her genital apparatus. A caesarian section and an antiviral treatment are recognized measures for reducing the risk of infection. The congenital anomalies that occur due to an in utero infection can be retarded growth, microcephalia 84 and mental deficiency. Non-viral pathogens • • Toxoplasmosis: The toxoplasmosis pathogen is an intracellular parasite (toxoplasma gondii), which gets through the placenta and infects the embryo. Pregnant women should avoid household pets and should consume no raw meat or non-pasteurized milk. In the case of a first infection, the danger of infection at the beginning of the pregnancy is limited but is elevated towards the end. The earlier the infection occurs, the worse it is. The parasite lives in the blood, in the tissues, in the epithelial cells and in the leucocytes. The consequences of an infection are extremely grave in the course of the embryonic period: cerebral abnormalities (calcification) and ophthalmic abnormalities (chorioretinitis), microcephalia, microphtalmia and hydrocephalus. If the infection occurs at this point it is often lethal. Congenital syphilis: In Europe congenital syphilis is seldom encountered. In America, on the other hand, the disease is becoming an increasingly larger problem (frequency of 0.1% as estimated by the US Preventive Services Task Force organization, 1989). The pathogenic agent is Treponema pallidum, which is transmitted via sexual intercourse. An infected mother transfers the disease to her child. The treponema pallidum is always able to get through the placenta barrier. Nevertheless, it seems the fetus is only threatened by an infection after the 4th month. It is the first infection of the mother during pregnancy that causes a congenital syphilis in the baby. This becomes worse the longer the infection lasts. A treatment with antibiotics (penicillin) kills the microorganism. The early symptoms of an untreated congenital syphilis are mental deficiency, hydrocephalus, deafness, blindness, bone malformations and pathognomic abnormalities of the teeth (Hutchinson's teeth). To the late symptoms number the Hutchinson triad: keratitis, deafness, "screwdriver teeth". 85 Physical agents • Ionizing radiation: Ionizing radiation causes breaks in DNA strands and thus disturbs replication. The effects it has on the embryo depends on the absorbed dose (lethal dose: 150 cgy - centi Gray - in gonad dose), and on the developmental stage of the embryo or fetus. In Hiroshima and Nagasaki after the nuclear irradiation one determined that especially injuries in the area of the nervous system and the eyes occurred that resulted in psychomotoric retardation, microcephalia, spina bifida cystica and ophthalmic abnormalities (cataracts). Cerebral malformations were never diagnosed when an irradiation was below 50 cGy. According to this data, during a pregnancy, the dose of radiation, directed at the gonads, should never exceed 10 cGy. During a radiodiagnostic examination 2 cGy are emitted. A single x-ray should not, therefore, be grounds for an abortion. Nevertheless, in pregnant women, for safety reasons, every radiodiagnostic examination should avoid the pelvic region when possible. 86 Further factors • Maternal diabetes: Maternal diabetes leads to a disorder of embryonic and fetal development. Especially in the embryonic period a badly controlled diabetes with continuous hyperglycemia and an associated ketosis can increase the risk for congenital abnormalities by two or three times. Besides a macrosomia (size) and the holoprosencephalia (error in the separation of the brain into two hemispheres), one also observes an increase in heart diseases and the "caudal atrophy syndrome" • Phenylketonuria (PKU): Maternal phenylketonuria is a potential, metabolic teratogenic factor that increases the risk of abnormalities of the CNS and heart. These abnormalities can be prevented when the mother holds to a phenylalanin poor diet. 87 Summary • Spontaneously, around 2 to 3% of the children are born with a visible abnormality. At the time of delivery many anomalies are not yet recognizable. One assumes that up to 10% of the newborns have congenital anomalies. • • • • • The distribution of these abnormalities and their causes is as follows: Multifactorial, inherited origins: 10 - 20% Chromosomal origins: 3 - 5% Connected with irradiation: >1% Connected with medications or chemical substances: 4-5% Unknown origin: 65 - 70% 88 Fetal phase 89 Fetal phase In obstetrics the pregnancy weeks (PW) are normally reckoned from the date of the Last Menstrual Period (LMP). This is a point in time that many women can easily remember. Computed this way, the pregnancy lasts 40 weeks and the embryonic period - accordingly - 10 weeks. Caution is advisable, though, when wishing to calculate the moment of ovulation - and thus fertilization, closely connected with it - because the moment of ovulation can vary and depends on many factors (conditioned by the environment and psychological aspects). In embryology the temporal indices (i.e., the PW), therefore, always refer to the moment of fertilization even though in practical midwifery the time following the LMP is still used for computations. 90 Fetal phase • After the 8th week, the fetus takes on typical human features, even though at the end of the first trimenon, the head is still relatively large in appearance. The eyes shift to the front and the ears and nasal saddle are formed. The eyelids are also clearly recognizable now. On the body, fine lanugo hairs are formed, which at the time of birth are replaced by terminal hairs. The physiologic umbilical hernia that arises in the embryonic period 15-20 has mostly disappeared. In the second trimenon the mother feels the first movements of the child. In the last trimenon the subcutaneous fatty tissue is formed and stretches the still wrinkled skin of the fetus. The skin becomes covered more and more with vernix caseosa. This is a whitish, greasy substance und consists of flaked off epithelial cells and sebaceous gland secretions. In neonatology this vernix caseosa is an important criterion for judging the maturity of the child. If the birth occurs post-term, it disappears again. Stage 23 Approx. 56th day 1 Umbilcal cord with hernia 2 Nose 3 Eye 4 Eyelid 5 Ear (a: tragus, b: antitragus ) 6 Mouth 7 Elbow 8 Finger 9 Toes 10 Atrophied embryonic tail bud 27 31 mm Telencephalon Diencephalon Mesencephalon Metencephalon Myelencephalon Spinal cord 91 Fetal phase Development of the form and position of the fetus • In the fetal period large changes of the form no longer take place. It is a period of growth. With the increase in size, especially of the inner organs, and with the overall growth of the fetus it stretches itself out again and takes on its typical shape. Normally, it positions itself so it is aligned with the longitudinal axis of the mother and, 96 % of the time, with its head downwards (head presentation). Probably, the pearshaped form of the uterus is responsible for this, in that the head fits better into the narrower lower part than the lower extremities do. 92 Fetal phase Weight development • The following hormones are responsible for the intrauterine growth of the child: - Growth hormone (somatotropin), produced in the adenohypophysis, and insulin-like factors from the liver stimulate the growth and metabolism of cartilage, bones and muscles.· - Glucocorticoid (e.g. ACTH), produced in the adrenal cortex, accelerates fetal maturation. - Thyroid hormones (T3 and T4) released by the thyroid gland have an influence on fetal growth. - Insulin is an endocrine regulator of prenatal growth. - Local growth factors influence tissue growth and development. - Placental hormones have a large influence on the child's growth. The placenta 93 produces factors that are partly protective and partly stimulating. Acknowledgments Physicians Dr. med. R. Moffat Dr. med. G. Sartorius Dr. med. A . Raggi Dr. Astrid Ahler Clinical Researcher Dr. Maria De Geyter Dr. Sofia Forte Researchlab Dr. Hong Zhang Dr. Anne-Catherine Feutz Schneider Brigitte PhD Student Nadira M'Rabet Xiaoli Shen Flurina Pletscher Wang Xinggan Prof. Dr. med. Christian De Geyter Technicians Helga Grässlin Kornelia Weber Nicole Crisante Nadja Kuratli Mylène Eby Nurses Sandra Brodbeck Jacqueline Amstutz Simone Gänser Britta Bernauer Caroline Bamert Lorenza Tinelli Evelyne Dold Administration Florije Gashi Secretary Hanna Flükiger 94 Swiss Center of Applied Human Toxicology