Langman's Chapter 3-6 Embryology.pdf

CHAPTER First Week of Development: Ovulation to Implantation OVARIAN CYCLE At puberty, the female begins to undergo regu­ lar monthly cycles. These sexual q^cles are controUed by the hypothalamus. Gonadotropinreleasing horm one (GnRH), produced by the hypothalamus, acts on cells o f the anterior lob...

CHAPTER First Week of Development: Ovulation to Implantation OVARIAN CYCLE At puberty, the female begins to undergo regu­ lar monthly cycles. These sexual q^cles are controUed by the hypothalamus. Gonadotropinreleasing horm one (GnRH), produced by the hypothalamus, acts on cells o f the anterior lobe (adenohypophysis) o f the pituitary gland, which in turn secrete gonadotropins. These hormones, foUicle-stimulating horm one (FSH) and luteinizing horm one (LH), stimulate and control cyclic changes in the ovary. At the beginning o f each ovarian cycle, 15 to 20 primary-stage (preantral) foUicles are stimulated to grow under the influence o f FSH. (The horm one is not necessary to pro­ m ote development o f primordial follicles to the prim ary follicle stage, but without it, these primary follicles die and becom e atretic.) Thus, FSH rescues 15 to 20 o f these cells from a pool o f continuously forming primary follicles (Figs. 3.1 and 3.2). Under norm al conditions, only one o f these follicles reaches full maturity, and only one oocyte is discharged; the others degenerate and becom e atretic. In the next cycle, another group o f primary follicles is recruited, and again, only one follicle reaches maturity. Consequently, m ost follicles degenerate with­ out ever reaching full maturity. W hen a follicle becom es atretic, the oocyte and surrounding follicular cells degenerate and are replaced by connective tissue, form ing a corpus atreticum. FSH also stimulates m aturation o f follicular (granulosa) cells surrounding the oocyte. In turn, proliferation o f these cells is mediated by growth differentiation factor 9, a m em ber o f the transform ing growth factor-(3 (TGF-[3) family. In cooperation, theca interna and gran­ ulosa cells produce estrogens: Theca interna cells produce androstenedione and testosterone, and granular cells convert these hormones O to estrone and 17 P-estradiol. As a result o f this estrogen production: The uterine endometrium enters the follicular or proliferative phase. Thinning o f the cervical mucus occurs to allow passage o f sperm. The anterior lobe o f the pituitary gland is stimulated to secrete LH. At midcycle, there is an LH surge that: Flevates concentrations o f maturationpromoting factor, causing oocytes to com ­ plete meiosis I and initiate meiosis II Stimulates production o f progesterone by follicular stromal cells (luteinization) Causes follicular rupture and ovulation Ovulation In the days immediately preceding ovulation, under the influence o f FSH and LH, the vesicu­ lar follicle grows rapidly to a diameter o f 25 mm to becom e a mature vesicular (graafian) fol­ licle. Coincident with final development o f the vesicular follicle, there is an abrupt increase in LH that causes the primary oocyte to complete meiosis I and the follicle to enter the preovulatory mature vesicular stage. Meiosis II is also initiated, but the oocyte is arrested in metaphase approximately 3 hours before ovulation. In the meantime, the surface o f the ovary begins to bulge locally, and at the apex, an avascular spot, the stigma, appears. The high concentration o f LH increases collagenase activity, resulting in digestión o f collagen fibers surrounding the follicle. Prostaglandin levels also increase in response to the LH surge and cause local muscular contractions in the ovarian wall. Those contractions extrude the oocyte, which together with its surrounding granulosa cells from the región o f the cumulus oophorus breaks free (ovulation) Chapter 3 First Week o f Deveiopment: Ovulation to Implantation o c.2 ^ E £ Q ^ 2 ¿ C U O ¡75 o c (U > E ^ o 2 5 3 (/) ^ 3 ^ o g | g | o l l l.£ -H.y 0) 5 ^ :5 T3 > & - g.i I O E E Ü3 CÜ 0 IO Igro >..E5 3 ^ - 0 “ i i ^ E C CT ^ ? l l ro E — o c i5 O) 5 tn 3 D. a; £- o ro 0 TO 0) | £ 2 15 i I ? & í “> o O) n: s S.Í I 2 t i £ o ^ 5 cn x. o> C CD l i é Q ^ I- q « S o üJ = en. □: i: 0> 3 ^ w o 0 0)-,- = iZ £ 5 £ í a _ P art I General Embryology Primary oocyte Granulosa Zona pellucida Growing follicle Vesicular follicle FIGURE 3.2 A. Primordial follicle. B. Growing follicle. C. Vesicular follicle. Every day from the pool of prim or­ dial follicles (A), some begin to develop into growing follicles (B), and this growth is independent of FSH. Then, as the cycle progresses, FSH secretion recruits growing follicles to begin developm ent into vesicular (antral) follicles (Cj. During the last few days of m aturation of vesicular follicles, estrogens, produced by follicular and thecal cells, stim ulate increased production of LH by the pituitary gland [Fig. 3.1], and this hormone causes the follicle to enter the m ature vesicular [graafian) stage, to complete meiosis I, and to enter meiosis II, where it is arrested in metaphase approxim ately 3 hours before ovulation. and floats out o f the ovary (Fig. 3.3). Some o f the cumulus oophorus cells then rearrange themselves around the zona pellucida to form the corona radiata (Figs. 3.25 to 3.6). Corpus Luteum After ovulation, granulosa cells remaining in the wall of the ruptured follicle, together with cells from the theca interna, are vascularized by surrounding vessels. Under the influence o f Clinical Correlatas O vulation D u ring o v u la tio n , som e w o m e n fe e l a s lig h t pain, called m itte is c h m e rz [G erm án fo r “ m id d ie p a in ” ), because it n o rm a lly o ccurs ne a r th e m id d ie o f th e m e n s tru a l cycle. O vu la tio n is aiso g e n e ra lly acco m p a n ie d by a rise in basal te m p e ra tu re , w h ic h can be m o n ito re d to aid co u p le s in beco m ing p re g n a n t or p re v e n tin g pre g n a n cy. Some w o m e n fa il to o v u la te because o f a lo w c o n c e n tra tio n o f g o n a d o tro p in s. In th e s e cases, a d m in is tra tio n o f an a g e n t to s tim u ­ la te g o n a d o tro p in release, and henee o v u la ­ tio n , can be e m p lo ye d. A lth o u g h such d ru g s are e ffe c tiv e , th e y o fte n p ro d u c e m ú ltip le o vu la tio n s , so th a t th e líke lih o o d o f m ú l­ tip le pre g n a n cie s is 10 tim e s h ig h e r in th e s e w o m e n th a n in th e gen e ra l p o p u la tio n. LH, these cells develop a yellowish pigment and change into lutein cells, which form the corpus luteum and secrete estrogens and progesterone (Fig. 3.3C). Progesterone, together with some estrogen, causes the uterine mucosa to enter the progestational or secretory stage in preparation for implantation o f the embryo. Oocyte Transport Shortly before ovulation, fimbriae o f the uterine tube sweep over the surface o f the ovary, and the tube itself begins to contract rhythmically. It is thought that the oocyte, surrounded by some granulosa cells (Figs. 3 3 B and 3.4), is carried into the tube by these sweeping movements o f the fimbriae and by m otion o f cilia on the epithelial lining. Once in the tube, cumulus cells withdraw their cytoplasmic processes from the zona pellucida and lose contact with the oocyte. Once the oocyte is in the uterine tube, it is propelled by peristaltic muscular contractions of the tube and by cilia in the tubal mucosa with the rate o f transport regulated by the endocrine status during and after ovulation. In humans, the fertilized oocyte reaches the uterine lumen in approximately 3 to 4 days. Corpus Albicans If fertilization does not occur, the corpus luteum reaches máximum development approximately 9 days after ovulation. It can easily be recognized as a yellowish projection on the surface o f the ovary. Subsequently, the corpus luteum shrinks Chapter 3 First Week o f Deveiopment: Ovulation to Im plantation Granulosa cells A Mature vesicular follicle B Ovulation _E¡r Luteal cells C Corpus luteum FIGURE 3.3 A. Mature vesicular follicle bulging at the ovarían surface. B. Ovulation. The oocyte, in metaphase o f meiosis II, is discharged from the ovary together w ith a large number of cumulus oophorus cells. Follicular cells remaining inside the collapsed follicle differentiate into lutein cells. C. Corpus luteum. Note the large size of the corpus luteum, caused by hypertrophy and accumulation of lipid in granulosa and theca interna cells. The remaining cavity of the follicle is filled with fibrin. because o f degeneration o f lutein cells (luteolysis) and forms a mass o f fibrotic scar tissue, the Corpus albicans. Simultaneously, progesterone production decreases, precipitating menstrual bleeding. If the oocyte is fertilized, degeneration of the corpus luteum is prevented by hum an chorion ic gonadotropin, a hormone secreted by the syncytiotrophoblast of the developing embryo. The corpus luteum continúes to grow and forms the corpus luteum o f pregnancy (corpus luteum graviditatis). By the end o f the third month, this structure may be one third to one half o f the total size o f the ovary. Yellowish luteal cells continué to secrete progesterone until the end of the fourth month; thereafter, they regress slowly as secretion of progesterone by the trophoblastic component o f the placenta becomes adequate for maintenance o f pregnancy. Removal o f the corpus luteum of pregnancy before the fourth m onth usually leads to abortion. FIGURE 3.4 Relation of fim briae and ovary. Fimbriae collect the oocyte and sweep it into the uterine tube. Part I General Embryology PH AS E 1 Penetration o f the corona radiata Acrosome, Sperm nucleus Corona radiata cells PH AS E 2 P enetration o f the zo n a pellucida Inner acrosomal membrane dissolves Secondary oocyte in 2nd meiotic división PH AS E 3 Fusión o f the sperm and oocyte cell m em branes FIGURE 3.5 A. Scanning electrón micrograph of sperm binding to the zona pellucida. B. The three phases of oocyte penetration. In phase 1, spermatozoa pass through the corona radiata barrier; in phase 2, one or more spermatozoa penetrate the zona pellucida; and in phase 3, one spermatozoon penetrates the oocyte mem ­ brane while losing its own plasma membrane. Inset shows normal sperm atocyte w ith acrosomal head cap. Chapter 3 First Week o f Deveiopment: Ovulation to Im plantation _ET Perivitelline space Male pronucleus Spindie 2nd maturation división Fetnale pronucleus Polar bodies Centrosome FIGURE 3.6 A. Oocyte im m ediately after ovulation, showing the spindie of the second m eiotic división. B. A spermatozoon has penetrated the oocyte, which has finished its second m eiotic división. Chromosomes of the oocyte are arranged in a vesicular nucleus, the female pronucleus. Heads of several sperm are stuck in the zona pellucida. C. Male and female pronuclei. D,E. Chromosomes become arranged on the spindie, spiit longitudinally, and move to opposite poles. F. Two-cell stage. FERTILIZATION Fertilization, the process by which male and female gametes fuse, occurs in the ampuUary región o f the uterine tube. This is the widest part o f the tube and is cióse to the ovary (Fig. 3.4). Spermatozoa may remain viable in the female reproductive tract for several days. Only 1% o f sperm deposited in the vagina enter the cervix, where they may sundve for many hours. Movement o f sperm from the cer­ vix to the uterine tube occurs by muscular contractions o f the uterus and uterine tube and very little by their own propulsión. The trip from cer­ vix to oviduct can occur as rapidly as 30 minutes or as slov^ as 6 days. After reaching the isthmus, sperm become less motile and cease their migration. At ovulation, sperm again become motile, perhaps because o f chemoattractants produced by cumulus cells surrounding the egg, and swim to the ampulla, where fertilization usually oc­ curs. Spermatozoa are not able to fertilize the oocyte immediately upon arrival in the female genital tract but must undergo (1) capacitatíon and (2) the acrosome reaction to acquire this capability. Capacitatíon is a period of conditioning in the female reproductive tract that in the human lasts approximately 7 hours. Thus, speeding to the am­ pulla is not an advantage because capacitatíon has not yet occurred and such sperm are not capable o f fertüizing the egg. Much o f this conditioning during capacitation occurs in the uterine tube and involves epithelial interactions between the sperm and the mucosal surface of the tube. During this time, a glycoprotein coat and seminal plasma proteins are removed from the plasma membrane that overlies the acrosomal región o f the spermatozoa. Only capacitated sperm can pass through the corona ceUs and undergo the acrosome reaction. The acrosom e reaction, which occurs after binding to the zona pellucida, is induced by zona proteins. This reaction culminates in the release o f enzymes needed to penetrate the zona pellucida, including acrosin- and trypsin-like substances (Fig. 3.5). The phases of fertílization include the foUowing: Phase 1, penetration o f the corona radiata Phase 2, penetration o f the zona pellucida Phase 3, fusión o f the oocyte and sperm cell membranes E]_ Part I General Embryology Phase 1: Penetratíon of the Corona Radiata O f the 200 to 300 million spermatozoa normally depositad in the female genital tract, only 300 to 500 reach the site of fertilization. Only one of these fertilizes the egg. It is thought that the others aid the fertilizing sperm in penetrating the barriers protecting the female gamete. Capacitated sperm pass freely through corona cells (Fig. 3.5). Phase 2: Penetratíon of the Zona Pellucida The zona is a glycoprotein shell surrounding the egg that facilitates and maintains sperm binding and induces the acrosome reaction. Both bind­ ing and the acrosome reaction are mediated by the ligand ZP3, a zona protein. Release o f acrosomal enzymes (acrosin) allows sperm to penetrate the zona, thereby coming in contact with the plasma membrane o f the oocyte (Fig. 3.5). Permeability o f the zona pellucida changes when the head o f the sperm comes in contact with the oocyte surface. This contact results in release o f lysosomal enzymes from cortical granules lining the plasma membrane o f the oocyte. In turn, these enzymes alter properties o f the zona pel­ lucida (zona reaction) to prevent sperm penetration and inactivate species-specific receptor sites for spermatozoa on the zona surface. Other spermatozoa have been found embedded in the zona pellucida, but only one seems to be able to penetrate the oocyte (Fig. 3.6). Phase 3: Fusión of the Oocyte and Sperm Cell Membranes The initial adhesión o f sperm to the oocyte is mediated in part by the interaction o f integrins on the oocyte and their ligands, disintegrins, on fT- sperm. After adhesión, the plasma membranes o f the sperm and egg fuse (Fig. 3.5). Because the plasma membrane covering the acrosomal head cap disappears during the acrosome reaction, ac­ tual fusión is accomplished between the oocyte membrane and the membrane that covers the posterior región o f the sperm head (Fig. 3.5). In the human, both the head and the tail o f the spermatozoon enter the cytoplasm o f the oocyte, but the plasma membrane is left behind on the oocyte surface. As soon as the spermatozoon has entered the oocyte, the egg responds in three ways: 1. Cortical and zona reactions. As a result o f the release o f cortical oocyte granules, which contain lysosomal enzymes, (1) the oocyte membrane becomes impenetrable to other spermatozoa, and (2) the zona pel­ lucida alters its structure and composition to prevent sperm binding and penetration. These reactions prevent polyspermy (pen­ etration o f more than one spermatozoon into the oocyte). 2. Resumption o f the second m eiotic divi­ sión. The oocyte finishes its second meiotic división immediately after entry o f the sper­ matozoon. One o f the daughter cells, which receives hardly any cytoplasm, is known as the second polar body; the other daughter cell is the definitive oocyte. Its chromosomes (22 plus X ) arrange themselves in a vesicular nucleus known as the female pronucleus (Figs. 3.6 and 3.7). 3. Metabolic activation o f the egg. The activating factor is probably carried by the spermatozoon. Activation encompasses the initial cellular and molecular events associated with early embryogenesis. i FIGURE 3.7 A. Phase contrast view of the pronuclear stage of a fertilized human oocyte w ith male and female pronuclei. B. Two-cell stage of human zygote. Chapter 3 First Week o f Deveiopment: Ovulation to Implantation The spermatozoon, meanwhile, moves forward until it lies cióse to the female pronucleus. Its nucleus becomes swollen and forms the m ale pronucleus (Fig. 3.6); the tail detaches and degenerates. Morphologically, the male and female pronuclei are indistinguishable, and eventually, they come into cióse contact and lose their nuclear envelopes (Fig. 3.7A). During growth o f male and female pronuclei (both haploid), each pronucleus must rep­ lícate its DNA. I f it does not, each cell o f the two-cell zygote has only half o f the normal amount o f DNA. Immediately after DNA synthesis, chromosomes organize on the spindle in preparation for a norm al m itotic división. The 23 maternal and 23 paternal (double) chrom o­ somes split longitudinally at the centromere, and sister chromatids move to opposite poles, providing each cell o f the zygote with the nor­ mal diploid number o f chromosomes and DNA (Fig. 3.6D,E). As sister chromatids move to op­ posite poles, a deep furrow appears on the surface o f the cell, gradually dividing the cytoplasm into two parts (Figs. 3.6F and 3.75). Clinical Correlates C ontraceptive M ethods B arrier m ethods o f co n tra c e p tio n in d u d e th e m ale condom , m ade o f lá te x and o fte n conta in in g chem ical sperm icides, w h ic h fits over th e penis, and th e fem a le condom , m ade of p o iyureth ane, w h ich lines th e vagina. O ther b arriers placed in th e vagina include th e diaphragm , th e cervical cap, and th e c o n tra c e p ­ tiv e sponge. Horm onal m ethods are a n o th e r c o m m o n ly used fo rm o f co n tra ce p tio n. These app roaches p rovid e th e fe m a le horm ones estro g e n a n d / or progestin. These h o rm ones produce th e ir e ffe c ts by in h ib itin g o vu la tio n (by preventin g th e release o f FSH and LH fro m th e p itu ita ry gland), chan ging th e linin g o f th e uterus, and th icke n in g cervical m ucus, m aking it d iffic u lt fo r sperm to e n te r th e uterus. H orm onal c o n ­ tra c e p tio n can be provid ed th ro u g h b irth c o n ­ tro l pills, a skin patch, vaginal ring, in jection , or im p la n t. There are tw o typ e s o f c o n tra c e p tiv e pills: The fir s t is a co m b in a tio n o f estro g e n and th e pro g e ste ro n e ana logue progestin ; th e second is com posed o f p ro g e stin alone. Both pills are e ffe ctive , b u t one m ay s u it som e w o m en b e tte r th a n o th e rs fo r vario u s h e a lth -re la te d issues. A m ale “pill” has been developed and te s te d in clinical triáis. It co n ta in s a s y n th e tic androgen th a t pre ve n ts both LH and FSH secre tio n and e ith e r sto p s sperm pro d u c tio n [70% to 9 0 % o f m en] o r reduces it to a level o f in fe rtility. The in trau terin e device [lUD] is a sm all T-shaped u n it and th e re are tw o types: h o r­ m onal and copper. The h o rm onal device releases pro g e stin th a t causes th ic k e n in g of cervical m ucus to p re v e n t sperm fro m e n te ring th e uterus. AIso, it m ay m ake sperm less a c tiv e and bo th eggs and sperm less viable. The c opp er ty p e releases c opp er in to th e u te ru s th a t p revents fe rtiliz a tio n o r in h ib its a tta c h m e n t o f th e fe rtiliz e d egg to th e u terine w a ll. It aiso helps p re v e n t sperm fro m e n tering th e u te rin e tubes. Em ergency contraceptive pills (ECPs) are used as b irth co n tro l m easures th a t m ay p re ­ v e n t pregna ncy if taken 120 h ou rs a fte r sexual in tercourse. These pills m ay be adm in istere d as high doses o f pro g e stin alone o r in c o m ­ bin a tio n w ith estro g e n [Plan B). O ther types o f ECPs [m ife p ris to n e [R U -486 ] and ulip ris ta l a c e ta te [Ella]] a c t as a n tih o rm o n a l agents. AIso, m ife p ris to n e is e ffe c tiv e as an a b o rtifa cie n t if taken a fte r th e tim e o f im p la n ta tio n. S terilization is a n o th e r fo rm o f b irth co n ­ tro l. The m eth od fo r m en is a vasectom y, w h ic h pre v e n ts th e release o f sperm by blocking th e d u c tu s deferens, th e tu b e th a t tra n s p o rts sperm fro m th e te s te s to th e penis. The s te riliz a tio n m eth od fo r w o m en is tu b a l s te ril­ iza tio n in w h ic h th e u te rin e tu b e s are blocked or ligated. These procedures fo r bo th m en and w o m e n can be reversed in som e cases. In fe rtility In fe rtility is a probiem fo r 15% to 3 0 % of couples. Male in fe rtility m ay be a re s u lt o f in s u ffid e n t num bers o f sperm a n d /o r poo r m otility. N orm ally, th e e jacula te has a vo lu m e o f 2 to 6 mL, w ith as m any as 100 m illio n sperm per m illilite r. Men w ith 20 m illio n sperm per m illilite r o r 50 m illio n sperm per to ta l ejaculate [continued] i a _ P art I General Embryology are usua lly fe rtile. In fe rtility in a w o m a n m ay be due to a n um ber o f causes, in cluding occluded u te rin e tu b e s (m ost co m m o n ly caused by pelvic in fla m m a to ry disease), hos tile c e rv i­ cal m ucus, im m u n ity to sperm ato zoa, absence o f ovula tio n , and others. Clom iphene c itra te (Clomid) is a drug used to increase FSH co n ce n tra tio n s to s tim u la te o vula tio n. The drug is given ea rly in th e m en­ stru a l cycle to cause o vu la tio n in w o m en w ho do n o t o vu la te or w h o o vu la te irregulariy. AIso, it is given to s tim u la te egg d e v e lo p m e n t fo r use in in v itro fe rtiliz a tio n procedures. One p e rce n t to 2% o f all pregnancies in th e U nited S tates occur using assisted reproductive technology (ARTj. O ffspring fro m these conce ptions s h o w increases in p re m a tu rity (< 3 7 w e eks’ g estatlon), lo w birth w e ig h t (< 2 ,5 0 0 g], v e ry lo w b irth w e ig h t (