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Ovid: Oxford Handbook of Medical Sciences

Editors: Wilkins, Robert; Cross, Simon; Megson, Ian; Meredith, David Title: Oxford Handbook of Medical Sciences, 1st Edition Copyright ©2006 Oxford University Press, 2006, except ‘Clinical aspects’ section of Chapter 2 (Copyright by Keith Frayn) > Table of Contents > Chapter 10 – Reproduction and development Chapter 10 Reproduction and development The Genital Systems Anatomy of the pelvis and perineum The pelvis Comprises bony and soft tissue. The bony pelvis forms a ring that protects the pelvic contents (rectum; ureters; bladder; urethra; male reproductive system—ductus deferens, seminal vesicles, prostate; female reproductive system—uterus, uterine tubes, ovary, vagina) and articulates with the femurs. See Table 10.1 for male/female differences.

  • It is formed by the two pelvic (innominate or hip) bones, the sacrum, and the coccyx. The pelvic bones meet anteriorly at the pubic symphysis (a secondary cartilaginous joint, usually immobile) and, posteriorly, they articulate with the sacrum at the sacroiliac joints (a synovial joint but allows only minimal movement, transmits weight of upper body to the hip bones)
  • The pelvis is divided into the greater pelvis which lies above the pelvic brim (pelvic inlet) and the lesser pelvis which lies between the pelvic inlet and outlet
  • The sacrum consists of the fused five sacral vertebrae and contains formainae for the passage of the sacral spinal nerves
  • The pelvic bones are formed by the fusion of the ilium, the ischium, and the pubic bone shortly after puberty. All three bones contribute to the formation of the acetabulum
  • The superior ramus of the pubic bone forms the superior border of the obturator foramen.

The pelvic floor The pelvic floor is a group of muscles around the terminal part of the rectum and the prostate and urethra in the male and vagina and the urethra in the female. Damage to the pelvic floor results in prolapse of the pelvic contents and incontinence. The perineum The perineum overlies the pelvic outlet. It can be divided into an anterior urogenital triangle and a posterior anal triangle. The perineum is the area between the skin and levator ani. The anal triangle

  • Is similar in both sexes and contains the two ischiorectal fossae separated by the anal canal, the annocygeal ligament, and the perineal body.

The female urogenital triangle

  • Includes perineal membrane, vagina, clitoris, perineal body (knot of tissue between the vagina and anal canal to which muscles are attached), vestibule, and labia.

The male urogenital triangle

  • Includes erectile tissue of corpora cavernosa and corpus spongiosum that form the penis, and scrotum.

The urogenital region in both sexes is supplied by the internal pudendal artery (branch of internal iliac artery) and branches, and innervated by the pudendal nerve.

Table 10.1 Male—female differences in the pelvis
  Male Female
Acetabulum Large Small
Build Robust Thin
Inferior pelvic aperture Relatively small Relatively large
Obturator foramen Round Oval
Pubic arch Narrow Wide
Superior pelvic aperture Heart-shaped Oval or rounded

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Male genital system The male reproductive system functions to produce a continuous supply of functional spermatozoa from puberty to old age.

  • Spermatozoa are produced in the testes which are located in the scrotum so that the temperature is correct for spermatogenesis
  • Spermatozoa are modified, concentrated, and stored in the epididymis and transported toward the urethra by the vas deferens (which passes into the abdominal cavity through the inguinal canal)
  • Each vas descends into the pelvis where its terminal dilated ampulla joins the duct of the seminal vesicle in the interval between the rectum and prostate
  • The combined ducts form an ejaculatory duct which pierces the prostate and empties into the urethra
  • The prostate surrounds the first part of the urethra as it leaves the bladder and its secretions drain into the urethra via a number of small ducts. Together, the secretions of the seminal vesicle and the prostate form the main part of the ejaculate
  • The prostatic urethra leaves the pelvis by piercing the perineal membrane that separates the pelvis from the perineum
  • In the perineum, the urethra dilates to form the bulb of the urethra which is surrounded by cavernous erectile tissue (corpus spongiosum) and by striated muscle (bulbospongiosus), contraction of which causes ejaculation of semen
  • Ducts of two small bulbo-urethral mucous secreting glands also enter the urethral bulb
  • On either side of the perineum, a second mass of erectile tissue (corpus cavernosum), covered with smooth muscle, joins with the corpus spongiousum and urethra to form the shaft of the penis.

Blood supply and innervation (Fig. 10.1)

  • The testes and vas deferens receive a dense plexus of autonomic fibres which reach them by running along their arteries. The prostate and seminal vesicles receive autonomic fibres from the pelvic plexuses
  • The testes are supplied by testicular arteries which arise from the abdominal aorta. The vas deferens, prostate, and seminal vesicles are supplied by branches of the internal iliac artery. The prostate also receives blood from the internal pudendal artery
  • Arteries of the penis derive from the internal pudendal artery.
Fig. 10.1 Nerve supply to the penis and accessory sex organs. (Reproduced with permission from Pocock G and Richards CD (2004), Human Physiology: The Basis of Medicine, 2nd edn, Oxford Univesity Press.)

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Female genital system The female reproductive system (Figs. 10.2, 10.3) functions to produce (usually) one ovum in each reproductive cycle and also to activate the spermatozoa and to house, nourish, and then expel the resultant offspring at the end of the pregnancy. The mammary glands then provide milk to nourish the infant.

  • Fertilizable ova are produced and ovulated by the ovaries then transported toward the uterus by the uterine (Fallopian) tubes (oviducts) in which fertilization usually occurs
  • Each uterine tube runs through the upper margin of the broad ligament to join the uterus (comprising muscular fundus and body and fibromuscular cervix), situated between the bladder and the rectum. Benign tumours of the uterine muscle wall form ‘fibroids’
  • During pregnancy, the uterus must expand to accommodate the developing foetus so that, at term, it nearly fills the abdominal cavity
  • The neck of the uterus is guarded by the cervix which opens into the anterior wall of the vagina. The cervix and, through it the uterus, are held in place by the fibromuscular tissue of the pelvic floor
  • The vagina pierces the perineal membrane to open onto the vestibule immediately behind the urethra
  • Within the vestibule, smaller masses of cavernous tissue form the bulb of the vestibule and clitoris and greater vestibular glands secrete mucous for lubrication
  • The vestibule is bounded on either side by labia (major and minor)
  • Because, during childbirth, the foetus must pass through the birth canal within the bony pelvis, the cavity of the female pelvis differs from that of the male in ways that facilitate the passage of the foetus
  • The mammary glands (breasts), situated on the anterior chest wall, develop during pregnancy so that after childbirth their secretory alveoli produce milk p.622
  • This milk is expelled through lactiferous ducts to collect in lactiferous sinuses which open onto the nipple and from which milk is extruded during suckling by the milk-ejection reflex.

Blood supply and innervation The uterus is supplied by the uterine artery (a branch of the internal iliac artery) which runs in the broad ligament and anastomoses with branches of the ovarian artery. The uterine artery also supplies the upper part of the vagina. The ovary is supplied by the ovarian artery (a branch of the abdominal aorta). Veins run in the broad ligament to drain into the internal iliac vein.

Fig. 10.2 Sagittal section of female pelvis. Note: the rectum is not normally distended until just before defaecation.
Fig. 10.3 MRI of the female pelvis mid line sagittal system. Normal uterus (U), cervix (arrow), vagina. The planes of the inlet and outlet are marked. B = bladder; S = sigmoid colon; R = rectum; SI = small intestine.

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Sexual differentiation (p.660)

  • In the fourth week of foetal life, primordial germ cells can be distinguished close to the root of the yolk sac
  • The primordial germ cells migrate up the posterior abdominal wall, multiplying en route until they reach the developing gonadal ridge, medial to each mesonephros.

Chromosomal sex XX = female; XO = female; XY = male; XXY = male. Generally, a Y chromosome nearly always leads to a male phenotype. Male differentiation

  • Embryos with XY sex chromosomes express the gene SRY (sex-determining region Y) on the Y chromosome which causes the gonad to develop as a testis
  • Mesoderm of the gonadal primordium differentiate into Sertoli cells and are enclosed by basement membrane to form primitive seminiferous tubules
  • In the interstitial tissue between the tubules, Leydig cells develop and begin to secrete testosterone by the seventh week
  • Testosterone diffuses locally to stimulate growth and differentiation of the male reproductive tract from the mesonephric/Wolffian system. The Sertoli cells also secrete anti-Mullerian hormone which suppresses development of the paramesonephric Mullerian system which forms the female reproductive tract
  • Testosterone is converted to dihydrotestosterone in target tissues to stimulate the differentiation and growth of male external genitalia via actions at androgen receptors encoded by the X chromosome
  • Testosterone converted to estrogen in the brain acts to sexually differentiate certain regions involved in sexual behaviour.

Female differentiation

  • In the absence of a Y chromosome, the mesonephros ducts begin to disappear and an invagination of the coelomic epithelium forms along each gonadal ridge to form the paramesonephric/Mullerian duct
  • The Mullerian duct differentiates to give the vagina, ovary, uterus, and uterine tubes.

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Reproductive Function Production of male gametes The primordial germ cells that give rise to the gametes in both male and females originate within the primary ectoderm of the embryo during week two. They then detach from the ectoderm and migrate to the yolk sac. Between four and six weeks, the primordial germ cells migrate from the yolk sac to the posterior body wall via the gut and mesentery (p.608). Dual function of the testes The adult testes:

  • Produce sperm—the male gametes
  • Secrete androgens—the steroid hormones which regulate full male development. The principal androgen is testosterone.

Structure of the testes

  • The testes consist of large numbers of tightly packed seminiferous tubules, each surrounded by a basement membrane and a sheath of peritubular myoid cells separated by an interstitial space containing blood vessels, lymphatics, and the endocrine Leydig cells
  • Leydig cells produce and secrete androgens from cholesterol
  • Within each seminiferous tubule are cells derived from primordial germ cells—spermatogonial stem cells, spermatocytes, spermatids, spermatozoa, and specialized epithelial Sertoli cells
  • The Sertoli cells control and co-ordinate the development of germ cells. Between the Sertoli cells are numerous tight junctions which divide the tubule into a basal and adluminal compartment. The tight junctions form a blood–testis barrier which prevents the uptake of compounds that could disrupt spermatogenesis. Spermatogenesis, which begins at puberty, produces numerous gene products which are foreign to the immune system. Sertoli cells could protect against autoimmune reactions.

Spermatogenesis produces many spermatozoa from one stem cell

  • The production of a spermatozoon capable of fertilization takes around 64 days
  • The diploid stem germ cells (the spertogonia) lie on the basement membrane of the tubule. These divide, first by mitosis, and then meiosis, to become spermatocytes, spermatids, and spermatozoa. Mature spermatozoa are designed to deliver the haploid complement of DNA to an oocyte surrounded by the cumulus oophora and zona pellucida within the female oviduct. The essential features of spermatogenesis are:
    • Production of rearranged haploid set of chromosomes by meiosis
    • Condensation of DNA to protect it from damage
    • Production of a flagellum to propel the spermatozoon into the female tract
    • Production of the acrosome—an enzymatic knife—to allow the spermatozoon to penetrate the layers surrounding the oocyte
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    • Development of the capacity to fertilize an ovum and development of recognition molecules to bind to the oocyte
  • Each spermatogonium undergoes five mitoses to yield a primary spermatocyte committed to meiosis. The first division of meiosis produces two secondary spermatocytes which then undergo a second division of meiosis to produce four round haploid spermatids. These mature into spermatozoa by spermiogenesis
  • When spermatozoa leave the testis they are incapable of directional movement or fertilization. They take up to a week to pass through the epididymis, in which further maturation takes place so that they are capable of traversing the female tract and fertilizing an oocyte
  • Each testis produces 30,000–70,000 spermatozoa/sec—large numbers are required for fertile sexual intercourse
  • Infertility can be caused by abnormalities in spermatozoa but, if there is only a partial problem, active sperm can be separated from inactive and used in artificial insemination.

Control of testis function by gonadotrophins (LH, FSH) and testosterone During childhood, the testes are inactive. At puberty, LH and FSH are secreted by the anterior pituitary gland in response to hypothalamic GnRH (p.572). These are the main hormones governing testis function.

  • LH receptors are only found on Leydig cells and FSH receptors, only on Sertoli cells
  • LH acts on the Leydig cells to stimulate androgen production
  • Testosterone stimulates the development of secondary sexual characteristics: deepening voice, increased muscle mass, body hair, behaviour, etc. Androgens also pass into the seminiferous tubules to affect spermatogenesis by local paracrine mechanisms
  • Excess secretion of androgens is prevented by a negative feedback loop acting at both the hypothalamus and the pituitary to inhibit LH release
  • FSH acts on Sertoli cells to stimulate their cell division and is important in spermatogenesis and spermiogenesis. In humans, mutations of the FSH receptor are associated with reduced fertility, but not infertility
  • Testosterone and a peptide from Sertoli cells—inhibin—exert negative feedback on FSH.

Functions of the epididymis, seminal vesicles, and prostate

  • The epididymis serves as a reservoir for sperm with their passage through it taking 1–21 days. The spermatozoa and testicular secretions are then transported along the vas deferens and into the ejaculatory ducts
  • The seminal vesicles (60%) and prostate (20%) contribute to the seminal fluid
  • The seminal fluid provides nutrients and is alkaline, helping to neutralize the acidic fluid of the vagina and, thus, to increase the motility and fertility of sperm.

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Erection, emission, and ejaculation Sexual intercourse involves penile erection, penetration of the vagina by the penis, emission of fluid from the seminal vesicles, vas deferens, and prostate gland, and ejaculation.

  • Erection is a result of sacral parasympathetic reflexes (via pelvic nerve-pelvic plexus-cavernous nerve). Via increased nitric oxide synthesis, parasympathetic stimulation triggers dilation of the internal pudendal artery resulting in increased blood flow and erection
  • Emission is stimulated by sympathetic activation (T11–L2 hypogastric nerve-pelvic plexus-cavernous nerve)
  • Ejaculation is stimulated by somatic fibres running in the pudendal nerves (motor and sensory). Activation of the pudendal nerves stimulates contractions of the bulbocavernous and ischiocavernous muscles, resulting in expulsion of semen from the penis.

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Production of female gametes Dual function of the ovary The adult ovary:

  • Produces ova (Fig. 10.4), released at ovulation, throughout the reproductive years of women
  • Produces estrogens (predominantly 17β-estradiol) and progesterone—steroids important in the regulation of female reproductive function.

Maturation of primordial follicles to pre-ovulatory follicles: the follicular phase (Fig. 10.4)

  • The first half of the menstrual cycle is the follicular phase (days 1–14) and is the period during which a follicle undergoes growth and development which culminates in ovulation—rupture of the follicle and release of the oocyte from the ovary
  • Normally, only one ‘dominant follicle’ matures to ovulation in each cycle. The remainder become atretic and die
  • Follicle development is regulated by pituitary LH and FSH and also by estrogens produced by the follicle in response to LH and FSH
  • The follicle is made of three components: the theca interna and externa (several layers of cells), the granulosa cells within the follicle, and the oocyte
  • LH causes thecal cells to grow, divide, and secrete androgens. FSH stimulates the division of granulosa cells and activates them to convert this androgen to estrogens by stimulating production of the aromatase enzyme. Both LH and FSH together elicit full folliculogenesis
  • During the pre-ovulatory stage, under the influence of high-circulating LH concentrations, the meiotic division of the oocyte is completed, progesterone secretion commences, and the follicle ruptures to release the oocyte—ovulation (day 14)
  • Ovulation is suppressed in starvation, severe exercise, and emotional stress
  • Estrogens produced during the follicular phase stimulate
    • Contractile activity in the fallopian tubes
    • Uterine endometrium proliferation, to prepare for gamete transport and implantation respectively
  • Also, estrogens stimulate the production of thin, watery cervical mucous that is easily penetrated by sperm.

The luteal phase: formation of corpus luteum; secretion of progesterone and estrogen; luteolysis (Fig. 10.5)

  • The second half of the menstrual cycle (days 14–28), following ovulation, is the luteal phase. The post-ovulatory follicle becomes a corpus luteum under the influence of LH
  • The corpus luteum secretes progesterone which prepares the uterus to receive and nourish an early embryo in the event of fertilization and maintains the endometrium in a condition suitable for implantation and placentation. Progesterone also reduces myometrium excitability. Estrogens are also produced.
    Fig. 10.4 Internal structure of ovary showing the stages of follicular development, ovulation, the formation of the corpus luteum, and its subsequent regression. (Reproduced with permission from Pocock G and Richards CD (2004), Human Physiology: The Basis of Medicine, 2nd edn, Oxford University Press.)
    Fig. 10.5 Changes in: (a) pattern of secretion of gonadotrophins (FSH and LH); (b) plasma levels of estradiol 17β and progesterone. (Reproduced with permission from Pocock G and Richards CD (2004), Human Physiology: The Basis of Medicine, 2nd edn, Oxford University Press.)
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  • In the absence of fertilization, the corpus luteum degenerates around days 24–28 and steroid production stops. This is the process of luteolysis and marks the end of one menstrual cycle
  • As progesterone concentrations fall, the endometrium built up during the cycle is shed, together with blood from spiral arteries (days 1–4). This process is menstruation and marks the start of another menstrual cycle.

The hypothalamo-pituitary axis; endocrine control of menstrual cycle; gonadal hormone feedback (Figs. 10.5, 10.6) Cyclical variations in the concentrations of steroids and LH and FSH act together to ensure the regular release of mature ova and to prepare the body for fertilization and pregnancy.

  • Estrogens and progesterone secreted by the ovary regulate the secretion of LH and FSH by both positive and negative feedback
  • Very high concentrations of estrogens stimulate the anterior pituitary to initiate an LH surge which is crucial for the pre-ovulatory phase and ovulation. For the remainder of the cycle, negative feedback prevails and LH and FSH output is relatively low.
Fig. 10.6 Cyclical changes in body temperature, cervical secretions, and uterine endometrium in relation to the circulating levels of estradiol 17βand progesterone. (Reproduced with permission from Pocock G and Richards CD (2004), Human Physiology: The Basis of Medicine, 2nd edn, Oxford University Press.)

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Pregnancy Coitus and orgasm Coitus is the act of sexual intercourse which results in the ejaculation of spermatozoa (male gametes) into the vagina. The sexual response can be divided into four phases (‘EPOR’):

  • Excitement—increasing sexual arousal causes penile erection, thickening of the labia, secretion of cervical mucous (all activated by para sympathetic stimulation)
  • Plateau phase—sexual arousal intensified, distension of penis and testes, mucus secretion greater
  • Orgasmic phase—ejaculation in the male, contractions of uterus and anal and urethral sphincters in the female
  • Resolution phase—loss of pelvic vasocongestion. Followed by a short refractory period in the male during which further arousal is not possible.

Fertilization and preparation of the uterus for pregnancy (pp.630–1)

  • A sperm is only capable of fertilizing an egg if it first undergoes the acrosome reaction (capacitation)
  • The first stage of fertilization occurs when an activated sperm fuses with an oocyte in the fallopian tube. The newly fertilized egg (the zygote) then completes its second meiotic division and undergoes the cortical reaction to create a fertilization membrane which prevents further sperm from fusing with it
  • Sperm retain fertility up to 48hr post-ejaculation, while ova are viable 12–24hr after ovulation. Therefore, a short time is available during which coitus must take place for pregnancy to occur
  • The zygote alerts the mother to its presence by secreting human chorionic gonadotrophin (hCG) which prolongs the secretory life of the corpus luteum. This ensures that progesterone and the specialized endometrial layers of the uterus are maintained until the pregnancy can be supported by placental progesterone (around 6–8 weeks gestation)
  • Once the zygote begins to divide, it is termed an embryo. It continues to divide as it is transported along the fallopian tube towards the uterus
  • Estrogen levels, high at ovulation, promote the embryo transport to the uterus and induce endometrial proliferation
  • Progesterone induces secretory changes in the endometrium that enable the blastocyst/embryo to be successfully implanted.

The process of implantation; status of the foetus as an allograft

  • At implantation, the trophoblast tissue of the fertilized egg invades the endometrial tissue of the uterus by the growth of chorionic villi containing the foetal capillaries. As a result of the invasion, the maternal spiral arteries of the uterus are eroded and spill their blood into the spaces between adjacent chorionic villi. In this way, a dialysis pattern of blood flow is set up within the placenta such that foetal capillaries dip into maternal blood spaces
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  • The foetus is an allograft—a mother would not accept a skin graft from a child, yet allows the foetus to remain in the uterus for nine months. The uterus is not an immunologically privileged site and, during pregnancy, there is no overall immunosuppression of the mother. The foetus expresses unique histocompatibility proteins and it has been proposed that there is a local barrier around the trophoblast, local hormonal downregulation of lymph nodes, and the presence of suppressor cells.

Structure and function of the placenta (Fig. 10.7); placental villi During foetal life, the placenta carries out the functions normally carried out by the lungs, kidneys, and GI tract in the adult.

  • Oxygen diffuses passively from maternal to foetal blood, and carbon dioxide in the opposite direction. Glucose and amino acids move across the placenta from maternal to foetal blood by carrier-mediated transport, while free fatty acids diffuse passively across the lipid-rich placental barrier
  • Foetal waste products such as urea and bilirubin diffuse from foetal to maternal plasma down their concentration gradients
  • The surface area available for exchange is immense due to the extensive branching of the chorionic villi.
Fig. 10.7 The placenta in relation to adjacent structures during early pregnancy. (Reproduced with permission from Pocock G and Richards CD (2004), Human Physiology: The Basis of Medicine, 2nd edn, Oxford University Press.)

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Production and roles of placental hormones during pregnancy The placenta is also an important endocrine organ, secreting a variety of steroid and peptide hormones:

  • hCG—prevents regression of the corpus luteum to ensure continued progesterone secretion for up to 10 weeks gestation (p.618)
  • hPL—human placental lactogen is secreted from week 10 gestation. It contributes to proliferative changes in the breast in preparation for lactation and exerts important metabolic effects in the mother. It stimulates an increase in the maternal plasma levels of glucose, amino acids, and free fatty acids, ensuring that placental availability of essential metabolites for the foetus is optimal
  • Relaxin—promotes the relaxation of the pelvic ligaments to allow the foetus to pass through the pelvis
  • Progesterone—the placenta takes over from the corpus luteum as the major source of progesterone at week 10 to maintain the endometrium and reduce myometrial excitability (via downregulation of oxytocin and oxytocin receptors) as well as stimulate mammary development in readiness for lactation
  • Estrogens are secreted by the placenta (made from precursors of both foetal and maternal origin). They prepare the body for labour and lactation.

Parturition The onset of labour is marked by regular, painful uterine contractions and progressive dilation of the cervix. Labour consists of three stages:

  • First stage: the time from onset to full cervical dilation. Uterine contractions become progressively stronger to propel the foetus down the birth canal. At the same time, the amniotic sac ruptures (‘waters break’)
  • Second stage: the time from full cervical dilation until birth. It usually lasts 40–60 minutes
  • Third stage: the time from birth to the delivery of the placenta. Ergometrine, a smooth muscle stimulant, is often administered to enhance contractions and promote placental delivery.

Mechanism of parturition; hormonal control—role of oxytocin and prostaglandins

  • The nature of the trigger for parturition is poorly understood but it is believed that the foetus plays a role in determining the time of its birth and involves mechanisms in both the maternal and foetal nervous and endocrine systems
  • Foetal cortisol initiates a switch in the placenta away from progesterone synthesis to estrogen synthesis in the last few days of pregnancy. Estrogens, together with oxytocin and prostaglandin F2α (PGF2α), increase the contractility of the myometrium to bring about delivery
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  • Oxytocin is a peptide hormone synthesized in the hypothalamus and released from the posterior pituitary which stimulates uterine contractions during labour. Oxytocin secretion is stimulated by uterine distension and vaginal stimulation as the foetus head descends which, in turn, stimulates more oxytocin release (positive feedback—the Ferguson reflex). The number of myometrium oxytocin receptors increase in late pregnancy as progesterone levels fall
  • Gap junctions form between myometrial cells, ensuring a rapid spread of contractions
  • PGF2α production (stimulated by oxytocin) is synthesized by the myometrium and stimulates muscle contraction and cervical ripening (cervix softens and dilates). Labour can be induced at term using vaginal pessaries containing PGF2α.

Premature and delayed parturition

  • Normal ‘term’ in humans is 40 weeks after the last menstrual period. Both pre-term and post-term labour are hazardous. Pre-term because the foetus is not yet prepared for extra-uterine life and post-term because continued foetal growth and placental insufficiency pose problems for both delivery and foetal nutrition
  • Toward the end of pregnancy, a number of changes must occur in the foetus in preparation for postnatal life. Most of these are induced by the secretion of glucocorticoids which increase markedly towards term. Such changes include:
    • Production of surfactant in the lungs to allow lung expansion when air is first breathed
    • Changes to gut and liver enzymes to allow the foetus to metabolize its postnatal milk diet
  • Post-term, it is usual to induce labour by 42 weeks’ gestation.

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Mammary glands and lactation Lactation is the synthesis and secretion of milk by the mammary gland. Structure of the mammary gland (Fig. 10.8)

  • In the embryo, the mammary glands develop from modified skin glands
  • At birth, the breasts are the same in the male and female, with very few acini. Further development does not occur in males
  • At puberty, in females estrogens stimulate lactiferous glands to branch and lobules containing abundant acini develop. Fat deposition and connective tissue growth increase the size of the breast
  • Cyclic breast changes occur with the menstrual cycle due to fluctuations in estrogens and progesterone (premenstrually, breasts become swollen and tender).

Breast development in pregnancy and lactation, and its hormonal control

  • Mammary glands develop and the alveoli mature in response to placental hormones (placental lactogen, estrogen, and progesterone) during pregnancy
  • Massive development of the tubero-alveolar structure of the epithelium and ducts occurs to give 12–20 galactopoetic units, emptying into a common sinus at the nipple.

Lactogenesis—prolactin and other hormones Prolactin stimulates milk production. Maternal anterior pituitary prolactin (p.573) release is controlled negatively by dopamine, and dopamine agonists can be used to inhibit lactation.

  • The maintenance of lactation depends upon maternal prolactin release elicited by the suckling stimulus
  • The first milk (colostrum) formed in the mothers breast contains an abundance of antibodies to protect the foetus against any local infections. The antibodies are of the IgA type which are able to readily pass across the gut epithelium of the baby.

Milk-ejection reflex—oxytocin

  • The ejection of milk is stimulated by oxytocin (p.573) release from the posterior pituitary, elicited by suckling
  • Oxytocin acts to contract the myoepithelial cell surrounding the alveoli within the breast which, together with the negative pressure of suckling at the nipple, ensures milk ejection.

Lactation, raised prolactin, and fertility

  • The daily suckling stimulus reduces the pulsatile release of GnRH. This is probably the mechanism by which lactation can act to suppress fertility
  • Hypersecretion of prolactin by pituitary tumours (prolactinomas OHCM6 p.322) may cause galactorrhoea and infertility.
Fig. 10.8 Structure of the adult non-pregnant mammary gland. (Reproduced with permission from Pocock G and Richards CD (2004), Human Physiology: The Basis of Medicine, 2nd edn, Oxford University Press.)

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Age and reproductive status Females: childhood and puberty

  • In females, the fertile years are defined by menarche (the commencement of menstrual cycles) and the menopause (the cessation of menstrual cycles). Menarche occurs around 12 years and the menopause around 50 years of age
  • During childhood, LH and FSH rise gradually. Prior to menarche, around age 10, pulsatile release of LH and FSH is established and spurts of secretion occur during sleep. This results in increased estrogen secretion from the ovary (gonadarche) which triggers breast development and changes in body composition (adult females have twice the body fat and reduced skeletal muscle mass of males)
  • Increased androgen secretion by the adrenal cortex (zona reticularis) stimulates pubic hair growth (adrenarche)
  • The trigger for menstruation is not understood but is thought to include:
    • Increased ovarian senstitivity to LH and FSH
    • Increased pituitary sensitivity of positive feedback effects of estrogens
    • Attainment of either a critical body mass (around 47kg) or ratio of fat to lean mass
  • Menstrual cycles are disrupted in girls who lose large amounts of weight through anorexia, excessive exercise, or starvation.

Females: the menopause Menopause is the progressive decline in the female reproductive system.

  • Numbers of oocytes in the ovaries are depleted by atresia and ovarian responsiveness to LH and FSH decreases
  • Cycles become anovular and irregular before ceasing altogether
  • Estrogen and progesterone concentrations fall. FSH and LH circulating concentrations are high because of the loss of negative feedback inhibition by estrogen but no LH surge is seen
  • The loss of ovarian steroids results in: vaginal dryness, uterine muscle fibrosis, loss of breast tissues, depression, night sweats, hot flushes, increased risk of myocardial infarction, increased bone resorption and resulting bone weakness
  • The changes can be treated with hormone replacement therapy (HRT).

Males: childhood and puberty Between 10–16 years of age, boys show a growth spurt and develop full reproductive capacity.

  • Infancy to start of puberty: LH and FSH secretion and testosterone secretion is low
  • Start of puberty: increase in secretion of pituitary LH resulting in maturation of the Leydig cells and initiation of spermatogenesis
  • Testosterone plasma concentrations rise and trigger the secondary sexual characteristics: enlargement of the testes and penis, growth of pubic hair, appearance of facial hair, deepening of the voice due to thickening of the vocal cords and enlargement of the larynx.

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Is there a male menopause? A small decline in male reproductive function occurs with age: sperm production declines between age 50 and 80; plasma testosterone in men over 70 decreases and plasma concentrations of LH and FSH increase (though much less dramatically than in females). Precocious puberty and delayed puberty

  • Precocious puberty can arise from: tumours of the posterior hypothalamus; activating mutations of the LH receptor; thecal, granulosa, or Leydig cell tumours; gonadotrophin-secreting tumours
  • Delayed puberty can arise from: Kallman’s syndrome—a deficit in formation and migration of GnRH neurones in the developing brain which results in GnRH deficiency and LH and FSH deficiency; tumours of the anterior hypothalamus.

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Pharmacology of sex hormones Oral contraceptives The combined pill

  • Contains an estrogen and a progesterone and is taken for 21 consecutive days out of 28
  • Estrogen inhibits FSH release from the pituitary and, therefore, inhibits follicle development
  • Progesterone inhibits LH release from the pituitary and, therefore, inhibits ovulation
  • Both estrogen and progesterone alter the endometrium such that the receptivity to blastocyst implantation is reduced. Cervical mucous thickens such that sperm penetrability is decreased
  • Withdrawal of the progesterone precipitates a withdrawal bleed that simulates a period.

The mini-pill Contains only progesterone and acts by thickening cervical mucous and decreasing receptivity of the endometrium to blastocyst implantation. The ‘morning after’ pill Contains a high concentration of estrogen and inhibits implantation by accelerating the transport of the embryo in the fallopian tube so that it reaches the uterus before the secretory phase has occurred. Side-effects of oral contraceptives include minor symptoms of early pregnancy—nausea, breast tenderness, fluid retension, hypertension, and, in rare cases, thromboses. Hormone replacement therapy (HRT) Prevents symptoms of the menopause (p.624) by estrogen replacement with or without progesterone. Treatment of female infertility: in vitro fertilization (IVF)

  • The patient is given a GnRH agonist to suppress spontaneous gonadal activity and is then treated with gonadotrophins to produce many large mature follicles
  • Just before ovulation, several ova are obtained by laparoscopy. The ova are cultured for several hours and sperm (washed free of seminal fluid) added. The injection of a single sperm into the oocyte can also be performed (intracytoplasmic sperm injection) where the man has very few sperm. After 2–3 days, several 4–6 cell conceptuses are transferred to the uterus via the cervix
  • Problems with this approach include the high incidence of multiple pregnancies and frequency of early miscarriage.

Male contraception Not currently available. Long-acting GnRH agonists combined with testosterone have been studied as a possible male contraceptive but are not always effective in blocking spermatogenesis. Progesterone implants combined with monthly testosterone injections are currently in clinical trials. P.627
Male infertility Male hypogonadism (OHCM6 p.318) may be due to hypothalamic-pituitary disorders (e.g. LH and FSH deficiency), gonadal abnormalities (e.g. Klinefelter’s syndrome), or androgen insensitivity (e.g. testicular feminization). Erectile dysfunction (impotence OHCM6 p.316) is the inability to achieve or maintain an erection that is adequate for sexual intercourse. Causes may be psychogenic or due to disturbances in the nerve or vascular supply to the penis due to, for example, diabetes, hypertension, smoking, aging. Treatment of erectile dysfunction: viagra (OHCM6 p.317)

  • A type V phosphodiesterase inhibitor that potentiates the effect of nitric oxide by inhibiting the breakdown of cyclic guanosine monophosphate. This causes enhanced dilation of the internal pudendal artery and its branches, resulting in increased blood flow and erection
  • Side-effects include headache and visual disturbances.

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Human Embryology Introduction Embryology covers the period of prenatal development, from fertilization (day 0) up to birth 38 weeks later. This continuous process is divided into three phases:

  • Pre-embryonic development (weeks 1 and 2) Period of initial cleavage of the zygote, implantation into the uterine wall, and formation of the bilaminar embryo
  • Embryonic development (weeks 3–8) When all the major body systems are laid down and established. This phase is a time of rapid and dramatic developmental change
  • Foetal development (weeks 9-birth) When tissues and organs formed during the embryonic phase grow, differentiate, and mature so they are ready to function in postnatal life.

Nomenclature of embryonic axes These are equivalent to the following adult anatomical terms:

Adult Anterior–posterior Superior–inferior Left–right
= = = =
Embryonic Ventral–dorsal Anterior–posterior Left–right
=
or rostral–caudal
or cranio–caudal

Cell-cell interactions Embryological development depends on inductive interactions between different cell/tissue layers e.g. epithelial-mesenchymal interactions An inductive process is an interaction between non-equivalent cell populations whereby the responding cells undergo a change in fate. Such interactions require cell–cell communication e.g. by direct contact via gap junctions, cell–cell contact, or the production of diffusible factors by one cell type which impinge on a responding population. Examples of inductive interactions:

  • Mesoderm induction
  • Neural induction
  • Limb bud initiation
  • Nephron formation.

Congenital malformations Defects in body structure. Incidence: ~3% live births (estimate influenced by definition, rate of detection, geographic variation). This value represents a fraction of the whole since ~75% structurally abnormal foetuses will be aborted spontaneously. Each part and organ of an embryo has a critical or sensitive period during which its development may be disrupted. P.629
Causes

  • Environmental

Environmental factors cause 7–10% congenital abnormalities. Teratogens are environmental agents that cause, or raise the incidence of, a developmental anomaly following maternal exposure. Include:

    • Ionizing radiation
    • Drugs e.g. thalidomide
    • Viruses e.g. rubella
    • Maternal effects e.g. metabolic disorders
    • Trauma
  • Genetic

Estimated to cause at least one third of all birth defects. Major genetic errors cause failure in late embryonic or early foetal stages and include:

    • Numerical defects e.g. trisomy, monosomy
    • Structural defects: translocations, deletions, inversions, duplications
    • Single gene defects: account for 7–8% congenital abnormalities
  • Multifactorial

Many common congenital abnormalities have distributions that suggest multifactorial inheritance i.e. multiple genes may be involved and/or there is a gene/environmental interaction (e.g. cleft/lip palates). P.630
Fertilization and pre-implantation development (weeks 1 and 2) Fertilization between the female oocyte and the male sperm creates the new individual—the zygote. The zygote begins a series of mitotic cell divisions, called cleavage, producing daughter cells, called blastomeres, which remain totipotent up to the 8-cell stage. Clinical implications:

  • In vitro fertilization (IVF)
  • Pre-implantation prenatal diagnosis.

The embryo moves down the oviduct, reaching the uterus by day 4. It now consists of 16–32 tightly aligned blastomeres, called the morula. Compaction occurs, tightly aligning blastomeres and segregating them into two groups:

  • Inner cell mass (ICM) (or embryoblast)—give rise to the embryo
  • Outer cell mass (OCM) (or trophoblast)—contribute to the placenta.

Fluid is accumulated, which collects inside the blastocoel cavity. The ICM becomes displaced to one side—the embryonic pole. The embryo is now called the blastocyst (Fig. 10.9a). Implantation Begins about day 6, when the embryo attaches to the uterus endometrium. Endometrial cells adjacent to the implanting blastocyst undergo the decidual reaction and start to secrete growth factors and metabolites to support the embryo. Trophoblastic cells invade the uterine wall and differentiate into two populations:

  • An inner layer of mononuclear cells—the cytotrophoblast
  • A highly invasive outer layer, without distinct cell boundaries—the syncytiotrophoblast.

The trophoblastic cells expand, surrounding the blastocyst so it becomes embedded in the endometrium. During week 2, these trophoblastic cells begin to collaborate with uterine tissue to form the placenta. Implantation is complete by day 13. Embryos that implant outside the uterus cause ectopic pregnancies (95% in uterine tubes). Formation of the bilaminar germ disc (day 14) (Fig. 10.9b) During implantation, the ICM differentiates into two layers:

  • The epiblast
  • The hypoblast—adjacent to the blastocoel.

These comprise the bilaminar germ disc. A cavity forms in the epiblast (the amniotic cavity), splitting it into two layers. The epiblast layer abutting the cytotrophoblast will form the amnion, which eventually envelops the embryo. Two cell populations (extra-embryonic endoderm and extra-embryonic mesoderm) migrate from the hypoblast to line the blastocoel cavity, transforming it first into the primary yolk sac and then, the definitive/secondary yolk sac. This does not contain yolk, but will be an important site of blood formation. Extra-embryonic mesoderm splits, forming the chorionic cavity. The bilaminar embryo, and its associated amniotic and yolk sac cavities, is suspended in it, connected to the outer wall by the connecting stalk.

Fig. 10.9 (a) Events of the first 6 days of development of a human embryo. 1: oocyte immediately after ovulation; 2: fertilization 12–24 hours later results in the zygote; 3: zygote contains male and female pronuclei; 4: first mitotic division; 5: two cell stage; 6: 3 day morula made up of up to 16 blastomeres; 7: morula stage (16–32 bastomeres) reaches the uterine lining; 8: early blastocyst; 9: implanation occurs at around day 6. (b) The site of implanation at the end of the second week.

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Gastrulation and the establishment of germ layers (weeks 3 and 4) Gastrulation

  • Converts the bilaminar embryo to the three-layered embryo
  • Involves a complex series of cell movements
  • Begins with formation of the primitive streak.

Primitive streak (Fig. 10.10)

  • Forms on day 14 when epiblast cells pile up at the future posterior edge of the blastodisc
  • Clearly defined by day 15 or 16; composed of a narrow groove with the primitive node (or organizer) at the anterior end
  • The node has neural inducing and organizing properties
  • Provides the first morphological sign of the main embryonic body axes
  • Epiblast cells move through the streak, in a process called invagination
    • First wave of invagination displaces the hypoblast creating embryonic endoderm
    • Second wave spreads between the endoderm and epiblast, forming embryonic mesoderm
    • Epiblast cells that do not go through the streak form embryonic ectoderm
    • These three germ layers give rise to all the tissues and organs in the embryo.

Germ layer derivatives Ectoderm: skin and central nervous system Neural-inducing signals from the node and notochord cause ectodermal cells to thicken, forming the neural plate which rolls up and closes (neurulation), creating the neural tube, separating from non-neural ectoderm (Fig. 10.11). Neural crest is induced at the lateral edges of the neural plate; forms diverse mesodermal and neural derivatives, including melanocytes, dorsal root ganglia, and enteric nervous system. Non-neural ectoderm forms skin and associated structures e.g. nails and teeth enamel. Mesoderm: all skeletal and connective tissue, blood, muscle Subdivided into:

  • Axial mesoderm (notochord)
    • Forms the basis of the midline axial skeleton
    • Source of neural-inducing and patterning signals
  • Paraxial mesoderm
    • Condenses in segments either side of the notochord
    • In the head, these form somitomeres which contribute to head mesenchyme
    • In the trunk, they form 37 pairs of somites
    • Somites reveal the underlying segmental organization of the embryo.
Fig. 10.10 (a) Diagrammatic view of the dorsal side of a 16-day embryo germ disc showing the movement of surface epiblast cells (solid black lines) through the primitive streak and node and the subsequent migration of cells between the hypoblast and epiblast (dashed lines). (b) Diagrammatic cross-section at 15 days through the cranial region of the primitive streak showing invagination of epiblast cells. The first cells to move inward displace the hypoblast to create the definitive endoderm. Once definitive endoderm is established inwardly moving epiblast forms mesoderm.
Fig. 10.11 Neuralation: neural tube formation results from formation and fusion of neural folds. The tube then detaches from the ectoderm.

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Somites differentiate into (Fig. 10.12):

  • The sclerotome which migrates medially forming
    • The vertebral body (surrounding notochord)
    • The vertebral arch (surrounding neural tube)
  • The dermamyotome which splits into:
    • Dermatome: contributes to dermis (fat and connective tissue of the neck and back)
    • Myotome: differentiates into muscles (dorsal epimere and ventral hypomere)
  • Intermediate mesoderm
    • Differentiates into urogenital structures
  • Lateral plate mesoderm
    • Divides to line the intra-embryonic coelom (primitive body cavity) forming:
      • Somatic (parietal) mesoderm—adjacent to ectoderm, forms dermis and limbs
      • Splanchnic (visceral) mesoderm—adjacent to endoderm; gives rise to gut wall and vascular system.

Mesoderm is absent at two sites:

  • Buccopharyngeal membrane (anterior)
  • Cloacal membrane (posterior).

These mark the future ends of the gut tube. Endoderm Folds extensively to form the gut tube and associated structures (pp.648–9). Primitive streak regression

  • During gastrulation, the embryonic disc grows and elongates along the anteroposterior axis
  • The primitive streak gradually shortens (regresses) towards the posterior end of the embryo, disappearing by the end of week 4
  • Gastrulation is now complete
  • The extended period of gastrulation creates an anteroposterior gradient of development—thus anterior structures begin to differentiate, while gastrulation continues posteriorly.
Fig. 10.12 Diagram of a transverse section through an embryo showing somite differentiation. The ventral medial quadrant of the somite gives rise to the sclerotome cells which migrate medially forming the vertebral body. The rest of the somite, the dermamyotome, forms the dermatome and myotome, which gives rise to the dermis, and all the trunk muscles. It also gives rise to muscle cells that migrate into the limb bud.

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Embryonic folding and formation of body cavities (weeks 4 and 5)

  • Folding turns the flat, three-layered embryonic disc into a 3D structure
  • It is driven by differential growth, since the embryo grows more than the yolk sac
  • Incorporates the primitive body cavity called the intra-embryonic coelom
  • Takes place in three directions (Figs. 10.13, 10.14).

Rostral (anterior) folding Results in ventral positioning of:

  • Buccopharyngeal membrane/mouth
  • Cardiogenic regions/heart
  • Septum transversum/diaphragm.

Caudal (posterior) folding Results in:

  • Ventral positioning of cloacal membrane/anus and urogenital openings
  • Displaces the connecting stalk so that it merges with the neck of the yolk sac (both contribute to umbilical cord)
  • Formation of the allantois (outpocket of hindgut) which forms part of the bladder.

Lateral folding Results in: fusion of all three germ layers at the ventral midline.

  • Endoderm forms the gut tube
  • Somatic (parietal) and splanchnic (visceral) lateral plate mesoderm fuse, lining and enclosing the intraembryonic coelom. Somatic mesoderm coats the inside of the body wall; splanchnic mesoderm coats the endodermal gut tube and associated structures
  • Ectoderm fuses, covering the outside of the body with skin.

Subdivision of the body cavity (5th week) The intra-embryonic coelom is partially divided into:

  • Thoracic (pericardial) and
  • Abdominal (peritoneal) portions

by a mesodermal bar called the septum transversum, which later forms part of the diaphragm. Two spaces at the dorso-lateral edges of the septum transversum—the pericardial-peritoneal canals—are later sealed by pleuroperitoneal membranes. The diaphragm is made up of four elements:

  • Septum transversum (central tendon)
  • Pleuroperitoneal membranes (posterior diaphragm)
  • Paraxial mesoderm of the body wall (T7–T12)
  • Dorsal mesentery surrounding the oesophagus (the crura).

Incidence of diaphragmatic hernias: 1/2000 The primitive pericardial cavity splits into:

  • Pleural cavities
  • Pericardial cavity

by pleurocardial folds that originate along the lateral body wall and grow medially towards each other, between the lungs and heart, fusing at the end of week 5.

Fig. 10.13 Transverse sections showing development of the mesodermal germ layer at days 17 (a), 19 (b), 20 (c) and 21 (d). The thin mesodermal sheet gives rise to paraxial mesoderm (future somites), intermediate mesoderm (future excretory units), and lateral plate, which is split into parietal and visceral mesoderm layers lining the intraembryonic cavity.
Fig. 10.14 Sagittal midline sections of embryos at various stages of development demonstrating cephalocaudal folding and its effect on position of the endoderm-lined cavity. Presomite embryo (a), 7 somite embryo (b), 14 somite embryo (c), one month embryo (d). Note the position of the angiogenic cell clusters in relation to the buccopharyngeal membrane.

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Limb development Limb specification and identity

  • Paired limb buds appear at the end of week 4
  • Upper limb buds appear and develop slightly ahead of hind limbs
  • Limb identity (i.e. upper versus lower) is specified before they grow out.

Limb bud initiation and bud outgrowth

  • The early limb bud is composed of a core of somatic lateral plate mesoderm covered in a jacket of ectoderm
  • Reciprocal epithelial-mesenchymal interactions between these cell layers govern limb initiation and outgrowth
  • Signals from the mesoderm cause the overlying ectoderm to thicken forming the apical ectodermal ridge (AER) which edges the distal tip of the bud
  • The AER maintains a region of dividing cells at the tip of the limb called the progress zone
  • Signalling between the AER and the progress zone is required for bud outgrowth. Disrupting this signalling halts outgrowth, causing limb truncations.

Limb patterning (Fig. 10.15) Limbs are asymmetric and patterned in 3D:

  • Proximal-distal (shoulder to fingertips): limbs grow progressively; digits form last. The progress zone model proposes cells measure time spent in this zone—those staying a short time form proximal structures, those staying longer, distal elements
  • Anteroposterior (thumb to little finger): patterned by long-range signals emanating from a group of mesenchymal cells at the posterior limb margin called the zone of polarizing activity. Cells closest to it form posterior structures; those further away form anterior structures
  • Dorsal-ventral (back to palm of hand; extensor-flexor): patterning across this axis is controlled by non-ridge ectoderm.
Fig. 10.15 Signalling regions in the early limb bud. Proximal–distal outgrowth is regulated by epithelial–mesenchymal interactions between the apical ectodermal ridge (AER) and progress zone (PZ). Anteroposterior patterning is controlled by cells in the zone of polarizing activity at the posterior edge of the bud. Dorsal–ventral patterning is directed by non-ridge ectoderm. (a) Limb axes, (b) early limb bud, (c) adult hand.

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Differentiation of limb structures

  • Skeletal elements: condense from lateral plate mesoderm
  • Skin and associated structures: form from ectoderm
  • Blood vessels: differentiate from angioblasts in mesoderm
  • Muscles: arise from somitic mesoderm which invades the limb as a dorsal and ventral muscle mass giving rise to dorsal extensor and ventral flexor muscles
  • Nerves: ventral branches of spinal nerves C5-T2 upper, L4-S3 lower, innervate limb muscles. They come together at the limb bud base forming the plexus (brachial, upper limb; lumbosacral, lower limb) before separating to enter the limb. Sensory nerves follow motor nerves (Figs. 10.16, 10.17).

Limb shaping Sculpting the axilla (armpit) and separating the digits depends on programmed cell death. During weeks 6–8, limbs rotate from their initial position (roughly at right angles to the trunk) to assume their adult position.

Fig. 10.16 Origin of tissues in the limb. The myoblasts migrate from the dermomyotome into the limb, where they form ventral (flexor) and dorsal (extensor) muscle masses. Motor innervation from the ventral root region of the neural tube migrates through the cranial half of each sclerotome, where it joins sensory (dorsal root ganglion) nerve cells and their processes and Schwann cells, both derived from neural crest cells. Other neural crest cells forming melanocytes migrate dorsal to the somites. Surface ectoderm forms skin, hair, nails, and sweat and sebaceous glands.
Fig. 10.17 Development of segmental sensory innervation (dermatomes) of skin of upper limb.

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Cardiovascular system development

  • Cardiovascular system (CVS) anomalies = most common congenital defects—average at least 1 in 200
  • This reflects the complex demands of having to combine development with efficient CVS function
  • CVS develops early because by week 3, the embryo cannot get sufficient oxygen and nutrients or remove waste products by diffusion alone.

Formation of early blood vessels and simple heart tube

  • CVS is derived from mesoderm
  • In the yolk sac mesoderm, blood islands form creating a network of vessels
  • These link with left (L) and right (R) dorsal aorta that condense in the embryo
  • Paired endocardial tubes develop in the horseshoe-shaped cardiogenic region, anterior to the gastrulating embryo, from splanchnic mesoderm
  • Embryonic folding draws these tubes together which fuse in the midline, forming the primitive heart tube by day 22
  • Contractile activity begins just before fusion
  • Heart tube has an inner endocardial layer coated in myocardium, enclosed in epicardium.

From inflow to outflow the heart tube consists of:

  • Sinus venosus
  • Primitive atria
  • Ventricle
  • Bulbus cordis.

Three pairs of veins drain blood to the heart via the sinus venosus—the common cardinal, the vitelline, and umbilical veins. Blood leaves the heart through 1st aortic arch, which hooks over the foregut, joining the paired dorsal aorta. Vitelline arteries branch off to supply the yolk sac, and umbilical arteries reach the placenta.

  • Primitive heart tube loops to form the basic definitive shape by 4½ weeks (Fig. 10.18)
  • Looping = first morphological sign of L/R asymmetry
  • Looping affects blood flow through the heart tube.
Fig. 10.18 Early development of the heart tube.

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Circulatory system development Asymmetric changes in the blood outflow tract (aortic arches) and inflow tract (venous system) accompany changes in heart shape, ultimately producing systemic and pulmonary circulatory systems. Development of the aortic arches

  • Initially, blood leaves the heart through one pair of aortic arches (1st)
  • As the embryo grows, a series of additional arches form, called 2,3,4, and 6
  • These are never all present at once, but instead form progressively in a rostral/caudal sequence
  • Important derivatives are:
    • Carotid arteries (third arch)
    • Aortic arch (left fourth arch)
    • Pulmonary artery (sixth arch), connected to aorta via the ductus arteriosus in the foetus

Development of the venous system

  • Initially, bilaterally symmetrical but asymmetric changes during weeks 5 and 6 bias blood flow to enter just the R side of the heart
  • Rostrally, returning blood flows through a new vessel, (left brachiocephalic vein) linking L and R anterior cardinal veins, which drains into the R side of the heart, via the superior vena cava
  • Caudally, a capillary network develops in the growing liver from vitelline and umbilical veins. To bypass this, the ductus venosus forms, shunting blood from L umbilical vein to enter the R side of the heart, via the inferior vena cava. The R umbilical vein regresses
  • Pulmonary veins form as outgrowths of the L atrial wall.
Fig. 10.19 Development of the great arteries.

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Division of the heart (Fig. 10.20) Haemodynamic influences Blood entering the asymmetric heart tube creates differential pressures that act on the internal walls of the heart. These haemodynamic forces fundamentally affect heart shape during septation and distortions in them (e.g. caused by defective inflow vessels) may cause septation defects. Division of the atrioventricular canal and outflow tract (truncus arteriosus) (early 5th week)

  • Divided by endocardial cushions, derived from either endocardium (AV canal) or neural crest (truncus arteriosus)
  • Fusion between inferior and superior endocardial cushions splits the single AV canal into R and L. The cushions also contribute to the mitral (bicuspid) valve on LHS, tricuspid valve on RHS
  • A spiral septum forms in the truncus arteriosus which separates the future aorta and pulmonary artery
  • Aortic and pulmonary semilunar valves form at the distal tips of the ventricles from three endocardial swellings
  • Abnormal blood flow through the AV canal or truncus arteriosus may cause septation defects (e.g. unequal partition—leading to Fallot’s tetrology).

Atrial septation (late 5th–7th weeks)

  • Common atrium is divided by the septum primum growing down from the roof
  • It perforates superiorly as a result of apoptosis just before reaching the fused endocardial cushions at the AV canal
  • Septum secundum grows to the right of the septum primum overlapping the perforations
  • Together, these create an interatrial valve—the foramen ovale
  • At birth, this is sealed by blood pressure changes pressing the septa together
  • Incidence of atrial septation defects: 6/10,000 live births.

Ventricular septation (late 5th–7th weeks)

  • The muscular interventricular septum forms between the enlarging ventricles, leaving a small interventricular gap above
  • This closes by fusion between the membranous interventricular septum with the base of the spiral septum in the outflow tract
  • Failure is common, leading to an interventricular septal defect: 12/10,00.

Changes at birth At birth, the source of oxygen switches from placenta to lungs resulting in:

  • Foramen ovale closes—becomes fossa ovalis
  • Umbilical arteries close—become medial umbilical ligaments
  • Ductus arteriosus closes—becomes ligamentum arteriosum
  • Umbilical vein closes—becomes ligamentum teres
  • Ductus venosus closes—becomes ligamentum venosum.
Fig. 10.20 Septation of the heart: the developing heart bisected sagitally and viewed from the right (a1, a2, a3) and bisected coronally and viewed from the front (b1, b2, b3). The diagrams show the division (septation) of the right and left atria and ventricles and the formation of the aorta and pulmonary artery from the bulbus cordis.

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Development of the gut and associated structures

  • Embryonic folding creates the endodermal gut tube and incorporates the intra-embryonic coelom
  • The gut is initially connected to the body wall by ventral and dorsal mesenteries formed from splanchnic mesoderm
  • This ventral connection (except at stomach and liver levels) breaks down, leaving the majority of the gut tube suspended by the dorsal mesentery.

Connective tissue, muscles, and blood vessels surrounding the gut tube derived from splanchnic lateral plate mesoderm. The gut is initially blind-ended, sealed by buccopharyngeal membrane (rostrally) and cloacal membrane (caudally). These membranes mark the borders between ectodermally derived portions of the digestive tract, stomodeum (first part of oral cavity), and proctodeum (last part of anal canal). The gut is divided into:

  • Pharyngeal gut—gives rise to the pharynx and related structures
  • Foregut, midgut, and hindgut.

Foregut development

  • Blood supply = coeliac axis
  • Gives rise to oesophagus, trachea, and lung buds (p.652), stomach, and cranial duodenum
  • Associated structures: liver, gall bladder, and pancreas—which all bud off the duodenum
  • The stomach is suspended by the dorsal mesogastrium (part of the dorsal mesentery) and connected to the ventral body wall by the ventral mesentery (derived from the septum transversum), that also encloses the developing liver. As it grows, it rotates along its longitudinal axis pressing the duodenum against the dorsal body wall, creating a space = lesser sac. The rest of the peritoneal cavity = greater sac
  • The endodermal liver bud sprouts into the ventral mesentery at the foregut–midgut junction; remains linked to foregut by the bile duct from which buds off the future gall bladder and cystic duct. The liver bud forms hepatic cords that become parenchyma. Bile formation begins during 12th week
  • The pancreas develops from a dorsal and ventral pancreatic bud, which fuse together. Both buds branch extensively. The tips of the endodermal branches form the acini of the exocrine pancreas. The endocrine pancreas consists of ~/1 million Islets of Langerhans, scattered among the acini. The pancreatic and common bile ducts enter the duodenum together at the duodenal papilla
  • Spleen: considered a gut-associated structure but originates from mesodermal cells, which condense in the dorsal mesogastrium.

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Midgut development (Fig. 10.21)

  • Supplied by the superior mesenteric artery
  • Forms the caudal duodenum, jejenum, ileum, caecum, appendix, ascending colon and 2/3 transverse colon
  • Lengthens rapidly and, by early 6th week, herniates, also rotating 90° anticlockwise, into the umbilical cord as a hairpin loop, which at its apex remains connected to the yolk sac via the vitelline duct. During 10th week, it retracts into the peritoneal cavity and rotates anticlockwise 180° (i.e. total 270°rotation). Failure to retract fully, or rotate incorrectly, are common defects
  • The vitelline duct normally regresses but persists as a Meckel’s diverticulum in ~2% live births.

Hindgut development

  • Supplied by inferior mesenteric artery and middle rectal artery
  • Forms the distal 1/3 transverse colon, descending colon, rectum, and upper part of the anal canal
  • Ends at the cloaca, sealed by the cloacal membrane
  • Cloaca is divided by the urorectal septum, so when the cloacal membrane breaks down there are two exterior openings—the urogenital sinus and anus. Abnormalities in separation or cloacal size can cause the anus to exit abnormally via the vagina or urethra (fistulas) or be absent (atresia).

Gut fixation and recanalization (Fig. 10.22)

  • After gut retraction and rotation, some parts of the gut fuse with the dorsal body wall (fixation)—abnormalities in rotation and fixation may cause gut strangulation
  • During 6th week, proliferation of the epithelial endoderm transiently blocks the gut lumen. Recanalization, forming the definitive gut tube, is completed by week 9—failure leads to stenosis (narrowing) or duplications.
Fig. 10.21 Embryo during the 6th week of development, showing blood supply to the segments of the gut and formation and rotation of the primary and intestinal loop. The superior mesentric artery forms the axis of this rotation and supplies the midgut. The celiac and inferior mesenteric arteries supply the foregut and hindgut, respectively.
Fig. 10.22 (a) Anterior view of the intestinal loops after 270ocounterclockwise rotation. Note the coiling of the small intestinal loops and the position of the cecal bud in the right upper quadrant of the abdomen. (b) Similar view as in (a), with the intestinal loops in their final position. Displacement of the cecum and appendix caudally places them in the right lower quadrant of the abdomen.

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Respiratory system development

  • Respiratory system buds off the ventral wall of the foregut during week 4 at the level of the oesophagus
  • Epithelia of the alveoli, bronchi, trachea, and larynx are endodermal
  • Muscles, cartilage, and connective tissue that surround this layer are splanchnic mesoderm derived
  • Respiratory bud elongates forming the trachea, and a lung bud appears at the caudal end. It is separated from the oesophagus by the tracheoesophageal septum, only joining the gut tube at the larynx. Defective separation leads to fistulas and oesophageal atresia.

The lung bud initially splits into the right and left primary bronchi which divide further, showing left–right asymmetry.

  • Right forms three secondary bronchi and three lung lobes
  • Left bud forms two secondary bronchi and two lung lobes
  • Lung endoderm goes on developing by branching morphogenesis and budding forming the entire bronchial tree, which expands into the pleural cavities.

Respiratory system differentiation

  • Lung endoderm becomes coated with mesenchymal tissue derived from splanchnic mesoderm. In the upper respiratory tract, this differentiates into cartilaginous rings around the trachea and bronchi
  • Lung endoderm differentiates into the respiratory epithelium, eventually forming terminal sacs called alveoli
  • This epithelium matures late (95% of ~300 million alveoli develop after birth)
  • Gaseous exchange between blood and air only becomes possible in the seventh month, so lung maturation limits survival of premature babies
  • Insufficiency causes respiratory distress syndrome.

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Head and neck development The vertebrate cranial region has:

  • A neurocranium associated with the brain and major sense organs (nose/eye/ear)
  • A viscerocranium, formed from the pharyngeal (branchial) arches, associated with the oral region and pharynx.

Embryonic components of the head and neck (Fig. 10.23)

  • Neural tube and ectodermal placodes form the brain and special sense organs
  • The neural crest contributes to face, palate, tongue, pharynx, larynx, external and middle ear, and also forms the intrinsic eye muscles
  • Cranial paraxial mesoderm forms the muscles of the head, including extrinsic eye muscles
  • Occipital somites form the occipital part of the skull and tongue muscles.

Structure and derivatives of the pharyngeal arches (Fig. 10.24)

  • Five bilateral pairs of pharyngeal arches appear during weeks 4–5
  • Composed of bars of mesenchyme sandwiched between surface ectoderm and pharyngeal endoderm
  • Each arch has its own artery, cranial nerve, muscles, and skeletal element
  • Separated by pharyngeal clefts on the outer surface and by pharyngeal pouches on inner surface (outpocketings of the pharyngeal foregut)
  • Pharyngeal arch-derived structures include face, palate, tongue, thyroid gland, pharynx, larynx, and the external and middle parts of the ear.
Fig. 10.23 Contributions of neural crest, paraxial and lateral plate mesoderm to (a) the connective and skeletal tissues of the developing head in a 7mm embryo, and (b) the skull and anterior neck skeleton at term.
Fig. 10.24 Views of 7mm embryo, to show the early development of nose, eye, ear pharyngeal arches, and somites.

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Facial development The face and jaw originate from primordia that surround the primitive mouth (Fig. 10.25).

  • Neural crest from the cranial neural folds migrates ventrally and rostrally forming paired mandibular and maxillary processes and nasal swellings
  • Mandibular processes fuse medially, forming the lower jaw
  • Medial and lateral nasal swellings grow and partially surround the paired nasal placodes, which deepen into two nasal cavities. These remain separated by the nasal septum but are continuous with the oral cavity
  • Medial nasal swellings fuse together creating the intermaxillary segment, which forms the median part of the nose, philtrum, and primary palate
  • Maxillary processes fuse with the lateral nasal swellings (forming the side of the nose) and the nasolacrimal duct forms along this line of fusion
  • Maxillary and mandibular processes partially fuse forming cheeks
  • Inside the oral cavity, the maxillary segments project downwards, either side of the tongue, as palatal shelves which elevate and fuse together in the midline, and also with the primary palate, creating the definitive palate
  • If any of these fusions fail, congenital facial clefting occurs—most commonly cleft lip and palate.

Skull development

  • Base of the skull (chondrocranium) formed by endochondral ossification.
  • Skull vault (neurocranium) formed by direct dermal ossification.
  • Skull bones do not fuse together until early childhood, allowing cranium to deform during birth then expand during childhood as brain enlarges.
Fig. 10.25 Development of face; frontal views at (a) 5.5 weeks, (b) 6 weeks, (c) 7 weeks, and (d) 8 weeks of foetal life.

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Kidney development Kidney development is intertwined with the genital system (pp.660–3), as both develop from intermediate mesoderm. Three overlapping kidney systems form in rostral-caudal sequence (Fig. 10.26). Pronephros

  • Forms and regresses during week 4
  • Rudimentary and non-functional.

Mesonephros

  • Forms week 4; extending from T1–L3
  • Has S-shaped tubules draining into mesonephric ducts, which in the male participates in genital system formation, but regresses in females.

Metanephros

  • Definitive kidney appears week 5
  • Forms from the ureteric bud that branches off mesonephric duct and metanephric blastema.

Collecting system

  • Ureteric bud forms collecting ducts, which project into the metanephric blastema
  • Reciprocal epithelial-mesenchymal interactions between these tissues cause the bud to dilate and divide forming the renal pelvis and major calyces
  • Further branching eventually forms minor calyces and approximately 1–3 million collecting ducts.

Nephrons

  • = functional units of the kidney
  • Develop from metanephric blastema
  • Reciprocal inductive interactions induce the blastema tissue to form renal vesicles which lengthen into S-shaped tubules, each supplied by a capillary that differentiates into a glomerulus
  • The tubule and glomeruli form the nephron
  • The proximal end of the tubule forms Bowman’s Capsule; the distal end links to the collecting duct
  • Tubule elongation creates the proximal and distal convoluted tubule and Loop of Henle
  • Nephrons are formed until birth, when there are ~1 million in each kidney.

Ascent of kidneys Kidneys ascend from the pelvis to the upper lumbar region. Occasionally, kidneys partially fuse together during their ascent forming a horseshoe kidney. P.659
Bladder formation

  • Endodermally derived from dilation of the allantois—a hindgut diverticulum
  • Distal ends of the ureters and mesonephric ducts (if male) drain into the bladder at the trigone, entering at an oblique angle to prevent urine reflux back to the kidneys.
Fig. 10.26 Development of urinary system and hindgut.

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Development of the reproductive system

  • Intimately linked to urinary system development (p.658–9)
  • Originates from intermediate mesoderm
  • Reproductive development is initiated by differential gene expression and propagated by endocrine signals.

Sex determination

  • Normal sex chromosome karyotypes: XX = female; XY = male
  • Sex-determining region on Y chromosome = SRY
  • SRY = transcription factor that initiates a gene cascade.

Gonad development (Fig. 10.27)

  • Gonads sexually indifferent until week 7
  • Appear week 6 as a pair of longitudinal tubes called genital ridges formed from mesonephric mesenchyme covered in epithelium, medial to the mesonephric (or Wolffian) and paramesonephric (or Mullerian) ducts
  • They are populated by primordial germ cells, which migrate from the endodermal wall of the yolk sac
  • Before and during primordial cell arrival, genital ridge epithelium proliferates, penetrating the underlying mesenchyme forming primitive sex cords which maintains a connection with the surface epithelium.

Testis differentiation

  • SRY transcripts are present in XY genital ridges
  • Sex cords proliferate forming horseshoe-shaped testis cords connected to the rete testis at their apex
  • Cords composed of primitive germ cells and Sertoli cells which start to secrete anti-Mullerian hormone (AMH; or Mullerian inhibitory substance, MIS)
  • Between the cords, mesenchymal Leydig cells begin to synthesize testosterone from week 9
  • Cords remain solid until puberty, when they differentiate into seminiferous tubules
  • A dense, fibrous layer—the tunica albuginae—separates the cords from surface epithelium.

Ovary differentiation

  • No SRY transcripts
  • Primitive sex cords degenerate
  • Instead, surface epithelium proliferates forming cortical cords, which surround the primordia germ cells, now oogonia
  • Cortical cells differentiate as follicular cells and oogonia first proliferate (~2 million present at birth), then, by week 20, arrest at meiotic prophase.
Fig. 10.27 Male and female gonadal development. The male and female genital systems are virtually identical through the 7th week. In the male, SRY protein produced by the pre-Sertoli cells causes the medullary sex cords to develop into presumptive seminiferous tubules and rete testis tubules and causes the cortical sex cords to regress. Antimüllerian hormone produced by the Sertoli cells then causes the paramesonephric ducts to regress and Leydig cells also develop, which in turn produce testosterone, the hormone that stimulates development of the male genital duct system, including the vas deferens and the presumptive efferent ductules.

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Genital duct system Indifferent stage (week 7)

  • Mesonephric ducts draining into bladder
  • Paramesonephric ducts, with funnel-shaped openings rostrally, fused together caudally—they do not enter the bladder.

Male

  • AMH causes paramesonephric ducts degeneration
  • Testosterone mediates differentiation of mesonephric ducts (future vas deferens) and tubules (some connect to duct = vas efferens)
  • Associated glands are seminal vesicles, prostate, and bulbourethral
  • Testes descend, entering the scrotal sacs via the inguinal ring.

Female

  • No AMH, so paramesonephric ducts persist
  • Cranially become fallopian tubes
  • Caudally joined—form uterus and upper vagina
  • Mesonephric ducts degenerate
  • Ovaries descend, to lie in the pelvis.

External genitalia Depends on conversion of testosterone to dihydrotestosterone, catalysed by 5α–reductase, synthesized by tissue around urogenital sinus. Indifferent (Fig. 10.28)

  • Has genital tubercle which divides into urethral folds flanking the urogenital sinus, all surrounded by genital swellings
  • Differentiation begins week 9.

Male (Fig. 10.29)

  • Genital tubercle extends rapidly to form the phallus, later the penis
  • Urethral folds close the urogenital sinus
  • Genital swellings become scrotal swellings.

Female (Fig. 10.30)

  • Genital tubercle elongates slightly, forming clitoris
  • Urethral folds become labia minora and urogenital sinus remains open
  • Genital swellings form major labia.
Fig. 10.28 Indifferent stages of the external genitalia, approximately 6 weeks.
Fig. 10.29 (a) Development of external genitalia in the male at 10 weeks. (b) newborn.
Fig. 10.30 Development of the external genitalia in the female at 5 months (a) and in the newborn (b).

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