2009 Lecture 16

From Embryology

Genital Development

Introduction

Human idiogram.gif Historic-testis.jpg Historic-ovary.jpg

This section of notes covers genital development. Differences in development are dependent on a protein product of the Y chromosome SRY gene. Mesonephric duct (Wolffian Duct) and paramesonephric (Mullerian Duct) contribute the majority of male and female internal genital tract respectively.

Stage 22 mesonephros

Objectives

  • Understand the role of the Y chromosome in sex determination.
  • Understand the differences in male/female duct develpoment (mesonephric/paramesonephric).
  • Compare the development of the cloaca in the male and female.
  • Understand the developmental abnormalities in male and female development.

Textbooks

  • Human Embryology (2nd ed.) Larson Ch10 p261-306
  • The Developing Human: Clinically Oriented Embryology (6th ed.) Moore and Persaud Chapter 13 p303-346


Lecture Audio Lecture Date: 22-09-2009 Lecture Time: 12:00 Venue: BioMed E Speaker: Mark Hill Genital

Three Stages

The mesonephric/paramesonephric duct changes are one of the first male/female differences that occur in development, while external genitaila remain indeterminate in appearance for quite a while.

  1. Differentiation of gonad (Sex determination)
  2. Differentiation of internal genital organs
  3. Differentiation of external genital organs

The 2nd and 3rd stages dependent on endocrine gonad. Reproductive development has a long maturation timecourse, begining in the embryo and finishing in puberty. (More? Puberty)

Urogenital Indifferent Urogenital Male Urogenital Female

Development Overview

Sex Determination

  • Humans (week 5-6)
  • Germ cells migrate into gonadal ridge
  • Gonads (male/female) identical at this stage, indifferent

Gonad development

  • dependent on sex chromosome
  • Y testes
  • No Y ovary

SRY

  • SRY protein (Testes determining factor, TDF) binds DNA
  • Transcription factor, Bends DNA 70-80 degrees

Internal Genital Organs

  • All embryos form paired
  • Mesonephric duct, see kidney development
  • Paramesonephric duct, Humans 7th week Invagination of coelomic epithelium Cord grows and terminates on urogenital sinus
  • Male Gonad (testes) secretes Mullerian duct inhibitory factor (MDIF) which causes regression of paramesonephric duct
  • Male Gonad (testes) secretes Testosterone which retains mesonephric duct

External Genital Organs

  • All embryos initially same (indifferent)
  • Testosterone differentiates male

Human Timeline

  • 24 days - intermediate mesoderm, pronephros primordium
  • 28 days - mesonephros and mesonephric duct
  • 35 days - uteric bud, metanephros, urogenital ridge
  • 42 days - cloacal divison, gonadal primordium (indifferent)
  • 49 days - paramesonephric duct, gonadal differentiation
  • 56 days - paramesonephric duct fusion (female)
  • 100 days - primary follicles (ovary)

Kidney

  • kidneys and genital ridge develop from intermediate mesoderm, which lies between the lateral plate mesoderm and the somites.
  • kidney develops in multiple stages, which occur in a rostrocaudal sequence.
  • earliest structure to form is the pronephros, in week 4, featuring a pronephric duct with associated nephrogenic mesenchyme.
  • pronephros degenerates early on, leaving only the duct system running down to the cloaca – this becomes known as the mesonephric duct, in the embryo.
  • next stage is the formation of the mesonephros, also in week 4. Its differentiation is induced by the pronephros.
  • mesonephros is also a transient structure. It provides a template for the adult metanephros, beginning on day 35-37.

Sex Determination

MBoC - Figure 20-18. Influence of Sry on gonad development

Y chromosome.jpg

Male (XY)

  • Y chromosome - 200+ genes, 50 million base pairs
  • Sry was discovered (1990) by studying a human XY female, resulting from a deletion in the Y chromosome that did not allow testis development. Subsequent mapping of this deletion allowed isolation and characterization of the SRY gene.
  • SRY encodes: encodes a 204 amino acid protein (Mr 23884 Da) that is a zinc-finger transcription factor. Transcription factors bind to specific sites of DNA and regulates the transcription (expression) of other genes, we still do not know all the genes SRY regulates.
  • SRY is expressed: when testes begin to form, in gonadal tissue and does not require the presence of germ cells.
  • induces cells to differentiate into Sertoli cells

Sertoli cells

  • produce signals that promote development of male characteristics
  • suppress development of female characteristics
  • induce primordial germ cells to commit to sperm development

Female (XX)

  • 1400+ genes, 150 million base pairs
  • In contrast to the Y chromosome, the X chromosome contains about 5% of the haploid genome and encodes house-keeping and specialized functions. The genetic content of the X chromosome has been strongly conserved between species.
  • Genes such as Wnt-4 and DAX-1 necessary for initiation of female pathway ovary development
    • female not considered a default process
  • An early discovery (1961) was that in order to have correct levels of X chromosome gene/protein expression (gene dosage), females must "inactivate" a single copy of the X chromosome in each and every cell. The initiator of the X inactivation process was discovered (1991) to be regulated by a region on the inactivating X chromosome encoding an X inactive specific transcript (XIST), that acts as RNA and does not encode a protein.
  • X inactivation occurs randomly throughout the embryo, generating a mosaic of maternal and paternally derived X chromosome activity in all tissues and organs.

Primordial Germ Cells

Primordial Germ Cell Migration

  • thought to be the first population of cells to migrate through the primitive streak in early gastrulation.
  • This population of cells then lie at the hindgut yolk sac junctional region and later migrate into the genital ridge (germinal ridge) in early embryonic development.
  • It is not the primordial germ cells which respond to SRY presence or absence, but the supporting cells within the developing gonad.

Gametogenesis

  • forming PGCs and getting them into genital ridge as gonad forms
  • formation of germ plasm and determination of PGCs
  • migration of PGCs into developing gonads
  • process of meiosis and modifications of meiosis for forming sperm and eggs
  • differentiation of sperm and egg
  • hormonal control of gamete maturation and ovulation

Male Gonadal Development

Media:Male_gonad_2.mov‎ This looped animation shows the development of the male gonad showing medullary sex cords.

  • The paramesonephric duct (red, left) degenerates under the influence of Mullerian duct inhibitory factor (MDIF) secreted by sertoli cells (differentiated by SRY expression).
  • The mesonephric duct (purple) differentiates under the influence of Testosterone secreted by Leydig cells. Within the testes these mesonephric tubules grow towards the medullary sex cords and will form the rete teste. The mesonephric duct extending out of the gonad forms the ductus deferens.
  • The medullary sex cords (orange) form testis cords that later differentiate into solid seminiferous tubules which become hollow and actively produce spermatazoa during puberty.

The tunica albuginea (white) covers the testis and bands extend inward to form connective tissue septa.

Anti-Mullerian Hormone

Anti-Mullerian hormone (AMH) or Mullerian Inhibiting Substance (MIS) hormone with at least two gonadal related functions:

  • In males, it is produced by supporting gonadal Sertoli cells and inhibits the development of the paramesonephric (Mullerian) duct system that forms the internal female genital tract. The hormone is also involved in Leydig cell steroidogenesis.
  • In females, it is produced by supporting gonadal granulosa cells and is involved in ovarian follice development.

Female Gonadal Development

Infant ovary
human oocyte number

File:Female gonad 2.mov This looped animation shows the development of the female gonad showing cortical sex cords.

  • The mesonephric duct (purple) degenerates, small remnants may remain as epoophoron and paroophoron (in the mesentry of the ovary) and Gartner's cycts (near vagina).
  • The paramesonephric duct (red, left) grows forming the oviduct (uterine horn) and the end opens into the peritoneal cavity and terminates in fimbria (finger-like extensions). Away from the ovary, the two paramesonephric ducts fuse in the midline to form the uterus.
  • The cortical sex cords (orange) form after the primary sex cords degenerate and mesothelium forms secondary cords. The surrounding connective tissue (pink) differentiates to form follicle cells.

Internal Genital Tract

Stage 22 Urogenital 1l.jpg
Paramesonephric duct
  • Week 7 – duct regression or preservation begins
  • All embryos initially form 2 paired indifferent duct systems
    • Mesonephric duct (also called the Wolffian duct)
    • Paramesonephric duct (also called the Mullerian duct)
  • Testes secretions ‐ Mullerian duct inhibitory factor (MDIF) causes regression of paramesonephric ducts and testosterone retains mesonephric ducts.
  • No Testes ‐ Paramesonephric ducts retained and mesonephric duct regresses.

Vagina Development

  • The embryonic origin of the vagina has been a historically hotly debated issue with several different contributions and origins described.
  • One description shows the vagina arising by downward growth of Wolffian and Mullerian ducts. The sinovaginal bulbs are the caudal ends of the Wolffian ducts. Vaginal development is also under negative control of androgens.

Fetal

Fetal uterus growth
  • late embryonic male genital development and now in fetal development we will firstly observe early fetal female development.


External Genitalia

External Genital | Endocrinology - Diagram of the development of the external genitalia

  • The external genitalia are initially identical and undergo male and female differentiation under the influence or absence of modified steroidal sex hormone.
  • Indifferent stage ‐ cloaca divided by proliferating mesenchyme forming urorecal septum, ventral urethral, dorsal anal pit.
  • Difference stage ‐ locally in this region the presence or absence of dihydroxytestosterone (DHT), generated from testosterone, determines male/female development.
    • Presence‐ DHT locally in this region leads to genital tubercle growth, maintenance and fusion of external male genitalia.
    • Absence‐ of DHT, genital tubercle remains small, bends caudally to form the clitoris. Urethral folds persist, do not fuse, and form labia minora. The open urogenital sinus forms a cleft into which urethra and vagina open. The labioscrotal swellings become the labia majora.

Female Genitalia Development

Newborn uterus

This looped animation shows the development of external female genitalia from the indifferent external structure, covering the approximate period of week 9 to 12.

Note the original cloacal membrane becomes separated into the urogenital membrane and anal membrane. The urogenital folds beneath the genital tubercle remain separate (unfused), forming the inner labia minora and second outer skin folds form the larger labia majora either side of the developing vestibule of the vagina. Note at the top of the animation, the changing relative size of the genital tubercle as it forms the glans of the clitoris.

Male Genitalia Development

Endocrinology - Box 6.6 The roles of testosterone (T) and 5α-dihydrotestosterone (DHT)

This looped animation shows the development of external male genitalia from the indifferent external structure, covering the approximate period of week 9 to 12.

Note the original cloacal membrane becomes separated into the urogenital membrane and anal membrane (identical to female). The urogenital folds beneath the genital tubercle begin to fuse in the midline. The skin folds either side for the scrotum, which too has a midline fusion, the raphe. The scrotal sac is initially empty and is an attachment site for the gubernaculum, descent of the testes begins generally during week 26 and may take several days.

Gonad Descent

  • Both kidney and gonads develop retroperitoneally, with the gonads moving into the abdomen or eventually into the scrotal sacs.
  • During fetal development the gubernaculum and fetal growth in both male and female, changes the gonads’ relative positions finally reaching their adult locations.

MH - These positional changes will be covered in this weeks lab.

Both female and male gonads undergo anatomical descent.

  • Ovaries ‐ undergo caudal and lateral shifts to be suspended in the broad ligament of the uterus, gubernaculum does not shorten, it attaches to paramesonephric ducts, causing medial movement into the pelvis.
  • Testes ‐ two anatomical phases in descent, transabdominal and transinguinal, under the influence of the shortening gubernaculum.

Testis-descent start.jpgTestis-descent end.jpg

The testis (white) lies in the subserous fascia (spotted) a cavity processus vaginalis evaginates into the scrotum, and the gubernaculum (green) attached to the testis shortens drawing it into the scotal sac. As it descends it passes through the inguinal canal which extends from the deep ring (transversalis fascia) to the superficial ring (external oblique muscle). Descent of the testes into the scrotal sac begins generally during week 26 and may take several days. The animation shows the path of a single testis. Incomplete or failed descent can occur unilaterally or bilaterally, is more common in premature births, and can be completed postnatally.

Data from a recent study of male human fetal (between 10 and 35 weeks) gonad position.

  • 10 to 23 weeks - (9.45%) had migrated from the abdomen and were situated in the inguinal canal
  • 24 to 26 weeks - (57.9%) had migrated from the abdomen
  • 27 to 29 weeks - (16.7%) had not descended to the scrotum

Postnatal - Puberty

Puberty growth

Puberty can occur over a broad range of time and differently for each sex:

  • girls (age 7 to 13)
  • boys (age 9 to 15)

The physical characteristics that can be generally measured are: genital stage, pubic hair, axillary hair, menarche, breast, voice change and facial hair.

Female

Female HPG Axis

In females, menarche (the first menstruation or a period) usually occurs after the other secondary sex characteristics, and will continue until menopause (permanent cessation of reproductive fertility).

The diagram shows the hormonal regulation pathway from the brain to the ovary and subsequent impact on uterine changes during the menstral cycle.

LHRH = Luteinizing Hormone-Releasing Hormone, also called gonadotropin-releasing hormone (GnRH). This peptide hormone is a decapeptide (10 amino acids) with a short half life (<15 minutes).

LH = Luteinizing Hormone

FSH = Follicle Stimulating Hormone

A similar endocrine axis is also found for regulation of the male gonad.

Puberty Abnormalities

  • Precocious Puberty - Premature development of the signs of puberty which can occur in both girls (before age 7 or 8) and in boys (before age 9).
  • Delayed Puberty - Determined in boys by a lack of increase in testicular volume by the age of 14 years. In girls, no breast development by the age of 13.5 years and a lack of menstruation by the age of 16 years. There can also be a "pubertal arrest" where there is no progress in puberty over 2 year period.

Sex Differences in Adult and Developing Brains

  • not known significance of brain sex differences
  • transient sex differences in gene expression in developing brains may cause permanent differences in brain structure
  • may prevent as well, by compensating for potentially differentiating effects of sex differences in gonadal hormone levels and sex chromosomal gene expression
  • Brains of males and females differ
    • in regions specialized for reproduction
    • in other regions (controlling cognition, etc) where sex differences are not necessarily expected
    • Differentially susceptible to neurological and psychiatric disease

2 sources of sexually dimorphic information

  • complement of sex chromosome genes
  • mix of gonadal hormones

Abnormalities

Human genital abnormalities are currently described as "Disorders of Sex Development" (DSD) and include: chromosomal, gonadal dysfunction, tract abnormalities, external genitalia and gonadal descent. Genital Abnormalities

Congenital adrenal hyperplasia

  • impairment of cortisol production by the adrenal cortex, is one of the most common causes of intersex genitalia at birth
  • genetically male (XY) infants born with undervirilized genitalia (androgen insensitivity syndrome, cloacal exstrophy) are generally assigned and reared as girls.

Cryptorchidism

Cryptorchidism
  • abnormality of either unilateral or bilateral testicular descent, occurring in up to 30% premature and 3-4% term males.
  • Descent may complete postnatally in the first year, failure to descend can result in sterility.

Testis descent is thought to have 2 phases:

  1. transabdominal descent - dependent on insulin-like hormone 3 (INSL3).
  2. inguinoscrotal descent - dependent on androgens.

Undescended Ovaries

  • reasonably rare gonad abnormality, often detected following clinical assessment of fertility problems and may also be associated with other uterine malformations (unicornuate uterus).
  • Due to the relative positions of the male (external) and female (internal) gonads and the pathways for their movement, failure of gonad descent is more apparent and common in male cryptorchidism than female undescended ovaries.

Hydrocele

  • Male Hydrocele is a fluid-filled cavity of either testis or spermatic cord, where peritoneal fluid passes into a patent processus vaginalis.
  • Female Hydrocele is a similar, but rarer, fluid-filled cavity occuring in the female as a pouch of peritoneum extending into the labium majorum (canal of Nuck).

Tract Abnormalities

Uterine abnormalities
Unicornate uterus

Many different forms

  • Uterine: associated with other anomolies, unicornuate uterus
  • Vagina: agenesis, atresia
  • Ductus Deferens: Unilateral or bilateral absence, failure of mesonephric duct to differentiate


Uterine Duplication (uterus didelphys, double uterus, uterus didelphis) A rare uterine developmental abnormality where the paramesonephric ducts (Mullerian ducts) completely fail to fuse generating two separate uterus parts each connected to the cervix and having an ovary each.

Septate Uterus

Cervical: cervical agenesis, cervical duplication

Vaginal: Mayer-Rokitansky syndrome (MRK anomaly, Rokitansky-Küster-Hauser syndrome, RKH syndrome, RKH) congenital absence of the vagina, dyspareunia, vaginal agenesis.

External Genitalia - Hypospadia

  • most common penis abnormality (1 in 300) from a failure of male urogenital folds to fuse in various regions and resulting in a proximally displaced urethral meatus.
  • The cause is unknown, but suggested to involve many factors either indivdually or in combination including: familial inheritance, low birth weight, assisted reproductive technology, advanced maternal age, paternal subfertility and endocrine-disrupting chemicals. Infants with hypospadias should not undergo circumcision.

Movies

Urogenital sinus 001 icon.jpg Urogenital septum 001 icon.jpg Trigone 001 icon.jpg Renal 001 icon.jpg
Urogenital Sinus Urogenital Septum Trigone Renal Nephron
Uterus 001 icon.jpg Female external 001 icon.jpg Male external 001 icon.jpg Testis 001 icon.jpg
Uterus Female External Male External Testis Descent


References

Textbooks

  • Before We Are Born (5th ed.) Moore and Persaud Chapter 14 p289-326
  • Essentials of Human Embryology, Larson Chapter 10 p173-205
  • Human Embryology, Fitzgerald and Fitzgerald Chapter 21-22 p134-152

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Course Content 2009

Embryology Introduction | Cell Division/Fertilization | Cell Division/Fertilization | Week 1&2 Development | Week 3 Development | Lab 2 | Mesoderm Development | Ectoderm, Early Neural, Neural Crest | Lab 3 | Early Vascular Development | Placenta | Lab 4 | Endoderm, Early Gastrointestinal | Respiratory Development | Lab 5 | Head Development | Neural Crest Development | Lab 6 | Musculoskeletal Development | Limb Development | Lab 7 | Kidney | Genital | Lab 8 | Sensory - Ear | Integumentary | Lab 9 | Sensory - Eye | Endocrine | Lab 10 | Late Vascular Development | Fetal | Lab 11 | Birth, Postnatal | Revision | Lab 12 | Lecture Audio | Course Timetable


Cite this page: Hill, M.A. (2019, July 22) Embryology 2009 Lecture 16. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/2009_Lecture_16

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