Lecture - Genital Development
- 1 Introduction
- 2 Objectives
- 3 Textbooks
- 4 Movies
- 5 Objectives
- 6 Stages of Sexual Differentiation
- 7 Human Timeline
- 8 1. Development of the indifferent gonad
- 9 2. Differentiation of gonad into testis or ovary
- 10 3. Differentiation of internal genital organs and ducts
- 11 4. Differentiation of External Genitalia
- 12 Gonad Descent
- 13 5. Postnatal - Puberty
- 14 Sex Differences in Adult and Developing Brains
- 15 Abnormalities
- 16 External Genitalia - Hypospadia
- 17 Movies
- 18 References
- 19 External Links
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.
|Lectopia Lecture Audio
Lecture Date: 2012-09-18 Lecture Time: 15:00 Venue: CLB 3 Speaker: Mark Hill
- Understand the development of the gonads in males and females
- Understand the chromosomal basis of sex determination
- Understand the differences in male/female internal duct develpoment.
- Understand the origins of the external genitalia
- Understand the developmental abnormalities in male and female development.
The Developing Human: Clinically Oriented Embryology
|Citation: The Developing Human: clinically oriented embryology 9th ed. Keith L. Moore, T.V.N. Persaud, Mark G. Torchia. Philadelphia, PA: Saunders, 2011. (links available to UNSW students)|
Larsen's Human Embryology
|Citation: Larsen's human embryology 4th ed. Schoenwolf, Gary C; Larsen, William J, (William James). Philadelphia, PA : Elsevier/Churchill Livingstone, c2009. (links available to UNSW students)|
- Understand the development of the gonads in males and females.
- Understand the chromosomal basis of sex determination.
- Understand the differences in male/female internal duct develpoment.
- Understand the origins of the external genitalia.
- Understand the developmental abnormalities in male and female development.
Stages of Sexual Differentiation
- Development of the indifferent gonad - (genital ridge) early embryo
- Differentiation of gonad - (testis or ovary) late embryo, defining event in sexual differentiation
- Differentiation of internal genital organs and ducts - late embryo to fetal
- Differentiation of external genitalia - fetal
- Development of secondary sexual characteristics - puberty
1. Development of the indifferent gonad
Gonad and adrenal early development (not required to know molecular information)
2. Differentiation of gonad into testis or ovary
Chromosomal Sex Determination
- Y Chromosome - 59 million base pairs, hypervariable in length, mostly non-functional repeats
- Current known protein-coding genes = 48 including SRY
- SRY encodes a 204 amino acid protein (TDF) that is a member of the HMG (High mobility group) box class of DNA-binding proteins. Transcription factors bind to specific sites of DNA and regulates the transcription (expression) of other genes.
- X Chromosome - 155 million base pairs, contains about 5% of the haploid genome and encodes house-keeping and specialized functions.
- Genes such as Wnt-4 and DAX-1 necessary for initiation of female pathway ovary development
- 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.
- The genetic content of the X chromosome has been strongly conserved between species because these genes have become adapted to working as a single dose - Ohno's law
- X inactivation occurs randomly throughout the embryo, generating a mosaic of maternal and paternally derived X chromosome activity in all tissues and organs. This can be seen in the fur colour of tortoiseshell cats.
Overview - MBoC - Figure 20-18. Influence of Sry on gonad development | image (image provides a good overview of the anatomy of sex determination, I will refer to this in the lecture and practical class)
- So called because they "support" the germ cells
- develop as Sertoli cells
- SRY is expressed in the primordia of the supporting cells, transforming them into Sertoli cells that surround the germ cells and form testis cords
- SRY is not expressed in the other cell types of the gonad
- therefore the Sertoli cells instruct the germ cells and the steroid secreting cells to take the male path of development
- Embryonic Sertoli cells secrete anti-Mullerian hormone (AMH)
- Adult Sertoli cells line the inside of the seminiferous tubules and support spermatogenesis.
- develop as Follicle cells (granulosa cells)
- Follicle cells surround and nurture the developing oocytes
- In response to FSH, follicle cells proliferate
- After ovulation, these cells become luteal cells of the corpus luteum secreting progesterone and oestrogens
Steroid secreting cell lineage
- Develop into Leydig cells (interstitial cells) which sit outside the seminiferous tubules
- Secrete testosterone in response to luteinizing hormone from the pituitary
- Develop into theca cells that secrete androstenedione which can be converted by the follicle cells into estrogens
Primordial Germ Cells
- Primordial germ cells (PGCs) are thought to be the first population of cells to migrate through the primitive streak in early gastrulation (week 3)
- cells then lie at the hindgut yolk sac junctional region
- later migrate into the genital ridge (germinal ridge) in early embryonic development.
|E9.0 Migration||E9.5 Migration||E10.5 Migration|
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- Not the primordial germ cells which respond to SRY presence or absence, but the supporting cells within the developing gonad.
- Germ cells occasionally migrate by mistake into the developing adrenal gland and in the absence of sertoli cells telling them what to do, abnormally begin to develop as oocytes, even in males
- Links: Germ cell migration pathway
- forming PGCs as a small population of migratory cells
- enter the gonad where they undergo several rounds of mitotic cell division
- female - the germ cells enter meiosis and become arrested at the dictyate (diplotene) stage of meiotic prophase 1. All oocytes are at this stage at birth
- male - the germ cells are enclosed by the developing Sertoli cells and are induced to arrest differentiation and cell division as T1 prospermatogonia until after birth.
3. Differentiation of internal genital organs and ducts
Human embryo (Carnegie stage 22, week 8) pelvic level cross-section.
|This looped animation shows the development of the male gonad showing medullary sex cords.
The tunica albuginea (white) covers the testis and bands extend inward to form connective tissue septa.
Anti-Mullerian hormone (AMH) or Mullerian Inhibiting Substance (MIS) hormone with at least two gonadal related functions:
- In males, it is produced by embryonic Sertoli cells and causes the loss of the paramesonephric (Mullerian) duct system that forms the internal female genital tract.
- In females, it is produced after puberty by follicle cells and suppresses the development of other primary follicles, thus restricting the number of follicles stimulated by FSH.
|This looped animation shows the development of the female gonad showing cortical sex cords.
- Week 7 – duct preservation or regression begins
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Paramesonephric duct development
- The embryonic origin of the vagina has been a historically hotly debated issue with several different contributions and origins described.
- Current molecular studies show the whole vagina is derived from the intermediate mesoderm-derived Müllerian duct (see review )
- bone morphogenic protein 4 (BMP4) reshapes the duct into the vaginal primordium.
- exhibits different features from the uterus
- stratified squamous epithelium
- insensitivity to anti-Müllerian hormone
- Links: Vagina Development
4. Differentiation of External Genitalia
- external genitalia are initially identical and undergo male and female differentiation under the influence or absence of steroidal sex hormones.
- Indifferent stage ‐ cloaca divided by proliferating mesenchyme forming the urorectal septum which separates the ventral urogenital sinus from the dorsal rectum.
- Difference stage ‐ locally in this region the presence or absence of dihydrotestosterone (DHT), generated from testosterone, determines male/female development.
- Male presence of DHT
- locally in this region leads to genital tubercle growth, form
- genital folds (urethral) initial maintenance and then fusion, forming perineal and penile raphe.
- labioscrotal swellings (lateral to urethreal folds) become the scrotum.
- Female absence of DHT
- genital tubercle remains small, bends caudally to form the clitoris.
- genital folds (urethral) persist, do not fuse, and form labia minora.
- open urogenital sinus forms a cleft into which urethra and vagina open.
- labioscrotal swellings become the labia majora.
This looped animation shows the development of external female genitalia from the indifferent external structure, covering the approximate period of week 9 to 12.
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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
This looped animation shows the development of external male genitalia from the indifferent external structure, covering the approximate period of week 9 to 12.
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Both female and male gonads undergo anatomical descent.
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 scrotal 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.
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
Incomplete or failed descent can occur unilaterally or bilaterally, is more common in premature births, and can be completed postnatally.
5. Postnatal - Puberty
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.
- Testosterone - adult testes produce about 6-10 mg /day in males (~0.5 mg / day in females) carried in circulation by a specific carrier globulin.
- masculinizing androgen - also at puberty, spermatogenesis in males
- development of secondary sexual characteristics - body and facial hair growth (male pattern baldness)
- anabolic effect - metabolism towards conservation of amino acids, promoting protein synthesis, muscle development
- neural - libido in both sexes, male pattern behaviour
- Sustentacular (Sertoli) cells - produce anti-mullerian hormone (AMH) to puberty.
- AMH - anti-Müllerian hormone (Müllerian inhibiting factor (MIF), Müllerian-inhibiting hormone (MIH), and Müllerian-inhibiting substance (MIS)).
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.
- GnRH = 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.
- 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
- Where chromosomal sex does not match phenotypic sex i.e. XX males or XY females
XX males - usually caused by a transfer of some Y chromosome DNA onto the X chromosome
- Gonads develop as testes, everything looks normal internally and externally but infertile due to a failure of spermatogenesis
- Similar to Kleinfelters syndrome (XXY)
XY females - usually steroidal origin
- Main cause is Androgen Insensitivity Syndrome (AIS) Complete (CAIS) Partial (PAIS) and Mild (MAIS) usually caused by mutations of the gene encoding the androgen receptor AR gene located on the X chromosome
- 5-alpha-reductase deficiency - again leads to a lack of complete steroidal induction of external genitalia
- Rare mutations in key sex determining genes including deletion or mutations of SRY
Human genital abnormalities are currently described as "Disorders of Sex Development" (DSD) and include: chromosomal, gonadal dysfunction, tract abnormalities, external genitalia and gonadal descent.
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 are often assigned and reared as girls.
- 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:
- transabdominal descent - dependent on insulin-like hormone 3 (INSL3).
- inguinoscrotal descent - dependent on androgens.
- 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.
- 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).
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 abnormalities||Unicornate uterus|
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.
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.
|Urogenital Sinus||Urogenital Septum||Ovary||Testis||Female External||Male External||Uterus||Testis Descent|
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- 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
- Developmental Biology (6th ed.) Gilbert Chapter 14 Intermediate Mesoderm
- Historic - Text-Book of Embryology. Bailey, F.R. and Miller, A.M. (1921). New York: William Wood and Co. Chapter 15. The Genital Glands
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- Embryo Images Unit: Urongenital Development | Internal Genitalia | Definitive Kidney | External Genitalia