REI - Reproductive Medicine Seminar 2018

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Adult endocrine organs


This is the partial online draft version of my presentation, as there was no internet I switched to powerpoint fversion for the final presentation. I will though update this online version as it will include full access to molecular data and all animations presented in my talk. Please feel free to contact me at any time with your embryology questions.

Seminar Topics
  1. Preimplantation
  2. Implantation
  3. Urogenital
  4. Endocrine
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Powerpoint Slides: 1 slide/page PDF | 3 slide/page PDF

3.1 Fetal Medicine Content  

General Aim

Candidates should understand and describe normal and abnormal human development and the principles of implantation, developmental embryology and early pregnancy maintenance.

Specific Objectives

3.1.1 Implantation Understand and describe;

  • Preimplantation development of the embryo in vitro and in vivo

  3.1.2 Developmental Embryology Understand and describe;

  • Embryonic development of the genital tract in the male and female, including factors controlling male and female gonadal primordia, internal duct systems and external genitalia

Embryology of the hypothalamic/pituitary, adrenal and thyroid endocrine systems

  • Development of the urological system
  • Development of the breast
  • Mechanism, diagnosis, and management of female patients with developmental abnormalities of the genital tract, including ambiguous genitalia, imperforate hymen, vaginal septa, uterine anomalies, Mullerian agenesis and gonadal dysgenesis
  • Mechanism, diagnosis, and management of male patients with developmental abnormalities, including failure of testicular development and / or testicular descent, penile abnormality, and ambiguous genitalia - Anomalies associated with the urological system in the male and female
Online Resources  
Week 1 Links: stage 1 | stage 2 | stage 3 | menstrual cycle | fertilization | zygote | morula | blastocyst | Lecture - Fertilization | meiosis | mitosis | Lecture - Week 1 and 2 | menstrual cycle | oocyte | spermatozoa | twinning | Genetic risk maternal age | Trisomy 21 | Trisomy 18 | Trisomy 13 | hydatidiform mole | GA week 3
Week 2 Links: stage 4 | stage 5 | stage 6 | Lecture - Week 1 and 2 | implantation | trophoblast | human chorionic gonadotropin | pregnancy test | twinning | Category:Week 2 | GA week 4
Genital Links: genital | Lecture - Medicine | Lecture - Science | Lecture Movie | Medicine - Practical | primordial germ cell | meiosis | endocrine gonad‎ | Genital Movies | genital abnormalities | Assisted Reproductive Technology | puberty | Category:Genital
Female | X | X inactivation | ovary | corpus luteum | oocyte | uterus | vagina | reproductive cycles | menstrual cycle | Category:Female
Male | Y | SRY | testis | spermatozoa | ductus deferens | penis | prostate | Category:Male
Historic Embryology - Genital 
General: 1901 Urinogenital Tract | 1902 The Uro-Genital System | 1904 Ovary and Testis | 1912 Urinogenital Organ Development | 1914 External Genitalia | 1921 Urogenital Development | 1921 External Genital | 1942 Sex Cords | 1953 Germ Cells | Historic Embryology Papers | Historic Disclaimer
Female: 1904 Ovary and Testis | 1904 Hymen | 1912 Urinogenital Organ Development | 1914 External Genitalia | 1914 Female | 1921 External Genital | 1927 Female Foetus 15 cm | 1927 Vagina | 1932 Postnatal Ovary
Male: 1887-88 Testis | 1904 Ovary and Testis | 1904 Leydig Cells | 1906 Testis vascular | 1909 Prostate | 1912 Prostate | 1914 External Genitalia | 1915 Cowper’s and Bartholin’s Glands | 1920 Wolffian tubules | 1935 Prepuce | 1935 Wolffian Duct | 1942 Sex Cords | 1943 Testes Descent | Historic Embryology Papers | Historic Disclaimer
Renal Links: renal | Lecture - Renal | Lecture Movie | urinary bladder | Stage 13 | Stage 22 | Fetal | Renal Movies | Stage 22 Movie | renal histology | renal abnormalities | Molecular | Category:Renal
Historic Embryology - Renal  
1905 Uriniferous Tubule Development | 1907 Urogenital images | 1911 Cloaca | 1921 Urogenital Development | 1915 Renal Artery | 1917 Urogenital System | 1925 Horseshoe Kidney | 1926 Embryo 22 Somites | 1930 Mesonephros 10 to 12 weeks | 1931 Horseshoe Kidney | 1932 Renal Absence | 1939 Ureteric Bud Agenesis | 1943 Renal Position
Endocrine Links: Introduction | BGD Lecture | Science Lecture | Lecture Movie | pineal | hypothalamus‎ | pituitary | thyroid | parathyroid | thymus | pancreas | adrenal | endocrine gonad‎ | endocrine placenta | other tissues | Stage 22 | endocrine abnormalities | Hormones | Category:Endocrine
Historic Embryology - Endocrine  
1903 Islets of Langerhans | 1903 Pig Adrenal | 1904 interstitial Cells | 1908 Pancreas Different Species | 1908 Pituitary | 1908 Pituitary histology | 1911 Rathke's pouch | 1912 Suprarenal Bodies | 1914 Suprarenal Organs | 1915 Pharynx | 1916 Thyroid | 1918 Rabbit Hypophysis | 1920 Adrenal | 1935 Mammalian Hypophysis | 1926 Human Hypophysis | 1927 Adrenal | 1927 Hypophyseal fossa | 1930 Adrenal | 1932 Pineal Gland and Cysts | 1935 Hypophysis | 1935 Pineal | 1937 Pineal | 1935 Parathyroid | 1940 Adrenal | 1941 Thyroid | 1950 Thyroid Parathyroid Thymus | 1957 Adrenal


  • Uterine Tube Biobank (Prof Ledger)
    • Molecular aspects of ectopic implantation
  • Trophoblast differentiation
    • Control of implantation and early placentation
  • Digital Embryology Consortium
    • The objective of this international partnership is to digitise, preserve, and make available for researchers the major embryology histological collections.
  • Kyoto Collection(eBook)
    • with Shiota, Yamada and Ho.
  • Human SEM (eBook)
    • in preparation with Sulik, Vekemans and Attié-Bitach.
  • UNSW Embryology

1. Preimplantation

Week 1 Links: stage 1 | stage 2 | stage 3 | menstrual cycle | fertilization | zygote | morula | blastocyst | Lecture - Fertilization | meiosis | mitosis | Lecture - Week 1 and 2 | menstrual cycle | oocyte | spermatozoa | twinning | Genetic risk maternal age | Trisomy 21 | Trisomy 18 | Trisomy 13 | hydatidiform mole | GA week 3

Week1 summary.jpg


  • Paternal - Genome 2 pronuclei stage
  • Male pronucleus demethylated
  • epigenetics


  • "embryonic" cell cycle S phases and M phases alternate without intervening G1 or G2
  • (MSMSMSMS, adult MG1SG2)

Day 4

  • solid ball 16-20 cells
  • peripheral cells flattened against zona pellucida

Day 5 - Blastocoel formation

  • 2 cell types and fluid-filled cavity (blastoceol)
  • Trophectoderm (TE)
    • peripheral flattened cells
    • placenta and placental membranes
    • Genes - CDX2
  • Inner cell mass (ICM)
  • rounder cells located on one wall
    • entire embryo
    • Genes - OCT4, NANOG and SOX2

Hippo Pathway

Fly Phenotype (dorsal view head thorax SEM)
Fly Hippo-type dorsal view head thorax SEM.jpg Fly WT dorsal view head thorax SEM.jpg
Hippo-type (hpo) Wild-type (WT)
Image source[1]

ROCK1 and ROCK2 signaling (bovine)

  • RHO-associated coiled-coil kinases
  • promote formation of TE
  • inhibit formation of ICM
  • by polarizing outer cells to inactivate Hippo signaling
  • tension-dependent junctional localization

HIPPO signalling (mouse)

  • ICM - active
  • TE – inactive
  • RHO/ROCK outside cells
    • apicobasal polarity
  • YAP/TAZ nuclear localization
    • transcriptional co-activators
    • downstream effectors of HIPPO

2. Implantation

Week 2 Links: stage 4 | stage 5 | stage 6 | Lecture - Week 1 and 2 | implantation | trophoblast | human chorionic gonadotropin | pregnancy test | twinning | Category:Week 2 | GA week 4


  • Species - Problem in literature
  • Trophoblast and endometrial factors
  • cytokines and other growth factors
  • Drive cell recruitment, invasion, and spatial distribution and communication
This animation shows the process of implantation, occurring during week 2 of development in humans.

The beginning of the animation shows: the uterus lining (endometrium epithelium), the hatched blastocyst with a flat outer layer of trophoblast cells (green), the inner cell mass which has formed into the bilaminar embryo (epiblast and hypoblast) and the large fluid-filled space (blastocoel).

green cells - trophoblast layer of the conceptus

blue cells - epiblast layer of the bilaminar embryo

yellow cells - hypoblast layer of the bilaminar embryo

white cells - uterine endometrium epithelium

red - maternal blood vessel

Implantation Movie Links: MP4 version | Week 2 Chorionic Cavity Movie | Implantation | Week 2 | Trophoblast | Human Chorionic Gonadotropin | Placenta Development | Movies
Stage5 bf08.jpg

Click Here to play on mobile device

Chorion 001 icon.jpg
Animation shows the events following implantation and focuses on changes in the the spaces surrounding the embryonic disc, the extraembryonic coelom.

The blastoceol cavity is converted into two separate spaces: the yolk sac and the chorionic cavity.

The third space lies above the epiblast layer of the embryonic disc, the amniotic cavity.

  • white cells - (left) endometrial gland (right) endometrial epithelium
  • blue - epiblast layer (forming ectoderm and amniotic cavity lining)
  • yellow - hypoblast layer (replaced with endoderm during gastrulation)
  • red cells - extraembryonic mesoderm layer
  • green - trophoblast layers (cytotrophoblast and syncytiotrophoblast)
  • red spaces - blood-filled spaces, maternal lacunae

3. Urogenital


Gestational Age
GA Week
Event Fertilization Age Week
5-6 primordial germ cells migrate during gastrulation 3-4
6 intermediate mesoderm, pronephros primordium 4
7 mesonephros and mesonephric duct (Wolffian duct) 5
8 ureteric bud, metanephros, genital ridge 6 (35 days)
9 cloacal divison, gonadal primordium - indifferent to first appearance of testis cords 7 (42 days)
10 paramesonephric duct (Mullerian duct), clear gonadal differentiation 8 (49 days)
11 paramesonephric duct fusion (female) 9 (56 days)
17 primary follicles (ovary) 15 (100 days)

Primordial Germ Cells

Primoridal Germ Cell Migration

Primordial Germ Cells (PGCs) are thought to be the first population of cells to migrate through the primitive streak in early gastrulation.

Stage7-sem2.jpgStage7 primitive streak labelled.jpg

Human Embryonic Disc (Stage 7 GA week 5)

GA Week 5

  • Human embryonic disc showing the primitive streak region where gastrulation occurs, generation the trilaminar embryo.
  • Arrows indicate direction of cell migration through the streak.

This population of cells then lie at the hindgut and yolk sac junctional region and later migrate into the germinal ridge in early embryonic development.

Stage9 bf2-primordial germ cell region.jpg

Human Embryo (Stage 9 GA week 5) primordial germ cell region (green)

  • Sacrococcygeal teratomas - Remnant primitive streak cells (most common solid tumor in newborn infants)
  • Germline teratoma - (Germinoma) abnormally differentiated/located PGCs fail to die.

Mouse PGC Migration

E9.5 E10.5

PGC motility 3 phases - initiation, migration and stopping

  • based upon normal actin cell motility.
  • no sex-specific differences

PGC Chemoattraction

  • Ligand
    • SDF-1 (Stromal cell-derived factors 1, now CXCL12, C-X-C motif chemokine ligand 12) expressed in the genital ridges and surrounding mesenchyme.
  • Receptor
    • CXCR4 (C-X-C motif chemokine receptor 4) expressed by PGCs.

See also reviews of PGC migration[2][3]

Stromal Derived Factor 1 (SDF-1, CXCL12) chemotaxis

Intermediate Mesoderm

Mesoderm Generation (chicken)[4]

Human trilaminar embryo {"Germ layers")

Trilaminar embryo.jpg

Intermediate mesoderm derives genital and renal systems.


Stage12 sem11.jpg

GA week 6-7 Urogenital Sinus Movie

It is not the primordial germ cells which respond to SRY presence or absence, but the supporting cells within the developing gonad.

Urogenital Septum

Click Here to play on mobile device

Urogenital septum 001 icon.jpg

GA Week 8

  • Initially the cloaca forms a common urinary, genital, GIT space
  • This is divided by formation of a septum into anterior urinary and dorsal rectal
    • superior - Tourneux fold
    • lateral - Rathke folds
  • septum fuses with cloacal membrane before it commences to degenerate.
  • hindgut - distal third transverse colon, descending and sigmoid colon, rectum.
  • anal pit - distal third of anorectal canal (ectodermal)

Mouse Gonad

Sertoli and Germ Cells - showing PGCs are not responsive to SRY signaling.

Mouse gonad sex determination 01.jpg

Sry Signaling[5]

  • red - Sertoli cells, showing Fgf9 expression (following Sry expression FGF9 is a downstream signaling molecule).
  • green - Germ cells and endothelial cells, showing PECAM expression.

Genital Ridge (early embryo)

Adrenal and gonad early development.jpg

Mouse- gonadal supporting cell development.jpg

  • green - gonadal supporting cells
  • blue - Sertoli cells (male)
  • pink - pre-granulosa cells (female)

RSPO1 R-Spondin Family, Member 1

Sex Development Genes

Mammalian Sexual Development Genes
Gene (OMIM) Protein Function Gonad Phenotype of Null Mice Human Syndrome

Bipotential gonad
Wt1 Transcription factor Blockage in genital ridge development Denys-Drash, WAGR, Frasier syndrome
Sf1 Nuclear receptor Blockage in genital ridge development Embryonic testicular regression syndrome
Lhx9 Transcription factor Blockage in genital ridge development a
Emx2 Transcription factor Blockage in genital ridge development a
M33 Transcription factor Gonadal dysgenesis a
Testis-determining pathway
Gata4/Fog2 Transcription/cofactor Reduced Sry levels, XY sex reversal a
Sry Transcription factor XY sex reversal XY sex reversal (LOF); XX sex reversal (GOF)
Sox9 Transcription factor XY sex reversal Campomelic dysplasia, XX sex reversal (GOF)
Sox8 Transcription factor XY sex reversal in combination with partial loss of Sox9 function a
Fgf9 Signaling molecule XY sex reversal a
Dax1 Nuclear receptor Impaired testis cord formation and spermatogenesis Hypogonadism
Pod1 Transcription factor XY sex reversal a
Dhh Signaling molecule Impaired differentiation of Leydig and PM cells XY gonadal dysgenesis
Pgdra Receptor Reduction in mesonephric cell migration a
Pgds Enzyme No phenotype a
Arx Transcription factor Abnormal testicular differentiation X-linked lissencephaly with abnormal genitalia
Atrx Helicase ND ATRX syndrome
Insl3 Signaling factor Blockage of testicular descent Cryptorchidism
Lgr8 Receptor Blockage of testicular descent Cryptorchidism
Hoxa10 Transcription factor Blockage of testicular descent Cryptorchidism
Hoxa11 Transcription factor Blockage of testicular descent Cryptorchidism
Amh Hormone No Müllerian duct degeneration Persistent Müllerian duct syndrome
Misrl1 Receptor No Müllerian duct degeneration Persistent Müllerian duct syndrome
Pax2 Transcription factor Dysgenesis of mesonephric tubules a
Lim1 Transcription factor Agenesis of Wolffian and Müllerian ducts a
Dmrt1 Transcription factor Loss of Sertoli and germ cells XY femaleb
Ovary-determining pathway
Wnt4 Signaling molecule Müllerian duct agenesis, testosterone synthesis, and coelomic vessel formation XY female (GOF)
FoxL2 Transcription factor Premature ovarian failure BPES
Dax1 Nuclear receptor XY sex reversal (GOF) XY sex reversal (GOF)
RSPO1 Signaling molecule XX sex reversal (LOF) XX sex reversal (LOF)
Table Legend
  • BPES - blepharophimosis-ptosis-epicanthus inversus syndrome
  • GOF - gain-of-function mutation
  • LOF - loss-of-function mutation
  • ND - not determined
  • WAGR - Wilms' tumor-aniridia-genitourinary malformations-mental retardation
a No mutations in human sexual disorders identified to date.

b Candidate gene for 9p deletion, XY sex reversal.

Table data modified[6]

Note new HUGO Gene Nomenclature Committee (HGNC)

  • Male sex - SF-1 (NR5A1) Nuclear Receptor Subfamily 5, Group A, Member 1
  • Female sex - DAX-1 (NR0B1) Nuclear Receptor Subfamily 0, Group B, Member 1


  1. Development of the indifferent gonad - (genital ridge) early embryo
  2. Differentiation of gonad - (testis or ovary) late embryo, defining event in sexual differentiation
  3. Differentiation of internal genital organs and ducts - late embryo to fetal
  4. Differentiation of external genitalia - fetal
  5. Development of secondary sexual characteristics - puberty

Male – Sertoli Cells

Human Y chromosome showing SRY region
Human Y chromosome showing SRY region
  • Human SRY activation not known
  • Mouse SRY activation - Wilms tumor 1 (Wt1), GATA binding protein 4 (Gata4), zinc fnger protein, fog family member 2 (Zfpm2), chromobox homolog 2 (Cbx2), mitogen-activated protein kinase 4 (Map3k4), insulin receptors.
  • SRY activates key transcription factor SOX9 in Sertoli cells
    • Sertoli also express SOX9, FGF9, and PTGDS (lipocalin-type prostaglandin D2 synthase, catalyzes conversion of prostaglandin H2 to prostaglandin D2)
  • SOX9 requires positive regulatory loop
  • Sox9 and FGF9 feed-forward loop upregulates Fgf9 expression
  • repression of a WNT4
  • Retinoic acid (RA) - required later for Sertoli to germ cells essential for adult mammalian spermatogenesis.

Human SOX Family  
Table - Human Sox Family
Approved Name Previous Symbols Synonyms Chromosome
SOX1 SRY-box 1 13q34
SOX2 SRY-box 2 3q26.33
SOX3 SRY-box 3 PHP Xq27.1
SOX4 SRY-box 4 6p22.3
SOX5 SRY-box 5 "L-SOX5, MGC35153" 12p12.1
SOX6 SRY-box 6 11p15.3
SOX7 SRY-box 7 8p23.1
SOX8 SRY-box 8 16p13.3
SOX9 SRY-box 9 "CMD1, CMPD1" SRA1 17q24.3
SOX10 SRY-box 10 "DOM, WS4, WS2E" 22q13.1
SOX11 SRY-box 11 2p25.2
SOX12 SRY-box 12 SOX22 20p13
SOX13 SRY-box 13 "Sox-13, ICA12, MGC117216" 1q32.1
SOX14 SRY-box 14 SOX28 3q22.3
SOX15 SRY-box 15 SOX20 "SOX27, SOX26" 17p13.1
SOX17 SRY-box 17 8q11.23
SOX18 SRY-box 18 20q13.33
SOX21 SRY-box 21 SOX25 13q32.1
SOX30 SRY-box 30 5q33.3
SRY sex determining region Y TDF Yp11.2
    Links: Developmental Signals - Sox | OMIM | HGNC | Tbx Family | Bmp Family | Fgf Family | Pax Family | R-spondin Family | Sox Family | Tbx Family

Female - Granulosa Cells

Human fetal ovary FOXL2[7]
  • Wnt4 (1p36.12) secreted protein, inhibit testis-specific processes
    • mesonephros migration of endothelial cells
    • repress steroidogenesis by Sf1 or blocking recruitment of steroidogenic cell precursors
  • RSPO1 (1p34.3) secreted protein
    • agonist WNT4 signalling
  • FOXL2 (3q22.3) transcription factor
    • repress Sox9 by synergistic interaction with estrogen receptors α and -β (ER-α-β)
    • postnatal follicle development and female fertility maintenance
    • FOXL2 gene are associated with syndromic and non-syndromic ovarian failure.
    • Mutations in FOXL2 result in blepharophimosis/ptosis/epicanthus inversus syndrome (BPES).
Human WNT Family  
Table - Human Wnt Family
Approved Name Previous
Synonyms Chromosome
WNT1 Wnt family member 1 INT1 12q13.12
WNT2 Wnt family member 2 INT1L1 IRP 7q31.2
WNT2B Wnt family member 2B WNT13 XWNT2 1p13.2
WNT3 Wnt family member 3 INT4 "MGC131950, MGC138321, MGC138323" 17q21.31-q21.32
WNT3A Wnt family member 3A 1q42.13
WNT4 Wnt family member 4 WNT-4 1p36.12
WNT5A Wnt family member 5A hWNT5A 3p14.3
WNT5B Wnt family member 5B 12p13.33
WNT6 Wnt family member 6 2q35
WNT7A Wnt family member 7A 3p25.1
WNT7B Wnt family member 7B 22q13.31
WNT8A Wnt family member 8A WNT8D 5q31.2
WNT8B Wnt family member 8B 10q24.31
WNT9A Wnt family member 9A WNT14 1q42.13
WNT9B Wnt family member 9B WNT15 WNT14B 17q21.32
WNT10A Wnt family member 10A 2q35
WNT10B Wnt family member 10B "WNT-12, SHFM6" 12q13.12
WNT11 Wnt family member 11 11q13.5
WNT16 Wnt family member 16 7q31.31
    Links: Developmental Signals - Wnt | OMIM Wnt1 | HGNC | Bmp Family | Fgf Family | Pax Family | R-spondin Family | Sox Family | Tbx Family | Wnt Family
Human Chromosomes: 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | 13 | 14 | 15 | 16 | 17 | 18 | 19 | 20 | 21 | 22 | X | Y  

Gonad Differentiation

Animations summarising the early morphological development of the male and female gonad.

Male Female

Testis Development Movie

Ovary Development Movie

  • Paramesonephric duct (red left, Müllerian duct) degenerates under the influence of Anti-Müllerian hormone (AMH) secreted by sertoli cells (differentiated by SRY expression).
  • Mesonephric duct (purple, Wolffian duct) 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.
  • Medullary sex cords (orange) form testis cords.
    • these later differentiate into solid seminiferous tubules that during puberty become hollow and actively produce spermatozoa.
  • The surrounding connective tissue (pink) differentiates to form stromal cells.
  • The tunica albuginea (white) covers the testis and bands extend inward to form connective tissue septa.
  • Mesonephric duct (purple, Wolffian duct) degenerates, small remnants may remain as epoophoron and paroophoron (in the mesentry of the ovary) and Gartner's cycts (near vagina).
  • Paramesonephric duct (red left, Müllerian duct) 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.
  • 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.


Testis Pre-Puberty Testis Post-Puberty
Testis histology.jpg Testis histology 02.jpg
Testis histology 006.jpg Testis histology 007.jpg


Ovary Pre-Puberty

Infant ovary.jpg

Human ovary non-growing follicle model.jpg

Internal Genital


Human Embryo (GA week 10, stage 22) pelvic level cross-section.
Stage 22 image 196.jpg Stage 22 image 214.jpg
G5 urogenital urogenital
Stage 22 image 302.jpg Stage 22 image 301.jpg Stage 22 image 194.jpg
peritoneal cavity rete tesits G3 testis
Male hormone levels
  • week 8 - males Sertoli cells secrete anti müllerian hormone (AMH), which causes regression of the paramesonephric ducts between the 8th and 10th weeks.
  • week 9 to 10 - gonadal cells begin to produce testosterone, which maintains the mesonephric ducts.
  • mesonephric ducts go on to form the internal genital tract:
    • rete testis
    • ductuli efferentes
    • vas deferens

Trigone - note trigone does not include mesonephric contribution, though the ducts do shift location to open into teh male urethra.


Paramesonephric duct.jpg

Mouse paramesonephric duct (Müllerian duct)[8]

This mouse image shows the relationship between the mesonephric and paramesonephric ducts opening into the urogenital sinus.
  • The paramesonephric duct began as an infold of surface epithelium lying along the surface of the genital ridge.
  • Estrogens, both maternal and fetal, stimulate its development and that eventually of the external female fetal genital structures.
  • In contrast, the mesonephric duct regresses, remnants of this duct may remain lying within the broad ligament.
Female Uterus and Vagina (between GA week 11 and 22)
Note - the entire vagina is formed from the paramesonephric (Müllerian) duct and does not have a contribution from the urogenital endoderm.

  • The initially paired ducts fuse in the midline forming the single body of the uterus.
  • The ducts remain separate laterally where they form the uterine tubes (Fallopian tubes, uterine horns).
  • The ducts peripheral attachment site to the urogenital sinus wall (yellow) is is described as the Müllerian tubercle.
  • The fused ducts also generate the vagina, under the influence of BMP4.
  • Estrogen will also later alter the vaginal epithelium.

The uterus and broad ligament will eventulaly divide the pelvic cavity into two separate pouches.

  • posteriorly - uterorectal pouch (pouch of Douglas)
  • anteriorly - uterovesical pouch

External Genital

See also this historic paper - Spaulding MH. The development of the external genitalia in the human embryo. (1921) Contrib. Embryol., Carnegie Inst. Wash. Publ. 81, 13: 69 – 88.

The unisex genital tubercle (GA week 12) is a major contributor to both sexes external genitalia.

Human week 10 fetus 03.jpgKeith1902 fig098.jpg

Male Female
Animation showing the development of external male genitalia from the indifferent external structure ((GA week 11 to 14 approximately).

The reduction of Testosterone to active metabolite, 5α-dihydrotestosterone (DHT) is carried out by the enzyme 5α-reductase expressed in the region or male external genitaila and prostate gland. Note that there are several 5α-reductase isoforms that differ in both tissue distribution and kinetics.

  • original cloacal membrane becomes separated into the urogenital membrane and anal membrane (identical to female).
  • urogenital folds beneath the genital tubercle begin to fuse in the midline
  • skin folds either side for the scrotum
    • which also has a midline fusion, the raphe
  • 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.
Animation showing the development of external female genitalia from the indifferent external structure (GA week 11 to 14 approximately).
  • original cloacal membrane becomes separated into the urogenital membrane and anal membrane
  • urogenital folds beneath the genital tubercle remain separate (unfused)
    • forming the inner labia minora
  • second outer skin folds form the larger labia majora
    • either side of the developing vestibule of the vagina
  • genital tubercle (top of the animation) forms the glans of the clitoris

Testosterone metabolism

Testosterone metabolism.jpg

Biochemical pathway showing testosterone metabolism, to a more active form, then inactivation and conjugation for elimination.

5-alpha reductase - enzyme that convert testosterone into the more potent dihydrotestosterone (DHT).

Testes Descent

Testis Descent Movie

The animation shows the descent of the testes (between GA week 9 to 38, birth).

Descent of the testes into the scrotal sac begins generally during week 26 and may take several days.

  • testis (white) lies in the subserous fascia (spotted)
  • a cavity processus vaginalis evaginates into the scrotum
  • gubernaculum (green) attached to the testis shortens drawing it into the scotal sac
  • as it descends it passes through the inguinal canal extends
  • from the deep ring (transversalis fascia)
  • to the superficial ring (external oblique muscle)

Incomplete or failed descent can occur unilaterally or bilaterally, is more common in premature births, and can be completed postnatally. (see also cryptorchidism).

Testis-descent start.jpgTestis-descent end.jpg Data from a study of male human fetal (between 10 and 35 weeks) gonad position[9]
  • 10 to 23 weeks - 10 % had migrated from the abdomen and were situated in the inguinal canal
  • 24 to 26 weeks - 58 % had migrated from the abdomen
  • 27 to 29 weeks - 17 % had not descended to the scrotum


Mouse mammary gland development (E14.5)[10]
  • Week 8 - epidermis placode down-growth into the dermis, modified sweat glands 
  • Key Molecular Factors - WNT10B, GLI3, [Hh
  • epithelia/mesenchyme inductive interaction, mesenchyme forms connective tissue and fat
  • mammary ridges - mammary bud formation, pair of ventral regions axilla to inguinal
  • buds branch to form lactiferous ducts, only main duct formed at birth
  • prior to puberty male and female glands the same

Lactiferous duct 01.jpg

Lactiferous duct

Puberty Changes

Mammary anatomy.jpg The Tanner scale is an anatomical staging system for measuring male/female sexual development at puberty. Stages were based upon genital and secondary sex characteristic development and named after James M. Tanner who, along with W.A. Marshall, published the stages for both girls (1969 [11]) and boys (1970 [12]). It is not a system for determining age. (More? Puberty Development | Tanner stages)

Tanner stages


This animation shows the process of early renal (kidney) development.


  • Ureteric Bud - developing ureter, pelvis, calyces, collecting ducts
  • Metanephric Blastema (intermediate mesoderm) - developing glomeruli, capsule, nephron tubules
Nephron development 01.jpg The morphological events and localization of renal progenitors occurring during nephron development in the adult human kidney.[13]

Mesenchymal cells near the tips of the branching ureteric bud undergo epithelial transition and differentiate through a series of forms made up of renal progenitors (red)

  • a - condensed aggregate forms
  • b - renal vesicle forms
  • c - S-shaped body (red), renal progenitors are localised, at this stage podocyte-committed progenitors (red + blue) as well as tubular-committed progenitors (orange) can already be seen.
  • d - mature nephron, renal progenitors (red), podocyte-committed progenitors (red + blue), as well as tubular-committed progenitors (orange) are distributed along the nephron.
  • e - glomerulus, renal progenitors (red) are localized at the urinary pole of the Bowman capsule. Podocyte-committed progenitors (red + blue) localize along the Bowman capsule.
Fetal nephron development 01.jpg After nephron development has completed and concomitant with the development of the renal papilla in the newborn, the thin ascending limb of Henle’s loops is generated as an outgrowth from the S3 segment of the proximal tubule and from the distal tubule anlage of the nephron. (birds and mammals)

4. Endocrine


Adrenal medulla.jpg
Week10 adrenal.jpg
  • Week 6 - fetal cortex, from mesothelium adjacent to dorsal mesentery; Medulla, neural crest cells from adjacent sympathetic ganglia
  • Fetal Adrenals - fetal cortex later replaced by adult cortex
  • Adult cortex - mesothelium mesenchyme encloses fetal cortex

Adrenal Cortex

  • Late Fetal Period - differentiates to form cortical zones
  • Birth - zona glomerulosa, zona fasiculata present
  • Year 3 - zona reticularis present

Adrenal Medulla

  • neural crest origin, migrate adjacent to coelomic cavity, initially uncapsulated and not surrounded by fetal cortex, cells have neuron-like morphology
  • 2 cell types - secrete epinepherine (adrenaline) 80%; secrete norepinephrine (noradrenaline) 20%
Adrenal medulla.jpg
 ‎‎Adrenal Medulla
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Adrenal gland development and steroid hormone synthesis
Fetal adrenal gland steroidogenesis.jpg

Overview cartoon of changes in adrenal gland structure and steroid hormone syntesis[14]

Ontogenesis of steroidogenic enzymes in the human fetal adrenal gland. This schematic representation is divided into portions showing the fetal adrenal gland (right) at the first, second and third trimesters of pregnancy, and the adult adrenal gland (left). During the first trimester, the fetal gland is composed of a definitive zone (DZ, light grey) and a fetal zone (FZ, dark grey).

Fetal zone (FZ) - expressing the P450C17 cytochrome, is responsible for massive secretion of DHEA and DHEA/S, used by the placenta as estrogen precursors.

Second trimester - chromaffin cells (CC, black) originating from the neural crests migrate through the fetal cortex to progressively colonize the center of the gland to form the future medulla (Med).

Third trimester - the newly constituted transitional zone (TZ, medium grey) acquires the enzyme 3ß-HSD while the expression of P450C17 remains, thus allowing the production of fetal cortisol. Near birth, cells of the definitive zone which

express only 3ß-HSD, acquire the P450aldo and begin to secrete mineralocorticoids such as aldosterone.

Neonatal - the fetal adrenal regresses strongly (mainly due to the regression of the fetal zone) and recovers progressively during the first years of extra-uterine life.

Adult - adult adrenal gland is composed of the zona glomerulosa (ZGlo, light grey), zona fasciculata (ZFasc , medium grey) and zona reticularis (ZRet, dark grey) responsible for the production of mineralocorticoids (aldosterone), glucocorticoids (cortisol) and androgens (DHEA-DHEA/S), respectively.

Links: Endocrine - Adrenal Development


Hypothalamus is a neuroendocrine organ linking the brain to the endocrine system. There are also hypothalamic cells that hormone-responsive during development and in the adult. Recently there has been shift in describing neurological development from the traditional morphological model of “primary and secondary vesicles” with developmental origin and gene expression model “prosomeric development”

  • Neuroectoderm - prosenecephalon then diencephalon after induction by the underlying prechordal plate.
    • Prosomeric model - hypothalamus and telencephalon are part of the secondary prosencephalon
  • ventro-lateral wall intermediate zone proliferation
  • Mamillary bodies - form pea-sized swellings ventral wall of hypothalamus

• Sonic hedgehog (Shh) - initially expressed in prechordal plate, is essential for inductive process.

Stage 13 image 061.jpg Stage 22 image 055.jpg Keith1902 fig167.jpg
Diencephalon region, shown by optic stalk
(Stage 13)
Late embryonic hypothalamus
(Stage 22)
Hypothalamus embryonic position

Hormones - Corticotrophin releasing hormone (CRH), Thyrotrophin releasing hormone (TRH), Arginine vasopressin (AVP), Gonadotrophin releasing hormone (GnRH), Growth hormone releasing hormone (GHRH), Somatostatin, Prolactin relasing factor (PRF), Dopamine

Links: Endocrine - Hypothalamus Development


Blue - neural tube ectoderm

Pituitary development animation.gif Red - surface ectoderm

Dual ectoderm origins

  • Neuroectoderm - prosenecephalon then diencephalon, neurohypophysis
  • Ectoderm - ectoderm roof of stomodeum, Rathke's pouch, adenohypophysis

Keith1902 fig015a.jpg Pituitary rabbit development.jpg


  • Anterior wall proliferates - pars distalis
  • Posterior wall little growth – pars intermedia
  • Rostral growth around infundibular stem – pars tuberalis


  • Infundibulum – median eminence, infundibulum, pars nervosa

Embryonic and fetal pituitary.jpg
Stage 22 image 220.jpg

Pituitary Timeline

Early Fetal (week 12)
  • Week 4 - hypophysial pouch, Rathke’s pouch, diverticulum from roof
  • Week 5 - elongation, contacts infundibulum, diverticulum of diencephalon
  • Week 6 - connecting stalk between pouch and oral cavity degenerates
  • Week 8 - basophilic staining cells appear
  • Week 9 - acidophilic staining cells appear
  • Week 10 - growth hormone and ACTH detectable
  • Week 16 - adenohypophysis fully differentiated and TSH increases to peak at 22 weeks
  • Week 20 to 24 - growth hormone levels peak, then decline
  • Birth - second TSH surge and decreases postnatally

Links: Endocrine - Pituitary Development | Embryo Images - Pituitary | Endocrinology


Stage 13 and Stage 22 thyroid development foramen caecum thyroid development
Embryo Stage 13 and 22 thyroid (GA week 6 and 10) Tongue foramen caecum Thyroglossal duct

  • thyroid median endodermal thickening in the floor of pharynx, outpouch – thyroid diverticulum.
  • tongue grows, cells descend in neck.
  • thyroglossal duct - proximal end at the foramen caecum of tongue.
  • thyroid diverticulum - hollow then solid, right and left lobes, central isthmus.

Thyroid Timeline

  • GA week 6 - thyroid median endodermal thickening in the floor of pharynx, outpouch – thyroid diverticulum (FA 24 days)
  • GA week 13 - colloid appearance in thyroid follicles, iodine and thyroid hormone (TH) synthesis. Growth factors (insulin-like, epidermal) stimulates follicular growth.
    • Fetal TH - initial secreted biologically inactivated by modification
  • GA 18-20 weeks - fully functional
    • late fetal secretion develops brown fat
  • Birth - TSH levels increase, thyroxine (T3) and T4 levels increase to 24 h, then 5-7 days postnatal decline to normal levels.

Maternal TH - iodine/thyroid status can affect development.

  • studies show that both high and low maternal thyroid hormone can impact on neural development [15])
  • Iodine deficiency - during prenatal period, leads to low fetal TH and neurological defects (cretinism).

Human thyroid system and neural development.jpg

Human thyroid system and neural development

Parathyroid - different embryonic origin

  • Endoderm - third and fourth pharyngeal pouches, could also have ectoderm and neural crest
    • 3rd Pharyngeal Pouch - inferior parathyroid, initially descends with thymus
    • 4th Pharyngeal Pouch - superior parathyroid

Links: Thyroid | Endocrine - Parathyroid Development|Parathyroid | Endocrinology |

Human Embryo Development

These sagittal MRI scans of GA week 8-10 show overall embryo development during this period.

Week 8 Week 10


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Cite this page: Hill, M.A. (2020, October 31) Embryology REI - Reproductive Medicine Seminar 2018. Retrieved from

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© Dr Mark Hill 2020, UNSW Embryology ISBN: 978 0 7334 2609 4 - UNSW CRICOS Provider Code No. 00098G