The female reproductive system Aleš Hampl November 2023 1. Oogenesis 2. Copulation – receives sperm from male 3. Hormone production 4. Provides sites for egg fertilization, implantation, and development 5. Acts as birth canal Functions of the female reproductive system Female genital organs – Gross anatomy 1 Female genital organs – Gross anatomy 2 Endometrium Myometrium Epimetrium Cervix of uterus Vagina Fundus of uterus Labia minora Labia majora Clitoris Uterine tube (fallopian) Ovary Ovary – Overall structure Length – 3 cm Width – 1.5 cm Thickness – 1 cm Medulla Cortex Hilum Cortex • Follicles • Highly vascularized stroma Medulla • Vessels • Loose connective tissue Ovary – Surface Cortex Surface epithelium (germinal) cuboidal cells Tunica albuginea dense connective t. Oogenesis - Key periods G2/M block mitotic division growth (months) meiotic maturation (hours) PGC & oogonia MI MII Resumption of meiosis Block of meiosis in diplotene of the 1. meiotic division Fertilizable egg, capable of supporting early embryonal development Primary oocytes Secondary oocyte Meiosis – two divisions instead of one DNA replication establishment of bivalents „crossing over“ 1. meiotic division Independent segregation of chromosomes 2. meiotic division Separation of chromatids 2n 2C 2n 4C 1n 2C 1n 2C 1n 1C 1n 1C Fully functional germ cells Oogenesis - Lifetime summary At the time of birth max. 500 thousands of primary oocytes At the end of 6 month of fetal development ~ 6 – 7 millions of primary oocytes At the time of menopause max. 100 – 1000 remaining oocytes At the time of birth ~ 500 thousands of primary oocytes Atresia Atresia Ovulation (~ 500 oocytes) Oogenesis – Polar body production Ooogenesis – stages of the oocyte development DiploteneoftheMeiosisI Inside the ovary Preantral follicle (multilaminar) Recruited follicle (unilaminar) Secondary (antral) follicle (medium size) Tertiary (Graafian) follicle Primordial follicle30 mm 20 mm Selection of the Dominant follicle (the one most sensitive to FSH) ~14 days Growth Primary follicles Massive hormone production Androstendione Theca folliculi interna Estradiole Granulosa cell Oogenesis – Overall picture inside the ovary Oogenesis – Primordial follicles Primary oocyte • Organelles around nucleus • Abundant mitochondria • Abundant RER Oogenesis – Primary follicles Unilaminar Multilaminar Zona pellucida (5-10 mm) Granulosa cells 15 Oogenesis – Secondary (antral) follicles 16 Antrum Membrana granulosa Theca folliculi Cumulus oophorus Oogenesis – Tertiary (Graafian, preovulatory) follicle Oogenesis – Wall of tertiary follicle Membrana granulosa Theca externa Theca interna Basal membrane (Slavjanski) Theca interna • Vascularized • Androstendione to granulosa cells - estradiol Theca externa • Fibrous with smooth m. cells Antrum with follicular fluid 18 Chromosomes Oogenesis – MI phase oocyte surrounded by corona radiata Polar body Oogenesis – MII phase oocyte Oogenesis – Ovulation tigma • initiated by LH surge • no blood flow at stigma – ischemia • smooth muscle contractions - theca f. externa 21 Oogenesis – Ovulated oocyte Corpus luteum 1 Granulosa cells – Granulosa lutein cells • large (20-30 mm) • 80 % of CL • convert androstendione to progesterone and estradiol Theca interna cells – Theca lutein cells • smaller (10-15 mm) • production of steroids • vascularized – fenestrated caps. 23 Granulosalutein cells Thecalutein cells Corpus luteum 2 Corpus luteum 3 Granulosalutein cells Thecalutein cells Gartner, Hiatt, 2001 Corpus luteum 4 CL graviditatis • diameter 2 – 3 cm • maintains pregnancy • mantained by chorionic gonadotropin (HCG) • maximal at 2 months • changes to c. albicans at month 4-5 CL menstruationis • 10 – 12 days • changes to c. albicans (dense connective tissue – collagen + fibroblasts) Corpus albicans Corpus luteum Corpus luteum & albicans 27 Corpus albicans 28 • all types of follicles • apoptosis of follicular cells • autolysis (autophagy) oocytes • phagocytosis by macrophages • zona pellucida and basal lamina persist the longest time Mescher, 2010 Follicular atresia Mescher, 2010 Ovarian cycle – 28 days Preovulatory phase • days 1 to 14 • growth and maturation of follicles • production of streid hormones Postovulatory phase • days 16 to 28 • corpus luteum • production of progesterone Ovulation • at day 15 • connect the ovaries to the uterus • 12 to 15 cm long x 0.7 to 5 cm in diameter • location of fertilization and early embryonic development Teachmeanatomy.info Uterine tubes = Fallopian tubes = Oviducts University of Leeds Histolgoy, histology.leeds.ac.uk Lumen Tunica mucosa T. muscularis T. serosa 31 Oviduct - Ampula • highly branched mucosa • longitudinal folds • labyrinth 32 Oviduct - Ampula 33 Oviduct - Isthmus • less branching 34 Oviduct Tunica mucosa ● lamina epithelialis – simple columnar epithelium 1.) CILIATED CELLS –possess many cilia- transport of the ovum and embryo 2.) SECRETORY CELLS (PEG) – secrete a nutrient rich medium ● lamina propria – loose connective tissue (is richly vascularized!) Uterus 1 • Mechanical protection and nutritional support to developing embryo • Bends anteriorly (anteflexion) • Stabilized by broad, uterosacral, round, and lateral ligaments Uterus 2 Uterine wall ~ 1.5 - 2 cm 1. Endometrium – T. Mucosa 2. Myometrium – T. muscularis 3. Perimetrium – T. Serosa ● consists of lamina epithelialis and lamina propria ● epithelial lining – simple columnar epithelium containing secretory and ciliated cells ● lamina propria – loose connective tissue with many stellate fibroblasts, contains abundant amorphous ground substance→ uterine glands – simple tubular glands (covered by simple columnar epithelial cells) 1. Stratum functionalis (~ 5 mm) ○ exhibit dramatic changes during menstrual cycle every month (hormone-driven) ○ shed during menstruation ! 2. Stratum basale (~ 1 mm) ○ undergoes little changes during the menstrual cycle ○ not shed during menstruation ! ○ provides a new epithelium and lamina propria for the renewal of the endometrium! Dartmouth Medical School, Virtual Histology http://www.dartmouth.edu/~anatomy/Histo Uterus – Endometrium 1 Simple columnar epithelium Endometrial glands Uterus – Endometrium 2 39 Gartner, Hiatt, 2001 Uterus – Endometrium - Blood supply Uterus – Menstrual cycle (28 days) Menstrual phase (days 1 – 4) Proliferative phase (days 5 – 15) (driven by estrogens) Secretory phase (days 16 – 27) (driven by progesteron) Ischemic phase (day 28) Endometrium – Proliferative phase • rising estrogen from the developing follicles • the stratum basalis is regrowing the stratum functionalis – new glands form • long and straight uterine glands which are not yet functional Sobotta, 1995 Endometrium – Secretory phase • under the control of estrogen and progesterone from the corpus luteum • the uterine glands of the stratum functionalis begin to function, producing glycogen • the curvy and dilated glands and elongated spiral arteries • lack of estrogen and progesterone from the dead corpus luteum • the stratum functionalis dies and loses its anatomical integrity, breaking lose and shedding from the stratum basalis Sobotta, 1995 uterine cavity myometrium shedding stratum functionalis Endometrium – Menstrual phase • three interwoven layers of smooth muscle • during pregnancy – smooth muscle cell hyperplasia + hypertrophy • contract in response to oxytocin during labor to expel the fetus from the uterus Uterus – Myometrium Dartmouth Pathology, http://www.dartmouth.edu/~anatomy/Histo • 2-3 cm in length • cylindrical shape • cervical canal connects lumen of uterus to lumen of vagina • numerous mucous glands • changes thickness throughout ovulation cycle • important for pregnancy and childbirth • contributes to capacitation The Cervix + Orificium externum uteri uvahealth.com Stratified squamous ep. Columnar ep. Abrupt junction of epithelia The Cervix Junction - collumnar to stratified squamous ep. Simple collumnar ep. Stratified squamous ep. Cervical glands (tubular, branched, mucus secreting) VAGINA Mescher, 2016 Vagina 1 • receives sperm during copulation • serves as birth canal 3 tissue layers a) mucosal layer – inner layer; non-keratinizing stratified squamous b) muscular layer – middle layer; smooth muscle in two layers c) adventitia – outer layer; areolar connective tissue 150-200 mm NO glands ! Vagina 2 Epithelial cells sythesize and accumulate glycogen (upon stimulation by estrogens) Vagina 3 Preovulatory state (all four layers) Released after ovulation • glycogen • Lactobacillus • acidification Cervical smear – Giemsa staining Contain glycogen 50 Labia minora Sebaceous glands Nerves Veins Covered by hairless skin cloaca Urogenital system – Overall picture Urogenital system – Reminder Urogenital system – Intermediate mesoderm Genital system Sexual dimorfism – individual can only have one type of genital organs Genetic determination: • Heterogametic (XY) – male • Homogametic (XX) - female Indifferent stage Differentiation into individual sexes 7th weekFertilization = genetic gender established (Barr body) Sertoli cells Leydig cells No MIS No Testosterone Sexual Determination Sexual Differentiation Genital system – Sry gene Sry gene – Sox family TF – on short arm of Y chromosome Default pathway Y chromosome decides XXY – male X0 - female Genital system – Sry gene Pairing of X and Y chromosomes in pseudoautosomal region during meiosis Rare crossing-over causes translocation of SRY to X chromosome: XY females or XX males Genital system – Primordial germ cells PGC - large spherical cells Primordial germ cells (PGC) • first recognizable at day 24 • from epiblast-derived extraembryonic msoderm • few cells among endodermal cells of the yolk sac • they migrate through the dorsal mesentery of the hindgut • migrate towards genital rigdes (plicae genitales) • proliferate during migration • reach (1-2 thousands) genital ridges on week 6 of gestation Males PGC stop dividing Females PGC enter meiosisX decided by somatic cells in the genital ridges Genital system – migration of PGC into gonadal anlagen Genital system – gonadal anlagen Steroidogenic mesoderm along the ventromedial border of the mesonephros caudal region = Genital ridges cranial region = Adrenocortical primordia cells of coelomic epithelium + cells from mesonephric ridge Week 4 – Th6 to S2 cranial + caudal parts involute Week 6 – L3 to L5 become populated by PGC at week 6 Genital system – indifferent gonade (week 6) Medulary cords Genital system – Sexual duct system – Indifferent stage Paramesonephric duct Develops at days 44 to 48 Cranially opens to coelomic cavity Week 7 Wolffian Mullerian Genital system – Differentiation of the testes Late 6th week Cord cells differentiate to Sertoli cells (meiosis-inhibiting factor, anti-mullerian substance, androgen binding factor) Tunica albuginea develops (sets barrier between coelomic epithelium and testis cords) Cord cells form seminiferous tubuli, tubuli recti, and rete testis Rete testis joints ductuli efferentes that are derived from mesonephric ducts (5th to 12th) Week 8 to 18 Leydig cells develop and function in developing testis • from coelomic epithelia and mesonphros • produce testosteron • support development of Wolfian (mesonephric) duct • support development of external genitalia Genital system – Sexual duct system – Male Mesonephric ducts (Wolffian) • Ductus epididymis • Ductus deferens • Ductus ejaculatorius • Seminal vesicle Paramesonephric ducts (Mullerian) regresses in week 8 (anti-M hormone) • Appendix testis (cranial part) • Utriculus prostaticus (caudal part) Mesonephros • Ductuli efferentes • Paradidymis (under the testis, nonfunctional) Genital system – Differentiation of the ovaries • PGC concentrate in the cortical region • PGC proliferate (max until week 22) and then enter meiosis – arrest in prophase • Ovarian follicles develop (somatic cell contribution is not understood) • Transient rete ovarii develops in medullary region • Medulla contains connetive tissue and vasculature derived from mesonephros Genital system – Sexual duct system – Female Mesonephric ducts (Wolffian) regresses (absence of testosterone) • Gartners cyst (caudal part) Paramesonephric ducts (Mullerian) • Uterine tubes (falopian t.) • Uterus • Vagina Mesonephros (+Mesonephric duct) • Epoophoron (appendix of ovary) • Paraophoron Genital system – Sexual duct system – Uterus Uterovaginal canal Genital system – Duct system – Uterovaginal channel Dorsal view Lateral view Paramesonephric (Mullerian) ducts fuse to form uterus and upper 1/3 of vagina Genital system – Uterovaginal channel - Anomalies Genital system – External genitalia - Indifferent stage They are derived from a complex mesodermal tissue located around cloaca. Week 8 Week 6 to 8 Genital tubercle – Phallus Urethral (genital) folds – Plicae urogenitales Genital swellings – Tori genitales Orificium urogenitale primitivum demarcated by: HORMONE-INDEPENDENT Genital system – External genitalia - Dimorphism Week 9 to 13 Weeks 12 + 13 are particularly critical = fusing of urethral folds Genital swellings Genital tubercle Genital (urethral) folds Clitoris Labia minora Labia majora Penis Urethra Scrotum MALE FEMALE Genital system – External genitalia - Male Genital tubercle elongates – penis (phallus) Genital swellings enlarge – scrotum Genital folds form the lateral walls of the urethral groove Genital folds form the spongy urethra Ventral epithelium of genital folds – urethra proper Corpora cavernosa develop from mesenchyme Scrotal raphe Urethral raphe Anus Scrotum Genital plate Fused genital folds + Canalized – urethra formed Genital groove Genital system – External genitalia – Urethral orifice • ectodermal ingrowth forms a cellular ectodermal cord Penis body Ectodermal cord Glans penis Spongy urethra Coronary groove Surface ectoderm Spongy urethra Spongy urethra Developing septum External urethral orifice Distal part of spongy urethra Prepuce Glandular part of urethra • the cord grows towards the root of the penis to meet the spongy urethra • the cord canalizes • circular ingrowth of ectoderm occurs at the periphery of the glans penis (week 12) • circular ingrowth breaks down forming prepuce (for some time adherent to the glans penis, hard to retract at birth) Genital system – External genitalia – Male hypospadia Normal midline raphe Raphe off center Genital system – External genitalia - Female urethra and vagina open into vestibule = from urogenital sinus urethra develops from the more cranial part of urogenital sinus – equivalent to prostatic urethra Thank you for your attention ! Questions and comments at: ahampl@med.muni.cz