Female Reproductive System

Organization of the female reproductive system

• Primary sex organs: gonads

  • Ovaries

    • Production/storage of gametes (oocytes)

    • Hormone production

• Secondary sex organs:

  • Internal genitalia

    • Uterine tubes

    • Uterus

    • Vagina

  • External genitalia

    • Vestibule

    • Labia minora

    • Labia majora

    • Mons pubis

Supporting structures

• Broad ligament: fold of peritoneum that covers the uterus and uterine tubes and attaches to walls of pelvic cavity

• Ovarian ligament: attaches ovary to the uterus

• Suspensory ligament: attaches ovaries laterally to pelvic wall

• Uterosacral ligament: attaches uterus to sacrum

Uterine prolapse

• The uterus slips into/protrudes out of vagina

• Can occur as ligaments wear and stretch

Ovaries

• Outer cortex and inner medulla

  • Medulla: blood/lymph vessels

• Cortex contains:

  • Follicles: an oocyte with surrounding cells (granulosa and theca cells)

  • Corpus luteum “yellow body”: residual structure remaining after a follicle empties its oocytes during ovulation

    • Produces hormones (primarily progesterone)

  • Corpus albicans “white body”: residual structure formed when corpus luteum breaks down and is no longer functional

Follicles

• Oocytes in different stages of development surrounded by specialized cells that produce hormones and support oogenesis

Overview of oogenesis

Primordial germ cells → oogonia → primary oocytes → secondary oocytes → ovum

In utero (oogenesis)

• Germ cells develop into oogonia

• Oogonia enter Meiosis I and freeze in prophase I (primary oocytes)

Puberty (oogenesis)

• Menstrual cycle begins - once a month, select primary oocytes complete Meiosis I and generate 1st polar body

  • Secondary oocyte is formed (haploid with duplicated chromosomes)

  • Meiosis II begins - freeze in metaphase II

  • Secondary oocyte is ovulated

Fertilization (oogenesis)

• Meiosis II completes

• Formation of second polar body

Folliculogenesis

Follicular maturation → begins in… and completes during…

• Development of follicles

• Follicular maturation: begins in utero and completes during menstrual cycle

• Primordial follicles

• Primary follicles

• Secondary follicles

• Tertiary follicles

• Graafian follicle

Primordial follicles

• Form in utero

• Single layer of cells surround the primary oocyte → granulosa cells (majority of follicles at any one point)

Primary follicles

• Sporadically form from primordial follicles

• Granulosa cells enlarge

Secondary follicles - requires what and when

• Requires gonadotropins (therefore onset of puberty and onward)

  • Granulosa layer thickens

  • Outer layer of cells develop → theca cells

Tertiary follicles

• Ongoing stimulation by gonadotropins

  • Thecal and granulosal layers continues to develop

  • A fluid filled antrum forms

Graafian follicle

• The follicle that will ovulate during the menstrual cycle

  • Oocyte now connected to the rest of the follicle by a stalk

Uterine tubes (oviducts)

• Around 5 inches in length, smooth muscular tubes lined with ciliated epithelium

• Infundibulum: funnel shaped segment adjacent to ovary, has finger like projections called fimbriae. Ovulated oocyte enters uterine tube at the infundibulum

• Ampulla: mid portion of the tube, the ampulla is the usual site of fertilization of oocyte

• Isthmus: segment that connects to the uterus

An early embryo travels down the uterine tube and implants in the uterus approximately 5-9 days post fertilization

Ectopic pregnancy

• Pregnancy outside the uterus, a common site for ectopic pregnancies is the uterine tube, a life threatening condition

Anatomy of the uterus

• Three regions

• Three layers of uterine wall

• Three regions

  • Fundus: rounded portion above entrance of uterine tubes

  • Body: largest region of uterus

  • Cervix: most inferior, narrowed region of the uterus

    • Internal os: opening to the uterine body

    • External os: opening to vagina

• Three layers of uterine wall

  • Endometrium: inner layer of epithelial cells, uterine glands, underlying stroma

  • Myometrium: smooth muscle layers - (longitudinal, circular, and oblique)

  • Perimetrium: serosa layer of outer surface

Blood flow of the uterus

• Uterine arteries (L and R) → Branches of uterine arteries → Arcuate arteries → Radial arteries → → Straight (feeding basilar) and Spiral arteries (feeding functional)

What is the endometrium divided into

• Basilar zone (stable)

• Functional zone (variable)

What is the vagina and what does it consist of

• Hollow, distensible muscular tube around 3-5 inches in length, walls are arranged into rugae

• Vaginal mucosa: stratified, squamous epithelium and underlying lamina propria

• Vaginal muscularis: smooth muscle layer, loosely arranged in circular and longitudinal layers

• Vaginal adventitia: outer layers of dense and connective tissue and elastic fibers

• Vestibular glands: near the vestibular opening, produce and secrete lubricating mucous particularly during sexual arousal

• Hymen: elastic epithelial fold that partially covers the vaginal opening

External genitalia

• Vulva: term that refers to external genitalia collectively

• Mons pubis: fatty region that overlies pubic symphysis

• Labia majora: outer protective folds (develop from same embryonic tissue as the scrotum in males)

• Labia minora: inner protective folds; mucous membrane and richly supplied with glands and blood vessels

• Vestibule: area enclosed by labia minora

  • Vaginal orifice: opening of vagina

  • Urethral orifice: opening of urethra

  • Clitoris: erectile tissue, rich in nerves; glans (visible) and body (deep)

Gonadotropins and female life cycle → in utero/early infancy

• In utero/early infancy: peak in gonadotropin release - second trimester and early infancy

Gonadotropins and female life cycle → in childhood

• In childhood: low levels of gonadotropin release

Gonadotropins and female life cycle → Puberty

• Puberty: nighttime pulsatility of GnRH release

  • Menarche: first menstruation around 13 years of age

Gonadotropins and female life cycle → In reproductive years

• Reproductive years: ongoing pulsatility of GnRH release, monthly surges of gonadotropins and cyclic pattern of estrogen and progesterone release

Gonadotropins and female life cycle → Menopause

• Menopause: decrease in estrogen and progesterone levels due to exhaustion of follicular pool, loss of negative feedback, higher levels of gonadotropins, no monthly surges

Images of gonadotropins and female life cycle

What is the menstrual cycle

• Cyclic changes in ovarian hormone production and uterine morphology over around a 28 day period in women of reproductive years

• Described according to ovarian changes (ovarian cycle) and uterine changes (uterine cycle)

  • Uterine changes are a result of changes in production of ovarian hormones

• 2 phases:

  • Before ovulation

    • Ovarian: follicular phase

    • Uterine: menses and proliferative phase

  • After ovulation

    • Ovarian: luteal phase

    • Uterine: secretory phase

Summary of sex steroids

• In the non-pregnant female of reproductive years, the most abundant progestin is progesterone

  • These hormones primarily originate from the ovary

• Androgens:

  • Biologically active: testosterone

  • Dihydrotestosterone (DHT)

• Estrogens:

  • Biologically active: estradiol

• Progestins:

  • Biologically active: progesterone

Estradiol synthesis requires…

• Two cells (theca and granulosa) and two gonadotropins (LH and FSH)

Two cell

• Theca cell:

  • Lacks aromatase

  • Cannot convert testosterone → estradiol

• Granulosa cell:

  • Lacks 17alpha hydroxylase

  • Cannot convert progesterone → androstenedione

• Theca cell: androstenedione synthesis, diffuses to nearby granulosa cell

• Granulosa cell: utilizes androstenedione as a precursor for estradiol synthesis

Two-gonadotropin

• LH receptors:

  • Theca cells (always)

  • Granulosa cells (late follicular and luteal phases)

• FSH receptors

  • Granulosa cells only

• LH: induces cholesterol desmolase enzyme activity (generate progesterone from cholesterol) and LDL receptor expression

• FSH: induces aromatase activity

Feedback control of ovarian hormones

What are the main big picture segments of the menstrual cycle

• Ovarian Cycle

• Uterine Cycle

Broadly → Ovarian cycle

• Day 1-14: Follicular phase: FSH

  • Follicular development of a cohort of follicles (around 7-12) under the influence of FSH

  • Only one will grow into a Graafian follicle to be ovulated

  • Rising estrogen production by follicles

  • Mid-cycle: LH surge due to positive feedback of estrogen

    • Ovulation and conversion of a Graafian follicle into the corpus luteum

• Day 14-28: Luteal phase: LH

  • Rising progesterone production by corpus luteum

  • Finite life span of corpus luteum

Uterine Broadly → Uterine cycle

• Day 1-7: Menses (days 1-7 of follicular phase)

  • Triggered by the dramatic decrease of estrogen and progesterone production of ovary

  • Shedding of endometrial layer

• Day 7-14: Proliferative Phase (days 7-14 of follicular phase)

  • Growth of endometrial layer under the influence of progressively rising estrogen

• Day 14-28: secretory phase (overlaps with luteal phase)

  • Conversion of built up endometrial layer into a secretory structure by the actions of progesterone

What does the ovarian follicular phase consist of

• Early follicular phase

• Late follicular phase

Early follicular phase

• FSH stimulates follicular growth in follicular cohort (7-12 follicles)

  • Increases aromatase activity (increased estradiol synthesis)

• By day 5 one dominant follicle outcompetes others for FSH ultimately becoming Graafian follicle

  • Rapidly grows and produces increasing higher levels of estradiol

Ovarian follicular phase → effects of circulating estradiol

• Increases FSH receptor expression of granulosa cells (leading to further production of estradiol)

• Estradiol increases estrogen and progesterone receptor expression in the uterus (estrogen priming)

Late follicular phase

• FSH induces LH receptor expression on granulosa cells of dominant follicle now responsive to LH

  • (also increases theca cell expression of LH receptor)

• Sustained levels of estradiol above threshold level for around 2 days

Late follicular phase → effects of LH on granulosa and theca cells

• Increased LDL receptor expression and cholesterol desmolase activity

• Increased available pregnenolone available as precursor for estradiol synthesis

• Combined greatly increased estradiol synthesizing capability of dominant follicle

Ovarian luteal phase

• LH surge: luteinization

  • Conversion of emptied follicle into a fluid filled corpus luteum

  • Abundant cholesterol available to granulosa luteal cells for progesterone synthesis (yellow color)

  • Granulosa cells now have abundant LH receptors

• Granulosa cells of luteum - increased capability of synthesizing progesterone

• 10 fold increase in progesterone levels during the luteal phase

  • Progesterone transform uterus into organ capable of supporting developing embryo

Ovarian luteal phase → if no pregnancy occurs

• If no pregnancy occurs, there is a finite life span of corpus luteum (14 days)

• After the corpus luteum breaks down (corpus albicans):

  • Progesterone and estrogen levels begin to drop

  • Decrease negative feedback

  • FSH levels begin to rise at the end of the luteal phase → recruitment of new cohort of follicles

Uterine cycle: Menses

• Menses: loss of hormonal support

• Early follicular phase

  • Shedding of outer endometrial layer (functional zone) accompanied with blood loss due to a decrease in hormonal support

  • Prostaglandins released by ruptured cells leads to smooth muscle contractions

  • Onset → 14 days after ovulation, average length: 4-6 days

Uterine cycle: Proliferative phase

• Proliferative phase: increasing estradiol

• Late follicular phase: increased estradiol

  • Thickening of endometrial layer:

    • Proliferation of epithelial cells of the endometrial layer (functional zone)

    • Increase estrogen receptor expression

    • Increase progesterone receptor expression: “estrogen priming:

  • Progressive increase in amount of cervical mucus, mucus thins: spinnbarkeit

Uterine cycle: Secretory phase

• Secretory phase: increased progesterone

• Luteal phase: increased progesterone

  • Differentiation of endometrial layer into a glandular epithelium with increased (secretions rich in glycogen and lipids)

  • Progesterone inhibits contraction of the myometrium

  • Cervical mucus production decreases, mucus thickens

  • Late secretory phase: if there is not a fertilized embryo in the uterus, the corpus luteum breaks down → loss of hormonal support: spasm of blood vessels: ischemic phase

Life span of ovulated (non-fertilized) oocyte

• 24 hours

Life span of spermatozoa within female reproductive tract

• 3-5 days

Fertilization occurs

• Within the uterine tubule (ampulla)

Window of fertility

• 5 days before ovulation and also the day of ovulation

Fertilization during the cycle

• Ovulation occurs → day 14 and fertilization must happen within 24 hours (typically in ampulla)

• Zygote reaches the uterus approximately 5-9 days later (around day 19- day 21) → uterus is in secretory phase

• Cells of the early embryo produce a hormone called human chorionic gonadotropin (hCG)

  • Once embryo implants in the uterine wall, this hormone enters the maternal circulation

  • hCG rescuers the corpus luteum and prevents it from breaking down

  • The corpus luteum maintains high levels of progesterone to maintain the uterus in a pregnancy friendly state during the first 2-3 months of the pregnancy until the placenta fully forms

  • Once the placenta fully forms, it takes over the production of maternal hormones needed to maintain pregnancy

    • CORPUS LUTEUM → PLACENTAL SHIFT