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FEMALE REPRODUCTIVE SYSTEM

organs

OVARY
STRUCTURE
surface epithelia = simple cuboidal ep. tunica albuginea = DCT capsule (of whitish colour) under the cuboidal ep. cortex = region (the most of ovary) houses the ovarian follicles in various stages of development + stroma = special spinocellular loose CT medulla = a smaller part containing a rich vascular bed and vegetative nerves within a CT

lab. classes

FUNCTION
oogenesis production of ovarian hormones (steroids) = estrogens and progesterone
primary growing follicle secondary (multilayered) follicle CORTEX Graafian mature (tertiary) follicle

hilum with vessels

primary follicle

MEDULLA corpus albicans Ovulation simple cuboidal ep.

(on the surface)

corpus luteum

OVARY

lab. classes

F = follicle CL = corpus luteum H = vessels in the MEDULLA (M) branches of ovarian artery L = broad ligament

CL = corpus luteum D = degenerating yellow corpuscles A = corpus albicans (white corpuscle) O = oviduct (close to ovary)

OVARIAN SPINOCELLULAR CT
= a special form of LCT which forms: a) stroma of ovarian cortex b) stroma of endometrium of uterus FUNCTION

lab. classes

the cells fibroblasts - are able to differentiate - into the theca-lutein cells which are producers of progesterone in the ovary - into the decidual cell (decidual or pseudodecidual transformation = large, light-stained cells with high content of glycogen and the other nutrients for the nourishment of blastocyst after its implantation) in the endometrium this highly plastic tissue allows changes in volume of the different structures: - the growth of ovarian follicles and then the shrinkage of stroma after the rupture of Graafian follicle - the growth (enlargement) of implanted blastocyst in the endometrium of uterus

STRUCTURE
spindle-shaped fibroblasts largely predominate over the reticular fibres and the ground substance they are arranged into typical whorls

OVARY
Originates from: mesoderm (gonadal ridges) = epithelial cc.: surface ep. + follicular (granulosa-luteine) cells mesenchyme (splanchnic) = CT cc. (incl. spinocellular fibroblasts) + vessels (endothelium + LCT) endoderm (yolk sac) = oogonia

OOGENESIS =

the sequence of events by which oogonia are transformed into ova (eggs) the process begins prenatally and is not completed until after puberty (i.e. at least after 12-14 years), and ends in menopause 1) Embryonic period oogonia: 46, XX, 2c DNA - migrate from the endoderm of the yolk sac to mesodermal gonadal ridges, where proliferation by mitosis starts (period of multiplication) - approx. to 4 millions of oogonia no oogonia develop after the birth - oogonia enlarge (period of growth) to primary oocytes (46, XX, 2c DNA) and form primordial follicles

2) 1st meiotic division begins by the time of birth (approx. 2 millions of prim. oocytes), - primary oocytes - approx. 400.000 almost complete prophase but are arrested in prophase (dictyotene stage) until puberty - primary oocytes are reduced by atresia (regression) and until puberty remain approx. only 40.000 of primary oocytes 3) at puberty hormones induce continuation of the cycle (period of maturation) primary oocyte successively becomes a part of primary, secondary and mature (tertiary) follicle - shortly before ovulation, the primary oocyte complete the 1st meiotic division secondary oocyte (23, X, 2c DNA + 1st polar body) - at ovulation, secondary oocyte begins the 2nd meiotic division, but progresses only to metaphase and ends only if ovum is fertilized (23, 1c DNA + 2nd polar body) - only about 400 secondary oocytes mature during the reproductive period (until menopause) and are expelled at ovulation

OOGENESIS (from 1 oogonia) 1 ovum (secondary oocyte) x SPERMATOGENESIS (from 1 spermatogonia) 4 mature sperms

intrauterine development period

OOGENESIS
44+XX oogonia (4 000 000) primary oocyte beginning of 1st meiotic division arrested in prophase (dictyotene stage) primordial follicles birth (400 000 cc.) puberty (40 000 cc.)

MULTIPLICATION

fertile period

primary follicle secondary follicle (vesicular) Graafian mature follicle (tertiary)

GROWTH
primary oocyte

ovulation: end of 1st meiotic division (400 cc.) 22+X secondary oocyte 2nd meiotic division arrested in metaphase - only if penetrated by sperm fertilization: 2nd meiotic division is completed fertilized egg (ovum)

1st polar body

MATURATION

sperm

2nd polar body

zygote (44+XX or 44+XY)

 of the oocyte 25 m

DEVELOPMENT OF OVARIAN FOLLICLES

I. PRIMORDIAL FOLLICLE

lab. classes 7

of the oocyte 125 m of mature follicle about 2.5 cm

Follicular cc. derive from original mesodermal (i.e. epithelial cc.) = epithelial cc.

Oocyte increases its volume approx. 5x during the oogenesis from about 25 m in the primord. follicle to 125 m in the Graafian follicle.

DEVELOPMENT OF OVARIAN FOLLICLES

II. PRIMARY unilaminar FOLLICLE III. PRIMARY growing (multilaminar) FOLLICLE

lab. classes

one layer of columnar follicular cc

and follicular cc

Zona pellucida = glycocalyx

Theca interna cc. develop from spinocellular CT fibroblasts.

DEVELOPMENT OF OVARIAN FOLLICLES

IV. SECONDARY (vesicular) FOLLICLE
are in both theca interna and t. externa (CT!)

- it derives from blood plasma

Theca externa cc. develop from common CT fibroblasts = common type of CT with vessels.

In the primary and secondary follicle, follicular cc. have FSH receptors on the surface.

zona pellucida primary oocyte with vesicular (light-stained)

nucleus and 1 prominent nucleolus

IV. SECONDARY FOLLICLE

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follicular cc. granulosa membrane spinocellular CT stroma theca interna ZONA PELLUCIDA = a thick glycoprotein layer = glycocalyx - probably the product of both follicular cells and oocyte - it is penetrated by long processes of follicular cc. (joined to oolema by gap junctions) and by oocyte microvilli

EM:

SEM:

(in prophase of 1st meiotic division)

FOLLICULAR CELLS are joint together by nexuses only (neither tight junctions nor hemato-follicular barrier are established), this system enables transportation of substances (nutrients and small informative macromolecular substances) from mother's blood to follicular fluid and reversely essential for the normal development of oocyte

lab. classes 11

IV. SECONDARY (vesicular) FOLLICLE formation of the antrum and layers of the wall
antrum with follicular (antral) fluid (FA) = estrogens

! STRUCTURE of the WALL

1. GRANULOSA MEMBRANE (ZG) = follicular cells (protein-secreting cells) - they convert androstendion (produced by the cells of theca interna) to estrogens (estradiol) released into the follicular (antral) fluid - these cells are under the influence of FSH - granulosa layer is avascular 2. BASAL LAMINA of follicular cells (very thick) 3. THECA FOLLICULI INTERNA (TI) - originates from spinocellular cell-rich CT (steroid-secreting cells) - the cells secrete androstendion (androgen) - they are under the influence of LH - with blood vessels 4. THECA FOLLICULI EXTERNA (TE) - is formed of common type of CT with blood vessels Early folliculogenesis
(in primary and secondary follicles) - functional synergism between follic. cc. (with FSH receptors) and theca interna cc., producers of androstendion (influenced by LH) production of estradiol

oocyt (O1) with zona pellucida (light blue)

cumulus oophorus (CO) = follicular cc of granulosa layer

corona radiata = 1 layer of follicular cells

DEVELOPMENT OF OVARIAN FOLLICLES

V. GRAAFIAN (MATURE, tertiary) FOLLICLE
Granulosa membrane = follicular cc.

lab. classes

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Granulosa membrane = follicular cc.

In the Graafian follicle, LH receptors appear and coexist with FSH receptors.

Follicular cc. of cumulus oophorus become loosely arranged (see next).

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V. GRAAFIAN (mature, tertiary) FOLLICLE

of this follicle is 1 2.5 cm; of oocyte is 120 - 150 m structure of the wall is similar to the growing secondary follicle, only the wall becomes thinner and the volume of the whole structure (mainly of antrum) is larger the intercellular spaces between granulosa cells becomes wider (by the increase of intercellular tissue fluid) preparation for ovulation

antrum with follic. fluid

GROWTH of the FOLLICLE and OOCYTE

the volume of oocyte enlarges about 5x (from primordial to mature follicle) it is influenced by FSH, epidermal growth factor (EGF), insulin-like growth factor I (IGF-I) and calcium ions (Ca2+) blood level division of the follicular cells is stimulated by estrogens (in the follicular fluid) when oocyte reaches the size about 130-150 m the secretion of OMI (oocyte maturation inhibitor) by follicular cc. into the fol. fluid begins to prevent the oocyte from spontaneous meiotic maturation

FOLLICULAR FLUID (liquor folliculi)

= slightly viscous fluid (filtrated from blood plasma) + estrogens + growth factors, gonadotropins, hyaluronic acid, proteins, salts etc. Function: content of estrogens participation for ovulation (increased intrafollicular pressure
and transportation of the ovum with coverings)

Oocyte (primary) starts to detach from c. oophorus

(formation of small lacunes filled in with tissue/follicular fluid and their fusion)

= preparation for ovulation.

OVULATION = ovulatory phase

it is a rupture of mature Graafian follicle and expulsion of the primary oocyte - at this point, 2nd meiotic division begins and oocyte becomes secondary oocyte (2nd meiotic division is arrested in metaphase until fertilization) it starts at about 1/2 of the menstrual cycle (14th day) the stimulus is the surge of LH (in blood) that blocks the secretion of estrogens into the follicular fluid LH induces changes (luteinization) which convert the follicle remnants into an endocrine structure = corpus luteum
Oocyte (with ZP and CR) is released towards the oviduct

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essential for endocrine secretion. (vasculogenesis)

STIGMA a clear transparent cone is an attenuation of the wall of follicle but also of ovary in limited area resulting from gradually interrupted blood circulation + collagenase activity (degradation of collagen in both t. albuginea and theca ext.) leading to the local cell necrosis and RUPTURE of the ovarian follicle wall + detach of oocyte which flows (with follicular fluid) into the oviduct The acquisition of LH receptors by follicular cc. in the stage of Graafian follicle is essential for the luteinization of the ruptured follicle following ovulation.

Formation of CORPUS LUTEUM = luteal phase

1 4 Immediately after the ovulation (3) 4 the formation of corpus luteum develops: a breakdown of the BL of follicular cells enables the invasion of blood vessels into formerly avascular follicular cell layer granulosa layer is folded and transformed into the granulosa-lutein cells (see next) theca interna forms the septa which cells become theca-lutein cells (see next) 5 - CORPUS LUTEUM a) of menstruation (10-14 days) b) of pregnancy (6 months) DEGENERATION (autolysis) of c. luteum the remnants are removed by macrophages fibrotic scar develops = CORPUS ALBICANS CORPUS LUTEUM a) of menstruation (regression starts
at about 7 day and lasts about 2 weeks)

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5 2 - stigma

b) of pregnancy (regression starts at the end of 3rd month - function assumed by placenta )

corp. luteum

3 - ovulation
OVARY

Lutein pigment inside the cells yellow colour of corpuscle

oviduct

CORPUS LUTEUM = temporary endocrine gland

GRANULOSA (follicular)-LUTEIN cells (G)

lab. classes

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- they develop from the follicular cells - they increase greatly in size (34x), and the lipid droplets accumulate in their cytoplasm - character of steroid-secreting cells secrete progesterone + estrogens in response to both FSH and LH stimulation

THECA-LUTEIN cells (T)

- they originate from the fibroblasts of CT septa (S) deriving from theca interna - they are smaller and stain more intensely than granulosa-lutein cc, also contain fat droplets in cytoplasm - character of the steroid-secreting cells progesterone in response to LH stimulation

FUNCTION of the corpus luteum

Granulosa

sinusoid capillaries

Granulosa-lutein cells and theca-lutein cells cooperation

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CORPUS ALBICANS
If fertilization does not occur, the corpus luteum undergoes the degeneration - and is gradually replaced by fibrotic scar tissue = corpus albicans

lab. classes

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small c. albicans

c. albicans remaining after c. luteum of pregnancy

FOLLICLE ATRESIA
most of ovarian follicles undergo follicular atresia the structure of atretic follicle is same as structure of corpus albicans most ovarian follicles undergo the degeneration in stage of primordial follicles during the foetal period apoptosis these follicles disappear (without any remnants) primary, secondary and tertiary follicles undergo atresia after the birth until few years after the menopause, in which follicular cells and oocytes die and are disposed of by phagocytic cells the place is then filled by invaded fibroblasts (stromal cc.) which results to the formation of fibrotic scar = corpus albicans
atresia of the primary follicle

atresia of the secondary follicle

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! HYPOTHALAMUS ADENOHYPOPHYSIS OVARY axis

of ENDOCRINE REGULATION
GnRH (gonadotrophin releasing hormone secreted by hypothalamus) 1) increases the production of FSH (by gonadotrophic basophilic cc. of adenohypophysis) which stimulates - the growth of ovarian follicles and production of estrogens by follicular cc. estrogens into follicular fluid back to the blood high level of estrogens in the blood feedback to the hypothalamus down-regulation of GnHR production 2) production of LH (by gonadotrophic basophilic cc. of adenohypophysis) a) its surge initiates ovulation b) LH stimulates the development of corpus luteum and production of progesteron and estrogens by granulosa-lutein cc. and theca-lutein cc. to blood feedback to the hypothalamus down-regulation of GnHR production decrease of production of LH degeneration of c. luteum low level of estrogens and progesterone (in blood) up-regulation of GnHR production initiates again the production of FSH by adenohypophysis ( new cycle begins) of menstrual cycle
stimulation (+) inhibition (-)

ADENOHYPOPHYSIS OVARY endocrine regulation

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lab. classes

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UTERINE TUBE (oviduct, Fallopian tube)

Paired tubular organ (10 12 cm long), that conduct the secondary oocyte/ovum/blastocyst from the ovary to the uterus also the site where fertilization takes place. Parts: infundibulum (with fimbriae), ampulla, isthmus and intramural part

STRUCTURE -

3 layers of the wall

small tubular organ t. mucosa is thrown into extensively branched long anastomosing folds 1. TM: a) simple columnar ep. 2 types of cells: ciliated and secretory b) LPM 2. TMEx (M): 2 layers of smooth muscle tissue 3. TSe (S) circular longitudinal

Ep: ciliated cc. secretory cc. mucosal folds: LPM (LCT - S) + simple columnar ep. (E)

large numerous vessels of mesosalpinx

UTERUS - corpus (body)

ENDOMETRIUM
Spiral arteries Basal arteries Straight arteries (aa. rectae)

UTERUS - parts:

lab. classes

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- corpus (body) - fundus + cornua - uteric cavity - cervix (+ isthmus) - cervical canal (endocervix); - portio vaginalis uteri (ectocervix)

STRUCTURE of the wall:

1) ENDOMETRIUM (t. mucosa)
a) simple columnar ep. - ciliated + secreting cc. b) LPM = endometrial stroma - special spinocellular CT with endometrial simple, tubular glands

2) MYOMETRIUM
= 3 layers (poorly defined) of smooth muscles; central part (circular) with abundant vessels (stratum vasculare), inner and outer layer are arranged obliquely or longitudinally - during the pregnancy - hypertrophy and hyperplasia of muscles occurs; the inhibition of contractions during pregnancy - relaxin (ovary + placenta); the contraction during parturition is controlled by oxytocin (neurohypophysis)

MYOMETRIUM

3) PERIMETRIUM (t. serosa - anterior + posterior face) or PARAMETRIUM (t. adventitia = broad ligament on lateral edges)

MENSTRUAL cycle
Days 1 - 4: menstrual phase - bleeding + necrotic functional layer of endometrium from previous cycle shed. Days 5 - 14: proliferative (estrogenic, follicular) phase - during this time endometrium regenerates - first the re-epitelization of naked surface from remaining ep. of glands (this healing process is not hormones dependent) - then new stright tubular glands + stroma grow from residual basal endometrium. Days 14 - 16: ovulatory phase - earliest sign of secretory activity in endometrial gl. Days 16 - 27: secretory (luteal, progestational) phase - thickness of endometrium reaches the maximum (compact + spongious zone in funct. layer); glands become tortuous and lumina fill with secretion - glycogen is accumulated in both gl epithelium and stromal cc = decidual-like cc. Days 27 - 28: ischemic (premenstrual) phase - spasm of spiral aa. ischemia necrosis of funct. layer + breakdown of spiral vessels bleeding = menstrual ph.

Arcuate arteries

PERIMETRIUM (t. serosa) or PARAMETRIUM (t. adventitia)

ENDOMETRIUM - proliferative phase

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SEPARATED blood supply

Endometrial glands - straight

- functional layer = spiral aa. - basal layer = basal aa.

STRAIGHT (radial) aa. in the endometrium (branches of arcuate aa.of the myometrium) give rise to 2 types of arteries: 1. BASAL aa. (of the basal zone) which are not affected by changes in blood level of hormones therefore the basal zone of endometrium remains intact during ischemic and menstrual phase, and is able to proliferate and regenerate new functional layer. 2. SPIRAL arteries (in the functional zone) are sensitive to changes in endocrine status in ischemic phase, they undergo the spasm resulting to the degeneration and disintegration of both functional zone and wall of spiral aa. bleeding during menstrual phase.

Endometrium consists of 2 functional layers: - superficial functional layer (zona functionalis) is lost during menstruation - basal layer - retained as the source of regeneration (of both ep. and CT cells) of a new functional layer following menstruation Morphological/functional changes in ENDOMETRIUM during menstrual cycle (28 days) are affected by: 1) changes in the blood levels of estrogens and progesterone 2) blood supply from spiral arteries (basal aa. are not affected)

lab. classes

ENDOMETRIUM
- proliferative phase
(estrogenic phase)

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Early proliferative phase

Ep. in glands:
- simple low columnar - occasional mitotic (M) figures

Late proliferative phase

Ep. in glands:
- simple columnar - high number of mitotic (M) figures

ENDOMETRIUM
- secretory phase
(luteal phase) Early secretory phase
Endometrial gl. become spiralized superficial functional layer compact zone spongious zone - basal layer (zone) Ep. in glands:
- tall columnar cc. - glycogen vacuoles are located basally

lab. classes Maximum thickness of endometrium

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CT stroma is composed of decidual-like (pseudodecidual) cc.

Late secretory phase

Ep. in glands:
- tall columnar cc. - glycogen vacuoles are located in apical part secretion is rich in glycogen

CT stroma becomes
richly vascularized, permeability of vessels increases oedema of stroma

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PREMENSTRUAL/ ISCHEMIC phase

1 Periodic constrictions of spiral aa. triggered by a reduction in progesterone lower oxygenation (hypoxia) of functional layer 2 results in breakdown of spiral aa. and flood of CT stroma with blood. 3 The functional layer (glands + decidual-like cc.) becomes necrotic, detaches and sheds into uterine cavity menstrual bleeding (menses). 4 Basal layer is not affected because of independent blood supply by basal aa.

Decidual reaction of CT stromal cc. (spinocellular fibroblasts) = their enlargement (influenced by progesterone) and accumulation of nutrients in their cytoplasm preparation to nidation of blastocyst. decidual-like cc. decidual cc. (placenta)

ENDOMETRIAL CYCLE

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HORMONAL REGULATION of ovarian and menstrual cycle

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GnRH

granulosa

If fertilization occurs (human) choriongonadotropic hormon (hCG) is produced by placenta + corpus luteum of pregnancy progesterone secretion continuation of pregnancy; placenta also produces estrogens, progesterone and other hormones. hCG is present in mother's blood from about day 6 detection of pregnancy

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POSTMENOPAUSAL CHANGES in endometrium

After the menopause the cyclical production of estrogens and progesterone from the ovaries ceases atrophic changes in the whole female genital tract: endometrium is reduced to the former zona basalis, the glands are sparse and inactive in some women the glands become dilated and form the cysts (C) (benign) filled in with fluid the stroma is much less cellular fibrotization of the stroma mitotic activity is not seen in the both either in the epithelial cells or in the stroma also myometrium becomes atrophic the whole uterus shrinks approx. to half its former size

UTERINE CERVIX (endocervix + ectocervix)

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lower part of uterus, protruding into vagina canal (endocervix) is lined by tall columnar mucus-secreting epithelium the mucosa does not desquamate during menstruation the cervical glands are branched, lined with mucus-secreting ep.; they undergo only slight variations (in a volume and quality of secretion) during menstrual cycle surface protruding into vagina (ectocervix) is covered by stratified squamous ep. squamous/columnar junction (abrupt transition of ep.) stroma is composed of smooth muscle embedded in CT; proportions of each vary according to age and parity

SQUAMOUS/COLUMNAR JUNCTION - ectropion, transformation zone (metaplasia) and Nabothian follicles usually they develop after hard or frequent labours - columnar ep. of endocervix protrudes (ectropion) onto vagina (Fig. 2) highly acidic pH of vagina permanently irritates ectropic epithelium the metaplasia (alteration) to the stratified squam. non-keratin. ep. (Fig. 3) = transformation zone it overgrows columnar ep. and sometimes also openings of glands retention of secretion development of cysts (benign) = Nabothian follicles (Fig. 3)

endocervical ep.

transformation zone squamous ep.

Nabothian follicles

normal

ectropion

transformation zone
+ Nabothian follicles = cystic alteration of gl.

VAGINA
STRUCTURE of the wall - 3 layers:

lab. classes

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1. TM: a) stratified squamous nonkeratinized ep. (E) - light-stained ("empty") cc. due to accumulation of (unstained) glycogen
during the fertile age, it is under the stimulation of hormones: Estrogens (proliferative phase) thickening of epithelial layer (it becomes the thickest at the time of ovulation; synthesis and accumulation of large quantity of glycogen light-stained ep. cells Glycogen is metabolized by vaginal bacteria (lactobacilus) to lactic acid which acidity (pH 4) protects the vagina from pathogens (fungi, other bacteria) the cause of vaginal fluor (inflammatory leaking) Progesterone (secretory phase) epithelial desquamation continues ep. becomes thinner, and the amount of glycogen and acidity decrease

b) LPM (LP) - LCT+ blood vessels, mainly thin-walled veins (diffusion of the water contribute to production of vaginal fluid)
no glands!

2. TMEx (SM): 2 layers of smooth muscle tissue

with CT = fibromuscular layer

circular longitudinal

3. TA (A)
Negative image of intracell. deposits of glycogen empty cc.

CYTOLOGICAL EXAMINATION
a) FUNCTIONAL (EXFOLIATIVE) CYTOLOGY = examination of the VAGINAL SMEAR - morphology of the cc. of vaginal ep. is influenced by estrogens and progesterone ep. cc. undergo typical changes during ovarian/menstrual cycle information about the hormonal status of woman whether the vaginal mucosa is under the normal estrogenic stimulation or diseased (mainly in relation to the menstrual cycle disorders in younger woman) b) ONCOLOGIC CYTOLOGY = examination of the CERVICAL SMEAR - for the prevention and early detection of cervical cancer (regularly after the 40th year of age - oncologic prevention)