October 31, 2001

The female reproductive system

I. Parts of the system

1.  Primary reproductive organs (gonads):  ovaries

2.  Internal genitalia:  

a.	Uterine tubes (a.k.a. oviducts or Fallopian tubes):  secretory cells, ciliary cells, mucous escalator

b.	Uterus (cervix, corpus, fundus)
-	corpus uteri:  
uterine cavity
endometrium (with uterine glands)
myometrium
perimetrium

-	cervix uteri:
cervical canal
cervical mucosa (with cervical glands  mucous plug)
connective tissue wall
c.	Vagina

3.  External genitalia

II.  The function of the system

1.  Oogenesis
2.  Reception of sperm and transport of sperm and ovum for conception
3.  Maintenance of the fetus (gestation)
4.  Parturition
5.  Lactation

III.  Characteristics:  

1.  Ovaries function until menopause  testes function until old age (only slight decline)

2.  Periodic preparation for fertilization and pregnancy and intermittent release of ova  continuous production of spermatozoa.

Hypothalamus (periodic changes in the frequency of GnRH bursts)
¯
Pituitary (periodic changes in FSH and LH release)
¯
Ovary (periodic changes in the release of estrogens and progesterone and periodic release of ovum;  ovarian cycle)
¯
-  corpus uteri (uterine cycle, a.k.a. menstrual cycle)
-  cervix uteri
-  vagina
-  breast

oogenesis

1. 	Oogonia (6-7 million):  undifferentiated stem cells in the fetus

During the prenatal period, oogonia develop into a more differentiated germ cell form:  primary oocytes.
At birth:  only primary oocytes are present

2. 	Primary oocytes (2 million at birth) + granulosa cells = primary follicle
 
At any given point of time, the majority of primary follicles is at developmental rest but a small population of primary follicles starts developing towards more differentiated form:  secondary oocytes

-  before puberty:  the developing population of primary follicles degenerates before reaching the secondary follicle stage (atresia)

-  after puberty:  	one of the simultaneously differentiating primary follicles will reach the fully mature form in every 28 days ( ovulation), the other simultaneously maturing primary follicles will degenerate

-  by menopause:  	no primary follicle is left (400 have reached the fully mature stage, the rest has degenerated)

3. 	Secondary oocytes (secondary follicles)  mature ovum

Ovarian cycle

Period length: average 28 days (20 to 40 days)

I. Before puberty:   

Primordial (primary) follicles:  
-  primary oocyte (meiotic arrest, diploid, 46 doubled chromosomes)
-  granulosa cells

Gonadotropin-independent phase of follicular maturation:  
-	non-cyclic 
-	250 days
-	starts during intrauterine life lasts till menopause
-	primordial follicles mature continuously to early antral phase but never reach complete maturation because there is no FSH and LH secretion from the pituitary.

II.  After puberty, before menopause:  Ovarian cycles

Principles:
-	Continuous, gonadotropin-independent maturation
-	The pituitary secretes FSH and LH.  If those follicles that reached a certain degree maturation are exposed to gonadotropins, they will enter the next phase of development, which is the gonadotropin-dependent maturation
-	Gonadotropin secretion is cyclic  gonadotropin-dependent maturation shows a cyclic pattern

1. 	Follicular phase:  several maturing follicles, only one matures fully

primary oocytes enlarge

Gonadotropin-independent

granulosa cells ­, differentiate (possess FSH and estrogen receptors)
zona pellucida
thecal cells appear and ­ (possess LH receptors)
follicular cells (granulosa cells + thecal cells) secrete estrogen and inhibin
¯
antrum appears		
¯
FSH-mediated “rescue” of a cohort of 1-25 follicles

Gonadotropin-dependent

a single follicle of the cohort becomes dominant and grows more rapidly
its ovum completes first meiotic division (secondary oocyte and first polar body)
preovulatory follicle (Graafian follicle)
		¯
                   rupture
		¯
                   ovulation
                        ¯
secondary oocyte in the abdomen (zona pellucida, corona radiata) 

2.   Luteal phase

follicular remnant (mainly outer layer of granulosa cells)

corpus hemorrhagicum
	¯
c. luteum:  secretes estrogen and progesterone
survives for 14 days (in pregnancy:  for 12 weeks)
	¯
c. albicans 

uterine (menstrual) cycle

Estrogen:  	myometrium ­, endometrium ­, progesterone receptors ­
Progesterone:  endometrium transformation, myometrium contractility ¯

1.  Menstrual phase (day 1-5)

At the onset of the follicular phase, when c. luteum regresses.

estrogens¯, progesterone¯, prostaglandins­

constriction of arterioles in endometrium  blood supply¯¯® necrosis of the endometrial lining ® arterioles dilate  necrotic vessel wall ruptures  discharge of blood and endometrial debris

uterus contractions (® dysmenorrhea)

After 5 days:  arterioles constrict again  bleeding stops

2.  Proliferative phase (day 6-14, lasts until the ovulation):  regeneration of endometrial lining

in response to ovarian estrogen:
- endometrium regenerates, thickness­­
- uterine glands enlarge ® length­  become coiled
- blood vessels grow  arterioles become coiled  blood supply 
- progesterone receptors synthesized   

3.  Secretory phase:  (day 15-28, coincides with the luteal phase of the ovaries)

In response to estrogens and (mainly) progesterone  progestational changes in the endometrium to prepare for possible implantation of the blastocyst

Endometrium:  	further increases in vascularization 
glands become more coiled, secretory activity ­  large amounts of nutrients secreted (glycogen ­)
cyclic changes in other organs

1.  Cervix

Mucosa:  no cyclic necrosis-regeneration
Secretory activity of the epithelial cells:  cyclic activity
days 1-14 (estrogen effect):  secretes watery, alkaline mucus  easily penetrated by sperm
days 15 (progesterone effect):  thick and viscous mucus  not easily penetrated by sperm

2.  Vaginal cycle

Days 6-14:  		epithelium thickens and accumulates glycogens (effect of estrogen)
	glycogen-rich surface cells continuously shed  glycogen released  lactobacillus acidophilus (normal flora)   keeps pH low  prevents colonization by other bacteria

Days 15-28: 	epithelium proliferates (effect of progesterone)
lymphocyte infiltration

3.  Breasts

Days 1-14:  proliferation of mammary ducts (estrogen)
Days 15-28:    lobuli­, alveoli ­ (progesterone)
hyperemia,  edema (® swelling, tenderness)

The control of the ovarian cycle

1.  Follicular phase

-  rising FSH levels (due to GnRH and the lack of the negative feedback from inhibin, progesterone)
-  rising LH levels 
-  estrogen secretion ­ by FSH (acting on granulosa) and LH (acting on thecal)
    estrogen acts:  local positive feed back (autocrine action)  follicular growth   estrogen 
systemically (uterus, GnRH¯, FSH¯¯ from day 9)
-  local production of IGF-1 in the follicles 
-  inhibin secretion 

2.  Midcycle (control of the ovulation)
-  Outer layer of granulosa cells starts expressing LH receptors 
-  LH surge (due to positive feedback of estrogen on hypothalamus, GnRH­)
-  FSH surge

LH surge causes:  	the final maturation of the oocyte

local PG­  ® vascular changes ® swelling 
collagenase digests follicle wall

ovulation:  ovum released into the abdominal cavity

follicular cells ® luteal cells

3.  Luteal phase

LH:  	maintains corpus luteum
stimulates progesterone and estrogen secretion

FSH and LH levels decrease (negative feedback of estrogens, progesterone, inhibin)
Luteolytic factors produced by c. luteum (oxytocin, prostaglandins)

luteolysis

estrogen, progesterone, inhibin

new cycle starts