PHYSIOLOGY OF FEMALE

REPRODUCTIVE SYSTEM
 Introduction
• The difference between males and females is due to
the Y chromosome(in males) and the paired
gonads(testes/ovaries)
• In both sexes, the gonads produce germ
cells(gametogenesis) and secrete sex
hormones(androgens/oestrogens)
• The ovaries also produce progesterone, relaxin and
inhibin B.
• Androgens are also secreted by adrenals in both sexes.
• The secretory and gametogenic functions of
the gonads are both dependent on the
secretion of anterior pituitary gonadotropins-
FSH and LH.
• The sex hormones(oestrogens/testosterone)
and inhibin feedback to inhibit gonadotropin
secretion.
 Sex Development
• Sex hormones genetically determine sex-X orY
• XX for females and XY for males.
• The Y chromosome is necessary for testicular
development.
• The sex-determining region of the Y chromosome
(SRY) is the testis-determining gene product.
• The gene for SRY is located near the tip of the
short arm of the Y chromosome.
 Embryology
• Early in fetal life, the primitive gonad arises from the
genital ridge which later develops into testes and ovaries.
• By week 7, the embryo develops both male and female
primordial genital ducts.
• In a normal female fetus, the Mullerian duct system
develops into oviducts and uterus.
• In the normal male fetus, the Wolffian duct system
develops into epididymis and vas deferens.
• By week 8, the urogenital slit is closed and a male genitalia
is formed or it remains opened and female genitalia forms.
• Disorders of development include
– True hermaphroditism
– Pseudohermaphroditism : which may be female or male
pseudohermaphroditism
• Chromosomal disorders include
– Turner’s syndrome
– Klinefelter syndrome
– Down syndrome
– Edward Syndrome
– Patau syndrome
– Super female
 Puberty
• It describes the period of final maturation of the
reproductive system. Also called adolescence.
• In girls, it follows the following sequence:
preadolescence, thelarche, pubarche, menarche.
• Initial menstrual periods are anovulatory.
• Ovulation becomes regular after one year
• Stages of breast development- breast buds,
elevation and enlargement of the breasts,
projection of the areolas, adult breasts.
• For boys, puberty follows the following sequence:
preadolescence, enlargement of testes, penile
enlargement, growth of glans penis and adult
genitalia.
• Onset of puberty is controlled by the pulsatile
release of GnRH.
• Adrenarche describes the increased secretion of
adrenal hormones that occurs during puberty.
• Onset of puberty( 8-13yrs in girls; 9-14 yrs in boys).
• Pubertal abnormalities:
– Precocious puberty: may be true precococious
puberty and precocious pseudopuberty.
– Delayed puberty- common factors involved include:
• A critical body weight is essential for puberty to occur.
Leptin may be the link between body weight and puberty.
• Hypeprolactinaemia blocks the action of gonadotropins
on the gonads. Dopamine is prolactin inhibiting hormone.
 Menstrual cycle
• The female reproductive organs include the
ovaries, uterus, fallopian tubes and breasts.
• The average length of the cycle is 28 days.
• The most prominent feature is menstruation.
• In humans, no new ova are formed after birth.
• At the time of birth, there are 2 million ova, but
50% of these are atretic. The remaining million
undergo first meiotic division and are arrested at
prophase.
• Atresia continues such that the number of ova in
both ovaries is <300,000 at puberty.
• Just before ovulation, the first meiotic division is
completed.
• Only one ova per cycle normally reaches
maturation.
• Menstrual cycle includes
– an ovarian cycle, uterine cycle, hormonal cycle.
– There are changes in the breast, vagina, cervix
• Ovarian cycle : divided into follicular, ovulation and
luteal phase
– Antrum formation: enlarged primordial follicle containing
immature ovum is surrounded by a cavity
– This cavity is filled with follicular fluid and one antrum
becomes dominant.
– The maturing ovarian follicle(Graffian follicle) consists of
theca externa, theca interna, granulosa and follicular fluid.
– At day 14, ovulation occurs.
– The ovum is picked up by the fimbriated ends of the uterine
tubes.
• Ovarian cycle:
– Formation of corpus haemorrhagicum: the ruptured
follicle fills with blood. The blood may track into the
peritoneum (Mittelschmerz)
– Formation of corpus luteum: the blood clots and is
replaced with lipid-laden cells. This initiates the luteal
phase during which the luteal cells secrete estrogen and
progesterone.
– Formation of corpus albicans: in the absence of
pregnancy, the luteal cells begins to generate by day 24
and is replaced by scar tissue (corpus albicans).
• Following ovulation,
– the ovum divides into 2 daughter cells: secondary
oocyte and first polar body.
– The first polar body disappears
– The secondary oocyte begins the second meiotic
division which stops at metaphase and is completed
only when a sperm penetrates the oocyte.
– The metaphase arrest is due to formation in the
ovum of the protein pp39mos which is destroyed by
calpain when fertilization ocurs.
• Uterine cycle
– Proliferative (follicular or preovulatory) phase: the
endometrium thickens and the uterine glands
enlarges.
– Ovulatory phase: the endometrium becomes highly
vascularized under the influence of estrogen and
progesterone from the corpus luteum.
– Secretory(luteal) phase: the uterine glands become
tortuous and they secrete a clear fluid
• Uterine cycle
– When the corpus luteum regresses, the
endometrium looses its hormonal support and
becomes thinner, degenerate and produce
menstrual flow.
– Normal menstruation occurs for 3-5 days, usally
<80 mls. Menstrual blood contains tissue debris,
prostaglandins, fibrinolysin. Clots are only seen
when flow is heavy.
• Hormonal cycle
– FSH is responsible for the early maturation of the
ovarian follicles.
– FSH and LH together are responsible for their final
maturation.
– LH burst is responsible for ovulation and initial
formation of corpus luteum.
– LH also stimulates the secretion of estrogen and
progesterone from the corpus luteum.
• Hormonal cycle (feedback effects)
– In the early follicular phase, inhibin is low and FSH is
modestly elevated, fostering follicular growth.
– LH secretion is held in check by the negative feedback
effect of the rising plasma estrogen.
– 36-48 hrs before ovulation, the estrogen feedback
effect becomes positive and this initiates the burst of
LH secretion (LH surge) that produces ovulation.
– Ovulation occurs 9hrs after the LH surge. FSH also
peaks.
• Hormonal cycle(feedback effect):
– During luteal phase, LH and FSH are low because of the
elevated levels of estrogen, progesterone and inhibin.
Inhibin from the granulosa cells inhibit FSH secretion.
– When circulating levels of progesterone are high, the
positive feedback effect of estrogen is inhibited.
– Regression of the corpus luteum (luteolysis) starts 3-4 days
before the menses.
– Luteolysis leads to a fall in estrogen and progesterone and
the secretion of FSH and LH increases to start the follicular
phase of the cycle again.
• Hormonal cycle:
– GnRH secreted in bursts stimulates the secretion of FSH
as well as LH. These bursts produce the circhoral peaks
of LH.
– The frequency of GnRH bursts is increased by oestrogens
and decreased by progesterone and testosterone.
– The frequency increases late in the follicular phase of
cycle culminating in the LH surge.
– During the secretory phase, the frequency decreases as
a result of the action of progesterone.
• Other cyclical changes:
– In the cervical mucus, estrogen makes the mucus
thinner. The mucus is thinnest at
ovulation(Spinnbarkeit test). Progesterone makes
it thick.
– In the vagina, estrogens makes the vaginal
epithelium becomes cornified. Progesterone
causes epithelial proliferation with leucocytic
infiltration.
• Other cyclical changes:
– In the breast, estrogen causes proliferation of
mammary ducts. Progesterone causes growth of
lobules and alveoli.
• During sexual intercourse
– Increased vaginal mucus secretion
– Exciting tactile stimuli from the breast, labia
minora, clitoris and stretching of the vagina build
up in a crescendo pattern to a climax known as
orgasm
– During orgasm, there is rhythmic contractions of
vaginal wall, bulbocavernosus and
ishiocavernosum.
• Anovulatory cycles
– Occurs when ovulation fails to occur during the
menstrual cycle.
– No corpus luteum
– Absent progesterone effect
– Estrogen continue to cause endometrial
proliferation which later sloughs.
– Common before the onset of menopause or in the
first year post menarche.
• Indicators of ovulation: May be useful for
increasing fertility and also in family planning.
They include:
– Increase in basal body temperature
– Spinnbarkeit test
– LH surge
– Increased progesterone levels
 Menopause
• Average aage of onset is 51 yrs( 45-55 yrs).
• A period characterized by the disappearance of
the sexual cycle as ovarian function declines
and become less responsive to gonadotropins
as age advances.
• Andropause (male menopause) is seen as
testicular function decline slowly with
advancing age. Also seen post bilateral
castration.
• Major features include:
– Preceeded by perimenopause
– Decline in ovarian function resulting in reduced secretion of
progesterone and estrogen
– Negative feedback is lost, therefore FSH is increased,LH
levels are moderately high.
– Uterus and vagina becomes atrophic.
– Most typical symptom is hot flushes
– Also seen following bilateral ovariectomy.
– Menopause is also associated with osteoporosis, ischaemic
heart disease.
 Ovarian Hormones- Estrogens
• Naturally occurring estrogens are 17β- estradiol,
estrone and estrone.
• Estrogens are secreted primarily by the granulosa
cells of the ovarian follicles, the corpus luteum
and the placenta.
• Aromatase converts testosterone to estradiol
and androstenedione to estrone.
• Conversion of androstenedione to estrone also
occurs in fat, liver, muscle and the brain.
• Estradiol is 98% bound to proteins and 2% is free.
• The estrogens are converted to glucoronide and
sulfate conjugates in the liver. They are excreted
in urine and bile
• Most of estrogen secreted is by the ovary with 2
peaks of secretion: one just before ovulation and
during the midluteal phase.
• After menopause, estrogen levels decline to low
levels.
• Mechanism of action:
– Estrogen binds to its receptors in the
nucleus(Nuclear receptors)-ERα and ERβ
– After binding, the receptors form heterodimers
and bind to DNA to alter its transcription.
– ERα is found in the uterus, kidneys, liver and
heart
– ERβ is found in ovaries, prostate, lungs, GIT,
haemopoeitic system and CNS.
• Synthetic estrogens:
– They include tamoxifen and raloxifene
– Are called selective estrogen receptor
modulators(SERMS)
– They do not combat the symptoms of menopause
but both have bone-preserving effects.
• Effects of estrogen:
– Facilitate the growth of the ovarian follicles and
increase the motility of the uterine tubes.
– Estrogen decrease FSH secretion. They may increase
or decrease LH secretion.
– Increases libido
– Causes breast enlargement, duct growth and areolae
pigmentation.
– Responsible for development of female secondary
sexual characteristics.
• Effects of estrogen:
• Other actions of estrogen include
– Salt and water secretion
– Cholesterol-lowering action
– Vasodilation: resulting in palmar erythema, spider
naevi and gynaecomastia seen in liver disease.
– Prevent formation of acne
 Ovarian Hormones- progesterone
• Progesterone is secreted by the corpus luteum,
the placenta and the follicle.
• An important intermediate in steroid biosynthesis
in all tissues that secrete steroid hormone.
• 98% bound, 2% free
• Short half life, converted in the liver to
pregnanediol, which is conjugated to glucoronic
acid and excreted in the urine.
• Target organs are uterus, breasts and brain.
• Mechanism of action:
– There are 2 isoforms of the progesterone receptor
(PRa and PRb). Both are bound to a heat shock
protein in the absence of progesterone.
– Progesterone binds to its receptor and release the
heat shock protein, exposing the DNA-binding
domain of the receptor
– DNA binds and initiate synthesis of new mRNA.
• Effects of progesterone
– Cyclical changes in the endometrium,cervix and vagina.
– Decrease the sensitivity of myometrial cells to oxytocin
essential for maintenance of early pregnacy.
– In the breast, progesterone stimulates the development of
lobules and alveoli. It supports the secretory function of the
breast during lactation.
– Progesterone is thermogenic, stimulates respiration and
produces natriuresis.
– Large doses of progesterone inhibit LH secretion and potentiate
the inhibitory effect of estrogens, preventing ovulation.
• Mifepristone(progesterone antagonist) –binds
to the progesterone receptor and blocks
binding of progesterone but does not release
the heat shock proteins.
• Substances that mimic the action of
progesterone are called progestational agents
(progestins, gestagens). They are used along
with synthetic estrogens as oral
contraceptives.
 Relaxin
• A polypeptide hormone
• Produced in the corpus luteum, uterus,
placenta and mammary glands in women and
in prostate gland in men.
• Inhibits uterine contractions during pregnancy
• Relaxin facilitates delivery. It relaxes the
symphysis pubis, softens and dilates the
uterine cervix.
• May play a role in development of mammary
glands
• Its function in non-pregnant female is
unknown.
• In men, it is found in semen, where it may
help maintain sperm motility and aid in sperm
penetration of the ovum.
 Contraception
• Defined as methods used to prevent conception.
• Permanent methods include vasectomy and
tubal ligation
• Other methods include: oral contraceptives,
IUD,implants, diaphragm, condom, withdrawal,
spermicide, rhythm method
• IUD’s contain metal or plastic. Drawbacks
include pelvic infections, pain, menorrhagia
Abnormalities of ovarian function
1. Menstrual abnormalities
– Anovulatory cycles: failure to ovulate
– Amenorrhea: absence of menstrual periods
– Hypomennorrhea: scanty menses
– Menorrhagia: abnormally profuse flow.
– Metorrhagia: bleeding form the uterus between
periods
– Oligomenorrhea: decreased frequency of periods
– Dysmenorrhea: painful menstruation
2. premenstrual syndrome
Characterized by irritability, bloating, edema,
depression, headache, constipation.
Seen in the last 7-10 days of the menstrual
cycle.
Attributed to salt and water retention.
May be treated with fluoxetine or alprazolam.
 Pregnancy
• Fertilization of the ovum by the sperm usually
occurs in the ampulla of the uterine tubes.
• It involves the following:
– Chemoattraction of sperm to ovum
– Adherence to zona pellucida
– Penetration of the zona pellucida and the
acrosome reaction
– Adherence of the sperm head to the cell
membrane of the ovum.
• The developing embryo(blastocyst) moves
down the tube into the uterus in 3-4 days.
• In the endometrium, the blastocyst becomes
surrounded by 2 layers-syncytiotrophoblast
and cytotrophoblast.
• Syncytiotrophoblast erodes the endometrium
and burrows into it (implantation).
• Endocrine changes in pregnancy
– The corpus luteum in the ovary persists following
fertilization and secretes estrogens, progesterone
and relaxin.
– The placenta produces sufficient estrogen and
progesterone to take over the function of the
corpus luteum after the 6th week of pregnancy.
– The function of the corpus luteum begins to decline
after 8 weeks of pregnancy, but it persists
throughout pregnancy.
• Endocrine changes in pregnancy
– Human chorionic gonadotropin is the placental
gonadotropin in humans. It is produced by the
syncytiotrophoblast. Its secretion decreases after
an initial rise. It is detected in blood by day 6 after
conception and in urine by day 14 post conception.
Small amounts are secreted by gastrointestinal and
germ cell tumours, fetal liver and kidney.
– Estrogen and progesterone increases until just
before parturition.
• Endocrine changes in pregnancy
– Human chorionic somatomammotropin: Also
called human placental lactogen or chorionic
growth hormone prolactin or maternal growth
hormone of pregnancy. A lactogenic hormone
secreted by the syncytiotrophoblast. It causes
retention of nitrogen, potassium, calcium, lipolysis
and decreased utilization of glucose in the mother
• Other placental hormones include:
– Proopiomelanocortin (POMC)
– Corticotropin releasing hormone
– Beta-endorphins
– Alpha melanocyte stimulating hormone
– Leptin
– Prolactin
– Dynorphin A
 Parturition
• The duration of pregnancy is about 270 days
from fertilization or 284 days from the first day
of the menstrual period preceeding conception.
• Mechanisms responsible for onset of labour:
– Increased circulating estrogens making the uterus
more excitable causing increased production of
prostaglandins. Estrogen increases the number of
oxytocin receptors in the myometrium.
– Increased fetal cortisol
• Labour is characterised by
– Cervical dilatation
– Increased plasma oxytocin via a positive feedback
loop that leads to more uterine contractions and
delivery of the fetus. Oxytocin acts directly on the
uterine smooth muscles or stimulate release of
prostaglandins.
– Spinal reflexes and voluntary contractions of the
abdominal muscles also aid in delivery of the fetus
through the birth canal.
 Lactation
• Breast Development
– Estrogens are primarily responsible for
proliferation of the mammary ducts. Progesterone
is responsible for the development of the lobules.
– During pregnancy, prolactin levels increase
steadily until term and levels of estrogens and
progesterone are elevated as well, producing full
lobuloalveolar development.
• The breasts enlarge during pregnancy in response
to high circulating levels of progesterone, estrogens,
prolactin and possibly hCG.
• Milk secretion starts as early as 5th month
• Secretion of milk
– Oxytocin causes contraction of the myoepithelial cells
lining the duct walls with consequent ejection of milk
through the nipple.
– Prolactin cause the formation of milk droplets and their
secretion into ducts.
• Initiation of lactation after delivery
– Levels of estrogen and progesterone abruptly decline
after expulsion of the placenta at parturition. The
drop in circulating estrogen initiate lactation.
– Estrogen antagonizes the milk producing effect of
prolactin on the breast and can be used to stop
lactation in women who do not want to breastfeed.
– Suckling evokes oxytocin release and milk ejection. It
also augments milk secretion by stimulating prolactin
release.
• Lactation and the menstrual cycle
– Breastfeeding stimulates prolactin release.
Prolactin inhibits GnRH and so antagonizes the
action of gonadotropins on the ovaries
– Ovulation is inhibited and the ovaries are inactive,
so estrogen and progesterone output falls to low
levels.
– Breast feeding amenorrhea lasts for 25-30 weeks.
And may serve as contraception.
 Gynaecomastia
• Is breast enlargement in males
• May be unilateral or bilateral
• Due to an increase in the plasma
estrogen/androgen ratio due to increased
circulating estrogens or decreased circulating
androgens.
• Seen in neonates, liver disease, digitalis use,
eunuchoidism, estrogen secreting tumours.
 Hormones and cancer
• Estrogen dependent breast cancer: seen in 35% of
breast cancer in women of childbearing age. Their
continued growth depends on the presence of
estrogens in the circulation.
• Women with estrogen-dependent tumours often
have a remission when their ovaries are removed.
• Inhibition of estrogens also produces remission.
Eg tamoxifen, aromatase inhibitors.
 Infertility
• Seen in 35% of males,45% of females 20% to
both partners and 5% (no cause).
• In vitro fertilization: removing mature ova,
fertilizing them with sperm and implanting ≥1
in the uterus at the 4 cell stage. 5-10% chance
of producing a live birth.
• Surrogate parenting