Week 3 reproductive system

L17- sex hormones

Testosterone
- produced in the adrenal cortex and in gonads
- Further converted to estradiol in ovaries in females or in peripheral tissues in males
Pathway for synthesis of sex steroids
Cholesterol -> pregnenolone
Glucocorticoid + mineralocorticoid pathway (Adrenal gland)
- pregnenolone -> progesterone -> deoxycorticosterone -> corticosterone -> aldosterone
(mineralocorcticoid)
- Pregenenolone -> progesterone -> deoxycortisol > cortisol (glucocorticoid)
Sex steroid pathway (adrenal glands & gonads)
- pregnenolone -> 17-OH pregnenolone -> DHEA -> androstenedione -> testosterone ->
estradiol

DHEA only synthesised in adrenal (if DHEA high most probably adrenal)

Androstenedione found in gonads as well as adrenal but more predominant in gonads (if
androstenedione main elevated androgen source is ovary/testis

Peripheral conversion of androgens only happen in gonads

Peripheral conversion of testosterone
- Testosterone -> DHT (via 5-a reductase)
• 5a reductase inhibitors treat BPH + male pattern hair loss

- Conversion in the ovary + peripheral tissue (e.g adipose tissue)

• Testosterone -> estradiol
• Testosterone -> estrone
By enzyme aromatase
Androgen insensitivity syndrome
- X linked disorder (more common in males)
- Males don’t respond to androgens
- 46,XY: ambiguous/female like external genitalia
- 46XX (heterozygous female): no e ect
Androgen hypersensitivity in female
- normal level of steroids but hirsutism

Mechanism of sex hormones in liver

- Liver hydroxylates estradiol to estriol (less potent form) -> inactivation
- In advanced liver cirrhosis -> delayed conversion of estradiol so males + females will have
estrogen excess

Disorders of sex hormones

High testosterone in female
- Exogenous androgens (anabolic steroids)
- PCOS
- Androgen secretion tumours
- Congenital enzyme de ciency (CAH)
PCOS
Mechanism
fi
ff
 - loss of pulsatile secretion of GnRH -> abnormal secretion of FSH & LH (LH very elevated) -> LH
stimulate theca cells of ovary to mainly make androgens
- High insulin levels (Insulin acts like IGF-1, stimulating theca cells -> increase androgen)
Associated with metabolic syndrome
- obesity, elevated cholesterol, hyperglycaemia/diabetes, hypertension
Clinical features
- multiple ovarian cysts
- Hirsutism
- Menstrual irregularities
- Infertility due to anovulation
- No cliteromegaly
Labs

Why is SHBG low in PCOS

⁃ Less SHBG -> more active testosterone -> more androgenic e ect

Sex hormone binding globulin (SHGB)

- Main function is carrier for transport of androgens (carries estradiol + testosterone)
- Has higher a nity to testosterone so it target testosterone and binds to free testosterone more
than estradiol (free form is more biologically active) in male we want free hormone to be high so
we should decrease SHBG
- So in male SHBG should be lower than female
- SHBG should be high in female to capture testosterone (so little biologically active
testosterone)
- In male w liver cirrhosis: abnormally increased SHBG main cause not understood (it will bind to
most test in circulation -> estrogenic e ect in male)

Testosterone in lab tests

Total testosterone =
- free testosterone + albumin bound testosterone + SHBG bound testosterone
Bioavailable testosterone =
- free testosterone + albumin bound testosterone (loosely bound -> active)
- Best indicator of biologically active hormone
- Important in conditions with altered SHBG
• e.g total testosterone may appear normal if SHBG high but free testosterone low -> androgen
de ciency symptoms
• Increase SHBG -> more testosterone bound -> free testosterone decrease -> more estrogenic
e ects
• Decrease SHBG -> more free testosterone -> more androgen e ects
SHBG bound testosterone
- tightly bound, biologically inactive
Anabolic steroids
- used for athletes to build muscle mass
- Medically used for: low testosterone diseases, muscle wasting, bone marrow stimulation in
some types of anemia
ff
fi
ffi
ff
ff
ff
 E ects
- premature growth cessation in adolescents
- Anger, aggression
- Acne, breast enlargement in men, clitoral enlargement in women + increased body hair
- Testicular atrophy (due to suppression of FSH levels). Infertility & loss of libido
- Cardiovascular: cardiac muscle thickening, high levels of LDL cholesterol
Disorders of sex hormones
Low testosterone levels in a male
- testosterone level drop slowly as men age (abnormally low testosterone is quite uncommon)
- Men with low testosterone:
• Decreased libido
• Erectile function
• Sperm production -> infertility
- Boys:
• Late puberty/inadequate development of sex characteristics (deepened voice, pubic hair,
enlarging penis)
Primary hypogonadism
- decrease in the testes production of testosterone in these conditions:
• Testicular trauma or disease (e.g orchitis due to mumps)
• Surgical orchiectomy (e.g testicular cancer)
• Testicular radiation
• Genetic (e.g kleinfelter + kartagene syndromes)
• 17-hydroxylase de ciency
Secondary hypogonadism
- decrease GnRH release -> decreasing testosterone production:
• Opiate drug use
• Hypopituitarism (may be due to disease or tumours or traumatic brain injury)

Low estrogen In females

Primary hypogonadism
- menopause is normal decline in estrogen levels seen in women aged in their late 40s -> early
60s
- Premature ovarian failure (loss of ovarian function before the age of 40, idiopathic)
- Radiation
- Drugs that reduce estrogen synthesis
- Ovarian insensitivity to LH/FSH (genetic)
- Genetic sex chromosome disorders (e.g Turner syndrome)
Hypogonadotrophic (or secondary) hypogonadism
- lack of e ective LH/FSH or GnRH release from the anterior pituitary or hypothalamus (tumours,
brain injury)
- Lactation
- Chronic medical illness
*Low estrogen men = asymptomatic

High estrogen levels

Clinical manifestation
Females
- amenorrhea/menstrual irregularities
- Abnormal postmenopausal vaginal bleeding
- Breast or uterine enlargement
- Girls -> early puberty
Males
- feminisation: gynecomastia (breast enlargement)
- Infertility, erectile dysfunction
Children (boys)
- slow growth
- Early closure of epiphyseal plates -> reduced nal
Medication e ect
- seen with drugs that inhibit testosterone production/block its receptor
ff
ff
ff
fi
fi
Cause
- neoplasms: ovarian tumours, pituitary adenomas
- Drugs/hormones: contraceptives, hormone replacement therapy
- Medication/herbs, phenothiazine tranquillisers, gingko biloba, ginseng
- Liver cirrhosis
- Genetic mutation in aromatase -> excessive estrogen synthesis
Complications/Risks
- increase risk of estrogen related adverse e ects: (especially in post menopausal women on
estrogen therapy)
• Breast cancer
• DVT
• Stroke

L18 - Anatomy of female reproductive system

Functions
- production of ova
- Production of sex hormones
- Support + nourishment of the developing embryo

Ovaries
Site:
-in ovarian fossa in lateral wall of pelvis
-Bounded posteriorly by ureter and internal iliac artery
Shape:
-almond shape
Orientation
-in nullipara (women that has never given birth): axis is vertical
(ovary has superior & inferior poles)
-In multipara (women that has given birth): superior pole
becomes lateral pole and inferior pole becomes medial
ff
Ends of ovary
Superior (tubal) end
-attached to mbria of uterine tube and lateral pelvic wall by suspensory
ligament of ovary
Inferior (uterine) end
-connected to the utero-tubal junction superiorly by the round ligament of
ovary (runs inside broad ligament of uterus)

Anterior border
-hilum
-Attached to superior (posterior) layer of broad ligament by short
peritoneal layer called mesovarian
Posterior border
-free

Surfaces of ovary

Lateral surface
-related to parietal peritoneum of ovarian fossa which separates ovary
from obturator nerve & obturator vessels
Medial surface
-related to uterine tube

Ligaments of ovary

Suspensory pigment of ovary

-short peritoneal fold between tubal end of ovary & lateral pelvic wall
Round ligament of ovary
-extends from uterine end of the ovary & utero-tubal junction
Mesovarian
-short peritoneal fold between anterior ovarian border + superior border
of broad ligament

Blood supply
Ovarian artery
-passes through suspensory ligament of ovary ->
mesovarium to enter hilum of ovary
-Anastomoses with the uterine artery within the broad
ligament

Venous drainage
-veins emerge at hilum of ovary as a papiniform plexus
-> gives rise to ovarian vein
-Right ovarian vein -> IVC
-Left ovarian vein -> left renal vein
fi
Lymphatic drainage

[Link] aortic lymph nodes

[Link] iliac lymph nodes -> lateral aortic lymph nodes
[Link] lymph nodes -> lateral aortic lymph nodes

Nerve supply
Ovarian plexus:
- SNS: T10,11 -> vasoconstrictor to blood vessels
- PNS: derived from uterine plexus & pelvic splanchnic nerves S2,3,4 -> vasodilator to blood
vessels
*Referred pain from ovary felt around umbilicus

Uterine/fallopian tube

Site
-medial 4/5 of the upper free border of the broad
ligament
Communications
-laterally: tube pierces upper layer of broad ligament to
open into the peritoneal cavity near the ovary
(abdominal ostium)
-Medially: opens into superior angle of utereus (uterine
ostium)

Infundibulum
-related to ovary
-Margin has irregular processes called mbriae (pick
ovum at ovulation)
Ampulla
-site of fertilisation
Isthmus
-thick wall
Interstital part
-shortest & narrowest part
-Pass through the wall of uterus & open into it

Blood supply of tube

- lateral 1/3 of ovarian vessels + medial 2/3 of uterine vessels
Lymphatic drainage
- lateral aortic + internal iliac lymph nodes
Nerve supply
- medial 2/3 by uterine nerve plexus
- Lateral 1/3 of ovarian nerve plexus
fi
Functions of the tubes
- carry the oocyte from ovaries and sperms from uterus to the ampulla which the site of
fertilisation
- Conveys the dividing zygote to the uterine cavity
Applied anatomy
- blockage of tubes (due to infection) is the main cause of sterility in women
- They are the most common site for ectopic pregnancy. Usually ruptures with haemorrhage into
abdominal cavity
- Abdominal ostium connects female genital tract directly with peritoneal cavity. Infections in the
uterus + tubes may result in peritonitis
- Ligation of the uterine tubes is one method of birth control
Uterus
- hollow thick walled, pear shaped muscular organ situated in the lesser pelvis between urinary
bladder & rectum
Communications
- at superolateral angles uterus recieves uterine tubes
- Inferiorly opens into vagina at external os
Description of uterus
- divided into large upper part : body/corpus & smaller lower part called the cervix through a
constriction called isthmus
- Body and cervix communicate at internal os

a. Body of uterus
- upper 2/3
- Upper part above openings of uterine tubes: fundus
i. Anterior (vesical) surface
- covered by peritoneum down to the level of internal os
- related to urinary bladder + utero-vesical pouch in between
ii. Posterior (intestinal) surface
- peritoneum which continued down into cervix and posterior
vaginal fornix
- related to sigmoid colon + small intestine
iii. Lateral borders
- each receives uterine tube at its upper end
- antero-inferior to the utero-tubal junction, the lateral border provides attachment for the
round ligament of uterus
- postero-superior to the utero-tubal junction, the round ligament of the ovary
- the uterine tube and 2 ligaments are all running in the broad ligament which stretches
from the lateral border to the lateral pelvic wall

b. Cervix of the uterus

- lower 1/3 of uterus
- Protrudes into the upper part of the vagina -> cervix has supra-vaginal and vaginal parts
i. Supra-vaginal part of cervix
Anteriorly: related to bladder & not covered with peritoneum
 Posteriorly: related to rectum + separated with Douglas pouch
On each side (not covered): uterine artery crosses the ureter
Ii. Vaginal part of the cervix
- projects into upper part of vagina -> divide part of vagina into 4 vaginal fornices
- Posterior vaginal fornix is deepest and only one covered by peritoneum
- Gynelogical signi cance of the external os
- In nulliparous women: small + circular
- In multiparous women: transverse slit, bound by anterior and posterior lips
Uterine cavity
- triangular in coronal section with base between the openings of the uterine tubes + its apex is
the internal os -> leading to cervical canal
Cervical canal
- fusiform broad at mid level
- Communicates with cavity of the body at the internal os and with the vagina by the external os
Normal position of uterus
Normally: uterus is anteverted, ante exed
Anteversion: angle between uterus and vagina, 90 degrees
Ante exion: angle between body of uterus + cervix , 170 degrees

Blood supply
-uterine artery
Venous drainage
-uterine venous plexus that
extend along the lateral
side of uterus within broad
ligament
-Lower part -> uterine
veins -> internal iliac veins
-Plexus communicates
with ovarian and vaginal
venous plexus

Lymphatic drainage
- fundus -> lateral aortic lymph nodes
- From the uterotuberal junction along the round ligament of uterus -> super cial inguinal lymph
nodes
- From body lymphatics pass through broad ligament -> external iliac lymph nodes
- From the cervix -> external, internal iliac and sacral lymph nodes
Nerve supply
- utero-vaginal nerve plexus
SNS: T12-L2 (cause relaxation of uterine muscles and vasoconstriction of blood vessels)
PNS: S2-S4 (cause contraction of the uterine muscles & vasodilation of blood vessels)

Vagina
- from uterus -> vestibule
Relations
Anterior wall: base of bladder, urethra
Posterior vaginal wall:
- upper 1/4 (covered with peritoneum) related to rectum with
Douglas pouch in between
- Middle 2/4 are related directly to rectum
- Lower 1/4 related to anal canal with perineal body in between
fl
fi
fl
fi
 Lateral
Upper part
-attached to mackenrodets ligaments in which
ureter is crossed by uterine artery
Middle part
-related to sphincter vaginae (levator ani)
Lower part
-related to muscles deep perineal pouch, bulbs of
vestibule & greater vestibular glands (super cial
perineal pouch)

Cavity of vagina

- Superior part: surrounds lower part of cervix and divided into 4 fornices
- Collapsed (H shaped in cross section) so that it’s anterior & posterior walls are in contact
- The vaginal ori ce has a thin mucosal fold called the hymen which is perforated at its center
Arterial blood supply
- vaginal artery + branches from uterine artery (azygous arteries)
Venous drainage

- vaginal venous plexus on the side of vagina -> vaginal vein -> internal iliac vein
Lymph drainage
- above hymen: internal, external, iliac & sacral lymph nodes
- Below hymen: super cial inguinal lymph nodes
Nerve supply
- autonomic bres from utero-vaginal plexus
- Lower inch of vagina supplied by pudendal nerve
External genitalia
Vulva
-pubic area -> rectum and includes
•Mons pubis: hairy skin covering the pubic bone
•Labia majora (homolog of scrotum): prominent folds of
skin indirectly provide protection for the urethral + vaginal
folds
•Labia minora: pair of smooth pink folds
Posterior: fourchette
Anterior: split to enclose clitoris
Cleft between labia minor: vestibule
Clitoris (homolog of penis): small pea shaped structure,
fi
fi
fi
fi
 plays important part in sexual excitement
Accessory glands
Greater vestibular (Bartholin’s)
- homolog of bulbourethral glands in male
- Located slightly below and to left and right of opening of vagina
- Secrete mucous to provide lubrication
Lesser vestibular (Paraurethral Skene’s)
- homolog of prostate in male
- Located on upper wall of vagina, around lower end of urethra
- Aid lubrication during intercourse

L19 - Ovarian & menstrual cycles

Oogenesis
- production of ova
- During fetal life: primordial germ cells migrate
to cortex of ovary
- Oogonia in embryonic ovary complete mitotic
replication + rst stage of meiosis starts by
5th month of fetal development
- The germ cell mitosis then ceases and no
additional oocytes formed
At birth
- females born with 1-2 million primary oocytes
At puberty
- 300,000-400,000 primary oocytes in 2 ovaries
During the reproductive year
- 450 ova expelled, one each month
Menopause
- only 1000 remain and they are atrophic
follicles

Ovarian cycle
- the cycle of events that prepares the egg from the ovaries for potential fertilisation by a sperm
-> pregnancy
- Depends on FSH & LH
- 28 days (usually a single oocyte released from follicle), occurs at puberty
Phases of the ovarian cycle
1. Follicular phase Anterior pituitary secretes FSH -> maturation of 6-12 primordial follicles
1. Proliferation of granulose cells of follicles (primary follicles)
2. Collection of layers of ovarian stromal cells that is divided into:
- granulosa cells (inner) -> secretes estrogen
- Theca cells (outer), highly vascular CT -> secretes follicular uid -> formation
of vesicular follicle (antral follicle)
Growth stimulated by
- FSH (mainly)
- LH (supports FSH)
- Estrogen
After 1 week of growth
- only 1 follicle outgrows and the other follicle and the remainders involute ->
become atretic follicles
fi
fl
 2. Ovulation phase - occurs at day 14 in female having 28 days menstrual cycle
Mechanism
- LH surge: peak in the estrogen level causes a pulsatile release of LH (positive
feedback mechanism) -> LH increases 6-10 fold, 2 days before ovulation ->
• Rapid growth of follicle
• Ovulation
• Start of progesterone secretion
(Without LH surge -> no ovulation)

3. Luteal phase - after expulsion of ovum -> granulose cell changed to form corpus luteum
( lled with lipid granules)
- Depends on LH hormone
Function of corpus luteum
- secretion of large quantities of progesterone + estrogen
- Secretes inhibin hormone
- Secretes relaxin hormone
- Theca cells secrete androgens
Fate of corpus luteum
No fertilisation: estrogen, progesterone and inhibin (negative feedback
mechanism) -> inhibit FSH + LH -> degeneration of corpus luteum -> decrease
estrogen and progesterone -> menstruation + removal of feedback inhibition of
FSH + LH -> increase the large quantity of FSH -> new ovarian cycle
Fertilisation: human chorionic gonadotrophin (hCG) produced by developing
embryo prevents degradation of corpus luteum during rst half of pregnancy
LH & FSH bind to receptors on ovarian theca cells (LH) & granulose cells (FSH)
This binding will jointly cause granulose cells to make estrogen (estradiol, E2)

Menstrual cycle
- prepares uterus for implantation of the fertilised egg + aligns with ovulatory cycle
- Duration 21-35 days (average 28 days)
- <21 days: polymenorrhea
- >35 days: oligomenorrhea
fi
fi
 1. Menstural phase 1-8 days (average 4 days)
Cause
- degeneration of corpus luteum -> sharp decline of estrogen + progesterone
-> ischemia + necrosis of super cial layers of uterine endometrium
Volume
- 40ml of non-clotted blood + 35 ml of serous uid
- Menstrual uid is normally non clotting because of brinolysin
2. Proliferative phase From with day of menstrual cycle -> ovulation 14th day (about 10 days)
Control
- under the e ect of estrogen (estrogen increases thickness of endometrium)
• Increases number of stromal cell
• Growth of endometrial glands + blood vessels
3. Secretory phase From 15th -> 28th day
Control
- under e ect of progesterone mainly + estrogen
• Progesterone: swelling + increase secretory development of the
endometrium (increase tortuosity of endometrial gland + blood vessels)
• Estrogen: increases cellular proliferation of endometrium
Function
- provide suitable conditions for implantation of fertilised ovum

Anovulatory cycle
- when the preovulatory LH surge is not su cient, ovulation wont occur
Characters
1. Lack of ovulation causes failure of development of corpus luteum, so there is no secretion of
progesterone during latter portion of cycle
2. Estrogen continues to cause growth of endometrium; proliferative endothelium becomes thick
enough to break down + begins to slough
3. Cycle is shortened by several days, but rhythm continues
*Progesterone not required for maintenance of cycle, although it can alter cycles rhythm
Causes
- Physiological
• First few cycles after onset of puberty
• Cycles occurring several months to years before menopause
ff
fl
ff
fi
fl
ffi
fi
- Pathological causes
• Polycystic ovary
• Thyroid disorders
• Hyperprolactinemia

L20 Functions of female sex hormones

Primary sex organs: Ovaries
Secondary sex organs: fallopian/uterine tubes, uterus, vagina, external genitalia
Female sex hormones
Synthesis Oestrogens: most important is estradiol
Progestins: most important is progesterone
Site of estrogen synthesis
- ovaries: in granulosa cells of ovarian follicle (E1 estrone & E2 estradiol are
formed)
- Extragonadal synthesis: adrenal cortex, adipose tissue, breast, skin, brain
LH bind to theca cell -> desmolase convert cholesterol to pregnenolone ->
androstenedione -> di use to granulosa cell
FSH bind to granulosa cell -> enzyme aromatase induced and convert
androstenedione to 17b estradiol
Aromatase also present in non ovarian cells but in lower levels
Site of progesterone synthesis
- luteal cells

Transport - transported in blood by albumin

Metabolism Estrogen
- liver conjugates estrogen to form glucoronide + sulfates
- Liver converts the potent oestrogens (estradiol + estrone) into estriol (weaker)
-> small amount excreted in urine
Progesterone
- major end product of progesterone degradation is pregnanediol that is
excreted in urine
In liver disease
- activity of oestrogen’s in body are increased -> hypersterinism causing palmar
erythema, gynecomastia & spider navei
Pregnanediol
- in urine used to estimate level of progesterone formation
Regulation Hypothalamic pituitary axis regulation
- hypothalamus secretes GnRH in pulsatile manner -> stimulate FSH and LH
secretion from anterior pituitary
- Both FSH and LH stimulate ovarian target cells -> increase estrogen +
progesterone
Feedback mechanism
Negative
- decrease sex hormones due to degradation of corpus luteum before
menstruation -> increase GnRH, FSH & LH -> follicular growth and start new
cycle
Positive
- increase estrogen before ovulation -> LH surge -> ovulation

Oestrogens
- secreted by ovaries + small amount by adrenal cortex
- During pregnancy also secreted by placenta
ff
 - Form of oestrogen’s: E1 estrone, E2 B-estradiol, E3 estriol
- Principal estrogen secreted by the ovaries is: b-estradiol (more potent than estrone + estradiol)
Functions of estrogen
Female secondary sex - feminising hormone
characteristics - Body changes at puberty: narrow shoulders, broad hips
- Female distribution of fat in breasts + buttocks
- High pitched voice

Size of reproductive organs - increase size in ovaries, fallopian tubes, uterus, vagina & breast
- External genitalia enlarge with deposition of fat in pubis
E ect on uterus - size of uterus increase 2-3x after puberty
- Increase uterine blood ow + amount of uterine muscle and its content
of contractile proteins so muscle becomes more active and excitable
- cause marked proliferation of endometrial stroma + increased
development of endometrial glands which later aid in providing nutrition
to implanted ovum
- Estrogen dominated uterus more sensitive to oxytocin

E ect on fallopian tubes - increase motility of uterine tubes

- Increase number of ciliated epithelial cells that line fallopian tubes
E ect on breasts - development of stromal tissues
- Growth of duct system
- Deposition of fat
- Pigmentation of areolas

Protein anabolic e ect - less than testosterone

Skeleton - inhibit osteoclastic activity in bones -> stimulate bone growth

- Closure of epiphyseal plate, no growth in height after puberty
- Menopausal women su er from osteoporosis
Body metabolism + Fat - cause deposition of fat in breasts, subcutaneous tissue, buttocks and
deposition thighs
- Decrease cholesterol -> decrease atherosclerosis
Electrolyte balance - have mineralocorticoid action (salt + water retention)

Little e ect on hair - hair in pubic region + axilla after puberty due to androgens from adrenal
distribution cortex

Skin - cause skin to develop texture that is soft + smooth

- Cause skin to become more vascular (associated with increased
warmth of skin + greater bleeding of cut than is observed in men
Progestin
- progesterone most important
- Released from corpus luteum
Functions of progesterone
On uterus - promotes secretory changes in uterine endometrium during secretory
phase of menstrual cycle
- Anti-androgenic e ect on myometrial cells -> decreasing excitability +
sensitivity to oxytocin
- Decreases frequency + intensity of uterine contractions -> help prevent
expulsion of implanted ovum

On fallopian tubes - promotes increased secretion by mucosal lining of fallopian tubes

(necessary for nutrition of fertilised ovum)

On breast - promotes development of lobules + alveoli of breast (alveogenesis) ->

alveolar cells proliferate, enlarge and become secretory In nature
- Also cause breasts to swell
ff
ff
ff
ff
ff
ff
fl
ff
 on body temperature - a ects hypothalamic thermoregulatory centre in brain
- Increases female temperature of 0.5 degrees Fahrenheit in luteal phase

L21 - Development of female reproductive system

Development of female genital ducts
- mesonephric ducts regress because of lack of testosterone
- Paramesonephric ducts develop because of absence of mullerian inhibitory factor
- Does not require ovaries or hormones (happens even without them)
Structure of Paramesonephric duct
1. Cranial vertical part
- opens into abdominal cavity
2. Horizontal part
- crosses mesonephric duct
3. Caudal vertical part
- fuses with its parter from opposite side
Female reproductive tract development
1. Fusion of horizontal + caudal part of paramesonephric duct -> utero-vaginal canal (give rise to
uterus + cervix)
2. When 2 ducts fuse there is a uterovaginal septum in midline -> then dissolves in caudo-cranial
direction (bottom -> top) -> forms endometrium + vaginal mucosa

Development of uterus + surrounding structures

- Endometrial stroma (CT + blood vessels) + Myometrium (smooth muscle layer of uterus
derived from splanchnic mesoderm
- When 2 paramesonephric ducts fuse in midline they not only form uterus but also
• Bring together 2 peritoneal folds -> become right and left broad ligament & 2 peritoneal
spaces: rectouterine pouch (pouch of Douglas) + vesicouterine pouch

Development of vagina
- Tip of utero-vaginal canal reaches urogenital sinus
- Solid tubercle formed -> split into 2 sinovaginal bulbs -> fuse to form solid vaginal plate
- Vaginal plate fuses with lower end of utero-vaginal canal
- By 5th month vagina entirely canalised
Vagina has dual embryological origin
Upper 1/3: from utero-vaginal canal (mullerian/paramesonephric duct)
Lower 2/3: from urogenital sinus (endoderm)
Fibromuscular wall of vagina
- made from surrounding splanchnic mesoderm (same as uterus)
ff
Hymen formation
- lumen of vagina until late fetal life remains separated from urogenital sinus by hymen (remnant
of sinus tubercle)
- Develops small opening before birth

Remnants of mesonephric ducts in females

- in females mesonephric duct regresses due to no
testosterone but in certain locations they persist
- Mesonephric tubules -> paraoophoron (found in
mesovarian)
- Mesonephric duct disappears except for
• Cranial portion = epoophoron
• Caudal portion = may be found in wall of vagina (later
in life may form Gartner’s cyst -> pain in vagina +
swelling)

Remnants of para-mesonephric duct in males

1. Appendix of testis
- present at upper pole of testis
- Derived from upper part of mullarian duct
2. Prostatic utricle
- present in prostatic urethra
- Derived from lower part of mullerian duct (utero-vaginal canal)
Anomalies of female genital ducts
- due to developmental arrest of utero-vaginal primordium during 8th week
Double uterus (uterus - from complete failure of fusion of
didelphys) para-mesonephric ducts
- Associated with double cervix +
double vagina

Bicornuate uterus - due to incomplete fusion of interior

parts of para-mesonephric ducts +
failure of fusion of them superiorly

Bicornuate uterus with a - occurs if growth of one

rudimentary bone paramesonephric duct is retarded
and this duct may or may not fuse
with other one
- Rudimentary horn may or may not
communicate with cavity of uterus

Septate uterus - due to incomplete absorption of the

wall between 2 mullerian tubes

Unicornuate uterus - develops when 1 para-mesonephric

duct doesn’t develop
- Results in uterus with one uterine
tube
- Many females fertile by may have
increased incidence of premature
delivery
Agenesis of vagina - failure of sino-vaginal bulbs to form
vaginal plane (upper vagina will be
short pocket)

Vaginal atresia - failure of canalisation of vaginal plate

-> results in blockage of vagina

Imperforate hymen - failure of inferior end of vaginal plate

to perforate
- At age of puberty there will be
period but blood will distend to
vagina (hematoclopos) -> then
uterus (hematometra)

Development of female genital glands

[Link]-urethral glands of Skene

-Parenchyma: endodermal outgrowth of
urethra (endoderm)
-Stroma: derived from surrounding splanchnic
mesoderm
-secrete mucus to lubricate urethra
2. Greater vestibular glands of bartholin
-parenchyma: endodermal outgrowth from
lower part of uro-genital sinus (endoderm) that
gave rise to distal vagina
-Stroma: derived from surrounding splanchnic
mesoderm
-secrete mucus to lubricate external genitalia
during intercourse
 L22 + 23 Endometrial disorders
Adenomyosis - presence of endometrial tissue soft boggy uniformly enlarged uterus
within uterine wall
(myometrium)
- Can co-exist with
endometriosis
Microscopic
- irregular nests of endometrial
stroma with glands arranged
within myometrium
Clinical symptoms
Especially during pre-menstrual
period
- menometrorrhagia
- Colicky dysmenorrhea
- dyspareunia
- Pelvic pain
Endometriosis
- ectopic normal endometrial tissue at site outside of uterus
- Includes endometrial glands + stroma
- In active reproductive life, most often third and fourth decades
- Ligation of bilateral fallopian tubes reduce change of developing endometriosis
Typical locations for endometriosis
- ovaries
- Uterine ligaments
- Pelvic peritoneum
- Laparotromy scars
- Distant locations: appendix, vagina, lungs
Clinical presentation
- Triad
- Dysmenorrhea
- Dyspareunia
- Infertility
- Pelvic pain usually cyclical
- Endometriosis that extends to bladder: dysuria + urinary frequency
- Endometriosis tissue known to overproduce prostaglandins + cytokines -> important mediators
of in ammatory response (compared with normal endometrial tissue)
Causes
1. Regurgitation theory
- endometrial tissue implants at ectopic sites via retrograde ow of menstrual endometrium
2. Endometrial cells enter vascular and lymphatic system
- travel to di erent locations of body -> implant + multiply
3. Coelomic metaplasia
- postulates that hormonal/immunological factors stimulate cells outside the uterus (peritoneal or
visceral mesothelial cells) to transform into endometrial cells
Gross morphology

-in areas of endometriosis blood is darker + small foci of

endometriosis gross appearance powder burns
-Small areas of endometriosis have reddish-brown to
bluish appearance
fl
ff
fl
 - ovaries become distorted by large cystic masses lled with
brown uid resulting from previous haemorrhage (chocolate
cysts or endometriomas)

Microscopic morphology
Diagnosis made when: endometrial glands and stroma are present with or without presence of
hemosiderin

-Endometriosis involving mucosa of colon

-Higher magni cation reveals endometrial glands +

stroma adjacent to normal colonic mucosa

-endometrial glands and stroma growing in fallopian tube

wall
fl
fi
fi
 Acute endometritis
- uncommon
- Limited to bacterial infections that arise after delivery/miscarriage
- In ammatory response limited to stroma
- Removal of retained gestational products by curettage
- Antibiotic therapy clears infections
Predisposing factor
- retained products of conception
Causative agents
- group A haemolytic streptococci, staphylococci
Signs and symptoms
- Fever
- Pelvic + lower abdominal pain
- Vaginal discharge/bleeding
Chronic endometritis
In association with
- chronic pelvic in ammatory disease
- Retained gestational tissue, post partum or post abortion
- Intrauterine contraceptive devices
- Tuberculosis
Diagnosis
- identi cation of plasma cells in stroma
Endometrial hyperplasia
- abnormal proliferation of endometrial glands relative to stroma -> increased gland to stroma
ratio when compared to normal proliferative endometrium
- Causes abnormal/excessive uterine bleeding (If patient postmenopausal + have uterine
bleeding -> suspect endometrial hyperplasia)
- Precursor to most common type of endometrial carcinoma (can progress to endometrial
cancer)
Genetic alteration in endometrial hyperplasia + endometroid endometrial carcinoma
- inactivation of PTEN tumour suppressor gene
A ects
- any age group but mostly after menopause (when progesterone levels decline)
Pathogenesis
- prolonged estrogenic stimulation of endometrium due to:
- Anovulation
- Increased estrogen production from endogenous sources
- Exogenous estrogen
Associated conditions
- obesity (adipose tissue conversion -> increase estrogen)
- Menopause
- PCOS (hormonal imbalance)
- Functioning granulosa cell tumours of ovary
- Prolonged administration of estrogenic substances (estrogen replacement therapy)
Classi cation
1. Hyperplasia
2. Atypical hyperplasia/ Endometrial intraepithelial neoplasia
- associated with increased risk of endometrial carcinoma
Morphology

Typical hyperplasia
-mild glandular crowding
-Cystic glandular dilation
-Cytologic features e.g proliferative
endothelium
-Increased gland-to-stroma ration
-Glands have variation in size + shape
-Focally some intervening stroma
retained
ff
fl
fi
fi
fl
 Atypical hyperplasia (endometrial intraepithelial neoplasia)

C: increase glandular crowding

D: rounded vesicular nuclei
with prominent nucleoli (arrow)
-complex pattern of
proliferating gland w nuclear
atypia
-Glands back to back w
complex outlines due to
branching structures
-Nuclei round w conspicuous
nucleoli
-Features have overlap with
well-di erentiated endometroid
adenocarcinoma

Treatment
- rst: progestins
- If endometrial biopsy shows atypia: surgical hysterectomy for females that dont want to be
pregnant
- If female wants to be pregnant: uterine cancer ruled out wit hysteroscopy + curettage & trial
of progestin and follow up is done
- After therapy if there is no regression, uterus removed
Endometrial polyps
- exophytic masses that project in endometrial cavity
- Can be single/multiple and usually sessile and small (only occasionally
large + pedunculate)
- Polyps may be asymptomatic/cause abnormal bleeding and infertility
- Rarely adenocarcinoma arises
- Polyps can be removed by local excision using curettage

How does endometrial hyperplasia -> endometrial carcinoma

Key genetic alteration
- inactivation of phosphatase and tensin homolog (PTEN) tumour suppressor gene
- Common in endometrial hyperplasia + endometrial carcinoma
Frequency of PTEN mutation
- >20% endometrial hyperplasia (w or without atypia)
- 30-80% endometrial carcinomas
Function of PTEN
- encodes lipid phosphatase that is negative regulator of phosphatidylinositol 3-kinase (PI3K)/
AKT growth regulatory pathway
- When PTEN function lost -> PI3K/AKT pathway becomes overactive ->
• Stimulates estrogen dependent gene expression -> overgrowth of cell types that depend on
estrogen e.g endometrial & mammary epithelial cells
fi
ff
Endometrial carcinoma
- most common invasive cancer of female genital tract
- Clinical presentation:
• Most patients postmenopausal -> main symptom abnormal uterine bleeding
• Premenopausal women: may report inter menstrual bleeding/heavy prolonged menstrual
bleeding
Types of endometrial carcinoma
Type 1 (endometrioid carcinoma) Type 2 (serous endometrial
carcinoma)

Age 55-65 65-75

Risk factors - unopposed estrogen - atrophy

- Obesity - 10 years older than those with
- Hypertension endometrioid carcinoma
- Diabetes
- Endometrial carcinoma type 1 can occur as
Lynch syndrome
• Increase risk of colorectal, endometrial
carcinoma, ovarian cancer
• So if patient with endometroid carcinoma
has family history of colon + ovarian cancer
-> consider Lynch syndrome

Precursor - hyperplasia which is associated with - serous endometrial

• Obesity intraepithelial carcinoma
• Diabetes
• Hypertension
• Infertility
• Unopposed estrogen stimulation (early
menarche + late menopause, estrogen
replacement therapy without progesterone,
nulliparity -> aggregate increase in estrogen
exposure over lifetime

Mutated genes/ - PTEN, PIK3CA, KRAS P53

genetic - Mistmatch repair genes (MLH1 & MSH2(
abnormalities

Behaviour - Indolent - agressive

- Spread by lymphatics - Intraperitoneal + lymphatic
- Good prognosis spread
- Most common - Bad prognosis
 Morphology
Type 1 Gross
- localised polyploid tumour or di use
in ltration of endometrial lining
Spread & invasion
- myometrial invasion -> direct extension to
adjacent organs
- Broad ligament invasion -> can produce
palpable mass
- Regionial lymph node dissemination
- Late metastasis -> lungs, bone liver
Microscopic
- glandular growth pattern resembling normal
endometrial epithelium

Well di erentiated (grade 1)

- almost all glands well formed (tumour contain
no more than 5% of solid component)
- Lack of intervening stroma

Moderately di erentiated (grade 2)

- well formed glands mixed with by areas
composed of solid sheets of cells (make up
50% or less of tumour)

Poorly di erentiated (grade 3)

- greater than 50% solid growth pattern
- Endometroid adenocarcinoma w
predominantly solid growth pattern

Type 2 Gross
- arise from small atrophic uteri
- Present as large bulky tumours that invade
myometrium
Microscopic
- papillary growth pattern
- Cells have marked cytologic atypia
• High nuclear to cytoplasmic ratio
• Atypical mitotic gures
• Hyperchromasia (dark staining nuclei)
• Prominent nucleoli
fi
ff
ff
ff
fi
ff
 Accumulation of mutated p53 protein in nuclei
(brown)

Treatment
- Best: surgical removal of uterus, fallopian tubes, ovaries & surrounding lymph nodes (total
abdominal hysterectomy with bilateral salpingopharyngeus nephrectomy)
- Radiation or chemotherapy may be added
- May sometimes respond to hormonal therapy e.g anti-estrogen agents (progestins)

Special variant: Malignant mixed mullerian

tumours [MMMTs] = carcinosarcomas
- mixed epithelial and mesenchymal tumours
Microscopic morphology
- epithelial component resembles poorly
di erentiated endometroid/serous
carcinoma
- Mesenchymal component : contain uterine
mesenchymal elements (stromal sarcoma,
leiomyoscarcoma)
- Others contain heterologous malignant cell
types (rhabdomyosarcoma,
chondrosarcoma)

Tumours of myometrium
Uterine Leiomyoma (Fibroids)
- most common tumour in women
- Benign smooth muscle neoplasms that occur singly but more often multiple
- Usually asymptomatic, submucosal leiomyoma produce abnormal bleeding, pressure and
interfere with fertility
- Arise in females of reproductive age
- Large tumours cause pressure e ects (urinary bladder), sudden pain (infarction) & complicate
pregnancy
- Diagnosed with ultrasonography
Gross features
- sharply circumscribed, discrete,
round rm gray-white nodules
- Size: tiny nodules-> large masses
- Cut section: classic whorled pattern
of smooth muscle bundles
Locations
- intramural -> within myometrium
- Submucosa -> beneath
endometrium
- Subserosal -> beneath serosa
ff
fi
ff
 Microscopic features
- well di erentiated regular spindle shaped smooth muscle cells
with hyalinisation
- Individual muscle cells: uniform in size and shape with oval
nucleus and long slender bipolar cytoplasmic processes
- Mitotic gures scarce

Uterine leiomyosarcoma
- malignant
Gross
- large
- Poorly circumscribed multi nodular mass
- Cut surface: soft, yellow-tan with foci of
haemorrhage + necrosis (no prominent whorled
appearance)
ff
fi
 BEAM
b: BONE
e: estrogenic features
a: anabolic
m: mineralocorticoid + blood clotting
L24 - Drug therapy for disorders of female reproductive system
Estrogen
Role
- development of female sex organs + secondary sex characteristics at puberty
- Metabolic e ects:
• maintenance of bone mass by retarding bone resorption
• anabolic e ect
• Mineralocorticoid (salt + water retention)
• Increase coagulability of blood
Mechanism of action
- binds to nuclear receptor proteins -> activated steroid-receptor complex interacts with nuclear
chromatin -> initiate RNA synthesis -> synthesise speci c proteins
Estrogen receptors (Era & Erb)
- Estradiol binds to Era & Erb with equal a nity but certain ligands have di erent a nities
Classes of estrogen
Natural estrogens (Steroidal estrogen) Synthetic estrogens

- Estradiol - Ethynyl estradiol

- Estrone + Estriol • Less rst pass metabolism than natural ->
General pharmacokinetics e ective orally at lower dose
*Readily absorbed through GIT, skin & mucous - Conjugated estrogen
membranes - Esteri ed estrogen
- Non steroidal Estrogens: Diethylstillbestrol (DES)
- mimic estrogen action
General pharmacokinetics
*Fat soluble, stored in adipose tissue & slowly
released -> prolonged action + higher potency
Therapeutic uses of estrogen
1. Post-menopausal hormone replacement therapy (HRT)
2. Replacement therapy in hypoestrogenism (delayed puberty in girls)
3. Oral contraceptives: combined with progestins
4. Dysmenorrhea Hot (HRT), Pretty (puberty - hypoestrogenism), Cute (contraceptives) Dolls (dysmenorrhea),
5. Acne: bene t through suppressing ovarian production ofAlways (acne) by inhibiting gonadotrophin
androgen
release from pituitary
Adverse e ects of estrogen
- vaginal, cervical, endometrial cancers + enhance growth of existing breast cancer
- Thromboembolism
- Salt and water retention (edema)
- Migraine
- Breast tenderness
- Amenorrhea
- Endometriosis e ect may be enhanced
- Gallstones
Selective estrogen receptor modulators (SERM)
- agonist + antagonistic e ects depending on tissue type
Tamoxifen
- estrogen antagonist on breast tissue -> used in treatment + prevention of breast carcinoma
- Agonistic e ect causes endometrial hyperplasia
Bazedoxifene
- estrogen agonist in bone -> reduces bone mass -> used for treatment/prevention of
osteoporosis in post menopausal women
- Antagonist on endometrium and breast -> prevents endometrial hyperplasia + breast cancer
risk

2 doors Tami & Bazi

Tami blocks the breast door but opens the endometrium door
Bazi locks breast and uterus doors and will strengthen the great wall of bone
ff
fi
fi
ff
ff
ff
fi
ff
ff
ff
ffi
fi
ff
ffi
 Progestogens
Progesterone: responsible to prepare uterus for implantation + maintenance of pregnancy
Mechanism of action
- bind to nuclear progesterone receptor -> undergoes conformational changes -> attaches to
progesterone response elements -> regulates gene transcription
Classi cation of progestogens
1. Natural progestogens: Progesterone
2. Synthetic progesterones: Progestins
3. Progesterone derivative: medroxyprogesterone acetate, etonogestrel
4. Testosterone derivatives: norethindrone, levonorgestrel, desogesterel
Uses
1. Contraception
- synthetic progestogens (progestins) used - more stable due to less rst pass metabolism ->
lower oral doses
- Preparations:
• Progestin + estrogen combined in oral contraceptive pill/patch No baby
• Progesterone only contraceptive pill (minipill) help lady
• Injectable/implantable progesterone only contraception stop pain
• Intrauterine contraceptive system fight cancer again
2. HRT
3. Endometriosis
4. Endometrial carcinoma (estrogen-dependent)
Adverse e ects
- Acne
- Fluid retention
- Weight change
- Depression All Fat Women Do Love Big Meals
- Change in libido
- Breast discomfort
- Menstural cycle irregularity
Post menopausal hormone replacement therapy (HRT)
- At menopause ovarian function declines -> estrogen levels fall
- HRT = low doses of estrogen without or without progesterone -> suppress menopausal
syndrome (vasomotor instability, psychological disturbances, atrophic changes)
- Estrogen only therapy less preferred
Manifestations of menopause
- Increase risk of CVS diseases: CAD, MI, stroke
- Vasomotor disturbances: hot ushes, chilly sensation, excess sweating
- Urogenital atrophy: decreased lubrication, thinned mucosa, urinary urgency, predisposition to
UTI
- Osteoporosis: thinning of bones (loss of osteoids + calcium)
- Dermatological changes: thinning + drying + loss of elasticity (wrinkles)
- Mental disturbances: irritability, depressed, anxiety, dementia
Mechanism of vasomotor disturbances
- estrogen withdrawal -> increase NE levels -> increase activation of a2 adrenoreceptors in
hypothalamus -> thermoregulatory neutral zone narrow (even small temperature change triggers a
response) -> autonomic reactions to cool body (sweating, ushing, vasodilation) -> hot ash
Advantage of adding progestogen
- block risk of endometrial carcinoma due to continuous estrogen stimulation of endometrium
Disadvantage of adding progestogen
- decrease metabolic + CV bene ts of estrogen
Types of HRT
1. Sequential/cyclic combined HRT
- Progestogen administered from day 12-28 of cycle along with continuous estrogen -> regular
withdrawal bleeding at end of each cycle
2. Contínuos combined HRT
- progestogen taken every day along with estrogen without any breaks -> prevents withdrawal
bleeding
3. Estrogen only therapy
- for women who have had hysterectomy or when progestogen is not tolerated/contraindicated
fi
ff
fl
fi
fl
fi
fl
 Adverse e ects of HRT
- Cyclic withdrawal bleeds -> avoided with continuous progesterone
- Headache, breast tenderness and muscle cramps (resolve over rst 3 months)
- Nausea + vomiting
- Acne/greasy skin, depression, irritability, loss of energy + poor concentration due to
progestogen
- Increased risk of endometrial cancer if estrogen is given unopposed by progestogen
- Increased risk of breast cancer + venous thromboembolism
Tibolone
- progestogen with selective tissue estrogenic activity
- Exhibits progestognenic, weak estrogenic + weak androgenic activity
- Can be used continuously with cyclical progesterone (no withdrawal bleeding)
Uses
- treatment of symptoms of estrogen de ciency + for postmenopausal prophylaxis of
osteoporosis when other prophylaxis is contraindicated (protective e ect on bone mass)
- Improves vasomotor + libido problems & vaginal atrophy
- No e ect on endometrium -> choice for women with a history of endometriosis
Adverse e ects
- weight gain
- Increased facial hair
Principles of management of menstrual disorders
Dysmenorrhea: Primary dysmenorrhea (No pathologic ndings, produced by uterine vasoconstriction
Spasmodic pain + prostaglandin mediated sustained contractions
during - NSADS (Ibuprofen, ketoprofen, mefnamic acid, naproxen) -> lower uterine PG
menstruation levels -> relieve pain
- Oral contraceptives (continuous use suppresses menstruation)
- Depot medroxyprogesterone acetate (suppresses ovulation + thins endometrium)
- Thiamine/Vit E may be used as they inhibit release of arachidonic acid and its
conversion to PG
Secondary dysmenorrhea (e.g endometriosis)
- periodic use of NSAIDS
- Oral contraceptives. GnRH agonists (Gonadorelin, leuprolide) & antiestrogen
(danazol) may give relief particularly in endometriosis (treat underlying cause)

Menorrhagia: - NSAIDS (reduce menstrual blood loss)

excessive/ - Iron supplements (IDA)
prolonged - Continuous progestin (levonorgestrel): uterine implant release levonorgestrel ->
menstural makes uterine lining thin + decrease menstrual blood ow & cramps
bleeding - Oral contraceptives (estrogen + progestins): stabilise endometrium -> reduce
incidence of breakthrough bleeding + helps regulate menstrual cycles and reduce
episodes of excessive/prolonged menstrual bleeding
- Tranexamic acid: anti brinolytic -> prevent blood clots from breaking down too
quickly -> decrease excessive bleeding
- Surgical removal/hysterectomy (refractory cases)

Premenstural Clinical features

syndrome - headache, uid retention, distention and breast tenderness few days preceding
menstruation
- Depression + mood disturbance (premenstrual dysphoric disorder)
Treatment
- Fluoxetine + other SSRIs (selective serotonin reuptake inhibitors) given daily on
symptom days -> decrease irritability + mood changes
- Mefenamic acid (NSAIDS) + dicyclomine (anticholinergic with antispasmodic e ect)
: in case of spasmodic uterine pain
- If severe : PMS requires suppression of ovulation by combined estrogen-
progesterone treatment given cyclically
ff
ff
ff
fl
fi
fi
fi
fl
fi
ff
ff