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REPRODUCTIVE PHYSIOLOGY

Reproductive system functions in gamete:

 Production
 Storage
 Nutrition
 Transport
 Fertilisation
Systems: gonads, ducts, accessory glands and organs, external genitalia

Males
 Testes produce spermatozoa

Females
 Ovaries produce oocytes which travel along the oviducts

Male Reproductive System

 Testes enclosed in tunica albuginea inside the scrotal sac
 Tunica albuginea: extends septa into testes, dividing them into lobules
 Lobules form a network: rete testis
 Rete testis then send three efferent ductules into the caput epididymis (top part of the epid
idymis)
 Epididymis: made of caput epididymis (first, top part) and corpus epididymis, corda epididy
mis which forms ductus/vas deferens. Nothing but a site of storage of formed spermatozoa
 External genitalia: penis and scrotum
 Epididymis: site of sperm maturation
 Vas/ductus deferens: transport sperm. Passes above bladder
 Ejaculatory duct: emerges from prostate
 Seminal vesicles, prostate, bulbourethral glands: accessory glands
 Urethra conducts semen to outside of the body
 Pathway of spermatozoa: Epididymis → ductus deferens → ejaculatory ducts

Descent of the Testes

 Movement of the testes through the inguinal canal into the scrotum, begin to descend in th
e first trimester
 Testes finish descent just before birth
 They start in the abdomen, form just beside the kidneys
 Spermatic cord passes through the superficial inguinal ring
 Spermatic cord: nerves, artery, venous plexus, ductus deferens
 Spermatic cord is enclosed in the cremaster muscle: can pull up scrotum when it contracts,
relax and move scrotum away from body
 Occurs during fetal development
 Testes remain connected to internal abdominal structures

Cryptorchidism
 Failure of the testes to descend from the abdomen into the scrotum
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 Can cause the tubular epithelium of the testes to degenerate
 Doctors wait for three months after birth before treatment

Musculature of the Scrotum

 Dartos muscle: causes wrinkling of the scrotal skin, no other function
 Cremaster muscle: pulls up or drops testes further down

Testes
 Up to 900 coiled seminiferous tubules
 Each seminiferous tubule is up to 1.5m long
 All the sminiferous tubules are not at the same stage at the same time, they are all at differ
ent stages: in a section of the testes, some may appear empty

Accessory Glands
 Two seminal vesicles: lie on either side of the protstate
 Bulbourethral glands: Cowper's glands

Spermatogenesis
 Starts with spermatogonia
 Spermatogonia (capable of mitosis) give rise to diploid primary spermatocytes
 Primary spermatocytes enlarge then divide by Meiosis I into Secondary spermatocytes
 Secondary spermatocytes divide by Meiosis II to form haploid spermatids
 Spermatids will then mature into spermatozoa
 One spermatogonium gives rise to four spermatids
 Spermiogenesis: the physical maturation of spermatids into spermatozoa. It is the last step
of spermatogenesis, when the sperm gain their tail
 Spermatogonia lie in layers on the inner surface of the seminiferous tubules, above the CT c
apsule of the seminiferous tubule
 Spermatogonia undergo mitosis starting at puberty and continue to differentiate through d
efinite stages of development
 Leydig cells: secrete testosterone which is important for sperm development and male seco
ndary sex characteristics. Lie in between seminiferous tubules
 Sertoli/nurse cells: large and surround the spermatogenic cells. Histologically may look like
spermatozoa arise from the Sertoli cells. Sperm heads are enclosed in grooves on the nurse
cell membrane

Spermatozoa
 Head, neck piece and tail
 Evolved to deliver its genetic material to the secondary oocyte
 Acrosomal cap: has enzymes which digest a path through the oocytes protective coat. Cove
rs half of the sperm head. Derived mostly from the Golgi body and contains enzyme similar
to those found in lysosomes. Enzymes include hyaluronidase (breaks down proteoglycans fil
aments) and Proteolytic enzymes
 Head region: contains genetic material and acrosomal cap.
 Body : has mitochondria to produce ATP to power the tails movement
 There is no source of energy inside the spermatozoa themselves, they obtain energy from t
he fructose rich secretions in semen
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 The sperm must undergo capacitation to become motile and able to fertilise the oocytes
 Tail: has central axoneme made of 11 microtubules, collection of mitochondria near the axo
neme in the body of the tail (considered to also be the body of the sperm) thin cell membra
ne covering the axoneme
 Normal sperm move at 1-4mm per minute

Maturation of Sperm
 Not mature as soon as they are produced
 Newly formed sperm stay in the epididymis for 18 to 24 hours and develop motility
 120 million sperms are formed each day by the two testes, they can remain stored and mai
ntaining fertility for up to 1 month. They are kept in a deeply suppressed inactive state by in
hibitory substance secreted by the ducts
 Once ejaculated, the life expectancy of sperm in the female genital tract is 1 to 2 days

Hormone Factors Regulating Spermatogenesis

1. Testosterone: secreted by the Leydig cells located in the interstitium of the testis, is essenti
al for growth and division of the testicular germinal cells, which is the first stage in forming s
perm
2. Luteinizing hormone: secreted by the anterior pituitary gland, stimulates the Leydig cells t
o secrete testosterone.
3. Follicle-stimulating hormone: secreted by the anterior pituitary gland, stimulates the Serto
li cells; without this stimulation, the conversion of the spermatids to sperm (the process of s
permiogenesis) will not occur.
4. Estrogens: formed from testosterone by the Sertoli cells when they are stimulated by follicl
e-stimulating hormone, are probably also essential for spermiogenesis.
5. Growth hormone (as well as most of the other body hormones): necessary for controlling b
ackground metabolic functions of the testes. Growth hormone specifically promotes early di
vision of the spermatogonia themselves; in its absence, as in pituitary dwarfs, spermatogen
esis is severely deficient or absent, thus causing infertility.

Leydig/Interstitial Cells
 Responsible for 95% of testosterone synthesis, constitute 20% of each testis
 Synthesize small quantities of other steroids
 The testes have a unique ability to convert androstenedione into testosterone
 Dihydrotestosterone is the most potent form of testosterone
 When tumors of these cells develop, large amounts of testosterone are produced

Sertoli Cells
 Supportive function to the developing germ cells
 Assist in movement of germ cells from basal lamina to lumen of Seminiferous tubule
 Engages in phagocytosis of damaged germ cells, and residual bodies shed by spermatogeni
c cells as they develop
 Synthesizes: androgen-binding protein which is autocrine (binds to testosterone and moves
it from Leydig cells to germ cells), anti-Müllerian hormone which is paracrine(induces regre
ssion of Müllerian structures in fetal life), inhibin (inhibits pituitary FSH secretion)
 Make up the blood-testis barrier, protect the germ cells from autoimmune attack
 Joined by tight junctions which forms the blood-testis
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Seminal Vesicles
 Are accessory glands
 Secrete a mucoid material that contains fructose, citric acid, prostaglandins and fibrinogen
 Empty their contents into the ejaculatory duct after the vas deferens empty their contents i
nto the ejaculatory ducts
 Prostaglandins react with cervical mucus helping in sperm movement towards oviducts
 Prostaglandins may also cause backward reverse peristaltic movements in the uterus and f
allopian tubes to move the ejaculated sperm towards the ovaries. A few sperm reach the up
per ends of the fallopian tubes within 5 minutes.

Prostate Gland
 Is an accessory gland
 Secretes thin milky fluid containing calcium, citrate, phosphate, clotting enzyme, fibrinolysi
n
 During emission, the capsule of the prostate contracts simultaneously with the vas deferens
so that the fluid of the prostate adds further to the bulk of the semen
 The acidity of the fluid in the vas deferens helps inhibit sperm fertility before ejaculation
 Mixture is alkaline to neutralise acidic vaginal secretions, and fluid of the vas deferens is al
so slightly acidic due to citric acid and end products of the sperm’s metabolism
 Vaginal secretions have pH of 3.5 to 4.0
 Fluid contains prostate-specific antigen (PSA) which breaks down semen and helps to relea
se sperm
 PSA can be measured in the blood and indicates the level of activity of the prostate

Clinical Correlates of the Prostate Gland

 Prostate cancer a common cancer which kills men
 Prostate problems are common in older males: prostatitis (infection), benign prostate hype
rplasia (increase in size of the gland, not malignant), prostate cancer (malignant)
 Benign prostate hyperplasia (BPH): encroaches on the urethra and hinders micturition. Dete
cted by PSA blood test, digital rectal examination (DRE)
 BPH Symptoms: only seen in advanced stage. Hematuria (blood in urine resulting in pink uri
ne), pain during urination, hesitancy, weak stream, terminal dribbling
 Prostate cancer: metastases can migrate to bones where they cause severe bone pain. Can
be treated (not necessarily cured) by removal of the testes and administration of estrogens
which also helps alleviate the bone pain.
 Digital Rectal Examination: finger is inserted into anus to check if prostate is enlarged
 PSA testing: PSA is a protein. Blood test is very accurate. Used for screening and monitoring
prostate activity. Normal PSA is considered to be less than 4 nanograms per ml. Anything a
bove that is abnormal
 PSA velocity: rate at which PSA rises with time. Slow steady rise indicates BPH, rapid rise ind
icates prostate cancer. Cut-off value is increase of 0.75 nanograms per ml per year
 Treatment: local prostectomy, external beam radiation, androgen deprivation for malignant
cancer

Semen
 Ejaculated during male sexual act and contains fluid and sperm
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 Composed of 10% fluid from vas deferens, 60% fluid from seminal vesicles, 30% from prosta
te and a small amount of mucus from the bulbourethral (Cowper’s) glands
 Prostatic fluid gives semen a milky appearance
 Clotting enzyme from the prostate acts on fibrinogen to form a weak coagulum which hold t
he sperm in the deeper regions of the vagina near the cervix. The coagulum them dissolves
within 15-30 minutes due to the action of prostatic fibrinolysin, releasing the sperm which
will then be highly motile
 Sperm do not become fully motile until the pH is about 6.0-6.5

Sperm Count and Motility

 Two important tests to determine fertility: sperm count and motility
 Usual quantity during each act of coitus: 3.5 ml containing 120 million sperm
 When the number is 20 million, it is termed oligospermia
 Absence of sperm: azoospermia
Motility
 Ranges from Grade 4 (most motile) to Grade 1 (lowest)
 Grade 4: strongest sperm, can swim in a straight line, sperm swim fast
 Grade 3: sperm move in a crooked motion but move forward
 Grade 2: sperm do not move forward, but tails move
 Grade 1: immotile and do not move forward
 Oligospermia: sperm concentration less than 15 million per ml

Penis
 Most is made of three parallel cylinders of erectile tissue
 Corpora cavernosa: two lying side by side with a central artery present in the middle of eac
h one. The two corpora cavernosa are covered by deep penile fascia
 Corpus spongiosum: lies under the cavernosa, encloses the urethra. Bulb and glans penis ar
e extensions of it.
 Is an erectile tissue
 During arousal: arteries fill with blood and erection occurs

Sexual response in males

 Controlled by autonomic nervous system
 Controlled by spinal reflexes
 Three phases: erection, emission, ejaculation
 Erection: controlled by parasympathetic nervous system
 Emission: controlled by sympathetic nervous system
 Ejaculation: controlled by sympathetic nervous system

Events leading to Erection

 The most important source of sensory nerve signals for initiating the male sexual act is the g
lans penis
 Controlled by stimuli: mechanical, neural activity in the brain
 Erection is caused by parasympathetic impulses that travel from the sacral portion of the s
pinal cord through the pelvic nerves to the penis
 Interneurons in spinal cord are stimulated
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 Interneurons act on parasympathetic nervous system, increasing discharge of its neurons to
the penis
 Parasympathetic neurons: release nitric oxide, vasoactive intestinal peptide and acetylcholi
ne which relaxes the arteries of the penis and the trabecular network of smooth muscles of
erectile tissue in the shaft of the penis. Venous outflow is decreased. Sinusoids in the erecti
le tissue become dilated and this presses against fibrous tissue surrounding it, causing the p
enis to become hard and elongated
 When parasympathetic is stimulated, arterioles dilate (relaxation of smooth muscles). Caus
es erectile tissue to enlarge
 Veins end up compressed leading to sustained enlargement of erectile tissue, blood flow ou
t of the penis is slowed
 This gives positive feedback, leading to further erection
 Release of nitric oxide: further relaxes smooth muscles, causing further accumulation of blo
od
 Major drugs used to enhance erection: Viagra (inhibits phosphodiesterase 5), cialis which in
crease blood flow to the penis
 Lubrication: parasympathetic stimulus causes urethral and bulbourethral glands to secrete
mucus, even though most lubrication during coitus comes from the female genital tract

Erectile Dysfunction
 Also called impotence
 Can be caused by: trauma (physical or psychological), deficient testosterone, alcohol, antide
pressants, neurological problems, hypertension, atherosclerosis, diabetes, decreased nitric
oxide
 Can be treated by phosphodiesterase inhibitors, increases cGMP levels

Emission
 Response to mechanical stimulus continues
 Controlled by sympathetic nervous system
 Allows contraction of epididymis, vas deferens, ejaculatory duct
 All secretions are poured into the internal urethra
 Results in movement of the semen into the urethra
 The filling of the internal urethra elicits sensory signals that travel through the pudendal ner
ves to the sacral region of the spinal cord giving the feeling of sudden fullness in the internal
genital organs

Ejaculation
 Response to mechanical stimulus
 Controlled by sympathetic nervous system
 Smooth and skeletal muscles of the urethra contract
 Urethral sphincter contracts, closing off bladder. No urine is passed during ejaculation
 Sensory signals from the pudendal nerves excite rhythmic contractions of the ischiocaverno
sus and bulbocavernosus muscles which compresses the bases of the erectile tissues togeth
er. This causes rhythmic wavelike increases in pressure in the erectile tissue, urethra and ge
nital ducts which ejaculates semen from the urethra to the exterior
 Semen is expelled from body through the urethra
 The processes of emission and ejaculation constitute the male orgasm
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Hormonal Control
 Arcuate nuclei in the hypothalamus synthesize and secrete GnRH
 GnRH stimulates anterior pituitary to release FSH and LH which are glycoproteins
 Anterior pituitary releases FSH and LH
 LH acts on Leydig cells, causing them to release testosterone which exerts negative feedbac
k on the hypothalamus, decreasing GHRH secretion
 FSH acts on Sertoli cells and stimulates them to grow and secrete spermatogenic substance
s

Testosterone
 Testes secrete androgens: male sex hormones
 Testosterone is the primary testicular hormone, formed by Leydig cells
 All androgens are steroids synthesized from cholesterol
 Testosterone is responsible for secondary sex characteristics of males
 Most potent form is dihydrotestosterone
 Estradiol (an oestrogen) is formed from testosterone, important for spermiogenesis
 Effect on body hair: hair grows over the pubis, upward along the linea alba sometimes to th
e umbilicus, on the face, usually on the chest and sometimes on other regions of the body s
uch as the back. Hair on most other regions of the body may also become prolific. Hair grow
th on the top of the head is decreased
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 Effect on the voice: hypertrophy of the laryngeal mucosa and enlargement of the larynx occ
ur. The effects first cause “cracking” but eventually result in the typical masculine voice
 Effect on skin: thickness of the skin and ruggedness of subcutaneous tissue increases. Rate o
f secretion by the sebaceous glands increases, which can contribute to acne due to excessiv
e secretion by sebaceous glands of the face.
 Effect on muscle: protein synthesis and deposition increases, leading to an increase in muscl
e mass
 Effect on bone: total quantity of bone matrix and calcium deposition are increased. Testoste
rone increases calcium retention due to anabolic effects. Pelvic outlet is narrowed, the pelvi
s is lengthened, shape of the pelvic cavity becomes more funnel-like and the strength of the
pelvis is increased for load bearing
 Effect on metabolism: basal metabolic rate is increased by 5-10%. Number of red blood cell
s is also increased due to increase in BMR.
 Testosterone also slightly increases sodium reabsorption, causing total body water to increa
se.

Female Reproductive System

Ovaries
 Whitish in colour
 Attached by ovarian ligaments to either side of the uterus
 Surface is pearly white before puberty, but after puberty it is corrugated and scarred from o
vulation every month

Oogenesis
 The timing is very different from spermatogenesis
 Female system produces a small number of gametes before birth and matures one at a time
between puberty and menopause
 Meiosis I comletes for a small number of ova each cycle, then goes on to meiosis II which on
ly completes if fertilisation occurs
 Oocyte remains at metaphase two until fertilisation. If fertilisation does not occur, the seco
nd meiotic division will not occur

Cells of ovary
 Follicular cells: flat epitheloid cells
 Granulosa cells: surrounded by follicular cells. Somatic cells of the sex cords. In multiple lay
ers depending on structure of follicle. Secrete sex steroids. FSH helps to aromatise androgen
s into estrogens
 Theca cells: follicle cells in tertiary stage. Produce androstenedione and androgens under in
fluence of LH
 Gametes: oocytes
 Germinal epithelium: simple cuboidal, but does not give rise to ova during puberty
 Medulla of ovary: highly vascular, no developing follicles
 Primordial follicle: ovum with single layer of granulosa cells. Ovum is still immature. Follicul
ar cells produce estrogens
 400 to 500 primordial follicles develop during reproductive years
 10 to 20 follicles develop in response to FSH every month, only one becomes dominant and
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releases its occyte
 Secondary follicle: antrum is formed. Inhibin prevents secretion of more FSH. Oocyte matur
ation inhibiting factor inhibits further completion of meiosis. Cuboidal cells secrete androge
ns
 Antrum: filled by liquor folliculi
 Graafian follicle: develops from secondary follicle, similar. Larger than secondary follicle. Co
vers about half of the ovary, 2.5cm in diameter. Oocyte is at one side of the follicle. Cumulu
s oophorus attaches oocyte and its zona pellucida to the graafian follicle
 99% of follicles which develop become atretic by autolysis and form wavy collagenous scar
which is taken up by macrophages

Cells of Corpus Luteum

 Granulosa lutein cells: large and pale staining. Secrete progesterone. Derived from granulos
a cells
 Theca lutein cells: secrete estrogens in smaller amounts
 Corpus albicans: dense CT scar replacing corpus luteum

Female Hormone System

 GnRH: 10 amino acid peptide released by hypothalamus, acts on anteror pituitary. Pulsatile
secretion, 20 to 25min every 1 to 2 hours. Essential for release of FSH and LH. Secreted by a
rcuate nuclei of hypothalamus
 FSH and LH: glycoprotyeins secreted by anterior pituitary in response to GnRH from the hyp
othalamus. Stimulate development of follicles in the ovary
 LH surge: causes ovulation to take place, formation of corpus luteum

Negative Feedback
 Estrogen in small amounts inhibits both FSH and LH strongly
 Progesterone presence increases inhibitory effects of estrogen
 Inhibin: secreted by granulosa cells. Inhibits FSH secretion

Ovarian Changes
 Stimulated by FSH and LH, totally dependent on the two hormones

Ovarian Cycle
 Primary oocytes in meiosis I are in clusters called egg nests. Surrounded by a single layer of
follicular cells
 Follicular phase: development of follicle. Period of follicular growth. Day 1 to 14. Stimulated
by FSH
 Ovulation: occurs in day 14. Stimulated by LH
 Luteal phase: period of corpus luteum activity. Day 14 to 28 of a normal 28 day cycle

Development of Antral and Vesicular Follicles

 Spindle cells: derived from ovary interstitium. Collect in several layers outside granulosa cell
s and give rise to theca cells
 Theca cells divide into two layers: theca interna and externa
 Theca interna: closest to the granulose cells. Develops epithelioid characteristics of granulo
sa cells and secretes estrogen and progesterone (steroid sex hormones)
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 Theca externa: outside the theca interna. Becomes capsule of developing follicle, develops i
nto highly vascular connective tissue capsule
 Granulosa cells: secrete follicular fluid rich in estrogens. Fluid forms the antrum region. Estr
ogens increase FSH receptors on granulose cells, making them more sensitive to FSH (positi
ve feedback). Estrogens and FSH together promote LH receptors on granulosa cells, allowin
g LH stimulation to occur which makes follicular secretion more rapid.
 Increasing estrogens from the follicle and pituitary LH act together to cause proliferation
of theca cells and increase their secretion.

Follicular Phase
 Early growth of primary follicles up to antral stage
 Stimulated by FSH
 Estrogen is secreted into follicles causing granulosa cells to up regulate FSH receptors. FSH a
nd estrogen then stimulate LH receptors, helping to stimulate LH secretion
 One follicle outgrows the rest and the other become atretic
 LH: acts on theca externa causing release of progesterone
 FSH: acts on granulosa and theca internal cells to cause estrogen secretion. Important to for
m large amounts of estrogens at one time
 Theca cells and granulosa cells take in LDLs for steroid hormone synthesis

Ovulation
 Occurs mid cycle, day 14 in 28 day cycle
 Initiation: within a few hours after LH surge. Theca externa releases Proteolytic enzymes fro
m lysosomes to degenerate the capsule and stigma, causing further swelling of the stigma.
Rapid growth of new blood vessels in follicle walls. Prostaglandins secreted into follicular ti
ssues to cause vasodilation. Plasma transudation into follicle occurs, increases swelling.
 Stigma: small area of ovary protrudes, in 30min fluid oozes out of it and 2min later it ruptur
es, releasing the secondary oocyte
 LH surge: necessary for final follicular development. Occurs 2 days before ovulation, secreti
on increases by 10x
 LH makes theca and granulosa cells secrete mainly progesterone

Luteal Phase
 Remaining granulosa cells and theca cells become lutein cells
 Enlarge in diameter, fill with lipid: luteinisation (means yellowing)
 Granulosa cells: form extensive SER and secrete more of progesterone, small amounts of es
trogens
 Grows to 1.5cm 7 to 8 days after ovulation then begins to involute if fertilisation has not occ
urred
 Corpus luteum: secretes large amounts of estrogens and progesterone
 All occurs in 12 days
 Lutein cells: secrete inhibin, inhibits FSH and LH secretion. Low blood levels of FSH and LH c
ause the corpus luteum to involute

Wall of the Uterus

 Perimetrium: epithelial cells and connective tissue. Is the outer layer
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 Myometrium: muscle layer. Smooth muscle in a thick layer. Is the middle layer
 Endometrium: layer of epithelial cells, highly vasculated connective tissue, numerous glands
. Is the inner layer. The functional layer is shed at menstruation and the basal layer remains
behind to regenerate

Uterine Cycle
 Proliferative phase: proliferaton of endometrium stimulated by estrogens
 Secretory phase: development of secretory changes in endometrium stimulated by progest
erone and estrogen
 Menstruation: desquamation of endometrium stimulated by death of corpus luteum

Proliferative Phase
 Stromal and epithelial cells proliferate and endometrium is re-epithelised from the basilar z
one which surivives and produces new epithelial cells. Takes 4 to 7 days after start of menst
ruation
 Endometrium increases in thickness and new blood vessels grow into it. Is 3 to 5cm thick at
the time of ovulation
 Glands especially those of cervix form thin stringy mucus which aligns along the length of th
e cervix, forming channels to guide sperm
 Arteries: spiral and normal become more numerous

Secretory Phase
 Occurs after ovulation
 Glands increase in coiling and excess secretory substance accumulates in the glandular cells
 Cellular changes: Lipid droplets in epithelial cells increase, cytoplasm of stromal cells increas
es, lipid and glycogen deposits increase in stromal cells
 Blood vessels become highly tortous and spiral
 Purpose: highly secretory endometrium with stored nutrients to provide appropriate conditi
ons for implantation of a fertilised ovum. Uterine milk provides nutrition for developing zyg
ote before it implants
 Cervical mucus also thickens and prevents entry of weaker sperm

Menstruation
 Occurs if oocyte is not fertilised
 Also called weeping of the uterus
 Caused mainly by reduction of estrogen and progesterone, especially progesterone
 Endometrium involutes
 Arteries become vasoplastic, secrete vasoconstrictive factors
 At first, blood seeps into vascular layer then hemorrhagic areas grow until all the superficial
layers have been desquamated
 Necrosis of endometrium occurs, decidua functonalis becomes ischemic and sloughs off
 Mass of desquamated endometrium, blood vessels, decaying substances stimulate uterine c
ontraction which expels the contents-menses
 40ml of blood and 35ml of serous fluid are lost every time
 Blood shed during menstruation does not clot due to fibrinolysin released from endometriu
m does not clot
 Clots: clinical evidence of clinical pathology
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 Large numbers of leukocytes (leukorrhea) are released along with necrotic material, uterus
is highly resistant to infection

Puberty
 Period when endocrine and gametogenic functions of gonads are fully developed
 Activity of cilia in fallopian tubes increases due to estrogens
 Thelarche: breast development occurs
 Pubarche: development of pubic and axillary hair
 Menarche: first menstrual period
 Estrogen: anabolic effects on female reproductive tract, thickening of vaginal mucosa, incre
ased fat deposition in breasts, hips, thighs, skin

Precocious Puberty

Delayed or absent Puberty

 Puberty is considered delayed if menarche has not occurred by age of 17 years
 Often associated with panhypopituitarism and dwarfism

Menopause
 Cessation of ovulation and menses
 Reproductive organs and breasts atrophy. Uterus and vagina become atrophic
 Skin blood vessels undergo dilation
 Ovaries become unresponsive to gonadotrophins, lose function and cause hot flushes
 Symptoms: anxiety, hot flushes, calcification of bones

Ovarian Hormones
 Two types: estrogens and progestins
 Most important estrogen: estradiol
 Most important progestin: progesterone
 Estrogens: mainly promote growth of specific cells in the body and female secondary sex ch
aracteristics
 Progestins: prepare uterus for pregnancy and breasts for lactation

Estrogen
 Is a steroid hormone, can be synthesized from cholesterol or acetyl-CoA
 Most powerful form is estradiol
 Three types: estradiol, estrone, estriol
 Estriol: most predominant circulating estrogen during pregnancy
 Estrone: most predominant circulating estrogen after menopause
 Estradiol: most predominant circulating estrogen during reproductive years
 Made by ovaries, adrenal glands (breasts, liver and fat cells to a smaller extent) after menop
ause using DHEA and androstenedione
 Affects memory mood, body structure
 Protects against heart disease: causes a reduction of plasma LDLs, causes vasodilation, incre
ases plasma HDLs

Chemistry of Estrogens
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 During pregnancy, estrogen is secreted by the placenta
 Potency of estradiol is 12 times that of estrone and 80 times that of estriol
 Estradiol is considered the major estrogen

Synthesis of Estrogens
 Synthesized from cholesterol in the ovaries
 Aromatase in the granulosa cells converts androgens into estrogens
 Theca cells produce androgens which diffuse out and into the granulose cells because theca
cells cannot produce estrogens

Transportation and Degradation of Estrogens

 Mainly bound to albumin and estrogen-binding globulin in blood
 Liver also converts estradiol and estrone to impotent estriol
 Diminished liver function can increase the activity of estrogens in the body

Function of Estrogens
 Primary: growth of reproductive organs
 Vaginal epithelium changes from cuboidal to stratified squamous
 Contractility of uterus increases
 Stromal tissue, ducts develop in breasts, fat deposition in breasts increases
 Epithelium of fallopian tubes changes from cuboidal to ciliated columnar
 Maintain heart health: dilates blood vessels, increases HDL, lowers Lp(a) reducing atheroscl
erosis
 Bone: slows bone loss, maintains balance between osteoclasts and osteoblasts, inhibits ost
eoclastic activity, causes uniting of epiphyses with the shaft of long bones (more potent tha
t testosterone-females stop growing earlier than males)
 Cause slight increase in total body protein
 Metabolic rate increases
 Deposition of fat in subcutaneous tissue increases
 Deposition of fat in thighs and buttocks increases
 Skin elasticity, thickness and moisture are maintained. Skin also becomes more vasculated,
making it warmer
 Important for adequate vaginal secretion
 Increases collagen production
 Increases dopamine, serotonin, norepinephrine in the brain: make women happy
 Important for critical learning, memory, attention span
 Protects neurons from glutamate toxicity, free radical damage
 Prevents dementia (increases acetylcholine) and prevents Alzheimer's disease
 Cause sodium and water retention by kidney tubules: oestrogen has slight mineralocorticoi
d activity (women retain a lot of water)
 Decrease libido

Common signs of Estrogen Deficiency

 Mental fogginess
 Depression
 Minor anxiety
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 Night sweats
 Hot flushes
 Reduced stamina
 Dry eyes, skin, vagina
 Symptoms of menopause
 Headaches, migraines

Symptoms of excess Estrogen

 Breast/nipple tenderness
 Large breasts

Progesterone
 Made by ovaries, adrenal glands
 Precursor of steroid hormones, stress hormones
 Balances effect of estrogens
 Enhances mood
 Activity is increased along with estrogen
 Beneficial for CVS health
 Causes secretory changes in uterus and fallopian tubes
 Prepares uterus for pregnancy
 Reduces contractility of uterus, helping implantation
 Prevents heavy periods and fibroids
 Prevents PMS and anxiety
 Prevents androgen excess symptoms- can be used to treat prostate cancer

Functions of Progesterone
 Helps in differentiation of breast tissue, but does not stimulate alveoli to secrete milk (done
by prolactin)
 Brain: calms and improves sleep, protects nervous system, limits brain damage, protects an
d rebuild blood brain barrier, cell death is reduced
 Stimulates new bone growth
 Facilitates thyroid function
 Prevents breast cancer
 Inhibits more than one follicle maturing
 Burns fat
 Natural diuretic
 Increases libido
 Upregulates estrogen receptors

Symptoms of decreased levels of Progesterone

 Absence/infrequent periods
 PMS
 Painful breasts
 Lumps in breasts
 Fibroids
 Endometriosis
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Symptoms of Progesterone excess

 Drowsiness
 Dizzines
 Sense of physical instability
 Feeling of drunkenness

Testosterone in Women
 Produced by ovaries, adrenal glands and fat tissue
 Increase libido
 Reduces fat and increases muscle mass

Female Sexual Act

 Sexual thoughts can lead to female sexual desire based on psychological and physiological d
esire
 Sexual desire increases in proportion to the level of sex hormones secreted
 Desire is high during time of ovulation and coincides with high estrogen during that period
 Sexual sensory signals are transmitted to the sacral nerves to the spinal cord then to the cer
ebrum
 The glans clitoris is especially sensitive for initiating sexual sensations

Female Erection and Lubrication

 Near the opening of the vagina/introitus is a small erectile tissue controlled by parasympath
etic innervation
 Arteries of erectile tissue dilate, increasing blood flow
 Introitus tightens around penis, aiding the male greatly in attaining of sufficient sexual stim
ulation for ejaculation to occur
 Bartholin/vestibular glands below beneath labia minora secrete mucus as a lubricant, impo
rtant for establishing a massaging sensation which will evoke appropriate reflexes that culm
inate in both male and female climaxes

Orgasm
 Perineal muscles contract rhythmically
 Uterine and fallopian motility increases, helping to transport sperm upward towards the ov
um
 Cervix can dilate for up to 30min for easy transport for sperm
 Cerebrum causes intense muscle tension throughout the body but is then followed by relax
ed peacefulness called resolution
 Human female is known to be more fertile when inseminated by normal sexual intercourse
rather than artificial methods

FERTILISATION

Terms
 Conception: union of ova and sperm
 Embryo: developing cluster of cells after fertilisation
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 Fetus: unborn baby
 Umbilical cord:
 Placenta:
 Prenatal: from conception to birth
 Ectopic pregnancy: growth of a zygote in another part of the body
 Identical twins: same zygote, divided by mitosis, same ovum and sperm, one placenta
 Fraternal twins: two different ova, two placenta
Takes place in the uterine tube
Sperm are viable for five days in the female tract
Sperm must first undergo capacitation

Fertile Period of each Sexual Cycle

 Ovum is viable for 24h after ovulation
 Sperm must be available soon after ovulation for fertilisation to take place
 Intercourse must happen four to five days before ovulation and a few hours after
 Female fertility during each month is four to five days
 Signs of ovulation: slight increase in basal body temperature due to progesterone, cervical
mucus becomes profuse (spinbarrkeit), cervical mucus shows fern like pattern under the mi
croscope, LH surge which is detected using blood, levels of progesterone in urine and blood
increase
 Female fertility period during each month is 4 to 5 days

Zona Pellucida
 Layer of ECM and glycoproteins around the oocyte, zygote and blastocyst

Capacitation
 Important process before fertilisation can take place, multiple changes take place. Requires
1 to 10 hours
 Uterus and fallopian tubes wash the inhibitory factors that suppress sperm activity
 Sperm deposited in the vagina will move away from cholesterol vesicles, losing cholesterol
deposited in the male genital ducts (to toughen the sperm cell membrane to prevent releas
e of enzymes) which makes the membrane of the acrosome weaker
 Membrane becomes more permeable to calcium ions, makes it easier for acrosome to relea
se enzymes to penetrate granulosa cells and zona pellucida
 Calcium ions enter and change activity of the flagellum/tail

Acrosome Reaction
 Acrosome: hyaluronidase which depolymerises hyaluronic acid holding together granulosa
cells.
 Proteases digest proteins in the structural elements of the tissue cells
 Hyaluronidase is important in digesting a pathway for sperm between the granulosa cells

Fertilisation
 Anterior membrane binds to receptor proteins of zona pellucida. Acrosome then dissolves a
nd enzymes are released
 Within minutes, the enzymes open a pathway for sperm head to penetrate through the zon
a pellucida
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 Once the sperm enters the ovum, meiosis II is completed forming the female pronucleus. T
he second polar body is formed
 The sperm nucleus forms the male pronucleus
 In 30min, the sperm nucleus and ovum nucleus fuse
 A few minutes after one sperm enters, calcium ions diffuse into ovum, release of cortical gr
anules to prevent more sperm from entering. Substances in granules penetrate zona pelluci
da and prevent other sperm from entering

Entry of Ovum into Fallopian tubes

 98% of all ova enter successfully into the ostium of the oviduct
 Inner surface of fimbriae has ciliated epithelium, the cilia are activated by estrogens from t
he ovaries
 An oocyte released from one ovary can enter the oviduct on the opposite side successfully

Transport of fertilised Ovum

 Takes 3 to 5 days until it reaches the uterus
 Aided by feeble fluid current and weak contractions
 Rapidly increasing progesterone promotes increasing progesterone receptors on fallopian t
ubes, relaxing the tubes and allowing the blastocyst entry into the uterus
 Delayed transport allows several cell divisions to occur, resulting in formation of the blastoc
yst which has about 100 cells
 Zona pellucida is shed at around day 6 to 7 after fertilisation: zona hatching

Implantation
 Blastocyst remains in the cavity for 1 to 3 days before implantation, obtains nutrients from
uterine milk
 Implantation occurs when trophoblast cells develop over blastocyst and give out finger like
projections which erode endometrium
 Trophobalst cells secrete Proteolytic enzymes that digest and liquefy surrounding cells of th
e endometrium
 Paracrines secreted: increase number of capillaries, allowing more oxygen and nutrients int
o the area

Amniotic Fluid
 Fluid in which fetus floats
 Normal volume is 500ml to 1L
 Water is replaced every 3h
 Electrolytes, such as sodium and potassium, are replaced every 15h
 A large portion of the fluid is derived from renal excretion by the fetus

Chorion
 Embryonic tissue which becomes the placenta
 It is the embryonic-derived portion of the placenta
 Chorionic villi: finger-like structures of the placenta composed of embryonic trophoblasts
 Chorionic villi invade endometrium
 Maternal and fetal blood do not mix, are separated by fetal trophoblasts and endothelial
cells
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Placental Functions
 Attach fetus to uterine wall
 Provide nutrition for fetus
 Allow fetus to transport waste products to mother

Anatomy of the Placenta

 About 21 days after fertilisation, embryos heart starts beating
 Blood sinuses supplied with maternal blood develop outside trophoblastic cords
 Trophoblasts send more projections which become placental villi into which fetal capillaries
grow
 Villi: carry fetal blood and are surrounded by sinuses containing maternal blood
 Nutrients and other substances pass through the placental membrane mainly by diffusion,
maternal and fetal blood never mix with each other
 Normal position is anterior superior wall of endometrium

Diffusion of Oxygen
 Passes into fetal blood by simple diffusion
Towards term:
 Mean partial pressure of oxygen in blood sinuses is 50mm Hg
 Mean partial pressure of oxygen in umbilical vein is 30mm Hg
 Mean partial pressure gradient is 20mm Hg
 Hemoglobin of the fetus is mainly fetal hemoglobin
 Fetal hemoglobin: has a low Km, so at low oxygen partial pressure it is saturated with oxyge
n. Fetal blood has haemoglobin concentration that is 50% higher than mother
 Bohr effect works in opposite directions in fetus and mother: called double Bohr effect

Diffusion of Foodstuffs
 Glucose is transported across placental membrane by carrier molecules on trophoblastic c
ells
 Fatty acids also diffuse to fetus, but at a slower rate than glucose
 Towards term, the fetus uses as much glucose as the mother
 Ketone bodies, sodium, potassium, chloride diffuse to the fetus relatively easily

Excretion of Waste
 CO2 diffuses from fetal blood to maternal blood and is then excreted along with other waste
products. These include non protein substances such as urea, uric acid, creatinine
 Diffusion of urea is easy, but that of creatinine is hard. Creatinine diffuses against its concen
tration gradient
 Maternal and fetal blood do not mix
 Other waste products pass from fetus to mother and are then excreted by the mother’s kid
neys

Embryonic Membranes
 Chorion: protects embryo from shock, villi project into endometrium and obtain nutrients f
or embryo
 Amnion: absorbs shock, forms amniotic fluid which supports embryo
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 Umbilical vessels: umbilical vein carries oxygenated blood to the fetal heart, umbilical arteri
es carry blood from the fetus to the placenta. There are two umbilical arteries and one umbi
lical vein n the umbilical cord
 Allantois: outgrowth of developing GIT

Hormones of Pregnancy
 hCG
 Estrogens
 Progesterone
 Placental lactogen
 Relaxin: causes symphysis pubis joint to loosen

hCGu
 Is a glycoprotein with weight of 39000 Da
 Prevents degeneration of corpus luteum at the end of the monthly cycle, its primary functi
on
 Causes corpus luteum to secreted large amounts of estrogens and progesterone
 If secretion fails, there can be instantaneous abortion. Abortion can also occur if corpus lute
um is removed before 7 weeks
 Causes corpus luteum to grow to twice its size then involutes in the 13th-17th week of gestat
ion
 Plasma levels to indicate pregnancy can be detected 6 days after fertilisation
 Urine levels which give positive pregnancy test result are seen two weeks after fertilisation

Estrogen
 Causes enlargement of the mother’s uterus, breasts, external genitalia
 Causes growth of duct system in breasts

Progesterone
 Causes decidual cells to develop in the endometrium
 Increases secretions of uterus and fallopian tubes to nourish the morula
 Decreases contractility of uterus so that embryo is not pushed out before implantation
 Helps estrogens prepare mother's breasts for lactation

Human chorionic Somatommamotropin

 Weight of 22 000 Da
 Begins to be secreted during the 5th week of pregnancy, secretion increases progressively
 Possible effects: similar action to growth hormone, breast development, decreased insulin s
ensitivity of mother, decreased glucose utilisation by mother

Relaxin
 Secreted by corpus luteum and placenta
 Secretion increased by stimulating effect of hCG
 48 AA peptide
 Causes relaxation of pelvic ligaments
 Softens cervix for birth at the time of delivery
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Other Hormones
 Pituitary: FSH and LH remain suppressed,50% increase in secretion of other hormones
 Adrenal glands: glucocorticoids help mobilise amino acids for synthesis of tissues in fetus an
d can cause gestational diabetes, 2 fold increase in aldosterone can induce hypertension of
pregnancy
 Thyroid gland: thyroid enlarges by 50%, increased thyroxine (T4)
 Parathyroid glands: enlarge if mother is on calcium deficient diet to compensate for maintai
ning normal calcium for fetus to ossify bones

How to Determine Pregnancy

1. If menstrual cycle stops
Progesterone continues to be produced
2. Early physical signs
Morning sickness, frequent urination
Frequent urination, enlarged breasts, darkening of nipples
3. Early pregnancy test
Checks for presence of hCG in urine
4. Physician's diagnosis
Can be detected as early as one week after missed period
5. RIA test: To detect hCG 5 days prior to missed period

Response of mother's body to pregnancy

 Body water metabolism: weight increases, retention of water, increase in fat deposition
 Additional water due to expansion of maternal blood volume
 Expanded adipose tissue
 Heart is displaced upwards and to the left, laterally rotated
 Cardiac output increases, looks like the heart has increased in size
 Stroke volume of heart increases
 Cardiac output is dependent on position
 Ribs flare out, transverse diameter of thorax increases
 Level of diaphragm increases by 4cm
 Feeling of Dyspnea caused by Progesterone
 Chronic mild respiratory alkalosis
 Chronic mild hyperventilation
 Increased CO2 gradient between mother and fetus
 Oxygen consumption increases by 20 to 40%
 RBC volume increases by 40%
 Iron requirement increases greatly in third trimester
 Supplementation of iron, 30mg daily, is recommended for second half of pregnancy
 Kidneys enlarge, dilation of renal pelvis, seen more on the right
 Ureters dilate
 GFR increases
 Glucose excretion increases, no increase in proteinuria
 Blunted taste
 Decreased gastric motility, constipation common
 Decreased gall bladder secretion, gallstones can form
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 Insulin resistance occurs after first trimester, diabetes of pregnancy seen

Gestation
 Human gestation lasts about 40 to 42 weeks
 First trimester: lasts 13 weeks, includes fertilisation, includes organ generation
 Second trimester: 14th to 27th week, heart develops further and beats faster, fetal movem
ent begins, fetus begins to look human
 Third trimester: 28th week to birth, fetus grows rapidly, final tissue differentiation occurs, h
air may begin to grow

Parturition
 Stage 1: lasts about 12 hours. Contractions begin, cervix dilates and flattens, amnion ruptur
es, 1l of fluid leaks out. Fetal stress has to occur, fetus releases ACTH, stimulates cortisol rel
ease from anterior pituitary of mother. Cortisol decreases estrogen and progesterone levels
, increase in prostaglandins. Uterine contractility increases, cervix stretches. Oxytocin cause
s extensive contraction
 Stage 2: 20min to 1 hour. Abdominal muscles used to push fetus
 Stage 3: 10 to 15min. Uterus contracts, loosens placental membranes, expelling placenta an
d fetus. Uterus begins to regenerate endometrium

Mammary Glands
 Prolactin: stimulates milk production by secretory alveoli
 Oxytocin: stimulates milk let down reflex, myoepithelial cells in the breast contract in respo
nse to oxytocin

Chromosomal Sex
 Sex of the fetus is determined by 2 chromosomes called sex chromosomes, X and Y
 Y chromosome is necessary to develop testes
 SRY gene on short arm of Y chromosome determines development of testes
 Sex is determined by the sperm
 SRY gene is the one that causes testes to develop

Development of Gonads
 Gonads develop into cortex and medulla
 At 7 to 8 weeks, sex differentiation of the gonads occurs, before that, male and female fetus
es are identical
 Males: cortex regresses, Leydig and Sertoli cells appear and secrete testosterone and anti-
Müllerian hormone. Wolffian ducts develop into epididymis and vas deferens
 Female: medulla regresses, cortex develops. Müllerian ducts develop into uterus and uterin
e tubes. Wolffian ducts regress

Infertility

Male Infertility

Causes
 Hormonal
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 Testicular
 Epididymis
 Coital disorders
 Abnormal sperm
 Seminal Vesicles
 Delayed puberty
 LH and FSH deficiency
 Congenital disease
 Hypogonadism: associated with abnormal sense of smell
 Destruction of pituitary and hypothalamic glands due to trauma, cancer, surgery, irradiation
 Pituitary adenoma

Hormonal Causes
 Primary testicular failure: low testosterone leading to azoospermia, oligospermia
 Absence of LH receptors: no testosterone secreted
 Germinal cell failure
 Congenital hypogonadism
 Kallman’s syndrome
 Hyperprolactinemia due to pituitary adenoma or side effects of some drugs

Accessory Glands
 Obstruction of seminal vesicles, eg by Chlamydia infection
 Infection of accessory organs
 Vasectomy

Abnormal Semen
 Necrospermia
 High viscosity of semen
 Periaxonemal abnormalities
 Pus in semen
 Abnormal prostaglandins
 Enzyme deficiency
 Zinc deficiency
 Bicarbonate deficiency
 Membrane malformations
 Disorders of calcium metabolism
 Decreased ATP

Female Infertiliy

Causes
 Cervical: laser conisation-low mucus secretion, anti-sperm antibodies, closed cervix
 Vaginal: imperforate hymen, infection, extremely narrow vagina, painful infections in the v
agina
 Uterus: congenital, fibroids, endometrial polyps, adenomyosis, fibrosis, fimbrial end destru
ction, Asherman Syndrome
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 Fallopian tubes: adhesions, fimbrial end destruction, short tubes, tubal tumours
 Ovaries: polycystic ovarian disease (20% of women have this), endocrine disorders, ovaria
n failure, hypothalamic or pituitary failure
 Chronic pelvic infections
 Congenital: undivided uterus, rudimentary horn shaped uterus, Asherman syndrome (uterin
e wall adhesion), adenomyosis

Stress and Infertiliy

 Stress is common cause of infertility
 Stress and worries cause changes in internal hormones, can also affect hypothalamic and ov
arian function
 Removal of the cause of stress often treats this infertility

Chromosomal Abnormalities
 Turner Syndrome: individuals have one X only. 96-98% do not survive to birth. No menstru
ation,no breast development, narrow hips, broad shoulders and neck, short stature, webbin
g of neck, no ovaries, edema
 Down Syndrome/Trisomy: more prevalent in male children. Can be chromosome 14/21 tra
nslocation or chromosome 21 trisomy due to nondisjunction. Individuals have short broad h
ands, rough skin, stubby fingers, impotency in males, mental retardation, small round face,
protruding tongue, short lifespan. Best known example of aneuploidy is trisomy 21
 Klinefelter Syndrome: people with at least two X chromosomes and one Y chromosome due
to nondisjunction of pair 23. Male appearance, develop female like breasts, small testes, sp
arse body hair, long limbs, low mental ability, sterility
 Trisomy X: individuals have three X chromosomes, called metafemales. Symptoms are varia
ble and worsen with each additional X chromosome; include mental retardation, menstrual
irregularity, sterility. Is aneuploidy
 Trisomy Y: individuals have three Y chromosomes, are agressive and often linked to criminal
cases. Is aneuploidy