Review of Endocrine; Endocrine Control of Growth

Two types of hormones: Hydrophilic & and Lipophilic

Hydrophilic
Protein/peptides and
Catecholamines
Synthesis occurs as a
prehormones
Stored in secretory
vesicles and released
by exocytosis
Receptor are on the
membrane and will
produce a 2nd
messenger or activate
receptor kinase

Lipophilic
Thyroid hormones, steroids
and vitamin D
Steroids derived from
cholesterol
Steroids not stored at
all; stored as
cholesterol esters
They will be bound to
plasma proteins in blood
Action generally
intracellular

Negative feedback loop

- Almost all systems use this system
Positive feedback loop
- Oxytocin during labor
Feed-Forward
- Increase hormone in response to a particular stimulus
Diurnal Rhythms
- Concentration increase occurs at the same time each day
Posterior Pituitary
- Produces ADH and oxytocin
- Produced by neurons in the hypothalamus
Anterior Pituitary
- Neurons in the hypothalamus that project blood vessels in the
base of the brain and release peptides into a portal system

Control of Body Growth

-

In the In Utero and Neonatal stages, there is no hormone control

The last three stages (Prepubertal, pubertal growth spurt and
cessation of growth) involve growth hormones and sex steroids
- Insulin and thyroid hormones are also involved, but they
are permissive

Permissive: You need a little of that hormone around for other

hormones to produce their effects
Growth Hormone (Somatotropin)
Produced by the anterior pituitary
Growth hormone is species specific
- If you take a growth hormone from a different animal and inject
in humans, then it wont work; it has to be human growth
hormone
It has growth-promoting actions (Indirectly through IGF-1)
- In soft tissues, its an anabolic hormone
- In bones, it increases osteoblastic activity
- It increases activity of new collagen synthesis
- In long bones, it increases cell division in epiphyseal
plates
It has metabolic actions (directly)
- It increases lipolysis in adipose
- It acts as an insulin antagonist
- It tends to increase blood glucose levels
- It uses the JAK-STAT Pathway
- The receptor is a tyrosine kinase-like receptor, but the
receptor doesnt have kinase activities. The receptor
dimerizes and recruits JAK (kinase). One of the major effector
proteins that JAK phosphorylates is STAT
Excess of GH can produce diabetes mellitus
Indirect Actions of GH
- GH stimulates the release of IGF-1 to the blood in the liver, where
it travels to the bone to stimulate growth

GH stimulates the local increase in IGF-1 and IG-2 to promote

tissue growth

1) Somatotropin(GH): stimulate body growth

2) Somatomedin (IGF-1): mediates action of GH
3) Somatostatin: inhibits GH secretion
IGF-1 works through a tyrosine-kinase receptor, where the receptor
autophosphorylates itself to produce a signaling cascade
Control of GH secretion: Negative Feedback
Growth Hormone Releasing Hormone (GHRH) stimulates GH secretion
and SS inhibits it
- If portal system is disrupted then GH goes down
IGF-1 also feeds back to the anterior pituitary where it inhibits GH
secretion and also feeds back to the hypothalamus to stimulate
release of SS (Long Loop)
GH can also inhibit its own secretion by stimulating release of SS in
hypothalamus (Short Loop)
GH secretion occurs episodic (in episodes) and diurnal
- Most is secreted in sleep
- Usually a challenge test is done to measure GH levels
Glucose inhibits growth hormone and some amino acids stimulate GH
secretion
Other Hormones that Control Body Growth
- Permissive (insulin for soft tissue, thyroid hormone for bone)
- Sex steroids (testosterone in males, estradiol in females)
- Go up in puberty
- Stimulate growth (1-2 years)
- With prolonged exposure (>3 yrs), they cause closure of
epiphyses
-

High excess of cortisol can inhibit body growth

- Contributes to slow growth in stressed children

1. An increase in which of the following would directly stimulate

bone formation?
a. IGF-1
b. PTH
c. 1,25-(OH)2-vitamin D
d. Interleukins
2. This hormone is synthesized as a preprohormone in the rough
endoplasmic reticulum.
a. PTH
b. 1,25-(OH)2-vitamin D
c. Both
d. Neither
3. Which of the following control mechanisms would maintain
constant hormone levels?
a. A negative feedback loop
b. A positive feedback loop
c. A neuroendocrine reflex
d. An endocrine rhythm
e. All of the above
4. A 18 year old male patient comes in to your office with his
parents because he has stopped growing. He is taller than most
of his friends who are all continuing to grow. The family lives on
a farm and butcher their own meat. The patient is an excellent
athlete and is hoping for a scholarship to college as a football
lineman. Which of the following is the most likely explanation for
the unusual growth pattern in this boy?
a. Ingestion of GH from cow pituitaries mixed in with meat
when cows were butchered
b. Hyperthyroidism
c. Patient has been taking GH preparations to enhance
muscle mass
d. Patient has been taking androgens to enhance muscle
mass

5. A 7-year old boy is referred to you by his pediatrician because he

is abnormally short for his age. Which of the following tests
would be useful in determining whether he is deficient in GH
secretion?
a. Measuring GH in a sample taken during his visit
b. Measuring GH in response to a low dose of IGF-1
c. Measuring GH in response to a low dose of insulin
d. Measuring GH in response to ingestion of a candy bar

Male Reproduction
Spermatogenesis
- Process by which undifferentiated cells (Spermatogonia (2x))
differentiate it into spermatozoa (1x)
- Spermatogonia undergo mitotic divisions to produce
spermatocytes (daughter cells).
- The spermatocytes then undergo meiotic division to produce
spermatids
- The spermatids then undergo extensive packaging to
produce spermatozoa
1) One of the daughter cells stays behind and the other one goes
on to differentiate
- The one that stays behind maintains the germ cell line
2) Not all cells make it successfully
3) This process is temperature sensitive
4) Cells undergo anatomical movement as they develop
Sertoli cells are also important
1) Provide nourishment for developing sperm (allows for rapid
nutrient exchange)
2) Maintains blood-testes barrier
- Prevents large molecules getting from interstitial fluid into
seminiferous tubule; this prevents the production of
antibodies against the sperm
3) Secrete fluid and substances into lumen
4) Mediate the actions of hormones on spermatogenesis
Primary hormone produced is testosterone and is made by the Leydig
cells
Hormone Production
1st Step
- Conversion of Cholesterol to Pregnenolone
- Rate limiting (whats limiting is the transport of cholesterol into
the mitochondria): StAR transport rate limiting
Testosterone can be converted to:

Dihydrotestosterone (DHT) by 5-reductase

- Much potent androgen than testosterone
Estradiol by aromatase
- One of the female sex steroids

Transport of Testosterone
1) Sex- steroid binding globulin (binds both testosterone and
estradiol)
2) Albumin (accounts for 40%)
3) Only 2% in the free form (active form)
Actions of Testosterone
1) Important in the differentiation of male reproductive tract,
maturation at puberty and maintenance in adult
2) Secondary sexual characteristics (deep voice, libido, increase in
muscle mass)
3) Other (aggression, pubertal growth spurt)
Mechanism of Action
Receptors for testosterone are in the nucleus
Testosterone is a lipophilic molecule, so it can diffuse across the
plasma membrane and diffuse into the nucleus. It will bind to androgen
receptor and dimerize. The dimer will then bind to a specific sequence
of DNA [Androgen Response Element (ARE)]
If testosterone is converted to estradiol, then it will bind to estrogen
receptor

1) Luteinizing hormone (LH)

- Controls hormone secretion
- Receptors are on Leydig cells
- Controlled by testosterone
2) Follicle stimulating hormone (FSH)
- Responsible for spermatogenesis
- Receptors are on Sertoli cells

Regulation of Testicular Function

PKA

- Controlled by testosterone & INHIBIN

Both are G-coupled receptors
Both are needed for normal spermatogenesis
High levels of testosterone are needed for spermatogenesis
If LH levels are low, then you are not going to maintain high levels of
testosterone for spermatogenesis
Both are made in the Anterior pituitary and are controlled by GnRH
(released from the hypothalamus).
Testosterone negatively feedbacks to the hypothalamus to decrease
GnRH, decreasing LH and FSH
FSH is also controlled by INHIBIN
- INHIBIN only acts on the anterior pituitary and it only affects
FSH
- Produced by Sertoli cells
Activin production acts on a paracrine factor to stimulate FSH
locally
Inhibin acts as an antagonist by binding to one of the activins
receptors

Characteristics of GnRH Neurons

Dont
have to
know this

1) They originate in olfactory bulb and migrate into brain during

development
2) They are secreted in an episodic pattern
- This episodic pattern is essential for secretion of both LH and
FSH
- Have to given every two hours or so if they need it.
3) Do not contain steroid receptors
- Other neurons must mediate feedback actions of steroids
- Kisspeptin stimulates GnRH

6. Which of the following is not true of GnRH?

a. It is carried from the brain to the anterior pituitary by
portal vessels
b. Its secretion is inhibited by inhibin secreted from the testes
c. GnRH neurons migrate into the brain during fetal
development
d. It must be secreted episodically for normal reproductive
function
7. Receptors for this hormone are found on Sertoli cells in the
testes:
a. LH
b. FSH
c. Both
d. Neither
1. Which of the following is true for StAR (Steroidogenic Acute
Regulatory) protein?
a. It is critical for binding of ribosomes to the rough
endoplasmic reticulum
b. It transports cholesterol into the mitochondria
c. It is responsible for sequestering cholesterol esters in lipid
droplets
d. It is necessary for the uptake of cholesterol from circulating
lipoproteins
e. None of the above
2. Which of the following is true of dihydrotestosterone (DHT)?
a. It is the primary androgen synthesized in the testes
b. It is converted to estradiol by the enzyme aromatase

c. It mediates all the actions of testosterone

d. It is a more potent androgen than testosterone
e. Measurement of DHT in urine provides a useful index of
testosterone production
3. Which of the following would not affect spermatogenesis?
a. Failure of the testes to descend into the scrotum
b. Breakdown of the blood-testes barrier
c. Absence of LH receptors on Sertoli cells
d. A deficiency in one of the enzymes needed for testosterone
synthesis
e. Failure of GnRH neurons to migrate from the olfactory
placode during development

4. What effect does increased inhibin have on FSH secretion in

men?
a. Increases
b. Decreases
c. No effect
8. Which of the following is true of testosterone?
a. It is the most potent androgen found in the body
b. It is synthesized in Sertoli cells
c. Stimulation of Protein Kinase A (PKA) will increase
testosterone secretion
d. In the circulation, it is bound primarily to thyroid binding
globulin

Female Reproduction I

1. Be able to make ova & ensure they are fertilized

Estradiol
- Produced in the follicle, which is composed of the
ovum, granulosa cells and theca cells
2. Maintain fetus for 9 months
Progesterone
- Produced by corpus Luteum (CL)

They function sequentially. To ensure that they function sequentially,

they are connected by a process called ovulation and luteinization
Menstrual cycle
1. Follicular phase (first 2 weeks)
- To get a mature ovum that is ready for fertilization. Then
it undergoes Ovulation & luteinization, leading to the next
phase
2. Luteal Phase (2 weeks)
- If pregnancy doesnt occur then the corpus luteum
regresses (luteolysis), which leads to menstruation and
process restarts
Follicle Stimulating Hormone (FSH)
- Stimulates follicular growth
- Needed for estradiol secretion
Luteinizing Hormone (LH)
- Primary regulator of steroid secretion
- Responsible for ovulation & luteinization

Oogenesis and follicular maturation

-

Folliculog
e-nesis

Primary germ cells go through mitotic divisions. They then start

going through meiosis and surrounded by granule cells, which
then everything stops. These are known as primordial follicles
- This only occur in utero
A small of those follicle cells leave that pool and start to grow.
They get a layer of theca cells and granulosa cells start to
proliferate.
- Once the follicle leaves that pool, it cant stop and rest
anymore. It is either going to be ovulated or stop developing
and die (Atresia)
- 99.99% are going to die
This process
ovulation
- Ovum
1.
2.

of follicular development is independent of

has to get out (ovulation)
Fluid movement into antrum and wall ruptures
Increase in enzymes that digest follicle wall

During ovulation, meiosis is resumed

- 1st meiotic division occurs at the time of ovulation (you get an
unequal distribution of cytoplasm)
- Ovum and polar body (which degenerates)
- 2nd meiotic division only occurs if fertilization occurs

Folliculogenesis is genetically controlled (no hormonal)

Follicular development is stimulated by FSH (& estradiol)
- But a fall in FSH is going to promote atresia
LH surge induces ovulation, causes luteinization and
triggers meiosis

Steroid Synthesis in Follicle

Estrogens
- Produce female characteristics
- Estrone (E1)
- Estradiol (E2)
- Estriol (E3)

Cholesterol is converted to pregnenolone in the mitochondria by side

chain cleavage, catalyzed by Cholesterol-side chain cleavage
- Testosterone is eventually produced
- This occurs in the Theca cells
- LH receptors are on theca cells and when it is bound,
there is an increase in StAR activity, eventually producing
more testosterone
In the final step, Testosterone is converted to Estradiol, Catalyzed by
Aromatase
- This occurs in the Granulosa cells
- FSH receptors are on the granulosa cells and it is
bound, there is an increase in aromatase activity
Needing both LH and FSH in known as two-cell, two-gonadotropin
hypothesis for E2 synthesis
LH and FSH are important in the early follicular phase. Towards the
end, LH becomes the primary regulator.
- LH receptors start to be part of the granulosa cells in the later
portion of the follicular phase and able to activate aromatase.
They are also important for ovulation
As follicle grows, you get an increase of granulosa cells. Therefore,
amount of E2 increases
Steroid Synthesis in Corpus Luteum
It produces primary progesterone, but it can also make some
estradiol
-

Cholesterol gets into the mitochondria and converted to

pregnenolone
Pregnenolone then gets converted to progesterone

Regulated by LH
- Induces StAR formation
- Permissive regulator
Luteolysis
If woman is not pregnant, then this occurs

- Primary luteotropin (increases life of CL) is LH

- Primary luteolysin (kills CL) is E2 from CL
Other luteotropin is hCG from placenta
Other luteolysin is PGF2a
Luteolysis: both low LH and high E2
Transport of steroids in blood
1.
2.
3.
4.

Estradiol: sex-steroid binding globulin

Progesterone: Corticosteroid binding globulin
Albumin binds both
About 1-3% are free

Actions of Ovarian Steroids

Uterus has:
- Myometrium: outer smooth muscle important for labor
- Endometrium: inner lining important for preparing for fertilization
- Cervix: connects to vagina
Estradiol
- Promote fertilization
- Promotes growth of breasts
- Increases bone growth and density
Progesterone
- Promote pregnancy
- Promote production of alveoli (where milk is produced and
secreted)
- Produces an increase in basal body temperature
At puberty, development of pubic, axillary hair & development of libido
is primarily due to Adrenal DHEA
Mechanism of Action

1. E2 diffuses into nucleus and binds to receptors

2. Receptor dimerizes, which binds to ERE
3. Induce synthesis of mRNA and eventually a protein is produced
Two types of estrogen receptors
- ER & ER
Tissues express different receptors and produce different responses
In terms progesterone, they follow similar mechanism
- In most tissues, progesterone receptors are induced by
estradiol
- If tissues have low estradiol, then they will have low
progesterone receptors and wont be responsive to progesterone

9. Which of the following is true of the process responsible for

creation of new follicles?
a. Elevated FSH concentrations initiate the process
b. This process only occurs during in utero development of
the ovary
c. This process ends when the ovum undergoes its second
meiotic division
d. A new follicle is formed once the ovum is surrounded by
theca and granulose cells
10.
This hormone is needed for estradiol synthesis and
secretion by the ovarion follicle:
a. LH
b. FSH
c. Both
d. Neither

11.
This hormone stimulates progesterone secretion from the
corpus luteum
a. LH
b. FSH
c. Both
d. Neither

5. Which of the following is true for meiosis of ova?

a. It is stimulated by elevated FSH concentrations at the
beginning of the follicular phase
b. The first steps begin when the primordial follicle leaves the
resting pool
c. Meiotic division is an early sign that a follicle is undergoing
atresia
d. It results in four cells with half the normal chromosomes,
all of which can be fertilized
e. The second meiotic division only occurs if an ovum is
fertilized
6. Which hormone is responsible for growth of pubic hair in pubertal
girls?
a. Estradiol
b. Progesterone
c. Both
d. Neither (its due to adrenal DHEA)
7. Which hormone is synthesized and released by cells of the
corpus luteum?
a. Estradiol
b. Progesterone
c. Both
d. Neither
8. An increase in LH concentrations produces which of the following
effects in cells of the follicle during the early follicular phase?
a. Increase testosterone synthesis in thecal cells
b. Increase aromatase activity in granulosa cells

c. Increase aromatase activity in thecal cells

d. Increase testosterone synthesis in granulosa cells

Female Reproduction II

Tonic secretion of FSH and LH

Tonic LH & LH surge have different mechanisms

GnRH travels down the portal circulation and stimulates LH and

FSH
LH acts on follicle to stimulate estradiol and on corpus luteum to
stimulate progesterone
FSH acts on the follicle to maintain aromatase and stimulate
estradiol
E2 inhibits FSH
E2 & progesterone inhibits tonic LH (both are needed)
LH surge is induced by high E2
- Mature ova is producing high levels of E2
- Positive feedback of estradiol
LH surge is blocked by progesterone
- Good for contraceptive pills

Control of the Menstrual Cycle

-

Average duration is 28 days

Follicular Phase
1. At the beginning, FSH levels are high to promote follicular growth
2. There is a gradual increase in LH (tonic), which stimulates E2
3. Increase in E2 inhibits FSH
- This decrease in FSH is responsible for atresia and
controls ovulation rate
- Acts on the endometrium to stimulate proliferation
(getting lining ready for implantation)
- When high enough, it induces LH surge

Induces ovulation and formation of CL

Bridge from follicular phase to luteal phase

Luteal Phase
1. As CL grows, it secretes more progesterone
2. High progesterone and E2
- Increases uterine secretions and blood flow to
endometrium (important for survival of embryo if fertilization
occurs)
- LH and FSH are inhibited
3. Low LH and/or high E2 induces luteolysis
Luteolysis & Menstruation
1. As CL dies, progesterone & E2 fall
2. The fall in those steroids is responsible for menstruation
- There is an increase in PGF2a, which cause contraction of
smooth muscle.
- Blood supply to endometrium is cut off, and the
tissue becomes hypoxic and dies and some blood goes
to uterine lumen
- The fall of progesterone and E2 allows FSH to increase and
the cycle starts again
Sexual Differentiation
Genetic sex (XX vs XY) Gonadal sex (ovaries vs testes) Phenotypic
sex (Male vs female
reproductive tract &
genitals)
Occurs in a hierarchy
Wollfian Ducts develop into Male reproductive tract
Mullarian Ducts develop into Female reproductive tract
Male structures require an active signal
In Males:
Y chromosome has testes determining factor (TDF) that acts on
undifferentiated gonads to cause them to differentiate into testes
- Sertoli cells produce anti-mullarian hormone (AMH)
- Causes mullarian ducts to regress
- Leydig cells produce testosterone
- Wollfian ducts form

- In this case, 5 reductase is important, which

converts testosterone to DHT and causes formation
of male genitalia

In Females
Since they dont have a Y chromosome, the TDF factor is not there.
In the absence of TDF, the gonads develop into ovaries
- No AMH, so mullarian ducts are formed
- Since there is no testosterone, the Wolffian ducts regress
- Since there is no DHT, then female genitalia forms
Age-Related Changes in Reproduction
Before puberty, GnRH is inhibited
- Direct neural inhibition
- Low levels of sex steroids are enough to negatively inhibit
GnRH
At puberty, there is an increase in kisspeptin, driving GnRH secretion
Menopause (between 40-45)
The ovaries cant produce new follicles
Depleted of follicles (they become infertile)
There is compensatory increase of FSH to maintain
ovulation
Hot flashes, loss of bone mineral
Male menopause
- There is a decrease in free testosterone

12.
Fall in concentrations of this hormone during the follicular
phase causes atresia of most follicles:
a. LH
b. FSH
c. Both
d. Neither

13.
On which of the following do estradiol and progesterone
have the same effects?
a.
b.
c.
d.

Blood flow to the endometrium

The LH surge
Viscosity of cervical mucus
Contractions of uterine myometrium

14.
Development of which of the following would be abnormal
in an individual with a defective androgen receptor?
a. Development of the Mllerian ducts into oviducts and
uterus in a female
b. Regression of the Mllerian ducts in a male
c. Development of the Wolffian ducts into prostate and
seminal vesicles in a male
d. Regression of the Wolffian ducts in a female

15.
As a primary care physician, you are presented with a 17year old girl who has never had a menstrual period, but is
otherwise in good health. Which of the following tests would not
provide information useful to diagnose the cause of her
amenorrhea?
a. Chromosomal analysis to determine if her genotype is XX
or XY
b. A pelvic examination to determine if she has a normal
uterus
c. A CT scan to determine if she has a tumor disrupting blood
flow to the pituitary
d. Blood analysis of LH or FSH to determine if she is deficient
in one of these hormones

9. Which of the following results from increased estradiol secretion

during the follicular phase?
a. The LH surge

b. The fall in FSH concentrations in the latter half of the

follicular phase
c. Increased proliferation of endometrial cells
d. Increased blood flow to the endometrium
e. All of the above
10.
An 18-year old girl is referred to you for primary
amenorrhea (shes never had a menstrual period). She has
normal pubic hair, but no evidence of breast development.
Based on this physical diagnosis, which of the following is a likely
explanation for her amenorrhea?
a. She is genetically a male with a deficiency in androgen
receptors
b. She is genetically a female with excessive anti-Mllerian
hormone production during development
c. She is genetically a female with a deficiency in estrogen
receptors
d. None of the above
e. All of the above

11.
a.
b.
c.
d.

Which hormone inhibits tonic LH secretion?

Estradiol
Progesterone
Both
Neither

12.
What is the effect of increased anti-Mllerian hormone on
development of the male reproductive tract in the female fetus?
a. Increases
b. Decreases
c. No effect
13. Which of the following occurs shortly before the onset of
menstruation during the normal menstrual cycle?
a. The LH surge
b. A progressive increase in circulating estradiol levels
c. The corpus luteum begins to die
d. Ovulation

14. In a male fetus with a mutation that completely inactivates the

enzyme 5-reductase (converts testosterone to DHT), which of
the following events in sexual differentiation would not occur
correctly?
a. Development of the testes
b. Differentiation of the genitalia into penis and scrotum
c. Development of the Wolffian ducts into the internal male
reproductive tract
d. Regression of the Mullarian ducts

Pregnancy I
Main reproductive hormone in males is testosterone
Main reproductive hormones in females are:
- Estradiol: Make mature ova & ensure they are fertilized
- Progesterone: Maintains fetus during pregnancy
Physiology of Sex
a) Excitement (arousal)
- Net effect is activation of parasympathetic outflow to the
genitals, increasing blood flow (vasodilation). This increase in
flow causes increase in blood volume, causing erection
- Action potential causes Ca+2 to be released and
ultimately NO is released. NO then activates cGMP,
causing relaxation
- Phosphodiesterase can be inhibited (by
drugs) to decrease the rate of cGMP degradation
b) Plateau
- Continued stimulation of parasympathetic
- In males, vasocongestion of penis (Increase in diameter)
- In females, vasocongestion of outer 1/3 of vagina (decreases
diameter of vagina) and the uterus moves up
c) Orgasm
- Discharge of sympathetic nerves to pelvic region
d) Resolution
- Sympathetic as stimulus that causes decreased vasocongestion
& detumescence
- In males, a refractory period
Journey faced by Sperm
- Sperm has to get to the oviduct, where fertilization occurs
1) Sperm swims to the cervix
2) Contractions of myometrium
3) Contractions of oviduct smooth muscle (anti-peristaltic)
Seminal fluid is important since it provides fructose and it buffers the
vagina
Fertilization

- Zona pellucida is important in protecting the

developing embryo
- Head of the sperm contains hyaluranidase,
which breaks the hyaluronic acid
The acrosome reaction is required to get through the zona
pellucida
The acrosome is a secretory vesicle at the head of the sperm that
contains multiple enzymes
1) A protein on the zona pellucida (ZP-protein) interacts with a
receptor on the sperm via G-protein coupled receptor
2) IP3 is increased
3) Release of Ca+2, which causes exocytosis
4) Contents are released
Results of Acrosome reaction
- The released enzymes start the breakdown of ZP (not fully broken
though)
- Activation of fusion proteins
- Exposes inner acrosomal membrane, which has enzymes that
break down the glycoprotein on ZP
Ovum Plasma Membrane: Fusion of Sperm and Ovum
- The sticky ends of the acrosomal membrane bind to microvilli
- Fusion proteins bind to the plasma membrane
- Sperm gets engulfed by membrane and DNA and sperm gets
moved to the cytoplasm of the ovum
- Cg (cortical granules) of ovum are exocytosed
Post Fusion Events
1) There is an increase in Ca+2, which causes oolemma hardening
2) The contents of Cg are released and become in contact with ZP
and causes hardening of ZP
3) 2nd meiotic division of ovum begins
4) Sperm nuclear decondensation begins
Implantation (6-7 days)
- The embryo travels down the oviduct and moves to the uteral lumen

Prevents
Polyspermia

- Formation of inner cell mass (stem cells) and outer portion

(trophoblast)
- The trophoblast is going to interact with the endometrium and form
the placenta
- Embryo hatches from ZP to be able to interact with endometrium
Changes in endometrium due to progesterone
Major structure of placenta is the chorion
Contraception
1) Barrier methods
2) Prevent fertilization
- Usually a combination of estrogen and progesterone
- Block LG surge (no ovulation)
- Inhibit sperm transport
3) Prevent implantation
- Morning after pill

1. Which of the following is NOT true of the acrosome reaction?

a. It is necessary for the sperm to get through the cumulus
oophoros
b. It is analogous to exocytosis
c. It exposes an important enzyme of the inner acrosomal
membrane
d. It activates proteins necessary for fusion of sperm and
ovum
16.
What is the effect of elevated progesterone levels on the
rate of sperm transport in the female reproductive tract?
a. Increases
b. Decreases
c. No change
17.
What is the effect of increased parasympathetic nerve
impulses on blood flow to erectile tissue in the genital area?
a. Increases
b. Decreases
c. No change
15.
Which hormone, in elevated concentrations, inhibits sperm
transport in the female reproductive tract?
a. Estradiol
b. Progesterone
c. Both
d. Neither
16.
What is the effect of increased sympathetic nerve activity
to the penis on its ability to achieve and maintain an erection?
a. Increases
b. Decreases
c. No effect

1. Which of the following is an important action of drugs for erectile

dysfunction, such as Viagra?
a. Cause constriction of vascular smooth muscle to decrease
venous drainage
b. Inhibit norepinephrine release from sympathetic nerves
c. Inhibit breakdown of cGMP in vascular smooth muscle
d. Increase activity of NO synthase (NOS) in parasympathetic
nerves
1. You are treating a couple who are having trouble conceiving.
This is the womans second marriage and she has a 10-year old
son from her first marriage? The medical work-up indicates that
there is no problem with the womans menstrual cycle and the
man is producing a normal number of sperm with no clear
indication of an increase in the percentage that are infertile. Use
of the in vitro fertilization technique known as ICSI
(intracytoplasmic sperm injection) results in a normal pregnancy.
Which of the following is a probable cause of this couples
infertility?
a. Mutation in the zona pallucida protein that initiates the
acrosome reaction
b. Mutation in the receptor for this protein in sperm
c. Cervical cells do not respond to E2 so cervical mucus is to
thick
d. The woman had an IUD inserted after her divorce that has
not been removed

Pregnancy II
Progesterone is needed for the maintenance of pregnancy
During preimplantation Progesterone is coming from normal CL
Implantation thru 1st trimester as the chorion forms it starts
releasing human Chorionic
Gonadotropin (hCG)
- hCG = LH + few aa and acts as a luteotropin (prevents
luteolysis)
- hCG is only produced during pregnancy and appears in
the urine (good for pregnancy test)
2nd & 3rd trimesters Progesterone is coming from placenta
- Inhibits myometrial contractions
- Inhibits milk secretion
- Acts as an immuno suppressant
Primary estrogen in pregnant women is estriol
- Fetus is producing DHEA-S and gets hydroxylated to 16OH-DHEAS in the liver
- 16OH-DHEA-S travels to the placenta, where sulfate is removed
and converted to 16OH-E2
Actions of E3
- Stimulates growth of myometrium
- Further development of mammary gland ducts
- Inhibits milk secretion
human Chorionic Somatomammotropins (hCSs)

Has growth hormone like activities & prolactin

- Decrease in insulin action
- Increases maternal glucose more glucose to fetus
Can lead to gestational diabetes and result in a bigger fetus and
cause problems during delivery
- May indicate that the pancreas is not functioning properly
and may develop Type II diabetes in the long run

Parturition (Delivery)
Preparation
- Softening of the cervix
- Due to the hormone relaxin produced from placenta

Initiation
- There might be an increase of cortisol from fetal adrenal
- Increase in fetal size may help initiate uterine contractions
- Local increase in E3 or decrease in progesterone
- We dont really know what triggers labor
Labor
- Primary purpose is to dilate cervix to 10cm so fetus can pass
through it
- Oxytocin released from posterior pituitary causes contractions
of uterine myometrium
- There are cervical stretch receptors that release action
potential to the hypothalamus to stimulate release of oxytocin
(Positive Feedback Loop)
- Once the system is activated, its going to maintain uterine
contractions until the cervix is dilated to 10cm and infant can be
deliver
- Delivery stops this loop, since there is no more pressure on the
cervix
- There is also neural reflex in case oxytocin levels are low
Mammary Gland
-

The alveolus is where the milk is produced

Positive pressure system
- Epithelial cells surround the alveolus & Myoepithelial cells
(smooth muscle) surround the epithelial cells
- Epithelial cells: where the milk is synthesized and
secreted

1. Prolactin needed for milk secretion

- Myoepithelial
2. Oxytocin needed for milk ejection
3. Oxytocin causes contraction of myoepithelial
cells
Lactation
-

During pregnancy, the high levels of E3 & Progesterone inhibit

milk secretion
After delivery, the levels of E3 & Progesterone decrease,
removing the inhibition

1. Infant sucks at the nipple

2. Action potentials are sent to the hypothalamus to innervate
oxytocin neurons
3. Oxytocin is released from the posterior pituitary
4. Milk ejection
This system is stress sensitive
Can become a conditioned reflex
-

Normally dopamine inhibits prolactin secretion

Suckling inhibits dopamine neurogenic neurons, stopping that
inhibition and releasing prolactin (replenishes milk)
How to shut down mechanism?
1. Signal that stimulates prolactin secretion is not there
anymore inhibits secretion
2. Oxytocin is no longer being stimulated No contraction of
myoepithelial cells Milk build up in the alveoli this
increases pressure, which inhibits secretion

18.
Which of the following is true of estrogen synthesis during
pregnancy?
a. The primary estrogen synthesized is estriol
b. Estrogen synthesis requires an interaction between the
fetus and placenta
c. Estrogen levels are much higher late in pregnancy than in
non-pregnant women
d. All of the above
19.

Which of the following is true for lactation?

a. An increase in prolactin induces milk letdown (milk
ejection)
b. Lactation is initiated by the increase in oxytocin secretion
at labor
c. Milk letdown can occur in response to the crying of the
mothers baby
d. When ovarian cycles resume, lactation is inhibited by
estradiol and progesterone which is responsible for
weaning

20.
Which of the following is not true of human Chorionic
Gonadotropin (hCG)?
a. Circulating concentration of hCG increase rapidly after
implantation
b. It is used clinically as an analogue for FSH
c. It is required for maintenance of pregnancy during the first
trimester
d. It is measured by commercially available pregnancy tests
21.
What is the effect of increased dopamine release from the
hypothalamus on prolactin secretion?
a. Increases
b. Decreases
c. No change

17.
Which of the following is essential for maintenance of
pregnancy?
a. hCG secretion from the placenta during the first trimester
b. Progesterone secretion from the corpus luteum during the
third trimester
c. Estriol secretion from the placenta during the second
trimester
d. Progesterone secretion from the placenta during the first
month after implantation
e. None of the above

18.
Which hormones secretion is controlled by dopamine
released from hypothalamic neurons?
a. Prolactin
b. Oxytocin
c. Both
d. Neither
19.
Increased secretion of which hormone initiates lactation
after parturition?
a. Prolactin

b. Oxytocin
c. Both
d. Neither
20.
Cessation of which hormone contributes to inhibition of
lactation after weaning?
a. Prolactin
b. Oxytocin
c. Both
d. Neither

Physiology of Bone
-

In soft tissues:
a. Free Ca+2 is a key signal
- Its critical to maintain constant calcium in the plasma
and interstitial fluid
b. PO4- is part of organic molecules

In the Bone, calcium and phosphate are in a complex called

hydroxyapatite

- It provides tensile strength of bone

- Acts as a large reservoir of Ca+2 and PO4- to maintain [interstitial
fluid] if needed
Types of Bone
Long bones: weight bearing
Flat bones: protective in nature (skull, ribs)
Trabecular: soft bone (middle of long bones) and doesnt contain too
much crystals
Cortical or compact: its the outer portion of pretty much all bones and
its very dense
Functional unit of bone: Osteon
- Osteoblast: where bone is made
- Osteocyte: formed when an osteoblast becomes embedded in the
matrix
- Canaliculi (little canals)
Bone remodeling
-

The process by which bone can repair itself

The ability to respond to different stressors (weight lifting)

Osteoclasts: Chew up bone

Osteoblasts: Lay down new bone
They act sequentially, osteoclasts acting first. They will essentially
make a 2nd lysosome
- H+: it will dissolved the hydroxyapeptite
- Collagenase: break down collagen
- Lysosomal enzymes: break down other proteins
The overall effect is to create a channel that can be rebuilt by the
osteoblasts (after osteoclasts undergo apoptosis)
The osteoblasts migrate around the periphery of the channel and
start secreting procollagen and collagen fibers are made
- Osteocalcin and osteonectic bind to the collagen fibers and act
as nucleases
- Will promote the precipitation of Ca+2/PO4- crystals
- As the bone is formed, the osteoblasts move inward and some
are trapped (osteocytes)

1. Osteoclasts are recruited by MCF and RANKL

2. They undergo apoptosis and release Chemotaxic agents that recruit
osteoblasts
3. Osteoblasts take over
Control of Remodeling
Promote Growth (Osteoblasts)
- GH, E2 and Calcitonin
- GF (mitogenic)
- BMP (bone morphogenic
proteins)
- IGF-1
-

Wnt & - catenin

- In the absence of Wnt, catenin is phosphorylated
and signals to be degraded
- When Wnt is present,
kinase is blocked and catenin moves into nucleus,
acting as a transcription
factor to produce mRNA that
is important in laying down
new bone

Endogenous inhibitor: Sclerostin

(from osteocytes)

Promote resorption (Osteoclasts)

- PTH & Vitamin D
- Cytokines (interleukins)
-

RANK Ligand & NF-kB

- When RANK is high, it will bind to
receptor and activate NF-kB
- NF-kB moves into nucleus and
activate synthesis of proteins
necessary for bone resorption

Endogenous inhibitor: Osteoprotegrin

(OPG) (from osteoblast)

Response of Bone to
Physiological Stimuli
As bone age, they get micro
fracture

Causes apoptosis of osteocytes

They release MCF and RANKL
- That piece of bone is chewed up
Osteoclasts then undergo apoptosis and release Wnt
Stimulation of new born formation
Sclerostin inhibitor from osteocytes is released

Response to Stress

Stress decreases the release of sclerostin, removing inhibitory

component
Wnt/b-catenin pathway is stimulated, increasing osteoblast activity
and bone density is increased

Response to Bone Fractures

1. Hematoma is formed
- Contains angiogenic factors start revascularization
- Chemotaxic cytokines Mesenchymal stem cells (MSC)
2. Repair stage
- MSC first form chondrocytes and cartilage is laid down (stabilized
fracture)
- Cartilage is gradually replaced with trabecular bone (soft bone)
- RANKL being activated, increasing osteoclasts and cartilage is
resorb
- New blood vessels are formed
- Wnt/b-catenin activated and osteoblasts lay new bone around
the blood vessels
3. Trabecular bone is replaced by compact bone by normal remodeling
process
Endocrine Regulation of Calcium and Phosphate
Calcium Homeostasis
- To maintain constant [Ca+2]
- Acts on a minute-to-minute basis (very rapidly)
Calcium Balance
- To ensure that over the long-term, Ca+2 intake = Ca+2 excretion
- Slow process (over weeks & months)

22.

Which of the following occurs during bone remodeling?

a. During the reversal phase, osteoclasts differentiate into
osteoblasts

b. Breakdown of bone by osteoclasts occurs in a large

extracellular lysosome
c. Osteoblasts begin at the middle of the osteon and move
outward as they lay down new bone
d. Osteoblasts begin at the middle of the osteon and move
outward as they lay down new bone

21.

Which of the following is true for osteocytes?

a. They line the inner canal of the osteon
b. They are dead cells that have not yet been removed from
bone
c. When activated, they become the osteoclasts that
breakdown bone
d. They are interconnected by cytoplasmic extensions
through the canaliculi
e. None of the above

22.
a.
b.
c.
d.
e.

Which of the following is not secreted by osteoclasts?

Hydrogen ion
Collagenase
Osteonectin
Lysosomal enzymes
None of the above are secreted

Regulation of Calcium and Phosphate

PTH, CT & Vitamin D act on the kidney, bone and GI tract
- Movement of calcium and phosphate between those tissues and
ECF
ECF of Ca+2 pool
- Free Ca+2 and interstitial fluid Ca+2
Calcium Movements
In the GI tract
- Ca+2 absorption is controlled by vitamin D
- Secretory process is not under endocrine control
In the Kidney
- PTH regulates Ca+2 reabsorption
In the bone
- Slow exchange, which is part of the process of bone remodeling
(Stabile bone pool Mineralized bone)
- In the fast exchange, it involves the labile bone pool
-The labile bone pool is calcium that is free in interstitial fluid
- It involves exchange between IF calcium and ECF across
the cell barrier (osteocytes being the cell barrier)
- Fast rapid movement of Ca+2 due to Canaliculi
Hormonal Control of Calcium and Phosphate
Parathyroid Hormone (PTH)
- Large protein hormone, so it is synthesized as a preproPTH
- It increases ECF Ca+2
- In the kidney, it increases Ca+2 reabsorption and decreases PO4reabsorption
- In the bone:
- Increases Ca+2 efflux from bone in IF (no PO4-) to ECF
(Rapid)
- Increases bone resorption (braking down the crystals)
movement of both Ca+2 and PO4- into ECF (slow)
- In the GI tract, Ca+2 & PO4- absorption increase but via Vitamin D
- PTH inhibited by Ca+2 (negative feedback)
- Ca+2 binds to Gq increases DAG PKC activated PTH
inhibited

Calcitonin
- Made by parafollicular cells of thyroid
- Acts to decrease ECF Ca+2
- Ca+2 stimulates calcitonin release
- Not physiologically important
Vitamin D
-

7-Dehydrocholesterol is stored in the skin and when exposed to

UV light, it turns into cholecalciferol (inactive)
In the liver, cholecalciferol is converted to 25-hydroxycholecalciferol
In the kidney, 25-hydroxy-cholecalciferol is converted to 1,25dihydroxy-cholecalciferol (biologic active)
- Catalyzed by 1-Hydroxylase (rate limiting enzyme)
PTH stimulates 1-hydroxylase activity and inhibits 24hydroxylase
PO4- inhibits 1-hydroxylase activity and stimulates 24hydroxylase
Transported in blood bound to plasma proteins
Theres a lag time of 8- hours, but effects are long lasting
- Since it takes too long to take effect, it is not important for
maintenance of Ca+2 homeostasis, but important for
maintaining Ca+2 balance

GI tract
- Increases Ca+2 & PO4- absorption
Bone
- Increases Ca+2 efflux from bone
- Increases bone resorption
Kidney
- Increases Ca+2 reabsorption

These
responses
increase to
PTH

Integration
Calcitonin No physiological importance
PTH Critical for Ca+2 homeostasis and Balance (regulates Ca+2 loss)
Vitamin D Critical for Ca+2 Balance (regulates Ca+2 intake)

An equilibrium exists
- If PO4- levels go up, then that drives the reaction to the right and
Ca+2 levels go down
- If Ca+2 levels go down, then PTH secretion goes up

23.
Circulating hormones of this hormone would increase if ECF
calcium concentrations fall
a. PTH
b. 1,25-(OH)2-vitamin D
c. Both
d. Neither
24.
This hormone acts directly on the GI tract to stimulate
calcium absorption
a. PTH
b. 1,25-(OH)2-vitamin D
c. Both
d. Neither
25.
This hormone plays an important role in maintenance of
calcium balance
a. PTH
b. 1,25-(OH)2-vitamin D
c. Both
d. Neither
26.
a.
b.
c.
d.
e.

Which of the following is true of vitamin D?

It can be synthesized by the skin
It travels in blood bound to plasma proteins
It is used to treat hypoparathryoidism
It is converted to 25-(OH)-vitamin D by a liver enzyme
All of the above

27.
Which of the following are important for calcium
homeostasis?
a. Stimulation of calcium absorption in the GI tract by 1,25
(OH)2 vitamin D

b.
c.
d.
e.

Inhibition of calcium efflux from bone by calcitonin

Stimulation of calcium reabsorption in the kidney by PTH
Stimulation of bone resorption by PTH
All of the above

a.
b.
c.
d.
e.

Which of the following would increases PTH secretion?

Increase in circulating phosphate levels
Increase in circulating calcium concentrations
Fracture of a long bone
Increase in production of 1,25-(OH)2 vitamin D
All of the above

23.

24.
Which of the following processes in bone remodeling takes
the longest to complete?
a. Bone resorption
b. Mineralization of new bone
c. Activation of osteoclasts
d. Recruitment of osteoblasts
e. Apotosis of osteoclasts

Adrenal Medulla
-

Adrenal medulla is part of the sympathetic nervous system

Innervated by sympathetic nerves and epinephrine is released
into the blood

Biosynthesis of Epinephrine
-

Synthesized from Tyrosine

1. Tyrosine Hydroxylase (TH) adds a hydroxyl (Rate
Limiting), forming L-DOPA
2. L-DOPA is decarboxylated to produce dopamine catalyzed
by Aromatic amino acid decarboxylase
3. A hydroxyl group is added to dopamine to form
norepinephrine catalyzed by dopamine-b-hydroxylase
- Dopamine gets transported to a vesicle because thats
where the DBH enzyme is
4. A Methyl group is transferred to norepinephrine to form
Epinephrine catalyzed by Phenyl-N-methyl transferase
(PNMT)
- Norepinephrine gets back into the cytoplasm, where it
is converted to epinephrine

TH is controlled by end-product inhibition

- It is inhibited by epinephrine and norepinephrine
PNMT is induced by high levels of cortisol
Secretion of epinephrine is innervated by pre-ganglionic activity Ach
is released, releasing Ca+2 and inducing exocytosis
At rest: Norepinephrine > Epinephrine
Stressor activation of adrenal medulla, which dumps out primarily
epinephrine Epinephrine >> Norepinephrine

Receptors
1: Epi = Norepi (heart)
2: Epi >> Norepi (Smooth muscle)

3: Epi >> Norepi (Adipose)

They act through cAMP
Activation of receptors is vasoconstrictive and activation of
receptors is vasodilatory.
-

In the skin and viscera, there are only receptors it will cause
vasoconstriction
In skeletal muscle, they have & receptors Epinephrine will
initially cause vasodilation and if it gets high enough it will cause
vasoconstriction

Actions of Epinephrine
-

At the heart, it will increase heart rate and contractility

Vasodilation in heart & skeletal muscle (where there are receptors)
Vasoconstriction in the skin, kidney and viscera

Overall metabolic effect is to increase energy to muscle & brain

(increase blood glucose)
Insulin levels are maintained constant
- b cells are receiving two signals:
1. Epinephrine, which inhibits insulin secretion
2. And glucose levels that are going up, which stimulate
insulin secretion
- Those two signals practically cancel each other out
In general, epinephrine causes relaxation of smooth muscles
Control of Secretion
-

Stressor activate SNS, which activates adrenal medulla

Other activators:
Hypoglycemia: decrease in glucose can cause release of epinephrine
Hemorrhage: primarily sympathetic nerves vasoconstriction
Metabolism: t1/2 1-2 mins

Inactivation:
1. Monoamine oxidase (MAO)
2. Catechol-O-methyl transferase (COMT)

Cortisol
- Via the HPA increase in ACTH increase of cortisol secretion
in adrenal cortex
Epinephrine will go up before cortisol
Effect is to further increase glucose levels via gluconeogenesis
Glycogen gets depleted first (due to epinephrine)

28.
Tissues containing the following receptor will respond to
epinephrine, but not norepinephrine.
a. 1
b. 2
c. 1
d. 2
29.
a.
b.
c.
d.
30.

Which of the following is inhibited by epinephrine?

Blood flow to skeletal muscles
Glycogen breakdown in muscle
Insulin secretion
Glucagon secretion

Which is not true for the tyrosine hydroxylase?

a. It is induced by high levels of cortisol
b. It is the rate limiting enzyme in the synthesis of
norepinephrine and epinephrine
c. It is found in the cytosol
d. Its activity is inhibited by norepinephrine and epinephrine

25.
a.
b.
c.
d.
e.

Which of the following is stimulated by epinephrine?

Heart rate
Glycogen breakdown in muscle
Blood flow to skeletal muscle
Glucagon secretion
All of the above

26.
Which of the following is true of cells of the adrenal
medulla, but not post-ganglionic sympathetic nerves?
a. They are innervated by nerves that release acetylcholine
(ACh)
b. They contain PNMT, the enzyme that converts
norepinephrine to epinephrine
c. They contain dopamine
d. They release catecholamines by diffusion across the
plasma membrane
e. All of the above

27.
Binding of epinephrine to which of the following receptors
would not alter intracellular cAMP levels?
a. 1
b. 2
c. 1
d. 2
e. All of the above