Reproduction

Spring 2013
The information given out in all the handouts for Reproduction this semester
is to help you understand better this complex subject. The following are some
references that you may find useful.

Berne RM and Levy MN (1998) Physiology 4th Edition

Greenspan FS and Gardner DG (2004) Basic and Clinical Endocrinology 7th
Edition
Kacsoh B (2000) Endocrine Physiology
Creasy RK et al. (2004) Maternal-Fetal Medicine 5th Edition

Make sure you can answer all of the learning objectives.

Prepared by: Dr Sean Holroyd

Lecturer: Dr. Vijaya Chellapilla

1
 Section 1

Male Reproductive Physiology

Learning Objectives
1. Describe and explain the hypothalamic-pituitary-gonadal axis in the male.
2. Discuss the various regulators of GnRH secretion from the hypothalamus.
3. Describe the mechanism of action of GnRH in synthesizing and releasing LH and
FSH. Explain the importance of pulsatile release.
4. Describe the mechanism of action of LH at the Leydig cell in the production of
testosterone.
5. Describe the mechanism of action of FSH at the Sertoli cell in the production of
important hormones for sperm production.
6. Discuss the physiological functions of the Sertoli and Leydig cells.
7. Explain the interrelationship between the Sertoli and Leydig cells and the importance
of this regarding male reproductive function.
8. Describe the synthesis and release of testosterone.
9. Describe the fate of testosterone in the bloodstream.
10. Discuss the mechanism of action of testosterone at its target cells.
11. Describe the physiological functions of testosterone at various stages during a males
life (including fetal).
12. Explain the negative feedback regulation of testosterone secretion
13. Discuss the role of the accessory organs in the formation of the ejaculate.
14. Describe the neural control of penile erection.
15. Describe the neural control of ejaculation.
16. Describe the underlying physiology of medical problems associated with altered
male reproductive system.

Readings
Chapter 36 of your textbook

Introduction
The major organ involved in maintaining male reproductive function is the testis. A
normal functioning testicle is required for the production of mature sperm and the
synthesis of the major male reproductive hormone testosterone.

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Hypothalamic-Pituitary Axis

Hypothalamus

GnRH

Anterior
Pituitary

LH and FSH

Testes

Testosterone

Figure 1. Simple flow chart showing the hypothalamic-pituitary-gonadal axis in the

male. GnRH is released in a pulsatile manner, the frequency and amplitude of the pulses
affect the ratio of LH/FSH synthesis by the gonadotrophs of the anterior pituitary. At this
point in time it is important to stress that the anterior pituitary contains gonadotrophic
cells that synthesize both LH and FSH. LH and FSH are very similar in structure with a
slight difference between their subunits. A subtle change in the release of GnRH will
alter the stimulation of the mRNA that produces each specific subunit. For example high
frequency release of GnRH preferentially stimulates LH synthesis over FSH. LH
stimulates the Leydig Cell of the testis to produce testosterone. FSH has a major
supporting role in male reproduction.

Gonadotropin Releasing Hormone

GnRH is a 10 AA peptide that is synthesized in the arcuate nucleus and stored in vesicles.
It is secreted into the portal system and binds to receptors on the gonadotrophs of the
anterior pituitary. It acts via IP3 and DAG to stimulate the synthesis and release of the
gonadotropins.

The release of GnRH must be pulsatile in order to have effect and is controlled by
dopamine, serotonin, neuropeptide Y and norepinephrine. It has a half-life of 2-4
minutes

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 And Negative feedback
Others
Sleep/wake cycle Stress

Hormones
Temperature

Hypothalamus

GnRH
RELEASE
Change in Change in
amplitude frequency

Figure 2. Diagram showing the regulators of GnRH secretion from the hypothalamus.
These regulators change both the amplitude and the frequency of GnRH release. As
stated earlier a change in frequency may change the LH/FSH synthesis ratio. As
discussed earlier many factors input on the hypothalamus therefore fertility in the male
can be affected by factors totally unrelated to reproductive physiology.

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 Gonadotroph
GnRH

Vesicles
containing
LH/FSH Also LH
IP3 & DAG PKC and FSH
synthesis

Release of Ca2+
LH/FSH via
exocytosis

Figure 3. Diagram showing the mechanism of action of GnRH at the gonadotroph of the
anterior pituitary. GnRH acts via the IP3 / DAG second messenger system to increase the
synthesis and release of LH and FSH. Remember some gonadotrophs have the ability to
synthesize both hormones due to the similarity in their structures. The ratio will be
determined to some extent by the frequency of GnRH release.

Hormones from the Gonadotrophs

Luteinizing and Follicle-stimulating Hormone
LH and FSH are glycoproteins with identical subunits and unique subunits. LH
stimulates testosterone production by the Leydig (interstitial) cells. FSH stimulates
testicular growth and the production of an androgen-binding protein by the Sertoli cells
(maintains high levels of testosterone in the testes). Both FSH and LH are required for
the maturation of sperm.

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 Leydig Cell
LH

Increased
testosterone
production
cAMP
Via PKA
cholesterol

DNA
transcription
testosterone

Figure 4. This diagram shows the mechanism of action of LH within the Leydig cell.
Acting via cAMP, the Leydig cell produces enzymes that are important for the
conversion of cholesterol to testosterone. In particular LH stimulates the affinity and
synthesis of cholesterol desmolase that converts cholesterol into pregnenolone in the
mitochondria.

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 Sertoli Cell
FSH

cAMP
Via PKA

Inhibin
Aromatase DNA
ABP transcription
Growth
Factors

Figure 5. This diagram shows the mechanism of action of FSH within the Sertoli Cell.
FSH acts via the cAMP second messenger system to stimulate the production of proteins
that are important for the successful production of sperm. This includes aromatase that
converts testosterone into estradiol, androgen binding protein that is important to
maintain testosterone levels in the seminiferous tubules and inhibin which is important in
the regulation of FSH release and hence has a role in regulating the LH/FSH ratio.

The testes
The role of the male testes are to produce the hormone testosterone as well as to produce
spermatozoa and prepare them ready for reproduction. The testis is made up of hundreds
of seminiferous tubules (where spermatogenesis takes place) within these tubules are
found the Sertoli cells. Leydig cells are found in the interstitial fluid surrounding the
seminiferous tubules. The Sertoli and Leydig cells have important roles with regards
spermatogenesis.

Function of the Sertoli cell

The Sertoli cell maintains close contact with developing sperm and provides structural
support and nutrition. They phagocytose residual bodies/damaged germ cells, secrete
fluids, assist in sperm detachment into lumen and synthesize transferrin (important for
sperm development). An important function is the production of Androgen-binding
protein that maintains high levels of androgens in the tubules and carries testosterone to
the epididymus.

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There is an important relationship between the Sertoli and Leydig Cells that is integral for
the normal functioning of the male testes and required for the production of viable sperm.
This is shown in the diagram below.

Figure 6. Diagram (Boron and Bolpaep, 2005) showing the interaction between the
Sertoli and Leydig cells. Remember that the Leydig cell is in the interstitial fluid while
the Sertoli cell is found within the seminiferous tubule. Note the forming spermatogonia
and developed spermatozoa indicated around the Sertoli cell. FSH binding to its receptor
acts via the second messenger cAMP to stimulate protein synthesis by the Sertoli cell.
These proteins include the androgen-binding protein which as you can see enters the
lumen of the seminiferous tubule with testosterone. Growth factors that are important for
maintaining the normal function of the Leydig Cell are also produced. In the Leydig cell,
LH binding to its receptor and acting via the cAMP second messenger system stimulates
the production of enzymes that increase the synthesis of testosterone. This testosterone
either passes into the capillary or into the seminiferous tubule.

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Spermatogenesis
Occurs in the seminiferous tubules. Mitosis of male germ cells, change in shape,
meisosis spermatozoa. (You have covered this previously)

Spermatogenesis occurs from puberty to end of life and has been shown to decline in the
elderly. It is initiated shortly before puberty (stimulated by testosterone/gonadotropins)
and is synchronized in the seminiferous tubules, which means you find sperm at various
stages of development in the seminiferous tubules at any one time. 65-70 days are
required for spermatogenesis and the number of sperm produced may be affected by
many factors including heat and hormonal release. New cycles initiated every 2-3 weeks
(this gives the term the spermatogenic wave)

Hormones and Spermatogenesis

High intratesticular levels of testosterone are required for spermatogenesis to occur.
Testosterone must work in concert with the Sertoli cells and has been shown to maintain
the levels of sperm in part by preventing cell apoptosis.

After Spermatogenesis
After release into the lumen of the seminiferous tubules, sperm are transported to the rete
testes efferent ductules epididymus. This movement is assisted by movement via
cilia (in efferent ductules), muscle contraction and tubular fluid flow

Sperm is stored, protected and transported in the epididymus. And after further
maturation here the sperm gain mobility. Most storage of sperm occurs in the
epididymus and vas deferens. (NB. Some texts will say one or the other).

Testosterone
Synthesis
Testosterone is synthesized in the Leydig cell (see Figure 6)

Release of Testosterone
Being a steroid testosterone passes across the Leydig cell membrane, some enters the
bloodstream and the rest passes into the Sertoli cells. Therefore the stimulator of
synthesis (LH) is the stimulator of release. An adult male will produce ~ 7mg of
testosterone / day, (this decreases to 4mg/day at 70 years old).

What happens after release into the bloodstream?

If testosterone does not enter the seminiferous tubule it enters the blood. In the blood
about half of the testosterone is bound to sex hormone-binding globulin (from the liver)
and about 35% is bound to albumin. The rest is free and therefore biologically active.

In many cases the testosterone is converted into another androgen in the target cell prior
to having its effect.

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 At the target tissues

Testosterone

Dihydrotestosterone

Modulation of gene proteins

expression

Figure 7. This diagram shows the basic mechanism of action of testosterone at its target
cell. Being a steroid hormone testosterone can pass across the plasma membrane by
simple diffusion. Once inside the cell it may bind to its receptor or be converted by
cytoplasmic enzymes into a different product (in this example dihydrotestosterone).
Once bound to the receptor like any steroid hormone it modulates gene expression and
protein synthesis.

10
Physiological Action of Testosterone and Associated Androgens.

An androgen is a substance that stimulates the growth of the male reproductive tract and
development of secondary sex characteristics. It is important to realize that androgens
affect most other tissues as well.

Figure 8. This graph (Boron and Bolpaep, 2005) shows the variance in testosterone
levels over a males life. Of particular physiological importance are the two peaks (one
during fetal life, the other after puberty). The peak observed shortly after birth does
occur however its role physiologically still remains in doubt.

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 Penis and scrotum

hCG Accessory Organs

Testosterone

Testicular descent

Female suppression

Fetal testes

Figure 9. Diagram showing the role of the testosterone released by the fetal testes. The
fetal release of testosterone is important for development of the male sexual organs,
testicular descent and suppression of the female sexual organs. Testosterone secretion is
stimulated by hCG (human chorionic gonadotrophin).

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 Reproductive
Organs Spermatogenesis

Testosterone
Long bone fusion
(Adult)

Secondary
Sexual
Characteristics
Sex Drive

Figure 10. Diagram showing the role of testosterone from puberty onwards. Increased
secretion of LH and FSH enlarge the testes leading to elevated testosterone synthesis.
This increase in androgen activity leads to the growth of the penis and scrotum. It also
promotes growth and an increase in the secretory activity of the epididymis and accessory
glands. It also takes part in the pubertal growth spurt (an interaction of GH, androgens,
nutrition and genetics). Testosterone also fuses the epiphyseal growth plates in long
bones stopping further linear growth (you can relate this when you think about the
difference between gigantism and acromegaly). There is still some argument with
respect to the action of testosterone with male sex drive, though testosterone receptors
have been found throughout the brain. There has been shown to be no correlation
between androgen levels and impotence or homosexuality.

13
 Body Hair and
Baldness Deep voice

Secondary
Acne Sexual
Characteristics

Protein formation
Muscle
Bone size and development
strength

Figure 11. This diagram shows the secondary sexual characteristics produced by
testosterone release at puberty and throughout adult life. It produces hair on the face,
chest and upper pubic triangle. It causes a deepening of the voice due to growth of the
larynx and vocal cord thickening. In concert with growth hormone testosterone
stimulates muscle mass. It also increases the secretory activity of the sebaceous glands
leading to acne.

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Hypothalamic-Pituitary-Gonadal Axis Control of Testosterone Secretion

Hypothalamus

Some testosterone GnRH

converted into
estrogens
Anterior
Pituitary

LH FSH

Leydig Sertoli
cell Cell

Testosterone Inhibin

Figure 12. This diagram shows the negative feedback regulation of testosterone
secretion by the gonads. Testosterone inhibits the secretion of GnRH from the
hypothalamus and the secretion of LH from the anterior pituitary (note that some of the
testosterone is converted into estradiol in the gonadotroph prior to inhibiting LH).
Inhibin inhibits the secretion of FSH. This negative feedback system is extremely
important as you now know that the amount of LH and FSH synthesized by the
gonadotroph is also related to the frequency and amplitude of GnRH release.

See Clinical Focus Boxes 36-1 and 36-2.

15
Formation of the Ejaculate and the Role of the Accessory Organs

As the sperm passes through the epididymus it matures (due to dihydrotestosterone), and
becomes more concentrated (fluid reabsorption).

The sperm is then stored in the epididymus and vas deferens waiting for ejaculation.
Sperm can remain viable here for up to 60 days as nutrition is supplied and inhibitory
factors decrease their energy use.

On ejaculation the sperm (and fluid) passes through the vas deferens, ejaculatory ducts
and finally through the urethra. During this passage the fluid content is increased due to
secretions from the accessory organs

Epididymus 10%
Sperm vas deferens
storage

Seminal vesicles

Sperm, fructose, prostaglandins, 60%

clotting precursors

Prostate gland

+ alkalization, semen clotters 30%

And unclotters

Figure 13. This diagram is a summary of the substances added to the sperm as it passes
through the male ductal system on the way to being ejaculated. As you can see
approximately 10% of the ejaculated semen is made up of the sperm and fluid stored in
the epididymus. As the sperm moves through the male reproductive tract on the stimulus
of ejaculation it first passes the seminal vesicles, where they release their fluid into the
ductus deferens (this makes up between 60-75% of total semen volume). This fluid
contains the following:

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Fructose - primary energy source for ejaculated sperm
Prostaglandins - stimulate contractions of the smooth muscle in both the male and female
reproductive tracts
Fibrinogen - fibrin precursor (clotting precursor)
Volume - the volume is important to dilute sperm and make semen less sticky

The semen then passes by the prostate gland that releases its fluid near the beginning of
the urethra. This fluid makes up about 30% of total semen volume. This fluid contains:

alkaline substances - to neutralize the acidic vaginal secretions

clotting enzymes - act on fibrinogen to clot the semen keeping it in the vagina
fibrinolysin - breaks down clot after withdrawal, releasing sperm

During intercourse the Bulbourethral Gland secretes mucus to help with lubrication
during sexual intercourse.

The Male Sex Act

In order for normal fertilization to take place the male must be able to deposit his
sperm in a way that allows it to travel to the Fallopian tube of the female in time to be
able to fertilize the ovum. There are two major components of the male sex act, erection
and ejaculation.

Erection
An erection is required to harden the penis in order for it to be able to enter the vagina. It
is caused by engorgement of the penis with blood. The neural control of an erection is
shown in Figure 14.

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 PSYCHOLOGICAL
AND/OR PHYSICAL
STIMULI

Parasympathetic Sympathetic
Activity Activity

Via NO
and/or
ACh
Vasodilation

Erection

Figure 14. Diagram showing the neural control of the erection reflex. The major
controller of the erection is the parasympathetic nervous system. ACh may release NO
via M3 receptors and/or the NO may also be released from the postganglionic terminal
with ACh. The important thing is that an elevated parasympathetic activity increases the
activity of NO. NO causes dilation of the penile arterioles by causing a cascade of
reactions that eventually lead to a decrease in intracellular calcium and/or a decrease in
myosin light chain activity.

An erection may best be described as engorgement of the penis erectile tissue with blood.
This is due to parasympathetic dilation of the penile arterioles increasing blood flow to
the penis and at the same time mechanical compression of the penile veins decreasing
blood flow out.

Ejaculation
Ejaculation is the forceful expulsion of semen into the urethra and out of the penis. It
may be separated into two phases, emission and expulsion.

Emission
We have looked at emission with respect to the makeup of the semen that leaves the
penis. The stimulator of emission is the sympathetic nervous system that produces
sequential contraction of the smooth muscle of the prostate, reproductive ducts and
seminal vesicles. This causes the stored sperm in the epididymus/vas deferens to be
forced into the reproductive ducts and receive fluid from the contracted seminal vesicles
and prostate glands. This leads to the semen entering the urethra.

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Expulsion
The filling of urethra with the semen produces nerve impulses that cause contraction of
skeletal muscles at base of the penis. This increases the pressure in the penis causing the
expulsion of semen out of the penis.

Medical problems
Hypogonadism
This is when the testes are non-functional. There is no steroidogenesis in the testes and
hence no spermatogenesis. The effects of hypogonadism are dependent upon when the
problem is initiated.

Not functional ever. There is no development of male sexual organs. In fact female
sexual organs develop as this is what happens if there are no sex hormones present.
Stop functioning prior to puberty. There is no development of secondary sexual
characteristics. The sexual organs to do not mature. Lack of testosterone means that
there is a delay in epiphyseal plate fusion meaning long bones are longer.
Stop functioning after puberty. May decrease the size of sexual organs, reverse some of
the secondary sexual characteristics and enlarge breasts. May cause erectile dysfunction
and infertility.

Primary hypogonadism is when there is dysfunction of the testes themselves. Secondary

hypogonadism is when there is a problem with the release of hormones from the anterior
pituitary (LH/FSH) or hypothalamus (GnRH) decreasing testosterone production.

Prostate cancer
Approximately 1 in 7 US men will be diagnosed with prostate cancer. The cancerous
cells are stimulated by testosterone and metastasize to the bone easily. Treatment
depends upon the state of the cancer, may include watchful waiting, prostatectomy and/or
radiotherapy. If more advanced; chemotherapy, hormone therapy (eg estrogens) or
nothing.

Infertility
In order to be fertile the male requires enough sperm that are both motile and have the
correct morphology. These sperm have to be able to be ejected from the male into the
female close to the cervix in order to maximize the chances for pregnancy.

Impotence
This is the inability to produce or maintain an erection. In most cases it is due to
problems with blood flow.

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 Section 2
Female Reproductive Physiology
Learning Objectives
1. Describe and explain the hypothalamic-pituitary-gonadal axis in the female.
2. Discuss the various regulators of GnRH secretion from the hypothalamus.
3. Describe the mechanism of action of GnRH in synthesizing and releasing LH and
FSH. Explain the importance of pulsatile release.
4. Describe the mechanism of action of LH at the Theca cell in the production of
androstenedione.
5. Describe the mechanism of action of FSH at the Granulosa cell in the production of
important hormones for estrogen production.
6. Discuss the physiological functions of the Thecal and Granulosa cells.
7. Explain the interrelationship between the Thecal and Granulosa cells and the
importance of this regarding female reproductive function.
8. Describe the changes in hormone levels over the whole ovarian cycle.
9. Describe the hormonal control of the early to mid-follicular phase of the ovarian
cycle.
10. Describe the hormonal control of the late follicular phase of the ovarian cycle.
11. Discuss the importance of progesterone in ovulation.
12. Describe the hormonal control of the early to mid-luteal phase of the ovarian cycle.
13. Describe the hormonal control of the late luteal phase of the ovarian cycle if
implantation has not occurred.
14. Discuss the synthesis and release of the estrogens and progesterone.
15. Discuss the fate of the estrogens and progesterone in the blood.
16. Describe the physiological functions of the estrogens and progesterone.
17. Discuss the menstrual cycle.
18. Discuss the physiology underlying puberty and menopause.
19. Describe the changes in reproductive hormone levels of the whole female life.
20. Describe the underlying physiology of medical problems associated with altered
female reproductive physiology.

Readings
Chapter 37 of your textbook

Introduction
The major organ involved in controlling female reproductive function is the ovary.
Normal functioning ovaries are required for the production of estrogens and progestins
that are important for the maintenance of the female reproductive cycle.

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Hypothalamic-Pituitary Axis

Hypothalamus

GnRH

Anterior
Pituitary

LH and FSH

Ovaries

Estrogens / Progestins

Figure 1. Simple flow chart showing the hypothalamic-pituitary-gonadal axis in the

female. As you can see it is quite similar to that of the male. The hypothalamus releases
GnRH which stimulates the release of LH and FSH from the gonadotrophs. Similarly to
the male the ratio of LH:FSH is determined by the frequency and amplitude of the pulses
of GnRH. The LH and FSH bind to receptors on cells found within the ovaries to elicit
their effects, the secretion of estrogens and progestins. The specific mechanism by which
this occurs will be discussed later.

Gonadotropin Releasing Hormone

GnRH is a 10 amino acid peptide that is synthesized by neurons that originate in the
arcuate nucleus. It is stored in vesicles and released into the portal system. It binds to
receptors on the gonadotrophs activating the IP3 and DAG second messenger system to
increase intracellular Ca2+ and protein kinase activity. This stimulates the synthesis and
release of the LH and FSH.

21
 Theca Cell
LH

cAMP
Via PKA
cholesterol

DNA
transcription
pregnenolone

Figure 2. Diagram showing the mechanism of action of LH on the thecal cell of the
ovarian follicle. LH acts via the cAMP messenger system to stimulate the production of
enzymes important for the conversion of cholesterol into pregnenolone as well as
increasing the uptake of LDLs into the thecal cell. This leads to the thecal cell
producing androstenedione which is important for the production of estradiol. The thecal
cell does not have the aromatase enzyme required to convert the adrostenedione into
estradiol (see Figure 4)

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 Granulosa Cell
FSH

Especially
Aromatase

cAMP
Via PKA

DNA
Enzymes transcription

Figure 3. This diagram shows the mechanism of action of FSH binding to its receptor on
the granulosa cells of the ovarian follicle. The granulosa cells do not have the enzymes
to convert progesterone into androstenedione so instead must receive androstenedione
from the thecal cell. FSH acts via the cAMP second messenger system to produce
enzymes such as the aromatase that converts androstenedione into estradiol. Therefore
you can see that there is an interaction between the thecal and granulosa cells in order to
produce estrogens. This is shown in the next figure.

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During the Follicular Phase

LH FSH
LDL

Cholesterol
Via cAMP Via cAMP

Pregnenolone
Estradiol

INTO THE
Androstenedione BLOOD

Thecal Cell Granulosa Cell

Figure 4. Diagram showing the two-cell theory of the follicular biosynthesis of

estradiol. Remember this is during the follicular phase. LH binds to its receptor on
the thecal cell causing an increase in uptake of LDLs into the cell as well as stimulating
the conversion of cholesterol into pregnenolone. This leads to the production of
androstenedione. This androstenedione leaves the thecal cell and moves into the
granulosa cell. The binding of FSH to its receptor on the granulosa cell increases the
production of the aromatase enzyme that converts androstendione into estradiol. This
estradiol then moves into the blood

24
During the Luteal Phase

LH
LDL

Cholesterol
Cholesterol
Via cAMP Via cAMP

Pregnenolone Pregnenolone

Progesterone
Progesterone

Androstenedione Via cAMP

Estradiol
Thecal Cell Granulosa Cell
INTO THE
BLOOD
FSH

Figure 5. This diagram shows what is happening in these two cells during the luteal
phase of the ovarian cycle. In this case it is important to note that you can now find LH
receptors on the granulosa luteal cell (these have been produced by the rise of estradiol
levels that occur prior to ovulation). The vascularization of the luteal cells also means
more LDLs are available to the granulosa cells (during the follicular phase they are
surrounded by follicular fluid (go back to Histology). So under the stimulation of LH
both the thecal and granulosa cells take up more cholesterol and convert it into
progesterone. The granulosa cell does not have the enzymes to convert progesterone
further down the steroid synthesis chain and so this progesterone is released into the
interstitial fluid where some enters the blood and the rest enters thecal cells where it will
be converted into 17-hydroxyprogesterone and androstenedione. The androstenedione
may be taken up by the granulosa cell to produce estradiol (this is stimulated by FSH).
Therefore the three major hormones released by the corpus luteum are progesterone, 17-
hydroxyprogesterone and estradiol.

25
The Ovarian Cycle

Figure 5. Diagram showing the fluctuation in gonadotropin and ovarian hormone

levels over the menstrual cycle. (Figure 37-6 of your textbook). If we start at the
beginning of menses it can be observed that FSH has reached its pre-menses peak, it is
believed these elevated levels of FSH are important for the recruitment of the primary
follicle that will become the developed ovum. During the menses LH levels rise due to
the lack of negative feedback from progesterone and estradiol (due to the breakdown of
the corpus luteum at the end of the luteal phase). Near the end of the follicular phase
estrogen levels begin to rise dramatically, this is due to a change from negative to
positive feedback. These elevated estradiol levels stimulate rapid rises in LH and FSH
(the FSH maybe dampened by rising inhibin levels). The rise in LH stimulates a rise in
progesterone levels that is important for the process of ovulation. After ovulation you get
the formation of the corpus luteum and an increase in the secretion of progesterone and
estradiol as described in Figure 4. Inhibin release during this stage causes FSH levels to
progressively decrease. The is maintained until the breakdown of the corpus luteum late
in the luteal phase which leaves us where we started.

The next series of diagrams show the complexity of the control mechanisms controlling
the ovarian cycle.

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The Ovarian Cycle Early to mid-Follicular Phase

Hypothalamus GnRH Anterior Priming GnRH

Pituitary receptors

LH FSH

Thecal androgens Granulosa

Cell Cell

Estrogens Inhibin

Figure 6. This flow chart shows the hormonal control of the early to mid-follicular phase
of the ovarian cycle. During this time GnRH from the hypothalamus is stimulating the
release of LH and FSH from the gonadotrophs of the anterior pituitary. LH is stimulating
androstendione production by the thecal cell, this androstenedione is taken up by the
granulosa cell and converted in estrogens (see Figure 3). Inhibin is also being produced
by the granulosa cell. During this time the estrogens are exerting a negative feedback on
both the hypothalamus and anterior pituitary. Inhibin specifically inhibits the levels of
FSH. It is generally accepted that during this stage the estrogens are also increasing the
number of working GnRH receptors on the gonadotrophs. This is in preparation for the
surges observed prior to ovulation.

If you look at Figure 5 this does not seem to make sense as estrogen levels are slowly
rising. This is because the number of cells of the primary follicle increase throughout the
follicular phase. Therefore even though the secretion from each cell might be less the
number of thecal and granulosa cells is increasing at a rate that overwhelms this factor.
Therefore the overall action is for estrogen levels to rise.

27
Ovarian Cycle Late Follicular Phase

Hypothalamus GnRH Anterior Priming GnRH

Pituitary receptors

LH FSH

Thecal androgens Granulosa

Cell Cell

Estrogens Inhibin
Progesterone

Figure 7. This flow chart shows the hormonal control during the late follicular phase of
the ovarian cycle prior to ovulation. LH and FSH are still acting in a similar manner on
the thecal and granulosa cells with the one exception that the elevated estrogen has begun
to stimulate the production of LH receptors on the granulosa cell. The estrogens now
exert a positive feedback effect on the hypothalamus and the granulosa cells itself. This
is the stage where estrogen levels are rising dramatically. This initiates the LH surge
which is also associated with a rise in progesterone. It is unknown what switches off this
positive feedback action of estrogen though it has been suggested that the elevated
progesterone caused by the LH surge may do this. We are now ready to look at
ovulation.

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 Just prior to ovulation
Progesterone

Helps LH Ovulation
surge processes

Role in FSH Inhibits

surge estrogen

Figure 8. This diagram shows the role of progesterone just prior to ovulation in the
female. You can see the importance of progesterone in ovulation itself, so do not be
fooled into believing that estrogen is before ovulation and progesterone is after
ovulation as this is incorrect.

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 Progesterone

prostaglandins
Collagenase

Breakdown
Hyperemia
of wall

Stigma Swelling of
degeneration follicle

Rupture
and
ovulation

Figure 9. This diagram shows the mechanisms by which progesterone is involved in

ovulation. Progesterone stimulates the production of collagenase in the follicular cell
initiating breakdown of the follicular wall. This helps in the production of the stigma that
degenerates for ovulation to occur. Progesterone also stimulates prostaglandin release
which increases blood flow to the follicle (as well as other roles not yet proven) that
causes follicle swelling, this exerts pressure on the follicular wall also leading to rupture
and ovulation.

30
Ovarian Cycle Luteal Phase

Hypothalamus GnRH Anterior

Pituitary

LH FSH

Corpus
Luteum

Progesterone Estrogens Inhibin

Figure 10. This diagram shows what is occurring in the luteal cells. After ovulation the
corpus luteum is formed from the old granulosa and thecal cells. LH and FSH are present
in high enough levels to produce progesterone and estrogen inhibiting the hypothalamic
release of GnRH. Inhibin is also released inhibiting FSH production and release. The
elevated levels of progesterone during the luteal phase are important to maintain the
uterine endometrium in a state that maximizes the chances of blastocyst implantation.
Both progesterone and estradiol levels remain elevated until about 10 days after ovulation
where they begin to fall due to breakdown of the corpus luteum (maybe due to LH levels
decreasing to amounts that are unable to maintain the corpus luteum).

See Clinical Focus Box 37-1.

31
Ovarian Cycle Late Luteal Phase

Hypothalamus GnRH Anterior

Pituitary

LH FSH

Less inhibin

Ovary
(follicles)

Follicular Recruitment

Figure 11. If pregnancy does not occur the corpus luteum degenerates and hence the
levels of progesterone, estrogens and inhibin decrease substantially. The decrease in
inhibin secretion leads to an elevation in FSH levels and this is believed to produce the
recruitment of new follicles for the ovarian cycle.

32
Estrogens
Basic Information
Estrogen is the word defining the family of sex hormones that include estradiol, estriol
and estrone. They are secreted in varying amounts by the ovary but all have similar
effects (though different potencies).

They are steroid hormones and so release follows synthesis. They travel in the blood
bound to albumin and specific binding globulins and are broken down in the liver and
excreted in bile or by the kidneys.

Physiological Function
It is important to remember that the concentration of estrogen in the blood follows a
specific cycle. Therefore some of the effects described below are going to occur at
specific times. This list describes what is observed in the post-pubertal cycling woman.

Fallopian Tube - increases the number of ciliated cells in the oviduct

Endometrium - involved in regenerating and proliferating
Uterine cervix - stimulates low-viscosity mucus
Vaginal epithelium - stimulates proliferation, thickening and glycogen storage
Osteoblasts - maintains bone calcium levels
Breast tissue - maintains connective and adipose tissue

The following actions of estrogen are important during pregnancy:

Liver - increases the levels of clotting factors, plasma carrier proteins
Electrolytes - activates renin and causes fluid retention
Smooth muscle - sensitizes uterine smooth muscle to oxytocin
Anterior Pituitary - increases prolactin synthesis and secretion

33
 Vaginal
Epithelium
Size of Trauma-resistant
Reproductive
organs
Initiation of
Estrogens Breast
(at Puberty) development

Epiphyseal Histological
Fusion Changes in
Uterine cells

Figure 12. At puberty the release of estrogens leads to an increase in the size of all
internal sex organs and external genitalia. The vaginal epithelium becomes both
infection and trauma resistant (to protect from intercourse), the uterine tissue changes so
it is prepared for blastocyst implantation. Estrogens also take part in initial breast
development and of fusion of the epiphyseal plates of long bones to prevent any further
growing. Interestingly estrogens do this a lot quicker than testosterone maybe giving
reason why on average women are slightly shorter than men.

34
 Further breast
no. and activity development
Of ciliated cells
At oviduct

Estrogens Protein
synthesis

Ovarian and
Menstrual Subcutaneous
function Fat deposition

Figure 13. This diagram shows the activity of the estrogens after puberty and up until
menopause. The estrogens as we have already seen are important in ovarian and
menstrual cycle function. They also promote the movement of the ovum into the oviduct
by increasing both the number and activity of the ciliated cells of the oviduct. Being a
steroid hormone estrogens stimulate protein synthesis but not to the level observed with
testosterone in male. It also stimulates breast development and subcutaneous fat
deposition.

Progestins
Basic Information
Two hormones that come under the umbrella of progestins are released by the ovary,
progesterone and 17--hydroxyprogesterone. The former is secreted in a much greater
amount and it is usual to put both under the name progesterone.

Steroid hormones

35
Progesterone travels in the blood bound to albumin and specific binding globulins and is
broken down in the liver.

Physiological Function
It is important to remember that the concentration of progesterone in the blood follows a
specific cycle. Therefore some of the effects described below are going to occur at
specific times. This list describes what is observed in the post-pubertal cycling women.

Fallopian tube - upregulates ciliary beating activity then s numbers of cells

Endometrium - stimulates secretory activity
Cervix - s mucus production, s mucus viscosity
Electrolytes - antagonizes aldosterone receptor Na+ reabsorption
Smooth muscle - s contractility, uterine contractility

Uterine Alveoli cells

endometrium of breast

Progesterone

Uterine excitability
Ovulation During pregnancy

Figure 14. Diagram giving a summary of the role of progesterone in the female.
Progesterone as we have already seen is important in the process of ovulation and after
ovulation prepares the uterine endometrium for implantation. During pregnancy
progesterone levels increase dramatically. Here it is important for decreasing uterine
excitability during pregnancy decreasing the chances of premature birth due to
spontaneous uterine contractions. During pregnancy it is also important for preparing the
alveoli cells of the breast for lactation.

36
The Endometrial (Menstrual) Cycle
The basics of this was covered in Histology in First Semester.

Hormonal regulation of the menstrual cycle

Broken up into 3 phases, menstrual, proliferative and secretory. The menstrual and
proliferative phases occur during the follicular phase of the ovarian cycle. The secretary
phase is associated with the luteal phase.

Menstrual phase
When the corpus luteum breaks down it leads to a decrease in progesterone secretion and
shedding of the endometrium. This phase usually lasts about 4 days and blood loss is ~
30ml (>80ml is abnormal)

Proliferative phase
During this phase there is an increase in estrogen levels which leads to the proliferation
of both stromal and epithelial cells of the endometrium. This regeneration occurs from
the basal portion of the endometrial glands left behind in the stratum basale during
menstruation

Secretory phase
During this phase there is an increase in progesterone levels. There is maturation of the
of the endometrium that has been prepared during the proliferative phase. This makes the
endometrium suitable for implantation of the blastocyst

Puberty
What starts puberty???
Answer: An increase in GnRH secretion (yes), an increase in GnRH receptors at the
pituitary (maybe).
What stimulates this???
Answer: No one is really sure.

This increase in GnRH activity and response to it by the anterior pituitary leads to an
increase in circulating estrogens. This itself leads to the induction of the secondary
sexual characteristics as discussed earlier.

This is followed by the first menstruation (menarche) that usually occurs around age 10 -
12 (though very variable). Ovulation usually does not occur until 6-12 months after this
as it takes time for the hypothalamic-pituitary axis to be fully responsive to the changes
in hormonal levels.

See Clinical Focus Box 37-2, and Bench to Bedside Box 37-1

Menopause
This is the time after which the final menses occurs. There is no more ovulation and
reproductive cycles so the ovaries atrophy, due to a decrease in estrogen secretion Not
surprisingly this increases FSH and LH levels due to a lack of negative feedback.

37
Figure 15. Diagram (Figure 37-2 of your text) showing the amount of LH found in
the serum of the female over her lifetime. There are two surges during fetal and neonatal
life (similar to the male). You can see that it is only after puberty that the ovarian cycle
begins then there is a rapid increase in levels during menopause. The profile of FSH
secretion is similar.

Menopause leads to many changes. The decrease in the estrogen / androgen ratio may
lead to hirsutism. The decrease in estrogen causes atrophy of breast and reproductive
tracts, vaginal dryness, urinary tract problems. While changes in the GnRH pulse
generator may cause changes in hypothalamic thermoregulation producing the
characteristic hot flushes.

38
Medical problems associated with abnormal female reproductive
physiology

Hypogonadism
This is less than normal secretion of hormones by the ovaries, usually due to either the
lack of, or poorly functioning ovaries. It may also be due to a problem with the secretion
of hypothalamic or pituitary hormones..

When this occurs prior to puberty it leads to lack of development of sex organs and
secondary sexual characteristics. Similarly to the male there will be a delay in bone
fusion leading to longer long bones.
If it occurs after puberty the female sexual organs decrease in size somewhat, the breasts
change and other secondary sexual characteristics may regress. This is similar to what is
observed during menopause. There will be a loss of the regularity of the ovarian and
menstrual cycles.

Sterility
Many things may lead to sterility in the female. These include hypogonadism,
endometriosis, salpingitis and others. Sterility is the inability for the sperm to meet the
egg in the oviduct and fertilize it and then for implantation to occur.

39
 Section 3

Pregnancy

Learning Objectives
1. Describe the physiological role of hCG in a successful pregnancy.
2. Explain the role of the maternal-placental-fetal unit in the production of reproductive
hormones.
3. Describe the physiological roles of the estrogens and progesterone in pregnancy.
4. Describe the physiological roles of hCS (hPL).
5. Discuss and explain the changes in maternal endocrine function during pregnancy.
6. Discuss and explain the role of the fetal endocrine system during pregnancy.
7. Explain the physiology underlying the mechanism by which the fetus maintains
adequate blood-gas concentrations and pH.
8. Compare and contrast the %oxygen saturation of Hb vs PO2 curve of the mother and
the fetus.
9. Briefly discuss the movement of substances across the placenta.
10. Discuss the changes in maternal cardiovascular function during pregnancy.
11. Discuss the changes in maternal and fetal glucose homeostatic mechanisms during
pregnancy.
12. Discuss the maintenance of an adequate calcium supply to the fetus during
pregnancy.
13. Describe the underlying physiology of medical problems associated with pregnancy.

Readings
Chapter 38 of your textbook

Introduction
Pregnancy involves many changes in the mother that are associated with the maintenance
of the optimal environment for the developing fetus. This lecture will look at these
changes.

40
Endocrinology of Pregnancy
Introduction
In order to understand pregnancy you must accept the fetus, placenta and mother all as
one unit. This section will discuss the hormone interactions within this unit and the
reasons underlying these changes.

Human Chorionic Gonadotropin

This hormone is very similar in structure to LH. It is produced by the embryo before
implantation and after implantation is secreted by the syncytiotrophoblast cells in the
intravillous space.

hCG can be detected in the serum or urine 7-8 days before the expected menses and is the
earliest detector of pregnancy. In fact some can now measure hCG levels 2 days after
fertilization has taken place.

hCG Corpus Luteum

Estrogens
Progesterone
Male Fetus

Figure 1. This diagram summarizes some of the actions of hCG in early pregnancy.
hCG is required to maintain the corpus luteum and this therefore produces sustained
progesterone and estrogen production. This must be maintained until the placenta takes
over progesterone secretion. As stated earlier hCG also is important in the development
of the male fetus causing the release of testosterone from the fetal gonads.

hCG works via the LH receptor and also stimulates production of estrogens, 17-
hydroxyprogesterone, relaxin and inhibin.

41
 Up to 6 Weeks 6-12 weeks More than 12 weeks

Corpus
Luteum Placenta

Progesterone Progesterone

Figure 2. This diagram shows the major controllers of progesterone synthesis and
release during pregnancy. In the first 6 weeks all progesterone is produced by the corpus
luteum. Between 6-12 weeks the placenta is developing and both the it and the corpus
luteum supply the progesterone. After 12 weeks and until birth the placenta supplies all
of the progesterone.

The Feto-placental Unit

The fetus and placenta must work together in order to coordinate the growth an
development and expulsion of the fetus from the uterus. In order for this to occur there
are many changes in hormonal secretion that occur both in the mother and the placenta
(less in the fetus).

42
 Gas exchange Nutrient
Waste
Exchange

Placenta

Barrier
Hormone
Production

Figure 3. This diagram summarizes the role of the placenta in maintaining the health and
wellbeing of the fetus. The placenta acts as the area of gas exchange between the mother
and the fetus, bringing in oxygenated blood and removing the carbon dioxide as well
nutrients and waste also pass across the placenta in both directions in order to maintain
fetal development and health. The placenta also acts as a barrier to prevent harmful
molecules and substances to pass from the mother to the fetus. The placenta is also
extremely important in the production of hormones that are important for both the mother
and the fetus. There is a special relationship between the fetus, placenta and mother in
the production of these hormones and this is known as the feto-placental unit.

43
Steroid Hormone synthesis of the Feto-placental unit

Figure 5. Diagram (Figure 38-7 of your text) showing the interrelationship between the
mother, placenta and fetus in the production of steroid hormones. Without a normal
functioning ovarian cycle the mother must look at another source of estrogens and
progestins. With respect to progesterone, most if not all progesterone is produced in the
placenta. The placenta takes up LDLs and cholesterol up from the mother and then
converts this into prenenolone and then on to progesterone, the placenta does not contain
17-hydroxylase and therefore can not convert this progesterone any further. This
progesterone leaves the placenta to supply the mother with her requirements and to
perform the important functions described below. With respect to the estrogens it is both
the fetus and the placenta are important in producing this group of hormones. The
pregnenolone from the placenta passes into the fetal circulation where it is taken up into
the fetal adrenal cortex and sulfated. The enzymes in the fetal andrenal cortex then
convert the pregnenolone sulfate into dehydroepiandrostenedione sulfate (DHEA-S)
which then is returned to the placenta to be converted into DHEA. The placenta contains
the enzymes which convert DHEA into both estradiol and estrone that then enter the
maternal circulation. The DHEA-S may also be converted into 16-OH DHEA-S which
is converted into estriol into the placenta prior to entering the maternal circulation.

What is the importance of the sulfating of the DHEA in the fetus??

44
Progesterone
As shown in Figure 5 the major source of progesterone during pregnancy is the placenta.
The progesterone is synthesized from maternal cholesterol.
Progesterone is secreted in order to

Endometrial cells
Of uterus Maintains
pregnancy

Progesterone

Cervical
Plug?? Final breast
development

Figure 6. This diagram is a summary of the action of progesterone in the mother during
pregnancy. Progesterone is important in maintaining the pregnancy in two major ways; it
helps in the maintenance of the endometrial cells of the uterus which helps to provide the
optimal environment for the fetus to develop, and it inhibits myometrial contractions (by
inhibiting smooth muscle directly and by inhibiting prostaglandin production).
Progesterone levels rise throughout pregnancy and it is important in the final
development of the maternal breast so that it is ready for lactation after birth. It is also
believed to be involved in the formation of the mucus plug of the cervix decreasing the
chance of infection reaching the fetus via the vagina.

45
Estrogens
The placenta produces estrogens using androgenic precursors from the fetal adrenal
cortex.

Prepare body for

parturition Development
Of Breast

Estrogens

Inhibits
Milk production Initiator of
(with progesterone) Parturition ???

Figure 7. This diagram is a summary of the actions of the estrogens during pregnancy.
They are very important in preparing the mother for parturition, it sensitizes the
myometrium to oxytocin (therefore preparing the uterus for the strong contractions that
are required to expel the fetus), it stimulates growth of uterus, the enlargement of external
genitalia and it relaxes pelvic ligaments (all of these are required for the mother to give
birth in a manner that decreases the chances of maternal, and fetal, death). Like
progesterone, estrogen is also important in the growth and development of the breast, and
as we saw in Section 2 of Endocrinology it stimulates prolactin production. Even though
it stimulates prolactin it inhibits milk production meaning that it prepares the breast for
lactation but stops the switch to begin milk production being switched on (milk
production prior to birth would divert important nutrients away from the developing
fetus). As we will discuss in the final section there is also some argument that the
elevated levels of estrogen found close to birth may actually initiate the parturition
process.

46
Human Chorionic Somatomammotropin (Human Placental Lactogen)
A 191AA polypeptide with 96% homology with GH
Produced by the syncytiotrophoblast cells and levels released are proportional to the size
of the placenta.

Growth Hormone
Effects ??? Decreases maternal
On breast Insulin sensitivity

Human Placental Lactogen

(hPL)

More glucose available

For fetus

Figure 8. This diagram is a summary of the speculated actions of human placental

lactogen (hPL). As pregnancy continues the maternal plasma levels of hPL also increase.
It is similar in structure to growth hormone and it has been suggested that it helps divert
glucose away from the mother and to the fetus (remember think of the fetus as a parasite).
It does this by decreasing glucose uptake by the muscle and adipose tissue of the mother
as well as increasing maternal liver glucose production. This elevates maternal blood
glucose giving a better exchange of glucose at the placenta. The mother reacts by
increasing her circulation of insulin and this leads eventually to peripheral insulin
resistance. In those who are already susceptible to Type II diabetes it may lead to
gestational diabetes. This is something you should think about when a person with Type
I diabetes gets pregnant.

47
Other Placental Hormones

There are many other placental hormones and it would not be surprising if more are
discovered over the next 20 years. The following are some that have recently been found
though their specific roles in pregnancy are still controversial. You will not be examined
on these it is more to make you aware of them.

Chorionic adrenocorticotropin
This is important as it is believed that this may have a major role is DHEA-S production
by the fetal adrenal that is important for Estradiol production in the mother.

Chorionic thyrotropin (hCT)

Is produced but physiological role under some doubt

Parathyroid Hormone-related peptide

Believed to increase calcium transport across the plasma.

Hypothalamic-like releasing hormones

Also found and thought to have in role in the production of hCG, hCT and POMC.

Human Placental Growth Hormone

Secreted throughout pregnancy by the placenta. It is believed to produce IGFs that
negatively feedback on maternal growth hormone production.

48
Maternal Changes in Endocrine Function During Pregnancy
The mother undergoes drastic changes due to the requirements of the feto-placental unit.
There are normal changes that occur in order for pregnancy to proceed and it is important
that you understand these changes.

Pituitary Gland

TSH
ACTH
PRL

Anterior
Pituitary

FSH
LH

Figure 9. This is a simple summary of the changes in hormonal secretion from the
maternal anterior pituitary during pregnancy. The pituitary actually may increase in size
by 50% during pregnancy. This is thought to mainly be due to the elevated number of
lactotrophs required in order to increase the amount of prolactin required as pregnancy
progresses. TSH secretion also increases maybe due to estradiol affecting TRH receptors
and also maybe due to the lower levels of free thyroid hormone in the body due to
estrogens stimulating the production of thyroid hormone binding globulin. ACTH levels
also increase due in part to the elevated levels of CRH observed during pregnancy (see
next section) and may be to stimulated the maternal adrenal to produce more DHEA-S for
placental estrogen production.

Why is there a decrease in FSH and LH levels during pregnancy?

49
Thyroid Gland

TSH

Thyroid
hCG BMR???
Gland

IS THERE ELEVATED
hCT FREE THYROID
HORMONE
LEVELS??
AS ELEVATED TBG

Figure 10. This is basic diagram showing the changes that occur in the thyroid gland
over pregnancy. The thyroid gland increases in size due to the stimulation of TSH, hCG
and hCT (the last two of course coming from the placenta). However the elevated levels
of TBG stimulated by high estrogen levels negate the effect of the elevated thyroid
hormone release, therefore the effect on basal metabolic rate is minimal.

50
Parathyroid Gland

Calcium for
fetus

Parathyroid
PTH
Gland

Calcium for
milk

Figure 11. This diagram shows the role of the maternal parathyroid gland in pregnancy.
The development of the fetal skeleton requires 30 g of calcium, this is supplied by the
mother with hyperplasia of the parathyroid gland elevating PTH levels. Although one
would expect calcium levels in the mother to increase because of this, the extra calcium is
quickly transferred across the placenta to the fetus and maternal levels of free ionized
calcium remain relatively unchanged. The parathyroid glands remain large after birth to
help supply enough calcium for the mother to produce milk.

51
Maternal Pancreas

But insulin
Resistance
In tissues

Pancreas Insulin

More glucose
For fetus

Figure 12. This diagram shows the changes that occur in the maternal pancreas during
pregnancy. The pancreatic Islets increase in size due to hyperplasia of the -cells.
Insulin levels start off at normal, increase in the 2nd trimester, and continue to do so from
then until birth producing a hyperinsulinemic state in the mother. This is due to the
elevated levels of maternal blood glucose caused in part by hCS and elevated levels of
cortisol. This elevated blood glucose is help by insulin resistance in tissues meaning a
decrease in maternal uptake of glucose. All of this supports the supply of more glucose
to the fetus.

The fetus requires the mother to provide it with adequate supplies of glucose. As a lot of
this elevated blood glucose goes to the fetus the metabolic needs of the mother are
provided by fatty acid metabolism. It is important for the mother to have a proper diet to
prevent ketosis.

52
Adrenal Cortex

AAs for fetus

Cortisol Stretch marks
Insulin resistance

Estrogen
DHEA-S production by
Adrenal the placenta
Gland

Aldosterone Cardiac output

Figure 13. This diagram shows the important role of the maternal adrenal gland during
pregnancy. All three of the major cortical hormones are increased during pregnancy.
Cortisol levels increase with plasma free cortisol levels almost doubling even though the
levels of cortisol binding globulin increase via estrogen (this increases the half-life of
cortisol. These elevated levels of cortisol mobilize amino acids from the mother to the
fetus, have a role in the insulin resistance of the mother and is most likely involved in the
appearance of stretch marks (poor wound healing). As discussed previously elevated
levels of DHEA-S occur to provide a substrate for the production of estrogens by the
placenta. There are also increases in aldosterone secretion and this may be in order to
counteract the elevated progesterone levels (progesterone antagonizes the
mineralocorticoid receptor) and it has also been postulated that this elevated aldosterone
helps to elevated cardiac output in the mother the supply the placenta with an adequate
blood flow.

53
Fetal Endocrinology
Introduction
The fetal endocrine system is one of the first body systems to function.

Anterior Pituitary Hormones

All releasing hormones from hypothalamus are present by ~ Week 10 with all hormones
present by Week 12. Fetal gonadotropins do not direct initial gonadal development but
are important for normal development of differentiated gonads and external genitalia.
ACTH release is important for maturation of the adrenal gland

Posterior Pituitary Hormones

Oxytocin and ADH are present by ~Week 15. It has been suggested that fetal oxytocin
may be important for the onset or maintenance of labor.

Thyroid Hormones

Thyroid Hormone

Thyroid
Gland Calcitonin

Parathyroid
Gland

Figure 14. This diagram summarizes the role of the both the fetal thyroid and
parathyroid glands. During the second trimester levels of TRH, TSH and T4 all rise in the
fetus with feedback inhibition occurring at Week 20 in the fetal hypothalamic-pituitary-
thyroidal axis. Thyroid hormone is important for somatic growth and neonatal
adaptation. It is also believed to be important for auditory maturation. Calcitonin levels
are elevated to help the fetus form bone.

The placenta actively transports calcium to the fetus and PTH secretion is suppressed in
order for the calcium to be used to form bone.

54
Figure 15. This diagram show the changes in the adrenal cortex that occur over the first
18 years of life, this includes fetal life (Creasy et al., 2004). As you can see during fetal
life (the far left box) the adrenal gland is comparatively large (in fact at mid-term they are
bigger than the fetal kidneys) due to a large area taken up with what is known as the fetal
cortex, this is the area involved with DHEA-S synthesis. As we have seen previously the
fetal adrenal cortex is important for the production of DHEA-S which is used by the
placenta to produce estrogens.

Note that the fetal zone is so large up until one month after birth where it rapidly
decreases in size.

55
The Movement of Substances Across the Placenta
Oxygen/Carbon dioxide
Oxygen travels to the fetus via the maternal blood supply. It diffuses across the placenta
with the amount proportional to blood flow. The placenta supplies ~8ml O2 per min / kg
fetal weight. Stores of oxygen in the fetus will only maintain the fetus for 1-2 minutes so
must be continuous supply.

Uterine Umbilical
Artery Vein Vein Artery
PO2 (mmHg) 95 40 27 15
O2Hb (%sat) 98 76 68 30
O2 content (ml/dl) 15.8 12.2 14.5 6.4
Hb (g/dl) 12 12 16 16
O2 capacity (ml O2/dl) 16.1 16.1 21.4 21.4
PCO2 (mmHg) 32 40 43 48
CO2 content (mM/l) 19.6 21.8 25.2 26.3
HCO3 (mM/l) 18.8 20.7 24 25
pH 7.4 7.34 7.38 7.35

Table 1: This shows the normal values for oxygen, carbon dioxide and pH in maternal
and fetal blood (this data is taken from late in gestation). You dont have to memorize
the numbers just understand what is going on.

It can be observed that the PO2 of the blood in the umbilical vein is much less than that of
the uterine artery. The movement of the fetal Hb-O2saturation curve to the left helps to
maintain Hb saturation in the fetus. Also note the greater concentration of Hb in the fetus
providing it with a greater O2 capacity. These two factors help to maintain an adequate
oxygen supply to the fetus. The higher PCO2 value of the umbilical vein would be
expected to decrease pH in the fetus however higher HCO3- levels buffer this maintaining
the pH.

56
Figure 16. Diagram showing a comparison between the oxygen-Hb saturation curve of
the fetus with the mother. As you can see the fetal oxygen-Hb saturation curve is shifted
to left meaning that fetal hemoglobin has a much greater affinity for oxygen. This is
important because as you can see from the preceding table the fetal circulatory system
works a much lower level of partial pressure of oxygen. The fetus requires high levels of
oxygen for normal growth and development and this special affinity of fetal hemoglobin
is important in delivering the fetus with enough oxygen.

57
Other Substances

Figure 17. This diagram (Figure 38-5 of your text) shows the direction of movement of
various substances across the placenta. The placenta forms an important barrier but must
also let important substances through.

58
Maternal cardiovascular and renal changes during pregnancy
Introduction
There are many changes that occur during pregnancy that would be considered abnormal
in the non-pregnant person. This section looks at these changes.

Cardiovascular Changes

Red Blood
Cells

Clotting
Factors

Cardiac
Output

Figure 18. This diagram shows some of the cardiovascular changes that occur in the
mother. There is an increase in the production of red blood cells most likely to increase
the oxygen carry capacity of the mother to meet the demands of the growing fetus. There
is a increase in the number of clotting factors most likely to improve the mothers
chances of survival if she hemorrhages during parturition. There is also and increase in
cardiac output, due in part to an increase in plasma, and hence stroke, volume, to supply
the increase blood flow to the placenta.

Glucose Homeostatic Changes

In the non-pregnant female there are the usual mechanisms to maintain adequate fuel
supply in the extracellular fluid. Fuel conservation in the fed state and the mobilization
of stored fuel in the fasting state.

In pregnancy this becomes more difficult as a continuous supply of nutrients to the fetus
must be maintained and integrated with the requirements of the mother. To prevent
growth retardation of the fetus amino acids and glucose must be preferentially delivered
to the fetus during fasting. Therefore the mother must satisfy her primary fuel
requirements from free fatty acids mobilization.

59
If there is diabetes of the mother (either IDDM or gestational diabetes), this leads to
higher maternal glucose levels which causes more glucose delivered to fetus. The fetal
pancreas will respond by releasing insulin (from ~Week15), this will cause fetal
hyperinsulinemia. This leads to high levels of glucose delivered to cells PLUS insulin
produces growth factor biological effects (via insulin and IGF receptors) causing fetal
macrosomia (>4kg), and the fetal head may grow to big for normal birth

By the third trimester there is elevated cortisol levels and GH-like activity (of hPL) in the
mother, this leads to a compensated state of insulin resistance or hyperglycemia is
prevented by hyperinsulinemia. You may observe plasma insulin levels ~2X that of
normal.

Medical Problems Associated with Pregnancy

Gestational Diabetes
Impaired glucose tolerance develops in 2-8% of all pregnant women.
Usually occurs during the second half of pregnancy.
Mainly due to insulin resistance.
Observed by abnormal glucose tolerance and postprandial hyperglycemia
If poorly controlled may lead to macrosomia, polyhydramnios, fetal retardation.

Pre-eclampsia
Hypertensive disease observed in pregnancy.
Occurs in about 5% of all pregnancies.
The cause remains unknown but believed to be associated with placental malfunction that
causes vasospasm, ischemia and thrombosis.
Usually develops after the 20th week of gestation
Signs and symptoms include; headache, visual disturbances, confusion, abdominal pain,
many vascular disturbances including pulmonary edema, fetal growth retardation.

60
 Section 4

Parturition and Lactation

Learning Objectives
1. Discuss the mechanism of action of oxytocin in uterine smooth muscle contraction.
2. Explain the concept of estrogen priming the uterine smooth muscle for parturition.
3. Compare and contrast the two major theories on the initiation of parturition
4. Discuss the changes in uterine structure prior to parturition.
5. Describe the physiology underlying the positive feedback mechanism that leads to
expulsion of the fetus.
6. List the mechanical stages of labor.
7. Describe the underlying physiology of dystocia.
8. Discuss the importance of breast milk for the neonate.
9. Describe the physiological role of the major hormones associated with lactation.
10. Discuss the role of the hypothalamic-pituitary-mammary axis in both milk
production (secretion) and ejection

Readings
Chapter 38 of your textbook

Introduction
At the end of pregnancy it is important the fetus is ready for delivery and the birthing
process is normal. There are many changes that occur within the mother prior to birth in
order to make sure this is so. Once born it is important for the baby to be able to gain
nutrition, antibodies and other important substances from the mothers milk. This lecture
discusses these processes.

61
The Female Reproductive Tract and Pregnancy
Uterine Contractility
The uterus must be primed to be ready for large contractions at the time of birth. In order
to understand these changes a knowledge of the factors involved in smooth muscle
contraction are required. The figure below shows the events that may occur within the
smooth muscle of the uterus

Role of oxytocin
Oxytocin

IP3 & DAG Ca2+

Contraction

Smooth muscle cell

Fig. 1. Diagram showing how oxytocin affects calcium levels and hence contractility of
the uterine myometrium. The hormone oxytocin uses the IP3 mechanism to produce
contraction. Uterine relaxants (such as 2-adrenergic agonists) work via activating
cAMP. Prostaglandins may cause contraction (via PLC) or relaxation (via cAMP) of
uterine smooth muscle (you will look at this more in Pharmacology).

Oxytocin
Oxytocin is a 9 AA hormone stored in axonal endings found in the posterior pituitary. It
is important in both parturition and lactation.

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Initiation of Parturition
Introduction
There is still much controversy and discussion over the mechanisms involved in the
initiation of the birthing process. It may be due to a in progesterone levels, an in
circulating CRH or an in estrogen levels, or all three.

Estrogen:Progesterone ratio

Figure 2. Graph (Figure 38-6 of your text) showing the changes of some important
hormones associated with pregnancy. Note the increase in estrogens compared with
progesterones in the weeks prior to birth. Progesterone has been shown to have a
calming effect on uterine smooth muscle. It inhibits oxytocin receptor synthesis,
stimulates cAMP production and inhibits the release of prostaglandins that will excite the
uterine smooth muscle. Estrogens oppose progesterone in many of these actions and will
also be involved in ripening the cervix and increasing the number of myometrial gap
junctions (to make a coordinated stronger contraction). It is believed that as the
pregnancy is nearing its end, the rise in estrogen levels while progesterone levels plateau
or even drop may lead to the excitatory actions of the estrogens overwhelming the
inhibitory action of progesterone leading the uterine contractions and birth.

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 levels of CRH

Figure 3. Diagram showing the changes in CRH and CRH-BP as birth approaches. Note
the rapid rise in CRH levels and associated fall in CRH-BP. This means there is increase
in the amount of free CRH available. This data does not prove that CRH is the initiator
of parturition but suggests that it may have a role. A large amount of this CRH is also
produced by the placenta as birth approaches.

The placental CRH is believed to act on the fetal zone of the adrenal cortex producing
and increase in DHEA-S production that is used to produce more estrogen by the placenta
(see below). This may be one of the initiators of the rapid rise in estrogen levels near
birth stimulating parturition as described previously.

The CRH also s the production of excitatory prostaglandins

Changes in uterine structure prior to birth

As pregnancy progressive the uterus begins to contract. There is still controversy as to
what initiates these contractions (uterine stretch??? Hormones) but they definitely do
occur and usually with greater strength and frequency as the pregnancy progresses.

Just prior to birth the uterus has developed into two distinct sections
1. Upper muscular section. For better propulsion of the fetus through the cervix.
2. Lower thinner section. Becomes less muscular and forms with the ripening cervix
and vagina a passive birth canal (allowing passage of the fetus).

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Initiation of the birthing process
As gestation continues the number of oxytocin receptors on the uterus increase
dramatically.

STRESS

Posterior
Pituitary
oxytocin
Hypothalamus
oxytocin
Neural
reflex Placenta
Uterus
pgs

oxytocin
Contractions
of
Fetus uterus

Figure 4. Diagram showing the positive feedback reaction causing more vigorous
contractions of the uterine smooth muscle in order to expel the fetus. It is believed that
the decent of the fetus (due to myometrial contractions caused by prostaglandins from the
placenta) activates stretch receptors located in the cervix and upper wall of the vagina
leading to oxytocin release and greater contraction (positive feedback). This oxytocin
also causes the release of prostaglandins from the placenta causing further contraction.
The fetus is also believed to release oxytocin during the birthing process to help with
uterine contraction.

See Clinical Focus Box 38-2.

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Medical Problems Associated with Labor
There are many problems that may occur during the process of labor and you will discuss
these in later semesters. An example of one such problem is Dystocia (abnormally slow
labor), this can be caused by problems with the uterus, the size of the fetus, the
positioning of the fetus as well as others (see figure below).

Figure 5. Pie chart showing the comparative frequency of the problems causing
Dystocia. As you can see the major problem is associated with cephalopelvic
disproportion, the baby being to large to come out quickly. Interestingly in our modern
times sedation and anesthesia also are major players in slowing down the birth process.

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Lactation
Introduction
The survival of the newborn requires lactation (under normal circumstances). The
healthy term infant is ready in most instances for the outside world (it can breathe, its
heart pumps blood etc) but some systems are still immature (immune, digestive system,
kidneys, neural and some endocrine). Therefore the maternal role in the survival of the
baby continues after birth.

Importance of breast milk

Breast milk is suitable for digestion and absorption by the immature digestive system
Provides optimal amount of water and electrolytes (to prevent the kidney not being able
to deal with imbalances)
Provides immunological protection
Contains hormones that may help with regulation of body systems (Vitamin D, TRH,
GnRH and many others)

Major Hormones Associated with Lactation

During pregnancy, several hormones working together stimulate the growth and
maturation of the mammary gland
- estrogens, progesterone, prolactin, hCS, cortisol, insulin, GH and others
- epithelial tissue expands and becomes activated
- estrogens and prolactin deposition of fat tissue
Important: high levels of estrogen (inhibits terminal differentiation) and progesterone
(inhibits lactogenesis)

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 Prolactin Required to
Inhibit
supply
during
ingredients
pregnancy

Estrogens GH, cortisol

Mammary Gland PTH, insulin
Progestins

Milk Production

Figure 6. This diagram shows how milk production is inhibited during pregnancy by
estrogens and progestins. Estrogens inhibit milk production during pregnancy by
preventing terminal differentiation and progesterone inhibiting lactogenesis. This is
important as the constituents of the milk are required to be delivered to the developing
fetus rather than provide storage for milk. After birth the levels of these two hormones
decrease dramatically and milk production begins with prolactin being the major
controller of this. After birth, the levels of progesterone and estrogens decline. This
leads to the final formation of the breast tissue and prolactin-stimulated milk secretion
(dont confuse with ejection). Therefore initially the baby gets colostrum as it takes 1-7
days for milk production to reach required levels. Other hormones important for the
maintenance of milk production are GH, cortisol, PTH and insulin, these help to supply
adequate nutrients etc for the milk. Sucking the nipple is the main regulator of prolactin
secretion during lactation as shown on the next page in Figure 7.

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 Suckling

Producing Via mechanoreceptors in nipple

more milk

Hypothalamus

PRF Dopamine

Anterior
Pituitary

Prolactin

Figure 7. Suckling by the baby will lead to spikes in the prolactin concentration in the
blood. There needs to be a number of these spikes throughout a 24 hour period to
maintain milk production. A decrease in the frequency in breast-feeding or regular long
breaks (eg overnight) may lead to milk production ceasing. The suckling inhibits
dopamine release from the hypothalamus while stimulating the release of PRF (prolactin
releasing factor).

Biological Actions of Prolactin

Lactation
- increase milk production
- promotes gene expression of milk proteins
- stimulates lactose synthesis
Reproduction
- in high levels GnRH secretion
- in high levels galactorrhea amenorrhea in females
impotence in males
- inhibits follicular development during breast feeding
Prolactin has recently been shown to be important for neural development in the fetus.
Accumulates breast tissue after priming by estrogens.

The hormone oxytocin is important as it allows the milk to be ejected from the breast (see
Figure 8 on the next page).

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 Suckling

Producing Via mechanoreceptors in nipple

milk
ejection
Hypothalamus

Posterior
Pituitary

Oxytocin

Fig 8. Diagram showing the role of oxytocin in the milk let-down reflex. Suckling
stimulates the nerve cells in the hypothalamus leading to the release of oxytocin from the
axon terminals in the posterior pituitary. This oxytocin contracts the myoepithelial cells
of the breast forcing the milk into the duct and making it available for the baby sucking at
the nipple.

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