Physiology of Reproduction (2019) Notes: Provided by Yvonne Hodgson

These notes accompany the lectures for 2019 in NUT2001.

Pre-lecture activity:
Watch the following videos from Mr Ford’s class:
https://www.youtube.com/watch?v=Ml29ezbvMuY 4.84 mins Anatomy of the Ovary
https://www.youtube.com/watch?v=bdeDSx3eKDk 3.45mins. Anatomy of the Uterus

Lecture Learning Outcomes:

After completion of this lecture and reading of the textbooks you should be able to:
1. Describe the steps involved in fertilization
2. List some of the hormonal factors involved in pregnancy
3. Describe the structure and functions of the placenta and the mechanisms of nutrient transfer
across the placenta
4. Describe the functions and composition of amniotic fluid?
5. Discuss the maternal adaptations that occur during pregnancy and how these facilitate growth and
development of the foetus
6. List the major developmental processes of the embryonic period

Reading Texts:
Medical Science. Naish, J., Revest, P and Syndercombe Court, D. Chapter 10, p501-510; 517-525; 528-530.
The Reproductive System at a glance. LJ Heffner and DJ Schust. 4th Ed chapter 16 -21 (p40-51)
Supplementary Reading: Essential Reproduction. Johnson and Everitt,

Fertility in the adult female is episodic

The ovary has two functions, i) to produce ova (oogenesis) and ii) to secrete female sex hormones, namely
estrogen and progesterone which support the development of the fetus and new born baby.
Oocytes are released from the ovary episodically at the time of ovulation during the menstrual cycle. The
pattern of release of estrogen and progesterone seen in plasma reflects the episodic release of these
hormones by oocytes. The period before ovulation is characterised by estrogen dominance while the
period after ovulation is characterised by progesterone dominance. This cycle of ovarian activity is
accompanied by changes in the uterus and together is termed the menstrual cycle.
The female reproductive tract serves to transport the gametes to the site of fertilisation and it also serves
to provide the site of implantation of the embryo and its subsequent development. Transport of the
gamete to the site of fertilisation occurs during the first, estrogenic, part of the cycle. During the second,
progesterone, part of the cycle the ovary prepares the uterus to receive and nurture the fertilised oocyte.

Steps in Fertilisation
Human development begins with the fusion of the sperm with the oocyte (egg) to form a zygote. The
zygote then goes on to develop into a human baby.

Combining chromosomes of ovum and sperm

During ovulation the dominant follicle in the ovary ruptures and the mature oocyte (ovum) is expelled with
its surrounding cumulus cells into the fimbria of the fallopian tubes or oviduct. The cilia lining the oviducts
sweep the ovum along the oviduct. Transport of the ovum along the oviduct is dependent on the presence
of the cilia and the cumulus cells. The ovum and the spermatozoa come together in the ampulla of the
oviduct, where fertilization takes place. The ovum is only viable for 6-24 hours.

Fertilization is no easy task. Millions of sperm leak from the vagina almost immediately post coitus (~99%).
Of those remaining, many are killed by vaginal acid and many get trapped in the thick mucous at the cervix.
Even if the sperm reaches the ova, it needs to wait for capacitation to occur before fertilisation can take
place. Capacitation is the final step in the maturation of the spermatozoa. In this process the surface of the
spermatozoa is stripped of the glycoprotein layer that it acquired during its passage through the epididymis
in the male reproductive tract. These changes to the surface of the spermatozoa destabilise it and
enhances its ability to fuse with the oocyte membrane. The capacitated spermatozoa that reach the zona
pellucida of the oocyte bind to specific zona proteins via sperm cell surface glycoprotein ZP3. The binding to
the zona then induces a dramatic change in the spermatozoa called the acrosome reaction. During this
reaction the acrosome of the spermatozoa swells and the enzymatic contents are exocytosed into the
space around the head of the sperm. The acrosome reaction exposes its proteolytic enzymes which digest
a pathway for the spermatozoa through the zona pellucida. The spermatozoa then comes to lie
tangentially to the oocyte and the two membranes bind and fuse and the sperm nucleus enters the oocyte
cytoplasm. Only capacitated spermatozoa that have undergone the acrosome reaction can bind and fuse
to the oocyte.
 Images taken from: https://www.osmosis.org/learn/Human_development_days_1-4

There are two issues facing the oocyte and spermatozoa, i) other spermatozoa need to be prevent from
entering/fusing with the oocyte and ii) the oocyte which is in suspended meiosis, needs to complete this
process. The cortical reaction of the oocytes prevents the binding and penetration by further spermatozoa.
In this step cortical granules in the oocyte cytoplasm fuse with the cell membrane and release their
contents into the zona pellucida which ten hardens and prevents any other spermatozoa from entering.

When meiosis in the oocyte resumes the second polar body results and undergoes apoptosis and extrusion
from the oocyte. The spermatozoa pronucleus (haploid) enters the oocyte (now haploid too) and the
paternal chromosomes line up with the maternal chromosomes on the mitotic spindle to form a diploid
cell, the zygote.

Test your learning:

During fertilsation:
A) The chromosomes of the sperm are expelled as the polar body
B) The chromosomes of the oocyte remain in a suspended state
C) The chromosome state becomes diploid
Beginning of pregnancy - Implantation
Zygote to blastocyst
As soon as the oocyte is fertilised, it becomes a zygote. During its time in the oviduct, the fertilised ovum,
also known as the conceptus, proceeds through a number of cellular divisions. At around the 8-16 cells
stage the cleaving conceptus changes its morphology to become a morula. In the morula the cells become
polarised, prompting the development of two cell types in the blastocyst, which forms at the 32-64 cell
stage. The blastocyst contains two distinctive cells types, an outer rim of trophoblast cells containing a fluid
filled cavity and an inner group of cells, called the inner cell mass.

Test your learning:

Which of the following structures consists of an inner cell mass, fluid filled cavity and a layer of trophoblast
cells?
A) Morula
B) Blastocyst
C) Zygote

We now have a zygote – what’s next?

The blastocyst is an important phase in pregnancy. The blastocyst gives rise to three important
components. It gives rise to i) the embryo, ii) the embryonic membranes and iii) the placenta. We will
cover each of these in turn.
Embryogenesis
In the first two weeks after fertilization, the zygote develops into the blastocyst and implants in the
endometrial wall. During the pregnancy, the blastocyst develops into three separate components, the
embryo, the fetal membranes and the placenta. These are complicated processes and the easiest way to
understand these processes is to visualise them with 3D animation. The three videos below show some of
the critical early phases of gastrulation, neurulation and embryonic folding to form the body cavities.

Gastrulation: description of events (3.32mins): https://www.youtube.com/watch?v=3AOoikTEfeo

Neurulation: description of events (1.50mins): https://www.youtube.com/watch?v=lGLexQR9xGs

Embryonic folding and generation of body cavities, including the gut: description of events (2.49mins):
https://www.youtube.com/watch?v=yXUv4MPuNTA

Other Youtube videos of gastrulation: https://www.youtube.com/watch?v=rDexsMXOu6s and

https://www.youtube.com/watch?v=ADlYn0ImTNg https://www.youtube.com/watch?v=yXUv4MPuNTA

Gastrulation (week 3)
As the blastocyst implants into the
endometrial wall the inner cell mass starts
to form into 3 discrete layers, known as
the germ layers. These three layers give
rise to all tissue in the developing embryo.
The germ layers are:
– Ectoderm (top layer). This forms the
epidermis (hair, nails and skin),
nervous system.
– Mesoderm (middle layer). This layer
forms the spine, kidneys, gonads,
heart, digestive system, blood vessels,
muscle and connective tissue
– Endoderm (bottom layer). This layer
forms the epithelial lining of glands,
digestive and respiratory tracts

Once the layers have formed they begin

their individual developments. The
mesoderm forms into somites
(Somitogenesis). The axial body plane
forms.

The ectoderm thickens to become the

neural plate, a midline grove develops and
the neural tube develops. The ectoderm
separates into the nervous tissue and skin
(epidermis; Neurulation.)

The endoderm folds inwards along its length, enclosing part of the yolk sac and becomes the primitive gut.
The anterior end form the foregut, with various evaginations becoming the respiratory tract, thyroid,
parathyroids and thymus. The midgut gives rise to the liver, pancreas and bladder. The hind gut gives rise
to the adrenal medulla, urinary bladder and the reproductive tract.

In week 4 the heart forms (Cardiogenesis ) and is the first functioning organ in the embryo. From week 4-8
there is early development of other organs , tissues and limbs. From conception to week 8 there is rapid
cell division and all major organs and systems are formed. This is the most critical time in the development
of the embryo/fetus where the embryo/fetus is highly susceptible to damage from alcohol, drugs, viruses,
infection, radiation and nutritional deficiencies. Some events must occur at specific times (critical periods)
so that development proceeds in an orderly fashion. Different organs / tissues have different critical
periods eg most brain cells need to be formed before birth, but muscle cells can exhibit “catch-up” growth.

The first 8 weeks of development are referred to as the embryonic period. After 8 weeks development
enters the fetal period. It is in the embryonic period that all the organs begin their development. During
the fetal period the organs continue to develop and grow in size. Given the complexity of the processes of
embryonic and fetal development it is not surprising that some errors do occur. Some result in the loss of
pregnancy, other cause problems with pregnancy or post natal development of the baby. Some errors may
be caused by external factors that cause serious developmental errors for the fetus.

Implantation and placental formation

The blastocyst floats freely in the uterine cavity for about 1 day before it implants. From the time the ovum
is shed until the blastocyst implants (usually complete by the 12th day after ovulation) the metabolic needs
of the zygote is met by the secretions of the oviduct and endometrium. The ovary, uterus and conceptus
engage in complex conversations to control the process of implantation. The blastocyst provokes a
response of considerable magnitude in the uterus, but there is a narrow window of time (about 3 days) in
which the endometrium is receptive to the zygote. This period coincides with the period of maximal
secretion of progesterone by the corpus luteum. The high levels of progesterone causes decidualisation of
the endometrium which involves cellular changes in the endometrium that permit implantation. The exact
details of this process are not fully understood but they involve the expression of a number of proteins and
growth factors.

The blastocyst becomes completely embedded in the endometrium by 12-14 days. The trophoblast forms
two layers the cytotrophoblast and the syncytiotrophoblast, which give rise to the embryonic/fetal
membranes and the placenta. The syncytiotrophoblast invades the endometrium engulfing the decidual
cells and giving rise to the placenta. The formation of the placenta is a complicated process. The video
below gives a good animation of how the placenta forms.

Video on placental formation (3.58 mins) https://www.youtube.com/watch?v=bped-RVWsLk

Some implantation issues
Even with a healthy embryo, the implantation failure is high. At least 2 out of 3 blastocysts fail to implant
and a further third of implanted embryos miscarry. If the embryo is passed, the lack of hCG decreases
estrogen and progesterone and sloughing of endometrium occurs. The reasons for implantation failure are
largely unknown. Some reasons are thought to be scarring of uterus (e.g. Pelvic Inflammatory Disease),
hormonal imbalances (PCOS, Endometriosis) and non-receptive endometrium (e.g. lack of appropriate
receptors, PCOS, Endometriosis). Other implantation issues include ectopic pregnancy where implantation
occurs outside uterus, Placenta praevia (blastocyst implants near opening of cervix), situations where the
placenta may cover opening to vagina, or where the placenta may separate prematurely either before term
or during labour.
The fetus depends on the placenta before birth

During the early stages of pregnancy the blastocyst

takes up materials from and excretes waste
products into the surrounding endometrial fluids.
These materials pass through the thin layer of the
trophoblast and are distributed by diffusion
through the cavities and tissues of the conceptus.
As the mesoderm develops, blood vessels develop
within it and then link up to form a network. Blood
formation occurs in the yolk sac and the primitive
heart forms in the cardiac mesoderm within the
developing embryo. This is the beginnings of the
circulatory system.

The human placenta is discoid (i.e. flat, circular form; disk-shaped), weighs ~500 grams and is heavily
supplied with fetal and maternal blood vessels. It is a temporary organ that originates from fetal and
maternal tissue. The survival of the fetus is independent of the fetal brain, lung, gut and kidneys. The fetus
depends on its liver/spleen (for hematopoeisis) and the cardiovascular system but is strongly dependent on
the placenta for delivery of all its nutrients.

The placenta consists of a fetal component,

the chorionic villi which develops from
trophoblast and mesoderm cells and contains
the fetal vasculature. The placenta also
consists of a maternal component which
arises from erosion of endometrial cells,
causes pooling of maternal blood around
chorionic villi. Gases are exchanged across the
space between the maternal and fetal
circulations.
The placenta contains 60-70 villous trees
which through branching give rise
to >100,000 villi. There is around 90km of villi
containing arterioles and venules.

The function of the placenta is to provide substrates for fetal metabolism (acts as gut), disposes of fetal
waste (acts as kidney) and exchanges respiratory gases for the fetus (acts as lung). The placenta also
functions as a partial immunological barrier (fetal genotype is foreign to mother) and produces hormones
such as progesterone, estrogens and protein hormones (hCG-human chorionic gonadotrophin) which are
important for pregnancy.
The placenta is permeable to alcohol, nicotine, drugs and some maternal pathogens which means that
abuse of these substances by the mother during pregnancy can lead to fetal complications. The placenta is
impermeable to large proteins (eg hormones and maternal immune defence) and to blood cells. Therefore,
fetal and maternal blood supplies are in close proximity to each other, but remain separate.
At birth the placenta becomes separated and is expelled harmlessly despite being highly vascularised!!
Placental abnormalities compromise fetal development. The diagrams below illustrate the example of fetal
alcohol syndrome and the critical periods in fetal development where impairment of placental function or
exposure to toxic agents can caused birth defects.

Fetal Alcohol Syndrome

Extraembryonic/fetal Membranes

The fetal membranes develop in a complex series

of developments from the endoderm, ectoderm
and mesoderm early in embryonic life. On about
day 8, the trophoblast cells constitute the first
extra-embryonic tissue. These cells do not
contribute to the embryo or fetus itself. Instead
they give rise to the fetal membranes.

Watch the 3 min video which describes the

development of the extraembryonic membranes
https://www.youtube.com/watch?v=HCsVtGG4s8s

The fetal membranes include the:

1. Chorion: This membrane encloses the embryonic body and all other membranes and helps form
the placenta
2. Amnion: This is a transparent sac filled with amniotic fluid to protect embryo and provide optimal
conditions for development
3. Yolk sac: This sac decreases in size and importance during early development
4. Allantois: This is a small outpocketing which becomes the base of the umbilical cord in humans
As pregnancy progresses the chorionic compartment and the yolk sac both decrease in size while the
amniotic compartment increases.
Amniotic Fluid
Amniotic fluid is vital to the well-being of the fetus. It cushions the fetus from injury, helps prevent
compression of the umbilical cord, and allows room for it to move and grow. In addition, its bacteriostatic
action helps prevent infection of the intra-amniotic environment.
The quantity of amniotic fluid at any time in gestation is the product of water exchange between the
mother, fetus, and placenta, and is maintained within a relatively narrow range. Disorders of this regulatory
process can lead to either polyhydramnios or oligohydramnios, in which too much or too little fluid exists,
respectively. These disorders may result from abnormal fetal or maternal conditions and, conversely, may
be responsible for alterations of fetal well-being as well. With the advent of real-time ultrasonography,
assessment of amniotic fluid has been possible, resulting in earlier recognition of abnormal conditions and
possible intervention.
Amniotic fluid is the product of complex and dynamic fetal and placental physiologic processes. Disruption
of the fine balance may result in overproduction or underproduction of fluid. Therefore, alterations in
amniotic fluid volume serve as important markers of both in utero developmental defects as well as
physiological responses to fetal hypoxemia and other metabolic disturbances such as maternal/fetal
hvperglycemia. Both polyhydramnios and oligohydramnios may be associated with either major congenital
anomalies or adverse perinatal outcomes.
Polyhydramnios, particularly when severe and detected early in gestation, can be treated antenatally with
serial amniocenteses. Oligohydramnios with intact membranes, especially when severe and in the absence
of anomalies, is usually managed by delivery.

Hormonal changes and maternal adaptations to pregnancy

If the implanting zygote is to survive it must signal
its presence to the mother and prevent the
withdrawal of progesterone and menstruation by
prolonging the life of the corpus luteum. The
blastocyst prolongs the life of the corpus luteum by
the production of a luteotrophic factor of its own,
human chorionic gonadotropin (hCG). hCG can be
detected in the mother’s blood one week after
fertilisation and continues to rise until the end of
the second month of gestation. It maintains the
production and secretion of progesterone and
estrogen by the corpus luteum. Measurement of
hCG levels in urine constitutes the standard
pregnancy test.
Progesterone is essential for maintenance of pregnancy. It keeps uterine muscle quiescent. It is produced
by the corpus luteum for the first 50 days, and then by the placenta for the remainder of gestation. Loss of
Progesterone action terminates pregnancy. This action has been exploited by pharmaceutical companies
with the synthesis of progesterone receptor blockers, eg Mifepristone (or RU-486) which is used to
chemically terminate pregnancy. Medical abortion using mifepristone is the most effective method of
abortion at gestations of less than 7 weeks.
The extended secretion of progesterone is critical for the initiation of pregnancy, and persists throughout
pregnancy. As pregnancy advances the levels of estrogen in the maternal blood also increase. At around 4
weeks the fetus begins to make all the steroid hormones required for pregnancy, and although the corpus
luteum remains active for the whole of pregnancy it can be dispensed with after only 4-5 weeks and only
plays a trivial role in total progesterone output at later stages. Progesterone is produced by the placental
trophoblast. The fetus and placenta cooperate to produce estrogens. The placenta can produce estrogen
from androgens but not from progesterone. The fetal liver synthesises androgens from progesterone which
supplies the placenta with the androgen substrate required for estrogen synthesis.

The corpus luteum maintains the pregnancy

til around week 8. After this time the fetal-
placental unit produces progesterone and
estrogen.
Note the fetal adrenal plays a critical role in
providing the high levels of estrogen present
during pregnancy.

Many of the maternal adaptations are driven by hormonal changes during pregnancy. Human chorionic
gonadotropin (hCG) is secreted by trophoblast cells, and then placenta and prompts the corpus luteum to
continue secretion of progesterone and estrogen. hCG levels rise until the end of the second month, then
decline as the placenta begins to secrete progesterone and estrogen. Progesterone and estrogen increase
more slowly at the start of pregnancy but continue to increase throughout gestation. Morning sickness
results during a time when the maternal organs are adapting to the increased concentrations of circulating
progesterone and estrogen. There are increases in a number of hormones during pregnancy. Some are
produced by the mother and some by the placenta and fetus. The placenta produces a number of
hormones that maintain pregnancy and the growth of the fetus. Hormones produced include hCG, hCS
(also called human placental lactogen), TSH, ACTH, GnRH, CRH, progesterone and estrogens. The precise
role of some of these hormones during pregnancy is not completely understood. Relaxin is produced by the
corpus luteum and also by the placenta.
 Figure taken from Goodman, Basic Medical Endocrinology.

Maternal Physiological Adaptations To Pregnancy

In the time between fertilisation and delivery the mother provides all the resources required for the
embryo/fetus to develop. Maternal homeostatic mechanisms control the temperature, oxygen supply,
waste removal and availability of nutrients, minerals and vitamins to the fetus, during pregnancy,
supporting the growth of the fetus and the placenta. Maternal adaptations to pregnancy are driven by the
hormones secreted into the maternal circulation by the placenta. Changes in maternal physiology must
accommodate the needs of the fetus without compromising those of the mother. Physiological changes
must also prepare the mother for the birthing process and for sustaining the baby through lactation once it
is born.

Cardiovascular changes: Maternal and fetal blood do not mix. Exchange of nutrients, wastes and gases
takes place by diffusion in the terminal villi of the placenta. During pregnancy there is an increase in blood
volume (40% via RAS) and cardiac output and a decrease in total peripheral resistance.
Renal changes: There is an increase in renal flow by as much as 70% which increases glomerular filtration
rate. There is an increase in sodium retention leading to an increase in blood volume and fluid retention.
Osmolarity: There is a decrease in plasma osmolarity, due to a reduced set point of osmoreceptors, but the
mechanisms for regulating osmolarity remain intact, via ADH.
Blood: There is an increase in the number of red blood cells but these don’t quite offset the increase in
plasma volume, hence the haematocrit is reduced during pregnancy.
Respiratory changes: There is an increase in ventilation which occurs during the luteal phase of the
menstrual cycle and continues steadily until the baby is delivered. The metabolic demands of the fetus and
placenta increase during pregnancy producing an increase in oxygen consumption (15%) and production of
carbon dioxide. Ventilation increases by 40% and this is attributed to the high concentrations of the actions
of progesterone.
Metabolic changes: The energy costs of pregnancy must be met by the maternal diet or fat reserves. One
third of the caloric intake supports the fetus, one third supports the placenta and one third supports the
mother. There is an increase in insulin resistance as pregnancy proceeds. Insulin levels increase but blood
glucose levels are usually maintained within normal limits.
GI tract: There is an increase in nutrient uptake; decreased motility
PR induced Vasodilation: smooth muscle relaxes – constipation, fainting, joints more flexible, remission
from arthritis
Corticosteroid secretion: ↑ glucocorticoids which may mobilise amino acids for use by the fetus
Thyroid gland: There is an increase in the size of thyroid gland and secretion of Thyroxine. This is thought
to be due to hCG and TSH secreted by the placenta
Parathyroid gland: There is an increase in the size of parathyroid gland and secretion of parathyroid
hormone which leads to increased plasma calcium
Relaxin: secretion of relaxin by ovaries and placenta, relaxes ligaments of the pelvic region and perhaps the
cervix

Perturbations in maternal adaptations

Maternal changes are adaptive changes, which increase oxygen and nutrient supply to the fetus and
newborn. Without these changes fetal growth and development is compromised. This can lead to
increased morbidity and mortality of the newborn and even fetal rejection.
Fetal complications often involve hypoxia and/or malnutrition and may be cause by placental insufficiency.
Hypoxia and malnutrition affects the development of many organs, particularly the fetal brain. Chronic
hypoxia leads to IUGR (intra-uterine growth restriction). Possible prenatal hypoxia is also a precursor for
cerebral palsy, sudden infant death syndrome, minimal brain dysfunction and schizophrenia.
Factors causing IUGR can be divided into maternal and placental factors. Maternal factors include high
blood pressure, chronic kidney disease, infection, substance abuse, cigarette smoking and poor general
nutrition. Uterine and placental factors include placental placement, infection in tissue surrounding the
fetus, reduced blood flow and multiple pregnancies.
Factors affecting fetal growth have been postulated to affect health in adult life. This is referred as the
“Fetal origins of adult diseases” or the “Barker hypothesis” (name after the scientist who first postulated
the relationship) which states that “disturbed intrauterine growth has a negative influence on the
development of the cardiovascular system and favours the occurrence of hypertension, insulin resistance
and high blood cholesterol levels in adult life. Poor maternal diet, maternal stress, hypoxia and placental
insufficiency are each associated with a constellation of overlapping adult pathologies which are called
“metabolic syndrome”. The diagram below illustrates some of the consequences thought to result from a
developmental programming of the fetus by maternal diet. The mechanisms for this area not completely
understood.
Journal of Human Hypertension (2012) 26, 405–419; Developmental origins of health and disease:
experimental and human evidence of fetal programming for metabolic syndrome M L de Gusmão Correia,
A M Volpato, M B Águila and C A Mandarim-de-Lacerda

Summary:
In summary we have looked at the development of the follicle in the ovary and the changes that occur in
the uterus and ovary during the menstrual cycle. We have also covered the process of fertilisation and
implantation. The implantation of the conceptus signals its presence to the mother to prevent the
withdrawal of prostagenic support by the corpus luteum. The trophoblast prolongs the life of the corpus
luteum and synthesise chorionic gonadotrophin (hCG). As pregnancy advances the placental trophoblast
becomes the principal source of estrogen and progesterone and a number of other hormones including
growth hormone promoting hormones. The fetal adrenal is critical for the synthesis of estrogen and
androgens by the placenta. The placenta is a site where the maternal and fetal circulations pass close to
each other but do not mingle and where exchange of nutrients and wastes is facilitated.
During early development there is a separation of a small embryonic stem cell population from the
extraembryonic tissues. The extraembryonic tissues develop into fetal membranes (chorion, yolksac,
amnion, allantois). The embryonic stage of development involves the formation of the germ cell layers and
the formation of all the organs (up to week 8). There are a number of maternal adaptations to support
pregnancy and the development of the fetus. Growth and development of the fetus is dependent upon
maternal and placenta function. Perturbations in either of these adversely affect fetal growth. Events
occurring during pregnancy can affect the adult life of the fetus.

Reflections:
What was the most important concept learned in this lecture?
What did you have trouble in understanding?