Endocrinology 7b – Endocrinology of Pregnancy
Anil Chopra
1. Describe the necessary changes which have to occur before the spermatozoon
becomes fully capable of fertilizing the ovum (including capacitation), explaining
how these changes take place and what endocrine background is required.
2. Describe the fertilization process and explain the importance of the acrosome
reaction.
3. Describe how the blastocyst is believed to signal its presence to the maternal
endometrium, and the principal initial developments which occur on implantation.
4. Describe the decidualization reaction and how it is initiated.
5. Describe the principal physiological role of hCG and identify the stage in
pregnancy when it first appears and when it peaks.
6. Draw flow diagrams to describe the placental synthesis of a) oestrogen, and b)
progestogen during pregnancy.
7. Draw a chart illustrating the changes in maternal circulating concentrations of
oestrogen, progesterone, hCG, hPL, LH and FSH throughout pregnancy.
8. Describe the value of hCG measurement in the management of trophoblastic
disease.
9. Identify the main hormone (and hormone fragment) measurements in maternal
blood during pregnancy which can be used clinically with regard to feto-placental
well-being.
10. Explain how hormones regulate the parturition process.
11. Explain how lactation is induced by suckling, naming the two principal hormones
concerned.
Fertilisation
 The spermatozoon has to travel over 100 000 times its own length on its journey
from the testes to the oviduct.
 Only 1 in 10 000 000 sperm actually reaches the ovum.
Male Reproductive Tract
Most of the tubular fluid in the male reproductive tract is reabsorbed within the rete
testis (network of tubules in the testicle hilum) and early epididymis under
OESTROGEN control (oestrogen mainly in tubular fluid produced by Sertoli cells).
The nutrients and other proteins (e.g. glycoproteins + fructose) which are secreted into
the epidydimal fluid for the spermatozoa are
under ANDROGEN control. These provide
energy for the sperm and the glycoproteins
coat the sperm to protect them from the hostile
environment.
Ejaculation
- Semen is ejaculated into female tract (usually
vagina, sometimes into cervical canal)
- Semen consists of
o Sperm – 50-150 x 106 /ml
o Seminal fluid 2-5ml
o Leucocytes
o Potentially, viruses, e.g. hepatitis, HIV,
Seminal fluid:
Produced by secondary sex glands:
- Epididymis
o inositol, carnitine, glycerylphosphorylcholine
- Seminal vesicles and Prostate
o Fructose
o Fibrinogen
o Citric acid
o Acid phosphatase
o Fibrinogenase
Spermatozoon Activation & Capacitation
- From seminiferous tubule
o Spermatozoa unable to fertilize ovum
- From vas deferens
o Spermatozoa capable of movement (“whiplash activity”) and some
capability for fertilizing an ovum. ACTIVATION
- Full activity and capacity to fertilise is only achieved in the oviduct.
CAPACITATION.
- Only 1% of spermatozoon in ejaculate enters the cervix.
1. Loss of glycoprotein “coat”
2. Exposure of acrosome
leading to ACROSOME REACTION
(swelling, exposure
3. Whiplash movements of tail
of contents to exterior)
This all takes place in the oviduct (an ionic and proteolytic environment). They are all
oestrogen dependent and the activation process is Ca2+ dependent.
The Process of Fertilisation
Once sperm have become “capacitated” in the oviduct, they bind to a binding site on
the ZP3 glycoprotein (zona pellucida 3) on the ovum. The progesterone causes a
huge influx of Ca2+ into the sperm and allows for the Ca-dependent acrosome
reaction.
This enables an exposed spermatozoon binding site to bind to a second glycoprotein
(ZP2). The sperm releases proteolytic enzymes (e.g. hyaluronidase) and penetrates
the zona pellucida and exposes itself to the egg.
-
occurs in the oviduct
results in the expulsion of second polar body
zona reaction occurs – prevents any other sperm from binding
once diploidy (full set of chromosomes) is established, then the cell begins to
divide into the conceptus.
Conceptus
• The conceptus continues to divide as it moves down from oviduct to uterus (3-4
days) => the free floating phase
• Until implantation the developing conceptus receives its nutrients from uterine
secretions
• This free-living phase can last for about 9-10 days
• Conceptus first compacts to 8-16 cell morula
• Then it becomes a blastocyst: two distinct cell populations resulting in inner cell
mass - which becomes the embryo - and outer trophoblast - which becomes the
chorion.
• It is transferred to the uterus at the blastocyst stage; this is facilitated by the
increasing progesterone to oestrogen ratio (luteal phase)
• It establishes physical and nutritional contact with maternal tissues
4-cell
conceptus
2-cell
conceptus
8-cell
conceptus
compaction
Inner cell mass
morula
Fertilized egg
Trophoblast cells
Blastocoelic
cavity
blastocyst
Implantation
• In humans is INVASIVE
• Involves an initial ATTACHMENT PHASE when outer trophoblast cells contact
uterine surface epithelium
• Within a few hours, results in DECIDUALIZATION of underlying uterine
stromal tissue
• This requires an endocrine background of PROGESTERONE DOMINATION
in the presence of OESTROGEN.
Uterine
blastocyst
secretory glands
LIF
OESTROGEN
Makes stroma
receptive
(global)
EGF receptors
on trophoblast
cells
ZP dissolution and
attachment/invasion
of endometrium
HSPG
Release of
HB-EGF
In epithelial cells
Initial signal from blastocyst?
adjacent to blastocyst
(local)
LIF = Leukaemia Inhibitory Factor
HB-EGF = Heparin-Binding EGF-epithelial growth factor
HSPG = surface Heparin Sulphate ProteoGlycans
Attachment
• Oestrogen-induced release of leukaemia inhibitory factor (LIF) from endometrial
secretory glands makes stroma receptive to implantation
• Oestrogen-induced release of heparin-binding epithelial growth factor (HB-EGF)
from endometrial cells.
• HB-EGF binds to EGF receptors and HS proteo-glycans on outer trophoblast cells
of blastocyst, and induces zona pellucida dissolution and promotes attachment and
invasion of adjacent endometrium
The Decidualisation Reaction
• Involves the invasion of the underlying uterine stromal tissue by the trophoblast
cells of the blastocyst
• Within hours, results in increased vascular permeability in the invasion region
associated with oedema of tissues, localized changes in intracellular composition
and progressive sprouting and growth of capillaries; the DECIDUALIZATION
REACTION
• Factors involved in the decidualization reaction include histamine, certain
prostaglandins, and TGFβ which promotes angiogenesis.
Pregnancy
In the first 5-6 weeks of pregnancy, the
ovaries produce gonadal steroids to maintain
the fetoplacental unit. After this point, hGC –
human chorionic Gonadotrophin takes over
this role and is produced by the developing
implanting blastocyst (syncitiotrophoblast).
Throughout pregnancy oestradiol and
progesterone levels rise and LH and FSH
are inhibited. From day 40 ovariectomy
no longer has any effect on pregnancy
since by this stage the role of the corpus
luteum has been taken over by the
fetoplacental unit.
Parturition
A number of different homones act on
the myometrium to induce contraction
including:
- Oxytocin
- Oestrogen
- Progesterone
This results in an influx of Ca2+ ions
and which allows the contraction of
the uterus through the action of
calmodulin-myosin kinase.
 When the fetus reaches a certain size fetal oestrogen switches off the hormonal
axis
 This acts to increase fetal steroid production so it is higher than the mother
 This initiates the parturition process – therefore the fetus is vital in dictating when
parturition begins
 The myometrial smooth muscle cells are activated at the later stages of parturition,
to enable contraction release of Ca
stores is needed to increase
intracellular Ca
 Oxytocin is released at the end
stage of pregnancy
Lactation
 Lactation is brought about by oxytocin and prolactin – both of which sit in
neuroendocrine reflex arcs:
 Suckling induces neural pathways to the hypothalamus which stimulates the
pituitary to produce oxytocin and prolactin which cause milk synthesis and
ejection
Hypothalamus
SUCKLING
(stimulus)
Neural
pathways
Pituitary
+
Neurohypophysis Adenohypophysis
Oxytocin
Milk ejection
Milk synthesis
Prolactin