Endocrinology of pregnancy

Question 1

Summarise the basic structure of the testes

Answer 1

The basic structure is the seminiferous tubule- which essentially consists of Sertoli cells.
Leydig cells, lymphatics and vasculature are found in the interstitum.

The Sertoli cells surround the seminiferous (luminal fluid0.

Question 2

Describe the reabsorption of tubular fluid in spermatogenesis

Answer 2

Leydig cells make testosterone in response to LH.
Sertoli cells contain aromatase and convert the testosterone to 17B-oestradiol, which then enters the seminiferous fluid.
Tubular fluid is reabsorbed, concentrating the spermatozoa.

Question 3

What will be the consequence of aromatase deficiencies in males

Answer 3

Osteoprosis
Tall stature (oestrogen causes fusion of the epiphyses).

Question 4

Where is most tubular fluid reabsorbed

Answer 4

Most tubular fluid reabsorbed within rete testis and epididymis under OESTROGEN control (oestrogen mainly in tubular fluid produced by Sertoli cells).

Question 5

Describe the importance of nutrient and glycoprotein secretion

Answer 5

Nutrients and other molecules (e.g. glycoproteins) secreted into the epididymal fluid under the influence ANDROGEN to a) provide energy for impending possible journey, and b) coat the surface of the spermatozoa (to protect them from hostile environment?).
produced by Sertoli cells under the influence of androgens.

Question 6

Summarise the passage of sperm in the male reproductive tract

Answer 6

From the seminiferous tubules, the spermatozoa pass into the retentions testis and epididymis (fluid reabsorption).
The spermatozoa are concentrated and stored in the muscular vas deferens
Sympathetic stimulation causes contraction of the vas deferens. this propels the spermatozoa
The vas deferens pass through the seminal vesicles, and join the vas deferens form the other side to form the ejaculatory duct in the prostate.
Becomes the urethra.

Question 7

Describe the vast distance that the spermatozoa has to travel

Answer 7

Travels 100,000 x its length from Testis to Fallopian tube

equivalent to 150km for a 1.5m human

Question 8

Describe the main components of semen

Answer 8

Spermatozoa 15-120 million/ml
Seminal fluid 2-5ml

Leucocytes
(potentially viruses e.g. hepatitis B, HIV)

Question 9

How many spermatozoa are successful in reaching the ovum

Answer 9

1/100 of spermatozoa in ejaculate enter the cervix
1/10,000 cervix to ovum
Overall 1/million reach ovum

Question 10

Where is seminal fluid produced

Answer 10

Small contribution from:
Epididymis/testis

Mainly from accessory sex glands:
Seminal vesicles (2/3rds)
Prostate (1/3rd)
Bulbourethral glands

Nutrients are added at the accessory sex glands.

Question 11

What components of the seminal fluid are produced by the epididymis/testis

Answer 11

Small contribution from epididymis/testis: including inositol & glycerylphosphorylcholine

Question 12

Describe the components of the seminal fluid produced by the accessory sex glands

Answer 12

Seminal vesicle: including fructose & fibrinogen
Prostate including citric acid (Ca2+ chelator, acid phosphatase, fibrinogenase (Also ampulla and bulbourethral glands)
After ejaculation, the semen initially clots and then must be broken down

Question 13

Summarise spermatozoa activation

Answer 13

Taken from the seminiferous tubule, spermatozoa are quiescent and incapable of fertilizing ovum.
Taken from the vas deferens, spermatozoa are capable of movement (“whiplash activity) and have some capability for fertilizing ovum.
However, full activity and fertilizing capacity is only achieved within the oviduct. This is known as CAPACITATION

Question 14

What is meant by capacitation and describe its 3 key features

Answer 14

Achieve fertilising capability in the female repro tract

Loss of glycoprotein ‘coat’
Change in surface membrane characteristics
Develop whiplash movements of tail

These changes all lead to the acrosome reaction.

Question 15

Where does capacitation take place

Answer 15

Takes place in ionic & proteolytic environment of the Fallopian tube (where the ovum release upon ovulation is normally found).
Oestrogen-dependent
Ca2+-dependent

Question 16

Describe the acrosome reaction

Answer 16

Spermatozoon binds to ZP3 glycoprotein on the zona pellucida

Once bound to ZP3, progesterone stimulates calcium influx into the spermatozoon- leading to the exposure of acrosome to the exterior

This results in a calcium-dependent acrosome reaction

This enables an exposed spermatozoon recognition site to bind to ZP2 on the zona pellucida

Once bound to ZP2, the acrosome releases its enzymes allowing penetration of the zona pellucida so that the head of the spermatozoon can enter the ovum
The head contains the nucleus- so we get a diploid cell produced.

Question 17

Describe the zonal reaction that takes place upon fertilisation.

Answer 17

The second polar body (of the ovum- where the cytoplasm has divided unevenly) is apoptosed.
Cortical granules release molecules that degrade the zona pellucida (including ZP3 and ZP2)- contain digestive enzymes.

This prevents further binding of other sperm

This is also CALCIUM dependent

Note: Cortical reaction = zonal reaction.

Question 18

Where is the progesterone (necessary for the acrosome reaction) produced

Answer 18

By the corpus luteum in the luteal phase after ovulation

Pro-gestation!!

Question 19

What type of receptor is the ZP3 receptor

Answer 19

o G-protein mediated action once ZP3 binding is established and progesterone, leads to influx of Ca2+ into the sperm.

Question 20

Summarise the development of the conceptus

Answer 20

Continues to divide as it moves down Fallopian tube to uterus (3-4 days)

Receives nutrients from uterine secretions

This free-living phase can last for ~ 9-10 days

Question 21

Describe the different cell stages in the development of the conceptus

Answer 21

Day 0 -fertilisation- cell containing sperm cell nucleus and egg cell nucleus.
Day 1- Zygote 
Day 2- 2-cell stage
Day 3- 8 egg cell stage 
Day 4- 16 egg cell stage (morula)

The inner cells in the Morula would have difficulty receiving sufficient nutrients by diffusion alone.

Day 5- Blastocyst (formation of inner cell mass and trophoblast)

Day 6-7 - Late-stager blastocyst (hatching)
Day8- 9 - Implanted blastocyst

Delivery by nutrients still depends on diffusion.

Question 22

Summarise implantation

Answer 22

Attachment phase: outer trophoblast cells contact uterine surface epithelium

THEN

Decidualisation phase : changes in underlying uterine stromal tissue (within a few hours)

Requires progesterone domination in the presence of oestrogen

Question 23

What are the two parts of the blastocyst

Answer 23

Inner cell mass – becomes the embryo

Trophectoderm – becomes the chorion (which becomes the placenta)

Question 24

What must happen before the attachment phase begins

Answer 24

Degradation of the zona pellucida secreted by the trophoblast cells or the endometrial lining.

Question 25

Summarise the blastocyst phase

Answer 25

It is transferred to the uterus at the blastocyst stage; this is facilitated by the increasing ratio of progesterone:oestrogen (luteal phase)
establishes physical and nutritional contact with maternal tissue

Question 26

Describe the molecules that enable the attachment phase of implantation

Answer 26

Leukaemia inhibitory factor (LIF) from endometrial secretory glands (& blastocyst?) stimulates adhesion of blastocyst to endometrial cells

Interleukin-11 (IL11) also from endometrial cells is released into uterine fluid, and may be involved

Many other molecules involved in process (e.g. HB-EGF)
Heparin-bound epidermal growth factor
also leptin

Question 27

Describe the endometrial changes in decidualisation

Answer 27

Endometrial changes due to progesterone

Glandular epithelial secretion
Glycogen accumulation in stromal cell cytoplasm
Growth of capillaries
Increased vascular permeability (→oedema)

Question 28

Describe the factors important for decidualisation

Answer 28

Interleukin-11 (IL11), histamine, certain prostaglandins & TGFβ (TGFβ promotes angiogenesis)

Question 29

Explain the decidualisation phase

Answer 29

Occurs within hours of the attachment phase
The outer trophoblast cells infiltrate the epithelial cells and penetrate the storm.
the stromal cells are transformed to decimal cells during the latter parts of the luteal phase, and these cells are then phagocytksed by the invading trophoblast cells which lose their membranes and interconnect, forming a synctiotrophoblast.
The decidua becomes a source of nutrients for the now impacting trophoblast, this is decidualisation.
The epithelial cells gradually re-form over the invading blastocyst.

Subsequent growth of the decimalised tissue and the development of maternal arteries and arterioles provide the basis for the formation of the placental interface between mother and fetus.

Question 30

What is the transfer of the conceptus to the uterus facilitated by

Answer 30

§ Then transferred to the uterus at this stage facilitated by increasing progesterone: oestrogen ratio (luteal phase).

Question 31

Summarise progesterone and oestrogen production during pregnancy

Answer 31

First 40 days
Produced in corpus luteum (in maternal ovary)
stimulated by hCG (produced by trophoblasts) which acts on LH receptors
Essential for developing fetoplacental unit
Inhibits maternal LH & FSH (-ve feedback)

From day 40
Placenta starts to take over

After day 40, and ovariectomy will not terminate the pregnancy.

Question 32

What feature does hCG share with TSH and LH

Answer 32

Common alpha subunit.

Question 33

When the fetoplacental unit takes over, which type of oestrogen is mainly produced

Answer 33

the less potent estriol, with the metabolite oestrone also being produced.

Question 34

What is the role of the mother in the fetoplacental unit

Answer 34

Provides the precursors necessary to make oestrogen and progesterone:
Releases cholesterol (which can be converted to pregenelone)
Releases DHEAS which can go to the placenta
The pregenelone can be converted to progesterone and then to 17a-hydroxyprogesterone S- which can enter the fetal adrenals.

Question 35

What is the role of the fetus in the fetoplacental unit

Answer 35

17a-HPS can be converted to DHEAS.
DHEAS - androstenedione- placenta - testosterone- Oestradiol

DHEAS- fetal liver- conjugated to 16a-HDEAS and 16aHATS- which can then enter the placenta and are deconjugated to OESTRIOL.

Question 36

Describe how oestrogen and progesterone levels change throughout pregnancy

Answer 36

Oestrogen and progesterone levels continue to rise through pregnancy with progesterone always being the dominant influence

Question 37

Describe how measurement of the urinary oestrogen excretion levels can be a useful indicator on fetal well-being

Answer 37

The estriol concentration is likely to be more adversely affected than the other two oestrogens when the fetus is distressed, since its precursor is almost entirely provided by it. In this case, the ratio of estriol to the sum of the other two oestrogens (17b-oestradiol and oestrone) is likely to be decreased.

Question 38

Describe the roles of oestrogen during the pregnancy

Answer 38

Vital for normal growth and development of the fetus
Necessary for preparing the mammary glands by stimulating their growth and development, as well as stimulating the production of prolactin (lactotroph hyperplasia)
Necessary for the preparation of SM of the myometrial lining of the uterus- stimulating the synthesis of oxytocin receptors and prostaglandins.
These effects are only noticeable near the approach of partition due to the inhibitory effects of prolactin.

Question 39

What is human placental lactogen

Answer 39

Metabolic role- promotes insulin resistance in the mother.
Mother will have a higher blood glucose concentration than normal- therefore promoting the delivery of nutrients to the baby.

Question 40

Which hormones are increased during pregnancy

Answer 40

ACTH
Adrenal steroids
Prolactin
IGF1 (stimulated by placental GH-variant)
Iodothyronines
PTH related peptides (increasing calcium- more available for lactation).

Question 41

Which hormones are decreased during pregnancy

Answer 41

Gonadotrophins
Pituitary GH
TSH- need to give hypothyroid patients extra thyroxine during pregnancy

Question 42

Describe the role of the fetus in initiating partition

Answer 42

When the fetus reaches a certain size, the fetal hypothalamus will make more CRH. This hormone controls the release of ACTH from the anterior pituitary, which will act on the fetal adrenals to release cortisol.
Cortisol will divert the steroid synthesis pathway in the adrenals from producing progesterone to producing oestrogens.

Question 43

Describe the role of the mother in parturition

Answer 43

Maternal oxytocin synthesis is increased in the oxytocinergic neurones of the hypothalamus, which act on the endometrial and myometrial receptors (up-regulated by oestrogen).
Release of oxytocin is triggered by the stretch of the cervix and uterine wall.
oxytocin stimulates the inward movement of calcium into the myometrial cells and stimulates prostaglandin (PGF2a) synthesis which is also stimulated by the oestrogen-assisted synthesis of the precursor arachidonic acid.
prostaglandins stimulate the release of calcium form the SER and microsomes.

Question 44

Describe the role of Ca2+ in bringing about contraction of the smooth muscle.

Answer 44

Ca2+ binds to calmodulin which then activates myosin kinase which stimulates the formation of actin-myosin bonds which comprise the sliding filament machinery.
You then get contraction.

Question 45

What are the 3 effects of oxytocin

Answer 45

Uterine contraction
Cervical dilation
Milk ejection

Question 46

What is the role of progesterone during labour

Answer 46

Progesterone keeps the effects of oestrogen under control

Progesterone inhibits oestrogen receptors

Progesterone inhibits the production of prostaglandins

Question 47

Which two hormones are involved in milk production and milk ejection

Answer 47

Prolactin – milk production

Oxytocin – milk ejection

These both have a similar neuroendocrine reflex arc stimulated by sucklin

Question 48

Describe the Neuroendocrine arc involved in lactation

Answer 48

Suckling stimulates the mechanoreceptors around the nipple- increased nerve impulses up the afferent pathway to the brain.
neural pathways to the hypothalamus:
stimulating oxytocinergic neurones which then release pulses of oxytocin from nerve terminals in the neurohypophysis.
activate an inhibitory pathway to dopaminergic neurones whilst stimulating the TRH neuonres- leading to prolactin release from the anterior pituitary.

As a result:
oxytocin- release of milk from alveoli by oxytocin.
prolactin- induced lactogenesis for subsequent feeding.

Question 49

Describe the negative feedback of prolactin

Answer 49

Prolactin: kisspeptin needed for GnRH release, prolactin receptors on kisspeptin cells inhibit release (also have leptin receptors, so anorexia where low leptin can lead to amenorrhoea)
Kisspeptin- also ER-a neurones- hence oestrogen can inhibit the HPG axis- no ER on GnRH.