Endocrinology of Pregnancy Flashcards
How is semen made?
- first there is a spermatogonium 44XY
- then primary spermatocytes (both 44XY) -> formed in basal fluid space surrounding seminiferous tubules
- then secondary spermatocytes (22X or 22Y) -> penetrate between the Sertoli cells, under the influence of Sertoli secretions they develop in to spermatids
- then spermatids (22X or 22Y)
- then spermatozoa (22X or 22Y) -> enter seminiferous fluid which is continuously secreted by Sertoli cells
- tubular fluid is concentrated/reabsorbed through the actions of oestrogen
- Nutrients (eg fructose) (-> for long journey) & glycoprotein (-> protection from hostile environment that it will encounter) secretion into epididymal fluid (induced by androgens)
What is in semen?
Spermatozoa 15-120 million/ml
Seminal fluid 2-5ml
Leucocytes
(potentially viruses e.g. hepatitis B, HIV)
How many sperm reach areas in female reproductive tract in ejaculation?
1/100 of spermatozoa in ejaculate enter the cervix
1/10,000 cervix to ovum
Overall 1/million reach ovum
Briefly summarise the male testis-HP axis
- pulsatile GnRH from hypothalamus
- LH and FSH from anterior pituitary
- LH acts on Leydig cells in the testis which are important for the production of testosterone and therefore virilisation and are important in spermatogenesis as well
- FSH acts on Sertoli cells which are responsible for spermatogenesis and also they produce inhibin
- testosterone and inhibin exert negative feedback on the hypothalamus and on the anterior pituitary
How long does sperm have to travel to reach the Fallopian tube?
Travels 100,000 x its length from Testis to Fallopian tube
-> equivalent of SK -> Brighton -> SK for 1.5m human
Where is seminal fluid produced?
Small contribution from:
- Epididymis/testis
Mainly from accessory sex glands:
- Seminal vesicles
- Prostate
- Bulbourethral glands
What are the accessory sex glands in males?
- Seminal vesicles
- Prostate
- Bulbourethral glands
What is capacitation of sperm?
-> achieve fertilising capacity in the female reproductive tract
- Loss of glycoprotein ‘coat’
- Change in surface membrane characteristics
- Develop whiplash movements of tail
Takes place in ionic & proteolytic environment of the Fallopian tube
Oestrogen-dependent
Ca2+-dependent
Acrosome
- organelle that contains enzymes that can break down the ovum outer membrane (zona pellucida)
- develops in the anterior half of the head of spermatozoa
- derived from the Golgi apparatus
What happens in people with aromatase deficiency?
-> cannot make oestrogen and also have high testosterone
- high testosterone causes acne, hirsutism etc.
- low oestrogen causes being tall because epiphyseal growth plate closure requires oestrogen so the epiphysis of bones keep on growing
-> not many cases known
Acrosome reaction
- Sperm binds to ZP3 (= sperm receptor)
- Ca2+ influx into sperm (stimulated by progesterone (from corpus luteum))
- Release of hyaluronidase & proteolytic enzymes
(from acrosome)
-> Spermatozoon penetrates the Zona Pellucida
Where does capacitation occur?
In the female reproductive tract (Fallopian tubes)
- dependent on oestrogen and calcium (the oestrogen dependency is why it has to occur in the female reproductive tract)
What is the sperm receptor on the ovum?
ZP3
-> sperm binding causes influx of calcium into the sperm (which is stimulated by progesterone from the corpus luteum) Progesterone=pro-gestation -> promotes pregnancy
Zona Pellucida
- outer membrane of ovum
- glycoprotein layer
- broken down and penetrated by spermatozoa after binding to ZP3
Polar body
- when female cells divide, they do not divide equally in terms of cytoplasm
- the polar body is the cell that has a very tiny amount of cytoplasm
- it ultimately undergoes apoptosis because it cannot maintain itself
Fertilisation
- Occurs within the Fallopian tube
- Triggers cortical reaction
- Cortical granules release molecules which degrade Zona Pellucida (e.g. ZP2 & 3)
- Therefore prevents further sperm binding as no receptors
- Haploid -> Diploid
How is the binding of further sperm cells prevented at fertilisation?
- cortical granules are released
- these degrade the zona pellucida and remove receptors
- further sperm cannot bind without receptors
Development of the conceptus
- 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 -> then blastocyst implants
What happens to the corpus luteum if pregnancy does or does not occur?
- if pregnancy occurs, the corpus luteum can be maintained by beta-HCG from the placenta
- if there is no pregnancy, the corpus luteum becomes a corpus albicans and stops producing progesterone
- you need a source of HCG to maintain the corpus luteum
Implantation
- Attachment phase: outer trophoblast cells contact uterine surface epithelium
THEN - Decidualisation phase : changes in underlying uterine stromal tissue (within a few hours) -> changes in endometrium due to progesterone
- Requires progesterone domination in the presence of oestrogen
What is the difference in terms of dosage between HRT and OCP?
HRT has a much lower dose than OCP
When does ovarian cancer tend to occur?
After child bearing age
What cells make up the blastocyst? What do they end up becoming?
- trophoblast cells make up the outer surface of the blastocyst and later make the placenta
- inner cell mass cells are found on the inside of the blastocyst and later make up the embryo
What mediators are released in the attachment of the blastocyst to the endometrium?
- 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)
What are the important factors for implantation?
- LIF
- IL-11
- Progesterone
What are important molecules in attachment?
- LIF
- IL-11
- maybe also some other factors
What occurs during decidualisation?
Endometrial changes due to progesterone
- Glandular epithelial secretion
- Glycogen accumulation in stromal cell cytoplasm
- Growth of capillaries
- Increased vascular permeability (→oedema)
=> all about getting nutrients to that area
What factors are involved in decidualisation?
- IL-11
- histamine
- certain prostaglandins
- TGF-beta (promotes angiogenesis)
Which is the first hormone to go up in pregnancy?
HCG
- > maintains corpus luteum
- > corpus luteum is the source of progesterone and oestrogen
- > the hCG is acting on LH receptors
Which hormones increase in pregnancy?
- hCG
- human placental lactogen?
- oestrogen (mainly oestriol)
- progesterone
hCG full name
human chorionic gonadotrophin
What are the effects of human placental lactogen?
-> metabolic
- promotes insulin resistance in the mother
- this is thought to promote nutrients going to the baby (higher blood sugar levels)
Why does the hCG only rise for some time?
- in the beginning it is there to maintain the corpus luteum and its progesterone (and oestrogen) production
- at a point (~10w) the placenta takes over O and P production so the hCG can fall again.
Progesterone and oestrogen production during pregnancy
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
Draw how the hormones in pregnancy change in level throughout the 40w
- hCG rises and declines at about 40d
- oestrogen and hpl have a similar curve, rising linearly and falling at 40w, slightly higher curve for oestrogen
- progesterone rises with a higher inclination than oestrogen, falls at 40w
Where is hCG secreted from?
- initially from sincitotrophoblasts from the conceptus
- then placenta
What does DHEAS stand for?
Dehydroepiandrosterone sulfate
What is the main source of oestrogens in pregnancy?
maternal and foetal DHEAS
Mother: DHEAS -> oestradiol, oestrone
Baby: makes DHEAS -> oestradiol, oestrogen and also makes 16-alpha-hydroxy DHEAS which is turned into oestrus via placenta
Prolactin levels in terms of prolactinoma
- increased
- levels of prolactin indicate how big the tumor is and how, whether it is changing
- if a woman with a prolactinoma is pregnant you cannot use levels of prolactin as a marker of tumor size any more because of lactotroph hyperplasia -> check visual fields in every trimester
Which hormones increase in pregnancy?
ACTH Adrenal steroids Prolactin IGF1 (stimulated by placental GH-variant) Iodothyronines PTH related peptides
Why do adrenal steroids increase in pregnancy?
because of increases in ACTH
Why does prolactin increase in pregnancy?
lactotroph hyperplasia
Why does IGF-1 increase in pregnancy?
It is stimulated by placental GH
Why do iodothyronines increase in pregnancy?
because hCG and TSH share an alpha subunit and therefore the thyroid gland it stimulated to an extent
Why are PTH related peptides increased in pregnancy?
- from breast tissue
- increased to mobilise calcium from the mothers skeleton to ensure that there is enough for the foetus.
Which hormones decrease in pregnancy?
- gonadotrophin (LH and FSH)
- pituitary GH
- TSH
Why do gonadotrophins decrease in pregnancy?
- there is high, LH and FSH independent production of oestrogen
- this oestrogen exerts negative feedback on the H and AP
Why is there a decrease in TSH in pregnancy?
because hCG does some of its job in terms of stimulating the thyroid gland so there is some more negative feedback to H and AP
What are the 3 key hormones in partuition?
- oxytocin
- oestrogen
- cortisol
What are the main functions of oxytocin?
- Uterine contraction
- Cervical dilation
- Milk ejection
What are some receptors that kisspeptin neurones have?
- prolactin (fertility problems in hyperprolactinaemia)
- leptin (fertility problems in anorexia)
- oestrogen (-ve feedback of O to Hypothalamus)
Endocrine control of lactation
- suckling stimulus to nipple
- neural pathways to the hypothalamus
- hypothalamus stimulates AP and PP to make prolactin and oxytocin respectively
- prolactin -> acts on breast tissue for milk production
- oxytocin -> acts on breast tissue for milk ejection
Why may marathon runners get low testosterone or galactorrhoea?
- nipple stimulation activating the axis
- high prolactin causes decreased sex steroid levels.
