L12 Control of ovulation and pathology

Question 0

What are the similarities and differences between polycystic ovarian syndrome and hypothyroidism?

Answer 0

• Similarity: ovulation doesn’t occur and irregular/ absent of period
• Differences: in polycystic ovarian syndrome, the level of oestrogen in the body is normal or slightly higher; while in hypothyroidism, there is a low oestrogen status

Question 1

What are the 2 main disease processes obstructing ovulation?

Answer 1

• polycystic ovarian syndrome and hypothyroidism

Question 2

What is the normal hypothalamic pituitary ovarian axis?

Answer 2

• Arcuate nucleus in the hypothalamus releases gonadotrophin hormones.
• the GnRH flows from arcuate nucleus to anterior pituitary gland, where it is being transferred via portal blood system.
• the rate of hormones being delivered to pituitary gland dependent on rate of pulses from arcuate nucleus
• GnRH then signals to release FSH into the general systemic blood from anterior pituitary gland
• The FSH does not only stimulate the growth and maturation of follicles, also stimulate production of oestrogen
• oestrogen then feedbacks to hypothalamus and pituitary gland and signals hypothalamus that the ovaries are ready to ovulate
• this causes the release of LH from anterior pituitary gland and ovulation occurs
• progesterone also is released to act as a stabilising molecule for the uterus lining

Question 3

What is the function of FSH?

Answer 3

• To stimulate the growth and maturation of folliicles

- Stimulate the production of oestrogen from anterior pituitary

Question 4

What is the function of oestrogen?

Answer 4

• To stimulate development of lining of uterus and promote release of LH
• Also has effects on bone and breasts

Question 5

What is the function of LH?

Answer 5

• To cause ovulation and also convert the follicle into corpus luteum, which in turns stimulate the release of progesterone

Question 6

What is the function of progesterone?

Answer 6

• To stablise the lining of uterus and release glucagon to produce more sugars
• when level of progesterone drops, it is when blood vessels of the lining shrink= lining of uterus becomes necrotic and blood floods out= menstrual cycle

Question 7

How is thyroid secreted normally?

Answer 7

• Hypothalamus arcuate nucleus releases TRH and triggers TSH release in anterior pituitary.
• This causes T3 and T4 production in the thyroid glands
• level of TRH can be suppressed by somatostatin and dopamine

Question 8

How is thyroid gland function usually monitored?

Answer 8

• By measuring level of TSH in blood.
• Usually it is a very sensitive measure as lack of T3 and T4 in peripheral blood would feedback to the hypothalamus which causes an increase of TRH release and hence TSH release

Question 9

What are the reasons in why the T4 level would reduce?

Answer 9

• Usually due to radioactivity and dietary, i.e. lack of iodine

Question 10

Why would hypothyroidism cause no ovulation?

Answer 10

• Because TRH does not only increase the conc of TSH but also stimulating prolactin.
• As mentioned before, lack of T3/T4 in peripheral blood causes arcuate nucleus in hypothalamus to produce more TRH = more prolactin
• prolactin has inhibitory effect on GnRH so reduction in FSH release and reduction in oestrogen release
• no mature follicle/ uterus lining= no ovulation

Question 11

What are the usual symptoms for patients who have hypothyroidism?

Answer 11

• lack of energy, dry skin, brittle hair, not growing

- no ovulation!

Question 12

What are the symptoms in patients who have polycystic ovarian syndrome?

Answer 12

• aranthosis nigricans ( brown patch at the back of the neck) and excess hair (hirsutism)

Question 13

What is the size of a normal ovary and a polycystic ovary?

Answer 13

• normal ovary= 2m X 3cm; polycystic= 6-8cm

Question 14

Where are the steroids synthesised in the ovary?

Answer 14

• In the theca cells: cholesterol (27carbons) -> progesterone (21C) -> androgen (19C) and then androgen is diffused into granulosa cells from theca cells
• granulosa cells: androgen(19C) -> oestrogen(18C)
• The rate limiting step of this pathway is the conversion of androgen into oestrogen

Question 15

What is the defect in the steroid synthesis pathway to result in no ovulation in polycystic ovarian syndrome?

Answer 15

• there is an up-regulation of cytochrome P450c17a and as a result, there is a higher production of progesterone into androgen
• However this does not mean there is a higher concentration of oestrogen because conversion of androgen into oestrogen is a rate limiting step
• this means normally high level of androgen would normally drive oestrogen to form but because it is a rate limiting step, oestrogen production does not increase
• so there is a higher level of androgen produced than required and acts on other parts of body, eg. acne on skin

Question 16

What would happen if there is a high level of androgen in blood?

Answer 16

• it can promote hirsutism and also travels to liver. There is a reduction in sex hormone binding protein, which is normally needed for androgen to circulate in blood.
• Therefore, more free androgens are found in blood and producing active effects, i.e. STIMULATE production of LH
• LH level no longer has peaks and falls, always remain around a constant level due to the androgens so results in a reduction of GnRH and FSH= no maturation of follicles. AND NO progesterone due to no peaks and falls

Question 17

Why is there NOT a fall in oestrogen level in blood for patients who have polycystic ovarian syndrome?

Answer 17

• Because there are many many follicles in the ovary and each of them still has a low level of FSH. This means, FSH can still stimulate the release of oestrogen
• Therefore, there is a summative effect of oestrogen
• At the same time, there is no release of progesterone despite a constant level of LH because progesterone release requires a peak in LH but LH level is now constant, no progesterone is being released.

Question 18

Role of Sex-hormone binding globulins in insulin’s activity

Answer 18

• insulin is secreted by pancreatic beta cells and in liver/ muscle cells, insulin is bind to the insulin receptors on muscle/liver cells and so glucose can be taken up by the cells and form glycogen. This process can be further amplified by ino-derived 2nd messengers (like inositolphosphoglycans)
• A negative feedback system is in place when there is a reduction in blood glucose = reduce insulin release

*This is given when liver and theca cells produce normal amount of SHBG and androgens

Question 19

What would happen if there is a reduction in sex hormone binding globulin proteins (like in polycystic ovarian syndrome)?

Answer 19

• That can lead to incompetent insulin receptors and so less glucose can be taken into cell. Also there is a reduction in level of ino-derived 2nd messenger which means less glucose can be converted into glycogen
• there is less of a negative feedback mechanism due to inadequate mechanism in reducing blood glucose
  = results in insulin resistance

-Also further increases LH level so FSH level remains low due to insulin secretion

Question 20

What are the treatments of polycystic ovarian syndrome?

Answer 20

• clomiphene citrate (selective oestrogen receptor modulator)
• metformin
• hMG, FSH
• ovarian diathermy
• myo-inositiol