Week 7 Endocrinology Gonadotrophs Flashcards
How do you tell the difference between and graafian follicle and a primary/ secondary follicle?
If there is a granulosa cell stalk connected to the oocyte this means its a graafian follicle as the oocyte is about to be ejected
What is the function of oxytocin and when is it’s production stimulated?
Oxytocin has major effects on smooth muscle contraction
- milk ejection
- contraction of uterus during childbirth
- Secretion is stimulated in response to stimulation of nipples or uterine distension.
Oxytocin is used to induce labour
In an adult what is the regular pattern of release of GNRH and why?
Pulsing release
- prevents receptor desensitisation & downregulation
What are kiss neurons
A new cell in the hypothalamus that helps regulate GNRH release and is influences but an array of factors including environmental clues, gonads, body fat and the adrenal gland
What is the function of anti mullerian hormone in ovarian function?
It is released by granulosa cells in the early stages of follicle development. So it is a measure of the ovarian reserve (how many follicle are ready to develop).
It can also be high in PCOS as there are many follicles frozen in early development.
What is the purpose of granulosa cells?
They convert androgens made by the theca cells into oestrogen
What is the ezyme found in granulosa cells that converta androgen into oestrogen?
Aromatase
How does a dominant follicle develop?
Everytime FSH is present multiple follicles develop. Eventually one gets mature enough that it stop becoming relient on FSH and begins releasing inhibin B which inhibits FSH
Purpose of FSH?
Stimulates the growth of follicles through the growth of granulosa cells.
This indurectly begine oestrogen production
What is the function of LH in women?
An LH surge triggers the release of the oocyte and ovulation begins.
It is then required in order to form and maintain the corpus leutium which makes progesterone (and some oestrogen) and gets the uterus ready for implantation.
It also stimulates theca cells to make androgens to become oestrogen.
Explain this
What happens to the hormones after pregnency?
hGC is initially made which mimics LH thus keeping the corpus leutium alive and maintaining progesterone production.
Eventually the placenta takes over progesterone.
This begins to stimulate prolactin and thus breatmilk production
What are the different orles of prolactin and oxytocin in milk?
Prolactin is required ot make milk and is also stimulated by suckling.
Oxytocin is required to release milk and is also stimulated by suckling
Secondary function of prolactin?
Inhibits FSH and LH to prevent further pregnecy duirng lactation
In early male development when is the HPG axis active?
Only active during foetal stage and then goes to sleep at birth
What are the foetal cells involved in the male HPG axis?
What do they make and what do they respond to?
Leydig cells -> respond to LH and produce testosterone
Sertoli cells -> respond to FSH and produce inhibin B and AMH
What is the function AMH in male foetal development
Anti-Mullerian hormone (AMH) is produced by testicular Sertoli cells
- Induces regression of Mullerian ducts:
Oviducts
Uterus
Vagina
What are the hallmarks of male hypogonadotrophic hypogonadism?
Low FSH and LH
Low Testosterone
What are the hallmarks of hypergonadotrophic hypogonadism?
High TSH and LH
Low Testosterone
What are these examples of
- Delayed puberty
- Congenital Hypog Hypog
- Brain tumours
- Radiotherapy
Hypog hypog
What are these examples of?
- Klinefelter Syndrome
- DSD/gonadal dysgenesis
- Chemo/radiotherapy
Hyperg hypog
What are the endometrial cells called that proliferate in response to oestrogen?
Endometrial stromal cells proliferate in response to rising estradiol levels from the growing dominant follicle
What are the two phases of endometrial growth?
Proliferative - before ovulation
Secretatory - after ovulation
What is the phase called after ovulation and broadly what happens?
Becomes inflamatory and you get the expression of receptivity genes ready for implantation
What does a disturbance of endometrial receptivity lead to?
- Implantation failure
- Pregnancy loss
- Gynaecological disorders
- Recurrent miscarriage
- Pre-eclampsia
- Intrauterine growth restriction
What causes endometriosis?
Endometrial cells shed via retrograde efflux (up the fallopian tubes) during menstruation
What is the long term result of endometriosis?
Inflammation and pain. This leads to an inbalance of hormone production at the sites with excess E2 and lack of P4.
In endometriosis E2 is pro inflamatory and P4 is anti-inflamatory
Which female cancers tend to be hormone dependent and why?
- Breast cancer
- Endometrial cancer
- Ovarian cancer
Because they come form cells which are naturally proliferated by oestrogen and progesterone
Which hormones promote the development of breast cancer?
Oestrogen and progesteorne
Which hormones make endometrial cancer worse and which make it better?
E2 worse
P4 better
Which hormones make ovarian cancer worse and which make it better?
E2 worse
P4 better
What are the risks of excess oestrogen?
Which female reproductive cancer are oestrogen dependent and which are progesterone allergic?
Breast - Oestrogen and Progesterone dependent as cells are proliferated by both.
Endometrial cells so endometrial cancer and endometriosis - Proliferate and made worse by oestrogen, progesterone encourages endometrial death so makes them better.
Ovarian cancer - oestrogen encourages growth so makes them worse where as progesterone encourages apoptosis.
What’s going on here:
Female patient presents with weight loss, over-exercise, stress and/or illness.
Tests are as follows.
What is the treatment
Hypog hypog caused by hypothalumus reacting to stress and not releasing enough GnRH.
lifestyle advice and HRT.
Specifically pulsatile GnRH or FSH/LH injections
What is going on here?
38 yo Female presents with menopausal symptoms, atrophic vaginitis and has a history of cancer treatment and the test results are as follows.
What is the treatment?
Premature ovarian insufficiency.
Treatment is oestrogen HRT for symptoms or egg donation for pregnancy.
What is atrophic vaginitis?
A condition that occurs when the body has low estrogen levels, causing the vaginal walls to thin, dry out, and become inflamed
What is going on here?
Female patient presents with visual problems and galactorrhoea (milk production) but has not recently had a baby and is not breast feeding. Examination reveals bitemporal hemianopia.
Results are as follows.
What is the treatment?
Hyperprolactinaemia due to a pituitary macroadenoma.
Macroadenoma reduces pituitary hormones and prevents dopamine reaching the anterior pituitary. Dompamine surpresses prolactin resulting in hyperprolactinaemia. It also compresses the optic chiasm causing the bitemporal hemianopia.
Treatment is surgery for macroadenoma and dompamine agonist to bring prolactin levels down.
What is going on here:
Female patient presents with hirsuitism, acne and weight gain.
Results are as follows.
What further investigations could you do. What is the treatment?
PCOS
Treatment involves:
- clomefine citrate to encourage FSH and LH for fertility
- letrozole to prevent endogenous oestrogen production
- FSH to further stimulate frozen follicles
- Before this treatment you first want to give progesterone to induce a period.
What is hirsuitism
Excess hair growth
Fill this in
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- Which hormone is required to maintain progesterone production during the menstrual cycle?
A) Estrogen
B) Follicle stimulating hormone
C) Human chorionic gonadotrophin
D) Luteinising hormone
E) Progesterone through positive feedback
D
Progesterone requires luteinising hormone to be produced. Removal of luteinising hormone in the luteal phase ceases progesterone production.
In some species estrogen reduces luteal progesterone and it is certainly not luteotrophic in women.
There are no FSH receptors in the corpus luteum as they are lost at ovulation.
Although there are progesterone receptors in the corpus luteum its role is not clear and certainly not as clear as LH.
HCG is like long-acting LH and it does drive progesterone synthesis from the corpus luteum in early pregnancy. It is not involved in the normal menstrual cycle. In early pregnancy hCG from the implanting blastocyst stops luteolysis and the progesterone the corpus luteum continues to produce maintains the early pregnancy.
- What problem limited the development of IVF as we know it now?
A) Failure of normal completion of meiosis
B) Inability to switch off inhibin B feedback
C) Lack of pure FSH
D) Premature LH surge
E) Stimulation of androgens increased
– D
Premature LH surges was the main problem with stimulated IVF. Not all eggs are good and the more eggs the more chance of a good egg. However, when increased FSH is given estrogen rises and there is an LH surge before the follicle and thus egg is mature.
Meiosis is completed at fertilisation but initiated by the LH surge.
Stimulated IVF started in the absence of pure recombinant FSH. LH and FSH were extracted from the urine of menopausal women in and were used together in a less pure preparation.
Inhibin feedback is overcome by giving more FSH.
Androgens are not stimulated as FSH will aid their conversion into estrogen.
- With regards to the menstrual cycle:
A) A period means that progesterone withdrawal has occurred
B) On mid-cycle ultrasound scanning the endometrial strip averages 5mm
C) Normal menstrual blood loss is 80 ml
D) A cycle of 35 days duration is abnormal
E) Prostaglandins increase bleeding at menstruation
E
Prostaglandins affect the vasculature and increase bleeding. They also increase pain. This is important as blocking prostaglandin production can improve both bleeding and pain.
While 80 ml of blood loss is at the very top of the normal range an average is 35ml. Some women with heavy menstrual bleeding can lose 500ml per period. Periods can happen without ovulation. These periods are sometimes heavy and prolonged and are known as anovulatory bleeding.
Cycles of 35 days are at the upper range of normal but they are normal. Interestingly the length of the luteal phase is fixed at 14 days and any variation of the menstrual is the length of time it takes to grow an egg.
The endometrium may be 5mm but there are two sides of the endometrium so it would average 10mm when the uterine midline stripe was measured.
- When is the best time in an average 28-day menstrual cycle to do a blood test for ovulation?
A) Day 14
B) Day 15
C) Day 18
D) Day 21
E) Day 28
D
The hormone we measure to confirm ovulation is progesterone. There are other reasons for high LH. So although the LH surge causes ovulation a high LH does not always mean ovulation. If there is progesterone there is a corpus luteum. If there is a corpus luteum there has been ovulation. We measure progesterone at its peak and in clinical practice we use day 21 progesterone assessment to confirm ovulation.
What are the differences between progesterone only contraceptive pill and the combines pill?
As most of the serious side effect of the combined contraceptive pill, such as blood clots, vascular changes and migraines are because of the estrogen, progesterone alone is a safer contraceptive and it is used in higher risk women.
However, unlike the combined pill which gives a regular cycle progesterone only contraception causes irregular bleeding which can be frequent and this is the major side effect.
What is Turner’s syndrome?
Turner syndrome, a condition that affects only females, results when one of the X chromosomes (sex chromosomes) is missing or partially missing.
Women with Turner’s syndrome run
out of eggs as a neonate and therefore have streak ovaries in adult life. They therefore cannot produce ovarian oestrogen in response to the increasing LH and FSH during puberty.
Hint: Was in an egg hunt. X marks the spot but I turned therefore didn’t find the eggs
Is testosterone an androgen?
Yes
Is oestrogen and androgen?
No, it’s made form androgens
What is going on here?
Normal Pregnancy
* Born at term
* Birthweight 3.3kg
* Midwife noted ‘ambiguous genitalia’
If XX it is overvirilisation - why? If XY it is undervitilisation - why?
We find out it is XY with cryptorchidism hypospadias.
Androgen Insensitivity Syndrome (Partial)
If 5alpha-reductase problem child would present female then with surge of testosterone at puberty present male.
What is Hypospadias?
Condition where the urethral opening (meatus) isn’t at the tip of the penis. Instead, the opening may be any place along the underside of the penis.
What is cryptorchidism
This is where the testes don’t decsend
Causes of Male hypog hypog
Delayed puberty
Kallmann’s syndrome
Idiopathic congenital
Brain Tumours
Radiotherapy
Cause of male hyperg hypog
- Klinefelter Syndrome
- DSD/Gonadal Dysgenesis
- Chemo/Radiotherapy
What is Klinefelter syndrome?
Congenital hyperg hypog where a child is born with an extra x chromasome.
Results in delayed puberty, infertility and small underdeveloped testes.
What is kallman’s syndrome?
Congenital hypog hypog with agnosia (reduced sense of smell).
3 congenital puberty conditions
Turners: X, run out of eggs prenatally, infertility and delayed puberty. Hyperg hypog.
Klinefelters: XXY, delayed puberty, underdeveloped testes, infertility. Hyperg hypog.
Kallmans: Congenital hypog hypog. Agnosia
Patient presents with this
Neonatal history:
* Cryptorchidism – repaired age 2
* Penile hypospadias
Current:
* Testicular volumes – 12mls:15mls
* Mass palpated in one testis - painless
What is it?
Testicular cancer
What are the bio-markers of testicular cancers?
hCG, AFP, LDH
What is the difference between a seminoma and a non-seminoma?
Seminomas
Grow slowly and are more common in men in their 40s and 50s. Sensitive to radiation therapy and chemotherapy, and often respond well to treatment. Many early seminomas can be cured with surgical removal of the testicle.
Nonseminomas
These tumors grow more quickly than seminomas and are more likely to spread beyond the testicle. They are less responsive to radiation therapy and chemotherapy. Nonseminomas come form germ cells so are often made up of more than one type of cell, including choriocarcinoma, embryonal carcinoma, teratoma, and yolk sac tumor.
Hint:
Seminoma - seminar - good for learning - good prognosis
Places that can be the source of obstructive azoospermia?
How can cystic fibrosis cause male infertility?
CFTR mutations have two effects:
1) Thickened Secretions
2) Congenital Bilateral Absence of Vas Deferens (CBAVD)
If a male has infertility due to due a lack of pituitary hormones what can you give as replacement?
FSH + hCG
Hint:
there’s no FSH without h
What causes a non-seminoma?
germ cell neoplasia in situ
GCNIS
Triggered by puberty
Why do you give hGC instead of LH in hormone replacement therepy?
It has a longer half life so you don’t need as many injection
It is more commercially available
Where is hCG made endogenously?
Made by the placenta in order to keep the corpus leutium alive until it starts making progesterone itself
What is the most common type of non-seminoma?
Embyonal carcinoma
