Gonads Flashcards
Recall the hypothalamo-pituitary testicular axis and its regulation
LH;
- is a hormone stimulating hormone
- causes androgen production in Leydig cells
- reduced by testosterone ( negative feedback)
FSH
- GnRH pulses from the hypothalamus stimulate the release of LH and FSH from the pituitary
- stimulates spermatogenesis in Sertoli cells
- reduced by INHIBIN negative feedback ( produced by Sertoli cells)
- Testosterone is needed for the final maturation sperm step.
- Testosterone has negative feedback on the hypothalamus and the pituitary
Phases of the Menstrual Cycle
- Follicular Phase
- Ovulation
- Luteal Phase
Hypothalamo-Pituitary-Gonadal Axis- Females Follicular Phase
- LH stimulates the production of oestradiol and progesterone in the ovaries
- FSH stimulates follicular development and inhibin
- By around day 10, the leading follicle develops into a Graffian Follicle
- Oestrogen initially has negatively inhibits LH and FSH secretion
- So in the follicular phase their HPG axis is basically the same as men
- LH surge needed to mature the eggs- critical for ovulation and fertility
Luteal Phase
- Once the oestrogen levels reach a certain point, it switches from negative feedback to positive feedback
·It increases GnRH release and increases LH sensitivity to GnRH
- This leads to a mid9cycle LH surge
- This triggers ovulation from the leading follicle
- If implantation does NOT occur, the endometrium is shed (menstruation)
- If implantation does occur you have pregnancy
Recall the hypothalamo-pituitary ovarian axis and its regulation
Same as testes but testosterone is replaced by estrogen
- GnRH pulses from the hypothalamus stimulate the release of LH and FSH from the pituitary
- LH then stimulates testosterone production in the testes (leydig cells)
- Testosterone is responsible for secondary sexual characteristics and aids
Spermatogenesis
- FSH stimulates sertoli cells in seminiferous tubules 99> sperm and inhibin A and B
- Testosterone has negative feedback on the hypothalamus and the pituitary
- Inhibin has negative feedback on pituitary FSH secretion
Using a labeled diagram, demonstrate the defects in the hypothalamo-pituitary gonadal axis in primary and secondary gonadal failure
Infertility
- Definition: inability to conceive after 1 year of regular unprotected sex
- 1/6 couples can be affected
- Caused by abnormalities:
- In males (30%)
- Or females (45%)
- Or unknown (25%)
Primary Gonadal Failure
- This is a defect of the gonads
- The testes or ovaries are not producing testosterone/oestrogen so there is no negative feedback on the HPG axis meaning that you get HIGH GnRH and HIGH LH and FSH
- You can’t measure GnTH because they are in the hypothalamic granules
Hypothalamic/Pituitary Disease
- This is caused by an inability of the pituitary gland to produce FSH and LH so their levels are LOW
- As a result of this, you also have LOW oestradiol/testosterone
List the clinical features, causes of male hypogonadism.
Male Hypogonadism - Clinical Features
- Loss of libido
- Impotence
- Small testes
- Decreased muscle bulk
- Osteoporosis (testosterone has an anabolic action in the bone)
Male Hypogonadism - Causes
- Hypopituitarism
- Kallmann Syndrome (anosmia and low GnRH – failure of GnRH secretion- embryologic basis olfactory nerve migrates near GnRH neurons)
50% of cases no genetic mutations -10% is genetic
3. Illness/underweight
* Mainly due to low levels of leptin (the body tells you that you’re too underweight, it’s not an appropriate time to reproduce)
4. Primary Gonadal Disease
Congenital: Klinefelters Syndrome (XYY
5. Acquired: Testicular torsion, chemotherap
6. Hyperprolactinaemia: This can inhibit gonadal function
7. Androgen Receptor Deficiency: Very RARE
Discuss investigations and treatment of male hypogonadism.
Investigations for Male Hypogonadism – Tests
1. LH, FSH and Testosterone
- If they are all LOW 99> MRI the pituitary to check for pituitary problem
2. Prolactin
3. Sperm Count
- Azoospermia = absence of sperm in ejaculate
- Oligospermia = reduced numbers of sperm in ejaculate
4. Chromosomal Analysis (see for congetnital genetic problem : Klinefelters 9 XYY)
- NOTE: now they can do intracytoplasmic sperm injections, so this can combat the infertility of someone with oligospermia
- You can also look at sperm under the microscope to check their numbers and motility
Treatment of Male Hypogonadism
- Replacement testosterone for all patients
* This will increase their muscle bulk and protect against osteoporosis (doesn’t cause spermatogenesis) - For fertility: if hypothalamic/pituitary disease
- You need gonadotrophins to stimulate testosterone release so you give subcutaneous gonadotrophin injections (mimic LH and FSH to induce it)
- This will induce spermatogenesis
- Hyperprolactinaemia
- Dopamine agonist
- Dopamine is the main hypothalamic influence over prolactin release and it has a negative effect on prolactin release
List the tissues that produce androgens and three endogenous androgens.
Endogenous Sites of Production of Androgens
- Interstitial Leydig cells of the testes
- Adrenal cortex (males and females)
- Ovaries
- Placenta
- Tumours
Androgens: testosterone, dihydrotestosterone, androstenedione
Explain the main physiological actions of testosterone and briefly explain its mechanism of action.
Main Actions of Testosterone
- Development of the male genital tract
- Maintains fertility in adulthood
- Control of secondary sexual characteristics
- Anabolic effects (muscle, bone)
Circulating Testosterone Binding
- Circulating testosterone is heavily protein bound
- In different tissues you get testosterone being converted to other things
- 5 aKreductaseconverts testosterone todihydrotestosterone (DHT)which then acts onandrogen receptors (AR)
- Aromatase can convert testosterone to 17bKOestradiol (E2) which acts via the oestrogen receptors (ER)
- DHT and E2 receptors act via nuclear receptors 9 they are intracellular and have to go into the nucleus to have an effect
List and explain the main clinical uses and major unwanted effects of testosterone.
Clinical Uses of Testosterone
Testosterone in adulthood will increase:
- Lean body mass
- Muscle size and strength
- Bone formation and bone mass (in young men)
- Libido and potency
- NOTE: it will NOT restore fertility, which requires treatment with gonadotrophins to restore normal spermatogenesis
Define amenorrhoea and list its causes.
Disorders in the Female
- Amenorrhoea
- Polycystic Ovarian Syndrome (PCOS)
- Hyperprolactinaemia
Amenorrhoea
- Absence of periods
- Primary Amenorrhoea = failure to develop spontaneous menstruation by the age of 16 years
- Secondary Amenorrhoea = absence of menstruation for 3 months in a woman who has previously had cycles
- Oligomenorrhoea = irregular long cycles
·Causes:
- PREGNANCY
- Lactation
- Ovarian Failure:
- Premature ovarian insufficiency (POF) (early menopause)
- Oophorectomy
- Chemotherapy
- Ovarian dysgenesis (Turner’s Syndrome (45 X)) 9 lacking an X chromosome
- Features of Turner’s Syndrome:
- Short stature
- Cubitus Valgus (where the forearm is angled away from the body to a greater degree than normal when fully extended)
- Gonadal dysgenesis (defective development)
- 1:5000 live female births
More causes of amenorrhoea
- Gonadotrophin Failure:
- Hypothalamic/pituitary disease
- Kallmann’s syndrome
- Low BMI
- Post-pill amenorrhoea
When on pill –oestrogen and progesterone exogenously but cause hypothalamus ans pituitary go to sleep (downregulates the hypothalamus andpituitary)
- If you use the pill for a long time, then your periods won’t come back for around 12 months after cessation of use
- This is why it is advised that you stop using the pill every 4 years
- Hyperprolactinaemia
- Androgen excess: gonadal tumour
- Easy to diagnose because testosterone will be in excess
Discuss investigations and treatment of amenorrhoea.
Investigation of Amenorrhoea
- Pregnancy Test
- LH, FSH and Oestradiol
- Day 21 Progesterone
- In the second half of the menstrual cycle the progesterone rises over a prolonged period of time
- There should be a rise in progesterone around this time to show that they are ovulating
- Prolactin
- Thyroid function test
- Hyper9 and hypothyroidism can cause problems with periods
- Androgens (testosterone, androstenedione, DHEAS
- Chromosomal Analysis (Turner’s)
- Ultrasound Scan Ovaries/Uterus
Treatment of Amenorrhoea
- Treat the cause (e.g. low weight BMI>21)
- Primary Ovarian Failure- infertile, HRT, infertile
- Hypothalamic/pituitary disease
- HRT for oestrogen replacement
- Fertility: gonadotrophins (LH and FSH) 9 part of IVF treatment
List the criteria used to diagnose polycystic ovary syndrome (PCOS).
List the clinical features, investigations and treatment of polycystic ovary syndrome (PCOS).
Polycystic Ovarian Syndrome
- 1 in 12 women of reproductive age
- Associated with:
oIncreased cardiovascular risk
- Insulin resistance (diabetes)
Criteria to Diagnose PCOS
- Need TWO of the following:
- Polycystic ovaries on the ultrasound scan
- Oligoovulation/anovulation
- Clinical/biochemical androgen excess:
- E.g. increased growth of hair in a male pattern
Clinical Features of PCOS
- Hirsuitism – excess hair growth
- Menstrual cycle disturbance
- Increased BMI
Treatment of PCOS K Fertility
1) Metformin
- Insulin sensitiser used in type II diabetes
2) Clomiphene - Anti9oestrogenic effect in the hypothalamo9pituitary axis
- Binds to oestrogen receptors in the hypothalamus thereby blocking the negative feedback
- This results in an increase in GnRH and gonadotrophin secretion
- This is used in short periods to kick9start the HPG axis
3) Gonadotrophin therapy as part of IVF treatment
Using a labelled diagram, explain the pathway controlling normal prolactin secretion.
Control of Prolactin Secretion
- In the case of prolactin, dopamine, which has a negative effect on prolactin release, is the main hypothalamic hormone controlling prolactin release
- TRH has a mild stimulatory effect
- Prolactin is needed to stimulate the production of milk in lactating women
- If it becomes dysregulated it will switch off gonadal function via LH actions on the ovaries and testes
- It also reduces GnRH pulsatility so that it is released basally all the time rather than in regular pulses
Causes of Hyperprolactinaemia
Control of prolactin is negative rather than positive – dopamine secreted by hypothalamus – switches of prolactin secretion
1)Dopamine Antagonists
- Anti-emetics (metoclopramide)
- Anti-psychotics (phenothiazines)
- NOTE: anti-emetics generally tend to be used in the short term which isn’t much of a problem but anti9psychotics tend to be used in the long term
2) Prolactinoma (benign tumor producing too much prolactin)
3) Stalk compression due to pituitary adenoma
- This means that the dopamine can’t get through to inhibit the prolactin release
4) PCOS
5) Hypothyroidism (elevated TRH – which san stimulate prolactin)
6) Oestrogens (oral contraceptive pill), pregnancy, lactation
7) Idiopathic
Clinical Features of Hyperprolactinaemia
- Galactorrhoea
- Reduced GnRH secretion/LH action leads to hypogonadism
- Prolactinoma:
- Headache
- Visual field defect
List the causes, clinical features, investigation and treatment of hyperprolactinemia.
Treatment of Hyperprolactinaemia
- Treat the cause 9 e.g. stop the drugs if that’s what’s causing it
1) Dopamine Agonists: - Bromocriptine
- Cabergoline (very potent – make prolactin levels shrink to nothing)
- This will also cause a decrease in the size of the tumour if it is being caused by a prolactinom
2) Prolactinoma:
- Dopamine agonist therapy
- Pituitary surgery rarely needed (because drugs usually
Menopause
Menopause
- Permanent cessation of menstruation
- Loss of ovarian follicular activity
- Average age 51 (45955)
-
Climacteric: period of transition
- You have normal regular cycles every month and then it becomes a little irregular (oligomenorrhoea) and then this progresses to amenorrheoa
- Amenorrhoea for more than 12 months is menopause
Symptoms of Menopause
- Hot Flushes
-
Urogenital Atrophy and dyspareunia (difficult or painful sexual intercourse)
- This is because of vaginal atrophy 99> leads to painful sex
- Sleep disturbance
- Depression
- Decreased libido
- Joint pain
- Symptoms usually diminish/disappear with time
Recap of the Hypothalamo-Pituitary Gonadal Axis
- GnRH from the hypothalamus stimulates the anterior pituitary to produce LH and FSH
- This makes ovaries make oestradiol and inhibin
- Oestradiol and inhibin inhibit LH and FSH
Changes in Menopause
- Low levels of oestradiol and inhibin B because of the follicular atresia
- This means that there is less negative feedback so gonadotrophin levels go up
- So in a 55 year old woman you’d expect the LH and FSH to be HIGH
Complications of Menopause
1) OSTEOPOROSIS
- This is the major complication of menopause
- This is caused by Oestrogen Deficiency
- Oestrogen is an anabolic hormone so reduced oestrogen will result in osteoporosis
- In osteoporosis there is less matrix and that predisposes these patients with oestrogen deficiency to osteoporotic fractures
- 10 fold increase in the risk of fracture in a post-menopausal woman
2) Cardiovascular Disease
- Protected against CVD before menopause
- Have the same risk as men after the age of 70
