Endocrine Infertility Flashcards
1
Q
Describe the hypothalamo-pituitary-testicular axis.
A
- GnRH released from hypothalamus in a pulsatile fashion
- This triggers FSH and LH release from anterior pituitary
- FSH stimulates the testes to produce inhibin
- LH stimulates the testes to produce testosterone
- Negative feedback
- Inhibin:
- Inhibits FSH secretion from anterior pituitary
- Inhibits GnRH secretion from hypothalamus
- Testosterone
- Inhibits LH secretion from anterior pituitary
- Inhibits GnRH secretion from hypothalamus
- Inhibin:
2
Q
What are the three phases of the menstrual cycle?
A
28 day cycle (on average)
- Follicular phase
- Ovulation
- Luteal phase
3
Q
Describe the hypothalamio-pituitary ovarian axis.
A
- GnRH released from hypothalamus in a pulsatile fashion
- This triggers FSH and LH release from anterior pituitary
- FSH and LH stimulate the ovaries to produce oestradiol (oestrogen), progesterone and inhibin
- Negative feedback
- Ostradiol, progesterone and inhibin
- Inhibits FSH and LH secretion from anterior pituitary
- Inhibits GnRH secretion from hypothalamus
- Ostradiol, progesterone and inhibin
4
Q
What happens during the follicular phase?
A
- At the beginning of the menstrual cycle, oestrogen and progesterone levels are low
- So there is little -ve feedback on hypothalamus and pituitary
- This leads to an increase in pulsatile release of GnRH and therefore release of FSH and LH
- FSH and LH stimulate the ovaries to produce oestradiol
- FSH also stimulates the ovaries to produce inhibin
- Negative feedback:
- High levels of oestradiol inhibit FSH and LH release from anterior pituitary
- Inhibin inhibts FSH release
5
Q
What happens during ovulation?
A
Extremely high concentrations of oestradiol (for long enough) results in:
- negative feedback → positive feedback
- This positive feedback triggers an LH surge
- LH surge → ovulation
NOTE: No FSH surge due to negative feedback by inhibin
6
Q
What happens during the luteal phase?
A
- Ovulation has already taken place
- If implantation does NOT occur → endometrium is shed (menstruation)
- If implantation DOES occur → pregnancy
NOTE: Implantation = the adherence of a fertilised egg to the uterus lining so that the egg may have a suitable environment for growth and development
7
Q
Define infertility.
A
Inability to conceive after 1 year of regular unprotected sex
NOTE:
- 1 in every 7 couples
- Caused by abnormalities in:
- males (30%)
- females (45%)
- unknown (25%)
8
Q
State the two main causes of infertility.
A
Primary gonadal failure
Hypothalamic/pituitary disease (i.e. tertiary/secondary failure)
9
Q
What is primary gonadal failure and what effects does it have on the hypothalamo-pituitary-gonadal (HPG) axis?
A
- It is a problem with the gonads (i.e. testes/ovaries)
- The testes/ovaries fail to produce enough testosterone/oestradiol
- Therefore, there is no negative feedback on the HPG axis → high GnRH, FSH and LH
10
Q
How does hypothalamic and pituitary disease affect the HPG axis?
A
Hypothalamic disease → low GnRH → low FSH and LH → low testosterone/oestradiol (tertiary hypogonadism)
Pituitary disease → low FSH and LH → low testosterone/oestradiol (secondary hypogonadism)
11
Q
State some of the clinical features of male hypogonadism.
A
- Loss of libido = sexual interest / desire
- Impotence
- Small testes
- Decreased muscle bulk
- Osteoporosis
NOTE: Testosterone stimulates protein synthesis (anabolic effect) → muscle and bone growth
12
Q
State some causes of male hypogonadism.
A
- Hypothalamic-pituitary disease
- Hypopituitarism
- Kallmans syndrome (characterised by anosmia = absent sense of smell & low GnRH)
- Illness / underweight
- Primary gonadal disease (i.e. failure of testes to produce sufficient testosterone)
- Congenital: Klinefelters syndrome (XXY)
- Acquired: testicular torsion, chemotherapy
- Testicular torsion = twisting of spermatic cord which supplies blood to the testes, leading to ischaemia
- Hyperprolactinaemia (this inhibits pulsatile release of GnRH which is essential for stimulating LH and FSH release)
- Androgen receptor deficiency (on end/target organs)
13
Q
What are the main investigations for male hypogonadism?
A
- LH, FSH and testosterone levels
- If all are low → pituitary MRI (to check if there is a problem with the pituitary gland)
- Prolactin levels (to check for hyperprolactinaemia)
- Sperm count
- Azoospermia – absence of sperm in ejaculate
- Oligospermia – reduced number of sperm in ejaculate
- Chromosomal analysis (check for Klinefelter’s: XXY)
14
Q
What is given to all patients with male hypogonadism?
A
Testosterone to increase muscle bulk and protect against osteoporosis
15
Q
How do you restore fertility in someone with male hypogonadism?
A
Subcutaneous gonadotrophin (i.e. FSH and LH) injections → stimulates testosterone release
16
Q
What is the treatment for hyperprolactinaemia?
A
Dopamine agonists
- These are essentially D2 receptor agonists to stimulate dopamine release from the hypothalamus
- Dopamine inhibts prolactin release from anterior pitutiary
- Increased dopamine release → decrease prolactin release → decreased inhibition of GnRH pulsatility (pulsatile release)
17
Q
State some endogenous sites of production of androgens.
A
- Interstitial Leydig cells of the testes
- Interstial - i.e. present in the interstitial fluid between the seminiferous tubules
- Adrenal cortex (males and females)
- Ovaries
- Placenta
- Tumours (of ovaries or adrenal cortex)
18
Q
What are the main actions of testosterone?
A
- Development of the male genital tract
- Maintains fertility in adulthood
- Control of secondary sexual characteristics
- Anabolic effects (muscle, bone)
19
Q
How is testosterone found in the circulation?
A
Heavily plasma protein bound - 98%
20
Q
State two products that testosterone can be converted to and the enzymes responsible for these conversions and the receptors via which testosterone acts.
A
These conversions are tissue-specific
- Testosterone → dihydrotestosterone (DHT)
- Enzyme: 5α-reductase
- Receptor: androgen receptor (AR)
- Testosterone → 17β-Oestradiol (E2)
- Enzyme: aromatase
- Receptor: oestrogen receptor (ER)
- ERs found in brain and adipose tissue
- Brain - behavooural effects
- Adipose tissue - metabolic actions on lipids
21
Q
What type of receptors does DHT and E2 act on?
A
Nuclear receptors (i.e. present in the nuclear)
22
Q
What are the clinical uses of testosterone in adulthood?
A
- Lean body mass (fat-free body mass)
- Muscle size and strength
- Bone formation and bone mass (in young men)
- Libido and potency
Testosterone alone does not restore fertility
- Infertility requires treatment with gonadotrophins (FSH and LH) to restore normal spermatogenesis
- FSH and LH stimulates spermatogenesis and testosterone production
- Testosterone regulates spermatogenesis and initiates the functional responses required to support spermatogenesis
NOTE: Potency = ability to get or keep an erection which allows the male to have sex
23
Q
What is amenorrhoea?
A
The absence of periods
24
Q
What is the difference between primary and secondary amenorrhoea?
A
Primary Amenorrhoea = failure to develop spontaneous menstruationby the age of 16 years
Secondary Amenorrhoea = absence of menstruation for 3 months in a woman who has previously had cycles
25
What is oligomenorrhoea?
Irregular long cycles
* *The normal cycle ranges from 21-35 days*
* *If the cycle is longer then 35 days, then periods are infrequent*
* *This is oligomenorrhoea (infrequent periods)*
26
List some causes of amenorrhoea.
Pregnancy
* *High oestrogen and progesterone inhibits further menstruation (suppresses FSH/LH and GnRH)*
Lactation
* *High prolactin stimulates milk production*
* *Prolactin suppresses GnRH pulsatility (pulsatile release)*
Ovarian failure:
* Premature ovarian failure *(early menopause becuase your ovaries stop working properly)*
* Ovariectomy / chemotherapy
* Ovarian dysgenesis (Turners 45 XO) *– lacking one chromosome*
Gonadotrophin failure:
* Hypothalamic/pituitary disease
* Kallmann’s syndrome (anosmia, Low GnRH)
* Low BMI
* Post pill amenorrhoea
* *When you stop taking the pill, it can take some time for your regular ovulation and menstruation to return*
* *Contraceptive pill - oestrogen only or oestrogen and progesterone*
* *They suppress GnRH, FSH and LH*
* *So it can take some time once you stop taking the pill to return to the normal production of these hormones*
Hyperprolactinaemia
Androgen excess: gonadal tumour
* *Excess androgen production suppresses GnRH, FSH and LH* *→ inhibits further menstruation*
27
State some features of Turner’s syndrome.
* Short stature
* Cubitus valgus (wide carrying angle)
* *Forearm is angled away from the body to a greater degree than normal when fully extended*
* Gonadal dysgenesis *(abnormal ovarian development)*
1:5000 live **female** births
28
Why does low BMI cause amenorrhoea?
* Leptin released by adipocytes
* Low BMI = low leptin
* Lack of leptin acting on the brain results in the brain shutting down the reproductive axis
* This is because lots of energy is required to reproduce
* Fat is an energy store
29
State some investigations for amenorrhoea.
* Pregnancy test
* LH, FSH, oestradiol
* Day 21 progesterone *(should be at its peak)*
* Prolactin, thyroid function tests
* *Hyperthyroidism → low BMI → amenorrhoea*
* Androgens (testosterone, androstenedione, DHEAS)
* *DHEA sulphate - steroid hormone produced in adrenal cortex, exists in conjugated form*
* *Androstenedione - produced in adrenal cortex and gonads*
* *Androstenedione and DHEA are precursors to testosterone*
* Chromosomal analysis (Turners 45 XO)
* Ultrasound scan ovaries / uterus
30
How can amenorrhoea be treated?
Treat the cause *(e.g. low weight)*
Primary ovarian failure (infertile) – HRT
Hypothalamic/pituitary disease
* HRT for oestrogen replacement
* Fertility: Gonadotrophins (LH & FSH)
* This usually part of IVF treatment
* *In IVF, gonadotrophins are given to stimulate development of _multiple_ eggs to increase chance of successful pregancy*
Explanation:
* Essentially if you have amenorrhoea, you are usually lacking oestrogen
* Lack of oestrogen makes you infertile
* However, oestrogen has other important functions *(e.g. anabolic effect on bone, effects on lipid metabolism)*
* Therefore, the first line of treatment should be oestrogen HRT but this alone is **not** enough to make you fertile
* Therfore you need to give FSH and LH *- need to give HRT if you have a hypothalamic/pituitary disease*
31
What is PCOS?
PCOS = Polycystic ovarian syndrome
* Syndrome = a group of symptoms which consistently occur together
* The main feature of PCOS is **excess androgens**
* This is likely to have multiple underlying pathophysiological mechanisms
* *Increased pulse frequency of GnRH → LH hypersecretion → increased androgen production within ovaries*
* *Metabolic disturbance → insulin resistance → compensatory hyperinsulaemia*
* *Insulin increases the ovarian response to LH so further increases androgen production*
* Incidence: 1 in 12 women of reproductive age
* Associated with insulin resistance *(leads to diabetes)*
* Leads to increased cardiovascular risk
32
What are the criteria for diagnosing PCOS?
They must have at least 2 of the following:
* Polycystic ovaries on ultrasound scan
* *These 'cysts' are actually immature follicles which have not been able to develop properly due to the ovaries not functioning as normal*
* Clinical/biochemical signs of androgen excess
* Oligoovulation/anovulation
* *Anovulation → infertility*
* *Anovulation due to follicles not being able to mature*
33
What are the clinical features of PCOS?
Hirsuitism *(due to androgen excess)*
Menstrual irregularities *(due to hormonal imbalance - androgen and LH excess)*
Increased BMI *(due to insulin resistance)*
34
Describe the treatment for PCOS.
Metformin
* *Makes tissues more sensitive to insulin*
* *This decresases insulin levels which improves fertility*
* *Insulin resistance causes compensatory hyperinsulaemia*
* *Hyperinsulaemia can impact ovarian function and lead to problems with ovulation*
Clomifene
* Is anti-oestrogenic in the hypothalamo-pituitary axis
* Bind to oestrogen receptors in the hypothalamus thereby blocking the normal negative feedback by oestrogen binding
* This results in an increase in the secretion of GnRH and gonadotrophins (FSH and LH)
Gonadotrophin therapy as part of IVF treatment
35
What hypothalamic hormone has a stimulatory effect on prolactin release?
Thyrotrophin releasing hormone (TRH)
36
What effect does hyperprolactinaemia have on the HPG axis?
It reduces GnRH pulsatility
* *GnRh released at constant low rate - no pulses where there is suddenly more release*
* *The pulse frequency affects the release of FSH or LH so is very important in regulating gonodotroph release*
It will inhibit LH actions on the ovaries and testes
* *Reduced gonadal function*
37
State some causes of hyperprolactinaemia.
**Dopamine antagonist drugs**
* Anti-emetics (metoclopramide)
* *Drug used to treat vomiting and nausea*
* *Dopamine receptors in vomiting centre - cause vomiting/nausea when stimulated*
* Anti-psychotics (phenothiazines)
* *Psychosis can be caused by problems with the dopamine system in certain parts of the brain*
* *e.g. schizophrenia patients have an overactive dopamine system*
* Dopaminergic neurones and dopamine receptors present throughout brain, including the parts involved in causing vomiting *(vomiting centre) and psychosis*
**Prolactinoma** *(pituitary adenoma of lactotrophs)*
**Stalk compression due to pituitary adenoma**
* *This prevents the dopamine from the hypothalamus from getting to and exerting its inhibitory effect on the lactotrophs (in the anterior pituitary)*
* *Lack of inhibition → increased prolactin production*
**Hypothyroidism**
* *Low levels of thyroid hormones means lack of suppression of TRH production*
* *More TRH to overcome dopamine inhibition and stimulate prolactin production*
**Oestrogens (oral contraceptive pill - OCP)**
* *Oestrogen - stimulates prolactin production and secretion (therefore involved in regulation of prolactin)*
**PCOS**
* *Results in high levels of androgens*
* *Androgens can be converted to oestrogen so also high levels of oestrogen*
**Pregnancy and lactation**
* *Levels of prolactin start increasing during pregnancy to prepare for lactation*
**Idiopathic** *(unknown cause)*
38
What are the clinical features of hyperprolactinaemia?
* Galactorrhoea
* Reduced GnRH secretion / LH action → hypogonadism *(reduced testosterone/oestrogen)*
* Prolactinoma
* Headache - *increased pressure (around pituitary gland)*
* Visual field defect - *compression of optic chiasm just above pituitary gland*
39
How is hyperprolactinaemia treated?
Treat the cause of hyperprolactinaemia
* By treating this and decreasing prolactin levels, this will increase fertility
* This is a better option than just giving the patient fertility drugs *(e.g. hormone replacement)*
Dopamine agonist - e.g:
* Bromocriptine
* Cabergoline
For a prolactinoma:
* Dopamine agonist therapy
* Pituitary surgery rarely needed
