Endocrine Infertility Flashcards
Describe the hypothalamo-pituitary-testicular axis.
- 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:
What are the three phases of the menstrual cycle?
28 day cycle (on average)
- Follicular phase
- Ovulation
- Luteal phase
Describe the hypothalamio-pituitary ovarian axis.
- 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
What happens during the follicular phase?
- 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
What happens during ovulation?
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
What happens during the luteal phase?
- 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
Define infertility.
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%)
State the two main causes of infertility.
Primary gonadal failure
Hypothalamic/pituitary disease (i.e. tertiary/secondary failure)
What is primary gonadal failure and what effects does it have on the hypothalamo-pituitary-gonadal (HPG) axis?
- 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
How does hypothalamic and pituitary disease affect the HPG axis?
Hypothalamic disease → low GnRH → low FSH and LH → low testosterone/oestradiol (tertiary hypogonadism)
Pituitary disease → low FSH and LH → low testosterone/oestradiol (secondary hypogonadism)
State some of the clinical features of male hypogonadism.
- Loss of libido = sexual interest / desire
- Impotence
- Small testes
- Decreased muscle bulk
- Osteoporosis
NOTE: Testosterone stimulates protein synthesis (anabolic effect) → muscle and bone growth
State some causes of male hypogonadism.
- 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)
What are the main investigations for male hypogonadism?
- 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)
What is given to all patients with male hypogonadism?
Testosterone to increase muscle bulk and protect against osteoporosis
How do you restore fertility in someone with male hypogonadism?
Subcutaneous gonadotrophin (i.e. FSH and LH) injections → stimulates testosterone release
What is the treatment for hyperprolactinaemia?
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)
State some endogenous sites of production of androgens.
- 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)
What are the main actions of testosterone?
- Development of the male genital tract
- Maintains fertility in adulthood
- Control of secondary sexual characteristics
- Anabolic effects (muscle, bone)
How is testosterone found in the circulation?
Heavily plasma protein bound - 98%
State two products that testosterone can be converted to and the enzymes responsible for these conversions and the receptors via which testosterone acts.
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
What type of receptors does DHT and E2 act on?
Nuclear receptors (i.e. present in the nuclear)
What are the clinical uses of testosterone in adulthood?
- 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
What is amenorrhoea?
The absence of periods
What is the difference between primary and secondary amenorrhoea?
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
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)
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
-
When you stop taking the pill, it can take some time for your regular ovulation and menstruation to return
Hyperprolactinaemia
Androgen excess: gonadal tumour
- Excess androgen production suppresses GnRH, FSH and LH → inhibits further menstruation
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
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
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
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
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
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
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)
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
What hypothalamic hormone has a stimulatory effect on prolactin release?
Thyrotrophin releasing hormone (TRH)
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
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)
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
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
