Download Endocrinology 7a – Endocrine Infertility

Endocrinology 7a – Endocrinology Infertility
Anil Chopra
1 Draw a diagram of the hypothalamo-pituitary gonadal axis in normal males and
females
2 Draw a diagram of the hypothalamo-pituitary gonadal axis in primary and
secondary gonadal failure
3 List the clinical features, causes, investigations and treatment of male
hypogonadism
4 Define amenorrhoea
5 List the causes, investigations and treatment of amenorrhoea
6 List the criteria used to diagnose PCOS
7. List the clinical features, investigations and treatment of PCOS
7 Draw a diagram of the pathway controlling normal prolactin secretion
8 List the causes, clinical features, investigation and treatment of
hyperprolactinaemia
Females - 28 Day menstrual cycle
Luteal Phase
 Follicle differentiates into corpus
luteum – secretes oestradiol and
progesterone. This causes the uterine
endometrium to proliferate for
implantation
 If implantation does not occur the
corpus luteum regresses and
progesterone levels fall – the
endometrium is shed (menstruation)
 If implantation does occur the
corpus luteum produces hGC (human
chorionic gonadotrophin) until 12
weeks – then the placenta takes over
making enough oestrogen and
progesterone to maintain the pregnancy
Infertility
 Infertility is defined as the inability of the couple to conceive after 1 year of
regular unprotected sex.
 It occurs in 1 in 10 couples
 Caused by abnormalities of
o males 30%
o females 45%
o unknown 25%
Primary Gonadal failure
Problem with the gonads themselves resulting in:
- Low testosterone/oestradiol
- High GnRH
- High LH and FSH
Hypopituitary Disease
Problem with Pituitary gland resulting in
- Low testosterone/oestradiol
- Low GnRH (or high in pituitary disease)
- Low FSH and LH
NB: “primary” is where the end organ does not function and secondary is when the
next step back fails (normally the pituitary).
Male Hypogonadism
Symptoms
• Loss of libido = sexual interest / desire
• Impotence = inadequate erection for satisfactory intercourse
• Small testes
• Decrease muscle bulk
• osteoporosis
Causes
 Hypothalamic pituitary disease
o Hypopituitarism
o Kallmans syndrome – anosmia (inability to smell) & low GnRH (Gonadotrophin)
o Illness/underweight
 Primary Gonadal disease
o Congenital - Klinefelters syndrome (XXY), 5-reductase deficiency
o Acquired: testicular torsion, chemotherapy.
 Hyperprolactinaemia
 Androgen receptor deficiency.
Investigations
- Measure LH, FSH, testosterone
o If all low  MRI pituitary
- Measure prolactin level
- Sperm count
o Azoopermia = absecnce of sperm in ejaculation
o Oligospermia = reduced numbers in ejaculation
- Chromosomal analysis (Klenefelters XXY)
Treatment
- Testosterone replacement
- For fertility: if they have hypothalamic/pituitary disease
o Give GnRH
o Give gonadotrophins (LH and FSH)
- If hyperprolactinaemia then give a dopamine agonist.
Female Disorders
1.




Amenorrhoea
Absence of periods
Primary of amenorrhoea = failure of periods to begin by the age of 16.
Secondary amenorrhoea = absence of menstruation for 3 months.
Oligomenorhoea = irregular cycles
Causes
 Pregnancy/lactation
 Ovariectomy/chemotherapy.
 Ovarian failure
o Premature ovarian failure
o Ovarian dysgenesis (ovaries have not developed properly) – can occur in
Turners Syndrome – XO.
 Turners Syndrome is characterised by wide carrying angle (when
arms are at sides at rest), gonadal dysgenesis, short stature.
 Gonadotrophin failure:
o Hypothalamic/ pituitary disease
o Kallmann’s syndrome (anosmia, Low GnRH)
o Low BMI
o Post pill amenorrhoea
 Hyperprolactinaemia – PCOS (polycystic ovary syndrome)
 Hypothyroidism
 Androgen excess: gonadal tumour
 Uterine/vaginal abnormality e.g. imperforate hymen, absent uterus
Investigation
 Pregnancy test
 Measure levels of LH, FSH, oestradiol
 Day 21 progesterone – tests ovulation for women trying to get pregnant. (only
useful for women with regular cycles)
 Prolactin, thyroid function tests.
 Test for androgens (testosterone, andtrostenedione, DHEAS)
 Chromosomal analysis (Turners 45 XO)
 Ultrasound of uterus, ovaries.
Treatment
- Gain weight
- Primary ovarian failure (infertile) use HRT
- If hypothalamic or pituitary disease, then treat with GnRH or LH & FSH.
Gonadotrophins:
- Mentrophin = purified extract of human post-menopausal urine containing
1:1 ratio of LH:FSH
- Human Chorionic Gonadotrophin (hGC) = the glycoprotein fraction
separated from the placenta and obtained from pregnant women. It has the
biological activity of LH
- Gonadotrophins can increase the risk of multiple follicles and so increase the
risk of:
o Multiple pregnancy
o Ovarian hyperstimulation – involving enlarged ovaries, abdominal pain
and fluid build up within the abdomen
- Patients should therefore be referred to a gynaecologist for follicle tracking
- Therefore can be used in the treatment of infertile women to induce super
ovulation for assisted conception (in vitro fertilisation)
- The gonadotrophins can also be used to treat hypogonadism due to pituitary
failure in men
- Drugs are given IM, or SC injection and the dose is tailored to the patients
needs
GnRH Analogues:
- Diagnostic, anti-cancer, fertility and potentially contraceptive drugs
- Gonadorelin (synthetic GnRH, a decapeptide):
o The hypothalamic normone stimulates the HPG axis in women
(follicular growth and ovulation) and in men (increased sperm count)
only if delivered as a SC pump with 90 min pulses to mimic natural
release
o Main use is in the assesement of pituitary function in adults via SC or
IM injection
- Long-acting GnRH Analogues (Buserelin, Goserelin)
o These peptide analogues are more resistant to degredation by
peptidases than GnRH – so increased duration of action
o Administered parenterally (SC)
o Buserelin is also available as a nasal spray
- Mechanism of action:
o Prolonged activation of GnRh hormones in the anterior pituitary leads
to gonadotrophin down-regulation and hence reduction in LH/FSH
production
o Follicular development, the LH surge and ovulation are reduced
- Clinical Uses:
o Prostate cancers which are particularly hormone sensitive
o Advanced breast cancer in pre-menopausal women
o Other steroid dependant cancers
o Endometriosis
o Infertility
o Precocious puberty
o Potential use as a contaceptive
- These drugs initially produce a stimulation of the HPG axis and the associated
increase in gonadal steroids could induce tumour flare in prostate cancers etc.
Therefore steroid blocker drug must be given a few days before use
- Unwanted actions:
-
o Menopausal symptoms in women – hot flushes, increased sweating,
vaginal dryness, loss of libido
o Orchidectomy-like symptoms in men (sexual dysfunction, changes in
breast size)
o Hypersensitivity reactions
o Headache, visual disturbances
o Gastrointestinal disturbances
o Sleep disorders
o Mood changes
Contraindications: - pregnancy, breast-feeding
2. Polycystic ovarian syndrome - PCOS
 Incidence 1 in 12 women of reproductive age.
 Associated with increased risk of CV disease and insulin resistance.
Diagnosis
To confirm diagnosis if PCOS 2 of the following are needed:
 Polycystic ovaries on USS (Cysts of ovaries on ultrasound)
 Biochemical androgen excess
 Oligoovulation (irregular)
 Anovulation (absent)
Clinical Features
 Ovarian enlargement with multiple small cysts detectable on ultrasound
 Hirsuitism
 Menstrual cycle disturbance – amenorrhoea, oligomenorrhoea, infertility
 Increased BMI
 Increased insulin resistance
 Insulin may promote local thecal cell androgen production
 Increased androgens of ovarian origin
 Androgens suppress FSH release, but LH release remains high
 Thecal cells produce androgens but granulosa cells do not convert them to
oestrogens due to lack of FSH stimulation
Investigations
 Looking for increased LH (LH and FSH ratios).
 Possible high testosterone with low sex hormone binding globulin (SHBG) which
means that the amount of free circulating testosterone is increased.
 Measure prolactin level – will be mildly raised.
 Ultrasound – ovarian cysts will be seen
Treatment
- Laser hair removal
- Oestrogen - Oral contraceptive pill
o Suppress androgen production
o Increase SHBG
- Reduce testosterone
o Cyproterone actetate - an anti-androgen.
- Metformin
o Insulin sensitising drug (treats diabetes). Used to make regular periods.
-
-
-
Reverse circadian prednisolone
o Suppress pituitary ACTH production which drives adrenal androgen
production.
Clomiphene
o Selective Estrogen Receptor Moldulator. Kick-starts ovulation and
periods. Oestrogen antagonist in hypothalamus.
Godadotrophin therapy.
3. Hyperprolactinaemia
Causes
- Dopamine antagonists drugs
o Anti-emetics (metoclopramide)
o Anti-psychotics (phenothiazides)
- Prolactinoma (acromegaly)
- Stalk compression due to pituitary adenoma.
- PCOS
- Hypothyroidism
- Oestrogens (OCP), pregnancy,
lactation,
- Idiopathic
Clinical Features
• Galactorrhoea
• Intertility
• Reduced libido
• Menstrual disturbances
• Reduced GnRH secretion / LH action
• Prolactinoma
– Headache
– Visual field defect
Investigations
- Drug History
- Serum prolactin
- Pregnancy test
- Thyroid function tests
- Anterior pituitary function
- MRI of Pituitary
- Test patients visual fields
Treatment
- Treat cause – stop drugs
- Dopamine agonist
o Promocriptine
o Cabergoline
- Pituitary Surgery occasionally
needed.