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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.