Investigation of Erectile Dysfunction and Amenorrhoea Flashcards
What is Menarche?
Age at first period
What is Oligomenorrhoea and Amenorrhoea?
- Amenorrhoea: Complete absence of menstruation or cycle length >6 months
- Oligomenorrhoea: Menstrual cycle length >6 weeks but <6 months
What is Primary and Secondary Amenorrhoea?
- Primary Amenorrhoea: Failure to begin spontaneous menstruation by age 16
- Secondary Amenorrhoea: Absence of menstruation for 3 months in a woman who has previously had cycles
What is Erectile Dysfunction?
Erectile dysfunction: Inability of the male to achieve or sustain an erection adequate for satisfactory intercourse
How is Gonadal function regulated?
Hypothalamic GnRH secreted
Pituitary LH & FSH secreted in response
Males
- LH stimulates testosterone synthesis in Leydig cells
- FSH stimulates spermatogenesis and synthesis of inhibin in Sertolli cells
- Negative feedback of inhibin on FSH and of testosterone on GnRH
Females
- LH & FSH (& follicular AMH) regulate E2 synthesis and oocyte maturation
What is the role of Kisspeptin Neurons?
- Kisspeptin neurons may act as central processors for relaying signals from the periphery to GnRH neurons
- Kisspeptins (Kiss1 gene) are secreted by neurons in discrete hypothalamic nuclei, directly innervating and stimulating GnRH neurons through GPR54 receptors (Kiss1r gene)
- They are required for puberty and normal reproductive function. Kiss1 and Kiss1r mutations cause profound hypogonadotropic hypogonadism
How do Kisspeptin neurons regulate GnRH?
- Kisspeptin neurons express E2 and androgen receptors and are direct targets for the action of gonadal steroids in males and females.
- Kiss1 mRNA is both negatively and positively regulated by sex steroids
What are the roles of Kisspeptin signalling?
- Negative feedback of sex steroids on gonadotropin secretion
- Generation of preovulatory GnRH/LH surge
- Triggering and guiding the tempo of sexual maturation at puberty
- Controlling seasonal reproduction
- Restraining reproductive activity during lactation
How is Kisspeptin signalling regulated?
- Hypothalamic-pituitary-adrenal axis
Metabolic cues
- Kiss1 may be induced by leptin
Environmental cues:
- Time of day via suprachiasmatic nucleus (SCN) of the hypothalamus
- Day length via melatonin from the pineal gland
How does Kisspeptin signalling take place in reproductive life?
Pulsatile GnRH stimulates pubertal LH & FSH release to causes gamete formation, gonadal steroid hormone production and feedback loops regulate GnRH, LH & FSH release
Kisspeptin neurons relay steroid feedback on GnRH
In Females: high oestrogen & progesterone levels
- Stimulate kisspeptin neurons of the AVPV to induce the preovulatory surge of GnRH & LH
- Inhibit Kiss1 expression in the arcuate nucleus (ARC)
In Males: High testosterone levels
- Suppress GnRH, LH & FSH release, partly via kisspeptinneurons of the ARC
What are factors of the examination considered in the clinical assessment of amenorrhoea?
- General health
- Body shape and skeletal abnormalities
- Weight and height
- Hirsutism and acne
- Evidence of virilization
- Maturity of secondary sexual characteristics
- Galactorrhoea
- Normality of vagina, cervix and uterus
What is involved in the biochemical assessment of amenorrhoea?
- LH, FSH & E2 (follicular ideally day 2-3)
- Prolactin
- Progesterone (day 21 or 7 days before expected bleed)
- >30 nmol/L = ovulation
- Testosterone, androstenedione, DHEAS & SHBG
- 17-hydroxyprogesterone (basal + ACTH-stimulated)
- Thyroid function tests
- HCG
- Steroid profiling
What are factors of the history considered in the clinical assessment of amenorrhoea?
- Date of onset
- Age of menarche, if any
- Sudden or gradual onset
- ? Pregnant
- General health
- Weight, absolute and changes in recent past
- Stress (job, lifestyle, exams, relationships)
- Excessive exercise
- Drugs
- Hirsutism, acne, virilization
- Headaches/visual symptoms
- Sense of smell
- PMH of pregnancies
- PMH of gynaecological surgery
What are some pituitary function tests?
- GnRH test – investigation of gonadotrophin deficiency
- Clomifene test
What is the GnRH test?
- 100 µg intravenous GnRH
- Samples at 0, 20, 60 min
- Expect LH & FSH increase; post-pubertal LH rise > FSH rise (reverse if pre-pubertal LH rise < FSH rise)
What is the Clomifene test?
- Selective oestrogen receptor modulator (SERM). Helps distinguish gonadotrophin deficiency from weight-related hypogonadism
- 50 mg clomifene given for 5 days and LH & FSH measured on day 0 and 7
- LH & FSH should increase to above reference range or 2x basal values
- Lack of response suggests LH & FSH deficiency due to pituitary/hypothalamic disease
What are side effects of Clomifene test?
- Depression
- Visual disturbances
What are non-biochemical assessments of amenorrhoea?
Imaging:
- MRI/CT scan
- Ovarian/trans-vaginal ultrasound
Surgical:
- Hysteroscopy
- Laparoscopy
- Biopsy
What are possible diagnoses of Primary Amenorrhoea?
- Ovarian dysgenesis
- Premature ovarian failure
- Steroid biosynthetic defect
- Oophorectomy
- Chemotherapy
What are tests for Primary Amenorrhoea?
- Karyotype
- Ultrasound of ovary/uterus
- Autoantibodies
- Laparoscopy/biopsy of ovary
- HCG stimulation
- Urine steroid profiling
What are biochemical tests for Primary Amenorrhoea?
- LH↑
- FSH↑
- E2↓
- PRL-
- T-
What are possible diagnoses for secondary/tertiary amenorrhoea?
- Kallmann’s syndrome*
- Hypothalamic amenorrhoea*
- Weight-related amenorrhoea*
- Exercise-induced amenorrhoea and anorexia*
- Post-pill amenorrhoea
- General illness*
- Hyperprolactinaemia
What are tests for causes of secondary/tertiary amenorrhoea?
- TSH, free T4 & free T3
- Prolactin
- GnRH test
- Clomifene test
- Consider full pituitary screen
- Pituitary MRI
What are biochemical markers of secondary/tertiary amenorrhoea?
- LH↓
- FSH↓
- E2↓
- PRL-
- T-
What are possible diagnoses for hyperprolactinaemia related amenorrhoea?
- Prolactinoma
- Idiopathic hyperprolactinaemia
- Hypothyroidism
- Polycystic ovarian disease
- Physiological in lactation
- Dopamine antagonist drugs
What are tests for hyperprolactinaemia related amenorrhoea?
- Serum free T4/TSH
- Other tests for PCOS
- Pituitary MRI
- (Macroprolactin)
What are biochemical markers of Hyperprolactinaemia related Amenorrhoea?
- LH ↓
- FSH ↓
- E2 ↓
- PRL ↑ or ↑↑
- T -
What are biochemical markers for PCOS and Cushing’s syndrome?
- LH: ↑/N
- FSH: N
- E2: N
- PRL: N/↑
- T: N/↑
What are tests for PCOS and Cushing’s syndrome?
Polycystic Ovarian Syndrome
- Androstenedione, DHEAS, cortisol
Cushing’s Syndrome (rarely)
- SHBG
- Ovarian ultrasound
What are biochemical markers of androgen excess, gonadal or adrenal tumour, and congenital adrenal hyperplasia?
- LH: N/↓
- FSH: N/↓
- E2: N/↓
- PRL: N
- T: ↑↑
What are tests for adrogen excess, gonanal or adrenal tumur, and congential adrenal hyperplasia?
- Androgen excess - Imaging ovary/adrenal
- Gonadal or adrenal tumour - 17α-OH-progesterone
- Congenital adrenal hyperplasia - Steroid profiling
What are biochemical markers of Uterine/Vaginal abnormality, Imperforate hymen, absent uterus and lack of endometrium?
- LH: N
- FSH: N
- E2: N
- PRL: N
- T: N
What are tests Uterine/vaginal abnormality, Imperforate hymen, Absent uterus, Lack of endometrium?
- Uterine/vaginal abnormality - Examination findings
- Imperforate hymen* - Ultrasound of pelvis
- Absent uterus* - Progesterone challenge
- Lack of endometrium - Hysteroscopy
How is Amenorrhoea treated?
- Treat underlying pathology if possible
- Lifestyle management
- Oestrogen replacement
What is Menopause?
- Cessation of menstruation at the end of a woman’s reproductive life
- Mean age of the menopause in the UK is about 53 years and average female life expectancy is 81 years
- A woman may thus spend nearly 40% of her life in an oestrogen-deficient state
- Premature menopause/ovarian failure defined as <40 years
- Hypergonadotrophic hypogonadism (↑↑↑ FSH & LH, ↓ E2)
What are symptoms of Menopause?
- Headaches and Hot flashes
- Teeth loose and Gums recede
- Breast droop and flatten
- Weight Gain and Abdomen loses muscle tone
- Backaches
- Vaginal dryness/itching
- Bones lose mass and more fragile
How is menopause diagnosised and managed?
Clinical diagnosis in women aged > 45 years:
- Perimenopause if vasomotor symptoms and irregular periods
- Menopause if 12 months no period and no hormonal contraception
Do NOT use FSH testing:
- In women aged > 45 years
- If combined contraception/high-dose progestogen
Do consider FSH if <40 years (? premature)
Do consider FSH if aged 40-45 with symptoms
What is Erectile dysfunction?
- Inability of the male to achieve or sustain an erection adequate for satisfactory intercourse
What are congenital casues of Erectile Dysfunction?
- Anorchia/Leydig cell agenesis
- Cryptorchidism (testicular maldescent)
- Chromosome abnormality (e.g. Klinefelter’s syndrome)
- Enzyme defects: 5α-reductase deficiency
- Androgen receptor deficiency/abnormality
- Sickle cell disease
What are acquired causes of Erectile Dysfunction?
- Testicular torsion
- Orchidectomy
- Local testicular disease
- Chemotherapy/radiation toxicity
- Orchitis (e.g. mumps)
- Chronic kidney disease
- Cirrhosis/alcohol
- Infections – STI
- Autoimmune
What are causes of secondary (pituitary) / tertiary (hypothalamic) erectile dysfunction?
- Reduced gonadotrophins (Hypopituitarism)
- Selective gonadotrophic deficiency (Kallmann’s syndrome)
- Normosmic idiopathic hypogonadotropic hypogonadism
- Severe systemic illness
- Severely underweight
- Hyperprolactinaemia
- Diuretics: Thiazides (e.g. bendroflumethiazide), spironolactone
- Anti-hypertensives: Methyldopa, clonidine, beta-blockers (e.g. propranolol), verapamil
- Fibrates: Clofibrate, gemfibrozil
- Antipsychotics: Phenothiazines (e.g. chlorpromazine), butyrophenones (e.g. haloperidol)
- Antidepressants: Tricyclics (e.g. amitriptyline), monoamine oxidase inhibitors (e.g. phenelzine), selective serotonin reuptake inhibitors (e.g. fluoxetine), lithium
- H2-antagonists: Cimetidine, ranitidine
- Hormones and hormone-modifying drugs: Oestrogens (e.g. estradiol), progesterone, corticosteroids (e.g. prednisolone), cyproteroneacetate, 5-alpha reductase inhibitors (e.g. finasteride)
- Cytotoxics: Cyclophosphamide, methotrexate
- Anti-arrhythmics and anticonvulsants: Disopyramide
How is Erectile dysfunction investigated?
- Fasting glucose / HbA1c (diabetic neuropathy)
- Semen analysis
- WHO/Kruger classification
- Karyotyping
- MRI/CT scan of pituitary
- USS of testes
- Testicular biopsy
- Laboratory
What are biochemical investigations of ED?
- Testosterone/SHBG (9 am)
- LH/FSH/E2
- Prolactin
- 17-OHP
- TFTs
- GGT/MCV/U&E
- (Seminal fluid fructose and zinc)
- Pituitary function tests
- GnRH test
- Clomifene citrate test (oestrogen antagonist)
- HCG stimulation test
What is the HCG stimulation test?
- 2000 IU HCG given on days 0 and 2
- Measure serum testosterone on days 0, 2 and 4.
- Normal response testosterone increases above normal RR
- No rise in testosterone indicates absence of functional testicular tissue
Useful if you think there is disrupted orchidogenesis
How is testosterone transported?
Testosterone and dihydrotestosterone circulate in plasma
- Unbound (‘free’) ~2–3% = biologically active
- Bound to non-specific proteins e.g. albumin = biologically available
- Bound to SHBG = biologically inactive
How can testosterone be measured?
Can be measured - technically difficult!
- Free testosterone assay measures unbound fraction
- Bioavailable testosterone includes free plus weakly bound to albumin
Can also be calculated
How is Erectile dysfucntion managed?
Counselling/Lifestyle
Medical
- DM/Cardiovascular disease - control
- PDE 5 inhibitor e.g. viagra (1st line treatment)
- Intracavernous injection (2nd line treatment)
- Penile implant (3rd line treatment)
- Testosterone: Supraphysiological replacement has a negative effect on spermatogenesis
- HCG: Hypogonadotrophic hypogonadism, intramuscularly twice weekly
- Dopamine agonists: Hyperprolactinaemia, with dopamine agonists
High-dose corticosteroids – used in patients with sperm autoantibodies (side effects!)
Surgery
What is Andropause?
- Age related testicular failure
- Poorly defined
- Decreased bioavailable testosterone due to increasing SHBG
- FSH tends to increase more with age than LH
- Gynaecomastia increases with age
