Gonadal Function Flashcards
What is the function of the gonads?
Steroid (Sex) Hormone production
- Predominantly Oestrogens in women
- Predominantly Androgens in men
Maturation of the germ cells
- Ova in women
- Sperm in men
Describe the features of GnRH
- Pulsatile release
- Stimulates LH & FSH release from pituitary gonadotrophes
- Regulated by circulating gonadal steroids (Testosterone, 17ß-oestradiol)
What is the function of FSH?
Stimulates
- spermatogenesis in male
- ovarian oestrogen secretion in female
What is the function of LH?
Testosterone secretion by the Leydig cells in men
Stimulates ovulation in the female
What is the function of the Hypothalamic-Pituitary-Gonadal-Axis?
It controls hormone release, that then controls the ovaries and testes
How does testosterone circulate?
Circulates as free (2%) and bound to sex hormone
binding globulin (60%), albumin (38%) and other
proteins (<1%)
When are testosterone levels highest?
Morning
What are the functions of testosterone?
- Spermatogenesis
- Secondary sexual characteristics
- Pubic and axillary hair
- Musculoskeletal development
- Libido
How is testosterone metabolised?
Metabolised by 5α-reductase to produce dihydrotestosterone
OR
Metabolised by aromatase to produce oestrodiol
What is the function of Sex Hormone Binding Globulin?
Blood transport protein for testosterone. Testosterone bound SHBG is not biologically active
• Reversible binding
What is the result of excess increase in SHBG?
Hypogonadism
Oestrogen
Hyperthyroidism
Liver cirrhosis
What is the result of excess decrease in SHBG?
Hypothyroidism Obesity Diabetes Glucocorticoid Nephrotic syndrome
What are the features of hypogonadism in men?
Defective spermatogenesis or testosterone production or both
Can be primary or secondary
What are the features of Primary Hypogonadism in men?
Testicular failure due to primary testicular disease
Serum testosterone ↓, FSH and LH ↑
Congenital - Klinefelter’s syndrome, testicular agenesis, 5 α- reductase, Haemochromatosis and other enzyme defects
Acquired - bilateral orchitis, irradiation, cytotoxic drugs,
bilateral varicocele
Treat the cause, Testosterone replacement
What are the features of Secondary Hypogonadism in men?
Testicular failure secondary to hypothalmic-pituitary
disease
Serum testosterone ↓ , FSH and LH normal or ↓
Pituitary disorders – tumours, panhypopituitarism
Hypothalamic disorders - Kallman’s syndrome
Treat the cause, Testosterone replacement, GnRH for fertility
How can Spermatogenesis be detected?
Semen analysis (NICE)
At least 2 samples should be assessed in the same
laboratory
Collection by masturbation at temp (15C to 38C) and
delivered quickly to the laboratory
FSH: FSH correlates with sperm count
- Obstructive azoospermia - Normal FSH
• Inhibin B: Low IB indicates Sertoli cell failure
• AMH: Low AMH indicates Sertoli cell failure
What tests can be performed to determine cause of problems with male fertility?
Semen Analysis Patient History Physical Exam Testosterone levels in morning LH and FSH levels
Medication and chronic illness need to be considered
What is the cause of excess prolactin in men?
Increased levels of prolactin in males can be caused by a pituitary tumour (MRI needed to confirm)
What is Gynaecomastia?
Breast development in men
What is the cause of Gynaecomastia?
Disturbance of the balance of oestrogen to androgens
Can be due to:
- Physiological causes
- Pharmacological causes
- Pathological causes
What are the pharmacological causes of Gynaecomastia?
Oestrogen Digoxins (binds to oestrogen receptors) Cytotoxics (testicular damage) Antiandrogens (spironolactone, cyproterone) Others- methyldopa, phenothiazines, etc.
What are the pathological causes of Gynaecomastia?
Increased oestrogens
- Chronic liver disease, established renal failure, Cushing’s syndrome, hyperthyroidism, tumors.
Decreased androgens
- Klinefelter’s syndrome
Androgen insensitivity
- Testicular feminization, refeeding after starvation
What is the function of oestrodiol?
Development of female sex organs and secondary sex
characteristics
Menstruation
When is oestrodiol normally low?
Very low levels in prepubertal girls
Decreases following the menopause
Where is Inhibin A produced?
Made by the dominant follicle and corpus luteum.
What is the function of Inhibin A?
Endocrine function, Suppresses FSH
When are increases in Inhibin A normally seen?
Rises in late follicular phase and maximal in luteal
phase. Thought that negative control of FSH in luteal phase shifts from E2 to IA.
Increases during pregnancy, from the foetoplacental
unit. Very high levels are seen at end of pregnancy
When is increase in Inhibin A seen in pathology?
Tumour marker for ovarian cancer
When can low Inhibin B be seen?
Ovarian failure
When can high Inhibin B be seen normally?
Raised IB may detect successful IVF treatment
Women with IB (>45pg/ml) are 6.8 times more likely to
conceive irrespective of age and day 3 FSH
When is high Inhibin B a pathological marker?
Raised in Polycystic Ovary Syndrome (marker for hyperstimulation?)
Tumour marker for ovarian cancer
When is progesterone secreted?
Secreted by the corpus luteum during the luteal phase of the menstrual cycle and by the placenta in pregnancy
What is the function of progesterone?
Prepares the endometrium of the uterus to receive a fertilised ovum, maintains early pregnancy.
What is a marker of ovulation?
Day 21 Progesterone >30nmol/L indicative of ovulation in a 28 day menstrual cycle
What are the features of Anti-Mullerian Hormone (AMH)?
- Very low pre-puberty
- Increased ovarian (antral follicles) production at puberty
- Steadily decline over their reproductive years
- Undetectable after menopause
- Unaffected by menstrual cycle
How can detection of AMH be used clinically?
- Useful in detecting ovarian reserve
- Best single marker to predict response to gonadotrophin stimulation
- Predicts likelihood of conception in IVF
- Tumour marker for granulosa cell cancers
- Increased in PCOS
What are the features of ovarian androgens?
- Androstenedione is the main ovarian androgen.
- Androstenedione is converted to oestrone and testosterone in extra-ovarian tissue.
- Small amount of testosterone is secreted directly by the ovaries
- Assay differences in testosterone
What is the Free Androgen Index (FAI)?
Free Androgen Index or FAI is a ratio used to determine abnormal androgen status in humans.
• FAI = (Total Testosterone (nmol/L) x 100) / SHBG (nmol/L)
Only applicable to women because the binding
capacity of SHBG for Testosterone is large because
of their relatively low testosterone and high SHBG
concentrations
How is ovarian reserve tested for?
- Day 3 FSH: > 10 IU/L correlates with poor IVF success
- AMH is the best single marker to predict response to gonadotrophin stimulation
- Antral Follicular Count (AFC) uses ultrasound in early follicular phase: Low AFC correlate with poor IVF success
Others – not recommended
• Clomiphene stimulation test
• Inhibin B: Women with IB (>45pg/ml) are 6.8 times more likely to conceive even when age and day 3 FSH are accounted for
What are the symptoms of ovarian dysfunction?
Presents with any or all of the following
- Amenorrhoea/Oligomenorrhoea
- Hirsutism with or without Virilism
- Infertility
What are the most common causes of Amenorrhoea?
Pregnancy
Menopause
What is Oligomenorrhoea?
Infrequent menstrual cycles
What is Menorrhagia?
Abnormally heavy menstrual bleeding
What is Amenorrhoea?
Lack of periods
- Primary- never menstruated >15years
- Secondary- absence of menstruation for (3-) 6 months in a woman with previous menses
What are the features of Hypogonadotrophic hypogonadism in women?
Characterised by Low FSH, LH & E2
Hypothalamic-pituitary disorders may present with primary or secondary amenorrhoea depending on onset of illness before or after puberty
Organic hypothalamic-pituitary disorders may be associated with other features of pituitary failure
What can cause organic hypothalamic-pituitary disorders?
As part of hypopituitarism
- Hypothalamic and Pituitary tumours
- Other Pituitary disease
- Head trauma
Without hypopituitarism
- Isolated hyperprolactinaemia
- Kallmann syndrome (Only 1o amenorrhoea)
- Isolated gonadotrophin deficiency (only primary amenorrhoea)
What can cause functional hypothalamic-pituitary disorders?
Chronic systemic disease
Malnutrition/ Anorexia Nervosa
Exercise induced
What are the diagnostic features of primary ovarian failure?
High FSH & LH & Low E2 ( Low IA, IB & AMH)
What can cause primary ovarian failure?
Primary Ovarian failure with Primary Amenorrhoea (most common) -
• Genetic Causes e.g. Turners Syndrome
• Disorders of sexual differentiation
Primary Ovarian failure with Secondary Amenorrhoea (Premature menopause)
• Idopathic
• Autoimmune
• Physical insults – e.g. chemotherapy
What are the features of Polycystic Ovarian Syndrome (PCOS)?
Presents with Triad of:
• Hyperandrogenism
• Ovulatory dysfunction
• Polycystic ovaries
Associated with:
• Obesity
• Metabolic syndrome
• Increased risk of uterine cancer
How does Hyperandrogenism present?
Clinically: Hirsuitism, acne, cliteromegaly
Biochemically:
- Increased Androgens (Testosterone, DHAS Androstenedione)
- Low SHBG (Increased FAI)
- (Increase LH:FSH ratio; Hyperprolactinaemia)
How does Ovulatory dysfunction present?
Oligomenorrhea/Amenorrhoea
How are polycystic ovaries diagnosed?
Ultrasound:
1. 12 or more follicles measuring 2-9 mm in diameter
or
2. Increased ovarian volume (> 10 cm3)
What is the menopause?
The menopause is defined as the twelve months
after a woman’s final menstrual period. It marks the
end cyclic ovarian function and ovulation and thus
reproductive capabilities
Describe the continuum of the menopause
Pre-menopause
Menopausal transition (Peri-menopause)
Post-menopause
Describe the biochemical progress of the menopause
Initial event is a decline in Inhibin B in early follicular phase, when cycle irregularity is first observed.
In late menopause transition insufficient E2 produced by reduced number of ovarian follicles to induce endometrial proliferation and subsequent bleeding also a fall in Inhibin A.
Decline in Inhibin A and E2 loss of -ve feedback on gonadotrophins results in elevated FSH and LH
How can menopause transition be detected?
- FSH best marker: LH increase is later and less consistent than FSH.
- LH>FSH (and E2 > 180pmol/L) indicate presence of viable oocytes or midcycle
- E2 declines but secretion remains cyclical.
- Results may be masked by Oral Contraceptive Pill (OCP) – repeat after stopping OCP for 6-8 weeks
However, in women 45-55 yr with
• Irregular cycles, 80% have FSH >15 U/L
• Regular cycles, 45% have raised FSH >15 U/L i.e “Normal FSH” does not exclude perimenopause
• FSH >15 U/L does not preclude possibility of ovulatory cycles i.e potentially fertile
What are the features of the post-menopause period?
- Increased FSH
- Increased LH
- Low E2
- (Low IA & IB)
FSH and LH fall in old age
Major post-menopausal oestrogen is oestrone - produced from peripheral conversion of androstenedione. oestrone has 20% cross reactivity with some E2 assay.
What are the symptoms of menopause?
• Vasomotor symptoms - Hot Flushes
• Insomnia
• Genital atrophy, Vulvovaginal dryness,
• Sexual dysfunction, Dyspareunia
• Depression, Anxiety, Labile mood, Fatigue Poor memory, Headache
• Dry skin, Thinning scalp hair, Hirsutism
Increased Risk of Osteoporosis, Cardiovascular
Disease, Alzheimers
What causes the symptoms of menopause?
Primarily related to oestrogen deficiency
How can the symptoms of menopause be treated?
Hormone Replacement Therapy
• Short term benefit for vasomotor symptoms
Some women are more suitable for HRT than others, however there are complications associated with HRT
What complications are associated with HRT?
Oestrogen and Progestin (Per 10,000 women, per annum) 7 more CHD Events 8 more strokes 8 more invasive breast cancers 18 more VTEs 8 more PEs 6 fewer colorectal cancer 5 fewer hip fractures
Oestrogen Alone (Hysterectomy) (Per 10,000 women, per annum) 5 fewer CHD events 12 more strokes 7 fewer breast cancers 7 more VTE 3 more PEs 1 more colorectal cancer 6 fewer hip fractures
