Reproductive Hormones Flashcards
Basic Physiology and Functions of LH/FSH
GnRH secreted episodically (1-2h) –> LH/FSH
LH/FSH are glycoproteins constructed on 2 polypeptide subunits
- -> alpha common to both (as with TSH, hCG)
- -> beta unique
LH
- male: leydig cells secrete testosterone (negative feedback on LH)
- female: surge causes ovulation, development of corpus luteum, stimulates progesterone secretion, production of androstenedione and testosterone at theca cells
FSH
- male: sertoli cells secrete androgen binding protein and sustain spermatogenesis (inhibin negative feedback)
- female: develops ovarian follicles, stimulates estrogen secretion (aromatisation of androstenedione and testosterone at granulosa cells)
Recall androgen synthesis pathway
Zona reticularis
Pregnenolone –> 17-OH pregenenolone –> DHEA –> Androstenedione –> testosterone or estrone –> estradiol
Testosterone –> DHT by 5 alpha reductase
DHEA –> DHEAS (or vice versa) by sulphokinase
Production of androgens in male
Potent androgens:
- testosterone (from testes) and dihydrotestosterone (conversion from T by 5 alpha reductase at target sites)
Weak androgens:
- DHEAS, androstenedione from adrenal glands
- requires conversion to T and DHT to express androgenic effect in peripheral tissues
Androgen actions (male)
Intracellular receptors (specific response elements in nucleus)
- Masculinisation of male foetus in before 10th wk
- stimulate development of secondary sexual characteristics after puberty e.g. penis, axillary/pubic/body hair, muscles, deepening of voice, bone growth etc.
Testosterone
- foetus: internal genitalia including Wolffian duct
- puberty: initiate spermatogenesis, psyochosexual behaviour, muscle, voice
DHT
- foetus: external genitalia
- puberty: prostate development, male pattern hair growth
Androgens in female (sources)
Testosterone (10% of male levels)
- from ovaries, adrenal glands
- 50% from circulating androstenedione
DHEA
- adrenal glands (95%)
Androstenedione
- 50% ovaries, 50% adrenal glands
==> essential precursor for oestrogen’s
==> bone growth and libido
Menstrual cycle
- Low levels of estrogen/progesterone at the beginning of cycle (shedding) –> less inhibition on FSH –> increase FSH
- FSH stimulates follicles to grow which secrete increasing estrogen
- Endometrium thickens and builds up due to estrogen
- During late follicular phase, high and rising estrogen stimulates LH surge with positive feedback
- Ovulation
- Under the influence of LH, progesterone is secreted by corpus luteum and peaks at day 21
- Progesterone converts endometrium to secretory form to prepare for pregnancy
- Increase progesterone = negative feedback on LH
- Suppressed LH = can’t maintain corpus luteum
- Regression of corpus luteum = progesterone decreases
- Decrease in steroids = disintegration of endometrium –> menses
(if ovum is fertilised, hCG from trophoblast takes over corpus luteum stimulation with continuous steroid production to maintain pregnancy during 1st 3 months)
Estrogen types, functions
Oestrone (E1) = from peripheral aromatisation of androstenedione
Oestradiol (E2) = most potent – from ovaries and testes, aromatisation of testosterone
Oestriol (E3) = during pregnancy
Functions
- secondary sex characteristics in females
- regulation of menstrual cycle
Mature follicle –> 1000-1500 pmol/L oestradiol
Peak just prior to ovulation followed by second minor peak during ensuing luteal phase
Sex hormone binding globulin
Major carrier protein for T and E2, produced mainly by liver with high affinity (T>E2)
Plasma levels increased by oestrogen and thyroxine, decreased by androgens
T:SHBG ratio (%) i.e. free androgen index indirectly reflects free T levels (though it tends to overestimate and doesn’t consider albumin-bound fraction)
<3% hormones circulation in free form, 40% weakly bound to albumin (also considered active)
==> free and albumin bound testosterone = bioavailable testosterone
Hypogonadism types
Primary = gonadal defect
- high FSH and LH
- hypergonadotrophic
Secondary = pituitary, hypothalamus
- low FSH and LH
- hypogonadotrophic - low GnRH
Presentation of hypogonadism in female
Prepubertal
- delayed puberty (after 13 yrs)
Reproductive
- amenorrhea (primary = haven’t began menses by 15 or secondary = miss 3 cycles in a row)
- infertility
- decreased libido
- osteoporosis
- hot flushes
Perimenopausal, menopause (senescent ovaries stop producing oestrogen)
Presentation of hypogonadism in male
Prepubertal
- delayed puberty (after 14 yrs)
Reproductive
- infertility
- decrease libido
- erectile dysfunctions
- osteoporosis
- decreased bear and body hair, breast enlargement, and muscle loss
- 1-2% decline in plasma testosterone per year after 30
Late onset hypogonadism (andropause)
Eunuchoidal proportions
Bone age delayed due to insufficient sex steroids –> delayed epiphyseal closure
==> long bones grow longer than they should leading to disproportionate arms and legs (arm span longer>height)
If an adults has hypogonadism with arm span = height –> defect after puberty
Hypergonadotrophic hypogonadism causes and examples
Male e.g. klinefelter syndrome (47,XXY), late onset male hypogonadism, anorchia or cryptochidism, androgen resistance
Female e.g. Turner syndrome (45,X), menopause
- gonadal dysgenesis/agenesis
- Gonadal diseases e.g. autoimmune, infection, irradiation, chemotherapy
- Steroidogenic enzyme deficiencies e.g. 17 alpha hydroxylase, 17,20 lyase, 20,22 desmolase, 17 beta HSD, 3 beta HSD
- haemochromatosis
Klinefelter Syndrome manifestations
47, XXY
1/1000 males - MC cause of hypoGn and infertility in men
–> small testes
–> poorly developed secondary sexual characteristics
–> tall with eunuchoidal proportions
–> learning disabilities
+/- gynaecomastia (risk of CA breast as for normal females)
+/- 50% have metabolic syndrome
Turner Syndrome
45,X
1/3000 females - MC cause of primary amenorrhea in girls
- -> short stature
- -> cubitus valgus
- -> webbed neck
- -> gonadal dysgenesis (no puberty, infertile)
- -> congenital heart (coarctation)
- -> kidney abnormalities
- -> hypothyroidism and DM
- -> normal intelligence
Hypogonadotrophic hypogonadism
Congenital
- prader-willi syndrome
- kallmann syndrome (isolated GnRH deficiency; affected sense of smell)
- Barnet-biedl syndrome
Acquired
- anorexia nervosa, malnutrition
- chronic illness
- Cushing’s syndrome
- hyperPRL (suppresses LH and FSH), hypothyroid, hypopituitarism
- tumours e.g. craniopharyngioma, acromegaly
Investigations
Serum
- LH, FSH, PRL
- Estradiol
- Testosterone
- 17-OH progesterone
- TFT
Urine
- steroid profile
Dynamic function tests
- GnRH stimulation test
Progestational withdrawal challenge in amenorrhea
- give progesterone and withdraw –> if menses occurs = estrogenisation of endometrium and uterovaginal anatomy is normal –> defect of progesterone production
Other tests:
- CBC
- sperm count (<5 million/mL = abnormal)
- genetic analysis
- USG gonads
- MRI/CT pituitary
Hirsutism and Virilism definitions, causes, investigations
Hirsutism = excessive terminal hair growth
- fairly common and mostly benign
Virilism = hirsutism + signs of androgen excess e.g. ambiguous genitalia, increased muscle mass, balding, deepening of voice, increased libido and clitromegaly, amenorrhea, breast atrophy
PCOS most common cause
Rare but important causes to be excluded e.g. CAH, androgen secreting tumours of adrenals or ovaries, Cushing’s syndrome, hyperPRL, hypothyroid, acromegaly, drugs
Important tests:
- androgens (T, DHEAS, Androstenedione and 17-OH progesterone, before and after ACTH stimulation – expect 17-OH to increase in CAH)
Polycystic Ovarian Syndrome diagnosis, associations, lab results
Very common, 5-10% women of child-bearing age
Rotterdam criteria (2/3)
- oligomenorrhoea or amenorrhea
- clinical and/or biochemical signs of hyperandrogenism
- polycystic ovaries on USG
Other conditions that mimic PCOS must be excluded e.g. late onset CAH –> measure 17-OH progesterone response to synacthen (+ve if >2x URL)
A/w insulin resistance, obesity, type 2 DM, endometrial hyperplasia/cancer
Lab
- take sample on day 1-5 of menstrual cycle – LH, FSH, T/FAI, PRL, TFT, random BG if have FHx of DM or BMI>30
- LH:FSH usually high >2 (but not diagnostic)
- increase free testosterone and FAI due to low SHBG
- if T >4 nmol/L –> measure androstenedione, DHEAS and 17-OH progesterone (late onset CAH)
Hormone replacement therapy
Treat hypogonadism but not infertility
Female - estrogen and progestogen (patch, pills)
- progestogen prevents endometrial hyperplasia/cancer
- small but significant increase in risk of CA breast, endometrial cancer and heart diseases
- measuring E and Gn not useful for monitoring
Male - testosterone (patch, gel, IM)
- efficacy assessed by T measurement
- LH should be normalised in primary hypoGn
- adverse effects e.g. CA prostate, BPH, erythrocytosis, venous thromboembolism, CVS risk
Amenorrhea and Infertility overall causes and approach
Causes
Hypothalamus: anorexia, Kallmann’s syndrome, tumours, severe weight loss
Pituitary: hyperPRL, hypopituitarism, functional tumours e.g. Cushing’s, isolated FSH/LH deficiency
Ovaries: PCOS, ovarian failure/tumour/dysgenesis (turner’s)
Receptors: androgen insensitivity syndrome
Others: DM, hypothyroidism, late-onset CAH (21-OH)
Approach to Dx
- take sample on day 1-5 of menstrual cycle – LH, FSH, T/FAI, PRL, TFT, random BG if have FHx of DM or BMI>30
Excluding pregnancy, thyroid diseases:
==> FSH >30 –> menopause, premature ovarian failure
==> raised FAI/T –> PCOS (rarely late onset CAH or adrenal/ovarian tumour)
==> raised PRL –> Ix hyperPRL
==> LH/FSH/E2 low –> exclude OCP, consider hypothalamic amenorrhea
Precocious puberty - definition, causes
girls <8, boys <9
Gonadotrophin dependent (central)
- idiopathic
- CNS tumours producing LH/FSH
Gonadotrophin independent (peripheral/pseudo)
- non-classical or late onset CAH
- adrenal gland/ovary/testis tumours
- McCune-Albright syndrome (autonomous receptor activation)
