Sex hormones Flashcards
What links testosterone and oestrogen?
androstenedione (testosterone precursor) is also a precursor to estrone via aromatase. both estrone and testosterone can be converted to estradiol.
testosterone -> estradiol also via aromatase
What is DHT?
dihydrotestosterone - a stronger angroden
Role of oestrogen in males?
still important - circulate at about 20% of the concentration in non pregnant females
thought to be important after puberty in sustaining spermatogenesis
Main features of the male reproductive tract?
- bladder, prostate (surrounds urethra)
- vas deferens
- epididymis
- testes
Functions of the testes?
sperm production, steroid hormone production
Function of the epididymis?
sperm collection and maturation
Function of the ductus deferens?
transport and storage
Structure of the testes?
Semineferous tubules - sperm production
Epididymis - sperm maturation
What are sertoli cells?
cells in the semineferous tubules, allow progression of germ cells to sperm cells
Which cells produce testosterone?
Leydig cells
In which cells does the testosterone to DHT conversion take place?
Sertoli cells
What is the nuclear receptor superfamily?
- receptors for all major classes of steroid hormone
- proteins that have two binding sites: one for the steroid and one for DNA
- binding of the steroid produces a complex that acts on DNA
- binding of the complex alters the repetoire of genes being expressed
- this activity defines steroid receptors as transcription factors
What is the androgen receptor?
- androgens are defined as compounds that act on the androgen receptor
- all major cell populations in the testes, epididymis and accessory glands express these receptors
- the cell types require androgen binding to fulfil their roles
- also found in tissues where secondary sexual characteristics appear
What is the HPG axis?
- hypothalamus releases GnRH
- A. pituitary releases gonadotrophins (LH and FSH)
- gonadotrophins control sex steroid production
- sex steroids control production of sperm/maturation
Action of FSH on the testes?
Binds to sertoli cells to convert testosterone to DHT
this then stimulates the rest of the process (spermatogenesis etc)
Feedback control of sex hormones in males?
Testosterone inhibits secretion of gonadotrophins and GnRH, inhibin also inhibits secretion of gonadotrophins
Why do men not have a monthly cycle of sex hormones?
No positive feedback regulation
Action of LH on the testes?
binds to Leydig cells to synthesise testosterone, which is then transported to sertoli cells
What is the function of the Myoid cells?
muscular - contract to move sperm along semineferous tubule. action is androgen dependent
Can the sperm swim when they leave the tubules?
No, this is acquired in the epididymis (DHT dependent)
Average volume of ejaculate?
1.5-5mL
Average sperm count?
40-250 million/mL
Composition of ejaculate?
Epididymis and ductus deferens secretion (sperm rich): 5%
Prostatic secretion: 13-33%
Seminal vesicle secretion: 46-80%
Bulbo-urethral gland secretion: 5%
Definition of erection?
Erectile tissue becomes engorged with blood, arterioles dilated as a result of parasympathetic nervous system activity
What is emission/ejaculation controlled by?
Sympathetic nervous system
Pathologic bases for erectile dysfunction?
psychogenic; neurogenic; vascular and endocrine
Latrogenic causes of impotence?
many drugs including tricyclics and SSRIs ; antihypertensives including beta blockers and calcium antagonists
Prevalence of prostate cancer?
- second leading caues of cancer death after lung
- overall lifetime risk 1 in 6
- risk factors: age, ethinicity, family history
Symptoms of prostate cancer?
- frequent/urgent urination
- nocturnal enuresis (involuntary urination)
- difficulty starting or emptying bladder
- urine flow weak, interrupted or difficult to control
- back or pelvic pain
Pharmacological management options for prostate cancer?
GnRH agonists and antagonists
Androgen antagonist - cyrproterone acetate
5-a-reductase inhibitors, dutasteride and finasteride
Clinical uses of anabolic steroids?
treatment of some aplastic anaemias
- protein building properties have not proved beneficial in a clinical setting
How would male contraception work?
Exogeneous testosterone: inhibit FSH and LH
would need high doses as difficult to decrease sperm count
What is Testosterone undecanoate ?
longer acting testosterone depot, better PK
Alternative possibility for male contraception?
Reversible Inhibition of Sperm Under Guidance
‘Vasalgel’ - gel injected into vas deferens, sperm cannot penetrate and are reabsorbed
Approx how many menstrual cycles do women have?
468
Name of the stage of menstrual cycle days 1-5?
menses
Name of the stage of menstrual cycle days 5-14?
ovary: follicular
endometrium: proliferative
Name of the stage of menstrual cycle days 14-28?
ovary: luteal
endometrium: secretory
What is the HPO axis?
- hypothalamus releases GnRH
- A pituitary releases gonadotrophins (FSH and LH)
- gonadotrophins control both sex steroid production and follicle maturation/ovulation in the ovary
Structure of GnRH?
10 amino acids
acts at GnRH receptor (a GPCR)
What is the significance of how GnRH is released?
pulsatile. FSH is stimulated by slow pulse frequencies, LH stimulated by faster ones
What are GnRH agonists and antagonists used for in females?
‘shut down’ the ovary before a controlled cycle of stimulation
Example of a GnRH agonist?
Buserelin. stimulates FSH and LH production long term effects: - GnRH receptor down-regulation - resulting GnRH insensitivity - loss of FSH and LH production
How does rising fat levels in girls trigger puberty?
rising fat levels triggers leptin release
leptin stimulates kisspeptin neurone, which acts on the GnRH neurone
Risks associated with early puberty?
higher chance of type 2 diabetes and CVD
Risks associated with late puberty?
Higher risk of osteoporosis, but lower risk for breast cancer
What happens in the ovarian cycle?
follicular development, then LH causes ovulation
corpus luteum forms then degrades
Hormone patterns throughout menstrual cycle?
- low oestrogen and progesterone levels stimulates release of FSH
- FSH triggers release of oestrogen
- Oestrogen triggers sharp release of LH (positive feedback for ovulation) (+ negative feedback on FSH)
- corpus luteum then secretes oestrogen and progesterone, which inhibits FSH and LH
- if no fertilisation, corpus luteum degrades, O+P fall and begins again
What inhibits GnRH?
Progesterone and oestrogen, or prolonged high oestrogen alone
What else does oestrogen do?
Stimulate growth of endometrium (DNA synthesis)
HOw do anti-oestrogens work?
bind to the oestrogen receptor, induces a conformational change in the receptor so cant bind to DNA
Mechanism of tamoxifen?
Partial agonist and partial antoagonist
Some of the positive effects of oestrogen?
- preserve bone density
- regulation of cholesterol production
- maturation of ovary and uterus
- menstrual regulation
- vaginal maintenance
Some of the negative effects of oestrogen?
- exposure can increase risk of breast cancer
- exposure may increase risk of uterine cancer
Definition of menopause?
permanent cessation of ovarian activity usually said to have occurred after 12 consecutive months of amenorrhoea
Definition of perimenopause?
period before menopause and 1st year after it
Climacteric?
transition from reproductive life to non-reproductive state
How does menopause affect life expectancy?
reduced 2% with each increasing year beefore reaching menopause
ischaemic heart disease 2% lower
risk of death from uterine or ovarian cancer increased by 5%
Effects of oestrogen withdrawal on other organs?
- vasomotor symptoms (flushing)
- dyspareunia (ainful sex)
- more UTIs
- improved depression scores
- slower wound healing
- more inflammation
- decreased bone density
Dose required to stimulate vagina and lower urethra?
10mcg/day
What is menstruation?
shedding of the superficial layer of the uterus
How does withdrawal of sex steroid support induce menstruation?
vasoconstriction, hypoxia, connective tissue breakdown, fragmentation
coagulation factors control blood loss locally
Where does fertilisation normally occur?
Upper fallopian tube
What is the pre-implantation stage?
- 30 hours of cleavage to the 8 cell stage
- Morula at 72 hours
- Blastocyst at4 days
- Implanted blastocyst at 6 days
What stage must fertilised cells reach in order to implant?
blastocyst
Where in the endometrium does the blastocyst implant?
interstitial - underneath the endometrium surface
What is the implantation window for a fertilised egg?
7-10 days post ovulation - corpus luteum cant sustain any longer
What is hCG?
Human chorionic gonadotrophin
- polypeptide, produced by the placenta
- use dfor pregnancy testing as appears in blood and urine soon after inplantation
- rescues the corpus luteum
- lack of hCG appearance probably accounts for the closure of the implantation window
How do hCG, progesterone and oestrogen levels change throughout pregnancy?
- hCG spikes at about 10 weeks, then declines again to basal level, then increases slightly again at 36 weeks
- oestrogen and progesterone increase steadily, p. tapers off slightly towards the end
Functions of progesterone during pregnancy?
- regulates the rate of transport of the egg/embryo through the Fallopian tube
- prepares the uterus to receive the implanting blastocyst
- sustains the uterine lining (endometrium) throughout pregnancy
- inhibits myometrial contractility
what is the luteoplacental endocrine switch?
placenta takes over secretion of progesterone and oestrogen from CL at 7-9 weeks
How are androgens/testosterone produced during pregnancy?
progesterone -> androgens in the fetus, then androgens to oestrogen in the mother
When is a pregnancy described as viable?
when heartbeat can be seen within gestational sac
- 5 weeks LMP vaginally
- 6 weeks abdo
Possible locations for ectopic pregnancy?
- fimbrium/infundibulum
- interstitial
- ovarian
- broad ligament
- ampulla
- isthmic
- abdominal
- cervical
Signs/management of ectopic pregnancy?
- abdominal pain
- hCG detected
- scan - no intrauterine body
- tube rupture can be fatal
- medical management or surgery?
- methotrexate
When can pregnancy termination be carried out?
up to 24 weeks, most are done before 13
What is mifepristone?
- antagonist at progesterone receptor
- counteracts effects of progesterone on pregnancy: blocks preparation of the endometrium for pregnancy
and counteracts the suppressive effect of P on myometrial contractility
can also be usedas contraception but not widely used
How is medical termination carried out?
mifepristone, followed by prostaglandin to initiate contractions
What is human placental lactogen
modulates intermediary metabolism by changing the level of insulin-like growth factor (IGF) - increases glucose and amino acid availability to the fetus
Key stages of human pregnancy?
- gestation 38 weeks
- 3 trimesters
- embryonic up to 10 weeks, formation of major organs
- fetal after 10 weeks, maturation, develpoment and growth
Hormonal control of labour?
- progesterone prevents contractility
- initiation of labour may be through inflammatory mediators
- stimulation with oxytocin, prostaglandins and thromboxane
Why is glucocorticoid treatment used in some pregnancies?
Mature the fetal lungs for early delivery
Which drugs are most likely to cross the placenta?
lipophilic (unionised), weakly basic
larger e.g. heparin negligible
What is Fetal Valproate syndrome?
birth defects, lifelong alterations to behaviour and development
Definition of preterm labour?
<37 weeks approx 5-10% of births are preterm - parental distress - expensive neonatal intensive care - some deaths - long term morbidity
Treatments that can help prolong pregnancy in early labour?
Ritodrine (beta agonist), Atosiban (oxytocin antagonist), Nifedipine (calcium channel blocker)
cautions for drug use in pregnancy?
- try to avoid all drugs in 1st
- taper to lower effective dose for essential therapy before conception
- if appropriate, switch to a safer one
