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Endocrinology of reproduction
17) Gonadal steroidogenesis and actions, 20) Endocrinology of growth and puberty, 22) Foetal origins of male reproductive disorders, Male + female reproductive workshops
Terms in this set (164)
What is androstenedione?
C-19 Adrenal androgen (prohormone)
Where is androstenedione made?
Zona reticularis of the adrenal gland
What 2 types of enzymes are involved in human sex steroid synthesis?
- Cytochrome p450s
- Steroid dehydrogenases
Give 3 examples of cytochrome P450s involved in human sex steroid hormone synthesis?
- 17, 20 lyase
Give 3 examples of steroid dehydrogenases involved human sex steroid hormone synthesis?
What do cytochrome P450 enzymes do?
Cleave cholesterol side chains
e.g. testosterone to oestradiol (aromatase)
What do steroid dehydrogenases do?
e.g. pregnenolone to progesterone (3BHSD)
What are leydig cells?
- Cells found in ovaries and testis
- Stimulated by LH to convert androstenedione to testosterone via the action of 17BHSD
How is dihydrotestosterone made?
Where is dihydrotestosterone made?
Sertoli cells of the testis
What enzyme converts testosterone to oestadiol?
Aromatase (cytochrome P450)
Where is gonadotropin releasing hormone produced?
Preoptic nucleus of the hypothalamus
Where does gonadotrophin releasing hormone act?
On the gonadotrophs in the anterior pituitary
What do gonadotrophs secrete?
FSH and LH
What hormones negatively feedback on the hypothalamus and pituitary in men?
What hormones negatively feedback on the hypothalamus and pituitary in women?
Where does LH act in the testis?
On the leydig cells to produce testosterone
Where does FSH act in the testis?
On the sertoli cells to make dihydrotestosterone and androgen binding protein
What happens to testosterone once it has been made by leydig cells in the testis?
- Moves to sertoli cells
- Converted to dihydrotestosterone
- Binds to ABP in luminal fluid of seminiferous tubules
What happens when there is a fall in androgen-binding protein?
- Increase in free testosterone
- Can lead to infertility
What effects do androgens have on primary male reproductive function?
- Prostate secretions
What effects do androgens have on secondary male reproductive function?
- Anabolic (muscle)
- Deep voice, facial and body hair
- Brain, libido and aggression
What effects do androgens have during foetal life?
- Male sex determination
- Genital development
What is androgen insensitivity syndrome?
Mutated testosterone receptor
- 46 XY but with variable phenotype (partial or complete)
How does partial androgen insensitivity present in males?
Male external genitalia and body shape, with mild spermatogenic deficit after puberty
How does an aromatase deficiency present in males?
- Tall + long arms (epiphyses not closed)
- Loss of bone mass
Where does LH act in females?
Thecal cells of primary follicle
What happens to testosterone after it has been produced by thecal cells of the primary follicle?
Moves to granulosa cells where it is converted to oestradiol under the action of FSH (aromatase)
What primary female sex characteristics is oestradiol responsible for?
Female genital development and differentiation
What secondary female sex characteristics is oestrogen responsible for?
- Body fat distribution
- CV system
- Epiphyseal closure
What does progesterone do?
- Promote endometrial secretion + vascularisation in luteal phase (corpus luteum)
- Prepares uterus for implantation of fertilised egg
What is atresia?
degeneration of primordial follicles (apoptosis)
What is a follicle?
Oocyte surrounded by granulosa and theca cells
What is the zona pellucida?
Barrier around oocyte
How do the granulosa cells change between primordial and primary follicles?
Primordial = squamous, single layer
Primary = cuboidal, multiple layers
How does the primary follicle change when it becomes a secondary follicle?
- More granulosa cells
- Develops thecal layer
How does the secondary follicle change when it becomes an early-antral follicle?
- Theca separates into theca interna + externa
- Fluid filled accumulation in granulosa layer
What can be found in the theca interna?
Glands and blood vessels
What else can you call an antral follicle?
How does the early-antral follicle change when it becomes an antral follicle?
- Fluid-filled gaps join together to form large antrum
- Pressure of fluid pushes granulosa cells
- Oocyte suspended in cavity by cumulus cell stalk
How can follicles be seen in vivo?
Transabdominal or transvaginal ultrasound
Give 2 examples of smooth muscle contractions controlled by oxytocin
- Milk ejection
- Contraction of uterus during childbirth
What is kisspeptin?
Integrates info from adrenal glands, gonads, body fat and environment to feedback to GnRH to be released or not
How do GnRH, FSH and LH act?
Via second messenger system
What effect does FSH have on the developing follicle?
Antral granulosa cell differentiation, proliferation and function
What effect does LH have on the developing follicle?
- Theca cell androgen production
Where is anti-mullerian hormone produced in women?
What effect does anti-mullerian hormone have on follicle development?
What must happen for follicle slection to take place?
FSH and oestrogen must interact with follicle to allow it to express LH receptors on thecal layer so follicle can respond to LH surge
What are the 2 phases of the menstrual cycle?
follicular phase and luteal phase
What triggers menstruation?
drop in estrogen and progesterone
How does the endometrium begin to thicken during the menstrual cycle?
- FSH released from pituitary following drop in oestrogen and progesterone
- Acts on follicle
- Follicle produces oestradiol which acts on endometrium
What causes the LH surge?
Oestrogen reaches threshold for positive feedback
What does the follicle become after ovulation?
What does the corpus luteum secrete?
Oestrogen and progesterone
Why is the corpus luteum yellow?
What happens to corpus luteum if there is no pregnancy?
- Regresses and forms corpus albicans
- Hormone levels drop
- Release of -ve feedback
- FSH rises and cycle repeats
What happens in the menestrual cycle when there is implantation?
- Developing embryo produces hCG
- Binds to LHr and prompts progesterone to be made
- Endometrium environment maintained
- Luteal-placental shift
When does the luteal-plancetal shift occur?
What is the luteal-placental shift?
- hCG from embryo and progesterone from CL decline
- Placenta produces progesterone and oestrogen
When can the mother produce milk?
Once the placenta has been removed (provides prolactin blockade)
What maintains prolactin levels?
What hormone is involved in milk expulsion?
What are the 3 key stages of growth?
- Infancy (0-2)
- Childhood (2-prepuberty)
- Growth (puberty-final height)
What has the biggest impact on growth during infancy?
What is faltering growth?
Baby/toddler that is not growing at the rate you would expect (failure to thrive)
What type of feeding problems could cause faltering growth?
- Too little intake
- Failure to absorb
- Chronic disease
What are 2 key indicators of abnormal growth during childhood?
- Stature out of prenatal target height
- Slow/rapid growth
What is looked for in the hands and feet of a child with growth problems?
- Short metacarpals
- Palmar creases
What is puberty?
the period during which adolescents reach sexual maturity and become capable of reproduction.
What does puberty involve?
- Growth and maturation of gonads and genitals
- Appearance of secondary sexual characteristics
What triggers puberty?
Pulsatile secretion of GnRH from hypothalamus
What is looked for when examining puberty in girls?
- Breast staging
- Pubic hair
- Axillary hair
- Body habitus
What is looked for when examining puberty in boys?
- Testicular volumes
- Genital stage
- Pubic hair
- Axillary hair
- Facial hair
- Body habitus
What is a Prader orchidometer?
Beads used to assess testis size
What is the testis size and onset of puberty?
Between what ages can boys begin to go through puberty?
9-14 then takes 5 years
What is the average adult testis size?
What is the range for onest of puberty in girls?
8-13 then takes 2.5years
What is adrenarche?
- Onset of production of adrenal androgens
- 2 years before puberty
- Maturation of ZR
What changes can be seen during adrenarche?
- Pubic hair
- Axillary hair
- greasy skin
- Body hair
When does menstruation occur?
At the end of sexual maturation (11-15)
What are red flags for growth problems?
- Slow growth and thin (chronic disease)
- Slow growth + fat (endocrine)
- Rapid growth in childhood (precocious puberty)
What problems can arise with puberty?
Too early (precocious)
Too late (delayed)
In wrong order
What are 2. types of precocious puberty?
- Central precocious puberty
What is central precocious puberty?
- Gonadotrophin dependent
- Breast/testis development too early
What is pseudopuberty?
- Gonadotrophin independent
- Pubertal events in wrong order
What is erectile dysfunction a very good marker of?
What is cryptorchidism?
What is hypospadias?
opening of the urethra on inferior surface of penis
Due to failure of the urethral folds to close
What is testicular dysgenesis syndrome hypothesis?
Idea that common male reproductive disorders have common prenatal origin involving a reduction in testosterone exposure
What is the primary determinant of testis size and sperm count?
Sertoli cell number
What determines anogenital distance in men?
Foetal androgen exposure during masculinisation programming window (8-12wks)
What is a good indicator of testicular dysgenesis?
Low anogenital distance (below 50th centile)
What factors acting via the mother can cause testicular dysgenesis?
- Maternal diet and lifestyle
- Medicine (paracetamol) during pregnancy
- (Environmental contaminants)
What drug is associated with decreased testosterone during the masculinisation programming window?
Paracetamol (+epigenetic effect)
Give examples of male reproductive disorders that can arise as a result of testicular dysgenesis syndrome
- Testicular cancer
How can gonads and internal reproductive structures be visualised?
What are the potential reproductive consequences of childhood cancer treatment?
- Delayed puberty
What is hypogonadotropic hypogonadism?
decrease in LH and FSH and testosterone
In what conditions might you see hypogonadotropic hypogonadism?
- Delayed puberty
- Congenital hypogonadotropic hypogonadism
- Brain tumours
What is hypergonadotropic hypogonadism?
- increase in FSH and LH
- decrease in testosterone
In what conditions might you see hypergonadotropic hypogonadism?
- Klinefelter syndrome
- Gonadal dysgenesis
What is a feature of hypogonadotrophic hypogonadism?
How is hypogonadotrophic hypogonadism treated?
- Testosterone to induce puberty
- Gonadortrophins to induce fertility
What are some markers of testicular tumours?
How is testicular cancer treated?
Orchidectomy +/- chemo/radio
How is fertility guaranteed when treating testicular cancer?
How is male infertility investigated?
- Hormone levels
- Sperm analysis
- Testicular biopsy
What 3 places can obstructive azoospermia take place?
- Vas deferens
- Ejaculatory duct
What can cause obstruction of the epididymis?
- Infections (such as epididymitis)
• Scrotal trauma/injury
• Rare genetic conditions e.g. Cystic fibrosis
What can cause obstruction of the vas deferens?
• Previous surgery for other reasons, including hernia repair
• Rare genetic conditions e.g. Cystic fibrosis
What can cause obstruction of the ejaculatory duct?
• Prior surgery
How is fertility preserved in obstructive azoospermia?
Testicular sperm extraction followed by ICSI
What happens to the endometrium during the menstrual cycle?
- Grows each month in preparation for implantation
- In absence of pregnancy, it breaks down and sheds
How is a woman's menstrual cycle expressed?
number of days bleeding / the number of days form the onset of one menses to the onset of the next (e.g. 5/28)
What is the range and average blood loss per period?
10-80ml (av 35)
Why is menstrual blood darker than normal blood?
Fibrinolysins are clot-dissolving agents present in uterus
Which layers of endometrium are shed?
Middle and superficial
The proliferation of which cells causes the endometrium to grow?
Glandular and stromal cells
How does progesterone stabilise the endometrium for implantation?
- Stops cell division
- Glands develop secretory vacuoles
- Increased oedema of stroma
How does follicle selection occur?
- Follicles grow + secrete estradiol and inhibin b
- Feedback on FSH mainly
- Reduced FSH cannot support all follicles so only most mature survive
What does the LH surge do to the follicle?
Switches on progesterone-producing enzymes
Why are periods inhibited during full lactation?
Prolactin from lactotrophs directly inhibits the output of gonadotrophs
What is primary amenorrhea?
Absence of menstruation by age 16
4 main groups of causes of primary amenorrhea?
- Secondary amenorrhea causes
- Permanent neurological abnormalities
- Genetic abnormalities of ovarian development (Turner)
- Developmental abnormalities
What is Kallman's syndrome?
No GnRH, anosmia (can't smell), more common in men
In patients with permanent neurological abnormalities causing primary amenorrhea, how is puberty triggered?
- Low does oestradiol, increasing gradually
- Eventual addition of progesterone
- LH + FSH required for pregnancy
What genetic abnormalities of ovarian development require puberty to be induced?
- Turner's (45XO)
- Female fragile X
How does Turner's syndrome present hormonally?
- Low estrogen and progesterone
- High FSH and LH
What are the 2 duct systems present in the fetus?
Wolffian and mullerian ducts
What 2 hormones does the testis produce once it has developed?
- AMH (causes mullerian ducts to regress)
- Testosterone (causes male genitalia to decelop)
What is Rotikansky syndrome?
- Failure of uterus to grow
- Normal ovaries, short vagina
What is an imperforate hymen?
- Bottom third of vagina incompletely joins to the top two-thirds
- Menstrual blood trapped in vagina
How does an imperforate hymen present?
- Primary amenorrhea
- Increasing pain and lower abdominal swelling
When investigating secondary amenorrhea, which hormone function tests should be performed?
If periods are irregular, when is the best time to measure hormone levels?
Within 5 days of period starting as this gives baseline hormones
5 main causes of secondary amenorrhea?
- Hypogonadotrophic hypogonadism
- Premature ovarian failure
- Uterine causes (Aschermann's)
- Hormone imbalance (PCOS)
What are the most common causes of hypogonadotrophic hypogonadism?
- Excessive exercise
- Low body fat seen in anorexia
why does low body fat lead to amenorrhea?
Puberty tends to occur when there is 20% fat (leptin)
Why is there a risk of osteoporosis in hypogonadotrophic hypogonadism?
Why does hyperprolactinaemia lead to amenorrhea?
Prolactin inhibits local gonadotrophin secretion
What are the hormone levels in hypogonadotrophic hypogonadism?
- Low GnRH
- Low LH
- Low/normal FSH
- Low oestradiol and testosterone
- Normal prolactin
What can cause hyperprolactinaemia?
- Adenoma/microademoma of pituitary
Why should visual fields be checked if someone has a pituitary tumour?
Optic nerves can be compressed leading to tunnel vision
How is hyperprolactinemia treated?
Dopamine agonists (bromocriptine, cabergoline)
What is premature ovarian failure?
Premature atresia of ovarian follicles in women of reproductive age
What are the hormone levels in premature ovarian failure?
- Oestradiol low
- Lh and FSH high
What symptoms is premature ovarian failure associated with?
- Night sweats
- Hot flushes
- Vaginal dryness
- Reduced concentration
What can cause premature ovarian failure?
- Iron storage problems
- Iatrogenic (cancer treatment, pelvic surgery)
How is premature ovarian failure treated?
HRT or low dose contraceptive pill up to the age of 50
What is the major uterine cause of secondary amenorrhea?
What is Aschermann's syndrome?
Endometrium is scarred after a surgical evacuation of the uterus for a miscarriage or termination of pregnancy
What are the hormone levels in Aschermann's syndrome?
Normal (endometrium does not grow)
What is the most common cause of secondary amenorrhea and irregular periods?
Polycystic ovary syndrome
What is the main hormone imbalance in PCOS?
LH higher than FSH (genetic)
What is the consequence of having more LH than FSH (PCOS)?
- More androgen than estradiol as not all is converted to estrogen
What are the hormone levels in PCOS?
- LH high
- FSH normal
- Oestradiol normal
- Testosterone high
Why do cysts arise in PCOS?
- More androgens
- Androgens are inhibitory to growing follicles
- Some follicles stop growing
- Forms cyst on ovary
What can exaggerate the hormone imbalances seen in PCOS?
Why does weight make PCOS worse?
- Decreases SHBG
- SHBG mops up testosterone
Why does insulin make PCOS worse?
Increases the action of LH on thecal cells leading to more testosterone production
How is PCOS treated?
- Weight loss
- Combined oral contraceptive
Why are people with PCOS at risk of endometrial cancer?
Risk of abnormal endometrial thickening
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