ENDOCRINOLOGY WK 6 Flashcards

1
Q

definition of infertility and subfertility

A

Infertility defined as inability to conceive after 1 yr of unprotected sex
Subfertility defined after 6 months

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2
Q

what has lead to a rise of infertility

A

On rise due to…
- STIs
- Obesity
o Hormones important become off-balanced in obesity
o If underweight hormones inbalanced
- Tobacco
o Worse for men > dec. blood flow in penis

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3
Q

formation of the ovarian reserve - stage of arrest of germ cells, and how this relates to chromosome instability in later life

A

Formation of ovarian reserve
- Primordial germ cells colonise the gonad
- Numbers expand by mitosis
- Germ cell enter, and then arrest in meiosis (form oogonial cycts)
o In these structures they begin meiosis
o This is when women is still a foetus (men only begin meiosis at puberty)
o Cysts breakdown and eggs get wrapped up by granulosa cell to form…
- Primordial follicles form
o Arrested at diplotene of meiosis 1
o Don’t resume meiosis til ovulation
o Vv important for connections between chromosomes to be stable for 30-40 yrs
o This is why old women have higher prevelance of down syndrome
o Bc/ connections between chromosomes are worse
- Folliculogenesis

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4
Q

the follicle stages

A

WHAT IS A FOLLICLE
- Reproductive unit of the ovary
- Comprised of egg(oocyte) and surrounded by granulosa cells
o Primordial follicle
 egg and single layer of squamous granulosa cells
o Primary follicle
 squamous granulosa cells become cuboidal and form layers around oocyte
 oocyte secretes a glycoprotein layer – zona pellucida
 zona pellucida is a barrier between oocyte and granulosa cells
o secondary follicle
 inc. number of granulosa cells
 extra layer called theca
 theca comes from surrounding stroma that differentiate
o early antral follicle
 theca differentiates into 2 parts
• theca interna – glands, blood vessels (important for getting nutrients and hormones)
• theca externa – big fibrous capsule to proect whole follicle
 fluid filled gaps secreted by granulosa cells
• folicular fluid/ antral fluid
• starts to build the antrum (fluid-filled space)
o ovulatory/ antral/ graafian follicle
 all the fluid form a big follicular antrum
 this pushes the oocyte out so it’s dnagling by granulosa cells in the antrum
 one layer of grnaulosa cells become attached to oocyte – corona radiata
 other granulosa cells more loosely associated – cumulus cells

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5
Q

HPG axis - what hormones involved etc

A
  • hypothalamus releases Gonadotrophin-releasing hormone
  • anterior pituitary gonadotroph cells makes FSH and LH
  • FSH and LH work on the ovary
  • The follicle makes oestrogen, progesterone, inhibin etc
    o These hormone signal back to pituitary and hypothalamus to regulate hormones
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6
Q

posterior pituitary (HPG axis)- what hormones and what are there roles

A
Posterior pituitary
-	Paraventricular and supraoptic neurone from hypothalamus to posterior pituitary
-	2 hormones made here
o	ADH
o	Oxytocin

OXYTOCIN
- Has major effects on smooth muscle contraction
o Milk ejection
o Contraction of uterus during childbirth
- Secretion is stimulated in response to stimulation of nipples or uterine distention
- Oxytocin is used to induce labour
- Released during female orgasm

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7
Q

anterior pituitary (HPG axis) - what hormones involved

A

Neurones run from hypothalamus to the hypophyseal capillary network
In the hypothalamus GnRH is made….
- GnRH has a pulsatile release
o Prevents receptor desensitisiation and downregulation
o Responds to ovarian hormonal feedback

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8
Q

kisspeptin

A
  • Small neuropeptide hormone
  • Feedback onto GnRH neurone
  • And regulate secretion of GnRH
  • Although it can receive signals from gonads can also integrate other hormones eg cortisol, leptin, environmental cues
    o May be why shift workers have fertility problems
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9
Q

water soluble hormone transport - what hormones and how

A

WATER SOLUBLE HORMONE TRANSPORT
- GnRH
- FSH
- LH
So can travel through blood freely
- At target site diffuse out
- Cell membranes are hydrophobic so can’t diffuse through this
- Need to bind to cell receptor to trigger and signalling cascade
- Involves CAMP to phosphorylate protein kinases > reaction in the cell itself

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10
Q

lipid soluble hormone transport - what hormones and how

A

LIPID SOLUBLE HOMRONE TRANSPORT
- Oestrogen
- Progesterone
Travel in blood on a transport protein
- When get to cell they can freely diffues through the cell membrane
- Travel into nucleus and bind to a nucelus receptor to change gene expression

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11
Q

what causes follicle activation

A

No one realy knows from primordial to primary follicle
- Doesn’t involve signals from brain
- Maybe due to changes in the ovary itself
At preantral stage gonadotrophins become vv important
- FSH and LH
- Granulosa cells have FSH recptors
o Then undergoe massive proliferation and start producing oestrogen
- Thecal cells have LH receptors
o LH important for antral expansion ond ovulation

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12
Q

anti-mullerian hormone

A
  • Made by granulosa cells
  • Absent in primordial follicles but present at later stages
  • Inhibitory effect on follicle development
  • Unaffected by gonaotrophins/ steroid hormones
    o Reliable reflection of growing follicles
  • AMH is seen as brown staining to the right
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13
Q

follicle secretion/ ovulation

A
  • To do with the LH receptor
  • Oestrogen and FSH induce the expression of the LH receptor on the thecal cells
  • Whatever follicle has the most number of LH receptors will receive all the LH hormone from pituitary > aka is ovulated
  • Humans developed mechanism to ovulate one follicle every month (or maybe 2) – nobody knows why
    o But does have something to do with LH recptor
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14
Q

the menstrual cycle - from menstruation up to the LH surge

A
THE MENSTRUAL CYCLE
-	Between 24-32 days 
-	Most women ~28 days
-	14-20 follicles grow every month
o	1 is ovulated
o	The rest die
Day 1 – menstruation
-	Due to dropping oestrogen and progesterone levles
-	Uterus lining begins to be shed
-	Pituitary gland then releases FSH which signals to follicles
-	Follicles are starting to grow 
-	Granulosa cell proliferate and start to make oestrogen
  • Oestrogen continues to rise
  • Oestrogen cause endometrium to thicken – produce nutrient
  • Oestrigen feedsback on pituitary causing FSH levels to drop slightly
  • Oestrogen levels continue to rise
  • As follicle grows it cont. secrete oestrogen but once it reaches threshold level becomes positive feedback instead of neg.
  • Oestrogen pos. signals to pituitary leading to release of LH
  • Causing LH SURGE
  • Together FSH and oestrogen stimulate LH binding sited on outer layers of granulosa cells
  • LH surge at day 14 > ovulation
  • Oocyte begins meiosis up to metaphase of second meiotic division then stops
  • Meiosis doen’t complete until it reaches the sperm
  • In response to these hormones there’s a sudden drop off of FSH and LH
  • Oestrogen drops as follicle is gone – corpus lutem produces some
  • Begin secretory phase of uterine cycle
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15
Q

menstrual cycle follicular rupture and corpus luteum and luteinisation

A

FOLLICULAR RUPTURE

  • Release follicular fluid taking egg
  • Egg is spilt into cavity and fimbriae sweep it up into oviduct
  • Then transported down into uterus
  • 30-40% of women can feel follicular rupture
  • After egg release there’s a corpus luteum that secretes progesterone
  • In reponse to this we have a fall in FSH and LH
  • Progesterone prepares the endometrium for pregnancy

CORPUS LUTEUM AND LUTEINISATION
- Ruptured follicle develops into corpus luteum
o Granulosa and theca cells
- Lutein cells – mitochondria, smooth ER, Golgi, lipid droplets, pigment lutein
- Luteinisation = progesterone secretion

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16
Q

hormonal contraception

A
  • Supresses ovulation via negative feedback of progesterone
    o Secondary effects on female genital tract
  • Combined pill
    o Oestrogen provides additional feedback and promotes progesterone recepotor expression
  • During ‘off period’ own HPG axis is awakened
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17
Q

hormones and breast development - prolactin

A
  • Released from pituitary in response to placental hormones
  • Important for breast feeding – breast makes milk
  • Breast can’t officially make milk until placental is delivered at birth

Prolactin levles maintained afterbirth for a few weeks

  • But needs suckling for it to be continuously signalled
  • This stimulates anterior pituitary to make prolactin
  • Alveoli swell and secrete milk
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18
Q

how/ why do the breasts release milk

A

Releasing milk

  • Need suckling > nerve impulse sent to the brain
  • Boosts oxytocin synthesis and secretion from posterior pituitary
  • Myoepithelial cell contraction around alveoli = milk expulsion
  • Milk ejection reflex can be conditioned
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19
Q

fertility during lactation

A

Fertility is reduced during lactation

  • Lactation can continue for months
  • Menstruation and ovulation re-established by 3-6 months
  • ~50% of unprotected nursing mothers fall pregnant during 9 months of lactation
  • Neg. feedback of prolactin of FSH/LH
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20
Q

how is oestrogen made in the follicle - granulosa an dthecal cell roles

A

Granulosa cells have lots of aromatase to convert andorgens into oestrogen when signalled to by FSH
- But granulosa cell don’t have
o P450sce
o 3B-HSD
o 17a-hydroxylase
- Granuslosa cells get androgens from elsewehere…
AKA FROM THECAL CELLS
- These are signalled by LH to make androgens

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21
Q

what tests to do for irregular periods

A
  • Meausre oestrogen
  • FSH and LH
  • Prolactin
  • Androgens
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22
Q

hypogonadotrophic hypogonadism - what, history, examination, ,management

A

what
- LH low, FSH low, E2 low, PRL normal
- Womens not having period because of low oestrogen > nothing to thicken endometrium
- Low oestrogen because of low FSH and LH
- Not an ovary problem
- Pituitary isn’t affected because prolactin is normal
- So problem is the hypothalamus
o If meausred GnRH in hypothalamus it would be low
o Would have low GnRH when you’re a child > this women has childlike hormones
o When body decides when to start puberty it does this by deciding if you have the capacity to nourish a child > looking at body fat
o Over weight girls go through puberty quicker
o If you don’t have enough fat – body swtiches off reproduction
- May be due to eating disorder or over-exercise, or stress

History
- Weight loss, low body fat, low BMI, stress, illness
Examination
- Scales – low weight
Management
- Encourage to gain weight, and stop exercise
- Hormone replacement therapy – oestrogen and progesterone (To help bones)
- If wanst to get pregnant – LH and FSH injections, or pulsatile GnRH

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23
Q

premature ovarian insufficiency - what, history, examination, management

A

what
- LH high, FSH high, E2 low, PRL normal
- Low oestrogen but normal LH and FSH
- So problem is in the ovary
- No oestrogen to feedback so FSH and LH is high
- This is due to ovary running out of eggs
o Can be women age 24/25
o Or during menopause
o Turners syndrome – goes through menopasue before puberty
- During IVF give large amounts of LH and FSH
o At time IVF started used to take urine from old ladies with high FSH and LH in urine
o European nuns sold their urine to drug companies to get FSH and LH
Causes
- Cancer killing eggs, autoimmune, don’t know

History
-	Treatment, fam. History, menopausal symptoms (hot flushes, thinning and drying of vagina)
Examination
-	Atrophic vaginitis
Management
-	Donor egg
24
Q

HYPERPROLACTINAEMIA - what, history, examination, management

A

WHAT
- LH low, FSH low, E2 low, PRL high
- Problem with the pituitary
- Pituitary producing too much prolcatin which switches off gonadotrophin
o Happens naturally during breastfeeding
- Can happen due to microadenoma making inc. levels of prolactin
- Galactorrhoea > leaking milk
- Do an MRI of the brain to look for growht in pituitary
o If there’s a growth – can impact the optic chiasma
o Outer parts of vision affected – bitemproal haemaenapia

History
-	Galactorrhoea
Examination
-	Galactorrhoea, bitemporal Hemianopia
Management
-	Switch of prolactin by giving dopamine agonists (bromocriptine)
25
Q

POLYCYSTIC OVARY SYNDROME - what, history, examination, management

A

WHAT
- LH high, FSH normal, E2 normal, PRL normal
- No issues with oestrogen = no problems with their bones
- Due to the environment the ovary finds itself in
o Doesn’t happen naturally in anytime of life
o It’s a pathology
- Hormone inbalance
o Inc. LH compared to FSH
o Still makes oestrogen
o Increased amount of androgens]
Androgens
- Made in the follicle and affect the follicle
- Androgesn don’t pause the little follicles – they pause follicle groht at 5-6mm
- So you can do a scan and you can see a build up of little paused follicles
o Didn’t know they were follicles til recently so were called cysts
o POLYCYCTSIC OVARIES

History
- Hair loss, hair growth, skin problems (spots/ extra hair), weight gain
Examination
- BMI, skin, (USS)
Management
- Anti-estrogen (clomifene citrate)
- If not want to get pregannt – take the pill

26
Q

treatment for PCOS

A

TREATMENT
- Want to lower LH which would lower androgens (which would allow follicles to grow)
o But don’t have any treatments to lower LH without lowering FSH
o Instead raise FSH so that convert androgen to oestrogen and take break off follicle this way
Raise FSH by…
- Oestrogen feedbacks to lower FSH
- Low levels of oestrogen will increase FSH
- So use an oestrogen blocker > chlomophene
- Use an oestrogen antagonist
Problems
- Oestrogen thickens endometrium – so this treatment doesn’t allow that
- Oestrogen causes LH surge
- So give clomifene citrate for 5 days at beginnign of cycle (day 3-7)
o Allows us to take it away to allow endometrium build up

27
Q

menopause - normal age range and 2 key events

A

Meopasue – wome’s last spontaneous menstrual period
- Average age – 51
- Normal range 45-55
2 key events
- Loss of fertility – quality and quantity of oocytes diminish
- Loss of ovarian hormonal function
o Estrogen and progesterone

28
Q

causes of premature ovarian insufficiency

A
  • Idiopathic (89%)
  • Autoimmune
  • Surgery / chemo or radiotherapy
  • Chromosomal
  • Infections
  • Metabolic
29
Q

biochemical profile for premature pvarian insufficiency

A

Estradiol – dec.
FSH and LH – inc.
- There may be many years of fluctuating levels in the perimenopause
- Most women don’t need hormone tests
- FSH >30 shows menopause
Predictors of menopause
- FSH – day 3 raised level
- AMH – anti-mullerian hormone – decline with age and useful marker of ovarian reserve
- Inhibin B – decline with age and protein hormone marker of ovarian reserve
- Ovarian antral follicle count from US

30
Q

symptoms from lack of oestrogen

A
  • Hot flushes and night sweats
  • Palpitationd and faintness
  • Esperiences by >80% of women
  • Debilitating, embarassing and unpleasant
  • Sleep deprivation
31
Q

urogenital ageing

A
  • Vaginal dryness and dyspareunia
  • Bladder neck syndrome – urgency, urge incontinence, nocturia, UTI
  • 30% of women admit that their UG symtpoms strongly affect daily life
  • Embarassemnt inhibits women getting hel
32
Q

hormone replacement therapy for premature ovarian insufficiency

A

Estrogen
Progesterone – for endometrial protection
Testosterone
- Restore hormoens to make women feel normal again but can’t restore fertility after menopause
Give estrogen – oral, skin patches and gel, subdermal implant, intra-uterine progestogen
- Second line for treatment of osteoporosis
- First line treatment for menopause

33
Q

benefits of HRT

A

Imporve quality of life
- Relieve vasomotor symptoms
- Lift depressed mood
- Improve vaginal symptoms
Protection against osteoporosis if given long enough
- Not given to women >60 most of the time
Protection against bowel cancer

34
Q

risks of HRT

A

Side effects
- Bleeding problems, bloatedness, breast pain, weight gain (a myth!!)
- Small extra risk of breat cancer with prolonged use
o Affect 1 in 8 women in western world – already common!
- Increased risk of venous thromboembolism 2x
- Small excess risk of stroke

35
Q

testicular dysgenesis syndrome features

A
  • Infertility
  • Testicular cancer
  • Hypogonadism
  • Cryptochidism
  • hypospadia
36
Q

disorders of sex development features

A
  • Ambiguous genitilia
  • Gonadal tumour (earlier in life)
  • Hypogonadism
  • Infertility
  • Gonadal tumour
37
Q

what time in fetal/infancy is the HPG axis active and why

A
  • HPG axis is active
  • Lasts until ~3 months postnatally
  • Window for investigating reprouctive function
38
Q

how to genetically investigate androgen insensitivity syndrome

A
  • sequence the androgen receptor gene on the x-chromosome
  • mutation identified in the ar
  • diagnosism- androgen insensitivity syndrome (partial)
    NB – AR mutation only identified in ~50% of individuals
39
Q

how can infertility be managed in young boys receiving radio/chemo therapy

A
  • No established option for preserving fertility
  • Take testicular tissue before treatemnt
  • Freeze testicular tissue
  • Re-transplant testicular tissue
40
Q

hypogonadotrophic hypogonadism in males - hormone levels, what symptom is associated and treatment

A
  • LH – low
  • FSH – low
  • Testosterone – low
  • Ansomia (Kallmanns) – can’t smell
  • 50% idiopathic
  • Numerous gene identified
    Treatment
  • Testosterone – induce puberty
  • Gonadotrophins – induce fertility
41
Q

hypergonadotrophic hypogonadism - hormone levels

A
  • LH – high
  • FSH – high
  • Testosterone – low
42
Q

testing for testicular cancer

A
Scrotal ultrasound
-	Testicular masses
-	Epididymal cysts
-	Varicocele
Tumour markers
-	hCG, AFP, LDH
43
Q

how to take a male fertility history

A
Couple
-	Age fo both partners
-	Duration
-	Prev. pregnancy/ paternity
Male
-	Past emd history 
o	Esp. cryptorchidism, hypospadias, orchitis, torsion, genital surgery, STIs
o	General medical/ surgical disorders
o	Prescribed drugs
-	Ability to get erection and ejaculate
44
Q

how to take a male fertility examination

A
General health 
Genital examination
-	Testis location
-	Testis size (12-25ml)
-	Excurrent duct
o	Epididymis, vas deferens
-	Penis (hypospadias, phimosis)
45
Q

semen analysis - how to get a samples

A
  • Produced by masturbation
  • Non-toxic sample container
  • Analysed within 60 mins of ejaculation
  • Ideally produced beside lab – so doesn’t need to travel
  • Normally asses 2 samples 4 – 12 weeks apart
  • Abstinence of 2-7 days before
46
Q

sperm donation - guidelines

A
  • Regulated by HFEA
  • Age 18-40
  • Anonymous donation
  • Screening tests
  • 10 childen allowed for one sperm donation
  • Female age – when to proceed to IVF
47
Q

cystic fibrosis as a cause of infertility in males

A

Due to…

  • Thickened secretions in tract
  • Congenital bilateral absence of vas deferens
48
Q

If XY chromosome compliment but looks feminine

A
  • Inactivating mutation of AR
  • Phenotypically normal female
  • Testes are present and are hormonally functional
  • Testosterone levels are elevated
  • Fallopian tubes, uterus and top part of vagina missing
  • Body fat distribution is female
  • Brain is female
49
Q

testicular dysgenesis syndrome - hypothesis

A

The commonest reproductive disorders of the developing and young adult male

TDS Hypothesis…

  • Subtle deficiencies in actions of testosterone in early fetal life disrupts normal events
  • So inc. risk of developing 1 or more of disorders
  • Nothing you can do to reverse this > programming gone wrong

What about penis size?

50
Q

the most common congenital disorders

A

Cryptorchidism
- Deficiencies in fetal androgens can cayse both disorders
- Testis should be descended – in this testis don’t descend
- Event that goes wrong most commonly
o When testis has to descend through pelvis – inguinal canal
o Acutely dependnet ont here being enough androgens – so can go wrong here
Hypospadias
- Urehtral opening isnt in the tip of penis
- Opening is beneath glands or further down on penis

51
Q

testicular germ cell cancer - what is it, and origins

A
The commonest cancer of young men
Dec risk as you get older
Risk factors…
-	Environmental
-	Lifestyle

TGCC has its origins in fetal life
- ‘faulty’ sertoli cells is the suspected cause
- Sertoli cells are what determine sperm count
o Sperm counts have fallen alor 52.4% declone 1970-> 2010

52
Q

sperm count and fertility

A
  • Once reach sperm count of 40 million/ml max chances of inpregnating partner
  • Sperm counts lower = chances decrease a lot
  • 1 out of 6 every young men in europe <20mill/mil sperm count

Societal changes lead to delayed pregnancy in couples
- Wait til women are in there 30s at which point female fertility declines

So low sperm coutn + women in 30s
-	Inc. risk of infertility
-	Inc. need for assisted reproduction
o	This is ~30% successful
o	Inc. ineffective with age
o	Bruising, traumatic process
53
Q

ICSI for infertility - issues involved

A

Intracytoplasmic sperm injection

  • The main (invasive) treatment for ICSI is to the female partner
  • Health consequences for ICSI children are unclear
  • Animal studies show variation in nutrition around the rime of conception (before implantation) can dramatically alter metabolic function of the offspring in adulthood
  • These effects may be passe don to the next generation (grandchildren)
    o Epigenetics
  • In IVF, embryos are cultured for several day in vitro (medium is not defined, may not be optimal – may be abel to induce epigenetic changes in embryo)
  • Sperm can also pass on epigenetic effects to offspring/ grand-offspring which can alter their metabolism and health
  • Long-term effect of ICSI on health of offspring are largely unknown, sperm counts are 50% lower in ICSI-derived human males
54
Q

why nay TGCC be associated with increasing levels in infertility

A
  • Because sertoli cells are affcted
    o Each sertoli cell can support a fixed number of germ cells during their 10-week development into sperm
    o So no. of sertoli cells you have determines how many sperm cells you can make
  • Only way to measure sertoli cells is to remove the testis, fix them and then count them microscopically
  • No. of sertoli cells in linearly associated to the amount of germ cells in indiv.
    o Very variant between men
    o Seroli cell no. determined suring fetal development
55
Q

anogenital distance

A

Anogenital distance (AGD)
Central between anal opening to the base of the penis/ vaginal opening
- Male AGD is usually 2x that of female
- Determined by fetal andorgen exposure
The masculinisation programming window (MPW)
- Male-female difference in AGD was induced by androgen exposure specifically in the MPW – masculinisation programing window

56
Q

what is the masculinisation programming window and how is it affected by maternal factors

A

There’s evidence that TDS disorders orignate in 1st trimester during the MPW

  • Supression of androgens in this time stops masculinisation
  • MPW is within the period 8-12 weeks

what factors acting via the mother may lead to TSD in the 1st trimester?
- >90% of research effort in this area over the last 20 yrs has focussed on exposure to environmental contaminants/ pollutants (‘endocrine disruptors’)
- The biggest changes have been to maternal diet and lifestyle
- Use of medicine during pregnancy has also increased substantially
o Effect of maternal acetaminophen/ painkiller (paracetamol) use in pregnancy and cryptochidism in sons – 2x the risk
o However is an assoc. studie so can’t prove cause and effect

57
Q

whats the effects of paracetamol on fertility in next generations (based on studies in rats)

A
  • Host mice were treated wit h paracetamol
    o Testosterone levels red. After 1 wk of paracetamol
    o Seminal vesicle weight also reduced
    o GERM CELLS WERE ALSO AFFECTED > given on to next generation
    o This is signif. In female as reduced fertility in adulthood
    o Impaired ovarian function in grandaughters irrespective to whether father or mother affected by analgesics