erectile dysfunction in overweight men
oestrogen plays a role in fat storing and is naturally present in small amounts in men, when you gain weight, oestrogen levels rise
this inhibits GnRH production and testosterone
results in erectile dysfunction etc
what is the rate limiting step for the production of steroids
the conversion of cholesterol to pregnenolone
synthesis of progesterone
synthesised from pregnenolone by the action of 3ß-HSD in the corpus luteum, by the placenta during pregnancy and by the adrenals (as a step in the androgen and mineralocorticoid synthesis)
oligomenorrhoea
reduction in frequency of periods to less than 9 a year
primary amenorrhoea
failure of menarche by the age of 16
think anatomical/congenital (Turner’s/Kallmann) cause?
secondary amenorrhoea
cessation of periods for >6 months in an individual who has previously menstruated
physiological causes of amenorrhoea
pregnancy
post menopause
causes of secondary amenorrhoea
Ovarian problem: PCOS, premature ovarian failure
Uterine problem: uterine adhesions
Hypothalamic dysfunction: weight loss (BMI <18.5), over exercise, stress, infiltrative
Pituitary: high PRL, hypopituitarism
symptoms of oestrogen deficiency
flushing, libido, breast tenderness, vaginal atrophy causing dyspareunia (painful sex)
vaginal atrophy
inflammation of the vagina due to thinning and shrinking of the tissue
can be due to oestrogen deficinecy
investigations of amenorrhoea
LH, FSH, Oestradiol (main oestrogen)
ovarian US ± endometrial thickness
testosterone if there is hirsutism
pituitary function tests and MRI pituitary if indicated
karotype if it is primary amenorrhoea/Turner’s symptoms
what is female hypogonadism identified by
low levels of oestrogen
primary hypogonadism
problem with ovaries - high FH/LSH = hypergonadotrophic hypogonadism
eg premature ovarian failure
secondary hypogonadism
problem with the hyothalamus/pituitary axis - low LH/FSH = hypogonadotrophic hypogonadism
WHO group 1 definition of anovulation
hypothalamic pituitary failure
- low LSH, FH, oestrogen deficiency, normal PRL, amenorrhoea
progesterone challenge test
used to evaluate a patient who is experiencing amenorrhoea
progesterone administered as an IM injection
if the patient has sufficient oestradiol, withdrawal bleeding should occur - indicating that the patients amenorrhoea is due to anovulation
if no bleeding occurs it is likely to be due to low serum oestradiol, HPA dysfunction etc
progesterone challenge test in WHO group 1 anovulation
negative
WHO group 2 definition of anovulation
hypothalamic pituitary dysfunction
- normal gonadotrophins/excess LH
- normal eostrogen levels - positive progesterone test
- oligo/amenorrhoea
PCOS
WHO group 3 definition of anovulation
ovarian failure
which WHO group of anovulation is PCOS classified into
2
premature ovarian failure
amenorrhoea, oestrogen deficiency and elevated gonadotrophins occuring <40 as a result of loss of ovarian function
there is a low likelihood of conception
biochemistry of premature ovarian failure
FSH >30 on 2 separate occasions more than one month apart
LH high
oestradiol low
causes of premature ovarian failure
autoimmune disease (eg associations with Addison’s, thyroid, APS1/2)
chromosomal abnormalities (e.g. Turner, Fragile X, XX gonadal agenesis)
gene mutations (eg in FSH/LH receptor)
iatrogenic - radio/chemo, bilateral oophorectomy
clinical features of premature ovarian failure
features of low oestrogen:
hot flushes
night sweats
atrophic vaginitis
treatment of premature ovarian failure
hormone replacement therapy
egg/embryo donation
counselling and support networks
secondary hypogonadism
hypogonadism as a result of hypothalamic or pituitary disease
characterised by low oestradiol and low/inappropriately normal LH and FSH
causes of secondary hypogonadism
hypothalamic problems:
- functional disorders: low weight (BMI <18.5), stress, extreme exercise)
- brain pituitary tumours
- Kallman’s syndrome
- IHH
pitutiary problems
miscellaneous: Prader/Willi and haemachromatosis
management of hypothalamic anovulation
- stabilise weight
- BMI >18.5
- pulsatile GnRH if hypog hypog
- -SC/IV, pulsatile administration every 90 minutes
- LH and FSH daily injections
- require US monitoring of response
what is the problem with gonadotrophin injections to treat secondary hypogonadism
higher multiple pregnancy rates
what is the ovulation rate with pulsatile GnRH treatment for secondary hypogonadism
90%
what are the 3 types of functional hypothalamic amenorrhoea
weight change
stress
extreme exercise
why does stress cause amenorrhoea
evolutionary mechanism to avoid conception during physiological stress
at which BMI does amenorrhoea tend to occur
<18.5 normal ovulatory cycle unlikely
<16 cycle usually stops
what happens to GnRH secretion in functional hypothalamic amenorrhoea
aberrations in pulsatile GnRH secretion, causes impairement of LH and FSH
there are complex hormonal changes manifested by profound hypooestrogenism
idiopathic hypogonadotrophic hypogonadism
- congenital absent/delayed sexual development associated with inappropriate low levels of gonadotrophic and sex hormones in the absence of anatomical/functional defects of HPA
- major defect is an inability to activate pulsatile GnRH secretion during puberty due to a genetic defect
what additional phenotype features may be present in IHH
anosmia
what mutations have been identified as a cause of IHH
mutations in GPCR KISS1R (GPR54) gene
the ligand for KISS1R - ‘Kisspeptin’ is a potent stimulator of GnRH secretion
GnRH neurone has Kisspeptin receptors on it, pulsatile release of Kisspeptin causes pulsatile release of FH and LSH
name 3 functions of Kisspeptin
gatekeeper of puberty and GnRH secretion
key regulator of male and female fertility
influence positive and negative feedback of oestrogen and therefore influence ovulation and menstrual cycle
what are most of IHH cases
60% kallman’s syndrome
40% normosmic IHH
kallman’s syndrome
genetic disorder characterised by loss of GnRH secretion and anosmia/hyposmia
causes primary amenorrhoea
why does kallman’s syndrome cause anosmia
absence of olfactory bulbs - are in close proximity to the hypothalamus during embryogenesis
what is pituitary function and imaging like in kallman’s syndrome
remainder of pituitary function normal and MRI imaging normal
inheritance of kallman’s syndrome
family history
variable patterns of inheritance
genetic heterogenity is displayed (same phenotype casued by different alleles on the same gene)
hyperPRL
inhibits GnRH secretion
- can be caused by a prolactinoma or drugs (eg dopamine antagonists)
what are some ovarian causes of amenorrhoea
ovarian failure (high gonadotrophins)
congenital problem with ovarian development (absence of uterus, vaginal atresia, Turner, CAH)
PCOS
PCOS
causes secondary oligo/amenorrhoea, infertility, obesity, acne and hirsutism
most common endocrine disorder in women
can be uni or bi lateral
inherited condition
what exacerbates PCOS
weight
diagnosis of PCOS
Rotterdam criteria (2/3):
- menstrual irregularity
- hyperandrogenism
- polycystic ovaries
what is acanthosis nigricans associated with
- Associated with obesity, insulin resistance, PCOS and adenocarcinoma of the stomach
what skin lesion is PCOS associated with
acanthosis nigricans
blood tests of PCOS
increased testosterone (high free androgen)
increased LH:FSH ratio
increased TSH and lipids
impaired glucose tolerance
US of PCOS
insulin resistance in PCOS
this is seen in 50-80% of patients
diminshed biological response to a given level of insulin, however as the pancreatic reserve is normal hyperinsulinaemia occurs
20% of patients have glucose intolerance or non-insulin dependent DM
exacerbated by obesity
what does hyperinsulinaemia in PCOS result in
raised LH levels (altered LH:FSH ratio). This leads to increased androgen synthesis and arrest of normal follicular development
lowered FSH - insufficient to stimulate granulosa cells (infertility?)
lowered SHBG levels, leading to increased free testosterone, leading to hyperandrogenism
management of PCOS
- weight loss and metformin
- local measures: shaving, wax, creams etc
- OCP - acne and hirsutism respond to this. Can add Crypoterone acetate
- cosmesis eg laser phototherapy, electrolysis
the risk of which 2 cancers is increased in PCOS
ovarian and endometrial
OCP action
suppresses ovarian androgen production and reduces free androgens by increasing SHBG levels
- hirsutism benefit and regulates cycles
what local anti-androgen creams are available for treatment of PCOS
elfornithine cream (Vaniqa) inhibits hair growth
what is used in the management of PCOS if the OCP has not been of much benefit
cyproterone acetate (steroidal anti-androgen of co-cyprindiol)
often combined with OCP as Dianette
use of Metformin in PCOS
to restore cycles and fertility, helps insulin resistance and so reduces androgen production
helps all aspects of PCOS
what cosmetic management can be performed in PCOS
electrolysis and laser phototherapy
pre-fertility treatment
weight loss to optomise results (BMI >30 has a poor treatment outcome)
lifestyle modifications: smoking and alcohol
folic acid 400mcg daily (5g if BMI >30)
check rubella immune
normal semen analysis
patent fallopian tube
what vaccine is given for rubella
MMR
(live attenuated vaccine)
UK VACCINATION SCHEDULE: given at 1 year and 3y4m
what are the 3 options for ovarian induction in PCOS
metformin may induce conception alone
Clomifene citrate
gonadotrophin therapy
laparoscopy ovarian diathermy
clomifene citrate (Ovulation Induction in PCOS )
- possible AE
inhibits oestrogen receptors in the hypothalamus, inhibiting negative feedback of oestrogen on gonadotrophin release, leading to up-regulation of HPG axis
may cause ovarian hyperstimulation syndrome
gonadotrophin therapy (Ovulation Induction in PCOS )
daily injections of recombinant FSH to stimulate the ovary directly
what are the risks with gonadotrophin therapy
multiple pregnancy and over stimulation
laparoscopic ovarian diathermy (Ovulation Induction in PCOS )
many singleton pregnancies
what is the risk with laparoscopic ovarian diathermy
destruction of ovaries
what are the risks of ovulation induction
ovarian hyperstimulation
multiple pregnancy
ovarian cancer
what happens in ovarian hyperstimulation
- Ovaries become swollen and painful. Ovarian enlargement, oedema, hypovolaemia, acute kidney injury
- Ranges from mild to severe
- There is an increased risk <35 years, and in PCOS
what are the biggest risks in multiple pregnancies
prematurity (half of twins are born before 36 weeks) and low birth weight
problems associated with prematurity:
- Neonatal intensive care may be required
- Breathing help
- RDS
- Long term: cerebral palsy, impaired sight, congenital heart disease
- Still birth/neonatal death
- Disability
hirsutism
excess hair, usually referring to women with male pattern hair distribution
caused by excess androgen at the hair follicle, due to either excess circulating androgen or increased peripheral conversion at the hair follicle
long history causes of hirsutism
PCOS, familial (ethnic origin, especially Mediterranean population), idiopathic, CAH
all present with a testosterone that is not dramatically elevated (<5nmol/L) and no virilisation
causes of hirsutism with a short history
adrenal/ovarian tumour (frequently benign)
high testosterone levels (>5nmol/L), signs of virilisation (deepening of voice and clitoromegaly)
MRI adrenal and ovaries for tumours (>1cm)
what can exposure to exogenous testosterone cause
hyperandrogenism
turner’s syndrome
affects women, 45X (one X chromosome missing)
can uncommonly be mosaicism
ovarian function in Turner’s syndrome
an early loss of ovarian function is common, a small percentage of females will retain normal ovarian function throughout young adulthood
most will be infertile
puberty in female’s with Turner’s syndrome
most fail to progress through puberty, 30% have some pubertal development
there is normal adrenarche and pubic hair development
breast development depends on when the ovaries fail (there may be none if they fail before puberty)
failure to develop 2y sexual characteristics is typical
how does Turner’s present in paediatrics
short stature
puberty abnormalities
how does Turner’s syndrome present in adults
primary or secondary amenorrhoea
infertility
clinical features of Turners
short stature
webbed neck
shield chest with wide spaced nipples
cubitis valgus
lymphoedema
coarctation of the aorta
XX gonadal dysgenesis
a form of female hypogonadism, in which there are absent ovaries, without any chromsomal abnormality
testicular feminization (androgen insensitivity syndrome)
a genetic disorders that makes XY fetuses insensitive to androgen
they are born externally looking like normal girls, and tend to identify with being female
define inferility
failure to achieve a clinical pregnancy after 12 months or more of regular unprotected sexual intercourse (in absence of known reason) in a couple who have never had a child.
define primary and secondary infertility
- primary - the couple have never conceived
- secondary- the couple have previously conceived (may nothave been successful)
list factors that increase the likelihood of conception
- Women <30
- Previous pregnancy
- Less than 3 years trying to conceive
- Intercourse occurring around ovulation
- Woman’s BMI 18.5 – 30
- Both partners are non-smokers
- Caffeine intake of less than 2 cups of coffee daily
- No use of recreational drugs
what drug has a direct correlation to still birth
cocaine
define anovulatory infertility
ovaries do not release an occyte during the menstrual cycle
hydrosalpinx
- distally blocked fallopian tube withc lear/serous fluid - may become distended
- can cause pain, discharge, infertility, menorrhagia and ectopic pregnancy
define endometriosis
the presence of endometrial glands otuside the uterine cavity
most common cause of endometriosis
retrograde menstruation - menstrual blood containing endometrial cells flows back out through fallopian tubes into pelvic cavity instead of out of the body
classical scan sign of endometriosis
chocolate cysts
examination of patient for infertility
- BMI
- general - body hair distribution, galactorrhoea
- pelvic - presence of vas deferens, varicocele (reduce sperm count)
investigation of female for infetility
- Endocervical swab for chlamydia
- Cervical smear if due
- Blood for rubella immunity
- Midluteal progesterone
- test of tubal patency
first line investigation for tubular assessment
Hysterosalpingiogram
when is laparoscopy first line for infertility
known pelvic disease/pathology
