Reproductive Endocrinology Flashcards
What are primordial germ cells?
earliest recognisable germ cells
What is oogonia?
Structure formed after the completion of the last pre-meiotic division before they become oocytes
Secondary oocytes have gone through how many meiosis cycles?
2
When is the first polar body formed in female germ cells?
One of the 2 products of the first stage of meiosis
How is the 2nd polar body formed?
When sperm enters the oocyte and the 2nd meiotic division is complete
What are the 2 phases of the ovarian cycle?
Follicular
Luteal
What happens in the follicular phase of the ovarian cycle?
Maturation of egg until it’s ready for ovulation at midcycle
What happens in the luteal phase of the ovarian cycle?
Development of the luteum
Induces preparation of the reproductive tract for pregnancy (if fertilisation occurs)
What are the primary follicles?
A layer of granulosa cells which surrounds the primary oocyte before birth
How many primary follicles are present in a female when she is born?
~2 million
Does the number of primary follicles in a females ovaries increase or decrease as she gets older?
Decrease
How is the secondary follicle formed?
The oocyte grows around 1000x its size and the follicle expands and becoems differentiated under the influence of hormones
How many eggs will be ovulated within a woman’s lifetime?
~400
What happens to the follicular cells after ovulation?
They undergo luteinisation to transform into the corpus luteum
What hormone does the corpus luteum secrete?
Progesterone
What hormone is secreted in the follicular phase?
Oestrogen
After ovulation for how long does the corpus luteum grow before reaching its maximum size?
8-9days
If the egg has not become fertilized then what will happen to the corpus luteum?
Lasts for ~14 days post-ovulation and then degenerates signalling a new ovarian cycle
If the egg DOES become fertilized then what happens to the corpus luteum?
It persists in teh ovary and produces progesterone and oestrogen in increasing amounts until after pregnancy
The hypothalamus secretes GnRH which acts next on which part of the body?
Anterior pituitary gland
Once acted upon by GnRH, what does the anterior pituitary release?
FSH
LH
What does FSH do in the ovarian cycle?
Acts on the ovary to stimulate follicle development
FSH and LH stimulate oestrodiol secretion and ovulation
What is the role of LH in the ovarian cycle?
Acts on the ovary to stimulate follicle maturation, ovulation and development of the corpus luteum
What do FSH and a little LH cause to happen in the ovary in the follicular phase?
Upto 15 follicles begin to mature i.e. their granulosa and theca cells develop
What do the theca cells cause to happen in the follicular phase?
Produce androgen which is converted by the granulosa to oestradiol which thickens the endometrium and thins the cervical mucous
What does the dominant follicle possess so that it can continue along the cycle?
LH receptor
At mid cycle, high levels of oestrogen are produced, the hypothalamus does what in response to this?
Release GnRH thus FSH and LH are released in a surge from the ant. pituitary
What happens to the FSH and LH levels during ovulation?
They begin to fall
after ovulation what happens to the remaining granulosa cells from the dominant follicle?
Proliferate to form the corpus luteum and secrete progesterone
What does hCG stand for?
Human chorionic gonadotrophin
What happens to the corpus luteum if it does not detect hCG after 12 days post-ovulation?
It degenerates and becomes the corpus albicans
When the corpus luteum becomes the corpus albicans progesterone and oestrogen levels fall, what can now happen?
A new cycle can recommence
If the corpus luteum does detect levels of hCG then what will it do?
Produces progesterone until ~6weeks into the pregnancy when the placenta takes over this role.
What hormones stimulate spermatogenesis?
FSH
Testosterone
What decreases FSH secretion in men?
Inhibin
What is the name of the cells which secrete androgen-binding globulin (ABG) and inhibin, and where are they found?
Sertoli cells in the seminiferous tubules
LH stimulates secretion of what other hormone?
Testosterone
What effect does testosterone have on the secretion of GnRH?
It decreases the rate of secretion
Testosterone goes on to form dihydrotestosterone, what does this do?
enlarges the male sex organs
given males their secondary sexual characteristics
anabolism
What is oligomenorrhoea?
A decrease in the frequency of periods to <9/year
What is primary amenorrhoea?
Failure of menarche by 16
What is secondary amenorrhoea?
Cessation of periods in an individual for >6months in an individual who has previously menstruated
What are the physiological causes of amennorhoea?
Pregnancy
Post-menopausal
What can cause primary amenorrhoea?
Congenital problems (Turner’s syndrome, Kallman’s syndrome)
What can cause secondary amenorrhoea?
Ovarian problems - PCOS, POF
Uterine adhesions
Hypothalamic dysfunction
Pituitary problems
What are the symptoms of oestrogen deficiency?
Flushing
Libido decreased
Dysparenuria
What are the features of PCOS/androgen excess?
Hirsutism
Acne
What is one of the main symptoms of hypopituitarism or a pituitary tumour?
Galactorrhoea
What investigations should be done in ALL woman presenting with amenorrhoea?
LH, FSH, Oestradiol
TFTs and prolactin
How is female hypogonadism identified?
Low levels of oestrogen
What are the signs/symptoms associated with primary hypogonadism?
Problem with the ovaries
High LH/FSH - hypergonadotrophic hypogonadism
e.g. POF
What are the signs/symptoms associated with secondary hypogonadism?
Problem with the hypothalamus or pituitary
Low FSH/LH - hypogonadotrophic hypogonadism
Low oestradiol
What happens in premature ovarian failure (POF)?
Amenorrhoea, low oestrogen and high gonadotrophins in women <40y/o as a result of loss of ovarian function
How is POF diagnosed?
FSH >40 on 2 separate occasions >1month apart
What can cause POF?
Chromosomal abnormalities
Gene mutations
AI disease
Iatrogenic (radio/chemo)
What are the symptoms of functional hypothalamic amenorrhoea?
Weight change
Stress
Exercise (too much)
Eating disorders
What are the causes of functional hypothalamic amenorrhoea?
Anabolic steroids Systemic illness Iatrogenic Recreational drugs Head trauma Infiltrative disorders
What happens within the body during functional hypothalamic amenorrhoea?
Abnormal hypothalamic GnRH secretion leading to decreased gonadotrophin pulsations
This leads to low LH and FSH and thus low oestradiol
What is Kallman’s syndrome?
A genetic disorder causing a loss of GnRH secretion +/- anosmia
Does Kallman’s syndrome affect males or females more?
Males (x4)
Why is anosmia found in 75% of Kallman’s syndrome sufferers?
There are no olfactory bulbs present
What pituitary disorders can lead to loss of LH/FSH stimulation?
Presence of a non-functioning pituitary macroadenoma (pressure mass effects lead to hypopituitarism)
Empty sella
Pituitary infarction
What pituitary disorders can lead to hyperprolactinaemia?
Presence of a micro- or macro-prolactinoma
Some drugs e.g. dopamine agonists
Other than hyperprolactinaemia and a loss of LH/FSH stimulation, what other signs can indicate a pituitary disorder?
low FSH/LH
Low oestradiol
What are the ovarian causes of amenorrhoea?
PCOS
Ovarian failure - high gonadotrophins
Congenital problem with ovarian development
What are the Rotterdam criteria, of which 2/3 must be present for a diagnosis of PCOS to be given?
Menstrual irregularity
Hyperandrogenism (hirsutism and high free testosterone)
Polycystic ovaries
What congenital problems of the ovaries can lead to amenorrhoea?
Absence of uterus Vaginal atresia (absence of normal opening) Turner's syndrome Testicular feminisation Congenital adrenal hyperplasia
What can a genetic predisposition to excess ovarian androgen secretion cause?
Polycystic ovaries
What can cause increased testosterone in a female?
Polycystic ovaries
Pituitary gland overproduction
Insulin resistance and hyperinsulinaemia
What can excess testosterone do in a female?
Increases LH
Causes insulin resistance and hyperinsulinaemia
Hirsutism
What is hirsutism?
Excess hair when referring to women with male pattern hair distribution
What causes hirsutism?
Androgen excess at the hair follicle
What conditions can cause hirsutism?
PCOS
Familial
Idiopathic
CAH
All of the above have long histories with not dramatically high testosterone levels and no signs of virilisation. All those below have a short history and deepening of voice and clitoromegaly
Adrenal or ovarian tumours
What is CAH?
An inherited group of disorders characterised by a deficiency in one of the enzymes necessary for cortisol synthesis.
What is 90% of CAH caused by?
21-alpha-hydroxylase deficiency causing excess testosterone
Autosomal recessive disorder with a varied clinical presentation
When is classic CAH diagnosed?
Diagnosed in infancy with virilisation and salt-wasting
When is non-classic (partial) CAH diagnosed?
In adolesence/ early adulthood with hirsutism, menstrual disturbance, infertility due to anovulation
What are androgen secreting tumours associated with?
Rapid onset of symptoms
Signs of virilisation
Increased testosterone
MRI showing adrenal and ovarian tumours >1cm diameter.
If hirsutism is caused by PCOS then how is it treated?
Oral contraceptive pill
Anti-androgens (local and general)
Cosmesis
If hirsutism is caused by late onset CAH, then what is it treated by?
low dose glucocoticoid to suppress ACTH drive
What is different about the genetic makeup of an individual with Turner’s syndrome?
A female with only 1 X chromosome
How common is Turner’s syndrome?
1 in 2000 live births
How does Turner’s syndrome present in paediatrics?
Short stature
Failure to progress through puberty
How does Turner’s syndrome present in adults?
Primary or secondary amenorrhoea
Infertility
What other signs or symptoms can affect the CVS in Turner’s syndrome?
Coarctication of the aorta
Bicuspid aortic valve
Hypoplastic left heart
What other signs or symptoms can affect the GI system in Turner’s syndrome?
GI bleeds
Increased incidence of Crohns and UC
What other signs or symptoms can affect the body in Turner’s syndrome?
Lymphoedema Hypothyroidism Osteoporosis Scoliosis 1/3 have renal abnormalities Otitis media
What is XX gonadal dysgenesis?
Absent ovaries but no chromosomal abnormality
What is testicular feministaion?
Androgen insensitivity syndrome
Genetically XY male (with testes) but in the complete form, phenotypically female
How long does a normal menstrual cycle last?
28-35 days
How long do oligomenorrhoea cycles last for?
> 35 days
The surge of what hormone triggers ovulation?
LH
What hormone peaks before ovulation?
Oestrodiol
What hormone peaks after ovulation?
Progesterone
How can ovulation be confirmed in an individual with regular cycles?
Midluteal (day21) serum progesterone (>30nmol/L) x 2 samples
Basal body temperature changes
Cervical mucous changes
If a cycle lasts longer than 28 days, which phase of the cycle is likely to be the one which lasts longer?
Follicular
How can you confirm ovulation in an individual with irregular cycles?
Midluteal progesterone (day 21) Early follicular phase (day 2-5) - Serum FSH/LH, oestradiol - Serum prolactin, TSH - Free androgen index Progesterone challenge test
What is the progesterone challenge test?
If a patient bleeds a week-10days after a 5 day course of progesterone then this indicates normal oestrogen levels
What radiological investigations can be done to assess ovulation?
Transvaginal USS ovaries to look for ovarian morphology and serial scans to look for follicular growth and ovulation
If required:
MRI pituitary fossa
Bone density scan
What is hypothalamic pituitary failure?
Where the hypothalamus does not release adequate GnRH.
What are the effects of hypothalamic pituitary failure?
Hypogonadotrophic hypogonadism
Oestrogen deficiency
Normal proclatin
Amenorrhoea
What can cause hypothalamic pituitary failure?
Stress Exercise Anorexia Brain/Pituitary tumours Head Trauma Kallman's syndrome Drugs (steroids/Opiates)
How is hypothalamic pituitary failure managed?
Stabilise weight - BMI >19
Give pulsatile GnRH every 90 mins SC or IV (pump worn continuously)
Gonadotrophin daily injections
Need to monitor response with USS
How does hypothalamic pituitary dysfunction manifest itself?
Normal gonadotrophins and oestrogen levels
Anovulation
PCOS
How often is insulin resistance seen in individuals with PCOS?
50-80% of patients
Why does compensatory hyperinsulinaemia occur in individuals with insulin resistance due to PCOS?
There is a normal pancreatic insulin reserve
What do 20% of patients with PCOS and insulin resistance also have?
Frank glucose intolerance and Non-insulin requiring DM
Insulin increases sex hormone binding globulin, what does this do to free testosterone levels?
Increases them and leads to hyperandrogenism
Before any treatment is given for anovulation associated with PCOS, what management should be implemented?
Weight loss Stop smoking + drinking alcohol Go on Folic acid 400mcg/5mg daily Check rubella immunity Check partners semen analysis Check fallopian tube is patent
What is the 1st line treatment for induction of ovulation in a woman with PCOS?
Clomifene citrate - an anti-oestrogen
50-100mg tab given on days 2-6 of the ovarian cycle
Only prescribable for 6-9months
Other than Clomifene citrate, what other treatments exist for ovulation induction in individuals with PCOS?
Gonadotrophin therapy
Laproscopic ovarian diathermy
Metformin - with lifestyle modification (reduces androgen production)
What are the features of ovarian failure?
Increased gonadotrophins
Decreased Oestrogen
What are the causes of ovarian failure?
Premature - Turner syndrome, XX gonadal agenesis, premature menopause
AI ovarian failure
Pelvic radio/chemo
What are the signs and symptoms of premature ovarian failure?
Menopause 30IU/L
Low oestradiol
How is premature ovarian failure treated?
HRT - hormone replacement therapy
Egg or embryo donation
Ovary/egg/embryo cryo-preservation prior to potentially POF causing treatments
Counselling/ support network
What questions should be asked in a history of somebody being investigated for hyperprolactinaemia?
Amenorrhoea?
Galactorrhoea?
Current medications?
What examination is it important to do when investigating hyperprolactinaemia and why?
Visual fields - Invading tumour on optic chiasm
What investigations should be done when investigating hyperprolactinaemia?
FSH/LH (normal) Oestrogen (low) Serum prolactin (high) TFTs (normal) MRI to diagnose micro/macro prolactinoma
How is hyperprolactinaemia treated?
Dopamine agonists
- Cabergoline - longer acting
- Bromocriptine - conventional
Should be stopped when pregnancy occurs
What are the risks of ovulation induction and ART?
Ovarian hyperstimulation
Multiple pregnancy
Potential risk of ovarian cancer if used for >12 months
How common is infertility?
Affects 1 in 6 couples
How is infertility defined?
Failure to achieve a clinical pregnancy after >12 months of regular unprotected sexual intercourse - in absence of any known reason
What is primary infertility?
Infertility in a couple who have never concieved a child
What is secondary infertility?
Infertility is a couple who have previously concieved (pregnancy may not have been successful)
What factors increase the chance of a successful pregnancy?
Woman <2 cups coffee daily
No recreational drugs
What factors decrease the chance of a successful pregnancy?
Woman >35 No previous pregnancy >3 years trying Intercourse mistimed Woman's BMI 30 1 or both partners smoke Caffeine intake = > 2 cups of coffee/day Regular recreational drugs Excess alcohol in either partner
What disorders other than those involved in the gynecological system can cause infertility?
CKD
testosterone secreting tumours
CAH
Drugs: depo-provera, explanom, OCP
What are the infective causes of tubal disease in women?
Pelvic inflammatory disease (STIs etc.)
Transperitoneal spread of appendicitis or an intra-abdominal abscess
Following invasive procedures or surgery of that area
What are the non-infective causes of tubal disease?
Endometriosis Surgical (sterilisation, ectopic pregnancy) Fibroids Polyps Congenital
What are the clinical features of tubal disease in women?
Abdo pain Febrile Cervical excitation Dysmenorrhoea Ectopic pregnancy Vaginal discharge Dyspareunia Menorrhagia Infertility
What is the prevalence of endometriosis?
approx 20%
What is endometriosis?
Presence of endometrial glands outside the uterine cavity
What are the clinical features of endometriosis?
Dysmenorrhoea Dysparenuia menorrhagia painful defecation chronic pelvic pain 'chocolate' cysts on ovary
What is a varicocele?
Varicose veins next to the testis (abnormal enlargement of pampiniform venous plexus in the scrotum)
What are the non-obstructive causes of male infertility?
Genetic - Klienfelters syndrome
Chemo/radio
undescended testes
idiopathic
What clinical features can arise from non-obstructive male infertility?
decreased testicular volume decreased secondary sexual characteristics Vas deferens present high LH/FSH Low testosterone
What are the obstructive causes of male infertility?
Congenital absence (CF)
Infection
Vasectomy
What clinical features are typical of obstructive male infertility?
Normal testicular volume
Secondary sexual characteristics
Vas deferens may be absent
Normal FSH, LH and testosterone
What endocrine disorders can cause male infertility?
Acromegaly Cushings Disease Hyperprolactinaemia Anorexia Hyper or hypothyroidism
What are the causes of erectile difficulties?
Diabetes
Spinal cord injury
Psychosexual
What disorders can affect the sperm?
Rare defects e.g. globospermia, Kortagne’s syndrome
When investigating infertility what examinations should be done of the female?
BMI
Body hair distribution and galactorrhoea
Pelvic exam - uterine and ovarian abnormalities/tenderness/mobility
When investigating infertility what examinations should be done of the Male?
BMI
Gential exam - size/position of testes, penile abnormalities, presence of vas deferens, presence of varicoceles
What investigations should be performed for an infertile woman?
Endocervical swab for chlamydia
Cervical smear if due
Blood for rubella immunity
Midluteal progesterione
What are 2 tests for tubal patency?
hysterosalpingiogram
Laparoscopy
What are the risk factors for a hysterosalpingiogram?
Tubal/pelvic pathology
When is laparoscopy indicated?
In possible tubal/pelvic disease
When is laparoscopy contraindicated?
Obesity
Previous pelvic surgery
Crohns
When would a hysteroscopy be necessary for testing tubal patency?
Suspected or known pathology e.g. uterine septum, adhesions, polyps
When would a pelvic ultrasound be indicated in testing for tubal patency?
When an abnormality is found on pelvic exam
When would an endocrine profile and chromosomal analysis be necessary for testing of tubal patency?
Anovulatory or infrequent periods
Hirsute
Amenorrhoea
What measurements should be taken when performing a semen analysis?
Volume pH Concentration Motility Morphology WBC
If semen analysis is abnormal what other tests should be done when investigating the infertile male?
LH/FSH
Testosterone
Prolactin
TFTs
If semen analysis is severely abnormal/azoospermic then what tests should be performed in the infertile male?
Endocrine profile
Chromosome analysis
Screen for CF (associated with absent vas deferens)
Testicular biopsy
If an abnormality is found on a genital exam of a male then what test should be done next?
Scrotal USS
What are the first line agents used in ovulation induction?
Antioestrogens - Clomifene citrate + tamoxifen
Aromatase inhibitors - Letrozole/Anastrozole (not in UK)
What are the 2nd line agents for ovulation induction?
Clomifene citrate + metformin
Gonadotrophin therapy - daily injections
Laproscopic ovarian diathermy (drilling)
How is male infertility treated?
Surgery for obstructed vas deferens
Intrauterine insemination in mild disease
Intracytoplamic sperm injection into egg (ICSI)
ICSI combined with surgical sperm aspiration from epididymis or testicle
Donor insemination
