Infertility

Question 1

Menstrual cycle

Answer 1

GnRH from hypothalamus -> release FSH and LH from anterior pituitary -> folliculogenesis -> follicles produce oestrogen -> one single follicle becomes dominant follicle and rest degenerate -> oestrogen level rise feedbacks to hypothalamus and leads to LH surge -> ovulation -> the oestrogen provides negative feedback to inhibit FSH -> oocyte released into abdomen -> fimbrae catch oocyte and into fallopian tube -> becomes corpus luteum which secretes progesterone to maintain endometrial lining -> unfertilised corpus luteum degenerates and progesterone levels fall -> menses

Phases:

• Follicular
• Ovulation
• Luteal

Question 2

Female Infertility

Answer 2

Infertility = inability to conceive pregnancy after 12 months of regular, unprotected sexual intercourse (6 months if >35yrs, <6months if >40yrs, or earlier if risk factors e.g. POI, endometriosis, previous chemo/radiation, male impotence, adult male mumps)
Fecundability = probability to achieve pregnancy within one menstrual cycle
Fecundity = probability of achieving a live birth per menstrual cycle

Causes: (* most common)
Primary hypothalamic-pituitary dysfunction
- Eating disorders
- Stress
- Hyperprolactinaemia
- Idiopathic hypogonadotropic hypogonadism
- Pituitary adenoma
- Kallman syndrome
- Trauma/radiation/tumour in hypothalamus or pituitary
- Sheehan's syndrome
Reproductive tract
- Ovulatory dysfunction* - WHO classification
- Endometriosis - anatomical distortion, damage to ovarian tissue by endometrioma and surgical resection, localised inflammation
- Fallopian tube abnormalities* - PID, adhesions
- POI
- Turner's syndrome
- AIS
- Tubal blockage
- Submucosal fibroids
- Uterine anomalies*
- Asherman's sydrome
- Cervical factors - trauma, stenosis, congenital malformations
Medications
- COCP/POP
- Antidepressant/antipsychotics
- Steroids
- Chemotherapy
Others
- Age
- Hyper/hypo thyroidism
- Chronic renal/liver disease
- Cushing's 
- CAH
- Thrombophilia
- Coeliac disease
- Genetics - Kallman's syndrome, Turner's syndrome, AIS, Fragile X
- Lifestyle factors
- Unexplained

Ovulatory disorders WHO classification

• Class 1: hypogonadotropic hypogonadal anovulation - least common; e.g. exercise, stress, low BMI; treat with lifestyle modification or gonadotropins
• Class 2: normogonadotropic normogonadism anovulation - most common; e.g. PCOS; treat with ovulation induction
• Class 2: hypergonadotropic hypogonadism anovulation e.g. POI, gonadodysgenesis; treat with gonadotropin therapy or IVF
• Hyperprolactinaemia

History:

• Duration of infertility
• Fertility in other relationships
• Medical, surgical Hx, gynae Hx, Hx of STI, menstrual Hx, Hx of chemo/radio
• Family Hx
• Medications
• Smoking, EtOH, other drugs
• Sexual dysfunction
• Frequency of intercourse
• Previous infertility testing

Ex:

• BMI, hirsutism, acne, secondary sexual characteristics, goitre
• Abdominal/pelvic exam - masses, cervical abnormalities, cervical motion tenderness, uterine enlargement

Ix:
BASIC
- Menstrual cycle - LH surge in urine prior to ovulation, day 21 progesterone for ovulatory function (must be >30)
- Pelvic US
MORE
- Bloods - bHCG, prolactin, TSH, FSH, testosterone, FAI, SHBG, 17-OHP
- HSG/HyCoSy for tubal patency and uterine cavity anomaly
- Day 3 FSH (must be >10)
- Day 3 oestradiol, AMH, AFC - assess ovarian reserve
- Clomiphene citrate challenge test - provocative test to measure FSH, give clomiphene on cycle day 5-9 and measure day 3 and day 10 FSH and day 3 oestradiol (good ovarian reserve will inhibit FSH, less ovarian reserve will not produce enough ovarian hormones to inhibit FSH so it rises early in the cycle)
- Hysteroscopy +/- curettings if indicated
- Laparoscopy - for endometriosis or other pathology, can do tubal dye test
- Karyotype - if Hx or FHx of POI or recurrent pregnancy loss

Management:

• Lifestyle - weight loss, cease smoking, limiting caffeine/EtOH
• Timed intercourse
• Remove hydrosalpinx - increases success of IVF
• Removal of endometriosis
• Endometriosis - IVF success rates improved if GnRH agonist given 3-6months prior, lap resection improves fertility but does not improve IVF outcomes, lap cystectomy for >4cm improves access to follicles but may reduce ovarian reserve, post op medical treatment does not improve pregnancy rates in mod-severe endo
• Hysteroscopic resection of uterine septum or polyps
• Removal of fibroids - if submucosal or intramural and deforms cavity as it improves fertility and reduces recurrent MC
• Social support

WHO 1 - weight gain, pulsatile GnRH, gonadotrophins
WHO 2 - lifestyle, ovulation induction (clomiphene +/- metformin, lap ovarian drilling)
WHO 3 - IVF, donor egg
Hyperprolactinaemia - dopamine agonist

Ovulation induction:

• Weight modulation
• Clomiphene - for class 2, SERM that increases gonadotropin release
• Aromatase inhibitors e.g. letrozole - adv over clomiphene is less follicles so less multiple pregnancy and shorter half life so less antioestrogen SE
• Metformin - in addition to weight loss
• Laparoscopic ovarian diathermy - to induce ovulation; only if alternate treatments fail
• Bromocriptine - only for hyperprolactinaemia
• ART - if failed all above, for tubal disease, for endometriosis especially if advanced, cervical factors, unexplained infertility (after trying clomiphene and aromatase inhibitors), first line to POI

Question 3

Male infertility

Answer 3

Causes:

• Hypogonadism
• Seminiferous tubule dysfunction
• Erectile dysfunction
• Azoospermia - no sperm
• Oligozoospermia - low sperm
• Teratozoospermia - abnormal sperm morphology
• Adult mumps
• Unexplained

Categories:

• Pre-testicular - hypothalamus (Kallman’s), anterior pituitary (adenomas), erectile dysfunction
• > Low FSH, low testosterone
• Testicular factors - genetic (Klinefelters XXY - produce little or no sperm), trauma (torsion), mumps, radio, chemo
• > Increased FSH, low testosterone
• Post-testicular - disorders of sperm transport (genetic no vas deferens in CF, retrograde ejaculation)
• > Normal FSH, normal testosterone

Ix:

• Hx - medical Hx, surgical Hx, STI, chemo/radio
• Ex - of external genitalia, orchidometer
• Semen analysis - repeat if abnormal in 3months
• Serum testosterone, LH, FSH, prolactin, TFT - only if abnormal sperm
• Scrotal US
• Karyotype
• Screen for CF - in CF, there is no vas deferens so low volume of ejaculate and acidic pH (<7.2); need ART

Mx:

• Lifestyle - cease smoking, loose underwear, no hot tubs
• Pre-testicular - gonadotrophin treatment, can give testosterone but this inhibits spermatogenesis
• Testicular - most factors not correctible, can do ART (IUI, ICSI, IVF), donor sperm
• Post-testicular - surgical correction of obstruction

Start with lifestyle -> clomiphene + IUI or letrozole + IUI -> IVF or laparoscopy -> donor egg -> surrogacy -> adoption

Question 4

Ovulation induction

Answer 4

Always start with weight loss prior to ovulation induction therapy

By disease:

• Hypothalamic amenorrhoea (class 1) -> pulsatile GnRH or gonadotropin
• PCOS -> weight loss, letrozole (first line) or clomiphene
• POI -> IVF with donor oocyte (no benefit with ovulation induction agents)
• Hyperprolactinaemia -> dopamine agonist

CLOMIPHENE - WHO II

• SERM
• Competitive inhibitor of oestrogen binding to oestrogen receptors -> binds to and depletes hypothalamic oestrogen receptors -> no negative feedback onto hypothalamus -> increase in GnRH pulse frequency -> increase in LH and FSH from anterior pituitary -> folliculogenesis -> increased oestrogen -> LH surge -> ovulation
• Risk of OHSS<1%
• Better efficacy if younger, lower BMI, oligo rather than amenorrhoea and low FAI
• Start on day 5 with 50mg daily for 5 days (increase to 100mg then 150mg daily if no ovulation) and continue for 4-6 cycles -> LH surge 5-12 days after last day of clomiphene
• Confirm ovulation by assessing serum progesterone levels are >3ng/mL day 22-25 - serial TV US not recommended due to cost and not improving pregnancy rates
• After 6 cycles and no pregnancy, consider other treatment and consider HSG for tubal patency
• Can give hCG if monitoring by US and no LH surge
• No increase in congenital anomalies
• SE: hot flashes, abdominal bloating, pain, N+V, breast tenderness, ovarian enlargement, multiple gestation, thins endometrium

AROMATASE INHIBITORS - LETROZOLE - WHO II

• Blocks peripheral conversion of testosterone to estradiol (aromatisation) decreased levels stimulate gonadotrophins to stimulate folliculogenesis and ovulation without blocking negative feedback hence no OHSS
• Given day 3-7
• Higher livebirth rates than clomiphene in BMI>30
• Can add FSH to aromatase inhibitor for multiple ovulation for IVF
• Start dose 2.5mg/day up to 5mg then 7.5mg if ovulation has not occurred
• Compared to clomiphene: higher livebirth rate in BMI>30, higher ovulation rate, less SE on endometrial and cervical mucous, more monofollicular development (less multiple pregnancies), shorter half-life
• SE: hot flahes, fatigue, dizziness, visual disturbance

METFORMIN

• In anovulatory women with PCOS, increases cycles and improves spontaneous ovulation
• Insulin sensitiser so reduces serum insulin and androgens to improve ovulation rates
• But does not improve livebirth rates alone or with clomiphene

PULSATILE GnRH THERAPY - WHO I

• Pulsatile GnRH -> increase FSH and LH -> ovulation
• The rise in FSH and LH still keep it within normal range so low risk of OHSS and multiple gestation
• Can give clomiphene beforehand

GONADOTROPHINS - WHO I

• For class 1 or PCOS who have failed weight loss clomiphene and letrozole or pulsatile GnRH not available
• Can give clomiphene beforehand or letrozole as an adjunct with unexplained infertility
• Give LH and FSH initially then hCG when ovarian follicles are mature (hCG mimics LH surge)
• Can give FSH alone in PCOS but LH and FSH for class 1
• Give day 2-5
• Monitor with TV US for follicle diameter and oestrogen
• Risk of OHSS and multiple pregnancy more than GnRH due to FSH stimulating multiple follicles
• If 3 or more follicles >15mm present, stop stimulation by FSH and withhold hCG

LAPAROSCOPIC OVARIAN DIATHERMY

• Second line for PCOS - after letrozole or clomiphene
• Need BMI<30
• Less likely to cause OHSS or multiple pregnancy than gonadotrophins

None of these have been shown to increase risk of ovarian cancer - infertility itself is a risk factor, not the medication to treat it
No increase risk of breast cancer either

Question 5

OHSS

Answer 5

Definition: complication from ART where fluid shifts from intravascular space to third space mainly abdominal cavity

Pathophys:

• Normally, small number of early antral follicles are recruited and one single dominant follicle is selected to ovulate due to LH surge
• In OHSS, large number of small antral follicles are recruited and there is ongoing development of these follicles until ovulation -> excessive vasoactive products released by hyperstimulated ovaries -> increased vascular permeability -> escape of follicular fluid and third space -> intravascular hypovolaemia + oedema/ascites/cardiac renal and lung perfusion

Risk factors:

• Ovarian stimulation with gonadotropins followed by ovulation
• GnRH agonist cycle
• Exogenous HCG
• PCOS
• Previous OHSS
• High AMH or AFC
• > 20 follicles >10mm diameter
• High serum oestradiol
• Pregnancy (due to persistent endogenous hCG)
• Age <30yrs
• Low BMI

DDx:

• Ectopic pregnancy
• Ovarian torsion
• Cyst rupture
• Appendicitis
• Pelvic infection
• Bowel perforation

Onset:

• Early onset - day 4-7 after hCG
• Late onset - >9 days after hCG, usually from early pregnancy and more severe as pregnancy increases hCG

Classification:
- MILD: ovarian enlargement, multiple cysts, abdominal distention/discomfort, mild nausea, normal biochemistry
MANAGEMENT: monitoring, simple analgesia (not NSAIDs), antiemetics, avoid strenuous activity, avoid intercourse, drink to thirst

• MODERATE: ascites on US, enlarged ovaries, worse GI symptoms, biochemistry shows increased haematocrit and WCC
  MANAGEMENT: fluid restriction 1-2L/day, avoid strenuous activity, avoid intercourse, daily weights and AC, daily urine output, bloods every 48hrs, repeat TV US, thromboprophylaxis
• SEVERE: ascites on US, severe abdominal pain, pleural effusion, hypoxia, weight gain, hypovolaemia, oligouria, biochemistry shows increased WCC/Cr, abnormal LFT, abnormal coags, hyponatraemia, hyperkalaemia, consider TV or TA drainage for ascites (if severe abdominal distention and pain, SOB or respiratory comproise, oligouria despite fluid replacement due to increased abdominal pressure)
  MANAGEMENT: admit, supportive care, monitoring bloods, IV isotonic crystalloids or IV albumin, thrombophrophylaxis
• CRITICAL: anuria and AKI, cardiac arrhythmia, DIC, pleural effusion, percardial effusion, sepsis, ARDS, VTE, encephalopathy, cerebral oedema, liver failure
  MANAGEMENT: ICU, strict fluid balance, daily weights and measure AC, bloods, hCG measurements, pelvic US, CXR, thromboprophylaxis, TEDS

Symptoms:

• Abdominal pain
• N+V
• Weight gain
• SOB
• Oligouria

Ix:

• TV US
• Bloods - FBC, UEC, LFT, coags
• Monitoring with serum oestradiol + TV US

Complications of OHSS:

• Pulmonary effusion
• Cardiac failure
• Renal failure
• Liver failure
• VTE
• Ovarian torsion
• Cerebral complications
• PET and preterm delivery in pregnancy

Prevention:

• Recognise risk factors
• Individualise ovarian stimulation regimens to use minimum dose and duration of gonadotropic treatment to ovulate
• Withholding hCG if high serum oestradiol (>3500) or development of many large follicles (>16mm)
• Use lower dose hCG or GnRH antagonist or agonist for final oocyte maturation
• If PCOS, pretreatment with metformin
• Progesterone instead of hCG for luteal phase support
• Frozen instead of fresh embryos
• Dopamine agonist in high risk women receiving hCG - given on day of hCG administration

Question 6

IVF

Answer 6

Process:

• Pharmacologic ovarian stimulation -> suppress ovulation (long - agonist cycle; short - antagonist cycle) -> monitor for follicle maturity with TV US + oestradiol -> trigger ovulation with hCG -> aspirate oocytes from ovaries with US -> fertilise oocytes in lab to form embryo -> embryo transferred into uterus -> progesterone for luteal support until 8wks -> freeze spare embryos day 2 -> test for pregnancy day 14 after egg collection
• This cycle is 2 weeks
• Embryo transfer day 2 or day 5 after fertilisation

Indications:

• Tubal pathology
• Male factor infertility
• POI
• Low ovarian reserve
• Other causes of infertility that did not respond to ovulation induction alone
• Same-sex couples
• PGD - for familial genetic disorders

Factors that impact IVF success:
Evidence for:
- Age of oocytes
- Poor ovarian reserve
- Hydrosalpinx - need salpingectomy
- Smoking
- Obesity
- Previous livebirth - positive impact
Less evidence for:
- Submucosal fibroids
- Endometrioma and endometriosis - surgery can damage ovarian reserve
No evidence for:
- Aspirin, heparin
- Endometrial thickness

IVF risks:

• OHSS
• VTE
• Infection
• Ectopic pregnancy
• PET
• AFE
• Abdominal bleeding
• Allergy
• Anaesthetic complications

IVF increases risk of:

• Multiple pregnancy
• Preterm birth
• Lower birthweight

Causes of IVF failure:

• Follicles not developing due to poor ovarian reserve
• Poor embryo quality
• Sperm abnormality
• Suboptimal ovarian stimulation
• Low endometrial receptivity - e.g. thin endometrium, uterine anomalies
• Inaccurate placement of embryos
• Traumatic ET

Question 7

PCOS and infertility questions

Answer 7

Feb 2017
Question 7 – Ovarian Hyperstimulation Syndrome

A 28year old woman presents to emergency department complaining of vomiting with abdominal pain and bloating. She is currently undergoing an IVF cycle for infertility treatment. She had an oocyte retrieval 10 days ago. You are asked to assess her as she may have ovarian hyperstimulation syndrome (OHSS)

a. Identify her differential diagnosis (3 marks)
- Ovarian cyst rupture
- Ovarian torsion
- Ectopic pregnancy
- Rupture of ectopic pregnancy
- Appendicitis
- Bowel perforation
- PID

b. What factors during her IVF cycle would have increased her risk for developing OHSS? (4 marks)
- Using hCG as an ovulation trigger
- Using gonadotrophins as ovulation induction
- GnRH agonist regime
- Large number of oocytes retrieved
- High dose FSH
- History of PCOS
- History of previous OHSS
- >20 follicles, each >10mm on baseline US
- High serum oestradiol with hCG trigger
- Embryo transfer with positive pregnancy test
- High AMH level
- High AFC
- Age <30years
- Currently pregnant

You organise a transvaginal ultrasound scan and a full blood count.

c. Explain how the results from each of these tests will assist you to assess the severity of her OHSS (2 marks)
- TV US – shows number of follicles, size of follicles - >20 follicles and >10mm diameter shows OHSS
- TV US may also show ascites which increases severity of OHSS (at least moderate)
- TV US may also show pregnancy which increases severity of OHSS
- TV US for signs of torsion
- FBC – increased haematocrit means there is third spacing of fluid and is intravascularly depleted so increases severity as well (at least moderate); also look for increased WCC

d. Provide a detailed discussion of the principles of management of OHSS (6 marks)
- History
o Symptoms – abdominal pain, bloating, bleeding, nausea, vomiting, breast tenderness (symptoms of pregnancy)
o IVF cycle – was hCG used, were gonadotrophins used, what was method of ovulation induction, cycle number if tried before
o History of PCOS
o History of previous OHSS
- Examination
o General – increased weight
o Obs – HR, RR
o Mucous membranes - dry
o BMI
o Hirsutism – for PCOS
o Abdominal exam – ascites (shifting dullness), increased abdominal circumference, tenderness
o Cardiac exam – arrythmias
o Lung exam – pleural effusions/dullness at bases
o Neuro exam – confusion, consider cerebral event
- Ix
o TV US – follicle size and number, ascites, pregnancy
o bHCG – pregnancy
o FBC – haematocrit
o UEC – electrolyte imbalance (hyponatraemia, hyperkalaemia), increased creatinine for AKI
o LFT – transaminitis
o Coags – abnormal coags
- Mx
o Based on symptoms, examination and investigation – discuss with senior gynaecologist whether admission is required
o If admission not required (mild, some moderate)
 Discharge home with follow up in next 2-3 days with IVF provider to repeat examination and bloods to ensure it is not worsening
 Drink to thirst
 No strenuous exercise
 No intercourse
 Simple analgesia – avoid NSAIDs
 Anti-emetics
 Advised to present if worsening
o If admission required (some mod, for severe or critical)
 Inform IVF provider
 Consider ICU referral
 Drink to thirst – only need IV fluids or albumin if severely intravascularly depleted
 Avoid diuretics
 VTE prophylaxis (clexane or heparin) and TEDS
 Analgesia – avoid NSAIDs
 Antiemetics
 Strict fluid balance
 Urine output
 Consider invasive monitoring if critical
 CXR – for pleural effusion
 Echo – for pericardial effusion
 CTPA if required
 Ascites – may require transabdominal or transvaginal drainage for symptom relief, and consider albumin replacement

 
Feb 2016
Question 10 - infertility

You are seeing a couple that has been trying to conceive for 2 years. Mr Smith is a healthy 32 year old. His semen analysis is normal. Mrs Smith is 34 years old. She has always had an irregular menstrual cycle, averaging every three months. Her BMI and physical examinations are normal. Her recent pelvic ultrasound shows 16 antral follicles in the right ovary and 18 antral follicles in the left ovary. Her tubes are bilaterally patent.

a. i) Outline the Rotterdam consensus criteria for the diagnosis of polycystic ovarian syndrome (PCOS) (2.5marks)
Need 2 of 3:
- Oligo or anovulation
- Clinical (acne, hirsutism on Ferriman-Gallwey score) or biochemical (high FAI, low SHBG, high free testosterone) hyperandrogenism
- Polycystic ovaries on ultrasound - >12 follicles per ovary 2-9mm or >10mL volume
- Exclude other causes of hyperandrogenism: Cushing’s syndrome, congenital adrenal hyperplasia, androgen secreting tumour

ii) Outcome the reasons why Mrs Smith has PCOS (1.5 marks)
- Fulfils 2 of the 3 criteria for oligo or anovulation with irregular cycles and polycystic ovaries on ultrasound as there are more than 12 follicles per ovary
- ? does this refer to pathophysiology

iii) List two other causes of anovulation that would need to be excluded (1 mark)
- Pregnancy
- Hyperprolactinaemia
- Hypothyroidism
- POI

b. Describe the pharmacological effects on the hypothalamic-pituitary-ovarian axis which result in clomiphene citrate increasing ovulation (4 marks)
- Clomiphene is a selective oestrogen receptor modulator – oestrogen agonist and antagonist properties
- Competes for oestrogen receptors in hypothalamus and depletes receptor concentration
- Circulating levels of oestrogen perceived by hypothalamus to be less
- Less free oestrogen means no negative feedback on hypothalamus so there is increased secretion of GnRH and therefore FSH and LH
- Increased FSH and LH from anterior pituitary causes folliculogenesis and oestrogen levels rise
- LH surge causes release of single dominant follicle and ovulation

c. Outline step by step your plan for Mrs Smith using clomiphene citrate:
i) First clomiphene citrate cycle (4 marks)
- Check not pregnant
- Induce withdrawal bleed with progesterone for 5 days if not menstruating frequently
- Can add metformin which improves ovulation in women with PCOS if BMI>30
- Start at low dose 50mg daily on day 5 of cycle and take for 5 days
- LH surge which usually occurs 5-12 days after completing clomiphene
- Ovulation 48hrs after LH surge
- For timed intercourse after ceasing clomiphene
- Confirm ovulation by assessing serum progesterone levels are >3ng/mL day 22-25
- Consider TV US as may not proceed with ovulation induction if high number of follicles >20 or high oestradiol levels >300 – this will be after ovulation, to avoid OHSS/multiple pregnancy, advised to avoid intercourse

ii) Subsequent clomiphene cycles assuming she is not pregnant (2 marks)
- Can increase dose to 100mg daily for next cycle then 150mg daily for another cycle but this is maximum dose
- However, monitor carefully for OHSS and multiple pregnancy
- Monitor number of follicles with TV US and oestradiol levels
- After 6 cycles and no pregnancy, consider other ovulation induction medications such as letrozole or for other causes of infertility or IVF

 
July 2015
Question 9 – Polycystic Ovarian Syndrome

Ovulation is a coordinated process that results in the release of a single mature oocyte.

a. i) Outline the sequential changes in gonadotrophins and ovarian hormone levels which occur from the start of the menstrual cycle to produce ovulation (2 marks)
- GnRH from hypothalamus -> release FSH and LH from anterior pituitary -> folliculogenesis -> FSH acts on ovary to produce oestrogen -> one single follicle becomes dominant follicle -> oestrogen level rise leads to LH surge -> ovulation -> oestrogen provides negative feedback to inhibit FSH -> oocyte becomes corpus luteum which secretes progesterone -> unfertilised corpus luteum degenerates and progesterone levels fall -> menses

iii) Correlate the hormonal changes with the changes in ovarian physiology which occur during the menstrual cycle and result in ovulation (2 marks)
- Follicular phase: primordial follicle recruitment, primary follicle and antral follicle form, dominant follicle selected for ovulation
- Ovulation: oocyte released from follicle
- Luteal phase: corpus luteum forms and degenerates if pregnancy does not occur

28 year old nulligravia with a BMI of 36, presents with amenorrhoea and anovulation. A recent pelvic ultrasound shows polycystic ovaries.

b. Summarise the biochemical/hormonal and ovarian pathophysiologic mechanisms associated with anovulation in this patient (5 marks)
- Increased androgens (testosterone) -> convert to oestrogen -> feedback to hypothalamus and pituitary to suppress LH and FSH -> no ovulation
- Less FSH -> less folliculogenesis
- High LH -> persistently high oestrogen levels due to increased adiposity and fat cells releasing oestrogen -> no rise in oestrogen to trigger LH surge and ovulation
- Insulin -> suppresses SHBG -> increase free testosterone

c. i) Name the two (2) most likely metabolic conditions she may have (2 marks)
- Polycystic ovarian syndrome
- Type 2 diabetes
- Obesity

ii) Outline the criteria you would use to diagnose each of these conditions (3 marks)
- Rotterdam criteria:
Need 2 of 3:
- Oligo or anovulation
- Clinical (acne, hirsutism on Ferriman-Gallwey score) or biochemical (high FAI, low SHBG, high free testosterone) hyperandrogenism
- Polycystic ovaries on ultrasound - >12 follicles per ovary 2-9mm or >10mL volume
- Exclude other causes of hyperandrogenism: Cushing’s syndrome, congenital adrenal hyperplasia, androgen secreting tumour

• Type 2 diabetes – fasting BSL >6.9mmol or random BSL or 2hr BSL >11.1 mmol

d. Name one (1) further long term health consequence this patient is at risk from developing as a result of her condition. Outline a strategy available to reduce her risk of developing this long term problem (1 mark).
- Cardiovascular disease
- Weight loss and exercise (30 mins aerobic exercise/day)

July 2019
PCOS and ovulation induction

A woman with oligomenorhoea, normal BMI. Husband NAD. 18 months no pregnancies. HyCoSy NAD.
You suspect she has PCOS.

a) What three investigations would you order to exclude other causes and the expected findings to diagnose them. You may use a table.
Investigations Cause to exclude Findings for diagnosis
Prolactin Hyperprolactinaemia High prolactin level
21 hydroxylase Congenital adrenal hyperplasia 21 hydroxylase deficiency, 17-OHP high
TSH, T3, T4 Hypothyroidism High TSH, low T3, low T4
FSH, LH, oestrogen Hypogonadotropic hypogonadism Low FSH, LH, low oestrogen

b) What is the pharmacological classification of clomiphene and Letrozole and their mechanisms of actions. You may use a table to answer.
Medication Clomiphene Letrozole
Pharmacological classification Selective oestrogen receptor modulator (SERM) Aromatase inhibitor
MOA Partial agonist and antagonist for oestrogen receptors in hypothalamus causing depletion of oestrogen receptors, no negative feedback on hypothalamus, increase in FSH and LH and ovulation Prevents convention of androgens to oestrogen so less oestrogen, no negative feedback on hypothalamus, increase in FSH and LH and ovulation

c) Letrozole is often used off label as the first line for ovulation induction, what are its benefits when compared to clomiphene.
- Less likely to cause OHSS
- Less likely to contribute to multiple pregnancy as leads to formation of one dominant follicle rather than many follicles
- More live birth rates than clomiphene for PCOS in BMI>30
- Higher ovulation rate
- Less side effects on endometrium (less likely to be thin) and cervical mucous
- Shorter half life

d) Compare the use of letrozole to gonadotrophins for ovulation induction in this woman.
- Letrozole: shorter half life, less likely to cause multiple pregnancies, less likely to cause OHSS
- Gonadotrophins: more likely to cause multiple pregnancies, more likely to cause OHSS

e) What is the indication for ovarian drilling /diathermy in this woman?
- If letrozole or clomiphene do not work for ovulation induction after multiple cycles
- Does not have low AMH as ovarian diathermy can reduce ovarian reserve
- BM<30 – less operative risk
- Less likely to cause OHSS or multiple pregnancy than gonadotrophins
 
August 2012
Question 12

A 30 year old woman presents with a 6 months history of amenorrhoea after stopping the oral contraceptive pill (COCP). She has been on the COCP for 10 years and recalls that she had normal menses prior to starting the COCP. She has a normal BMI and serum prolactin level. Her husband has a normal semen analysis. She wants to get pregnant and is asking what can be done so she can start to ovulate.

a. List 3 categories of ovulation dysfunction relevant in this woman. Give one example of each category (3 marks)
- WHO class 1: hypogonadotrophic hypogonadism e.g. anorexia nervosa
- WHO class 2: normogonadotrophic normogonadism e.g. PCOS
- WHO class 3: hypergonadotrophic hypogonadism e.g. POI

b. Further investigation indicates that she has polycystic ovarian syndrome (PCOS)
i) List the pharmacological ovulation induction agents that may be considered for use in this woman (3 marks)
- Clomiphene (SERM)
- Letrozole (aromatase inhibitor)
- Gonadotrophins – FSH / LH
- Pulsatile GnRH
- Metformin with clomiphene
ii) Outline briefly the mode of action of each agent (3 marks)
- Clomiphene: selective oestrogen receptor modulator – binds to oestrogen receptors in hypothalamus to deplete them -> less peripheral oestrogen -> less negative feedback on hypothalamus -> secrete GnRH -> FSH and LH secrete from anterior pituitary -> folliculogenesis -> oestrogen secreted -> LH rise -> ovulation
- Letrozole: aromatase inhibitor – prevents androgens becoming oestrogen -> less peripheral oestrogen -> stimulate FSH and LH secrete from anterior pituitary -> folliculogenesis -> oestrogen secreted -> LH rise -> ovulation
- Gonadotrophins (LH and FSH, +/- hCG) – exogenous LH and FSH to cause folliculogenesis, oestrogen secretion, LH surge and ovulation; can give hCG to mimic LH surge but increases risk of OHSS
- Metformin: insulin sensitiser so reduces serum insulin and androgens to improve ovulation rates

c. List the risks for this woman associated with
i) Ovulation induction (2 marks)
- OHSS
- Multiple pregnancy
- Nausea/vomiting, hot flushes, visual disturbance
- Failed ovulation induction
ii) PCOS (4 marks)
- Infertility
- OHSS
- Metabolic syndrome
- Insulin resistance / diabetes
- Cardiovascular disease
- Hypertension
- OSA
- Endometrial hyperplasia and cancer
- Depression/anxiety

 
2013 February SAQ

Question 2
Alison and Richard are referred to you for assessment of primary infertility.

a. Define infertility in the context of this couple. (1 mark)

Not conceiving after 12 months of frequent, unprotected intercourse. If maternal age >35 years, this can be 6 months.

Alison is aged 38 years. She has a regular 32 day cycle. Her baseline investigation results are as follows (normal ranges in brackets): 
o	Day 3 FSH 14 U/L (3-10) 
o	Day 21 Progesterone 14 nmol/L (>15) 
o	Rubella Immune 
o	Testosterone 0.9 nmol/L (0.2-1.8) 
o	Serum hormone binding globulin 78 nmol/L (30-110) 
o	Free androgen index 1.2% (0.3-4.0) 
o	AMH 7 pmol/L (14-30) 
o	TSH 5.0 mU/L (0.5-4.5) 
o	Prolactin 175 mIU/L (150 – 450) 

b. Interpret these results. (3 marks)

High FSH – FSH being secreted from anterior pituitary to attempt to stimulate oocyte formation and folliculogenesis and oestrogen secretion however, there is less oestrogen secretion from the ovaries so less negative feedback onto anterior pituitary so FSH is high and trying to stimulate ovaries; suggests low ovarian reserve and predicts poor response to ovarian stimulation; needs to be repeated >1 month apart
Low day 21 progesterone – has not ovulated yet; with 32 day cycle, need to do it 4 days later (day 25) to confirm ovulation; does not necessarily mean she will not or cannot ovulate
Low AMH – low ovarian reserve which could be contributing to infertility as less oocytes to mature and ovulate; less likely to respond to ovarian stimulation but does not predict ability to conceive
High TSH – underlying hypothyroidism; check T4 to confirm if clinical or subclinical and may require treatment

c. Richard smokes 20 cigarettes per day and he also uses marijuana daily. His semen analysis findings are as follows (normal ranges in brackets):
• Volume: … 1.5 ml (>1.5 ml)
• Sperm concentration: … 14 million /ml (> 15 million/ml)
• Total sperm number per ejaculate: … 21 million (>39 million)
• Morphology: … 3% normal forms (>4%)
• Vitality: … 60% live (>58%)
• Motility – progressive: … 20% (>25%)
• Total motility (progressive + non-progressive): 40% (>50%)

Richard comes to you for a follow-up consultation regarding his semen analysis results. Discuss the important issues you should counsel him about. (7 marks)

Lifestyle:

• Cease or reduce smoking and marijuana as these impact quality of sperm, cause abnormal sperm and reduce number of sperm
• Reduce BMI if it is high, aim <30
• Less tight underwear
• Less hot environments e.g. sauna

Semen analysis:

• Results – oligospermia with low volume of semen; may be incomplete collection
• Need to repeat sperm analysis 3 months later for accurate information – encourage abstinence for 2-5 days
• Male infertility is solely responsible in 20% of couples and contributes in 30-40% of couples
• Review medical history, examination, previous pregnancies with other women, cardiovascular disease risk factors, history of STI/testicular torsion/mumps/radiation etc, alcohol use
• However, lifestyle changes important as these can affect results
• If changes still persist, need to discuss alternative solutions for pregnancy
• Encourage ongoing unprotected, frequent intercourse and discuss regular ejaculation
• Discuss erectile dysfunction if it is an issue
• However, may require alternatives including ICSI (intracytoplasmic sperm injection) as the sperm motility is low and therefore IUI (intrauterine insemination) and spontaneous pregnancy less successful as this involves direct injection of sperm into oocyte for fertilisation so overcomes issue of sperm motility

d. Alison asks about having her tubes checked.
i) List 3 investigations that could be used to check Alison’s tubes. (1 mark)
- Laparoscopy and dye studies
- HyCoSy (hysterosalpingo-contract sonography)
- Pelvic ultrasound
- HSG (hysterosalpingogram)

ii) List an advantage for each investigation. A different advantage must be given for each investigation. (1.5 marks)

• Laparoscopy and dye studies – can also look for other causes of infertility such as endometriosis
• HyCoSy – can look for uterine anomaly
• Pelvic ultrasound – can look for hydrosalpinx
• HSG – provides info on proximal or distal occlusion, tubal architecture

iii) List a disadvantage for each investigation. A different disadvantage must be given for each investigation. (1.5 marks)
You may use a table to answer the question.

• Laparoscopy and dye studies – requires surgery and anaesthetic
• HyCoSy – expensive and not readily available in all radiography places as it requires specialised equipment
• Pelvic ultrasound – does not show patency of tube
• HSG – low sensitivity, discomfort during procedure, exposure to radiation

 
2014 July SAQ
Question 9 - Hirsutism

a. Regarding the Ferriman-Gallway hirsutism scoring system:
i) Briefly describe this hirsutism scoring system. (3 marks)
- Scoring system is based on 9 different body areas (upper lip, chin, chest, abdomen, pubic region, arms, thighs, upper back, lower back) and are graded 1 to 4 based on amount of hair in each area
- Total score is added and number informs where there is mild, moderate or severe hirsutism
- <8 = normal
- 8-15 = mild
- >15 = moderate or severe

ii) Name 2 potential problems in the clinical utility of this scoring system. (2 marks)
- Is subjective – bias in interpretation of amount of hair
- Ethnicity influences amount of hair and may not be pathologic
- Laser hair removal can influence result

You are asked to see a 12 year old girl who reports an increase in thickening of hair on her back and face, consistent with hirsutism.

b. List 3 possible conditions that could cause this clinical finding. (3 marks)
- PCOS
- CAH
- Cushing’s syndrome
- Hyperprolactinaemia
- Virilising ovarian tumour
- Adrenal tumour

c. With respect to the conditions you have listed above:
i) List 4 important pathology tests you would perform to help to distinguish between each condition. (4 marks)
ii) Tabulate the test results [Normal (N), increased (inc) or decreased (dec)] you might expect for each condition. (3 marks)

• PCOS – normal 21 hydroxylase, increased testosterone, reduced SHBG, increased FAI
• CAH – less 21 hydroxylase, normal testosterone, normal SHBG, normal FAI
• Cushing’s syndrome – normal 21 hydroxylase, normal testosterone, normal SHBG, normal FAI

Condition	LH:FSH	FAI	Testosterone	DHEAS
PCOS	Inc	Inc	Inc	N
Virilising ovarian tumour
-	Sertoli-leydig cell tumour
-	Granulosa-theca cell tumour	N	N	Inc	N
Adrenal tumour	N	N	N	Inc
Congenital adrenal hyperplasia				
Severe insulin resistance syndromes				
Hyperprolactinaemia				
Cushing’s syndrome				

 
February 2015
Question 7 – tubal disease and infertility

You are called to the operating theatre to attend a laparoscopy being performed by the general surgeons. The patient is a 22 year old non-pregnant nulligravida with an acute abdomen with presumed acute appendicitis. The only obvious abnormality the surgeons have noted is a right hydrosalpinx.

a. Outline and justify the intra-operative steps required to manage this patient. (6 marks)
- Check history – any symptoms or history of hydrosalpinx, any history of STI, any history of infertility, any previous pregnancies
- Check symptoms she presented with
- Check examination findings
- Need to look around the abdomen to look for other abnormalities – signs of endometriosis, signs of PID, adhesions, Fitz-Hugh-Curtis syndrome
- Look at other tube to see if it is normal and do methylene blue dye test to see if it is patent
- Look at ovaries for cysts
- Check consent form – unlikely to have been consented for further than appendicectomy
- Can call next of kin and discuss results – explain that if she is trying to conceive, hydrosalpinx likely affecting fertility especially if wanting IVF; however, if not currently causing issues can leave and monitor in outpatient gynaecology clinic follow up
- Cannot remove fallopian tube if not consented for this
- Take pelvic washings and any purulent discharge
- Discuss plan with senior gynaecologist and see if agreeing with plan
- Likely surgeon will remove appendix anyway
- Post-operatively, debrief patient and document intra-op findings and take pictures if possible
- Organise gynaecology clinic follow up with outpatient pelvic ultrasound

b. List:
i) The common microorganisms that this patient should be treated for postoperatively. (1½ marks)

ii) For each microorganism, name the appropriate antibiotic to be used. (1½ marks)
(Use a table to set out your answer)

Chlamydia – STAT azithromycin 1g PO or doxycycline 100mg BD for 14 days
Gonorrhoea – ceftriaxone 500mg IV
Gardnerella and mycoplasma – metronidazole 400mg PO for 14 days

c. Excluding subfertility, list the long-term sequelae associated with hydrosalpinx. (3 marks)
- Pain
- Infection
- Rupture of fallopian tube causing widespread infection and sepsis
- Ectopic pregnancy
- Dyspareunia
- Recurrent PID

d. List 3 management options for infertility associated with bilateral hydrosalpinges and describe a different benefit for each option. (3 marks)
- Attempt natural conception – avoid costs of IVF
- Bilateral salpingectomy + IVF – improves success of IVF
- IVF alone – avoid salpingectomy surgery
- ICSI – less expensive than IVF
- Surrogacy – does not rely on own ovum quality

 
Feb 2009
Question 7 – Pre-pregnancy counselling

A 32-year-old nulliparous woman seeks your advice for pre-pregnancy counselling. She has essential hypertension which was previously thoroughly investigated and is now well controlled on an ACE inhibitor. Her partner has a brother severely affected by classical cystic fibrosis. Her body mass index (BMI) is 42 and blood pressure is 135/85. She has had no other medical problems.

a. List the possible effects that her BMI could have on her fertility and pregnancy.

Fertility – increased risk of:

• Subfertility
• Miscarriage
• Not suitable for IVF
• Anovulation due to BMI and subfertility

General:
- Increased risk of cardiovascular disease, OSA, hyperlipidaemia

Antenatal - increased risk of

• LGA
• Gestational diabetes / T2DM
• Essential hypertension with superimposed pre-eclampsia
• VTE
• Abruption
• Preterm labour
• UTI
• Difficult growth US
• Congenital anomalies
• Stillbirth

Intrapartum:

• Obstructed labour
• OASIS tears
• PPH
• Shoulder dystocia
• Difficult instrumental
• Difficult caesarean section
• Difficult to monitor with external CTG
• Difficult IV access
• Increased IOL
• Reduces success of VBAC
• Increased failure of epidural/spinal
• Increased risk of aspiration under GA
• Difficult intubation
• Post-op atelectasis

Postpartum:

• Caesarean section wound infection
• UTI
• Endometritis
• VTE
• Pressure sores
• Prolonged hospital stay

Neonatal:

• Mortality
• Jaundice
• Hypoglycaemia
• Childhood obesity

b. What advice would you (or a medical geneticist) give regarding her concern of having a child with cystic fibrosis?
- Is an autosomal recessive condition so if her partner’s brother is affected with both genes, both his parents are carriers so 50% chance he is a carrier
- Would recommend he is tested and to test herself as 25% chance of offspring having cystic fibrosis and 50% chance of baby being a carrier
- If both carriers, need to see geneticist regarding pre-pregnancy counselling
- Can offer IVF + PGD or can become pregnant with natural conception and test baby with amniocentesis or chorionic villus sampling or post delivery neonatal screen
- Would discuss whether diagnosis of CF would affect their decision to continue pregnancy

c. What other steps would you recommend prior to pregnancy?
- Essential hypertension
Cease ACE inhibitor as teratogenic and change to medication known to be safe in pregnancy
(labetalol, methyldopa) and monitor BP
Want BP well controlled due to risk of PET
Baseline bloods to check for renal or liver impairment, and urine PCR
Consider commencing aspirin in 1st trimester after confirming viable pregnancy
- Oral glucose tolerance test or HbA1c
Check for pre-existing diabetes due to risk factors (BMI, hypertension)
Refer to endocrinologist for pre-pregnancy BSL stabilisation if required
- BMI 42
Weight loss – all the above conditions increased with BMI
Diet, nutrition, exercise
Refer to dietician if required
- Pre-pregnancy vitamins
Commence multivitamin/elevit
High dose folate 5mg/day due to BMI
- Normal serology and baseline bloods
Rubella immunity
Iron supplements if needed
- CST up to date
- Psychosocial wellbeing
 
Feb 2011
Question 4

A couple presents to you for investigation of primary infertility. A semen analysis reveals
severe oligospermia.
a. What lifestyle factors can contribute to oligospermia? (3 marks)
- Smoking
- Other drugs – marijuana
- Tight clothing
- Heat e.g. sauna
- Exposure to radiation, pesticides
- Increased BMI
- Poor ejaculation – actually has more sperm but not indicated in this sample

b. Which commonly used drugs depress sperm quantity and quality? (3 marks)
- Smoking
- Alcohol
- Antidepressants
- Chemotherapy
- Spironolactone
- Anabolic steroids
- Tetracyclines
- Sulfasalazine
- Findasteride

c. The male member of your couple is able to adjust some adverse lifestyle factors which
were contributing to the oligospermia. When will you order a repeat semen analysis to
see any beneficial effect? Justify your answer. (2 marks)
Repeat in 3 months – takes 3 months for spermatogenesis to occur so the effects of change in lifestyle factors will not be seen earlier

d. If the semen analysis had revealed azoospermia, what extra investigations could be
appropriate for the male partner? Justify each investigation. (7 marks)
- History – of cancer, mumps, radiation, undescended
- Examination – of testicles too look for size, abnormalities
- Karyotype – look for genetic conditions contributing e.g. fragile X, Klinefelters, Y gene deletion
- Cystic fibrosis screen – could have absent vas deferens
- Prolactin – for hyperprolactinaemia
- TSH – for thyroid dysfunction
- Testosterone, FAI, DHEAS – low levels of androgen could be contributing to less sperm
- FSH, LH – if less stimulation from pituitary then less sperm production
- Testicular ultrasound – varicoele, tumour, obstruction
- Testicular biopsy – for obstruction cause

 
February 2019 - PCOS

a) Describe the ovarian/pituitary axis
- Hypothalamus secretes GnRH -> stimulates anterior pituitary to secrete FSH and LH -> stimulates ovaries to secrete oestrogen and stimulate folliculogenesis, LH stimulates androgen production from thecal cells
- Excess oestrogen or progesterone has negative feedback onto anterior pituitary and hypothalamus to reduce secreting FSH/LH and GnRH respectively

b) The physiology of ovulation
- Hypothalamus secretes GnRH -> stimulates anterior pituitary to secrete FSH and LH -> stimulates folliculogenesis and production of androgen from thecal cells -> follicles created in ovary and single dominant follicle is chosen -> follicles also secrete oestrogen -> dominant follicle stays and rest degenerate -> when oestrogen reaches specific level, triggers LH surge and inhibits FSH -> ovulation and single dominant follicle is released -> becomes corpus luteum to await fertilisation and secretes progesterone -> endometrium builds up in preparation for fertilisation -> if fertilisation doesn’t occur the corpus luteum degenerates -> no progesterone secreted to maintain endometrial wall lining -> menses

c) Hormone pathophysiology of PCOS
- Driven by hyperandrogenism and increased oestrogen
- In PCOS, there is excess androgens that convert to oestrogen, excess oestrogen secreted by adipose tissue and increased LH/FSH ratio
- This excess oestrogen contributes to persistent high oestrogen which means there is no trigger for LH surge so ovulation does not occur or occurs irregularly
- Insulin suppresses SHBG and increases free testosterone and FAI

d) How would you counsel a woman about the long term PCOS
- Mainstay of treatment is weight loss, diet, exercise
- Hormonal treatment of COCP for ovulation
- Metabolic risks – CVD, obesity, insulin resistance/T2DM, OSA
- Endometrial hyperplasia and cancer
- Depression/anxiety
- Infertility - can have ovulation induction

 
February 2018
Question 9 – Male Infertility

a. They gave a semen analysis and you had to describe what sort of infertility it was.
• Want > 1.5mL, >15million/mL, motility > 40% (progressive > 32%), morphology > 4%
• Single defect = mild (IUI), 2 = moderate (IVF), 3 = severe (ICSI)

b. What could have caused it?
• For all parameters – think
o Collection/processing prob (frequent ejaculation for volume/[ ]; infrequent for motility)
o Drugs (smoking, marijuana, cocaine)
• Low volume/[ ] – think CBAVD, hypogonadotrophic hypogonadism, infective, genetic
• Low motility – think sperm antibodies, varicocoele, iatrogenic
• Low morphology – think idiopathic, iatrogenic

c. What investigations would you do?
•	If think poor collection – repeat semen analysis in 2/52, ensure correct advice re: abstinence for 3-4/7, keeping warm and getting to lab ASAP
•	FSH, LH, testosterone
•	CBE, EUC, LFTs, Fe studies
•	TFTs, PRL
•	STI screen (chlamydia, gonorrhoea)
•	Mumps serology
•	Urine MCS
•	USS scrotum (varicocoele, CA)
•	If suspect CBAVD – MRI prostate

d. They then had an azoospermia and you had to say what genetic investigation you’d do.
• Karyotype (Klinefelter XXY), balanced translocation and CF mutation
• Y chromosome microdeletion test

 
October 2020 – Male infertility

1. Interpret semen analysis
   - Oligospermia
2. List 2 reasons why this would be, and the expected results for TSH, prolactin, FSH, testosterone level for each condition
   - Cystic fibrosis - normal all bloods
   - Kallman’s syndrome – normal TSH, normal prolactin, low FSH, low testosterone
   - Hyperprolactinaemia – low TSH, high prolactin, low FSH, low testosterone
   - Anabolic steroids – normal TSH, normal prolactin, low FSH, low testosterone
3. All those results came back normal. Now what investigation will you do and justify (3)
   - Karyotype – look for abnormalities e.g. Klinefelter’s (XXY) as this causes little to no sperm production
   - Scrotal ultrasound – abnormal size, inflammation, can affect production of sperm
   - Cystic fibrosis screen – may be affected and have absent vas deferens, autosomal recessive
4. If this person had absence of vas deferens, what difference in the semen analysis would you see?
   - Low volume ejaculate
   - Low sperm or no sperm
   - Acid pH <7.2
5. What genetic abnormality associated with absence of vas deferens?
   - Cystic fibrosis