O&G JC111: I Want To Have A Baby: Male And Female Infertility

Question 1

Infertility

Answer 1

A disease characterised by failure to establish a clinical pregnancy after 12 months of regular unprotected sexual intercourse

Failure to achieve pregnancy with unprotected intercourse
- within **12 months in women <35
- within **6 months in >35

Epidemiology:
- 10-15% couples affected

Question 2

Normal fertility components

Answer 2

1. Sperm production
2. Follicle development (FSH) + ovulation (LH)
3. Fertilisation + Embryo (implantation after 6-7 days of fertilisation)

Question 3

Pregnancy rate

Answer 3

Peak monthly pregnancy rate: ~30%
- cumulative pregnancy rate in 1 year ~80% (~60% in recent studies)
- cumulative pregnancy rate in 2 years ~90%

Important in interpretation of pregnancy rate by assisted methods

Question 4

***Causes of infertility

Answer 4

Multiple factors common

5 important causes:
1. Ovulatory dysfunction / Anovulation
2. Tubal problems
3. Endometriosis
4. Male factors
5. Unexplained (after exclusion of presence of ovulation + patent tube + normal semen)

Female factors (2/3 cases):
1. **Ovulatory (15%)
2. **Tubal (20%)
3. ***Endometriosis (25%)
4. Others: Cervical, Immunological, Coital

Male factors (1/3 cases):
1. **Subnormal sperms due to production defects (e.g. idiopathic, endocrine, trauma, genetic)
2. **Obstruction defect —> No sperms (e.g. absent vas, vasectomy, infection)
3. Coital

Unexplained:
- Infertility despite Normal ovulation + Patent tube + Normal sperm

Question 5

Endometriosis

Answer 5

Causes of Endometriosis:
- **Sampson theory
—> **Retrograde menstruation: Menstrual blood spread backwards
—> implant into different areas (unknown area)
—> causes ***adhesion
—> affect tubal function
—> infertility

Question 6

History taking of Infertility

Answer 6

Female:
1. Age
2. **Menstrual period (regularity: 21-35 days + <=4-5 days variation between cycles)
3. **History of pelvic infection / surgery (potential tubal problems)
4. Previous investigations / treatment

Male:
1. Age (less important) / **Occupation (hot temp exposure e.g. chef, chemical exposure)
2. Past health
3. Coital history
4. **Smoking / Alcoholic (less predictable effect)

Question 7

P/E of Infertility

Answer 7

Female:
1. Body weight (obese / overweight)

2. Vaginal examination
   - **Uterine size (↑ in adenomyosis, fibroid)
   - **Mobility (adhesions)
   - ***Adnexal mass (e.g. endometriosis)

Male:
1. ?Necessary (if normal semen analysis)
2. **Testicular size (↓ if azospermia)
3. Vas + Epididymis (induration, absence that may indicate obstruction)
4. **Varicocele (associated with ↓ sperm quality)

Question 8

Early referral to Assist reproduction unit

Answer 8

More detailed investigation + early treatment

Female:
1. **>35 yo
2. **Irregular cycles (indicate anovulation: may need drug to induce ovulation)
3. Previous pelvic surgery
4. Previous STD (higher risk of obstruction)
5. Abnormal pelvic examination

Male:
1. **Systemic illness
2. Previous genital pathology
3. Previous STD
4. **Varicocele
5. Abnormal genital examination

Question 9

***Investigations of Male infertility

Answer 9

**Basic investigations only
1. Semen analysis
- give a lot of information
- non-invasive
- **2-3 samples after 2-3 days of ***sexual abstinence

WHO criteria (2010):
- Volume: >=1.5 ml
- Concentration: >=15 million/ml
- Motility: >=32% forward motility
- Morphology: >=4%
—> 1 abnormal semen sample —> repeat semen analysis in 2-3 months
- ***Low predictive values: Extensive overlap between fertile + infertile semen analysis

Other investigations:
2. ***Hormonal assay
- FSH, Prolactin, Testosterone

3. ***Karyotype + Y microdeletion for testicular failure
4. Vasogram (if suspect obstruction)
5. Testicular biopsy (not routine, diagnostic and may be of prognostic value, can be therapeutic —> freeze sperm if sperm present)

Question 10

***Causes of Male infertility

Answer 10

1. Disorders of testicular control (by higher centres) (Pre-testicular)
   - Hypothalamic-pituitary disorders
   - **Hypogonadotrophic hypogonadism
   - **Hyperprolactinaemia
2. Primary testicular disorders (Testicular)
   - **Chromosomal: Klinefelter’s syndrome (47XXY)
   - **Varicocele / Testicular hyperthermia
   - Infections (Mumps)
   - **Trauma (testicular torsion)
   - **Cryptorchidism (high temp)
   - Previous RT / Chemotherapy
   - Chronic illness
3. Obstructive disorders (Post-testicular)
   - Infections
   - ***Congenital absence of vas
   - Surgery (Vasectomy)
4. Genetic causes
   - Klinefelter’s syndrome
   - ***Y chromosome microdeletions
   —> 3 deletion regions (AZFa to AZFc) of Yq11 linked with male infertility
   —> different deletion regions affect distinct + separate phase of spermatogenesis
   —> poor prognosis
   —> all deleted —> severe azospermia

Question 11

***Investigations of Female infertility

Answer 11

Investigations of Anovulation
1. Ovulation
- Regular cycle:
—> Serum ***Mid-luteal progesterone levels (21st day: a week before next expected period —> highest progesterone level)
(NB: regular cycle already a good indication of ovulation —> may not need to measure progesterone level)
—> Prolactin / Thyroxine not indicated

• Irregular cycle:
  —> **Hormone profile: FSH, Prolactin, Thyroxine
  —> **USG: Ovarian morphology (PCO)

Tests of ovulation:
- **Pregnancy (gold standard)
- Other tests inferential (BBT, Urinary LH kits, Pelvic USG)
- Regular cycles (21-35 days) suggest **95% chance of ovulation
- Surrogate markers: Serum progesterone level, **Basal body temperature, **Urine LH kits, **Pelvic USG, **Endometrial biopsy

2. Imaging
   - PCOS
3. FSH + Prolactin
   - high FSH (>25) indicate primary ovarian insufficiency
   - stress
   - weight loss
4. T4, Morning cortisol
   - Thyroid, Adrenal gland

Other investigations:
5. Tubal patency
- **Hysterosalpingogram (HSG) (inject dye into uterine cavity through catheter)
—> less invasive + outpatient procedure
—> can assess uterine cavity
—> False +ve (if spasm in proximal end)
—> Peritubal adhesion not detected
—> 4-5% pelvic inflammatory disease after hysterosalpingogram
—> for women with **no comorbidities (e.g. previous PID / ectopic pregnancy), with clinical s/s of endometriosis

• **Laparoscopy (direct visualisation of peritoneal cavity)
  —> operative procedure requiring GA
  —> more accurate
  —> diagnostic + therapeutic
  —> detect + **treat endometriosis, **pelvic adhesion
  —> reserved for those with **co-morbidities, symptoms, abnormal physical findings
• Hysterosalpingo-contrast-USG
  —> alternative to HSG

6. Rubella status, MCV, Endocervical swab for chlamydia (SpC Revision)

Question 12

Serum progesterone levels

Answer 12

• Taken in ***mid-luteal phase (7 days before expected onset of next period)
• > 10 nmol/L or >3 ng/ml as presumptive and sufficient evidence of recent ovulation

Limitations:
- Serum P levels can fluctuate by 7x over a few hours (∵ secreted in pulsatile manner)
- NOT assess ***quality of luteal phase

Question 13

Basal body temperature

Answer 13

• Body temp ↓ at time of ovulation
• 1 day later ↑ by 0.5oC, stay at higher level till next menstruation
• ↑ Progesterone —> ↑ BBT
• Around similar time over 3-4 months

Problem:
- Not accurate ∵ ovulation was between 6 days before + 4 days after nadir
- Difficult to interpret in many cases (e.g. unwell, sleep late)
- Time the intercourse

Question 14

Urinary LH kits

Answer 14

• May induce anxiety
• not really improve chance of conception if already regular intercourse

Question 15

Pelvic USG

Answer 15

5 parameters of ovulation:
1. Progressive follicular growth
2. Sudden collapse of pre-ovulatory follicle
3. Loss of clearly defined follicular margins
4. Appearance of internal echoes within the corpus luteum
5. ↑ in cul-de-sac fluid volume

Limitation:
- Repeated scanning —> Labour intensive

Question 16

Causes of anovulation

Answer 16

1. Hypothalamus
   - Weight change: obesity, anorexia nervosa
   - Drugs: tranquilliser
   - Psychological disturbance
2. Pituitary
   - Tumours
   - Sheehan’s syndrome
   - Hyperprolactinaemia
3. Ovary
   - Ovarian insufficiency: Chromosomal disorders (Turner syndrome 45X), Surgery, RT, Chemotherapy, Mumps
   - PCOS
4. Other endocrine disorders
   - Thyroid disorders
   - Adrenal disorders

Question 17

Investigations that should NOT be routinely ordered

Answer 17

1. ***Laparoscopy for unexplained infertility
2. ***Advanced sperm function testing (e.g. DNA fragmentation testing)
3. Postcoital testing
4. Thrombophilia testing
5. Immunologic testing
6. Karyotype
7. Endometrial biopsy (replaced by serum P, LH, USG)
8. Prolactin

Question 18

Treatment of infertility

Answer 18

1. Pre-pregnancy advice
   Female:
   - **0.4mg Folic acid whilst trying to conceive (1-2 months) + during first 12 weeks of pregnancy to prevent neural tube + facial defects
   - **↓ body weight in obese woman
   - stop smoking
   - stop alcohol
2. ***Ovulation induction

Male:
- ***stop smoking
- avoid excessive alcohol
- if poor quality sperm
—> wear loose fitting underwear + trousers
—> avoid occupational / social situations that may cause testicular hyperthermia

Question 19

Ovulation induction

Answer 19

Aim: Development of ***single follicle (not >=1 ∵ risk of multiple pregnancy)

FSH + Prolactin level:
1. ↑ FSH (>25)
—> Ovarian insufficiency —> ***Donor eggs

2. ↑ Prolactin
   —> Hyperprolactinaemia
   —> MRI pituitary gland to exclude pituitary adenoma
   —> ***Bromocriptine, Cabergoline
3. **Normal / Low FSH
   —> USG
   —> PCOS / Hypothalamic-pituitary
   —> Optimise weight / **Drugs / Surgery

Treatment of PCOS:
1. Optimise weight

2. Drugs
   - **Letrozole (1st line)
   - **Clomiphene citrate
   - ***Gonadotrophin (injection)
   - Metformin (↓ insulin level)
3. Surgery
   - ***Ovarian drilling in PCOS —> ↓ Testosterone level

Question 20

Letrozole

Answer 20

• 1st line oral therapy in PCOS
• Aromatase inhibitor —> ↓ Estrogen from Testosterone conversion —> ↓ suppression of FSH —> allow maturation of follicle
• 2.5-7.5 mg/day for 5 days (from day 2-6)

Complications / SE:
- Less multiple pregnancy compared with Clomiphene citrate
- Drowsiness / Tiredness
- Ovulation / Pregnancy rates after 5-6 cycles ***~50–60% (higher than Clomiphene citrate)

Question 21

Clomiphene citrate (CC)

Answer 21

• Anti-estrogen acting at Hypothalamus —> ↓ -ve feedback (self notes) —> ↑ GnRH pulse frequency (wiki) —> ↑ FSH, LH —> ↑ Ovulation
• 50–150 mg/day for 5 days, up to 6 cycles

Complications / SE:
- **Hot flushes
- **Multiple pregnancy (10%)
- Ovarian cysts
- Abdominal distension / pain
- Blurring of vision / Peripheral neuropathy (idiosyncratic)

Ovulation rate: 50-80%
Pregnancy rate: ***30-50%

Question 22

Gonadotrophin (FSH+LH / Recombinant FSH injections)

Answer 22

• **FSH+LH / **Recombinant FSH injections
• Acts directly on ovaries + very effective
• High risk of ***OHSS (Ovarian hyperstimulation syndrome) + Multiple pregnancy (up to 40-50%)
  —> Requires careful monitoring

OHSS:
- 1-5%
- life-threatening condition
- Vasodilation (∵ corpus luteum secrete vasoactive substances VEGF)
—> Ovarian enlargement —> burst in blood vessels —> **Hemoperitoneum
—> Ascites (water leak out in blood vessels)
—> Hydrothorax —> difficult to breathe
—> Hypovolemia (↓ vascular volume —> ↓ urine output) —> electrolyte imbalance + platelet closer together —> **Arterial thromboembolism

Question 23

Bromocriptine

Answer 23

• Dopamine agonist
• useful in Hyperprolactinaemia
• Ovulation rate >90%
• Pregnancy >80% (normal)
• SE: Nausea, postural hypotension

Question 24

Ovarian insufficiency

Answer 24

• Medical treatment NOT effective
• Oocyte donation
  —> Oocyte obtained from donor
  —> Oocyte fertilised by husband’s sperms
  —> Embryo replaced into recipient’s uterus

Question 25

Treatment for Tubal factors

Answer 25

1. **Tubal surgery
   - Microsurgical technique
   - Laparotomy / Laparoscopy
   - **Adhesiolysis, **Re-anastomosis, **Salpingostomy —> make tube patent again
   - Results take time
2. ***IVF / Embryo transfer (IVF-ET)

Tubal surgery vs IVF-ET depends on:
1. Lesion severity (***IVF 1st line for moderate to severe tubal disease (SpC OG PP))
2. Infertile couple (age)
3. Medical service / Expertise

Question 26

Treatment of minimal / mild Endometriosis

Answer 26

1. Medical treatment
   - does NOT enhance fertility
   - suppress ovulation —> may actually reduce fertility (although treating endometriosis)
2. ***Surgical ablation (diathermy / laser)
   - improves fertility

Empirical treatment:
3. Ovarian stimulation + Intrauterine insemination

4. IVF-ET

Question 27

Treatment for Male infertility

Answer 27

Only serve a small % of Infertile men
1. **Varicocele treatment
2. Vasectomy reversal / overcome correctable obstruction
3. **Gonadotrophins / GnRH for Hypogonadotrophic hypogonadism
4. ***Bromocriptine for Hyperprolactinaemia
5. Surgery for Pituitary adenoma

Empirical treatment:
1. **Ovarian stimulation + **Intrauterine insemination (IUI)
2. ***IVF-ET with conventional insemination (將精子放近卵子) / intracytoplasmic sperm injection (ICSI) (將精子直接打入去)

Obstructive azoospermia + Failed surgery:
- Aspirate sperm from epididymis for ICSI (MESA: microsurgical epididymal sperm aspiration) (100%)

Non-obstructive azoospermia (due to testicular failure):
- Obtain sperm from testicular extraction (TESE: testicular sperm extraction) (only 40-50%)

If all fail:
- Artificial insemination by ***donor sperm

Question 28

Ineffective treatment / Treatment of doubt value in Male infertility

Answer 28

1. Anti-estrogens, Androgens, Bromocriptine, Kinin-enhancing drugs
   - for abnormalities of semen quality
2. Antioxidants, Mast cell blockers, α blockers
   - need further evaluation
3. Systemic corticosteroids
   - for antisperm Ab

Question 29

Treatment of Unexplained infertility

Answer 29

1. Expectant treatment (Watchful waiting) 1-2 years
2. IVF

• Clomiphene citrate NOT recommended —> no benefit
• Unstimulated IUI NOT recommended —> no benefit

Question 30

Treatment of coital problem

Answer 30

1. Investigate cause + treat accordingly
   - Psychotherapy
   - Drugs for erectile dysfunction e.g. ***Viagra
2. Artificial insemination (IUI) by husband’s sperms at time of ovulation
   - close to ovulation time —> ask man to get semen —> select most motile sperm —> inject close to site of fertilisation (usually uterine cavity)

Question 31

In-vitro fertilisation (IVF)

Answer 31

Procedures:
1. Stimulation of ovaries
- **GnRH agonist / antagonist —> prevent LH surge during controlled ovarian hyperstimulation —> prevent ovulation
- **Daily FSH (10-12 days) —> USG to track follicular development
- ***hCG (13th day) —> induce ovulation (∵ function ~ to LH)

2. Oocyte pickup
3. Fertilisation in laboratory
4. Embryo transfer
   - Fresh (即整即打) vs Frozen (整好 —> 雪左 —> Fresh唔得再打)

Effectiveness:
- ***~50% cumulative live birth rate <=35
- 41% 36-40 yo
- 13% >=40 yo

Question 32

2 fertilisation methods

Answer 32

1. Conventional insemination
   - inject sperm so that in close proximity to egg
2. Intracytoplasm sperm injection
   - injecting single sperm into an egg
   - if bad sperm quality

Question 33

Embryo transfer

Answer 33

After egg collection
- Embryo (Day 2)
or
- Blastocyst (Day 5)

Place 1 embryo:
- reduce risk of multiple pregnancies

Place 2 embryos:
- for >=38 at IVF / not pregnancy after 2 IVF cycles
AND
- no livebirth before

Question 34

Summary

Answer 34

Age of women is an important factor —> Older women should be investigated + treated early

***3 most important investigations:
1. Semen analysis
2. Serum progesterone (for ovulation)
3. HSG / Laparoscopy (for tubal patency)

Effective treatment should be offered for long standing infertility