O&G JC111: I Want To Have A Baby: Male And Female Infertility Flashcards
Infertility
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
Normal fertility components
- Sperm production
- Follicle development (FSH) + ovulation (LH)
- Fertilisation + Embryo (implantation after 6-7 days of fertilisation)
Pregnancy rate
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
***Causes of infertility
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
Endometriosis
Causes of Endometriosis:
- **Sampson theory
—> **Retrograde menstruation: Menstrual blood spread backwards
—> implant into different areas (unknown area)
—> causes ***adhesion
—> affect tubal function
—> infertility
History taking of Infertility
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)
P/E of Infertility
Female:
1. Body weight (obese / overweight)
- 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)
Early referral to Assist reproduction unit
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
***Investigations of Male infertility
**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
- ***Karyotype + Y microdeletion for testicular failure
- Vasogram (if suspect obstruction)
- Testicular biopsy (not routine, diagnostic and may be of prognostic value, can be therapeutic —> freeze sperm if sperm present)
***Causes of Male infertility
- Disorders of testicular control (by higher centres) (Pre-testicular)
- Hypothalamic-pituitary disorders
- **Hypogonadotrophic hypogonadism
- **Hyperprolactinaemia - 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 - Obstructive disorders (Post-testicular)
- Infections
- ***Congenital absence of vas
- Surgery (Vasectomy) - 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
***Investigations of Female infertility
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
- Imaging
- PCOS - FSH + Prolactin
- high FSH (>25) indicate primary ovarian insufficiency
- stress
- weight loss - 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
- Rubella status, MCV, Endocervical swab for chlamydia (SpC Revision)
Serum progesterone levels
- 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
Basal body temperature
- 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
Urinary LH kits
- May induce anxiety
- not really improve chance of conception if already regular intercourse
Pelvic USG
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
Causes of anovulation
- Hypothalamus
- Weight change: obesity, anorexia nervosa
- Drugs: tranquilliser
- Psychological disturbance - Pituitary
- Tumours
- Sheehan’s syndrome
- Hyperprolactinaemia - Ovary
- Ovarian insufficiency: Chromosomal disorders (Turner syndrome 45X), Surgery, RT, Chemotherapy, Mumps
- PCOS - Other endocrine disorders
- Thyroid disorders
- Adrenal disorders
Investigations that should NOT be routinely ordered
- ***Laparoscopy for unexplained infertility
- ***Advanced sperm function testing (e.g. DNA fragmentation testing)
- Postcoital testing
- Thrombophilia testing
- Immunologic testing
- Karyotype
- Endometrial biopsy (replaced by serum P, LH, USG)
- Prolactin
Treatment of infertility
- 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 - ***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
Ovulation induction
Aim: Development of ***single follicle (not >=1 ∵ risk of multiple pregnancy)
FSH + Prolactin level:
1. ↑ FSH (>25)
—> Ovarian insufficiency —> ***Donor eggs
- ↑ Prolactin
—> Hyperprolactinaemia
—> MRI pituitary gland to exclude pituitary adenoma
—> ***Bromocriptine, Cabergoline -
**Normal / Low FSH
—> USG
—> PCOS / Hypothalamic-pituitary
—> Optimise weight / **Drugs / Surgery
Treatment of PCOS:
1. Optimise weight
- Drugs
- **Letrozole (1st line)
- **Clomiphene citrate
- ***Gonadotrophin (injection)
- Metformin (↓ insulin level) - Surgery
- ***Ovarian drilling in PCOS —> ↓ Testosterone level
Letrozole
- 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)
Clomiphene citrate (CC)
- 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%
Gonadotrophin (FSH+LH / Recombinant FSH injections)
- **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
Bromocriptine
- Dopamine agonist
- useful in Hyperprolactinaemia
- Ovulation rate >90%
- Pregnancy >80% (normal)
- SE: Nausea, postural hypotension
Ovarian insufficiency
- Medical treatment NOT effective
- Oocyte donation
—> Oocyte obtained from donor
—> Oocyte fertilised by husband’s sperms
—> Embryo replaced into recipient’s uterus
Treatment for Tubal factors
-
**Tubal surgery
- Microsurgical technique
- Laparotomy / Laparoscopy
- **Adhesiolysis, **Re-anastomosis, **Salpingostomy —> make tube patent again
- Results take time - ***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
Treatment of minimal / mild Endometriosis
- Medical treatment
- does NOT enhance fertility
- suppress ovulation —> may actually reduce fertility (although treating endometriosis) - ***Surgical ablation (diathermy / laser)
- improves fertility
Empirical treatment:
3. Ovarian stimulation + Intrauterine insemination
- IVF-ET
Treatment for Male infertility
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
Ineffective treatment / Treatment of doubt value in Male infertility
- Anti-estrogens, Androgens, Bromocriptine, Kinin-enhancing drugs
- for abnormalities of semen quality - Antioxidants, Mast cell blockers, α blockers
- need further evaluation - Systemic corticosteroids
- for antisperm Ab
Treatment of Unexplained infertility
- Expectant treatment (Watchful waiting) 1-2 years
- IVF
- Clomiphene citrate NOT recommended —> no benefit
- Unstimulated IUI NOT recommended —> no benefit
Treatment of coital problem
- Investigate cause + treat accordingly
- Psychotherapy
- Drugs for erectile dysfunction e.g. ***Viagra - 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)
In-vitro fertilisation (IVF)
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)
- Oocyte pickup
- Fertilisation in laboratory
- 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
2 fertilisation methods
- Conventional insemination
- inject sperm so that in close proximity to egg - Intracytoplasm sperm injection
- injecting single sperm into an egg
- if bad sperm quality
Embryo transfer
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
Summary
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
