Subfertility

Question 1

Define infertility/subfertility

Answer 1

failure to conceive after:
12 months of regular unprotected intercourse (USI) <35yo
6 months in >35yo (WHO)

Question 2

What is the epidemiology of subfertility

Answer 2

85% will become pregnant naturally within 1 year with regular USI , 92% will do so within the 2nd year cumulatively (93% third year)
1:7 couples struggle to conceive naturally
1 in 6 recognised pregnancies miscarry

Question 3

What are the causes of subfertility

Answer 3

Ovulatory (F): 45%
Tubular (F): 25%
Male factors: 30%
Unexplained: 25%, usually failure of implantation

40% due to male and female factors

Question 4

What is the normal length and blood loss of the menstrual cycle

Answer 4

Length: variable, 21-25 days in between normal
Average 35ml, >60ml = heavy

Question 5

Describe the ovarian menstrual cycle

Answer 5

1. Menstruation
2. 5-13 (proliferative)
   - Pulsatile GnRH release from the hypothalamus
   - LH and FSH release → follicular growth
   - Follicles secrete oestradiol and inhibin → negative feedback on FSH and LH release (prevents <1 follicle growth)
   Oestradiol levels increase as the Graafian follicle emerges
3. day 14 (ovulation)
   Oestradiol levels reach threshold to trigger a positive feedback response → LH surge (12h duration) → meiosis of the egg
   The follicle ruptures and a mature egg is released 36 hours after the surge
4. 14-28 (luteal/secretory)
   The remaining ruptured follicle becomes corpus luteum, which secreted progesterone
   If fertilisation has not occurred, the corpus luteum degrades, so progesterone and oestradiol release also decreases

If fertilisation has occurred, the release of beta-hCG maintains progesterone release

Question 6

Describe the endometrial menstrual cycle

Answer 6

1. Menstruation
   The endometrium breaks down and is shed
2. 5-13 (proliferative)
   Oestrogen release allows for proliferative changes
   Stromal cells proliferate
   Glands elongate
3. day 14 (ovulation)
4. 14-28 (luteal/secretory)
   Progesterone release allows secretory changes
   Glands swell
   Blood supply increases

Question 7

What is the role of AMH

Answer 7

AMH is produced from small ovarian follicles and reduces oestrogen release As the follicles grow, the production of AMH reduces and oestrogen levels increase

Question 8

What are the important features to ascertain for the subfertility in women

Answer 8

See the male and female individually

1. Age
2. How long have they been trying for (+frequency, partner)
3. Have they had a previous pregnancy (+outcome)
4. Menstrual cycle - is bleeding regular
5. Sexual history - is the sex regular? Unprotected? Vaginal? Penetrative? Ejaculatory? Any STIs?

Question 9

What should you look for on examination for subfertility in women

Answer 9

General: BMI, hirsutism, acne
Breast: galactorrhoea
Abdo: ?mass, ?cyst
Pelvic: ?STIs, vaginismus

Question 10

What are the important features to ascertain for the subfertility in men

Answer 10

Has he gotten anyone pregnant before
Any difficulties in sex
Occupation (affects time of sex)
Cannabis use
PMHx: mumps, STIs, testicular trauma/torsion

Question 11

What investigations should be done for women with subfertility

Answer 11

LH (OTC urine kits) - Surge in LH can be detected the morning after it has occurred in the urine, rarely measured due to the small time frame (12h)

FSH (day2-3 of cycle)
Oestradiol (?ovulation)
Mid-luteal progesterone (7 days before predicted menstruation) - suggests ovulation (high)
AMH - ovarian reserve
Testosterone
SHBG
Prolactin

Pelvis USS
Hysterosalpingogram (HSG) - radio-opaque contrast injected through cervix, using X-ray
HyCoSy: Contrast injected, TVUSS used
Laparoscopy and dye test

Question 12

What are the investigations for men with subfertility

Answer 12

Sperm:
1. Count - >15 mil per ml, 500,000 are required for a chance of fertilisation
2. Motility - 50% are motile, 25% are progressively motile, asthenospermia = not motile
3. Morphology - 4% have normal morphology

FSH
LH
Prolactin
Testosterone
TFTs
Karyotype (?Klinefelter’s)
Sweat test for CF
Testicular USS

Question 13

What are the options for management in the following male factors contributing to subfertility: abnormal sperm, oligospermia, moderate-severe oligospermia, azoospermia

Answer 13

Abnormal: Optimise lifestyle factors, Examine scrotum
Oligospermia: Intrauterine insemination
Moderate-severe oligospermia: IVF ± ICSI
Azoospermia: Examine for presence of vas deferens, Check karyotype, CF, hormone profile, Surgical sperm retrieval → IVF + ICSI, Donor insemination

Question 14

What are the ovulatory causes of subfertility in women

Answer 14

Hypog Hypog (hypothalamic)
- Stress/exercised-induced
- Anorexia nervosa
- Sheehan’s
- Pituitary tumours - adenoma or hyperplasia
- Kallman’s syndrome (GnRH-secreting neurones fail to develop)
Normogonadotrophic
- PCOS (80%)
Hypergonadotrophic
- Primary ovarian insufficiency
Hypo/hyperthryoidism

Question 15

What is the management for subfertility due to PCOS

Answer 15

Lifestyle: weight loss, healthy diet, more exercise

First line: Clomiphene
± metformin (weight loss, ovulation)
Second line: Letrozole (aromatase inhibitor) = induces ovulation
Third line: gonadotrophic induction followed by HCG injection

Question 16

Describe the use of clomiphene and what are the side effects

Answer 16

Blocks oestrogen receptors → increases FSH/LH release → endogenous oestrogen release
Given on day 2-6 of the cycle
Limited to 6 months use
Ovulation in 70%< live birth in 40%
Monitor with TVUSS in the first month to assess ovarian response

SE:
May cause thinning of the endometrium
Increased risk of multiple pregnancy

Question 17

What is the management of Pituitary causes of subfertility in women

Answer 17

Kallman’s: exogenous gonadotrophins, GnRH pump
Pituitary cause: dopamine agonist e.g. bromocriptine, cabergoline

Question 18

What are the tubal causes of subfertility

Answer 18

Infection/endometriosis
PID (Fitz-Hugh-Curtis): Adhesions within and around the fallopian tubes
Previous pelvic surgery: adhesions
Sterilisation -> IVF or open microsurgical tubal re-anastamosis (increased ectopic risk)

Question 19

What is ovarian hyperstimulation syndrome and what are the risk factors

Answer 19

Gonadotropin overstimulates the follicles, which get large and painful.
Intravascularly deplete and third space fluid
More common in IVF than ovarian induction standalone
RF: <35yo, gonadotrophin stimulation, PCOS, low BMI

Question 20

What are the symptoms of ovarian hyperstimulation syndrome

Answer 20

Pain
SOB (Pleural effusion)
Abdominal distension (Ascites)
Nausea and vomiting
Loss of appetite
Reduced urinary frequency/volume

Question 21

What is the management for ovarian hyperstimulation syndrome

Answer 21

Expectant - keep patient stable and not intravascularly deplete
Consider clexane for increased VTE risk
Drain any ascitic fluid

Question 22

What is the general management for subfertility

Answer 22

1. Re-assure, inform on stats about conception
2. Advise regular intercourse throughout the cycle (temp, charts, LH detection not recommended)
3. Lifestyle advice:
   - Use folic acid
   - Rubella and cervical screening
   - Stress management (affects libido)
   - BMI 19-25
   - Seek advice from occupational health at work
   - Stop alcohol consumption
4. Refer to British infertility counselling association

Question 23

Describe Intra-uterine insertion (procedure, live birth rate, contra-indications)

Answer 23

Sperm injected directly into the cavity of the uterus
5-10%
Tubes are not patent

Question 24

Describe In-vitro fertilisation (procedure, live birth rate, contra-indications)

Answer 24

Embryo fertilised outside the uterus and transferred back
<36 = 35%
Ovarian failure

Question 25

What is ICSI

Answer 25

Intracytoplasmic sperm injection Injection of sperm into the oocyte cytoplasm Used for male factor infertility

Question 26

What are the options for assisted contraception

Answer 26

Intra-uterine insertion (IUI) In-vitro fertilisation (IVF) Intracytoplasmic sperm injection (ICSI) Frozen embryo replacement (FER) Oocyte donation Preimplantation genetic diagnosis and screening (PGD/PGS) Surrogacy

Question 27

What are the indications for assisted conception

Answer 27

All other methods have failed Unexplained subfertility Male factor subfertility Tubal blockage Endometriosis Genetic disorders

Question 28

What are the complications of IVF

Answer 28

Superovulation: multiple pregnancy, ovarian hyperstimulation Egg collection: intra-peritoneal haemorrhage and pelvic infection Pregnancy complications: ectopic pregnancy, increased morbidity and mortality

Question 29

Describe the IVF procedure

Answer 29

1. Multiple follicular development a. 2 weeks of daily SC gonadotrophin injections 2. Ovulation and egg collection a. Drugs are stopped b. Single HCG injection (or LH) to trigger final oocyte maturation c. Egg collection 35-58h later 3. Fertilisation and culture a. Until blastocyst stage b. Can save spares for FER 4. Embryo transfer Luteal phase support until 4-8 weeks (LH or HCG)