Infertility
Background
Overview
- Definition: failure to conceive despite regular unprotected intercourse. WHO defines it as 1 year, NICE used to define it as 2 years (but now doesn't specify).
- Investigate couples who are having difficulty after 1 year of trying.
- 85% of people conceive within 1 year, and 92% within 2 years.
- 50% are due to female causes, 30% male, and 20% unexplained. Sometimes both male and female causes are present.
Female causes
- Usually ovulatory – commonly PCOS – or tubal – commonly PID or endometriosis.
- Age is the most important determinant of fertility. Declines steeply in late 30s.
Ovulatory:
- WHO class 1 (HPO failure → hypogonadotrophic hypogonadal): anorexia nervosa, intense exercise, Kallmann syndrome (congenital ↓GnRH, anosmia).
- WHO class 2 (normogonadotrophic normoestrogenic): mainly PCOS, which causes 90% of anovulatory infertility.
- WHO class 3 (primary ovarian failure → hypergonadotrophic hypoestrogenic): amenorrhea including premature menopause, radiation or chemotherapy, Turner's, fragile X, galactosaemia.
- Hyperprolactinaemia, usually due to a prolactinoma, which inhibits GnRH release.
Tubal:
- PID is the commonest tubal cause. Chlamydia and gonorrhea cause 25%.
- Adhesions: endometriosis, appendicitis, IBD, abdominal surgery.
- Endometriosis can also cause tubal inflammation and distortion.
Other:
- Uterine abnormalities: fibroids, Asherman's syndrome (adhesions).
- Cervical: mucus problems.
- Irregular cycles e.g. >35 days or <23 days.
Male causes
- Unexplained low sperm count is the commonest male cause.
- Drugs: alcohol, anabolic steroids, sulfasalazine.
- Genetic: CF, Klinefelter's, Kartagener's (plus situs inversus).
- Infection: previous mumps, chlamydia.
- Anatomical: varicocele, cryptorchidism (undescended testes), retrograde ejaculation.
- Trauma and surgery: hernia repair, vasectomy.
- And ask about erectile dysfunction – some 'infertile' couples aren't even having sex.
History and examination
- Most of the history should be done with both partners present, but make sure to check when each is alone if there's anything else they'd like to say.
- Ask women the standard gynae history.
- Ask men about any groin surgery, mumps, alcohol, and erectile dysfunction.
- Ask about sex and relationship: frequency and timing, mood, technique.
- Examine the female abdomen and pelvis.
Investigations
Men
- Oligospermia is not enough sperm: may be secondary to hormonal problems or varicocele, but often idiopathic.
- Azoospermia is no sperm. Non-obstructive causes include chromosomal causes. Obstructive causes include CF, infection, or vasectomy.
- Asthenozoospermia is reduced sperm motility. Seen in Kartagener's.
Normal ranges in semen analysis:
- ≥1.5 ml
- pH ≥7.2
- ≥15 million/ml and ≥39 million per ejaculate.
- Motility: ≥40% total or ≥32% progressive.
- Vitality: ≥58% alive.
- ≥4% normal morphology i.e. it is still normal for over 90% of sperm to be abnormal.
Repeat semen analysis:
- Immediately if azoospermia or severe oligozoospermia found.
- After 3 months for any other abnormality.
Further investigations if semen abnormal:
- Endocrine: PRL, FSH (↑ in testicular failure), LH and free and total testosterone (↓ in hypogonadotrophism), estrogen, sex hormone-binding globulin.
- Chromosomal and genetic testing.
- Testes biopsy if there is severe oligospermia or azoospermia.
- Antisperm antibodies not routinely recommended, as there is no treatment.
Women
- Mid-luteal progesterone, 7 days before period. >30 nmol/L = ovulation. If cycles are irregular, check sequential progesterone in luteal phase (every 2-3 days).
- Day 2-5 gonadotrophins: ↑FSH suggests ovarian failure including premature menopause, ↑LH (specifically ↑LH/FSH ratio) suggests PCOS or menopause.
Further endocrine testing:
- ↑Testosterone in PCOS.
- ↑Prolactin
Transvaginal ultrasound:
- Polycystic ovaries.
- Endometriomas
- Fibroids
- Uterine polyps.
Further tests for tubal disease:
- Chlamydia: vaginal swab and PCR.
- Investigate tubal patency and anatomy with hysterosalpingogram contrast XR (HSG) or laparoscopy plus dye. The latter is a gold standard, but more invasive.
Not routinely recommended:
- Cervical mucus testing: poor prediction of pregnancy success.
- TFT, unless features of thyroid disease present.
Management
Primary care
- Sex every 2-3 days.
- Stop smoking.
- Get BMI under 30. This can cure anovulation in PCOS, and makes IVF more successful. Him too, as obesity → ↓sperm. If BMI under 19 in women, get it above this.
- Folic acid.
- Check rubella immune status and immunize if required.
- Check smears up to date.
After 1 year of trying, offer formal assessment, starting with:
- Full history and female abdo/PV exam.
- Testing: bloods to check for ovulation in women (if history unclear), semen analysis in men.
- Referral to secondary care for further management and investigation.
Indications for earlier referral:
- Features of an underlying cause of infertility e.g. dysmenorrhea, pain, PMH of gynae problems.
- Female >35 years old and trying for 6 months.
Secondary care
Female cause
Class 2 anovulation (PCOS):
- Lose weight.
- Clomifene (1st line) and/or metformin (2nd line).
- 3rd line: ovarian drilling – as the fragile-walled new vessels that re-grow release hormones more easily – or gonadotrophins.
- Letrozole may be more effective, but use is currently off-label.
Other ovulatory causes:
- Class 1 anovulation (e.g. anorexia): gain weight, pulsed GnRH.
- Class 3: IVF.
- Bromocriptine – a dopamine agonist – if there is ↑PRL.
Tubal disease:
- IVF is best, but other options are worth trying as are often more available.
- Resect or ablate any endometriosis.
- Salpingostomy for distal blockage.
- Adhesiolysis
Male cause
- Medical: gonadotrophins if hypogonadotrophism, bromocriptine if ↑PRL.
- Intracytoplasmic sperm injection (ICSI) directly into egg if there is a motility problem.
- If there is obstructive azoospermia: surgical correction of epididymal blockage is 1st line, and sperm retrieval from testis/epididymis is 2nd line.
- Surgery for varicoceles does not improve fertility.
Unexplained infertility
If unable to conceive after 2 years of trying, despite normal investigations:
- IVF
- Intrauterine insemination (IUI) with ovarian stimulation (e.g. clomifene, gonadotrophins) is a cheaper alternative which may be more widely available.
Other options
IUI (without ovarian stimulation) is a useful alternative to sex for:
- Those with difficulty having sex e.g. disabled, erectile dysfunction.
- Those requiring sperm washing e.g. HIV +ve man.
- Same-sex couples.
Donor gametes:
- Egg and sperm donors no longer have a right to anonymity: children can find out at 18 years old.
- Egg sharing: a couple requiring eggs can pay some of the IVF costs of another couple, who will then give some of their eggs.
- Both altruistic and named egg donations are allowed.
Clomifene
Mechanism
Indications
- Anovulation due to PCOS.
- Not effective for women who are ovulating or with unexplained infertility.
Side effects
- Flushes
- Visual
- Abdo pain
- ↑Risk of multiple pregnancies: 10% twins.
- Ovarian cancer.
In vitro fertilisation (IVF)
Background
- 30% success per cycle if <35 years old, but only 5% if >40 years old.
- Only available on NHS to those with a BMI <30 and no kids.
- First screen couple for HIV, hep B, and hep C, to prevent transmission to fetus or woman.
Procedure
- GnRH analogues used to suppress natural ovulation.
- Follicle growth stimulated with FSH, then hCG given to trigger ovulation.
- Oocyte retrieval via transvaginal ultrasound.
- Oocyte fertilised with sperm via IVF or intracytoplasmic sperm injection (ICSI).
- Oocytes cultured for 2-3 days, then graded.
- 2 embryos are transferred via catheter into the uterus.
- Pregnancy test 2 weeks later.
Complications
- >20 ova form due to artificial ovulatory stimulation.
- Presents a few days after hCG injection, with abdo pain/distention, nausea, and vomiting.
- Manage with supportive care: analgesia, DVT prophylaxis.
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