Infertility

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Chapter 10 Infertility

Anusch Yazdani

Definitions. Infertility is the failure to achieve a successful pregnancy after 12 months or more of regular unprotected intercourse. Primary infertility is no previous pregnancy, regardless of the outcome. Secondary infertility is previous pregnancy, regardless of the outcome. Fecundability is the probability of achieving a pregnancy per menstrual cycle. Fecundity is the probability of achieving a live birth per menstrual cycle.

Incidence. The overall incidence of primary infertility is 10%–15% of couples. Female fertility declines with age and the incidence of infertility increases: 5% under the age of 25; 10% under the age of 30; 15% under the age of 35; 30% under the age of 40; and 60% over the age of 40.

Conception

Conception requires:

• sperm∗

• adequate (quantity, quality)
• deposition (in vicinity of cervix, prior to/at ovulation, permeable cervical mucus)
• ovulation∗
• at least one patent fallopian tube to allow fertilisation∗
• transport to endometrial cavity
• implantation

Probability of conception

The probability of conception is time dependent:

• after 3 months: 60%
• after 6 months: 75%
• after 12 months: 85%
• after 24 months: 95%

Therefore, the majority of couples who have not conceived after 1 year are likely to conceive in the subsequent year.

Aetiology

The requirements for conception determine the aetiological factors that contribute to infertility:

• male factors: 40%

• pretesticular factors: hypothalamic–pituitary abnormalities
• testicular factors: primary testicular abnormalities, varicocoele, torsion, trauma, orchiditis, cytotoxic drug treatment, radiotherapy, undescended testes
• post-testicular factors: genital tract obstruction, may be congenital (congenital absence of vas deferens), inflammatory, Young’s syndrome, postvasectomy, vasectomy

• female factors: 50%

• tubal and pelvic pathology: 40%

— endometriosis, adhesions, hydrosalpinges, pelvic inflammatory disease, fibroids, congenital abnormalities

• ovulatory dysfunction: 40%

— primary ovarian abnormalities, polycystic ovary syndrome, obesity, age
— hypothalamic–pituitary disorders

• other: 20%

• unexplained: 10%

History

Female

• history of infertility

• primary or secondary infertility

— previous pregnancies: same or different partner, time to conceive, outcome of pregnancy

• duration of infertility

• sexual history

• history of contraception
• sexual function

— dyspareunia
— coital frequency, timing during cycle

• menstrual history

• regularity, frequency of cycles, evidence of ovulation (such as mucus changes)
• dysmenorrhoea

• evidence of endocrine disorder

• galactorrhoea, hirsutism, acne
• weight gain

• past medical history

• obesity
• hypertension, renal disease, gastrointestinal disease
• thyroid disease
• pelvic inflammatory disease
• peritonitis, appendicitis, ovarian or pelvic surgery
• endometriosis

• medications
• social history, including smoking, alcohol or other substance abuse
• family history, including birth defects, mental retardation or reproductive failure

Male

• history of infertility

• pregnancies to other partners

• sexual function

• erectile or ejaculatory dysfunction

• past medical history

• varicocoele, undescended testicle, mumps
• orchidopexy, inguinal hernia repair
• urinary tract infection, sexually transmitted disease
• testicular injury or infections

• medications
• social history, including smoking, alcohol or other substance abuse
• family history, including birth defects, mental retardation or reproductive failure

Examination

Female

• general

• pulse rate, blood pressure, body mass index (BMI)
• dysmorphic features, secondary sexual characteristics

• endocrine

• breast and thyroid, hirsutism, acne, galactorrhoea, striae, acanthosis

• reproductive

• vaginal examination

— cervical cytology, microbiological studies, including Chlamydia
— pelvic assessment (e.g. fixed retroversion of the uterus)

Male

• general

• pulse rate, blood pressure, BMI
• dysmorphic features, secondary sexual characteristics

• endocrine

• gynaecomastia, hair distribution

• reproductive

• phallus
• spermatic cord: presence of vas, varicocoele
• testicular size and consistency

Investigations

Initial investigations

Initial investigations focus on the three main factors causing infertility (ovulatory, pelvic and male factors) and assess the suitability for pregnancy (antenatal screening).

• ovulatory factor assessment

• a regular cycle with symptoms of ovulation is evidence of ovulation
• basal body temperature (BBT) chart

— progesterone is thermogenic and raises BBT after ovulation, which is maintained during the luteal phase
— 20% of ovulatory women have a monophasic BBT

• serum progesterone

— tested in the luteal phase on day 21 of an ideal 28-day cycle or 7 days prior to menses
— raised progesterone in the luteal range is evidence of ovulation in that cycle

• pelvic factor assessment

• ultrasound scan of pelvis: ovarian morphology, evidence of pelvic disease, such as fibroids

• antenatal screening tests (include cervical screening, rubella serology)
• male factor assessment

• seminal analysis

— requires 3 days abstinence before collection
— volume >2 mL
— density >20 million sperm/mL
— motility >50%
— morphology >15% normal

Extended investigations

Extended investigations are performed when the initial investigations have not identified a cause or when further elucidation is required.

• ovulatory factor assessment

• follicle-stimulating hormone (FSH), luteinising hormone (LH) and oestradiol in the follicular phase in those menstruating, or randomly when cycles irregular or absent
• serum prolactin, thyroid function tests
• endometrial biopsy in secretory phase
• if hirsutism is present, serum testosterone, androstenedione, dehydroepiandrosterone sulfate (DHEAS), sex hormone binding globulin and 17-hydroxyprogesterone

• pelvic factor assessment

• assessment of tubal function

— provides information regarding uterine cavity and tubes but no extratubal view: hysterosalpingogram, hysterosonography (HyCoSy)

• laparoscopy, hysteroscopy, dye pertubation

— detailed survey of the reproductive organs, hydrotubation to assess (and treat) tubal patency, pelvic adhesions, endometriosis

• male factor assessment

• seminal analysis: if the initial test is abnormal, repeat in 2–3 months (long development cycle of sperm may be affected by, for example, fever)
• antisperm antibodies: immunobead test, mixed antiglobulin reaction test
• endocrine tests

— FSH/LH/total testosterone: to distinguish between obstructive disorders and primary testicular failure
— inhibin, prolactin, thyroid-stimulating hormone (TSH)

• chromosomal analysis

— indications: azoospermia, raised FSH, reduced testicular volume, prolonged unexplained infertility, congenital abnormalities
— in infertility clinics, 2% of males are chromosomally abnormal, rising to 15% in the azoospermic male

• testicular biopsy

— indication: obstructive azoospermia, diagnostic uncertainty

Management

Management of infertility is directed by the assessment of the three main factors (ovulatory, pelvic and male) as above.

Principles

• optimise conception

• lifestyle modification if required
• folic acid supplementation in line with National Health and Medical Research Council (NHMRC) requirements
• appropriate coital timing

• correct any primary pathology

• treatment of endocrine disorders

• manage any non-correctible factors

Ovulatory factor infertility

Management options include:

• ovulation induction: induce ovulation in anovulatory or oligovoulatory females
• superovulation: induce the formation of two or three mature follicles in women who are ovulating
• controlled ovarian hyperstimulation: induce the formation of multiple mature follicles for the purposes of in vitro fertilisation (IVF)

Clomiphene

• description

• a non-steroidal agent distantly related to diethylstilbestrol
• the principally antagonistic effect at the level of the hypothalamus activates the oestrogen–gonadotrophin feedback to the pituitary, causing a rise in FSH and LH (but especially FSH), which leads to induction of ovulation

• dose

• 50–150 mg/day for 5 days on days 5–9 or days 2–6 of the menstrual cycle
• a lower dose is often required in polycystic ovarian syndrome
• a rise in luteal serum progesterone on day 21 confirms ovulation

• adverse reactions

• vasomotor symptoms, breast and abdominal discomfort, visual changes, alopecia, multiple pregnancies (8%)

Follicle-stimulating hormone (FSH)

• description

• FSH in stimulation regimen may be derived from two sources:

— synthetic FSH, a manufactured recombinant glycoprotein
— purified urinary menopausal gonadotrophins, containing both FSH and LH, though the latter has minimal clinical efficacy

• dose

• 50–450 IU/day self-administered from days 2–5 of the menstrual cycle
• dosing determines whether one or multiple follicles are developed
• response is monitored by ultrasound scanning and oestrogen-level measurement

• adverse reactions

• breast and abdominal discomfort, multiple pregnancies (25%), ovarian hyperstimulation syndrome

Gonadotropin-releasing hormone (GnRH) agonist/antagonists

• Unless the pituitary is suppressed, the rising oestrogen levels will cause spontaneous LH surge and ovulation prior to follicles reaching the correct size for an egg pick-up.
• GnRH agonists administered in a non-pulsatile fashion (either as injections or nasal sprays) will cause GnRH receptor down-regulation and suppress the mid-cycle LH surge and ovulation; this effect requires 7–10 days.
• GnRH antagonists act as competitive inhibitors and can therefore be administered only at the time suppression is required.

Human chorionic gonadotrophin (hCG)

• Purified urinary or recombinant hCG may be used to induce final oocyte maturation (analogous to the LH surge in a natural cycle).
• It is a cheaper alternative to LH.
• In ovulation induction or superovulation, ovulation is induced for IVF.
• In IVF, a transvaginal egg pick-up is performed prior to ovulation.

Pelvic factor infertility

Tubal factors

• success of repair depends on the site, nature and severity of the tubal damage

• interstitial tubal obstruction

— tubal reimplantation has a poor prognosis and is an indication for IVF

• proximal tubal obstruction

— has an excellent prognosis, particularly if resulting from sterilisation
— tubal reanastomosis requires at least one tube of over 4 cm in length with a healthy ampulla and fimbria
— best results are with isthmo-isthmic anastomosis
— pregnancy rate >60%; 10% ectopic

• distal tubal obstruction

— has a poor prognosis, as it is most often associated with severe tubal damage
— neosalpingostomy 25% intrauterine pregnancy and 30% ectopic pregnancy rate

• success rates of tubal surgery must be compared to assisted reproductive techniques
• hydrosalpinges should be corrected or removed prior to any assisted reproduction

Adhesions

Removal of adhesions around the ovary and fimbriae, if the tube is otherwise normal, have a 50% chance of a live birth and a 10% risk of ectopic pregnancy.

Endometriosis

(See Ch 4.)

Fibroids

(See Ch 20.)

Male factor infertility

Pretesticular factors

• gonadotrophin deficiency: gonadotrophin therapy
• note that testosterone supplementation results in a feedback suppression of gonadotrophins and cessation of spermatogenesis

Testicular factors

• most testicular factors are not correctible

• if spermatogenesis persists, sperm may be used for insemination, IVF or intracytoplasmic sperm injection (ICSI)
• in the absence of spermatogenesis, donor sperm will be required

• varicocoele (with abnormal seminal analysis) may be repaired
• sperm auto-antibodies: corticosteroids are rarely useful; IVF–ICSI is now considered the primary treatment of choice

Post-testicular factors

• surgical correction of obstruction may be considered depending upon the level of obstruction
• alternatively, testicular or epididymal sperm retrieval for IVF–ICSI has a high success rate

Coital disorders

• correction of primary pathology
• pharmacotherapy for erectile dysfunction
• psychosexual counselling

Assisted reproduction

Definitions. IVF: in-vitro fertilisation; ICSI: intracytoplasmic sperm injection.

Success rates. IVF—fresh embryo transfer: 35–40%; frozen embryo transfer: 25–30%.

Steps in assisted reproduction

The aim of assisted reproduction is to induce the development of multiple mature ovarian follicles. There are five steps.

Step 1: Controlled ovarian hyperstimulation

• administration of FSH, commencing on day 3–5 of the cycle
• combined with pituitary down-regulation to prevent a premature LH surge and ovulation
• ovarian response is carefully monitored by oestradiol assays and/or transvaginal ultrasound scans over a period of 9–12 days
• ovarian follicles grow at a predictable rate of approximately 2 mm/day
• once follicles have reached maturity (>18 mm in diameter), an injection of hCG is given to initiate the final process of egg maturation

Step 2: Egg collection

• performed under a local or general anaesthetic using a vaginal ultrasound probe at 36–38 hours following the hCG
• the needle is guided through the top of the vagina into the ovary and each follicle is aspirated
• the follicular fluid is assessed by a scientist for the presence of an egg

Step 3: Fertilisation and embryo culture

• the semen sample (collected by masturbation) or surgically retrieved sperm is prepared in the laboratory
• the oocyte is prepared

• IVF: the prepared oocytes are cultured with prepared sperm
• ICSI: the prepared oocytes are directly injected with a single sperm

• fertilisation is completed the following day and the embryo develops in culture
• 2–3 days after egg collection, the embryos have reached the 2–8 cell stage

Step 4: Embryo transfer

• performed in the day theatres without anaesthetic or sedation
• a maximum of two embryos may be transferred, but couples should consider the transfer of a single embryo to prevent a twin pregnancy
• luteal support in the form of hCG injections or progesterone pessaries may be required after the embryo transfer to support the uterine lining

Step 5: Embryo freezing and subsequent cycles

• spare embryos may be frozen and stored for future use
• in subsequent cycles, an embryo is thawed and transferred in synchrony with a natural cycle and drug therapy is usually not required

Ovarian hyperstimulation syndrome

Ovarian hyperstimulation syndrome (OHSS) is an exaggerated response to ovulation/ovulation triggers characterised by increased vascular permeability, intravascular depletion and third space fluid sequestration. It is usually an iatrogenic, self-limiting disorder associated with ovulation induction/ovarian stimulation. It may be:

• early onset: related to hCG trigger

• flare of GnRH therapy

• late onset: related to ensuing pregnancy, especially multiple

Incidence. Severe OHSS occurs in 0.5% episodes of assisted reproduction.

Pathophysiology. OHSS occurs in response to endogenous or exogenous LH or hCG, resulting in increased vascular permeability, arterial dilation, fluid shift from vascular to third space, intravascular depletion and circulatory dysfunction.

Risk factors

Patient factors

• young age
• low body weight
• history of OHSS
• polycystic ovaries

Cycle factors

• agonist down-regulated cycles are more likely to result in OHSS
• GnRH antagonists reduce incidence of severe OHSS
• high doses of exogenous gonadotrophins
• high absolute or rapidly rising oestradiol (E2)
• large number of developing follicles or oocytes retrieved (>20)
• high-dose hCG ovulation trigger

Management

Outpatient

Mild forms may be managed as an outpatient.

• simple analgesia
• simple antiemetics
• maintain oral intake
• encourage mobilisation

Inpatient

Moderate to severe forms require admission.

Indications

• pain
• intractable nausea/vomiting/diarrhoea
• haemodynamic compromise
• respiratory compromise

Investigations

• haematocrit >45 L/L
• white cell count >15 x109/L
• hyponatraemia
• hyperkalaemia
• abnormal liver function test
• renal impairment (creatinine >0.12 μmol/L; creatinine clearance <50 mL/minute)

Assessment

• regular assessment of vital signs (every 2–8 hours)
• daily weight
• daily abdominal circumference
• fluid balance sheet
• pulse oximetry
• ward test of urine

Investigations

• full blood examination
• electrolytes and liver function tests
• coagulation profile
• pelvic ultrasound scan
• chest X-ray if respiratory compromise
• echocardiogram if respiratory or cardiovascular compromise

Management

• bed rest
• analgesia
• antiemetic
• thromboprophylaxis
• fluid management
• oral
• intravenous fluids
• type
• normal saline preferred initial resuscitation
• paracentesis

Intensive care unit admission

Indications are:

• haemodynamic compromise requiring invasive monitoring
• renal compromise requiring invasive monitoring (central venous pressure monitoring), dopamine agonist therapy or dialysis
• respiratory compromise requiring ventilation/positive end-expiratory pressure (PEEP)/oxygen

Further reading

Cahill D.J., Wardle P.G. Management of infertility. British Medical Journal. 2002;325:28-32.

Grudzinskas JG (ed) 2003 The management of subfertility. Best Practice and Research Clinical Obstetrics and Gynaecology 17(2):169–367

∗ denotes common problem.

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