Infertility and Subfertility

Introduction

Infertility (or subfertility, the term many clinicians prefer since it implies a reduced rather than absent chance of conception) is conventionally defined as failure to conceive after 12 months of regular unprotected intercourse.¹ It affects roughly 1 in 7 couples in the UK, and around half of those who do not conceive within a year will do so with no treatment at all within the following year, which is an important point for reassurance before assuming pathology.

Causes are broadly divided into female factors (around one-third), male factors (around one-third), combined male and female factors, and unexplained infertility (together making up the remainder), with age - particularly female age - the single strongest predictor of natural conception and treatment success.²

When to investigate

NICE recommends offering investigation and referral after 12 months of failed conception attempts in couples having regular unprotected intercourse, but earlier referral is appropriate where there is a known reason to expect difficulty: age 36 or over, a history of amenorrhoea or oligomenorrhoea, previous pelvic surgery, chemotherapy, known or suspected uterine, tubal or peritoneal disease (such as previous PID or endometriosis), or a known cause of male infertility.¹

Initial advice for any couple trying to conceive, and useful reassurance for those not yet meeting referral criteria, includes: regular intercourse every 2-3 days throughout the cycle (timing intercourse to a predicted ovulation day is not necessary and can increase stress without improving success rates), folic acid supplementation, achieving a healthy BMI, smoking cessation, and reducing alcohol intake.

History and examination

A joint history from both partners covers duration of attempted conception, frequency and timing of intercourse, menstrual history (cycle length and regularity as a marker of ovulation), previous pregnancies with either current or previous partners, relevant medical and surgical history (pelvic infection, surgery, chemotherapy, endocrine disease), and lifestyle factors including smoking, alcohol, recreational drug use and occupational exposures.¹

Examination in the woman includes BMI, signs of androgen excess or thyroid disease, and pelvic examination if indicated by symptoms. In the man, examination assesses for testicular size and consistency, presence of the vas deferens bilaterally, and signs suggestive of a varicocele or hypogonadism.

Investigating ovulation

A regular cycle (typically 21-35 days) is a reasonably reliable indicator of ovulation, but mid-luteal serum progesterone (taken 7 days before the expected next period - day 21 in a standard 28-day cycle, adjusted for cycle length) confirms it directly, with a level above around 30 nmol/L consistent with recent ovulation.³

Where anovulation is suspected (irregular or absent periods), further investigation includes gonadotrophins (LH, FSH), prolactin, thyroid function tests, and, where polycystic ovary syndrome is suspected, testosterone and pelvic ultrasound looking for polycystic ovarian morphology. Polycystic ovary syndrome is the most common cause of anovulatory infertility, discussed in its own article.

Investigating tubal and uterine factors

Tubal patency is most commonly assessed by hysterosalpingography (HSG), a radiological or ultrasound-based (HyCoSy) study in which contrast is injected through the cervix and its passage through the tubes observed, in women with no known risk factors for tubal disease.¹ In women with a history suggesting tubal or pelvic pathology (previous PID, endometriosis, previous pelvic surgery), laparoscopy and dye test is preferred, as it also allows direct visualisation and, where appropriate, simultaneous treatment of endometriosis or adhesions.

Pelvic ultrasound assesses uterine and ovarian anatomy, identifying fibroids, endometrial polyps or congenital uterine anomalies that might impair implantation, and antral follicle count as a component of ovarian reserve assessment.

Investigating male factor infertility

Semen analysis is the first-line investigation for the male partner, assessing volume, concentration, motility and morphology against World Health Organization reference values, and should be repeated after around 3 months (the duration of a full cycle of spermatogenesis) if the initial result is abnormal, before drawing firm conclusions.⁴

• Azoospermia: no sperm - further assessed with hormone profile (FSH, LH, testosterone) to distinguish obstructive from non-obstructive causes
• Oligozoospermia: low sperm concentration
• Asthenozoospermia: reduced sperm motility
• Teratozoospermia: abnormal sperm morphology
• Causes include varicocele, previous testicular surgery or trauma, cryptorchidism, infection (e.g. mumps orchitis, chlamydia), chemotherapy or radiotherapy, hypogonadotrophic hypogonadism, and lifestyle factors (smoking, alcohol, anabolic steroid use, obesity)

Management: general measures

Optimising modifiable factors is first-line regardless of cause: achieving a healthy BMI (both very low and very high BMI reduce fertility and treatment success), smoking cessation in both partners, moderating alcohol intake, and folic acid supplementation in the woman.¹ Underlying conditions identified on work-up, such as thyroid disease or hyperprolactinaemia, should be treated in their own right, which may restore fertility without further intervention.

Ovulation induction

For anovulatory infertility, most commonly due to PCOS, letrozole (an aromatase inhibitor) is now generally preferred first-line over clomifene citrate (a selective oestrogen receptor modulator), as it is associated with higher live birth rates and a lower multiple pregnancy rate, though clomifene remains widely used and is well established.⁵ Both work by disrupting negative feedback at the hypothalamus/pituitary to increase FSH secretion and drive follicular development, with ultrasound monitoring of response and dose titration to reduce the risk of multiple pregnancy from over-response.

Gonadotrophin injections (exogenous FSH, with or without LH) are used where oral ovulation induction fails or is inappropriate, again with careful monitoring given the higher risk of ovarian hyperstimulation and multiple pregnancy compared to oral agents.

Intrauterine insemination and IVF

Intrauterine insemination (IUI) places prepared sperm directly into the uterine cavity around the time of ovulation, and is used for mild male factor infertility, where intercourse is not possible (for example, due to a disability or in same-sex female couples using donor sperm), or for unexplained infertility, though it is less effective than IVF for the latter.⁶

In vitro fertilisation (IVF) involves controlled ovarian stimulation, egg collection, fertilisation with sperm in the laboratory (with intracytoplasmic sperm injection, ICSI, used for more severe male factor infertility), and transfer of one or more resulting embryos into the uterus. It is the treatment of choice for tubal factor infertility (since it bypasses the fallopian tubes entirely), moderate-to-severe male factor infertility, and unexplained infertility that has not responded to simpler measures.

NHS funding and access

NICE fertility guidance recommends up to three full cycles of IVF for eligible women under 40, and one cycle for women aged 40-42 without evidence of low ovarian reserve, but funding decisions are made locally by integrated care boards, and eligibility criteria (age, BMI thresholds, smoking status, existing children, length of infertility) vary significantly by area, meaning access to NHS-funded treatment is not uniform across the country despite the national guidance.¹

Complications of treatment

Ovarian hyperstimulation syndrome (OHSS) is the most important complication of ovulation induction and IVF stimulation, ranging from mild abdominal bloating to severe, life-threatening third-space fluid shifts, ascites, pleural effusion and thromboembolic risk, and is more common with gonadotrophin injections than oral agents. Assisted reproduction, particularly IVF with multiple embryo transfer, also carries an increased risk of multiple pregnancy, which itself carries higher obstetric and neonatal risk - a key reason single embryo transfer is now standard practice in most cases.

Red flags

Prognosis

Prognosis depends heavily on the underlying cause and, above all, on female age: ovulatory disorders generally respond well to induction, tubal factor infertility is effectively bypassed by IVF, and unexplained infertility has a reasonable chance of natural or IUI-assisted conception, particularly in younger women, but success rates for all treatments decline progressively from the mid-30s onwards as ovarian reserve falls, which is why timely referral and investigation - rather than prolonged empirical waiting - matters most in older couples.