Chapter 115: The subfertile couple

Infertility is defined as the absence of conception after a period of 12 months of normal unprotected sexual intercourse.¹ The inability to conceive can be a very distressing and emotional problem for a couple, who need considerable care, empathy and relatively rapid investigation of their problem. In assessing a couple with the problem of subfertility (this term is a preferable way of describing the condition to the patients), it is appropriate to involve both partners in the consultation.

Human fertility depends on a complex series of events including:²

• production of gametes (sperm and oocytes) capable of fertilisation

• release of the oocyte into the fallopian tube after ovulation

• the right number of sperm have to be placed in the right place at the right time

• implantation and development of the embryo in the hormonally primed uterine mucosa

• maintenance of the growing fetus in the uterus until pregnancy is full term

As a general rule, the major factors limiting fertility are approximately one-third female, one-third male and one-third combined male and female. In addition, there are couples who fulfil the three primary fertility factors (egg, sperm and tubes) but do not conceive. This is known as unexplained (idiopathic) subfertility and accounts for 10–20% of subfertile couples.²

Male fertility

Fertility in the male requires:

• normal hypothalamic function producing gonadotrophin-releasing hormone (GnRH)

• normal pituitary function producing the gonadotrophin hormones—follicle stimulating hormone (FSH) and luteinising hormone (LH)

• normal seminiferous tubule and Leydig cell function

• normal sperm transport and delivery

Facts about sperm viability:

• the maximum number of viable sperm is found in the ejaculate after a 48-hour abstinence

• after entering receptive cervical mucus, sperm are capable of fertilising an egg for at least 48 hours

• sperm survive for less than 30 minutes in the vagina due to an acidic environment

Female fertility

Fertility in the female requires:

• normal function of the ovulatory cycle, which requires:

  • – normal hypothalamic–pituitary function producing the hormones GnRH, FSH and LH

  • – normal ovarian function with follicular response to FSH and LH (see FIG. 115.1)

  • – appropriate prolactin levels (which are normally low); excessive prolactin secretion (hyperprolactinaemia) causes anovulation

• normal tubal transport and access of the ovum to incoming sperm

• receptive cervical mucus

• normal uterus to permit implantation of the fertilised ovum

Probabilities of pregnancy

About 50% of normal couples, having unprotected intercourse at least twice a week, will probably achieve pregnancy in 6 months, 85% in 1 year and 95% in 2 years.⁶

Significant causes of infertility are summarised in TABLE 115.1 and illustrated in FIGURE 115.2.

History

Ask each partner for their age and take a general medical history, including family history, medication and drug use. Enquire about previous pregnancies in current or past relationships and outcomes.

• Sexual function (problems with erections, ejaculation)

• Age of puberty

• Previous testicular problems/injury (e.g. orchitis, trauma, undescended testes, torsion)

• Past history (PH) of STIs

• PH of mumps

• PH of urethral problems

• Genitourinary surgery (e.g. hernia, vasectomy reversal)

• Occupational history (exposure to heat, pesticides, herbicides)

• Medications and drug use:

  • – alcohol

  • – smoking

  • – chemotherapy

  • – radiotherapy

  • – anabolic steroids

  • – aminoglycoside antibiotics

  • – sulphasalazine

  • – cimetidine/ranitidine

  • – colchicine

  • – spironolactone

  • – antihypertensive agents

  • – narcotics

  • – phenytoin

  • – nitrofurantoin

  • – marijuana

• Onset of menarche

• Menstrual history

• Symptoms of ovulation (cervical mucus changes, mittelschmerz)

• Symptoms of endometriosis (dysmenorrhoea, pelvic pain, dyspareunia)

• PH of STIs and pelvic infection

• Previous IUCD use

• PH of intra-abdominal surgery (e.g. appendicitis, ovarian cyst)

• PH of genitourinary surgery

• Medications and drug use:

  • – alcohol

  • – smoking, especially >20/day

  • – past contraception, especially depot provera

  • – anabolic steroids

• Time trying to conceive

• Frequency and timing of intercourse

• Attitudes to pregnancy and subfertility

• Expectations for the future

Examination

A general assessment of body habitus, BMI, general health and secondary sexual characteristics should be noted in both man and woman.

• Secondary sexual characteristics; note any gynaecomastia

• Genitalia

  • – size and consistency of the testes—can compare to an orchidometer: normal range 15–35 mL (average 18 mL); small in Klinefelter syndrome (approx. 7–8 mL)

  • – palpate epididymis and vas (present and non-tender is normal)

  • – evidence of varicocele

  • – PR: check prostate

  • – note penis and location of urethra (always retract the foreskin for examination)

• Secondary sexual characteristics

• Thyroid status

• Note skin for acne, hirsutism

• Vaginal and pelvic examination:

  • – assess uterus and ovaries (normal—present, mobile and non-tender)

  • – the adnexae (any masses)

Investigations

These are usually performed after referral but the family doctor should organise initial investigations to assess where to refer (e.g. andrologist, endocrinologist, gynaecologist or fertility specialist).

Male—semen analysis⁷

Collection should be made directly into a sterile container 2–3 days after sexual abstinence. If collected at home, semen should be kept at body temperature during transport to the laboratory and examined within 1 hour of collection. A repeat test in 1–3 months is indicated if the first is abnormal.⁷

• Normal values (based on WHO criteria):

  • – volume ≥1.5 mL (average 2–6 mL)

  • – pH ≥7.2

  • – concentration ≥15 million sperm/mL

  • – total sperm count ≥39 million

  • – motility after 2 hours ≥32%

  • – vitality ≥58%

  • – normal forms ≥4%

  • – leukocytes <1.0 x 10⁶/ml

Female—ovulation status³

In most cases, regular menstrual cycles between 26 and 34 days, with appropriate variation in cervical mucus (thin at mid-cycle and thicker in the luteal phase) suggest ovulation is occurring. If ovulatory dysfunction is suspected, the following investigations are appropriate:

• serum LH, FSH and oestradiol (help identify primary hypothalamic-pituitary failure or dysfunction and primary ovarian disease; see TABLE 115.2)

• midluteal phase progesterone (day 21 of 28 day cycle, or 7 days before next expected period); >30 nmol/L can be used to confirm ovulation

• androgens (free testosterone, SHBG, free androgen index, 17-OH progesterone)

• thyroid function tests

• serum prolactin

• transvaginal high-resolution ultrasound (day 5–9 of cycle) for ‘antral follicule count’—allows assessment of ovarian reserve, ovarian pathology or uterine structural abnormalities.

• anti-Mullerian hormone (AMH)—a predictor of ovarian function and reserve. Not essential although useful. Interpretation may be complicated and require specialist input.

Further investigations³

Male

If azoospermia or severe oligospermia (usually under specialist guidance):

• serum FSH level (if 2.5 times normal, indicates irreversible testicular failure)

• LH

• testosterone

• prolactin

• antisperm antibodies (in serum, semen or directly bound to sperm)

• sperm function tests

• genetic testing:

  • – karyotype

  • – Y chromosome microdeletions

  • – cystic fibrosis gene mutation

• ultrasound of the scrotum +/− urogenital tract

• post-ejaculatory urine analsis (for retrograde ejaculation)

Female¹⁰

• routine preconception screening

• thyroid antibodies (TPO antibody-positive females have a higher incidence of subfertility)

• chlamydia (first-pass urine NAAT) if indicated

• consider genetic testing for fragile X gene mutation, cystic fibrosis and spinal muscular atrophy

Specialised investigations:

• hysterosalpingo-contrast-ultrasonography (Hy-Co-Sy)

• hysteroscopy/laparoscopy

• tubal dye studies

Management principles

• Both partners should be involved in management decisions since fertility is a couple’s issue.

• All couples should be encouraged to optimise their general health through lifestyle changes such as weight optimisation, exercise, smoking cessation and minimised alcohol intake.

• Infertility can cause considerable emotional stress, including the taking or placing of blame by a partner and subsequent feelings of guilt. Sensitive and empathetic support is essential. This may include marital counselling.

Fertility awareness

Couples may require the following education on timing of intercourse:

• it is ideal to have intercourse every 2 days in the week before the expected time of ovulation³

• ova can survive up to 24 hours and sperm up to 5 days within the female genital tract

• ovulation generally occurs 14 days before menstruation

• ovulation may be identified with cervical mucus changes, when mucus becomes more slippery or like egg white

• the chance of fertilisation is best on the day of ovulation or during the time of the slippery sensation

• 2 days after ovulation, basal temperature rises slightly, around ¼–½ a degree

• recording temperature every morning for a few months can show if ovulation is regular and help predict the day of ovulation

• many women find fertility tracking websites or apps a useful aid

• urine-based ovulation detection kits are available but can be difficult to interpret

• for women with irregular periods, ovulation tracking may be of value through fertility laboratories in the treatment setting

‘Fertility awareness practitioners’ are available for couples interested in pursuing natural fertility methodology as an alternative to assisted reproductive technology.

Polycystic ovarian syndrome⁴

PCOS is a common condition, present in 12–18% of women of reproductive age.¹¹ It should be noted that it is not the same as polycystic ovaries, which occur in approximately 25% of asymptomatic, normal women.¹²

General features

Patients may present with the following:

• ovarian dysfunction—subfertility, oligomenorrhoea, anovulation

• androgen excess—acne, hirsutism and malepattern balding

• metabolic features—upper truncal obesity, impaired glucose tolerance, dyslipidaemia, diabetes

• psychological symptoms—anxiety, depression, eating disorders

Aetiology²

Polycystic ovary syndrome is typically associated with insulin resistance. Insulin resistance and hyperinsulinaemia drive ovarian androgen production and suppress sex hormone–binding globulin (SHBG), leading to greater bioavailability of androgens. There is a strong hereditary basis and it is more common in Aboriginal and Torres Strait Islander and South-East Asian women. The onset can be triggered by environmental factors, particularly weight gain.

Diagnosis/investigations

Diagnosis of PCOS is made using the Rotterdam criteria, in which 2 of the following criteria are required:

• history of oligo/anovulation

• hyperandrogenism

  • – clinical (hirsutism or, less commonly, malepattern alopecia), or

  • – biochemical (raised FAI or free testosterone)

• polycystic ovaries on ultrasound (at least 10 small antral follicles seen in each ovary)

Note: In young women, menstrual cycles may take up to 2 years to regulate after menarche. Irregular cycles persisting into the third year post-menarche should be investigated for PCOS.

Ultrasound is not reliable in the diagnosis of polycystic ovaries in adolescent and young women. Up to 70% of young women may have polycystic ovaries on ultrasound.

Suggested screening for all women with PCOS

• smoking history

• blood pressure

• fasting blood glucose levels

• oral glucose tolerance test (every 2 years in women with additional risk factors)

• lipid profiles

Management strategies

First-line⁴

• lifestyle modification—weight reduction and exercise (even 5% weight loss may restore normal ovarian function)

• consider PCOS support group or psychological support

For women with subfertility

• screening and treat if necessary:

  • – impaired glucose intolerance and diabetes mellitus

  • – hyperlipidaemia

  • – hypertension

• primary treatment of insulin resistance:

  • – metformin

• ovulation induction—clomiphene/letrozole/gonadotrophins

• laparoscopic ovarian surgery/drilling (second-line after medical treatment)

• assisted reproductive technology (ART)

The counselling of subfertile couples has to be adapted to the level reached by the couple along the infertility pathway. The needs of each couple may be very different depending on their emotional nature, their lifestyle, and their moral, religious and ethical beliefs. However, their suffering can run very deep and deserves attention, time and opportunities for free expression of feelings and concerns.

The medical counselling model developed by Colagiuri and Craig¹³ (see FIG. 5.1 in CHAPTER 5) is very useful as it empowers patients to make their own decision through facilitation as opposed to the directive and advisory medical model.

The couple are provided initially with accurate and appropriate information. Anxiety is alleviated by reassurance and by dispelling myths.

The facilitation process enables the couple to ventilate any feelings of guilt, anxiety, fear, anger and sexuality. The style of questioning should aim to explore the influence that the problem has had on the couple and then the influence they have over it. These processes then lead to decision making by the couple about further management strategies.

A graph of emotional responses to the infertility (see FIG. 115.3) can be used to help the couple explore their current and past emotional responses to their problem. Apart from helping them realise that their problem is not unique, it provides opportunities for ventilation of important feelings that can act as a basis for counselling.

Treatment options for female subfertility:

• Ovulation induction

  • – metformin (for women with PCOS, use alone or with clomiphene)

  • – clomiphene citrate

  • – letrozole

  • – gonadotrophins

    • FSH

    • LH

    • human chorionic gonadotrophin (hCG)

  • – bromocryptine for hyperprolactinaemia

• Endometriosis

  • – surgical ablation/excision of deposits and division of adhesions

• Surgical repair of tubal obstruction, removal of uterine septum, myomectomy and hysteroscopic resection of intrauterine adhesions are other surgical treatment options.

Treatments for male subfertility:⁷

• gonadotrophin therapy for men with hypogonadotrophic hypogonadism

• microsurgical vasovasostomy (vasectomy reversal)

• surgical correction of varicocele with oligozoospermia (role unclear)

• sympathomimetic agents (e.g. pseudoephedrine) may correct retrograde ejaculation

Assisted reproductive technologies (ARTs) such as in vitro fertilisation (IVF) have revolutionised the treatment of infertility. It is estimated that more than 1.8 million ART cycles were undertaken worldwide in 2010, and that more than 6 million children have been conceived using these technologies over the last three decades.¹⁴

A recent study in Australia and New Zealand estimated the cumulative live birth rate of ART for all ages was 32.7% for the first complete cycle, rising to 54.3–77.2% by the eighth cycle. Success rates were significantly lower in women aged over 40, with an estimated cumulative live birth rate of 10.7% for the first complete cycle, rising to 21.0%–37.9% by the eighth cycle. IVF is rarely recommended to women aged over 44 years.⁵

Treatment options include:¹²

• IUI (intrauterine insemination with the partner‘s sperm)

• IVF (in vitro insemination)

  • – involves the retrieval of ova, which are mixed with sperm and incubated for 2–6 days—the resultant embryo is then transferred into the uterus via the cervix

  • – embryos can be frozen and stored cryogenically for up to 10 years; frozen embryos can be thawed and transferred to the uterus

• ICSI (intra-cytoplasmic sperm injection)

  • – a single sperm is injected into an egg for fertilisation outside the body and then replaced into the uterus

• PGD (preimplantation genetic diagnosis)

  • – recommended if a partner is affected by or carries a known genetic disease, if a couple have had multiple miscarriages or have had a number of failed embryo transfers

Since poor outcomes in subfertile couples are associated with delay in identification and treatment, early investigation instituted by the GP is important to expedite possible specialist involvement.

Referral is recommended after planned conception for:³

• 1 year if the woman is ≤35 years

• 6 months if the woman is >35 years

Consider early referral for women with amenorrhoea or oligomenorrhoea, or for couples with a known reason for infertility.