Introduction

Subfertility (also described as “infertility”) is diagnosed if a couple fails to conceive in one year of regular, unprotected sexual intercourse. It is estimated that one in seven couples in the UK has difficulty conceiving.

80% of couples will conceive after one year of regular, unprotected sexual intercourse, as long as the female partner is aged <40

Of the 20% who fail to conceive, half of these will conceive in the second year, giving an overall pregnancy rate over 2 years of 90%

Couples should be offered investigation and treatment if they fail to conceive after one year of regular intercourse

Subfertility can be a result of male or female reproductive issues. In about 25% of cases, no cause is found. In the cases in which a cause is found, about half of the time a male cause will be identified, and about half of the time a female cause will be found. In 40% of cases, disorders are found in both men and women.

The main causes of infertility are:

Unidentified – 25%

Ovulation disorder – 25%

Tubal damage – 20%

Male infertility disorder – 30%

Female Causes

25% anovulation

20% tubal disorders

5% Cervical problem (scarring after surgery, mucus dysfunction)

5% Sexual problem

30% Defective implantation due to endometrial problem (fibroids, adhesions or polyps)

Sometimes causes of subfertility remain unexplained. Couples should be advised that modifiable factors such as increased BMI, use of recreational drugs and heavy smoking can reduce fertility.

For women, Polycystic ovary syndrome (PCOS) is by far the commonest cause. Other causes of aovulation include hypothalamic hypogonadism, hyperprolactinaemia, premature ovarian failure and thyroid disease (both hyper- or hypothyroidism can cause subfertility)

At this point, it is probably worth a quick mental refresher of The Menstrual Cycle !

Causes of female infertility can be divided into:

Problems of ovulation

Problems of the tubes, uterus or cervix (anatomical disorders)

Other Hypoerprolactinaemia Premature Ovarian Failure Chromosomal disorders



Disorders of ovulation

There are 3 types:

Group I – Hypothalamic Pituitary failure

Hypogonadotrophic hypogonadism – There is a failure of the hypothalamic-pituitary axis to produce the required amounts of FSH and LH. The end result is that there is no ovulation.

Group II

Sometimes referred to in this context as hypothalamic-pituitary-ovarian dysfunction.

The result of PCOS

This is the most common cause of ovulation disorders

The excess androgens that are associated with PCOS inhibit ovulation

Group III – Ovarian failure

Hypergonadotrophic hypogonadism – there is normal function of the hypothalamus and pituitary gland, however, there are insufficient follicles in the ovary. As a result, follicles do not develop fully and not as much oestrogen is produced. As a result – ovulation does not occur.

Premature ovarian failure

Defined as cessation of menses before the age of 40 (many gynaecologists use age <45). Typically as a result of exhaustion of the supply of oocytes. Affects about 1% of women. Can be caused by:

Genetic factors

Autoimmune disease

Damage to ovaries by radiotherapy, chemotherapy, surgery or other cause

Hyperprolactinaemia

A very common cause of female infertility

Prolactin is another hormone usually produced by the pituitary gland, and as such, it can affect the hypothalamic pituitary axis

High levels of prolactin inhibit the release of GnRH from the hypothalamus as part of a feedback loop. As a result, in hyperprolactinaemia normal levels of FSH and LH that are normally produced by the pituitary are reduced. This can result in anovulation.

the release of GnRH from the hypothalamus as part of a feedback loop. As a result, in hyperprolactinaemia normal levels of FSH and LH that are normally produced by the pituitary are reduced. This can result in anovulation. Common causes include: Hypothyroidism Pituitary tumour

Other pituitary tumours can also cause anovulation

Chromosomal disorders

Turner Syndrome (X-) Loss or abnormality of the second X chromosome Ovaries typically do not develop, or are very underdeveloped

Klinefelter’s Syndrome – XXY

XXX karyotype The most common female chromosomal abnormality 1 in 1000 females Typically normal fertility, but an increased risk of premature ovarian failure



Problems of tubes, uterus and cervix

Fallopian tubes are the most commonly damaged part of the anatomy. There are delicate structures with cilia that helps to ‘waft’ the egg from the ovary towards the uterus. Problems can be congenital (about 2%) or acquired (98%). Causes of acquired problems include:

Pelvic inflammatory disease Chlamydia and gonorrhoea are the most common causes

Previous termination Rarely seen if done in western world by qualified gynaecologist. “Back street abortions” may cause fallopian damage

Postpartum infections in previous pregnancies

Abdominal infections (typically as a result of adhesions) – e.g. previous appendicitis

Endometriosis – again, due to adhesions

Cone biopsy may alter the anatomy of there uterus and reduce fertility

Cervical mucus issues

Fibroids

History and Examination

Age, occupation – female fertility significantly declines after the age of 40; occupational exposure to pesticides, nitrous oxide, formaldehyde, and solvents can reduce fertility

– female fertility significantly declines after the age of 40; occupational exposure to pesticides, nitrous oxide, formaldehyde, and solvents can reduce fertility Any previous pregnancies – to identify whether it is primary or secondary subfertility

– to identify whether it is primary or secondary subfertility Length of time spent trying for pregnancy

spent trying for pregnancy Length of time since stopping contraception and type of contraception – make sure that there are no problems that may explain the inability to conceive, such as a ‘lost’ intrauterine contraceptive device.

and type of contraception – make sure that there are no problems that may explain the inability to conceive, such as a ‘lost’ intrauterine contraceptive device. Coital frequency – to identify any difficulty with intercourse. Advised should be having regular (at least 2-3x per week) intercourse. Assess if any difficulties such as inadequate penetration or dyspareunia

– to identify any difficulty with intercourse. Advised should be having regular (at least 2-3x per week) intercourse. Assess if any difficulties such as inadequate penetration or dyspareunia Menstrual history

Previous history of pelvic inflammatory disease (PID) or other STI. When was her last STI check?

(PID) or other STI. When was her last STI check? Previous medical and surgical history Particularly for previous chemotherapy – e.g. for childhood leukaemia, or surgery or radiotherapy Medical conditions that are relevant include – SLE, CKD, diabetes, anorexia nervosa

Previous fertility treatment

Previous sterilisation

Cervical smear history

General health – screen for history of thyroid disorders, diabetes, excessive exercise, weight loss, or psychological distress.

General observations – BP, pulse, height and weight – both increased and decreased BMI is associated with reduced fertility BMI <19 – advised increasing BMI likely to increase fertility BMI >30 – likely to take longer to conceive and is associated with anovulation (probably related to PCOS) Participation in group programs involving diet and exercise advice – rather than simply receiving doctors weight loss advice – is associated with higher rates of pregnancy

Alcohol Advise drinking no more than ??2 units (??2 standard drinks) on 2 days per week, to avoid intoxication and advise that alcohol can cause serious harm to the developing foetus and after conception, total abstinence is recommended.

Smoking is associated with Reduced fertility Increased risk of miscarriage Increased risk of obstetric complications Intrauterine growth restriction Delayed reading ability at least to phage of 7 in the child

Abdominal examination Any masses?

Pelvic examination – Any uterine pathology such as fibroids?

Vaginal / bimanual examination – may be indicated – typically by specialist

Signs of hirsutism – may indicate PCOS Facial hair Acne Male pattern baldness Male pattern pubic hair growth

– may indicate PCOS

Male causes

Can be roughly divided into:

Disorders of the testes and spermatogenesis

Disorders of the genital tract

Other

Disorders of the testes and spermatogenesis

Azoospermia is the absence of motile sperm in the semen

is the absence of motile sperm in the semen The lower the sperm count, the worse the prognosis

Persistent azoospermia is incompatible with fertility

Genetic disorders Kliefleter’s syndrome – XXY – associated with hypogonadism and disorders of spermatogenesis. It is the most common chromosomal disorder associated with infertility Kallman syndrome Androgen insensitivity syndrome – XY karyotype, but outwardly appears female due to insensitivity to androgens

Cryptorchidism Failure of the testes to descend Early orchidopexy (age 6-12 months) improves spermatogenesis and fertility in adulthood

Varicocoele Associated with reduced fertility Repair may improve sperm counts (controversial)

Testicular tumours

Trauma

Pituitary causes Pituitary tumours Hyperprolactinaemia May cause reduction of GnRH secretion, which in tern leads to reduction in FSH and LH, and reduced testosterone. Rare in men. Usually the result of a pituitary tumour. Symptoms may include reduced libido and erectile dysfunction Cushing’s disease Panhypopituitarism



Disorders of the genital tract

Congenital

Previous vasectomy Even if the procedure is revered, sperm antibodies have often developed, making proper spermatogenesis difficult

Obstruction of epididymis, ejaculatory ducts or seminal ducts Can be acquired following trauma, surgery or infection May be congenital



Other Causes

Retrograde ejaculation, anejaculation

Erectile dysfunction

Idiopathic No cause is identified in about 45% of men



History and Examination

Fathered any previous pregnancies?

History of mumps or measles – oligospermia due to previous testicular infection, testicular trauma, surgery to testis, testicular torsion, any history of STI

History of treatment for previous malignancy – e.g. chemotherapy or radiotherapy

Obesity – there is direct relationship between the BMI and the quality of the sperm. Men with a BMI should be informed that they likely have reduced fertility due to their weight

Smoking – proven to reduce male fertility

Tight fitting underwear – known to reduce sperm quality – probably due to the increased scrotal temperature associated with this type of underwear

Alcohol – excessive alcohol intake reduced fertility. Drinking in within safe recommended limits has not been associated with a reduction in fertility

Ilicit drugs – the following have all been associated with reduced fertility: anabolic steroids, marijuana, opioids, cocaine, methamfetamines.

Testicular examination – testicular volume, consistency, masses, absence of vas deferens (associated with Cystic Fibrosis), variocele, evidence of surgical scars

Investigations

Female

Cervical sample for ??pap smear (??HPV DNA) and chlamydia + gonorrhoea (NAAT) ??May not be covered by medicare if not part of normal cervical screening programme – warn the patient it will cost around $120

FBC, blood group, TFTs, rubella, syphillis varicella, hepatitis B and C, HIV serology

Day 1-3 of cycle (baseline) profile – FSH, LH, TSH, prolactin, free testosterone, free androgen index – to check for hypothalamic-pituitary-ovarian axis dysfunction ↑FSH – >10 indicates reduced ovarian reserve, >40 indicated ovarian failure ↓FSH – indicates hypothalamus-pituitary axis disorder Consider testing progesterone 7 days before menses ( Day 21 progesterone ) if periods are regular enough to predict this – “Mid-luteal progesterone” (should be raised if woman has ovulated, low if ovulation is not occurring. Repeat second time if low on first test as ovulation does not occur every month) ↑LH – compared to FSH suggests PCOS Note that oestrogen is NOT a useful test

Anti-Mullerian Hormone (AMH) produced by ovarian granulosa cells is a marker for ovarian reserve (controversial). Women with premature ovarian failure will have very low AMH count (and post-menopausal women will have an undetectable AMH count) If low – suggests need for treatment (prompt referral to specialist if in primary care) Often raised in PCOS Normal range is dependent on age Can be performed at any time of the cycle providing is not taking COCP

Transvaginal USS to assess for PCOS, fibroids and other pelvic pathology

Check tubal patency by hysterosalpinogram (HSG): dye injected into the uterus and view under X-ray or hysterocontrast synography (HyCoSy0: using ultrasound [both screening tests] or operative laparoscopy and dye test [the diagnostic test]

When assessing ovarian reserve, additional specialist tests are often used in relation to IVF. These include:

Antral follicle count

Ovarian blood flow and volume

Inihibin B

Estradiol (E2)

Male

Semen analysis (after patient has abstained from sexual intercourse for 3-4 days)

Advise the patient to discuss with the laboratory before they collect the sample for the specific instructions / requirements Sample should be produced by masturbation without a condom as these often contain spermicides The specimen needs to be kept warm and delivered to the lab promptly – usually within 1 hour. This also often needs prior arrangement with the lab so that they are ready to assess the specimen promptly when it arrives

Normal parameters for semen analysis (WHO criteria)

Volume >1.5ml pH >7.2 Sperm concentration >15 million per mL Total sperm number >40 million per ejaculate Motility >32% grade a or b (that move forward – progressive motility) Morphology >4% normal forms

Oligozoospermia – <15 million per ml

<15 million per ml Asthenozoospermia – <32% motile sperm

<32% motile sperm Teratozoospermia – <4% normal forms

<4% normal forms If abnormal, repeat in 6 weeks If azoospermia – repeat as soon as practicable

Absence of motile sperm is referred to as azoospermia

If the repeat test is abnormal: Test FSH, LH prolactin and testosterone levels ↑FSH – suggests primary spermatogenesis failure. Consider referral for karyotyping (e.g. Klinefelter’s syndrome) ↔FSH – suggests obstructive cause ↓FSH – suggests pituitary disorder (rare) Do USS scrotum to look for obstructive causes Consider testicular biopsy. In 60% of patients with non-obstructive azoospermia, sperm can be harvested by this method Screen for HIV, Hep B and Hep C Fasting glucose or HbA1c to screen for diabetes mellitus

Assisted conception (see below) may be useful for couples where the man has a slightly abnormal sperm count, or if the cause is unknown.

Management – Female Infertility

There are three types of infertility treatment.

Medical

Group I ovulation disorders

This is women with hypothalamic-pituitary failure

Advise to increase BMI to >19 if low, and advise about over-exercising

Pulsatile GnRH (gonadotrophin release hormone) OR GnRH with LH can induce ovulation in these patients

Ovulation induction with anti-oestrogen drugs

This is useful for women with Group II Ovulation disorder (PCOS)

Clomifene citrate – CC (+ hCG) is an effective treatment for anovulation and may be used in women in PCOS. CC is an anti-oestrogen. hCG (function is similar to LH in this circumstance) is injected later to induce final oocyte maturation and its release Clomifene SE: hot flushes and reversible ovarian enlargement hCG injection can cause ovarian hyperstimulation syndrome (OHSS), with the development of vascular hyperpermeability and the resulting shift of fluids into the third space – causing pleural effusion and ascites Women with BMI >30 should be advised to have BMI <30 before treatment Women should be monitored regularly by ultrasound (for ovarian changes) Maximum treatment duration: 6 months

Metformin may be added in women with PCOS and a BMI greater than 25 who are unresponsive to clomifene.

Gonadotrophins These may be offered to women with clomifene-resistant anovulatory infertility, but they carry a significant risk of multiple pregnancy.

Dopamine agonists can be considered for women with ovulatory disorders secondary to hyperprolactinaemia.

Surgical

Tubal surgery may be effective in women with mild tubal disease. Tubal catheterization or cannulation improves the chance of pregnancy in women with proximal tubal obstruction.

Laparoscopic surgery appears to improve the chance of pregnancy in women with all grades of endometriosis

Surgical correction of epididymal blockage in men with obstructive azoospermia is likely to restore patency of the duct and improve fertility.

Assisted Conception

Intrauterine insemination (IUI)

In this process, which is timed to coincide with ovulation, sperm is placed in the woman’s uterus using a fine plastic tube.

Can be performed with natural or induced menstrual cycles

Recommended for for couples with mild male factor fertility problems, unexplained fertility problems, or minimal to mild endometriosis Donor sperm can be used in cases of more severe male fertility

factor fertility problems, unexplained fertility problems, or minimal to mild endometriosis Women must have patent Fallopian tubes

Patients may consider skipping this step if they have already been trying to conceive for 2 years

In-vitro fertilization (IVF)

About 25% of IVF treatments result in a live birth About 65% of women who undergo IVF are >37 The chances of success reduce with advancing age ??NHS guidelines suggest to offer 3 cycles of IVF to women <40 A single NHS funded cycle to women >40 if they have never had IVF before

Ovarian stimulation therapy is given with USS monitoring

The next step involves retrieval of one or more eggs, which are mixed with sperm and incubated for 2–3 days; the resultant embryo is then injected into the uterus via the cervix. Usually a single embryo only is transferred In the past 2-3 were often implanted, commonly resulting in the birth of twins and triplets

Recommended for all couples in which the woman is aged 23–39 years at the time of treatment and who have an identified cause for their fertility problems (e.g. azoospermia or bilateral tubal occlusion) or who have infertility of at least 2 years’ duration, or have had at least 12 attempts of IUI

Women must have functional ovaries

Can be performed with partner’s or donor sperm

Ovarian hyperstimulation syndrome (OHSS)

Beware of ovarian hyper stimulation syndrome (OHSS) as a result of some of the hormonal therapies used to stimulate ovulation. OHSS is a purely iatrogenic condition.

It is particularly associated with the use of hCG, and less so with clomifene. It can occur as part of the process of IVF, or as part of ovulation induction in PCOS.

OHSS is a systemic condition, caused by increased vascular capillary permeability as a result of a rise in serum hCG – produced by the stimulated follicles.

OHSS can be fatal (rare)

The severity of the condition is correlated to the size of the ovaries. Ovaries >12cm suggest severe OHSS.

A mild degree of OHSS occurs in about 30% of IVF cycles

Severe cases occur in about 1% of IVF cycles

Risk factors include: PCOS Age <30 hCG use in the luteal phase Low body weight Rapidly rising oestrogen levels Large number of follicles Large ovaries

Symptoms include: Abdominal pain Bloating Ascites Increased ovarian size Nausea Vomiting Diarrhoea Tachycardia Hypotension Oliguria Electrolyte abnormalities Pleural effusions

Symptoms typically start within 24 hours of hCG use and develop over a period of 7-10 days

Management is essentially supportive Withhold hCG Egg collection can still occur, but embryos should be frozen and not implanted Paracetamol Avoid NSAIDs Oral fluids to replace intravascular fluid losses Milder cases managed at home with checkups every few days In moderate cases hospital admission and thromboprophylaxis may be appropriate Severe cases may need ICU and / or IV fluids, albumin, aspiration of ascites, management of ARDS, pleural effusion



Many studies have looked at the risks and causes of OHSS, and recommendations to reduce its incidence include:

Individualised stimulation regimens

Use of GnRH rather than hCG as the ovulation trigger Reduced OHSS but also reduces live birth rates

Use of progesterone instead hCG for luteal phase

Use of cabergoline at same time as hCG administration Reduces risk in high risk patients



Intracytoplasmic sperm injection (ICSI)

This involves injecting an individual sperm directly into the egg, to bypass natural barriers that prevent fertilization.

Used as an adjunct to IVF where previous IVF cycles have failed to produce fertilisation

Other methods include donor insemination (for male with little to no sperm, absent vas deferens), oocyte donation (for female with premature ovarian failure), embryo donation and Gamete intra-fallopian transfer (GIFT).

Management – Male Infertility

Abnormal sperm counts

If an obstructive cause is found, surgery should be offered as it is often able to restore patency of the tract and restore fertility

Persistent non-obstructive azoospermia is usually incompatibly with fertility Advise patients they may wish to seek a sperm donor It may be possible in some circumstances to “harvest” sperm directly from a testicular biopsy – depending on the cause

Advise about lifestyle factors: Wear loose fitting clothing Smoking cessation Maintain healthy BMI Healthy diet and regular exercise

Treatments not routinely recommended Hormonal therapies – e.g. anti-oestrogen, or androgen, or kinin-enhancing therapies therapy – not proven to be effective Corticosteroids for anti-sperm anitboies (if present) has not been proven effective Antibiotics for leukocytes positive semen – have not been proven to improve fertility in the absence of a proven infection Surgery for varicocele – (controversial) – has not been consistently shown to improve pregnancy rates

routinely recommended

Disorders of the genital tract

Hypotrophic hypogonadism Gonadotrophins can improve fertility

Cryptoorchidism (undescended testes) Orchidopexy (surgical lowering of the testicle) can improve sperm counts – unclear if that actually increases fertility

Obstructive lesions Should be surgically fixed



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References

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