What you need to know about infertility
Gynaecologists Dr Ingrid Granne and Dr Tim Child answer Dr Sabby Kant’s questions on semen testing, tests to carry out before referral and what to advise couples worried about conception
Gynaecologists Dr Ingrid Granne and Dr Tim Child answer Dr Sabby Kant's questions on semen testing, tests to carry out before referral and what to advise couples worried about conception
1 Could you give a brief description of the different types of infertility and their definitions?
Sub-fertility, whether primary or secondary, can broadly be divided into four categories:
• Male factor – this may be due to disorders of spermatogenesis and most commonly no underlying cause is found. Less commonly, low or absent sperm counts may be caused by primary testicular failure (with a raised FSH and low testosterone) or hypogonadotrophic hypogonadism (where both FSH and testosterone are low). Obstruction or congenital absence of the epididymis, vas deferens or seminal vesicles may be the cause of azoospermia.
• Anovulation – this is most commonly caused by polycystic ovarian syndrome (PCOS). In PCOS, FSH levels are normal. Hypogonadotrophic hypogonadism, where FSH is low, may be due to low body weight or excessive exercise or it may be idiopathic. Premature menopause, and a resulting high FSH, may be genetic, occur secondary to chemotherapy or radiotherapy, or be idiopathic.
• Tubal factor – the most common cause of tubal disease is a previous sexually transmitted infection, especially chlamydia. The incidence in the teenage population in some areas is as high as 12%. Chlamydia is often asymptomatic and may only be diagnosed years later at laparoscopy when tubal occlusion and classical adhesions are seen. Tubal damage may also occur as a result of adhesions after pelvic surgery and obviously surgery for ectopic pregnancy may result in removal of a tube.
• Other causes – endometriosis is known to be found more commonly in women who are subfertile than in the fertile population – 20% compared with 5%. Fibroids may be found in up to 30% of women. Those that are polypoid or are very near to the endometrium may be clinically relevant and in these patients removal may increase the chance of pregnancy. There is evidence to suggest that the presence of intramural fibroids decreases the chance of embryos implanting during IVF.
Up to 25% of patients presenting to a fertility clinic may ultimately be given a diagnosis of ‘unexplained subfertility' where sperm parameters, tubal patency and ovulation are all found to be normal. This can often be a frustrating diagnosis for patients but we currently do not have tests that tell us about sperm or egg quality or the ability of sperm to fertilise an egg.
2 I sometimes see couples who are worried they haven't conceived as little as six months after starting to try. How long should couples have tried to conceive before I consider starting investigations and possibly referring?
About 84% of couples who try to conceive while having regular intercourse will do so within one year of trying. The cumulative pregnancy rate after two years is 92%. So after six months of trying the appropriate advice for most couples is reassurance as well as giving pre-pregnancy counselling regarding folic acid, rubella immunity, weight, smoking and alcohol intake. It is also essential to be sure that couples are having regular intercourse.
With regard to the appropriate time to refer, this does somewhat depend on the age of the female partner. A 27-year-old with regular periods and no other gynaecological history, for example endometriosis, presenting with six months of subfertility would certainly be best advised to try for a year before starting any investigation.
After a year it would be appropriate to confirm ovulation and check a semen analysis. If these were normal, waiting another year before referral would be reasonable, if the couple agreed.
Advice to a woman approaching 40 would be different. Both natural fertility and success rates of assisted conception decline very rapidly at this age. Thus referral after a year would be appropriate.
Of course there are some patients who warrant more immediate investigation and referral – for example, women with a history of pelvic inflammatory disease or PCOS with absent periods.
3 What do you say to couples who ask about the best time to have sex to maximise the chance of conception?
It's very common for couples to seek advice regarding timing of sex and they often spend a lot of time, effort and money on predicting ovulation and having intercourse when they assume ovulation to be occurring.
But the best way of optimising the chance of pregnancy is to have intercourse every two to three days throughout the menstrual cycle. Timing intercourse for most couples is likely to make the whole experience more stressful and clinical but won't increase the chance of pregnancy.
4 Can you summarise what's measured in a sperm test and how to interpret and manage an abnormal sperm test?
Sperm test results should be compared to the World Health Organization reference values (see box).
The total number of normally moving sperm is essentially a multiplication of the semen volume, the concentration of sperm per millilitre and the percentage of motile sperm. So a sample with a volume of 4.5ml and a count of 85 million/ml with a forward progression of 30% would be an overall normal picture despite the relatively low motility.
Sperm test results do vary over time and if the findings of a sperm test are mildly abnormal – for example, a count of 17 million/ml – then the test should be repeated. An initial test may have been affected by an earlier febrile illness.
Waiting three months before repeating the test allows time for the sperm to recover, as a cycle of spermatozoa formation takes about 70 days. But if the test is very poor – with very few or no sperm found – then a repeat test and immediate referral is appropriate.
It is always worth checking with a patient that they followed advice about appropriate days of abstinence before producing the sample (two to five) and that the sample was taken to the pathology department immediately after production, as a delay will result in reduced motility.
5 What different methods are there to confirm that the woman is ovulating?
Women with a regular menstrual cycle are likely to be ovulating. The luteal phase of the menstrual cycle is fairly constant, lasting about 14 days. Progesterone levels peak at the mid point of the luteal phase. Therefore blood progesterone levels should be taken one week prior to the anticipation of a period – for example, on day 21 of a 28-day cycle or 27 of a 34-day cycle.
Women with irregular cycles may need a progesterone test to be repeated weekly until menses occurs in order to assess when ovulation occurred in a long cycle.
Many women are keen on home methods of tracking ovulation. Some measure their basal body temperature daily. This works on the premise that body temperature is higher in the luteal phase of the cycle.
Many commercial urine dipstick kits are available to identify the luteinising hormone (LH) surge. LH is the hormone that triggers ovulation and is at its highest about 36 hours before ovulation occurs.
Urine LH tests are started daily from about day 11 of a 28-day cycle and the start date adjusted depending on cycle length.
But for most women with regular cycles, these methods are time-consuming and often costly. They may well increase anxiety and there is no evidence that using them increases pregnancy rates.
6 What investigations should GPs perform before they refer patients to hospital?
It may be worth contacting your local fertility clinic to be certain what local clinicians want. But there are some basic investigations worth doing before referring any patients.
• Semen analysis – this should be taken from all male partners even if they have children from previous relationships.
• Mid-luteal progesterone to confirm ovulation – in women with an irregular cycle it may be helpful to repeat the progesterone several times in one month, for example at day 21 and day 28.
• FSH, TSH and prolactin – this is appropriate in women with irregular cycles. This profile is also used to assess ovarian reserve before assisted conception. Blood should be taken between day one and day five of the cycle. FSH is a surrogate marker of ovarian reserve and in postmenopausal women is very high – greater than 40mIU/ml. In younger women levels greater than 12mIU/ml may be reflective of decreased ovarian reserve. In a woman with ovulatory cycles the finding of reduced ovarian reserve will not affect the immediate chance of natural conception but can reduce the chance of IVF success.
8 Can you outline the more specialised tests that are carried out after referral? I've read about calls to make hysterosalpingography (HSG) available open access. What's your opinion?
For men with a low or absent sperm count we would offer a screen for common cystic fibrosis carrier mutations and a full karyotype. We would also check FSH levels and testosterone.
More detailed andrology assessment will find some sperm that can be frozen and used for IVF and ICSI (intracytoplasmic sperm injection) in about 20% of men in whom no sperm is seen at a routine semen analysis.
Surgical sperm retrieval is another option. In men with a normal FSH, sperm can be found surgically in more than 50% of cases.
The most common intervention that may be offered to women in the secondary care setting is laparoscopy.
A laparoscopy and dye test is most appropriate when we consider that there is a significant possibility of finding pathology, such as endometriosis or adhesions, which may be treated, or when a procedure such as ovarian diathermy – an effective way of inducing ovulation in women with PCOS – could be done at the same time.
We see no problem with direct referral for HSG as long as local protocols are in place so that patients who may require laparoscopy do not undergo an unnecessary procedure.
NICE guidelines do recommend that chlamydia screening is done before instrumentation of the uterus so this should be done prior to referral.
9 Describe the physiological principles and the drugs used for harvesting eggs for IVF.
GnRH analogues are used to cause pituitary desensitisation and therefore low FSH levels. This means that ovulation is prevented and oestrogen and progesterone levels are low. The GnRH analogue is continued and a gonadotrophin is added in. Gonadotrophins used in supraphysiological doses stimulate the ovaries into producing multiple follicles and eggs.
The first gonadotrophins used were human menopausal gonadotrophins (HMG) derived from urine of postmenopausal women, but recombinant FSH is now widely used. The continued use of the GnRH agonist alongside the FSH prevents ovulation. Once the follicles are an optimum size, a final injection of human chorionic gonadotrophin (HCG) is given. HCG has a very similar structure to LH and acts to mature the eggs in a similar way to a physiological LH surge. Eggs must be then retrieved between 38 and 40 hours, otherwise spontaneous ovulation may occur.
10 Could you briefly summarise the other techniques used in infertility centres and their respective success rates?
Intrauterine insemination (IUI) can be used where infertility is unexplained or where there is a mild to moderate sperm problem. This may be done in a natural cycle. But by stimulating the ovaries to produce eggs and by placing the best-quality sperm closer to the tubes, the chance of pregnancy is increased. IUI can only be undertaken where the sperm is suitable and the woman has at least one, preferably two, open fallopian tubes. Live-birth rates vary but may be in the region of 5-10%.
Donor insemination is available to couples where the male partner has a severe sperm problem or for same-sex couples and single women. Again the live-birth rates vary but are in the order of 15% per cycle in women under 35 and 5% for women aged between 40 and 42.
For women with ovarian failure, egg donation may be an option. Most eggs are obtained from egg-sharing schemes whereby women aged 35 or younger who require IVF treatment themselves agree to anonymously donate 50% of their eggs to another woman. In return, the cost of their treatment cycle may be decreased. The live-birth rate for this treatment is related to the age of the person who donated the eggs and is therefore comparable with the live-birth rate of the under-35s. There is an ongoing shortage of donor gametes in the UK and many patients do seek donor gamete treatment abroad, so-called ‘reproductive tourism'.
In-vitro maturation is a new technique suitable for women under 38 whose ovaries appear polycystic. The procedure involves taking immature eggs from unstimulated ovaries and then maturing them in the laboratory for one to two days. It involves no FSH stimulation and carries no risk of ovarian hyperstimulation syndrome (OHSS). Success rates are lower than for conventional IVF.
More recently, it has become possible to screen embryos for single-gene defects using pre-implantation genetic diagnosis (PGD) or aneuploidy using pre-implantation genetic screening (PGS). The biopsies can be performed from the eggs or embryos at the day-three or day-five stage. PGS may potentially increase the overall pregnancy rate, although its effectiveness is controversial.
11 Could you summarise the different IVF techniques, their indications, methods and success rates?
The most common type of IVF cycle (known as a long-protocol cycle) begins with the use of a GnRH analogue in the form of a nasal spray or subcutaneous injections for two-to-three weeks. This process is known as down-regulation.
Daily FSH injections are then used to stimulate follicle development. The follicles are monitored by ultrasound. Eggs are retrieved under transvaginal ultrasound guidance while the patient is sedated.
On average about eight eggs are retrieved but numbers vary enormously – from one or two up to 20 or 30. After preparation of the sperm, fertilisation occurs in the lab overnight.
Approximately 60-70% of eggs will fertilise normally and, depending on the number of embryos available and the quality of those embryos, they will be cultured in the lab for between two and five days. This extended culture, particularly to blastocyst (day 5), allows us to select for transfer the one or two embryos with the highest implantation potential.
The success rate of IVF is very dependent on female age. Currently, here at the Oxford Fertility unit women under 35 have a live-birth rate per IVF cycle of 43%. A 40-year-old is likely to have more like a 15% chance of a live-birth per cycle started.
Success rates between clinics do vary significantly and patients should be advised to look at individual success rates for clinics. Data from each UK clinic is published by the Human Fertilisation and Embryolgy Authority on its very informative website.
ICSI is recommended for patients who have few sperm, sperm that are not moving well or who have in the past failed to achieve fertilisation. It involves injecting a single sperm into the centre of the egg so giving poor quality sperm a better chance of fertilisation. Using this technique approximately 70% of eggs will be fertilised. Overall live-birth rates are then the same as for IVF.
Dr Ingrid Granne is clinical research fellow and Dr Tim Child is consultant gynaecologist at the Oxford Fertility Unit, University of Oxford
Dr Granne was a contributor to the Oxford Handbook of Obstetrics and Gynaecology published by Oxford University Press, ISBN 9780199227242 and co-author of the ABC of Medical Law published by BMJ Books ISBN 9781405176286What I will do now What I will do now
Dr Sabby Kant considers the responses to his questions
Men often ask for a detailed explanation of the parameters measured in a sperm test. So it is useful to be familiar with the WHO standard as well as to remind anxious couples with an ‘abnormal' result that sperm quality varies and the test should be repeated after three months. It is heartening to see that even in men who have negative results, the specialists can coax out viable sperm.
For the woman with irregular menses, I'll remember to test progesterone throughout the cycle.
It's also useful to read about the limited value of ovulation kits or of worrying about the timing of intercourse as this causes much anxiety.
It is understandable that sub-endometrial or polypoid fibroids contribute to infertility but interesting that even deep-seated intramural ones can too.
Dr Sabby Kant is a GP in Hillingdon, Middlesex