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This fourth best practice review examines four series of common primary care questions in laboratory medicine are examined in this review: (1) safety monitoring for three common drugs; (2) use of prostate‐specific antigen; (3) investigation of vaginal discharge; and (4) investigation of subfertility. The review is presented in question–answer format, referenced for each question series. The recommendations represent a precis of the guidance found using a standardised literature search of national and international guidance notes, consensus statements, health policy documents and evidence‐based medicine reviews, supplemented by Medline Embase searches to identify relevant primary research documents. They are not standards but form a guide to be set in the clinical context. Most of them are consensus based rather than evidence based. They will be updated periodically to take account of new information.
This is the fourth in a series of reviews which answers several questions that arise during the use of pathology in primary care.
Each topic is introduced with a brief summary of the type of information found and is handled separately.
Although the individual topics are not related because they cover the disciplines of clinical biochemistry, microbiology, immunology, haematology and cellular pathology, they are designed, once completed, to form a resource that will be indexed and cover a wide range of the most common issues in primary care laboratories, to be made available to users.
In instances where the new UK General Medical Services (GMS) contracts make specific reference to a laboratory test, the indicator or target is appended at the end of the answer.
Three questions that examine the safety monitoring required for drugs used to treat hyperthyroidism, digoxin and amiodarone are answered here. Further questions on other drugs commonly used in primary care will follow. The complications of treatments with these drugs are well known, and relatively close consensus exists on the safety monitoring required. These should be easy to incorporate into clear pathways and there seems to be good evidence that appropriate monitoring reduces the incidence of adverse effects.
Agranulocytosis (absolute neutrophil count <500×106/l) is a rare but serious complication of these anti‐thyroid drug treatments and also of thyrotoxicosis per se. It is not dose related1 and is reported as developing in 0.2–0.5% of patients in Asian populations,2,3 although the incidence in European populations seems to be far lower (0.03%).4 Extrapolation to the UK setting is hampered because the most common drug used in these studies was methimazole, which is not used in the UK. The most common presenting diagnoses were pharyngitis, tonsillitis, pneumonia or urinary tract infection (8%). Agranulocytosis occurred within the first 3 months of treatment in most patients.2,3,4 Elderly people are reported as being at most risk.3,5 Conversely, a fall in neutrophil count, the absolute count remaining above 2000×106/l and not progressing to agranulocytosis, occurs in 1–5% of patients, does not seem to be associated with infection and does not require discontinuation of the drug.6
Discontinuation of the drug should be considered if the leucocyte count <1500×106/l.7 In view of the sudden onset and morbidity and mortality of agranulocytosis, we recommend that, in patients whose white cell count <1500×106/l or neutrophil count 500×106/l in a primary care context, the drug is stopped and the patient referred for immediate specialist assessment and treatment where applicable.6
Opinions are divided on the monitoring of routine blood count when these drugs are started. An article in the Drugs and Therapeutics Bulletin7 recommended that blood count monitoring for agranulocytosis be performed fortnightly during the first 3 months of treatment, analogous to sulphasalazine, for which the incidence of agranulocytosis is similar. This advice was based on a prospective Japanese study,8 which detected neutrophil counts <1500 in 43 of 55 patients from a cohort of over 15000 patients with thyrotoxicosis treated with methimazole or propylthiouracil. All the patients recovered when the drug was stopped and 29 patients did not have any infection. The reported incidence of agranulocytosis was, however, far higher than that reported for European populations and the diagnostic threshold was conservative. The Christian Science Monitor9 did not adopt this recommendation when it reviewed the topic in 1999, but did highlight the need to inform patients of the potential presenting symptoms. These recommendations are restated in the British National Formulary (BNF).10
GMS contract indicator: none.
We recommend the following during the measurement of plasma digoxin:
A limited relationship exists between the level of plasma digoxin and clinical outcome,11 and a slowing of the heart rate is the clinical indicator of efficacy.12 The routine measurement of levels of digoxin is not recommended by several sources.11,12,13,14,15 One expert group, however, recommended routine measurements every 10 months and in the other situations listed below. With these criteria, it found that only 52% of digoxin measurements were appropriate in an outpatient setting, and 16% in an inpatient setting.16 Most inappropriate outpatient requests were due to early routine monitoring (median repeat time 56 days) in patients in a stable condition.
One meta‐analysis, however, suggests that monitoring may reduce toxicity17 and several documents recommend measurement in specific situations: toxicity, potential toxicity arising from a change in digoxin dose or the patient's clinical state (notably renal function and hydration status), a change in concomitant drugs (notably those influencing renal or hydration status or lowering serum potassium), or to investigate questionable compliance.12,16,18,19,20
Among others, hypokalaemia, hypomagnesaemia and hypothyroidism predispose to the toxic effects of digoxin,12 and renal dysfunction results in raised concentrations of digoxin for equivalent dose compared with normal renal function.14 These should be taken into account and appropriate electrolyte monitoring should be carried out in patients predisposed to hypokalaemia (eg, loop diuretics), in dosing in patients with renal dysfunction14 and in elderly people. No clear guidance was found for monitoring frequency. This would be expected to vary considerably depending on a patient's medical and drug history. Similarly, the BNF14 highlights the risks associated with hypokalaemia, but makes no specific recommendations on monitoring electrolytes. It should be noted, however, that the diagnosis of digoxin toxicity is clinical, and that measured serum concentration inside or outside a target range does not in itself diagnose either toxicity or absence of toxicity.
Although some texts suggest that blood must be withdrawn a minimum of 6 h after a dose, more recent statements recommend 8–12 h18,19,20 after a dose of digoxin has been taken, or 7 days after a change in dose because of the long half‐life of digoxin18,19,20 (up to 21 days may be required to reach steady‐state concentrations in patients with renal insufficiency15). These recommendations are consistent with the pharmacokinetics of digoxin. In addition to invalidating the result, early measurements may potentially lead to inappropriate change in dosage or other clinical management.
A detailed list of drugs influencing concentrations of digoxin or toxicity is provided in the BNF.21 This provides dosing recommendations, which are of particular importance in renal insufficiency, as one study of patients with chronic kidney disease found excess dosing compared with the recommended doses for degree of kidney failure to occur commonly, digoxin being one of the drugs most frequently incriminated.22
GMS contract indicator: none.
We recommend the following minimum safety monitoring at baseline and every 6 months on amiodarone if levels are within the population reference range:
We recommend that the following assessments be carried out annually:
We recommend additional safety monitoring in patients receiving warfarin:
An American evidence‐based review of amiodarone efficacy and safety states that routine monitoring of plasma concentrations of amiodarone is not considered useful in patients who are stable.22 The recommendations found in all reviews concentrate on safety monitoring with other indicators. Concentrations of total and desethylamiodarone in excess of 255 mg/l have, however, been associated with increased risk of toxicity.24,25 The ratio of amiodarone to desethylamiodarone can also be used as an indicator of adherence.26
One meta‐analysis of double‐blind trials of amiodarone use26 disclosed the complication rates of non‐cardiac amiodarone toxicity to be 1% for pulmonary toxicity, 0.6% for hepatic toxicity, 0.3% for peripheral neuropathy, 0.9% for hyperthyroidism and 6% for hypothyroidism, annually. Thyroid dysfunction, however, varies depending on environmental iodine content, and the rates for countries with high environmental iodine such as the UK have been estimated to be 1.7% for hyperthyroidism and 13% for hypothyroidism.28
As amiodarone reduces clearance of warfarin, it can produce sudden large rises in the prothrombin ratio (international normalised ratio),29 the peak effect occurring about 7 weeks after warfarin treatment is started, although the kinetics of the international normalised ratio are altered from the first day.29 Close measurement of the prothrombin ratio is therefore required during that period, the recommended period being for the first 7 weeks of treatment.30 Administration of amiodarone also increases levels of digoxin owing to reduced renal digoxin clearance and requires doses of digoxin to be reduced (usually by one half) and concentrations of digoxin to be monitored closely in view of potential toxicity.31 A literature review of more than 20 sets of published amiodarone guidelines32 concluded that evidence supporting the guidelines was limited, but constructed minimum quality standards for amiodarone safety monitoring summarised earlier and based principally on the North American Society of Pacing and Electrophysiology.33 For laboratory tests, these guidelines are consistent with recommendations of the BNF and others. The same review found large variations among guidelines drawn from editorials and personal views. No outcome studies were identified and the authors used the minimum “boundary” standards to assess clinical practice in a small group of 99 patients over 14 months in one teaching hospital. These are consistent with the BNF with respect to laboratory liver and thyroid monitoring34 and a review for UK Medicines information.35
Compliance with these standards was poor, in the region of only 40% for thyroid and liver biochemistry in an American setting, where proportionally far more laboratory tests are ordered. The Committee on Safety of Medicine also recommends regular monitoring of urea and electrolytes (for example, every 6 months in patients taking diuretics).36
Other clinical toxic effects to be assessed in a clinical evaluation include referral for ophthalmological evaluation in patients with visual deterioration and assessment for symptoms of gastrointestinal, dermatological or neurological toxicity, which are not considered here.
GMS contract indicator: none.
The answers presented here do not deal with the current debate in laboratory medicine about the relative utility of different forms of measurement (free, total, calculated ratios) of prostate‐specific antigen (PSA). The use of PSA in the general community has been widely debated on both sides of the Atlantic, although occasionally the implications and limitations of the widespread use of PSA in unselected populations or in those at lower risk has been lost in the emotive and political debate. These answers attempt to put that debate in perspective.
In England and Wales, the number of cases of prostate cancer diagnosed has more than doubled in a decade, mainly because of the widespread use of PSA testing.37 Despite being the most common cancer in men, with nearly 27000 new cases diagnosed in 2002, there is no evidence to support routine PSA screening of prostate cancer in asymptomatic men. Even though screening often detects early “curable cancers” in most patients, there is inconclusive evidence from one randomised controlled trial that screening and early detection improves life expectancy or quality of life,37 and one American study reported no increase in longevity, but increased morbidity in a two‐centre comparison of PSA measurement with surgery versus PSA with “watch‐and‐wait” approach.39
A randomised study from Sweden has shown a modest survival benefit from radical surgery over watchful waiting.40 Longitudinal studies in the UK and USA, however, indicate that most men with localised low‐grade prostate cancer have only a small risk of dying from prostate cancer and hence are unlikely to benefit from an early diagnosis of their cancer.41,42 Only about a third of patients with prostate cancer will die from their disease.42
Even though up to two thirds of men over the age of 70 are found to have prostate cancer in autopsy series, prostate cancer is responsible for only 3.5% of all deaths in men.43,44 Screening for PSA need not therefore be proactively discussed with asymptomatic men.
Two large randomised screening trials, the Prostate, Lung, Colorectal and Ovary Cancer Trial45 in the USA and the European Randomized Screening for Prostate Cancer Trial46 in Europe are currently assessing the benefits of screening for prostate cancer.
While awaiting the results of the studies on PSA screening, the PSA test should not be denied to men who request it. This should be conducted after proper counselling about the drawbacks of the PSA test (false‐positive and false‐negative results), the natural history of prostate cancer, the treatment options for cancer, and the physical, psychological and financial implications of detection of a cancer that may never have affected health had it been detected during the lifetime of the person.47,48,49
Prostate cancer is rare in men <50 years of age.44 In asymptomatic men who elect to undergo screening, PSA tests therefore should be started at the age of 50 years (or 45 years in the higher‐risk population). Annual or biannual PSA alone, without a rectal examination, is sufficient to identify men who are at high risk of prostate cancer. PSA testing is not usually recommended for asymptomatic men with a life expectancy of <10 years.50,51
PSA is both a diagnostic and a screening test. UK National Health Service (NHS)52 guidance recommends that PSA should be measured, if clinically appropriate, in men with refractory lower urinary tract symptoms, erectile dysfunction, hard irregular prostate, haematuria or bone pain with weight loss or other clinical situations compatible with prostate cancer.
Various procedures, activities and diseases can affect the levels of PSA. Hence, the exclusion criteria of a PSA test are:
If an asymptomatic man has PSA level higher than the age‐specific range, he should be counselled about further options, which include a prostate biopsy.
PSA is a protein produced almost exclusively in the epithelial cells of the prostate gland. It is normal for men to have low levels of PSA in their blood, and there is no specific normal or abnormal PSA level. Both prostate cancer and benign conditions can increase the levels of PSA.
An isolated increase in the PSA level should be confirmed several weeks later, before proceeding with further testing, including prostate biopsy.
If practical, the man should have the PSA test before the digital rectal examination (DRE). If not, it is recommended that the PSA test be delayed by 1 week. The blood sample should reach the laboratory (and be separated) <16 h after the sample is taken.52,53
Age is an important factor in increasing levels of PSA. For this reason, the NHS Prostate Cancer Risk Management Programme recommends age‐adjusted levels of PSA to determine when diagnostic tests are needed. The programme recommends the following cut‐off values for referral:
A very high PSA value is strongly suggestive of cancer. A level of PSA >100 μg/l, with an abnormal prostate gland on DRE, is almost certainly caused by prostate cancer. In an elderly man with extensive comorbidities and grossly raised PSA, biopsy is therefore not necessary before starting hormone therapy.54
If an asymptomatic man has a level of PSA higher than the age‐specific range, he should be counselled about further options, which include:
Hopefully, the ongoing NHS Health Technology Assessment‐funded ProtecT trial,55 evaluating the effectiveness of various treatment options, including active surveillance for clinically localised prostate cancer, will benefit future decision making.
Changes in levels of PSA over a 3–6‐month period can be prognostic. A PSA that doubles in the 6 months of follow‐up after surgery indicates an aggressive cancer and points towards “incurable” systemic relapse rather than a “potentially curable” local relapse.56 We therefore recommend PSA checks every 3–6 months in men with prostate cancer.
In general, after radical treatment for prostate cancer, when there are no signs of recurrence, PSA levels should be measured every 3 months for 1–2 years, every 6 months until the fifth year; and after 5 years annual checks should suffice.57,58 Unlike other cancers, late recurrence and progression can occur even after 10–15 years. Thereafter, it is recommended that periodic measurements of PSA be continued for life.57,58
The frequency of PSA checks may be altered in specific cases for various reasons. Elderly or frail men may require PSA levels to be measured less often and only if clinical intervention is practical and realistic.
After radiation with either seeds (brachytherapy) or external beam or cryotherapy, the PSA will drop slowly, often reaching its nadir after several years. After 18–24 months following radiation, PSA levels are usually <1.0. A slow fall in the levels of PSA is not a cause for concern; paradoxically, the slower the fall, the better the prognosis.61 It is not uncommon after prostate radiation to see a temporary rise, or “bounce”, in the level of PSA, which then falls spontaneously. The classic PSA bounce timing is about 1–2 years after treatment and may be seen in up to 30% of patients. Levels of PSA should later fall and remain <1.0.62
After hormone therapy alone, nadir levels are quite variable and depend on the extent of the cancer and its aggressiveness. In general, nadir levels of PSA <2.0 indicate good prognosis. After hormone therapy, stable levels are reassuring and any rise in PSA is a cause for concern.63
Patients on active surveillance (wait‐and‐watch policy) should have the PSA levels checked every 3–6 months. If there is a major rise in PSA, the patient should be counselled about treatment options again. It is important to note that the rate of rise in PSA is more important than the absolute levels of PSA.66,67
GMS contract indicator: none.
This advice and template has been produced by the Health Protection Agency, Primary Care Research Group (http://www.hpa.org.uk/infections/topics_az/primary_care_guidance/menu.htm). Their website also provides advice on treatment. The guidance is in agreement with other guidance on primary care, including the Scottish Intercollegiate Guidelines Network (www.sign.ac.uk), PRODIGY (www.prodigy.nhs.uk) and British Association for Sexual Health and HIV (www.bashh.org), for which specific references are provided.
We recommend that a high vaginal swab (HVS) be sent to the microbiology laboratory to investigate abnormal vaginal discharge or vaginitis in the following circumstances:
Also, see national guidelines on the management of STIs in children and young people for more information.69 These guidelines cover the management of sexual abuse and suspected STI in patients <18 years of age.
The templates are designed so that the recommendations can be changed to suit local service delivery and sampling protocols. Laboratory methods, for example, may influence the samples that are suitable for diagnosis.
Submission of genital swabs to microbiology laboratories varies greatly, from 5 to 40 per 1000 population, and includes many for candidiasis and bacterial vaginosis, which should be diagnosed from clinical symptoms and signs. Bacterial vaginosis is the most common cause of abnormal vaginal discharge and is caused by overgrowth of anaerobic organisms. The UK national guidelines70 provide extensive evidence‐based guidance on the management of genitourinary infections. Trichomoniasis is a less common cause of vaginal discharge in the UK. Candidiasis is also a common cause of abnormal vaginal discharge.70,71,72 Most women do not need a swab to be taken in this situation. We suggest that diagnosis can be made in most cases on clinical symptoms, signs and results of a narrow range pH paper (see fig 11).). An HVS should be taken if other causes are being considered. These guidelines are summarised in fig 11.
Specimens should also be taken for chlamydia testing from:
The UK Department of Health advocates opportunistic screening in:
We recommend that:
Always consider STI and take an endocervical chlamydia HVS in patients at risk: sexually active younger women <25 years, or those >25 years with a new partner for <12 months and no condom use.70,71,92,93,94
How often chlamydia swabs should be taken in sexually active young women is a matter for debate. In theory, whenever a person has a new partner and continues to have unprotected intercourse you should retest. Retesting studies are currently in progress.
C trachomatis and Neisseria gonorrhoeae cause acute pelvic infection with vaginal discharge and intermenstrual bleeding, recent deep dyspareunia, lower abdominal pain, adnexal tenderness and cervical excitation pain.
If screening a woman, a first‐catch urine specimen may be submitted if molecular techniques using nucleic acid amplification are used in the local laboratory.
In men, first‐void early‐morning urine, which is less traumatic for the patient, or a urethral swab (insert 1–4 cm inside and rotate once) is the sample of choice.96
In women with PID or lower abdominal pain, serology should also be carried out.97
GMS contract indicator: none.
The National Institute for Health and Clinical Excellence (NICE) 2004 guidance98 provided a detailed review on the current advice on subfertility testing. In addition to reviewing the testing approaches for the main different clinical scenarios that may present, these answers distinguish those tests that may reasonably be requested in primary care from those for which secondary care input may be recommended, although this division is not based on published recommendations. This guidance does not include additional testing, which may be dictated by the clinical presentation (eg, anaemia, other systemic diseases).
We recommend investigation of both partners of couples who have been unable to achieve pregnancy:
We recommend clinical examination followed by:
SFA is routinely used to determine male infertility. Although semen analysis lacks specificity, there is no better test at present.99
Results of the semen analysis should be compared against the World Health Organization100 reference values. Successful fertilisation declines as sperm morphology drops below 15%.
Adherence to a strict collection protocol is essential for the accuracy of results. The man must abstain from ejaculation for 2–3 days before the semen sample is collected. The semen specimen should be collected into a wide‐mouthed, sterile plastic pot, by masturbation and not by coitus interruptus. It should be protected from extremes of temperature during transportation.100,101
If the result of the first SFA is abnormal, a repeat confirmatory test should be offered, ideally 3 months after the initial analysis, to allow time for a new cycle of spermatozoa formation to be completed. But if gross spermatozoa deficiency (azospermia or severe oligospermia) has been detected, the test should be repeated as soon as possible.98
Levels of luteinising hormone, FSH and testosterone in serum are useful investigations in repeated azospermia.102 In non‐obstructive azospermia owing to primary testicular dysfunction, FSH is invariably raised.
Further investigation of primary testicular dysfunction showed that reduced levels of serum testosterone and raised levels of serum luteinising hormone are indicative of Leydig cell dysfunction, whereas high levels of serum FSH in the presence of normal serum levels of luteinising hormone and testosterone are indicative of Sertoli cell dysfunction. High serum levels of FSH and luteinising hormone with an inappropriately normal or low level of testosterone confirms testicular failure. In a few cases, low levels of FSH, luteinising hormone and testosterone indicate hypogonadotrophic hypogonadism, and in about 50% of these cases fertility can be restored with exogenous gonadotrophins.103 Men with hypogonadotrophic and hypergonadotrophic hypogonadism should be referred to an endocrinologist for further evaluation, investigation and treatment.
Anti‐sperm antibodies: Anti‐sperm antibodies are present in 5–10% of the infertile population.
Routine screening for anti‐sperm antibodies is not recommended, as there is no evidence of effective treatment to improve fertility.98
Karyotyping: This test is indicated in men found to have non‐obstructive azospermia and hypergonadotrophic hypogonadism, as it allows for the detection of problems such as Klinefelter's syndrome (47XXY). Azospermia in association with eunoichoid features suggests a diagnosis of Klinefelter's syndrome.
Sperm function tests: The advent of intracytoplasmic sperm injection, used in conjunction with in vitro fertilisation for male factor subfertility, has rendered the various sperm function tests far less relevant.104
Women with regular menstrual cycles are likely to be ovulating.105 Ovulation can, however, be confirmed by measurement of serum progesterone in the mid‐luteal phase of the cycle. The sample should be taken 7 days before the expected onset of menses (eg, day 21 of a 28‐day cycle or day 24 of a 31‐day cycle).102 A mistimed sample is a common cause of abnormal results.
A concentration of serum progesterone >30 nmol/l is considered proof of adequate ovulation in that cycle.106
In women with prolonged and irregular menstrual cycles, serum progesterone may need to be measured later in the cycle (eg, day 28 of a 35‐day cycle) and repeated weekly thereafter until the next menstrual cycle starts.98
Taken on days 2–4 of the cycle,107,108 the tests recommended earlier will identify the main causes of ovulatory failure—namely, normogonadotropic anovulation, hyperprolactinaemia, hypogonadotropic hypogonadism and hypergonadotropic hypogonadism. Thyroid function, prolactin and atestosterone can be measured at other times in the cycle, although for practical simplicity the intended tests are best ordered at the same time as FSH or luteinising hormone, which should be taken on days 2–4 of the cycle.
In the absence of menstruation, a markedly raised FSH (>20 mU/ml) is indicative of ovarian failure.
Estimation of serum prolactin should be limited to women who have ovulatory disorders or galactorrhoea.98
Estimation of thyroid function should be confined to subfertile women with clinical features of thyroid disease.98 The routine measurement of thyroid function in an initial investigation for subfertility is not recommended.
Serum testosterone is a reasonable initial investigation in primary care, supplemented as indicated in secondary care by dehydroepiandrosterone sulphate, 17‐OH‐progesterone and androstenedione.
A leading example of androgen excess as a cause of subfertility is polycystic ovarian syndrome (PCOS).
The level of serum testosterone is also raised in congenital adrenal hyperplasia, adrenal tumours and androgen‐producing ovarian tumours. We recommend advice on secondary care in cases of clinical and biochemical androgen excess not explained by PCOS, to exclude congenital adrenal excess, adrenal and ovarian neoplasia.
We recommend investigation:
The following tests should be carried out when secondary sexual characteristics are present:
When secondary sexual characteristics are absent, the following tests are required:
Primary amenorrhoea is a relatively rare condition (0.3% prevalence112) and anatomical abnormalities of the genital tract constitute the most common cause in the presence of normal secondary sexual characteristics. Genital examination and an ultrasound scan of the pelvis are therefore imperative in these cases.113
When normal secondary sexual characteristics are present, the appropriate tests for the investigation of primary amenorrhoea should seek to exclude obstruction of the outflow tract.114
A pelvic ultrasound scan will determine the presence or absence of a uterus and any obstruction of the outflow tract. In addition, it may aid in the diagnosis of PCOS.115
Levels of serum gonadatrophins, oestradiol and prolactin, in the presence of normal pelvic anatomy, normal or low levels of serum luteinising hormone and FSH, may indicate a hypothalamic cause for the amenorrhoea (constitutional delay), the most common cause of primary amenorrhoea.116 Levels of gonadotrophin will be raised in resistant ovary syndrome and the luteinising hormone is increased in PCOS and associated with raised testosterone (or free androgen index).
Irrespective of the presence or absence of secondary characteristics, persistently raised levels of serum prolactin (in the absence of a history of medication or drugs that may raise the level of prolactin) constitute an indication for referral.113
Both hypothyroidism and hyperthyroidism can cause primary amenorrhoea. Estimation of TSH is useful in ruling out subclinical hypothyroidism even in the absence of thyroid‐related symptoms.113
It is important to exclude pregnancy during investigation of primary amenorrhoea. This is understandably sensitive and should be considered only in appropriate cases (ie, when the teenager is sexually active).
In the absence of secondary sexual characteristics, constitutional delay, Turner's syndrome and gonadotrophin deficiency are the most common causes of primary amenorrhoea.114
Karyotyping will normally be requested in conjunction with secondary care to differentiate between premature ovarian failure, resistant ovary syndrome or gonadal agenesis (46XX), testicular feminisation syndrome owing to testicular enzymatic failure (46XY), Turner's syndrome (45XO) or Turner mosaic when gonadotrophins are raised.
We recommend investigation:
Pregnancy remains the most common cause of secondary amenorrhoea (with a prevalence about 3%), and a pregnancy test should always be considered.111
Secondary amenorrhoea is commonly caused by PCOS, hyperprolactinaemia, premature ovarian failure and hypothalamic dysfunction.118 The above‐mentioned tests will guide further investigations in conjunction with secondary care.
Levels of FSH are raised in ovarian failure. Women <30 years of age with ovarian failure should be told about, or referred to, secondary care to arrange karyotyping to exclude chromosomal abnormalities.119
Raised levels of luteinising hormone are suggestive of PCOS. Ratios may be >2,120,121,122 particularly when combined with raised testosterone and low oestradiol. No one test is diagnostic, although the predictive value increases when several tests are abnormal. This will guide the decision to request a pelvic ultrasound.115
Levels of luteinising hormone and FSH combined with low levels of oestrogen are low in hypothalamic or pituitary dysfunction. This group includes women with amenorrhoea secondary to exercise, low weight, anorexia and stress.
Persistently raised levels of serum prolactin (in the absence of a history of drugs that may raise prolactin) constitute an indication for referral, as magnetic resonance imaging is recommended.115
Both hypothyroidism and hyperthyroidism can cause primary and secondary amenorrhoea associated with anovulation. Estimation of TSH is useful in ruling out subclinical hypothyroidism even in the absence of thyroid‐related symptoms.115 In the UK, however, NICE recommends TFTs in the investigation of subfertility only in patients with clinical features of thyroid disease.98 Although the NICE recommendation is for investigation of infertility and not specifically for investigation of amenorrhoea, the two situations are evidently associated. As the incidence of thyroid disease is extremely low in patients who do not have at least two signs or symptoms of the disease, it would seem reasonable to adopt the NICE approach and not recommend TFTs as an initial investigation unless the patient has other clinical indicator(s).
GMS contract indicator: none.
This review brings to a running total 58 main question and answer sets written to provide an overview of current advice in the use of laboratory tests in primary care. Answers to the first two question–answer sets can be found elsewhere.123,124,125 They have all used a common search methodology,126 although where recent systematic reviews have been carried out, the guidance relies heavily also on the findings of these reviews. Authors wishing to consult the UK General Medical Services Contract and related Quality and Outcomes Framework can find these on their respective websites.127,128
We thank Mrs Susan Richardson for typing this manuscript, Mrs GC Smellie for help in collating answers into this article and the following people who kindly reviewed the work: Professor IS Young (Association of Clinical Biochemists), Professor R Gama (Association of Clinical Pathologists), Dr AJ Mifsud (Association of Medical Microbiologists), Dr AB Provan (British Society for Haematology), Dr R Neal, Dr N Campbell (Royal College of General Practitioners), Professor KG Kerr, Dr E Logan (Royal College of Pathologists), and the other council members of these associations and colleges who have assisted in recruiting reviewers. This work has been supported by the Association of Clinical Biochemists,* Association of Clinical Pathologists,* Association of Medical Microbiologists, British Society for Haematology, Royal College of General Practitioners, Royal College of Pathologists* and the Sowerby Centre for Health Informatics in Newcastle (SCHIN), the representatives of which have contributed to the reviewing process. The opinions stated are, however, those of the authors.
*These organisations contributed direct funding to support the start up of the project.
BNF - British National Formulary
DRE - digital rectal examination
FSH - follicular stimulating hormone
GMS - General Medical Services
HVS - high vaginal swab
NHS - National Health Service
NICE - National Institute of Health and Clinical Excellence
PCOS - polycystic ovary syndrome
PID - pelvic inflammatory disease
PSA - prostate‐specific antigen
SFA - seminal fluid analysis
STI - sexually transmitted infection
TFT - thyroid function test
TSH - thyroid‐stimulating hormone
iResistance has not increased with over‐the‐counter antifungals. Samples should be cultured before embarking on long‐term suppressive treatment as only 16% with recurrent symptoms have candidiasis.
Competing interests: None declared.