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SEPTEMBER 2010

Selected Topics in Men’s and Women’s HealthQuiz Feedback: Screening

We would like to acknowledge the following people for their guidance and expertise in developing this edition:

Dr Anna Fenton, Christchurch

Dr Steve Soule, Christchurch

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best tests | September 2010 | 1

2 Selected topics in men’s health

Erectile dysfunction

Gynaecomastia

Late-onset hypogonadism

Delayed puberty in males

8 Selected topics in women’s health

Laboratory investigation of amenorrhoea

Polycystic ovary syndrome

An overview of dysfunctional uterine bleeding

Perimenopause and menopause

Sexual dysfunction - loss of libido

16 Quiz Feedback: screening tests

CONTENTS

Selected topics inMEN’S HEALTH

Erectile dysfunctionGynaecomastia

Late-onset hypogonadismDelayed puberty in males

2 | September 2010 | best tests

www.bpac.org.nz keyword: menshealth


Erectile dysfunction

Erectile dysfunction (ED) can be defined as the persistent inability to achieve or maintain penile erection sufficient for satisfactory sexual performance. Evaluation and consideration of treatment are indicated when ED persists for at least three months.

The prevalence of ED increases with age.1 The Massachusetts Male Aging Study was the first major epidemiological investigation of ED and one of the largest population-based studies in this field to date. It was estimated that 52% of non-institutionalised men aged between 40 and 70 years, had some degree of ED – 17% minimal, 25% moderate and 10% complete.2

Causes: organic or psychogenic

ED may result from organic or psychogenic causes (or components of both). Even in men with an obvious organic cause, there are psychological factors that may play a role in either exacerbating or sustaining the condition.

There is much variation among men with ED in the way they present, in terms of severity of the disorder and associated co-morbidities.1

Men with an organic cause for their ED usually present with a gradual onset and the difficulty becomes progressively worse over time.2

Conversely, when the cause of ED is psychogenic, it can occur suddenly with a complete and immediate loss of sexual function which may vary with the partner or

situation. It may also be difficult to differentiate between ED from organic or psychogenic causes. A useful clinical indicator is that men with psychogenic ED usually continue to experience early morning erections.1, 2

Most causes of ED were once considered to be psychogenic, but evidence suggests that up to 80% of cases have an organic cause.1 Organic causes include vasculogenic, neurogenic and hormonal aetiologies (Table 1). Vasculogenic aetiologies represent the largest group, with arterial or inflow disorders being the most common. Abnormalities of venous outflow (corporeal veno-occlusive mechanism) are much less common.

Hormonal dysfunction, contrary to popular opinion, is a rare cause of ED. Hormonal treatment produces little improvement in ED other than in men with severe androgen deficiency. Regardless of the primary aetiology, a psychological component frequently coexists.3

Diagnostic evaluation of erectile dysfunction

When a patient first presents with ED, it is essential to obtain a full history (both medical and sexual) and perform a targeted clinical examination.

A detailed medical history is important as many disorders are associated with ED including hypertension, diabetes mellitus, ischaemic heart disease, dyslipidaemia, chronic kidney disease, hypogonadism, neurological and psychiatric disorders and many chronic illnesses. Genitourinary and rectal surgery, and medicines such

Table 1: Common causes of erectile dysfunction2

Organic Psychogenic

■ Vascular disease ■ Diabetes mellitus ■ Medicines e.g. antidepressants, psychotropics,

antihypertensives■ Cigarette smoking ■ Alcohol ■ Neurological disorders ■ Severe hypogonadism

■ Performance anxiety ■ Generalised anxiety■ Major depression


as antihypertensive and psychotropic drugs, may also cause ED. Chronic misuse of alcohol, marijuana, codeine, pethidine, methadone or heroin is also associated with a high prevalence of ED.4

Examination should include measurement of blood pressure and evaluation for peripheral vascular disease and diabetes and an assessment for possible hypogonadism (gynaecomastia, reduced androgenic body hair and decreased testicular volume).

Laboratory tests

There is a lack of consensus regarding the best choice of laboratory tests for the evaluation of patients with ED. Given the association of ED with vascular disease and diabetes, it is recommended that a cardiovascular risk assessment is performed and screening for diabetes is undertaken.

Some guidelines propose measurement of testosterone as part of the initial work up for all cases of ED,5 whereas others suggest testosterone measurement is only necessary if the history or clinical examination indicates possible hypogonadism.6 More recently, due to insufficient evidence to determine net benefits and harms, the American College of Physicians announced that it was unable to recommend either for or against routine use of hormonal blood tests or hormonal treatment in

the management of patients with ED7 (see sidebar). It was recommended that clinicians consider the presence or absence of symptoms of androgen deficiency (decreased libido, fatigue) and of physical findings (reduced androgenic hair, gynaecomastia, testicular atrophy) before measuring hormone levels in individual patients.

Testosterone replacement

Testosterone therapy is not usually indicated for ED in men with normal testosterone levels.8

Testosterone replacement is appropriate when a man with ED is diagnosed with hypogonad-ism. Adverse effects associated with exogenous testosterone therapy include gynaecomastia, in-creased haematocrit, alterations in lipid profile, hypertension and infertility.

The initiation of testosterone replacement is not a simple issue and requires careful consideration and supervision by a specialist.9 It is important conditions such as polycythaemia and prostate malignancy are excluded.

Gynaecomastia Gynaecomastia (GM), a benign enlargement of male breast tissue, is a common condition which indicates an imbalance between free oestrogen and androgen action in the breast tissue. True GM can be distinguished from an accumulation of adipose tissue (lipomastia or pseudo-gynaecomastia) in which glandular tissue is not palpable. Breast enlargement can also be rarely caused by a primary or secondary breast malignancy. If there is doubt about the cause of GM, further evaluation is required.10

There are several situations in which GM occurs physiologically. Transient neonatal GM lasting one to two months is a common phenomenon which occurs in 65–90% of neonates.10 It is caused by the transplacental passage of maternal oestrogen. GM is also common

during mid to late puberty, when relatively higher levels of oestrogen are produced by the testes and peripheral tissues, before testosterone reaches adult levels. In 95% of cases this resolves within one to two years.10 As men age, the frequency of GM again increases and is assumed to be related to a fall in free testosterone levels.10

In the early stages of the development of GM, the breast tissue is in a “proliferative” stage, but as the ductal system increases, eventually fibrosis develops. GM is generally reversible if managed early, however once GM has evolved to the stage of extensive fibrosis, the process may be irreversible and is unlikely to regress, either spontaneously or with medical therapy.11

There are numerous conditions associated with GM (see sidebar). These include disorders which either impair


androgen production (hypogonadism) or increase oestrogen levels (rare tumours, cirrhosis, thyrotoxicosis). Some medicines can cause gynaecomastia, therefore review of a patients medicine list is important.

A physical examination is useful for differentiating true GM from pseudo-gynaecomastia. In patients with true GM a concentric, rubbery or firm mound of tissue around the nipple-areolar complex can be felt, whereas in patients with pseudo-gynecomastia, this is not found. A hard or firm mass palpable outside the areolar area may suggest the presence of a tumour and further follow-up is recommended.12

Diagnosis of gynaecomastia

Although laboratory evaluation may be appropriate, abnormalities are not detected in the majority of patients with GM. Endocrine evaluation in adolescent patients, and in adult patients with longstanding fibrotic GM, is contentious.

If an adult male presents with unilateral or bilateral GM that is of acute onset, particularly if tender, and if the patient’s history and physical examination do not reveal the cause, then serum testosterone, LH, oestradiol and hCG are usually sufficient. Other tests depend on clinical findings or suspicion.13

In older men, GM may be the result of late onset hypogonadism (see below) and measurement of morning testosterone and LH is reasonable. A low testosterone and elevated LH suggests primary testicular failure, whereas a low testosterone with normal or low LH suggests secondary hypogonadism.

Late-onset hypogonadism

As healthy men age, the serum concentration of testosterone, particularly free testosterone but also total testosterone, declines by 0.4 – 2.6% per year after the age of 40 years. This results in a total testosterone level that is below the normal laboratory range in approximately 25% of men aged over 70 years and 50% aged over 80 years.

As testosterone levels fall, a variety of physical changes occur, including loss of muscle mass and strength,

Estimated prevalence of underlying disease processes in gynaecomastia

In males seeking medical attention for GM, it is estimated that the prevalence of underyling aetiologies is as follows:10

■ Persistent pubertal gynaecomastia – 25%

■ Medicines – 10–25%

■ No detectable abnormality – 25%

■ Cirrhosis or malnutrition – 8%

■ Primary hypogonadism – 8%

■ Testicular tumors – 3%

■ Secondary hypogonadism – 2%

■ Hyperthyroidism – 1.5%

■ Chronic renal insufficiency – 1%

Referral

Referral to an endocrinologist should be considered, after initial screening investigations, for any patient with pathological GM which is not related to use of a medicine or another recognised cause (cirrhosis, renal failure, thyrotoxicosis).

Treatment with tamoxifen 20 mg daily for up to three months may be initiated if the GM is of recent onset. This results in regression of GM in up to 80% of patients.10

an accumulation of adipose tissue, reduced bone density and sexual dysfunction. These features are also commonly seen in patients with true androgen deficiency.

Diagnosis of late-onset hypogonadism

The association between aging-related testosterone reduction and late-onset hypogonadism in men remains


a controversial concept due to the high prevalence of hypogonadal symptoms in the aging male population and the non-specific nature of these symptoms.

The issue is further complicated by the impact of a variety of medical conditions on the male gonadal axis, the diurnal variation in testosterone levels (more than one pre-9am sample is essential) and the limitations of available total and free testosterone assays.13 Androgen deficiency has a broad differential diagnosis, ranging from primary testicular disorders (such as orchitis, chemotherapy, Klinefelter’s

syndrome) to central disorders (pituitary tumours, haemochromatosis, diabetes). Appropriate treatment for a patient with an unequivocally low testosterone level may therefore require more than just androgen replacement.

Androgen replacement could be considered in elderly men with clinically significant symptoms of androgen deficiency and low morning total testosterone on more than one occasion. However, there is a lack of consensus from international experts on the thresholds for normal testosterone levels.

Delayed puberty in males

Delayed puberty in males is defined by the absence or incomplete development of secondary sexual characteristics by age 14 years, i.e. the age at which 95% of males have initiated sexual maturation.15 An increase in testicular size is the first sign of sexual maturation. If there has been some increase in testicular volume then the patient can be reassured that they are likely to progress through puberty normally, although perhaps later than their peers.15

Delayed puberty in boys may be due to:

■ Functional causes e.g. constitutional delay in puberty, chronic illness, excessive exercise, malnutrition, stress

■ Associated pathologies e.g. hypothalamic or pituitary tumours

■ Genetic causes e.g. Klinefelter’s syndrome

Constitutional delay of puberty

The most common cause of delayed puberty is constitutional delay in growth and puberty. This diagnosis, as opposed to permanent central hypogonadism, can only be made retrospectively once full sexual maturation has occurred. At the expected time of puberty, the height of males with constitutional growth delay begins to deviate further from the growth curve because of delay in the onset of the pubertal growth spurt. Catch-up growth, onset of puberty and the pubertal growth spurt occur later than average, but result in normal adult stature, sexual development and fertility.15

EvaluationFor a boy aged under 16 years, watchful waiting should reliably distinguish those with constitutional delay (who will eventually spontaneously progress through puberty) from those with other causes of delayed puberty. A positive family history for constitutional delay of puberty, especially in the father, can be useful for helping to confirm this. Reassessment of the patient may be considered after six months.16

A thorough history should identify nutritional problems, medical illness or excessive exercise. When examining the patient include measurements of height, weight, arm span (see below) and presence of secondary sexual characteristics. Sometimes these features may be present but unnoticed by the patient or family and identifying them can be reassuring. Serial measurements made over one to two years can often be helpful.15

An arm span exceeding the height by more than 5 cm suggests delayed epiphyseal closure secondary to hypogonadism (sex steroids are required for epiphyseal closure).

Males with constitutional delay of puberty typically have a delayed bone age, indicating residual growth potential. An x-ray of the left wrist and hand to evaluate bone age may be obtained.15


Classification of delayed puberty according to LH and FSH levels

Delayed puberty syndrome can be classified according to the circulating levels of the gonadotrophins LH and FSH:

■ High serum LH and FSH levels are associated with various causes of gonadal disease, termed primary hypogonadism

■ Low or normal LH and FSH levels indicate disorders at the hypothalamic-pituitary level, termed secondary hypogonadism. Rarely, this can be due to hypothalamic dysfunction, hypopituitarism, hypothyroidism or hyperprolactinaemia.

Constitutional delay of puberty is typically associated with low levels of LH and FSH.

Laboratory tests for delayed puberty in males

■ Tests directed at possible medical or nutritional disorders, based on history and examination findings e.g. CBC, liver function, creatinine, coeliac serology

■ Hormonal tests: LH and FSH, serum testosterone, serum prolactin, TSH (and FT4 if a pituitary cause is suspected)

Random growth hormone (GH) testing is of little value because of the pulsatile nature of GH secretion by the pituitary.

Depending on the results of these initial tests, further testing may be indicated, but specialist advice is recommended.

References1. Jack G, Zeitlin SI. The role of routine serum testosterone

testing: routine hormone analysis is not indicated as an initial screening test in the evaluation of erectile dysfunction. Rev Urol 2004; 6(4):203-6.

2. Feldman HA, Goldstein I, Hatzichristou DG, et al. Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol 1994;151(1):54-61.

3. Miller TA. Diagnostic evaluation of erectile dysfunction. Am Fam Physician 2000;61:95-104,109-10.

4. Wespes E, Amar E, Hatzichristou D, et al. Guidelines on erectile dysfunction. European Association of Urology. March 2004. Available from : www.urotoday.com/prod/pdf/eau/22891_Erectile_Dysfunction.pdf (Accessed August, 2010).

5. Hatzimouratidis K, Amar E, Eardley I, et al. Guidelines on male sexual dysfunction: erectile dysfunction and premature ejaculation. Eur Urol 2010 [EPub ahead of print].

6. Ralph D, McNicholas T. UK management guidelines for erectile dysfunction. BMJ 2000;321:499-503.

7. Qaseem A, Snow V, Denberg TD, et al. Hormonal testing and pharmacologic treatment of erectile dysfunction: A clinical practice guideline from the American College of Physicians. Ann Intern Med 2009;151:639-49.

8. Montague DK, Jarrow JP, Broderick GA, et al. Management of erectile dysfunction. American Urological Association 2006. Available from: www.auanet.org (Accessed August, 2010).

9. Bhasin S, Cunningham G, Hayes F, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocinol Metab 2010;95(6):2536-59.

10. Emedicine. Gynecomastia, March 2010. Available from: http://emedicine.medscape.com/article/120858-overview (Accessed August, 2010).

11. Chantra PK, So GJ, Wollman JS, et al. Mammography of the male breast. Am J Roentgenol 1995;164(4):853. Available from: www.ajronline.org/cgi/reprint/164/4/853 (Accessed August, 2010).

12. Braunstein GD. Gynecomastia. N Engl J Med 2007;357:1229-37.

13. Diagnostic Medlab (DML). A handbook for the interpretation of laboratory tests, 4th edition. DML, Auckland, 2008.

14. Stanworth RD, Jones TH. Testosterone for the aging male: current evidence and recommended practise. Clin Int Aging 2008;3(1):25-44.

15. Pralong F, Crowley W. Diagnosis and treatment of delayed puberty. UpToDate 2007. Available from: www.uptodate.com (Accessed August, 2010).

16. Levy S. Delayed puberty. The Merck manual for healthcare professionals. Merck 2009. Available from: www.merck.com/mmhe/sec23/ch271/ch271b.html (Accessed August, 2010).

ACKNOWLEDGEMENT: Thank you to Dr Steve Soule, Endocrinologist, Canterbury DHB for expert guidance in developing this article.

Laboratory investigation of amenorrhoea

Polycystic ovary syndromeAn overview of dysfunctional

uterine bleedingPerimenopause and menopause

Sexual dysfunction - loss of libido

WOMEN’S HEALTHSelected topics in


www.bpac.org.nz keyword: womenshealth


AmenorrhoeaAmenorrhoea is the absence of menstruation flow. It can be classified as either primary or secondary,1 relative to menarche:

■ Primary amenorrhoea: absence of menses by age 16 years in a female with appropriate development of secondary sexual characteristics; or absence of menses by age 13 years and no other pubertal maturation2

■ Secondary amenorrhoea: lack of menses in a previously menstruating, non-pregnant female, for greater than six months2

Primary amenorrhoeaKey messages:

■ The most common cause of primary amenorrhoea in a female with no secondary sexual characteristics is a constitutional delay in growth and puberty. In the first instance, watchful waiting is the most appropriate course.

■ For females with primary amenorrhoea but who have secondary sexual characteristics, pelvic ultrasound is indicated.

Evaluation of primary amenorrhoeaCauses of primary amenorrhoea should be evaluated in the context of the presence or absence of secondary sexual characteristics.2

Absence of secondary sexual characteristics

The most common cause of primary amenorrhoea in a female with no secondary sexual characteristics is hypogonadotropic (i.e. low LH and FSH) hypogonadism, often due to a constitutional delay in growth and puberty. A detailed family history may reveal a familial aspect to this. If there is a positive family history, watchful waiting is appropriate in the first instance, although the time will depend upon the age of the patient at presentation.

Testing LH and FSH is unhelpful in determining constitutional delay of puberty as low levels can be due to a delay but also a number of other conditions (Figure 1).

Causes of primary amenorrhoea2

■ Hypergonadotropic hypogonadism/primary hypogonadism/gonadal failure:

– Abnormal sex chromosomes e.g. Turner syndrome

– Normal sex chromosomes e.g. premature ovarian failure

■ Hypogonadotropic hypogonadism/secondary hypogonadism:

– In many cases this may be due to a familial delay in puberty and growth. Other causes include congenital abnormalities e.g. isolated GnRH deficiency, acquired lesions, endocrine disturbance, tumour, systemic illness or eating disorder.

■ Eugonadism:

– Anatomic e.g. congenital absence of the uterus and vagina, intersex disorders or inappropriate endocrine feedback mechanisms

In a large case series of primary amenorrhoea, the most common aetiologies were:2

■ Chromosomal abnormalities causing gonadal dysgenesis (ovarian failure due to the premature depletion of all oocytes and follicles) – 50%

■ Hypothalamic hypogonadism including functional hypothalamic amenorrhoea – 20%

■ Absence of the uterus, cervix and/or vagina, Müllerian agenesis – 15%

■ Transverse vaginal septum or imperforate hymen – 5%

■ Pituitary disease – 5%


Primary amenorrhoea in females with no secondary sexual characteristics may also be caused by hypergonadotropic (i.e. high LH and FSH) hypogonadism. This is usually caused by premature ovarian failure, or gonadal dysgenesis – the most common form of female gonadal dysgenesis is Turner syndrome (45X0 karyotype).

Presence of secondary sexual characteristics

It is recommended that a female aged 16 years or over with secondary sexual characteristics, presenting with primary amenorrhoea, is referred for a pelvic ultrasound to determine if the uterus is present. Absence of the uterus may be the result of androgen insensitivity syndrome,

where a person has a female external appearance despite a 46XY karyotype and undescended testes. It can also be due to Müllerian ageneis which is a congenital malformation characterised by a failure of the Müllerian ducts to develop, resulting in a missing uterus and variable malformations of the vagina.

If the uterus is normal, outflow tract obstruction should be considered. An imperforate hymen or a transverse vaginal septum can cause outflow obstruction. This is most often associated with cyclic lower abdominal pain from blood accumulation in the uterus and vagina. If there is no evidence of outflow obstruction, investigate as for secondary amenorrhoea (Table 1).

History and physical examination completed for a patient with primary amenorrhoea

Secondary sexual characteristics present?

Perform ultrasonography of the uterusConsider watchful waiting

FSH and LH < 5 IU per L FSH > 20 IU per L and LH > 40 IU per L

Hypogonadotrophic hypogonadism

Hypergonadotrophic hypogonadism

Karyotype analysis

46, XX 45, XO

Turner syndrome

Premature ovarian failure

Figure 1: Investigations for primary amenorrhoea (adapted from Master-Hunter, 2006)3

Diagnostic pathway for primary amenorrhoea

Uterus absent or abnormal

Karyotype analysis

46, XY 46, XX

Androgen insensitivity syndrome

Müllerian agenesis

Uterus present or normal

Outflow obstruction?

Evaluate for secondary amenorrhoea

Imperforate hymen or transverse

vaginal septum

Measure FSH and LH levels

NO YES

NOYES


Table 1: Laboratory findings in common causes of secondary amenorhoea6

Condition FSH Prolactin Testosterone

Hyperprolactinaemia Normal/low High Normal

Polycystic Ovary Syndrome Normal Normal/slightly increased in 5–30%

Normal/moderately increased

Free androgen index increased

Ovarian failure High Normal Normal

Hypothalamic e.g. weight loss, excessive exercise, or stress

Low/normal Normal Normal

Causes of secondary amenorrhoea

After excluding pregnancy (and breast feeding), the most common causes of secondary amenorrhoea are:4,5

■ Ovarian disease (40%) – ovarian failure due to normal or early menopause, hyperandrogenism e.g. PCOS, testosterone supplementation

■ Functional hypothalamic anovulation (35%) – due to excessive exercise, eating disorders, stress or some medicines e.g. oral contraceptives, depot medroxyprogesterone

■ Pituitary disease (19%) – has a similar presentation to functional hypothalamic amenorrhoea except for the occasional additional finding of galactorrhoea in some women. Rare causes are sellar masses, other disease of the pituitary and primary hypothyroidism.

■ Uterine disease (5%) – Asherman’s syndrome is the only uterine cause of secondary amenorrhoea. This syndrome results from acquired scarring of the endometrial lining, usually secondary to postpartum hemorrhage or endometrial infection following instrumental procedure such as a dilatation and curettage.

Secondary amenorrhoea

Secondary amenorrhoea is defined as a lack of menses for six months in a non-pregnant patient who was previously menstruating.

Key messages:

■ Exclude pregnancy as it is the most common cause of secondary amenorrhoea

■ Other than pregnancy , most cases of secondary amenorrhoea are caused by menopause, polycystic ovary syndrome (PCOS) or functional anovulation e.g. excessive exercise, eating disorder, stress or certain medicines

■ FSH, TSH and prolactin measurements will help identify most causes of secondary amenorrhoea. If there is suspicion of pituitary disease, FT4 should also be tested.

Diagnostic evaluation of secondary amenorrhoea

Pregnancy should be first excluded by either urine pregnancy test or a serum hCG, rather than relying solely on history.

The history, physical examination and measurement of FSH, TSH and prolactin will help identify the most common causes of amenorrhoea. In addition, for women with evidence of hyperandrogenism e.g. assessment of hirsutism and acne, and measurement of testosterone would also be indicated.

Results can often be difficult to interpret (Table 1) therefore review or advice from a relevant specialist may be appropriate.


Polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is reported to affect between 5–10% of women of reproductive age.2, 3

As well as taking a full history, examination of a woman with suspected PCOS should include an assessment of:■ Weight (both BMI and hip/waist ratio)

■ Acne and hirsutism

■ Blood pressure

Diagnostic criteria have been developed for PCOSPCOS is a syndrome, so there is no single diagnostic test. There are several definitions of PCOS, but generally PCOS is defined by the presence of hyperandrogenism (clinical or biochemical), ovarian dysfunction (oligo-anovulation or polycystic ovaries), and the exclusion of related disorders.7

Table 2 compares diagnostic criteria for PCOS.

Investigation of PCOS

A clinical or biochemical finding of increased androgen levels along with either menstrual abnormalities or

polycystic ovaries on ultrasound will satisfy the current diagnostic criteria (Table 2). Other tests that should be considered when investigating PCOS include FSH, TSH and prolactin levels.

Once the diagnosis of PCOS is established, fasting glucose and lipids are recommended. For women with fasting glucose >5.5 mmol/L an oral glucose tolerance test (OGTT) is indicated. In addition, some clinicians recommend that OGTT should be done for all women with PCOS who have a BMI > 30 and for all women aged over 40 years even if of normal weight.

For more information about investigating PCOS see “Understanding polycystic ovary syndrome” BPJ 12, April 2008.

Limited role of LH/FSH ratio8

In the past, the diagnosis of PCOS was often based upon the finding of an elevated ratio of LH to FSH in serum. Women with PCOS tend to have elevated LH concentrations, with normal to low FSH. However, while some clinicians still test LH and FSH, this is not required for a diagnosis of PCOS.

Table 2: Diagnostic criteria for PCOS

NIH criteria (1990) Rotterdam Criteria (2003) AES Criteria (2006)

All three of the following:■ Clinical or biochemical evidence

of hyperandrogenism■ Oligomenorrhoea and/or

anovulation■ Exclusion of other disorders

At least two of the following:■ Oligomenorrhoea and/or

anovulation■ Clinical or biochemical signs of

hyperandrogenism■ Polycystic ovaries

PCOS can be diagnosed only after the exclusion of related disorders (e.g. severe insulin resistance, androgen-secreting neoplasms, Cushing’s syndrome, hyperprolactinaemia and thyroid abnormalities)

All three of the following:■ Hyperandrogenism (clinical or

biochemical)■ Ovarian dysfunction

(oligomenorrhoea or anovulation and/or polycystic ovarian morphology)

■ Exclusion of other androgen excess or related disorders

PCOS is predominantly a disorder of androgen excess

The NIH Critera were developed first and therefore are most commonly used. The Rotterdam criteria expanded the NIH definition. The AES reviewed all available data and recommended an evidence-based definition.

NIH = National Institutes of Health, Rotterdam = European Society for Human Reproduction and Embryology and the American Society for Reproductive Medicine, AES = Androgen Excess Society


An overview of dysfunctional uterine bleedingAny uterine bleeding which is outside the normal menstrual patterns can be termed as dysfunctional uterine bleeding.9 It can be caused by a wide variety of local and systemic diseases or related to medicines e.g. hormonal contraceptives. However, most cases of dysfunctional uterine bleeding are related to anovulatory cycles, menopause, pregnancy, structural uterine pathology e.g. fibroids, polyps or adenomyosis or a disorder of haemostasis or neoplasia. Trauma and infection are less common causes.

Laboratory studies for dysfunctional uterine bleeding

Investigations depend on individual presentation and examination.12 In many cases, it will be appropriate to first exclude pregnancy and cervical or uterine cancer as causes of uterine bleeding.

A pregnancy test is indicated for women of reproductive age with dysfunctional uterine bleeding, to exclude intrauterine or ectopic pregnancy, or gestational trophoblastic disease (hydatiform mole).

Any malignancy of the genital tract can cause dysfunctional bleeding. It can be difficult to determine whether bleeding is from an endocervical or endometrial source, so cervical cancer must be excluded. Any visible cervical lesion should be biopsied, even if cervical cytology is negative for malignancy.

Depending upon the history, clinical exam and initial evaluations, a second tier of laboratory testing may be appropriate. This may include:

■ Ultrasound examination and hysteroscopy – useful for further evaluating women whose findings on pelvic examination are uncertain

■ TSH – In women with signs and symptoms of hypo or hyper-thyroidism

■ Coagulation tests – only in women with history suggestive of haemostatic defect e.g. frequent nosebleeds, easy bruising

■ Complete blood count (CBC) – in women with evidence of anaemia

Terminology for dysfunctional uterine bleeding

There are a number of terms used to define abnormal frequency, duration or volume of uterine bleeding.10

Menorrhagia — prolonged (greater than seven days) or excessive ( > 80 mL daily) uterine bleeding occurring at regular intervals

Oligomenorrhoea — regular bleeding that occurs at an interval greater than 35 days

Polymennorrhoea — regular bleeding that occurs at an interval less than 24 days

Metrorrhagia and menometrorrhagia – metrorrhagia refers to light bleeding at irregular intervals. Menometrorrhagia refers to heavy bleeding at irregular intervals

Intermenstrual bleeding — bleeding that occurs between menses or between expected hormone withdrawal bleeds in women using hormonal contraception or postmenopausal hormone therapy

Premenstrual spotting — light bleeding preceding regular menses

Post menopausal bleeding — recurrence of bleeding or spotting in a menopausal women at least six months to one year after cessation of cycles

Postcoital bleeding — vaginal bleeding or spotting that is noted within 24 hours of vaginal intercourse

■ Chlamydia/gonorrhoea – if cervicititis, vaginal discharge and/or pelvic tenderness

■ Prolactin – useful in women complaining of oligomenorrhoea, particularly with galactorrhoea


The average women begins menopause at approximately age 50 years. It is a retrospective diagnosis made following the cessation of menses for 12 months or more. The menopausal transition begins with variations in menstrual cycle length and ends with the final menstrual period. The perimenopausal period ends one year after the final menstrual period.11,12

Although hormone levels change throughout the menopausal period, hormone measurements are not useful for predicting the stage of the transition, or the date of the final menstrual period. FSH levels can vary significantly across cycles, so the use of FSH for predicting menopause in individual women is limited. 11,12

In women aged over 45 years with symptoms suggestive of menopausal transition e.g. irregular menstrual cycles and menopausal symptoms such as hot flushes, sleep disturbance, vaginal dryness or joint and muscle aches, no laboratory testing is required.11,12

In women aged under 45 years with symptoms suggestive of menopausal transition, consider the following investigations: initially exclude pregnancy, if negative consider possible PCOS and measure prolactin, TSH, FSH levels and testosterone.11,12

Loss of libido has been reported to affect up to 40% of women at some time in their life.13

A full history and clinical examination, including sexual history and relationship factors is important. A key requirement for the evaluation of female sexual dysfunction is to determine whether sexual issues are associated with personal stress.13

The presence of any serious medical condition is likely to impair sexual function not only because of the condition itself, but also due to the associated impact on psychological well-being. In addition, poor self-assessed health is often associated with sexual problems.13

Laboratory evaluation of sexual dysfunction

Laboratory testing should be performed only if indicated by history or examination.

Except in limited specialist settings, androgen levels are not helpful when evaluating the cause of a sexual problem. The correlation between androgen levels and sexual dysfunction is considered weak, apart from a few well defined situations such as proven pituitary or adrenal insufficiency or past bilateral oophorectomy. Similarly, testing oestradiol or other hormones e.g. FSH and prolactin, has limited utility in evaluating sexual dysfunction.13

Perimenopause and menopause

Sexual dysfunction – loss of libido


References 1. Assessment of secondary amenorrhoea. Best Practice.

BMJ Publishing Group. Available from: http://bestpractice.bmj.com/best-practice/monograph/1102.html (Accessed August, 2010).

2. Welt C, Barbieri R. Etiology, diagnosis and treatment of primary amenorrhoea. UpToDate 2009. Available from: www.uptodate.com (Accessed August, 2010).

3. Master-Hunter T, Heiman D. Amenorrhoea: evaluation and treatment. Am Fam Physician. 2006;73(8):1374-82.

4. Pinkerton JV. Amenorrhoea. The Merck Manuals. Available from: www.merck.com/mmpe/sec18/ch244/ch244b.html#CBBFFDAF (Accessed August, 2010).

5. Welt C, Barbieri R. Etiology, diagnosis and treatment of secondary amenorrhoea. UpToDate 2008. Available from: www.uptodate.com (Accessed August, 2010).

6. Clinical Knowledge Summaries (CKS). Amenorhoea. Available from: www.cks.nhs.uk/amenorrhoea (Accessed August, 2010).

7. Azziz R, Carmina E, Dewailly D, et al. Position statement: Criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: An Androgen Excess Society Guideline. J Clin Endocrinol Metab. 2006; 91:4237-45.

8. Barbieri R. Treatment of hirsutism. UpToDate 2010. Available from: www.uptodate.com (Accessed August, 2010).

9. Emedicine. Dysfunctional uterine bleeding: differential diagnoses & workup. Feb 1, 2010. Available from: http://emedicine.medscape.com/article/795587-diagnosis (Accessed August, 2010).

10. Goodman A. Terminology and evaluation of abnormal uterine bleeding in premenopausal women. UpToDate 2009. Available from www.uptodate.com (Accessed August, 2010).

11. Casper R. Clinical manifestations and diagnosis of menopause. UpToDate 2009. Available from: www.uptodate.com (Accessed August, 2010).

12. Fertnstert J. The menopausal transition. Fertility Sterility 2008;90(Suppl 3):S61.

13. Shifren J. Sexual dysfunction in women: Epidemiology, risk factors, and evaluation. UpToDate 2010. Available from: www.uptodate.com (Accessed August 2010).

ACKNOWLEDGEMENT: Thank you to Dr Anna Fenton, Endocrinologist, The Oxford Clinic, Christchurch for expert guidance in developing this article.

Screening tests


QUIZ FEEDBACK

IntroductionThis quiz feedback provides an opportunity to revisit the July 2010 “Best Tests” document and accompanying quiz which focused on appropriate use of laboratory screening tests in the primary care setting. All general practitioners who responded to this quiz will receive personalised online feedback and CME points

www.bpac.org.nz keyword: screeningquiz


1. Which of the following is true about screening tests?

Your peers Preferred

All screening tests do more good than harm 11%

A test can only qualify as a screening test, if there is robust scientific evidence to support its use

83% The health service must have sufficient capacity to cope with diagnosis, follow-up and treatment

96% Patients should be given sufficient information to allow them to decide for themselves whether or not they should be screened

90%

Comment:Screening tests should be based on sufficient evidence that the test demonstrates more good than harm. An example of possible “harm” (in the form of anxiety, unnecessary referrals etc) is in the theoretical case of a PSA test being ordered in an asymptomatic, well male aged > 75 years. Here a raised PSA level result may cause increased anxiety and lead to unnecessary referrals for treatment, when it is less likely that prostate cancer in an asymptomatic older male will impact on that patient’s lifespan and health.

The provision of information and discussion about screening tests may take considerable effort, time and skill, and many GPs are not able to easily fit this into the usual 15 minute consultation. This is where written information about testing in the form of patient information leaflets can be invaluable e.g. pamphlets discussing the benefits, limitations and harms of PSA testing.

2. Mark each of the following as a harm and/or benefit of screening

Your peers PreferredHarm Benefit Harm Benefit Harm Benefit

Reassurance from a negative result 60% 80% Earlier treatment options 17% 99% Diagnosis earlier in the course of the disease 36% 94% Screening available to everyone in the target group 12% 90%

Comment:Intuitively it seems that screening would be the ideal way to identify people early in the course of a potential disease process. However screening can cause harms as well as benefits to the patient.

Those with true negative test results may be reassured, however for some a negative result will be false reassurance as it may actually be a false-negative result, with the possibility of later treatment and a worse prognosis.


Earlier treatment options may include less expensive treatment, less radical treatment and a cure for some early cases, with improved quality of life. But this needs to be balanced against the possibility of over-treatment of questionable abnormalities.

Earlier diagnosis in the course of an illness can cause lead-time bias. This is where a person may not actually have a better survival (or extended life) but just spends a longer time living with the known illness.

3. Why are tumour markers not recommended as screening tests?


They may be elevated by other conditions 97% Not all people with the condition will be positive 91% Tests are not widely available 15%

They are better suited for use as monitoring tests 95%

Comment:In primary care the key role for most tumour markers, with the exception of PSA, is in the management of patients with established malignancy. Nearly all tumour markers show some correlation with the clinical course of disease, with marker elevation in any stage declining to normal after a curative intervention.

Tumour markers are not recommended for screening asymptomatic patients for malignancy because they generally:

■ Lack specificity – many patients may have an elevated result due to benign disease

■ Lack sensitivity – many patients with malignancy will have a normal result

4. Which of the following factors are controversial, when considering PSA testing in asymptomatic men?


Testing reduces prostate cancer mortality 74% Benefits of treatment 72% Harms from testing 77% Adoption of a national screening programme in New Zealand 74%

Comment:The New Zealand mortality rate, due to prostate cancer, has remained static for approximately 50 years (according to data collected by the Cancer Society of New Zealand) despite the increase in the number of PSA tests being performed in recent years.


Two recent trials, the European Randomised Study of Screening for Prostate Cancer (ERSPC) and the Prostate, Lung, Colon and Ovary Trial (PLCO), have not helped to clarify whether more benefit than harm is achieved with PSA screening. In the ERSPC trial fewer prostate cancer-related deaths occurred in the screened group than in the control group.1 However in the PLCO trial researchers found no difference in prostate cancer-related deaths between the screened and control groups.2

A national screening programme has not been recommended in New Zealand as there is a lack of consensus if the benefits of screening outweigh the harms.

There is no PSA level below which a man can be completely reassured he does not have prostate cancer. A significant number of men with prostate cancer will have a normal PSA.

1. Schroder F, Hugosson J, Roobol M, et al. Screening and prostate-cancer mortality in a randomised European study. N Engl J Med 2009;360:1320-8.

2. Andriole G, Crawford E, Grubb R, et al. Mortality results from a randomised prostate-cancer screening trial. N Engl J Med 2009;360:1310-9.


5. What should be considered when discussing PSA testing with patients?


Present a balanced picture of the harms and benefits 98% Support the patient to make the best decision for him 96% Point out the increased risk due to age or family history 92% Let him know that a normal result can reassure him that he is free of prostate cancer 3%

Comment:GPs are the “gate-keepers” for PSA testing – they influence who does and does not get tested. The New Zealand Guidelines Group recommends that every man has the right to decide for himself whether or not to be tested and that GPs should advise patients of the risks and benefits of testing, as well as the likelihood of them developing prostate cancer.

Under the Code for Health and Disability Services Consumers’ Rights Regulations 1996, doctors and other practitioners have a duty to provide good, balanced information on prostate cancer, prostate cancer treatment and the possible benefits and harms of PSA testing.

The risk of prostate cancer increases with a positive family history. The risk is greater if a close relative is diagnosed before age 65 years or if more than one close relative is affected.

6. Which is true about bowel cancer screening in New Zealand?


A programme is to be piloted before a final decision is to be made 92% Development of all stages of the screening pathway is happening now 28%

A number of developed countries already have bowel cancer screening programmes 95% At this stage, a national screening programme in New Zealand is scheduled to start in 2011 16%

Comment:Bowel cancer screening programmes are currently running in many developed countries, including Australia and the United Kingdom. New Zealand has no national bowel cancer screening programme but is to undertake a screening pilot, anticipated to begin in 2011. It will operate in one or two regions of New Zealand and will run for four years. A decision on whether New Zealand adopts a national bowel cancer screening programme will be made following the evaluation of this pilot programme.


7. CA 125 may be elevated by which of the following conditions?


Benign ovarian cysts 97% Menstruation 93% Irritable bowel syndrome 1%

Endometriosis 99%

Comment:

Carbohydrate antigen 125 (CA 125) may be raised in a variety of non-malignancy related gynaecological conditions e.g. menstruation, pregnancy, benign ovarian cysts, PID and endometriosis, non-gynaecological conditions e.g. cirrhosis, ascites, renal failure and pericarditis and in ovarian cancer.

Although CA 125 is frequently requested when investigating suspected ovarian cancer, its main role is for the management of ovarian cancer in secondary care. CA 125 is not recommended for screening or diagnosis and its role in primary care is limited. In rare situations, CA 125 may be used to help distinguish benign from malignant disease, particularly in post-menopausal women, presenting with pelvic masses or in women from families with a history of hereditary ovarian cancer. In these situations, it is recommended that CA 125 be performed in conjunction with transvaginal ultrasound.

8. Which of the following would be an appropriate use of CEA?


Screening of a suspected bowel cancer1%

Used in conjunction with other tumour markers, to help exclude malignancy in patients with unusual symptoms

7%

Monitoring patients with bowel cancer98%

Rarely indicated in primary care70%

Comment:Carcinoembryonic antigen (CEA) may be raised with cancer of the colon but also in other cancers (lung, breast, liver, pancreas, thyroid, stomach and ovary) or non-cancerous conditions e.g. ulcerative colitis and smoking.

CEA is not recommended as a screening or diagnostic test for colorectal cancer due to its poor sensitivity and specificity, and because of the low prevalence of colorectal cancer in asymptomatic people.

C L I N I C A L AU D I T S

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