Commenting on amenorrhoea, or Commenting on amenorrhoea, or how to get suedhow to get sued

Five cases will be presentedFive cases will be presented

25 of the audience will be asked to assess 25 of the audience will be asked to assess interpretative ideas or whole comments on interpretative ideas or whole comments on each Case. Each Case and each comment is each Case. Each Case and each comment is realreal

Each assessor will hold up a numbered cardEach assessor will hold up a numbered card The numbers range from 1 (awful) to 5 The numbers range from 1 (awful) to 5

(brilliant)(brilliant) Each assessor will not be able to see the Each assessor will not be able to see the

marks given by other assessorsmarks given by other assessors The assessment may give us an idea of The assessment may give us an idea of

which comments are most appropriate which comments are most appropriate

Case 1Case 1

A 32 year old woman, visiting her A 32 year old woman, visiting her Family Doctor. Clinical information Family Doctor. Clinical information given is ’15 months amenorrhoea, given is ’15 months amenorrhoea, cause?’ Serum results arecause?’ Serum results are

Normal U & E, LFTs, TFTsNormal U & E, LFTs, TFTs HCG < 3 U/LHCG < 3 U/L LH 24 U/L, FSH 6 U/LLH 24 U/L, FSH 6 U/L Testosterone 2.5 nmol/LTestosterone 2.5 nmol/L

Interpretative ideasInterpretative ideas

HCG not suggestive of pregnancyHCG not suggestive of pregnancy Early pregnancy cannot be excludedEarly pregnancy cannot be excluded High LH/ FSH ratio and borderline High LH/ FSH ratio and borderline

testosterone suggestive of PCOStestosterone suggestive of PCOS Possible ovulation peakPossible ovulation peak Suggest repeat in 3 months if Suggest repeat in 3 months if

amenorrhoea persistsamenorrhoea persists

Case 1: the outcomeCase 1: the outcome

The patient presented to A & E 3 weeks The patient presented to A & E 3 weeks later with abdominal pain, and although later with abdominal pain, and although there was little radiological evidence, there was little radiological evidence, an ectopic pregnancy was diagnosedan ectopic pregnancy was diagnosed

The patient sued the laboratory for the The patient sued the laboratory for the pain and distress caused by erroneous pain and distress caused by erroneous results/ incorrect adviceresults/ incorrect advice

The laboratory mounted a robust The laboratory mounted a robust defence, and the case was later defence, and the case was later droppeddropped

Case 1: learning pointsCase 1: learning points

Non-extraction female testosterone Non-extraction female testosterone assays are of poor qualityassays are of poor quality

The utility of an LH/ FSH ratio in The utility of an LH/ FSH ratio in diagnosing PCOS is debatablediagnosing PCOS is debatable

However, with the clinical However, with the clinical information given, PCOS was much information given, PCOS was much more likely than an ovulation peakmore likely than an ovulation peak

But the Duty Biochemist must be But the Duty Biochemist must be very careful!very careful!

Guidelines for diagnosis of PCOSGuidelines for diagnosis of PCOS

ESHRE Rotterdam 2003 consensus states ESHRE Rotterdam 2003 consensus states that 2 of the following 3 criteria should be that 2 of the following 3 criteria should be met: oligo/ anovulation; evidence of met: oligo/ anovulation; evidence of hyperandrogenism (either clinical or hyperandrogenism (either clinical or biochemical); ovarian polystic evidence on biochemical); ovarian polystic evidence on ultrasoundultrasound

AACE guidelines mention that an LH/ FSH AACE guidelines mention that an LH/ FSH ratio of greater than 2 is seen in 60 – 70% ratio of greater than 2 is seen in 60 – 70% of PCOS cases and suggest these of PCOS cases and suggest these measurementsmeasurements

Case 2Case 2

A 56 year old woman seeing her A 56 year old woman seeing her Family Doctor, clinical information Family Doctor, clinical information ‘able to stop progesterone-only pill?’‘able to stop progesterone-only pill?’

Serum FSH 22 U/LSerum FSH 22 U/L An FSH 5 months previously was 50 An FSH 5 months previously was 50

U/LU/L

Comments on Case 2Comments on Case 2 FSH can fluctuate markedly in the FSH can fluctuate markedly in the

perimenopausal period. The age and FSH perimenopausal period. The age and FSH results suggest that the use of the results suggest that the use of the progesterone-only pill for contraception is progesterone-only pill for contraception is now unnecessary in this patientnow unnecessary in this patient

Previous FSH in post-menopausal period. Previous FSH in post-menopausal period. Diagnosis of the menopause basically Diagnosis of the menopause basically clinical. Results probably consistent with clinical. Results probably consistent with perimenopausal statusperimenopausal status

?Suppression of FSH by exogenous ?Suppression of FSH by exogenous oestrogens or use of creams/ herbal oestrogens or use of creams/ herbal remedies with oestrogen-like action. If so, remedies with oestrogen-like action. If so, discontinuediscontinue

Case 2 learning pointsCase 2 learning points Menopause: amenorrhoea for at least 1 year due Menopause: amenorrhoea for at least 1 year due

to cessation of ovarian function in women over to cessation of ovarian function in women over the age of 45the age of 45

Perimenopause: a span of 4 – 6 years preceding Perimenopause: a span of 4 – 6 years preceding menopause when menstrual cycles may be menopause when menstrual cycles may be irregular and symptoms appear such as hot irregular and symptoms appear such as hot flashesflashes

Diagnosis is clinical (and retrospective): FSH can Diagnosis is clinical (and retrospective): FSH can only be used to support the diagnosisonly be used to support the diagnosis

With a raised FSH, the prudent comment is ‘FSH With a raised FSH, the prudent comment is ‘FSH suggestive of (peri)menopausal status, but the suggestive of (peri)menopausal status, but the possibility of further fertile cycles cannot be possibility of further fertile cycles cannot be excluded’excluded’

Case 3Case 3

A 26 year old woman seeing her GP. A 26 year old woman seeing her GP. Clinical information ‘negative Clinical information ‘negative pregnancy test a few days ago but pregnancy test a few days ago but period now 8 days late, breast period now 8 days late, breast tenderness’tenderness’

Serum hCG 122 U/L (DPC Immulite)Serum hCG 122 U/L (DPC Immulite)

Comments on Case 3Comments on Case 3

Suggest repeat serum hCG in 2 days to Suggest repeat serum hCG in 2 days to confirm satisfactory increase in hCG confirm satisfactory increase in hCG consistent with pregnancyconsistent with pregnancy

Please repeat in 1 weekPlease repeat in 1 week Possible ectopic pregnancy or missed Possible ectopic pregnancy or missed

abortion. Advise repeat in 48 hoursabortion. Advise repeat in 48 hours hCG result may indicate early normal hCG result may indicate early normal

uterine pregnancy or ectopic pregnancy. uterine pregnancy or ectopic pregnancy. Suggest repeat in 48 hours which should Suggest repeat in 48 hours which should show at least a 2fold increase if normal show at least a 2fold increase if normal pregnancypregnancy

Average hCG in early pregnancyAverage hCG in early pregnancy

Day 25:Day 25: 63 U/L63 U/L 30:30: 240 U/L240 U/L Day 35:Day 35: 940940 40:40: 4 3004 300 Day 45:Day 45: 18 00018 000 50:50: 46 00046 000 Day 55:Day 55: 74 00074 000 60:60: 101 000101 000 Summarised data for the Royal Summarised data for the Royal

Berkshire Hospital from apparently Berkshire Hospital from apparently normal pregnancies (Bayer Centaur normal pregnancies (Bayer Centaur method)method)

Rate of increase of hCGRate of increase of hCG

‘‘At least doubling every 2 days’ is At least doubling every 2 days’ is widely quotedwidely quoted

The maximum 2-day increase is 1.9 The maximum 2-day increase is 1.9 between days 35 and 45between days 35 and 45

Before and after this period, the Before and after this period, the average rate of increase is less, and average rate of increase is less, and after day 60 hCG values plateau and after day 60 hCG values plateau and begin to declinebegin to decline

Utility of this hCG dataUtility of this hCG data

There is considerable individual There is considerable individual variation, but because of the rapid variation, but because of the rapid rise, errors in dating are quite smallrise, errors in dating are quite small

67% of pregnancies give a dating 67% of pregnancies give a dating within 3 days of averagewithin 3 days of average

95% give a dating within 9 days of 95% give a dating within 9 days of averageaverage

Bias differences between different Bias differences between different methods make little differencemethods make little difference

Case 3 learning pointsCase 3 learning points

An hCG result much less than the average An hCG result much less than the average value may suggest incorrect dating or an value may suggest incorrect dating or an ectopic or failing pregnancyectopic or failing pregnancy

In this Case, the expected hCG from the In this Case, the expected hCG from the clinical information given was 1 300 U/L clinical information given was 1 300 U/L and the possibility of an ectopic pregnancy and the possibility of an ectopic pregnancy was raisedwas raised

Five days later, the patient was admitted Five days later, the patient was admitted with acute abdominal pain, and an ectopic with acute abdominal pain, and an ectopic pregnancy was identifiedpregnancy was identified

Case 4Case 4

A 22 year old woman seeing her GP. A 22 year old woman seeing her GP. No clinical information was given on No clinical information was given on the request form. Serum hCG was 14 the request form. Serum hCG was 14 U/LU/L

Two weeks earlier, information was Two weeks earlier, information was ‘LMP 15 weeks ago, inconclusive ‘LMP 15 weeks ago, inconclusive USS’. Serum hCG was 21 U/LUSS’. Serum hCG was 21 U/L

Two months earlier, information was Two months earlier, information was ‘?pregnant’. Serum hCG was 121 U/L‘?pregnant’. Serum hCG was 121 U/L

Comments on Case 4Comments on Case 4 Exclude ectopic pregnancyExclude ectopic pregnancy Beta hCG reaches a peak at about 10 weeks in Beta hCG reaches a peak at about 10 weeks in

normal pregnancy and then begins to decline. normal pregnancy and then begins to decline. These data are compatible with pregnancy. Is she These data are compatible with pregnancy. Is she likely to have another USS?likely to have another USS?

Decline in hCG not consistent with pregnancy. Decline in hCG not consistent with pregnancy. Result suggestive of previous missed abortion or Result suggestive of previous missed abortion or ectopic pregnancy. Please send repeat sample in ectopic pregnancy. Please send repeat sample in 2 weeks to confirm decline in hCG2 weeks to confirm decline in hCG

Still detectable hCG may indicate retained Still detectable hCG may indicate retained products of conception but trophoblastic disease products of conception but trophoblastic disease and possible interfering antibodies should be and possible interfering antibodies should be considered. Suggest early gynae referralconsidered. Suggest early gynae referral

Case 4 learning pointsCase 4 learning points

Following an abortion or termination of Following an abortion or termination of pregnancy, in around 65% of patients the pregnancy, in around 65% of patients the hCG declines to non-detectable values after hCG declines to non-detectable values after around 4 weeks; in at least 95% of patients around 4 weeks; in at least 95% of patients after around 8 weeksafter around 8 weeks

In the period 4 – 8 weeks after TOP with In the period 4 – 8 weeks after TOP with detectable hCG, it is useful to suggest a detectable hCG, it is useful to suggest a repeat hCG to confirm declining valuesrepeat hCG to confirm declining values

After 8 weeks, a still detectable hCG After 8 weeks, a still detectable hCG suggests either retained products of suggests either retained products of conception or a new pregnancy: a further conception or a new pregnancy: a further repeat is usefulrepeat is useful

Case 5Case 5

You are telephoned by a Consultant You are telephoned by a Consultant Oncologist. He has been treating a 46 Oncologist. He has been treating a 46 year old lady for breast cancer. She year old lady for breast cancer. She finished chemotherapy 6 months ago, finished chemotherapy 6 months ago, and is now prescribed Tamoxifen. She and is now prescribed Tamoxifen. She has had amenorrhoea for nearly a has had amenorrhoea for nearly a year and has menopausal symptoms. year and has menopausal symptoms. He asks which tests you would advise He asks which tests you would advise to check if she is menopausalto check if she is menopausal

Case 5 commentsCase 5 comments FSHFSH Tamoxifen can cause suppression of Tamoxifen can cause suppression of

menstruation in pre-menopausal women. menstruation in pre-menopausal women. Measure TSH, T4, Prolactin, LH, FSH, E2 and Measure TSH, T4, Prolactin, LH, FSH, E2 and progesteroneprogesterone

TSH usual test for menopause. Tamoxifen TSH usual test for menopause. Tamoxifen increases FSH and LH, thus FSH unreliable. No increases FSH and LH, thus FSH unreliable. No other test usefulother test useful

No test will reliably distinguish menopause from No test will reliably distinguish menopause from Tamoxifen side effects (FSH release induced by Tamoxifen side effects (FSH release induced by drug) Oestrogen Rx (o.c. or HRT) contra-drug) Oestrogen Rx (o.c. or HRT) contra-indicated. If serum oestradiol is low, may help. indicated. If serum oestradiol is low, may help. Check TFTsCheck TFTs

Case 5 learning pointsCase 5 learning points

Tamoxifen blocks oestrogen Tamoxifen blocks oestrogen receptors, and may cause increases receptors, and may cause increases in both FSH and oestradiolin both FSH and oestradiol

A high FSH does not rule in the A high FSH does not rule in the possibility of menopausal status (a possibility of menopausal status (a low FSH may rule this out)low FSH may rule this out)

A low oestradiol may support a A low oestradiol may support a diagnosis of menopause, but not diagnosis of menopause, but not conclusively soconclusively so

Case 5 serum resultsCase 5 serum results

FSH 2.3 U/L; LH 5.2 U/L; oestradiol 3200 FSH 2.3 U/L; LH 5.2 U/L; oestradiol 3200 pmol/Lpmol/L

Two months later, FSH 21.5 U/L; LH 22.6 Two months later, FSH 21.5 U/L; LH 22.6 U/L; oestradiol 1800 pmol/LU/L; oestradiol 1800 pmol/L

All results were checked at dilution and in All results were checked at dilution and in different assay systemsdifferent assay systems

Do these results rule in or rule out Do these results rule in or rule out perimenopausal status?perimenopausal status?

Similar interpretational problems arise in Similar interpretational problems arise in patients on progestogen-based HRT or patients on progestogen-based HRT or contraceptioncontraception

General pointsGeneral points

Clinicians (particularly GPs) very much Clinicians (particularly GPs) very much welcome advice in this areawelcome advice in this area

It is difficult to provide appropriate It is difficult to provide appropriate adviceadvice

But the Cases we find difficult are But the Cases we find difficult are likely to be equally difficult to our likely to be equally difficult to our Clinicians (if not even more so)Clinicians (if not even more so)

There is no gold standardThere is no gold standard Assessment of our advice is just as Assessment of our advice is just as

difficult as the advice itself!difficult as the advice itself!

Thank you for listening to meThank you for listening to me