1. Commenting on amenorrhoea, or how to get sued

2. Five cases will be presented 25 of the audience will be asked to assess interpretative ideas or whole comments on each Case. Each Case and each comment is real 25 of the audience will be asked to assess interpretative ideas or whole comments on each Case. Each Case and each comment is real Each assessor will hold up a numbered card Each assessor will hold up a numbered card The numbers range from 1 (awful) to 5 (brilliant) The numbers range from 1 (awful) to 5 (brilliant) Each assessor will not be able to see the marks given by other assessors Each assessor will not be able to see the marks given by other assessors The assessment may give us an idea of which comments are most appropriate The assessment may give us an idea of which comments are most appropriate

3. Case 1 A 32 year old woman, visiting her Family Doctor. Clinical information given is ’15 months amenorrhoea, cause?’ Serum results are A 32 year old woman, visiting her Family Doctor. Clinical information given is ’15 months amenorrhoea, cause?’ Serum results are Normal U & E, LFTs, TFTs Normal U & E, LFTs, TFTs HCG < 3 U/L HCG < 3 U/L LH 24 U/L, FSH 6 U/L LH 24 U/L, FSH 6 U/L Testosterone 2.5 nmol/L Testosterone 2.5 nmol/L

4. Interpretative ideas HCG not suggestive of pregnancy HCG not suggestive of pregnancy Early pregnancy cannot be excluded Early pregnancy cannot be excluded High LH/ FSH ratio and borderline testosterone suggestive of PCOS High LH/ FSH ratio and borderline testosterone suggestive of PCOS Possible ovulation peak Possible ovulation peak Suggest repeat in 3 months if amenorrhoea persists Suggest repeat in 3 months if amenorrhoea persists

5. Case 1: the outcome The patient presented to A & E 3 weeks later with abdominal pain, and although there was little radiological evidence, an ectopic pregnancy was diagnosed The patient presented to A & E 3 weeks later with abdominal pain, and although there was little radiological evidence, an ectopic pregnancy was diagnosed The patient sued the laboratory for the pain and distress caused by erroneous results/ incorrect advice The patient sued the laboratory for the pain and distress caused by erroneous results/ incorrect advice The laboratory mounted a robust defence, and the case was later dropped The laboratory mounted a robust defence, and the case was later dropped

6. Case 1: learning points Non-extraction female testosterone assays are of poor quality Non-extraction female testosterone assays are of poor quality The utility of an LH/ FSH ratio in diagnosing PCOS is debatable The utility of an LH/ FSH ratio in diagnosing PCOS is debatable However, with the clinical information given, PCOS was much more likely than an ovulation peak However, with the clinical information given, PCOS was much more likely than an ovulation peak But the Duty Biochemist must be very careful! But the Duty Biochemist must be very careful!

7. Guidelines for diagnosis of PCOS ESHRE Rotterdam 2003 consensus states that 2 of the following 3 criteria should be met: oligo/ anovulation; evidence of hyperandrogenism (either clinical or biochemical); ovarian polystic evidence on ultrasound ESHRE Rotterdam 2003 consensus states that 2 of the following 3 criteria should be met: oligo/ anovulation; evidence of hyperandrogenism (either clinical or biochemical); ovarian polystic evidence on ultrasound AACE guidelines mention that an LH/ FSH ratio of greater than 2 is seen in 60 – 70% of PCOS cases and suggest these measurements AACE guidelines mention that an LH/ FSH ratio of greater than 2 is seen in 60 – 70% of PCOS cases and suggest these measurements

8. Case 2 A 56 year old woman seeing her Family Doctor, clinical information ‘able to stop progesterone-only pill?’ A 56 year old woman seeing her Family Doctor, clinical information ‘able to stop progesterone-only pill?’ Serum FSH 22 U/L Serum FSH 22 U/L An FSH 5 months previously was 50 U/L An FSH 5 months previously was 50 U/L

9. Comments on Case 2 FSH can fluctuate markedly in the perimenopausal period. The age and FSH results suggest that the use of the progesterone-only pill for contraception is now unnecessary in this patient FSH can fluctuate markedly in the perimenopausal period. The age and FSH results suggest that the use of the progesterone-only pill for contraception is now unnecessary in this patient Previous FSH in post-menopausal period. Diagnosis of the menopause basically clinical. Results probably consistent with perimenopausal status Previous FSH in post-menopausal period. Diagnosis of the menopause basically clinical. Results probably consistent with perimenopausal status ?Suppression of FSH by exogenous oestrogens or use of creams/ herbal remedies with oestrogen-like action. If so, discontinue ?Suppression of FSH by exogenous oestrogens or use of creams/ herbal remedies with oestrogen-like action. If so, discontinue

10. Case 2 learning points Menopause: amenorrhoea for at least 1 year due to cessation of ovarian function in women over the age of 45 Menopause: amenorrhoea for at least 1 year due to cessation of ovarian function in women over the age of 45 Perimenopause: a span of 4 – 6 years preceding menopause when menstrual cycles may be irregular and symptoms appear such as hot flashes Perimenopause: a span of 4 – 6 years preceding menopause when menstrual cycles may be irregular and symptoms appear such as hot flashes Diagnosis is clinical (and retrospective): FSH can only be used to support the diagnosis Diagnosis is clinical (and retrospective): FSH can only be used to support the diagnosis With a raised FSH, the prudent comment is ‘FSH suggestive of (peri)menopausal status, but the possibility of further fertile cycles cannot be excluded’ With a raised FSH, the prudent comment is ‘FSH suggestive of (peri)menopausal status, but the possibility of further fertile cycles cannot be excluded’

11. Case 3 A 26 year old woman seeing her GP. Clinical information ‘negative pregnancy test a few days ago but period now 8 days late, breast tenderness’ A 26 year old woman seeing her GP. Clinical information ‘negative pregnancy test a few days ago but period now 8 days late, breast tenderness’ Serum hCG 122 U/L (DPC Immulite) Serum hCG 122 U/L (DPC Immulite)

12. Comments on Case 3 Suggest repeat serum hCG in 2 days to confirm satisfactory increase in hCG consistent with pregnancy Suggest repeat serum hCG in 2 days to confirm satisfactory increase in hCG consistent with pregnancy Please repeat in 1 week Please repeat in 1 week Possible ectopic pregnancy or missed abortion. Advise repeat in 48 hours Possible ectopic pregnancy or missed abortion. Advise repeat in 48 hours hCG result may indicate early normal uterine pregnancy or ectopic pregnancy. Suggest repeat in 48 hours which should show at least a 2fold increase if normal pregnancy hCG result may indicate early normal uterine pregnancy or ectopic pregnancy. Suggest repeat in 48 hours which should show at least a 2fold increase if normal pregnancy

13. Average hCG in early pregnancy Day 25:63 U/L30:240 U/L Day 25:63 U/L30:240 U/L Day 35:94040:4 300 Day 35:94040:4 300 Day 45:18 00050:46 000 Day 45:18 00050:46 000 Day 55:74 00060:101 000 Day 55:74 00060:101 000 Summarised data for the Royal Berkshire Hospital from apparently normal pregnancies (Bayer Centaur method) Summarised data for the Royal Berkshire Hospital from apparently normal pregnancies (Bayer Centaur method)

14. Rate of increase of hCG ‘At least doubling every 2 days’ is widely quoted ‘At least doubling every 2 days’ is widely quoted The maximum 2-day increase is 1.9 between days 35 and 45 The maximum 2-day increase is 1.9 between days 35 and 45 Before and after this period, the average rate of increase is less, and after day 60 hCG values plateau and begin to decline Before and after this period, the average rate of increase is less, and after day 60 hCG values plateau and begin to decline

15. Utility of this hCG data There is considerable individual variation, but because of the rapid rise, errors in dating are quite small There is considerable individual variation, but because of the rapid rise, errors in dating are quite small 67% of pregnancies give a dating within 3 days of average 67% of pregnancies give a dating within 3 days of average 95% give a dating within 9 days of average 95% give a dating within 9 days of average Bias differences between different methods make little difference Bias differences between different methods make little difference

16. Case 3 learning points An hCG result much less than the average value may suggest incorrect dating or an ectopic or failing pregnancy An hCG result much less than the average value may suggest incorrect dating or an ectopic or failing pregnancy In this Case, the expected hCG from the clinical information given was 1 300 U/L and the possibility of an ectopic pregnancy was raised In this Case, the expected hCG from the clinical information given was 1 300 U/L and the possibility of an ectopic pregnancy was raised Five days later, the patient was admitted with acute abdominal pain, and an ectopic pregnancy was identified Five days later, the patient was admitted with acute abdominal pain, and an ectopic pregnancy was identified

17. Case 4 A 22 year old woman seeing her GP. No clinical information was given on the request form. Serum hCG was 14 U/L A 22 year old woman seeing her GP. No clinical information was given on the request form. Serum hCG was 14 U/L Two weeks earlier, information was ‘LMP 15 weeks ago, inconclusive USS’. Serum hCG was 21 U/L Two weeks earlier, information was ‘LMP 15 weeks ago, inconclusive USS’. Serum hCG was 21 U/L Two months earlier, information was ‘?pregnant’. Serum hCG was 121 U/L Two months earlier, information was ‘?pregnant’. Serum hCG was 121 U/L

18. Comments on Case 4 Exclude ectopic pregnancy Exclude ectopic pregnancy Beta hCG reaches a peak at about 10 weeks in normal pregnancy and then begins to decline. These data are compatible with pregnancy. Is she likely to have another USS? Beta hCG reaches a peak at about 10 weeks in normal pregnancy and then begins to decline. These data are compatible with pregnancy. Is she likely to have another USS? Decline in hCG not consistent with pregnancy. Result suggestive of previous missed abortion or ectopic pregnancy. Please send repeat sample in 2 weeks to confirm decline in hCG Decline in hCG not consistent with pregnancy. Result suggestive of previous missed abortion or ectopic pregnancy. Please send repeat sample in 2 weeks to confirm decline in hCG Still detectable hCG may indicate retained products of conception but trophoblastic disease and possible interfering antibodies should be considered. Suggest early gynae referral Still detectable hCG may indicate retained products of conception but trophoblastic disease and possible interfering antibodies should be considered. Suggest early gynae referral

19. Case 4 learning points Following an abortion or termination of pregnancy, in around 65% of patients the hCG declines to non-detectable values after around 4 weeks; in at least 95% of patients after around 8 weeks Following an abortion or termination of pregnancy, in around 65% of patients the hCG declines to non-detectable values after around 4 weeks; in at least 95% of patients after around 8 weeks In the period 4 – 8 weeks after TOP with detectable hCG, it is useful to suggest a repeat hCG to confirm declining values In the period 4 – 8 weeks after TOP with detectable hCG, it is useful to suggest a repeat hCG to confirm declining values After 8 weeks, a still detectable hCG suggests either retained products of conception or a new pregnancy: a further repeat is useful After 8 weeks, a still detectable hCG suggests either retained products of conception or a new pregnancy: a further repeat is useful

20. Case 5 You are telephoned by a Consultant Oncologist. He has been treating a 46 year old lady for breast cancer. She finished chemotherapy 6 months ago, and is now prescribed Tamoxifen. She has had amenorrhoea for nearly a year and has menopausal symptoms. He asks which tests you would advise to check if she is menopausal You are telephoned by a Consultant Oncologist. He has been treating a 46 year old lady for breast cancer. She finished chemotherapy 6 months ago, and is now prescribed Tamoxifen. She has had amenorrhoea for nearly a year and has menopausal symptoms. He asks which tests you would advise to check if she is menopausal

21. Case 5 comments FSH FSH Tamoxifen can cause suppression of menstruation in pre-menopausal women. Measure TSH, T4, Prolactin, LH, FSH, E2 and progesterone Tamoxifen can cause suppression of menstruation in pre-menopausal women. Measure TSH, T4, Prolactin, LH, FSH, E2 and progesterone TSH usual test for menopause. Tamoxifen increases FSH and LH, thus FSH unreliable. No other test useful TSH usual test for menopause. Tamoxifen increases FSH and LH, thus FSH unreliable. No other test useful No test will reliably distinguish menopause from Tamoxifen side effects (FSH release induced by drug) Oestrogen Rx (o.c. or HRT) contra-indicated. If serum oestradiol is low, may help. Check TFTs No test will reliably distinguish menopause from Tamoxifen side effects (FSH release induced by drug) Oestrogen Rx (o.c. or HRT) contra-indicated. If serum oestradiol is low, may help. Check TFTs

22. Case 5 learning points Tamoxifen blocks oestrogen receptors, and may cause increases in both FSH and oestradiol Tamoxifen blocks oestrogen receptors, and may cause increases in both FSH and oestradiol A high FSH does not rule in the possibility of menopausal status (a low FSH may rule this out) A high FSH does not rule in the possibility of menopausal status (a low FSH may rule this out) A low oestradiol may support a diagnosis of menopause, but not conclusively so A low oestradiol may support a diagnosis of menopause, but not conclusively so

23. Case 5 serum results FSH 2.3 U/L; LH 5.2 U/L; oestradiol 3200 pmol/L FSH 2.3 U/L; LH 5.2 U/L; oestradiol 3200 pmol/L Two months later, FSH 21.5 U/L; LH 22.6 U/L; oestradiol 1800 pmol/L Two months later, FSH 21.5 U/L; LH 22.6 U/L; oestradiol 1800 pmol/L All results were checked at dilution and in different assay systems All results were checked at dilution and in different assay systems Do these results rule in or rule out perimenopausal status? Do these results rule in or rule out perimenopausal status? Similar interpretational problems arise in patients on progestogen-based HRT or contraception Similar interpretational problems arise in patients on progestogen-based HRT or contraception

24. General points Clinicians (particularly GPs) very much welcome advice in this area Clinicians (particularly GPs) very much welcome advice in this area It is difficult to provide appropriate advice It is difficult to provide appropriate advice But the Cases we find difficult are likely to be equally difficult to our Clinicians (if not even more so) But the Cases we find difficult are likely to be equally difficult to our Clinicians (if not even more so) There is no gold standard There is no gold standard Assessment of our advice is just as difficult as the advice itself! Assessment of our advice is just as difficult as the advice itself!

25. Thank you for listening to me