Commenting on amenorrhoea, or how to get sued

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Commenting on amenorrhoea, or how to get sued
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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
• Each assessor will hold up a numbered card
• The numbers range from 1 (awful) to 5 (brilliant)
• 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

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Case 1

• 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
• HCG lt 3 U/L
• LH 24 U/L, FSH 6 U/L
• Testosterone 2.5 nmol/L

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Interpretative ideas

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

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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 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

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Case 1 learning points

• Non-extraction female testosterone assays are of
  poor quality
• 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
• But the Duty Biochemist must be very careful!

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

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Case 2

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

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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
• 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

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Case 2 learning points

• 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
• 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

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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
• Serum hCG 122 U/L (DPC Immulite)

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Comments on Case 3

• Suggest repeat serum hCG in 2 days to confirm
  satisfactory increase in hCG consistent with
  pregnancy
• Please repeat in 1 week
• 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

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Average hCG in early pregnancy

• Day 25 63 U/L 30 240 U/L
• Day 35 940 40 4 300
• Day 45 18 000 50 46 000
• Day 55 74 000 60 101 000
• Summarised data for the Royal Berkshire Hospital
  from apparently normal pregnancies (Bayer Centaur
  method)

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Rate of increase of hCG

• At least doubling every 2 days is widely quoted
• 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

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Utility of this hCG data

• 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
• 95 give a dating within 9 days of average
• Bias differences between different methods make
  little difference

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Case 3 learning points

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

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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
• 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

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Comments on Case 4

• 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?
• 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

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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
• 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

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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

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Case 5 comments

• FSH
• 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
• 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

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Case 5 learning points

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

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Case 5 serum results

• 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
• All results were checked at dilution and in
  different assay systems
• Do these results rule in or rule out
  perimenopausal status?
• Similar interpretational problems arise in
  patients on progestogen-based HRT or contraception

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General points

• Clinicians (particularly GPs) very much welcome
  advice in this area
• 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)
• There is no gold standard
• Assessment of our advice is just as difficult as
  the advice itself!

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Thank you for listening to me