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Case 671: But I have not had a period for so long?
Authors and Affiliations
Professor Roger Pepperell,
Penang Medical College
Associate Professor Paul Duggan,
School of Paediatrics and Reproductive Health,
University of AdelaideThis case discusses a common and important problem of secondary
amenorrhoea.
Case Overview
Learning Objectives
The graduating student should be able to explain†¦
The
possible causes of secondary amenorrhoea and the important questions to ask to define the
likely cause, and the appropriate treatment.
A
logical plan of the initial assessment and management of this problem.
An
appropriate plan of longer term management.
Question 1 : MS
Question Information:
Olivia is a 26-year-old woman who presents to her general practitioner because she has not had a
period for the last 6 months. She believes she is not pregnant. Her last gynaecologic review which
included smear testing, was done 12 months ago and she was told †œeverything is normal†•.
Some information will be required from the history to try and determine the cause of her amenorrhoea.
Question:
Which of the following are key elements in the history in determining a diagnosis or planning
management?
Choice 1: The age of menarche Score : -1
Choice Feedback:
Incorrect. While the age of menarche is generally sought in a complete menstrual history, it will unlikely
be useful in determing the cause of secondary menorrhoea.
Choice 2: Has she been taking the combined oestrogen/progestogen oral contraceptive pill (OCP)? Score : 1
Choice Feedback:
Correct. In 1-2% of women amenorrhoea can last for more than 12 months after ceasing the OCP.
Prolonged amenorrhoea after cessation of the OCP is associated with irregular cycles prior to going on
the OCP. There is considerable debate whether the OCP makes any contribution to prolonged
amenorrhoea, and alternative causes must always be ruled out in these cases.
Choice 3: Whether she is currently having any hot flushes? Score : 1
Choice Feedback:
Correct. The presence of hot flushes would suggest the amenorrhoea is due to a premature
menopause.
Choice 4: Whether she wishes to conceive in the next few months? Score : 1
Choice Feedback:
Correct. This is an important question to ask, not for diagnostic purposes, but because the treatment is
likely to be very different if she wishes to conceive, than if that is not a priority now.
Choice 5: Has she had any gynaecological operative procedures performed? Score : 1
Choice Feedback:
Correct. This is a most important question to ask as a gynaecological procedure could be the cause of
the current secondary amenorrhoea, for example due to Asherman's syndrome following curettage or
cervical stenosis following cone biopsy. In the latter haematometra would be present (and detectable by
ultrasound) because menstrual loss would not be expelled externally, but retained in the uterine cavity.
This is usually associated with cyclical pain.
Choice 6: Has she experienced any recent change in weight? Score : 1
Choice Feedback:
Correct. This is an important question to ask because any recent gain in weight of 5 - 10kg may be
sufficient to lead to amenorrhea. If this is the case, reversal of the weight gain can lead to spontaneous
restoration of the menstrual cycle. Conversely excessive weight loss (which might be part of anorexia
nervosa) can also result in amenorrhoea.
Choice 7: Had she been exercising excessively or under any unusual stress in the months prior to her
amenorrhoea? Score : 1
Choice Feedback:
Correct. Both excessive exercise and stress can cause amenorrhoea.
Choice 8: Does she take any medication? Score : 1
Choice Feedback:
Correct. Neuroleptics such as chlorpromazine or stelazine often cause prolactin levels to become
elevated which in turn results in the GnRH pulses being suppressed.
Choice 9: Has she experienced any milk production from her breasts? Score : 1
Choice Feedback:
Correct. The presence of galactorrhoea would suggest the prolactin levels are elevated and could be
the cause of the amenorrhoea due to GnRH suppression.
Question 2 : MS
Question Information:
Olivia has always had irregular menstrual cycles of between 8-12 weeks length, ever since menarche at
the age of 14 years. She took the OCP Microgynon 30 for the 12 months before her amenorrhoea
commenced. Whilst taking the OCP she had regular periods of 4 days duration, however she has not
had a period since she ceased taking the OCP, apart from the one immediately after its cessation.
Whilst on the OCP her BMI had increased from 25 to the current 30. For the last few years she has
noticed an increase in hair growth on her chest and abdomen, and has had some acne. However, her
greatest concern is that she will not be able to conceive if her cycle remains irregular/absent. She does
very little exercise. She is on no medications. She has not had any dyspareunia or bleeding during
intercourse, has no hot flushes nor any galactorrhoea. She has had no previous operative procedures.
Clinical examination of Olivia shows no obvious abnormality, apart from being overweight (BMI=30).
There is mild hirsutism. On a bimanual pelvic exam, her uterus is anteverted, of normal size, and both
adnexae are unremarkable. The clitoris is not enlarged.
Question:
Which of the following investigations would be appropriate?
Choice 1: Serum progesterone level. Score : -1
Choice Feedback:
Incorrect. This test is a test done in the luteal phase of a regular menstrual cycle as it will show if the
cycle is ovulatory. It is usually not relevant to perform in a woman with secondary amenorrhoea.
Choice 2: Follicular Stimulating Hormone (FSH) and Luteinising Hormone (LH) Score : 1
Choice Feedback:
Correct. Estimation of FSH and LH will provide an indication of the likelihood of primary ovarian failure.
These and other hormone estimations (TSH, prolactin) are necessary in a patient who has been shown
not to be ovulating or who has secondary amenorrhoea as they will usually define the cause of the
amenorrhoea and will often indicate what treatment is advisable. If the FSH level was elevated a repeat
test is required. Additionally, an elevated LH to FSH ratio may indicate polycystic ovarian syndrome and
prompt the need for further androgen testing.
Choice 3: Serum oestradiol level Score : 1
Choice Feedback:
Correct. This test can be of value in limited cases, but is not nearly as important as other hormonal
studies. A level below 50pmol/L would indicate extremely low levels irrespective of the cause and
indicate a need for hormone replacement therapy, if a pregnancy is not desired. A very high oestradiol
level could indicate the presence of an ovarian oestrogen producing tumour which could cause
secondary amenorrhoea. Normal levels are usually seen in PCOS.
Choice 4: Serum androgen levels Score : 1
Choice Feedback:
Correct. The androgens commonly measured are serum Testosterone (T), Dehydroepiandrosterone
Sulphate (DHEAS) and Androstenedione. The Free Androgen Index (FAI) requires Sex Hormone
Binding Globulin (SHBG) to be measured. SHBG has high affinity for T and only the unbound fraction
has bio-availability. Very high levels of T would suggest an androgen producing ovarian tumour, very
high levels of DHEAS would suggest an androgen producing adrenal tumour, and minimal elevations of
the androgens would be consistent with PCOS.
Choice 5: Urine pregnancy test Score : 1
Choice Feedback:
Correct. This test is mandatory to exclude pregnancy.
Choice 6: MRI or CT head Score : -1
Choice Feedback:
Incorrect. This test is usually not done unless the patient is found to have elevated prolactin (PRL)
levels or low FSH and LH levels, and hypothalamic or pituitary pathology is suspected.
Choice 7: Hysterosalpingogram (HSG) Score : -1
Choice Feedback:
Incorrect. This radiologic procedure provides information about the patency of the Fallopian tubes, and
the appearance of the uterine cavity. While this test may form part of a complete infertility work-up, it is
not yet necessary in this patient and is unlikely to reveal the cause of her amenorrhoea.
Choice 8: Pelvic ultrasound examination Score : 1
Choice Feedback:
Correct. An ultrasound examination can identify features of PCOS, where multiple small cystic follicles
would be evident in the periphery of each ovary. It could also define the presence of an ovarian tumour.
Choice 9: Serum prolactin Score : 1
Choice Feedback:
Correct. Hyperprolactinaemia (which may be due to a pituitary adenoma) can be excluded by
performing a serum prolactin estimation.
Choice 10: Thyroid stimulating hormone (TSH) Score : 1
Choice Feedback:
Correct. TSH estimation will be able to exclude hypothyroidism (and rarely hyperthyroidism) as a cause
for Olivia's amenorrhoea.
Question 3 : SC
Question Information:
Olivia undergoes a number of endocrine investigations. The values in brackets are the normal levels
seen in the reproductive years between the age of 15 and 45 years.
Urine pregnancy test: negative.
Serum FSH: 6 IU/L (5-15, except at mid-cycle)
Serum LH: 14 IU/L (5-20, except at mid-cycle)
Serum prolactin: 252 pmol/L (50-750)
Serum TSH: 1.4 mU/L (1-4)
Serum Free Testosterone: 720 pmol/L (35-700)
Serum DHEAS: 11 nmol/L (2-10)
Serum oestradiol: 250 pmol/L (75-1250)
Question:
Which one of the following is the most likely explanation for the secondary amenorrhoea?
Choice 1: Obesity Score : 0
Choice Feedback:
Incorrect. Although this may be a contributing factor, her investigations point to a different cause.
Furthermore, in a patient with amenorrhoea from obesity, you would have expected her cycles to be
regular prior to her weight gain.
Choice 2: Psychological stress Score : 0
Choice Feedback:
Incorrect. Although this may be a contributing factor, her investigations point to a different cause.
Choice 3: Pituitary tumour Score : -1
Choice Feedback:
Incorrect. Most patients with secondary amenorrhoea due to a pituitary tumour will have elevated serum
prolactin levels - and Olivia's is within normal range, making this diagnosis unlikely. She also has no
symptoms to suggest a tumour. About 60% of women with elevated prolactin levels will have an
underlying pituitary tumour.
Choice 4: Polycystic ovarian syndrome (PCOS) Score : 1
Choice Feedback:
Correct. This is the most likely cause because she has a long-standing problem of irregular menstrual
cycles prior to going on the OCP and gaining weight, has an increased LH/FSH ratio, has clinical and
biochemical evidence of mild androgenisation, and would probably have evidence of polycystic ovaries
if a pelvic ultrasound examination is done.
To make this diagnosis, two of the three following features need to be evident:
irregular
clinical
menstrual cycles
or biochemical evidence of androgen excess
polycystic
ovaries on ultrasound
PCOS is the commonest cause of irregular cycles or amenorrhoea not related to pregnancy in women
aged 20-35 years.
Choice 5: Premature menopause Score : -1
Choice Feedback:
Incorrect. This is not the cause in Olivia because her FSH level is normal. Premature menopause is
also an uncommon cause of secondary amenorrhoea in women of this age.
Question 4 : SC
Question Information:
Based on her menstrual history and hormone studies Olivia is most likely to have PCOS. She has
indicated she is keen to conceive and would like to have at least two children. She would like some
advice on the most appropriate treatment to help her conceive.
Question:
Which one of the following would be most appropriate?
Choice 1: Weight reduction Score : 1
Choice Feedback:
Correct. Weight loss should be the first line of management offered to the patient. A healthy BMI (18.525) is associated with better pregnancy outcomes and conception rates. Obesity is associated with
reduced fertility, even when ovulation induction agents are used, and is also associated with an
increased risk of pregnancy complications.
Choice 2: Treatment with metformin Score : 0
Choice Feedback:
Incorrect. This is not an appropriate treatment unless Olivia is shown to be insulin resistant or to have
Type 2 Diabetes. In a woman with Type 2 Diabetes, metformin can be used as a second-line
medication for infertility in association with clomiphene citrate therapy. Olivia should have an oral
glucose tolerance test to determine her need for this treatment.
Choice 3: Treatment with clomiphene citrate Score : 0
Choice Feedback:
Partially correct. Once her weight issues have been addressed, clomiphene is is the most appropriate
treatment to induce ovulation. It is usually given in a dose of 50mg per day for 5 days (usually days 5-9
after a period has occurred spontaneously or been induced). Higher doses can be given if ovulation
does not occur following treatment with this dose, and sometimes mid-cycle hCG (which mimics the
action of LH) is required as well. If Olivia failed to lose weight consideration may be given to
clomiphene. There is increased risk of pregnancy complications and multiple pregnancies in women
who conceive and who are obese or morbidly obese, and this must be clearly explained before using
clomiphene or any other form of fertility assistance.
Choice 4: Controlled ovarian hyperstimulation and intra-uterine insemination of her partner†™s sperm Score :
0
Choice Feedback:
Incorrect. This would only be used if pregnancy did not result following successful ovulation induction
during treatment with medication alone.
Choice 5: Ovulation induction with injections of FSH and hCG Score : 0
Choice Feedback:
Incorrect. This would only be used if ovulation could not be achieved with treatment with oral
medication.
Choice 6: Treatment with bromocriptine Score : 0
Choice Feedback:
Incorrect. This agent, a dopamine agonist, is only applicable to use if the prolactin level is elevated, and
this is not the case for Olivia.
Choice 7: Refer her for in-vitro fertilization Score : 0
Choice Feedback:
Incorrect. This would only be appropriate if ovulation induction could not be achieved with medical
management, or pregnancy did not occur following at least 6 cycles of satisfactory ovulation induction.
Question 5 : MS
Question Information:
Olivia loses 10kg in weight, conceives spontaneously and has a healthy baby girl. She is now six
months postpartum, has ceased breastfeeding, and is menstruating spontaneously with a variable cycle
length of between 32-37 days. She would now like some advice on the most appropriate contraceptive
to help space her family.
Question:
Which of the following would be appropriate?
Choice 1: Oral medroxyprogesterone acetate Score : -1
Choice Feedback:
Incorrect. Oral medroxyprogesterone acetate (MPA) will not provide adequate contraceptive cover. The
benefits of cyclical MPA in women who do not need contraception are regular periods, and protection
from the development of endometrial cancer that is otherwise increased in PCOS. Depo MPA (IM route)
is an effective contraceptive but may be associated with prolonged amenorrhoea and has also been
associated with weight gain and is not a good choice in Olivia's case
Choice 2: Condoms Score : 1
Choice Feedback:
Correct. Properly used, barrier methods are suitable for family spacing.
Choice 3: Diane 35 Score : 0
Choice Feedback:
Partially correct. Diane 35 is a combined OCP containing 35mcg ethinyl estradiol and 2mg cyproterone
acetate (an anti-androgen). It will reduce hirsutes, will result in regular light periods, will protect her
against endometrial cancer, and is an effective contraceptive. However, Diane 35 is relatively expensive
and is associated with a 7-fold increased risk of venous thromboembolism. It should be reserved for
cases where androgenism is severe or when a conventional OCP has been ineffective.
Choice 4: Cyproterone acetate Score : -1
Choice Feedback:
Incorrect. This is not a contraceptive medication regimen. Although such therapy (50mg twice daily for
14 days each month) would reduce her hirsutes, this problem is not severe enough to justify such
treatment.
Choice 5: A second generation low dose combined oral contraceptive pill Score : 1
Choice Feedback:
Correct. A standard, second generation 30mcg oral contraceptive pill is an effective contraceptive and
is cheap. Olivia has had problems with hirsutism and mild acne. The 2008 consensus guideline on
management of hirsutism recommends an oral contraceptive with the addition of an anti-androgen after
6 months if hirsutism persists. There is no evidence-based preference for which oral contraceptive
regimen to choose, and all preparations may be expected to reduce hirsutism and acne to some extent.
A 2011 Cochrane review reports there is currently no evidence to support weight gain as a side effect of
oral contraception. Although levonergestrel and norethisterone acetate (the progestagens in these
regimens) are derivatives of testosterone, and are considered to be androgenic progestagens, all oc
pills markedly elevate sex hormone binding globulin (SHBG) and thus reducing available testosterone,
with beneficial effects on acne and hirsutes. It is testosterone converted by 5 alpha reductase in the hair
follicle to the active dihydrotestosterone that is responsible for the hirsutism - the SHBG effect is likely
to overwhelm any hypothetical effect of an 'androgenic' progestagen.
A sensible approach would be to start with a standard oc pill and re-evaluate after 6-12 months,
reserving Diane 35 or the newer drosperinone-containing oral contraceptive pills for those who do not
get a good result on a standard regimen, noting reports that the latter are both associated with an
increased risk of thromboembolism, and are substantially more expensive.
Choice 6: Mirena IUS Score : 1
Choice Feedback:
Correct. Mirena is highly reliable and reversible. The levonorgestrel in Mirena is minimally absorbed and
is not likely to be associated with androgenic effects.
Synopsis
1. Causes of secondary amenorrhoea:
Apart from a pregnancy, which is the commonest cause for secondary amenorrhoea, causes can be at
the level of the hypothalamus (weight change, excessive exercise, psychological stress and
pharmacologic preparations), pituitary, thyroid, adrenal, ovary and uterus. Each of these need to be
assessed on history, endocrine investigations, and in some instances by ultrasound examination of the
ovaries and uterus, and radiologic assessment of the pituitary and hypothalamus. Clinical examination
is of limited use in defining the cause.
Between 25-35 years, apart from pregnancy, the commonest causes of secondary amenorrhoea are
hypothalamic dysfunction and PCOS (each about 30%), with less common causes including pituitary
adenoma and premature menopause. As women reach the age of 40 years and beyond, menopause
becomes more common and by the age of 50 years is the cause of secondary amenorrhoea in virtually
all women.
2. Usual endocrine assessment and treatment of women with secondary amenorrhoea of more than 6
months duration:
In women under the age of 45 years, the following are usually measured; beta-hCG (pregnancy test),
FSH, LH, prolactin, TSH, DHEAS, testosterone, SHBG, and 17OH progesterone. Screening for Cushing
syndrome (dexamethasone suppression test or 24h urinary cortisol) is required if clinical stigmata are
evident. The results of these hormone tests enable recognition of the likely cause of the amenorrhoea,
further investigations (if any) required, and the treatment to recommend if conception is desired.
If
the FSH is elevated this is indicative of ovarian failure; ovum donation, within IVF, will probably be
required to achieve a pregnancy in such patients. In women under the age of 35 years, menstrual
cycles can return but fertility is still very poor.
If
the PRL level is elevated, a pituitary adenoma needs to be excluded and treatment with a
dopamine agonist such as bromocriptine or cabergoline may be required. Surgical removal of the
adenoma is rarely required. PRL is often slightly raised in PCOS, when it does not require specific
treatment.
If
thyroid function is not normal, this should be corrected and fertility is then generally improved.
If
the FSH, LH, prolactin and TSH levels are all normal, any hypothalamic problem should be
corrected (eg obesity, psychological stress, excessive exercise, drug therapy) and then ovulation
induction with clomiphene given if the problem is still present.
If
PCOS is suspected, serum lipids should be measured and a glucose tolerance test performed to
define if insulin resistance +/-diabetes is present. The patient will also require pelvic ultrasound.
Treatment to achieve fertility would be as indicated in the current case. In all patients with PCOS,
regular assessment of blood lipid and fasting blood glucose levels is needed, as these patients are at
increased risk of developing insulin resistance and coronary artery disease. If a pregnancy is not
desired, ovulation induction should not be undertaken. An oral contraceptive pill or hormone
replacement therapy may be of use to reduce the likelihood of bone loss, to improve vaginal lubrication,
to produce regular periods, and to protect against endometrial cancer if the oestrogen levels are
normal. The hormonal therapy advised must also take into account whether the woman also requires
contraception. In PCOS, long term follow-up is essential because of the increased risk of metabolic and
neoplastic problems. Follow-up is also important for women found to have a pituitary adenoma, or
abnormal thyroid function.
References:
Assessment
and management of polycystic ovary syndrome: summary of an evidence-based
guideline. MJA Supplement Sep 2011; 195 (6), S69-S111
Ehrmann
DA. Polycystic ovary syndrome. New England Journal of Medicine. 352(12); 1223-1236.
2005 eMedici case on contraception
Gallo
MF, Lopez LM, Grimes DA, Schulz KF, Helmerhorst FM. Combination contraceptives: effects
on weight. Cochrane Database Syst Rev. 2011 Sep 7;9:CD003987.
Huber
J, Walch K. Contraception. 2006 Jan;73(1):23-9. Epub 2005 Sep 26. Treating acne with oral
contraceptives: use of lower doses.
Martin
KA, Chang RJ, Ehrmann DA, Ibanez L, Lobo RA, Rosenfield RL, Shapiro J, Montori VM,
Swiglo BA. Evaluation and treatment of hirsutism in premenopausal women: an endocrine society
clinical practice guideline. J Clin Endocrinol Metab. 2008 Apr;93(4):1105-20. Epub 2008 Feb 5.
This case has been produced at the University of Adelaide. Support for its evaluation and peer review
has been provided by the Australian Learning and Teaching Council Ltd, an initiative of the Australian
Government Department of Education, Employment and Workplace Relations. The views expressed in
this case do not necessarily reflect the views of the Australian Learning and Teaching Council.
Adelaide
December 2011
Updated September 2016