Findings that shed new light on the possible pathogenesis of a disease
or an adverse effect
Premature ovarian failure 3 years after menarche in a
16-year-old girl following human papillomavirus vaccination
Deirdre Therese Little,1 Harvey Rodrick Grenville Ward2
1Department of General Practice, North Bellingen Medical Services, Bellingen, Australia
2Department of Obstetrics and Gynaecology, The University of New South Wales Rural Medical School in Coffs Harbour, Coffs Harbour, Australia
Correspondence to Dr Deirdre Therese Little, email@example.com
Premature ovarian failure in a well adolescent is a rare event. Its occurrence raises important questions about causation, which may signal
other systemic concerns. This patient presented with amenorrhoea after identifying a change from her regular cycle to irregular and scant
periods following vaccinations against human papillomavirus. She declined the oral contraceptives initially prescribed for amenorrhoea. The
diagnostic tasks were to determine the reason for her secondary amenorrhoea and then to investigate for possible causes of
the premature ovarian failure identiﬁed. Although the cause is unknown in 90% of cases, the remaining chief identiﬁable causes of this
condition were excluded. Premature ovarian failure was then notiﬁed as a possible adverse event following this vaccination. The young
woman was counselled regarding preservation of bone density, reproductive implications and relevant follow-up. This event could hold
potential implications for population health and prompts further inquiry.
Since secondary amenorrhoea and its causes may have
A 16-year-old girl presented with a history of 5 months
great signiﬁcance for a woman’s future health, investiga-
amenorrhoea, preceded by approximately 12 months oli-
tion of such presentations is warranted and is best
gomenorrhoea. Menarche had occurred at the age of 13 in
addressed prior to potential masking by the oral contra-
2007 with initially light periods which became heavier
ceptives (OC). Subsequent diagnosis of premature ovarian
and developed a regular monthly pattern over the follow-
failure, as in this young woman, will signiﬁcantly affect
ing 12 months.
her future health management. The occurrence of prema-
Early in 2009 menses became irregular. In early 2010
ture ovarian failure, previously known as premature
they became scant and occurred infrequently, two or
menopause, in mid-teen years is extremely rare. The
more months apart. Menstrual periods ceased in January
annual incidence of premature ovarian failure has been
2011. Following the development of amenorrhoea, the
reported as 10/100 000 person-years between the ages of
patient experienced hot ﬂushes. She identiﬁed that an
15 and 29 years.1 The cause of ovarian failure before age
alteration in the menstrual pattern had started following
40 years remains unknown in up to 90% of cases.2 After
diagnosis, evaluation for autoimmune disorder, genetic
On ﬁrst presentation to her local doctor she was pre-
defect and exposure to ovarian toxins is important for
scribed the OC for amenorrhoea after exclusion of preg-
counselling, surveillance for associated illnesses, for treat-
nancy. She elected not to take the contraceptive pill at
ment and to further our understanding of the pattern of
that time and sought further opinion regarding her con-
disease prevalence of premature ovarian insufﬁciency.
Recent data presented to the European Society of
There was no past or present history of signiﬁcant
Human Reproduction and Embryology Conference in
other illness, stressors or surgery, no known exposure to
Stockholm in 20113 suggest that unexplained premature
radiation or toxins and no other medications were being
ovarian failure may have a current incidence sixfold
taken during or preceding this time. She was a non-
greater than previously thought.
smoker. There was no known family history of genetic
The unexplained occurrence of premature ovarian failure
abnormalities, premature menopause or of autoimmune
may reﬂect speciﬁc toxins or certain genotypes which cur-
disease. There were no abnormal ﬁndings on clinical
rently available genetic examinations are not adequate to
examination; her weight was 56 kg, and body mass index
explore. Premature ovarian failure developing here, however,
was 22.6. The absence of a clinical basis for amenorrhoea
after human papillomavirus (HPV) vaccination prompted
prompted more evaluation.
inquiry concerning ovarian histology of vaccinated rats at
intervals of postvaccination. There was no record obtainable
of these histological ovarian assessments. It also raised sug-
Further assessment revealed a normal full blood count,
gestions that long-term follow-up studies of natural cycles
and normal renal, liver and thyroid function. Prolactin
and fertility of vaccinated women should be considered.
level and androgen proﬁle were also within normal limits.
BMJ Case Reports 2012; doi:10.1136/bcr-2012-006879
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Follicle stimulating hormone (FSH) was raised at 108 U/l
Each 0.5 ml dose of the quadrivalent human papilloma-
(menopausal range is 20–140 U/l); luteinising hormone
virus virus-like particle vaccine (HPV VLP vaccine) contains
was 31 U/l, (menopausal range is 10–65 U/l); estradiol
proteins of HPV types 6, 11, 16 and 18; 225 mcg of alumin-
was low at 63 pmol/l (normal follicular phase range is
ium (as amorphous aluminium hydroxyphosphate sulphate
greater than 110, menopausal range is 40–200 pmol/l).
adjuvant); 9.56 mg of sodium chloride; 0.78 mg of L-histidine;
Progesterone was low at 1.1 nmol/l (menopausal range is
50 mcg of polysorbate 80; 35 mcg of borax and water.
less than 2.2 nmol/l). Anti-Mullerian hormone was low at
It is not known whether this event of premature
less than 1.0 pmol/l (levels below 14 pmol/l suggest
ovarian failure is linked to the quadrivalent HPV vaccine.
failing ovulatory reserve). Serology was consistent with
More detailed information concerning rat ovarian hist-
known previous mumps vaccination.
ology and ongoing fecundity post-HPV vaccination was
Karyotype was established as 46 XX. No ovarian anti-
sought from the Therapeutic Goods Administration
bodies were detected, and there were no adrenal anti-
(TGA). Although the TGA’s Australian Public Assessment
bodies. Thyroid peroxidase antibodies were 2 IU/ml and
Report for Human Papillomavirus Quadrivalent Vaccine,
thyroglobulin antibodies were 44 IU/ml (levels up to
February 2011, does report on the histology of vaccinated
100 IU/ml can occur in normal subjects). Galactosaemia
rat testes and epididymides,4 no histological report has
screen was negative (Gal-1-P uridyl transferase-RC was
been available for vaccinated rat ovaries.
0.42 U/g haemoglobin, the normal range is 0.26–0.52).
The TGA subsequently agreed to a freedom of information
Fragile X (Cytosine-Guanine-Guanine) n Repeats 28 was
application in the public interest (FOI 001-1112) requesting
normal (normal range is less than 50). Pelvic ultrasound
documented rat ovarian histology post-quadrivalent HPV
vaccination that may have been performed by the sponsor
and forwarded to the TGA. However, a histological report of
the ovaries of vaccinated rats remained unavailable beyond a
The presence of menopausal gonadotrophin levels in asso-
numbering of the corpora lutea present at postweaning
ciation with over 3 months of amenorrhoea or oligomenor-
euthanasia following the ﬁrst litter (Extract Study no.
rhoea before age 40 years deﬁnes premature ovarian failure.
TT#03-703-0(CTD Module 4, volumes 1–3) summary for
Following an elevated FSH level it was next conﬁrmed
non-clinical study report ‘Intramuscular developmental tox-
that this young woman’s anti-Mullerian hormone demon-
icity and immunogenicity study in rats with postweaning
strated no measurable ovarian reserve. The exclusion of
genetic causes such as Turner’s syndrome, Fragile X and
galactosaemia was necessary together with investigation
for other endocrine or autoimmune disorders.
Since there can be many causes of secondary amenor-
New South Wales Health has conﬁrmed that three
rhoea, from physiological to constitutional, systemic and
Quadrivalent Human Papillomavirus (types 6, 11, 16 and 18)
failure of the hypothalamic–pituitary–ovarian axis, deter-
Recombinant Vaccinations were administered to the client
mining the aetiology requires broad considerations. In this
in the high-school vaccination programme in February,
woman it required exclusion of metabolic, other endo-
May and August 2008.
crine, autoimmune and genetic disorders.
Results consistent with premature ovarian insufﬁciency
in a 16-year-old girl have signiﬁcant consequences for her
This young woman was referred for specialist gynaeco-
future health and for her prospects of motherhood.
logical review and management. She was advised of
Had this young woman taken the OC as prescribed for cor-
the need for adequate calcium, vitamin D, exercise and
rection of her oligomenorrhoea/amenorrhoea, her diagnosis
hormone replacement for bone density preservation.
of premature ovarian insufﬁciency may not have been deter-
Implications for future childbearing and the need for peri-
mined for perhaps some years. The possibility of its link to
odic review were discussed. Hormone replacement was
an adverse pharmaceutical event might also have been lost.
started in the form of the OC to treat menopausal symp-
Anecdotal evidence from an informal discussion with
toms as she approached matriculation studies. Plans were
high-school students suggests that one in three girls of
outlined for future follow-up of these issues together
this age is taking an OC for reasons of cycle control, acne
with monitoring side effects and complications of the
management or for contraception. Given the prevalence of
OC usage in this age group, combined with the possibility
of initial OC prescription for the management of oligome-
OUTCOME AND FOLLOW-UP
norrhoea ( presumably to reduce associated anxiety,
Baseline bone mineral density (BMD) was assessed, but
re-establish a ‘normal’ cycle and to protect bone mass,
standard references ranges for BMD do not extend to this
etc), conditions affecting menstrual function in this age
patient’s young age, so special reference ranges were used.
group will be undetected and undiagnosed. Menstrual
These suggested femoral neck BMD of 0766 g/cm2 to be
abnormalities and particularly ovarian insufﬁciency at this
in the low range for age, height and weight, and lumbar
time may therefore be under-reported as possible adverse
spine BMD of 0.903 g/cm2 to be normal for height and
events following vaccination or other medication.
weight but lower than the expected range for age. Interval
In addition, as the Australian sponsor of this vaccine
reassessment is planned.
has stated after notiﬁcation: ‘the postmarket reporting of
Premature ovarian failure has been notiﬁed as a possible
adverse events is voluntary and from a population of
adverse event to the Therapeutic Goods Administration of
uncertain size, and consequently it is not always possible
Australia (reference no. 285383) and to the company
to reliably estimate the frequency of these reactions or
which produces this vaccine and to the sponsor.
establish a causal relationship to product exposure’.
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BMJ Case Reports 2012; doi:10.1136/bcr-2012-006879
Acknowledgements Helen Cleland Wyborn BSc (Nursing) (Chicago);
Dip Med Ethics (Chicago); Michael Driscoll PhC; FACPP.
Competing interests None.
▸ It is suggested that oligomenorrhoea and amenorrhoea
Patient consent Obtained.
even in young women be investigated prior to the start
of the oral contraceptives.
▸ It is also suggested that development of
1. Coulam CB, Adamson SC, Annegers JF. Incidence of premature ovarian
oligomenorrhoea or amenorrhoea after establishment of
failure. Obstet Gynecol 1986;67:604–6.
regular menses be considered for notiﬁcation as
2. Nelson LM. Primary ovarian insufﬁciency. N Engl J Med 2009;360:606–14.
possible adverse events where they follow vaccination
3. Islam R, Cartwright R. Socioeconomic Class and Smoking Linked to
Premature Menopause. Presented to European Society of Human
Reproduction and Embryology Conference Stockholm 6 July 2011.
▸ Assessment of vaccinated rat ovarian histology at
4. Wise DL, Jayanthi JW, Caplanski CV, et al. Lack of effects on fertility and
intervals after vaccination is relevant and appropriate.
developmental toxicity of a quadrivalent HPV vaccine in Sprague-Dawley rats.
▸ Since there may potentially be a group for whom this
Birth Defects Res (Part B) 2008;83:561–72. Merck research laboratories,
vaccine is contraindicated, and since the occurrence of
this event may possibly represent broader public health
implications, it is also suggested that long-term
follow-up of ovarian function in a cohort of vaccinated
girls and women be undertaken.
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2012;10.1136/bcr-2012-006879, Published XXX
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