Download Acute Ovarian Torsion and Primary Hypothyroidism

CASE REPORT
Acute Ovarian Torsion and Primary Hypothyroidism
AUTHORS: Debika Nandi-Munshi, MD, Angela Tridgell, MD,
and Craig E. Taplin, MD
abstract
Seattle Children’s Hospital, Division of Endocrinology and
Diabetes, Department of Pediatrics, University of Washington,
Seattle, Washington
A 12-year-old girl presented with acute abdominal pain due to an
acute ovarian torsion. She required an oophorectomy. Clinical and
laboratory assessment confirmed severe primary hypothyroidism. In
this report, we review this rare complication of untreated primary
hypothyroidism and the physiologic mechanisms proposed to explain
this phenomenon. Pediatrics 2013;132:e233–e238
KEY WORDS
abdominal pain/diagnosis, child, female, humans,
hypothyroidism/diagnosis, hypothyroidism/drug therapy, ovarian
cysts/drug therapy, puberty, precocious/diagnosis, puberty,
precocious/drug therapy, puberty, precocious/metabolism,
thyroxine/therapeutic use
ABBREVIATIONS
FSH—follicle stimulating hormone
LH—luteinizing hormone
NL—normal limits
TSH—thyroid stimulating hormone
Dr Nandi-Munshi reviewed the literature, drafted the initial
manuscript with further revisions, and approved the final
manuscript as submitted; Dr Tridgell reviewed the literature,
drafted the initial manuscript, provided care for the patient
described, and approved the final manuscript; and Dr Taplin
reviewed, revised, and approved the final manuscript and was
involved in the direct care of the patient described.
www.pediatrics.org/cgi/doi/10.1542/peds.2012-3574
doi:10.1542/peds.2012-3574
Accepted for publication Mar 12, 2013
Address correspondence to Craig E. Taplin, MD, Seattle Children’s
Hospital, Division of Endocrinology and Diabetes, 4800 Sand Point
Way NE, Seattle WA 98105. E-mail: [email protected]
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2013 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: The authors have indicated they have
no financial relationships relevant to this article to disclose.
FUNDING: No external funding.
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e233
Primary hypothyroidism is frequently
seen in children, with a prevalence of
∼2.5%,1 and autoimmune thyroiditis
the most common cause of acquired hypothyroidism. Hypothyroidism can have
deleterious effects on linear growth and
pubertal timing, causing characteristic and easily recognizable changes
on the growth chart.2 Primary hypothyroidism has been noted to cause
ovarian enlargement and precocious
puberty, described as early as 1905.3
Decades later, Van Wyk and Grumbach
proposed that this phenomenon may
be secondary to overlap in pituitary
hormonal feedback.4 More recently,
the promiscuity of the gonadotropin
receptors, especially the follicle stimulating hormone (FSH) receptor has
been described, likely due to the homologous binding domains that are
shared between the glycoprotein hormone receptors, FSH receptor, luteinizing hormone (LH) receptor, and
thyroid stimulating hormone (TSH)
receptor.5
Previous reports have shown that the
bilateral ovarian enlargement seen in
hypothyroidism resolves with levothyroxine replacement.6–8 However, the
devastating complication of ovarian
torsion leading to infarction is rare
and, to our knowledge, has been
reported only once before in a child, in
a case from India.9 We describe a case
of a 12-year- old girl with delayed diagnosis of hypothyroidism that ultimately resulted in ovarian torsion and
loss of 1 ovary. We draw attention to the
importance of accurate growth charts
as diagnostic clues to hypothyroidism
and review the pathophysiology with
evidence for a primary role for TSH in
ovarian hyperstimulation.
PATIENT PRESENTATION
A 12-year, 8-month old girl presented to
the emergency department with acute
abdominal pain. Her vital signs (temperature 35.5°F, heart rate 63 beats per
minute, blood pressure 119/81 mm Hg)
were discordant with her distress. Her
general appearance was notable for
short stature, obesity, and coarse facial features. Her abdomen was distended with diffuse tenderness without
appreciable masses. She had Tanner
stage 2 breast development without
other secondary sexual characteristics. Her skin was dry with a distinctly
doughy texture. Deep tendon reflexes
showed a slowed relaxation phase. Her
thyroid gland was not clinically enlarged.
An ultrasound of her abdomen (Fig 1)
was performed and revealed massive
cystic bilateral ovarian enlargement
(right: 11.7 3 6.5 3 10.5 cm; left 9.9 3
5.4 3 9.1 cm). Absence of blood flow to
the right ovary was seen. Radiographic
suspicion for ovarian torsion led to
emergent laparotomy. Her right ovary
and fallopian tube were found to be
infarcted and were removed. The histology of both ovaries was consistent
with benign follicular cysts.
Thyroid function was evaluated given
a high level of clinical suspicion at
presentation for primary hypothyroidism. TSH was elevated at 903 mIU/mL
(normal limits [NL]: 0.36–5.8), total thyroxine was undetectable at ,1 mg/dL
(NL 4.9–10), as was total triiodothyronine at ,17 ng/dL (NL: 80–200).
Thyroid autoantibodies showed an
antithyroglobulin antibody titer of 485
IU/mL (NL: 0–40), and thyroid peroxidase antibodies were ,10 IU/mL (NL:
0–35). Her bone age was significantly
delayed at 7 years, 10 months.10 The
patient was diagnosed with primary
hypothyroidism with secondary ovarian enlargement leading to acute
ovarian torsion.
Review of her medical record revealed
minimal linear growth between age 8
and 12 years (Fig 2). Her height z score
at presentation was –4.4. Beginning at
10 years of age, she had irregular
vaginal spotting (Fig 3). Breast development began before age 10 years,
without evidence adrenarche. She had
constipation, cold intolerance, weight
gain, and hair thinning. She had difficulties at school secondary to extreme
FIGURE 1
A, Pelvic ultrasound with enlarged right (RT) ovary including multiloculated cyst, composed of daughter cysts and thick, irregular walls. Left (LT) ovary is also
enlarged and contains multiple cysts. B, Pelvic ultrasound with Doppler showing lack of blood flow to the right ovary (RTOV), consistent with ovarian torsion. Left
ovary (LT OV) has normal blood flow.
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CASE REPORT
FIGURE 2
Growth chart reproduction illustrating height and weight measurements. Hypothyroidism likely occurred around age 8 years. Circles illustrate raw height and
weight data; triangle is height for adjusted bone age of 7 years, 10 months.
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e235
replacement.12,13 However, when left
untreated or unrecognized, ovarian
torsion can occur.
FIGURE 3
Pelvic ultrasound of the uterus with a thick endometrium (14.7 mm) demonstrating estrogen effect.
fatigue. She was started on daily levothyroxine, and 8 weeks after her surgery, she was euthyroid with a normal
TSH (1.45 mIU/mL) and total thyroxine
(6.8 mg/dL). Her luteinizing hormone
(ultrasensitive assay) was prepubertal
(0.04 mIU/mL [NL: 0.04–10.8]) at her
initial presentation but rose to the pubertal range (2.73 mIU/mL) after 2
months on levothyroxine. Subsequent
laboratory evaluation after initiation of
levothyroxine revealed a pubertal estradiol (25 pg/mL [NL: 5–370]), FSH of
5.7 mIU/mL (NL: 0–15), and elevated
prolactin level (36 ng/mL [NL 3–18]).
On a pelvic ultrasound performed 10
weeks after initiation of levothyroxine,
her left ovary had returned to normal
size (3.5 3 3.9 3 1.9 cm). Her weight
had decreased by 7.5 kg. Her symptoms
of fatigue, cold intolerance, and skin
changes resolved. Linear growth in the
first year after initiation of levothyroxine therapy was 10.3 cm, and her mean
growth velocity for the 2 years after
diagnosis was 8.85 cm per year. As
expected, bone age also rapidly advanced in the first 12 to 18 months.
Given this, along with the patient’s reluctance to undergo adjunctive growthpromoting therapies, she attained
a final height of 145 cm, significantly
below the midparental height of 162 cm.
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DISCUSSION
Hypothyroidism is not typically viewed
as either a surgical emergency or an
acutely life-threatening condition. We
report a case of a child with acute
ovarian torsion, resulting in ovarian
infarction necessitating oophorectomy
as a direct consequence of severe
undiagnosed hypothyroidism. To our
knowledge, this specific outcome has
not been reported in the United States
before. Several reports have been
published detailing the constellation of
precocious puberty, large bilateral
multicystic ovaries, and premature
menarche in the context of severe hypothyroidism. However, the devastating
complication of ovarian loss as in this
case is rare, reported only once previously, in India.9 Ovarian removal has
been performed in several cases of
ovarian hypertrophy without ovarian
torsion, often due to the severity of the
presentation, without hypothyroidism
being known or clear evidence to support the procedure.11 In most situations,
oophorectomy can be avoided if the
diagnosis of hypothyroidism is considered. Where bilateral ovarian enlargement exists, hypothyroidism must be
definitively excluded because strong
evidence exists that the ovaries return
to normal with simple levothyroxine
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In 1960, Van Wyk and Grumbach proposed a lack of negative feedback to
the pituitary in children with profound
hypothyroidism, leading to elevated
gonadotropins concurrent with TSH,
resulting in manifestations of atypical
precocious puberty.4 However, subsequent cases have revealed that
gonadotropins are not routinely elevated.8,13–15 Indeed, in our case, LH was
prepubertal despite a history of thelarche and intermittent vaginal bleeding.
Given that integrity of the hypothalamicpituitary-gonadal axis is known to be
dependent on normal thyroid function,
this would be expected. Thus, our case
supports the notion that classic
gonadotropin-dependent (and LHdominant) central precocious puberty
is not likely to explain the Van Wyk and
Grumbach syndrome. Rather, it is more
probable that homology between the
glycoprotein hormones and their
receptors explains ovarian stimulation.
Both the TSH and FSH receptors are part
of the glycoprotein family of hormone
receptors, all of which have a binding
region located in the extracellular domain. The backbone of this domain is
nearly identical for the FSH and TSH
receptors.16 At normal levels, TSH
binding to the FSH receptor produces
minimal biologic effect, but at high
concentrations of TSH, as found in
profound hypothyroidism, the biologic
activity may be sufficient to cause
ovarian stimulation, follicle formation,
and estrogen secretion. This process is
independent from the gonadotropin
releasing hormone–FSH axis, which
does not undergo feedback inhibition.17 Affinity of the FSH receptor for
TSH would also explain the typical
presentation for boys with pubertal
changes in the context of hypothyroidism. Testosterone levels are not
CASE REPORT
elevated, with minimal virilization, but
testicular enlargement is seen, likely
as a result of FSH receptor stimulation.
Conversely, pubertal changes from LH
receptor activation lead to Leydig cell
stimulation and testosterone secretion
without significantly enlarged testes.17
The pubertal changes and ovarian enlargement seen in this case, as in others, support this hypothesis that TSH,
at high levels, binds to the FSH receptor.
Our patient’s lack of growth would
have provoked additional investigation;
however, she had been lost to primary
care follow-up at around age 7 years.
The characteristic growth pattern of
acquired hypothyroidism consists of
a plateau in height gain with either
unaffected weight or relative weight
gain. When severe, final adult height is
known to be affected despite appropriate treatment of the hypothyroidism
once it is detected, as in this case.
Other modalities to promote linear
growth as an adjunct to thyroid
hormone replacement, such as growth
hormone, gonadotropin-releasing hormone analogs, or aromatase inhibitors, have not been shown to affect
height recovery.18
Leaving final height aside, the usefulness of a growth chart in avoiding such
a devastating outcome as ovarian loss
cannot be understated. The diagnosis of
acquired hypothyroidism in childhood
is often delayed. In a retrospective review of 21 children with profound hypothyroidism, mean bone age at the
time of diagnosis of hypothyroidism
was 4.1 standard deviations below the
mean.18 Unfortunately, this appears to
have changed little since reports from
the 1980s.19 Because skeletal age progresses little, or not at all, after the
onset of hypothyroidism, bone age at
diagnosis times the likely onset of the
hypothyroidism. In our patient, despite
a chronologic age of 12-years, 8months, bone age was delayed by almost 5 years. This could be prevented
with appropriate annual growth
assessment and targeted investigation
in the presence of slow linear growth.
Clearly, a delayed diagnosis of hypothyroidism can be shown to cause
ovarian infarction along with adverse
final height outcome, among other sequelae.
In summary, acute ovarian torsion in
children can be caused by unrecognized
primary hypothyroidism. The mechanism of pubertal symptoms and ovarian
enlargement is not consistent with
classic central precocious puberty but
rather displays, in stark clinical context,
the homology evident in the glycoprotein family of hormone receptors. Of
utmost importance is that hypothyroidism should be considered in any
child with precocious puberty with
discordant supportive findings, such as
growth failure or delayed bone age.
More children may be at risk for acute
ovarian torsion than previously recognized, and vigilance must be maintained
to avoid this catastrophic presentation
of a common childhood condition.
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Acute Ovarian Torsion and Primary Hypothyroidism
Debika Nandi-Munshi, Angela Tridgell and Craig E. Taplin
Pediatrics; originally published online June 10, 2013;
DOI: 10.1542/peds.2012-3574
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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1948. PEDIATRICS is owned, published,
and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk
Grove Village, Illinois, 60007. Copyright © 2013 by the American Academy of Pediatrics. All
rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
Downloaded from by guest on June 18, 2017
Acute Ovarian Torsion and Primary Hypothyroidism
Debika Nandi-Munshi, Angela Tridgell and Craig E. Taplin
Pediatrics; originally published online June 10, 2013;
DOI: 10.1542/peds.2012-3574
The online version of this article, along with updated information and services, is
located on the World Wide Web at:
/content/early/2013/06/05/peds.2012-3574
PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1948. PEDIATRICS is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2013 by the American Academy
of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
Downloaded from by guest on June 18, 2017