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Otolaryngology -- Head and Neck Surgery
http://oto.sagepub.com/content/145/4/561
The online version of this article can be found at:
DOI: 10.1177/0194599811414511
2011 145: 561 originally published online 12 July 2011Otolaryngology -- Head and Neck Surgery
Noah B. Sands, Richard J. Payne, Valerie Côté, Michael P. Hier, Martin J. Black and Michael Tamilia
Female Gender as a Risk Factor for Transient Post-Thyroidectomy Hypocalcemia
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Otolaryngology–
Head and Neck Surgery
145(4) 561 –564
© American Academy of
Otolaryngology—Head and Neck
Surgery Foundation 2011
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DOI: 10.1177/0194599811414511
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Abstract
Objectives. Transient post-thyroidectomy hypocalcemia is a
common complication following thyroid surgery. Studies have
identified risk factors and possible ways to help predict post-
thyroidectomy hypocalcemia with the intent of ultimately
limiting its incidence. This study evaluates the role of patient
gender as a potential risk factor.
Study Design. A retrospective case series with chart review of
270 consecutive total thyroidectomy patients was conducted.
Setting. Jewish General Hospital, a McGill University–affiliated
hospital in Montreal, Canada.
Subjects and Methods. 219 women and 51 men were included. Post-
operative hypocalcemia was defined as any 1 of the following: total
serum calcium 1.90 mmol/L or less, or signs and symptoms of hy-
pocalcemia. The following were evaluated as potential confounding
factors in the study: age, menopause, preoperative calcium, para-
thyroid hormone, magnesium and phosphate levels, presence of
carcinoma in the surgical specimen, number of parathyroid glands
preserved in situ, thyroid gland volume, and nodule size.
Results. Female patients experienced transient postoperative
hypocalcemia in 24.7% (54/219) of cases, which was signifi-
cantly greater than the 11.8% (6/51) incidence detected in
men (P < .05). This represents a female/male relative risk ratio
of 2.1 (confidence interval, 1.0-4.6). There was no significant
difference in rates of hypocalcemia between premenopausal
and postmenopausal women (22.7% vs 26.6%).
Conclusion. These findings suggest that being female is likely
a risk factor for transient post-thyroidectomy hypocalcemia.
Although this association is statistically significant, its magni-
tude and clinical relevance are uncertain and may be trivial.
Additional research is needed to ascertain the physiologic
mechanisms underlying this gender difference.
Keywords
thyroidectomy, hypocalcemia, hypoparathyroidism, risk factors
Received May 18, 2009; revised May 16, 2011; accepted June 1, 2011.
Transient hypocalcemia frequently complicates postop-
erative care of patients who have undergone total thy-
roidectomy and poses potentially deleterious risks to
their health. Post-thyroidectomy hypocalcemia arises because
of parathyroid removal, devascularization, and damage, which
induce a state of transient hypoparathyroidism.1-3 Additional
mechanisms, such as vitamin D deficiency, an acute increase
in calcitonin, surgical stress, and “hungry bone syndrome,”
are believed to contribute to this process.2,4
Numerous studies have investigated factors that have the
potential to reliably predict postoperative hypocalcemia. The
roles of quantitative measures such as parathyroid hormone
(PTH) levels and serum-corrected calcium levels in the first
hours following total thyroidectomy have since been validated
repeatedly.2,5-10 Such laboratory measures play an integral role in
identifying patients at significant risk for hypocalcemia and have
allowed for earlier supplementation of these patients with cal-
cium and vitamin D.5-8 These predictors have also enabled sur-
geons to select patients who can safely undergo same-day
discharge following total thyroidectomy.11 Reductions in the
overall incidence of post-thyroidectomy hypocalcemia as well as
significant cost savings to the healthcare system have subse-
quently been achieved.6,8
Despite this recent progress, postoperative hypoparathy-
roidism remains a clinical challenge for thyroid surgeons
because of its frequency and the limited number of established
414511OTOXXX10.1177/0194599811414511San
ds et alOtolaryngology–Head and Neck Surgery
© The Author(s) 2010
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1Department of Otolaryngology–Head and Neck Surgery, Jewish General
Hospital, McGill University, Montreal, Canada
2Department of Endocrinology, Jewish General Hospital, McGill University,
Montreal, Canada
This article was presented at the 2008 AAO-HNSF Annual Meeting;
September 23, 2008; Chicago, Illinois.
Corresponding Author:
Richard J. Payne, 3755 Cote Ste. Catherine, Suite E903, Montreal, Quebec,
Canada H3T 1E2
Email: rkpayne@sympatico.ca
Female Gender as a Risk Factor for Transient
Post-Thyroidectomy Hypocalcemia
Noah B. Sands, MD1, Richard J. Payne, MD, FRCS1,
Valerie Côté, MD1, Michael P. Hier, MD, FRCS1,
Martin J. Black, MD, FRCS1, and Michael Tamilia, MD, FRCP2,
Original Research—Endocrine Surgery
at SOCIEDADE BRASILEIRA DE CIRUR on November 11, 2011oto.sagepub.comDownloaded from
562 Otolaryngology–Head and Neck Surgery 145(4)
preoperative predictors. In this study, we sought to evaluate
the role of patient gender as a potential risk factor for postop-
erative hypocalcemia.
Materials and Methods
A retrospective analysis was conducted of 270 consecutive
patients who underwent total thyroidectomy at a university
teaching hospital between October 2004 and December 2006.
Approval by the hospital institutional review board (research
ethics committee) was received prior to the chart review.
Patients who underwent subtotal thyroidectomy, completion
thyroidectomy, extended neck dissection, or concurrent
planned parathyroidectomy were excluded. Our sample con-
sisted of 51 men and 219 women with a mean age of 50 years
(standard deviation ± 13) and a range of 20 to 84 years.
Women younger than 50 years of age (n = 110) were consid-
ered premenopausal, and women older than 50 years (n =
109) were regarded as postmenopausal based on previously
published data from the National Institute of Aging (Table 1).
A blood testing protocol was applied for all patients that
measured serum calcium and albumin at 6, 12, and 20 hours
postoperatively and twice daily thereafter. Serum magnesium
and phosphate levels were drawn at 12 hours and daily thereaf-
ter. Normal values for serum calcium ranged from 2.12 to 2.62
mmol/L (8.48-10.48 mg/dL). The serum calcium levels were
corrected for measured abnormal serum albumin levels. Serum
PTH was drawn at 1, 6, 12, and 20 hours postoperatively and
then twice daily. Blood testing ceased for patients meeting our
6-hour critical level of PTH 28 ng/L or more and simultaneous
corrected calcium 2.14 mmol/L (8.56 mg/dL) or more.5
Parathyroid hormone levels were measured using the Roche
Elecsys System 2010 electrochemiluminescence immunoassay
(Roche Diagnostics, Mannheim, Germany), which measures
both the N- and C-terminal fragments of the hormone.
Postoperative hypocalcemia was defined as any one of the
following: corrected serum calcium of 1.90 mmol/L (7.6 mg/
dL) or less up to 1 month following surgery or signs and
symptoms of hypocalcemia such as perioral numbness, pares-
thesias of the upper extremity digits, or a positive Chovstek’s
or Trousseau’s sign. These patients were started on one of the
following regimens based on serum corrected calcium levels:
intravenous calcium, oral calcium, oral vitamin D, or a combi-
nation of the 3. Patients needing substitutive therapy to main-
tain normocalcemia 1 year after surgery were considered to
have permanent hypocalcemia.
All patients with a 1-hour PTH 8 ng/L or less were included
within the hypocalcemic group based on previous studies that
have shown that all patients below this threshold 1-hour value
subsequently develop transient hypocalcemia.5-7,11 These patients
were prophylactically treated with calcium carbonate (1.5 g, 3
times daily) and vitamin D (0.25 µg/d) supplementation as per
the standard protocol at our institution. Patients were considered
normocalcemic if they did not reach the criteria requiring inter-
vention within 1 month after surgery. Patients on preoperative
calcium or vitamin D were continued on their usual regimens
postoperatively. Abnormalities in magnesium levels were cor-
rected with supplementation immediately upon detection.
A chi-square test was used to evaluate for statistically signifi-
cant differences between groups with respect to rates of transient
hypocalcemia and potential confounding factors. The following
factors were accounted for: age, menopause, preoperative cal-
cium, PTH, magnesium and phosphorus levels, presence of car-
cinoma in the surgical specimen, number of parathyroid glands
preserved, nodule size, and thyroid gland volume.
Results
Following total thyroidectomy, women were found to experi-
ence transient hypocalcemia in 24.7% of cases (54/219),
whereas men encountered this postoperative complication in
11.8% of cases (6/51). This is significantly different for a P
value of .046 and a female/male relative risk ratio of 2.14
(confidence interval [CI], 1-4.6) (Table 2). The mean differ-
ence measured 0.13 (CI, 0.0015-0.2164). There was no sig-
nificant difference in rates of transient hypocalcemia between
premenopausal women (25/110, 22.7%) and postmenopausal
women (29/109, 26.6%) (Table 3). Permanent hypocalcemia
affected 1 man (<1%) and 1 woman (<1%) within this cohort.
Mean preoperative calcium levels were as follows: 2.43
mmol/L in men, 2.42 mmol/L in all women, 2.39 mmol/L in
premenopausal women, and 2.48 mmol/L in postmenopausal
women. The disparities in these values were all statistically
nonsignificant. Differences in mean preoperative PTH levels
were also statistically nonsignificant (51.4 ng/L in men, 52.1
ng/L in all women, 52.7 ng/L in premenopausal women, 51.5
ng/ L in postmenopausal women). Mean levels of magnesium
and phosphate were also nearly equivalent in all groups at 12
hours postoperatively (Table 4).
Women were found to have a slightly lower mean 1-hour
postoperative PTH than men (36.8 vs 41.9 ng/L, respectively).
This difference was nonsignificant (P = .2). In addition, a higher
Table 1. Patient Characteristics
Men Women Premenopausal Postmenopausal
Subjects, n 51 219 110 109
Mean age, y 53 49 39 60
Preoperative Ca++
supplementation, n
0 5 0 5
Table 2. Rates of Transient Hypocalcemia by Gendera
Hypocalcemia
n %
Men 6/51 11.8
Women 54/219 24.7
aP value = .046 (confidence interval, 1.0-4.6). Female/male relative
risk = 2.1.
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Sands et al
563
proportion of women were found to have a 1-hour PTH value
below the critical threshold value of 8 mmol/L (28/219, 12.8%
compared with 2/51, 4.0%, P not significant) (Table 5).
The mean number of parathyroid glands identified within sur-
gical specimens was 0.43 in men and 0.53 in women. Histological
analysis of specimens revealed cancer in 92.2% of men (47/51)
and in 80.4% of women (176/219) (Table 6).
Only negligible differences in thyroid gland volume and
dominant nodule size (according to largest dimension) were
found between genders.
Discussion
Postoperative hypocalcemia is one of the most immediate and
most common surgical complications of total thyroidectomy,
occurring in as many as 30% of patients.12 In recent years, there
has been a great deal of interest in identifying preoperative and
perioperative factors that help predict the development of hypo-
calcemia.2,3,5,7,9-11 To our knowledge, despite much recent prog-
ress in this area of research, this is the first report of a significantly
higher rate of post-thyroidectomy hypocalcemia identified
within women when compared with men. It should be men-
tioned, however, that a trivial association between gender and
outcome cannot be excluded based on the lower tail of the 95%
CI (1.0). Although our findings imply that female gender is an
independent risk factor for postoperative hypocalcemia, the spe-
cific mechanisms underlying this gender difference can only be
inferred. Reports from a number of previous studies imply that
differences in gender may exist at a number of physiologic and
anatomic levels. None of these studies investigated biological
disparity between genders as a primary objective.
The gender disparity may be related to the effects of sex ste-
roids on PTH secretion. Research to date, however, has failed to
identify such a physiologic mechanism. Sandelin et al13 identified
the presence of female sex steroid and cortisol receptors in para-
thyroid tissue by using various ligand-binding techniques.
Although the existence of androgen receptors in parathyroid tissue
has not been directly evaluated, Pizzi et al14 found the transcrip-
tional regulation of PTH-related peptide within the rat prostate to
be at least in part regulated by the interaction of male hormones
with their native receptors.
The observed gender difference can partially be accounted for
at the molecular level by various regulators of monoclonal prolif-
eration and mitosis of parathyroid tissue. Despite being charac-
terized by a low rate of cell turnover and division,15 mitosis of
parathyroid cells can be stimulated by conditions of functional
demand such as a hypocalcemic state.16 Although the precise
molecular mechanisms involved in this process have yet to be
defined, various growth factors and cell-cycle regulators have
been implied.17 Males may possess polymorphisms of these reg-
ulatory genes that confer them a proliferation advantage over
females and that enhance their ability to maintain calcium
homeostasis in conditions of transient functional demand. In
addition to stimulating cell division, conditions of hypocalcemia
have been demonstrated to increase both the gene expression of
the PTH gene and the secretion of mature PTH peptide from
parathyroid cells.18 Genetic variation may also exist among fac-
tors within the respective cell-signaling pathways.
It is possible that the identified gender difference identified is
unrelated to the any of the aforementioned physiologic mecha-
nisms but is instead secondary to anatomic and morphologic dif-
ferences between the male and female parathyroid gland. A
cadaver study by Dufour and Wilkerson19 revealed that glandular
weights were significantly higher in men than in women. Other
autopsy studies have suggested that the parathyroids of men and
women may in fact differ in composition.20 Varying proportions
of parenchymal fat and stromal fat have been detected, the func-
tional significance of which remains unknown.
The female predisposition to post-thyroidectomy hypocalce-
mia may also be iatrogenic in nature. Previous studies have
shown the intensity and frequency of early hypocalcemia to be
directly related to the number of parathyroid glands preserved
during surgery.1 Perhaps a greater degree of mechanical trauma is
imposed upon the parathyroid glands of females during thyroid-
ectomy because of a more diminutive operative field. Conceivably
women are predisposed to a higher rate of accidental parathyroid
gland removal during thyroidectomy. Our data support this
Table 3. Rates of Hypocalcemia in Femalesa
Hypocalcemia
n %
Premenopausal 25/110 22.7
Postmenopausal 29/109 26.6
aP value not significant.
Table 4. Preoperative Laboratory Values
Males Females P Value
Calcium, mmol/L 2.43 2.42 NS
PTH, ng/L 51.4 52.1 NS
Magnesium, mmol/L 0.75 0.74 NS
Phosphorus, mmol/L 1.08 1.08 NS
Abbreviations: NS, not significant; PTH, parathyroid hormone.
Table 5. Postoperative Laboratory Values
Males Females P Value
1-h PTH, ng/L 41.9 36.8 0.2
1-h PTH ≤8, n (%) 2/51 (4) 28/219 (12.8) NS
Abbreviations: NS, not significant; PTH, parathyroid hormone.
Table 6. Pathology
Males Females
Thyroid cancer, n (%) 47/51 (92.2) 176/219 (80.4)
Number of parathyroid glands
in situ
3.57 3.47
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564 Otolaryngology–Head and Neck Surgery 145(4)
theory, as women had a slightly higher rate of accidental parathy-
roid gland removal (P not significant).
Although there is a small discrepancy in rates of malig-
nancy between genders in this cohort, this is unlikely to have
had any substantial bearing on rates of hypocalcemia, as
hypocalemia rates were almost equivalent according to final
diagnosis (22.3% [51/223] for patients with carcinoma, 19.1%
[9/47] for patients with benign pathology, P not significant).
We did, however, identify that 52% (113/219) of women
within our study had evidence of Hashimoto’s/chronic lym-
phocytic thyroiditis on final pathology compared with only
16% (8/51) of men. This may have accounted for a consider-
ably higher rate of post-thyroidectomy hypocalcemia among
women in our study, as a greater likelihood of hypocalcemia
existed among patients with chronic lymphocytic thyroiditis
(36% vs 26%, P not significant). Other authors have made
previous references to a possible association in this regard.21
Graves disease was more prevalent among women (2.3%,
5/219) compared with men (0%, 0/51) in our study. But con-
sidering that only a small subset of women were implicated,
this is unlikely to have independently accounted for a consid-
erable increase in rates of hypocalcemia.
Conclusion
The findings within this study suggest that being female is a
significant risk factor for transient post-thyroidectomy hypo-
calcemia; however, the clinical relevance of these findings is
uncertain based on a modest sample size and a CI that
includes 1.0. Nonetheless, females appear to encounter this
postoperative complication more than twice as frequently as
males. This implies that females could conceivably benefit
from earlier and possibly preoperative calcium supplementa-
tion to help reduce its occurrence. A prospective study would
be necessary to confirm such a hypothesis. Further research is
also needed to elucidate the specific physiologic mechanisms
and anatomic variations underlying the greater predisposition
of females to post-thyroidectomy hypocalcemia.
Author Contributions
Noah B. Sands, first author, data collector; Richard J. Payne, supervisor,
hypothesis development; Valerie Côté, data collector; Michael P. Hier,
proofreader, consultant, attending surgeon; Martin J. Black, attending
surgeon, consultant; Michael Tamilia, proofreader, consultant.
Disclosures
Competing interests: None.
Sponsorships: None.
Funding source: None.
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