The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 2 424-427
Copyright © 1999 by The Endocrine Society
Maintenance of Serum Calcium by Parathyroid Hormone-Related Peptide During Lactation in a Hypoparathyroid Patient
K. J. Mather,
C. L. Chik and
B. Corenblum
Division of Endocrinology (C.L.C.), Department of Medicine,
University of Alberta, Edmonton AB Canada, and Division of
Endocrinology (K.J.M., B.C.), Department of Medicine, University of
Calgary, Calgary AB Canada T2N 2T9
Address all correspondence and requests for reprints to: Dr. B. Corenblum, Division of Endocrinology, Department of Medicine, 3330 Hospital Dr. NW, Calgary AB T2N 4N1; E-mail:
corenblu{at}acs.ucalgary.ca
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Abstract
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We describe the changes in calcium homeostasis seen in a
hypoparathyroid woman during the third trimester and with lactation
following her second pregnancy. During lactation her need for
supplemental calcium and calcitriol abated, and in fact she was
transiently hypercalcemic and hypophosphatemic. This change was
associated with a rise of serum parathyroid hormone-related peptide
(PTHrP) released systemically during lactation. This is the first
documentation of the time course of serum PTHrP levels from the late
third trimester throughout lactation in a hypoparathyroid woman. In
this context PTHrP may have sufficient biological activity to
compensate for parathyroid hormone deficiency.
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Introduction
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ALTHOUGH initially known only for its role
in humoral hypercalcemia of malignancy, parathyroid hormone-related
peptide (PTHrP) is now known to be physiologically present in a number
of tissues (1, 2). Most notable of these is breast milk, where it
reaches concentrations 102 to 105 those seen in
the serum (1). Its role in this location is not established, but a
paracrine role in control of total milk calcium content is postulated,
and PTHrP may also regulate mammary blood flow through vasodilatory
mechanisms (3). It also reaches the systemic circulation in varying
amounts (4, 5, 6, 7, 8). PTHrP has therefore come under investigation as a
potential mediator of derangements in calcium metabolism and of bone
loss during lactation. Depending on the sensitivity of the assay used,
up to 95% of lactating women and the majority of nonlactating women
have measurable serum PTHrP (3, 6, 7, 9, 10). Systemic levels during
lactation correlate with bone loss (6.) Also, isolated case reports of
hypercalcemia associated with elevated PTHrP levels during lactation
(3, 11, 12, 13) further suggest that it is biologically active, but its
physiologic role and the mechanisms controlling its release remain
uncertain. Investigations are hampered in part by the complexity of the
calcium homeostatic mechanism.
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Case Report
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A 28-yr-old patient with surgical hypoparathyroidism consequent to
total thyroidectomy for a thyroid nodule was referred for ongoing
thyroid followup during her first pregnancy. She had undergone a
near-total thyroidectomy at age 24 and became symptomatically
hypoparathyroid 18 months later, with a nadir serum calcium of 2.05
mmol/L. While she was lactating subsequent to her first pregnancy, she
became hypercalcemic on her previously stable calcium and calcitriol
supplements, and between weeks 2 and 6 of lactation they were
withdrawn. The requirement reasserted itself after cessation of
breastfeeding. We subsequently followed her through her second
pregnancy, with frequent measurements of relevant ions and
calciotrophic hormones, including PTHrP, as described below. In
accordance with our institutional ethical standards, full informed
consent was obtained with regard to the supplemental peripartum blood
and urine samples.
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Materials and Methods
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Postpartum samples were collected within 1 h after
lactation. Prolactin (PRL, normal range 3–30 µg/L) and intact
parathyroid hormone (PTH, normal range 10–55 ng/L or 1.0–5.5 pmol/L)
were measured by a dual-site IRMA. The INCSTAR Corp. (Stillwater, MN) kit was used for PTH
determinations, with a detection limit of 0.07 pmol/L; variances were
3.4% at 4.9 pmol/L and 4.6% at 28.5 pmol/L. Intact PTHrP was measured
using a dual-site IRMA kit from Nichols Institute Diagnostics (San Juan Capistrano, CA). With this assay
the detection limit was 0.2 pmol/L, and at 3.4 pmol/L our inter- and
intra-assay variance were 8.8% and 4.0% respectively. Values of
0.93 ± 0.08 pmol/L and 0.38 ± 0.04 were seen previously in
lactating and nonlactating euparathyroid women respectively (8).
Samples for PTHrP were collected in prechilled Vacutainers containing
heparin and a peptidase inhibitor cocktail including aprotinin and
leupeptin (Nichols Institute Diagnostics); all samples
were centrifuged immediately and frozen within 30 min of collection.
All PTHrP measurements were performed in a single assay in duplicate;
the mean of these results is reported. The Foothills Hospital
(Calgary, Alberta) clinical chemistry laboratory was used for
measurement of calcium (normal range 2.12–2.54 mmol/L), inorganic
phosphate (0.80–1.50 mmol/L), 1,25-(OH)2D (35–140 pmol/L), and
creatinine (60–124 µmol/L). Prepartum values for calcium were
corrected for the serum albumin concentration, which varied normally
through the patient’s pregnancy. Postpartum albumin concentrations
were normal, requiring no correction of the measured total serum
calcium.
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Results
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The patient’s thyroid levels were maintained within the normal
range throughout the study by dosing adjustments according to serum
thyrotropin levels measured every 4–6 weeks. Her prepregnancy dose of
0.112 mg daily was increased to 0.175 mg, 6 days per week, 0.35 mg
Sundays, by 36 weeks gestation. Her dosing requirement had decreased
again to 0.112 mg daily by 16 weeks postpartum.
The time course of the alterations in her mineral metabolism is
depicted in Fig. 1
. Lactation began
immediately postpartum and continued for 72 weeks, with weaning over
the last 12 weeks. Calcium supplements were withdrawn over the first 2
weeks postpartum, and her calcitriol dose was progressively reduced
until it was withdrawn entirely at 7 weeks postpartum, again with
maintenance of normal serum calcium levels. PTH levels were
undetectable or below the lower limit of normal throughout the study
period. The serum PTHrP level was elevated to within the normal range
for PTH (using the same units) by the first week postpartum, and PTHrP
levels corresponded temporally to the observed changes in mineral
homeostasis. The week 0 sample was obtained 4 h postpartum, and
although it continued the slight upward prepartum trend, the first
frank elevation was seen at 1 week postpartum. At that time the PTHrP
level was within the normal range for PTH.
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Figure 1. Changes in minerals and calciotropic hormone
levels through lactation. The patient lactated to 72 weeks postpartum.
Light boxes indicate normal ranges; in the bottom panel
the box indicates the normal range for PTH (1.0–5.5 pmol/L). The top
two panels represent daily doses of calcium citrate and calcitriol. The
vertical line is at week 0, the day of delivery, at
which time breast feeding was initiated.
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Table 1 reports average pre- and
postpartum levels of urinary calcium and calcium clearance, calculated
tubular reabsorption of phosphate (TRP), and serum calcium, phosphate,
and 1,25-(OH)2D. The prepartum values were measured in the third
trimester, and the postpartum values represent measurements within the
first 12 weeks postpartum. Urinary calcium excretion did not change
significantly following initiation of lactation. The TRP fell with
lactation compared to prepartum levels, but serum phosphate levels
remained in the high normal range. This was concurrent with decreasing
calcitriol supplements and ongoing lactation, and is consistent with a
PTH-like action. Serum 1,25-(OH)2D decreased coincident with the
decreased supplementation, but was spontaneously maintained within the
normal range (Fig. 1
).
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Discussion
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We describe the persisting normalization of serum calcium without
need for supplementation for 72 weeks postpartum in a hypoparathyroid
woman, corresponding to continuing lactation and persistence of PTHrP
in the serum. The PTHrP levels observed were comparable to those
reported in women with intact parathyroids studied during lactation (4, 5). However, our observed postpartum levels were higher than most
reported values in a similar group of 33 lactating women, measured
between 6 weeks and 6 months postpartum (8).
PTH and PTHrP act through a shared receptor, and we found evidence that
this receptor was being activated. The 1,25-(OH)2D levels rose with
lactation, allowing withdrawal of supplements. Further, the changes in
serum phosphate and calculated TRP argue that renal phosphate handling
was altered consistent with a PTH receptor-mediated mechanism, as
described in euparathyroid women (3, 5). The level of PTHrP after the
first week of lactation rose to within the normal range for PTH. Both
molecules are equipotent at the PTH receptor (1), but a relatively
magnified response in this hypoparathyroid patient may have been seen
due to hypersensitivity or up-regulation of the receptor. Therefore,
PTHrP was likely responsible for the observed alterations in calcium
homeostasis.
As with her first delivery she became hypercalcemic during early
lactation while still on supplements, implying a separation of the
mechanisms of systemic PTHrP release and calcium regulation. The
normalization of her serum calcium levels may be an uncontrolled effect
of the serum PTHrP levels produced by lactation rather than a result of
regulated secretion. In case reports similar to ours, calcium
supplements have been successfully reduced or withdrawn (14, 15, 16, 17).
Others have documented hypercalcemia, even in euparathyroid patients
(12). Other evidence exists suggesting that altered maternal calcium
metabolism is simply a side effect of the presence of circulating
PTHrP. The calcium concentration in milk correlates well with
C-terminal PTHrP concentration in milk (18). The serum levels, however,
vary significantly among lactating women (3, 5, 7), and no correlation
of serum levels with milk calcium content has been described. The
variety of assays used may account for this variation, but it could
result from unregulated PTHrP "spill" into the systemic
circulation, as PTHrP in breast milk is 102 to
105 the levels seen in serum (1). A role for PTHrP in local
control of mammary blood flow has been proposed (1, 3, 19), and perhaps
this is a determinant of systemic PTHrP release. PTHrP has been
proposed as a polyhormone (1, 20), and in the fetal circulation there
is evidence that the midportion (rather than the usual N-terminal
portion) of the molecule is the active site (21). In the maternal
circulation an undescribed action away from the traditional PTH
receptor-mediated mechanism cannot be ruled out, and this could be a
separate locus of regulation of systemic release.
The literature suggests a strong dependence of PTHrP secretion on the
action of PRL (3, 4, 5, 22). Even in nonlactating patients with
prolactinomas, PTHrP was present in greater concentrations than in
controls, although lactating women had still higher levels (8). The
phenomenon of lactation-related remission of hypoparathyroidism has
been previously attributed to hyperprolactinemia (16). In our patient,
despite markedly elevated peripartum PRL, the PTHrP levels did not rise
significantly until the first week postpartum. At that time lactation
was established, and the serum PRL had fallen to levels similar to
other lactating women (8). The lactogenic actions of PRL on the breast
are known to be inhibited by high levels of estradiol present in the
last trimester. Later in lactation, on-going PRL spikes with nipple
stimulation produce elevated integrated PRL levels, and lactogenesis is
dependent on this ongoing net elevation (23). This effect continues
well past the point when PRL levels are sufficient to suppress
gonadotropin production, and therefore lactation is not dependent on
the absence of ovarian products. Evidence from goats (24) and rats (25)
suggests that there is a significant degree of local control of PTHrP
secretion, related principally to the recent volume of milk production.
An autocrine regulatory mechanism has been proposed (1, 2, 22), given
that there is a positive relation of milk PTHrP concentration with
volume of milk produced. Limited evidence supporting a similar
mechanism in humans also exists (14, 26). Accordingly, although
lactation proper depends on PRL activity, milk PTHrP itself may be
separately regulated. The factors involved in this regulation and the
control mechanisms remain obscure, and the question of whether systemic
or milk concentrations of the hormone are the principal targets of
regulation is open.
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Conclusion
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In this hypoparathyroid patient, systemic PTHrP levels rose
with lactation into the normal range for PTH. At these levels there was
apparently sufficient PTH action to obviate the need for calcium and
calcitriol supplementation during lactation. However, the determinants
of systemic release are unclear, and in particular Ca and PO4 do not
appear to control this phenomenon. Further study of PTHrP levels in
serum and milk during lactation in women with derangements in calcium
metabolism, such as hypoparathyroidism and familial hypocalciuric
hypercalcemia, will help confirm the supposed independence of systemic
PTHrP release from maternal calcium levels. More frequent measurements
in the first days of lactation will clarify the relation of the onset
of lactation with the changes in systemic PTHrP.
Received July 16, 1998.
Revised October 28, 1998.
Accepted November 6, 1998.
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Abstract
Introduction
