Chemistry and Physiology of the Parathyroid
Hormone
FRANKLIN C. McLEAN

AND

ANN M. BUDY

Department of Physiology, The University of Chicago, Chicago, Illinois
Page
I. Introduction.. . . . . . . . . . . . . . . . .
11. Chemistry of the Parathyroid
111. Biologic Activity of the Parathyroid Hormone, . . . . . . . . . . . . . . . . . . . . . . . .
168
IV. Peripheral Actions of the Parathyroid Hormone.. . . . . . . . . . . . . . . . . . . . . . .
168
1. Mode of Action of the Parathyroid Hormone on Bone.. . . . . . . . . . . . . . . 168
2. Effects of the Parathyroid Hormone on Renal Excretion of Phosphate
and Calcium.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
171
3. The Parathyroid Hormone and Gastrointestinal Absorption of Calcium. 173
4. The Effect of the Parathyroid Hormone on Ground Substance.. . . . . . 174
5. Other Peripheral Effects of the Parathyroid Hormone.. , . , . , . , , , , . , . , 174
V. Unifying Concepts of Parathyroid Hormone Activity. . . . . . . . . . . . . . . . . . 177
177
1. A Unifying Concept at the Cellular Level.. . . . . . . . . . . . . . . . . . . . . . . . . . .
2. An Integrated Concept a t the Organ Level. . . . . . . . . . . . . . . . . . . . . . . . . .
178
VI. The Parathyroids and Calcium Homeostasis.. . . . . . . . . . . . . . . . . . . . . . . . . . .
179
1. Precursors of Parathyroid Secretion. . . . . .
...
179
2. Evocation of Parathyroid Secretion . . . . . . .
. . . . . . . . . . . . . . . . . . 180
181
3. Mechanisms of Calcium Homeostasis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4. The Parathyroids and Vitamin D . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
182
VII. Biologic Assay of the Parathyroid Hormone. . . . . . . . . . . . . . . . . . . . . . . . . . .
183
VIII. Pathologic Physiology of the Parathyroid Glands. , , . .
183
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184

I. INTRODUCTION
During the year 1960, some thirty-five years after the first preparation of
an active extract of the parathyroid glands, the chemistry and physiology of
the parathyroid hormone entered a new era. For the first time the hormone
was isolated in pure form and characterized, and small amounts were made
available for experimental purposes, supplementing the crude extracts upon
which virtually all the work on the physiologic activity of the hormone
had been based. Work with the purified hormone has already clarified some
important problems, and it may be confidently expected that other major
advances will follow.
The transition into the new era was signalized by a Symposium on
Parathyroid Research Trends, held a t Rice Institute, now Rice University,
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FRANKLIN C. MCLEAN AND ANN M. BUDY

Houston, Texas, February 343,1960, at which much of the work in progress
with the new hormone was reported. The contributions to the symposium
have been published under the title “The Parathyroids” (Roy 0. Greep
and Roy V. Talmage, eds.), and this volume includes much of the work
that will stand in the literature as distinguishing the new approach to
the chemistry and physiology of the parathyroid hormone.
This does not, however, detract from the investigations that are represented by the pre-1960 literature. The parathyroid glands were first
described by Sandstrom (1880). Gley (1891) rediscovered the external
parathyroids, and Kohn (1895) again described the internal pair. The
relationship of the glands to tetany was established by Vassale and Generali
(1896) ; thyroidectomy without protection of the parathyroids had previously led to attributing tetany to removal of the thyroid gland. The role of
the parathyroids in calcium metabolism was described by MacCallum and
Voegtlin (1909). The skeletal changes, incident to hyperparathyroidism,
although imperfectly understood, were described by von Recklinghausen
(1891), and Askanasy (1904) reported the association of a parathyroid
tumor and generalized osteitis fibrosa. Erdheim (1907) described three
cases of osteomalacia in which the parathyroid glands were hyperplastic.
Schlagenhaufer (1915) pointed out that in many cases of skeletal disease,
only one parathyroid was enlarged; this helped to establish a distinction
between primary and secondary hyperparathyroidism. The period between
1909 and 1925 was also marked by many contributions to the literature on
experimental, as well as clinical hypoparathyroidism; experimental hyperparathyroidism was not yet within reach.
The period of tentative exploration of parathyroid physiology came to
an abrupt end. Hanson (1923, 1924) and Collip (1925) independently
accomplished the successful isolation of a physiologically active extract of
the glands; Hoffheinz (1925) collected data on 45 cases in which enlargement of the parathyroid glands had been found at necropsy, including 27
cases with skeletal disease; and Mandl (1925) performed the first parathyroidectomy. Following these developments the field was actively
explored, and contributions have continued to multiply.
It is not within the scope of this review to trace the history of parathyroid
physiology in detail. The developments of the period between 1925 and
1960 may be followed with the aid of reviews and monographs that appeared during this time (Collip, 1926; Dragstedt, 1927; Thomson and
Collip, 1932; Shelling, 1935; Albright, 1941 ; Mandl, 1947; Gilmour, 1947;
Albright and Reifenstein, 1948; Greep, 1948; Black, 1953; Bartter, 1954;
Escamilla, 1954; Reifenstein and Howard, 1954; Greep and Kenny, 1955;
Howard, 1957; McLean, 1956, 1957; Tepperman and Tepperman, 1960;
Munson, 1960; Kenny, 1961a). The clinical aspects of hypoparathyroidism

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167

and hyperparathyroidism and the pathologic changes in the parathyroid
glands and in the skeleton in hyperparathyroidism, have been dealt with
at length elsewhere; they will not require attention here.
11. CHEMISTRY
OF

THE

PARATHYROID
HORMONE

Between 1925 and 1960 there were many efforts to extract and purify the
active principle of the parathyroid glands; that they were not completely
successful until recently was owing in part to the difficulties inherent in the
procedures and to the degradation of the hormonal molecule during extraction, and in part also to the need of modern instrumentation for extraction
and separation of substances in solution. Hot dilute hydrochloric acid and
hot concentrated acetic acid were used successfully for extraction of hormonal activity from minced glands, but not without damage to the molecule
(Rasmussen, 1961). Aurbach (1959a, b) developed a superior extraction
method using aqueous phenol solutions.
The isolation of the pure hormone has been achieved (Rasmussen and
Craig, 1961) by sequential phenol extraction, solvent and salt fractionation, trichloroacetic acid precipitation, and prolonged countercurrent
distribution. The hormone is a protein; consists of a single polypeptide
chain; contains no cystine; and has a single N-terminal amino acid, alanine.
The preparation obtained behaves as a single substance by paper and
column partition chromatography, ultracentrifugation, and countercurrent distribution. Its molecular weight estimated from ultracentrifugal
analysis agrees well with that calculated from its amino acid composition
and is in the range of 9500 f 100. The tentative empirical formula assigned
to the polypeptide chain is: Lysg , His4 , Arg, , Asp9 , Thrl , Sere , Glull ,
Pro2 , Gly4 , Ala7, Val8, Methz , Ileua , Leu8, Tyrl , Phez , Try, , and
(-CONH2)9 .
The hormone molecule exhibits a certain degree of instability, and this,
together with its association with other tissue components, is in large part
responsible for the difficulty encountered in its separation and purification.
It also loses biologic activity when oxidized with hydrogen peroxide,
regaining all or part of this activity when reduced with cysteine or other
reducing agents. The reversibility of this reaction is pH dependent, being
more rapid in alkaline solution. The degree to which this instability will
affect the storage of the purified hormone has not been clarified.
An unusual feature of the parathyroid hormone is that fragmentation of
the molecule may occur during acid extraction, and that the fragments
retain a portion of the biologic activity of the entire molecule. Rasmussen
(1960) has reported the isolation of a series of separate fragments, with
molecular weight,s between 3800 and 5600, and potencies of 750-1250
U.S.P. units per milligram of dry weight, as compared with a molecular

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FRANKLIN C. McLEAN AND ANN M. BUDY

weight of 9500 and a potency of 2000 units per milligram or more for the
entire molecule.
Rasmussen and Craig (1961) have also reported on the stability of the
hormone to different methods employed in extraction and purification.
Earlier preparations, initially extracted with hot 0.2 N hydrochloric acid
or with hot concentrated acetic acid, yielded biologically active fragments;
aqueous phenol extraction has given the best results. In the further processing of the material, the procedure of highest resolving power and specificity has been countercurrent distribution. For this, two solvent systems
have been employed; of these, the one giving the more successful results
is a pyridine system described by Rasmussen and Craig (1961). Even
with this system there were indications that some of the hormone was
being degraded. Further work on stabilization, both during extraction and
purification and during storage, appears to be required.

111. BIOLOGIC
ACTIVITY
OF THE PARATHYROID
HORMONE
An important feature of the recent work on purification of the parathyroid hormone has been that all purified preparations have exhibited
both calcium-mobilizing and phosphaturic activity in comparable amounts.
This, together with the evidence for homogeneity of the preparations,
affords what may be regarded as conclusive evidence to the effect that the
parathyroids elaborate one hormone only, and that this hormone is responsible for all the physiologic effects observed following its administration.
Previous efforts to account for parathyroid activity on the basis of two
hormones, one calcium-mobilizing and the other phosphaturic, are not
supported by the current findings.
Related to this is the problem of the stimulus to the parathyroid glands
controlling their output of hormone, by virtue of a negative feedback
mechanism. It has been believed by some that the concentration of organic
phosphate in the plasma exerts an influence upon the secretory activity of
the parathyroid glands; according to this view, a n increase in phosphate
concentration may lead to increased secretion of the parathyroid hormone
(Crawford et al., 1950). Such evidence for this as exists is indirect and
inconclusive; now that it is demonstrated that the parathyroids secrete
only one hormone, with both calcemic and phosphaturic activity, the case
for a second stimulus is weakened, although not excluded.
IV. PERIPHERAL
ACTIONSOF

THE

PARATHYROID
HORMONE

1. Mode of Action of the Parathyroid Hormone o n Bone

It is now conceded that bone is one of the primary targets of the biologic
activity of the parathyroid hormone. There is, therefore, no present need

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for a new review of the steps, extending over many years, by which this
agreement has been reached. There is also agreement that the hormone
exerts its influence upon cellular constituents; there is now no suggestion
that the hormone directly affects the solubility of the bone mineral in
the fluids of the body. Accordingly, the scope of this section of the review
is narrowed to a consideration of the cellular mechanisms through which
the parathyroid hormone may influence bone and, more specifically, may
affect the transfer of calcium from bone to blood. The subject currently
receiving the most attention in this connection is whether the hormone
affects bone primarily or exclusively through its control of osteoclastic
resorption of the stable fraction of bone, or whether it also affects the
transfer of labile calcium from bone to blood, acting through a n effect on
the glycolytic cycle in the cells of bone tissue.
It is believed (Neuman and Neuman, 1958) that the mineral of bone
exists in two forms, of which one is variously designated as labile, reactive,
or exchangeable, and the other as stable, nonreactive, or nonexchangeable.
The fraction of bone containing labile mineral, now estimated as less than
1%, has been referred to by Vincent and Haumont (1960) as metabolic
bone; the bone made up of stable mineral, constituting more than 99% of
the total, they call structural bone.
There is very little difference of opinion with reference to the ability of
the parathyroids to release the stable calcium of bone to the fluids of the
body, and Woods and Armstrong (1956) and Talmage et al. (1960) have
demonstrated that the parathyroid hormone has access to the stable fraction. There is also general agreement that the parathyroids, by virtue of
their ability to regulate osteoclastic resorption of bone, including its stable
fraction, are responsible for monitoring the calcium ion concentration in
the plasma and for correcting deviations from the normal.
There are, however, divergent views concerning the mechanism of
transfer of labile calcium from bone to blood. The dual mechanism, as
proposed by McLean and Urist (1955) included the assumption that labile
calcium is capable of being transferred from bone to blood by passive physicochemical means, as in an ion exchange column, and it was explicitly
stated that the contribution of this part of the dual mechanism was not
under the influence of a feedback, this term being reserved for the part of
the mechanism under the control of the parathyroid glands.
More recently Neuman and his collaborators have advanced the view
that the transfer of labile calcium from bone to blood is also under parathyroid control. As originally advanced (Neuman et al., 1956; Neuman and
Neuman, 1958) emphasis was placed on the observation first reported by
Dickens (1941) of a high concentration of citrate in bone; this was supported by direct evidence that the parathyroid hormone not only increased

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FRANKLIN C. McLEAN AND ANN M. BUDY

the citrate content of blood collected from spongy bone, but also increased
the blood content of radiostrontium administered to the animal. The
assumption then was that a cellular mechanism, under the control of the
parathyroids, regulates the transfer of calcium from bone to blood by
formation of a calcium-citrate complex. Since the originators of this hypothesis have now changed their emphasis on the sequence of events set in
motion by the parathyroid hormone (Terepka et al., 1960), we shall not
pursue the citrate hypothesis further, in spite of the numbers of publications stimulated by it, but will follow the current version of these events.
Neuman and Neuman (1958) suggest that the blood plasma, and even
the bulk of extravascular fluids in contact with bone, are not representative
of equilibrium with the crystals of the bone mineral. Instead, there is
postulated a hydrogen ion gradient between the pH at the surface of the
crystal and that in the circulating fluids; the nature of such a hypothetical
barrier or gradient has not been elucidated. MacGregor and Nordin (1960)
postulate a hydrogen ion concentration corresponding to pH 6.8 at the
surface of the crystals; Terepka et al. (1960) state that the pH in the immediate environment of the crystals must be lower than 6.8, and believe
that the gradient between this and the hydrogen ion concentration in the
circulating fluids of the body is maintained by the production of acid by
the cells of bone. Borle et al. (1960) also support the concept that the concentrations of calcium and phosphate found in the extracellular fluid are
the result of organic acid production at the bone mineral surface, chiefly as
lactate.
The physiologic significance of such a pH gradient, from the surface of
the bone mineral to the blood, would be that acid is essential for the solubilization of the mineral and for its movement from bone to blood. It is
believed that the production of acid in the glycolytic cycle is controlled
by the parathyroid hormone and by vitamin D. In support of this thesis
there is quoted a report of Cretin (1951), who states that the pH is low in
areas of resorption of bone.
While we are prepared to accept the postulate that the production of
acid in bone, including production of the citrate ion, plays a part in the
solubiliiation of the mineral, and hence its transfer from bone to blood,
we do not accept the idea that there is a pool of fluid, at pH 6.8 or below,
surrounding the crystals in process of dissolution; in fact, we regard the
concept of pH itself at the crystal surfaces as of doubtful validity. We are
prepared to believe that hydrogen ions, liberated from the glycolytic cycle,
may react with the crystal surfaces, as H+ becomes available, in such a
manner as to convert an insoluble salt of calcium and phosphate to soluble
ions. We prefer, however, to think of such a reaction as occurring in a
stepwise fashion, rather than in the presence of a pool of excess acid.

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171

As has been pointed out (Rasmussen, 1961) osteoclastic resorption of
bone, although regulated by parathyroid activity, is not under the exclusive
control of the parathyroids. Jowsey et al., (1958) studied haversian remodeling of bone in thyroparathyroidectomized dogs, and found that
while there was a decrease in the number of absorption cavities formed,
osteoclastic resorption and the consequent formation of new metabolic
bone continued. Similarly the resorption incident to remodeling and increase in length of the long bones of growing animals is not halted by
parathyroidectomy .
2. Efects of the Parathyroid Hormone on Renal Excretion of
Phosphate and Calcium

a. Renal Excretion of Phosphate. The inorganic phosphate of the plasma
is, a t least in greater part, freely filterable through the glomeruli, and a
portion of that so filtered is reabsorbed by the renal tubules; such reabsorption occurs in the first third of the proximal tubules. There is not agreement a s t o active tubular secretion of phosphate in the higher vertebrates,
believed by Nicholson and Shepherd (1959) to occur in the distal tubules;
tubular secretion occurs in the aglomerular fishes; and there is also evidence
for such secretion in the chicken and in the alligator.
That the parathyroid hormone increases the urinary output of phosphate,
and that hypoparathyroidism reduces it, is common knowledge. Albright
and Ellsworth (1929) first demonstrated the phosphaturic action of parathyroid extract in a patient with idiopathic hypoparathyroidism, and
regarded the effect of the parathyroid hormone on the serum calcium level
as secondary to the fall in the plasma concentration of phosphate. Largely
as the result of inability to resolve the uncertainty concerning tubular
secretion, it is not a t present possible to form a firm judgment as to the
manner in which parathyroid hormone influences renal transport of phosphate in higher animals. The conflicting data and opinions on this subject
have been reviewed a t length b y Lotspeich (1958, 1959), Leaf (1960), and
Bartter (1961). Nicholson (1959), a supporter of the concept of active
tubular secretion of phosphate, concludes that the site of renal action of
parathyroid hormone on phosphate excretion is in the distal tubule, and
that this action is stimulation of tubular secretion.
A source of uncertainty concerning the renal action of the parathyroid
hormone has been the occurrence of hemodynamic effects, following administration of parathyroid extract and resulting in increased renal plasma
flow and increased glomerular filtration rate. This uncertainty now appears
to have been resolved. Pullman and associates (1960) and, in another
paper, Lavender et al. (1961) have reported on the direct renal action of
purified parathyroid hormone. They administered the hormone by slow

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FRANRLIN C. McLEAN AND A N N M. BUDY

infusion into one renal artery in the dog and found in a majority of the
animals studied that the resultant phosphaturia was exclusively or preferentially unilateral. No systematic changes in renal hemodynamics or of
plasma phosphate concentration were observed during 3 4 hours of intrarenal infusion. It was concluded that the hormone acts directly on the
kidney in the dog and produces phosphaturia by depressing net tubular
reabsorption. These results appear to rule out the idea, frequently encountered
in the literature, that the effect of parathyroid hormone on the excretion
of phosphate by the kidneys is exerted by means of hemodynamic changes
in glomerular filtration.
Levinsky and Davidson (1957), utilizing the renal portal venous system
of the chicken for unilateral infusion of phosphate showed that phosphate
excretion in some periods was nearly double the filtered load of phosphate,
indicating that the tubules of the chicken kidney secrete phosphate. They
showed also, by infusion of parathyroid extract, that phosphate excretion
by the infused kidney could exceed the filtered load, thus demonstrating
unilateral increase in phosphate secretion, as influenced by the hormone.
Bartter (1961) has reviewed the evidence for renal tubular secretion of
phosphate. He accepts the evidence of Levinsky and Davidson (1957) for
such secretion by the renal tubules of the chicken, and of Hernandez and
Coulson (1956) for the alligator. He concludes, however, that tubular
secretion of phosphate has not been established for dog or man and that
with the exception of scattered, isolated data, the findings in these species
can be explained on the assumption that phosphate is filtered in the glomerulus and partially reabsorbed by the tubules.
Another source of disagreement has been the establishment of a maximal
phosphate reabsorption rate, TmP. Such a phosphate Tm appears to have
been established for man (Schiess et al., 1948) and for the dog (Pitts and
Alexander, 1944)) but not for the cat (Eggleton and Shuster, 1954). Bartter
(1961) also reported that a Tm for phosphate is readily established in the
dog and in man, phosphate reabsorption remaining constant over a wide
range of filtered phosphate load. I n man, however, Thompson and Hiatt
(1957a)b) have reported that a considerable variability in TmP often
occurs within a given experiment, and between experiments; such variations have also been observed with changes in the parathyroid status (Hiatt
and Thompson, 1957).
b. Renal Excretion of Calcium. In addition to the phosphaturic activity
of the parathyroid hormone, there is also evidence (Talmage, 1956; Buchanan et al., 1959; Buchanan, 1961; Kleeman et al., 1961) that in mice,
rats, dogs, and man, the parathyroid hormone enhances the reabsorption of
calcium by the renal tubules, while parathyroidectomy results in less tubular
reabsorption. The net effect of the parathyroid hormone on renal excretion of

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173

calcium, however, is not as striking as that on phosphate. Buchanan (1961)
also studied renal excretion of calcium in chickens, and found a n increase in
the output, in contradistinction to the results as reported on mammals.
He suggests that this difference may be related to the special problems of
calcium metabolism in the chicken in connection with the egg-laying cycle.
Horwith et al. (1961) administered purified parathyroid hormone preparations, extracted from bovine glands by acetic acid or phenol, to seven patients with hypoparathyroidism. The acetic acid preparation, designated as
PT H B, and now known to be a fragment of the total molecule, regularly
increased the glomerular filtration rate and renal flow. No data were
obtained on a possible hemodynamic effect of the product of phenol
extraction (PTH C). The conclusion was reached that highly purified
parathyroid hormone exerts effects on both calcium and phosphorus
metabolism. The effect on renal excretion of calcium observed was, however,
contrary to that reported by others in that an unexplained small but
significant increase in output of calcium by the kidneys was observed.
3. The Parathyroid Hormone and Gastrointestinal Absorption of Calcium

Contrary to earlier views, it is now proposed that the parathyroid
hormone influences the absorption of calcium in the gastrointestinal tract,
being synergistic with vitamin D in this respect. Talmage and Eliott
(1958) found that parathyroidectomy led within 2 4 hours to a significant
decrease-approximately 50 %-in the rate of absorption of radiocalcium
from a n isolated loop of the small intestine of the rat in vivo. Rasmussen
(1959), using isolated sacs of rat small intestine in vitro, showed that prior
parathyroidectomy led to a decrease in the ability of the sacs to develop
and maintain a concentration gradient of calcium between serosal and
mucosal fluid. Similar results have been reported by Dowdle et al. (1960).
Rasmussen also added parathyroid hormone B to sacs from 12 parathyroidectomized rats, with equivocal results. Cramer et al. (1961), employing
both in vivo and in vitro methods, concluded that administration of parathyroid extract increased the absorption of dietary calcium, although
their results with radiocalcium were inconclusive, and in part contradictory
of those reported by other workers. The method used by Schachter and
Rosen (1959) demonstrated the effect of vitamin D in promoting active
transport of Ca46from the mucosal to the serosal surfaces against concentration gradients; that the active transport mechanism is dependent upon
oxidative phosphorylation; and that it is a t least partially dependent on
the dietary intake of vitamin D. A similar effect of vitamin D with the
addition of the vitamin to the gut sac in vitro does not appear to have been
reported. Because of the unphysiologic conditions in the in vitro experiments,
and the inconclusive results from observations in vivo, it cannot be regarded

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FRANKLIN C. McLEAN AND ANN M. BUDY

as established that the parathyroid hormone exerts a significant influence
upon the absorption of calcium under strictly physiologic conditions.

4. The Effect of the Parathyroid Hormone on Ground Substance
There have been suggestions in the literature that peripheral effects of
the parathyroid hormone are exerted on the mucopolysaccharides of the
bone matrix, and perhaps on those of other connective tissues. Engel (1952)
observed an elevation of the seromucoid in rats after administration of
parathyroid extract and believed that this might represent liberated degraded bone matrix material. Engel and Catchpole (1953) found in rats,
under the influence of large doses of parathyroid extract, an increased
urinary excretion of mucoprotein carbohydrate, correlated in time with
dissolution of bone matrix and with an increase in plasma mucoprotein.
Engel et al. (1953) also reported increases in the urinary mucoprotein
levels, following administration of parathyroid hormone, and attributed
this to the effect of the hormone on bone. For clarification of the terminology
of the polysaccharides, the review of Kenny (1961a) should be consulted.
Shetlar et al. (1961) reject the simple hypothesis that parathyroid extract
causes a depolymerization of the bone matrix to more soluble components,
which then pass into the blood stream and into the urine. They speculate
that there may be a general effect of the hormone on mucopolysaccharides
or glycoproteins of various tissues. There is as yet, however, not sufficient
evidence to support the view that the parathyroid hormone produces an
effect common to the ground substance of all forms of connective tissue.
We have above referred to the current belief that the influence of the
parathyroid hormone on resorption of bone is mediated through its effects on
cells. Heller-Steinberg (1951) has described changes in staining reactions
around lacunae housing osteocytes, following administration of parathyroid
hormone, attributed by her to changes in the degree of polymerization of
the ground substance, and indicating beginning resorption. If her interpretations are correct, this could mean that osteocytes, as well as osteoclasts, are capable of mediating the effects of the parathyroid hormone;
this would not be surprising, in view of the close interrelationships of these
two types of cells common to bone. There appears to be no evidence in
the literature, however, for an effect of parathyroid hormone on the cells
of other forms of connective tissue.
6. Other Peripheral Effects of the Parathyroid Hormone

a. Mammary Glands. Munson (1955) reported that parathyroidectomy,
in lactating rats, resulted in an increase in the concentration of calcium in
the milk, instead of the decrease expected from intact rats on a low-calcium
diet. This observation was confirmed by Toverud and Munson (1956), with

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175

the additional information that administration of parathyroid extract, while
preventing a decrease in the serum calcium and in the water content of
the milk, did not consistently prevent the increase in the concentration of
calcium in the milk. von Berswordt-Wallrabe and Turner (1959, 1960a,b)
have studied replacement therapy in lactating thyroparathyroidectomized,
and mammogenesis in ovary-thyroparathyroidectomized rats. Under the
conditions of their experiments they found that administration of estrogens
could stimulate mammogenesis in the absence of both the thyroid and the
parathyroid glands. Successful replacement therapy in thyroparathyroidectomized lactating rats required optimal amounts of thyroxine as well as
parathyroid extract. These authors did not study the output of calcium
in the milk.
b. Salivary Glands. Because of the possibility that saliva is a physiologic
fluid that may play a role in mineral and electrolyte balance, and because of
reports that the salivary glands, in their morphology, physiology, and
pathology, are related closely to the endocrine system, Kraintz (1961) has
investigated the relationship of these glands to the parathyroids in rats.
He found that (1) removal of salivary glands did not significantly alter
serum calcium changes found after parathyroidectomy ; (2) the serum
calcium response to parathyroid extract was enhanced by the removal of
salivary glands of rats maintained on a standard laboratory diet; and (3)
the difference in response to parathyroid extract could be eliminated by
starvation during the experimental period. These findings are, as yet, not
sufficient to establish a specific physiologic interrelationship between the
salivary and the parathyroid glands.
c. Mineral Metabolism. In addition to the effects of the parathyroid
hormone on the metabolism of calcium and phosphate, which have been
most explored, attention has also been directed to other elements and ions.
Bronner (1961), for example, has studied the metabolism of sulfate in rats,
with special attention to its interrelations with calcium and to the bearing
of the isotope studies on the response of the constituents of bone to the
parathyroid hormone. His findings were interpreted as indicating that
(1) parathyroid extract induces bone resorption which proceeds by way of
simultaneous removal of both organic and inorganic bone constituents;
(2) parathyroid hormone increases the turnover of bone constituents,
resulting in increased accumulation of both Ca4Sand S36in the bone ends;
and (3) the most recently deposited bone mineral is the first to be removed
when resorption is increased as a result of parathyroid action.
Although the role of citrate in transfer of calcium from bone to blood is
now discounted (Terepka et al., 1960), there is interest in the production,
metabolism, and physiologic significance of citrate in bone, and especially
in the influence of the parathyroids on the behavior of citrate. Freeman

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FRANKLIN C. McLEAN AND ANN M. BUDY

et al. (1961) have studied the relation of citrate to calcium metabolism,
centering their attention largely on the elevation in plasma citrate following
nephrectomy ; parathyroid extract produced a marked decrease in this
response in male rats, but had less effect in females. Kenny (1961b) studied
citric acid production in resorbing bone in tissue culture, and found that
increased oxygen tension led to an accumulation of citrate. Krane et al.
(1961) studied citric acid metabolism in slices and homogenates of cortical
bone, but made no observations on the influence of theparathyroid hormone.
Lekan and associates (1960) reported on the conversion of C14-labeled
sodium pyruvate to citrate in metaphyseal bone slices from normal rabbits
and from a group in which bone resorption was produced by parathyroid
extract. Under the influence of the hormone there was approximately twice
as much radioactive citrate present. These are random samples from a
rapidly accumulating literature on citrate metabolism; this deserves a
thorough analysis, independently of such connections as can be established
between citrate and parathyroid hormone or vitamin D.
Greenwald (1960) has called attention to observations on the excretion of
sodium, potassium, and chloride, following parathyroidectomy in dogs,
and has shown that retention of these elements may far exceed the change
in the urinary excretion of phosphate; this is in agreement with observations to the effect that administration of parathyroid extract increases the
excretion of these substances.
d. Enzymatic Activities. Neuman et al. (1956) reported that parathyroid
extract had been shown spectrophotometrically to destroy the chromophoric
group (340 mp) of coenzyme I1 (triphosphopyridine nucleotide, TPN) in
uitro, rendering it practically nonabsorbent. Neuman and Neuman (1958)
interpreted this to mean that the parathyroid hormone, in vivo, could
block the pentose shunt in the glycolytic cycle and could also inhibit the
utilization of isocitrate in the Krebs cycle; the net effect would be an accumulation of acids, including pyruvic, lactic, oxalacetic, citric, isocitric,
and aconitic acids. The physiologic significance of the original observation,
in vitro and without cellular intervention, remains to be established. Martin
and associates subsequently (1958) confirmed the report of the interaction
between coenzyme I1 and crude extracts of the hormone, but reported also
that there was evidence that the agent affecting the coenzyme was separable
from the calcium-mobilizing principle. Spratt and Ho (1960) were unable
to demonstrate an effect of parathyroid extract on the metabolic pathway
of glucose.
Majno et al. (1951) demonstrated a marked increase in the proteolytic
activity of the serum, under the influence of the parathyroid hormone,
with a pH optimum of 2.5-1.8. Tessari (1960) made comparisons of the
glutamic-oxalacetic transaminase (GOT) activity of metaphyseal segments

THE PARATHYROID HORMONE

177

of the tibias of parathyroid-treated rats with those of controls; GOT activity was found to be significantly increased. It was concluded that
parathyroid hormone exerts a marked influence on protein metabolism
a t the transaminase step, and that this may be related to the resorpt,ion of
bone.
It is quite probable that the parathyroid hormone influences a variety
of enzymatic activities. Caution must be exercised, however, in interpreting
results obtained in vitro with crude extracts of the parathyroid glands.
e. Distribution of Plasma Calcium. McLean et al. (1935), using the frogheart method for estimation of Ca++ concentrations, found that the
McLean-Hastings (1935) mass-law equation was valid in cats over the
entire range from the hypocalcemia following thyroparathyroidectomy to
the maximum hypercalcemia following administration of parathyroid
extract. They concluded further that the changes in the state of the serum
calcium under these conditions were simply the quantitative changes predicted by the mass-law relationship, there being no evidence of a qualitative
change in its state. This conclusion has now been challenged by Lloyd
and Rose (1958) and by Fanconi and Rose (1958). Using a murexide method
for estimation of Ca++ concentrations in ultrafiltrates of serum, they report
that the ratio Ca++:total Ca is increased in hyperparathyroidism, indicating
that the plasma protein in the hyperparathyroid state has less affinity
for calcium than in the normal or hypoparathyroid state.
Breen and Freeman (1961) fractionated plasma calcium into proteinbound and free fractions in normal, hypoparathyroid, and hyperparathyroid dogs, and in normal and hypoparathyroid rats by means of a n
ultracentrifuge. They found a greater proportion of diffusible plasma calcium
in normal and hyperparathyroid animals than in the hypoparathyroid
state, but they found also that recalcification of hypoparathyroid dog serum
in vitro by adding calcium chloride, without diluting the plasma and while
maintaining the normal pH and COz tension of the plasma, gave a calcium
distribution similar to that observed in the animals with hyperparathyroidism. Although they raise some questions concerning the mass-law equation,
as usually expressed, they found no evidence that parathyroid extract
induces qualitative changes in the plasma proteins leading to changes in
the affinity for calcium.

V. UNIFYINGCONCEPTSOF PARATHYROID
HORMONE
ACTIVITY
1. A Unifying Concept at the Cellular Level

Neuman and Dowse (1961) and in another version, Terepka et al. (1960)
have presented a summary of their unifying concept of the physiologic
activities of the parathyroid hormone. Their conclusion is that all aspects

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FRANKLIN C. MCLEAN AND ANN M. BUDY

of parathyroid physiology can a t present be explained in terms of the
hormone’s postulated ability to enhance the transport of inorganic phosphate into and across cells (accompanied in part by calcium) with a n
associated increase in acid production through glycolysis. This concept
attempts to bring together all the peripheral actions of the parathyroid
hormone, in biochemical terms, a t the cellular level.
As applied to bone, their working hypothesis is that phosphate, a n
important intracellular ion, is intimately concerned with transport as well
as metabolism, and that it may be the key to the mechanism of calcium
metabolism. They find, in contradistinction to the classic Pasteur effect,
that bone cells continue to produce lactic acid in the presence of 0 2 ,and
that the effect of parathyroid hormone seems to involve a reversal of the
Pasteur effect, in that the hormone increases lactic acid production in the
presence of O2. They attribute this action of the parathyroid hormone to
phosphate transfer into the cells of bone, and believe that the production
of acid, which they regard as essential to the transfer of calcium from bone
to blood, is a secondary but vital consequence of the hormonal control of
phosphate transfer.
As applied to the kidney, they accept the postulate that following
glomerular filtration, most or all of the filtered phosphate is reabsorbed in
the renal tubules, and that, further down the tubule, phosphate ion is resecreted. I n accord with their own concept, the parathyroid hormone should
increase both phosphate reabsorption and secretion; calcium reabsorption
should also be increased in the upper part of the tubule and affected only
slightly in the distal tubule, where phosphate is being secreted. The net
effect should be increased renal clearance of phosphate and decreased
clearance of calcium.
As applied to the intestine, their postulate is that phosphate must be
required for the transfer of calcium across the gut wall. By their experimental approach to this problem, using aluminum hydroxide gel to prevent
absorption of phosphate, they reach the conclusion that with no free
phosphate in the lumen of the intestine, the entire calcium intake, plus
some of the calcium secreted into the intestine, is found in the feces.
2. An Integrated Concept at the Organ Level

Rasmussen (1961) has also proposed an integrated concept of the mechanism of action of the parathyroid hormone, but on the organ rather than the
cellular level. He points out that calcium homeostasis is the resultant of
the influence of the hormone upon at least four sites, namely the bones,
kidneys, gastrointestinal tract, and lactating mammary glands. I n each
case the effects are such as to increase the Ca++ activity in the plasma,
and in addition the renal effect decreases the HPO4- - activity in the plasma,

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179

thus exerting a n additional, but indirect, effect tending also to increase
the Ca++ activity. He emphasizes that the renal regulator is rapid to respond and sensitive to small changes in hormone concentration, but of
limited capacity, while the bone regulator is slow to respond, insensitive,
but of nearly unlimited capacity. I n this scheme neither kidney nor bone
is considered the primary site of action; the integration of the response of
the two effector organs gives the organism a greater degree of control than
would be the case with either one alone. The responses of the gastrointestinal
tract and of other organs have not been included in the scheme, owing to the
lack of sufficient quantitative data.

VI. THEPARATHYROIDS
AND CALCIUM
HOMEOSTASIS
Whatever may be the mechanisms of the peripheral actions of the parathyroid hormone, there can be no doubt that the primary function of the
parathyroid glands is the homeostatic control of the calcium ion concentration in the circulating fluids of the body. This results in the maintenance of a relatively constant level of these ions in the blood plasma,
in spite of their extraordinarily rapid movement into and out of the blood.
Current estimates are that one out of four calcium ions leaves the blood of
adult man every minute, while the exchange in a young animal may amount
to as much as 100% of the serum calcium per minute.
Such self-regulating mechanisms as are represented by the parathyroids
have acquired t,he designation of feedback; information concerning the
output is fed back to an earlier stage, so as to influence its action and hence
to change the output itself. Such a feedback mechanism, as represented
by the control of retention of sodium in the organism, characteristically
includes an information center, coupled with a chain of command, which
then leads to the corrections that must be carried out to maintain homeostasis. Calcium homeostasis appears t o constitute a special case, in that,
so far a s is known, the parathyroid glands act as their own information
center, without participation of the central nervous system, the adenohypophysis, or the adrenal cortex (McLean, 1960).
1. Precursors of Parathyroid Secretion

Davis and Enders (1961) have reviewed the evidence obtained from
both light and electron microscope studies of the parathyroid glands for
identification of the intracellular antecedents of the parathyroid hormone,
and have added their own observations. They describe cytoplasmic inclusions in parathyroid cells, as observed with the electron microscope,
similar t o those described by others in the adenohypophysis, the thyroid,
and the exocrine pancreas, in which groups of Golgi membranes have
been found surrounded by numerous secretory droplets in what appear

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FRANKLIN C. McLEAN A N D A N N M. BUDY

to be formative stages. These droplets consist of smooth envelopes enclosing
an electron-opaque substance, and the number of such droplets, in the
other glands named, has been found to depend upon experimental stimulation. The cytoplasmic inclusions in the parathyroid glands are intimately
associated with the Golgi complex, and the numbers of these particles were
greatly increased in rapidly secreting cells of nephrectomized animals.
Thus both morphologic and behavioral characteristics suggest that these
inclusions represent the intracellular precursor of the parathyroid hormone.
There is so far no satisfactory method of identifying the secretory material
by means of the light microscope.

2. Evocation of Parathyroid Secretion
The chief, and perhaps the only stimulus to secretion of the parathyroid
hormone is a lowered calcium ion concentration in the blood plasma. This
conclusion rests mainly on the observations of Patt and Luckhardt (1942),
who demonstrated an increase in parathyroid activity in decalcified plasma
perfused through the thyroid-parathyroid apparatus of dogs. Talmage and
Toft (1961) have reinvestigated the problem of the control of parathyroid
secretion, after having pointed out that while very few hold to the possibility of a specific hypophyseal hormone, similar to thyrotropic hormone,
which might control the parathyroids, other factors, such as circulating
phosphate levels, changes in magnesium levels, or a hormone produced in
the central nervous system (such as that demonstrated for aldosterone) had
not been ruled out. I n their own experiments, Talmage and Toft adopted
the osteoclast count in the femur, made under standardized conditions,
as an index of parathyroid activity. By a study of the changes in this index
following nephrectomy and during experiments utilizing their method of
peritoneal lavage, in which the calcium and phosphate concentrations in
the lavage fluids were varied, they arrived a t the conclusion that it is the
calcium level, and riot the phosphate level in the plasma, that results in
changes in the physiologic activity of t,he parathyroid glands.
Older work by Tornblom (1949) and by Engfeldt (1950), has demonstrated that the anterior pituitary exerts an effect made manifest by increase
in the phosphate and decrease in the calcium concentration of the plasma,
but both agree that this is not transmitted through the parathyroid glands.
Engfeldt reports that adrenalectomy brings about elevation of the blood
phosphate level; that the parathyroids of adrenalectomized animals present
pictures suggesting overactivity ; and that the parathyroids of rats with
experimental pancreatic diabetes are distinctly enlarged. Tornblom lists
approximately 50 observations upon the effects of hypophysectomy and
of administration of pituitary extract upon the parathyroids, as well as upon
serum calcium and serum phosphate, concluding that the effect of the

THE PARATHYROID HORMONE

181

pituitary upon the serum calcium and phosphate is direct, and that any
possible effect on the parathyroids is secondary. He recalls the older literature on parathyroid hyperplasia in acromegaly, and in Cushing’s syndrome,
and again interprets this as a reaction of the parathyroids to the increase
in the plasma phosphate by an overactivity of the hypophyseal-adrenocortical system.
Crawford and associates (1950), among others, have postulated that
hyperphosphatemia per se stimulates increased parathyroid activity. Although the literature on this subject is still confused, there seems to be
no reason a t present, especially in view of the demonstration of a single
parathyroid hormone, to assume that the parathyroids are directly concerned in the homeostasis of the phosphate concentration in the plasma.
Nor does there seem to be any evidence for a parathyrotropic factor, in
the ordinary sense, in the anterior lobe of the pituitary. The recent successful demonstration of a complex mechanism, originating in the midbrain, for the control of the retention of sodium, acting through a glomerulotropic hormone and aldosterone secretion by the adrenal cortex, does
suggest however, that some central control for parathyroid activity may
be present. That such a control, if present, operates through humoral, rather
than nervous pathways, is suggested by the maintenance of parathyroid
activity by transplants of the glands (Chang, 1951).
3. Mechanisms of Calcium Homeostasis

With removal of the parathyroid glands the calcium in the plasma falls
rapidly to a concentration of approximately 7 mg. %, as contrasted with
the normal of 10 mg. %, and is held a t the new level for a n indefinite period.
It is thus evident that there is a mechanism for the control of the serum
calcium level that operates independently of the parathyroid glands.
Because of this McLean and Urist (1955) found it necessary to postulate a
dual mechanism for calcium homeostasis, one part of which is independent
of the parathyroid glands, while the second part is mediated by parathyroid
activity. This proposal has found support from the experiments of Woods
and Armstrong (1956), Talmage et al. (1960), Copp et al. (1960, 1961),
and others. Sanderson and associates (1960) have also described calcium
and phosphorus homeostasis in the parathyroidectomized dog, and conclude that a secondary mechanism, reacting more sluggishly, is revealed
when the parathyroids are removed.
After removal of the parathyroid glands, and in spite of the fall in the
serum calcium level, the transfer of calcium ions between bone and blood
continues a t a rapid rate. This is demonstrated in the experiments of Copp
et al. and of Talmage et al., above referred to, from which it is clear that
the parathyroidectomized animal is able to restore calcium to plasma,

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FRANKLIN C. McLEAN AND ANN M. BUDY

depleted of this element, a t a rate corresponding to that observed in the
normal animal, and that in both instances the source of calcium returned
to the blood is from the skeleton. A striking feature of these observations is
that the level attained in the plasma by transfer of calcium from the skeleton
corresponds to the level characteristic of the state of the animal before
depletion; i.e., in the absence of the parathyroid glands the serum calcium
will not rise above the level characteristic of parathyroidectomy.

4. The Parathyroids and Vitamin D
It has been indicated above that vitamin D plays a part in the homeostatic control of the calcium ion concentration in the blood; the mechanism of this action has not been fully clarified.
Vitamin D exerts an influence on the citrate content of bone; this effect
has been attributed to more rapid conversion of pyruvate to citrate in the
tricarboxylic acid cycle. Vitamin D elevates the citrate content; vitamin
D deficiency reduces it. Until recently it was postulated that production of
citrate was a n important factor in the transfer of calcium from bone t o
blood, and that parathyroid hormone and vitamin D, although acting at
different points in the glycolytic cycle, were synergistic in this respect (Neuman and Neuman, 1958). Now that the emphasis has been shifted to acid
production in bone, and especially to lactic and pyruvic acids, and since
acid production occurs before vitamin D is believed to exert its influence on
glycolysis and citrate production, the possible role of vitamin D is less clear.
This does not deny an effect of vitamin D on mobilization of bone
mineral; there is much evidence for such an effect, even a t low dosage
levels (Carlsson, 1952; Bauer et al., 1955). It has been suggested that this
action of vitamin D is essential to calcium homeostasis, and that the
maintenance of blood levels as high as 7 mg. % in the absence of the parathyroid glands depends upon this action. It was demonstrated as early as
1930, however (Jones et al., 1930; Jones, 1934)) that both dogs and rats
can survive in the absence of both vitamin D and the parathyroid glands.
There is no evidence that vitamin D liberates H+ in glycolysis. For the
present, although we accept the evidence for mobilization of calcium under
the influence of vitamin D, the details of such an action remain obscure.
The weight of current evidence is to the effect that the actions of the
parathyroid hormone and of vitamin D are complementary, or synergistic,
in regulating calcium homeostasis. It appears, however, that the organism,
when deprived of both, is still able to maintain levels of Ca++ compatible
with life. I n this connection the observation of Harrison et al. (1958) to
the effect that vitamin D-deficient rats fail to respond to parathyroid extract,
unless primed with vitamin D, provides additional evidence for a synergistic action of the hormone and the vitamin.

THE PARATHYROID HORMONE

VII. BIOLOGIC
ASSAYOF

183

PARATHYROID
HORMONE
According to Munson (1961), only two methods are currently in extensive use for the biologic assay of the parathyroid hormone. The official
U.S.P. method is based on the serum calcium of the intact dog 18 hours
after subcutaneous injection of the hormone preparation. The second
method, as described by Munson (1961) is based on the serum calcium of
young rats, 6 hours after parathyroidectomy and subcutaneous injection
of the extract containing parathyroid activity. Clark et al. (1960) describe
a new method using intact rats injected with radiocalcium a t least 40 days
previously; the assay is based on the ability of the hormone to mobilize
Ca45from the stable fraction of the bone. Among other methods proposed
for biologic assay, dependent upon the calcemic activity of the hormone,
is that of Davies et al. (1954), who also used parathyroidectomized rats.
Since present evidence supports the thesis that the phosphaturic activity
of the parathyroid hormone is induced by the same active principle governing calcemic activity, there would no longer seem to be a necessity for a
separate bioassay, based on the effect on renal excretion of phosphorus.
Such methods are, however, available. Davies et al. (1955) described a
method using saline-loaded mice, based on the increase in the rate of
urine phosphate excretion during 345 hours after injection of the material
containing parathyroid activity. Kenny and Munson (1959) propose
another method based on the increased urinary excretion of inorganic
phosphate by 2-month-old male rats during the first G hours after parathyroidectomy .
THE

VIII. PATHOLOGIC
PHYSIOLOGY
OF THE PARATHYROID
GLANDS
Until purification of the parathyroid hormone was achieved, it was not
possible to study chronic experimental hyperparathyroidism in animals,
owing to the resistance to parathyroid extract developed after a few days’
administration. The same limitation has also prevented continued replacement therapy with parathyroid extract in patients with hypoparathyroidism.
There is now reason to believe that the end of these difficulties is in sight.
Observation of the physiologic activity of parathyroid extract in animals
has for the most part been limited to experiments of short duration,
conducted with manifestly toxic doses. Consequently extrapolation of the
results to physiologic conditions has been of limited validity.
McLean (1961) has reviewed the unsolved problems of parathyroid
physiology and has pointed out some of the directions that future work,
especially with the purified hormone, may take. In the same volume, in a
section on Parathyroid Dysfunction in Man, Black (1961) has reviewed the
pathology and surgery of the parathyroid glands; Yendt and Jaworski
(1961) have reported on the relationship of urinary phosphate changes to

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FRANKLIN C. MCLEAN AND ANN M. BUDY

parathyroid activity; and Howard (1961) has described the clinical picture
of hyperparathyroidism. Fraser (1960) has reviewed such clinical tests of
parathyroid function as have been proposed, concluding that estimation of
serum calcium levels is still the best initial screening test in suspected cases
of hyperparathyroidism.
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