The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 4 1562-1567
Copyright © 2001 by The Endocrine Society
Basal, Pulsatile, Entropic, and 24-Hour Rhythmic Features of Secondary Hyperprolactinemia Due to Functional Pituitary Stalk Disconnection Mimic Tumoral (Primary) Hyperprolactinemia
Ronald Groote Veldman,
Marijke Frölich,
Steve M. Pincus,
Johannes D. Veldhuis and
Ferdinand Roelfsema
Department of Endocrinology and Metabolic Diseases (R.G.V., F.R.),
Leiden University Medical Center, 2333AA Leiden, The Netherlands;
Department of Clinical Chemistry (M.F.), Leiden University Medical
Center, 2333AA Leiden, The Netherlands; Guilford (S.M.P.), Connecticut
06437; and Division of Endocrinology and Metabolism (J.D.V.), Center
for Biomathematical Technology, General Clinical Research Center,
Department of Internal Medicine, University of Virginia Health Sciences
Center, Charlottesville, Virginia 22908
Address all correspondence and requests for reprints to: Dr. F. Roelfsema, Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Albinusdreef 2, 2333AA Leiden, The Netherlands. E-mail: F.Roelfsema{at}umail.leidenuniv.nl
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Abstract
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Under physiological conditions, PRL secretion is regulated precisely by
various stimulating and inhibiting factors. Hyperprolactinemia may
arise as a primary consequence of a PRL-secreting pituitary adenoma.
Secondary hyperprolactinemia (SH) may emerge in patients with
hypothalamic disease, hypophyseal stalk compression, or suprasellar
extension of a (nonlactotrope) pituitary adenoma. The latter may
reflect diminished delivery of dopamine or other inhibitory factors to
normal lactotropes. We hypothesized that diurnal and ultradian rhythms
of PRL secretion would differ in secondary (e.g.
hypothalamic) and primary (e.g. tumoral states)
hyperprolactinemia (PH), assuming that the underlying pathophysiologies
differ. To test this clinical postulate, we investigated the patterns
of 24-h PRL release in eight patients with SH associated with
functional hypothalamo-pituitary disconnection and in eight patients
with PH attributable to microprolactinoma. Data in each group were
compared with values in healthy gender-matched controls. PRL time
series were obtained by repetitive 10-min blood sampling, followed by
high- precision immunofluorometric assay. PRL concentration
profiles were analyzed by the complementary tools of model-free
discrete peak detection, waveform-independent deconvolution analysis,
cosinor regression, and the approximate entropy metric to quantitate
pulsatile, basal, 24-h rhythmic, and pattern-dependent (entropic) PRL
secretion.
Patients with tumoral hyperprolactinemia (PH) showed a 2-fold higher
24-h mean serum PRL concentration than patients with SH (62 ± 13
µg /L vs. 30 ± 6.9 µg/L, respectively,
P = 0.029). Estimated PRL pulse frequency (events/24 h)
was similar in the two patient groups (18.5 ± 0.7 vs.
17.6 ± 0.8; P = 0.395) but elevated over that in
euprolactinemic controls (P < 0.0001 for both).
Deconvolution analysis disclosed a mean daily PRL secretion rate of
790 ± 170 µg in PH patients vs. 380 ± 85 µg
in SH patients (P = 0.030). Nonpulsatile PRL secretion
comprised nearly 70% of total secretion in both patient groups and
50% in controls (P < 0.0001). Cosinor analysis
revealed similar acrophases in all three study cohorts. The mean
skewness of the statistical distribution of the individual PRL sample
secretory rates was reduced, compared with controls (P
< 10 -5 for each), but
equivalent in SH and PH patients (0.83 ± 0.12 vs.
0.78 ± 0.08, respectively), denoting a loss of the normal
spectrum of low- and higher-amplitude secretion rates. Approximate
entropy, a regularity statistic, was markedly elevated in both patient
groups over controls (P < 10
-6 for each) and was
slightly higher in PH patients than in SH patients (1.639 ± 0.029
vs. 1.482 ± 0.067, P = 0.048).
In summary, patterns of PRL secretion in PH and SH states exhibit an
equivalently increased frequency of PRL pulses, a comparably marked
rise in nonpulsatile (basal) PRL secretion. Despite overlap, the
regularity of PRL release patterns is disrupted even more
profoundly in PH (tumoral), compared with SH. Assuming that the
orderliness of serial PRL output monitors normal integration within a
feedback-controlled neurohormone axis, then the more disorderly
patterns of tumoral PRL secretion point to greater regulatory
disruption in PH. The latter may reflect abnormal secretory behavior
associated with lactotrope neoplastic transformation and/or isolation
of the tumor cell mass from normal hypothalamic controls.
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Introduction
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PRL SECRETION is regulated by a composite
of stimulatory and inhibitory factors derived from the hypothalamus
(e.g. dopamine), the systemic circulation (e.g.
estradiol), and the pituitary gland itself (e.g. autocrine
and paracrine signals). Implicitly, the foregoing ensemble of effectors
governs the orderly, physiologically pulsatile, and 24-h rhythmic
secretion of PRL (1). Hyperprolactinemia emerges in
several physiological states (such as pregnancy and lactation) and in
diverse pathophysiological contexts, including stress, uremia,
treatment with dopaminergic antagonists, prolactinomas, and various
lesions that interfere with the transport of hypothalamic factors
regulating PRL release. For example, infiltrative or destructive
hypothalamic processes and interruption of the pituitary stalk can
diminish the availability of dopamine to the pituitary gland and elicit
secondary hyperprolactinemia (SH), presumptively associated with
otherwise normal lactotropes (2, 3, 4). Conversely, tumoral
or primary hyperprolactinemia (PH) is driven by autonomous PRL
secretion, which (by analogy with other neuroendocrine tumors) would be
expected to show distinctive dysregulation of pulsatile, 24-h rhythmic,
and/or entropic (pattern-dependent) output (5, 6, 7, 8, 9, 10).
The present study tests the latter prediction by comparing ultradian,
nyctohemeral (diurnal), and entropic features of PRL release in
patients with PH and SH.
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Subjects and Methods
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Subjects
The patient cohort comprised eight individuals with SH (four men
and four women; mean age, 46 yr; range, 3266 yr) and eight with PH
(mean age, 35 yr; range, 2443 yr). The diagnosis of SH required
sustained hyperprolactinemia unassociated with renal or hepatic
disease, drug use, primary hypothyroidism, undue stress, pregnancy, or
lactation. Clinically, a nonsecretory pituitary tumor (below) with
suprasellar extension was demonstrated by magnetic resonance imaging
(MRI) (seven patients), or primary hypothalamic disease was present
(one patient). Immunohistochemical investigation of the adenoma was
possible in six patients, two of whom exhibited no hormone staining,
and four exhibited FSH ß-subunit staining. None showed detectable PRL
immunoreactivity. One patient received nonsurgical treatment with
quinagolide, which normalized PRL but did not decrease the suprasellar
extension, as observed by yearly MRI scans over 6 yr (11).
Thyroxin levels were in the low-normal range in five SH patients with
an adenoma, and subnormal in two others, who were subsequently
substituted with T4 before the sampling studies
were performed. A delayed response of TSH to iv TRH administration was
found in all six investigated patients. Testosterone levels were
decreased in two male patients, and serum estradiol was low in one
premenopausal woman. Delayed LH increase to GnRH was present in all
subjects. In two other patients, GH and ACTH (cortisol) responses to
insulin-induced hypoglycemia and GHRH and CRH were both investigated.
In these subjects, the GH and ACTH responses to hypoglycemia were
subnormal, in contrast to the normal increase of these hormones to
direct pituitary stimulation. One of these subjects subsequently
received hydrocortisone substitution.
The diagnosis of PH required secondary amenorrhea, galactorrhea,
elevated serum PRL concentration, and a MRI diagnostic of a pituitary
microadenoma (i.e. tumor diameter less than 1 cm). Three
patients underwent adenomectomy and immunohistochemistry confirmation
of tumoral PRL. Staining was negative for ACTH, GH, TSH, intact
gonadotropins, and their subunits. In the group of SH patients, 2 women
were receiving stable estrogen replacement, and 3 men had received
hydrocortisone substitution. Two PH patients with secondary amenorrhea
were taking estrogen before the correct diagnosis of prolactinoma was
made. Twelve healthy men and 15 healthy women (mean age, 43 yr; range,
2177 yr) with normal body mass indexes served as controls for
comparison with the SH patients (SH controls), and 15 women in this
group (mean age, 45 yr; range, 2177 yr) served as controls for PH
patients (PH controls). Premenopausal controls were studied in the
follicular phase of the menstrual cycle.
In SH patients, sampling studies were generally carried out shortly
before surgery; and in PH patients, before dopaminergic drug therapy
was started. An indwelling iv cannula was inserted in a forearm vein,
60 min before sampling began, and blood samples were withdrawn at
10-min intervals, starting at 0900 h, for the next 24 h.
Subjects were free to ambulate but not to sleep during the daytime.
Meals were served at 0800, 1230, and 1730 h. Lights were turned
off between 2200 and 2400 h. No electroencephalogram sleep
recording was performed. Plasma samples were collected on ice in
heparinized tubes and centrifuged at 4 C and stored at -20 C until
assay. Informed consent was obtained from all the patients, as approved
by the ethical committee of the Leiden University Medical Center.
Assays
Plasma PRL concentrations were measured in duplicate with a
sensitive and precise time-resolved fluoroimmunoassay (Wallac, Inc. Oy, Turku, Finland). The standards were calibrated against
the World Health Organization 3rd International Standard for PRL 84/500
(to convert µg/L to mU/L, multiply by 36). The limit of detection
(defined as 2 SDs above the mean zero standard) was 0.04
µg/L. The intraassay coefficient of variation varied from 2.03.3%,
in the assay range from 3.080 µg/L, with a corresponding interassay
coefficient of variation of 3.46.2%. All samples from one individual
were run in the same batch.
Analytical techniques
Pulsatile PRL release was quantitated by discrete peak
detection, using the Cluster program. Criteria included a 2'2 cluster
size to test for significant upstrokes and downstrokes in the data (two
samples in both the test nadir and in the test peak) and critical t
statistics of 2.0 for both an increase and decrease to constrain the
false-positive rate to less than 5% on signal-free noise (12, 13). The following peak features were quantitated: the total
number of PRL concentration peaks per 24 h, peak duration (min),
maximal peak height (highest PRL concentration attained in the peak),
incremental peak height (amplitude) above preceding nadir, incremental
peak area, and interpulse valley and nadir PRL concentrations.
A waveform-independent deconvolution technique (Pulse) was used to
estimate sample PRL secretion rates without model assumptions
(14, 15). To this end, the two-component half-life for PRL
was recalculated, by nonlinear regression, using the original data set
in healthy controls of Sievertsen et al. (16).
The half-life of the fast component was 18.4 ± 4.0 min; and that
of the slow component, 139 ± 25 min. The fractional contribution
of the slow component to the overall decay amplitude was 49.5 ±
15%. The following secretory measures were estimated: basal (no
significant variation in consecutive sample secretion rates), pulsatile
(nonzero secretion flanked by successive positive and negative first
derivative changes at P < 0.05), and total (basal plus
pulsatile) daily secretion rates.
Cosinor analysis was performed to quantitate the diurnal variation of
plasma PRL concentrations in our patients. The following parameters
were calculated: mesor (mean value around which the 24-h oscillation
occurs), amplitude (one-half the difference between the highest and
lowest value), and the acrophase (time of maximum concentration).
The irregularity of serial hormone measurements was quantitated by the
approximate entropy (ApEn) statistic using parameter choices of m
= 1 (pattern length) and r = 20% of the SD of the
individual subjects hormone concentration time-series as the
threshold (17, 18). This set of parameter choices provides
a normalized (concentration-independent) ApEn measure with high
statistical replicability, sensitivity, and validity for series of this
length.
Statistical analysis
Results are expressed as the mean ± SEM.
Derived measures were analyzed after logarithmic transformation. The
Students unpaired, two-tailed t test was used to compare
hormone concentration measures between groups. Statistical analysis was
performed with SPSS, Inc. for Windows (release 8.0;
SPSS, Inc., Chicago, IL). Differences were considered
significant for P < 0.05.
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Results
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Figure 1
illustrates 24-h plasma PRL
concentration profiles obtained by sampling blood every 10 min in one
PH patient, one SH patient, and one control subject. PRL release was
pulsatile and varied diurnally in all subjects. Cluster analysis
documented 2-fold higher PRL concentration-dependent parameters in PH
than in SH patients; viz. 24-h mean and integrated plasma
PRL concentrations, maximal peak height, incremental peak amplitude,
peak area, and interpeak valley and nadir concentrations (see Table 1
). PH patients exhibited 12-fold higher
24-h mean and integrated PRL concentrations, nadir values, and maximal
PRL peak heights and 3- to 4-fold higher incremental peak amplitudes
and peak areas than controls. SH patients maintained 7-fold higher 24-h
mean and integrated PRL concentrations, nadir concentrations, and
maximal peak heights and 2-fold increased incremental peak amplitudes
and peak areas over controls. PRL peak frequency and duration were
comparable in the two patient groups: i.e. the peak
frequency for PH and SH patients was, respectively, 18.5 ± 0.7
vs. 17.6 ± 0.8 per 24 h (P =
0.395), and peak duration was 55 ± 2.5 vs. 58 ±
3.9 min (P = 0.490). Both PRL peak frequencies exceeded
control values.

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Figure 1. Illustrative 24-h plasma PRL concentrations
measured by immunofluorometric assay in blood collected every 10 min in
one PH (tumoral) patient (top), one SH patient
(middle), and one control subject
(bottom).
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Table 1. Discrete pulse detection applied to 24-h plasma
prolactin concentration profiles in hyperprolactinemic patients and
euprolactinemic controls
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Deconvolution analysis disclosed significantly elevated daily PRL
secretion in PH (13-fold) and SH (8-fold) patients (Table 2
). Nonpulsatile (basal) PRL secretion
approximated 70% of total secretion in the two patient groups,
compared with 50% in controls (P <
10-6).
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Table 2. Deconvolution analysis of basal (nadir), pulsatile,
and total 24-h PRL secretion in patients and controls
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Cosinor analysis revealed similar acrophases and amplitudes of 24-h
rhythmic PRL release in all three study cohorts (Table 3
). The mesor was elevated in both
patient groups but higher in PH than in SH patients. The fractional
amplitude (ratio of amplitude/mesor, expressed as a percentage) was
lower in PH than SH patients, P = 0.011 (Fig. 2
).

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Figure 2. Mesor (cosine-derived) values and fractional
(%) amplitudes of the 24-h plasma PRL concentration rhythms in
patients and controls.
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The statistical distribution of individual sample secretory rates in
patients and controls was quantitated by the relative skewness of the
corresponding histograms. Skewness values were similar in PH and SH
patients (0.78 ± 0.09 vs. 0.83 ± 0.12,
respectively; P = 0.747) but less than in corresponding
controls [PH controls, 3.35 ± 0.40; SH controls, 3.61 ±
0.28; P <
10-5 for each (Figs. 3
and 4
)].
The foregoing loss of skewness in PH and SH denotes reduced secretory
rate variability about the mean in both hyperprolactinemic states,
i.e. blunting of expected occasional high and low extremes
observed in the normal subjects.

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Figure 3. Illustrative individual sample PRL secretory
rates in one PH patient (top), a SH- patient
(middle), and a control subject (bottom).
Each histogram depicts the relative distribution of 145 sample PRL
secretory rates. PH and SH patients manifest a higher mean and
reduced pulse-related (and hence, right-skewed) deviation about the
mean, compared with the control.
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Figure 4. Logarithmic distribution curves of PRL
secretory rates, in patients and controls, approximated by skewed or
Gaussian fits. Each curve reflects a fitted individual histogram of
secretion rates (see Fig. 3 ). PH and SH patients exhibit marked loss of
leftward skewness, thereby denoting loss of normal variability in
sample secretory rates.
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PRL secretion in PH patients was more irregular than that in SH
patients, as quantified by higher ApEn values (1.639 ± 0.029 and
1.482 ± 0.067, respectively, P = 0.048). ApEn
values in both patient groups were remarkably higher than those in
respective controls (PH controls, 0.813 ± 0.079; and SH controls,
0.841 ± 0.055; P <
10-6 for each). There was
complete separation between values in PH patients and controls
(Fig. 5).
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Discussion
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Very little is known about the neuroregulatory pathophysiologies
of PH and SH. To our knowledge, this is the first clinical study to
quantitate detailed distinctions between the dynamics of PH (tumoral)
and SH, and also establish substantive similarities. To this end, we
compared PRL release properties in eupituitary hyperprolactinemic
patients with PH and SH along with gender-specific controls, using a
high-precision immunofluorometric assay of 24-h plasma PRL
concentrations obtained by repetitive (10-min) blood sampling. PRL time
series were then analyzed via statistically independent, but
thematically complementary, techniques to evaluate basal, pulsatile,
24-h rhythmic and entropic (pattern-sensitive) features. Thereby, we
could identify both common and distinct alterations in PRL secretion in
the two hyperprolactinemic groups. Daily PRL secretion was elevated in
both PH and SH groups and was about 2-fold higher in the former. Both
groups maintained markedly increased basal (i.e.
nonpulsatile) and pulsatile PRL secretion, blunting of the normal
dispersion of sample secretion rates, and an elevated 24-h rhythmic
(cosine) mesor with normal acrophase. Each of the foregoing secretory
abnormalities in PH and SH also occurs in the tumoral hypersecretion
associated with aldosterenoma, acromegaly, and Cushings disease
(6, 9, 19). Indeed, the single distinguishing dynamic
between PH and SH was the more disorderly secretory pattern associated
with tumoral hyperprolactinemia.
We observed an increase in PRL pulse frequency in patients with PH and
SH. The latter finding contrasts with that of Samuels et al.
(20). The higher precision of
immunofluorometric assay (compared with immunoradiometric
assay) a more intensive sampling paradigm, and/or our choice of
gender- and age-matched controls might contribute to this difference.
Based on analogy with the GH axis, both secondary (i.e.
fasting-associated) and tumoral (e.g. acromegaly) hormone
hypersecretion can elevate secretory burst frequency, possibly because
of, respectively, withdrawal of hypothalamic somatostatin release and
tumoral autonomy (5, 19, 21, 22). Thus, it is
conceivable that SH mutes activity of a hypothalamic inhibitory factor
that normally restrains PRL pulse frequency, and/or that microadenomas
in PH sustain a relatively autonomous high-frequency of (irregular) PRL
secretory events.
Most endocrine glands signal via episodic hormone release (23, 24). Pulsatile-like hormone release is also evident in
vitro, although at accelerated pulse frequencies and reduced
amplitudes (25 27). Thus, low-frequency and
high-amplitude in vivo pulsatility likely requires intra-
and interglandular synchronization (28). Partial
preservation of normal PRL pulsatility mechanisms by microadenomas,
and/or escape from putative hypothalamic frequency restraint in SH,
could thus account for the marked overlap in their secretory
properties.
PRL secretion is regulated by an array of apparently stimulatory and
inhibitory factors. Reported agonists include TRH, vasoactive
intestinal polypeptide, GnRH, dopamine, angiotensin II, antidiuretic
hormone, and PRL-releasing peptide (29, 30). PRL-releasing
peptide is expressed in the hypothalamus and the pituitary gland,
including in PRL- (and GH-) secreting adenomas. Which of these (or
other) regulatory factors would best account for the present
observations is not clear, because dopaminergic blockade does not
accelerate PRL pulse frequency (31). Likewise, the
imperfect correlation between pulsatile PRL and TSH release would
question the primacy of TRH in driving joint PRL pulsatility
(32). To our knowledge, few data exist to define further
the precise mechanisms of putative PRL pulse-frequency control in the
human.
Both PH and SH patients maintained a normal PRL acrophase, suggesting
preserved coupling of lactotrope output to central nervous system
sleep-wake cycle and/or circadian timing systems. Our finding for PRL
is comparable with that for GH and ACTH in many, but not all, patients
with acromegaly or Cushings disease (6, 19). However,
available studies have not excluded more subtle disruption of true
circadian periodicity or phase, evaluated in the absence of
environmental time cues or with sleep-wake cycle reversal.
The ApEn statistic was used to monitor the minute-to-minute
reproducibility of PRL release patterns. This metric quantitates
nonpulsatile and noncircadian features of hormone secretion
(33). Both hyperprolactinemic groups manifested elevated
PRL ApEn, which in principle would denote loss of coordinate feedback
and/or feedforward control within the lactotropic axis. The generally
higher PRL ApEn values quantitated here in PH, than in SH, agree with
data in other tumoral or autonomous states, such as for GH in
acromegaly, ACTH in Cushings disease, and aldosterone in
aldosterenoma (5, 6, 19), as well as sustained exogenous
secretagogue drive (34, 35).
In summary, the present clinical investigation establishes certain
common neuroendocrine alterations in PH and SH; e.g.
increases in basal, pulsatile, entropic, and 24-h rhythmic PRL
secretion. In addition, we observe more prominently greater process
irregular PRL secretion patterns in tumoral PH than SH, pointing to
greater loss of coordinate neurosecretory control by the microadenoma.
Impaired secretory-pattern regulation in prolactinomas may reflect
neoplasia-associated secretory autonomy rather than any space-occupying
effect, because SH associated with larger nonsecretory tumors with
suprasellar extension does not manifest equivalent feedback
disarray.
Received July 24, 2000.
Revised October 23, 2000.
Revised December 5, 2000.
Accepted December 10, 2000.
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