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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 3 1083-1090
Copyright © 1999 by The Endocrine Society

From the Clinical Research Centers

Mechanisms Subserving the Physiological Nocturnal Relative Hypoprolactinemia of Healthy Older Men: Dual Decline in Prolactin Secretory Burst Mass and Basal Release with Preservation of Pulse Duration, Frequency, and Interpulse Interval1—A General Clinical Research Center Study

A. Iranmanesh, T. Mulligan and J. D. Veldhuis

Endocrine Section, Medical Service, Salem Veterans Affairs Medical Center (A.I.), Salem, Virginia 24153; Geriatrics Medicine, Hunter Holmes McGuire Veterans Affairs Medical Center (T.M.), Richmond, Virginia 23249; and the Division of Endocrinology, Department of Internal Medicine, National Science Foundation Center for Biological Timing, University of Virginia Health Sciences Center (J.D.V.), Charlottesville, Virginia 22908

Address all correspondence and requests for reprints to: Dr. Johannes D. Veldhuis, Division of Endocrinology, Department of Internal Medicine, Box 202, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908. E-mail: jdv{at}virginia.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Increasing age is accompanied by decrements in randomly obtained, fasting, or frequently sampled serum PRL concentrations. The precise neuroendocrine mechanisms underlying such relative hypoprolactinemia in aging are incompletely understood. In the present study, we sampled blood at 2.5-min intervals overnight in 11 young (aged 21–34 yr) and 8 older (aged 62–72 yr) healthy men for subsequent chemiluminescence-based assay of serum PRL concentrations. The mean (±SEM) serum PRL concentration was significantly reduced at 4.3 ± 0.78 µg/L in older men compared with 9.5 ± 1.2 µg/L in young volunteers (P = 0.0049). PRL concentrations correlated with serum testosterone (r = 0.473; P = 0.041), dehydroepiandrosteroen sulfate (r = + 0.455, P = 0.05), and insulin-like growth factor I (r = 0.494; P = 0.032) levels. Deconvolution analysis was used to evaluate combined pulsatile and basal modes of PRL secretion. In older men, discrete PRL secretory bursts were marked by a significantly (2.4-fold) attenuated mass of hormone secreted per burst (amount of PRL secreted per unit distribution volume), viz. 1.6 ± 0.23 (older) vs. 3.9 ± 0.57 µg/L (young; P < 0.01). In contrast, PRL secretory burst frequency, interpulse interval, and pulse duration were invariant of age. Concomitantly, basal PRL secretion was reduced by 2-fold in older subjects, namely to 0.00030 ± 0.00027 (older) vs. 0.00065 ± 0.0002 µg/L/min (young; P < 0.01). The amount of total PRL secretion that was pulsatile averaged 82 ± 5.3% in young and 99 ± 0.13% in older men (P = 0.012), indicating preferential loss of the basal mode of PRL release in aging.

Assuming that basal PRL secretion mirrors functional pituitary lactotroph cell secretory mass, whereas pulsatile PRL release reflects effective (net) intermittent hypothalamic drive to responsive lactotroph cells, then our results suggest both an attrition in lactotroph cell mass and an impoverishment of net positive hypothalamic (agonistic) input to lactotrophs in older men. Given the multiple roles of PRL reported in experimental animals (e.g. on the one hand to support immune function and adrenal androgen biosynthesis and on the other hand to activate intraprostatic growth factors), we suggest that the nocturnal relative hypoprolactinemia observed in healthy aging men may have both adaptive and maladaptive clinical implications to target tissues.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
PRL RELEASE in experimental animals is governed jointly by hypothalamic inhibitory and (putatively) stimulatory signals (1). In experimental animals and humans, PRL release is both episodic (pulsatile, ultradian) and circadian/nyctohemeral (2, 3, 4, 5, 6, 7). Recent clinical studies indicate that a basal/nonpulsatile (or constitutive) mode of PRL release also exists (8, 9). For example, within the first day of life, a physiological (relative) hyperprolactinemia is evident that is nearly time invariant (albeit dopamine suppressible) (10, 11). The basal-like mode of PRL secretion in the neonate is replaced by admixed basal and pulsatile PRL release in the adult (5, 7, 8, 9, 12, 13, 14), when 24-h variations in serum PRL concentrations also emerge. Nyctohemeral rhythms arise mechanistically from controlled variations in the amounts of pulsatile and basal PRL release, e.g. as assessed recently by waveform-independent deconvolution analysis (8).

In limited clinical studies, healthy aging appears to reduce PRL release in both men and (postmenopausal) women (15, 16, 17, 18). The relative hypoprolactinemia of aging is thematically analogous to the hyposomatotropism recognized in older individuals (somatopause), as lactotropic and somatotropic cells share an embryonic anlage and are regulated in part by common hypothalamic pathways. However, in contrast to abundant studies of the neuroendocrine mechanisms that subserve relative GH deficiency in aging (19), fewer clinical data exist to our knowledge concerning the hypothalamo-pituitary changes that engender the (physiological) age-related decline in PRL concentrations.

To evaluate the neuroendocrine mechanisms that mediate reduced PRL secretion in healthy older men, we studied young and older volunteers in the absence of confounding illness, drug ingestion, stress, acute sex-steroid changes, etc., and after the subject’s adaptation to the study unit. To capture the majority of PRL secretion, we sampled blood every 2.5 min during the hours of sleep. PRL was measured by a random access chemiluminescence-based assay, and pulsatile secretion was quantitated via deconvolution analysis to estimate the frequency, interpulse interval, amplitude, mass, and duration of underlying PRL secretory bursts (20). By applying earlier kinetic estimates of PRL disappearance in the human (9, 21), we could simultaneously evaluate the basal (nonpulsatile) and pulsatile modes of PRL production.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Clinical protocol

Eleven healthy young (aged 21–34 yr) and eight healthy older (aged 62–72 yr) men were recruited for study at the General Clinical Research Center at the University of Virginia Health Sciences Center. After providing written informed consent, each volunteer underwent 1 night of adaptation in the study unit, followed by overnight blood sampling at 2.5-min intervals. A long venous catheter was placed in a forearm vein and used to sample blood for an average of 7 h during sleep. No volunteer was receiving medications, had any illness, had undertaken recent transmeridian travel, or had any evidence by screening laboratory assessments, physical examination, or medical history of hepatic, renal, hematological, metabolic, or endocrine diseases. Baseline morning (fasting) serum concentrations of LH, FSH, PRL, GH, TSH, insulin-like growth factor I (IGF-I), T4, resin T3 binding, testosterone, and estradiol were all normal for age (22, 23, 24).

Assays

PRL was assayed in an automated, random access, chemiluminescence-based immunoassay in singlet (22) (ACS: 180, Chiron Diagnostics, Corp., Walpole, MA). Independent studies demonstrated a linear correlation between PRL measured under these circumstances and values obtained in an immunoradiometric assay (Nichols Institute Diagnostics, San Juan, Capistrano, CA; r = 0.938; P < 0.001; n = 18 pooled samples). Based on replicate sample pools, the within-assay coefficient of variation was less than 6.5%, and the between-assay coefficient of variation was less than 10% (22). All samples from an individual volunteer were analyzed together to eliminate interassay variability. Dehydroepiandrosterone sulfate (DHEA-S), testosterone, estradiol, and IGF-I were assayed by RIA using the reagents provided, respectively, by Diagnostic Products (Los Angeles, CA) and Nichols Institute Diagnostics.

Secretion analysis

Deconvolution analysis was used to estimate concurrent pulsatile and basal PRL secretion from the overnight serum PRL concentration-time series, as described previously (23, 24). Briefly, we computed basal (interpulse, nonpulsatile) PRL secretion as well as the number, duration, amplitude, mass, and interpulse interval of statistically significant (P < 0.05, by joint confidence intervals) PRL secretory bursts (20, 25). To this end, we first recalculated biexponential PRL kinetics using clinical PRL infusion data reported previously (21). This yielded a mean (±SEM) rapid phase PRL half-life of 18.4 ± 4.0 min, a slower component value of 139 ± 25 min, and a fractional amplitude of the slower component (to the total decay) of 0.495 ± 0.15 (9).

PRL secretory measures included the mass of hormone released per burst (micrograms per L, or integral of the calculated secretory event), amplitude of the PRL secretory burst (micrograms per L/min, or maximal rate of calculated PRL secretion attained within a release episode), frequency (number of events observed per sampling session), and interpulse interval (mean time in minutes separating consecutive PRL secretory bursts). Basal PRL secretory rates are expressed as micrograms of PRL secreted per unit distribution volume (liter) per min. Total PRL production represents the sum of pulsatile (mean pulse mass multiplied by PRL burst number) and basal secretory rates (mean secretory rate multiplied by total duration of the sampling interval). The percent pulsatile PRL secretion was the (percentage) ratio of observed pulsatile to total PRL release overnight (20, 25).

Statistics

Statistical comparisons were made by two-tailed unpaired Student’s t test for mean serum PRL concentrations and by Wilcoxon’s unpaired nonparametric test for deconvolution measures. P < 0.05 was construed as statistically significant. Linear regression analysis was employed to evaluate the relationship between overnight serum PRL and DHEA-S, testosterone, estradiol, or IGF-I concentrations.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
As shown in Fig. 1AGo, there was a significant contrast between mean (overnight) serum PRL concentrations (micrograms per L) in older and young men (P = 0.0049). Overnight integrated serum PRL concentrations were 3083 ± 353 in older and 1157 ± 288 µg/L·min in the young individuals (P < 0.01). Serum DHEA-S concentrations in the two age groups also were different (P = 0.0017; Fig. 1BGo). In contrast, mean serum total testosterone levels were similar in older (425 ± 48 ng/dL) and young (523 ± 40 ng/dL) men (P = NS; Fig. 1CGo).



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  		Figure 1. Serum PRL (A) and (pooled) DHEA-S (B) or total testosterone (C) concentrations determined by sampling every 2.5 min overnight in 11 young and 8 older healthy men. Separate symbols denote individual mean overnight hormone concentrations for each volunteer. The numerical values are the group mean ± SEM. P values were determined by unpaired two-tailed Student’s t testing.

 
Figure 2AGo illustrates typical overnight profiles of serum PRL concentrations in three young men and three older individuals. PRL release profiles were visually pulsatile in both age groups. Deconvolution analysis was used to quantitate overnight pulsatile and basal PRL secretion (Fig. 2BGo). This analysis delineated a marked diminution in mean PRL secretory burst mass in older volunteers. As shown in Fig. 3Go, the calculated (mean ± SEM) amount (mass) of PRL released per secretory episode per L distribution volume (micrograms per L) was reduced approximately 2.5-fold in older men, viz. 1.6 ± 0.23 (older) vs. 3.9 ± 0.57 (young; P < 0.01). Reduced PRL secretory burst mass was associated with a lower PRL secretory pulse amplitude (maximal rate of PRL secretion attained within a release episode), namely 0.30 ± 0.07 (older) vs. 0.51 ± 0.10 (young) µg/L·min. In contrast, PRL secretory burst half-duration, pulse frequency, and intersecretory burst interval were statistically indistinguishable in young and older men (Table 1Go).



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  		Figure 2. Illustrative overnight PRL release profiles in three young and three older men sampled every 2.5 min during the hours of sleep. Data are sample serum PRL concentrations (mean ± interpolated assay SD), which were determined by an automated chemiluminescence assay (see Materials and Methods). The visually evident tendency for pulsatile PRL release was quantitated by deconvolution analysis. A, Measured serum PRL concentrations with the deconvolution-predicted fits of the data (continuous curves); B, the calculated PRL secretory rates (micrograms per L/min) over time.

 


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  		Figure 3. PRL secretory burst mass in 11 young vs. 8 older men sampled overnight, as assessed by deconvolution analysis (see Materials and Methods). Data are otherwise presented as described in Fig. 1Go, except that P values were determined by the unpaired Wilcoxon (nonparametric) rank sum test.

 

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  		Table 1. Measures of prolactin secretion in healthy young and older men sampled overnight

 
Analysis of the basal (interpeak) PRL secretory rate revealed a 2-fold reduction in older individuals (P < 0.01 for young vs. older men; Fig. 4Go).



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  		Figure 4. Basal (interpulse) PRL secretory rates estimated by deconvolution analysis in 11 young and 8 older men sampled every 2.5 min overnight. Data are presented as described in Fig. 3Go.

 
Figure 5Go shows the partitioning of total (overnight) PRL secretion into its computed pulsatile and basal components in young and older men. Each measure of PRL secretion was significantly lower in older men (P = 0.0044 to P = 0.0003). The percentage of total overnight PRL secretion that was pulsatile averaged 82 ± 5.3 in young men and 99 ± 0.139 in older subjects (P = 0.012). This difference was due to a nearly complete loss of calculated basal PRL release in older volunteers.



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  		Figure 5. Bar graphs quantitating the partitioning of total (bottom) overnight PRL secretion into its pulsatile (top) and basal (middle) components in 11 young and 8 older men. Data are the mean ± SEM.

 
Figure 6Go presents the positive linear correlations between overnight serum PRL and DHEA-S (r = 0.455; P = 0.05), IGF-I (r = 0.494; P = 0.032), and testosterone (r = 0.473; P = 0.041) concentrations in the group of 19 men studied here.



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  		Figure 6. Linear regression analyses of the relationships between (mean) serum PRL and DHEA-S (A), IGF-I (B), or total testosterone (C) concentrations. Data represent a combined analysis of 11 young (+) and 8 older men (•) sampled every 2.5 min overnight.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
One physiological concomitant of human aging is a significant decrement in circulating PRL concentrations in men and women. This clinical feature of aging contrasts with a striking proclivity for hyperprolactinemia in the older rodent (1, 2, 15, 16, 17, 26, 27). Indeed, in the aging rat, elevated PRL secretion in male and female animals can be accompanied by pituitary lactotroph-cell hyperplasia and/or adenoma formation (28). On the other hand, available studies in humans demonstrate that serum PRL concentrations tend to fall with age, e.g. in older men and estrogen-unreplaced postmenopausal women (15, 16, 18). Other changes in the PRL axis may coexist with this relative hypoprolactinemia in human aging. For example, PRL-derived amyloid accumulates in the aging human pituitary gland (29), and PRL-binding sites in the choroid plexus, hippocampus, and hypothalamus decrease in older individuals (27, 30). Moreover, the bioactivity of circulating PRL may falls in elderly men and postmenopausal (vs. premenopausal) women (15, 16). A comparable quantitative reduction in PRL secretion is recognized in critically ill individuals (31) as well as in patients with poorly controlled type I diabetes mellitus (12). Here, we have evaluated the specific neuroendocrine mechanisms that underlie the physiological, age-related, relative diminution in PRL secretion in healthy older unmedicated men by the 3-fold strategy of intensive (every 2.5 min) overnight blood sampling, chemiluminescence-based assay, and deconvolution-assisted pulse analysis. Overnight blood sampling at a high frequency was used to capture the time-varying outpouring of PRL during the hours of sleep. We observed that impoverished PRL secretory pulse mass and remarkedly limited basal PRL release jointly explicate the (relative) hypoprolactinemia in aging men. This age-associated decline in overnight PRL production was accompanied by parallel reductions in circulating concentrations of IGF-I (somatopause), testosterone (andropause), and DHEA-S (adrenopause).

PRL secretion is governed by multiple neurotransmitters, peptide modulators, and sex hormones (1). In relation to sex hormones, in the aging rat chronic exposure to estrogen can induce PRL-secreting adenomas and nodular lactotroph hyperplasia (26, 28). In contrast, in the human, such a pathophysiology is not evident (32). Additionally, a variety of (nonsex steroid) medications can stimulate PRL secretion acutely, whereas other pharmacological agents inhibit PRL release. Numerous other factors also modulate serum PRL concentrations, including hepatic and/or renal function. Consequently, in the present study, we adapted each study subject to the sampling protocol for 1 night to limit stress and excluded any volunteer with underlying hepatic or renal disease, receiving neuroendocrine-active medications, experiencing physical or psychological stress, or undertaking transmeridan travel. Under these conditions, we could demonstrate a sharp distinction in the amount and mode of overnight PRL release in healthy, unmediated, and unstressed older vs. young individuals.

Deconvolution analysis provided an explication of the neuroendocrine secretory mechanisms of aging-associated relative hypoprolactinemia. In particular, we observed a significant and consistent diminution in calculated PRL secretory burst mass (amount of PRL secreted per unit distribution volume/pulse) in older men. The reduction in estimated PRL burst mass was accompanied by a decline in the maximal PRL secretory rate achieved within each pulse (calculated underlying secretory event amplitude), but no abbreviation of burst duration.

The pulsatile mode of PRL secretion is presumptively driven by intermittent hypothalamic stimulatory input(s), such as TRH, and/or episodic withdrawal of brain inhibitory signals, such as dopamine (33). Studies in the experimental animal and human indicate that pulsatile PRL secretion continues prominently after pharmacological blockade of dopamine-2 receptors (34, 35, 36). Thus, the generation of a PRL pulse is probably not attributable solely to momentary withdrawal of hypothalamic dopamine. Accordingly, other pertinent inhibitors of PRL release and/or relevant hypothalamic PRL-releasing factors may play a role in initiating or coordinating episodic PRL secretion bursts (37). Either or both of these effector pathways may be altered in aging, as predicted by our finding of attenuated PRL burst mass.

Episodic PRL release is also evident in rat and primate pituitary glands in vitro, albeit at a significantly higher frequency and lower amplitude (microbursts) than those recognized in vivo (37, 38). The exact relationship, if any, between such in vitro ultradian PRL oscillations occurring every 5–12 min and the higher amplitude, less frequent (every 45–90 min), and more prolonged PRL secretory events observed in vivo in the intact animal and human is not known. One plausible hypothesis is that various hypothalamic and/or intrapituitary factors act in concert in vivo to orchestrate sustained PRL secretory bursts by synchronizing multiple, otherwise lower amplitude and brief, intrapituitary PRL secretory microbursts. We speculate that aging in the human may disrupt the robustness of such postulated lactotroph cell synchrony. In favor of this hypothesis is the tendency we observed toward greater quantifiable disorderliness (higher approximate entropy; P = 0.095) of PRL release in the older men studied here. This postulated idea would thematically complement the significantly more irregular secretory patterns reported previously for both pituitary GH and LH release in older men (39, 40).

Attenuation of PRL secretory burst mass in aging also could arise mechanistically from a decrease in lactotroph cell responsiveness to available secretagogue(s) and/or a reduction in lactotroph cell mass. Clinical data cannot yet distinguish between these possibilities. TRH’s stimulation of PRL secretion in older individual is either normal (in women) or reduced (in men) (15, 17). PRL release evoked by exercise, sleep, surgical stress, insulin-induced hypoglycemia, or dopamine antagonists often declines in older individuals (1, 4, 17). Diminished lactotroph responsiveness would suggest a primary reduction in lactotroph cell mass or secondarily reduced lactotroph cell mass due to a relatively prolonged diminution in hypothalamic PRL-releasing activity and/or a sustained excess of hypothalamic inhibitors. In favor of altered hypothalamic inputs to lactotrophs are numerous changes in brain neurotransmitter pathways that accompany healthy aging, including those in dopaminergic, serotoninergic, cholinergic, and noradrenergic systems (1, 26, 41). Alternatively, in support of a primary age-dependent attrition of lactotroph cell mass is the 2-fold lower basal PRL secretory rate observed here in older men. The basal rate of hormone release is presumptively a measure of the constitutive secretory capacity of the endocrine gland and, hence, putatively mirrors active secretory cell mass [e.g. in parathyroid-gland hyperplasia, acromegaly, etc. (42, 43, 44)].

The clinical implications of relative hypoprolactinemia in healthy aging men are not known. Among other experimental considerations, PRL may serve as a protective factor against stress (45). In addition, pharmacological suppression of PRL release for several weeks in young men decreased subsequent hCG-stimulated testosterone secretion (46). To our knowledge, no clinical studies have tested the converse hypothesis, namely that restoration of PRL secretion in older men reconstitutes the diminished Leydig cell responsiveness to LH/hCG stimulation recognized in aging (47). PRL in some animals also maintains immune function, influences sleep stage, and stimulates adrenal androgen secretion (1, 48, 49). In the last regard, serum PRL concentrations in the present study correlated positively with serum DHEA-S concentrations. However, this statistical relationship does not establish a causal linkage between relative hypoprolactinemia and reduced adrenal androgen secretion in older men. Indeed, reduced serum IGF-I and testosterone concentrations also correlated with the fall in PRL levels in aging men, suggesting a plausible 4-fold association among the somatopause, andropause, adrenopause, and "lactopause" (41).

The reduction in PRL secretion with healthy aging may alternatively serve one or more adaptive functions; for example, in the rat, PRL inhibits copulatory behavior (50) and stimulates the expression of intraprostatic IGF-I peptide and receptors as well as androgen receptors, which (in combination with others factors) probably govern overall prostatic growth (51). Clinical experiments would be required to test any (unproven) proposition of protective effects of the age-related relative hypoprolactinemia on sexual function or prostatic growth in older men.

In summary, the present studies demonstrate significant nocturnal relative hypoprolactinemia in healthy older men. Deconvolution analysis revealed selectively decreased PRL secretory burst mass and the basal PRL secretory rate. The number of PRL secretory pulses generated overnight was age invariant, which would suggest that any (putative) hypothalamo-pituitary PRL pulse-generating mechanisms are preserved in older individuals. In contrast, the aging male GnRH-LH-FSH axis is marked by an accelerated frequency of lower amplitude LH secretory bursts, and, in contradistinction to PRL, an augmentation of FSH secretory burst mass with elevated basal FSH secretion rates (52, 53, 54). Attenuated PRL secretory burst mass with aging more closely emulates the well recognized decline in GH secretory burst mass in older individuals (19, 39). Further studies of the neuropharmacology and neuroendocrinology of aging should thus be helpful in elucidating the mechanistic linkages (if any) among relative hypoprolactinemia, hyposomatotropism, reduced DHEA-S, and inappropriately restrained LH release in the aging male.


   Acknowledgments
 
We thank Patsy Craig for her skillful preparation of the manuscript; Paula P. Azimi for the deconvolution analysis, data management, and graphics; Brenda Grisso and Ginger Bauler for performance of the immunoassays; and Sandra Jackson and the expert nursing staff at the University of Virginia General Clinical Research Center for conduct of the research protocols.


   Footnotes
 
1 This work was supported in part by NIH Grant MO1-RR-00847 (to the General Clinical Research Center of the University of Virginia Health Sciences Center), Baxter Healthcare Corp. (Round Lake, IL; to J.D.V.), the NIH-supported Clinfor Data Reduction Systems, the University of Virginia Pratt Foundation and Academic Enhancement Program, the NSF Center for Biological Timing (Grant DIR89–20162), the NIH U-54 Specialized Cooperative Centers Program in Reproductive Research (HD-28934), NIA Grant AG-14799–01 (to J.D.V.), and Veterans Affairs Merit Review Research Funds (to T.M.). Back

Received August 25, 1998.

Revised November 11, 1998.

Accepted November 20, 1998.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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