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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2005-2491
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 7 2520-2525
Copyright © 2006 by The Endocrine Society

Prolactin Deficiency Is Independently Associated with Reduced Insulin-Like Growth Factor I Status in Severely Growth Hormone-Deficient Adults

A. Mukherjee, W. D. J. Ryder, A. Jöstel and S. M. Shalet

Departments of Endocrinology (A.M., A.J., S.M.S.) and Medical Statistics (W.D.J.R.), Christie Hospital, Manchester M20 4BX, United Kingdom

Address all correspondence and requests for reprints to: Professor S. M. Shalet, Department of Endocrinology, Christie Hospital, Wilmslow Road, Manchester M20 4BX, United Kingdom. E-mail: annice.mukherjee{at}christie-tr.nwest.nhs.uk.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Background: In adult life, considerable overlap in IGF-I status exists between normal and severely GH-deficient (GHD) subjects defined by conventional dynamic testing of GH secretion. IGF-I is not therefore widely viewed as a reliable diagnostic marker for GHD. Recognized factors influencing serum IGF-I level in GHD include age, gender, timing of onset of GHD, and exogenous estrogen therapy, but these do not fully explain GH/IGF-I discordance in severe GHD. The primary structures of prolactin and GH are closely related. Effects of hypoprolactinemia are not well described in humans, but laboratory studies suggest a role for prolactin in hepatic IGF-I release, possibly through a signal transducer and activator of transcription 5 (STAT5) pathway. The purpose of this study was to evaluate a potential contribution of prolactin to IGF-I status in severely GHD adults.

Patients and Methods: Using multiple regression analysis techniques, contributions of the following variables to age-adjusted IGF-I SD scores were evaluated in 162 (85 female) GHD adults: gender, timing of onset of GHD, presence or absence of prolactin deficiency, body mass index, number of additional pituitary deficits, and underlying pathology.

Results: Childhood onset GHD (P < 0.0001) and presence of prolactin deficiency (P < 0.0001) were independently associated with reduced IGF-I status. The contributions of these parameters to IGF-I SD scores were –2.55 and –2.67, respectively. Gender (P = 0.06), body mass index (P = 0.99), number of additional pituitary deficits (P = 0.64), and underlying pathology (P = 0.06) did not significantly influence IGF-I status.

Conclusions: Prolactin deficiency is independently associated with reduced IGF-I status in hypopituitary adults. It is possible that prolactin deficiency is a surrogate for the degree of severity of GHD, implying a GHD paradigm undetected by conventional GH provocative tests; alternatively, it remains plausible that circulating prolactin contributes to IGF-I release in the absence of GH, possibly through a signal transducer and activator of transcription 5 (STAT5) pathway.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
THE REGULATION OF IGF-I secretion in adults is complex and is not solely dependent on GH status. The considerable overlap that exists for IGF-I levels between normal subjects and those with GH deficiency (GHD) supports this observation (1, 2, 3, 4, 5). This overlap remains apparent even among patients with the most severe degree of GHD identified by provocative tests of GH secretion or number of additional pituitary hormone deficits (5). Therefore, although IGF-I may be reduced in severe GHD, IGF-I is not widely viewed as a reliable marker for the diagnosis of GHD. Recognized factors influencing IGF-I status in GHD patients include age (6), gender (7, 8, 9, 10, 11, 12, 13), timing of onset of GHD (2, 14, 15), and exogenous estrogen therapy (16).

The primary structures of prolactin and GH are closely related, and genetic, structural, binding, and functional studies of these hormones have demonstrated that they belong to a unique family of proteins (17, 18, 19). Furthermore, laboratory studies have suggested a role for prolactin in hepatic IGF-I release in some animal models (20, 21). However, the interaction between GH and prolactin and their receptors appears species specific, being strong in some animal models and weak in others. To date, the vast number of biological actions of prolactin documented in laboratory studies (22) have not been reported in a human model of hypoprolactinemia, although its existence is well recognized in the context of mutations in the Pit-1 gene (23). Therefore, in the current study, we investigate the impact of hypoprolactinaemia on IGF-I status in the context of other factors known to influence IGF-I in a large series of adults with hypopituitarism.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
The study was approved by the South Manchester Local Research Ethics Committee. Severely GHD adults with baseline age-adjusted IGF-I SD scores (SDS) were identified from our database of adult hypopituitary patients under consideration for GH replacement. Those with congenital prolactin deficiency related to pituitary transcription factor gene mutations or an elevated prolactin level caused by prolactinoma, acromegaly, or drug therapy and any patient treated with a drug known to lower prolactin levels were excluded. Before entering the study, each patient underwent a general physical examination. In all patients, replacement therapy with sex steroids, T4, hydrocortisone, and 1-deamino-8-D-arginine vasopressin was optimized as appropriate and stable for at least 6 months before the establishment of the diagnosis of GHD or prolactin deficiency.

One hundred sixty-two patients (85 female, 77 male) meeting the specified criteria were included. The median age was 37.5 yr (range, 15.7–77.5 yr). Women of postmenopausal age were included. Of the 85 women in the study, 20 were aged 50 yr and older. Of these, seven were receiving oral and three transdermal estrogen, nine were receiving no hormone replacement therapy, and data were missing for one patient. Eighteen women of reproductive age were not gonadotropin deficient and were not taking exogenous estrogen; two were gonadotropin deficient with contraindications to estrogen therapy. The remaining 45 women were on estrogen therapy, 39 receiving oral and six transdermal replacement.

One hundred twelve patients in the study had primary pituitary disease, 43 had pituitary damage resulting from either primary brain tumors in the region of the hypothalamo-pituitary axis or radiotherapy for brain tumors anatomically distant from the hypothalamo-pituitary axis, and seven had pituitary damage resulting from radiotherapy for leukemia. Of those with primary pituitary disease, the commonest underlying diagnoses were nonsecreting pituitary adenoma (n = 32), Cushing’s disease (n = 21), and craniopharyngioma (n = 19). Twenty-one patients (13 females, eight males) had persistently undetectable prolactin levels. All patients were categorized as to whether they had no, one, two, or three anterior pituitary hormone deficits in addition to GHD but not including prolactin deficiency.

Diagnosis of GHD

GH status was assessed using an insulin tolerance test (ITT) (soluble insulin, 0.2 IU/kg iv), glucagon stimulation test (glucagon, 1 mg im), or arginine stimulation test (20 g/m2 arginine iv as a 20% solution infused over 30 min). In patients with childhood-onset GHD, retesting of GH reserve was performed after discontinuation of childhood GH replacement. GHD was defined as a peak GH response of less than 3 µg/liter to all stimulation tests undertaken.

One hundred thirteen patients in the study underwent an ITT. These patients also underwent a second provocative test of GH secretion if they did not have multiple pituitary hormone deficits (3). Resulting data were missing from two pan-hypopituitary patients who had undergone such testing. Forty-seven patients did not undergo an ITT generally because this was contraindicated for medical reasons. The same diagnostic approach was used in these cases; one test was deemed satisfactory in the 36 cases where an inadequate response to the test (< 3 µg/liter) occurred in the presence of multiple anterior pituitary hormone deficits. In 11 cases, the patient had no or one other anterior pituitary hormone deficit and achieved a peak GH of less than 3 µg/liter during two dynamic tests of GH reserve that were not ITTs, i.e. glucagon stimulation test or arginine stimulation test.

Diagnosis of prolactin deficiency

Prolactin deficiency was defined as a prolactin level below the limit of detection of the prolactin assay (detection limit, 1.8 ng/ml) on at least three separate occasions. The normal ranges for basal prolactin levels in females and males were 3–19 and 3–16 ng/ml, respectively.

Assays

IGF-I. IGF-I assays were performed by a hydrochloric acid-ethanol extraction RIA method using synthetic IGF-I for labeling. The assay was performed by Pharmacia (Uppsala, Sweden) until October 1997 (in-house assay), between October 1997 and November 2002 by extraction (RIA kit from Nichols Institute Diagnostics, San Juan Capistrano, CA), and thereafter by a chemiluminescence immunoassay (Nichols Advantage System; Nichols Institute Diagnostics, San Clemente, CA). The reference range of the pre-October 1997 assay was calculated using normative data from 156 healthy Swedish individuals, that between October 1997 and November 2002 was calculated using normative data from 400 healthy Swedish individuals, and the reference range of the assay after November 2002 was calculated using reference values based on the study by Brabant et al. (24).

Prolactin. Serum prolactin level was determined by a heterogeneous sandwich magnetic separation assay (Immuno 1 System; Bayer Diagnostics, Newbury, UK). The interassay coefficient of variation for a prolactin level of 4.7 ng/ml was 1.9%. The minimum detectable concentration of prolactin for this assay is 0.1 ng/ml. This is a multisystem estimate of two times the within-run SD of the zero calibrator. For prolactin levels of 1.8 ng/ml, the interassay coefficient of variation was less than 10%; below this level, reporting of absolute prolactin was not routinely provided. However, during the study, reproducibility/precision of very low prolactin levels using this assay were determined. The following were the results of two such samples: sample 1 prolactin results (ng/ml) were 0.61, 0.58, 0.58, 0.58, 0.61, 0.61, and 0.61; sample 2 prolactin results (ng/ml) were 0.11, 0.11, 0.14, 0.11, 0.11, 0.14, and 0.18.

Statistical methods

For most analyses, standard multiple regression techniques were used and F tests were employed to test parameter significance. Multiple regression analysis with IGF-I SDS as the response variable was performed on the whole cohort. Response variables included in the first regression were age of onset of pituitary disease (childhood or adult onset), gender, underlying diagnosis, number of additional anterior pituitary hormone deficits, body mass index (BMI), and prolactin status (deficient/replete) (Table 1Go). A second multiple regression analysis with IGF-I SDS as the response variable was performed on the whole cohort including absolute prolactin levels rather than prolactin status as a response variable (data not shown), and subgroup analysis was performed on 74 pan-hypopituitary cases; these patients, by various other established criteria are those with the most severe GHD, and therefore any true correlation between prolactin level and IGF-I level, independent of GH effects, would be anticipated to be most evident in this group. For data relating to absolute prolactin levels, in the patients with prolactin below the level of quantification of the assay (LOQ), the missing value was imputed as 0.5 x LOQ. A locally weighted regression (25) scatterplot smoother was used descriptively to illustrate the relationship between prolactin and IGF-I SDS in prolactin-replete cases with pan-hypopituitarism (see Fig. 2Go). All regression analyses were performed using S-PLUS software (26).


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  		TABLE 1. Multiple regression fit with IGF-I SDS as the response variable (n = 162 cases)

 

Figure 2
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  		FIG. 2. IGF-I SDS plotted against baseline prolactin in a subgroup of 74 pan-hypopituitary cases. Prolactin-deficient cases are denoted with white circles and their group mean by the short horizontal line. Prolactin replete cases are denoted with black circles along with a locally weighted regression scatterplot smoother.

 
Simple comparisons were performed using unpaired t tests for between-group comparisons and paired t tests for within-group determination of treatment effects.

As three different IGF-I assays were used during the study [Pharmacia up to October 1997 (period 1), RIA Nichols from October 1997 until November 2002 (period 2), and Nichols advantage November 2002 onward (period 3)], the ratios of prolactin-deficient/total patients in each time period were calculated as follows: period 1, five of 30 (16.7%); period 2, 14 of 109 (12.8%); and period 3, two of 23 (8.7%). The regression analysis was rerun to include a factor with all three assay-period levels in the regression model. Here the adjusted difference between prolactin-deficient/replete groups for IGF-I SDS was –2.654 (SE = 0.614; P < 0.0001) (data not shown), i.e. similar to the original analysis. Furthermore, the factor assay period was not itself significant in the model; P = 0.39.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Multiple regression analyses of 162 severely GHD adults with IGF-I as the response variable are shown in Table 1Go. Significant independent effects of age of onset of pituitary disease (P < 0.0001) and prolactin status (P < 0.0001) were demonstrated. Individual IGF-I SDS categorized by age of onset of GHD (adult vs. childhood onset) and prolactin status (deficient vs. replete) are shown in Fig. 1Go.


Figure 1
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  		FIG. 1. IGF-I SDS categorized by prolactin deficiency status and childhood-/adult-onset pituitary disease (n = 162; vertical lines denote the group means).

 
Forty-six of the 85 women in the study were receiving oral and nine transdermal estrogens, 18 had normal reproductive axis on no treatment, and 11 were gonadotropin deficient and not replaced. Estrogen replacement data were missing in one patient. IGF-I SDS was not significantly different between these four subgroups by estrogen status (P = 0.11). Furthermore, an independent contribution of gender in the regression analysis did not reach statistical significance (P = 0.06). Underlying pathology also failed to reach statistical significance (P = 0.06). BMI (P = 0.99), and number of additional pituitary hormone deficits (P = 0.64) did not contribute to IGF-I status.

No difference in median prolactin levels between the four overall classifications of hypopituitarism, i.e. GHD 0, 1, 2, and 3, was detected (P = 0.53), although clearly all prolactin-deficient cases were in categories 2 and 3 (the minority in category 2 were patients with underlying Cushing’s disease who were not ACTH deficient). Median prolactin level was not significantly different between patients with underlying cancer diagnoses, in whom GHD was predominantly caused by radiation-induced hypothalamic damage and those with primary pituitary pathology (P = 0.22).

Multiple regression analysis demonstrated no further contributory effect of absolute prolactin level on IGF-I status within the prolactin-replete group for the whole study cohort (data not shown) and in a subgroup of 74 pan-hypopituitary subjects (Table 2Go and Fig. 2Go).


View this table:
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  		TABLE 2. Multiple regression fit with IGF-I SDS as the response variable (n = 74 pan-hypopituitary cases)

 

   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
Regulation of IGF-I in adults is complex, and IGF-I status is clearly dependent on other factors in addition to GH, i.e. nutrition, thyroid status, etc. The considerable overlap between IGF-I levels in normal subjects and those with severe GHD defined by conventional dynamic testing of GH secretion reflects this complexity (1, 2, 3, 4, 5). A number of factors have been recognized to contribute to IGF-I status in GHD adults in addition to GH, the most profound and well established being the timing of onset of GHD, such that childhood-onset GHD contributes negatively to age-adjusted IGF-I SDS by as much as 2.6 SDS (15). In adult-onset GHD, although age (6), gender (7, 8, 9, 10, 11, 12, 13), and exogenous estrogen therapy (16) are factors recognized to influence IGF-I status, they do not fully explain the considerable overlap of IGF-I levels between normal and GHD individuals.

In this study, we have demonstrated that prolactin deficiency is independently associated with significantly lower IGF-I status than in prolactin-replete individuals in the context of severe GHD, to an extent equivalent to the effect of childhood-onset GHD compared with adult-onset GHD (2.6 SDS). This observation has at least two potential explanations. First, the prolactin deficiency may be an epiphenomenon, reflecting global pituitary damage and a more severe degree of GHD associated with more profound IGF-I deficiency. Alternatively, the circulating prolactin level may contribute to IGF-I generation in the absence of GH, potentially resulting in IGF-I levels that overlap with the normal range. In favor of the former argument, patients with prolactin deficiency usually have a history of ablative pituitary therapy (27). Indeed, all patients with prolactin deficiency are deficient in all anterior pituitary hormones, an observation that itself predicts the presence of a severe degree of GHD (3, 28, 29). Although this hypothesis is tenable, counterarguments exist. As already indicated, IGF-I status in GHD is clearly influenced by factors such as gender and age of onset of pituitary disease, independent of GH status and extent of hypopituitarism (3). Discordance between GH status and IGF-I levels in GHD adults with multiple pituitary hormone deficits, a marker of severity of pituitary disease, is well recognized (5). Indeed, other factors being equal, the number of additional anterior pituitary deficits, although clearly reflecting severity of GHD by conventional standards, did not influence IGF-I status in our study, whereas prolactin deficiency did.

The suggestion that prolactin may contribute to IGF-I generation, in the context of absent or severely diminished GH secretion, is also a plausible possibility. The considerable structural homology between GH and prolactin and their respective receptors suggests that they may originate from one ancestral gene, and the two hormones share some important functional properties (22). The signal transducer and activator of transcription STAT5 is activated by multiple hormones including GH and prolactin in different biological contexts, and STAT5 may represent part of a common pathway by which different extracellular signals converge and are transduced intracellularly to regulate cell function. Prolactin may not be biologically important in nonmammary tissue in the presence of normal GH levels, but we hypothesize that it may become relevant in the context of GH secretory failure by, for instance, producing biological effects in relation to IGF-I production. Thus, in the presence of severe GHD and prolactin deficiency, a double hit on IGF-I production may occur, resulting in a greater IGF-I deficit than that occurring in hypopituitary adults with normal or raised prolactin. Indeed, limited animal data include reports of prolactin contributing to IGF-I release (20, 21, 30, 31). However, the comparison between human and various animal models must be performed with caution because of the very strong species-specific interaction between the lactotrope and somatotrope system in animals. This is particularly important for the interaction between GH, prolactin, and their receptors, which is very strong in some animal models and weak in others.

Our results demonstrating no firm correlation between the actual prolactin level and IGF-I levels in the pan-hypopituitary subgroup do not exclude the possibility of prolactin contributing to IGF-I release; the effects of very high circulating levels of prolactin on IGF-I have not been fully evaluated in our study because of the exclusion criteria of patients with prolactinoma and acromegaly. Patients therefore generally had prolactin levels that were within the normal range or mildly elevated. To determine whether a positive contributory effect of prolactin on IGF-I exists would require a study of GHD adults that included patients with very high prolactin levels. In 1981, Clemmons et al. (32) described the ability of prolactin to raise levels of somatomedin C in hypopituitary adults. This study included patients with very high prolactin levels, and a strong correlation was demonstrated between prolactin and somatomedin C in GHD adults (32). Nonetheless, from existing data, it would appear that if a positive effect of a raised prolactin level on IGF-I status exists, it is likely to be modest.

The prolactin receptor has a wide distribution, and prolactin has been shown to have more than 300 separate actions in various vertebrate species (22). Inhibition of pituitary-derived prolactin is commonplace in the treatment of prolactinoma with dopamine agonist therapy. Recently, there has been interest in the development of a prolactin receptor antagonist, which could be used therapeutically to target autocrine prolactin production with the aim of reducing growth-promoting actions in breast cancer (33). This concept of global prolactin inhibition is unprecedented in humans and symbolizes a potential new modality of targeting breast cancer; the potential benefit may be real, but the effects of inducing profound prolactin deficiency in tissues other than the breast need due consideration. In relation to the latter, many questions remain unanswered, such as whether prolactin deficiency in this context will result in perturbation of IGF-I status or other homeostatic processes related to prolactin status, in the absence of pituitary disease, and whether a particular phenotype will emerge in adults with normal GH/pituitary status treated with such therapy. These issues need to be considered and more comprehensively explored as more powerful prolactin-lowering therapies become more widely used in humans.

This study demonstrates that prolactin deficiency is independently associated with reduced IGF-I status in severely GHD adults. The observation adds to our understanding of the complexity of the relationship between GH and IGF-I in GHD adults. The prolactin deficiency may simply be a surrogate for the degree of severity of the GHD, implying a GHD paradigm undetected by conventional GH provocative tests or, alternatively, that pituitary prolactin contributes to IGF-I generation in the absence of GH. The correct explanation for the observation needs to be identified by additional studies as more powerful pharmacological tools to either lower the prolactin level, or its biological activity, enter clinical practice.


   Footnotes
 
First Published Online April 18, 2006

Abbreviations: BMI, Body mass index; GHD, GH deficiency or deficient; ITT, insulin tolerance test; SDS, SD score.

Received November 15, 2005.

Accepted April 6, 2006.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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