Archives of Gerontology and Geriatrics

35 (2002) 1–8

Age related prolactin secretion in men afterfentanyl anaesthesia

Giuseppe Aliberti a,*, Isabella Pulignano a,Angelo Schiappoli a, Leonilde Cigognetti b, Luigi Tritapepe b,

Maria Proietta a

a Dipartimento di Scienze Cliniche, Uni�ersita di Roma ‘La Sapienza’, Policlinico Umberto L,Viale del Policlinico, 00161 Rome, Italy

b Istituto di Chirurgia del Cuore e dei Grossi Vasi, Uni�ersita di Roma ‘La Sapienza’,Policlinico Umberto I, Viale del Policlinico, 00161 Rome, Italy

Received 14 May 2001; received in revised form 15 October 2001; accepted 16 October 2001

Abstract

The aim of this study was to investigate the role of age in the hormonal response to opiateanaesthetic fentanyl. In 90 patients undergoing aortocoronary bypass, 59.6�9.2 years meanage, 35–81 age range, prolactin (PRL), thyroid stimulating hormone (TSH), follicle stimulat-ing hormone (FSH), luteinizing hormone (LH), human growth hormone (HGH), insulin-likegrowth factor I (IGF I), glucagon and insulin were measured in venous blood samples drawnfrom fasting patients immediately before, at 8 h in the morning, and 60 min after theinduction of anaesthesia with 30 �g/kg intravenous fentanyl bolus, 30 min after a second 7�g/kg fentanyl bolus. Results showed a higher 60 min PRL peak in older, �65 years, inrespect to younger, �50 years, patients (57.6�23.3 vs. 40.6�13.8 �g/l, P�0.005), with asignificant upward trend with age across the entire age span (r=0.32; P�0.002), while nodifference by age was found for the basal concentrations. No differences were found betweenthe respective basal and 60 min concentrations for the other hormones investigated. Asexpected, differences by age were found for FSH, higher in �65 and in 51–65-year-oldsthan in younger patients (for the basal values, respectively, P�0.02 and P�0.05); IGF Iwas lower in �65 in respect to�50 (P�0.02) and to 51–65-year-old patients (P�0.05),with a significant negative correlation with age (r= −0.33; P�0.005). The study shows anage related increase of PRL concentrations after fentanyl administration. It may be due tothe reduction of the hypothalamic dopaminergic tone with aging. IGF I levels have been

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* Corresponding author. Fax: +39-6-499-70524.E-mail address: giuseppe.aliberti@uniroma1.it (G. Aliberti).

0167-4943/02/$ - see front matter © 2002 Published by Elsevier Science Ireland Ltd.

PII: S0167 -4943 (01 )00209 -6

G. Aliberti et al. / Arch. Gerontol. Geriatr. 35 (2002) 1–82

confirmed to be inversely correlated with age. © 2002 Published by Elsevier Science IrelandLtd.

Keywords: Fentanyl; Prolactin; Aging men; Hypophyseal hormones; Insulin-like growth factor I

1. Introduction

The mu-opiate receptor agonists are known to exert a potent stimulatory effecton prolactin (PRL) secretion (Grossman, 1988; Pan and Teo, 1989). Thus, asignificant PRL peak after opiate fentanyl anaesthesia is a common finding (Sebelet al., 1981; Salomaki et al., 1993; O’Leary et al., 1996; Reber et al., 1998), whilefor other hormones, such as the growth hormone, the secretion is found stimulatedby fentanyl at the highest dose and with marked interindividual differences (Hoeheet al., 1984, 1988) or not affected (Sebel et al., 1981; Giesecke et al., 1988).

On the other hand, age related changes have been shown in the anterior pituitarysecretion physiology as a consequence of anatomical involution in aging humans,revealed by decrease in size of the gland with increase in patchy fibrosis, vascularalterations and focal necrosis, prevalence of (micro)adenomas. Moreover, agerelated alterations in the amount or biological activity of hypothalamic hormonesor neurotransmitters acting on adenohypophysis have been described. However, thePRL secretory physiology has been variously reported in aging (Blackman et al.,1995).

The aim of this study was, therefore, to further investigate the secretory responseof some anterior pituitary hormones after fentanyl anaestesia in aging patientsundergoing surgery.

2. Patients and methods

The study was carried out, after informed consent was obtained, in 90 malepatients, 59.6�9.2 years mean age, 35–81 age range, undergoing aortocoronarybypass for atherosclerotic coronary disease. Patients with endocrine and metabolicdiseases or with renal and liver impairment were excluded, as well as patients takingmedication known to influence hormonal secretion, such as sympaticoliytic, betablocking, neuroleptics in the phenothiazine and butyrophenone classes, or antide-pressants. Moreover, no testicular atrophy, gynecomastia or galactorrhea wasrevealed by clinical observation in the patients included in the study.

The day of surgery, at 8 h in the morning, from fasting patients, peripheralvenous blood samples were drawn for basal determinations immediately before theinduction of anaesthesia with 30 �g/kg fentanyl intravenous bolus, a second 7 �g/kgfentanyl bolus was intravenously administered 30 min after the induction; 30 minafter the second bolus, 60 min after the induction, peripheral venous blood sampleswere drawn, before anaesthesia was continued and before intubation, sternotomy,heparin anticoagulation, hypothermia and extracorporeal circulation were per-

G. Aliberti et al. / Arch. Gerontol. Geriatr. 35 (2002) 1–8 3

formed. This schedule was adopted in reason of the different response time of thehormones investigated. Moreover, the time of the highest PRL response to fentanylhas been reported to be 30 min and longer for HGH (Hoehe et al., 1988). On theother hand, prolonged pharmacological stimuli have been performed in hormonalstudies (Blackman et al., 1986; Giesecke et al., 1988; Salomaki et al., 1993).

By immunoradiometric assay we measured PRL, human growth hormone(HGH), follicle stimulating hormone (FSH), luteinizing hormone (LH; BioChemImmunoSystems Italia S.p.a., Casalecchio di Reno (BO), Italy); thyroid stimulatinghormone (TSH) (Radim S.p.a., Pomezia (Rome), Italy). By radioimmunoassay wemeasured insulin (IRI), glucagon (IRG) and insulin-like growth factor I (IGF I;BioChem ImmunoSystems Italia S.p.a.).

Basal and 60 min samples from each patient were measured in the same assay runand each value was the mean of a duplicate assay. The patient population wasstudied as a whole and divided into age subgroups, �50 years (n ; 15, 45.6�4.7mean age, 35–50 age range); 51–65 years (n ; 51, 58.6�3.9 mean age); �65 years(n ; 24, 70.7�4.0 mean age, 66–81 age range). Student’s t-test for dependent andindependent samples and Pearson coefficient of linear correlation were used forstatistical analysis (STATISTICA software, Stat Soft Inc., 1993).

3. Results

Results, shown in Table 1, showed a significant increase of PRL levels 30 minafter the second fentanyl bolus, 60 min after the induction, and no significantchanges in comparison with the respective basal levels for TSH, FSH, LH, HGH,IGF I, IRG and IRI. The same was observed in the patients subdivided by age. Thecomparison between the age subgroups showed significantly higher 60 min PRLvalues in the �65 years subgroup when compared with the �50 years subgroup,while no significant difference was found between �65 and 51–65 and between51–65 and �50 years subgroups. There was no significant difference between thesubgroups for the PRL basal levels.

No significant differences between the subgroups were observed for either thebasal or 60 min values of TSH, LH, HGH, IRG and IRI. Both basal and 60 minFSH levels were significantly higher in �65 and in 51–65 in comparison with �50years subgroup; between the �65 and 51–65 years subgroups the difference wasnot significant. In�65 years old patients the basal and 60 min IGF I levels incomparison to �50 years old patients and the basal levels in comparison to 51–65years old patients were significantly lower; no differences were found for basal and60 min IGF I values between the 51–65 and �50 years subgroups.

Between the 60 min PRL concentrations and the age a 0.32 coefficient of positivelinear correlation was found (Fig. 1, P�0.002), while no significant correlationshipwas found for the basal PRL concentrations (r=0.10, NS). The basal and 60 minIGF I values showed a significant inverse correlationship with age (r= −0.33,P�0.005). No significant correlationship, instead, was found for basal and 60 minvalues of TSH, FSH, LH, GH, IRG and IRI with age.

G. Aliberti et al. / Arch. Gerontol. Geriatr. 35 (2002) 1–84

Tab

le1

Bas

alan

daf

ter

fent

anyl

adm

inis

trat

ion

valu

es(m

ean

�S.

D.)

ofth

eho

rmon

alpa

ram

eter

sin

mal

epa

tien

tsas

aw

hole

and

divi

ded

byag

esu

bgro

ups

�50

51–6

5�

65n.

r./l

Tot

al

9.80

�2.

74(n

:15

)8.

91�

4.21

(n:

51)

10.0

2�

4.17

(n:

24)

0m

inP

RL

(1.0

–20

�g)

9.35

�4.

01(n

:90

)57

.60

�23

.26*

c40

.57

�13

.79*

47.4

7�

20.8

7*49

.02

�21

.16*

60m

in1.

45�

1.31

(n:

33)

0m

in1.

78�

1.92

(n:

13)

(0.2

5–4.

0m

U)

1.48

�1.

40(n

:59

)1.

20�

1.04

(n:

13)

TSH

1.84

�1.

511.

18�

0.88

1.46

�1.

031.

50�

1.13

60m

in4.

90�

2.76

°(n

:20

)0

min

7.86

�6.

40b

(n:

10)

(1–1

4I.

U.)

5.10

�3.

49(n

:41

)2.

96�

2.12

(n:

11)

FSH

4.87

�2.

85°

60m

in7.

62�

6.31

a4.

97�

3.99

3.00

�2.

043.

84�

2.81

(n:

10)

2.41

�2.

52(n

:11

)2.

50�

1.44

(n:

20)

2.71

�2.

08(n

:41

)L

H(1

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.2I.

U.)

0m

in2.

53�

2.43

2.47

�1.

353.

22�

2.62

2.66

�1.

9760

min

1.16

�1.

71(n

:15

)H

GH

1.88

�1.

98(n

:32

)1.

80�

2.10

(n:

12)

0m

in1.

68�

2.00

(n:

59)

(0.1

–5.0

�g)

1.72

�2.

0260

min

1.05

�1.

691.

60�

1.96

1.87

�1.

9714

3.53

�41

.14

(n:

39)

0m

in11

9.60

�41

.61b

�(n

:17

)(1

44–3

60�g

)14

0.89

�44

.55

(n:

69)

160.

76�

49.8

4(n

:13

)IG

FI

120.

80�

44.5

8b16

2.12

�51

.73

143.

61�

44.2

814

1.48

�45

.61

60m

in83

.89

�52

.31

(n:

23)

IRG

0m

in(6

0–20

0ng

)81

.60

�51

.76

(n:

65)

84.7

0�

62.9

8(n

:14

)80

.48

�48

.87

(n:

28)

85.5

4�

50.8

686

.13

�63

.37

79.3

2�

�49

.21

82.4

5�

50.1

560

min

65.8

6�

49.5

0(n

:49

)0

min

62.8

5�

51.1

5(n

:29

)(1

4–17

9pm

ol)

68.2

3�

51.3

7(n

:90

)90

.47

�86

.96

(n:

12)

IRI

77.3

5�

82.3

663

.57

�42

.18

70.3

1�

44.2

667

.37

�50

.79

60m

in

S.D

.,St

anda

rdde

viat

ion;

n.r.

,no

rmal

rang

e;fe

ntan

ylsc

hedu

lede

fined

inth

ete

xt.

Val

ues

ofP

(�):

60m

invs

.ba

sal,

*=

0.00

1;�

65vs

.�

50,

a=

0.05

,b=

0.02

,c=

0.00

5;�

65vs

.51

–65,

� =0.

05;

51–6

5vs

.�

50,

°=0.

05.

G. Aliberti et al. / Arch. Gerontol. Geriatr. 35 (2002) 1–8 5

4. Discussion

This study confirms that the mu-opiate agonist fentanyl employed in anaestheticpractice exerts a relevant stimulatory effect on PRL secretion, as previouslyreported by many authors (Sebel et al., 1981; Salomaki et al., 1993; O’Leary et al.,1996; Reber et al., 1998), while TSH, FSH, LH, HGH, IGF I, IRG and IRIremained unchanged in respect to their basal levels.

The basal PRL concentrations were not significantly different in the age sub-groups and no relationship with age was demonstrated across the entire age span.This agrees with many investigators reporting no difference in PRL basal levelswith age in men (Yamaji et al., 1976; Wasada, 1978; Hossdorf and Wagner, 1980;Rolandi et al., 1982; Davidson et al., 1983; Govoni et al., 1983; Arnetz et al., 1984;Neaves et al., 1984; Giusti et al., 1992), although some authors found an increasein older age (Vekemans and Robyn, 1975; Blackman et al., 1986; Sawin et al., 1989)or a decrease (De Rivera et al., 1976). The inconsistency of these findings,consisting, however, of overall quantitatively small differences between older andyounger subjects, may be in part due to different selection criteria and to thepossible pharmacological interference in the aged subjects.

According to many authors (Corpas et al., 1993; Blackman et al., 1995), norelationship with age nor differences between the age subgroups was found for thebasal levels of TSH, LH, IRG, IRI, HGH. As expected the FSH levels were higherin the older subjects in respect to the younger subgroup with no linear correlation-ship with age, being the increase not a continuous process. Moreover, as previouslyreported (Copeland et al., 1990; Reeves et al., 2000), IGF I concentrations showed

Fig. 1. Distribution by age of individual PRL concentrations reached after fentanyl administration inmale patients (r, 0.33; P�0.002). The anaesthetic schedule is defined in the text.

G. Aliberti et al. / Arch. Gerontol. Geriatr. 35 (2002) 1–86

a significant negative linear correlation with age, attributed to decreased physicalactivity, as well as to a decrease with age of the HGH production rate or activity,that accompanies the decrease in protein synthesis and the reduction in lean bodymass.

While these hormones showed no changes, an almost fivefold increase of PRLconcentrations was documented 60 min after the fentanyl induction, 30 min afterthe second fentanyl bolus. The 60 min PRL values were significantly higher in theolder subgroup when compared with the younger subgroup and showed a signifi-cant positive linear correlation with age across the entire age span. This age relatedrise of PRL concentrations after fentanyl administration seems not to be previouslynoticed. Instead, the response of PRL to intravenous stimulation with thyrotropinreleasing hormone (TRH) has been variously reported to be delayed (Yamaji et al.,1976), augmented and delayed (Hossdorf and Wagner, 1980), unchanged (Wasada,1978) or reduced (Rolandi et al., 1982) in older men. Blackman et al. (1986)reported in healthy aging men a maximum PRL secretory response to constantinfusion of TRH that was earlier and greater in the oldest.

Since a direct pituitary site of action of opioid peptides and of opiate alkaloidsis unproved, their effect on PRL secretion has been attributed principally to adecreased release of hypothalamic dopamine into hypophyseal portal blood (Gross-man, 1988). Thus, the age related increase of the PRL response to fentanyladministration seems to agree with the commonly accepted hypothesis of a dimin-ished hypothalamic dopaminergic tone in the elderly. The reported age relateddamage to hypothalamic dopaminergic neurons and decreased hypothalamic con-tent and turnover of dopamine in aged female rats (Damarest et al., 1982; Sarkaret al., 1982), as well as the stronger inhibitory effect on PRL secretion of L-Dopain elderly subjects (Rolandi et al., 1982), support this hypothesis, although no agerelated dopamine depletion or thyrosine hydroxylase activity reduction have beendemonstrated in a limited number of hypothalami from aged humans (Robinson etal., 1977; Adolfsson et al., 1979).

On the other hand, the age related changes in PRL secretion after fentanyl doesnot seem to be due to an increase of the stored pool of PRL in aged, since thesecretory response was documented 30 min after a second fentanyl dose fullyeffective in PRL stimulation (Hoehe et al., 1988) and 60 min after the first moreconsistent bolus. Moreover, no significant age dependent changes in anteriorpituitary content of PRL, HGH and TSH and increased contents of FSH and to alesser extent of LH have been documented with cytochemical investigations and noage related alterations in numbers of PRL and HGH cells have been shown(Blackman et al., 1995). This agrees with necroscopy studies showing an ageinvariated prevalence of prolactinomas (Burrows et al., 1981), while many PRLcontaining adenomas were found do not usually secrete the hormone in older(Burrows et al., 1981; Parent et al., 1982; McComb et al., 1982). Moreover, nopatient in our study showed clinical signs or PRL values, which may suggestprolactinoma. Thus, the age related PRL response to fentanyl seems to reflect agreater stimulation of lactotropic cells to PRL synthesis and secretion with aging.With regard to this hypothesis, it has been reported that in isolated adenohypophy-

G. Aliberti et al. / Arch. Gerontol. Geriatr. 35 (2002) 1–8 7

seal cells from old female rats the PRL secretory function is increased dispropor-tionately to the PRL cell number (Chuknyiska et al., 1986).

In conclusion, fentanyl administration is accompanied by a PRL secretoryresponse that is greater in older in respect to younger subjects and shows asignificant positive correlation with age, while no modification has been found forthe other hormones investigated. It may be due to a progressive reduction of thehypothalamic dopaminergic tone with aging, resulting in an increased PRL synthe-sis and secretion per lactotropic cell in response to the pharmacological stimulus.The IGF I levels have been confirmed to be negatively correlated with age.

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