Department of Medicine (III) and of Clinical Endocrinology, University Hospital "Dijkzigt", Erasmus University, Rotterdam and Department of BiologyO, The Netherlands Cancer Institute, Amsterdam, The Netherlands

THE DYNAMICS OF GROWTH HORMONE AND

PROLACTIN SECRETION IN ACROMEGALIC PATIENTS WITH "MIXED" PITUITARY TUMOURS

By Steven W.

J. Lamberts, Jan G. M. Klijn, Giok and Jan C. Birkenh\l=a"\ger

H. Kwa

ABSTRACT The dynamics of growth hormone (GH) and prolactin (PRL) secretion in response to thyrotrophin-releasing hormone (TRH) and bromocriptine were evaluated in 15 untreated and 1 previously unsuccessfully treated patients with acromegaly. In 7 of these patients elevated basal PRL levels were found. In 4 of the 7 hyperprolactinaemic patients plasma PRL concentrations followed closely the pattern of GH secretion in response to TRH (400 \g=m\g). The maximal paradoxical increment of GH in response to TRH was paralleled by a delayed PRL response, while a close relationship was observed between the suppression of the elevated GH and PRL levels in these patients after one single dose of 2.5 mg bromocriptine. In one of these patients parallel escapes of plasma GH and PRL during bromocriptine treatment were seen. In addition, a significant higher sensitivity to the GH-lowering effect of 2.5 mg bromocriptine was noted from 2 up to 8 h in these 4 patients with presumably "mixed" GH/PRL secreting pituitary adenomas, compared with the response in 9 untreated acromegalic patients with normal basal PRL levels. In the 3 acromegalic patients with slightly elevated PRL levels, no or a normal increase of PRL levels in response

Reprint requests: Dr. S. W. J. Lamberts, University Hospital "Dijkzigt", waterplein, Rotterdam, The Netherlands.

40 Moole-

was observed, while the suppressive effect of bromocriptine on plasma GH concentrations was not different from that seen in the acromegalic patients with normal PRL levels. However, as a group the 7 patients with hyperprolactinaemia showed a significantly higher GH\x=req-\ lowering effect to 2.5 mg bromocriptine than the 9 normoprolactinaemic acromegalic patients. A close relationship between the magnitude of the increment of GH in response to TRH and the decrease of plasma GH after 2.5 mg bromocriptine was present in the whole group of 16 acromegalics (P < 0.01). No such correlation was shown in the type of response of plasma GH to an oral glucose load or the coefficient of variation of basal plasma GH levels on 5 different days. It is concluded that in the population of acromegalic patients with elevated plasma PRL levels a sub-population of patients is present with "mixed" pituitary adenomas which secrete GH and PRL in a parallel

to TRH

The characteristics of the secretion of both hormones, in these be recognized as a parallel, delayed response of both horto TRH and an increased sensitivity to the suppressive effect of

manner.

patients mones

can

bromocriptine.

plasma prolactin (PRL) levels were found in 44 out of 104 untreated acromegalie patients mentioned in recent literature (Frantz et al. 1972; Sinha et al. 1973; Samaan et al. 1974; Franks et al. 1976; Wass et al. 1977). A subject of speculation has been as to whether normal or tumour cells are responsible for the hypersécrétion of PRL. The growth hormone (GH)-pro¬ ducing tumour may interfere with the transport of prolactin-inhibiting-factor (PIF), resulting in hypersécrétion of PRL by the normal lactotrophs no longer restrained by the hypothalamic PIF (Franks et al. 1976). Hyperprolactinaemia may also be caused, however, by the secretion of PRL as well as GH by pituitary adenomas (Zimmerman et al. 1974; Corenblum et al. 1976; Guyda et al. 1973). In 16 untreated acromegalie patients we investigated prospectively the basal PRL levels and the dynamics of GH and PRL secretion in response to thyrotrophin-releasing hormone (TRH) and bromocriptine. Part of this study has been reported previously (Lamberts et al. 1976). Elevated

MATERIAL AND METHODS Plasma GH levels were measured by a homologous radioimmunoassay. Inhibition curves of standard human GH were repeatedly compared with inhibition curves of patient plasma and were always found to be parallel. Plasma PRL levels were deter¬ mined according to Kwa et al. (1973); this radioimmunoassay is based on highly puri¬ fied human prolactin (iodinated with '251 and used as a reference preparation) and an antiserum induced in rats. All samples were assayed in at least 5 serial (1:2) dilutions. Results were expressed as ng/ml, one ampoule of MRC 71/222 was considered to con¬ tain the equivalent of 300 ng of highly purified PRL. No cross-reactivity of GH was

found under 150 ng/m!. Basal plasma PRL levels are normal up to 12 ng/ml in men and up to 15 ng/ml in women. The biochemical diagnosis of acromegaly was made on the basis of the absence of a suppression of plasma GH concentrations to less than 5 ng/ml in response to an oral glucose load (100 g). No medication that might account for an elevated PRL level was taken and the existence of primary hypothyroidism was excluded. Sixteen patients with active acromegaly were investigated. Twelve were male and 4 female. The mean age of the patients was 43 years with a range from 24 to 76 years (Table 1). Fifteen patients were untreated; only patient D had been treated unsuccess¬ fully 10 years before by transfrontal hypophysectomy and external pituitary irradia¬ tion. Basal plasma GH levels were investigated in all patients at least on 5 different days and the mean and standard deviation of these determinations are also shown in Table 1. In 7 patients (A-G) an elevated plasma PRL level was found, while in 6 patients (5 of those with hyperprolactinaemia) galactorrhoea was present. Patient Q had suprasellar extension of the pituitary adenoma, while in patient D a suprasellar extension was present before surgical treatment only.

Table 1. General data

Patient

M/F

Age

A

M

Ii

F

c D*

M

45 44 50 31

F

E

5.4

F

2>J 47

G II I Is 1. M N O I"

Q

M M M M M M M M M

on

71» 4S 47

33 24 32 54 36 33

16 untreated

patients with acromegaly.

Basal GH

Basal PRL

ng/ml

ng/ml

26 16 244 142

± ± ± ±

8 6 143 106

30 ± 5 30 ± 13 35 ± 20 77 33 47 69 75 44

± ± ± ± ±

±

11 ± 23 ± 80 ±

29 16 24 16 18 7 3 8 6

69 160 145 141

± ± ± ±

Galac¬ torrhoea

6 87 104 47

Suprasellar extension

H

42, 56 45 ± 16 19 ± 7

11,7 8 ± 2 6, 10 7 ± 3 5 ± 1 10 ± 3 4 ± 3 10 ± 3

3,6

Basal GH and PRL are mean ± sd of at least 5 determinations on different (Only two PRL determinations were done in patients . , and Q). *

This

patient had been

tary irradiation.

treated

unsuccessfully by hypophysectomy

and external

days. pitui¬

RESULTS

Plasma GH responses to the oral ingestion of glucose in our 16 patients with active acromegaly were investigated. In 9 patients no change in plasma GH levels followed glucose ingestion. Three patients showed a paradoxical increase of more than 50 °/o of the basal value, while in 4 patients plasma GH was sup¬ pressed to less than 50 °/o. In 15 patients the reaction of plasma GH and PRL to the administration of 400 ßg TRH was investigated. In patient -D a distinctly elevated plasma PRL concentration (65-447 ng/ml) was accompanied by galactorrhoea in pa¬ tients B, C and D. In these 4 acromegalie patients a close relationship between the secretion of GH and PRL was seen in response to the administration of TRH: a paradoxical increase of GH was accompanied by a delayed response of plasma PRL. In contrast, such a parallel response was not observed in the 3 patients with slightly elevated PRL levels (E-G) and in the patients with a normal basal plasma PRL concentration (I-Q) (Table 2).

Table 2. The reaction of

plasma GH (ng/ml) and plasma PRL (ng/ml) intravenously in 16 acromegalie patients.

GH

(ng/ml) (min)

PRL

to 400 ug TRH

Maximal increment

(ng/ml) (min)

Patient 0

A

C D

E F (i

10

20

30

60

120

82 37 26 11 175 336 360 110 54 128 163 167 147 90 265 583 750 575 353 240

26 15 71

26 19 7S

-

-

-

70 20 74

43 2(1

71

42 l'i 51

0

10

20

30

65 99 92 98 228 307 290 447 562 546 601 158 210 224 288 -

60

104 94 330 209 72.9 653 157 148

51 83 38

32 69 3.9

9 21 15 20 15 16 20 11 3 27 24 19 4 11 33 30 16 16 10 14 678/3 6 12 14 12 8 56 8 12

12 15

30 31

IS 1S

7')

18

44

Vi

89

74 27

120

26 25

ICH + 56 +345 + 96 +485

I PRL + 39 +232 +282

+130

44+3 +12 +61 1 +21 + +

-

H 1

L M N O P O

34 78 78 57 75 53 21 56 62 32 34 67 203 121 58 39 100 487 425 325 145 44 56 44 42 44 8-9 976 21 56 49 43 43 87 106 78 78 77 -

-

-

-

+ 44 + 12 9 12 +53+9 +136 + 24 11 4 17 7 +387 + 29 16 10 +12+6 74+1+7 10 4 +35+8 +19+48 4 3

Table 3. The relation between the reaction of plasma GH to one dose of 2.5 mg bromocriptine, to 400 tig TRH and to 100 g glucose in 16 acromegalie patients. Reaction to 2.5 mg

Patient

bromocriptine

At least one

plasma

GH

< 50 % of basal level

Reaction to 400 fig TRH

Mean of plasma GH 2-8 h after Maximal GH above the gift < 50 °/o > 100% basal level of basal level

Reaction to 100 g

glucose

Orally (response see text)

A li

C D

E F

G II I

Î .

d. I

+

I. M

I t

O

Q

In all 16 patients the course of plasma GH concentration was investigated for 24 h after the single oral administration of 2.5 mg bromocriptine. Twelve patients showed a lowering of at least one of the GH levels to less than 50 °/o of the basal level at 8 a. m. (Table 3). In only 9 patients the mean plasma GH concentration from 2 till 8 h after the administration was less than 50 °/o of the basal value. The response of plasma GH levels to the administration of bromocriptine in our 16 patients was compared with the response to TRH, glucose and the variability in the basal plasma GH concentration (Table 3). A homogeneity in the responses to TRH (maximum GH level more than 100% above the basal concentration) and to bromocriptine (average GH level from 2-8 h after the administration of less than 50 % of the basal concentration) was observed in 12 of the 15 patients in which this was investigated. Only in patients F,

and L was this relation not present, while in patient H the TRH-test was not done. This homogeneity in the responses of plasma GH is also reflected in the extent of the reaction: the maximal increment of plasma GH after TRH ad¬ ministration correlated significantly (/>