Pituitary effects of somatostatin

Pituitary Effects of Somatostatin

Reginald Hall, M. Snow, M. Scanlon, B. Mora. and A. Gomez-Pan

OMATOSTATIN S (SRIF) has been shown to have a variety of effects on pituitary hormone secretion. Studies with SRIF may be divided into three

categories: pharmacologic, pathologic, and physiologic. In pharmacologic studies SRIF is given by intravenous infusion to normal

volunteers and circulating levels of pituitary hormones are measured, usually by radioimmunoassay. Conclusions drawn from such an approach may not reflect the physiologic situation since SRIF is administered into the systemic venous circula-

tion, usually in large doses, whereas it is likely that normally much smaller amounts of SRIF reach the pituitary via the portal venous circulation or reach other areas in the hypothalamus by axonal flow or local diffusion. Again, incuba- tion of pituitary fragments in vitro with SRIF is a highly artificial situation for measurement of hormone in the gland or medium.

In pathologic studies infusions of SRIF are given to patients with a variety of pituitary diseases. Tumor tissue may well respond in an abnormal way, and SRIF and other hormone receptors on tumor cells may differ from those on normal pituitary cells.

Physiologic studies bearing on the role of SRIF in hypothalamiccpituitary function in normal man are difficult to perform. It is not possible to measure SRIF in the portal venous circulation, and assays of peripheral levels of SRIF are subject to methodologic problems. One ingenious approach has been devised by Ferland et al.’ and Tanjasiri et al.‘These workers either incubated rat pituitary tissue with

antibodies to SRIF or infused the antiserum into rats and observed the effects on pituitary hormone secretion. In the event of a role of SRIF in the physiologic control of growth hormone (GH) and thyrotropin (TSH) secretion the antiserum should neutralize endogenous SRIF and lead to an increase in the plasma or medium levels of these two hormones. The release of both GH and TSH in these ex- periments lends strong support to the view that SRIF exerts a physiologic effect in the control of GH and TSH secretion in the rat. Unfortunately, it is not possible to carry out similar studies in man, but if pharmacologic methods can be developed to inhibit or stimulate endogenous secretion of SRIF, similar information might be obtained.

ACTIONS OF SRIF ON GH

The initial report of the biologic effects of SRIF showed that it inhibited the secretion of GH from cultured pituitary cells.” Subsequent studies have demonstrated that SRIF is a very powerful suppressor of GH secretion in vitro and in vivo in animals and man. It blocks the GH response to exercise,l insulin-

From the Endocrine Unit, Department of Medicine, Royal Victoria Infirmary. Newcastle upon Tyne. England.

Address reprint requests to Dr. Reginald Hall, Endocrine Unir, Department OJ Medicine, Royal Victoria Infirmary. Newcastle upon Tyne. England.

~9 1978 b.v Grune & Stratton, Inc. 0026-0495/78/27/3-0025$01.00/O

Metabolism, Vol. 27, No. 9. Suppl. 1 (September). 1978 1257

1258 HALL ET AL

induced hypoglycemia,” L-dopa,” arginine,‘.’ sodium pentobarbital,” electrical stimulation of the ventromedial and basolateral amygdaloid nuclei of the hypothalamus, I” isoprenaline and chlorpromazine,” dibutyryl CAMP,” and hyperthermia.“’ It also inhibits episodic GH surges during the alert” and sleep states.‘“.“’ Probably because of the low basal circulating level of GH, no effect of

SRIF on basal levels of this hormone in normal man have been demonstrated thus far,“. ii

SRIF lowers the elevated circulating GH levels observed in patients with liver and renal failure.‘” The plasma disappearance half-time in these patients was not different from that seen in normal subjects, indicating that the high GH levels found in these patients result from hypersecretion rather than impaired clearance. Similar conclusions have been reached in patients with protein-calorie malnutrition. “’

Elevated GH levels in patients with acromegaly can be suppressed by SRIF.“.‘“.” The minimum effective infusion rate is I .3 pg/min. Prolonged SRIF infusions (28 hr) suppress GH, insulin, and glucagon secretion in acromegalic patients and prevent both spontaneous GH surges and those occurring in response to feeding.” It appears that secretion of the monomeric form of circulating GH is preferentially blocked by SRIF.“” The GH response to thyrotropin-releasing hormone (TRH) frequently seen in patients with acromegaly can be effectively inhibited by SRIF.”

The effects of SRIF on GH levels in acromegaly are short lived and after an intravenous infusion levels remain suppressed for only about 30 min.“.“’ The effects of single intravenous, intramuscular, or subcutaneous injections of SRIF last for about I hr but can be prolonged by mixing SRIF with arachis oil or protamine zinc.‘)” Deletion of the N-terminal dipeptide (Ala’ Gly’) and acylation of the third moiety in the molecule of SRIF [Des (Ala’-Gly”) N-acetyl-somatostatin] has been reported to produce greater biologic activity and prolonged action in rats.‘” On testing this analogue both in the N-acetyl and N-benzoyl form in man, we could not find any prolongation of action.“’

The usefulness of SRlF as a therapeutic agent in acromegaly is limited by its short duration of action and its multiple effects on other systems. It would be necessary to find an analogue with prolonged action and preferential GH-sup- pressive activity before its therapeutic potential could be realized in acromegalic patients. Ferland et al.” studied the effects of 6 SRIF analogues on GH release in the rat. They found that Tyr,’ D-Ala,’ N-acetyl-Cys;’ and N-benzoyl-Cys”deriva- tives had identical activity to the parent peptide, while D-Lys,’ des-amino,’ and des-carboxyl” had 10% of the activity of the native hormone. D-Trp’-SRIF is 6 8 times more potent than SRIF in the suppression of GH, insulin, and glucagon in rats. Other SRIF analogues are currently being studied. GH may regulate its own secretion via a short-loop positive-feedback action on hypothalamic SRIF. In support of this, Baker and Yen” found that hypophysectomy reduced the amount of immunoreactive SRIF in the median eminence of rats. Further direct evidence for such a mechanism is still required. As mentioned previously, evidence of a physiologic role for SRIF in the control of GH release in animals has come from the use of antibodies to SRIF. Animals infused with such antibodies show an elevation of basal GH levels and an impaired stress-induced fall in GH.“’

PITUITARY EFFECTS 1259

ACTIONS OF SRIF ON THE GONADOTROPINS

Basal secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) is not affected by SRIF,“.” nor is the response to gonadotropin-releasing hormone.” However, the small elevation in FSH levels induced by TRH in man is inhibited by SRIF.,5 This suggests that the mechanisms whereby TRH releases TSH and FSH are closely related, but independent of that controlling prolactin release. It seems unlikely that SRIF plays any physiologic role in the control of gonadotropin secretion.

ACTIONS OF SRIF ON CORTICOTROPIN (ACTH) AND CORTISOL

ACTH secretion is unaffected by SRIF in normal subjects” both basally and in response to insulin-induced hypoglycemia. However, Tyrrel et al.“” have demonstrated a significant fall in the elevated ACTH levels in four patients with Nelson’s syndrome and in one patient with pituitary-driven Cushing’s disease in response to SRIF infusions. These results suggest that the mechanism determining release of ACTH by adenoma cells differs from that in normal pituitary cells. SRIF has also been reported to lower ACTH where basal levels are elevated due to suboptimal cortisol replacement or Addison’s disease.“‘.“2 In the study by Fehm et al ‘x’ however, suppression of ACTH was only partial under the conditions usedi’and hormone levels never reached the normal range. ACTH hypersecretion in primary adrenal insufficiency appears to be less susceptible to the action of SRIF; the changes noted were slight and could have been due to other factors

such as episodic secretion. SRIF did not inhibit cortisol secretion from a ma- lignant adrenal tumor causing Cushing’s syndrome. It seems unlikely that SRIF is involved in normal ACTH secretion in man.

ACTIONS OF SRIF ON PROLACTIN

Studies of the action of SRIF on prolactin in man and animals in vivo have been conflicting, possibly because different experimental designs were used and, since prolactin is a stress hormone, basal levels tend to fall spontaneously after the stress of cannulation.

SRIF was reported to have no effect on either basal prolactin levels or their response to insulin-induced hypoglycemia or TRH.“.‘.“” The rise in serum prolactin induced by arginine infusion in man was not affected by SRIF, nor was the decrease in prolactin levels induced by L-dopa.” It has been reported that

SRIF suppresses prolactin secretion from rat pituitary cells in vitro,“’ and there have also been reports of SRIF inhibition of prolactin release in patients with acromegaly”’ and in normal subjects.“” We have not observed this in our patients with acromegaly”” or the carcinoid syndrome.

ACTIONS OF SRIF ON TSH

Recent evidence suggests that SRIF may have a physiologic inhibitory control over TSH release in animals. Elevation of basal TSH levels and enhancement of both cold-induced TSH release’ and TRH-induced TSH release”” have been described following administration of SRIF antiserum to rats. There is no such direct evidence in man, although SRIF infusion suppresses the TSH response to

1260 HALL ET AL

TRH in a dose-dependent, noncompetitive fashion in euthyroid subjects”.‘.“,‘.,” and in patients with primary hypothyroidism:“‘,“” The dissociation of the TSH and prolactin responses to TRH by SRIF suggests different mechanisms for the release of TSH and prolactin, only the former being affected by SRIF. The degree of inhibition of the TRH-induced TSH release in hypothyroidism depends on the dose of SRIF used; it is appreciably greater at an infusion rate of 13.3 pg/min

than at 1.3 pg/min. This observation contrasts with the inhibition of GH in acromegaly, where infusions of SRIF at these doses are equally effective. The

effect of SRIF on basal TSH secretion in normal men is difficult to elucidate due to the technical problem of assay sensitivity in the normal range. However, Weeke

et al.“!’ have clearly demonstrated suppression of the nocturnal elevation in basal TSH levels using SRIF infusions. Similarly, the elevated basal TSH levels in patients with primary hypothyroidism are suppressed by SRIF infusion over several hours.“.“”

Reschini et al.“’ have described a man with hyperthyroidism who had elevated plasma levels of TSH, triiodothyronine (T,+), and thyroxine (T,) and evidence of a pituitary tumor. TRH did not produce any alteration in circulating TSH levels and administration of T.<, 60 /*g/day, for 10 days caused only a slight reduction in basal TSH levels. SRIF infusion at a dose of 2.5 pg/min for 60 min (after an initial bolus of 50 pg) produced a fall in TSH levels which lasted throughout the infusion and was followed by a rebound after termination of the infusion. This suggests that the thyrotrophs still possessed receptors sensitive to SRIF. The lack of TSH response to TRH may have reflected primary overproduction of TRH, although this possi- bility must obviously remain speculative in the absence of any direct measurement

of TRH. A reciprocal relationship between GH and TSH secretion in man has been ap-

preciated for some time, although its precise nature remains obscure. It has been postulated that GH may induce the synthesis and release of SRIF via a short-loop positive feedback, and that the increased endogenous levels of SRIF would in turn suppress both GH and TSH release. In this context it is interesting that Lippe et al.” described six children with idiopathic GH deficiency who became hypothyroid

during treatment with exogenous GH. They showed a decline in growth rate associated with clinical and biochemical hypothyroidism. In four of the six children, the TSH response to TRH was either absent or reduced. The hypothyroidism was reversible on cessation of GH treatment. On the other hand, Illig et al.” reported slightly elevated basal TSH levels in six patients with idiopathic GH deficiency who were also clinically hypothyroid. The nature of this apparent inverse relationship between GH and TSH production demands further critical study in a variety of pathologic and pharmacologic situations. The above finding also implies that the hypothalamic regulatory factors involved may have a role in determining the biologic activity of the TSH that is secreted.

CONCLUSIONS

From the data summarized above, it seems likely that in the rat, and possibly in man, SRIF plays a role in the physiologic control of GH and TSH secretion, although further evidence is required to confirm this view. The effects of SRIF on other pituitary hormones in pharmacologic and pathologic situations seem unlikely to have physiologic relevance. The role of SRIF excess in causing idiopathic

PITUITARY EFFECTS 1261

deficiencies of GH and TSH and of SRIF deficiency in causing acromegaly and

TSH-secreting pituitary tumors is entirely speculative until direct measurements of SRIF become available, although studies using centrally acting drugs and animal models could provide valuable information. Finally, it has not yet been possible to define a positive therapeutic role for SRIF since its effects are short- lasting and complex. The production of more selective analogues with a longer duration of action that can be administered orally remains an attractive goal.

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Pituitary effects of somatostatin