J Clin Endocrinol Metab 44: 1222, 1977 EFFECT OF PROLACTIN ON PLASMA DHEA(S) Alex Vermeulen,
Edward Suy
and Robert
LEVELS Rubens
Departments of Endocrinology and Metabolism, Academic Hospital, Rijksuniversiteit, 9000 Ghent, Belgium and "psychiatric Institutes Mater Dei, Sleidinge, Belgium. ABSTRACT. Plasma DHEA and DHEA-S levels were significantly higher (P < 0.001) in women with elevated prolactin levels, due either to chronic treatment with psychotropic drugs or to a prolactinoma, than in untreated controls. This increase was also observed in 3 male patients with prolactinoma. It is suggested that this increase is the consequence of a direct effect of prolactin on the adrenal cortex and that prolactin might be responsible for the ACTH independent adrenocortical androgen secretion.
Plasma levels of dehydroepiandrosterone MATERIALS AND METHODS (DHEA) and of its sulfate(DHEA-S) show Selection of subjects important variations with age (1-4). Several groups of subjects were studBoth these steroids have mainly an ied. adrenal origin and as secretion of cor1. In two normal women with known ovutisol does not change significantly latory cycles, hormone levels were dewith age, it is improbable that these termined daily both during a control variations are secondary to variations cycle and during a cycle on treatment in ACTH secretion. This suggests that with sulpiride (Dogmatil )100 mg daily. other factors might modulate DHEA(S) 2. Hormone levels were determined in a secretion. Abraham and Maroulis(5)suggroup (n=30) of normal postmenopausal gested lack of estrogens to be responwomen selected as previously described sible for a decrease in adrenal DHEA(S) secretion in postmenopausal women; how- (3) (age 50-90 yrs), and compared to levels obtained in a group (n=10) of ever neither we ourselves(6)nor Anderpostmenopausal women selected using son and Yen(7)observed a restoration similar criteria, but treated chronof DHEA(S) levels to premenopausal valically (> 2 months) in an open psychiues after ethinylestradiol treatment atric institute for depression or defor either 14 days at a dosage of 400 mentia senilis, with either phenothiAig/day (6) or for 6 weeks at a dosage azines or butyrophenones, sometimes of 50 Aig/d (7). We considered the poscombined with tricyclic antidepressibility that prolactin might influsants in usual dosages. ence androgen secretion by the adrenal cortex and therefore we decided to 3. In order to evaluate the eventual study the influence of chronically elerole of depression or dementia senilis vated prolactin levels on plasma DHEA, itself on hormonal levels, the latter DHEA-S, androstenedione (A), estrone were determined in a small group of (El) and estradiol (E2) , as well as LH comparable patients before the start and FSH levels. of treatment. 4. Hormone levels were also obtained Submitted March 3, 1977 in 3 women and 3 men with prolactinoma without pituitary deficiencies. Supported by grant n°. 20.477 from the F.W.G.O.
1222
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RAPID COMMUNICATIONS
1223
Table I ; Hormonal plasma levels at normal and high prolactin concentration
Normal cycle (n=2) foil.ph. (LH-4/-8) in SE lut.ph. (LH+3/+7) in SE Sulpiride treat.cycle(n=2) foil.ph.(LH-4/8) lut.ph. (LH+3/+7)
Normal postm.wom.(n=30) m in age 68(52-68) SE Treat.postm.wom.(n=10) m in age 65(55-78) SE Untreat.postm.wom.(n=4) m in age 66(63-72) SE
El
E2 ng/100ml
DHEA
DHEA-S Aiq/ 100ml
95 19 159 16
313 26 331 30
77 6 81 3
10.8 1.0 11.8 0.8
127 4 166 8
372 42 435 38
107 5 119** 7
1.2 0.2 1.5 0.4 1.6 1.0
86 9 89 11 72 20
220
53
655** •91 312 42
77** 7 48 10
Prol.
LH FSH ng/ml
3.3 0.2 5.1 1.0
112 26 139 26
693 51 575 51
11.5 1.3 11.9 1.2
13.4 1.3 12.9 1.8
123** 2 137** 8
152 84 132 84
760 51 608 84
9.5 1.0 8.9 0.5
7.3 2.6 65 20 8.3 2.6
878 125 680 238 422 119
5019 456 3515 524 3718 304
3.2 0.3 4.2 0.5 3.7 0.9
A
AM
* p < 0.01; ** p < 0.001 LH -4/-8 = values during period from day 8 till day 4 before LH peak LH +3/+7 = values during period from day 3 till day 7 after LH peak Untreat.postm.wom. : postmenopausal women with either depression or dementia senilis before treatment. Methods Blood samples for hormone determinations were obtained in the fasting patients between 0800 and 1000 h. Steroid hormone levels were determined as previously described (1); DHEA-S levels were determined after solvolysis (8) by RIA of DHEA and are expressed as DHEA; LH, FSH and prolactin levels were assayed by a double antibody method using the commercial CEA-IRE-SORIN (Belgium) kits. LH and FSH levels are expressed in ng LER 907/ml; prolactin levels in ng/ml (1 mg NIH = 40 IU MRC). The correlation coefficient was calculated by the method of least squares. RESULTS AND DISCUSSION It is evident from table I that during sulpiride treatment, DHEA and DHEA-S levels were significantly higher than during the control cycle. During the latter the values observed in these 2 women (age 40 and 41 respectively)
were however lower than previously reported by us in a group of younger women (9). The increase during the treatment cycle was highly significant for DHEA-S both during the midfollicular (Pig/ 100 ml). Hence these results suggest strongly increased prolactin levels to be responsible for the increase in DHEA(S) levels. Indeed although a direct effect of the psychotropic drugs cannot be excluded with certainty, in the view of the high levels observed in prolactinoma a prolactin mediated increase seems to be the most probable mechanism. An increase in plasma levels is the consequence of either an increased blood production rate or a decreased
JCE & M • 1977 Vol 44 • No 6
metabolism (MCR). Although the latter has not been disproved for the moment, it is tempting to consider an increased secretion as the responsible mechanism. This is suggested by the increased urinary DHEA excretion recently reported by Bassi et al (10)in patients with hyperprolactinemic amenorrhea and by the increased urinary 17ketosteroid excretion reported in similar patients by Donabedian et al (11). As DHEA(S) has an almost exclusive adrenal origin, and as the increase in plasma levels was also observed in ovariectomized women with high prolactin levels, it is suggested that the increased levels are a consequence of a prolactin effect on the adrenal cortex. Specific binding sites for prolactin have been described in a variety of target organs, including the adrenals (12-14), but a physiologic in vivo effect of prolactin on the human adrenal has never been conclusively proved. Edwards et al (15) suggested that prolactin might modulate aldosterone secretion but 01gaard et al (16) on the other hand did not observe any influence of lowering prolactin levels on plasma aldosterone levels. Nevertheless Lichtenstein et al (17) observed a direct stimulating effect of prolactin on aldosterone secretion by rat adrenals. Recently Donabedian et al(ll) described 8 patients with either hyperprolactinemia and/or galactorrhea with unexplained elevation of urinary 17ketosteroids; plasma cortisol levels and 17-hydroxysteroid excretion were normal. Boyar and Hellman (18) reported a case of hvperprolactinemia with associated bilateral adrenal hyperplasia and suggested a. tropic effect of prolactin on the adrenal cortex, whereas Bassi et al (10) finally, recently reported increased plasma DHEA-S levels in patients with hyperprolactinemic amenorrhea and suggested that prolactin can stimulate secretion of some androgens by the adrenal cortex. Our results suggest a direct effect of chronically elevated prolactin levels on adrenal androgen secretion. The eventual physiological significance of
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 26 October 2015. at 22:47 For personal use only. No other uses without permission. . All rights reserved.
RAPID COMMUNICATIONS this effect, is still unclear and whether prolactin is the long sought for second adrenocorticotropic hormone, increasing specifically androgen secretion, needs further study. REFERENCES 1. Vermeulen, A. and L.Verdonck, Radioimmunoassay of 17/?-hydroxy-5«androstan-3-one, 4-androstene-3,17 dione, dehydroepiandrosterone, 17-hydroxyprogesterone and progesterone and its application to human male plasma, J Ster Biochem ]_:1, 1976. 2. Sekihara, H., N.Ohsawa and H.Ibayashi.A radioimmunoassay for serum dehydroepiandrosterone sulfate. Steroids 2£:813, 1972. 3. Vermeulen, A. The hormonal activity of the postmenopausal ovary. J Clin Endocrinol Metab 42^247, 1976. 4. Maroulis, G.B. and G.E.Abraham Ovarian and adrenal contribution to peripheral steroid levels in postmenopausal women. Obstet & Gynecol 418:150, 1976. 5. Abraham, G.E. and G.B. Maroulis. Effect of exogenous estrogen on serum pregnenolone, cortisol and androgens in postmenopausal women. Obstet & Gynecol 45:271,1975. 6. Vermeulen, A., Plasmaspiegels en herkomst van de geslachtshormonen bij de postmenopausale vrouwen. in : "Problemen van het climacterium in de medische praktijk". European Press, Ghent (Belgium) Eds. Branolte J., Brouwer W., Van Keep P. en Schellen A. 7. Anderson, D.C. and S.C.C.Yen. Effects of estrogens on adrenal 3(1hydroxysteroid dehydrogenase in ovariectomized women. J Clin Endocrinol Metab 43_:561, 1976. 8. Andre, C M . and V.H.T.James. Assay of plasma dehydroepiandrosterone and its sulfate by competitive protein binding. Clin Chim Acta, 4_3_:295, 1973. 9. Vermeulen, A. Plasma androgen levels during the menstrual cycle.
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Am J Gynecol & Obstetr 125:491, 1976. 10. Bassi, F., G.Giusti, L.Borsi, S.Cattaneo, P.Gianotti, G.Fosti, M.Pazzagli, C.Vigiani and M.Serio. Plasma androgens in women with hyperprolactinaemic amenorrhea. Clin Endocrinol 6^5, 1977. 11. Donabedian, R.K., P.B.May and S.Y.Tan. Abnormal adrenal steroidogenesis in patients with hyperprolactinemia, galactorrhea, or both. 56th Ann meeting Endocr Soc 1976, Abstr n°372. 12. Posner, B.I., P.A.Kelly, R.P.C. Shin and H.G.Friesen. Studies of insulin, growth hormone and prolactin binding : tissue distribution, species variation and characterization. Endocrinology 95:5 21, 1975. 13. Marshall, S., M.Gelato, and J. Meites. Serum prolactin levels and prolactin binding activity in adrenals and kidneys of male rats after dehydration, salt loading and unilateral nephrectomy. Proc Soc Exp Biol Med 14£:185, 1975. 14. Marshall S., G.S.Kledzik, M. Gelato, G.A.Campbell and J.Meites. Effects of estrogen and testosterone on specific prolactin binding in the kidneys and adrenals of rats. Steroids 22:187, 1976. 15. Edwards, C.R.W., M.O.Thorner, P.R.Miall, E.A.S. Al-Dujaili, J.P. Hanker and G.M.Besser. Inhibition of the plasma aldosterone response to frusemide by bromocriptine. Lancet 1^:903, 1975. 16. 01gaard K., C.Hagen, S.Madsen, L.Hummer. Aldosterone and prolactin. Lancet ii:959, 1976. 17. Lichtenstein, S., J.A. Colwell and J.H.Levine. Prolactin stimulates aldosterone biosynthesis. Abstr Vth Int Congr Endocr 1976, Abstr n°212. 18. Boyar, R.M. and L.Hellman. Syndrome of benign nodular hyperplasia associated with feminization and hyperprolactinemia. Ann Int Med 80:389, 1974.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 26 October 2015. at 22:47 For personal use only. No other uses without permission. . All rights reserved.
Edward Suy
and Robert
LEVELS Rubens
Departments of Endocrinology and Metabolism, Academic Hospital, Rijksuniversiteit, 9000 Ghent, Belgium and "psychiatric Institutes Mater Dei, Sleidinge, Belgium. ABSTRACT. Plasma DHEA and DHEA-S levels were significantly higher (P < 0.001) in women with elevated prolactin levels, due either to chronic treatment with psychotropic drugs or to a prolactinoma, than in untreated controls. This increase was also observed in 3 male patients with prolactinoma. It is suggested that this increase is the consequence of a direct effect of prolactin on the adrenal cortex and that prolactin might be responsible for the ACTH independent adrenocortical androgen secretion.
Plasma levels of dehydroepiandrosterone MATERIALS AND METHODS (DHEA) and of its sulfate(DHEA-S) show Selection of subjects important variations with age (1-4). Several groups of subjects were studBoth these steroids have mainly an ied. adrenal origin and as secretion of cor1. In two normal women with known ovutisol does not change significantly latory cycles, hormone levels were dewith age, it is improbable that these termined daily both during a control variations are secondary to variations cycle and during a cycle on treatment in ACTH secretion. This suggests that with sulpiride (Dogmatil )100 mg daily. other factors might modulate DHEA(S) 2. Hormone levels were determined in a secretion. Abraham and Maroulis(5)suggroup (n=30) of normal postmenopausal gested lack of estrogens to be responwomen selected as previously described sible for a decrease in adrenal DHEA(S) secretion in postmenopausal women; how- (3) (age 50-90 yrs), and compared to levels obtained in a group (n=10) of ever neither we ourselves(6)nor Anderpostmenopausal women selected using son and Yen(7)observed a restoration similar criteria, but treated chronof DHEA(S) levels to premenopausal valically (> 2 months) in an open psychiues after ethinylestradiol treatment atric institute for depression or defor either 14 days at a dosage of 400 mentia senilis, with either phenothiAig/day (6) or for 6 weeks at a dosage azines or butyrophenones, sometimes of 50 Aig/d (7). We considered the poscombined with tricyclic antidepressibility that prolactin might influsants in usual dosages. ence androgen secretion by the adrenal cortex and therefore we decided to 3. In order to evaluate the eventual study the influence of chronically elerole of depression or dementia senilis vated prolactin levels on plasma DHEA, itself on hormonal levels, the latter DHEA-S, androstenedione (A), estrone were determined in a small group of (El) and estradiol (E2) , as well as LH comparable patients before the start and FSH levels. of treatment. 4. Hormone levels were also obtained Submitted March 3, 1977 in 3 women and 3 men with prolactinoma without pituitary deficiencies. Supported by grant n°. 20.477 from the F.W.G.O.
1222
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RAPID COMMUNICATIONS
1223
Table I ; Hormonal plasma levels at normal and high prolactin concentration
Normal cycle (n=2) foil.ph. (LH-4/-8) in SE lut.ph. (LH+3/+7) in SE Sulpiride treat.cycle(n=2) foil.ph.(LH-4/8) lut.ph. (LH+3/+7)
Normal postm.wom.(n=30) m in age 68(52-68) SE Treat.postm.wom.(n=10) m in age 65(55-78) SE Untreat.postm.wom.(n=4) m in age 66(63-72) SE
El
E2 ng/100ml
DHEA
DHEA-S Aiq/ 100ml
95 19 159 16
313 26 331 30
77 6 81 3
10.8 1.0 11.8 0.8
127 4 166 8
372 42 435 38
107 5 119** 7
1.2 0.2 1.5 0.4 1.6 1.0
86 9 89 11 72 20
220
53
655** •91 312 42
77** 7 48 10
Prol.
LH FSH ng/ml
3.3 0.2 5.1 1.0
112 26 139 26
693 51 575 51
11.5 1.3 11.9 1.2
13.4 1.3 12.9 1.8
123** 2 137** 8
152 84 132 84
760 51 608 84
9.5 1.0 8.9 0.5
7.3 2.6 65 20 8.3 2.6
878 125 680 238 422 119
5019 456 3515 524 3718 304
3.2 0.3 4.2 0.5 3.7 0.9
A
AM
* p < 0.01; ** p < 0.001 LH -4/-8 = values during period from day 8 till day 4 before LH peak LH +3/+7 = values during period from day 3 till day 7 after LH peak Untreat.postm.wom. : postmenopausal women with either depression or dementia senilis before treatment. Methods Blood samples for hormone determinations were obtained in the fasting patients between 0800 and 1000 h. Steroid hormone levels were determined as previously described (1); DHEA-S levels were determined after solvolysis (8) by RIA of DHEA and are expressed as DHEA; LH, FSH and prolactin levels were assayed by a double antibody method using the commercial CEA-IRE-SORIN (Belgium) kits. LH and FSH levels are expressed in ng LER 907/ml; prolactin levels in ng/ml (1 mg NIH = 40 IU MRC). The correlation coefficient was calculated by the method of least squares. RESULTS AND DISCUSSION It is evident from table I that during sulpiride treatment, DHEA and DHEA-S levels were significantly higher than during the control cycle. During the latter the values observed in these 2 women (age 40 and 41 respectively)
were however lower than previously reported by us in a group of younger women (9). The increase during the treatment cycle was highly significant for DHEA-S both during the midfollicular (Pig/ 100 ml). Hence these results suggest strongly increased prolactin levels to be responsible for the increase in DHEA(S) levels. Indeed although a direct effect of the psychotropic drugs cannot be excluded with certainty, in the view of the high levels observed in prolactinoma a prolactin mediated increase seems to be the most probable mechanism. An increase in plasma levels is the consequence of either an increased blood production rate or a decreased
JCE & M • 1977 Vol 44 • No 6
metabolism (MCR). Although the latter has not been disproved for the moment, it is tempting to consider an increased secretion as the responsible mechanism. This is suggested by the increased urinary DHEA excretion recently reported by Bassi et al (10)in patients with hyperprolactinemic amenorrhea and by the increased urinary 17ketosteroid excretion reported in similar patients by Donabedian et al (11). As DHEA(S) has an almost exclusive adrenal origin, and as the increase in plasma levels was also observed in ovariectomized women with high prolactin levels, it is suggested that the increased levels are a consequence of a prolactin effect on the adrenal cortex. Specific binding sites for prolactin have been described in a variety of target organs, including the adrenals (12-14), but a physiologic in vivo effect of prolactin on the human adrenal has never been conclusively proved. Edwards et al (15) suggested that prolactin might modulate aldosterone secretion but 01gaard et al (16) on the other hand did not observe any influence of lowering prolactin levels on plasma aldosterone levels. Nevertheless Lichtenstein et al (17) observed a direct stimulating effect of prolactin on aldosterone secretion by rat adrenals. Recently Donabedian et al(ll) described 8 patients with either hyperprolactinemia and/or galactorrhea with unexplained elevation of urinary 17ketosteroids; plasma cortisol levels and 17-hydroxysteroid excretion were normal. Boyar and Hellman (18) reported a case of hvperprolactinemia with associated bilateral adrenal hyperplasia and suggested a. tropic effect of prolactin on the adrenal cortex, whereas Bassi et al (10) finally, recently reported increased plasma DHEA-S levels in patients with hyperprolactinemic amenorrhea and suggested that prolactin can stimulate secretion of some androgens by the adrenal cortex. Our results suggest a direct effect of chronically elevated prolactin levels on adrenal androgen secretion. The eventual physiological significance of
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 26 October 2015. at 22:47 For personal use only. No other uses without permission. . All rights reserved.
RAPID COMMUNICATIONS this effect, is still unclear and whether prolactin is the long sought for second adrenocorticotropic hormone, increasing specifically androgen secretion, needs further study. REFERENCES 1. Vermeulen, A. and L.Verdonck, Radioimmunoassay of 17/?-hydroxy-5«androstan-3-one, 4-androstene-3,17 dione, dehydroepiandrosterone, 17-hydroxyprogesterone and progesterone and its application to human male plasma, J Ster Biochem ]_:1, 1976. 2. Sekihara, H., N.Ohsawa and H.Ibayashi.A radioimmunoassay for serum dehydroepiandrosterone sulfate. Steroids 2£:813, 1972. 3. Vermeulen, A. The hormonal activity of the postmenopausal ovary. J Clin Endocrinol Metab 42^247, 1976. 4. Maroulis, G.B. and G.E.Abraham Ovarian and adrenal contribution to peripheral steroid levels in postmenopausal women. Obstet & Gynecol 418:150, 1976. 5. Abraham, G.E. and G.B. Maroulis. Effect of exogenous estrogen on serum pregnenolone, cortisol and androgens in postmenopausal women. Obstet & Gynecol 45:271,1975. 6. Vermeulen, A., Plasmaspiegels en herkomst van de geslachtshormonen bij de postmenopausale vrouwen. in : "Problemen van het climacterium in de medische praktijk". European Press, Ghent (Belgium) Eds. Branolte J., Brouwer W., Van Keep P. en Schellen A. 7. Anderson, D.C. and S.C.C.Yen. Effects of estrogens on adrenal 3(1hydroxysteroid dehydrogenase in ovariectomized women. J Clin Endocrinol Metab 43_:561, 1976. 8. Andre, C M . and V.H.T.James. Assay of plasma dehydroepiandrosterone and its sulfate by competitive protein binding. Clin Chim Acta, 4_3_:295, 1973. 9. Vermeulen, A. Plasma androgen levels during the menstrual cycle.
1225
Am J Gynecol & Obstetr 125:491, 1976. 10. Bassi, F., G.Giusti, L.Borsi, S.Cattaneo, P.Gianotti, G.Fosti, M.Pazzagli, C.Vigiani and M.Serio. Plasma androgens in women with hyperprolactinaemic amenorrhea. Clin Endocrinol 6^5, 1977. 11. Donabedian, R.K., P.B.May and S.Y.Tan. Abnormal adrenal steroidogenesis in patients with hyperprolactinemia, galactorrhea, or both. 56th Ann meeting Endocr Soc 1976, Abstr n°372. 12. Posner, B.I., P.A.Kelly, R.P.C. Shin and H.G.Friesen. Studies of insulin, growth hormone and prolactin binding : tissue distribution, species variation and characterization. Endocrinology 95:5 21, 1975. 13. Marshall, S., M.Gelato, and J. Meites. Serum prolactin levels and prolactin binding activity in adrenals and kidneys of male rats after dehydration, salt loading and unilateral nephrectomy. Proc Soc Exp Biol Med 14£:185, 1975. 14. Marshall S., G.S.Kledzik, M. Gelato, G.A.Campbell and J.Meites. Effects of estrogen and testosterone on specific prolactin binding in the kidneys and adrenals of rats. Steroids 22:187, 1976. 15. Edwards, C.R.W., M.O.Thorner, P.R.Miall, E.A.S. Al-Dujaili, J.P. Hanker and G.M.Besser. Inhibition of the plasma aldosterone response to frusemide by bromocriptine. Lancet 1^:903, 1975. 16. 01gaard K., C.Hagen, S.Madsen, L.Hummer. Aldosterone and prolactin. Lancet ii:959, 1976. 17. Lichtenstein, S., J.A. Colwell and J.H.Levine. Prolactin stimulates aldosterone biosynthesis. Abstr Vth Int Congr Endocr 1976, Abstr n°212. 18. Boyar, R.M. and L.Hellman. Syndrome of benign nodular hyperplasia associated with feminization and hyperprolactinemia. Ann Int Med 80:389, 1974.
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