0021-972x/92/7401-0217$03.00/0
Journal of Clinical Endocrinology and Metabolism Copyright 0 1992 by The Endocrine Society
Vol. 74, No. 1 Printed in u. LS.A.
Effects of Dopamine and Somatostatin Pituitary Glycoprotein Secretion* M. H. SAMUELS,
P. HENRY,
on Pulsatile
AND E. C. RIDGWAY
Division of Endocrinology, University of Texas Health Sciences Center (M.H.S.), San Antonio, Texas 782847877; and the Division of Endocrinology and Metabolism, University of Colorado Health Sciences Center (P.H., E.C. R.), Denver, Colorado 80262
ABSTRACT. The hypothalamic factors dopamine (DA) and somatostatin (SRIH) inhibit pituitary glycoprotein secretion, but little is known regarding the effects of these factors on glycoprotein pulses. To address this question, 12 healthy volunteers underwent frequent blood sampling over 12 h at baseline and during 12-h infusions of DA and/or SRIH. TSH, LH, FSH, and a-subunit (a) levels were measured in all samples, and hormone pulses were located by Cluster analysis. Both DA and SRIH suppressed TSH pulse amplitude by 70%, while SRIH decreasedTSH pulse frequency as well. Both infusions decreased LH pulse amplitude by 30-35%, but had no effect on pulse frequency. In contrast, neither infusion significantly altered
FSH pulse parameters, although mean FSH levels declined 15%. DA had no effect on pulsatile a secretion, while SRIH decreased o pulse frequency. Serum thyroid hormone levels declined during both infusions, but there were no major changes in serum sex steroid levels. Thus, the hypothalamic inhibitory factors DA and SRIH had divergent effects on glycoprotein hormone pulses. The major effects on pulse amplitude, rather than frequency, imply that these factors do not play major roles in the generation of glycoprotein pulses, although SRIH may directly affect the TSH and a pulse generators. (J Clin Endocrinol Metab 74: 217222, 1992)
U
NDER normal conditions, the pituitary glycoproteins TSH, LH, FSH, and n-subunit (a) are secreted in pulses (1). Although the importance of TSH pulses is unknown, many conditions alter reproductive function by disrupting gonadotropin pulses (2). The study of factors that cause similar or divergent changes in glycoprotein pulses can reveal potential control sites for these pulses in normal and disease states. The hypothalamic factor dopamine (DA) inhibits pituitary glycoprotein secretion. For example, DA or DA agonists suppress TSH levels by 40-70% (3, 4) and abolish the nocturnal TSH surge (5), while DA antagonists increase TSH levels (6). Studies of DA control of gonadotropins have been more variable; some report 2040% inhibition of LH (7-9) and lo-25% inhibition of FSH (7) levels, while others fail to find significant effects, especially on FSH (8-10). Differences between these studies may be due to variability in DA doses and patient selection. A single study of CYresponses to DA found a 33% decrease in serum cylevels during DA infusion (3). Like DA, somatostatin (SRIH) suppresses TSH levels
by 30-70% (11) and abolishes the nocturnal TSH surge (12). In contrast, SRIH appears ineffective in suppressing gonadotropin levels (13), although one study showed inhibition of GnRH-induced LH secretion (14). Little is known about possible in uivo effects of SRIH on (Y secretion. Few studies have investigated the effects of DA or SRIH on pulsatile glycoprotein release. In two recent reports, DA, metoclopramide, and SRIH affected TSH pulse amplitude in normal subjects without altering pulse frequency (15, 16). LH pulse frequency and amplitude were decreased by DA or bromocriptine in two studies involving men or postmenopausal women (17, 18), but were unaffected in other studies involving premenopausal women (19-21). There are no reports of possible effects of SRIH on gonadotropin pulses or effects of either factor on N pulses. To investigate how these factors affect glycoprotein pulses, we designed a study to answer the following questions. 1) Do DA or SRIH alter pulsatile TSH, LH, FSH, or free (Y secretion in normal individuals? 2) Do the effects of DA or SRIH on pulsatile hormone secretion differ for each glycoprotein?
Received February 25, 1991. Address requests for reprints to: Dr. M. H. Samuels, Department of Medicine, Division of Endocrinology, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, Texas 78‘284-7877. * This work was supported in part by Adult GCRC Grant MOl-RR00051 and NIH Grants DK-36843-03 (to M.H.S.) and CA-47411-01 and DK-36843 (to E.C.R.).
Subjects
and Methods
Patients Two groups of’ subjects were studied at the University of Colorado Health Science Center Clinical Research Center: 1) 217
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218
SAMUELS,
HENRY,
AND
RIDGWAY
JCE&Y*1992 Vol74*Nol
five healthy men, aged 18-30 yr, receiving no medications, with normal physical examinations and serum thyroid hormone and testosterone concentrations; 2) seven healthy women, aged 1830 yr, receiving no medications, with normal menstrual cycles, physical examinations, and serum thyroid hormone and estradiol levels. All were studied on days 3-7 of their menstrual cycles. Each subject underwent a baseline study, during which 3mL blood sampleswere withdrawn via indwelling iv catheters every 15 min for 12 h, between 1800-0600h. This time period was chosenbecausethe nocturnal rise in TSH accounts for most of the total TSH secretedover 24 h (1). Thus, the effects of DA or SRIH on TSH might be more apparent at night and might have increasedphysiological significance over daytime effects. Nine subjects(four men and five women) underwent similar studiesduring iv infusions of DA at 4 rg/kg. min. Eight subjects(five men and three women) underwent similar studies during iv infusions of SRIH at 500 rg/h. Studies were performed in random order separatedby at least 2 weeks.Doses of DA and SRIH were chosenbasedon previous studiesusing similar infusions with documentedeffects on one or more of the glycoproteins (3, 4, 7-12, 16, 17, 20, 22). Blood samples were centrifuged, and serumwasfrozen at -20 C.
< 0.0001). DA did not alter TSH pulse frequency, but pulse amplitude decreased 73%, from 3.0 f 0.6 to 0.8 zk 0.1 mU/L (P = 0.005). Serum T., levels were 86 + 6 nmol/L before and 80 + 6 nmol/L after infusion, and serum T,RU levels were 0.27 k 0.01 before and 0.28 k 0.01 after infusion (P = NS). Serum Ts levels declined from 1.6 f 0.2 to 1.4 f 0.1 nmol/L during DA infusion
Hormone
FSH
assays
Basal blood sampleswere assayedfor serumT1, TB, TBresin uptake (RU), testosterone, and estradiol using previously described methodologies(23-25). All sampleswere assayedfor TSH, LH, and FSH by immunoradiometric assays(26-28) and for (Yby a doubleantibody RIA (29). Mean intra- and interassay coefficientsof variation were, respectively, 6% and 7% for TSH, 6% and 11% for LH, 6% and 12% for FSH, and 12% and 20% for (Yat the hormonerangespresent in the subjects.Detection limits were 0.08 mU/L for TSH, 0.5 IU/L for LH, 0.5 IU/L for FSH, and 0.1 ng/mL for (Y. The cross-reactivity of LH and FSH in the (Y assay was 3%. All serum samplesfrom an individual were run in the sameassay. Statistical
analysis
Hormone pulses were identified by Cluster analysis (30), usingcoefficients of variation calculatedfrom samplereplicates in each subject’shormone series.Cluster parameterswere two points for test nadirs and two points for test peaks for each hormone.The t statistics were 1.0 for LH and FSH, and 2.0 for TSH and(Y.Significant differencesin pulseparametersbetween studieswere determinedby paired t tests. Twelve-hour hormone time seriesduring DA or SRIH infusionswere comparedto baseline 12-h time seriesby repeated measuresanalysisof variance, using subject number and infusion regimenas independentvariables.
Results DA study
(Table
1)
(I’ = 0.06). LH
Twelve-hour mean LH levels were 6.3 + 1.4 IU/L at baseline and 3.8 & 0.8 IU/L during DA infusion (P < 0.0001). DA did not alter LH pulse frequency. Pulse amplitude decreased 33%, from 8.1 + 1.7 to 5.4 + 0.9 IU/ L, although this did not quite reach statistical significance (P < 0.10). Serum testosterone levels in men were 15.3 & 2.4 nmol/L before and 14.7 k 3.7 nmol/L after infusion (P = NS). Serum estradiol levels in women were 212 + 66 pmol/L before and 169 of: 93 pmol/L after infusion (P = NS) .
Twelve-hour mean FSH levels were 6.0 f 1.0 IU/L at baseline and 5.5 + 1.0 IU/L during DA infusion (P < 0.0001). Twelve-hour FSH pulse frequency was 6.7 f: 0.3 at baseline and 6.2 k 0.3 during DA infusion (P = NS). Pulse amplitude was 7.1 _+ 1.1 IU/L at baseline and 6.1 + 0.9 IU/L during DA infusion (P = NS). cu-Subunit
Twelve-hour mean N levels were 1.1 k 0.1 ng/mL at baseline and during DA infusion. Twelve-hour CYpulse frequency was 6.3 + 0.7 at baseline and 5.0 + 0.6 during DA infusion (P = NS). Pulse amplitude was 1.4 + 0.2 ng/mL at baseline and during DA infusion. For each hormone, results were similar when data from men and women were analyzed separately (data not shown). Figure 1 shows TSH, LH, FSH, and LYpulse patterns from representative subjects at baseline and during DA infusions. SRIH
study
(Table
1)
TSH
Twelve-hour mean TSH levels were 2.5 zk 0.7 mU/L at baseline and 0.8 + 0.2 mu/L during SRIH infusion (P < 0.0001). SRIH decreased TSH pulse frequency 28%, from 5.0 + 0.4 to 3.6 + 0.5 mU/L (P = 0.04). TSH pulse
TSH
Twelve-hour mean TSH levels were 2.4 f 0.6 mU/L at baseline and 0.7 + 0.1 mU/L during DA infusion (P
amplitude decreased 66%, from 2.9 + 0.7 to 1.0 It 0.2 mU/L (P = 0.01). Serum T4 levels declined from 90 zk 9 to 72 + 8 nmol/L during the infusion (P = O.OOS),while
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HYPOTHALAMIC TABLE
1. Glycoprotein
A. DA study TSH (mu/L) LH (W/L) FSH (NJ/L)
responses 12-h mean
CY(ng/mL)
2.4 6.3 6.0 1.1
B. SRIH
12-h mean
study
TSH (mu/L) LH (NJ/L) FSH (NJ/L) (Y (ne/mL) All mean L?P DP
2.5 8.1 5.7 0.8
+ + -c f
+ + + +
0.6 1.4 1.0 0.1
0.7 1.5 1.1 0.1
to 12-h infusions 12-h mean 0.7 3.8 5.5 1.1
+ + -c f
12-h mean 0.8 5.6 4.9 1.1
+ t + +
+ DA 0.1” 0.8” 1.0” 0.1 + SRIH 0.2” 1.3” 0.9” 0.2”
CONTROL
OF GLYCOPROTEIN
PULSES
219
of DA or SRIH 12-h frequency 4.7 7.2 6.7 6.3
t 0.4 f 0.5 3~ 0.3 f 0.7
3.7 6.1 6.2 5.0
12-h frequency 5.0 7.8 7.1 7.4
12-h frequency
* t* f
values are the mean + SEM. Sienificant differences between levels and by paired t tests for pulse frequency and amplitude. < 0.01. < 0.05.
0.4 0.7 0.4 0.5
LH Twelve-hour mean LH levels were 8.1 _+ 1.5 IU/L at baseline and 5.6 + 1.3 IU/L during SRIH infusion (P < 0.0001). SRIH infusion did not change LH pulse frequency, but pulse amplitude decreased 31%, from 10.5 + 1.7 to 7.2 + 1.4 II-I/L (P = 0.05). Serum testosterone levels in men were 14.7 + 1.0 nmol/L before and 19.3 + 2.7 nmol/L after infusion (P = NS). Serum estradiol levels in women were 225 + 45 pmol/L before and 141 + 8 pmol/L after infusion (P = NS).
FSH Twelve-hour mean FSH levels were 5.7 _+ 1.1 IU/L at baseline and 4.9 f 0.9 IU/L during SRIH infusion (P < 0.0001). At baseline, 12-h FSH pulse frequency was 7.1 + 0.4, and pulse amplitude was 6.1 + 1.1 IU/L. During SRIH infusion, FSH pulse frequency was 6.5 + 0.4 (P = NS), and pulse amplitude was 5.4 f 0.9 (P = NS). a-Subunit Twelve-hour mean (Y levels were 0.8 + 0.1 ng/mL at baseline and 1.1 f 0.2 ng/mL during SRIH infusion (P < 0.0001). During SRIH infusion, LY pulse frequency decreased 44%, from 7.4 + 0.5 to 4.1 + 0.3, with no change in pulse amplitude (1.0 +- 0.1 us. 1.3 + 0.2 ng/ mL). For each hormone, results were similar when data from men and women were analyzed separately (data not shown). Figure 2 shows TSH, LH, FSH, and (Ypulse patterns from representative subjects at baseline and during SRIH infusions.
3.0 8.1 7.1 1.4
0.5 0.4 0.3 0.6
12-h frequency + SRIH --__ ___~~~~ 3.6 + 0.5h 6.6 * 0.6 6.5 + 0.4 4.1 + 0.3”
baseline
serum TBRU levels were 0.27 & 0.01 before and 0.29 + 0.01 after the infusion (P = NS). Serum T,, levels declined from 1.7 + 0.1 to 1.4 + 0.1 nmol/L during the infusion (P = 0.003).
f + + 2
12-h amplitude
+ DA
and infusion
values
-c * ++
12-h amplitude
0.6 1.7 1.1 0.2
0.8 5.4 6.1 1.4
12-h amplitude 2.9 10.5 6.1 1.0 were
0.1” 0.9 0.9 0.1
12-h amplitude
+ 0.7 -c 1.7 31 1.1 + 0.1
calculated
+ + + k
1.0 7.2 5.4 1.3 by analysis
f + + +
+ __-.-DA
+ SRIH 0.2” 1.4h 0.9 0.2
of variance
for 12-h
Discussion
A growing body of evidence indicates that the normal mode of pituitary hormone secretion is pulsatile, and that such secretory patterns may affect end-organ function. It is, therefore, important to determine which hypothalamic factors control pituitary hormone pulses. To this end, the current study found that each glycoprotein is suppressed to a different degree by DA and SRIH, mediated largely via changes in pulse amplitude, rather than frequency. DA had major effects on TSH secretion, suppressing mean TSH levels and TSH pulse amplitude by 70%. This pulsatile analysis confirms and extends previous clinical studies that show direct inhibition of TSH secretion at doses similar to those used in the present study (3-6,15, 16). It should be noted that these doses of DA lead to supraphysiological serum DA levels (4, 19), and more physiological doses may be even less likely to affect TSH pulse frequency. In addition, in vitro studies show direct inhibition of TSH synthesis and secretion by DA (31, 32). It is, thus, unlikely that DA gives rise to TSH pulses, since it has no effect on pulse frequency, but endogenous DA may be an important mediator of the amount of TSH secreted in each pulse. SRIH also had major effects on TSH secretion, decreasing mean TSH levels and TSH pulse amplitude by 66%. These data are supported by a previous clinical study (16) and by in vitro studies that showed direct inhibition of TSH synthesis and secretion by SRIH (13, 33). In contrast to the previous report, however, SRIH also decreased TSH pulse frequency. This may be due to the higher dose of SRIH used in the present study. If TSH pulses depend on TRH, SRIH may decrease TSH pulse frequency by decreasing TRH secretion, as suggested by previous in vitro reports (13,34). Alternatively, SRIH and TRH could exert opposing effects on TSH pulses, in analogy to the interactions between GH-re-
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220
SAMUEL&
HENRY,
o&l
okI0
AND
RIDGWAY
zJCE&M.ISY:: V"ll4 * Fit, 1
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$" 6,
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FIG. 1. Effects of DA on 12-h TSH (upper left), LH (upper right), FSH (lower left), and CY(lower right) pulses in representative subjects. Solid lines indicate levels during baseline studies, while dotted lines indicate levels during DA infusions. *, Location of hormone pulses during baseline studies; +, location of hormone pulses during DA infusions.
leasing hormone and SRIH that control GH pulses (13). However, since the location of the TSH pulse generator is unclear, such hypotheses remain speculative. Serum TB levels fell during both infusions (although the decline with DA did not reach statistical significance), and serum Tq levels fell during SRIH infusion. These changes probably result from direct effects on peripheral thyroid hormones as well as the observed effects on TSH secretion (12). Since these changes were more pronounced with SRIH than with DA, despite similar suppression of TSH levels, SRIH may have greater effects than DA on thyroid hormone secretion and metabolism. LH levels and LH pulse amplitude decreased by 3035% during DA or SRIH infusion in both men and women, with no significant changes in pulse frequency. In previous studies LH responses to these factors have been variable (13, 14, 17-21) and dependent on gonadal steroid levels (22, 35). The present study suggests that DA and SRIH exert suppressive effects on LH secretion in men and premenopausal women, primarily by suppressing LH pulse amplitude. Differences from previous studies may be due to doses of DA or SRIH, duration of infusions, or an escape phenomenon seen during pro-
longed DA infusion (7). For example, two previous studies using graded doses of DA showed lesser or no decreases in LH levels with lower doses of DA (19, 20). The effects of DA and SRIH on LH pulse amplitude were much less impressive than those on TSH pulse amplitude. This could be partially due to experimental design, since these experiments were performed during the nocturnal TSH surge. However, previous studies performed during the day have shown similar degrees of TSH suppression by DA and SRIH (3-7). Therefore, the current findings probably reflect different sensitivities of thyrotrophs and gonadotrophs to direct suppression by these factors. DA or SRIH did not alter FSH pulse parameters, although mean FSH levels decreased 15%. Past studies also reported lo-25% decreases in serum FSH during DA infusions at similar doses (although these changes were not always significant) (7-lo), but no changes with SRIH infusions (13). Thus, this study confirms a relative lack of effect of these factors on FSH secretion and extends such observations to pulsatile FSH release. Although LH and FSH pulses are both controlled by GnRH, discordant FSH control has been shown in the past by altering the GnRH pulse frequency (36, 37).
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HYPOTHALAMIC
CONTROL OF GLYCOPROTEIN
t
PULSES
t
*
i-
+
..\ L/b-.
+ %. ? ‘,
1600
2lM
.-“-..,
+ +
+
,: J; ..
-.
___
1
’
.j
.>.,--1
.
2400 r-
? .. I
A.
cuoo
06al
0 1600
r 2100
24m
03m
06m
CII
1.6 '
0.4 l600
2100
2466
o300
‘ o600
--pl)
FIG. 2. Effects of SRIH on 12-h TSH (upper left), LH (upper
FSH (lower left), and CY(how right) pulses in representative subjects. Solid lines indicate levels during baseline studies, while dotted lines indicate levels during SRIH infusions. *, Location of hormone pulses during baseline studies; +, location of hormone pulses during SRIH infusions. right),
Results from the present study may be further evidence for independent control of FSH secretion. Serum estradiol or testosterone levels did not change significantly during DA or SRIH infusions, although the levels were variable in this small sample. Since these factors appear to decrease LH pulse amplitude, they may have subtle effects on gonadal function. However, the small sample size in the present study precludes extrapolation of these findings. The current study is the first to examine effects of DA and SRIH on pulsatile a secretion. DA infusion had no effect on mean (Y levels or (Y pulse parameters, despite moderate to marked decreases in intact TSH and LH pulse amplitudes. This could be due to preferential inhibition of P-subunit synthesis. However, past in uitro studies have not shown such discordant effects (3, 34, 36). Alternatively, the contribution of the gonadotrophs, especially FSH-secreting cells, to the circulating N pool may outweigh any significant effects on thyrotroph-derived (Y. Surprisingly, SRIH increased mean cy levels and (Y pulse amplitude slightly (although the latter did not reach statistical significance), despite a decrease in pulse frequency. Previous in uitro studies have not shown
preferential stimulation of cylevels by SRIH (33). However, cysecretion from pituitary tumors can be dissociated from intact glycoprotein secretion by GnRH (38). The current results may represent another instance of discordant hypothalamic regulation of LY. In conclusion, there are two major findings from this study of the effects of DA and SRIH on pulsatile pituitary glycoprotein secretion. 1) The different glycoproteins are suppressed to a variable degree by these hypothalamic hormones. At the doses used in this study, TSH suppression is marked (70%), LH suppression is moderate (3035%), FSH suppression is mild (15%), and (Y levels are unchanged or slightly increased. 2) These changes are mediated largely through effects on pulse amplitude, rather than frequency. This implies that these factors do not play major roles in the generation of glycoprotein pulses, although SRIH may directly affect the TSH and N pulse generator, perhaps by interacting with hypothalamic TRH release. Acknowledgments The authors thank the University of Colorado Health Science Center Endocrinology and General Clinical Research Cen-
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222
SAMUELS,
HENRY,
ter Laboratory staff for performing the hormone assays. We thank Dr. Douglas Robertson for statistical assistance.
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.I(‘E & M. ii&W Vol71. Nu 1
infusions do not ablate luteinizing hormone pulses in women. Am J Obstet Cynecol. 1988;159:898-903. Andersen AN, Hagen C, Lange P, et al. Dopaminergic regulation of gonadotropin levels and pulsatility in normal women. Fertil Steril. 1987;47:391-7. Berga SL, Loucks AB, Rossmanith WG, Kettel LM, Laughlin GA, Yen SSC. Acceleration of luteinizing hormone pulse frequency in functional hypothalamic amenorrhea by dopaminergic blockade. d Clin Endocrinol Metab. 1991:72:151-6. Judd HJ, Rigg LA, Yen SSC. The effects of ovariectomy and estrogen treatment on the dopamine inhibition of gonadotropin and prolactin release. J Clin Endocrinol Metab. 1979;49:182-4. Gautuik KM, Tashjian AH, Kourides IA, et al. Thyrotropin-releasing hormone is not the sole physiologic mediator of prolactin release during suckling. N Engl J Med. 1974;290:1162-4. Ismail AA, Astley P, Burr WA et al. The role of testosterone measurements in the investigation of androgen disorders. Ann Clin Biochem. 1986;23:113-34. Bergquist C, Nillius SJ, Wide L. Human gonadotropin therapy. I. serum e&radio1 and progesterone patterns during conceptual cycles. Fertil Steril. 1983;39:761-5. van Heynigen V, Abbott SR, David SG, Anderson LJ, Ridgway EC. Development and utility of a monoclonal-antibody-based highly sensitive immunoradiometric assay of thyrotropin. Clin Chem. 1987;33:1387-90. Hunter WM, Bennie JG, Kellett HA, et al. A monoclonal antibodybased immunoradiometric assay for h-LH. Ann Clin Biochem. 1984;21:275-83. Filicori M, Marseguerra M, Mimmi P, et al. The pattern of LH and FSH pulsatile release: physiological and clinical significance. In: Flamigni C, Givens JR, eds. The gonadotropins: basic science and clinical aspects in females. London: Academic Press: 1982;36576. Kourides IA, Weintraub BD, Ridgway EC, Maloof F. Pituitary secretion of free alpha and beta subunit of human thyrotropin in patients with thyroid disorders. J Clin Endocrinol Metab. 1975;40:872-85. Veldhuis JD, Johnson ML. Cluster analysis: a simple, versatile and robust algorithm for endocrine pulse detection. Am J Physiol. 1986;250:E486-98. Shupnik MA, Greenspan SL, Ridgway EC. Transcriptional regulation of thyrotropin subunit genes by thyrotropin-releasing hormone and dopamine in pituitary cell culture. J Rio1 Chem. 1986;261:12675-9, Greenspan SL, Shupnik MA, Klibanski A, Ridgway EC. Divergent dopaminergic regulation of TSH, free alpha subunit, and TSH/3 in pituitary cell culture. Metabolism. 1986;35:843-6. Ridgway EC, Klibanski A, Martorana MA, Milbury P, Kieffer JD, Chin WW. The effect of somatostatin on the release of thyrotropin and its subunits from bovine anterior pituitary cells in uitro. Endocrinology. 1983;112:1937-42. Hirooka Y, Hollander CS, Suzuki S, Ferdinand P, Juan SI. Somatostatin inhibits release of thyrotropin releasing factor from organ cultures of rat hypothalamus. Proc Nat1 Acad Sci USA. 1978;75:45OS-13. Kletzky OA, Shangold GA. Variability and selectivity of anterior pituitary response to dopamine agonists throughout the normal menstrual cycle. Am J Obstet Gynecol. X&$154:362-7. Gross KM, Matsumoto AM, Bremner WJ. Differential control of luteinizing hormone and follicle-stimulating hormone secretion by luteinizing hormone-releasing hormone pulse frequency in man. J Clin Endocrinol Metab. 1987;64:675-80. Hall JE, Brodie TD, Badger TM, et al. Evidence of differential control of FSH and LH secretion by gonadotropin-releasing hormone (GnRH) from the use of a GnRH antagonist. J Clin Endocrinol Metab. 1988;67:524-31. Klibanski A. Jameson JL. Biller BMK. et al. Gonadotronin and osubunit responses to chronic gonadotropin-releasing hormone analog administration in patients with glycoprotein hormone-secreting pituitary tumors. J Clin Endocrinol Metab. 1989;68:81-6.
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Journal of Clinical Endocrinology and Metabolism Copyright 0 1992 by The Endocrine Society
Vol. 74, No. 1 Printed in u. LS.A.
Effects of Dopamine and Somatostatin Pituitary Glycoprotein Secretion* M. H. SAMUELS,
P. HENRY,
on Pulsatile
AND E. C. RIDGWAY
Division of Endocrinology, University of Texas Health Sciences Center (M.H.S.), San Antonio, Texas 782847877; and the Division of Endocrinology and Metabolism, University of Colorado Health Sciences Center (P.H., E.C. R.), Denver, Colorado 80262
ABSTRACT. The hypothalamic factors dopamine (DA) and somatostatin (SRIH) inhibit pituitary glycoprotein secretion, but little is known regarding the effects of these factors on glycoprotein pulses. To address this question, 12 healthy volunteers underwent frequent blood sampling over 12 h at baseline and during 12-h infusions of DA and/or SRIH. TSH, LH, FSH, and a-subunit (a) levels were measured in all samples, and hormone pulses were located by Cluster analysis. Both DA and SRIH suppressed TSH pulse amplitude by 70%, while SRIH decreasedTSH pulse frequency as well. Both infusions decreased LH pulse amplitude by 30-35%, but had no effect on pulse frequency. In contrast, neither infusion significantly altered
FSH pulse parameters, although mean FSH levels declined 15%. DA had no effect on pulsatile a secretion, while SRIH decreased o pulse frequency. Serum thyroid hormone levels declined during both infusions, but there were no major changes in serum sex steroid levels. Thus, the hypothalamic inhibitory factors DA and SRIH had divergent effects on glycoprotein hormone pulses. The major effects on pulse amplitude, rather than frequency, imply that these factors do not play major roles in the generation of glycoprotein pulses, although SRIH may directly affect the TSH and a pulse generators. (J Clin Endocrinol Metab 74: 217222, 1992)
U
NDER normal conditions, the pituitary glycoproteins TSH, LH, FSH, and n-subunit (a) are secreted in pulses (1). Although the importance of TSH pulses is unknown, many conditions alter reproductive function by disrupting gonadotropin pulses (2). The study of factors that cause similar or divergent changes in glycoprotein pulses can reveal potential control sites for these pulses in normal and disease states. The hypothalamic factor dopamine (DA) inhibits pituitary glycoprotein secretion. For example, DA or DA agonists suppress TSH levels by 40-70% (3, 4) and abolish the nocturnal TSH surge (5), while DA antagonists increase TSH levels (6). Studies of DA control of gonadotropins have been more variable; some report 2040% inhibition of LH (7-9) and lo-25% inhibition of FSH (7) levels, while others fail to find significant effects, especially on FSH (8-10). Differences between these studies may be due to variability in DA doses and patient selection. A single study of CYresponses to DA found a 33% decrease in serum cylevels during DA infusion (3). Like DA, somatostatin (SRIH) suppresses TSH levels
by 30-70% (11) and abolishes the nocturnal TSH surge (12). In contrast, SRIH appears ineffective in suppressing gonadotropin levels (13), although one study showed inhibition of GnRH-induced LH secretion (14). Little is known about possible in uivo effects of SRIH on (Y secretion. Few studies have investigated the effects of DA or SRIH on pulsatile glycoprotein release. In two recent reports, DA, metoclopramide, and SRIH affected TSH pulse amplitude in normal subjects without altering pulse frequency (15, 16). LH pulse frequency and amplitude were decreased by DA or bromocriptine in two studies involving men or postmenopausal women (17, 18), but were unaffected in other studies involving premenopausal women (19-21). There are no reports of possible effects of SRIH on gonadotropin pulses or effects of either factor on N pulses. To investigate how these factors affect glycoprotein pulses, we designed a study to answer the following questions. 1) Do DA or SRIH alter pulsatile TSH, LH, FSH, or free (Y secretion in normal individuals? 2) Do the effects of DA or SRIH on pulsatile hormone secretion differ for each glycoprotein?
Received February 25, 1991. Address requests for reprints to: Dr. M. H. Samuels, Department of Medicine, Division of Endocrinology, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, Texas 78‘284-7877. * This work was supported in part by Adult GCRC Grant MOl-RR00051 and NIH Grants DK-36843-03 (to M.H.S.) and CA-47411-01 and DK-36843 (to E.C.R.).
Subjects
and Methods
Patients Two groups of’ subjects were studied at the University of Colorado Health Science Center Clinical Research Center: 1) 217
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218
SAMUELS,
HENRY,
AND
RIDGWAY
JCE&Y*1992 Vol74*Nol
five healthy men, aged 18-30 yr, receiving no medications, with normal physical examinations and serum thyroid hormone and testosterone concentrations; 2) seven healthy women, aged 1830 yr, receiving no medications, with normal menstrual cycles, physical examinations, and serum thyroid hormone and estradiol levels. All were studied on days 3-7 of their menstrual cycles. Each subject underwent a baseline study, during which 3mL blood sampleswere withdrawn via indwelling iv catheters every 15 min for 12 h, between 1800-0600h. This time period was chosenbecausethe nocturnal rise in TSH accounts for most of the total TSH secretedover 24 h (1). Thus, the effects of DA or SRIH on TSH might be more apparent at night and might have increasedphysiological significance over daytime effects. Nine subjects(four men and five women) underwent similar studiesduring iv infusions of DA at 4 rg/kg. min. Eight subjects(five men and three women) underwent similar studies during iv infusions of SRIH at 500 rg/h. Studies were performed in random order separatedby at least 2 weeks.Doses of DA and SRIH were chosenbasedon previous studiesusing similar infusions with documentedeffects on one or more of the glycoproteins (3, 4, 7-12, 16, 17, 20, 22). Blood samples were centrifuged, and serumwasfrozen at -20 C.
< 0.0001). DA did not alter TSH pulse frequency, but pulse amplitude decreased 73%, from 3.0 f 0.6 to 0.8 zk 0.1 mU/L (P = 0.005). Serum T., levels were 86 + 6 nmol/L before and 80 + 6 nmol/L after infusion, and serum T,RU levels were 0.27 k 0.01 before and 0.28 k 0.01 after infusion (P = NS). Serum Ts levels declined from 1.6 f 0.2 to 1.4 f 0.1 nmol/L during DA infusion
Hormone
FSH
assays
Basal blood sampleswere assayedfor serumT1, TB, TBresin uptake (RU), testosterone, and estradiol using previously described methodologies(23-25). All sampleswere assayedfor TSH, LH, and FSH by immunoradiometric assays(26-28) and for (Yby a doubleantibody RIA (29). Mean intra- and interassay coefficientsof variation were, respectively, 6% and 7% for TSH, 6% and 11% for LH, 6% and 12% for FSH, and 12% and 20% for (Yat the hormonerangespresent in the subjects.Detection limits were 0.08 mU/L for TSH, 0.5 IU/L for LH, 0.5 IU/L for FSH, and 0.1 ng/mL for (Y. The cross-reactivity of LH and FSH in the (Y assay was 3%. All serum samplesfrom an individual were run in the sameassay. Statistical
analysis
Hormone pulses were identified by Cluster analysis (30), usingcoefficients of variation calculatedfrom samplereplicates in each subject’shormone series.Cluster parameterswere two points for test nadirs and two points for test peaks for each hormone.The t statistics were 1.0 for LH and FSH, and 2.0 for TSH and(Y.Significant differencesin pulseparametersbetween studieswere determinedby paired t tests. Twelve-hour hormone time seriesduring DA or SRIH infusionswere comparedto baseline 12-h time seriesby repeated measuresanalysisof variance, using subject number and infusion regimenas independentvariables.
Results DA study
(Table
1)
(I’ = 0.06). LH
Twelve-hour mean LH levels were 6.3 + 1.4 IU/L at baseline and 3.8 & 0.8 IU/L during DA infusion (P < 0.0001). DA did not alter LH pulse frequency. Pulse amplitude decreased 33%, from 8.1 + 1.7 to 5.4 + 0.9 IU/ L, although this did not quite reach statistical significance (P < 0.10). Serum testosterone levels in men were 15.3 & 2.4 nmol/L before and 14.7 k 3.7 nmol/L after infusion (P = NS). Serum estradiol levels in women were 212 + 66 pmol/L before and 169 of: 93 pmol/L after infusion (P = NS) .
Twelve-hour mean FSH levels were 6.0 f 1.0 IU/L at baseline and 5.5 + 1.0 IU/L during DA infusion (P < 0.0001). Twelve-hour FSH pulse frequency was 6.7 f: 0.3 at baseline and 6.2 k 0.3 during DA infusion (P = NS). Pulse amplitude was 7.1 _+ 1.1 IU/L at baseline and 6.1 + 0.9 IU/L during DA infusion (P = NS). cu-Subunit
Twelve-hour mean N levels were 1.1 k 0.1 ng/mL at baseline and during DA infusion. Twelve-hour CYpulse frequency was 6.3 + 0.7 at baseline and 5.0 + 0.6 during DA infusion (P = NS). Pulse amplitude was 1.4 + 0.2 ng/mL at baseline and during DA infusion. For each hormone, results were similar when data from men and women were analyzed separately (data not shown). Figure 1 shows TSH, LH, FSH, and LYpulse patterns from representative subjects at baseline and during DA infusions. SRIH
study
(Table
1)
TSH
Twelve-hour mean TSH levels were 2.5 zk 0.7 mU/L at baseline and 0.8 + 0.2 mu/L during SRIH infusion (P < 0.0001). SRIH decreased TSH pulse frequency 28%, from 5.0 + 0.4 to 3.6 + 0.5 mU/L (P = 0.04). TSH pulse
TSH
Twelve-hour mean TSH levels were 2.4 f 0.6 mU/L at baseline and 0.7 + 0.1 mU/L during DA infusion (P
amplitude decreased 66%, from 2.9 + 0.7 to 1.0 It 0.2 mU/L (P = 0.01). Serum T4 levels declined from 90 zk 9 to 72 + 8 nmol/L during the infusion (P = O.OOS),while
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HYPOTHALAMIC TABLE
1. Glycoprotein
A. DA study TSH (mu/L) LH (W/L) FSH (NJ/L)
responses 12-h mean
CY(ng/mL)
2.4 6.3 6.0 1.1
B. SRIH
12-h mean
study
TSH (mu/L) LH (NJ/L) FSH (NJ/L) (Y (ne/mL) All mean L?P DP
2.5 8.1 5.7 0.8
+ + -c f
+ + + +
0.6 1.4 1.0 0.1
0.7 1.5 1.1 0.1
to 12-h infusions 12-h mean 0.7 3.8 5.5 1.1
+ + -c f
12-h mean 0.8 5.6 4.9 1.1
+ t + +
+ DA 0.1” 0.8” 1.0” 0.1 + SRIH 0.2” 1.3” 0.9” 0.2”
CONTROL
OF GLYCOPROTEIN
PULSES
219
of DA or SRIH 12-h frequency 4.7 7.2 6.7 6.3
t 0.4 f 0.5 3~ 0.3 f 0.7
3.7 6.1 6.2 5.0
12-h frequency 5.0 7.8 7.1 7.4
12-h frequency
* t* f
values are the mean + SEM. Sienificant differences between levels and by paired t tests for pulse frequency and amplitude. < 0.01. < 0.05.
0.4 0.7 0.4 0.5
LH Twelve-hour mean LH levels were 8.1 _+ 1.5 IU/L at baseline and 5.6 + 1.3 IU/L during SRIH infusion (P < 0.0001). SRIH infusion did not change LH pulse frequency, but pulse amplitude decreased 31%, from 10.5 + 1.7 to 7.2 + 1.4 II-I/L (P = 0.05). Serum testosterone levels in men were 14.7 + 1.0 nmol/L before and 19.3 + 2.7 nmol/L after infusion (P = NS). Serum estradiol levels in women were 225 + 45 pmol/L before and 141 + 8 pmol/L after infusion (P = NS).
FSH Twelve-hour mean FSH levels were 5.7 _+ 1.1 IU/L at baseline and 4.9 f 0.9 IU/L during SRIH infusion (P < 0.0001). At baseline, 12-h FSH pulse frequency was 7.1 + 0.4, and pulse amplitude was 6.1 + 1.1 IU/L. During SRIH infusion, FSH pulse frequency was 6.5 + 0.4 (P = NS), and pulse amplitude was 5.4 f 0.9 (P = NS). a-Subunit Twelve-hour mean (Y levels were 0.8 + 0.1 ng/mL at baseline and 1.1 f 0.2 ng/mL during SRIH infusion (P < 0.0001). During SRIH infusion, LY pulse frequency decreased 44%, from 7.4 + 0.5 to 4.1 + 0.3, with no change in pulse amplitude (1.0 +- 0.1 us. 1.3 + 0.2 ng/ mL). For each hormone, results were similar when data from men and women were analyzed separately (data not shown). Figure 2 shows TSH, LH, FSH, and (Ypulse patterns from representative subjects at baseline and during SRIH infusions.
3.0 8.1 7.1 1.4
0.5 0.4 0.3 0.6
12-h frequency + SRIH --__ ___~~~~ 3.6 + 0.5h 6.6 * 0.6 6.5 + 0.4 4.1 + 0.3”
baseline
serum TBRU levels were 0.27 & 0.01 before and 0.29 + 0.01 after the infusion (P = NS). Serum T,, levels declined from 1.7 + 0.1 to 1.4 + 0.1 nmol/L during the infusion (P = 0.003).
f + + 2
12-h amplitude
+ DA
and infusion
values
-c * ++
12-h amplitude
0.6 1.7 1.1 0.2
0.8 5.4 6.1 1.4
12-h amplitude 2.9 10.5 6.1 1.0 were
0.1” 0.9 0.9 0.1
12-h amplitude
+ 0.7 -c 1.7 31 1.1 + 0.1
calculated
+ + + k
1.0 7.2 5.4 1.3 by analysis
f + + +
+ __-.-DA
+ SRIH 0.2” 1.4h 0.9 0.2
of variance
for 12-h
Discussion
A growing body of evidence indicates that the normal mode of pituitary hormone secretion is pulsatile, and that such secretory patterns may affect end-organ function. It is, therefore, important to determine which hypothalamic factors control pituitary hormone pulses. To this end, the current study found that each glycoprotein is suppressed to a different degree by DA and SRIH, mediated largely via changes in pulse amplitude, rather than frequency. DA had major effects on TSH secretion, suppressing mean TSH levels and TSH pulse amplitude by 70%. This pulsatile analysis confirms and extends previous clinical studies that show direct inhibition of TSH secretion at doses similar to those used in the present study (3-6,15, 16). It should be noted that these doses of DA lead to supraphysiological serum DA levels (4, 19), and more physiological doses may be even less likely to affect TSH pulse frequency. In addition, in vitro studies show direct inhibition of TSH synthesis and secretion by DA (31, 32). It is, thus, unlikely that DA gives rise to TSH pulses, since it has no effect on pulse frequency, but endogenous DA may be an important mediator of the amount of TSH secreted in each pulse. SRIH also had major effects on TSH secretion, decreasing mean TSH levels and TSH pulse amplitude by 66%. These data are supported by a previous clinical study (16) and by in vitro studies that showed direct inhibition of TSH synthesis and secretion by SRIH (13, 33). In contrast to the previous report, however, SRIH also decreased TSH pulse frequency. This may be due to the higher dose of SRIH used in the present study. If TSH pulses depend on TRH, SRIH may decrease TSH pulse frequency by decreasing TRH secretion, as suggested by previous in vitro reports (13,34). Alternatively, SRIH and TRH could exert opposing effects on TSH pulses, in analogy to the interactions between GH-re-
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220
SAMUEL&
HENRY,
o&l
okI0
AND
RIDGWAY
zJCE&M.ISY:: V"ll4 * Fit, 1
10
6
$" 6,
6
5 1 0
2io
24k7 Tam IN
FIG. 1. Effects of DA on 12-h TSH (upper left), LH (upper right), FSH (lower left), and CY(lower right) pulses in representative subjects. Solid lines indicate levels during baseline studies, while dotted lines indicate levels during DA infusions. *, Location of hormone pulses during baseline studies; +, location of hormone pulses during DA infusions.
leasing hormone and SRIH that control GH pulses (13). However, since the location of the TSH pulse generator is unclear, such hypotheses remain speculative. Serum TB levels fell during both infusions (although the decline with DA did not reach statistical significance), and serum Tq levels fell during SRIH infusion. These changes probably result from direct effects on peripheral thyroid hormones as well as the observed effects on TSH secretion (12). Since these changes were more pronounced with SRIH than with DA, despite similar suppression of TSH levels, SRIH may have greater effects than DA on thyroid hormone secretion and metabolism. LH levels and LH pulse amplitude decreased by 3035% during DA or SRIH infusion in both men and women, with no significant changes in pulse frequency. In previous studies LH responses to these factors have been variable (13, 14, 17-21) and dependent on gonadal steroid levels (22, 35). The present study suggests that DA and SRIH exert suppressive effects on LH secretion in men and premenopausal women, primarily by suppressing LH pulse amplitude. Differences from previous studies may be due to doses of DA or SRIH, duration of infusions, or an escape phenomenon seen during pro-
longed DA infusion (7). For example, two previous studies using graded doses of DA showed lesser or no decreases in LH levels with lower doses of DA (19, 20). The effects of DA and SRIH on LH pulse amplitude were much less impressive than those on TSH pulse amplitude. This could be partially due to experimental design, since these experiments were performed during the nocturnal TSH surge. However, previous studies performed during the day have shown similar degrees of TSH suppression by DA and SRIH (3-7). Therefore, the current findings probably reflect different sensitivities of thyrotrophs and gonadotrophs to direct suppression by these factors. DA or SRIH did not alter FSH pulse parameters, although mean FSH levels decreased 15%. Past studies also reported lo-25% decreases in serum FSH during DA infusions at similar doses (although these changes were not always significant) (7-lo), but no changes with SRIH infusions (13). Thus, this study confirms a relative lack of effect of these factors on FSH secretion and extends such observations to pulsatile FSH release. Although LH and FSH pulses are both controlled by GnRH, discordant FSH control has been shown in the past by altering the GnRH pulse frequency (36, 37).
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HYPOTHALAMIC
CONTROL OF GLYCOPROTEIN
t
PULSES
t
*
i-
+
..\ L/b-.
+ %. ? ‘,
1600
2lM
.-“-..,
+ +
+
,: J; ..
-.
___
1
’
.j
.>.,--1
.
2400 r-
? .. I
A.
cuoo
06al
0 1600
r 2100
24m
03m
06m
CII
1.6 '
0.4 l600
2100
2466
o300
‘ o600
--pl)
FIG. 2. Effects of SRIH on 12-h TSH (upper left), LH (upper
FSH (lower left), and CY(how right) pulses in representative subjects. Solid lines indicate levels during baseline studies, while dotted lines indicate levels during SRIH infusions. *, Location of hormone pulses during baseline studies; +, location of hormone pulses during SRIH infusions. right),
Results from the present study may be further evidence for independent control of FSH secretion. Serum estradiol or testosterone levels did not change significantly during DA or SRIH infusions, although the levels were variable in this small sample. Since these factors appear to decrease LH pulse amplitude, they may have subtle effects on gonadal function. However, the small sample size in the present study precludes extrapolation of these findings. The current study is the first to examine effects of DA and SRIH on pulsatile a secretion. DA infusion had no effect on mean (Y levels or (Y pulse parameters, despite moderate to marked decreases in intact TSH and LH pulse amplitudes. This could be due to preferential inhibition of P-subunit synthesis. However, past in uitro studies have not shown such discordant effects (3, 34, 36). Alternatively, the contribution of the gonadotrophs, especially FSH-secreting cells, to the circulating N pool may outweigh any significant effects on thyrotroph-derived (Y. Surprisingly, SRIH increased mean cy levels and (Y pulse amplitude slightly (although the latter did not reach statistical significance), despite a decrease in pulse frequency. Previous in uitro studies have not shown
preferential stimulation of cylevels by SRIH (33). However, cysecretion from pituitary tumors can be dissociated from intact glycoprotein secretion by GnRH (38). The current results may represent another instance of discordant hypothalamic regulation of LY. In conclusion, there are two major findings from this study of the effects of DA and SRIH on pulsatile pituitary glycoprotein secretion. 1) The different glycoproteins are suppressed to a variable degree by these hypothalamic hormones. At the doses used in this study, TSH suppression is marked (70%), LH suppression is moderate (3035%), FSH suppression is mild (15%), and (Y levels are unchanged or slightly increased. 2) These changes are mediated largely through effects on pulse amplitude, rather than frequency. This implies that these factors do not play major roles in the generation of glycoprotein pulses, although SRIH may directly affect the TSH and N pulse generator, perhaps by interacting with hypothalamic TRH release. Acknowledgments The authors thank the University of Colorado Health Science Center Endocrinology and General Clinical Research Cen-
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222
SAMUELS,
HENRY,
ter Laboratory staff for performing the hormone assays. We thank Dr. Douglas Robertson for statistical assistance.
References 1. Samuels MH, Veldhuis JD, Henry P, Ridgway EC. Pathophysiology of pulsatile and copulsatile release of thyroid-stimulating hormone, luteinizing hormone, follicle-stimulating hormone, and alpha subunit. J Clin Endocrinol Metab. 1990;71:425-32. 2. Santoro N. Filicori M. Crowlev WF. Hvnoeonadotronic disorders in men and women: diagnosis and therapy with pulsatile gonadotropin-releasing hormone. Endocr Rev. 1986;7:11-23. 3. Cooper DS, Klibanski A, Ridgway EC. Dopaminergic modulation of TSH and its subunits: in uiuo and in vitro studies. Clin Endocrinol (Oxf). 1983;18:265-75. 4. Agner T, Hagen C, Andersen AN, Djursing H. Increased dopaminergic activity inhibits basal and metoclopramide-stimulated prolactin and thvrotronin secretion. J Clin Endocrinol Metab. 1986;62:778-82: 5. Sowers JR, Catania A, Hershman M. Evidence for dopaminergic control of circadian variations in thyrotropin secretion. J Clin Endocrinol Metab. 1982;54:673-5. 6. Scanlon MF, Weightman DR, Shale DJ, et al. Dopamine is a physiological regulator of thyrotrophin (TSH) secretion in normal man. Clin Endocrinol (Oxf). 1979;10:7-15. I. Kaptein EM, Kletzky OA, Spencer CA, Nicoloff JT. Effects of prolonged dopamine infusion on anterior pituitary function in normal males. J Clin Endocrinol Metab. 1980;51:488-91. 8. Ferrari C, Rampini P, Malinverni A, et al. Inhibition of luteinizing hormone release by dopamine infusion in healthy women and in various pathophysiological conditions. Acta Endocrinol (Copenh). 1981;97:436-40. 9. Matsubara M, Tango M, Nakagawa K. Effects of dopaminergic agonists on plasma luteinizing hormone-releasing hormone (LRH) and gonadotropins in man. Horm Metab Res. 1987;19:31-4. 10. Leebaw WF, Lee LA, Woolf PD. Dopamine affects basal and augmented pituitary hormone secretion. J Clin Endocrinol Metab. 1978;47:480-7. 11. Williams TC, Kelijman M, Cerlin WC, Downs TR, Frohman A. Differential effects of somatostatin (SRIH) and a SRIH analog, SMS 201-995, on the secretion of growth hormone and thyroidstimulating hormone in man. J Clin Endocrinol Metab. 1988;66:3945. 12. Weeke J, Christensen SE, Hansen AP, Laurberg P, Lundbaek K. Somatostatin and the 24 h levels of serum TSH, Ts, TJ and reverse Ta in normals, diabetics and patients treated for myxoedema. Acta Endocrinol (Conenhl. 1980:94:30-7. 13. Lamberts SWJ-. The role ‘of somatostatin in the regulation of anterior pituitary hormone secretion and the use of its analogs in the treatment of human pituitary tumors. Endocr Rev. 1988;9:41736. 14. Lightman SL, Fox P. Dunne MJ. The effect of SMS 201-995, a long-acting somatostatin analogue, on anterior pituitary function volunteers. Stand J Gastroenterol. in healthy male 1986;119(Suppl):84-95. 15. Rossmanith WG, Mortola JF, Laughlin GA, Yen SSC. Dopaminergic control of circadian and pulsatile pituitary thyrotropin release in women. J Clin Endocrinol Metab. 1988;67:560-4. 16. Brabant G, Prank K, Hoang-vu C, Hesch RD, von zur Muhlen A. Hypothalamic regulation of pulsatile thyrotropin secretion. J Clin Endocrinol Metab. 1991;72:145-50. 17. Huseman CA, Kugler JA, Schneider IG. Mechanism of dopaminergic suppression of gonadotropin secretion in men. J Clin Endocrinol Metab. 1980;51:209-14. 18. Gambacciani M, Melis GB, Paoletti AM. Pulsatile luteinizing hormone release in postmenopausal women: effect of chronic bromocriptine administration. J Clin Endocrinol Metab. 1987;65:4658. 19. Martin MC, Monroe SE, Weiner RI, ,Jaffe RB. Low-dose dopamine
AND
20.
21.
22. 23. 24. 25. 26.
27. 28.
29.
30. 31.
32. 33.
34.
35. 36
.,‘17,
38.
RIDGWAY
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