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Effect of dexamethasone on gonadotropin responsiveness to luteinizing hormone–releasing hormone and clomiphene in women with secondary amenorrhea
Effect of dexamethasone on gonadotropin . 1 • . . \.,. 1 . responsiveness to 1Utein1Z1ng uormone-ie1eas1ng hormone and clomiphene in women vvith secondary amenorrhea JAMES R. SOWERS, M.D. JAMIL FAYEZ, M.D. /(ansas (:it)', Alissouri We have studied the effects of administration of dexamethasone, 2 mg orally every 6 hours, for 5 days on the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) induced by luteinizing hormone-releasing hormone (LHRH) in six women with secondary amenorrhea and on the release of these gonadotropins induced by clomiphene citrate in 10 women with secondary amenorrhea. Dexamethasone suppressed baseline serum levels of LH and FSH and blunted the LHRH-induced release of LH and FSH in six women. Following dexamethasone administration, the LH and FSH response to clomiphene citrate, which competes for gonadal steroid receptor binding sites in the hypothalaiTIUS, resulting in increased reiease of LHRH, was blunted in the 10 women studied. The data indicate that short-term administration of pharmacologic doses of glucocorticoids suppresses the secretion of LH and FSH by a direct effect on the anterior pituitary and possibly by an effect at the suprahypophyseallevel with inhibition of release of LHRH. (AM. J. OBSTET. GYNECOL. 134:325, 1979.)
IT HAS BEEl\' PREVIOUSLY observed that women experience disorders of menstruation when receiving glucocorticoids. 1 Evidence from animal studies suggests that the suppressive effects of glucocorticoids on the hypothalamic-pituitary axis are exerted by impairment of gonadotropin secretion by a direct action on the anterior pituitary or by their effects at the suprahypophyseal level with inhibition of release of luteinizing hormone-releasing hormone (LHRH). 2- 4 One prior report indicated that short term administration of dexamethasone did not result in suppression of basal levels of follicle-stimulating hormone (FSH) in man:' Long-term administration of glucocorticoids has been shown to suppress basal and midcycle luteinizing From the Endocrine Section, Departmmt of Medicine and Department of Obstetrics and G}necology, University of Missouri. Receivedfor publication April 7, 1978. Acceptedjuly 13, 1978. Reprint requests: Dr. James R. Sowers, Endocrine Research Laboratory, Universiry of Missouri at Kansas City, 2411 Holmes St., Kansas City, Missouri 64108.
0002-9378179/110325+04$00.40/0
©
1979 The C. V. Mosby Co.
hormone (LH) peak levels in normally cycling women 6 and to suppress the LH response to LHRH in women with disorders of menstruation. 1 The present study was performed to determine the effects of short-term administration of high doses of glucocorticoids on LH and FSH responses to LHRH and clomiphene in women with secondary amenorrhea.
Material and methods Sixteen women (aged 21 to 37 years) with secondary amenorrhea and infertility were studied. The subjects had normal serum prolactin levels, normal lateral skull films, and normal visual fields and none had galactorrhea. Most of these patients were obese; they had high normal LH and normal FSH levels and slightly elevated serum testosterone and urinary 17-ketosteroid levels. The diagnosis of polycystic ovary disease was confirmed at laporoscopy in four of the subjects. · LHRH studies. Six women (aged 23 to 37) were given an intravenous bolus of 100 ~J-g of LHRH at 0800 hours before and after they received dexamethasone, 2
325
326 Sowers and Fayez Am.
.
J
.June I. 1979 Obstet. (,vnt·tol
7.0-
50
2D 1.0 0~--,----r---.---,---,.---,
-15
0
15
30
45
60
90
Fig. 2. Mean serum FSH responses to LHRH (given at 0 time) in six women with secondary amenorrhea before (solid-line) and after (broken line) dexamethasone administration; vertical bars show standard errors of the means.
I
15
I
I
30 MlrMes
90
Fig. 1. Mean serum LH responses to LHRH (given at 0 time) in six women with secondary amenorrhea before (solid line) and after (broken line) dexamethasone administration; vertical bars show standard errors of the means.
mg orally every 6 hours for 5 days. Baseline samples of blood (-15 and 0 minutes) were drawn through an indwelling 19 gauge needle and further blood samples ;vere obtained at 15, 30, 45, 60, and 90 minutes after injection of LHRH. Clomiphene studies. Ten of the subjects (aged 21 to 34) were given 100 mg of clomiphene citrate orally for 5 days. Two weeks later the subjects received 100 mg of clomiphene citrate daily with simultaneous administration of dexamethasone, 2 mg orally every 6 hours for 5 days. On each occasion three blood samples were drawn at 0800, 0900, and 1000 hours prior to (day 1) and after (day 6) clomiphene citrate administration. Radioimmunoa~says. Serum was stored at - 20° C and all LH and FSH samples from each study were measured in duplicate in one assay to avoid interassay variation. Serum levels of LH and FSH were measured by double-antibody radioimmunoassays; human antipituitary preparation LE-907 supplied by the National Pituitary Agency was used as the assay standard. 7 The iower iimits of sensitivity were 1.0 rniU/ml for LH and 0.5 miU/ml for FSH. The within-assay coefficients ~~· .,~...;~.;~~ wa~a
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Statistics. Statistical comparisons of serum hormone
responses to LHRH and clomiphene before and after dexamethasone administration were made with Student's paired t test.
Resu!ts The average basal (mean of -15 and 0 values) serum LH level for the six women receiving LHRH was significantly less (p < 0.025) after administration of dexamethasone (5.5 ± 2.5 miU/ml) than with no pretreatment (10.2 ± 3.7 miU/ml) (Fig. 1). The mean serum LH response to LHRH in the six \vomen after dexamethasone was less (p < 0.05) at the sampling times of! 5; 45; 60; and 90 minutes after LHRH administration than the response with no dexamethasone pretreatment (Fig. 1). Dexamethasone administration resulted in a reduction (p < 0.01) in the average basal serum FSH value from 3.7 ± 0.3 miU/ml to 2.7 ± 0.3 miU/ml (Fig. 2). The FSH response to LHRH in these six women was less (p < 0.005) after dexamethasone pretreatment at all sampling times from 15 through 90 minutes after LHRH administration. Table I shows that administration of dexamethasone in 10 subjects resulted in a reduction (p < 0.01) in the incremental LH and FSH responses to clomiphene citrate.
Comment In this study basal levels of LH and FSH were clearly lowered by short-term administration ofhigh doses of dexamethasone, ·v;hich is in a-greement with a previous observation in young women 6 and which differs from
Effect of dexamethasone on gonadotropin responsiveness
Volume 134 Number 3
327
Table I. rvfean (± standard error of the mean) responses of LH and FSH in 10 \Vomen after oral administration of 100 mg of clomiphene citrate daily for 5 days
No dexamethasone With dexamethasone
Baseline LH (miU/ml)
Baseline FSH (miU/ml)
LH after clomiphene (mlU/ml)
FSH after clomiphene (miU!ml)
5.0 ± 0.7 4.9 ± 0.7
2.7 ± 0.5 2.7 ± 0.4
8.8 ± 1.4 5.9 ± 1.2
4.0 ± 0.6 3.3 ± 0.5
BFSH (mlU/ml)
3.8 ± 0.8
1.1 * ± 0.6
1.2 ± 0.2 0.6* ± 0.1
*Significant difference in the response to clomiphene during oral dexamethasone (2 mg every 6 hours) compared to the response in the absence of dexamethasone administration.
the previous report of no suppression by glucocorticoids of FSH levels in young men. o These observed differences in the effects of glucocorticoids on basal LH and FSH secretion are probably related to dose and duration of administration and to sexually related differences in sensitivity to glucocorticoid suppression. Sowers and co-workers 8 have previously shown that short-term high-dose dexamethasone administration suppresses basal thyroid-stimulating hormone (TSH) and prolactin (PRL) secretion in man. The results of these studies may indicate that pharmacologic doses of glucocorticoids exert a general inhibitory effect on the basal secretion of anterior pituitary hormones. The observation in this study that short-term administration of high doses of dexamethasone suppresses the LH and FSH response to LHRH and clomiphene is consistent with prior observations in women receiving long-term glucocorticoid therapy. 1 The findings in these studies indicate a direct inhibitory effect of glucocorticoids at the level of the anterior pituitary. Clomiphene citrate stimulates gonadotropin secretion, probably by competing for gonadal steroid binding sites in the hypothalamus, thus blocking the negative feedback action of estrogen on LHRH secretion. 9 Our observation that dexamethasone administration inhib-
REFERENCES l. Sakakura, M., Takebe, K., and Nakagawa, S.: Inhibition
2.
3.
4. 5.
of luteinizing hormone secretion induced by synthetic LRH in long-term treatment with glucocorticoids in human subjects,]. Clin. Endocrinol. Metab. 40:774, 1975. Zor. U., Ailabonni, H., and Sulman, F. G.: The combined effects of monamine oxidase inhibitors and corticosteroids on the pituitary-gonadal system of male rats, J. Endocrinol. 35:217, 1966. Euker, J. S., Meites, J., and Reigle, G. D.: Effects of acute stress on serum LH and prolactin in intact, castrate and dexamethasone-treated male rats, Endocrinology 96:85, 1975. Baldwin, M.D., and Sawyer, C. H.: Effects of dexamethasone on LH release and ovulation in the cyclic rat, Endocrinology 94:1397, 1974. Faiman, C., and Winter,]. S.D.: Diurnal cycles in plasma FSH, testosterone and cortisol in man, J. Clin. Endocrinol. Meta b. 33: 186, 1971.
its the LH and FSH response to clomiphene suggests that glucocorticoids may also act at the level of the hypothalamus to inhibit the release of LHRH. In support of this concept is the previous observation that cortisol implants in the medial basal hypothalamus in immature rats delay sexual maturation, 10 suggesting an action of glucocorticoids at the suprahypophyseal level. However, the blunted gonadotropin response to clomiphene that we observed could also represent direct inhibition by glucocorticoids at the level of the anterior pituitary. In man glucocorticoids exert suppressive effects at the hypothalamic-pituitary level not specific to the adrenocorticotropic axis. Glucocorticoids suppress hypoglycemia-induced growth hormone release, 1 1• 12 eliminate the periodicity of TSH secretion, 13 and biunt the TSH and PRL response to thyrotropin-releasing hormone. 8 • 14 • 1 .; We further observed that glucocorticoids lower basal secretion of LH and FSH and blunt the gonadotropin response to LHRH and clomiphene in women with disorders of menstruation. However, these observations may not be applicable to \Vomen with normal menstrual cycles. The authors v,-ish to thank ~~1s. Jean Graeff for the preparation of the manuscript.
6. Cortis-Gallegos. V., Gallegos, A. J., Bedolla Tovar, N., Cervantes, D., and Parra, A.: Effect of paramethasone acetate on ovarian steroids and gonadotropins. I. Normal menstrual cycle,]. Clin. Endocrrnol. Metab. 41:215, 1975. 7. Midgley, A. R.: Radioimmunoassay for follicle-stimulating hormone,]. Clin. Endocrinol. Metah. 27:29.5, 1967. 8. Sowers, J. R., Carlson, H. E., Brautbar, N., and Hershman, J. M.: Effect of dexamethasone on prolactin and TSH responses to TRH and rrietoclopramide in man, J. Clin. Endocrinol. Metab. 44:237, 1977. 9. McArthur, J.: Induction of ovulation, in Givens, J. R., editor: Gynecologic Endocrinology. 1st Edition. Chicago, 1977, Year Book Medical Publishers, Inc., pp. 143-156. 10. Smith, E. R., Johnson, J., and Weich, R. F.: Inhibition of the reproductive system in immature rats by intracerebral implantation of cortisol, Neuroendocrinology 8:94, 1971. II. Frantz, A. G., and Rabkin, M. T.: Clinical measurement response to hypoglycemia and suppression by corticosteroids, N. Engl.J. Med. 271:1375, 1964.
328
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of plasma f\rowth hormone and corticosteroids to insulin and arginine with or without prior administration of dexamethasone,]. Clin. Endocrinol. Metab. 29:35. 1969. l:l. 1\'icoloff, .J. T., Fisher, D. A., and Applem;m, M.D.: The role of glucocorticoids in the regulation of thyroid function in man, J. Clin. Invest. 49:1922, 1970. 14. Dussalt, J. H.: The effect of dexamethasone on TSH and prola('tin secret inn after ·rRH ~timulation, Can ~-led. A~.; soc..J. 111:1195,197-1.
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ann nana, ~.:
June l. Jqitet (;,new!
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glucocorticoids on TRH-induced TSH response in man. J. Clin. Endocrinol. Metab. 36:95, Jfl7:l. Hi. Capinski, G .. L'Hermite. :\L Ledet
Copyright information
The appearance of a code at the bottom of the first page of an original article in this JouRNAL indicates the copyright owner's consent that copies of the article may be i:nad(' for personal or internal use, or for the personal or internal use of specific clients, This consent is given on the condition, however, that the copier pay the stated per copy fee through the Copyright Clearance Center, Inc., P.O. Box 765, Schenectady, 1\i. Y. 1230.1, (518) 374-4430, for copying beyond that permitted by Section i07 or i08 of the U. S. Copyright Law. This consent does not extend to other kinds of copying, such as copying for general distribution, for advertising or promotional ptir~"Jses, for creating-ncn· ciJllective works, or for resale.
IT HAS BEEl\' PREVIOUSLY observed that women experience disorders of menstruation when receiving glucocorticoids. 1 Evidence from animal studies suggests that the suppressive effects of glucocorticoids on the hypothalamic-pituitary axis are exerted by impairment of gonadotropin secretion by a direct action on the anterior pituitary or by their effects at the suprahypophyseal level with inhibition of release of luteinizing hormone-releasing hormone (LHRH). 2- 4 One prior report indicated that short term administration of dexamethasone did not result in suppression of basal levels of follicle-stimulating hormone (FSH) in man:' Long-term administration of glucocorticoids has been shown to suppress basal and midcycle luteinizing From the Endocrine Section, Departmmt of Medicine and Department of Obstetrics and G}necology, University of Missouri. Receivedfor publication April 7, 1978. Acceptedjuly 13, 1978. Reprint requests: Dr. James R. Sowers, Endocrine Research Laboratory, Universiry of Missouri at Kansas City, 2411 Holmes St., Kansas City, Missouri 64108.
0002-9378179/110325+04$00.40/0
©
1979 The C. V. Mosby Co.
hormone (LH) peak levels in normally cycling women 6 and to suppress the LH response to LHRH in women with disorders of menstruation. 1 The present study was performed to determine the effects of short-term administration of high doses of glucocorticoids on LH and FSH responses to LHRH and clomiphene in women with secondary amenorrhea.
Material and methods Sixteen women (aged 21 to 37 years) with secondary amenorrhea and infertility were studied. The subjects had normal serum prolactin levels, normal lateral skull films, and normal visual fields and none had galactorrhea. Most of these patients were obese; they had high normal LH and normal FSH levels and slightly elevated serum testosterone and urinary 17-ketosteroid levels. The diagnosis of polycystic ovary disease was confirmed at laporoscopy in four of the subjects. · LHRH studies. Six women (aged 23 to 37) were given an intravenous bolus of 100 ~J-g of LHRH at 0800 hours before and after they received dexamethasone, 2
325
326 Sowers and Fayez Am.
.
J
.June I. 1979 Obstet. (,vnt·tol
7.0-
50
2D 1.0 0~--,----r---.---,---,.---,
-15
0
15
30
45
60
90
Fig. 2. Mean serum FSH responses to LHRH (given at 0 time) in six women with secondary amenorrhea before (solid-line) and after (broken line) dexamethasone administration; vertical bars show standard errors of the means.
I
15
I
I
30 MlrMes
90
Fig. 1. Mean serum LH responses to LHRH (given at 0 time) in six women with secondary amenorrhea before (solid line) and after (broken line) dexamethasone administration; vertical bars show standard errors of the means.
mg orally every 6 hours for 5 days. Baseline samples of blood (-15 and 0 minutes) were drawn through an indwelling 19 gauge needle and further blood samples ;vere obtained at 15, 30, 45, 60, and 90 minutes after injection of LHRH. Clomiphene studies. Ten of the subjects (aged 21 to 34) were given 100 mg of clomiphene citrate orally for 5 days. Two weeks later the subjects received 100 mg of clomiphene citrate daily with simultaneous administration of dexamethasone, 2 mg orally every 6 hours for 5 days. On each occasion three blood samples were drawn at 0800, 0900, and 1000 hours prior to (day 1) and after (day 6) clomiphene citrate administration. Radioimmunoa~says. Serum was stored at - 20° C and all LH and FSH samples from each study were measured in duplicate in one assay to avoid interassay variation. Serum levels of LH and FSH were measured by double-antibody radioimmunoassays; human antipituitary preparation LE-907 supplied by the National Pituitary Agency was used as the assay standard. 7 The iower iimits of sensitivity were 1.0 rniU/ml for LH and 0.5 miU/ml for FSH. The within-assay coefficients ~~· .,~...;~.;~~ wa~a
VI.
"CI.J.J.CI.UVJ.J.
VV\...J.\,..
r;. 101.
..Jo.A./U
+~~ J."-'.l
TU
......,.._..,
~nrl
QJ.J....._
L1.LooJ/V 001. ..._.._, +nr J<'O:J-I ... .a. .....,..._£•
Statistics. Statistical comparisons of serum hormone
responses to LHRH and clomiphene before and after dexamethasone administration were made with Student's paired t test.
Resu!ts The average basal (mean of -15 and 0 values) serum LH level for the six women receiving LHRH was significantly less (p < 0.025) after administration of dexamethasone (5.5 ± 2.5 miU/ml) than with no pretreatment (10.2 ± 3.7 miU/ml) (Fig. 1). The mean serum LH response to LHRH in the six \vomen after dexamethasone was less (p < 0.05) at the sampling times of! 5; 45; 60; and 90 minutes after LHRH administration than the response with no dexamethasone pretreatment (Fig. 1). Dexamethasone administration resulted in a reduction (p < 0.01) in the average basal serum FSH value from 3.7 ± 0.3 miU/ml to 2.7 ± 0.3 miU/ml (Fig. 2). The FSH response to LHRH in these six women was less (p < 0.005) after dexamethasone pretreatment at all sampling times from 15 through 90 minutes after LHRH administration. Table I shows that administration of dexamethasone in 10 subjects resulted in a reduction (p < 0.01) in the incremental LH and FSH responses to clomiphene citrate.
Comment In this study basal levels of LH and FSH were clearly lowered by short-term administration ofhigh doses of dexamethasone, ·v;hich is in a-greement with a previous observation in young women 6 and which differs from
Effect of dexamethasone on gonadotropin responsiveness
Volume 134 Number 3
327
Table I. rvfean (± standard error of the mean) responses of LH and FSH in 10 \Vomen after oral administration of 100 mg of clomiphene citrate daily for 5 days
No dexamethasone With dexamethasone
Baseline LH (miU/ml)
Baseline FSH (miU/ml)
LH after clomiphene (mlU/ml)
FSH after clomiphene (miU!ml)
5.0 ± 0.7 4.9 ± 0.7
2.7 ± 0.5 2.7 ± 0.4
8.8 ± 1.4 5.9 ± 1.2
4.0 ± 0.6 3.3 ± 0.5
BFSH (mlU/ml)
3.8 ± 0.8
1.1 * ± 0.6
1.2 ± 0.2 0.6* ± 0.1
*Significant difference in the response to clomiphene during oral dexamethasone (2 mg every 6 hours) compared to the response in the absence of dexamethasone administration.
the previous report of no suppression by glucocorticoids of FSH levels in young men. o These observed differences in the effects of glucocorticoids on basal LH and FSH secretion are probably related to dose and duration of administration and to sexually related differences in sensitivity to glucocorticoid suppression. Sowers and co-workers 8 have previously shown that short-term high-dose dexamethasone administration suppresses basal thyroid-stimulating hormone (TSH) and prolactin (PRL) secretion in man. The results of these studies may indicate that pharmacologic doses of glucocorticoids exert a general inhibitory effect on the basal secretion of anterior pituitary hormones. The observation in this study that short-term administration of high doses of dexamethasone suppresses the LH and FSH response to LHRH and clomiphene is consistent with prior observations in women receiving long-term glucocorticoid therapy. 1 The findings in these studies indicate a direct inhibitory effect of glucocorticoids at the level of the anterior pituitary. Clomiphene citrate stimulates gonadotropin secretion, probably by competing for gonadal steroid binding sites in the hypothalamus, thus blocking the negative feedback action of estrogen on LHRH secretion. 9 Our observation that dexamethasone administration inhib-
REFERENCES l. Sakakura, M., Takebe, K., and Nakagawa, S.: Inhibition
2.
3.
4. 5.
of luteinizing hormone secretion induced by synthetic LRH in long-term treatment with glucocorticoids in human subjects,]. Clin. Endocrinol. Metab. 40:774, 1975. Zor. U., Ailabonni, H., and Sulman, F. G.: The combined effects of monamine oxidase inhibitors and corticosteroids on the pituitary-gonadal system of male rats, J. Endocrinol. 35:217, 1966. Euker, J. S., Meites, J., and Reigle, G. D.: Effects of acute stress on serum LH and prolactin in intact, castrate and dexamethasone-treated male rats, Endocrinology 96:85, 1975. Baldwin, M.D., and Sawyer, C. H.: Effects of dexamethasone on LH release and ovulation in the cyclic rat, Endocrinology 94:1397, 1974. Faiman, C., and Winter,]. S.D.: Diurnal cycles in plasma FSH, testosterone and cortisol in man, J. Clin. Endocrinol. Meta b. 33: 186, 1971.
its the LH and FSH response to clomiphene suggests that glucocorticoids may also act at the level of the hypothalamus to inhibit the release of LHRH. In support of this concept is the previous observation that cortisol implants in the medial basal hypothalamus in immature rats delay sexual maturation, 10 suggesting an action of glucocorticoids at the suprahypophyseal level. However, the blunted gonadotropin response to clomiphene that we observed could also represent direct inhibition by glucocorticoids at the level of the anterior pituitary. In man glucocorticoids exert suppressive effects at the hypothalamic-pituitary level not specific to the adrenocorticotropic axis. Glucocorticoids suppress hypoglycemia-induced growth hormone release, 1 1• 12 eliminate the periodicity of TSH secretion, 13 and biunt the TSH and PRL response to thyrotropin-releasing hormone. 8 • 14 • 1 .; We further observed that glucocorticoids lower basal secretion of LH and FSH and blunt the gonadotropin response to LHRH and clomiphene in women with disorders of menstruation. However, these observations may not be applicable to \Vomen with normal menstrual cycles. The authors v,-ish to thank ~~1s. Jean Graeff for the preparation of the manuscript.
6. Cortis-Gallegos. V., Gallegos, A. J., Bedolla Tovar, N., Cervantes, D., and Parra, A.: Effect of paramethasone acetate on ovarian steroids and gonadotropins. I. Normal menstrual cycle,]. Clin. Endocrrnol. Metab. 41:215, 1975. 7. Midgley, A. R.: Radioimmunoassay for follicle-stimulating hormone,]. Clin. Endocrinol. Metah. 27:29.5, 1967. 8. Sowers, J. R., Carlson, H. E., Brautbar, N., and Hershman, J. M.: Effect of dexamethasone on prolactin and TSH responses to TRH and rrietoclopramide in man, J. Clin. Endocrinol. Metab. 44:237, 1977. 9. McArthur, J.: Induction of ovulation, in Givens, J. R., editor: Gynecologic Endocrinology. 1st Edition. Chicago, 1977, Year Book Medical Publishers, Inc., pp. 143-156. 10. Smith, E. R., Johnson, J., and Weich, R. F.: Inhibition of the reproductive system in immature rats by intracerebral implantation of cortisol, Neuroendocrinology 8:94, 1971. II. Frantz, A. G., and Rabkin, M. T.: Clinical measurement response to hypoglycemia and suppression by corticosteroids, N. Engl.J. Med. 271:1375, 1964.
328
Sowers and Fayez \m
1 U
1 L.
""1 1_ _ _ _ ~~cu.;
_
TT
"I" 1 ___ '
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of plasma f\rowth hormone and corticosteroids to insulin and arginine with or without prior administration of dexamethasone,]. Clin. Endocrinol. Metab. 29:35. 1969. l:l. 1\'icoloff, .J. T., Fisher, D. A., and Applem;m, M.D.: The role of glucocorticoids in the regulation of thyroid function in man, J. Clin. Invest. 49:1922, 1970. 14. Dussalt, J. H.: The effect of dexamethasone on TSH and prola('tin secret inn after ·rRH ~timulation, Can ~-led. A~.; soc..J. 111:1195,197-1.
l.ii. ()Lsuki . .\1., uaKoru,
t\<1..
J
ann nana, ~.:
June l. Jqitet (;,new!
inHueJHT oi
glucocorticoids on TRH-induced TSH response in man. J. Clin. Endocrinol. Metab. 36:95, Jfl7:l. Hi. Capinski, G .. L'Hermite. :\L Ledet
Copyright information
The appearance of a code at the bottom of the first page of an original article in this JouRNAL indicates the copyright owner's consent that copies of the article may be i:nad(' for personal or internal use, or for the personal or internal use of specific clients, This consent is given on the condition, however, that the copier pay the stated per copy fee through the Copyright Clearance Center, Inc., P.O. Box 765, Schenectady, 1\i. Y. 1230.1, (518) 374-4430, for copying beyond that permitted by Section i07 or i08 of the U. S. Copyright Law. This consent does not extend to other kinds of copying, such as copying for general distribution, for advertising or promotional ptir~"Jses, for creating-ncn· ciJllective works, or for resale.