Regulation of extragonadal insulin-like growth factor-binding protein-3 by testosterone in oophorectomized women

R. Azziz, C. L. Deal, H. D. Potter, S. E. Gargosky, Ronald (Ron) Rosenfeld

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3) is the principal carrier protein of IGF-I in the circulation. IGF-I has been postulated to play a role in the genesis and maintenance of the polycystic ovary syndrome. Regardless of the exact mechanism of action of IGF-I on ovarian steroidogenesis, alterations in the level of IGFBP-3 may play a significant role in regulating the concentration of IGF-I in hyperandrogenism. We have postulated that androgens reduce the circulating IGFBP-3 concentration through a mechanism similar to its suppression of the hepatic production of sex hormone-binding globulin (SHBG), thereby increasing bioavailable IGF-I and amplifying its impact on ovarian steroidogenesis. To test this hypothesis, we studied seven oophorectomized women (aged 39-51 yr; body mass, 20.9-35.8 kg/m2) during 3 weeks of testosterone (T) propionate administration (20 mg, three times weekly). All subjects were receiving 0.625 or 1.25 mg conjugated estrogens/day. Blood was sampled before (week 0), during (weeks 1-3), and after (week 4) T administration. Serum was assayed for total T, GH, and SHBG, and plasma was assessed for IGF-I, insulin (INS), and IGFBP-3. IGFBP-3 was measured by both RIA and Western ligand blotting; (expressed as a percentage of the control value). Circulating T increased from 1.51 ± 1.06 to 30.8 ± 13.8 nmol/ L by week 2 (P <0.001). During T administration, IGF-I increased (from 55 ± 23 ng/mL at week 0 to 124 ± 37 ng/mL at week 4; P <0.05); INS did not change, with the exception of a higher fasting level 1 week after discontinuing therapy, and GH decreased (from 1.7 ± 2.3 μg/L at week 0 to 0.4 ± 0.4 μg/L at week 4; P <0.03), as did the circulating SHBG concentration (397 ± 205 to 273 ± 93 nmol/L by week 2; P <0.01). IGFBP-3 levels determined by Western ligand blot were higher during the second and third weeks of T administration (265 ± 28% and 218 ± 43% of control values, respectively; P <0.05) compared to that at week 0 (165 ± 44% of control values). However, there was no difference in the circulating concentration of IGFBP-3, determined by RIA, at weeks 0, 1, 3, and 4 (3.59 ± 0.35, 4.00 ± 0.79, 3.48 ± 0.56, and 3.65 ± 0.52 μg/mL, respectively). Nonetheless, the plasma IGF-I concentration increased (from 55.0 ± 23.4 μg/mL at week 0 to 123.9 ± 37.3 μg/mL at week 4; P <0.05), and the immunoreactive IGF-I to IGFBP-3 ratio increased linearly (from 16.1 ± 5.7 at week 0 to 27.6 ± 8.7 at week 4; P <0.03). In conclusion, an increase in the circulating T concentration did not suppress circulating IGFBP-3 levels, as occurred with SHBG. Nonetheless, a linear increase in the IGF-I to IGFBP-3 ratio was noted, suggesting that free IGF-I may increase with androgen excess. The clinical significance of these findings in the maintenance of the polycystic ovary syndrome remains to be determined, because the T levels achieved in this study were well above those normally found in affected women. Finally, the impact of androgens on hepatic production/secretion appears to differ for SHBG vs. IGFBP-3.

Original languageEnglish (US)
Pages (from-to)1747-1751
Number of pages5
JournalJournal of Clinical Endocrinology and Metabolism
Volume79
Issue number6
StatePublished - Dec 1994

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Insulin-Like Growth Factor Binding Protein 3
Insulin-Like Growth Factor I
Testosterone
Sex Hormone-Binding Globulin
Androgens
Polycystic Ovary Syndrome
Western Blotting
Maintenance
Insulin
Ligands
Hyperandrogenism
Plasmas
Conjugated (USP) Estrogens
Testosterone Propionate
Liver
Propionates
Fasting
Carrier Proteins
Blood

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology, Diabetes and Metabolism

Cite this

Regulation of extragonadal insulin-like growth factor-binding protein-3 by testosterone in oophorectomized women. / Azziz, R.; Deal, C. L.; Potter, H. D.; Gargosky, S. E.; Rosenfeld, Ronald (Ron).

In: Journal of Clinical Endocrinology and Metabolism, Vol. 79, No. 6, 12.1994, p. 1747-1751.

Research output: Contribution to journalArticle

Azziz, R. ; Deal, C. L. ; Potter, H. D. ; Gargosky, S. E. ; Rosenfeld, Ronald (Ron). / Regulation of extragonadal insulin-like growth factor-binding protein-3 by testosterone in oophorectomized women. In: Journal of Clinical Endocrinology and Metabolism. 1994 ; Vol. 79, No. 6. pp. 1747-1751.
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abstract = "Insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3) is the principal carrier protein of IGF-I in the circulation. IGF-I has been postulated to play a role in the genesis and maintenance of the polycystic ovary syndrome. Regardless of the exact mechanism of action of IGF-I on ovarian steroidogenesis, alterations in the level of IGFBP-3 may play a significant role in regulating the concentration of IGF-I in hyperandrogenism. We have postulated that androgens reduce the circulating IGFBP-3 concentration through a mechanism similar to its suppression of the hepatic production of sex hormone-binding globulin (SHBG), thereby increasing bioavailable IGF-I and amplifying its impact on ovarian steroidogenesis. To test this hypothesis, we studied seven oophorectomized women (aged 39-51 yr; body mass, 20.9-35.8 kg/m2) during 3 weeks of testosterone (T) propionate administration (20 mg, three times weekly). All subjects were receiving 0.625 or 1.25 mg conjugated estrogens/day. Blood was sampled before (week 0), during (weeks 1-3), and after (week 4) T administration. Serum was assayed for total T, GH, and SHBG, and plasma was assessed for IGF-I, insulin (INS), and IGFBP-3. IGFBP-3 was measured by both RIA and Western ligand blotting; (expressed as a percentage of the control value). Circulating T increased from 1.51 ± 1.06 to 30.8 ± 13.8 nmol/ L by week 2 (P <0.001). During T administration, IGF-I increased (from 55 ± 23 ng/mL at week 0 to 124 ± 37 ng/mL at week 4; P <0.05); INS did not change, with the exception of a higher fasting level 1 week after discontinuing therapy, and GH decreased (from 1.7 ± 2.3 μg/L at week 0 to 0.4 ± 0.4 μg/L at week 4; P <0.03), as did the circulating SHBG concentration (397 ± 205 to 273 ± 93 nmol/L by week 2; P <0.01). IGFBP-3 levels determined by Western ligand blot were higher during the second and third weeks of T administration (265 ± 28{\%} and 218 ± 43{\%} of control values, respectively; P <0.05) compared to that at week 0 (165 ± 44{\%} of control values). However, there was no difference in the circulating concentration of IGFBP-3, determined by RIA, at weeks 0, 1, 3, and 4 (3.59 ± 0.35, 4.00 ± 0.79, 3.48 ± 0.56, and 3.65 ± 0.52 μg/mL, respectively). Nonetheless, the plasma IGF-I concentration increased (from 55.0 ± 23.4 μg/mL at week 0 to 123.9 ± 37.3 μg/mL at week 4; P <0.05), and the immunoreactive IGF-I to IGFBP-3 ratio increased linearly (from 16.1 ± 5.7 at week 0 to 27.6 ± 8.7 at week 4; P <0.03). In conclusion, an increase in the circulating T concentration did not suppress circulating IGFBP-3 levels, as occurred with SHBG. Nonetheless, a linear increase in the IGF-I to IGFBP-3 ratio was noted, suggesting that free IGF-I may increase with androgen excess. The clinical significance of these findings in the maintenance of the polycystic ovary syndrome remains to be determined, because the T levels achieved in this study were well above those normally found in affected women. Finally, the impact of androgens on hepatic production/secretion appears to differ for SHBG vs. IGFBP-3.",
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T1 - Regulation of extragonadal insulin-like growth factor-binding protein-3 by testosterone in oophorectomized women

AU - Azziz, R.

AU - Deal, C. L.

AU - Potter, H. D.

AU - Gargosky, S. E.

AU - Rosenfeld, Ronald (Ron)

PY - 1994/12

Y1 - 1994/12

N2 - Insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3) is the principal carrier protein of IGF-I in the circulation. IGF-I has been postulated to play a role in the genesis and maintenance of the polycystic ovary syndrome. Regardless of the exact mechanism of action of IGF-I on ovarian steroidogenesis, alterations in the level of IGFBP-3 may play a significant role in regulating the concentration of IGF-I in hyperandrogenism. We have postulated that androgens reduce the circulating IGFBP-3 concentration through a mechanism similar to its suppression of the hepatic production of sex hormone-binding globulin (SHBG), thereby increasing bioavailable IGF-I and amplifying its impact on ovarian steroidogenesis. To test this hypothesis, we studied seven oophorectomized women (aged 39-51 yr; body mass, 20.9-35.8 kg/m2) during 3 weeks of testosterone (T) propionate administration (20 mg, three times weekly). All subjects were receiving 0.625 or 1.25 mg conjugated estrogens/day. Blood was sampled before (week 0), during (weeks 1-3), and after (week 4) T administration. Serum was assayed for total T, GH, and SHBG, and plasma was assessed for IGF-I, insulin (INS), and IGFBP-3. IGFBP-3 was measured by both RIA and Western ligand blotting; (expressed as a percentage of the control value). Circulating T increased from 1.51 ± 1.06 to 30.8 ± 13.8 nmol/ L by week 2 (P <0.001). During T administration, IGF-I increased (from 55 ± 23 ng/mL at week 0 to 124 ± 37 ng/mL at week 4; P <0.05); INS did not change, with the exception of a higher fasting level 1 week after discontinuing therapy, and GH decreased (from 1.7 ± 2.3 μg/L at week 0 to 0.4 ± 0.4 μg/L at week 4; P <0.03), as did the circulating SHBG concentration (397 ± 205 to 273 ± 93 nmol/L by week 2; P <0.01). IGFBP-3 levels determined by Western ligand blot were higher during the second and third weeks of T administration (265 ± 28% and 218 ± 43% of control values, respectively; P <0.05) compared to that at week 0 (165 ± 44% of control values). However, there was no difference in the circulating concentration of IGFBP-3, determined by RIA, at weeks 0, 1, 3, and 4 (3.59 ± 0.35, 4.00 ± 0.79, 3.48 ± 0.56, and 3.65 ± 0.52 μg/mL, respectively). Nonetheless, the plasma IGF-I concentration increased (from 55.0 ± 23.4 μg/mL at week 0 to 123.9 ± 37.3 μg/mL at week 4; P <0.05), and the immunoreactive IGF-I to IGFBP-3 ratio increased linearly (from 16.1 ± 5.7 at week 0 to 27.6 ± 8.7 at week 4; P <0.03). In conclusion, an increase in the circulating T concentration did not suppress circulating IGFBP-3 levels, as occurred with SHBG. Nonetheless, a linear increase in the IGF-I to IGFBP-3 ratio was noted, suggesting that free IGF-I may increase with androgen excess. The clinical significance of these findings in the maintenance of the polycystic ovary syndrome remains to be determined, because the T levels achieved in this study were well above those normally found in affected women. Finally, the impact of androgens on hepatic production/secretion appears to differ for SHBG vs. IGFBP-3.

AB - Insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3) is the principal carrier protein of IGF-I in the circulation. IGF-I has been postulated to play a role in the genesis and maintenance of the polycystic ovary syndrome. Regardless of the exact mechanism of action of IGF-I on ovarian steroidogenesis, alterations in the level of IGFBP-3 may play a significant role in regulating the concentration of IGF-I in hyperandrogenism. We have postulated that androgens reduce the circulating IGFBP-3 concentration through a mechanism similar to its suppression of the hepatic production of sex hormone-binding globulin (SHBG), thereby increasing bioavailable IGF-I and amplifying its impact on ovarian steroidogenesis. To test this hypothesis, we studied seven oophorectomized women (aged 39-51 yr; body mass, 20.9-35.8 kg/m2) during 3 weeks of testosterone (T) propionate administration (20 mg, three times weekly). All subjects were receiving 0.625 or 1.25 mg conjugated estrogens/day. Blood was sampled before (week 0), during (weeks 1-3), and after (week 4) T administration. Serum was assayed for total T, GH, and SHBG, and plasma was assessed for IGF-I, insulin (INS), and IGFBP-3. IGFBP-3 was measured by both RIA and Western ligand blotting; (expressed as a percentage of the control value). Circulating T increased from 1.51 ± 1.06 to 30.8 ± 13.8 nmol/ L by week 2 (P <0.001). During T administration, IGF-I increased (from 55 ± 23 ng/mL at week 0 to 124 ± 37 ng/mL at week 4; P <0.05); INS did not change, with the exception of a higher fasting level 1 week after discontinuing therapy, and GH decreased (from 1.7 ± 2.3 μg/L at week 0 to 0.4 ± 0.4 μg/L at week 4; P <0.03), as did the circulating SHBG concentration (397 ± 205 to 273 ± 93 nmol/L by week 2; P <0.01). IGFBP-3 levels determined by Western ligand blot were higher during the second and third weeks of T administration (265 ± 28% and 218 ± 43% of control values, respectively; P <0.05) compared to that at week 0 (165 ± 44% of control values). However, there was no difference in the circulating concentration of IGFBP-3, determined by RIA, at weeks 0, 1, 3, and 4 (3.59 ± 0.35, 4.00 ± 0.79, 3.48 ± 0.56, and 3.65 ± 0.52 μg/mL, respectively). Nonetheless, the plasma IGF-I concentration increased (from 55.0 ± 23.4 μg/mL at week 0 to 123.9 ± 37.3 μg/mL at week 4; P <0.05), and the immunoreactive IGF-I to IGFBP-3 ratio increased linearly (from 16.1 ± 5.7 at week 0 to 27.6 ± 8.7 at week 4; P <0.03). In conclusion, an increase in the circulating T concentration did not suppress circulating IGFBP-3 levels, as occurred with SHBG. Nonetheless, a linear increase in the IGF-I to IGFBP-3 ratio was noted, suggesting that free IGF-I may increase with androgen excess. The clinical significance of these findings in the maintenance of the polycystic ovary syndrome remains to be determined, because the T levels achieved in this study were well above those normally found in affected women. Finally, the impact of androgens on hepatic production/secretion appears to differ for SHBG vs. IGFBP-3.

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