Growth Without Growth Hormone Receptor: Estradiol Is a Major Growth Hormone-Independent Regulator of Hepatic IGF-I Synthesis

Abstract

The role of estrogens in the regulation of pubertal growth independently of GH and its receptor was studied in male mice with disrupted GHRKO. E 2 rescued skeletal growth rates in GHRKO associated with an increase in hepatic and serum IGF-I. These data show that E 2 rescues pubertal growth during GH resistance through a novel mechanism of GHR-independent stimulation of hepatic IGF-I production.Introduction: Growth hormone (GH) and estrogen play a pivotal role in pubertal growth and bone mineral acquisition. Estrogens can affect GH secretion and thereby provide a GH-dependent mechanism for their effects on skeletal growth. It is presently unclear if or to what extent estrogens are able to regulate pubertal growth and bone mineral accrual independently of GH and its receptor. Materials and Methods: Estradiol (E 2 ; 0.03 g/day by subcutaneous silastic implants) was administered to orchidectomized (ORX) male mice with disrupted GHR (GHRKO) and corresponding WTs during late puberty (6-10 weeks). Longitudinal and radial bone growth, IGF-I in serum and its expression in liver, muscle, and bone, and liver gene expression were studied by histomorphometry, RIA, RT-PCR, microarrays, and Western blotting, respectively. Results: E 2 stimulated not only longitudinal (femur length and growth plate thickness) and radial growth (cortical thickness and periosteal perimeter), but also rescued longitudinal and periosteal growth rates in ORX GHRKO, whereas no significant changes occurred in WT. E 2 thereby upregulated serum IGF-I and liver IGF-I synthesis (+21% and +52%, respectively) in ORX GHRKO, whereas IGF-I synthesis in femur or muscle was unaffected. Study of the underlying mechanism of the stimulation of hepatic IGF-I expression showed that E 2 restored downregulated receptor signaling systems, such as the estrogen receptor ␣ and the prolactin receptor. E 2 thereby recovered the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway as evidenced by a significantly increased activation of the transcription factor STAT5 in ORX GHRKO. Conclusions: Our data show a stimulation of skeletal growth through upregulation of hepatic IGF-I by a hormone other than GH. E 2 rescues pubertal skeletal growth during GH resistance through a novel mechanism of GHR-independent stimulation of IGF-I synthesis in the liver.

Androgen receptor (AR) in osteocytes is important for the maintenance of male skeletal integrity: Evidence from targeted AR disruption in mouse osteocytes

“…(24,34) Finally, more indirect AR-regulated mechanisms-including an impact on growth hormone secretion and its actions-may also be involved in the development of male cortical bone structure, a concept supported by observations of less cortical bone changes in male orchidectomized growth hormone receptor knockout mice. (35) In conclusion, in male mice, AR activation in osteocytes contributes to the decrease of trabecular bone but appears less or not important for the development of cortical bone during puberty.…”

Beneficial effect of recombinant human growth hormone on the intestinal mucosa barrier of septic rats

“…These findings indicated that sepsis reduced STAT5 phosphorylation and activity in liver as well as plasma IGF-1 following rhGH administration. The study by Venken et al (21) indicated that estradiol restored down-regulated receptor signaling systems, such as the estrogen receptor alpha and the prolactin receptor. Estradiol thereby recovered the JAK/ STAT pathway as evidenced by a significantly increased activation of the transcription factor STAT5.…”

“…In the present study, we used female rats, which mainly secrete estrogen. Estrogen is a major GH-independent regulator of hepatic IGF-1 synthesis (21). We assume that, in septic female rats, estrogen may increase activation of the transcription factor STAT5 and the hepatic IGF-1 gene transcription as well as plasma IGF-1 levels following rhGH administration.…”

The mutual dependence between bone and gonads

“…In addition to the sex steroid hormones, several studies have shown that other hormones negatively regulated by estrogen, such as growth hormone (GH) and insulin-like growth factor 1 (IGF1), may further contribute to the development of the skeletal sexual dimorphism (Lupu et al 2001, Venken et al 2005, Callewaert et al 2010a. IGF1 levels are higher in males vs females during early puberty (Callewaert et al 2010b,c), and mice lacking GH receptor (GHR), IGF1, or both show a severe bone growth retardation (Lupu et al 2001).…”