Ciliary neurotrophic factor inhibits bone formation and plays a sex-specific role in bone growth and remodeling.
"Ciliary neurotrophic factor (CNTF) receptor (CNTFR) expression has been described in osteoblast-like cells, suggesting a role for CNTF in bone metabolism. When bound to CNTF, neuropoietin (NP), or cardiotrophin-like-cytokine (CLC), CNTFR forms a signaling complex with gp130 and the leukemia inhibitory factor receptor, which both play critical roles in bone cell biology. This study aimed to determine the role of CNTFR-signaling cytokines in bone. Immunohistochemistry detected CNTF in osteoblasts, osteocytes, osteoclasts, and proliferating chondrocytes. CNTFR mRNA was detected in primary calvarial osteoblasts and was upregulated during osteoblast differentiation. Treatment of osteoblasts with CNTF or CLC, but not NP, significantly inhibited mineralization and osterix mRNA levels. Twelve-week-old male CNTF ( -/- ) mice demonstrated reduced femoral length, cortical thickness, and periosteal circumference; but femoral trabecular bone mineral density (Tb.BMD) and tibial trabecular bone volume (BV/TV) were not significantly different from wild-type, indicating a unique role for CNTF in bone growth in male mice. In contrast, female CNTF ( -/- ) femora were of normal width, but femoral Tb.BMD, tibial BV/TV, trabecular number, and trabecular thickness were all increased. Female CNTF ( -/- ) tibiae also demonstrated high osteoblast number and mineral apposition rate compared to wild-type littermates, and this was intrinsic to the osteoblast lineage. CNTF is expressed locally in bone and plays a unique role in female mice as an inhibitor of trabecular bone formation and in male mice as a stimulus of cortical growth."
So in males CNTF increases both limb height and torso height(cortical thickness+periosteal circumference). In females, CNTF decreases the number of trabeculae. So different responses to CNTF could explain height differences between males and females.
"Femoral length was significantly lower in CNTF −/− mice of both sexes"
"Global deletion of CNTF resulted in a mild reduction in bone length, consistent with the short bone phenotypes of the gp130 knockout, the LIFR knockout, and the gp130ΔSTAT signaling mutant"
Sexual dimorphism in cortical bone size and strength but not density is determined by independent and time-specific actions of sex steroids and IGF-1: evidence from pubertal mouse models.
"Although it is well established that males acquire more bone mass than females, the underlying mechanism and timing of this sex difference remain controversial. The aim of this study was to assess the relative contribution of sex steroid versus growth hormone-insulin-like growth factor 1 (GH-IGF-1) action to pubertal bone mass acquisition longitudinally in pubertal mice. Radial bone expansion peaked during early puberty (3 to 5 weeks of age) in male and female mice, with significantly more expansion in males than in females (+40%). Concomitantly, in 5 week old male versus female mice, periosteal and endocortical bone formation was higher (+70%) and lower (-47%), respectively, along with higher serum IGF-1 levels during early puberty in male mice. In female mice, ovariectomy increased radial bone expansion during early puberty as well as the endocortical perimeter. In male mice, orchidectomy reduced radial bone expansion only during late puberty (5 to 8 weeks of age), whereas combined androgen and estrogen deficiency modestly decreased radial bone expansion during early puberty, accompanied by lower IGF-1 levels. GHRKO mice with very low IGF-1 levels, on the other hand, showed limited radial bone expansion and no skeletal dimorphism. From these data we conclude that skeletal sexual dimorphism is established during early puberty and depends primarily on GH-IGF-1 action. In males, androgens and estrogens have stimulatory effects on bone size during late and early puberty, respectively. In females, estrogens limit bone size during early puberty. These longitudinal findings in mice provide strong evidence that skeletal dimorphism is determined by independent and time-specific effects of sex steroids and IGF-1."
Remember as shown in the CNTF study, males and females could respond to chemicals differently. Estrogen may inhibit bone growth in females but not in males.
Use of aromatase inhibitors in children and adolescents: what's new?
"Aromatase inhibitors have been reported to increase height prediction in boys with short stature, and in boys and girls with gonadotropin-independent precocious puberty. The following review discusses data published since 2008 regarding the safety and efficacy of aromatase inhibitors in pediatric patients. RECENT FINDINGS: Third-generation aromatase inhibitors in combination with antiandrogens appear effective in preventing bone age advancement and virilization in boys with familial male-limited precocious puberty (FMPP). Letrozole, but not anastrozole, decreased bleeding episodes and bone age advancement in girls with McCune-Albright syndrome (MAS), despite ovarian enlargement. Letrozole-treated boys with idiopathic short stature (ISS) had no loss of bone density but were noted to have more vertebral abnormalities than a placebo group. Two years of letrozole therapy did not increase predicted adult height in pre and peripubertal boys with ISS when re-assessed 4 years after the treatment period. SUMMARY: Aromatase inhibitors together with an antiandrogen appear to be a very promising treatment for FMPP. Further longer-term studies with letrozole are needed in MAS. The prevalence of vertebral deformities should be evaluated prospectively in patients treated with aromatase inhibitors. Adult height data are still lacking in pediatric patients treated with aromatase inhibitors. Two years of therapy in pre and peripubertal short boys does not appear to increase adult height. Hemogram, lipids, and bone density should be periodically assessed in treated patients. Further controlled studies are needed to demonstrate safety and efficacy of aromatase inhibitors in pediatric patients."
So there's not enough evidence that aromatase inhibitors can increase final height in males.
My theory: Estrogen is responsible for decreasing height in women but not men. Aromatase inhibitors in women will increase height but not men. Estrogen therapy will decrease height in women but not men. Men and women respond differently to estrogen.
Skeletal Sexual Dimorphism: Relative Contribution of Sex Steroids, Growth Hormone - Insulin-Like Growth Factor-I (GH-IGF-I) and Mechanical Loading.
"Structural gender differences in bone mass - characterized by wider but not thicker bones - are generally attributed to opposing sex steroid actions in men and women. Recent findings have redefined the traditional concept of sex hormones as the main regulators of skeletal sexual dimorphism. Growth hormone (GH) - insulin-like growth factor-I (IGF-I) action is likely to be the most important determinant of sex differences in bone mass. Estrogens limit periosteal bone expansion but stimulate endosteal bone apposition in females, whereas androgens stimulate radial bone expansion in males[radial = bone width]. Androgens not only act directly on bone through the androgen receptor (AR) but also activate estrogen receptor-alpha or -beta (ERalpha or ERbeta) following aromatization into estrogens. Both AR and ERalpha pathways are needed to optimize radial cortical bone expansion, whereas AR signaling alone is the dominant pathway for normal male trabecular bone development. Estrogen/ERalpha-mediated effects in males may - at least partly - depend on interaction with IGF-I. In addition, sex hormones and their receptors impact on the mechanical sensitivity of the growing skeleton. AR and ERalpha signaling may limit the osteogenic response to loading in males and females, respectively, while ERalpha may stimulate the response of bone to mechanical stimulation in the female skeleton. Overall, current evidence suggests that skeletal sexual dimorphism is not just the end result of differences in sex steroid secretion between sexes, but depends on gender differences in GH-IGF-I and mechanical sensitivity to loading as well."
So you may not need an aromatase inhibitor but an aromatase receptor inhibitor. Sex related differences are due to how different pathways respond to stimulus.
The age of puberty determines sexual dimorphism in bone structure: a male/female co-twin control study.
"We hypothesized that sex differences in stature and bone structure are the result of sex differences in the duration but not the rate of prepubertal and pubertal growth.
We measured bone dimensions in 90 male/female co-twin pairs aged 7–18 yr using anthropometry and dual x-ray absorptiometry. Forty-two pairs had follow-up assessments. Within-pair differences were expressed as a percentage of the pair mean.
Thirty percent of the 1–1.5 SD sex difference in bone widths and midfemur bending strength observed in 11 postpubertal pairs was present in 43 prepubertal pairs. In prepubertal pairs, annual growth in leg length was about 1.5 times truncal growth, but neither rate differed by sex. During puberty, truncal growth in both sexes was higher than before puberty but did not differ by sex. The longer period of pre- and intrapubertal growth in males produced most of the sex difference in bone morphology observed in postpubertal twins.
Sex differences in bone morphology are the result of the later onset of puberty in males, not more rapid growth. Differences in bone widths are partly established before puberty."<-this means that age of puberty matters for height growth but not that other factors don't matter.
"Of the 90 male/female pairs, 66 were concordant for pubertal stage (43 pre-, 12 peri-, and 11 postpubertal), and 24 were discordant with females being more advanced in maturity than males (16 pre/peri, seven peri/post, and one pre/post). In the prepubertal twins, there were no sex differences in height, sitting height, leg length, weight, lean mass, fat mass, or hours of weight-bearing exercise (2.2 ± 0.3 vs. 1.7 ± 0.3 h/wk). However, bone widths were 4–7% (∼0.5 SD) greater in prepubertal males than females. This difference was one third of the 12–15% (∼1.5 SD) sex difference in the 11 mature twin pairs"
Thus perhaps constitutional delay can help you grow taller.
Sex-Specific Response of Rat Costochondral Cartilage Growth Plate Chondrocytes to 17β-Estradiol Involves Differential Regulation of Plasma Membrane Associated Estrogen Receptors.
"Both male and female rat growth plate chondrocytes express estrogen receptors (ERs); however 17β-estradiol (E(2)) induces membrane responses leading to activation of phospholipase A(2) (PLA(2)), phospholipase C (PLC), prostaglandin E(2) (PGE(2)) production, protein kinase C (PKC), and ultimately mitogen protein kinase (MAPK) only in female cells. Resting zone chondrocytes (RCs) showed 2-3 times more ERα in plasma membranes (PMs) from female cells than male cells. Tunicamycin blocked E(2)-dependent ER-translocation to the PM, indicating palmitoylation was required. E(2) induced complex formation between ER isoforms only in female RCs. To examine if the lack of response on PKC and PGE(2) in males is due to differences in signaling, we examined involvement of ERs and the role of PLC and PLA(2). Selective ERα (propylpyrazole triol, PPT) and ERβ (diarylproprionitrile, DPN) agonists activated PKC in female RCs only. The PLC inhibitor, U73122 blocked E(2)'s effect on PKC and the cytosolic PLA(2) inhibitor, AACOCF3 inhibited the effect on PGE(2) in female RCs, confirming involvement of PLC and PLA(2) in the mechanism. The PLC activator, m-3M3FβS activated PKC and PLAA peptide increased PGE(2) levels in male and female RCs, showing the signaling pathways are present."
"Although the binding affinity of E2 for ERs in growth plate chondrocytes was comparable in cells from both male and female rats, female cells had greater numbers of receptors than male cells"
"The nuclear fraction from both [male and female resting zone chondrocytes] exhibited all three ERα isoforms: ERα68, ERα46 and ERα36. Plasma membranes from female chondrocytes had all three isoforms, but male cells lacked ERα36. This was also the case for caveolae. ERβ59 was present in plasma membranes and nuclear fraction from female and male cells and was present in caveolae from female cells but not male cells "