Inhibiting Estrogen to Increase Height

It's important to evaluate inhibiting Estrogen to increase height after we found that estrogen inhibits TGF-Beta induced Smad3 signaling which induces chondrogenesis.

Use of aromatase inhibitors to increase final height. 

"During puberty in both sexes, the mechanism involved in epiphyseal fusion is mediated by the action of estrogen through a cascade of events including proliferation, differentiation, and apoptosis of chondrocytes. The enzyme P450 aromatase catalyzes the aromatization of C19 androgens (androstenedione and testosterone) to C18 estrogens (estrone and estradiol). Inhibition of estrogen action by aromatase inhibitors (AIs) appears to decelerate the process of growth plate fusion[Note delaying growth plate fusion may not increase final height if growth velocity does not also increase], and thus AIs may be used therapeutically to increase adult height. The clinical experience with AIs in the pediatric setting is limited to testolactone, fadrozole, letrozole, and anastrozole. Testolactone, a nonselective steroidal AI, has been used successfully as an adjunct to antiandrogen and gonadotropin-releasing hormone analogue (GnRHa), therapy for children with familial male-limited precocious puberty (FMPP) and congenital adrenal hyperplasia (CAH), and with some success in girls with McCune-Albright syndrome. The limitations of testolactone include its relatively low potency and the need for frequent dosing. Results of a randomized placebo-controlled trial in boys with delayed puberty treated with letrozole, a selective nonsteroidal AI, found that boys treated with letrozole + testosterone experienced delayed bone maturation and good growth response and achieved an increase in predicted adult height[keyword: PREDICTED adult height]. In this study, only minor differences in bone density were seen between the placebo and letrozole treatment groups[bone density takes into account bone size as well so that means that bone size did not increase], both of which were receiving concomitant testosterone therapy. No adverse effects on testis size or inhibin B concentration were noted." 

"bone in both men and women has the capacity to convert androgen to estrogen in the bone"

"mean predicted adult stature was 143.0 ± 7.8 cm before treatment and 147.3 ± 11.5 cm after 3 years" with AI treatment.

"an increase in predicted adult height was seen for all but one boy in the letrozole + testosterone group (range, 2.5–8.8 cm); predicted adult height decreased by 3.5 cm for the one remaining boy."

Impact of growth plate senescence on catch-up growth and epiphyseal fusion. 

"In mammals, longitudinal bone growth occurs rapidly in prenatal and early postnatal life, but then slows and eventually ceases. This deceleration, which reflects a decline in chondrocyte proliferation, was previously attributed to a hormonal or other systemic mechanism. However, new evidence suggests that it is due to a local mechanism within the growth plate[See not estrogen, GH, IGF-1, or testosterone]. growth plate chondrocytes have a finite proliferative capacity that is gradually exhausted, causing growth to slow and finally stop." 

"With age, there is a decrease in the overall height of the growth plate, associated with a decline in the number of proliferative and hypertrophic chondrocytes per column. In addition, the individual hypertrophic cells do not grow as large in an older animal, and the columns become more widely spaced with more intervening cartilage matrix. The number of apoptotic growth plate chondrocytes detected by the TUNEL assay increases with age and might thus contribute to the age-dependent decline in growth rate"

"in rabbits, estrogen accelerates growth plate senescence despite decelerating longitudinal bone growth"

"estrogen does not stimulate ossification of cartilage directly but instead accelerates the normal process of growth plate senescence, secondarily inducing earlier fusion"

So, this study states that estrogen can not help increase height because final height is due to a finite proliferative capacity of chondrocytes within the growth plates.  What does that mean for Lateral Synovial Joint Loading? 

Fundamental limits on longitudinal bone growth: growth plate senescence and epiphyseal fusion. 

"The decline in [long bone] growth rate is caused primarily by a decrease in the rate of chondrocyte proliferation and is accompanied by structural changes in growth plate cartilage. This programmed senescence does not appear to be caused by hormonal or other systemic mechanisms but is intrinsic to the growth plate itself. In particular, recent evidence indicates that senescence might occur because stem-like[mesenchymal red bone marrow stem] cells in the resting zone have a finite proliferative capacity, which is exhausted gradually. In some mammals, including humans, proliferative exhaustion is followed by epiphyseal fusion, an abrupt event in which the growth plate cartilage is replaced completely by bone." 

Lateral synovial joint loading helps transport new stem-like cells to the resting zone by distracting the growth plates and increasing interstitial fluid flow which sends red bone marrow stem cells into the growth plates thus potentially restoring proliferative capacity!  Here's a study that states that estrogen inhibition does not impact final height and only growth rate: 

Depletion of resting zone chondrocytes during growth plate senescence. 

"With age, the growth plate undergoes senescent changes that cause linear bone growth to slow and finally cease. Based on previous indirect evidence, we hypothesized that this senescent decline occurs because growth plate stem-like cells, located in the resting zone, have a finite proliferative capacity that is gradually depleted. Consistent with this hypothesis, we found that the proliferation rate in rabbit resting zone chondrocytes (assessed by continuous 5-bromo-2'-deoxy-uridine labeling) decreases with age, as does the number of resting zone chondrocytes per area of growth plate. Glucocorticoid excess slows growth plate senescence. To explain this effect, we hypothesized that glucocorticoid inhibits resting zone chondrocyte proliferation, thus conserving their proliferative capacity. Consistent with this hypothesis, we found that dexamethasone treatment decreased the proliferation rate of rabbit resting zone chondrocytes and slowed the numerical depletion of these cells. Estrogen is known to accelerate growth plate senescence. However, we found that estradiol cypionate treatment slowed resting zone chondrocyte proliferation. Our findings support the hypotheses that growth plate senescence is caused by qualitative and quantitative depletion of stem-like cells in the resting zone and that growth-inhibiting conditions, such as glucocorticoid excess, slow senescence by slowing resting zone chondrocyte proliferation and slowing the numerical depletion of these cells, thereby conserving the proliferative capacity of the growth plate[i.e. estrogen only slows down growth rate, it does not eliminate the proliferate capacity of the growth plate]. We speculate that estrogen might accelerate senescence by a proliferation-independent mechanism, or by increasing the loss of proliferative capacity per cell cycle." 

"the resting zone chondrocytes serve as a pool of stem-like cells that generate columnar clones of proliferative zone chondrocytes"

"Estrogen treatment did not significantly affect the number of resting zone chondrocytes"  "Serum estradiol concentration, measured 7 days after the second injection of estradiol cypionate, was 11 ± 2 pg/mL, compared to < 5 pg/mL in animals treated with the vehicle. Estrogen treatment did not significantly affect serum IGF-I concentration (88 ± 6 ng/mL vs 108 ± 6 ng/mL, estrogen vs control, P=NS)."<-This amount seems significant to me though.

"The decline in number of resting zone chondrocytes could also affect growth rate by a paracrine mechanism. For example, a decrease in the number of resting zone chondrocytes might decrease the overall production of parathyroid hormone-related protein (PTHrP), which could lead to earlier hypertrophy of proliferative zone chondrocytes."

"[estrogen] decreased proliferation rate and had no significant effect on cell numbers"  No obvious mechanisms as to how estrogen affects growth plate senescence were observed.

"We speculate that estrogen might increase the loss of proliferative capacity that occurs with each cell cycle, or that estrogen might cause loss of proliferative capacity by a cell-cycle-independent mechanism. For example, if senescence is caused by epigenetic changes such as loss of DNA methylation with each cell cycle, then estrogen might act by decreasing expression of maintenance methylases, causing greater loss of methylation with each cell replication. The effects of estrogen on the resting zone chondrocytes could be mediated by the estrogen receptor-α or -β, both of which are expressed by resting zone chondrocytes in humans, rabbits, and rats. The combination of a decreased rate of growth (in most mammals) and an increased rate of senescence seems to be an effect specific to estrogen"

"Estrogen appears to accelerate growth plate senescence without accelerating resting zone chondrocyte proliferation or accelerating the numerical depletion of these cells"<-Thus estrogen may decrease height.

They do state however that estrogen might accelerate growth plate fusion by a method not dependent on proliferation or that estrogen might reduce final height by another mechanism. 

17β-Estradiol regulates rat growth plate chondrocyte apoptosis through a mitochondrial pathway not involving nitric oxide or MAPKs.

"Estrogens cause growth plate closure in both males and females, by decreasing proliferation and inducing apoptosis of postproliferative growth plate chondrocytes. In vitro studies using 17β-estradiol (E(2)) conjugated to bovine serum albumin (E(2)-BSA) show that rat costochondral growth plate resting zone chondrocytes also respond to E(2). Moreover, they are regulated by E(2)-BSA via a protein kinase C and ERK MAPK signaling pathway that is functional only in female cells.  Rat resting zone chondrocytes cells were treated with E(2) or E(2)-BSA. E(2) caused apoptosis in male and female resting zone and growth zone chondrocytes in a dose-dependent manner, based on elevated DNA fragmentation, terminal deoxynucleotidyl transferase dUTP nick end labeling staining and caspase-3 activation[Now you don't really want apoptosis in the resting zone but still studies have shown positive benefits from lower estrogen levels and these rats could have already been above equilibrium estrogen]. E(2) also up-regulated p53 and Bax protein (Bcl-2-associated X protein) levels and induced release of cytochrome C from the mitochondria, indicating a mitochondrial apoptotic pathway. The apoptotic effect of E(2) did not involve elevated nitric oxide production or MAPKs. It was reduced by ICI 182780, which is an estrogen receptor (ER) antagonist and blocked by antibodies to Erα36, a membrane-associated ER. E(2)-BSA reduced cell viability and increased caspase-3 activity; ICI 182780 had no effect, but anti-ERα36 antibodies blocked the effect. The results indicate that estrogen is able to directly affect the cell population kinetics of growth plate chondrocytes by regulating apoptosis, as well as proliferation and differentiation in both resting zone and growth zone cells."

"High doses of estrogens also induce activation of caspase-3 in the growth plate, indicating involvement of apoptosis"

"The effects of estrogen on proliferation and differentiation of rat costochondral resting zone (RC) chondrocytes involve a membrane receptor-related pathway, which acts through activation of protein kinase C (PKC) and MAPK"

"Pi[extracellular inorganic phosphate] is able to induce resting zone chondrocyte apoptosis in an NO-dependent pathway"

"Resting zone chondrocytes differ from growth zone chondrocytes with respect to their morphology, the composition of their extracellular matrix, the phospholipid composition and levels of alkaline phosphatase activity in their matrix vesicles, and the production and activity of neutral vs. acid matrix metalloproteinases"

"resting zone chondrocytes respond to the vitamin D metabolite 24R,25(OH)2D3, whereas the growth zone chondrocytes respond to 1α,25(OH)2D3. Both vitamin D metabolites are produced actively in the growth plate in a regulated way by TGFβ1 in a zone-specific manner"<-There have been evidence of Vitamin D effects on growth plates but also studies have shown that Vitamin D polymorphisms have a "negligible effect" on human height.  Vitamin D regulates IL-1, PGE2, and PKC in GP chondrocytes.

"The 1α,25(OH)2D3-dependent activation of PKC involves activation of phospholipase A2 (PLA2) and arachidonic acid production, whereas 24R,25(OH)2D3-dependent activation of PKC involves PLD activation "

"E2 caused a dose-dependent decrease in cell viability based on MTT activity and in cell number in both male and female resting zone chondrocytes [in addition to the dose dependent effects on apoptosis]"<-Note only three dosages were used so this does not disprove that there is an equilibrium level of estrogen that increases height.

E2 does not affect apoptosis by a nitric oxide or inorganic phosphate mechanism.  The apoptosis mechanism is related to caspase-3 and caspase-1.

Now here's a study that mentions Stanozol to increase cellular proliferation.  Stanozol is a controlled substance.

Stanozolol regulates proliferation of growth plate chondrocytes via activation of ERalpha in GnRHa-treated adolescent rats.

"Stanozolol (ST) is a synthetic derivative of androgen. In this study, we investigated the effects and the mechanisms of ST on the proliferation of growth plate chondrocytes isolated from adolescent rats treated with gonadotropin-releasing hormone analogue (GnRHa). Treatment with ST resulted in time- and concentration-dependent effects on proliferation[the effectiveness of Stanozol was dependent on the concentration and the time that stanozol was in the system note that it's unclear whether this is a linear relationship]. ST increased the phosphorylation level of the estrogen receptor alpha (ERalpha)[so if there was a legal substance that increased the phosphorylation of ERalpha that would be beneficial as well], but not the androgen receptor (AR). Pharmacological inhibition of ERalpha and mitogen-activated protein kinase (MAPK) attenuated the effects of ST on the proliferation of growth plate chondrocytes[If ERalpha was inhibited by other means than the effects of Stanozol were diminished(attenuated).  Also, Stanozol seems to operate along the MAPK pathway]. A molecular dynamics simulation showed hydrophobic interactions between ST and ERalpha[cartilage is hydrophillic(water loving) so stanozol is likely effective at bypassing water and getting straight to ERalpha]. These results suggested that ERalpha, but not AR, partially mediates the ST-driven proliferation of growth plate chondrocytes."

So increasing phosphorylation of ERalpha may be one way to increase height growth if the increase in cellular proliferation also increases chondrocyte proliferative capacity.

"in some patients, growth is suppressed to subnormal velocity during the GnRHa therapy."

"mini-dose of estrogen replacement can normalize the slowdown of the growth rate during GnRHa therapy in girls with CPP"

"[ST] may impair adult height"

"In pediatric patients with Turner syndrome who treated with oxandrolone, height velocity increased without significant bone age progression"

"ST promoted chondrocytes proliferation independent of the AR."  Possibly via ER or MAPK pathways

"ER α phosphorylation can mediate the promotion or inhibition of long bone growth and epiphysis fusion"

High circulating Estradiol levels may inhibit chondrogenesis:

Estradiol inhibits chondrogenic differentiation of mesenchymal stem cells via nonclassic signaling.

"The existence of intracellular and membrane-associated E2 receptors was shown at various stages of chondrogenesis. Smaller aggregates and significantly lower type II collagen and sGAG content were detected after treatment with E2 and E2-BSA in a dose-dependent manner. Furthermore, E2 enhanced type X collagen and MMP-13 expression. Compared with estradiol alone, the coincubation of ICI 182.780 with estradiol enhanced suppression of chondrogenesis. Treatment with specific GPR-30 agonists alone (G-1 and ICI 182.780) resulted in a considerable inhibition of chondrogenesis. In addition, we found an enhancement of hypertrophy by G-1. Furthermore, the specific GPR-30 antagonist G15 reversed the GPR-30-mediated inhibition of chondrogenesis and up-regulation of hypertrophic gene expression.
The experiments revealed a suppression of chondrogenesis by estradiol via membrane receptors (GPR-30)."

So reducing estradiol levels or GPR-30 receptor levels may be a way to increase height.

"MMP-13 expression was significantly up-regulated after treatment with E2 or G-1 as compared with control"<-Maybe the increase in MMP-13 expression is related in somehow to the inhibition of chondrogenesis(MMP-13 gets beat up on a lot).

"During chondrogenesis, no proliferative or apoptotic effects of estradiol were detected"

"estradiol showed a dose-dependent inhibition of 3-D chondrogenesis with macroscopically smaller aggregates as well as reduced GAG and type II collagen deposition as compared with controls. Estradiol treatment did not disturb aggregate condensation and did not completely suppress chondrogenic differentiation."<-Thus high Estradiol levels should not be the cause of lack of LSJL results but they could be the cause of the reduction of the results.

"extracellular matrix can “store” E2"<-If there's no growth plate in the epiphysis then estrogen can't really be stored there.

Here's a study that shows that estrogen may accelerate closure but that doesn't mean that inhibiting estrogen can allow you to go beyond senescence.

The role of estrogen receptor-α and its activation function-1 for growth plate closure in female mice.

"High estradiol levels in late puberty induce growth plate closure and thereby cessation of growth in humans[cessation of growth can occur before closure however]. In mice, the growth plates do not fuse after sexual maturation, but old mice display reduced longitudinal bone growth and high-dose estradiol treatment induces growth plate closure. Estrogen receptor (ER)-α stimulates gene transcription via two activation functions (AFs), AF-1 and AF-2. To evaluate the role of ERα and its AF-1 for age-dependent reduction in longitudinal bone growth and growth plate closure, female mice with inactivation of ERα (ERα(-/-)) or ERαAF-1 (ERαAF-1(0)) were evaluated. Old (16- to 19-mo-old) female ERα(-/-) mice showed continued substantial longitudinal bone growth, resulting in longer bones (tibia: +8.3%, P < 0.01) associated with increased growth plate height (+18%, P < 0.05) compared with wild-type (WT) mice. In contrast, the longitudinal bone growth ceased in old ERαAF-1(0) mice (tibia: -4.9%, P < 0.01). Importantly, the proximal tibial growth plates were closed in all old ERαAF-1(0) mice while they were open in all WT mice. Growth plate closure was associated with a significantly altered balance between chondrocyte proliferation and apoptosis in the growth plate. In conclusion, old female ERα(-/-) mice display a prolonged and enhanced longitudinal bone growth associated with increased growth plate height, resembling the growth phenotype of patients with inactivating mutations in ERα or aromatase.  ERαAF-1 deletion results in a hyperactive ERα, altering the chondrocyte proliferation/apoptosis balance, leading to growth plate closure. This suggests that growth plate closure is induced by functions of ERα that do not require AF-1 and that ERαAF-1 opposes growth plate closure."

So you actually want ERalphaAF-1 to grow taller.

"A patient with a point mutation in exon 2 of the estrogen receptor (ER)α (estrogen-resistant man) experienced a continued growth long into adulthood, but at the age of 33.5 yr his growth plates were nearly fused."<-the man grew to about 80 inches tall.

Roles of transactivating functions 1 and 2 of estrogen receptor-alpha in bone.

"estrogen receptor-α (ERα) stimulates target gene transcription through two activation functions (AFs), AF-1 in the N-terminal and AF-2 in the ligand binding domain. To evaluate the role of ERα AF-1 and ERα AF-2 for the effects of estrogen in bone in vivo, we analyzed mouse models lacking the entire ERα protein (ERα(-/-)), ERα AF-1 (ERαAF-1(0)), or ERα AF-2 (ERαAF-2(0)). ERα AF-2 is required for the estrogenic effects on all parameters evaluated, whereas the role of ERα AF-1 is tissue-specific Selective ER modulators stimulating ERα with minimal activation of ERα AF-1 could retain beneficial actions."

"a normal negative feedback regulation of serum sex steroids requires an intact AF-1 and an intact AF-2 in ERα"

Tamoxifen is a selective ERalpha inhibitor but tamoxifen may decrease height.  One study found tamoxifen increasing longitudinal growth in female rats whereas the other study found tamoxifen decreasing longitudinal growth in male rats.  This could be due to differing responses to hormones or that females were more likely to be above equilibrium due to higher endogenous estrogen production.

Gender- and region-specific variations of estrogen receptor α and β expression in the growth plate of spine and limb during development and adulthood.

"The effects of ER inactivation on bone growth are sex and age dependent, and may differ between the axial and appendicular regions. In this study, the spatial and temporal expression of ERα and β in the tibial and spinal growth plates of the female and male rats during postnatal development was examined to explore the possible mechanisms. The level of mRNA was examined and compared with quantitative real-time PCR. The spatial location was determined by immunohistochemical analysis. The 1-, 4-, 7-, 12- and 16-week age stages correspond to early life, puberty and early adulthood after puberty, respectively. Gender- and region-specific differences in ERα and β expression were shown in the growth plates. Mainly nuclear staining of ERα and β immunoreactivity was demonstrated in the spinal and tibial growth plate chondrocytes for both genders. [There's a] significant effect of gender on temporal ERα and β expression and of region on temporal ERα/ERβ expression ratio. However, spatial differences of region-related ERα and β expression were not observed. Gender-related spatial changes were detected only at 16 weeks of both spine and limb growth plates. ERα and β immunoreactivity was detected in the resting, proliferative and prehypertrophic chondrocytes in the early life stage and during puberty. After puberty, ERα expression was mainly located in the late proliferative and hypertrophic chondrocytes in female, whereas the expression still extended from the resting to hypertrophic chondrocytes in males."

"a significant decrease in the length of femoral bone was observed in ERα-knockout (ERKO) females; in contrast, a slight decrease was shown in ERKO males"

"In the female rat, gonadectomy [removal of the ovaries] resulted in a bigger femur"

"In growing female rats, estrogen deficiency leads to an increase in the length of appendicular bones, while growth was normal at spine"

"Compared with WT controls, the axial skeletal growth increase was bigger than that of the appendicular in BERKO female mice"

"a significant decrease in length of lumbar vertebrae was demonstrated in ERKO male and female mice"

This study finds that ERalpha knockout may increase height:

The role of estrogen receptor α in growth plate cartilage for longitudinal bone growth.

"we developed a mouse model with cartilage-specific inactivation of ERα. Although mice with total ERα inactivation displayed affected longitudinal bone growth associated with alterations in the GH/IGF-1 axis, the skeletal growth was normal during sexual maturation in mice with cartilage-specific ERα inactivation. High-dose estradiol treatment of adult mice reduced the growth plate height as a consequence of attenuated proliferation of growth plate chondrocytes in control mice but not in cartilage-specific ERα(-/-) mice. Adult cartilage-specific ERα(-/-) mice continued to grow after 4 months of age, whereas growth was limited in control mice, resulting in increased femur length in 1-year-old cartilage-specific ERα(-/-) mice compared with control mice. We conclude that during early sexual maturation, ERα in growth plate cartilage is not important for skeletal growth. In contrast, it is essential for high-dose estradiol to reduce the growth plate height in adult mice and for reduction of longitudinal bone growth in elderly mice."

"female GPR30−/− mice displayed reduced longitudinal bone growth and reduced growth plate height"

"reduced femur and crown-rump lengths in the 17-week-old male total ERα−/− mice were associated with a significant reduction of serum IGF-1 levels (–20% ± 6% versus control littermates, p < .01), whereas serum IGF-1 levels were unchanged in Col2α1-ERα−/− mice (14% ± 7% versus control littermates, nonsignificant)."

Maybe you can increase IGF-1 levels exogenously to make up for loss of systemic ERalpha to get a total increase in height(since it will be hard to generate an ERalpha cartilage specific knockout).

The genetic basis of human height : the role of estrogen

" It has been hypothesised that estrogen functions to regulate growth plate fusion by stimulating chondrocyte apoptosis, angiogenesis and bone cell invasion in the growth plate. Another theory has suggested that estrogen exposure exhausts the proliferative capacity of growth plate chondrocytes, which accelerates the process of chondrocyte senescence, leading to growth plate fusion. The height-related genes FGFR3, CBFA1, ER and CBFA1 were screened for novel polymorphisms using denaturing HPLC and RFLP analysis. In total, 24 polymorphisms were identified. Two SNPs in ER (rs3757323 C>T and rs1801132 G>C) were strongly associated with adult male height and displayed an 8 cm and 9 cm height difference between homozygous genotypes, respectively{about 4 inches}. The TC haplotype of these SNPs was associated with a 6 cm decrease in height and remarkably, no homozygous carriers of the TC haplotype were identified in tall subjects. No significant associations with height were found for polymorphisms in the FGFR3, CBFA1 or VDR genes. Another hypothesis of this study was that estrogen exerted its effects in the growth plate by influencing chondrocyte proliferation and mediating the expression of chondrocyte marker genes. While estrogen did not dramatically alter the proliferation of the SW1353 cell line, gene expression experiments identified several estrogen regulated genes. Sixteen chondrocyte marker genes were examined in response to estrogen concentrations ranging from 10-12 M to 10-8 M over varying time points. Of the genes analysed, IHH, FGFR3, collagen II and collagen X were not readily detectable and PTHrP, GHR, ER , BMP6, SOX9 and TGF 1 mRNAs showed no significant response to estrogen treatments. However, the expression of MMP13, CBFA1, BCL-2 and BAX genes were significantly decreased. Interestingly, the majority of estrogen regulated genes in SW1353 cells are expressed in the hypertrophic zone of the growth plate{so estrogen likely affects peak chondrocyte hypertrophy and optimizing growth per hypertrophic chondrocyte}. Estrogen is also known to regulate systemic GH secretion and local GH action. At the molecular level, estrogen functions to inhibit GH action by negatively regulating GH signalling. GH treated SW1353 cells displayed increases in MMP9 mRNA expression (4.4-fold) and MMP13 mRNA expression (64-fold) in SW1353 cells{Thus MMP13 may be a pro-height protein}. Increases were also detected in their respective proteins. Treatment with AG490, an established JAK2 inhibitor, blocked the GH mediated stimulation of both MMP9 and MMP13 mRNA expression. The application of estrogen and GH to SW1353 cells attenuated GH-stimulated MMP13 levels, but did not affect MMP9 levels. Investigation of GH signalling revealed that SW1353 cells have high levels of activated JAK2 and exposure to GH, estrogen, AG490 and other signalling inhibitors did not affect JAK2 phosphorylation. Interestingly, AG490 treatment dramatically decreased ERK2 signalling, although GH did stimulate ERK2 phosphorylation above control levels. AG490 also decreased CBFA1 expression, a transcription factor known to activate MMP9 and MMP13. Finally, GH and estrogen treatment increased expression of SOCS3 mRNA{up in LSJL}, suggesting that SOCS3 may regulate JAK/STAT signalling in SW1353 cells. The modulation of GH-mediated MMP expression by estrogen in SW1353 cells represents a potentially novel mechanism by which estrogen may regulate longitudinal bone growth. "

In GH transgenic mice, SOCS2 overexpression further increases height.  BCL2 is protective against apoptosis in hypertrophic chondrocytes while Caspase 3 is pro-apoptotic.  CBFA1 induces Ihh expression.

FGFR3 knockout increases Ihh levels.  Retinoic Acid increases MMP2 and can induce chondrocyte hypertrophy.  BCL2 may increase Sox9 activity.  BCL2 knockout decreases height.  PTHrP increases BCL2 in chondrocytes.

An ERa mutation increases height in males and females.  An ERb mutation increases height in females.  BSM I(associated with VDR) knockout decreases height.  VDR mutations associated with increased height.  Vitamin D deficiency decreases CBFA1.  PPARG3 mutation that decreases activity resulted in increased height.  DRD2(associated with dopamine) knockout decreases height.  Mutation in PTHR1 increases height.

Stage specific effect of leptin on the expressions of estrogen receptor and extracellular matrix in a model of chondrocyte differentiation.

"The aim of our study was to investigate the effect of leptin on the expression of estrogen receptors and extracellular matrix in ATDC5 cells, an in vitro model of endochondral ossification. First, we quantified the physiological expressions of estrogen receptors α, β (ERα, ERβ), leptin receptor (Ob-Rb), type II and type X collagens in definite stages of endochondral ossification in ATDC5 cells using real-time PCR. Dynamic and stage specific expression characteristics of these target genes were observed. Simultaneous expressions of Ob-Rb with ERα or ERβ in ATDC5 cells were also found with dual-label confocal immunofluorescency. Then using Western blotting analysis and/or real-time PCR, we detected that, leptin treatment up-regulated the expressions of ERα, ERβ and type II collagen, but down-regulated type X collagen expression and the ERα/ERβ ratio in the chondrogenic differentiation stage. Meanwhile, leptin down-regulated the expressions of ERα, type II and type X collagens, and the ERα/ERβ ratio, but up-regulated the expression of ERβ in the hypertrophic differentiation stage. Significant positive correlation existed between ERα and type II collagen expression, and between the ratio of ERα/ERβ and type X collagen production. In summary, the crosstalk between leptin and estrogen receptor might be differentiation stage specific in ATDC5 cells."

"In a mandibular condyle organ culture model, leptin treatment increased overall condylar height"

The role of estrogen receptor α in the regulation of bone and growth plate cartilage.

"rapid responses to E2 are mediated by second messenger systems, e.g., cAMP and protein kinase A (PKA), while other responses are mediated by membrane-based ion fluxes, involving, e.g., Ca2+ and Ca2+-dependent K+ channels, which are capable of responding to estrogens"

"A mouse model, believed to lack the entire ERα (K-ERα−/−) had an opposite growth plate phenotype compared to the estrogen-resistant man, in that these mice completely fused their growth plates"

"Young adult (4 months old) female ERα−/− mice had normal longitudinal bone growth. Interestingly, old (16–19 months) female ERα−/− mice showed continued longitudinal bone growth, resulting in longer bones, associated with increased growth plate height compared with WT mice "

"male ERα−/− mice had a reduced longitudinal bone growth during sexual maturation, resulting in shorter bone length, while the male Col2α1-ERα−/− mice had a normal growth"

Membrane Effects of Sex Hormones on Growth Plates Chondrocytes 

"E2 caused rapid increases in Ca++ ion transport and activation of protein kinase C (PKC) and phospholipase A2 in female chondrocytes but not in male cells."

"Testosterone had no effect on PKC in male chondrocytes at any of the times tested, whereas DHT caused a rapid increase in PKC activity at 9 minutes that was still present at 90 minutes"

"DHT induced the PKC activity in dose dependent manner, which was significant at 10-9 to 10-7 M DHT"

 

"DHT induced PKC activity via two mechanisms: influx of extracellular Ca2+ via voltage gated calcium ion channels, and Ca2+ mobilization from the endoplasmic reticulum. Thapsigargin abolished the effect of DHT on PKC activity on a dose dependent manner"

 

"Once PKC is activated, it can initiate a protein phosphorylation cascade that ultimately affects cell differentiation."

"DHT signaling via the AR plays a role in chondrocyte maturation by increasing [35S]-sulfate incorporation, suggesting an increase in the synthesis of a sulfated proteoglycan extracellular matrix."

Why doesn't LSJL upregulate Smad3?

TGF-Beta induces chondrogenesis via Smad3 but Smad2 or 3 were not altered above threshold by LSJL. Note that just because LSJL does not upregulate Smad3 does not mean it does not phosphorylate Smad3. And Smad 3 was shown as not having a fold change so lack of observation of Smad3 was not likely to be possible.  It should be noted though that bone samples were harvested and not cells from the bone marrow specifically although there were likely some bone marrow cells contained within.

Upregualtion of BMP-2 antagonizes TGF-β1/ROCK-enhanced cardiac fibrotic signaling through activating of Smurf1/Smad6 complex.

"TGF-β1-induced ROCK elevation suppressed the antagonizing effects evoked by BMP-2[LSJL BMP-2 upregulation is predicted] and strengthened fibrotic response. Exogenous BMP-2 supply could attenuate TGF-β1 signaling through Smad6-Smurf-1 complex activation[LSJL alteration of Smurf1 is predicted]. In vitro, mechanical stretch upregulated cardiac TGF-β1 and TGF-β1-dependent ROCK. While BMP-2 level was upregulated after blocking TGF-β1 signaling by SB-431542 or inhibition of ROCK by Y-27632. Dose-dependent TGF-β1 induction could activate ROCK and suppress endogenous BMP-2 level in cardiomyocytes. Knock-down BMP-2 in cardiomyocytes enhanced TGF-β1-mediated PKC-δand Smad3 signaling cascades. In contrast, application of Y-27632 or SB-431542 suppressed TGF-β1 pathway, but BMP-2 was only upregulated by Y-27632. BMP-2 silencing abolished Y-27632 but not SB-431542 mediated suppression of TGF-β1 pathway. Further experiments showed that the inhibitory Smad6 and Smurf1 were required for BMP-2-evoked antagonizing effects. Smad6 overexpression attenuated TGF-β1-induced activation of PKC-δand Smad3, promoted TGF-β RI degradation in BMP-2 knock-down cardiomyocytes Smad6 or Smurf1 siRNA could abolish the antagonizing effect of BMP-2 on TGF-β1 pathway, in which Smad6/Smurf1 complex formation was critically involved. In vivo data showed that pressure overload-induced collagen deposition were attenuated and TGF-β1-dependent activation of PKC-δand Smad3 were reduced after 2 weeks treatment with rhBMP-2(0.5mg/kg) or Y-27632 (10mg/kg) in mice underwent surgical transverse aortic constriction."

"Overexpression BMP-2 in renal interstitial fibroblast cells effectively antagonized TGF-β1 mediated fibrosis by enhancing the catabolism of type I TGF-β receptors (TGF-β RI)."

"pressure overload activated Rho related kinase (ROCK) and suppressed the endogenous BMP-2 expression"<-So maybe more pressure is needed to suppress BMP-2 signaling and induce Smad3.

According to Smurf1 facilitates myogenic differentiation and antagonizes the bone morphogenetic protein-2-induced osteoblast conversion by targeting Smad5 for degradation., Smurf1 reduces Smad5 levels but has no effect on Smad3 levels.

Inihibiting Estrogen may inhibit Smurf1.

Estrogen inhibits transforming growth factor beta signaling by promoting Smad2/3 degradation.

"Estrogen is a growth factor that stimulates cell proliferation. The effects of estrogen are mediated through the estrogen receptors, ERalpha and ERbeta, which function as ligand-induced transcription factors and belong to the nuclear receptor superfamily. TGF-beta acts as a cell growth inhibitor, and its signaling is transduced by Smads. ERalpha inhibits TGF-beta signaling by decreasing Smad protein levels. ERalpha-mediated reductions in Smad levels did not require the DNA binding ability of ERalpha, implying that ERalpha opposes the effects of TGF-beta via a novel non-genomic mechanism. Our analysis revealed that ERalpha formed a protein complex with Smad and the ubiquitin ligase Smurf, and enhanced Smad ubiquitination and subsequent degradation in an estrogen-dependent manner."

So you may want to inhibit estrogen to allow for TGF-Beta to induce Smad3 signaling which can induce chondrogenesis while performing LSJL.  Note that despite no Smad3 signaling, there were still signs of chondrogenesis in LSJL like chondrogenic ECM protein production.

Ski may be involved in Smad3 signaling:

Ski inhibits TGF-β/phospho-Smad3 signaling and accelerates hypertrophic differentiation in chondrocytes

"Since transforming growing factor-β (TGF-β)/Smad signaling inhibits chondrocyte maturation, endogenous negative regulators of TGF-β signaling are likely also important regulators of the chondrocyte differentiation process. One such negative regulator, Ski, is an oncoprotein that is known to inhibit TGF-β/Smad3 signaling via its interaction with phospho-Smad3 and recruitment of histone deacetylases (HDACs) to the DNA binding complex. Based on this, we hypothesized that Ski inhibits TGF-β signaling and accelerates maturation in chondrocytes via recruitment of HDACs to transcriptional complexes containing Smads. We tested this hypothesis in chick upper sternal chondrocytes (USCs), where gain and loss of Ski expression experiments were performed. Over-expression of Ski not only reversed the inhibitory effect of TGF-β on the expression of hypertrophic marker genes such as type X collagen (colX) and osteocalcin, it induced these genes basally as well. Conversely, knockdown of Ski by RNA interference led to a reduction of colX and osteocalcin expression under basal conditions. Furthermore, Ski blocked TGF-β induction of cyclinD1 and caused a basal up-regulation of Runx2, consistent with the observed acceleration of hypertrophy. Regarding mechanism, not only does Ski associate with phospho-Smad2 and 3, but its association with phospho-Smad3 is required for recruitment of HDAC4 and 5. Implicating this recruitment of HDACs in the phenotypic effects of Ski in chondrocytes, the HDAC inhibitor SAHA reversed the up-regulation of colX and osteocalcin in Ski over-expressing cells. These results suggest that inhibition of TGF-β signaling by Ski, which involves its association with phospho-Smad3 and recruitment of HDAC4 and 5, leads to accelerated chondrocyte differentiation."

So Ski is likely bad for height growth but we don't know for sure.

"Ski is required for the association between pSmad3 and HDAC4 and HDAC5"

"inhibition of the TGF-β pathway by Smad7 leads to reduced chondrocyte proliferation and proteoglycan synthesis in chondrocyte cultures. Inhibition of BMP signaling with either Smad6 or noggin leads to deceleration of the chondrocyte hypertrophic program in vitro"

Anisomycin can downregulate Ski according to Downregulation of Ski and SnoN co-repressors by anisomycin.

Aromatase deficiency and tall stature

Lately, we've been linking endocronilogical factors to local growth factors.  HGH may affect DNA Methylation by increasing levels of DNA Methyltransferse, IGF-1 may determine peak chondrocyte hypertrophy, Testosterone inhibits Myostatin, and Estrogen...

Estrogen is more complicated.  The usage of aromatase inhibitors to increase height is controversial in effectiveness.  Normalized levels of estrogen seem essential for maximizing growth.  Growth plate senescence is regulated by DNA Methylation and not estrogen.  Fusion is regulated by estrogen but that does not occur until post senescence.

And yet, there are several cases of aromatase deficient individuals with tall stature.  The number of studies of aromatase deficiency are extremely limited so it's possible that there are normal stature individuals that have aromatase deficiency but are undiagnosed.  The tall stature and aromatase deficiency could share the same cause.

There's also the possibility that because extremely low levels inhibit fusion, it gives an opportunity to wander into the hyaline cartilage growth plate line.  Those stem cells then differentiate into chondrocytes resulting in height growth.  This gets around DNA Methylation as these new stem cells come with methyl counters.  This is the mechanism that LSJL works by too, sending new stem cells into the hyaline cartilage growth plate line.  Stem cells were found to be able to differentiate organically into chondrocytes as well just with Type I collagen(which is a part of all bone) and hydrostatic pressure(which is induced by LSJL).

Alternatively, estrogen has numerous effects on growth and some are positive and negative.  Perhaps, the positive aspects of estrogen inhibition counteract the negative ones. 

GPR30 deficiency causes increased bone mass, mineralization, and growth plate proliferative activity in male mice. 

"Estrogen regulation of the male skeleton was first clearly demonstrated in patients with aromatase deficiency or a mutation in the ERalpha gene. Estrogen action on the skeleton is thought mainly to occur through the action of the nuclear receptors ERalpha and ERbeta. The G-protein coupled receptor GPR30 is a functional ER. GPR30 deficient mouse models have been generated to study the in vivo function of this protein. We have characterized size, body composition, and bone mass in adult male GPR30 knockout (GPR30KO) mice and their wildtype (WT) littermates. GPR30KO mice weighed more and had greater nasal anal length. Both lean mass and percent body fat were increased in the knockout mice. Femur length was greater in GPR30KO mice as was whole body, spine, and femoral areal bone mineral density. GPR30 mice showed increased trabecular bone volume and cortical thickness. Mineralized surface was increased in GPR30KO mice. [There was] greater proliferation in the growth plate of GPR30KO mice. Under osteogenic culture conditions GPR30KO femoral bone marrow cells produced fewer alkaline phosphatase positive colonies in early differentiating osteoblast cultures but showed increased mineralized nodule deposition in mature osteoblast cultures. Serum IGF-I levels were not different." 

Note that other research shows that female mice without the GPR30 gene have reduced growth.  "A small age-dependent decrease in crown-rump and femur lengths, measures of skeletal growth, [occurred] in Gpr30 KO female mice but not males. "

"Estradiol treatment of ovariectomized mice reduced longitudinal skeletal growth, as measured by femur length, and decreased growth plate height in WT not Gpr30 KO mice."

"GPR30 somehow functions to limit matrix mineralization."

"Gpr30 is a Runx2-responsive gene and acts in a promitogenic fashion through a Cdk pathway."

"GPR30 expression in the human has been shown to change with age during puberty, and it is postulated to regulate longitudinal bone growth.  Conceivably, at low doses, when E is postulated to stimulate long bone growth, the conventional ERs are dominant. On the other hand, at higher doses of E, the action of GPR30 may come into play, thereby limiting or terminating long bone growth."

For the first time optimal ranges of estrogen are given in this study(but for female only):


Impact of Estrogen Replacement throughout Childhood on Growth, Pituitary-Gonadal Axis and Bone in a 46,XX Patient with CYP19A1 Deficiency.

"We studied the impact of oral 17β-estradiol treatment, on longitudinal growth, bone age maturation, pituitary gonadotropin feedback, multicystic ovaries and bone mass in the long-term follow-up of a girl compound heterozygote for two point mutations of the CYP19A1 gene. Low doses of 17β-estradiol were needed to achieve normal height velocity and adequate bone age maturation from early childhood on"

"The doses of 17β-estradiol needed during [early childhood] range between 50 and 100 µg."

" In our patient withdrawal of E2 resulted in arrest of bone age maturation and decrease of height velocity"

"in late prepuberty and puberty the patient showed a discordant picture between an already decreasing bone age maturation indicating relative estrogen deficiency, and a rising height velocity indicating sufficient serum estradiol levels."

" when off [estrogen] treatment the patient showed increasing bone age delay and decreasing height velocity"

The girl ended up with slightly above normal predicted height.

Having low estrogen is much better than having high estrogen(which causes apoptosis).  Low estrogen levels may delay senescence by lowering cell proliferation rates and enabling more new stem cells with methyl groups to arrive at the hyaline cartilage growth plate line.  Specific actions of estrogen on various growth stimulators and inhibitors needs to be studied further.

Aromatase Inhibitors may not increase height

The anti-Estrogen craze lives on despite a lot of evidence that estrogen may not be that bad for height.  Evidence that estrogen affects height may be only circumstantial.  As I wrote previously about aromatase inhibitors: aromatase inhibitors may impair growth; estrogens play an important role in vascular endothelial growth factor(which stimulates blood vessal growth in bone); estrogen deficiency may result in chondrocyte reduction in growth plates; and both estrogen deficiency and surplus had bad affects although the negative effects of estrogen deficiency were less detrimental than estrogen surplus.  Some research on estrogen has shown that it is due to intrinsic growth plate factors that determine final height(number of stem cells in the hyaline cartilage growth plate line which we try to get more of by increasing hydrostatic pressure and interstitial fluid flow through LSJL) and not estrogen which mainly modifies growth rate.

Peripubertal Aromatase Inhibition in Male Rats has Adverse Long-term Effects on Bone Strength and Growth and Induces Prostatic Hyperplasia.

"Aromatase inhibitors have been increasingly used in boys with growth retardation to prolong the duration of growth and increase final height. Multiple important roles of oestrogen in males point to potential adverse effects of this strategy. Although the deleterious effects of aromatase deficiency in early childhood and adulthood are well documented, there is limited information about the potential long-term adverse effects of peripubertal[very early in development] aromatase inhibition. To address this issue we evaluated short and long term effects of peripubertal aromatase inhibition in an animal model. Peripubertal male Wistar rats were treated with aromatase inhibitor letrozole or placebo and followed until adulthood. Letrozole treatment caused sustained reduction in bone strength and alteration in skeletal geometry, lowering of insulin like growth factor I levels, inhibition of growth resulting in significantly lower weight and length of treated animals and development of focal prostatic hyperplasia. Our observation of adverse long-term effects after peripubertal male rats were exposed to aromatase inhibitors highlights the need for further characterization of long term adverse effects of aromatase inhibitors in peripubertal boys before further widespread use is accepted. Furthermore, this suggests the need to develop more selective oestrogen inhibition strategies in order to inhibit oestrogen action on the growth plate whilst beneficial effects in other tissues are preserved."

Some of the research suggests that estrogen needs to be in a proper range and unless that range is measured by(you can't self-medicate with aromatase inhibitors) then you should not be taking aromatase inhibitors.  Here's the latest on the clinical view of aromatase inhibitors:

Strategies for maximizing growth in puberty in children with short stature.

"The approach to the child with growth retardation who is in puberty remains an important clinical challenge. The use of high-dose growth hormone (GH), suppression of puberty with GnRH analogs in combination with GH, and the use of selective inhibitors of the aromatase enzyme with aromatase inhibitors (also in combination with GH) are all therapeutic choices that have been studied. Aromatase blockade effectively blocks estrogen production in males with a reciprocal increase in testosterone, and a new generation of aromatase inhibitors, including anastrozole, letrozole and exemestane, is under investigation in adolescent subjects with severe growth retardation. This class of drugs, if judiciously used for a window of time, offers promise as an adjunct treatment of growth delay in pubertal patients with GH deficiency, idiopathic short stature, testotoxicosis, and other disorders of growth[ie. if estrogen is not in the optimal range]. These evolving uses of aromatase inhibitors, however, represent off-label use of the product, and definitive data on their efficacy are not available for each of the conditions mentioned. Safety issues regarding bone health also require further study."

Increase in predicted adult height means nothing.  Here's a study for the contrary however:

Update on the role of aromatase inhibitors in growth disorders

"Without oestrogen action, the fusion of the growth plates is postponed and longitudinal growth continues for an exceptionally long period of time. Aromatase inhibitors that block oestrogen biosynthesis have therefore emerged as a new potential treatment option for children with short stature. Results from three prospective randomised controlled trials using potent third-generation aromatase inhibitors have recently been published. These studies all show that treatment with the aromatase inhibitors letrozole and anastrozole effectively delays bone maturation and increases predicted adult height in boys with constitutional delay of growth and puberty (CDGP), idiopathic short stature and growth hormone deficiency. Long-term follow-up data from the study in which boys with CDGP were treated with letrozole for 1 year during adolescence suggest that the achieved gain in predicted adult height also results in taller final adult height."

So they did find that having a height predicted adult height also resulted in having a taller adult height.  However, they only treated boys who have extremely short stature.  Boys with extremely short stature are likely to have many different causes for it including excessive estrogen levels.  Thus, we don't know if the anti-estrogen therapy merely knocked estrogen into the optimal range.

The role of estrogen receptor-alpha in growth plate cartilage for longitudinal bone growth

"Estrogens enhance skeletal growth during early sexual maturation while high estradiol levels during late puberty result in growth plate fusion in humans. Although the growth plates do not fuse directly after sexual maturation in rodents, a reduction in growth plate height is seen by treatment with a high dose of estradiol. It is unknown whether the effects of estrogens on skeletal growth are mediated directly via estrogen receptors (ERs) in growth plate cartilage and/or indirectly via other mechanisms such as the GH/IGF-I axis. To determine the role of ERalpha in growth plate cartilage for skeletal growth, we developed a mouse model with cartilage-specific inactivation of ERalpha. Although mice with total ERalpha inactivation displayed affected longitudinal bone growth associated with alterations in the GH/IGF-I axis, the skeletal growth was normal during sexual maturation in mice with cartilage-specific ERalpha inactivation[Estrogen affects the GH/IGF-1 Axis but is not detremental specifically to the growth plate]. High dose estradiol treatment of adult mice reduced the growth plate height as a consequence of attenuated proliferation of growth plate chondrocytes in control mice but not in cartilage-specific ERalpha(-/-) mice[Estrogen reduced proliferation of chondrocytes as a result of changes in the GH-IGF-1 Axis]. Adult cartilage-specific ERalpha(-/-) mice continued to grow after four months of age while growth was limited in control mice, resulting in increased femur length in one-year-old cartilage-specific ERalpha(-/-) mice compared with control mice. We conclude that during early sexual maturation ERalpha in growth plate cartilage is not important for skeletal growth. In contrast, it is essential for high dose estradiol to reduce the growth plate height in adult mice and for reduction of longitudinal bone growth in elderly mice."

So, estrogen inhibiton changes the GH-IGF-1 axis so it's no wonder that Letrozole increses height with people with a growth hormone deficiency.  Here's another study that might indicate the effectiveness of aromatase inhibitors:

Tall stature without growth hormone: four male patients with aromatase deficiency.

From preliminary observations, GH-IGF-I seems to be compromised in men with aromatase deficiency. The GH deficiency (GHD) coexists paradoxically with tall stature, raising the question whether or not a true GHD is part of this rare syndrome.
To evaluate the GH secretion in aromatase-deficient men, their GH response to the GHRH plus arginine (GHRH-ARG) test was compared with that of normal subjects. The effect of estrogen replacement treatment on the GH-IGF-I axis in aromatase-deficient men was evaluated before and during therapy.
Four adult men with aromatase deficiency were compared with 12 normal subjects.
We measured the GH response to GHRH-ARG in aromatase-deficient men (at baseline and during estrogen treatment) and in normal subjects. Basal serum IGF-I was measured in both patients and controls.
The response of GH to GHRH-ARG was severely impaired in men with aromatase deficiency and resulted in significantly lower levels than in normal subjects. Although normal, serum IGF-I levels were also significantly lower than in normal subjects. Both GH peak and IGF-I concentrations were not modified by estrogen therapy in men with aromatase deficiency.
In aromatase-deficient men, GH response to potent provocative stimuli is impaired and is not restored by exogenous estrogens. Furthermore, a tall stature may be reached, notwithstanding the coexistence of GHD, if a prolonged time for growth is available due to a delay in bone maturation, and other growth factors different from GH (mainly insulin) promote growth."

So in men with tall stature the GH-IGF-1 axis was not affected by exogenous estrogen.  Maybe, these four people have a genetic mutation that causes them to grow that's different from traditional GH and IGF-1(Insulin is mentioned as a possible cause).

Estrogen inhibition seems to work by increasing growth hormone levels and by modifying cellular proliferation rates(which may be perserved).  Unless, estrogen is high enough to enduce apoptosis(otherwise growth capacity is maintained) in the chondrocytes it may not improve final height.  For now aromatase inhibitors should be considered for people with low growth hormone levels and people with high estrogen levels.

Aromatase inhibitors to augment height: continued caution and study required.

Both are tall.  Both have insulin resistance which may be important to their height growth.

"Only nine patients have been followed to near-final height and there are no available data regarding adult heights from any of the controlled trials. Moreover, one of the studies involving patients with GH deficiency found no change in mean predicted adult height among patients who were treated with AIs."

"AIs have been promising in delaying BA advancement and, in most, but not all studies, in improving predicted adult height."<-but predicted adult height is worth nothing.  It's actual adult height that matters.

Effectiveness of aromatase inhibitors on normal people has not been sufficiently proven.

Do aromatase inhibitors increase height in males?

Males and females can respond to sex hormones differently.  Estrogen may inhibit growth in females but augment growth in males. Estrogen is speculated to affect chondrocyte proliferative capacity.  Can the usage of aromatase inhibitors increase height in males?  Estrogen has been used to accelerate growth plate fusion(although cessation is more accurate a word as you stop growing as a result of exhaustion of mesenchymal stem cells from the hyaline cartilage growth plate line) in females but only by one or two inches.  And there's no real way to know how tall a female would've been if she had not been injected with excess estrogen.  What affect can aromatase inhibitors have on a naturally developing bone of a male?  Aromatase Inhibitors stop the body from converting Testosterone to Estrogen. 

Impaired body weight and tail length gain and altered bone quality after treatment with the aromatase inhibitor exemestane in male rats. 

"Estrogen deficiency induced by aromatase inhibitors may be a novel treatment modality for growth enhancement in short children, but may have adverse effects on bone, brain and reproduction.  26-day-old prepubertal rats received intramuscular injections with placebo or the aromatase inhibitor exemestane at a dose of 10, 30 or 100 mg/kg/week [E10, E30, E100(6)] for 6 weeks, completely covering the sexual maturation phase, or with 3 weeks E100 followed by 3 weeks placebo [E100(3)]. Growth parameters and histology of the testis, seminal vesicle and brain were analyzed. Bone architecture was studied with X-ray microtomography. Results: Exemestane dose-dependently decreased body weight and tail length gain, as well as liver and seminal vesicle weights, but did not affect nose-anus length gain, growth plate width or radial growth. E100(6) decreased trabecular thickness (epiphysis and metaphysis) and number (metaphysis). Normal IGF-I levels and brain, testis and seminal vesicle morphology were observed. E100(3) resulted in decreased tail length gain only. Exemestane treatment during sexual maturation did not augment linear growth in male rats, but caused impaired body weight and tail length gain and osteopenia." 

"However, estradiol levels in male rats are very low and are expected to be even lower during treatment with an aromatase inhibitor."<-So, Estrogen levels may be below equilibrium already and that's why height decreased.  An Estrogen inhibition regime seemed to slow down cellular proliferation which again seems to suggest being below equilibrium

Expression of vascular endothelial growth factor in the growth plate is stimulated by estradiol and increases during pubertal development. 

"Longitudinal bone growth is regulated in the growth plate. At the end of puberty, growth velocity diminishes and eventually ceases with the fusion of the growth plate through mechanisms that are not yet completely understood. Vascular endothelial growth factor (VEGF) has an important role in angiogenesis, but also in chondrocyte differentiation, chondrocyte survival, and the final stages of endochondral ossification. Estrogens have been shown to up-regulate VEGF expression in the uterus and bone of rats. In this study, we investigated the relation between estrogens and VEGF production in growth plate chondrocytes both in vivo and in vitro. The expression of VEGF protein was down-regulated upon ovariectomy and was restored upon estradiol (E(2)) supplementation in rat growth plates. In cultured rat chondrocyte cell line RCJ3.1C5.18, E(2) dose dependently stimulated 121 and 189 kDa isoforms of VEGF, but not the 164 kDa isoform. Finally, VEGF expression was observed at both protein and mRNA levels in human growth plate specimens. The protein level increased during pubertal development, supporting a link between estrogens and local VEGF production in the growth plate. We conclude that estrogens regulate VEGF expression in the epiphyseal growth plate, although the precise role of VEGF in estrogen-mediated growth plate fusion remains to be clarified." 

So Estrogen is linked to VEGF but does VEGF inhibit chondrocyte proliferation or anything that would cause growth plate cessation?  VEGF signaling is essential to proper endochondral ossification.  Inhibiting Estrogen while finding alternative methods to upregulate VEGF may be a way to grow taller.  TGF-Beta1 for instance can activate VEGF.

"VEGF-A has been shown to be expressed in the growth plate and also believed to be most important in the regulation of longitudinal bone growth"

"Vegfa conditional knockout mice driven by a Col2a1 promoter showed delayed invasion of blood vessels into the primary ossification center and delayed removal of terminal hypertrophic chondrocytes together with massive cell death in chondrocytes throughout the growth plate, demonstrating the importance of VEGFA in chondrocyte survival"<-lack of VEGF-A results in reduced height growth

"VEGF expression is up-regulated by estrogens"

"we confirmed that VEGF is expressed in the human pubertal growth plate and that the VEGF protein level increases with pubertal progression, supporting a link between estrogens and local VEGF production in the growth plate."

No link between VEGF and fusion was found in the study likely because fusion does not occur post cessation and since VEGF helps with chondrocyte survival it delays the point until cessation.  Since VEGF is essential, some mechanism to increase TGF-Beta1 levels may be needed to upregulate VEGF while taking aromatase inhibitors.

Estrogen deficiency leads to decrease in chondrocyte numbers in the rabbit growth plate. 

"In the pubertal growth plate, sex hormones play important roles in regulating the proliferation, differentiation, maturation, and programmed death of chondrocytes. Although many studies have been reported on the regulation of estrogen in long-bone growth, some of the mechanisms have remained unclear, including its role in cell kinetics in growth plate chondrocytes. The aim of this study was to clarify the effect of a deficiency of estrogen on growth plate chondrocytes. METHODS: We obtained growth plates of the femoral head from normal and ovariectomized Japanese white rabbits at 10, 15, 20, and 25 weeks of age. The effects of estrogen deficiency on the cell kinetics of growth plate chondrocytes were investigated immunohistochemically using antibodies for an apoptotic marker, caspase-3, and for proliferating cell nuclear antigen (PCNA). RESULTS: Both the length of the femur and the height of the growth plate in the ovariectomized rabbits tended to be larger than those in the normal rabbits. There were fewer chondrocytes in the ovariectomized rabbits than in the normal ones. Caspase-3-positive cells were detected mainly in the hypertrophic zone, whereas PCNA-positive cells were found in the proliferating to upper hypertrophic zones. The ovariectomized rabbits showed a higher caspase-3-positive rate at 20 weeks of age and a lower PCNA-positive ratio in all age groups than the normal rabbits. CONCLUSIONS: This study indicated that ovariectomy led to a decreased number of growth plate chondrocytes, which resulted from decreased cell-proliferating ability and probably acceleration of the number of chondrocytes undergoing apoptosis." 

Estrogen deficiency did not increase cell-proliferating capacity in females.  Oestrogen is the specific form of estrogen speculated to be responsible for growth plate senescence.  What's the conclusion? 

"Recent studies indicated that ER-α up-regulates cyclin D1, and PCNA then stimulates both cell progression
and prevents the apoptotic cascade, whereas ER-β down-regulates proliferation and has pro-apoptotic
properties"<-Both of these may be essential for growth has you need a reduction in proliferation and for apoptosis in the hypertrophic zone.

Normal bone growth requires optimal estrogen levels: negative effects of both high and low dose estrogen on the number of growth plate chondrocytes 

"Endochondral bone formation at epiphyseal growth plate consists of the synchronized processes of chondrogenesis and cartilage ossification. Estrogen, the major female sex hormone, plays an important role in this process, particularly during the pubertal growth spurt. However, its effects on the growth plate are not completely understood. The aims of this study were to clarify the effects of estrogen on the kinetics of chondrocytes in the growth plates of 10- to 25-week-old female rabbits by studying the effects of ovariectomy or high-dose administration of estrogen on the balance between cell proliferation and death. Forty-eight Japanese white rabbits were divided into three groups: sham operated, ovariectomized, or ovariectomized with subsequent weekly injection of high dose estrogen from 10 weeks. The chondrocyte kinetics was investigated by histomorphometry and immunohistochemistry, using antibodies for caspase-3, a marker of apoptosis, and for proliferating cell nuclear antigen. Both ovariectomized and estrogen-injected rabbits showed a declination of the chondrocyte number although the latter animals indicated a more dramatic effect. Estrogen-injected rabbits showed a decrease in the cell proliferating ability together with an increase in chondrocytes undergoing apoptosis while ovariectomy mainly reduced the cell proliferating ability. Given the known importance of estrogen for bone growth, one would expect that ovariectomy and high-dose administration of estrogen would have opposite effects. However, the present study indicated that both low and high concentration had a similar effect: a decrease in the chondrocyte number compared with control, suggesting that estrogen has to be maintained within a narrow range for optimal bone growth." 

So estrogen does affect cell proliferating ability but it enhances it however only to a certain point.  So you need estrogen at an equilibrium point for optimal bone growth.  This would be true even if you're trying to increase height post growth plate senescence either with LSJL or a fracture method.  You'd want your estrogen to be at that optimal level to maximize chondrocyte proliferative capacity. 


Marked increase of final height by long-term aromatase inhibition in a boy with idiopathic short stature.

"We present a 14.5-year-old boy with ISS and a height of 142.7 cm [standard deviation score (SDS) -2.79]. Based on the baseline bone age (BA) of 13.5-14 years, his predicted adult height (PAH) by Bayley/Pinneau was 154 cm (SDS -3.77)-158.2 (SDS -3.15). After a 5-year letrozole monotherapy, FH was 169 cm (SDS -1.57) showing a height difference between PAH and FH from 10.8 to 15 cm[So future height was actually higher than predicted height]. No permanent side effects of the medication have been observed. Both a transient occurrence and a spontaneous recovery of decreased bone mineral apparent density were seen, verified by dual-energy X-ray absorptiometry. Spinal magnetic resonance imaging revealed no vertebral abnormalities."

A novel mutation in the human aromatase gene: Insights on the relationship among serum estradiol, longitudinalgrowth and bone mineral density in an adult man under estrogen replacement treatment

"We report on a new case of human aromatase deficiency in a man of 26 years of age and present the results of five year follow-up during trandermal estradiol (tE2) substitution, focusing on bone growth and mineralization. The lack of patient's compliance to tE2 treatment [resulted] in low but detectable serum estradiol levels."

"Eunuchoid body proportions, unfused epiphyses, tall stature, osteopenia, increase fasting insulin, mild astenozoospermia and a history of right cryptorchidism were present. Baseline serum FSH was slightly above the normal range and estradiol was undetectable. Genetic analysis revealed a pattern of compound heterozygosity due to 23 bp deletion in exon IV and a point mutation in the first nucleotide of intron IX of the CYP19A1 gene, respectively. The closure of epiphyseal cartilage, the normalization of bone BMD and bone turnover markers, and the improvement of insulin levels were reached during tE2 only when serum estradiol raised above 73 pmol/L. Sperm parameters and overweight did not improve with substitutive therapy."

"Months of therapy  0                          24 months             60 months
Therapy               None             Estradiol gel 0.75 mg/day Estradiol gel 0.75 mg/day
Age (years)        26.8                    30.5                                33.6
Height (cm)        193                   193.6                              193.6
Weight (kg)        109                    117                                120
BMI (kg/m2)        29.3                    31.2                                 32
Arm span (cm)         212                    213                                213
Upper-to-the-lower segment ratio
                               0.89                    0.91                                0.91"

"The patient had a history of right cryptorchidism, which was surgically corrected when he was 3 year old. "<-he was missing a right testicle.

Pre-treatment he had almost twice as much testosterone as normal.  Estrogen levels were almost non-existant.  60 months of estrogen treatment halved his free testosterone levels.  PTH and AkP were halved by estrogen treatment.  Osteocalcin and fasting insulin levels went down by a third.

"GH response to a standard GHRH + Arginine test [before estrogen treatment] showed a severely impaired GH peak (2.8 μg/L; normal values > 9 μg/L), according to the cut-offs used in the general population together with a serum IGF-I in the lowest quartile of the normal range (20.7 nmol/L; n.v. 14.4–50.3)."

"[It's possible] that the long period of treatment was able itself to promote bone maturation notwithstanding the very low doses of estradiol due to the poor patient's compliance and finally that this is only one case report"

Growth Plate Theory: Endocronilogical Control or Localized Control

Height FX is a dedicated height seeker and the producer of the Height Effects.  Whether he is wrong or right, he is still a devoted height seeker and is capable at minimum of producing constructive failures that we can learn from(in contrast to scams like Height Max which provide no relevant information).

Here's what I've said about inhibiting Estrogen to Increase Height.  Essentially I found data that supported the hypothesis that growth plate de-activation occurs as a result of depletion of mesenchymal stem cells in the growth plate.  This theory is good for Lateral Synovial Joint Loading as it does not preclude the fact that the growth plates merely deactivate rather than fuse and thus are subject to the recruitment of new mesenchymal stem cells into the growth plate.

Height FX has a different theory and believes that inhibiting Estrogen is the key to unlimited height.  Under Height FX's model Lateral Synovial Joint Loading will only work in children by trabecular microfractures enabling the recruitment of new stem cells and in adults by Lateral Synovial Joint Loading stretching the cortical bone.  He believes that Growth Plate Fusion is a constant war between chondrogenesis and osteogenesis.  If you can tip the scales in favor of chondrogenesis(whether through localized methods or endocronoligical ones) over osteogenesis(slow it down by inhibiting Estrogen) then you can increase your final maximum height.  

The Michael Phelps paradox of long arms without long legs shows how important localized factors are.  It is completely explainable by endocronological means to have a long torso but short arms and legs as they are determined by different endocronological mechanisms.  But for people like Michael Phelps who has the leg length of a 5'8" male and the arm span of someone who is 6'8" that can only be explained by factors localized within the growth plate.

If Estrogen plays such a large role in growth plate fusion, then how do high bodyfat percentage people(body fat produces estrogen) like Queen Latifah, Vincent D'Onofrio, and Dr. Phil manage to be so tall?  They most likely have enhanced sensitivity to insulin.  Bone does have metabolic factors.  Their enhanced sensitivity to insulin enables them to more rapidly gain height(plus muscle and fat mass) faster than the estrogen can take it away.

The correlation between body size and height is also explainable by the exhaustion of proliferative capacity growth plate model.  The correlation is only perceived and height is mostly determined by localized factors within the growth plate(with possibly things that affect mesenchymal stem cells like IGF-1 making a difference).

Height FX recommends Letrozole as it suppresses Estrogen activity but he also believes that chondrogenesis must be accelerated by extraneous IGF-1/HGH.  The reason that HGH doesn't cause gigantism is that HGH accelerates both chondrogenesis and osteogenesis. 

It remains to be seen whether the endochronolocial model or the localized stem cell model is correct or whether a third model is in place.