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"