Increasing height with Letrozole?

Estrogen is a needed compound that needs to be at an equilibrium point to maximize height.  Estrogen has positive effects on cellular proliferation however ER-alpha and ER-Beta receptors in the growth plate may reduce height.  However, some of the positive benefits of can be replicated by compounds like Alfalfa without the negative effects on the ER-alpha and ER-Beta receptors in the growth plate.  Tamoxifen is an aromatase inhibitor that has benefits independent of it's Estrogen inhibition.  However, sustained usage of Tamoxifen has negative consequences thus a proper cycling regime of Tamoxifen has to be in place before starting to take Tamoxifen to get only the good benefits of Tamoxifen.  Tamoxifen is unique as it targets directly the estrogen receptor that reduces height.

Can you use Letrozole and Alfalfa plus other estrogenic compounds to get the benefits of estrogen without the ER-Alpha and ER-Beta mediated side effects?

However, it may be that ER-Alpha can be activated even during Aromatase inhibition.

An “Omics” Approach to Determine the Mechanisms of Acquired Aromatase Inhibitor Resistance

"Although these drugs work effectively,  [individuals acquire] resistance to the AIs. To characterize the resistant mechanisms, a set of MCF-7aro cell lines that acquired resistance to the AIs was generated. Through an “Omics” approach, we found that the resistance mechanisms of the three AIs (anastrozole, letrozole, and exemestane) differ and activation of estrogen receptor alpha (ERα) is critical for acquired AI resistance. Our results reveal that growth factor/signal transduction pathways are upregulated after ERα-dependent pathways are suppressed by AIs, and ERα can then be activated through different crosstalk mechanisms[ER-alpha can still be activated after aromatase has been inhibited]."

"One clinical feature associated with AI treatment is the lack of crossresistance among the three AIs, suggesting that the different AIs use different resistance mechanisms or that AI-resistant cells developed supersensitive responses to ER"<-So you may want to cycle between three aromatase inhibitors

"We found that T or E2 induced proliferation of MCF-7aro cells at a rate six times faster than the untreated cells. In addition, the T-induced proliferation of MCF-7aro cells was effectively suppressed by LET, ANA, or TAM."<-this is the problem with aromatase inhibitors it decreases cellular proliferation by a factor of 1/6.  Although this can be mediated somewhat with Ipriflavone(Alfalfa).

If Letrozole can be effective without other compounds replicating the good effects of estrogen, imagine if letrozole was used with estrogen-like compounds that stimulated cellular proliferation.

A double-blind, placebo-controlled comparison of letrozole to oxandrolone effects upon growth and puberty of children with constitutional delay of puberty and idiopathic short stature.

"We compared the effects of letrozole with that of oxandrolone on predicted adult height (PAH), puberty, bone mineral density, serum insulin-like growth factor 1 (IGF-1) and blood lipoproteins.
 In a prospective, double-blind, randomized, placebo-controlled clinical trial, 91 CDGP boys (12.6-14.6 years old) with predicted short stature were treated with letrozole (2.5 mg/day), oxandrolone (2.5 mg/day), or placebo, at the outpatient pediatric endocrine clinic of Mofid Children's Hospital in Tehran for 2 years.[this is a pretty long time]
Letrozole differed from oxandrolone and placebo in significantly increasing PAH (p < 0.05), and slightly but significantly decreasing HDL-cholesterol. Oxandrolone, and to a lesser degree letrozole, significantly increased the height standard deviation score and bone age compared to placebo[interesting that both increased cellular proliferation rate which is not what you would expect with estrogen inhibition, maybe the boys had too high estrogen and the aromatase inhibitors knocked them down to the optimal range].
This first randomized controlled clinical trial in CDGD teenage boys with predicted short stature shows that letrozole increases PAH more than oxandrolone and advances pubertal stage and bone mineralization less."

"There was no significant difference [in BMD] between the letrozole and the placebo group during treatment[this is not what you'd expect as you'd think that with estrogen levels decreasing BMD would go down, this again makes it seem like the boys had above equilibrium levels of estrogen and these aromatase inhibitors knocked them down to equilibrium]. BMD in the oxandrolone group progressively increased over the 2-year period to 1.2 ± 0.8 in the lumbar spine and 1.1 ± 0.7 in the femoral neck. These both became significantly higher than on (p < 0.001) letrozole (–1.5 ± 0.9 and –1.2 ± 0.7, respectively) or placebo (–1.5 ± 1.1 and –1.2 ± 0.6, respectively), which did not differ significantly"


Aromatase inhibitors in pediatrics.


"Aromatase, an enzyme located in the endoplasmic reticulum of estrogen-producing cells, catalyzes the rate-limiting step in the conversion of androgens to estrogens in many tissues. The clinical features of patients with defects in CYP19A1, the gene encoding aromatase, have revealed a major role for this enzyme in epiphyseal plate closure, which has promoted interest in the use of inhibitors of aromatase to improve adult height. The availability of the selective aromatase inhibitors letrozole and anastrozole--currently approved as adjuvant therapy for breast cancer--have stimulated off-label use of aromatase inhibitors in pediatrics for short stature in boys.  Although aromatase inhibitors appear effective in increasing adult height of boys with short stature and/or pubertal delay, safety concerns, including vertebral deformities, a decrease in serum HDL cholesterol levels and increase of erythrocytosis, are reasons for caution."


Normal individuals would have to be treated with letrozole to see if the benefits of letrozole are due to high estrogen individuals knocked down to the equilibrium way as only people with short stature were used which are expected to have some differentiation from mean.  Alternatively, higher doses of letrozole could be used to see how much the benefits are dose dependent.  Given that letrozole was shown to decrease height in prepubertal rats and prepuberty it's expected that estrogen levels are below equilibrium, it is likely that the benefits of letrozole are based on your deviation from equilbrium in addition to acquired estrogen receptor alpha resistance.

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.