Wednesday, September 8, 2010

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.

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