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.