One of the most basic principles/ideas I learned about how the human body goes through the process at the end of puberty to close the growth plates was the influence of the hormone estrogen. Estrogen appears and again when I was doing research to see whether any type of steroids or growth hormones was being tried by others to help them increase height. Almost all of the other posters besides the original inquirer who asked about using steroids or growth hormones for height increase stated that height increase had become become impossible because estrogen caused the closure of the growth plates. This post was to study and research deeper into what the estrogen really does, how it does it, and how we might inhibit it or decrease its amounts to allow for a longer length of time for our growth plates to work and give us some extra height.
I choose again to just go to google and types in “estrogen growth” and see what is available. Fortunately 3 scientific articles with titles signaled that there has already been a lot of research and experiments done to see the link of estrogen and bone formation and growth plates closure.
I will first take the abstract for each article and post it here. Then I will do a quick personal educated analysis on what was the most important takeaway we should get from the article.
Article 1: “Estrogens and growth”
Authors: Simm PJ, Bajpai A, Russo VC, Werther GA.
Journal: Pediatr Endocrinol Rev. 2008 Sep;6(1):32-41.
Source : Department of Endocrinology and Diabetes, Royal Children’s Hospital Melbourne, Parkville, Australia. firstname.lastname@example.org
Reference Link: US National Library Of Medicine. National Institute Of Health. Resource Link.
Estrogen is critical for epiphyseal fusion in both young men and women. In this study, we explored the cellular mechanisms by which estrogen causes this phenomenon. Juvenile ovariectomized female rabbits received either 70 μg/kg estradiol cypionate or vehicle i.m. once a week. Growth plates from the proximal tibia, distal tibia, and distal femur were analyzed after 2, 4, 6, or 8 weeks of treatment. In vehicle-treated animals, there was a gradual senescent decline in tibial growth rate, rate of chondrocyte proliferation, growth plate height, number of proliferative chondrocytes, number of hypertrophic chondrocytes, size of terminal hypertrophic chondrocytes, and column density. Estrogen treatment accelerated the senescent decline in all of these parameters. In senescent growth plates, epiphyseal fusion was observed to be an abrupt event in which all remaining chondrocytes were rapidly replaced by bone elements. Fusion occurred when the rate of chondrocyte proliferation approached zero. Estrogen caused this proliferative exhaustion and fusion to occur earlier. Our data suggest that (i) epiphyseal fusion is triggered when the proliferative potential of growth plate chondrocytes is exhausted; and (ii) estrogen does not induce growth plate ossification directly; instead, estrogen accelerates the programmed senescence of the growth plate, thus causing earlier proliferative exhaustion and consequently earlier fusion.
In mammals, longitudinal bone growth occurs at the growth plate by endochondral bone formation. The growth plate consists of three principal zones: resting, proliferative, and hypertrophic. The resting zone lies adjacent to the epiphyseal bone and contains infrequently dividing chondrocytes. The proliferative zone contains replicating chondrocytes arranged in columns parallel to the long axis of the bone. The proliferative chondrocytes located farthest from the resting zone stop replicating and enlarge to become hypertrophic chondrocytes (1). These terminally differentiated cells maintain a columnar alignment in the hypertrophic zone. The processes of chondrocyte proliferation, hypertrophy, and cartilage matrix secretion result in chondrogenesis. Simultaneously, the metaphyseal border of the growth plate is invaded by blood vessels and bone cell precursors that remodel the newly formed cartilage into bone (1). The synchronized processes of chondrogenesis and cartilage ossification lead to longitudinal bone growth.
With increasing age, the growth plate undergoes structural and functional changes. The rate of longitudinal bone growth decreases, in large part, because of a decline in chondrocyte proliferation (2–6). These functional senescent changes are accompanied by structural senescent changes. There is a gradual decline in the overall growth plate height (7), proliferative zone height (3), hypertrophic zone height (2), size of hypertrophic chondrocytes (2, 6, 8), and column density (9).
In some mammals, including humans, the growth plate is resorbed at the time of sexual maturation. This process, epiphyseal fusion, terminates longitudinal bone growth. Estrogen is pivotal for epiphyseal fusion in both young men and women (10). This key role for estrogen was confirmed only recently with the recognition of two genetic disorders, estrogen deficiency due to mutations in the aromatase gene (11) and estrogen resistance due to mutations in the estrogen receptor-α gene (12). In both conditions, the growth plate fails to fuse and growth persists into adulthood. Conversely, premature estrogen exposure, e.g., precocious puberty, leads to premature epiphyseal fusion (13).
The mechanism by which estrogen promotes epiphyseal fusion is not known. Previous reports suggest that estrogen accelerates growth plate ossification by stimulating vascular and bone cell invasion of the growth plate cartilage, causing ossification to advance beyond the hypertrophic zone into the proliferative and resting zones (14–16). This proposed mechanism of estrogen action would be expected to induce epiphyseal fusion promptly, a prediction that does not match clinical experience. Prompt fusion occurs only in estrogen-deficient adults treated with estrogen (10, 17, 18). In children, epiphyseal fusion occurs only after years of estrogen exposure. The accelerated ossification hypothesis does not readily explain this delayed action.
The current study was designed to explore the underlying cellular mechanisms by which estrogen causes growth plate fusion. Because this process involves chondrocytes, osteoblasts, osteoclasts, and endothelial cells interacting within the complex structure of the growth plate, an in vivo model was chosen. Rabbits were selected for this study because rabbits, like humans but unlike rodents, fuse their epiphyses at the time of sexual maturation and in response to sex steroids (19–21). We also used physiological doses of estradiol and initiated treatment at the expected age of onset of sexual maturation (22) to mimic physiological conditions.
Me: In my opinion, this abstract is critically important for anyone who is serious about doing scientific research to find a solution to stimulate increased height growth after one passes puberty and the growth plates are believed to have fused. I didn’t want to do a complete summary of the entire abstract but will instead choose to highlight the parts that are the most important for the reader to read and understand
Article 3: The role of estrogen in bone growth and formation: changes at pubertyAuthors: Divya Singh, Sabyasachi Sanyal, Naibedya Chattopadhyay
Journal: Cell Health and Cytoskeleton – Published Date December 2010 Volume 2011:3 Pages 1 – 12 DOI: http://dx.doi.org/10.2147/CHC.S8916
Source: Division of Endocrinology, 2Division of Drug Target Discovery and Development, Central Drug Research Institute (Council of Scientific and Industrial Research), Lucknow, Uttar Pradesh, India
Reference Link: Dovepress, Open Access to Scientific and Medical Research. Resource Link.
Abstract: A high peak bone mass (PBM) at skeletal maturity is a good predictor for lower rate of fracture risks in later life. Growth during puberty contributes significantly to PBM achievement in women and men. The growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis has a critical role in pubertal bone growth. There is an increase in GH and IGF-1 levels during puberty; thus, it is assumed that sex steroids contribute to higher GH/IGF-1 action during growth. Recent studies indicate that estrogen increases GH secretion in boys and girls, and the major effect of testosterone on GH secretion is via aromatization to estrogen. Estrogen is pivotal for epiphyseal fusion in young men and women. From studies of individuals with a mutated aromatase gene and a case study of male patient with defective estrogen receptor-alpha (ER-α), it is clear that estrogen is indispensable for normal pubertal growth and growth plate fusion. ER-α and estrogen receptor-beta (ER-β) have been localized in growth plate and bone. ER knockout studies have shown that ER-α-/- female mice have reduced linear appendicular growth, while ER-β-/- mice have increased appendicular growth. No such effect is seen in ER-β-/- males; however, repressed growth is seen in ER-α-/- males, resulting in shorter long bones. Thus, ER-β represses longitudinal bone growth in female mice, while it has no function in the regulation of longitudinal bone growth in male mice. These findings indicate that estrogen plays a critical role in skeletal physiology of males as well as females.
Me: It would appear that not only does estrogen seem to influence an regulate the fusion process of the growth plates, it is also the trigger that starts the increased longitudinal growth rate of bones when a human reaches the puberty stage. Estrogen increases growth hormone secretion in young men and women and the effect of testosterone on growth hormone secretion only happens after it aromatizes into estrogen. There are two types of estrogen receptors on the growth plates, alpha and beta. The alpha seems to be the receptor that tells the growth plates to speed up the senescence of the growth plates for females and males. The beta seems to be the receptor that tells the growth plates to slow down the senescence process of the growth plates in females but not the males.
Article 4: The genetic basis of human height : the role of estrogen
Authors: Carter, Shea L.
Source: PhD thesis, Queensland University of Technology.
Reference Link: Queensland University of Technology. Brisbane, Australia. Resource Link
Height is a complex physical trait that displays strong heritability. Adult height is related to length of the long bones, which is determined by growth at the epiphyseal growth plate. Longitudinal bone growth occurs via the process of endochondral ossification, where bone forms over the differentiating cartilage template at the growth plate. Estrogen plays a major role in regulating longitudinal bone growth and is responsible for inducing the pubertal growth spurt and fusion of the epiphyseal growth plate. However, the mechanism by which estrogen promotes epiphyseal fusion is poorly understood. 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 overall objective of this study was to gain a greater understanding of the molecular mechanisms behind estrogen-mediated growth and height attainment by examining gene regulation in chondrocytes and the role of some of these genes in normal height inheritance. With the heritability of height so well established, the initial hypothesis was that genetic variation in candidate genes associated with longitudinal bone growth would be involved in normal adult height variation. 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. 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. In the epiphyseal growth plate, chondrocyte proliferation, matrix synthesis and chondrocyte hypertrophy are all major contributors to long bone growth. As estrogen plays such a significant role in both growth and final height attainment, 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. The examination of genes regulated by estrogen in chondrocyte-like cells aimed to identify potential regulators of growth plate fusion, which may further elucidate mechanisms involved in the cessation of linear growth. 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 TGF1 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. 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. 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, 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. However, further investigation is required in order to elucidate the precise mechanisms behind estrogen and GH regulation of MMP13 expression in SW1353 cells. This study has provided additional evidence that estrogen and the ER gene are major factors in the regulation of growth and the determination of adult height. Newly identified polymorphisms in the ER gene not only contribute to our understanding of the genetic basis of human height, but may also be useful in association studies examining other complex traits. This study also identified several estrogen regulated genes and indicated that estrogen modifies the expression of genes which are primarily expressed in the hypertrophic region of the epiphyseal growth plate. Furthermore, synergistic studies incorporating GH and estrogen have revealed the ability of estrogen to attenuate the effects of GH on MMP13 expression, revealing potential pathways by which estrogen may modulate growth plate fusion, longitudinal bone growth and even arthritis.
Me: I’ll just highlight the most important findings within this Ph. D Thesis. Again, You can get the Full PDF of the Thesis by clicking HERE.