Grow Taller with Testosterone

Testosterone inhibits myostatin and myostatin inhibits cell differentiation which can inhibit chondrogenesis.  Thus, testosterone definitely can lead to height increase that way but are there any other ways testosterone can increase height?

Testosterone and the male skeleton: a dual mode of action.

"Testosterone is an important hormone for both bone gain and maintenance in men. Hypogonadal men have accelerated bone turnover and increased fracture risk. In these men, administration of testosterone inhibits bone resorption and maintains bone mass. Testosterone, however, is converted into estradiol via aromatization in many tissues including male bone. The importance of estrogen receptor alpha activation as well of aromatization of androgens into estrogens was highlighted by a number of cases of men suffering from an inactivating mutation in the estrogen receptor alpha or in the aromatase enzyme. All these men typically had low bone mass, high bone turnover and open epiphyses{open epiphyses doesn't always mean tall stature it just means failure to complete endochondral ossification}. Estradiol contributes to the maintenance of bone mass after reaching peak bone mass, with an association between estradiol and fractures in elderly men. Estrogen receptor activation, but not androgen receptor activation, is involved in the regulation of male longitudinal appendicular skeletal growth in mice. Both the androgen and the estrogen receptor can independently mediate the cancellous bone-sparing effects of sex steroids in male mice. Selective KO studies of the androgen receptor in osteoblasts in male mice suggest that the osteoblast in the target cell for androgen receptor mediated maintenance of trabecular bone volume and coordination of bone matrix synthesis and mineralization. Testosterone has a dual mode of action on different bone surfaces with involvement of both the androgen and estrogen receptor."

In the studies description of aromatase deficiency and estrogen resistance both involve persistent growth into adulthood but this could merely mean a decrease in growth rate and not an increase in adult height as delayed bone age was involved in both.

In the information regarding removal of testes, the researchers found either equal or greater amount of length increase after additional testosterone.

"ERα is also involved in longitudinal bone formation but its action on periosteal surface as well as growth plate may be mediated indirectly by the GH-IGF-I axis"

This study found that testosterone had no effect on the growth plate when adrogen receptor was blocked:

Androgen receptor modulation does not affect longitudinal growth of cultured fetal rat metatarsal bones.

"Systemic administration of the nonaromatizable androgen oxandrolone{oxandrolone does not suppress testosterone in low dosage but it does in high dosages} stimulates growth in girls with Turner syndrome and boys with a constitutional delay of growth and puberty

Metatarsal bones from female and male rat fetuses (day E20) were cultured for 14 days in the presence of oxandrolone, testosterone or the androgen receptor (AR) antagonist flutamide with/without insulin-like growth-factor-I (IGF-I) or charcoal-treated serum.

The AR was found to be expressed in both male and female fetal rat metatarsal bones. Neither oxandrolone nor testosterone had any effect on metatarsal bone growth when tested at a wide concentration range (1 nM to 10 microM), not even in the presence of IGF-I (100 ng/ml) or charcoal-treated serum (10%). Bone growth was also unaffected when the AR was blocked by flutamide. Metatarsal bone growth was significantly stimulated by IGF-I.

Modulation of AR activity in the fetal rat growth plate does not affect linear bone growth. Extrapolating from these in vitro data, it could be speculated that oxandrolone stimulates longitudinal bone growth in treated children by acting indirectly{likely through myostatin inhibition} rather than directly through AR activation in growth plate chondrocytes."

So Testosterone stimulates linear bone growth but not through direct receptor activation.

"More controversial is the effect of oxandrolone on adult height in these boys. Some studies show no effect on adult height, while others suggest that there might be a positive effect also on adult height in boys who start the treatment before puberty"<-so maybe testosterone requires an equilibrium value and if you're above it there's no height increasing benefit but if you're below it like before puberty it increases height.

"On day 14 of culture, bone lengths compared to control were 96 ± 1% in male and 98 ± 2% in female bones treated with oxandrolone"<-So bone length decreased when testosterone was added above equilibrium and bone length increased(by 102% in testosterone challenged males) when testosterone was added below equilibrium.

"Chondrocyte mineralization [is] impaired by oxandrolone and testosterone"

"Our finding that testosterone, in contrast to oxandrolone, a nonaromatizable androgen, promotes chondrocyte proliferation, suggests that local aromatization of testosterone to estrogens may occur in the growth plate."

Thus Testosterone may only increase height by increasing IGF-1 levels and inhibiting myostatin, it likely does not have direct effects in the growth plate other than converting into estrogen.   Too much testosterone even when not converted to estrogen may also have negative effects on growth.

According to Analysis of testosterone effects on sonic hedgehog signaling in juvenile, adolescent and adult sprague dawley rat penis., testosterone in adults decreases Shh protein levels but increases Shh transcription.  "Testosterone treatment did not alter SHH signaling in juvenile rats. Shh mRNA increased 3.2-fold and SHH protein increased 1.2-fold in rats castrated during puberty. In adult rats, castration decreased Shh mRNA 3.2-fold but did not alter SHH protein. Testosterone supplement in adult rats increased Shh mRNA 2.3-fold and decreased SHH protein 1.3-fold."  Since SHH is pro-chondrogenic this can be a negative effect.  The fact that Shh protein increased 1.2 fold in rats after castration indicates that there may be an equilibrium level of testosterone.

Rapid membrane responses to dihydrotestosterone are sex dependent in growth plate chondrocytes.

"17β-Estradiol regulates proliferation and differentiation of female chondrocytes via a membrane-associated signaling pathway in addition to its estrogen receptor (ER) mediated effects. In contrast, testosterone does not elicit a similar membrane response, either in male or female cells. Whereas female rat growth plate chondrocytes convert testosterone to 17β-estradiol, male chondrocytes produce 5α-dihydrotestosterone (DHT). DHT was found to mediate sex-specific effects of testosterone in male cells. In this study, we hypothesized that DHT can induce sex-specific rapid membrane effects similar to other steroid hormones. Confluent cultures of chondrocytes isolated from resting zones of growth plates of both male and female rats were treated with 10(-10)-10(-7)M testosterone or DHT for 3, 9, 90 and 270min and protein kinase C (PKC) and phospholipase A2 (PLA2) activities were measured. To examine potential signaling pathways involved in PKC activation, male chondrocytes were treated with 10(-7)M DHT for 9min in the presence or absence of the phospholipase C (PLC) inhibitor U73122, the secretory PLA2 inhibitor quinacrine or the cytosolic PLA2 inhibitor AACOCF3; the Gαi inhibitor pertussis toxin (PTX) or Gαs activator cholera toxin (CTX), and the general G-protein inhibitor GDPβS; thapsigargin, an inhibitor of a Ca-ATPase pump in the endoplasmic reticulum; verapamil and nifedipine, inhibitors of specific L type Ca2+ channels on the cell membrane; and cyproterone acetate (CPA), which is an inhibitor of the classical androgen receptor (AR); as well as the transcription inhibitor actinomycin D, or the translation inhibitor cycloheximide. DHT induced a dose-dependent increase in PKC and PLA2 activity in male cells with the highest increase at 10(-7)M DHT{highest dose}, whereas testosterone had no effect. PKC activity was augmented at 9 and 90 min, and then decreased to baseline at 270min. Neither testosterone nor DHT affected PKC in female cells. U73122, quinacrine, and AACOCF3 inhibited DHT-induced activation of PKC. DHT treatment for 9 min had no effect in [(3)H]-thymidine incorporation in quiescent confluent cultures but caused a dose dependent increase in alkaline phosphatase specific activity. Inhibition of PLC reduced the response of to DHT in a dose dependent manner, indicating that PLC is involved. In conclusion, our study indicates that DHT, but not testosterone, has sex-specific rapid membrane effects in male growth plate chondrocytes involving PLC and PLA2-mediated PKC signaling pathways."

LSJL gene expression data was done on female rats.

"E2 causes a rapid activation of Ca2+ influx and activation of PKC only in cells from female rats"

"PKCα [is likely involved] in the mechanism [of DHT response]"

"inhibition of Ca2+ influx blocks the stimulatory effect of DHT on PKC. Gα proteins have also been shown to activate PI-PLC and PLC was required for DHT-dependent PKC activation, since specific inhibition of PI-PLC blocked activation of PKC by DHT. Moreover, inhibition of release of Ca2+ ions from the endoplasmic reticulum also reduced DHT‘s effect. PI-PLC catalyzes the release of IP3, which opens these Ca2+ ion channels and resulting DAG translocates the active PKC to the plasma membrane. Although Gαq is generally associated with PI-PLC activation, Gαi has also been shown to do so"

"Gαi is activating PLA2, and that is upstream of PI-PLC, as we have shown for 1α,25-dihydroxyvitamin D3-dependent activation of PKC in growth plate chondrocytes. DHT activated PKC via a PLA2-dependent pathway. DHT caused a rapid increase in PLA2 activity and inhibition of PLA2 blocked the stimulatory effect of DHT on PKC. Production of lysophospholipid and release of arachidonic acid are catalyzed by PLA2 via phospholipid hydrolysis. Arachidonic acid can act as co-factor for PKCα and also provides a substrate for constitutively active cyclooygenase-1 (Cox-1) in growth plate chondrocytes, which leads to prostaglandin production. In addition, lysophospholipid can activate PLC, and can then initiate the downstream PLC-PKC pathway"

C2C12 myoblastoma cell differentiation and proliferation is stimulated by androgens and associated with a modulation of myostatin and Pax7 expression.

"Androgens are modulators of skeletal muscle adaptation and regeneration processes. The control of satellite cell activity is a key mechanism during this process. In this study, we analyzed the ability of dihydrotestosterone (DHT) and anabolic steroids to induce and modulate the differentiation of C2C12 myoblastoma[muscle cell tumor] cells toward myotubes. C2C12 cells were dose-dependently treated with DHT and anabolic steroids. The treatment with DHT and anabolic steroids resulted in a stimulation of C2C12 cell proliferation and CK[creatine kinase] activity. The antiandrogen flutamide was able to antagonize this effect. The expression of the androgen receptor, SOX8, SOX9{up}, Delta, Notch, myostatin, and paired box gene7 (Pax7){LSJL downregulates Pax7a} was modulated by androgens. The treatment with DHT and anabolic steroids resulted in a strong stimulation of myostatin expression not only in undifferentiated cells{since MSCs are undifferentiated cells DHT will affect LSJL too} but also in myotubes. The stimulation could be antagonized by flutamide. The expression of Pax7 was detectable in C2C12 cells early after treatment with DHT. Our results demonstrate that the key mechanisms of satellite cell differentiation are modulated by androgens. Androgens stimulate the proliferation of C2C12 cells, accelerate the process of differentiation, and increase the expression of myostatin in undifferentiated and differentiated cells."

Both DHT-6 and DHT-9 tended to decrease Sox9 expression.