Peritubular cells also secrete proteins that act on other nearby cells, in a paracrine manner. Contraction of the peritubular cells moves the sperm closer to the lumen as it matures. Peritubular cells, which lie on the surface of the seminiferous tubules, are smooth muscle cells that can contract. For men with low blood testosterone levels and symptoms most likely caused by a low level, the benefits of hormone replacement therapy usually outweigh potential risks. Testosterone therapy is approved for the treatment of delayed male puberty and abnormally low production of testosterone secondary to malfunction of the testes, pituitary or hypothalamus. Estrogen therapy increases sex hormone binding globulin and, like aging men, this reduces the amount of free, active testosterone in the body. One treatment available for many of these problems is spironolactone, a special type of diuretic (water pill) that blocks the action of male sex hormones. It is essential to the development of male growth and masculine characteristics. During puberty, children who are genetically male with 5-alpha reductase deficiency experience a lack of facial hair growth. This causes them to not have secondary sexual characteristics and to have infertility. The age at which puberty begins varies between individuals; usually, puberty begins between 10 and 13 years of age. A common definition for the onset of puberty is physical changes to a person's body. Rising levels of androgens can change the fatty acid composition of perspiration, resulting in a more "adult" body odor. During this period, also in response to rising levels of estrogen, the lower half of the pelvis and thus hips widen (providing a larger birth canal). The mucosal surface of the vagina also changes in response to increasing levels of estrogen, becoming thicker and duller pink in color (in contrast to the brighter red of the prepubertal vaginal mucosa). Stage 5 refers to spread of pubic hair to the thighs and sometimes as abdominal hair upward towards the navel. The average age at which the onset of puberty occurs has dropped significantly since the 1840s. The average age at which puberty begins may be affected by ethnicity as well. The age at which puberty begins is affected by both genetic factors and by environmental factors such as nutritional state and social circumstances. There are separate Tanner stages for changes in genitalia and pubic hair. Some girls never have pubic hair reach Tanner Stage 5; that may be their "normal." In Stage 4, puberty hits full stride. There are five stages of puberty for girls. There are separate Tanner stages for changes in breasts and pubic hair. Pubic hair may extend out to their thighs, and some boys may have a line of hair up to their belly button. Many may not develop facial hair until this step in the process. It’s most common between the ages of 11 and 15 years. But it typically resolves by the end of puberty. In this stage, boys haven’t experienced any visible changes, but their adrenal glands are maturing. For parents, the Tanner stages can serve as an excellent guide to the changes you can expect to see in your son. Most girls reach their peak height by age 16, but some may continue growing through age 20. Free testosterone (T) is transported into the cytoplasm of target tissue cells, where it can bind to the androgen receptor, or can be reduced to 5α-dihydrotestosterone (5α-DHT) by the cytoplasmic enzyme 5α-reductase. This additional information could suggest, contrarily, that testosterone may encourage greed or selfishness. Moreover, the conversion of testosterone to estradiol regulates male aggression in sparrows during breeding season. A few studies indicate that the testosterone derivative estradiol might play an important role in male aggression. The Annals of the New York Academy of Sciences has found that the use of anabolic steroids (which increases testosterone) among teenagers is correlated with increased likelihood of using violence. It is therefore the challenge of competition among males that facilitates aggression and violence. There has been speculation that these changes in testosterone result in the temporary reduction of differences in behavior between the sexes. The chemical synthesis of testosterone from cholesterol was achieved in August that year by Butenandt and Hanisch. The Organon group in the Netherlands were the first to isolate the hormone, identified in a May 1935 paper "On Crystalline Male Hormone from Testicles (Testosterone)". Testosterone has been detected at variably higher and lower levels among men of various nations and from various backgrounds, explanations for the causes of this have been relatively diverse. Immunofluorescence assays exhibit considerable variability in quantifying testosterone concentrations in blood samples due to the cross-reaction of structurally similar steroids, leading to overestimating the results.