The placement of germ cells within seminiferous tubules during spermatogenesis is shown in Figure 44.6. Free cholesterol is converted to progesterone, 17-hydroxyprogesterone, and androstenecholesterol through the actions of cholesterol ester hydrolase and 3β-hydroxysteroid dehydrogenase (3β-HSD). These products are then transferred to the outer mitochondrial membrane and subsequently to the inner mitochondrial membrane by CYP17, which is a bifunctional enzyme with 17-hydroxylase and 17,20-lyase activities. CYP17 is highly active in Leydig cells and is regulated by the steroidogenic acute regulatory (StAR) protein. Similar to the zona reticularis cell, the Leydig cell converts cholesterol to pregnenolone through the actions of CYP11A1. However, the Leydig cell expresses a higher level of 3β-HSD, favoring the Δ4 pathway. In addition, the Leydig cell expresses a Leydig cell-specific isoform of 17β-hydroxysteroid dehydrogenase (17β-HSD type 3), which efficiently converts androstenedione to testosterone (Figure 44.7). The testosterone produced by Leydig cells has multiple fates and actions. Significant amounts of testosterone diffuse into the seminiferous tubules and become concentrated within the adluminal compartment by androgen-binding protein (ABP). This high concentration of testosterone within the seminiferous tubules is essential for normal spermatogenesis. Sertoli cells express the enzyme CYP19 (aromatase), which converts a small amount of testosterone into estradiol-17β. Local production of estrogen in human sperm cells optimizes spermatogenesis. Testosterone can also be converted to estrogen in several tissues, particularly adipose tissue, through peripheral conversion. Estrogen is important for bone maturation and biology in men and has other effects such as promoting insulin sensitivity, improving lipoprotein profiles, and exerting negative feedback on gonadotropins at the pituitary and hypothalamus. Dihydrotestosterone is another product of testosterone metabolism.
CHAPTER 44 The Male and Female Reproductive Systems 791 • Fig. 44.6 Placement of germ cells within seminiferous tubule as they progress through spermatogenesis (From Carlson BM. Human Embryology and Developmental Biology. Philadelphia: Mosby; 2004.) ). Free to progesterone, 17-hydroxyprogesterone, and androstenecholesterol is generated by a cholesterol ester hydrolase and dione by 3β-hydroxysteroid dehydrogenase (3β-HSD) and transferred to the outer mitochondrial membrane and then CYP17 (
Fig. 44.8).
CYP17 to the inner mitochondrial membrane in a steroidogenic is a bifunctional enzyme with 17-hydroxylase activity acute regulatory (StAR) protein–dependent manner. and 17,20-lyase activity. CYP17 displays a robust level As in all steroidogenic cells, cholesterol is converted to of both activities in the Leydig cell. In this respect the pregnenolone by CYP11A1. Pregnenolone is then processed Leydig cell is similar to the zona reticularis cell, except that it expresses a higher level of 3β-HSD, so the Δ4 pathway is ultimately favored. Another major difference is that the Leydig cell expresses a Leydig cell–specific isoform of •Fig. 44.7 Histologyoftheperitubularspace(betweenthreesemi-niferoustubules)containingLeydigcells(L)andrichlyvascularizedbyperitubularcapillaries(cap).(ModifiedfromYoungBetal.Wheater’s Functional Histology. A Text and Colour Atlas. 5thed.London:ChurchillLivingstone;2006.)capSeminiferoustubuleSeminiferoustubuleSeminiferoustubuleLcapSeminiferoustubuleSeminiferoustubuleSeminiferoustubuleL 17β-hydroxysteroid dehydrogenase (17β-HSD type 3), which efficiently converts androstenedione to testosterone (see
Fig. 44.8
Fates and Actions of Androgens
The testosterone produced by Leydig cells has several fates and multiple actions. Because of the proximity of Leydig cells to the seminiferous tubules, significant amounts of testosterone diffuse into the seminiferous tubules and become concentrated within the adluminal compartment by ABP (see
Fig. 44.8 ). Testosterone levels within the seminiferous tubules that are greater than 100 times more concentrated than circulating testosterone levels are absolutely required for normal spermatogenesis. As mentioned earlier, Sertoli cells express the enzyme CYP19 (aromatase), which converts a small amount of testosterone into the highly potent estrogen estradiol-17β. Human sperm cells express at least one isoform of the estrogen receptor, and there is some evidence from aromatase-deficient men that this locally produced estrogen optimizes spermatogenesis in humans.
Peripheral Conversion to Estrogen
In several tissues (especially adipose tissue), testosterone is converted to estrogen (see
Fig. 44.8 ). Studies involving men with aromatase deficiency have shown that an inability to produce estrogen results in tall stature because of the lack of epiphyseal closure in long bones, as well as osteoporosis. Thus peripheral estrogen plays an important role in bone maturation and biology in men. These studies also implicated estrogen in promoting insulin sensitivity, improving lipoprotein profiles (i.e., increasing HDL, decreasing triglycerides and LDL), and exerting negative feedback on gonadotropins at the pituitary and hypothalamus.
Peripheral Conversion to Dihydrotestosterone