Increased Bone Mass as a Result of Estrogen Therapy in a Man with Aromatase Deficiency

The role of estrogen receptor α in growth plate cartilage for longitudinal bone growth

“…The increased appendicular but not axial skeletal growth in the elderly female cartilage-specific ERa À/À mice resembles the eunuchoid habitus seen in patients with aromatase deficiency and in the man with an inactivating ERa mutation. (2)(3)(4)(5)(6)(7)(8) Although there are clear species differences between humans and mice, these findings of the importance of ERa in growth plate cartilage both for high-dose E2 to reduce growth plate height in adult mice and for age-dependent reduction of longitudinal bone growth in adult mice suggest that growth plate-located ERa also may be essential for growth plate fusion and cessation of longitudinal bone growth in humans.…”

“…(2)(3)(4)(5)(6)(7)(8) We have found recently that elderly female mice with complete inactivation of ERa and no remaining ERa protein also continue to grow for a much longer time than their control littermates, reflected by increased femur length in elderly female ERa À/À mice compared with control littermates. (19) To evaluate the role of growth plate cartilage-located ERa in growth during adulthood, we followed the skeletal growth of female mice with cartilage-specific ERa inactivation up to 1 year of age.…”

“…(19) Importantly, the increased growth plate height and continued growth in elderly female mice with complete inactivation of ERa resemble the lack of growth plate fusion and continued growth seen in the patients with aromatase deficiency and in the man with an inactivating ERa mutation. (2)(3)(4)(5)(6)(7) Although ERa is the main ER regulating skeletal growth, it is unknown whether the different effects of estrogens on skeletal growth are mediated via growth plate-located ERa and/or via indirect mechanisms not requiring ERa in growth plate cartilage. Estrogens are crucial regulators of the growth hormone/insulinlike growth factor 1 (GH/IGF-1) axis, and therefore, some of the effects of estrogens on skeletal growth might be indirect via modulation of the GH/IGF-1 axis.…”

“…(2) The key role of estrogens for skeletal growth is demonstrated by the findings that both males and females with estrogen deficiency, caused by a mutation in the aromatase gene, display no clear pubertal growth spurt and continue to grow into adulthood owing to a lack of epiphyseal fusion in the long bones, which results in increased adult height. (2)(3)(4)(5)(6)(7) One male patient with a point mutation in exon 2 of the estrogen receptor (ER) a had a similar phenotype, demonstrating that ERa is the major ER to mediate the effects of estrogens on longitudinal bone growth. (8) Estrogen therapy resulted in rapid growth plate closure in patients with aromatase deficiency but not in the man with a mutation in the ERa gene.…”

“…(8) Estrogen therapy resulted in rapid growth plate closure in patients with aromatase deficiency but not in the man with a mutation in the ERa gene. (3,4,8) In rodents, the growth plates do not fuse directly after sexual maturation, but high-dose ORIGINAL ARTICLE…”