Impact of Estrogen Replacement Therapy in a Male with Congenital Aromatase Deficiency Caused by a Novel Mutation in the CYP19 Gene

Abstract

Recent reports of the impact of estrogen receptor ␣ and aromatase deficiency have shed new light on the importance of estrogen for bone formation in man. We describe a novel mutation of the CYP19 gene in a 27-yr-old homozygous male of consanguinous parents. A C to A substitution in intron V, at position ؊3 of the splicing acceptor site before exon VI of the CYP19 gene, is the likely cause of loss of aromatase activity. The mRNA of the patient leads to a frameshift and a premature stop codon 8 nucleotides downstream the end of exon V. Both parents were shown to be heterozygous for the same mutation. Apart from genua valga, kyphoscoliosis, and pectus carniatus, the physical examination was normal including secondary male characteristics with normal testicular size. To substitute for the deficiency, the patient was treated with 50 g transdermal estradiol twice weekly for 3 months, followed by 25 g twice weekly. After 6 months estrogen levels (<20 at baseline and 45 pg/ml at 6 months; normal range, 10 -50) and estrone levels (17 and 34 ng/ml; normal range, 30 -85) had normalized. Bone maturation progressed and the initially unfused carpal and phalangeal epiphyses began to close within 3 months and were almost completely closed after 6 months. I N A WIDE VARIETY of tissues, including testis, ovary, placenta, and adipose tissue, the aromatase cytochrome P450, as the product of the CYP19 gene, catalyzes the conversion of androgens to estrogens (1, 2). Reports of osteopenia and osteoporosis in animals and humans with gene defects in the estrogen receptor (3-5) and both in females and males with aromatase deficiency (6 -9) have called attention to the importance of estrogen for skeletal maturation (10). The precise role of estrogen in human male physiology remains largely unknown, especially which effects on bone mineralization and metabolism in the male are mediated by estrogens derived from the aromatization of androgens. Many studies have demonstrated that gonadal failure in males is associated with a decrease in bone mass, but less is known about the role of genetic disorders associated with estrogen resistance or deficiency (11). First descriptions of young men affected by congenital estrogen deficiency have shed new light on the importance of estrogen for bone formation in man (7,8,11,12). These findings suggest that epiphyseal closure does not develop without the action of estrogen even in males and that androgen alone is not sufficient to promote normal skeletal mineralization. Recently two mutations in the CYP19 gene in males have demonstrated the role of estrogen on bone mineralization and their effect on glucose and lipid metabolism (6 -9, 13, 14).We now present the third case of a 27-yr-old man with open epiphysis caused by a new mutation in the CYP19 gene (aromatase deficiency), the effect of estrogen replacement on bone mineralization/maturation and glucose and lipid metabolism. Subjects and Methods Case reportThe propositus was the only child of consanguineous parents (second cousins, Fig. 1). His mother d...

Vertebral morphology in aromatase inhibitor–treated males with idiopathic short stature or constitutional delay of puberty

“…The AM:MP ratios, which were of 1.0 of less in all deformed vertebral bodies, suggest that disturbed growth is more likely, although the index has been validated only in adults. (15) Estrogen is a wellknown regulator of endochondral bone growth and is critical for bone maturation and epiphyseal fusion, (1)(2)(3)(4)(5)16) but it is not known whether estrogen (or estrogen deprivation) influences endochondral bone growth and maturation similarly in the axial and appendicular skeleton. In juvenile rabbits and mice, estrogen treatment reduces chondrocyte proliferation and growth plate height, whereas letrozole may decrease the differentiation rate of growth plate chondrocytes and increase growth plate height.…”

“…(1)(2)(3)(4)(5) These findings have prompted clinical researchers to investigate whether in children or adolescents with growth disorders a delay in bone maturation and ultimately an increase in adult height can be achieved by blocking of estrogen biosynthesis with aromatase inhibitor (AI) treatment.…”

Teasing out the role of aromatase in the healthy and diseased testis

“…46 76 and in some cases cryptorchidism is evident. 73,74 The lack of patient consent for human ejaculate samples and testicular biopsies hampers the ability to draw solid conclusions about the effect of aromatase deficiency on spermatogenesis, but from the data that is available it appears a lack of aromatase is associated with Sertoli cell only syndrome, 74 hypospermatogenesis, 75 oligospermia, 46,47 reduced sperm motility 47 and complete sperm immobility, 46 many of which are in concert with findings from the ArKO model (reviewed in ref. 6)· Further qualitative analyses on the histological architecture of the testis noted seminiferous tubules of normal appearance 75 and those that were hypotrophic.…”

“…This concurs with findings from the aromatase deficient mouse (ArKO) (reviewed in ref. 6), and human, 46,47 highlighting a potential link between local estrogen production and sperm motility. New data report an association between a mouse 13 and rooster.…”

Total estradiol, rather than testosterone levels, predicts osteoporosis in aging men

“…The lower the testosterone levels, the lower the aromatization to estradiol (E2). Recently, estrogen role in male bone homeostasis has been demonstrated through congenital estrogen deficiency description: estrogen resistance due to inactivating mutation in the estrogen alpha receptor gene (5,6) and aromatase (the enzyme that catalyzes androgens conversion into estrogens) deficiency (7)(8)(9)(10). In both cases, lack of estrogen activity was associated with osteoporosis or severe osteopenia, demonstrated by low BMD at lumbar and femoral sites (3).…”