Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens

Abstract

The aromatase enzyme complex catalyzes the conversion of androgens to estrogens in a wide variety of tissues, including the ovary, testis, placenta, brain, and adipose tissue. Only a single human gene encoding aromatase P450 (CYP19) has been isolated; tissue-specific regulation is controlled in part by alternative promoters in a tissue-specific manner. We report a novel mutation in the CYP19 gene in a sister and brother. The 28-yr-old XX proband, followed since infancy, exhibited the cardinal features of the aromatase deficiency syndrome as recently defined. She had nonadrenal female pseudohermaphrodism at birth and underwent repair of the external genitalia, including a clitorectomy. At the age of puberty, she developed progressive signs of virilization, pubertal failure with no signs of estrogen action, hypergonadotropic hypogonadism, polycystic ovaries on pelvic sonography, and tall stature. The basal concentrations of plasma testosterone, androstenedione, and 17-hydroxyprogesterone were elevated, whereas plasma estradiol was low. Cyst fluid from the polycystic ovaries had a strikingly abnormal ratio of androstenedione and testosterone to estradiol and estrone. Hormone replacement therapy led to breast development, menses, resolution of ovarian cysts, and suppression of the elevated FSH and LH values. Her adult height is 177.6 cm (+2.5 SD). Her only sibling, an XY male, was studied at 24 yr of age. During both pregnancies, the mother exhibited signs of progressive virilization that regressed postpartum. The height of the brother was 204 cm (+3.7 SD) with eunuchoid skeletal proportions, and the weight was 135.1 kg (+2.1 SD). He was sexually fully mature and had macroorchidism. The plasma concentrations of testosterone (2015 ng/dL), 5 alpha-dihydrotestosterone (125 ng/dL), and androstenedione (335 ng/dL) were elevated; estradiol and estrone levels were less than 7 pg/mL. Plasma FSH and LH concentrations were more than 3 times the mean value. Plasma PRL was low; serum insulin-like growth factor I and GH-binding protein were normal. The bone age was 14 yr at a chronological age of 24 3/12 yr. Striking osteopenia was noted at the wrist. Bone mineral densitometric indexes of the lumbar spine (cancellous bone) and distal radius (cortical bone) were consistent with osteoporosis; the distal radius was -4.7 SD below the mean value for age- and sex-matched normal men; indexes of bone turnover were increased. Hyperinsulinemia, increased serum total and low density lipoprotein cholesterol, and triglycerides and decreased high density lipoprotein cholesterol were detected.(ABSTRACT TRUNCATED AT 400 WORDS)

Novel Treatment of Delayed Male Puberty with Aromatase Inhibitors

“…It is noteworthy that bone maturation was slower in the boys treated with testosterone/letrozole, despite the considerably higher androgen concentrations, than in the boys treated with testosterone alone. This finding confirms the view that oestrogens are more important than androgens in bone maturation in pubertal males and agrees with observations on males who lack oestrogen action [2, 3, 4]. Furthermore, we noted that, even after discontinuation of all treatments, the progression of bone maturation was slower in the boys treated with testosterone/letrozole than in the boys treated with testosterone alone, indicating that the effect of the treatment outlasts the period of treatment [22].…”

“…The role of oestrogens in the growth of males was further clarified in three different reports of cases in which oestrogen action was suppressed by mutations in the genes for the oestrogen receptor α [2]or for the enzyme P450 aromatase [3, 4]. At the age of over 20 years, all these men were taller than 190 cm, had unfused epiphyses of the long bones, and were still growing.…”

The skeleton: a multi-functional complex organ. The growth plate chondrocyte and endochondral ossification

“…1). In human males as well as females, oestrogen regulates this process, as demonstrated by the failure of normal growth plate closure in patients with oestrogen deficiency or oestrogen resistance (Smith et al 1994, Morishima et al 1995. It is thought that growth plate closure occurs when the chondrocytes exhaust their proliferative potential, and that the role of oestrogen is to accelerate this process of senescence (Weise et al 2001).…”

Aromatase and Intracrinology of Estrogen in Hormone-Dependent Tumors

“…This raises the question of what physiological functions estrogen exerts in various tissues. Analysis of aromatase-deficient patients [34, 35, 36, 37]and aromatase knockout (ArKO) mice [38, 39]partly answered this question. Various abnormalities in extragonadal tissues as well as gonadal tissues were detected.…”

“…It induces syntheses of NGF, acetylcholine synthetase, choline acetyltransferase, and nicotinic acetylcholine receptor, suppresses the synthesis of apolipoprotein E, and inhibits monoamine oxidase and catechol- O -methyltransferase. The important role of aromatase and estrogen in bone maintenance was also suggested by findings of low bone mineral density and mass, and delayed skeletal maturation (delayed epiphyseal fusion) in the aromatase-deficient patients [36]and ArKO mice [unpubl. data].…”