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)

Aromatase (CYP19) gene variants influence ovarian response to standard gonadotrophin stimulation

“…Whereas, when each CYP19(TTTA) n allele was analyzed separately, significant associations of CYP19(TTTA) 7 allele with higher serum FSH levels, lower follicle and large follicle numbers as well as with small follicle size were observed in our study population. The increased estrogen biosynthesis in endometrial tumours of (TTTA) 11 /(TTTA) 11 and (TTTA) 11 /(TTTA) 12 carriers [22] as well as the CYP19(TTTA) 11 allele presence in all members of a family with aromatase excess syndrome [23] have suggested a possible association of long CYP19 alleles with an enhanced aromatase activity. On the other hand, PCOS women homozygous for short alleles had higher testosterone/ estradiol ratios, higher testosterone levels and higher LH/FSH ratios compared to women homozygous for long alleles [17], probably due to their reduced aromatase activity.…”

“…Chi-square test analysis was used Short CYP19(TTTA)n alleles: CYP19(TTTA) 7 , CYP19(TTTA) 8 , CYP19(TTTA) 9 Long CYP19(TTTA)n alleles: CYP19(TTTA) 10 , CYP19(TTTA) 11 predominantly small follicles than CYP19(TTTA) 7 allele-non carriers (35.5% vs. 19%, p<0.01). However, no significant association was found between CYP19(TTTA) 7 allele presence and pregnancy rates.…”

“…Throughout puberty, these females show primary amenorrhea, multiple large ovarian cysts, breast development absence and further enlargement of clitoris [11,12]. Finally, hypergonadotropic hypogonadism, congenital genital ambiguity, pubertal failure, virilisation, multicystic ovaries primary amenorrhea, breast development absence and infertility become more evident at adulthood [8,11].…”

Effect of CGS 20267 on ovarian aromatase and gonadotropin levels in the rat

“…More recent data from two sources suggest that estradiol is not necessary for this permissive effect. Animals with knockout of their estrogen receptor and women with aromatase deficiency have enlarged ovaries in response to gonadotropin increments [13][14].…”

Expressing urine from a gel disposable diaper for biomonitoring using phthalates as an example

“…Estrogens do not seem to play an essential role in sexual differentiation, since normal development is possible in the absence of estrogen receptors (Smith et al, 1994;Couse & Korach, 1999) and the aromatase enzyme that is needed for conversion of androgens to estrogens (Morishima et al, 1995). However, excess estrogens can inhibit insulin-like hormone 3 activity and thereby contribute to cryptorchidism (Emmen et al, 2000;Nef et al, 2000).…”