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Journal of Clinical Endocrinology & Metabolism, Vol 80, 3689-3698, Copyright © 1995 by Endocrine Society

ARTICLES

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

A Morishima, MM Grumbach, ER Simpson, C Fisher and K Qin
Department of Pediatrics, Columbia University College of Physicians and Surgeons, New York, New York, USA.

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)


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J. D. Veldhuis, J. N. Roemmich, E. J. Richmond, A. D. Rogol, J. C. Lovejoy, M. Sheffield-Moore, N. Mauras, and C. Y. Bowers
Endocrine Control of Body Composition in Infancy, Childhood, and Puberty
Endocr. Rev., February 1, 2005; 26(1): 114 - 146.
[Abstract] [Full Text] [PDF]

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 PediatricsHome page
P. Zhou, B. Shah, K. Prasad, and R. David
Letrozole Significantly Improves Growth Potential in a Pubertal Boy With Growth Hormone Deficiency
Pediatrics, February 1, 2005; 115(2): e245 - e248.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
J. D. Veldhuis and A. Iranmanesh
Short-Term Aromatase-Enzyme Blockade Unmasks Impaired Feedback Adaptations in Luteinizing Hormone and Testosterone Secretion in Older Men
J. Clin. Endocrinol. Metab., January 1, 2005; 90(1): 211 - 218.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Endocrinol. Metab.Home page
S. E. Borst, J. H. Lee, and C. F. Conover
Inhibition of 5{alpha}-reductase blocks prostate effects of testosterone without blocking anabolic effects
Am J Physiol Endocrinol Metab, January 1, 2005; 288(1): E222 - E227.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
L. Gennari, R. Nuti, and J. P. Bilezikian
Aromatase Activity and Bone Homeostasis in Men
J. Clin. Endocrinol. Metab., December 1, 2004; 89(12): 5898 - 5907.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
I. Van Pottelbergh, S. Goemaere, H. Zmierczak, and J. M. Kaufman
Perturbed Sex Steroid Status in Men with Idiopathic Osteoporosis and Their Sons
J. Clin. Endocrinol. Metab., October 1, 2004; 89(10): 4949 - 4953.
[Abstract] [Full Text] [PDF]

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 Hum Reprod UpdateHome page
L.M. Rivera-Woll, M. Papalia, S.R. Davis, and H.G. Burger
Androgen insufficiency in women: diagnostic and therapeutic implications
Hum. Reprod. Update, September 1, 2004; 10(5): 421 - 432.
[Abstract] [Full Text] [PDF]

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 Endocr. Rev.Home page
T. M. Doherty, L. A. Fitzpatrick, D. Inoue, J.-H. Qiao, M. C. Fishbein, R. C. Detrano, P. K. Shah, and T. B. Rajavashisth
Molecular, Endocrine, and Genetic Mechanisms of Arterial Calcification
Endocr. Rev., August 1, 2004; 25(4): 629 - 672.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
V.-V. Valimaki, H. Alfthan, K. K. Ivaska, E. Loyttyniemi, K. Pettersson, U.-H. Stenman, and M. J. Valimaki
Serum Estradiol, Testosterone, and Sex Hormone-Binding Globulin as Regulators of Peak Bone Mass and Bone Turnover Rate in Young Finnish Men
J. Clin. Endocrinol. Metab., August 1, 2004; 89(8): 3785 - 3789.
[Abstract] [Full Text] [PDF]

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 ReproductionHome page
C. A Oliveira, G. A B Mahecha, K. Carnes, G. S Prins, P. T K Saunders, L. R Franca, and R. A Hess
Differential hormonal regulation of estrogen receptors ER{alpha} and ER{beta} and androgen receptor expression in rat efferent ductules
Reproduction, July 1, 2004; 128(1): 73 - 86.
[Abstract] [Full Text] [PDF]

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 Endocr. Rev.Home page
D. Vanderschueren, L. Vandenput, S. Boonen, M. K. Lindberg, R. Bouillon, and C. Ohlsson
Androgens and Bone
Endocr. Rev., June 1, 2004; 25(3): 389 - 425.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
L. Gennari, L. Masi, D. Merlotti, L. Picariello, A. Falchetti, A. Tanini, C. Mavilia, F. Del Monte, S. Gonnelli, B. Lucani, et al.
A Polymorphic CYP19 TTTA Repeat Influences Aromatase Activity and Estrogen Levels in Elderly Men: Effects on Bone Metabolism
J. Clin. Endocrinol. Metab., June 1, 2004; 89(6): 2803 - 2810.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
C. Meier, P. Y. Liu, L. P. Ly, J. de Winter-Modzelewski, M. Jimenez, D. J. Handelsman, and M. J. Seibel
Recombinant Human Chorionic Gonadotropin But Not Dihydrotestosterone Alone Stimulates Osteoblastic Collagen Synthesis in Older Men with Partial Age-Related Androgen Deficiency
J. Clin. Endocrinol. Metab., June 1, 2004; 89(6): 3033 - 3041.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
C. Wang, G. Cunningham, A. Dobs, A. Iranmanesh, A. M. Matsumoto, P. J. Snyder, T. Weber, N. Berman, L. Hull, and R. S. Swerdloff
Long-Term Testosterone Gel (AndroGel) Treatment Maintains Beneficial Effects on Sexual Function and Mood, Lean and Fat Mass, and Bone Mineral Density in Hypogonadal Men
J. Clin. Endocrinol. Metab., May 1, 2004; 89(5): 2085 - 2098.
[Abstract] [Full Text] [PDF]

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 NeurologyHome page
S. Iivonen, E. Corder, M. Lehtovirta, S. Helisalmi, A. Mannermaa, S. Vepsalainen, T. Hanninen, H. Soininen, and M. Hiltunen
Polymorphisms in the CYP19 gene confer increased risk for Alzheimer disease
Neurology, April 13, 2004; 62(7): 1170 - 1176.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
Q. Wang, P. H. F. Nicholson, M. Suuriniemi, A. Lyytikainen, E. Helkala, M. Alen, H. Suominen, and S. Cheng
Relationship of Sex Hormones to Bone Geometric Properties and Mineral Density in Early Pubertal Girls
J. Clin. Endocrinol. Metab., April 1, 2004; 89(4): 1698 - 1703.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
S. Khosla, B. L. Riggs, E. J. Atkinson, A. L. Oberg, C. Mavilia, F. Del Monte, L. J. Melton III, and M. L. Brandi
Relationship of Estrogen Receptor Genotypes to Bone Mineral Density and to Rates of Bone Loss in Men
J. Clin. Endocrinol. Metab., April 1, 2004; 89(4): 1808 - 1816.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
K. N. Hewitt, K. Pratis, M. E. E. Jones, and E. R. Simpson
Estrogen Replacement Reverses the Hepatic Steatosis Phenotype in the Male Aromatase Knockout Mouse
Endocrinology, April 1, 2004; 145(4): 1842 - 1848.
[Abstract] [Full Text] [PDF]

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 JDRHome page
T. Fujita, J. Ohtani, M. Shigekawa, T. Kawata, M. Kaku, S. Kohno, K. Tsutsui, K. Tenjo, M. Motokawa, Y. Tohma, et al.
Effects of Sex Hormone Disturbances on Craniofacial Growth in Newborn Mice
Journal of Dental Research, March 1, 2004; 83(3): 250 - 254.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
L. Maffei, Y. Murata, V. Rochira, G. Tubert, C. Aranda, M. Vazquez, C. D. Clyne, S. Davis, E. R. Simpson, and C. Carani
Dysmetabolic Syndrome in a Man with a Novel Mutation of the Aromatase Gene: Effects of Testosterone, Alendronate, and Estradiol Treatment
J. Clin. Endocrinol. Metab., January 1, 2004; 89(1): 61 - 70.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
J. Somner, S. McLellan, J. Cheung, Y. T. Mak, M. L. Frost, K. M. Knapp, A. S. Wierzbicki, M. Wheeler, I. Fogelman, S. H. Ralston, et al.
Polymorphisms in the P450 c17 (17-Hydroxylase/17,20-Lyase) and P450 c19 (Aromatase) Genes: Association with Serum Sex Steroid Concentrations and Bone Mineral Density in Postmenopausal Women
J. Clin. Endocrinol. Metab., January 1, 2004; 89(1): 344 - 351.
[Abstract] [Full Text] [PDF]

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 Circ. Res.Home page
M. Kimura, K. Sudhir, M. Jones, E. Simpson, A.-M. Jefferis, and J. P.F. Chin-Dusting
Impaired Acetylcholine-Induced Release of Nitric Oxide in the Aorta of Male Aromatase-Knockout Mice: Regulation of Nitric Oxide Production by Endogenous Sex Hormones in Males
Circ. Res., December 12, 2003; 93(12): 1267 - 1271.
[Abstract] [Full Text] [PDF]

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 Endocr. Rev.Home page
B. C. J. van der Eerden, M. Karperien, and J. M. Wit
Systemic and Local Regulation of the Growth Plate
Endocr. Rev., December 1, 2003; 24(6): 782 - 801.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
N. Mauras, J. Lima, D. Patel, A. Rini, E. di Salle, A. Kwok, and B. Lippe
Pharmacokinetics and Dose Finding of a Potent Aromatase Inhibitor, Aromasin (Exemestane), in Young Males
J. Clin. Endocrinol. Metab., December 1, 2003; 88(12): 5951 - 5956.
[Abstract] [Full Text] [PDF]

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 Circ. Res.Home page
R. Lew, P. Komesaroff, M. Williams, T. Dawood, and K. Sudhir
Endogenous Estrogens Influence Endothelial Function in Young Men
Circ. Res., November 28, 2003; 93(11): 1127 - 1133.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
A. Belgorosky, C. Pepe, R. Marino, G. Guercio, N. Saraco, E. Vaiani, and M. A. Rivarola
Hypothalamic-Pituitary-Ovarian Axis during Infancy, Early and Late Prepuberty in an Aromatase-Deficient Girl Who Is a Compound Heterocygote for Two New Point Mutations of the CYP19 Gene
J. Clin. Endocrinol. Metab., November 1, 2003; 88(11): 5127 - 5131.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
L. Gennari, D. Merlotti, G. Martini, S. Gonnelli, B. Franci, S. Campagna, B. Lucani, N. Dal Canto, R. Valenti, C. Gennari, et al.
Longitudinal Association between Sex Hormone Levels, Bone Loss, and Bone Turnover in Elderly Men
J. Clin. Endocrinol. Metab., November 1, 2003; 88(11): 5327 - 5333.
[Abstract] [Full Text] [PDF]

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 The OncologistHome page
C. A. Thompson, T. D. Shanafelt, and C. L. Loprinzi
Andropause: Symptom Management for Prostate Cancer Patients Treated With Hormonal Ablation
Oncologist, October 1, 2003; 8(5): 474 - 487.
[Abstract] [Full Text] [PDF]

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 Mayo Clin Proc.Home page
K. K. Dhatariya and K. S. Nair
Dehydroepiandrosterone: Is There a Role for Replacement?
Mayo Clin. Proc., October 1, 2003; 78(10): 1257 - 1273.
[Abstract] [PDF]

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 EndocrinologyHome page
K. N. Hewitt, W. C. Boon, Y. Murata, M. E. E. Jones, and E. R. Simpson
The Aromatase Knockout Mouse Presents with a Sexually Dimorphic Disruption to Cholesterol Homeostasis
Endocrinology, September 1, 2003; 144(9): 3895 - 3903.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
S. Wickman, E. Kajantie, and L. Dunkel
Effects of Suppression of Estrogen Action by the P450 Aromatase Inhibitor Letrozole on Bone Mineral Density and Bone Turnover in Pubertal Boys
J. Clin. Endocrinol. Metab., August 1, 2003; 88(8): 3785 - 3793.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
R. M. Martin, C. J. Lin, M. Y. Nishi, A. E. C. Billerbeck, A. C. Latronico, D. W. Russell, and B. B. Mendonca
Familial Hyperestrogenism in Both Sexes: Clinical, Hormonal, and Molecular Studies of Two Siblings
J. Clin. Endocrinol. Metab., July 1, 2003; 88(7): 3027 - 3034.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
I. Van Pottelbergh, S. Goemaere, and J. M. Kaufman
Bioavailable Estradiol and an Aromatase Gene Polymorphism Are Determinants of Bone Mineral Density Changes in Men over 70 Years of Age
J. Clin. Endocrinol. Metab., July 1, 2003; 88(7): 3075 - 3081.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
B. A. L. Crawford, P. Y. Liu, M. T. Kean, J. F. Bleasel, and D. J. Handelsman
Randomized Placebo-Controlled Trial of Androgen Effects on Muscle and Bone in Men Requiring Long-Term Systemic Glucocorticoid Treatment
J. Clin. Endocrinol. Metab., July 1, 2003; 88(7): 3167 - 3176.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
R. A. Anderson, A. M. Wallace, N. Sattar, N. Kumar, and K. Sundaram
Evidence for Tissue Selectivity of the Synthetic Androgen 7{alpha}-Methyl-19-Nortestosterone in Hypogonadal Men
J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2784 - 2793.
[Abstract] [Full Text] [PDF]

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 Endocr. Rev.Home page
F. C. W. Wu and A. von Eckardstein
Androgens and Coronary Artery Disease
Endocr. Rev., April 1, 2003; 24(2): 183 - 217.
[Abstract] [Full Text] [PDF]


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