Genetic and clinical spectrum of aromatase deficiency in infancy, childhood and adolescence

Hormone Research

Volumn 72, Issue 6, 2009, Pages 321-330

  Belgorosky, A ^a   Guercio, G ^a   Pepe, C ^a   Saraco, N ^a   Rivarola, M A ^a  

^a HOSPITAL DE PEDIATRÍA PROF DR JUAN P GARRAHAN   (Argentina)

Author keywords

Androgen excess; Aromatase deficiency; Estrogen replacement; Hypothalamo pituitary gonadal axis; Insulin insensitivity

Indexed keywords

ANDROGEN; AROMATASE; GONADOTROPIN; LIPID;

ADOLESCENCE; AROMATASE DEFICIENCY; BONE AGE; BONE GROWTH; BONE MATURATION; BONE MINERALIZATION; CHILDHOOD; CONGENITAL ADRENAL HYPERPLASIA; ENZYME ACTIVITY; ENZYME DEFICIENCY; GENE MUTATION; GENETIC ANALYSIS; GENETIC DISORDER; GENETIC VARIABILITY; HOMEOSTASIS; HUMAN; HYPOTHALAMUS HYPOPHYSIS GONAD SYSTEM; INFANCY; INNER CELL MASS; INSULIN SENSITIVITY; NEWBORN PERIOD; OVARY CYST; PHENOTYPE; PREPUBERTY; PRIORITY JOURNAL; PUBERTY; SEXUAL DEVELOPMENT; SHORT SURVEY; TESTIS CELL; VIRILIZATION;

ADOLESCENT; ANDROGENS; AROMATASE; BONE DEVELOPMENT; CHILD; FEMALE; GENITALIA; HUMANS; HYPOTHALAMO-HYPOPHYSEAL SYSTEM; INFANT; INFANT, NEWBORN; INSULIN RESISTANCE; LIPIDS; MALE; MODELS, BIOLOGICAL; MUTATION; PHENOTYPE; PREGNANCY; PUBERTY;

EID: 70350057027     PISSN: 03010163     EISSN: None     Source Type: Journal    
DOI: 10.1159/000249159     Document Type: Short Survey

References (41)

1. Belgorosky A, Rivarola MA: Physiology and pathophysiology of estrogens: lessons from pediatric patients with complete aromatase deficiency. Endocrinologist 2004; 14: 1-8.
2. Jones ME, Boon WC, McInnes K, Maffei L, Carani C, Simpson ER: Recognizing rare disorders: aromatase deficiency. Nat Clin Pract Endocrinol Metab 2007; 3: 414-421.
3. Meinhardt U, Mullis PE: The aromatase cytochrome P-450 and its clinical impact. Horm Res 2002; 57: 145-152.
4. Zirilli L, Rochira V, Diazzi C, Caffagni G, Carani C: Human models of aromatase deficiency. J Steroid Biochem Mol Biol 2008; 109: 212-218.
5. Jones M, Boom W, Proietto J, Simpson ER: Of mice and men: the evolving phenotype of aromatase deficiency. Trends Endocrinol Metab 2006; 17: 53-62.
6. Rochira V, Balestrieri A, Madeo B, Spaggiari A, Carani C: Congenital estrogen deficiency in men: a new syndrome with different phenotypes; clinical and therapeutic implications in men. Mol Cell Endocrinol 2002; 193: 19-28.
7. Means GD, Mahendroo MS, Corbin CJ, Mathis JM, Powell FE, Mendelson CR, Simpson ER: Structural analysis of the gene encoding human aromatase cytochrome P- 450, the enzyme responsible for estrogen biosynthesis. J Biol Chem 1989; 264: 19385-19391.
8. Graham-Lorence S, Amarneh B, White RE, Peterson JA, Simpson ER: A three-dimensional model of aromatase cytochrome P450. Protein Sci 1995; 4: 1065-1080.
9. Shozu M, Akasofu K, Harada T, Kubota Y: A new cause of female pseudohermaphroditism: placental aromatase deficiency. J Clin Endocrinol Metab 1991; 72: 560-566.
10. Harada N, Ogawa H, Shozu M, Yamada K: Genetic studies to characterize the origin of the mutation in placental aromatase deficiency. Am J Hum Genet 1992; 51: 666-672.
11. Conte FA, Grumbach MM, Ito Y, Fisher CR, Simpson ER: A syndrome of female pseudohermaphrodism, hypergonadotropic hypogonadism, and multicystic ovaries associated with missense mutations in the gene encoding aromatase (P450arom). J Clin Endocrinol Metab 1994; 78: 1287-1292.
12. Ito Y, Fisher CR, Conte FA, Grumbach MM, Simpson ER: Molecular basis of aromatase deficiency in an adult female with sexual infantilism and polycystic ovaries. Proc Natl Acad Sci USA 1993; 90: 11673-11677.
13. Morishima A, Grumbach MM, Simpson ER, Fisher C, Qin K: Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens. J Clin Endocrinol Metab 1995; 80: 3689-3698.
14. Mullis PE, Yoshimura N, Kuhlmann B, Lippuner K, Jaeger P, Harada H: Aromatase deficiency in a female who is compound heterozygote for two new point mutations in the P450arom gene: impact of estrogens on hypergonadotropic hypogonadism, multicystic ovaries, and bone densitometry in childhood. J Clin Endocrinol Metab 1997; 82: 1739-1745.
15. Portrait-Doyen, Forest MG, Nicolino M, Morel Y, Chatelain PC: Female pseudohermaphortidism resulting from aromatase (P450arom) deficiency associated with a novel mutation (R457X) in the CYP19 gene. Horm Res 1996; 46(suppl 2):14.
16. Ludwig M, Beck A, Wickert L, Bolkenius U, Tittel B, Hinkel K, Bidlingmaier F: Female pseudohermaphroditism associated with a novel homozygous G-to-A (V370-to-M) substitution in the P-450 aromatase gene. J Pediatr Endocrinol Metab 1998; 11: 657-664.
17. Belgorosky A, Pepe C, Marino R, Guercio G, Saraco N, Vaiani E, Rivarola MA: 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 2003; 88: 5127-5131.
18. Lin L, Ercan O, Raza J, Burren CP, Creighton SM, Auchus RJ, Dattani MT, Achermann JC: Variable phenotypes associated with aromatase (CYP19) insufficiency in humans. J Clin Endocrinol Metab 2007; 92: 982-990.
19. Pepe C, Saraco, Baquedano S, Guercio G, Vaiani E, Marino R, Pandey A, Flück C, Rivarola MA, Belgorosky A: The cytochrome P450 aromatase lacking exon 5 is associated with a phenotype of non-classic aromatase deficiency, and it is also present in normal human steroidogenic tissues. Clin Endocrinol (Oxf) 2007; 67: 698-705.
20. Harada N, Ogawa H, Shozu M, Yamada K, Suhara K, Nishida E, Takagi Y: Biochemical and molecular genetic analyses on placental aromatase (P-450AROM) deficiency. J Biol Chem 1992; 267: 4781-4785.
21. Richter-Unruh A, Schmidt M, Verhoef-Post M, Themmen APN: Aromatase deficiency: delayed puberty in a German girl is due to 2 new mutations of the CYP19 gene. 90th Annl Meet Endocrine Soc, San Francisco, 2008; abstr P2-590.
22. Carani C, Qin K, Simoni M, Faustini-Fustini M, Serpente S, Boyd J, Korach KS, Simpson ER: Effect of testosterone and estradiol in a man with aromatase deficiency. N Engl J Med 1997; 337: 91-95.
23. Herrmann BL, Saller B, Janssen OE, Gocke P, Bockisch A, Sperling H, Mann K, Broecker M: Impact of estrogen replacement therapy in a male with congenital aromatase deficiency caused by a novel mutation in the CYP19 gene. J Clin Endocrinol Metab 2002; 87: 5476-5484.
24. Maffei L, Murata Y, Rochira V, Tubert G, Aranda C, Vazquez M, Clyne C, Davis S, Simpson ER, Carani C: Dysmetabolic syndrome in a man with a novel mutation of the aromatase gene: effects of testosterone, alendronate and estradiol treatment. J Clin Endocrinol Metab 2004; 89: 61-70.
25. Deladoëy J, Fluck C, Bex M, Yoshimura N, Harada N, Mullis PE: Aromatase deficiency caused by a novel P450arom gene mutation: impact of absent estrogen production on serum gonadotropin concentration in a boy. J Clin Endocrinol Metab 1999; 84: 4050-4054.
26. Bouillon R, Bex M, Vanderschueren D, Boonen S: Estrogens are essential for male pubertal periosteal bone expansion. J Clin Endocrinol Metab 2004; 89: 6025-6029.
27. Pura M, Mittre H, Carreau S, Kottler ML: Clinical findings in an adult man with a novel mutation in the aromatase gene. 85th Ann Meet Endocrine Soc, Philadelphia, 2003; abstr P1-467.
28. Maffei L, Rochira V, Zirilli L, Antunez P, Aranda C, Fabre B, Simone ML, Pignatti E, Simpson ER, Houssami S, Clyne CD, Carani C: A novel compound heterozygous mutation of the aromatase gene in an adult man: reinforced evidence on the relationship between congenital oestrogen deficiency, adiposity and the metabolic syndrome. Clin Endocrinol (Oxf) 2007; 67: 218-224.
29. Lanfranco F, Zirilli L, Baldi M, Pignatti E, Corneli G, Ghigo E, Aimaretti G, Carani C, Rochira V: A novel mutation in the human aromatase gene: insights on the relationship among serum estradiol, longitudinal growth and bone mineral density in an adult man under estrogen replacement treatment. Bone 2008; 43: 628-635.
30. Belgorosky A, Rivarola MA: Irreversible increase of serum IGF-1 and IGFBP-3 levels in GnRH-dependent precocious puberty of different etiologies: implications for the onset of puberty. Horm Res 1998; 49: 226-232.
31. Britt KL, Drummond AE, Cox VA, Dyson M, Wreford NG, Jones ME, Simpson ER, Findlay JK: An age-related ovarian phenotype in mice with targeted disruption of the CYP19 (aromatase) gene. Endocrinology 2000; 141: 2614-2623.
32. Risma KA, Clay CM, Nett TM, Wagner T, Yun J, Nilson JH: Targeted overexpression of luteinizing hormone in transgenic mice leads to infertility, polycystic ovaries, and ovarian tumors. Proc Natl Acad Sci USA 1995; 92: 1322-1326.
33. Risma KA, Hirshfield AN, Nilson JH: Elevated luteinizing hormone in prepubertal transgenic mice causes hyperandrogenemia, precocious puberty, and substantial ovarian pathology. Endocrinology 1997; 138: 3540-3547.
34. Kumar TR, Wang Y, Lu N, Matzuk MM: Follicle stimulating hormone is required for ovarian follicle maturation but not male fertility. Nat Genet 1997; 15: 201-204. (Pubitemid 27061644)
35. Pelletier G, Labrie C, Labrie F: Localization of oestrogen receptor, oestrogen receptor - and androgen receptors in the rat reproductive organs. J Endocrinol 2000; 165: 359-370.
36. Weil S, Vendola K, Zhou J, Bondy CA: Androgen and follicle-stimulating hormone interactions in primate ovarian follicle development. J Clin Endocrinol Metab 1999; 84: 2951-2956.
37. Bilezikian JP, Morishima A, Bell J, Grumbach MM: Increased bone mass as a result of estrogen therapy in a man with aromatase deficiency. N Engl J Med 1998; 339: 599-603.
38. Herrmann BL, Janssen OE, Hahn S, Broecker- Preuss M, Mann K: Effects of estrogen replacement therapy on bone and glucose metabolism in a male with congenital aromatase deficiency. Horm Metab Res 2005; 37: 178-183.
39. Guercio G, Di Palma MI, Pepe C, Saraco NI, Prieto M, Saure C, Mazza C, Rivarola MA, Belgorosky A: Metformin, estrogen replacement therapy and gonadotropin inhibition fail to improve insulin sensitivity in a girl with aromatase deficiency. Horm Res 2009, in press.
40. Berensztein EB, Baquedano MS, Gonzalez CR, Saraco NI, Rodriguez J, Ponzio R, Rivarola MA, Belgorosky A: Expression of aromatase, estrogen receptor alpha and beta, androgen receptor, and cytochrome P- 450scc in the human early prepubertal testis. Pediatr Res 2006; 60: 740-744.
41. Berensztein EB, Sciara MI, Rivarola MA, Belgorosky A: Apoptosis and proliferation of human testicular somatic and germ cells during prepuberty: high rate of testicular growth in newborns mediated by decreased apoptosis. J Clin Endocrinol Metab 2002; 87: 5113-5118.