General reaction for the conversion of testosterone to estradiol catalyzed by aromatase. Steroids are composed of four fused rings (labeled A-D). Aromatase converts the ring labeled "A" into an aromatic state.
The gene expresses two transcript variants. In humans, the gene CYP19, located on chromosome 15q21.1, encodes the aromatase enzyme. The gene has nine coding exons and a number of alternative non-coding first exons that regulate tissue specific expression.
Aromatase is generally highly present during the differentiation of ovaries. It is also susceptible to environmental influences, particularly temperature. In species with temperature-dependent sex determination, aromatase is expressed in higher quantities at temperatures that yield female offspring. Despite the fact that data suggest temperature controls aromatase quantities, other studies have shown that aromatase can overpower the effects of temperature: if exposed to more aromatase at a male-producing temperature, the organism will develop female and conversely, if exposed to less aromatase at female-producing temperatures, the organism will develop male (see sex reversal). In organisms that develop through genetic sex determination, temperature does not affect aromatase expression and function, suggesting that aromatase is the target molecule for temperature during TSD (for challenges to this argument, see temperature-dependent sex determination). It varies from species to species whether it is the aromatase protein that has different activity at different temperatures or whether the amount of transcription undergone by the aromatase gene is what is temperature-sensitive, but in either case, differential development is observed at different temperatures.
Role in neuroprotection
Aromatase in the brain is usually only expressed in neurons. However, following penetrative brain injury of both mice and zebra finches, it has been shown to be expressed in astrocytes. Furthermore, it has also been shown to decrease apoptosis following brain injury in zebra finches. This is thought to be due to the neuroprotective actions of estrogens, including estradiol. Research has found that two pro-inflammatory cytokines, interleukin-1β (IL-1β) and interleukin-6 (IL-6), are responsible for the induction of aromatase expression in astrocytes following penetrative brain injury in the zebra finch.
A number of investigators have reported on a rather rare syndrome of excess aromatase activity. In boys, it can lead to gynecomastia, and in girls to precocious puberty and gigantomastia. In both sexes, early epiphyseal closure leads to short stature. This condition is due to mutations in the CYP19A1 gene which encodes aromatase. It is inherited in an autosomal dominant fashion. It has been suggested that the pharaoh Akhenaten and other members of his family may have suffered from this disorder, but more recent genetic tests suggest otherwise. It is one of the causes of familial precocious puberty—a condition first described in 1937.
This syndrome is due to a mutation of gene CYP19 and inherited in an autosomal recessive way. Accumulations of androgens during pregnancy may lead to virilization of a female at birth (males are not affected). Females will have primary amenorrhea. Individuals of both sexes will be tall, as lack of estrogen does not bring the epiphyseal lines to closure.
The inhibition of the enzyme leads to profound hypoestrogenism (low estrogen levels). Thus, aromatase inhibitors have become useful in the management of patients with breast cancer whose lesion was found to be estrogen receptor positive. An example of an aromatase inhibitor is letrozole, marketed originally under the name 'Femara.' Aromatase inhibitors are also beginning to be prescribed to men on testosterone replacement therapy as a way to keep estrogen levels from spiking once doses of testosterone are introduced to their systems.
^PDB3EQM; Ghosh D, Griswold J, Erman M, Pangborn W (January 2009). "Structural basis for androgen specificity and oestrogen synthesis in human aromatase". Nature457 (7226): 219–23. doi:10.1038/nature07614. PMID19129847.
^Vaz ADN (2003). "Chapter 1: Cytochrome activation by cytochromes P450: a role for multiple oxidants in the oxidation of substrates". In Fisher, Michael; Lee, Jae Kyu; Obach, Robert E. Drug metabolizing enzymes: cytochrome P450 and other enzymes in drug discovery and development. Lausanne, Switzerland: FontisMedia SA. ISBN0-8247-4293-1.
^ abcdDuffy TA, Picha ME, Won ET, Borski RJ, McElroy AE, Conover DO (August 2010). "Ontogenesis of gonadal aromatase gene expression in atlantic silverside (Menidia menidia) populations with genetic and temperature-dependent sex determination". J Exp Zool A Ecol Genet Physiol313 (7): 421–31. doi:10.1002/jez.612. PMID20623799.
^Fukami M, Shozu M, Soneda S, Kato F, Inagaki A, Takagi H, Hanaki K, Kanzaki S, Ohyama K, Sano T, Nishigaki T, Yokoya S, Binder G, Horikawa R, Ogata T (June 2011). "Aromatase excess syndrome: identification of cryptic duplications and deletions leading to gain of function of CYP19A1 and assessment of phenotypic determinants". J. Clin. Endocrinol. Metab.96 (6): E1035–43. doi:10.1210/jc.2011-0145. PMID21470988.
^Braverman IM, Redford DB, Mackowiak PA (April 2009). "Akhenaten and the strange physiques of Egypt's 18th dynasty". Annals of Internal Medicine150 (8): 556–60. PMID19380856.
^Ziora K, Oświecimska J, Geisler G, Broll-Waśka K, Szalecki M, Dyduch A (2006). "[Familial precocious puberty -- a variant of norm or pathology?]". Endokrynol Diabetol Chor Przemiany Materii Wieku Rozw (in Polish) 12 (1): 53–8. PMID16704862.
^Chen S, Oh SR, Phung S, Hur G, Ye JJ, Kwok SL, Shrode GE, Belury M, Adams LS, Williams D (December 2006). "Anti-aromatase activity of phytochemicals in white button mushrooms (Agaricus bisporus)". Cancer Res.66 (24): 12026–34. doi:10.1158/0008-5472.CAN-06-2206. PMID17178902.
Richards JA, Petrel TA, Brueggemeier RW (2002). "Signaling pathways regulating aromatase and cyclooxygenases in normal and malignant breast cells". J. Steroid Biochem. Mol. Biol.80 (2): 203–12. doi:10.1016/S0960-0760(01)00187-X. PMID11897504.
Balthazart J, Baillien M, Ball GF (2002). "Interactions between aromatase (estrogen synthase) and dopamine in the control of male sexual behavior in quail". Comp. Biochem. Physiol. B, Biochem. Mol. Biol.132 (1): 37–55. doi:10.1016/S1096-4959(01)00531-0. PMID11997208.
Chen S, Ye J, Kijima I, et al. (2005). "Positive and negative transcriptional regulation of aromatase expression in human breast cancer tissue". J. Steroid Biochem. Mol. Biol.95 (1–5): 17–23. doi:10.1016/j.jsbmb.2005.04.002. PMID15955695.