Aromatase excess syndrome (AES or AEXS) is a rarely diagnosed genetic and endocrine syndrome which is characterized by an overexpression of aromatase, the enzyme responsible for the biosynthesis of the estrogen sex hormones from the androgens, in turn resulting in excessive levels of circulating estrogens and, accordingly, symptoms of hyperestrogenism. It affects both sexes, manifesting itself in males as marked or complete phenotypical feminization (with the exception of the genitalia; i.e., no ambiguous genitalia) and in females as hyperfeminization.[1][2][3][4]
| Aromatase excess syndrome | |
|---|---|
| Other names | Hereditary prepubertal gynecomastia |
 | |
| AEXS results when the function of aromatase is hyperactive. The aromatase protein (pictured) is responsible for the biosynthesis of estrogens like estradiol in the human body. | |
| Specialty | Endocrinology |
To date, 30 males and 8 females with AEXS among 15 and 7 families, respectively, have been described in the medical literature.[1][2]
Signs and symptoms
editObserved physiological abnormalities of the condition include a dramatic overexpression of aromatase and, accordingly, excessive levels of estrogens including estrone and estradiol[5] and a very high rate of peripheral conversion of androgens to estrogens. In one study, cellular aromatase mRNA expression was found to be at least 10 times higher in a female patient compared to the control, and the estradiol/testosterone ratio after an injection of testosterone in a male patient was found to be 100 times greater than the control.[2] Additionally, in another study, androstenedione, testosterone, and dihydrotestosterone (DHT) were found to be either low or normal in males, and follicle-stimulating hormone (FSH) levels were very low (likely due to suppression by estrogen, which has antigonadotropic effects as a form of negative feedback inhibition on sex steroid production in sufficiently high amounts),[6] whereas luteinizing hormone (LH) levels were normal.[7]
According to a recent review, estrone levels have been elevated in 17 of 18 patients (94%), while estradiol levels have been elevated only in 13 of 27 patients (48%).[1] As such, estrone is the main estrogen elevated in the condition.[1] In more than half of patients, circulating androstenedione and testosterone levels are low to subnormal.[1] The ratio of circulating estradiol to testosterone is >10 in 75% of cases.[1] FSH levels are said to be consistently low in the condition, while LH levels are in the low to normal range.[1]
It is notable that gynecomastia has been observed in patients in whom estradiol levels are within the normal range.[1] This has been suggested to be due to in situ conversion of adrenal androgens into estrone and then estradiol (via local 17β-HSD) in breast tissue (where aromatase activity may be particularly high).[1]
The symptoms of AEXS, in males, include heterosexual precocity (precocious puberty with phenotypically-inappropriate secondary sexual characteristics; i.e., a fully or mostly feminized appearance), severe prepubertal or peripubertal gynecomastia (development of breasts in males before or around puberty), high-pitched voice, sparse facial hair, hypogonadism (dysfunctional gonads), oligozoospermia (low sperm count), small testes, micropenis (an unusually small penis), advanced bone maturation, an earlier peak height velocity (an accelerated rate of growth in regards to height),[8] and short final stature due to early epiphyseal closure. The incidence of gynecomastia appears to be 100%, with 20 of 30 male cases opting for mastectomy according to a review.[1]
In females, symptoms of AEXS include isosexual precocity (precocious puberty with phenotypically-appropriate secondary sexual characteristics), macromastia (excessively large breasts), an enlarged uterus, menstrual irregularities, and, similarly to males, accelerated bone maturation and short final height. Of seven females described in one report, three (43%) had macromastia.[2] Pubertal breast hypertrophy in association with AEXS has been described in two young girls.[9][10]
Fertility, though usually affected to one degree or another—especially in males—is not always impaired significantly enough to prevent sexual reproduction, as evidenced by vertical transmission of the condition by both sexes.[2][3][4]
Cause
editThe root cause of AEXS is not entirely clear, but it has been elucidated that inheritable, autosomal dominant genetic mutations affecting CYP19A1, the gene which encodes aromatase, are involved in its etiology.[2][4][7] Different mutations are associated with differential severity of symptoms, such as mild to severe gynecomastia.[1][11] For example, duplications result in relatively mild gynecomastia, while deletions, resulting in chimeric genes, cause moderate or severe gynecomastia.[11]
Diagnosis
editGenetic tests are now available to identify the variants in CYP19A1 associated with AEXS. The National Institutes of Health maintains a list.[12]
Treatment
editSeveral treatments have been found to be effective in managing AEXS, including aromatase inhibitors and gonadotropin-releasing hormone analogues in both sexes, androgen replacement therapy with non-aromatizable androgens such as DHT in males, and progestogens (which, by virtue of their antigonadotropic properties at high doses, suppress estrogen levels) in females. In addition, male patients often seek bilateral mastectomy, whereas females may opt for breast reduction if warranted.[2][3][4]
Medical treatment of AEXS is not absolutely necessary, but it is recommended as the condition, if left untreated, may lead to excessively large breasts (which may necessitate surgical reduction), problems with fertility, and an increased risk of endometriosis and estrogen-dependent cancers such as breast and endometrial cancers later in life.[2][13] At least one case of male breast cancer has been reported.[2]
Society and culture
editNotable cases
editIt has been hypothesized that the Pharaoh Akhenaten (husband of Queen Nefertiti) and other members of the 18th Dynasty of ancient Egypt may have had AEXS.[14] Akhenaten and his relatives, including men and young girls, many of whom were the product of inbreeding, are described as having breasts and wide hips, and Akhenaten was described as having a "beautiful and feminine voice," unusual physical features that could be explained by AEXS or another form of hereditary hyperestrogenism.[14] However, numerous other physical abnormalities were also present in the Akhenaten family, and a variety of other conditions have been proposed to explain the observations instead.[15] Most recently, Loeys–Dietz syndrome was proposed as a probable cause, with gynecomastia and feminization possibly being caused by liver cirrhosis-induced hyperestrogenism.[15]
See also
editReferences
edit- ^ a b c d e f g h i j k Shozu, Makio; Fukami, Maki; Ogata, Tsutomu (2014). "Understanding the pathological manifestations of aromatase excess syndrome: lessons for clinical diagnosis". Expert Review of Endocrinology & Metabolism. 9 (4): 397–409. doi:10.1586/17446651.2014.926810. ISSN 1744-6651. PMC 4162655. PMID 25264451.
- ^ a b c d e f g h i Martin, Regina M.; Lin, Chin J.; Nishi, Mirian Y.; Billerbeck, Ana Elisa C.; Latronico, Ana Claudia; Russell, David W.; Mendonca, Berenice B. (2003). "Familial Hyperestrogenism in Both Sexes: Clinical, Hormonal, and Molecular Studies of Two Siblings". The Journal of Clinical Endocrinology & Metabolism. 88 (7): 3027–3034. doi:10.1210/jc.2002-021780. ISSN 0021-972X. PMID 12843139.
- ^ a b c Stratakis CA, Vottero A, Brodie A, et al. (April 1998). "The aromatase excess syndrome is associated with feminization of both sexes and autosomal dominant transmission of aberrant P450 aromatase gene transcription". The Journal of Clinical Endocrinology and Metabolism. 83 (4): 1348–57. doi:10.1210/jcem.83.4.4697. PMID 9543166. S2CID 5723607.
- ^ a b c d Gregory Makowski (22 April 2011). Advances in Clinical Chemistry. Academic Press. p. 158. ISBN 978-0-12-387025-4. Retrieved 24 May 2012.
- ^ Binder G, Iliev DI, Dufke A, et al. (January 2005). "Dominant transmission of prepubertal gynecomastia due to serum estrone excess: hormonal, biochemical, and genetic analysis in a large kindred". The Journal of Clinical Endocrinology and Metabolism. 90 (1): 484–92. doi:10.1210/jc.2004-1566. PMID 15483104.
- ^ de Lignières B, Silberstein S (April 2000). "Pharmacodynamics of oestrogens and progestogens". Cephalalgia: An International Journal of Headache. 20 (3): 200–7. doi:10.1046/j.1468-2982.2000.00042.x. PMID 10997774. S2CID 40392817.
- ^ a b Fukami, Maki; Shozu, Makio; Ogata, Tsutomu (2012). "Molecular Bases and Phenotypic Determinants of Aromatase Excess Syndrome". International Journal of Endocrinology. 2012: 1–8. doi:10.1155/2012/584807. ISSN 1687-8337. PMC 3272822. PMID 22319526.
- ^ Meinhardt U, Mullis PE (2002). "The aromatase cytochrome P-450 and its clinical impact". Hormone Research. 57 (5–6): 145–52. doi:10.1159/000058374 (inactive 2024-11-10). PMID 12053085. S2CID 24115725.
{{cite journal}}: CS1 maint: DOI inactive as of November 2024 (link) - ^ Agarwal VR, Sasano H, Takayama K, et al. Excessive levels of aromatase P450arom and its transcripts in breast adipose tissue of a girl with pubertal macromastia [Abstract P1–393]. Proceedings of the 79th Annual Meeting of the Endocrine Society; 1997 June 11–14; Minneapolis, MN, USA. Endocrine Society Press.
- ^ Madeira J, Silva CC, Otto AP, Trarbach EB, Nishi MY, Rocha RI, Mendonca BB, Carvalho L (April 2015). "Aromatase Excess Syndrome in a 10-Year Old Girl with Gigantomastia". Endocrine Reviews. 36 (2 Suppl).
- ^ a b Fukami M, Miyado M, Nagasaki K, Shozu M, Ogata T (2014). "Aromatase excess syndrome: a rare autosomal dominant disorder leading to pre-or peri-pubertal onset gynecomastia". Pediatric Endocrinology Reviews. 11 (3): 298–305. PMID 24716396. Archived from the original on 2019-07-10. Retrieved 2019-07-10.
- ^ "Aromatase excess syndrome - Conditions - GTR - NCBI". www.ncbi.nlm.nih.gov. Archived from the original on 2022-02-08. Retrieved 2022-02-08.
- ^ Shozu, Makio; Sebastian, Siby; Takayama, Kazuto; Hsu, Wei-Tong; Schultz, Roger A.; Neely, Kirk; Bryant, Michael; Bulun, Serdar E. (2003). "Estrogen Excess Associated with Novel Gain-of-Function Mutations Affecting the Aromatase Gene". New England Journal of Medicine. 348 (19): 1855–1865. doi:10.1056/NEJMoa021559. ISSN 0028-4793. PMID 12736278.
- ^ a b Braverman IM, Redford DB, Mackowiak PA (2009). "Akhenaten and the strange physiques of Egypt's 18th dynasty". Ann. Intern. Med. 150 (8): 556–60. doi:10.7326/0003-4819-150-8-200904210-00010. PMID 19380856. S2CID 24766974.
- ^ a b Eshraghian, Ahad; Loeys, Bart (2012). "Loeys-Dietz syndrome: A possible solution for Akhenaten's and his family's mystery syndrome". South African Medical Journal. 102 (8): 661–4. doi:10.7196/SAMJ.5916 (inactive 2024-11-10). hdl:10067/1011150151162165141. ISSN 2078-5135. PMID 22831939.
{{cite journal}}: CS1 maint: DOI inactive as of November 2024 (link)