Aromatase excess syndrome

Aromatase excess syndrome
File:File:Protein PGR PDB 1a28.png
Synonyms	Hereditary prepubertal gynecomastia
Pronounce
Field	Endocrinology
Symptoms
Complications
Onset
Duration
Types
Causes
Risks
Diagnosis
Differential diagnosis
Prevention
Treatment
Medication
Prognosis
Frequency
Deaths

Aromatase excess syndrome (AES or AEXS) is a rare 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 pseudohermaphroditism) and in females as hyperfeminization.<ref name="ShozuFukami2014">,

 Understanding the pathological manifestations of aromatase excess syndrome: lessons for clinical diagnosis, 
 Expert Review of Endocrinology & Metabolism, 
 2014,
 Vol. 9(Issue: 4),
 pp. 397–409,
 DOI: 10.1586/17446651.2014.926810,
 PMID: 25264451,
 PMC: 4162655,</ref><ref name="MartinLin2003">, 
 Familial Hyperestrogenism in Both Sexes: Clinical, Hormonal, and Molecular Studies of Two Siblings, 
 The Journal of Clinical Endocrinology & Metabolism, 
 2003,
 Vol. 88(Issue: 7),
 pp. 3027–3034,
 DOI: 10.1210/jc.2002-021780,
 PMID: 12843139,</ref><ref name="pmid9543166">, 
 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, 
 
 Vol. 83(Issue: 4),
 pp. 1348–57,
 DOI: 10.1210/jc.83.4.1348,
 PMID: 9543166,
 
 
 Full text,</ref><ref name="Makowski2011">{{{last}}}, 
 Gregory Makowski, 
  
 Advances in Clinical Chemistry. online version, 
  
 Academic Press, 
  
  
  
 ISBN 978-0-12-387025-4,</ref>

To date, 30 males and 8 females with AEXS among 15 and 7 families, respectively, have been described in the medical literature.<ref name="ShozuFukami2014" /><ref name="MartinLin2003" />

Signs and symptoms

Observed physiological abnormalities of the condition include a dramatic overexpression of aromatase and, accordingly, excessive levels of estrogens including estrone and estradiol<ref name="pmid15483104">,

 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, 
 
 Vol. 90(Issue: 1),
 pp. 484–92,
 DOI: 10.1210/jc.2004-1566,
 PMID: 15483104,
 
 
 Full text,</ref> 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.<ref name="MartinLin2003" /> 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),<ref name="pmid10997774">, 
 Pharmacodynamics of oestrogens and progestogens, 
 Cephalalgia: An International Journal of Headache, 
 
 Vol. 20(Issue: 3),
 pp. 200–7,
 DOI: 10.1046/j.1468-2982.2000.00042.x,
 PMID: 10997774,</ref> whereas luteinizing hormone (LH) levels were normal.<ref name="FukamiShozu2012">, 
 Molecular Bases and Phenotypic Determinants of Aromatase Excess Syndrome, 
 International Journal of Endocrinology, 
 2012,
 Vol. 2012,
 pp. 1–8,
 DOI: 10.1155/2012/584807,
 PMID: 22319526,
 PMC: 3272822,</ref>

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%).<ref name="ShozuFukami2014" /> As such, estrone is the main estrogen elevated in the condition.<ref name="ShozuFukami2014" /> In more than half of patients, circulating androstenedione and testosterone levels are low to subnormal.<ref name="ShozuFukami2014" /> The ratio of circulating estradiol to testosterone is >10 in 75% of cases.<ref name="ShozuFukami2014" /> FSH levels are said to be consistently low in the condition, while LH levels are in the low to normal range.<ref name="ShozuFukami2014" />

It is notable that gynecomastia has been observed in patients in whom estradiol levels are within the normal range.<ref name="ShozuFukami2014" /> 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).<ref name="ShozuFukami2014" />

A 21-year-old male patient with AEXS displaying symptoms of feminization and hypogonadism.

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),<ref name="pmid12053085">Meinhardt U, Mullis PE,

 The aromatase cytochrome P-450 and its clinical impact, 
 Hormone Research, 
 2002,
 Vol. 57(Issue: 5–6),
 pp. 145–52,
 DOI: 10.1159/000058374,
 PMID: 12053085,</ref> 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.<ref name="ShozuFukami2014" />

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.<ref name="MartinLin2003" /> Pubertal breast hypertrophy in association with AEXS has been described in two young girls.<ref name=”AgarwalSasano1997”>Template:Cite conference</ref><ref name=”MadeiraSilva2015”>,

 Aromatase Excess Syndrome in a 10-Year Old Girl with Gigantomastia, 
 Endocrine Reviews, 
 
 Vol. 36(Issue: 2 Suppl),
 
 
 
 
 
 Full text,</ref>

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.<ref name="MartinLin2003" /><ref name="pmid9543166" /><ref name="Makowski2011" />

Cause

The 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.<ref name="MartinLin2003" /><ref name="Makowski2011" /><ref name="FukamiShozu2012"/> Different mutations are associated with differential severity of symptoms, such as mild to severe gynecomastia.<ref name="ShozuFukami2014" /><ref name="FukamiMiyado2014">,

 Aromatase excess syndrome: a rare autosomal dominant disorder leading to pre-or peri-pubertal onset gynecomastia., 
 Pediatric Endocrinology Reviews: PER, 
 2014,
 Vol. 11(Issue: 3),
 pp. 298–305,
 
 PMID: 24716396,
 
 
 Full text,</ref> For example, duplications result in relatively mild gynecomastia, while deletions, resulting in chimeric genes, cause moderate or severe gynecomastia.<ref name="FukamiMiyado2014" />

Treatment

Several 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.<ref name="MartinLin2003" /><ref name="pmid9543166" /><ref name="Makowski2011" />

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.<ref name="MartinLin2003" /><ref name="ShozuSebastian2003">,

 Estrogen Excess Associated with Novel Gain-of-Function Mutations Affecting the Aromatase Gene, 
 New England Journal of Medicine, 
 2003,
 Vol. 348(Issue: 19),
 pp. 1855–1865,
 DOI: 10.1056/NEJMoa021559,
 PMID: 12736278,</ref> At least one case of male breast cancer has been reported.<ref name="MartinLin2003" />

Society and culture

Names

AEXS has also been referred to as familial hyperestrogenism, familial gynecomastia, and familial adrenal feminization.

Notable cases

It has been hypothesized that the Pharaoh Akhenaten (husband of Queen Nefertiti) and other members of the 18th Dynasty of ancient Egypt may have suffered from AEXS.<ref name="pmid19380856">,

 Akhenaten and the strange physiques of Egypt's 18th dynasty, 
 Ann. Intern. Med., 
 2009,
 Vol. 150(Issue: 8),
 pp. 556–60,
 DOI: 10.7326/0003-4819-150-8-200904210-00010,
 PMID: 19380856,</ref> 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.<ref name="pmid19380856" /> 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.<ref name="EshraghianLoeys2012">, 
 Loeys-Dietz syndrome: A possible solution for Akhenaten's and his family's mystery syndrome, 
 South African Medical Journal, 
 2012,
 Vol. 102(Issue: 8),
 pp. 661–4,
 DOI: 10.7196/SAMJ.5916,
 PMID: 22831939,</ref> Most recently, Loeys–Dietz syndrome was proposed as a probable cause, with gynecomastia and feminization possibly being caused by liver cirrhosis-induced hyperestrogenism.<ref name="EshraghianLoeys2012" />

See also

• Androgen insensitivity syndrome
• Aromatase deficiency
• Congenital estrogen deficiency
• Disorders of sex development
• Estrogen insensitivity syndrome
• Hyperestrogenism
• Inborn errors of steroid metabolism

External links

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