Aromatase excess syndrome

Aromatase excess syndrome
AES 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.
Classification and external resources
Specialty	Endocrinology
OMIM	139300
MeSH	C537436

Aromatase excess syndrome (AES or AEXS), also sometimes referred to as familial hyperestrogenism or familial gynecomastia, 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, and in females as hyperfeminization.^[1]^[2]^[3]

To date, 10 families with AES have been fully described in the medical literature, of which 23 males and at least 6 females were characterized as displaying symptoms of the condition.^[1]^[4]

Cause

The root cause of AES 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.^[1]^[3]^[4]

Observed physiological abnormalities of the condition include a dramatic overexpression of aromatase and, accordingly, excessive levels of estrogens including estradiol and estrone,^[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.^[1] 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.^[4]

Symptoms

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

Prepubertal gynecomastia in two siblings, a 9-year-old boy (left) and a 7.5-year-old girl (right), both due to AES.

In Males

The symptoms of AES, 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)
hypogonadism (dysfunctional gonads), oligozoospermia (low sperm count)
small testes, micropenis (an ususually small penis)
advanced bone maturation, an earlier peak height velocity (an accelerated rate of growth in regards to height),^[7] and
short final stature due to early epiphyseal closure.

In Females

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.

In Both

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.^[1]^[2]^[3] Individuals with AES may be at higher risk of developing estrogen-sensitive cancers such as breast and endometrial cancer.^[8]^[9] At least one patient, a male with the condition, was reported as having developed carcinoma of the breast.^[1]

Treatment

Several treatments have been found to be effective in managing AES, 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.^[1]^[2]^[3]

Medical treatment of AES is not absolutely necessary, but it is recommended as the condition, if left untreated, can lead to excessively large breasts (which may necessitate surgical reduction), problems with fertility, and possibly an increased risk of estrogen-dependent cancers later in life.^[1]

References

1 2 3 4 5 6 7 8 Martin RM, Lin CJ, Nishi MY; et al. (July 2003). "Familial hyperestrogenism in both sexes: clinical, hormonal, and molecular studies of two siblings". The Journal of Clinical Endocrinology and Metabolism 88 (7): 3027–34. doi:10.1210/jc.2002-021780. PMID 12843139.
1 2 3 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/jc.83.4.1348. PMID 9543166.
1 2 3 4 Gregory Makowski (22 April 2011). Advances in Clinical Chemistry. Academic Press. p. 158. ISBN 978-0-12-387025-4. Retrieved 24 May 2012.
1 2 3 Fukami M, Shozu M, Ogata T (2012). "Molecular bases and phenotypic determinants of aromatase excess syndrome". International Journal of Endocrinology 2012: 584807. doi:10.1155/2012/584807. PMC 3272822. PMID 22319526.
↑ 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.
↑ 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. PMID 12053085.
↑ Czajka-Oraniec I, Simpson ER (2010). "Aromatase research and its clinical significance". Endokrynologia Polska 61 (1): 126–34. PMID 20205115.
↑ Persson I (November 2000). "Estrogens in the causation of breast, endometrial and ovarian cancers - evidence and hypotheses from epidemiological findings". The Journal of Steroid Biochemistry and Molecular Biology 74 (5): 357–64. doi:10.1016/S0960-0760(00)00113-8. PMID 11162945.

Diseases of the endocrine system (E00–E35, 240–259)

Pancreas/
glucose
metabolism

Hypofunction	Diabetes mellitus types: type 1 type 2 MODY 1 2 3 4 5 6 complications coma angiopathy ketoacidosis nephropathy neuropathy retinopathy cardiomyopathy insulin receptor (Rabson–Mendenhall syndrome) Insulin resistance

Hyperfunction	Hypoglycemia beta cell (Hyperinsulinism) G cell (Zollinger–Ellison syndrome)

Hypothalamic/
pituitary axes

Hypothalamus

gonadotropin
- Kallmann syndrome
- Adiposogenital dystrophy
CRH (Tertiary adrenal insufficiency)
vasopressin (Neurogenic diabetes insipidus)
general (Hypothalamic hamartoma)

Pituitary

Hyperpituitarism	anterior Acromegaly Hyperprolactinaemia Pituitary ACTH hypersecretion posterior (SIADH) general (Nelson's syndrome)

Hypopituitarism	anterior Kallmann syndrome Growth hormone deficiency Hypoprolactinemia ACTH deficiency/Secondary adrenal insufficiency GnRH insensitivity FSH insensitivity LH/hCG insensitivity posterior (Neurogenic diabetes insipidus) general Empty sella syndrome Pituitary apoplexy Sheehan's syndrome Lymphocytic hypophysitis

Thyroid

Hypothyroidism	Iodine deficiency Cretinism Congenital hypothyroidism Myxedema Euthyroid sick syndrome

Hyperthyroidism	Hyperthyroxinemia Thyroid hormone resistance Familial dysalbuminemic hyperthyroxinemia Hashitoxicosis Thyrotoxicosis factitia Graves' disease

Thyroiditis	Acute infectious Subacute De Quervain's Subacute lymphocytic Autoimmune/chronic Hashimoto's Postpartum Riedel's

Goitre	Endemic goitre Toxic nodular goitre Toxic multinodular goiter Thyroid nodule

Parathyroid

Hypoparathyroidism	Hypoparathyroidism Pseudohypoparathyroidism Pseudopseudohypoparathyroidism

Hyperparathyroidism	Primary Secondary Tertiary Osteitis fibrosa cystica

Adrenal

Hyperfunction	aldosterone: Hyperaldosteronism/Primary aldosteronism Conn syndrome Bartter syndrome Glucocorticoid remediable aldosteronism AME Liddle's syndrome 17α CAH cortisol: Cushing's syndrome (Pseudo-Cushing's syndrome) sex hormones: 21α CAH 11β CAH

Hypofunction/ Adrenal insufficiency (Addison's, WF)	aldosterone: Hypoaldosteronism 21α CAH 11β CAH cortisol: CAH Lipoid 3β 11β 17α 21α sex hormones: 17α CAH

Gonads

general: Hypogonadism (Delayed puberty)
Hypergonadism
- Precocious puberty
Hypoandrogenism
Hypoestrogenism
Hyperandrogenism
Hyperestrogenism
Postorgasmic illness syndrome

Height

Multiple

Autoimmune polyendocrine syndrome multiple
- APS1
- APS2
Carcinoid syndrome
Multiple endocrine neoplasia
- 1
- 2A
- 2B
Progeria
Woodhouse-Sakati syndrome

Genetic disorder, protein biosynthesis: Transcription factor/coregulator deficiencies

(1) Basic domains

1.2	Feingold syndrome Saethre–Chotzen syndrome

1.3	Tietz syndrome

(2) Zinc finger
DNA-binding domains

2.1	(Intracellular receptor): Thyroid hormone resistance Androgen insensitivity syndrome PAIS MAIS CAIS Kennedy's disease PHA1AD pseudohypoaldosteronism Estrogen insensitivity syndrome X-linked adrenal hypoplasia congenita MODY 1 Familial partial lipodystrophy 3 SF1 XY gonadal dysgenesis

2.2	Barakat syndrome Tricho–rhino–phalangeal syndrome

2.3	Greig cephalopolysyndactyly syndrome/Pallister–Hall syndrome Denys–Drash syndrome Duane-radial ray syndrome MODY 7 MRX 89 Townes–Brocks syndrome Acrocallosal syndrome Myotonic dystrophy 2

2.5	Autoimmune polyendocrine syndrome type 1

(3) Helix-turn-helix domains

3.1	ARX Ohtahara syndrome Lissencephaly X2 MNX1 Currarino syndrome HOXD13 SPD1 Synpolydactyly PDX1 MODY 4 LMX1B Nail–patella syndrome MSX1 Tooth and nail syndrome OFC5 PITX2 Axenfeld syndrome 1 POU4F3 DFNA15 POU3F4 DFNX2 ZEB1 Posterior polymorphous corneal dystrophy Fuchs' dystrophy 3 ZEB2 Mowat–Wilson syndrome

3.2	PAX2 Papillorenal syndrome PAX3 Waardenburg syndrome 1&3 PAX4 MODY 9 PAX6 Gillespie syndrome Coloboma of optic nerve PAX8 Congenital hypothyroidism 2 PAX9 STHAG3

3.3	FOXC1 Axenfeld syndrome 3 Iridogoniodysgenesis, dominant type FOXC2 Lymphedema–distichiasis syndrome FOXE1 Bamforth–Lazarus syndrome FOXE3 Anterior segment mesenchymal dysgenesis FOXF1 ACD/MPV FOXI1 Enlarged vestibular aqueduct FOXL2 Premature ovarian failure 3 FOXP3 IPEX

3.5	IRF6 Van der Woude syndrome Popliteal pterygium syndrome

(4) β-Scaffold factors
with minor groove contacts

4.2	Hyperimmunoglobulin E syndrome

4.3	Holt–Oram syndrome Li–Fraumeni syndrome Ulnar–mammary syndrome

4.7	Campomelic dysplasia MODY 3 MODY 5 SF1 SRY XY gonadal dysgenesis Premature ovarian failure 7 SOX10 Waardenburg syndrome 4c Yemenite deaf-blind hypopigmentation syndrome

4.11	Cleidocranial dysostosis

(0) Other transcription factors

0.6	Kabuki syndrome

Ungrouped

Transcription coregulators

Coactivator:	CREBBP Rubinstein–Taybi syndrome

Corepressor:	HR (Atrichia with papular lesions)

Inborn error of steroid metabolism

Mevalonate pathway

HMG-CoA lyase deficiency

To cholesterol

desmosterol path: Desmosterolosis

Steroids

Corticosteroid
(including CAH)

aldosterone: Glucocorticoid remediable aldosteronism

Sex steroid

To androgens	17-beta-hydroxysteroid dehydrogenase deficiency 5-alpha-reductase deficiency Pseudovaginal perineoscrotal hypospadias

To estrogens	Aromatase deficiency Aromatase excess syndrome

Other

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