Aromatase excess syndrome

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Aromatase excess syndrome
Other namesHereditary prepubertal gynecomastia
Protein PGR PDB 1a28.png
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

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 pseudohermaphroditism) and in females as hyperfeminization. [1] [2] [3] [4]

Contents

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

Observed 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

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. [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

Genetic tests are now available to identify the variants in CYP19A1 associated with AEXS. The National Institutes of Health maintains a list. [12]

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. [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

Names

AEXS has also been referred to as familial hyperestrogenism, familial gynecomastia, and familial adrenal feminization.[ citation needed ]

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 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

Related Research Articles

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Estrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal activity: estrone (E1), estradiol (E2), and estriol (E3). Estradiol, an estrane, is the most potent and prevalent. Another estrogen called estetrol (E4) is produced only during pregnancy.

<span class="mw-page-title-main">Estradiol</span> Chemical compound

Estradiol (E2), also spelled oestradiol, is an estrogen steroid hormone and the major female sex hormone. It is involved in the regulation of female reproductive cycles such as estrous and menstrual cycles. Estradiol is responsible for the development of female secondary sexual characteristics such as the breasts, widening of the hips and a female-associated pattern of fat distribution. It is also important in the development and maintenance of female reproductive tissues such as the mammary glands, uterus and vagina during puberty, adulthood and pregnancy. It also has important effects in many other tissues including bone, fat, skin, liver, and the brain.

<span class="mw-page-title-main">Anastrozole</span> Chemical compound

Anastrozole, sold under the brand name Arimidex among others, is an antiestrogenic medication used in addition to other treatments for breast cancer. Specifically it is used for hormone receptor-positive breast cancer. It has also been used to prevent breast cancer in those at high risk. It is taken by mouth.

Hypogonadism means diminished functional activity of the gonads—the testicles or the ovaries—that may result in diminished production of sex hormones. Low androgen levels are referred to as hypoandrogenism and low estrogen as hypoestrogenism. These are responsible for the observed signs and symptoms in both males and females.

<span class="mw-page-title-main">Aromatase</span> Enzyme involved in estrogen production

Aromatase, also called estrogen synthetase or estrogen synthase, is an enzyme responsible for a key step in the biosynthesis of estrogens. It is CYP19A1, a member of the cytochrome P450 superfamily, which are monooxygenases that catalyze many reactions involved in steroidogenesis. In particular, aromatase is responsible for the aromatization of androgens into estrogens. The enzyme aromatase can be found in many tissues including gonads, brain, adipose tissue, placenta, blood vessels, skin, and bone, as well as in tissue of endometriosis, uterine fibroids, breast cancer, and endometrial cancer. It is an important factor in sexual development.

<span class="mw-page-title-main">Polyestradiol phosphate</span> Chemical compound

Polyestradiol phosphate (PEP), sold under the brand name Estradurin, is an estrogen medication which is used primarily in the treatment of prostate cancer in men. It is also used in women to treat breast cancer, as a component of hormone therapy to treat low estrogen levels and menopausal symptoms, and as a component of feminizing hormone therapy for transgender women. It is given by injection into muscle once every four weeks.

<span class="mw-page-title-main">Estrogen insensitivity syndrome</span> Medical condition

Estrogen insensitivity syndrome (EIS), or estrogen resistance, is a form of congenital estrogen deficiency or hypoestrogenism which is caused by a defective estrogen receptor (ER) – specifically, the estrogen receptor alpha (ERα) – that results in an inability of estrogen to mediate its biological effects in the body. Congenital estrogen deficiency can alternatively be caused by a defect in aromatase, the enzyme responsible for the biosynthesis of estrogens, a condition which is referred to as aromatase deficiency and is similar in symptomatology to EIS.

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Aromatase deficiency is a rare condition characterized by extremely low levels or complete absence of the enzyme aromatase activity in the body. It is an autosomal recessive disease resulting from various mutations of gene CYP19 (P450arom) which can lead to ambiguous genitalia and delayed puberty in females, continued linear growth into adulthood and osteoporosis in males and virilization in pregnant mothers. As of 2020, fewer than 15 cases have been identified in genetically male individuals and at least 30 cases in genetically female individuals.

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<span class="mw-page-title-main">Gynecomastia</span> Endocrine system disorder of human male breast

Gynecomastia is the abnormal non-cancerous enlargement of one or both breasts in males due to the growth of breast tissue as a result of a hormone imbalance between estrogens and androgens. Gynecomastia can cause significant psychological distress or unease.

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References

  1. 1 2 3 4 5 6 7 8 9 10 11 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.
  2. 1 2 3 4 5 6 7 8 9 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.
  3. 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/jcem.83.4.4697 . PMID   9543166. S2CID   5723607.
  4. 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.
  5. ↑ 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.[ permanent dead link ]
  6. ↑ 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.
  7. 1 2 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.
  8. ↑ 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. S2CID   24115725.
  9. ↑ 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.
  10. ↑ 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).
  11. 1 2 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.
  12. ↑ "Aromatase excess syndrome - Conditions - GTR - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2022-02-08.
  13. ↑ 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.
  14. 1 2 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.
  15. 1 2 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 . hdl: 10067/1011150151162165141 . ISSN   2078-5135. PMID   22831939.
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