Introduction:
Excess aromatase enzymes can lead to increased levels of circulating estrogen in the body, eventually leading to an aromatase excess syndrome. The condition was earlier known as familial gynecomastia. The condition occurs due to a gain-of-function mutation in the gene CYP19A1, which is the gene responsible for aromatase. The females affected by the condition generally do not exhibit any unusual symptoms except for enlargement of the breasts and irregular periods. At the same time, males show several signs, including gynecomastia (breast enlargement in men), loss of facial hair, precocious puberty (onset of puberty before the average age), high-pitched voices, etc.
What Is Aromatase?
Aromatase is an enzyme that is responsible for helping the body in the production of estrogen. It is also known as estrogen synthetase or synthase because of its essential role in production. Enzymes are proteins that aid in the body's chemical reactions. Aromatase is primarily responsible for converting androgens to estrogens (through aromatization). The gonads, fatty tissues, placenta (the organ that develops in the uterus during pregnancy), blood vessels, brain, and skin contain aromatase. Aromatase is also detected in the tissues of uterine fibroids, endometriosis, endometrial cancer, and breast cancer patients. Furthermore, the aromatase enzyme is vital for sexual development.
What Is Aromatase Excess Syndrome?
Aromatase excess syndrome is an endocrine disorder occurring due to a gain-of-function genetic mutation of the aromatase gene, which results in high levels of estrogen (female sex hormone) in males and females. Aromatase is the enzyme responsible for the production of estrogen (from androgens) in the body, and overexpression of the gene responsible for the aromatase enzyme causes excess aromatase syndrome in an individual. This increased level of circulating estrogen in the body causes symptoms associated with hyperestrogenism.
Hyperestrogenism is a clinical condition characterized by a prolonged state of sexual receptivity, infertility, a more extended period of sexual incompetence, a change in the structure of testes or ovaries, etc. Aromatase excess syndrome affects both sexes. It causes feminization but with no genitals in males and hyper-feminization in females.
What Causes Aromatase Excess Syndrome?
The exact cause of aromatase excess syndrome is unknown; however, genetic mutation is suspected of playing a vital role in the development of the condition in an individual. Mutation of the gene CYP19A1, which encodes the aromatase enzyme, is the cause of aromatase excess syndrome. Aromatase activity can be reduced or increased in case of mutation of this gene. The aromatase enzyme converts a group of hormones known as androgens (male sex hormones) into estrogen. Different mutations of the gene determine different levels of symptom severity. For example, duplication of the CYP19A1 gene causes mild gynecomastia in an affected male, whereas deletion results in mild to moderate gynecomastia (growth of breast tissues in men).
Is Aromatase Excess Syndrome a Common Condition?
Aromatase excess syndrome is rare, and the exact prevalence rate is unknown. In addition, there are only 30 to 40 known cases of aromatase excess syndrome in the medical literature.
Is Aromatase Excess Syndrome Inherited?
Aromatase excess syndrome is a hereditary condition which means it is passed down from parents to their children. Aromatase excess syndrome is inherited in an autosomal recessive pattern, which means one copy of the genetic mutation of CYP19A1 in each cell can cause the disorder. The affected individual inherits the condition of one of the affected parents.
What Are the Other Names for Aromatase Excess Syndrome?
Alternative names of aromatase excess syndrome are:
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AEXS.
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Familial gynecomastia without hypogonadism.
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Familial gynecomastia due to increased aromatase activity.
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Increased aromatase activity.
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Hereditary gynecomastia.
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Familial adrenal feminization.
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Familial hyperestrogenism.
What Are the Symptoms of Aromatase Excess Syndrome?
The symptoms of excess aromatase syndrome in males include:
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The start of gynecomastia in response to increased estrogen production is the most characteristic symptom of aromatase excess syndrome. The earliest sign of gynecomastia starts around mid-childhood, around seven to 14 years. The onset of gynecomastia in adulthood is very rare.
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Precocious puberty with atypical secondary sexual character development and feminized appearance.
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High-pitched voice or sharp voice.
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The sparsity of facial hair.
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Dysfunctional gonads or hypogonadism.
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Low sperm count.
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Testes that are smaller than usual.
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Small penis or micropenis.
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Advanced bone maturation.
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Accelerated growth rate especially increase in height. This occurs when estrogen levels are high through the prepubertal phase, bone growth is accelerated, and patients grow taller than most people of their age.
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Short stature in adulthood due to premature epiphyseal closure.
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No effect on fertility.
The symptoms of excess aromatase syndrome in females include:
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Precocious puberty with the development of typical secondary sexual features.
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Enlargement of breasts.
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Enlargement of the uterus.
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Irregular menstrual cycles.
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Accelerated growth rate and increase in height. This occurs when estrogen levels are high through the prepubertal phase, bone growth is accelerated, and patients grow taller than most people their age.
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Short stature in adulthood due to premature epiphyseal closure.
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No effect on fertility.
How Is Aromatase Excess Syndrome Diagnosed?
Aromatase excess syndrome is diagnosed with the help of the following tests:
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A detailed medical and family history, physical examination, and analysis of the clinical signs and symptoms are necessary to reach a proper diagnosis.
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Several blood examinations are done to check the levels of hormones like estrogen and testosterone, and the level of aromatase enzyme is also checked.
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Follicle-stimulating hormone levels are low, and Luteinizing hormone-releasing hormone responsiveness is poor.
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Genetic tests can now identify the variations in CYP19A1 linked to aromatase excess syndrome. This method is the definitive diagnostic approach.
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Since gynecomastia is the distinguishing symptom of the condition, a four-point criterion has been developed to confirm the diagnosis of aromatase excess syndrome based on the symptoms of gynecomastia. These include; gynecomastia should be bilateral and more than equal to stage 2, the onset of gynecomastia should be right before puberty or around puberty, exclusion of any other possible cause of gynecomastia like symptomatic gynecomastia, and finally, the presence of a genetic trait.
How Is Aromatase Excess Syndrome Treated?
The treatment of aromatase excess syndrome is multitargeted and involves the following procedures:
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Aromatase inhibitors block the functioning of the aromatase enzyme, eventually lowering the levels of circulating excess estrogen in the body. Anastrozole, a third-generation selective inhibitor, has generally been found to reduce serum estrone and estradiol levels while increasing serum testosterone levels. In addition, aromatase inhibitors can relieve gynecomastia in 6 months and may be helpful in preventing recurrence after surgery.
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Gonadotropin-releasing hormones have also helped reduce aromatase activity and lower estrogen levels in both sexes.
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Another goal of AEXS treatment is to prevent premature bone closure. Aromatase inhibitors are presently used off-label to help males with short stature gain adult height. However, using aromatase inhibitors to increase adult height is uncertain. It is often not helpful when the inhibitors are given after developing gynecomastia or several years after growth spurts. Therefore, early intervention is necessary to increase the adult height of the individual.
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Sex hormone replacement therapy also helps curb the excess estrogen levels in the body. In males, androgen replacement therapy with non-aromatizable androgens is used, whereas, in females, progestogens are used to reduce estrogen levels.
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Mastectomy is the surgical removal of breasts (one or both). In addition, several males with advanced gynecomastia undergo a bilateral mastectomy.
Conclusion:
Aromatase excess syndrome is a rare and non-life-threatening condition. The hallmark symptom of the condition is the development of gynecomastia (breast enlargement) in men around puberty. However, the treatment of aromatase excess syndrome has a multidisciplinary approach where the aromatase enzyme levels are controlled, estrogen and testosterone levels are restored, and surgical intervention is implied to treat gynecomastia in males. Females affected by aromatase excess syndrome rarely manifest symptoms but may experience excessive breast growth, irregular menstrual cycles, and short adult height. Men and women with aromatase excess syndrome have normal fertility.
