Recognizing rare disorders: aromatase deficiency

Abstract

Aromatase deficiency is rare in humans. Affected individuals cannot synthesize endogenous estrogens. Aromatase is the enzyme that catalyzes conversion of androgens into estrogens, and if aromatase is nonfunctional because of an inactivating mutation, estrogen synthesis cannot occur. If the fetus lacks aromatase activity, dehydroepiandrosterone sulfate produced by the fetal adrenal glands cannot be converted to estrogen by the placenta, so is converted to testosterone peripherally and results in virilization of both fetus and mother. Virilization manifests as pseudohermaphroditism in female infants, with hirsutism and acne in the mother; the maternal indicators resolve following delivery. To date, only seven males and seven females with aromatase deficiency have been reported. Affected females are typically diagnosed at birth because of the pseudohermaphroditism. Cystic ovaries and delayed bone maturation can occur during childhood and adolescence in these girls, who present at puberty with primary amenorrhea, failure of breast development, virilization, and hypergonadotrophic hypogonadism. Affected males, on the other hand, do not present with obvious defects at birth, so are diagnosed much later in life, presenting with clinical symptoms, which include tall stature, delayed skeletal maturation, delayed epiphyseal closure, bone pain, eunuchoid body proportions and excess adiposity. Estrogen replacement therapy reverses the symptoms in male and female patients.

Are declining testosterone levels a major risk factor for ill-health in aging men?

“…Testosterone can be converted by the enzyme 5a-reductase into dihydrotestosterone (DHT), which has greater binding affinity for the androgen receptor, or by the enzyme aromatase into estradiol, which interacts with the estrogen receptor. 1,2 Nonclassical pathways of androgen action also have been identified that do not involve nuclear androgen receptor-mediated transcriptional activation of target genes. 3 However, the central role of androgens acting through the androgen receptor in the regulation of male physiology is elegantly illustrated by androgen insensitivity syndrome where 46XY males possessing a mutated androgen receptor unresponsive to androgen have the outward appearance of normal females.…”

Role of sex hormones in modulation of brown adipose tissue activity

“…Aromatase deficiency, a rare disorder in which affected individuals cannot synthesize endogenous estrogen, is associated with metabolic abnormalities including obesity in humans (Jones et al 2007). In women, it is well known that hyperandrogenism is often associated with increased intra-abdominal fat accumulation and the metabolic syndrome (as for the case of polycystic ovary syndrome; Gambineri et al 2009), and the decline of estrogen after menopause is known to determine an increase in intraabdominal fat mass (Lobo 2008).…”

Estradiol for the mitigation of adverse effects of androgen deprivation therapy

“…Global aromatase knockout mice have more fat mass and less muscle mass than wild type mice, and men and postmenopausal women have a different body fat distribution pattern than premenopausal women (Jones et al 2000). Case reports of men with congenital aromatase deficiency describe excess adiposity and insulin resistance (Jones et al 2007) and AI treatment in healthy men reduces insulin sensitivity (Gibb et al 2016). Similarly, mice (Bryzgalova et al 2006) and men with defective ERα have insulin resistance.…”

“…However, case reports of men with congenital aromatase deficiency have generally reported normal sexual function, and whether there is improvement with estrogen replacement is controversial (Jones et al 2007). In the context of PCa, better maintenance of sexual function has been suggested in men receiving ADT that is estrogen based (Wibowo et al 2011), but there have been no prospective randomized trials and firm conclusions cannot be drawn.…”