Dysmetabolic Syndrome in a Man with a Novel Mutation of the Aromatase Gene: Effects of Testosterone, Alendronate, and Estradiol Treatment

Abstract

We present the fourth case of an adult man (29 yr old) affected by aromatase deficiency resulting from a novel homozygous inactivating mutation of the CYP19 (P450(arom)) gene. At first observation, continuing linear growth, eunuchoid body proportions, diffuse bone pain, and bilateral cryptorchidism were observed. The patient presented also a complex dysmetabolic syndrome characterized by insulin resistance, diabetes mellitus type 2, acanthosis nigricans, liver steatohepatitis, and signs of precocious atherogenesis. The analysis of the effects induced by the successive treatment with high doses of testosterone, alendronate, and estradiol allows further insight into the roles of androgens and estrogens on several metabolic functions. High doses of testosterone treatment resulted in a severe imbalance in the estradiol to testosterone ratio together with the occurrence of insulin resistance and diabetes mellitus type 2. Estrogen treatment resulted in an improvement of acanthosis nigricans, insulin resistance, and liver steatohepatitis, coupled with a better glycemic control and the disappearance of two carotid plaques. Furthermore, the study confirms previous data concerning the key role of estrogens on male bone maturation, at least in part, and regulation of gonadotropin secretion. The biopsy of the testis showed a pattern of total germ cell depletion that might be due to the concomitant presence of bilateral cryptorchidism. Thus, a possible role of estrogen in male reproductive function is suggested but without revealing a direct cause-effect relationship. Data from this case provide new insights into the role of estrogens in glucose, lipid, and liver metabolism in men. This new case of aromatase deficiency confirms previous data on bone maturation and mineralization, and it reveals a high risk for the precocious development of cardiovascular disease in young aromatase-deficient men.

Teasing out the role of aromatase in the healthy and diseased testis

“…46 76 and in some cases cryptorchidism is evident. 73,74 The lack of patient consent for human ejaculate samples and testicular biopsies hampers the ability to draw solid conclusions about the effect of aromatase deficiency on spermatogenesis, but from the data that is available it appears a lack of aromatase is associated with Sertoli cell only syndrome, 74 hypospermatogenesis, 75 oligospermia, 46,47 reduced sperm motility 47 and complete sperm immobility, 46 many of which are in concert with findings from the ArKO model (reviewed in ref. 6)· Further qualitative analyses on the histological architecture of the testis noted seminiferous tubules of normal appearance 75 and those that were hypotrophic.…”

Estrogens and atherosclerosis: insights from animal models and cell systems

“…Studies on males with defective estrogen action add further support to the notion that these hormones exert potent atheroprotective effects. Actually, accelerated development of atherosclerosis has been observed in male subjects deficient in P450 aromatase, an enzyme that converts androgens to estrogens, and characterized by estradiol (E 2 ) levels below the detection limit (Maffei et al 2004). More importantly, estrogen treatment in aromatase-deficient subjects reversed atherosclerotic changes in the carotid artery.…”

A high pretreatment plasma oestradiol level is associated with a low risk of acute myocardial infarction in parenteral oestrogen therapy for locally advanced prostate cancer

“…In men, the major proportion of endogenous oestradiol is derived from the aromatization of testosterone in the peripheral tissues The endogenous testosterone level is inversely associated with severe aortic atherosclerosis and its progression [14], and genetic defects of oestrogen synthesis or action will lead to the development of premature atherosclerosis [15,16]. The androgen receptor and oestrogen receptors α and β are all expressed in the intima, media and adventitia of the male coronary arteries, and decreasing androgen receptor expression in the media and increasing oestrogen receptor-β expression in the intima correlate with more extensive early coronary atherosclerosis [17].…”

“…It is obvious that physiological levels of endogenous oestradiol with adequate local function are needed for the normal development of coronary arteries [15,16]. In addition, as oestradiol is produced in the vascular tissues, it has a direct local effect in an autocrine and paracrine manner [10,21] but also a greater systemic effect [22].…”