Human models of aromatase deficiency.

Estrogens exert a wide range of biological effects in both sexes also on non-reproductive systems and organs. Human congenital estrogen deficiency, due to an inactivating mutation of the aromatase gene, leads to the lack of the estrogen synthesis, with gonadotropins and circulating testosterone ranging from normal to elevated. The aromatese-deficient females show hyperandrogenism and virilization at birth with ambiguous genitalia. During childhood there are a dysfunction in the LHRH-LH/FSH axis and a progressive delay in bone age. At puberty they show primary amenorrhea, no breast development, worsening of the virilization and the absence of growth spurt. The clinical phenotype in the male affected subjects comprises tall stature, persistent linear growth and delayed bone age, osteopenia/osteoporosis, eunuchoid body proportion, different degrees of glucose-insulin and of fertility impairment. These phenotypes suggest the physiological role of estrogens on the skeleton, on pituitary function, on the reproductive system, on glucose metabolism, being the precise mechanism on each of these functions not yet known in detail. The estradiol replacement treatment leads to a complete epiphyseal closure and to the skeletal maturation. Moreover, the increasing knowledge on the role of estrogen in several metabolic pathways could be important for a better management of several metabolic diseases.

The osteoporotic male: overlooked and undermanaged?

Age-related bone loss in men is a poorly understood phenomenon, although increasing data on the pathophysiology of bone in men is becoming available. Most of what we know on bone pathophysiology derives from studies on women. The well-known association between menopause and osteoporosis is far from been disproven. However, male osteoporosis is a relatively new phenomenon. Its novelty is in part compensated for by the number of studies on female osteoporosis and bone pathophysiology. On the other hand, the deeper understanding of female osteoporosis could lead to an underestimation of this condition in the male counterpart. The longer life-span exposes a number of men to the risk of mild-to-severe hypogonadism which in turn we know to be one of the pathogenetic steps toward the loss of bone mineral content in men and in women. Hypogonadism might therefore be one among many corrigible risk factors such as cigarette smoking and alcohol abuse against which clinicians should act in order to prevent osteoporosis and its complications. Treatments with calcium plus vitamin D and bisphophonates are widely used in men, when osteoporosis is documented and hypogonadism has been excluded. The poor knowledge on male osteoporosis accounts for the lack of well shared protocols for the clinical management of the disease. This review focuses on the clinical approach and treatment strategy for osteoporosis in men with particular attention to its relationship with male hypogonadism.

Skeletal effects of long-term estrogen and testosterone replacement treatment in a man with congenital aromatase deficiency: evidences of a priming effect of estrogen for sex steroids action on bone.

The relative contribution of each sex steroid (i.e. estrogen and androgen) on bone in men and the relationships among sex steroids and changes in BMD and bone strength are still unknown. A defective BMD of bone tissue is constantly present in men with aromatase deficiency. This study evaluates the effects of different regimens of treatment with sex steroids over 7.3 years follow-up on BMD in an adult man affected by aromatase deficiency and by a concomitant mild hypogonadism, as previously described. The aim of the study is to provide additional data on the relative roles of androgens and estrogens in male bone metabolism. The effects of testosterone (T) treatment alone and estrogen (tE(2)) treatment alone as well as the effects of the combined treatment with testosterone and estradiol (T plus tE(2)) on areal BMD (aBMD) at dual-energy X-ray absorptiometry (DXA) and the effects of T plus tE(2) on volumetric BMD (vBMD), particular at cortical site, measured by peripheral quantitative computed tomography (pQCT), are investigated. Hormones and markers of bone turnover were monitored during all phases of the study. Treatment with tE(2) normalized serum estradiol, but only the combined treatment with T plus tE(2) normalized both serum estradiol and testosterone. Markers of bone turnover reached a pattern close to normality during T plus tE(2). The aBMD was little modified by T, but increased more during tE(2). T plus tE(2) resulted in a further increase in both aBMD at DXA and vBMD at pQCT. Cortical thickness increased during T plus tE(2) both in radius and tibia. Only the combined treatment led to optimal parameters of aBMD suggesting that testosterone needs estrogens as a permissive factor for a direct androgen anabolic action on bone in men.

Sex steroids and sexual desire in a man with a novel mutation of aromatase gene and hypogonadism.

Sexual behavior was investigated by a sexological interview in a man with aromatase deficiency and hypogonadism. The study was performed at the end of a long testosterone treatment, during transdermal estradiol treatment and during estradiol and testosterone associated treatment. Sexual behavior did not show abnormalities. As assessed by a sexological interview and by a sexological questionnaire gender-identity was male, sexual orientation was heterosexual and libido was normal. Sexual function was limited to masturbation and was seemingly unaffected by testosterone or estradiol alone; only the associated treatment induced a great increase in libido and in frequency of masturbation and sexual fantasies when both testosterone and estradiol reached the range of normality. Sexual behavior is mainly under the control of cognitive functions in men, but sex steroids may modulate some aspects of male sexuality. Our findings suggest that in men estrogens could play a role in sexual activity.