Vincenzo Rochira

Role of oestrogen in male sexual behaviour: insights from the natural model of aromatase deficiency

In order to evaluate the role of oestrogens on human male sexual behaviour, the gender‐identity, psychosexual orientation and sexual activity of a man with a congenital lack of oestradiol resulting from an inactivating mutation of the aromatase P450 gene was investigated. The psychosexual and sexual behavioural evaluations were performed before and during testosterone treatment and before oestradiol treatment, during three phases of different dosages of oestradiol treatment.

A novel compound heterozygous mutation of the aromatase gene in an adult man: reinforced evidence on the relationship between congenital oestrogen deficiency, adiposity and the metabolic syndrome

Background  Descriptions of new cases of human aromatase deficiency are useful for a better understanding of male oestrogen pathophysiology, as some aspects remain controversial.

A novel mutation in the human aromatase gene: Insights on the relationship among serum estradiol, longitudinal growth and bone mineral density in an adult man under estrogen replacement treatment

OBJECTIVE Here we report on a new case of human aromatase deficiency in a man of 26 years of age and present the results of five year follow-up during trandermal estradiol (tE2) substitution, focusing on bone growth and mineralization. The lack of patients compliance to tE2 treatment, resulting in low but detectable serum estradiol levels, provides helpful information about the physiological estradiol needed in serum to guarantee a complete bone maturation and mineralization. DESIGN Clinical case report study. METHODS Genetic, biochemical and hormonal evaluations and the study of bone health were performed before and during estrogen treatment. RESULTS Eunuchoid body proportions, unfused epiphyses, tall stature, osteopenia, increase fasting insulin, mild astenozoospermia and a history of right cryptorchidism were present. Baseline serum FSH was slightly above the normal range and estradiol was undetectable. Genetic analysis revealed a pattern of compound heterozygosity due to 23 bp deletion in exon IV and a point mutation in the first nucleotide of intron IX of the CYP19A1 gene, respectively. The closure of epiphyseal cartilage, the normalization of bone BMD and bone turnover markers, and the improvement of insulin levels were reached during tE2 only when serum estradiol raised above 73 pmol/L. Sperm parameters and overweight did not improve with substitutive therapy. CONCLUSIONS This new case of aromatase deficiency underlines the role of estrogen on skeletal maturation, BMD, metabolic abnormalities and gonadal axis. It provides evidence on the need not only of a continuous estrogen replacement, but also of ensuring adequate estradiol levels in serum in order to ensure a complete bone maturation and mineralization and to prevent the worsening of body skeletal proportions. The comprehension of this physiological aspect has relevant clinical significance especially for the development of new therapeutic strategies useful to treat growth disorders by targeting serum estradiol in men.

Premature decline of serum total testosterone in HIV-infected men in the HAART-era.

Background Testosterone (T) deficiency remains a poorly understood issue in men with Human Immunodeficiency Virus (HIV). We investigated the gonadal status in HIV-infected men in order to characterize T deficiency and to identify predictive factors for low serum T. Methodology/Principal Findings We performed a cross-sectional, observational study on 1325 consecutive HIV male outpatients, most of them having lipodystrophy. Serum total T<300 ng/dL was used as the threshold for biochemical T deficiency. Morning serum total T, luteinizing hormone (LH), estradiol, HIV parameters, and body composition parameters by CT-scan and Dual-Energy-X-ray-Absorptiometry were measured in each case. Sexual behavior was evaluated in a subset of 247 patients. T deficiency was found in 212 subjects, especially in the age range 40–59, but was frequent even in younger patients. T deficiency occurred mainly in association with low/normal serum LH. Adiposity was higher in subjects with T deficiency (p<0.0001) and both visceral adipose tissue and body mass index were the main negative predictors of serum total T. Osteoporosis and erectile dysfunction were present in a similar percentage in men with or without T deficiency. Conclusions/Significance Premature decline of serum T is common (16%) among young/middle-aged HIV-infected men and is associated with inappropriately low/normal LH and increased visceral fat. T deficiency occurs at a young age and may be considered an element of the process of premature or accelerated aging known to be associated with HIV infection. The role of HIV and/or HIV infection treatments, as well as the role of the general health state on the gonadal axis, remains, in fact, to be elucidated. Due to the low specificity of signs and symptoms of hypogonadism in the context of HIV, caution is needed in the diagnosis of hypogonadism in HIV-infected men with biochemical low serum T levels.

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.

Congenital estrogen deficiency in men: a new syndrome with different phenotypes; clinical and therapeutic implications in men.

The report focuses on the role of estrogens in human male, dealing with two human models of congenital estrogen deficiency: estrogen resistance and aromatase deficiency. Similarities and differences of clinical phenotypes of these models are described and progresses of estrogen treatment of aromatase-deficient men are reported. Finally, the putative use of estrogen in men and the use of aromatase inhibitors and antiestrogen for male disorders are discussed.

Aromatase deficiency in men: a clinical perspective.

Human aromatase deficiency is a very rare syndrome characterized by congenital estrogen deprivation that is caused by loss-of-function mutations in CYP19A1, which encodes aromatase. Here, we review the presentation, diagnosis and treatment of aromatase deficiency in men to provide useful advice for clinical management of the condition. At presentation, all men with aromatase deficiency have tall stature, delayed bone maturation, osteopenia or osteoporosis and eunuchoid skeletal proportions. Diagnosis of the condition is supported by the presence of unfused epiphyses and undetectable serum estradiol levels; the condition can be further substantiated by genetic sequencing of CYP19A1. Transdermal estradiol treatment at a daily dose of about 25 µg might be adequate for lifelong replacement therapy. BMD and levels of serum estradiol, luteinizing hormone and testosterone should be monitored carefully and considered powerful biochemical markers of adequate estrogen substitution in clinical practice. Early diagnosis is important to initiate estrogen therapy as soon after puberty as possible to avoid the skeletal complications that are associated with this condition.

Congenital estrogen deficiency: in search of the estrogen role in human male reproduction.

Recently, a remarkable progress has been made in our understanding about the role of sex steroids in male physiology. In this paper, we consider the clinical aspects of congenital estrogen deficiency - notably, estrogen resistance and aromatase deficiency - in men and we discuss both well-established and supposed estrogen roles in the human male reproductive function. These topics include the role of estrogens in the control of gonadotropin secretion, in male fertility determination and psychosexual behavior. Briefly, estrogens play a pivotal role in the control of serum gonadotropin concentrations in the human male. Furthermore, a possible role of estrogens on both human male fertility and sexuality has also been suggested by recent studies, even though the available data are far from being conclusive. Conversely, for what concern fertility and sexual behavior, a well-established effect of estrogens has been provided by recent studies on male rodents, which show impaired sexual behavior and fertility as a consequence of estrogen defect.

Role of estrogen on bone in the human male: insights from the natural models of congenital estrogen deficiency

The reports of congenital estrogen deficiency - notably, estrogen resistance and aromatase deficiency - have completely changed our knowledge on the role of estrogen on bone in males. Particularly, the bone changes at puberty, which were classically considered androgen-dependent, are now considered to be induced at least in part by estrogen action. Clinical cases of congenital estrogen deficiency have clearly demonstrated that the role of estrogens in epiphyseal closure, skeletal proportions and bone mineralization is crucial not only in women but also in men. In addition progress have been made in the treatment of such a rare disease even though further studies are needed to a definitive understanding of this issue.

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.