Aromatase-deficient Men Research Articles

Estrogens in Human Male Gonadotropin Secretion and Testicular Physiology From Infancy to Late Puberty.

Several reports in humans as well as transgenic mouse models have shown that estrogens play an important role in male reproduction and fertility. Estrogen receptor alpha (ERα) and beta (ERβ) are expressed in different male tissues including the brain. The estradiol-binding protein GPER1 also mediates estrogen action in target tissues. In human testes a minimal ERα expression during prepuberty along with a marked pubertal up-regulation in germ cells has been reported. ERβ expression was detected mostly in spermatogonia, primary spermatocytes, and immature spermatids. In Sertoli cells ERβ expression increases with age. The aromatase enzyme (cP450arom), which converts androgens to estrogens, is widely expressed in human tissues (including gonads and hypothalamus), even during fetal life, suggesting that estrogens are also involved in human fetal physiology. Moreover, cP450arom is expressed in the early postnatal testicular Leydig cells and spermatogonia. Even though the aromatase complex is required for estrogen synthesis, its biological relevance is also related to the regulation of the balance between androgens and estrogens in different tissues. Knockout mouse models of aromatase (ArKO) and estrogen receptors (ERKOα, ERKOβ, and ERKOαβ) provide an important tool to study the effects of estrogens on the male reproductive physiology including the gonadal axis. High basal serum FSH levels were reported in adult aromatase-deficient men, suggesting that estrogens are involved in the negative regulatory gonadotropin feedback. However, normal serum gonadotropin levels were observed in an aromatase-deficient boy, suggesting a maturational pattern role of estrogen in the regulation of gonadotropin secretion. Nevertheless, the role of estrogens in primate testis development and function is controversial and poorly understood. This review addresses the role of estrogens in gonadotropin secretion and testicular physiology in male humans especially during childhood and puberty.

Tall Stature without Growth Hormone: Four Male Patients with Aromatase Deficiency

From preliminary observations, GH-IGF-I seems to be compromised in men with aromatase deficiency. The GH deficiency (GHD) coexists paradoxically with tall stature, raising the question whether or not a true GHD is part of this rare syndrome. To evaluate the GH secretion in aromatase-deficient men, their GH response to the GHRH plus arginine (GHRH-ARG) test was compared with that of normal subjects. The effect of estrogen replacement treatment on the GH-IGF-I axis in aromatase-deficient men was evaluated before and during therapy. A case-control study was conducted. Four adult men with aromatase deficiency were compared with 12 normal subjects. We measured the GH response to GHRH-ARG in aromatase-deficient men (at baseline and during estrogen treatment) and in normal subjects. Basal serum IGF-I was measured in both patients and controls. The response of GH to GHRH-ARG was severely impaired in men with aromatase deficiency and resulted in significantly lower (P < 0.001) levels than in normal subjects. Although normal, serum IGF-I levels were also significantly lower (P < 0.001) than in normal subjects. Both GH peak and IGF-I concentrations were not modified by estrogen therapy in men with aromatase deficiency. In aromatase-deficient men, GH response to potent provocative stimuli is impaired and is not restored by exogenous estrogens. Furthermore, a tall stature may be reached, notwithstanding the coexistence of GHD, if a prolonged time for growth is available due to a delay in bone maturation, and other growth factors different from GH (mainly insulin) promote growth.

The effects of long-term raloxifene and estradiol treatments on bone in a patient with congenital aromatase deficiency

Introduction In adult aromatase-deficient men, estrogen treatment has always resulted in a rapid skeletal maturation with epiphyseal closure and improved BMD. Raloxifene is a SERM with proven estrogen agonist action on bone that leads to an improvement in BMD and a reduction in bone turnover. The present study reports the effects of raloxifene and transdermal estradiol treatment, respectively, on epiphyseal closure and BMD in an aromatase-deficient man, over a 24-month follow-up, with the aim of obtaining further insight into the role of estrogens in the male skeletal homeostasis. Materials and methods A 25-year-old Caucasian man with aromatase deficiency, a bone age of 15.3 years, unfused epiphyses and an impaired BMD was initially administered raloxifene (60 mg/day per os) for 12 months, while transdermal estradiol (25 μg twice weekly) was administered for the subsequent 12 months. During the follow-up, the effects of the two treatments on epiphyseal closure, BMD and bone turnover markers were investigated. An iliac crest bone biopsy was performed only before and after the raloxifene treatment, but it was not repeated after transdermal estradiol treatment. Results No changes in bone age were observed after raloxifene therapy, whereas a complete epiphyseal closure was achieved with transdermal estradiol treatment. Compared with baseline values, raloxifene treatment led to improved BMD both at the ultradistal forearm and 33% radius; the transdermal estradiol treatment resulted in a further slight increase in BMD at the 33% radius, but not at the ultradistal forearm. The baseline bone biopsy showed elevated bone remodelling in trabecular bone, while the second biopsy following raloxifene treatment revealed a decrease in remodelling. Discussion This study shows that the management of aromatase deficiency in the male cannot consider raloxifene as a first choice treatment, but should be still based on estrogen replacement treatment since in this patient the completion of bone maturation has only been obtained once estradiol substitution was performed. The present case also demonstrates that raloxifene is able to improve BMD in aromatase-deficient men.

Testosterone action on erythropoiesis does not require its aromatization to estrogen: Insights from the testosterone and estrogen treatment of two aromatase-deficient men

Androgens act on erythropoiesis, but the relative role of testosterone (T) and estradiol (E 2) on erythropoietic parameters in men is a poorly investigated issue. In order to evaluate separately the effects on erythropoiesis of high-dose T administration alone and of physiological dose of E 2 administration alone two adult men with aromatase deficiency were assessed before and during each treatment. Blood cell count, hemoglobin (Hb), hematocrit (Hct), erythrocyte mean cell volume (MCV), erythrocyte mean corpuscular hemoglobin (MCH), erythrocyte mean corpuscular hemoglobin concentration (MCHC), serum ferritin, iron and total iron-binding capacity (TIBC), serum erythropoietin, serum total testosterone and estradiol were evaluated. Hb, Hct and red cell count rose during testosterone treatment, consistently with the increase in circulating testosterone, but failed to increase during estradiol treatment. A decrease in Hb, Hct and red cell count was recorded in one of the two subjects during estradiol treatment, with a concomitant decrease in serum testosterone. Circulating T alone is capable of and sufficient to influence erythropoiesis, especially at supraphysiological dosage, while circulating E 2 have not the same effect on erythropoietic parameters, suggesting the hypothesis that the erythropoietic changes induced by androgens are not mediated via its aromatization to estrogens.

Estrogen and Fracture Risk in Men

Estrogen and Fracture Risk in Men

Hypothalamic–pituitary–gonadal axis in two men with aromatase deficiency: evidence that circulating estrogens are required at the hypothalamic level for the integrity of gonadotropin negative feedback

In men, the feedback of gonadotropins is regulated by estrogens that come from the aromatization of testosterone, but the relative contribution to the inhibition of LH and FSH secretion by the amount of locally produced estrogens within the hypothalamus and/or the pituitary, and the amount of circulating estrogens still remains unknown. In order to evaluate the effect of regulation induced by estradiol on the hypothalamic-pituitary-gonadal (HPG) axis, we studied the pulsatility of LH and FSH in two aromatase-deficient men (called subject 1 and subject 2), in which the production rate of estrogen (both local and circulating) is completely, or at least severely, impaired. FSH and LH were evaluated in terms of their pulsated secretion and as GnRH-stimulated secretion in two phases: phase 1, before estrogen treatment; and phase 2, during estrogen treatment with 25 microg transdermal estradiol twice weekly. Blood samples were taken during phase 1 and phase 2 at 0800 h for basal measurements of LH, FSH, inhibin B, testosterone, and estradiol. The analysis of the pulsatility of LH and FSH was performed by sampling every 10 min for 8 h in the two phases. Gonadotropin response to GnRH-stimulation test was studied by serial standard sampling after 100 microg GnRH i.v. bolus in phases 1 and 2. Estrogen treatment led to a significant reduction in both LH-pulsated frequency (7.5 +/- 0.7 in phase 1, 4.5 +/- 0.7 in phase 2) and amplitudes (3.5 +/- 0.006 in phase 1, 1.9 +/- 0.4 in phase 2) of peaks, whereas FSH showed only a conspicuous reduction in serum levels and a trend towards the reduction of the amplitudes of its peaks without modification of the frequency of the pulses. Both testosterone and gonadotropins decreased during phase 2, whereas estradiol reached the normal range in both subjects. Transdermal estradiol treatment significantly lowered the peaks of both serum LH and FSH after GnRH as well as the incremental area under the curve after GnRH administration in both subjects. Basal serum inhibin B levels were slightly higher before transdermal estradiol treatment (phase 1) than during estrogen treatment (phase 2) in both subjects. The administration of estrogen to aromatase-deficient men discloses the effects of circulating estrogens on LH secretion, exerted both at pituitary level, as shown by the decrease of basal and GnRH-stimulated secretion of LH and the LH pulsed amplitude, and at hypothalamic level as shown by the reduction of the frequency of LH pulses. The present study, coupling the outcomes of basal, GnRH-stimulated and the pulsatile evaluation of LH and FSH secretion in two aromatase-deficient men, demonstrates that circulating estrogens play an inhibitory role in LH secretion by acting on the hypothalamus and the pituitary gland of men. The discrepancy among testosterone levels, the arrest of spermatogenesis and a slightly inappropriate respective increase of serum FSH (lower than expected) suggests a possible role of estrogens in the priming and the maturation of HPG axis in men, an event that has never occurred in these two subjects as a consequence of chronic estrogen deprivation.

Aromatase Activity and Bone Homeostasis in Men

It is known that sex steroid hormones play an important role in the maintenance of bone mass in males as well as in females. Even though androgens are the major sex steroids in men, their primacy in regulating male skeletal remodeling has been increasingly questioned as direct and indirect evidence emerged suggesting that estrogens may also play a major role in male skeletal health. Recent data suggested that a threshold level of bioavailable estradiol is needed to prevent bone loss, and that with aging an increasing percentage of elderly men begin to fall below this level. The testes account for, at most, 15% of circulating estrogens in the male; the remaining 85% comes from peripheral aromatization of androgen precursors in different tissues, including bone. Human models of aromatase deficiency were the first to demonstrate the critical importance of the conversion of circulating androgens into estrogen in regulating male skeletal homeostasis. All four cases of aromatase-deficient men reported to date showed an identical skeletal phenotype, characterized by tall stature due to continued longitudinal growth, unfused epiphyses, high bone turnover, and osteopenia. Studies using knockout mice along with experimental observations in rats treated with an aromatase inhibitor provided useful information about the importance of aromatase in the male skeleton. Confirmatory evidence comes from recent interventional studies in adult men using aromatase inhibition, which confirmed that estrogens are critically important to the male skeleton by helping to control rates of bone remodeling. Intriguingly, common polymorphisms at the human aromatase (CYP19) gene have been associated with differences in aromatase activity, bone turnover, and rates of bone loss in elderly men, suggesting that variations in aromatase efficiency may also be relevant for skeletal homeostasis. Several additional mechanisms have been proposed in which aromatase activity could be modulated under certain circumstances in different tissues. Additional studies are needed to identify how these genetic, environmental, pathological, and pharmacological influences might modulate aromatase activity in vivo, increasing or reducing estrogen production in males and thereby affecting skeletal health.

The importance of oestrogens in males.

For a long time oestrogens in the human male have been regarded as a mere by-product of testosterone synthesis. Only since the description of an oestrogen-resistant man (Smith et al ., 1994) has it been fully realized that oestrogens play an import role in bone homeostasis, cardiovascular health and pituitary–gonadal interactions in men. Due to a disruptive homozygous oestrogen receptor alpha (ER α ) mutation, this man was virtually insensitive to oestrogens which lead to osteoporosis, unfused epiphyses resulting in linear growth into adulthood, increased gonadotrophin levels and evidence of premature atherosclerosis (Sudhir et al ., 1997a) and endothelial dysfunction (Sudhir et al ., 1997b). Additionally, there was low viability of sperm and glucose intolerance with acanthosis nigrans. Two adult aromatase-deficient men showed, besides undetectable oestrogen levels, low bone mass, unfused epiphyses, increased gonadotrophins and a unfavourable lipid profile (Morishima et al ., 1995; Carani et al ., 1997). Earlier, Korach (1994) described similar observations in ER α knockout mice. Heterozygous mice exhibited no obvious phenotypic abnormalities. Homozygous male mice proved to be infertile, showing smaller testes with dysmorphic seminiferous tubules and a sperm count of less than 10% compared to normal mice. Finally, bone mineral density was 20–25% lower in male and female mutants compared to wild-type animals. These reports indicate that oestrogens also play a central role in several metabolic processes in men. The interrelation between testosterone and oestrogen biosynthesis makes it difficult to separate their respective biological effects. Therefore, it is not unlikely that biological effects formerly attributed to testosterone actually represent effects of oestrogens. In light of the observations in oestrogen-resistant or -deficient males, and because of the wealth of evidence for the role of oestrogens in the (patho)physiology of bone and lipid metabolism, cardiovascular disease and the hypothalamo–pituitary– gonadal axis in women, this review will discuss these areas, focusing on the clinical importance of oestrogens in males.

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 and estrogen resistance: from molecular genetics to clinic.

Our knowledge of the physiologic roles of estrogen in women and men has been advanced by recent descriptions of mutations disrupting estrogen biosynthesis and action. Aromatase deficiency results from autosomal recessive inheritance of mutations in the CYP19 gene. It gives rise to ambiguous genitalia in 46,XX individuals. At puberty, affected girls have hypergonadotropic hypogonadism, fail to develop secondary sexual characteristics, and exhibit progressive virilization. The affected 46,XY individuals have normal male sexual differentiation and pubertal maturation. These men are extremely tall and have eunuchoid proportions with continued linear growth into adulthood, lack of epiphyseal closure, and osteoporosis due to estrogen deficiency. Although estrogen was shown to be essential for normal sperm production and function in mice, its role in fertility is not clear in men. Thus far, one estrogen-resistant human, a man with a mutant estrogen receptor-alpha gene, has been described. His clinical presentation was similar to that of aromatase-deficient men.