Background: In men, the feedback of gonadotropins is regulated by estrogens that come from the ar... more Background: 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. Objective: In order to evaluate the effect of regulation induced by estradiol on the hypothalamicpituitary-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. Design: 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 mg transdermal estradiol twice weekly. Methods: 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 mg GnRH i.v. bolus in phases 1 and 2. Results: Estrogen treatment led to a significant reduction in both LH-pulsated frequency (7.5G0.7 in phase 1, 4.5G0.7 in phase 2) and amplitudes (3.5G0.006 in phase 1, 1.9G0.4 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. Conclusions: 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.
In adult aromatase-deficient men, estrogen treatment has always resulted in a rapid skeletal matu... more 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. 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 microg 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. 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. 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.
We present the fourth case of an adult man (29 yr old) affected by aromatase deficiency resulting... more 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.
From preliminary observations, GH-IGF-I seems to be compromised in men with aromatase deficiency.... more 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.
Androgens act on erythropoiesis, but the relative role of testosterone (T) and estradiol (E 2 ) o... more 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.
Descriptions of new cases of human aromatase deficiency are useful for a better understanding of ... more Descriptions of new cases of human aromatase deficiency are useful for a better understanding of male oestrogen pathophysiology, as some aspects remain controversial. To present a new case of an adult man affected by aromatase deficiency, along with a description of clinical phenotype, and hormonal and genetic analysis. Case report study. A 25-year-old man with continuing linear growth, eunuchoid body habitus and diffuse bone pain. Amplification and sequencing of all coding exons with their flanking intronic sequences of the CYP19A1 gene. Aromatase expression of the mutant human cDNAs was compared with wild type. Serum LH, FSH, testosterone, oestradiol, insulin, glucose, glycosylated haemoglobin (HbA1c), serum lipids and liver enzymes were measured. Histological analysis of liver and testis biopsies was performed. Two novel heterozygous compound inactivating mutations of the CYP19A1 gene were disclosed. The first mutation is at bp380 (T-->G) in exon IV and the second one at bp 1124 (G-->A) in exon IX. LH and testosterone were normal, FSH was slightly elevated, and serum oestradiol undetectable. The subject showed a metabolic syndrome characterized by abdominal obesity, hyperinsulinaemia, acanthosis nigricans and nonalcoholic fatty liver disease. These novel mutations improve our knowledge on genetics of the CYP19A1 gene. This new case of aromatase deficiency sheds new light on the heterogeneity of mutations in the CYP19A1 gene causing loss of function of the aromatase enzyme. The evidence of metabolic syndrome and of obesity associated with congenital oestrogen deprivation emphasizes the role of oestrogens in fat accumulation and distribution in men, a role that has long been partially overlooked in these patients.
To assess long-term efficacy and tolerability of dapagliflozin versus glipizide as add-on to metf... more To assess long-term efficacy and tolerability of dapagliflozin versus glipizide as add-on to metformin in patients with inadequately controlled type 2 diabetes. Study findings at 52 and 104 weeks (NCT00660907) showed that dapagliflozin had similar glycaemic efficacy to glipizide and was associated with weight loss and lower incidence of hypoglycaemia. The 4-year data are now reported. This was an extension of the earlier randomized, double-blind, phase 3 study of dapagliflozin (n = 406) vs glipizide (n = 408) to 208 weeks (4 years). Patients continued to receive their assigned medication. No statistical treatment-group comparisons were calculated. At 208 weeks, dapagliflozin produced sustained reductions in HbA1c (-0.30% [95% confidence interval (CI), -0.51 to -0.09]), total body weight (-4.38 kg [95% CI -5.31 to -3.46]) and systolic blood pressure (SBP; -3.67 mmHg [95% CI -5.92 to -1.41]), compared with glipizide. The HbA1c coefficient of failure was significantly lower for dapagli...
The Journal of Steroid Biochemistry and Molecular Biology, 2009
Androgens act on erythropoiesis, but the relative role of testosterone (T) and estradiol (E(2)) o... more 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.
The Journal of Steroid Biochemistry and Molecular Biology, 2005
1. J Steroid Biochem Mol Biol. 2005 May;95(1-5):3-8. Estrogen, a fundamental player in energy hom... more 1. J Steroid Biochem Mol Biol. 2005 May;95(1-5):3-8. Estrogen, a fundamental player in energy homeostasis. Simpson E, Jones M, Misso M, Hewitt K, Hill R, Maffei L, Carani C, Boon WC. Prince Henry's Institute of Medical Research, Clayton, Vic. 3168, Australia. ...
Sexual behavior was investigated by a sexological interview in a man with aromatase deficiency an... more 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.
Nature Clinical Practice Endocrinology & Metabolism, 2007
Aromatase deficiency is rare in humans. Affected individuals cannot synthesize endogenous estroge... more 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.
The Journal of Clinical Endocrinology & Metabolism, 2004
We present the fourth case of an adult man (29 yr old) affected by aromatase deficiency resulting... more 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.
The Journal of Clinical Endocrinology & Metabolism, 2010
From preliminary observations, GH-IGF-I seems to be compromised in men with aromatase deficiency.... more 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.
Background: In men, the feedback of gonadotropins is regulated by estrogens that come from the ar... more Background: 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. Objective: In order to evaluate the effect of regulation induced by estradiol on the hypothalamicpituitary-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. Design: 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 mg transdermal estradiol twice weekly. Methods: 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 mg GnRH i.v. bolus in phases 1 and 2. Results: Estrogen treatment led to a significant reduction in both LH-pulsated frequency (7.5G0.7 in phase 1, 4.5G0.7 in phase 2) and amplitudes (3.5G0.006 in phase 1, 1.9G0.4 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. Conclusions: 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.
Background: In men, the feedback of gonadotropins is regulated by estrogens that come from the ar... more Background: 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. Objective: In order to evaluate the effect of regulation induced by estradiol on the hypothalamicpituitary-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. Design: 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 mg transdermal estradiol twice weekly. Methods: 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 mg GnRH i.v. bolus in phases 1 and 2. Results: Estrogen treatment led to a significant reduction in both LH-pulsated frequency (7.5G0.7 in phase 1, 4.5G0.7 in phase 2) and amplitudes (3.5G0.006 in phase 1, 1.9G0.4 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. Conclusions: 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.
In adult aromatase-deficient men, estrogen treatment has always resulted in a rapid skeletal matu... more 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. 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 microg 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. 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. 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.
We present the fourth case of an adult man (29 yr old) affected by aromatase deficiency resulting... more 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.
From preliminary observations, GH-IGF-I seems to be compromised in men with aromatase deficiency.... more 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.
Androgens act on erythropoiesis, but the relative role of testosterone (T) and estradiol (E 2 ) o... more 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.
Descriptions of new cases of human aromatase deficiency are useful for a better understanding of ... more Descriptions of new cases of human aromatase deficiency are useful for a better understanding of male oestrogen pathophysiology, as some aspects remain controversial. To present a new case of an adult man affected by aromatase deficiency, along with a description of clinical phenotype, and hormonal and genetic analysis. Case report study. A 25-year-old man with continuing linear growth, eunuchoid body habitus and diffuse bone pain. Amplification and sequencing of all coding exons with their flanking intronic sequences of the CYP19A1 gene. Aromatase expression of the mutant human cDNAs was compared with wild type. Serum LH, FSH, testosterone, oestradiol, insulin, glucose, glycosylated haemoglobin (HbA1c), serum lipids and liver enzymes were measured. Histological analysis of liver and testis biopsies was performed. Two novel heterozygous compound inactivating mutations of the CYP19A1 gene were disclosed. The first mutation is at bp380 (T-->G) in exon IV and the second one at bp 1124 (G-->A) in exon IX. LH and testosterone were normal, FSH was slightly elevated, and serum oestradiol undetectable. The subject showed a metabolic syndrome characterized by abdominal obesity, hyperinsulinaemia, acanthosis nigricans and nonalcoholic fatty liver disease. These novel mutations improve our knowledge on genetics of the CYP19A1 gene. This new case of aromatase deficiency sheds new light on the heterogeneity of mutations in the CYP19A1 gene causing loss of function of the aromatase enzyme. The evidence of metabolic syndrome and of obesity associated with congenital oestrogen deprivation emphasizes the role of oestrogens in fat accumulation and distribution in men, a role that has long been partially overlooked in these patients.
To assess long-term efficacy and tolerability of dapagliflozin versus glipizide as add-on to metf... more To assess long-term efficacy and tolerability of dapagliflozin versus glipizide as add-on to metformin in patients with inadequately controlled type 2 diabetes. Study findings at 52 and 104 weeks (NCT00660907) showed that dapagliflozin had similar glycaemic efficacy to glipizide and was associated with weight loss and lower incidence of hypoglycaemia. The 4-year data are now reported. This was an extension of the earlier randomized, double-blind, phase 3 study of dapagliflozin (n = 406) vs glipizide (n = 408) to 208 weeks (4 years). Patients continued to receive their assigned medication. No statistical treatment-group comparisons were calculated. At 208 weeks, dapagliflozin produced sustained reductions in HbA1c (-0.30% [95% confidence interval (CI), -0.51 to -0.09]), total body weight (-4.38 kg [95% CI -5.31 to -3.46]) and systolic blood pressure (SBP; -3.67 mmHg [95% CI -5.92 to -1.41]), compared with glipizide. The HbA1c coefficient of failure was significantly lower for dapagli...
The Journal of Steroid Biochemistry and Molecular Biology, 2009
Androgens act on erythropoiesis, but the relative role of testosterone (T) and estradiol (E(2)) o... more 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.
The Journal of Steroid Biochemistry and Molecular Biology, 2005
1. J Steroid Biochem Mol Biol. 2005 May;95(1-5):3-8. Estrogen, a fundamental player in energy hom... more 1. J Steroid Biochem Mol Biol. 2005 May;95(1-5):3-8. Estrogen, a fundamental player in energy homeostasis. Simpson E, Jones M, Misso M, Hewitt K, Hill R, Maffei L, Carani C, Boon WC. Prince Henry's Institute of Medical Research, Clayton, Vic. 3168, Australia. ...
Sexual behavior was investigated by a sexological interview in a man with aromatase deficiency an... more 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.
Nature Clinical Practice Endocrinology & Metabolism, 2007
Aromatase deficiency is rare in humans. Affected individuals cannot synthesize endogenous estroge... more 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.
The Journal of Clinical Endocrinology & Metabolism, 2004
We present the fourth case of an adult man (29 yr old) affected by aromatase deficiency resulting... more 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.
The Journal of Clinical Endocrinology & Metabolism, 2010
From preliminary observations, GH-IGF-I seems to be compromised in men with aromatase deficiency.... more 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.
Background: In men, the feedback of gonadotropins is regulated by estrogens that come from the ar... more Background: 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. Objective: In order to evaluate the effect of regulation induced by estradiol on the hypothalamicpituitary-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. Design: 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 mg transdermal estradiol twice weekly. Methods: 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 mg GnRH i.v. bolus in phases 1 and 2. Results: Estrogen treatment led to a significant reduction in both LH-pulsated frequency (7.5G0.7 in phase 1, 4.5G0.7 in phase 2) and amplitudes (3.5G0.006 in phase 1, 1.9G0.4 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. Conclusions: 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.
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