Importance of Frailty in Kidney Transplant Recipients.

BACKGROUND: Frailty is a persistent chronic inflammatory syndrome present in many patients with chronic kidney disease. After kidney transplant (KT), it has been associated with complications such as delayed graft function, hospital readmission, or poorer KT survival. PURPOSE: To assess the impact of frailty on the results of KT. METHODS: Longitudinal prospective study of 65 patients included on the waiting list (WL) between October 2019 and October 2021. We used the FRAIL scale and recorded clinical characteristics, including demographic, dependency scales, and analytical parameters at the moment of the inclusion on the WL and at months 3 and 12 after KT. RESULTS: The mean age was 58 years old, and 70% of KT were men. The comorbidity burden was 26% diabetes, 83% hypertension, and 12% ischemic heart disease. Forty patients (61.5%) presented ≥1 point on the FRAIL scale, and 25 (38.4%) were robust. Frail patients (FRAIL score≥3) had a higher Charlson comorbidity index at the time of KT, a lower Barthel index, and a lower quality of life measured by KDQOL-36. No significant differences were observed in other variables, such as days of admission, surgical complications, or delayed graft function. There were 3 graft losses censored for death and 4 deaths, all in frail or prefrail patients. These patients had lower graft survival (P = .164) and patient survival (P = .096). At 12 months post KT, frailty improved in 67% of patients evaluated. CONCLUSION: Frailty is a common condition among patients on the WL, leading to poorer quality of life, greater dependency, and a higher risk of graft loss and mortality. Frailty conditions can be reversed in many patients after KT.

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. OBJECTIVE: 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. DESIGN: Case report study. PATIENT: A 25-year-old man with continuing linear growth, eunuchoid body habitus and diffuse bone pain. MEASUREMENTS: 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. RESULTS: 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. CONCLUSIONS: 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.

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.

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 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. 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 microg 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 microg GnRH i.v. bolus in phases 1 and 2. RESULTS: 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. 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.

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.