来曲唑-芳香化酶抑制剂

1、Aromatase inhibitors in men 概要 Background1 Safety and concerns5 Aromatase inhibitors3 Aromatase2 Effects of aromatase inhibitior4BackgroundThe role of estradiol gaining and maintaining bone mass closing of the epiphyses the feedback on gonadotropin secretionEstrogen excess premature closure of the e

2、piphyses gynecomastia low gonadotropin low testosterone levels.5/28/2022 AromataseAromatase Aromatase, also known as estrogen synthetase, is the key enzyme in estrogen biosynthesis. The enzyme, localized in the endoplasmic reticulum of the estrogen-producing cell, is encoded by the CYP19A1 gene，whic

3、h is localized on chromosome 15 and comprises nine exons， the start codon for translation is located on exon 2.CYP19 gene Men with estrogen deficiency caused by a mutation in the CYP19 gene suffer from：I. low bone mineral density (BMD) II. unfused epiphyses, III. high gonadotropinIV. high testostero

4、ne levels . Aromatase activity gonads placenta brain fat tissue muscle hair bone vascular tissueIt has been demonstrated in: Estradiol production direct testicular secretion conversion of testicular androgens peripheral conversion of adrenal androgens 5/28/2022 Aromatase inhibitorsMechanism Nonstero

5、idal enzyme inhibitors such as anastrozole and letrozole inhibit enzyme activity by binding with the heme iron of the enzyme. Incomplete efficacy Although aromatase inhibition by anastrozole and letrozole is reported to be close to 100%, administration of these inhibitors to men will not suppress pl

6、asma estradiol levels completely. In men third-generation aromatase inhibitors will decrease the mean plasma estradiol/testosterone ratio by 77% .Cause of incomplete efficacy Aromatase is less suppressed in the testis compared to adipose and muscle tissue. Advantage It prevents excessive reduction o

7、f estrogen levels in men and the possible associated adverse effects. In postmenopausal women with breast carcinoma, long-term use of potent aromatase inhibitors reduces circulating estradiol levels by 88% and is associated with adverse effects on bone. Effects of aromatase inhibitiorEffect Lowering

8、 estradiol levels, by administering an aromatase inhibitor such as letrozole, is associated with an increase in levels of LH, FSH and testosterone through the feedback of hypothalamo-pituitary-gonadal axis.Epiphysial closure Lower estradiol levels and thereby slow down epiphysial maturation. Aromata

9、se inhibitors, mostly combined with agonists of GRH proved effective for the prevention of premature epiphysial closure in boys with pubertas praecox.There is also evidence that aromatase inhibitors can be used in boys with idiopathic short stature and boys with constitutional delay of puberty to in

10、crease adult height. SpermatogenesisIncrease gonadotropin secretionstimulate Leydig and Sertoli cell function stimulate sperm productionClinical use We investigated whether letrozole (2.5 mg per day) improves sperm count in NOA patients. 4 men were included in this study, and they had FSH and other

11、hormone levels within the normal range and no varicoceles or chromosomal aberrations. These four patients were administered letrozole for 3 months.Clinical use All patients suffered losses of libido despite the supra-physiological levels of T,FSH and LH; however, in a study on the sexual behaviour o

12、f men with aromatase congenital deficiency, a loss of libido occurred even with supra-physiological levels of testosterone.This suggests that oestrogens could have a role in supporting libido.Clinical use We present the case of an infertile man with small testes and an elevated FSH level, which was

13、diagnosed as NOA, hypospermatogenesis proven by testicular biopsy. After taking letrozole for 3 months, semen analyses by computer-aided sperm analysis present that this man had normal spermatogenesis. Clinical use The study group consisted of 29 infertile men with a low serum T/E2 ratio (10). Patie

14、nts were divided into two groups. Group A included 15 patients treated with 2.5 mg letrozole orally once daily for 6 months, and Group B consisted of 14 patients treated with 1 mg anastrazole orally every day for 6 months.Clinical use The increase in average TFSF in the letrozole group after treatme

15、nt compared with the pretreatment value was 31.6%, and the increase in average TFSF in the anastrazole group after treatment compared with the pretreatment value was 21.1%. Clinical use We investigated the effect of letrozole, an aromatase inhibitor, on body mass index, serum hormones, and sperm par

16、ameters in infertile men with decreased T/E2 ratios. Clinical use 2 of the 10 oligospermic men (20%) achieved spontaneous pregnancy after the letrozole treatment. In 4 of 17 azoospermic men (23.5%), spermatozoa appeared in the ejaculate with a mean total motile sperm counts of 1.11 0.69 million, although 13 men (76.5%) remained azoospermic after letrozole treatment. Safety and concerns Long-term use in postmenopausal women is associated with a moderate increase in bone resorption and a modest decrease in BMD compared with placebo. In most studies utili