A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women

OBJECTIVE: To evaluate the ovarian follicular dynamics of cycle modification with the aromatase inhibitor letrozole compared with clomiphene citrate in normal ovulatory women. DESIGN: Randomized double-blind controlled trial. SETTING: Tertiary care hospital. PATIENT(S): Nineteen ovulatory female volunteers, ages 18-35 years. INTERVENTION(S): Subjects were monitored in one control cycle. Subjects then received either letrozole 2.5 mg daily or clomiphene citrate 50 mg daily on days 5-9 after menses. MAIN OUTCOME MEASURE(S): Number of mature follicles, endometrial thickness and endometrial pattern at ovulation, and follicular profiles of LH, FSH, and E(2). RESULT(S): The number of mature follicles at the LH surge in natural cycles was 1.0 with an exaggerated response seen for treatment both with clomiphene and letrozole. There was no difference in the endometrial thickness at midcycle during either the natural cycles or the medicated cycles. LH surges and spontaneous ovulation were documented in all natural and medicated cycles. When measured daily, follicular profiles of LH and FSH are similar between the groups in both the natural and medicated cycles. In the medicated cycles, clomiphene results in a significant increase in E(2) levels, while E(2) levels in letrozole-stimulated cycles appeared lower than in natural cycles. CONCLUSION(S): Transient inhibition of aromatase activity in the early follicular phase with the aromatase inhibitor letrozole results in stimulation of ovarian folliculogenesis similar to that seen with clomiphene citrate with no apparent adverse effect on endometrial thickness or pattern at midcycle.     

芳香化酶抑制剂在妇科内分泌治疗中的应用效果观察

目的探讨芳香化酶抑制剂在妇科内分泌治疗中的应用效果。方法选取本院2009年8月-2012年10月收治的74例妇科内分泌患者,针对所有患者的临床资料及实际情况进行分析．并对患者采用芳香化酶抑制剂进行治疗,主要包括依西美坦、阿那曲唑及来曲唑,评估患者的治疗效果。结果74例患者中,基本治愈39例．显效21例,好转9例,无效5例,治疗总有效率为93．2％;无效的5例患者主要是由于其心理因素影响．与医护人员的配合度不高所致。结论临床上应用芳香化酶抑制剂治疗妇科内分泌疾病的效果较为显著,对于促进患者病情的改善及生活质量提高具有重要意义,值得在临床推广应用。     

Confounder factors masking a Leydig-cell ovarian tumor in a post-menopausal woman treated for androgen-positive receptor breast cancer

Post-menopause hyperandrogenism is a condition that needs careful evaluation. Aromatase inhibitors (AI), which are important in the management of positive estrogen breast cancer, and chronic kidney disease (CKD) can puzzle the evaluation of this condition. A postmenopause female with type-2 diabetes and advanced CKD was attended due to progressive virilization, which has started after the introduction of an AI for breast cancer 5?years earlier. Clinical and radiological investigation has confirmed a pure Leydig cell tumor as source of hyperandrogenism. Re-evaluation of the breast tumor immunohistochemistry has shown positive androgen receptor expression and negative expression for estrogen, progesterone and HER-2 receptors. Even though an ovarian tumor was the source of androgen excess, we discuss that AI could exert a slight contribution to patient’s virilization by reducing estradiol counterbalance. Also, although the onset of hyperandrogenic symptoms was unclear, we could not exclude that the ovarian tumor had produced enough androgens to play a role in breast tumor progression. This case report supports the literature regarding the possible association between Leydig cell tumor and androgen-receptor-positive breast cancer development. Finally, progressive hyperandrogenic symptoms in postmenopause, even under AI therapy or the presence of advanced CKD, impose a more detailed investigation.     

Immunocytochemical localization of aromatase in the brain

An immunocytochemical peroxidase-antiperoxidase procedure using a purified polyclonal antibody raised against human placental aromatase was used to localize aromatase-containing cells in the Japanese quail brain. Immunoreactive cells were found only in the preoptic area and hypothalamus, with a high density of positive cells being present in the sexually dimorphic medial preoptic nucleus, in the ventromedial nucleus of the hypothalamus and in the infundibulum. The positive material was localized in the perikarya and in adjacent cytoplasmic processes. Aromatase-containing cells were a specific marker for the sexually dimorphic preoptic nucleus. Treatment with testosterone produced a 6-fold increase in the aromatase activity of the preoptic area and a 4-fold increase in the number of immunoreactive cells in the medial preoptic nucleus. Thus, the increase in aromatase activity observed after testosterone administration is caused by a change in enzyme concentration.     

芳香化酶基因表达调控与乳腺癌关系的研究进展

芳香化酶是绝经后乳腺局部雌激素生成的限速酶,其编码基因CYP19的结构、功能和表达具有组织特异性.在多种调控因素影响下,该基因通过选择性利用不同的启动子及相应的外显子I进行组织特异性调节,影响芳香化酶表达.CYP19基因表达在正常的乳腺组织中主要是通过启动子PI.4,起决定作用的外显子I是1b;在癌变组织则主要是启动子PⅡ、PⅠ.3,变为外显子1c占主导地位.CYP19基因的特异性表达为从基因水平治疗乳腺癌提供了理论基础.     

Letrozole as primary therapy for endometrial hyperplasia in young women.

OBJECTIVE: To study letrozole as a primary therapeutic agent for endometrial hyperplasia with or without atypia in young women. METHODS: Five premenopausal women presenting for infertility were diagnosed as having endometrial hyperplasia. A second biopsy was performed after they were treated for 3 months with 2.5 mg of letrozole per day. Serum levels of estradiol and progesterone were measured each month. RESULTS: Curettage of the endometrium at the end of treatment revealed no evidence of endometrial hyperplasia or atypia in any of the patients. Low serum levels of estradiol were found in all patients. CONCLUSION: This case series indicates that aromatase inhibitors deserve attention for the conservative treatment of endometrial hyperplasia. However, more studies are needed to confirm the efficacy and safety of this agent.     

In vitro estrogenic and antiestrogenic potential of chlorostyrenes

Chlorostyrenes (CSs) are primarily derived from industrial by-products and are persistent and accumulative in the environment. In this study, the estrogenic and antiestrogenic activities of CSs (o-CS, m-CS, p-CS, DiCS, octa-CS) were evaluated using in vitro bioassays. o-CS and octa-CS have both estrogenic and antiestrogenic activity in the E-SCREEN assay and the ERE-reporter gene assay, indicating effects on a classical ER-mediated pathway. m-CS showed estrogenic activity in E-SCREEN but not in ERE-reporter gene assays, indicating that it may work through a non-classical ER-mediated pathway. Finally, DiCS only showed antiestrogenic activity via an ER-independent pathway, which can be induced by depletion of endogenous E₂ level by the inhibition of aromatase activity and the stimulation of E₂ metabolism. Although CSs have structural similarities to dioxins/furans, they did not have AhR agonist effects. This study is the first to show the estrogenic and antiestrogenic activity of several CSs using in vitro bioassay systems, including whether the compounds work via ER-mediated or/and non-ER-mediated pathways.     

Steroidogenesis-disrupting compounds can be effectively studied for major fertility-related endpoints using in vitro cultured mouse follicles

Biologically relevant bioassays are needed to test various endocrine disrupters (EDs). A mouse follicle culture model could allow measuring steroidogenic enzyme function in combination with oocyte growth and meiotic maturation using routine methodology. Three steroidogenesis-disrupting ‘model’ chemicals were tested; vorozole (VOR), aminoglutethimide (AMG), and ketoconazole (KCZ). Along with visual assessment of follicular growth, differentiation and oocyte growth and maturation by conventional light microscopy, steroid secretion measurements allowed to confirm literature findings from in vivo animal studies and more complex in vitro tests. The bioassay was applied for a dose–response study of mono(2-ethylhexyl)phthalate (MEHP), a chemical known to disrupt several steroidogenic enzymes. This bioassay was able to confirm an increased inactivation of E₂ to E₁ and an induced precocious progesterone increase, implying that MEHP can disrupt follicle differentiation and impact the reproductive axis. This in vitro ovarian model allows to reduce animal use by performing synchronous culture of large numbers of early preantral ovarian mouse follicles and is informative on multiple fertility-related endpoints.     

Influence of an Aromatase Inhibitor (4-Acetoxy-4-Androstene-3,17-Dione) on Experimentally Induced Impairment of Spermatogenesis in Immature Rats/Einfluß eines Aromatasehemmers (4-Acetoxy-4-Androsten-3,17-dion) auf die experimentell induzierte Hemmung der Spermatogenese bei immaturen Ratten

Subcutaneous treatment of immature male rats with an estrogen precursor, 19-hydroxy-testosterone (19-OHT), at a daily dose of 1 mg/animal for 14 days leads to a significant decrease in the weight of testis, ventral prostate and seminal vesicle. The peripheral levels of LH are lowered. Testicular histology indicates that the effects of 19-OHT are very similar to the known of effect induced by estradiol-17 beta. 19OHT induces a marked impairment of spermato- and spermiogenesis. The maturation division is completely inhibited. The effect of 19-OHT on spermatogenesis is partially reversed by concomitant administration of an aromatase inhibitor (4-acetoxy-4-androstene-3.17-dione, (4-AA] at a dose of 1 mg/animal/day s.c. Meiotic activity is restored, and the weights of genital organs and the serum LH values increase. 4-AA alone has no appreciable effect on the parameters examined in this study. The present results suggest that specific inhibitors of estrogen biosynthesis might not only be useful to investigate the patho-physiological role of estrogens on spermatogenesis, but also be suitable to some extent for the treatment of estrogen-induced infertility in men suffering from idiopathic oligozoospermia.