OBJECTIVE: To observe the regulatory effects of moxibustion at "Guanyuan" (CV4) on the synthesis of extragonadal estradiol (E₂) and the expression of estrogen receptor (ER) in ovariectomized rats, aiming to explore the mechanism of moxibustion treatment for perimenopausal syndrome. METHODS: Forty-eight SD female rats of SPF grade were randomly divided into a sham-operation group, a model group and a moxibustion group, with 16 rats in each group. The model group and the moxibustion group underwent bilateral ovariectomy by the back incision method. Ten days after surgery, moxibustion was applied at "Guanyuan" (CV4) in the moxibustion group, 30 min each time, once a day for 10 days. After intervention, in the 3 groups, the body mass and uterus weight were measured; the serum levels of follicle stimulating hormone (FSH), luteinizing hormone (LH) and E₂, as well as the skin and hypothalamus levels of E₂ were detected by ELISA; the mRNA expression of aromatase (P450arom) in the skin and hypothalamus was detected by real-time PCR; the expression of ERα and ERβ in the hypothalamus, skin, and uterus was observed by immunofluorescence staining, and the density of positive cells was calculated using the Aipathwell digital pathology image analysis software. RESULTS: Compared with the sham-operation group, the body mass was increased (P<0.01) and the uterus weight was decreased (P<0.001) in the model group. Compared with the model group, the body mass was decreased in the moxibustion group (P<0.01). Compared with the sham-operation group, in the model group, the serum, hypothalamus and skin levels of E₂ were decreased (P<0.01, P<0.05), while the serum levels of FSH and LH were increased (P<0.01); the expression of ERα and ERβ in the skin, hypothalamus and uterus was decreased (P<0.05, P<0.001). Compared with the model group, in the moxibustion group, the serum levels of E₂ and LH, as well as the hypothalamus and skin levels of E₂ were increased (P<0.05, P<0.01); the mRNA expression of P450arom, as well as the expression of ERα and ERβ in the skin and hypothalamus were increased (P<0.05). CONCLUSION Moxibustion at "Guanyuan" (CV4) reduces the body mass of ovariectomized rats by enhancing the synthesis of extragonadal E₂ and increasing the expression of ER in the skin and hypothalamus, yet it does not alleviate uterine atrophy.
Animals ; Female ; Moxibustion ; Rats ; Ovariectomy ; Acupuncture Points ; Rats, Sprague-Dawley ; Humans ; Receptors, Estrogen/genetics* ; Estrogens/metabolism* ; Estradiol/metabolism* ; Hypothalamus/metabolism* ; Follicle Stimulating Hormone/blood* ; Aromatase/genetics* ; Luteinizing Hormone/blood* ; Skin/metabolism*

BACKGROUND: In the interim analysis of MONARCH plus, adding abemaciclib to endocrine therapy (ET) improved progression-free survival (PFS) and objective response rate (ORR) in predominantly Chinese postmenopausal women with HR+/HER2- advanced breast cancer (ABC). This study presents the final pre-planned PFS analysis. METHODS: In the phase III MONARCH plus study, postmenopausal women in China, India, Brazil, and South Africa with HR+/HER2- ABC without prior systemic therapy in an advanced setting (cohort A) or progression on prior ET (cohort B) were randomized (2:1) to abemaciclib (150 mg twice daily [BID]) or placebo plus: anastrozole (1.0 mg/day) or letrozole (2.5 mg/day) (cohort A) or fulvestrant (500 mg on days 1 and 15 of cycle 1 and then on day 1 of each subsequent cycle) (cohort B). The primary endpoint was PFS of cohort A. Secondary endpoints included cohort B PFS (key secondary endpoint), ORR, overall survival (OS), safety, and health-related quality of life (HRQoL). RESULTS: In cohort A (abemaciclib: n  = 207; placebo: n  = 99), abemaciclib plus a non-steroidal aromatase inhibitor improved median PFS vs . placebo (28.27 months vs . 14.73 months, hazard ratio [HR]: 0.476; 95% confidence interval [95% CI]: 0.348-0.649). In cohort B (abemaciclib: n  = 104; placebo: n  = 53), abemaciclib plus fulvestrant improved median PFS vs . placebo (11.41 months vs . 5.59 months, HR: 0.480; 95% CI: 0.322-0.715). Abemaciclib numerically improved ORR. Although immature, a trend toward OS benefit with abemaciclib was observed (cohort A: HR: 0.893, 95% CI: 0.553-1.443; cohort B: HR: 0.512, 95% CI: 0.281-0.931). The most frequent grade ≥3 adverse events in the abemaciclib arms were neutropenia, leukopenia, anemia (both cohorts), and lymphocytopenia (cohort B). Abemaciclib did not cause clinically meaningful changes in patient-reported global health, functioning, or most symptoms vs . placebo. CONCLUSIONS: Abemaciclib plus ET led to improvements in PFS and ORR, a manageable safety profile, and sustained HRQoL, providing clinical benefit without a high toxicity burden or reduced quality of life. TRIAL REGISTRATION ClinicalTrials.gov (NCT02763566).
Humans ; Female ; Fulvestrant/therapeutic use* ; Breast Neoplasms/metabolism* ; Aminopyridines/therapeutic use* ; Benzimidazoles/therapeutic use* ; Middle Aged ; Aromatase Inhibitors/therapeutic use* ; Aged ; Receptor, ErbB-2/metabolism* ; Adult ; Letrozole/therapeutic use* ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Anastrozole/therapeutic use*

OBJECTIVE: This study aimed to compare 9 perfluoroalkyl sulfonic acids (PFSA) with carbon chain lengths (C4-C12) to inhibit human placental 3β-hydroxysteroid dehydrogenase 1 (3β-HSD1), aromatase, and rat 3β-HSD4 activities. METHODS: Human and rat placental 3β-HSDs activities were determined by converting pregnenolone to progesterone and progesterone secretion in JEG-3 cells was determined using HPLC/MS-MS, and human aromatase activity was determined by radioimmunoassay. RESULTS: PFSA inhibited human 3β-HSD1 structure-dependently in the order: perfluorooctanesulfonic acid (PFOS, half-maximum inhibitory concentration, IC ₅₀: 9.03 ± 4.83 μmol/L) > perfluorodecanesulfonic acid (PFDS, 42.52 ± 8.99 μmol/L) > perfluoroheptanesulfonic acid (PFHpS, 112.6 ± 29.39 μmol/L) > perfluorobutanesulfonic acid (PFBS) = perfluoropentanesulfonic acid (PFPS) = perfluorohexanesulfonic acid (PFHxS) = perfluorododecanesulfonic acid (PFDoS) (ineffective at 100 μmol/L). 6:2FTS (1H, 1H, 2H, 2H-perfluorooctanesulfonic acid) and 8:2FTS (1H, 1H, 2H, 2H-perfluorodecanesulfonic acid) did not inhibit human 3β-HSD1. PFOS and PFHpS are mixed inhibitors, whereas PFDS is a competitive inhibitor. Moreover, 1-10 μmol/L PFOS and PFDS significantly reduced progesterone biosynthesis in JEG-3 cells. Docking analysis revealed that PFSA binds to the steroid-binding site of human 3β-HSD1 in a carbon chain length-dependent manner. All 100 μmol/L PFSA solutions did not affect rat 3β-HSD4 and human placental aromatase activity. CONCLUSION Carbon chain length determines inhibitory potency of PFSA on human placental 3β-HSD1 in a V-shaped transition at PFOS (C8), with inhibitory potency of PFOS > PFDS > PFHpS > PFBS = PFPS = PFHxS = PFDoS = 6:2FTS = 8:2FTS.
Humans ; Pregnancy ; Female ; Rats ; Animals ; Placenta ; Progesterone/pharmacology* ; Aromatase/pharmacology* ; Cell Line, Tumor ; Fluorocarbons ; Alkanesulfonic Acids ; Structure-Activity Relationship ; Hydroxysteroid Dehydrogenases/pharmacology*

Peripheral precocious puberty(PPP),also known as puberty independent from hypothalamic-pituitary axis activation,is stimulated by hormones from other sources, with only partial sexual characteristics development but without mature sexual function. The secondary sexual characteristics development occurs before 7.5 years of age in girls and before 9 years of age in boys. Clinical manifestations are diverse, and PPP has varied etiology including congenital adrenal hyperplasia, McCune-Albright syndrome, ovarian cyst, adrenal tumor, ovarian tumor, testicular tumor, human chorionic gonadotropin producing tumor, familial male precocious puberty, aromatase excess syndrome, and environmental estrogen. Early identification of etiology, accurate differential diagnosis and prenatal gene screening play a significant role in the prevention, diagnosis and treatment of the disease.
Female ; Humans ; Male ; Child ; Puberty, Precocious/therapy* ; Fibrous Dysplasia, Polyostotic/complications* ; Aromatase

Objective: To compare the effect of different endocrine therapy drugs on liver function in patients with early breast cancer. Methods: A retrospective cohort study was conducted to include 4 318 patients with early breast cancer who received adjuvant endocrine therapy in Department of Breast Surgery, Peking Union Medical College Hospital from January 1, 2013 to December 31, 2021. All the patients were female, aged (51.2±11.3) years (range: 20 to 87 years), including 1 182 patients in the anastrozole group, 592 patients in the letrozole group, 332 patients in the exemestane group, and 2 212 patients in the toremifene group. The mixed effect model was used to analyze and compare the liver function levels of patients at baseline, 6, 12, 18, 24, 36, 48, 60 months of medication, and 1 year after drug withdrawal among the three aromatase inhibitors (anastrozole, letrozole, exemestane) and toremifene. Results: ALT and AST of the 4 groups were significantly higher than the baseline level at 6 months (all P<0.01), and there were no significant differences in total bilirubin, direct bilirubin and AST levels among all groups one year after drug withdrawal (P: 0.538, 0.718, 0.061, respectively). There was no significant difference in the effect of all groups on AST levels (F=2.474, P=0.061), and in the effect of three aromatase inhibitors (anastrozole, letrozole, and exemestane) on ALT levels (anastrozole vs. letrozole, P=0.182; anastrozole vs. exemestane, P=0.535; letrozole vs. exemestane, P=0.862). Anastrozole and letrozole had significantly higher effects on ALT levels than toremifene (P<0.01, P=0.009). The proportion of abnormal liver function in each group increased significantly at 6 months compared with baseline, and then the proportion showed a decreasing trend over time. Conclusions: Three aromatase inhibitors (anastrozole, letrozole, and exemestane) and toremifene can significantly increase the level of ALT and AST in patients with breast cancer, and the levels can gradually recover to the baseline after 1 year of drug withdrawal. The effect of non-steroidal aromatase inhibitors (anastrozole, letrozole) on ALT levels is greater than toremifene.
Female ; Humans ; Anastrozole ; Aromatase Inhibitors/therapeutic use* ; Bilirubin ; Breast Neoplasms/drug therapy* ; Letrozole ; Liver ; Retrospective Studies ; Toremifene ; Young Adult ; Adult ; Middle Aged ; Aged ; Aged, 80 and over

Endocrine therapy is one of the primary treatment methods for hormone receptor-positive breast cancer patients. As of June 1 2023, the National Medical Product Administration has approved 56 drugs related to endocrine therapy in patients with HR+ /HER-2- breast cancer (including generic drugs that have passed the consistency evaluation), including 44 endocrine drugs which can be categorized according to their mechanisms of action into selective estrogen receptor modulators, selective estrogen receptor down-regulators, aromatase inhibitors, luteinizing hormone-releasing hormone analogs, and progestogens and 12 targeted drugs for combined with endocrine therapy, including CDK4/6 inhibitors, mTOR inhibitors, and HDAC inhibitors. The different pharmacological characteristics, mechanisms of action, and long-term medication factors of breast cancer endocrine therapy-related drugs can directly affect patients' medication adherence and medication safety. To standardize the pharmaceutical care of endocrine therapy drugs for breast cancer and promote rational use in clinical settings, the Oncology Specialty Pharmacist Subcommittee, in conjunction with multidisciplinary experts nationwide, has developed the "Guidelines for pharmaceutical care of endocrine therapy drugs for breast cancer (2023 edition)". The guidelines is based on clinical evidence-based evidence, relevant regulations of pharmaceutical management, and pharmaceutical care practices. The Delphi method and expert interviews were used to formulate the guidelines. The GRADE approach was used for assessing the certainty of evidence. This guideline mainly focuses on endocrine therapy for HR+ /HER-2- breast cancer patients. Due to space constraints, HER-2 positive targeted drugs were not included in the guideline. It covers 6 dimensions and 22 key problems of pharmaceutical care in the whole process of drug therapy, providing a scientific basis for pharmacists to carry out pharmaceutical care of such drugs.
Humans ; Female ; Breast Neoplasms/drug therapy* ; Aromatase Inhibitors/therapeutic use* ; Receptors, Estrogen

Aromatase deficiency (AD) is a rare autosomal recessive genetic disease caused by loss-of-function mutations in aromatase gene (CYP19A1), leading to congenital estrogen deficiency syndrome. Both mothers of AD patients during pregnancy and female AD fetus show virilization, while male patients are usually diagnosed in adulthood due to continued height increase and metabolic abnormalities. In 2019, a patient with AD was admitted in the Second Xiangya Hospital. The patient was a 37-year-old adult male who continued to grow linearly after adulthood. His estradiol was below the measurable line, the follicle-stimulating hormone (FSH) increased, bone age delayed, epiphysis unfused, and the bone mass reduced. CYP19A1 gene detection showed that c.1093C>T, p.R365W was homozygous mutation. This disease is rare in clinic. Clinicians need to raise awareness of the disease for early diagnosis and treatment to improve the long-term prognosis of patients.
46, XX Disorders of Sex Development/genetics* ; Adult ; Aromatase/metabolism* ; Female ; Gynecomastia/genetics* ; Humans ; Infertility, Male ; Male ; Metabolism, Inborn Errors ; Mutation ; Pregnancy

OBJECTIVE: To assess the efficacy and safety of aromatase inhibitors (AIs) combined growth hormone in treatment of adolescent boys with short stature. METHODS: One hundred and fifty-one short stature pubertal boys with age of 10-14 years and bone age of 13-15 years, who were admitted to the Department of Pediatrics, the First Affiliated Hospital, Zhejiang University School of Medicine, were included in this trial. According to their own or parents' intention, the children were divided into recombinant human growth hormone (rhGH)+AI group ( =108) and rhGH group ( =43). All children were injected subcutaneously with rhGH 0.15-0.2 IU·kg ·d , and those in rhGH+AI group were additionally given 2.5 mg/d letrozole or 1 mg/d anastrozole, orally for 12 months or longer. The children were followed-up every 3 months. During the follow-up visit, the predicted adult height (PAH), sex hormone level, glucose and lipid metabolism, and other indicators were measured, and adverse reactions were monitored. RESULTS: After intervention, there were significant differences in ΔBA(bone age)/ΔCA(chronological age), ΔHtSDS (height standard deviation score based on bone age)and ΔPAH between rhGH+AI group and the rhGH group( < 0.05 or < 0.01). During follow-up, 63.9%of the children in the rhGH+AI group had elevated uric acid and 51.9%had decreased high-density lipoprotein (HDL); 25.9%showed severe acne, excitement, hyperactivity and irritability, 11.1%had knee pain; 4.6%had fracture; 2.8%had mild renal dysfunction; 1.9%had inactivity, drowsiness, memory loss and performance decline; 1.9%showed mild abnormal liver function; 0.9%showed impaired fasting glucose; 0.9%showed granulocytopenia. In the rhGH group, 11.6%of the children presented with knee pain and 2.3%with impaired fasting glucose. CONCLUSIONS AI combined with rhGH can delay the growth of BA and effectively improve the PAH of adolescent boys with larger bone age. However, the occurrence of adverse reactions of AI should be closely monitored during treatment.
Adolescent ; Aromatase Inhibitors ; therapeutic use ; Body Height ; Child ; Growth Disorders ; Human Growth Hormone ; Humans ; Male ; Recombinant Proteins

OBJECTIVE: To evaluate the efficacy and safety of the third-generation aromatase inhibitor letrozole in the treatment of McCune-Albright syndrome (MAS) girls with peripheral precocious puberty. METHODS: Twenty-one MAS girls with peripheral precocious puberty treated in Pediatrics Department of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine from March 2012 to June 2017 were enrolled in the study. Patients presented with repeated vaginal bleeding, premature breast enlargement, café-au-lait spots or dysplasia of bone fibers, and low levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH); and the congenital adrenal hyperplasia, estrogen-producing tumors, and exogenous estrogen intake were excluded. Letrozole were administrated at a dose of 0.5-2 mg·m ·d for 6 to 12 months. The patients were observed for changes in breast staging, vaginal bleeding, sex hormone levels, liver function and bone age changes, and changes in uterine and ovarian volume. RESULTS: After treatment, bone age/chronological age (BA/CA)was decreased from 1.23±0.30 to 1.11±0.18 ( < 0.01); the predicted adult height (PAH) increased from (156.2±5.9)cm to (158.4±2.1)cm after treatment ( < 0.05); the vaginal bleeding was reduced and the estradiol level decreased, while the teststosterone level and the uterus showed no significant increase, and no adverse reactions such as ovarian torsion and abnormal liver function were observed. CONCLUSIONS Precocious puberty is one of the most common endocrine manifestations in MAS. Our findings suggest that letrozole may be an effective and safe therapy to precocious puberty in girls with McCune-Albright Syndrome.
Aromatase Inhibitors ; Child ; China ; Female ; Fibrous Dysplasia, Polyostotic ; Humans ; Letrozole ; Puberty, Precocious

Aromatase is the rate-limiting enzyme in estrogen biosynthesis. The third generation aromatase inhibitors (AIs), represented by letrozoleand and anastrozole, can combine with aromatase, effectively reducing the estrogen level in the body. Because of its high efficiency, selectivity and reversibility, it has been used in the treatment of McCune-Albright syndrome, familial male-limited precocious puberty, gynecomastia, and adolescent boy with short stature. The good efficacy and safety of AIs have been observed. However, so far the drug instructions of AIs usually do not show indications for children; there are risks of adverse reactions involving liver and kidney function, lipid metabolism, hyperandrogenemia and bone metabolism; especially the long-term effects on reproductive system and bone metabolism are still not clear. Therefore, it is necessary to prescribe it carefully and follow up closely. It was not recommended that AIs be routinely used to improve adult height of adolescent boy with short stature. And more clinical evidences are needed for the safety and effectiveness of AIs prescribed in pediatrics.
Adolescent ; Aromatase Inhibitors ; therapeutic use ; Child ; Estrogens ; Humans ; Male ; Puberty, Precocious