Diagnosis and Clinical Features of Perianal Lesions in Newly Diagnosed Crohn's Disease: Subgroup Analysis from Inception Cohort Registry Study of Patients with Crohn's Disease (iCREST-CD).

BACKGROUND AND AIMS: Perianal lesion is a refractory phenotype of Crohn's disease [CD] with significantly diminished quality of life. We evaluated the clinical characteristics of perianal lesions in newly diagnosed CD patients and the impact of perianal lesions on the quality of life in Japanese patients with CD. METHODS: Patients newly diagnosed with CD after June 2016 were included between December 2018 and June 2020 from the Inception Cohort Registry Study of Patients with CD [iCREST-CD]. RESULTS: Perianal lesions were present in 324 [48.2%] of 672 patients with newly diagnosed CD; 71.9% [233/324] were male. The prevalence of perianal lesions was higher in patients aged <40 years vs ≥40 years, and it decreased with age. Perianal fistula [59.9%] and abscess [30.6%] were the most common perianal lesions. In multivariate analyses, male sex, age <40 years and ileocolonic disease location were significantly associated with a high prevalence of perianal lesions, whereas stricturing behaviour and alcohol intake were associated with low prevalence. Fatigue was more frequent [33.3% vs 21.6%] while work productivity and activity impairment-work time missed [36.3% vs 29.5%] and activity impairment [51.9% vs 41.1%] were numerically higher in patients with than those without perianal lesions. CONCLUSIONS: At the time of CD diagnosis, approximately half of the patients had perianal lesions; perianal abscesses and perianal fistulas were the most common. Young age, male sex, disease location and behaviour were significantly associated with the presence of perianal lesions. The presence of perianal lesion was associated with fatigue and impairment of daily activities. CLINICAL TRIALS REGISTRY: University Hospital Medical Information Network Clinical Trials Registry System [UMIN-CTR, UMIN000032237].

[A Case of Breast Cancer Complicated by Fibrous Dysplasia That Was Difficult to Differentiate from Bone Metastasis].

A 58-year-old woman with HER2-negative hormone-sensitive postmenopausal breast cancer underwent preoperative bone scintigraphy and CT to search for distant metastasis. Bone metastasis was suspected in the spinous process of the seventh cervical vertebra. MRI revealed a mass that was hypointense on T1- and T2-weighted images and hyperintense on diffusion- weighted images, with intense contrast enhancement, indicating bone metastasis at cT1N0M1, Stage Ⅳ(M: OSS). The patient underwent partial mastectomy and sentinel lymph node biopsy. The postoperative diagnosis was pT2N0cM1, Stage Ⅳ, with the status of bone metastasis being key to staging. PET-CT showed uptake in the spinous process of the seventh cervical vertebra but no other metastatic findings. However, solitary bone metastasis to the cervical spinous process is atypical. CT-guided needle biopsy confirmed benign fibrous dysplasia, and the final diagnosis was breast cancer at pT2N0M0, Stage ⅡA. Fibrous dysplasia is characterized by impaired osteogenesis leading to fibroplasia and commonly occurs in the skull, jaw bones, ribs, and limbs. Solitary fibrous dysplasia in the cervical spinous process is rare. The lesion was asymptomatic and pathologically benign, requiring no treatment. The patient underwent postoperative radiation therapy for the conserved breast and is followed up with endocrine therapy.

[A Case of Breast Cancer Brain Metastases Successfully Treated with Pembrolizumab Therapy after Disease Progression with Atezolizumab Therapy].

A 39-year-old woman was diagnosed with right breast cancer(cT3N1M0, cStage ⅢA, triple negative type). After preoperative chemotherapy using dose-dense doxorubicin and cyclophosphamide, followed by dose-dense paclitaxel every 2 weeks, the patient underwent right modified radical mastectomy. Postmastectomy radiotherapy to the right chest wall and right supraclavicular area and oral capecitabine therapy were administered. Computed tomography 1 year after surgery showed multiple lung metastases. The patient received atezolizumab and nab-paclitaxel therapy. Six months after the first chemotherapy, metastatic brain tumor in right frontal lobe, 12 mm in size, was observed along with enlargement of lung metastases. Because the brain tumor showed rapid growth after CyberKnife therapy, emergency tumorectomy was performed. One month after cranial surgery, new 3 brain metastases were appeared. Gamma knife therapy to brain metastases and pembrolizumab, carboplatin, gemcitabine therapy was started. Although insufficient doses of carboplatin and gemcitabine were administered due to bone marrow suppression, no progression was observed for about 1 year after initiation of pembrolizumab therapy. Pembrolizumab therapy may show anti-tumor effect to breast cancer brain metastases, even after a failure of atezolizumab therapy.

Characteristics of adult patients newly diagnosed with Crohn's disease: interim analysis of the nation-wide inception cohort registry study of patients with Crohn's disease in Japan (iCREST-CD).

BACKGROUND: The Inception Cohort Registry Study of Patients with Crohn's Disease aimed to clarify clinical characteristics and disease course of newly diagnosed Crohn's disease patients in Japan throughout a 4-year period. Results from an interim analysis of the largest nation-wide registry study that covers approximately 1% of Crohn's disease patient population in Japan are reported. METHODS: This prospective, observational registry study was conducted at 19 tertiary centers in Japan. Patients newly diagnosed with Crohn's disease after June 2016 (age ≥ 16 years at informed consent) were enrolled between December 17, 2018 and June 30, 2020. Patient demographics, diagnostic procedures and categories, disease location and lesion behavior (Montreal classification) at the time of diagnosis were recorded. RESULTS: Of 673 patients enrolled, 672 (99.9%) were analyzed (458: men, 214: women), male-to-female ratio: 2.1, median age at diagnosis 25 (range 13-86) years; peak age of disease diagnosis: 20-24 years. Most common disease location was L3 (ileocolonic; 60.1%). Non-stricturing, non-penetrating (B1) disease was most common behavior (62.8%); 48.9% reported perianal lesions. Notably, age-wise analysis revealed disease phenotypes varied between patients aged < 40 and ≥ 40 years in terms of male-to-female ratio (2.5/1.3)/disease location (L3: 66.3%/37.0%)/disease behavior (B1: 66.4%/50.0%)/perianal lesion: (55.7%/20.5%) at Crohn's disease diagnosis, respectively. CONCLUSIONS: Interim analysis of this nation-wide Inception Cohort Registry Study of Patients with Crohn's Disease revealed the demographics and disease characteristics of newly diagnosed Crohn's disease patients in Japan and demonstrated that disease phenotype varied between patients aged < 40 and ≥ 40 years, serving as important information for management of individual patients.

[A Case of Intraductal Papilloma of the Male Breast].

Male breast cancer accounts for approximately 1% of the overall incidence of breast cancer. We report a rare case of intraductal papilloma(intracystic papilloma)in a 73-year-old man, which was suspected to be breast cancer as it presented as an approximately 6 cm mass below the left nipple in various imaging studies. The patient was aware of a mass measuring a few millimeters below the left nipple for 5 years, but had not sought treatment. He visited our department 3 months after redness and pain were noted around the nipple; the mass had enlarged. Palpation revealed a 6 cm smooth-surfaced mass as well as nipple retraction; diagnostic imaging showed a cystic tumor with a solid internal structure. Fine-needle aspiration cytology and core needle biopsy did not indicate a definitive diagnosis, and a left mastectomy and sentinel lymph node biopsy were performed based on a preoperative diagnosis of breast cancer. Pathological examination confirmed the diagnosis of intraductal papilloma, based on findings such as infarction-induced hemorrhagic necrosis, stromal and epithelial proliferation, apocrine metaplasia, and squamous epithelial metaplasia. Reports of a large-diameter intraductal papilloma(intracystic papilloma)suspicious for breast cancer in men are rare; therefore, surgical resection and detailed histopathological exploration of the whole tumor were required.

[A Case of Primary Acinic Cell Carcinoma of the Breast].

Acinic cell carcinoma(ACC)is an invasive malignancy primarily characterized by proliferation of tumor cells that resemble acinar cells of the salivary glands and pancreas. ACC of the mammary glands is rare. We report a case of primary ACC of the breast. Two masses were revealed in the left mammary gland of a 57-year-old woman who visited our hospital through screening mammography. The lesions were identified as synchronous multiple breast carcinoma of 2 different histological types; ACC and tubulolobular carcinoma. For treatment, left mastectomy and sentinel lymph node biopsy were performed, followed by postoperative chemotherapy and endocrine therapy. Hematoxylin-eosin staining of ACC revealed abundant acinar- like structures formed by tumor cells with prominent eosinophilic granules in the cytoplasm. Immunostaining was positive for S-100 protein, α1-antichymotrypsin, α1-antitrypsin, and lysozyme. The tumor cells were negative for estrogen, progesterone, and HER2 receptors, which indicated that they had a triple-negative phenotype. Although primary ACC of the breast is regarded as low-grade triple-negative breast carcinoma with a favorable prognosis, further accumulation of cases may be needed to elucidate the biological features of ACC and investigate appropriate therapeutic strategies.

[Importance of Local Therapy for Oligometastatic Breast Cancer-A Case Report].

A case of successful local treatment for metachronous oligometastases to the lung and mediastinal lymph nodes in a postmenopausal woman with breast cancer is presented. A 44-year-old woman underwent partial mastectomy and left axillary lymph node dissection for right breast cancer. Thirteen years and 3 months after the operation, she was referred to our hospital for a right lung mass detected by mass screening and diagnosed with a metastatic lung tumor from left breast cancer following CT-guided biopsy. She was simultaneously diagnosed with right breast cancer, and pulmonary metastasectomy, right partial mastectomy, and sentinel lymph node biopsy were performed. Two years after the second operation, follow-up CT showed a swollen lymph node at the pre-tracheal space, and endobronchial ultrasound-guided transbronchial needle aspiration confirmed the diagnosis of metastatic breast cancer. The mediastinal lymph node metastasis showed no change in size for 2 years and 7 months with fulvestrant therapy, and no other metastases were found. Proton beam therapy of 60 GyE in 30 fractions was administered to the metastatic lymph node. Substantial tumor shrinkage with no severe toxicity was observed, and to date, the patient has remained disease-free. More cases need to be studied to investigate the appropriate strategy for local therapy in patients with oligometastatic breast cancer.

Durable clinical benefit of letrozole in leptomeningeal metastasis of breast cancer.

A case of a woman in her 60s with breast cancer, whose leptomeningeal metastasis (LM) of breast cancer improved remarkably with letrozole monotherapy, is reported. The patient complained of numbness of her left hand and hoarseness, followed by progressive asymmetric extremity weakness and a bladder and rectal disturbance. The patient had undergone surgery for left breast cancer 18 years earlier and was concerned about recurrence of breast cancer, but there were no typical findings with some imaging modalities. The third lumbar puncture showed the malignant cytology of breast cancer, and the patient was diagnosed with recurrent breast cancer. Her performance status was very poor, and it was difficult to administer systemic chemotherapy. Letrozole was started because immunohistochemistry was positive for estrogen and progesterone receptors. After 4 months of letrozole therapy, the symptoms improved gradually. LM has a poor prognosis, and there is little evidence on which to base treatment, but hormone therapy may be an option for LM when the tumor is hormone receptor-positive, slow growing, and has a small volume.

Efficacy and safety of ustekinumab in Japanese patients with moderately to severely active Crohn's disease: a subpopulation analysis of phase 3 induction and maintenance studies.

BACKGROUND/AIMS: Efficacy and safety of ustekinumab were evaluated in a Japanese subpopulation with moderately to severely active Crohn's disease (CD) in UNITI-1, UNITI-2 and IM-UNITI studies and results were compared with the overall population. METHODS: Overall, patients in UNITI-1 (Japan, n=56; failed response to tumor necrosis factor antagonist) and UNITI-2 (Japan, n=26; failed response to prior conventional therapy) were randomized to placebo or ustekinumab intravenous induction (130 mg or ~6 mg/kg) at week 0. Responders to ustekinumab induction therapy (Japan, n=21) were randomized to placebo or ustekinumab (90 mg, subcutaneous) maintenance (every 12 weeks [q12w] or 8 weeks [q8w]) in IM-UNITI. The primary endpoint was clinical response at week 6 for induction studies and clinical remission at week 44 for maintenance study. RESULTS: Percentage of patients achieving clinical response at week 6 was greater in ustekinumab 130 mg and ~6 mg/kg groups than in the placebo group (UNITI-1: 36.8% and 31.6% vs. 27.8%, respectively, for Japanese; 34.3% and 33.7% vs. 21.5%, respectively, for overall; UNITI-2: 37.5% and 55.6% vs. 11.1%, respectively, for Japanese; 51.7% and 55.5% vs. 28.7%, respectively, for overall). Clinical remission rate at week 44 during maintenance was greater in the ustekinumab 90 mg SC q12w and q8w groups than in the placebo group (50.0% and 55.6% vs. 25.0%, respectively, for Japanese; 48.8% and 53.1% vs. 35.9%, respectively, for overall). Efficacy and safety results observed in the Japanese subpopulation were generally consistent with those in the overall population. CONCLUSIONS: Ustekinumab could be considered as a new therapeutic option for moderately to severely active CD in Japanese patients. Both ustekinumab induction and maintenance treatments were generally well tolerated (Clinical Trial Registration: NCT01369329, NCT01369342, NCT01369355).

Liver resection for HER2-enriched breast cancer metastasis: case report and review of the literature.

Liver metastasis from breast cancer usually results in the development of systemic metastasis. We report a breast cancer patient with an early isolated liver recurrence who survived more than 7 years with no recurrence. She was treated with aggressive HER2-directed chemotherapy and hepatic metastasectomy. Local hepatectomy with effective medical oncological therapy with curative intent is worth trying in patients with breast cancer liver metastasis.

Correlation between Ultrasound Findings of Tumor Margin and Clinicopathological Findings in Patients with Invasive Ductal Carcinoma of the Breast.

BACKGROUND: Breast ultrasound findings regarding tumor margins are crucial in judging whether a tumor is malignant or benign. However, the relationships between the margins and clinicopathological characteristics remain largely unknown. In this study, we examined the clinicopathological characteristics of patients with invasive ductal carcinoma whose ultrasound images showed either well-defined and rough or indistinct margins. METHODS: Of all consecutive patients diagnosed with invasive ductal carcinoma at the Division of Breast and Endocrine Surgery of Tottori University Hospital from January 2012 to December 2014, 122 patients whose ultrasound images showed either "well-defined and rough" or "indistinct" tumor margins were included in this study. Mammography and ultrasound images taken at the initial examination were reviewed. Patients were divided into two groups based on ultrasound findings of the tumor margins: the "well-defined and rough group" and the "indistinct group." The relationships among ultrasound findings, mammography findings and clinicopathological findings were investigated in the two groups. RESULTS: The well-defined and rough group was more likely to contain solid-tubular carcinoma, while the indistinct group was more likely to contain scirrhous carcinoma. The MIB-1 index was higher in the well-defined and rough group than in the indistinct group. Additionally, the proportion of patients with nuclear grade 3, estrogen receptor-negative/progesterone receptor-negative, and triple-negative breast cancer was greater in the well-defined and rough group than in the indistinct group. CONCLUSION: Invasive ductal carcinomas with well-defined and rough margins on ultrasound were likely to be malignant and proliferative than those with indistinct margins.

[A case of recurrent breast cancer with brain metastases successfully treated with vinorelbine and anastrozole after multiple chemo-endocrine therapies].

We report a case of recurrent hormone receptor-positive breast cancer with brain metastases that showed good response to vinorelbine(VNR)and anastrozole(ANA). A 49-year-old woman with a history of left breast cancer had initially undergone modified radical mastectomy, but was diagnosed with lung metastases 8 years postoperatively. Despite treatment with docetaxel and tamoxifen, multiple brain metastases were detected 10 years postoperatively. To achieve prompt improvement of neurological symptoms, surgical resection was performed for two large brain foci. Stereotactic radiosurgery using a gamma- knife was applied for the remaining multiple brain metastases. Histological examination identified the brain tumors as estrogen receptor-positive, HER2-negative metastatic breast cancer. Despite the use of cyclophosphamide, adriamycin and 5- fluorouracil(CAF therapy)and capecitabine, brain metastases recurred twice along with pleuritis carcinomatosis and bone metastasis. In addition to gamma-knife re-treatment, therapy was started with VNR and ANA. All metastatic sites including brain showed a good response to therapy with few adverse reactions, and no recurrence has been observed over 3 years.

Transcriptional responses of host peripheral blood cells to tuberculosis infection.

Host responses following exposure to Mycobacterium tuberculosis (TB) are complex and can significantly affect clinical outcome. These responses, which are largely mediated by complex immune mechanisms involving peripheral blood cells (PBCs) such as T-lymphocytes, NK cells and monocyte-derived macrophages, have not been fully characterized. We hypothesize that different clinical outcome following TB exposure will be uniquely reflected in host gene expression profiles, and expression profiling of PBCs can be used to discriminate between different TB infectious outcomes. In this study, microarray analysis was performed on PBCs from three TB groups (BCG-vaccinated, latent TB infection, and active TB infection) and a control healthy group. Supervised learning algorithms were used to identify signature genomic responses that differentiate among group samples. Gene Set Enrichment Analysis was used to determine sets of genes that were co-regulated. Multivariate permutation analysis (p < 0.01) gave 645 genes differentially expressed among the four groups, with both distinct and common patterns of gene expression observed for each group. A 127-probeset, representing 77 known genes, capable of accurately classifying samples into their respective groups was identified. In addition, 13 insulin-sensitive genes were found to be differentially regulated in all three TB infected groups, underscoring the functional association between insulin signaling pathway and TB infection.

Early transcriptional responses of HepG2-A16 liver cells to infection by Plasmodium falciparum sporozoites.

Invasion of hepatocytes by Plasmodium sporozoites deposited by Anopheles mosquitoes, and their subsequent transformation into infective merozoites is an obligatory step in the initiation of malaria. Interactions between the sporozoites and hepatocytes lead to a distinct, complex and coordinated cellular and systemic host response. Little is known about host liver cell response to sporozoite invasion, or whether it is primarily adaptive for the parasite, for the host, or for both. Our present study used gene expression profiling of human HepG2-A16 liver cells infected with Plasmodium falciparum sporozoites to understand the host early cellular events and factors influencing parasite infectivity and sporozoite development. Our results show that as early as 30 min following wild-type, non-irradiated sporozoite exposure, the expressions of at least 742 genes was selectively altered. These genes regulate diverse biological functions, such as immune processes, cell adhesion and communications, metabolism pathways, cell cycle regulation, and signal transduction. These functions reflect cellular events consistent with initial host cell defense responses, as well as alterations in host cells to sustain sporozoites growth and survival. Irradiated sporozoites gave very similar gene expression pattern changes, but direct comparative analysis between liver gene expression profiles caused by irradiated and non-irradiated sporozoites identified 29 genes, including glypican-3, that were specifically up-regulated only in irradiated sporozoites. Elucidating the role of this subset of genes may help identify the molecular basis for the irradiated sporozoites inability to develop intrahepatically, and their usefulness as an immunogen for developing protective immunity against pre-erythrocytic stage malaria.

CJ-023,423, a novel, potent and selective prostaglandin EP4 receptor antagonist with antihyperalgesic properties.

The prostaglandin (PG) EP(4) receptor subtype is expressed by peripheral sensory neurons. Although a potential role of EP(4) receptor in pain has been suggested, a limited number of selective ligands have made it difficult to explore the physiological functions of EP(4) or its potential as a new analgesic target. Here, we describe the in vitro and in vivo pharmacology of a novel EP(4) receptor antagonist, N-[({2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl) phenyl]ethyl}amino) carbonyl]-4-methylbenzenesulfonamide (CJ-023,423). In vitro, CJ-023,423 inhibits [(3)H]PGE(2) binding to both human and rat EP(4) receptors with K(i) of 13 +/- 4 and 20 +/- 1 nM, respectively. CJ-023,423 is highly selective for the human EP(4) receptor over other human prostanoid receptor subtypes. It also inhibits PGE(2)-evoked elevation in intracellular cAMP at the human and rat EP(4) receptors with pA(2) of 8.3 +/- 0.03 and 8.2 +/- 0.2 nM, respectively. In vivo, oral administration of CJ-023,423 significantly reduces thermal hyperalgesia induced by intraplantar injection of PGE(2) (ED(50) = 12.8 mg/kg). CJ-023,423 is also effective in models of acute and chronic inflammatory pain. CJ-023,423 significantly reduces mechanical hyperalgesia in the carrageenan model. Furthermore, CJ-023,423 significantly reverses complete Freund's adjuvant-induced chronic inflammatory pain response. Taken together, the present data indicate that CJ-023,423, a highly potent and selective antagonist of both human and rat EP(4) receptors, produces antihyperalgesic effects in animal models of inflammatory pain. Thus, specific blockade of the EP(4) receptor signaling may represent a novel therapeutic approach for the treatment of inflammatory pain.

Coactivation of liver receptor homologue-1 by peroxisome proliferator-activated receptor gamma coactivator-1alpha on aromatase promoter II and its inhibition by activated retinoid X receptor suggest a novel target for breast-specific antiestrogen therapy.

Aromatase inhibitors target the production of estrogen in breast adipose tissue, but in doing so, also decrease estrogen formation in bone and other sites, giving rise to deleterious side effects, such as bone loss and arthralgia. Thus, it would be clinically useful to selectively inhibit aromatase production in breast. In this regard, we have determined that the orphan nuclear receptor liver receptor homologue-1 (LRH-1) is a specific transcriptional activator of aromatase gene expression in human breast preadipocytes but not in other tissues of postmenopausal women. In this study, we show that the coactivator peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) is a physiologically relevant modulator of LRH-1, and that its transcriptional activity can be inhibited effectively using receptor-interacting peptide antagonists that prevent PGC-1alpha recruitment. Interestingly, we note that all of these peptides also interact in an agonist-dependent manner with retinoid X receptor alpha (RXRalpha), suggesting that these two receptors may compete for limiting cofactors within target cells. In support of this hypothesis, we show that 9-cis-retinoic acid, acting through RXR, inhibits both the basal and PGC-1alpha-induced transcriptional activity of LRH-1. The importance of this finding was confirmed by showing that LRH-1-dependent, PGC-1alpha-stimulated regulation of aromatase gene expression in primary human breast preadipocytes was effectively suppressed by RXR agonists. We infer from these data that LRH-1 is a bona fide target whose inhibition would selectively block aromatase expression in breast, while sparing other sites of expression.

Differential expression of factors involved in fat metabolism with age and the menopause transition.

OBJECTIVES: Changes in the hormonal milieu at the menopause are associated with an increase in total adiposity and a more android pattern of fat distribution, with the latter associated with an increased risk of the metabolic syndrome. The aim of this study was to explore potential mechanisms that might contribute to the changes in body composition associated with the menopause transition. METHODS: Using real-time PCR analysis, we have compared the expression of various factors involved in fat metabolism in subcutaneous abdominal and gluteal fat in premenopausal (Group 1; n=11), postmenopausal (Group 2; n=10) and postmenopausal women taking estrogen therapy (Group 3; n=10). RESULTS: All subjects were of normal body mass index, euglycemic and normolipemic. The postmenopausal women were older (Group 1, 43.1+5.0 versus Groups 2 and 3, 57.9+/-7.4 years, P<0.001 and 56.1+/-4.5 years, P<0.001, respectively). Expression analysis revealed that levels of transcripts encoding adiponectin, peroxisome proliferator-activated receptor gamma and fatty acid transporter, each associated with insulin sensitivity, were significantly greater in gluteal fat from estrogen deplete postmenopausal women than in fat from the other two groups (P<0.05). In contrast, levels of transcripts for acetyl CoA carboxylase alpha, long chain acyl CoA dehydrogenase and hormone sensitive lipase were significantly greater in abdominal fat from premenopausal women than either postmenopausal groups (P<0.05). CONCLUSIONS: These findings indicate both aging and the menopause transition are associated with changes in fat metabolism, which may contribute to the accumulation of body fat after menopause.

Adipose aromatase gene expression is greater in older women and is unaffected by postmenopausal estrogen therapy.

OBJECTIVE: Although natural menopause is associated with loss of ovarian estrogen production, this life phase is followed by a significant increase in estrogen-related cancers, namely breast and endometrial cancer. These tissues, as well as adipose, skeletal, and vascular tissues and the brain are important sites of postmenopausal estrogen production. Circulating C19 steroid precursors are essential substrates for extragonadal estrogen synthesis; however, the levels of these androgenic precursors decline markedly with advancing age. This implies an increase in capacity for extragonadal tissues to produce estrogen with age. DESIGN: To explore this, and the effects of the menopause transition and postmenopausal estrogen therapy on extragonadal estrogen biosynthesis, we have compared the expression of the aromatase gene and estrogen (ER) and androgen receptors (AR) in subcutaneous abdominal and gluteal fat taken from premenopausal (group 1: n = 11), postmenopausal (group 2: n = 10), and postmenopausal women taking estrogen therapy (group 3: n = 10). All subjects were of normal body mass index, euglycemic, and normolipemic. RESULTS: The postmenopausal women were older (group 1, 43.1 +/- 5.0 vs groups 2 and 3, 57.9 +/- 7.4 years, P < 0.001 and 56.1 +/- 4.5 years, P < 0.001, respectively) and had lower serum estradiol levels (group 2, 22.2 +/- 3.2 vs group 1, 442.5 +/- 248.2 pmol/L, P < 0.05), which were restored to premenopausal levels with estrogen therapy. Expression analysis revealed that levels of transcripts encoding aromatase were greater in gluteal than abdominal depots in each group in postmenopausal versus premenopausal women (P < 0.05). Use of hormone therapy did not influence aromatase gene expression in either depot. No differences were detected in the expression of ER or AR between groups of between tissue depots. CONCLUSION: Thus, the capacity of adipose tissue to produce estrogen seems to increase significantly with age at the time of menopause and to be unaltered by exogenous estrogen therapy. This difference in extragonadal estrogen production with age may play a pivotal role in the increase in estrogen-dependent malignancies in the postmenopausal years.

Dysmetabolic syndrome in a man with a novel mutation of the aromatase gene: effects of testosterone, alendronate, and estradiol treatment.

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 aromatase knockout mouse presents with a sexually dimorphic disruption to cholesterol homeostasis.

The aromatase knockout (ArKO) mouse cannot synthesize endogenous estrogens due to disruption of the Cyp19 gene. We have shown previously, that ArKO mice present with age-progressive obesity and hepatic steatosis, and by 1 yr of age both male and female ArKO mice develop hypercholesterolemia. In this present study 10- to 12-wk-old ArKO mice were challenged for 90 d with high cholesterol diets. Our results show a sexually dimorphic response to estrogen deficiency in terms of cholesterol homeostasis in the liver. ArKO females presented with elevated serum cholesterol; conversely, ArKO males had elevated hepatic cholesterol levels. In response to dietary cholesterol, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase transcript levels were significantly reduced in females, whereas males showed more modest changes. Neither low density lipoprotein nor sterol regulatory element-binding protein expression levels were significantly altered by diet or genotype. The expression of Cyp7a, which encodes cholesterol 7 alpha-hydroxylase, was significantly reduced in ArKO females compared with wild-type females and was increased by cholesterol feeding. Cyp7a expression was significantly elevated in the wild-type males on the high cholesterol diet, although no difference was seen between genotypes on the control diet. The ATP-binding cassette G5 and ATP-binding cassette G8 transporters do not appear to be regulated by estrogen. The expression of acyl-coenzyme A:cholesterol acyltransferase 2 showed a sexually dimorphic response, where estrogen appeared to have a stimulatory effect in females, but not males. This study reveals a sexually dimorphic difference in mouse hepatic cholesterol homeostasis and roles for estrogen in the regulation of cholesterol uptake, biosynthesis, and catabolism in the female, but not in the male.