Effects of progestogens used in menopause hormone therapy on the normal breast and benign breast disease in postmenopausal women.

Hormone replacement therapy in menopause is used to improve climacteric syndrome in women whose quality of life is affected. However, given the wide variety of progestogens available, it is important to evaluate their differential benign changes (radiological, cellular, and clinical) on the breast. This review aimed to determine the different benign changes of progestogens used in postmenopausal combined hormone therapy on the breast (radiological, cellular, and clinical), in women without mammary pathology, in order to establish their safety profile. A systematic review of the literature was carried out with a balanced search strategy for the identification of relevant references in the MEDLINE, BVSalud, EMBASE, ProQuest, and Cochrane databases until November 2019. The search terms used were 'menopause' or 'hormonal replacement therapy' or 'progestins' or 'estrogen' or 'mastodynia' or 'benign breast disease' or 'mammography'. Data were collected from the 'eligible' articles by two researchers (ARF and SHA), and possible discrepancies in inclusion were resolved by consensus. A total of 1886 articles were identified; 60 full-text articles were reviewed, and 17 articles that met the inclusion criteria were included for the qualitative analysis. In conclusion, combined hormone replacement therapy is associated with benign effects on the breast, such as mastodynia and increased mammographic density.

Testosterone therapy and breast histopathological features in transgender individuals.

Testosterone therapy (TT) is administered to enhance masculinization in transgender individuals. The long-term effect of exogenous testosterone on breast tissues remains unclear. Our study evaluated the modulation of breast morphology by TT in transgender individuals with special attention to duration of TT. We reviewed 447 breast surgical specimens from gender affirming chest-contouring surgery, and compared histopathological findings including degree of lobular atrophy, and atypical and non-atypical proliferations between subjects who did (n = 367) and did not (n = 79) receive TT. TT for one patient was unknown. TT for >12 months was associated with seven histopathological features. Longer duration of TT was significantly associated with higher degrees of lobular atrophy (p < 0.001). This relationship remained significant after accounting for age at surgery, ethnicity, body mass index, and presurgical oophorectomy (adjusted p < 0.001). Four types of lesions were more likely to be absent in breast tissues exposed to longer durations of TT: cysts (median = 16.2 months; p < 0.01; adjusted p = 0.01), fibroadenoma (median = 14.8 months; p = 0.02; adjusted p = 0.07), pseudoangiomatous stromal hyperplasia (median = 17.0 months; p < 0.001; adjusted p < 0.001), and papillomas (median = 14.7 months; p = 0.04; adjusted p = 0.20). Columnar cell change and mild inflammation were also less likely to occur in subjects receiving TT (p < 0.05), but were not linked to the duration of TT. Atypia and ductal carcinoma in situ were detected in 11 subjects (2.5%) all of whom received TT ranging from 10.1 to 64.1 months. The incidental findings of high-risk lesions and carcinoma as well as the risk of cancer in residual breast tissue after chest-contouring surgery warrant the consideration of culturally sensitive routine breast cancer screening protocols for transgender men and masculine-centered gender nonconforming individuals. Long-term follow-up studies and molecular investigations are needed to understand the breast cancer risk of transgender individuals who receive TT.

Analysis of Data From Breast Diseases Treated With 5-Alpha Reductase Inhibitors for Benign Prostatic Hyperplasia.

OBJECTIVE: 5-alpha reductase inhibitors (5ARIs) decrease the androgen levels in vivo and are currently used for the treatment of benign prostatic hyperplasia (BPH) in men. However, these inhibitors can also increase the risk of gynecomastia, breast tenderness, and breast cancer. Hence, we did a systematic review and meta-analysis to evaluate the rate of breast-related diseases in men treated with 5ARIs. MATERIALS AND METHODS: PubMed, Embase, Cochrane, and CNKI databases were searched for randomized controlled trials using 5ARIs in patients with BPH. Data were analyzed by using Cochrane Collaboration review manager program and Stata 12.0 software. RESULTS: In total, 14 studies were included in the meta-analysis. Gynecomastia was significantly more common with 5ARIs treatment when compared with placebo (3.30% vs. 1.84%; P < .00001) or alpha blockers (ABs) monotherapy (2.33% vs. 1.00%; P = .0009). Both dutasteride (2.03% vs. 0.90%; P < .00001) and finasteride (4.08% vs. 2.43%; P < .00001) are associated with significantly higher risk of gynecomastia than placebo. Risk for breast tenderness was elevated in 5ARIs users (0.83% vs. 0.25%; P = .01) or in users having combination therapy with ABs (2.48% vs. 0.58%; P < .0001). Finasteride is associated with significantly higher risk of breast tenderness than placebo (0.80% vs. 0.25%; P = .02). CONCLUSION: In male patients with BPH, 5ARIs have significantly increased the risk of gynecomastia and breast tenderness but may be not to the breast cancer. In addition, combination therapy is significantly associated with higher risk of breast tenderness compared to single ABs monotherapy.

A MOUSE MODEL OF MAMMARY HYPERPLASIA INDUCED BY ORAL HORMONE ADMINISTRATION.

BACKGROUND: Mammary hyperplasia is one of the most common benign breast disorders. Although traditional Chinese medicine has a vast experience in the treatment of mammary hyperplasia, it is not accepted widely due to its unclear mechanism. METHODS AND MATERIALS: To address the mechanism, we developed a mouse model of mammary hyperplasia. We gave mice estradiol valerate tablets and progesterone capsules sequentially for one month by intragastric administration. RESULTS: Mice treated by this method had a series of pathological changes which are similar to those detected in women with mammary hyperplasia, including ectopic level of estradiol and progesterone in serum, hyperplasia of mammary glands and increased expression of ERα and PR. CONCLUSION: This model will facilitate the mechanical study of traditional medicine on mammary hyperplasia.

Increased vascular calcification in patients receiving warfarin.

OBJECTIVE: Matrix gla protein is a vitamin K-dependent inhibitor of medial arterial calcification whose synthesis and activity are blocked by warfarin. Warfarin induces arterial calcification in experimental models, but whether this occurs in humans is unclear. This was addressed by examining breast arterial calcification, which is exclusively medial and easily identified on mammograms. APPROACH AND RESULTS: Screening mammograms from women with current, past, or future warfarin use were examined for the presence of arterial calcification and compared with mammograms obtained in untreated women matched for age and diabetes mellitus. Women with a serum creatinine >2.0 mg/dL or a history of end-stage renal disease were excluded. In 451 women with mammograms performed after ≥1 month of warfarin therapy, the prevalence of arterial calcification was 50% greater than in 451 untreated women (39.0% versus 25.9%; P<0.0001). However, in 159 mammograms performed before warfarin therapy, the prevalence of arterial calcification was not increased (26.4% versus 25.8%). The increased prevalence varied with duration of treatment, from 25.0% for <1 year to 74.4% for >5 years. In a multivariable logistic model, only age and duration of warfarin, but not the period of time after stopping warfarin, were significant determinants of arterial calcification in women with current or past warfarin use. CONCLUSIONS: The prevalence of breast arterial calcification is increased in women with current or past warfarin use independent of other risk factors and conditions predating warfarin use. This effect appears to be cumulative and may be irreversible.

Tocopherols inhibit oxidative and nitrosative stress in estrogen-induced early mammary hyperplasia in ACI rats.

Oxidative stress is known to play a key role in estrogen-induced breast cancer. This study assessed the chemopreventive activity of the naturally occurring γ-tocopherol-rich mixture of tocopherols (γ-TmT) in early stages of estrogen-induced mammary hyperplasia in ACI rats. ACI rats provide an established model of rodent mammary carcinogenesis due to their high sensitivity to estrogen. Female rats were implanted with 9 mg of 17ß-estradiol (E2) in silastic tubings and fed with control or 0.3% γ-TmT diet for 1, 3, 7, and 14 d. γ-TmT increased the levels of tocopherols and their metabolites in the serum and mammary glands of the rats. Histological analysis revealed mammary hyperplasia in the E2 treated rats fed with control or γ-TmT diet. γ-TmT decreased the levels of E2-induced nitrosative and oxidative stress markers, nitrotyrosine, and 8-oxo-dG, respectively, in the hyperplastic mammary tissues. 8-Isoprostane, a marker of oxidative stress in the serum, was also reduced by γ-TmT. Noticeably, γ-TmT stimulated Nrf2-dependent antioxidant response in the mammary glands of E2 treated rats, evident from the induced mRNA levels of Nrf2 and its downstream antioxidant enzymes, superoxide dismutase, catalase, and glutathione peroxidase. Therefore, inhibition of nitrosative/oxidative stress through induction of antioxidant response is the primary effect of γ-TmT in early stages of E2-induced mammary hyperplasia. Due to its cytoprotective activity, γ-TmT could be a potential natural agent for the chemoprevention of estrogen-induced breast cancer.

Establishment of novel rat models for premalignant breast disease.

BACKGROUND: Breast cancer has become one of the most common malignant tumors among females over the past several years. Breast carcinogenesis is a continuous process, which is featured by the normal epithelium progressing to premalignant lesions and then to invasive breast cancer (IBC). Targeting premalignant lesions is an effective strategy to prevent breast cancer. The establishment of animal models is critical to study the mechanisms of breast carcinogenesis, which will facilitate research on breast cancer prevention and drug behaviors. In this study, we established a feasible chemically-induced rat model of premalignant breast cancer. METHODS: Following the administration of the drugs (carcinogen, estrogen, and progestogen) to Sprague-Dawley (SD) rats, tumors or suspicious tumors were identified by palpation or ultrasound imaging, and were surgically excised for pathological evaluation. A series of four consecutive steps were carried out in order to determine the carcinogen: 7,12-dimethylbenzaanthracene (DMBA) or 1-methyl-1-nitrosourea, the route of carcinogen administration, the administration period of estrogen and progestogen, and the DMBA dosage. RESULTS: Stable premalignant lesions can be induced in SD rats on administration of DMBA (15 mg/kg, administered three times) followed by administration of female hormones 5-day cycle. RESULTS: were confirmed by ultrasound and palpation. CONCLUSION: Under the premise of drug dose and cycle, DMBA combined with estrogen and progestogen can be used as a SD rat model for breast premalignant lesions.

[Imaging in silicone breast implantation]. / Beeldvormende technieken bij siliconenborstprothesen.

Recently, there have been concerns regarding the use of breast implants from Poly Implant Prothèse (PIP, Seyne sur Mer, France) for breast augmentation due to their tendency to rupture and the possibility of having toxic contents. MRI using a specific silicone-sensitive sequence has proven to be the most sensitive and specific technique in the detection of intra- and extracapsular implant rupture. However, given its high costs, it is important that this technique is used sparingly. In this clinical lesson, we compare the sensitivity and specificity of mammography, ultrasound, CT and MRI for the detection of breast implant rupture. Based on two cases, a diagnostic approach is given in order to reduce health care costs.

Efavirenz-induced gynecomastia in a prepubertal girl with human immunodeficiency virus infection: a case report.

BACKGROUND: Prepubertal gynecomastia is a rare condition and most frequently classified as idiopathic. In HIV-infected adults gynecomastia is a recognised but infrequent side-effect of antiretroviral treatment (ART) and mostly attributed to efavirenz use. Gynecomastia should be distinguished from pseudogynecomastia as part of the lipodystrophy syndrome caused by Nucleoside Reverse Transcriptase Inhibitors (NRTIs) to avoid incorrect substitution of drugs. In the medical literature only five cases of prepubertal gynecomastia in children taking ART are described and underlying pathogenesis was unknown. The occurrence of adverse effects of ART may interfere with therapy adherence and long-term prognosis and for that reason requires attention. We report the first case of prepubertal gynecomastia in a young girl attributed to efavirenz use. CASE PRESENTATION: A seven-year-old African girl presented with true gynecomastia four months after initiation on ART (abacavir, lamivudine, efavirenz). History, physical examination and laboratory tests excluded known causes of gynecomastia and efavirenz was considered as the most likely cause. Six weeks after withdrawal of efavirenz the breast enlargement had completely resolved. CONCLUSIONS: Efavirenz-induced gynecomastia may occur in children as well as in adults. With the increasing access to ART, the possibility of efavirenz-exposure and the potential occurrence of its associated side-effects may be high. In resource-poor settings, empirical change from efavirenz to nevirapine may be considered, providing no other known or alarming cause is identified, as efavirenz-induced gynecomastia can resolve quickly after withdrawal of the drug. Timely recognition of gynecomastia as a side-effect of efavirenz is important in order to intervene while the condition may still be reversible, to sustain adherence to ART and to maintain the sociopsychological health of the child.

Bilateral breast reconstruction with a pedicled transverse rectus abdominis myocutaneous flap after subcutaneous mastectomy for symptomatic injected breasts.

Breast deformities after augmentation with injectable materials carried out by uncertified medical personnel present challenging problems. Materials include liquid silicone, paraffin, polyacrylamide hydrogels, and unknown gels. They usually cause granulomatous reactions, erythema, pain, and even skin necrosis. Tender masses that cannot be differentiated from breast cancers are the major concern. This retrospective study presents the authors' experience in managing 10 symptomatic injected breasts in five patients during the past 8 years. Subcutaneous mastectomies were carried out using periareolar, inverted "T", or inframammary approaches combined with breast reconstruction using bilateral pedicled transverse rectus abdominis myocutaneous (TRAM) flaps. All flaps survived well and gave a satisfactory cosmetic appearance. There was no major complication or late occurrence of breast cancers over the following 8 years. Injectable materials used for breast augmentation should be prohibited until more scientific data are available about the long-term effect of these materials in breast tissues. Once the injected breasts become symptomatic, subcutaneous mastectomy and reconstruction with bilateral pedicled TRAM flaps is a reasonable option for the patient.

Benign breast diseases, contraception and hormone replacement therapy.

The term benign breast disease includes a wide and heterogenous spectrum of lesions different for histology and natural history. Approximately 70% of women who undergo a biopsy for benign breast disease have non-proliferative lesions with no increased risk of breast cancer, 26% have typical hyperplasia which is associated with a two-fold increased risk, and only 4% have atypical hyperplasia which is associated with a five-fold increased risk. The data on the effect of steroid hormones on benign breast disease come from observational studies with several potential bias. Most papers have reported that oral contraceptives protect against benign breast disease, whereas some others have suggested that effects of pill are not yet fully clear. As far as hormone replacement therapy (HRT) is concerned, some studies have shown an increased incidence of benign breast disease in long-term HRT users, whereas other investigations have found either no effect or a protective effect. The use of HRT does not appear to influence the clinical pattern of benign breast disease in postmenopausal women, although enlargement of pre-existing cysts or fibroadenomas has been sometimes reported. The limited available data failed to detect a deleterious effect of HRT use in women with benign breast disease, even in those with increased breast cancer risk due to a family history or high-risk benign breast conditions.

Coumadin-induced skin necrosis of the breasts: case report.

A case report of coumadin-induced skin necrosis (CISN) is presented, followed by a topic review of CISN, which reviews presentation, pathophysiology, differential diagnosis, prevention, and management of this disorder. The prevalence of CISN is low (0.01%-0.1% of patients receiving coumadin). However, of those affected, over 50% required some form of surgical debridement or reconstruction. Although skin necrosis secondary to coumadin therapy is rare, it is essential for plastic surgeons to be aware of this clinical entity in order to make the correct diagnosis and provide appropriate treatment.

Imaging findings of breast augmentation with injected hydrophilic polyacrylamide gel: patient reports and literature review.

Hydrophilic polyacrylamide gel (PAAG) is a nonresorbable soft tissue filler that has been used as implant material for breast augmentation in some countries, particularly from the Asian continent. Many complications associated with hydrogel use have been reported in the clinical literature including inflammation, persistent mastodynia, formation of multiple lumps, poor cosmetic results, glandular atrophy, and significant spread of hydrogel into the surrounding tissue. Data on long-term toxicity is currently unavailable. The radiologic features of PAAG injection mammoplasty frequently constitute a diagnostic challenge for radiologists. Indeed, the imaging appearances of uncomplicated PAAG implants may mimic conventional implants on mammography, sonography and MRI, with some distinguishing features. The location and local spread of the injected PAAG, and the eventual detection of local inflammation, are best evaluated by ultrasonography and especially MRI, considered the most sensitive technique for assessment of PAAG mammoplasty. MRI clearly depicts the volume and the distribution of gel within the breast; contrast medium enhancement allows delineation of areas of inflammation and infection. It is important to be familiar with the spectrum of imaging findings in order to make an accurate diagnosis and offer proper management. This paper aims to review the normal and abnormal mammographic, sonographic, and MR imaging characteristics of PAAG augmentation mammoplasty through presented patient reviews of three women having undergone direct PAAG injection.

Proteinograma e teores de cobre, ferro e zinco no soro sanguíneo de ovelhas da raça Santa Inês com mastite experimental por staphylococcus aureus / Proteinogram and serum concentrations of copper, iron and zinc in Santa Inês ewes with staphylococcus aureus experimentally induced mastitis

Este estudo teve por objetivo avaliar o proteinograma e os teores de cobre, ferro e zinco no soro sangüíneo de ovelhas com mastite induzida por cepa de campo de Staphylococcus aureus. Foram utilizadas 10 ovelhas da raça Santa Inês, primíparas, recém-paridas, com aproximadamente dois anos de idade e bom estado nutricional. Inoculou-se na metade direita da glândula mamária 1,0x10(4) UFC/mL da bactéria, enquanto que a metade esquerda serviu como controle. Os animais foram acompanhados diariamente e a partir do diagnóstico clínico de mastite, procedeu-se colheita do material para realização do proteinograma sérico em gel de poliacrilamida contendo dodecil sulfato de sódio (SDS-PAGE) e para determinação do teor plasmático de fibrinogênio e das concentrações séricas de cobre, ferro e zinco em 16 momentos a saber: antes da inoculação (controle) e 12h, 24h, 36h, 48h, 60h, 72h, 84h, 96h, 108h, 120h, 132h, 168h, 180h, 288h e 336h após a inoculação (p.i.). Todas as ovelhas apresentaram quadro clínico de mastite, com perda da funcionalidade da glândula mamária. O proteinograma permitiu a identificação de 23 proteínas, cujos pesos moleculares (PM) variaram de 26.000 a 185.000 dáltons (Da), incluindo proteínas de fase aguda, IgG e IgA. Notou-se aumento significativo nas concentrações de haptoglobina e ceruloplasmina, assim como de IgG e IgA. Não se constatou alteração nos teores de antitripisina e de glicoproteína ácida .Verificou-se diminuição nos teores de ferro e zinco e elevação na concentração de cobre. Constatou-se correlação positiva entre o teor plasmático de fibrinogênio e as concentrações séricas de ceruloplasmina (r=0,74), a haptoglobina (r=0,62) e IgA(r=0,62). Estes resultados mostram a importância das proteínas de fase aguda ceruloplasmina e haptoglobina como indicadores auxiliares da infecção intramamária de ovelhas, assim como ratifica a relevância do fibrinogênio como marcador inflamatório em razão de sua alta correlação com as proteínas...

The aim of the present study was to evaluate the effect of Staphylococcus aureus experimentally induced mastitis on proteinogram and serum concentrations of cupper, iron and zinc levels of Santa Ines primiparous ewes . The right mammary gland of ten healthy ewes was inoculated with 1,0x10(4) UFC/mL of S. aureus. Clinical examination and determination of serum concentrations of proteins by electrophoresis in polyacrylamide gel (SDS-PAGE), cupper, iron and zinc, as well plasma level of fibrinogen were measured before the inoculation (control) and 12h, 24h, 36h, 48h, 60h, 72h, 84h, 96h, 108h, 120h, 132h, 168h, 180h, 288h and 336h after bacteria inoculation. All animals experimentally infected presented clinical mastitis and subsequent loss of mammary gland function. The electrophoretogram allowed the identification of 23 proteins with molecular weights (MW) ranged from 26.000 to 185.000 daltons (Da) including acute-phase proteins, IgG and IgA. A significant increase (P<0,05) in haptoglobin, ceruloplasmin, IgG and IgA concentrations was observed. Antitrypsin and acid glicoprotein concentrations did not alter. The levels of iron and zinc decreased and the cupper concentration increased . A positive correlation between plasma fibrinogen and serum ceruloplasmin (r=0.74), haptoglobin (r=0.62) and IgA (r=0.62) was also identified. Results showed the importance of ceruloplasmin and haptoglobin as acute-phase proteins in ewes with intramammary infections and confirms fibrinogen as an inflammatory marker because its high correlation with specific proteins. The alterations in the serum levels of Cu, Fe and Zn suggest the action of inflammatory mediators triggered by S. aureus.

Long-term endometrial and breast safety of a specific, standardized soy extract.

OBJECTIVE: To assess the effects of an oral soy isoflavone extract (Phytosoya) on endometrium and breast in postmenopausal women treated for 3 years. METHODS: A total of 395 postmenopausal women were included in this international prospective, open-label study. The number of patients who completed the 3-year study was 197. The women were treated for 3 years with a specific, standardized soy isoflavone extract (total 70 mg/day). Endometrial biopsy, transvaginal ultrasonography and mammography were performed before and after 3 years of treatment. RESULTS: No case of hyperplasia/cancer was diagnosed among the 192 interpretable biopsies at 3 years. Only one case of simple hyperplasia was diagnosed among 197 post-baseline interpretable biopsies. The endometrial safety of this extract has been demonstrated (point estimate 0.5%). There was no statistically significant change in endometrial thickness after 3 years (98.4% inactive or atrophic and 0.3% proliferative endometrium at 1 year). Mammography results showed no notable change from baseline. No patient in any set developed an ACR classification of 4 or 5 after 3 years of treatment. The global safety was rated as either 'excellent' or 'good' by 99.1% of investigators and 99.0% of patients after 3 years of treatment. The adverse events were as follows: eight patients had metrorrhagia and seven patients had at least one breast adverse event: three patients had 'breast pain', two patients reported 'breast tenderness' and two patients had 'hypertrophic breast' (most of them were possibly treatment-related). CONCLUSIONS: As no case of hyperplasia was diagnosed among the 301 interpretable biopsies at 1 year and there was only one case of simple hyperplasia in the 197 post-baseline biopsies at 3 years, the endometrial safety of this extract has been demonstrated. Furthermore, as demonstrated by the lack of change in endometrial thickness associated with the histologic results, we suggest that this extract does not exert a mitogenic effect on the endometrium. These results suggest that daily administration of 70 mg of a specific, standardized isoflavone extract for 3 years could be a safe treatment for both endometrium and breast.