Breast Pathology That Contributes to Dysfunction of Human Lactation: a Spotlight on Nipple Blebs.

Nipple blebs are blister-like fibrinous lesions that form on the surface of the nipple during lactation, and can result in orifice obstruction and mastitis. They likely result from superficial extension of underlying ductal plugging, and can present concurrently with hyperlactation and mammary dysbiosis. Despite their prevalence, few formal reports on nipple blebs exist. In this perspective, we review the experience of a breastfeeding medicine practice that receives referrals for patients with nipple blebs, and provide preliminary insight into etiology, management, and outcomes of these lesions.

Topical Alpha-1 Adrenergic Receptor Agonist Applied to the Nipple/Areola Complex Improves Female Orgasmic Function.

Background: The impact of nipple sensation and its relationship to sexual function have often been neglected in medical literature. However, several recent studies report the importance of the nipple/areola complex (NAC) in sexual arousal and overall function. The nipple is composed of smooth muscle that can be erected via adrenergic nerves. In two complementary studies, we demonstrate that stimulation of the alpha-1 adrenergic receptor in the NAC with topical adrenergic agents can initiate erection of the nipple, increase NAC sensitivity, and improve sexual function. Materials and Methods: Thirteen breast surgery patients with nipple sensitivity loss were recruited to an unblinded study of topical phenylephrine hydrochloride. Sensitivity to pressure was measured before and after the application of the intervention to the NAC. In a second pilot study, 35 women completed a double-blinded placebo-controlled trial of a novel formulation, RJ101, containing a norepinephrine releasing agent. The intervention or placebo was applied to the NAC 30 minutes before sexual activity over the 4-week trial period. The arousal, lubrication, and orgasm domains of the female sexual function index (FSFI) were used to measure sexual function. Results: The application of phenylephrine hydrochloride was shown to increase nipple sensitivity to pressure by an average of 20% in our cohort of 13 breast augmentation patients. In addition, it was shown that intermittent application of the alpha-1 agonist for 8 weeks increased basal NAC sensitivity. In the follow-up pilot study, we demonstrate that stimulation of the NAC with RJ101 produced statistically significant increases versus placebo in the lubrication and orgasm domains of the FSFI, p = 0.0226 and p = 0.0269, respectively. Conclusion: For the first time, we demonstrate that the application of a topical alpha-1 adrenergic receptor agonist or a norepinephrine-releasing agent increases the sensitivity of the NAC and subsequently significantly improves sexual function.

Maternal exposure to mixtures of dienestrol, linuron and flutamide. Part I: Feminization effects on male rat offspring.

Exposure to endocrine-disrupting compounds (EDCs) during pregnancy can result in negative health effects in later generations, including sex changes and feminization. The present study assessed the feminization effects on male offspring rats of three EDCs: Dienestrol (DIES), Linuron (LIN), and Flutamide (FLU). Sexually mature female rats were exposed from gestation day (GD) 6 until postnatal day (PND) 21 to: 0.37, 0.75, 1.5, 3.12 or 6.25 µg/kg/day of DIES, 1.5, 3, 6, 12.5, 25 or 50 mg/kg/day of LIN, 3.5, 6.7, 12.5, 25 or 50 mg/kg/day of FLU, and the following mixtures: FLU + DIES (mg/kg/day+µg/kg/day), 3.5 + 0.37, or 3.5 + 3, 25 + 0.37, or 25 + 3; FLU + LIN (mg/kg/day + mg/kg/day), 3.5 + 12.5, or 25 + 12.5; and DIES + LIN (µg/kg/day + mg/kg/day), 0.37 + 12.5, or 3 + 12.5. Anogenital distance (AGD), nipple retention (NR) and cryptorchidism were evaluated. FLU produced a decrease of AGD, an increase of NR, and an increase of cryptorchidism at the highest dose. None of these three endpoints were significantly affected by LIN or DIES treatments alone. Combinations of FLU + LIN and FLU + DIES increased NR, and decreased AGD, while DIES + LIN did not produce any effects in male pups. Results show that FLU is able to induce feminization in male pups, while binary combinations of LIN and DIES did not modify the effects produced by FLU.

Mammary Dysbiosis and Nipple Blebs Treated With Intravenous Daptomycin and Dalbavancin.

INTRODUCTION: Mammary dysbiosis, also known as subacute mastitis, may be associated with nipple blebs. These overlapping diagnoses represent a challenging clinical scenario during lactation. Little research has been published on etiology, management strategies, and outcomes of these concurrent diagnoses. MAIN ISSUE: We document the treatment and outcome of a patient who presented with left-breast dysbiosis and nipple blebs and whose milk culture grew multi-drug-resistant, methicillin-resistant Staphylococcus aureus. She was treated safely and effectively with intravenous daptomycin and dalbavancin. This has not been described previously in the lactation literature. MANAGEMENT: The 35-year-old lactating gravida 3, para 3 patient presented at 6 months postpartum to a breast surgery clinic with a 1-week history of worsening deep left-breast pain, blebs, and recurrent plugging. She was afebrile and she had no erythema or induration on her breast exam. A culture of her milk grew multi-drug-resistant, methicillin-resistant Staphylococcus aureus, and she was referred to infectious disease for assistance with intravenous antibiotic therapy. She continued to feed expressed milk throughout treatment and demonstrated complete resolution of symptoms 8 weeks later. CONCLUSIONS: We report that in patients with a multi-drug-resistant, methicillin-resistant Staphylococcus aureus-positive human milk culture and a clinical presentation of mammary dysbiosis and nipple blebs, intravenous daptomycin and dalbavancin may be an effective treatment.

Novel topical formulation applied to the nipple-areola complex improves female orgasm.

BACKGROUND: The nipple-areola complex (NAC) is an often overlooked but important erogenous zone in the female sexual response and sexual functional repertoire. Research suggests that nipple stimulation is significant to female sexual satisfaction in as many as 80% of women. Previously, we have reported that stimulation of the arrector pili muscle in the NAC increases nipple sensitivity and has a positive impact on female sexual function. AIMS: To study the effect of RJ-101 on female orgasm. METHODS: A randomized double-blinded placebo-controlled study of RJ101, a novel topical formulation that stimulates the arrector pili muscle of the NAC, in 59 women. Each subject completed a survey composed of Likert scale questions in order to identify changes in orgasm after topical application of RJ101 or placebo. RESULTS: We demonstrated a positive increase in the perceived intensity of orgasm and orgasmic satisfaction/pleasure in women using RJ101 vs those in the placebo group. After 4 weeks of treatment, 76% of the women in the RJ101 arm reported a positive improvement in satisfaction with orgasm versus 47% in the placebo cohort. The mean change in score for overall satisfaction with orgasm in the RJ101 group was statistically significant (P = .007) compared to placebo. CONCLUSION: The application of RJ101 to the NAC 30 minutes prior to sexual activity can improve orgasmic strength, pleasure, and satisfaction.

Promising effects of purslane cream on the breast fissure in lactating women: A clinical trial.

OBJECTIVES: The traditional uses of Portulaca oleracea L. (purslane) with anti-inflammatory and anti-cancer activity as well as anti-oxidants properties were expressed previously. This is a double-blind randomized clinical trial to evaluate the protective effects of purslane cream on the nipple fissure. METHODS: After expressing the goals and methods of the study and obtaining written consent from 86 lactating women with nipple fissure, they were randomly divided into two groups: 43 in purslane cream group and 43 in lanolin ointment group. The score of nipple fissure before the intervention and on the third and eighth day after the study was measured using the Stour scale. RESULTS: The mean score of left and right breast fissures in the group of treatment with lanolin group similar to the group of treatment with purslane cream showed a significant decrease at the third day and eighth day (P=0.001). Mann-Whitney test comparing mean score of the fissure between two groups showed that two groups were homogeneous before the intervention, but there was a significant difference between two groups on the third and eighth days (p < 0.001). The recovery process occurred faster in the group of treatment with purslane cream. CONCLUSION: We showed that the use of purslane cream without any complications could accelerate the repairing of nipple fissure. Based on this clinical trial, purslane cream (2% w/w) can be used as an accelerator for improving the nipple fissure in lactating women.

Natural latex-glycerol dressing to reduce nipple pain and healing the skin in breastfeeding women.

BACKGROUND: Nipple pain is the second most common reason for early weaning, exceeded only by the insufficient milk supply. Nipple fissures can bring other problems, acting also as a portal for bacteria and leading to mastitis. This work proposes the breast protector composite development using materials with tissue repair and moisturizing properties, aligned with a low-cost procedure, aiming not only to relieve pain, but also to heal the nipple fissures caused by breastfeeding. MATERIALS AND METHODS: For the dressings, production was used Natural Latex extracted from the rubber tree and glycerol. The Samples were evaluated chemically and physically by the techniques of Scanning Electron Microscopy, Fourier transform infrared spectroscopy, mechanical traction, and contact angle. The samples were also biologically evaluated by the hemolytic and cytotoxic activity assays. RESULTS: From the physical-chemical assays, the matrix with glycerol has high pore density; the natural latex and glycerol do not covalently interact, indicating that the glycerol can be released; the glycerol addition makes the matrix more elastic but fragile, and increase the wettability. From the biological assays, both materials showed no hemolytic effects; and the cytotoxicity results showed that glycerol did not present cytotoxicity in the fibroblasts, but show a dose-dependent influence in the keratinocytes. CONCLUSION: The material developed for application in breast fissures has mechanical properties similar to those found for materials for dermal applications, present high wettability and pore density. Furthermore, the material showed no cytolytic activity and the tests with skin cell cultures demonstrated the biocompatibility.

Chemoprevention of Breast Cancer by Transdermal Delivery of α-Santalol through Breast Skin and Mammary Papilla (Nipple).

PURPOSE: Almost all breast cancers originate from epithelial cells lining the milk ducts in the breast. To this end, the study investigated the feasibility of localized transdermal delivery of α-santalol, a natural chemopreventive agent to the breast. METHODS: Different α-santalol formulations (cream, solution and microemulsion) were developed and the in vitro permeability was studied using excised animal (porcine and rat) and human breast skin/mammary papilla (nipple). The in vivo biodistribution and efficacy studies were conducted in female rats. A chemical carcinogenesis model of breast cancer was used for the efficacy studies. RESULTS: Phospholipid based α-santalol microemulsion showed the highest penetration through the nipple and breast skin. Delivery of α-santalol through the entire breast (breast skin and nipple) in vivo in rats resulted in significantly higher concentration in the mammary gland compared to transdermal delivery through the breast skin or nipple. There was no measurable α-santalol concentration in the blood. Transdermal delivery of α-santalol reduced the tumor incidence and tumor multiplicity. Furthermore, the tumor size was significantly reduced with α-santalol treatment. CONCLUSIONS: The findings from this study demonstrate the feasibility of localized transdermal delivery of α-santalol for chemoprevention of breast cancer.

Investigations of putative reproductive toxicity of low-dose exposures to vinclozolin in Wistar rats.

The current investigation examines whether the fungicide vinclozolin, which has an anti-androgenic mode of action, is capable of disrupting endocrine homeostasis at very low doses. The data generated clarify whether a non-monotonic dose-response relationship exists to enhance the current debate about the regulation of endocrine disruptors. Moreover, it is part of a series of investigations assessing the dose-response relationship of single and combined administration of anti-androgenic substances. A pre-postnatal in vivo study design was chosen which was compliant with regulatory testing protocols. The test design was improved by additional endpoints addressing hormone levels, morphology and histopathological examinations. Doses were chosen to represent an effect level (20 mg/kg bw/d), the current NOAEL (4 mg/kg bw/d), and a dose close to the "ADI" (0.005 mg/kg bw/d) for the detection of a possible non-monotonic dose-response curve. Anti-androgenic changes were observable at the effect level but not at lower exposures. Nipple/areola counts appeared to be the most sensitive measure of effect, followed by male sex organ weights at sexual maturation, and finally gross and histopathological findings. The results indicate the absence of evidence for effects at low or very low dose levels. A non-monotonic dose-response relationship was not evident.

Lanolin for the treatment of nipple pain in breastfeeding women: a randomized controlled trial.

Nipple pain and damage are commonly experienced by breastfeeding women and are associated with negative breastfeeding outcomes. Health care providers often recommend the application of lanolin to treat painful/damaged nipples, yet no randomized controlled trial has evaluated the effectiveness of lanolin on nipple pain and breastfeeding outcomes. The purpose of this study was to evaluate the effect of lanolin on nipple pain among breastfeeding women with damaged nipples. A randomized, single-blind, controlled trial was conducted at a tertiary care hospital in Hamilton, Ontario, Canada. Breastfeeding women (N = 186) identified as having nipple pain/damage were randomized to apply lanolin (intervention group; n = 93) or to receive usual postpartum care (control group; n = 93). The primary outcome was nipple pain at 4 days post-randomization measured by the Numeric Rating Scale. Additional outcomes included nipple pain measured by the Short Form McGill Pain Questionnaire, breastfeeding duration/exclusivity, breastfeeding self-efficacy, and maternal satisfaction with lanolin treatment versus usual care. The results revealed no significant group differences in mean pain scores at 4 days post-randomization. Women in both groups experienced clinically relevant decreases in nipple pain by 7 days post-randomization. Significantly, more women in the lanolin group reported that they were satisfied with treatment compared with those receiving usual care. No significant group differences were found for other secondary outcomes. While more women were satisfied using lanolin, its application to sore/damaged nipples was ineffective for reducing nipple pain or improving breastfeeding outcomes.

Efficacy of Topical Application of Emu Oil on Areola Skin Barrier in Breastfeeding Women.

Appropriate hydration and skin surface pH are of fundamental importance in preventing areola skin barrier damage and breastfeeding success. We studied the dermal effects of emu oil on areola skin soon after birth in 70 at-term breastfeeding mothers by noninvasive bioengineering method. Emu oil-based cream was found to be effective in improving stratum corneum hydration of breast areolae (mean ± standard deviation, from 56.9 ± 18.2 to 65.0 ± 17.2 conventional units, P < .003) and did not affect skin pH, temperature, or elasticity. The significant improvement in hydration values was more pronounced in the puerperae presenting with basal hydration in the lower quartiles (mean ± standard deviation, from 41.6 ± 17.2 to 59.6 ± 21.2 conventional units, P < .001). Further studies are warranted to confirm the long-term beneficial effects of this preparation in a very sensitive patient population.

Evaluation of the effectiveness of a silver-impregnated medical cap for topical treatment of nipple fissure of breastfeeding mothers.

OBJECTIVE: This study evaluated the effectiveness of a medical topical treatment device named Silver Cap(®) (Depofarma S.P.A., Mogliano Veneto, Treviso, Italy) for the treatment of nipple fissure in lactating women and its local tolerability, compared with the standard of care for nipple fissure treatment during breastfeeding. SUBJECTS AND METHODS: From December 2013 to September 2014, we recruited 40 women for symptomatic nipple fissures during lactation. Participants were randomized into two groups: the Silver Cap group (20 women; group A) or the control group (20 women; Group B, standard of breastfeeding care). All participants received breastfeeding education provided by a board-certified lactation consultant. Group A was instructed to use the Silver Cap. Group B had a handbook with the standard of care for nipple treatment after each breastfeeding. Both groups received a questionnaire for a daily assessment. The duration of both treatments was 15 days. We performed a clinical evaluation on Days 0 and 2 and a follow-up by telephone on Day 7, and all participants underwent final evaluation face to face on Day 15. We performed photographic recording of the nipple on Day 0 and Day 15. RESULTS: There were no statistical differences in follow-up between the two treatments at Day 2. There was a significant and a more rapid resolution of painful symptoms in the Silver Cap group compared with the control group (p<0.05) at Days 7 and 15. Treatment with Silver Cap was more appreciated by the participants than standard care (p<0.05). Four participants in the Silver Cap group and six in the control group dropped out of the study. No local or systemic reactions were reported following Silver Cap application. CONCLUSIONS: Results of treatment with Silver Cap were more effective than standard care of nipple fissure treatment in term of resolution of painful symptoms. It promoted the healing process of lesions, and it was well tolerated and accepted by participants.

Bilateral areolar hyperpigmentation following transdermal application of compounded hormone replacement therapy.

A 61 year-old post-menopausal Caucasian woman presented to the pharmacy to re-initiate hormone therapy after having discontinued treatment for three years. She had discontinued previous hormone therapy due to severe hyperpigmentation of both nipples and areola. She stated that her nipples and areola had turned black, as if they had been burned. This reaction seemed unique, and we felt that it warranted further investigation.

Reproductive and behavioral effects of diisononyl phthalate (DINP) in perinatally exposed rats.

Diisononyl phthalate (DINP) is a plasticizer abundantly used in consumer products as a substitute for other plasticizers prohibited in certain products due to reproductive toxicity. As anti-androgenic effects of DINP are suspected, DINP effects on reproduction and sexually dimorphic behavior were studied. Pregnant Wistar rats were gavaged from gestation day 7 to postnatal day (PND) 17 with vehicle, 300, 600, 750 or 900 mg DINP/kg bw/day. In fetal testes histopathological effects typical of phthalates were observed. In male offspring, DINP caused increased nipple retention, reduced anogenital distance, reduced sperm motility and increased sperm count. DINP affected spatial learning as female offspring performed better than controls and similarly to control males in the Morris Water Maze, indicating masculinization of behavior in DINP exposed females. These results show that DINP causes anti-androgenic effects on reproductive development, though less potent than DEHP, DBP and BBP, and further safety evaluation of DINP appears warranted.

Effects of in utero exposure to DI(n-Butyl) phthalate on development of male reproductive tracts in Sprague-Dawley rats.

The purpose of this study was to determine the effects of di(n-butyl) phthalate (DBP) administration on male reproductive organ development in F1 Sprague-Dawley rats following in utero exposure. During gestation days (GD) 10-19, pregnant rats were administered daily, orally, DBP at 250, 500, or 700 mg/kg or flutamide (1, 12.5, or 25 mg/kg/d) as a positive control. The male offspring were sacrificed at 31 d of age. DBP and flutamide dose-dependently significantly increased the incidence of hypospadias and cryptorchidism in F1 male offspring. The weights of testes and accessory sex organs (epididymides, seminal vesicles, ventral prostate, levator ani plus bulbocavernosus muscles (LABC), and Cowper's glands) were significantly reduced in DBP-treated animals. Furthermore, cauda agenesis of epididymides and ventral prostate atrophy were observed in high-dose 700-mg/kg DBP males. Anogenital distance (AGD) and levels of dihydrotestosterone (DHT) and testosterone were significantly decreased in the DBP (700 mg/kg/d)-treated groups. In particular, the expression of androgen receptor (AR) and 5α-reductase type 2 in the proximal penis was markedly depressed following administration of DBP (700 mg/kg/d) or flutamide (25 mg/kg/d). The expression of sonic hedgehog (Shh) in the urethral epithelium of the proximal penis was significantly less in the DBP (700 mg/kg/d)- or flutamide (25 mg/kg/d)-treated groups. In addition, DBP dose-dependently significantly increased the expression of estrogen receptor (ER α) in the undescended testis. Data demonstrated that in utero exposure to DBP produced several abnormal responses in male reproductive organs, and these effects may be due to disruption of the stage-specific expression of genes related to androgen-dependent organs development.