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PubMed2005

Inhibition of skin pigmentation by an extract of Lepidium apetalum and its possible implication in IL-6 mediated signaling.

The development of effective skin-lightening agents is an increasingly important area of research aimed at the treatment of hyperpigmentation induced by UV irradiation or by medical conditions such as melasma, postinflammatory melanoderma and solar lentigo. Although some inhibit tyrosinase, identifying and understanding the mechanisms of action of other agents is an important goal if more effective pigmentation inhibitors are to be developed. We present here that an extract of Lepidium apetalum (ELA) decreased UV-induced skin pigmentation in brown guinea pigs and melanogenesis of HM3KO human melanoma cells. Interestingly, ELA did not reduce melanogenesis in HM3KO cells unless they were co-cultivated in keratinocyte-conditioned medium prepared by culturing keratinocytes with ELA. Under these conditions, ELA decreased tyrosinase mRNA and protein expression as well as melanin content via an ELA-mediated increase in keratinocyte IL-6 production which in turn was shown to decrease in the expression Mitf, a transcription factor implicated in tyrosinase gene expression and melanocyte differentiation. The results reveal that ELA may be an effective inhibitor of hyperpigmentation caused by UV irradiation or by pigmented skin disorders through a mechanism involving IL-6-mediated downregulation of Mitf rather than a direct inhibition of tyrosinase activity.

Animals↗

PubMed2004

Nelson's syndrome: complete remission with cabergoline but not with bromocriptine or cyproheptadine treatment.

A woman affected by Cushing's disease underwent bilateral adrenalectomy followed by radiotherapy of the hypothalamic-pituitary area when she was 18 years old. Thereafter, she used hydrocortisone acetate replacement therapy (35.5 mg divided into two daily doses). At the age of 26 years, the patient exhibited the clinical signs of the Nelson's syndrome, i.e. skin and gingival hyperpigmentation accompanied by amenorrhea, and elevated ACTH plasma levels (2,850 pg/ml, normal range 15-80 pg/ml). The magnetic resonance imaging (MRI) analysis of the sellar region evidenced a pituitary macroadenoma, measuring 14 x 13 mm. The patient was initially treated with cyproheptadine hydrochloride (12 mg/day) for 18 months. There was a partial improvement of the symptoms, with a reduction of the ACTH plasma levels to 112 pg/ml, but without any modification of the tumor mass. Due to sleepiness and weight gain, the cyproheptadine treatment was interrupted and substituted by a cabergoline (0.5 mg twice a week) therapy. Soon after cabergoline was applied an improvement of the clinical symptoms and signs was observed such as a regression of the tumor mass and the normalization of the ACTH plasma titers (38 pg/ml). Later, cabergoline was substituted by bromocriptine (7.5 mg/day) and the plasma levels of ACTH increased again (247 pg/ml), and headache and cutaneous hyperpigmentation were recorded. When cabergoline was reintroduced there was a clinical improvement and normalization of ACTH plasma levels (64 pg/ml). The MRI analysis of the sella region demonstrated a complete remission of the pituitary adenoma. The results obtained show for the first time that a long-term treatment with cabergoline also brings about a complete remission of Nelson's syndrome in the presence of a pituitary macroadenoma.

Adenoma↗

PubMed1993

Topical retinoic acid for photoaging: clinical response and underlying mechanisms.

Photoaging is primarily composed of wrinkling, mottled hyperpigmentation and a tactile roughness of the skin, all three of these parameters improve following use of topical retinoids. It appears that smoothening of the skin results from a combination of epidermal changes including thickening, stratum corneum compaction and glycosaminoglycan deposition. Lightening of actinic lentigines and mottled hyperpigmentation correlates with a reduction in epidermal melanin content maybe resulting from inhibition of tyrosinase activity. Effacement of wrinkling in mice correlates with new collagen synthesis, and there is evidence that this is also the case in humans. An irritant dermatitis is a feature of retinoid-treated skin but this diminishes in severity during treatment despite continued improvement in photoaging. Thus it is unlikely that irritation per se is responsible for clinical improvement.

Administration, Topical↗

PubMed1997

Oxyhemoglobin is a quantifiable measure of experimentally induced chronic tretinoin inflammation and accommodation in photodamaged skin.

Chronic exposure to a weak irritant leads to inflammatory changes which may be followed by pigmentary changes and accommodation. The inflammatory responses to acute exposure to an irritant have been extensively studied. This study investigated quantitatively the inflammatory reactions produced in photodamaged skin with chronic application of a weak chemical irritant (tretinoin cream 0.025%) over a period of 9 months (36 weeks). Forty-eight subjects with moderately to severely photodamaged skin were enrolled in a 36-week, double-blind placebo-controlled study. Tretinoin cream was applied nightly on the distal two thirds of one dorsal forearm and placebo on the other. The proximal third of each dorsal forearm received no treatment and served as control. Clinical assessments and diffuse reflectance measurements were made at 7 time points during treatment. Apparent concentrations of oxyhemoglobin (HbO2), deoxyhemoglobin (Hb) and melanin were estimated by analysis of the diffuse reflectance spectra. No changes were observed in the apparent HbO2 or the Hb concentration of the placebo-treated or control sites, thus establishing a reliable baseline. The apparent HbO2 concentration of the tretinoin-treated sites increased significantly from baseline to a maximum at 12-18 weeks of treatment, then returned to baseline with continued applications. The changes in HbO2 concentration agreed closely with clinical assessments of erythema. The apparent melanin concentration, corresponding to diffuse hyperpigmentation, showed a large seasonal decrease in both the control and the treated sites, with an additional decrease in the treated sites between 12 and 18 weeks. Erythema appeared after repeated applications and eventually resolved under continuous treatment. The maximum decrease in hyperpigmentation occurred simultaneously with the maximum increase in erythema.

Administration, Oral↗

PubMed2005

Tear film dynamics in floppy eyelid syndrome.

PURPOSE: Floppy eyelid syndrome (FES) presents nonspecific ocular surface irritation. The hypothesis for the current study was that one contributing factor is the abnormality in tear film dynamics. METHODS: Sixteen patients with FES were consecutively examined. Tear film dynamics were evaluated by kinetic tear interference images, infrared thermometry, water evaporation rate, tear break-up time, and fluorescein clearance test. Data showing evaporation rate and thermometry were compared with those of 10 normal subjects. RESULTS: There was a high correlation between the eye with the worse symptoms and the eyes with the more severe floppy lids (P < 0.01) and with ocular surface evaporation rate (P = 0.02). Except for one patient, all others showed abnormal tear film, with an average tear break-up time of 2.9 +/- 3.7 seconds. Kinetic analysis of tear interference images revealed that lipid spread in a vertical or mixed pattern in 18 eyes (75%) with a delayed spread time (P = 0.0007), indicating that most of the patients had lipid tear deficiency. The ocular skin temperature and water evaporation rate were higher in the FES group (P = 0.0003 and 0.026, respectively). Nearly all patients with FES showed eyelid hyperpigmentation. The ocular surface evaporation rate in the FES group was also higher than that of the normal subjects (P < 0.0001). Multiple regression analysis showed that a vertical pattern of lipid spread had a significant influence on ocular surface evaporation rate (P = 0.003). CONCLUSIONS: Tear film abnormality is prevalent in patients with FES and is characterized by lipid tear deficiency, leading to rapid tear evaporation. The FES lid skin is also characterized by high temperature, high water evaporation rate, and hyperpigmentation. Studies directed to investigating the linkage of lid changes and meibomian gland dysfunction may shed new lights on the pathogenesis of FES.

Adult↗

PubMed1969

Normal and abnormal regulation of beta-msh in man.

The regulation of plasma beta-melanocyte-stimulating hormone (beta-MSH) in man has been studied utilizing a radioimmunoassay previously described (1). In normal subjects plasma beta-MSH values ranged from 20 to 110 pg/ml. Metyrapone increased and dexamethasone decreased plasma beta-MSH levels. Surgical stress stimulated beta-MSH secretion. Plasma beta-MSH levels were elevated in patients with untreated Addison's disease and untreated congenital adrenal hyperplasia, and these levels fell to normal during glucocorticoid therapy. In patients with Cushing's syndrome due to pituitary adrenocorticotropic hormone (ACTH) excess, plasma beta-MSH was slightly elevated before treatment. In those patients who developed pituitary tumors and hyperpigmentation after bilateral adrenalectomy, plasma beta-MSH was greatly elevated. In patients with Cushing's syndrome due to adrenal tumor, plasma beta-MSH was subnormal. In patients with the ectopic ACTH syndrome, the levels of plasma beta-MSH were high. Plasma beta-MSH had a diurnal variation in normal subjects, patients with Addison's disease, and patients with congenital adrenal hyperplasia; but the normal diurnal variation was lost in patients with Cushing's disease. In patients with high plasma beta-MSH, simultaneous determinations of plasma ACTH showed close correlation between the degree of elevation of ACTH and that of beta-MSH. In extracts of tumors from patients with the ectopic ACTH-MSH syndrome the quantities of the two hormones were roughly equivalent. In patients with hyperpigmentation due to a variety of disorders other than pituitary-adrenal abnormalities, plasma beta-MSH was normal. It is concluded that the secretion of beta-MSH is regulated by the same factors that regulate ACTH.

Addison Disease↗

PubMed1983

A pituitary parasellar tumor with extracranial metastases and high, partially suppressible levels of adrenocorticotropin and related peptides.

We report the history, laboratory findings, and studies performed on a 27-yr-old patient with a metastatic parasellar adenoma of the pituitary and Cushing's syndrome. She developed intense hyperpigmentation and extraordinarily high ACTH levels after bilateral adrenalectomy in 1974. With the exception of marked hyperpigmentation, she did well on glucocorticoid replacement therapy until August 1979, when multiple hepatic nodules were observed during a cholecystectomy. Histological studies and immunoperoxidase staining indicated that these lesions were pituitary tumor metastases. What were presumed to be metastatic lesions also developed in lungs and bone. This combination of liver, bone, and lung metastases from primary pituitary tumors has not previously been reported. Immunoreactive plasma ACTH concentrations were as high as 230,000 pg/ml. Similarly, high levels of plasma immunoreactive beta MSH and immunoreactive beta-endorphin were found. High doses of glucocorticoids reduced the concentration of ACTH to one seventh to one tenth the basal level. The sensitivity of plasma ACTH to exogenous steroid administration strongly suggests that an intact intracellular mechanism for negative feedback control of ACTH secretion persisted within the tumor cells. The rapid rise in ACTH and related peptides and the development of metastases after adrenalectomy suggest that both the secretory capacity and the oncogenic potential of the parasellar tumor were chronically inhibited by glucocorticoid hormones.

Adenoma↗

PubMed1994

Studies of cuticle drugs from natural sources. II. Inhibitory effects of Prunus plants on melanin biosynthesis.

The inhibitory effects of 50% ethanolic extracts from dried leaves of 38 plants collected in the herbal garden of Kinki University were investigated in vitro on melanin biosynthesis which is closely related to hyperpigmentation. Of the 38 extracts, Prunus yedoensis, P. zippeliana, P. amygdalus, P. persica, P. armeniaca, Thea sinensis and Chaenomeles sinensis showed a potent inhibition of tyrosinase, the enzyme which converts 3-(3,4-dihydroxyphenyl)alanine (dopa) to dopachrome in the biosynthetic process. Furthermore, the extracts from the leaves of P. yedoensis and P. zippeliana among the Prunus plants used in this experiment inhibited the production of melanin from dopachrome by autoxidation. These inhibitory effects of P. zippeliana on melanin biosynthesis were observed in cultured B-16 mouse melanoma cells. These results suggest that the leaves of P. zippeliana inhibit melanin biosynthesis which is involved in hyperpigmentation and could be used as a whitening agent for the skin.

Animals↗

PubMed2006

McCune-Albright syndrome: clinical picture and natural history in children and adolescents.

The classical triad of McCune-Albright syndrome (MAS) consists of polyostotic fibrous dysplasia (FD), skin hyperpigmentation (café-au-lait spots), and endocrine dysfunction, frequently seen in females as precocious puberty. Patients with MAS display mosaicism of activating somatic mutations of the alpha-subunit of Gs. Thus, the clinical presentation of each individual is dependent on the particular distribution of affected cells, causing a broad spectrum of endocrine and non-endocrine manifestations. Typical endocrinopathies are precocious puberty, hyperthyroidism, growth hormone excess, hyperprolactemia, and hypercortisolism. The onset of these manifestations is usually during infancy and childhood. Since specific treatment is required, the prognosis depends on the severity of each individual endocrine manifestation. Additionally, there are non-endocrine manifestations, such as fibrous dysplasia of bone (FD), renal phosphate wasting, and skin hyperpigmentation, i.e. café-au-lait spots. FD, mostly polyostotic, causes fractures needing surgical and orthopedic treatment. Since previous studies have suggested the overall prognosis of patients with McCune-Albright syndrome to be non-fatal, recent data have drawn our attention to non-endocrine affections, including hepatobiliary dysfunction and cardiac disease, which are probably an important risk factor for early death. In summary, the clinical picture in MAS is related to its mosaic nature, i.e. any cell, tissue and organ in any site of the body could be affected to varying degrees, ranging from one or two mild clinical signs with excellent long-term prognosis to a severe life-threatening multiorgan disease.

Adolescent↗

PubMed2005

Rosiglitazone for prevention or adjuvant treatment of Nelson's syndrome after bilateral adrenalectomy.

OBJECTIVE: To investigate the effect of Rosiglitazone in three patients treated with bilateral adrenalectomy followed by hyperpigmentation and hypersecretion of ACTH. PATIENTS AND METHODS: One patient had increasing ACTH after previous transsphenoidal surgery for Nelson's syndrome, and two patients without pituitary adenomas had recurrence of Cushing's disease after primary and repeated transsphenoidal surgery with need for bilateral adrenalectomy. The patients developed hyperpigmentation and increasing ACTH at nadir 2-4 h after morning hydrocortisone dose. ACTH during Rosiglitazone therapy (4 mg/day for 4 weeks and then 8 mg/day) was measured at regular intervals 24 h after the latest dose of hydrocortisone. RESULTS: In two patients there was a decrease in ACTH by 40% after 5 months. The first of these patients showed an escape with increasing ACTH to the initial value after 11 months. In the third patient no effect was observed. Tumour development or progression on magnetic resonance imaging was not observed. CONCLUSION: Rosiglitazone might represent an adjuvant therapy in patients with ACTH hypersecretion. Larger long-term studies are needed.

Adrenalectomy↗

PubMed1996

Treatment of photoaged skin. Efficacy, tolerability and costs of available agents.

Photoaging is a cumulative degenerative process induced by solar irradiation with well defined clinical and histological correlates. Because of its huge psychological impact, there is much demand for effective treatment. Many well constructed trials confirm the clinical efficacy of topical tretinoin for improving fine wrinkling and mild to moderate hyperpigmentation; coarse wrinkling and severe hyperpigmentation respond less well. Histological improvement is well documented, but the precise relationship to clinical response is not clearly established. Tolerability can be a problem. Optimal concentrations are not firmly established and vary between patients. Claims that topical isotretinoin is better tolerated than tretinoin need to be confirmed with well constructed trials. Despite many claims, there have been no adequate trials documenting the efficacy of fish cartilage polysaccharide extracts or alpha-hydroxy acids. Careful patient selection with consideration of alternative treatments such as chemical peeling, dermabrasion and surgery is important to successful management of photoaging.

Economics, Pharmaceutical↗

PubMed2001

Exogenous ochronosis. An update on clinical features, causative agents and treatment options.

Exogenous ochronosis is clinically and histologically similar to its endogenous counterpart; however, it exhibits no systemic effects and is not an inherited disorder. It is characterized by an asymptomatic hyperpigmentation of the face, sides and back of the neck, back, and extensor surfaces of the extremities. The associated ochronotic discoloration most commonly results from use of products containing hydroquinone. It also occurs following use of antimalarials and products containing resorcinol, phenol, mercury or picric acid. The etiology of hydroquinone-induced hyperpigmentation in exogenous ochronosis remains speculative. The majority of patients with this condition are Black, but it has been reported to occur in Hispanics and Caucasians. Exogenous ochronosis is prevalent among South African Blacks, but is believed relatively uncommon within the US. The reasons for this phenomenon are not clear, but it could be a result of the use of skin care products containing resorcinol in combination with hydroquinone or the use of hydroquinone in a hydroalcoholic lotion. Treatment of this condition is difficult. The offending agent must be avoided, but improvement occurs only slowly. A number of topical agents have been studied as have dermabrasion and the use of lasers. Controlled studies in larger numbers of patients are require to determine the true efficacy of newer treatments.

Adrenal Cortex Hormones↗

PubMed1979

Tattooing, a new hope for secondary leukoderma.

A 10-year material of 1,000 post-burn patients have been reviewed. Dyschromia was found to be one of the commonest post-burn sequelae in both partial thickness and superficial burn. Patches of leukoderma surrounded by a zone of hyperpigmentation was the main feature in partial thickness burn, while hyperpigmentation follows superficial burn. Tattooing was tried on 30 patients as a permanent camouflage for leukodermic patches in exposed areas. Histological studies on 7 volunteers were carried out, showing the histological pattern of dyschromia and tattooing. The trial proved to be a success, though it still needs further refinement and improvement.

Burns↗

PubMed1996

Linear and whorled nevoid hypermelanosis with delayed psychomotor development.

We report a case of a 25-month-old girl presented to us for the evaluation of a severe delayed psychomotor development who also has pigmentary abnormalities. Linear and whorled hyperpigmentations following Blaschko's lines were noticed on her entire body except on her face, palms, soles, eyes and mucous membranes, which closely resembled those found in hypomelanosis of Ito, but inversely pigmented. Histologic examination revealed basal layer hyperpigmentation without incontinence of pigment or dermal melanophages. Chromosomal analysis of cultured peripheral leukocytes and fibroblasts from the hyperpigmented and the hypopigmented skin revealed normal female karyotype with no evidence of mosaicism or chimerism. This entity represents a kind of neurocutaneous syndrome-referred to by some authors as linear and whorled nevoid hypermelanosis.

Child Development↗

PubMedDate not supplied

The inhibitory effect of DL-alpha-tocopheryl ferulate in lecithin on melanogenesis.

Oral vitamin E (alpha-tocopherol) supplementation has been reported to improve facial hyperpigmentation. The compound of alpha-tocopherol and ferulic acid, also an antioxidant connected with an ester bond, alpha-tocopheryl ferulate (alpha-TF) can absorb ultraviolet (UV) radiation and thus maintain tocopherol in a stable state. Our aim was to determine whether alpha-TF can be applied to improve and prevent facial hyperpigmentation induced by UV as a whitening agent as well as an antioxidant. In this study, the effects of alpha-TF on melanogenesis were examined using cultured human melanoma cells and normal human melanocytes in vitro. alpha-TF solubilized in 0.5% lecithin inhibited melanization significantly at the concentration of 30 micrograms/ml compared with arbutin (100 micrograms/ml), kojic acid (100 micrograms/ml), ascorbic acid (600 micrograms/ml), and tranexamic acid (600 micrograms/ml). alpha-TF had no effect on the protein amounts of tyrosinase, TRP (tyrosinase related protein)-1, and TRP-2 of human melanoma cells exposed to UV radiation, but inhibited tyrosine hydroxylase activity. alpha-TF neither directly inhibited tyrosinase activity of the large granule fraction extracted from melanoma cells, nor modulated glycosylation of tyrosinase. These results suggest that alpha-TF may be a candidate for whitening agent which suppresses melanogenesis, possibly by inhibiting tyrosine hydroxylase activity in an indirect manner. Further, alpha-TF decreased the amount of 8-hydroxydeoxyguanosine produced indirectly through active oxygen species (AOS) in guinea pig skin exposed to 2 times the minimal erythema dose of UVB radiation, but did not suppress the direct formation of cyclobutane pyrimidine dimers and (6-4) photoproducts. Thus alpha-TF may reduce AOS-induced DNA damage and thereby contribute at least in part to suppressing or retarding skin cancer development.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed2000

Acquired brachial cutaneous dyschromatosis: a common pigmentary disorder of the arm in middle-aged women.

We studied 20 Caucasian middle-aged patients, mostly women, who had asymptomatic, gray-brown patches with geographic borders, occasionally interspersed with hypopigmented macules, on the dorsum of the forearms, mostly bilaterally. The distal aspect of the arms was also involved in 2 patients; the face was always spared. Civatte's poikiloderma was associated with this hyperpigmentation in 9 patients. Epidermal atrophy, basal layer hyperpigmentation, elastosis and angiectases were histopathologic features. Pregnancy, menopause, local inflammation, and cosmetics were not predisposing factors. Undue sun exposure, oral contraceptives or estrogens were found only occasionally. Sixty-five percent of patients had hypertension and had been taking antihypertensive drugs, especially angiotensin-converting enzyme inhibitors, for years before pigmentation began. Acquired brachial cutaneous dyschromatosis (ABCD) is the suggested title of this disorder, which is not rare. Its prevalence in postmenopausal women, the hypopigmented macules, and the absence of a relation with estrogens, pregnancy, or hormone replacement therapy, all help to distinguish ABCD from melasma. An association with Civatte's poikiloderma as well as hypertension and/or antihypertensive drugs is suggested.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1979

[Macroscopic and microscopic study of human corpse skin grafting on athymic mice nu/nu].

32 thin grafts (500 to 700 mu) of different human corpse skin set apart during the first 24 hrs after the death have retaken on athymic Mousse whatever the reason of death and the age of the donor. 20 thick grafts have retaken at 30%. These skins preserve the aspects and behaviour of normal human skin but after 1 month they have a heavy melanic hyperpigmentation. These skins preserve their normal histological aspect during the first 3 days, then, when revascularisation is setting in, superficial areas of epidermic mortification, opposite dermal hypovascularised zones, appear. Between the 15th and the 21st day the epidermic alterations disappear and a heavy melanic hyperpigmentation is set up. The revascularisation is certainly the result of the human dermal vessels repermeabilisation. Till the 76th day neither dystrophy, dysplasia nor important inflammatory process exist.

Adult↗

PubMedDate not supplied

[Depigmentation for cosmetic purposes: prevalence and side-effects in a female population in Senegal].

BACKGROUND: Use of depigmenting agents by black women for cosmetic purposes is a long-standing practice. Most depigmenting agents contain topical steroids and hydroquinone. The purpose of this study was to clarify prevalence data on use of depigmenting agents in a female population in Senegal and to report the incidence and main features of adverse skin reactions in addition to possible associations with diabetes, hypertension and renal insufficiency. PATIENTS AND METHODS: A cross-sectional study was made in a representative sample of 147 hospitalized women aged from 15 to 60 years. The incidence of adverse skin reactions, diabetes, hypertension and serum creatinine in 41 women admitting use of depigmenting agents was compared to those found in 85 women who maintained they had never used depigmenting agents. Two patients who refused to participate in the study and 19 others who did use depigmenting products and had stopped their use for at least 3 months were excluded from the analysis. RESULTS: The prevalence of use of depigmenting agents was 27.9% (47/147). Adverse skin reactions were significantly more frequent among these patients. Effects observed were similar to those reported for prolonged use of topical steroids but also included periorbitary dyschromia, exogenous ochronosis, infectious dermatosis, and, in particular, extended dermatophytosis and necrotizing cellulitis, contact eczema, and certain hyperpigmentation when depigmenting agents were discontinued. Presence of relative hyperpigmentation of the dorsal phalanges identified use of depigmenting agents with a 100% specificity. Prevalence of diabetes and hypertension was significantly higher among the group of women using depigmenting agents (46.3% and 8.2%, versus 34.1% and 8.2% respectively). There was no difference for renal insufficiency. The risk increased independently of age depending on whether duration of use was less than 10 years or not with a relative risk that rose from 3.63 (1.2-10.47) to 6.47 (3.41-12.32) for diabetes and from 1.34 (0.45-3.96) to 2.65 (1.27-5.51) for hypertension, clearly suggesting a possible dose effect. DISCUSSION: The prevalence of use of depigmenting agents in this first published hospital series confirms the widespread nature of this phenomenon in Senegal. While certain patent skin signs are similar to those described in the literature, and excluding specific features related to the hospital setting, this is the first report of a dose-effect between use of depigmentation agents and diabetes and hypertension, probably via the effect of topical steroids.

Administration, Topical↗