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Pigmentation and the Endocrinologist
Symposium on Endocrine Disorders
Pigmentation and the Endocrinologist Lawrence E. Koppers, MD., and Pasquale J. Palumbo, MD.
Dermatologic changes not infrequently signal the clinician that a systemic disease is present. In particular, increase or decrease of pigmentation often alerts the physician to underlying endocrinopathy; and here we shall review abnormalities in pigmentation and their relation to the endocrine system. The color of normal skin depends primarily on its content of melanin, carotene, and oxyhemoglobin or reduced hemoglobin. Pathologic changes of skin pigmentation may be produced endogenously or exogenously - by bile, hemosiderin, homogentisic acid, heavy metals, or a tattoo pigment. With carotenemia, a characteristic orange-yellow pigment is deposited in the skin, most commonly in the palms of the hands. Carotenemia may be normal in infants and it may be related to dietary intake, but it occurs also in male castrates and in patients whose conversion of carotene to vitamin A is impaired by panhypopituitarism, myxedema, or diabetes. B, 2:l Skin pigmentation depends largely on the melanin content of the keratinocytes, and is not visible unless melanosomes have entered the keratinocytes. lO , 11 The leptomeninges, inner ear, uveal tract, and pigmentary layer of the retina are other locations that normally contain pigment. The skin becomes pigmented by an orderly sequence outlined in Table 1. The melanocyte, which is of neural origin, is the basic structural unit of the melanin pigmentary system in man. It contains specialized pigment organelles called "melanosomes" which are the site of melanin synthesis and are rich in the enzyme tryosinase. (Fully melanized melanosomes lose their tyrosinase activity and become melanin granules.) Melanin is a polymer of 5, 6-indole quinone, and the initial step in its formation is the oxidation of tyrosine to 3, 4-dihydroxyphenylalanine (dopa) in the presence of tyrosinase. The melanocyte and its associated group of keratinocytes form a structural-functional unit. In all races, skin has the same proportion of melanocytes. 1o • 11 The variations in skin color are due to genetically determined and acquired differences in the production of the melanosomes within the melanocyte and the rate at which these melanin granules are transferred to the keratinocytes. Even albino skin has a normal complement of melanocytes, but Medical Clinic s of No,·th America- Vo!. 56, No. 4, July 1972
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Table 1. 1. 2. 3. 4.
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Process of Melanin Pigmentation
Formation of mela nos.omes in the mela nocyte Melanization of the melanosome s in the melanocyte s Secretion of the melanosomes into the keratinocytes Transport of m elanosomes by the keratinocytes, with de gradation of the melanosomes within the lysosome-like organelles in cauca soids or without degradation in n egroids
they lack tyrosinase for melanin synthesis. Melanin pigmentation is needed for protection against ultraviolet radiant energy, and deficiency of this pigmentation is accompanied by increased incidence of photosensitivity and skin cancer. Various metabolic, endocrine, and nutritional factors; chemical, physical, and pharmacologic agents; inflammations, infections, neoplasms, and miscellaneous influences may contribute to changes in pigmentation. l l In fish, amphibians, and reptiles, beta adrenergic agents darken the skin and alpha adrenergic agents, melatonin, and possibly acetylcholine inhibit the darkening effect of melanotropin (melanocyte-stimulating hormone; MSH) and ACTH.H The alpha and beta adrenergic effects are blocked by alpha and beta adrenergic antagonists. Thus alpha stimulation inhibits formation of cyclic adenosine monophosphate (AMP), induces aggregation of melanosomes , and lightens the skin. Beta stimulation has the opposite effect. Our discussion will be confined to the endocrine factors involved in pigmentation. Hormonal influences are important regulators of skin pigmentation in man as well as the lower species. 10, 11 MSH and ACTH increase melanin pigmentation, supposedly through an effect on cyclic AMP in the melanocyte and consequent activation of the enzyme tyrosinase. Thus, steps 1 and 2 of pigmentation (Table 1) are most likely to be under hormonal influence. The distribution of excess melanin pigmentation (hypermelanosis) may be circumscribed, as in acanthosis nigricans and melasma, or diffuse, as in hemochromatosis, adrenal disease, ACTH therapy, and ectopic MSH-ACTH production. Deficiency of melanin pigmentation (hypo me 1anosis) may be circumscribed, as in vitiligo, or diffuse, as in albinism, hypopituitarism, and hypogonadism. (Albinism has already been mentioned.) Vitiligo may be seen in various endocrine diseases and may be associated with diffuse pigmentation, as in Addison's disease. The influence of the pineal, hypothalamic, pituitary, adrenal, and thyroid glands and the gonads on pigmentation will be taken up under separate headings.
CIRCUMSCRIBED HYPERMELANOSIS Acanthosis nigricans is a symmetric, hyperpigmented, verrucous and hyperkeratotic reaction of the folds of the skin which most clinicians associate with presence of a visceral malignant tumor. ("Pseudoacanthosis
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nigricans" is a term applied to cases in which the patients are markedly obese and in which no cause for the pigmentary disturbance can be determined.) Abnormalities of the endocrine system have been noted in a number of cases of acanthosis nigricans, especially if the patients were in puberty or young adulthood. Winkelmann et al.2 4 found that of 29 patients with benign pubertal and postpubertal acanthosis nigricans, 9 had associated endocrinologic abnormalities (Table 2). Acanthosis nigricans has been reported in association with insulin-resistant diabetes 4 , 9, 22 and in association with congenital lipodystrophy as well as hyperlipidemia and growth abnormalities. 4 Brown et al. reported seven cases of acanthosis nigricans with acromegaly or gigantism and collected six others from the literature. The mechanisms of the association between these particular pituitary disorders and acanthosis nigricans are not known. Melasma (chloasma) is a circumscribed hyperpigmentation occurring almost exclusively in women and localized to the face, involving
Table 2.
Pigmentary Disturbances in Endocrine Disease
I. Circumscribed hypermelanosis A. Acanthosis nigricans 1. Pituitary basophilism 2. Gigantism and acromegaly 3. Hypogonadotropic hypogonadism 4. Cushing's disease 5. Addison's disease 6. Stein-Leventhal syndrome 7. Hyperthyroidism 8. Hypothyroidism 9. Diabetes mellitus B. Melasma 1. Pregnancy 2. Ovarian tumors 3. Oral contraceptives C. Miscellaneous 1. Albright's syndrome 2. Diabetes mellitus ("shin spots")
11. Circumscribed hypo melanosis (vitiligo) A. Addison's disease B. Hyperthyroidism C. Hashimoto's thyroiditis D. Diabetes mellitus E. Hypoparathyroidism Ill. Diffuse hypermelanosis A. Hemochromatosis B. Increased ACTH-MSH concentrations 1. Addison's disease (untreated) 2. Post-bilateral adrenalectomy for Cushing's disease 3. Ectopic ACTH-MSH syndrome IV . Diffuse hypo melanosis A. Hypopituitarism B. Hypogonadism
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predominantly the forehead, cheeks, and upper lip. This form of pigmentation may occur without unusual circumstances and in pregnancy, with ovarian tumors, and with oral contraceptive therapy. I" It appears to be hormonally related, but no consistent hormonal elevations have been found in melasma except when it was associated with pregnancy or with contraceptives given orally. The mechanism of this pigmentary disturbance is not known. The melanocyte distribution is uniform over the body, except that an increased cell population is located on the face and forehead. The face is most exposed to sunlight and has increased melanocyte population that protects aganist solar radiation. How hormones interact with this melanocyte population to produce the circumscribed pigmentation of melasma has not been elucidated. Localized nipple pigmentation may occur with pregnancy and with estrogen therapy.lI How the hormones interact to produce this localized pigmentation is speculative. In girls with Albright's syndrome, melanotic macules (cafe au lait spots) may appear in association with precocious puberty and polyostotic fibrous dysplasia.;) The interrelationships of the changes in skin, bone, and possibly ovaries have not been worked out. Hyperpigmented "shin spots" frequently are noted in diabetes mellitus. 7 This dermopathy is more prevalent in male diabetics and increases in frequency with the duration of the diabetes. The skin lesion, however, is not specific for diabetes. These localized areas of pigmentation may be related to trauma or small-vessel disease. The relationship of the diabetes mellitus and this circumscribed hypermelanosis is not known.
CIRCUMSCRIBED HYPOMELANOSIS (VITILIGO) Vitiligo is a circumscribed depigmentation associated with the absence of melanocytes in the affected areas. IO • 11 Thus its basis is a structural defect rather than tyrosinase deficiency in the existing melanocytes (the latter being seen in albino skin). Vitiligo is found in 1 per cent of the normal population. It can begin at any age, but in half of all cases the onset is before the age of 20. It rarely is present at birth, so a loss of melanocytes occurs between birth and onset. More than half the persons with vitiligo have a family history of vitiligo or premature graying of the hair. Probably the disorder is inherited as an autosomal dominant characteristic. Three hypotheses have been proposed to explain the mechanism for vitiligo, but confirmatory data are lacking. I 1-1:1 The first is that vitiligo is an autoimmune disorder resulting from formation of an antimelanocyte autoantibody. Vitiligo is associated with a number of diseases believed to be of autoimmune origin (Table 2). Antibodies to several tissues (thyroid, gastric, adrenal, and others) in vitiligo have been reported. However, vitiligo may occur in Addison's disease , whether idiopathic (autoimmune) or related to tuberculosis. An anti-melanin antibody may be found in the serum of patients with vitiligo and anti-melanoma cell antibodies have been demonstrated in the serum of patients with melanoma (which
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may be associated with vitiligo). However, no specific melanocytotoxic antibody has yet been demonstrated in patients with vitiligo. The second hypothesis is that vitiligo is caused by a neurogenic factor perhaps elaborated at peripheral-nerve endings. This factor would decrease melanogenesis and thus lighten the skin. l !. 12 A more recent hypothesis postulated self-destruction of melanocytes as the cause of vitiligo." - 1:J A melanin precursor may p:roduce a lethal effect on the melanocytes in the manner of phenolic and thio compounds, which stop melanin production in man and animals and produce depigmentation. Catechol derivatives also may have an influence in melanocyte destruction and vitiligo. Increased responsiveness of hyperthyroid patients to epinephrine has been postulated as an etiologic factor in vitiligo among them. J S Clinically, vitiligo tends to affect areas of active melanogenesis. Melanocytes in these areas may be more susceptible to damage, owing to accumulation of a pigment-cell toxin.ll , 12 What part the hormones may have in the etiology of vitiligo is not known.
HEMOCHROMATOSIS The pigmentation seen in hemochromatosis is diffuse and generalized, but is darker on the exposed areas, scars, extensor surfaces, and pressure points. 6 The oral mucosa is pigmented in only about 15 per cent of cases. The skin pigmentation is primarily the result of melanin deposition. Hemosiderin is deposited almost exclusively in the dermis , supposedlyaround the sweat glands, and contributes little if any to the pigmentation seen in hemochromatosis. The metallic gray hue so characteristic of the disease is probably related to the depth of the pigment in the skin. The endocrine pancreas is classically involved in hemochromatosis: diabetes mellitus develops in approximately 82 per cent of cases. 6 Pituitary insufficiency also may be demonstrated by careful testing, but the adrenal gland rarely if ever is significantly implicated. 21 The melanin pigmentation of hemochromatosis does not seem to be dependent on involvement of the endocrine glands, with or without hormonal changes. The treatment for the pigmentary disturbance in hemochromatosis is the treatment for the underlying disorder, namely phlebotomy.
ENDOCRINE INFLUENCES Pineal Considerable evidence suggests that pineal activity, at least in lower vertebrates, participates in the control of pigmentary mobility and adaptation.26 Temporary blanching of the skin has been noted in frogs and tadpoles fed mammalian pineal tissue or given injections of pineal extracts or melatonin. The opposite effect-that is, granule dispersion and skin darkening-is produced by the action of MSH (which will be discussed later).
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Lerner and associates' 4 discovered melatonin and tested the ability of this indole to lighten human skin but found no influence of that kind. The lack of such an effect could be related to the lack of homology between the melanocytes of humans and melatonin sensitivity of melanophores of amphibians. Alternatively, it could result from the fact that much of the melanin pigment in the human skin is stored outside the melanocyte in the squamous epithelial cells (keratinocytes)Yi. 26 Nevertheless, melatonin does not appear to have a significant influence on skin pigmentation in man. The enzyme 5-hydroxyindole-O-methyl transferase has been identified in some pineal tumors,25 but pigmentary disturbances do not occur among significant numbers of patients with pinealoma. Brown et al,4· 5 had two patients with malignant pinealomas and acanthosis nigricans. In addition, hypopituitarism may be associated with pineal tumors, perhaps as a result of deficiencies of the hypothalamic releasing factors."6 It is therefore difficult to define a significant function of melatonin in human pigmentation.
H ypothalamic Hypothalamic factors may inhibit synthesis and release of MSH in the frog.11 Secretion of an MSH-inhibiting factor (MIF) from the hypothalamus may occur in the frog and in mammals, but its physiologic function is not well understood at this time. It has not been demonstrated in man. Moriya et al. have recently reported on the possibility of two hypo thalamic factors in frogs: one may inhibit synthesis of MSH and the other inhibit release of it. The multiple hypothalamic releasing factors that affect pituitary function may have an influence in pigmentation which has not yet been delineated. Whether corticotropin-releasing factor (CRF) is significant in the pigmentation of Cushing's disease or adrenal disease is not known. There may be other, still undefined hypothalamic factors that influence pigmentation in man.
Pituitary and Adrenal Two melanocyte-stimulating hormones have been isolated from the pituitary: alpha MSH , containing 13 amino acids with a molecular weight of 1,823, and beta MSH, a polypeptide containing 22 amino acids with a molecular weight of 2,734. Alpha MSH has a 13-amino acid sequence in common with ACTH. Beta MSH has a 7-amino acid sequence in common with ACTH. Alpha MSH is the more potent of the two in producing melanin pigmentation. With recently devised techniques, it is possible to measure beta MSH in the blood. Normal values range from 20 to 110 picograms per mP The secretion of beta MSH by the normal pituitary is regulated by three factors." (1.) Glucocorticoids act suppressively, thus diminishing beta MSH. Subnormal values for beta MSH have been found with functioning adrenocortical neoplasms. (2.) Some factor gives a diurnal rhythm to the concentration of beta MSH, for increased values are found in the morning hours. (3.) Stress (for instance, laparotomy) may cause an increase in beta MSH. Altogether, the secretion of beta MSH is strikingly similar to that of ACTH.
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In patients with hypopituitarism, beta MSH values are subnormal. In patients with Cushing's disease, the beta MSH values are increased and diurnal rhythm is absent. In patients with the ectopic ACTH-MSH syndrome, high values for beta MSH have been measured. Recently Shapiro et al. have found that some tumors with increased biologic MSH activity may produce an ectopic MSH which is heterogeneous and structurally different from alpha MSH, beta MSH, and ACTH. That is the first report of biologic MSH activity in the ectopic ACTH-MSH syndrome which is not accounted for immunoreactively by alpha and beta MSH and ACTH. Obviously, further work is needed to clarify this situation. Apparently beta MSH is the principal pigmentary hormone in man. ACTH does have intrinsic melanotropic activity, but this is believed to be only about 4 per cent; and alpha MSH, though very potent, seems to have been too low to measure. I S Disorders and other circumstances that may be associated with increased levels of beta MSH are shown in Table 2. The pigmentation usually is diffuse and deeper in the skin of the exposed areas, scars, areola, palmar creases, knuckles, pressure areas, extensor surfaces, and oral mucosa. Vitiligo also may be seen in Addison's disease, as has been noted already. With treatment for primary adrenal insufficiency, the skin pigmentation lessens and usually reverts to the premorbid state. However, pigmentation that follows bilateral adrenalectomy for Cushing's disease does not lessen with adequate treatment for the adrenal insufficiency; apparently the ACTH-MSH regulatory mechanisms (so-called rheostats) require high concentrations of plasma adrenal steroids (Cushing's disease) to control production of ACTH and MSH. In approximately 20 per cent of cases of bilateral adrenal hyperplasia, there are pituitary tumors and increased production of ACTH-MSH; but what part adrenalectomy may have in producing these pituitary tumors is uncertain. Though ectopic ACTH-MSH production usually is corrected by resection of the neoplasm involved, metastasis always occurs and the prognosis is poor. Hyperpigmentation, most often acanthosis nigricans, has been noted in patients with acromegaly (as described above). Whether growth hormone causes the excess of the pigmentation or whether MSH production is increased in association with acromegaly is not known. Diffuse hyperpigmentation with normal MSH values has been noted in renal tubular acidosis, hyperthyroidism, urticaria pigmentosa, hepatic cirrhosis, and Hodgkin's disease. 2
Thyroid The skin of patients with hyperthyroidism may darken, but certainly the most important pigmentary concomitant is vitiligo.IHAs mentioned, increased responsiveness of hyperthyroid patients to epinephrine may predispose them to vitiligo.
Gonadal Melasma and its possible relationship to gonadal hormones have been reviewed above. Hypogonadism may be associated with diffuse hypomelanosis, but the mechanism for this decrease of pigmentation is not known. It is tempting to speculate that testosterone in the male and
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possibly estrogen in the female influence melanin pigmentation. Puberty heralds changes in the size, texture, and pigmentation of the external genitalia under the influence of gonadotropin and the gonadal hormones estrogen and testosterone. Little else is known about gonadal hormone influence in pigmentation.
SUMMARY Diffuse or circumscribed pigmentary changes may signal endocrine disease. (Melanogenesis and the hormonal factors involved are reviewed.) MSH and ACTH are major factors in the process of pigmentation in pituitary and adrenal disease and in the ectopic ACTH-MSH syndrome. ACTH and MSH affect pigmentation by stimulating tyrosinase synthesis, perhaps via cyclic AMP. Circumscribed hyperpigmentation (acanthosis nigricans and melasma) and circumscribed hypopigmentation (vitiligo) may occur in association with endocrine dysfunction, but the mechanism of action for these pigmentary disturbances is not yet defined. Autoimmunity and genetic factors may be involved.
REFERENCES 1. Abe K, Nicholson WE, Liddle GW, et al: Radioimmunoassay of f3·MSH in human plasma and tissues. J Clin Invest 46:1609-1616, 1967 2. Abe K, Nicholson WE, Liddle GW, et al: Normal and abnormal regulation of f3-MSH in man. J Clin Invest 48:1580-1585, 1969 3. Benedict PH, Szab6 G, Fitzpatrick TB, et al: Melanotic macules in Albright's syndrome and in neurofibromatosis. JAMA 205:618-626, 1968 4. Brown J, Winkelmann RK: Acanthosis nigricans: a study of 90 cases. Medicine (Baltimore) 47:33-51, 1968 5. Brown J, Winkelmann RK, Randall RV: Acanthosis nigricans and pituitary tumors: report of eight cases. JAMA 198:619-623, 1966 6. Cartwright GE: Hemochromatosis. In Harrison's Principles of Internal Medicine. Vol 1. Sixth edition. Edited by MM Wintrobe, GW Thorn, RD Adams, et al. New York, McGraw-Hill Book Company, Inc., 1970, pp 606-608 7. Danowski TS, Sabeh G, Sarver ME, et al: Skin spots and diabetes mellitus. Am J Med Sci 251:570-575, 1966 8. Eisert J: Diabetes and diseases of the skin. Med Clin North Am 49:621-632, 1965 9. Field JB, Johnson P, Herring B: Insulin-resistant diabetes associated with increased endogenous plasma insulin followed by complete remission. J Clin Invest 40:1672-1683, 1961 10. Fitzpatrick TB, Seiji M, McGugan AD: Melanin pigmentation. N Engl J Med 265:374-378; 430-434, 1961 11. Kawamura T, Fitzpatrick TB, Seiji M: Biology of Normal and Abnormal Melanocytes. Baltimore, University Park Press, 1971 12. Leading Article: Aetiology of vitiligo. Lancet 2:1298-1299,1971 13. Lerner AB: On the etiology of vitiligo and gray hair. Am J Med 51:141-147,1971 14. Lerner AB, Case JD, Heinzelman RV: Structure of melatonin. J Am Chem Soc 81:6084-6085, 1959 15. Lerner AB, McGuire JS: Melanocyte-stimulating hormone and adrenocorticotrophic hormone: their relation to pigmentation. N Engl J Med 270:539-546, 1964 16. McGuire J, Miiller H: Differential responsiveness of dermal and epidermal melanocytes of Rana pipiens to hormones. Endocrinology 78:367-372, 1966 17. Moriya T, Kikuyama S, Yasumasu I: Possible control mechanisms of release and synthesis of melanophore-stimulating hormone. In Biology of Normal and Abnormal Melanocytes. Edited by T Kawamura, TB Fitzpatrick, M Seiji. Baltimore, University Park Press, 1971, pp 47-55
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18. Ochi Y, DeGroot LJ: Vitiligo in Graves' disease. Ann Intern Med 71 :935-940, 1969 19. Resnik S: Melasma induced by oral contraceptive drugs. JAMA 199:601-605, 1967 20. Shapiro M, Nicholson WE, Orth DN , et al: Differences between ectopic MSH and Pituitary MSH. J Clin Endocrinol Metab 33:377-381,1971 21. Stocks AE, Martin FIR: Pituitary function in haemochromatosis. Am J Med 45:839-845 1968 ' 22. Tucker WR, Klink D, Goetz F, et al: Insulin resistance and acanthosis nigricans. Dia betes 13:395-399, 1964 23. Walton KW, Scott PJ, Dykes PW , et al: The significance of alterations in serum lipids in thyroid dysfunction. n . Alterations of the metabolism and turnover of ':I'I-Iow-density lipoproteins in hypothyroidism and thyrotoxicosis. Clin Sci 29:217-238, 1965 24. Winkelmann RK, Scheen SR Jr, Underdahl LO: Acanthosis nigricans and endocrine disease. JAMA 174:1145-1152, 1960 25. Wurtman RJ: Diseases of the pineal gland. In Harrison's Principles of Internal Medicine. Vol1. Sixth edition. Edited by MM Wintrobe, GW Thron, RD Adams, et a l. New York, McGraw-Hill Book Company , Inc., 1970, pp 573-577 26. Wurtman RJ, Axelrod J, KelJy DE: The Pineal. New York , Academic Pres s, Inc., 1968 Mayo Clinic Rochester, Minnesota 55901
Pigmentation and the Endocrinologist Lawrence E. Koppers, MD., and Pasquale J. Palumbo, MD.
Dermatologic changes not infrequently signal the clinician that a systemic disease is present. In particular, increase or decrease of pigmentation often alerts the physician to underlying endocrinopathy; and here we shall review abnormalities in pigmentation and their relation to the endocrine system. The color of normal skin depends primarily on its content of melanin, carotene, and oxyhemoglobin or reduced hemoglobin. Pathologic changes of skin pigmentation may be produced endogenously or exogenously - by bile, hemosiderin, homogentisic acid, heavy metals, or a tattoo pigment. With carotenemia, a characteristic orange-yellow pigment is deposited in the skin, most commonly in the palms of the hands. Carotenemia may be normal in infants and it may be related to dietary intake, but it occurs also in male castrates and in patients whose conversion of carotene to vitamin A is impaired by panhypopituitarism, myxedema, or diabetes. B, 2:l Skin pigmentation depends largely on the melanin content of the keratinocytes, and is not visible unless melanosomes have entered the keratinocytes. lO , 11 The leptomeninges, inner ear, uveal tract, and pigmentary layer of the retina are other locations that normally contain pigment. The skin becomes pigmented by an orderly sequence outlined in Table 1. The melanocyte, which is of neural origin, is the basic structural unit of the melanin pigmentary system in man. It contains specialized pigment organelles called "melanosomes" which are the site of melanin synthesis and are rich in the enzyme tryosinase. (Fully melanized melanosomes lose their tyrosinase activity and become melanin granules.) Melanin is a polymer of 5, 6-indole quinone, and the initial step in its formation is the oxidation of tyrosine to 3, 4-dihydroxyphenylalanine (dopa) in the presence of tyrosinase. The melanocyte and its associated group of keratinocytes form a structural-functional unit. In all races, skin has the same proportion of melanocytes. 1o • 11 The variations in skin color are due to genetically determined and acquired differences in the production of the melanosomes within the melanocyte and the rate at which these melanin granules are transferred to the keratinocytes. Even albino skin has a normal complement of melanocytes, but Medical Clinic s of No,·th America- Vo!. 56, No. 4, July 1972
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Process of Melanin Pigmentation
Formation of mela nos.omes in the mela nocyte Melanization of the melanosome s in the melanocyte s Secretion of the melanosomes into the keratinocytes Transport of m elanosomes by the keratinocytes, with de gradation of the melanosomes within the lysosome-like organelles in cauca soids or without degradation in n egroids
they lack tyrosinase for melanin synthesis. Melanin pigmentation is needed for protection against ultraviolet radiant energy, and deficiency of this pigmentation is accompanied by increased incidence of photosensitivity and skin cancer. Various metabolic, endocrine, and nutritional factors; chemical, physical, and pharmacologic agents; inflammations, infections, neoplasms, and miscellaneous influences may contribute to changes in pigmentation. l l In fish, amphibians, and reptiles, beta adrenergic agents darken the skin and alpha adrenergic agents, melatonin, and possibly acetylcholine inhibit the darkening effect of melanotropin (melanocyte-stimulating hormone; MSH) and ACTH.H The alpha and beta adrenergic effects are blocked by alpha and beta adrenergic antagonists. Thus alpha stimulation inhibits formation of cyclic adenosine monophosphate (AMP), induces aggregation of melanosomes , and lightens the skin. Beta stimulation has the opposite effect. Our discussion will be confined to the endocrine factors involved in pigmentation. Hormonal influences are important regulators of skin pigmentation in man as well as the lower species. 10, 11 MSH and ACTH increase melanin pigmentation, supposedly through an effect on cyclic AMP in the melanocyte and consequent activation of the enzyme tyrosinase. Thus, steps 1 and 2 of pigmentation (Table 1) are most likely to be under hormonal influence. The distribution of excess melanin pigmentation (hypermelanosis) may be circumscribed, as in acanthosis nigricans and melasma, or diffuse, as in hemochromatosis, adrenal disease, ACTH therapy, and ectopic MSH-ACTH production. Deficiency of melanin pigmentation (hypo me 1anosis) may be circumscribed, as in vitiligo, or diffuse, as in albinism, hypopituitarism, and hypogonadism. (Albinism has already been mentioned.) Vitiligo may be seen in various endocrine diseases and may be associated with diffuse pigmentation, as in Addison's disease. The influence of the pineal, hypothalamic, pituitary, adrenal, and thyroid glands and the gonads on pigmentation will be taken up under separate headings.
CIRCUMSCRIBED HYPERMELANOSIS Acanthosis nigricans is a symmetric, hyperpigmented, verrucous and hyperkeratotic reaction of the folds of the skin which most clinicians associate with presence of a visceral malignant tumor. ("Pseudoacanthosis
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nigricans" is a term applied to cases in which the patients are markedly obese and in which no cause for the pigmentary disturbance can be determined.) Abnormalities of the endocrine system have been noted in a number of cases of acanthosis nigricans, especially if the patients were in puberty or young adulthood. Winkelmann et al.2 4 found that of 29 patients with benign pubertal and postpubertal acanthosis nigricans, 9 had associated endocrinologic abnormalities (Table 2). Acanthosis nigricans has been reported in association with insulin-resistant diabetes 4 , 9, 22 and in association with congenital lipodystrophy as well as hyperlipidemia and growth abnormalities. 4 Brown et al. reported seven cases of acanthosis nigricans with acromegaly or gigantism and collected six others from the literature. The mechanisms of the association between these particular pituitary disorders and acanthosis nigricans are not known. Melasma (chloasma) is a circumscribed hyperpigmentation occurring almost exclusively in women and localized to the face, involving
Table 2.
Pigmentary Disturbances in Endocrine Disease
I. Circumscribed hypermelanosis A. Acanthosis nigricans 1. Pituitary basophilism 2. Gigantism and acromegaly 3. Hypogonadotropic hypogonadism 4. Cushing's disease 5. Addison's disease 6. Stein-Leventhal syndrome 7. Hyperthyroidism 8. Hypothyroidism 9. Diabetes mellitus B. Melasma 1. Pregnancy 2. Ovarian tumors 3. Oral contraceptives C. Miscellaneous 1. Albright's syndrome 2. Diabetes mellitus ("shin spots")
11. Circumscribed hypo melanosis (vitiligo) A. Addison's disease B. Hyperthyroidism C. Hashimoto's thyroiditis D. Diabetes mellitus E. Hypoparathyroidism Ill. Diffuse hypermelanosis A. Hemochromatosis B. Increased ACTH-MSH concentrations 1. Addison's disease (untreated) 2. Post-bilateral adrenalectomy for Cushing's disease 3. Ectopic ACTH-MSH syndrome IV . Diffuse hypo melanosis A. Hypopituitarism B. Hypogonadism
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predominantly the forehead, cheeks, and upper lip. This form of pigmentation may occur without unusual circumstances and in pregnancy, with ovarian tumors, and with oral contraceptive therapy. I" It appears to be hormonally related, but no consistent hormonal elevations have been found in melasma except when it was associated with pregnancy or with contraceptives given orally. The mechanism of this pigmentary disturbance is not known. The melanocyte distribution is uniform over the body, except that an increased cell population is located on the face and forehead. The face is most exposed to sunlight and has increased melanocyte population that protects aganist solar radiation. How hormones interact with this melanocyte population to produce the circumscribed pigmentation of melasma has not been elucidated. Localized nipple pigmentation may occur with pregnancy and with estrogen therapy.lI How the hormones interact to produce this localized pigmentation is speculative. In girls with Albright's syndrome, melanotic macules (cafe au lait spots) may appear in association with precocious puberty and polyostotic fibrous dysplasia.;) The interrelationships of the changes in skin, bone, and possibly ovaries have not been worked out. Hyperpigmented "shin spots" frequently are noted in diabetes mellitus. 7 This dermopathy is more prevalent in male diabetics and increases in frequency with the duration of the diabetes. The skin lesion, however, is not specific for diabetes. These localized areas of pigmentation may be related to trauma or small-vessel disease. The relationship of the diabetes mellitus and this circumscribed hypermelanosis is not known.
CIRCUMSCRIBED HYPOMELANOSIS (VITILIGO) Vitiligo is a circumscribed depigmentation associated with the absence of melanocytes in the affected areas. IO • 11 Thus its basis is a structural defect rather than tyrosinase deficiency in the existing melanocytes (the latter being seen in albino skin). Vitiligo is found in 1 per cent of the normal population. It can begin at any age, but in half of all cases the onset is before the age of 20. It rarely is present at birth, so a loss of melanocytes occurs between birth and onset. More than half the persons with vitiligo have a family history of vitiligo or premature graying of the hair. Probably the disorder is inherited as an autosomal dominant characteristic. Three hypotheses have been proposed to explain the mechanism for vitiligo, but confirmatory data are lacking. I 1-1:1 The first is that vitiligo is an autoimmune disorder resulting from formation of an antimelanocyte autoantibody. Vitiligo is associated with a number of diseases believed to be of autoimmune origin (Table 2). Antibodies to several tissues (thyroid, gastric, adrenal, and others) in vitiligo have been reported. However, vitiligo may occur in Addison's disease , whether idiopathic (autoimmune) or related to tuberculosis. An anti-melanin antibody may be found in the serum of patients with vitiligo and anti-melanoma cell antibodies have been demonstrated in the serum of patients with melanoma (which
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may be associated with vitiligo). However, no specific melanocytotoxic antibody has yet been demonstrated in patients with vitiligo. The second hypothesis is that vitiligo is caused by a neurogenic factor perhaps elaborated at peripheral-nerve endings. This factor would decrease melanogenesis and thus lighten the skin. l !. 12 A more recent hypothesis postulated self-destruction of melanocytes as the cause of vitiligo." - 1:J A melanin precursor may p:roduce a lethal effect on the melanocytes in the manner of phenolic and thio compounds, which stop melanin production in man and animals and produce depigmentation. Catechol derivatives also may have an influence in melanocyte destruction and vitiligo. Increased responsiveness of hyperthyroid patients to epinephrine has been postulated as an etiologic factor in vitiligo among them. J S Clinically, vitiligo tends to affect areas of active melanogenesis. Melanocytes in these areas may be more susceptible to damage, owing to accumulation of a pigment-cell toxin.ll , 12 What part the hormones may have in the etiology of vitiligo is not known.
HEMOCHROMATOSIS The pigmentation seen in hemochromatosis is diffuse and generalized, but is darker on the exposed areas, scars, extensor surfaces, and pressure points. 6 The oral mucosa is pigmented in only about 15 per cent of cases. The skin pigmentation is primarily the result of melanin deposition. Hemosiderin is deposited almost exclusively in the dermis , supposedlyaround the sweat glands, and contributes little if any to the pigmentation seen in hemochromatosis. The metallic gray hue so characteristic of the disease is probably related to the depth of the pigment in the skin. The endocrine pancreas is classically involved in hemochromatosis: diabetes mellitus develops in approximately 82 per cent of cases. 6 Pituitary insufficiency also may be demonstrated by careful testing, but the adrenal gland rarely if ever is significantly implicated. 21 The melanin pigmentation of hemochromatosis does not seem to be dependent on involvement of the endocrine glands, with or without hormonal changes. The treatment for the pigmentary disturbance in hemochromatosis is the treatment for the underlying disorder, namely phlebotomy.
ENDOCRINE INFLUENCES Pineal Considerable evidence suggests that pineal activity, at least in lower vertebrates, participates in the control of pigmentary mobility and adaptation.26 Temporary blanching of the skin has been noted in frogs and tadpoles fed mammalian pineal tissue or given injections of pineal extracts or melatonin. The opposite effect-that is, granule dispersion and skin darkening-is produced by the action of MSH (which will be discussed later).
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Lerner and associates' 4 discovered melatonin and tested the ability of this indole to lighten human skin but found no influence of that kind. The lack of such an effect could be related to the lack of homology between the melanocytes of humans and melatonin sensitivity of melanophores of amphibians. Alternatively, it could result from the fact that much of the melanin pigment in the human skin is stored outside the melanocyte in the squamous epithelial cells (keratinocytes)Yi. 26 Nevertheless, melatonin does not appear to have a significant influence on skin pigmentation in man. The enzyme 5-hydroxyindole-O-methyl transferase has been identified in some pineal tumors,25 but pigmentary disturbances do not occur among significant numbers of patients with pinealoma. Brown et al,4· 5 had two patients with malignant pinealomas and acanthosis nigricans. In addition, hypopituitarism may be associated with pineal tumors, perhaps as a result of deficiencies of the hypothalamic releasing factors."6 It is therefore difficult to define a significant function of melatonin in human pigmentation.
H ypothalamic Hypothalamic factors may inhibit synthesis and release of MSH in the frog.11 Secretion of an MSH-inhibiting factor (MIF) from the hypothalamus may occur in the frog and in mammals, but its physiologic function is not well understood at this time. It has not been demonstrated in man. Moriya et al. have recently reported on the possibility of two hypo thalamic factors in frogs: one may inhibit synthesis of MSH and the other inhibit release of it. The multiple hypothalamic releasing factors that affect pituitary function may have an influence in pigmentation which has not yet been delineated. Whether corticotropin-releasing factor (CRF) is significant in the pigmentation of Cushing's disease or adrenal disease is not known. There may be other, still undefined hypothalamic factors that influence pigmentation in man.
Pituitary and Adrenal Two melanocyte-stimulating hormones have been isolated from the pituitary: alpha MSH , containing 13 amino acids with a molecular weight of 1,823, and beta MSH, a polypeptide containing 22 amino acids with a molecular weight of 2,734. Alpha MSH has a 13-amino acid sequence in common with ACTH. Beta MSH has a 7-amino acid sequence in common with ACTH. Alpha MSH is the more potent of the two in producing melanin pigmentation. With recently devised techniques, it is possible to measure beta MSH in the blood. Normal values range from 20 to 110 picograms per mP The secretion of beta MSH by the normal pituitary is regulated by three factors." (1.) Glucocorticoids act suppressively, thus diminishing beta MSH. Subnormal values for beta MSH have been found with functioning adrenocortical neoplasms. (2.) Some factor gives a diurnal rhythm to the concentration of beta MSH, for increased values are found in the morning hours. (3.) Stress (for instance, laparotomy) may cause an increase in beta MSH. Altogether, the secretion of beta MSH is strikingly similar to that of ACTH.
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In patients with hypopituitarism, beta MSH values are subnormal. In patients with Cushing's disease, the beta MSH values are increased and diurnal rhythm is absent. In patients with the ectopic ACTH-MSH syndrome, high values for beta MSH have been measured. Recently Shapiro et al. have found that some tumors with increased biologic MSH activity may produce an ectopic MSH which is heterogeneous and structurally different from alpha MSH, beta MSH, and ACTH. That is the first report of biologic MSH activity in the ectopic ACTH-MSH syndrome which is not accounted for immunoreactively by alpha and beta MSH and ACTH. Obviously, further work is needed to clarify this situation. Apparently beta MSH is the principal pigmentary hormone in man. ACTH does have intrinsic melanotropic activity, but this is believed to be only about 4 per cent; and alpha MSH, though very potent, seems to have been too low to measure. I S Disorders and other circumstances that may be associated with increased levels of beta MSH are shown in Table 2. The pigmentation usually is diffuse and deeper in the skin of the exposed areas, scars, areola, palmar creases, knuckles, pressure areas, extensor surfaces, and oral mucosa. Vitiligo also may be seen in Addison's disease, as has been noted already. With treatment for primary adrenal insufficiency, the skin pigmentation lessens and usually reverts to the premorbid state. However, pigmentation that follows bilateral adrenalectomy for Cushing's disease does not lessen with adequate treatment for the adrenal insufficiency; apparently the ACTH-MSH regulatory mechanisms (so-called rheostats) require high concentrations of plasma adrenal steroids (Cushing's disease) to control production of ACTH and MSH. In approximately 20 per cent of cases of bilateral adrenal hyperplasia, there are pituitary tumors and increased production of ACTH-MSH; but what part adrenalectomy may have in producing these pituitary tumors is uncertain. Though ectopic ACTH-MSH production usually is corrected by resection of the neoplasm involved, metastasis always occurs and the prognosis is poor. Hyperpigmentation, most often acanthosis nigricans, has been noted in patients with acromegaly (as described above). Whether growth hormone causes the excess of the pigmentation or whether MSH production is increased in association with acromegaly is not known. Diffuse hyperpigmentation with normal MSH values has been noted in renal tubular acidosis, hyperthyroidism, urticaria pigmentosa, hepatic cirrhosis, and Hodgkin's disease. 2
Thyroid The skin of patients with hyperthyroidism may darken, but certainly the most important pigmentary concomitant is vitiligo.IHAs mentioned, increased responsiveness of hyperthyroid patients to epinephrine may predispose them to vitiligo.
Gonadal Melasma and its possible relationship to gonadal hormones have been reviewed above. Hypogonadism may be associated with diffuse hypomelanosis, but the mechanism for this decrease of pigmentation is not known. It is tempting to speculate that testosterone in the male and
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possibly estrogen in the female influence melanin pigmentation. Puberty heralds changes in the size, texture, and pigmentation of the external genitalia under the influence of gonadotropin and the gonadal hormones estrogen and testosterone. Little else is known about gonadal hormone influence in pigmentation.
SUMMARY Diffuse or circumscribed pigmentary changes may signal endocrine disease. (Melanogenesis and the hormonal factors involved are reviewed.) MSH and ACTH are major factors in the process of pigmentation in pituitary and adrenal disease and in the ectopic ACTH-MSH syndrome. ACTH and MSH affect pigmentation by stimulating tyrosinase synthesis, perhaps via cyclic AMP. Circumscribed hyperpigmentation (acanthosis nigricans and melasma) and circumscribed hypopigmentation (vitiligo) may occur in association with endocrine dysfunction, but the mechanism of action for these pigmentary disturbances is not yet defined. Autoimmunity and genetic factors may be involved.
REFERENCES 1. Abe K, Nicholson WE, Liddle GW, et al: Radioimmunoassay of f3·MSH in human plasma and tissues. J Clin Invest 46:1609-1616, 1967 2. Abe K, Nicholson WE, Liddle GW, et al: Normal and abnormal regulation of f3-MSH in man. J Clin Invest 48:1580-1585, 1969 3. Benedict PH, Szab6 G, Fitzpatrick TB, et al: Melanotic macules in Albright's syndrome and in neurofibromatosis. JAMA 205:618-626, 1968 4. Brown J, Winkelmann RK: Acanthosis nigricans: a study of 90 cases. Medicine (Baltimore) 47:33-51, 1968 5. Brown J, Winkelmann RK, Randall RV: Acanthosis nigricans and pituitary tumors: report of eight cases. JAMA 198:619-623, 1966 6. Cartwright GE: Hemochromatosis. In Harrison's Principles of Internal Medicine. Vol 1. Sixth edition. Edited by MM Wintrobe, GW Thorn, RD Adams, et al. New York, McGraw-Hill Book Company, Inc., 1970, pp 606-608 7. Danowski TS, Sabeh G, Sarver ME, et al: Skin spots and diabetes mellitus. Am J Med Sci 251:570-575, 1966 8. Eisert J: Diabetes and diseases of the skin. Med Clin North Am 49:621-632, 1965 9. Field JB, Johnson P, Herring B: Insulin-resistant diabetes associated with increased endogenous plasma insulin followed by complete remission. J Clin Invest 40:1672-1683, 1961 10. Fitzpatrick TB, Seiji M, McGugan AD: Melanin pigmentation. N Engl J Med 265:374-378; 430-434, 1961 11. Kawamura T, Fitzpatrick TB, Seiji M: Biology of Normal and Abnormal Melanocytes. Baltimore, University Park Press, 1971 12. Leading Article: Aetiology of vitiligo. Lancet 2:1298-1299,1971 13. Lerner AB: On the etiology of vitiligo and gray hair. Am J Med 51:141-147,1971 14. Lerner AB, Case JD, Heinzelman RV: Structure of melatonin. J Am Chem Soc 81:6084-6085, 1959 15. Lerner AB, McGuire JS: Melanocyte-stimulating hormone and adrenocorticotrophic hormone: their relation to pigmentation. N Engl J Med 270:539-546, 1964 16. McGuire J, Miiller H: Differential responsiveness of dermal and epidermal melanocytes of Rana pipiens to hormones. Endocrinology 78:367-372, 1966 17. Moriya T, Kikuyama S, Yasumasu I: Possible control mechanisms of release and synthesis of melanophore-stimulating hormone. In Biology of Normal and Abnormal Melanocytes. Edited by T Kawamura, TB Fitzpatrick, M Seiji. Baltimore, University Park Press, 1971, pp 47-55
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18. Ochi Y, DeGroot LJ: Vitiligo in Graves' disease. Ann Intern Med 71 :935-940, 1969 19. Resnik S: Melasma induced by oral contraceptive drugs. JAMA 199:601-605, 1967 20. Shapiro M, Nicholson WE, Orth DN , et al: Differences between ectopic MSH and Pituitary MSH. J Clin Endocrinol Metab 33:377-381,1971 21. Stocks AE, Martin FIR: Pituitary function in haemochromatosis. Am J Med 45:839-845 1968 ' 22. Tucker WR, Klink D, Goetz F, et al: Insulin resistance and acanthosis nigricans. Dia betes 13:395-399, 1964 23. Walton KW, Scott PJ, Dykes PW , et al: The significance of alterations in serum lipids in thyroid dysfunction. n . Alterations of the metabolism and turnover of ':I'I-Iow-density lipoproteins in hypothyroidism and thyrotoxicosis. Clin Sci 29:217-238, 1965 24. Winkelmann RK, Scheen SR Jr, Underdahl LO: Acanthosis nigricans and endocrine disease. JAMA 174:1145-1152, 1960 25. Wurtman RJ: Diseases of the pineal gland. In Harrison's Principles of Internal Medicine. Vol1. Sixth edition. Edited by MM Wintrobe, GW Thron, RD Adams, et a l. New York, McGraw-Hill Book Company , Inc., 1970, pp 573-577 26. Wurtman RJ, Axelrod J, KelJy DE: The Pineal. New York , Academic Pres s, Inc., 1968 Mayo Clinic Rochester, Minnesota 55901