Dermatological manifestations

The excess GH can cause an increase in skin thickness, which is due to the increase of dermal collagen, and not to the expansion of the epidermis due to the proliferation and maturation of keratinocytes⁸. In addition, these patients may have swollen skin due to the accumulation of glycosaminoglycans in the dermis, which is more prominent on the face, hands, and feet⁹. Skin tags, which are usually related to insulin resistance and diabetes mellitus (DM), are present in most individuals affected by acromegaly. It is unclear if its appearance is due to excess GH and IGF-1 or if it is a consequence of another metabolic dysregulation¹⁰. Excessive sweating is found in 50% to 88% of patients, due to the trophic effect of GH on the cutaneous sweat glands, as well as growth of the periglandular nerves¹¹.

Dermatological manifestations

Dry, cold, and rough skin, due to decreased blood flow and secretion from the acinar glands, in response to a drop in thyroid hormones, are the most common manifestations, resulting in flaking, itching, and hypersensitive skin¹⁴. Changes in skin pigmentation are also observed. Pallor may occur due to decreased cutaneous blood supply, a yellowish coloration is usually due to increased serum carotene levels, and also cutaneous hyperpigmentation can be observed when hypothyroidism is associated with primary adrenal insufficiency¹⁵.

There may also be weakening of the nails, which become brittle, fragile and prone to flaking. This is due to hypothermia caused by hypothyroidism, resulting from a decrease in metabolic rate, which leads to a compensatory secondary vasoconstriction. Vasoconstriction decreases blood flow, with a deficit in the supply of nutrients and oxygen to skin structures, causing slow growth and brittle nails¹⁶.

The hair may also become coarse, brittle, dry, develop slow growth, and eventually lead to alopecia¹⁷.

In addition, myxedema may occur in the lower limbs, a soft and painless edema, giving the skin a thick and flaccid appearance, especially on the face, periorbital region, hands, and feet which results from the infiltration of the skin with glycosaminoglycans with associated water retention¹⁸.

Dermatological manifestations

Among the most common dermatological manifestations are warm, moist, and smooth skin. Heat is due to increased cutaneous blood flow and peripheral vasodilation, resulting from increased metabolism and may be accompanied by hyperhidrosis²². The skin may appear thin, soft, and fragile, becoming more susceptible to injuries and bruises, because of the decrease in the keratin layer. Diffuse or generalized alopecia (Fig. 1) may also be found²³.

Figure 1 Alopecia in a patient with hyperthyroidism (source: Lauro de Souza Lima Institute). 

Nails can present with onycholysis, also called Plummer’s nails, which comprises the separation of the nail from the nail bed, and onychodystrophy, which involves changes in the shape and texture of the nails. Some patients may develop cutaneous hyperpigmentation, especially in the areas exposed to the sun. The mechanism is related to cortisol deficiency, due to its accelerated degradation that occurs in these patients, which leads to an increased production of pro-opiomelanocortin (POMC), a prohormone that is subsequently cleaved into adrenocorticotropic hormone (ACTH) and melanocyte-stimulating hormone (MSH). Elevated serum levels of MSH stimulate increased melanin synthesis, which leads to hyperpigmentation²⁴.

If the cause of hyperthyroidism is Graves’ disease, periorbital edema and protrusion of the ocular globe may also be found. This is due to the enlargement of the eye muscles, caused by inflammation due to the accumulation of inflammatory cells and proliferation of fibroblasts in the interstitial tissue. Thus, this muscle enlargement ends up impairing the venous drainage of the orbital contents, causing periorbital and conjunctival edema²⁵.

Other autoimmune diseases affecting the skin can also observed more frequently in these patients, namely, vitiligo and chronic urticaria²⁶.

Dermatological manifestations

Several alterations can be found in affected patients, such as hirsutism²⁹ and acne, resulting from hyperandrogenism³⁰,³¹. This is due to the fact that androgens are the main hormonal regulators of hair growth and sebum production and secretion. In women with PCOS, excess androgen production by the ovaries increases serum levels of testosterone and dihydrotestosterone which interact with androgen receptors in hair follicles and promote differentiation from fleece hair (small, thin, and poorly pigmented) into terminal hair (thick, long, and pigmented)³² and enhance the activity of sebaceous glands. Hirsutism occurs mainly in the genital area and can progress along the medium line, groins, lumbar region, face, chin, intermammary region, and around the nipples³³. Acne in PCOS affects especially the face, but also the neck, upper trunk, and back regions.

Acanthosis nigricans (Fig. 2), characterized by dark, thick patches of skin, can also be found, especially in areas of body folds, such as the neck, armpits, and groin. It is strongly related to insulin resistance present in PCOS, with excessive production of insulin and IGF-1, which leads to increased stimulation of keratinocytes and fibroblasts²⁹.

Figure 2 Acanthosis nigricans in a patient with polycystic ovary syndrome (source: University Hospital of Coimbra). 

Dermatological manifestations

Cutaneous hyperpigmentation (Fig. 3) is the most characteristic finding, occurring in about 90% of patients³⁵, which is a consequence of cortisol deficiency and increased production of POMC and MSH by the hypophysis. Elevated MSH results in increased melanin synthesis in basal melanocytes (Fig. 4), causing hyperpigmentation³⁶. This hyperpigmentation is most common in sun-exposed areas and in skin folds, such as joints and scars. The color varies from light brown to dark brown and can be more intense on mucous membranes, such as gums, tongue, cheeks, and lips³⁸.

Figure 3 Hyperpigmentation on the lips of a patient with Addison’s disease (source: University Hospital of Coimbra). 

Figure 4 Histopathology (H and E ×40) of basal melanocytes of a patient with Addison’s disease (source: University Hospital of Coimbra). 

Vitiligo, in unequal areas and often bilateral, may be present in 10% to 20% of patients with Addison’s disease with autoimmune etiology, due to the autoimmune aggression of melanocytes³⁹.

Dermatological manifestations

One of the most prevalent manifestations is the presence of stretch marks in various regions of the body, such as the abdomen, thighs, arms, and breasts⁴² (Fig. 5), which are reddish or purplish in the acute phase and become thinner and whitish over time⁴³. Their presence is related to the reduction in skin elasticity caused by excess cortisol, which decreases the production of collagen and elastin, important components for skin integrity. High levels of cortisol can also inhibit cell regeneration and proper skin healing. When the skin is thin, it is more vulnerable to injury, and may present frequent bruising⁴⁴.

Figure 5 Stretch marks in a patient with Cushing’s syndrome (source: University Hospital of Coimbra). 

Another common skin manifestation when the cause is a pituitary tumor producing high levels of ACTH is hyperpigmentation, which can develop in sun-exposed areas, as well as in skin folds, armpits, groin, and neck. The skin in these areas may become darker, and the coloration may vary from light brown to dark brown⁴⁵.

Cushing’s syndrome can also lead to the development of oily skin and monomorphic papular acne, due to the hyperstimulation of the sebaceous glands caused by cortisol. Facial erythema and flushing can also be found, especially on the cheeks and nose, a condition known as facial erythema⁴⁶.

Dermatological manifestations

Dermatologic findings depend on which glands are compromised and which hormones are insufficient. In case of insufficiency in the production of thyroid-stimulating hormone the skin may become dry, cold, and rough, due to the resulting hypothyroidism, with all the clinical manifestations of this disease⁴.

In addition, the decrease in the production of gonadotropins follicle-stimulating hormone, and luteinizing hormone results in secondary hypogonadism in men and women, with a consequent decrease in body hair and also alopecia, since sex hormones are essential for the maintenance of hair and hair follicles⁴⁴.

Dermatological manifestations

Diabetic dermopathy is present in about 40% of patients and is often related to some DM-related chronic complication, such as kidney disease, retinopathy, or neuropathy⁵². The disease tends to appear in the lower extremities and in older men and can result from minor trauma⁵³. It is characterized by painless, and rarely itching, atrophic and hyperpigmented macules, located on the anterior region of the legs. They are oval or round, depressed, shiny, irregularly contoured, sometimes bilateral but with asymmetrical distribution⁵⁴.

Skin infections occur in 20-50% of patients with DM⁵⁵, particularly in those with type 2 DM. Overall, they are associated with poor glycemic control. Several factors favor the onset of infections in these patients, mainly those with chronic vascular or neurological complications. Alterations in immune response are frequently found, especially reduced neutrophil chemotaxis and phagocytosis, with increased adhesion between epithelial cells and pathogens (such as Candida albicans in the oral and vaginal mucosa and Escherichia coli in the urinary tract)⁵⁶.

Acanthosis nigricans often precedes the diagnosis of hyperglycemia, is characterized by dark, thick patches of skin, and is most often found in areas of body folds, such as the neck, armpits, and groin. It is strongly related to insulin resistance, which promotes the excessive production of IGF-1, which leads to hyperstimulation of keratinocytes and fibroblasts. The result is the appearance of hyperkeratosis and epidermal papillomatosis, which can be observed in histopathological analysis. Hyperkeratosis is mainly responsible for the clinical manifestation²⁸.

Vulvovaginal candidiasis is a prevalent disorder found in women with DM (Fig. 6), especially in those with poor glycemic control, and is a frequent cause of vulvar pruritus⁵⁶. It is clinically manifested by erythema of the genital area (with or without fissures) and satellite pustules. It is sometimes accompanied by whitish vaginal discharge. Its pathophysiology is related to the immune deficit of individuals with DM since they present inhibition of neutrophil activity, which increases the proliferation, adhesion, and virulence of this microorganism⁵⁷.

Figure 6 Groin candidiasis in a type 1 diabetic patient with poor glycemic control (source: University Hospital of Coimbra). 

Diabetic foot is the most devastating of DM-related complication. It is usually due to a combination of vasculopathy, neuropathy, and mechanical trauma, which occurs in 15-25% of all people with DM, and in about a quarter of these patients can lead to the onset of infections and osteomyelitis, which can lead to amputation of the affected limb⁵⁸. It is generally due to an unnoticed trauma to cutaneous areas with neuropathy and calluses, such as on the soles of the feet and tips of toes. The healing process is generally seriously compromised, due to hyperglycemia, impaired chemotaxis, cell proliferation, and migration⁵⁹. In addition, the increase in pro-inflammatory chemokines hinders wound healing, leading to the appearance of plantar ulcers. The presence of neuropathy and vasculopathy in these feet can cause muscle atrophy and bone deformation, with important changes in bone architecture, causing the collapse of the arch of the foot, a condition called Charcot foot.

Chronic pruritus is a common manifestation of DM, occurring in 3-49% of patients, significantly affecting their quality of life⁶⁰. Diabetic polyneuropathy with sweating dysfunction due to sympathetic nervous system impairment may play a role in the pathogenesis of pruritus in these patients⁶¹.

Vitiligo (Fig. 7), is found in 2-10% of patients with type 1 DM⁶², occurring spontaneously with a progressive course. Its pathophysiology is related to autoimmune mechanisms, an intrinsic characteristic of this type of DM⁶³.

Figure 7 Vitiligo in a patient with type 1 diabetes (source: Lauro de Souza Lima Institute). 

Necrobiosis lipoidica (Fig. 8) affects 0.3-1.2% of all patients with DM, with a higher prevalence in women than in men, and is commonly located in the ventral area of the legs, often with symmetrical distribution⁶⁴. It usually begins with erythematous papules, which slowly evolve into a brownish-yellow plaque with atrophic center and telangiectasia. In up to 35% of patients, lesions may ulcerate and present secondary bacterial infections. The pathophysiological mechanisms are still unknown, but the histopathology of the lesions shows degeneration of dermal collagen with a palisading granulomatous inflammatory infiltrate under an atrophic epidermis⁶⁵. Glycemic control has no significant effect on the evolution of these lesions, and no study has convincingly proven the efficacy of the various types of drugs used in the treatment of necrobiosis lipoidica, namely, topical or intralesional corticosteroids injected into the lesion edges, and also ultraviolet A⁵⁶.

Figure 8 Necrobiosis lipoidica in a patient with type 2 diabetes (source: University Hospital of Coimbra).