Clinics in Dermatology (2006) 24, 266–275

Dermatologic manifestations of

Jordan L. Geller, MD, Glenn D. Braunstein, MD*

Department of Medicine, Division of , Diabetes, and Metabolism, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA

Abstract Hypopituitarism is characterized by diminished or absent secretion of one or more pituitary . The clinical features of hypopituitarism vary depending on age, rapidity of onset, hormones involved, and degree of deficiency. Dermatologic signs of hypopituitarism may involve alterations in pigmentation, the epidermal and dermal skin structures, and the pilosebaceous unit. We describe the causes and presentation of hypopituitarism with an emphasis on its dermatologic manifestations. D 2006 Elsevier Inc. All rights reserved.

Introduction the gland is enclosed by the diaphragma sellae, a dural reflection that protects the gland from cerebrospinal fluid The is often referred to as the bmaster pressure. Pituitary disease often violates these tight bound- glandQ because it exerts control over many other endocrine aries, threatening vital adjacent structures such as the optic glands and physiologic processes, such as water homeosta- chiasm and hypothalamus superiorly, the cavernous sinuses sis, metabolism, growth, and reproduction. Hypopituitarism, laterally (housing cranial nerves III, IV, V, as well as VI and which is characterized by a relative or absolute deficiency of the internal carotid artery), and the sphenoid sinus inferiorly. one or more pituitary hormones, may also reveal the in- Disruption of these boundaries may therefore result in visual fluence of the pituitary gland on the integumentary system, loss, cranial neuropathies, hypothalamic dysfunction, and including the hair, nails, epidermis, dermis, pigmentation, cerebrospinal fluid rhinorrhea. and sebaceous as well as eccrine glands. We summarize the The pituitary gland is composed of anterior and posterior effects of anterior and posterior pituitary deficiency lobes. The posterior lobe develops as an evagination of the on the skin and dermal appendages. ventral hypothalamus and third ventricle. This neurohy- pophysis (neural undergrowth) contains axons and nerve endings of neurons originating in the hypothalamus. The Functional anatomy of the pituitary gland anterior pituitary or adenohypophysis (glandular under- growth) develops from Rathke’s pouch, an evagination of Measuring roughly 13 Â 9 Â 6 mm, the bean-shaped the oropharynx that migrates cranially to meet the neuro- pituitary gland is seated within the sella turcica at the skull hypophysis. The anterior pituitary gland consists of 3 lobes, base. It is bordered anteriorly by the posterior projection of the largest of which is the anterior lobe or pars distalis. the sphenoid wings and anterior clinoid and posteriorly by After development, the pituitary remains functionally the dorsum sellae and posterior clinoid process. Superiorly, dependent on the hypothalamus, which lies superior to the diaphragma sella and just posterior to the optic chiasm. The * Corresponding author. Tel.: +1 310 423 5140; fax: +1 310 423 0437. hypothalamus is coupled to the pituitary by the pituitary E-mail address: [email protected] (G.D. Braunstein). stalk, which houses the hypophyseoportal capillary system

0738-081X/$ – see front matter D 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.clindermatol.2006.04.014 Dermatologic manifestations of hypopituitarism 267 and hypothalamic neurons. Through a small opening in the is stimulated by the pulsatile release of the hypothalamic diaphragma sella, the stalk permits delivery of hypothalam- corticotropin-releasing factor. This is reflected in a diurnal ic hormones, which regulate anterior pituitary gland pattern of ACTH and cortisol release that peaks in the early function, as well as neuropeptides, destined for systemic morning. In the setting of severe physical, biochemical, or release from the posterior pituitary.1 emotional stress, this pattern is overridden and ACTH and Hypopituitarism is a condition in which there is dimin- cortisol release will increase severalfold. ACTH is inhibited ished or absent secretion of one or more pituitary hormones. by negative feedback at the level of both the hypothalamus The clinical features of hypopituitarism vary depending on and the pituitary. This may occur through either early non- age, rapidity of onset, hormones involved, and degree of nuclear–mediated (fast feedback) or late nuclear-mediated deficiency. The simultaneous loss of multiple hormones (long feedback) mechanisms.6 may modify the effect of the deficiency of any single hormone. The onset of pituitary dysfunction can be delayed Thyroid-stimulating hormone for years or decades after an insult, particularly in patients 2-5 Thyroid-stimulating hormone (TSH) is a glycoprotein with a history of cranial irradiation or head trauma. composed of 2 subunits, a and b. The a subunit is homo- logous to that of the follicle-stimulating hormone (FSH), luteinizing hormone (LH), and human chorionic gonadotro- Pituitary hormones pin; therefore, it is the unique b subunit that confers specific biologic activity to the TSH. In the thyroid gland, TSH Table 1 provides a summary of the pituitary hormones regulates iodine uptake (the rate-limiting substrate in thyroid discussed in this section, along with the target glands, hormone synthesis) as well as the incorporation of iodine stimulators, and inhibitors involved. into thyroglobulin for the formation and storage of thyroxine Adrenocorticotropic hormone (T4) and triiodothyronine (T3) and induces thyroglobulin resorption and subsequent release of T4 and some T3. Most Adrenocorticotropic hormone (ACTH) is a peptide T3 compounds are generated by peripheral deiodination of 7,8 hormone produced from a precursor molecule, proopiome- T4, much of which occurs in the skin. Interestingly, there lanocortin. It serves as a potent trophic factor for the adrenal is also extensive expression of functional TSH receptors in cortex and induces steroidogenic proteins critical in the the skin, although their role remains elusive.9 Because of the formation of glucocorticoids and adrenal androgens.6 ACTH gland’s capacity to store preformed hormones, abrupt loss of

Table 1 Pituitary hormones Hormone Target gland Stimulators Inhibitors ACTH Adrenal CRH; ADH Cortisol; synthetic glucocorticoids TSH Thyroid TRH; low T4 or T3; estrogen T4;T3; somatostatin; dopamine; glucocorticoids; chronic illness GH Muscle; bone; Ghrelin; metenkephalins; Somatostatin; hyperglycemia; GH viscera; fat exercise; physical stress; postprandial state LH Ovarian theca cells; Fast pulsatile GnRH; estrogen Continuous GnRH; testicular Leydig cells high-dose estrogen; progesterone; testosterone FSH Ovarian granulosa cells; Slow pulsatile GnRH Continuous GnRH; testicular Sertoli cells high-dose estrogen; progesterone; inhibin; testosterone PRL Breast TRH; estrogen; stress; Dopamine; calcitonin; serotonin; VIP; FGF; EGF endothelin 1; transforming growth factor b1 ADH Renal distal tubules and Hyperosmolality; hemorrhage; Withdrawal of stimuli collecting ducts; peripheral hypoxia; hypoglycemia; arterial system; anterior nausea; emesis; angiotensin II pituitary corticotrophs OT Breast; uterus Estrogen; vaginal and Withdrawal of stimuli cervical dilation; suckling; psychologic stimuli CRH indicates corticotropin-releasing factor; ADH, antidiuretic hormone; VIP, vasoactive intestinal peptide; EGF, epidermal growth factor; TRH, thyrotropin-releasing hormone; FGF, fibroblast growth factor. 268 J.L. Geller, G.D. Braunstein

TSH will not necessarily cause immediate . the hypothalamus and returns GnRH pulses to the FSH- Thyroid-stimulating hormone synthesis and release are promoting profile. Estradiol and progesterone also wield stimulated by the pulsatile release of the hypothalamic negative feedback at the hypothalamus and pituitary. In thyrotropic-releasing hormone (TRH). The pituitary re- male individuals, pulsatile release of GnRH stimulates LH sponse to the TRH is bimodal, typified by an initial release and FSH release. In the Leydig cells of the testes, LH of preformed hormones followed by subsequent increased stimulates testosterone production, whereas the FSH pro- gene transcription of TSH. Thyroid-stimulating hormone motes adjacent Sertoli cells to support spermatogenesis. synthesis is also directly stimulated by low serum T4 and T3, Testosterone and estrogen, much of which are produced by low intrathyrotroph T3, and estrogens, which increase TRH peripheral aromatization of testosterone, feed back at the receptors. The T3 exerts negative feedback at the hypothal- hypothalamus and pituitary to stem gonadotropins, as does amus and pituitary to inhibit TRH and TSH syntheses, Sertoli cell–derived inhibin.11 respectively. Somatostatin, dopamine, glucocorticoids, and chronic illness may also inhibit TSH.6

Growth hormone Prolactin (PRL) deficiency is extremely rare, even after significant pituitary damage has occurred, and in fact is (GH) is the most abundant hormone in more likely to be elevated in hypopituitarism.1 Prolactin is a the pituitary, accounting for 35% to 45% of the gland’s polypeptide hormone produced by the lactotroph cells in the hormones. GH promotes somatic growth and regulates body anterior pituitary. The near doubling of the pituitary gland composition by influencing protein and carbohydrate metab- during pregnancy is largely caused by lactotroph hyperpla- olism. The metabolic effects of GH are numerous, including sia under the influence of estrogen. The primary role of PRL increasing hepatic glucose output; decreasing insulin sensi- is to stimulate the production of milk proteins in hormonally tivity; and promoting lipolysis, amino acid uptake, and primed breast tissues. Although not required for pubertal protein synthesis. Hypothalamic growth hormone–releasing breast development, PRL (along with estrogen, progester- hormone promotes the synthesis and pulsatile release of GH, one, and IGF-1) is required for breast proliferation in the which peaks 1 to 4 hours after the onset of sleep. Other GH third trimester of pregnancy. Before delivery, estrogen and secretagogues include ghrelin, metenkephalins, sleep, exer- progesterone blunt the ability of PRL to cause lactation. In cise, physical stress (malnutrition, sepsis, fasting), and the the postpartum state, as these hormones decline, PRL action postprandial state. Most GH actions are mediated through becomes unrestrained and lactation ensues. Concurrently, insulin-like growth factor-1 (IGF-1), produced in the liver.10 PRL decreases the pulsatile release of gonadotropins, pre- venting simultaneous pregnancy. In the non-gravid state and Luteinizing hormone and in male individuals, PRL is released episodically throughout follicle stimulating hormone the day, with peak levels occurring during sleep. Prolactin is unique in that it is the only pituitary hormone under tonic Collectively referred to as gonadotropins, the luteinizing inhibition. Under normal conditions, PRL secretion is res- hormone (LH) and follicle stimulating hormone (FSH) arise trained by dopamine produced in the hypothalamus and from a single cell type within the pituitary. As in the case of transported to the lactotrophs through the hypothalamic TSH, the unique b subunits of these glycoproteins confer stalk. Anything that disrupts dopamine transport, such as their biologic activity. In the testicles and ovaries, LH and compression of the pituitary stalk from an intrapituitary or FSH promote the synthesis of sex steroids and gametogen- parasellar mass, will therefore result in hyperprolactinemia.1 esis. Stimulation and inhibition of LH and FSH are Other factors that stimulate PRL include TRH, physical largely dependent on variations in the frequency and stress, nipple stimulation, and vasoactive intestinal peptide. amplitude of the hypothalamic gonadotropin-releasing hormone (GnRH). In women, slow pulsatile release of the GnRH favors FSH secretion and maturation of the ovarian follicular unit consisting of theca and granulosa cells. The Vasopressin (arginine vasopressin or antidiuretic hor- concurrently rising LH stimulates theca cells to produce mone [ADH]) is produced by neurons in the supraoptic and androgens. In neighboring granulosa cells, FSH induces paraventricular nuclei of the hypothalamus. Along with a aromatase to convert androgens to estrogens. FSH also binding peptide, neurophysin II, ADH-containing granules elevates inhibin, which feeds back at the pituitary to inhibit migrate via axoplasmic flow to nerve endings in the neuro- further FSH release. Rising estradiol exerts positive hypophysis from which they are released. The ADH mobi- feedback at the hypothalamus by increasing the frequency lizes water channels to increase water reabsorption in the of and pituitary sensitivity to GnRH release. Concomitantly, distal tubules and collecting ducts of the kidney, enhances estradiol increases LH receptors on granulosa cells and the action of the corticotropin-releasing factor on pituitary enables the follicle to respond vigorously to the ensuing rise ACTH release, and produces vasoconstriction. These effects in LH (LH surge), which heralds ovulation. Progesterone are mediated by varying tissue distributions of the ADH 12 secreted by a ruptured follicle exerts negative feedback at receptors, V1,V2, and V3. Dermatologic manifestations of hypopituitarism 269

the placenta and contraction of the uterus to inhibit additional blood loss. After parturition, OT release is further stimulated by nipple suckling, as well as visual or psychologic stimuli such as an infant’s cry. At this stage, it promotes contraction of the breast myoepithelium and expulsion of milk.11,13

Causes of hypopituitarism

Hypopituitarism may be broadly classified as primary intrinsic pituitary disease or secondary occurring as a result of hypothalamic disease. Etiologies include neoplastic lesions (), vascular abnormalities (ische- mic necrosis), infiltrative diseases (sarcoidosis), autoim- mune disorders (autoimmune ), trauma (stalk destruction), infections (tuberculosis), congenital disorders (Rathke’s cleft cyst), and iatrogenic (radiotherapy) as well as idiopathic causes. One particularly well-described cause of acquired hypopituitarism is postpartum pituitary necrosis or Sheehan’s syndrome. After extensive blood loss during delivery, there is reflexive vasospasm of the hypophyseal blood vessels, leading to ischemic necrosis of the pituitary gland. It is estimated that up to one third of women experiencing peripartum hemorrhage will develop some amount of hypopituitarism, usually alactogenesis. The Fig. 1 Prepubertal hypopituitarism. A 16-year-old girl with the posterior lobe is typically spared because of its rich arterial Hand–Schqller–Christian variety of Langerhans cell histiocytosis blood supply. Many of the original descriptions of derma- with short stature and prepubertal hypogonadotropic hypogonadism. tologic changes associated with hypopituitarism have come by way of studies on patients with Sheehan’s syndrome.13 -15 Antidiuretic hormone release is stimulated by increased Table 2 provides a comparative summary of the systematic extracellular fluid osmolality as sensed by hypothalamic and dermatological manifestations of hypopituitarism. osmoreceptors and by decreased blood pressure as sensed by baroreceptor-mediated signals transmitted to the hypo- Nondermatologic manifestations thalamus. These stimuli generate an action potential in hypo- thalamic neurons, causing an influx of calcium. Calcium of hypopituitarism then induces exocytosis of arginine vasopressin–containing Adrenocorticotropic hormone deficiency usually has an neurosecretory granules into the capillary system of the pos- insidious onset with nonspecific symptoms such as fatigue, terior pituitary. As osmolality and blood volume normalize, 12 anorexia, and nausea. Postpubertal women may feel lack of the stimulus for ADH is removed and levels decline. libido and display scant axillary and pubic hair from the loss Oxytocin of adrenal androgens. Because mineralocorticoids are regulated by the renin–angiotensin–aldosterone axis, addi- Produced in the hypothalamic nuclei by an ancestral gene sonian crises are rare. In the setting of severe illness, patients related to the ADH, oxytocin (OT) promotes contractions in may develop cardiovascular collapse refractory to volume the smooth muscle of the uterine wall during parturition and resuscitation or pharmacologic vasopressors, nevertheless.1,6 the myoepithelium of the breast during lactation. The Symptoms of hypothyroidism reflect a global defect in synthesis and release of OT follow a similar pathway as energy metabolism and include weight gain, fatigue, and cold does the ADH, albeit with a different binding hormone, intolerance. Children with acquired central hypothyroidism neurophysin I. Before the onset of parturition, OT is may have impaired growth, coarsening features, and delayed stimulated by rising levels of estrogen, which increases puberty, whereas those with congenital hypothyroidism may OT receptor density in the uterus and lowers the threshold have profound mental retardation. If left untreated, hypothy- for muscle cell excitation. After the initiation of parturition, roidism can progress to myxedema coma, characterized by vaginal and cervical dilations stimulate strong pulsatile stupor, hypothermia, and cardiovascular collapse. release of the hormone, ensuring vigorous and coordinated Growth hormone deficiency is most pronounced in uterine contractions. Oxytocin continues to play a role in children, in whom it causes short stature with normal the second phase of delivery by promoting expulsion of proportions, usually recognizable by 12 to 18 months of 270 J.L. Geller, G.D. Braunstein

Fig. 2 Postpubertal hypopituitarism. Frame A shows lateral thinning of the eyebrows and fine facial wrinkling in a man with panhypopituitarism; Frame B, sparse body and pubic hair, gynecomastia, and gynecoid body habitus with decreased lean body mass (from Braunstein GD. Testes. In: Greenspan FS, Gardner DG, editors. Basic & Clinical Endocrinology. 7th ed. New York: McGraw-Hill; 2004). age. In adults, GH deficiency is associated with impaired loss of consciousness, ophthalmoplegia, and other neuro- quality of life, altered musculoskeletal composition, im- logic abnormalities. paired cardiac function, and increased cardiovascular risk factors.16 Loss of gonadotropins before puberty inhibits the Dermatologic manifestations development of normal secondary sexual characteristics in of hypopituitarism both sexes, resulting in delayed puberty. Girls fail to develop normal breast tissue as well as uterine growth and Hair exhibit primary amenorrhea (Fig. 1). Boys fail to experience deepening of their voice, muscle development, or penile and Up to one half of all patients with hypothyroidism testicular enlargement. Postpubertal gonadotropin deficien- will develop disruption or premature arrest of the anagen cy leads to secondary amenorrhea as well as loss of breast (growing phase) of the hair cycle, causing generalized 17-20 glandular tissue in women and a gradual decrease in size as alopecia. In particular, there may be loss of hair from 8,20 well as consistency of the testes in men, who may also the lateral third of the eyebrow and dull, coarse, and brittle experience a decrease in libido and erectile dysfunction. scalp hair. Thyroid hormone replacement will increase the 20 Clinically, hyperprolactinemia presents with proportion of telogen (resting phase) hair. and amenorrhea in women and decreased libido in men.1,10 Androgens induce epithelial cell differentiation in hair causes alactogenesis in women. follicles. Androgens are the main regulators and promoters 21 In children and adults, ADH deficiency limits the ability of hair growth, whereas estrogens inhibit it. In men, gona- to concentrate urine, resulting in with dotropin deficiency causes loss of androgen-mediated polyuria and polydipsia. Patients lacking thirst mechanism or virilization, the severity of which will depend on whether access to water will develop profound hypovolemic hyper- the pituitary insult occurs before or after puberty. Adoles- natremia. Oxytocin deficiency is not associated with specific cent boys will have decreased or absent facial as well as clinical manifestations. body hair and a smooth scrotum with absence of hair and Hemorrhage into large pituitary tumors may result rugae. Postpubertal men will show a slowing of beard in with the acute onset of hypotension, growth and uniformly decreased body hair, initially in the Dermatologic manifestations of hypopituitarism 271 axillae22 (Fig. 2A and B). In women, most androgens are onstrate decreased facial folds and fine wrinkling around the produced by the adrenal glands.23 The loss of LH-mediated eyes and mouth (Fig. 2A). ovarian androgens therefore does not have a significant Growth hormone deficiency also causes thin and dry skin impact on axillary or pubic hair, although prepubertal with abnormal epidermal differentiation and cornification. women will have loss of other secondary sexual character- Histomorphological studies on skin of patients with GH istics. Deficient adrenal androgens will reduce axillary and deficiency demonstrate thinning of the epidermis; decreased pubic hair in women, however.23 size of eccrine sweat glands; and decreased number, mor- There is a growing body of clinical and experimental phology, and organization of elastin fibers.32,33 evidence that PRL plays a role in the hair cycle. Prolactin and Glucocorticoid deficiency has not been reported to have its receptor are colocalized in murine hair follicles (which, direct effects on the skin. Patients with anorexia, nausea, or like those in human beings, are seasonally independent). vomiting caused by may however There, PRL is believed to promote the anagen phase of the appear dehydrated, with findings suggestive of interstitial hair cycle.24 These findings support the clinical observations fluid loss. Physical examination may reveal decreased skin of hair changes in human beings with either excess or turgor, dry skin (particularly in the axilla),34 and diminished deficient PRL. Estrogen is a potent stimulator of PRL release salivary excretions. One peculiar dermatologic sign associ- and prolongs the anagen phase of the hair cycle. This may ated with long-standing cortisol deficiency is auricular explain the increased frequency of hypertrichosis observed calcification.35 during pregnancy.24 Hyperprolactinemia is one recognized cause of hirsutism and may be successfully reversed with Skin pigmentation the PRL inhibitor bromocriptine.25,26 T4 accelerates the hepatic conversion of b-carotene Skin texture (provitamin A) to 2 molecules of vitamin A (retinol). Hypothyroidism causes hyper–b-carotenemia, which accu- 18,22 T4 stimulates the production of the epidermal growth mulates in the stratum corneum of the epidermis. This factor and increases its affinity for the epidermal growth causes a yellowish tint in the palms, soles, and nasolabial 8 factor receptor, whereas the T3 regulates epidermal folds that may be distinguished from jaundice by scleral turnover and promotes the differentiation of keratinocytes. sparing.22,27 Pallor is also common as hypothyroidism, a Loss of these trophic stimuli results in dry, rough, hyper- reflection of the hypometabolic state and reflex cutaneous keratotic, and scaly skin often described as parchment- vasoconstriction.22,27 This is compounded by the accumula- like.18 Hyperkeratosis also causes plugging of eccrine tion of water and mucopolysaccharides (see below) in the glands, further aggravating dry and coarse skin. Nails are dermis that alters the refraction of light.20 Unless there similarly dry and cracked. Because thyroid hormone is concurrent anemia, mucous membranes will retain their promotes the incorporation of sterols into the epidermis, characteristic hue. hypothyroidism causes abnormal lipid content in the skin, The precursor to ACTH, proopiomelanocortin, is also the adding to ichthyosis and hypohidrosis.19,20 Deficient source of the a-melanocyte–stimulating hormone (a-MSH).1 keratinocyte proliferation is believed to account for the Both a-MSH and ACTH mediate skin pigmentation by impaired wound healing observed in hypothyroidism.20,27 binding to the melanocortin receptors MC-1R and MC-2R. In the presence of T3, moreover, human keratinocyte gene Pituitary ACTH deficiency will cause hypopigmentation as a expression is preserved when compared with thyroid result of due loss of ACTH and a-MSH.31 Patients present hormone–deficient cells. This suggests that optimal thyroid with diffuse pallor particularly in the genital area, breast hormone replacement may play an important role in areolae, and face, which exhibits a decreased malar flush. wound healing.28 The inability to tan may lead to severe sunburn after sunlight Sex hormones stimulate the growth of keratinocytes and exposure.18 There is also a lack of normal skin reaction to the activity of melanocytes.8 Estrogen deficiency causes chronic environmental or occupational heat exposure (ery- atrophic, dry, and pruritic skin. This occurs because of the thema ab igne). Anemia, edema, and decreased cutaneous loss of estrogen-mediated hyaluronic acid production, which blood flow caused by concurrent hypothyroidism may normally retains water in the skin,29 as well as of decreased further exacerbate pallor.18 Proopiomelanocortin also medi- sebaceous and sweat gland production. Both androgens and ates follicular pigmentation, and patients with pituitary estrogens stimulate the synthesis, maturation, and turnover proopiomelanocortin gene mutations will have red hair of collagen.8,22,23 A decrease in estrogen-mediated collagen pigmentation in addition to early onset of obesity and and elastin production leads to thin skin with decreased adrenal insufficiency.36 Recent evidence have shown that resilience and pliability.22 Such dry and thin skin may be ACTH and a-MSH are also expressed within follicular easily traumatized, while at the same time having compro- melanocytes and epidermal keratinocytes, where they act in mised healing.29-31 The loss of androgen-mediated collagen an autocrine and paracrine manner, respectively.37,38 Amphi- synthesis and maturation also causes thinning of the skin bians can convey their pigmentation requirements by secret- and subcutaneous tissues. Patients characteristically dem- ing thyrotropin-releasing hormone from the skin to stimulate 272 J.L. Geller, G.D. Braunstein

Table 2 Systemic and dermatologic manifestations of hypopituitarism Hormone Major clinical manifestations of deficiency Major dermatologic manifestations of deficiency ACTH Fatigue; anorexia; nausea; hypotension; Skin hypopigmentation; decreased skin turgor; hypoglycemia; hypothermia; dry skin; auricular calcification; diminished axillary loss of libido in women and pubic hair in women TSH Fatigue; constipation; Dry, rough, and scaly skin weight gain; cold intolerance GH Impaired quality of life; Thin and dry skin; fat deposition altered musculoskeletal composition; in chest and abdomen impaired cardiac function; increased cardiovascular risk LH/FSH Amenorrhea; decreased libido; In men – decreased facial folds, impotence; infertility fine wrinkling around eyes and mouth, absent facial and body hair, smooth scrotum; in women – dry, atrophic, and pruritic skin; wrinkling as above PRL Alactogenesis None ADH Diabetes insipidus Decreased skin turgor; anhidrosis OT None None pituitary a-MSH production.39,40 An analogous system in also play a role in the regulation of sweat electrolytes, human beings has not yet been described. IGF-1, thymic T lymphocytes, and type II collagen.24,44 - 49 Vasopressin and OT have also been investigated for their Eccrine and sebaceous glands contribution to sweat rate and/or composition. Increased The decreased sympathetic drive of hypothyroidism will sweat chloride concentrations have been reported in patients with ADH resistance (ie, nephrogenic diabetes insipidus) but cause a reduction in sebaceous, eccrine, and apocrine gland 50 secretions. Androgens increase and estrogens decrease the not in those with pituitary ADH deficiency. Others have described anhidrosis in idiopathic diabetes insipidus that production of sebum, whereas the effects of progestins are 51 variable. Receptor density varies depending on anatomical resolved with desmopressin therapy. In that case, it was site, but the overall density of progesterone receptors is postulated that diabetes insipidus-induced hypovolemia higher than that of any other receptor.8 Regardless of the inhibited hypothalamic sudomotor activity, decreasing sym- cause, decreased sebaceous and eccrine sweat gland pathetic outflow to the skin. Restoration of euvolemia with production contributes to skin dryness. desmopressin restored sympathetic nerve activity and the Growth hormone deficiency can have profound effects on sweating apparatus. Human sweat glands have been reported thermoregulation and skin morphology. GH and IGF-1 may to express OT receptors, and in vitro electrophysiologic 41 experiments have shown an increase in the sodium chloride serve as trophic factors for the sweat gland epithelium. At 52 rest, core body temperature is maintained independently of content and rate of sweat production after exposure to OT. perspiration. With exercise or infection and in high ambient Body morphology temperatures, however, sweating becomes essential.32 In such settings, adults with GH deficiency have impaired Hypothyroidism causes an accumulation of the mucopo- thermoregulation41 and risk developing hyperthermia.42,43 lysaccharides hyaluronic acid and chondroitin sulfate B in This occurs not only because of a reduced number of sweat the dermis.20,22,27 When complexed with protein, these glands,32 but also because of functional disturbances in molecules attract water, producing myxedema. This is aggra- autonomic innervation.41 Sheehan and Davis,14 in their vated by protein extravasation into tissues and delayed original description of postpartum hypopituitarism, de- lymphatic drainage.18 In contrast to cardiogenic edema, scribed a reduction in sebaceous glands as well, although myxedematous tissue is typically nonpitting and is most this was not specifically attributed to GH deficiency. apparent around the eyes, supraclavicular fossae, and dorsum Sebaceous glands also appear to be regulated by PRL. of the hands and feet.18,20,22,27 In more advanced cases, there Patients with Parkinson’s disease (characterized by a may be macroglossia and thickening of the pharyngeal deficiency of dopamine) often develop seborrhea.24 The and laryngeal mucous membranes. On physical examination, increased sebum in these patients, as well as in those with patients may appear puffy, with drooping eyelids and slow acne vulgaris, improves with PRL inhibitors such as facial expressivity. The separation of elastic tissue and bromocriptine. Other diseases associated with dysregulated collagen by mucinous material can disrupt the support of PRL include psoriasis, hidradenitis suppurativa, acanthosis dermal blood vessels, causing ecchymoses and purpura. This nigricans, and systemic lupus erythematosus. Prolactin may may be exacerbated by deficiencies in clotting factors Dermatologic manifestations of hypopituitarism 273 also observed in hypothyroidism.20,22,27,53,54 Generalized pituitary hypofunction. These include tuberculosis, syphilis, myxedema of hypothyroidism may be fully reversed with disseminated pyogenic or fungal infections, HIV (and related thyroid hormone replacement. opportunistic infections), Korean hemorrhagic fever, and Other changes in body habitus are more pronounced in various other viral disorders. Survivors of snakebites from prepubertal children with hypopituitarism. The sine qua non Russell’s viper species in South Asia have also been found of GH deficiency is short stature in children. There may also to have a high prevalence of hypopituitarism from venom- be frontal bossing, delayed dentition, and excess fat depo- induced intravascular coagulation. In such patients, the sition in the chest and abdomen. Congenital GH deficiency immediate skin manifestations are a result of hemorrhagic can be associated with midline developmental defects such tissue necrosis and include ecchymoses and mucous as cleft lip or palate. Prepubertal boys with gonadotropin membrane bleeding.55 deficiency will have a small penis hidden within the fat pad of the mons pubis. Testes remain small and soft, generally less than 2 mL in volume. In men and women with Diagnosis of hypopituitarism hypogonadism, the pubertal growth spurt will be slow and a eunuchoid body habitus will evolve as a result of delayed The evaluation of suspected hypopituitarism begins with closure of the epiphyses of the long bones. Normal adult the concurrent measurement of pituitary and relevant height may ultimately be achieved.10 peripheral hormones. These include cortisol with ACTH, free T4 with TSH, IGF-1 with GH, and estradiol (women) or testosterone (men) with LH and FSH. In hypopituitarism Diseases associated with both hypopituitarism caused by or stalk effect, PRL measurements and dermatologic manifestations are useful for confirming a diagnosis and serving as biomarkers of subsequent disease recurrence. In hormones Several diseases are associated with hypopituitarism and that are regulated by feedback mechanisms, a low target the dermatologic manifestations of the underlying disorder. hormone (eg, T4) should prompt a rise in its associated Langerhans cell histiocytosis is a focal or systemic prolif- pituitary hormone (eg, TSH). Low or inappropriately normal eration of histiocytes with a predilection for the hypothal- levels of pituitary hormones imply hypothalamic or pituitary amus, pituitary stalk, and posterior pituitary. Patients dysfunction. Provocative stimulation testing is then needed commonly present with a brownish red papular or crusted to determine the extent of deficiency and to distinguish eruption, oral and genital ulcers, and diabetes insipidus pituitary from hypothalamic causes. This entails well- caused by destruction of vasopressin neurons. Hypothalamic defined protocols in which synthetic hypothalamic stimu- disease may also cause GH and gonadotropin deficiency lating hormones are administered intravenously while serial (Fig. 1). Sarcoidosis is a multisystem granulomatous disease measurements of both pituitary and target hormones are with rare hypothalamic or pituitary involvement, usually made. Normalization of pituitary and peripheral hormones presenting as hypothalamic hypopituitarism or diabetes after infusion of hypothalamic hormones suggests a insipidus. Skin findings include a maculopapular eruption hypothalamic deficiency, whereas no change implies a (commonly on the alae nares, lips, eyelids, forehead, neck at primary pituitary disorder, although there is overlap. the hairline, and sites of prior trauma) and, if chronic, Biochemical and/or clinical suspicion of hypopituitarism violaceous plaques. Wegener’s granulomatosis is a systemic necessitates magnetic resonance imaging of the pituitary and vasculitis presenting with epistaxis and palpable purpuric adjacent structures, along with formal visual field testing.1 lesions. Posterior and, less commonly, anterior pituitary hypofunctions have been described. Hemochromatosis is a disorder of extensive tissue deposition of iron, with an Management of hypopituitarism affinity for the pituitary gonadotrophs and, less commonly, lactotrophs. Male individuals commonly develop endocrine Treatment of hypopituitarism consists of replacing the manifestations, including decreased libido and impotence. individual peripheral hormones through oral, transdermal, The skin has a bronze hyperpigmentation. Whereas the intramuscular, intranasal, or subcutaneous routes. It is anterior pituitary gland does not have a major systemic essential that patients understand the importance of hormone blood supply, the posterior gland does via the inferior supplementation and (in the case of cortisol) the need for hypophyseal artery. This makes the posterior gland vulner- dosage adjustment during acute illness or stress. able to systemic metastases from lymphomas, leukemias, Glucocorticoids are usually replaced through hydrocor- and solid organ tumors. Skin findings may vary depending tisone in 2 divided doses totaling 15 to 25 mg/d. This must on the type of malignancy. Some common examples in- be done before thyroid hormone replacement, as the latter clude the generalized scaling of the skin (ichthyosis) of therapy may precipitate adrenal insufficiency. Mineralocor- Hodgkin’s disease and erythroderma in cutaneous T-cell ticoid replacement is rarely needed because aldosterone is lymphoma as well as acute leukemia. A multitude of regulated primarily via the renin–angiotensin axis. Hypo- infectious processes may share dermatologic findings and natremia may develop in the setting of adrenocortical 274 J.L. Geller, G.D. Braunstein insufficiency but is usually transient from inappropriately References elevated vasopressin and will resolve with cortisol replace- ment. Hypothyroidism is treated with 1 to 2 lg/kg of oral 1. Melmed S, Kleinberg D. Anterior pituitary. In: Larson PR, l-T given once daily. Physicians need to be aware that Kronberg HM, Melmed S, Polonsky KS, editors. Williams text- 4 7 various medications or physiologic states may interfere with book of endocrinology. 10th ed. Philadelphia Elsevier Science; 2003. p. 177-280. absorption or drug action and that periodic monitoring of 2. Toogood AA. Endocrine consequences of brain irradiation. Growth 56 serum free T4 is necessary during dose titration. 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Because of the possibility of occult hypopituitarism: screening study at 3 months after the brain injury. prostate cancer, men receiving androgen replacement should Clin Endocrinol (Oxf) 2004;61:320-6. have baseline and periodic measurements of prostate- 6. Aron DC, Findling JW, Tyrrell JB. Hypothalamus and pituitary gland. In: Greenspan FS, Gardner DG, editors. Basic and clinical endocri- specific antigen in conjunction with digital rectal examina- nology. 7th ed. New York7 Lange; 2004. p. 106-75. tions. The risk of erythrocytosis also necessitates periodic 7. Zouboulis CC. Human skin: an independent peripheral endocrine 57 monitoring of hemoglobin levels. In hypothalamic hypo- organ. Horm Res 2000;54:230-42. pituitarism, ovulation may be induced with clomiphene 8. Grando SA. Physiology of endocrine skin interrelations. J Am Acad citrate or GnRH injections that mimic the natural pulsatile Dermatol 1993;28:981-92. secretion. Patients with primary pituitary failure can be 9. 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