Progesterone secreting adrenal mass in a cat with clinical signs of hyperadrenocorticism
Mona Boord, DVM, and Craig Griffin, DVM
> Bilaterally symmetrical alopecia has multiple caus- es in cats. Hormonally induced alopecia may devel- op in cats secondary to high blood concentrations of progesterone.
> Clinical signs commonly associated with hyperad- renocorticism are polyuria, polydipsia, diabetes mellitus, temperament changes, cutaneous atro- phy, and alopecia. These clinical signs may also develop as the result of high blood concentrations of progesterone in cats.
A 7-year-old 7-kg (16-lb) male neutered Himalayan cat was referred to the Animal Dermatology Clinic of San Diego for a nonpruritic progressive alopecia of 9 months’ duration. The cat had a tentative diagnosis of endocrine-induced alopecia and had been treated accordingly. The diagnosis had been made on the basis of clinical findings of a nonpruritic, bilaterally sym- metrical, truncal alopecia. Sixteen weeks prior to refer- ral, results of CBC, serum biochemical analysis, feline viral screening tests, and serum thyroid concentration determination revealed mild hyperglycemia (206 mg of glucose/dl; reference range, 75 to 160 mg/dl) as the only abnormality. Treatment at that time included IM administration of 12.5 mg of methyltestosterone. Ten weeks prior to referral, the cat was treated with an additional 12.5 mg of methyltestosterone and 0.5 mg of estradiol IM because of a poor response to the initial treatment. The cat also had a poor response to the sec- ond treatment, which resulted in referral to the clinic.
The history obtained from the owner at the time of referral revealed that the problem had initially started 9 months previously with unusual matting of the undercoat. During a 2-month period, this progressed to loss of hair that started on the abdomen, medial aspect of thighs, and inguinal area. During the next 7 months, the alopecia progressed to the lateral aspect of the body, caudal area of the thighs, and thorax. Recently, the owner noticed the cat had become more aggressive, and had increased its drinking and urination.
Physical examination revealed a bright, alert responsive cat. At the commissures of the mouth near the mucocutaneous junction, a small number of come- dones were observed. Along the dorsal midline and lat- eral area of the thorax partial alopecia, scale, and a greasy unkempt coat quality were observed. The inguinal area, abdomen, medial and caudal areas of the thighs, ventral area of the thorax, and axilla were com-
Supported in part by the University of Tennessee Endocrinology Laboratory, Knoxville, TN 37901.
pletely alopecic. In the inguinal area, the skin appeared thin with easily visible blood vessels and poor elastici- ty (Fig 1). Two focal areas on the inguinal area that were 1 mm in diameter and approximately 5 mm apart were regrowing small tufts of hair. The owner reported that this developed after her other cat had bitten this cat at that site. The distal portion of the extremities and paws had a slightly greasy coat quality.
The problem list included progressive bilaterally symmetrical truncal alopecia, greasy coat quality, scale, thin skin with poor elasticity, comedones, polyuria, polydipsia, aggressive behavior, and previously docu- mented mild hyperglycemia. Differential diagnoses included hyperadrenocorticism, dermatomycosis, demodectic mange, hypothyroidism, sex hormone abnormality, mite (Cheyletiella spp) infestation, myco- sis fungoides, alopecia areata, sebaceous adenitis, and paraneoplastic syndrome.
Diagnostic tests performed included fungal cul- tures for dermatophytes, skin scrapings, flea combing, and tape striping, the results of which were all nega- tive. After withholding food, the blood glucose con- centration was 112 mg/dl (reference range, 75 to 160 mg/dl). Biopsy specimens of the alopecic areas of skin were obtained, and histologic evaluation of the speci- mens revealed a noninflammatory condition with moderate hyperkeratosis, follicular dilation, and follic- ular hyperkeratosis. Dermal atrophy was observed, and hair in the active phase of growth (anagen) was not observed. These histologic results were, therefore, compatible with an endocrinopathy.
An ACTH stimulation test was performed, using 0.125 mg of synthetic ACTH (cosyntropin) adminis-
| Variable | Affected cat before adrenalectomy | Clinically normal cat | Affected cat after adrenalectomy | |||
|---|---|---|---|---|---|---|
| Before | After | Before | After | Before | After | |
| Testosterone (ng/ml) | 0.19 | 0.50 | 0.12 | 0.18 | 0.32 | 0.34 |
| DHEA + S (ng/ml) | 1.78 | 4.59 | 1.16 | 1.19 | 3.85 | 4.25 |
| Andro (ng/ml) | 2.17 | 5.12 | 1.41 | 1.35 | 1.46 | 1.27 |
| Esterdiol (pg/ml) | 58.70 | 64.70 | 46.60 | 45.80 | 53.60 | 54.00 |
| 17 alpha-hy (ng/ml) | 0.19 | 0.66 | 0.10 | 0.18 | 0.00 | 0.08 |
| Progesterone (ng/ml) | 3.62 | 27.6 | 0.06 | 0.11 | 0.03 | 0.06 |
| DHEA + S = dihydroepiandrostenedione; Andro = androstenedione; 17 alpha-hy = 17 alpha- hydroxy-progesterone. | ||||||
tered IM. The resting serum cortisol concentration was 2.2 µg/dl (reference range, 1.0 to 5.0 µg/dl) and corti- sol concentration at 1 hour after ACTH stimulation was low at 4.4 ug/dl. One hour after ACTH stimula- tion, the reference range for serum cortisol concentra- tion of the testing laboratory was 5.0 to 12.5 µg/dl. These results were suggestive of iatrogenic hypoad- renocorticism, yet the cat had no history of corticos- teroid administration.
One month later, the cat was hospitalized for addi- tional diagnostic tests. At that time, bruising readily developed at sites of venipuncture. Results of CBC and serum biochemical analysis revealed a mild azotemia with a BUN concentration of 48 mg/dl (reference range, 10 to 30 mg/dl), and a high blood glucose con- centration of 299 mg/dl (reference range, 75 to 160 mg/dl), a slightly high serum sodium concentration of 158 mEq/L (reference range, 146 to 155 mEq/L), and a low serum potassium concentration of 3.1 mEq/L (ref- erence range, 3.7 to 5.2 mEq/L). A urine sample was obtained via cystocentesis and urinalysis revealed a specific gravity of 1.022, positive results for urine glu- cose (1,000 mg/dl), and mild proteinuria. Results of urine bacteriologic cultures were negative.
A low-dose dexamethasone suppression test, using 0.1 mg of dexamethasone sodium phosphate/kg (0.05 mg/lb) of body weight administered IV, was performed. This dosage of dexamethasone was chosen because 15 to 20% of clinically normal cats will fail to suppress cortisol production when administered 0.01 mg of dex- amethasone/kg (0.005 mg/lb).1 Serum cortisol concen- trations were determined at 0 hour (before dexametha- sone administration) and at 4, 6, and 8 hours after dexamethasone administration and were within the expected reference range limits for healthy cats. However, compared with the resting concentration of cortisol (1.7 µg/dl), the suppression of cortisol produc- tion seemed delayed in that the cortisol concentrations in the 4-hour (1.3 µg/dl) and the 6-hour (1.1 µg/dl) samples were not as low as in the 8-hour sample (< 0.5 ug/dl). The next day, a thyroid stimulation test, using 0.5 U of thyrotropin/kg administered IV, was per- formed.2 Blood samples were obtained at 0 hour (before thyrotropin administration) and 6 hours after thyrotropin administration. Total thyroxine, free thy- roxine, and free triiodothyronine concentrations all doubled during the 6 hours (from 21 to 53 nmol/L, from 15 to 29 pmol/L, and from 0.4 to 1.2 pmol/L,
respectively). The total triiodothyronine concentration was unchanged (from 0.7 to 0.8 nmol/L). These results were all within reference range limits.
Abdominal ultrasonography revealed a 2.5 X 3.0- cm mass cranial to the left kidney and left of the aorta that was believed to be the left adrenal gland. The mass was compressing the caudal vena cava. The right adrenal gland could not be imaged. The problem list now additionally included hyperglycemia, glucosuria, hypernatremia, hypokalemia, overt bruising, and an adrenal mass. Differentials at this time included hyper- adrenocorticism (despite the results of ACTH stimula- tion and low-dose dexamethasone suppression tests), sex hormone-secreting adrenal mass, periadrenal mass, nonproductive adrenal mass, or pheochromocytoma.
Adrenalectomy was debated as a treatment option. Although alopecia was a cosmetic problem, the cat had additional progressive problems, including hyper- glycemia and thinning skin. The cat was a better can- didate for surgery at this time, before potential fragile skin and overt signs of diabetes mellitus developed. Prior to adrenalectomy, results of a coagulation panel were within reference range limits. Blood samples were obtained before (baseline samples) and after ACTH stimulation to measure androstenedione, estradiol, progesterone, testosterone, dihydroepiandrostene- dione, and 17 alpha-hydroxy-progesterone concentra- tions. Reference range concentrations of these hor- mones are not well documented in cats; therefore, a clinically normal, neutered male age-matched cat was tested concurrently (Table 1). Because of the marked- ly high progesterone concentrations measured in the blood samples of the cat of this report before and after ACTH stimulation, a progesterone-secreting adrenal mass was suspected.
During the adrenalectomy, biopsy specimens of the adrenal mass were obtained, and a histologic eval- uation of the specimens revealed that the cat had a well-differentiated adrenal cortical carcinoma. An attempt was made during surgery to view the right adrenal gland. It was not found in the perirenal fat and was assumed to be atrophic.
The cat was transferred to an internist for postsurgical follow-up evaluation of the hyper- glycemia, potential hypoadrenocorticism, and renal disease. Following surgery, the cat’s hyperglycemia and glucosuria resolved, the serum electrolyte concentra- tions remained within reference range limits, and the
azotemia persisted with BUN concentrations between 40 to 50 mg/dl. The cat also developed a mild anemia thought to be associated with the renal disease.
Four months following surgery, the cat was being maintained daily with prednisone (1.25 mg, PO, q 24 h) and administration of fluids, SC. The cat was exam- ined and had lost weight. The blood vessels could no longer be easily viewed in the inguinal area. The skin elasticity had improved. On the neck and cranioventral portion of the abdomen there was hair that was approximately 2 cm in length. Long primary hairs were found on the lateral portion of the body. Mild dry scale was still noticeable and the coat was still slightly greasy. Blood samples were again obtained to measure the concentration of sex hormones before and after ACTH stimulation (Table 1). The hyperprogesterone- mia had resolved. At the time of this writing, it was 12 months after surgery, and the cat was being treated for chronic renal disease. According to the owner, the cat’s normal coat quality had returned.
Bilaterally symmetrical alopecia has multiple caus- es in cats. Among those, multiple hormones have been implicated. The cat in this report had hormonally induced alopecia secondary to high blood progesterone concentrations. Progesterone is produced by the zona reticularis of the adrenal cortex, as well as the corpus luteum of the ovary.3 Little is actually known about adverse effects of high concentrations of natural pro- gesterones. What information is available is based on the adverse effects of progestins (pharmacologics that mimic progesterone).
Natural progesterone has a half-life in the blood of only a few minutes. It is converted to pregnanedione by 5-alpha-steroid reductase. Progesterone is a precur- sor hormone for androgens, estrogens, and cortisol. Progesterone binds to albumin, cortisol binding pro- tein (CBP), and sex hormone binding protein (SHBP). High blood progesterone concentrations also cause a decrease in SHBP. Progesterone competes with cortisol for CBP as well as with estrogens and androgens for SHBP. Free or unbound cortisol and sex hormones are active. High progesterone concentrations may cause high concentrations of free cortisol and sex hormones, thereby explaining how increases in progestogens can simulate the actions of glucocorticoids, estrogens, and androgens on a variety of tissues. Although proges- terone binds directly to the glucocorticoid receptors in humans and dogs,“ binding has not yet been deter- mined in cats. Progestogens act as glucocorticoid ago- nists, and have long-lasting suppressive effects on the hypothalamic-pituitary-adrenocortical axis.5 Modified progestogens can simulate glucocorticoid effects on many tissues6; for example, megestrol acetate and medroxyprogesterone acetate are potent progestational compounds with marked glucocorticoid activity.7
Adverse effects of glucocorticoids as well as progestogens observed in the cat of this report includ- ed polyuria, polydipsia, diabetes mellitus (transient or permanent), temperament change, cutaneous atrophy, and alopecia. A decreased serum cortisol concentration following ACTH stimulation was also observed in this cat. The polyuria and polydipsia may have been from the direct glucocorticoid-like effects of progesterone,
high free concentrations of cortisol, or from the hyper- glycemia and glucosuria. Transient and permanent dia- betes mellitus has developed in dogs, cats, and humans on progestogen treatment.6 This may result from the direct glucocorticoid activity of the progestogen, high free cortisol concentrations, or via an increase in growth hormone concentrations (dogs and humans, not cats) causing insulin resistance. In the cat of this report, the intermittent hyperglycemia and glucosuria resolved fol- lowing surgery, as can be seen in diabetes mellitus that is induced by progestogens or glucocorticoids.
Progestins have been used for many behavioral problems, and usually have a mellowing effect on tem- perament. Progestogens are thought to suppress the pain and punishment centers of the brain by binding to the dorsomedial nucleus.6,8 However, progesterone may also have androgenic effects, which could cause aggressive behavior. In the cat of this report, the mildly high con- centration of androgenic steroids, which were twice that of the clinically normal cat after ACTH stimulation, may have contributed to the reported aggressive behavior.
Adrenal suppression following administration of exogenous progestins is more powerful than that fol- lowing cortisol administration.6 In humans, this is thought to be caused by suppression of endogenous ACTH while the intrinsic adrenal function is normal. In the cat of this report, the cortisol concentration was low following ACTH administration indicating a direct effect on adrenal function as in dogs.5 Binding of pro- gesterone to glucocorticoid receptors or CBP receptors may result in an increase in free cortisol with subse- quent adrenal gland suppression. Alternatively, if the adrenal tumor was deficient in the enzymes required to convert progesterone to cortisol, then cortisol produc- tion could be maximal (not necessarily high), and ACTH concentrations would already be high. This would potentially explain the suppression of cortisol production observed in this cat in response to the low- dose dexamethasone suppression test, which is other- wise difficult to explain. This test was performed 10 weeks after the administration of testosterone and estrogen. Because these hormones inhibit luteinizing hormone and follicle stimulating hormone (but not ACTH) and they do not compete for CBP, their admin- istration should not have influenced the results of the low-dose dexamethasone suppression test.
Epidermal atrophy has been reported at the site of injection of megestrol acetate in cats,6 and bilateral flank alopecia has been observed in a dog with a tes- ticular Sertoli’s cell tumor and hyperprogesteronemia.9 The cause of alopecia associated with high proges- terone concentrations is unknown, but in theory relates to binding at the hair follicles.3
The cat of this report had clinical signs of endocrine-induced alopecia and hyperadrenocorti- cism. However diagnostics were not supportive of hyperadrenocorticism. In humans, high doses of prog- estins have lead to clinical signs of hyperadrenocorti- cism. A high blood concentration of progesterone has been shown to have multiple effects on tissues in the body, via the direct effect of progesterone binding to glucocorticoid receptors or via competitive binding and down-regulation of receptors causing high free
blood concentrations of cortisol, estrogens, and andro- gens. This may explain why animals have a variety of signs such as behavior changes or gynecomastia in cases of hyperadrenocorticism. Hormones are thought of as having specific actions, which they do, but they also have interactions and effects on each other.
Endocrine-induced alopecia is rare and often clini- cal signs are treated. However, diabetic cats with cuta- neous signs including poor greasy coats and scale is more common. Since this writing, the author has mea- sured sex hormones in a diabetic cat with a poor coat and poorly regulated diabetes that had negative test results for hyperadrenocorticism and high progesterone concentrations. Because sex hormones are steroid hor- mones and are produced by the adrenal glands, perhaps we should be evaluating cats with signs of hypera- drenocorticism not only for abnormal cortisol concen- trations, but also for sex hormone abnormalities-espe- cially cats with concurrent disease affecting quality of life, such as poorly controlled diabetes mellitus.
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