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å¡ CASE REPORT å¡

Adrenocortical Insufficiency Associated with Long-term High-dose Therapy for Prostatic Carcinoma Hiroshi Iida, Ichiro Miyamoto, Yatsugi Noda, Masaru Sawaki* and Yukihiro Nagai** A 59-year-old manwas admitted to our hospital because of muscular pain, weakness, and anorexia. He had been treated with 600 mg/day of fosfestrol, a synthetic , for 10 years for prostatic carcinoma. Endocrinological studies demonstrated adrenocortical insufficiency due to inadequate ACTHsecretion. After initiation of replacement therapy, his symp- toms subsided rapidly. To our knowledge, an association between estrogenic agents, including fosfestrol, and secondary adrenocortical insufficiency has not been previously reported. Physi- cians whotreat patients with long-term and high-dose strong estrogenic agents should be cau- tious about the possible emergence of secondary adrenocortical insufficiency. (Internal Medicine 38: 804-807, 1999) Keywords: estrogen, endocrine therapy, acetate

Introduction height, 167.0 cm; weight, 49.8 kg; blood pressure, 138/78 mmHg;pulse, 72 bpmand regular. The palpebral conjunctivae Fosfestrol is a synthetic estrogenic agent widely used in the were pale. Nogoiter or lymphadenopathy was observed. Ex- treatment of prostatic carcinoma. It exerts its clinical effect by aminations of lungs, heart, and nervous system were unremark- reducing the release of -releasing hormone from able. Noabnormal skin pigmentation was present. Axillary and the hypothalamus, thereby leading to a decrease in serum tes- pubic hair were preserved. Pretibial and pedal edema were tosterone concentration (1, 2). , an noted. Laboratory data on admission revealed the following: antiandrogenic agent which is also used for prostatic carcinoma, white blood cell count, 9,400/|il, with 23% segmented neutro- often induces secondary by suppressing phils, 1% banded neutrophils, 1 1% eosinophils, 57% lympho- the hypothalamic-pituitary axis whenadministered in high cytes, and 4%monocytes; red blood cell count, 301xl04/|Lil; doses (3, 4). To our knowledge, however, there has been no hemoglobin, 8.9 g/dl; hematocrit, 26.8%; platelet count, report of an association betweenestrogenic agents andadreno- 19.8x104/|li1; serum total protein, 5.5 g/dl; serum albumin, 3.57 cortical insufficiency. Wereport a patient whodeveloped sec- g/dl; serum sodium, 137 mEq//; serum potassium, 4.6 mEq//; ondary adrenocortical insufficiency 10 years after the initia- serum chloride, 104 mEq//; serum , 4.3 mEq//; alka- tion of high-dose fosfestrol therapy for prostatic carcinoma. line phosphatase, 143 IU//; creatinine phosphokinase, 1 16 IU/ /; total , 124 mg/dl; and triglyceride, 64 mg/dl. He- Case Report patic and renal functions and urinalysis were normal. Fasting blood glucose was 73 mg/dl. The endocrinological data on ad- A 49-year-old man was diagnosed with prostatic carcinoma mission are shown in Table 1. The basal plasma con- in the Department of Urology of our hospital in 1988. Radio- centration was decreased. The plasma adrenocorticotropin therapy and endocrinotherapy using a synthetic estrogen, (ACTH)concentration was undetectable at baseline. Twenty- fosfestrol, were initiated, and oral treatment with 600 mg/day four-hour urinary determinations of 1 7- of fosfestrol was continued for 10 years in the urological out- ( 17-OHCS), 17-ketosteroids (1 7-KS), and free cortisol revealed patient clinic. In July 1997, he was admitted to our department low . The plasma concentrations of free testoster- at the age of 59 because of slowly progressive muscular pain, one, (LH), and follicle stimulating hor- weakness, and anorexia that had continued for 3 months. The mone(FSH) concentrations were decreased due to physical examination on admission revealed the following: endocrinotherapy using fosfestrol. The circadian rhythm of Fromthe Department of Internal Medicine, *the Department of Urology, ToyamaRohsai Hospital, Toyamaand **the First Department of Internal Medicine, School of Medicine, Kanazawa University, Ishikawa Received for publication January 7, 1999; Accepted for publication May 29, 1999 Reprint requests should be addressed to Dr. Ichiro Miyamoto, the Department of Internal Medicine, ToyamaRohsai Hospital, 992 Rokuroumaru, Uozu, Toyama 937-0042

804 Internal Medicine Vol. 38, No. 10 (October 1999) Fosfestrol and Adrenocortical Insufficiency Table 1. Endocrinological Data (Basal Hormone Levels) B l o o d s a m p l e : A C T H < 5 p g/ m l ( 9 - 5 2 ) F T , 4. 8 p g /m l ( 3 .0 - 6. 0 ) G H 1. 2 3 n g /m l (< 1 .4 6 ) F T 4 0. 9 p g /m l ( 0 .8 - 2. 0 ) T S H 2 . 84 u U / m l ( 0 . 2 5 - 3. 1 ) C o rtis o l 0. 6 n g/ d l (5 . 6- 21 . 3) L H 0. 4 m l U/ m l ( 0 .7 - 6 . 5 ) A ld o ste ro n e 3. 3 n g/ d l (2 - 13 ) F S H 0. 3 m l U/ m l ( 1 .8 - 9 . 8 ) A V P 0. 3 p g/ m l ( 0. 3 -4 . 2 ) P R L 6. 2 n g/ m l ( 1. 5 -9 . 7) T e sto ste ro n e < 0 . 1 n g /m l (2 .7 - 1 0 .7 )

U r i ne s a m pl e : fre e c ort isol 3 2 u g / d a y ( 3 5 - 1 6 0 ) 1 7 - O H C S 0 . 5- 1 .3 m g/ d ay (2 . 9 -1 1. 6 ) 17 -K S 0 . 4 - 1. 8 m g /d a y ( 4 .6 - 1 6 . 4)

ACTH:adrenocorticotropin, GH: growth hormone, TSH: thyroid stimulating hormone, LH: luteiniz- ing hormone, FSH: follicle stimulating hormone, PRL: , FT3: free triiodothyronine, FT4: free thyroxine, AVP: arginine vasopressin, 17-OHCS: 17-hydroxycorticosteroids, 17-KS: 17-ketosteroids.

ACTHand cortisol was completely eliminated (Table 2A), and tween Japan and Western countries in the evaluation of this the rapid ACTHstimulation test (250 |ig) demonstrated a di- agent's efficacy against prostatic carcinoma. The efficacy of minished adrenal response (Table 2B). Table 2C shows the this drug is controversial in Western countries, and its adverse detailed hormonal investigations. The responses of plasma effects, especially cardiovascular complications, are stressed ACTHand cortisol to corticotropin-releasing hormone (CRH) in the case of its oral administration (5). Aspecific study con- were very diminished, while thyrotropin (TSH), prolactin ducted by the European Organization for Research on Treat- (PRL), and growth hormone (GH) were all adequately stimu- ment of Cancer reported the following adverse effects of lated by their respective releasing hormones. The responses of fosfestrol: fluid retention ( 1 6%), electrocardiograph^ changes plasma LH and FSH to LH-releasing hormone (LH-RH) were (3.6%), myocardial infarction ( 10.7%), arterial hypertension suppressed by fosfestrol. The responses of plasma ACTHand (1.8%), and thromboembolic lesions (6.3%) (6). Accordingly, cortisol to insulin-induced hypoglycemia were unequivocally cyproterone acetate, an antiandrogenic and progestational agent, low (Table 2D). The cranial magnetic resonance image showed is morewidely used for the treatment of prostatic carcinoma in no evidence of organic disorder. Precontrast computed tomog- Western countries (2, 3). In Japan, however, there are many raphy demonstrated normal adrenal glands. Antithyroidal, papers that demonstrate the usefulness of fosfestrol in the treat- antiadrenal, and antipituitary antibodies were all negative. ment of prostatic carcinoma with only minimal side effects Based on these data, we madea diagnosis of adrenocortical when given appropriately (7, 8). insufficiency due to inadequate ACTHsecretion. Fosfestrol was The causes of secondary adrenocortical insufficiency are discontinued immediately, and oral administration of hydro- primary pituitary disorders or causes secondary to hypotha- (20 mg/day) was initiated from August 1997. The lamic disorders such as tumors, apoplexy, , trauma, symptomssubsided in two weeks, and his anemia and eosino- immunological disorders, and adverse reactions to drugs and philia also improved. At this writing, almost two years later irradiation to the sella (9). The clinical history of the present (April 1999), he performs his typical activities but still receives case shows that pituitary apoplexy, trauma, and irradiation to glucocorticoid replacement therapy. the sella were unlikely. Moreover, based on his laboratory data and radiological findings, tumors, infection, and autoimmune Discussion hypophysitis can be excluded from the causative factors. There- fore, the secondary adrenocortical insufficiency of this case Endocrine therapy is accepted as an effective method for mayhave been due to the fosfestrol administration. In general, managing advanced prostatic carcinoma. Fosfestrol is a syn- drug-induced adrenocortical insufficiency constitutes a rare but thetic estrogenic agent widely used in the endocrine treatment important cause of hypoadrenalism (10-12). Several classes of prostatic carcinoma (1, 2). Fosfestrol exerts its clinical ef- of drugs, i.e. glucocorticoid, antiadrenal agents, anticoagula- fect by reducing the release of gonadotropin-releasing hormone tion agents, , , and cyproterone acetate, from the hypothalamus, thereby leading to a reduction in the can contribute to partial or complete adrenal failure (10-12). release of FSHand LHfrom the pituitary, and a consequent Of these drugs, only glucocorticoid and cyproterone acetate decrease of serum concentrations ( 1 , 2). Fosfestrol are knownto induce secondary adrenocortical insufficiency also exerts its effect by inhibiting the formation of 5a- (9). High-dose administration of cyproterone acetate is well (DHT)from testosterone in the cells of knownto cause secondary adrenal insufficiency by suppres- prostatic carcinoma (1 , 2). There are obvious differences be- sion of the hypothalamic-pituitary axis (3, 4, 13). Savage and

Internal Medicine Vol. 38, No. 10 (October 1999) 805 Iida et al

Table2. EndocrinologicalStudies A. Daily profile ofACTH an d C o r t is o l

T im e 8 :0 0 1 2 :0 0 1 6 :0 0 2 0 :0 0

A C T H ( p g / m l ) < 5 < 5 < 5 < 5 C ortisol (iig /d l) < 1 .0 < 1 .0 < 1 .0 < 1.0

B. Rapid ACTH stimulation t es t

T i m e a f t e r t h e i n j e c t i o n ( m i n ) 0 3 0 6 0

C ortisol (jLig /d l) < 1 .0 2 .0 4 .3 A ldo steron e (n g/dl) 3 .3 7 .2 6 .8

C . Provoca tive test s by C R H , G R H , T R H , a n d L H - R H

T i m e a f te r t h e i nj e c t i o n ( m i n ) 0 1 5 3 0 6 0 9 0 1 2 0

A C T H ( p g / m l ) < 5 7 1 1 < 5 C ortisoi (u g /d l) < 1 .0 < 1 .0 1 .2 1 .5 1 .3 < 1. 0 G H ( n g / m l ) 1 . 2 3 1 9 . 7 2 2 . 8 1 6 . 7 1 1 . 1 4 .7 2 T S H (u U /m l) 2 .0 3 1 0 .8 1 10 .9 1 1 0 .5 6 9 .5 4 7 .5 3 P R L ( n g / m l ) 6 . 2 2 2 . 8 2 1 . 9 1 8 . 5 1 7 12 .8 L H ( m I U / m l ) 0 . 4 0 . 7 0 . 7 0 . 8 1 . 0 0. 8 F S H ( m I U / m l ) 0 . 3 0 . 4 0 . 4 0 . 5 0 . 5 0. 5

100 |ng ofCRH, 100 jig ofGRH, 500 jig ofTRH, and 100 \ig ofLH-RH were administered intravenously at 0 minute. D. Insulin tolerance test

Timeafter the injection (min) 0 30 60 90 1 20

G lu c o se (m g /d l) 6 8 2 7 3 5 3 8 4 2 A C T H ( p g / m l ) < 5 . 0 8 . 0 8 . 0 6 .0 7. 0 C o rtis o l (u g /d l) < 1 .0 < 1 .0 < 1 .0 < 1. 0 1. 0 G H ( n g / m l ) 2 . 4 4 4 . 3 2 2 1 . 9 2 5. 3 2 1. 2 Abbreviations and normal values are shown in Table 1. 蝣

Swiftreportedthat a doseof 2 mg/kgper dayof cyproterone verseeffectsinducedbyfosfestrol,ledto a pituitaryinfarction acetateconsistentlyhada suppressanteffectonthe hypotha- andconsequentACTHdeficiency. Smallpituitary infarctions lamic-pituitary-adrenalaxis, but that the adrenocorticalfunc- sometimesgoentirelyundetectedbyradiologicalexaminations tionreturnedtonormala fewweeksafterthewithdrawalof (16). the drug(4). Thepresentcasehasneverbeenadministeredany Althoughthe mechanismof secondaryadrenocorticalin- of the abovedrugs.Regardingfosfestrol, it is well knownthat sufficiencyremainedunclearin the presentcase, physicians estrogentreatmentresultsin theelevationofserumcortisol shouldbecautiousaboutthepossibleemergenceof secondary andplasmaACTHlevels (14, 15). Therefore, it is unlikely that adrenocorticalinsufficiency,especiallywhenpatientstreated fosfestrolinducedthe secondaryadrenocorticalinsufficiency withlong-termandhigh-doseestrogentherapycomplainof directly. symptomssuchas muscularpain,weakness,andanorexia. Wecannotdenythe possibility that the isolated ACTHdefi- ciency,a developmentwhoseetiologywasunclear,mighthave References occurredcoincidentallyin the presentcase. However,it is also possiblethat a thromboembolism,oneof thecharacteristicad- 1 ) NakamuraK.,distributionandpharmacokineticsof dieth-

806 Internal MedicineVol. 38, No. 10 (October1999) Fosfestrol and Adrenocortical Insufficiency

ylstilbestrol converted from diphosphate in patients with 12 years in the single institute. Nippon Hinyokika Gakkai Zasshi 85: prostatic cancer. Hiroshima J Med Sci 35: 325-338, 1986. 1256-1262, 1994 (Abstract in English). 2) Kitahara S, Yoshida K, Ishizaka K, et al. Stronger suppression of serum 9) Kannan CR. Addison's disease, in: TheAdrenal Gland. Kannan CR, Ed. testosterone and FSHlevels by a synthetic estrogen than by castration or Plenum Publishing Corporation, New York, 1988: 31-96. an LH-RHagonist. Endocr J 44: 527-532, 1997. 10) PontA, Graybill JR, Craven PC, et al. High-dose ketoconazole therapy 3) Girard J, Baumann JB, Buhler U, et al. Cyproteroneacetate and ACTH and adrenal testicular function in humans. Arch Intern Med 144: 2150- adrenal function. J Clin Endocrinol Metab 47: 581-586, 1978. 2153, 1984. 4) Savage DCL, Swift PGF. Effect of cyproterone acetate on adrenocortical 1 1) Fellows IW, Byrne AJ, Allison SP. Adrenocortical suppression with function in children with precocious puberty. Arch Dis Child 56: 218- etomidate. Lancet 2: 54-55, 1983 (letter). 222, 1981. 12) Elansary EH, Earis JE. Rifampicin and adrenal crisis. BrMed J (Clin Res 5) Droz J-P, Kattan J, Bonnay M, ChraibiY, Bekradda M, Culine S. High- Ed)286: 1861-1862, 1983. dose continuous-infusion fosfestrol in hormone-resistant . 13) Lamberts SWJ, Uitterlinden P, de Jong FH. Rat prostatic weight regres- Cancer71: 1 123-1130, 1993. sion in reaction to ketoconazole, cyproterone acetate, and RU23908 as 6) deVoogt HJ, Smith PH, Pavone-Macaluso M, De Pauw M, Suciu S. Car- adjuncts to a depot formulation of gonadotropin-releasing hormone ana- diovascular side effects of diethylstilbestrol, cyproterone acetate, logue. Cancer Res 48: 6063-6068, 1988. medroxyprogesteroneacetate, and phosphate used for the 1 4) Schurmeyer T, GraffJ, Senge T, Nieschlag E. Effect of oestrogen or cypro- treatment of advanced prostatic cancer: results from European Organiza- terone acetate treatment on adrenocortical function in prostate carcinoma tion for Research on Treatment of Cancer trials 30761 and 30762. J Urol patients. Acta Endocrinol (Copenh) 111: 360-367, 1986. 135: 303-307, 1986. 15) Saoud CJ, WoodCE. Modulation ofovine fetal adrenocorticotropin se- 7) Oishi K, Arai Y, Takeuchi H,Yoshida O. Side effects of estrogen admin- cretion by and 17 beta-. AmJ Physiol 272: istration to prostatic cancer patients: clinical and statistical survey of 109 R1128-R1134, 1997. prostatic cancer cases of Kyoto University Hospital. Hinyokika Kiyo 39: 16) Wieland RG, Wieland JM. Isolated adrenocorticotropic hormone defi- 23-28, 1993 (in Japanese). ciency with antepartum pituitary infarction in a type I diabetic. Obstet 8) Hayakawa K, Kimura S, Ikeuchi K. The usefulness of Gynecol 65: 58S-59S, 1985. in the treatment of prostatic cancer-clinical analysis of 160 cases over

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