The Effect of Testosterone on the Azotemic Patient: An Intermediary Report

'I'HE JOURNAL OF UROLOGY

Vol. 83 1 Ko. 1, January 1960

Printed in U.S.A.

THE EFFECT OF TESTOSTERONE ON THE AZOTE}VIIC PATIEKT: A~'\ INTERMEDIARY REPORT J. LESTER vVILKEY, LLOYD J. BARSON, LAYTON KEST

AND

A. BRAGAGXl II!.

Vro1n the Departments of Urology, Cook County Hosp£tal and Colwnbus Hospital,

One of the consequences of the expanding scope of the field of urology is the increased number of facets of medicine the urologist must explore. In his unique position of seeing renal disease of all types, the urologist encounters azotemic patients, both medical and surgical. \Vith all the urologic diagnostic aids available to him, the urologist is best able to evaluate and initiate a therapeutic regimen for the recently discovered urerme patient. In October 1956, we first presented a preliminary report on the use of testosterone in the azotemic patient. 1 The clinical results since then have been so gratifying that we are now present-ing a series of 88 patients ,Yith a more complete evaluation of serum electrolyte patterns. Testosterone belongs to the same class of compounds as such familiar substances as cholesterol, estrogens and adrenocortical hormone (c:yc:lopcntano perhydrophenanthrinc). Androgens are present in the testes, the ovary and the adrenal cortex. There is a suggestion that andro-gens may be present in the placenta, epididymis and anterior pituitary. Testosterone cydopentylpropionate in oil is unique as a long acting androgen, for usually oil solutions arc more rapidly absorbed. Estrogens in aqueous suspension are much more slowly ab-sorbecl than when dissolved in oil. Selyc 2 first noticed in 1939 that when he gave testosterone to rats, their kidneys increased in size and weight. Increasing the close did not increase the kidney weight To see if the action was specific, he gave cholesterol. This had no effect on kidney weight. Histologic examination revealed three changes in kidnry structure: 1) hypertrophy

of the epithelial cells of the proximal and distal convoluted tubules, 2) thickening of the lamina of Bowman's capsule and :3) c:onsiderable thickening of the cortex of the kidney. Freedman and Spencer invPstigated the use of testosterone in a small group of azotPrnic patients. 3 They found no change in tbc urea clearance of quantity of protein though the blood urea was !owned. to our findings, their patients noticed no inmwdiatc feeling of well being. Lattimm-'1 found that human renal furn:tion as measured by inulin and cliodrnst. excretory methods did not increase signific:antlv as a result of large doses of testosterone pro. pionatc. He found in animals that inulin dear-ance and diodrast T:\I increasc\d in to the increase in renal tissue. However, \Yclsh'' found that the glornerular filtration rnte and the pffective renal blood flow were una.ffected testosterone treatment. Selye 6 in a series of experiments made two interesting observations un testosterone therapy in animals. Ra.ts with bilateral nephrectomies had a significantly survival time when treated with testosterone. demonstrated that pre-treatment with testo: tcrone propionate could protect mice D, lethal dose of mercuric chloride. [t was first noted in 182F that urea accmnnlatcs in the blood of an animal following; tiw removal of both kidneys. Subs<\quent to many of the dinical features of renal insntTicicncy wen) aceurately traced to nitrogen rdention. Autopsy on uremic: patients reveals nrnny organic changes in the nervous system, sHch 0,-

3 Freedman, P. and Spencer, A .. Testost.crn1HJ propionate in treatment of renal failure. Clrn Sc., 16: 4 Lat.timer, J. K.: Action of testosterone nate upon kidneys of rats, dogs and men. Uroi.

Accepted for publication June 8, 1959. Presented as the presidential address before the Chicago Urological Society in 1958. Publication delayed to permit follmvup of patients. Depo-testosterone (cyclopentylpropionate) was supplied by the Upjohn Company, Kalamazoo, Mich. 1 Wilkey, J_ L., Barson, L_ J. and Kest, L.: Effect of testosterone on azotemic patient. J. Urol., 78: 179, 1957. 2 Selye, H.: Effect of testosterone on kidney. J. Urol., 42: 637, 1939.

48: 778, 1942.

5 Welsh, C. Rosenthal, A., Duncan, M. T . and Taylor, H. Jr.: Testosterone propionatn and renal function. Am. J, Phvsiol , 137: :ns.

1W2.

.

Selye, H.: Effect of testosterone on kidm,y Canad. Med. Assoc. J., 42: 189, 1940. 7 Ann. de Chim. et Phys., 23 (second seriefil · 6

90, 1821.

25

26

WILKEY, BARSON, KEST AKD BRAGAGNI TABLE

1 Cases

Polycystic disease. . ................ . Acute or chronic glomerulonephritis .. . Pyelonephritis with or without nephrosclerosis (decompensated) ... Obstructive uropathy, postoperative ..

22 30 10

26 88

Total.

TABLE

2. Effect of testosterone Improved

Potassium level. NPN level .. ........ Creatinine level. ... ... Feeling of well-being ..

37 58

39 81

% Im-

Same

Worse

--

-

--

12 2 9 0

31 65.5 44 92

39 28 40 7

proved

sclerosis of cerebral vessels, accumulation of urea in the cerebral cortex and edema of the brain. Well known is the almost universal symptomatology of azotemia with its lethargy, headaches, weakness and gout, intestinal and respiratory symptoms. 8 We have used androgen therapy to help the damaged kidney to accommodate to its azotemic loads by taking advantage of the anticatabolic properties of testosterone propionate. By decreasing tissue breakdown, the nitrogenous excretory load to the damaged kidneys can also be decreased. For example, a patient with chronic uremia and an average urea clearance of 6 cc per minute, who excretes 2 cc of urine per minute and requires the excretion of 5.0 gm. of urea nitrogen per clay, would have a blood urea nitrogen of 58 mg. per 100 cc. C urea=

:g: B

XV

However, with the aid of the anticatabolic effect of androgen therapy this same patient may be able to achieve nitrogen equilibrium with the excretion of 4.0 gm. protein nitrogen per day and a subsequent reduction of his blood urea nitrogen to 46 mg. per 100 cc. This hormonal crutch may be the difference between marked azotemic symptoms and a clinically improved, satisfied patient. 8 Fishberg, A. M.: Hypertension and Nephritis. Philadelphia: Lea and Febiger, 1954, p. 57.

Many other avenues of exploitation of the "renal protective action" of testosterone are potentially available to the urologist. Selye 9 in 1941 noted that testosterone postponed renal atrophy following ligature of a ureter. This observation has been confirmed by other investigators. The urologist, presented with a patient with obstructive uropathy and azotemia, might do well to inaugurate testosterone therapy along with concomitant mechanical relief of obstruction. Two types who fall into this category are the prostatism patient with acute retention and the patient with accidental bilateral ureteral ligation. The "protective" action of testosterone in these cases might be used to prepare the kidneys for rapid return to adequate function. We have observed 88 patients with various types of uropathy and concomitant uremia in order to evaluate the possibility of different responses to androgen therapy. Pre-renal azotemia such as that caused by hemorrhage or liver disease was excluded from the study. Obstructive uropathy with resulting azotemia was not treated by androgens alone. However, as an adjunct to surgical relief of the obstruction it was felt that there was a more rapid reduction of the azotemia. In primary kidney disease it was found that there must be some kidney reserve left in order to obtain any clinical improvement. Surprisingly good results were obtained in proven polycystic kidney cases. The results in chronic glomerulonephritis and chronic pyelonephritis in general varied with the severity of intrinsic kidney involvement. The optimum clinical dose of testosterone has been variously recommended by other workers 3 to be somewhere between 10 mg. to 25 mg. per day to 80 mg. per day. We have used in our series (table 1) an adult dose of 50 mg. of testosterone propionate in oil per day with a final maintenance dose of 100 mg. per week. In severe cases the dose was 100 mg. of depotestosterone daily for 7 days. The results are shown in table 2, and figures 1 and 2. vVe must emphasize that testosterone is not a cure-all for kidney disease. However, it may be used when there is some kidney reserve left as an intelligent adjunct in selected cases of azotemia to produce gratifying results. Although the sta9 Selye, H. and Friedman, S. l\1.: Beneficial action of testosterone in experimental renal atrophy caused by ligature of ureter. Endocrinol., 29: 80, 1941.

BFFECT OF TESTOSTERONE ON AZ0'£E;\HC PA'rIENT Na

Ca

K

+

II!'

180

9

170

8

14

@)


'11

HiO

12

7

~

I)

0

~

150

6

11

JAO

5

l!J

130

4

120

0 tl>"',:,'11 '11.,

•@

8

Weeks

}'ru. 1. Composite average electrocyte levels. UN

or,liil.t@ ::i,,;,

300

12

275

ll

250

10

225

9

200

6

175

7

150

6

125

5

100

4

75

:5

50

2

25

l

lf)ftl@

Ill..

.

!'i!-,v.'lt·

0

l

7

2

8

9

Weeks Fm. 2. Composite average response of azotemia.

tistical results are self-evident, we would like to present several representative cases to better illustrate with the actual nature of testosterone therapy.

CASE REPORTS

Case 1. E. a 36-year old man, 1ni.s charged from a Veterans' Hospital and told tn a kidney specialist. The patient was infonnic:d

28

WILKEY, BARSON, KEST AND BRAGAGNI

that he had chronic nephritis after being hospitalized for 6 weeks. Presenting complaints were: frequency of urination every one to two hours; nocturia 2-3 times; weakness and poor appetite; failing vision and severe headaches. The blood pressure was 250/100. Urinalysis revealed 4 plus albumin, specific gravity 1.011, many casts and several red blood cells per high power field. The blood chemistry determinations were: nonprotein nitrogen 87 mg./100 ml., creatinine 5.8 mg./100 ml., sodium 199 meq/L, calcium 12 mg./100 ml., potassium 7.6 meq/L. The patient was given 100 mg. of testosterone (cyclopentylpropionate) intramuscularly every week. After 1 week, he felt much improved, with increased appetite, headaches gone and vision clearer. The patient says, "remarkable, I cannot believe it." Four weeks later, the blood nonprotein nitrogen had declined to 44 and the creatinine to 4.2. He has been wonderful for a year now, working steadily. Subjectively, he feels "500 per cent better." The maintenance dose of testosterone (cyclopentylpropionate) is 100 mg. intramuscularly monthly and halotestin 5 mg. orally daily. One year after institution of therapy, the blood chemistry is as follows: nonprotein nitrogen 44.5 mg., creatinine 4 mg., calcium 9.0 mg., sodium 140.0 and potassium 5.6. The blood pressure fluctuates between 180/100 and 200/100. Urinalysis reveals a specific gravity of 1.013-1.016 and albumin 2 plus. Case 2. J. G., a 47-year-old man, had proven bilateral polycystic kidney disease. He entered the hospital complaining of weakness, headaches and transient nausea. On admission, the urine revealed 4 plus albumin casts, specific gravity 1.012. The blood chemistry determination revealed nonprotein nitrogen 55.5 mg./100 ml., creatinine 3.15 mg./100 ml., sodium 222 meq/L, potassium 7.2 meq/L. Edema was present. Following is the chart on his 5 week hospital stay. Ca

-End of 1st week ......... alb. End of 2nd week ......... alb. End of 3rd week ......... alb. End of 4th week ......... alb. End of 5th week .... '" .. · I alb.

"'

NPN -

5

K

Na -

-

Blood Pr

"'~

.;

Urine

Present specific gravity is 1.016-1.018. The patient is now receiving halotestin 5 mg. orally twice daily, and 100 mg. testosterone intramuscularly weekly. He is working, has no symptoms and feels fine. Case 3. P. G., a 30-year-old woman, came into the office complaining of "chronic nephritis," saying she was dying. She claimed a high nonprotein nitrogen output, and weakness, nervousness, dizziness and nausea. Urine study revealed 4 plus albumin, casts, white and red blood cells. Blood chemistry studies revealed: nonprotein nitrogen 93 mg./100 ml., creatinine 7.5 mg./100 ml., sodium 212 meq/L, potassium 5.2 meq/L. One week later, after taking 100 mg. of depotestosterone daily, she felt much better. Two weeks later, blood studies showed the following: nonprotein nitrogen 81, creatinine 6.8, sodium 180, potassium 4.8, calcium 12.5. Urine study showed 3 plus albumin, and specific gravity 1.010. Four weeks later blood studies revealed: nonprotein nitrogen 75 mg./100 ml., creatinine 5.5 mg./100 ml., sodium 150 meq/L, potassium 4.2 meq/L. Now after a year of oral halotestin 5 mg. daily, and 100 mg. of testosterone intramuscularly weekly, the nonprotein nitrogen is 71, the creatinine 4.8, sodium 130, potassium 4.0, calcium 10. The urine shows 1 plus albumin and specific gravity 1.016. Presently the patient feels fine, does her housework, but her main concern is amenorrhea. She misses three to four periods, then worries and wants an AschheimZondek test. In this patient acne also developed from the drug. Case 4. A. H., a 48-year-old man with proven polycystic disease of the kidneys, complained of nausea, weakness, dizziness, headaches, poor appetite. He was treated with depo-testosterone intramuscularly 100 mg. daily for 6 days then 3 times weekly.

J>l

-

4+ 12.5 47

3

2+ 12

44

3.1 191 5.2 2+

2+ 11

38.5 2.9 148 4.8 I+

184 6.9 2+

1+ 10

40

2.0 146 4.00

1+ 10

42.5 2.2 14514.1 0

Urine

S.G.

- - --- -- -

"O

Admission .. After 1st week ....... After 2nd. week ....... After 3rd week ...... After 4th week .......

z~

j -

K

INa -

-

Ca

-

180/100 alb. 3+

1.012 96 7.5 202 8.3

13

170/100 alb. 3+

1.016 70 4.5 160 5.5

11

160/100 alb. 2+

1.018 60 3

130 4.3

10

160/100 alb. 2+

1.018 54 2.8

125 3.7

9

165/100 alb. 2+

1.020 46 1.80 120 3.5

9

---

Present blood studies: nonprotein nitrogen 47 mg./100 ml., creatinine 1.95 mg./100 ml. sodium 130 meq/L, potassium 4.0 meq/L,

J,JFFEC'l' OF TES'l'OS'l'ERONE ON AZOTEMIC p_"'-TIE;\/T

cakium 9.5 mg./100 ml. l-rine, 1 plus albumin, specific gravity 1.016-1.018. The patient feds fine; he received 100 mg. depo-testosteronc intramuscularly every 2 weeks for 2 ?Cars. Hci plays par golf, works every day. Case 5. S. L., a 60-ycar-old man, is a case of primary nephrosclerosis and benign prostatic hypertrophy. His complaints were weakness, nausea, frequency of urination ancl nocturia 2-3 times. The following chart summarizes his course. I

I I

I

Blood Pr

II I

Urine

! I'

i~

i"'

I- -

-1160/1101

Admission. After 1st week 1160/100, After 2nd week. .. 148/H8 I After 3rd week. ... 148/90 I After 4th ,Yeek. .. 146/98 I

I

·

!

S

...., H

::! .....

u~

Ii -~§ I Cal'

[/]

-

.

oum

Q

'"8

0 '

~

U)

-

--

"Jh. 2+ 92 '7.61607.613 alb. 2+

"'1, _,n,

,_

0-1,

1

alb. 2+ 6'-l 6 0,15016.011.5 alb. 1+ 50 4.2 13814. 2 9. 7

alb. l+ 144 ,4.3 13014.319.5 I I

He is now stronger, and fods better. The nocturia has decreased to 1-2 times. Case 6. H. A., a 7-year-old boy, is a patient of Dr. Herman JU. Soloway There was a history of sore throat for 7 days, followed by hematuria, vomiting and edema of the face and eyelids. The patient's blood pressure on admission was 110 /70 and the initial urinalysis revealrcl specific gravity J .020 with 4 plus albumin and many red blood cells. "\.dmission blood nonprotein nitrogen was 86 mg./100 ml. ancl the blood urea nitrogen 68 mg./100 ml. The patient received depotestosterone 10 mg. intramuscularly daily for 4 days, Five days after hormone therapy had been instituted, the nonprotcin nitrogen ,vas 46 and the blood urea nitrogen was 32. After 13 days of therapy the nonprotein nitrogen was 32 and the blood urea nitrogen 17. The child is fine, is active, eating heartily and the urine is normal. DISCUSSION

\YhcnevPr a hormone is used, side effects and untoward results must be eonsiderecl. In women some of the problems that havr been reported are baldness, deepening of thr voice, growth of beard, and acne. 4 The only condition that we have encountered is a minor degree of acne which has never been a problem. One patient complained that her libido had increased to such a

degree that it had become a marital probll'm. Nu definitive therapy was instituted. lnasmuch no adolesrents were treated for prolonged we had no experience witb prrmaturC' dosurP of epiphyses. Degenerative changes in serninifrrom, tubules have been reported with prolonged andro gen therapy. \\'t, do not consider this contraindication to therapy. In our series of cases ,ve ha,'<' encmmterPd no sensitivity to the oil basl' of the tcstoskr011c propionate. Although edema, secondary 1-(' renal disease:, developed in some of our pH· tients no increase in edema or development edema was notPd following tcstoskrmw Several eases of nephrocaleinosis and calccmia han, been report\ d in patients under androgen therapy. Since these romplications ha,,e occurred only in bed-ridden patients, it lrn.:', believed to be more probably clue to imrnobiliza · tion than to androgen therapy. 1n women un occasional complication is intermittent amcno 1••• rhea; therefore, these patients are told in advm1cb that the: situation may occur in order to apprehension. 0

0

CONCLUSIONS

The results of the use of testosterone .in 14,,; cases of azotemia have 1.w(,n prcsc:nkd. Tlw literature has been reviewed. Testosterone kw definite place in the treatment of uremia .. \J though it is not a curC'-all, intelligc:nt use: of the hormone, bearing in mind its nniquP physiologi,· and pharmacologic properties, will bring definitr· results. 1Yc have found testosterone to be of nwt,1: effective use in acute Pxaccrbations of chronic renal disease and the minimally kidney. Testosterone also tends to n·vcrse tii,, trend of progressive chronic renal involn'mer,l, COJ\ll\llcl\TT

The urologist is known to the laity as t]u, "kidney spPcialist." He is called upon to treat, not only the surgical conditions of the kidney, lrn t the medieal conditions as well. Consequently, a knowlc,dge of fluicl electrolyte balance, and the blood proteins k, necessary to the modern urologist.'8 nmm· mentarium, willingly or unwillingly. REFERE"l\JCES R. I. A:\'D SHIPLEY, R. A.: Androgmrn New York: ,J. Wiley & Sons, 195G. KocHAKIA:,.r, C. D.: Comparison of protein awt,bolic property of various androgens in ca,. trated rat. Am. J Physiol., 160: 53, HlDO. DORFMAN,