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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND% [: k2 K( I+ A, f* `9 f8 p
GONADOTROPIN
( L: d% P4 l: ~) H4 |! v1 ZRICHARD C. KLUGO* AND JOSEPH C. CERNY
* Y% C/ p7 I, H* E2 `: \From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
5 \1 }4 n/ h0 ^/ r4 Y4 {ABSTRACT
8 k/ q8 A' k' |Five patients were treated with gonadotropin and topical testosterone for micropenis associated, t4 q Y6 c3 |, O' s
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
* z$ w" F6 p: k& t1 ~tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
, |; s2 \0 q2 o! ?0 d: K& scream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
( H8 N! `; w6 m6 C& l# I! {for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
7 {3 r9 p' ^5 \9 Z, J5 f! bincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
% ^( u3 {0 M0 o# `1 bincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response5 h$ q. n- H" }
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
( [+ J7 R- E+ w* U1 r, U3 U; Tstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
- _0 Y, y# B- P% T" G4 J# bgrowth. The response appears to be greater in younger children, which is consistent with previ-! S& W5 o/ f9 z4 O' n% Z
ously published studies of age-related 5 reductase activity.
; U: A# Z$ p" g8 t1 @9 P% _Children with microphallus regardless of its etiology will. r6 M) N( H% P* u/ v
require augmentation or consideration for alteration of exter-/ F e8 N8 e# M( n" ?( B
nal genitalia. In many instances urethroplasty for hypo-
9 z0 \: E5 y: q ]# h7 f# Gspadias is easier with previous stimulation of phallic growth.
. h8 V5 S4 \3 ]3 j3 n* \2 c) kThe use of testosterone administered parenterally or topically+ J7 S$ c4 H7 o% {
has produced effective phallic growth. 1- 3 The mechanism of
' H! r, @- n3 P3 C+ G* {response has been considered as local or systemic. With this; m3 [ Q$ r0 k; W
in mind we studied 5 children with microphallus for response" X% M, [: A, Y% { v+ U
to gonadotropin and to topical testosterone independently.$ C5 S$ d4 U9 v* Z
MATERIALS AND METHODS
; P, P* N4 U: y( i8 J0 n5 aFive 46 XY male subjects between 3 and 17 years old were
0 F* R1 t+ @+ d0 devaluated for serum testosterone levels and hypothalamic
) r% W& q2 Y6 W1 ~7 p; zfunction. Of these 5 boys 2 were considered to have Kallmann's( F, ?+ |: @! B' W
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
; ]% `# Q- W. d4 ^lamic deficiency. After evaluation of response to luteinizing2 Z8 C9 s: X( c( S N% w
hormone-releasing hormone these patients were treated with, D/ p! a( F7 e, ]5 \% g0 g
1,000 units of gonadotropin weekly for 3 weeks. Six weeks# f2 l( N, W3 N) R4 w; _8 @
after completion of gonadotropin therapy 10 per cent topical
9 L; F6 y1 b( ~ Y6 E& h' F% Rtestosterone was applied to the phallus twice daily for 3 weeks.
: Q& k! k9 {. z4 u# fSerum testosterone, luteinizing hormone and follicle-stimulat-/ M' K0 M& J, w3 t
ing hormone were monitored before, during and after comple-
+ O: {$ I9 O. l! y. z4 ?1 |tion of each phase of therapy. Penile stretch length was
6 {5 _! O$ g9 a$ n* G* w2 |; J' Bobtained by measuring from the symphysis pubis to the tip of
) }; Z# m! E& Cthe glans. Penile circumferential (girth) measurements were. o- ^, D2 {# f& ^3 w* p
obtained using an orthopedic digital measuring device (see0 Q1 R* s5 w, [( ?! `, d, p
figure).
3 P7 r7 |$ C* ], GRESULTS
' E, Q3 h1 q5 gSerum testosterone increased moderately to levels between. K- w/ e6 \/ J
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-+ @/ J. {. }- s3 M& r" `4 D* Y3 ^
terone levels with topical testosterone remained near pre-
$ ?* m0 ]3 k, u0 x @, U$ {treatment levels (35 ng./dl.) or were elevated to similar levels
% d9 M/ N& u' T# x# i- ]& ^3 V- j5 {# E' odeveloped after gonadotropin therapy (96 ng./dl.). Higher
- ]* m. `1 Q3 j; ~# Q' o0 hserum levels were noted in older patients (12 and 17 years old),. P3 T4 _; x) G
while lower levels persisted in younger patients (4, 8, and 10
1 R5 j# D- h% G: Oyears old) (see table). Despite absence of profound alterations
6 s3 p' i5 M* G& a( h2 w# xof serum testosterone the topical therapy provided a greater
3 e$ @/ Q2 S* \. a/ h9 S( V3 S: x7 fAccepted for publication July 1, 1977. ·
8 I" w `2 L! V3 k$ JRead at annual meeting of American Urological Association,$ f) D- b) V% \' S, S
Chicago, Illinois, April 24-28, 1977.
$ h7 n" I4 t$ {, e6 @* Requests for reprints: Division of Urology, Henry Ford Hospital,7 f) k9 D" q6 F. Y
2799 W. Grand Blvd., Detroit, Michigan 48202.( S' T& G: ^, S- v* G
improvement in phallic growth compared to gonadotropin.
4 p% ~( [5 j% o7 y( A( hAverage phallic growth with gonadotropin was 14.3 per cent, n4 D2 J% p, `/ {9 D; z0 j
increase in length and 5.0 per cent increase of girth. Topical! u9 q5 m! F5 s0 [
testosterone produced a 60.0 per cent increase of phallic length
5 t7 T& n* E( _: T6 ^& F% Aand 52.9 per cent increase of girth (circumference). The3 k) R- A7 c4 \
response to topical testosterone was greatest in children be-: L% j; [# K5 \1 p
tween 4 and 8 years old, with a gradual decrease to age 179 y/ o G, {! G
years (see table).
+ h# n+ Q# s! d, k& U* qDISCUSSION
1 i7 h, P7 m( P b; }3 cTopical testosterone has been used effectively by other
$ V0 [. U, {5 i0 Mclinicians but its mode of action remains controversial. Im-
6 j$ ?) r5 B( zmergut and associates reported an excellent growth response
# |2 Q' X& y; y& Fto topical testosterone with low levels of serum testosterone,: s q4 t3 R! k% r& \' Q' q
suggesting a local effect.1 Others have obtained growth re-3 @% W) ^9 i6 P S, I7 B
sponse with high. levels of serum testosterone after topical
5 N7 J4 ~9 M4 K+ `administration, suggesting a systemic response. 3 The use of
3 y1 n8 E' N; Wgonadotropin to obtain levels of serum testosterone compara-
( {( }% [) w& O9 D! c0 i* Cble to levels obtained with topical testosterone would seem to
2 w' M8 q5 \% _9 I9 m" xprovide a means to compare the relative effectiveness of& c$ \7 K1 g: w/ n) T
topical testosterone to systemic testosterone effect. It cer-! \: F+ a* o1 c' v# R, V
tainly has been established that gonadotropin as well as par-
, G, n, R5 Q8 E% r/ k; g) W7 benteral testosterone administration will produce genital5 X1 @6 t* F( }1 `9 T+ T0 x1 Y4 L5 G
growth. Our report shows that the growth of the phallus was0 O+ h. v* H1 V5 Q
significantly greater with topical applications than with go-
9 b7 |5 V* v; l! J+ I Y# _nadotropin, particularly in children less than 10 years old.6 i! U8 Y J4 ?8 r2 M
The levels of serum testosterone remained similar or lower
, [. d1 y1 {* W; P: [1 Gthan with gonadotropin during therapy, suggesting that topi-
: n3 @: s. t1 a/ E; h) U* Scal application produces genital growth by its local effect as
' q$ v! g" X6 z/ _. g3 fwell as its systemic effect.
; J2 y4 t/ z+ @1 TReview of our patients and their growth response related to
+ s3 b0 i" R$ Qage shows a greater growth response at an earlier age. This is( t ^8 u) Q% v+ W7 Y7 T
consistent with the findings of Wilson and Walker, who
: F% a9 w0 {8 P% j% t( v7 Lreported an increased conversion of testosterone to dihydrotes-
9 t4 O( m C) v* s4 otosterone in the foreskin of neonates and infants.4 This activ-
2 {7 s' s4 r) a8 Qity gradually decreases with age until puberty when it ap-5 o: M# B7 u! D: E/ R% z3 z( F0 Y
proaches the same level of activity as peripheral skin. It may: [5 i% M& F; h' |; Q4 t w5 G# g( H; i
well be that absorption of testosterone is less when applied at; e/ h6 |0 l+ l% G$ T
an earlier age as suggested by lower serum levels in children9 |* q# T: h d9 G1 J- S
less than 10 years old. This fact may be explained by the
% _7 S6 Z8 w6 N& v8 `* G4 j1 q. Ngreater ability of phallic skin to convert testosterone to dihy-- S: D/ P7 H; ~# p& l
drotestosterone at this age. Conversely, serum levels in older$ q6 S2 c1 x7 U1 o$ l& ^% c5 a$ F8 Z
patients were higher, possibly because of decreased local
" ~; W8 k4 z, y0 W. m1 a667# K& I4 E/ U* U) O
668 KLUGO AND CERNY! ?) D; R. ]5 q7 ?1 u- G6 w
Pt. Age
! [/ D( U. R5 E(yrs.)6 M( X. a- J. }4 b0 j9 a, o
Serum Testosterone Phallus (cm.) Change Length
$ a+ B2 X3 o' ]0 s(ng./dl.) Girth x Length (%)9 U C- W5 P! i
4" B3 Y r/ F6 [
8* _5 ]6 B9 D# R r+ O; A& P! M. O
10
l! d8 R/ }+ a9 r5 A* }0 Z12: a* m3 u! R; X I% W
176 l& F' g' @$ n, l6 l" R
Gonadotropin5 [9 _! N) s* \9 j) `( p; h
71.6 2.0 X 3 16.6
6 s( i; r5 P+ E50.4 4.0 X 5.0 20.0
4 q `$ i8 o7 F8 V) Q22.0 4.5 X 4.0 25.0
3 J- G3 `9 B. R4 R2 d) d2 y84.6 4.0 X 4.5 11.1
' b0 E3 `0 e0 z& q. S85.9 4.5 X 5.5 9.0 s, Z/ j7 m0 F& t" M( o
Av. 14.3& C, c, L. |3 s! a3 R/ ~5 F
4
4 `; U; \6 [. v W; B8
9 `/ P1 l9 m8 ]; _. r10
t* F2 g6 g* _' V- S12" n4 {/ H9 _; }, m5 y, C
17
# r! k7 x; u0 Q# `Topical testosterone
, o0 T" H, Z! D34.6 4.5 X 6.5 85! g; N# } G( `
38.8 6.0 X 8.5 70
7 k- [+ @5 n' g* p40.0 6.0 X 6.5 62.5
% r# W- z; m1 H8 M% ?93.6 6.0 X 7.0 55.57 y8 K7 k6 P6 H0 L7 I' i
95.0 6.5 X 7.0 27.2% E6 k) e6 [8 z6 [
Av. 60.0$ K ^$ T; b2 Z1 f
available testosterone. Again, emphasis should be placed on
" q) R0 P# o% W# Gearly therapy when lower levels of testosterone appear to
1 U( \3 m) [8 ? d1 X; uprovide the best responses. The earlier therapy is instituted# x0 J- H0 o) P* q! G
the more likely there will be an excellent response with low
# k& t7 Q! W2 Q! L% i7 C) Aserum levels. Response occurs throughout adolescence as; e* p+ M" v* M/ z
noted in nomograms of phallic growth. 7 The actual response
6 ~/ Z5 N7 p5 T. _to a given serum level of testosterone is much greater at birth& S4 T! x# k6 R4 E! j: H
and gradually decreases as boys reach puberty. This is most
6 A( q8 b; E- B" c" g$ P/ l- dlikely related to the conversion of testosterone to dihydrotes-
% l t; C' s' y8 c0 t6 Z& gtosterone and correlates well with the studies of testosterone
7 E2 Y, U# f+ w3 o7 p6 ^& Lconversion in foreskin at various ages.
8 p3 \& C& L7 @+ dThe question arises regarding early treatment as to whether/ x* D; ]) H$ q% e4 [6 M4 K/ Z0 X
one might sacrifice ultimate potential growth as with acceler-
/ Y5 H) w. }! D$ ]- x# r# gated bone growth. The situation appears quite the reverse X4 O5 A, _$ w; n
with phallic response. If the early growth period is not used
5 ?# Z* Y9 e% A" D) j* O1 Vwhen 5a reductase activity is greatest then potential growth
5 ?5 v) X% k* E# z- u2 C7 O, bmay be lost. We have not observed any regression of growth" @9 D: W1 T. G3 ]
attained with topical or gonadotropin therapy. It may well
M' R: v. x" q Lbe that some patients will show little or no response to any
, F, D2 f& P7 [" G7 A1 B3 `form of therapy. This would suggest a defect in the ability to1 ]- w$ Q% ?' l, E2 Q, L( f* \) G
convert testosterone to dihydrotestosterone and indicate that
" t. ]/ o$ g, ^/ Rphallic and peripheral skin, and subcutaneous tissue should0 n. e" ?( p: f4 i
be compared for 5a reductase activity.
# T4 G* `) v' o5 @% o# @A, loop enlarges to measure penile girth in millimeters. B,
/ ]7 H/ K% j# \0 D% ]example of penile girth computed easily and accurately." P$ a# x% y, _
conversion of testosterone to dihydrotestosterone. It is in this
. Y1 X. f. b$ ]7 ]' d( r# yolder group that others have noted high levels of serum% P) [& O' {% d& v$ M; `2 s
testosterone with topical application. It would also appear
3 S8 E$ d; \6 P2 Hthat phallic response during puberty is related directly to the
$ B/ d) G3 a d* s! Hserum testosterone level. There also is other evidence of local
* e: U7 U B: w3 sresponse to testosterone with hair growth and with spermato-- ~$ o" @! @5 l( z% }6 K# [* S- z. R# r
genesis. 5• 6
/ h! @) g% A. mAdministration of larger doses of gonadotropin or systemic! M! V m6 B9 I/ |/ Z4 x2 L
testosterone, as well as topical applications that produce8 b I( ~1 o7 {3 [- O+ N" Z5 C
higher levels of serum testosterone (150 to 900 ng./dl.), will1 ^! s# e- j3 b( z5 P% K3 z3 H
also produce phallic growth but risks accelerated skeletal0 A/ l# k2 ?8 c
maturation even after stopping treatment. It would appear8 N4 A6 E+ { { c, `1 x
that this may be avoided by topical applications of testosterone
% Z' k( C/ c% |. Nand monitoring of serum testosterone. Even with this control
; p# J9 q& Y% ~8 J5 F' Zthe duration of our therapy did not exceed 3 weeks at any
5 t1 s: ]- s; W' @7 {time. It is apparent that the prepuberal male subject may4 U7 f. g- R5 W5 C2 N3 \
suffer accelerated bone growth with testosterone levels near
- Q: R3 p5 _0 `0 ^. W200 ng./dl. When skeletal maturation is complete the level of
9 R0 c7 c) h$ fserum testosterone can be maintained in the 700 to 1,300 ng./
. S9 D$ g5 Z% }6 fdl. range to stimulate phallic growth and secondary sexual
/ T5 a; M- G5 y( p4 jchanges. Therefore, after skeletal maturation parenteral tes-) _; Q# b' P) o0 `# k, @; e
tosterone may be used to advantage. Before skeletal matura-: e, S; w- K4 H- o6 `! k( s. c4 O
tion care must be taken to avoid maintaining levels of serum- x3 q$ d. J0 ]- H$ h9 I
testosterone more than 100 ng./dl. Low-dose gonadotropin) [& d% {0 k* ]% ]2 z
depends upon intrinsic testicular activity and may require; S& d' z. Q& R5 a# ?9 ^
prolonged administration for any response." H/ A3 k2 }4 H5 `
Alternately, topical testosterone does not depend upon tes-
( }$ q5 F1 U/ p8 F4 U6 u3 q/ m9 ?ticular function and may provide a more constant level of0 p( [6 C$ _$ b1 M8 v" L1 q
REFERENCES' R& x# l+ E; k
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
; G' H9 d3 p- A6 s" B) nR.: The local application of testosterone cream to the prepub-
3 ]5 A% l8 u) O) ]ertal phallus. J. Urol., 105: 905, 1971.
4 }! z+ W% M2 K4 ]- y8 s6 H2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
! x2 _2 [" E; ktreatment for micropenis during early childhood. J. Pediat.,3 a+ j/ h: D* m" W" |$ X9 ?- J' t
83: 247, 1973.% e6 o A( m* n$ r; g+ |0 P
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-7 ]- l B$ X# q" z C- ~4 b
one therapy for penile growth. Urology, 6: 708, 1975.1 |; R3 | X2 x' g z- ^
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
/ T1 X) _9 ]8 E! C* f1 eto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by: y" c8 U6 ~0 r& I7 a9 ^
skin slices of man. J. Clin. Invest., 48: 371, 1969.
! Q9 L5 v6 o5 x+ \: e% H, }3 d" t, `5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth$ D3 Q0 G. ?1 T7 |& u5 P
by topical application of androgens. J.A.M.A., 191: 521, 1965.
2 X y. e4 u! v* w, l6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local0 _2 [! _' s$ {9 q) G
androgenic effect of interstitial cell tumor of the testis. J.
+ s0 @( I5 v% \ f* y. ]. r8 p' GUrol., 104: 774, 1970." F: X2 ]% Q& N. A Q
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
. v; a8 a0 Q/ ]$ ]0 htion in the male genitalia from birth to maturity. J. Urol., 48: |
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