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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND/ }! ?1 e. z3 B* T3 b) R7 k
GONADOTROPIN2 O- w( V2 N( k4 N" d3 C
RICHARD C. KLUGO* AND JOSEPH C. CERNY
( T$ H% J( M6 ^From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
5 B4 ?7 {, q, f1 t0 e2 Y4 Z0 |# IABSTRACT# T. N$ R$ }- ^# e% [
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
9 B$ {- Q* v' S8 a2 a5 fwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-5 v: f5 d8 |* m, b
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone+ c- m8 x% ]2 v' S9 Q
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent! ?* `' H1 [; l) G. Y6 n4 X& I3 G
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
2 p6 x- O* k( v! tincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
: \( V1 [0 E& G, b0 r* Q/ R( vincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
5 c/ F- H* Y# u- Aoccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This# z% z  \* s- ]* r/ p, n5 a+ H  z
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
1 X/ B  D1 t/ \3 c* Wgrowth. The response appears to be greater in younger children, which is consistent with previ-2 s1 h3 s4 l% L* r
ously published studies of age-related 5 reductase activity.
# d' R' B: @; E- mChildren with microphallus regardless of its etiology will, B' }( P5 L3 @7 C- D
require augmentation or consideration for alteration of exter-+ k: I( `, ^* E4 S8 [( v$ X
nal genitalia. In many instances urethroplasty for hypo-
9 d0 \5 H% L" Rspadias is easier with previous stimulation of phallic growth.
- Z9 X- u; j- h% r/ H7 w6 v2 vThe use of testosterone administered parenterally or topically
; y. c1 {1 @% |, q* [( [; ~3 ahas produced effective phallic growth. 1- 3 The mechanism of2 D/ `1 o# y6 f  c
response has been considered as local or systemic. With this, }% m0 u" C* C+ U! Y
in mind we studied 5 children with microphallus for response
) I& u( y. \# L( x; pto gonadotropin and to topical testosterone independently.4 m9 i. O' P- u! ~! d5 x
MATERIALS AND METHODS* h( A  r% Z, j9 p+ i- J0 n
Five 46 XY male subjects between 3 and 17 years old were
# ?- m- P: k, Q0 B4 E0 b" t# B) M. oevaluated for serum testosterone levels and hypothalamic$ o& Q; W3 \7 ~
function. Of these 5 boys 2 were considered to have Kallmann's
) {* _7 `) ?$ Y2 Psyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
+ E5 X( o, a# f8 zlamic deficiency. After evaluation of response to luteinizing( z. w6 r# b0 O  |# d8 c
hormone-releasing hormone these patients were treated with) c2 n  `' c- w' Z: |6 C, Q1 a4 h
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
7 m  K6 Y3 C, w- Vafter completion of gonadotropin therapy 10 per cent topical
3 q* D, e! {! |  K6 M% U5 B! ntestosterone was applied to the phallus twice daily for 3 weeks.
; K8 P* a5 a$ c% D. M2 f0 ESerum testosterone, luteinizing hormone and follicle-stimulat-
" K3 |6 Q: t: O0 D3 xing hormone were monitored before, during and after comple-4 d# K  N, T, G# Q7 s4 d
tion of each phase of therapy. Penile stretch length was
& h+ y6 K1 [& K. J3 |obtained by measuring from the symphysis pubis to the tip of) W' {7 s5 z" L" Q
the glans. Penile circumferential (girth) measurements were
* Y5 M1 l* m* r4 Mobtained using an orthopedic digital measuring device (see, p; K2 c, T2 D4 O0 B
figure).
; g- K+ U! U4 @7 o/ HRESULTS% Q1 a$ F; S! u' g. B( R/ v- f, _
Serum testosterone increased moderately to levels between9 x2 Y  ~+ [, u% _9 R
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
; B1 B4 U! U* Z7 ~terone levels with topical testosterone remained near pre-
: Q5 u5 z& Y* u6 \  P" Ltreatment levels (35 ng./dl.) or were elevated to similar levels
1 x( K4 O% k) a" R' B" Cdeveloped after gonadotropin therapy (96 ng./dl.). Higher. x! L% G5 D; W2 |. \0 f' A5 G( p
serum levels were noted in older patients (12 and 17 years old),
$ O+ L$ O1 k4 Z1 _! Nwhile lower levels persisted in younger patients (4, 8, and 10
4 n/ g/ q  s, I- k( Q/ hyears old) (see table). Despite absence of profound alterations
# J3 y; h1 A# z" jof serum testosterone the topical therapy provided a greater# ~) O0 D/ S, z
Accepted for publication July 1, 1977. ·6 V* j: w" ?0 c# j' E  P
Read at annual meeting of American Urological Association,
9 O6 `' k8 |% q1 A, q# IChicago, Illinois, April 24-28, 1977.% G, V+ m. f  W% O2 _9 |
* Requests for reprints: Division of Urology, Henry Ford Hospital,: r8 k$ Q: H; w+ j- p" J& S+ |& Q
2799 W. Grand Blvd., Detroit, Michigan 48202.
5 K& \! C2 Z* W- {' D* {% D, M4 w1 rimprovement in phallic growth compared to gonadotropin.0 z: x) c. F$ D
Average phallic growth with gonadotropin was 14.3 per cent
; _0 x9 g- O+ y9 eincrease in length and 5.0 per cent increase of girth. Topical4 f. M0 l$ o9 _5 F6 f
testosterone produced a 60.0 per cent increase of phallic length( X8 F3 T) C- n/ G6 S
and 52.9 per cent increase of girth (circumference). The0 ?( E- U" ^: B0 N) F
response to topical testosterone was greatest in children be-* {! ]  ~5 W) d0 k) w0 m
tween 4 and 8 years old, with a gradual decrease to age 17
0 B! F% @6 [7 w0 f( F7 Q. U( Xyears (see table).
8 a7 e6 Z1 `. i# V" D! o) x  H9 YDISCUSSION. X  b2 o6 P6 c# a- _* b$ Q& V
Topical testosterone has been used effectively by other; |# Z+ J! a8 q3 P4 q
clinicians but its mode of action remains controversial. Im-) @" t0 w8 V& R( L: O7 }$ q
mergut and associates reported an excellent growth response) a( e4 [* Z% U7 Y/ g( J* P  J4 T1 P
to topical testosterone with low levels of serum testosterone,
5 F/ Q0 e8 |/ |7 K( O8 A' Xsuggesting a local effect.1 Others have obtained growth re-
3 E6 n8 K$ ~/ Q% p% ]sponse with high. levels of serum testosterone after topical( d4 O2 R$ G) q) e  ~2 D
administration, suggesting a systemic response. 3 The use of
7 ^/ y# M, l) U- m: t) Z  ?$ Igonadotropin to obtain levels of serum testosterone compara-
  V2 R  u4 I0 ~$ T) rble to levels obtained with topical testosterone would seem to- {) o' S4 _0 M7 `+ [, ]
provide a means to compare the relative effectiveness of
& E+ U9 W8 {+ X( o; A: h: ltopical testosterone to systemic testosterone effect. It cer-, W/ G2 t' X1 T. Q5 o
tainly has been established that gonadotropin as well as par-; A) Y# ~" R$ Z) e
enteral testosterone administration will produce genital
! k, ?9 J/ \' q# {  K% Z* k; agrowth. Our report shows that the growth of the phallus was
0 F2 U6 J  c4 e. Nsignificantly greater with topical applications than with go-
; P: B$ R* ?$ I" N+ C; Bnadotropin, particularly in children less than 10 years old.- p& t- ?7 F: l( D1 `  o3 w% |
The levels of serum testosterone remained similar or lower
1 D& z, s  Z; C6 N9 a! [than with gonadotropin during therapy, suggesting that topi-: y' Q2 q1 p0 E2 P! q
cal application produces genital growth by its local effect as
8 Q4 `& [. P9 Vwell as its systemic effect.
2 _8 n$ r: Q$ T$ y& fReview of our patients and their growth response related to0 @4 ^) N) v! B3 O/ P' ?# m- g
age shows a greater growth response at an earlier age. This is
1 u0 O7 v7 f/ Z7 }/ Iconsistent with the findings of Wilson and Walker, who
0 d! D4 h) S5 n3 B! \. L3 Areported an increased conversion of testosterone to dihydrotes-
6 a* S9 j, o* r  X  E2 Utosterone in the foreskin of neonates and infants.4 This activ-: y. f0 Z3 ~, L# r+ @4 b+ z
ity gradually decreases with age until puberty when it ap-
; |! r1 J+ U5 P4 uproaches the same level of activity as peripheral skin. It may
4 y# H. |/ _) g. K+ e: ?5 S% u. ^) N2 Ewell be that absorption of testosterone is less when applied at% c7 U  ^2 e6 W) E. p; a& |: X" |3 h
an earlier age as suggested by lower serum levels in children7 s& w" `" \- d7 O# _2 V5 }9 y# I6 p
less than 10 years old. This fact may be explained by the
: W8 E2 @2 o9 T; i6 }3 m* g* M; ?greater ability of phallic skin to convert testosterone to dihy-
7 f6 V4 v5 G6 ~/ Rdrotestosterone at this age. Conversely, serum levels in older
* \; }' H* E* |$ Spatients were higher, possibly because of decreased local
# H, o7 c; A2 h* y. N' X9 J! M1 e667
2 O  V4 d( Q/ o( y* @: l7 ?+ R7 e668 KLUGO AND CERNY  c6 J$ h5 k* f; P+ P0 N
Pt. Age
: _, q' k* ~6 h& u" Y; p(yrs.)
+ t9 i2 Q0 \1 i- DSerum Testosterone Phallus (cm.) Change Length
! \% |! Q2 q. Y, p: p4 o2 W6 ?(ng./dl.) Girth x Length (%)# R  {+ L2 Q& f( v( W. A" v) w9 {
46 b: D! e. X: {: W- p; y' `7 Z
89 H! g4 g  _' ]7 K
10
- [5 I4 X9 O9 a& G% I12) x) b4 G# f) o6 u0 L
177 F# a% v# d& ~5 T0 e$ U) i
Gonadotropin
4 N, G6 |) r8 {+ ^. e/ Y71.6 2.0 X 3 16.6
' f# b% w- z9 s2 s& W/ W0 Q+ [50.4 4.0 X 5.0 20.04 I# ?6 P0 @( p: A3 _4 V" j
22.0 4.5 X 4.0 25.0/ {" p0 h" s  Y* L! {' w
84.6 4.0 X 4.5 11.1
$ {7 b6 Z! ?0 Y  Y: ~85.9 4.5 X 5.5 9.0
! `. G; r$ X7 mAv. 14.3" x: w  t7 a3 D0 w. u
4
0 ?/ [. A5 X/ W! e- E1 f8
5 S4 n8 w- n" t9 n5 R4 N10+ x, {& d. H& m
12
/ H" P8 y" h. l17
$ a* M2 o) Z- A$ g' PTopical testosterone- [6 i; m2 U2 C& K6 {$ M0 l9 J
34.6 4.5 X 6.5 85
$ j5 s9 h" D% }7 L38.8 6.0 X 8.5 70, D; Q  s) S, a( K  U4 {
40.0 6.0 X 6.5 62.50 B4 k5 i$ I1 O
93.6 6.0 X 7.0 55.5% |# L, L  h. @. Z- y; X
95.0 6.5 X 7.0 27.2  M; ~( \+ v4 s1 F8 r* |
Av. 60.0
) q: P$ L& U# }8 u9 x" ~$ Y2 M6 Uavailable testosterone. Again, emphasis should be placed on$ d$ j8 x7 e8 [! i% F* _
early therapy when lower levels of testosterone appear to/ A8 s0 g  O. r6 E: d2 ^
provide the best responses. The earlier therapy is instituted
% g' b+ q+ f4 r- qthe more likely there will be an excellent response with low
3 x5 y9 v) g, j& T( W1 V0 oserum levels. Response occurs throughout adolescence as; b' ]; ~' B8 a* S
noted in nomograms of phallic growth. 7 The actual response: ~+ z: t2 q3 ?% G: W8 u2 _0 d
to a given serum level of testosterone is much greater at birth. A' G$ @4 P) Z9 p0 g7 x
and gradually decreases as boys reach puberty. This is most
3 S3 c6 s# I9 x, d! Ilikely related to the conversion of testosterone to dihydrotes-; p& n/ P3 H/ n
tosterone and correlates well with the studies of testosterone
) c" B0 r2 }; i7 X& Jconversion in foreskin at various ages.
6 ?& \; S' ^- S0 }$ TThe question arises regarding early treatment as to whether
. R: d; k; e' A' ^one might sacrifice ultimate potential growth as with acceler-5 H, ~5 k& Y5 e, z* B
ated bone growth. The situation appears quite the reverse1 m( u* t5 A* ~
with phallic response. If the early growth period is not used
& B4 E. e9 \% l& {when 5a reductase activity is greatest then potential growth* Y/ O& L* J7 z6 M8 ]
may be lost. We have not observed any regression of growth- ^' Z# s3 t7 n: w
attained with topical or gonadotropin therapy. It may well
2 S% B7 J0 B2 q0 O& w& _$ W( ?be that some patients will show little or no response to any
- n5 ~( d) C# [2 e9 I1 s5 Tform of therapy. This would suggest a defect in the ability to2 H3 C! L* m  D2 |
convert testosterone to dihydrotestosterone and indicate that# U! N( t) E; n- z5 |  N! t( A
phallic and peripheral skin, and subcutaneous tissue should
5 M! c% ~- }. @# l0 {be compared for 5a reductase activity.; ^& B) r+ c* [( {% ?' J
A, loop enlarges to measure penile girth in millimeters. B,
5 g; p6 R0 D) @2 Q5 h; c# nexample of penile girth computed easily and accurately.$ m, S3 R6 S4 O- D0 I" w' D0 [
conversion of testosterone to dihydrotestosterone. It is in this
8 D7 q8 W' I# }' }+ n: P4 ~older group that others have noted high levels of serum
1 b$ ~* W/ }* N0 V0 b5 Jtestosterone with topical application. It would also appear4 p$ L9 g: \/ Z) c$ ]& o
that phallic response during puberty is related directly to the! s: Z5 F6 M. F1 u
serum testosterone level. There also is other evidence of local
+ M% S" g) I: z* P  H, g# P5 Uresponse to testosterone with hair growth and with spermato-4 t+ E) V) w" h% D
genesis. 5• 6
+ L5 ^* `4 A; p6 JAdministration of larger doses of gonadotropin or systemic
: L5 J* T; W0 i! Qtestosterone, as well as topical applications that produce8 I  g9 U3 |. `) K9 t
higher levels of serum testosterone (150 to 900 ng./dl.), will! W: w1 O; ]" J/ }. N
also produce phallic growth but risks accelerated skeletal$ O$ R+ q1 X: `7 i" W2 Q
maturation even after stopping treatment. It would appear
7 z# B/ R9 r  O2 M  @, p2 pthat this may be avoided by topical applications of testosterone" q7 h- V% P+ \( g
and monitoring of serum testosterone. Even with this control
" T9 t% P+ |6 T: v$ fthe duration of our therapy did not exceed 3 weeks at any* [- L8 u  T2 h, Y
time. It is apparent that the prepuberal male subject may; I" e& ~3 c' S3 k
suffer accelerated bone growth with testosterone levels near7 `/ R8 k0 A, h; Q- b
200 ng./dl. When skeletal maturation is complete the level of5 E0 \- ^; a# @- V
serum testosterone can be maintained in the 700 to 1,300 ng./4 x& G! F- X' ~# W- s, r- x5 V
dl. range to stimulate phallic growth and secondary sexual
" B$ u' U7 s1 _changes. Therefore, after skeletal maturation parenteral tes-
- O7 u' f; x/ j' ttosterone may be used to advantage. Before skeletal matura-
0 x  w  U3 r$ `tion care must be taken to avoid maintaining levels of serum
" k: V! T3 |* qtestosterone more than 100 ng./dl. Low-dose gonadotropin) B$ ~+ ]; L" x( s+ |
depends upon intrinsic testicular activity and may require
8 v, Q# L0 c+ ~/ L  jprolonged administration for any response.
" ^+ r/ h& t1 F0 o. n. i/ y- L. u# mAlternately, topical testosterone does not depend upon tes-
  W1 h/ I( U/ W+ |ticular function and may provide a more constant level of3 S4 C4 z! |: W' h/ k6 ~1 K
REFERENCES$ P% h; z- C+ X$ T2 A5 c/ Y  \5 V
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
$ k+ B  d+ \4 n  oR.: The local application of testosterone cream to the prepub-
+ i7 M+ n* c! F: M- v/ I+ Y2 D# Hertal phallus. J. Urol., 105: 905, 1971.& q  q# L& B  Y% \) k0 p
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone0 j% z- }, G& c. N- ]  [; A# m
treatment for micropenis during early childhood. J. Pediat.,! o& X! v0 W' |2 v( [# F$ ~
83: 247, 1973.
. X# @$ r( k( k  |7 O- n3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-1 I/ U# O* \7 y6 j, M
one therapy for penile growth. Urology, 6: 708, 1975.9 ^9 `) `. {7 ~2 x9 y2 k
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
( N$ H# E1 I$ t" x: e8 l+ S. yto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
# _" F/ U9 U4 g2 @% u! c; qskin slices of man. J. Clin. Invest., 48: 371, 1969.
% M) d$ V% u+ p7 R/ g* D5 A5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
) \& Q0 ]+ k9 C& j6 Uby topical application of androgens. J.A.M.A., 191: 521, 1965.& d' g6 C: a$ {7 ?/ \* s& q) n
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
/ J! \( x/ C  T7 Q+ I1 }androgenic effect of interstitial cell tumor of the testis. J.1 X4 ~7 i+ F. S* r
Urol., 104: 774, 1970.9 N6 o0 Y' y' V" h
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-* A5 v$ }. ?" a/ b: C: P" B
tion in the male genitalia from birth to maturity. J. Urol., 48:
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