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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND" o% I( T& n+ |# P* H- N
GONADOTROPIN- w$ z! W: Y3 a0 Z% A2 w2 G( S; p' b
RICHARD C. KLUGO* AND JOSEPH C. CERNY
" c% s) g. a1 r; [! ZFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan6 o- ]7 E( l- T! I" P& Z
ABSTRACT
0 t% U1 q1 Y# a7 c$ I; n* gFive patients were treated with gonadotropin and topical testosterone for micropenis associated
6 a% e" n  ]5 y$ O6 P) N$ cwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-' s: s4 _7 A' x" T$ m# d
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone5 h& o# i* V0 F9 w% s
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent, m6 g% f; _1 i0 N& D3 Q
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
& r9 }. w% j: M7 C) Mincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average4 r4 M% ]5 h  L% [
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
/ |# Q: V, e! ?; i+ l# }" Goccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This  S5 [7 p8 W% R7 }' y6 ^
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
0 K: k* {0 c" {! G! G1 cgrowth. The response appears to be greater in younger children, which is consistent with previ-
* A1 _/ l5 o" T) kously published studies of age-related 5 reductase activity.
3 {! P, B1 P0 U. XChildren with microphallus regardless of its etiology will- D. K6 p+ ?4 P7 s) w% l
require augmentation or consideration for alteration of exter-+ `# k* H! j4 I4 f
nal genitalia. In many instances urethroplasty for hypo-
3 l6 S7 I( p6 P/ u9 kspadias is easier with previous stimulation of phallic growth.
: b+ m9 E4 @1 v, mThe use of testosterone administered parenterally or topically' l- h; A1 Z2 ^7 s$ @
has produced effective phallic growth. 1- 3 The mechanism of
: G7 g$ m: t+ ?( H& g8 m" s/ F& hresponse has been considered as local or systemic. With this' V* v+ M! Z& ]8 M# n& I
in mind we studied 5 children with microphallus for response
: e, g$ {7 ^+ P% V4 s2 ~to gonadotropin and to topical testosterone independently.  e6 s& r, n0 ~0 ~
MATERIALS AND METHODS
( u- F# r2 n' |& NFive 46 XY male subjects between 3 and 17 years old were' @9 @, u' f( g1 \; D# y
evaluated for serum testosterone levels and hypothalamic7 B$ o; v( Q: {" X  D
function. Of these 5 boys 2 were considered to have Kallmann's
9 W. F) k% p8 q. a; v( |syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-1 h3 C3 r0 ~+ `. A  Y
lamic deficiency. After evaluation of response to luteinizing( `2 p/ L* B, X6 a2 l8 j
hormone-releasing hormone these patients were treated with" Q! |+ F' g/ R
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
& a( E% c9 \. T8 m0 {' V1 R. Fafter completion of gonadotropin therapy 10 per cent topical9 R  y' f4 i; r; w
testosterone was applied to the phallus twice daily for 3 weeks.3 w4 o. X! ^, ^5 \) m, k; F0 U
Serum testosterone, luteinizing hormone and follicle-stimulat-
. T0 P' t2 p+ _/ j% D# uing hormone were monitored before, during and after comple-2 ^) J! |( E/ o  a& A$ U4 x1 D6 q5 U
tion of each phase of therapy. Penile stretch length was( X! z+ W& u' K7 @' W! Y
obtained by measuring from the symphysis pubis to the tip of
5 c, p! a9 Z6 n; y5 F! A: Dthe glans. Penile circumferential (girth) measurements were
8 J. Q' }# u) x& e5 m+ A- K* qobtained using an orthopedic digital measuring device (see! n; ^1 X+ `1 Q- t3 q$ y. z6 ~
figure).
/ s2 G$ Q# E2 a& p9 ~/ I' F; e- ~RESULTS- z$ g/ w5 m( ^5 T/ `9 k
Serum testosterone increased moderately to levels between7 t) f, B) [7 ^7 p) z: o
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-2 A) i' C7 S* B6 e6 Z  @2 |6 k
terone levels with topical testosterone remained near pre-
9 h2 H7 g. o0 wtreatment levels (35 ng./dl.) or were elevated to similar levels) n# Z& z# A* ?% q/ Q. i$ P
developed after gonadotropin therapy (96 ng./dl.). Higher1 C& J/ `5 _; j# R
serum levels were noted in older patients (12 and 17 years old),* E+ `3 m: u  L/ @! N2 j
while lower levels persisted in younger patients (4, 8, and 10/ l% Z9 {$ ^4 n1 Q5 Y$ |
years old) (see table). Despite absence of profound alterations
" e0 x- p6 k* M# d' Q4 mof serum testosterone the topical therapy provided a greater6 D& O5 b6 \; B% K
Accepted for publication July 1, 1977. ·
% V% l4 C4 ]3 p! }. @9 U; VRead at annual meeting of American Urological Association,
+ |/ X$ E7 \3 Q$ t# r! y# a8 V# R5 uChicago, Illinois, April 24-28, 1977.; y, l7 d/ B! Z  U, ~3 P4 h
* Requests for reprints: Division of Urology, Henry Ford Hospital,
* F. {8 [4 ^9 r$ e. l! e2799 W. Grand Blvd., Detroit, Michigan 48202.
1 z6 F! u8 _# ?+ R+ l0 k: r. H  nimprovement in phallic growth compared to gonadotropin.
6 c- p$ V+ D. ^* _3 _, f# [7 JAverage phallic growth with gonadotropin was 14.3 per cent
# B0 ^6 c( P& ?' lincrease in length and 5.0 per cent increase of girth. Topical! \; c6 W7 F& a" z' H
testosterone produced a 60.0 per cent increase of phallic length
" y  N$ [3 l; n8 hand 52.9 per cent increase of girth (circumference). The% |& S/ _5 o6 O* F4 r1 x2 k
response to topical testosterone was greatest in children be-
! u# G) D1 q6 N0 R- qtween 4 and 8 years old, with a gradual decrease to age 174 t! Z) L4 D+ M
years (see table).9 r, y9 G2 E& X2 S# k" [
DISCUSSION( M* b8 j8 ]: z8 l& Q
Topical testosterone has been used effectively by other
+ k# W0 c9 |; s1 @: o; R, V  }clinicians but its mode of action remains controversial. Im-
0 F* n% M% q/ m9 Q5 o9 D/ I5 Z0 Zmergut and associates reported an excellent growth response) C  F4 a+ t$ P" S6 F
to topical testosterone with low levels of serum testosterone,* Q2 \4 T, ]5 _$ _/ V3 y' {
suggesting a local effect.1 Others have obtained growth re-; r- W. N# h+ J2 J8 h
sponse with high. levels of serum testosterone after topical9 [' r4 @8 T/ a
administration, suggesting a systemic response. 3 The use of
7 k. ^1 _6 b) Ygonadotropin to obtain levels of serum testosterone compara-% @7 D5 ]" J9 O0 p
ble to levels obtained with topical testosterone would seem to/ o5 f5 s2 [* f* e+ R' n
provide a means to compare the relative effectiveness of/ v! o0 f% A8 |9 r! l6 _% w8 ^5 F
topical testosterone to systemic testosterone effect. It cer-% r4 F$ E  e! ]# H
tainly has been established that gonadotropin as well as par-4 u6 l  E& U6 l
enteral testosterone administration will produce genital
' {1 d% L3 Z- N' p7 }: m) R% b( ~5 Cgrowth. Our report shows that the growth of the phallus was
4 p2 q+ A3 w- w. k$ ]$ hsignificantly greater with topical applications than with go-8 @4 {: w1 p$ g7 r" p. D
nadotropin, particularly in children less than 10 years old.
' k9 b7 N4 P! ]7 r$ IThe levels of serum testosterone remained similar or lower
0 l3 u% h9 h+ x( y7 C; M/ r; r& n. Athan with gonadotropin during therapy, suggesting that topi-
) l  k" _7 H) ?; Acal application produces genital growth by its local effect as
. h4 O2 L1 `& b; W8 h& T  fwell as its systemic effect.
( ]& p2 g4 ^( b, G2 T# k+ WReview of our patients and their growth response related to
- W, ^8 z8 H, ]7 q' j$ gage shows a greater growth response at an earlier age. This is' z4 c3 e1 V2 |8 O/ J2 b# Q, {
consistent with the findings of Wilson and Walker, who; R) f; Z; ]" t- w& z+ w. d1 \: ]
reported an increased conversion of testosterone to dihydrotes-
, A% y+ h' z  |3 p  J" Vtosterone in the foreskin of neonates and infants.4 This activ-7 o# {; B  x5 L8 k$ I4 e: W$ [; ~3 u
ity gradually decreases with age until puberty when it ap-1 A2 v, z2 U) U. x
proaches the same level of activity as peripheral skin. It may4 m3 F" @3 V+ ], o4 S
well be that absorption of testosterone is less when applied at
/ X0 F0 {: j7 x2 Nan earlier age as suggested by lower serum levels in children
! h2 i. d! m7 }* Uless than 10 years old. This fact may be explained by the( u& L- ], w( c  O
greater ability of phallic skin to convert testosterone to dihy-
* g2 R6 A$ Y4 H" d, tdrotestosterone at this age. Conversely, serum levels in older  L1 k/ ?; R6 i3 x2 W' k, [
patients were higher, possibly because of decreased local
. G" [, R, v6 Z1 J# C5 b667
; b; b# C+ r5 w" k/ m668 KLUGO AND CERNY# U7 S" r0 k; r' Z, _
Pt. Age% `7 e7 B7 e8 E7 M
(yrs.)2 r( ^# r+ L" L
Serum Testosterone Phallus (cm.) Change Length# N2 q( Q  Z9 z9 D: P& W. n
(ng./dl.) Girth x Length (%)
2 }' l+ Q) m* D8 T. ^43 G- Y: q& h  S+ p7 i) {' A: s" C
8* n3 Y* u# }2 K8 X+ f0 {# m. c; O
10
# E* J; K+ @1 I0 |& V  B8 T3 [( m121 G( u7 A7 @, y7 I& k. l2 R
17$ M: a4 K; S1 Q4 h. d
Gonadotropin; ~5 L" p2 R) Q4 l2 _, m
71.6 2.0 X 3 16.6" b3 u0 O, l& T  \! p8 T8 p
50.4 4.0 X 5.0 20.0
2 w' n, @6 r$ E& u- {* O22.0 4.5 X 4.0 25.0
  x  `, \, a. s2 j2 L' q1 f84.6 4.0 X 4.5 11.10 J! T) F# Q. O1 c  I1 o9 d
85.9 4.5 X 5.5 9.0
" X0 a& t* E8 o' S4 BAv. 14.3
; ^  L5 y( n* j  F  Y3 r5 T4* W8 o8 E; c' Z: Y# m5 s7 q
8
9 T3 D: H) f* a- q( F: q7 V10: |$ H# |, @" W+ A: ^3 V
122 r8 Z5 J* u. g$ q
17
/ q- ^( b- W' ^7 J+ B* ETopical testosterone
5 y" h' t5 b2 D  J34.6 4.5 X 6.5 855 i1 W5 L0 K# q- G* H$ n; v
38.8 6.0 X 8.5 705 W) |  k' a8 j. S
40.0 6.0 X 6.5 62.5
7 r$ Z% h2 u4 j' U6 [# o93.6 6.0 X 7.0 55.5
; U1 N5 B3 z' V' V' A0 d% {95.0 6.5 X 7.0 27.2
; O  e& s& j& \7 O/ P" F1 }Av. 60.0
) e& g& W* i  K' `available testosterone. Again, emphasis should be placed on
5 y7 f% C0 F) S+ J" D) |early therapy when lower levels of testosterone appear to1 l* ^7 f2 z$ L& R2 k
provide the best responses. The earlier therapy is instituted2 Z# Y/ B' V& b, J1 |( i; q! i
the more likely there will be an excellent response with low; n: k" C1 Y3 g- y( i
serum levels. Response occurs throughout adolescence as/ }% c! j( {6 d; ?! f' K
noted in nomograms of phallic growth. 7 The actual response4 f( T* O+ q% j
to a given serum level of testosterone is much greater at birth
0 o& _* @3 H4 \0 U) F9 |and gradually decreases as boys reach puberty. This is most( i: o# @1 I1 D
likely related to the conversion of testosterone to dihydrotes-* E( W/ x6 x5 O/ x' k% ?7 K
tosterone and correlates well with the studies of testosterone
1 @  g% e" R: ^2 m9 U6 Bconversion in foreskin at various ages.
$ y) R( q/ P5 f' U. ~9 \The question arises regarding early treatment as to whether# u6 p3 E6 V& E# Y1 D3 Q
one might sacrifice ultimate potential growth as with acceler-
- C4 s5 G2 N# y) o7 A8 g! Wated bone growth. The situation appears quite the reverse
/ V- e2 @" ~+ ]1 L1 |with phallic response. If the early growth period is not used3 q) |  K9 F1 S0 ]
when 5a reductase activity is greatest then potential growth
; e$ T1 M- d, _6 amay be lost. We have not observed any regression of growth
. B0 }  R; a& @' d* B8 y7 O. q% c0 P; \attained with topical or gonadotropin therapy. It may well
8 R" L) y& o- _' H6 c6 m+ c; Gbe that some patients will show little or no response to any, K4 P9 x! y  ?6 B$ K
form of therapy. This would suggest a defect in the ability to
3 v, E5 u3 r4 W1 g, ]# D0 K3 i+ ^convert testosterone to dihydrotestosterone and indicate that$ ?* X; r3 i7 ]9 w+ T3 ?$ {
phallic and peripheral skin, and subcutaneous tissue should
* F6 G- e6 U6 y5 @be compared for 5a reductase activity.
9 i+ L" L! z! A$ PA, loop enlarges to measure penile girth in millimeters. B,
& t0 W( ^5 `. y" N6 uexample of penile girth computed easily and accurately.+ l  ?, O0 v. S( M2 g2 h# `
conversion of testosterone to dihydrotestosterone. It is in this4 Z( j/ N3 O9 b4 q) j. Z
older group that others have noted high levels of serum
! z; X- B, I, T5 P& mtestosterone with topical application. It would also appear
6 s  }1 P: p5 p1 d5 @* E- vthat phallic response during puberty is related directly to the! \2 T7 z+ m: l
serum testosterone level. There also is other evidence of local
$ _7 g- s3 ^$ G6 `6 hresponse to testosterone with hair growth and with spermato-
% k4 B6 s* o' n- Cgenesis. 5• 60 X! d" Z# G  g/ L" f& J/ z8 D
Administration of larger doses of gonadotropin or systemic$ ^  G; B; C; K! n
testosterone, as well as topical applications that produce
' v' m6 A" ]7 s  z" Shigher levels of serum testosterone (150 to 900 ng./dl.), will
$ h7 h1 _! B3 O1 s) yalso produce phallic growth but risks accelerated skeletal
( t) B6 G. `3 c3 a, T$ ]maturation even after stopping treatment. It would appear
5 x* [* f0 ~* t7 d; g6 F/ Ythat this may be avoided by topical applications of testosterone
5 Y6 r6 H/ _4 k$ M6 oand monitoring of serum testosterone. Even with this control
5 @/ o5 x& j: {0 {the duration of our therapy did not exceed 3 weeks at any
; d9 P4 w7 x% L7 @, Qtime. It is apparent that the prepuberal male subject may
/ J! y2 g7 I( U9 l4 @- z6 [+ gsuffer accelerated bone growth with testosterone levels near+ P: X& H# _. r* i% L" V
200 ng./dl. When skeletal maturation is complete the level of5 p) ^8 S$ ?0 L& ]4 C. }4 A
serum testosterone can be maintained in the 700 to 1,300 ng./
. i# k- [; Q6 W8 b. ndl. range to stimulate phallic growth and secondary sexual% }$ X( k+ _% |4 e! f
changes. Therefore, after skeletal maturation parenteral tes-
9 p, r, J0 s! g3 A& p" R, [tosterone may be used to advantage. Before skeletal matura-
; b) O" _- p' rtion care must be taken to avoid maintaining levels of serum
- A1 K; y0 [! ]testosterone more than 100 ng./dl. Low-dose gonadotropin7 w& j+ @: u0 j1 e3 }$ k8 R) F
depends upon intrinsic testicular activity and may require- @* h$ D2 o1 i% y
prolonged administration for any response.- [7 f; |; [1 [# N4 }( |
Alternately, topical testosterone does not depend upon tes-5 {$ ?6 m" O* I, K  H+ V3 G
ticular function and may provide a more constant level of
/ G( ^" d' F+ z. Z7 O$ r' G2 @1 I* U* [REFERENCES% g2 ?' y- E' H: t# t
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,* ?. I1 X0 m" Z8 o. d* d
R.: The local application of testosterone cream to the prepub-
: ]% ~: E9 M; f: I' T+ |ertal phallus. J. Urol., 105: 905, 1971.
, s. ?, f. m7 O, m1 b$ ?& s) f2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
, E$ J" f- b4 K7 G- Ytreatment for micropenis during early childhood. J. Pediat.,) N- a; L+ V2 R2 o( O7 h  a
83: 247, 1973.( M5 ^, O7 B: [1 }& b1 U& T$ l
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
, ~5 c( U& I0 Z, oone therapy for penile growth. Urology, 6: 708, 1975.
$ a4 M0 R. d- a! J  J5 _5 x4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone) P6 r7 e  d4 N. ?: h
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
# p+ k5 K, `& P) B( a/ W6 jskin slices of man. J. Clin. Invest., 48: 371, 1969.
, S: o9 d2 u( z5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth2 B6 d( M  B5 T/ @' F) p
by topical application of androgens. J.A.M.A., 191: 521, 1965.) f3 b9 G8 X& i
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local* }3 p& q3 ^1 w2 z" M
androgenic effect of interstitial cell tumor of the testis. J.2 e) s7 K' V/ D& C7 R: _, C7 ?  m. z
Urol., 104: 774, 1970.4 K( L) h. x4 m
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-; g4 J  w" m& n5 ?3 K% o* n% H
tion in the male genitalia from birth to maturity. J. Urol., 48:
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