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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
- f+ ~4 i! F" K0 `- k4 P; |6 vGONADOTROPIN5 B/ [) K5 M$ ]$ i/ g) w, @; X
RICHARD C. KLUGO* AND JOSEPH C. CERNY4 T% f- `9 ?, j
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
  |$ |) Z" N, P0 yABSTRACT
' m; @0 E8 \$ h0 A) oFive patients were treated with gonadotropin and topical testosterone for micropenis associated
- n9 v8 J6 o% M  Hwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-! o/ i) k2 |1 r4 ]2 {! T* {8 o8 _
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
/ c* s% i" N2 j+ h$ jcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent: }' L- y1 F0 a3 Z3 G0 C% `
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
0 V9 [. B7 G3 Y% D, ^increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
1 J" ]' S) e( c8 jincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response6 o/ p+ K1 K; V, Z" h
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
3 J- b% r' k' F& |& Cstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile6 _& x6 Q+ u  ~5 @6 G
growth. The response appears to be greater in younger children, which is consistent with previ-
$ M. k0 I8 V  @ously published studies of age-related 5 reductase activity.% h. w7 Y1 Y* e+ {
Children with microphallus regardless of its etiology will
5 c- j. c, _5 Frequire augmentation or consideration for alteration of exter-& x' o) K1 ~& D% w, C
nal genitalia. In many instances urethroplasty for hypo-
( A+ V9 J7 ]! J- Q& q1 v5 Yspadias is easier with previous stimulation of phallic growth.
$ f6 |8 O; m1 l* N" gThe use of testosterone administered parenterally or topically( T1 \. E& t! r  \7 U
has produced effective phallic growth. 1- 3 The mechanism of  o  j# d) G* j5 Q! X
response has been considered as local or systemic. With this
! [  }+ b0 p4 T8 c0 F" Uin mind we studied 5 children with microphallus for response% |' ]( |. _" }4 H5 T7 `
to gonadotropin and to topical testosterone independently.2 |4 v: `+ X9 B  [) ^
MATERIALS AND METHODS
& `; u6 B" ]- Q* ~" Y/ q; VFive 46 XY male subjects between 3 and 17 years old were
# V% d7 i0 w  ]* ?1 {! Revaluated for serum testosterone levels and hypothalamic
& s/ f/ B6 i- i  Z; X! Nfunction. Of these 5 boys 2 were considered to have Kallmann's# W# j, K5 L9 I, Q/ {! H) e* e
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-  ^' j# J- V0 B  J+ W# y( r
lamic deficiency. After evaluation of response to luteinizing, T" x4 A: H: ^1 n/ x
hormone-releasing hormone these patients were treated with
' ~) q( \8 u0 ?( Q- _1,000 units of gonadotropin weekly for 3 weeks. Six weeks
$ d9 M: x/ {" hafter completion of gonadotropin therapy 10 per cent topical
! M4 l- h8 Y5 [& @testosterone was applied to the phallus twice daily for 3 weeks.9 f, G3 u7 ]" Q3 x
Serum testosterone, luteinizing hormone and follicle-stimulat-: O8 y6 F( J# p1 ^
ing hormone were monitored before, during and after comple-
) g+ P/ I2 P4 h6 U( A! Btion of each phase of therapy. Penile stretch length was
% y5 ~) L( P% Yobtained by measuring from the symphysis pubis to the tip of1 z! d7 M0 Z2 ^& a
the glans. Penile circumferential (girth) measurements were  d* X: r9 u+ A) P% K
obtained using an orthopedic digital measuring device (see6 `2 N- E& ^0 v* u/ r
figure).$ q4 i3 d9 D1 {; ^5 {% E
RESULTS# k  k! x$ a# ?: g$ B
Serum testosterone increased moderately to levels between* L: t/ c* i6 m+ u- ^! H
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-- n3 C9 L5 e8 S& b
terone levels with topical testosterone remained near pre-! d# ]5 W; E1 M% X2 G; |
treatment levels (35 ng./dl.) or were elevated to similar levels1 E: o5 R9 c. n: q: f
developed after gonadotropin therapy (96 ng./dl.). Higher
& L0 v4 W+ e  z/ Iserum levels were noted in older patients (12 and 17 years old),
3 T% i/ A6 |& h7 {while lower levels persisted in younger patients (4, 8, and 10( ^& A/ b5 M/ }" D2 t- w# |  n
years old) (see table). Despite absence of profound alterations; j, R0 G- e/ L* b
of serum testosterone the topical therapy provided a greater$ v' ?- K5 j* z/ Q# ^/ w2 w" i
Accepted for publication July 1, 1977. ·
3 A" }. a3 ?0 {Read at annual meeting of American Urological Association,2 u$ [: K$ w5 e2 w% @9 V) U
Chicago, Illinois, April 24-28, 1977.
- u, ^" y8 Q$ A9 f* l  g* Requests for reprints: Division of Urology, Henry Ford Hospital,
9 E8 m8 c* ^' C$ _2799 W. Grand Blvd., Detroit, Michigan 48202.8 T1 g; ]0 }- ]' }  T& |* b
improvement in phallic growth compared to gonadotropin.
. b* E9 P) m8 U4 a5 VAverage phallic growth with gonadotropin was 14.3 per cent
/ V- J. `7 I: H# H1 t$ bincrease in length and 5.0 per cent increase of girth. Topical
& G  d5 v9 o5 ~6 xtestosterone produced a 60.0 per cent increase of phallic length# ?" h% p, D6 u9 L
and 52.9 per cent increase of girth (circumference). The
5 [0 [. M* q0 Tresponse to topical testosterone was greatest in children be-. r" O: _; Y$ j
tween 4 and 8 years old, with a gradual decrease to age 17
' i/ `4 h( G( J8 G8 h3 ?( H! Gyears (see table).$ y7 n; X6 c0 w5 ]- b! P
DISCUSSION
3 ]8 V- s5 q  dTopical testosterone has been used effectively by other7 v: z1 P( o' _3 j  ?" R+ J
clinicians but its mode of action remains controversial. Im-
6 r: f+ d; u' z1 ^mergut and associates reported an excellent growth response* w+ |# w2 ]6 w  g6 b4 _; t: I& C
to topical testosterone with low levels of serum testosterone,6 S" q/ d: }5 P& e
suggesting a local effect.1 Others have obtained growth re-
& B/ e9 D6 f# X* f, J3 W! ?- m; H& Tsponse with high. levels of serum testosterone after topical
. m- \* c2 J7 Ladministration, suggesting a systemic response. 3 The use of
* F8 R$ _2 j$ T1 P' c4 J! Bgonadotropin to obtain levels of serum testosterone compara-- s5 o8 r+ y1 p& H0 b
ble to levels obtained with topical testosterone would seem to$ S* G5 j& j3 E
provide a means to compare the relative effectiveness of
7 x7 Q- H2 J  [7 M2 w* B: ztopical testosterone to systemic testosterone effect. It cer-* U# [; N% l0 O; a, X9 y3 l
tainly has been established that gonadotropin as well as par-. e0 Y$ {5 K9 u2 p. J
enteral testosterone administration will produce genital7 [2 y" X) Z3 f! Q- u7 v2 k
growth. Our report shows that the growth of the phallus was
+ V) \  [' u: g+ x2 h* J0 C0 ksignificantly greater with topical applications than with go-) |& \& h) u/ _7 R  g0 U
nadotropin, particularly in children less than 10 years old.
5 h8 ~. [2 v2 x0 O' N# a/ q* \  j2 @The levels of serum testosterone remained similar or lower/ V" h; v0 U% s9 e
than with gonadotropin during therapy, suggesting that topi-) M* ^6 b8 S. C. p5 s0 Z
cal application produces genital growth by its local effect as0 ?: G: E6 W/ L) M3 \
well as its systemic effect.
9 k! r8 A3 l& [5 oReview of our patients and their growth response related to
" {6 a& f2 H1 g6 O9 G9 U7 oage shows a greater growth response at an earlier age. This is" F( u4 M+ l( @. r3 V# ]6 E8 X' H" I
consistent with the findings of Wilson and Walker, who
/ i: j3 J5 e4 Areported an increased conversion of testosterone to dihydrotes-9 ?- M; J9 y. F- C  r+ Z. C
tosterone in the foreskin of neonates and infants.4 This activ-
3 f8 t$ W" `2 u, P  M4 }7 l  xity gradually decreases with age until puberty when it ap-/ F2 `' h0 q0 m! k( l, ?6 \! Q
proaches the same level of activity as peripheral skin. It may
8 c3 z/ Y5 z0 z: V7 ~well be that absorption of testosterone is less when applied at* O* w4 l- z9 z% u- E) N$ U
an earlier age as suggested by lower serum levels in children" m& @& @& E/ S2 q; J# P9 }" ]6 s
less than 10 years old. This fact may be explained by the
# O; t) R7 O% H: ]" A- }8 n/ zgreater ability of phallic skin to convert testosterone to dihy-$ k+ w9 U8 ]' H5 e
drotestosterone at this age. Conversely, serum levels in older
6 x  f: \4 @' O/ `5 \8 s2 ~2 u$ Dpatients were higher, possibly because of decreased local
& W$ u$ a1 f3 z/ _; u( m/ S. t667' D3 l/ Z0 A. y0 i
668 KLUGO AND CERNY  B+ `" g' k9 ~" z, K$ f
Pt. Age+ |6 a7 G; F' o' F0 ^
(yrs.)
/ N2 c, ?+ l( `! g7 tSerum Testosterone Phallus (cm.) Change Length
2 U; k6 \8 \+ H# I(ng./dl.) Girth x Length (%)5 J; n7 |5 r3 x$ O+ p
4- W& M. p' I3 \% K
8
, Z- ~3 y: K) j7 J2 g, x6 m10
/ [: n9 r% I  H( a4 q: D, I) k12  Y  w! x6 N: }2 c) w
17$ ], B8 i8 ^- Y' e! B
Gonadotropin8 ]  d3 r+ T9 ?% }' D' c7 z6 ~% {
71.6 2.0 X 3 16.6
6 g# ^, O. _: t7 f; j3 V6 j- P50.4 4.0 X 5.0 20.0
% M3 X" Y- u4 Y) a# \' n! v/ j22.0 4.5 X 4.0 25.0
0 s+ o5 R. I: \1 Q- r84.6 4.0 X 4.5 11.1
4 e( m  H8 C& S) }85.9 4.5 X 5.5 9.0
* I7 k% O! h# I+ L0 ~  QAv. 14.3' q8 l" B  R6 U
4: ~0 _- U$ }0 m% x
8  c( L) S# [% y/ h) G- S
10
' [" ^; f* y- |0 `12
# N, b4 [5 U) M" Y  S2 M17
6 @7 |: o, j. k& H8 e/ {: tTopical testosterone- ?. H$ u/ [3 J7 r8 T# X  Z* c4 a
34.6 4.5 X 6.5 85
' y; E# }1 ?7 E( c. P6 M- n% g38.8 6.0 X 8.5 70
. K) @( H: Q' o) i/ I; a! ~. D7 R40.0 6.0 X 6.5 62.5
  F9 l( F9 n9 D$ Z3 I5 [93.6 6.0 X 7.0 55.5$ r6 P" w8 t  g# L1 x
95.0 6.5 X 7.0 27.2" ~9 @- X4 T( I1 x6 t5 A# B% B
Av. 60.0
  j% A; p$ Q2 R0 davailable testosterone. Again, emphasis should be placed on
, ]3 {, t; Z3 I0 P8 ]! i3 X7 `* Rearly therapy when lower levels of testosterone appear to
8 ^4 i+ W- I' z9 Q5 S* \provide the best responses. The earlier therapy is instituted1 ~: z0 Q1 L1 y7 s' y
the more likely there will be an excellent response with low  z. J9 K& ^9 _  P8 l6 _
serum levels. Response occurs throughout adolescence as
2 E: v2 ?2 }6 Y& Q8 }) y: k: mnoted in nomograms of phallic growth. 7 The actual response
1 o2 U0 U5 v7 \$ |/ t8 Pto a given serum level of testosterone is much greater at birth
2 p0 o+ H* \3 Q% \/ @. cand gradually decreases as boys reach puberty. This is most
, f, d6 D6 _2 Z: Zlikely related to the conversion of testosterone to dihydrotes-) y& _/ \5 f6 D
tosterone and correlates well with the studies of testosterone) r0 o! c5 b( Z1 b; j
conversion in foreskin at various ages.( S+ W' P# ^  G+ s* @, I7 S3 c3 k
The question arises regarding early treatment as to whether
4 S, I$ m) N3 x  e! k6 H# l/ v. Done might sacrifice ultimate potential growth as with acceler-
3 |6 W8 r# h$ m4 U2 J1 H' L# ^ated bone growth. The situation appears quite the reverse
/ e$ g4 _" x# F" p+ \2 mwith phallic response. If the early growth period is not used
% O% L; `, W3 \7 V# zwhen 5a reductase activity is greatest then potential growth
# ]; H* O- ?6 q8 {" `% S) X! vmay be lost. We have not observed any regression of growth
! P5 x9 c. N" p2 aattained with topical or gonadotropin therapy. It may well
% ]( Q. \2 q  V1 H! R; V; Vbe that some patients will show little or no response to any/ i. i- r+ f$ h; Y
form of therapy. This would suggest a defect in the ability to+ E( U& B5 s  e' E3 ^7 d
convert testosterone to dihydrotestosterone and indicate that
* p; \0 D# Y) s- q* Jphallic and peripheral skin, and subcutaneous tissue should+ X" s& Q! j7 u/ }9 a0 [
be compared for 5a reductase activity.
  E( ~" q# g: L% a6 y! J$ IA, loop enlarges to measure penile girth in millimeters. B,7 D8 o* j5 b5 n1 ]- P
example of penile girth computed easily and accurately.
& o- i! z* D$ V& k) t9 K2 n# yconversion of testosterone to dihydrotestosterone. It is in this8 l6 Z; l% s7 C: e; m
older group that others have noted high levels of serum
0 q& q  W% x  `7 a. Y* Ftestosterone with topical application. It would also appear9 L) A. O! f* j# {, O8 m( w9 }# \/ m
that phallic response during puberty is related directly to the" D7 |, d0 x0 F/ s
serum testosterone level. There also is other evidence of local
( ?5 x  N4 [9 e2 D& ~7 q. zresponse to testosterone with hair growth and with spermato-$ V) }. d% _* J& r2 p! Y3 Z8 H
genesis. 5• 6! a% |6 w. t+ I) J( ?2 e
Administration of larger doses of gonadotropin or systemic2 a/ Y# c+ q7 c# u  A4 b
testosterone, as well as topical applications that produce8 {* x% h+ k6 U; ?+ Y+ k
higher levels of serum testosterone (150 to 900 ng./dl.), will
* r9 m, ?. L/ N# P/ {9 b" c% {5 yalso produce phallic growth but risks accelerated skeletal
6 ?" J4 ~0 I) F, o9 h5 ~8 qmaturation even after stopping treatment. It would appear8 S! W+ Y1 X. I( w
that this may be avoided by topical applications of testosterone5 z6 T# |, c0 c! m4 t
and monitoring of serum testosterone. Even with this control  w1 H; I, o! k
the duration of our therapy did not exceed 3 weeks at any0 v/ Q% |7 ]7 q1 h9 O
time. It is apparent that the prepuberal male subject may  d* v! W3 g3 s
suffer accelerated bone growth with testosterone levels near( Z  X( b5 W0 M  r7 D& ?
200 ng./dl. When skeletal maturation is complete the level of: u7 M8 l- H" W
serum testosterone can be maintained in the 700 to 1,300 ng./
  {  d! A. f: j8 X# gdl. range to stimulate phallic growth and secondary sexual# x# h- G, x9 v  P* w* [' E
changes. Therefore, after skeletal maturation parenteral tes-
  x2 W+ p$ I6 N: v) j9 ytosterone may be used to advantage. Before skeletal matura-. [& D% ^3 p- W- @1 b. C. G+ L0 {
tion care must be taken to avoid maintaining levels of serum; `3 u6 E6 q9 q# o
testosterone more than 100 ng./dl. Low-dose gonadotropin- j( ~( y! M) b) D/ ?
depends upon intrinsic testicular activity and may require. f9 @4 _* {; E7 `  e
prolonged administration for any response.8 u7 b3 \6 Z, ?/ ?
Alternately, topical testosterone does not depend upon tes-$ h/ S9 u& Y" Y. f% f
ticular function and may provide a more constant level of; i' e+ g( b5 R6 R. Y2 B
REFERENCES- }# _& V; h: P6 \! o" a' R
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
; s( g4 A: L: {" TR.: The local application of testosterone cream to the prepub-
: G) d  y* @7 [! L, c/ Y; wertal phallus. J. Urol., 105: 905, 1971.
; i7 X) G- [2 j( `) a/ |1 Z" Q4 ?2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone3 l2 i$ U& n; _0 M4 G, Z
treatment for micropenis during early childhood. J. Pediat.,
+ Q$ Z5 F& r+ `; p( i* m- q83: 247, 1973.
# x: f) ~) p8 Q4 ~4 R$ @3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
( U" P4 ?1 z  w# ?0 [7 M; ]& `4 lone therapy for penile growth. Urology, 6: 708, 1975.
) I& f; e8 N* \2 X( q4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
5 a1 ^6 X4 R0 D/ t7 B5 p; c7 Mto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
; k; R9 U# z- H; r  D7 V. s( M, xskin slices of man. J. Clin. Invest., 48: 371, 1969.: }8 h) l+ Z/ L. r; X
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
) {( |; v$ j7 w( L/ w% P- kby topical application of androgens. J.A.M.A., 191: 521, 1965.
/ h2 O: Z( b& x6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local% c4 o" O( l; C, o& r
androgenic effect of interstitial cell tumor of the testis. J.3 u8 C. _2 L4 f  u
Urol., 104: 774, 1970.
, ?& x9 Q0 _  d8 A9 B5 T7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
2 s9 n( N  l; b2 k* ?% @+ Z3 Dtion in the male genitalia from birth to maturity. J. Urol., 48:
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