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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
8 `5 b, l3 I) ]% f5 X: b5 eGONADOTROPIN: {: ~  _7 c5 U  o/ K. R
RICHARD C. KLUGO* AND JOSEPH C. CERNY
7 i- |- g, `2 EFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
$ A" V: i; L, J$ O2 G- UABSTRACT
5 V! Z0 W: c% x2 k) H! Q! gFive patients were treated with gonadotropin and topical testosterone for micropenis associated
$ P  p! i3 p4 S: {# i& l+ Iwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
: w! n# _$ ]1 Q# |9 v+ u) _& R' Ptropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone' u6 \6 l2 O6 K5 F  _9 o( u0 ]
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent& t- ^% d7 D, [+ k3 |
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
: ?' I  P! M6 N. }) Sincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
2 r& P  T  @6 w" U2 Sincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
$ {4 c8 L+ i6 foccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This0 b/ X7 j3 ]# O3 u; n$ i
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile! K. ]9 B$ w# R8 w8 s2 _
growth. The response appears to be greater in younger children, which is consistent with previ-: f/ P4 @7 }/ w" z9 o" R
ously published studies of age-related 5 reductase activity.) P5 u+ v  n4 A& D" d1 H
Children with microphallus regardless of its etiology will
1 _, L, O8 {- T8 F# ]require augmentation or consideration for alteration of exter-
8 }. K' v5 d  [( R2 Bnal genitalia. In many instances urethroplasty for hypo-2 j1 n: x3 p9 C! n% o5 r1 r$ w. o
spadias is easier with previous stimulation of phallic growth., ~4 y0 h2 b) a& F) r
The use of testosterone administered parenterally or topically$ [+ n  J, Z* K3 W4 O% y
has produced effective phallic growth. 1- 3 The mechanism of' U* X. p# }4 q. w% W0 S) {
response has been considered as local or systemic. With this
' W& }' ?# R( y. f0 _) X+ oin mind we studied 5 children with microphallus for response
8 @* ^. |! m: J; [. ~  a: M3 I% d) `to gonadotropin and to topical testosterone independently.
' S9 a8 @6 q  o7 t# |( V! k5 s- XMATERIALS AND METHODS
7 [& U1 J6 \' Y2 W; P/ qFive 46 XY male subjects between 3 and 17 years old were
; |+ i6 ]& p" \4 K4 E. g2 i+ yevaluated for serum testosterone levels and hypothalamic
5 }, ]( }( s2 i  x  V7 {function. Of these 5 boys 2 were considered to have Kallmann's8 K6 K$ m4 G1 b1 c" w3 a# G
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-; v( f% O5 h- S/ O
lamic deficiency. After evaluation of response to luteinizing4 s8 ^/ ?9 B- e/ k
hormone-releasing hormone these patients were treated with
, x5 B9 _# F) n. J' x1,000 units of gonadotropin weekly for 3 weeks. Six weeks6 u7 ?* L. w! p3 K$ Z
after completion of gonadotropin therapy 10 per cent topical/ `" n1 L1 u9 P+ x% a! F- V
testosterone was applied to the phallus twice daily for 3 weeks.( B% ~" F" w4 x5 ^+ w
Serum testosterone, luteinizing hormone and follicle-stimulat-: W. ^, n. I# O  V+ d$ u
ing hormone were monitored before, during and after comple-+ D) o- S: n$ T/ P2 n6 b/ J
tion of each phase of therapy. Penile stretch length was
: P3 s7 @+ x6 ~# j/ robtained by measuring from the symphysis pubis to the tip of
" D: D% D7 `' ~0 `+ U: r7 l+ F  othe glans. Penile circumferential (girth) measurements were
8 W& e* w. z+ Q  K3 X# dobtained using an orthopedic digital measuring device (see* S! F( L4 _( ~) c' `
figure).
4 [# }5 O. H7 n# |1 HRESULTS7 u" R8 N& U7 T& B( [* J
Serum testosterone increased moderately to levels between
; F+ b) h. m) m! T) G4 l50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-$ P. ]3 I; H8 Q4 q
terone levels with topical testosterone remained near pre-' E9 d$ A  [1 f1 n
treatment levels (35 ng./dl.) or were elevated to similar levels
- a9 Z8 i/ o+ u/ t  J7 q" X5 Edeveloped after gonadotropin therapy (96 ng./dl.). Higher
# \8 A8 x. e9 a; J' C- Eserum levels were noted in older patients (12 and 17 years old),
$ P( V2 o6 {4 B+ twhile lower levels persisted in younger patients (4, 8, and 10
! \1 T9 d  B0 i) a, f9 Y: Y& Fyears old) (see table). Despite absence of profound alterations
4 _0 c" K5 F- ^3 q2 jof serum testosterone the topical therapy provided a greater
6 d% k$ L, d- B1 F& a  m+ x" JAccepted for publication July 1, 1977. ·3 a+ s8 l# w% V6 W1 u+ n$ o# Z
Read at annual meeting of American Urological Association,, a1 S# r+ W+ V3 V* y# H, a
Chicago, Illinois, April 24-28, 1977.' N' x! n' U1 ?6 r' D: t
* Requests for reprints: Division of Urology, Henry Ford Hospital,& V3 S0 u. h8 {& ~" U: C( e
2799 W. Grand Blvd., Detroit, Michigan 48202.. a8 v3 b' F0 i8 Z) @* ^8 _- ]: Z" v
improvement in phallic growth compared to gonadotropin.# ?) ]1 r* q+ f
Average phallic growth with gonadotropin was 14.3 per cent
) z. t- u, L1 q; |increase in length and 5.0 per cent increase of girth. Topical1 O0 S7 j& k2 ]% y$ a) ]; G+ @
testosterone produced a 60.0 per cent increase of phallic length
9 A: z4 e# D4 w5 Y! eand 52.9 per cent increase of girth (circumference). The
5 |; V/ C. w" }# @; Iresponse to topical testosterone was greatest in children be-! r' K$ @, G* K0 d2 i$ \- o4 ^
tween 4 and 8 years old, with a gradual decrease to age 17+ E; F! F# \# Y/ R5 u) O
years (see table).3 _$ ]  g- u. f& ?
DISCUSSION
6 v6 Q2 ^3 h. g* d% T# e0 VTopical testosterone has been used effectively by other' d+ ]- K6 V8 z5 N& Y: ~% T
clinicians but its mode of action remains controversial. Im-: I6 I2 O, E$ S
mergut and associates reported an excellent growth response9 v& ?5 {' ]* |5 R
to topical testosterone with low levels of serum testosterone,* S1 l0 {$ x$ Z3 Q  ^
suggesting a local effect.1 Others have obtained growth re-% y1 p/ q6 r1 Z7 M
sponse with high. levels of serum testosterone after topical
9 j7 R8 o0 V, X6 T0 C& Yadministration, suggesting a systemic response. 3 The use of- y# Y2 C2 V) Y4 a9 s# b
gonadotropin to obtain levels of serum testosterone compara-
% R+ B% p4 m8 W. hble to levels obtained with topical testosterone would seem to
& h/ A1 O3 k; E6 }/ W6 Rprovide a means to compare the relative effectiveness of# _4 y& R9 c5 `
topical testosterone to systemic testosterone effect. It cer-) T6 a; a9 \6 C& k, a
tainly has been established that gonadotropin as well as par-
, F) E: D& @6 e% aenteral testosterone administration will produce genital
( K- D5 x9 x0 S$ O: Ogrowth. Our report shows that the growth of the phallus was1 C' v5 v% R4 O
significantly greater with topical applications than with go-
9 w' j0 D+ V8 o' k, G7 m2 knadotropin, particularly in children less than 10 years old.
' W( B# Q! X% S# j" i) j: rThe levels of serum testosterone remained similar or lower
2 H& g$ k! m3 J& S5 Vthan with gonadotropin during therapy, suggesting that topi-) q2 {* v8 g8 H- Y; l* q7 ~9 g
cal application produces genital growth by its local effect as
) p. I4 Y8 @; J, B0 ~' Owell as its systemic effect.
  L" N1 v+ E$ n2 I+ u4 C4 XReview of our patients and their growth response related to8 P" q3 O) A# g* P7 E; O
age shows a greater growth response at an earlier age. This is
, n# C- U6 C9 W) yconsistent with the findings of Wilson and Walker, who8 S  w/ {( i' `0 w; I* K- o) O
reported an increased conversion of testosterone to dihydrotes-
; g. ]) Q" ]( ~/ B- Stosterone in the foreskin of neonates and infants.4 This activ-
! ]2 z# r2 q, N8 V6 Eity gradually decreases with age until puberty when it ap-
9 k1 k& s4 w# x6 ~proaches the same level of activity as peripheral skin. It may
! R* z2 c4 v. g  ?3 Z# X+ |6 k+ z& ]well be that absorption of testosterone is less when applied at0 {  T: m, |" Z) M* Y: Z
an earlier age as suggested by lower serum levels in children! A4 Q+ K& t7 \8 m+ u& F
less than 10 years old. This fact may be explained by the
  S2 G* ]# h5 e# l4 O  }greater ability of phallic skin to convert testosterone to dihy-
1 y" T. G) L. H2 @" Mdrotestosterone at this age. Conversely, serum levels in older
$ s$ E$ @- {" J: x* Ppatients were higher, possibly because of decreased local7 @# x1 S6 W& k* X9 f9 C0 O
667
. F4 H0 {7 p% ^1 L668 KLUGO AND CERNY" E" g! W, t0 O: V$ R& E$ F
Pt. Age
8 ]( B6 j2 [& K, x/ f0 q(yrs.); P5 T* Y7 A; {; s; g
Serum Testosterone Phallus (cm.) Change Length+ x8 f; V. x6 a; M/ N/ M
(ng./dl.) Girth x Length (%)
7 T# i, a2 W! b- ~  D$ G& O. f2 O4
8 z( t- h6 r$ s  L% t! z# T8
! P  B! J: \; \& k6 T, o/ u3 r10# S$ f9 \1 ?5 @0 _, \4 J0 d
12" {' L. Z2 N+ K0 }6 w
17
: P/ t, @! D. \2 c5 H7 pGonadotropin
7 |4 k. a6 h# s71.6 2.0 X 3 16.6
9 |. m1 h6 P& P' x; L3 [, E0 k50.4 4.0 X 5.0 20.0: n  x7 ]+ ~' a4 t2 l6 U
22.0 4.5 X 4.0 25.05 B" Q) b9 w/ z5 n# [
84.6 4.0 X 4.5 11.1! V( \0 m8 @, q! M3 ^* d  p
85.9 4.5 X 5.5 9.0" d! Z2 E" X& d5 W
Av. 14.3
6 G, u0 k! ~8 G$ [; D- n4
+ V( N$ a: h. W, w) i( P8: k) `4 W! ~! {% F0 L, V
10
( ?- z) a- v0 K8 E& j12) R/ O5 Q. X% K  {! @' ]
17
5 ^) }8 J6 F' A9 V0 O# STopical testosterone7 G" w* v. z& M
34.6 4.5 X 6.5 851 I& T( X* O/ |" E3 [8 p
38.8 6.0 X 8.5 70
# Q" {% d- v9 s" u6 e40.0 6.0 X 6.5 62.5+ A) M2 s5 ]2 B1 f9 o
93.6 6.0 X 7.0 55.5
' k" D; U  T9 I; e/ U95.0 6.5 X 7.0 27.2" \/ h! a( i* Z: g
Av. 60.0
% M+ `+ x- v& I+ C. Davailable testosterone. Again, emphasis should be placed on3 ]3 U' x) C6 Y% w& }
early therapy when lower levels of testosterone appear to
( V7 A7 F2 h% q9 R# [0 h0 Vprovide the best responses. The earlier therapy is instituted
) K# j) ]2 i/ ]7 \the more likely there will be an excellent response with low% n( D/ |; z  \/ |9 L- q
serum levels. Response occurs throughout adolescence as0 R. f9 f5 P& r: p
noted in nomograms of phallic growth. 7 The actual response% O7 r8 n$ _: E" p- l
to a given serum level of testosterone is much greater at birth8 z( d( T* h3 @0 \
and gradually decreases as boys reach puberty. This is most" F, M- E/ X, J9 ]
likely related to the conversion of testosterone to dihydrotes-
* c* Y! D# N9 o* X1 Gtosterone and correlates well with the studies of testosterone
- T% H9 X( Z* {, T/ g! vconversion in foreskin at various ages.
& W( U7 G, N0 a- `The question arises regarding early treatment as to whether  u8 _6 A* D7 J$ f! y& @* E
one might sacrifice ultimate potential growth as with acceler-9 i/ ]) b5 W: s0 o+ y9 J
ated bone growth. The situation appears quite the reverse- H! y7 o5 ]2 A4 w: [
with phallic response. If the early growth period is not used4 y$ z$ p6 X9 f4 @' t7 p
when 5a reductase activity is greatest then potential growth! g9 G/ P% c, Q! _2 K+ }5 b0 c
may be lost. We have not observed any regression of growth* k' q6 l6 q. w( q  M- L  u5 N
attained with topical or gonadotropin therapy. It may well  u; W3 N* b& z, E6 e; e( m; \
be that some patients will show little or no response to any
( `" D0 b. D6 o) Yform of therapy. This would suggest a defect in the ability to
  P$ {# b) t5 h) T8 x" Uconvert testosterone to dihydrotestosterone and indicate that  N0 G$ A. I4 S# O3 ^4 }
phallic and peripheral skin, and subcutaneous tissue should# a6 W" }7 B3 R/ w% J
be compared for 5a reductase activity.: f' @8 E0 N- x2 w9 ]; y
A, loop enlarges to measure penile girth in millimeters. B,! V2 O# k' h0 z8 y* z9 f) R( R
example of penile girth computed easily and accurately.
( k7 G# q; v  _8 x% l5 R1 Gconversion of testosterone to dihydrotestosterone. It is in this
7 |% F5 q; O! N: ]+ Wolder group that others have noted high levels of serum
, e7 @+ ^) h/ g% ^7 s& P/ D8 _testosterone with topical application. It would also appear
& l/ W8 q- [4 ]3 S' d# Sthat phallic response during puberty is related directly to the
% z) I* ]9 i6 Fserum testosterone level. There also is other evidence of local2 ~- J) R4 x9 X, N* S- S
response to testosterone with hair growth and with spermato-2 X8 v+ f3 k5 I6 Y* a! [
genesis. 5• 6" R& H: L/ j* D" i4 k. ^/ x
Administration of larger doses of gonadotropin or systemic
$ V& e& P- _  m! q; w% j) M% T+ Htestosterone, as well as topical applications that produce( H3 S% _8 O: B& l5 T6 d
higher levels of serum testosterone (150 to 900 ng./dl.), will
9 ?0 V% i; S! F4 N) lalso produce phallic growth but risks accelerated skeletal$ x/ l2 m# |* R0 O* R6 d) b4 B5 P
maturation even after stopping treatment. It would appear$ g  i1 P, s+ G% i2 ?5 j# d
that this may be avoided by topical applications of testosterone
: T" Q8 ?/ A8 o% Cand monitoring of serum testosterone. Even with this control
2 x8 T4 f+ [: [4 Mthe duration of our therapy did not exceed 3 weeks at any
" ~2 b3 {1 s/ n" {, d. ?8 Atime. It is apparent that the prepuberal male subject may; v8 t) l- ?1 P9 g9 j* o. X% t6 c6 l
suffer accelerated bone growth with testosterone levels near
; Y9 j. r/ v8 z& G200 ng./dl. When skeletal maturation is complete the level of
  a: K& y' W1 Z/ N+ Lserum testosterone can be maintained in the 700 to 1,300 ng./' K+ n' y" i& Z9 l$ {% ]
dl. range to stimulate phallic growth and secondary sexual
8 }( b4 O% T, }7 R/ S; `9 b' Echanges. Therefore, after skeletal maturation parenteral tes-
4 m8 j3 T! Q: X. K, U/ Gtosterone may be used to advantage. Before skeletal matura-2 ^/ r6 d' M' z2 _( e
tion care must be taken to avoid maintaining levels of serum
( F# S8 W: f# B  Z$ l0 atestosterone more than 100 ng./dl. Low-dose gonadotropin1 P8 \/ x& D2 v  r
depends upon intrinsic testicular activity and may require
4 i# _9 @- D5 S7 j" Sprolonged administration for any response.
2 K# {# }) c/ n/ u( q  ], u! @Alternately, topical testosterone does not depend upon tes-
" |/ C/ |4 X9 i7 n' c( Sticular function and may provide a more constant level of' G: K9 \# _/ {+ v$ Y; @1 y
REFERENCES
- v, e0 W4 m& x; c& e1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,% X$ U6 n0 p8 M  ]
R.: The local application of testosterone cream to the prepub-
! E9 O! f3 a# J6 W0 Dertal phallus. J. Urol., 105: 905, 1971.
0 L$ N0 ?6 w! r5 [& |8 b2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
) P( v8 N, U1 R7 g5 i4 q7 `treatment for micropenis during early childhood. J. Pediat.,4 V! F$ v3 T" m
83: 247, 1973.4 Z& ~$ k8 X$ Z$ w
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-, V% Y% Z  @' a" `. Z; m5 ?
one therapy for penile growth. Urology, 6: 708, 1975.2 w# C6 Z4 K$ \1 P& a, Z
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone) ?( p2 g% ^9 o- ~6 E' N
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by/ K: n$ z. ^( m: W. Z- L
skin slices of man. J. Clin. Invest., 48: 371, 1969.
8 J( K# h6 c) B, e5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
. r  o* \! |: I$ I, sby topical application of androgens. J.A.M.A., 191: 521, 1965.
- D* s. I. D! Q5 ]6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
. W' H$ m# @0 W# z% Oandrogenic effect of interstitial cell tumor of the testis. J.2 Z8 w, s. Q4 n- }; ^' s8 \
Urol., 104: 774, 1970.
. B; `+ y4 q6 _) K7 B% u7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-; w: l( S6 c- x$ b9 @2 ^
tion in the male genitalia from birth to maturity. J. Urol., 48:
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