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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
. y+ M* p6 ]; {% sGONADOTROPIN
( k5 g: i% e/ C6 P2 O) K0 M' IRICHARD C. KLUGO* AND JOSEPH C. CERNY
- ]7 m" Z) {( c( R: bFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan+ j3 U; Q0 Y# q
ABSTRACT
# S- \: X  Y, |Five patients were treated with gonadotropin and topical testosterone for micropenis associated
! r. N% F& t% v  E* u' gwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
; h# U5 n) ~* e2 U5 O( c; vtropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone# G* Z. P/ ~! B, K
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
7 A+ ~1 P, V8 F* O) pfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent$ E: I9 g) f& B( `% ~4 h
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average! ^& H( G  I; j. s- w" H6 X
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
; V, X: _: h- j, Q# moccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
- ?* j6 |- D+ Nstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
* |1 Z, O2 c: t" ygrowth. The response appears to be greater in younger children, which is consistent with previ-! e8 s, \2 d3 M7 W& Z
ously published studies of age-related 5 reductase activity.
9 z3 @: t2 f' N5 w0 r+ vChildren with microphallus regardless of its etiology will
& m) b2 Q6 {+ `, _; prequire augmentation or consideration for alteration of exter-
1 e2 F- b3 @' G- B; |3 mnal genitalia. In many instances urethroplasty for hypo-4 f$ A9 H' c5 R  d' A
spadias is easier with previous stimulation of phallic growth.1 m4 J5 A$ o2 N
The use of testosterone administered parenterally or topically
2 K# A$ Q% N( D/ k: n) rhas produced effective phallic growth. 1- 3 The mechanism of
9 _* i. V; `, ?. z# z. \response has been considered as local or systemic. With this9 i7 H/ U1 ~3 u  S2 B6 K6 l  I
in mind we studied 5 children with microphallus for response- j  {. P4 N1 S, j' ^6 X7 M
to gonadotropin and to topical testosterone independently.1 P: \! m5 n  E" F+ n. I
MATERIALS AND METHODS
6 ^, W: X7 F  ?$ M3 `' p2 ~Five 46 XY male subjects between 3 and 17 years old were
* x* v% B5 e; @. Z' g" h3 wevaluated for serum testosterone levels and hypothalamic, S) Q2 |# U# Z/ ?+ x3 G- a& R( t
function. Of these 5 boys 2 were considered to have Kallmann's
1 e- r& S! a# g6 s* r5 }4 L# \syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-/ I/ {1 X$ W( H$ d1 W
lamic deficiency. After evaluation of response to luteinizing
( @, P% a5 k* a/ W9 s( y0 khormone-releasing hormone these patients were treated with5 k- p2 e+ a' f# N% F  }
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
& f- V8 F% i5 i9 Wafter completion of gonadotropin therapy 10 per cent topical! C1 z3 r3 b4 n
testosterone was applied to the phallus twice daily for 3 weeks.
; t1 v# c2 ^# ~  n4 RSerum testosterone, luteinizing hormone and follicle-stimulat-
! n0 t; p( A( W( t% e7 m" Ling hormone were monitored before, during and after comple-' j* b/ _0 v& X$ o2 p
tion of each phase of therapy. Penile stretch length was2 ]* j2 o- B' V; g9 U
obtained by measuring from the symphysis pubis to the tip of: L, _' F* v* D5 j; z4 E, j
the glans. Penile circumferential (girth) measurements were/ P/ _9 K' V1 h( D4 R; j6 |6 h
obtained using an orthopedic digital measuring device (see
6 @4 C$ u: U" |; [1 ]figure).
5 f3 p# ~& t7 s" g7 d4 JRESULTS# u* q3 h: _7 c& W, V9 E
Serum testosterone increased moderately to levels between. X7 ^' Y. g4 r/ y5 N/ i; w
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-+ x4 p! Y8 C0 {9 i# b
terone levels with topical testosterone remained near pre-& z. \* U( j/ U6 o8 |* z8 i
treatment levels (35 ng./dl.) or were elevated to similar levels
7 }' T8 d3 M$ G+ c0 e' t$ Ldeveloped after gonadotropin therapy (96 ng./dl.). Higher
# b2 d& D5 v& [9 Y7 Userum levels were noted in older patients (12 and 17 years old),
: L6 E# E9 m9 p. J' C! B: ]while lower levels persisted in younger patients (4, 8, and 10
4 A2 e% J  b5 `9 |/ ]' a/ oyears old) (see table). Despite absence of profound alterations3 m' t1 w! x; b. z) h
of serum testosterone the topical therapy provided a greater# v$ r) f3 I7 U+ ?
Accepted for publication July 1, 1977. ·4 o- a( {- J3 [. i# P3 n4 }
Read at annual meeting of American Urological Association,/ }4 C: n/ m* {8 y0 E/ [
Chicago, Illinois, April 24-28, 1977.
2 I9 e4 n& r3 C7 f: J/ U* j* Requests for reprints: Division of Urology, Henry Ford Hospital,
% o# \; E1 I: m- ]2799 W. Grand Blvd., Detroit, Michigan 48202.
; e2 g0 k2 Y. e. W( P, rimprovement in phallic growth compared to gonadotropin.8 _, o8 ?3 Z0 ?8 G) F6 \
Average phallic growth with gonadotropin was 14.3 per cent
& B$ r! m" y) h9 _. mincrease in length and 5.0 per cent increase of girth. Topical
; y  j5 c7 P0 B: p2 Y/ Ctestosterone produced a 60.0 per cent increase of phallic length5 L5 B1 v8 q3 n% o
and 52.9 per cent increase of girth (circumference). The# w7 b0 O0 m, |" X* K
response to topical testosterone was greatest in children be-
2 n3 X/ ^1 s6 x- M# l% Rtween 4 and 8 years old, with a gradual decrease to age 17
3 f2 P1 C3 ~! T4 ~6 ]4 ^years (see table).: W# o4 T7 C) d
DISCUSSION- `+ d; k! V' M/ f  r
Topical testosterone has been used effectively by other; a+ J! v+ d; `0 J  O+ A
clinicians but its mode of action remains controversial. Im-
: c5 d  Q6 ^1 j+ omergut and associates reported an excellent growth response! c9 {: l& g0 J2 R& i0 ?# K3 I
to topical testosterone with low levels of serum testosterone,  t3 L) u' N0 [: o, B
suggesting a local effect.1 Others have obtained growth re-- c4 N5 A# o9 O, C
sponse with high. levels of serum testosterone after topical5 w6 {6 }, u5 |$ v7 N% j0 J
administration, suggesting a systemic response. 3 The use of# A# }  c+ `. A( B% U
gonadotropin to obtain levels of serum testosterone compara-* ]2 U9 |" k! W" m" ^
ble to levels obtained with topical testosterone would seem to8 {2 z$ a. r8 }( A
provide a means to compare the relative effectiveness of7 Y7 T/ c: X  D3 E0 R4 |% p
topical testosterone to systemic testosterone effect. It cer-
! n+ @. P" Q3 l' I. c2 j, wtainly has been established that gonadotropin as well as par-! U: {7 C0 q$ z6 u8 W1 V9 p
enteral testosterone administration will produce genital
1 G0 G  V! n# w* C. Ngrowth. Our report shows that the growth of the phallus was
& H4 _2 j" |1 l. Q" e5 P: u+ Dsignificantly greater with topical applications than with go-+ d. E# i- X7 \/ D% P
nadotropin, particularly in children less than 10 years old.
. [! N. a1 w) dThe levels of serum testosterone remained similar or lower
7 W; k+ b8 l( zthan with gonadotropin during therapy, suggesting that topi-
4 C, O  \9 G2 S9 A: p) E0 e: L4 V" Pcal application produces genital growth by its local effect as  i9 w, j$ u) N- o' r
well as its systemic effect.
1 G  b! [1 D5 B+ D8 c: M6 \: KReview of our patients and their growth response related to
( v8 n2 u6 [- aage shows a greater growth response at an earlier age. This is
0 n$ w: [2 Z: l( Rconsistent with the findings of Wilson and Walker, who2 y: v- Y, a1 k; f8 h3 o. Y
reported an increased conversion of testosterone to dihydrotes-
# m- Z% r- t3 A& l; g& Xtosterone in the foreskin of neonates and infants.4 This activ-
1 T. C. O0 [) C) _: R+ \* @. Xity gradually decreases with age until puberty when it ap-% E/ y: K- C; z0 A. C
proaches the same level of activity as peripheral skin. It may6 \/ J5 ~5 `- _3 L! W- N6 l
well be that absorption of testosterone is less when applied at
1 d) o! {' c8 Yan earlier age as suggested by lower serum levels in children
4 a, F$ c- p) Q) l9 W+ E$ Wless than 10 years old. This fact may be explained by the( b5 V1 |* ?' B! k
greater ability of phallic skin to convert testosterone to dihy-/ T# I/ J; m8 v2 t! {
drotestosterone at this age. Conversely, serum levels in older* j9 q" i9 Y) H
patients were higher, possibly because of decreased local
& E' V! w7 b: j2 r667# j0 w! t' q! p8 |' C( s  N
668 KLUGO AND CERNY
2 M' M: d3 p9 S1 ]2 g& \Pt. Age7 i+ Q3 P" L( w; v
(yrs.)
3 O/ D4 `  h# \5 x  SSerum Testosterone Phallus (cm.) Change Length$ i- b0 b- z) G1 F! b
(ng./dl.) Girth x Length (%)
) ~. T% }& n! ~9 u6 i1 F4
, f- u, p. q% g: |/ w. a84 N0 O  F: I# R  t$ g
10
4 a) J- b" W) @$ P! p1 L12
# l" b/ `3 b3 K17  r) T8 e0 d1 _1 \% w3 f
Gonadotropin
  H% ?. m+ S* }% r8 {% c2 Q3 C3 J71.6 2.0 X 3 16.6
, G8 }+ T* s8 r$ g5 u50.4 4.0 X 5.0 20.0
7 ?$ n) W8 c8 [22.0 4.5 X 4.0 25.0
: L0 _4 a! G5 h: g8 N84.6 4.0 X 4.5 11.1
0 K& k3 G% F9 c" v7 \- d/ E# v  H85.9 4.5 X 5.5 9.0
0 G0 L6 D9 @; p; x, ~* o4 b9 _8 ^Av. 14.3
6 q6 o3 j" k' N8 i9 O4+ j" e8 k3 Y2 O6 k. C
8
( N% m" L4 F% C% I, X104 x3 j2 {, ]( d
12
0 H) m6 Q, U6 l# Q17. D2 x; c* ~* I3 f% r+ t9 A
Topical testosterone
: [# K  J/ ?) V3 u34.6 4.5 X 6.5 85
) D  u- [- I" |38.8 6.0 X 8.5 70
5 P, L# {; @- H# G6 R, C40.0 6.0 X 6.5 62.5( C: K, P6 L0 h! D
93.6 6.0 X 7.0 55.5
8 R8 N( q1 }: h95.0 6.5 X 7.0 27.2
, t, M  I/ W4 GAv. 60.0( h/ N. a" {; s( V' q! d7 ?/ v
available testosterone. Again, emphasis should be placed on- P# J2 w1 `1 F, x+ _% V0 H' e5 M
early therapy when lower levels of testosterone appear to( H( E; V+ j  T3 F
provide the best responses. The earlier therapy is instituted
- T# A$ P( F/ Rthe more likely there will be an excellent response with low
7 Q0 O" }" T# U- q& H" ]serum levels. Response occurs throughout adolescence as$ V0 j& D$ D7 i. S# R, }, W
noted in nomograms of phallic growth. 7 The actual response
! i! {% [9 w* {; \7 z+ i1 i7 Mto a given serum level of testosterone is much greater at birth
; c5 j0 M" j  `3 T% b5 K5 sand gradually decreases as boys reach puberty. This is most. b$ o2 b% I. E/ m6 u* W/ s  z
likely related to the conversion of testosterone to dihydrotes-, i' L- s( k$ `: W" D
tosterone and correlates well with the studies of testosterone. `2 q3 m0 s  V6 c
conversion in foreskin at various ages.
2 G' w2 P+ F4 r! jThe question arises regarding early treatment as to whether4 c8 j4 e0 h0 `5 M
one might sacrifice ultimate potential growth as with acceler-' L/ p2 d* F. h7 s3 q
ated bone growth. The situation appears quite the reverse
6 G5 K) J7 k1 n9 cwith phallic response. If the early growth period is not used
9 T! X# O1 K, M7 a$ G9 Lwhen 5a reductase activity is greatest then potential growth) D% _& a+ T+ P9 D0 P8 r
may be lost. We have not observed any regression of growth$ t4 l# E. M9 u7 d9 [
attained with topical or gonadotropin therapy. It may well6 [7 l. x* l$ U* |7 A# [3 \. T
be that some patients will show little or no response to any
5 J- v5 n# g$ sform of therapy. This would suggest a defect in the ability to. {  P  M. x+ e
convert testosterone to dihydrotestosterone and indicate that. N6 g, [$ T3 p) a
phallic and peripheral skin, and subcutaneous tissue should8 `" ~' k4 V/ f
be compared for 5a reductase activity.9 f+ N( n$ i, B
A, loop enlarges to measure penile girth in millimeters. B,6 J8 k' A0 l0 X/ ~  I$ P6 @
example of penile girth computed easily and accurately.
# `5 |9 U, {; _: b7 x* N3 I: hconversion of testosterone to dihydrotestosterone. It is in this
  e' Z, y0 H; \& T2 aolder group that others have noted high levels of serum$ h  j+ B# I" f4 U0 p  c& k9 O2 I
testosterone with topical application. It would also appear9 e1 h6 Z' B4 j" C4 j( w2 i6 F" u! r3 y
that phallic response during puberty is related directly to the
. l) x  y6 @0 m7 l. lserum testosterone level. There also is other evidence of local
1 {) O; h/ Q& X* \response to testosterone with hair growth and with spermato-4 q* u- ^+ e0 [$ {; V
genesis. 5• 6
8 O! \! \4 |7 l6 S* d" x# GAdministration of larger doses of gonadotropin or systemic  G4 Y5 i( R' k  e0 N
testosterone, as well as topical applications that produce$ {8 [" L, b' L
higher levels of serum testosterone (150 to 900 ng./dl.), will& O* s+ u4 V( Z& x% h, u4 B- y
also produce phallic growth but risks accelerated skeletal" f- ?: }  D6 M, k6 v
maturation even after stopping treatment. It would appear
3 A$ |0 ?8 |' Z' j: v, p7 T/ ^! Ethat this may be avoided by topical applications of testosterone
% ^# K- o+ u$ G/ q& Qand monitoring of serum testosterone. Even with this control
: P3 f7 R9 i5 M" [7 ?  @the duration of our therapy did not exceed 3 weeks at any8 P) ^& A8 n# U% A) p; x7 W
time. It is apparent that the prepuberal male subject may( b; d$ i8 N; @5 X4 k
suffer accelerated bone growth with testosterone levels near
; B1 ?6 j* j* N$ Z5 a) ?200 ng./dl. When skeletal maturation is complete the level of
* u$ C: C  o5 ]; X) cserum testosterone can be maintained in the 700 to 1,300 ng./, c* Y; x# P" k! [
dl. range to stimulate phallic growth and secondary sexual
9 @! m; i. r. \3 l8 U8 Echanges. Therefore, after skeletal maturation parenteral tes-
. N6 g$ E5 x5 [tosterone may be used to advantage. Before skeletal matura-6 J* h: R5 n! E( ~0 i' z1 Z: e
tion care must be taken to avoid maintaining levels of serum6 ?' @0 d+ t, o( O0 y6 M
testosterone more than 100 ng./dl. Low-dose gonadotropin
9 o& ]1 R7 L' [: a* zdepends upon intrinsic testicular activity and may require. L% K) o( {: y2 d, {# N! K
prolonged administration for any response.
# b4 j! `4 A* q: p( [' }Alternately, topical testosterone does not depend upon tes-
% g- X; Y4 e, A9 Iticular function and may provide a more constant level of
" B6 b- X3 l. m: Q# fREFERENCES
9 N* U2 s' t# `  Q/ J' E% ]  i2 G1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
; i2 ^+ B6 ?# D6 W1 r- B/ `; eR.: The local application of testosterone cream to the prepub-" G" p: ?" \, C' {. Q! @
ertal phallus. J. Urol., 105: 905, 1971.: [7 K! B3 V" i* W% M2 U
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
9 v' o, Q6 [, ptreatment for micropenis during early childhood. J. Pediat.,2 ?7 l% B7 H& I$ p
83: 247, 1973.
( P: M& K: r9 @  d$ H. Z3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
# l( c, _# ^% o# D& }4 aone therapy for penile growth. Urology, 6: 708, 1975.: A2 c/ `% f+ p7 A9 W
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone7 L8 a- R, O% z
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
9 W6 o- V2 ?) Pskin slices of man. J. Clin. Invest., 48: 371, 1969.
) |+ p3 E" {+ s3 e: O6 X; F% E4 F5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
4 a& [* w: Q& w3 sby topical application of androgens. J.A.M.A., 191: 521, 1965.
. S7 s( Z+ g" P3 F/ W8 G/ M6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local$ i# y( ?+ o- b! F/ L( D
androgenic effect of interstitial cell tumor of the testis. J.+ ]4 ~6 _5 V* f. x# w
Urol., 104: 774, 1970.6 [# M1 L0 g" h' O5 s; F) z
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-& l. ^2 S* B. _: c6 k( C7 |  p3 y
tion in the male genitalia from birth to maturity. J. Urol., 48:
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