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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
; O0 m, I1 [8 J. ]) u5 T: WGONADOTROPIN5 ^5 I" L) w, O3 T- F+ {7 V
RICHARD C. KLUGO* AND JOSEPH C. CERNY6 J( C; P& y" s; ?1 s' i' y
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan- {' y+ F) s8 x6 [0 P3 \5 u1 a
ABSTRACT
" a3 V1 h& z/ e' @, {Five patients were treated with gonadotropin and topical testosterone for micropenis associated
* h( ?4 Y2 g3 I# Q8 twith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
% |( ~# n4 `& F: _2 btropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
0 n: v3 t3 z& m+ g. X+ lcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent0 C6 ~0 e3 q* ~3 v
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
; w6 n. i1 A+ _) E; t( wincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
+ G( I( L# k* W% w" {8 k+ }increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response! T% H' b# v( q4 R3 M
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This" `2 b3 @' M1 o% B2 L# \
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
1 J+ b1 s! \7 ?$ rgrowth. The response appears to be greater in younger children, which is consistent with previ-$ }. ^6 S% A+ T, W3 ~, B
ously published studies of age-related 5 reductase activity.
8 U2 z' r, |$ `3 J) K$ iChildren with microphallus regardless of its etiology will  G4 g/ P0 {7 N3 G% m! ]
require augmentation or consideration for alteration of exter-& |  _. D0 T9 i* w" F8 r
nal genitalia. In many instances urethroplasty for hypo-
* T- c: g2 \8 U* |spadias is easier with previous stimulation of phallic growth.+ N$ u  _! g- L/ o/ K  N
The use of testosterone administered parenterally or topically
- D1 E, {- o9 ~' E3 E: Hhas produced effective phallic growth. 1- 3 The mechanism of# a+ @5 c9 S! i1 F; y$ T- v  B% o  `
response has been considered as local or systemic. With this6 r6 k: a  R, _; n8 \
in mind we studied 5 children with microphallus for response
* Z" z% @8 h/ n' k$ Cto gonadotropin and to topical testosterone independently.
+ ~+ K( |' x( P2 v0 JMATERIALS AND METHODS
5 b+ L  h  U( o. }: ~+ Q3 l4 mFive 46 XY male subjects between 3 and 17 years old were7 B& w/ Q% `, B& t
evaluated for serum testosterone levels and hypothalamic
1 K/ D3 e. X$ u* p0 c' Q3 `function. Of these 5 boys 2 were considered to have Kallmann's3 V/ Y  Z' s  p" r  K+ d' j
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
+ g8 M/ {5 F6 c% G* F) llamic deficiency. After evaluation of response to luteinizing
* V! n7 G; I9 q9 U$ E5 chormone-releasing hormone these patients were treated with! c0 r9 ~* e% {$ u: v
1,000 units of gonadotropin weekly for 3 weeks. Six weeks8 V; ]2 {- z7 E& x/ p* K0 R
after completion of gonadotropin therapy 10 per cent topical7 I5 l0 W% ^7 R2 Z' R9 n/ x) o, ]
testosterone was applied to the phallus twice daily for 3 weeks.
; ~3 b7 K* I8 q! {7 m3 NSerum testosterone, luteinizing hormone and follicle-stimulat-
4 G4 L1 O$ [" I0 d3 f  f' Fing hormone were monitored before, during and after comple-) e& }2 S. W& F" h: b) m( ?
tion of each phase of therapy. Penile stretch length was
/ u" ]$ |; g# |1 }obtained by measuring from the symphysis pubis to the tip of9 |0 s& j+ @2 L5 m8 V! M, r
the glans. Penile circumferential (girth) measurements were
2 R6 e- L& `0 dobtained using an orthopedic digital measuring device (see
! r5 h+ g7 H5 B% U- ~6 O: Nfigure).; x/ K% l4 S& ]' d% G
RESULTS
. c$ v: u  J0 _! [, Q/ bSerum testosterone increased moderately to levels between& q% o! U0 G) S
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-0 l- {. S9 J3 b$ l8 P9 ]: ]2 z
terone levels with topical testosterone remained near pre-. O6 ~: s+ T) G
treatment levels (35 ng./dl.) or were elevated to similar levels
& \" v# j& V: Q2 h5 D& S6 ddeveloped after gonadotropin therapy (96 ng./dl.). Higher
  G/ [& v" a5 `& s3 Dserum levels were noted in older patients (12 and 17 years old),+ k  M" L2 `  k: J
while lower levels persisted in younger patients (4, 8, and 10
. ?5 S5 t" h( O. byears old) (see table). Despite absence of profound alterations
7 o5 l9 w9 M& h# p/ c0 u. Rof serum testosterone the topical therapy provided a greater: i! U, Q$ m5 ]/ X
Accepted for publication July 1, 1977. ·
5 Y+ n9 F% Y6 |# f+ PRead at annual meeting of American Urological Association,: S- C: g& T) U% O$ F3 I  F
Chicago, Illinois, April 24-28, 1977.: g$ A- v3 `+ r5 I& R
* Requests for reprints: Division of Urology, Henry Ford Hospital,& n: Q3 @* G& X; C. `' }! q
2799 W. Grand Blvd., Detroit, Michigan 48202.
7 |" q" i; K; N) nimprovement in phallic growth compared to gonadotropin.) B  X) T- _! Y4 l8 m1 k& C( `
Average phallic growth with gonadotropin was 14.3 per cent4 e6 n1 P) Y* k. W0 |  J( O
increase in length and 5.0 per cent increase of girth. Topical- |; l" k* K' {, Q! `  t2 u9 Y
testosterone produced a 60.0 per cent increase of phallic length5 M2 x% U2 O# O% X$ t% G% C5 k
and 52.9 per cent increase of girth (circumference). The1 S# ]4 M- ~, N, o, H1 }1 l) l
response to topical testosterone was greatest in children be-, j) T/ O: _3 b
tween 4 and 8 years old, with a gradual decrease to age 17
0 }& V+ L+ h1 m" d( w3 a* l6 X; F! Pyears (see table).5 z3 w9 f5 m5 _1 H1 @& K+ a
DISCUSSION5 t2 A' s6 g% _
Topical testosterone has been used effectively by other
- }$ k% G5 ?8 N/ D; ^clinicians but its mode of action remains controversial. Im-5 b# R9 a$ z4 A3 C) v$ V$ |3 G
mergut and associates reported an excellent growth response1 X% E3 F$ }; t0 @
to topical testosterone with low levels of serum testosterone,
+ k5 D" q# b: [2 [# u+ o8 ssuggesting a local effect.1 Others have obtained growth re-
, O  X% |7 h& @9 M6 t" E3 H8 y$ Esponse with high. levels of serum testosterone after topical$ M0 m/ d, n: b# Y4 l; v0 h% M2 E# Q
administration, suggesting a systemic response. 3 The use of
, ?9 o3 g% Q) ^+ u" V8 zgonadotropin to obtain levels of serum testosterone compara-4 Q! v7 F5 t  n: }( A1 c
ble to levels obtained with topical testosterone would seem to
( J6 f& ]# ?, _+ i( G" P1 Yprovide a means to compare the relative effectiveness of/ W; O2 x9 \& y1 H
topical testosterone to systemic testosterone effect. It cer-- i4 y+ b% t& U  A8 A3 d
tainly has been established that gonadotropin as well as par-2 W* Y" H' U6 M* I$ x/ P  L
enteral testosterone administration will produce genital% e8 S6 o4 ^9 ^( c5 d
growth. Our report shows that the growth of the phallus was( Y3 L0 [* }0 k* e
significantly greater with topical applications than with go-
7 `9 }! B* N8 _8 K0 knadotropin, particularly in children less than 10 years old.
- p" T, b2 Z0 E! {2 v# vThe levels of serum testosterone remained similar or lower
# O6 A/ j( c# u$ vthan with gonadotropin during therapy, suggesting that topi-
2 ?" I; V2 @- d4 U" X: D" t- z) _& Ycal application produces genital growth by its local effect as
( e. e* B3 {/ ]+ J$ K2 uwell as its systemic effect.& |( ~$ L  Z- v
Review of our patients and their growth response related to$ N. z; d6 w# [+ _- v" @
age shows a greater growth response at an earlier age. This is" c: z1 |2 l$ w7 `4 o# `
consistent with the findings of Wilson and Walker, who
, o7 H; z; n- ^% q6 k; Y3 I8 qreported an increased conversion of testosterone to dihydrotes-
% Y' C' V9 J7 T1 W' P5 g' z1 O5 itosterone in the foreskin of neonates and infants.4 This activ-: [, y/ A+ i2 u* e
ity gradually decreases with age until puberty when it ap-
0 f8 z& |0 D+ t9 W" @( Q) Q4 jproaches the same level of activity as peripheral skin. It may
: G3 b" ?, C; \9 f7 jwell be that absorption of testosterone is less when applied at
/ {$ ]) `) F9 x5 y5 L% ian earlier age as suggested by lower serum levels in children
: U& X2 q/ z3 R. aless than 10 years old. This fact may be explained by the6 q5 u* j  w! S6 B  I# V
greater ability of phallic skin to convert testosterone to dihy-
/ P* Y  a# O8 {& `4 j7 P+ g% Q+ Jdrotestosterone at this age. Conversely, serum levels in older) Z2 e9 {( C& }: @1 K: B
patients were higher, possibly because of decreased local  }" i0 U7 X  Q& }# w$ {
667
9 z: N% Z& q0 W0 X7 V9 O9 {5 \668 KLUGO AND CERNY
0 z! h( j/ i; uPt. Age! c$ ?" S  `7 w0 a" R
(yrs.)0 \9 @/ f+ o/ Z3 g+ E
Serum Testosterone Phallus (cm.) Change Length& q: N" |. r$ ~7 F
(ng./dl.) Girth x Length (%)6 t6 e' a! _5 l" @) |. @. A' m
4
( |2 @. A5 I6 _. @. v- [8' G, E/ f+ T% |
10
) e1 q$ c9 I' x12! R( J" P; P# Q: h
17/ @7 y0 e; `& q$ u; V% q- w
Gonadotropin9 F+ e# ~$ F" S  ^6 ?
71.6 2.0 X 3 16.6
# n3 v6 ]5 K& t/ W50.4 4.0 X 5.0 20.04 s7 v+ R, k- v/ P$ S$ X
22.0 4.5 X 4.0 25.0
; X; [- U7 |5 ]  Z: B84.6 4.0 X 4.5 11.1, X, U% z, S9 T0 r; u
85.9 4.5 X 5.5 9.01 a, g# q! V4 `3 f( t
Av. 14.36 k- L% _, h  d$ V- Y9 Q+ E
4$ Y' J! }9 o$ C8 J# M% t
8
! `" v6 ^# |! `- m; E105 H" M% ]& F1 j7 ~5 A* z1 E
121 a" S' j2 l; O( T, r( A) L8 v
17
9 C# I/ h. T3 c; m# {7 hTopical testosterone  c) }) P; |2 P$ p8 p
34.6 4.5 X 6.5 85# |6 ^2 }% f6 U0 O' R' q  U
38.8 6.0 X 8.5 70
: U# n, z* S1 Z, X40.0 6.0 X 6.5 62.5# R9 v# q! M; @5 @
93.6 6.0 X 7.0 55.5
, f' p) l, E/ p9 e. A95.0 6.5 X 7.0 27.2
; V) ?4 q1 d# H: }7 d3 n( ]Av. 60.0
& I- p+ v. c5 |0 `2 W6 S  Favailable testosterone. Again, emphasis should be placed on
: h; \. b6 O4 J8 Z6 T( |4 {5 vearly therapy when lower levels of testosterone appear to
* [) d& Y5 L1 T& \' U: w: Hprovide the best responses. The earlier therapy is instituted
  \+ w; G5 F4 ^6 G, a' F' Cthe more likely there will be an excellent response with low
/ s" W7 D- i, b+ u! k- y- fserum levels. Response occurs throughout adolescence as1 O! X% D3 L" L' ~: W! t
noted in nomograms of phallic growth. 7 The actual response
) }- `7 O- f: P# P1 Fto a given serum level of testosterone is much greater at birth0 Y. S0 }: i1 Q
and gradually decreases as boys reach puberty. This is most
4 }# m! s" R, Y! ~4 Llikely related to the conversion of testosterone to dihydrotes-2 D( x! P* Y4 Y* @7 _+ e! Z
tosterone and correlates well with the studies of testosterone0 `  h6 B# i! G, n- K6 f* C( y/ _
conversion in foreskin at various ages.
% c5 t% U) X$ e- tThe question arises regarding early treatment as to whether! V% ]9 u6 k) n* S
one might sacrifice ultimate potential growth as with acceler-4 S9 \! r& m9 a& @
ated bone growth. The situation appears quite the reverse5 u& `  }, R$ v
with phallic response. If the early growth period is not used! O2 ^" i- I  a9 r, Q
when 5a reductase activity is greatest then potential growth5 a9 O0 a: C! K8 V
may be lost. We have not observed any regression of growth
& a8 T& N# O. Oattained with topical or gonadotropin therapy. It may well
5 ^( |0 H( n2 I$ Ybe that some patients will show little or no response to any
0 v5 @# r$ E" `; Cform of therapy. This would suggest a defect in the ability to
$ d% Q7 W) B* R: ~, w3 V/ U# J# Yconvert testosterone to dihydrotestosterone and indicate that
7 n* M% X6 m( u8 A4 Jphallic and peripheral skin, and subcutaneous tissue should% n7 e+ c" n! R0 x; W
be compared for 5a reductase activity." e, H, p& A8 X8 w1 ^4 W
A, loop enlarges to measure penile girth in millimeters. B,
% Z# ]- k, B/ c' D- uexample of penile girth computed easily and accurately.* B) A1 U9 i& E
conversion of testosterone to dihydrotestosterone. It is in this
2 ~6 B( W3 t4 P6 ?+ |older group that others have noted high levels of serum  m- f9 L5 _9 S7 Q3 l+ o2 ]
testosterone with topical application. It would also appear
4 W) G& L+ ~! \1 h1 e) M6 Wthat phallic response during puberty is related directly to the
* p9 V2 z! A$ `serum testosterone level. There also is other evidence of local: ^5 D. a2 p0 [, S' L* Q0 X
response to testosterone with hair growth and with spermato-5 T3 |( c/ g. p6 W' f" a
genesis. 5• 6
* v- k( f  Z" {9 RAdministration of larger doses of gonadotropin or systemic
6 `1 F) f1 Y$ ltestosterone, as well as topical applications that produce
8 `2 s4 @3 N1 J9 G3 H. mhigher levels of serum testosterone (150 to 900 ng./dl.), will
* p0 D; M( n- p& L! f; ]also produce phallic growth but risks accelerated skeletal
3 B5 v$ F7 x. x3 o* g2 Zmaturation even after stopping treatment. It would appear
" L, ]0 p/ f0 i. f2 u' ythat this may be avoided by topical applications of testosterone
+ e- r* p7 A' u. V! h1 k6 Y1 X5 f8 aand monitoring of serum testosterone. Even with this control
: c: L0 Q; z& Ythe duration of our therapy did not exceed 3 weeks at any
  Z) u5 {% k! {+ wtime. It is apparent that the prepuberal male subject may" c" p. \1 r# }* B
suffer accelerated bone growth with testosterone levels near
# c( }) E. ]: n200 ng./dl. When skeletal maturation is complete the level of
) \" W" j, ~( kserum testosterone can be maintained in the 700 to 1,300 ng.// M6 |4 P+ t5 D$ f0 m# B
dl. range to stimulate phallic growth and secondary sexual# v1 k: a/ ]. C/ i6 n
changes. Therefore, after skeletal maturation parenteral tes-
/ n$ v! |; J# r5 E% k  F" s/ k% utosterone may be used to advantage. Before skeletal matura-( w) V/ {% @; c, \9 E* p( ]& x: I
tion care must be taken to avoid maintaining levels of serum
- z+ [6 c- P7 J$ R2 F1 Ztestosterone more than 100 ng./dl. Low-dose gonadotropin
( ?9 N0 ^% r0 ?$ Z6 M' U9 pdepends upon intrinsic testicular activity and may require
* ^  ^3 L5 K, sprolonged administration for any response.
# R/ w; i5 F4 Q# tAlternately, topical testosterone does not depend upon tes-# c% }8 v0 G" |0 h' a* g
ticular function and may provide a more constant level of$ z. M" i! G- J6 L& O
REFERENCES
# L/ e1 ~6 {+ P5 I5 b1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,9 q# G! i! b2 E$ _9 Q' V9 }( n; j
R.: The local application of testosterone cream to the prepub-
. G& g& O! n5 v/ a# {3 Lertal phallus. J. Urol., 105: 905, 1971.
4 G! L9 o; G% ?- @4 R1 H2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
! e0 y2 ]+ M# X/ p0 M: i6 Itreatment for micropenis during early childhood. J. Pediat.,
: @* f7 D- h7 N0 ~' a83: 247, 1973.2 H2 z8 K5 r% U& @* Q9 Q. A0 b
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-6 O- @) U- @6 j
one therapy for penile growth. Urology, 6: 708, 1975.5 _5 B( e. j6 p2 z, W5 {% `  o, \6 H
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
/ @# M0 \! j! O9 M4 |* G; {1 {8 qto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
9 v/ U" q3 L6 v* }skin slices of man. J. Clin. Invest., 48: 371, 1969.
( O* b# m- _, e! {, w5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth# @/ N! T7 M5 l. s: @
by topical application of androgens. J.A.M.A., 191: 521, 1965.1 Z$ Q- Y+ d8 X# N9 T5 ~
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
, ~2 i4 h0 A) O7 |6 tandrogenic effect of interstitial cell tumor of the testis. J.! o: s' D9 k7 w$ _/ Z
Urol., 104: 774, 1970.
" L7 x* S" B% X7 n2 m2 w7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-0 _% u3 m; ]- p' x1 x
tion in the male genitalia from birth to maturity. J. Urol., 48:
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