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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND4 x" C- }" _$ Q6 I! e
GONADOTROPIN
4 d3 C7 ^# T; {* J- j" y1 FRICHARD C. KLUGO* AND JOSEPH C. CERNY
0 ^% H" T# J9 xFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
* n0 m& o3 F2 p4 gABSTRACT
. s2 ~7 i! v' E  O, jFive patients were treated with gonadotropin and topical testosterone for micropenis associated  O) R8 S! s3 I. w" W& e- @% v
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-/ q/ `3 `) z* A6 D- A
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone- e* K9 B0 n0 G4 w" H7 y
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
5 e$ a# h& T% T  h7 o) O  h# Ufor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
) ?; e. Q# ]) B0 d  C4 wincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average; z0 ?* N: P4 o& B" m' j
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
/ d. u0 l, M) h7 B/ @occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This. G, Q: V& g; u9 X; g0 I) g
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
( s8 {; @( y" N" G+ \" y  ggrowth. The response appears to be greater in younger children, which is consistent with previ-' j( r6 v1 ~1 D
ously published studies of age-related 5 reductase activity.+ m1 C, v5 q' t! u3 ?4 J, x4 n
Children with microphallus regardless of its etiology will
" E9 \4 a; k4 f4 R6 m) g5 {% trequire augmentation or consideration for alteration of exter-
! g+ l! _4 y3 K1 z! n- ~/ xnal genitalia. In many instances urethroplasty for hypo-  \( R1 z# e# y7 a6 e) x
spadias is easier with previous stimulation of phallic growth.! C6 Q7 V& ?5 ~2 L
The use of testosterone administered parenterally or topically
* N! ]7 C- z5 uhas produced effective phallic growth. 1- 3 The mechanism of
( T! [  j: f  g; Bresponse has been considered as local or systemic. With this
# A8 C( j4 M1 \9 I4 din mind we studied 5 children with microphallus for response+ o6 ?, ^7 w; b2 I
to gonadotropin and to topical testosterone independently.
8 Z% e. \8 n. Q3 V& nMATERIALS AND METHODS. Z5 V2 @+ V3 u/ |; B4 Z
Five 46 XY male subjects between 3 and 17 years old were
$ n, x$ g0 k" Uevaluated for serum testosterone levels and hypothalamic
6 e% q% M8 I8 b& Yfunction. Of these 5 boys 2 were considered to have Kallmann's+ P5 ^5 Q/ I; f
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
& m0 J* A% B$ Z! t/ C0 Z6 ~lamic deficiency. After evaluation of response to luteinizing
, I( c% n  e6 _2 K; D" U8 h1 Ghormone-releasing hormone these patients were treated with
& f* U$ N1 N/ F5 A" Q/ x. Q1,000 units of gonadotropin weekly for 3 weeks. Six weeks7 ?/ K) {, h, X
after completion of gonadotropin therapy 10 per cent topical
. ]/ ?' P3 P* Q( y+ Y# ^  mtestosterone was applied to the phallus twice daily for 3 weeks.
+ i, a+ }+ N1 G3 zSerum testosterone, luteinizing hormone and follicle-stimulat-
" z" B1 ]# F2 qing hormone were monitored before, during and after comple-5 @8 S6 W8 \. U; ~) s1 b; h4 z) O
tion of each phase of therapy. Penile stretch length was
6 G3 K0 I7 X. l. n7 G+ e: Nobtained by measuring from the symphysis pubis to the tip of
+ R+ K3 E6 B; V$ F# }0 n+ o" C% u, l8 Kthe glans. Penile circumferential (girth) measurements were
* [( n1 f6 r! G1 }0 Kobtained using an orthopedic digital measuring device (see) V7 S1 S/ R2 {  n6 J
figure).
8 U0 B, O5 B! N! mRESULTS' J: s. f0 Y2 A4 U3 T
Serum testosterone increased moderately to levels between
1 k/ Y# R9 d( ]% H* F* ]7 V' E50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
' X, \% n; R! f# v$ |: Y2 u  Cterone levels with topical testosterone remained near pre-, D$ _( g$ V9 S
treatment levels (35 ng./dl.) or were elevated to similar levels
3 G) Z# G* V- g7 k' Ideveloped after gonadotropin therapy (96 ng./dl.). Higher3 d; e6 v. ~8 B( f" X
serum levels were noted in older patients (12 and 17 years old),# {* g0 z. u/ j: f: N+ |
while lower levels persisted in younger patients (4, 8, and 10
9 n0 q4 \5 P9 `, o: yyears old) (see table). Despite absence of profound alterations
7 T, R' F$ R+ R5 f1 D1 Jof serum testosterone the topical therapy provided a greater
! N- @1 s% i5 p' z8 `Accepted for publication July 1, 1977. ·) r4 b" j: Z* k6 h! u
Read at annual meeting of American Urological Association,7 \+ m% c4 J& m4 o
Chicago, Illinois, April 24-28, 1977.
" F% e7 ^- l2 x. E: o4 S* Requests for reprints: Division of Urology, Henry Ford Hospital,4 w+ H3 [: l8 v9 q: t* \5 m
2799 W. Grand Blvd., Detroit, Michigan 48202.
" p7 }/ u8 E& r' Oimprovement in phallic growth compared to gonadotropin.; A) @3 D; D* U5 B
Average phallic growth with gonadotropin was 14.3 per cent
* e* r( O+ x& S/ Aincrease in length and 5.0 per cent increase of girth. Topical5 F* D! Z. b) |+ {$ B
testosterone produced a 60.0 per cent increase of phallic length
& h$ X& _4 E) z( }% |and 52.9 per cent increase of girth (circumference). The
4 J1 e( G+ D- X$ y. lresponse to topical testosterone was greatest in children be-
" F- m; @: L. t* C1 wtween 4 and 8 years old, with a gradual decrease to age 17; M0 V6 n2 p9 J3 W
years (see table).$ t: O6 h4 P4 \/ h6 ?! \7 z8 O
DISCUSSION
  k) U) @) X# |1 YTopical testosterone has been used effectively by other+ H5 e  I1 Q0 }
clinicians but its mode of action remains controversial. Im-6 T; m' `( c/ h. \0 |# w, U
mergut and associates reported an excellent growth response. f* b% u% E4 V8 y# C: F0 d! w
to topical testosterone with low levels of serum testosterone,
0 |2 H/ }9 E3 O8 jsuggesting a local effect.1 Others have obtained growth re-
2 n- x9 |6 k2 Z% S/ Z/ Tsponse with high. levels of serum testosterone after topical/ @  ^7 R% e; I& Z
administration, suggesting a systemic response. 3 The use of* M1 h# d6 |' Y4 b0 \
gonadotropin to obtain levels of serum testosterone compara-+ O( i6 J4 g/ |
ble to levels obtained with topical testosterone would seem to" H4 y1 e, f) Y  ?
provide a means to compare the relative effectiveness of; C. c" }5 V2 G) S
topical testosterone to systemic testosterone effect. It cer-2 H9 v7 @  a7 Y7 {6 L; F9 ^) S
tainly has been established that gonadotropin as well as par-
, s% ~/ l. M: ^9 Q* `/ ienteral testosterone administration will produce genital
0 ~" p& i) h( P, H, Vgrowth. Our report shows that the growth of the phallus was
! G' R! F* B6 L% c* {9 Wsignificantly greater with topical applications than with go-* e6 p4 H) W& Z4 t1 t$ h! v# ^
nadotropin, particularly in children less than 10 years old." f( W; u, n& \. L7 r1 {  \% q( @
The levels of serum testosterone remained similar or lower
4 n( q8 L3 F3 U8 ^- vthan with gonadotropin during therapy, suggesting that topi-
1 Y/ o  s# Y& Ocal application produces genital growth by its local effect as8 j' z8 |) g' B5 q, Z3 I/ f" J
well as its systemic effect.5 g; J2 v* D0 m4 b8 V7 D: \* U
Review of our patients and their growth response related to* R" h' z9 N9 w$ R. |" F! u0 n
age shows a greater growth response at an earlier age. This is9 H' I$ _; \9 i0 u" V
consistent with the findings of Wilson and Walker, who  G) }2 K& w! s8 ]+ n
reported an increased conversion of testosterone to dihydrotes-7 J$ o; c' H* Y  p4 m
tosterone in the foreskin of neonates and infants.4 This activ-
1 c2 X0 Q' W8 E# Pity gradually decreases with age until puberty when it ap-- m3 U$ G. W2 v
proaches the same level of activity as peripheral skin. It may
* v) @! l( u3 jwell be that absorption of testosterone is less when applied at) {! I/ ]( |* P# \2 J$ J2 X
an earlier age as suggested by lower serum levels in children+ c4 H- W% @* Z9 I5 x: P
less than 10 years old. This fact may be explained by the
/ D" d" I5 e  c" ~" n1 z# N& vgreater ability of phallic skin to convert testosterone to dihy-
# G; f. U, A+ idrotestosterone at this age. Conversely, serum levels in older
$ I& [+ e) Z. S: K7 N* Upatients were higher, possibly because of decreased local3 @3 e  Q' j6 f- v
667: [( F4 \/ V# A. G7 S
668 KLUGO AND CERNY4 B, G- ]( z5 c$ u+ r* f( j
Pt. Age
, {; J' \( d, H* t" n# Q4 D(yrs.)4 c& w. Q1 N$ l4 ~# }. F& I
Serum Testosterone Phallus (cm.) Change Length) A8 P* B3 Z$ [
(ng./dl.) Girth x Length (%)
! d0 }$ C: }) n4$ \3 E' U, q  E, B  _/ B
82 R" K7 Z8 `, F" V; P! g7 m; s
10* {7 R, i( Z4 `: {+ x
123 g0 Z  d0 e+ Q
17
; J+ {2 m0 m  G# f; g8 s' sGonadotropin
* I  B$ P5 _: X0 B: g8 C3 c71.6 2.0 X 3 16.6
! F9 W: [( Y6 s. m+ @6 `50.4 4.0 X 5.0 20.0
  y) N* G; i$ x1 [+ ?22.0 4.5 X 4.0 25.0
5 O$ H& v9 h+ o; L84.6 4.0 X 4.5 11.1) k1 w! _: D8 g7 X. t& F
85.9 4.5 X 5.5 9.0
- @9 r' V: `: M. z. GAv. 14.3
# n' e2 G7 \" o# N4
4 q2 ^! F( `' M& p% w- k4 k6 {0 h80 [9 L7 r9 K% H5 T* n/ r$ q
10# f/ O' K+ u6 {+ Y  d
12: w- @; G& W1 Z
17+ L# x3 w. X" _
Topical testosterone/ M% D! m" s: _. M( [& N. H7 T$ `
34.6 4.5 X 6.5 85
* t8 ], w( ]+ m' H/ U38.8 6.0 X 8.5 700 ?5 J2 N, o2 m! k7 f
40.0 6.0 X 6.5 62.5
0 P; y" X5 M9 _6 P! w0 D0 m93.6 6.0 X 7.0 55.5  G% I% b8 i- g
95.0 6.5 X 7.0 27.2
4 P; E8 U- H5 E$ l* ]( J$ Z' |Av. 60.00 u; r( P4 E- N- v% {" a( D* j
available testosterone. Again, emphasis should be placed on
" B$ u% H' d- j0 Qearly therapy when lower levels of testosterone appear to$ X+ u( Z/ g. V. R. @! Z- v; ?  T; W
provide the best responses. The earlier therapy is instituted* J& H( c# f- S$ r% z0 i' L1 d
the more likely there will be an excellent response with low
; m" i1 S* V7 `- H. ^9 y) Tserum levels. Response occurs throughout adolescence as' S1 V: p+ X$ b1 u
noted in nomograms of phallic growth. 7 The actual response6 D' D" h& J) w# X) E
to a given serum level of testosterone is much greater at birth
/ t5 r: a' R4 C, k! _and gradually decreases as boys reach puberty. This is most
& e% i* U: M  ]! }2 L6 Wlikely related to the conversion of testosterone to dihydrotes-% n# `/ ~! H$ v1 C+ P0 R( S/ Q& H
tosterone and correlates well with the studies of testosterone6 }: O7 t1 l6 ]8 I0 K6 y# r
conversion in foreskin at various ages.
/ g, w! A6 T/ q& a2 R6 qThe question arises regarding early treatment as to whether
% x& Q/ Y/ j% x% t$ B9 A% s7 aone might sacrifice ultimate potential growth as with acceler-: b! a: B5 X# o2 J$ R& M6 g! h0 s
ated bone growth. The situation appears quite the reverse
3 O1 Y1 v* f. K4 U( {with phallic response. If the early growth period is not used. l+ ^9 Q6 S& q# I0 W
when 5a reductase activity is greatest then potential growth
( l. f( |6 p% @4 |6 u9 |may be lost. We have not observed any regression of growth
( O% C" `, [, x5 rattained with topical or gonadotropin therapy. It may well+ H& ]0 Q$ N. q8 a/ X/ A7 N( D
be that some patients will show little or no response to any
" g+ E& M' _! g/ o  m) O7 C, O, B1 qform of therapy. This would suggest a defect in the ability to
' f2 f( r+ |8 }- X, p( }" h, r& @convert testosterone to dihydrotestosterone and indicate that
( Q. J, i# s; v- v% nphallic and peripheral skin, and subcutaneous tissue should$ F# r0 c& H+ p# X9 C8 u
be compared for 5a reductase activity.
0 Z& d; G% I5 g, b) |4 MA, loop enlarges to measure penile girth in millimeters. B,
0 M3 w, O. v1 {: ^. E- i; E& Gexample of penile girth computed easily and accurately.
; Y$ a) W% j3 P; J0 Wconversion of testosterone to dihydrotestosterone. It is in this5 l3 I9 r) P6 y
older group that others have noted high levels of serum
9 r1 i. c7 A1 G' ^& Q5 _' ]testosterone with topical application. It would also appear
8 N3 j4 v- f4 n  K0 x0 T: _that phallic response during puberty is related directly to the) \1 K# j, K! k+ I1 j
serum testosterone level. There also is other evidence of local
! c. ~$ ~% B# r3 r) B) @' vresponse to testosterone with hair growth and with spermato-6 F4 F  N) @9 p0 Y2 t
genesis. 5• 6
1 ~3 `6 B' H5 p1 \5 \+ cAdministration of larger doses of gonadotropin or systemic
2 B3 v/ x8 ^* `! u4 Ltestosterone, as well as topical applications that produce
5 ?3 ~% z3 b) Chigher levels of serum testosterone (150 to 900 ng./dl.), will( W  O$ w& S; ]/ v# `
also produce phallic growth but risks accelerated skeletal" a' v1 i1 J7 B: I( U- o+ u6 Y
maturation even after stopping treatment. It would appear4 g6 Y) I7 ~" Y2 |8 H0 r- v
that this may be avoided by topical applications of testosterone( g, U, J2 {0 d' ^, l; r0 w3 h
and monitoring of serum testosterone. Even with this control
$ r7 E! |( B; b+ nthe duration of our therapy did not exceed 3 weeks at any
5 `/ Y% _% K, ?' btime. It is apparent that the prepuberal male subject may
9 s) `: P* ~3 {; f$ }. o- Ysuffer accelerated bone growth with testosterone levels near
7 d9 x) R! a9 @6 `5 k0 O6 \" i200 ng./dl. When skeletal maturation is complete the level of
& g1 x* n5 s+ c, Rserum testosterone can be maintained in the 700 to 1,300 ng./8 ~- T( H4 W  J; L( t5 U
dl. range to stimulate phallic growth and secondary sexual0 O; Q7 H" j0 [% u% l0 s$ @
changes. Therefore, after skeletal maturation parenteral tes-8 M1 `" k! N! p8 P0 f% x
tosterone may be used to advantage. Before skeletal matura-3 J" F' U- g" {) p! n/ A1 n7 [
tion care must be taken to avoid maintaining levels of serum8 O  k' u- l; ~; l) k! Q
testosterone more than 100 ng./dl. Low-dose gonadotropin
7 `7 \: k* u$ d0 m, F+ w  d* p7 Ddepends upon intrinsic testicular activity and may require
' [0 ]/ Y! i: W& d* s- sprolonged administration for any response.
: R+ w8 E9 v# m# l; ]0 RAlternately, topical testosterone does not depend upon tes-
+ o, m% R, [6 Nticular function and may provide a more constant level of1 ]' y- Z$ b% D5 G+ Q" h- F
REFERENCES- A6 O, X4 l/ T0 I, r  A6 r
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,& x7 n; B1 C" T- p$ N4 X
R.: The local application of testosterone cream to the prepub-  E" e% i+ g$ L3 B4 r. t" ], f3 _
ertal phallus. J. Urol., 105: 905, 1971.
+ a7 G4 }( [: L( _' n9 C- u5 L3 q2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
4 G* P( I! `, |treatment for micropenis during early childhood. J. Pediat.,
' O: @* M4 E; T* N9 @0 C# m/ ^83: 247, 1973.
2 l* k: z2 J3 U3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-. A+ D3 ^2 W) X& L
one therapy for penile growth. Urology, 6: 708, 1975.
/ D! p9 B- B- b0 N: Q% y) |4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone4 [2 T; a& d. z! _; G8 a
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
  N8 l: H4 Z9 x0 O. |$ n3 s! i; Askin slices of man. J. Clin. Invest., 48: 371, 1969.; s, j2 R6 E/ C9 W& t( I8 q: U* }
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
( E9 `9 R; e- e6 |  Sby topical application of androgens. J.A.M.A., 191: 521, 1965./ K/ `5 j; a3 E( Q. ]
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local- @  [+ H$ i* \0 l/ a3 P) Q6 u
androgenic effect of interstitial cell tumor of the testis. J.
/ `" |5 }/ y; K" e  n2 e/ G# y! sUrol., 104: 774, 1970.
4 z% D. ~- d8 ^2 S7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
0 A; R* J* b0 _+ N3 ?% Ction in the male genitalia from birth to maturity. J. Urol., 48:
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