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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
: Z& X- I' c# p, |2 B3 VGONADOTROPIN
5 `1 P/ m  W* J* SRICHARD C. KLUGO* AND JOSEPH C. CERNY) I# v6 d  [$ k: x. v2 l
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
5 Q9 [! y/ F% y' {0 qABSTRACT  P) s0 l4 A$ i  p
Five patients were treated with gonadotropin and topical testosterone for micropenis associated* K8 `+ b% ^& q& B
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-  s& A& a: i) @) G' F
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone. A$ m- X7 l) Q( U5 _
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
1 \/ o/ A  o* e7 ?for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
4 ^9 n. o. S& c+ n* sincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average- b2 b. o' a$ h4 E2 V
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response) `' G: ?) R9 u
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
8 l8 z$ t, B. Q& sstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile0 O9 o1 L, G9 j1 u
growth. The response appears to be greater in younger children, which is consistent with previ-5 `( f, g0 g2 z5 d9 f: S: a
ously published studies of age-related 5 reductase activity.
5 `8 ~0 H8 V9 |+ p5 f. E$ MChildren with microphallus regardless of its etiology will2 X, `0 M' f$ a) y4 v  m- T
require augmentation or consideration for alteration of exter-
3 j: T- P6 H* @& Onal genitalia. In many instances urethroplasty for hypo-" `1 W) t& s% f7 |6 s8 s8 S
spadias is easier with previous stimulation of phallic growth.
5 `1 Y& |$ x/ M3 gThe use of testosterone administered parenterally or topically
  A( u& M! C2 zhas produced effective phallic growth. 1- 3 The mechanism of
& P7 s* s0 e" y' V4 `% `, yresponse has been considered as local or systemic. With this
1 ~5 N& `) A5 z- v: z4 B" d2 Ain mind we studied 5 children with microphallus for response! v% u" d. W$ D* p- x4 }  {
to gonadotropin and to topical testosterone independently.
% u3 o* I$ o) }" V* HMATERIALS AND METHODS
1 d. r; N# Z: e  U) EFive 46 XY male subjects between 3 and 17 years old were* c. o2 T% M% b) {# R+ }
evaluated for serum testosterone levels and hypothalamic) N5 ^0 L/ {+ o3 _9 t5 l
function. Of these 5 boys 2 were considered to have Kallmann's
0 e) A2 a+ r) E* Tsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
) W- d( y3 |7 Y/ tlamic deficiency. After evaluation of response to luteinizing
% U, a' Q& N& ?9 Hhormone-releasing hormone these patients were treated with) ?7 I6 m: ]: g, K( h
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
6 |2 y- N3 F  i0 V' Lafter completion of gonadotropin therapy 10 per cent topical$ s2 v$ I4 G( c  D+ s1 o
testosterone was applied to the phallus twice daily for 3 weeks.
$ C- x3 j) I: M" {Serum testosterone, luteinizing hormone and follicle-stimulat-- q* D  V  }; r
ing hormone were monitored before, during and after comple-7 T% r3 Z1 K0 o+ m3 F+ h  Y; |
tion of each phase of therapy. Penile stretch length was- _+ C8 t2 B/ d2 \
obtained by measuring from the symphysis pubis to the tip of- u) ]# `7 f0 H3 W
the glans. Penile circumferential (girth) measurements were1 }$ j' n0 S$ a/ }, J+ C
obtained using an orthopedic digital measuring device (see
9 M, |3 O. U) F$ Lfigure).# a1 A) k6 C. Z8 A2 }$ ?( P
RESULTS
( y' X( S" E; ]Serum testosterone increased moderately to levels between/ ]7 M7 `4 Y& d  j6 k) ]
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
0 S/ D; e; K- p" [; k) B7 C" fterone levels with topical testosterone remained near pre-6 a$ a* U0 l) l. s& m) K5 \- S9 C
treatment levels (35 ng./dl.) or were elevated to similar levels, p, `8 R' U4 f. Q# O
developed after gonadotropin therapy (96 ng./dl.). Higher
- f% `3 X6 J+ Z  b) yserum levels were noted in older patients (12 and 17 years old),9 |9 W/ H" i; |  n
while lower levels persisted in younger patients (4, 8, and 105 n$ S  O0 m% o4 w9 ?
years old) (see table). Despite absence of profound alterations! c6 V, l) ]; [" @
of serum testosterone the topical therapy provided a greater
5 a9 e  x" C; S9 `* e, W' ?+ CAccepted for publication July 1, 1977. ·
+ u" _3 v* M% T0 }+ M+ ^2 O" R0 W; c7 V) cRead at annual meeting of American Urological Association,: L3 E5 n) s. W) q8 F- S
Chicago, Illinois, April 24-28, 1977.! [9 Z4 P- p: _2 A& _1 j8 G: d
* Requests for reprints: Division of Urology, Henry Ford Hospital,1 d% r' u) g! A& j- b) X( V
2799 W. Grand Blvd., Detroit, Michigan 48202.
( Z. R& {, c3 x' b+ }improvement in phallic growth compared to gonadotropin.
8 P( c# X+ @: T( {% G1 C4 o' U1 Z0 YAverage phallic growth with gonadotropin was 14.3 per cent
7 I. [! s  E" D8 Kincrease in length and 5.0 per cent increase of girth. Topical
1 c( ~- ?2 m1 ztestosterone produced a 60.0 per cent increase of phallic length/ v7 T0 U# A& t0 P1 F
and 52.9 per cent increase of girth (circumference). The: y; Z: Q& x9 o* @/ `8 U* Q  Z
response to topical testosterone was greatest in children be-
# G% P& F5 z. v' r* @& f( _' ]tween 4 and 8 years old, with a gradual decrease to age 17
9 w1 t6 f8 G: k9 Q4 W6 Fyears (see table).
8 d5 k8 \8 _  TDISCUSSION( |) j7 t5 S" }2 }; g3 C
Topical testosterone has been used effectively by other8 |  y, A% X1 f
clinicians but its mode of action remains controversial. Im-
; K* D( Y+ v8 y/ gmergut and associates reported an excellent growth response
$ ~8 ^. W4 |: Gto topical testosterone with low levels of serum testosterone,
( Z; r. |( ~1 ^( a2 asuggesting a local effect.1 Others have obtained growth re-+ G" T9 W6 R- o2 m; C' }
sponse with high. levels of serum testosterone after topical
7 S; n- ]9 S& j* g! R6 ~3 _administration, suggesting a systemic response. 3 The use of
. y. j2 p/ I& k$ Y/ ugonadotropin to obtain levels of serum testosterone compara-
  E% y4 y4 e5 F9 |& E  W, Vble to levels obtained with topical testosterone would seem to9 O! i. a& Z1 b% h" z8 f# f
provide a means to compare the relative effectiveness of
0 T# H) F; t6 h0 b. {4 R! A. |topical testosterone to systemic testosterone effect. It cer-
' s, o$ w9 h* O8 q% K# Dtainly has been established that gonadotropin as well as par-
7 x# u! i( G6 g8 t2 s# \  A4 I: Jenteral testosterone administration will produce genital3 A/ J& q- ~9 r/ K% ^
growth. Our report shows that the growth of the phallus was; s* P! r* B' w9 }. t5 ]( b% o/ M
significantly greater with topical applications than with go-
# P) s3 d* N* S. h6 w4 A5 F* anadotropin, particularly in children less than 10 years old.
" S' Z3 a9 b0 K2 hThe levels of serum testosterone remained similar or lower
% L. ]6 O: d; J4 a& t2 J4 f8 Othan with gonadotropin during therapy, suggesting that topi-
9 D9 k* r& Y; ], bcal application produces genital growth by its local effect as
7 }8 w* j7 B, j  C9 awell as its systemic effect.
9 [- L. L* {" J) q! r( PReview of our patients and their growth response related to! F! M7 a! f! J$ I/ B( y
age shows a greater growth response at an earlier age. This is9 Z& v* f: A$ H  {, ?
consistent with the findings of Wilson and Walker, who
: E+ D; [/ Q+ m' K0 V" ]4 e+ treported an increased conversion of testosterone to dihydrotes-
! `9 d% O' J  Q0 K# Rtosterone in the foreskin of neonates and infants.4 This activ-5 k5 m6 G% P5 `. S# k
ity gradually decreases with age until puberty when it ap-' r7 `# _- z9 E: a* u: [8 g
proaches the same level of activity as peripheral skin. It may; p& Q( w5 g- ~( V, n, b
well be that absorption of testosterone is less when applied at
: A1 n" X  A/ {( A& ~# F3 Uan earlier age as suggested by lower serum levels in children3 y4 h% s  j4 }+ K8 i7 L
less than 10 years old. This fact may be explained by the9 w* o8 v# ]: A* |. O
greater ability of phallic skin to convert testosterone to dihy-
# E1 z) d" |2 `. Tdrotestosterone at this age. Conversely, serum levels in older! ^3 P! y" K2 p( x2 a$ R) B
patients were higher, possibly because of decreased local
, b+ f: A, C6 b/ ^! w667& g. L; B! F! ?0 d4 v  y; y
668 KLUGO AND CERNY: E' ]1 F8 L. l& `0 V# g; W
Pt. Age
1 |& g  D! Z1 d9 @1 E9 c1 |4 w(yrs.)
* L; s$ h  t) U: i, oSerum Testosterone Phallus (cm.) Change Length/ G  B1 Q- A9 H  i5 `
(ng./dl.) Girth x Length (%)- F+ o1 ^* T+ r) G
4
: k  C1 f) u4 E0 k8 O83 t. D6 {: E) t* g% q& a3 t
10
* A& Q2 f! d" Z  z# O  p, f4 j12! u  z) W* L/ K
17
6 Z  U4 x: u; A1 m1 ?; {+ j% wGonadotropin
- F" z* @# D* q' b- @  I71.6 2.0 X 3 16.6' F8 n. S. E% P- M5 }7 b
50.4 4.0 X 5.0 20.0" m$ @$ t5 @* _2 Q+ a' c+ Y
22.0 4.5 X 4.0 25.0% @; A# ~, k( j7 V; r$ B) s  v
84.6 4.0 X 4.5 11.1
2 g) j  ^: s1 D$ _7 r6 ?3 V0 m85.9 4.5 X 5.5 9.0
6 o! b2 X2 z8 K4 G, @4 s1 cAv. 14.3
+ ]; t* o1 X( M; Z$ c; X2 o8 F" L4  A+ m) q/ R6 S6 D2 ]8 _) a# V
8
# A$ l3 ?5 N- I9 F( g- M. s& y/ A/ K- n10
# W- T; S' W3 d. B& O, y! C- `12
, k" N+ m( H: o17! y# K# E3 j8 e+ v+ Q% _0 U
Topical testosterone% i( f- Z% R# k' x
34.6 4.5 X 6.5 85: J6 l3 m( G; r* w- [" k
38.8 6.0 X 8.5 704 U& r: ~7 w2 O+ ^; t3 d( C( R4 y& t
40.0 6.0 X 6.5 62.5
; r$ E( k# L; T& C4 I9 K8 @7 D93.6 6.0 X 7.0 55.5- m; X$ p3 `+ v! ?* e8 p5 D
95.0 6.5 X 7.0 27.2' |6 ?. j- i5 r; e7 o0 O! T
Av. 60.0
; |9 C- k1 n1 r* p( j) O7 pavailable testosterone. Again, emphasis should be placed on. d# c3 P6 y. J3 J$ T5 D! }' H
early therapy when lower levels of testosterone appear to
$ m- |2 n! R6 xprovide the best responses. The earlier therapy is instituted
7 u$ M5 g% F: N9 P9 Q( ?the more likely there will be an excellent response with low
1 W+ H7 B2 S3 V  h, q& H' Qserum levels. Response occurs throughout adolescence as
! M* k6 _, S3 Inoted in nomograms of phallic growth. 7 The actual response# @7 j( i9 P2 N/ U  T6 _$ U) t+ a
to a given serum level of testosterone is much greater at birth
' [/ F) Y. t! k7 a9 x  x6 {and gradually decreases as boys reach puberty. This is most
9 ~- c5 q  s; j. Elikely related to the conversion of testosterone to dihydrotes-
" [0 z' J1 W" p/ ?& j% {tosterone and correlates well with the studies of testosterone
$ G! k7 J( a' l" L, y; pconversion in foreskin at various ages.& i: M" P1 d% G
The question arises regarding early treatment as to whether
2 ]/ [4 }( K0 `: g( Vone might sacrifice ultimate potential growth as with acceler-
: {0 H# N- f3 @( U, B- h1 x/ j8 |ated bone growth. The situation appears quite the reverse5 C: _" N2 i8 |% c' N( `* h7 u
with phallic response. If the early growth period is not used* ?, C3 n0 B; j$ D, H
when 5a reductase activity is greatest then potential growth7 }  o$ A2 n8 R5 s7 b
may be lost. We have not observed any regression of growth" B& R2 T. N$ \; D; a
attained with topical or gonadotropin therapy. It may well
$ u4 m1 m% q3 @( J" u$ J8 K6 Bbe that some patients will show little or no response to any
8 A$ t4 m9 p6 H' m1 D, f) l0 y/ n0 kform of therapy. This would suggest a defect in the ability to
  x! Z7 ?* W# p8 n5 z5 a; jconvert testosterone to dihydrotestosterone and indicate that# R, d1 T/ N! b: q7 ?- m% b$ g
phallic and peripheral skin, and subcutaneous tissue should" y6 |' H- E) r8 Q: X+ S
be compared for 5a reductase activity.% j' p+ j6 b& y$ V8 e) Z
A, loop enlarges to measure penile girth in millimeters. B,2 t! T9 ]# g8 ]$ W% b
example of penile girth computed easily and accurately.- J& y' P7 ~  s& G# F2 R
conversion of testosterone to dihydrotestosterone. It is in this2 x4 X3 W. J# o  T: u( q- Y3 ~3 T
older group that others have noted high levels of serum
7 o( L# i0 Y- K  |1 qtestosterone with topical application. It would also appear9 m4 t" j0 ^: \* Q) }" ~
that phallic response during puberty is related directly to the( w; M1 _9 @$ E) B0 v
serum testosterone level. There also is other evidence of local2 I7 z9 o- @6 f6 @; k% b
response to testosterone with hair growth and with spermato-9 Z. S6 P( K) `9 b4 Z
genesis. 5• 6
2 c2 {# m! |: r* a' P4 M6 uAdministration of larger doses of gonadotropin or systemic
7 B% R' d/ e1 q- H; l% z; Ntestosterone, as well as topical applications that produce
9 s' o6 ~5 i: G7 L1 Z$ ~higher levels of serum testosterone (150 to 900 ng./dl.), will0 x7 `3 X1 J: `5 T5 G0 g
also produce phallic growth but risks accelerated skeletal
/ i9 Y) {! }& amaturation even after stopping treatment. It would appear
+ x# N0 M; ~2 }that this may be avoided by topical applications of testosterone
; R9 F6 u* C6 ~# H3 R6 ]( Q3 iand monitoring of serum testosterone. Even with this control
8 o: {: N& D  n4 H3 m* Sthe duration of our therapy did not exceed 3 weeks at any
1 d7 R: }# T! F* G6 Q) v8 D, [3 B4 J9 w1 Atime. It is apparent that the prepuberal male subject may
; V# O% _5 j8 l  e; I  Usuffer accelerated bone growth with testosterone levels near
  ?3 z6 N9 X1 |) E3 Q, c$ M200 ng./dl. When skeletal maturation is complete the level of1 a" q! y% N$ P, A1 j
serum testosterone can be maintained in the 700 to 1,300 ng./! Y" p) q+ y8 ~7 ~* ?4 U5 o
dl. range to stimulate phallic growth and secondary sexual
+ L" X! g' h1 ]2 fchanges. Therefore, after skeletal maturation parenteral tes-$ g. M3 s- U! n' F, }- A3 c. m
tosterone may be used to advantage. Before skeletal matura-
  A& Y" Q3 X6 ution care must be taken to avoid maintaining levels of serum
, t$ C2 z( s, ^( u+ `testosterone more than 100 ng./dl. Low-dose gonadotropin
1 x6 _* l' E5 J5 m% v1 a% }6 Y7 Vdepends upon intrinsic testicular activity and may require
1 Z" S5 Z8 [/ U7 m# Mprolonged administration for any response.! C  N7 ~# @% ~+ i4 E3 D
Alternately, topical testosterone does not depend upon tes-4 y6 |7 p  R  f( J! B: O
ticular function and may provide a more constant level of8 Q2 n6 z$ ?/ x4 _- H1 \: J6 G
REFERENCES
/ B9 W3 e7 j" Q: g0 D& t1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,8 ~0 h% H9 I0 n& o: x8 q
R.: The local application of testosterone cream to the prepub-2 k4 a& s$ z% U! z" E
ertal phallus. J. Urol., 105: 905, 1971.
4 h+ [+ `' {% Y0 q) L/ X2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone# Z, S& X' N; l" q$ }) ~6 U& P
treatment for micropenis during early childhood. J. Pediat.,* d0 y8 S1 B* q0 [' y# c# W
83: 247, 1973.9 W; m; J( J# G9 X) f/ N. W( v& e
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
: i; a- R  R" _3 None therapy for penile growth. Urology, 6: 708, 1975.
- {- {! G0 d0 ]2 c* A6 y" q4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
. c/ o" ~/ c5 z6 p2 K( Ato 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
7 X$ k/ e! S* nskin slices of man. J. Clin. Invest., 48: 371, 1969.
8 m( x1 i  ^, p& E' S5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
) N* B$ Y0 z8 x4 ~by topical application of androgens. J.A.M.A., 191: 521, 1965.) W8 ^+ a. b1 g& D; T
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local! q: C. b: ^1 m( ]; N0 e
androgenic effect of interstitial cell tumor of the testis. J." m! I) ^! E8 E8 B# G4 a
Urol., 104: 774, 1970.
0 \6 G: g" d; E4 v  u9 \7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-# i8 q& d' ^/ r8 X) a& w
tion in the male genitalia from birth to maturity. J. Urol., 48:
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