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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND8 A2 c" I4 n3 C$ Q
GONADOTROPIN
* c8 y* K5 P* v. vRICHARD C. KLUGO* AND JOSEPH C. CERNY6 @+ F6 M: ?4 _: `; r9 u$ Q
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
- z- c, R( R- XABSTRACT
& ]  s  W/ F4 _0 ~1 EFive patients were treated with gonadotropin and topical testosterone for micropenis associated" o- C7 t% k6 e7 i, \  h3 P
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
6 n- h/ d5 ^  A* `tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone+ d! ~" l: e& {( U9 \
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
" c# B5 n  ]8 \5 rfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent$ {# T6 j; f6 I8 t* ^1 e4 I
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
! G' @4 H2 `' e& e3 @increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
4 M7 `8 A) M( B% |occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
( b* C, E( M/ u/ A/ U+ n4 Lstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
' w: Q6 {8 H/ O0 r6 z4 O7 Lgrowth. The response appears to be greater in younger children, which is consistent with previ-
; n2 E- ?5 l4 Z& L  M  Wously published studies of age-related 5 reductase activity.
1 Z6 P% E7 ^0 _4 L1 ]Children with microphallus regardless of its etiology will
6 o! ~" E1 S! K+ r3 w5 k' o- P2 _) Krequire augmentation or consideration for alteration of exter-+ K' j' s% V$ O0 e2 T9 Q) \
nal genitalia. In many instances urethroplasty for hypo-
# {! r9 o) g; X4 u" Vspadias is easier with previous stimulation of phallic growth.
8 B+ s& Y' M  i7 d6 NThe use of testosterone administered parenterally or topically! H! s8 g6 _( `# F' a& P$ [9 Y2 P. K
has produced effective phallic growth. 1- 3 The mechanism of
, h. r; Y. Q% Cresponse has been considered as local or systemic. With this
) H3 D. `5 `' v* g- Tin mind we studied 5 children with microphallus for response
3 s1 d1 \( Z6 \0 pto gonadotropin and to topical testosterone independently.$ @9 N; n9 ?# k. o0 _  j
MATERIALS AND METHODS
# O$ \3 G7 Z& ~" W7 }. {- H8 G0 kFive 46 XY male subjects between 3 and 17 years old were& R" u, t! {6 U9 E# e5 a6 u/ Q  ^
evaluated for serum testosterone levels and hypothalamic
8 E3 F! @) \: C0 v# U5 a- wfunction. Of these 5 boys 2 were considered to have Kallmann's
8 W0 r4 u, v2 }syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
' d4 \6 Z, _+ m, w" b: N4 @) Nlamic deficiency. After evaluation of response to luteinizing6 ]$ H- ]- {% H: m, J
hormone-releasing hormone these patients were treated with4 M6 M. k: u8 o+ }; W+ k, w
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
" G7 h' V  O: G" Fafter completion of gonadotropin therapy 10 per cent topical
) N! L5 D% j: d/ C* F4 }4 n+ K+ ltestosterone was applied to the phallus twice daily for 3 weeks.
& d. [$ K3 i; b: {- [& dSerum testosterone, luteinizing hormone and follicle-stimulat-
- f* V$ n# V6 g1 q' Z, @ing hormone were monitored before, during and after comple-
/ d& Y, s; y* b3 c- }9 ltion of each phase of therapy. Penile stretch length was) n3 p/ Z4 R1 g  L
obtained by measuring from the symphysis pubis to the tip of4 W3 H+ D8 Q  D( L3 ^9 l$ K( f5 `6 B# R
the glans. Penile circumferential (girth) measurements were" ?* L, ?! [8 q3 _7 `
obtained using an orthopedic digital measuring device (see) `/ x( p+ ?) Y' h& N- _' r( m- d
figure).( I) B& V) B  d; C
RESULTS
# U3 K4 t% L5 USerum testosterone increased moderately to levels between
  d6 M* j  t: V3 p50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
/ ~0 V" r' |% t( Nterone levels with topical testosterone remained near pre-
% n" F( R) F5 F8 ~# L) A( d  Ltreatment levels (35 ng./dl.) or were elevated to similar levels* r' x% I1 ?4 I+ F
developed after gonadotropin therapy (96 ng./dl.). Higher4 k5 l' m* D' H; Y1 ^
serum levels were noted in older patients (12 and 17 years old),
- J6 E, ?8 V& d' U5 I1 [while lower levels persisted in younger patients (4, 8, and 10% m& F( F- {- @  Q# G, U# ?
years old) (see table). Despite absence of profound alterations; M; K5 J6 v9 W9 Z' d& O
of serum testosterone the topical therapy provided a greater
1 {8 I- K. T8 _% K* ~! R' i$ MAccepted for publication July 1, 1977. ·2 G  z* M, f1 c3 M. p
Read at annual meeting of American Urological Association,  A% P2 x: ~/ R/ e# Y6 _4 w7 O
Chicago, Illinois, April 24-28, 1977.
4 J& c0 S5 g% |0 n8 n6 m* Requests for reprints: Division of Urology, Henry Ford Hospital,, t- X' e5 ]' D5 ^
2799 W. Grand Blvd., Detroit, Michigan 48202.
/ ~6 g# P7 S, K$ n0 r6 [( _. bimprovement in phallic growth compared to gonadotropin.# v* t: k" p! K& {; F
Average phallic growth with gonadotropin was 14.3 per cent9 p: @# w- ]$ q* s7 V, S! o
increase in length and 5.0 per cent increase of girth. Topical9 K+ {, D9 L0 H, D# d2 H5 a) D, }# `
testosterone produced a 60.0 per cent increase of phallic length* b  x) D# Z9 N) g, Z1 e
and 52.9 per cent increase of girth (circumference). The
0 E& W; C& r  {; W1 @' V3 \response to topical testosterone was greatest in children be-( R  H8 S2 A6 |1 ~0 W4 Z+ X
tween 4 and 8 years old, with a gradual decrease to age 17
( {# }8 P, Q! t  syears (see table).# f9 H; t: I9 b+ A5 ]) R
DISCUSSION
3 W( H3 E; D9 t0 w+ A% L5 bTopical testosterone has been used effectively by other" U+ Y, I& @' U, ]0 [6 b9 c: O5 w
clinicians but its mode of action remains controversial. Im-
. F6 g& i0 \* q% x( O2 Cmergut and associates reported an excellent growth response' B& d+ Z: ]9 T6 Z
to topical testosterone with low levels of serum testosterone,3 ?, c2 k  X" z9 B
suggesting a local effect.1 Others have obtained growth re-
! z5 l8 Y0 t' Csponse with high. levels of serum testosterone after topical! g1 _: x) n9 H5 T
administration, suggesting a systemic response. 3 The use of
# K: _2 [7 `  Wgonadotropin to obtain levels of serum testosterone compara-1 @5 N, `. T/ w$ m- A* j: ?8 o
ble to levels obtained with topical testosterone would seem to( A2 B' w$ b7 d7 I& }! z
provide a means to compare the relative effectiveness of
0 r- o6 a9 @( Atopical testosterone to systemic testosterone effect. It cer-) e3 }& `# j& I
tainly has been established that gonadotropin as well as par-
3 V) ?: \( ^* x) t; b5 lenteral testosterone administration will produce genital* W, o* z+ G7 ?, w; E' l) g
growth. Our report shows that the growth of the phallus was+ @: w) G7 |; i9 q
significantly greater with topical applications than with go-/ Y3 w4 `+ {7 Y% Y
nadotropin, particularly in children less than 10 years old.; h. @! w& g+ g; n) W
The levels of serum testosterone remained similar or lower* o  w6 l# Z8 q& f, H: Q
than with gonadotropin during therapy, suggesting that topi-9 Q' j4 C, B- y' r& m7 ]( h8 ~" V
cal application produces genital growth by its local effect as% }* O) ?* ]  z1 \
well as its systemic effect.2 L4 p6 ?4 o2 t3 R' o
Review of our patients and their growth response related to- s) w2 r" x4 K- U" r
age shows a greater growth response at an earlier age. This is/ K. H4 v; f9 C: O( v
consistent with the findings of Wilson and Walker, who
% [7 c1 ^- |( |& breported an increased conversion of testosterone to dihydrotes-
( x9 h+ I( R% q* `0 K2 |tosterone in the foreskin of neonates and infants.4 This activ-6 h/ M8 T4 W3 S1 a  M
ity gradually decreases with age until puberty when it ap-- u  n8 C/ A. \1 y2 |. t
proaches the same level of activity as peripheral skin. It may
! o+ m+ K( Y" L* S. m& pwell be that absorption of testosterone is less when applied at9 ~* ?$ E: h' H5 {9 ]8 Z( W
an earlier age as suggested by lower serum levels in children
; O; A8 m7 n6 [less than 10 years old. This fact may be explained by the; e5 R4 L, W) y$ [- X& E
greater ability of phallic skin to convert testosterone to dihy-! M/ ^; u. R& J( o0 }
drotestosterone at this age. Conversely, serum levels in older! Q/ w7 O: L! i
patients were higher, possibly because of decreased local- R+ p7 \5 k% _
667% ?, q  W( N+ p* z! u: Z7 [) K
668 KLUGO AND CERNY2 F* J8 q8 m  Y0 H4 ]
Pt. Age
. }* O: i) g6 Z* g# K(yrs.)
- v/ Z. U/ ^) zSerum Testosterone Phallus (cm.) Change Length
+ F# n1 |! X' a7 O9 c( T(ng./dl.) Girth x Length (%). \1 m' k9 c* d! B' U9 x/ ]4 G7 R
4# I! ~+ @- h2 E0 s1 K- w
8
9 l/ E: o- Z& D' W$ C& m10. p( C* R1 s& U4 t" F) v
12
% m9 e  O" d* a5 E9 j5 `7 {+ F17& }& ]- d2 N& L6 ?
Gonadotropin
  R' e8 z: D+ d, T/ x71.6 2.0 X 3 16.6- ?6 S. _# Q  m6 f& ^  y
50.4 4.0 X 5.0 20.05 O. ]; a/ J1 [- f# Q% X2 N
22.0 4.5 X 4.0 25.0
) g" ]1 a( d% ^  T: y84.6 4.0 X 4.5 11.1- E8 H: f6 K* C+ m; t9 T
85.9 4.5 X 5.5 9.0
/ }& u' y2 I  q( U/ y' p% QAv. 14.3* O3 x! e( S! G$ a
4
. t2 T5 S6 P% C# V2 @& {% N8
* q' o# ]* ^$ M5 |3 f5 C10; C5 y2 c& F# M
12
$ F* I3 m4 V- F9 s) G, |) q6 F3 L6 j17" N# `) f+ f/ A# ]
Topical testosterone
5 p% @2 Z& b  C4 p) Y! e+ S34.6 4.5 X 6.5 851 Z5 l* n& N7 G/ Q. p9 b: n. o
38.8 6.0 X 8.5 703 @. D3 D, b  [
40.0 6.0 X 6.5 62.5# E+ S3 k& X6 i9 V
93.6 6.0 X 7.0 55.54 I" R$ Z  Q2 r* j9 E& L
95.0 6.5 X 7.0 27.2
& H' i6 L; @) b' u/ UAv. 60.0! o' h1 p. ?% y& `+ C3 g
available testosterone. Again, emphasis should be placed on
1 I4 C. j6 w# k0 B1 U- H1 f2 Yearly therapy when lower levels of testosterone appear to
3 K% B  y/ U# m0 O+ Zprovide the best responses. The earlier therapy is instituted2 G+ J& u3 w1 f( |+ B
the more likely there will be an excellent response with low
' O8 E6 i) n) J' Pserum levels. Response occurs throughout adolescence as
5 d/ Y; g) s8 B7 Z3 nnoted in nomograms of phallic growth. 7 The actual response
, U# [: s" @& L1 Eto a given serum level of testosterone is much greater at birth
0 @: P5 ]$ _# r* C6 J  [and gradually decreases as boys reach puberty. This is most4 E8 S( a4 }7 o& z
likely related to the conversion of testosterone to dihydrotes-. U* i+ r5 W, K& o
tosterone and correlates well with the studies of testosterone4 U, ~! I  {4 E% h
conversion in foreskin at various ages.
3 B4 @% \% g3 z- b6 WThe question arises regarding early treatment as to whether
  I4 P( F+ P9 v3 G: t4 Done might sacrifice ultimate potential growth as with acceler-1 e) V) g$ X$ o
ated bone growth. The situation appears quite the reverse
9 C* W& \# v6 Y2 `' ^. zwith phallic response. If the early growth period is not used: ?+ \/ s' A: z. n7 g
when 5a reductase activity is greatest then potential growth! ]' E- m  z, Z/ s, I
may be lost. We have not observed any regression of growth
4 w. a5 L' [0 g3 Sattained with topical or gonadotropin therapy. It may well
3 N0 r% b: ^" F& Ybe that some patients will show little or no response to any  a) i* ?, y9 H
form of therapy. This would suggest a defect in the ability to
, s2 z" x* U8 \0 b4 c0 xconvert testosterone to dihydrotestosterone and indicate that6 W  T3 s7 A( U) k( e) ]
phallic and peripheral skin, and subcutaneous tissue should% k5 Y  E) p: _7 e& g# j
be compared for 5a reductase activity.
6 {# A' ]2 ^3 i1 B7 pA, loop enlarges to measure penile girth in millimeters. B,
0 a1 R$ i. |& yexample of penile girth computed easily and accurately.
9 e, k4 f  L7 q" E4 _/ z2 Tconversion of testosterone to dihydrotestosterone. It is in this
, \) r8 m8 V: D. Eolder group that others have noted high levels of serum
' u. `1 _) K. t/ Z) ], \testosterone with topical application. It would also appear
; C# @; u$ B! @. v$ e* ^0 o% kthat phallic response during puberty is related directly to the' m, D! z$ f* x- u+ j) Y
serum testosterone level. There also is other evidence of local  x4 e8 U& c" `. }4 w3 T
response to testosterone with hair growth and with spermato-: s2 p: ]4 V/ n
genesis. 5• 64 V- S/ [& s: G* k$ Q
Administration of larger doses of gonadotropin or systemic
- v$ y+ ~# m' L2 vtestosterone, as well as topical applications that produce' c' l3 ^# {( L  _5 u
higher levels of serum testosterone (150 to 900 ng./dl.), will
6 }9 Q( N! _6 v) e2 g& w+ f7 Salso produce phallic growth but risks accelerated skeletal0 ]. Q; U8 Z+ p* a: ?
maturation even after stopping treatment. It would appear9 E5 C7 N& R$ H3 x( z# b) X: y
that this may be avoided by topical applications of testosterone: g1 w$ Z5 F) y/ U0 x* E  R  |' q
and monitoring of serum testosterone. Even with this control
; A- ]# S+ F0 R+ Ythe duration of our therapy did not exceed 3 weeks at any! o! {, A# j8 {0 ]) v$ L& J" n! ^; q
time. It is apparent that the prepuberal male subject may6 u$ n2 Q5 `) l' a2 d* i. a
suffer accelerated bone growth with testosterone levels near' s) C" l6 f$ L+ E6 H2 u
200 ng./dl. When skeletal maturation is complete the level of
. M8 g& ^2 T, B: Jserum testosterone can be maintained in the 700 to 1,300 ng./
' M" r0 b& i8 ~/ \dl. range to stimulate phallic growth and secondary sexual# w5 V) y- i8 f' e& E
changes. Therefore, after skeletal maturation parenteral tes-9 v- K& D6 t* X! [4 Z1 F: Q1 g/ j. _! K
tosterone may be used to advantage. Before skeletal matura-
, |1 L: ?2 I8 [+ Btion care must be taken to avoid maintaining levels of serum
$ l8 Z$ _3 R* g+ H7 btestosterone more than 100 ng./dl. Low-dose gonadotropin
4 d' j9 n" e7 q+ }: i2 }8 jdepends upon intrinsic testicular activity and may require
& z& Y9 z1 q+ V2 M, _: I# Eprolonged administration for any response.
- b2 S2 z7 F9 X6 A6 WAlternately, topical testosterone does not depend upon tes-
( I  B1 c) @. Z. i0 u5 q3 Dticular function and may provide a more constant level of' n7 I+ k% G9 m+ _0 |
REFERENCES
; V, p+ s+ _8 ?9 }7 c) f1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
  f9 _7 Y- f$ SR.: The local application of testosterone cream to the prepub-! L' ?. a- @# Q- z9 m8 u
ertal phallus. J. Urol., 105: 905, 1971.
1 e) j  u8 o% O, Q6 m! Z2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
" G( g/ ^- D8 c5 w" w4 ftreatment for micropenis during early childhood. J. Pediat.,/ ~! C, ?& s  R6 v" b
83: 247, 1973.
! D. H2 p0 B3 c1 i2 c2 _! [) K5 z3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-* y. L: G4 ^0 q) L4 u# b
one therapy for penile growth. Urology, 6: 708, 1975.; ?  A0 o. u& F. O
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone1 i8 j$ s5 X3 T- a7 @
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by" r. |1 f# M$ r8 e( t9 U
skin slices of man. J. Clin. Invest., 48: 371, 1969.4 K( [/ K: Z% y1 T7 L" M
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth+ p: ]/ o- ]+ I# I) z
by topical application of androgens. J.A.M.A., 191: 521, 1965.
; U1 n; @; w: {2 G2 O' l6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local$ E6 B0 N7 H: ^9 w) K& ]. o& |$ [* [
androgenic effect of interstitial cell tumor of the testis. J.
5 c; Q  T( _& K5 }: t$ e. AUrol., 104: 774, 1970.
+ h! Q6 ]; I$ R% z7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
$ }. z1 H) @0 r& L2 D! `, F/ Gtion in the male genitalia from birth to maturity. J. Urol., 48:
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