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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND/ p$ J( z6 b  V
GONADOTROPIN
- ^" M# F' _$ x2 F) [RICHARD C. KLUGO* AND JOSEPH C. CERNY
/ M0 l4 A3 f* N& L  [& |' RFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan# H3 [; H& B( s! Q$ @) U; G) C; W
ABSTRACT
3 X$ |# D* `& R0 Z. j6 o7 J9 @" p. RFive patients were treated with gonadotropin and topical testosterone for micropenis associated& X9 M3 w' O6 _7 M9 V; f- K; u
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
+ }* N+ p2 f& _) S, otropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone; M/ C# g# |  ^0 e0 x
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
: d% [3 H. V! ~) @" hfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent% [3 k* d5 W* ^* s$ t+ l
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
6 g0 d7 S- g/ p! H: W' G, J; lincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response; a& s% ^& j& Q9 r2 W+ R
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
) y4 b5 n2 ?1 _8 v& ~# m. }- Kstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile' D# q) B1 F; m! p9 t
growth. The response appears to be greater in younger children, which is consistent with previ-% e) ^0 y! r& @' {( h
ously published studies of age-related 5 reductase activity.; ~0 V2 K& j: ?
Children with microphallus regardless of its etiology will, L) U  e4 F: Z( S( ]) V8 b/ o
require augmentation or consideration for alteration of exter-
6 S9 D1 l4 D9 `2 Unal genitalia. In many instances urethroplasty for hypo-
7 }6 w8 N& |1 {. ^% j7 Bspadias is easier with previous stimulation of phallic growth.; ^7 \$ g( ~  A, A+ |
The use of testosterone administered parenterally or topically
+ i) d) a6 g+ dhas produced effective phallic growth. 1- 3 The mechanism of
& o+ Z4 ?6 p9 `8 I' A- u$ Nresponse has been considered as local or systemic. With this  b5 \& M2 h0 k& b4 C8 L
in mind we studied 5 children with microphallus for response* n7 P9 s: @) D
to gonadotropin and to topical testosterone independently.2 Y1 I% h# t" h: @9 r$ D6 Y
MATERIALS AND METHODS
' p! R* x8 O( z1 U3 E5 Q2 cFive 46 XY male subjects between 3 and 17 years old were
7 a- P& A$ C2 C4 B, F3 J" |2 v* `0 wevaluated for serum testosterone levels and hypothalamic6 Z/ }. `  h; k1 ?% H0 @# \
function. Of these 5 boys 2 were considered to have Kallmann's1 L: f0 Z% ]  V
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
2 T) ]! z" B8 G# K0 ^$ Clamic deficiency. After evaluation of response to luteinizing
) S$ u8 _3 v! q3 c% uhormone-releasing hormone these patients were treated with
/ t1 R* b$ G7 l9 h1,000 units of gonadotropin weekly for 3 weeks. Six weeks# ~; O8 v) @- ~0 P$ x  p( S
after completion of gonadotropin therapy 10 per cent topical
, v: Q9 A$ P$ J* htestosterone was applied to the phallus twice daily for 3 weeks.
, h/ ?' E  B+ W+ E0 QSerum testosterone, luteinizing hormone and follicle-stimulat-0 h- R: Z* Y" i+ [7 F7 h
ing hormone were monitored before, during and after comple-7 S3 ?/ b9 t, z, E8 j7 t& G4 e. w: W# D
tion of each phase of therapy. Penile stretch length was
0 P  @# F" v1 ?. c9 h0 a  v$ gobtained by measuring from the symphysis pubis to the tip of
' `; d3 O+ s/ k( y" R9 athe glans. Penile circumferential (girth) measurements were6 s, v" J' h7 H* ?; {- X5 o
obtained using an orthopedic digital measuring device (see. m  N4 E% V3 U; W* Z/ b
figure).# m5 B; r- u+ n# P0 T" e
RESULTS
" Z4 N( o7 M# k/ cSerum testosterone increased moderately to levels between
' V% A0 |5 T+ {8 {+ W% G50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
) B: b% l- a& v% lterone levels with topical testosterone remained near pre-
, r4 w" Z8 x# E, M9 j5 f  Q; ~treatment levels (35 ng./dl.) or were elevated to similar levels. N  j1 ~" Y4 D2 E' u9 c
developed after gonadotropin therapy (96 ng./dl.). Higher  q4 u$ O% \4 C! C- D5 O  o
serum levels were noted in older patients (12 and 17 years old),& O  V# `2 Y6 D- ^
while lower levels persisted in younger patients (4, 8, and 10
: g. r% v" i1 @' M# q7 M- j4 @: z# J- Tyears old) (see table). Despite absence of profound alterations
$ u+ r' h5 n! n1 t# [  wof serum testosterone the topical therapy provided a greater& L- f7 T2 z+ n6 [
Accepted for publication July 1, 1977. ·
' J) {" C6 J1 M/ F% j# @Read at annual meeting of American Urological Association,+ o+ Q$ R: p4 }- f3 c
Chicago, Illinois, April 24-28, 1977.. y. u) \  u/ D  @* \
* Requests for reprints: Division of Urology, Henry Ford Hospital,
% `/ F) o1 r, z# f2 X  J2799 W. Grand Blvd., Detroit, Michigan 48202.
1 d5 Y8 N+ i; z, {' simprovement in phallic growth compared to gonadotropin.8 K& {3 P4 o- X* R; d
Average phallic growth with gonadotropin was 14.3 per cent
( [. Y& n  Z3 x6 Qincrease in length and 5.0 per cent increase of girth. Topical
" T* A( G0 ]* D. Ztestosterone produced a 60.0 per cent increase of phallic length
8 i4 W$ T# T5 N/ p( l4 wand 52.9 per cent increase of girth (circumference). The
& v  `2 K7 \- {2 O7 Xresponse to topical testosterone was greatest in children be-
! U' U4 K) [* A! M- _tween 4 and 8 years old, with a gradual decrease to age 17$ t' w9 K) J4 [, H# O% x7 W
years (see table).
. }' x7 g4 {. c' e$ s4 B& w- ?DISCUSSION
- v. H1 @. ^, ?$ fTopical testosterone has been used effectively by other
8 @" B+ {; T, X% W5 Y7 t& Iclinicians but its mode of action remains controversial. Im-; Z9 B; z6 T% H+ _; }; y( r5 Y& m) F
mergut and associates reported an excellent growth response: u. y; z3 u& X( M1 a& }
to topical testosterone with low levels of serum testosterone,
4 M+ B* |& S: k! H; y7 Gsuggesting a local effect.1 Others have obtained growth re-9 W0 l6 |+ z6 g( ~- ~
sponse with high. levels of serum testosterone after topical
4 J3 u$ l3 X+ [! x+ ?administration, suggesting a systemic response. 3 The use of, o  ^* b* A* Q, Z1 ?
gonadotropin to obtain levels of serum testosterone compara-7 @# r- T) R' L5 Y! P) b
ble to levels obtained with topical testosterone would seem to. m9 e: U1 `8 s2 @$ K1 g
provide a means to compare the relative effectiveness of8 h- A; i3 j4 x, g6 Z  M+ S
topical testosterone to systemic testosterone effect. It cer-& }& v( W2 |0 d2 m/ R- F) I: c& s7 R
tainly has been established that gonadotropin as well as par-
' H% f" r1 N+ ^% ^" Renteral testosterone administration will produce genital
* r6 F: d5 |, F/ X# zgrowth. Our report shows that the growth of the phallus was
# _, d* R% T) g$ v5 e' D% b: ^significantly greater with topical applications than with go-1 l0 F3 m, F- g  ]* K
nadotropin, particularly in children less than 10 years old.
9 Z. L0 K% i- n- K4 z2 hThe levels of serum testosterone remained similar or lower. T; B- B$ ?# H
than with gonadotropin during therapy, suggesting that topi-. w8 L4 m- Z( w! K, f
cal application produces genital growth by its local effect as+ ~. l2 G, j+ [, h. r4 q; j& B
well as its systemic effect.5 M1 B  O  @7 G# l  o+ M- y! G- d4 B
Review of our patients and their growth response related to" o( ~1 b1 Z4 {9 L2 m2 U6 I
age shows a greater growth response at an earlier age. This is7 x) s, V9 ?% M+ J
consistent with the findings of Wilson and Walker, who+ l( g: [8 t* G: o
reported an increased conversion of testosterone to dihydrotes-
- V, m" M5 O% [- Vtosterone in the foreskin of neonates and infants.4 This activ-. m, T3 r6 D: m% t* ^9 b
ity gradually decreases with age until puberty when it ap-/ K& E, o4 M, Z$ h( f! d# ~# w/ w
proaches the same level of activity as peripheral skin. It may
+ O9 s! I3 R- N; ^9 B0 z0 w/ i% uwell be that absorption of testosterone is less when applied at
/ Z8 c7 y4 q0 y9 dan earlier age as suggested by lower serum levels in children
) m0 m) c* x! c, Hless than 10 years old. This fact may be explained by the( F$ O- m6 K2 G: `2 ?( K2 _9 R
greater ability of phallic skin to convert testosterone to dihy-
, `0 r3 V0 A; \9 H- _7 Q, W( h4 L8 Ldrotestosterone at this age. Conversely, serum levels in older
( \( \$ V; J" C# qpatients were higher, possibly because of decreased local
- a  v, B- b/ l/ U: y2 E6672 u& q& F/ {  C! h% L! u! h+ ?/ Y
668 KLUGO AND CERNY) V: g% W3 Z- f" I0 S
Pt. Age
& O' d; q8 k- o) B1 o(yrs.)5 Y% v. }- v+ j. E: q8 p
Serum Testosterone Phallus (cm.) Change Length
' ~: K. H) w& I; ~2 [! g$ a6 e(ng./dl.) Girth x Length (%)  k5 r$ n+ r( E8 |
4
; }# q! y8 r) z- X7 j/ y& y8
3 f% v2 T/ `6 y' U0 o5 [10
' @$ W9 |& D; {4 I% L$ I" [12
! t/ `: x' V6 K: K& w17
$ h! B) L9 i8 _! Z: \Gonadotropin( k8 V2 M6 g% \3 C) ~, L
71.6 2.0 X 3 16.6
# {: K( U6 O: [5 G) k50.4 4.0 X 5.0 20.09 \$ n. C. q) [( [
22.0 4.5 X 4.0 25.0
+ l/ O* Q: d: m' G7 D3 j5 f) _) g84.6 4.0 X 4.5 11.1
/ }: z& p" ^$ U+ q$ I. R85.9 4.5 X 5.5 9.0+ m+ L' }0 `3 |* n
Av. 14.3$ K9 N& Z* d$ p6 _
45 \# M( H- p9 E! Q. Z& B! V
8
) c2 I! k& z( i. y10
( e1 t+ [& r& w0 r12
% |' \. j) Z# S9 V17
; W3 A0 E  L9 s7 O- ?, XTopical testosterone/ i& @0 y7 R: K2 L
34.6 4.5 X 6.5 851 N$ `) r* v' q# U
38.8 6.0 X 8.5 70
0 K. U; v0 P3 T$ D) ~' H0 R3 l40.0 6.0 X 6.5 62.5% ]7 D" o. `6 W9 Y' O: T
93.6 6.0 X 7.0 55.5
: ]& ?# c8 n3 x# |; y6 i95.0 6.5 X 7.0 27.2
4 s/ Z: ~7 b* |- wAv. 60.0
# }: Y, W% Q+ O! `% j  S0 S, Y) tavailable testosterone. Again, emphasis should be placed on
2 n8 C( ?1 `, R( jearly therapy when lower levels of testosterone appear to- \9 S- L& J' o6 b0 [" T
provide the best responses. The earlier therapy is instituted
  S8 U& x% e2 `3 M  ?the more likely there will be an excellent response with low
8 H9 z2 W6 J$ p2 A! A% Cserum levels. Response occurs throughout adolescence as% J7 y) O  A2 ^6 V  h4 |& `) N# l
noted in nomograms of phallic growth. 7 The actual response; B& X% d: ]0 }8 D6 E* n1 y" }
to a given serum level of testosterone is much greater at birth
5 o# i0 G0 n8 Y, c! k! ^! o$ B5 Hand gradually decreases as boys reach puberty. This is most8 u1 q! y4 C  N& b* U
likely related to the conversion of testosterone to dihydrotes-  }, c. K/ ^4 r+ d: F8 @
tosterone and correlates well with the studies of testosterone
5 f; Q% U% v; Y1 Hconversion in foreskin at various ages.. q5 S$ i0 I% a( \# @! U. X
The question arises regarding early treatment as to whether7 q; z% o  {8 _4 k/ K6 r
one might sacrifice ultimate potential growth as with acceler-6 I3 r' m* |2 C8 o
ated bone growth. The situation appears quite the reverse7 ~9 @; e5 W8 o
with phallic response. If the early growth period is not used7 F# \4 e. M! i: p. j4 u" s. A& c$ x/ U
when 5a reductase activity is greatest then potential growth
9 P1 m  d# M5 K$ R, Imay be lost. We have not observed any regression of growth! u' l0 W$ A- _; P+ W/ Q" ^5 W/ e1 b
attained with topical or gonadotropin therapy. It may well" P- w5 X$ j$ u. f
be that some patients will show little or no response to any
9 C$ ]. S8 j: e( u4 ^. qform of therapy. This would suggest a defect in the ability to
$ I+ ]0 f) H6 a, ]$ ^+ gconvert testosterone to dihydrotestosterone and indicate that; M0 e9 |0 B' l: l/ h
phallic and peripheral skin, and subcutaneous tissue should
' b1 r0 K" b. N( sbe compared for 5a reductase activity./ h* x: w* H, f7 U+ U. p
A, loop enlarges to measure penile girth in millimeters. B,6 x6 g  h4 B$ m
example of penile girth computed easily and accurately.& R1 w5 a8 F5 |: O# C: t
conversion of testosterone to dihydrotestosterone. It is in this+ H, M3 _1 y8 u  w9 a- Q
older group that others have noted high levels of serum& |  q0 `3 x8 a) |$ P
testosterone with topical application. It would also appear
) S+ l' A; W) [that phallic response during puberty is related directly to the2 e$ _* T$ f* q
serum testosterone level. There also is other evidence of local
- s& l" w: X- F* M0 r3 i5 Gresponse to testosterone with hair growth and with spermato-
, y! \' W& G4 K1 \. A* Dgenesis. 5• 6
/ _7 n4 o' o5 h4 c; G4 WAdministration of larger doses of gonadotropin or systemic4 k7 \3 V; q; Y5 R1 A
testosterone, as well as topical applications that produce5 l" M: O: F: @) Y% L* B
higher levels of serum testosterone (150 to 900 ng./dl.), will! S4 H- F) a( m
also produce phallic growth but risks accelerated skeletal
9 i9 O: p5 W  H) Rmaturation even after stopping treatment. It would appear' i3 c# R  T* x9 E0 r1 E
that this may be avoided by topical applications of testosterone/ J0 z/ L( u$ t4 p- o" J8 E# D
and monitoring of serum testosterone. Even with this control
- F3 i  j* M, F: y( m2 h3 xthe duration of our therapy did not exceed 3 weeks at any
$ r* w2 S# T% J. _3 b* L, n6 Ktime. It is apparent that the prepuberal male subject may
' w4 a% H) b7 O' _) Z. s3 f$ x: Fsuffer accelerated bone growth with testosterone levels near. y" m( w4 J. a+ O  `. e: T
200 ng./dl. When skeletal maturation is complete the level of
2 i# P$ U# H, ^- c( }serum testosterone can be maintained in the 700 to 1,300 ng./* X, O* p/ H2 ?3 h
dl. range to stimulate phallic growth and secondary sexual  X* A8 C. A! T
changes. Therefore, after skeletal maturation parenteral tes-6 p. g$ B( W" P! D  ^- H' N3 @
tosterone may be used to advantage. Before skeletal matura-
# @* I  U4 P+ j* X3 Q) n4 Ztion care must be taken to avoid maintaining levels of serum
: F) I3 M/ ?% h1 vtestosterone more than 100 ng./dl. Low-dose gonadotropin
; A7 S& `9 E3 M) u9 u& W! F! mdepends upon intrinsic testicular activity and may require
- H4 L# ?0 ^# R1 Y% {, y6 @prolonged administration for any response.
' E  F4 }% ?1 q" s: Y. aAlternately, topical testosterone does not depend upon tes-
* j' Q3 b2 D6 C" u' s) ^- aticular function and may provide a more constant level of2 R. h/ A% r- |' H% \) {
REFERENCES' L0 ^9 Q, {1 O* r& V+ _8 c
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
; V, F+ y3 u7 K( `' K8 V1 bR.: The local application of testosterone cream to the prepub-
% W0 q9 U: H# h: Tertal phallus. J. Urol., 105: 905, 1971.
3 q: V+ [  B8 T: {, j& s$ q/ e: W2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone- M) B- B0 _. ]
treatment for micropenis during early childhood. J. Pediat.,4 W& H9 w" T! ]
83: 247, 1973.
3 T6 N- h2 F4 z, C3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
, Y/ h0 g' H/ M6 h$ |one therapy for penile growth. Urology, 6: 708, 1975.0 ^# K4 d5 w- Y* q' h
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
. ^+ V% d9 M  }& P6 z* L: F) eto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by% {0 _. J; h( X% F& b" a; L- k
skin slices of man. J. Clin. Invest., 48: 371, 1969.
9 u5 d7 j) O6 I1 D: R5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth) R' m# l2 M; c$ m
by topical application of androgens. J.A.M.A., 191: 521, 1965.
- Z* s) q8 t, b: ~9 m! o6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local& Z2 w# ?1 _7 o) L7 W
androgenic effect of interstitial cell tumor of the testis. J.
& d" O5 q" M7 S; RUrol., 104: 774, 1970.2 E' A; p& [; `, M
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
" B8 R* L5 l3 G. M6 I4 P2 [! [tion in the male genitalia from birth to maturity. J. Urol., 48:
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