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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND* X4 ]0 M3 S! [( Q8 z
GONADOTROPIN
) w1 c5 F. ]" g# L+ aRICHARD C. KLUGO* AND JOSEPH C. CERNY$ B' r# T7 V! O, e- x$ y, A
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
$ i8 `  x4 T! b4 O2 Q1 nABSTRACT
) t. m: K; m; I7 [( w  e/ XFive patients were treated with gonadotropin and topical testosterone for micropenis associated
2 y1 I& Z" A9 p  d( C& Bwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-, e5 h: E, C  r
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
) o4 p2 H8 t2 i1 y  F( Icream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
* D! a( |2 f5 l" Yfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent/ z! M/ X" b7 |, p; _
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
6 G9 a: k5 v/ E  N3 S/ Cincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
) S" n* P6 ^! m7 Joccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This6 w4 E2 g1 _% f
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
( _  r) p5 J6 W' e$ \growth. The response appears to be greater in younger children, which is consistent with previ-
! t1 A4 E$ T/ a  hously published studies of age-related 5 reductase activity.+ z' M& `3 P. K# z7 L
Children with microphallus regardless of its etiology will4 [2 a& h. {/ v7 ~, z
require augmentation or consideration for alteration of exter-* X8 v. M& @3 N' U
nal genitalia. In many instances urethroplasty for hypo-
) {% q5 g# |. Y* m* d7 Nspadias is easier with previous stimulation of phallic growth.
9 ~" g1 b5 x  b* r6 E$ z: @The use of testosterone administered parenterally or topically
: ~. B( q4 |% Y; F; zhas produced effective phallic growth. 1- 3 The mechanism of
) y/ V$ U0 A: P2 U. F) Zresponse has been considered as local or systemic. With this
8 f6 f: t+ b5 F2 ^in mind we studied 5 children with microphallus for response
* ]" Z- S& ^! _to gonadotropin and to topical testosterone independently.$ d) N+ e* x7 N2 w! p4 g0 b7 {
MATERIALS AND METHODS
9 t# y* |& r( c0 ]& g/ h& ?Five 46 XY male subjects between 3 and 17 years old were* x5 U  C! s; U- Q6 W
evaluated for serum testosterone levels and hypothalamic0 Z2 G3 R; x/ d! x. V
function. Of these 5 boys 2 were considered to have Kallmann's0 L; p) l$ h9 q: [; q
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-3 K7 b% P, X" c$ G5 V- Q8 E
lamic deficiency. After evaluation of response to luteinizing1 @0 H7 l& p& z5 u9 L
hormone-releasing hormone these patients were treated with
( k3 x: O: F/ x$ K9 Q1,000 units of gonadotropin weekly for 3 weeks. Six weeks
6 t# v1 ^' J, Kafter completion of gonadotropin therapy 10 per cent topical
2 Y. o% a% D7 ^8 ?0 z5 o: y  r  \testosterone was applied to the phallus twice daily for 3 weeks.4 g5 B5 P. A) p2 u" L
Serum testosterone, luteinizing hormone and follicle-stimulat-
, y7 p) M8 \) U1 e2 t+ |  aing hormone were monitored before, during and after comple-
2 i6 y$ y" ]) F* [0 V' |, c1 ltion of each phase of therapy. Penile stretch length was& o. C* U+ L* V& G# S
obtained by measuring from the symphysis pubis to the tip of
: Q, z+ Q7 |3 E2 R. [8 p0 B8 dthe glans. Penile circumferential (girth) measurements were- B( w1 l& a# S0 a5 |! f3 b$ {
obtained using an orthopedic digital measuring device (see8 q% W4 [$ W% n: |
figure).6 w* s5 E8 h& E
RESULTS3 J% L! O; d, U. S8 F9 s
Serum testosterone increased moderately to levels between, j" o2 p# }/ D) x4 |1 z
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-  m. K" U- M; M* s7 H4 o
terone levels with topical testosterone remained near pre-! j9 P: F2 Q6 g0 W+ E0 W
treatment levels (35 ng./dl.) or were elevated to similar levels( J5 m2 D9 {! A& B& A2 w
developed after gonadotropin therapy (96 ng./dl.). Higher8 a* z% a$ H( X! _  A
serum levels were noted in older patients (12 and 17 years old),
2 M% k3 F" z& Y, Q( [while lower levels persisted in younger patients (4, 8, and 10
" }! ?% L6 a9 Z+ W0 pyears old) (see table). Despite absence of profound alterations$ ~/ V9 k+ g0 [7 D; U% F
of serum testosterone the topical therapy provided a greater
5 S: |9 z6 Z- H1 k; m+ p2 yAccepted for publication July 1, 1977. ·
5 W: ?# O1 U% k, G- Z* R! O7 k$ mRead at annual meeting of American Urological Association,0 [" u" g& E4 q, d) E( b
Chicago, Illinois, April 24-28, 1977.2 e2 E2 k! u8 X: U3 G
* Requests for reprints: Division of Urology, Henry Ford Hospital,
9 v; ?5 E7 w( A6 W/ g- \2799 W. Grand Blvd., Detroit, Michigan 48202.
# Z% v4 F! n- ?  F# j! D1 Q+ Kimprovement in phallic growth compared to gonadotropin.( Q7 C  K' z) S4 Y! F$ E7 L. L
Average phallic growth with gonadotropin was 14.3 per cent- H6 t4 }/ ^' Z; {7 Q2 E
increase in length and 5.0 per cent increase of girth. Topical* ^( U; u8 D( x) k+ y" J: O, N
testosterone produced a 60.0 per cent increase of phallic length/ Z7 u5 U6 F6 C4 O
and 52.9 per cent increase of girth (circumference). The
( O/ O- G3 N8 C  V: \+ H! kresponse to topical testosterone was greatest in children be-1 j1 c  u+ T% p% o% _
tween 4 and 8 years old, with a gradual decrease to age 17
3 {) Y; q% |+ S: Q2 Z3 Ayears (see table).
! F! b9 z( u4 W5 K+ W. oDISCUSSION
% _4 }- C9 W5 z" k, ~  m& S7 Y6 }Topical testosterone has been used effectively by other
, b7 @  n. F# uclinicians but its mode of action remains controversial. Im-
1 t' P' k6 V( M, J2 N% |mergut and associates reported an excellent growth response1 N4 X4 I/ ^0 J  q
to topical testosterone with low levels of serum testosterone,' `7 w% q5 @1 S2 m# ~
suggesting a local effect.1 Others have obtained growth re-* X- @& D6 W+ ?  w+ }0 g5 }
sponse with high. levels of serum testosterone after topical
7 G% b* I0 v$ fadministration, suggesting a systemic response. 3 The use of
+ U2 m+ ^" s' ugonadotropin to obtain levels of serum testosterone compara-
9 N  ~+ H3 y5 ?9 f) ?2 L9 C) Dble to levels obtained with topical testosterone would seem to( j$ i+ K, G, ^' N
provide a means to compare the relative effectiveness of
# p; c) i1 e" U: w; _9 ^topical testosterone to systemic testosterone effect. It cer-
. ]! Y" U* N0 x2 ?, g: z. }tainly has been established that gonadotropin as well as par-1 v4 R) O6 s, s( l; t- a
enteral testosterone administration will produce genital
8 M/ C" B/ e- v; W0 ogrowth. Our report shows that the growth of the phallus was
" B: q& z* A% R. a* p. m+ C# Vsignificantly greater with topical applications than with go-8 o6 y* e! @' H, c, P) p* `
nadotropin, particularly in children less than 10 years old.
0 D8 i* j( P' m) TThe levels of serum testosterone remained similar or lower
( b& o" I. c  u  {than with gonadotropin during therapy, suggesting that topi-/ ?2 f0 e" n! S, _6 ~
cal application produces genital growth by its local effect as
, H9 A1 U* g& R; a  _1 Bwell as its systemic effect./ D/ K) x  B9 Z7 A
Review of our patients and their growth response related to! s3 l4 o! Y  i  v" @4 l
age shows a greater growth response at an earlier age. This is$ u6 J5 t5 N( }" I% E! N
consistent with the findings of Wilson and Walker, who# a1 {% e& B; m' h
reported an increased conversion of testosterone to dihydrotes-
  g) D9 C: p9 m6 R0 v0 Wtosterone in the foreskin of neonates and infants.4 This activ-
5 w) A4 i! @& i( e3 n# Nity gradually decreases with age until puberty when it ap-
. N* x5 u4 \( B: ?proaches the same level of activity as peripheral skin. It may+ u3 _2 h9 }( }9 O  z$ x
well be that absorption of testosterone is less when applied at
) ]! }8 d. G; ?( ^6 q" }an earlier age as suggested by lower serum levels in children$ Y# l; P2 d# F
less than 10 years old. This fact may be explained by the$ r1 u1 A/ n" a& q$ v
greater ability of phallic skin to convert testosterone to dihy-( S; \% z' i, C- o- k) n
drotestosterone at this age. Conversely, serum levels in older! r% t% Q' u& f6 D& l+ O) R
patients were higher, possibly because of decreased local
  ]7 m" ?* h% p! R. O& n9 ~6676 G( S" Y) R* _( P7 O4 Y* y
668 KLUGO AND CERNY9 h; j' z8 T. u
Pt. Age; q9 M5 v$ Z6 Z: d+ l( E$ ?( r( H
(yrs.)9 e' y2 l. f" ?+ o
Serum Testosterone Phallus (cm.) Change Length# z* r7 `$ |, V, }  b
(ng./dl.) Girth x Length (%)) ^* S# T: f( R* A. u! k
4
* J7 o2 H6 j, B7 c0 W: V" w" K8
- V. u- ^* c& m2 o9 |/ f10
! n! c- F$ J. L6 Y6 ?12. c( q4 P4 T1 b# P
17
: B0 e7 k2 G% s4 _8 X" AGonadotropin
5 n' F9 v0 w" O. V71.6 2.0 X 3 16.6( h  F' I# g8 v9 f$ D3 @. j) N
50.4 4.0 X 5.0 20.06 ]! U! L/ Q( ]9 O2 l
22.0 4.5 X 4.0 25.0
2 R/ i( p1 W+ m7 `9 j$ o  w8 J$ f84.6 4.0 X 4.5 11.1
, e" P" q% p. r. L85.9 4.5 X 5.5 9.0' b4 `* H% K7 y" U- D, N/ r
Av. 14.3$ f; f3 _5 T8 h7 A
4
) Q1 Y2 v5 d' |' D9 K0 N8
9 h$ @; g2 x9 ^. v. C6 D1 I; o10
) `4 c" }* a8 w- V128 h% a4 X2 p9 R3 {% ^" |  s5 }
17" p, A  {7 B0 _- Y
Topical testosterone- j1 N3 k. E+ H  u8 V$ {" H
34.6 4.5 X 6.5 85
* A6 p, ~, M/ V8 ?38.8 6.0 X 8.5 70
2 i' n0 m* O) m; R40.0 6.0 X 6.5 62.5
8 n! g+ [( i/ v; ]93.6 6.0 X 7.0 55.5
9 Z0 u2 d; ~# I) Y3 n( Q- D95.0 6.5 X 7.0 27.2- \6 O( H$ s5 _9 v$ v% M
Av. 60.0# ^5 A* d) S" V7 R
available testosterone. Again, emphasis should be placed on
9 ^, O1 i% `4 q' y6 K! m5 b; Dearly therapy when lower levels of testosterone appear to7 m. E) {2 ^: t: b
provide the best responses. The earlier therapy is instituted
, q  i0 Q& e( {; @. m0 Mthe more likely there will be an excellent response with low
, @. @. o- G5 l/ N4 D1 sserum levels. Response occurs throughout adolescence as
; T8 p5 l+ t; S6 |& p3 onoted in nomograms of phallic growth. 7 The actual response3 `: F$ R3 A+ y1 c; r- y
to a given serum level of testosterone is much greater at birth
& Z" |4 e& d0 U  _4 D+ tand gradually decreases as boys reach puberty. This is most
( D* ^5 N1 v  k( Q  _- B, x! Qlikely related to the conversion of testosterone to dihydrotes-( A+ g; z( B- b  U6 H; d5 n, k/ y
tosterone and correlates well with the studies of testosterone
( _8 d' u3 W; T8 z1 X0 c, L# _conversion in foreskin at various ages.
: A' ~9 n7 z6 YThe question arises regarding early treatment as to whether7 E: [5 }& m% o8 r4 ~
one might sacrifice ultimate potential growth as with acceler-
& P1 R) K% _& o" V) m; Qated bone growth. The situation appears quite the reverse' _, }$ v% S, u8 Y# o
with phallic response. If the early growth period is not used
/ M- D4 o- ^5 J1 y8 ?% R3 ]( Mwhen 5a reductase activity is greatest then potential growth
. Q7 P8 J9 n) \3 w$ ~& W7 nmay be lost. We have not observed any regression of growth
$ T5 f7 Q* P( T/ ]attained with topical or gonadotropin therapy. It may well# h% W, S; g% L
be that some patients will show little or no response to any
; c+ \" ^3 t# H0 H* q1 m  Eform of therapy. This would suggest a defect in the ability to$ l7 N5 W( p- P* H( l
convert testosterone to dihydrotestosterone and indicate that8 Q9 W- Q! F/ A7 ]# e' y
phallic and peripheral skin, and subcutaneous tissue should% v/ g% Z. s/ h) c
be compared for 5a reductase activity.
) o( h# W' `5 U5 v/ NA, loop enlarges to measure penile girth in millimeters. B,
% T  S  n: o9 _7 fexample of penile girth computed easily and accurately.
/ G; F$ E2 q5 y' F2 K9 [conversion of testosterone to dihydrotestosterone. It is in this* D8 s, T+ m3 |% E
older group that others have noted high levels of serum4 J; W# a# \4 `+ K+ \
testosterone with topical application. It would also appear
9 w3 ]) @" |1 @+ a) s3 nthat phallic response during puberty is related directly to the
8 M" W+ R& s0 g  R/ Iserum testosterone level. There also is other evidence of local0 @1 n0 P+ J) K/ T; e3 [4 \/ ^
response to testosterone with hair growth and with spermato-/ L, c3 P6 D1 A7 o: {6 ~  [
genesis. 5• 6
/ a0 n$ Q7 y1 }" a8 p* nAdministration of larger doses of gonadotropin or systemic9 i8 U( m% _2 i) ~9 V. E9 I
testosterone, as well as topical applications that produce
7 U9 M; P( m$ N" J& \' Z7 z8 Zhigher levels of serum testosterone (150 to 900 ng./dl.), will
1 w: n: h7 h  Y$ |" U$ t1 a8 `3 ialso produce phallic growth but risks accelerated skeletal. S# u: }. W6 g' {4 |( _! T6 C! t
maturation even after stopping treatment. It would appear
! h6 Q1 E' b9 q% X  J$ rthat this may be avoided by topical applications of testosterone$ N2 @/ B/ p5 c- r& m  P
and monitoring of serum testosterone. Even with this control9 T9 ]! ?1 _8 l8 U1 S
the duration of our therapy did not exceed 3 weeks at any; E7 Y3 N( a# L' A/ n  Y
time. It is apparent that the prepuberal male subject may
" K7 G/ }2 V+ w. H, D: |. {suffer accelerated bone growth with testosterone levels near
) q" p5 H3 Y( n4 W: g; ~5 ]200 ng./dl. When skeletal maturation is complete the level of4 K' C2 R9 v: D1 @; c
serum testosterone can be maintained in the 700 to 1,300 ng./. N6 R  a, \2 q5 f
dl. range to stimulate phallic growth and secondary sexual
8 i* K* d- D% S1 j' Nchanges. Therefore, after skeletal maturation parenteral tes-
2 I% M2 w2 M$ T5 N7 i# C- Ptosterone may be used to advantage. Before skeletal matura-
8 E; w# W7 t: h; ~0 s$ ption care must be taken to avoid maintaining levels of serum  b) w' C1 n' t7 h3 e
testosterone more than 100 ng./dl. Low-dose gonadotropin) A0 q& v/ T7 z+ c4 z
depends upon intrinsic testicular activity and may require' o3 n/ P. u9 h& E$ b3 P$ k
prolonged administration for any response.
' P. P% G% D3 \1 ^1 mAlternately, topical testosterone does not depend upon tes-
6 n" n6 D4 ^$ xticular function and may provide a more constant level of
1 `1 {. C) P& A2 J* G' UREFERENCES$ b. {8 _3 U" U) P( M
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,# |$ R( Y9 b. s  K- K& t# j& [
R.: The local application of testosterone cream to the prepub-
! L' Y" k2 w" n0 Z- `' C2 Bertal phallus. J. Urol., 105: 905, 1971.
* D- ^" @+ s1 B3 i: u2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone6 @. w& N( U) E6 O+ z
treatment for micropenis during early childhood. J. Pediat.,
, p* S* `9 i: c8 s  b; }83: 247, 1973.- \% [+ a' \! ~$ l
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-* q+ h7 v3 i% [2 k  b6 d
one therapy for penile growth. Urology, 6: 708, 1975.$ v9 c& m8 q7 N& y
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
3 {: W  D. F0 @: A0 ^to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by) {: e. |' t6 O. Y! a# Q
skin slices of man. J. Clin. Invest., 48: 371, 1969.* h; _3 Y1 X/ H# Z8 C% A- D
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
4 p* g4 W! d* g9 `9 V1 q' O( tby topical application of androgens. J.A.M.A., 191: 521, 1965.
7 u% }- l9 M- u0 _6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
% E% r( G! M8 I* o. ~& Uandrogenic effect of interstitial cell tumor of the testis. J.
6 ]7 z* e8 n9 |, c' B, k1 xUrol., 104: 774, 1970.
/ |2 Q" ^' o- N7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-8 F- w; T& O. _3 p8 [. l
tion in the male genitalia from birth to maturity. J. Urol., 48:
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