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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND0 U$ r5 T* R7 }
GONADOTROPIN7 x6 X) b& I, i' N# f/ V& o
RICHARD C. KLUGO* AND JOSEPH C. CERNY; K0 X+ R9 m0 O
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
9 k" ]( Y9 q1 N( HABSTRACT, }# ~* P: g( b9 y" y! h& X
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
( f5 F# i9 B$ ~/ l0 @* `with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-  `: J7 {! d# ~; l& |# v
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone; C6 z0 R+ }! k/ O  j: J
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
; i% x1 L% V3 K& \* D1 Vfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent! ]% M3 F9 B1 t/ d; A! |( Y
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average0 u0 h7 o5 J0 o1 k. d  z* k
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response0 {9 j* I7 `# X8 h8 p3 v: Q
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
- h& g/ t0 z# R. t; A+ {9 M& gstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile$ R2 E8 F+ ?! i2 A) c
growth. The response appears to be greater in younger children, which is consistent with previ-
$ b% O' w/ D& e8 p4 ~. Iously published studies of age-related 5 reductase activity.
' L/ Y9 L/ S4 q& }' H2 dChildren with microphallus regardless of its etiology will9 u, c' Z- K4 r: R/ ?  @$ ~9 R3 v
require augmentation or consideration for alteration of exter-
- ]. w1 l  x/ M4 q: h9 T/ n( |3 Pnal genitalia. In many instances urethroplasty for hypo-
/ C& V* X9 u# N0 ?: S' G" ^spadias is easier with previous stimulation of phallic growth.
9 G9 ~) Z- A" p, O) mThe use of testosterone administered parenterally or topically4 r  j, u0 |( T
has produced effective phallic growth. 1- 3 The mechanism of
- b' L+ t4 X# [( Q  B7 Jresponse has been considered as local or systemic. With this/ W9 E' }$ @: P0 n' ?5 }) {) Z
in mind we studied 5 children with microphallus for response
4 Y7 B; S# I' M: W, d/ h8 ito gonadotropin and to topical testosterone independently.
. T  b8 ?  ^" r. rMATERIALS AND METHODS
' y6 o, ]+ }5 d) m6 W9 }Five 46 XY male subjects between 3 and 17 years old were5 [6 o3 l3 C0 \2 @
evaluated for serum testosterone levels and hypothalamic) {6 Q1 p" x6 |! C0 p6 w
function. Of these 5 boys 2 were considered to have Kallmann's" C  {) N2 ~: \4 O  |/ X# ^
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
2 J( O' ~) `5 R' Llamic deficiency. After evaluation of response to luteinizing; K& Y7 H/ `1 a, X8 i* h
hormone-releasing hormone these patients were treated with: c2 G- e* g7 A2 D; B
1,000 units of gonadotropin weekly for 3 weeks. Six weeks: _4 n! M( L8 F: z! E- L# P+ Z
after completion of gonadotropin therapy 10 per cent topical
; Q& ~8 x; m8 U% e2 Ltestosterone was applied to the phallus twice daily for 3 weeks.
. U0 N6 I5 c' ^' u; }Serum testosterone, luteinizing hormone and follicle-stimulat-1 e0 a$ u2 y$ ~2 @; w8 N" O1 V' {- S. z
ing hormone were monitored before, during and after comple-( }) o$ Y7 {- G' i
tion of each phase of therapy. Penile stretch length was" S" ]; G# Y1 A5 C% F
obtained by measuring from the symphysis pubis to the tip of1 P( V* e6 z$ Z4 k
the glans. Penile circumferential (girth) measurements were5 w, T4 D. t& \( Q. d) S) }2 V4 k' t
obtained using an orthopedic digital measuring device (see+ j& k+ Z0 Z: F2 x9 D8 h7 O' a
figure).6 M! d# `$ @  T5 m5 \- f2 D# m
RESULTS  A  r8 R- U  U
Serum testosterone increased moderately to levels between
" M' H, `& n5 R8 y50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-5 R2 o* L' O( @3 n
terone levels with topical testosterone remained near pre-
% ^( {6 v9 P8 T/ ttreatment levels (35 ng./dl.) or were elevated to similar levels: {7 m" P- v/ V: |6 X" _2 |! x1 R4 ]
developed after gonadotropin therapy (96 ng./dl.). Higher4 I3 k' N" @$ y. Y' {( o
serum levels were noted in older patients (12 and 17 years old),
, b5 Z* C& Q, e( ~3 J$ Owhile lower levels persisted in younger patients (4, 8, and 104 |8 F6 }% b: r6 y2 e
years old) (see table). Despite absence of profound alterations
: ^9 i3 O6 Q4 wof serum testosterone the topical therapy provided a greater# F1 W; ~& v$ E4 Z/ V
Accepted for publication July 1, 1977. ·
" }# L  ?( d/ e3 {( rRead at annual meeting of American Urological Association,% z3 z% a# M# ]2 e) r& p" V- q5 E- u* Z
Chicago, Illinois, April 24-28, 1977.
  }. d4 n' b- t* Requests for reprints: Division of Urology, Henry Ford Hospital,# o' E4 [3 @: y7 n2 ~% S6 }. t
2799 W. Grand Blvd., Detroit, Michigan 48202.5 a2 M7 U1 Q( T( c
improvement in phallic growth compared to gonadotropin.
8 ~* x9 h3 p2 c+ {Average phallic growth with gonadotropin was 14.3 per cent7 Z" b1 V) x1 \/ H* @
increase in length and 5.0 per cent increase of girth. Topical
2 {; A4 i2 V( J/ J, q% Ktestosterone produced a 60.0 per cent increase of phallic length+ i; N' [2 M; h' I
and 52.9 per cent increase of girth (circumference). The) b" Y/ X7 U7 [+ ~+ A2 H/ ~- J* s. O
response to topical testosterone was greatest in children be-
2 _4 q, W$ D8 b: l# Y* L: ztween 4 and 8 years old, with a gradual decrease to age 17( F/ }2 ?2 y3 D- W7 i1 T) q
years (see table).
6 t, U, W' x' T' iDISCUSSION4 _. i3 O" c7 Y9 m4 A* V* _0 H% l
Topical testosterone has been used effectively by other
+ W' d9 _3 S) }, N) L2 Zclinicians but its mode of action remains controversial. Im-; _( z0 V# F( ^1 h2 ~# K$ M
mergut and associates reported an excellent growth response, D4 Y0 H. B* R7 I
to topical testosterone with low levels of serum testosterone,9 M" j4 q( s* i" {; u
suggesting a local effect.1 Others have obtained growth re-
" C9 P1 i7 I* M, r  {* Ksponse with high. levels of serum testosterone after topical2 J0 d  q% _6 X8 i$ @) k4 }
administration, suggesting a systemic response. 3 The use of" ?7 g0 j4 Y# A! u4 J
gonadotropin to obtain levels of serum testosterone compara-! ?) m6 z4 c. j
ble to levels obtained with topical testosterone would seem to! T0 _4 [: D0 K+ o8 {8 @
provide a means to compare the relative effectiveness of
9 a& ?# Y' b' c# |* O4 Utopical testosterone to systemic testosterone effect. It cer-
2 a5 N: }8 w( D( W, K- xtainly has been established that gonadotropin as well as par-
3 D8 L/ _1 F: n% xenteral testosterone administration will produce genital
: A7 x2 P! R* `* K+ y9 [" |growth. Our report shows that the growth of the phallus was
7 b2 I/ |! ^# A7 [% F# Fsignificantly greater with topical applications than with go-* q/ `# Q& G. [! c& \3 V: |  B( d
nadotropin, particularly in children less than 10 years old.
2 x, I8 f" A/ @/ H0 P- U* ^8 cThe levels of serum testosterone remained similar or lower
  R. b% f! T* A1 c" t9 q" L" [! ?5 xthan with gonadotropin during therapy, suggesting that topi-$ J4 m) d$ H1 G
cal application produces genital growth by its local effect as
3 B. V/ \& U4 h& G9 W+ p7 o7 cwell as its systemic effect.! u  q& }  y5 _
Review of our patients and their growth response related to' P" S3 N5 q' a2 g; |7 C1 |4 B9 j
age shows a greater growth response at an earlier age. This is4 M. Q' J0 o4 h: ?5 i8 j3 Z
consistent with the findings of Wilson and Walker, who
4 e# _& q7 s% M( |. M/ A3 R" _4 F8 Nreported an increased conversion of testosterone to dihydrotes-9 ]5 M, ~8 s. p( G% S3 W" Q4 g. j
tosterone in the foreskin of neonates and infants.4 This activ-
$ }  G1 a" p5 b5 }% m$ wity gradually decreases with age until puberty when it ap-$ A1 s( ^4 \+ ^1 H
proaches the same level of activity as peripheral skin. It may/ V, t+ X2 p( T; I5 G
well be that absorption of testosterone is less when applied at8 `! Z1 j0 W$ K* ^* ^
an earlier age as suggested by lower serum levels in children' [/ p+ x$ {' m# u2 ]3 v8 e
less than 10 years old. This fact may be explained by the8 Y- ]( i! _- V
greater ability of phallic skin to convert testosterone to dihy-
8 R  T2 T# J5 Q  Ndrotestosterone at this age. Conversely, serum levels in older
9 ]2 f9 ^1 _2 G7 R% O: h. Rpatients were higher, possibly because of decreased local' }4 ^: e: U2 c  M* A1 G
667
3 k3 B& r3 N# \0 h668 KLUGO AND CERNY
: q6 f# _/ a+ M) p5 l* y9 e/ x/ Y# uPt. Age& A1 a2 N) o' q0 |9 g; V6 `+ o
(yrs.)8 F& ?  q/ m) Q( d0 {5 J/ x
Serum Testosterone Phallus (cm.) Change Length
; E4 k% w" |+ s' [(ng./dl.) Girth x Length (%)4 N9 _) Z- [! ^; V  H  t6 ~0 I
4' |# C* n' m  X' T! X- K, q
8
* U7 y3 b1 Y& c2 N  h) K10
  q0 u. i* c7 e! Q/ T4 O) ^123 @% s" a' `9 N- v1 A+ Y
17" G$ F2 i  |# U5 I2 A4 X& F7 u
Gonadotropin
! H+ G; @8 M- E71.6 2.0 X 3 16.6) J- Q+ ^# r; i& ~/ K* t+ j
50.4 4.0 X 5.0 20.0; s# V9 J5 ^5 n  R1 |, t
22.0 4.5 X 4.0 25.0: ?% _% J) z8 x/ C) B& S
84.6 4.0 X 4.5 11.1( q8 l9 ?; T% E( ^: [6 S
85.9 4.5 X 5.5 9.0
/ e1 [6 K% V4 F! R( D( zAv. 14.3
% H. |  W# j- U3 y2 p8 d4
2 L  \$ ^: {1 ]8
  J8 u' \, E  N& M( y10
/ J/ Q' t2 s( _$ @12
* [# U: z- g6 `, T2 z1 q* S17
0 i# m$ ?6 Y! xTopical testosterone
5 m0 Y' A2 c3 P- K( x) Y7 b' |34.6 4.5 X 6.5 853 _" i" F% \! r9 u
38.8 6.0 X 8.5 701 Q0 c! h  ~5 s1 r) n
40.0 6.0 X 6.5 62.5) f4 g7 @& V, D$ j! b; Q
93.6 6.0 X 7.0 55.5
+ L. f5 k1 u" f( B95.0 6.5 X 7.0 27.2
0 z6 e( b) M. Z: g  J: n; m( \Av. 60.0
* k. N1 D. ~5 n3 B5 f3 qavailable testosterone. Again, emphasis should be placed on
: ]  W- n; A, u, ?! K4 }3 b5 [early therapy when lower levels of testosterone appear to
' S) M3 K' D, M% M+ [provide the best responses. The earlier therapy is instituted
5 u- F# w# N% _the more likely there will be an excellent response with low, L0 C  a) ]0 O
serum levels. Response occurs throughout adolescence as
4 ]0 }" @; d7 ^4 jnoted in nomograms of phallic growth. 7 The actual response
/ A/ n4 `- x8 {+ ]+ Oto a given serum level of testosterone is much greater at birth
; x  E' e5 s9 t$ M% n6 Rand gradually decreases as boys reach puberty. This is most0 {# I) c* E; x# ~
likely related to the conversion of testosterone to dihydrotes-
8 C# ~- P6 |/ Ttosterone and correlates well with the studies of testosterone
+ L/ v4 \9 D" b: n7 {' u4 C( ^conversion in foreskin at various ages.0 l5 J% P* N, F+ P
The question arises regarding early treatment as to whether
5 W$ [' j5 v* b+ V) b5 fone might sacrifice ultimate potential growth as with acceler-
( @- M/ v+ A1 r7 V. K5 vated bone growth. The situation appears quite the reverse
' M3 N: `5 Q; V3 D8 q6 r- ?2 w% N; Vwith phallic response. If the early growth period is not used
3 K! G- G# j$ B& `when 5a reductase activity is greatest then potential growth
2 B* w6 i5 g, qmay be lost. We have not observed any regression of growth' H# E8 Z5 q; q& q: N' ^+ ~
attained with topical or gonadotropin therapy. It may well
- K6 }+ Y1 [# G/ S0 t# Ybe that some patients will show little or no response to any, \- G3 ^9 {9 F  g5 J& f
form of therapy. This would suggest a defect in the ability to
$ `  }- j# e* G/ n; r. G" K7 ~) mconvert testosterone to dihydrotestosterone and indicate that
7 }. r. w. d0 R0 n- tphallic and peripheral skin, and subcutaneous tissue should
7 e5 e0 R$ _; |. vbe compared for 5a reductase activity.
( T1 D" V# d* O0 vA, loop enlarges to measure penile girth in millimeters. B,$ @8 ?9 S$ X4 z' g+ q
example of penile girth computed easily and accurately.& W+ g# t/ A* O
conversion of testosterone to dihydrotestosterone. It is in this
% O6 M! i# j' ^: i5 m. qolder group that others have noted high levels of serum
) h% V. d) A7 _1 A% }testosterone with topical application. It would also appear/ n  f# x1 {+ t1 \' p
that phallic response during puberty is related directly to the; i7 h5 [+ H8 s" r6 f0 f$ x4 q
serum testosterone level. There also is other evidence of local
/ L% R* r# S! j/ ]) n! dresponse to testosterone with hair growth and with spermato-# q: l* b& F# L/ o) m
genesis. 5• 6
* v( K7 `, G; n) N6 lAdministration of larger doses of gonadotropin or systemic$ \9 a& ~6 ?2 u( g
testosterone, as well as topical applications that produce
8 q" e9 \4 f/ M( Q& w% hhigher levels of serum testosterone (150 to 900 ng./dl.), will- }  k3 B% T$ }& ]" l1 Z( G
also produce phallic growth but risks accelerated skeletal
* T* W; d, I1 [  b# ^, ]  }) |maturation even after stopping treatment. It would appear
0 k" E# _" e- mthat this may be avoided by topical applications of testosterone# q- A- W/ E7 r1 V6 \8 Z0 C
and monitoring of serum testosterone. Even with this control7 N+ C( W/ p7 Q& }' S
the duration of our therapy did not exceed 3 weeks at any
: v- q5 k2 a) l0 ]+ @" _3 k1 Wtime. It is apparent that the prepuberal male subject may
0 v1 M* @, v$ K& B) N% W' r! ^! hsuffer accelerated bone growth with testosterone levels near
! q( u. u9 P* n: g200 ng./dl. When skeletal maturation is complete the level of
) B2 o6 d) k7 N/ rserum testosterone can be maintained in the 700 to 1,300 ng./
) \. Q  c" p. ^& Rdl. range to stimulate phallic growth and secondary sexual
# e; d8 e3 W" L$ H. w& [# ychanges. Therefore, after skeletal maturation parenteral tes-
" ?% F1 @1 P8 I# A& s3 T- M8 q- gtosterone may be used to advantage. Before skeletal matura-+ [  |6 r5 g# Q3 X+ R* Q
tion care must be taken to avoid maintaining levels of serum
4 f/ m6 w8 z) B8 D. ~  f' H: S# F# wtestosterone more than 100 ng./dl. Low-dose gonadotropin- C* n) u' z! t: o+ l2 B7 Y/ l
depends upon intrinsic testicular activity and may require8 `1 q0 Y2 n% ^2 ~9 f( H7 U& x
prolonged administration for any response.
8 x% W7 F- p( U2 }5 I7 f! e9 [8 HAlternately, topical testosterone does not depend upon tes-
+ J2 R. J$ U! R& B$ A7 n! Cticular function and may provide a more constant level of
/ ?" R" |9 |) r8 i1 @, F, QREFERENCES* s2 J- D( ?3 k" m) Q# L: {
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
1 ~+ P  l0 \% v# z  Z1 HR.: The local application of testosterone cream to the prepub-
  ~7 F8 R2 M1 g# certal phallus. J. Urol., 105: 905, 1971.
& ^" y3 `% @: x, A2 k2 d+ U2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
. K6 J/ U3 S7 {7 R- \$ t: ~/ t# xtreatment for micropenis during early childhood. J. Pediat.,
8 J. v8 Z9 |. z9 P& T3 P83: 247, 1973.
6 W( Z7 i" G! l: [& G3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
9 t/ V6 Q1 N7 k; \one therapy for penile growth. Urology, 6: 708, 1975.
6 r6 q. l  X& b4 ^4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone4 o( @5 o9 p' c
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
' |- ~0 n* R9 {( jskin slices of man. J. Clin. Invest., 48: 371, 1969.
6 l) z+ r8 ]" E2 _5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
4 B( G3 n; V8 r3 U, @5 N, gby topical application of androgens. J.A.M.A., 191: 521, 1965.+ l  P1 K3 v, t
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
5 Q) s/ J% j# G" landrogenic effect of interstitial cell tumor of the testis. J.
6 L  q) O/ s- \9 T5 AUrol., 104: 774, 1970.
  ^3 J* r$ G8 \' r# |1 v7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
  s/ z3 a- S- S# Z# [tion in the male genitalia from birth to maturity. J. Urol., 48:
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