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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND0 I9 [, y3 Z: o9 d, C
GONADOTROPIN
% R; M9 K: K, H, a/ G1 L, e5 eRICHARD C. KLUGO* AND JOSEPH C. CERNY) \- ~. P" B2 B4 [
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
& R. [1 J( q4 ?: R+ N* J3 `* D2 qABSTRACT R& J, F1 h* h2 B# F1 K
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
. C7 ]- @% H0 O, I. Hwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
/ o. ]- ^7 c! E% a4 wtropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
9 r. m% Q! o* ~" \& b& u' fcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
: ?6 T, b. i3 L* d' i+ Nfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent( V3 Q6 b4 {9 N. G1 H
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
) s* U( m' u: N9 H/ eincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
1 r8 D& g. [7 O8 yoccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
# V( g' v) q1 S' \study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
1 a" k! O; M. ~2 A. V4 k- f+ agrowth. The response appears to be greater in younger children, which is consistent with previ-$ W P8 [0 t( U$ {; x4 S0 W
ously published studies of age-related 5 reductase activity.
, i9 M! @) u( j0 T3 P! B9 bChildren with microphallus regardless of its etiology will8 j# h& Q9 l# n( N- x5 Z5 l
require augmentation or consideration for alteration of exter-
3 N# B4 ~1 h/ L4 h8 N+ i5 ~nal genitalia. In many instances urethroplasty for hypo-
" X0 u0 Y7 o$ p1 @0 v0 E' k6 ospadias is easier with previous stimulation of phallic growth.- x2 G1 J( N4 @% h0 \* \
The use of testosterone administered parenterally or topically/ s% b; _, r8 m/ m
has produced effective phallic growth. 1- 3 The mechanism of' j6 j' L! u) \ B
response has been considered as local or systemic. With this
1 Z- A) g6 A- f& R$ @8 O: }: Q- U2 ?in mind we studied 5 children with microphallus for response
8 I* Q9 W: y9 Z3 c1 Ito gonadotropin and to topical testosterone independently.
$ y' T6 G4 Z k# H5 sMATERIALS AND METHODS
1 E+ K; m7 Q8 _Five 46 XY male subjects between 3 and 17 years old were; }- |' [# c: O1 }5 U/ q
evaluated for serum testosterone levels and hypothalamic6 G8 ]& z( z8 n$ c. k: O
function. Of these 5 boys 2 were considered to have Kallmann's; D" l$ s' b4 _0 S/ S
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-1 b) l$ [' X. d" k5 {, O. A' h
lamic deficiency. After evaluation of response to luteinizing7 f' {5 D: L( u: j a/ ^6 ?4 F; B
hormone-releasing hormone these patients were treated with
1 G5 @5 Y9 v, g, N6 D0 @1,000 units of gonadotropin weekly for 3 weeks. Six weeks
Y" U* Q$ O6 B- O0 J4 m% D Iafter completion of gonadotropin therapy 10 per cent topical: B2 p/ |4 N7 o4 U8 Z9 o
testosterone was applied to the phallus twice daily for 3 weeks.
1 y$ [& u( G: S, k4 k* V. ?; mSerum testosterone, luteinizing hormone and follicle-stimulat-
+ G( `/ h; B. B2 S' n7 G7 ?1 Fing hormone were monitored before, during and after comple-. C, u; v2 G. ?0 E% E
tion of each phase of therapy. Penile stretch length was
/ A8 q& ] X1 a, S7 Zobtained by measuring from the symphysis pubis to the tip of+ m$ s+ A2 h. p& } _, ^+ N* k
the glans. Penile circumferential (girth) measurements were
% w; H' E/ j& Z; ]) T. l, iobtained using an orthopedic digital measuring device (see
. |; m3 }$ L0 W5 S9 ~5 Pfigure).
' G7 A; c1 v; j5 M9 q* gRESULTS
3 e& c: Y+ I0 ?, a- P. j0 [, @Serum testosterone increased moderately to levels between
/ |* K# z2 T+ y) ?+ w; e _/ f50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
/ t4 C# k& a) I, c. \# A, bterone levels with topical testosterone remained near pre-
1 E F. D- [$ T* Ktreatment levels (35 ng./dl.) or were elevated to similar levels' t; W2 w8 N1 I! W5 ?- r
developed after gonadotropin therapy (96 ng./dl.). Higher
9 |5 W4 |* G! c8 Vserum levels were noted in older patients (12 and 17 years old),
@% e1 x1 f' i$ Q# Swhile lower levels persisted in younger patients (4, 8, and 10
1 P% ]3 X3 R: c1 Zyears old) (see table). Despite absence of profound alterations
4 q& ?; J% P8 B3 j9 y* ]& t3 Uof serum testosterone the topical therapy provided a greater1 O* X5 P2 d- }
Accepted for publication July 1, 1977. ·
: g5 m+ l" J! E) z+ ~: b! ERead at annual meeting of American Urological Association,
9 G4 p. N% B6 Y3 @7 WChicago, Illinois, April 24-28, 1977.
; Q! v2 y3 n N; x% _ @" F& a* Requests for reprints: Division of Urology, Henry Ford Hospital,2 a! R/ {! A" G# T+ R( w/ d
2799 W. Grand Blvd., Detroit, Michigan 48202.1 U2 @3 W f* p& \
improvement in phallic growth compared to gonadotropin.: F! W6 v0 a; f; ?% @7 _. J
Average phallic growth with gonadotropin was 14.3 per cent
" W- ^4 `. ?) J/ B7 F T# w- ^increase in length and 5.0 per cent increase of girth. Topical
, e) I5 [! Y$ X. r+ K% n. k2 s+ Atestosterone produced a 60.0 per cent increase of phallic length
" n3 ]( o) B2 X3 @and 52.9 per cent increase of girth (circumference). The- O$ ~- q# `+ A# I6 O
response to topical testosterone was greatest in children be-
8 B- x E2 r( ?tween 4 and 8 years old, with a gradual decrease to age 17* w; W# h7 O8 f5 Z8 e9 }2 _/ n
years (see table).* L+ | }( b9 N: l, S" q" k
DISCUSSION* k' g, y1 m" t k. F4 T
Topical testosterone has been used effectively by other, L5 g: [$ x, k( P6 g/ k* i
clinicians but its mode of action remains controversial. Im-; e( @2 b# `9 U" n! i9 c
mergut and associates reported an excellent growth response. a- q, h% K* F
to topical testosterone with low levels of serum testosterone,7 g! D! M! j, j1 d: y5 W x
suggesting a local effect.1 Others have obtained growth re- c; f# L2 K6 ^6 t: t
sponse with high. levels of serum testosterone after topical
- X2 o) b7 J4 v- b. O+ Qadministration, suggesting a systemic response. 3 The use of [) m, U6 e% A2 O7 ]
gonadotropin to obtain levels of serum testosterone compara-
8 J, o8 y6 v$ Nble to levels obtained with topical testosterone would seem to' b+ L1 M0 ^" U9 M
provide a means to compare the relative effectiveness of
: p# i& s+ G( Z# c+ ltopical testosterone to systemic testosterone effect. It cer-# @2 ?) O% a$ }' P
tainly has been established that gonadotropin as well as par-
1 h0 X# m0 \0 A: `4 wenteral testosterone administration will produce genital
% N9 q! @1 T( A. K& `. n8 f3 ngrowth. Our report shows that the growth of the phallus was- e( P( {* r7 G4 W0 s/ z( b
significantly greater with topical applications than with go-
/ S x( I6 B' S$ J0 Y& R, W( Ynadotropin, particularly in children less than 10 years old.: i0 g7 P3 _$ r& u' r8 M+ _ Y& W
The levels of serum testosterone remained similar or lower
8 S/ a1 b2 | O" @, Nthan with gonadotropin during therapy, suggesting that topi-' e5 A8 c: ?5 d) ? t9 m
cal application produces genital growth by its local effect as
" _) d( ]0 q5 j$ M Gwell as its systemic effect.
4 Z. S8 E9 K m2 I9 M( H7 T4 yReview of our patients and their growth response related to
) |" Y6 Q3 B. C2 s# Rage shows a greater growth response at an earlier age. This is6 e% b0 c" }" |; @
consistent with the findings of Wilson and Walker, who9 }' v5 l( i9 w9 f6 O
reported an increased conversion of testosterone to dihydrotes-
; g% X; ^- W# w% g( dtosterone in the foreskin of neonates and infants.4 This activ-
6 C2 O& ]) g* E, J6 Zity gradually decreases with age until puberty when it ap-
7 B) o4 L* { f1 {! dproaches the same level of activity as peripheral skin. It may+ a( r! w `2 N% h
well be that absorption of testosterone is less when applied at
8 Q$ Y' t* a5 x* Ean earlier age as suggested by lower serum levels in children
: E4 K, ?) Y* |( Uless than 10 years old. This fact may be explained by the" u" ^( J0 f6 o$ f- F, T, _! @
greater ability of phallic skin to convert testosterone to dihy-& U, ?$ k! }0 v- p. I7 ?
drotestosterone at this age. Conversely, serum levels in older
5 |. R1 R* N6 o: @7 B0 ~patients were higher, possibly because of decreased local
* T+ b# U( o m- V) s667, f8 d9 k$ [( k+ H! h( w7 `+ k
668 KLUGO AND CERNY
: I( d0 U1 t4 o& [ g2 u! VPt. Age
9 c& Z4 Z! b% v7 i/ O9 d(yrs.). `0 K% a N# w2 X& M3 m; d: J
Serum Testosterone Phallus (cm.) Change Length/ i- q% y" D X# |. {1 W }) ^% @
(ng./dl.) Girth x Length (%)8 Y+ i' w7 p9 s1 Z S
4
2 N! B* E! Y9 A0 r8
' P! D+ y% U8 s1 R+ p; z- N7 G9 S# ?$ n10
& D6 _2 p! c! t; E12" h1 s2 ]& I* |: D6 G& G- h! {: l
17; S: N# O- E, b \: A
Gonadotropin* [" z/ a* M- Y8 H6 |
71.6 2.0 X 3 16.6" {; `6 X* n7 E
50.4 4.0 X 5.0 20.04 U1 ?. h N. x# k% F1 |% b. w
22.0 4.5 X 4.0 25.0
; G$ F6 g2 _: k1 m2 ] T4 ]84.6 4.0 X 4.5 11.1
3 v4 d3 \- j! S: z/ ]& `85.9 4.5 X 5.5 9.0
8 j r6 \ [/ W0 V0 W6 Q# vAv. 14.3& s* K7 m4 B+ L9 t6 `
4/ p) |2 G; x; V2 K V
8
' p( x+ L. D2 g3 Y7 v109 B6 }( ~ m, X4 e0 A& Q
124 ?& H' H. `) `' }7 v
17
, p% B$ Q7 g& X6 |3 `* OTopical testosterone
1 I i9 k6 f1 A) ?& k- y34.6 4.5 X 6.5 852 q; m1 ?6 A4 ]! l( e' T- N
38.8 6.0 X 8.5 70+ _, Q3 I& E I/ ~% ~$ T9 _& i% i; O
40.0 6.0 X 6.5 62.5
0 l( Y* @' u- h. X93.6 6.0 X 7.0 55.55 _; t% H3 B5 t* h( S/ u
95.0 6.5 X 7.0 27.2
- @+ D& | r4 O+ i0 N- E9 UAv. 60.0
8 A& f2 k% B5 \: M- E; aavailable testosterone. Again, emphasis should be placed on
# F( B! w0 B. q0 c2 k, |8 k/ p* Zearly therapy when lower levels of testosterone appear to
9 B, b0 {# I0 `& u; Rprovide the best responses. The earlier therapy is instituted: c/ l% F, }$ T u; U0 J
the more likely there will be an excellent response with low( }0 h. @* ~7 V) _( L
serum levels. Response occurs throughout adolescence as
, W! L8 ^7 G# s O& s+ Xnoted in nomograms of phallic growth. 7 The actual response
4 K6 h( H9 t. x% `7 \6 j! Tto a given serum level of testosterone is much greater at birth6 k, s; @) F; @( V, s1 K
and gradually decreases as boys reach puberty. This is most; x3 u' `( R# x1 y7 S
likely related to the conversion of testosterone to dihydrotes-
3 `1 x( a/ a$ gtosterone and correlates well with the studies of testosterone
- }+ x2 a, l. H4 H8 L2 A" U0 a }conversion in foreskin at various ages.
; ^& `$ K) m; j, q7 u$ B; TThe question arises regarding early treatment as to whether
' M; L# e7 M8 y1 S+ @! Fone might sacrifice ultimate potential growth as with acceler-* W% w& G: F0 m" u' n0 ?0 s z: y
ated bone growth. The situation appears quite the reverse
2 Y+ y2 M2 e5 j- o/ Wwith phallic response. If the early growth period is not used# \4 q1 s5 P6 f8 d
when 5a reductase activity is greatest then potential growth4 u9 m9 L$ `2 E$ U9 x \6 j8 O' |
may be lost. We have not observed any regression of growth
8 j# O( j* w6 @) |6 u" l. Tattained with topical or gonadotropin therapy. It may well2 H4 ?/ N O( w
be that some patients will show little or no response to any
+ V* j' ~5 u1 Iform of therapy. This would suggest a defect in the ability to5 ^$ L+ x+ q9 X" F# G! [1 w
convert testosterone to dihydrotestosterone and indicate that+ D$ S' g3 N* k( _1 P& y' |, j% e
phallic and peripheral skin, and subcutaneous tissue should
0 u' \( d+ ?- w' [" `5 nbe compared for 5a reductase activity.
- J9 S$ U# Y2 i4 YA, loop enlarges to measure penile girth in millimeters. B,
& z% x% _: I9 i* W) _% R/ @4 jexample of penile girth computed easily and accurately.
% n8 e ~9 n& }1 {5 ]/ q: mconversion of testosterone to dihydrotestosterone. It is in this
9 q1 N8 ]" V4 z' P' y7 O+ b: b2 dolder group that others have noted high levels of serum
1 [3 E" P* f1 J) L$ I" A* `% _testosterone with topical application. It would also appear6 R0 X/ m6 V D1 r" }9 n
that phallic response during puberty is related directly to the
a, `: ]5 b9 D9 @$ r$ F- Lserum testosterone level. There also is other evidence of local8 d1 r* j# A- N% u4 r
response to testosterone with hair growth and with spermato-
6 C2 v5 A" Z- A3 S% ngenesis. 5• 6
7 F1 w) B7 l3 Y$ a: q/ X EAdministration of larger doses of gonadotropin or systemic
' G" X) U5 ^; E' F/ F, Q$ ]" @testosterone, as well as topical applications that produce
2 }2 e) ]' X( l7 k/ ]higher levels of serum testosterone (150 to 900 ng./dl.), will r6 } H$ M/ w% |( I
also produce phallic growth but risks accelerated skeletal
% e% F) M6 f2 _9 Fmaturation even after stopping treatment. It would appear
- e6 y' m0 ?7 Zthat this may be avoided by topical applications of testosterone
, g! a5 x/ t- V6 }& k) L' {and monitoring of serum testosterone. Even with this control S- B) j/ O- u! r' y7 W% k
the duration of our therapy did not exceed 3 weeks at any
! N( H. U% A% X: H# L. r2 \time. It is apparent that the prepuberal male subject may
+ \$ |3 R" h( w; c1 Xsuffer accelerated bone growth with testosterone levels near" D# _. l- w2 z. t( z
200 ng./dl. When skeletal maturation is complete the level of, o% Q& d5 M5 {0 J8 G
serum testosterone can be maintained in the 700 to 1,300 ng./
5 a' j$ V3 i* ~6 zdl. range to stimulate phallic growth and secondary sexual
U: O7 M* ]8 J7 V: ichanges. Therefore, after skeletal maturation parenteral tes-
; V" {9 Y. q% o% ltosterone may be used to advantage. Before skeletal matura-- M$ m, k' P# i3 @9 U( C
tion care must be taken to avoid maintaining levels of serum
" R* I u( ^; Q; q1 r: }testosterone more than 100 ng./dl. Low-dose gonadotropin
+ g4 U6 v; {" d8 Rdepends upon intrinsic testicular activity and may require1 K1 C) W- A$ g4 q- Q6 ]
prolonged administration for any response.# |2 C* b* T( p
Alternately, topical testosterone does not depend upon tes-8 n- U# k8 Q5 L, m
ticular function and may provide a more constant level of
7 l; y3 F2 V/ I1 B" {REFERENCES
0 [4 l$ k; ?$ d" \4 S1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,8 M m* e8 y' h/ u7 o, m& G0 a
R.: The local application of testosterone cream to the prepub-) U) h0 h: U7 ^4 K9 L( B
ertal phallus. J. Urol., 105: 905, 1971.) v! _- P6 z: w# L
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
% W I6 ]9 A" g+ Z3 T9 U) g4 dtreatment for micropenis during early childhood. J. Pediat.,
% G- j' T/ Q1 ^' z83: 247, 1973.% m; |& ~# G |3 n7 E$ l
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
* D' h( Y3 M8 s- C @# Kone therapy for penile growth. Urology, 6: 708, 1975.- f7 u2 W$ ^1 i
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
" I! z/ M' i) t& [to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
% G1 l9 V8 y! Askin slices of man. J. Clin. Invest., 48: 371, 1969./ C0 C; d( W; q+ g9 z7 I( j- M
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
6 r: {; ^/ l- _1 }/ q6 ]by topical application of androgens. J.A.M.A., 191: 521, 1965.9 l+ U/ N- E% ?' b) m K: z) j9 G8 r
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
/ r9 b+ j; \0 R- w1 g" `androgenic effect of interstitial cell tumor of the testis. J.( f6 h% e' b r( P) v/ F
Urol., 104: 774, 1970.. f' G8 U; }) {9 h7 y! Z3 D$ M _
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
+ K+ ?4 O6 @" l+ t8 p( p/ a0 c" Etion in the male genitalia from birth to maturity. J. Urol., 48: |
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