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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
, U$ G0 H& o: D/ l: l2 t5 h- GGONADOTROPIN
9 e" r, g# x% D8 u0 V5 E7 fRICHARD C. KLUGO* AND JOSEPH C. CERNY
, @0 G+ J" e" q" c/ H! ]From the Division of Urology, Henry Ford Hospital, Detroit, Michigan# \7 L( ^4 k( O9 F
ABSTRACT
* l. Y- i; U0 t, T2 ]& Y. sFive patients were treated with gonadotropin and topical testosterone for micropenis associated: v x6 U: Y& m9 h
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
0 \- v2 v" |* B6 U Rtropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
7 t5 [6 @. j5 g9 \cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
4 s/ w( D9 m: Afor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
( A: x- g/ L: L. a8 u6 fincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
# N* i5 w" z% v9 j/ M- nincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
/ p4 x7 G/ w2 M g3 ~9 X2 Toccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This$ y4 k+ F: S$ l F
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
$ p6 z0 s8 o) m, @! Q. G' Ggrowth. The response appears to be greater in younger children, which is consistent with previ-
: r& s4 D9 d1 zously published studies of age-related 5 reductase activity.- i3 Z3 q5 A. u( b& m
Children with microphallus regardless of its etiology will
, S$ i6 J4 J) f' f3 E* d6 grequire augmentation or consideration for alteration of exter-# W3 y' n8 b; x- s! b
nal genitalia. In many instances urethroplasty for hypo-
6 V3 i; C9 p( espadias is easier with previous stimulation of phallic growth.
0 s+ W, @* y" |6 YThe use of testosterone administered parenterally or topically7 X) g! A* z4 ~1 i. B
has produced effective phallic growth. 1- 3 The mechanism of# o9 j9 R; S }3 J$ |
response has been considered as local or systemic. With this' d& [$ a- i) c @, ]" A
in mind we studied 5 children with microphallus for response
$ Z0 ~0 e* g/ B5 kto gonadotropin and to topical testosterone independently.2 Z t! a6 c Y7 E9 C3 X2 k
MATERIALS AND METHODS' Q: ?- k- n& ^, O/ ^5 Z& `! c4 Q9 k
Five 46 XY male subjects between 3 and 17 years old were
) S& }! v% w/ c/ e+ T) Zevaluated for serum testosterone levels and hypothalamic
( A" ?4 K% T$ m5 wfunction. Of these 5 boys 2 were considered to have Kallmann's
: B# d$ v" v2 w6 g6 ^4 _( isyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
# `* Q0 t5 e; @) N& `, flamic deficiency. After evaluation of response to luteinizing
' i, I. |9 ^3 B2 {8 U; ~7 r( d% Zhormone-releasing hormone these patients were treated with- l4 ~- C9 D* e4 g7 }# e! h
1,000 units of gonadotropin weekly for 3 weeks. Six weeks3 Q% d+ Z7 ?: m# f; A) I
after completion of gonadotropin therapy 10 per cent topical
3 Y7 m: h* r, @! F4 Y0 qtestosterone was applied to the phallus twice daily for 3 weeks.) {8 _- b& _3 x: r2 c
Serum testosterone, luteinizing hormone and follicle-stimulat-' F1 _2 X1 _- E6 c* }" X6 n
ing hormone were monitored before, during and after comple-
/ {! P* E3 q3 f: X3 k: Etion of each phase of therapy. Penile stretch length was
% y# X6 R: _( L0 [. I) h, T4 ^2 pobtained by measuring from the symphysis pubis to the tip of/ N. O3 |* |- Z* P. Q i# q
the glans. Penile circumferential (girth) measurements were# q1 k1 n. ?4 K
obtained using an orthopedic digital measuring device (see3 e# ]9 s. k' P& g0 `
figure).3 O3 N j1 @7 U: G6 v& h
RESULTS
* [7 k% T+ ]7 K/ K2 R* N1 qSerum testosterone increased moderately to levels between
1 u# G: G; |3 C Z/ V# y2 z50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-( M! G8 B }" }
terone levels with topical testosterone remained near pre- F# M4 D$ c' P- v: K
treatment levels (35 ng./dl.) or were elevated to similar levels% p+ g1 z- V- c1 L F
developed after gonadotropin therapy (96 ng./dl.). Higher
" F* e5 e1 D# _" b7 \8 ]serum levels were noted in older patients (12 and 17 years old),
( _5 L: k% E/ i# G2 f5 O/ n- x6 i1 nwhile lower levels persisted in younger patients (4, 8, and 10
7 y9 F; W' \: O; eyears old) (see table). Despite absence of profound alterations
- x- s0 R" D9 ?. M" d, d9 vof serum testosterone the topical therapy provided a greater% k# G# j9 K6 K; N" E* ]9 f
Accepted for publication July 1, 1977. ·
& v$ Z h1 Y% j s R/ PRead at annual meeting of American Urological Association,
9 Y1 V3 h- R" E; \5 uChicago, Illinois, April 24-28, 1977.
* M* O) c! G+ s3 Y* Requests for reprints: Division of Urology, Henry Ford Hospital,
8 I. z1 o t+ l0 @* g3 c4 L2799 W. Grand Blvd., Detroit, Michigan 48202.
7 a9 A) N* r% o8 X, y0 \2 j/ }improvement in phallic growth compared to gonadotropin.
2 L) e: ~$ D. z1 C1 r) L, NAverage phallic growth with gonadotropin was 14.3 per cent
8 x* `) h1 f4 H- ^# wincrease in length and 5.0 per cent increase of girth. Topical" v: M6 X+ i9 y9 K+ D \
testosterone produced a 60.0 per cent increase of phallic length
6 S% |$ P& | w: }% C; C# q1 Pand 52.9 per cent increase of girth (circumference). The
( r4 F4 x5 e: q) q, t5 C; Y* Xresponse to topical testosterone was greatest in children be-
" [+ i$ p2 \8 \0 Xtween 4 and 8 years old, with a gradual decrease to age 17
& B3 R9 g: C N/ Cyears (see table)., b5 D1 X- _0 |* {; ^8 \3 r' ^* \: I
DISCUSSION
- k2 @! f6 H) r6 w. {Topical testosterone has been used effectively by other
, y2 J4 ^1 T a7 W' s; b. N8 W" Zclinicians but its mode of action remains controversial. Im-
7 {, a2 F) E9 K8 ^) Vmergut and associates reported an excellent growth response' I. V& b/ b6 q4 @% |
to topical testosterone with low levels of serum testosterone,
3 g( P/ R; C* ksuggesting a local effect.1 Others have obtained growth re-
7 D; C* H' t# w6 Esponse with high. levels of serum testosterone after topical0 {- S J. i8 i% y- Y* j- y) R
administration, suggesting a systemic response. 3 The use of
: r- G1 @' e0 V; @gonadotropin to obtain levels of serum testosterone compara-6 X) A0 Q$ i; d. m
ble to levels obtained with topical testosterone would seem to
) ^$ Y/ L8 }8 d% r+ k/ Y& E% w: Fprovide a means to compare the relative effectiveness of1 \: f* \; @: m9 {
topical testosterone to systemic testosterone effect. It cer-
) _& |% m! S8 ytainly has been established that gonadotropin as well as par-( i( m6 ]4 e: F9 S& T1 m. F" N! E4 a
enteral testosterone administration will produce genital' O* h# ^/ p/ z5 X- s# h; ^7 e
growth. Our report shows that the growth of the phallus was
x" {+ S) `: W8 B) fsignificantly greater with topical applications than with go-
% [5 g# ~; G. u5 f. `nadotropin, particularly in children less than 10 years old.5 P o+ [) u% y; N5 h6 _
The levels of serum testosterone remained similar or lower
- w* L4 d2 G& K. U/ Othan with gonadotropin during therapy, suggesting that topi-' q& C% e4 w" ~6 O
cal application produces genital growth by its local effect as5 F1 t5 U3 F; }7 \
well as its systemic effect.& ^7 `6 n6 K1 C; a! y* p
Review of our patients and their growth response related to
+ b/ m" S! y' c0 tage shows a greater growth response at an earlier age. This is
. S1 Q& u' ]# ^$ F/ h e( Xconsistent with the findings of Wilson and Walker, who5 J' m- }* k: J) ?9 {2 N
reported an increased conversion of testosterone to dihydrotes-
! ^/ D- s; X! y) }+ r2 \tosterone in the foreskin of neonates and infants.4 This activ-
8 B. O$ N" y0 n, I7 Mity gradually decreases with age until puberty when it ap-) q9 s! s4 s& L# n* F* J
proaches the same level of activity as peripheral skin. It may& v5 e' Y& S: B" D" z
well be that absorption of testosterone is less when applied at
" B* d+ R" x5 C, fan earlier age as suggested by lower serum levels in children( T4 N4 a, H m% g1 M! V
less than 10 years old. This fact may be explained by the
, S H3 y% U$ T( Sgreater ability of phallic skin to convert testosterone to dihy-
* e, y! H$ y- [9 Ldrotestosterone at this age. Conversely, serum levels in older
. |/ k: \1 M6 g q( I. L, l1 ypatients were higher, possibly because of decreased local
% q4 m2 W6 D6 k" z8 v6678 x2 e6 k& m1 T$ i; x, \
668 KLUGO AND CERNY
. f7 H t5 R, n. R$ QPt. Age
7 M) w0 R% O( S" h1 ?(yrs.)/ V5 F1 y' A& {6 w
Serum Testosterone Phallus (cm.) Change Length9 }9 G; P9 V- Q! `
(ng./dl.) Girth x Length (%)
8 J- r, L6 Y/ R$ ?4 a45 M# l3 W( B5 \$ u' B/ i
88 |7 c* w$ ]' n+ N: P' f9 i
106 w1 _- B: j9 }! \0 a% Z
12
0 J, k) m& z* _) E171 f r9 ~1 Y6 P' F4 K! v# C6 B$ e
Gonadotropin) ^6 I0 X0 j& L) P
71.6 2.0 X 3 16.68 t* d: ]5 H! Y2 y3 I
50.4 4.0 X 5.0 20.0' S' K3 i# m7 r' d) |* o4 p& o
22.0 4.5 X 4.0 25.0# A+ R ~: v; m* P, ~
84.6 4.0 X 4.5 11.1 P0 x0 U! ~4 w
85.9 4.5 X 5.5 9.04 C$ K* W/ S$ b3 F: p
Av. 14.3: [9 e1 g) m J
4
4 k3 Y; k; N7 j+ x u. i1 K5 F8+ U% C! K5 X8 F1 D' u4 {
10
$ ^* y# `( m2 o! @12
; R4 O. L& n' }# y3 k2 q; t# m177 t) Y" v f- Z u
Topical testosterone
. h4 ~, u+ j; |* j5 x0 l# {34.6 4.5 X 6.5 85
; f9 f' t7 P! [ u$ v0 P, I# X38.8 6.0 X 8.5 70
1 V9 d0 X9 v1 M40.0 6.0 X 6.5 62.50 F1 ^+ j/ z) f1 @8 c
93.6 6.0 X 7.0 55.5
: S* V/ y+ O4 K7 z95.0 6.5 X 7.0 27.26 I' A, R4 r& ]$ S) B
Av. 60.0
9 U8 N; {$ d* W# ^# \ c2 a9 pavailable testosterone. Again, emphasis should be placed on* O `. l1 M0 O" t1 c2 K* O
early therapy when lower levels of testosterone appear to0 o; `( Q' f, i6 W T" m! x. r$ V- V. l
provide the best responses. The earlier therapy is instituted" J- U) x. L/ G: o9 G
the more likely there will be an excellent response with low
5 Z& k+ S* K+ E# _7 i$ kserum levels. Response occurs throughout adolescence as
& \ I1 C8 Y! E, H7 L( b% Enoted in nomograms of phallic growth. 7 The actual response1 s5 Z; v! o4 L- ^1 ?
to a given serum level of testosterone is much greater at birth
- a% ~+ v, l0 R- pand gradually decreases as boys reach puberty. This is most
5 n+ L3 \4 H4 a9 `likely related to the conversion of testosterone to dihydrotes-
6 n# a* M( h( X/ Ytosterone and correlates well with the studies of testosterone
; |- K9 h+ Y$ P; j6 K$ Lconversion in foreskin at various ages.
2 E* J0 q0 {2 FThe question arises regarding early treatment as to whether: i0 h x* J8 v' @
one might sacrifice ultimate potential growth as with acceler-9 c2 A8 V" }% V; c
ated bone growth. The situation appears quite the reverse) Z1 o0 { c) Q- `5 G4 i1 O
with phallic response. If the early growth period is not used9 }4 |. u+ Y8 j# ~" B; `
when 5a reductase activity is greatest then potential growth) X1 S" D4 r$ K+ q2 y/ m& `; I
may be lost. We have not observed any regression of growth) b3 T; j* m& ?5 L( s
attained with topical or gonadotropin therapy. It may well
. \3 Z! y5 z( u/ E4 N' F3 |be that some patients will show little or no response to any( j+ o M& _' H4 P! w7 _7 H
form of therapy. This would suggest a defect in the ability to7 f, ?4 ~) Y) u7 b; o$ |4 n
convert testosterone to dihydrotestosterone and indicate that a; F3 d# f. c% N+ y6 h$ u& Q+ K
phallic and peripheral skin, and subcutaneous tissue should
. Y$ }5 n. K! O$ f- Ebe compared for 5a reductase activity.
7 _- `+ H1 O$ J3 N, [3 j/ cA, loop enlarges to measure penile girth in millimeters. B,
8 o n- e7 w! v% g1 xexample of penile girth computed easily and accurately.
' ]* ?+ b4 h# O! Rconversion of testosterone to dihydrotestosterone. It is in this
/ e$ o/ `, r2 Z: O+ d! A& }/ xolder group that others have noted high levels of serum3 X; b3 j+ t4 U) i" w! L
testosterone with topical application. It would also appear
7 i2 v$ J; W; ]7 |that phallic response during puberty is related directly to the
( c4 @9 H. j9 A: [- U- N7 P1 C" F& ^serum testosterone level. There also is other evidence of local
' S$ H. }" \' ?- dresponse to testosterone with hair growth and with spermato-
' T1 m- k4 I* y; l3 w) ^ `# J% Egenesis. 5• 6" t# Q8 z2 }1 r' v6 Q8 q; b. O
Administration of larger doses of gonadotropin or systemic
2 ?6 l! a! T* ^, J3 i. F7 Z5 j+ U- Utestosterone, as well as topical applications that produce
6 V; @3 f/ _. Z; p& T) shigher levels of serum testosterone (150 to 900 ng./dl.), will& X' r2 K& |8 L( B# { P3 x# v
also produce phallic growth but risks accelerated skeletal* ? z& s7 f- H$ w
maturation even after stopping treatment. It would appear7 Z+ T" w- U$ C) n! X5 n
that this may be avoided by topical applications of testosterone
7 d/ U" _% ]5 P, [* R: o" ~, {and monitoring of serum testosterone. Even with this control/ p5 ~) q) J& x: O4 A; `1 ~, b
the duration of our therapy did not exceed 3 weeks at any# Z/ c0 I5 u6 C4 d
time. It is apparent that the prepuberal male subject may
0 e3 s8 V6 t' w& j6 z) P- ssuffer accelerated bone growth with testosterone levels near/ N, V" H' F7 Q" H d; o
200 ng./dl. When skeletal maturation is complete the level of
3 p1 o/ v/ F* J' T" `0 Hserum testosterone can be maintained in the 700 to 1,300 ng./9 D0 z& M; L8 N5 C! I u6 }$ l8 ?
dl. range to stimulate phallic growth and secondary sexual
) L* X) J: @$ V% w+ Echanges. Therefore, after skeletal maturation parenteral tes-) d4 [3 z- w/ K- U; O5 a) y
tosterone may be used to advantage. Before skeletal matura-
; _' E7 {. x, x/ Ltion care must be taken to avoid maintaining levels of serum. F2 D% D9 j9 K: ?
testosterone more than 100 ng./dl. Low-dose gonadotropin
$ L+ {+ _/ a! n* ]" k D- \" n+ Mdepends upon intrinsic testicular activity and may require
, v5 c& s, l/ b1 Aprolonged administration for any response.
8 J5 J% B) I; bAlternately, topical testosterone does not depend upon tes-3 \7 v* e( |- j# f9 t- [9 a
ticular function and may provide a more constant level of" J. _6 }0 s4 {
REFERENCES
! ], A3 a6 I0 ]* q6 [1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
$ j8 Q9 d" @ m; F6 h7 G! LR.: The local application of testosterone cream to the prepub- `9 S8 o ~; s" G( ~
ertal phallus. J. Urol., 105: 905, 1971. m; u( _ `+ ?. y* F9 ] [
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
: J, o n% a [$ |7 ztreatment for micropenis during early childhood. J. Pediat.,
7 f b5 m/ {" _' U. P8 k83: 247, 1973.- a4 G E' f2 Y, @! e! v
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-; C7 H, g" B# O6 M& ]. q
one therapy for penile growth. Urology, 6: 708, 1975.
6 K" G- k$ y/ @4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
2 g# y t: C& y, l" E& J7 F' L: Nto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by, D' ?. a* A. s
skin slices of man. J. Clin. Invest., 48: 371, 1969.
6 S7 C: n4 \. Q- H& |1 b. k$ q# L5 `/ J5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
- _6 e. B3 z3 y, b; yby topical application of androgens. J.A.M.A., 191: 521, 1965.
4 A! P4 j$ ?2 B: |' l6 J/ v, R6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
3 |" D% [6 Q) E. W: oandrogenic effect of interstitial cell tumor of the testis. J.
6 h- B$ n R y' m; \Urol., 104: 774, 1970.
" _, j( u; G8 z0 G" w$ [0 d. r- ~# B7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
1 N4 ^, n: X) K, P' Ction in the male genitalia from birth to maturity. J. Urol., 48: |
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