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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND, ^- H! v% E( h7 H/ e% s4 S1 d+ Q
GONADOTROPIN2 u; N3 S1 ]! b$ z
RICHARD C. KLUGO* AND JOSEPH C. CERNY& a" p/ D- b$ A m
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
/ i( D* v6 w! U0 o) y' ~ABSTRACT
! D* k/ O' N! D* {Five patients were treated with gonadotropin and topical testosterone for micropenis associated
1 _6 i, ]! i+ ?7 V Vwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
5 j- _1 P. ~2 X# Q3 ?2 P) Y' ]9 Wtropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
+ i- f |3 [0 Y6 D) }cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent( X2 I$ [! X' ?' T" c' s( C
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent6 H2 A) ]# _7 `' B
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average& N; i8 [$ N. N X1 z
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response: G; X9 a/ L$ a/ O
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
" p h& {+ \+ N% L/ P; istudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile* h8 T) c- M$ p% y" W3 d+ p
growth. The response appears to be greater in younger children, which is consistent with previ-
# O4 E7 o4 J- ~0 c; L0 ^2 v# W8 Jously published studies of age-related 5 reductase activity.4 A5 o. ?: L1 j) w/ S
Children with microphallus regardless of its etiology will
0 F5 |% m! c' r5 r1 {- x; ^ qrequire augmentation or consideration for alteration of exter-
! W1 A; J& J3 `2 ^( S2 z: mnal genitalia. In many instances urethroplasty for hypo-
. U6 t# H) v8 D; f* U% Sspadias is easier with previous stimulation of phallic growth.) O2 J8 c2 I2 i! n
The use of testosterone administered parenterally or topically
/ ~3 G% r- m/ E7 ~- w4 Ahas produced effective phallic growth. 1- 3 The mechanism of
0 S K8 ~) f; h% Y4 j" b& iresponse has been considered as local or systemic. With this
- y: I3 _& W, W6 Iin mind we studied 5 children with microphallus for response
* j" \9 r9 f1 jto gonadotropin and to topical testosterone independently.3 _1 n: C" p7 i- U/ \1 j* u D
MATERIALS AND METHODS& j& y+ c, t" g3 }
Five 46 XY male subjects between 3 and 17 years old were
2 C8 f8 R. Y- l" ~" A) [7 ], p+ _2 Oevaluated for serum testosterone levels and hypothalamic
$ c' |% H `3 k" X7 o0 r) R/ Bfunction. Of these 5 boys 2 were considered to have Kallmann's
7 |( n$ U8 }& ~& H# v4 Ssyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-7 N* @& j* |- E' c w" X
lamic deficiency. After evaluation of response to luteinizing
& L8 o2 a- `# f1 qhormone-releasing hormone these patients were treated with
# q2 [7 s `& Q% ?1,000 units of gonadotropin weekly for 3 weeks. Six weeks9 O: h( H4 l X/ _* k& w( i
after completion of gonadotropin therapy 10 per cent topical
% C2 X) G& v# z* F: w1 Utestosterone was applied to the phallus twice daily for 3 weeks.
f7 Z( z1 Y: S m+ e2 h. r" jSerum testosterone, luteinizing hormone and follicle-stimulat- A& F7 n3 b3 f' O n9 G% s
ing hormone were monitored before, during and after comple-
. j% \) C8 |' N6 D8 W% Ttion of each phase of therapy. Penile stretch length was Y* y( } G. I, q
obtained by measuring from the symphysis pubis to the tip of0 K) X( n8 k* x/ z; I$ Z
the glans. Penile circumferential (girth) measurements were
' f% X. J( J. {3 E2 p% L$ i. \obtained using an orthopedic digital measuring device (see
& W% @/ J. \6 O% ]9 g1 g8 @figure).
4 H( w2 K5 f7 u' s# v3 c GRESULTS
3 J/ s/ U4 |; @& {0 }4 [Serum testosterone increased moderately to levels between
4 U5 H$ q3 d; t' S5 ^4 c Z50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
6 g, ?7 l$ z S/ U- Oterone levels with topical testosterone remained near pre-
4 \* h+ r2 D3 Q* j f4 W& Ttreatment levels (35 ng./dl.) or were elevated to similar levels2 T7 Z8 J& Q3 {
developed after gonadotropin therapy (96 ng./dl.). Higher
7 e4 r* J6 h" Q6 {# lserum levels were noted in older patients (12 and 17 years old),2 R! i. c8 T8 f, C
while lower levels persisted in younger patients (4, 8, and 10 i8 _" h% T9 C- N4 c7 K
years old) (see table). Despite absence of profound alterations
& X& _+ V% ^) i/ u$ }of serum testosterone the topical therapy provided a greater0 u8 n7 I7 _, O' z
Accepted for publication July 1, 1977. ·
+ r+ c9 S% H! \+ hRead at annual meeting of American Urological Association,
; M) d3 d- M! c, ]$ TChicago, Illinois, April 24-28, 1977.9 q( y+ w& j9 h7 ]. T @# B+ _2 U6 B
* Requests for reprints: Division of Urology, Henry Ford Hospital,) Z9 u/ D$ U* Y" K) b: t+ v
2799 W. Grand Blvd., Detroit, Michigan 48202.
7 p0 h* t/ q [) H- Uimprovement in phallic growth compared to gonadotropin.4 J3 J1 l% Z' [$ H0 F9 @7 }
Average phallic growth with gonadotropin was 14.3 per cent, C8 L0 v% |7 {
increase in length and 5.0 per cent increase of girth. Topical! r) g5 {: U- {
testosterone produced a 60.0 per cent increase of phallic length
1 j+ a( J! H( v% k5 t! eand 52.9 per cent increase of girth (circumference). The# W" G( f: U Q2 E0 Z
response to topical testosterone was greatest in children be-
1 }* @3 j7 t: z5 C' U& Ytween 4 and 8 years old, with a gradual decrease to age 17& T- o! Z0 B* J7 p' O: \
years (see table).2 r0 i, N, f6 d4 }- D$ e3 V
DISCUSSION; M( K% {+ h( N( |( g4 b
Topical testosterone has been used effectively by other
. O6 D' o4 ?* Vclinicians but its mode of action remains controversial. Im-
9 \( M2 q i& v0 emergut and associates reported an excellent growth response, l. n( V/ O4 v9 Y# c% M+ C
to topical testosterone with low levels of serum testosterone,
. h5 w9 C# g3 W, P" Esuggesting a local effect.1 Others have obtained growth re-
6 M1 b% ~2 s3 N i! fsponse with high. levels of serum testosterone after topical
1 d, T6 |, a' H+ B* \) }1 Q% h# dadministration, suggesting a systemic response. 3 The use of6 E" a) F% o0 e4 m0 |
gonadotropin to obtain levels of serum testosterone compara-
, l: S' T/ U. `* \* b) y( S8 uble to levels obtained with topical testosterone would seem to+ |8 l* @- M0 X1 c! r8 Q8 v- Y
provide a means to compare the relative effectiveness of
/ u/ P3 z0 k: A6 [0 K& \+ A. Mtopical testosterone to systemic testosterone effect. It cer-# P5 N* [0 r( w) A+ K0 x( I) Q9 O
tainly has been established that gonadotropin as well as par-
% D' |0 y/ Y+ ?5 s# G# ~# g- Q1 kenteral testosterone administration will produce genital# x& b6 H9 G Y# Y3 P: u( K: N0 V! L
growth. Our report shows that the growth of the phallus was4 x w9 _, ]) I1 Z* V3 B
significantly greater with topical applications than with go-
9 ?9 r$ c4 @ Znadotropin, particularly in children less than 10 years old.; G. D; R. r8 M! L |
The levels of serum testosterone remained similar or lower
. E. f9 y, V+ o! ^. A! S$ \2 d$ athan with gonadotropin during therapy, suggesting that topi-
3 D0 b( }4 ?3 C6 B0 t# Ical application produces genital growth by its local effect as* o4 H' ?; h) V1 ?
well as its systemic effect.6 E1 y0 Q. ` b& S) i: u
Review of our patients and their growth response related to, ~+ m5 v- c* L, n: Z. P4 {# n6 u
age shows a greater growth response at an earlier age. This is
# |% ]& r- L6 z7 a) ]consistent with the findings of Wilson and Walker, who
2 v+ O- a; b3 U! E7 ereported an increased conversion of testosterone to dihydrotes-
: _ y3 T( D/ k X2 P+ A4 Ptosterone in the foreskin of neonates and infants.4 This activ-
8 S$ S" f9 h+ R( e! {, S5 T( Uity gradually decreases with age until puberty when it ap-( X. h7 h9 o/ g' G) ^
proaches the same level of activity as peripheral skin. It may
! x5 r! p% t2 Jwell be that absorption of testosterone is less when applied at
0 P3 M/ G- X9 ean earlier age as suggested by lower serum levels in children, N) @( H6 j( n; E9 e/ D
less than 10 years old. This fact may be explained by the
3 U- O. }' T+ ~8 i1 Wgreater ability of phallic skin to convert testosterone to dihy-* P* m$ Q( r0 r8 m
drotestosterone at this age. Conversely, serum levels in older8 ~8 \4 `* H% T+ X w+ r' i
patients were higher, possibly because of decreased local# }. |5 S8 v' U1 h* @9 `8 h
667
2 S% k3 e ]3 ^7 X7 |, ]( P* ?% K c668 KLUGO AND CERNY
# j6 V3 p" P" w9 aPt. Age
4 E" w9 \) R4 J) E! Z7 ](yrs.)* r4 @. R; d( Y D5 f8 R
Serum Testosterone Phallus (cm.) Change Length9 q5 d7 j: S& m
(ng./dl.) Girth x Length (%)* S% E, @) \- d/ X+ m4 F
4
; `# j/ ^- ~/ ]2 n) L+ S( ~- `. i88 h- _' `& I5 G5 l
10
" U) g! R3 O8 @5 K) d12
$ y% A. M, G" V6 v. o# {17
/ k" ? F) I4 L& g5 AGonadotropin+ ^( A! F6 @# }+ F
71.6 2.0 X 3 16.6
. e7 Z5 m) `# @4 w2 o3 l, [' W50.4 4.0 X 5.0 20.0# e1 T% ?- v8 M% `* R5 V
22.0 4.5 X 4.0 25.0: J7 g' ?1 |& G( I
84.6 4.0 X 4.5 11.1
4 k3 \. c5 Q+ O, b85.9 4.5 X 5.5 9.0
/ d3 {/ Z7 i/ AAv. 14.3
, j( b' @$ h) M3 S0 n4
6 z. P9 z6 {0 ?( D, {8
5 d( I6 c, X+ B8 x* N10" z" Y" F0 @5 K
125 v$ L; S4 P7 h1 q
17
( W' d' ^, G5 I. E1 J7 MTopical testosterone+ B/ f, }' R% ?8 H' x" |2 {, J, i
34.6 4.5 X 6.5 85: D" a1 P. Q: M+ G
38.8 6.0 X 8.5 70
) w2 w4 `. ~- M: N6 t3 Q1 ], w [& D' Z40.0 6.0 X 6.5 62.5; D% G- P% U' f4 s* [2 m
93.6 6.0 X 7.0 55.5
7 X# z" a, r9 R) }95.0 6.5 X 7.0 27.2
$ S- [+ A) A1 I0 N. T# i5 R8 L* ?Av. 60.01 u" n# q4 v( j* u9 B7 \7 V
available testosterone. Again, emphasis should be placed on
4 S# x7 y" H0 D1 l1 Z& ?6 Bearly therapy when lower levels of testosterone appear to! ]+ ?+ C1 d9 h z, N- g
provide the best responses. The earlier therapy is instituted
* I+ H8 `. b0 F, Q! fthe more likely there will be an excellent response with low
; ^' |, L1 \4 K) A$ H9 Vserum levels. Response occurs throughout adolescence as9 G3 u9 W+ R4 i4 P8 [7 I
noted in nomograms of phallic growth. 7 The actual response, H7 D, r a" _! e
to a given serum level of testosterone is much greater at birth
9 T. I2 I7 r2 O# l0 ?% Land gradually decreases as boys reach puberty. This is most" _" {2 e. P9 \" q3 E5 C& F4 d0 c+ g
likely related to the conversion of testosterone to dihydrotes-
" v; J( `3 b9 _: d5 Qtosterone and correlates well with the studies of testosterone3 c0 A) M; v! b
conversion in foreskin at various ages.
% E/ _6 f. u7 B$ n) N6 g+ B; TThe question arises regarding early treatment as to whether
, v+ o- a2 n# I' P* S# yone might sacrifice ultimate potential growth as with acceler-
6 q' O C3 P q8 V- u8 x- fated bone growth. The situation appears quite the reverse
8 F: q: W; V @3 xwith phallic response. If the early growth period is not used7 W6 }) N$ b; u' p' b
when 5a reductase activity is greatest then potential growth
& g; v3 v9 V9 Z, N! G$ smay be lost. We have not observed any regression of growth) c3 M, E5 ~* l7 Z! m
attained with topical or gonadotropin therapy. It may well
9 M* }: Z5 H6 b- A a% \7 [, a: {. [be that some patients will show little or no response to any* R1 O0 z2 V' `- D4 V
form of therapy. This would suggest a defect in the ability to- f+ H1 }/ Y8 I+ a0 U. s! L' \
convert testosterone to dihydrotestosterone and indicate that4 H7 s; l: F2 P' K, f# d4 }
phallic and peripheral skin, and subcutaneous tissue should- W' A6 n; W) _* X7 m) {
be compared for 5a reductase activity.
6 e2 y3 s5 A2 nA, loop enlarges to measure penile girth in millimeters. B,
$ Q6 P5 {# i. X Wexample of penile girth computed easily and accurately.
7 i. l w! r0 ^/ M. i) Zconversion of testosterone to dihydrotestosterone. It is in this
8 t3 W0 P5 [) Y+ t. M7 ]older group that others have noted high levels of serum
* i8 A: |3 G- l$ L5 [& T% ptestosterone with topical application. It would also appear
' o1 |) k% X; I6 _that phallic response during puberty is related directly to the
K- A3 M5 c% B+ ^2 [% _# xserum testosterone level. There also is other evidence of local
; h2 d- r2 L4 F* Yresponse to testosterone with hair growth and with spermato-1 Y* v- a1 d. D# [
genesis. 5• 6# ]% N. u% P* D, M0 K- E. a
Administration of larger doses of gonadotropin or systemic
/ a: y6 J; _4 b. J; M) Q0 Wtestosterone, as well as topical applications that produce2 `9 g( `) }- N1 h# j
higher levels of serum testosterone (150 to 900 ng./dl.), will0 |( M2 t: z3 y' A4 z
also produce phallic growth but risks accelerated skeletal
" x' C7 `0 v! O! n4 ]maturation even after stopping treatment. It would appear
% P( ^& E. J1 P3 Y; H: S2 gthat this may be avoided by topical applications of testosterone1 w! v- U0 c7 Z# u9 k) d! i
and monitoring of serum testosterone. Even with this control2 u9 e e! l, w
the duration of our therapy did not exceed 3 weeks at any- Q" w; S. Y1 I' w" F c
time. It is apparent that the prepuberal male subject may% D2 H: Y& N, W) ?. ?8 l: r* i
suffer accelerated bone growth with testosterone levels near+ K5 _% K- p' G8 n+ }
200 ng./dl. When skeletal maturation is complete the level of) p& X0 K( R$ u5 W, P5 x, A
serum testosterone can be maintained in the 700 to 1,300 ng./- K9 g' {4 u* A" |
dl. range to stimulate phallic growth and secondary sexual
3 o0 `1 p1 u: Q2 Fchanges. Therefore, after skeletal maturation parenteral tes-) K+ M$ r' d9 ~& K( j- e, O
tosterone may be used to advantage. Before skeletal matura-
& z. ^6 o, S& Etion care must be taken to avoid maintaining levels of serum
1 d+ G* z! A7 otestosterone more than 100 ng./dl. Low-dose gonadotropin/ _& r, e0 g9 X' C
depends upon intrinsic testicular activity and may require
- x* i" p% k9 J% C |# C7 d0 U8 V& \prolonged administration for any response.
" n5 P0 z5 F. k. b3 P. R5 @Alternately, topical testosterone does not depend upon tes-
1 i/ R9 W" |6 F% [. ~9 fticular function and may provide a more constant level of
) D% T; r4 w/ q) [' q% ^REFERENCES+ `' ]+ W' \$ u/ B F( f
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,$ G1 B6 y. e- ]7 P0 a* D
R.: The local application of testosterone cream to the prepub-3 t" t6 C5 I! G$ [' j
ertal phallus. J. Urol., 105: 905, 1971.9 I( j# u |" t* g) B/ x
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
6 w( s$ U" s. N8 _6 e4 ntreatment for micropenis during early childhood. J. Pediat.,
6 k" e9 d9 W- }6 T5 H8 _83: 247, 1973.3 _2 @/ v) {# k' m3 P. d
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-9 f. ]: q+ B% r+ Y, E* E
one therapy for penile growth. Urology, 6: 708, 1975.
- K; y4 J! g: A/ J$ A4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone( S" r& I: q- L7 V" e2 x
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by f/ W+ h8 m+ b2 R0 r
skin slices of man. J. Clin. Invest., 48: 371, 1969.
* l: \# k ?% ^2 [! B% ~5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
7 b: S4 R# ^# z# ?: hby topical application of androgens. J.A.M.A., 191: 521, 1965.
2 c y2 W& u4 U m3 q2 C# O8 n6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
f w5 w+ u8 }( x7 s+ I% y7 gandrogenic effect of interstitial cell tumor of the testis. J.
2 U4 L! Y8 b; ^7 X# Z8 MUrol., 104: 774, 1970./ ?& K( Q+ b1 Z* e$ s5 v
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-' W8 y1 K/ ~" p( @! A% p) f/ C1 Z
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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