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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
/ n# f" T. | G/ ?' |GONADOTROPIN
/ I3 O0 l R8 }0 [1 K$ O' m2 QRICHARD C. KLUGO* AND JOSEPH C. CERNY
! ?2 M# `' @# i- H% c# D% k' XFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan7 j5 H3 J0 I# v+ P
ABSTRACT
J" \$ n% f- x! Z# aFive patients were treated with gonadotropin and topical testosterone for micropenis associated- r( }, U9 v1 o$ G* g. d- E
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-: n/ t4 f' q7 w: b1 E! `6 r! j
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
4 o0 j+ r" J7 wcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent7 j) x# A+ Q* ^7 Q [+ w6 V
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent, ~8 H1 F* J9 k! u3 |
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average) x7 x U* P) l9 O0 i
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
" m8 h B9 h& ^) n( D' Woccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This5 `8 Y) P* m2 y& T& t" d
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
/ G& l N" ^1 [5 Sgrowth. The response appears to be greater in younger children, which is consistent with previ-5 o+ N0 d" B ]( R
ously published studies of age-related 5 reductase activity.1 @! h9 b6 O% C4 L
Children with microphallus regardless of its etiology will
! h5 i2 h5 C$ I' G6 \8 Zrequire augmentation or consideration for alteration of exter-
2 ], F# H" U# s7 J9 h1 bnal genitalia. In many instances urethroplasty for hypo-8 D7 a. J M4 _$ e, h
spadias is easier with previous stimulation of phallic growth.% n. R' N6 }& P
The use of testosterone administered parenterally or topically
6 S y# V" S1 g7 w) M" `has produced effective phallic growth. 1- 3 The mechanism of9 o& t `2 U) M
response has been considered as local or systemic. With this6 h$ [0 A& G- m+ Z* s3 E3 z
in mind we studied 5 children with microphallus for response
; Y: c# i+ _8 S1 r' B8 kto gonadotropin and to topical testosterone independently.
" a& ^# ~9 ^, L' f# g2 A; RMATERIALS AND METHODS7 }/ [6 v; `5 u+ N3 B2 D# p, H2 w
Five 46 XY male subjects between 3 and 17 years old were
8 k6 [; ]; E( `+ }evaluated for serum testosterone levels and hypothalamic
! _6 F6 e5 l/ N: lfunction. Of these 5 boys 2 were considered to have Kallmann's& X3 R% |) U5 E6 z+ c J7 B
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
& q2 y2 _& m' l, _6 ?9 p, U8 mlamic deficiency. After evaluation of response to luteinizing! }+ h, I! A( v3 f8 b9 @
hormone-releasing hormone these patients were treated with' m! o2 l) }' ~( L1 @2 |: O
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
0 ^2 ~& n, ]# }1 yafter completion of gonadotropin therapy 10 per cent topical
# o9 j% X' H4 h, Z, C$ a% Ltestosterone was applied to the phallus twice daily for 3 weeks.( N+ D1 f! C5 M9 }3 j) i0 W
Serum testosterone, luteinizing hormone and follicle-stimulat-$ g( N" g, \; @
ing hormone were monitored before, during and after comple-
* Z) U) |' T& Y% a etion of each phase of therapy. Penile stretch length was0 f2 Z* b# c, x/ l/ Y. I
obtained by measuring from the symphysis pubis to the tip of
3 t: ]8 b2 Z! c7 Q0 t8 y# B* {the glans. Penile circumferential (girth) measurements were
" P, Z1 l4 ~) K4 z& T# Xobtained using an orthopedic digital measuring device (see
( K# u: g8 ^, [/ O y: P$ Hfigure).) k N- z4 N8 z
RESULTS
( _1 o8 o% P9 v7 H& f2 D5 d) USerum testosterone increased moderately to levels between
" ^* ~" n2 j! ^1 O) L0 w w9 Q50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-/ v4 k+ B7 Q1 z. L5 ?5 W
terone levels with topical testosterone remained near pre-
3 P' t% x7 S* Ftreatment levels (35 ng./dl.) or were elevated to similar levels s1 a u% Y" y* F- s
developed after gonadotropin therapy (96 ng./dl.). Higher# u7 I. V# k/ k) C
serum levels were noted in older patients (12 and 17 years old),
: N7 b- h( f3 X; n: L6 B* zwhile lower levels persisted in younger patients (4, 8, and 10
- `6 }% i7 _* z: U1 q, v, xyears old) (see table). Despite absence of profound alterations" j. v7 H/ z7 D$ t
of serum testosterone the topical therapy provided a greater
- ]& U6 l+ J$ J4 S( K! E5 ]Accepted for publication July 1, 1977. ·
4 [6 x/ `# b8 ?# D2 ?Read at annual meeting of American Urological Association,4 o: |3 {0 M; X. {4 Z. r
Chicago, Illinois, April 24-28, 1977.( C* w+ w7 w% u. B+ W
* Requests for reprints: Division of Urology, Henry Ford Hospital,
9 d1 f5 ]6 K8 @2799 W. Grand Blvd., Detroit, Michigan 48202.+ T: E+ q+ Q( I1 H
improvement in phallic growth compared to gonadotropin.4 W$ l1 I( i) C) J: o, j0 f
Average phallic growth with gonadotropin was 14.3 per cent4 Y t+ P$ P! [7 E
increase in length and 5.0 per cent increase of girth. Topical4 K! J5 q$ s9 P- S- C) k: J
testosterone produced a 60.0 per cent increase of phallic length& c+ D& S. t( `8 x9 S- t" R. f" F
and 52.9 per cent increase of girth (circumference). The8 P4 M3 ~# k: G0 W# z' @
response to topical testosterone was greatest in children be-
% d% k' C; q! W9 J5 Y; o! atween 4 and 8 years old, with a gradual decrease to age 17/ P; M- Q* M0 ]9 c
years (see table).
! i& m- n. P0 O8 xDISCUSSION: s4 X' h; a& ]. M8 ` Q
Topical testosterone has been used effectively by other( @* u$ V* c- E L3 [0 I( K
clinicians but its mode of action remains controversial. Im-
9 p8 \9 w- A, w6 n) s& J5 mmergut and associates reported an excellent growth response3 N' ]# T* E$ g: ^( I, n# r/ Z
to topical testosterone with low levels of serum testosterone,0 d" j( f+ }0 }5 g/ Z3 b9 G
suggesting a local effect.1 Others have obtained growth re-
, e2 }8 O) r* D! W! P; ]sponse with high. levels of serum testosterone after topical
, f" g% d. s, K0 t3 w6 i# Madministration, suggesting a systemic response. 3 The use of8 R( H' X' _' C {. P" Q* C9 [
gonadotropin to obtain levels of serum testosterone compara-
4 t/ T0 E) e: Xble to levels obtained with topical testosterone would seem to0 X8 ?3 e; c: \9 a: ?+ p
provide a means to compare the relative effectiveness of! m' Y i. y+ r& f5 |* {
topical testosterone to systemic testosterone effect. It cer-# l, `. P! l" }
tainly has been established that gonadotropin as well as par-. X% d9 D* D2 Y0 ]& I+ T* V4 v' c
enteral testosterone administration will produce genital
3 k, @# [" B1 y, W! Rgrowth. Our report shows that the growth of the phallus was" z2 c- B# Y- X% t: j1 A% O. R
significantly greater with topical applications than with go-
2 b* \' N3 I+ c3 q$ L- m: R) w/ unadotropin, particularly in children less than 10 years old.! c% F7 a. m4 O/ r8 p
The levels of serum testosterone remained similar or lower
i3 x2 o0 [ p: i" w% t. uthan with gonadotropin during therapy, suggesting that topi-( K7 G1 H/ U7 u( L' e
cal application produces genital growth by its local effect as, y0 [, |3 ~. `4 G' _) ^4 S
well as its systemic effect./ i* s1 ?# B0 s
Review of our patients and their growth response related to
- a* Y5 M8 h$ k) L( Sage shows a greater growth response at an earlier age. This is
: j4 ?0 u; d" b4 R0 w5 Rconsistent with the findings of Wilson and Walker, who
2 e. O, W! E# u; r5 i; Y. r5 treported an increased conversion of testosterone to dihydrotes-
: `7 f) p0 b2 b6 W0 H$ ftosterone in the foreskin of neonates and infants.4 This activ-
- |; G6 E- f A0 ^ity gradually decreases with age until puberty when it ap-5 M, L* V* _% B" G1 o
proaches the same level of activity as peripheral skin. It may
$ O5 M' P- `$ ?+ r0 d* Jwell be that absorption of testosterone is less when applied at; e$ f. {8 n) s$ P5 g: r# h6 O
an earlier age as suggested by lower serum levels in children
) O& `7 D: S0 Fless than 10 years old. This fact may be explained by the
! R4 g+ G9 g9 l+ P' N4 L2 [, j! m: Sgreater ability of phallic skin to convert testosterone to dihy-
, A, e$ [% h. c/ n3 bdrotestosterone at this age. Conversely, serum levels in older
8 X, @/ f) A5 j5 a* M3 Vpatients were higher, possibly because of decreased local
- q+ _9 w3 s" Y' V" g667
8 }3 p# E" y- }) G* z* V0 B3 e1 Q668 KLUGO AND CERNY
& G7 T4 t$ u( N3 _3 Q* KPt. Age
" W% j0 c3 _9 P* @5 {(yrs.)3 n' s- t' {( D0 T3 C
Serum Testosterone Phallus (cm.) Change Length8 y8 T/ |5 S; q3 y
(ng./dl.) Girth x Length (%)4 o- G) r: E9 k* d. ]9 J
4
$ R& \+ j1 k9 v6 f8
' c- R' a" l# d: E/ C8 R10
. K+ v0 G6 d, u12
" _2 @3 O% f, f& w7 |7 R' n. |17
& M! _6 U1 ?; D h1 W$ ?% K+ M& _, mGonadotropin
5 Q, H6 u% T2 w* P) Q71.6 2.0 X 3 16.61 y; t% K! i d$ F% z, i
50.4 4.0 X 5.0 20.07 N8 y" [; r& g! e
22.0 4.5 X 4.0 25.0/ z: U$ P9 R) v- M4 d( C4 n
84.6 4.0 X 4.5 11.1 D3 r7 M; d% C
85.9 4.5 X 5.5 9.0, Y$ C: J s1 {7 q
Av. 14.3
7 \2 X0 k9 o) L1 b. x& D4
7 d( Q$ L0 R/ r5 `5 E7 X88 [2 I5 _7 I2 [
10
( c# H" W& q5 i3 j: ^12 ~! h1 h" N# T3 j r# X
172 @2 {$ _! X# p H, j' B. d
Topical testosterone- j5 b! M f# A8 Q: f2 S/ ~
34.6 4.5 X 6.5 85
' w# w) k1 z$ _3 n38.8 6.0 X 8.5 703 O* M- \% `2 _) L1 I3 ^ \' l. u6 X* D
40.0 6.0 X 6.5 62.5+ {9 I: H9 D. X, P. E9 E; x
93.6 6.0 X 7.0 55.5
8 F, Y5 Z8 c: |: K95.0 6.5 X 7.0 27.2' B o- B$ A, |) E8 L4 h' g
Av. 60.0
/ L6 p) [* q4 m' ^/ C% r4 N2 b; s! Gavailable testosterone. Again, emphasis should be placed on
! W+ m9 X! ~+ A; D/ rearly therapy when lower levels of testosterone appear to
; r/ I& H7 n+ s! P' C2 O" @provide the best responses. The earlier therapy is instituted
6 A- l% k3 @4 c- ~the more likely there will be an excellent response with low
$ v9 O! `7 Y s, y3 l1 Aserum levels. Response occurs throughout adolescence as7 ]6 B+ z# U/ T7 A8 D" X1 g
noted in nomograms of phallic growth. 7 The actual response
9 r2 \! F0 w# b$ u2 s5 v7 b- Kto a given serum level of testosterone is much greater at birth" B& m5 ~: ^" t5 Q) c
and gradually decreases as boys reach puberty. This is most
; m' Y4 Z( H& f# flikely related to the conversion of testosterone to dihydrotes-/ b' {# Q( E/ |
tosterone and correlates well with the studies of testosterone( z* _0 S: R- f
conversion in foreskin at various ages." T/ Y) N$ M! ~
The question arises regarding early treatment as to whether
3 a! F4 U' [( k8 @one might sacrifice ultimate potential growth as with acceler-
9 Q& U' @/ G# Y3 x6 ] m+ N7 G2 ?* nated bone growth. The situation appears quite the reverse T8 u0 P/ }* {( n% S
with phallic response. If the early growth period is not used, U8 M0 a. S+ e& v
when 5a reductase activity is greatest then potential growth% J! c% d8 s+ Z$ H
may be lost. We have not observed any regression of growth1 z4 |2 G* f% R- G C
attained with topical or gonadotropin therapy. It may well
$ R2 T- @6 v3 O2 g9 n, M; f& ~be that some patients will show little or no response to any
+ Y, e; J7 Q+ K2 wform of therapy. This would suggest a defect in the ability to
3 g8 d2 ?! Y0 d( m9 Hconvert testosterone to dihydrotestosterone and indicate that8 I8 D* ]1 X- r$ b; U# ?, G5 H! y
phallic and peripheral skin, and subcutaneous tissue should: P# I7 e' Y8 }7 g- ~7 K( ?
be compared for 5a reductase activity.( \/ Z2 m0 o$ P) g: x+ J
A, loop enlarges to measure penile girth in millimeters. B,9 g0 I+ ~" a' d" h1 l: f% L4 m7 v/ i
example of penile girth computed easily and accurately.: Q& P; s9 e5 Y, _) J& [
conversion of testosterone to dihydrotestosterone. It is in this+ a, K' ^, T. s V: e
older group that others have noted high levels of serum7 N0 }: j$ V g, O# i* G
testosterone with topical application. It would also appear
! @+ {; V, |0 Q. E1 S$ M. ], h U, mthat phallic response during puberty is related directly to the% n6 W8 ? F5 R) f5 g1 i3 k! {5 U1 ^
serum testosterone level. There also is other evidence of local: U- j$ L$ V0 H
response to testosterone with hair growth and with spermato-
. y( f$ j7 k( c0 t; c# ~/ vgenesis. 5• 6+ I A0 q6 ]5 K- M5 ^/ w
Administration of larger doses of gonadotropin or systemic/ _2 ^4 q, B& ^# ]7 O
testosterone, as well as topical applications that produce; w2 b: e) `# `; o
higher levels of serum testosterone (150 to 900 ng./dl.), will$ o' p3 c$ |) R5 {! o
also produce phallic growth but risks accelerated skeletal1 f$ C, ~1 S# s9 w" S& n
maturation even after stopping treatment. It would appear
$ K, \& x& X# f# ]4 Tthat this may be avoided by topical applications of testosterone0 Y7 s6 N9 O9 L% _) x* D
and monitoring of serum testosterone. Even with this control
' R7 l0 A& l/ X7 Sthe duration of our therapy did not exceed 3 weeks at any
0 [3 X! g: C7 t) q4 A0 L ?time. It is apparent that the prepuberal male subject may
& J9 A q* h* M, qsuffer accelerated bone growth with testosterone levels near6 H9 U! [/ v) i3 O3 ?
200 ng./dl. When skeletal maturation is complete the level of
5 j" s7 |! n9 C% f) F jserum testosterone can be maintained in the 700 to 1,300 ng./
' l' C2 `2 F% x& t; [9 Y1 Qdl. range to stimulate phallic growth and secondary sexual' n. d& p, m- c8 L( `7 _2 e
changes. Therefore, after skeletal maturation parenteral tes-
9 K* D5 p5 }* H( l) ~/ itosterone may be used to advantage. Before skeletal matura-: L. C6 W4 j% W9 O b
tion care must be taken to avoid maintaining levels of serum
2 A+ o) X' m5 _. X' y& _9 X! Itestosterone more than 100 ng./dl. Low-dose gonadotropin/ i: A# W5 s2 k
depends upon intrinsic testicular activity and may require
6 A) F3 q6 B! o* y9 lprolonged administration for any response.
2 k- Z! I: f C3 e6 y: BAlternately, topical testosterone does not depend upon tes-- h3 |9 D2 {" ^$ J3 x
ticular function and may provide a more constant level of; L' i& ]' ]9 L* [; H7 Q
REFERENCES
/ ^$ o/ x, O! L. X; B: R1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,* u' I3 N( j6 \/ l$ g a
R.: The local application of testosterone cream to the prepub-
$ O& F% y3 ^1 v; iertal phallus. J. Urol., 105: 905, 1971. [/ k+ A( U: J
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone7 q" M+ c& H% F7 t/ h6 }
treatment for micropenis during early childhood. J. Pediat.," O) e+ t- ]! |5 J
83: 247, 1973.. L) |5 y3 Z# B! t& [9 D
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-3 j9 P7 @0 f0 L4 m. }
one therapy for penile growth. Urology, 6: 708, 1975.
& r2 E" Y1 \3 ~$ `4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
( M+ Y4 h; B" m2 |8 Cto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
3 {* O" L' G/ ]3 ^) x' b; O! Rskin slices of man. J. Clin. Invest., 48: 371, 1969.
; {% z8 E2 e% Y Z* d9 E5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
7 _1 B" U$ v8 R! Fby topical application of androgens. J.A.M.A., 191: 521, 1965.
. G9 v) u# X' K; [8 B6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local6 Q, A$ x5 U0 \$ ~' E
androgenic effect of interstitial cell tumor of the testis. J.
4 |7 T q6 X% Y) qUrol., 104: 774, 1970.
2 u4 s: Q5 P) r; Q. i$ H" y7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-% ]8 a8 |, ?9 B/ d6 N
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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