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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND* f$ L% b; b+ S
GONADOTROPIN
( r' }: N! x+ n$ i, O- rRICHARD C. KLUGO* AND JOSEPH C. CERNY
* a( I Q" I& P% WFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan N( O- d& t, {4 v6 P
ABSTRACT7 H5 }) @0 {+ S- v# C3 B
Five patients were treated with gonadotropin and topical testosterone for micropenis associated3 {/ a8 p- C/ i, Y1 }5 `% j
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
) f; s, a# O% k( \+ m9 q. q. r5 ctropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
% N; ]: Z: \( A& mcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent& |5 ]! ]( A8 [) f$ I3 x0 S8 {. v
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent4 }- c+ S% N8 a0 i+ u/ O
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average. R- n8 Y" O* O
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response6 C1 n: }. r0 b0 u0 m* ?, v
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
6 j1 P2 a$ F3 Jstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
6 f% d9 b @4 L$ Jgrowth. The response appears to be greater in younger children, which is consistent with previ-
. L- T C3 F8 J* s8 J$ |: Aously published studies of age-related 5 reductase activity. I) T u* i# y
Children with microphallus regardless of its etiology will/ T. ?$ {1 x$ x3 V0 D* z
require augmentation or consideration for alteration of exter-
& M/ p. @$ W3 |+ Vnal genitalia. In many instances urethroplasty for hypo-
; w1 B# ]' H: U! Z ?spadias is easier with previous stimulation of phallic growth.0 p9 l' \9 C# Y1 |& B: b) `
The use of testosterone administered parenterally or topically
K9 X: q0 X5 Z; Yhas produced effective phallic growth. 1- 3 The mechanism of
: E4 } J% R; p: C* x" b; u3 lresponse has been considered as local or systemic. With this
5 G7 ]8 K2 n% yin mind we studied 5 children with microphallus for response
! K- y% ^9 E' l! g6 g* rto gonadotropin and to topical testosterone independently.0 O) ?- J% B$ D; [6 i8 b
MATERIALS AND METHODS
. z/ R& Q8 ]+ k# q! O/ x) M8 l& U7 vFive 46 XY male subjects between 3 and 17 years old were
/ n- b \5 j) k0 n4 ^6 oevaluated for serum testosterone levels and hypothalamic! a- U1 s. ^, ^" I, T. I
function. Of these 5 boys 2 were considered to have Kallmann's
( c# H z0 i, o- z/ M2 xsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
% r- v L# ]% i3 y3 r( [" Y' Dlamic deficiency. After evaluation of response to luteinizing
/ Q1 v7 t4 o- ^hormone-releasing hormone these patients were treated with5 d! Y: p7 G, s5 C
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
) A5 _% x/ t! J S0 Eafter completion of gonadotropin therapy 10 per cent topical4 [, g0 o1 k% i9 r8 A9 l: U; ~
testosterone was applied to the phallus twice daily for 3 weeks.2 s" D! Y: \2 F% S7 X
Serum testosterone, luteinizing hormone and follicle-stimulat-
+ D2 a* U2 G5 N5 g$ A) k$ | W1 d0 ?ing hormone were monitored before, during and after comple-
' H& y* o( n+ j; Q. }tion of each phase of therapy. Penile stretch length was" k; S3 r5 p" U& c" Y M, B
obtained by measuring from the symphysis pubis to the tip of
; a. h# T: N5 |% E7 O7 Q) xthe glans. Penile circumferential (girth) measurements were/ H$ }% E2 J2 ]! S @2 u F
obtained using an orthopedic digital measuring device (see5 {+ T4 X6 d% i" _, Q
figure).- I1 t3 V& `6 k' `; O
RESULTS
1 H4 n$ ?, I; WSerum testosterone increased moderately to levels between' [! @) [6 T- x- r' R5 {% }
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
% X- l& O' v* dterone levels with topical testosterone remained near pre-
~' g- x% I. n( `- c) @treatment levels (35 ng./dl.) or were elevated to similar levels
. L; |( N/ W' I3 Y5 {& Ddeveloped after gonadotropin therapy (96 ng./dl.). Higher& L) k, E0 v% s7 a: _3 G% {5 [2 Z
serum levels were noted in older patients (12 and 17 years old),
1 w6 J* J3 `- z" {while lower levels persisted in younger patients (4, 8, and 109 j, K' s1 b0 h O# q+ O# C
years old) (see table). Despite absence of profound alterations
0 v& c6 ^/ ^7 R6 x. p# I9 t) Q. Jof serum testosterone the topical therapy provided a greater5 x! u S6 X4 [/ c9 a9 n- p
Accepted for publication July 1, 1977. ·4 b1 x" T. D2 S, w
Read at annual meeting of American Urological Association,0 m& ]0 s- M* m7 |0 T' I
Chicago, Illinois, April 24-28, 1977.
2 Y( ?! O: Z( h; p8 W* Requests for reprints: Division of Urology, Henry Ford Hospital,
# A- I+ ]2 t+ P; S) s- h% ~, U: G4 r2799 W. Grand Blvd., Detroit, Michigan 48202.
7 M4 _! }1 e z1 W! s+ D0 t7 }improvement in phallic growth compared to gonadotropin.
5 N! b. j+ }6 Y! J: UAverage phallic growth with gonadotropin was 14.3 per cent
2 T V3 I. `( c8 bincrease in length and 5.0 per cent increase of girth. Topical
" p( Y0 c8 T8 F8 j, ptestosterone produced a 60.0 per cent increase of phallic length7 c1 T+ A1 V0 j- Z
and 52.9 per cent increase of girth (circumference). The
' g) X! B: W" S# N6 eresponse to topical testosterone was greatest in children be-4 I" Z7 f* g/ S
tween 4 and 8 years old, with a gradual decrease to age 17
! m% k' }( z/ ~4 [years (see table).
) }5 B& U! \; qDISCUSSION
8 o& I- ~6 H% |3 LTopical testosterone has been used effectively by other! |/ J( N( D, `/ T- ~: r3 r
clinicians but its mode of action remains controversial. Im-
& h+ C9 {/ c; Smergut and associates reported an excellent growth response" R. \/ g0 k: ~2 l/ b
to topical testosterone with low levels of serum testosterone,
5 {7 Y1 [& N( q8 ~- U* Osuggesting a local effect.1 Others have obtained growth re-
( I7 U% m3 R* |1 {2 Q6 L+ g0 b0 wsponse with high. levels of serum testosterone after topical
. d5 S3 U9 f4 e8 w8 @3 A( I* b" Uadministration, suggesting a systemic response. 3 The use of* c9 z+ G' D! M$ ~& W
gonadotropin to obtain levels of serum testosterone compara-3 J" {. \; h- J
ble to levels obtained with topical testosterone would seem to
* m, w8 D8 A' uprovide a means to compare the relative effectiveness of3 v0 m6 v# Y/ s
topical testosterone to systemic testosterone effect. It cer-
8 q- J+ q" ?( c- C) ]8 vtainly has been established that gonadotropin as well as par-/ u/ l& U0 \: S$ U" ~1 D: x, X
enteral testosterone administration will produce genital( d" z! }2 u4 p7 H. F
growth. Our report shows that the growth of the phallus was
/ m! z/ L9 X6 Q% ^* C) ]significantly greater with topical applications than with go-
# n [0 u* B% M6 N7 b& Wnadotropin, particularly in children less than 10 years old./ z S; z3 R$ t V# @+ H4 j
The levels of serum testosterone remained similar or lower
' c# T1 n: v8 G M$ P4 ithan with gonadotropin during therapy, suggesting that topi-0 [% }8 b( R% N+ |
cal application produces genital growth by its local effect as
% L/ z$ s& V: ?5 t1 dwell as its systemic effect.+ l6 E3 t& }1 @* U* ]6 k7 m
Review of our patients and their growth response related to
+ _! m$ T% ^; J' d1 d+ Lage shows a greater growth response at an earlier age. This is# X0 T2 m w# e& b. J) R
consistent with the findings of Wilson and Walker, who
/ |6 V5 `2 }/ V/ ]/ t- Kreported an increased conversion of testosterone to dihydrotes-
. v5 v0 j o" Wtosterone in the foreskin of neonates and infants.4 This activ-
8 q' N+ ], k. fity gradually decreases with age until puberty when it ap-' M$ Z N4 K) M. ]( j. k8 ^
proaches the same level of activity as peripheral skin. It may& v; P+ o1 F! _: R4 w1 H8 j
well be that absorption of testosterone is less when applied at
: B0 ]' A; Z7 E* o! g) T% }& ian earlier age as suggested by lower serum levels in children
2 p& v" L* n0 F- _2 ~less than 10 years old. This fact may be explained by the% ~. e8 i& Y. f7 W1 s) Y
greater ability of phallic skin to convert testosterone to dihy-4 g8 M. Q% P/ i2 ]: L0 s5 e- O
drotestosterone at this age. Conversely, serum levels in older
) }! G8 A2 `. ~+ i5 F1 R3 Gpatients were higher, possibly because of decreased local
, ]; q7 U8 W( [# q9 F6676 b! x+ Y, p' `5 b9 Q- i ^- ^
668 KLUGO AND CERNY
& y& W* S5 ~) T( A6 j4 APt. Age
# H3 i9 D; s6 V9 j(yrs.)
$ R* w/ a) S. q% x6 q2 M v; ?Serum Testosterone Phallus (cm.) Change Length) u% G' r% ^ A+ C: S6 b- q8 V
(ng./dl.) Girth x Length (%)
6 H6 y' [, U, p4
) e7 i; y' l, J( W2 b8
; L3 h: m* b. r104 ?: W5 ?. ~$ P8 o8 g! }% v/ r
12
- P7 f3 v; P, m' m" N; e171 Z/ u2 V8 Q' l6 C
Gonadotropin
6 P$ `( y' }% \71.6 2.0 X 3 16.6
: }2 y& }+ {! I; v50.4 4.0 X 5.0 20.0- Q* p5 \7 M" m$ y
22.0 4.5 X 4.0 25.0
% a! R- m- m/ c4 U8 p; ?+ B84.6 4.0 X 4.5 11.1. w" S' x. D, V4 I" \- r
85.9 4.5 X 5.5 9.0
! p8 T3 F( u$ e& A0 |Av. 14.3
' p: w! m6 I* }4
& \0 Y1 p% {& `" _5 h8
5 {# u L3 d% R104 L/ r' z3 V8 t7 P: e# u9 H
120 ?1 S+ o5 m r# X3 y# ]
17
# D+ }7 [# f$ s9 }/ L3 U" mTopical testosterone
$ \! s! ]; t1 A! i2 U34.6 4.5 X 6.5 85
& i& S% t. U, x$ G38.8 6.0 X 8.5 70
! a1 H6 Y W; O5 y( r40.0 6.0 X 6.5 62.55 M( E0 w! R- A# ]* Q! g: ]$ P
93.6 6.0 X 7.0 55.5) a+ T& Z3 g! k- L* S
95.0 6.5 X 7.0 27.2& Y+ Z2 y) k. @ B0 k$ x- b/ l q
Av. 60.0, n2 }+ g4 M' T# t' w" b+ g
available testosterone. Again, emphasis should be placed on
! n' S1 _5 C5 @' q' Q8 Kearly therapy when lower levels of testosterone appear to
! i! l0 L1 [8 Zprovide the best responses. The earlier therapy is instituted
$ {& t; Z( P& }5 y0 {the more likely there will be an excellent response with low1 Z( A8 D, X6 J+ u# B9 m! V
serum levels. Response occurs throughout adolescence as
& g9 f- E* D3 znoted in nomograms of phallic growth. 7 The actual response
& e0 M6 a, H/ a1 D6 S8 i3 Ato a given serum level of testosterone is much greater at birth5 F3 r! M% A$ j! w) b( ]) ]9 |
and gradually decreases as boys reach puberty. This is most
' x1 o+ Z% Z- {likely related to the conversion of testosterone to dihydrotes-
7 e% |1 r: g5 L7 E! e5 ?8 atosterone and correlates well with the studies of testosterone* w) F' b2 _0 C8 ?2 B% D
conversion in foreskin at various ages.- ~, l/ e/ W* v% I% l
The question arises regarding early treatment as to whether
+ b" w9 R4 d$ F, E2 b- T! F$ rone might sacrifice ultimate potential growth as with acceler-
5 W7 M" o3 k4 @) K4 |ated bone growth. The situation appears quite the reverse
' @/ b r, d' T8 \0 hwith phallic response. If the early growth period is not used
) q. }) R0 e6 P( @" K) y5 dwhen 5a reductase activity is greatest then potential growth
( S- R3 v2 ?+ n( t+ i: Jmay be lost. We have not observed any regression of growth2 C; W# G8 s" z1 s8 `/ t0 n
attained with topical or gonadotropin therapy. It may well
( d6 Y x9 t$ R, P6 O/ j _/ cbe that some patients will show little or no response to any
8 E( b. Q) `. M0 ~% v( t6 ^form of therapy. This would suggest a defect in the ability to
& R3 }: ^) o& h" t* O0 `# U, fconvert testosterone to dihydrotestosterone and indicate that
4 W. ?* l% n) K! zphallic and peripheral skin, and subcutaneous tissue should5 Z z' K# e( \0 k9 |% H
be compared for 5a reductase activity.2 ?5 r/ A5 @% @: z& X4 E+ `
A, loop enlarges to measure penile girth in millimeters. B,
4 l( }) h5 U% _2 F5 H( B; A- v% kexample of penile girth computed easily and accurately.+ t$ J9 c5 f2 x: `+ ^1 h4 }/ D4 h
conversion of testosterone to dihydrotestosterone. It is in this
1 z% B* z4 D- x) T- y6 d# {older group that others have noted high levels of serum
( N1 S, u' S( Q% r, B+ Utestosterone with topical application. It would also appear/ w, q; t. h: S0 [5 ]
that phallic response during puberty is related directly to the
+ H+ |2 z/ j0 Gserum testosterone level. There also is other evidence of local0 T8 S# [9 Q1 l# g% u
response to testosterone with hair growth and with spermato-
2 \1 a# J) \7 y2 O9 y; jgenesis. 5• 6
/ y1 W5 E# e3 w; Q) Q# ?* VAdministration of larger doses of gonadotropin or systemic. @* W- E' o0 @0 o# d0 M7 S+ j
testosterone, as well as topical applications that produce
) G Q2 i+ ^0 S, khigher levels of serum testosterone (150 to 900 ng./dl.), will
; r% |5 W* _% d( P' Malso produce phallic growth but risks accelerated skeletal
) j9 v! Z6 r8 p/ G* [2 b6 Z/ k1 Dmaturation even after stopping treatment. It would appear
8 Q9 Q" S5 I; q6 u: O# Bthat this may be avoided by topical applications of testosterone
0 T% m+ c3 P5 ^7 wand monitoring of serum testosterone. Even with this control1 e% L6 E2 }$ T
the duration of our therapy did not exceed 3 weeks at any/ Q' c& i; B& I2 N) q
time. It is apparent that the prepuberal male subject may
* Q2 F' X& Q6 Y5 Osuffer accelerated bone growth with testosterone levels near/ D! N; U1 i; i/ R# \6 g
200 ng./dl. When skeletal maturation is complete the level of0 @) T9 L' I$ _% u; z2 z) r, q
serum testosterone can be maintained in the 700 to 1,300 ng./( ^# H# _+ E5 D3 b8 P- N. T
dl. range to stimulate phallic growth and secondary sexual% x8 J/ p. D( X
changes. Therefore, after skeletal maturation parenteral tes-
) @; s3 {4 J$ ntosterone may be used to advantage. Before skeletal matura-
2 w& R" N/ r6 Z/ e L0 ition care must be taken to avoid maintaining levels of serum
5 q1 b9 ^9 ^+ a+ J+ D3 j7 ntestosterone more than 100 ng./dl. Low-dose gonadotropin- O# i: W' @8 |$ t/ n
depends upon intrinsic testicular activity and may require
4 e0 U& ?$ R1 {: F! ^) \4 Lprolonged administration for any response.
) \0 T: z0 R7 ?+ |' gAlternately, topical testosterone does not depend upon tes-& v0 \! T Q' b9 C2 y: i( g
ticular function and may provide a more constant level of% B& J! p" @" A3 O7 {
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1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,: I1 N4 N1 r' h+ D' }
R.: The local application of testosterone cream to the prepub-1 ?3 g6 p; h2 m+ b
ertal phallus. J. Urol., 105: 905, 1971.5 G1 b1 k1 O/ y9 }3 o, P" O
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone5 b V0 O: ~9 F5 }/ e; U, o
treatment for micropenis during early childhood. J. Pediat.,
5 H& p" C4 q6 [( c8 x$ v83: 247, 1973.: s7 R* u7 {: q
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-3 u. [& {( q) U) s6 e
one therapy for penile growth. Urology, 6: 708, 1975.
8 k" j4 _, w; Q2 q' O3 u: U% Z2 J/ P4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
% _7 l# h- A+ y$ }- E3 kto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
! K; v0 Q7 q0 o3 `; V O# tskin slices of man. J. Clin. Invest., 48: 371, 1969.4 ]- w, I* ?5 H; w5 t! B, F C. X
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
( P" j5 @! n5 `, z1 Xby topical application of androgens. J.A.M.A., 191: 521, 1965.
7 O) n- e7 {( j. B6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
9 O# V& D8 Q0 N( jandrogenic effect of interstitial cell tumor of the testis. J.; w" W/ ?5 g' U) x9 |- X# d
Urol., 104: 774, 1970.
6 B! v( L$ o& H0 j7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-$ d) r/ |$ r4 u; l% H1 _
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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