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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND; V4 m( t" T2 T' [8 I ~) k( ^
GONADOTROPIN; Y5 ^$ R+ a4 z) P3 {: {
RICHARD C. KLUGO* AND JOSEPH C. CERNY
% H3 ^# ?' g: U" s7 ~From the Division of Urology, Henry Ford Hospital, Detroit, Michigan2 t* w! o$ z' p( \6 a; v# F8 Z
ABSTRACT0 i0 l, H; V2 |) j% d2 B" Y$ L$ j
Five patients were treated with gonadotropin and topical testosterone for micropenis associated6 ^/ H8 u3 U8 d: r; ~0 ^
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-8 j' X+ S( K; j l% n
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
) x0 A, {* Z5 ]1 A/ v! scream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent. _& ~7 X/ _4 b
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent4 i& E. C+ _; P c, M c& }
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average6 Q3 a6 @# [- C3 {6 L
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response/ ~- T3 Z. \# L& A' ~: t; x' P0 ]
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This7 H1 v% I0 T7 L5 y& c
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile1 s& \' V J/ \ w- H
growth. The response appears to be greater in younger children, which is consistent with previ-
+ w2 ]% W' N# ?7 n) h% y, m$ Yously published studies of age-related 5 reductase activity.
4 \! ]1 g R5 v1 V& eChildren with microphallus regardless of its etiology will
: `& K/ ]+ e$ P1 y; Grequire augmentation or consideration for alteration of exter-4 T) m, i; {+ T
nal genitalia. In many instances urethroplasty for hypo-7 y. W9 M4 `! R! Z8 P+ v
spadias is easier with previous stimulation of phallic growth.. e" J# L$ K9 ^( s! {- [
The use of testosterone administered parenterally or topically
$ ?5 Z9 R& [/ \$ x& i3 }( q7 Xhas produced effective phallic growth. 1- 3 The mechanism of
" B f+ P# |3 w! y3 |) w) uresponse has been considered as local or systemic. With this' {5 r' q+ L' Y5 L
in mind we studied 5 children with microphallus for response
: o7 g% j* @- B2 |9 f1 `) H; p1 kto gonadotropin and to topical testosterone independently.
" I7 j; A9 N' m% vMATERIALS AND METHODS9 W; [+ b# g) d# v
Five 46 XY male subjects between 3 and 17 years old were
2 O/ m: M5 }) eevaluated for serum testosterone levels and hypothalamic
' J2 U2 C% o! A0 p" L# f6 ?function. Of these 5 boys 2 were considered to have Kallmann's
& A% w9 x3 B9 I3 B2 E" o9 e8 @syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-# ?: a. Y% j$ A' m" A7 M
lamic deficiency. After evaluation of response to luteinizing5 ]8 s/ J3 Q5 P2 A' C% ^$ I. x- O4 l
hormone-releasing hormone these patients were treated with
H& I/ H8 W7 J1,000 units of gonadotropin weekly for 3 weeks. Six weeks9 } C( D7 `6 z7 a! {
after completion of gonadotropin therapy 10 per cent topical; ~1 j3 N, T/ c# g( w/ F. r$ B
testosterone was applied to the phallus twice daily for 3 weeks.
8 T1 t5 n' H2 FSerum testosterone, luteinizing hormone and follicle-stimulat-
2 b4 h G F' e' qing hormone were monitored before, during and after comple-
# A$ b/ N" y4 M- G; @' V3 @1 @tion of each phase of therapy. Penile stretch length was
1 `6 G- y6 k* G/ e/ `* f1 | Z9 Oobtained by measuring from the symphysis pubis to the tip of* E# e$ Y2 D8 v5 J1 M
the glans. Penile circumferential (girth) measurements were) W0 K& z7 H: Y
obtained using an orthopedic digital measuring device (see
, x; F. m6 G9 j1 H+ D! l9 I- @figure).; g3 E2 `6 o" s5 f6 F
RESULTS7 O M6 H: \0 K# b5 t
Serum testosterone increased moderately to levels between0 Q B% i- A/ f! b2 `! q. W
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
' K. t2 j6 O( `! }& d+ mterone levels with topical testosterone remained near pre-2 q/ g1 p6 ~) W
treatment levels (35 ng./dl.) or were elevated to similar levels
/ ]4 @8 `1 O. \5 E8 }# J& udeveloped after gonadotropin therapy (96 ng./dl.). Higher" P- i. W9 ]1 E% C
serum levels were noted in older patients (12 and 17 years old),
: D- J+ w7 y2 c$ i& @while lower levels persisted in younger patients (4, 8, and 10
& F4 z0 w: E# c) [; k2 Oyears old) (see table). Despite absence of profound alterations
, v* z# U6 v' Gof serum testosterone the topical therapy provided a greater
B* B m- `: {2 O3 Y' nAccepted for publication July 1, 1977. ·
' z9 \9 w0 Q+ P8 a' ERead at annual meeting of American Urological Association,
4 D! f* Z( O8 lChicago, Illinois, April 24-28, 1977.
& p2 v0 e0 m5 q+ z* T* o5 b6 ]4 O* Requests for reprints: Division of Urology, Henry Ford Hospital,/ U8 m$ n% u l( Y; G
2799 W. Grand Blvd., Detroit, Michigan 48202.+ E5 x& ]4 m7 D$ ~( g
improvement in phallic growth compared to gonadotropin.
; C8 j T q1 Z; E0 s8 KAverage phallic growth with gonadotropin was 14.3 per cent
/ h. z, J: U: _' o. s0 h6 S8 d( Lincrease in length and 5.0 per cent increase of girth. Topical
8 V! M) o5 c7 ]+ {* Ktestosterone produced a 60.0 per cent increase of phallic length
7 D8 W9 G1 f9 O* B. Y& u; A, Zand 52.9 per cent increase of girth (circumference). The% q" h9 J+ P5 v* _( a2 R0 R4 F: L9 D
response to topical testosterone was greatest in children be-/ n+ V: c: l W1 B% Q# B
tween 4 and 8 years old, with a gradual decrease to age 17, J" ^1 i) v3 \, |9 q! u
years (see table).
& U0 _/ B. y( e" j# k" e. vDISCUSSION
' I. z3 s" ~! k4 Q9 ^3 u) U" gTopical testosterone has been used effectively by other) m4 k! i* x7 C! j0 u- J& z, ] R
clinicians but its mode of action remains controversial. Im-5 z; ~3 t0 J. Y; s O, Q
mergut and associates reported an excellent growth response
1 y2 ^+ l" A( w6 Q: ~to topical testosterone with low levels of serum testosterone,' A5 j% t9 H, `4 Q& |
suggesting a local effect.1 Others have obtained growth re-
- N+ {, c- t4 j' r% Lsponse with high. levels of serum testosterone after topical6 ~6 ^6 {2 G* x
administration, suggesting a systemic response. 3 The use of
6 O' O! e1 V P( U' v3 bgonadotropin to obtain levels of serum testosterone compara-! v9 I4 \8 s" D6 B- H! a
ble to levels obtained with topical testosterone would seem to0 [$ F: m0 P& R
provide a means to compare the relative effectiveness of
. @& @% n' u' Ztopical testosterone to systemic testosterone effect. It cer-0 ^( j" A, i) Y7 ~. D8 |' ?
tainly has been established that gonadotropin as well as par-
^+ b1 `% n% N8 ?, Qenteral testosterone administration will produce genital% J" D2 X# \9 Z$ N/ ^% ^. S
growth. Our report shows that the growth of the phallus was
, L+ K6 [+ g* ksignificantly greater with topical applications than with go-
0 v9 g7 _. p- [6 \7 ?$ jnadotropin, particularly in children less than 10 years old.+ r$ Y2 i: Y5 ~6 M8 `
The levels of serum testosterone remained similar or lower; e% i4 C( P/ P) m
than with gonadotropin during therapy, suggesting that topi-0 W( |+ j( _0 S& C
cal application produces genital growth by its local effect as8 M) n3 f, f% |. v P% F
well as its systemic effect.
% `9 p; r$ F; y- JReview of our patients and their growth response related to! B8 P3 C2 l1 k4 c1 T6 ]
age shows a greater growth response at an earlier age. This is
2 f3 l2 G7 Q& y7 U! ?consistent with the findings of Wilson and Walker, who- v3 @' Q& `: C
reported an increased conversion of testosterone to dihydrotes-
0 R' C" |: a; [) k# j8 stosterone in the foreskin of neonates and infants.4 This activ-
% Z+ o/ X2 @; @2 W# R! Tity gradually decreases with age until puberty when it ap-
9 E' c% L; s2 K d$ y3 a3 h) ^- Q# Fproaches the same level of activity as peripheral skin. It may
+ y& K# S8 y; ]$ zwell be that absorption of testosterone is less when applied at
8 @# y0 t) G8 man earlier age as suggested by lower serum levels in children7 }3 I O/ l7 p8 K' \
less than 10 years old. This fact may be explained by the3 j4 e% I: f% V t
greater ability of phallic skin to convert testosterone to dihy-
% F, R x& A9 D7 }* Zdrotestosterone at this age. Conversely, serum levels in older5 _, w2 N" G2 j; Y& S3 z
patients were higher, possibly because of decreased local
& v9 T6 @. |1 r% e, w ^; b6674 L7 A/ L- h) n0 c5 \' {) T
668 KLUGO AND CERNY
3 X4 }- `2 Y3 }7 IPt. Age4 H* [& l; `, ^' e1 f
(yrs.)' u6 [6 @0 W( a6 B
Serum Testosterone Phallus (cm.) Change Length
# Z& v/ t. q* h3 z+ C4 a0 p(ng./dl.) Girth x Length (%)" t( V9 q* Q9 O! s* } V' Q9 |
4
6 X; Z( o" X5 s; h n8
! L7 q6 y/ ~/ o% u4 A5 ]103 F' Y5 n$ j6 r# X
12
. o, ^6 p3 W. U, H: R# X+ d17( N) U! z6 j) z% d; b" K+ f
Gonadotropin
8 ^: W- Z# R7 Q8 M9 ^% o; H/ w71.6 2.0 X 3 16.6 p- G: Z9 [* F
50.4 4.0 X 5.0 20.0
, Z; q7 b. ] d2 j4 z22.0 4.5 X 4.0 25.09 u7 P }+ h* f
84.6 4.0 X 4.5 11.1" q" J# U- Y2 b# `
85.9 4.5 X 5.5 9.0
( L, y/ S" s: SAv. 14.3
/ g A U) p) I9 u) r4 x/ e9 \0 m7 E
8
( L7 e% K0 ]7 x7 e10/ J1 b* B1 Y; D; x P
129 k9 t c+ \* P5 j$ ?2 w' B" i
17
" w, C& S& m( P- b5 O6 [% TTopical testosterone7 [4 t" k8 v" B5 n& e
34.6 4.5 X 6.5 85, u7 ^+ ? m$ F' A+ \
38.8 6.0 X 8.5 70$ t; q' B. y- J. S# b" S* }
40.0 6.0 X 6.5 62.5
* X; h7 ?, z) H3 N93.6 6.0 X 7.0 55.52 u) M7 _6 d: {( D y6 |
95.0 6.5 X 7.0 27.2
" n m. I2 a) a3 h6 k5 L- o: A7 nAv. 60.0* I" \. |; I+ v! n' c% A* c1 t7 l
available testosterone. Again, emphasis should be placed on& E' _1 R% K% R3 s/ _
early therapy when lower levels of testosterone appear to
( v* ~9 X% a) d v3 ]6 Iprovide the best responses. The earlier therapy is instituted6 c9 ~6 X" B: Q5 u4 ]3 x
the more likely there will be an excellent response with low0 n. Y4 C( M V+ K3 X
serum levels. Response occurs throughout adolescence as
" R; r/ u0 X5 A& D' jnoted in nomograms of phallic growth. 7 The actual response* b$ e b, t$ j. s; _) E
to a given serum level of testosterone is much greater at birth
/ a- G, f, f8 u& M! z% Rand gradually decreases as boys reach puberty. This is most
. V# T" r) x; _2 ^* Olikely related to the conversion of testosterone to dihydrotes-
0 `" u W% ~9 L, B& v1 I+ ?tosterone and correlates well with the studies of testosterone) l- w8 _# x* ~7 l# f, K5 H8 D! M- k
conversion in foreskin at various ages.* @2 L+ ]4 s8 I y, ^3 y
The question arises regarding early treatment as to whether
& l2 Y( r4 J D( C3 Q; Kone might sacrifice ultimate potential growth as with acceler-" U# h r% p+ b9 s% R# W; K
ated bone growth. The situation appears quite the reverse
5 ^/ i: i( @* g. F7 {% U0 r9 I$ Rwith phallic response. If the early growth period is not used
0 Z. |+ B/ R. j/ J; f+ Xwhen 5a reductase activity is greatest then potential growth
5 a2 o0 [1 Y- L" U/ Q7 Q0 kmay be lost. We have not observed any regression of growth
$ ] f' ?( i- Sattained with topical or gonadotropin therapy. It may well
/ {2 W: K" U( b1 cbe that some patients will show little or no response to any
/ i9 @& ?; A% p6 [form of therapy. This would suggest a defect in the ability to
. a. o5 y; e: x/ G% ^: nconvert testosterone to dihydrotestosterone and indicate that
% L5 b- V) x7 \* `0 H9 K) @phallic and peripheral skin, and subcutaneous tissue should+ H/ D: a6 ~' U: I
be compared for 5a reductase activity.
1 A% V9 p9 z1 G! tA, loop enlarges to measure penile girth in millimeters. B,
V$ j+ F. q! x& p- A1 K N# C: O9 Vexample of penile girth computed easily and accurately.1 H) K: u" P' Q7 ^0 }
conversion of testosterone to dihydrotestosterone. It is in this
' B/ o, u9 n( ^; Holder group that others have noted high levels of serum2 @4 }% [4 R& A2 c' l% s# p6 k1 U
testosterone with topical application. It would also appear, h6 x* ]; y7 `; ?7 M2 E
that phallic response during puberty is related directly to the
3 e/ X8 u4 F2 L' b' N0 Q! vserum testosterone level. There also is other evidence of local
, _: Y% \: v. q( Z$ z Yresponse to testosterone with hair growth and with spermato-/ N8 u( F7 w: F6 X* s
genesis. 5• 6
( Y" o- g$ n h( r0 x1 R% CAdministration of larger doses of gonadotropin or systemic
6 A/ @2 r: _- V% V& qtestosterone, as well as topical applications that produce2 v) c, w0 T2 P1 r/ z1 v
higher levels of serum testosterone (150 to 900 ng./dl.), will$ J1 j; I- ?6 C- R
also produce phallic growth but risks accelerated skeletal
! l6 O6 R, M Z6 s5 D) Tmaturation even after stopping treatment. It would appear
; x( E. `2 c* v* Ethat this may be avoided by topical applications of testosterone
1 t, E. N' u ?and monitoring of serum testosterone. Even with this control
4 T! r# S, }8 R& D' |/ lthe duration of our therapy did not exceed 3 weeks at any
( {- e) @4 B/ q! v) e. mtime. It is apparent that the prepuberal male subject may
6 M7 |4 i# b; X" \) ^; wsuffer accelerated bone growth with testosterone levels near
. [7 w2 u8 P) z8 X- o' ?200 ng./dl. When skeletal maturation is complete the level of5 g0 {; {7 w; n& F2 S$ z
serum testosterone can be maintained in the 700 to 1,300 ng./
9 V! z' _& r6 W! M" T# wdl. range to stimulate phallic growth and secondary sexual
* |, r7 v- }) j$ G( u1 t nchanges. Therefore, after skeletal maturation parenteral tes-& g5 C {5 u: g, H8 D- p- d8 R; K+ m
tosterone may be used to advantage. Before skeletal matura-
1 h9 t/ L# U2 a7 Ltion care must be taken to avoid maintaining levels of serum# X. x- H6 t9 J' C& g# a' Z; P
testosterone more than 100 ng./dl. Low-dose gonadotropin$ O+ ^* v7 V9 C4 p; q: I
depends upon intrinsic testicular activity and may require: c! u) X" y/ v4 f6 ?% x* k8 l0 s, B( O
prolonged administration for any response. p5 l4 G$ X3 t& G1 W) |8 }' Q1 l/ c0 p
Alternately, topical testosterone does not depend upon tes-
& R6 @. F' X/ g0 Aticular function and may provide a more constant level of
( E( f' a2 u' Z" eREFERENCES
* d$ [/ ]* @3 g& @1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,7 }2 o# |$ e9 r+ ^8 T. `' s& }
R.: The local application of testosterone cream to the prepub-% I; q5 F; P7 t) I7 V1 M
ertal phallus. J. Urol., 105: 905, 1971.
( D/ @9 x2 s% H& A2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone* A' w9 U2 g6 U; P7 V
treatment for micropenis during early childhood. J. Pediat.,- Q8 V2 U4 I; _; j$ a3 V
83: 247, 1973.8 \! m, @4 t/ u* x% l1 k
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-& G8 j3 B3 H. X R* Z$ M4 H- T# B
one therapy for penile growth. Urology, 6: 708, 1975.
# L9 B$ T& R/ w* J4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
" G) m2 e% E* H- W5 E& Eto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by5 G0 A. b* }9 K
skin slices of man. J. Clin. Invest., 48: 371, 1969.
! d' q6 T9 K$ d5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth# n. Z7 h5 @# k! Z
by topical application of androgens. J.A.M.A., 191: 521, 1965., E4 \6 m0 _: a6 L* Q" o
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local$ t7 f. v+ x# H1 |/ c# z. L# W+ f
androgenic effect of interstitial cell tumor of the testis. J.# ]- S) F( O! y) [7 h( |
Urol., 104: 774, 1970.
. f# F! }) j. @) }7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
1 x: b/ N/ l7 N# W+ Ution in the male genitalia from birth to maturity. J. Urol., 48: |
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