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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
! y) q- A7 D& Y5 s. z3 UGONADOTROPIN, ~& O& h$ b5 [7 C
RICHARD C. KLUGO* AND JOSEPH C. CERNY
0 I4 u# H. l4 X& r, LFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
' `5 @! C6 H2 Q6 C$ B: h' m5 }ABSTRACT
2 v; u; ?* S+ O2 P* N& ^& B3 fFive patients were treated with gonadotropin and topical testosterone for micropenis associated
4 h0 [9 J l, pwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-' I: P. }, {0 B8 R5 r+ Q
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
, A' j% U/ B# P r1 A- tcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent+ d( D* h4 g( `3 h& F U# t
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
7 E2 N; {0 {" yincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average4 \, ?" r, K( Z
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response7 u6 R5 l7 n4 J) a5 l+ g
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This- R" ~& i4 H8 z7 j/ f% C2 z
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
+ I: k1 Y2 T8 r" v8 k3 X' l" cgrowth. The response appears to be greater in younger children, which is consistent with previ-6 r6 l- ~) H0 n: e
ously published studies of age-related 5 reductase activity.4 b0 i: h% w) i: `# P. E
Children with microphallus regardless of its etiology will
% q- M) _8 t, |) n2 A- crequire augmentation or consideration for alteration of exter-
$ R' h* Z# e2 j7 B# t4 Y! {# tnal genitalia. In many instances urethroplasty for hypo-' z0 X# s& c4 C( w2 R0 `
spadias is easier with previous stimulation of phallic growth.4 |! e# }& u% V
The use of testosterone administered parenterally or topically6 y1 ]- @* }# g3 T1 Q# i; h
has produced effective phallic growth. 1- 3 The mechanism of
, v9 w6 |) d% @; Kresponse has been considered as local or systemic. With this& y2 O2 m _$ A$ m$ q
in mind we studied 5 children with microphallus for response6 W3 Q* v+ D, r7 F4 ?) R
to gonadotropin and to topical testosterone independently.
8 v" C1 ~0 {9 t( |MATERIALS AND METHODS
6 N( ~$ F* L( a& p5 f' B XFive 46 XY male subjects between 3 and 17 years old were
' a7 o/ c- y f; U `$ A0 Vevaluated for serum testosterone levels and hypothalamic' }# d) w: C$ U1 w: i) u/ s3 ~
function. Of these 5 boys 2 were considered to have Kallmann's
( b$ F5 | I; e! p. i+ R3 I# Bsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-/ f X: ~: b6 G" Z. m
lamic deficiency. After evaluation of response to luteinizing) n9 |2 ^& y6 Z0 H4 c
hormone-releasing hormone these patients were treated with
# F: ] W& R) } \8 J1,000 units of gonadotropin weekly for 3 weeks. Six weeks% r) s @+ j8 m. F D& C
after completion of gonadotropin therapy 10 per cent topical
+ J7 f" Q4 H$ n, b5 W1 @" a2 w& G# K: Ktestosterone was applied to the phallus twice daily for 3 weeks.
0 v# m& }0 d- r" p# n# }0 x W; ?Serum testosterone, luteinizing hormone and follicle-stimulat-
. W! B- \ n# }7 N' aing hormone were monitored before, during and after comple-
* n2 `' p6 ~6 d9 K( S* \" ytion of each phase of therapy. Penile stretch length was
Y, J9 y) P( U' p- Mobtained by measuring from the symphysis pubis to the tip of; J7 _+ L# l- c$ A" z( e
the glans. Penile circumferential (girth) measurements were0 @0 q0 z; z+ g2 o( |; a
obtained using an orthopedic digital measuring device (see6 ^/ b9 x/ R$ m/ O: H7 v) c# n
figure).
1 G0 O0 m6 A* @; A, M$ t$ ?4 hRESULTS
K# z. L9 P5 Y3 ISerum testosterone increased moderately to levels between
) Z ~, g4 ~ ^+ P/ n/ f) M3 g50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-- E( u2 ~( f. A' L
terone levels with topical testosterone remained near pre-; K+ s8 N, _% s
treatment levels (35 ng./dl.) or were elevated to similar levels
4 q0 [: }5 d/ U9 f( Edeveloped after gonadotropin therapy (96 ng./dl.). Higher
+ ~: @0 r( k% B. ~9 Dserum levels were noted in older patients (12 and 17 years old),: p# h; |: k! G
while lower levels persisted in younger patients (4, 8, and 10
& X- w4 `6 O8 v' A( Cyears old) (see table). Despite absence of profound alterations! C2 R2 k- H+ ^4 k, Q- I2 [
of serum testosterone the topical therapy provided a greater# J2 ^, M4 e/ K2 t3 _4 s; c
Accepted for publication July 1, 1977. ·
( B: ~, C r& s7 p. ZRead at annual meeting of American Urological Association,
* Z+ Q# a. H" n7 ~" D0 H3 lChicago, Illinois, April 24-28, 1977.
) u6 l4 H2 ], y8 v( L! ]* Requests for reprints: Division of Urology, Henry Ford Hospital,9 Q3 ^9 z; S9 `/ h# @1 H& h7 e1 o( X
2799 W. Grand Blvd., Detroit, Michigan 48202.5 e0 f$ {' Y# N+ u
improvement in phallic growth compared to gonadotropin.9 B! j& r$ B4 L7 e5 G/ z2 }; L
Average phallic growth with gonadotropin was 14.3 per cent
) D2 E' m# C+ B* ^9 {/ Mincrease in length and 5.0 per cent increase of girth. Topical
; M) |& v: Q+ ^+ M* z- jtestosterone produced a 60.0 per cent increase of phallic length' j' a3 _6 h v0 C5 Y$ F: T' h7 P: A
and 52.9 per cent increase of girth (circumference). The
7 I8 A5 g" W+ }% X! {/ q7 Tresponse to topical testosterone was greatest in children be-
2 M2 r7 d7 R G1 t R1 S; }& Ptween 4 and 8 years old, with a gradual decrease to age 171 i- Q; T) [: v0 @
years (see table).& R1 n: l3 z' [7 a* \
DISCUSSION- S- S; h- t. ^7 S" Z
Topical testosterone has been used effectively by other
/ _; H+ V% t6 V( l6 lclinicians but its mode of action remains controversial. Im-9 k% D' l9 J7 z) s e3 z8 G
mergut and associates reported an excellent growth response
- K2 S7 h. ]+ y" p; tto topical testosterone with low levels of serum testosterone,! h8 J8 p& |9 F; {
suggesting a local effect.1 Others have obtained growth re-- c& A" s3 j( ^2 V( i
sponse with high. levels of serum testosterone after topical
+ w( `5 J+ v3 T+ k+ A Gadministration, suggesting a systemic response. 3 The use of8 a9 _* `! z) `" J# @
gonadotropin to obtain levels of serum testosterone compara-9 r1 h- {5 C8 x* E. l
ble to levels obtained with topical testosterone would seem to
* ]3 |* E; ?; A4 F; Mprovide a means to compare the relative effectiveness of1 \5 z% X4 C+ j" `4 Z6 X
topical testosterone to systemic testosterone effect. It cer-
6 D: K; m/ s4 c9 ltainly has been established that gonadotropin as well as par-
- b8 w, o' `8 J6 t' p: n Henteral testosterone administration will produce genital
9 }# Z, E( v, i9 p( O" Ggrowth. Our report shows that the growth of the phallus was5 _4 L) q+ @8 Z6 X9 _2 \
significantly greater with topical applications than with go-
4 z/ J; N3 c% K4 }nadotropin, particularly in children less than 10 years old.
) _$ f" O& n/ l b9 r8 qThe levels of serum testosterone remained similar or lower7 ]/ U; v2 r; }1 o* ?. }6 w
than with gonadotropin during therapy, suggesting that topi-
: d- O9 t; V6 c- `7 fcal application produces genital growth by its local effect as" |5 \% R) v. v; R
well as its systemic effect.# n: V5 H; L3 _( s! h/ p% F9 \
Review of our patients and their growth response related to% ~) K$ p/ T8 G) B: I
age shows a greater growth response at an earlier age. This is3 m, P) R0 e0 b1 _
consistent with the findings of Wilson and Walker, who' K! i8 ?6 }/ a( h* [' ~
reported an increased conversion of testosterone to dihydrotes-1 i5 N2 u( t$ g4 p$ X7 S3 F
tosterone in the foreskin of neonates and infants.4 This activ-
2 f: z* g Z6 R' T- m7 j2 y2 Q! _ y# tity gradually decreases with age until puberty when it ap-
' e! X' w- R6 T0 E+ x! Nproaches the same level of activity as peripheral skin. It may
/ V0 s& e$ ]4 zwell be that absorption of testosterone is less when applied at- H5 b, e8 z* m" O! }# B6 Z" q; o
an earlier age as suggested by lower serum levels in children! b; n7 f( {. N0 E$ K8 S w
less than 10 years old. This fact may be explained by the% T( K4 `6 F3 G0 L
greater ability of phallic skin to convert testosterone to dihy- G- A# [2 Y4 ^
drotestosterone at this age. Conversely, serum levels in older, U( Y) `* L6 \) V4 m7 I0 P& I
patients were higher, possibly because of decreased local8 [. g/ I* s* c5 a
667; ^8 z3 r6 X$ u. y6 K4 f% Z. s
668 KLUGO AND CERNY
9 r2 W7 n5 V/ [5 ?Pt. Age4 z8 `$ T( k) I* q9 P
(yrs.)1 x0 y: M5 l( N
Serum Testosterone Phallus (cm.) Change Length8 Y; R0 M1 s- j \
(ng./dl.) Girth x Length (%)
6 i$ w2 @7 Q0 F. w% c& t% w$ b4
+ J0 n1 Y4 _; u! h8 ~8. Z: f8 {2 _+ J7 C3 p' Z2 A
10
% ?4 N9 ]* M: s, b5 D12
- G, C% k( g; `. |& r; x8 b17: j ~+ O, x2 b" E
Gonadotropin1 N4 v/ r6 V" ^$ E
71.6 2.0 X 3 16.6# `' a- G# [" n G H
50.4 4.0 X 5.0 20.0" k4 A( y0 M, }4 j9 `- W
22.0 4.5 X 4.0 25.0
1 t# G4 E5 \. H& m$ a84.6 4.0 X 4.5 11.10 P: l P7 M" A
85.9 4.5 X 5.5 9.04 f3 Z& x! f; f( f' O: p4 \. E
Av. 14.3! G H$ P; o9 L) O- v5 @4 ]
4' w4 I) r' v& g' ?2 k5 c. W
8/ ~& \( R: r* k3 x) C
10
0 w O; z @0 F) Q; L6 t12+ ]8 G: n/ S" i1 b) z5 j
17
8 Y" c) Y) P6 T2 b' hTopical testosterone- |3 Z- j5 J" }
34.6 4.5 X 6.5 85
* y! L2 X& B( b; N38.8 6.0 X 8.5 70
& k! c- G9 A6 n, w# v40.0 6.0 X 6.5 62.54 ?& W. Y* U- {( o
93.6 6.0 X 7.0 55.5) ]% y: y' i8 v- k& [
95.0 6.5 X 7.0 27.2
# X7 V$ e" W' SAv. 60.0. q5 `8 H- t" c( s" J3 R
available testosterone. Again, emphasis should be placed on
( X* n2 N" O1 E4 [5 Mearly therapy when lower levels of testosterone appear to/ @1 t7 `# a) {8 M7 h: M+ Z i
provide the best responses. The earlier therapy is instituted
3 E/ S) w$ @, rthe more likely there will be an excellent response with low
1 n- \1 o, n* @% Yserum levels. Response occurs throughout adolescence as
. X) E0 i' ~- D$ d0 A+ Dnoted in nomograms of phallic growth. 7 The actual response
/ a/ M1 H% k( ~ n% t+ M7 B8 }0 uto a given serum level of testosterone is much greater at birth! V9 X& ^& K% E' m/ t; E
and gradually decreases as boys reach puberty. This is most: t( D: Q) F2 c( |: F
likely related to the conversion of testosterone to dihydrotes-0 @5 N) A- f: ^ G6 L+ h2 n
tosterone and correlates well with the studies of testosterone! K" L# v+ D7 r d# T3 A+ y
conversion in foreskin at various ages.' Z. `2 F& S! _& ]& i& L7 p( O
The question arises regarding early treatment as to whether4 z& n" ^; P/ ~; O2 ^! c; x
one might sacrifice ultimate potential growth as with acceler-5 P6 ]% I) B& p2 D3 y
ated bone growth. The situation appears quite the reverse
6 T+ y1 P8 B/ e, v% r2 Uwith phallic response. If the early growth period is not used
9 h& F" h) ~4 r" e( U( }, X$ dwhen 5a reductase activity is greatest then potential growth. W6 |% L1 o& _" |# Q3 P
may be lost. We have not observed any regression of growth
1 [7 D. q/ ^' N' j) {4 P6 nattained with topical or gonadotropin therapy. It may well
0 [) P0 t+ ^' G' i' b _% t b- Abe that some patients will show little or no response to any. A' g* r/ I! ~* G7 i( L
form of therapy. This would suggest a defect in the ability to: l$ z$ u0 _2 o$ J: Q7 {& C0 k
convert testosterone to dihydrotestosterone and indicate that
* c& c2 e" R/ m2 d9 w! e; O% d. Yphallic and peripheral skin, and subcutaneous tissue should
% v [2 T3 I: w2 Fbe compared for 5a reductase activity.
" Y0 R+ O# p9 zA, loop enlarges to measure penile girth in millimeters. B,7 y5 x3 r3 u) m* q c
example of penile girth computed easily and accurately.
5 m5 T: ]8 y2 d1 iconversion of testosterone to dihydrotestosterone. It is in this# W4 U2 ^' l2 g9 O+ l
older group that others have noted high levels of serum
- K" A: W9 C: d6 f, {% b! Y* Ltestosterone with topical application. It would also appear
8 d2 O; f! `! n' o- h0 u' i( ethat phallic response during puberty is related directly to the
" \ H: ]/ y% Zserum testosterone level. There also is other evidence of local
: Y: p: i+ b3 vresponse to testosterone with hair growth and with spermato-0 b9 |$ A3 p: N# d6 a3 p/ r
genesis. 5• 6) m' E* ~( _. U
Administration of larger doses of gonadotropin or systemic
0 D4 W; t* o" W. N e& dtestosterone, as well as topical applications that produce
) z- @) D$ t3 h7 N1 Ghigher levels of serum testosterone (150 to 900 ng./dl.), will
% P7 `" V1 _8 a& s: Q2 L! Palso produce phallic growth but risks accelerated skeletal, o4 L2 G4 p1 A; e0 E2 j: Q) O, y
maturation even after stopping treatment. It would appear' w2 c+ ]! b. P; f2 t
that this may be avoided by topical applications of testosterone7 I% L& f% k! w5 V, D8 j1 Y; g
and monitoring of serum testosterone. Even with this control; f, Z9 _& f/ Q
the duration of our therapy did not exceed 3 weeks at any
0 H+ u" H( ^ E6 L9 B$ ?* [time. It is apparent that the prepuberal male subject may
* D; i3 D9 E. E' E# msuffer accelerated bone growth with testosterone levels near9 f) v# \* q z! o' L# M
200 ng./dl. When skeletal maturation is complete the level of
! H6 C/ B0 \* G9 c' Userum testosterone can be maintained in the 700 to 1,300 ng./2 l+ ]9 t: A Y0 L3 p9 t
dl. range to stimulate phallic growth and secondary sexual* o, V1 B# l( z. h, g! K& e( B
changes. Therefore, after skeletal maturation parenteral tes-
7 k% |2 [. r; ]7 Q8 Itosterone may be used to advantage. Before skeletal matura-
' j8 Y7 p6 O6 t# R+ O0 ?tion care must be taken to avoid maintaining levels of serum
) Z0 U9 c- H3 K h7 Ytestosterone more than 100 ng./dl. Low-dose gonadotropin" X! @- j E; [9 B8 ]
depends upon intrinsic testicular activity and may require3 R) M W& O( e1 j% [$ z9 ~
prolonged administration for any response.
+ }+ h, w1 H$ [) n# r" z5 J& mAlternately, topical testosterone does not depend upon tes-
% i0 l) }& K- d2 ]# dticular function and may provide a more constant level of+ y4 f5 |: s7 N" Y) H
REFERENCES
K9 N/ I% }8 a" o4 p$ O+ m9 L5 F1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,- c; R% S% H! i' e
R.: The local application of testosterone cream to the prepub- `0 b/ y# n G
ertal phallus. J. Urol., 105: 905, 1971.
- ]& T4 M' i* {7 I$ D0 Y2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone+ {$ ^" Q3 r4 ~7 {% K6 a7 w6 \4 n
treatment for micropenis during early childhood. J. Pediat.,
# k$ H i( i2 A; c- F83: 247, 1973.8 \; z0 ?3 Y( K* h
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
9 I) B; p" N2 ?5 Y8 F; oone therapy for penile growth. Urology, 6: 708, 1975.* N) s$ F4 H5 c0 V; E: s
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
! \+ C$ u4 y9 u: o( Q- i4 ato 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
8 W: j8 I% l0 j7 B e2 Lskin slices of man. J. Clin. Invest., 48: 371, 1969.
& ]/ t6 E7 p) f4 k8 \- b7 h" E5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
' c P- c" q; n9 L; bby topical application of androgens. J.A.M.A., 191: 521, 1965.
8 Y4 C0 I1 ~" l# U& k0 m- l7 @6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
/ s" v" u* C( v9 ]3 z- Dandrogenic effect of interstitial cell tumor of the testis. J.
' r! `- m! A* {1 SUrol., 104: 774, 1970.
# O6 H- N! U x5 p8 D7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
8 q( I9 ^- T5 `: J6 Z% ction in the male genitalia from birth to maturity. J. Urol., 48: |
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