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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
: @1 `7 Y% E `/ \+ kGONADOTROPIN
6 A# W$ R0 Q: F' m7 R4 ^# D1 D, bRICHARD C. KLUGO* AND JOSEPH C. CERNY) n# b$ z7 g$ B- ^
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
4 t) I7 A+ a5 {ABSTRACT; U' R7 x) B. y) O: Z3 ~9 w: D1 o
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
, F/ r& C: T7 d, U8 dwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
* x# `) b* K2 C! c! S( K3 d5 x/ i0 V$ utropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone2 s- x/ a3 ~1 @; @) y
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent2 U; g4 R9 P# Q }8 f" b3 g" y
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent3 I0 G6 [6 K6 C( ~: l) l5 x1 k
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average$ X" L) \4 c) Z8 V: N
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
4 S' I) F1 N* k4 k: Xoccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This( f$ ]( s F9 H* T2 V( B9 w& J
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile9 y9 N2 R! @$ ?+ Y" `
growth. The response appears to be greater in younger children, which is consistent with previ-
$ X p+ K; o% r$ T l+ Fously published studies of age-related 5 reductase activity.
" C( H: `6 z6 g) f2 ^( cChildren with microphallus regardless of its etiology will
6 Y8 }9 J8 u! k# Lrequire augmentation or consideration for alteration of exter-
$ N/ q4 ?% c. Y, d( znal genitalia. In many instances urethroplasty for hypo-8 x( K( R3 }, S2 ?
spadias is easier with previous stimulation of phallic growth.* w E$ I# O, ?+ c
The use of testosterone administered parenterally or topically( R- u7 \: |8 l5 o3 m& d8 f) h9 P8 q
has produced effective phallic growth. 1- 3 The mechanism of! W! b @5 d* v' N5 J
response has been considered as local or systemic. With this8 V0 \2 D% R' }! x& s
in mind we studied 5 children with microphallus for response7 K3 c1 z' u2 N5 g: V" y) {5 e
to gonadotropin and to topical testosterone independently.' W c& b. ~1 U3 v7 d4 {
MATERIALS AND METHODS
& n. s! Q! \. w$ }& l/ A* ^Five 46 XY male subjects between 3 and 17 years old were
) Z3 N4 \3 m5 c0 m( Revaluated for serum testosterone levels and hypothalamic
D5 v' q3 H) O6 d2 @; Gfunction. Of these 5 boys 2 were considered to have Kallmann's
6 X8 Q, j& N a) [syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-0 |' z4 n4 H% {& u2 c( n
lamic deficiency. After evaluation of response to luteinizing% W! x) a+ y* d- G( {+ G3 O
hormone-releasing hormone these patients were treated with1 @. H% x2 D# Q$ `7 q' P5 a
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
/ k4 M+ g0 G: o5 v0 A2 e, L! e; zafter completion of gonadotropin therapy 10 per cent topical- L) W: G- k8 q5 n2 ]
testosterone was applied to the phallus twice daily for 3 weeks.8 r. Z5 A* C L7 O5 [" d0 V; n
Serum testosterone, luteinizing hormone and follicle-stimulat-
4 i' T) _7 n+ f7 K( I: Ring hormone were monitored before, during and after comple-+ M& B* x/ l0 o( w4 Z* r, m; [+ k; [5 c
tion of each phase of therapy. Penile stretch length was) |9 J# t- h2 U5 P1 c0 h
obtained by measuring from the symphysis pubis to the tip of8 {. R L6 F5 t1 B
the glans. Penile circumferential (girth) measurements were
3 F# P, x* A' ^/ P! Z% Pobtained using an orthopedic digital measuring device (see* g% V$ c1 M* F' U$ c
figure).
- p& ~0 V7 p+ c: F( T9 f8 s0 }RESULTS1 m" z$ Y* g# O! y3 r
Serum testosterone increased moderately to levels between
1 b% ^; R% ?5 \5 x50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
0 e6 I. v# h) \- J1 D4 u' n5 Vterone levels with topical testosterone remained near pre-* I% U. V0 F/ ^) Z! _
treatment levels (35 ng./dl.) or were elevated to similar levels
. y9 i9 F* S6 P8 _+ K, ddeveloped after gonadotropin therapy (96 ng./dl.). Higher
* A2 y( Q2 t; S$ W# Wserum levels were noted in older patients (12 and 17 years old),8 e6 M' B& o2 @- ?1 n+ G5 b
while lower levels persisted in younger patients (4, 8, and 10% g& A& S8 o0 V
years old) (see table). Despite absence of profound alterations( k ~7 v4 Z( |* ?/ H1 G' P
of serum testosterone the topical therapy provided a greater
% f4 V3 b5 p& I3 ?3 JAccepted for publication July 1, 1977. ·
! Q0 J7 ?# R5 H, t) w2 L: wRead at annual meeting of American Urological Association,
" _( O) A$ h0 b. c0 hChicago, Illinois, April 24-28, 1977.6 H! X* W1 D, I9 b+ A
* Requests for reprints: Division of Urology, Henry Ford Hospital,7 m5 b" @& R, W! T: q- H
2799 W. Grand Blvd., Detroit, Michigan 48202.; ^6 l3 x0 U0 V* z# b+ l. O. f/ y
improvement in phallic growth compared to gonadotropin.5 |% t1 Y/ a6 t0 M, u: b" v4 v `
Average phallic growth with gonadotropin was 14.3 per cent, H# c; Q# w3 r8 C
increase in length and 5.0 per cent increase of girth. Topical- K! ~& |+ r+ N
testosterone produced a 60.0 per cent increase of phallic length
6 w E. i1 ?" _3 s7 Iand 52.9 per cent increase of girth (circumference). The3 L$ ^2 P# K, I2 ^
response to topical testosterone was greatest in children be-
. w$ R- o V( z! T) R! Htween 4 and 8 years old, with a gradual decrease to age 17- v8 v) i/ e7 {8 I
years (see table).& F' U' ]$ [+ |
DISCUSSION z0 P! b4 x$ ^: c) g
Topical testosterone has been used effectively by other; ^3 ?" Z& ?, D
clinicians but its mode of action remains controversial. Im-+ G( i5 J9 ?. }/ W8 K3 V
mergut and associates reported an excellent growth response
; q& b! I# M4 d5 gto topical testosterone with low levels of serum testosterone,
7 @% _, T: X& t3 C0 U1 m# n* asuggesting a local effect.1 Others have obtained growth re-+ ^* |4 w& B. m
sponse with high. levels of serum testosterone after topical3 }8 I+ k8 D" K @" p/ g
administration, suggesting a systemic response. 3 The use of
2 H' G) g, H) z* H5 l4 G4 Lgonadotropin to obtain levels of serum testosterone compara-0 i( h h3 b& r( G3 Q6 B
ble to levels obtained with topical testosterone would seem to
3 U' y0 j) T2 G: R2 |1 V+ } F. l" ]8 N& kprovide a means to compare the relative effectiveness of
* P3 x5 v; U% B+ W' r6 X' y' h Ptopical testosterone to systemic testosterone effect. It cer-3 Z, a7 ?: z$ y& J% m) G% J
tainly has been established that gonadotropin as well as par-
9 J6 [) a: I7 t& I$ Z! \enteral testosterone administration will produce genital
3 }, H2 b5 J$ X& l2 a( ngrowth. Our report shows that the growth of the phallus was" H! D8 {8 D5 ?: M$ w
significantly greater with topical applications than with go-
+ {0 r( l5 [( s6 d, C- Hnadotropin, particularly in children less than 10 years old.! _* C( v* o# N0 i3 x% w, z
The levels of serum testosterone remained similar or lower! R9 o& z5 Y& h
than with gonadotropin during therapy, suggesting that topi-0 K" z) x& ^5 b9 k, }: i% H4 }1 n
cal application produces genital growth by its local effect as0 o6 C \# b( o, }; e: ~5 `
well as its systemic effect.
) ]# z9 Z! |; G; s! A; _Review of our patients and their growth response related to
! |' H! L8 T% h1 F3 K" s# p. ~age shows a greater growth response at an earlier age. This is8 [0 w8 [; i9 t
consistent with the findings of Wilson and Walker, who! X) i$ |) i5 N
reported an increased conversion of testosterone to dihydrotes-
. h/ \+ x% h& Gtosterone in the foreskin of neonates and infants.4 This activ-7 t& ^2 u' Z% p4 u, I
ity gradually decreases with age until puberty when it ap-
! I, O% G! O+ A" Y; \- ?proaches the same level of activity as peripheral skin. It may5 I4 t+ G% Y3 q% ?: r
well be that absorption of testosterone is less when applied at
$ \2 G( n6 o8 A1 @. t5 X f9 Kan earlier age as suggested by lower serum levels in children) e0 m7 t0 q6 [" N5 z0 K
less than 10 years old. This fact may be explained by the+ y: s0 Q8 b& a. R: K
greater ability of phallic skin to convert testosterone to dihy-) S1 l$ V% A% q" i* a( R
drotestosterone at this age. Conversely, serum levels in older
8 _/ u8 _& u- g n7 x1 m9 G9 Tpatients were higher, possibly because of decreased local
; d2 `, B5 v' S7 I e' X+ ]. [667
# X8 x* B& d& N668 KLUGO AND CERNY
8 r1 o& o3 ^ E+ D( R5 P2 R7 u! SPt. Age- x& {# [& O# Q3 A7 k m
(yrs.)
: v9 z* O/ |& P f; P6 PSerum Testosterone Phallus (cm.) Change Length, s% R7 ]: h0 o6 L; F) ^
(ng./dl.) Girth x Length (%)
, U h9 S* y$ h! Z0 H5 y, q4% Y1 @0 ]3 P, ^! l" B1 g
8
- @5 w4 @1 R* N% ^108 G% b9 r# e1 Y/ Q
12
8 w9 F/ |# `, `) ^1 r; N' H17" [( p" E0 T( z& U5 `- V) T) g/ S
Gonadotropin( q" K( F/ _8 Q; H) [; K
71.6 2.0 X 3 16.6
- g/ J+ A R1 {+ x50.4 4.0 X 5.0 20.0$ r5 J8 n4 y6 y, g( K r3 g
22.0 4.5 X 4.0 25.0- f$ e, z1 l* Z2 O$ n
84.6 4.0 X 4.5 11.19 z9 t1 M3 X" W
85.9 4.5 X 5.5 9.0
. N' `9 d7 d5 _0 W! S9 L: u ^Av. 14.3& s7 ?0 T, F, W8 s2 v) l
4
, S; V5 H7 \; b- p9 T( m5 g8
% c$ U& V: i- A6 O ]: j$ \10/ s7 _5 m* o7 i: ^7 j
128 e" E/ y: `" w" I# M1 A
17
9 R( Y; O1 C$ rTopical testosterone0 [. ]; C( a, u- u/ Y# e3 F5 O
34.6 4.5 X 6.5 85
% H+ X9 [6 M4 E& w, j. C38.8 6.0 X 8.5 70
* N3 m# e: h0 E$ r40.0 6.0 X 6.5 62.57 [& v9 Q" V% D$ ]! s0 D
93.6 6.0 X 7.0 55.5
7 B2 p6 b( l0 d6 Q3 \2 w2 T95.0 6.5 X 7.0 27.2
, `! W- E+ q- A. `- YAv. 60.0
- F( z! [3 N# m$ K" e5 q |available testosterone. Again, emphasis should be placed on
7 [: C0 G) F' x' xearly therapy when lower levels of testosterone appear to
* O& e( W, U' I5 n9 C0 Kprovide the best responses. The earlier therapy is instituted, N; M1 O! B% m. _+ `+ Y& t9 W2 n# a
the more likely there will be an excellent response with low# t, K; j- m ^. c! T7 ?
serum levels. Response occurs throughout adolescence as* p2 |7 g2 U5 z7 H1 b) [+ }! M- ~
noted in nomograms of phallic growth. 7 The actual response
" Z2 J( ~+ U6 |to a given serum level of testosterone is much greater at birth c# A) t! P! c2 B. W$ y! j* Y
and gradually decreases as boys reach puberty. This is most: X3 W' i9 b! j5 I5 p! m$ O
likely related to the conversion of testosterone to dihydrotes-
' n5 w5 ~" g7 C1 b' }2 g5 Ytosterone and correlates well with the studies of testosterone2 x, D% I x* t7 y* m( T) F! g
conversion in foreskin at various ages.+ F3 `1 O) j# r: q
The question arises regarding early treatment as to whether; a g5 e7 _! w. Q
one might sacrifice ultimate potential growth as with acceler-5 b4 ] l" }# o7 t9 M1 T( X- b
ated bone growth. The situation appears quite the reverse
- L& X/ V& v( W: Z8 d4 j. @% t, }with phallic response. If the early growth period is not used
1 x2 l1 H0 h4 kwhen 5a reductase activity is greatest then potential growth
7 S, u6 F% a$ G+ Omay be lost. We have not observed any regression of growth# L$ ^/ z' R, s1 t& }1 C0 @
attained with topical or gonadotropin therapy. It may well7 x: B7 |0 }8 I% g
be that some patients will show little or no response to any
" h4 ]1 `7 Z3 A! s! V) m. ?! x" ^form of therapy. This would suggest a defect in the ability to
- C( |% {& N9 G) y$ Pconvert testosterone to dihydrotestosterone and indicate that
+ m5 B) Y# t, K, n; xphallic and peripheral skin, and subcutaneous tissue should2 G' q( a8 v- z$ l
be compared for 5a reductase activity.
6 F! W: c, a7 p( dA, loop enlarges to measure penile girth in millimeters. B,3 U2 w$ d$ l9 g( h6 i7 {/ J
example of penile girth computed easily and accurately.: r8 `* J9 i! g' D
conversion of testosterone to dihydrotestosterone. It is in this
0 W/ `# e) u. B B; p6 qolder group that others have noted high levels of serum
6 L6 O6 ]- v: Y4 z& ]# g8 Btestosterone with topical application. It would also appear
% e) u: h! i9 H: Q; \that phallic response during puberty is related directly to the
. K! C# v# j. I3 r0 W, `3 d% ~serum testosterone level. There also is other evidence of local
% p! w" F, Y8 X# @0 a$ Fresponse to testosterone with hair growth and with spermato-
1 A) [* P* r/ ]+ R$ ]; b5 Tgenesis. 5• 6
8 ]" Z9 G0 x" j* y0 x# C9 uAdministration of larger doses of gonadotropin or systemic6 y$ |( C' r& [
testosterone, as well as topical applications that produce: a4 z5 {! M0 P6 g `; F
higher levels of serum testosterone (150 to 900 ng./dl.), will
* A# G3 W; s/ b6 h A8 aalso produce phallic growth but risks accelerated skeletal8 L5 S6 E& W' s# C( q0 P; k: e
maturation even after stopping treatment. It would appear
. }3 U( l- N; m# qthat this may be avoided by topical applications of testosterone5 f: S6 x; _/ L
and monitoring of serum testosterone. Even with this control4 g& X, a# X' |! G5 B6 |
the duration of our therapy did not exceed 3 weeks at any4 I4 B4 I9 w" N& X; L: P* O$ V
time. It is apparent that the prepuberal male subject may% q& w! \* H$ B
suffer accelerated bone growth with testosterone levels near* C; m( C" r4 C$ P
200 ng./dl. When skeletal maturation is complete the level of
# D: G; q4 B. K1 K% @. Eserum testosterone can be maintained in the 700 to 1,300 ng./
& R* B: o9 _) }2 E# Idl. range to stimulate phallic growth and secondary sexual
7 U) @8 U9 W9 X8 d! x% F2 qchanges. Therefore, after skeletal maturation parenteral tes-6 A( ^6 {6 s% _& e0 n% D. E1 m
tosterone may be used to advantage. Before skeletal matura-8 ~: d# Z& [: Z
tion care must be taken to avoid maintaining levels of serum
1 ?* O- k; R3 otestosterone more than 100 ng./dl. Low-dose gonadotropin
$ P6 p% D) F' m2 o" @/ Qdepends upon intrinsic testicular activity and may require
/ Q; U- v" G9 Q2 |/ h6 qprolonged administration for any response.
' O! b; f5 b/ m8 @& z8 QAlternately, topical testosterone does not depend upon tes-
+ G, A' V5 m2 T* I5 Z$ n Lticular function and may provide a more constant level of m- X4 A; V0 ?( |1 ^% K( y6 n/ g# G/ P
REFERENCES
+ {& z6 q3 [0 K1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,1 ^ x1 x* l( Z+ L; u+ Z9 {; J+ O
R.: The local application of testosterone cream to the prepub-
$ |1 d" K6 C/ iertal phallus. J. Urol., 105: 905, 1971.
& y, s J$ V. O. s& U, r2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone3 k2 F9 r" ]* I i% v+ G, B# X
treatment for micropenis during early childhood. J. Pediat.," E6 a" m" @& Y. L0 W7 p
83: 247, 1973.% L5 C6 F& m- j, T1 P5 f- D( M
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
: Q4 \( H1 f9 [1 m" R, R9 Wone therapy for penile growth. Urology, 6: 708, 1975.& {4 x9 s; |! X X' W
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone+ ]& ^! E, s m; ?2 V
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
9 w, Y; z; t+ Z3 y! Y" P& eskin slices of man. J. Clin. Invest., 48: 371, 1969.
: H+ ]( D+ O1 m, ]5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth5 s* ~; }+ w# F( [8 T
by topical application of androgens. J.A.M.A., 191: 521, 1965.* u! _7 S4 ]1 u" |% ~6 r
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local+ C' ~4 J& V, m
androgenic effect of interstitial cell tumor of the testis. J.: S) ?2 u6 M- A! m- ] [
Urol., 104: 774, 1970.5 y, }) S A6 X- B
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
( K- C. ~9 V( R8 x# [; k6 p% Qtion in the male genitalia from birth to maturity. J. Urol., 48: |
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