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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
& D* m* f5 H8 M; n3 @: I0 m) _" QGONADOTROPIN
1 {! s% r$ a N7 y4 z" W3 Q GRICHARD C. KLUGO* AND JOSEPH C. CERNY$ t+ x5 Y6 O T: B2 V; n
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
6 N' W1 V. D% x" Z( r: Y0 ]8 `ABSTRACT9 u0 _: p# d" A- J- d" }; {* r
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
6 L& S1 {2 q+ J' Y$ H8 B) Qwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
& @: q" u5 M6 ?6 Mtropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone$ B# U/ K/ t. S( W7 {. J) T( K
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent X' q% X/ ^- h
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
# S0 r- o: J) v$ p" |. Eincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average/ F) d5 j* I4 K) U% T
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
$ W. ] w% ], w% L/ K! Goccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This3 n1 P2 l& Z J$ u
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile! i. B% u% s3 P' ?
growth. The response appears to be greater in younger children, which is consistent with previ-% Z0 x! \3 [; Y- T- `, a2 H
ously published studies of age-related 5 reductase activity.
) {5 a! r3 g9 K' B6 |% H% sChildren with microphallus regardless of its etiology will& Q5 k$ ]- W7 s0 Y# N& C! [( N
require augmentation or consideration for alteration of exter-
3 E2 v1 y8 k+ Rnal genitalia. In many instances urethroplasty for hypo-
! v; t5 O* m9 o1 T0 S! w5 m" qspadias is easier with previous stimulation of phallic growth./ v' n S& `. w' j. v1 `" u; L
The use of testosterone administered parenterally or topically4 n& c8 f2 D: q; S0 ~, X4 _6 Z1 A
has produced effective phallic growth. 1- 3 The mechanism of" ~! A- ~- u: a3 K; \9 ^" U
response has been considered as local or systemic. With this
4 m; e* u5 g4 ]8 l0 V" y; Cin mind we studied 5 children with microphallus for response
: K: }# g S! S" G# Xto gonadotropin and to topical testosterone independently.
1 v: ?% S8 {9 S3 }* y' j" BMATERIALS AND METHODS) x4 K; ]# c, Z
Five 46 XY male subjects between 3 and 17 years old were* \' O' _& _- ]' u% k
evaluated for serum testosterone levels and hypothalamic
4 `+ _3 Q" R4 v( h$ M! @: \# j w6 g, ufunction. Of these 5 boys 2 were considered to have Kallmann's
+ {0 \; B3 T" G2 c$ `; F0 qsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
7 J' p8 r( m4 e( h3 f4 Llamic deficiency. After evaluation of response to luteinizing6 A. L# ]4 D& c# f- w( V
hormone-releasing hormone these patients were treated with+ _. `* }% C, R; d! f+ v
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
9 j* B& d2 w K8 jafter completion of gonadotropin therapy 10 per cent topical
% Q. W J" M, F6 f, t- dtestosterone was applied to the phallus twice daily for 3 weeks.
( l/ W& d: \- N mSerum testosterone, luteinizing hormone and follicle-stimulat-
( B0 W. V! c$ {1 Q6 L8 ?ing hormone were monitored before, during and after comple-
! C& T5 H" z+ E+ \. _tion of each phase of therapy. Penile stretch length was, t$ `5 Q' t6 C6 s# S5 B4 Q
obtained by measuring from the symphysis pubis to the tip of
% a" _! F* H( O% athe glans. Penile circumferential (girth) measurements were
& }4 t% C$ _+ P* [5 Q* Dobtained using an orthopedic digital measuring device (see5 c! R, M4 A3 l( n3 I
figure).
- O; B- o7 V! B' G8 |1 nRESULTS
" c# g0 m; _4 p: a+ P+ P" ^. USerum testosterone increased moderately to levels between
3 \6 J* I3 l( @50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
/ P- I$ u! A8 w5 \terone levels with topical testosterone remained near pre-
8 H' @$ V M& Q, r5 Q$ q" _( ltreatment levels (35 ng./dl.) or were elevated to similar levels
6 a: X/ k, r1 sdeveloped after gonadotropin therapy (96 ng./dl.). Higher9 D1 P0 ?8 u+ n) \) W
serum levels were noted in older patients (12 and 17 years old),
0 w$ [- [& T8 R% L6 H7 mwhile lower levels persisted in younger patients (4, 8, and 10
$ N6 @$ l- y4 {, _$ x! f0 vyears old) (see table). Despite absence of profound alterations! ^. N8 m. h, ^, L- {; K
of serum testosterone the topical therapy provided a greater
; I. s4 {. I! B5 uAccepted for publication July 1, 1977. ·
1 Z* o; E; g# y! Z0 q0 xRead at annual meeting of American Urological Association,
( n, i% c* g; J: N6 cChicago, Illinois, April 24-28, 1977.3 a' k% _2 Y: Y- b- \' F3 `
* Requests for reprints: Division of Urology, Henry Ford Hospital,
8 O, [! m4 \* q( D2799 W. Grand Blvd., Detroit, Michigan 48202.
) z$ Z1 G7 D# V- Jimprovement in phallic growth compared to gonadotropin.. a+ Y6 {% F3 |
Average phallic growth with gonadotropin was 14.3 per cent2 \; o4 o2 I; ?) U* e& `# y
increase in length and 5.0 per cent increase of girth. Topical
% b, q& j- I% v5 l0 X6 Atestosterone produced a 60.0 per cent increase of phallic length
5 }7 G. x1 M% G0 ?6 W- f6 cand 52.9 per cent increase of girth (circumference). The
6 {2 S( f8 H6 H2 `3 Oresponse to topical testosterone was greatest in children be-
$ ]) H. L4 C! h. _- l- U* ?" Q# _tween 4 and 8 years old, with a gradual decrease to age 17
% W! g2 I$ f6 }( u9 f( g6 ^years (see table).
7 `( h, m; V8 V9 D0 v6 f4 S& xDISCUSSION+ f6 N2 E4 V' H; n2 x! _
Topical testosterone has been used effectively by other
U7 i8 W: n$ u2 q) E2 T; Aclinicians but its mode of action remains controversial. Im-
6 }) S9 f8 r, l" c; Smergut and associates reported an excellent growth response
. M0 \. d# u0 _ j0 U$ j6 Nto topical testosterone with low levels of serum testosterone,
/ X0 X2 k @3 U" v* u8 ^# Bsuggesting a local effect.1 Others have obtained growth re-
" R5 |& A( G5 Y( m, N$ psponse with high. levels of serum testosterone after topical# m: B, i( M; e
administration, suggesting a systemic response. 3 The use of( A2 \+ L. o% D2 h7 N7 s5 |
gonadotropin to obtain levels of serum testosterone compara-
D5 E: {" {. T1 Vble to levels obtained with topical testosterone would seem to
8 \" |9 I' z9 D' u9 @ c9 xprovide a means to compare the relative effectiveness of
0 X9 Q4 j- b9 P, q% q6 s( otopical testosterone to systemic testosterone effect. It cer-
6 Z% Y6 ~. ^& E: Rtainly has been established that gonadotropin as well as par-
" ~" B5 I+ N Z/ f) y3 K- C! x! Xenteral testosterone administration will produce genital" L \ _! p b: N
growth. Our report shows that the growth of the phallus was; K7 U' _2 i8 A$ X: x% u
significantly greater with topical applications than with go-9 I6 D) U- _& ~" W
nadotropin, particularly in children less than 10 years old.
# U* |: g) {- _+ r% ~The levels of serum testosterone remained similar or lower/ [) f: j8 ~" \% x* t
than with gonadotropin during therapy, suggesting that topi-8 w! }9 B- \% L, @) s8 r/ S8 Y
cal application produces genital growth by its local effect as B" U' R+ o$ x0 p; [. Q
well as its systemic effect.
- A! C( @/ Y* WReview of our patients and their growth response related to
. A- R& k: q+ `; p* @. ~/ Bage shows a greater growth response at an earlier age. This is/ {6 \' V6 ]. e6 S3 O1 M, ^
consistent with the findings of Wilson and Walker, who
. e1 K! l9 n$ Y6 r* v! l$ Freported an increased conversion of testosterone to dihydrotes-
0 e) E) }5 X( c1 i# Q3 ttosterone in the foreskin of neonates and infants.4 This activ-' ]8 }% k: D% A4 H7 _1 a
ity gradually decreases with age until puberty when it ap-
, @8 f/ ]" A D8 g0 Y7 g/ G' K9 W/ Uproaches the same level of activity as peripheral skin. It may
( V8 i% N" v& R3 |well be that absorption of testosterone is less when applied at8 @; q( d1 M$ l( E
an earlier age as suggested by lower serum levels in children! r: J9 M% a7 i: T6 u- d" a
less than 10 years old. This fact may be explained by the. `% \$ g d5 d- F$ x+ w
greater ability of phallic skin to convert testosterone to dihy-# a; n$ ?& Z* O
drotestosterone at this age. Conversely, serum levels in older
% k0 Z0 z7 u! Y+ Mpatients were higher, possibly because of decreased local
4 x0 }9 d/ O9 n5 f7 Q$ i3 a* K. F667 |" C( l6 ]+ P* z
668 KLUGO AND CERNY1 I( I( s. ?% _# F
Pt. Age
; U5 e8 U) _+ c9 C8 n) X(yrs.)7 v. f( ]6 X/ ~6 I9 S5 t
Serum Testosterone Phallus (cm.) Change Length
* f# N5 H% q$ s: V. y) ]8 N(ng./dl.) Girth x Length (%)2 \3 x) ?; Z0 M! E! o" n8 {, C
4! S& U/ q2 c! h. `
8
3 i7 P* u% d, R8 j# s! w1 m10
1 I2 Q3 [0 x4 l. ~7 l124 q- U+ K3 V3 _; X3 H% D7 f
17
$ P" x( `# t6 pGonadotropin
" ?# U* b3 K0 F8 e5 _71.6 2.0 X 3 16.6; |+ x9 r& J. R0 ]! e' w
50.4 4.0 X 5.0 20.0
9 ]# J3 I2 E$ i; w22.0 4.5 X 4.0 25.0
{/ H9 y+ k4 k4 |; m# {+ V84.6 4.0 X 4.5 11.1 K: C4 n& }, L/ m
85.9 4.5 X 5.5 9.0! [8 n, X2 T% f7 u
Av. 14.3
) H$ Q8 ?! |5 a/ f- F4
9 d- p8 Y$ s, j7 Q. B3 i# o8; u$ {+ I/ h+ Z6 I5 X @$ Y
10% x- F2 [$ v$ C( n/ a
12
: z+ P" q' j0 H* l9 [3 C6 b17
- d5 _+ y8 v6 O$ t# ?Topical testosterone1 U+ m" D& E$ E& U
34.6 4.5 X 6.5 85
' _ R7 A9 e( R: ?0 `: F38.8 6.0 X 8.5 706 I. R- F8 G. H" }8 n5 u
40.0 6.0 X 6.5 62.5
% N- M! u @7 g; N* _3 R) C- w93.6 6.0 X 7.0 55.5! M1 S" `" N) o5 r- A
95.0 6.5 X 7.0 27.2% q( Q+ T) B& z9 P: B
Av. 60.0# k5 i5 X7 w9 A* U2 G
available testosterone. Again, emphasis should be placed on1 L8 D3 E9 c% L* y$ ?9 A2 Q# X
early therapy when lower levels of testosterone appear to% t' [) p* L6 L: c% e; w
provide the best responses. The earlier therapy is instituted: Z( b7 K, I6 P7 r- _7 g* l
the more likely there will be an excellent response with low& J( b5 K7 r2 x9 a h/ ?
serum levels. Response occurs throughout adolescence as
$ Z3 z0 R+ ~. r5 @noted in nomograms of phallic growth. 7 The actual response
% z6 z( g5 E0 c$ Y/ S5 k; yto a given serum level of testosterone is much greater at birth
( }+ T! Z$ y' ~* b: P" Zand gradually decreases as boys reach puberty. This is most ]6 h* D4 i, P$ ~
likely related to the conversion of testosterone to dihydrotes-
$ e: |$ a! N$ t6 Ftosterone and correlates well with the studies of testosterone% z! |, D/ U7 G
conversion in foreskin at various ages.; ?9 O# g% l. q3 s9 B4 |) o
The question arises regarding early treatment as to whether- k( N# H) y# R( _+ a- j
one might sacrifice ultimate potential growth as with acceler-
4 O' ^+ }# j/ y' |- s& Uated bone growth. The situation appears quite the reverse
8 r+ t9 Q: I* S4 R: F: ^9 wwith phallic response. If the early growth period is not used/ M) R5 w& \4 D1 ?1 n
when 5a reductase activity is greatest then potential growth% a1 ]4 ]* T" T( H
may be lost. We have not observed any regression of growth
& L' X6 h* F6 a" A- o ] E# Vattained with topical or gonadotropin therapy. It may well! U5 U! A$ D5 N: v- m1 D. R) @( o
be that some patients will show little or no response to any
8 v* e$ b$ f2 s0 y2 `8 @# \0 m' N4 Aform of therapy. This would suggest a defect in the ability to
3 m+ F& E# U* L! @convert testosterone to dihydrotestosterone and indicate that/ E4 A- a/ W: D
phallic and peripheral skin, and subcutaneous tissue should
6 r8 v% X& C3 e$ Nbe compared for 5a reductase activity.
5 f$ h8 ~, h7 WA, loop enlarges to measure penile girth in millimeters. B,
7 I' [- w& T" h+ n' _( P+ sexample of penile girth computed easily and accurately.8 {9 F% Y, d+ a6 F9 h' l
conversion of testosterone to dihydrotestosterone. It is in this
) F0 b) f5 X9 I1 w+ polder group that others have noted high levels of serum
4 ~! W6 E) n, e! Utestosterone with topical application. It would also appear! j0 Y. ~4 k% T* s0 C8 S
that phallic response during puberty is related directly to the/ l; O5 J3 n& }; o* n0 n
serum testosterone level. There also is other evidence of local
) i ]- X3 B' iresponse to testosterone with hair growth and with spermato-( \# h% j0 n) t0 X2 j
genesis. 5• 6
, T0 t$ K' q8 [7 l% w4 @Administration of larger doses of gonadotropin or systemic2 {5 d9 M/ X: _2 ]8 L2 [, ^' [
testosterone, as well as topical applications that produce
" K2 f$ D, v% I6 ahigher levels of serum testosterone (150 to 900 ng./dl.), will
% k% e) v6 q# C) Yalso produce phallic growth but risks accelerated skeletal
: Y# Z# j9 _8 P# i8 pmaturation even after stopping treatment. It would appear
) s( `" `8 F3 V( N& H& u( athat this may be avoided by topical applications of testosterone
6 c5 r3 ?* r; h* ^4 Hand monitoring of serum testosterone. Even with this control
) t+ v0 B( f7 K# B% b+ pthe duration of our therapy did not exceed 3 weeks at any
z2 X. t4 w7 _0 h) |' v3 itime. It is apparent that the prepuberal male subject may
$ q" N/ [( h; r! Q9 ]6 S3 ^9 I& S! Isuffer accelerated bone growth with testosterone levels near1 C7 q& {$ t$ F9 t
200 ng./dl. When skeletal maturation is complete the level of& u+ h, E6 N, k- q0 ^
serum testosterone can be maintained in the 700 to 1,300 ng./; n: Q1 _0 [5 g
dl. range to stimulate phallic growth and secondary sexual% _$ u5 e; ~+ i
changes. Therefore, after skeletal maturation parenteral tes-
' o5 ^0 P: U$ Ytosterone may be used to advantage. Before skeletal matura-* h; p U& |" i
tion care must be taken to avoid maintaining levels of serum, V3 `! v/ { R/ I3 A
testosterone more than 100 ng./dl. Low-dose gonadotropin0 S% C' v) H9 V/ C5 c# O8 }& ~
depends upon intrinsic testicular activity and may require& M0 D3 f2 j5 b( o3 s8 O# D
prolonged administration for any response.
8 O% B2 t9 G8 ^: t) A) P. MAlternately, topical testosterone does not depend upon tes-3 V6 K+ N! c. r4 x% ^7 ~
ticular function and may provide a more constant level of# ?9 R: P4 ^1 h, w2 T
REFERENCES' E8 S* j1 J) R+ e" h* p
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,; F: x; M q. ]
R.: The local application of testosterone cream to the prepub-
" a8 ?% E Y' Z) jertal phallus. J. Urol., 105: 905, 1971.# S7 S0 r4 B/ m
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone( P e# ~8 M* @
treatment for micropenis during early childhood. J. Pediat.,8 U8 t6 X: o) c5 v1 ~8 H
83: 247, 1973.
f6 O$ h4 }* c% L& M& H* f3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-6 \) l6 }' P) v9 ?8 ^
one therapy for penile growth. Urology, 6: 708, 1975.- ~& M4 d# C' b& Q7 Z
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone6 P! Y- O/ k7 x
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by1 f4 q) l0 K& n- a7 K" t) v' H
skin slices of man. J. Clin. Invest., 48: 371, 1969.
, E# d/ d3 r6 @- E$ v3 h5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
. p [$ \1 Y+ Vby topical application of androgens. J.A.M.A., 191: 521, 1965.4 U' \- O2 _+ g8 {$ \. z
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
9 X4 F6 \; j& v2 r- y* @4 Fandrogenic effect of interstitial cell tumor of the testis. J.
1 P4 M' M/ Z/ J- Z! Q' Z9 QUrol., 104: 774, 1970.; }% \# x9 k7 A# w
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia- K: B7 c: I# @& G1 m2 n
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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