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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
5 L+ Z f* t& ^) L, X3 U, }/ BGONADOTROPIN
) b1 F7 P6 v: g iRICHARD C. KLUGO* AND JOSEPH C. CERNY9 S# `0 V2 T4 j+ G, R2 U7 |* I
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan2 p6 H; u3 U) I8 m9 B" `
ABSTRACT% P6 I [' @3 y3 P, Z7 n
Five patients were treated with gonadotropin and topical testosterone for micropenis associated' t5 Z* {" h; b
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
, ^, _7 T! q5 Ftropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone/ b: T1 |6 }0 T& t4 s
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent* {+ \+ B+ `8 B5 F ~
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
e# B& I! T J, F& J- O) iincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
2 p, Y$ E+ ?/ Y' Sincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
3 j" y/ J4 d! J9 y8 H6 T3 f0 ioccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This6 F! _! k0 B0 y
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile/ ]* U5 Y6 O/ J8 h
growth. The response appears to be greater in younger children, which is consistent with previ-
0 N: q" G" }! V8 zously published studies of age-related 5 reductase activity." k5 u. m$ H c
Children with microphallus regardless of its etiology will6 Q& G$ a, p* x" E4 w
require augmentation or consideration for alteration of exter-
0 \9 I9 q) u8 V2 V) ^7 s9 Bnal genitalia. In many instances urethroplasty for hypo-
6 k ?. ~5 M' w' e# ]$ xspadias is easier with previous stimulation of phallic growth.0 I, u4 e2 c3 _- {' s
The use of testosterone administered parenterally or topically9 T# {3 o8 h3 z) J( ^9 Q% ^/ U
has produced effective phallic growth. 1- 3 The mechanism of
/ S. j$ p7 G5 Hresponse has been considered as local or systemic. With this- o- B6 x' h- J9 v
in mind we studied 5 children with microphallus for response
+ F9 u! E9 R: P+ h9 D6 k8 v& fto gonadotropin and to topical testosterone independently.9 F% s1 \3 K% |, H" B# ~
MATERIALS AND METHODS
& x! C2 I6 a4 ?4 l! t' r$ {; MFive 46 XY male subjects between 3 and 17 years old were
. c$ Q4 I* K3 s: _6 ?2 \evaluated for serum testosterone levels and hypothalamic
7 P0 Q5 j/ w, Y# x6 ufunction. Of these 5 boys 2 were considered to have Kallmann's1 K+ s. ]: R# ?* g: q, V
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-! B4 A. ^. P6 V) u8 J& N6 s7 v
lamic deficiency. After evaluation of response to luteinizing
0 ]. P6 b* J6 c; l* Ghormone-releasing hormone these patients were treated with
% E0 ^( r4 I/ {5 l' W1,000 units of gonadotropin weekly for 3 weeks. Six weeks* Y2 `* P! H6 x
after completion of gonadotropin therapy 10 per cent topical8 t: Y: U4 \" _) I
testosterone was applied to the phallus twice daily for 3 weeks.
- B- @. ]2 M! K; ISerum testosterone, luteinizing hormone and follicle-stimulat-- w# _/ W: u* {. ]) o2 T
ing hormone were monitored before, during and after comple-- j% N$ x9 `6 |7 N0 [0 j
tion of each phase of therapy. Penile stretch length was
2 V" y. b$ G9 k& |8 n* Gobtained by measuring from the symphysis pubis to the tip of" R( b$ s7 O k. F( R( z
the glans. Penile circumferential (girth) measurements were
, |1 P2 O( H. M' a$ _9 K6 E6 hobtained using an orthopedic digital measuring device (see/ U+ N4 U' r9 d( j: f: J
figure).' f. n& e l4 A8 o$ [
RESULTS. {' h, `9 ?1 W5 Y0 q# h+ q
Serum testosterone increased moderately to levels between
& z: p, @- _5 w; [; K( e& A" K50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
7 E! M; o% c) F( S8 }terone levels with topical testosterone remained near pre-) w$ f; \$ v& K$ ]
treatment levels (35 ng./dl.) or were elevated to similar levels
& J6 F# I$ P! F8 k4 l. ?developed after gonadotropin therapy (96 ng./dl.). Higher
& B, Z/ d! ?) n/ @8 @- Mserum levels were noted in older patients (12 and 17 years old),1 o2 ]- i: A2 w) ~! z5 @7 g/ J
while lower levels persisted in younger patients (4, 8, and 10' Y% ]! y, `9 ~5 s, L6 i
years old) (see table). Despite absence of profound alterations! B. O8 \$ a! `$ ~/ E
of serum testosterone the topical therapy provided a greater! E1 p: `' O/ h, W; r& |
Accepted for publication July 1, 1977. ·
+ @! p0 f7 t: u2 o3 QRead at annual meeting of American Urological Association,. v) L, h# k2 P- G( J0 f
Chicago, Illinois, April 24-28, 1977.
8 E/ T( [$ z$ ]$ c* Requests for reprints: Division of Urology, Henry Ford Hospital,
2 w5 {$ ^' X0 A5 O/ w2799 W. Grand Blvd., Detroit, Michigan 48202.; e& K; c0 I- O- W2 O Q
improvement in phallic growth compared to gonadotropin.% _: }% s( {8 p( r+ l3 _
Average phallic growth with gonadotropin was 14.3 per cent
/ y4 e7 L: j2 N1 a. j7 dincrease in length and 5.0 per cent increase of girth. Topical
z; P. G7 e( J6 ntestosterone produced a 60.0 per cent increase of phallic length
+ A' r% _8 v/ D/ Vand 52.9 per cent increase of girth (circumference). The
" n, L9 T' @- r# W0 l4 B: i) S& jresponse to topical testosterone was greatest in children be-
' f* a! d# J! r k. p9 Atween 4 and 8 years old, with a gradual decrease to age 17
, D* p- P/ N1 U& @; u4 L5 [5 Gyears (see table).
5 R/ U- h8 R) Z7 lDISCUSSION8 _* a2 b/ W0 J( H9 I6 B' E
Topical testosterone has been used effectively by other
: m( c! B7 P: R* K& T8 I! ~clinicians but its mode of action remains controversial. Im-
7 b3 z, h2 R0 t2 u8 D9 P5 emergut and associates reported an excellent growth response; d1 `: `2 C. Y3 \
to topical testosterone with low levels of serum testosterone,% C$ m8 a3 f3 x. K' J
suggesting a local effect.1 Others have obtained growth re-
' s2 x1 R, D1 t* z4 I( ^5 H3 l. Asponse with high. levels of serum testosterone after topical$ N) i" R- y! c$ c: ~! T8 G( a
administration, suggesting a systemic response. 3 The use of
- s, O, ^+ n( egonadotropin to obtain levels of serum testosterone compara-3 I# I3 O" U; l* Q* X
ble to levels obtained with topical testosterone would seem to
n$ W0 V2 Z! B0 f) J, i" M3 Jprovide a means to compare the relative effectiveness of
3 g! T( F6 }+ b1 u% B; rtopical testosterone to systemic testosterone effect. It cer-- {$ h3 Y1 i8 D6 G$ q
tainly has been established that gonadotropin as well as par-
8 _7 e$ ^) Z$ k c; Nenteral testosterone administration will produce genital
- _; J9 T0 ^5 N: x' O' Ngrowth. Our report shows that the growth of the phallus was
: ^$ A* q& m$ l: \- Fsignificantly greater with topical applications than with go-6 O0 d0 j* S y9 x+ I4 w
nadotropin, particularly in children less than 10 years old.
+ ~& |% i3 H% B8 yThe levels of serum testosterone remained similar or lower
4 B3 B! a7 Y9 m! athan with gonadotropin during therapy, suggesting that topi-
5 q- j! O2 U) u6 ?cal application produces genital growth by its local effect as
, y5 B2 c- W; P n2 A' @( }well as its systemic effect.
# D1 g3 R9 f* E9 s$ DReview of our patients and their growth response related to
; N: _ U7 ~) s/ Y, F7 N- s. |age shows a greater growth response at an earlier age. This is9 @1 O3 S. I/ M: J: a# G
consistent with the findings of Wilson and Walker, who
! x% K# @% L/ f2 j: \reported an increased conversion of testosterone to dihydrotes-, ]+ `, s) [1 T4 t& {: |
tosterone in the foreskin of neonates and infants.4 This activ-5 E: T# _% r. |" y& F; Y
ity gradually decreases with age until puberty when it ap-2 w5 _8 i) I& `, A9 y0 Z
proaches the same level of activity as peripheral skin. It may1 L" H$ l+ w" J! g* g' C
well be that absorption of testosterone is less when applied at0 b. ? ]0 n6 L0 o9 f& y9 M
an earlier age as suggested by lower serum levels in children
+ K( e% ]4 e4 y- {6 @* h0 nless than 10 years old. This fact may be explained by the
8 G' P6 K) m, `" P+ {greater ability of phallic skin to convert testosterone to dihy-7 y% j2 r# m% K' H. J) ~( o9 P
drotestosterone at this age. Conversely, serum levels in older
- e1 A/ @$ O( lpatients were higher, possibly because of decreased local
3 `4 }9 k, ]2 A8 N# j5 x6676 K9 d! o. k1 I Z! T* x
668 KLUGO AND CERNY3 W, |3 {' g0 ^! w
Pt. Age) z' y2 f, P3 j
(yrs.)5 E/ i. a' Z }6 U8 S8 }* m
Serum Testosterone Phallus (cm.) Change Length
5 o' G4 ^& |& D* [0 n(ng./dl.) Girth x Length (%)
- j/ F9 Z' B- Y5 ~/ @$ w4$ V1 K/ t B3 P: _/ w
8
7 d! o! ?( R' J) Q% s6 Y10
8 V8 @0 y- t B0 F9 G0 Q12
: P$ I3 T% A7 I7 B) @17
9 I3 i: c/ P" PGonadotropin
1 N9 S' P3 E" k b71.6 2.0 X 3 16.6
' T \" z) x0 c0 u- F9 ^" S2 n50.4 4.0 X 5.0 20.0) A0 K3 m' f, p2 s/ i
22.0 4.5 X 4.0 25.0# y' @/ q2 p; z: g! G
84.6 4.0 X 4.5 11.1
1 x; K. L7 G5 G85.9 4.5 X 5.5 9.0
+ B2 m0 T( x3 D HAv. 14.3
! T- w3 z J/ U& M: ^7 k4
) c' c+ j+ X* w! x) ^- }8# v/ V* [& r0 ~1 g
10
, c$ c5 l0 A5 A7 C# G1 N12/ q/ s9 R, n7 s' K0 i
17
8 q- r3 C( n6 d% X! }Topical testosterone
' S4 t6 B) L/ t/ f& _4 x34.6 4.5 X 6.5 85% ~. i" _# M8 O3 `5 f! w% C0 p
38.8 6.0 X 8.5 70
, i x# ?, S; w5 J& }40.0 6.0 X 6.5 62.54 a2 p: h2 v2 ?6 b4 P% D0 D
93.6 6.0 X 7.0 55.52 O! }. x) H, w0 r4 L
95.0 6.5 X 7.0 27.2
6 A h1 w0 A* b' s0 x; q$ W1 Q( QAv. 60.04 v" Y2 c- _0 L: X9 s
available testosterone. Again, emphasis should be placed on# a6 \8 B5 H( @% ~
early therapy when lower levels of testosterone appear to: L1 p: X. y+ _3 T' j
provide the best responses. The earlier therapy is instituted
" Y: z& n- [* i Z1 lthe more likely there will be an excellent response with low/ P$ t, K" Q( e3 C! l9 O7 D4 x2 c
serum levels. Response occurs throughout adolescence as
/ o; ?$ K: L0 z$ ~' v' P' S9 a" Jnoted in nomograms of phallic growth. 7 The actual response
& k' Q& _5 q: r; dto a given serum level of testosterone is much greater at birth, w3 [2 E. |. d0 D S' y
and gradually decreases as boys reach puberty. This is most
l) Q+ G$ E Q, A+ D5 S& plikely related to the conversion of testosterone to dihydrotes-0 N- j Q0 A/ d) \* I& X
tosterone and correlates well with the studies of testosterone
. C8 G6 \ P) H8 y/ C1 t3 {conversion in foreskin at various ages. |$ S, ]! v+ U: d* W
The question arises regarding early treatment as to whether0 V1 c$ e4 @: F
one might sacrifice ultimate potential growth as with acceler-& p, I! ^: P1 J2 Z3 _& z8 f! g
ated bone growth. The situation appears quite the reverse2 a4 U" W, j' G9 p$ z6 z7 `1 o
with phallic response. If the early growth period is not used& E2 J5 v' g* y8 s4 ?! v: @
when 5a reductase activity is greatest then potential growth
3 ]# p$ C0 q7 F) j# zmay be lost. We have not observed any regression of growth
" E. s' g/ ?& h9 x+ Oattained with topical or gonadotropin therapy. It may well6 \9 N L) Y) W
be that some patients will show little or no response to any
4 Q2 e0 M3 l1 \ |form of therapy. This would suggest a defect in the ability to
% ~* I7 b$ y; @0 l# `! Rconvert testosterone to dihydrotestosterone and indicate that
' s6 A/ E! E) w! ophallic and peripheral skin, and subcutaneous tissue should) `. n, D) _& I- K' t
be compared for 5a reductase activity.
( ~) Z9 b2 Y# JA, loop enlarges to measure penile girth in millimeters. B,: a# U; _* F+ w6 T: b3 ^
example of penile girth computed easily and accurately.
. p f- F& `' w2 I# y) h/ tconversion of testosterone to dihydrotestosterone. It is in this* e) T. y* J+ t* R4 u1 [
older group that others have noted high levels of serum
: x( ?7 I7 I7 f8 D' X% qtestosterone with topical application. It would also appear- v9 V3 {3 Y6 H) Y
that phallic response during puberty is related directly to the6 z4 `% x; I" s1 x- J% h5 t
serum testosterone level. There also is other evidence of local# n9 Z4 _8 s$ b& T* v: Z
response to testosterone with hair growth and with spermato-3 ?* j' i2 Y* c4 }" ^! B5 O0 d
genesis. 5• 6
& j% F% D% {0 D: F$ j1 tAdministration of larger doses of gonadotropin or systemic
( C# v, N9 t, c+ Atestosterone, as well as topical applications that produce
4 v: i( U/ A( B q3 C6 N Chigher levels of serum testosterone (150 to 900 ng./dl.), will
- O5 C' y; \/ w/ dalso produce phallic growth but risks accelerated skeletal
' D* ~# w3 B0 D9 D* N4 n. E$ r& Pmaturation even after stopping treatment. It would appear# H/ h" E \3 B6 [
that this may be avoided by topical applications of testosterone
' m2 |. T" g$ c, h9 b$ n" t) z3 iand monitoring of serum testosterone. Even with this control
$ ?( x0 i8 h. c- \" Sthe duration of our therapy did not exceed 3 weeks at any- f, a. n- T9 |, t
time. It is apparent that the prepuberal male subject may
! W# O2 U3 H' p/ W5 |suffer accelerated bone growth with testosterone levels near9 V( i6 f1 F( A4 m8 P; Z# J+ Q4 s/ O/ `
200 ng./dl. When skeletal maturation is complete the level of* D9 d! B4 N2 _ F& p J
serum testosterone can be maintained in the 700 to 1,300 ng./ `4 X+ ?8 w1 p! }" e4 A& G
dl. range to stimulate phallic growth and secondary sexual- \) k6 w2 H/ N1 G: f
changes. Therefore, after skeletal maturation parenteral tes-/ X9 m( \& S9 X
tosterone may be used to advantage. Before skeletal matura-
1 j9 q; `5 J" B6 P- Ktion care must be taken to avoid maintaining levels of serum6 ?. {; A1 u" ~0 m+ ~
testosterone more than 100 ng./dl. Low-dose gonadotropin
_& ^/ H& y; T2 I( Sdepends upon intrinsic testicular activity and may require1 v* G) W" \3 ?, M6 C3 e, z
prolonged administration for any response.5 [$ i; R% G+ f1 {
Alternately, topical testosterone does not depend upon tes-
, Z6 ?0 Q- W: gticular function and may provide a more constant level of0 U5 I* f! x% K6 e4 n) ]0 O3 Z
REFERENCES' E, a4 J* D. B% x+ P
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,. G! r" r% g, V* v2 Q. R7 p
R.: The local application of testosterone cream to the prepub-7 ^+ I! k; K# D) ]
ertal phallus. J. Urol., 105: 905, 1971. t# b1 _7 U1 E0 E3 F
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
+ e+ n1 `: @1 L$ jtreatment for micropenis during early childhood. J. Pediat.,5 j; R6 Z3 l5 o
83: 247, 1973.2 J V* g. p$ {: W1 `# ?
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
+ Y9 {! e; N9 R6 L+ H7 @" t! bone therapy for penile growth. Urology, 6: 708, 1975.! f! j% \: i: [: l& g) S
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone$ T1 t; p* s* `! D
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by( c5 t! y7 o, G4 d: y
skin slices of man. J. Clin. Invest., 48: 371, 1969., W* j/ ?3 w& l: K$ L; \+ ~$ X
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
$ b& {$ W3 Y% N" r# Fby topical application of androgens. J.A.M.A., 191: 521, 1965./ y5 H2 X! ~+ ^) L5 |! ?
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
) g, F# X- b% R" i6 O9 Landrogenic effect of interstitial cell tumor of the testis. J.
: Y2 C8 x& u2 kUrol., 104: 774, 1970.! ?+ F4 A$ r- [* Q, o* q% X! K
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-7 n4 ?5 {; ?. k% v$ a6 C
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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