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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
/ a' L5 [% `5 g- X2 h* ^GONADOTROPIN
. J& _1 ~9 p: `0 A7 H2 URICHARD C. KLUGO* AND JOSEPH C. CERNY+ e. [* o& y; ?* T8 ]* a
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
+ I% J9 X  |2 A3 J9 NABSTRACT
& a& O8 b! `, P, C% R5 AFive patients were treated with gonadotropin and topical testosterone for micropenis associated; D% I0 K( n5 a" W" g& L% g
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-) f- q1 l/ n' U" q$ T
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
3 h5 W4 K3 J. t3 @; R& Hcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent5 E7 j# v2 q- b4 ~! l
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
5 Y1 {( o- I, D6 \$ \increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
" u8 Q* D5 E: e# ?increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
+ T5 ^) ^  w8 Roccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This( u. L1 Q# ~% d/ J* h0 i. P: K
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile+ P$ R* i# ~9 C9 ^
growth. The response appears to be greater in younger children, which is consistent with previ-6 J% j: b7 K6 M. m, h& L/ r
ously published studies of age-related 5 reductase activity.# T- }) A9 u, H! A9 H$ ?( [
Children with microphallus regardless of its etiology will% L+ d( D. ]/ _" C- G6 P7 P
require augmentation or consideration for alteration of exter-. T# B# Q3 {$ ~8 A( a2 o$ u$ c
nal genitalia. In many instances urethroplasty for hypo-
1 U7 k! Y4 p# w# cspadias is easier with previous stimulation of phallic growth.
: h6 x4 v, t( o* DThe use of testosterone administered parenterally or topically
5 C5 C3 H  y% ?6 k8 a. zhas produced effective phallic growth. 1- 3 The mechanism of
& E4 o# G- H. {: U- f2 s: \6 T* _4 aresponse has been considered as local or systemic. With this
8 i' z. ?2 b- D5 ?5 @in mind we studied 5 children with microphallus for response
4 R% s- y# P* O1 ^, ?6 [' d: Zto gonadotropin and to topical testosterone independently.
0 {& I; E/ Z1 P/ ^MATERIALS AND METHODS+ M" z0 W. y. Y& ]7 }8 d7 N
Five 46 XY male subjects between 3 and 17 years old were% _, H7 m0 I/ }5 ^1 s
evaluated for serum testosterone levels and hypothalamic
7 a. R. @/ |5 D+ P% |& efunction. Of these 5 boys 2 were considered to have Kallmann's
$ A- T0 \' n% P2 {syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-# }+ o4 |6 y0 ]; q" E1 R6 c# d8 G6 I
lamic deficiency. After evaluation of response to luteinizing
/ B6 Q( n* ?. Z$ S# K; ~% thormone-releasing hormone these patients were treated with! [' s& s+ j2 }3 b( n! V
1,000 units of gonadotropin weekly for 3 weeks. Six weeks( s: g& Z. S3 w# T
after completion of gonadotropin therapy 10 per cent topical
( }- x* q( q; E3 V+ I; t- \: Z* ltestosterone was applied to the phallus twice daily for 3 weeks.
5 G+ v4 g! M* P! ^" G) M3 iSerum testosterone, luteinizing hormone and follicle-stimulat-: [6 K0 q/ {0 j& e
ing hormone were monitored before, during and after comple-0 s0 h6 }! Z4 N$ d" ]% C$ p# v3 y
tion of each phase of therapy. Penile stretch length was
+ B- _  c" X. Y( n! Y8 lobtained by measuring from the symphysis pubis to the tip of
7 g3 B% @  |# E, R' _; y1 ythe glans. Penile circumferential (girth) measurements were) C0 d0 _$ n0 d* x* X, Z- {+ w6 U9 k
obtained using an orthopedic digital measuring device (see
8 |4 x/ O% B$ q. sfigure).
0 U/ r/ s5 p+ r* ~RESULTS" z% @) b+ a0 K* J( V" n
Serum testosterone increased moderately to levels between
1 a" e9 e, S9 f% p6 t6 `50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
/ N( z7 Z9 Y7 I0 nterone levels with topical testosterone remained near pre-5 W4 N; S( h0 D& Z  q2 A; ~
treatment levels (35 ng./dl.) or were elevated to similar levels# g, t8 D4 A% `
developed after gonadotropin therapy (96 ng./dl.). Higher! v( ^: m3 K) u. I9 i5 j- G* y
serum levels were noted in older patients (12 and 17 years old),
2 V# F! B+ O8 i3 }, R' _, ?- Mwhile lower levels persisted in younger patients (4, 8, and 10
7 T. r- }/ V4 d- g1 S1 a$ S5 M/ V. eyears old) (see table). Despite absence of profound alterations
( p  ]) v3 X7 r) Eof serum testosterone the topical therapy provided a greater+ L! R4 R- B2 t% y
Accepted for publication July 1, 1977. ·9 i# Q' a9 A9 n3 O3 ~: g6 I9 b. ?' d
Read at annual meeting of American Urological Association,7 l% V/ y7 g- |( J- k, y
Chicago, Illinois, April 24-28, 1977.; F" ]. _' _' a6 o/ ~
* Requests for reprints: Division of Urology, Henry Ford Hospital,9 e, U' O( }2 h$ J
2799 W. Grand Blvd., Detroit, Michigan 48202./ L& m/ H+ U% T# w
improvement in phallic growth compared to gonadotropin.1 K% T7 n0 r! l$ D
Average phallic growth with gonadotropin was 14.3 per cent$ j# e3 [( H6 K9 `. ?8 C' G4 A3 V
increase in length and 5.0 per cent increase of girth. Topical
' q7 y! v* f  {! c' t. ?testosterone produced a 60.0 per cent increase of phallic length
2 S+ d0 D5 C! ?7 nand 52.9 per cent increase of girth (circumference). The
7 d- D; P* g1 O. }# y# Yresponse to topical testosterone was greatest in children be-* g- T$ [9 \* O+ C" d" b
tween 4 and 8 years old, with a gradual decrease to age 173 t. @3 ]% H+ ]1 W! U$ [$ `% E
years (see table).2 O1 Z( ^/ {6 U0 |1 n
DISCUSSION
: D/ p) r! ?; `' q! Y, F2 [Topical testosterone has been used effectively by other2 v, p, o; N& ]1 v
clinicians but its mode of action remains controversial. Im-
/ K5 E8 \: X: {7 T) b/ H1 Amergut and associates reported an excellent growth response
2 u/ n7 v7 `. hto topical testosterone with low levels of serum testosterone,$ V3 P8 k1 g  x) P( h/ w, ^
suggesting a local effect.1 Others have obtained growth re-6 f- X$ }- }2 t5 [. j/ q0 s
sponse with high. levels of serum testosterone after topical
* Z4 @5 T0 \/ V! Wadministration, suggesting a systemic response. 3 The use of
; u4 y" n+ j3 w( W; b$ Egonadotropin to obtain levels of serum testosterone compara-
7 x+ k: G. o$ [3 n: J$ Nble to levels obtained with topical testosterone would seem to; K( ?) H6 t) {' g$ L' v. W
provide a means to compare the relative effectiveness of. ]6 B- g4 N3 d  o+ V% a
topical testosterone to systemic testosterone effect. It cer-# `' ^0 m& C2 Q! }2 `6 Y4 R- C- b
tainly has been established that gonadotropin as well as par-6 B. I0 I5 J0 G5 x. E, z  c
enteral testosterone administration will produce genital
. U4 w, ]% |* i! f# w, c9 Xgrowth. Our report shows that the growth of the phallus was- V2 B' [. l4 |% E; Y7 x: S8 J  T
significantly greater with topical applications than with go-
4 B' z1 h' ^% Snadotropin, particularly in children less than 10 years old.
- B: Q8 u$ J0 w7 CThe levels of serum testosterone remained similar or lower0 z5 _8 c- V# ?6 U
than with gonadotropin during therapy, suggesting that topi-) J+ O. @8 i$ q" ^9 n  Y  H0 j5 u
cal application produces genital growth by its local effect as
( r" t7 u* C3 c4 R- dwell as its systemic effect.
# Z- C1 z6 F# _5 T: s" Q! TReview of our patients and their growth response related to
& T- c% q2 p& \& ^5 Aage shows a greater growth response at an earlier age. This is0 @9 P, ~  \8 E6 F: B0 |9 C
consistent with the findings of Wilson and Walker, who/ H7 y1 B, y" f* t9 n
reported an increased conversion of testosterone to dihydrotes-) u8 A3 W2 I" k4 @. k% Z
tosterone in the foreskin of neonates and infants.4 This activ-& J* M& r) ?' ^; |! m
ity gradually decreases with age until puberty when it ap-
) c: b/ a, W9 C3 S. xproaches the same level of activity as peripheral skin. It may$ f" e' c+ I6 |& [4 Y: k
well be that absorption of testosterone is less when applied at
- s1 `- a7 B  ran earlier age as suggested by lower serum levels in children
6 R5 a  Y' ~' H8 }0 oless than 10 years old. This fact may be explained by the
+ F# ]- K) [! c1 Egreater ability of phallic skin to convert testosterone to dihy-
9 c7 I0 P+ v* h% E: z7 ^) Bdrotestosterone at this age. Conversely, serum levels in older
( y& ~" a+ D# Q1 Wpatients were higher, possibly because of decreased local7 w4 P7 m0 M: C+ Q
667; u' D- H2 n7 l6 S. b# _9 L# e. W3 {) O
668 KLUGO AND CERNY7 p2 J7 \- F; Q) @$ \
Pt. Age: R+ `; R$ V4 s/ ?# E8 _) T
(yrs.)$ c0 ^! g1 j# U6 U" y7 H. h
Serum Testosterone Phallus (cm.) Change Length
- k' S5 p! Q) \6 w1 H! Q; G  X! J) A(ng./dl.) Girth x Length (%)+ E! F! a$ K0 z* i: v1 j5 m6 Q
45 h' B0 J" W4 ^' q% p
8
5 t. }0 r+ r( k! M. c. y10
: }+ b4 P; @% N! b: I6 H1 p12: V$ c# g% }# @, I  V
179 k9 W! p  t! w; ^- ^0 E
Gonadotropin
1 ]: w4 N2 p# j! ~0 _" O71.6 2.0 X 3 16.6
$ A: E/ f9 a" R! W50.4 4.0 X 5.0 20.0
7 ~' x6 t. E5 m22.0 4.5 X 4.0 25.0  P- ?1 a8 E9 g
84.6 4.0 X 4.5 11.1* S# M+ s! D& W) |
85.9 4.5 X 5.5 9.0
1 ?+ e, n7 Z& ^1 u' y; gAv. 14.3# j1 ?  v7 l3 h9 V- b
4  [  ]& Q0 o- m! U  h6 U
86 H! j6 [/ N' a$ R
10) K1 }% w+ q! c/ E8 P: w
12$ d, q2 ^5 q; I8 X( G1 H
17
5 @- a) R5 c4 ~8 OTopical testosterone
4 f: }! U+ ^' v& O& ]  U34.6 4.5 X 6.5 859 s2 O; v% |% T& E$ F
38.8 6.0 X 8.5 70
4 P% K$ T% |# \40.0 6.0 X 6.5 62.5# @$ {. O( ?0 e* J
93.6 6.0 X 7.0 55.5% n1 d1 @1 O; l; L% X) ]' K, f, s
95.0 6.5 X 7.0 27.2
- H. q. j8 ?" |$ C' c$ z- e  aAv. 60.0  f+ s% z7 n3 |
available testosterone. Again, emphasis should be placed on
/ [$ @3 r7 M% ~% Z+ ^early therapy when lower levels of testosterone appear to; U4 I0 H% b+ M  z, u+ _9 d
provide the best responses. The earlier therapy is instituted2 S' h* O3 E; S! m- a  L# T
the more likely there will be an excellent response with low
0 G/ A9 |3 _: x7 W" Zserum levels. Response occurs throughout adolescence as
3 f$ x1 B8 w2 ^( F/ v- T! Q+ qnoted in nomograms of phallic growth. 7 The actual response% f/ b. l- I  ^; k6 t& s
to a given serum level of testosterone is much greater at birth
! _$ e& K8 p& d% s* b' J3 aand gradually decreases as boys reach puberty. This is most. S2 Q. \! R6 @( \; ~
likely related to the conversion of testosterone to dihydrotes-2 V$ v8 Y( h' k' w) [1 ^2 Q
tosterone and correlates well with the studies of testosterone
8 F  H; L' \( u: s# k+ |" @$ bconversion in foreskin at various ages.# V% E  x0 r) Q
The question arises regarding early treatment as to whether
: N: R& u8 |4 \, s2 X( pone might sacrifice ultimate potential growth as with acceler-
0 `* z! t1 r) Q1 M4 t" Vated bone growth. The situation appears quite the reverse
& P! o1 _8 m( P. d/ z% J8 |$ Awith phallic response. If the early growth period is not used
7 q1 Q; D1 {2 Jwhen 5a reductase activity is greatest then potential growth
5 d! R+ Y- G6 e2 B' L# Gmay be lost. We have not observed any regression of growth
' D: I4 k; E* C( ~, t+ Hattained with topical or gonadotropin therapy. It may well
/ i1 M9 \! j2 T% @  ?be that some patients will show little or no response to any
) z3 `0 `  m# H6 [) r8 _1 tform of therapy. This would suggest a defect in the ability to2 s! n: K; G5 s& r' d2 x& [
convert testosterone to dihydrotestosterone and indicate that! A* O" b) Z5 o2 ^
phallic and peripheral skin, and subcutaneous tissue should! I' k0 X8 A9 Z$ O: S
be compared for 5a reductase activity.
+ X+ _9 y  V& \, XA, loop enlarges to measure penile girth in millimeters. B,! k# U: [5 Z. I* y+ L& w
example of penile girth computed easily and accurately.) d: U7 E. i: @7 Q& x
conversion of testosterone to dihydrotestosterone. It is in this
4 a- @' \# y+ oolder group that others have noted high levels of serum3 [: i, [( l+ m% T
testosterone with topical application. It would also appear5 {5 |" R3 n' u# L) D% {/ ]
that phallic response during puberty is related directly to the
' A" k  \! L0 M" ]serum testosterone level. There also is other evidence of local
! l) `8 A- ]% m" Y) n0 o  iresponse to testosterone with hair growth and with spermato-( N, w# J. j. i* D
genesis. 5• 6
+ ^3 w2 Q) ~) W& L+ QAdministration of larger doses of gonadotropin or systemic
0 r9 e( U+ R) \0 f7 gtestosterone, as well as topical applications that produce
# {3 y  N  o6 q+ k' g7 F; w" mhigher levels of serum testosterone (150 to 900 ng./dl.), will/ U; ~1 I0 a* o" \' V: K
also produce phallic growth but risks accelerated skeletal. k; p# z  ^& i0 y0 D, b# i! \
maturation even after stopping treatment. It would appear
# |: m; ~2 r8 ~that this may be avoided by topical applications of testosterone
$ f2 f1 @! s, g9 y1 land monitoring of serum testosterone. Even with this control) X. b( X2 U$ I0 [* h! I
the duration of our therapy did not exceed 3 weeks at any
& L3 J8 {5 ]+ w* V" j9 ?; Xtime. It is apparent that the prepuberal male subject may
5 \2 U4 B' F' @" \suffer accelerated bone growth with testosterone levels near
; v6 C6 w) I" [" s5 b3 f: N200 ng./dl. When skeletal maturation is complete the level of
' _+ ^1 O1 q+ R1 cserum testosterone can be maintained in the 700 to 1,300 ng./+ v- o7 o* N0 q) a! C- }: T
dl. range to stimulate phallic growth and secondary sexual# c( K! v3 k/ H( C
changes. Therefore, after skeletal maturation parenteral tes-! c9 a' L) V$ M5 _; k
tosterone may be used to advantage. Before skeletal matura-
* y) R  S0 o" b# {7 \0 T0 M% L# dtion care must be taken to avoid maintaining levels of serum
1 L$ g1 b- N  F. `' X+ ntestosterone more than 100 ng./dl. Low-dose gonadotropin
1 t6 w* J! }* Z* }& w6 z, u# Ydepends upon intrinsic testicular activity and may require, Y/ E  c/ e5 S' {! j" E  |: a
prolonged administration for any response.1 o5 L. f7 R% l
Alternately, topical testosterone does not depend upon tes-& a4 F$ s) Z3 N3 W
ticular function and may provide a more constant level of2 c+ o+ B& J4 F5 e. J/ |+ \! k& Q
REFERENCES) n! ~$ P2 D2 ~! E# w  w
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
4 M4 f  ]4 L# `$ q# K( e, |R.: The local application of testosterone cream to the prepub-' g- C" ?; b5 c
ertal phallus. J. Urol., 105: 905, 1971.% F6 V2 `& W/ e5 w7 U  C7 m1 B  }
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone& O) \) H! |& n& Z4 d
treatment for micropenis during early childhood. J. Pediat.,
% D# p1 X0 m0 {0 ~5 J3 K83: 247, 1973.6 I0 i# A* F: w  a- Z& e# |; F- P
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
  i3 s% S6 q  _* j; Sone therapy for penile growth. Urology, 6: 708, 1975.
% N4 V9 H& a% o4 p' H5 s4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
; L) Z5 L& Z; Y+ F1 Q9 Eto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by. ?7 w) t# [7 D1 ?( O" F7 ~. n. j$ |
skin slices of man. J. Clin. Invest., 48: 371, 1969.1 X/ T& ^' X: w+ L! d/ M
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
5 z8 ?0 j. G* {9 A% Y! Q6 wby topical application of androgens. J.A.M.A., 191: 521, 1965.& h, M( Y6 Y! J: M+ b9 K! D3 Z( B
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local6 h+ ?) W5 ?  o  T+ k( b8 p
androgenic effect of interstitial cell tumor of the testis. J.
$ L. L+ }' R( A6 s: K/ WUrol., 104: 774, 1970.
* v9 }* g1 q) Y, c, d6 I7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
+ n# i6 t4 u; N( `. t. etion in the male genitalia from birth to maturity. J. Urol., 48:
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