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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND- d9 S1 d! @5 b  ~0 a: Y- h7 k
GONADOTROPIN
4 ~# @3 p$ U; n0 A# w5 \2 g& j8 ~RICHARD C. KLUGO* AND JOSEPH C. CERNY
$ m: f/ z8 U6 k( qFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
% R5 u  `- _6 EABSTRACT
2 c) @- a5 y5 S5 U6 qFive patients were treated with gonadotropin and topical testosterone for micropenis associated; U, B! ?* L$ n0 q. ?& B& _/ m+ N
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
' @' x) W1 N8 {9 {$ L0 ^  qtropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
' s! e& J& ], r" jcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent, r& m9 A9 h: j6 x* a7 S  j
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
5 S' r' {; c  i& }2 a3 p' ~. k5 cincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
3 l. o6 f1 d# k5 N: V4 Qincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
. F& p! t, g: w/ v8 z6 h9 J9 F: Poccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This8 o4 ?" Y* v+ W$ C
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
) e1 V* a5 D; S) R0 Rgrowth. The response appears to be greater in younger children, which is consistent with previ-
( o' [* d- p) y( N$ T2 Mously published studies of age-related 5 reductase activity.
1 W1 @0 G/ O* ?* P- h6 N+ E. F2 v0 qChildren with microphallus regardless of its etiology will
% D( W4 s1 T, F) H7 Z3 V: ^7 Orequire augmentation or consideration for alteration of exter-
5 X8 p8 L2 @, t3 D) pnal genitalia. In many instances urethroplasty for hypo-
. ~0 l: X: X8 y2 |, qspadias is easier with previous stimulation of phallic growth.
& h4 Q3 E; L8 o2 p7 p( RThe use of testosterone administered parenterally or topically
0 h9 m4 Q1 k' l3 @7 F+ T0 U7 Xhas produced effective phallic growth. 1- 3 The mechanism of
8 Y; ]! A1 k/ d% S/ D. Z; Zresponse has been considered as local or systemic. With this
& O) C" \* ^8 }9 V  nin mind we studied 5 children with microphallus for response/ Y4 b$ H' G* y" g9 O2 _/ j
to gonadotropin and to topical testosterone independently.- M  w/ y) I: d& H: t
MATERIALS AND METHODS
8 V2 ^: }$ ]3 Y! rFive 46 XY male subjects between 3 and 17 years old were
4 @  J/ z, ?. y4 nevaluated for serum testosterone levels and hypothalamic
4 y5 ^8 b, P2 ?7 p% Mfunction. Of these 5 boys 2 were considered to have Kallmann's
! D8 b) p. x! y; h7 \# }syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
0 o% v2 z! Z. p* Plamic deficiency. After evaluation of response to luteinizing
5 G& ]; P1 h4 o# ~. Ohormone-releasing hormone these patients were treated with0 H3 u/ f/ J' C% V' \, q
1,000 units of gonadotropin weekly for 3 weeks. Six weeks. Z" K2 y* K" |9 b: l: @
after completion of gonadotropin therapy 10 per cent topical
7 U& y# Z: ]0 d  ktestosterone was applied to the phallus twice daily for 3 weeks.
- [! e  H% j8 g+ LSerum testosterone, luteinizing hormone and follicle-stimulat-
$ n1 o1 s) ?; A1 ling hormone were monitored before, during and after comple-' ]+ I9 ~0 d- O/ y' k1 b" s9 E- {
tion of each phase of therapy. Penile stretch length was
7 ~3 ]. b3 ~) G( \obtained by measuring from the symphysis pubis to the tip of
5 d5 c7 N2 q) P6 Cthe glans. Penile circumferential (girth) measurements were
( p6 l8 Q, I9 {0 u; U' N) robtained using an orthopedic digital measuring device (see
% R" ]/ M' `0 O% dfigure).) r6 Q9 i$ B7 \, ~& K
RESULTS
* \( R1 Y, ^+ o, T; u, z- j0 @Serum testosterone increased moderately to levels between7 }" h- D: P5 y" _9 V$ R4 Y
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
4 V, _3 \" e' ?' Iterone levels with topical testosterone remained near pre-# |, _. x( Q/ }) w5 Z- i: T
treatment levels (35 ng./dl.) or were elevated to similar levels+ E$ o4 K) n, a& X: i& y3 s0 q/ k
developed after gonadotropin therapy (96 ng./dl.). Higher2 r$ s1 s: T6 e/ A# y
serum levels were noted in older patients (12 and 17 years old),
& W) f) Q! o- q. C- Twhile lower levels persisted in younger patients (4, 8, and 10
0 p  h& K& _6 R% f9 x: Gyears old) (see table). Despite absence of profound alterations
$ @: h5 R7 m' \/ |) iof serum testosterone the topical therapy provided a greater$ k" q! e  E  K1 _  e3 q
Accepted for publication July 1, 1977. ·! f1 R3 @) ~& s2 [
Read at annual meeting of American Urological Association,- T$ N) G- A1 t( x
Chicago, Illinois, April 24-28, 1977.4 R- M: G) `; B5 W5 I4 O
* Requests for reprints: Division of Urology, Henry Ford Hospital,9 _: E* W- Z+ V( H
2799 W. Grand Blvd., Detroit, Michigan 48202.$ L2 l; [( I' J! A( \
improvement in phallic growth compared to gonadotropin.
' i( x& T2 S" ]# q* `Average phallic growth with gonadotropin was 14.3 per cent5 j* S0 g( j, u0 E
increase in length and 5.0 per cent increase of girth. Topical3 |/ ?, u1 u4 \4 C
testosterone produced a 60.0 per cent increase of phallic length
  j# I  R  J' g1 band 52.9 per cent increase of girth (circumference). The
* m/ h! b; I: N- x( u8 d; lresponse to topical testosterone was greatest in children be-
; Z0 I! u) j: H  X9 B, {tween 4 and 8 years old, with a gradual decrease to age 175 }  C+ [, `% q& v  O( \- y! \; z
years (see table).5 P# g/ |  s2 |5 s; W
DISCUSSION
# X; `6 y; X: Z0 @# ~: q- \Topical testosterone has been used effectively by other/ U8 N5 h* e+ x' Y5 `, x$ t1 f) |
clinicians but its mode of action remains controversial. Im-* O% H5 c% R/ V# _; v# J# X; a
mergut and associates reported an excellent growth response
9 J% E: e, B8 \3 p4 {to topical testosterone with low levels of serum testosterone,
& \, B0 q* M9 asuggesting a local effect.1 Others have obtained growth re-" Y3 p' Q/ J* B$ s6 Q
sponse with high. levels of serum testosterone after topical
3 D/ `0 `# {+ Jadministration, suggesting a systemic response. 3 The use of
* ]' `/ P1 o0 H4 t/ Bgonadotropin to obtain levels of serum testosterone compara-
1 B  N$ b6 g( J' M7 d6 |ble to levels obtained with topical testosterone would seem to- e' v/ b- `% B+ W* Z* F  [
provide a means to compare the relative effectiveness of6 K2 [! R8 E5 [, D* {& I5 w
topical testosterone to systemic testosterone effect. It cer-
) b# C( l! {; p/ Ltainly has been established that gonadotropin as well as par-( `$ n9 |9 c3 S
enteral testosterone administration will produce genital
6 W6 Z) q8 S/ ^- f- j( R! s- M2 zgrowth. Our report shows that the growth of the phallus was
# e% y5 |* O1 x; e1 bsignificantly greater with topical applications than with go-3 ?2 D/ i7 d3 ?7 B  m! k/ [( X! l
nadotropin, particularly in children less than 10 years old.  Q! y/ K: g, v- r1 |( G
The levels of serum testosterone remained similar or lower) s0 a/ }  y7 Y
than with gonadotropin during therapy, suggesting that topi-# I0 F6 P6 n2 |+ [" B
cal application produces genital growth by its local effect as
- j" ^" k0 m6 L7 T; Hwell as its systemic effect.
$ w# j# A. s3 n7 e! C8 W# sReview of our patients and their growth response related to3 z8 I$ n8 Z, E+ T3 V9 h" M
age shows a greater growth response at an earlier age. This is
+ X  F+ F( U1 c( aconsistent with the findings of Wilson and Walker, who
) I, S/ O7 q) |/ b, ?reported an increased conversion of testosterone to dihydrotes-9 l) h2 j$ f4 Y& R( \3 O+ T
tosterone in the foreskin of neonates and infants.4 This activ-
9 \  [  V0 v" G5 r% V! zity gradually decreases with age until puberty when it ap-
5 E( Q( f4 L0 {! |. Z) uproaches the same level of activity as peripheral skin. It may
7 a. e5 e( R! V* K: m& H! o7 ~well be that absorption of testosterone is less when applied at4 B! @9 ]' K. M+ P' ?& S
an earlier age as suggested by lower serum levels in children
0 J$ `+ i4 Q6 U5 G* R5 D( ^* A# ~( `9 Eless than 10 years old. This fact may be explained by the* u2 ]% K& T- S3 B7 R1 l' v
greater ability of phallic skin to convert testosterone to dihy-+ U% v0 C8 f& m: N6 z1 s; C6 b
drotestosterone at this age. Conversely, serum levels in older2 `$ X/ I3 }/ P- d, @: `
patients were higher, possibly because of decreased local
, U! E# {# D0 B  o8 u& n1 Q667
2 a- _& w# \$ u# R668 KLUGO AND CERNY
% E) F: c2 V3 z0 ?& ~; I; [% nPt. Age
7 B; ]! M, E0 p; y(yrs.)
" l( K- X8 d' ^6 ]+ |7 HSerum Testosterone Phallus (cm.) Change Length+ z( l7 q6 K' d
(ng./dl.) Girth x Length (%)3 p- ^# [, b( f3 E4 P% j+ b0 M
4
3 K. B# p& j) X2 w; P8
$ v  w7 Y+ Q8 g10' J% y% g0 s5 M* c: \
12$ j$ Y2 J& s+ y. J/ w- u
173 P7 Y7 h( k0 l( R4 X3 p
Gonadotropin, u, M& {" T( ^8 i& s3 e
71.6 2.0 X 3 16.68 N5 i. |) k/ L( w; c& ^
50.4 4.0 X 5.0 20.0
) [5 e8 I  ?# o. A9 _0 ~. n' U22.0 4.5 X 4.0 25.0
" M7 r9 F+ K. W; ~3 h- V% a+ I84.6 4.0 X 4.5 11.1
3 S7 X+ I$ j* s6 R5 I85.9 4.5 X 5.5 9.0
, R) Y- F8 I, J/ k! m% n4 Z( t4 MAv. 14.3
, j, z- D0 n+ g4 A* Y/ G0 U40 H+ a& a* \% A/ X" a
8
* D: H4 s8 Y7 V# d10" L" q: l/ |/ W5 \! l0 Y
12' B- _& H/ C% B: g8 S) v
17' N8 ~- n+ a5 Y/ E0 M$ v! x
Topical testosterone
( V* W& h$ m4 F) _6 T. e34.6 4.5 X 6.5 85
+ w  V2 S, d' Y( Q38.8 6.0 X 8.5 70' b" b2 W* z2 a' s, X) ^" m, _
40.0 6.0 X 6.5 62.5
% j$ g$ F4 T& G- ]- P+ I2 Q93.6 6.0 X 7.0 55.58 R" g& _- \" G; o* `/ T( ~
95.0 6.5 X 7.0 27.24 ]# _- t! v% ]
Av. 60.0
& R" f+ v" W1 z) m' `3 {5 Yavailable testosterone. Again, emphasis should be placed on
: z2 b$ R8 n+ ]8 A0 \$ e$ Q5 ?early therapy when lower levels of testosterone appear to
9 F- |9 \1 U! Y  l' [provide the best responses. The earlier therapy is instituted4 t  W! F# O% u
the more likely there will be an excellent response with low9 u* P; j$ t2 B1 c  H! C4 M; ?
serum levels. Response occurs throughout adolescence as2 q/ u- A7 i- W8 F) s3 ^" o
noted in nomograms of phallic growth. 7 The actual response) A0 {  U4 H; b( ~
to a given serum level of testosterone is much greater at birth& G7 D1 n1 Y6 s5 ^) a: [
and gradually decreases as boys reach puberty. This is most. G! j# _0 w9 k% s. g9 H
likely related to the conversion of testosterone to dihydrotes-
0 s/ K: a2 Z) S6 }- n; {! t( dtosterone and correlates well with the studies of testosterone
- D& F, [- @$ f8 A4 v0 i5 p) ^+ Bconversion in foreskin at various ages.
0 T0 q) u% q4 j1 }8 @) WThe question arises regarding early treatment as to whether
! ]$ Z# \# N: T) P. y  j( Vone might sacrifice ultimate potential growth as with acceler-0 a2 Q) z$ u# T4 V9 r2 X
ated bone growth. The situation appears quite the reverse
* b" T+ E7 v; Z6 b. x4 }with phallic response. If the early growth period is not used- f0 W/ C) ~* K0 r0 }& z1 Z# k( i
when 5a reductase activity is greatest then potential growth
% D; F6 \+ a! G" j0 g$ gmay be lost. We have not observed any regression of growth& Q: |, m4 N  A6 ]) ~( G; v( G
attained with topical or gonadotropin therapy. It may well
8 X6 v& e  R* C7 `be that some patients will show little or no response to any9 I. ]; R  L/ q) O
form of therapy. This would suggest a defect in the ability to" b* P) m$ E! l0 _: A# v' i- T
convert testosterone to dihydrotestosterone and indicate that  r( @; J  N- F# {' [8 O
phallic and peripheral skin, and subcutaneous tissue should7 v$ l/ }, P9 J" @5 J) s3 K
be compared for 5a reductase activity.
% b( W* |# ^0 }  U" a3 d5 t1 z6 HA, loop enlarges to measure penile girth in millimeters. B,* E6 K2 `* j- m) H( L3 }4 T8 u
example of penile girth computed easily and accurately.. m9 _/ v9 J7 ~" }  i/ }
conversion of testosterone to dihydrotestosterone. It is in this, D, Z. T/ V; [. U
older group that others have noted high levels of serum
2 V" @/ E& L0 }& L1 otestosterone with topical application. It would also appear
( f# H) [$ Y% v+ n+ Fthat phallic response during puberty is related directly to the
2 P$ ^0 z0 S# d6 @: v+ aserum testosterone level. There also is other evidence of local+ I; g6 G& q2 V. i7 L. }( D
response to testosterone with hair growth and with spermato-
, s# T* O" i1 _genesis. 5• 6
3 n# n& j  d) o8 p8 v1 YAdministration of larger doses of gonadotropin or systemic' Y" k/ ~- V: x% C7 P
testosterone, as well as topical applications that produce
( d, ?$ g( f! l5 k4 P. E( ?7 Jhigher levels of serum testosterone (150 to 900 ng./dl.), will$ Y9 }. R: z0 q0 |$ _" S4 u% |2 a
also produce phallic growth but risks accelerated skeletal7 [2 _5 c& q) O8 ^7 V# ?/ J8 V
maturation even after stopping treatment. It would appear0 n: U/ L/ E9 q; D/ [1 w/ n
that this may be avoided by topical applications of testosterone
% W1 G8 h. g1 F' hand monitoring of serum testosterone. Even with this control: t% S# n5 S1 @
the duration of our therapy did not exceed 3 weeks at any/ L' e( }3 n( R3 X
time. It is apparent that the prepuberal male subject may, h7 d5 i% @: Y/ Q  K3 ?
suffer accelerated bone growth with testosterone levels near
# Q: k) |7 q: z. j# [" w3 l9 W200 ng./dl. When skeletal maturation is complete the level of8 t0 e. [' l6 l* J0 B
serum testosterone can be maintained in the 700 to 1,300 ng./
2 p# T. B9 }4 A" X- C4 r3 P; vdl. range to stimulate phallic growth and secondary sexual: }( D* `7 e* \6 F  c
changes. Therefore, after skeletal maturation parenteral tes-1 P* I9 G9 u7 v5 r
tosterone may be used to advantage. Before skeletal matura-0 H+ B6 R8 ^5 ^
tion care must be taken to avoid maintaining levels of serum$ t3 Z0 n3 r$ I8 P& }5 Z6 |& P* M
testosterone more than 100 ng./dl. Low-dose gonadotropin
# R) u  Q3 X6 Q- Q( Y/ Zdepends upon intrinsic testicular activity and may require
3 R  m% |1 X2 e( l* b4 w2 ]# Pprolonged administration for any response.2 L" f+ Z# i5 L: Z* e
Alternately, topical testosterone does not depend upon tes-* I3 p7 r* A- S! e* F2 L
ticular function and may provide a more constant level of% E$ s1 I4 O& P7 \6 ~
REFERENCES
4 w& }" t: M4 ]! B* C1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,) p& E( H3 |+ z9 G1 U6 w
R.: The local application of testosterone cream to the prepub-; X: x8 L+ E! v3 w
ertal phallus. J. Urol., 105: 905, 1971.
4 D3 e7 ~& c5 H2 V8 b2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone) b9 R- }6 o2 x3 k" w
treatment for micropenis during early childhood. J. Pediat.,1 P  k3 @! b( r, J( v% ^
83: 247, 1973.0 J' u8 B" ]  [& E, t
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
; f3 @8 t& u3 }: V7 j. V6 l, Eone therapy for penile growth. Urology, 6: 708, 1975.
/ W0 ^* Y7 Q& Y1 d4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
; y7 V* ?0 z: Pto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by: K/ D4 g$ p( I! V" f; @$ o
skin slices of man. J. Clin. Invest., 48: 371, 1969.
, E$ [# K6 @; k5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth. D0 ~2 @6 T6 Z: |* B
by topical application of androgens. J.A.M.A., 191: 521, 1965.
: E- L2 R2 N2 w% E9 Y, O6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
) c1 q' }$ t0 Jandrogenic effect of interstitial cell tumor of the testis. J.
& k8 f! K0 B( j: k; nUrol., 104: 774, 1970.! y6 J7 _: e- z& U
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-4 A! C4 S* X. v1 L* ~
tion in the male genitalia from birth to maturity. J. Urol., 48:
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