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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
9 v! s0 l2 I/ s4 h& E0 B* T9 D; `5 vGONADOTROPIN
8 V5 V. D0 B0 H0 uRICHARD C. KLUGO* AND JOSEPH C. CERNY/ r7 p7 N; l! |! `9 I' b
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
$ U* l9 L/ l# k2 l( b" tABSTRACT
5 O8 ~9 M$ {: @' D/ SFive patients were treated with gonadotropin and topical testosterone for micropenis associated' B  l/ k5 b9 J& g3 J
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
; t8 Z' ]' u9 f' A, \* vtropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
/ f* D" A3 v3 L$ Mcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent/ C" V: o) P% i
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent  r0 m( {1 j% d5 k
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
4 w6 L- w# j5 a& y% B) ^, H/ Gincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
1 u( O) C% C5 k$ Q! R! H" k* j  qoccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
4 j/ E" \6 j) F" T* `study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile" P$ Y. ]7 [+ ^+ F( N' \
growth. The response appears to be greater in younger children, which is consistent with previ-
3 V/ a' Y3 s% r4 |; |ously published studies of age-related 5 reductase activity.
3 p; K& Y. V( t7 d5 h! nChildren with microphallus regardless of its etiology will
( D# Z. i2 f. c4 Z: ~. Qrequire augmentation or consideration for alteration of exter-- e: W5 Q: t  V8 n$ y( |
nal genitalia. In many instances urethroplasty for hypo-
- j' [" G8 y) k* c3 ^spadias is easier with previous stimulation of phallic growth.! `3 i8 [1 M) [! Z2 Y
The use of testosterone administered parenterally or topically
) {# \+ ^% H5 |9 m7 b1 Rhas produced effective phallic growth. 1- 3 The mechanism of
0 j3 g% l+ ~) C' Sresponse has been considered as local or systemic. With this
* O' x7 K  Q- N/ K8 o& i$ sin mind we studied 5 children with microphallus for response
, W/ R& m3 x2 K2 ]  g2 I6 bto gonadotropin and to topical testosterone independently.3 I5 z1 R- {) q& ~
MATERIALS AND METHODS: Z+ D5 N0 Q9 T4 d7 Q' r
Five 46 XY male subjects between 3 and 17 years old were
. B/ J3 v  Y: F/ uevaluated for serum testosterone levels and hypothalamic' ]% r; O8 G' r
function. Of these 5 boys 2 were considered to have Kallmann's
9 w% X0 s+ D7 ?8 g! Y5 y2 Msyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-1 q4 \' \! D& A0 ]. D! q9 s
lamic deficiency. After evaluation of response to luteinizing
6 `1 B, X  j+ ]+ D9 Ghormone-releasing hormone these patients were treated with" J" S% G9 y) h2 q1 B
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
, `$ s9 j# q5 _$ ]after completion of gonadotropin therapy 10 per cent topical
7 B/ S- H$ ?  C  D: Mtestosterone was applied to the phallus twice daily for 3 weeks.
$ j& v6 |7 t; |/ H- t( B2 @# c/ aSerum testosterone, luteinizing hormone and follicle-stimulat-0 i( q& F% Y2 D! {3 B
ing hormone were monitored before, during and after comple-
" W$ X5 z) L. ~. I+ ^tion of each phase of therapy. Penile stretch length was' l: {3 G$ S& K8 ?% ^1 ~
obtained by measuring from the symphysis pubis to the tip of" v: w1 F9 l+ p9 `  Y6 j
the glans. Penile circumferential (girth) measurements were
7 H/ g* x( |/ k/ Z5 R7 U+ gobtained using an orthopedic digital measuring device (see8 I" H( g1 s* n
figure).
6 O: j, P. A6 q) K) E- @RESULTS: a  n$ y' h' s" b0 I3 m# d
Serum testosterone increased moderately to levels between0 H0 q7 H* @4 {  l
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
/ O) v; d8 L4 n  s) A% l1 {+ zterone levels with topical testosterone remained near pre-" o0 v/ v" I' @1 n5 P
treatment levels (35 ng./dl.) or were elevated to similar levels
5 u& Y# U$ i" \developed after gonadotropin therapy (96 ng./dl.). Higher
' i- o0 \7 o/ F" c+ x' fserum levels were noted in older patients (12 and 17 years old),
; \3 R8 g1 z! {$ i8 w$ Ewhile lower levels persisted in younger patients (4, 8, and 10
" C$ f" Z0 q6 U0 myears old) (see table). Despite absence of profound alterations4 j4 S6 Z7 j% X1 r! `9 u0 \
of serum testosterone the topical therapy provided a greater
/ v& ^: A/ j0 @. Y! xAccepted for publication July 1, 1977. ·' {& p/ j* F  X1 u3 m1 ~7 s! r
Read at annual meeting of American Urological Association,
& p; y6 M3 ]  m* _3 q) UChicago, Illinois, April 24-28, 1977.3 k* {) G$ `) `
* Requests for reprints: Division of Urology, Henry Ford Hospital,
+ a& x+ C, I' o; J2799 W. Grand Blvd., Detroit, Michigan 48202.2 o, A5 g& z5 ]8 j9 b3 C( b. g
improvement in phallic growth compared to gonadotropin.& ~6 J' @5 A9 c, e
Average phallic growth with gonadotropin was 14.3 per cent
; ~! v, E: t3 y6 M+ a$ Wincrease in length and 5.0 per cent increase of girth. Topical% p+ {3 f7 }$ ^. Z9 m
testosterone produced a 60.0 per cent increase of phallic length
! i) N# D+ v8 q! U$ Dand 52.9 per cent increase of girth (circumference). The
' `, N6 f- R  xresponse to topical testosterone was greatest in children be-
$ ^1 @6 D5 p( ?9 C0 Ptween 4 and 8 years old, with a gradual decrease to age 17
8 y* V, E8 \- t7 d# {. syears (see table).+ G9 o+ H# k, Z
DISCUSSION" q0 u5 ^! D' z% V  Z
Topical testosterone has been used effectively by other
  f% j( a+ ]  L9 o/ j( hclinicians but its mode of action remains controversial. Im-
( q- J! ]1 U7 C. q: dmergut and associates reported an excellent growth response
0 Q9 [  U8 E. ?7 Gto topical testosterone with low levels of serum testosterone,7 j4 w. j/ f9 ]4 O- ?3 s0 S- |
suggesting a local effect.1 Others have obtained growth re-
$ B9 y6 z9 ^+ e! `; [9 ~" }/ asponse with high. levels of serum testosterone after topical
; p8 ^  L2 N2 P. `+ d; aadministration, suggesting a systemic response. 3 The use of. W. a5 ^/ K; X4 K8 g
gonadotropin to obtain levels of serum testosterone compara-
+ n# W7 z3 ]. e) fble to levels obtained with topical testosterone would seem to+ I6 V8 `7 q9 T, `# K
provide a means to compare the relative effectiveness of$ K; |4 A" |. }: D4 H
topical testosterone to systemic testosterone effect. It cer-- s8 V2 r5 ~  q9 q
tainly has been established that gonadotropin as well as par-  K, L; h8 C7 s; ?/ P/ N
enteral testosterone administration will produce genital8 I. K0 `1 t0 ?
growth. Our report shows that the growth of the phallus was
1 G, g8 S1 W" k' i' vsignificantly greater with topical applications than with go-+ ?' ?- m+ X$ S! i, e% w
nadotropin, particularly in children less than 10 years old.
/ l7 Y) r) S- V3 BThe levels of serum testosterone remained similar or lower# c0 P! v% \+ r1 u
than with gonadotropin during therapy, suggesting that topi-0 M, Y! X! M# g! j8 J2 m4 [& Q5 s
cal application produces genital growth by its local effect as
+ z6 W6 c3 V) |/ @1 @well as its systemic effect.
. Y. k( k' w3 Q! n! X  f/ Y# ]Review of our patients and their growth response related to
1 V& p/ j' _' t( _5 Eage shows a greater growth response at an earlier age. This is
, X$ p/ i& F2 L8 T; u5 lconsistent with the findings of Wilson and Walker, who* P- A4 Q; F' Z! Z4 c
reported an increased conversion of testosterone to dihydrotes-+ p! U7 h6 T% I+ D# v9 g
tosterone in the foreskin of neonates and infants.4 This activ-$ C- S5 `7 Z. x  T- P! y7 d3 \/ w) Y7 D
ity gradually decreases with age until puberty when it ap-
5 ]: |# y$ }; s: Yproaches the same level of activity as peripheral skin. It may' y5 k+ s7 h5 l9 z( G
well be that absorption of testosterone is less when applied at( l8 V7 R5 m8 r- P% n
an earlier age as suggested by lower serum levels in children  R# z* ]: O5 N9 H% o0 h# k1 {
less than 10 years old. This fact may be explained by the
2 w( ?+ O  f; Y. h; R' G+ [, Agreater ability of phallic skin to convert testosterone to dihy-
3 e/ m0 L$ P! w3 T& @drotestosterone at this age. Conversely, serum levels in older3 x, W( C. b) ?7 W" W5 V  `
patients were higher, possibly because of decreased local
0 P% h3 r) p% s) U; u8 r7 k5 N667+ w7 o6 m; [# Z5 J  o  C9 k* M% o
668 KLUGO AND CERNY
0 R; {' Z' U/ c2 l6 Q& X# {& `6 LPt. Age
4 w, l0 Z: o; o6 M(yrs.)
7 F8 H; V  c, W2 n$ P; t) `9 [Serum Testosterone Phallus (cm.) Change Length
3 [2 W' J& z5 G( x8 S1 T(ng./dl.) Girth x Length (%)
/ X0 I' a2 a7 j4. W. G; a9 [) ^0 O3 A9 S
8
8 a( @: n3 V/ y0 n/ e) E10
1 W8 w$ ]9 r' ^& A/ O% S12
, l' p& X" u$ \+ B0 G* [, l17! R+ T  b8 i7 l" U& _( p
Gonadotropin, t* W7 i  K% s# s9 W
71.6 2.0 X 3 16.6
9 U; a! z5 c* e. q9 i' r50.4 4.0 X 5.0 20.0+ o+ t. @' k% ?& W+ L1 h
22.0 4.5 X 4.0 25.0
2 K7 g1 v+ A! o# e, p84.6 4.0 X 4.5 11.1
' |7 Z! q( T9 b7 r2 E8 O85.9 4.5 X 5.5 9.0+ Y  G8 h7 ^$ X# Y) o: M  s) V
Av. 14.3
! E" Y4 _3 N3 j* G% ?# b5 K3 _4
  E4 T/ R' ~/ L8% j2 C6 I6 M4 s3 ^1 t7 \+ G
101 H; e. ?& O% t' E* d% p1 t6 B& _
12
: N6 ~( h. o- L" F( S2 a170 `8 Q! h6 Z: N2 H! d4 w/ m
Topical testosterone6 N' c% }9 N* ?) U% `
34.6 4.5 X 6.5 85
! S8 Z# S; _0 _0 E% c4 h0 X38.8 6.0 X 8.5 70
7 i. o( R$ Z1 F, }* s40.0 6.0 X 6.5 62.55 G1 ]! C+ ^$ w
93.6 6.0 X 7.0 55.5
8 \$ l- T; n- q- _' {95.0 6.5 X 7.0 27.2
2 Z6 a& Y' o; qAv. 60.0
4 p! j, [% v2 ~available testosterone. Again, emphasis should be placed on
5 ?/ {/ k. ~  G0 c: W$ H6 d3 dearly therapy when lower levels of testosterone appear to3 N: e$ j; y- c4 `) I8 t; i
provide the best responses. The earlier therapy is instituted
1 J9 Q( @. Z) q( A/ u2 Sthe more likely there will be an excellent response with low
$ S- j% B6 g& Eserum levels. Response occurs throughout adolescence as+ f. O* T+ c1 T. K" |
noted in nomograms of phallic growth. 7 The actual response* _+ x0 q; P9 [2 P8 d
to a given serum level of testosterone is much greater at birth$ d' o! u5 U1 _" k# ]" |
and gradually decreases as boys reach puberty. This is most7 R( N( ?' U) j; ?7 c- v8 X
likely related to the conversion of testosterone to dihydrotes-5 d) V8 u/ G2 u! h$ B0 |& d2 E) t
tosterone and correlates well with the studies of testosterone* C+ m2 [- c. p( ]2 |% b! A7 n: y
conversion in foreskin at various ages., t4 o" }2 j% N; G7 j! x5 K. N+ p
The question arises regarding early treatment as to whether5 r; n( P8 L6 ]6 z
one might sacrifice ultimate potential growth as with acceler-  R0 m# o8 T+ C! v# K8 U4 Z2 I
ated bone growth. The situation appears quite the reverse* z! s+ e) G5 \! S; ^
with phallic response. If the early growth period is not used
! z/ v1 d6 O5 j0 swhen 5a reductase activity is greatest then potential growth4 X5 F8 m" s6 n" k
may be lost. We have not observed any regression of growth
0 ~% n3 \& |4 i. L1 y! P# u4 T7 cattained with topical or gonadotropin therapy. It may well
8 J1 v" ]3 Z+ e  Xbe that some patients will show little or no response to any
4 H" K  r& I* j" \: \form of therapy. This would suggest a defect in the ability to
4 Y$ U# E) o5 [  M$ Rconvert testosterone to dihydrotestosterone and indicate that
5 \* I2 |% P; y( nphallic and peripheral skin, and subcutaneous tissue should
; L0 Z! F4 W4 Z; P8 K7 ^( Mbe compared for 5a reductase activity.
, u' B/ P4 |4 O: J  hA, loop enlarges to measure penile girth in millimeters. B,2 w- i) S: l* n
example of penile girth computed easily and accurately.
3 R! x" R) D5 d) X+ ~& z( C/ G! J8 jconversion of testosterone to dihydrotestosterone. It is in this% F7 s1 }) T( T$ _* j, g
older group that others have noted high levels of serum8 |/ o; ~) `" J3 a+ T) P" }* t
testosterone with topical application. It would also appear
/ C* Q" [5 C+ K& zthat phallic response during puberty is related directly to the; x  T0 K, u! \0 K) o
serum testosterone level. There also is other evidence of local
% m9 O3 ^( @" w3 \response to testosterone with hair growth and with spermato-
' k& `3 Y0 |3 k' ?6 m$ c  zgenesis. 5• 6+ [& e: P- t! P
Administration of larger doses of gonadotropin or systemic) A+ h# R: z1 ~0 ?* r% ?
testosterone, as well as topical applications that produce. y4 l0 A1 ]$ z% S5 O# O( D5 f
higher levels of serum testosterone (150 to 900 ng./dl.), will
. [, V" m. ]" h6 Balso produce phallic growth but risks accelerated skeletal
) }2 h$ k+ w& x* {maturation even after stopping treatment. It would appear; l; R! s; J. w0 H
that this may be avoided by topical applications of testosterone2 s" j2 S7 l, M" A+ |. E1 X5 n5 s  n# c
and monitoring of serum testosterone. Even with this control9 o6 D! p4 J# |2 H( b% ]0 N
the duration of our therapy did not exceed 3 weeks at any
+ u: C% Q8 W# Z8 c& y$ |6 |& c0 ytime. It is apparent that the prepuberal male subject may
0 u% p) `* D/ S4 nsuffer accelerated bone growth with testosterone levels near' z$ x2 `8 R3 a! c, `" M: `8 k
200 ng./dl. When skeletal maturation is complete the level of
  E) m/ a$ V# q# |* Vserum testosterone can be maintained in the 700 to 1,300 ng./
7 G3 |/ V% S/ L8 L' g0 |. j& {9 \dl. range to stimulate phallic growth and secondary sexual
  q  i2 `5 Y8 H9 r7 C2 ^changes. Therefore, after skeletal maturation parenteral tes-
) j9 g& [% J) E" {tosterone may be used to advantage. Before skeletal matura-
; l; j2 D: k2 `. s% jtion care must be taken to avoid maintaining levels of serum
6 }" B2 n0 C/ R0 m8 Q6 w$ G0 Z: ~) Otestosterone more than 100 ng./dl. Low-dose gonadotropin7 H7 N0 v3 `3 ~8 ?3 O
depends upon intrinsic testicular activity and may require
3 [8 ^4 X' y- Xprolonged administration for any response." G6 T+ b+ P% O0 V, M/ O+ A
Alternately, topical testosterone does not depend upon tes-
4 J" s& [' Z+ ]- y' p/ nticular function and may provide a more constant level of  n# ]2 k/ k* w/ o. B4 y2 B! |5 Z
REFERENCES+ B( P4 I: G9 ^6 ~+ c$ p
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
1 f: ]0 W# m! q8 k# s& XR.: The local application of testosterone cream to the prepub-
9 K+ b0 H1 z; N7 c" }ertal phallus. J. Urol., 105: 905, 1971.
. j" \' L2 Q% ]* @, F. J: d6 V2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone9 e$ i% L4 q& _7 [3 S; y
treatment for micropenis during early childhood. J. Pediat.,3 P+ E# A( K# c& Q) q9 T
83: 247, 1973.
1 s" w7 H: M% W3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
  U- [1 ?! ]4 W! m! ^# u, I4 ?one therapy for penile growth. Urology, 6: 708, 1975." Z7 C+ h' `. T# Z4 u3 U+ X
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone3 F, N" q* a) U
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
" z- R, J" c- v1 hskin slices of man. J. Clin. Invest., 48: 371, 1969.
1 u8 i4 l# f) B& y& Q( {5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
. O- h+ I% @9 Oby topical application of androgens. J.A.M.A., 191: 521, 1965.
# u4 h3 t& L' w6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
, P0 Q. Q# X  X1 F* e; T! {. Qandrogenic effect of interstitial cell tumor of the testis. J.: L7 t+ [; [* {. b1 y3 [
Urol., 104: 774, 1970.
3 Q  @9 E6 P7 b7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
6 a8 {7 o% h8 I1 Y& A7 D8 ztion in the male genitalia from birth to maturity. J. Urol., 48:
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