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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND, N3 s: P' F9 s+ @. ]
GONADOTROPIN6 z3 Z0 G4 S( Q* X+ s: ]3 v) N/ @' o
RICHARD C. KLUGO* AND JOSEPH C. CERNY# x+ b9 [' @" E) z) h4 _8 h
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan: b' X/ \5 f5 [1 c
ABSTRACT
0 G' b8 p% D3 V( B9 SFive patients were treated with gonadotropin and topical testosterone for micropenis associated' M; w8 t! }9 O9 ~( [1 c
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-9 N& Y/ `2 Z: R8 B
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone" `- y) ~( v& j. k
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
6 H' g& m# z& H6 Z5 o# |1 nfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent* L) z, j; h9 l
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average7 Z9 T, ^/ Y/ b/ P. P3 B  J* O9 C
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response, {7 ^. x( m8 n4 A- u
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This. G* q* J4 H: ~& @9 W# I( r
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile$ m; V# u8 [4 l# z9 c' ^$ l+ g8 Z
growth. The response appears to be greater in younger children, which is consistent with previ-+ U; r, z0 P! S" X
ously published studies of age-related 5 reductase activity.2 H/ B1 d# v' B% o: L' x# N" y$ k
Children with microphallus regardless of its etiology will
* `) u# l8 p( |' U. V/ urequire augmentation or consideration for alteration of exter-
5 q' h- l2 b% l: D4 t- L* n  Pnal genitalia. In many instances urethroplasty for hypo-  q" T! |3 j4 K; e. m1 w. |
spadias is easier with previous stimulation of phallic growth.
4 n6 \/ b( F( ?+ ^: Y$ ~7 @The use of testosterone administered parenterally or topically$ o& q3 ]. u  {# h
has produced effective phallic growth. 1- 3 The mechanism of9 F9 x$ s5 ^8 Z1 x3 D8 Y7 S. {2 ^4 i
response has been considered as local or systemic. With this
- Z  ]. ?9 o0 b- v9 N6 F0 O6 kin mind we studied 5 children with microphallus for response
  {. `" H' X4 bto gonadotropin and to topical testosterone independently.
. x8 B* R& K- o, q; p- NMATERIALS AND METHODS
7 U9 K; n! i, v% k# b0 ZFive 46 XY male subjects between 3 and 17 years old were
7 u) Q5 Z7 o4 p9 `6 xevaluated for serum testosterone levels and hypothalamic
6 H4 {) L% c( H2 Kfunction. Of these 5 boys 2 were considered to have Kallmann's
% f4 `: Z* y* N, l" W# U& C) Usyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
& y% o* w! G+ b! |8 s7 m  C9 m2 nlamic deficiency. After evaluation of response to luteinizing  A6 j! H# {  ]( a; V
hormone-releasing hormone these patients were treated with9 r! Z0 L# U/ [8 I: f& W
1,000 units of gonadotropin weekly for 3 weeks. Six weeks7 B: Q5 W' w  v7 [0 l. x
after completion of gonadotropin therapy 10 per cent topical
! @# z# f4 S& m2 `; B. e# ]testosterone was applied to the phallus twice daily for 3 weeks.
2 f4 Y, C1 l5 z4 Z2 @) s$ U+ G/ TSerum testosterone, luteinizing hormone and follicle-stimulat-* _; F( G* b% V1 V- N0 |
ing hormone were monitored before, during and after comple-+ O4 D0 q) }( _9 r6 J9 s) o$ b
tion of each phase of therapy. Penile stretch length was1 v3 K/ N% R6 M0 v4 k4 X" x) c
obtained by measuring from the symphysis pubis to the tip of
  k0 w* P9 u/ lthe glans. Penile circumferential (girth) measurements were
: k2 _+ j+ {3 @. \0 T6 wobtained using an orthopedic digital measuring device (see
3 g" a/ s1 X$ g) C' X6 ~; Lfigure).; g3 y7 |/ r; A  A# l/ t
RESULTS# z8 S1 U# J  H/ g& F1 R3 b# }
Serum testosterone increased moderately to levels between  J8 X, }3 |0 ~# k
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
7 H. F, f3 g5 J* t0 u5 Nterone levels with topical testosterone remained near pre-
; j, S+ R5 L& N' f9 b/ D1 Otreatment levels (35 ng./dl.) or were elevated to similar levels8 T" ~3 A4 [3 J# V
developed after gonadotropin therapy (96 ng./dl.). Higher/ B( z) q4 h7 n( b7 R" c
serum levels were noted in older patients (12 and 17 years old),
3 k' u* L' `" o3 zwhile lower levels persisted in younger patients (4, 8, and 10
( x+ }; i) @7 I1 b: ~! myears old) (see table). Despite absence of profound alterations
. R5 m+ I4 R6 Y- Y: C" dof serum testosterone the topical therapy provided a greater
+ G! x- z0 \: AAccepted for publication July 1, 1977. ·# N) J3 c  V& P8 j' Q7 k
Read at annual meeting of American Urological Association,4 X8 H* `5 W, m/ l' [% P$ b, L! u
Chicago, Illinois, April 24-28, 1977.& {9 U( B, j0 @4 C
* Requests for reprints: Division of Urology, Henry Ford Hospital,
7 t& i' Y0 o5 B2799 W. Grand Blvd., Detroit, Michigan 48202.3 c, q, L( O! e% K, K
improvement in phallic growth compared to gonadotropin., c  J) f! q/ K+ o
Average phallic growth with gonadotropin was 14.3 per cent% V- W+ s% H8 Z- t1 A& k
increase in length and 5.0 per cent increase of girth. Topical
7 |$ v5 K5 V. W! d2 ^3 C! Ztestosterone produced a 60.0 per cent increase of phallic length' P- G1 h7 {' B3 g( ^& k3 K! z
and 52.9 per cent increase of girth (circumference). The
2 I; A  d9 |5 U3 U0 l2 p, v# a3 vresponse to topical testosterone was greatest in children be-
; `* t! V5 S2 Q  Q: G8 c3 ttween 4 and 8 years old, with a gradual decrease to age 17
! l+ t. S* k' {2 v/ I) h$ Lyears (see table).
- y# S7 K: K" K/ xDISCUSSION
! ~# ~- _! h+ _" j3 G( b1 h8 eTopical testosterone has been used effectively by other
4 L* i/ Q' ?& v0 q: E+ dclinicians but its mode of action remains controversial. Im-
* r6 m$ n9 v( S/ D  b+ Rmergut and associates reported an excellent growth response( j, n9 _: m/ M* `$ g$ F; ?$ G
to topical testosterone with low levels of serum testosterone,
" n  |( @% ^  i2 ?% L! Usuggesting a local effect.1 Others have obtained growth re-$ P* b7 t) @) v  ^0 F% v3 U/ R& `
sponse with high. levels of serum testosterone after topical
4 e3 [; x1 G% z' hadministration, suggesting a systemic response. 3 The use of
6 |0 V/ l6 B% i# d, \# Lgonadotropin to obtain levels of serum testosterone compara-
6 \1 L6 W- I" t5 n: W7 bble to levels obtained with topical testosterone would seem to
# z) r" y, |$ Lprovide a means to compare the relative effectiveness of
% I" B+ R5 e' |; htopical testosterone to systemic testosterone effect. It cer-
; ^$ J. i. Y; ?1 _" l# ~- \tainly has been established that gonadotropin as well as par-& C% S9 ]- [  ~
enteral testosterone administration will produce genital. a. X1 T4 h1 y
growth. Our report shows that the growth of the phallus was
$ `* B1 z. M; bsignificantly greater with topical applications than with go-
! E' `* r. I& [nadotropin, particularly in children less than 10 years old.
0 y* [: x+ ^, |' q) w5 y. gThe levels of serum testosterone remained similar or lower
- A6 |( h. F$ \: V7 ~6 |0 Othan with gonadotropin during therapy, suggesting that topi-
: M& o6 J2 @4 \& `* X: Mcal application produces genital growth by its local effect as
& f7 I: v* H* X, I$ K' ?7 cwell as its systemic effect.6 |$ j) B9 q/ w) h! ~
Review of our patients and their growth response related to
; A& ?" |3 U6 T( N2 _1 Uage shows a greater growth response at an earlier age. This is0 p4 E1 @$ @/ @2 _1 [0 h
consistent with the findings of Wilson and Walker, who! w2 I6 r  ?1 g4 I
reported an increased conversion of testosterone to dihydrotes-) i7 h$ f' b" l* @4 |
tosterone in the foreskin of neonates and infants.4 This activ-! S/ l1 k+ i8 E( M4 T7 N0 W
ity gradually decreases with age until puberty when it ap-
7 B, U- z- A  p% j; n& Sproaches the same level of activity as peripheral skin. It may
3 F( J, Y; V7 s8 s9 ~/ Y/ rwell be that absorption of testosterone is less when applied at7 j/ C" n  b3 n% R6 S3 B
an earlier age as suggested by lower serum levels in children
) w5 L* E7 Y% q3 g) l1 hless than 10 years old. This fact may be explained by the; T- e& x! _/ U
greater ability of phallic skin to convert testosterone to dihy-7 A2 f. d, S' P, P& [
drotestosterone at this age. Conversely, serum levels in older; _; r( g! t) d, Z8 M3 s$ K/ G, }
patients were higher, possibly because of decreased local
, T8 \0 u8 A$ P1 V! t5 S1 a8 M0 {7 C667
2 f4 z# r+ f' @9 q# W: G668 KLUGO AND CERNY$ |7 ]/ n* x) t1 ^+ @
Pt. Age
& y; k) \( r$ I' x, s0 ~8 c; J(yrs.)
7 W, U$ ]  j6 z+ F% tSerum Testosterone Phallus (cm.) Change Length
9 T) I% ?5 n3 O. g% C. P(ng./dl.) Girth x Length (%)
& y4 p1 i5 z8 |4& r! K; r! ~4 i: C- k' V9 ?
8
/ t" N2 N& k; \4 r10
3 v1 Y+ v- W) ^  S" x4 }9 u122 Q( W, _  p' u. ~  s4 g. H
17
6 s, H" L+ i0 n" z5 U2 D7 `$ UGonadotropin. C7 [0 o% W6 G) K. }
71.6 2.0 X 3 16.6
0 z! ]1 F* F, _, R& R0 o50.4 4.0 X 5.0 20.0
! X( O+ }2 {+ c- N- l22.0 4.5 X 4.0 25.0
, n! I% J/ a1 G6 q: j2 W84.6 4.0 X 4.5 11.1" p! l/ w2 n: j& j9 B$ G, ~$ ?& P4 d
85.9 4.5 X 5.5 9.0+ m* d' Z. K' b- E) L" u
Av. 14.3) o3 Y; o* l/ O6 h! {* R
4
3 [$ r8 X( j2 c3 u8" }0 f2 Y' M, j' f" T* F0 O
100 G( B3 ^7 x5 b4 O
12) o9 m) M, J2 |+ j' E
17- w& n$ S0 h. o% R
Topical testosterone
- z) A9 x4 X6 d3 C" ]  L' x4 c34.6 4.5 X 6.5 85% b4 f/ X% `7 N' J) X5 e
38.8 6.0 X 8.5 70  o( \* U8 E* u, f8 T- g* _2 Y
40.0 6.0 X 6.5 62.56 {$ @. @; O& Q! J1 E4 y
93.6 6.0 X 7.0 55.5
- }/ A, Z" B$ h" C: u95.0 6.5 X 7.0 27.24 Z8 \% k# |& J7 E8 i6 n. A3 R
Av. 60.0
: O* [! h# ~3 G+ a. x2 C! x/ ravailable testosterone. Again, emphasis should be placed on
; T5 i2 P2 ~: Z4 y1 ~6 _( |early therapy when lower levels of testosterone appear to9 \, @3 s6 ?2 e$ z% i* _2 ]
provide the best responses. The earlier therapy is instituted  A5 {: m# j" ?9 j/ i
the more likely there will be an excellent response with low
2 l. V5 s  ~" \0 l  Aserum levels. Response occurs throughout adolescence as
: p2 O: P) t" O8 `1 P" Nnoted in nomograms of phallic growth. 7 The actual response8 ?  Z8 Y: E; {+ \$ y
to a given serum level of testosterone is much greater at birth5 y. }/ ^! N* ]+ v. A1 C
and gradually decreases as boys reach puberty. This is most
6 `& M1 E/ p: U7 zlikely related to the conversion of testosterone to dihydrotes-) W) H3 p" Z/ G$ c7 R! L+ Q
tosterone and correlates well with the studies of testosterone/ h0 H, J7 C0 U3 }3 p2 Q% n
conversion in foreskin at various ages.
4 _$ X& i0 b0 t% O0 o) _The question arises regarding early treatment as to whether) F$ D, v3 G9 p8 L- i6 @
one might sacrifice ultimate potential growth as with acceler-
8 w  }7 I' v; s5 J/ Mated bone growth. The situation appears quite the reverse
% }- ]! r: V( F7 ~with phallic response. If the early growth period is not used
9 Q8 M7 u& _- k- wwhen 5a reductase activity is greatest then potential growth
) Y3 ^8 p) i, M8 s( M3 l4 lmay be lost. We have not observed any regression of growth$ [5 f: ?6 x  }' _
attained with topical or gonadotropin therapy. It may well
3 i) s3 @- L2 x  h$ D8 \; `! |* Hbe that some patients will show little or no response to any
2 f9 g) G7 a* `# S: d0 Qform of therapy. This would suggest a defect in the ability to
& v  R' w9 J; ?: M5 lconvert testosterone to dihydrotestosterone and indicate that: I3 q" \" ?+ m0 O0 A
phallic and peripheral skin, and subcutaneous tissue should+ g( p4 T4 H/ ~6 E5 M0 R
be compared for 5a reductase activity.
- u% ~) |# x' U, V/ EA, loop enlarges to measure penile girth in millimeters. B,- R% \# S! ~2 s+ q
example of penile girth computed easily and accurately.
- t5 ]. Y  X1 n. W& i3 J$ i% r" ]1 fconversion of testosterone to dihydrotestosterone. It is in this6 v4 o8 i; `5 Y8 [; d# a
older group that others have noted high levels of serum
- t( \. u6 h! V3 mtestosterone with topical application. It would also appear
3 E' i7 Q+ S# G' h  p  W: dthat phallic response during puberty is related directly to the
  V  n& g! k; I3 |serum testosterone level. There also is other evidence of local
9 Y4 U5 f3 ?" U2 q( R/ H6 A/ Xresponse to testosterone with hair growth and with spermato-
/ u2 I: q' o. b7 Egenesis. 5• 63 [- ^- e! V' L$ Y1 W3 S* @
Administration of larger doses of gonadotropin or systemic
# L/ `  U3 E: Ytestosterone, as well as topical applications that produce$ e8 }, a6 @9 `7 A& M4 H1 E9 A
higher levels of serum testosterone (150 to 900 ng./dl.), will8 m( w7 k% O8 ?/ a4 A6 m, f4 ]+ C5 Y/ J, X0 F
also produce phallic growth but risks accelerated skeletal
+ ]( ^( h, U- _  R8 rmaturation even after stopping treatment. It would appear9 f: A" x, d/ [  q
that this may be avoided by topical applications of testosterone
; \6 T! y$ ~3 c- t: o1 A+ oand monitoring of serum testosterone. Even with this control
  k- `+ d0 @8 ]the duration of our therapy did not exceed 3 weeks at any4 l; I, M# _% ~) R2 e
time. It is apparent that the prepuberal male subject may8 b( |! q4 t- W7 s+ ?# H- I$ u
suffer accelerated bone growth with testosterone levels near
9 i+ L( L* i7 ?; Y' ^2 T( u200 ng./dl. When skeletal maturation is complete the level of
3 E$ X2 d  j3 G. z' e5 P' jserum testosterone can be maintained in the 700 to 1,300 ng./, \$ y+ c: b7 e/ ]
dl. range to stimulate phallic growth and secondary sexual# J5 s9 ?" Y; ?6 |$ ?8 p
changes. Therefore, after skeletal maturation parenteral tes-
. G! w7 `  D/ x7 atosterone may be used to advantage. Before skeletal matura-- Y0 x4 v  f$ n* w% [# x0 Q5 i. n) u& `. N
tion care must be taken to avoid maintaining levels of serum1 U: |2 l' B1 J
testosterone more than 100 ng./dl. Low-dose gonadotropin6 h- Z( T$ u9 w! f% X# R$ ^
depends upon intrinsic testicular activity and may require$ q8 ]5 ]3 J  ]& O. ]+ x
prolonged administration for any response.; E1 V, ^+ Q* M, S! V) x) H
Alternately, topical testosterone does not depend upon tes-' V8 g+ d' ]. H. H4 V4 M
ticular function and may provide a more constant level of) ?$ ~# R; |( ^+ \
REFERENCES
) ^# y( K* D3 B) j" y% T. r1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,8 n6 T' T+ E7 r& `9 Y
R.: The local application of testosterone cream to the prepub-* ]$ P3 L* }$ m/ J$ D4 `) T; ]
ertal phallus. J. Urol., 105: 905, 1971.
5 Z6 k5 V9 f% N2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
) {. b9 z* S. L" P, M5 streatment for micropenis during early childhood. J. Pediat.,+ c5 g) a% D  \% Y
83: 247, 1973.+ S8 U) m! @, B* V) U
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
! M! t) _! O  [/ K& t% d# I# z, Tone therapy for penile growth. Urology, 6: 708, 1975.
, D0 A% g  ?: c/ N, o+ k" L* P4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone) n" a! k4 b2 h: B5 C8 g
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
) [8 w2 t  J# O# O" Eskin slices of man. J. Clin. Invest., 48: 371, 1969.6 |% v' i) ~& Y& ~- O  G( W& v
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
# u3 L: Q2 \+ m% T" }by topical application of androgens. J.A.M.A., 191: 521, 1965.
- ~4 b, a, i" S5 S5 y5 W6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local! a/ L+ [- P+ ?0 C
androgenic effect of interstitial cell tumor of the testis. J.1 Z6 U. v+ U- x% B
Urol., 104: 774, 1970.9 z. l' f! O, A3 G9 \7 _6 W# Z
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-* ]* b/ u# R6 j% z( A
tion in the male genitalia from birth to maturity. J. Urol., 48:
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