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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
- A8 a) B  [2 o( I1 KGONADOTROPIN
4 \' K- Z2 ~9 i# {. f) f$ D+ p6 |RICHARD C. KLUGO* AND JOSEPH C. CERNY. h" V, y9 O; W
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan* {$ ^4 G9 m& b& x0 F0 a  z* |
ABSTRACT
1 I0 g+ n& x* S: U0 _Five patients were treated with gonadotropin and topical testosterone for micropenis associated
7 {9 ?) J& X# E5 Xwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
9 N5 G. [# A9 k. Jtropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
- O) E8 B1 F, I3 ]% Ecream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
! v! q7 c. K. r0 t) Hfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
/ ]  S$ E) u( H& V$ |increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average# }0 H* J9 F" }7 _
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response& h. C2 Z7 S3 I, {
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
% s# W' c% u/ Mstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
, \7 w  \. e4 P5 F" cgrowth. The response appears to be greater in younger children, which is consistent with previ-
' O3 t. g, g8 Q% b) lously published studies of age-related 5 reductase activity.; n. A  N- Q" u4 E+ f/ m3 @
Children with microphallus regardless of its etiology will) e& N' X' N- N! L$ W% y( d
require augmentation or consideration for alteration of exter-& k& ]& M- Z7 q% O# g8 Y
nal genitalia. In many instances urethroplasty for hypo-
" ~* t, ^: l6 l* C6 nspadias is easier with previous stimulation of phallic growth.7 Q1 }0 z. u: l+ T  ]! Z7 |* t* r: T
The use of testosterone administered parenterally or topically: _$ k  _+ `) p  x* i
has produced effective phallic growth. 1- 3 The mechanism of$ J3 @6 H" ^$ K% r4 Q: a
response has been considered as local or systemic. With this: ]: _5 A2 j- S' V5 @6 A
in mind we studied 5 children with microphallus for response  k: I- w3 p* E4 b
to gonadotropin and to topical testosterone independently.
7 X4 N9 Z2 W3 z, y1 |MATERIALS AND METHODS' x: N4 b% \$ T) Q5 b3 B
Five 46 XY male subjects between 3 and 17 years old were, d$ v6 g3 ]2 p6 l# `
evaluated for serum testosterone levels and hypothalamic# u* p, c8 i# n1 U4 x
function. Of these 5 boys 2 were considered to have Kallmann's8 n# o( t* g4 j& v; [
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
! T3 r% d& }5 x7 V. X2 s- V& [lamic deficiency. After evaluation of response to luteinizing
$ D5 l* b0 V% d- G5 i; Ohormone-releasing hormone these patients were treated with2 P% _$ P' {$ _: O% a6 W
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
& l2 D* C. q& V5 c% Y& s5 Nafter completion of gonadotropin therapy 10 per cent topical
3 F- a& Q# j1 B/ D' ?testosterone was applied to the phallus twice daily for 3 weeks.
4 g' S9 l  C- o/ D; k$ NSerum testosterone, luteinizing hormone and follicle-stimulat-
2 l3 K3 y& H( s# P2 A1 Y, ^8 bing hormone were monitored before, during and after comple-
% ?* C0 X$ X; E: Ation of each phase of therapy. Penile stretch length was
( n8 n5 v9 {7 O$ i" u' Uobtained by measuring from the symphysis pubis to the tip of" \4 b# k5 e) u, Z6 v
the glans. Penile circumferential (girth) measurements were- X+ R, ^/ b9 ^7 @
obtained using an orthopedic digital measuring device (see
/ G1 Z0 i: @6 K3 V, j' }3 C3 gfigure).
1 P" ^! t2 k0 f! D& S4 ^RESULTS
6 O1 d$ j- x5 g1 \% P/ b! A4 oSerum testosterone increased moderately to levels between! v: L1 D" {/ C. R1 |
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
. z' ?' R- Z5 sterone levels with topical testosterone remained near pre-
, r1 p& L, J& C, Ztreatment levels (35 ng./dl.) or were elevated to similar levels5 E: K4 o4 t8 n
developed after gonadotropin therapy (96 ng./dl.). Higher; R$ X6 W- l) `2 a5 m: d
serum levels were noted in older patients (12 and 17 years old),% T! L1 c( U7 n+ K
while lower levels persisted in younger patients (4, 8, and 107 g! ~4 b0 I* |. S: k: e
years old) (see table). Despite absence of profound alterations$ I2 j% T5 D0 }3 W4 T! i6 v! w  Z
of serum testosterone the topical therapy provided a greater
  s3 }8 g! ^/ ]8 i, OAccepted for publication July 1, 1977. ·
8 H) N- S8 ]* y+ TRead at annual meeting of American Urological Association,* B- u" ^8 }& x
Chicago, Illinois, April 24-28, 1977.
& u% k2 K2 g: [' H, ?, G* Requests for reprints: Division of Urology, Henry Ford Hospital,
. c1 K9 E/ a) q8 Q2799 W. Grand Blvd., Detroit, Michigan 48202.& f2 z: A' U, H. l/ C: B1 l
improvement in phallic growth compared to gonadotropin.
& M% @/ i4 `6 Y/ nAverage phallic growth with gonadotropin was 14.3 per cent4 u, I- C  V- T
increase in length and 5.0 per cent increase of girth. Topical8 x& P* X# j8 ?
testosterone produced a 60.0 per cent increase of phallic length+ f+ I$ J3 S: O6 V8 l  s
and 52.9 per cent increase of girth (circumference). The" a  J) J# }1 K1 Z% N
response to topical testosterone was greatest in children be-2 s" ^+ s4 X5 U5 x
tween 4 and 8 years old, with a gradual decrease to age 17
% M. H' w& x$ c! I. Qyears (see table).$ \2 a" g: o( u" P0 _( Q. B
DISCUSSION
3 ~& f# `' v1 O* X0 v* `1 kTopical testosterone has been used effectively by other
/ ]2 P6 R; L! Z4 _; qclinicians but its mode of action remains controversial. Im-
& d/ `1 a3 c/ Nmergut and associates reported an excellent growth response
) n$ B& A& _, r: ]- I, m2 W  @. zto topical testosterone with low levels of serum testosterone,' c5 S& ?. ]- D# I9 i
suggesting a local effect.1 Others have obtained growth re-( f) s! U4 }% y  T$ `* q
sponse with high. levels of serum testosterone after topical( G* h7 ~2 R8 n+ I' G7 q; G# Z2 Z
administration, suggesting a systemic response. 3 The use of
) i! A' W" ^3 S: Agonadotropin to obtain levels of serum testosterone compara-) }# n  B& I: A7 }2 K7 I
ble to levels obtained with topical testosterone would seem to9 f5 \/ N. @, w1 q! b0 ^; a
provide a means to compare the relative effectiveness of  @# ~; T! k7 Q" B
topical testosterone to systemic testosterone effect. It cer-
* I( e: r" V; ktainly has been established that gonadotropin as well as par-9 P2 S; R: d" d7 `# R
enteral testosterone administration will produce genital4 k* r  X8 d( W7 @( F) e9 R$ E
growth. Our report shows that the growth of the phallus was5 u3 }* |: x3 G6 n
significantly greater with topical applications than with go-
! ]. z! J( M$ x. R# F5 ?nadotropin, particularly in children less than 10 years old.
& X/ N. |, B2 [- H0 TThe levels of serum testosterone remained similar or lower
! F4 j+ s9 j& L0 I, N5 d* qthan with gonadotropin during therapy, suggesting that topi-
+ P# C% ^! E: w. {/ E8 x! Ccal application produces genital growth by its local effect as; `% P' _: S4 U! c
well as its systemic effect.
( Q5 e2 c$ o, |% @" KReview of our patients and their growth response related to9 O1 j! \" m! [6 h0 M$ u; W) ^) X
age shows a greater growth response at an earlier age. This is5 B$ o) F  p9 O
consistent with the findings of Wilson and Walker, who
9 C7 \! T* z- l  Z. V3 Qreported an increased conversion of testosterone to dihydrotes-
( c! y$ [1 W( t& _/ _; b- ]; I3 Ztosterone in the foreskin of neonates and infants.4 This activ-5 p/ i) c* I6 R6 w1 G$ ]8 w( a
ity gradually decreases with age until puberty when it ap-! Z- ?# z4 x0 d* [8 V1 c
proaches the same level of activity as peripheral skin. It may5 j, E: P9 W  L  d+ u9 `
well be that absorption of testosterone is less when applied at
1 v. T+ c% _8 Dan earlier age as suggested by lower serum levels in children* C7 l( [; @# L8 l9 t
less than 10 years old. This fact may be explained by the
2 Y; ?2 d7 R" B+ I8 H0 jgreater ability of phallic skin to convert testosterone to dihy-0 {4 `2 r$ E" Q+ d; L8 ^
drotestosterone at this age. Conversely, serum levels in older
) h0 B$ o) l' m7 ]5 I# z2 ~! ]9 cpatients were higher, possibly because of decreased local0 o% ?0 J  j/ ]$ v
667
. m% A4 M2 C8 v3 \! U& U668 KLUGO AND CERNY! a4 p) W$ `4 \
Pt. Age9 b7 s( A; y- T8 d0 J  t
(yrs.)
) l# e4 @  ]6 L/ f. A& m4 ~4 }3 NSerum Testosterone Phallus (cm.) Change Length
8 |, `5 a/ N  t& H(ng./dl.) Girth x Length (%)
4 K: X; Z1 U- |! S5 D4" |9 y# I& j( p. |+ u* w
8
! i: q. j9 K9 l10' P  f. U8 W, ]7 L8 N6 u$ M
122 Z! f; f1 s/ ?8 r
17
) ~( s- Z$ ]  UGonadotropin
2 C- T3 Y' ]7 x" t71.6 2.0 X 3 16.6
+ Y3 Y0 b& q- E. ?9 z5 G2 x50.4 4.0 X 5.0 20.0
- E/ y$ F7 |! A# Y; W) q9 m  N7 C22.0 4.5 X 4.0 25.0
% g+ s) a0 n6 N, S) B5 y; x8 K84.6 4.0 X 4.5 11.10 P, B1 |& H# m5 t. `
85.9 4.5 X 5.5 9.0
. |3 r+ V. z! }1 H, h3 PAv. 14.3
4 J2 W! \) g0 B: s4
3 m  w- H! l' M& o  d8% L! B8 r' M" X: Q8 K# K
10
+ D- }* l" L& e12
5 d. t5 B( d2 E2 B2 _6 A0 n17
0 {" n, K9 j0 o5 Z, }6 ZTopical testosterone
0 ?# Z0 Z/ v* E- E+ g# j34.6 4.5 X 6.5 85) f* W; m7 f. t" F$ J: b1 l! o
38.8 6.0 X 8.5 70$ Q. K) C1 l' L; h$ w% x
40.0 6.0 X 6.5 62.5# W7 y/ u, J% ~
93.6 6.0 X 7.0 55.5
+ `  X+ p/ j3 ~0 r* D4 v95.0 6.5 X 7.0 27.2
( {% x* V* K! H  h- GAv. 60.08 z% G: o! [# U  T3 o) ?
available testosterone. Again, emphasis should be placed on* g% ^" d* b! g- ?
early therapy when lower levels of testosterone appear to
  s' z! F/ x. c9 K! [4 o8 Wprovide the best responses. The earlier therapy is instituted
, @3 g8 a5 U5 l; pthe more likely there will be an excellent response with low+ C' {# F  k8 P- b9 y
serum levels. Response occurs throughout adolescence as
6 u+ b! g* B% @/ d7 A2 [, nnoted in nomograms of phallic growth. 7 The actual response- D# m+ c% @( n7 K$ J/ Y; w
to a given serum level of testosterone is much greater at birth2 C/ l9 a; }0 B3 p, D! V
and gradually decreases as boys reach puberty. This is most
* ]! s& a5 K) a0 f4 ulikely related to the conversion of testosterone to dihydrotes-) H: ^9 [! [1 x  f: j$ i
tosterone and correlates well with the studies of testosterone% u6 B: L5 d% e- K/ x4 n1 Z
conversion in foreskin at various ages." d6 E" |! i$ Y6 C$ O
The question arises regarding early treatment as to whether
+ ^9 e7 {: b9 \- s6 x! Pone might sacrifice ultimate potential growth as with acceler-
' Y7 n9 r. ?; L  Gated bone growth. The situation appears quite the reverse& ]$ k6 p6 S( B3 }+ r( E# v6 H
with phallic response. If the early growth period is not used- A- p# C+ y- ?  E
when 5a reductase activity is greatest then potential growth4 k! e% r4 E$ j% ^  a; Q/ [
may be lost. We have not observed any regression of growth3 S. T; ~- U% D. ]) C/ K1 P
attained with topical or gonadotropin therapy. It may well
" w/ m, G& ^" q  a* pbe that some patients will show little or no response to any( U5 z* l! C1 w2 F1 W1 |
form of therapy. This would suggest a defect in the ability to! k/ x$ c3 i- v
convert testosterone to dihydrotestosterone and indicate that
$ m4 d5 |) F$ i+ cphallic and peripheral skin, and subcutaneous tissue should1 S- u1 B( U* x& g: l) T9 J3 \; V
be compared for 5a reductase activity.
' S9 ~; |- c" Z; kA, loop enlarges to measure penile girth in millimeters. B,. [* ^. N' P/ x( P( W$ R
example of penile girth computed easily and accurately.2 C$ l+ Q9 S" A# R! m
conversion of testosterone to dihydrotestosterone. It is in this/ _% F; Y+ ~( F& X+ f0 U
older group that others have noted high levels of serum
; T, [# a8 @! b+ Utestosterone with topical application. It would also appear
6 r$ H! {" j  l5 H8 Ythat phallic response during puberty is related directly to the
. q" L& ^' F5 `3 Qserum testosterone level. There also is other evidence of local
8 ]" Z! ?* c3 ^response to testosterone with hair growth and with spermato-
, D- y; ~* C' Dgenesis. 5• 6
, ~5 C* h" B1 [( [3 b0 O- i, MAdministration of larger doses of gonadotropin or systemic7 q2 Q# _" Y6 I* f3 f7 j! Y8 J/ S
testosterone, as well as topical applications that produce# F! _/ h0 J$ z0 N
higher levels of serum testosterone (150 to 900 ng./dl.), will8 c. O  |" u) |+ p; M
also produce phallic growth but risks accelerated skeletal
0 k4 {; Q# A* ?- {maturation even after stopping treatment. It would appear
; {$ M* j$ W2 v: O! I. k* {that this may be avoided by topical applications of testosterone
; N' P) i2 R! ^7 X) {, n" jand monitoring of serum testosterone. Even with this control2 x% l) Y7 }1 J* }8 k: E# A
the duration of our therapy did not exceed 3 weeks at any1 K. B2 g! R, U5 Q8 a( v
time. It is apparent that the prepuberal male subject may
* b  w7 B$ F3 K3 Q  S. z' ?" g  Usuffer accelerated bone growth with testosterone levels near
3 ~! f% @9 c: W1 ]200 ng./dl. When skeletal maturation is complete the level of
5 ^  ~; K' Q4 E5 C$ |serum testosterone can be maintained in the 700 to 1,300 ng./# t4 |, O7 N* ~. _7 I, ^$ d% I. V
dl. range to stimulate phallic growth and secondary sexual
. a9 }! e( b& r  {- P" Jchanges. Therefore, after skeletal maturation parenteral tes-
2 U) c1 T: l9 r7 Y$ |8 Vtosterone may be used to advantage. Before skeletal matura-
$ y. l1 }- L( Z* `$ _- T+ c/ ?tion care must be taken to avoid maintaining levels of serum  w1 O# ^' w6 x; Z4 c% {
testosterone more than 100 ng./dl. Low-dose gonadotropin, n4 O- }6 i4 c
depends upon intrinsic testicular activity and may require
9 g  m# k# ~* d1 [% E! z) `, A" Qprolonged administration for any response.
6 ^1 l4 q+ B+ _7 Y' o# x/ J; Z& N3 tAlternately, topical testosterone does not depend upon tes-
% w% w8 m, R' N' J* q; Yticular function and may provide a more constant level of
1 G$ l' u4 g. O) j6 B$ |REFERENCES
0 ]+ @% v; u+ |) u& y" q" D: ~# P1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,7 x* y$ b$ ^4 N/ o. ^; S
R.: The local application of testosterone cream to the prepub-. V4 W# Z; A' t4 q
ertal phallus. J. Urol., 105: 905, 1971.# J; Q* w) H" L
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
, F8 ]+ I3 e$ Dtreatment for micropenis during early childhood. J. Pediat.,% [  P( w* o; T& O7 G
83: 247, 1973.5 Y7 X) c) k$ V$ p5 G# e( a( K
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-2 n# B. p, s, ]$ _
one therapy for penile growth. Urology, 6: 708, 1975.
  p. n: L3 Q5 }) S+ ^* R4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
/ m- L  T! r/ o8 eto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
" x; w3 \0 q, M5 ~5 Vskin slices of man. J. Clin. Invest., 48: 371, 1969.
. I- ?4 G6 f# P) |7 x- {5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth# r6 y8 s6 W- D+ W' [" h
by topical application of androgens. J.A.M.A., 191: 521, 1965." @. B- ^8 x: N* X, x. W5 B9 T1 d
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
8 Z4 l* _. l5 l- B# E) |  \8 Jandrogenic effect of interstitial cell tumor of the testis. J.1 e/ T/ r6 H0 U) Z: {; ^
Urol., 104: 774, 1970., a& O/ v' U! k2 c1 R
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
3 ?1 E0 q2 R. k% m9 r4 D7 m! t5 Ttion in the male genitalia from birth to maturity. J. Urol., 48:
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