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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
, v+ j  b$ ?, z2 f) RGONADOTROPIN1 E) o. y& M# G8 ^3 O7 {& A
RICHARD C. KLUGO* AND JOSEPH C. CERNY
$ t; u2 k0 h/ |' \1 vFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
- U+ P9 M, T6 ?! X: U: ^6 G# AABSTRACT5 `" g( A- T9 H% C+ Y) f6 t
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
) R; B/ j2 {; R  m9 g- Qwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
5 l+ ^) M0 n. J; y# |) v" vtropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone! Q, I5 ]# C7 T* `4 ]7 B
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent0 N3 Q9 D% |. P8 P# ~0 u6 \; \; o
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent. L  ^0 y: e5 N1 I) G& b6 D) D7 [7 ~3 W
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
+ H# J4 O! |( u- aincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response5 h! F" P( z- E0 e, D) |
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
( F+ @  U% s1 o( j, M) O+ Cstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
/ g6 i! `/ c) A! ogrowth. The response appears to be greater in younger children, which is consistent with previ-* c" U/ m5 m- I
ously published studies of age-related 5 reductase activity.
! K) O, ^2 _$ Y7 b* zChildren with microphallus regardless of its etiology will4 s( i7 v* U% w/ X. \
require augmentation or consideration for alteration of exter-
# s! t) `( T! W4 v  ^nal genitalia. In many instances urethroplasty for hypo-
7 R: Z3 u; z6 P& H/ S3 N, fspadias is easier with previous stimulation of phallic growth.
+ H5 k; s/ v$ z( V! ?: vThe use of testosterone administered parenterally or topically+ q  T( i$ `1 j
has produced effective phallic growth. 1- 3 The mechanism of
4 W2 G# Y% t# R8 U7 P9 w) D' bresponse has been considered as local or systemic. With this
+ A: d4 S& c2 M  {$ tin mind we studied 5 children with microphallus for response) {. q0 t4 O' Q+ l! d4 T
to gonadotropin and to topical testosterone independently." ^7 b! G) C6 v% I" `1 }6 H
MATERIALS AND METHODS
' J2 K! f( P; _+ S- l6 qFive 46 XY male subjects between 3 and 17 years old were
+ H) M1 e# U8 f& ]  Hevaluated for serum testosterone levels and hypothalamic; Y/ Y" s% Z& F$ w5 v% J8 w
function. Of these 5 boys 2 were considered to have Kallmann's) k% r. ~- n( G+ o/ S' T7 [6 @
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-7 p% f& M/ b0 M8 o
lamic deficiency. After evaluation of response to luteinizing
% p1 Y7 [, u( R4 _5 Vhormone-releasing hormone these patients were treated with% v: F" b3 N% a  Q
1,000 units of gonadotropin weekly for 3 weeks. Six weeks/ V5 u1 ]( a/ |4 D* `' v- z; v) m
after completion of gonadotropin therapy 10 per cent topical
* u8 E& n9 h, B1 \" c+ f% j" Ntestosterone was applied to the phallus twice daily for 3 weeks.1 e4 S7 A! K' T/ q) n+ n; k- m
Serum testosterone, luteinizing hormone and follicle-stimulat-
$ P& w7 h$ e% |1 K9 ^6 V( Z8 Oing hormone were monitored before, during and after comple-! @# Z0 ^; ]: m/ u6 p3 G6 ^( |+ ~" d
tion of each phase of therapy. Penile stretch length was
9 N- p/ r8 w' H& tobtained by measuring from the symphysis pubis to the tip of
# i  q. Y$ i3 G: Xthe glans. Penile circumferential (girth) measurements were
3 z5 }$ n! L9 z) z7 E; Tobtained using an orthopedic digital measuring device (see
5 P+ c2 [0 K6 W% v- v- ?& Q# Wfigure)." V& a1 F) }3 Z9 y5 h) t" `
RESULTS
5 a7 S  O9 [( w& C5 @! w# eSerum testosterone increased moderately to levels between
2 \7 T  c! O/ {0 m50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
! V6 Q: F. l4 T7 S% @terone levels with topical testosterone remained near pre-* B4 q6 a, T5 b& ?8 P0 P( ?
treatment levels (35 ng./dl.) or were elevated to similar levels
) {# N8 p2 t* F. Y$ W- z* Kdeveloped after gonadotropin therapy (96 ng./dl.). Higher2 f! B5 u0 ?/ f, f. f  X- R
serum levels were noted in older patients (12 and 17 years old),1 B$ b5 n  [- ]# Y0 O3 c
while lower levels persisted in younger patients (4, 8, and 109 {" [, y% P4 W& v$ |# T
years old) (see table). Despite absence of profound alterations
3 a# s# U9 l% cof serum testosterone the topical therapy provided a greater
) j/ q% V& H# P( q. j' F2 MAccepted for publication July 1, 1977. ·5 A5 ^0 ]$ v$ J# d* {3 n
Read at annual meeting of American Urological Association,
* v& X" R1 g3 H! XChicago, Illinois, April 24-28, 1977.
9 y% J( ^; G, d  l" ]# x& j5 E* Requests for reprints: Division of Urology, Henry Ford Hospital,
# F6 h* E+ X! \. T2799 W. Grand Blvd., Detroit, Michigan 48202.# E' S0 g5 U/ R% e/ B6 s0 J$ `
improvement in phallic growth compared to gonadotropin.6 {( m2 T, l% Y) U& w
Average phallic growth with gonadotropin was 14.3 per cent# p6 q, w) P% X0 I/ B) \9 z
increase in length and 5.0 per cent increase of girth. Topical
# g2 b; k1 L" ]( ^. O& q2 y" z6 ~testosterone produced a 60.0 per cent increase of phallic length
3 h/ X' q5 G+ [% g) R  G! M0 L2 oand 52.9 per cent increase of girth (circumference). The: |; i! Z6 T/ F
response to topical testosterone was greatest in children be-
7 |6 u' o, A* a* d% Gtween 4 and 8 years old, with a gradual decrease to age 173 Z5 W8 D' f" \' K5 _  \
years (see table).
( D* ]5 }5 [' x$ |) JDISCUSSION
/ W1 {4 n& T+ l* W0 w. l- ~Topical testosterone has been used effectively by other
# U$ G+ {2 F1 D0 W9 Zclinicians but its mode of action remains controversial. Im-- d$ f0 {6 ~. }3 }$ m' D
mergut and associates reported an excellent growth response$ y- v% @( x. J! N0 |
to topical testosterone with low levels of serum testosterone,  s$ V/ T% z% L% I$ L5 I$ F! W
suggesting a local effect.1 Others have obtained growth re-
1 y/ Q  ~! a3 t3 v: Bsponse with high. levels of serum testosterone after topical
) c/ v: z5 a! B: ?; tadministration, suggesting a systemic response. 3 The use of% v; [4 M2 @+ z( n  g6 ^% y
gonadotropin to obtain levels of serum testosterone compara-
' y* P8 h' m" C5 h! N2 mble to levels obtained with topical testosterone would seem to
. B# i1 }6 M* B* iprovide a means to compare the relative effectiveness of
# A" W- \3 y  D! M8 s$ Ptopical testosterone to systemic testosterone effect. It cer-
9 k( A* R7 c5 _2 I4 [  }tainly has been established that gonadotropin as well as par-) Q1 K0 g2 b$ H8 @
enteral testosterone administration will produce genital$ S: U; C8 D2 ]7 Q" b
growth. Our report shows that the growth of the phallus was
) F; ?7 E" D9 F1 ~1 lsignificantly greater with topical applications than with go-# {1 O5 j, @9 W+ d3 U- `+ f' z
nadotropin, particularly in children less than 10 years old.
1 g5 z$ r  w7 g) I) u) k/ dThe levels of serum testosterone remained similar or lower& Z1 A# x; L6 r$ O8 E
than with gonadotropin during therapy, suggesting that topi-) n0 T( _" }' M% F2 Z$ j3 J- x0 ^
cal application produces genital growth by its local effect as
; ^& d/ H; A9 a* ^! x; K2 Fwell as its systemic effect.
5 O3 ]7 W+ f" pReview of our patients and their growth response related to
) T5 f9 c9 Q8 H( P( Mage shows a greater growth response at an earlier age. This is
2 g2 t4 c1 |: ^& aconsistent with the findings of Wilson and Walker, who2 m* Y6 g, d6 P6 r
reported an increased conversion of testosterone to dihydrotes-- ]3 D' P/ Y9 N2 u* ~/ o" B3 w
tosterone in the foreskin of neonates and infants.4 This activ-' T: P) [: v# n+ w9 H8 u% Q) Y
ity gradually decreases with age until puberty when it ap-4 e& Q: x, `# [- y
proaches the same level of activity as peripheral skin. It may
, j+ d3 _5 J/ W( @7 Q2 B5 [well be that absorption of testosterone is less when applied at% _1 I/ U) D" s8 _. m! n
an earlier age as suggested by lower serum levels in children
0 }4 B7 w2 E; S" {& e3 gless than 10 years old. This fact may be explained by the
; ^/ T) D# u; o' }greater ability of phallic skin to convert testosterone to dihy-
! W# J! P5 ?6 W% r9 N! Zdrotestosterone at this age. Conversely, serum levels in older9 H7 }+ _9 K: u& \* j
patients were higher, possibly because of decreased local& X) ~5 |" {! I$ V! o, x: ?" `/ B
667
5 I2 g  v6 Y5 E. A668 KLUGO AND CERNY% @; |9 P3 d' z8 f
Pt. Age: b2 H: ]' W9 B$ U# f/ z( s
(yrs.)
* l" v2 g" [6 ?7 v8 BSerum Testosterone Phallus (cm.) Change Length
2 [6 y- m( e$ o' M1 h(ng./dl.) Girth x Length (%)
, A0 O2 w) L/ Y) A5 }3 N49 w3 t% Y; ]' R4 {. X5 K. Y* |1 v
8( Q% s  d; q4 G5 n" ]0 A; S( F
10
: f4 u2 g7 A. T, ^* d12
) y1 R5 I9 T% {1 |. L8 X17
" C- m/ Y3 @; |3 F5 TGonadotropin' l# f9 P* E4 a# c% J. {7 n9 k/ X
71.6 2.0 X 3 16.6
1 O/ y2 G. x* T9 j/ `0 [50.4 4.0 X 5.0 20.0
- j) s; J9 m* e( q# y6 y! D, M* d22.0 4.5 X 4.0 25.04 \  J5 w' z- s$ y. s& m$ [% B+ w
84.6 4.0 X 4.5 11.1# p% x: G$ o& p- x, i4 R
85.9 4.5 X 5.5 9.0  D# v, @+ L, A
Av. 14.35 d0 [4 N2 p' L  u2 Y# A+ }
4* L$ j3 n. S: Y8 \& M  Y: Q
8
: D8 F$ r& ]7 V8 o10
: S0 Y& `$ l3 \8 C. l* J' m12  G: Q( A2 L0 Z" c2 ]
17; k* g! x+ W( |& C/ D$ I
Topical testosterone8 z2 T5 o0 B5 s  g5 F
34.6 4.5 X 6.5 85, P9 H  f  s: t$ g8 V
38.8 6.0 X 8.5 70
& _* |! o- q! E% y* R+ E40.0 6.0 X 6.5 62.5
3 k% w: v3 c2 z+ @6 w( T93.6 6.0 X 7.0 55.5
8 T( C8 \$ C' C0 D, j2 ?% E95.0 6.5 X 7.0 27.2
6 }3 p; c7 Y- x$ kAv. 60.0
  O6 w0 ?; l& }: M6 K7 w7 Savailable testosterone. Again, emphasis should be placed on9 K/ z" m: _: K, r5 m* i
early therapy when lower levels of testosterone appear to1 @3 B$ [" t* c& d# y! @# Z
provide the best responses. The earlier therapy is instituted
) H. _7 R' X7 i/ Z1 L, S/ Kthe more likely there will be an excellent response with low
: g7 R0 e; ?! r/ I7 Z3 g. xserum levels. Response occurs throughout adolescence as
( s8 Q7 P# x1 c  E# onoted in nomograms of phallic growth. 7 The actual response
+ O0 q" H. R  ~, Oto a given serum level of testosterone is much greater at birth: C2 k3 a* g, I
and gradually decreases as boys reach puberty. This is most
5 C+ s, Q, s1 R6 u: y1 Klikely related to the conversion of testosterone to dihydrotes-3 U6 D) p& s# b2 G- v7 \7 ]
tosterone and correlates well with the studies of testosterone
  G# n) d3 h/ mconversion in foreskin at various ages.
) J4 H! G$ J$ k- PThe question arises regarding early treatment as to whether2 ^" C0 @5 Z8 @! @! C- o
one might sacrifice ultimate potential growth as with acceler-9 n' ?5 e- `' Q' i0 \
ated bone growth. The situation appears quite the reverse6 Y( x: l  n7 c1 |/ q
with phallic response. If the early growth period is not used
4 l0 N! o# G. N4 ~( V* m! Nwhen 5a reductase activity is greatest then potential growth
0 w1 p5 g/ o, T# Y8 mmay be lost. We have not observed any regression of growth+ D( P. g! `: E) k: O( F$ f" f
attained with topical or gonadotropin therapy. It may well
  G, t+ M& a' r( q9 M) lbe that some patients will show little or no response to any5 p. v" n/ g! k0 u  O9 ?! M
form of therapy. This would suggest a defect in the ability to4 E0 L. w+ O3 a) S) d; @: J" D/ Y
convert testosterone to dihydrotestosterone and indicate that, y; c+ q8 e: a3 L2 [* c. v: O5 Z5 O0 p
phallic and peripheral skin, and subcutaneous tissue should! P* d' V3 |- C1 i& I2 p' J1 A
be compared for 5a reductase activity.
/ |4 {1 Y2 M; K4 {& h  G# n8 D, tA, loop enlarges to measure penile girth in millimeters. B,
" @- s4 R* C6 A! E! u5 Yexample of penile girth computed easily and accurately.* d+ y  G, F- E: Q* a9 W, f  G! ?; {
conversion of testosterone to dihydrotestosterone. It is in this
  ~$ L5 I$ x1 ?4 solder group that others have noted high levels of serum: \0 J& n! f, J& B9 B) b2 Q, V
testosterone with topical application. It would also appear7 k5 q. F0 r8 U' j. G+ s
that phallic response during puberty is related directly to the5 v" ]/ m: k/ U+ w' g% [+ e$ o) t# N
serum testosterone level. There also is other evidence of local
" H* ]6 {# i; H+ Uresponse to testosterone with hair growth and with spermato-
! u2 }. G* ~; U" |' |genesis. 5• 60 Q( v) M/ I$ k. @6 ]# g+ L6 P
Administration of larger doses of gonadotropin or systemic* {: |! p! ~" K) K$ z* b1 n% s6 u
testosterone, as well as topical applications that produce
1 X& |4 _9 L7 H* A: [9 ?; ~higher levels of serum testosterone (150 to 900 ng./dl.), will
4 e/ v. Q. N5 }0 S, I5 b3 ^& @8 ualso produce phallic growth but risks accelerated skeletal
0 x- ?# ~% D- V" gmaturation even after stopping treatment. It would appear2 A5 x5 _3 q" W# Q. Y. W4 Z- I- Y
that this may be avoided by topical applications of testosterone6 A0 ?  F" O$ K4 ^
and monitoring of serum testosterone. Even with this control
$ p2 ~$ @: E. ]9 L+ x" Ethe duration of our therapy did not exceed 3 weeks at any
" u! h, h; F3 Z4 M( Ltime. It is apparent that the prepuberal male subject may
& \+ W+ L1 }6 m. H8 z0 W8 rsuffer accelerated bone growth with testosterone levels near
0 ?/ ^- H2 ]  P" |7 b& _200 ng./dl. When skeletal maturation is complete the level of9 K! f0 h; ~' m- f
serum testosterone can be maintained in the 700 to 1,300 ng./
6 F; h8 v. y) P, i0 i- e" Ydl. range to stimulate phallic growth and secondary sexual
9 b- w8 j7 z' |" Tchanges. Therefore, after skeletal maturation parenteral tes-  `0 J, I! V- j4 Z5 E6 b
tosterone may be used to advantage. Before skeletal matura-+ F4 ^0 O" y% i2 J
tion care must be taken to avoid maintaining levels of serum# L& R0 i+ x- x6 @! l
testosterone more than 100 ng./dl. Low-dose gonadotropin
, }4 r  m# i' N" i! mdepends upon intrinsic testicular activity and may require
, w3 B5 r6 J2 m3 r( ~5 g- A( Eprolonged administration for any response.
! d5 o4 ~' Z; T$ LAlternately, topical testosterone does not depend upon tes-, L/ A  s- B/ D# y; j: B% d7 F
ticular function and may provide a more constant level of) I1 W1 {1 i7 Z9 w! L* M
REFERENCES) s6 L/ r  s- W) C! o# _' }
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
; \3 y1 i4 f- w! U3 ^3 DR.: The local application of testosterone cream to the prepub-/ e9 x0 H  H, I" A% U
ertal phallus. J. Urol., 105: 905, 1971.
" K# {# A. Z: E+ |0 J- O" b2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
# Z, D) w% C* v& I8 I4 @treatment for micropenis during early childhood. J. Pediat.,
/ Q( n/ ?# T' w' y$ ~83: 247, 1973.
3 V7 I: \: u( l" i, r3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
+ I" b1 x; [' t/ i1 wone therapy for penile growth. Urology, 6: 708, 1975.( s9 l2 r+ ]+ |
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone- I, U; R% N2 e1 v  m
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by$ h( D1 |. ~9 o, z
skin slices of man. J. Clin. Invest., 48: 371, 1969.' w5 ~' @3 d) I4 k9 j& X
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth( i/ b: I5 X; O0 ?7 k/ Y
by topical application of androgens. J.A.M.A., 191: 521, 1965.
4 F' |% Y' ?# w# A% M# j6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
) B$ V5 N; ~- Wandrogenic effect of interstitial cell tumor of the testis. J.' c2 i: B2 Z* [/ D
Urol., 104: 774, 1970.) J% g! Q- d' F( ?9 y& x
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
( _- C  d. F% B, ^tion in the male genitalia from birth to maturity. J. Urol., 48:
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