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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND7 j* p) o0 r/ B8 n. `' }; J- m
GONADOTROPIN) ?, |% e& Q, H( m$ H
RICHARD C. KLUGO* AND JOSEPH C. CERNY* {% T& D* J5 u
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
# y" g3 l* _7 n# E) s+ HABSTRACT9 T% ~9 a( l- @  [  s: D2 h
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
  d' N2 ^& T) V! B. J3 L+ iwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
1 T, |0 y' k) m- K6 x6 K4 h0 j& \2 Q6 Mtropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone& N4 ^  e: l5 i$ c' k- c) F
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent- q$ L6 j. s0 J  w! |- p
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
7 M- ~- b" Z* @' qincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average: E) N$ r$ [( w0 m: H1 x
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
5 P6 Q( r3 ], X# A/ f+ Foccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
0 G' t) r6 ^5 b0 Q5 L- o, sstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
; ]1 z4 a6 ^' l- Q2 g% qgrowth. The response appears to be greater in younger children, which is consistent with previ-8 _# l2 k' t5 F+ F, w
ously published studies of age-related 5 reductase activity.& S0 r7 A( q. W6 z$ l
Children with microphallus regardless of its etiology will
% t' {% A! Q$ `require augmentation or consideration for alteration of exter-
& r, T+ z- h8 t3 cnal genitalia. In many instances urethroplasty for hypo-
0 W& j. b* l. }' z; Yspadias is easier with previous stimulation of phallic growth.. T* q; y, c& y6 j
The use of testosterone administered parenterally or topically& U9 O/ D! [# M
has produced effective phallic growth. 1- 3 The mechanism of
  m# Q2 E7 N* `# |response has been considered as local or systemic. With this# K* T( e5 H% p' _
in mind we studied 5 children with microphallus for response5 Y* Z: X8 x/ v# v/ A
to gonadotropin and to topical testosterone independently.0 M9 K) Z* U5 w2 @1 R" Q/ `1 F' B6 m
MATERIALS AND METHODS
" r* O* Y' Y1 S3 p( }Five 46 XY male subjects between 3 and 17 years old were. H# x5 h' H  o( M
evaluated for serum testosterone levels and hypothalamic
: G2 x; z" a8 S0 Sfunction. Of these 5 boys 2 were considered to have Kallmann's( N* w1 n+ z0 M, J$ a' J
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
' h1 ^1 ?4 [4 q4 \lamic deficiency. After evaluation of response to luteinizing
2 `0 [6 ^0 x+ W$ z' r6 }hormone-releasing hormone these patients were treated with
" b' z& @. B, {% u; U1,000 units of gonadotropin weekly for 3 weeks. Six weeks
' i3 d1 u8 H8 Y8 L/ {6 g7 @0 e1 vafter completion of gonadotropin therapy 10 per cent topical
; I1 d: F5 m$ r' F+ k. dtestosterone was applied to the phallus twice daily for 3 weeks.
, j# b- @! v6 `( ?Serum testosterone, luteinizing hormone and follicle-stimulat-/ |3 K0 U  n0 P# h0 j
ing hormone were monitored before, during and after comple-
  ]/ s/ ^  \* y' p" htion of each phase of therapy. Penile stretch length was
5 O' f+ o1 h' h1 C- I, O4 Mobtained by measuring from the symphysis pubis to the tip of5 {4 W# y; E# h
the glans. Penile circumferential (girth) measurements were
& E1 j8 v1 Z( Q+ a1 d1 mobtained using an orthopedic digital measuring device (see3 e1 R0 B9 J! o+ i
figure).
* l+ S0 h: n1 C$ t; V# S1 PRESULTS
2 B( b  B& ]' S6 USerum testosterone increased moderately to levels between& ~1 W3 w+ r" |# U, O7 |. v
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-5 z+ W! w$ E, D" z; v) M
terone levels with topical testosterone remained near pre-# E1 S1 h3 e2 n! \8 c# O
treatment levels (35 ng./dl.) or were elevated to similar levels  \3 _2 O0 l9 O$ X
developed after gonadotropin therapy (96 ng./dl.). Higher( @5 z  M6 y+ q& V9 V2 M) L
serum levels were noted in older patients (12 and 17 years old),/ E2 [0 K4 C* a4 J7 M3 Q! I
while lower levels persisted in younger patients (4, 8, and 10! |- F7 \' J& E4 O2 o. N9 o
years old) (see table). Despite absence of profound alterations
: e6 ~- q! U. N8 i( a7 l0 ^+ R, v9 _of serum testosterone the topical therapy provided a greater: ]9 z/ g+ F3 C) B; |! ]. i
Accepted for publication July 1, 1977. ·
# b! X, I3 v9 D+ H- p' e' l3 |Read at annual meeting of American Urological Association,
5 y4 z! d3 P) X* ^5 TChicago, Illinois, April 24-28, 1977.
. ~- L9 k0 s4 _: `2 S% o* Requests for reprints: Division of Urology, Henry Ford Hospital,- I! H* `: H1 j. q4 i. |
2799 W. Grand Blvd., Detroit, Michigan 48202.
# F; X- _/ n4 P2 Gimprovement in phallic growth compared to gonadotropin.
  U3 W+ h8 b5 N4 FAverage phallic growth with gonadotropin was 14.3 per cent
3 x/ {/ c% \; s. g/ S( M! [increase in length and 5.0 per cent increase of girth. Topical7 h# W7 E+ ]3 a
testosterone produced a 60.0 per cent increase of phallic length
$ T$ o) H! E# Gand 52.9 per cent increase of girth (circumference). The! z  ]' L' ^8 X0 T+ G
response to topical testosterone was greatest in children be-6 b+ p4 m6 r9 G0 `& J
tween 4 and 8 years old, with a gradual decrease to age 17
" A0 R& z1 A8 [$ t7 E5 |years (see table).( l* {' i" Z4 p$ A
DISCUSSION
# F5 g/ L, B9 {  ^8 c9 c# yTopical testosterone has been used effectively by other3 ^. M5 U5 i. P7 A& H7 |" Z
clinicians but its mode of action remains controversial. Im-
' K. T8 q# S1 w0 _mergut and associates reported an excellent growth response
4 |: B8 i% m; l% T( Bto topical testosterone with low levels of serum testosterone,
$ |5 \1 F4 P( @! g8 c- M/ Fsuggesting a local effect.1 Others have obtained growth re-  {3 d1 a* p( f- K
sponse with high. levels of serum testosterone after topical4 O( V6 T* w3 p" i- G
administration, suggesting a systemic response. 3 The use of) U1 w$ H& k9 K' P
gonadotropin to obtain levels of serum testosterone compara-& f, i& g8 A( y  r& D" ?: C$ m/ M. F, g
ble to levels obtained with topical testosterone would seem to7 r7 J8 N1 m2 O' X5 z, x7 a
provide a means to compare the relative effectiveness of  D' ^# e  C, g% X& j- v
topical testosterone to systemic testosterone effect. It cer-
! ^+ r3 p  u" x! a" p; q# Wtainly has been established that gonadotropin as well as par-" t+ ^% f% N" U; i0 f# D/ _
enteral testosterone administration will produce genital! L2 G+ @2 R' ^& |# M  p
growth. Our report shows that the growth of the phallus was
1 f4 F, Y$ o$ X# a0 O" ]* f3 C: esignificantly greater with topical applications than with go-
$ V) k8 L5 V5 G2 wnadotropin, particularly in children less than 10 years old.$ I6 L9 F$ e* X6 U, d
The levels of serum testosterone remained similar or lower
/ X+ K/ E# l2 a% N+ I6 ythan with gonadotropin during therapy, suggesting that topi-
& P- j. T$ n. Qcal application produces genital growth by its local effect as
) S+ n0 g- R8 Q8 K- {' O. xwell as its systemic effect.
2 d# U- M0 n& b, Z$ {* {Review of our patients and their growth response related to+ A9 R+ w4 i2 g) J( ~0 m1 l
age shows a greater growth response at an earlier age. This is
- N* y9 d+ k+ \) ^consistent with the findings of Wilson and Walker, who
1 x9 {; y8 c7 Q! }reported an increased conversion of testosterone to dihydrotes-
* g+ S/ @/ E/ ?! ]tosterone in the foreskin of neonates and infants.4 This activ-
5 [1 u' v. K) City gradually decreases with age until puberty when it ap-& Q' R- \/ o! G5 I; W
proaches the same level of activity as peripheral skin. It may
4 f' U  Z9 G! S( a* |9 \well be that absorption of testosterone is less when applied at
9 S. j6 E: N' H( v4 uan earlier age as suggested by lower serum levels in children
+ K5 f  u+ v1 M0 [# Q' Kless than 10 years old. This fact may be explained by the# c0 C& g# b3 L" ~. V8 G6 @
greater ability of phallic skin to convert testosterone to dihy-# N- a$ B1 v% B' x5 D2 Y
drotestosterone at this age. Conversely, serum levels in older
$ D7 q4 e; i0 P! L1 \; Kpatients were higher, possibly because of decreased local
( w) H' N7 f8 \' C; D; P9 p667. {+ h6 d/ `" e! _
668 KLUGO AND CERNY, V9 N  {: w5 _5 f7 I5 G  C
Pt. Age* F1 N( E! E. ^9 N# c
(yrs.)% F! X! g5 z1 I8 s6 U- M( u
Serum Testosterone Phallus (cm.) Change Length! u+ @; g- X( K( |
(ng./dl.) Girth x Length (%)
" i  V3 f% ^6 O6 _+ ]5 _4& I3 y" y, P: O; a
8
% n3 m" ^2 w" J$ M- G5 Q. T, ~; r10
& m' w9 x5 @) E+ H* S4 D* p12
1 `* I) H1 M& ]( r/ h+ R7 a3 G17$ F$ o2 M* S3 I" o
Gonadotropin0 F6 G" f; L& `0 d/ a
71.6 2.0 X 3 16.6
' t/ i6 Q& a1 X2 J' {' c/ K/ T% e50.4 4.0 X 5.0 20.0
7 ]& R1 Y8 |; _- w  Z22.0 4.5 X 4.0 25.0
+ H" n/ U/ r( H% W84.6 4.0 X 4.5 11.1% T4 ]2 k: t  Y9 h4 t. E2 P* V
85.9 4.5 X 5.5 9.0
) ]9 s/ ]" N. ]# \! x5 d! H6 CAv. 14.3) V; \6 W) [$ O# s, j4 g
4
/ }3 K9 p8 S7 |8 L3 L- r. `4 I& R$ S8& ]' u) h" U1 f  z; C7 I6 J/ ?2 q
10
6 V* p  @6 G8 P! w# p. y: {- L12
7 [+ U& {3 {( ^6 ~17
, i- l& Q/ X4 t% Y6 M& |" VTopical testosterone5 E# w+ P2 o5 v4 A. y! l. w: Y8 l
34.6 4.5 X 6.5 85
( P' T' \! ?# i; ~3 a. m+ n( a38.8 6.0 X 8.5 70/ f% v' x2 b8 s) ^# Q
40.0 6.0 X 6.5 62.57 m6 L/ Y6 X2 Y
93.6 6.0 X 7.0 55.5
6 A" l* V. `. H8 G) K, x- b) e95.0 6.5 X 7.0 27.2. w2 v2 Q1 g; I3 S
Av. 60.0
* E$ v5 X* l- r- I) e9 _; Bavailable testosterone. Again, emphasis should be placed on
4 Q* \* Q+ C6 j1 Jearly therapy when lower levels of testosterone appear to
( I0 x5 y* K/ c- n0 E" Rprovide the best responses. The earlier therapy is instituted
; `" H, f: v0 x+ b2 o8 Gthe more likely there will be an excellent response with low/ L8 r+ s* h' V
serum levels. Response occurs throughout adolescence as9 ?" L% W* j2 N4 C8 Q& a
noted in nomograms of phallic growth. 7 The actual response3 T1 B1 D" F( m
to a given serum level of testosterone is much greater at birth# Y5 X% v! Z* K/ N- @
and gradually decreases as boys reach puberty. This is most
- Q3 N# O( R1 }7 C+ A& Dlikely related to the conversion of testosterone to dihydrotes-+ C. \# R# J: N2 w( W8 C
tosterone and correlates well with the studies of testosterone$ a" n# b/ Q. r4 v
conversion in foreskin at various ages.# o, _" u5 j. v+ F+ h9 ~" U
The question arises regarding early treatment as to whether) v1 M# |) o8 P% z9 ?/ ?
one might sacrifice ultimate potential growth as with acceler-0 X. X9 |" x1 q% Q5 ?
ated bone growth. The situation appears quite the reverse
* t& Q7 C4 ~0 @( O  s6 Pwith phallic response. If the early growth period is not used
1 L: `9 X) R, A, {when 5a reductase activity is greatest then potential growth
5 W! ], [5 T4 s& j% ?& ^may be lost. We have not observed any regression of growth
3 U4 \7 U- ~2 l% lattained with topical or gonadotropin therapy. It may well
' e6 C* V( J4 C" L0 Y% m5 abe that some patients will show little or no response to any
3 q1 A* l. m3 Xform of therapy. This would suggest a defect in the ability to+ |5 N! e$ V1 ^" h1 t6 t
convert testosterone to dihydrotestosterone and indicate that
$ a7 g5 K1 U8 g7 Z- ?/ o: wphallic and peripheral skin, and subcutaneous tissue should
7 X% I3 C2 v; q! \+ c. xbe compared for 5a reductase activity.0 D, K7 d6 O3 O, D$ U1 i! r4 L! F: Z2 W) a
A, loop enlarges to measure penile girth in millimeters. B,, X/ @2 t, K% h+ a( B
example of penile girth computed easily and accurately.
7 b8 Q! J& c4 j; V4 e2 U" Aconversion of testosterone to dihydrotestosterone. It is in this
7 ^# M5 z4 A9 p( G- ~older group that others have noted high levels of serum
5 w, N& l- k) d- y& u7 e) ~testosterone with topical application. It would also appear
% q6 Q" F6 Z" x- m" B; Tthat phallic response during puberty is related directly to the" [7 q/ Y3 r2 f
serum testosterone level. There also is other evidence of local
/ D! Z- X: F4 X% Gresponse to testosterone with hair growth and with spermato-8 v+ p, q) \' @3 |2 t% B9 q2 @- x
genesis. 5• 64 |- r1 L/ v' c8 h. L& d+ w
Administration of larger doses of gonadotropin or systemic2 `/ U, l3 \& Q5 G+ k9 v  T: D
testosterone, as well as topical applications that produce
& m$ a8 W# b  g7 Jhigher levels of serum testosterone (150 to 900 ng./dl.), will0 k  _) ^  m/ X: |) b- ~' e/ X
also produce phallic growth but risks accelerated skeletal
9 `# V& r( B- M9 }" T7 Umaturation even after stopping treatment. It would appear
  a# y# Q8 Q7 x0 F* Vthat this may be avoided by topical applications of testosterone
6 F# K" W2 N( X. W8 jand monitoring of serum testosterone. Even with this control
1 p7 T) Q( U  q+ R: J( _  dthe duration of our therapy did not exceed 3 weeks at any
: t3 v3 n% c+ C8 l6 g0 P4 w3 Stime. It is apparent that the prepuberal male subject may- V$ W- m- ?4 P# i
suffer accelerated bone growth with testosterone levels near- g% A; `8 \% T% y1 r6 }
200 ng./dl. When skeletal maturation is complete the level of
, [* T9 E& q6 Z# T0 [5 ~* qserum testosterone can be maintained in the 700 to 1,300 ng./
# t0 X. J+ c; I  _/ bdl. range to stimulate phallic growth and secondary sexual
: y: t" d: `6 o! ~4 L" K7 r1 F& ~6 Rchanges. Therefore, after skeletal maturation parenteral tes-
/ ~5 ]7 ^0 b9 dtosterone may be used to advantage. Before skeletal matura-, ~1 r+ W2 v- r( A/ B. m
tion care must be taken to avoid maintaining levels of serum
* T- k7 `+ l% T; {5 v' u3 dtestosterone more than 100 ng./dl. Low-dose gonadotropin6 p; P$ C& `- C! K3 |
depends upon intrinsic testicular activity and may require
1 S# J' z& I4 e' F, j  ]prolonged administration for any response.
; A2 J* d5 h4 G) Q1 G$ {Alternately, topical testosterone does not depend upon tes-2 Y9 K! |# e/ T8 l5 \- N
ticular function and may provide a more constant level of( p  i- D* w- a, L! }
REFERENCES
2 ~6 P" H' G, }1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
& Y" J  t: ]" P0 y2 aR.: The local application of testosterone cream to the prepub-% V. h: p' k9 R* V0 k
ertal phallus. J. Urol., 105: 905, 1971.
' U) X8 V: a* N' Z2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone2 g5 T5 ^3 k% R- @5 _9 V
treatment for micropenis during early childhood. J. Pediat.,$ E4 H5 o5 y; R3 W
83: 247, 1973.
2 F1 P0 R: k( P3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
& q2 V3 C% ~# R4 jone therapy for penile growth. Urology, 6: 708, 1975.  @* U/ v9 a! L9 y$ l
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
: R: J% x% X6 p  l! X+ e4 c7 w! J$ Wto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
5 k# z3 Y" j' X( G( wskin slices of man. J. Clin. Invest., 48: 371, 1969.
* n, f/ d* `: Y+ |+ U5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth- q/ f  H: D7 \5 q5 C1 n
by topical application of androgens. J.A.M.A., 191: 521, 1965.
  N. O0 y" B- K5 G7 Z9 Z6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
+ f$ \, Y+ {* {0 ?androgenic effect of interstitial cell tumor of the testis. J.( s0 H/ R( o+ o. t& m
Urol., 104: 774, 1970.& s, u3 d, I; \) [5 c
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
9 _5 H2 y9 S3 |  j- P; [  Stion in the male genitalia from birth to maturity. J. Urol., 48:
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