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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND7 A' P' q2 M, x+ E
GONADOTROPIN) y6 t. P+ k1 W# z# J
RICHARD C. KLUGO* AND JOSEPH C. CERNY* {2 T6 [$ o' d# D+ j. S
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan7 q4 {; F  e2 V. v
ABSTRACT
8 ?8 V) J* j( d- Z" d( L, |! {* kFive patients were treated with gonadotropin and topical testosterone for micropenis associated; ?* I  y2 ]! d- k
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-/ E; M5 p9 l$ l& b
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone% P* N) X9 @9 \0 }8 t
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent& ]6 O9 }" y3 D, C" x
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
6 i+ ^4 b* I) r9 i: Fincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average" L3 O0 j" j& ~( b) v
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
# y& ~3 `+ e% B: q. S4 Xoccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
; ]$ M$ F% ]4 a& \+ y$ @% w! Astudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
; x; O* b2 R4 u& J2 Mgrowth. The response appears to be greater in younger children, which is consistent with previ-
+ h5 Z! W0 n+ n  o3 Y# Bously published studies of age-related 5 reductase activity.% L, C2 L3 x) x" ~" J
Children with microphallus regardless of its etiology will
6 x8 x+ a  _0 u, x( x  T9 wrequire augmentation or consideration for alteration of exter-( W% p; P3 T* B7 i* g
nal genitalia. In many instances urethroplasty for hypo-% T  U) a) N0 L6 i4 X) f
spadias is easier with previous stimulation of phallic growth.
6 g- p& S. D' W0 G( M# \The use of testosterone administered parenterally or topically
& E7 @- ]5 _: O, W5 g/ Y+ uhas produced effective phallic growth. 1- 3 The mechanism of
$ B5 b$ K8 x) A0 f9 @/ Y% J; B: dresponse has been considered as local or systemic. With this
% X* d' S( ^# `# p' R3 Pin mind we studied 5 children with microphallus for response
# g4 g$ w5 ]$ e4 v7 X3 [8 a8 mto gonadotropin and to topical testosterone independently.
2 Y5 E2 x8 @* U2 GMATERIALS AND METHODS  y) Q* H9 V0 F( k. Q
Five 46 XY male subjects between 3 and 17 years old were, Y$ n  e8 a- r, v$ D: `
evaluated for serum testosterone levels and hypothalamic6 n. E) x+ s: W! a3 `
function. Of these 5 boys 2 were considered to have Kallmann's
: V- M/ m( S- W9 m/ ?: n2 Ksyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-9 [. d) x# D- |
lamic deficiency. After evaluation of response to luteinizing
7 {& [& |% C% ^! H- s  @0 ihormone-releasing hormone these patients were treated with
# ?$ `1 t+ [; Z2 ?' h7 S1,000 units of gonadotropin weekly for 3 weeks. Six weeks( n$ i( u* E2 R9 k2 s4 @
after completion of gonadotropin therapy 10 per cent topical& O) i( q+ K2 w/ b/ Z2 Q$ d; G8 N
testosterone was applied to the phallus twice daily for 3 weeks.( d2 h! w5 C- [& l
Serum testosterone, luteinizing hormone and follicle-stimulat-
# k' m$ _8 ]; l8 x! O# M. ying hormone were monitored before, during and after comple-
, V& l2 M3 ]0 }5 c  S  Z3 ~( P% Qtion of each phase of therapy. Penile stretch length was& ^/ d  w1 l9 E$ g, \
obtained by measuring from the symphysis pubis to the tip of4 o$ {7 x) l7 G2 J! p
the glans. Penile circumferential (girth) measurements were
" ^3 D; D1 l+ }$ |# i; lobtained using an orthopedic digital measuring device (see
6 Y( S% C# o7 X6 Q& X+ K5 [8 Ffigure).' j- [7 _9 Z& a  M+ @- g
RESULTS# H' ~# E6 R! ]* C4 E
Serum testosterone increased moderately to levels between8 P! E/ m% p9 i1 i( ^+ Q( Y
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
4 X0 P0 Q! h6 Y2 b) sterone levels with topical testosterone remained near pre-+ u! J7 ]* v/ \1 ?7 K- u4 M
treatment levels (35 ng./dl.) or were elevated to similar levels
7 Q$ V( z' @9 d# Z! }developed after gonadotropin therapy (96 ng./dl.). Higher" N8 n8 U* _) A" D! I3 z: k% G: g
serum levels were noted in older patients (12 and 17 years old),
3 K6 N+ t7 F/ s  ~while lower levels persisted in younger patients (4, 8, and 10
/ L- i; x9 o7 ^1 |- oyears old) (see table). Despite absence of profound alterations
1 J; J4 Q* o8 t9 c! M7 k% iof serum testosterone the topical therapy provided a greater/ J- p4 v$ \/ p4 a$ Y! P5 P/ w
Accepted for publication July 1, 1977. ·
( f, ^, K6 y% eRead at annual meeting of American Urological Association,5 d; X4 i. b6 P1 d# l9 O
Chicago, Illinois, April 24-28, 1977.0 P7 }( S, L& }# ]* z% k
* Requests for reprints: Division of Urology, Henry Ford Hospital,5 @8 C. h- d& n! s% Y. Z
2799 W. Grand Blvd., Detroit, Michigan 48202.( I' e8 {; ^- V# D9 x
improvement in phallic growth compared to gonadotropin.( F( e) g% [2 y. s& m' c3 ^
Average phallic growth with gonadotropin was 14.3 per cent
* \8 D) s* [( h2 ?9 G4 u' Sincrease in length and 5.0 per cent increase of girth. Topical
/ M3 A& x+ Z( h% l" V, l; s5 |. n- Htestosterone produced a 60.0 per cent increase of phallic length
6 P# n# l# X  R! {and 52.9 per cent increase of girth (circumference). The
: s" S9 \; X' I' d1 iresponse to topical testosterone was greatest in children be-
5 b+ R$ K! _4 ^+ F4 n/ Etween 4 and 8 years old, with a gradual decrease to age 174 `# r, W0 a* l" P& I1 y
years (see table).' s* @& l$ V) E9 Y: [- f
DISCUSSION
  t. e7 y( O  I, a3 K0 i# ]Topical testosterone has been used effectively by other4 U' K4 B6 [- x! `& |
clinicians but its mode of action remains controversial. Im-
' ^7 d% C! i& P3 Tmergut and associates reported an excellent growth response
8 g$ e- U. C; \7 ito topical testosterone with low levels of serum testosterone,
( J* Q  f2 e2 e: Z- @4 xsuggesting a local effect.1 Others have obtained growth re-2 N; k( c" X+ n& J, ]7 R% p
sponse with high. levels of serum testosterone after topical
6 f* C. C/ L* \  M. k" `administration, suggesting a systemic response. 3 The use of
/ z* D8 I; [0 k& O7 y. z! ~gonadotropin to obtain levels of serum testosterone compara-
- L8 K# R8 m$ B* O: D4 uble to levels obtained with topical testosterone would seem to
. h/ U$ ?% F( ?+ Y5 |5 ^6 Dprovide a means to compare the relative effectiveness of
' ?9 l6 v  L2 |topical testosterone to systemic testosterone effect. It cer-2 @4 P  u. k& k' i" U
tainly has been established that gonadotropin as well as par-
7 k. K* J+ T. Centeral testosterone administration will produce genital
! y, `3 l0 j% q. Z* K1 ?growth. Our report shows that the growth of the phallus was
' ?; t9 T3 g6 E5 Y3 Isignificantly greater with topical applications than with go-
2 w" j- \8 k2 snadotropin, particularly in children less than 10 years old.
' I' h/ ^' a& m& d; H) q9 }The levels of serum testosterone remained similar or lower' E* _* k# G& J8 `0 g5 M
than with gonadotropin during therapy, suggesting that topi-
* B( Z9 r' C: w6 o) b7 ~8 J5 T1 scal application produces genital growth by its local effect as
" f+ s8 K, L* P7 {. Owell as its systemic effect.' j" a9 Q/ N8 |4 ~+ c0 S6 m' Y' {
Review of our patients and their growth response related to$ D- [3 A; Z. i. W
age shows a greater growth response at an earlier age. This is+ o; U" n/ R" P  u, c4 Y
consistent with the findings of Wilson and Walker, who
) G- ^4 s" o8 d' Q7 Breported an increased conversion of testosterone to dihydrotes-" J- n) G$ q% g: _- u$ b
tosterone in the foreskin of neonates and infants.4 This activ-
  t( @2 n: Y; X$ ~8 D; Kity gradually decreases with age until puberty when it ap-( ^; x8 G# z' Y* N" V
proaches the same level of activity as peripheral skin. It may
3 C; F+ Z& S; v8 Y$ kwell be that absorption of testosterone is less when applied at
$ e, c" o# G& y; x& `2 m; J$ {* S2 }; Gan earlier age as suggested by lower serum levels in children
2 r5 M  A! _" N9 jless than 10 years old. This fact may be explained by the
. e( [# j5 x7 u1 b* egreater ability of phallic skin to convert testosterone to dihy-/ z+ t0 U- i+ k* p- i8 S
drotestosterone at this age. Conversely, serum levels in older8 X) d( O0 I) w) W' B# n
patients were higher, possibly because of decreased local
+ q* Z- J4 x0 v& }8 S% C; e5 b667
/ A3 {1 G/ ]: ]9 F- y5 L668 KLUGO AND CERNY
5 F3 Y4 X. J6 n2 F  o# _6 H: wPt. Age& P9 \( B; {0 C# [+ u! U
(yrs.)/ {' w: ?& L: }% K! c& x, `5 N
Serum Testosterone Phallus (cm.) Change Length3 ^4 c: M/ \+ d2 z$ z
(ng./dl.) Girth x Length (%)
* M7 k& V/ g( \8 j) I% X( V4) T+ z' J8 c5 |' G" D' z
8- E% d  k' \; m" y! c. K
10) d" Q* p6 j, `( j3 a4 p& q# c
125 ]: G2 Y, Z" v" d. H1 g
17% _, |, a$ m# H" P( E9 M5 M& \9 O  T
Gonadotropin
  s; B4 G2 ^8 i/ {# J4 g, e  O4 S+ _; J71.6 2.0 X 3 16.6
1 u7 L9 D" I2 z50.4 4.0 X 5.0 20.04 N' ]' S/ y8 y
22.0 4.5 X 4.0 25.0) {! ]2 h2 |% z- U) @) [
84.6 4.0 X 4.5 11.1
6 f( H8 ~4 C0 P9 h6 `  k85.9 4.5 X 5.5 9.03 j' u# _: c- W, x+ `- r: F' b
Av. 14.3
  R- I7 P. c, T2 F  b4
. N  M# A8 ^; V8
  W5 H. _( f7 w9 H; f10
. ~7 S+ I3 y0 h( R1 b12
8 H) U( s9 ~+ S17
7 m& q; O  y9 F5 KTopical testosterone  v* {  X) r9 `% L: F/ c" ]
34.6 4.5 X 6.5 85% u- s2 g6 Q% ?1 I
38.8 6.0 X 8.5 701 S  `! B2 e4 ^$ E1 h
40.0 6.0 X 6.5 62.5/ U: b  W/ G' d3 G, N' M
93.6 6.0 X 7.0 55.5+ P( }- x- D3 f8 `
95.0 6.5 X 7.0 27.2+ V) ?# K6 E; I
Av. 60.0, h! `& v- Q7 V1 _; Q. y% `) G$ w
available testosterone. Again, emphasis should be placed on2 C2 a1 V) t% ?
early therapy when lower levels of testosterone appear to3 H" x6 `) E% F0 }/ U
provide the best responses. The earlier therapy is instituted
) Q  K5 H2 d# y2 S8 Othe more likely there will be an excellent response with low
: C# e' D& a) \serum levels. Response occurs throughout adolescence as, e* h2 ]. a4 ?/ k
noted in nomograms of phallic growth. 7 The actual response- m3 E" M: p( b0 K: ]2 p/ o4 J
to a given serum level of testosterone is much greater at birth! [/ [( m( z; H% N
and gradually decreases as boys reach puberty. This is most% D5 i' G$ Z; L3 Q- U
likely related to the conversion of testosterone to dihydrotes-" `; J6 I$ c; h' w2 f; x7 `
tosterone and correlates well with the studies of testosterone
4 G: V( P: v# Z& K2 |4 Fconversion in foreskin at various ages.) ~0 @) m  u, o) ~$ k0 b/ U$ p6 O
The question arises regarding early treatment as to whether
+ t4 _- w; i3 K1 X4 z! w9 M2 rone might sacrifice ultimate potential growth as with acceler-( b4 Q) O6 X# Q, s6 {" l0 n. Z
ated bone growth. The situation appears quite the reverse
5 @# F( ^/ u/ a, z) Q# iwith phallic response. If the early growth period is not used
0 k; P/ y5 ^0 L8 s+ i: b7 Xwhen 5a reductase activity is greatest then potential growth7 ?- A- m8 |' ~4 M0 K& `
may be lost. We have not observed any regression of growth1 ]' w; `3 ]  n6 U/ r) R4 x* k) r
attained with topical or gonadotropin therapy. It may well, X" F- ^/ D2 }# ]$ s
be that some patients will show little or no response to any" M. t& [5 Y1 L4 X0 Z8 o2 j+ m
form of therapy. This would suggest a defect in the ability to( Q% P  Z$ M3 z! Y; a
convert testosterone to dihydrotestosterone and indicate that7 o- g* o2 y. `+ ]
phallic and peripheral skin, and subcutaneous tissue should9 R+ m2 b* U( w4 u
be compared for 5a reductase activity.3 _' {5 E( u- D, L7 l
A, loop enlarges to measure penile girth in millimeters. B,6 O' I' e8 N$ ?+ j% L/ U4 }
example of penile girth computed easily and accurately.
8 W# P+ l; \4 q, {conversion of testosterone to dihydrotestosterone. It is in this, m7 t) U0 j5 o0 c
older group that others have noted high levels of serum5 w* M9 d7 e& y- V- ]3 h
testosterone with topical application. It would also appear
/ h) V; D9 v! zthat phallic response during puberty is related directly to the, |6 |; ^9 S% Y. p
serum testosterone level. There also is other evidence of local
* `8 q( ]& g+ `8 r. v% n, Lresponse to testosterone with hair growth and with spermato-% u3 @" u! v$ }$ D1 z% ]
genesis. 5• 6, ]. B0 R% I; |! D6 R0 O
Administration of larger doses of gonadotropin or systemic
  w  b/ |1 ^! J8 p7 Ctestosterone, as well as topical applications that produce
' q% d* m7 M) g% R/ C9 K% Whigher levels of serum testosterone (150 to 900 ng./dl.), will
! z, a% \3 }  a8 L+ [8 w- Kalso produce phallic growth but risks accelerated skeletal  z7 X9 x/ |: I3 a9 G
maturation even after stopping treatment. It would appear& y$ T% F" h7 `# u5 A, I# {
that this may be avoided by topical applications of testosterone! a( B, }% A  d% m
and monitoring of serum testosterone. Even with this control+ Z: r- R& x0 e3 Y: B) C) e
the duration of our therapy did not exceed 3 weeks at any! F, A" _1 ^0 B7 x
time. It is apparent that the prepuberal male subject may
8 w1 u# C. U" X6 S# esuffer accelerated bone growth with testosterone levels near8 i  v) U( _+ @$ L. |2 r* E5 s
200 ng./dl. When skeletal maturation is complete the level of
# s0 b& K# g' Q( G2 t, |+ `0 jserum testosterone can be maintained in the 700 to 1,300 ng./) Y8 I# [+ k1 X: A/ i: z
dl. range to stimulate phallic growth and secondary sexual
& g5 x: `- i0 z0 Ochanges. Therefore, after skeletal maturation parenteral tes-
! F4 a% s. [/ u: Ltosterone may be used to advantage. Before skeletal matura-
7 L; r3 w% z* P2 \+ v; g% V0 ttion care must be taken to avoid maintaining levels of serum
  V9 Y* A  n8 g, d4 o/ j1 W" ^% Etestosterone more than 100 ng./dl. Low-dose gonadotropin) I- Q, ~" A0 w
depends upon intrinsic testicular activity and may require
5 @& \4 e5 q9 K7 f) A2 s' T6 ^prolonged administration for any response.1 |+ `* ~' j8 X# c4 q! i( J
Alternately, topical testosterone does not depend upon tes-
0 u% \& a; N: w+ M. E# a0 r" k1 oticular function and may provide a more constant level of! g  N; C) a8 w, `  a5 S6 S4 Z% O
REFERENCES6 d) [9 ?2 q1 o/ h2 m& ]
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
, w# J9 r2 _0 M: l9 }7 r: mR.: The local application of testosterone cream to the prepub-, D! J7 V4 i$ Z3 k: D
ertal phallus. J. Urol., 105: 905, 1971.8 z4 v5 O0 V5 n/ X; d  P% u8 M
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone. i$ A; z: `; ]8 G
treatment for micropenis during early childhood. J. Pediat.,- U5 _, L$ H8 U3 c2 _8 @- w
83: 247, 1973.6 ]6 s; u, V+ u# n" p
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-% D3 A  B  F1 g! x, l: q: A( Z8 J
one therapy for penile growth. Urology, 6: 708, 1975.
) G, t$ U/ e5 T# P4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
0 T$ g/ t5 f* _2 Gto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by3 r9 Z5 s+ [6 Z. B
skin slices of man. J. Clin. Invest., 48: 371, 1969.5 C- U  W6 w+ m, i& O
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
4 a$ x/ y+ [2 Y, n+ J/ T/ l6 A1 f* gby topical application of androgens. J.A.M.A., 191: 521, 1965.
( g! Q- s! j& z2 c# |6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
* p. L9 w: \$ `9 y& L* X& Qandrogenic effect of interstitial cell tumor of the testis. J.; f5 f, B" c% D9 e
Urol., 104: 774, 1970.
+ N- E, r4 j8 p7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-4 Q6 p  w" t$ f% e5 g' H1 C
tion in the male genitalia from birth to maturity. J. Urol., 48:
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