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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
( ]( `& J" E/ J+ iGONADOTROPIN
+ X5 v2 H  v  \" H% r; M) O# eRICHARD C. KLUGO* AND JOSEPH C. CERNY
0 c  L/ e2 U1 |9 jFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan/ h; s! g4 z' D( t- H5 Z; O
ABSTRACT! Q& c  A3 u9 Z7 f1 x4 W  Y( l  m
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
; C$ m+ _2 t' k5 Wwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
, |! p* i! k6 Y( _- y# ?- stropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
& _) p* y' K1 Y2 J2 t- |+ e% {* o7 Bcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
1 Y" m' v; R2 h3 W2 K% i3 Pfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent  {* I6 _$ H  {1 X) ~% g4 [8 E7 \
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
+ w/ t5 c: S5 G& B- \0 U5 Qincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response0 C! f2 ?8 L4 U/ E
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
) C# {$ R! |6 x1 l4 nstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
8 X) q5 |( Z* ~) ~growth. The response appears to be greater in younger children, which is consistent with previ-% i# J% I' f# v
ously published studies of age-related 5 reductase activity., {! Y9 b& ^2 l: l2 [; l" Y' T
Children with microphallus regardless of its etiology will
$ ]- \) l- j- M$ `! {require augmentation or consideration for alteration of exter-
/ |, ?# a) l: q' \5 Pnal genitalia. In many instances urethroplasty for hypo-
% y! c8 {: W9 M3 Gspadias is easier with previous stimulation of phallic growth.4 A; @, d4 D& t: L0 v
The use of testosterone administered parenterally or topically
) k! X2 ]9 R% K( _. P2 r5 r0 }& h, Chas produced effective phallic growth. 1- 3 The mechanism of4 d+ B% w6 v' {2 N5 S+ w- n
response has been considered as local or systemic. With this
2 A) _8 n+ `' Q1 R/ q3 Zin mind we studied 5 children with microphallus for response. _* q7 `% Q: F; Z3 f, u, v
to gonadotropin and to topical testosterone independently.1 D4 P- u( n+ i) r: \0 e1 |5 y5 v' i
MATERIALS AND METHODS$ F  k% }# ?/ I4 f
Five 46 XY male subjects between 3 and 17 years old were
5 x$ M- I) u# ^% y8 R) gevaluated for serum testosterone levels and hypothalamic
3 i8 z' N& S7 p4 ~6 Ufunction. Of these 5 boys 2 were considered to have Kallmann's6 E  h- D) l4 Y( S) L. Q6 h  {( j
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-2 j1 y* |/ Y& b0 G5 d
lamic deficiency. After evaluation of response to luteinizing3 v2 {: n% u4 M& }4 U4 x+ u
hormone-releasing hormone these patients were treated with: E3 j$ ^0 D: U
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
8 K9 y  g2 {. mafter completion of gonadotropin therapy 10 per cent topical
2 D3 {% B& E5 Y' d& ttestosterone was applied to the phallus twice daily for 3 weeks., p2 f  _4 R5 L; g0 P
Serum testosterone, luteinizing hormone and follicle-stimulat-! N3 g" s* K, p# m- w7 a9 z0 D
ing hormone were monitored before, during and after comple-1 n. W4 u3 l9 c! V! H
tion of each phase of therapy. Penile stretch length was
! w( _, t9 c# n) ^, M3 n: B. fobtained by measuring from the symphysis pubis to the tip of6 r% v: j* }: h0 e3 c% I
the glans. Penile circumferential (girth) measurements were( O' U$ M. A, o7 L5 A
obtained using an orthopedic digital measuring device (see
$ ]3 R) J5 j* ?" i& w2 Efigure).
7 u" a; `5 t5 v) ARESULTS* s+ }5 R4 o3 A6 ~/ b9 M
Serum testosterone increased moderately to levels between2 |" R, @5 U5 u* p& v8 s  ?- v; M
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
7 x, T1 @9 c, e. J4 }3 D& l  Cterone levels with topical testosterone remained near pre-$ S7 t4 f; v0 F8 D
treatment levels (35 ng./dl.) or were elevated to similar levels
& Z" T7 T( x. M1 c; ydeveloped after gonadotropin therapy (96 ng./dl.). Higher
3 ]4 D$ p( Y8 Kserum levels were noted in older patients (12 and 17 years old),
4 s6 N+ f3 C) y& J& Iwhile lower levels persisted in younger patients (4, 8, and 10! Y/ @$ ~3 d) U/ n
years old) (see table). Despite absence of profound alterations
% D" `6 T, w& n2 k! h& Bof serum testosterone the topical therapy provided a greater3 b7 ~8 @2 o" x' }; q" R
Accepted for publication July 1, 1977. ·
% i( v; R. |# w4 cRead at annual meeting of American Urological Association,
( y2 ^9 Z8 I9 W9 h& |Chicago, Illinois, April 24-28, 1977.
$ K4 a8 |4 B0 a. ^( v8 v* Requests for reprints: Division of Urology, Henry Ford Hospital,
& e' L% @& v9 ?, {7 z2799 W. Grand Blvd., Detroit, Michigan 48202.
* `0 |' I$ K% O/ A. W0 j* Qimprovement in phallic growth compared to gonadotropin.
5 l. ?" U: @8 M, oAverage phallic growth with gonadotropin was 14.3 per cent3 i+ o! v6 K* l2 J
increase in length and 5.0 per cent increase of girth. Topical
( p: x# ~- a1 Q2 b! c, e' I. x; Ftestosterone produced a 60.0 per cent increase of phallic length
1 U8 N8 e9 Z  l) P/ Jand 52.9 per cent increase of girth (circumference). The
" b' S* x& A5 H$ G1 Dresponse to topical testosterone was greatest in children be-; w7 n. k' w' i$ h
tween 4 and 8 years old, with a gradual decrease to age 17
. b. p9 Y3 {( i: ^# Z& Yyears (see table).
8 R6 H3 E6 V- r4 H: V4 I2 FDISCUSSION
# F) w; v5 {) D' g' M" F" STopical testosterone has been used effectively by other
; e' \5 ?* @' f( ^. K9 Iclinicians but its mode of action remains controversial. Im-
4 b; G; L* \9 E9 W! m$ p& X5 Imergut and associates reported an excellent growth response
9 e7 D& P- u# H$ L; hto topical testosterone with low levels of serum testosterone,
+ @/ y! _: U9 @& a0 g8 Q# o4 t7 ksuggesting a local effect.1 Others have obtained growth re-# Y( _0 z3 r( j' n! U" P, e
sponse with high. levels of serum testosterone after topical
) l- c. p4 |6 u# @1 i" ?) qadministration, suggesting a systemic response. 3 The use of
5 _* j( {( Q% y: g" }9 S: T' Ygonadotropin to obtain levels of serum testosterone compara-% B# u" h# j) o- P4 L5 P- X
ble to levels obtained with topical testosterone would seem to, e6 E4 {' n7 o
provide a means to compare the relative effectiveness of! J; a/ c/ ^3 M9 |
topical testosterone to systemic testosterone effect. It cer-
3 s5 S) E0 L! U: j0 j& Wtainly has been established that gonadotropin as well as par-0 C+ W3 e! h! L3 a
enteral testosterone administration will produce genital
0 T4 w- k/ I. y  ]" `+ o. X8 E7 @' Kgrowth. Our report shows that the growth of the phallus was
. k/ V3 E+ t5 k! nsignificantly greater with topical applications than with go-
! E2 v* {6 T5 d% Snadotropin, particularly in children less than 10 years old.
; M! r+ G( u: C% S& m1 f( i3 v9 ^1 A- EThe levels of serum testosterone remained similar or lower- V& i: Y" j" K+ g& k
than with gonadotropin during therapy, suggesting that topi-! t3 t- l" e7 J/ ?
cal application produces genital growth by its local effect as$ G7 @% y5 f& ^
well as its systemic effect.5 B1 ]9 w2 p' u& [
Review of our patients and their growth response related to- x5 G" y  O5 `* g8 u4 g3 S! X4 K
age shows a greater growth response at an earlier age. This is% s0 }) h7 x  n
consistent with the findings of Wilson and Walker, who" Z* a7 v0 ]5 ]7 o1 V- T* C
reported an increased conversion of testosterone to dihydrotes-7 ~/ t# B9 x: W' K- o! s
tosterone in the foreskin of neonates and infants.4 This activ-% @# N  k+ y* R: \; ]% E
ity gradually decreases with age until puberty when it ap-# d, }/ I4 f% u! I" s0 Y
proaches the same level of activity as peripheral skin. It may
0 O0 t+ n' N0 r  Xwell be that absorption of testosterone is less when applied at& e0 A" J; c6 S# U9 B8 H8 ~
an earlier age as suggested by lower serum levels in children
$ x$ g- x7 Z/ q- s! n4 ]less than 10 years old. This fact may be explained by the
, `. J1 w! \" _! mgreater ability of phallic skin to convert testosterone to dihy-4 @8 K# L9 S! w- K- k0 x
drotestosterone at this age. Conversely, serum levels in older
( I6 J, _. z4 g/ f4 Opatients were higher, possibly because of decreased local
7 u3 C, N6 [) q8 D, f9 t/ \3 e5 ]6673 y. ]) x6 x% O+ F. {& Q) s
668 KLUGO AND CERNY- a% ]% _0 M: S. h  G/ @' v
Pt. Age; T# w) n3 g7 B/ d
(yrs.), L" {, u; r8 q2 U7 d2 Z3 I
Serum Testosterone Phallus (cm.) Change Length
0 q' p+ y6 s' k% |7 J" [/ b(ng./dl.) Girth x Length (%)
0 f: @, t3 d' c4 K3 \4: J% q  z  F8 s5 w  u
8, a+ U( A* f$ C2 p# y4 f# u; h  y
10& b3 Z; q% G  [; {; }
12. T7 w+ m/ O8 H0 Q& I4 l: d& x
17
+ P) _: @' A* w7 [+ N; dGonadotropin
. Z6 G& x! J! V/ P6 Q71.6 2.0 X 3 16.6
( W5 P% S" Z3 n3 D50.4 4.0 X 5.0 20.0- r5 t  z2 s8 h0 h4 q6 S% j
22.0 4.5 X 4.0 25.04 W& s" Y+ H" [" D
84.6 4.0 X 4.5 11.1
: I, o# T2 N- ^2 X. J7 |85.9 4.5 X 5.5 9.0
) P# t) r$ N9 s4 p  {1 \- uAv. 14.3
% S% v4 N/ U3 B0 }& U( Q( \7 n5 e4. f9 _; j5 E2 e$ `5 x0 y
8
+ X7 Z7 g, j6 h  K& |100 O* ]) m* Z9 a  F; `' S2 H
12
. [* O0 _, S. L; {8 N17
/ |, y( @1 a9 \8 h: [% TTopical testosterone3 V3 G% x9 d; `5 g( B
34.6 4.5 X 6.5 85
% ?- W+ }/ u. G3 w  m3 l38.8 6.0 X 8.5 70
4 ]  _% E. g* L) n+ O% F* J; z; S40.0 6.0 X 6.5 62.5* \3 W; q/ I; l% P% Q
93.6 6.0 X 7.0 55.5
$ B1 g2 d. b3 }95.0 6.5 X 7.0 27.2
2 f/ F5 l0 H7 Z( GAv. 60.0
  l  M5 k3 S: x/ C, m. e: a4 E# Y( ?available testosterone. Again, emphasis should be placed on6 T7 Y: _0 O1 i1 l2 n
early therapy when lower levels of testosterone appear to
5 e4 m+ Y+ c1 a0 [; n  r8 J  g2 Kprovide the best responses. The earlier therapy is instituted
: @; S" {! k: S) q4 vthe more likely there will be an excellent response with low
; }6 [0 e4 o: R7 F7 w' V7 ?serum levels. Response occurs throughout adolescence as: Z4 ~; U3 _8 J& p4 \
noted in nomograms of phallic growth. 7 The actual response
1 B$ {! \# X) Q. u  U, |8 C) M  nto a given serum level of testosterone is much greater at birth
4 ~% [$ s0 K: y/ tand gradually decreases as boys reach puberty. This is most
9 o1 }% W: K/ J& k  u6 M" ^/ zlikely related to the conversion of testosterone to dihydrotes-
9 X0 x; [3 y9 J0 ^: c% G6 H7 Etosterone and correlates well with the studies of testosterone+ g  ~' X# Z  g3 m, Q- o* a* `
conversion in foreskin at various ages.
0 w& s9 }6 w. u+ \# M1 j3 pThe question arises regarding early treatment as to whether/ r7 l' r3 z9 ~
one might sacrifice ultimate potential growth as with acceler-
4 C! k* _# Z6 \0 Y1 K- Fated bone growth. The situation appears quite the reverse
' V( f) u! {$ @4 s5 vwith phallic response. If the early growth period is not used4 A% _% X& a' }; l- P* z  Z1 _6 C2 s3 o
when 5a reductase activity is greatest then potential growth
9 t/ C, }0 [1 y( V- }may be lost. We have not observed any regression of growth' {- s6 y8 [2 y6 z
attained with topical or gonadotropin therapy. It may well
- g3 a% l$ m% o2 G( Wbe that some patients will show little or no response to any* I( e% R2 _2 t& L" Q+ @* {
form of therapy. This would suggest a defect in the ability to
! D, r3 @$ [# a# K0 [9 Aconvert testosterone to dihydrotestosterone and indicate that; n6 |5 t6 o3 D1 M; f8 c  @$ _/ f
phallic and peripheral skin, and subcutaneous tissue should6 \5 f+ o6 |; O; Q- R7 C
be compared for 5a reductase activity.+ a+ B+ Z8 q# ~1 h3 R  n$ P
A, loop enlarges to measure penile girth in millimeters. B,$ m" U2 t9 F" e8 j
example of penile girth computed easily and accurately." R7 y( T# m* w7 h+ i5 d
conversion of testosterone to dihydrotestosterone. It is in this' @3 T1 N, x9 U9 c4 `1 X
older group that others have noted high levels of serum- ]( W% Y7 x3 o3 y/ `4 q7 x
testosterone with topical application. It would also appear  l. b0 w4 o" N3 e. D$ \
that phallic response during puberty is related directly to the) b9 P8 b$ e3 t
serum testosterone level. There also is other evidence of local
9 m8 F0 S' `2 F& @3 Vresponse to testosterone with hair growth and with spermato-" y( P1 |& \+ }0 ?9 l% u- d
genesis. 5• 6
* E7 t4 Q1 m/ |! h7 I1 w5 R& @Administration of larger doses of gonadotropin or systemic5 I+ Y: m, u% A. _0 @! k7 f' r
testosterone, as well as topical applications that produce( q. v* b- i3 i; u. y$ P
higher levels of serum testosterone (150 to 900 ng./dl.), will
" B$ ^# t3 C4 j( Y- o* S! calso produce phallic growth but risks accelerated skeletal
4 d2 t4 d! Q  t* n2 n/ z) Lmaturation even after stopping treatment. It would appear
- B5 o3 U8 |6 ~" |0 j5 j4 Ethat this may be avoided by topical applications of testosterone
2 I2 Q* r  c6 O# f& Yand monitoring of serum testosterone. Even with this control
! V, f3 H% [; T3 L! x' Z; Rthe duration of our therapy did not exceed 3 weeks at any3 p% g* |9 d/ t0 t6 H/ _
time. It is apparent that the prepuberal male subject may4 k  Z: o) t- a! a" e% M
suffer accelerated bone growth with testosterone levels near
" z/ W. c0 ?* j; l8 U8 O200 ng./dl. When skeletal maturation is complete the level of
% O# K2 E+ C+ q" d8 t- Yserum testosterone can be maintained in the 700 to 1,300 ng./! M7 O( A7 A3 r6 v1 O9 J$ @6 d; C
dl. range to stimulate phallic growth and secondary sexual
; M3 d: v) q) O  G( J  m' `changes. Therefore, after skeletal maturation parenteral tes-! b  D- U: I2 d! C$ {
tosterone may be used to advantage. Before skeletal matura-! Q- i  o# C' x
tion care must be taken to avoid maintaining levels of serum: i0 m5 w( G( }9 z) Q
testosterone more than 100 ng./dl. Low-dose gonadotropin
3 k. E, `: S3 _depends upon intrinsic testicular activity and may require
+ o0 M- f; f, u9 I$ B8 c; Wprolonged administration for any response.2 D) C( }+ L. C# o6 k3 w
Alternately, topical testosterone does not depend upon tes-/ m1 Y" {6 Q9 N( R0 `1 Z: N2 k: n8 v
ticular function and may provide a more constant level of
: x  ]3 b; w0 e1 w- e( kREFERENCES
( J. @1 R# @7 c  e$ ?: H1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
; L5 L/ G2 Y* j( G+ ^5 ~+ i' {( T; bR.: The local application of testosterone cream to the prepub-
6 `- s7 l, {7 L6 g) Z6 g* J* W$ Zertal phallus. J. Urol., 105: 905, 1971.1 X' }; S# ]1 E  n# c$ P+ {$ b
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone" p! F4 I- Z, D
treatment for micropenis during early childhood. J. Pediat.,
& k8 I6 ^0 f6 j3 {) t' L" t: }83: 247, 1973.
9 C, f) H" n  K3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
, W6 U( V2 `/ D2 z2 q* |% Aone therapy for penile growth. Urology, 6: 708, 1975., Z/ M1 B4 Q4 g; y/ n
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone" @) L- R% _. ~3 E
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by% p. o- z7 C9 C6 b
skin slices of man. J. Clin. Invest., 48: 371, 1969.
5 V" d, n5 p; f, B' H0 C. ~6 o5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
6 L0 v; w' ?6 S& D- S7 A2 ^by topical application of androgens. J.A.M.A., 191: 521, 1965.8 k; e8 g) b' j; U$ F9 e2 y1 w6 Z
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
9 Y: C, ?7 N8 bandrogenic effect of interstitial cell tumor of the testis. J.1 I5 N) D5 U. W  u7 P  ?$ a
Urol., 104: 774, 1970.; a2 t: W  q  z! W
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-, V9 H4 o/ `- D9 k$ r& h
tion in the male genitalia from birth to maturity. J. Urol., 48:
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