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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
# V( B' s+ o0 j. c1 k3 k; UGONADOTROPIN. b2 `' Q. W0 z
RICHARD C. KLUGO* AND JOSEPH C. CERNY
  T+ @/ Y" A+ c) e# Y  AFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan% ~* q" `5 m& E& N2 n
ABSTRACT, B& ?5 w9 Y. H" n; |6 }
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
8 P. U: {: H1 z0 a3 @with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
0 o4 Y0 ?- ]; C/ Y' stropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
+ \- q9 H9 I, c' Z7 vcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
' B9 F% n7 b5 g- ~! F! Mfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent4 m9 n: Q) C: n  q4 e. S1 r& ~
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
! M9 J; H0 J' f$ _$ a5 @& vincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response0 [  H" s/ O6 {1 c
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
# F: A& u) h" [" `study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
3 Z1 g" z* i6 b: H9 j3 Y3 Zgrowth. The response appears to be greater in younger children, which is consistent with previ-" |5 v' g' b" a- R) l0 t
ously published studies of age-related 5 reductase activity.7 U$ o* m  N% t& A6 F8 g9 j
Children with microphallus regardless of its etiology will
- [# A. I3 u4 @/ hrequire augmentation or consideration for alteration of exter-
0 F1 D9 k8 d# [( l8 c5 R+ I+ [nal genitalia. In many instances urethroplasty for hypo-
9 O* j+ t0 f8 L* Tspadias is easier with previous stimulation of phallic growth.
0 {1 n4 W2 w8 I, ?! E0 |The use of testosterone administered parenterally or topically( _( j& W2 r. q& z* l, T
has produced effective phallic growth. 1- 3 The mechanism of0 n# {: B( ~4 c
response has been considered as local or systemic. With this8 K: D1 J/ A# ~" b8 m+ F; g
in mind we studied 5 children with microphallus for response% F8 V2 G9 G9 A% T
to gonadotropin and to topical testosterone independently.
1 y& a  H& R: I2 l( ZMATERIALS AND METHODS2 n: U# J1 g+ b  d: Z! D
Five 46 XY male subjects between 3 and 17 years old were
* L& r8 J, I( {, }0 I) hevaluated for serum testosterone levels and hypothalamic
& K2 U1 [4 I' {4 {) D/ y* rfunction. Of these 5 boys 2 were considered to have Kallmann's  T1 O5 Q. ^& \/ w% l& @
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
6 T! I. t: L0 Slamic deficiency. After evaluation of response to luteinizing
) e+ h9 V! U3 Ghormone-releasing hormone these patients were treated with
6 }  D( t* B4 T1,000 units of gonadotropin weekly for 3 weeks. Six weeks
! V' Z# c+ b1 q! L+ O4 l# m0 y, hafter completion of gonadotropin therapy 10 per cent topical* a% _# w0 T4 T* _7 k( ^% f6 j) o: p
testosterone was applied to the phallus twice daily for 3 weeks.
& ]% M" U2 }8 G7 Y8 A3 vSerum testosterone, luteinizing hormone and follicle-stimulat-
6 V3 h- ?( [9 f' W2 {ing hormone were monitored before, during and after comple-
1 y7 K& B! p. x$ X& ]5 Q& L: Etion of each phase of therapy. Penile stretch length was# v% ]) P7 G! o" P
obtained by measuring from the symphysis pubis to the tip of1 e2 N# @& ^- {1 Z* p6 g  H* s$ A
the glans. Penile circumferential (girth) measurements were$ \0 z( F$ @/ l0 E  r& v, v% [8 y
obtained using an orthopedic digital measuring device (see6 X7 s5 c# q$ v% Y4 K" v2 p5 E
figure).
6 t5 |$ }+ m2 j  Q" b: O! Y0 S3 YRESULTS0 f& p! V- H( B0 Q# R) Y2 z# h
Serum testosterone increased moderately to levels between$ ^  b1 v+ ]. G/ [+ y$ F
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
2 S4 Q- X( E, s* z% y( A/ O. L: nterone levels with topical testosterone remained near pre-
7 }2 R# \# B1 ^) Q, G! Itreatment levels (35 ng./dl.) or were elevated to similar levels3 ?! m) C* O8 V" f
developed after gonadotropin therapy (96 ng./dl.). Higher
1 P+ S1 _( L7 r; z2 o4 S5 y" Iserum levels were noted in older patients (12 and 17 years old),
/ ?( i2 p( ], _/ @1 d# K2 ?- dwhile lower levels persisted in younger patients (4, 8, and 10: j& ~1 o4 m7 X6 w  E
years old) (see table). Despite absence of profound alterations- B; P; o1 E1 W# h  W. J
of serum testosterone the topical therapy provided a greater( I5 R! p  I8 d/ W/ f0 e5 z: b
Accepted for publication July 1, 1977. ·
" Y0 E# i. R! [& }, WRead at annual meeting of American Urological Association,, f- y* j* Z8 x' V( U+ K/ c# t  [
Chicago, Illinois, April 24-28, 1977.7 R& D7 T' Z9 E! R2 n% U2 z4 P$ f
* Requests for reprints: Division of Urology, Henry Ford Hospital,& z. S2 u& Q" G0 l7 F
2799 W. Grand Blvd., Detroit, Michigan 48202.
! O2 o0 d  {5 {improvement in phallic growth compared to gonadotropin.
' V9 J( q6 v* L" h4 k- z3 [Average phallic growth with gonadotropin was 14.3 per cent
' M8 n  l' \' J6 g9 ^0 Oincrease in length and 5.0 per cent increase of girth. Topical8 Z. b$ R- Z: z  \+ J8 O$ q
testosterone produced a 60.0 per cent increase of phallic length7 t2 ^! F6 [8 z: ^) A$ e
and 52.9 per cent increase of girth (circumference). The+ }7 R( Y; ^  n
response to topical testosterone was greatest in children be-) d; c. O% M$ A: }  r$ K; e
tween 4 and 8 years old, with a gradual decrease to age 17
& \2 H6 w. j. `0 u7 @9 Zyears (see table).
# v" \$ Y8 ~' k. a' Y4 C3 WDISCUSSION6 N3 w3 P/ ~6 c  O, w
Topical testosterone has been used effectively by other' ^9 o* C  U, i9 d- s. B
clinicians but its mode of action remains controversial. Im-
- W: g3 a: E5 G3 Cmergut and associates reported an excellent growth response
/ b- [/ M1 j4 N6 W5 Y; T! s7 Fto topical testosterone with low levels of serum testosterone,
! W+ K! w. r( b; j0 m  `suggesting a local effect.1 Others have obtained growth re-) B  h8 _" Z1 T, j, X
sponse with high. levels of serum testosterone after topical
  I, I/ [2 f5 [/ N! R" }administration, suggesting a systemic response. 3 The use of3 V) C. x) H4 t# m  [) O! g
gonadotropin to obtain levels of serum testosterone compara-
/ }, B0 g2 F$ Nble to levels obtained with topical testosterone would seem to
* U# D" v7 J' ~5 o) X4 F- y& qprovide a means to compare the relative effectiveness of% N3 e' S: q& a+ e& K$ r& D, A
topical testosterone to systemic testosterone effect. It cer-+ z. o  i2 m+ z( W7 ]: f  L
tainly has been established that gonadotropin as well as par-4 j  ^  X1 O( v
enteral testosterone administration will produce genital) A' o" h- `: W, n6 `! @: ?& f0 {% y
growth. Our report shows that the growth of the phallus was
- O* S: M# n! q5 [! asignificantly greater with topical applications than with go-( L% u& u) k, z. O
nadotropin, particularly in children less than 10 years old.+ ]# L1 H- e8 b4 C2 \# _5 e' A+ N
The levels of serum testosterone remained similar or lower  O4 ?3 T. I7 P5 L  `  P* f& m0 V! ]
than with gonadotropin during therapy, suggesting that topi-. P5 p2 o' [' e1 U
cal application produces genital growth by its local effect as* a# r5 B7 k/ Z( |' w
well as its systemic effect.
" l. W$ e/ h& Z- i2 ~Review of our patients and their growth response related to, v  ]: c; Z# S6 Y
age shows a greater growth response at an earlier age. This is
) N& L" c: D- [5 \consistent with the findings of Wilson and Walker, who" G! ~% E2 c+ I8 _3 X( y3 B
reported an increased conversion of testosterone to dihydrotes-
) }! J7 W7 {  \* u9 Htosterone in the foreskin of neonates and infants.4 This activ-: \6 Y$ I! |% j* S0 r$ a/ P
ity gradually decreases with age until puberty when it ap-& m7 M4 u0 J  ]; g1 P
proaches the same level of activity as peripheral skin. It may; V! X2 f) r$ b! F
well be that absorption of testosterone is less when applied at
0 D5 l: Q' }1 K- l# Yan earlier age as suggested by lower serum levels in children
6 O. K4 S4 P5 |+ O0 S2 l# m: u2 L8 Dless than 10 years old. This fact may be explained by the
& N5 P# n# k0 }1 T0 t( }+ Z* Ogreater ability of phallic skin to convert testosterone to dihy-. A* g9 j0 c+ J# [, @
drotestosterone at this age. Conversely, serum levels in older
; M1 H( l3 S0 C' gpatients were higher, possibly because of decreased local
/ q. E+ z4 u5 e  u* M# ?* m# }667
" [. q% j% X& G668 KLUGO AND CERNY( c0 `) F/ k& Q6 A" U
Pt. Age
1 T( P: U# c! s(yrs.)
4 G; s8 h! Z' t& ISerum Testosterone Phallus (cm.) Change Length
. O; ~8 p0 j( @. ?$ E  ](ng./dl.) Girth x Length (%)" j9 J" E$ d  K1 N% i- j" U
4( w% K8 E' X. g! v1 R
8
1 M+ \  A0 P! X* |3 b10
4 J3 d) `  i* f9 ^$ I1 T3 r/ w& f% C124 q! G( ?2 L/ Y6 ^" e+ ^
174 W) V$ B0 L, w3 M' I
Gonadotropin* H' h8 ^+ D" `0 N/ n* n
71.6 2.0 X 3 16.63 r+ H; j  {. c& B
50.4 4.0 X 5.0 20.01 w0 v- M) w9 u) F' ~
22.0 4.5 X 4.0 25.04 \% f9 o6 d- e
84.6 4.0 X 4.5 11.1
, c  ^4 _% a# W/ O: G  @7 ]; D85.9 4.5 X 5.5 9.0
, m% U7 T( y5 a& oAv. 14.3
' i4 Q+ |) A" D# N! i- G2 ]' Z7 c46 j; ]! j  |: n' B" ?
84 O7 x8 c8 N( v2 _) a
105 Q' T2 h. U9 Z$ Q4 @2 ]
12  D2 I3 ]! i1 v3 k! l1 @
17) F; C- g* A+ e
Topical testosterone
  w5 ]4 ]& m- p' i9 p34.6 4.5 X 6.5 85
( n1 i6 b4 K8 {- e38.8 6.0 X 8.5 702 e/ ~' t! y* ?6 h3 `  T
40.0 6.0 X 6.5 62.5- u. X& [( v/ c. x+ L2 n
93.6 6.0 X 7.0 55.5  |3 L; [! ^$ U7 f3 s- C; L
95.0 6.5 X 7.0 27.2- G' G3 S2 R3 k. [' O
Av. 60.00 n! t8 c3 F, n# I- p. Y
available testosterone. Again, emphasis should be placed on8 n( _3 A  B+ r, O4 }1 R% t
early therapy when lower levels of testosterone appear to
1 [8 i, l8 b) j/ N& Zprovide the best responses. The earlier therapy is instituted9 [# m5 B: L2 E7 i
the more likely there will be an excellent response with low; V: v' X5 f: B* f# _
serum levels. Response occurs throughout adolescence as  y+ F0 m/ @* _8 h
noted in nomograms of phallic growth. 7 The actual response4 B$ H" S, B, ]- N
to a given serum level of testosterone is much greater at birth
( A. g. Z. `- k7 g0 uand gradually decreases as boys reach puberty. This is most; J# [& @7 h8 B
likely related to the conversion of testosterone to dihydrotes-
- k) v/ r) t* a& R1 j0 Y( {% T4 ntosterone and correlates well with the studies of testosterone/ f: p8 r7 M2 j* |2 j
conversion in foreskin at various ages.$ P% W; b) {7 z. i$ h" E* @9 u
The question arises regarding early treatment as to whether
9 z  [9 X1 F+ t, Q) uone might sacrifice ultimate potential growth as with acceler-" \+ V- |  ]* Q2 }3 s
ated bone growth. The situation appears quite the reverse
' O# E: }; ~: N& k" T7 Ewith phallic response. If the early growth period is not used
8 W5 S" b4 j/ M: Wwhen 5a reductase activity is greatest then potential growth& V3 i+ Y8 _1 W" `
may be lost. We have not observed any regression of growth, ]; d2 x2 t5 n2 g" v
attained with topical or gonadotropin therapy. It may well, J! `% e; Z0 O/ `5 Z5 @
be that some patients will show little or no response to any  `: R! [0 g( g, M0 E
form of therapy. This would suggest a defect in the ability to
* n5 Y1 n1 ~8 [) nconvert testosterone to dihydrotestosterone and indicate that
4 j* U8 a5 M! B' iphallic and peripheral skin, and subcutaneous tissue should
1 u, t( J- O7 kbe compared for 5a reductase activity.1 [3 }! S+ W" v( y9 w- C
A, loop enlarges to measure penile girth in millimeters. B,& h3 A% u. e) c# E. e# B
example of penile girth computed easily and accurately.9 x" x! R7 E1 M$ N* N6 \' a
conversion of testosterone to dihydrotestosterone. It is in this
0 D7 c7 H; e' polder group that others have noted high levels of serum0 F5 ^; t$ I( @7 ?
testosterone with topical application. It would also appear
' Z* B  `- q2 q! O% v7 Gthat phallic response during puberty is related directly to the9 q3 I  d7 d* s6 c0 ~
serum testosterone level. There also is other evidence of local# Z, X+ J9 g/ Y' W& @
response to testosterone with hair growth and with spermato-
+ K/ }: h' y- F, xgenesis. 5• 67 \' [, ?( j, H' \" Q+ ]
Administration of larger doses of gonadotropin or systemic) B! Z+ h- e" \
testosterone, as well as topical applications that produce
7 d, \( D1 g1 {: Mhigher levels of serum testosterone (150 to 900 ng./dl.), will8 t7 E0 E# V; ^8 V% ^; T# i1 [
also produce phallic growth but risks accelerated skeletal
. f/ U8 P& C1 p7 z, K' {maturation even after stopping treatment. It would appear
; x! ?% p! L% v/ t2 t6 sthat this may be avoided by topical applications of testosterone
2 n# {  A0 S' Y) @2 u7 z( Kand monitoring of serum testosterone. Even with this control
- g( S& z9 B' \8 `' A% e% Dthe duration of our therapy did not exceed 3 weeks at any* z1 n+ Z( ^8 B: J; k$ C2 a5 r
time. It is apparent that the prepuberal male subject may$ b3 c1 q2 z  R" Q, O% M' N$ j
suffer accelerated bone growth with testosterone levels near
7 k+ n: D7 _' U' M6 B200 ng./dl. When skeletal maturation is complete the level of
1 g, e% g" z1 w: t) H( Cserum testosterone can be maintained in the 700 to 1,300 ng.// F9 A0 @8 ~9 \% F2 W) B! i" Y
dl. range to stimulate phallic growth and secondary sexual: R9 E& Z% s/ c
changes. Therefore, after skeletal maturation parenteral tes-& v" m9 U/ @2 q
tosterone may be used to advantage. Before skeletal matura-$ f; Y3 X: x, l  d2 J
tion care must be taken to avoid maintaining levels of serum# E( ?2 D$ R; k- Z
testosterone more than 100 ng./dl. Low-dose gonadotropin8 X$ i3 F7 U( b
depends upon intrinsic testicular activity and may require& ^; r! j6 U0 E
prolonged administration for any response.
: T5 i& M* D2 kAlternately, topical testosterone does not depend upon tes-9 f- n/ i- n4 f6 x" i( O  e
ticular function and may provide a more constant level of! y# ?% E; W. T: B
REFERENCES
2 G4 ^2 x# c# ?* @: N, S1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
% `4 d' B6 s( N! |: A; O- B% nR.: The local application of testosterone cream to the prepub-
! A( b- v# |, \ertal phallus. J. Urol., 105: 905, 1971.
$ |% }1 O9 e5 m. @2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone$ D; N& C! p5 i6 v6 N5 ^" G
treatment for micropenis during early childhood. J. Pediat.,1 C% t3 F8 P/ _7 U
83: 247, 1973.
: s4 A1 m. p4 v, E: D( H; o+ ^3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
9 H7 p* q1 W! a0 r3 \  pone therapy for penile growth. Urology, 6: 708, 1975.. H; I& `: }4 z* s9 b$ }
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
2 M: r# ^  x# C5 z  R5 |to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
/ d5 @: p5 b: r+ I' Askin slices of man. J. Clin. Invest., 48: 371, 1969.
2 X& _$ g: O2 |1 \2 H5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth, [/ G+ ?5 [- l! a  ?
by topical application of androgens. J.A.M.A., 191: 521, 1965.$ ~2 J) {; p  m7 ?( H# m" h6 e" P
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local: v0 F( O1 a7 Q- [
androgenic effect of interstitial cell tumor of the testis. J.
9 g0 Y; X/ d; G$ OUrol., 104: 774, 1970.( F0 D3 L) `) D* j
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
0 X( [" {" j# j  c, ?9 g% G. p8 r3 [tion in the male genitalia from birth to maturity. J. Urol., 48:
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