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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND, p) g1 f) w" W$ J
GONADOTROPIN
( V; f, _1 W" l" n. g# r: zRICHARD C. KLUGO* AND JOSEPH C. CERNY2 r4 n% G4 H. H# e& i4 z, E
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
8 _' X2 L. Q1 ^! q1 H; U) aABSTRACT
: S& ^* W! \7 ~$ C2 u! ^# sFive patients were treated with gonadotropin and topical testosterone for micropenis associated
! o4 W) D, v. Z) C8 h( D" k3 zwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
; n# J& t) D% V1 \- Stropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone3 i! g: S# {6 D7 T- d6 j5 m
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent3 l% u8 _  d/ s& M/ u
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent' ?7 \; v& I4 ^3 K
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
- [% e5 e' ^9 V3 Oincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response+ q  Z2 ?# c5 L+ a9 Y0 h/ `5 B3 V8 k
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
/ b' J( ~; H% t1 d: |* H5 xstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
, a, ]7 X& S' Tgrowth. The response appears to be greater in younger children, which is consistent with previ-( \/ D- S9 z( d" X
ously published studies of age-related 5 reductase activity.
  m! m! x6 Z; }$ U0 u# N7 Q+ yChildren with microphallus regardless of its etiology will
; Q9 X% j+ S' t# k' h/ D+ Qrequire augmentation or consideration for alteration of exter-6 D' J6 V4 U% V
nal genitalia. In many instances urethroplasty for hypo-
0 z% @8 C/ g4 I! [3 Mspadias is easier with previous stimulation of phallic growth.
" i, q4 V7 L. b2 H: R: IThe use of testosterone administered parenterally or topically! A2 |" v; |  D1 H% g& l% Z
has produced effective phallic growth. 1- 3 The mechanism of
( _  X5 _5 P- d) l  j5 Y9 Fresponse has been considered as local or systemic. With this3 {; }  D) [* @% Q4 H. V, \0 K
in mind we studied 5 children with microphallus for response
% N  q/ W, y+ P6 c( Sto gonadotropin and to topical testosterone independently.5 P. N* y6 [* \8 U& T* D! P
MATERIALS AND METHODS
8 E5 Y0 n: F" f9 LFive 46 XY male subjects between 3 and 17 years old were
5 |- x+ z4 _. Z2 b' uevaluated for serum testosterone levels and hypothalamic/ q# I- B7 B' C+ ^
function. Of these 5 boys 2 were considered to have Kallmann's; Q* G1 V( D3 I
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
, T6 M7 J; i# ]% ~: s- f# Alamic deficiency. After evaluation of response to luteinizing7 B9 L, ~9 O( v5 X" T4 G
hormone-releasing hormone these patients were treated with: k' z4 l0 l% O) s- A8 e
1,000 units of gonadotropin weekly for 3 weeks. Six weeks3 r2 U6 |' J0 g6 v! q
after completion of gonadotropin therapy 10 per cent topical
( H4 ~7 n+ @+ ^0 ]0 k- ]testosterone was applied to the phallus twice daily for 3 weeks.
: u1 F) ]+ ?" @* r+ ?/ zSerum testosterone, luteinizing hormone and follicle-stimulat-+ r2 v) Z; g: Q6 L$ D$ ]# L
ing hormone were monitored before, during and after comple-0 a4 P6 u9 l" k( ]: _! c
tion of each phase of therapy. Penile stretch length was
5 l, s  L$ s- L/ x6 C. @4 e& q4 Nobtained by measuring from the symphysis pubis to the tip of
0 X' L' Q% x+ x6 j4 j" }4 b4 e# j# D2 Ithe glans. Penile circumferential (girth) measurements were, d( V7 r- H; O. ?. A, b/ V
obtained using an orthopedic digital measuring device (see
+ z) H' E6 a  V0 r9 jfigure).
6 g$ z$ a1 f1 B- b. J( FRESULTS
( r" T: u* a0 d) ?4 S6 }Serum testosterone increased moderately to levels between
+ ~! `0 L! f/ a50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
  s9 R* |  c" q$ f% _5 l) ~. Zterone levels with topical testosterone remained near pre-7 Q, U0 g. E- x
treatment levels (35 ng./dl.) or were elevated to similar levels
5 T* ^" B$ u9 ^" Ldeveloped after gonadotropin therapy (96 ng./dl.). Higher
* S' T5 `2 p& Q5 u' |$ Pserum levels were noted in older patients (12 and 17 years old),( F0 f- B" I6 k+ y/ Q$ a4 |0 S
while lower levels persisted in younger patients (4, 8, and 10% {1 c6 _7 I* G/ _
years old) (see table). Despite absence of profound alterations0 S: ?& R% a4 k2 {( y% W3 u$ w% X
of serum testosterone the topical therapy provided a greater3 z; ], i! Y- n8 q
Accepted for publication July 1, 1977. ·
  }! _$ @% ~2 |* p: ?# xRead at annual meeting of American Urological Association,
9 y2 D1 v. u: }5 M' }: aChicago, Illinois, April 24-28, 1977.
$ D: r8 ~! T" ]* Requests for reprints: Division of Urology, Henry Ford Hospital,
# n5 H* v5 h# i1 K" h! V2799 W. Grand Blvd., Detroit, Michigan 48202.
' Q# j1 x. [5 [% v2 L$ Zimprovement in phallic growth compared to gonadotropin.# @3 X- D7 J( J3 v; Q
Average phallic growth with gonadotropin was 14.3 per cent- p9 P. \" z4 v  q9 T( J, b' \
increase in length and 5.0 per cent increase of girth. Topical$ i. l8 U" z/ ?5 D! D- \  Z
testosterone produced a 60.0 per cent increase of phallic length
4 z$ T5 u0 D: E6 \% U/ u7 Eand 52.9 per cent increase of girth (circumference). The
1 X$ r. ^0 _" g# A1 i0 l; `- p, wresponse to topical testosterone was greatest in children be-
2 K3 Y1 q9 l, @6 H$ ?tween 4 and 8 years old, with a gradual decrease to age 17
6 H2 v) h! f" z; `! k1 f: I2 oyears (see table).
0 o0 ^1 l% g- n  [' t0 I1 k, pDISCUSSION* A0 D1 m6 g2 S9 C2 G( w4 x2 `
Topical testosterone has been used effectively by other  S" E& U9 p( l
clinicians but its mode of action remains controversial. Im-
$ u+ q# w* P' Q. }% W0 Tmergut and associates reported an excellent growth response2 D1 P4 B8 P) G
to topical testosterone with low levels of serum testosterone,
  d+ ~% z6 ?4 \2 n6 K; t3 b# Ysuggesting a local effect.1 Others have obtained growth re-
8 y# K3 d( u9 H; \/ lsponse with high. levels of serum testosterone after topical
8 C; T& V9 O2 d( a! c& b( madministration, suggesting a systemic response. 3 The use of& l. b" {3 |- N7 Z5 p- h
gonadotropin to obtain levels of serum testosterone compara-" X/ c/ z0 Q5 j8 E( E
ble to levels obtained with topical testosterone would seem to
2 N! }1 ?$ V- A$ C6 K" Y3 lprovide a means to compare the relative effectiveness of
, S. m+ J& c+ [$ [topical testosterone to systemic testosterone effect. It cer-
! L1 W5 d( g/ s8 ]2 X1 @1 [# n" Jtainly has been established that gonadotropin as well as par-7 s. J/ j1 p( g7 w, o) c
enteral testosterone administration will produce genital
6 F0 K% ]" L$ C4 a/ Fgrowth. Our report shows that the growth of the phallus was
: j# A& ~( y; E7 s4 ]: qsignificantly greater with topical applications than with go-
& s3 K9 ?! |- X5 [- w8 ~nadotropin, particularly in children less than 10 years old.
, A5 k5 ?1 b" D' GThe levels of serum testosterone remained similar or lower' b' J# Q1 T' j  U6 s
than with gonadotropin during therapy, suggesting that topi-7 c) X) M/ T6 z2 n' \
cal application produces genital growth by its local effect as
+ a7 Z7 T, k% ]well as its systemic effect.8 O, k; z# \# c3 o8 F# j& O, [
Review of our patients and their growth response related to( ]' B# O3 s* f/ c! M% G
age shows a greater growth response at an earlier age. This is7 X$ ~" V  o, S4 D( }' |5 q
consistent with the findings of Wilson and Walker, who+ t4 K+ \% @+ q' J5 r, J) {
reported an increased conversion of testosterone to dihydrotes-1 O) c" e3 @1 D  c0 d+ j9 D( |* e! S* f
tosterone in the foreskin of neonates and infants.4 This activ-, B7 j, a" B& s5 w
ity gradually decreases with age until puberty when it ap-) V2 A0 F7 A+ G9 T& e7 L2 ^; @
proaches the same level of activity as peripheral skin. It may
6 [3 U+ t" E7 }+ {, w9 v: Lwell be that absorption of testosterone is less when applied at
& O: A$ A7 Q" V9 Q" ?; J5 q0 ^an earlier age as suggested by lower serum levels in children
7 h# R/ x" A) u; F/ M4 sless than 10 years old. This fact may be explained by the; |! P' z+ j( [- i
greater ability of phallic skin to convert testosterone to dihy-7 O; O6 ?3 z7 \1 b, L
drotestosterone at this age. Conversely, serum levels in older
6 N8 ~- n. N2 T1 Opatients were higher, possibly because of decreased local9 T! |6 e) c% U$ @! Z+ _
667
! v: h' u. e! ~, E" v% C668 KLUGO AND CERNY
. v# n! F$ X6 }: z- W8 ?Pt. Age
4 V0 r% }, z. r(yrs.)
4 S% F, s, j- f; _+ g6 xSerum Testosterone Phallus (cm.) Change Length
+ {2 c7 B' S" n5 y5 R; h: |$ L(ng./dl.) Girth x Length (%)
  ^8 M: l. k" S7 O4; ]# f! W$ M# a  P- P1 u- d
8. ?5 c6 O. Q8 u# e: S
10
; l- d. Z0 R* k12
5 q5 j0 a* x" N- X) g& C172 A) s: ^1 `& M3 p5 e
Gonadotropin4 d. N1 B7 @& a1 o4 ~' m+ K
71.6 2.0 X 3 16.6
( K/ O0 Q( `' ~; K50.4 4.0 X 5.0 20.0
8 F- C1 `# F, N# M( c22.0 4.5 X 4.0 25.0
" ^  j( y) D* O' c84.6 4.0 X 4.5 11.1+ V) O- t6 |4 N
85.9 4.5 X 5.5 9.00 X$ ]* r( H: J' @, x4 K
Av. 14.3" B8 }' M* z/ y7 x) F. {
4
! j+ l$ p- j. I/ S8! H& O- q  g4 {$ G( I
10, d- w" ?# T' a( Z- \
12- m" }- H* s5 U' |; ]2 {2 g( V. i
17
, J2 @( d& S9 H, ETopical testosterone2 h2 Z8 ~& p+ X; b- r) G* s
34.6 4.5 X 6.5 85
0 j* ]4 Z. F, a( ^5 L( b38.8 6.0 X 8.5 70+ T' U4 p2 w2 ]" W- \% g
40.0 6.0 X 6.5 62.56 E3 O: G7 Q$ c, K4 g
93.6 6.0 X 7.0 55.5$ D+ ~' @4 z' [9 y0 b
95.0 6.5 X 7.0 27.2' f; W* ^6 C( Q2 B$ t
Av. 60.0
1 j6 ?; ]. I9 E# d3 \7 Uavailable testosterone. Again, emphasis should be placed on# o, O6 {) F! J$ G
early therapy when lower levels of testosterone appear to
, V( e: C  I( b' [: ^provide the best responses. The earlier therapy is instituted
$ f; b8 e8 T( V0 n. ethe more likely there will be an excellent response with low
4 m( G& ~( g6 d: p2 o0 h9 pserum levels. Response occurs throughout adolescence as
: k3 d) m5 m. f1 j+ Snoted in nomograms of phallic growth. 7 The actual response4 B, P9 e7 t0 O2 u
to a given serum level of testosterone is much greater at birth
* K4 F/ _2 Q8 ^& b' ]; Eand gradually decreases as boys reach puberty. This is most8 y& ]( g+ X, y0 \1 \( G
likely related to the conversion of testosterone to dihydrotes-
! p- e- Q  D1 p9 Y/ l$ R: xtosterone and correlates well with the studies of testosterone
, w: e9 x1 I3 C6 cconversion in foreskin at various ages.5 ^$ S( P! f! D& u$ E& P9 _( X+ G5 ~7 {
The question arises regarding early treatment as to whether
" T& h8 `6 A' I& ?0 L4 ]one might sacrifice ultimate potential growth as with acceler-
3 z, h' Y$ V& Wated bone growth. The situation appears quite the reverse
: X) ?* }9 T6 z3 wwith phallic response. If the early growth period is not used# c- i- g/ I2 V* E4 Q3 t
when 5a reductase activity is greatest then potential growth- m& H$ G2 `) `8 P  ^% {8 A
may be lost. We have not observed any regression of growth! @* @! w& R6 l/ a" `& c0 Z. [
attained with topical or gonadotropin therapy. It may well4 I% i' I8 t/ B, S3 C- i
be that some patients will show little or no response to any
8 M4 A* ?5 N1 |4 K& X( y  Qform of therapy. This would suggest a defect in the ability to
+ W2 @$ i& W; e, T# qconvert testosterone to dihydrotestosterone and indicate that& `& B" [& b4 D4 w! u% X
phallic and peripheral skin, and subcutaneous tissue should3 a% J1 B# D. n, X- m/ _9 H+ M
be compared for 5a reductase activity.9 v. I/ m: G8 V6 i/ D9 L# O
A, loop enlarges to measure penile girth in millimeters. B,' _& n# [( Z! l6 `" e: i
example of penile girth computed easily and accurately.  u# C9 M% F! @1 _! d
conversion of testosterone to dihydrotestosterone. It is in this1 h. s9 h! j8 s6 f
older group that others have noted high levels of serum
2 U% o( K6 A- w$ a4 N) t: _" stestosterone with topical application. It would also appear3 g- T6 w* ~! d
that phallic response during puberty is related directly to the
6 b1 d$ W% _* B' |3 `0 ?serum testosterone level. There also is other evidence of local
7 z- J; E% H/ w% Kresponse to testosterone with hair growth and with spermato-/ Y1 C% {" a# F5 a
genesis. 5• 6
( J  w5 r+ R$ yAdministration of larger doses of gonadotropin or systemic8 M( @7 {1 C/ V0 H6 B  |; @" p3 x4 P
testosterone, as well as topical applications that produce
8 m' U* \' {2 G  B3 chigher levels of serum testosterone (150 to 900 ng./dl.), will
8 Z% s# v0 Z$ u& G8 v+ Salso produce phallic growth but risks accelerated skeletal
% l2 E! F3 t$ T  omaturation even after stopping treatment. It would appear
- p3 x& z. k, ^$ n2 ^, Nthat this may be avoided by topical applications of testosterone
6 e; W; h% V. J' S3 Tand monitoring of serum testosterone. Even with this control$ r9 S/ g0 C& P" D; |5 t: e+ ~
the duration of our therapy did not exceed 3 weeks at any
# L! D: i) N" Z9 q+ P6 Btime. It is apparent that the prepuberal male subject may7 [; s7 z1 r4 j0 I  i
suffer accelerated bone growth with testosterone levels near
9 I# {9 I/ d0 W1 K$ D" _0 a200 ng./dl. When skeletal maturation is complete the level of8 {  ?5 h. m( E% k8 ]3 F$ M1 ^
serum testosterone can be maintained in the 700 to 1,300 ng./
. ]* o5 T  {! b2 B# i7 qdl. range to stimulate phallic growth and secondary sexual
1 k2 y6 l7 S% gchanges. Therefore, after skeletal maturation parenteral tes-
, n) E) Z( k6 a( Y% ]9 Dtosterone may be used to advantage. Before skeletal matura-
% O$ D6 G- F# B' P/ C! `4 h( _, o1 mtion care must be taken to avoid maintaining levels of serum) {& h& h% r( i  D( Z8 w) A
testosterone more than 100 ng./dl. Low-dose gonadotropin% I' k: c- l- J, @
depends upon intrinsic testicular activity and may require
2 L$ }9 p! l" W) }* M. z- X0 jprolonged administration for any response./ `& H$ a# `! T, T4 O) u& L
Alternately, topical testosterone does not depend upon tes-
' F$ l: _# V7 I3 F! I- p3 gticular function and may provide a more constant level of
4 o5 L* h, V+ d- S$ D: PREFERENCES: K1 i" [: U% S! a0 |& j& L
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,1 q) P) i; w% Z/ i5 ]
R.: The local application of testosterone cream to the prepub-
/ v2 O! o0 F6 O6 vertal phallus. J. Urol., 105: 905, 1971.; P+ Z' R" x# F2 H0 j. g" t
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone, ~. a; H" x: j8 x" O
treatment for micropenis during early childhood. J. Pediat.,
1 l9 S& W8 E  ~: r5 G5 p* v83: 247, 1973.1 n/ c8 ]; U' ]/ D
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-. U6 x/ c1 _% C) ~! h8 v
one therapy for penile growth. Urology, 6: 708, 1975.: V! M4 ]  W5 Q8 a& C7 D0 O
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
+ [# b. [8 Z; Mto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
5 ^* f5 `, U% [- t4 Hskin slices of man. J. Clin. Invest., 48: 371, 1969.
: g  q% f4 n8 z8 v6 N" I5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
* M# [4 S+ a" R/ j' Mby topical application of androgens. J.A.M.A., 191: 521, 1965.
8 P! m0 J% f- o# Q6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local' k, a: X2 s5 J. U
androgenic effect of interstitial cell tumor of the testis. J.$ T: \/ |  V6 ^( m/ ~4 {
Urol., 104: 774, 1970.
& ~. M0 w) m6 G1 S6 Y) \" w" F1 Q7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
. S) v8 Y- ^6 j8 e! Ftion in the male genitalia from birth to maturity. J. Urol., 48:
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