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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
$ g8 X$ g1 ~ g- V* o2 }1 m; ^GONADOTROPIN: i6 m' W' `8 s# ^
RICHARD C. KLUGO* AND JOSEPH C. CERNY, {, `/ k/ `# {% J+ k% s/ j
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
' {/ ?7 @$ S3 B- g: ^9 q3 N# MABSTRACT" F: p5 ~# E9 p# @
Five patients were treated with gonadotropin and topical testosterone for micropenis associated: X8 E: g2 R, Q; X8 G. T4 I8 `
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
+ }7 m: [% Q# `$ Y1 Vtropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone* }( {5 H# W. G/ @+ ]* d! W
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
' p' |, A B( W _/ ~* ufor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
" E. V l: ?/ iincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
; g$ C3 s6 m$ tincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
' D2 b3 X+ d& y) O- t2 d; l/ i) G4 Ooccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
5 T, r6 D/ s/ @5 Gstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile, _" e% C9 ?; y" ]3 Q/ I
growth. The response appears to be greater in younger children, which is consistent with previ-
( x) H) o6 Q/ f4 `9 J7 Rously published studies of age-related 5 reductase activity.
; X$ Y w, U4 p* rChildren with microphallus regardless of its etiology will* D3 k& n. K3 H% P) F. l( _
require augmentation or consideration for alteration of exter-( `# s+ h o! X
nal genitalia. In many instances urethroplasty for hypo-; y5 A" v4 a. K8 r' S
spadias is easier with previous stimulation of phallic growth.8 y9 j+ F4 ^% ]( d
The use of testosterone administered parenterally or topically
1 w6 c( n" f$ M% u& |+ |has produced effective phallic growth. 1- 3 The mechanism of
& Z" C `0 m, E1 `response has been considered as local or systemic. With this. Z' I$ }2 }6 r; [) S( R$ m5 o
in mind we studied 5 children with microphallus for response4 `+ a5 V, X1 G4 B( T
to gonadotropin and to topical testosterone independently.
% ?+ }! y( W. S O" r0 l3 U( WMATERIALS AND METHODS) m1 N! M# p P; A) I: f8 C
Five 46 XY male subjects between 3 and 17 years old were
8 n) L+ q! l3 p; q( ?3 `evaluated for serum testosterone levels and hypothalamic
4 o# r: R9 h0 L2 O0 x; i' M0 g3 hfunction. Of these 5 boys 2 were considered to have Kallmann's! b' A7 \8 \+ i/ M
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-, h7 y- W7 P. l
lamic deficiency. After evaluation of response to luteinizing
+ f0 A& o: D* x0 F- X9 Phormone-releasing hormone these patients were treated with5 Q9 N* `2 z' C
1,000 units of gonadotropin weekly for 3 weeks. Six weeks8 J4 m4 [5 `! b: W% _& @7 H
after completion of gonadotropin therapy 10 per cent topical6 M: F$ a. x _' n) w0 n k
testosterone was applied to the phallus twice daily for 3 weeks., Y4 E/ `8 I! M j' b* ^
Serum testosterone, luteinizing hormone and follicle-stimulat-2 Q; d1 w! y" \" d# r
ing hormone were monitored before, during and after comple-
# k* V7 M8 A; S) L8 f' ltion of each phase of therapy. Penile stretch length was
8 v+ w7 S5 e: f0 V/ ?; e1 P9 Q, ]obtained by measuring from the symphysis pubis to the tip of
8 z: C) z+ _* \2 `the glans. Penile circumferential (girth) measurements were; Q5 k0 e( _$ f# v" `
obtained using an orthopedic digital measuring device (see& x8 x8 g) A, R, g2 j2 U
figure).' Y. j. N% A9 y; P: n9 c# f3 X
RESULTS
+ B5 h5 Z- u; F4 j/ ^" CSerum testosterone increased moderately to levels between. M6 I/ w7 u- O, R; A
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
, B/ i, C, m' D. Eterone levels with topical testosterone remained near pre-
. }5 x5 x* N2 z0 @ ^treatment levels (35 ng./dl.) or were elevated to similar levels8 U. _! s4 b3 l. @# e: c8 U, p
developed after gonadotropin therapy (96 ng./dl.). Higher
\5 J0 e2 R6 P, x5 c6 ]serum levels were noted in older patients (12 and 17 years old),' r1 h S8 \- Y- g' Y4 a- t
while lower levels persisted in younger patients (4, 8, and 10
! h( O. j+ ~3 {4 uyears old) (see table). Despite absence of profound alterations+ ?6 A# F& I: S) L
of serum testosterone the topical therapy provided a greater$ c- p9 l$ [0 C6 U
Accepted for publication July 1, 1977. ·0 J5 \6 N* B& c7 E( ]1 d. g
Read at annual meeting of American Urological Association,
1 g1 O( g% h- f8 M5 q6 YChicago, Illinois, April 24-28, 1977.- t j5 J$ Q+ g/ I; D
* Requests for reprints: Division of Urology, Henry Ford Hospital,: h% r. z* a- [! ?' o6 l5 l
2799 W. Grand Blvd., Detroit, Michigan 48202.- j) W, F9 a2 ~
improvement in phallic growth compared to gonadotropin.$ w. j5 C: w- J! [1 V O+ j
Average phallic growth with gonadotropin was 14.3 per cent2 m7 w9 m6 G1 ]9 c4 s S3 D# V
increase in length and 5.0 per cent increase of girth. Topical
2 G6 g+ \$ r* C" s- ctestosterone produced a 60.0 per cent increase of phallic length8 r/ U8 H" a; ^0 i/ C2 d' ]
and 52.9 per cent increase of girth (circumference). The
3 r- _; n4 d0 Kresponse to topical testosterone was greatest in children be-8 B4 M3 M1 }1 g% U3 K
tween 4 and 8 years old, with a gradual decrease to age 17( R& M/ B6 p' L T% P! ^
years (see table)., y& _0 t8 A d$ A' W" q9 w3 \+ M* G
DISCUSSION
, |" ^5 B# x6 C' K5 `' KTopical testosterone has been used effectively by other
& @/ j6 I" Z1 n: F2 [clinicians but its mode of action remains controversial. Im-
; [ Q/ ] p4 e: V) Q' ~4 @mergut and associates reported an excellent growth response/ E# V. h8 X) j- _9 }
to topical testosterone with low levels of serum testosterone,' k2 {- k$ c, H; E, s+ p5 R8 z/ z
suggesting a local effect.1 Others have obtained growth re-
, l0 _( _7 p+ {+ ?( L/ ^sponse with high. levels of serum testosterone after topical7 [8 G6 Y2 Z4 R
administration, suggesting a systemic response. 3 The use of
9 C6 i2 e9 v3 J) B, vgonadotropin to obtain levels of serum testosterone compara-
6 {" B! l6 S1 N) a- Sble to levels obtained with topical testosterone would seem to
: K8 ?- _! P8 P* I7 p/ wprovide a means to compare the relative effectiveness of
3 ]/ r! H" T) otopical testosterone to systemic testosterone effect. It cer-
4 a; l& s7 N2 V. s5 Utainly has been established that gonadotropin as well as par-* n+ N( @. q" f5 x5 C) V/ [# e
enteral testosterone administration will produce genital
7 I0 {3 a$ o. ?growth. Our report shows that the growth of the phallus was2 p# j f0 }- r' ~
significantly greater with topical applications than with go-) J8 s# ~: c9 |2 i
nadotropin, particularly in children less than 10 years old.& \. g+ k2 \( K, H, _* H
The levels of serum testosterone remained similar or lower
) {7 i' w! r8 Y8 |than with gonadotropin during therapy, suggesting that topi-
: L! n* L- }' a4 gcal application produces genital growth by its local effect as
) f& ?3 T# Z' S" dwell as its systemic effect.
3 k# x0 S; z/ p. KReview of our patients and their growth response related to6 u) S7 x( R! g" K
age shows a greater growth response at an earlier age. This is$ N- W: \$ k& _( j- ?
consistent with the findings of Wilson and Walker, who
( M: `- g" Z5 G* O J/ F% A+ Qreported an increased conversion of testosterone to dihydrotes-
L( p/ W, \3 G, e" ltosterone in the foreskin of neonates and infants.4 This activ-2 ~- P" r6 e& h. ~/ L
ity gradually decreases with age until puberty when it ap-( D( Y9 v1 f8 |/ F3 y- s
proaches the same level of activity as peripheral skin. It may* Q5 d2 D: L" b7 G/ _
well be that absorption of testosterone is less when applied at
# i& s" R t* F$ v' {an earlier age as suggested by lower serum levels in children
" x/ b- b0 M: S; hless than 10 years old. This fact may be explained by the
$ a ^& g5 Q* ^0 |; Z) t% W1 ugreater ability of phallic skin to convert testosterone to dihy-% b, a+ E% h- D# t ]; W
drotestosterone at this age. Conversely, serum levels in older6 f/ \0 _$ W& q
patients were higher, possibly because of decreased local
2 h- l$ o! Q1 \! ]# i. a! Y4 J' d* @. h667/ S) a, ?* D m' Z _" C
668 KLUGO AND CERNY
' h& ~- k B) [8 @# sPt. Age
3 s9 d. [1 G2 L+ T6 V# q(yrs.)$ N3 e6 O( N$ |1 Y
Serum Testosterone Phallus (cm.) Change Length
" v, K3 W$ `0 R0 ?3 h(ng./dl.) Girth x Length (%)3 |4 _0 n; P! e- e' _% J
4
) X8 o2 g* C! i5 F- Z8# e" M4 o" n, Y/ ~
101 N: H/ F+ e9 C" ^ j: t
12! n- F* K. `1 q5 a
17
5 u; a" n! u* B" F5 zGonadotropin3 V4 d$ Z3 m, Y
71.6 2.0 X 3 16.6# C: b4 a& |- U/ H7 \4 Q3 S
50.4 4.0 X 5.0 20.0
; ^; r! I' k& ?4 E. g* |8 l1 W22.0 4.5 X 4.0 25.0 k7 t% u+ j& W/ Q ?3 S4 Z- W* v
84.6 4.0 X 4.5 11.1- Y/ C9 R9 T5 c' z! O% }
85.9 4.5 X 5.5 9.03 |4 m+ Z1 j4 u
Av. 14.3* P# w ~; M+ r* S. j
4
- ]# B% Y4 _6 y% G5 N8
1 v+ ~! [& H- G% u a10
7 K! F5 N. l2 _5 }5 d- c4 o124 D2 T6 s) B; m& H$ ]
17
4 r6 \7 K& V" T! U" |$ u' k9 ^2 sTopical testosterone$ b: }2 w/ Y" f- k) P' U
34.6 4.5 X 6.5 85" ~5 |# {7 i T5 M& u2 K, }
38.8 6.0 X 8.5 70
; q" e" S1 e5 c, w4 r0 k" Z: g40.0 6.0 X 6.5 62.5
9 M$ d0 {1 |) a9 M. D+ F2 A93.6 6.0 X 7.0 55.5
, D/ G: I$ P/ R* m4 T) h95.0 6.5 X 7.0 27.27 _* `' y M5 k) b" R
Av. 60.09 n9 `& d5 H K, X8 o" Y- }
available testosterone. Again, emphasis should be placed on
J9 U( u* x6 J1 W# E# tearly therapy when lower levels of testosterone appear to8 f, I: n2 K8 @% v5 I D
provide the best responses. The earlier therapy is instituted; Q: H! e0 U1 N: b9 c
the more likely there will be an excellent response with low
! v* ?( s6 M& W Y2 j7 i$ B" gserum levels. Response occurs throughout adolescence as
+ r7 Y" ]6 W6 _+ h! n- xnoted in nomograms of phallic growth. 7 The actual response
2 c/ e2 V: H3 F8 s% ito a given serum level of testosterone is much greater at birth5 X6 p7 Y" s/ |
and gradually decreases as boys reach puberty. This is most0 }# j* Q3 b, s$ d
likely related to the conversion of testosterone to dihydrotes-3 B8 h( K4 O( T5 ^
tosterone and correlates well with the studies of testosterone: x$ B$ q+ |/ L$ C
conversion in foreskin at various ages.
0 M+ }+ C0 \% Z# G% k. M, `The question arises regarding early treatment as to whether5 K" |5 y8 K( U# L4 K, g m
one might sacrifice ultimate potential growth as with acceler-1 C7 w ~. g( Q3 w6 A- D
ated bone growth. The situation appears quite the reverse1 r; d; k- X" I9 A
with phallic response. If the early growth period is not used) G& x5 b) K. C8 G' s s5 b
when 5a reductase activity is greatest then potential growth
9 Z( D: V, `- T* [( v% Xmay be lost. We have not observed any regression of growth4 n; t$ K7 r4 [! _: `8 b) y/ o
attained with topical or gonadotropin therapy. It may well1 P4 ^! r9 A9 W3 X
be that some patients will show little or no response to any
9 w) m8 R0 X& A3 z; Aform of therapy. This would suggest a defect in the ability to6 o( m' o' c/ e( o& K4 F1 R
convert testosterone to dihydrotestosterone and indicate that( ~1 X1 \% A4 i* W! l$ P
phallic and peripheral skin, and subcutaneous tissue should! i9 _" m& y C6 m# N5 S- k
be compared for 5a reductase activity.
- {, D! s: ~! U- }2 ^- Q8 EA, loop enlarges to measure penile girth in millimeters. B,0 K) d/ g5 f+ @/ P
example of penile girth computed easily and accurately.' @) s% E% j4 T
conversion of testosterone to dihydrotestosterone. It is in this
- V& X8 {9 e9 F! rolder group that others have noted high levels of serum
# Z" R: J3 {; Ptestosterone with topical application. It would also appear
. ]' H2 |. m) fthat phallic response during puberty is related directly to the
: }0 |) c5 ?& [2 I# y4 }serum testosterone level. There also is other evidence of local: U. n {& f2 G- s* l i7 t4 N
response to testosterone with hair growth and with spermato-
: S$ g/ ^& T1 T2 Dgenesis. 5• 6- X1 ?! J, Q! Z2 g3 o, ], p
Administration of larger doses of gonadotropin or systemic. i! `5 l0 H' |. y/ S, F% S6 m3 _
testosterone, as well as topical applications that produce
& w, C0 b& x0 Ohigher levels of serum testosterone (150 to 900 ng./dl.), will2 q% v. A ~: t) Q2 T5 j! L
also produce phallic growth but risks accelerated skeletal
2 s/ ]% P# o: n9 _6 o' t. Hmaturation even after stopping treatment. It would appear
& E" x. y% M8 \that this may be avoided by topical applications of testosterone
4 h7 n4 y2 s m0 f9 l% Eand monitoring of serum testosterone. Even with this control
* ^1 J5 u7 E* f$ b2 Rthe duration of our therapy did not exceed 3 weeks at any
4 e- r# R0 [& d! N2 i4 ltime. It is apparent that the prepuberal male subject may) C3 R: ~* [+ T! m T' m+ E5 u
suffer accelerated bone growth with testosterone levels near
+ _0 N. U9 o6 H0 d# X% \" v200 ng./dl. When skeletal maturation is complete the level of; i9 D$ X& i! `
serum testosterone can be maintained in the 700 to 1,300 ng./( U5 ^% R: ?1 G
dl. range to stimulate phallic growth and secondary sexual
: [3 w/ F0 ~# a) x" K4 t2 Xchanges. Therefore, after skeletal maturation parenteral tes-
* o/ p; O! R+ d4 Rtosterone may be used to advantage. Before skeletal matura-
! W8 ~5 }' x- |, q: r3 S( R# X3 s# F dtion care must be taken to avoid maintaining levels of serum: Z' p$ Q$ h# J
testosterone more than 100 ng./dl. Low-dose gonadotropin8 D! ]& Z9 I1 Y4 H% A$ p6 d
depends upon intrinsic testicular activity and may require
# ?$ a7 Y. h" m0 wprolonged administration for any response.% R, X5 z6 @9 n) u
Alternately, topical testosterone does not depend upon tes-
- j9 \, e4 p6 C3 I4 T* Bticular function and may provide a more constant level of
7 R* t' H2 t5 z; dREFERENCES
4 w: b$ F9 w0 t# R- J6 v# }2 C1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
3 O7 @3 ~! P0 t: m; }* ?6 z6 S9 }4 }* zR.: The local application of testosterone cream to the prepub-
$ E5 ?5 h/ O% _5 o9 h. Mertal phallus. J. Urol., 105: 905, 1971.
& v2 ~% p8 g" Y5 h6 |2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
# w& f }- X3 mtreatment for micropenis during early childhood. J. Pediat.,
, U* s7 h% ]+ k83: 247, 1973.
- G' `- f' e% q4 o0 D _3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-6 ?6 R7 L" I; g) r4 Q
one therapy for penile growth. Urology, 6: 708, 1975.
' v! y% R* \( Z# {" p/ m' ?* f! h+ H4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone7 h' t2 A- a# i: O; P9 v
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
: r; B! S$ ]; E5 z% F6 R( Z. hskin slices of man. J. Clin. Invest., 48: 371, 1969.$ J B6 q( X# t5 t" E; H/ D' r
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
* M7 k- |+ |; t0 X2 |0 T/ pby topical application of androgens. J.A.M.A., 191: 521, 1965.
" g2 l5 {; U9 T. j6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local4 Z' r' S7 T. J/ F# }
androgenic effect of interstitial cell tumor of the testis. J.
$ F) }0 K8 }6 M8 EUrol., 104: 774, 1970. k* e* v6 r5 L3 a+ N% y6 @
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
* c+ a& N4 D9 V- Z( j$ \0 U+ ytion in the male genitalia from birth to maturity. J. Urol., 48: |
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