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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
1 `: p: m" ~ p" S" J NGONADOTROPIN, g$ F# r8 F9 M0 [' T' B& T
RICHARD C. KLUGO* AND JOSEPH C. CERNY W9 C( H E( D9 [3 Q+ {' V- C# |
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
7 l, E6 o0 R- R0 F# ?9 RABSTRACT! b& F+ K c2 y8 a
Five patients were treated with gonadotropin and topical testosterone for micropenis associated) [& _% }5 _) t+ ]
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
8 V9 Q3 r. Q& f- `# }$ o7 u& v1 ctropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
9 O g Q: r6 {. m9 `+ {. ]cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent: P6 m) Y& u$ B1 u3 X
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
; k1 i- [2 f% m" I, H' I4 xincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
5 [3 C. S4 [$ v8 R8 bincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
: ~" ]- q% i/ G7 P- Qoccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This! @' g" r8 b8 H! e2 z( O3 \
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
4 D! n: n1 S1 u5 \- q+ |, cgrowth. The response appears to be greater in younger children, which is consistent with previ-5 G1 H, z' R' m2 y7 g
ously published studies of age-related 5 reductase activity.
3 i- h: G; G& L u2 iChildren with microphallus regardless of its etiology will
/ P( F% S d6 W# M; }5 O3 n7 erequire augmentation or consideration for alteration of exter-
. ^" B2 Z p1 |; C) Unal genitalia. In many instances urethroplasty for hypo-
: z& C2 B! Y y, Jspadias is easier with previous stimulation of phallic growth.
& Z9 M. i* t: H; f1 r$ ~0 j. oThe use of testosterone administered parenterally or topically
6 y+ R0 E9 E0 M) _has produced effective phallic growth. 1- 3 The mechanism of
! }; S" v% U% |, J- Dresponse has been considered as local or systemic. With this9 Z2 h X5 H* }2 @
in mind we studied 5 children with microphallus for response( h3 E& f8 r5 m
to gonadotropin and to topical testosterone independently.' ?5 [" y* V1 d" I0 @4 `9 Y' |( Q
MATERIALS AND METHODS
7 D; O& \' n! r: eFive 46 XY male subjects between 3 and 17 years old were& q4 b. I6 F& i+ b
evaluated for serum testosterone levels and hypothalamic
: ^! Q9 j! F, p: f9 h0 X7 i# _function. Of these 5 boys 2 were considered to have Kallmann's( S$ v4 S3 H1 M2 w: ~) e4 B0 U! n9 C
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
, [; |! p% N6 ?lamic deficiency. After evaluation of response to luteinizing
. U) B( h: p" Z; g1 h* ~ |* {( Thormone-releasing hormone these patients were treated with) J3 x2 K9 w' [. O3 G' R
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
@1 |3 F0 ~6 ~" |% |- dafter completion of gonadotropin therapy 10 per cent topical' ^8 W% x4 I0 _5 |6 C' A
testosterone was applied to the phallus twice daily for 3 weeks.* j( \! n) R8 q) \6 `
Serum testosterone, luteinizing hormone and follicle-stimulat-
# n( d' n6 a! X6 b2 d( uing hormone were monitored before, during and after comple-' X! ]* r; Y) {/ n5 T" S! X; p3 y
tion of each phase of therapy. Penile stretch length was
! [( a% D; H! X, w9 ~obtained by measuring from the symphysis pubis to the tip of! }$ q) l' }% O, C0 p% y# f/ p
the glans. Penile circumferential (girth) measurements were2 k" P$ ^+ b3 k4 K7 q
obtained using an orthopedic digital measuring device (see3 O' r8 N5 }! ~7 }
figure).& s, c& {9 M' Q+ H) ~; L
RESULTS! j$ T, E+ W' @
Serum testosterone increased moderately to levels between, o o0 P1 {4 R9 d) O1 d
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
/ r* G+ Y+ X' k t0 b" Eterone levels with topical testosterone remained near pre-; J' J N# Q# m; ?! s: g5 H
treatment levels (35 ng./dl.) or were elevated to similar levels
4 O) S2 C0 a, u$ Z1 l. e) Q3 |developed after gonadotropin therapy (96 ng./dl.). Higher; i4 K# ]; f/ D8 K8 F
serum levels were noted in older patients (12 and 17 years old),
w) g+ g6 G" s% n* o* h) Vwhile lower levels persisted in younger patients (4, 8, and 10
: ]7 Q' `( P5 vyears old) (see table). Despite absence of profound alterations
' Y1 ~ _6 Q# C4 _, Qof serum testosterone the topical therapy provided a greater
5 X& ]8 ~1 Z" f' S: OAccepted for publication July 1, 1977. ·
$ y- H. z8 r% q' @Read at annual meeting of American Urological Association, S5 L) L- l# r1 {! M7 i, I) ]
Chicago, Illinois, April 24-28, 1977.( I1 z2 ]1 o0 ^0 _. e1 M0 G
* Requests for reprints: Division of Urology, Henry Ford Hospital,
, N& Z6 F2 N" N4 G A, _2799 W. Grand Blvd., Detroit, Michigan 48202.
) n- B4 Y, A3 @3 ]improvement in phallic growth compared to gonadotropin.$ J4 s& p% ^" S( w5 u
Average phallic growth with gonadotropin was 14.3 per cent
7 C. C5 f; A5 h& \$ g$ {$ N, ]increase in length and 5.0 per cent increase of girth. Topical! k" J) q6 E* q! N2 i$ l$ K( y
testosterone produced a 60.0 per cent increase of phallic length
8 s1 m; t& b! C+ b6 N/ Mand 52.9 per cent increase of girth (circumference). The
7 {3 O8 _! t: X5 l: g' cresponse to topical testosterone was greatest in children be-
) F, [/ |4 \ o2 \0 ]0 Htween 4 and 8 years old, with a gradual decrease to age 17) D$ f- Z; S+ g/ V* o
years (see table).
, b* Q( t5 d8 _DISCUSSION/ x# O1 E( o. G. `
Topical testosterone has been used effectively by other" w( E0 o1 t% r" K
clinicians but its mode of action remains controversial. Im-
' t" i+ `, ?, G8 {+ F$ F8 Xmergut and associates reported an excellent growth response
# f) R1 P; q9 a( J' C+ Q+ @' T3 B0 h9 |* `to topical testosterone with low levels of serum testosterone,; E7 ~6 Q: k. J& h
suggesting a local effect.1 Others have obtained growth re-. v! c ]2 u) `
sponse with high. levels of serum testosterone after topical' f9 R% \* l/ U. n, S4 ~' p( \* y* d
administration, suggesting a systemic response. 3 The use of
6 a5 I# N& w( s/ h$ x$ [gonadotropin to obtain levels of serum testosterone compara- V1 v$ y7 J) g' J' |) p' T
ble to levels obtained with topical testosterone would seem to
4 {, I7 g. C3 I- t# Q& U* {provide a means to compare the relative effectiveness of5 N, q1 V s: F# [4 J* o( V$ m4 _
topical testosterone to systemic testosterone effect. It cer-$ q" F9 l e4 B# s0 G
tainly has been established that gonadotropin as well as par-2 C* S( t" j6 b! b4 S
enteral testosterone administration will produce genital0 z# U0 K' C* j0 F. S
growth. Our report shows that the growth of the phallus was: c1 \! T \- W8 E6 I
significantly greater with topical applications than with go-
* T) @2 j6 ^# m0 _nadotropin, particularly in children less than 10 years old.( q7 e* j4 Q/ g, P# G, Q* R: L
The levels of serum testosterone remained similar or lower
T) g3 \3 ~3 {6 v Cthan with gonadotropin during therapy, suggesting that topi-2 T1 q- w* f* C! Y
cal application produces genital growth by its local effect as" B+ T5 t% |& \1 g, g
well as its systemic effect.8 h, s) C) Y3 Y; j( W/ b6 b0 E
Review of our patients and their growth response related to# ]. _4 W0 x5 ^3 n& x
age shows a greater growth response at an earlier age. This is# z3 j; H/ [& H5 {
consistent with the findings of Wilson and Walker, who
3 A% K! t( B t3 K- c* h, L5 hreported an increased conversion of testosterone to dihydrotes-+ |/ d( C( j+ j6 ?% H# p% c
tosterone in the foreskin of neonates and infants.4 This activ-
* D J* v4 K( ?) F/ J# h" }$ m& ^ity gradually decreases with age until puberty when it ap-
% \2 X; N, k% m- a4 {% }$ bproaches the same level of activity as peripheral skin. It may& c% M. L' n6 r: M- U7 b' @
well be that absorption of testosterone is less when applied at
* S: g- i/ C) q+ W' U' aan earlier age as suggested by lower serum levels in children
- L9 s* T$ [, R# G. ?# J5 X, j' Hless than 10 years old. This fact may be explained by the/ S( J( p" J9 D7 K( F; T9 A- \
greater ability of phallic skin to convert testosterone to dihy-
8 I$ {% A) p1 x2 [drotestosterone at this age. Conversely, serum levels in older
% i; w: d' v4 m' w) qpatients were higher, possibly because of decreased local) q2 Q, a' \! |: v: m! i8 D3 u+ r- x
667
4 N8 q ^' X$ p8 C668 KLUGO AND CERNY
7 D6 z% U" @" ~' b- v5 M5 p- D" lPt. Age) a0 A% l5 D4 U( ]& N" q# F
(yrs.)# [1 n/ @/ j8 b# t
Serum Testosterone Phallus (cm.) Change Length0 _5 X" U/ q G$ ~9 m5 e6 c; D
(ng./dl.) Girth x Length (%)
1 f$ }4 d# a+ `7 U4
. \$ Q j- n% ]+ @3 G. T+ \. g2 x b8
/ ^. J, E M% p! _. {/ Q$ E! f& h10
! e! L( n. C3 x' c12, ^0 T4 z, o; s7 Y9 v. E+ ?0 H
17
2 A9 P* q& S# l$ x4 G) Y! IGonadotropin
% p6 w5 r9 m1 r# W, h9 H( K71.6 2.0 X 3 16.6
, ~3 g0 ~; V) y- u% T; {50.4 4.0 X 5.0 20.0
( A( g8 G$ o* t22.0 4.5 X 4.0 25.0
; r7 r1 B, t, a" L1 Y, w) n- u6 s$ M84.6 4.0 X 4.5 11.1) B% s' `. U5 k |! [
85.9 4.5 X 5.5 9.0: F8 P ^2 T6 Q1 [7 Y; O! O M
Av. 14.3
7 F Y& A+ M4 o* O. H, f4( ]$ L& {) `0 \. W
8* V, s8 v5 [6 q4 R4 n
10
3 w& o6 k5 A9 V7 H126 [" T) d" f6 }: I
17
& B/ b9 @' v, d7 w3 e) G4 i! J! RTopical testosterone
7 j/ [4 M# l r6 d) s! E; K34.6 4.5 X 6.5 85
) M J' B& y& P6 G38.8 6.0 X 8.5 70
- w, V/ ^. M+ m/ k; B! p; f0 Z40.0 6.0 X 6.5 62.51 e" H, @7 N% |+ y# d: w- N& ]' ^
93.6 6.0 X 7.0 55.5& }) [9 d/ b4 u
95.0 6.5 X 7.0 27.2
9 ^7 I# y# ]' N* sAv. 60.0
. D0 S t5 p* y+ d5 a# Ravailable testosterone. Again, emphasis should be placed on
2 b& ~) X( t7 L2 o: jearly therapy when lower levels of testosterone appear to" E! f: L- y, _) F% [5 v) R3 E# F
provide the best responses. The earlier therapy is instituted7 n9 X- A0 u* v% Z( W) ?( P+ M
the more likely there will be an excellent response with low' Q( F5 z' o6 f
serum levels. Response occurs throughout adolescence as
! x% R1 k: \: r. j2 b1 }noted in nomograms of phallic growth. 7 The actual response
, P4 C0 U, D) j8 T' O# F% ^1 d' l. Hto a given serum level of testosterone is much greater at birth
$ Q5 w; c& O q- land gradually decreases as boys reach puberty. This is most+ L4 p! O3 Y* q# p
likely related to the conversion of testosterone to dihydrotes-
9 ^2 S- t3 ^7 stosterone and correlates well with the studies of testosterone4 d- K) U: B/ @; `' F! u
conversion in foreskin at various ages.. i4 n7 z$ N$ S+ C5 }' }, w
The question arises regarding early treatment as to whether7 t2 |! m, i( A7 N
one might sacrifice ultimate potential growth as with acceler-
$ e5 t1 r3 i: ]1 T+ y+ sated bone growth. The situation appears quite the reverse. R( Z2 M0 D+ |- f6 D( h5 Z! f
with phallic response. If the early growth period is not used7 t% J% i- o: E4 B1 u, _
when 5a reductase activity is greatest then potential growth
4 E K& m5 h2 B' `may be lost. We have not observed any regression of growth8 w" `9 O/ L- N8 ]# m
attained with topical or gonadotropin therapy. It may well
4 n0 |3 u, ~* |7 h% tbe that some patients will show little or no response to any
: M) f# K, ?6 ~9 |5 _ D# oform of therapy. This would suggest a defect in the ability to; e! W' p n% k) e# {7 v+ u
convert testosterone to dihydrotestosterone and indicate that; K( q/ y/ d, s3 ?& N
phallic and peripheral skin, and subcutaneous tissue should, A4 |; Q" T/ b
be compared for 5a reductase activity.
1 F, a2 D: y+ T- O' VA, loop enlarges to measure penile girth in millimeters. B,
& C- H' W" T; O+ g$ B# ^example of penile girth computed easily and accurately.
" d! A' P5 G G5 `+ mconversion of testosterone to dihydrotestosterone. It is in this2 `% ], Y7 o6 U" A0 W
older group that others have noted high levels of serum8 c* N7 n0 q0 v0 h c# n. Y
testosterone with topical application. It would also appear
; F# u4 S( q% h; c' M* K, _* K% Wthat phallic response during puberty is related directly to the
2 \/ b' O5 P) ]( _serum testosterone level. There also is other evidence of local0 P/ `4 q, `/ j8 P( h
response to testosterone with hair growth and with spermato-2 O6 t* o& [2 P, U! R8 P
genesis. 5• 6
( e8 Q8 ^ D! n; X9 V3 v- ]Administration of larger doses of gonadotropin or systemic2 b! w4 y7 P0 ]* ?) P
testosterone, as well as topical applications that produce
. @. p9 o+ _2 P% E/ whigher levels of serum testosterone (150 to 900 ng./dl.), will
6 c: O# t3 l# b" {- y O7 ualso produce phallic growth but risks accelerated skeletal |6 J+ O% P1 k6 L g
maturation even after stopping treatment. It would appear
% ~" I) g* Y: \that this may be avoided by topical applications of testosterone' T9 F8 Z# { Z7 P
and monitoring of serum testosterone. Even with this control
4 ?% {! b Z# h3 ]8 h- @the duration of our therapy did not exceed 3 weeks at any- K4 I5 v6 ?2 j& I- _- V/ ~1 |6 V. E
time. It is apparent that the prepuberal male subject may
3 B2 @9 m( J* d" {suffer accelerated bone growth with testosterone levels near
& H( [9 o0 T) N* g D7 o9 d# e200 ng./dl. When skeletal maturation is complete the level of
* [) E! b: g6 e2 d0 |serum testosterone can be maintained in the 700 to 1,300 ng./ d2 Y+ L# |9 M& V- D( ^; B4 n' x
dl. range to stimulate phallic growth and secondary sexual
. H% z6 Z8 ^3 }% }changes. Therefore, after skeletal maturation parenteral tes-0 R6 L" B9 u# ?( u& c" a: ~
tosterone may be used to advantage. Before skeletal matura-
8 Q8 C& C$ R( c( v2 }% ]tion care must be taken to avoid maintaining levels of serum
% @6 m2 V' }" F& j! F btestosterone more than 100 ng./dl. Low-dose gonadotropin9 y+ N; l' {% o; `
depends upon intrinsic testicular activity and may require
( j& |' I0 B& \: Vprolonged administration for any response.5 N: ^( J# N# ~$ @& g5 O O
Alternately, topical testosterone does not depend upon tes-
) t8 J- O, [; t7 pticular function and may provide a more constant level of& |4 p( B' r# b) I
REFERENCES4 b; g' ~2 ?# `( O I
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
& _/ D: ?0 w% n- s) o" x- xR.: The local application of testosterone cream to the prepub-
4 S P8 l" t0 o; r o) v: I3 ~ertal phallus. J. Urol., 105: 905, 1971.( k4 M& G5 U& S# i
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone2 k0 m. b% A, U6 z$ `5 _
treatment for micropenis during early childhood. J. Pediat.,
. b% |# X) s& Z2 a: k2 q' Z; m S83: 247, 1973.( n3 X3 h2 A: w) ?# ^9 _
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
% w# S2 J/ c9 v# Q4 _) Oone therapy for penile growth. Urology, 6: 708, 1975.
3 M. G+ ]0 @% t' Q3 E4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
, r) @$ H8 A$ D0 nto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by+ [: p8 ?8 `) e& ~* j
skin slices of man. J. Clin. Invest., 48: 371, 1969.
7 K' r4 P. t q/ e5 f5 J5 }5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth# L2 ?, H2 G9 h% |) Z y' Y
by topical application of androgens. J.A.M.A., 191: 521, 1965.
. X# W' M" V: k# U+ i* d8 F( W! N6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local, i& n# i ^: ~* N
androgenic effect of interstitial cell tumor of the testis. J.
7 O) {. q5 c0 q) [! rUrol., 104: 774, 1970.( y% t H1 F- U9 v/ [2 e! i- v1 x
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-! r. f: _- E, Q/ Q& |
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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