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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
$ Y3 k9 p9 D5 bGONADOTROPIN
6 n: G; G `' v( y w" j$ W. D) DRICHARD C. KLUGO* AND JOSEPH C. CERNY) a+ f' x3 ]+ U2 W- r( \, ^. K
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
6 w4 u4 c1 v- v4 Q1 o) X, V. S0 L+ ~) XABSTRACT, o% n" X& _; r$ q7 O n- z' a
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
, S! F- g* j- U0 s7 k3 Gwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
9 K) E8 r( B) j, z- f% i3 ttropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
# Z# f; t0 _* U4 |cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
9 w. w, i8 j0 f, ~, dfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
9 Y3 u+ l% U U0 z- Pincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average- Z5 P$ c! u2 D4 ]( Z" l
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response: `, r8 F: `7 d
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
, Y: [# F7 C X4 }/ S3 `( T" jstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
) C& D2 g" e, c& K" m$ ~4 V {growth. The response appears to be greater in younger children, which is consistent with previ-' Z1 w* L/ M! G1 t
ously published studies of age-related 5 reductase activity.$ _1 N1 c, e& K& l
Children with microphallus regardless of its etiology will
2 T# S" i+ l- E8 _' ~6 s' k% h6 Erequire augmentation or consideration for alteration of exter-% \1 [; b+ J3 R8 F G! l' Y
nal genitalia. In many instances urethroplasty for hypo-% I5 I3 J) M2 n7 I7 f/ Q
spadias is easier with previous stimulation of phallic growth.
* x7 i# |; E" hThe use of testosterone administered parenterally or topically% u0 I/ `: v2 X& y$ C5 t% b
has produced effective phallic growth. 1- 3 The mechanism of" e$ M0 T$ a7 X+ Z$ W, a7 A
response has been considered as local or systemic. With this
* n& Y) C; y# y0 Rin mind we studied 5 children with microphallus for response! t& U% c- L% d+ m2 H2 r! k P V. i
to gonadotropin and to topical testosterone independently.& U1 v( c& W( W( U( w
MATERIALS AND METHODS5 [; P4 j) \$ _# R# Z2 E2 i
Five 46 XY male subjects between 3 and 17 years old were7 _% d( h! W% M6 O
evaluated for serum testosterone levels and hypothalamic
1 D& N$ {+ D4 J% i9 V4 Qfunction. Of these 5 boys 2 were considered to have Kallmann's) X% }6 N" Z6 }! L2 h
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
; j* e ]6 p4 e0 z6 o. |- i/ ulamic deficiency. After evaluation of response to luteinizing
2 G6 g N; Z0 n* H0 P' vhormone-releasing hormone these patients were treated with
# B+ Q3 K+ h/ Z! V( `1,000 units of gonadotropin weekly for 3 weeks. Six weeks
! _5 x5 H$ D; y9 j. l# Aafter completion of gonadotropin therapy 10 per cent topical: ` A9 ~. B5 A; w" B& g% l
testosterone was applied to the phallus twice daily for 3 weeks.8 m1 S: c6 L% H6 z0 l
Serum testosterone, luteinizing hormone and follicle-stimulat-
; b$ w, f: K, L I, ring hormone were monitored before, during and after comple-% |- N2 u& p9 @+ _; ^ K( I5 y2 w& e
tion of each phase of therapy. Penile stretch length was: K* I h/ e; y2 W( u- Q
obtained by measuring from the symphysis pubis to the tip of
3 k, T$ ~ n# @$ Y5 _the glans. Penile circumferential (girth) measurements were
4 x1 H5 q; ~5 y) G% V- H5 Aobtained using an orthopedic digital measuring device (see5 B6 f1 k6 g, Y, l3 L7 r9 O3 `% W
figure).
, k( U$ G! Q- h; G/ X; cRESULTS
6 A! z( Y5 _# }, nSerum testosterone increased moderately to levels between
' J s4 J4 j1 S; @4 I4 |4 }50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
1 m0 P! v, W6 c) ?terone levels with topical testosterone remained near pre-
4 N% A% ]9 ^4 ^$ Y% ^treatment levels (35 ng./dl.) or were elevated to similar levels: {& [! J0 q# [9 f- Y7 ^
developed after gonadotropin therapy (96 ng./dl.). Higher
2 S& k' k* b/ \. |( bserum levels were noted in older patients (12 and 17 years old),
4 Y5 Y+ f; b- \4 C1 k. Y" {" Wwhile lower levels persisted in younger patients (4, 8, and 10
) V+ C& a/ S. B/ Byears old) (see table). Despite absence of profound alterations& L% Z0 O' J' @ r; b: ?; u
of serum testosterone the topical therapy provided a greater6 z% F* x' o D# P
Accepted for publication July 1, 1977. ·
0 A; [ B6 m1 j5 l% {2 {Read at annual meeting of American Urological Association,; V0 K G/ j% R( s( V
Chicago, Illinois, April 24-28, 1977.
* ^, R# |1 X; B) D5 |4 X( k& i; s* Requests for reprints: Division of Urology, Henry Ford Hospital,; ~5 o3 f1 g6 ^) m
2799 W. Grand Blvd., Detroit, Michigan 48202.% C' {& U9 o' t4 l! V5 A( P
improvement in phallic growth compared to gonadotropin.
7 X7 o) T& x {- L' {Average phallic growth with gonadotropin was 14.3 per cent* a/ }) d0 w- M' i
increase in length and 5.0 per cent increase of girth. Topical* q9 v8 l \. w) v0 S
testosterone produced a 60.0 per cent increase of phallic length- q. K4 l: H! W4 q
and 52.9 per cent increase of girth (circumference). The4 Q, u% `/ K/ R8 p9 m% @: \, f! W
response to topical testosterone was greatest in children be-
e2 i: `. ^* n: t* etween 4 and 8 years old, with a gradual decrease to age 17
) `+ p" V1 a' Zyears (see table).
6 |* Z9 \# V9 x; WDISCUSSION
$ R$ t* v) v2 i; \0 [, e$ fTopical testosterone has been used effectively by other# h& ^! D3 _ ?! W( }
clinicians but its mode of action remains controversial. Im-
! e4 } ~" E0 B5 e( O3 ymergut and associates reported an excellent growth response
& t7 J" v g) Z2 e* Oto topical testosterone with low levels of serum testosterone,2 p/ S& O! Y3 N- i- J
suggesting a local effect.1 Others have obtained growth re-
3 z( z& e; y0 B6 b$ l# Fsponse with high. levels of serum testosterone after topical1 X8 R! Q3 }. }2 [
administration, suggesting a systemic response. 3 The use of# W: Q5 o" G9 B3 o6 W$ L9 Z8 p0 y
gonadotropin to obtain levels of serum testosterone compara-' \( k% f, V( l2 J
ble to levels obtained with topical testosterone would seem to# L: g5 { L7 ]& G' ?3 y
provide a means to compare the relative effectiveness of/ B/ E2 W2 |# P/ L3 |% O
topical testosterone to systemic testosterone effect. It cer-
% \1 N- F: o6 r8 f; | Y5 ^tainly has been established that gonadotropin as well as par-
6 m; h$ {5 y! m, `5 n+ @enteral testosterone administration will produce genital
4 s2 Z( v0 N3 X! @3 Kgrowth. Our report shows that the growth of the phallus was @5 B8 W3 a% g. b2 y d
significantly greater with topical applications than with go-
8 `4 l5 F" O. `. i" g: @, Inadotropin, particularly in children less than 10 years old. [ t1 U+ D/ Y4 F' T
The levels of serum testosterone remained similar or lower
6 B- A+ s* k: kthan with gonadotropin during therapy, suggesting that topi-
& A3 j3 }; v6 \) y8 f! M5 n/ W+ Tcal application produces genital growth by its local effect as: U$ C0 r/ @, C! V1 U* O. Z& ]
well as its systemic effect.
3 ~$ y( X3 } q# Y8 NReview of our patients and their growth response related to
) q) C4 Z0 Y7 g( p- ?age shows a greater growth response at an earlier age. This is
/ [) z, y+ p: r$ ?! i! p& Z3 jconsistent with the findings of Wilson and Walker, who
6 t) c0 w4 D; w/ B8 l8 creported an increased conversion of testosterone to dihydrotes-: P- h5 c2 {* Y+ ]) i) t3 f5 q
tosterone in the foreskin of neonates and infants.4 This activ-
3 G; X: M' k& G+ Y$ u( Sity gradually decreases with age until puberty when it ap-
' c( o7 ?. Z5 z3 r+ X: k* Aproaches the same level of activity as peripheral skin. It may
' n8 X; d; j! M- \ gwell be that absorption of testosterone is less when applied at
) d; f9 E: F3 @3 k: san earlier age as suggested by lower serum levels in children6 \, S- M. @" G
less than 10 years old. This fact may be explained by the
7 q6 l. D( c7 d, F' _. Fgreater ability of phallic skin to convert testosterone to dihy-
0 ]; n) S, g% |0 f6 W& j# [drotestosterone at this age. Conversely, serum levels in older+ i% ~- o) |# G$ N" x: {
patients were higher, possibly because of decreased local
( ?8 l( Z. y" x9 k: o0 s1 W2 u667( I; f/ g( y+ D1 ]9 t$ o& n+ g+ k- H
668 KLUGO AND CERNY& F# @1 d0 K! }
Pt. Age
$ i, W0 U1 O: V2 q(yrs.)7 n) O1 S z" T4 J' \% w _* p! [
Serum Testosterone Phallus (cm.) Change Length; E% F" W4 a! h9 C3 T5 M
(ng./dl.) Girth x Length (%)
g$ U; N/ V9 M: |9 m" K: `4
* t/ H' ~# B4 ]# h, Q8
& O9 v6 M% W$ I. h0 W108 J0 K! M* b- b& e9 v# z! ~' Z. v, |
12: {# E& E! u8 J/ D5 S
17
7 y# ?0 c# r) x2 N% KGonadotropin
5 p% ^1 U) f8 l; [71.6 2.0 X 3 16.6
$ j" k) b2 v$ D$ T6 L50.4 4.0 X 5.0 20.0
* s3 S3 K6 M( ?# G: t22.0 4.5 X 4.0 25.00 F9 Q1 f) W- x! I4 }; C5 P
84.6 4.0 X 4.5 11.1
6 \! p" m( q, j$ D% v6 w1 e85.9 4.5 X 5.5 9.05 ^; Q5 N1 N4 J# z
Av. 14.3
) s( E( [' V0 E6 o2 ?( k4, v/ \2 \3 T& l4 C" G1 e
81 u/ ^9 c6 ~3 h' J# |) o& y, q
10
0 z. j! R3 m! y; u7 d6 C( s* m12; V' }# D/ R# \5 q+ T) Q
17! h3 n }$ V: ?) B$ G) m+ R0 g
Topical testosterone- ~; y$ @8 ~! I9 \( j( o% ?& {1 A
34.6 4.5 X 6.5 85
]1 q2 |# s9 M, Z38.8 6.0 X 8.5 70; q! X$ l9 v- X
40.0 6.0 X 6.5 62.5
( m! K0 m+ O$ \6 p3 | o' ]$ V: D93.6 6.0 X 7.0 55.5
* ^- B- N+ f: d& r( Q95.0 6.5 X 7.0 27.2
6 P( x" [7 V/ h0 a) f3 wAv. 60.0
- n6 a5 \" U3 Uavailable testosterone. Again, emphasis should be placed on% v: T+ l: E& c# _+ N5 a9 T) H$ s$ D
early therapy when lower levels of testosterone appear to
- j1 x0 E" Q' ~provide the best responses. The earlier therapy is instituted
% B1 U$ @& }- Athe more likely there will be an excellent response with low
, r* \4 o+ I8 a8 p i* r5 Z* {serum levels. Response occurs throughout adolescence as( v7 Y% I. j' N7 z- \% n& L" ^
noted in nomograms of phallic growth. 7 The actual response; \8 @6 ^6 p0 n4 m8 e' V% I0 l
to a given serum level of testosterone is much greater at birth
/ Q5 O0 V3 Z7 c/ H6 | n! jand gradually decreases as boys reach puberty. This is most
+ i" ?% O( s# \# o5 \, y, j/ \5 Clikely related to the conversion of testosterone to dihydrotes-$ i: i# q6 S* f9 H' h
tosterone and correlates well with the studies of testosterone
$ x( Q8 D0 a4 n' e7 x1 D, @conversion in foreskin at various ages.8 N2 r6 X3 f- [0 w7 E& L. P
The question arises regarding early treatment as to whether s3 B, h0 L0 ^; A+ v# u5 C
one might sacrifice ultimate potential growth as with acceler-
/ z/ t) G; @3 y# f9 lated bone growth. The situation appears quite the reverse! F( m7 V Q: a3 D; F; `- d' m$ p
with phallic response. If the early growth period is not used
% [" L, ~! F, bwhen 5a reductase activity is greatest then potential growth3 |8 y8 a- z. S% Z; S
may be lost. We have not observed any regression of growth
4 y& T2 `3 E# Y* J2 rattained with topical or gonadotropin therapy. It may well
( S* n' J/ I) y3 Nbe that some patients will show little or no response to any6 v9 r: ]) r0 o+ D
form of therapy. This would suggest a defect in the ability to$ I P7 ^* Q' X# i$ z
convert testosterone to dihydrotestosterone and indicate that
5 q% T5 D7 A/ rphallic and peripheral skin, and subcutaneous tissue should# R5 ?; B1 }( f4 S4 e) ?
be compared for 5a reductase activity.
& q T8 K4 S! r; G$ y4 {A, loop enlarges to measure penile girth in millimeters. B,. Y& S* v5 H9 S
example of penile girth computed easily and accurately.
0 S! e( |- H5 M% ]2 m& Q5 P7 a* Xconversion of testosterone to dihydrotestosterone. It is in this7 n2 @8 j8 h7 `3 r! m: z- H
older group that others have noted high levels of serum
9 U% P9 w. z4 D }" Ltestosterone with topical application. It would also appear9 b& I2 ^- o$ b$ ?
that phallic response during puberty is related directly to the5 g) `( k$ Q# l& ?, w1 B+ I
serum testosterone level. There also is other evidence of local. J4 |# S9 a% ^' f
response to testosterone with hair growth and with spermato-
8 q, n4 A. o4 i8 i; y4 N; P6 dgenesis. 5• 6
, N6 Z: w: w" _4 Y% {% B8 `# r# R8 x1 oAdministration of larger doses of gonadotropin or systemic
8 N: ?+ ?4 e( E" E& Ltestosterone, as well as topical applications that produce
9 B. y: S6 W7 }0 U+ ?" o( fhigher levels of serum testosterone (150 to 900 ng./dl.), will7 L# z. z9 t4 I
also produce phallic growth but risks accelerated skeletal
0 l% E# l a; N; s. W& c1 y: Dmaturation even after stopping treatment. It would appear3 b1 W6 w, A: E% P' _( |
that this may be avoided by topical applications of testosterone6 J) Z6 i2 {- I$ X7 Z& E
and monitoring of serum testosterone. Even with this control4 Z' A2 L( P/ t8 r2 D; I, a
the duration of our therapy did not exceed 3 weeks at any- r/ }7 T% G( I6 b6 ^& O
time. It is apparent that the prepuberal male subject may' ]; i$ k# v, d8 b1 d j
suffer accelerated bone growth with testosterone levels near
- X" u: G8 i/ L9 C3 R200 ng./dl. When skeletal maturation is complete the level of
2 _5 s3 q# r# S( }serum testosterone can be maintained in the 700 to 1,300 ng./) ^. ~! A$ D7 f1 p* ^
dl. range to stimulate phallic growth and secondary sexual
/ w4 Z0 g, c+ y# F( i* V C& bchanges. Therefore, after skeletal maturation parenteral tes-( |4 G" X" y% v; C- q5 }3 X1 h
tosterone may be used to advantage. Before skeletal matura-$ R# T/ E$ t( g3 q9 {3 e D+ R
tion care must be taken to avoid maintaining levels of serum! L( w" A3 x# ^$ m# v# O3 ]5 F3 K
testosterone more than 100 ng./dl. Low-dose gonadotropin1 t6 W) d. Z& r3 @. Z: @6 X) u; B5 V
depends upon intrinsic testicular activity and may require1 y5 K4 m' m- d; o
prolonged administration for any response.4 S, @" J$ Y% i( y4 P
Alternately, topical testosterone does not depend upon tes- v3 b) t6 Y, p/ Y
ticular function and may provide a more constant level of9 E/ J* `) r6 z0 J$ @
REFERENCES- W9 D; u, e3 |5 T$ o/ u( ^7 h# M: O4 i
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
" Y) @& p$ C+ RR.: The local application of testosterone cream to the prepub-( M2 a' K; M4 O+ l: b* Z0 E; M
ertal phallus. J. Urol., 105: 905, 1971.
$ b. o$ {6 J j. o5 V( f3 x# ~: ^) O- u2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone7 L4 B! V' W7 ~; p- U, _
treatment for micropenis during early childhood. J. Pediat.,
) A+ m% F6 N' b( @ d83: 247, 1973.3 q6 p+ q" p, i' ?4 k0 z3 L
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
1 c m* a& z) _one therapy for penile growth. Urology, 6: 708, 1975.+ z! F4 Q5 V3 A( r0 h) E# N$ V* k9 R \
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
- U) @+ ~0 U5 a: n V' U7 pto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
% n, l" r2 S, e2 Lskin slices of man. J. Clin. Invest., 48: 371, 1969.
5 \& k; |# S! u1 @" l4 M/ k5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
/ z$ R, ^$ A% p& i+ uby topical application of androgens. J.A.M.A., 191: 521, 1965.
8 ]& c% G; {0 s3 L% _7 f6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local" e1 j! O" x. }2 ~. J
androgenic effect of interstitial cell tumor of the testis. J.
- C! Y5 f' G! Q0 T- o6 _Urol., 104: 774, 1970.( @1 s: j L: S
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-% h; r/ R% V/ W T2 F7 [
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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