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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
8 O# U5 V2 C4 t' D. OGONADOTROPIN2 _7 Y; T" B3 N* l+ V I- P
RICHARD C. KLUGO* AND JOSEPH C. CERNY
# d( `+ |" s* i5 }6 Y6 S9 MFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
' a& }, }2 ~& y0 w1 U- u: QABSTRACT
: D5 p# G. C$ n/ jFive patients were treated with gonadotropin and topical testosterone for micropenis associated
9 R/ ~, O: \+ v) [7 C1 Lwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
+ @4 e7 T, X* l2 _. q. t$ ztropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone k4 H, [/ g, Q7 d& r! M4 y0 Q
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
$ G( l/ p$ j4 g$ zfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
+ C8 w6 t3 m& S+ c/ rincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
$ N2 `- n1 V+ y6 T9 X: x" wincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
, c8 Y5 |" |6 ?. ~6 p' i) J& ^occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
# S# ^% @- t5 u3 Z5 b c1 ]study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
6 J$ w0 e5 e6 |5 z( Rgrowth. The response appears to be greater in younger children, which is consistent with previ-
" u. f2 J9 w* j: zously published studies of age-related 5 reductase activity.5 U; x# Y$ k5 @. j; O' I
Children with microphallus regardless of its etiology will
# U! o! i( p! L% k7 ^require augmentation or consideration for alteration of exter-
- a' b* |* @" Z$ I, |. ^nal genitalia. In many instances urethroplasty for hypo-
5 O" g1 d" }/ z' |) M& ?spadias is easier with previous stimulation of phallic growth.
6 d$ T' x0 S3 p: }The use of testosterone administered parenterally or topically- T' Y) Q3 @( L0 [, a# M. w t
has produced effective phallic growth. 1- 3 The mechanism of$ c+ j. M+ K8 g( W1 b' E9 i" @1 l
response has been considered as local or systemic. With this
* B; [* E$ t3 K* a3 |: d2 E6 _ Cin mind we studied 5 children with microphallus for response) @8 @5 B& o, [2 y. g- f* j
to gonadotropin and to topical testosterone independently.
$ N. p. D6 K! M. j& O. lMATERIALS AND METHODS# P* t7 y A! |" H% ~; V) F* \
Five 46 XY male subjects between 3 and 17 years old were
9 H, | K d; Uevaluated for serum testosterone levels and hypothalamic
' W/ w. z! h A. {- k; ]5 D5 u5 ^function. Of these 5 boys 2 were considered to have Kallmann's7 b6 S x. a2 J
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
3 ] Q7 _0 _# G2 T( C' ]) H! elamic deficiency. After evaluation of response to luteinizing# ^9 b4 D }# ]8 e
hormone-releasing hormone these patients were treated with: z! \3 s5 M5 y' b
1,000 units of gonadotropin weekly for 3 weeks. Six weeks+ J- D3 y# K$ v$ ~
after completion of gonadotropin therapy 10 per cent topical
3 S0 O I; o1 U" }- Z0 T: p+ `* qtestosterone was applied to the phallus twice daily for 3 weeks., N' \9 d9 N7 {( o) `
Serum testosterone, luteinizing hormone and follicle-stimulat-
2 Q( y: O' N( b4 ~+ h( x0 Ming hormone were monitored before, during and after comple-7 t* Y+ k5 B# G7 e( h! _9 X
tion of each phase of therapy. Penile stretch length was
0 s$ n# X! `2 `- d2 O! A4 R" Mobtained by measuring from the symphysis pubis to the tip of
. x2 q' a3 {1 e* rthe glans. Penile circumferential (girth) measurements were( ^5 {1 \8 [. j4 p& Z
obtained using an orthopedic digital measuring device (see2 ~8 i% a2 g( N/ P! m7 J+ b
figure).
5 I q! Z9 F6 l, `& \RESULTS' Y/ v9 ^ p% {% v9 I
Serum testosterone increased moderately to levels between
4 d# t* }1 z7 t. H1 m7 U50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-- q2 _' J& ^! @
terone levels with topical testosterone remained near pre-0 H4 D4 b9 u n {6 g) }; G
treatment levels (35 ng./dl.) or were elevated to similar levels
y" \$ O. Y2 m0 q( C( Udeveloped after gonadotropin therapy (96 ng./dl.). Higher
. l% ^6 R" f: E6 Fserum levels were noted in older patients (12 and 17 years old),; ~& r6 T9 g7 J- l. `% v" G
while lower levels persisted in younger patients (4, 8, and 10
1 m1 o9 I; E3 @. r* a. ]3 byears old) (see table). Despite absence of profound alterations" Z5 ]2 E/ n! J
of serum testosterone the topical therapy provided a greater
# t' A# t. U) O8 o! t8 ], q0 nAccepted for publication July 1, 1977. ·
- R) N' h# M$ [9 B( A0 fRead at annual meeting of American Urological Association,
" C% O N1 o+ f+ y9 MChicago, Illinois, April 24-28, 1977.5 g* H& w3 Z- E P* W$ w
* Requests for reprints: Division of Urology, Henry Ford Hospital,. T8 h- t* d9 C$ d7 z: l
2799 W. Grand Blvd., Detroit, Michigan 48202.; s. a# A/ d% `1 f
improvement in phallic growth compared to gonadotropin.; W, q+ A3 K" v
Average phallic growth with gonadotropin was 14.3 per cent/ c" b' z. d6 V3 o
increase in length and 5.0 per cent increase of girth. Topical: A, N: A4 ]6 o/ s+ o
testosterone produced a 60.0 per cent increase of phallic length
% Z* N5 A! [) l4 e& E' x& uand 52.9 per cent increase of girth (circumference). The4 A1 U2 [2 S. x2 w: j. j
response to topical testosterone was greatest in children be-7 z. a( t5 M' F( f/ W D! e) j
tween 4 and 8 years old, with a gradual decrease to age 17: S$ F3 `- I- w, k: M
years (see table).
, k$ m0 w" B0 r+ {0 d% ^" dDISCUSSION
( ^( D; c& C* z V7 FTopical testosterone has been used effectively by other& f/ \# K* P" y! q5 z9 T* ^
clinicians but its mode of action remains controversial. Im-% y4 Q9 ~7 f: m0 V1 H7 t
mergut and associates reported an excellent growth response
8 \& p9 h. C; W0 a8 D" M% g' G5 Fto topical testosterone with low levels of serum testosterone,1 Y, Y7 } u/ f
suggesting a local effect.1 Others have obtained growth re-
0 ~2 A P+ y. ?4 T! A4 ^; J( Jsponse with high. levels of serum testosterone after topical
( \% _* f: S$ Q; ^% C9 Sadministration, suggesting a systemic response. 3 The use of
4 \0 w) x p( c$ S4 y1 K. Pgonadotropin to obtain levels of serum testosterone compara-' Y( d2 d- H: o1 Q5 a& W$ I3 C
ble to levels obtained with topical testosterone would seem to
" Z0 i1 h& P* i$ M. [. s- ]% w! s! M3 Eprovide a means to compare the relative effectiveness of
- x0 o) n' M2 H9 [7 K9 O) \topical testosterone to systemic testosterone effect. It cer-
; [, Z# Z" u* o( k4 Btainly has been established that gonadotropin as well as par-
5 q0 W' g) ~3 z, g5 X/ ^/ z8 oenteral testosterone administration will produce genital
& {& P/ o+ f- N) u: @6 ggrowth. Our report shows that the growth of the phallus was {4 s" v5 I2 @8 g$ x$ X
significantly greater with topical applications than with go-( R, M+ T5 h6 X; ~5 f( l
nadotropin, particularly in children less than 10 years old.
* `3 I' f0 V& O+ Q5 PThe levels of serum testosterone remained similar or lower
8 T( i3 c4 c# `8 y+ Cthan with gonadotropin during therapy, suggesting that topi-& j3 o3 M/ {( B: n, o/ w
cal application produces genital growth by its local effect as- I8 x4 S" w% K* G
well as its systemic effect.
- D* u* ~& b3 C7 w- _Review of our patients and their growth response related to
2 r' {4 G3 H1 U c: m$ Zage shows a greater growth response at an earlier age. This is1 U, d# D+ e8 m. O
consistent with the findings of Wilson and Walker, who
* W: |7 [; G# g( ^3 V: nreported an increased conversion of testosterone to dihydrotes-
" }% |7 B: A c- P2 Itosterone in the foreskin of neonates and infants.4 This activ-
6 f; h/ J5 ]! Rity gradually decreases with age until puberty when it ap-- s2 q a3 j7 T6 h }
proaches the same level of activity as peripheral skin. It may
7 q. E K/ b6 y P5 ~2 @! }well be that absorption of testosterone is less when applied at% m$ _, Z- L. R! n
an earlier age as suggested by lower serum levels in children
2 G3 r5 J9 ^& i+ f6 s' {3 @less than 10 years old. This fact may be explained by the( i* C+ k. l& u |' U5 ]! z( q
greater ability of phallic skin to convert testosterone to dihy-
. \% { P! _# o* |drotestosterone at this age. Conversely, serum levels in older* p. A6 U2 A2 K! @
patients were higher, possibly because of decreased local C `5 T7 f2 E/ z7 N
667
; C, g; {7 h; o' L8 y668 KLUGO AND CERNY
3 R- ^2 Y& [1 o- y* WPt. Age
1 T: `: `% `) {2 m) R- l9 u(yrs.)! f8 } u3 f: E7 C1 J7 R I
Serum Testosterone Phallus (cm.) Change Length9 Y! I! Z4 P1 ?8 D
(ng./dl.) Girth x Length (%)# u+ h" P- I3 C2 a- [
4
* R4 u1 Y1 R! L2 m( _2 A8
6 r3 ?0 U) D7 L# t/ P' o10) h% ~* [* J( Q! z2 i$ W. I
12
2 M# |; v$ ~+ }% c+ C1 |6 D17$ Z0 L& J1 O9 V4 i& `4 z" Z
Gonadotropin
! X( b( h# `. y( w9 Y71.6 2.0 X 3 16.6
# v& N9 U! S2 M0 p- `' T$ G50.4 4.0 X 5.0 20.0
0 B0 ?# K2 `) w$ J$ G' ^. B22.0 4.5 X 4.0 25.0
) Q' l+ A6 \% ]& `; X% L. M84.6 4.0 X 4.5 11.17 T5 ^/ o5 M1 ]' ^, K
85.9 4.5 X 5.5 9.06 d7 A F8 I3 `# d: ?( N9 L2 {- g
Av. 14.3
/ u# R8 f5 U) `! L: x8 x! ]4/ ?7 Q2 {: x- o% E
8
9 l% c Z O% Q) `! p6 ]& g& y10
. \- O( E, H" {" s! `12
2 K: f ~$ a' W6 x) S& G' m17
# V4 n) i- o; ]2 C+ ?8 _2 S) T# fTopical testosterone
2 {2 M# M3 I5 t S/ m; f B. t5 a s34.6 4.5 X 6.5 85
3 b Y' w, ]% G" V* ]0 o38.8 6.0 X 8.5 70; G, J d8 \( [0 Y$ n8 H
40.0 6.0 X 6.5 62.5
. ?4 a2 ?# U4 f0 ?4 {93.6 6.0 X 7.0 55.5
$ T3 ?! b J; C6 ~1 u95.0 6.5 X 7.0 27.2! M4 s+ o- r9 L0 n( G
Av. 60.00 }1 a$ N' F: m
available testosterone. Again, emphasis should be placed on7 U& I7 Y2 R; Y s2 r6 Y
early therapy when lower levels of testosterone appear to
& |7 y7 c8 R0 o8 U* O- |' oprovide the best responses. The earlier therapy is instituted
! w4 k3 I' d0 C! qthe more likely there will be an excellent response with low8 |0 v! S1 p; d( N. E
serum levels. Response occurs throughout adolescence as
: T; q+ ]5 h- pnoted in nomograms of phallic growth. 7 The actual response
E/ S! B/ t6 Mto a given serum level of testosterone is much greater at birth1 j8 x& ~3 m2 M8 _7 Q
and gradually decreases as boys reach puberty. This is most
3 y- n, B+ Y: nlikely related to the conversion of testosterone to dihydrotes-& r6 X, z9 ` }8 Y3 t+ U
tosterone and correlates well with the studies of testosterone8 p7 ] S% l- [+ u
conversion in foreskin at various ages.3 I0 W* L$ ~1 m/ s
The question arises regarding early treatment as to whether2 x' K5 X7 ^" I( D# ~
one might sacrifice ultimate potential growth as with acceler-! g T3 t" l7 J# k# _
ated bone growth. The situation appears quite the reverse
2 A! ` Q8 F' h8 ^6 D8 {" uwith phallic response. If the early growth period is not used
5 d" e3 B. H, V5 `6 T6 {when 5a reductase activity is greatest then potential growth
9 Y8 d2 i4 J# b. I5 Vmay be lost. We have not observed any regression of growth
8 \: O! @5 F) G0 y2 r5 Rattained with topical or gonadotropin therapy. It may well
" `- p; H- t8 Z' k" ?be that some patients will show little or no response to any
4 R/ k' Z5 J- s7 J) {9 wform of therapy. This would suggest a defect in the ability to+ O* q" ~, Q4 E& O% @+ f; {
convert testosterone to dihydrotestosterone and indicate that0 v" ]7 K3 l% U
phallic and peripheral skin, and subcutaneous tissue should
; F3 L1 ?, _. V5 \4 Kbe compared for 5a reductase activity.! u% I$ C( [# u) r, ~% `, m
A, loop enlarges to measure penile girth in millimeters. B,
5 g7 t% n. ?: Kexample of penile girth computed easily and accurately.
1 o4 o M3 }0 M! G: n7 Econversion of testosterone to dihydrotestosterone. It is in this1 e, y( V4 U/ x
older group that others have noted high levels of serum
9 M' O& r5 _& S& ~* stestosterone with topical application. It would also appear
" T. p% @% J4 r' a( ^that phallic response during puberty is related directly to the
2 a4 ~+ {# m1 m( u; Qserum testosterone level. There also is other evidence of local, V7 m6 R- U* t0 U
response to testosterone with hair growth and with spermato- ` ^. ?( r2 ~% q
genesis. 5• 6
/ B' ?1 U6 U+ h6 O& f. KAdministration of larger doses of gonadotropin or systemic2 L7 b3 s. e( o$ I8 q9 e2 G
testosterone, as well as topical applications that produce
, A }! e9 d4 Phigher levels of serum testosterone (150 to 900 ng./dl.), will6 C- w: T T, ^+ _) q( R! u! j
also produce phallic growth but risks accelerated skeletal
. j& i, z$ C) R. F, rmaturation even after stopping treatment. It would appear
' q9 `7 t: j/ Zthat this may be avoided by topical applications of testosterone
: ^! {% N5 Q: u3 d. g- y: o/ yand monitoring of serum testosterone. Even with this control
: F7 w) p* [5 {& M0 w) fthe duration of our therapy did not exceed 3 weeks at any
- ]! S- y: s. @5 z& S' [, ?; \+ xtime. It is apparent that the prepuberal male subject may
; a, H Q# d# T, O# s8 usuffer accelerated bone growth with testosterone levels near
/ L* h' K n7 z# N9 T* |200 ng./dl. When skeletal maturation is complete the level of
3 E" D G+ P) `' V, z2 G( ?- D' |serum testosterone can be maintained in the 700 to 1,300 ng./# a" b7 I& ^) O0 h/ ?* s: m V4 W2 z
dl. range to stimulate phallic growth and secondary sexual) E1 }# C0 t0 r4 Z2 Z% G
changes. Therefore, after skeletal maturation parenteral tes-
+ j2 H3 k/ N6 [( c. Y8 H$ `tosterone may be used to advantage. Before skeletal matura-
4 s# U: A- l9 ption care must be taken to avoid maintaining levels of serum- K$ Y" I6 H2 F6 g& L5 V
testosterone more than 100 ng./dl. Low-dose gonadotropin1 r r, {3 T/ e& N' d6 x
depends upon intrinsic testicular activity and may require& A# R9 X7 T8 a
prolonged administration for any response.
3 o' M+ y4 t3 q9 A% h, s. D- b- BAlternately, topical testosterone does not depend upon tes-: [2 M4 i! V% u$ m! Y7 V( C- x5 _
ticular function and may provide a more constant level of0 m4 r M0 \% Z6 d3 C, }7 v
REFERENCES3 k5 G' x3 N! q1 a1 K
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,/ k b! e( x* a6 h! x% Z# ^' e- C
R.: The local application of testosterone cream to the prepub-
D# j$ E4 J. X4 v- R9 M* Y0 b0 Dertal phallus. J. Urol., 105: 905, 1971.9 O( b* h8 Y4 x- y! ?, N8 Z
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
n( Z. S7 y' ^7 v1 p0 B. g* ptreatment for micropenis during early childhood. J. Pediat.,5 J9 U: t6 n* k d# P& A+ m
83: 247, 1973.
: W3 g+ c1 H5 O: Y }. |3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
& n4 y, h% ]; `- Q j( f/ N% N- G ^one therapy for penile growth. Urology, 6: 708, 1975., R( [0 K) K! J+ ?# m5 G
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone7 y' w! m$ Y8 r
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by+ M( }& u! | g; t' M
skin slices of man. J. Clin. Invest., 48: 371, 1969.
. M8 t" ~; ]1 Z5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth: Q* B% A; J0 B, I3 a
by topical application of androgens. J.A.M.A., 191: 521, 1965.: ]% H R7 r/ |3 q0 U. @2 X: P
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local4 D8 ?1 y( T$ A" o4 X# e
androgenic effect of interstitial cell tumor of the testis. J.7 N3 J2 _; H/ ~
Urol., 104: 774, 1970.
& p- h" z$ T! z0 I3 D1 l7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia- y% ~- _8 O9 p$ j! A
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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