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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND) r2 D% w; B7 P! ~- H7 z5 x" k* u+ A
GONADOTROPIN
! H3 ?' O; ~, L7 J& v" jRICHARD C. KLUGO* AND JOSEPH C. CERNY" M W$ O& X4 \ H
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan3 c I4 j9 k0 Z, z
ABSTRACT8 }2 v Q* |8 d; O2 V* z
Five patients were treated with gonadotropin and topical testosterone for micropenis associated4 o* I5 J& T0 v: l* Y
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
) V+ C& Y9 o9 p9 S3 ctropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
" z) C: E. V3 Q8 pcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
( n) k- L. i# `+ e! |/ ~for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
9 u# W9 \3 L6 j# w7 n; |. U* Rincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average/ b( {# Z1 }$ N0 W7 f v
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
% f: d- c( e1 x/ @9 Yoccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This3 P3 g/ |* \% y. r* j9 I6 }
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile/ L, Y: H# u! ]; F+ F/ T
growth. The response appears to be greater in younger children, which is consistent with previ-) ?; ?$ \* V; c
ously published studies of age-related 5 reductase activity.1 J4 v+ ~$ L+ e3 P% q' f
Children with microphallus regardless of its etiology will
6 q }5 ]! v4 x' Urequire augmentation or consideration for alteration of exter-. K9 z% ?. f3 B3 X9 D5 @
nal genitalia. In many instances urethroplasty for hypo-
; M9 Y+ X7 X8 I; bspadias is easier with previous stimulation of phallic growth.3 P8 ]3 R; h7 S; G0 a0 s. k$ f
The use of testosterone administered parenterally or topically4 V, D% m$ d. H
has produced effective phallic growth. 1- 3 The mechanism of& x( A& u/ B$ V* G4 R
response has been considered as local or systemic. With this
* K$ O4 V. C7 [% b& ?3 f1 M5 U; yin mind we studied 5 children with microphallus for response
" A- n: \+ B3 l8 ~8 E# k+ x4 Dto gonadotropin and to topical testosterone independently.! Y( [7 P( t( c8 y v
MATERIALS AND METHODS
5 t2 ]9 [4 _9 N7 ?3 O AFive 46 XY male subjects between 3 and 17 years old were g4 Q4 S+ o; ]. T
evaluated for serum testosterone levels and hypothalamic
C! I4 x+ e5 L* u D: ^function. Of these 5 boys 2 were considered to have Kallmann's
# {& w' e+ x$ G" z- w3 i+ t$ z8 Gsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-, g8 N+ J! w" ^/ e& }* Q
lamic deficiency. After evaluation of response to luteinizing, I+ c( K* U+ U: w
hormone-releasing hormone these patients were treated with5 O4 x& f/ Y& U
1,000 units of gonadotropin weekly for 3 weeks. Six weeks$ c1 v- E: e" n9 G2 C
after completion of gonadotropin therapy 10 per cent topical
$ s/ U; g4 O0 k; D5 H) [testosterone was applied to the phallus twice daily for 3 weeks.* F! P1 @5 l: }0 j' h: X2 a
Serum testosterone, luteinizing hormone and follicle-stimulat-
& ~+ r7 S1 _3 d+ ping hormone were monitored before, during and after comple-
9 r8 h% w/ t3 m7 _tion of each phase of therapy. Penile stretch length was
! ?4 A, W) o+ J& l$ w; U" K$ O9 aobtained by measuring from the symphysis pubis to the tip of4 ~+ [- \! V4 H, z8 ]6 b
the glans. Penile circumferential (girth) measurements were. g1 M! I, J# U7 @/ k
obtained using an orthopedic digital measuring device (see' q4 {6 R. j' j
figure).+ C$ |, ], o* H/ v& B/ r
RESULTS. b* p& ]9 S+ Q7 d8 p) m
Serum testosterone increased moderately to levels between
# d6 j- [9 N" q6 W50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
; E7 v% Z" f- l- j* s5 g9 Kterone levels with topical testosterone remained near pre-& r: ^) ?# Z& R: ^9 u6 ]' V
treatment levels (35 ng./dl.) or were elevated to similar levels4 I& c, d ~, @3 J0 R# I- T
developed after gonadotropin therapy (96 ng./dl.). Higher
* |/ I Y0 C! Q/ Iserum levels were noted in older patients (12 and 17 years old),
$ p5 N$ K# j/ n( Z& qwhile lower levels persisted in younger patients (4, 8, and 10
( j- A. R6 Q- S& B) B2 w( n1 A- gyears old) (see table). Despite absence of profound alterations
5 ]. C! p- J. |8 N% E" J: Y. O% yof serum testosterone the topical therapy provided a greater
9 Q! a. u0 i& W3 z6 y) t* Q/ cAccepted for publication July 1, 1977. ·
7 Q5 V% s2 _6 w7 N& \0 P9 Z! ARead at annual meeting of American Urological Association,5 M) a4 Y+ I/ {/ D$ m ^/ K
Chicago, Illinois, April 24-28, 1977.. q3 M; [8 o6 l" E9 O5 T
* Requests for reprints: Division of Urology, Henry Ford Hospital,- ]: V1 O& b# W( F, R' [/ f" X3 ?
2799 W. Grand Blvd., Detroit, Michigan 48202.
8 n# R( j1 |# s5 e! U0 Himprovement in phallic growth compared to gonadotropin.% y# n! P) U+ k% {; |0 _
Average phallic growth with gonadotropin was 14.3 per cent
; _' _3 f G( g9 h' Aincrease in length and 5.0 per cent increase of girth. Topical
9 ]" y1 L7 d' n$ X; b! Dtestosterone produced a 60.0 per cent increase of phallic length m0 e/ Q+ J7 h' H3 J" H
and 52.9 per cent increase of girth (circumference). The
+ U* h) O- J6 ~* V& B6 u% hresponse to topical testosterone was greatest in children be-. Y4 Q, @* A; R; I
tween 4 and 8 years old, with a gradual decrease to age 179 _8 p7 s9 E- ?4 C) k( o
years (see table).
' B6 |* {# ^* s0 v6 Y d2 {2 mDISCUSSION
6 s- E- f. s. Z# M) k6 u4 T' c% PTopical testosterone has been used effectively by other
$ w3 M# @- Q9 P* r. `clinicians but its mode of action remains controversial. Im-/ h. Z0 J: n( v9 \4 d& c* T
mergut and associates reported an excellent growth response; A9 U/ {6 N3 x( g/ [' n
to topical testosterone with low levels of serum testosterone,! N( _0 f" a/ b: H
suggesting a local effect.1 Others have obtained growth re-1 v; m! W H9 {! j/ X# y
sponse with high. levels of serum testosterone after topical) C' M4 I- _' B. q" }
administration, suggesting a systemic response. 3 The use of
# x! A" Z9 Y' u$ J* |0 Y: ogonadotropin to obtain levels of serum testosterone compara-
: ~3 S6 q2 k& F' ]ble to levels obtained with topical testosterone would seem to
9 D! X; J6 r A, Iprovide a means to compare the relative effectiveness of
! ^. J, e' B6 x* _ @) G: N. Ktopical testosterone to systemic testosterone effect. It cer-
# @, l# J0 n: j$ utainly has been established that gonadotropin as well as par-- w: X; L; ]2 a& w, ] z0 E7 F
enteral testosterone administration will produce genital
# w- h/ q j8 {/ Y% K$ Y* tgrowth. Our report shows that the growth of the phallus was
& E( q) o2 Z9 Z- ssignificantly greater with topical applications than with go-+ {& V2 s" m! n# f4 @3 a
nadotropin, particularly in children less than 10 years old., |6 U) c* g+ J2 S$ C% U1 V
The levels of serum testosterone remained similar or lower
' w. ~4 z+ ~# }* [% ^than with gonadotropin during therapy, suggesting that topi-
s/ j# @$ U) p9 Y8 X+ wcal application produces genital growth by its local effect as
% M) X, o4 B& ^( p$ ^0 ^well as its systemic effect. l) [3 f3 i/ q; M# U+ p7 p
Review of our patients and their growth response related to
7 A, { [/ N, F9 W: wage shows a greater growth response at an earlier age. This is# z7 ~( ]3 l+ g$ j/ C9 _
consistent with the findings of Wilson and Walker, who
. |6 l5 W9 f! H D/ m6 ~reported an increased conversion of testosterone to dihydrotes-0 b% R5 c6 {7 p, }
tosterone in the foreskin of neonates and infants.4 This activ-
$ x+ o/ D: G8 S3 j- Fity gradually decreases with age until puberty when it ap-
; Q X1 L9 |/ v; n% t# u/ Vproaches the same level of activity as peripheral skin. It may
q8 }1 `9 ?# `' d: Z3 I8 ~% {' o+ mwell be that absorption of testosterone is less when applied at
+ o& ~' n! k; [8 }# san earlier age as suggested by lower serum levels in children
0 a' G( Z+ S! e' n9 wless than 10 years old. This fact may be explained by the
$ N4 N! i [6 w7 \6 [. Zgreater ability of phallic skin to convert testosterone to dihy-1 C; t3 }0 c1 L+ Z1 v
drotestosterone at this age. Conversely, serum levels in older
8 G# P+ ~" [* \2 o% N: M, ipatients were higher, possibly because of decreased local! g" M# r0 S4 s+ t
667
, C! @( n/ E" V# k* \( }668 KLUGO AND CERNY( }* u. A5 `/ T( c8 Z9 ^5 p2 {
Pt. Age
5 s$ I2 N3 H0 k2 q f(yrs.)+ {' t9 b" l3 w6 @, U/ v
Serum Testosterone Phallus (cm.) Change Length
- M$ b; F- V! m) t(ng./dl.) Girth x Length (%)
- _5 g# u/ `% @. B1 ^0 G+ y4
3 u- d! w/ G+ {7 `" S+ R8
- U7 B0 K7 {3 g; ]" x" ]10$ r8 }5 |# b/ m/ ^
12
' t F- r! k. M4 c17& b5 r9 W$ G% f$ m5 v7 k+ ^" ?
Gonadotropin m2 J; }+ _5 c$ d/ c
71.6 2.0 X 3 16.68 a) y) G8 ^9 w. f$ {
50.4 4.0 X 5.0 20.0+ ?' J2 V5 ]! N) d. t
22.0 4.5 X 4.0 25.05 q% m4 x% h! ~$ w
84.6 4.0 X 4.5 11.1
& m) e! ^9 J8 L6 _85.9 4.5 X 5.5 9.03 t: W# v2 B# W: z9 h$ Q2 D# I1 ?
Av. 14.36 d/ P0 @) ^0 h: i; m
4
0 y ]; L* T' U( D% X' n8
& R: g* @0 g# a3 |105 F1 G* B2 z6 d t) n4 h( t* }" p
12
1 t' E& Y, o, l+ C: a170 x# |$ @, T3 F8 h
Topical testosterone) k4 T9 G: S0 B' e7 s# M, j P
34.6 4.5 X 6.5 85& ?0 |7 ~; K/ Z" c. U& v( R# P8 h
38.8 6.0 X 8.5 70. [( C* h/ |7 I% \! w
40.0 6.0 X 6.5 62.52 V! F- V- Y# h0 K
93.6 6.0 X 7.0 55.5* x. K/ i* O4 A. N/ e, _8 {$ p8 z
95.0 6.5 X 7.0 27.2
# C5 D# K J$ G, d. uAv. 60.0: {* N( ^- |% v" k. ]
available testosterone. Again, emphasis should be placed on
6 ~- |& I u0 U# A. q) Q' d% }' zearly therapy when lower levels of testosterone appear to
- c& L1 I" v' N( P9 O7 i' {provide the best responses. The earlier therapy is instituted
4 u U* B/ z9 M0 J4 gthe more likely there will be an excellent response with low ?6 K3 {3 {2 ~) ~" u* {" C8 E
serum levels. Response occurs throughout adolescence as) {' ]9 q- N {+ n1 \% O2 N3 [8 s
noted in nomograms of phallic growth. 7 The actual response
, x) Z3 k: `- z6 |1 Tto a given serum level of testosterone is much greater at birth
2 M: i8 x' U& I' f5 dand gradually decreases as boys reach puberty. This is most5 J; t2 h- j4 H- s6 b
likely related to the conversion of testosterone to dihydrotes-
/ }3 D* M4 U: w. I5 A' \% `tosterone and correlates well with the studies of testosterone7 X" o- Y& S8 v V$ y
conversion in foreskin at various ages.1 f1 J7 x5 F: c
The question arises regarding early treatment as to whether
4 e/ {( w; t' w i) z, none might sacrifice ultimate potential growth as with acceler-
! C1 h# O. l. y6 `- `3 qated bone growth. The situation appears quite the reverse$ z5 S2 S: h* \! U# X G) y
with phallic response. If the early growth period is not used0 z3 n* [, Z" [
when 5a reductase activity is greatest then potential growth
3 A. v& L5 |- s' e Imay be lost. We have not observed any regression of growth
3 x2 F1 ]2 v% xattained with topical or gonadotropin therapy. It may well
* M5 K8 @5 p8 Lbe that some patients will show little or no response to any) H6 Q- n& |- P" w6 W: N1 c
form of therapy. This would suggest a defect in the ability to
2 f5 X' |- m. s/ g% b; Mconvert testosterone to dihydrotestosterone and indicate that
8 B# T0 a/ P: p" \' xphallic and peripheral skin, and subcutaneous tissue should( I/ E; E% I6 e$ h5 \1 Q
be compared for 5a reductase activity.
$ `8 i: l2 a+ {$ [# OA, loop enlarges to measure penile girth in millimeters. B,6 Q% E, w V( J4 c z- T3 J
example of penile girth computed easily and accurately./ J) {/ \3 A& y' [" K
conversion of testosterone to dihydrotestosterone. It is in this$ T* u6 ^3 n4 K- c; \* {
older group that others have noted high levels of serum9 W3 R8 T' o+ W7 V% @8 P
testosterone with topical application. It would also appear
: V5 ?1 o; p5 f( hthat phallic response during puberty is related directly to the
& x3 t- d# @8 b- p" g* I" pserum testosterone level. There also is other evidence of local
g+ H; S8 r6 c3 y( O. g$ F- j, gresponse to testosterone with hair growth and with spermato-
$ y1 |# T: w& s- Bgenesis. 5• 61 n/ [! ]% [" N! h0 {1 L: O) c. m
Administration of larger doses of gonadotropin or systemic d- j# k7 m% C# k: K' j
testosterone, as well as topical applications that produce
- S8 b$ W8 f+ M4 W( |higher levels of serum testosterone (150 to 900 ng./dl.), will7 n# F a- }. G* T
also produce phallic growth but risks accelerated skeletal! |3 R% A5 ~5 ?9 I; @
maturation even after stopping treatment. It would appear8 @$ Q. [/ z i# u. E- l
that this may be avoided by topical applications of testosterone( a4 k, X- T0 ]3 U$ {% ^0 ~
and monitoring of serum testosterone. Even with this control* ]3 ]) z. G3 A% z3 j
the duration of our therapy did not exceed 3 weeks at any
) C" `6 D6 b6 v$ ~1 f+ Ptime. It is apparent that the prepuberal male subject may8 {% r+ w: i- U) H& @
suffer accelerated bone growth with testosterone levels near: W$ W8 [# {- G$ i' F# b
200 ng./dl. When skeletal maturation is complete the level of/ q5 H9 L( @) a, e0 _
serum testosterone can be maintained in the 700 to 1,300 ng./
% E& P, _% w6 ~ o1 V- `. tdl. range to stimulate phallic growth and secondary sexual$ g$ I0 ?8 v' S3 W5 x4 a
changes. Therefore, after skeletal maturation parenteral tes-
3 [2 w+ X! q8 g* o6 Itosterone may be used to advantage. Before skeletal matura-
6 E6 S" d' z2 V. m3 f" T1 `tion care must be taken to avoid maintaining levels of serum- Y! K. r5 w7 Z: G3 Z/ {
testosterone more than 100 ng./dl. Low-dose gonadotropin
" Y" B/ G5 z6 q Q) X6 W1 |& wdepends upon intrinsic testicular activity and may require
. m E) M: f5 p) k9 a! I0 Iprolonged administration for any response.( j( G- v9 T; l; Q! m. j( B
Alternately, topical testosterone does not depend upon tes-
& m! n9 l( w! {6 p3 F+ f0 [ticular function and may provide a more constant level of
8 J! y/ j7 {% RREFERENCES, h" f9 A" O- \$ A1 L4 _
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,+ `6 `2 u$ c) b5 R
R.: The local application of testosterone cream to the prepub-. R" t I5 b/ S
ertal phallus. J. Urol., 105: 905, 1971.
. F- k; { w' Z4 g; s; v- `0 A( Z2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
Q) O6 X! T) w& q& q& i* b) qtreatment for micropenis during early childhood. J. Pediat.,7 R: C4 \; o# o ~+ k/ I/ J
83: 247, 1973.
% `/ q, g" E. Q' {; ~/ m3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-6 H- g+ k1 l O, ~+ H) g: ^. N$ \& a
one therapy for penile growth. Urology, 6: 708, 1975.- U+ l2 R" i; F* u
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
& b6 E9 Z0 o7 [ Yto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
! H1 V: e" U' |, k! u( pskin slices of man. J. Clin. Invest., 48: 371, 1969.8 v$ W% A; t8 |# B
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth6 [) T7 A' q* [+ O7 ?6 H& k D
by topical application of androgens. J.A.M.A., 191: 521, 1965.6 v. H, e: f& G8 [
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
+ w0 B8 a0 }* q1 b. g* |5 x3 uandrogenic effect of interstitial cell tumor of the testis. J.
4 G$ v, V( q/ J2 D% vUrol., 104: 774, 1970.
6 Z+ |# L# D# p7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-7 g( m3 O: p+ k
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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