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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
1 o6 I$ x: L2 H4 wGONADOTROPIN
) k5 s/ F4 [. H7 ~' `RICHARD C. KLUGO* AND JOSEPH C. CERNY0 M! R1 @' F* x( [! ?5 q
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
: C, M& q( f; A% gABSTRACT5 L' H) B8 T' r% W! |! ~
Five patients were treated with gonadotropin and topical testosterone for micropenis associated8 k5 ^ P' `- \; e- Z9 s! N
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
* r0 I1 S$ y, i# v5 htropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
# b2 x R% G" z9 z4 S4 S% qcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
' f' B. w& g# {7 u: jfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent* P$ X" h4 W% C: x7 b; ~
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
2 z; `0 K [4 Kincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
" Z: v# {7 ~. w) @3 k7 ^. i2 Boccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
3 O# W2 G$ r* Q$ s1 U+ _study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile+ J- L, u# ^3 L$ h. w
growth. The response appears to be greater in younger children, which is consistent with previ-
& W" ^' x/ u0 ?! k+ {2 oously published studies of age-related 5 reductase activity.1 w* M: z$ A2 X9 J
Children with microphallus regardless of its etiology will
, F4 |# _9 _" ]require augmentation or consideration for alteration of exter-+ ~$ t7 P) @2 l' N# a
nal genitalia. In many instances urethroplasty for hypo-
+ G5 n$ W+ E1 j: s4 wspadias is easier with previous stimulation of phallic growth.0 r+ D; y5 z- m4 e! y
The use of testosterone administered parenterally or topically9 S, Q8 S$ K/ W: d2 u$ Z5 E+ y
has produced effective phallic growth. 1- 3 The mechanism of
, P- [! M8 n% I3 `6 O9 Z/ F7 U# eresponse has been considered as local or systemic. With this
6 p+ D/ a5 {0 o0 I0 W$ Win mind we studied 5 children with microphallus for response
* k8 R: B. U4 K) `' Pto gonadotropin and to topical testosterone independently.
# Z6 O2 ?6 f, HMATERIALS AND METHODS1 [/ T1 w/ C# m* t0 [
Five 46 XY male subjects between 3 and 17 years old were
; s0 P: R" K1 U. [/ b' {evaluated for serum testosterone levels and hypothalamic8 R) t( q% b4 |4 r+ K4 T2 N1 I
function. Of these 5 boys 2 were considered to have Kallmann's6 A: D5 P) O) a# _) d
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-% g; P- k0 O# h
lamic deficiency. After evaluation of response to luteinizing0 k6 w5 {. [5 u4 e0 L
hormone-releasing hormone these patients were treated with' }2 o/ v9 T0 X3 [. W6 x( U
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
! K* c2 |' w9 {/ E+ o/ ^after completion of gonadotropin therapy 10 per cent topical
. M: D* y2 T& O+ D4 y& E% a0 Btestosterone was applied to the phallus twice daily for 3 weeks.
/ z8 Z9 ^$ B2 F% q9 |: |0 ]; LSerum testosterone, luteinizing hormone and follicle-stimulat-7 B) i6 z! ?/ \# c) w
ing hormone were monitored before, during and after comple-1 {: i9 q0 a" h* X" O2 F6 M! S
tion of each phase of therapy. Penile stretch length was- u, N3 _6 r' e* ^- q
obtained by measuring from the symphysis pubis to the tip of
3 x2 k! e O/ E/ y+ z) r' k" ]the glans. Penile circumferential (girth) measurements were
/ e1 U' x/ u' g: t; {obtained using an orthopedic digital measuring device (see
" M- Q+ C9 ~9 u. N' e vfigure).! L. y* N* i' Y, T
RESULTS
; ~& h( X c6 P9 H. P- qSerum testosterone increased moderately to levels between& O% Q* y* d- w$ a2 j% p
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-6 H) a! T& N( M3 g3 m5 w, X& V4 A% E8 x
terone levels with topical testosterone remained near pre-
/ |) s+ [9 f% B$ Y1 b4 Streatment levels (35 ng./dl.) or were elevated to similar levels
( p& h' ]# @! adeveloped after gonadotropin therapy (96 ng./dl.). Higher3 O$ i* @$ L' V& J! A8 w
serum levels were noted in older patients (12 and 17 years old),9 B6 ~1 I. v& O
while lower levels persisted in younger patients (4, 8, and 10 X+ w% g2 v* d+ U& i
years old) (see table). Despite absence of profound alterations3 O/ v; B/ l+ S5 b4 L
of serum testosterone the topical therapy provided a greater _ o3 d+ q, P' Z8 h! D: f
Accepted for publication July 1, 1977. ·
; }- L# _3 w# URead at annual meeting of American Urological Association,5 k% O8 ^0 z$ S$ T/ Q
Chicago, Illinois, April 24-28, 1977.: g4 x( `7 H( _, ]
* Requests for reprints: Division of Urology, Henry Ford Hospital,
3 x, B- J6 f4 S. T" ]. {" _0 E2799 W. Grand Blvd., Detroit, Michigan 48202.
6 S4 s% P, ?% I: Ximprovement in phallic growth compared to gonadotropin.
7 g W+ P: @: [* a( B0 n) g5 u3 |) SAverage phallic growth with gonadotropin was 14.3 per cent
" C A% ?; r# H2 Q. t4 Jincrease in length and 5.0 per cent increase of girth. Topical
. V/ b9 T/ o; y6 U9 c4 m" L2 I% ltestosterone produced a 60.0 per cent increase of phallic length
& ?) F, b( X/ {" `0 {& N/ P$ z- {and 52.9 per cent increase of girth (circumference). The' M4 ~& i, _5 x) O/ o# s
response to topical testosterone was greatest in children be-
, b' z, C1 y, K0 U+ itween 4 and 8 years old, with a gradual decrease to age 17/ {$ `6 J* n: Q8 h" W* ?
years (see table)., C# n+ I: v, f0 l2 X) h
DISCUSSION
5 |/ i# p0 Z/ bTopical testosterone has been used effectively by other
- W; p5 y! {$ q9 a+ N: Hclinicians but its mode of action remains controversial. Im-, r( L3 B! L* }+ J! u/ U3 ]
mergut and associates reported an excellent growth response
9 B9 [! g. b2 T, S3 q7 f8 n% yto topical testosterone with low levels of serum testosterone,
8 c6 ~5 U& p ?9 Csuggesting a local effect.1 Others have obtained growth re-
5 ? B7 o5 l! G8 x/ ^ V$ osponse with high. levels of serum testosterone after topical! y- K' n8 m% U, U/ i
administration, suggesting a systemic response. 3 The use of
+ d1 t" W4 x* {) F$ r m4 d8 Egonadotropin to obtain levels of serum testosterone compara-: M# k9 D/ f) W9 G2 p8 Q
ble to levels obtained with topical testosterone would seem to. x% Z- h0 T8 S# a1 P1 g
provide a means to compare the relative effectiveness of
2 Y! t* q! p5 s p5 Ntopical testosterone to systemic testosterone effect. It cer-% H0 V! h4 ~5 n+ O& g8 C' D, ?
tainly has been established that gonadotropin as well as par-
4 j Z. x7 B/ P6 denteral testosterone administration will produce genital
5 o, M8 ~; m; U7 Y* D1 A* |growth. Our report shows that the growth of the phallus was) {$ h& r; d3 J3 A$ a& g+ H0 P, _
significantly greater with topical applications than with go-5 O% z1 w0 P- |; O9 Q2 L- Z
nadotropin, particularly in children less than 10 years old.) }, E, {/ A5 Z6 t0 S
The levels of serum testosterone remained similar or lower
* l( Q9 g! ^( Q1 C$ qthan with gonadotropin during therapy, suggesting that topi-
) w* R, g7 S. q( k% Ecal application produces genital growth by its local effect as/ ~) K' o4 _& c6 Y
well as its systemic effect.
* u* q- f( n4 W4 w0 b9 bReview of our patients and their growth response related to% U( a. O1 D* L/ G
age shows a greater growth response at an earlier age. This is
/ _/ E. L! }9 T; fconsistent with the findings of Wilson and Walker, who
4 ~1 D7 d. b, N; J, |, p) Areported an increased conversion of testosterone to dihydrotes-
" y. d( j* U, A" I( [4 B- utosterone in the foreskin of neonates and infants.4 This activ-% w/ ~# o3 |' F$ ~ q, [7 `
ity gradually decreases with age until puberty when it ap-) J1 E' j t; k$ F
proaches the same level of activity as peripheral skin. It may) E Q6 r5 y) F) B4 U$ [/ W8 I
well be that absorption of testosterone is less when applied at
: u; _, n+ a2 p4 m- ?+ |an earlier age as suggested by lower serum levels in children; k. X& {' {, |7 y' t6 ?7 w
less than 10 years old. This fact may be explained by the$ R. ? R6 x. a5 y0 q! K
greater ability of phallic skin to convert testosterone to dihy-
" |3 d$ F z1 x/ X: J9 Pdrotestosterone at this age. Conversely, serum levels in older; c! T E3 ?/ i& C" l; n' _
patients were higher, possibly because of decreased local- _8 m5 Q0 e' r7 a: o5 Q2 u
667' P5 d ?& i! m$ H$ T
668 KLUGO AND CERNY* {0 K1 l+ q0 M0 g2 T
Pt. Age
* e& ?: ?9 l" f; C6 q2 V(yrs.)
$ Y( c; |1 N) h0 z* USerum Testosterone Phallus (cm.) Change Length7 A( J2 _" |' x
(ng./dl.) Girth x Length (%)/ D6 ]8 { T, U2 c+ x+ d) ^6 X
4* q% N/ j" y' k
8* k, @# T1 w D/ O1 M) p
10
" g6 J- `+ ]9 J I0 P6 q123 i$ }* T. | s, u9 l+ E
17
2 j! {: c0 l$ D; k! D& ]. hGonadotropin& n% x, a: W: I
71.6 2.0 X 3 16.6
) X7 h# L. a* z% N50.4 4.0 X 5.0 20.0
' J1 F5 Q& L* i( S22.0 4.5 X 4.0 25.0
F9 q) v, x, \3 \84.6 4.0 X 4.5 11.1( x" W0 T7 k0 o e
85.9 4.5 X 5.5 9.0 }! @% z3 g7 u! C7 U! k5 Z( Z
Av. 14.37 i `- P3 K: e! F5 i. x
4: V7 Q* ?' r- C; e$ E
8
+ P9 U2 Q* B. j; s5 |; E# V2 K/ f10
9 {. w; |; j% Z& `! J0 r12
. k* T4 {# w6 ~' u4 ]6 [1 @17
$ t; C% y" d9 vTopical testosterone. P* X5 L4 Y5 A- y" v$ n6 k1 A
34.6 4.5 X 6.5 85
% c5 W; r' b* N% C! M38.8 6.0 X 8.5 70
* c6 N5 F0 @* @ {. s/ h" X5 C40.0 6.0 X 6.5 62.5& d* f, l. G3 C9 ~7 |
93.6 6.0 X 7.0 55.5: I$ B' D U, w5 i9 m- J6 I) K* O
95.0 6.5 X 7.0 27.2+ T2 x' `) P9 t: U8 |
Av. 60.0 |3 W1 ^, [! ^7 c, ? t+ w ^
available testosterone. Again, emphasis should be placed on- V/ h2 ~, D# n0 m+ x2 ~
early therapy when lower levels of testosterone appear to, T4 @. \& ]7 \' Y% O/ Q& K* Y
provide the best responses. The earlier therapy is instituted! `. L' D. |5 \* ] T) c
the more likely there will be an excellent response with low$ b. } ?* n4 N+ N8 _5 i
serum levels. Response occurs throughout adolescence as
: e8 s3 s% f1 n. Vnoted in nomograms of phallic growth. 7 The actual response
2 k+ ~1 S. o" B& f7 T! Lto a given serum level of testosterone is much greater at birth. l+ t! i' r g0 I: X" l
and gradually decreases as boys reach puberty. This is most
0 s( ^5 G. e5 ^' v8 ~% [/ Ilikely related to the conversion of testosterone to dihydrotes-
3 N \2 g2 ]5 J) u& Z+ atosterone and correlates well with the studies of testosterone
! T5 }, ]" A6 u: _7 J; s1 tconversion in foreskin at various ages.
/ u, D6 |: c6 m7 {: H- CThe question arises regarding early treatment as to whether# D8 g5 O: E; }; V/ m' l; u
one might sacrifice ultimate potential growth as with acceler-% l. ^2 ~5 I* X
ated bone growth. The situation appears quite the reverse) Z1 J1 P' ^6 ]. N+ v. D
with phallic response. If the early growth period is not used: z9 {7 \; ]# G' }7 _1 }+ b) d
when 5a reductase activity is greatest then potential growth
; ^4 U4 J- ?! Wmay be lost. We have not observed any regression of growth8 o5 Y! E0 K0 \* U5 [
attained with topical or gonadotropin therapy. It may well' R, k4 h' v% b0 b4 P0 R
be that some patients will show little or no response to any# ]5 M, m. |( \) R( d* f
form of therapy. This would suggest a defect in the ability to' q" R; e8 Q) R# A4 F9 a" S
convert testosterone to dihydrotestosterone and indicate that
# U1 T% W9 G$ @2 }$ t! Kphallic and peripheral skin, and subcutaneous tissue should8 u9 U) l: c+ S2 a- T' S
be compared for 5a reductase activity.$ H; Y9 l0 I& ]! m
A, loop enlarges to measure penile girth in millimeters. B,, V- G) W* |2 D" n! X9 N( k7 S+ M/ Y
example of penile girth computed easily and accurately.; U" L' F8 R7 O- L
conversion of testosterone to dihydrotestosterone. It is in this; z+ X& v# C9 @! r- w R6 |
older group that others have noted high levels of serum
9 k* ?$ H% b7 a- e6 H5 Itestosterone with topical application. It would also appear
& d; a' }" `3 ^5 \5 q. cthat phallic response during puberty is related directly to the
1 `8 W; A0 k) N! v8 E4 Fserum testosterone level. There also is other evidence of local
* R& H1 g8 z6 m5 Hresponse to testosterone with hair growth and with spermato-7 Q3 Q7 n1 p1 x! m
genesis. 5• 6
# }4 ~9 \$ E A9 u' X9 jAdministration of larger doses of gonadotropin or systemic, p! [. |+ S/ \, }1 [ `
testosterone, as well as topical applications that produce
1 G: y- U' t% f- e) zhigher levels of serum testosterone (150 to 900 ng./dl.), will
! Z# z9 `7 t- Walso produce phallic growth but risks accelerated skeletal
& V U5 }8 c# x$ ] J; r Umaturation even after stopping treatment. It would appear
6 b6 w% L2 c' N* S( mthat this may be avoided by topical applications of testosterone
( O, ]9 x" _" Z Z0 A) s$ d1 Sand monitoring of serum testosterone. Even with this control
! P3 H- o4 d. p" f5 ^the duration of our therapy did not exceed 3 weeks at any% b+ w0 H! Q& D
time. It is apparent that the prepuberal male subject may& y' l. |) a9 v5 _
suffer accelerated bone growth with testosterone levels near
5 X5 y4 m6 O- O1 X$ j2 K& i200 ng./dl. When skeletal maturation is complete the level of+ ^0 l/ O3 z5 @( y( S$ B+ }3 m* Y
serum testosterone can be maintained in the 700 to 1,300 ng./
! f; w5 K9 F5 q& x, I( j% Pdl. range to stimulate phallic growth and secondary sexual
0 n* [& F9 S" h) k( I9 Pchanges. Therefore, after skeletal maturation parenteral tes- u' q0 K3 |7 h
tosterone may be used to advantage. Before skeletal matura-
/ S4 w* i- j9 l# D$ ?) `( ztion care must be taken to avoid maintaining levels of serum% ~# {7 m3 B# ^; c" m( u/ c/ y5 C
testosterone more than 100 ng./dl. Low-dose gonadotropin' _ P" X6 W) i3 N( r, g! ~. u' j
depends upon intrinsic testicular activity and may require; E8 R2 A2 g5 Z& ]* o& f
prolonged administration for any response.
# G) N- D8 _9 X/ Q6 H1 x) YAlternately, topical testosterone does not depend upon tes-# |: {1 e' R4 L) i. R2 F" I* b
ticular function and may provide a more constant level of* B5 R! T3 A, K @1 \
REFERENCES
$ ^3 _7 O6 `$ i: W1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,: E G i/ J, r7 z. k
R.: The local application of testosterone cream to the prepub-
5 ^1 V( y; u# Y+ Eertal phallus. J. Urol., 105: 905, 1971.% |. h9 F; [! D9 b, {; l6 Y
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone" c- m; F4 ?% T7 N- D7 m
treatment for micropenis during early childhood. J. Pediat.,
8 D) M0 H# J# e9 y83: 247, 1973.
- c2 V$ E$ l, n ]; e/ h4 E" u, O# C3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-/ T/ @% X/ w B* R7 t8 ?- v
one therapy for penile growth. Urology, 6: 708, 1975.# y+ u' h9 [- u/ ~
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone7 H9 [* ~2 q9 L$ n9 W
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by* Q% h' Q2 b, R8 t7 N
skin slices of man. J. Clin. Invest., 48: 371, 1969.
" W3 K; t" k# ]' j+ w" J: |5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth7 A; W! \' s1 D4 c
by topical application of androgens. J.A.M.A., 191: 521, 1965.. b0 ^7 c7 L! T; a
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local: k7 ^3 B0 g* E% u m; u6 Z& Z
androgenic effect of interstitial cell tumor of the testis. J.
; @* t' z3 f( R2 } \- S `% _Urol., 104: 774, 1970.
; C% L5 T" d# i0 _) W+ w5 g* \7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-) W* ? u$ @: p: R' m9 ?( [1 |
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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