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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND3 K* n0 P( Q/ \/ {5 _
GONADOTROPIN0 W8 u) b2 g& t- O
RICHARD C. KLUGO* AND JOSEPH C. CERNY
" g2 p3 r9 S; QFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
2 O L! }( D6 ?ABSTRACT& `* h8 u) Y. ]7 K- `9 S4 X, n
Five patients were treated with gonadotropin and topical testosterone for micropenis associated; k9 _% D* ~1 N( k! v, i9 x
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-- Z$ U# U5 \. W: _; h2 i
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone, `) F6 D$ V2 D0 j! X
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent2 O) e) o# }* G' C9 F
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
" u6 t3 N/ o/ R6 `2 m5 d @& |increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
9 X# K7 @. v) L7 A, wincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response/ I5 P/ B1 s! Y( S
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This+ t8 @7 h' Y: x- [0 H% P
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
; ~! k8 ^+ c. q# R3 v( Y! zgrowth. The response appears to be greater in younger children, which is consistent with previ-. E. a+ ~6 h1 Y: ^: h; `
ously published studies of age-related 5 reductase activity.
/ n' E' K: a) xChildren with microphallus regardless of its etiology will
+ c8 v0 D3 z. p9 z, N, R" ]) |require augmentation or consideration for alteration of exter-- w, S" j" I6 H- q! @! i
nal genitalia. In many instances urethroplasty for hypo-5 j3 k5 R5 C! @6 F% B2 D6 L3 `) n
spadias is easier with previous stimulation of phallic growth.1 \2 g6 m$ |5 v9 a) l' e6 A
The use of testosterone administered parenterally or topically' z! ]3 i- X1 k, l
has produced effective phallic growth. 1- 3 The mechanism of5 F; }& H3 I4 ?0 E' t7 s
response has been considered as local or systemic. With this& u, ~) I- u1 a5 j' e6 {* p
in mind we studied 5 children with microphallus for response8 K2 K' G3 n; R7 D0 f* L) V3 t
to gonadotropin and to topical testosterone independently.
: U9 m5 w5 F, Q+ t7 NMATERIALS AND METHODS/ K+ m+ i- [4 }; E# B
Five 46 XY male subjects between 3 and 17 years old were
, t' m( C9 g& ^$ F. i3 m% nevaluated for serum testosterone levels and hypothalamic
9 x8 U) E* V( Bfunction. Of these 5 boys 2 were considered to have Kallmann's
5 u$ R" N1 d5 y7 q9 j. csyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
8 k+ t& b" L$ y9 }- Olamic deficiency. After evaluation of response to luteinizing5 M! c1 E6 O: h* e5 L P
hormone-releasing hormone these patients were treated with
9 T3 C W6 v/ j [; ~% k4 j4 V# B1,000 units of gonadotropin weekly for 3 weeks. Six weeks7 O4 K7 L/ [% j
after completion of gonadotropin therapy 10 per cent topical! W' s! `" G) p2 o% W; x
testosterone was applied to the phallus twice daily for 3 weeks.4 u6 L1 P. Z/ n: @) D, b) ~
Serum testosterone, luteinizing hormone and follicle-stimulat-5 {- G8 f: D9 I, @3 o8 n9 @$ U
ing hormone were monitored before, during and after comple-8 W, _; E0 o# F0 O3 V& e! R
tion of each phase of therapy. Penile stretch length was
* S, `% E+ I/ k3 z `obtained by measuring from the symphysis pubis to the tip of
/ i. P7 s" F/ ythe glans. Penile circumferential (girth) measurements were
# ]: w7 x) G' v- J9 o6 pobtained using an orthopedic digital measuring device (see% ?% H8 m. o# f
figure)." x) e( c9 q, Q
RESULTS( i* Z/ K7 b! I% G! f" s
Serum testosterone increased moderately to levels between9 ?1 K. v0 l1 V' o0 F3 z
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
1 R4 t6 C5 M0 P6 Z/ pterone levels with topical testosterone remained near pre-
7 A6 u2 Y" h8 x# O n0 H2 otreatment levels (35 ng./dl.) or were elevated to similar levels
8 k, { }/ g6 @2 {# pdeveloped after gonadotropin therapy (96 ng./dl.). Higher
3 e0 L3 R$ \( _$ C2 q+ ?) W1 rserum levels were noted in older patients (12 and 17 years old),
) n) F& ~) v/ N- s3 z& pwhile lower levels persisted in younger patients (4, 8, and 10, r1 {9 L5 Z; ~0 f; A
years old) (see table). Despite absence of profound alterations
% j4 K9 `/ K$ ] U1 Q5 Cof serum testosterone the topical therapy provided a greater. C' k4 \, A4 p4 k' b( `4 V' Y
Accepted for publication July 1, 1977. ·
0 v7 b( b1 ^/ z6 u0 C( {- F: L* NRead at annual meeting of American Urological Association,, c5 s# ^8 t# E' U0 ]) x
Chicago, Illinois, April 24-28, 1977.1 s$ z) g; w+ @6 O& d
* Requests for reprints: Division of Urology, Henry Ford Hospital,# N# h' r% O/ m& L3 z8 c% l7 ^* d/ \% C
2799 W. Grand Blvd., Detroit, Michigan 48202.
- R, {5 }9 w0 t# mimprovement in phallic growth compared to gonadotropin./ N7 x4 ~% X4 p$ @" s& D
Average phallic growth with gonadotropin was 14.3 per cent
4 u* U+ F2 S' E! b- f' y- S' mincrease in length and 5.0 per cent increase of girth. Topical4 j7 G$ b; I, o$ @. j; w7 E
testosterone produced a 60.0 per cent increase of phallic length4 }* R5 o2 M% y; w G
and 52.9 per cent increase of girth (circumference). The# ~* d& m+ R( o9 v0 t E$ q- n
response to topical testosterone was greatest in children be-
( N( K) a& J8 b8 U& Xtween 4 and 8 years old, with a gradual decrease to age 178 Y5 q1 J9 A, I
years (see table).
$ {4 L7 l. M) Z- ?3 oDISCUSSION. s+ @* K; m5 O5 R8 M
Topical testosterone has been used effectively by other
* |* g: K. w1 }9 zclinicians but its mode of action remains controversial. Im-; Z# O3 w1 C4 a9 B
mergut and associates reported an excellent growth response3 l4 a. a+ i' _% J/ }
to topical testosterone with low levels of serum testosterone,
- X4 e" K' m& v+ ssuggesting a local effect.1 Others have obtained growth re-
! [3 O1 C$ q: V5 B7 s8 A) V4 jsponse with high. levels of serum testosterone after topical! x3 O- w% Y+ p
administration, suggesting a systemic response. 3 The use of: B4 [9 C1 a* z$ Q4 A
gonadotropin to obtain levels of serum testosterone compara-4 N0 g- `, K2 ]/ }0 ?( a. |8 `1 M" x
ble to levels obtained with topical testosterone would seem to
. E1 T7 y2 \. d* g1 S+ Y7 Sprovide a means to compare the relative effectiveness of/ A- p7 x: M% X4 X% W. p% u% x! |
topical testosterone to systemic testosterone effect. It cer-# B' E% H4 V# G3 [, ~6 d
tainly has been established that gonadotropin as well as par-3 c4 }& A1 W; O' t* g
enteral testosterone administration will produce genital
) Q7 n& V, G0 r! p5 l2 |/ g5 tgrowth. Our report shows that the growth of the phallus was; Q5 P" O: Y: b. u6 b, `$ ^
significantly greater with topical applications than with go- w: a A* y0 ]0 A
nadotropin, particularly in children less than 10 years old.0 |; |- y* ` c6 H
The levels of serum testosterone remained similar or lower
% m- K% H* V0 L. T, r6 dthan with gonadotropin during therapy, suggesting that topi-8 R# V# p$ E3 U) [3 z
cal application produces genital growth by its local effect as
0 @! f" q7 g5 ^9 _4 kwell as its systemic effect.# ]1 _& L; d9 @& ^! B! T
Review of our patients and their growth response related to
7 ^: G7 ?2 u1 Z: A1 ?* Wage shows a greater growth response at an earlier age. This is! ~7 t# C$ y3 s1 ]# ^
consistent with the findings of Wilson and Walker, who% H* b* S3 x" B/ S
reported an increased conversion of testosterone to dihydrotes-9 h. v" d" }' Q R; @* l
tosterone in the foreskin of neonates and infants.4 This activ-" Z. j6 o2 H$ ^5 J
ity gradually decreases with age until puberty when it ap-. ]2 t1 U7 o n9 L0 d7 z
proaches the same level of activity as peripheral skin. It may
2 c/ I( N/ \4 y# cwell be that absorption of testosterone is less when applied at
) w3 x+ Y9 a4 b* z" ]7 pan earlier age as suggested by lower serum levels in children6 u# a5 |$ N* m1 ^/ F) [" g
less than 10 years old. This fact may be explained by the
' [* F# H8 A6 n6 N. ^- H2 Ogreater ability of phallic skin to convert testosterone to dihy-* o$ ^- t% f) U' N* C4 g: n! s
drotestosterone at this age. Conversely, serum levels in older4 q/ `1 e9 Z+ L. l7 u
patients were higher, possibly because of decreased local3 H- z7 y$ D, p$ n+ A2 S
667
: a! J) A* U; M668 KLUGO AND CERNY
! A) r$ m) n& ^1 { o. kPt. Age3 ]2 U9 o. l7 B! V' O. f; q7 K/ o
(yrs.)
: X8 e% a! ~2 w2 USerum Testosterone Phallus (cm.) Change Length
, m+ m, B- K5 C' @( d" f(ng./dl.) Girth x Length (%); f" i- S- S$ |8 j. S0 P
4 L5 z+ e2 {3 J/ h
8
3 _+ E1 o& O( a2 I7 F10
. N, u% I7 e& u2 ~( H7 G! Z12
4 r7 j, B" x: ?1 ~- X! n6 Q! b6 k17+ H( B9 f2 e* q6 x8 _3 ]
Gonadotropin
! X3 ]! ]+ O9 ~71.6 2.0 X 3 16.6
4 b* _+ ?. c" M) p. ~# b: L50.4 4.0 X 5.0 20.0
k6 _: `4 N, g: q% [9 M( x, r6 h) C22.0 4.5 X 4.0 25.0
0 i% f6 Z }9 t E7 w2 t3 d84.6 4.0 X 4.5 11.14 S* R' H( d7 L0 Q+ L* z6 L- ]
85.9 4.5 X 5.5 9.0
0 v2 Q7 H! S. T7 O8 ^7 c: d; P O ^Av. 14.3- ?/ a; v; t0 w9 k
4( C6 }( C2 \( r0 L1 ?& f
8
( x8 E% T$ S; t9 Z) R% Q" n10. w) i E% ]2 ?+ t" q6 N
12
0 A* R! @: j2 V# k5 l+ G17
N( c9 T" b; ~* [Topical testosterone; \- X9 f" A1 T1 G( D$ I: C3 [
34.6 4.5 X 6.5 85
$ S$ e: D- x( K2 O4 }/ R38.8 6.0 X 8.5 70- \) T9 J; K7 D. N' O
40.0 6.0 X 6.5 62.5
+ F2 j9 o8 H4 S( O) H93.6 6.0 X 7.0 55.5
2 ]9 X( P5 ^8 d, y+ g& U- r95.0 6.5 X 7.0 27.22 v; |% y8 p% Y, a5 j" \
Av. 60.0
! q8 ?! I ?* u* Kavailable testosterone. Again, emphasis should be placed on
/ E! y7 q/ ]" \. k' Dearly therapy when lower levels of testosterone appear to: D; z5 y. a8 m7 @1 `* b- i
provide the best responses. The earlier therapy is instituted( A9 c+ ~$ I$ M1 A
the more likely there will be an excellent response with low
8 f8 Z; f& J8 {. f/ l9 Z/ Kserum levels. Response occurs throughout adolescence as4 Z( R7 ?2 U. T% [& N& X# R- U
noted in nomograms of phallic growth. 7 The actual response4 S# j. R0 ]$ V0 Z; T
to a given serum level of testosterone is much greater at birth n* @2 X5 g4 w" N
and gradually decreases as boys reach puberty. This is most, o+ \1 d* ~* r5 }1 G. x
likely related to the conversion of testosterone to dihydrotes-+ J# t. h6 J( ^, {5 y
tosterone and correlates well with the studies of testosterone
. i& ` s+ R( x5 {' }5 `conversion in foreskin at various ages.
( Q9 i1 P" h6 D+ \6 nThe question arises regarding early treatment as to whether8 {3 i0 y8 k# i- p# p& d- V
one might sacrifice ultimate potential growth as with acceler-
0 a/ S! f% E, b! p# l! a8 K) Qated bone growth. The situation appears quite the reverse; M: t. F4 N/ [- _ Y
with phallic response. If the early growth period is not used7 }( p/ g9 m; `
when 5a reductase activity is greatest then potential growth
1 ]/ a# R* r: Mmay be lost. We have not observed any regression of growth4 t1 [5 \6 |0 s# j. `5 Y0 a' p4 x/ g
attained with topical or gonadotropin therapy. It may well; s$ E' X# R8 n1 r m" } f& \
be that some patients will show little or no response to any+ G$ T6 V6 c7 H; q: \& x7 I
form of therapy. This would suggest a defect in the ability to! O6 A6 r# T h
convert testosterone to dihydrotestosterone and indicate that
* {- B# P# g4 P) {; nphallic and peripheral skin, and subcutaneous tissue should
$ t6 F9 v7 D u% H- [8 @be compared for 5a reductase activity.
3 f2 q# k3 \3 R3 b! D% e3 qA, loop enlarges to measure penile girth in millimeters. B,6 ]: f) `4 Y8 }
example of penile girth computed easily and accurately.
2 L0 [6 W% n5 v! ]0 Z/ M5 lconversion of testosterone to dihydrotestosterone. It is in this7 y/ Q; @; |" `0 u" u" z" K
older group that others have noted high levels of serum
; _' t& `$ Z. V, w* Ptestosterone with topical application. It would also appear
; H c+ `6 }6 B Hthat phallic response during puberty is related directly to the
& ?: |( a6 X* n7 D' [$ ?+ yserum testosterone level. There also is other evidence of local
4 d( h' a6 i J. @response to testosterone with hair growth and with spermato-
8 A" z% S1 J/ j7 n: ?; g; cgenesis. 5• 6
) k) |4 |6 V2 M& {- uAdministration of larger doses of gonadotropin or systemic
% Q( V" W0 r3 w$ q. q* Ctestosterone, as well as topical applications that produce, \4 ^/ ^( B( ]* U* w
higher levels of serum testosterone (150 to 900 ng./dl.), will
' ]/ M* ^# Z+ I4 \+ M$ [$ Y/ w" ralso produce phallic growth but risks accelerated skeletal. ^( i1 h; @& s7 \4 l s
maturation even after stopping treatment. It would appear( U- h. n8 m9 v) Q
that this may be avoided by topical applications of testosterone( r: S3 ]0 \* [% |; l% \
and monitoring of serum testosterone. Even with this control' x& Y$ C) K# x/ t" Z# }+ R# @
the duration of our therapy did not exceed 3 weeks at any
7 q: R7 u7 @4 |time. It is apparent that the prepuberal male subject may; F7 i+ K7 D) @' q! O
suffer accelerated bone growth with testosterone levels near
( i$ D# z# z. u* c200 ng./dl. When skeletal maturation is complete the level of. _* D+ ~2 |- T% V
serum testosterone can be maintained in the 700 to 1,300 ng./4 [$ }1 N$ B) ^( W% q( q
dl. range to stimulate phallic growth and secondary sexual' g7 [6 I2 H7 L4 Q' l6 z
changes. Therefore, after skeletal maturation parenteral tes-
8 X% r( s1 I& c; c. t5 j+ ntosterone may be used to advantage. Before skeletal matura-
- J2 C# f* t- v* Y/ C, ption care must be taken to avoid maintaining levels of serum
+ W D l4 c% \( Otestosterone more than 100 ng./dl. Low-dose gonadotropin- F, N) x' S1 N4 G6 [+ c
depends upon intrinsic testicular activity and may require5 {3 J5 @3 q6 G- S2 T( y3 J
prolonged administration for any response.
* w1 |* `" t% @6 F! LAlternately, topical testosterone does not depend upon tes-& {( q8 H2 l0 j
ticular function and may provide a more constant level of! b/ F4 C( v4 [- l) D- j
REFERENCES
, b3 _" n: K' ^) S1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,) f1 p2 y# s: J i7 [4 U3 |& P/ g
R.: The local application of testosterone cream to the prepub-
2 d5 L) `9 ]3 i3 |9 P$ }( T3 lertal phallus. J. Urol., 105: 905, 1971.% l* T! k% I2 N) L0 k: A0 k
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone# l7 v% O) [, C8 p: A W0 l1 ]' }
treatment for micropenis during early childhood. J. Pediat.,) O9 E) F8 m- i# m# E+ o7 e! v5 W; [
83: 247, 1973.. L& X; @2 ^6 ~& o
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
3 X- {3 [6 n- vone therapy for penile growth. Urology, 6: 708, 1975.
! n* g- A8 G( M4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone& u& w# ]8 k1 Q/ I% t
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
$ ?' s0 N* u1 y+ a2 ^% _% X, h: g0 Nskin slices of man. J. Clin. Invest., 48: 371, 1969.
/ v2 I) H$ O' ^: W5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
3 _% e- U. v$ l% bby topical application of androgens. J.A.M.A., 191: 521, 1965., n5 `4 y. R$ M
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
8 X. o. Q) |1 f7 Landrogenic effect of interstitial cell tumor of the testis. J.2 B0 o( N0 D4 o! m+ Q
Urol., 104: 774, 1970. n7 g4 H" r7 H
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-0 |% f4 \2 m" U6 D. s4 x) e, ~' x
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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