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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND' t5 n3 g! F& X V! T2 Q, j
GONADOTROPIN# E9 n9 ?' K& |+ o3 N
RICHARD C. KLUGO* AND JOSEPH C. CERNY
% M) g; ?8 l ]4 I8 E" ~$ q8 jFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
\! K; J5 I4 t$ ?2 q$ {ABSTRACT
( v) U% F4 s6 k6 } eFive patients were treated with gonadotropin and topical testosterone for micropenis associated
+ b9 \2 ?7 h, W9 B- \& n% X. {with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-# k; W. i; I- A( h- N& ^
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone# U; k. ^+ w( D- {- W7 w Y a
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent4 d4 n* y# r( S- V/ e" d
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
6 u: D+ |% e) A1 [/ A4 tincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average7 H7 a Q, E1 b( y
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
. J3 A. z0 l; ~3 A0 M! U. Koccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
8 Y! o4 c1 d9 Z1 ?7 v& tstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
- C) [6 O% j ugrowth. The response appears to be greater in younger children, which is consistent with previ-0 i6 ]0 Q2 ?7 E8 W* P
ously published studies of age-related 5 reductase activity., k! H6 s6 v! z, v+ s( `
Children with microphallus regardless of its etiology will
, t1 E* F* z$ ~: Wrequire augmentation or consideration for alteration of exter-
' A$ W4 g0 o" B z* Ynal genitalia. In many instances urethroplasty for hypo-# W/ C4 Y P& O$ N: ~: ~( i5 Z
spadias is easier with previous stimulation of phallic growth.) s+ z0 x# C, \
The use of testosterone administered parenterally or topically
1 s0 `2 }# h* b: @- zhas produced effective phallic growth. 1- 3 The mechanism of
U4 V& R& M8 H2 C0 T4 nresponse has been considered as local or systemic. With this
4 _% H$ }) ]1 s0 n# f# I4 Bin mind we studied 5 children with microphallus for response
0 z V# |! U, `2 R* _to gonadotropin and to topical testosterone independently.; @% J; _8 ?, q& T
MATERIALS AND METHODS4 L/ x% Y+ u8 \, O
Five 46 XY male subjects between 3 and 17 years old were
, c) r$ b- ]7 U" b; i6 z' cevaluated for serum testosterone levels and hypothalamic( F0 G* F% T, [' F$ e
function. Of these 5 boys 2 were considered to have Kallmann's
' h; ^- e0 Q2 }syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-' S p5 w( q& B0 h. H
lamic deficiency. After evaluation of response to luteinizing
7 M* _5 j4 _; J) H9 Jhormone-releasing hormone these patients were treated with
. X J V$ u% G. h1,000 units of gonadotropin weekly for 3 weeks. Six weeks
. v# B C/ m( U3 L8 kafter completion of gonadotropin therapy 10 per cent topical
' E" W0 B3 w0 E# m+ itestosterone was applied to the phallus twice daily for 3 weeks.
* h; A4 J2 A, n" v, ^Serum testosterone, luteinizing hormone and follicle-stimulat-
! W" S; q8 h) B3 ting hormone were monitored before, during and after comple-1 u' X h# T" c* U. Q9 Q
tion of each phase of therapy. Penile stretch length was: _) _: K: l9 ~& e4 F0 X
obtained by measuring from the symphysis pubis to the tip of3 K$ z. \; U* p1 f4 C7 V
the glans. Penile circumferential (girth) measurements were" E) M, f* ]8 \8 b& {
obtained using an orthopedic digital measuring device (see& Z, [5 Z. N/ \( y6 t
figure).
" f) Y1 ~' ~* \RESULTS: [: a7 r" _5 U/ F3 z) F8 S
Serum testosterone increased moderately to levels between
/ k3 N f" \% T& E4 L/ y: L/ Y8 f50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-& G; z& C( ]4 Q! h8 F/ _7 |& A/ f
terone levels with topical testosterone remained near pre-0 _ T3 K, c% W* o; e9 }' L$ `( n! E. Z
treatment levels (35 ng./dl.) or were elevated to similar levels
* \& W: ~' y5 O/ V# Fdeveloped after gonadotropin therapy (96 ng./dl.). Higher0 ]$ Z+ [- a1 h# T; R0 e
serum levels were noted in older patients (12 and 17 years old),
# g. d0 K U& Swhile lower levels persisted in younger patients (4, 8, and 10) A4 f! Z2 m- ?* j2 Q
years old) (see table). Despite absence of profound alterations
+ G3 {" H' F% w4 A _) Vof serum testosterone the topical therapy provided a greater
3 A, v! I6 h& BAccepted for publication July 1, 1977. · b1 X6 F7 d/ n. Q3 T
Read at annual meeting of American Urological Association,6 o) C' L0 `) E- i- t
Chicago, Illinois, April 24-28, 1977. F7 `* t) J3 k0 g/ w3 t
* Requests for reprints: Division of Urology, Henry Ford Hospital,
" g9 L1 b) d$ ~2799 W. Grand Blvd., Detroit, Michigan 48202.
- L1 y8 I2 X* _improvement in phallic growth compared to gonadotropin.
$ `" h+ w- ^. ~- C! r' g+ M; b! VAverage phallic growth with gonadotropin was 14.3 per cent! V; Z* i& _3 H& a! e2 U
increase in length and 5.0 per cent increase of girth. Topical- \* Y/ t" C, v. U' E) |9 ^
testosterone produced a 60.0 per cent increase of phallic length9 c% x& V q9 X3 z$ w
and 52.9 per cent increase of girth (circumference). The [* k+ ~4 } f/ G% m7 N
response to topical testosterone was greatest in children be-
0 k$ i0 k! R0 D9 Y1 Y3 c7 @6 Htween 4 and 8 years old, with a gradual decrease to age 17& C2 O& J- Q+ O) ^
years (see table).: M% f- q+ ?) Z+ w, I9 \% J
DISCUSSION, O% G9 a! v, g: w& E+ q5 I
Topical testosterone has been used effectively by other
& r! k5 V" C3 X j/ mclinicians but its mode of action remains controversial. Im-+ F! Y+ ]4 j* o$ y
mergut and associates reported an excellent growth response
# Y/ X! m0 y/ ]4 V! v$ o' tto topical testosterone with low levels of serum testosterone,
5 C0 _- x. p2 E; g ]8 tsuggesting a local effect.1 Others have obtained growth re-
7 p0 g' J$ R" Q/ S$ i. Z2 D: [sponse with high. levels of serum testosterone after topical/ E8 H: L4 B" b! r. @
administration, suggesting a systemic response. 3 The use of
# e1 o. o/ ^6 N7 y! }gonadotropin to obtain levels of serum testosterone compara-: r$ ?; |2 J& c) u' b; l. @4 \
ble to levels obtained with topical testosterone would seem to
3 E, y) V# I$ l$ |" fprovide a means to compare the relative effectiveness of
) b( j2 B! q% J ?8 o5 U/ t( stopical testosterone to systemic testosterone effect. It cer-
. u/ F1 F: ~$ e. stainly has been established that gonadotropin as well as par-
3 Y5 b. n$ o: Ienteral testosterone administration will produce genital
i& Z0 D/ l9 n& ^" ] C: ^8 Ogrowth. Our report shows that the growth of the phallus was# U1 u: N: V: l, ~1 U! b* Y
significantly greater with topical applications than with go-
7 c x) g# R2 q2 g5 b, v, B" inadotropin, particularly in children less than 10 years old.6 {; P9 Z. ?/ l9 {
The levels of serum testosterone remained similar or lower. v9 C" t) a% ^
than with gonadotropin during therapy, suggesting that topi-
- g6 p8 K0 Z+ ? ycal application produces genital growth by its local effect as7 g7 j! P4 K$ a' ^
well as its systemic effect.0 L9 i# m+ c. W3 s' f3 n. d m
Review of our patients and their growth response related to
5 t5 _9 ^# L+ h. u3 H1 Nage shows a greater growth response at an earlier age. This is& a8 \* |0 w4 Q9 j- G
consistent with the findings of Wilson and Walker, who; T5 P6 S' D9 D. x
reported an increased conversion of testosterone to dihydrotes-6 u+ A# `5 Y8 y6 x, R
tosterone in the foreskin of neonates and infants.4 This activ-( c5 ?9 a9 I# d# [& a
ity gradually decreases with age until puberty when it ap-
: U8 y3 A7 G4 yproaches the same level of activity as peripheral skin. It may) |0 v' L1 j$ x
well be that absorption of testosterone is less when applied at* X; \* S5 ^1 m0 J: W
an earlier age as suggested by lower serum levels in children
8 G ^5 m. H! |" Eless than 10 years old. This fact may be explained by the" W: F W1 h) |5 ~5 z
greater ability of phallic skin to convert testosterone to dihy-- u& j/ P9 @% {/ F
drotestosterone at this age. Conversely, serum levels in older z, W' M: T$ v5 l
patients were higher, possibly because of decreased local }' g6 M$ S, a
6672 h* ^% Q! l0 z1 V: m( Z7 _ S
668 KLUGO AND CERNY
- c- ~! h+ k+ U& o* }' l" IPt. Age
4 z: i6 k9 @; C# V3 _" |/ ]# ?(yrs.)& O$ S y4 Q# W& f
Serum Testosterone Phallus (cm.) Change Length
4 W2 g: K; t; v# j6 R: C(ng./dl.) Girth x Length (%)/ X/ @ r3 g, ]$ m- V0 Y% d2 u B
45 s8 q3 }8 Y9 \9 H3 A6 }
8$ e( d( {" g# R8 C7 J) E7 e F
10" W. n2 W9 R/ @. _1 }% B+ {6 H
12
& h8 N* d# y% X5 S17
7 W1 X& W, a* [) EGonadotropin$ x' W7 \) W# k7 ^1 S
71.6 2.0 X 3 16.6
3 z" P2 m, s7 n. y* J1 C50.4 4.0 X 5.0 20.0
$ M" S( J$ e6 M! j" s( ]' h22.0 4.5 X 4.0 25.0! e+ `, D) l! b6 s1 O# l, M
84.6 4.0 X 4.5 11.1( N# d3 [& }. ]/ G7 K
85.9 4.5 X 5.5 9.0
, c0 ]% V* M, X3 [9 fAv. 14.3' q7 ?% C2 P9 B
44 G; |' J& i3 P7 F& W- i$ r
8" w5 \' g' h8 h( Q* ^/ w$ Y: R. O. O
10
9 ^$ |- w4 B& Z/ H: \# d129 `6 F+ C( B4 P" p/ u
178 W2 T; _: x" C* n
Topical testosterone
# X$ W2 _1 I9 B1 V# |9 w34.6 4.5 X 6.5 85
- E# N. G7 ~. u' Z0 k& X c/ B& j38.8 6.0 X 8.5 70
5 ~4 m. J, s- q9 D( H( I) a40.0 6.0 X 6.5 62.5
. E" n6 C/ H/ k4 W7 r! }+ u93.6 6.0 X 7.0 55.5
P0 y" G9 x/ | o0 \* J4 q95.0 6.5 X 7.0 27.2 R1 O7 I [9 |, \& v
Av. 60.0" ^ Z1 X( P' R# J3 z/ ]
available testosterone. Again, emphasis should be placed on
0 d2 w; ^" ?" j4 P7 Mearly therapy when lower levels of testosterone appear to
' |3 a9 K' W ~: f: H7 [provide the best responses. The earlier therapy is instituted
, x. Z' ^6 \0 m, A( ^' Sthe more likely there will be an excellent response with low
S+ Z6 d# n/ z' A. d8 W( d! kserum levels. Response occurs throughout adolescence as5 T4 Y( H1 n) B* c% y( E
noted in nomograms of phallic growth. 7 The actual response+ Q$ R2 n, S- s
to a given serum level of testosterone is much greater at birth
. u8 {' _( v- J6 J/ ]. [2 cand gradually decreases as boys reach puberty. This is most
" O5 Y) V) S8 T6 S, }likely related to the conversion of testosterone to dihydrotes-
9 V% e. M/ n. _4 d3 P# Z R P7 ltosterone and correlates well with the studies of testosterone
7 [6 Y' n$ `( Z* o+ F; S: F) iconversion in foreskin at various ages.
; h9 t$ F4 J) l% I0 {* l* vThe question arises regarding early treatment as to whether* R( @8 m* j6 _; C! T9 D: E$ {. m2 ^
one might sacrifice ultimate potential growth as with acceler-
% Z0 R0 {3 [* A, sated bone growth. The situation appears quite the reverse
2 a2 [& |, n: a' Q/ ewith phallic response. If the early growth period is not used2 I- ~8 E3 Q" z. _! a, @/ r' w
when 5a reductase activity is greatest then potential growth
) g4 f4 |; D, N' \4 y/ V5 N5 i9 [may be lost. We have not observed any regression of growth# Y+ [9 L8 [/ Z7 }
attained with topical or gonadotropin therapy. It may well
- k3 @; e/ |% _1 ~* I( zbe that some patients will show little or no response to any x( W# ?# N( h3 a, f+ A4 x
form of therapy. This would suggest a defect in the ability to
, H0 L/ G7 \9 U8 \# }3 Iconvert testosterone to dihydrotestosterone and indicate that
* U' l1 p+ K8 p. {phallic and peripheral skin, and subcutaneous tissue should
% t! t9 Y- y+ L: e) n2 e9 Gbe compared for 5a reductase activity.) i3 Y: t. A% y" V
A, loop enlarges to measure penile girth in millimeters. B,
/ c: h( z$ V) N ]example of penile girth computed easily and accurately.9 }. ]: s& l7 X d) d( R
conversion of testosterone to dihydrotestosterone. It is in this
/ C; ~2 k) ~. h8 p# K; E( x$ w8 B* q# @older group that others have noted high levels of serum3 b! {$ C) G6 j" D- `: m
testosterone with topical application. It would also appear
& |9 R, g& K( h( n* Rthat phallic response during puberty is related directly to the1 ^3 Y6 |) y6 E0 L, i% S, ^/ K
serum testosterone level. There also is other evidence of local
& j5 j5 N# u0 V8 Iresponse to testosterone with hair growth and with spermato-. g5 {0 f- e' W4 f% w+ G$ K
genesis. 5• 6/ F* e4 Z. J" n' ]% J7 X" [9 [. \
Administration of larger doses of gonadotropin or systemic7 |# O, W$ d0 j3 A M, c W4 f
testosterone, as well as topical applications that produce2 _* M# l8 ?$ Q1 I# ~/ O, t- d
higher levels of serum testosterone (150 to 900 ng./dl.), will& S8 P2 U+ ?/ S( k) p$ @
also produce phallic growth but risks accelerated skeletal
+ b8 M8 @* y* ~% nmaturation even after stopping treatment. It would appear
0 v& M1 m% b5 ]4 t5 d3 u, Wthat this may be avoided by topical applications of testosterone, b- O- L4 X; `: ]1 G$ _5 b; N. {1 r
and monitoring of serum testosterone. Even with this control
! @' j0 x) W$ M0 d" [; n e3 Dthe duration of our therapy did not exceed 3 weeks at any5 j/ c; ]' g2 [& D
time. It is apparent that the prepuberal male subject may
# v: ~! y; c' E1 ?! C& psuffer accelerated bone growth with testosterone levels near4 J6 l2 C( A* N5 T* A0 c( O1 R
200 ng./dl. When skeletal maturation is complete the level of5 ?3 K" c7 t7 D9 c5 S
serum testosterone can be maintained in the 700 to 1,300 ng./
1 u" g" i( g3 p4 W: X; jdl. range to stimulate phallic growth and secondary sexual
# _$ N2 h3 y ochanges. Therefore, after skeletal maturation parenteral tes-5 W9 Q. Q O `! b# L1 _& g
tosterone may be used to advantage. Before skeletal matura-2 D8 s4 J! O0 G) W6 R0 m
tion care must be taken to avoid maintaining levels of serum9 `- P+ g, N8 d& _( x: M
testosterone more than 100 ng./dl. Low-dose gonadotropin* @( {4 ^. \+ g
depends upon intrinsic testicular activity and may require
) R& q$ [9 h. E4 O$ Dprolonged administration for any response.& D) j: }5 }4 W- L' L8 g
Alternately, topical testosterone does not depend upon tes-
1 P" K( ~/ z* C, v2 u! nticular function and may provide a more constant level of0 ]$ p+ F7 D" }5 y' _+ R! D
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- b- J6 F, ~. |# X0 V/ A+ P4 z# n- x2 r9 t1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,$ X; [1 l# ]+ N7 T s
R.: The local application of testosterone cream to the prepub-
, _/ r- o/ Z' v) `ertal phallus. J. Urol., 105: 905, 1971.9 k) H9 f+ b: w2 J: }7 `6 @$ O l5 h, P
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone Z# u/ @/ U! r$ W
treatment for micropenis during early childhood. J. Pediat.,2 _( ?3 z$ P. A9 {- ?: Q3 @
83: 247, 1973." K+ S4 R6 @" O4 @0 {& v- e
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-; R( L4 q; q4 W, S' G4 Y
one therapy for penile growth. Urology, 6: 708, 1975.: w" [0 I) z' V$ v& [
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone- }( N2 k' a9 ~* z+ d" s) w
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
! Q# ^. u9 b) X; ^: A7 Rskin slices of man. J. Clin. Invest., 48: 371, 1969.6 V: ?; U- y1 g. g8 n
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
+ O1 g* \: c4 e" n: f* v! Rby topical application of androgens. J.A.M.A., 191: 521, 1965.
6 g$ u( X' e* |# w7 b9 L' Z6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local& o. e+ C7 w/ y6 p, Z+ u
androgenic effect of interstitial cell tumor of the testis. J.
& j$ Q% B8 c8 ]* hUrol., 104: 774, 1970.; W6 E6 {5 N( c% E1 B
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-0 ]# A) a6 v+ U# _, o6 P) w3 W
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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