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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND W2 B% Q$ H. P$ R* ` x
GONADOTROPIN& o- F- y8 a- i5 M- A
RICHARD C. KLUGO* AND JOSEPH C. CERNY
) P; b$ f, N% K$ ~8 HFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
7 V7 V# v* a' Q* p* u% u* |ABSTRACT
1 r* P- e g5 ~( X3 d. d0 GFive patients were treated with gonadotropin and topical testosterone for micropenis associated6 l5 s/ ]5 ^( g+ h5 t# r, k
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
4 g; x# K, }; w. u% y0 S6 }/ Ptropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone& t0 u# [3 X" h% O
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
" j6 ~ o# W5 v7 U! Hfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
- z# O$ J% h) Mincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
: A( h9 s7 E0 r9 c7 v9 Yincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
7 Q$ A9 r- P, ?) {* [ Uoccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This7 `1 y% K% ?2 I& {. I
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile7 i' _& j1 m+ D X9 f" w) `6 ~
growth. The response appears to be greater in younger children, which is consistent with previ-4 P/ E" ?# A) b$ Q. u. c
ously published studies of age-related 5 reductase activity.
$ a6 _5 b9 m& `( t% r+ Q& EChildren with microphallus regardless of its etiology will
5 u Q z# }% a- d( J. u3 jrequire augmentation or consideration for alteration of exter-5 a$ o2 S0 ]4 [. J: ?3 C& c1 [
nal genitalia. In many instances urethroplasty for hypo-0 c7 K* U4 V! ~. U* ]
spadias is easier with previous stimulation of phallic growth.. J. h. D$ K8 ?( {+ c. t u' ^% I* v9 V
The use of testosterone administered parenterally or topically5 m/ Z) l# l5 p3 S# X% W+ X
has produced effective phallic growth. 1- 3 The mechanism of
) B! X! k; ?0 i( |& Y F# xresponse has been considered as local or systemic. With this/ _% ~4 |. m+ H& Y6 F' ?
in mind we studied 5 children with microphallus for response
* B( W: B {; e* f, O6 c$ sto gonadotropin and to topical testosterone independently.3 W h4 W& n+ |5 k0 q
MATERIALS AND METHODS! C" F+ j1 q# Y
Five 46 XY male subjects between 3 and 17 years old were
, {! M/ a) q8 o" |0 u; \0 wevaluated for serum testosterone levels and hypothalamic
7 U& h' S' e% p5 g, D0 U( ^function. Of these 5 boys 2 were considered to have Kallmann's" Y* L0 N, y* F. ]& p
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-1 u. `- ~4 @8 g" @" V K Q3 V
lamic deficiency. After evaluation of response to luteinizing
2 s- |2 Y, ]3 N, B0 K) P: |2 K' n bhormone-releasing hormone these patients were treated with/ ]$ }! O9 x5 K; S) ]1 B$ J
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
4 J4 ]' ]5 G: y* Eafter completion of gonadotropin therapy 10 per cent topical
4 g0 \2 }' l- V" xtestosterone was applied to the phallus twice daily for 3 weeks.
# L/ ~3 Z/ V: j7 a( x- X8 Y3 KSerum testosterone, luteinizing hormone and follicle-stimulat-
7 _7 f. m- O; I- }ing hormone were monitored before, during and after comple-
. ~$ a4 W z. E( }, Z7 }tion of each phase of therapy. Penile stretch length was
. E9 f4 z6 G/ Q. tobtained by measuring from the symphysis pubis to the tip of, j, p, y. ]- U8 i* m
the glans. Penile circumferential (girth) measurements were
. m0 K" t" S& H: Eobtained using an orthopedic digital measuring device (see$ |( R" N. c: O% c4 ~: W
figure).
1 {" l0 m! \# ~$ N- Y$ vRESULTS* W9 K' S- w+ B! a4 E: W% _) v+ J# [3 G
Serum testosterone increased moderately to levels between
$ q/ J' u' [, Z0 M: ~* M50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-7 u m1 H5 F) D4 f
terone levels with topical testosterone remained near pre-4 ]( z/ k+ g5 n; s
treatment levels (35 ng./dl.) or were elevated to similar levels+ H$ z; `" w; Z; l6 A6 e9 I; a: B" }
developed after gonadotropin therapy (96 ng./dl.). Higher; ~+ R1 D: x2 z% D" I* E8 i
serum levels were noted in older patients (12 and 17 years old), f0 u1 T: F7 y6 b8 I
while lower levels persisted in younger patients (4, 8, and 10
3 ?* K2 r3 e, n# ^8 ]5 [$ myears old) (see table). Despite absence of profound alterations% [1 ~: p' v5 i# A! E) v
of serum testosterone the topical therapy provided a greater( O) C; t M2 d
Accepted for publication July 1, 1977. ·/ t; t) C# m& i* G0 J1 R
Read at annual meeting of American Urological Association,; ~7 C$ b$ A# L0 F; K
Chicago, Illinois, April 24-28, 1977.
6 @& O- A$ g& f/ k, x6 N; d- W* Requests for reprints: Division of Urology, Henry Ford Hospital,
9 t% Q7 s* Z) ] Q# X$ v2799 W. Grand Blvd., Detroit, Michigan 48202.
) P- n( ]( v5 Y+ ^+ Q& mimprovement in phallic growth compared to gonadotropin.
: N. Q* h5 A G2 l7 ^Average phallic growth with gonadotropin was 14.3 per cent
- Q: z6 ]% S7 tincrease in length and 5.0 per cent increase of girth. Topical
9 g; F; {! y# ]& rtestosterone produced a 60.0 per cent increase of phallic length
8 Y+ ~# M" p2 {0 Wand 52.9 per cent increase of girth (circumference). The' E# H# I8 I6 P9 p+ b1 |$ Q( Q
response to topical testosterone was greatest in children be-
) |9 G7 S9 m" J3 B! ttween 4 and 8 years old, with a gradual decrease to age 17
+ ~! f1 ~ ~2 C! h- T" s. xyears (see table).6 S8 Y! j. [" T: h
DISCUSSION
$ S5 y1 ]# M* ?7 {3 r0 mTopical testosterone has been used effectively by other
, U7 j6 x& `1 b6 [clinicians but its mode of action remains controversial. Im-$ t- C. L0 @$ q
mergut and associates reported an excellent growth response
6 i7 R2 y$ {6 V! Q6 l2 O, Y8 U! bto topical testosterone with low levels of serum testosterone,% Y! ?% V3 u+ u# n6 S
suggesting a local effect.1 Others have obtained growth re-8 }: ?4 C2 M/ |% l3 I1 O% `6 a
sponse with high. levels of serum testosterone after topical
1 K$ g3 `8 Q% X B& `administration, suggesting a systemic response. 3 The use of* N2 a4 ?9 |: }* z. _- `- M0 _
gonadotropin to obtain levels of serum testosterone compara-) k% e p- G1 H( K+ Y
ble to levels obtained with topical testosterone would seem to
( g& {. S. j: n! ~provide a means to compare the relative effectiveness of/ E: Q" C1 A" x+ v+ C! _
topical testosterone to systemic testosterone effect. It cer-
6 H+ C! e6 i$ l; L6 G$ _tainly has been established that gonadotropin as well as par-
3 W D X. _: i, N& Ienteral testosterone administration will produce genital
0 t$ g# U" L$ |- ? { P1 Bgrowth. Our report shows that the growth of the phallus was
& e- l5 _6 d, nsignificantly greater with topical applications than with go-
! V9 t9 Y& a% q- knadotropin, particularly in children less than 10 years old.' v* B# {% s+ S- Y0 U
The levels of serum testosterone remained similar or lower
& }9 {" n" i# S/ K) L: D# |- Lthan with gonadotropin during therapy, suggesting that topi-' K7 T/ Q& [9 Y% J
cal application produces genital growth by its local effect as* `4 r0 b2 O+ E& S0 ~( I$ Q6 v
well as its systemic effect.# P2 h- J. J/ a" X$ B0 L& N$ B$ N
Review of our patients and their growth response related to
* S/ n/ k# ]2 x, H1 Rage shows a greater growth response at an earlier age. This is$ E# E, n V5 [- s, b+ y
consistent with the findings of Wilson and Walker, who0 R( X* M- y* p
reported an increased conversion of testosterone to dihydrotes-. W, b% [+ K2 |5 r. h2 c1 W/ P! O
tosterone in the foreskin of neonates and infants.4 This activ-
) j- d- S, y4 {( q8 vity gradually decreases with age until puberty when it ap-3 g0 \9 D. B/ P
proaches the same level of activity as peripheral skin. It may H: ]/ w4 v; o3 Y, P
well be that absorption of testosterone is less when applied at$ T* }3 M0 l: ~3 A
an earlier age as suggested by lower serum levels in children
8 _. X0 B! C* d% O" A9 zless than 10 years old. This fact may be explained by the! L7 e0 y# _0 C: O# g5 U$ K' E* f
greater ability of phallic skin to convert testosterone to dihy-
Y9 w c8 Y( T; q F4 O" ~4 Idrotestosterone at this age. Conversely, serum levels in older
1 _! ?9 f6 \- C! B( ipatients were higher, possibly because of decreased local
+ }/ k" G; L- {. V; d0 v* f0 n/ U667
0 k4 Z) z9 I! I8 V668 KLUGO AND CERNY
! x3 s$ `* j/ \- H$ ^1 B& G3 BPt. Age
( N, I2 ?6 j1 [. N* j% f. \& n(yrs.): E/ z2 P# E* s
Serum Testosterone Phallus (cm.) Change Length6 n' }0 J' S5 F$ M5 G0 d
(ng./dl.) Girth x Length (%)& _+ N. i, [1 d6 v$ S% N1 ]# E
4
N% E2 A; C: T; A9 X e8/ A0 X1 l- w- r1 s( q" T5 H5 _
10
/ s/ w& z5 n3 r9 c; N5 P# R122 t( [& l- P$ F9 j$ \4 j7 [% U
17
2 Q" ]6 g+ [# e. O; N8 u& D2 NGonadotropin/ s9 E- z' ]! n1 f5 @! ^ m6 U
71.6 2.0 X 3 16.68 X& l2 Z7 ]( ?; [0 R
50.4 4.0 X 5.0 20.0% T. r. q, W( ^& ^/ ]( v, q/ U
22.0 4.5 X 4.0 25.0+ k6 G# h; j2 [: P6 b, y1 ?/ R
84.6 4.0 X 4.5 11.11 s; V$ T0 N8 d( z1 u
85.9 4.5 X 5.5 9.0
$ H5 V1 G; z0 i- G+ XAv. 14.3+ g1 o( y- b' P& ?; \, U
4
# ~* ^6 \6 |: X7 u% d( f! w/ y8
4 [& [: W& K/ F5 g. s100 W- D$ ?; h/ r- _% o3 A/ N/ n
12
: S$ w/ V% P9 o3 m3 a176 r3 g$ B9 o3 d
Topical testosterone
: L* e$ `5 J0 Q- d6 `34.6 4.5 X 6.5 85/ ^% Y6 K8 k* S$ b9 d! u' y; C
38.8 6.0 X 8.5 70
- K4 X& e% @' d/ c- d1 U40.0 6.0 X 6.5 62.57 e' f+ n" {$ y. r, f0 h
93.6 6.0 X 7.0 55.5
, n/ u, ?, ~3 r& w H9 H95.0 6.5 X 7.0 27.2" b2 Z# j" G) U2 N: V
Av. 60.0" i/ H6 G( G+ r
available testosterone. Again, emphasis should be placed on
& f7 @* o1 `6 M) K$ N! e! Zearly therapy when lower levels of testosterone appear to5 F8 C8 }$ }( e& D% y% l7 m
provide the best responses. The earlier therapy is instituted1 |/ v3 J5 w6 Q+ x9 ]
the more likely there will be an excellent response with low
, _& U6 [1 l* @( Z/ v( _serum levels. Response occurs throughout adolescence as( ^3 X- g: v$ \
noted in nomograms of phallic growth. 7 The actual response9 X6 h- T }1 d) G
to a given serum level of testosterone is much greater at birth1 P9 T, ~1 |0 ~& _4 |" c; ~3 B8 J
and gradually decreases as boys reach puberty. This is most/ J6 y# v0 _0 u7 F
likely related to the conversion of testosterone to dihydrotes-/ X# M4 e0 Y# E8 F$ Z! F
tosterone and correlates well with the studies of testosterone
/ {$ ~; h& r$ Xconversion in foreskin at various ages.- \ u# k/ m8 t+ p
The question arises regarding early treatment as to whether! f6 b" p1 d& N# |2 l9 J
one might sacrifice ultimate potential growth as with acceler-
6 u/ g. o& K# K* w/ T* J/ ?7 Qated bone growth. The situation appears quite the reverse
6 `' h0 Q- F: `1 K3 o. m: Bwith phallic response. If the early growth period is not used" W9 V- B. Y& [+ f; y1 ?$ J' W
when 5a reductase activity is greatest then potential growth2 o& [7 x* Q; p
may be lost. We have not observed any regression of growth# s5 T( C0 L0 m9 g4 u
attained with topical or gonadotropin therapy. It may well6 _/ {5 N$ V( B* D: m
be that some patients will show little or no response to any
" M# A& N$ P' z( k4 g. r; g8 i4 \form of therapy. This would suggest a defect in the ability to' `4 S$ A8 @* H' I$ S* L2 }: l
convert testosterone to dihydrotestosterone and indicate that0 n- Y4 G4 T9 e- w. T" I
phallic and peripheral skin, and subcutaneous tissue should
# ], j4 T$ {& S5 x, F% `# h: ~be compared for 5a reductase activity.2 a& Q; I' A; W/ Z9 {& S# d" Q
A, loop enlarges to measure penile girth in millimeters. B,9 V9 r# L+ N8 k( w, D
example of penile girth computed easily and accurately.
8 Z: g8 u" ^+ c4 V% hconversion of testosterone to dihydrotestosterone. It is in this
1 h9 z8 a8 C% ]older group that others have noted high levels of serum
% W7 c, E, @( o6 v- ftestosterone with topical application. It would also appear
' B$ \9 Z2 t/ z# P: |7 i: Kthat phallic response during puberty is related directly to the
% Y5 @8 m% Q7 r; bserum testosterone level. There also is other evidence of local7 ]8 p) _" y& E1 V8 i" z& X" c; _
response to testosterone with hair growth and with spermato-" [0 @0 W6 L5 U9 S
genesis. 5• 6$ Q O6 t& a- M5 ?: z3 V) A
Administration of larger doses of gonadotropin or systemic
2 B: D9 @6 n' S; v: \1 d6 c( Xtestosterone, as well as topical applications that produce
1 H f+ R/ o' l5 g( [: l* H! F" Rhigher levels of serum testosterone (150 to 900 ng./dl.), will
1 z1 z! `6 V/ _) c4 b l! ?; b+ \also produce phallic growth but risks accelerated skeletal0 J, w$ `/ | a0 U
maturation even after stopping treatment. It would appear
% m1 q5 ~0 T& }) [ {. D4 C7 M7 Qthat this may be avoided by topical applications of testosterone" a4 K! U% K/ I
and monitoring of serum testosterone. Even with this control9 ~1 P% z9 d: N- G) S
the duration of our therapy did not exceed 3 weeks at any
0 c- a! D/ F$ V4 f. ]3 ^time. It is apparent that the prepuberal male subject may& }: q- {2 k) J: w
suffer accelerated bone growth with testosterone levels near: R6 q, @$ ~1 S9 p
200 ng./dl. When skeletal maturation is complete the level of3 a! X. O4 v; Z$ s$ y/ l1 _0 G
serum testosterone can be maintained in the 700 to 1,300 ng./
& ^9 I* B3 I9 Tdl. range to stimulate phallic growth and secondary sexual5 H( v8 _! h" }9 p( s# `
changes. Therefore, after skeletal maturation parenteral tes-
% L1 ?9 D- [9 Qtosterone may be used to advantage. Before skeletal matura-0 d9 ^( O. U' E1 D, L" c2 c" w; {# g
tion care must be taken to avoid maintaining levels of serum$ h* e8 o& w6 j; H, Z
testosterone more than 100 ng./dl. Low-dose gonadotropin
$ g& D/ i# W+ m, N( V& ]7 Qdepends upon intrinsic testicular activity and may require
; |: {# j! e5 C Gprolonged administration for any response./ G V# [+ G3 [( ?1 A* @3 x
Alternately, topical testosterone does not depend upon tes-
6 t; \. _1 ^7 ]: |ticular function and may provide a more constant level of, u |" S8 B6 @; X1 u
REFERENCES9 G% z( E& u( ]) d4 m
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,8 J' x6 t! \+ t- h" r& u2 G2 ^
R.: The local application of testosterone cream to the prepub-
9 l( \7 Q4 L' T4 a [6 _5 n8 jertal phallus. J. Urol., 105: 905, 1971.: T d* O% u) g/ I
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone/ {! |1 ~% p5 X' g$ P
treatment for micropenis during early childhood. J. Pediat.,1 I* n, e& I* R l6 _
83: 247, 1973.
% f1 X' }+ o Z* N# l2 \& `3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
4 o. Q6 s* I& zone therapy for penile growth. Urology, 6: 708, 1975.8 u" F+ Y# r4 `8 H* S& Z" N$ n5 j
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
* T" h, t% D0 @+ _to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by* ~+ w* y/ o; w. U8 ?
skin slices of man. J. Clin. Invest., 48: 371, 1969.
4 ?. ^8 c4 }' y* v% n* H( k5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth! U, v1 _% ?0 Z
by topical application of androgens. J.A.M.A., 191: 521, 1965.
% U4 w/ ?7 C7 j9 s6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
$ D+ S' F7 G0 sandrogenic effect of interstitial cell tumor of the testis. J.
# ^( B& P. X( x$ w, @, [1 e! A$ MUrol., 104: 774, 1970.
4 j* M4 k$ A( @, D' |; e3 O7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
6 S* G& @% @0 A" Y( \ ^ ]tion in the male genitalia from birth to maturity. J. Urol., 48: |
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