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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
; D* ?* m0 m% R- {/ [/ gGONADOTROPIN+ x" }8 |: B; t4 Y. v
RICHARD C. KLUGO* AND JOSEPH C. CERNY
7 N: a9 A$ e1 b0 m/ lFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
' Z x" a' Z* g. GABSTRACT3 C s6 x5 [% F( I; q$ U3 W$ d4 E
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
% Y( x! _: C! z$ t9 \9 H7 S# y5 Owith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
8 W. k; j8 u1 h8 P$ g) Q+ Xtropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
! M* G% l" u6 y4 D8 ?( t# `- ccream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent$ `7 R$ j, q8 s i. H# I8 R
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
1 W, n9 c: x& x' X! f- N& cincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average9 x3 A$ }2 J' v5 P8 V* ?& C
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response7 o/ v% v/ R0 j; A1 U2 X
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This% L% _* p$ |& H! U0 `
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile% j7 I( c9 [, A
growth. The response appears to be greater in younger children, which is consistent with previ-! Y* f0 m; @/ j4 |4 E0 ?7 i- m
ously published studies of age-related 5 reductase activity.8 j' n- u9 s3 U; T4 a
Children with microphallus regardless of its etiology will
, z, c1 S/ k- @3 t1 A" Zrequire augmentation or consideration for alteration of exter-5 C# O' r8 _2 u9 Q6 }
nal genitalia. In many instances urethroplasty for hypo-$ k2 r* z+ u: Z
spadias is easier with previous stimulation of phallic growth.- M0 u2 ^1 V, T. w9 t) F
The use of testosterone administered parenterally or topically
' M" G! B6 `9 N6 ?, p0 l4 d1 }has produced effective phallic growth. 1- 3 The mechanism of
0 b; x2 h# o0 U5 r& Dresponse has been considered as local or systemic. With this
2 l# y) C( D7 J' o' \# lin mind we studied 5 children with microphallus for response$ |- T" T) u4 b# {. o2 F
to gonadotropin and to topical testosterone independently.
' p4 X5 v+ L3 h! fMATERIALS AND METHODS2 E8 f6 \; F& U0 K; b- o+ e
Five 46 XY male subjects between 3 and 17 years old were
1 ~: D1 Z# M9 |evaluated for serum testosterone levels and hypothalamic
3 j0 Z6 E9 I3 Lfunction. Of these 5 boys 2 were considered to have Kallmann's1 A0 v: }/ P( _! ~4 l5 z0 C
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-* t4 R- l% t" P
lamic deficiency. After evaluation of response to luteinizing" }& q1 d) M7 }8 U6 R. l
hormone-releasing hormone these patients were treated with8 T- s9 B% \) N7 l; ]* r# @
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
( L+ t; F2 q* Z! z: C9 U+ |after completion of gonadotropin therapy 10 per cent topical
. Y' Q" ~6 ]/ ]4 Ktestosterone was applied to the phallus twice daily for 3 weeks.# T3 a' V* }1 V- b
Serum testosterone, luteinizing hormone and follicle-stimulat-
6 h! a* P4 n. n: b5 x6 ]ing hormone were monitored before, during and after comple-) x8 W/ y) I( @' V" c" ]) V+ A
tion of each phase of therapy. Penile stretch length was
0 F8 P( d7 [* n' e `) ]9 v( |+ R* Iobtained by measuring from the symphysis pubis to the tip of: Q* ]1 e5 t# x$ l3 ?7 }
the glans. Penile circumferential (girth) measurements were% P" X3 R3 [, O7 s8 h! g
obtained using an orthopedic digital measuring device (see
+ F( a, n) w3 T/ g: \) D# Qfigure).
! o8 e, P, S6 r$ Q0 r& nRESULTS Q' H. P# Q; T9 p$ m9 m
Serum testosterone increased moderately to levels between0 c# D5 y- k' d; P/ P
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
% {" o& a* E2 ]" Tterone levels with topical testosterone remained near pre-7 R! C( {7 ~4 z! r& M* F" ^
treatment levels (35 ng./dl.) or were elevated to similar levels
( R. x" z( M6 z$ W; `% m2 z; [$ Gdeveloped after gonadotropin therapy (96 ng./dl.). Higher; n. X( P1 ]5 Q' F: o; T9 O
serum levels were noted in older patients (12 and 17 years old),$ Y5 ?/ T4 _3 R, X4 b
while lower levels persisted in younger patients (4, 8, and 101 _3 @- q7 o1 C! b. z! ?1 J
years old) (see table). Despite absence of profound alterations; u4 P" h& q+ M; l& L0 D/ R
of serum testosterone the topical therapy provided a greater
. b; h' [( H: p; N9 X/ \8 XAccepted for publication July 1, 1977. ·: S* h; J7 y& j
Read at annual meeting of American Urological Association,
9 v; U" X7 L8 HChicago, Illinois, April 24-28, 1977.8 D2 y0 H+ @2 _2 w
* Requests for reprints: Division of Urology, Henry Ford Hospital,' }/ C% B" J- x: ~
2799 W. Grand Blvd., Detroit, Michigan 48202.8 y5 [2 j3 s! c8 w, d b8 j
improvement in phallic growth compared to gonadotropin.
5 t7 b6 c% s# z" s+ u; L7 `8 DAverage phallic growth with gonadotropin was 14.3 per cent
4 p4 S( S7 D8 ^8 w" Wincrease in length and 5.0 per cent increase of girth. Topical
+ R! {: e. h( Z) x6 A! rtestosterone produced a 60.0 per cent increase of phallic length
5 f, j% M) S6 land 52.9 per cent increase of girth (circumference). The
, h# m* T- l" D$ k1 v( M9 vresponse to topical testosterone was greatest in children be-
8 T6 c! x% R9 Qtween 4 and 8 years old, with a gradual decrease to age 178 U6 x5 v; c& Y8 ^8 R- Y8 p4 O
years (see table).! Q' Y/ G [+ `" i/ r4 q' G1 S
DISCUSSION
0 M' u* W! q! X- ^3 ]* X2 W; vTopical testosterone has been used effectively by other
( r5 k3 F/ w: e6 }3 {/ q) Cclinicians but its mode of action remains controversial. Im-- b/ L- D8 Z* L# \7 {" L3 h
mergut and associates reported an excellent growth response
$ w; P4 o& O6 u2 [6 Cto topical testosterone with low levels of serum testosterone,0 g' g; v5 H5 ~$ L0 {# `- J
suggesting a local effect.1 Others have obtained growth re-8 Y" v5 A1 f3 ^& |0 b
sponse with high. levels of serum testosterone after topical
. f5 q; z! m9 xadministration, suggesting a systemic response. 3 The use of
. F2 l$ l, p, `# Ngonadotropin to obtain levels of serum testosterone compara-
3 d; H4 Y4 A# ~( K1 {$ y: _- X3 lble to levels obtained with topical testosterone would seem to* Q# l9 u3 U5 E4 X" A! E) k
provide a means to compare the relative effectiveness of1 S% O8 e; }! q0 Z; f
topical testosterone to systemic testosterone effect. It cer-
1 O' K( `# m7 z; Mtainly has been established that gonadotropin as well as par-+ T& _/ z, Z/ a9 x. O5 q
enteral testosterone administration will produce genital
7 t2 V* s9 q! S( n/ |# ^; n9 zgrowth. Our report shows that the growth of the phallus was( |% R% I' L# N9 N
significantly greater with topical applications than with go-
, ]0 K5 m6 j& T# l. j& `: \! |nadotropin, particularly in children less than 10 years old.' z7 u6 u5 a7 {3 K5 D5 Y# D
The levels of serum testosterone remained similar or lower- ]5 G5 s" N: p0 A( `% u+ p
than with gonadotropin during therapy, suggesting that topi-+ w- M2 h/ i! [3 r2 z
cal application produces genital growth by its local effect as
_" b" p6 `$ n# Owell as its systemic effect.+ x$ f" [! [ X0 Y" v
Review of our patients and their growth response related to
5 t' n+ U u4 W9 r: eage shows a greater growth response at an earlier age. This is
: C" k1 V, g$ E5 Sconsistent with the findings of Wilson and Walker, who
- N z X- P" }+ q& ?+ Xreported an increased conversion of testosterone to dihydrotes-' d! P, R, ~: e9 e
tosterone in the foreskin of neonates and infants.4 This activ-) N5 \* v3 t- b% F$ s# L! B; w
ity gradually decreases with age until puberty when it ap-0 E2 P( z0 b. t; _/ U
proaches the same level of activity as peripheral skin. It may
, @, }: d! }& h$ @) e: U# Nwell be that absorption of testosterone is less when applied at1 x4 V% a( B' q3 l* \! ^ i4 d
an earlier age as suggested by lower serum levels in children4 [, P* A: m7 W: |& P
less than 10 years old. This fact may be explained by the5 N8 A. ~/ y' n' \
greater ability of phallic skin to convert testosterone to dihy-
! T, N; O# O' x jdrotestosterone at this age. Conversely, serum levels in older
: ~+ F9 `+ t1 j+ x* a1 cpatients were higher, possibly because of decreased local' l1 @" Z* h; K0 Z: `+ ?
667
2 Y$ e$ C m! {668 KLUGO AND CERNY$ N m# ]! }9 k% M( Q- N. g
Pt. Age7 L& N. S4 {' g) I/ ~
(yrs.)- X7 }8 t: p% P% `
Serum Testosterone Phallus (cm.) Change Length
3 A1 `7 |4 D6 O" u# s) e: g A5 h(ng./dl.) Girth x Length (%)4 N" B0 x+ U8 M5 g( \6 X5 r, E
4
F+ [ u% g8 `& z' A! g% ?$ a6 l" q8
% g4 ~5 k- m% P" R* o7 |$ J102 a1 g; X. f4 f9 a9 T/ @$ p
12
: x1 _9 G3 x) p8 |( v17
; w3 r1 ~9 F6 w( x/ DGonadotropin
* ] i* b( b, ]8 F( X W$ c71.6 2.0 X 3 16.6
) Z! M% |' I l# O6 @50.4 4.0 X 5.0 20.03 ~1 O) U) k& R7 r/ ]- s7 y4 h
22.0 4.5 X 4.0 25.0
+ H, a+ z0 I3 C, ^84.6 4.0 X 4.5 11.1) p6 L9 @7 G2 k+ s6 g a
85.9 4.5 X 5.5 9.00 H, O5 G6 h Z# K4 J S3 m! D
Av. 14.3
& V/ [, o. B: o: a7 g$ L. D, L45 W& I: k8 N- V. K& ~
8
/ A* o6 d- i/ m% X5 f10
! I9 z( z+ f+ m9 O: R12
2 e8 M2 r7 i" `* e17# x& L# G3 {- ]2 R
Topical testosterone
3 T; z. d1 l, E3 c) b34.6 4.5 X 6.5 85, j8 Q+ l& r" P6 b8 j9 ~: N4 _
38.8 6.0 X 8.5 70; V, Z0 X/ F5 E+ @6 y
40.0 6.0 X 6.5 62.5$ E# R. `) S# F" A1 @4 ^7 d2 k- `7 p
93.6 6.0 X 7.0 55.5
/ I! w* n% _, D$ ^7 p0 s5 b( {% P95.0 6.5 X 7.0 27.2
/ N# Z$ u( H& [4 D. vAv. 60.0
( l. E$ C3 O! F( s7 W+ pavailable testosterone. Again, emphasis should be placed on% F% }) j- h. K+ c) F, d, Z
early therapy when lower levels of testosterone appear to
* K* B* I. d y/ t9 {* i: V( Eprovide the best responses. The earlier therapy is instituted
' u; ?" L4 ?8 @the more likely there will be an excellent response with low3 e2 d/ ~3 p- U7 ^+ R- S9 P# s
serum levels. Response occurs throughout adolescence as2 i3 ?# X7 }+ H/ N9 b) x
noted in nomograms of phallic growth. 7 The actual response
2 d V3 k D5 s: q$ G- }to a given serum level of testosterone is much greater at birth% G/ f% K5 |' m( r0 H" p
and gradually decreases as boys reach puberty. This is most
0 c% u3 M; w: t. b4 ?likely related to the conversion of testosterone to dihydrotes-1 Y( ~7 e3 ^ j7 d' ?3 v+ Y, }
tosterone and correlates well with the studies of testosterone" M& z$ N& \3 x8 u2 b
conversion in foreskin at various ages.
! ?9 {$ \: B& I. `/ R6 s8 L1 `The question arises regarding early treatment as to whether
2 n8 s: l& N4 _) V2 n e. K) Vone might sacrifice ultimate potential growth as with acceler-% V6 }6 D. x W- K% p; N, [
ated bone growth. The situation appears quite the reverse2 i2 z! o/ u7 l1 W; H6 [2 F
with phallic response. If the early growth period is not used' G8 q3 Z& g. h5 }) I
when 5a reductase activity is greatest then potential growth$ n+ q# E% E" K% y, R
may be lost. We have not observed any regression of growth
* R$ a% v, y3 ]. iattained with topical or gonadotropin therapy. It may well
' T; q# j H2 I* Mbe that some patients will show little or no response to any& p& U$ V+ N0 T
form of therapy. This would suggest a defect in the ability to
8 a5 c7 p& a, x/ e1 V. Econvert testosterone to dihydrotestosterone and indicate that
4 a0 M" c2 v1 Q$ G# Jphallic and peripheral skin, and subcutaneous tissue should
- C2 |) Q3 S0 \& w2 Gbe compared for 5a reductase activity.
* H; t6 R3 x) CA, loop enlarges to measure penile girth in millimeters. B,4 f, K! O! h: I% k7 n% F# J
example of penile girth computed easily and accurately.
' O- l% r* D1 e P3 }conversion of testosterone to dihydrotestosterone. It is in this
) S5 h' c7 _) Jolder group that others have noted high levels of serum
4 p+ v6 Q: U u3 Xtestosterone with topical application. It would also appear
; f9 Z% P! p2 Z3 ythat phallic response during puberty is related directly to the3 n& t8 y- |7 S4 n
serum testosterone level. There also is other evidence of local3 t7 m1 l9 O5 |8 E @
response to testosterone with hair growth and with spermato-
e" J; i" J) i. l3 E+ ` agenesis. 5• 6! B& X0 x+ h; D r% G) H2 ~4 w
Administration of larger doses of gonadotropin or systemic
! m, }9 W0 h4 c i2 k% h) b8 o; \: Ktestosterone, as well as topical applications that produce2 ^7 z: d# t6 t8 i+ K$ \# J A& V
higher levels of serum testosterone (150 to 900 ng./dl.), will
8 A0 D7 C* `. x& y' z! Xalso produce phallic growth but risks accelerated skeletal$ X% y- R0 e. z4 \
maturation even after stopping treatment. It would appear" N3 [ J( e% [* R' U2 O! C% Y- [
that this may be avoided by topical applications of testosterone6 X! d4 S! _! P0 A
and monitoring of serum testosterone. Even with this control
. c1 r: A* ~: x2 N) Z" b- mthe duration of our therapy did not exceed 3 weeks at any7 ^) y$ O$ O/ f0 q2 r. G+ g8 `
time. It is apparent that the prepuberal male subject may
$ c+ p4 w( q1 w' fsuffer accelerated bone growth with testosterone levels near
5 x! {8 H3 [6 a7 m3 r& Z0 R200 ng./dl. When skeletal maturation is complete the level of |9 E7 {7 k; e( e* m. [2 [
serum testosterone can be maintained in the 700 to 1,300 ng./1 Z, G# k- H! m, I U# v
dl. range to stimulate phallic growth and secondary sexual1 ^; ?2 }6 S8 p, {5 a9 \1 u
changes. Therefore, after skeletal maturation parenteral tes-# {+ \# d- {, t. x4 z( T7 s
tosterone may be used to advantage. Before skeletal matura-
& [' r$ Q4 l3 S$ `tion care must be taken to avoid maintaining levels of serum
0 ]5 t& y x$ I/ @& _/ F4 Gtestosterone more than 100 ng./dl. Low-dose gonadotropin$ A1 V; S. d, Y( _" Q4 ^. C4 {
depends upon intrinsic testicular activity and may require; P' L4 X; M. O T G; U: W
prolonged administration for any response.& Q7 S c. [6 H. v+ I' B2 g
Alternately, topical testosterone does not depend upon tes-
- Y" d5 L) ~% i8 w& R) f1 gticular function and may provide a more constant level of* u! Y$ S$ d+ C3 o, V6 u
REFERENCES$ r4 v4 O" E/ m% r" U
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,% p8 B* b Y) r, B% g; H, y
R.: The local application of testosterone cream to the prepub-/ _# i6 d+ k& V9 c
ertal phallus. J. Urol., 105: 905, 1971.( P' m% p* W9 Q1 I+ W
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone( A, d$ V9 f3 F3 p
treatment for micropenis during early childhood. J. Pediat.,, f: l% w4 x, M% D. C z) f
83: 247, 1973.. s4 }& u0 O+ F3 ~& P$ k
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
g$ p! o7 |! D5 F1 Aone therapy for penile growth. Urology, 6: 708, 1975.
- `+ A$ Y' n* m6 }4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone4 w5 c4 R1 u8 Y ^5 |, M
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by2 N+ I3 I% H3 G9 I6 U
skin slices of man. J. Clin. Invest., 48: 371, 1969.6 T' O* ^: Y5 c p0 s
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
. N w9 k& e6 bby topical application of androgens. J.A.M.A., 191: 521, 1965.7 |! S$ O+ v) J. l! [) }0 E
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local) n7 P8 k6 [ x% O3 {
androgenic effect of interstitial cell tumor of the testis. J.( s' Q# z* j' c5 x" A
Urol., 104: 774, 1970.) ~+ N" a: e, m! \6 P
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
7 p$ A; d- r& U3 [: G- X, e% {tion in the male genitalia from birth to maturity. J. Urol., 48: |
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