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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
' Y% X0 P" S4 q1 ]. N/ V; [0 s+ K& HGONADOTROPIN* B. x4 Z$ l# j* _* T
RICHARD C. KLUGO* AND JOSEPH C. CERNY+ o. E% b6 U- g5 R
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan) C# t0 E u a+ n3 k& v
ABSTRACT
0 y- R9 P* g; z& g" ?. BFive patients were treated with gonadotropin and topical testosterone for micropenis associated9 Q2 L* C: @% }* z2 A& \
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-2 ^ ^0 ?% T' B- ?3 T
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone6 d+ S$ R& H) J3 |
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent2 C- ?5 U" F& ^, k b
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
7 s. o* k2 ~! N9 W$ e/ rincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
: v+ k; t, z+ s3 I. b5 iincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
+ N1 A* c& l' I: d; noccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
$ q5 v$ B2 @/ R6 p/ |0 g; ~study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile, R7 j/ R: C- E; `! P
growth. The response appears to be greater in younger children, which is consistent with previ-
9 l) L8 C4 P! A, H. ]/ s8 o7 c6 Sously published studies of age-related 5 reductase activity.
- P' J/ U; W% vChildren with microphallus regardless of its etiology will( m* C9 r) A4 U
require augmentation or consideration for alteration of exter-# B+ s. R- J2 p3 F, Z1 y0 m
nal genitalia. In many instances urethroplasty for hypo-
3 ?, E" w1 j# ], cspadias is easier with previous stimulation of phallic growth.
% v* l3 k" U% R* H- }$ ~# CThe use of testosterone administered parenterally or topically1 P* a2 y" ` R+ r0 u
has produced effective phallic growth. 1- 3 The mechanism of
% W- s& ?. t9 l- Z8 presponse has been considered as local or systemic. With this* f2 b2 R# B3 N" g9 c/ M
in mind we studied 5 children with microphallus for response5 h: o0 Z% K6 y) b. v+ a$ I
to gonadotropin and to topical testosterone independently.( y: E% N C( g* G4 { S
MATERIALS AND METHODS
+ z4 T: L: m4 k/ oFive 46 XY male subjects between 3 and 17 years old were
& i: _: v8 T' z9 ~: M' Z( _5 nevaluated for serum testosterone levels and hypothalamic
( b. h% t$ \+ Y) o( sfunction. Of these 5 boys 2 were considered to have Kallmann's+ J, E8 \" K9 Q) U
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-: T# p9 e3 H% N4 _5 [* S! z
lamic deficiency. After evaluation of response to luteinizing
( p" r5 U7 p7 P- G4 s; \hormone-releasing hormone these patients were treated with$ Y4 x) c. g% Z* t8 Q0 c7 C
1,000 units of gonadotropin weekly for 3 weeks. Six weeks1 @6 r3 _3 C+ U1 u" r
after completion of gonadotropin therapy 10 per cent topical
1 X8 E5 r7 E7 W8 o+ ^testosterone was applied to the phallus twice daily for 3 weeks.
, ?3 s1 C9 h2 W' {! m! mSerum testosterone, luteinizing hormone and follicle-stimulat-# @$ p: `# V: G
ing hormone were monitored before, during and after comple- G) v: N0 X+ E! v7 u- r; q7 B3 i; ^
tion of each phase of therapy. Penile stretch length was& g b; v+ o9 a
obtained by measuring from the symphysis pubis to the tip of
& D. ^$ O2 e+ mthe glans. Penile circumferential (girth) measurements were
4 N* Z/ @, A" d I8 l% _, z7 Z7 O: gobtained using an orthopedic digital measuring device (see* O9 Z4 i* e! i
figure).# u! y5 E- H$ T
RESULTS8 I, h. n ~6 J" Z0 I; B, D3 }
Serum testosterone increased moderately to levels between) Q7 p3 C: r: h1 A# f" e
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-" J8 w! s3 _* ^ K0 y1 Q% B
terone levels with topical testosterone remained near pre-
2 n8 S, a+ t. y! Ntreatment levels (35 ng./dl.) or were elevated to similar levels7 A! f$ ^4 T8 z1 y( B
developed after gonadotropin therapy (96 ng./dl.). Higher$ I& e9 q: h+ x1 y
serum levels were noted in older patients (12 and 17 years old),* z6 M; \' p$ i! A# `% Y- F" C
while lower levels persisted in younger patients (4, 8, and 10! ]5 m/ g4 ^5 u: G7 P9 u
years old) (see table). Despite absence of profound alterations9 p# S0 D7 l1 d! `0 g0 k/ R
of serum testosterone the topical therapy provided a greater% @: h4 G3 w3 v o" `5 r( j4 [1 ~* B
Accepted for publication July 1, 1977. ·, ~% Q" C$ L! L' B2 u, t! \
Read at annual meeting of American Urological Association,* \2 s' X9 \ \- u% n$ w# u- S" v% a
Chicago, Illinois, April 24-28, 1977. V- D6 ]0 P3 X: e6 I! s
* Requests for reprints: Division of Urology, Henry Ford Hospital,
' k2 x$ R7 c E6 I2 x- d( _) I2799 W. Grand Blvd., Detroit, Michigan 48202.
& z* q' s3 b2 gimprovement in phallic growth compared to gonadotropin." }. c) F5 A; t+ @% Z; M7 m
Average phallic growth with gonadotropin was 14.3 per cent
0 |' s2 Y" ]4 Eincrease in length and 5.0 per cent increase of girth. Topical
/ C( K$ N' Z. Z) x Utestosterone produced a 60.0 per cent increase of phallic length
/ L8 M/ g4 R' u6 Fand 52.9 per cent increase of girth (circumference). The
4 T# A+ I1 I! d2 o3 N9 L o1 A4 Kresponse to topical testosterone was greatest in children be-" [, y+ i1 x) o0 V% Z! ]* i4 e+ N
tween 4 and 8 years old, with a gradual decrease to age 17* x5 P% J( u& Y* C2 K9 B0 R
years (see table).
* o4 |) `& F p- U5 Q/ g% O0 aDISCUSSION$ R( P2 ~! C0 [* h, `. n( G& i
Topical testosterone has been used effectively by other
* t, Y& }. t! `$ I" rclinicians but its mode of action remains controversial. Im-3 k( n. i, \/ J& U6 v; V
mergut and associates reported an excellent growth response
( v8 P" t& a* V; C3 I% eto topical testosterone with low levels of serum testosterone,3 ], v) [' Z9 ]7 m @5 K
suggesting a local effect.1 Others have obtained growth re-" m1 w7 ] n% o
sponse with high. levels of serum testosterone after topical( u9 r* I- q1 ^' B+ N) e" r/ k; E
administration, suggesting a systemic response. 3 The use of
) j8 H9 }* h2 @3 [! @gonadotropin to obtain levels of serum testosterone compara-
, R4 Q+ \5 I' ^: ?7 g5 @5 _" C0 Mble to levels obtained with topical testosterone would seem to" ^6 D6 N3 O. g% g# I( t* }
provide a means to compare the relative effectiveness of
! y5 S0 Z5 S; z! d5 u/ Ctopical testosterone to systemic testosterone effect. It cer-" G4 l% o9 [% W5 \
tainly has been established that gonadotropin as well as par-
5 |$ g0 H6 ]- k# {) Denteral testosterone administration will produce genital$ T5 h1 L* `4 [, M( y& H
growth. Our report shows that the growth of the phallus was
$ H3 k( ~( b- T. [0 ~, Bsignificantly greater with topical applications than with go-
! k% N3 H- B- h8 pnadotropin, particularly in children less than 10 years old.) U) i# Z0 C# K% y+ b8 I
The levels of serum testosterone remained similar or lower7 Q. Y* S+ W# x# C$ ?' Y4 G! T3 G
than with gonadotropin during therapy, suggesting that topi-
, X0 g M& C9 L& S3 [cal application produces genital growth by its local effect as
4 h2 C( [ w% C% t7 A, \& vwell as its systemic effect.
& C2 N' {; f' {* A5 @/ CReview of our patients and their growth response related to
8 v4 u: W2 z$ A8 l% v1 s* vage shows a greater growth response at an earlier age. This is3 n& N1 N. Z2 `1 b8 ?
consistent with the findings of Wilson and Walker, who
5 E6 F- [ c+ q% d) I- c2 g3 p f8 E; A7 Ireported an increased conversion of testosterone to dihydrotes-
) @7 p5 z5 p" Wtosterone in the foreskin of neonates and infants.4 This activ-
! D7 o6 L9 z5 O) fity gradually decreases with age until puberty when it ap-, v4 \% X) z& L; F% O
proaches the same level of activity as peripheral skin. It may: ]. V9 w5 h( H& n# h( h3 z
well be that absorption of testosterone is less when applied at
3 B3 Y7 {" q- t) R, |, M _an earlier age as suggested by lower serum levels in children
' O. Q2 q) L9 u' X7 u2 Kless than 10 years old. This fact may be explained by the
- R( L# K8 p* ?. pgreater ability of phallic skin to convert testosterone to dihy-( B: i5 w) G* T+ |% \
drotestosterone at this age. Conversely, serum levels in older
: Q- o5 E6 c! M* @6 M4 D% C y) mpatients were higher, possibly because of decreased local
) N& h' p: f) }. g5 P# `! q667
8 v7 R/ b9 \! o. I; E3 e" O668 KLUGO AND CERNY4 Z3 X/ R" p$ h' X. M
Pt. Age, p4 ?# ?8 {- v
(yrs.)
- ]" u( Q) `& D- F( CSerum Testosterone Phallus (cm.) Change Length, }; h& Y+ ^2 S: ^& {
(ng./dl.) Girth x Length (%)
# K8 C, ~, f& K2 j; M/ B4
) z( i$ C! A9 S: c) w# r8
, C1 L# Z* N1 V6 b( p103 D: M! i( N2 V$ i( P, O
12
i; C U% u, j, \17
4 X" P* }4 q- A2 n' U3 c! G' r, IGonadotropin, ?0 A% A! ?2 v R
71.6 2.0 X 3 16.6
! J! @8 Z8 G, o( @% `% x- }50.4 4.0 X 5.0 20.0/ w& Z. p- A" H/ u
22.0 4.5 X 4.0 25.0
7 S+ V, H( p3 s& M; I84.6 4.0 X 4.5 11.1
! f) F, [# u5 O( W5 G- `* v85.9 4.5 X 5.5 9.0
4 k2 T: J( E \$ ]; g5 a/ [$ `9 xAv. 14.3
_! ?2 G4 @8 p" c% |6 a4# i- y, m1 d/ k5 _
8! I& t P( N' X4 C2 ?! T
10
5 U1 E. F! H4 [12
5 q5 J# g: w/ l" {- H+ a* j: b17
5 r: h9 D# q( h6 YTopical testosterone
+ o/ I. C' y9 N4 }. H! B34.6 4.5 X 6.5 85* v* `- w- |% c9 ?* d# E
38.8 6.0 X 8.5 70
0 z& Q) ~4 B1 ?9 k40.0 6.0 X 6.5 62.5
$ x, c5 K8 z% ]93.6 6.0 X 7.0 55.5+ ~6 [/ ~; u# L: c+ L# f. s
95.0 6.5 X 7.0 27.2
$ }+ e! y: g3 J2 l9 `) GAv. 60.0
- x# G8 [/ b" u/ N1 R% Cavailable testosterone. Again, emphasis should be placed on) ]% J) u" ^; Q% g6 y
early therapy when lower levels of testosterone appear to" P7 A- [# h) l# m
provide the best responses. The earlier therapy is instituted
1 x! M/ [* m, [& Vthe more likely there will be an excellent response with low3 b' R: w9 w" i" H: N J
serum levels. Response occurs throughout adolescence as
% m. n4 C' S$ I, inoted in nomograms of phallic growth. 7 The actual response
) N8 e3 L4 w* j8 sto a given serum level of testosterone is much greater at birth
; e; s; I) g! \9 V/ s0 Z/ L4 Xand gradually decreases as boys reach puberty. This is most r. k" z6 |/ E
likely related to the conversion of testosterone to dihydrotes-; ]6 w. O4 S) a6 y
tosterone and correlates well with the studies of testosterone; c' M I- d/ c3 S! t5 L/ ?
conversion in foreskin at various ages.# R8 Y2 @- ?7 U% `- L7 ^1 }
The question arises regarding early treatment as to whether0 h$ e3 z) F: O5 A2 ^1 i) R4 j
one might sacrifice ultimate potential growth as with acceler-
( ~! h( A! q3 R8 r7 o. oated bone growth. The situation appears quite the reverse/ p* F2 v0 L1 l. s! }$ M
with phallic response. If the early growth period is not used7 j O+ `/ O2 r. b7 @4 x# F
when 5a reductase activity is greatest then potential growth
2 R w+ d% @& J, ]) w! fmay be lost. We have not observed any regression of growth
! V8 z) ^: { p8 wattained with topical or gonadotropin therapy. It may well2 Z. z3 f4 \7 X
be that some patients will show little or no response to any: J$ k$ i J2 a; `
form of therapy. This would suggest a defect in the ability to5 M. r+ Y0 d4 k
convert testosterone to dihydrotestosterone and indicate that
& f% L( U7 c% `5 sphallic and peripheral skin, and subcutaneous tissue should3 s: h+ {# Z, |0 u* ~4 |) p' b' y
be compared for 5a reductase activity.
. K5 A6 y: s3 n* PA, loop enlarges to measure penile girth in millimeters. B,
' p e( k. U vexample of penile girth computed easily and accurately.% P- I8 Q5 r$ e4 d1 W- u. b8 ?/ G
conversion of testosterone to dihydrotestosterone. It is in this5 }! I) _9 G2 B5 b. Q( Y0 Y
older group that others have noted high levels of serum3 z. s6 J- G, C1 ~ N! i
testosterone with topical application. It would also appear
, I( x/ j$ w+ A1 z7 P5 x& lthat phallic response during puberty is related directly to the
# S. D# R! \: l) u. Zserum testosterone level. There also is other evidence of local
d9 Q) o+ X" W% xresponse to testosterone with hair growth and with spermato-, e# O3 A% o3 ]' d {/ j
genesis. 5• 6
( ` v8 v4 c# k- c; v6 qAdministration of larger doses of gonadotropin or systemic
. d# V) _# ? p) ]testosterone, as well as topical applications that produce
6 ^! R( @, b. X& b- Khigher levels of serum testosterone (150 to 900 ng./dl.), will
; v8 k4 o) U' [; ealso produce phallic growth but risks accelerated skeletal
$ O$ N) l5 W j+ k' fmaturation even after stopping treatment. It would appear
P) j" r( N" v7 O8 x: ^, W8 lthat this may be avoided by topical applications of testosterone1 F5 B# S& H/ h# w& ~- A2 Z
and monitoring of serum testosterone. Even with this control
) e) v2 I0 e1 b0 l2 ethe duration of our therapy did not exceed 3 weeks at any' ]2 O. k0 |! l7 |. c( k! c9 j
time. It is apparent that the prepuberal male subject may
9 s$ E# ?; X G" @( k5 Ksuffer accelerated bone growth with testosterone levels near
* r: v- z! @* ^1 G200 ng./dl. When skeletal maturation is complete the level of- k) x" j: ]0 V" Z1 l
serum testosterone can be maintained in the 700 to 1,300 ng./
$ Y# T' ]( J/ Ndl. range to stimulate phallic growth and secondary sexual
* k( I9 g7 ?9 q, T7 U% Tchanges. Therefore, after skeletal maturation parenteral tes-
a$ M4 ?! w; ]tosterone may be used to advantage. Before skeletal matura-
0 m$ L) d/ D# X# N! J) V3 N9 Btion care must be taken to avoid maintaining levels of serum
! q4 K4 L, G, e% y- @( k0 @' S8 vtestosterone more than 100 ng./dl. Low-dose gonadotropin9 q; G9 R& k0 R- x: c( t8 [
depends upon intrinsic testicular activity and may require) S8 [; g0 r+ V6 ~( q! \4 U
prolonged administration for any response.
) b; M# ]: k/ Q) I+ U0 ?Alternately, topical testosterone does not depend upon tes-& f! y& D# X8 w, F4 }
ticular function and may provide a more constant level of
# E! y6 w2 v! H% p y y+ `REFERENCES
9 r2 R* N# q7 e4 D _# z& u1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
8 d: ^: L, o1 [9 G/ T: CR.: The local application of testosterone cream to the prepub-3 k+ U7 o3 i( D, ~6 `; _& m+ o- |
ertal phallus. J. Urol., 105: 905, 1971." @6 c9 F: V1 {+ s$ X2 L$ x$ e3 K
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
5 f ?! G/ I% w9 m; ztreatment for micropenis during early childhood. J. Pediat.,+ h% O7 U4 E4 e' k" @4 o
83: 247, 1973.
, i) Y9 V/ o" J3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
3 c- [ [7 b1 O* g# m1 Aone therapy for penile growth. Urology, 6: 708, 1975.
) O/ }1 V B- s+ q/ U# A4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
7 Q: [. ?0 i" _3 u/ t( A( n3 mto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by; d5 H7 O" v9 v$ B% k2 n. }( M
skin slices of man. J. Clin. Invest., 48: 371, 1969.
, V; k+ M+ U5 G4 N% M9 V7 ]" u5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth2 [# q x) L+ n* M* d/ ]
by topical application of androgens. J.A.M.A., 191: 521, 1965.
3 M9 L% h: l5 Q2 {- @% O* K$ ?% b6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
, Q- J; i. x' R, l9 Iandrogenic effect of interstitial cell tumor of the testis. J.
6 u1 J$ t, d0 S: \. }9 uUrol., 104: 774, 1970./ w% ^+ b* \( ? `
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-, t u+ _0 ]# w) O7 U
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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