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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
" \! v) A( @2 A& Z" @+ dGONADOTROPIN
1 ?8 S) z+ o* S/ d' a! ?RICHARD C. KLUGO* AND JOSEPH C. CERNY4 O0 w L) w, Y: k
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
0 X( s$ \5 f; Z9 m3 P* i& z4 fABSTRACT
# e( X, a4 M% }0 }Five patients were treated with gonadotropin and topical testosterone for micropenis associated- b$ q0 v5 f$ s/ v7 D" f
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
+ \* s4 O% f' `) s2 p) c2 Atropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone) _" d2 V% Q5 O `# E% u/ c" }
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
; G% C6 R. C' k; X M, bfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
+ K; q9 O- @! l: a7 R# P5 zincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
% \2 w; _* K: q( eincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response; b9 s3 Y3 V% c! H2 i. y' z# Y
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
' w3 t, }, K# ~6 d& p) D, Zstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
& F- S A; X0 P1 b- N2 dgrowth. The response appears to be greater in younger children, which is consistent with previ-
5 K- L8 V5 i8 K( ^$ i0 {9 ]ously published studies of age-related 5 reductase activity.
4 @. X" }+ r2 n' r. ^2 N- ^Children with microphallus regardless of its etiology will; {& h2 R, T% s% c2 L
require augmentation or consideration for alteration of exter-
8 h I% O) F+ u! [* E& p0 @* k9 ^9 N3 enal genitalia. In many instances urethroplasty for hypo-
" m9 \, f, n6 w* r" \$ dspadias is easier with previous stimulation of phallic growth.0 b: O6 u. ]) g6 a0 U
The use of testosterone administered parenterally or topically
; T A; P; k6 w% o6 K4 xhas produced effective phallic growth. 1- 3 The mechanism of
- \! f& k& y" a2 presponse has been considered as local or systemic. With this
/ i/ [7 f" _* \, Din mind we studied 5 children with microphallus for response
( U- |- _9 s/ x: ^' \# Xto gonadotropin and to topical testosterone independently.
% ^ h/ \* v- d5 o* VMATERIALS AND METHODS( g+ @& ]) u) C5 N1 ~2 F
Five 46 XY male subjects between 3 and 17 years old were
# n# f, m& S7 i$ ]' C0 oevaluated for serum testosterone levels and hypothalamic
. |% t, q3 P/ y0 v" a: efunction. Of these 5 boys 2 were considered to have Kallmann's: ~7 B2 z( q6 N# _& v% }: x
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
' y- y8 n; w% A9 y. r! z2 p9 j& olamic deficiency. After evaluation of response to luteinizing
1 w6 U* s5 }, B# Y4 H# G) ^hormone-releasing hormone these patients were treated with
; ~& k# _. H$ {+ S) y4 \1,000 units of gonadotropin weekly for 3 weeks. Six weeks, o& ^8 W! ]& f2 b) X
after completion of gonadotropin therapy 10 per cent topical
, v& r2 S% x Rtestosterone was applied to the phallus twice daily for 3 weeks.: }- B7 R: p W. c8 n, Q
Serum testosterone, luteinizing hormone and follicle-stimulat-1 h/ [2 a) g5 h0 h
ing hormone were monitored before, during and after comple-& w) L( R# g' D
tion of each phase of therapy. Penile stretch length was; k# U0 M% n. E6 m
obtained by measuring from the symphysis pubis to the tip of6 f8 n0 J! ^' Y
the glans. Penile circumferential (girth) measurements were% J2 \0 c6 ?. d/ \
obtained using an orthopedic digital measuring device (see
+ s$ c# V# D& Mfigure).
4 }% U0 k+ U+ V4 ^RESULTS# |1 i/ p, I$ _( t
Serum testosterone increased moderately to levels between
) ?0 I6 K2 @! B: w50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-8 j9 R" R9 L5 w
terone levels with topical testosterone remained near pre-
% y+ Q4 ~, [" t8 |treatment levels (35 ng./dl.) or were elevated to similar levels3 ]! J6 ~; g& B) d+ [
developed after gonadotropin therapy (96 ng./dl.). Higher; R6 R3 E" F D0 q* {5 I
serum levels were noted in older patients (12 and 17 years old),
/ B7 w$ F8 `- B- hwhile lower levels persisted in younger patients (4, 8, and 101 K. v4 o4 g" V6 }2 |
years old) (see table). Despite absence of profound alterations% ?7 x2 T0 k, l, D1 ^; T
of serum testosterone the topical therapy provided a greater+ g; i6 C, H/ N
Accepted for publication July 1, 1977. ·
( C# z! v5 e% O: H# nRead at annual meeting of American Urological Association,
8 J( z6 z+ |, W `5 N/ tChicago, Illinois, April 24-28, 1977. E4 \# {) S4 \9 _- g
* Requests for reprints: Division of Urology, Henry Ford Hospital,/ ]8 k) W1 t, l6 D5 ~( Q' v4 F+ d* i
2799 W. Grand Blvd., Detroit, Michigan 48202.
3 u$ y7 w: b& a/ J/ ?2 D) }5 k' _improvement in phallic growth compared to gonadotropin.. o9 z! F; N9 W
Average phallic growth with gonadotropin was 14.3 per cent' z* \, a5 w" Q$ f
increase in length and 5.0 per cent increase of girth. Topical
" b" r2 w- t6 D# r9 `) n5 S7 V3 etestosterone produced a 60.0 per cent increase of phallic length
: k9 l2 B/ d; c5 h; }1 h# Vand 52.9 per cent increase of girth (circumference). The+ x: V5 H) ]3 |8 Z
response to topical testosterone was greatest in children be-
( w. O! T7 t8 O: Ltween 4 and 8 years old, with a gradual decrease to age 17
`$ U1 \9 Q' A2 ~5 Yyears (see table).
. h" e! B! v% {5 s: TDISCUSSION9 i/ i0 `; b9 V; b: E$ f1 Y
Topical testosterone has been used effectively by other( G1 g0 v+ {+ R$ c1 v
clinicians but its mode of action remains controversial. Im-
# j* w. U: ?9 @+ b# R3 @( Dmergut and associates reported an excellent growth response% `4 S& v) B Z7 j9 o: h8 C
to topical testosterone with low levels of serum testosterone,1 \1 e+ |# s5 x
suggesting a local effect.1 Others have obtained growth re-9 _6 u6 J$ k7 J) d: @$ @2 X
sponse with high. levels of serum testosterone after topical' \' x4 X* z& W; x
administration, suggesting a systemic response. 3 The use of& q4 ]5 z/ R4 t
gonadotropin to obtain levels of serum testosterone compara-/ u1 g$ Q8 h' `5 F1 Z d7 n8 E, J8 L) X
ble to levels obtained with topical testosterone would seem to
: C" ^# k* Z m! E- p) f% Dprovide a means to compare the relative effectiveness of9 p$ ~! w. g! K& W
topical testosterone to systemic testosterone effect. It cer-7 \* W: E% Z. T0 }- @3 f% b
tainly has been established that gonadotropin as well as par-
. \& v# f" }1 C+ L* }0 Senteral testosterone administration will produce genital
6 l I4 r: r( w4 w9 ugrowth. Our report shows that the growth of the phallus was" Q& d+ e7 p- J4 L) I5 m" G
significantly greater with topical applications than with go-: w8 {8 L3 U& m* `1 _# H( f
nadotropin, particularly in children less than 10 years old.
' R9 |8 L$ m7 t3 hThe levels of serum testosterone remained similar or lower5 _0 u) i' C4 l
than with gonadotropin during therapy, suggesting that topi-
. p. \! P: M. M: Y8 kcal application produces genital growth by its local effect as
8 Z/ @) k$ R8 Pwell as its systemic effect.
' G* V* |! D$ ~& R9 n. zReview of our patients and their growth response related to$ x. \" |- B% I; r: W+ }
age shows a greater growth response at an earlier age. This is6 u6 u9 g7 W- s% c" |9 z5 [
consistent with the findings of Wilson and Walker, who
7 E3 i* ^8 l7 V6 Mreported an increased conversion of testosterone to dihydrotes-
8 [! a/ X' W1 ttosterone in the foreskin of neonates and infants.4 This activ-
3 q$ C3 ^ u2 o- Mity gradually decreases with age until puberty when it ap-( _ ~) B% U/ h& n" _6 B1 p0 e Y
proaches the same level of activity as peripheral skin. It may
. W! g( ^; K* c1 W' owell be that absorption of testosterone is less when applied at+ ~" A% T# N$ l7 l+ k
an earlier age as suggested by lower serum levels in children
! l# j; q& m8 Kless than 10 years old. This fact may be explained by the) e- J! N5 l* x* K) w
greater ability of phallic skin to convert testosterone to dihy-: u: C" v5 p9 w& H
drotestosterone at this age. Conversely, serum levels in older
{# ~7 Y q9 T$ f2 h* j3 m7 r$ opatients were higher, possibly because of decreased local& _ B! A: M- p& a! M2 O N. t" k
667( t; L. e+ l5 J! u
668 KLUGO AND CERNY
( {1 C% b. T1 iPt. Age
2 T& {1 z: g" V" G1 y) Q(yrs.)
# }: s) `( m, Y8 l- S: LSerum Testosterone Phallus (cm.) Change Length
N3 L/ }7 f. [* A(ng./dl.) Girth x Length (%)0 c# e! S1 L H
4
/ q! n3 ]9 ^5 B0 u6 \2 `8
- t* N. U2 ~9 h+ _2 n9 w2 {4 h; i10
6 d* Y: V4 ^' H' D; c12
; ]: U5 I. a8 W% u4 a/ S; q17
) }/ K* }9 t5 ^, d3 h3 aGonadotropin
' O0 p. u) v" b h& h71.6 2.0 X 3 16.6
1 B$ U u3 z/ ^) j1 o4 s& I) m50.4 4.0 X 5.0 20.0
l9 p! s7 }' a* s' J; ~22.0 4.5 X 4.0 25.0
4 t: I, ~* G' X* M( q7 G84.6 4.0 X 4.5 11.1
2 w" |+ O, F4 U+ [( Q- W( i85.9 4.5 X 5.5 9.0
8 l; E2 T( T! Y! b2 `* `7 [7 lAv. 14.36 ~: E2 S0 c# h% W/ _1 L
4
4 o; z% D" r6 u' P3 ^& p87 p W# F7 n$ P' f$ K
108 @1 a$ T$ U1 s3 W+ D' ~- P
128 ^+ e8 W* i7 @- F$ z; W! [
17- E6 i, F1 E$ E0 D$ d. c9 q/ o' P
Topical testosterone
) k r% ^' D8 A34.6 4.5 X 6.5 85
6 ~5 h. k& `# L; N) F38.8 6.0 X 8.5 70
, d# G& A8 r/ K) y40.0 6.0 X 6.5 62.59 h, ^1 J+ A; e- N9 {
93.6 6.0 X 7.0 55.5
; M X7 _% ~1 H8 S. {& }95.0 6.5 X 7.0 27.2
% I2 @- f& |( SAv. 60.0( d7 t- X' O# [4 x k% p
available testosterone. Again, emphasis should be placed on z' U" q8 C7 z o: [
early therapy when lower levels of testosterone appear to# s$ m, g0 m0 ?: M" l9 [0 K
provide the best responses. The earlier therapy is instituted+ v4 a5 q- ?# } r* y0 n* s: S
the more likely there will be an excellent response with low
; P! w u/ a" r0 xserum levels. Response occurs throughout adolescence as
) q& ]) a" j, ]noted in nomograms of phallic growth. 7 The actual response+ F1 t( N' G# `2 d
to a given serum level of testosterone is much greater at birth
$ m; B8 S1 |: s5 I* V land gradually decreases as boys reach puberty. This is most6 Q) |! W% {5 _8 f! ]% U. {+ @
likely related to the conversion of testosterone to dihydrotes-+ _+ I2 E, A2 T" n. m) Z. O
tosterone and correlates well with the studies of testosterone
4 K7 ]/ q1 X8 R. hconversion in foreskin at various ages.
; J0 O9 L7 x4 f/ a0 l8 tThe question arises regarding early treatment as to whether
G+ a, h+ J4 x; k1 ~' l& Qone might sacrifice ultimate potential growth as with acceler-
- \) G5 S, i7 R- y# g7 V' v4 R+ Tated bone growth. The situation appears quite the reverse
Y/ V2 c7 B: D7 a7 _7 ~7 I5 nwith phallic response. If the early growth period is not used1 [7 _- m7 v+ I* M( @' l
when 5a reductase activity is greatest then potential growth
/ v7 M7 }1 T- x+ H4 Zmay be lost. We have not observed any regression of growth3 Q# ?; _! o4 o9 S
attained with topical or gonadotropin therapy. It may well8 Y- E7 K" L/ C% j
be that some patients will show little or no response to any% v" f; {/ W; `! V0 L3 Z- S
form of therapy. This would suggest a defect in the ability to
0 j. ^1 V! o0 P+ t1 Uconvert testosterone to dihydrotestosterone and indicate that
+ k3 M/ F# @; `2 P1 i8 Tphallic and peripheral skin, and subcutaneous tissue should
) ^ P4 t" h0 I% `7 P U& Wbe compared for 5a reductase activity.* i+ U4 L6 n) e8 j7 l0 b. w" `9 P
A, loop enlarges to measure penile girth in millimeters. B,' q3 s1 b' ^, V. C% ~) @
example of penile girth computed easily and accurately., x6 e3 _% T' C: O- O
conversion of testosterone to dihydrotestosterone. It is in this4 y6 i% e1 B7 Y- b; K! w
older group that others have noted high levels of serum
/ y/ E$ J& @- d: }testosterone with topical application. It would also appear
$ y* o% i. l+ e6 F: Bthat phallic response during puberty is related directly to the
: m. O, f+ c f2 l, S& E* G! K& \5 xserum testosterone level. There also is other evidence of local
% T( g% L' R1 `, n `response to testosterone with hair growth and with spermato-0 I. y. d- r1 C3 w- J
genesis. 5• 6
$ u" A7 {$ v# f( R8 x! Z$ D5 |1 uAdministration of larger doses of gonadotropin or systemic
9 H+ b+ W6 `/ r# q9 b Ntestosterone, as well as topical applications that produce% ^6 g% M5 v: N+ b1 N Z- y: g
higher levels of serum testosterone (150 to 900 ng./dl.), will
9 o( @2 V6 {( ^! K" s( Y& X/ [1 {also produce phallic growth but risks accelerated skeletal0 I4 l4 v2 y7 U; N5 P' Y
maturation even after stopping treatment. It would appear
. ?: R/ e5 h8 K* S* [that this may be avoided by topical applications of testosterone
6 S2 T6 O. E* h" @- `/ ?! D: }and monitoring of serum testosterone. Even with this control, v9 @( D# o B! \) q$ c
the duration of our therapy did not exceed 3 weeks at any
& G; {8 A4 w8 y% O5 G$ utime. It is apparent that the prepuberal male subject may
& k$ h5 ]) r2 U% b4 Rsuffer accelerated bone growth with testosterone levels near/ R+ L1 Y3 K* e
200 ng./dl. When skeletal maturation is complete the level of
" V& Q/ H# h% |) ?- Z/ X2 P% L; b# d* C- Gserum testosterone can be maintained in the 700 to 1,300 ng./" `; @0 [3 X: N6 a* x2 T
dl. range to stimulate phallic growth and secondary sexual
$ x) v5 v+ @, g" j0 _changes. Therefore, after skeletal maturation parenteral tes-% t9 ?3 \" i! x0 X6 o7 z
tosterone may be used to advantage. Before skeletal matura-! d+ v' E1 m* K6 H" i
tion care must be taken to avoid maintaining levels of serum
0 Q, j; h1 u$ R$ R$ D& w5 K# Ytestosterone more than 100 ng./dl. Low-dose gonadotropin
" m9 e" b/ p# @depends upon intrinsic testicular activity and may require3 H" p, V6 B( |* {5 S
prolonged administration for any response.
9 y- b& o1 f2 p8 KAlternately, topical testosterone does not depend upon tes-
( }1 D+ b* d0 {ticular function and may provide a more constant level of
$ a1 R: h1 ^7 _REFERENCES9 O/ h5 K h0 W/ g z2 ~& K3 O
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
* Z4 n+ s( z! r) [" \R.: The local application of testosterone cream to the prepub-
+ i; z/ i; V# X/ rertal phallus. J. Urol., 105: 905, 1971.
$ w" r' [- u3 g# K" B2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
/ }+ K! J: z6 N; W itreatment for micropenis during early childhood. J. Pediat.,: j2 o; H' q1 k8 b
83: 247, 1973.
, ^6 c; O7 Z6 l: L) C3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-% k. u! w/ X1 ]8 \0 |( t# e
one therapy for penile growth. Urology, 6: 708, 1975.
- I/ M( }- D8 F3 T4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
3 d# O8 b" ]4 ?4 Pto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by+ V3 }7 {# s: Z' Y/ Y" S% d
skin slices of man. J. Clin. Invest., 48: 371, 1969.1 X) y; O# x. c+ B9 w
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth8 F# U4 ^+ a, ?- d* b
by topical application of androgens. J.A.M.A., 191: 521, 1965.
/ B" B" L* R/ e3 U. ?: i; I6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local, {/ s% E- V2 Q
androgenic effect of interstitial cell tumor of the testis. J.! B: a2 K3 }3 m( K/ ~ f
Urol., 104: 774, 1970.' F7 d% P7 G' f
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
- K6 j; T6 t# i4 l0 s' ction in the male genitalia from birth to maturity. J. Urol., 48: |
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