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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
$ H- Q& E L. x! z) G- t9 H# GGONADOTROPIN
5 F# I9 r1 a q& iRICHARD C. KLUGO* AND JOSEPH C. CERNY" `2 \+ Y2 {3 Y9 z2 P
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan. q0 ^) f4 s# G9 \* T$ v) L* R
ABSTRACT9 f- ^) O7 _3 D4 \4 E( W
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
8 |. h& h7 @ e+ p8 _5 Vwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
" b) _" U% W* xtropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
5 y% _5 m2 Q* f" {7 f" Y! dcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent8 R0 \+ q/ z. [
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
4 ]2 U6 u$ a |& C, u+ qincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average1 h/ i0 E! m8 y X/ f
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
' m1 \/ |# P. ?occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
5 Z: l5 K2 b$ }! l1 K. w% nstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
: Y- h) O3 _8 e6 X% \/ c! wgrowth. The response appears to be greater in younger children, which is consistent with previ-
4 V3 ^% X3 v# y7 ?0 i1 h, K: w# F$ rously published studies of age-related 5 reductase activity.
' |8 t0 Y: c: l7 W! {* w6 [: c2 M5 @Children with microphallus regardless of its etiology will
/ t$ s" [& U+ l' l( I1 G4 Erequire augmentation or consideration for alteration of exter-& [% C. x# ]* p5 n L
nal genitalia. In many instances urethroplasty for hypo-+ k. Z* @: ]* o0 N" p1 c' n
spadias is easier with previous stimulation of phallic growth.
- p" J: C; D5 o! yThe use of testosterone administered parenterally or topically
+ h) U' ~; t' [has produced effective phallic growth. 1- 3 The mechanism of
4 H) w% b& Z3 J% gresponse has been considered as local or systemic. With this4 p4 _7 _ y" K- x
in mind we studied 5 children with microphallus for response7 x6 }! o0 T7 b
to gonadotropin and to topical testosterone independently.
" e" }( i: O7 m* IMATERIALS AND METHODS
1 }! k8 T8 s, KFive 46 XY male subjects between 3 and 17 years old were0 _3 T& N/ E. T* V: D0 h8 M
evaluated for serum testosterone levels and hypothalamic
4 Z4 d& w' i! {6 o& J& ufunction. Of these 5 boys 2 were considered to have Kallmann's
. M3 K% a, `: w/ o" O% L3 Z/ Ysyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
" Q0 x1 E& r& L% K+ Vlamic deficiency. After evaluation of response to luteinizing# _( D! ~$ g( M/ [
hormone-releasing hormone these patients were treated with: i. r" ^" j2 `, j
1,000 units of gonadotropin weekly for 3 weeks. Six weeks) E5 Z: |, g* M6 l2 `% C
after completion of gonadotropin therapy 10 per cent topical
' q" r# K& p0 Vtestosterone was applied to the phallus twice daily for 3 weeks.1 j" n. P9 [7 E
Serum testosterone, luteinizing hormone and follicle-stimulat-
( a( b7 I# ^- N. W$ U/ Ying hormone were monitored before, during and after comple-
7 U' s2 _" a- d" [5 xtion of each phase of therapy. Penile stretch length was
; ]3 K5 M, s4 N$ tobtained by measuring from the symphysis pubis to the tip of
: p# H& y; |* qthe glans. Penile circumferential (girth) measurements were S4 C& k g% R: }8 s$ r3 [- f9 \
obtained using an orthopedic digital measuring device (see- w6 E& r9 G7 ?5 \
figure).
& R: _4 H {2 `0 I4 u; \* _- A& oRESULTS
0 c: |8 F$ o: o# R" a" e' _* |* J* zSerum testosterone increased moderately to levels between( T% _) i. ]/ b
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-9 j* W2 G5 D6 D
terone levels with topical testosterone remained near pre-
( g4 E! d% O2 A. [1 F- ftreatment levels (35 ng./dl.) or were elevated to similar levels
4 x! w3 }$ N, h9 N2 b: zdeveloped after gonadotropin therapy (96 ng./dl.). Higher
" [+ ^: o% N- [; S% Dserum levels were noted in older patients (12 and 17 years old),& Y/ T) q: Y3 ?
while lower levels persisted in younger patients (4, 8, and 10
9 \: R) E5 S1 z, Xyears old) (see table). Despite absence of profound alterations
) y5 b2 r1 `* _of serum testosterone the topical therapy provided a greater
" A* \' ?' U" F' X# i2 BAccepted for publication July 1, 1977. ·
7 F) ~& B; }* T* Q6 T! PRead at annual meeting of American Urological Association,, B; U* }; l$ e; h X8 b
Chicago, Illinois, April 24-28, 1977.. s. v5 A3 j5 A- O5 T. d
* Requests for reprints: Division of Urology, Henry Ford Hospital,
7 B3 d! |! x+ g6 u$ Q0 t6 G2799 W. Grand Blvd., Detroit, Michigan 48202.% o) Y" _( F; W9 R$ V8 H/ d
improvement in phallic growth compared to gonadotropin.
6 h- i( l: V* ]. [8 j3 ^9 O) k5 pAverage phallic growth with gonadotropin was 14.3 per cent, v3 A7 k3 U8 [7 a0 e, |; X0 E% M
increase in length and 5.0 per cent increase of girth. Topical
# h& z# M2 b- f3 ?testosterone produced a 60.0 per cent increase of phallic length8 T. ~2 V I2 u9 w. y7 r* K2 C+ k
and 52.9 per cent increase of girth (circumference). The5 T$ L7 S9 P. S* r3 ~! e
response to topical testosterone was greatest in children be-9 f, Y8 h' k( a% @% {( z
tween 4 and 8 years old, with a gradual decrease to age 17
6 H5 Y. H$ B) w& s. j$ R4 lyears (see table).
- P2 S. I0 V( { r( FDISCUSSION3 q2 p. @+ B# Z
Topical testosterone has been used effectively by other$ d8 r, Q, m* ]) F
clinicians but its mode of action remains controversial. Im-& M3 s: A# H' m. Y. G' M! p: J
mergut and associates reported an excellent growth response6 R5 f5 x$ v$ ~0 J' H3 n
to topical testosterone with low levels of serum testosterone,- A" V5 k" I/ W. r. s0 ?! q
suggesting a local effect.1 Others have obtained growth re-/ j4 c$ e' D# m
sponse with high. levels of serum testosterone after topical
6 f& b3 U B2 k8 O/ M3 g/ ~administration, suggesting a systemic response. 3 The use of/ N" _4 K4 r) J9 D. c9 a& ?
gonadotropin to obtain levels of serum testosterone compara-
4 f* R/ ]: r* \- l6 k3 f1 Uble to levels obtained with topical testosterone would seem to( \; p3 }4 a5 t( a7 I
provide a means to compare the relative effectiveness of# J. A( X) E, P* p$ w
topical testosterone to systemic testosterone effect. It cer-
0 a) d& n, S" e( Itainly has been established that gonadotropin as well as par-
5 x/ Q: w" j' q* K* `! {enteral testosterone administration will produce genital
z! K6 s8 n0 {; M: l5 }growth. Our report shows that the growth of the phallus was
6 {( O' I f) _$ Z1 y: l3 Esignificantly greater with topical applications than with go-
8 F0 ~" X( v1 ?8 @/ n+ Fnadotropin, particularly in children less than 10 years old.
+ Y/ Q8 j; l: P! d1 h' fThe levels of serum testosterone remained similar or lower
9 L% z6 a6 s6 H( s3 Z: {than with gonadotropin during therapy, suggesting that topi-
3 n5 Y7 C- e8 ]; s( n( tcal application produces genital growth by its local effect as4 \+ P" P W5 X9 E) U7 r/ H" @
well as its systemic effect.% i: `+ y) E# {6 e, \! b
Review of our patients and their growth response related to
( A. a7 H2 m8 z) }# s* C, |" i/ W: jage shows a greater growth response at an earlier age. This is2 |, t& b, X+ f1 B1 w6 J; r" u
consistent with the findings of Wilson and Walker, who
/ V0 @! w: k4 ?. @9 p) _+ M8 d1 xreported an increased conversion of testosterone to dihydrotes-
6 e- Q. H, k7 V2 ?$ m" B3 f5 gtosterone in the foreskin of neonates and infants.4 This activ-( a, ?1 \, N: d4 c
ity gradually decreases with age until puberty when it ap-9 k" }$ _& m5 M& Y
proaches the same level of activity as peripheral skin. It may, Q; f/ z1 |3 l$ r
well be that absorption of testosterone is less when applied at1 [" I5 I" }7 K/ V/ F
an earlier age as suggested by lower serum levels in children
m+ j7 O L- @: ~7 k: {5 U Yless than 10 years old. This fact may be explained by the! e# K9 x; L* l; ?6 A: q* q) I
greater ability of phallic skin to convert testosterone to dihy-8 k3 E2 w( B( h0 R) X0 q, E
drotestosterone at this age. Conversely, serum levels in older8 p' L0 _ J; u
patients were higher, possibly because of decreased local3 w( k* Z7 x6 U6 y: l9 c4 h# V
667* C4 ^ \5 t1 e
668 KLUGO AND CERNY
% c$ a$ z4 X5 ~+ R( s. @% L6 sPt. Age# q$ A8 H' [3 P# n5 Z5 T2 X& s$ z
(yrs.)
/ p+ ?9 t# z( B6 E% E8 dSerum Testosterone Phallus (cm.) Change Length
2 L* ~; W4 ]! }5 g0 ^(ng./dl.) Girth x Length (%)
2 V! _. ]- n2 {0 {7 o2 T- b6 m4' K+ D# g" t$ ?$ V3 }) ~$ ]
8
$ R# h; Z* Y! N3 M3 G# _6 K10" Q5 P) u% g5 b) o
12
. O0 K$ f# q+ X( d; p) t ?17% K5 k+ V* j5 `9 e9 `
Gonadotropin! n s3 a0 f9 D, s
71.6 2.0 X 3 16.6
( j: `/ {0 I. R8 h( n/ |' I) Y50.4 4.0 X 5.0 20.0
0 H% I' i# x4 e" Z9 E7 B1 j22.0 4.5 X 4.0 25.0
* v. j$ ~0 A5 ~3 y& E84.6 4.0 X 4.5 11.1
: T' h: E' a8 Q9 ^85.9 4.5 X 5.5 9.0
, q2 P% d! K2 ^2 F! yAv. 14.3
6 e2 x* H- J, F3 A4 K49 O# L n2 ~9 a+ B
87 z8 X% Y- c0 ?' o, r
10
, U6 p. L. Y1 R/ R12' K( Y, J2 n. k$ [% r9 T+ ^
17, o: S ^4 B9 I" E: ?
Topical testosterone( p9 [; ?, s O# T+ P) O
34.6 4.5 X 6.5 855 A7 G6 e) Q5 u& l- e# U
38.8 6.0 X 8.5 701 F7 ~4 k# h9 Z% u& S& I; r7 s' T
40.0 6.0 X 6.5 62.51 }) W9 _0 ~6 k! g$ y& j! _
93.6 6.0 X 7.0 55.5
. G9 a0 ^: ^( j8 ?0 ^95.0 6.5 X 7.0 27.25 u- _1 s v- P2 P5 ?& {
Av. 60.06 d8 r5 a- n: u& b- b, t
available testosterone. Again, emphasis should be placed on2 ], D! J! K4 Z- X- O, c6 g
early therapy when lower levels of testosterone appear to7 W, a6 @6 }4 ]
provide the best responses. The earlier therapy is instituted; z- r2 }. R+ ?+ f0 S1 n) s; ?
the more likely there will be an excellent response with low% r! p. A! G. B* C
serum levels. Response occurs throughout adolescence as
8 z0 j' x- P1 Wnoted in nomograms of phallic growth. 7 The actual response; X0 D. O& J- r6 @$ N* g* x$ j
to a given serum level of testosterone is much greater at birth' F6 o/ e% {3 x4 g! O
and gradually decreases as boys reach puberty. This is most
2 d4 k( e S% @7 V) hlikely related to the conversion of testosterone to dihydrotes-
$ L" x8 }! |, G& O8 P& f8 R5 F+ ftosterone and correlates well with the studies of testosterone
8 i5 P5 }' I1 \8 Qconversion in foreskin at various ages.% Z W7 g! A/ ^, a. u
The question arises regarding early treatment as to whether Q# A, [) W/ R6 P" A
one might sacrifice ultimate potential growth as with acceler-
: e; ?& t; k7 o; p# X8 V% \1 Uated bone growth. The situation appears quite the reverse- G4 H8 F& Y% E e, b
with phallic response. If the early growth period is not used* M$ u* q8 m5 q# \; m7 \+ | w4 g! _% E
when 5a reductase activity is greatest then potential growth& a Z# d. a. c5 ]- Z
may be lost. We have not observed any regression of growth2 t8 \- m( h" U' ]
attained with topical or gonadotropin therapy. It may well, w; \( p* E' W ?& P& g3 e. r
be that some patients will show little or no response to any: g8 q% M. }6 Y
form of therapy. This would suggest a defect in the ability to3 I0 I; C! D6 @0 Q; O* C/ A9 {
convert testosterone to dihydrotestosterone and indicate that
" C' w6 x! ^: s& y9 }5 ?1 n0 ophallic and peripheral skin, and subcutaneous tissue should. } D, e2 H8 |8 d0 y' K4 I
be compared for 5a reductase activity.' X9 H u3 e+ W0 c3 E# d2 v
A, loop enlarges to measure penile girth in millimeters. B,6 W' Y6 G% P! h% ]- y3 g
example of penile girth computed easily and accurately. I& l2 H3 ^5 Y K
conversion of testosterone to dihydrotestosterone. It is in this9 Y/ ?- Z0 b9 n1 P" {' Q- k
older group that others have noted high levels of serum( |8 P/ S* Q4 u
testosterone with topical application. It would also appear
3 h* L% D7 ]1 s! [* hthat phallic response during puberty is related directly to the
! w! k& e" l5 _1 h, b( l. nserum testosterone level. There also is other evidence of local2 ?+ v' @0 f: z
response to testosterone with hair growth and with spermato-
& D3 u& c$ T. N2 Y! q) P! n; l9 Cgenesis. 5• 61 z; F+ N/ q8 _8 ?; K/ `8 V6 G7 g
Administration of larger doses of gonadotropin or systemic
0 u, l1 u. [" z4 C* Atestosterone, as well as topical applications that produce
/ ^; u# M+ X- ~& q6 \4 Dhigher levels of serum testosterone (150 to 900 ng./dl.), will
# `0 ~. s8 K/ q- j7 xalso produce phallic growth but risks accelerated skeletal. M8 \7 [/ m) @# v* B8 f
maturation even after stopping treatment. It would appear
8 z/ {2 N# A5 ythat this may be avoided by topical applications of testosterone
- e' K1 ~7 C! h" M# G2 mand monitoring of serum testosterone. Even with this control
2 h- q+ E) e. b3 x. t5 j( jthe duration of our therapy did not exceed 3 weeks at any3 b8 [& G/ i) v3 @' {( x! B d
time. It is apparent that the prepuberal male subject may
0 {/ |9 T8 z: I, Vsuffer accelerated bone growth with testosterone levels near9 P& P/ i; r4 W/ @% P- T4 b
200 ng./dl. When skeletal maturation is complete the level of
d, d+ p4 w. a, G( ?serum testosterone can be maintained in the 700 to 1,300 ng./
" B$ ]$ b) I/ y4 U# x' Ndl. range to stimulate phallic growth and secondary sexual
. N) S, l- w( a/ |! p. K7 xchanges. Therefore, after skeletal maturation parenteral tes-5 w7 ?4 G. y1 z) s
tosterone may be used to advantage. Before skeletal matura-
4 t( {6 Q! j5 w% \4 b, B, Ation care must be taken to avoid maintaining levels of serum
: j& X/ L9 x; V7 ]( C5 z' l& {6 |testosterone more than 100 ng./dl. Low-dose gonadotropin
4 `& \% j3 K, K6 F pdepends upon intrinsic testicular activity and may require
4 S' Z) \, A9 X* M" T* }prolonged administration for any response.! Q+ ]& |- }- j3 }) l) j
Alternately, topical testosterone does not depend upon tes-
6 _# e* J7 m6 c; Y& aticular function and may provide a more constant level of2 w/ i8 w6 G, K$ t6 [% a% X
REFERENCES; R; m6 X0 R" X; S6 [! [; G
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
# F* ~- A' Z- @ O8 T# d6 q) ?R.: The local application of testosterone cream to the prepub-
/ @, \/ u1 }+ m/ D! u& w" R. K1 r& fertal phallus. J. Urol., 105: 905, 1971.& b- H- N' R: ~: [% O0 X3 ^
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone' b* c( C0 m# Y0 \' c
treatment for micropenis during early childhood. J. Pediat.,
, e2 n. q. ^( w0 a2 @9 C83: 247, 1973.
9 p1 F8 G! E% X' H3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster- j( t( ~0 Q3 Y8 Q( ?
one therapy for penile growth. Urology, 6: 708, 1975.
! c0 N$ F0 E6 s2 m4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone A( d5 L6 F5 Q$ ~5 q5 o; p
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
, _; A# R2 d: f9 \: }; w" a% Pskin slices of man. J. Clin. Invest., 48: 371, 1969. q0 R9 }5 W' H3 S/ k
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
5 ]+ ]% s6 c) F3 B8 Pby topical application of androgens. J.A.M.A., 191: 521, 1965.
5 R. ?: G1 ?, L/ U6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
; }( ~2 @# G' I$ candrogenic effect of interstitial cell tumor of the testis. J.6 _- F, a3 S* h1 f
Urol., 104: 774, 1970.
1 Z5 |2 @; h* D; q+ }5 p0 h) i7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
1 h2 \) A$ y6 w2 l3 Mtion in the male genitalia from birth to maturity. J. Urol., 48: |
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