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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
F4 |: n# \2 P( cGONADOTROPIN
/ Z0 c' K1 Y, b! ] N" dRICHARD C. KLUGO* AND JOSEPH C. CERNY
- ?! @) [6 E1 ?, M2 |! BFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
. Q# Z3 h' t% b6 G& NABSTRACT
! D r9 r5 m! f. b6 ^Five patients were treated with gonadotropin and topical testosterone for micropenis associated( g$ b) B) w$ o2 @5 c7 u
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
$ N$ ?" O, x" Etropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone! ]+ S2 y% U) C6 V \- Z8 u
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent2 \5 d7 K0 C7 \9 f- _- c9 ]! D
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent1 M' q) [. E1 I9 z! [
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
" w. g C% g" U) E5 N8 Uincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
/ D3 K, V4 Q' Zoccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
7 m2 A0 F2 }" Mstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
4 u6 G2 o& P9 i/ V! l0 cgrowth. The response appears to be greater in younger children, which is consistent with previ-# y$ D% z; z! u5 P3 r: p2 o
ously published studies of age-related 5 reductase activity.0 J g4 R$ Q7 f7 H7 c
Children with microphallus regardless of its etiology will
! g1 e9 ^4 B! X, }% I* @) z; N rrequire augmentation or consideration for alteration of exter-+ K/ K9 k# L0 d) T5 {8 n/ j9 e
nal genitalia. In many instances urethroplasty for hypo- U' S$ i" @2 \: |
spadias is easier with previous stimulation of phallic growth.
4 V( x/ p; j+ vThe use of testosterone administered parenterally or topically
$ b( f6 N4 X* h8 ohas produced effective phallic growth. 1- 3 The mechanism of
, s0 o' X: e2 |# ?! |0 rresponse has been considered as local or systemic. With this
+ l3 Z$ R) J7 ?% t' {0 [2 Bin mind we studied 5 children with microphallus for response% M) g% _6 O& L1 t+ E9 f. c2 s
to gonadotropin and to topical testosterone independently.
3 E) y7 ~: W. y! h. @MATERIALS AND METHODS/ _7 `" W. D( @6 R
Five 46 XY male subjects between 3 and 17 years old were
0 _7 O' s8 l* ?4 U4 n. Jevaluated for serum testosterone levels and hypothalamic' K( M t1 ]% d# K e" W
function. Of these 5 boys 2 were considered to have Kallmann's
! H2 |; K3 o0 U& R8 Q: ssyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
, Y- K& j: D8 e0 z9 Qlamic deficiency. After evaluation of response to luteinizing
4 Q4 R! z4 Z# \2 rhormone-releasing hormone these patients were treated with
5 G# s9 N8 J2 u" _2 w$ d. ?1,000 units of gonadotropin weekly for 3 weeks. Six weeks5 O" M: D" Z9 A, l9 h* k% l
after completion of gonadotropin therapy 10 per cent topical; g! f. c" d5 r8 p& p2 A. M9 [
testosterone was applied to the phallus twice daily for 3 weeks.
3 M: i' I# e! M: o. lSerum testosterone, luteinizing hormone and follicle-stimulat-: I" [! {" ]# ~ H$ `
ing hormone were monitored before, during and after comple-
8 g: e. Q6 D- {1 I/ @7 H- n* Y/ ~tion of each phase of therapy. Penile stretch length was
7 X. m# o$ v4 k3 j' I yobtained by measuring from the symphysis pubis to the tip of# T. j% W# _* P, |, \0 T
the glans. Penile circumferential (girth) measurements were
" }* u* y* h { B; `% Nobtained using an orthopedic digital measuring device (see& j+ v1 H4 V2 E1 e" E4 m# z
figure).
. Z9 L: d" {5 q0 f& u& ORESULTS
7 n0 s8 H- K+ E6 P7 XSerum testosterone increased moderately to levels between
) e# s. d! S% M2 V50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
Q: }, e9 B! d: v! @9 oterone levels with topical testosterone remained near pre-- t) A* c5 C9 u/ I# N9 D8 i
treatment levels (35 ng./dl.) or were elevated to similar levels
1 O2 d' f2 i. f- B% x' t8 F5 l7 ldeveloped after gonadotropin therapy (96 ng./dl.). Higher0 p0 U! Q6 W; w8 h0 S
serum levels were noted in older patients (12 and 17 years old), U: Z$ _$ q" {
while lower levels persisted in younger patients (4, 8, and 105 d7 A8 t5 V: k' Q- U2 K
years old) (see table). Despite absence of profound alterations
0 \9 S$ B& O" ?* N. g6 Pof serum testosterone the topical therapy provided a greater( ]! I4 n; h0 x7 h
Accepted for publication July 1, 1977. ·# ^ I# A3 j7 @6 y$ s
Read at annual meeting of American Urological Association,
* W" E: L9 `/ m1 K. AChicago, Illinois, April 24-28, 1977.
$ m+ h. M; A& w' J9 e. p* Requests for reprints: Division of Urology, Henry Ford Hospital,
, g' d+ H: c& `5 n( ]7 K3 s# t; m2799 W. Grand Blvd., Detroit, Michigan 48202.( g a% L* t( y8 H! [5 J a/ {
improvement in phallic growth compared to gonadotropin.; C7 W5 Q& \" E& | C( p
Average phallic growth with gonadotropin was 14.3 per cent; V6 D- l) M$ m* ^
increase in length and 5.0 per cent increase of girth. Topical
. C `: U" U7 }! p$ {# xtestosterone produced a 60.0 per cent increase of phallic length
! t$ y0 s# j* land 52.9 per cent increase of girth (circumference). The! ?" s7 u4 ?& n! R
response to topical testosterone was greatest in children be-# e9 p2 E: `* o4 {0 X4 v3 w& y
tween 4 and 8 years old, with a gradual decrease to age 17
8 |2 s, T9 r. ?years (see table).- p3 b" P- i+ ~1 L& O
DISCUSSION* t% Q5 L8 e7 `& t3 O1 m
Topical testosterone has been used effectively by other4 m1 O( w* j+ w& s/ w" G) t
clinicians but its mode of action remains controversial. Im-
+ H+ S& |/ B/ m; I8 ~mergut and associates reported an excellent growth response/ M) x4 ~2 K* g$ y- F+ R, B' L
to topical testosterone with low levels of serum testosterone,3 S0 X; t7 h# G V7 N- \+ |
suggesting a local effect.1 Others have obtained growth re-
: A4 h% R5 c6 O- ?5 R5 K" W- tsponse with high. levels of serum testosterone after topical6 k2 y V: h+ s& l3 m1 r1 H! i% W8 y
administration, suggesting a systemic response. 3 The use of
1 r7 @* i: }& p& ogonadotropin to obtain levels of serum testosterone compara-/ T- y. W& f9 H! M
ble to levels obtained with topical testosterone would seem to! D( ]/ V$ V _* w8 B7 j
provide a means to compare the relative effectiveness of
* C% Y) ?$ K9 w. M) Ktopical testosterone to systemic testosterone effect. It cer-# k" C5 C) ~ D2 D
tainly has been established that gonadotropin as well as par-
/ m) ]: e5 I" S) j; Henteral testosterone administration will produce genital
. J$ y9 B% B$ ]$ Z/ C0 Fgrowth. Our report shows that the growth of the phallus was; w8 C% j8 m! s! a- E2 U
significantly greater with topical applications than with go-' V, _) t$ C2 O! |- R2 y
nadotropin, particularly in children less than 10 years old.
1 K h+ x! d, C9 v( w& b5 d) ~, ~: ZThe levels of serum testosterone remained similar or lower
9 ~ j7 T5 J7 h5 @" I$ rthan with gonadotropin during therapy, suggesting that topi-' ?( Z( k5 V$ W$ _9 D
cal application produces genital growth by its local effect as& _0 r6 J; m' _( \6 F
well as its systemic effect.3 B$ e# T& F: N$ e
Review of our patients and their growth response related to) L k7 }9 W: J R3 _( |% q: S" @: ?2 N
age shows a greater growth response at an earlier age. This is, {8 e5 Z' x5 E& F; O
consistent with the findings of Wilson and Walker, who
' c% A1 T7 F& R/ `. p3 b- q% n; x1 treported an increased conversion of testosterone to dihydrotes-, K" p) [$ w" V4 Y1 A
tosterone in the foreskin of neonates and infants.4 This activ-
^( S4 u/ b9 r. r qity gradually decreases with age until puberty when it ap-& B+ I8 m; G* f3 X4 a
proaches the same level of activity as peripheral skin. It may
' S! K; @9 Q3 U7 E5 Twell be that absorption of testosterone is less when applied at2 t+ g! f# }8 e! S5 p8 t" y( h
an earlier age as suggested by lower serum levels in children
; X# ^6 ^ K% Wless than 10 years old. This fact may be explained by the
& L' M' v8 B" d% b: y8 @6 L/ Tgreater ability of phallic skin to convert testosterone to dihy-# H$ [$ i% W( x+ J' O O# @
drotestosterone at this age. Conversely, serum levels in older
' [1 b" Y1 d8 p& _6 Ipatients were higher, possibly because of decreased local
" T. w8 \* d: S* n& ~667
7 \+ M! L$ h% g8 A. @668 KLUGO AND CERNY& r; p# \% v$ y
Pt. Age
5 l* o- e% g3 ]$ |; S' z% T( @(yrs.)
8 C! A+ L/ ^: i- o* Q" q( Y0 \Serum Testosterone Phallus (cm.) Change Length
5 D' C/ O3 H: _(ng./dl.) Girth x Length (%)
+ J6 x5 U& v0 H: T4
0 p( x5 g2 c3 B+ ]( u8
# Y3 Z3 i0 x1 h2 s/ v& A% w( e0 d10
. W- J2 A* ?/ p126 m/ H' X: Y* m6 @; @
17. r5 y# u+ j- Z: Y. ?
Gonadotropin5 \- l+ c: D8 M0 c/ L" k) J
71.6 2.0 X 3 16.6
. R- U5 |3 @/ E$ j5 n50.4 4.0 X 5.0 20.0
5 ^8 Y N/ w/ b, `9 h+ s22.0 4.5 X 4.0 25.0
( y! r* A( L, o3 ]! y2 q1 A% X- E1 Q84.6 4.0 X 4.5 11.1
+ U! k4 ] f; o. J# M85.9 4.5 X 5.5 9.0
|! |) e2 e* g% ?. kAv. 14.3 R- Y1 X% Q- ?# B( l
4
) x+ ]0 t$ Q0 n( _) F" ^8# V1 W) v7 {1 P' H$ q' T: K
10- d( e1 W6 B& T$ o; \
12
9 H, v6 W3 U, R+ H2 Z& w& l17
" B! Y$ M7 l5 c9 o# |Topical testosterone
7 m5 Y+ P. `* M; `2 U# C0 [34.6 4.5 X 6.5 85
7 E y$ O: m# r6 C38.8 6.0 X 8.5 70
9 F9 V# ^. t$ F$ g( d1 f7 J40.0 6.0 X 6.5 62.5
6 I6 z, R8 o5 l4 O1 t93.6 6.0 X 7.0 55.5
* A. Z- Y: \. @- h! f& j: D95.0 6.5 X 7.0 27.2
. f) x7 ~6 G$ X7 {5 \7 [: iAv. 60.0
: g6 } x7 D, Y' T2 O$ u: B9 \available testosterone. Again, emphasis should be placed on
+ e) c6 p) E* b; searly therapy when lower levels of testosterone appear to" q2 m' o- F8 @* Q1 H
provide the best responses. The earlier therapy is instituted7 P' S" B0 W( t* k5 b, U
the more likely there will be an excellent response with low: p i5 n) B8 \; [5 P
serum levels. Response occurs throughout adolescence as" h# c4 y8 W/ o: E' y. r* P7 f
noted in nomograms of phallic growth. 7 The actual response- f5 Q* H+ t' t0 \
to a given serum level of testosterone is much greater at birth
( I/ T" k( `- m" |/ N Xand gradually decreases as boys reach puberty. This is most
1 g5 i2 J& L6 Y* ?7 i$ Blikely related to the conversion of testosterone to dihydrotes-& l( N3 x$ s, u9 a! ~% K. }- g2 O
tosterone and correlates well with the studies of testosterone/ D' u; R- o3 a; Y
conversion in foreskin at various ages.3 P1 ~: C4 w$ Y8 q2 `% u* O; r
The question arises regarding early treatment as to whether) |/ m! L( J& a, v
one might sacrifice ultimate potential growth as with acceler-6 [) s! B' C$ V' P) z* s
ated bone growth. The situation appears quite the reverse
$ R8 \, K x. R4 T, d! pwith phallic response. If the early growth period is not used1 q ^* {, w$ r: r1 q
when 5a reductase activity is greatest then potential growth
( }! z9 e5 t/ b5 zmay be lost. We have not observed any regression of growth
: g% g8 E: [0 T3 T9 G: Mattained with topical or gonadotropin therapy. It may well6 Y+ J0 i8 j p9 ` t) l3 H! E; g
be that some patients will show little or no response to any) z9 U! n$ d& h
form of therapy. This would suggest a defect in the ability to9 D9 Z- S- `; ~) m/ g. n* ]: Z
convert testosterone to dihydrotestosterone and indicate that- q2 B! j! Y1 i# O7 B! S
phallic and peripheral skin, and subcutaneous tissue should5 C/ h" U5 P! J2 F& m
be compared for 5a reductase activity.
1 |: v/ P1 {( L- {- dA, loop enlarges to measure penile girth in millimeters. B,4 z1 W; D9 J) C- v! S
example of penile girth computed easily and accurately.
9 X, j2 i0 `, pconversion of testosterone to dihydrotestosterone. It is in this
7 _/ L; t, K" X3 {) Wolder group that others have noted high levels of serum
' E n) }& n6 O: r' X+ v' W% p7 ptestosterone with topical application. It would also appear
- I2 ~! |, G: o2 Y# S- Q- x: ?that phallic response during puberty is related directly to the
5 H$ e4 W; \9 w% n% userum testosterone level. There also is other evidence of local
# F6 ~( Y- j) v' s& N) j# dresponse to testosterone with hair growth and with spermato-4 w+ \/ k9 C" I! i6 U" u; k
genesis. 5• 6+ Q, T; g/ R' [ W) `
Administration of larger doses of gonadotropin or systemic
7 x4 b4 t3 R) a* b5 s. Ptestosterone, as well as topical applications that produce
! x" ~ ^' w$ x( ~higher levels of serum testosterone (150 to 900 ng./dl.), will
2 i: _; Y3 I' A$ I T$ oalso produce phallic growth but risks accelerated skeletal/ O- s C p$ P" N5 ~
maturation even after stopping treatment. It would appear
+ {- o9 r" P9 g8 V, @1 l Xthat this may be avoided by topical applications of testosterone
}" Z. @, p8 w, {8 F' _and monitoring of serum testosterone. Even with this control" k9 y p/ v0 A% |8 p7 d+ O8 g
the duration of our therapy did not exceed 3 weeks at any! A1 ` i2 N% q
time. It is apparent that the prepuberal male subject may! F; |5 c9 p9 P3 f
suffer accelerated bone growth with testosterone levels near; T# v) _' ^8 T
200 ng./dl. When skeletal maturation is complete the level of) r! ~% r2 ]: z* j, L" y, k S
serum testosterone can be maintained in the 700 to 1,300 ng./
0 e: C4 d! g) x( Zdl. range to stimulate phallic growth and secondary sexual) k! n. O( W- W$ a
changes. Therefore, after skeletal maturation parenteral tes-6 i0 C3 `) W( d9 q- N2 E
tosterone may be used to advantage. Before skeletal matura-- \4 U" J x/ n# E# X f
tion care must be taken to avoid maintaining levels of serum0 e3 A' S& d$ X1 x L* y
testosterone more than 100 ng./dl. Low-dose gonadotropin8 L2 k. D6 [, {
depends upon intrinsic testicular activity and may require) N/ @2 u5 Y* G& v0 o5 f
prolonged administration for any response.
. j) w2 G8 s \Alternately, topical testosterone does not depend upon tes-# V/ J" O& x5 d; T1 @+ x1 { s' l
ticular function and may provide a more constant level of
* P9 ^ I& p6 s# H U5 x% v: [REFERENCES4 a4 v8 P# R- S9 n& i9 O* b Z
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,. L1 k+ [. g) H2 |" N; V6 G6 G
R.: The local application of testosterone cream to the prepub-; z- l, Z4 t/ s" n! s) A
ertal phallus. J. Urol., 105: 905, 1971.
2 P; U& a, r$ A& o) H; M2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone& j2 G: p8 ~' i
treatment for micropenis during early childhood. J. Pediat.,- o& r/ @. \5 W2 `, ^
83: 247, 1973.
' F W. G% ?1 q5 ~3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-7 Q& n" |: K0 [: {
one therapy for penile growth. Urology, 6: 708, 1975.
. C8 D3 Z& r) l" Z$ K4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone/ ^. B, A% S; S8 d T, H! g [
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by% q& \6 Y1 F* w3 t
skin slices of man. J. Clin. Invest., 48: 371, 1969.
% w2 D2 {: h7 w! X [) v5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
9 \* l: t* t: j' |; r' wby topical application of androgens. J.A.M.A., 191: 521, 1965.8 x; A9 A3 ]: ^9 _* H- s
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
+ Z0 u& k) n3 P/ M; W( S: R7 Tandrogenic effect of interstitial cell tumor of the testis. J.# d9 }* Y* _# C. m; J
Urol., 104: 774, 1970.
( ~) J4 P. u/ ?8 ^7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
/ b& x3 I& z2 }$ Z, ]6 xtion in the male genitalia from birth to maturity. J. Urol., 48: |
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