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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND1 d u5 Z% r9 I6 B1 x
GONADOTROPIN* D1 Z; ?! S2 k1 R
RICHARD C. KLUGO* AND JOSEPH C. CERNY' A: b- c2 [) L# b; O
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
: j# ~; r; p& c2 F0 [ABSTRACT" |1 C6 U0 p; j$ K
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
- c7 V% E: Q; [$ R' m, awith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-/ ^# m3 g! \) K) m
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
. |( g4 {3 s7 V, acream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent9 \" \$ i! M$ e$ @, X3 v% q
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
( ?- F& J+ } v7 Q: wincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
% @( ?; H7 A( o* e5 q* R! ] cincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
& @; X; z' I2 F# F# T) Eoccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
4 ^; H( l' }- E% sstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile% V1 F' S0 W' J/ \4 q9 p
growth. The response appears to be greater in younger children, which is consistent with previ-, P1 Q" r3 z4 A6 J. \
ously published studies of age-related 5 reductase activity.
" ~- Y$ k# O1 FChildren with microphallus regardless of its etiology will
/ x# f1 |6 z( y) h+ B# a# [require augmentation or consideration for alteration of exter-3 Y* w1 f A: z# V, i; |' r
nal genitalia. In many instances urethroplasty for hypo-
( x! ]3 D# {7 E0 A0 [spadias is easier with previous stimulation of phallic growth.
7 l, ^7 Q& t* n7 aThe use of testosterone administered parenterally or topically
) y7 d/ ]7 }6 Q7 N* e. Q2 E3 ohas produced effective phallic growth. 1- 3 The mechanism of8 S: H/ `, W1 u# t* Y
response has been considered as local or systemic. With this
2 D2 U5 b% c* c$ h4 sin mind we studied 5 children with microphallus for response
$ y! q1 d7 g" O2 `* E; zto gonadotropin and to topical testosterone independently.
) C* \! x. H$ f; m% fMATERIALS AND METHODS
4 O* ]2 X5 B. X. l2 X* e+ A3 T7 P# lFive 46 XY male subjects between 3 and 17 years old were) b0 O, ]5 M% T6 A
evaluated for serum testosterone levels and hypothalamic
# |0 f# V! j! Y2 Ofunction. Of these 5 boys 2 were considered to have Kallmann's# |& t* T' G6 T2 B, F
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
2 k+ y9 y7 A# S) Q, a0 olamic deficiency. After evaluation of response to luteinizing s4 r: P% c) a8 W8 ]; s1 R/ o
hormone-releasing hormone these patients were treated with
& w$ C2 A& b' v) J7 V$ b1,000 units of gonadotropin weekly for 3 weeks. Six weeks
2 I# H9 z2 h* n/ Bafter completion of gonadotropin therapy 10 per cent topical+ S* F- g( I6 M6 @0 q4 g
testosterone was applied to the phallus twice daily for 3 weeks.8 O& B/ V s' j1 Q
Serum testosterone, luteinizing hormone and follicle-stimulat-- a- z$ P$ t3 r$ R
ing hormone were monitored before, during and after comple-7 d2 v3 P+ h$ t/ ?8 R v
tion of each phase of therapy. Penile stretch length was
N/ H; G* t$ q% R" U1 ^, nobtained by measuring from the symphysis pubis to the tip of
& @9 b) C$ X! k7 R0 s- e1 y' y7 vthe glans. Penile circumferential (girth) measurements were
5 p! |) I' O/ d/ \" xobtained using an orthopedic digital measuring device (see
4 e3 }: s, \8 [3 E* b Cfigure).- R8 O# }4 _, ?$ ]4 [
RESULTS
" Q# I ]/ K$ q& N/ a, BSerum testosterone increased moderately to levels between
/ k( x' }4 ?$ P50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
7 b, z0 U2 _0 sterone levels with topical testosterone remained near pre-
" E, B$ ?; T% B/ ?9 ntreatment levels (35 ng./dl.) or were elevated to similar levels
; w( }6 l- v8 u( ?- U: g8 ^7 Ideveloped after gonadotropin therapy (96 ng./dl.). Higher" _- S* R/ u) d4 r& P- n
serum levels were noted in older patients (12 and 17 years old),) t. v7 S3 P) @! g/ \: G k
while lower levels persisted in younger patients (4, 8, and 10* A T8 Y( U# H: O
years old) (see table). Despite absence of profound alterations
# [+ N+ \+ m& k2 l( iof serum testosterone the topical therapy provided a greater
! N; L- s3 w! z$ |Accepted for publication July 1, 1977. ·
0 d2 X. P; T: L3 m) URead at annual meeting of American Urological Association,
' o8 ]0 R) m) w9 y0 M9 T6 mChicago, Illinois, April 24-28, 1977.
( ^3 ^; k' ]- _" R! B* i4 L* Requests for reprints: Division of Urology, Henry Ford Hospital,
2 S. ^" V8 v+ m4 e+ k, D2799 W. Grand Blvd., Detroit, Michigan 48202.! r; c f1 `1 M, m5 c0 U' v l
improvement in phallic growth compared to gonadotropin.
& m' l& }, r5 A. ~, ]Average phallic growth with gonadotropin was 14.3 per cent* R1 q/ Z0 X! {
increase in length and 5.0 per cent increase of girth. Topical
. f7 d7 _" \/ f9 V1 Y3 I, rtestosterone produced a 60.0 per cent increase of phallic length
& [2 g5 ~; ~( O7 L) I" pand 52.9 per cent increase of girth (circumference). The2 ]1 @ p7 g/ J, @ X
response to topical testosterone was greatest in children be-
! z: \+ u; j1 Z( q- U, Jtween 4 and 8 years old, with a gradual decrease to age 17. Z1 z1 L6 x5 x9 S2 w9 l2 E5 s
years (see table).
9 p1 ?% w3 |2 ~0 S0 k4 @7 SDISCUSSION
6 `( _3 C, v+ o; Y6 S# e6 [Topical testosterone has been used effectively by other$ W7 V5 M. b! @6 {
clinicians but its mode of action remains controversial. Im-
! g5 g/ @' c6 ?; G0 n9 umergut and associates reported an excellent growth response2 J( C/ Z3 t ^2 F( a
to topical testosterone with low levels of serum testosterone,
' G- S- M6 d, }6 [/ L6 W S0 ksuggesting a local effect.1 Others have obtained growth re-
0 Y* B$ l3 \& h+ u" X zsponse with high. levels of serum testosterone after topical" a8 {. x/ M% g l5 p H9 Z* `
administration, suggesting a systemic response. 3 The use of
& L4 h8 q) F) `. Xgonadotropin to obtain levels of serum testosterone compara-
# c4 [: L9 I) I2 X9 t# sble to levels obtained with topical testosterone would seem to+ ]4 N8 m6 C/ A# K) ~ U9 C
provide a means to compare the relative effectiveness of
- v: b) }" W: b% s `$ i( w$ Dtopical testosterone to systemic testosterone effect. It cer-2 z( F) Q: @$ ?& v
tainly has been established that gonadotropin as well as par-
; k% F& O1 j$ D& M3 S v' \: fenteral testosterone administration will produce genital
4 u( T9 M/ D; kgrowth. Our report shows that the growth of the phallus was# K5 Q; A! z. P9 S
significantly greater with topical applications than with go-) y. y p- W* R B$ r
nadotropin, particularly in children less than 10 years old.
$ W4 w2 \9 \' j: X4 TThe levels of serum testosterone remained similar or lower* O& { K) H" {- o. Y
than with gonadotropin during therapy, suggesting that topi-7 t- M. {3 ^8 @& l# c
cal application produces genital growth by its local effect as
: w) p" W; `. ^( \7 M4 `# y5 V+ zwell as its systemic effect.
& O: b% C U- z' {" EReview of our patients and their growth response related to. o" a! ?1 { X8 p: @) i
age shows a greater growth response at an earlier age. This is" W0 W( C. g1 |/ u
consistent with the findings of Wilson and Walker, who
1 N& @- B: f: ]# }2 P! t* Jreported an increased conversion of testosterone to dihydrotes-
/ V& v; y% C$ M* W! O8 u4 r' d9 Ftosterone in the foreskin of neonates and infants.4 This activ-2 K* }0 L$ H$ z
ity gradually decreases with age until puberty when it ap-
6 v, A6 D! Q' b, y7 Iproaches the same level of activity as peripheral skin. It may
; {8 V; `$ h) G3 L7 M" Q. n; swell be that absorption of testosterone is less when applied at
4 s( r+ O% `- zan earlier age as suggested by lower serum levels in children
" l7 m6 G6 a, `1 Fless than 10 years old. This fact may be explained by the: P- U. r: t: ^- ]: [6 I
greater ability of phallic skin to convert testosterone to dihy-# n9 E ?* [$ }) Z% h$ _; \
drotestosterone at this age. Conversely, serum levels in older
9 F/ B m% U0 f! X3 d Gpatients were higher, possibly because of decreased local
9 C6 S6 e9 Y2 P' e4 R5 y667
8 @7 F$ L' n3 ]0 d Z% N- u9 {668 KLUGO AND CERNY
1 J* H0 q2 T1 B+ v* nPt. Age
; S8 _! K$ G/ k* C9 y7 _, N* M(yrs.)$ S) H; e# ~+ Q4 v& ~ T" Q+ x
Serum Testosterone Phallus (cm.) Change Length( H2 ` p+ `: i8 Q6 {' A
(ng./dl.) Girth x Length (%)' a2 j' N# u) U$ {) O7 F' I
4, q$ U, u' R; T! k% _
8" S" K2 S4 ?5 Z5 K1 X; ^
104 g- ]# S* Y' B) k2 n
12- U" U S d7 w2 I
17; r( x2 Q# _% G0 [
Gonadotropin4 H4 l9 p: d7 _
71.6 2.0 X 3 16.6
# a9 R! w7 J$ v% C4 y H50.4 4.0 X 5.0 20.09 ]0 d8 B4 ?/ _3 [; r
22.0 4.5 X 4.0 25.0
/ D: t) y1 p3 [; N6 ?0 g( k, b# V84.6 4.0 X 4.5 11.1
) Y. D: O. W3 z2 i8 {* e85.9 4.5 X 5.5 9.0
8 \9 u7 s& D. h/ B/ V* l/ XAv. 14.32 D( f+ s$ w$ j& f& n% M
4
3 [6 w% @+ b/ L6 C5 k81 Z& L' y; M. `3 |. h2 X
10" L% l6 f6 ?' C5 z6 r$ u
12
7 ?4 ]4 ^) S6 h# _17+ z% J, ^9 X& {: K0 \
Topical testosterone1 |* A" H$ ^% z6 U2 j
34.6 4.5 X 6.5 85
, D0 I6 {% O* A38.8 6.0 X 8.5 70
~+ H6 `3 Q8 s5 G% X7 c) m40.0 6.0 X 6.5 62.5
/ |4 A2 ~ W6 N93.6 6.0 X 7.0 55.58 _" I% O, \- a; M1 h& g( ]5 ^) r
95.0 6.5 X 7.0 27.2: M# P" ?8 S- E: }: h
Av. 60.0! o* g z" Y4 n& T( H7 d
available testosterone. Again, emphasis should be placed on
$ c0 @, f+ ~) z' Zearly therapy when lower levels of testosterone appear to
* i! @( D; [, T" Q hprovide the best responses. The earlier therapy is instituted
6 t; \. b7 J$ C7 D! n+ _the more likely there will be an excellent response with low
! b% t+ e$ C# @0 B! u8 q0 }4 B% @5 userum levels. Response occurs throughout adolescence as: ~% U* g6 J+ [2 ]2 s
noted in nomograms of phallic growth. 7 The actual response
% c8 ?2 D" g+ E7 Jto a given serum level of testosterone is much greater at birth
9 H$ z; o; t1 j4 o7 kand gradually decreases as boys reach puberty. This is most
( u6 ~0 R8 k' A/ L! p% Blikely related to the conversion of testosterone to dihydrotes-; P4 t7 r; W2 f7 ?& s& b
tosterone and correlates well with the studies of testosterone
1 j0 ^# e1 s7 }& jconversion in foreskin at various ages.* j! E1 i% V; N; M) n& Q2 c* B! ^
The question arises regarding early treatment as to whether
" \. C: n t. y' E3 V Rone might sacrifice ultimate potential growth as with acceler-# f+ g7 P$ ^) q/ h) y: h6 p* o) }
ated bone growth. The situation appears quite the reverse h1 K" b/ a' H1 F2 _1 p2 x
with phallic response. If the early growth period is not used
: K; d* F' ]. D j' ^- }6 X) H# Owhen 5a reductase activity is greatest then potential growth; O. l( H9 [8 a+ B# g
may be lost. We have not observed any regression of growth0 v k" I7 L. u3 e$ ]
attained with topical or gonadotropin therapy. It may well
, {% R% u( @3 h3 j% r$ O; @% Jbe that some patients will show little or no response to any8 V; B7 {0 E5 b/ h2 O
form of therapy. This would suggest a defect in the ability to7 `" N- ?# v" \: l. x% v
convert testosterone to dihydrotestosterone and indicate that6 d1 e9 d2 {0 c8 U4 Y% A: ^
phallic and peripheral skin, and subcutaneous tissue should7 r$ } m$ c) _
be compared for 5a reductase activity.! B+ {0 @# i& J+ S
A, loop enlarges to measure penile girth in millimeters. B,
, `0 c8 _* Z8 i$ t: Hexample of penile girth computed easily and accurately.
- S, h+ s5 N- k" e+ a* Rconversion of testosterone to dihydrotestosterone. It is in this. r9 c) r8 B" h0 i. F5 |8 u" i
older group that others have noted high levels of serum% z9 Z! C; x$ \4 t
testosterone with topical application. It would also appear2 `# u" Z2 A* G
that phallic response during puberty is related directly to the
' R, O( i8 J! h- B1 Rserum testosterone level. There also is other evidence of local
. Y- A& a, k6 _ \. o( x- n4 v$ yresponse to testosterone with hair growth and with spermato-
3 `7 P9 H: V+ o G( V# a+ Tgenesis. 5• 68 ]% t% E. T+ b2 t& z5 o( [0 y
Administration of larger doses of gonadotropin or systemic2 r% l6 V8 ]' ]* o' b' j
testosterone, as well as topical applications that produce# ?$ J6 g8 o) E
higher levels of serum testosterone (150 to 900 ng./dl.), will- ^3 @" [' B6 A) ~2 ~2 u5 X* z
also produce phallic growth but risks accelerated skeletal# S5 b& P" ^% D: `& h& v! b
maturation even after stopping treatment. It would appear
; p% ^9 c3 A6 \6 U. H6 ethat this may be avoided by topical applications of testosterone) R0 o" m q0 T0 h, J8 O& r* z
and monitoring of serum testosterone. Even with this control
W% n5 u. D7 r' V# C" vthe duration of our therapy did not exceed 3 weeks at any# d! V+ i4 ^8 w" Y
time. It is apparent that the prepuberal male subject may
: h; B2 u' p/ M% |suffer accelerated bone growth with testosterone levels near
8 E4 _# J5 h) n" {0 M200 ng./dl. When skeletal maturation is complete the level of
, \' @/ X* L! s) n) `# Z( L9 ]; ?serum testosterone can be maintained in the 700 to 1,300 ng./1 O0 i8 @& r4 |9 z
dl. range to stimulate phallic growth and secondary sexual
( f9 D* K5 c% j$ h2 _changes. Therefore, after skeletal maturation parenteral tes-
- O g9 h# M+ Xtosterone may be used to advantage. Before skeletal matura-
& f2 j" t- H- v" i8 Otion care must be taken to avoid maintaining levels of serum+ F6 @) E3 T1 e" z6 l) O$ l
testosterone more than 100 ng./dl. Low-dose gonadotropin
2 ~. o4 m4 h* idepends upon intrinsic testicular activity and may require4 y$ a# d8 N/ ?1 C% L
prolonged administration for any response.
; z) X G7 S1 w ^' C" Z! t+ W# kAlternately, topical testosterone does not depend upon tes-$ |/ b5 n/ |) L/ |5 T. p
ticular function and may provide a more constant level of
( X, D' k3 l9 N' N9 A- Q$ DREFERENCES" g, h" E9 V" P, R9 z
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
) s5 d3 U. o, yR.: The local application of testosterone cream to the prepub-) t) p4 O, f0 t8 l
ertal phallus. J. Urol., 105: 905, 1971.* \6 v. D) E3 l! v* B
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
% L+ V, C) @0 A( ~7 B& Ctreatment for micropenis during early childhood. J. Pediat.,
1 |1 A1 i6 G, ?! \83: 247, 1973.
! d, U9 D a5 Q$ d9 g3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster- c2 ^6 }+ @. D1 n) G& g
one therapy for penile growth. Urology, 6: 708, 1975.
+ N0 E8 E7 q4 d9 E$ ?4 u0 i4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
1 q* S" l' Z$ ^/ U% u0 G( a8 f# Tto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
. ?3 }- G0 K( X$ i( F2 x: q$ Iskin slices of man. J. Clin. Invest., 48: 371, 1969.: |+ h: C7 P( w1 r( e
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth1 F3 d. _+ z# ]4 L8 O% E' N$ F& J7 s
by topical application of androgens. J.A.M.A., 191: 521, 1965.
. c! O: m5 R: g0 Y: ~2 @6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
1 \2 m' t! t; h( } A" C2 iandrogenic effect of interstitial cell tumor of the testis. J.: w. x) O% N; z% `
Urol., 104: 774, 1970.
8 D2 o. ~; Y( A0 T. r5 S% ?7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
; Y7 s) j% K/ j/ {5 q. U& }& ntion in the male genitalia from birth to maturity. J. Urol., 48: |
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