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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
5 U9 j3 V1 v* b* Z u8 WGONADOTROPIN" B4 R$ B3 z) D
RICHARD C. KLUGO* AND JOSEPH C. CERNY! b2 B v) \2 x* T* G- O# L: N
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
5 X1 ^! o; J% v% NABSTRACT* q% E0 ]$ _9 ^% I" g
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
( h6 W* }, b. o* Jwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
. P. z3 t/ H: F: r; Y1 ztropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone4 k1 @/ Q( Y* d- r5 V
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
# T! D+ p! @6 C6 d' P+ C3 ]3 Y% Ofor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
+ r: {5 e1 ~, K9 @) o) v' iincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
1 o+ o2 W* a6 Z' n# n7 W& z* |$ v6 _increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
& g3 [ L8 u4 K X: x, Noccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
$ Q+ U8 a X* i3 f. wstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile! {# e) j O# i7 ^% X$ M o0 m
growth. The response appears to be greater in younger children, which is consistent with previ-
8 v3 I- O; \( h' Q6 T3 wously published studies of age-related 5 reductase activity.% j- v& P4 }" D3 B: Z1 o
Children with microphallus regardless of its etiology will: n' u& b1 ^1 w0 r% L
require augmentation or consideration for alteration of exter-
- Y0 P% H1 R R) E4 I, Snal genitalia. In many instances urethroplasty for hypo-! B2 K9 L5 `9 {1 g# p: V( N
spadias is easier with previous stimulation of phallic growth.+ [+ Y d0 R3 E, |+ ~( ]9 c
The use of testosterone administered parenterally or topically6 z \6 T) Y7 ~1 l
has produced effective phallic growth. 1- 3 The mechanism of
! [7 L/ h+ z/ [, `, Hresponse has been considered as local or systemic. With this
( x$ c: _% ]3 M" f$ z3 Lin mind we studied 5 children with microphallus for response) l) l7 b& T4 `
to gonadotropin and to topical testosterone independently.
( `$ I: n( r% E+ U$ O" r% MMATERIALS AND METHODS
. o1 L. r( c! m: E D: ZFive 46 XY male subjects between 3 and 17 years old were
* k$ u( i4 J" {+ l6 m& Z5 ~evaluated for serum testosterone levels and hypothalamic" c& G/ B$ d# A& O# U- e" r+ M" ^4 m$ v
function. Of these 5 boys 2 were considered to have Kallmann's4 O9 t' _" a& P# K6 o* x
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-; y) d2 ~7 \) M( E
lamic deficiency. After evaluation of response to luteinizing! y/ m' I! H6 }
hormone-releasing hormone these patients were treated with5 Y# }* j! R( u1 H
1,000 units of gonadotropin weekly for 3 weeks. Six weeks) }# w+ `- B* N2 q0 B7 t/ ` k
after completion of gonadotropin therapy 10 per cent topical
4 L( y5 T6 o: o! c* stestosterone was applied to the phallus twice daily for 3 weeks.
0 W, [, r5 \3 }! ], [6 X% XSerum testosterone, luteinizing hormone and follicle-stimulat-
4 [0 ~3 ~* p& Ying hormone were monitored before, during and after comple-6 j; {$ O, m0 l3 T! L2 U
tion of each phase of therapy. Penile stretch length was, r4 @2 s/ V% ^
obtained by measuring from the symphysis pubis to the tip of
; c) D- o9 ~1 Z5 gthe glans. Penile circumferential (girth) measurements were0 B r8 L( s* c7 K \$ {6 F+ h. _! k
obtained using an orthopedic digital measuring device (see) X/ w9 B: Z8 ?- y/ ^: ]
figure).
$ x9 x$ P3 M+ [5 @RESULTS3 J+ R! ]5 X. i8 ^* q9 p* N3 y
Serum testosterone increased moderately to levels between
& [ ]+ r; w, z7 c2 f5 X9 E! t50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-9 ? g" [" W# p! C
terone levels with topical testosterone remained near pre-
" Y C3 U" B% r8 }; Ctreatment levels (35 ng./dl.) or were elevated to similar levels! }5 A- }1 C7 ~; m
developed after gonadotropin therapy (96 ng./dl.). Higher7 x6 {$ b- j) P; ]- H i+ Q+ c
serum levels were noted in older patients (12 and 17 years old),
1 J+ @) K, B) \: ]0 m2 Gwhile lower levels persisted in younger patients (4, 8, and 10
7 L$ c7 C* \; A- ^5 myears old) (see table). Despite absence of profound alterations3 W+ b2 c/ L6 K+ z/ V5 M
of serum testosterone the topical therapy provided a greater
+ z* m6 F3 k" `7 r2 \% {+ [Accepted for publication July 1, 1977. ·
- i0 Z* _" }' [% M+ S. aRead at annual meeting of American Urological Association,' X" G& E* ^+ W. c0 g! \
Chicago, Illinois, April 24-28, 1977.
8 F; `' u, d. F* Requests for reprints: Division of Urology, Henry Ford Hospital,
. l8 j( V; M/ F% D6 W" O- f5 y2799 W. Grand Blvd., Detroit, Michigan 48202.0 a# V0 g; D. c& E
improvement in phallic growth compared to gonadotropin.
* o: p- p6 R, f% EAverage phallic growth with gonadotropin was 14.3 per cent
0 s; u" z% I/ r% r3 a! M! P9 dincrease in length and 5.0 per cent increase of girth. Topical" j: A v& n# t5 r+ Z4 s
testosterone produced a 60.0 per cent increase of phallic length
& y6 s5 m1 r- [: t$ j2 W5 G p" F8 hand 52.9 per cent increase of girth (circumference). The! g. Y- i! T; i3 Q0 H1 `
response to topical testosterone was greatest in children be-2 }+ o3 d' N! i/ \% g
tween 4 and 8 years old, with a gradual decrease to age 178 M9 M N9 R C2 z
years (see table).
' J5 w7 S* n7 O+ F& u0 WDISCUSSION' W' p5 n+ q4 K) `
Topical testosterone has been used effectively by other% ?0 K+ q& t/ Y: a2 k2 q
clinicians but its mode of action remains controversial. Im-
: B, [. u3 }4 Q/ ~mergut and associates reported an excellent growth response: J2 L) q+ C* }# z. f( i
to topical testosterone with low levels of serum testosterone,
: t3 f0 J1 h1 |, m, y$ \suggesting a local effect.1 Others have obtained growth re-, p8 Y7 W0 F7 d6 \
sponse with high. levels of serum testosterone after topical* \! l9 J4 T5 y. D! e( l1 H: ~
administration, suggesting a systemic response. 3 The use of
- I, z4 P! f6 Y# [: tgonadotropin to obtain levels of serum testosterone compara- @2 d' P0 v" V& N, C
ble to levels obtained with topical testosterone would seem to
1 S" H# L& N" l; q4 aprovide a means to compare the relative effectiveness of
# j6 Z3 P. Q2 I) Z# Utopical testosterone to systemic testosterone effect. It cer-2 S& r5 j* L, x5 W
tainly has been established that gonadotropin as well as par-; `- ]* P: b+ A3 f2 f
enteral testosterone administration will produce genital: X3 g" m! w/ d% c
growth. Our report shows that the growth of the phallus was
: S. Z0 Q" ~3 l0 usignificantly greater with topical applications than with go-/ T! C, V1 s+ m; g7 w6 u0 ^! q
nadotropin, particularly in children less than 10 years old.
- I. E9 a4 f$ G" Q0 ~, y! XThe levels of serum testosterone remained similar or lower1 ?$ }8 t& X+ k. |/ z6 p+ _) `
than with gonadotropin during therapy, suggesting that topi-+ w% L6 A6 `: n3 a% L
cal application produces genital growth by its local effect as9 ~6 j: o5 `7 O1 B& o7 |
well as its systemic effect.
: f+ b* c8 J+ e+ uReview of our patients and their growth response related to
/ z4 }6 T/ A3 e) c; _3 o }age shows a greater growth response at an earlier age. This is
& X3 H5 }! j4 x, t4 ~$ D2 Q- d# Kconsistent with the findings of Wilson and Walker, who/ x" ?0 r) d' ?
reported an increased conversion of testosterone to dihydrotes-
0 r: k: b. j% ~( r! I, d) k- wtosterone in the foreskin of neonates and infants.4 This activ-
0 ?. ]' M; `; J5 ~' U, tity gradually decreases with age until puberty when it ap-% I8 Y3 ~/ @0 m }6 c" N: l% f
proaches the same level of activity as peripheral skin. It may H% p4 s! q% Z. \7 [' }
well be that absorption of testosterone is less when applied at" y; P2 n; }0 z. u
an earlier age as suggested by lower serum levels in children
' Q" K2 Y8 a9 b7 H1 Qless than 10 years old. This fact may be explained by the
; @+ A0 r8 {' d5 N/ fgreater ability of phallic skin to convert testosterone to dihy-
& v" m9 a" y9 G9 C; cdrotestosterone at this age. Conversely, serum levels in older
" J# H8 Z$ e5 i h4 apatients were higher, possibly because of decreased local
' G: w3 q& T; ]0 \, G0 F6673 u& T! n' N+ d- }4 F. G
668 KLUGO AND CERNY
/ H3 g0 _1 V. @/ Q# OPt. Age+ @6 I' G+ {, Z, Z5 V
(yrs.)+ q* y) a/ @* U1 r! D! f5 C& m
Serum Testosterone Phallus (cm.) Change Length: r0 d1 b1 a: }( d1 m2 u7 a) y3 H% |
(ng./dl.) Girth x Length (%)
/ J! A6 N* L$ ^% }$ U$ d, D( |4* _2 L C. e) d! B. Z w
8
( s+ ^; \9 t5 G2 a# Y) y2 {10
% p5 Q9 Y; ?! P& a+ P12" Y2 E6 h- S3 h- f1 ~+ _
17
" e8 {2 D- q8 [0 o0 K {Gonadotropin) C- ~/ n& f6 v5 t
71.6 2.0 X 3 16.6
$ Y- |8 I# J7 m, L50.4 4.0 X 5.0 20.0
) g p7 Q( Z4 \* ^( R' k! H" v22.0 4.5 X 4.0 25.0
% [! i# h$ g+ D/ q3 k3 z) l* {1 D84.6 4.0 X 4.5 11.1
' S6 ~. c; U; m' {2 a85.9 4.5 X 5.5 9.0
! Q: L% u' z- b3 \# _Av. 14.3
0 U, b7 [- Y) {42 v, ^4 U+ y, ~' n
8
/ b7 @$ q; U2 y) W+ q G10( k6 y# n( j4 {! e3 [6 }- Z
12' r8 |* T( P% `! c
17# R9 z: S- V- l' F
Topical testosterone: a9 B! N! h e. \& I' ^' Y
34.6 4.5 X 6.5 85
. E9 ~8 _& `5 G) a, T6 r38.8 6.0 X 8.5 70& X2 R9 X% Q9 r) e# g
40.0 6.0 X 6.5 62.50 X* B+ \( X8 _
93.6 6.0 X 7.0 55.5, _8 L$ b- O) u; f; Y3 L
95.0 6.5 X 7.0 27.2
$ L, |/ R8 W: ?9 cAv. 60.04 }- u% P8 `( x* G+ h( l, a
available testosterone. Again, emphasis should be placed on
& s& I/ G& M$ o! A2 |early therapy when lower levels of testosterone appear to. m* o: {. ^ k+ R$ G6 |
provide the best responses. The earlier therapy is instituted4 a) X& d( U7 b2 n: e
the more likely there will be an excellent response with low, ^* k# O4 A! {
serum levels. Response occurs throughout adolescence as
5 m$ Z2 Q4 n F: g$ Anoted in nomograms of phallic growth. 7 The actual response8 I0 r2 M; u8 \/ e% T& [% }
to a given serum level of testosterone is much greater at birth9 c, M: p9 v7 l6 s# ?2 w1 B1 v! J
and gradually decreases as boys reach puberty. This is most
/ O) Y1 {8 Q$ ]7 e; H4 \likely related to the conversion of testosterone to dihydrotes-) R+ Z6 O( O* H9 U# f# o/ n
tosterone and correlates well with the studies of testosterone5 V. d( b! N8 o+ r
conversion in foreskin at various ages.
" s1 i- L" r6 Q1 k& k0 C% E: x$ k1 I) hThe question arises regarding early treatment as to whether
2 T! \7 @! A3 l+ s* \. sone might sacrifice ultimate potential growth as with acceler-
* U% U5 ?' T8 D2 R6 M2 eated bone growth. The situation appears quite the reverse( g! G, P0 s$ @) g
with phallic response. If the early growth period is not used# v) n6 S. Z4 E9 X% I
when 5a reductase activity is greatest then potential growth
e+ N. S! _, v6 Jmay be lost. We have not observed any regression of growth
+ j5 I+ f* I0 i7 pattained with topical or gonadotropin therapy. It may well: @- X7 z5 ^- F1 ]6 N
be that some patients will show little or no response to any
" w1 r' Q- h, e: O' f$ X( Cform of therapy. This would suggest a defect in the ability to9 y( c7 z; d$ d
convert testosterone to dihydrotestosterone and indicate that' @* n7 M. z# |, A+ T7 t
phallic and peripheral skin, and subcutaneous tissue should8 L8 `; H q6 O( E& }# P) u
be compared for 5a reductase activity. a4 X2 a7 p" F
A, loop enlarges to measure penile girth in millimeters. B,
6 g4 ?7 f# r2 F+ j" ]+ s% O, ~example of penile girth computed easily and accurately./ U3 H3 t- c5 Y* Y/ y0 t1 n9 {- `
conversion of testosterone to dihydrotestosterone. It is in this
* z: J' e* N1 {, `older group that others have noted high levels of serum& E; P7 [' M' W% t( G, o
testosterone with topical application. It would also appear3 e" J9 i- D$ c9 j, H' P
that phallic response during puberty is related directly to the
! k/ g. K# _3 J/ d% Gserum testosterone level. There also is other evidence of local
8 u- ~) {- k5 K) ]$ H- B0 r( p+ J% Rresponse to testosterone with hair growth and with spermato-8 ^- S6 |0 X' n( q* |# n
genesis. 5• 6
0 ~$ V1 d9 P( d5 g) r: LAdministration of larger doses of gonadotropin or systemic
4 B4 ^4 n! V$ I' o: _3 Htestosterone, as well as topical applications that produce$ X7 E$ L% S& Y% p& H$ [
higher levels of serum testosterone (150 to 900 ng./dl.), will: Y0 @6 z, b# ?
also produce phallic growth but risks accelerated skeletal+ K6 Z `1 \7 h( h# y
maturation even after stopping treatment. It would appear- O! s6 [- _: ~6 o8 o4 g l
that this may be avoided by topical applications of testosterone& D# `: K9 u$ V1 ?$ H
and monitoring of serum testosterone. Even with this control2 ]% _% j/ L/ p( k
the duration of our therapy did not exceed 3 weeks at any
8 a( [2 ~" a# @. |) |time. It is apparent that the prepuberal male subject may
( h( U0 m/ o6 f* ^) `# Tsuffer accelerated bone growth with testosterone levels near
; v) E6 U& b4 J2 O4 x2 j200 ng./dl. When skeletal maturation is complete the level of% G3 p5 H4 v$ A* q7 ]+ @* M
serum testosterone can be maintained in the 700 to 1,300 ng./
. a1 p1 U2 t. M: i7 q, ddl. range to stimulate phallic growth and secondary sexual, C+ Y+ R6 Y) e, a
changes. Therefore, after skeletal maturation parenteral tes-0 \3 e" Y, j/ y: r
tosterone may be used to advantage. Before skeletal matura-9 d( u: G! P8 D6 Z$ i
tion care must be taken to avoid maintaining levels of serum
6 E7 ?1 O1 Z) {/ V& f% W/ Ktestosterone more than 100 ng./dl. Low-dose gonadotropin
) N$ P" P* J; v y! z- ]$ w Udepends upon intrinsic testicular activity and may require
$ c' Y# v6 ~- k. _% tprolonged administration for any response.. L2 z0 j9 |* q$ w# i
Alternately, topical testosterone does not depend upon tes-3 W2 z% v5 t3 B8 o
ticular function and may provide a more constant level of/ n) u5 i5 i5 N4 u2 x
REFERENCES2 [; C$ P+ H# s3 D' d* k3 H
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,0 q) W9 t% s7 q) |+ _
R.: The local application of testosterone cream to the prepub-4 J* g/ j) {; D
ertal phallus. J. Urol., 105: 905, 1971.
3 c! Y% W2 @9 B* A2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone1 C3 x _$ W' u2 L3 `
treatment for micropenis during early childhood. J. Pediat.,, G* \, \% @( g8 V* T6 \& B% E
83: 247, 1973.
0 c9 s p& ~- {8 {' J3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-, D2 F- ?+ Z* G4 ^
one therapy for penile growth. Urology, 6: 708, 1975.
& a0 c! P; M+ Q: j: z4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
% }2 q) G. s4 l" ?1 `* a1 b& Yto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by" O0 O6 e& |& o: U A. z
skin slices of man. J. Clin. Invest., 48: 371, 1969.
. u+ G ?( _/ R, k( b5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth. I$ E7 F0 h0 d# g' V
by topical application of androgens. J.A.M.A., 191: 521, 1965.
: S: ~* \% Z% h& O/ s6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local1 f) U: z' K9 ]7 F$ O1 B
androgenic effect of interstitial cell tumor of the testis. J./ u# ? ~1 m4 `- D
Urol., 104: 774, 1970.% v4 G' J6 h: X
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
+ S( E7 v( a, h: _" \- Y: Xtion in the male genitalia from birth to maturity. J. Urol., 48: |
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