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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
+ i6 E$ \( i7 o v9 ^GONADOTROPIN
8 T5 v) m: L4 eRICHARD C. KLUGO* AND JOSEPH C. CERNY2 }$ k7 M; G% O o w
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
R' V& D- E0 Z8 C) n% ~+ Z0 XABSTRACT
5 f# o8 l( N5 eFive patients were treated with gonadotropin and topical testosterone for micropenis associated1 q1 b9 g3 L6 g! U1 ~/ r
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado- B5 h1 O/ ]3 W/ I2 H
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
4 J0 F: R7 g, [2 Acream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
7 e" X/ \, z0 z( Ofor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
7 k% n* ?2 ~3 F ]increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average; \: ]6 B |: J: s+ h: l K
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
- w( w4 E# r$ Y8 c# _occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
( `' e; j9 h7 h( Cstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
: b& D$ J7 ?% egrowth. The response appears to be greater in younger children, which is consistent with previ-
! e& c5 b0 S' Eously published studies of age-related 5 reductase activity.9 D& {9 ]1 g& w4 S' i! S" m
Children with microphallus regardless of its etiology will5 I, p9 U$ U9 @4 V' i# ]
require augmentation or consideration for alteration of exter-
, ^9 F7 F; F8 Q& Gnal genitalia. In many instances urethroplasty for hypo-! O# _8 h+ G7 p* E( E2 `# [! o" c
spadias is easier with previous stimulation of phallic growth.
+ o/ Z6 r# ^/ ~0 p) g: K) i- g) rThe use of testosterone administered parenterally or topically
4 w# e2 B [, J) \. _has produced effective phallic growth. 1- 3 The mechanism of
8 O" R& |! W" Cresponse has been considered as local or systemic. With this) K2 }, o' A- q3 H8 ?( X4 F$ Y! X
in mind we studied 5 children with microphallus for response0 O4 s9 m1 ]% P3 C' F' }, }3 J: Y
to gonadotropin and to topical testosterone independently.
8 r. K/ y+ G# o5 e x2 c7 I+ F. q [MATERIALS AND METHODS
2 `+ H4 u6 s! n/ T9 b1 ~2 H9 WFive 46 XY male subjects between 3 and 17 years old were) C: f- f: {9 ~7 |3 y3 ^& ]
evaluated for serum testosterone levels and hypothalamic
3 H# w: n! ?0 p' Y, K5 ~. D& nfunction. Of these 5 boys 2 were considered to have Kallmann's7 n/ w2 c& e. x2 `/ h/ R6 @
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-' |2 i; B) H! }4 ]5 \4 p6 y5 d3 @
lamic deficiency. After evaluation of response to luteinizing& Y" q" E' i+ {5 |, }& {( L9 }
hormone-releasing hormone these patients were treated with' Q" o* }8 k, k" J6 u% C
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
8 S, W" Z( N, G' ?7 F" Q/ Mafter completion of gonadotropin therapy 10 per cent topical
) [6 q, n4 {( [7 ^2 B; x* utestosterone was applied to the phallus twice daily for 3 weeks.
& U5 [- [- `0 _/ E& sSerum testosterone, luteinizing hormone and follicle-stimulat-
3 Z3 _& k/ [+ `9 king hormone were monitored before, during and after comple-
+ f. q- o2 d) J8 p7 ktion of each phase of therapy. Penile stretch length was5 J$ R' j7 s' Y, a$ }- q
obtained by measuring from the symphysis pubis to the tip of
8 B& M2 }5 C/ _1 tthe glans. Penile circumferential (girth) measurements were
0 \( w* Q; O+ X% c# m1 V: s, Uobtained using an orthopedic digital measuring device (see( p- o8 N% t) U7 }7 A
figure).
( ?8 U+ D8 F- `* s6 _" I+ ZRESULTS7 g) v$ [5 ~" y0 G
Serum testosterone increased moderately to levels between
$ q; u) N, n0 \50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
/ Y1 R8 v! z& j, Xterone levels with topical testosterone remained near pre-
0 s$ N" o7 B3 g8 X+ \+ htreatment levels (35 ng./dl.) or were elevated to similar levels5 N$ i4 k6 ? l8 I9 j% K" }
developed after gonadotropin therapy (96 ng./dl.). Higher( Z( i, f/ d9 h$ x4 w
serum levels were noted in older patients (12 and 17 years old),
2 ^! m& A2 k2 W9 n0 c" j( {while lower levels persisted in younger patients (4, 8, and 10
. N3 J/ u& r Y$ P0 Kyears old) (see table). Despite absence of profound alterations/ f& R1 X& {/ P0 |0 L+ r
of serum testosterone the topical therapy provided a greater# `; F2 F5 }: t) M2 ?, P' }
Accepted for publication July 1, 1977. ·
( S# J6 L; a" i. v% i u7 A7 L* |6 oRead at annual meeting of American Urological Association,6 e, J8 _- X2 i* N5 d2 y8 p
Chicago, Illinois, April 24-28, 1977.0 f7 ^8 l" L( |2 d7 J7 _9 i
* Requests for reprints: Division of Urology, Henry Ford Hospital,0 W9 |3 Y9 @, N' b5 G7 i
2799 W. Grand Blvd., Detroit, Michigan 48202.. E2 O( t5 L, J- G& S; I
improvement in phallic growth compared to gonadotropin.9 Y h! n, K8 q
Average phallic growth with gonadotropin was 14.3 per cent
4 ?6 S8 y6 e+ q T) \: B& V2 pincrease in length and 5.0 per cent increase of girth. Topical
- T, L: E1 w# X; Jtestosterone produced a 60.0 per cent increase of phallic length
3 H# f# \! z0 y; xand 52.9 per cent increase of girth (circumference). The9 j/ y) k+ K7 D7 M2 D ^
response to topical testosterone was greatest in children be-5 Z- o) A9 O( m* _+ g' W
tween 4 and 8 years old, with a gradual decrease to age 173 u! f" n7 e; y2 [6 K' V3 E S
years (see table).. X2 a% D3 ]# `, a
DISCUSSION
4 F* F: y+ c9 i/ ?5 Z- n! [Topical testosterone has been used effectively by other0 ?, `: N! G7 n3 C* Y- E
clinicians but its mode of action remains controversial. Im-" `0 d& L1 \" ]1 _
mergut and associates reported an excellent growth response
+ }' U( S2 ?; S1 L4 Jto topical testosterone with low levels of serum testosterone,
0 x& |8 n* G7 y) `( ]suggesting a local effect.1 Others have obtained growth re-3 f3 h- L$ }3 m S" B0 y
sponse with high. levels of serum testosterone after topical/ |7 w5 M+ G$ w& t8 R) [3 m
administration, suggesting a systemic response. 3 The use of" v' M3 p8 [, v& B) c" C' K
gonadotropin to obtain levels of serum testosterone compara-) l) l$ @* a r! s* S
ble to levels obtained with topical testosterone would seem to
) J8 N" w" M0 K; F( b5 @ nprovide a means to compare the relative effectiveness of( l0 d6 J, [8 F3 S! Z! Y$ O
topical testosterone to systemic testosterone effect. It cer-5 _8 f7 z) z7 O5 I
tainly has been established that gonadotropin as well as par-9 O3 `5 B9 `, i/ l
enteral testosterone administration will produce genital4 f, V E- \! d3 ^
growth. Our report shows that the growth of the phallus was
. |* e+ `2 w1 |9 g( t# \3 Msignificantly greater with topical applications than with go-" a/ C6 b) ^) X7 ]0 A
nadotropin, particularly in children less than 10 years old." [. b. H& M0 {
The levels of serum testosterone remained similar or lower
6 r* E( F+ t0 `) Qthan with gonadotropin during therapy, suggesting that topi-
, i) t! W3 k' E6 ?0 Jcal application produces genital growth by its local effect as$ t2 M+ h: T0 _, |" k$ x/ D* f
well as its systemic effect.! \2 Q/ G8 }# S- ]5 l5 g
Review of our patients and their growth response related to3 `( e$ m; Q3 I/ y
age shows a greater growth response at an earlier age. This is
2 x' f8 |, a2 q3 v6 {8 Z8 aconsistent with the findings of Wilson and Walker, who2 Z3 R: d7 h d$ P7 [) x
reported an increased conversion of testosterone to dihydrotes-
: y' p5 f. h/ I7 wtosterone in the foreskin of neonates and infants.4 This activ-
# Y4 H! o6 H/ `& L7 j- fity gradually decreases with age until puberty when it ap-% b$ t: j f5 D
proaches the same level of activity as peripheral skin. It may! \7 w! W5 `& r( F6 g
well be that absorption of testosterone is less when applied at4 q9 C2 ]3 P3 B6 h; F7 c& J
an earlier age as suggested by lower serum levels in children
2 I( K4 R8 X6 m- Q2 Mless than 10 years old. This fact may be explained by the
4 h7 ?+ [, @7 t; P- Fgreater ability of phallic skin to convert testosterone to dihy-8 Y* K4 o. N$ ?3 t
drotestosterone at this age. Conversely, serum levels in older
4 v+ u. ^7 P% y4 H2 h' }! b" ^) ~2 Hpatients were higher, possibly because of decreased local9 N& Y' n2 E1 B6 T( v1 b( S
667
, b _! R* m6 t: P0 r b668 KLUGO AND CERNY
7 s/ S* ?6 e( I0 p6 E8 R* c! v9 k/ rPt. Age
+ x$ O* ~1 @# }$ y(yrs.)% @9 `. g. g7 e& j" S, t
Serum Testosterone Phallus (cm.) Change Length
- [* }" R* k3 v2 O4 W- B' y(ng./dl.) Girth x Length (%)
4 Y' ~5 p0 T, I1 a* `1 @; z4# W5 l+ ^( `& B1 \* ~
83 [3 e0 @2 }2 _ w" J o- E& c
10
Z" g! [9 K0 n- N7 g1 y; x0 J12
6 B" y! s3 J ?9 q8 ^- J& |/ e178 g6 I1 B* I6 Z6 I0 `
Gonadotropin+ a0 t4 A) a% V; i
71.6 2.0 X 3 16.6
, e* |7 c; b% v: |% x50.4 4.0 X 5.0 20.03 X. `, F9 V3 Y9 E
22.0 4.5 X 4.0 25.0
) W. M& [: k, `) A84.6 4.0 X 4.5 11.1
' q9 J* r, ?0 Q85.9 4.5 X 5.5 9.0; L- E' ~* v: M, ^4 z( h1 B
Av. 14.37 ~( S7 ?$ H4 L. N, C) M4 Y# J* S
4
& h% | W' x: [- w0 |. y8! w5 |% r z- r- q
100 h) Q$ p m2 O! s& g# c* ~3 B; G
12
0 o3 W: D. V% k9 ?3 j* Z( |17
3 g' w: A: D7 ^5 Z! ]7 z+ BTopical testosterone
# p- G) o) M% R; @; M; I6 {34.6 4.5 X 6.5 85: n/ p# u+ S0 p; o
38.8 6.0 X 8.5 705 b0 O! g( A! V& z) x8 @
40.0 6.0 X 6.5 62.5! F8 ?1 ^1 i* H# z4 y5 j6 n, o
93.6 6.0 X 7.0 55.5
; I- N, a) }5 z/ b& Y2 ~95.0 6.5 X 7.0 27.2
U! v; v9 L6 g' e2 I% JAv. 60.03 K' X2 v/ e& y. |- v
available testosterone. Again, emphasis should be placed on
, q; u: x" Q: C' U5 X. gearly therapy when lower levels of testosterone appear to3 _% i/ z; ?+ `
provide the best responses. The earlier therapy is instituted
; F2 Y5 s$ b2 q6 Xthe more likely there will be an excellent response with low9 ?, Y& `& F: d
serum levels. Response occurs throughout adolescence as) `! \. E; ~ j- D% I k
noted in nomograms of phallic growth. 7 The actual response; O6 K1 [9 G* @6 H* e1 e6 U
to a given serum level of testosterone is much greater at birth* x# i9 u. p1 {
and gradually decreases as boys reach puberty. This is most
. W0 v% S% d( k& e: n: wlikely related to the conversion of testosterone to dihydrotes-1 q# M4 j4 |- u* `3 }
tosterone and correlates well with the studies of testosterone
1 A/ U& g- n& ^conversion in foreskin at various ages.
& s, z0 Y. c" A1 S. x9 T5 EThe question arises regarding early treatment as to whether- N; \: S4 T6 _5 K6 {
one might sacrifice ultimate potential growth as with acceler-1 N5 x; g1 a9 T6 L6 T
ated bone growth. The situation appears quite the reverse* e" V! E- D4 j/ e
with phallic response. If the early growth period is not used- w6 I, T, Z9 B: X( [# Z
when 5a reductase activity is greatest then potential growth
# o3 U5 }, P/ c, ^% Kmay be lost. We have not observed any regression of growth
/ B1 r6 O% ]+ p0 b/ x# A& tattained with topical or gonadotropin therapy. It may well& ?7 q% T& S" h
be that some patients will show little or no response to any
# O# B7 X# C% Pform of therapy. This would suggest a defect in the ability to
7 w# Q7 a" Z4 s- vconvert testosterone to dihydrotestosterone and indicate that
# G5 O2 W! z0 \3 Sphallic and peripheral skin, and subcutaneous tissue should( Z9 i. |! e q, X& U8 n
be compared for 5a reductase activity.
: B: f( d) e6 e% TA, loop enlarges to measure penile girth in millimeters. B,
" n8 R& b* }# {example of penile girth computed easily and accurately.
' B$ P9 Q) e; M" k: F6 F& Vconversion of testosterone to dihydrotestosterone. It is in this- P% b8 b/ l- R. K5 x
older group that others have noted high levels of serum
* G8 l2 A X9 B! c! F6 n$ X% i1 j" wtestosterone with topical application. It would also appear
' k" u. s! Q' r% @+ M9 m9 U8 G) Uthat phallic response during puberty is related directly to the
! J- [0 S3 ^( W5 s# a" Iserum testosterone level. There also is other evidence of local% J+ r+ n/ P& P. ?3 J6 c
response to testosterone with hair growth and with spermato-
3 l! P1 ^8 k- @& L( e; F# T% Agenesis. 5• 6
1 n& s a! h& D/ wAdministration of larger doses of gonadotropin or systemic5 A9 A% t* x0 l+ Z' F s! V! W
testosterone, as well as topical applications that produce
! }+ N& k& I2 G- \1 ^' Chigher levels of serum testosterone (150 to 900 ng./dl.), will3 E5 b& N, J f+ {
also produce phallic growth but risks accelerated skeletal3 _" ~4 z! x- S- F/ m$ z. K" m' Y
maturation even after stopping treatment. It would appear4 G* Y0 j# X) P8 X+ e4 v: ]
that this may be avoided by topical applications of testosterone
# {1 m% A/ T( q7 L( d$ r. v3 {5 yand monitoring of serum testosterone. Even with this control% ~; H& _0 R: R) K/ f j* E( k- @
the duration of our therapy did not exceed 3 weeks at any- Y0 e7 m( o- d* v! r# n/ P
time. It is apparent that the prepuberal male subject may
0 H9 L) d& e, O9 Ksuffer accelerated bone growth with testosterone levels near9 P" Z2 @8 L% p9 {0 x+ A
200 ng./dl. When skeletal maturation is complete the level of
& i3 |$ j' B1 d7 V8 oserum testosterone can be maintained in the 700 to 1,300 ng./# i+ Y2 X/ ]' O k* b4 O/ h9 f
dl. range to stimulate phallic growth and secondary sexual' z" i9 v# n6 e+ M
changes. Therefore, after skeletal maturation parenteral tes-$ y p1 q8 x8 [) b; r% Y7 B
tosterone may be used to advantage. Before skeletal matura-
2 z) z$ @( j( Etion care must be taken to avoid maintaining levels of serum$ I' c' u' {, ?+ y K) g
testosterone more than 100 ng./dl. Low-dose gonadotropin
* D. }4 G: _8 Z4 K: Bdepends upon intrinsic testicular activity and may require
2 g* P- C2 W! gprolonged administration for any response.
$ ?% z3 [6 K- vAlternately, topical testosterone does not depend upon tes-
/ Q5 \4 [+ j% Hticular function and may provide a more constant level of
. ^2 r2 u, O+ X+ JREFERENCES
4 a, v$ y; R! p1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
0 F+ L" W- q/ |5 O( w s8 MR.: The local application of testosterone cream to the prepub-
4 z. \ I6 V! l# \# |ertal phallus. J. Urol., 105: 905, 1971.. S) @6 j7 W. o( l* c1 f
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
8 Q! m) I0 l/ }# H- g3 Ptreatment for micropenis during early childhood. J. Pediat.,0 {" ^$ U9 f7 D: x$ k- r9 i0 |3 G
83: 247, 1973.
5 e4 V+ w: R3 i9 a& ~3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-$ v! [: Y0 `$ D' V
one therapy for penile growth. Urology, 6: 708, 1975.
1 S+ }9 Q8 [! a. |; E4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone' X: U& ]8 n) @1 U9 Y
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
2 q# R5 F7 G# E8 ~, [, }skin slices of man. J. Clin. Invest., 48: 371, 1969.
' J- d7 N+ ?- U6 d5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
* m q" g: l+ b$ H5 a, M9 U8 p5 _by topical application of androgens. J.A.M.A., 191: 521, 1965.
+ E% H) A; ]8 R1 @8 p. E# J g6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local; L6 W4 z+ U$ I, w% _$ l& D5 m
androgenic effect of interstitial cell tumor of the testis. J.# g; ^( r" u1 j% |% W
Urol., 104: 774, 1970.( ^7 q$ u+ W7 E; W$ N
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
0 ?$ w* ]* A" [1 T/ ltion in the male genitalia from birth to maturity. J. Urol., 48: |
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