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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
" v) w/ w- W, V. v; l) o3 OGONADOTROPIN0 }/ F& _4 ]* ? X P9 i* f
RICHARD C. KLUGO* AND JOSEPH C. CERNY
. Q1 q5 b) p3 F) q oFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
, K3 Z6 p# p* `! p1 N `$ w* hABSTRACT
+ h2 H" ^7 g$ h. ZFive patients were treated with gonadotropin and topical testosterone for micropenis associated
# T/ t" @2 T! [with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
+ x! T* L$ |4 M6 Rtropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
, I: p- s/ X4 Ccream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
/ b9 T' o# Y5 d0 w) wfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent8 c, M, p' k3 d2 ?& i. Y2 L8 K
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average& j' n }7 D, |0 l. ?( u/ a' @
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
6 _& E5 i# Y, Roccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
3 O& I" G3 r7 f; z" q' @/ gstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
* P+ @) ~ n8 b, ?2 Q+ kgrowth. The response appears to be greater in younger children, which is consistent with previ-) _5 R! `1 ?9 h: z& }6 \2 Y, F
ously published studies of age-related 5 reductase activity.
1 p* f; K# M8 J+ {$ `. \" lChildren with microphallus regardless of its etiology will
7 y+ P3 y L' G3 F1 Rrequire augmentation or consideration for alteration of exter-
9 E8 }, G) i; ?$ o. H" s% |nal genitalia. In many instances urethroplasty for hypo-
! a% y6 X" {) J8 k( dspadias is easier with previous stimulation of phallic growth.% a, l& M) y2 Z9 O0 q
The use of testosterone administered parenterally or topically
7 k- \/ Z# ]* @$ jhas produced effective phallic growth. 1- 3 The mechanism of
% `2 x- P: [: A3 j3 ~. bresponse has been considered as local or systemic. With this
2 ]4 U* P; V/ z4 e5 A( S6 P/ X# o8 F6 uin mind we studied 5 children with microphallus for response# @ [. e" s3 \5 h5 R( J8 V
to gonadotropin and to topical testosterone independently., W! q7 O% Q. \$ Y1 g {8 ~8 s" b; a
MATERIALS AND METHODS# U; T: r& ^) r0 e& h
Five 46 XY male subjects between 3 and 17 years old were
: V1 T! U8 T, `( z1 R0 Uevaluated for serum testosterone levels and hypothalamic
3 t1 ^" I/ \! D* i& x% E" w) F1 Sfunction. Of these 5 boys 2 were considered to have Kallmann's
# a; u& z& z' m h7 [2 xsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha- z: ~8 J, Y2 F4 }$ w6 Y- \- \
lamic deficiency. After evaluation of response to luteinizing
% D* E u+ v0 \2 _( ]1 S* R5 ehormone-releasing hormone these patients were treated with# v2 ]7 N! c/ ?5 d& A
1,000 units of gonadotropin weekly for 3 weeks. Six weeks; N$ J( c: |) @+ y( n9 ~& g
after completion of gonadotropin therapy 10 per cent topical
9 k% r" z2 L) Utestosterone was applied to the phallus twice daily for 3 weeks.
& Q1 Z. F$ f" o# ^& F$ g. WSerum testosterone, luteinizing hormone and follicle-stimulat-( _0 }5 S4 `# L4 }
ing hormone were monitored before, during and after comple-
' f3 v: P e5 j" l2 k9 K6 xtion of each phase of therapy. Penile stretch length was
8 j$ Q4 x% ?; H/ fobtained by measuring from the symphysis pubis to the tip of
: o$ ?8 z+ d0 }- d, [the glans. Penile circumferential (girth) measurements were S3 @6 `8 J0 S3 E
obtained using an orthopedic digital measuring device (see3 E1 H2 [/ R/ }- V
figure).
& _9 H# g! d6 m4 D% g9 TRESULTS. r2 R- W" g0 l% Q% ? C& Q
Serum testosterone increased moderately to levels between
, N* Q$ |- P; z- t7 V50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-8 } G8 p4 e$ L1 d) z
terone levels with topical testosterone remained near pre-& @: d& {! P* K
treatment levels (35 ng./dl.) or were elevated to similar levels
0 `/ W. F4 _# w2 Vdeveloped after gonadotropin therapy (96 ng./dl.). Higher
7 _! s h8 j* @7 a+ \9 u) Y2 J1 Z, ~serum levels were noted in older patients (12 and 17 years old),
. d$ F% f/ {& ywhile lower levels persisted in younger patients (4, 8, and 107 r/ u6 I4 I( G. x
years old) (see table). Despite absence of profound alterations6 ]7 R+ [& k& B" P }, M4 ]
of serum testosterone the topical therapy provided a greater8 w t9 t7 q) P( e1 x
Accepted for publication July 1, 1977. ·
) o% M2 f' k" QRead at annual meeting of American Urological Association,
: B! V3 c Z$ J* L9 uChicago, Illinois, April 24-28, 1977.
/ i& x# X) y/ r% e' n* Requests for reprints: Division of Urology, Henry Ford Hospital,0 Y2 b( U R; f) F' i) ?) T
2799 W. Grand Blvd., Detroit, Michigan 48202.6 }5 f4 l2 _( q8 ]7 ]9 ?7 \
improvement in phallic growth compared to gonadotropin.- L: S+ T( J4 F, \2 J
Average phallic growth with gonadotropin was 14.3 per cent
3 A2 _/ w* y* p9 N3 W5 A4 `increase in length and 5.0 per cent increase of girth. Topical* g& Z1 B3 w5 g
testosterone produced a 60.0 per cent increase of phallic length
9 P0 c( z0 p6 pand 52.9 per cent increase of girth (circumference). The) R4 o! r5 i7 k% m; a% J
response to topical testosterone was greatest in children be-
! p* i9 ^& X: O5 C4 Y6 f) n1 _tween 4 and 8 years old, with a gradual decrease to age 17; f V7 e+ J5 f* _: W0 b
years (see table).
0 Q, h S$ a2 K0 [DISCUSSION
2 |# k: s7 V7 _5 n( CTopical testosterone has been used effectively by other
' B- [$ z D- }7 F0 ~clinicians but its mode of action remains controversial. Im-
5 k8 I% r; ~# A7 `1 Tmergut and associates reported an excellent growth response
) Y- }( D- O! fto topical testosterone with low levels of serum testosterone,
& D6 t& V7 Y$ x2 z& F2 ]3 }, }suggesting a local effect.1 Others have obtained growth re-) y, z8 w) k/ H# o/ v0 T: g
sponse with high. levels of serum testosterone after topical! G$ d6 j( Q7 a. M1 }1 s6 @
administration, suggesting a systemic response. 3 The use of) `2 `; b# p3 G2 J5 ^
gonadotropin to obtain levels of serum testosterone compara-( y7 y9 n: M4 P' c$ _. o5 E
ble to levels obtained with topical testosterone would seem to
# M0 T0 K) M2 F2 @% Z& m1 tprovide a means to compare the relative effectiveness of6 \4 a8 o* o9 s9 M* P" c1 j! @* F
topical testosterone to systemic testosterone effect. It cer-
# a* T. j3 t$ @tainly has been established that gonadotropin as well as par-+ \; G% y/ J! y2 R' Z; L( [
enteral testosterone administration will produce genital
8 v C# t( I% Y, b* a2 Kgrowth. Our report shows that the growth of the phallus was
7 ~) ~2 `+ p2 @# w. fsignificantly greater with topical applications than with go-
6 ], N1 R3 V, N/ I* g" E% s/ V6 _nadotropin, particularly in children less than 10 years old.) G+ c, t( ~% w( X$ k& d: j* y
The levels of serum testosterone remained similar or lower
7 C9 m, T4 q, Z0 H0 s& @; pthan with gonadotropin during therapy, suggesting that topi-2 B/ |* j u+ k8 Q- M
cal application produces genital growth by its local effect as. `5 m6 W) s |, G3 z8 o$ w
well as its systemic effect., _2 o0 @9 K d
Review of our patients and their growth response related to/ V+ o3 t- q0 `. h, @6 L
age shows a greater growth response at an earlier age. This is/ A/ N( U% C1 o. u- F% W2 o
consistent with the findings of Wilson and Walker, who
% F2 L" ]; g$ P3 ]* z) c/ ^reported an increased conversion of testosterone to dihydrotes-/ X/ P) S3 O$ h, @0 ^" P3 N
tosterone in the foreskin of neonates and infants.4 This activ-6 m! S' @5 ?, A" ]- t
ity gradually decreases with age until puberty when it ap-+ x: _3 o! I3 Y1 Y. Z0 u8 |
proaches the same level of activity as peripheral skin. It may% m B2 {* p h3 s9 E% z$ h) {5 e
well be that absorption of testosterone is less when applied at
) m" |- M ]1 J8 P" f A. san earlier age as suggested by lower serum levels in children2 X: |/ A: S- y' U4 t, a
less than 10 years old. This fact may be explained by the
# D2 p# K; e) ^, j# O3 Agreater ability of phallic skin to convert testosterone to dihy-
0 E! h7 y2 g7 k- K1 U1 I5 A) U' ydrotestosterone at this age. Conversely, serum levels in older
& L2 C' e# E. L9 B6 Wpatients were higher, possibly because of decreased local* I U/ h4 w# Q1 N+ p" v2 e/ `
667
5 B; p1 b8 C3 F$ B5 O668 KLUGO AND CERNY6 S- A6 q w; [6 h% c/ k8 `' G
Pt. Age" \7 E* b4 L o7 o8 a4 ~4 M
(yrs.)9 E/ E; V. O3 J$ a4 @
Serum Testosterone Phallus (cm.) Change Length
; \! P: ]0 h4 l) d7 E) l& [(ng./dl.) Girth x Length (%)
, d2 o& z. _3 t, f4 x! R4! k+ B5 K+ |, x% B& \& x. b1 z
8
8 b* `$ j5 g- I p: O5 g+ I2 s10
' U: S3 M' H! A! }2 r3 F' i12
1 D3 m# r& [5 y17
) I" D5 X2 L' N) x1 H5 t# w; WGonadotropin# q, w' d) X, n8 k
71.6 2.0 X 3 16.6
# w% ~8 I. Z. s9 Y" K+ E' ^$ H+ @50.4 4.0 X 5.0 20.0
5 k: z9 a. F7 E6 t6 p% E22.0 4.5 X 4.0 25.0. l0 F3 c& B- O, U
84.6 4.0 X 4.5 11.1
/ s- k5 I/ c7 e" M; e% p85.9 4.5 X 5.5 9.00 q- |; r5 q2 n" X6 R9 Y% y
Av. 14.3
: M* z' d' i- g' k2 {; E% n8 H+ b4! M* G7 B2 F% T5 z- _8 i) F5 `
8
5 V8 p7 ^" H0 ^0 N107 B1 k+ l* K3 S# O. B
12
; W" c6 T" j3 u17
7 H& M# F9 p2 C% R$ ~. hTopical testosterone" M/ u K) K8 o& f/ j
34.6 4.5 X 6.5 85
% w+ I6 u0 b, J b9 }4 l- K38.8 6.0 X 8.5 70
; P9 F! ]! ]- R) w% @) @5 q, e9 A40.0 6.0 X 6.5 62.5) }( P) K+ O2 j9 l% j
93.6 6.0 X 7.0 55.5
! `" @, q8 ?5 T$ _95.0 6.5 X 7.0 27.2
" ^! M7 s7 \. FAv. 60.07 u" ]. j/ L( c2 b$ f$ O9 o
available testosterone. Again, emphasis should be placed on2 f8 [* U7 T1 L" _/ ^- {
early therapy when lower levels of testosterone appear to
% `* d; M `% H' I6 l: @provide the best responses. The earlier therapy is instituted
5 D% j9 v: I2 i% w* fthe more likely there will be an excellent response with low4 ^# I, p0 O. Z B" M' n3 Y
serum levels. Response occurs throughout adolescence as
' f( D) R0 W! V R& @* k9 Xnoted in nomograms of phallic growth. 7 The actual response
$ M2 o4 |7 G# ]8 W- B0 Yto a given serum level of testosterone is much greater at birth
' e5 o* R1 W& Y! ?and gradually decreases as boys reach puberty. This is most2 Y. i% i% p" v6 ^' A
likely related to the conversion of testosterone to dihydrotes-
. r& w2 |2 c; O i4 Rtosterone and correlates well with the studies of testosterone; s: _0 | F I
conversion in foreskin at various ages.0 @4 p# L4 p4 y( n5 b/ X& \
The question arises regarding early treatment as to whether
1 C& D, |+ d8 U9 F% D4 E: t$ Vone might sacrifice ultimate potential growth as with acceler-
5 U& B' v- d% V1 ^ated bone growth. The situation appears quite the reverse1 T. H& u5 K( a# s
with phallic response. If the early growth period is not used
4 E- p5 h8 ?/ f H( O" L" d& Fwhen 5a reductase activity is greatest then potential growth
* }# H6 E$ k4 Z2 K( H/ amay be lost. We have not observed any regression of growth
, q% t7 H. g! c5 S' Xattained with topical or gonadotropin therapy. It may well4 l! V% u' u3 A9 i, \, ~7 L
be that some patients will show little or no response to any* z$ m6 i0 D5 [4 B1 V& }0 e6 C! d
form of therapy. This would suggest a defect in the ability to
, e* w) S3 K8 Z' R" w' I, Econvert testosterone to dihydrotestosterone and indicate that: `0 }3 Y& F ?2 v* X- _: ~/ V& @& s
phallic and peripheral skin, and subcutaneous tissue should
- z: H" Z2 w1 @3 dbe compared for 5a reductase activity." a+ ]; A# Q$ v- b2 L
A, loop enlarges to measure penile girth in millimeters. B,
8 T( ^7 @- f* Q. S Vexample of penile girth computed easily and accurately./ _( ]# w: x5 Q5 D* @3 \' W
conversion of testosterone to dihydrotestosterone. It is in this
" `% Z5 m! s z8 l: j2 {8 ~older group that others have noted high levels of serum2 J* l+ p( ?7 E4 D3 N* X2 _
testosterone with topical application. It would also appear% U1 J$ a7 P& A2 M! B; f7 X1 O
that phallic response during puberty is related directly to the
4 X* D# D& O+ wserum testosterone level. There also is other evidence of local
7 @- h( G/ z3 A& v6 O: mresponse to testosterone with hair growth and with spermato-
% b& P$ J _! Q2 ~& H3 }; \, P, C$ pgenesis. 5• 6; C, d3 c( U( I* |3 O5 B
Administration of larger doses of gonadotropin or systemic- O7 D" d0 Y1 g+ q& a) C1 p5 I
testosterone, as well as topical applications that produce) ]$ ?0 H& I8 ?2 D
higher levels of serum testosterone (150 to 900 ng./dl.), will- T8 f' ?* ^0 P5 B1 Y# ^1 i# m$ E
also produce phallic growth but risks accelerated skeletal
* h/ a0 Y# H. b; v8 J' c5 E& Kmaturation even after stopping treatment. It would appear
3 Q1 u z) f3 E2 W$ |that this may be avoided by topical applications of testosterone
2 U3 l) _" \) N2 \and monitoring of serum testosterone. Even with this control
/ j. f# c. Y" @' N% U! vthe duration of our therapy did not exceed 3 weeks at any
- C& o: L; c, @: D/ Stime. It is apparent that the prepuberal male subject may! u! @+ B: M, |
suffer accelerated bone growth with testosterone levels near! e, t$ C: } t9 y L
200 ng./dl. When skeletal maturation is complete the level of
& m5 W" }2 @5 a ?) q* Aserum testosterone can be maintained in the 700 to 1,300 ng./
1 U5 D' E1 V9 ^3 q- c! ~$ Sdl. range to stimulate phallic growth and secondary sexual
8 J" u. Q4 m' Y4 v' c2 k+ qchanges. Therefore, after skeletal maturation parenteral tes-
4 E- g: M4 M6 F& T; utosterone may be used to advantage. Before skeletal matura-
( t' `) j3 t: l* G7 k0 U; Z3 ftion care must be taken to avoid maintaining levels of serum" X5 Y# ?5 A9 }- y+ {
testosterone more than 100 ng./dl. Low-dose gonadotropin
5 x- {: o6 w1 _7 r; Ddepends upon intrinsic testicular activity and may require
9 q! u* H, i+ S3 pprolonged administration for any response./ }4 \$ R# ]- S- o8 G ]
Alternately, topical testosterone does not depend upon tes-+ J( \( a" j9 s. Q& g8 C
ticular function and may provide a more constant level of
4 J: [7 t' V) d0 U. C+ A( iREFERENCES
5 L, ?8 ?' S9 f" K& e) E7 p1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
6 W3 N: R( j+ DR.: The local application of testosterone cream to the prepub-) E4 s0 M' w* o3 L( F
ertal phallus. J. Urol., 105: 905, 1971.
6 @" V7 b0 ^: r0 r. Y Q( t2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
$ y" w) M( E- ^5 H5 |, atreatment for micropenis during early childhood. J. Pediat.,. A* J( k( w0 ] d4 B- G) N I: B! a' X
83: 247, 1973.! j/ H* M) D+ ?0 H7 Q1 ^
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
' e# i1 f, b$ e: [one therapy for penile growth. Urology, 6: 708, 1975.% `& k' p5 X! C' {
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
- m9 @$ Z7 R5 X: p3 Pto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
1 M# z$ f4 A+ `' ? C$ P9 g; \skin slices of man. J. Clin. Invest., 48: 371, 1969.1 g) @* o! B1 Y# S! U6 K1 C3 [' J$ j
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth0 ^+ L7 M! s2 ^, T ~) Q
by topical application of androgens. J.A.M.A., 191: 521, 1965.
. X' j1 k( `0 @& q) V" z6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
/ R4 \. `4 L- e+ w% fandrogenic effect of interstitial cell tumor of the testis. J.
7 s; `' O: p* w- k% W0 I9 iUrol., 104: 774, 1970.
' G' b5 l/ e" q) R7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
" n2 v' Y; ]6 j: ?" L: b2 g! Ktion in the male genitalia from birth to maturity. J. Urol., 48: |
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