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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
" J$ d& W1 H% N0 V% cGONADOTROPIN$ _: q: h2 K' h! } ^. q
RICHARD C. KLUGO* AND JOSEPH C. CERNY
3 b7 O2 F: Q1 HFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
. ]& b; R5 e4 D, yABSTRACT5 O1 Q ?/ ^9 B% E% g
Five patients were treated with gonadotropin and topical testosterone for micropenis associated5 ^- ~! B0 V) d% U ~
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-9 ~$ B$ q% P$ V( G0 U
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
; h* j8 ~0 H7 j" i5 Jcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
. m4 v" T' w# G, ?" C! _/ `for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
/ J8 r$ q* W* [4 Wincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average+ S) D* r3 }! I6 w
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
; V4 L/ y& x9 T. \% ?( Voccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This [* C7 g Y, n& v; w& d* D! U
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
1 t6 k4 d, N3 c( {growth. The response appears to be greater in younger children, which is consistent with previ-
6 Y& N- k4 v' a$ t9 U2 Rously published studies of age-related 5 reductase activity.8 B1 Y2 e3 j7 l% j5 B
Children with microphallus regardless of its etiology will9 }3 u9 v' A2 }) O8 @( G
require augmentation or consideration for alteration of exter-
$ ^. }- w& A, r' U# f! onal genitalia. In many instances urethroplasty for hypo-' P% @- f- D2 @4 w0 T
spadias is easier with previous stimulation of phallic growth.
; N1 S/ O+ d+ [0 h* {The use of testosterone administered parenterally or topically
/ t6 n' S# |1 r& g6 hhas produced effective phallic growth. 1- 3 The mechanism of
9 {5 p" t, |5 w9 U/ Fresponse has been considered as local or systemic. With this' c% Z; V7 U5 z3 Q; o$ O0 n
in mind we studied 5 children with microphallus for response
* t/ L$ a4 {- ?& a4 Q4 Yto gonadotropin and to topical testosterone independently.) }' S/ X* ?6 ^5 I$ r3 c5 S
MATERIALS AND METHODS
# ~2 y3 F! J6 s* F- N/ y/ b( Q% KFive 46 XY male subjects between 3 and 17 years old were( h! @: `6 N" D- V- H3 @' P
evaluated for serum testosterone levels and hypothalamic
5 w% g+ t$ B2 t' Rfunction. Of these 5 boys 2 were considered to have Kallmann's
) ^: m4 ]! Y8 H5 e" Z! Q- ]syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha- a4 U) k4 p4 y6 v6 M t( f
lamic deficiency. After evaluation of response to luteinizing
- g% X# f0 d$ chormone-releasing hormone these patients were treated with, O9 u; u( i' q; U" c: k$ R
1,000 units of gonadotropin weekly for 3 weeks. Six weeks9 w3 R5 `9 x! b! R
after completion of gonadotropin therapy 10 per cent topical- A% ^4 v+ ^: V# L1 _ l
testosterone was applied to the phallus twice daily for 3 weeks.: q: l) Q$ {3 w0 B) N
Serum testosterone, luteinizing hormone and follicle-stimulat-! s0 Q4 s D* _$ U
ing hormone were monitored before, during and after comple-
! A' \0 T% |) C+ Q# j; n4 j8 R! Dtion of each phase of therapy. Penile stretch length was
8 @5 C5 T! E9 ]; fobtained by measuring from the symphysis pubis to the tip of0 b" R4 T; O* m
the glans. Penile circumferential (girth) measurements were ^, z" [# G: B6 S/ V+ f* ^9 `
obtained using an orthopedic digital measuring device (see8 u/ R$ Z! B% F5 y* K* r1 X# U+ F
figure).2 u- D7 Z4 Q' P" B) a
RESULTS
+ @ P: I% b0 X8 ESerum testosterone increased moderately to levels between! q' b; I' \* g8 d, p3 J1 m
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
+ z/ g/ T* f1 |: V' Tterone levels with topical testosterone remained near pre-8 t6 w* I' R2 C& \) W
treatment levels (35 ng./dl.) or were elevated to similar levels
) W! B; O0 Y' `; y: L; l% @; C' Edeveloped after gonadotropin therapy (96 ng./dl.). Higher. `/ J" G/ P+ K/ E+ O0 P
serum levels were noted in older patients (12 and 17 years old),, ^) |: M, h% v9 F! c) I' p0 ]
while lower levels persisted in younger patients (4, 8, and 108 g2 V H4 l( z5 A, d8 Z# [
years old) (see table). Despite absence of profound alterations
& C+ M' U+ P$ }1 pof serum testosterone the topical therapy provided a greater
' O- m: ?! h4 J+ f; S- yAccepted for publication July 1, 1977. ·
# ~: r6 W/ U5 U6 {$ M& K" uRead at annual meeting of American Urological Association,
9 m& |9 z, i5 t7 f7 Q2 r/ TChicago, Illinois, April 24-28, 1977.
* z3 I& ^6 h! f; ^3 H+ `( h* Requests for reprints: Division of Urology, Henry Ford Hospital,
# G% {& D9 _: U* g1 p, g) o2799 W. Grand Blvd., Detroit, Michigan 48202.6 V& N2 ]! X- Q; `
improvement in phallic growth compared to gonadotropin.
, J( X' J$ \6 y6 j( KAverage phallic growth with gonadotropin was 14.3 per cent* B8 t/ p- T* `. Z6 [% I9 j4 x
increase in length and 5.0 per cent increase of girth. Topical
% e+ g, j/ v$ e3 }testosterone produced a 60.0 per cent increase of phallic length+ {* F5 z/ I( u" b
and 52.9 per cent increase of girth (circumference). The( ~, |9 t2 y' k) [
response to topical testosterone was greatest in children be-
0 F8 w2 v+ r B3 O0 w; etween 4 and 8 years old, with a gradual decrease to age 17) R0 F5 t5 s; d& l' k5 e
years (see table).- l# `5 U- X( t' y
DISCUSSION( ]- t5 p* Y. l+ r2 z& w
Topical testosterone has been used effectively by other
+ a) Z1 m% m/ Pclinicians but its mode of action remains controversial. Im-5 `+ C4 w7 U9 {8 d2 O
mergut and associates reported an excellent growth response% ?& y3 D3 Z" N9 [7 Z/ A
to topical testosterone with low levels of serum testosterone,8 T" H6 l+ E3 C/ ~ s2 K
suggesting a local effect.1 Others have obtained growth re-
: e8 Q4 F+ |' N, `1 E7 s$ J3 esponse with high. levels of serum testosterone after topical
* B3 a: F2 ~, Qadministration, suggesting a systemic response. 3 The use of
$ L& s: ~3 }7 `' f- w, ^2 P. u8 Pgonadotropin to obtain levels of serum testosterone compara-
$ X: h5 t/ W1 a* |6 k0 K6 Eble to levels obtained with topical testosterone would seem to. [7 G* Y/ v8 o, s: X
provide a means to compare the relative effectiveness of
& V6 Z2 h7 F6 D; Utopical testosterone to systemic testosterone effect. It cer-0 Q. `8 U! ^3 K1 K( R p( Y+ C: e
tainly has been established that gonadotropin as well as par-3 n/ s* Q1 o, T- P- E
enteral testosterone administration will produce genital6 e( M8 ?! H& d
growth. Our report shows that the growth of the phallus was
$ y( z4 p1 N# L- jsignificantly greater with topical applications than with go-2 x* o/ t5 j" K; r+ y
nadotropin, particularly in children less than 10 years old.
( Y4 z" K" G! TThe levels of serum testosterone remained similar or lower1 M) ?) Y X0 k5 r0 J( b" \8 ^/ x
than with gonadotropin during therapy, suggesting that topi-: N& E8 k1 m5 x/ M& k8 p/ N
cal application produces genital growth by its local effect as( _& J+ Y( N6 e* ]0 r: U9 K
well as its systemic effect.
! s( B0 h( B+ J8 m8 j% VReview of our patients and their growth response related to
/ B* D1 _* c& H8 o7 |& Oage shows a greater growth response at an earlier age. This is# |4 Q, f+ R, T2 h5 b+ |) Z
consistent with the findings of Wilson and Walker, who: k! @% ^% T1 T# F
reported an increased conversion of testosterone to dihydrotes-
* J0 q# l* G1 t4 F+ o4 Atosterone in the foreskin of neonates and infants.4 This activ-' \5 Z# r( ^& ~
ity gradually decreases with age until puberty when it ap-
* m% N& U b# h3 J3 oproaches the same level of activity as peripheral skin. It may
; e$ |/ z; X. W _5 q \well be that absorption of testosterone is less when applied at
- U0 v. X S3 L/ L# @an earlier age as suggested by lower serum levels in children: L. S, T! U* Y8 x: ^$ }
less than 10 years old. This fact may be explained by the
c( k4 r" Z1 }( `# x4 c* wgreater ability of phallic skin to convert testosterone to dihy-
( \, ~+ S) [: g* j+ ]' F! Idrotestosterone at this age. Conversely, serum levels in older
: X% e e7 }3 _( J* spatients were higher, possibly because of decreased local- C/ g# f" H7 Q8 N& L- l
667
+ l1 x" M! \: p" j, L668 KLUGO AND CERNY
4 a& P2 j3 \# \7 s( Y/ r$ IPt. Age
1 v. T/ q5 w1 Q(yrs.)9 ~. Q# X( E( M
Serum Testosterone Phallus (cm.) Change Length9 f4 t4 N: m& M1 l* Z( z3 E3 H7 ?
(ng./dl.) Girth x Length (%)' n5 J4 E$ l3 w
4# f8 M4 p+ N0 u4 ^
8% n; [3 m* w2 e! L+ V) m
10* G- Z9 a$ B: I9 ?4 u* Y
12& |: ^) N1 t C9 b; i) x, j& R
17
: {' S% f: M! Y' v$ O1 A( bGonadotropin. L: }% R* Q) U- ]: {* P1 x2 d
71.6 2.0 X 3 16.6: j0 u6 X; M: c, b s+ L* O* v
50.4 4.0 X 5.0 20.0
1 ^/ A A. y5 G) V$ \# @8 h22.0 4.5 X 4.0 25.0
+ Y3 I* B5 ]6 D. B: Z: R1 ]84.6 4.0 X 4.5 11.1. H3 |8 \( Q' W- K( ?/ T: M' K
85.9 4.5 X 5.5 9.0: i' m- M; ]2 d4 ]) A( b
Av. 14.3
9 b, A5 w; H1 a& q0 R44 s8 f% X6 E1 F' g1 |/ _
8
% B4 l& P2 q: _9 s2 \ f10! [( m, S7 [+ P g
12
. N- m4 h( z3 d$ Z- @, h17
n9 u, w' t) _# F8 t3 y( ~Topical testosterone: v$ _( I% v+ _
34.6 4.5 X 6.5 85
$ ?2 Q3 _8 _9 S- s# ?3 A% M38.8 6.0 X 8.5 70- N- I5 u+ z7 n) O! j. M+ w, p% w
40.0 6.0 X 6.5 62.5
3 e" C# m- G; P! b& J5 m$ l$ e93.6 6.0 X 7.0 55.52 [0 a# i5 r. W
95.0 6.5 X 7.0 27.2
5 N, ]9 L/ A6 M: f& AAv. 60.0& U( J$ `8 Z3 R* x7 F3 |( W% X0 {
available testosterone. Again, emphasis should be placed on0 c2 p( B( L6 u7 W
early therapy when lower levels of testosterone appear to
9 |. h& D1 b. z/ s5 [5 Aprovide the best responses. The earlier therapy is instituted
7 w; q! a- \* mthe more likely there will be an excellent response with low/ [; W% v z6 P8 D' }
serum levels. Response occurs throughout adolescence as
( R! c: P4 Q. a/ q+ u- @noted in nomograms of phallic growth. 7 The actual response
# S+ g+ L9 W( d' Lto a given serum level of testosterone is much greater at birth2 ]& D6 q1 h$ R. q
and gradually decreases as boys reach puberty. This is most3 f* S! q% [* i( V2 X
likely related to the conversion of testosterone to dihydrotes-) ~2 ~, `, r5 w
tosterone and correlates well with the studies of testosterone
6 w5 p) C' y" \6 u/ Dconversion in foreskin at various ages.2 }! c8 D' |( n% y( u
The question arises regarding early treatment as to whether
: o& W$ M) S& Gone might sacrifice ultimate potential growth as with acceler-9 s- Y: e9 Q' C0 B
ated bone growth. The situation appears quite the reverse
d2 @/ [- x+ ]3 _( s6 ?8 ~with phallic response. If the early growth period is not used
* p) b& {- j4 @when 5a reductase activity is greatest then potential growth/ [) P/ o/ o0 ~. S8 F* a+ x1 T3 j$ P
may be lost. We have not observed any regression of growth# c% e% i W% z- J3 l2 }
attained with topical or gonadotropin therapy. It may well1 L% q4 z- _ L' z* @
be that some patients will show little or no response to any
- P3 _7 b% Z x: o7 p$ Dform of therapy. This would suggest a defect in the ability to
% T; T7 M4 z% u9 ?7 r( ~% M+ Tconvert testosterone to dihydrotestosterone and indicate that
5 Z0 ?4 w+ K! d9 sphallic and peripheral skin, and subcutaneous tissue should* Y' {: u! v5 P( S
be compared for 5a reductase activity.
+ |0 y8 u& ?2 e& ?A, loop enlarges to measure penile girth in millimeters. B,
; }0 B9 ?6 Q$ V' `8 bexample of penile girth computed easily and accurately.9 e8 z0 q6 z$ q! l# l- e& g ?$ W( v
conversion of testosterone to dihydrotestosterone. It is in this
2 z; V3 m5 l1 w6 J. C9 qolder group that others have noted high levels of serum
8 I. k" l5 l2 O& c9 Z% ztestosterone with topical application. It would also appear( d G9 v# j/ Q0 q& ]$ i
that phallic response during puberty is related directly to the5 i1 E3 X' J: J/ i- P1 U1 S
serum testosterone level. There also is other evidence of local
( m, \% @# L5 q% r# M8 j @5 Nresponse to testosterone with hair growth and with spermato-: o" G6 `) T( h. [+ m
genesis. 5• 6) U# e- \1 x/ k7 e8 ]! C& l8 x
Administration of larger doses of gonadotropin or systemic# P6 P* I. O" |1 B3 B3 x0 ^
testosterone, as well as topical applications that produce
- J$ h# Y0 }0 v/ }. L; N w, _higher levels of serum testosterone (150 to 900 ng./dl.), will
d/ Y% `5 _4 yalso produce phallic growth but risks accelerated skeletal) e2 f8 }' [; v4 D% d! j, c
maturation even after stopping treatment. It would appear
( e# N! e/ ?+ _that this may be avoided by topical applications of testosterone7 N. A: ?8 _' B% l" }6 q, A' x3 S
and monitoring of serum testosterone. Even with this control
9 ~2 p: M' W3 i# g4 \the duration of our therapy did not exceed 3 weeks at any0 P1 s! H5 y: ^9 {; ~2 [& p$ v; Q
time. It is apparent that the prepuberal male subject may y* @# v" O2 n
suffer accelerated bone growth with testosterone levels near; L$ k0 k4 W0 W0 D7 x7 L: V2 m
200 ng./dl. When skeletal maturation is complete the level of- V7 ?2 @! g, z/ b7 j
serum testosterone can be maintained in the 700 to 1,300 ng./
6 i/ B& Z: v9 R0 Gdl. range to stimulate phallic growth and secondary sexual: M; }, p5 W( J5 Z E
changes. Therefore, after skeletal maturation parenteral tes-; e( L* V5 {8 X' Z7 a
tosterone may be used to advantage. Before skeletal matura-
% b: V7 L4 O% I, Z# Ftion care must be taken to avoid maintaining levels of serum
# ?! k# t: S" Z+ Mtestosterone more than 100 ng./dl. Low-dose gonadotropin: b- e# \' ?8 A/ j
depends upon intrinsic testicular activity and may require) N) b/ E9 q- C( _' _
prolonged administration for any response.$ @- w$ g+ Q) r9 S) A/ ~
Alternately, topical testosterone does not depend upon tes-
H: s4 P0 L' \7 B; Cticular function and may provide a more constant level of9 _/ m8 j# o# ]
REFERENCES7 I4 @7 [3 g9 |. C: s
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,! k. A0 k4 C7 n# `8 N
R.: The local application of testosterone cream to the prepub-3 r9 C6 i: w/ u1 M
ertal phallus. J. Urol., 105: 905, 1971.
9 X) w7 L& z1 U. c" e8 W; g4 r2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
# q5 r; J6 x5 P, k ~. t; Ntreatment for micropenis during early childhood. J. Pediat.,6 Y" g+ d- T: f: O0 H5 j b
83: 247, 1973.
6 v4 n: B5 W; d3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
, y0 @" o; v, _6 y% `6 vone therapy for penile growth. Urology, 6: 708, 1975.
( d- }2 Z9 _( p: @$ ~4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone, ]6 r% Q2 P( S$ `1 c. d
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
( X. a2 o3 t) S, S; H7 |8 A, ^skin slices of man. J. Clin. Invest., 48: 371, 1969.
9 Z. R; N0 w( W+ ~& e; y% e2 m5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
5 S7 o4 X0 W2 Z7 B' [4 {by topical application of androgens. J.A.M.A., 191: 521, 1965.
! c4 x* B' D, m3 Y$ N: Q( o0 X, E( u6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local" G& Y- e0 _0 B9 k. m# u
androgenic effect of interstitial cell tumor of the testis. J.2 u# e- F; G3 f# M
Urol., 104: 774, 1970.+ t. O0 T" q- a# x4 z
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
. L& R# o8 U4 [: }! g4 G) qtion in the male genitalia from birth to maturity. J. Urol., 48: |
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