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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND5 z& Z+ j. S+ P) T* X/ _
GONADOTROPIN
: ~- e+ ^. s+ XRICHARD C. KLUGO* AND JOSEPH C. CERNY
0 r: E3 h. {2 p4 H% ?From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
1 i) W4 W' W& k( ~9 a5 NABSTRACT0 F* S; }) T8 x( _
Five patients were treated with gonadotropin and topical testosterone for micropenis associated7 d( d" P& N4 y0 N; N, U9 I) t
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
6 p$ w; w) t* C4 P* dtropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone0 Q: ^' Q3 F5 F6 [/ B
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
- B, a) Z3 J7 _8 v7 g' Qfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
6 `6 W, Y- q- \. ]" ^increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
% m1 [0 |8 v7 C1 l# T, {0 v Cincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
2 ?" \$ d' F3 O5 [1 Loccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
% X: c2 Y- x) m$ d$ f4 A( ^) Y* Estudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile4 R/ Z8 N: A- C' j' H, e
growth. The response appears to be greater in younger children, which is consistent with previ-
* Q8 e% V% g: t( p8 x4 @ously published studies of age-related 5 reductase activity.* n7 @; c4 d% q [& G$ d9 M9 r
Children with microphallus regardless of its etiology will$ y1 a* H6 r% w4 G0 Z
require augmentation or consideration for alteration of exter-! U$ [5 P' H2 Q2 `: i" M
nal genitalia. In many instances urethroplasty for hypo-: S. y }: U9 g: G6 x
spadias is easier with previous stimulation of phallic growth.
! M7 w2 D( y4 p0 V, y/ QThe use of testosterone administered parenterally or topically
6 R. a# s* W8 C* dhas produced effective phallic growth. 1- 3 The mechanism of
. ?( p6 h, N* H8 d4 Rresponse has been considered as local or systemic. With this5 t: u/ {1 w% _7 u, {% i
in mind we studied 5 children with microphallus for response" w* u4 Z. \0 r {9 h: i
to gonadotropin and to topical testosterone independently. z2 L `0 X" s9 H/ X
MATERIALS AND METHODS' ?3 c& K- L# D8 V
Five 46 XY male subjects between 3 and 17 years old were
- h- g7 p- a( k; l8 W# R8 Fevaluated for serum testosterone levels and hypothalamic
7 j# ~3 j( }" {# Gfunction. Of these 5 boys 2 were considered to have Kallmann's
- U5 A3 D' M/ x& B' Osyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-' D8 V# l5 s) r( O9 k
lamic deficiency. After evaluation of response to luteinizing; e3 N3 E! b1 u, ~
hormone-releasing hormone these patients were treated with
0 g' Y6 N# _* B3 F) a6 y" y( i1,000 units of gonadotropin weekly for 3 weeks. Six weeks! f5 ~& X* l8 J( s" X: M/ n9 n: e
after completion of gonadotropin therapy 10 per cent topical& |* Q e! }4 i0 |! \& @
testosterone was applied to the phallus twice daily for 3 weeks.
$ B/ b; q9 E' [3 B7 p5 R5 k/ [) ISerum testosterone, luteinizing hormone and follicle-stimulat-
Y& u. m3 ]) O6 K! N( ging hormone were monitored before, during and after comple-5 ^8 H9 ?3 B+ P$ \3 ^% M7 S
tion of each phase of therapy. Penile stretch length was0 f0 P( j* R) A4 A8 k
obtained by measuring from the symphysis pubis to the tip of
; y: s* y- Q, z+ I2 Wthe glans. Penile circumferential (girth) measurements were
8 F" s/ p& @ q; Fobtained using an orthopedic digital measuring device (see! b3 U* g( F+ K4 k7 E
figure).
. p3 y% D0 L `$ \9 oRESULTS
2 u$ \' Y' R I' a% _5 }; wSerum testosterone increased moderately to levels between
0 ]$ t$ j1 Z: ~5 R50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
1 ^: m7 \ A4 n! X4 I2 s3 ~terone levels with topical testosterone remained near pre-
8 P* h) [4 a8 E/ Z. z! t* _* Qtreatment levels (35 ng./dl.) or were elevated to similar levels B# D" Q! k2 C0 P+ j0 T, K
developed after gonadotropin therapy (96 ng./dl.). Higher/ [! x% h. l5 R {0 |2 B0 _$ k7 @) a, S
serum levels were noted in older patients (12 and 17 years old),
/ I0 s( M- }; n2 X( Q S6 J. xwhile lower levels persisted in younger patients (4, 8, and 10
% W, K6 g7 s2 C- ~, F! ryears old) (see table). Despite absence of profound alterations
4 a/ E z0 l% A$ Vof serum testosterone the topical therapy provided a greater
1 V7 F2 ]" z6 k& l( X" HAccepted for publication July 1, 1977. · N' D; E$ f- o: n$ a: ^- Y
Read at annual meeting of American Urological Association,4 J A- R5 L: {+ |/ i/ t3 M
Chicago, Illinois, April 24-28, 1977.
8 _/ B' o4 I3 \* Requests for reprints: Division of Urology, Henry Ford Hospital,
# d" l F6 P# x; n2799 W. Grand Blvd., Detroit, Michigan 48202.
' d- p" e, S6 @7 @. `improvement in phallic growth compared to gonadotropin.
) Y# i5 J7 h; GAverage phallic growth with gonadotropin was 14.3 per cent+ ?# s; k ]: ]; g& c
increase in length and 5.0 per cent increase of girth. Topical8 h: [) ?- m& a) N9 N6 b
testosterone produced a 60.0 per cent increase of phallic length
% K0 R2 r; W" @, z3 v0 _7 O9 nand 52.9 per cent increase of girth (circumference). The
: H$ a, \' R7 C/ Yresponse to topical testosterone was greatest in children be-
. J% \1 u8 |3 k9 [$ q6 B. Etween 4 and 8 years old, with a gradual decrease to age 17
) T6 B' Y5 @" c" l9 T h+ n* byears (see table).
# b3 N1 O. l; P* O- QDISCUSSION, s* |1 \3 O$ h5 o* V6 p
Topical testosterone has been used effectively by other
X- u3 v8 E- f7 T/ Xclinicians but its mode of action remains controversial. Im-
& w. t& Z& M0 X \4 K- E" y2 ^7 r/ Vmergut and associates reported an excellent growth response
8 a' x, `& @/ e% M9 Ato topical testosterone with low levels of serum testosterone,
0 x% `; h* m4 ]8 R9 }8 Ysuggesting a local effect.1 Others have obtained growth re-' q2 r- g' ^0 C- f
sponse with high. levels of serum testosterone after topical3 P1 x' P3 f1 H* ~/ {6 N
administration, suggesting a systemic response. 3 The use of# z( ?3 ^$ x- T# u7 K" R7 q
gonadotropin to obtain levels of serum testosterone compara-
+ u3 R5 }0 O) Q+ mble to levels obtained with topical testosterone would seem to
" x# h# N8 Q% j7 J) p! pprovide a means to compare the relative effectiveness of* O: e' o9 ?8 X3 o$ o
topical testosterone to systemic testosterone effect. It cer-
# X" N& q$ }( s) x, Q @tainly has been established that gonadotropin as well as par- D0 z/ F/ n8 [9 a7 q0 `
enteral testosterone administration will produce genital" v% f4 u( C5 } n: K7 M
growth. Our report shows that the growth of the phallus was
. t0 L5 H6 r$ @8 k! u4 qsignificantly greater with topical applications than with go-
8 E7 P F3 p, X4 ynadotropin, particularly in children less than 10 years old.
- M3 D! L! ~* G- X6 qThe levels of serum testosterone remained similar or lower( @4 P H' ]% Y1 J: ]% m
than with gonadotropin during therapy, suggesting that topi-# C' N G3 p" a/ U1 S
cal application produces genital growth by its local effect as+ f, @( q# g* Z6 x/ G% c+ R
well as its systemic effect.3 B2 k3 {2 I" P$ {
Review of our patients and their growth response related to
* d, F _ l3 d" G6 H0 `3 Xage shows a greater growth response at an earlier age. This is
; @8 p t) O5 U' Kconsistent with the findings of Wilson and Walker, who
* U9 C6 X) g" D0 o2 Ureported an increased conversion of testosterone to dihydrotes-
/ x) \+ {3 d: S2 U6 [% i8 ptosterone in the foreskin of neonates and infants.4 This activ-: b( ?- ]( _& r+ k, y( y3 [
ity gradually decreases with age until puberty when it ap-
$ u) E7 S. A* K( dproaches the same level of activity as peripheral skin. It may/ N# I# ^, |7 F/ }
well be that absorption of testosterone is less when applied at# x6 V; R6 j, |7 m1 J+ _1 l- q
an earlier age as suggested by lower serum levels in children
1 _% ?+ n- E6 S1 sless than 10 years old. This fact may be explained by the
' h7 W$ J9 O+ O) v9 Z, bgreater ability of phallic skin to convert testosterone to dihy-( n+ |- G# s4 F* v* A! p
drotestosterone at this age. Conversely, serum levels in older' ~; V% u* U, z0 z
patients were higher, possibly because of decreased local
! Q2 |1 b5 Z; o8 h0 N0 F667
, y" F! n9 G3 w, n5 S9 U668 KLUGO AND CERNY
% C# }# t+ t7 e$ H, d4 ~Pt. Age7 `# X$ j( c! ^8 Y
(yrs.)
7 U& c5 k& f6 h* N, P7 XSerum Testosterone Phallus (cm.) Change Length2 Y( S; u- U+ @5 d- v5 K) M" l
(ng./dl.) Girth x Length (%)
@) D2 }) T4 z5 y6 R4 n) E40 w8 p O9 Q9 t; I" m% t
8
1 `! d1 B% Z. e) F7 ^10
' E' n8 W0 }4 }, R' ?12
* g" X% d9 ?4 F178 r7 f2 N6 R; T# L9 t! Z! f
Gonadotropin' q- D8 G' H0 F$ _2 ?
71.6 2.0 X 3 16.6. R& t+ f0 u9 n8 E$ Q
50.4 4.0 X 5.0 20.0$ f5 C9 Y, w8 ]( S# v
22.0 4.5 X 4.0 25.08 w5 K: h# r% C- X
84.6 4.0 X 4.5 11.1
" X: `8 m" C! W* u' g. c8 W( E85.9 4.5 X 5.5 9.0
8 q, |* J+ Q) T) X' G% H2 QAv. 14.30 X4 S* P q& R: m9 S( T
4
" N8 \* g1 K" O4 \3 }0 T8
- ~4 p$ l# O( t( M; p6 @108 A9 T$ v# l, _/ P5 {
12
+ d0 |5 ^$ c& x/ }, r% T& L17$ `4 f0 x, \. g# M
Topical testosterone
^6 V B3 b# C8 ?' ]9 x% L& S34.6 4.5 X 6.5 85
1 S \, b* i8 A v/ ^) D8 d1 f7 e38.8 6.0 X 8.5 70% G9 u2 P7 x2 l$ u; s
40.0 6.0 X 6.5 62.5
3 P* R6 Y# }- |& G3 L$ h- K93.6 6.0 X 7.0 55.5
% Y& k- z0 c" O+ y- D$ M# ?95.0 6.5 X 7.0 27.2
: {9 f9 A3 F) E$ _, j# MAv. 60.0) J3 m3 X$ S9 u" T5 [2 h
available testosterone. Again, emphasis should be placed on3 ?, ?: y( h8 x6 ~# W
early therapy when lower levels of testosterone appear to
3 B. ]0 l, X5 f: y) l8 Rprovide the best responses. The earlier therapy is instituted
: B: l7 {# i8 L! G0 U' hthe more likely there will be an excellent response with low
1 P: l) ~3 Y( @' u* Eserum levels. Response occurs throughout adolescence as
, w: q. P/ d% l1 mnoted in nomograms of phallic growth. 7 The actual response+ n+ R" a+ H5 A+ \3 h$ N4 J" l; O
to a given serum level of testosterone is much greater at birth% a* e+ @# V9 J
and gradually decreases as boys reach puberty. This is most
8 [/ H% a$ `) J: jlikely related to the conversion of testosterone to dihydrotes-' f* i: N- S7 q7 C H
tosterone and correlates well with the studies of testosterone
+ i5 M- T& x' k4 m! qconversion in foreskin at various ages.& I4 N: V1 I8 Q& d
The question arises regarding early treatment as to whether& y9 b, @) X+ N# e% l# |+ {
one might sacrifice ultimate potential growth as with acceler-
* j3 V* c: e4 U$ j6 y& h# vated bone growth. The situation appears quite the reverse; ?2 X4 u2 K/ B4 J% m* ^# J
with phallic response. If the early growth period is not used, a+ Y; ^* C1 H' q
when 5a reductase activity is greatest then potential growth' t! W, n/ T( W4 e% j
may be lost. We have not observed any regression of growth! F/ i4 t' j1 `( h* C9 D, B; g/ l# d
attained with topical or gonadotropin therapy. It may well: ]# |9 N1 U) i% o5 x% s$ S
be that some patients will show little or no response to any
! V/ p1 v' M+ g& }) k0 J0 ^form of therapy. This would suggest a defect in the ability to
. z3 D6 M2 C% z' Q, H: gconvert testosterone to dihydrotestosterone and indicate that7 @; L% ~ b/ G- \9 c7 D
phallic and peripheral skin, and subcutaneous tissue should
$ p3 K7 w$ k$ D4 }be compared for 5a reductase activity.
5 `2 Q a- D* P! N# Z- r: A) fA, loop enlarges to measure penile girth in millimeters. B,
# t" t9 K# u# y' W1 F+ V( ]example of penile girth computed easily and accurately.
S" d5 i6 u4 j/ l& h0 ^ `conversion of testosterone to dihydrotestosterone. It is in this
% e2 r5 p) B& W: @0 ]older group that others have noted high levels of serum
( b& ]. m8 N' L- I, Z% ?/ btestosterone with topical application. It would also appear6 |' x' |3 C7 Z9 I/ n# N( s3 }
that phallic response during puberty is related directly to the
1 |* R, F3 a4 _6 \0 E' _9 r- `2 ^$ bserum testosterone level. There also is other evidence of local% ^* @4 x! h2 J9 @# r( h4 y+ m p/ J& f4 p
response to testosterone with hair growth and with spermato-
0 ]) t* \/ ~' W) V) \- j" G0 D- |+ k xgenesis. 5• 6
( a) F: L; A3 H+ q: |0 {Administration of larger doses of gonadotropin or systemic
8 f! U8 U/ S3 [& `. L8 M b5 ztestosterone, as well as topical applications that produce3 J! t& y& l: Z9 f$ y# x' v) q8 L
higher levels of serum testosterone (150 to 900 ng./dl.), will
; z8 k7 N; \2 G6 A# R, \! A2 walso produce phallic growth but risks accelerated skeletal) O* I3 |/ ~2 m
maturation even after stopping treatment. It would appear: n1 ]5 i# c/ A. I( a5 @, T
that this may be avoided by topical applications of testosterone
4 d3 V8 A8 q2 J$ Y( cand monitoring of serum testosterone. Even with this control
! F: {# |6 k0 {( wthe duration of our therapy did not exceed 3 weeks at any$ t! \! S S7 V+ D" o* ~
time. It is apparent that the prepuberal male subject may
& }5 n3 f R! u2 h8 ?/ F# y/ j/ nsuffer accelerated bone growth with testosterone levels near8 `: h; H+ X- t4 I% T l
200 ng./dl. When skeletal maturation is complete the level of' X5 X: q+ i) h! p. a9 ], T
serum testosterone can be maintained in the 700 to 1,300 ng./
1 i D% [5 _7 A- Sdl. range to stimulate phallic growth and secondary sexual
6 I- b4 A' u+ r% A5 kchanges. Therefore, after skeletal maturation parenteral tes-6 w2 f! j, F' }% V0 `2 I6 r! u6 O
tosterone may be used to advantage. Before skeletal matura-1 D' d, m p5 s# c. f& c
tion care must be taken to avoid maintaining levels of serum: g2 c/ H, }9 I: A w
testosterone more than 100 ng./dl. Low-dose gonadotropin* B% J/ h7 R$ o" n' q
depends upon intrinsic testicular activity and may require8 ?: H, W s; {1 O0 \+ d4 i% @
prolonged administration for any response.
9 Q. a" w7 [. b7 Y: ?) T6 mAlternately, topical testosterone does not depend upon tes-
" n; i$ B4 [! i8 Z* j$ f7 gticular function and may provide a more constant level of) k9 T' d; _! t' @7 l5 i- Q( u
REFERENCES8 d/ x6 i5 q" \- {
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
1 }5 ~& O. Y: vR.: The local application of testosterone cream to the prepub-. Y( G; x. Y+ ]1 k0 m$ M
ertal phallus. J. Urol., 105: 905, 1971.- P- d: Y2 P ]( E
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
: E. g& F1 H" z, {treatment for micropenis during early childhood. J. Pediat.,
$ o+ Y! O) ~, \83: 247, 1973.
: V7 {7 y9 B0 ]0 ?2 o6 ]9 [9 F3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
6 o1 k$ H- _( vone therapy for penile growth. Urology, 6: 708, 1975.$ {. x" y! r" w$ T; B6 r; a# i; d9 g3 W
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
R* O+ g$ E$ I6 s) U4 Fto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
& k% a# Q+ I" ^6 f3 Q! A3 uskin slices of man. J. Clin. Invest., 48: 371, 1969.
4 j& i2 w% h4 A1 a: L- o0 t: X5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
) }8 ^- O) D/ @# Zby topical application of androgens. J.A.M.A., 191: 521, 1965.
, P* F. t: A) S. L6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local$ a2 i& Q& l3 _/ R0 X( a2 p
androgenic effect of interstitial cell tumor of the testis. J.
5 d5 b7 M; A8 dUrol., 104: 774, 1970.& N, C7 d9 k2 o& |( B0 N
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
& @0 F* z' O/ F! ]4 Dtion in the male genitalia from birth to maturity. J. Urol., 48: |
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