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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND q( w& A* K$ b: F3 z" U9 g
GONADOTROPIN
6 ?+ y0 ?4 X6 Q3 l4 V# p" WRICHARD C. KLUGO* AND JOSEPH C. CERNY, u M2 L8 C4 S& z
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan. q, J4 V2 e! Q) u x5 p2 ^5 o
ABSTRACT* k1 E7 G( s# n& \( g z: K
Five patients were treated with gonadotropin and topical testosterone for micropenis associated+ J! e/ G+ F; Z) |& X2 n- |: ]
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
7 O8 g( ?; i" k! P3 `, [tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
5 j2 G& C! {* q9 O( jcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent# e, L- ?$ f* O5 l
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
5 P/ r, L% ^ D( Y7 Iincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average; ~7 \) J8 D+ ]& z
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response$ k2 ] I& e1 v* D0 J' S
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
0 r6 ~* f$ [' E1 R- E+ ustudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile8 P! [4 a3 }1 A4 v" p
growth. The response appears to be greater in younger children, which is consistent with previ-$ a% |) b: l" E" c0 c
ously published studies of age-related 5 reductase activity.9 {4 E+ t+ j6 d. k( \" _9 f
Children with microphallus regardless of its etiology will3 [2 y8 F2 b* ], h$ i# G# v2 k1 N d
require augmentation or consideration for alteration of exter-
9 ~4 G" c2 }3 p6 Z& A! a* B+ Ynal genitalia. In many instances urethroplasty for hypo-& X% K- w, j; G5 d' d8 z0 W# G- u- v
spadias is easier with previous stimulation of phallic growth.& C5 o* c9 i. G5 j* A
The use of testosterone administered parenterally or topically
8 r( H) C) M# q" P) |4 \% a/ G7 q( ]has produced effective phallic growth. 1- 3 The mechanism of
8 z& u5 {1 |$ Y0 d+ W/ wresponse has been considered as local or systemic. With this9 ^' m3 ? D/ h3 ~0 D" B9 ?. [. T
in mind we studied 5 children with microphallus for response
8 B$ o) X+ V6 f0 H' C3 j) [to gonadotropin and to topical testosterone independently.
* u: C* k# d" V6 k; \0 f, UMATERIALS AND METHODS" d9 \0 X+ Q4 x, `! v5 u+ @
Five 46 XY male subjects between 3 and 17 years old were
& v; [ S/ ?# eevaluated for serum testosterone levels and hypothalamic
1 W! G0 I/ S& u, H' P. Mfunction. Of these 5 boys 2 were considered to have Kallmann's. D1 B5 W0 l* U, }8 Z' A. e
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-' j/ H/ t, [$ Z+ B- S+ a
lamic deficiency. After evaluation of response to luteinizing
6 e, N: n7 M0 o$ }7 q. C0 phormone-releasing hormone these patients were treated with
8 t+ l6 d: `; ^( ~1,000 units of gonadotropin weekly for 3 weeks. Six weeks; ?2 x# l* c+ o& I
after completion of gonadotropin therapy 10 per cent topical
* b3 q, W3 j$ W, ftestosterone was applied to the phallus twice daily for 3 weeks.
9 {% b2 v d1 ~6 h4 D1 G% L% G/ XSerum testosterone, luteinizing hormone and follicle-stimulat-' \( K' k$ `, Q, A" I
ing hormone were monitored before, during and after comple-
* h* n( I( V7 j/ k mtion of each phase of therapy. Penile stretch length was
) J# b" s- t# t) j9 N4 zobtained by measuring from the symphysis pubis to the tip of
) t8 j; c4 X4 T5 f5 N1 ^the glans. Penile circumferential (girth) measurements were! n$ y3 i U4 R8 |: ]
obtained using an orthopedic digital measuring device (see0 h1 t% G/ o2 F: N `# a% p Q
figure).1 u4 c1 J, M% N- V m2 ]1 i
RESULTS6 d; s- E% r; x$ [$ L1 {+ R7 w8 r E8 B
Serum testosterone increased moderately to levels between
7 f& f/ \% \9 Q; i' u) a50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-1 F/ N" J1 B6 O# A$ V S
terone levels with topical testosterone remained near pre- Y( v. d$ J; H; g- y( ?& h9 T
treatment levels (35 ng./dl.) or were elevated to similar levels& Y, o" N" y+ [! i" ^4 z; H2 p
developed after gonadotropin therapy (96 ng./dl.). Higher( P; D$ b, `- ?! B, W' {, K$ M
serum levels were noted in older patients (12 and 17 years old),: Y* I3 @! \0 E+ f+ L
while lower levels persisted in younger patients (4, 8, and 10
; y3 T6 d) P9 w# B& v6 i, a myears old) (see table). Despite absence of profound alterations- Y9 m9 C+ ~5 j$ f* V; O: ]3 p/ W
of serum testosterone the topical therapy provided a greater }" a5 z& k* B9 T* B8 u
Accepted for publication July 1, 1977. ·$ @" e9 ]% j1 r' y, q
Read at annual meeting of American Urological Association,: N" a6 Q2 j. h
Chicago, Illinois, April 24-28, 1977.; t9 \9 [' N) s
* Requests for reprints: Division of Urology, Henry Ford Hospital,# o( F6 H$ g G8 P
2799 W. Grand Blvd., Detroit, Michigan 48202.# Q: ^3 F% e c; S! |
improvement in phallic growth compared to gonadotropin.
5 x& y3 t2 N4 r3 fAverage phallic growth with gonadotropin was 14.3 per cent
/ v3 X. P ]# G Q) v# [increase in length and 5.0 per cent increase of girth. Topical8 N- v% }( f7 U Y2 v- D
testosterone produced a 60.0 per cent increase of phallic length' U' G4 i; v$ h6 l) y6 @: S
and 52.9 per cent increase of girth (circumference). The6 e; H! r$ a x
response to topical testosterone was greatest in children be-
2 Y2 p2 {# T4 x( g8 b3 mtween 4 and 8 years old, with a gradual decrease to age 178 n9 q. l: w2 R$ \
years (see table).
$ m; j" R9 V0 s7 YDISCUSSION
+ B' Y |# c$ j- }Topical testosterone has been used effectively by other% H+ j8 f2 g+ D J; ]" _
clinicians but its mode of action remains controversial. Im-( w! ]& L. Z& g
mergut and associates reported an excellent growth response
- u' u0 y* x3 L% zto topical testosterone with low levels of serum testosterone,
3 G! x6 { i+ U9 x( Ksuggesting a local effect.1 Others have obtained growth re-
' Q# |+ y0 V. b9 c* Lsponse with high. levels of serum testosterone after topical
+ @- U; n' s% o( V& _4 fadministration, suggesting a systemic response. 3 The use of
+ X, W$ p& }4 Z+ [/ }; y: ~gonadotropin to obtain levels of serum testosterone compara-* Y0 r1 p9 a! `! l% y) D
ble to levels obtained with topical testosterone would seem to# F; i: h; K' p, Y8 y( W& `
provide a means to compare the relative effectiveness of
' ^: P7 l( @6 x( h( L. l; ~8 ~. Vtopical testosterone to systemic testosterone effect. It cer-7 t/ t6 t Q' M- A" F0 G1 B x
tainly has been established that gonadotropin as well as par-
. o% {' w; `) c) P& n; X6 `; qenteral testosterone administration will produce genital
) P. r9 k" s- t o8 mgrowth. Our report shows that the growth of the phallus was
* Q1 ^% a2 B4 A# @. j" m- W: Esignificantly greater with topical applications than with go-$ |+ e% N8 Q9 B' j
nadotropin, particularly in children less than 10 years old.4 {- `) l- l4 H& {& Y/ @! l6 D
The levels of serum testosterone remained similar or lower6 }9 c6 ?. m" x
than with gonadotropin during therapy, suggesting that topi-
$ |! _0 ^, d n+ k" h* G: Ocal application produces genital growth by its local effect as# D6 D% r" j! @' K, G* D* J
well as its systemic effect.4 f, o) r! A" v% n; ^
Review of our patients and their growth response related to5 t) J' M5 }5 \: B9 I
age shows a greater growth response at an earlier age. This is4 T$ Y& n& |1 X$ L) h8 a9 ] h8 t
consistent with the findings of Wilson and Walker, who
) Z, n1 s5 O/ X0 R2 x0 _reported an increased conversion of testosterone to dihydrotes-- k0 n8 X" l/ J+ V4 W
tosterone in the foreskin of neonates and infants.4 This activ- \! w3 P A/ |( X; e0 A% v- A8 p8 y6 M
ity gradually decreases with age until puberty when it ap-8 [ e D- y/ C _) \4 Q
proaches the same level of activity as peripheral skin. It may
. ?0 V/ g) E6 W V2 ?2 V0 {well be that absorption of testosterone is less when applied at% h k" E" [# D! K( b/ g+ y3 k
an earlier age as suggested by lower serum levels in children+ ] V9 `& w" S5 d: w0 a5 ?
less than 10 years old. This fact may be explained by the Y3 {3 M7 w/ Z% { J
greater ability of phallic skin to convert testosterone to dihy-" ]' N% q3 `% w$ S
drotestosterone at this age. Conversely, serum levels in older
' y5 q4 _5 y7 ~: [8 R# {patients were higher, possibly because of decreased local! F M6 b% M2 Y0 L5 v. {; a
667
5 x0 M: K! Q! B: G3 s; E K668 KLUGO AND CERNY3 G5 d; z W& g" a' k
Pt. Age
' ~. v! Z' a" h% r(yrs.)
5 {" U6 R; m4 j) gSerum Testosterone Phallus (cm.) Change Length
$ u! @* q6 M+ I6 l/ B(ng./dl.) Girth x Length (%)
; S( X( W V, E5 C/ v43 y+ H1 h+ p1 b
8
7 T$ k9 S* ~- O: p10: [$ @+ `6 v \# K8 @$ M0 {0 ^
12
% `# ^3 J) g- q# N) [4 u7 N17
$ U: m/ g: g- w8 {3 ~1 H/ g. UGonadotropin
, ]- `2 |8 M1 b- e71.6 2.0 X 3 16.61 b0 H% h" \* h9 ]0 `1 w
50.4 4.0 X 5.0 20.0
! {- ~+ c2 x0 q$ X2 B6 U22.0 4.5 X 4.0 25.0
) E" ~; \/ f) e0 b/ r2 M1 Y84.6 4.0 X 4.5 11.1 c$ O, H, |8 A1 O* L
85.9 4.5 X 5.5 9.0
) s: S% `; d& J& ^' D5 I* z6 rAv. 14.3
O& a& Q3 Z- x4 M5 [4 z3 }4
/ i5 }/ j1 O5 w7 B6 T5 I% I8$ i& v2 J; A. m5 Z
10/ ]9 G( O/ m( W8 @
126 ~7 l$ U: ~$ Z" ?; L# `0 g' q V
171 P1 L! j7 E' k! H5 j0 |0 Z
Topical testosterone
3 c' W6 d9 @, v: k34.6 4.5 X 6.5 85
6 V+ s" i6 s" c9 u; O38.8 6.0 X 8.5 70
" f$ P: Q% x, C% `40.0 6.0 X 6.5 62.5
2 t1 L. b" b% l! o0 {93.6 6.0 X 7.0 55.58 o6 {8 b+ }% C# O
95.0 6.5 X 7.0 27.2
' h& F( L" U+ Y0 RAv. 60.0
, `7 L \, Q6 f- Kavailable testosterone. Again, emphasis should be placed on
' j+ W, C6 j" F6 Vearly therapy when lower levels of testosterone appear to/ l* ` x+ j& r; {2 D4 R
provide the best responses. The earlier therapy is instituted0 |3 q& ~ z. e1 `& M2 |
the more likely there will be an excellent response with low% I6 |* @; k2 U0 \% ~
serum levels. Response occurs throughout adolescence as
4 i1 Z0 \! B1 u8 T$ hnoted in nomograms of phallic growth. 7 The actual response6 Y7 {8 `$ X/ s, k5 d K3 K+ ]8 C
to a given serum level of testosterone is much greater at birth
! }0 g: d) ?* W% M4 W" }5 e# rand gradually decreases as boys reach puberty. This is most7 r e9 y0 P" p7 A4 u
likely related to the conversion of testosterone to dihydrotes-8 B' v" Q" y5 P: C" n! L e
tosterone and correlates well with the studies of testosterone, `$ A; h" o; U" K& l9 Y% G
conversion in foreskin at various ages.
( ]* D9 |' d2 R9 _8 G" r) _The question arises regarding early treatment as to whether
& `6 g7 [5 f7 u5 l6 l# G/ }! b( uone might sacrifice ultimate potential growth as with acceler-
$ g3 b4 o5 x7 Z3 j$ m, b# `ated bone growth. The situation appears quite the reverse0 y! j/ K5 C( b( m
with phallic response. If the early growth period is not used
+ B! ?0 r# ]% V8 R9 S; n Awhen 5a reductase activity is greatest then potential growth
/ d, \" c, Z( D" N8 Umay be lost. We have not observed any regression of growth) Z) H) r l* ^7 V' J6 U$ p5 g
attained with topical or gonadotropin therapy. It may well) ?9 d* A# n+ t" p
be that some patients will show little or no response to any) h: q8 H# B( ]
form of therapy. This would suggest a defect in the ability to8 o5 ^6 k% y2 Q5 ?" {, W
convert testosterone to dihydrotestosterone and indicate that2 V% q+ A6 z) _# Q) R J5 z" c' T
phallic and peripheral skin, and subcutaneous tissue should
; `8 m9 I1 `0 x7 o, `be compared for 5a reductase activity.* n( o5 R; j8 y6 ^& I9 q
A, loop enlarges to measure penile girth in millimeters. B,0 o" j. Y) B0 E1 w( Y
example of penile girth computed easily and accurately.4 Q9 W; Y' D+ i/ ?. F
conversion of testosterone to dihydrotestosterone. It is in this
. j6 j: ]% M% Kolder group that others have noted high levels of serum
; ?4 R" j* a; I/ ]# Ltestosterone with topical application. It would also appear( t2 w4 P" z' D4 v
that phallic response during puberty is related directly to the% @( j2 f: {& d# V T
serum testosterone level. There also is other evidence of local
5 j2 e8 C0 c, L! l3 dresponse to testosterone with hair growth and with spermato-/ O/ P7 Q9 {/ }; y6 y5 {5 X' C5 p
genesis. 5• 6
, c. x" G8 r& p; [( I$ ~! ~4 ]Administration of larger doses of gonadotropin or systemic
: f8 ]: D( K5 A/ x: o# J4 Vtestosterone, as well as topical applications that produce( R* H3 K6 t' n% @8 W8 U
higher levels of serum testosterone (150 to 900 ng./dl.), will( N8 @5 B; ?( n9 p1 L% ?
also produce phallic growth but risks accelerated skeletal
, I. h3 P' _1 q7 ]% E: h* P3 Ymaturation even after stopping treatment. It would appear) o0 M3 w- D) h
that this may be avoided by topical applications of testosterone+ q) H8 q& E$ l) I2 Z9 D
and monitoring of serum testosterone. Even with this control
6 c. j1 N; S' p% G% uthe duration of our therapy did not exceed 3 weeks at any" }, Q" X Q" F# o3 P# ~, L
time. It is apparent that the prepuberal male subject may5 a2 y0 [8 ^; w6 N7 h/ L
suffer accelerated bone growth with testosterone levels near0 n z! C8 K. C1 |. u( `
200 ng./dl. When skeletal maturation is complete the level of- P3 x9 a8 _' \1 m+ n/ P
serum testosterone can be maintained in the 700 to 1,300 ng./
$ T+ N! Y4 E# E. sdl. range to stimulate phallic growth and secondary sexual
# L9 K2 K3 o8 |& W1 g9 Hchanges. Therefore, after skeletal maturation parenteral tes-
% J& }$ _1 g; B4 d' Wtosterone may be used to advantage. Before skeletal matura-( B9 D/ T9 k0 s; H; t4 c
tion care must be taken to avoid maintaining levels of serum
- l' |5 M# l+ [0 Y& b T% ctestosterone more than 100 ng./dl. Low-dose gonadotropin$ N1 W8 _6 E- E( U; R) w
depends upon intrinsic testicular activity and may require" O3 U) q( n" t
prolonged administration for any response.! v0 W' U8 O5 J
Alternately, topical testosterone does not depend upon tes-$ i! k o0 k5 m+ k
ticular function and may provide a more constant level of
. n5 z; F6 M. b" `) u0 oREFERENCES/ l4 c, e& w! O1 ?! R0 Y5 K* ~
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,5 z& } H# H7 h4 \* [+ u, L
R.: The local application of testosterone cream to the prepub-
# U" I4 i0 Q8 e; G2 L) p0 X9 rertal phallus. J. Urol., 105: 905, 1971.2 {9 `$ [1 X& P- M- o: Y
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
' i9 A9 R, l& c1 J+ `9 ptreatment for micropenis during early childhood. J. Pediat.,6 {% k5 |! W- p/ v
83: 247, 1973.; h. X/ d# [" c9 E* p$ x1 Y$ N
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
5 l1 e7 M- t. D/ s' E9 hone therapy for penile growth. Urology, 6: 708, 1975.
9 g$ Z7 p8 ]- d5 {7 G; w$ c4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
+ }0 }% g% a/ d4 }0 A. {2 Uto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
* d; X" K6 F( ]' m* @skin slices of man. J. Clin. Invest., 48: 371, 1969.! D' ^' n' G4 I+ ^% _ I: N, a+ Y
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
5 I/ F" V& u: l/ w8 rby topical application of androgens. J.A.M.A., 191: 521, 1965.
r% b. S4 p- E6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local+ O2 r U# r) `
androgenic effect of interstitial cell tumor of the testis. J." E f+ m4 ^0 P& u; V
Urol., 104: 774, 1970. }' ~6 s! @) y* `9 _
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-% O, U! ^( X: Y/ p
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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