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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND0 j" j9 V$ P: L& n
GONADOTROPIN: A1 X& E- v1 k
RICHARD C. KLUGO* AND JOSEPH C. CERNY
! [4 N* s) o9 |( A- h% ^9 _From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
) e( ~8 ~* q% B8 }3 vABSTRACT
9 i1 P) P7 j7 I- n. }4 B' e3 MFive patients were treated with gonadotropin and topical testosterone for micropenis associated% D% H0 V( k. ]" _3 a' m8 G9 b
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
5 T9 `# J( q. H8 l+ z* Ztropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone. |$ s2 w/ s& R' }' v
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
: o7 ?' T( R4 o. L& g& Z  i1 ifor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
( J; v3 ?4 C5 Pincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average
3 m; B0 I% @' a5 G& R$ Cincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response, O& F6 Z! L, u4 k
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This0 u" h9 D) [( H* a' u' a2 k
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile% j* C, d5 O' n9 w
growth. The response appears to be greater in younger children, which is consistent with previ-
! E, e2 ~! ~% @  {! u4 k7 Hously published studies of age-related 5 reductase activity.& \) |; v4 n1 L1 o! o9 V
Children with microphallus regardless of its etiology will
* u: l6 Z. m& X3 _3 x# irequire augmentation or consideration for alteration of exter-
5 u1 ]$ K0 I0 }4 H3 q+ hnal genitalia. In many instances urethroplasty for hypo-
5 J1 X- P1 c& Z1 X4 Bspadias is easier with previous stimulation of phallic growth.  a& A* L9 c# H; O" D  o: J1 z
The use of testosterone administered parenterally or topically
' Z* M/ x& l- e+ k- }7 `& @9 T% Jhas produced effective phallic growth. 1- 3 The mechanism of: L" F4 H* k& [
response has been considered as local or systemic. With this1 V* U# D; w( R$ n. F7 P
in mind we studied 5 children with microphallus for response- Z' L! d* }! W
to gonadotropin and to topical testosterone independently.
7 J; Y! s, x$ [$ ZMATERIALS AND METHODS- z+ Q% p- P: N8 G; t
Five 46 XY male subjects between 3 and 17 years old were
& _8 W# D3 B( I7 `evaluated for serum testosterone levels and hypothalamic
* I5 I: U0 D# b9 kfunction. Of these 5 boys 2 were considered to have Kallmann's8 T0 h8 P) f: ?, Y
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
5 o% I" v( }, X$ X4 mlamic deficiency. After evaluation of response to luteinizing
8 p2 i; r7 q3 U. {1 Ghormone-releasing hormone these patients were treated with; F  i( K8 d6 B6 P
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
. f2 d: F, }  v8 u6 e- E$ Iafter completion of gonadotropin therapy 10 per cent topical9 f- {* Z3 ^: l9 n' p
testosterone was applied to the phallus twice daily for 3 weeks.1 S- Y" R! w2 o: Z! v- g( f
Serum testosterone, luteinizing hormone and follicle-stimulat-
" \0 L& C( C& g/ Sing hormone were monitored before, during and after comple-
: R$ X% D5 ~* ]0 @9 M0 dtion of each phase of therapy. Penile stretch length was
3 q6 Q0 E  ?: L# iobtained by measuring from the symphysis pubis to the tip of" V3 m! r  b/ ^9 y
the glans. Penile circumferential (girth) measurements were, p3 {4 M3 }3 c6 K; \. I8 R* Q
obtained using an orthopedic digital measuring device (see
" U3 R& C7 L/ I) d) f0 dfigure).% O$ k$ S( x* @2 }5 h7 C- y0 K
RESULTS' D  Y% P4 q( n
Serum testosterone increased moderately to levels between
! g9 B5 Q- U5 O! z% c4 r50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
) `- E, z) g' \terone levels with topical testosterone remained near pre-; i- m) Z& P/ p9 _. c" V; Y" l
treatment levels (35 ng./dl.) or were elevated to similar levels
- [1 S" R. |# |. mdeveloped after gonadotropin therapy (96 ng./dl.). Higher
1 D8 n5 i8 N3 _serum levels were noted in older patients (12 and 17 years old),0 n( Q( o. H: \6 O- F
while lower levels persisted in younger patients (4, 8, and 10
; |6 W+ L1 V) X% h3 S( o# J9 B' Gyears old) (see table). Despite absence of profound alterations
0 I9 u% q7 o! ?" o- tof serum testosterone the topical therapy provided a greater
$ e1 X" P; }0 X9 T8 L  R/ r8 p% n2 MAccepted for publication July 1, 1977. ·; h" _4 h! h. [0 f4 k
Read at annual meeting of American Urological Association,
3 B  c6 N) G# V1 @8 s! bChicago, Illinois, April 24-28, 1977.
# a0 N* ]- e: d" z* Requests for reprints: Division of Urology, Henry Ford Hospital,5 J/ b6 I( I& a& j
2799 W. Grand Blvd., Detroit, Michigan 48202.
) L# B' E4 v/ v% I* H' S+ M+ ^improvement in phallic growth compared to gonadotropin.
8 e1 o- U5 C/ \' MAverage phallic growth with gonadotropin was 14.3 per cent
1 J0 A4 p! c0 I; H9 xincrease in length and 5.0 per cent increase of girth. Topical' i- r! X2 M# X* N
testosterone produced a 60.0 per cent increase of phallic length6 j$ L1 ]' z9 s3 l/ v1 P5 E
and 52.9 per cent increase of girth (circumference). The
1 [: _' i; l! R, `response to topical testosterone was greatest in children be-+ a" U- O1 @) i% i2 y8 Z
tween 4 and 8 years old, with a gradual decrease to age 17
1 {( T9 V# S! n: K; `% Myears (see table).; o( J, `  y" W1 g+ W
DISCUSSION3 p0 v2 f1 l" R2 l5 ?9 L: ~/ k
Topical testosterone has been used effectively by other4 B8 R+ P2 f- V; ^4 U% [3 T+ Q
clinicians but its mode of action remains controversial. Im-7 R4 T, C, A3 _; X7 T2 a/ D' s
mergut and associates reported an excellent growth response$ ^( n. y  }. t; y: c3 v
to topical testosterone with low levels of serum testosterone,
+ y( ^, ]" ~* fsuggesting a local effect.1 Others have obtained growth re-. m- P4 _7 v9 t9 z9 A
sponse with high. levels of serum testosterone after topical3 T0 L- J9 E- K8 b7 _' H, M1 b
administration, suggesting a systemic response. 3 The use of& |* w. D. ?6 ^. \0 `0 g
gonadotropin to obtain levels of serum testosterone compara-2 y/ f1 L6 |& k) s9 L( g
ble to levels obtained with topical testosterone would seem to
# B" S& u# p# [2 x0 d' Zprovide a means to compare the relative effectiveness of
. f% r6 ~4 v" {- ftopical testosterone to systemic testosterone effect. It cer-# j7 X+ U6 i: B6 r$ y
tainly has been established that gonadotropin as well as par-
, h! }% i( N- _0 wenteral testosterone administration will produce genital
  U* w2 G9 P: ugrowth. Our report shows that the growth of the phallus was' h7 i! {' Z/ N
significantly greater with topical applications than with go-* E1 t5 x$ J. \
nadotropin, particularly in children less than 10 years old.
& M  [- T, R. z0 m7 q+ m' aThe levels of serum testosterone remained similar or lower5 C5 Y0 ?$ ^) G3 u8 L' ]
than with gonadotropin during therapy, suggesting that topi-+ i1 i6 a# o4 r
cal application produces genital growth by its local effect as( I" O1 f6 X: U$ q3 P! V) l: l4 i7 ~
well as its systemic effect.% p/ h1 t7 n' @+ i
Review of our patients and their growth response related to
2 `) M# E0 d( k. {8 T6 uage shows a greater growth response at an earlier age. This is
( z% }/ j  m: k% S# c8 fconsistent with the findings of Wilson and Walker, who
( x% E  y. D$ L3 o7 X6 U# wreported an increased conversion of testosterone to dihydrotes-
8 L' W5 ]  [2 e# }" X, g& u: ftosterone in the foreskin of neonates and infants.4 This activ-8 d  I' ]$ ]# y$ a) K6 J) ?
ity gradually decreases with age until puberty when it ap-
7 d8 W; ~1 J% B- _proaches the same level of activity as peripheral skin. It may
1 c( Q5 l9 o5 _well be that absorption of testosterone is less when applied at
7 m& K4 d6 h% Q# [an earlier age as suggested by lower serum levels in children
: u$ `! N. z3 @$ K: e+ d+ Lless than 10 years old. This fact may be explained by the2 P* g5 a/ D8 |! t, b+ O
greater ability of phallic skin to convert testosterone to dihy-2 Z4 o- m) j+ Y: G# z3 |
drotestosterone at this age. Conversely, serum levels in older
2 n8 H2 h% m5 O' a  o9 k) }) b, N- Npatients were higher, possibly because of decreased local
1 i( F7 o  H: N0 h- [$ x' s+ K6671 B5 e% Y; b& Y, E# z4 A
668 KLUGO AND CERNY
5 r7 X5 O+ L, H6 v5 \. j. ?0 }Pt. Age- t- g+ O, I6 G$ _
(yrs.)
5 g7 Z- f. }+ D$ dSerum Testosterone Phallus (cm.) Change Length* I/ s$ M9 c8 b( K
(ng./dl.) Girth x Length (%)
+ ~0 B/ r. O# L! [46 A( u2 G+ p6 @5 S$ ?
8% _; z% h* F) p& d7 k8 b% U
107 l) q* a0 c! G$ s' m
12
& n3 h1 s' K3 o- ]17
9 a# ]8 g, Z8 e" }; n6 g2 T: s9 mGonadotropin
/ D6 T7 W5 V, S  Z' b# S71.6 2.0 X 3 16.6
; B% n$ l* z+ U6 b+ o50.4 4.0 X 5.0 20.0/ n) L5 K/ I* L" y5 ?
22.0 4.5 X 4.0 25.0; H1 b: o6 U3 ~
84.6 4.0 X 4.5 11.19 y# b, [1 L1 q* B+ M! p
85.9 4.5 X 5.5 9.0
+ y* h( l6 K6 _4 Q/ \5 H, lAv. 14.34 N+ f# o# u5 M7 B  Q1 I
4
# P- K! Q( `" a/ I; Y88 K6 y6 R% g+ y; h: O
108 |% |" y: y* j. i
12) {6 m1 a& T) z6 t' a) S
17
/ Z+ I9 M3 O% M, b) M4 L, C7 aTopical testosterone; N% ?+ ?& {: p0 l/ B6 W5 c
34.6 4.5 X 6.5 85- n- r+ C5 Q7 B0 O  h1 h
38.8 6.0 X 8.5 70, d3 e4 I- B. v+ C2 @: f
40.0 6.0 X 6.5 62.5
" Y* ]8 l9 _0 `: s93.6 6.0 X 7.0 55.5
! q1 m1 j8 M5 f) n" _2 E. d95.0 6.5 X 7.0 27.2) b+ m* X; |# v) K1 T: a
Av. 60.0/ S; Q: g0 S: v% N+ g
available testosterone. Again, emphasis should be placed on
$ T+ J3 _  ?0 `early therapy when lower levels of testosterone appear to
. _" u, h4 [; R9 cprovide the best responses. The earlier therapy is instituted
! C, q% o' q, D0 dthe more likely there will be an excellent response with low
/ G! Y6 q6 w& P7 E$ Iserum levels. Response occurs throughout adolescence as" P3 b, y7 F3 }8 y
noted in nomograms of phallic growth. 7 The actual response# k3 \6 V0 D) |7 t0 ~( Q
to a given serum level of testosterone is much greater at birth1 B+ f! Z9 L" b, N: I: x8 D; X
and gradually decreases as boys reach puberty. This is most
. H) v/ {1 J7 w) F2 llikely related to the conversion of testosterone to dihydrotes-5 W9 ^6 B# d$ e
tosterone and correlates well with the studies of testosterone) S8 n( F. \. g
conversion in foreskin at various ages.
6 y1 ^9 |0 I& Q. Q7 V8 W: kThe question arises regarding early treatment as to whether
" a2 ~# q6 |+ Q, ^, y2 Gone might sacrifice ultimate potential growth as with acceler-8 ?( K! m1 L- M' b) s
ated bone growth. The situation appears quite the reverse. A6 t! ^4 ^# D) j& \% c/ e9 J$ m/ l1 j
with phallic response. If the early growth period is not used
8 h. E1 j7 [8 G  L) gwhen 5a reductase activity is greatest then potential growth/ t* D6 B3 Y7 i" v- N8 X, @3 s8 n
may be lost. We have not observed any regression of growth
, D* |! y" R% z$ e" W+ U; ~7 oattained with topical or gonadotropin therapy. It may well* r2 U; Y2 z( o, X) }9 B6 |
be that some patients will show little or no response to any/ X- X0 D! f- N$ }
form of therapy. This would suggest a defect in the ability to
. h& q; t6 G7 L( Iconvert testosterone to dihydrotestosterone and indicate that" i1 C1 A4 ?3 |( i% ~
phallic and peripheral skin, and subcutaneous tissue should
" v0 f( ]  l, u8 ]- G+ X/ bbe compared for 5a reductase activity.5 L  S) m, ^6 z) T6 \$ f  h! m
A, loop enlarges to measure penile girth in millimeters. B,/ W( S& a$ m* V7 M, C0 |" l, C
example of penile girth computed easily and accurately.% m& E6 s- q( }- M( R
conversion of testosterone to dihydrotestosterone. It is in this7 a0 _. \; h4 a  \
older group that others have noted high levels of serum. |3 y' c" l' y4 i
testosterone with topical application. It would also appear
8 o0 h' |' Y" j9 B, e6 |: a1 q% cthat phallic response during puberty is related directly to the
, p; |2 N( R4 K" D8 K$ cserum testosterone level. There also is other evidence of local
: L. O8 z, y; |% Cresponse to testosterone with hair growth and with spermato-
2 ]5 y& b) T  m4 n2 Tgenesis. 5• 6) j9 O( P; n5 j) U$ o
Administration of larger doses of gonadotropin or systemic& a4 }5 ]7 }1 n7 x6 z$ [- Y! {' w$ y
testosterone, as well as topical applications that produce
9 K7 `  s6 C7 K1 w: k8 R+ Qhigher levels of serum testosterone (150 to 900 ng./dl.), will
6 p! V# u: I8 l/ B6 Dalso produce phallic growth but risks accelerated skeletal
- \7 p$ W9 I" v: x, ?! n  N! t5 [maturation even after stopping treatment. It would appear
% [% V0 C6 w4 Qthat this may be avoided by topical applications of testosterone( P" a- j$ M* K) u; V9 D
and monitoring of serum testosterone. Even with this control
" f$ x8 d2 O1 h# w* y+ ^7 Vthe duration of our therapy did not exceed 3 weeks at any
7 F: D( J( a0 L4 [: m# v$ D$ Z; {- Qtime. It is apparent that the prepuberal male subject may
7 D$ p$ o- k, {( P4 A: x& |suffer accelerated bone growth with testosterone levels near/ w+ E6 A; P8 @, t. u
200 ng./dl. When skeletal maturation is complete the level of0 i. E! I( [& B8 |0 f
serum testosterone can be maintained in the 700 to 1,300 ng./- N3 c- U0 B5 [$ G, I" ?8 w3 O
dl. range to stimulate phallic growth and secondary sexual
$ z8 x& K7 L+ I, C# J; I1 {) jchanges. Therefore, after skeletal maturation parenteral tes-$ \) q' R( V1 y# x2 P0 V
tosterone may be used to advantage. Before skeletal matura-$ ]# O# g: N. i2 X  _+ D6 `: b
tion care must be taken to avoid maintaining levels of serum* l: v. |: I! k# ]) M! L+ d6 ~% f
testosterone more than 100 ng./dl. Low-dose gonadotropin! S6 ?1 Z* b0 `& w/ P# a8 C
depends upon intrinsic testicular activity and may require6 h; [  w& E. R$ @" _
prolonged administration for any response.% ]/ R: n' N$ D* _9 ^0 t: Z9 M. p
Alternately, topical testosterone does not depend upon tes-
/ r- l( M* j( L9 ~( Lticular function and may provide a more constant level of
: }" i; i$ c  y9 \5 ]REFERENCES
* S# A. j; A. R" B1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
6 p7 G3 r) A/ W5 p/ WR.: The local application of testosterone cream to the prepub-
( H, h# A( O# k- B- P+ Aertal phallus. J. Urol., 105: 905, 1971.; ]/ D5 Z# c/ ^
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
1 k) v' ~; Q8 N( d( e& G) ^6 ptreatment for micropenis during early childhood. J. Pediat.,
/ q8 O: |# v5 _$ Q9 ^83: 247, 1973.
  m: {- M, Q; Z# w3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
" o7 c7 s3 v' a  ~+ }. ?: i+ C" Ione therapy for penile growth. Urology, 6: 708, 1975.7 Z0 L3 e3 _0 H% R
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
$ `! F+ R# `) O  k* Dto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by3 f; |9 n" C4 H$ T( T, E
skin slices of man. J. Clin. Invest., 48: 371, 1969.9 d! b: q2 O* [' \
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
4 P+ `9 A$ x, Q" wby topical application of androgens. J.A.M.A., 191: 521, 1965.
6 h7 Q  ^7 `5 l6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local. P6 z. R& s" B: C+ N
androgenic effect of interstitial cell tumor of the testis. J., v- N: }3 K/ L- [9 y0 F
Urol., 104: 774, 1970.
$ X1 x, Z; V3 _' x# d( A" p$ F7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
2 {% O! }+ a7 z2 s" ~7 u' _: Vtion in the male genitalia from birth to maturity. J. Urol., 48:
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