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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
) ^/ O: B+ P9 W3 x$ h/ P* I7 g, ^GONADOTROPIN
: H! V5 n3 z) C: R- o6 x2 ARICHARD C. KLUGO* AND JOSEPH C. CERNY9 R& _1 K, C9 |
From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
6 K( X2 N+ m! Y5 X/ P- K5 p* ^ABSTRACT- C$ s- u8 c: {/ X0 F& Y$ l
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
1 ^) h* S- V/ V% i7 F  |with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-$ v: ~" ]! L1 \4 @- y$ j. ]5 }
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone. M$ w5 P6 X8 F" \5 i
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
, k+ S" l8 F4 ^4 A: sfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
% q6 H2 ]" M$ ]# l; p$ @$ i% S0 Fincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average! b1 @! T. S* W3 C% M0 g0 b
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
7 U) W! }  a' O8 loccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
% W2 R. U" p/ ]3 Vstudy suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
% y/ [/ T( o8 Y( b1 Z) l1 y/ [growth. The response appears to be greater in younger children, which is consistent with previ-  a4 s8 g0 ]! D6 `0 V* q
ously published studies of age-related 5 reductase activity.
- B& y) H- K- I) ~Children with microphallus regardless of its etiology will; m3 ]9 J  q( W/ a( a9 _
require augmentation or consideration for alteration of exter-
3 a- c+ r  Q; I  Q; E! d/ |& lnal genitalia. In many instances urethroplasty for hypo-5 {4 ?+ e" a6 j# ]& f
spadias is easier with previous stimulation of phallic growth.
: i! P3 C* v; z3 [7 hThe use of testosterone administered parenterally or topically
6 o+ X: ^# a+ L) N) z# g1 mhas produced effective phallic growth. 1- 3 The mechanism of
# _4 Q" l% S) L0 kresponse has been considered as local or systemic. With this
0 ^' F% W9 [' K( _in mind we studied 5 children with microphallus for response
# `) g/ A$ f( `% V( fto gonadotropin and to topical testosterone independently.3 o+ k. |5 H0 X0 K5 b
MATERIALS AND METHODS
6 |( ^6 b* R. r+ t5 e9 a: ~9 {Five 46 XY male subjects between 3 and 17 years old were% j/ M8 J) d) n; @. h; l
evaluated for serum testosterone levels and hypothalamic
5 W! W1 s9 f5 ^3 {$ ^- Jfunction. Of these 5 boys 2 were considered to have Kallmann's
4 L6 C, m; f3 p, J" [5 ^# |syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-& b! L+ q9 ~- i( u2 p
lamic deficiency. After evaluation of response to luteinizing
9 q, V, m' b' M" N6 W0 g' z. b  Qhormone-releasing hormone these patients were treated with
+ t+ p; \" {/ G/ E  g6 c1,000 units of gonadotropin weekly for 3 weeks. Six weeks# O. ]! L" W* a7 g! ?! G- f
after completion of gonadotropin therapy 10 per cent topical8 T/ j) m' o  Y2 [" H* B. W
testosterone was applied to the phallus twice daily for 3 weeks.4 C( \( z9 |8 H; @! n0 a
Serum testosterone, luteinizing hormone and follicle-stimulat-5 z, L8 v+ S3 L9 s
ing hormone were monitored before, during and after comple-
1 N( K- x3 O2 F3 ?0 ?% X8 H* g- [tion of each phase of therapy. Penile stretch length was+ G: R0 d, B9 D1 @% [
obtained by measuring from the symphysis pubis to the tip of8 I5 x' r/ _* z! ]4 I* X
the glans. Penile circumferential (girth) measurements were
6 g* w! l5 z. y& F6 C( Mobtained using an orthopedic digital measuring device (see  p# U8 g: t, K" E
figure).
, K3 ^6 Q, l8 [2 V5 \RESULTS7 D+ E$ h" i. r5 m0 T% q. R
Serum testosterone increased moderately to levels between. d0 a: y' i* b2 r6 t$ b* G1 o9 m
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
1 h' }5 U5 n7 M  lterone levels with topical testosterone remained near pre-
$ o0 h: M; ^, E% B4 ~treatment levels (35 ng./dl.) or were elevated to similar levels
1 d, @& i) g; ]" {& f: hdeveloped after gonadotropin therapy (96 ng./dl.). Higher/ q; f/ l' |8 s
serum levels were noted in older patients (12 and 17 years old),
& Y  N, l% }- [: |while lower levels persisted in younger patients (4, 8, and 10
% L0 K( S/ s" B" |+ v% i3 myears old) (see table). Despite absence of profound alterations+ s1 e# p3 `* Y4 [
of serum testosterone the topical therapy provided a greater  P4 @0 d3 u: c- o& ~( n
Accepted for publication July 1, 1977. ·
, ^: [+ l' N* v7 e# xRead at annual meeting of American Urological Association,
0 n9 B6 @7 V- Z) q% O) e* UChicago, Illinois, April 24-28, 1977.1 \4 r$ l! p% r& r" v. o. w
* Requests for reprints: Division of Urology, Henry Ford Hospital,6 m  D- j, u, r( o
2799 W. Grand Blvd., Detroit, Michigan 48202.! |3 f4 k; Q9 y# \) w3 @
improvement in phallic growth compared to gonadotropin.3 Q$ l0 L& N( B  I3 N
Average phallic growth with gonadotropin was 14.3 per cent, R6 w1 U1 p' p# j$ c/ z+ F4 _
increase in length and 5.0 per cent increase of girth. Topical
2 g- O6 R/ I, W; t9 v' m* j3 J+ z% wtestosterone produced a 60.0 per cent increase of phallic length
8 j* M' E7 t- u+ q4 n: k, Eand 52.9 per cent increase of girth (circumference). The
! D# I- l" u" v/ g: lresponse to topical testosterone was greatest in children be-8 U2 }- Z5 s! X- ]- I- |' [0 r
tween 4 and 8 years old, with a gradual decrease to age 17; A. h9 A6 p! b% o7 ], I3 P0 T
years (see table).
3 ^/ [( p1 s0 d# D. m4 N* ODISCUSSION
% L5 d5 C1 i. w% DTopical testosterone has been used effectively by other% q1 w4 m6 Z/ G1 V. D
clinicians but its mode of action remains controversial. Im-
5 r4 a+ ]6 m2 Y& U+ G6 tmergut and associates reported an excellent growth response
" f+ b+ [0 |! u' e4 x% A0 vto topical testosterone with low levels of serum testosterone,. Z3 z  G- q) ]' i+ j
suggesting a local effect.1 Others have obtained growth re-
* m$ c; V% u  e2 Tsponse with high. levels of serum testosterone after topical
0 h6 R1 D/ W: j  T: t: tadministration, suggesting a systemic response. 3 The use of7 p8 ]7 }; s5 I# c) s& k2 |/ Q4 d
gonadotropin to obtain levels of serum testosterone compara-
3 P: Y1 ~" M9 U/ U- }ble to levels obtained with topical testosterone would seem to( ~, h, r7 k! z) V' ~6 \
provide a means to compare the relative effectiveness of' ]- R& b( x; o( U$ @8 Z' `
topical testosterone to systemic testosterone effect. It cer-( T9 m. k6 h# H( k% k
tainly has been established that gonadotropin as well as par-
: u  w  k/ O) J0 m; ]" f7 q9 J0 uenteral testosterone administration will produce genital. R' k( v+ V  K- I
growth. Our report shows that the growth of the phallus was
% w" z, h" c% P; k9 x% ]3 Esignificantly greater with topical applications than with go-4 l6 f9 V: }. V1 P) _/ R$ h
nadotropin, particularly in children less than 10 years old.
) w) f5 I. n* |The levels of serum testosterone remained similar or lower" @: b! F7 K8 `
than with gonadotropin during therapy, suggesting that topi-
& B/ E5 [4 V7 k, s) W4 d* Pcal application produces genital growth by its local effect as0 b* e+ ~. [; Q$ ?4 H- H( |5 K
well as its systemic effect.
: ?: @9 J% J& M7 S  n7 QReview of our patients and their growth response related to0 j: s& a3 `# E$ c: V7 B
age shows a greater growth response at an earlier age. This is3 E# U6 f9 S0 g: `
consistent with the findings of Wilson and Walker, who4 K- C5 x7 C: B( N$ d4 X% D) H
reported an increased conversion of testosterone to dihydrotes-
( V* K  ]7 a" j) H+ |tosterone in the foreskin of neonates and infants.4 This activ-2 {+ E; Z& S8 o  E; T$ `
ity gradually decreases with age until puberty when it ap-1 T5 w1 H& O+ k0 d, b$ f" X
proaches the same level of activity as peripheral skin. It may
, L0 |; V4 H" q% b/ Ewell be that absorption of testosterone is less when applied at
: s. t* `! `/ p7 I3 ian earlier age as suggested by lower serum levels in children
+ B5 i. J( M2 J! M" C  {less than 10 years old. This fact may be explained by the
3 Y5 u: ?5 v! i) ?1 V' q9 xgreater ability of phallic skin to convert testosterone to dihy-
2 ]$ V3 e  m; ?/ ~drotestosterone at this age. Conversely, serum levels in older  M2 Q' f8 z8 {. a1 u8 B! `( M! E4 V; l
patients were higher, possibly because of decreased local
( R+ R. E4 b; H0 v$ c3 q667- I. P" D4 w- o; o
668 KLUGO AND CERNY
$ P9 U  O1 \, T& R0 j" U$ mPt. Age
. N, o; d$ j; m& `(yrs.)6 E! W3 I; q* H9 v* O- ?3 Q: n
Serum Testosterone Phallus (cm.) Change Length
' D5 M6 K" X; G(ng./dl.) Girth x Length (%)7 w# t- G0 c" S% h# {: w1 D3 n
4
# Z7 Y  I" V* Y8
* }' T" G+ u5 q7 q6 k3 V  f8 @10& K2 n& e8 K- D+ f8 S8 ^8 i2 o
12
3 I$ b' U: [: \3 W# l8 u1 Q2 w: N17# C0 D7 a& _: _( y& ^( c$ q
Gonadotropin' i" R- x9 {  y3 t2 U6 k- O
71.6 2.0 X 3 16.6* X, r7 |8 d* P3 O6 ]# f7 N0 d# A8 o
50.4 4.0 X 5.0 20.0
2 j' d8 O/ u. {" B0 F6 |22.0 4.5 X 4.0 25.0. z7 F$ S! L7 ^9 J( C' Y
84.6 4.0 X 4.5 11.10 W4 j: I, t6 R0 R- c
85.9 4.5 X 5.5 9.03 ?& D  M; L( U3 O" @/ e
Av. 14.3
: n4 c4 ]. w' s3 o! s6 z: _4
& s4 p% V" n1 B# G2 \8
) T5 l, D, S" ]1 Q" s% J103 @) Q6 C/ S; Y; d
12
; d8 t9 S, P6 c& _. V$ T: T7 @17
1 J/ c7 v# |( }6 @# B4 ~/ _, r2 oTopical testosterone# l# [' N6 q- a
34.6 4.5 X 6.5 85/ z' q0 X, S0 O* {7 ]1 y% W* ], N7 p
38.8 6.0 X 8.5 70
) J# m* L. H5 j: F4 F7 J1 c40.0 6.0 X 6.5 62.5
. C/ L8 B0 Z& X, H93.6 6.0 X 7.0 55.5" s3 {& J( \# j: H
95.0 6.5 X 7.0 27.2$ |$ g* o* q0 f8 a9 {+ I
Av. 60.0; O/ W% m6 w& W9 S: G  `7 T! y
available testosterone. Again, emphasis should be placed on
: Q( F9 w2 m- k6 iearly therapy when lower levels of testosterone appear to7 ?) Q( U. r1 E5 B7 ]
provide the best responses. The earlier therapy is instituted0 W$ Q( h% ~. H# |- h+ q
the more likely there will be an excellent response with low
! z, [- E% N/ Q4 Bserum levels. Response occurs throughout adolescence as2 w7 j" a, e+ P  k0 `" ~. f! O$ h
noted in nomograms of phallic growth. 7 The actual response$ R$ \' s. B" H% K+ p% [# v* \
to a given serum level of testosterone is much greater at birth
. D0 ~9 w' O  ^! R3 s8 Aand gradually decreases as boys reach puberty. This is most
; w. w( Z1 h8 Zlikely related to the conversion of testosterone to dihydrotes-
. E; Q, A8 l+ T; mtosterone and correlates well with the studies of testosterone. g; z8 L) S. q$ Q
conversion in foreskin at various ages.
/ o0 N) `" z6 X$ w* e5 R9 pThe question arises regarding early treatment as to whether
) V4 p- b! O4 Q' y7 h" kone might sacrifice ultimate potential growth as with acceler-
- f6 {6 {, z# y' Q  z* U& Oated bone growth. The situation appears quite the reverse
/ O; z6 K& q: lwith phallic response. If the early growth period is not used- w" T! D2 |- q2 _' P
when 5a reductase activity is greatest then potential growth
" @  }6 n! G4 U: Amay be lost. We have not observed any regression of growth3 j" P  p7 O9 N8 N( T$ T
attained with topical or gonadotropin therapy. It may well
( y4 `0 X+ [; ube that some patients will show little or no response to any
6 M6 f- g6 ]6 {7 H4 b4 P6 S# \form of therapy. This would suggest a defect in the ability to
: r: k6 @9 ?3 ^, s5 n4 ?  `" Hconvert testosterone to dihydrotestosterone and indicate that
! }5 N6 b. o" ]- _; yphallic and peripheral skin, and subcutaneous tissue should: `  M; \8 b1 {8 A9 V/ g* t! p; {9 d
be compared for 5a reductase activity.9 `% |! @4 ?( J; p- ~5 Z; P
A, loop enlarges to measure penile girth in millimeters. B,
+ `0 x# {# J7 g1 ?example of penile girth computed easily and accurately.
3 ^9 F5 c2 b9 Y- V! {2 }3 M6 I' `conversion of testosterone to dihydrotestosterone. It is in this
7 w$ \' X7 U  o& x8 solder group that others have noted high levels of serum
8 N( M3 B; s5 M: mtestosterone with topical application. It would also appear: V3 X5 O2 P/ ?+ ?6 y; i& F
that phallic response during puberty is related directly to the% ], R: J; W' L/ N3 U
serum testosterone level. There also is other evidence of local
5 r' k  ]% }7 }( B+ U8 H  v: ~response to testosterone with hair growth and with spermato-* A1 x& d, Y. T. n! e
genesis. 5• 6
1 k2 N0 `4 f9 R+ t' q. U" V8 D0 l+ CAdministration of larger doses of gonadotropin or systemic
* b( Y# [5 ?# E' S+ Gtestosterone, as well as topical applications that produce6 g7 a9 B8 b% x
higher levels of serum testosterone (150 to 900 ng./dl.), will6 l+ m/ T+ z1 m) e( F" ]
also produce phallic growth but risks accelerated skeletal8 V" p5 ^" E/ j. C
maturation even after stopping treatment. It would appear$ D8 }& Y1 n; E0 P) @& X- i& {
that this may be avoided by topical applications of testosterone
4 E! S4 ]$ B3 }0 }2 ]" _  }and monitoring of serum testosterone. Even with this control
2 a: b1 Z7 |8 ~3 \& Cthe duration of our therapy did not exceed 3 weeks at any
6 w" f+ o/ \: ?, Atime. It is apparent that the prepuberal male subject may2 @" m3 E7 d# |7 n! s  L: I% W# p. ~
suffer accelerated bone growth with testosterone levels near
3 f# y- ~3 ~, }% Z200 ng./dl. When skeletal maturation is complete the level of
+ R/ h3 l  v1 ~6 L% L$ [  eserum testosterone can be maintained in the 700 to 1,300 ng./! |/ H* @0 K* ?  |1 i
dl. range to stimulate phallic growth and secondary sexual
+ s2 E" U8 i3 ?* }  T! qchanges. Therefore, after skeletal maturation parenteral tes-
% r$ x# {& ~% {$ R+ |' \" M7 S) ?tosterone may be used to advantage. Before skeletal matura-
% F: ?3 H5 h( K; w5 \tion care must be taken to avoid maintaining levels of serum9 m  w' |( D; ~' l
testosterone more than 100 ng./dl. Low-dose gonadotropin
  [! O# A$ m, o- ydepends upon intrinsic testicular activity and may require; `" ^6 {$ n0 d. Z; w8 ?
prolonged administration for any response.
" y' k/ G0 Q# {0 ~! B$ Q' {Alternately, topical testosterone does not depend upon tes-
: f( z, r$ D5 a9 Z- L2 lticular function and may provide a more constant level of+ K$ g( x% z+ n
REFERENCES
) T; O5 A# V: a1 n9 H1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,6 |2 w: c1 V$ I  Y  X
R.: The local application of testosterone cream to the prepub-
. d) r+ `% Z5 |$ \' k# uertal phallus. J. Urol., 105: 905, 1971.- _+ B1 \  _* Y+ P6 j+ a
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone6 H7 h$ M- M7 y1 S/ |1 h/ d
treatment for micropenis during early childhood. J. Pediat.,' b* q+ ~& O4 R8 {
83: 247, 1973.
# m# g9 m7 W4 J+ R, D3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
8 h! c- n! ?" J' r* Wone therapy for penile growth. Urology, 6: 708, 1975.
) e- u) s5 @3 r4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone) n! R: k; V- Y4 `5 A# f1 l, [- J
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
7 j  i" j- T7 G1 U" ~skin slices of man. J. Clin. Invest., 48: 371, 1969.
0 v) `+ F/ A2 m7 u5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
8 g1 O4 w# X$ S3 U& Gby topical application of androgens. J.A.M.A., 191: 521, 1965.
7 T. U0 Y9 s; @6 r1 w# f( U6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local* _8 K! T  N0 P8 p( R
androgenic effect of interstitial cell tumor of the testis. J.
7 c: ^8 s# Z0 h7 x4 T# sUrol., 104: 774, 1970./ k8 i. U& \2 E0 ~6 ^3 d2 _
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-( E2 W8 y' Y9 |" W: k2 D/ k! ~# J4 o
tion in the male genitalia from birth to maturity. J. Urol., 48:
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