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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND+ |: C3 v) B7 C' A. S
GONADOTROPIN
* g1 D0 i  h/ i, N; a) t! s0 o9 }4 TRICHARD C. KLUGO* AND JOSEPH C. CERNY
( U' @6 [9 L9 CFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan' L8 D, d5 d) m, z# l0 X
ABSTRACT# y+ u0 r) A1 Q' A7 n/ F: q* Y/ H
Five patients were treated with gonadotropin and topical testosterone for micropenis associated: v- t! n) ?6 k& ?* C9 V9 w
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-( l0 G- n5 m! u" y2 Z
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone3 G  k" B1 O; ^1 y1 x) L% L0 n7 @
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
2 r" [; o, l3 `2 z; w" y2 b! N% N) h8 mfor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent0 F, S+ Y, f$ t0 \" k5 l: m& t
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average+ ]7 U( a& W- J
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response7 d. ], a* V4 z; I1 ^
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This
1 g' S3 s* [" }6 @study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile" R% L$ ~, m$ y' l% A
growth. The response appears to be greater in younger children, which is consistent with previ-
/ x: p! z5 v8 A4 B; gously published studies of age-related 5 reductase activity.
* N: ]$ _- v1 |Children with microphallus regardless of its etiology will+ {+ V' t& a% q4 O2 D2 L& o
require augmentation or consideration for alteration of exter-1 ]. b+ Z8 g9 X3 Q/ B
nal genitalia. In many instances urethroplasty for hypo-
+ p- r8 q( E4 z& g& N9 K& W$ E4 Ospadias is easier with previous stimulation of phallic growth.
9 p3 L6 p) D- `2 j4 M' yThe use of testosterone administered parenterally or topically
! j7 T, W2 l: [9 [7 m( |& _* S9 uhas produced effective phallic growth. 1- 3 The mechanism of
5 E8 u' U; [1 lresponse has been considered as local or systemic. With this
+ O. W  C/ z* D) Oin mind we studied 5 children with microphallus for response4 O+ d4 a* d* _
to gonadotropin and to topical testosterone independently.  g, u! r( u% p3 o  C0 s- H
MATERIALS AND METHODS1 |0 F2 T2 [: e. `2 M
Five 46 XY male subjects between 3 and 17 years old were
0 j# d0 q) L' `( ]) ^+ Yevaluated for serum testosterone levels and hypothalamic
" ~! f' B% |. {8 O1 D: U$ nfunction. Of these 5 boys 2 were considered to have Kallmann's' `& z7 {( l6 k' }3 |8 H
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
2 _7 T6 f) `# {8 `7 y2 t8 I# K3 _" }lamic deficiency. After evaluation of response to luteinizing3 w$ ^+ d) i+ d  B
hormone-releasing hormone these patients were treated with
( B7 m8 c% _) Z9 Y5 ~9 [# U/ T1,000 units of gonadotropin weekly for 3 weeks. Six weeks  S- Q/ `5 n' G' [
after completion of gonadotropin therapy 10 per cent topical+ u5 ^" K- o  H
testosterone was applied to the phallus twice daily for 3 weeks.1 v9 y. Z/ Q+ {) A/ V* m
Serum testosterone, luteinizing hormone and follicle-stimulat-
, n3 _% m/ a9 n5 ^; P2 @ing hormone were monitored before, during and after comple-. y$ J' [5 q( I# f# _
tion of each phase of therapy. Penile stretch length was
7 o$ [( t6 |- V! J7 d* Y$ qobtained by measuring from the symphysis pubis to the tip of3 W( h) {* O4 H7 T4 b% c
the glans. Penile circumferential (girth) measurements were
7 t  I1 d9 C+ m; u+ g) k. Q  m3 q8 O+ qobtained using an orthopedic digital measuring device (see
+ l# U, I! h8 `5 N0 s& _: nfigure).
1 W4 d0 {* L* y. {RESULTS2 X7 k+ ]9 j4 m. |+ \5 M% v! J2 h
Serum testosterone increased moderately to levels between9 h& P1 ^7 h: G. I1 I3 A0 }
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
9 E0 J- ]% T6 aterone levels with topical testosterone remained near pre-
7 i/ u/ p- x) R/ Etreatment levels (35 ng./dl.) or were elevated to similar levels. b+ l; W# F; ]" j# D, E
developed after gonadotropin therapy (96 ng./dl.). Higher
- J/ g. B8 n: h% l2 S6 mserum levels were noted in older patients (12 and 17 years old),
* I6 Q- b( F, I% E0 N$ H, v, [while lower levels persisted in younger patients (4, 8, and 10( P: @% y' U  g# m
years old) (see table). Despite absence of profound alterations
5 A. Y8 H) Q7 s) j6 `of serum testosterone the topical therapy provided a greater
6 z- e2 N: u. \" q1 H) w- fAccepted for publication July 1, 1977. ·
, W0 Z$ N) a. }6 _# aRead at annual meeting of American Urological Association,' I& G- g- l* X+ v: X& `
Chicago, Illinois, April 24-28, 1977.
$ J) o# M) m& q1 v3 {* Requests for reprints: Division of Urology, Henry Ford Hospital,2 M' k6 ~& C' W! G
2799 W. Grand Blvd., Detroit, Michigan 48202.' o1 U2 _  Z. o( @' A
improvement in phallic growth compared to gonadotropin.
" p9 U5 o$ H! Y" l, G" z; R  ]) ZAverage phallic growth with gonadotropin was 14.3 per cent
- N: n: i& h  s; S) }+ x8 u. bincrease in length and 5.0 per cent increase of girth. Topical
/ x- W# F9 e5 Y' x2 q/ vtestosterone produced a 60.0 per cent increase of phallic length5 d- F- }2 C0 d' J2 A% q7 ?
and 52.9 per cent increase of girth (circumference). The
" }8 Q% U8 E# @response to topical testosterone was greatest in children be-
2 S" [# A' Z/ dtween 4 and 8 years old, with a gradual decrease to age 17
8 Y/ h5 i8 k* T* Kyears (see table).
" r: y' e. v- }8 `5 l8 n% rDISCUSSION4 h2 n1 g( ]) s3 d& ]4 \2 O1 ^
Topical testosterone has been used effectively by other- f- N" _" S% b) V8 I
clinicians but its mode of action remains controversial. Im-
2 L- [' y7 h; L/ X0 y+ g/ _7 Z2 J9 `: emergut and associates reported an excellent growth response
7 E0 s# B+ g$ B8 V  ]! i+ G5 I0 bto topical testosterone with low levels of serum testosterone,# b8 b$ @* f1 L
suggesting a local effect.1 Others have obtained growth re-
6 G( i  o1 L. ?sponse with high. levels of serum testosterone after topical# m1 ]0 C# P! z* ?# q: N! n
administration, suggesting a systemic response. 3 The use of
8 G! N1 F% {) J+ ugonadotropin to obtain levels of serum testosterone compara-3 p+ U. K% C+ h+ J
ble to levels obtained with topical testosterone would seem to
) ^" R5 G+ _: c5 O: z- B1 ]: aprovide a means to compare the relative effectiveness of5 \1 L" L: B0 r
topical testosterone to systemic testosterone effect. It cer-
) W- a7 E( B7 d! V0 v. ptainly has been established that gonadotropin as well as par-! L% f1 ], }% k' @5 P) ^
enteral testosterone administration will produce genital
- j4 W- U9 d' V# C5 rgrowth. Our report shows that the growth of the phallus was
" Y) P4 I. B" l1 c2 K) Rsignificantly greater with topical applications than with go-
& c5 i: f: X5 L5 Xnadotropin, particularly in children less than 10 years old.
. O# I% i- `5 |" R6 f7 IThe levels of serum testosterone remained similar or lower
/ {  T4 |5 n4 Y0 wthan with gonadotropin during therapy, suggesting that topi-) ~$ R9 o5 k4 @, H3 v* K: g
cal application produces genital growth by its local effect as. h& Q( l4 b( E  d3 l
well as its systemic effect.
) t0 ?- |# L$ LReview of our patients and their growth response related to
& m( r" f0 j) Z# ^  b% R7 dage shows a greater growth response at an earlier age. This is
8 E' n$ ?+ j% }, T* econsistent with the findings of Wilson and Walker, who, `) ^4 u0 R7 C" n9 h9 E/ a
reported an increased conversion of testosterone to dihydrotes-$ |4 W3 `" P+ \/ d9 Z8 \
tosterone in the foreskin of neonates and infants.4 This activ-9 U$ f1 o2 K# _' q" t+ V& Z, V
ity gradually decreases with age until puberty when it ap-4 J$ I" v8 u, V8 C9 c2 Y1 G
proaches the same level of activity as peripheral skin. It may! a$ Z# k1 d2 ]; O
well be that absorption of testosterone is less when applied at
3 z" Z' p$ o' P3 V# r* Y$ B. ]; Gan earlier age as suggested by lower serum levels in children
9 ~8 y7 l& ~- q9 ]less than 10 years old. This fact may be explained by the
& o/ k4 ~' [2 g/ {5 h) N1 I, ~greater ability of phallic skin to convert testosterone to dihy-
- Q: g8 {4 x7 Mdrotestosterone at this age. Conversely, serum levels in older  C  U0 S3 `9 e
patients were higher, possibly because of decreased local& K1 I; |" Y! v9 v
667
& _# q# m* P! y6 [668 KLUGO AND CERNY; g4 m4 }- I/ T8 Z( C7 `6 t; s
Pt. Age
# P! E. e) s. w6 Z# \7 \(yrs.)
% ]2 h5 C4 @. zSerum Testosterone Phallus (cm.) Change Length! E, s- T3 I  a9 ]! m
(ng./dl.) Girth x Length (%)
: I0 a9 A3 c, [" [! B1 A4- M/ i; B' s# x, O# \
8
' {2 d" l% S/ p10
6 ?- ~4 G) \- M# A3 t2 ~7 }12' e" P  X% L! D1 g
17
" t. h4 \0 e9 I+ u4 f! p6 kGonadotropin1 ^, {6 c1 K; K: o
71.6 2.0 X 3 16.6# R+ f6 p) C0 H, e8 _+ [
50.4 4.0 X 5.0 20.0
" l) n0 k8 k: G6 h- \0 \5 d$ {22.0 4.5 X 4.0 25.0' O# l/ ~# x0 I* z; ^- J7 ^
84.6 4.0 X 4.5 11.1
+ ]) H. w2 L( z7 X0 z8 J85.9 4.5 X 5.5 9.0) b3 z- [7 O6 Q; H4 J* B
Av. 14.3
' g) m5 c+ a/ O! N3 j4
' J/ i. ^9 K$ I/ @: R( ^. T5 Y8
% A" ]9 e9 M4 b% A3 l1 Y' t10
6 n3 ?4 I2 Y0 t, I12
, r; ]% R% j8 U4 h1 D# Y2 Y17
4 m( `1 b& ~" K- ETopical testosterone$ u  V, V; @) g6 j' C
34.6 4.5 X 6.5 85
7 A4 t0 Y+ a* r38.8 6.0 X 8.5 70$ [2 q4 X( Q; A& w% K8 r
40.0 6.0 X 6.5 62.5
2 H, P6 e1 n+ A& e/ ]% i8 V93.6 6.0 X 7.0 55.5
& P% l0 C4 N# {! f' @7 b95.0 6.5 X 7.0 27.2) q7 ]- R# x$ Y$ D
Av. 60.0
3 M7 w1 j; i5 S# |available testosterone. Again, emphasis should be placed on
' ^/ g( w" {/ A. x3 X8 x# ~early therapy when lower levels of testosterone appear to8 `7 D# S- ?5 N: N; O
provide the best responses. The earlier therapy is instituted5 Y/ \6 i6 j3 k! g: [% J& K
the more likely there will be an excellent response with low
3 g0 }# z" E3 @: d$ hserum levels. Response occurs throughout adolescence as
# O. _" U& E1 B8 z7 cnoted in nomograms of phallic growth. 7 The actual response0 U- Z1 r& a4 Y" k$ z$ ^: ^. i! m: w
to a given serum level of testosterone is much greater at birth7 Q1 z8 F6 X* j
and gradually decreases as boys reach puberty. This is most$ S4 {: f% K! R4 z, F" U0 E
likely related to the conversion of testosterone to dihydrotes-
0 }! o+ W/ a. \& i$ e: w( etosterone and correlates well with the studies of testosterone
0 e0 F  ^' B( }1 b' o1 ~conversion in foreskin at various ages.
* b  R, F0 l( d8 s$ G" ^0 K' Q7 a' _* VThe question arises regarding early treatment as to whether
$ l8 _# d; |; V" n8 zone might sacrifice ultimate potential growth as with acceler-3 `4 k* l+ X3 Y4 ~
ated bone growth. The situation appears quite the reverse6 ^, c+ c' _6 c& e5 y
with phallic response. If the early growth period is not used
  q3 K2 m1 H! Awhen 5a reductase activity is greatest then potential growth; j9 b6 `0 H1 }7 v# s
may be lost. We have not observed any regression of growth
- w' S5 y8 l5 K; z- b! Jattained with topical or gonadotropin therapy. It may well
. L; u' j: f, O- \, ybe that some patients will show little or no response to any
+ l+ F# h! f% f) @6 j: o& Sform of therapy. This would suggest a defect in the ability to
, H+ w. Q- X$ s: Y* |  ?3 v1 Oconvert testosterone to dihydrotestosterone and indicate that; B+ p) `' `# R, _
phallic and peripheral skin, and subcutaneous tissue should6 _1 ^; g$ [5 L/ L  }
be compared for 5a reductase activity.' e/ K/ I, }( Q: W* }8 S1 u
A, loop enlarges to measure penile girth in millimeters. B,
& t: [% q* _6 bexample of penile girth computed easily and accurately.! y- u9 |( o9 Y* e9 p
conversion of testosterone to dihydrotestosterone. It is in this6 F$ e" S: N- d& R: t
older group that others have noted high levels of serum
7 h7 `) `4 `2 \9 l% Y5 itestosterone with topical application. It would also appear" ~& c. B+ O( S( K- a
that phallic response during puberty is related directly to the# o2 _2 ], |" p# @2 e7 d  b
serum testosterone level. There also is other evidence of local" m) B* w- |1 |* A2 {" U- j
response to testosterone with hair growth and with spermato-
* K8 g+ h$ R* f: d1 V# Ngenesis. 5• 6
; V2 }- f6 o  qAdministration of larger doses of gonadotropin or systemic+ X- c3 y' W' e5 b2 d: n% R6 Y
testosterone, as well as topical applications that produce- P3 [9 I* y: J) i4 L. `3 v
higher levels of serum testosterone (150 to 900 ng./dl.), will1 e9 `' T' ~' ^, ]
also produce phallic growth but risks accelerated skeletal7 {8 g3 G; i  Q% F8 H5 l7 r
maturation even after stopping treatment. It would appear& u4 D0 Z5 ?% Q! Q3 C& s3 E
that this may be avoided by topical applications of testosterone$ ^$ P5 }8 E- k
and monitoring of serum testosterone. Even with this control
' G, `- ^' v# H2 `) dthe duration of our therapy did not exceed 3 weeks at any
% @; V. L6 ]# ~time. It is apparent that the prepuberal male subject may
& V. P9 I% E. C- ~* d& Z7 [5 X8 L- csuffer accelerated bone growth with testosterone levels near
0 e6 _- l" p9 G+ s( |  j200 ng./dl. When skeletal maturation is complete the level of4 |1 n* \  S5 F
serum testosterone can be maintained in the 700 to 1,300 ng./# ~' w$ O; r2 U/ T
dl. range to stimulate phallic growth and secondary sexual
8 L# F9 b: |' Jchanges. Therefore, after skeletal maturation parenteral tes-
6 f& A1 f" B$ K4 h2 Ptosterone may be used to advantage. Before skeletal matura-; ^) x( q) j; y3 q- p' H
tion care must be taken to avoid maintaining levels of serum4 k7 s+ F) W6 E# M
testosterone more than 100 ng./dl. Low-dose gonadotropin) u* X' d& ^( g4 a) X, h0 l: E2 [
depends upon intrinsic testicular activity and may require7 |( t2 K; _; O; h5 f+ ?" Y
prolonged administration for any response.
) G4 ^* J: @- B6 P% JAlternately, topical testosterone does not depend upon tes-
5 ^: m- l! B: \* w' ?% _ticular function and may provide a more constant level of
/ _9 F. p- {8 R  t& TREFERENCES2 o) W" \, J0 c
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
2 A; u& |4 Y6 R$ X1 }- sR.: The local application of testosterone cream to the prepub-: m) T" y2 Z  c6 b1 z+ p1 v' Q
ertal phallus. J. Urol., 105: 905, 1971.
& B( b7 `' ]* \& x2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone
5 @* }. K: n* g' z) Rtreatment for micropenis during early childhood. J. Pediat.,' [* W+ H3 M! s; {
83: 247, 1973.. t- z2 F1 [- C& S) B
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-. G9 \% y/ `- Z3 W
one therapy for penile growth. Urology, 6: 708, 1975.4 n; }7 [! w3 c5 u; C
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
1 v) @" G, {* b% T  ?8 w- A+ U+ Bto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
3 |- R6 }. ?1 M7 bskin slices of man. J. Clin. Invest., 48: 371, 1969.
) `' d* g" f6 S2 e5 I5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth  R' h# A/ J5 h2 S# y: w* B# I6 t
by topical application of androgens. J.A.M.A., 191: 521, 1965.+ L* y2 J2 S" Z- I# J
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local& g) m: K" A$ x6 c4 L/ ~3 s
androgenic effect of interstitial cell tumor of the testis. J.
& Z- r) s* w! i) K4 [Urol., 104: 774, 1970.
9 o4 f! B. i" p% @4 e0 ~7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
; v# y& W3 l1 [* p" k' E5 `9 |7 ttion in the male genitalia from birth to maturity. J. Urol., 48:
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