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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND% o8 j2 E2 b% M4 p" x+ m6 P- t
GONADOTROPIN
% C) Y0 `( s0 b9 r! rRICHARD C. KLUGO* AND JOSEPH C. CERNY
4 }4 K$ S$ s8 ZFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan
+ b  _$ P; E: |* Q0 h2 i- S$ cABSTRACT5 a# j/ H1 `9 Y) A" h* K9 J
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
3 A3 R/ V/ w" X4 v  wwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-' A. {4 k5 {4 j7 O# i! a
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone6 f  `: y/ m5 v( S. [
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent( |: i3 s3 K" |6 b
for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
+ \- A/ l6 @5 K% q9 e6 x" w* q( ~. I# ]increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
( r: D) ?. \( c+ F3 D1 Nincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response) a' k6 Z/ |8 |/ ?! \8 D
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This# i3 z7 _' Y! [) p
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile1 L/ R5 w1 x4 }3 y9 d. v
growth. The response appears to be greater in younger children, which is consistent with previ-
$ O, i% n; V  u# w6 r- P5 Y$ xously published studies of age-related 5 reductase activity.
1 I2 |% P# g8 p( z7 o: A: fChildren with microphallus regardless of its etiology will
) L: E9 Z  T5 o5 E7 \require augmentation or consideration for alteration of exter-3 `( u$ u8 V; A& y. z
nal genitalia. In many instances urethroplasty for hypo-. d- P' o' j0 j- a0 x2 U8 D9 C
spadias is easier with previous stimulation of phallic growth.
# o+ ]' W! z, g- [) x/ LThe use of testosterone administered parenterally or topically
) {, c% n# v7 Y, f, Q$ F5 lhas produced effective phallic growth. 1- 3 The mechanism of
* k: ?4 S! X$ w' S( S8 @# Tresponse has been considered as local or systemic. With this
6 Q/ H' P4 d# f( pin mind we studied 5 children with microphallus for response
) C& S7 F7 W  x( ^& T) \to gonadotropin and to topical testosterone independently.
3 \, h  n0 Y- jMATERIALS AND METHODS( Q# d' A9 |+ ?1 j5 T/ K
Five 46 XY male subjects between 3 and 17 years old were
) H5 G' c! Z  |7 s6 H" q7 B1 V8 gevaluated for serum testosterone levels and hypothalamic) I/ w  R/ `$ z0 A$ W( ^8 x  [5 u
function. Of these 5 boys 2 were considered to have Kallmann's
2 e; \2 a+ G. @( ?( I8 {; Nsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
9 N7 s) q1 r" o# T0 ~2 Clamic deficiency. After evaluation of response to luteinizing
$ x! H& z$ K0 S) z9 ehormone-releasing hormone these patients were treated with; s: p" ?. X" [/ ]' N& }
1,000 units of gonadotropin weekly for 3 weeks. Six weeks
( N) v4 Q  t. n$ R. O* @9 |after completion of gonadotropin therapy 10 per cent topical
0 z* i6 O& a" P- Y1 v& U8 ztestosterone was applied to the phallus twice daily for 3 weeks.3 \) Z% M5 D2 H5 g0 e! [
Serum testosterone, luteinizing hormone and follicle-stimulat-
# q0 C, X- J. g. U& ]1 n* |8 ling hormone were monitored before, during and after comple-
6 L  Z) w& \( Y1 q) N" ption of each phase of therapy. Penile stretch length was
! ?5 T6 x) o0 y" D2 aobtained by measuring from the symphysis pubis to the tip of
! {: X. P# u3 s9 Hthe glans. Penile circumferential (girth) measurements were% P5 T' |* w, t4 `
obtained using an orthopedic digital measuring device (see
) \, p& Q/ F' z; E+ Hfigure).% L- V5 Q6 Q( N$ h
RESULTS1 Z, C, K$ Z/ z& s8 j
Serum testosterone increased moderately to levels between
, A5 d7 b2 ]$ V+ P/ L$ e$ W50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
% ^& ~! i. l" j# O4 z" z2 Bterone levels with topical testosterone remained near pre-
$ \! }! x# i. u( Y' Jtreatment levels (35 ng./dl.) or were elevated to similar levels' q% l# E6 s6 Q0 Z: R8 n8 i+ ~3 p
developed after gonadotropin therapy (96 ng./dl.). Higher' K& S; j+ l( ~, V- d
serum levels were noted in older patients (12 and 17 years old)," Z+ C8 L" b5 Z
while lower levels persisted in younger patients (4, 8, and 10
* _" D. I9 ~. F/ V8 M' |7 Q( Hyears old) (see table). Despite absence of profound alterations, L2 C" C4 v: c' W* D
of serum testosterone the topical therapy provided a greater- }" A/ Z- |; F2 x. Q! H
Accepted for publication July 1, 1977. ·
) n3 f% P* i9 ^4 a! K9 F, GRead at annual meeting of American Urological Association,
* X9 `0 i4 m1 M7 r0 j' O4 pChicago, Illinois, April 24-28, 1977.
5 C* Z& p# s6 j; K+ L2 t8 M  a* Requests for reprints: Division of Urology, Henry Ford Hospital,
0 ~: W5 @9 c, K: `! g2799 W. Grand Blvd., Detroit, Michigan 48202.
, t+ R, s' D, S& ximprovement in phallic growth compared to gonadotropin.
1 W& |" o- R# m- LAverage phallic growth with gonadotropin was 14.3 per cent
3 y$ X  t) h; r* E4 jincrease in length and 5.0 per cent increase of girth. Topical2 v% Y: N9 a1 b. X6 ~8 I* Y
testosterone produced a 60.0 per cent increase of phallic length" Z+ f1 Q3 }4 ?0 D
and 52.9 per cent increase of girth (circumference). The
$ c8 z3 a# }9 [4 X. W/ w! \response to topical testosterone was greatest in children be-* V/ Y$ m: E% e. m! ~% ]
tween 4 and 8 years old, with a gradual decrease to age 17
" k# M7 y4 \2 `- b( Cyears (see table).  ]$ E( h9 L4 I- p( a( |$ |2 V
DISCUSSION
' b% t, x5 F2 yTopical testosterone has been used effectively by other6 u9 L4 v1 B* ^/ \
clinicians but its mode of action remains controversial. Im-
$ ^! g  A9 V2 N5 Hmergut and associates reported an excellent growth response- n' z8 h$ n, I: E( z
to topical testosterone with low levels of serum testosterone,/ r$ _8 U; \# @' @
suggesting a local effect.1 Others have obtained growth re-" R- A# Y& j7 K2 `0 ^$ I- V
sponse with high. levels of serum testosterone after topical8 m! E% O6 B. q) Q9 ]
administration, suggesting a systemic response. 3 The use of" u' q, b. d4 o1 g- b: f8 ?
gonadotropin to obtain levels of serum testosterone compara-
0 m; K8 E% r7 d& o$ \  f7 zble to levels obtained with topical testosterone would seem to* x% v& Y. T( F! c8 T
provide a means to compare the relative effectiveness of2 n8 ^8 [; }  n
topical testosterone to systemic testosterone effect. It cer-
; w) T) B" f6 e$ k/ `+ i; ftainly has been established that gonadotropin as well as par-
+ \/ p0 h, ?4 m5 M, k: Penteral testosterone administration will produce genital4 Y1 e9 ~" ~0 @( U$ e
growth. Our report shows that the growth of the phallus was" l. h, |3 N4 E, m$ R
significantly greater with topical applications than with go-
/ e& M1 h# V) p  H9 X2 y& cnadotropin, particularly in children less than 10 years old.
4 @' L+ n: y4 S) fThe levels of serum testosterone remained similar or lower
- g- I: j6 Y0 uthan with gonadotropin during therapy, suggesting that topi-
; N3 c3 ~3 P, a, M! o( l. o( P% Ical application produces genital growth by its local effect as% C: C+ E: G' v* B" C* j- H
well as its systemic effect.
+ D2 i4 j! u9 _. C  |Review of our patients and their growth response related to' L. g4 L1 W- {, K2 K  k' ~- Y) [
age shows a greater growth response at an earlier age. This is4 M8 z* F$ p+ S& {
consistent with the findings of Wilson and Walker, who
; g2 x2 ~! L7 e( ^/ Nreported an increased conversion of testosterone to dihydrotes-
( L) j1 o( T# z% Ftosterone in the foreskin of neonates and infants.4 This activ-
1 F0 T% _+ W8 E) w' ?ity gradually decreases with age until puberty when it ap-+ A" M/ C1 ], t3 p' e# [
proaches the same level of activity as peripheral skin. It may
9 J4 H/ m" l* l8 O9 k" v0 \5 a! Hwell be that absorption of testosterone is less when applied at. K$ J8 K6 \' l2 i
an earlier age as suggested by lower serum levels in children
# @; E- Q- a9 s8 @2 Hless than 10 years old. This fact may be explained by the' {1 {+ g; ]* y  |8 M; l
greater ability of phallic skin to convert testosterone to dihy-
2 Z# }* y3 x3 Hdrotestosterone at this age. Conversely, serum levels in older, |( G( ?7 r3 F8 X% g' ?6 L3 g- I0 q
patients were higher, possibly because of decreased local0 k5 s! J/ J9 f5 F& I" J
6679 d) M0 v# d6 K) C
668 KLUGO AND CERNY' m9 c; e8 O$ R9 i( e8 y
Pt. Age
/ A# I$ q6 w* r5 F' l(yrs.): u3 a& O3 Z3 g- O9 ]$ i5 Y
Serum Testosterone Phallus (cm.) Change Length
, D! e+ Y1 t2 p5 {3 V2 O(ng./dl.) Girth x Length (%)
0 ]' u5 W( Q8 B6 v- q4% B0 i$ m0 b4 R- e" {, O
8
5 T" ~( z3 d; y6 ]5 a5 [, t  c100 W# I1 n: x2 R- Q" h' N
12! c8 u! _" T  J+ O9 u
17; d3 ~! }. X0 k1 D9 n+ ^
Gonadotropin
) ^* p" C; W" y+ p/ y+ Q4 X+ T6 i71.6 2.0 X 3 16.6
2 e+ v0 P8 d) N$ _/ G1 F50.4 4.0 X 5.0 20.0' ?: G8 M+ V: J8 J3 ]* @/ Z! |
22.0 4.5 X 4.0 25.0
" a; g& P( ]! m! S84.6 4.0 X 4.5 11.15 U4 q$ Q1 j7 x% c9 e) z
85.9 4.5 X 5.5 9.0
) R4 F* ~4 f2 X1 ZAv. 14.35 f6 t1 f! c8 O% A4 @
4% K, q0 @* [4 E5 {. d. `, }
80 T- k) `* A# E
10
# ~4 K* m# i) W3 S, w" g12
" j3 T7 m& U. P5 Z! R17
( N- S0 F' B; r' }7 A, S8 c4 WTopical testosterone& O' G' B3 _$ A& \
34.6 4.5 X 6.5 85
+ \3 Q% w' Q5 w' l( y, e38.8 6.0 X 8.5 70
0 z! o* y4 O( Y8 o! h40.0 6.0 X 6.5 62.5
( o9 g4 U; P- b0 K9 m7 y8 h2 @, x93.6 6.0 X 7.0 55.5# w: O8 i' a' J& c! {2 m( e& V6 h
95.0 6.5 X 7.0 27.2
8 I) r( S/ z* ]6 e- w* IAv. 60.0
  c; {* Q5 Y; ~& V+ q" aavailable testosterone. Again, emphasis should be placed on
- j0 B2 q, Q1 o$ v) m1 Zearly therapy when lower levels of testosterone appear to9 Y# m! J% w- ]  p
provide the best responses. The earlier therapy is instituted
3 O& T$ j" A4 R8 |4 A0 J' Mthe more likely there will be an excellent response with low3 ?* D. b) j5 }* L4 }, A/ h
serum levels. Response occurs throughout adolescence as
, x' q, O' F. onoted in nomograms of phallic growth. 7 The actual response1 z5 ]+ p2 k9 n& V) S8 x
to a given serum level of testosterone is much greater at birth
8 j2 W" L' Z, Eand gradually decreases as boys reach puberty. This is most
& @) ?& g* c% \& J+ olikely related to the conversion of testosterone to dihydrotes-# ?: W$ ]3 D+ L$ ^. T3 ?* m
tosterone and correlates well with the studies of testosterone
+ x3 I. X5 c! w! i2 Uconversion in foreskin at various ages.
, W; `, ^' z$ L. h& AThe question arises regarding early treatment as to whether
( F7 [( n8 B' ]6 c) B8 `one might sacrifice ultimate potential growth as with acceler-( B+ L/ r( g' P  t* [! a
ated bone growth. The situation appears quite the reverse$ [6 @% h, o3 W9 G3 v. |
with phallic response. If the early growth period is not used0 R" ]2 o+ J+ g1 ~* i8 s  z" w
when 5a reductase activity is greatest then potential growth0 c1 Q: X/ ]0 ]# D- _
may be lost. We have not observed any regression of growth
* v" O' W1 D8 y0 m6 Vattained with topical or gonadotropin therapy. It may well9 R: Z( G' m( X% ?
be that some patients will show little or no response to any
# |9 \! e% l' N6 h4 S5 w2 G% p* A& Wform of therapy. This would suggest a defect in the ability to
4 I% Q* [! h- u7 L6 Zconvert testosterone to dihydrotestosterone and indicate that1 g% c' c; M( @7 u- N$ q  }7 O
phallic and peripheral skin, and subcutaneous tissue should. T& f# Y$ N  R- n
be compared for 5a reductase activity.) O& K8 O0 |' ]
A, loop enlarges to measure penile girth in millimeters. B,) s! G3 z0 J- f% ]
example of penile girth computed easily and accurately.
( A% x2 {) u# l  a. P! V& ?conversion of testosterone to dihydrotestosterone. It is in this& J# F& a* ?( P7 @( V# E
older group that others have noted high levels of serum% O9 I4 C7 m7 z) S/ y1 u) z7 D
testosterone with topical application. It would also appear4 m# C6 V/ m) u; ?# k
that phallic response during puberty is related directly to the
3 F% S, A. _, a# {  w0 i5 sserum testosterone level. There also is other evidence of local* ~- v/ J  a5 R+ k( g* K
response to testosterone with hair growth and with spermato-
: h" A  R+ `2 F6 V+ Q0 jgenesis. 5• 6
9 `) j5 m$ W0 ]1 k3 \Administration of larger doses of gonadotropin or systemic/ `1 Y- O' K% s: I6 ]: p, r8 J
testosterone, as well as topical applications that produce$ t+ R% S3 f+ L6 A: U1 x, t1 {: }
higher levels of serum testosterone (150 to 900 ng./dl.), will4 i1 }# m$ }; H9 v8 O
also produce phallic growth but risks accelerated skeletal
( ^. w3 I6 s7 N- S/ |: q* Bmaturation even after stopping treatment. It would appear
& N' u: v$ h8 q% K6 w1 Qthat this may be avoided by topical applications of testosterone
* P8 H1 n& H% E4 W0 d* r8 ^' ]  xand monitoring of serum testosterone. Even with this control! F0 r9 P) u; K$ I7 `
the duration of our therapy did not exceed 3 weeks at any
8 ^( W( e, Y5 ctime. It is apparent that the prepuberal male subject may
) g" f  {8 ]! ^0 nsuffer accelerated bone growth with testosterone levels near
. x" [  |* [5 b200 ng./dl. When skeletal maturation is complete the level of
' b! w( k: M$ A1 N' |/ n7 W% oserum testosterone can be maintained in the 700 to 1,300 ng.// O! }* C1 B( K& I2 _
dl. range to stimulate phallic growth and secondary sexual
$ g# H6 E3 t7 w4 W4 f" Mchanges. Therefore, after skeletal maturation parenteral tes-
" K2 e1 e: a  X- _& d7 E; Utosterone may be used to advantage. Before skeletal matura-
, A% G$ i! G; B! X+ O+ c( [, H+ Ztion care must be taken to avoid maintaining levels of serum
+ C' B9 B9 @2 D; Atestosterone more than 100 ng./dl. Low-dose gonadotropin
, |* U' G( E' t) W9 |6 q9 c9 d) \depends upon intrinsic testicular activity and may require
0 ^9 Z* a  u, Z& [( Kprolonged administration for any response.
6 U+ C% z6 E9 H# k% G; z2 q; @Alternately, topical testosterone does not depend upon tes-
7 L) g% [( M8 P7 M! _2 Vticular function and may provide a more constant level of4 c& L, @! Z, j& R8 Q: z
REFERENCES% B* c2 f: F0 P) F2 x
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
: l2 J2 ~! C: a  _$ @; NR.: The local application of testosterone cream to the prepub-& X7 p; H: c1 X# v( W+ ^
ertal phallus. J. Urol., 105: 905, 1971.5 H8 Y+ m5 O6 R0 Q" K! J/ B* H
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone2 w/ ]- S% t1 m* I, W% |3 h* q
treatment for micropenis during early childhood. J. Pediat.,6 j- p2 |) r! E! E
83: 247, 1973.5 {) [: K) a- l/ _# O- _
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-
" n* u0 K" [  O6 f. W/ @( o, R: qone therapy for penile growth. Urology, 6: 708, 1975.
# w0 Z; d  N0 K0 @3 c2 d: k4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
: M/ M) _  r  lto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
. g& c- e* a2 q- Mskin slices of man. J. Clin. Invest., 48: 371, 1969.' {, b, O, v  R2 ^' ?  e
5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth! n( C+ S& y6 k
by topical application of androgens. J.A.M.A., 191: 521, 1965.
0 Z% G6 z2 @  ^! E7 A' {7 i! f6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local+ G  R9 ]$ q" T
androgenic effect of interstitial cell tumor of the testis. J./ B7 p$ L# Z' _7 Y$ h- {1 L; g0 e
Urol., 104: 774, 1970.+ U* ?# M  ~1 N$ x: c' ?
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-* w" T4 I5 \8 E& ]
tion in the male genitalia from birth to maturity. J. Urol., 48:
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