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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND& X4 Y3 a$ Y/ R' j
GONADOTROPIN
% g, m$ ~2 F9 J6 G, `( wRICHARD C. KLUGO* AND JOSEPH C. CERNY
$ j3 N: }! J/ U( |/ y9 \From the Division of Urology, Henry Ford Hospital, Detroit, Michigan
, |; \: O" M* V, WABSTRACT
; L6 d4 P2 B) fFive patients were treated with gonadotropin and topical testosterone for micropenis associated- r" l: T" e) L9 w
with hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-- _3 e% N: t% ?, t
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone
" B6 M0 O5 E: i. `2 R/ Dcream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
9 [, B$ t. n7 d+ k5 ~# d1 efor both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent+ C- i. [$ X9 z* ]: Q
increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average+ Z. v& ]' J; p! M9 S D
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
7 m0 n8 Q$ z- ~9 P, C9 F; ioccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This4 X' Z1 E0 Y! [! ?9 m- Q6 q
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile+ N1 H3 A9 n6 Q7 s W
growth. The response appears to be greater in younger children, which is consistent with previ-
, c+ l6 o8 B8 [ously published studies of age-related 5 reductase activity.* J( t8 V' ~, z( V+ G
Children with microphallus regardless of its etiology will
) h5 |8 d! z9 X0 v) Q+ ]$ ~require augmentation or consideration for alteration of exter-0 u, W( o" f& g' `" |
nal genitalia. In many instances urethroplasty for hypo-
; w/ h) N9 \& [! n3 W! Vspadias is easier with previous stimulation of phallic growth.8 n' r3 g$ @2 Q" D& C0 W
The use of testosterone administered parenterally or topically
4 X; m- o( d* B! v- R) Zhas produced effective phallic growth. 1- 3 The mechanism of; ?5 X7 i, U" n
response has been considered as local or systemic. With this. X9 W0 M2 ]# F5 N5 b
in mind we studied 5 children with microphallus for response+ \+ t8 G" w: I/ N2 t
to gonadotropin and to topical testosterone independently.4 h# h+ O) t0 X3 s) D) A
MATERIALS AND METHODS6 [* _5 U" @ r3 I. t8 h, [
Five 46 XY male subjects between 3 and 17 years old were' S8 B3 O+ l5 c3 |0 H1 R7 Y4 k
evaluated for serum testosterone levels and hypothalamic
3 D$ ~& w6 C$ _, Z T: ?* ~function. Of these 5 boys 2 were considered to have Kallmann's
( s h- A( ]0 Z- e+ g; f: W& _) Wsyndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
& {; i4 C1 w) [lamic deficiency. After evaluation of response to luteinizing1 ?+ |" c" R! `; G! I
hormone-releasing hormone these patients were treated with
/ n& w: g1 S6 `9 i' C1,000 units of gonadotropin weekly for 3 weeks. Six weeks
" L) F2 M5 g$ e0 Z7 Zafter completion of gonadotropin therapy 10 per cent topical. L$ G" F, q) A! ^% m1 c X
testosterone was applied to the phallus twice daily for 3 weeks.; q" K% J* Q D- I; e; T0 ^0 D
Serum testosterone, luteinizing hormone and follicle-stimulat-
$ X0 B& s7 T( x* h2 Cing hormone were monitored before, during and after comple-
: ?8 L+ a& e+ K; xtion of each phase of therapy. Penile stretch length was
8 H S/ A$ ?% r, z& Robtained by measuring from the symphysis pubis to the tip of3 c( k- m( d( z! e# S
the glans. Penile circumferential (girth) measurements were
7 K* C6 Z: w0 Z& H0 zobtained using an orthopedic digital measuring device (see
" N/ v& M- q1 t3 S" e# N7 i4 h8 Cfigure).
$ Z! F8 ?- V( r9 JRESULTS
- i8 M. Q o7 N9 @Serum testosterone increased moderately to levels between
1 x8 ^- i( d" [2 s5 e7 \50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-
! S' c9 X2 l: Mterone levels with topical testosterone remained near pre-5 B0 i& b j: j9 s8 @( a; R
treatment levels (35 ng./dl.) or were elevated to similar levels" T, S* o3 C8 z! F! f4 W; g! x& d
developed after gonadotropin therapy (96 ng./dl.). Higher
- Q! H4 d1 f6 T5 @serum levels were noted in older patients (12 and 17 years old),
# x$ m) [ [' |6 V' b% K" |" cwhile lower levels persisted in younger patients (4, 8, and 10% b! G( d2 Q) d a' k0 x
years old) (see table). Despite absence of profound alterations
! n* A7 H, o9 W( Z9 nof serum testosterone the topical therapy provided a greater7 T8 P% v3 u. N! h1 L
Accepted for publication July 1, 1977. ·" O* E( _( {# d4 J
Read at annual meeting of American Urological Association,
" G* U8 d8 H& C) BChicago, Illinois, April 24-28, 1977.' w9 ]0 R# k* U$ u" Q( |2 R
* Requests for reprints: Division of Urology, Henry Ford Hospital,) N" s+ t5 ~6 j# ~3 R
2799 W. Grand Blvd., Detroit, Michigan 48202.
7 r* @) i5 x* Y( G* yimprovement in phallic growth compared to gonadotropin.* c. p! I$ W" h
Average phallic growth with gonadotropin was 14.3 per cent4 T1 J! b$ X' } F9 S L5 `2 m
increase in length and 5.0 per cent increase of girth. Topical
! W+ ^3 A, U# `0 Jtestosterone produced a 60.0 per cent increase of phallic length. x& m% b5 J& m
and 52.9 per cent increase of girth (circumference). The
) T, q- D% r/ d6 n9 j3 X) _response to topical testosterone was greatest in children be-
+ n' C8 }3 d" P" b. [7 [( Ptween 4 and 8 years old, with a gradual decrease to age 17' p% w7 R& y: M2 l. O
years (see table).
! u* S" T; Q1 Y/ p3 V. J) D. {DISCUSSION. F6 K) T+ K8 ?- D9 v/ K
Topical testosterone has been used effectively by other
& A6 [8 A/ C- _% [/ ~' v3 qclinicians but its mode of action remains controversial. Im-5 }1 ]: ^% Q$ |/ j
mergut and associates reported an excellent growth response! g6 Y; t/ x% D& c
to topical testosterone with low levels of serum testosterone,
6 S3 I4 A: G4 [! c# z- E7 O( Asuggesting a local effect.1 Others have obtained growth re-
: H4 M; a5 O7 x" y6 K1 x0 psponse with high. levels of serum testosterone after topical
3 y* S" b% S5 |4 i3 |: Dadministration, suggesting a systemic response. 3 The use of. z9 ?- z+ ^' @6 I, v* }" L7 C
gonadotropin to obtain levels of serum testosterone compara-
9 z- y$ V& J# t E' s2 `: N5 K7 d$ eble to levels obtained with topical testosterone would seem to
- M( y) T2 U2 M3 [0 T aprovide a means to compare the relative effectiveness of) ]. _* `# r# \3 v
topical testosterone to systemic testosterone effect. It cer-
& c+ v& V# h9 b' P8 x: y. p7 rtainly has been established that gonadotropin as well as par-
4 [6 T6 \* D n8 o. U* menteral testosterone administration will produce genital
' ^+ S" {9 X( E2 `growth. Our report shows that the growth of the phallus was6 w; i* U6 X8 q( C
significantly greater with topical applications than with go-3 H5 n" D: `$ I* u3 I/ K
nadotropin, particularly in children less than 10 years old.+ N, E1 e: u M# _ s* S
The levels of serum testosterone remained similar or lower
, p0 G8 B1 b% M- B2 wthan with gonadotropin during therapy, suggesting that topi-' N5 w& q' D8 c% H1 ^1 `
cal application produces genital growth by its local effect as
~- q5 e2 F+ s5 s. y+ T/ K, l# T4 j( Lwell as its systemic effect.
+ Z6 W9 V- @: @3 d6 iReview of our patients and their growth response related to- U7 m0 s! L- {
age shows a greater growth response at an earlier age. This is8 @) h: O7 W9 {9 m0 K) f
consistent with the findings of Wilson and Walker, who
% |7 a N1 H M; I$ \# ireported an increased conversion of testosterone to dihydrotes-
0 N: z3 q5 L; l% ]% B- Vtosterone in the foreskin of neonates and infants.4 This activ-; C, ?1 ~3 n: ^; C+ Y
ity gradually decreases with age until puberty when it ap-& P9 f& P3 P9 l8 E6 i
proaches the same level of activity as peripheral skin. It may
# i& J- E8 W7 q( H4 d5 Bwell be that absorption of testosterone is less when applied at
2 G* w6 M( l3 x. t8 b7 z2 ean earlier age as suggested by lower serum levels in children/ \% S/ X3 m! Z5 I: r% c
less than 10 years old. This fact may be explained by the ?+ w. B0 S: m- v. c* d
greater ability of phallic skin to convert testosterone to dihy-
' b6 S3 a7 ~2 x" T# S/ M- `drotestosterone at this age. Conversely, serum levels in older& a+ B2 d$ l% n6 h4 y2 _ |
patients were higher, possibly because of decreased local
$ n3 Q* `7 P- H, s' c% u' r ?667
6 X4 q! |) q6 _$ R- w3 `668 KLUGO AND CERNY( G8 ~4 F% z2 a! T K
Pt. Age- U x- c% {/ _. O
(yrs.)
9 B2 N4 |" t- D+ uSerum Testosterone Phallus (cm.) Change Length7 b/ g: R6 V7 w* N* o
(ng./dl.) Girth x Length (%)$ B7 Y' D; g, j/ F _4 w9 Z2 Y
4
" ]8 a( _+ a4 M3 l( F, o8
, s; ~! {$ j( A9 \' |10
1 G% j3 Z$ Z2 y+ E& } T12; q2 |; Y# y: o. J. o
17
8 N& s6 t8 ~/ y! J% fGonadotropin4 |/ T9 _$ G! c0 x# J, \6 m U2 I. W
71.6 2.0 X 3 16.6
' P8 i$ n$ D& Z# E* {50.4 4.0 X 5.0 20.0! X! h7 o' W: U& Z" x
22.0 4.5 X 4.0 25.0 E9 u8 c: S& j* B" N) A+ c2 y* D
84.6 4.0 X 4.5 11.1- N# q& X! c/ A2 Z, Y" L0 l- [
85.9 4.5 X 5.5 9.0
' \& x) t5 j. gAv. 14.3
% W) E' d/ X1 t" m4
2 ~; X9 L4 D% x: _8
! r. [0 Y) m4 t7 [8 e10
) \, `0 F" X- Y1 @12
: s9 d+ [6 |, L" P0 c17
: {# Q2 z: ?& _; GTopical testosterone
& V9 d& F$ E' z" W; F. p34.6 4.5 X 6.5 85+ G7 \( N* E8 G( J
38.8 6.0 X 8.5 70
) s3 F; l# w0 l* \40.0 6.0 X 6.5 62.5- _6 {- U8 D! `6 ]
93.6 6.0 X 7.0 55.5
4 l& m4 g$ v0 K: s" N95.0 6.5 X 7.0 27.2
+ h& f: H" {5 o. L2 hAv. 60.0
( L# K$ R2 h. L e; [. g0 Q Ravailable testosterone. Again, emphasis should be placed on/ S+ j: w. S/ K
early therapy when lower levels of testosterone appear to7 e1 R# m+ K& m2 N5 \, i
provide the best responses. The earlier therapy is instituted' f7 V) X) w& S2 f2 m& z* X6 N
the more likely there will be an excellent response with low
" i( \" v9 ]' S3 pserum levels. Response occurs throughout adolescence as& E, R. o; m+ I7 H
noted in nomograms of phallic growth. 7 The actual response! T+ `5 D& W2 a
to a given serum level of testosterone is much greater at birth$ x% }. A4 n2 Y( h
and gradually decreases as boys reach puberty. This is most# f% s/ `4 E4 D5 g+ t6 T$ X
likely related to the conversion of testosterone to dihydrotes-
7 }0 B2 ]2 a- d( D- N7 Mtosterone and correlates well with the studies of testosterone% y9 }) d8 U0 Q4 d7 B
conversion in foreskin at various ages.
- Y) C& J" U) C# r/ o& l% iThe question arises regarding early treatment as to whether# c; K. B% N: S' E% I8 w5 w
one might sacrifice ultimate potential growth as with acceler-0 M/ p$ Y2 }# S- ^5 P# w- M
ated bone growth. The situation appears quite the reverse
b2 t1 [3 ^7 w5 R2 \) a) `with phallic response. If the early growth period is not used! A: t' r6 x8 n+ `$ h& e1 R, A) x
when 5a reductase activity is greatest then potential growth" y& T3 ~" Z. C- l& `
may be lost. We have not observed any regression of growth3 y" i, z6 U: D
attained with topical or gonadotropin therapy. It may well
0 u; v6 G" F# a, kbe that some patients will show little or no response to any; q, ]- s* J3 Q; E0 z
form of therapy. This would suggest a defect in the ability to% c* e- ` H' Q! e: ]
convert testosterone to dihydrotestosterone and indicate that7 P( Z& F6 o+ f" K) e& B
phallic and peripheral skin, and subcutaneous tissue should
9 [2 _9 q+ ]3 Ibe compared for 5a reductase activity.' n+ k) T. N$ A! N
A, loop enlarges to measure penile girth in millimeters. B,
6 d4 i7 b$ `4 y" t, Z; e: Gexample of penile girth computed easily and accurately.: h) N1 r. l0 }
conversion of testosterone to dihydrotestosterone. It is in this4 b& ]: |- c6 {, I. l m) B0 `$ ^" E
older group that others have noted high levels of serum
; C* R4 @* @, V& @2 g; R, Z# Mtestosterone with topical application. It would also appear
% j( e2 L1 u$ a, o. Q" {# }7 jthat phallic response during puberty is related directly to the. a! V! l- M A2 v* o
serum testosterone level. There also is other evidence of local
% Q( D1 L* B) v( N: sresponse to testosterone with hair growth and with spermato-' `' Y0 e0 w# U; a
genesis. 5• 6
4 ]* F% ]: C" v# x( W0 v$ X- HAdministration of larger doses of gonadotropin or systemic
0 _9 X- b( \, g a3 o! R2 rtestosterone, as well as topical applications that produce
% {3 Z4 C) e' Jhigher levels of serum testosterone (150 to 900 ng./dl.), will
/ I8 Y3 [8 S( Y1 c, j" Salso produce phallic growth but risks accelerated skeletal
* T! J& t4 v! U9 v# i. h& Lmaturation even after stopping treatment. It would appear% x& H* N+ P4 ~3 ~1 o2 ?. w
that this may be avoided by topical applications of testosterone: \. B8 n( \& T. a4 t4 t
and monitoring of serum testosterone. Even with this control
- l$ O, [9 X0 V5 q; ^- d) Y$ S9 gthe duration of our therapy did not exceed 3 weeks at any7 \7 N% y/ [. o
time. It is apparent that the prepuberal male subject may D; ^) ~3 m% q' k* k
suffer accelerated bone growth with testosterone levels near
9 D5 q! {, v1 n& I200 ng./dl. When skeletal maturation is complete the level of
; B8 y9 i* `3 N1 H& \serum testosterone can be maintained in the 700 to 1,300 ng./
" ^8 O( b) g5 H$ \" ]dl. range to stimulate phallic growth and secondary sexual0 \5 p" ]0 Z2 a7 t- d
changes. Therefore, after skeletal maturation parenteral tes-
# C7 B) G0 i1 I6 J( g2 W$ k9 Rtosterone may be used to advantage. Before skeletal matura-: ?% w! D- N6 h& {0 g3 \, z6 `& _
tion care must be taken to avoid maintaining levels of serum7 H5 d# s8 G' w1 }; U3 L S
testosterone more than 100 ng./dl. Low-dose gonadotropin& n6 C6 S8 r9 l& @; Z. v/ A' u
depends upon intrinsic testicular activity and may require6 [: j) O4 A$ e# v0 X% x
prolonged administration for any response.; p' R- a7 M3 x! E$ K
Alternately, topical testosterone does not depend upon tes-; w, M8 Z# V/ |9 D
ticular function and may provide a more constant level of8 q) r! F+ u. s7 n1 I
REFERENCES
W+ ], e" W, d( n# c, A1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,- X6 u2 ^8 g' @, |
R.: The local application of testosterone cream to the prepub-
' R5 q, E' W$ v5 n$ _/ C: d4 r- pertal phallus. J. Urol., 105: 905, 1971.
' g. {) X3 C$ `( T, `: D& B- s2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone" z( v6 @) G1 z
treatment for micropenis during early childhood. J. Pediat.,
- N" R. I& e0 m5 _$ l83: 247, 1973.. Y) h- ~* m! j! ^( k0 G- }
3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-. x1 H7 @8 s% @3 ]/ |' c; G% d. A
one therapy for penile growth. Urology, 6: 708, 1975.
+ B1 }3 _, Z9 Z, l9 Q+ V+ \4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone
( B9 J5 Q! a* P5 |7 V' U5 X; qto 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
- ]6 [0 v5 j% i+ B' a0 U5 iskin slices of man. J. Clin. Invest., 48: 371, 1969.
& D( [7 J% c6 w+ S+ C2 x5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
0 |( r3 d5 O7 i9 n V* ?by topical application of androgens. J.A.M.A., 191: 521, 1965.2 A# ~' P2 f! x* s; @$ h
6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
/ Q0 a! r. [1 |androgenic effect of interstitial cell tumor of the testis. J.
* H7 W0 G3 }" e& h6 yUrol., 104: 774, 1970.
, t2 m( u9 `, R# {: i: G6 b7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
$ Z1 j) j4 t6 w9 K s }tion in the male genitalia from birth to maturity. J. Urol., 48: |
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