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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND
# h7 I% |5 X) nGONADOTROPIN
- B2 W+ i }% d2 x" RRICHARD C. KLUGO* AND JOSEPH C. CERNY
! ?$ E/ g1 v8 R0 j9 \ B! ^' ?From the Division of Urology, Henry Ford Hospital, Detroit, Michigan' [ o. j/ m3 t8 W- B/ x
ABSTRACT0 v& D& ]4 F& Z0 Y! e- l; Y$ c
Five patients were treated with gonadotropin and topical testosterone for micropenis associated
+ z4 V! h' U% n3 W/ fwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-3 q8 R! l6 {' O2 L
tropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone- l; i' k1 H# a: `
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
% b$ X/ ?1 @: |for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
/ q; l$ M( M F& ?: T0 O; b* }/ K% r5 Uincrease in length and 5.0 per cent increase of girth. Topical testosterone produced an average+ N3 I* s& V. ~
increase of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response% u5 j( g0 g- l j
occurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This$ ?; a- |& K1 A' l6 v, W
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
, x1 ]6 K% P {8 A' cgrowth. The response appears to be greater in younger children, which is consistent with previ-
) Y' t& T% ~. e6 n4 S& }4 c) q3 sously published studies of age-related 5 reductase activity.0 ~% w2 R' t, a) y/ f x
Children with microphallus regardless of its etiology will. z' A. }" _! y; P, Y' h
require augmentation or consideration for alteration of exter-
% s8 \# V1 a1 _0 j+ M8 w3 Cnal genitalia. In many instances urethroplasty for hypo-
* K4 _, V4 n I& n5 X* mspadias is easier with previous stimulation of phallic growth.& B( ]$ T$ |) X, I$ E: l* @ `& ]
The use of testosterone administered parenterally or topically
. b8 {8 }7 w# ~has produced effective phallic growth. 1- 3 The mechanism of
' L& t- h( l2 q: Qresponse has been considered as local or systemic. With this
0 Y. K# `* ~$ P$ \( |5 zin mind we studied 5 children with microphallus for response
: j. L- t0 A/ s7 H! h Oto gonadotropin and to topical testosterone independently.) s2 s6 C$ f. {4 [
MATERIALS AND METHODS1 X9 `6 ?4 u# l; Q% ^
Five 46 XY male subjects between 3 and 17 years old were
" W8 w( e- k. o: gevaluated for serum testosterone levels and hypothalamic
7 c+ q- h6 V- Z7 i% x* Wfunction. Of these 5 boys 2 were considered to have Kallmann's
' i9 E! p$ m$ d7 [) d, ^$ \syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-( Y0 D5 z2 p' N+ G" |/ i
lamic deficiency. After evaluation of response to luteinizing
4 m& d% t, D; d5 s' d0 G- `hormone-releasing hormone these patients were treated with
3 O, ]; k6 D+ _% h' I1,000 units of gonadotropin weekly for 3 weeks. Six weeks
% v2 [* j5 X$ {: d5 iafter completion of gonadotropin therapy 10 per cent topical( y' T' v. F9 z$ c5 u( `' j
testosterone was applied to the phallus twice daily for 3 weeks.$ a, J d Z. F6 l- m
Serum testosterone, luteinizing hormone and follicle-stimulat-3 y; A! K) E: g. X
ing hormone were monitored before, during and after comple-7 _. B( V2 `. A5 z+ N0 I
tion of each phase of therapy. Penile stretch length was
3 j2 T0 J. V$ |- hobtained by measuring from the symphysis pubis to the tip of( b; h% G- S$ [. X3 r* C/ |
the glans. Penile circumferential (girth) measurements were# b1 {. n( O O* g$ Z% ?0 A1 k
obtained using an orthopedic digital measuring device (see( b C5 b; ]; W; _3 z, A
figure).
" Z# r9 T8 J0 O+ GRESULTS6 A/ k+ p' |4 L* ~* w
Serum testosterone increased moderately to levels between' f' @$ d, _' ` F7 I1 V3 G
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-0 k, l1 K$ W( }; {& b
terone levels with topical testosterone remained near pre-
2 j/ w" t. [$ `& etreatment levels (35 ng./dl.) or were elevated to similar levels
9 g) [+ g& [, V) P3 f! T3 Y ]9 Rdeveloped after gonadotropin therapy (96 ng./dl.). Higher$ X8 M# H% \5 j- z6 `7 z- s
serum levels were noted in older patients (12 and 17 years old),
' n6 r" ~. X6 ]& _6 e& a5 Awhile lower levels persisted in younger patients (4, 8, and 10
) g' L6 `9 }. F% Syears old) (see table). Despite absence of profound alterations
( J' L5 ?2 |1 k2 e$ `of serum testosterone the topical therapy provided a greater
/ N8 v) `$ \" eAccepted for publication July 1, 1977. ·# |3 e6 `, w% n: p
Read at annual meeting of American Urological Association,1 P% O v: ^2 G1 m: l# r. q' K: R
Chicago, Illinois, April 24-28, 1977.- r7 _2 D" n! H" B i
* Requests for reprints: Division of Urology, Henry Ford Hospital,: k( J( B) W7 W, x1 N0 z8 Y
2799 W. Grand Blvd., Detroit, Michigan 48202.& s2 U1 n* A& E0 |9 a$ g+ C7 E2 L, H
improvement in phallic growth compared to gonadotropin.
4 t* u t! |1 P2 }( M! w- fAverage phallic growth with gonadotropin was 14.3 per cent- n5 V6 ]( O2 T1 O2 _
increase in length and 5.0 per cent increase of girth. Topical
& |7 l7 Q, u3 t N2 e3 d8 i9 \testosterone produced a 60.0 per cent increase of phallic length! e) g- a. U7 c% E9 d
and 52.9 per cent increase of girth (circumference). The; l2 m" R# A) m$ N: b
response to topical testosterone was greatest in children be-
5 S' P6 R% e) I0 N7 B* _+ N5 Q2 x) w7 Etween 4 and 8 years old, with a gradual decrease to age 176 u3 c5 R7 L$ W, D$ S, [% @2 _
years (see table).
4 C2 a O0 U$ Z/ A z. s& j' |8 ]DISCUSSION
2 b2 ?! i; v8 pTopical testosterone has been used effectively by other, O( ^( _, K: f: c5 A
clinicians but its mode of action remains controversial. Im-
- ?; y( ^, k" M5 k; ymergut and associates reported an excellent growth response
; g" a8 k0 w, X% ^5 nto topical testosterone with low levels of serum testosterone,
* ^. a: A0 i$ S2 q; u9 u8 E5 Jsuggesting a local effect.1 Others have obtained growth re-
* K0 b5 b5 o; ?' C. @( hsponse with high. levels of serum testosterone after topical
: a3 q2 Y' ], Q/ @administration, suggesting a systemic response. 3 The use of
! N4 f9 E- I0 C+ m1 v9 L/ ~ [0 B. N8 {! Ogonadotropin to obtain levels of serum testosterone compara-7 |5 J4 l! C0 t) i9 P" V$ Z# D
ble to levels obtained with topical testosterone would seem to& S: _1 r7 D0 y, e4 F `
provide a means to compare the relative effectiveness of" J- a! X; q7 H( D
topical testosterone to systemic testosterone effect. It cer-3 M/ [$ k; N0 ^; S* q( S" J- [
tainly has been established that gonadotropin as well as par-3 @. a8 I! M( w4 s! e7 ^
enteral testosterone administration will produce genital' S8 S' F- \# }$ y7 s* a- l" T
growth. Our report shows that the growth of the phallus was% p' D4 w1 r) C' r& a6 f
significantly greater with topical applications than with go-2 Q* |7 J4 H4 k% p& T2 p* V& n
nadotropin, particularly in children less than 10 years old.5 S& J+ ?3 x$ i# e' X
The levels of serum testosterone remained similar or lower
( z+ f. ^% k. D- J) C7 u7 lthan with gonadotropin during therapy, suggesting that topi-
9 N F( l7 E( _3 Vcal application produces genital growth by its local effect as
/ e" ^) r) Y% Q" b9 @well as its systemic effect.6 T) y; j5 F3 Q; Z+ s
Review of our patients and their growth response related to
. X3 Y3 C1 L( U, z& {- W3 Dage shows a greater growth response at an earlier age. This is. O$ L8 o( a$ i
consistent with the findings of Wilson and Walker, who) ]0 p) A; U2 T8 p) Q+ `' S
reported an increased conversion of testosterone to dihydrotes-: |6 W( y8 w8 P5 ^- Z
tosterone in the foreskin of neonates and infants.4 This activ-
" N* W; }7 a% Z6 M" w& s `& l; X: Zity gradually decreases with age until puberty when it ap-( X S, w! L8 h( {: f
proaches the same level of activity as peripheral skin. It may* m% F0 W% O# K3 D
well be that absorption of testosterone is less when applied at9 x7 f# A, P# r8 M! z
an earlier age as suggested by lower serum levels in children
0 G1 V$ C" _# D; _9 J# Oless than 10 years old. This fact may be explained by the
& N+ Z/ |3 |& agreater ability of phallic skin to convert testosterone to dihy-
. D- Q0 z1 }$ r5 ?7 V I8 Tdrotestosterone at this age. Conversely, serum levels in older+ l% Y) }3 O! \8 j- F d2 F; K& L5 A
patients were higher, possibly because of decreased local
* ?2 W- ^& r! c9 T6 a* q667$ {, D, V# Z9 G1 i
668 KLUGO AND CERNY, P$ B( Z2 G; Q+ X3 m
Pt. Age
& |6 d5 i0 n6 k" \% b(yrs.)3 r# [9 z9 `& s L
Serum Testosterone Phallus (cm.) Change Length" ?0 M: B8 d3 \/ e; k* s* r
(ng./dl.) Girth x Length (%)2 [* S$ s5 r# L6 U4 F3 b3 ]
4# k" _$ X+ N: U6 S( }- h2 x% p/ }
8
( [# G2 D" ]$ c* j- e o105 [8 }' Q1 @$ Q$ Y
12$ ^ z+ ^& d( D- o
17
. g1 ~4 {# p+ S2 yGonadotropin0 v' P( X9 K' U2 ]2 o6 C
71.6 2.0 X 3 16.6
) O: y! z) w& o50.4 4.0 X 5.0 20.0
* _& B" }3 A% l0 l' ?$ [3 o22.0 4.5 X 4.0 25.0' k% U! v( \7 S3 F% q
84.6 4.0 X 4.5 11.1! G- `' s2 q$ t$ v" x
85.9 4.5 X 5.5 9.0. p( H8 d- |9 h g* K0 P
Av. 14.3
! F8 S3 o9 W0 ?1 `4
2 A! h& {: v+ w$ S- c3 q88 g% U; B* M: U0 _0 I5 C
100 x# v( p! f0 x( S9 R* W+ D
12
3 s) x9 [& a) q9 ]9 k/ ~2 k' T# D. b17
7 ^, l! L' N8 kTopical testosterone6 O& A6 Y% N; P& ~( g. b8 m
34.6 4.5 X 6.5 85) _! V8 A6 e3 |/ _0 }4 C
38.8 6.0 X 8.5 70! {4 Z- `1 q0 o
40.0 6.0 X 6.5 62.51 B2 N$ f) Q! W' j9 q* {# T
93.6 6.0 X 7.0 55.57 Y# W# s8 t: H. U6 N7 o% [
95.0 6.5 X 7.0 27.2
* W+ ?3 D+ n1 m5 pAv. 60.0
) j5 e# }8 W. U4 F0 e( {: a9 aavailable testosterone. Again, emphasis should be placed on! R. r1 s, M8 N& e$ s5 N% E
early therapy when lower levels of testosterone appear to
. @: V( W: I) d+ {provide the best responses. The earlier therapy is instituted9 U3 I4 y ]1 ]- T- s- N
the more likely there will be an excellent response with low$ Y- k+ G) }: n: n3 B+ H. {
serum levels. Response occurs throughout adolescence as
B R v3 n9 W: i* F7 mnoted in nomograms of phallic growth. 7 The actual response
# t% L6 T, G: i j* Oto a given serum level of testosterone is much greater at birth- P1 Y3 _! \0 R& _' D. u
and gradually decreases as boys reach puberty. This is most. ~3 @+ X/ x9 B4 i: G9 F# v1 B
likely related to the conversion of testosterone to dihydrotes-
; `& A, v" z9 m% f! {tosterone and correlates well with the studies of testosterone
3 L. A1 j7 H3 _3 g1 X O( Nconversion in foreskin at various ages.3 l; m5 S6 i: b/ j3 G
The question arises regarding early treatment as to whether1 x& }7 y3 d. c- |# k) ^6 o
one might sacrifice ultimate potential growth as with acceler-
0 ?9 ?; ?# U6 S6 D. B3 v2 Z+ Jated bone growth. The situation appears quite the reverse
: R+ X/ a" X. \with phallic response. If the early growth period is not used! @& l. |* I7 q! O9 n/ g/ `8 e
when 5a reductase activity is greatest then potential growth
* C8 c$ @: ]! G* J( Omay be lost. We have not observed any regression of growth) F5 @7 S5 J3 x0 H- g0 }8 g
attained with topical or gonadotropin therapy. It may well# O' E; {& J- P/ y
be that some patients will show little or no response to any
8 ~) r, M+ R7 D, B$ Z( Q3 ~form of therapy. This would suggest a defect in the ability to6 i! N8 r5 ~0 N+ T% M3 P9 E/ j
convert testosterone to dihydrotestosterone and indicate that
% k% ?1 t$ D1 ~# ]) E) |3 Yphallic and peripheral skin, and subcutaneous tissue should
$ A- U6 M! H/ G5 F; p& Obe compared for 5a reductase activity.! o5 ^8 d' B& v- ]* U
A, loop enlarges to measure penile girth in millimeters. B,, H' T) V; ]$ B; Z
example of penile girth computed easily and accurately.
0 |4 [, |9 Q0 x. f; P+ v* `conversion of testosterone to dihydrotestosterone. It is in this
3 {& M' L- c, K* E/ J1 \older group that others have noted high levels of serum
( ], o1 T* ]; h8 ~( g- itestosterone with topical application. It would also appear
5 Y9 I$ w# }" w) ^) A, X0 Z( Nthat phallic response during puberty is related directly to the! n5 q7 d. h/ x$ i
serum testosterone level. There also is other evidence of local/ M$ I) D& @7 m
response to testosterone with hair growth and with spermato-7 x4 I1 e4 I6 u
genesis. 5• 62 m. C" L) q1 M4 b( h$ \
Administration of larger doses of gonadotropin or systemic" Z4 I, M1 W5 W5 i
testosterone, as well as topical applications that produce1 t2 L# B0 g M8 v' n! A9 W
higher levels of serum testosterone (150 to 900 ng./dl.), will
# g2 E9 N& H: _4 r0 \" }) C/ Palso produce phallic growth but risks accelerated skeletal* y& z: o2 \3 J0 s5 ~% ]2 I9 H0 T# w! t
maturation even after stopping treatment. It would appear) W/ }4 J' @/ ?3 J- p" D
that this may be avoided by topical applications of testosterone7 d; [; C5 [" g+ u0 z& j
and monitoring of serum testosterone. Even with this control) `; X! x$ \5 H( D% w% Z
the duration of our therapy did not exceed 3 weeks at any' `! A5 t, ]) Y$ ]' d9 w
time. It is apparent that the prepuberal male subject may* h4 M6 q F( ~9 l* Q- u
suffer accelerated bone growth with testosterone levels near
, S9 k$ B, Z& x9 J; B6 H200 ng./dl. When skeletal maturation is complete the level of( [ h* w/ w5 K9 l0 D. @
serum testosterone can be maintained in the 700 to 1,300 ng./
7 Y# b4 C$ r. o; P- _% {0 H8 ]dl. range to stimulate phallic growth and secondary sexual
# y8 F t- d$ `" h/ [' x/ gchanges. Therefore, after skeletal maturation parenteral tes-
5 G# u% o. {6 L7 y5 mtosterone may be used to advantage. Before skeletal matura-8 k2 I+ z! K8 t/ s
tion care must be taken to avoid maintaining levels of serum6 e6 F6 h5 R }) u$ U0 l% M
testosterone more than 100 ng./dl. Low-dose gonadotropin9 k+ S% V8 I+ \2 M
depends upon intrinsic testicular activity and may require
* v" k8 h( [' @/ W2 eprolonged administration for any response.5 P6 E5 {5 c' d, W. L" ]6 r1 [
Alternately, topical testosterone does not depend upon tes-0 j5 n, k# e& w p6 l
ticular function and may provide a more constant level of1 s1 ~; x9 ^5 R- T/ ~3 h- D: B$ ?6 A
REFERENCES. j7 V% X" Y# P: U) Q
1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,
0 A5 D9 h8 N# l4 i- Q3 uR.: The local application of testosterone cream to the prepub-
$ ^% m2 @/ h& s2 a0 @9 Rertal phallus. J. Urol., 105: 905, 1971.5 g# @* A- a5 z; \% H% x6 R V
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone4 f9 k; d6 B2 i9 h% @# |( \0 |- d
treatment for micropenis during early childhood. J. Pediat.,8 g' }4 \( g) t: _ m7 y
83: 247, 1973.
% o3 k; _7 R6 Q( f9 H$ T7 F1 ^3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-' U5 m* A$ T( ?5 Q7 T* P" c
one therapy for penile growth. Urology, 6: 708, 1975.
; f* n* u$ B* Z6 y) y4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone/ b; v; r' q+ _2 O( q. S
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by; J1 e7 {7 d) P3 d( j5 |
skin slices of man. J. Clin. Invest., 48: 371, 1969.
' k: ^, E' u2 Q- z' e5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
- }" t& P- n# Z& \- C' d1 Vby topical application of androgens. J.A.M.A., 191: 521, 1965.
3 G s/ k; `- i0 L# F6 E3 e6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
8 u( k6 {2 u! W6 ]( j. gandrogenic effect of interstitial cell tumor of the testis. J.
6 z& M4 y# b9 o% q4 o# t/ yUrol., 104: 774, 1970.- n* R( R8 f h* s* [$ w
7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-
0 W% D9 V' V- A' H Xtion in the male genitalia from birth to maturity. J. Urol., 48: |
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