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RESPONSE OF MICROPENIS TO TOPICAL TESTOSTERONE AND% [$ n4 I0 w! Y9 P
GONADOTROPIN
$ ]9 H5 M0 N9 H$ K3 O* {; gRICHARD C. KLUGO* AND JOSEPH C. CERNY
H6 |. H2 U1 F) D1 [ _ LFrom the Division of Urology, Henry Ford Hospital, Detroit, Michigan" A& ~" `8 [# y* {( C e
ABSTRACT
0 J0 _; \) M* J5 x$ OFive patients were treated with gonadotropin and topical testosterone for micropenis associated
! _1 N! Y/ Y) f. kwith hypothalamic hypogonadotropic hypogonadism. All patients received 1,000 units of gonado-
3 l# r; A0 d2 rtropin weekly for 3 weeks, with a 6-week interval followed by 10 per cent topical testosterone* m; _( y9 |( ^/ l$ K! a& i* w
cream twice daily for 3 weeks. Serum testosterone levels were measured and remained equivalent
/ k3 V3 X- l& U/ r5 {/ \for both modes of therapy. Average penile growth response with gonadotropin was 14.3 per cent
8 b, k0 g$ a6 B: `$ A& J9 }increase in length and 5.0 per cent increase of girth. Topical testosterone produced an average
4 L1 z4 p8 R7 ~5 H) ?) Oincrease of 60 per cent in penile length and 52. 9 per cent in girth. The greatest growth response
8 f) n+ V m7 |9 Z* u$ noccurred in prepuberal male subjects with a minimal response in postpuberal male subjects. This5 v7 a* F9 R- T$ B
study suggests that 10 per cent topical testosterone cream twice daily will produce effective penile
0 }) A: z$ n( j) ~: l2 Sgrowth. The response appears to be greater in younger children, which is consistent with previ-
% Z9 m: f/ h+ y( T1 f) b8 a* }: Yously published studies of age-related 5 reductase activity.' ~- M" g+ `9 X# S
Children with microphallus regardless of its etiology will
z% k1 T! a, z8 _* krequire augmentation or consideration for alteration of exter-
9 h6 u1 ^1 J7 B- C x Y! knal genitalia. In many instances urethroplasty for hypo-8 V1 b# Z [+ p5 _7 {6 r( t
spadias is easier with previous stimulation of phallic growth.4 B0 F/ q5 d* R7 { L$ ?. Q8 V5 p
The use of testosterone administered parenterally or topically% N8 |8 g4 ^: a. y1 ?5 j& j
has produced effective phallic growth. 1- 3 The mechanism of% Q- }" O9 y' o1 H5 {
response has been considered as local or systemic. With this
8 L+ L- S3 A, L" a: k8 ]in mind we studied 5 children with microphallus for response
1 n$ l# W! R& c* ~* B. H8 Eto gonadotropin and to topical testosterone independently.
5 M4 F N+ t. @8 _ EMATERIALS AND METHODS/ C% @1 E& M0 g3 g$ f
Five 46 XY male subjects between 3 and 17 years old were! `- X8 `* H7 m. d1 g O8 S! X
evaluated for serum testosterone levels and hypothalamic# b% \. ~7 h) E" v, K, A
function. Of these 5 boys 2 were considered to have Kallmann's. ~+ `# ]2 A7 F# j$ ^8 J
syndrome, 1 Prader-Willi syndrome and 2 idiopathic hypotha-
' i4 @) \: S% I. L* J& ^lamic deficiency. After evaluation of response to luteinizing
" f. A" E, L& T2 Lhormone-releasing hormone these patients were treated with+ E: b. l2 M j2 T
1,000 units of gonadotropin weekly for 3 weeks. Six weeks( |! B. P9 b2 }$ V0 ?6 s7 ~
after completion of gonadotropin therapy 10 per cent topical
, d* `9 p) L% d2 _! C5 h# Etestosterone was applied to the phallus twice daily for 3 weeks.( q2 f, ?3 v7 T1 q0 |% r
Serum testosterone, luteinizing hormone and follicle-stimulat-
" i9 I' e2 @& Y) k/ y: Sing hormone were monitored before, during and after comple-
$ ~% g1 y) @" P( S3 \tion of each phase of therapy. Penile stretch length was
+ |2 B- v Q2 c2 S. H% e1 z1 Z" Mobtained by measuring from the symphysis pubis to the tip of
& b& ], t& v2 wthe glans. Penile circumferential (girth) measurements were3 d3 `4 Z$ i# h
obtained using an orthopedic digital measuring device (see
) U8 P7 W A; c& e; Z/ m# efigure).2 g( Q) ^1 ]: O, `6 Q) Z- z2 d( ^
RESULTS# R! s- B3 t# T( m( k1 T
Serum testosterone increased moderately to levels between' d2 z' o! T- G! ~+ M ]4 V$ }
50 and 86 ng./dl. with gonadotropin stimulation. Serum testos-7 w& X3 P& Q, g2 d7 `/ U6 O! N
terone levels with topical testosterone remained near pre-
8 i' \( @ m% O2 x$ streatment levels (35 ng./dl.) or were elevated to similar levels
4 e/ C: n. m8 R; h( `- V# D) zdeveloped after gonadotropin therapy (96 ng./dl.). Higher
3 _% @3 m7 r5 w) A. _) Gserum levels were noted in older patients (12 and 17 years old),
5 _. j. W, q: D5 Hwhile lower levels persisted in younger patients (4, 8, and 10& }2 x2 x4 ~) w' ^2 g3 T+ H
years old) (see table). Despite absence of profound alterations+ S) w0 d" g. R, A# t. R
of serum testosterone the topical therapy provided a greater
' h, s9 i# I) ~% R( `0 A5 t- n2 GAccepted for publication July 1, 1977. ·- H. D! X5 |) E& Y& A
Read at annual meeting of American Urological Association,
: I* M: N, Y0 P2 N) `8 i- E XChicago, Illinois, April 24-28, 1977., d4 ~5 y! L% n4 w2 q, r, J; L3 a; K
* Requests for reprints: Division of Urology, Henry Ford Hospital,, p; W& U5 D) P3 d+ u; A
2799 W. Grand Blvd., Detroit, Michigan 48202.8 g& ~4 @# ]. ?) j5 _ s3 ~! s
improvement in phallic growth compared to gonadotropin.
$ M2 V8 K& p: l, ?* g: HAverage phallic growth with gonadotropin was 14.3 per cent, j, ^/ ~2 n0 |4 V: k* V
increase in length and 5.0 per cent increase of girth. Topical7 o6 r$ r! u* D
testosterone produced a 60.0 per cent increase of phallic length0 d- `3 @) t! G
and 52.9 per cent increase of girth (circumference). The
7 z) I6 P: h( j' y3 m6 yresponse to topical testosterone was greatest in children be-4 U4 H* Y: T8 ]1 G' b- \. {
tween 4 and 8 years old, with a gradual decrease to age 17. O2 L" M! y5 t
years (see table).
$ P) e2 H7 H7 w1 \ g wDISCUSSION" L9 F) q4 M0 o6 F, d5 T
Topical testosterone has been used effectively by other
4 t) z6 ` `- ~# q" F8 Q$ G: H* Kclinicians but its mode of action remains controversial. Im-, ?( J7 r5 X0 \7 \6 P" T! c+ T
mergut and associates reported an excellent growth response
9 N4 ^" d3 [/ w$ j2 ^% |to topical testosterone with low levels of serum testosterone,
+ l* T* @8 ^0 K2 S0 O5 Qsuggesting a local effect.1 Others have obtained growth re-( A; h2 ^+ c& p) C2 q- u
sponse with high. levels of serum testosterone after topical3 O9 M( W* v* t/ J( u( Q$ t
administration, suggesting a systemic response. 3 The use of
8 |- k9 e- V, R# p5 v4 g3 I2 f1 Tgonadotropin to obtain levels of serum testosterone compara-
+ Z1 J; Q* |1 Q B" able to levels obtained with topical testosterone would seem to. M& D1 i1 a L/ F
provide a means to compare the relative effectiveness of
: L( B4 N @) ltopical testosterone to systemic testosterone effect. It cer-2 r- g% q2 q# G) }' o. q* @/ h
tainly has been established that gonadotropin as well as par-
7 q; ~- x1 _8 U* o0 @' h Uenteral testosterone administration will produce genital
- C4 a" p7 S& C( z5 {0 Xgrowth. Our report shows that the growth of the phallus was
3 L% o% D( T" W' K; Ksignificantly greater with topical applications than with go-
; [* B. m: A2 dnadotropin, particularly in children less than 10 years old.
4 s0 v2 ~4 S( ]" R6 KThe levels of serum testosterone remained similar or lower
8 f8 t' D+ M0 ?* cthan with gonadotropin during therapy, suggesting that topi-
- ~3 n% R! A9 e5 C3 P1 V8 M* |cal application produces genital growth by its local effect as5 N0 r* o. a" b% M; R4 v: D
well as its systemic effect./ j: J+ @/ e, A
Review of our patients and their growth response related to% Q' j" H: R) w0 C
age shows a greater growth response at an earlier age. This is* ?$ Z5 I/ H% S* u- l B
consistent with the findings of Wilson and Walker, who
) h0 }4 U6 G2 [. Freported an increased conversion of testosterone to dihydrotes-
$ c. \ Q( b7 u9 z: `tosterone in the foreskin of neonates and infants.4 This activ-! i% s7 [' D; o1 O6 E: N8 b
ity gradually decreases with age until puberty when it ap-6 f- A, I6 V5 i* P6 U" w% }
proaches the same level of activity as peripheral skin. It may4 n& f8 ^+ x2 s' _0 `
well be that absorption of testosterone is less when applied at
" Y; v4 K# C' C0 U8 aan earlier age as suggested by lower serum levels in children
! N$ X! h- G' \- D; a/ ?less than 10 years old. This fact may be explained by the
! ] \" k* [# @; ^& \' f' ngreater ability of phallic skin to convert testosterone to dihy-( b' P2 C. ^* g/ w
drotestosterone at this age. Conversely, serum levels in older$ K% O# d h% K3 d
patients were higher, possibly because of decreased local
& t0 n/ |% H% C& {667" O1 [; z0 b, W& \' `, z, j
668 KLUGO AND CERNY
0 g; A- V8 b6 j+ o0 SPt. Age
2 u" W& t7 b& P5 |(yrs.)
* ^, Q. G( k( V, y2 e/ |2 T( |Serum Testosterone Phallus (cm.) Change Length' r: C0 W% A3 G. \
(ng./dl.) Girth x Length (%)
- w' n O0 c+ c/ @# H) p0 R9 t% |4
# W) m1 ?+ C1 K4 E, F8
8 v+ a( S% c& [- _9 i10: u1 `+ G) Q* \2 u7 ?0 q
12+ `2 Q" F8 ^0 \$ V- ~! ?7 D
17/ @. r) h1 A* Q% ^) j
Gonadotropin
% C; m4 D; w r9 G) a! G% D71.6 2.0 X 3 16.6/ Y" |+ T- @! h8 t/ q5 Z* [. r4 ~
50.4 4.0 X 5.0 20.0& G5 @, ~" d6 j4 I5 |$ L$ {
22.0 4.5 X 4.0 25.0& C3 t/ \9 g$ r6 a H" v; C8 ]
84.6 4.0 X 4.5 11.1
6 j7 r; u/ B2 k( ?( d5 V85.9 4.5 X 5.5 9.08 U* c0 k+ _: d- a$ K2 v0 a
Av. 14.3
9 r1 u1 u+ S4 F( g* R! U; T45 S! b' q! P D; Q7 O
8* A6 ` C ^ K: s: F6 m; ^+ l O6 }
10
5 f5 R3 V5 n. K7 _9 r6 v/ u121 c: V ^0 ^) l7 Q) P
176 V0 X! g9 @7 c
Topical testosterone
6 L, a; Q' \1 `0 N& \34.6 4.5 X 6.5 85
* f- f" V# D/ E- K/ P U38.8 6.0 X 8.5 70% [( _/ t6 g. T
40.0 6.0 X 6.5 62.5/ O/ O+ p/ _* Q" @9 p4 U/ j# |
93.6 6.0 X 7.0 55.5: ?9 J3 @( V; ]* g1 Z
95.0 6.5 X 7.0 27.2* ^4 H; C2 ?* S5 P
Av. 60.09 u( q: y% R1 D
available testosterone. Again, emphasis should be placed on
0 `3 O9 J4 B& R0 W q9 Zearly therapy when lower levels of testosterone appear to% K% y( H; P4 h$ W h2 ^
provide the best responses. The earlier therapy is instituted7 k8 T- \; H4 t6 I9 d
the more likely there will be an excellent response with low
n* a; ^& F3 n$ L/ rserum levels. Response occurs throughout adolescence as
2 n7 t. M( w$ ^* Z6 U5 onoted in nomograms of phallic growth. 7 The actual response
" f9 h; ~' X, T. kto a given serum level of testosterone is much greater at birth: M+ ^ F$ b, W$ e. S% P! y/ |
and gradually decreases as boys reach puberty. This is most
' E1 j% v3 Y% l* _! Zlikely related to the conversion of testosterone to dihydrotes-
. v' L6 J& c2 y5 y2 p6 ctosterone and correlates well with the studies of testosterone( ~. E3 i8 o B* k% m Q
conversion in foreskin at various ages.
4 }# h7 H6 s) Q7 aThe question arises regarding early treatment as to whether6 D" U1 z6 Y$ E* X) D6 u2 B
one might sacrifice ultimate potential growth as with acceler-
4 {/ d! s: c9 \: o" J3 U; [ated bone growth. The situation appears quite the reverse: W4 S& `2 z/ ^# q
with phallic response. If the early growth period is not used6 n7 p i+ k! c2 H7 N0 @$ B9 ]
when 5a reductase activity is greatest then potential growth
1 p. k4 T# G% `9 gmay be lost. We have not observed any regression of growth
9 o% z& u$ w* y. [$ x" z; [attained with topical or gonadotropin therapy. It may well
' h" y) Z: a$ g" p+ vbe that some patients will show little or no response to any
6 ]7 s5 y) v7 t1 jform of therapy. This would suggest a defect in the ability to; X4 Q- \: y9 a# l( ^
convert testosterone to dihydrotestosterone and indicate that; A! |$ t! [2 `& z
phallic and peripheral skin, and subcutaneous tissue should$ E3 B* }4 D! P: z: {
be compared for 5a reductase activity.
- ~9 t1 f# d: l- y. f2 L3 q; L' g3 U oA, loop enlarges to measure penile girth in millimeters. B,
. d A+ X" X: u" [example of penile girth computed easily and accurately., l9 k/ e. Q! V& V5 J9 x4 }
conversion of testosterone to dihydrotestosterone. It is in this$ C1 p6 t: S& z# V1 a# `
older group that others have noted high levels of serum/ T, j8 a8 d6 J- b
testosterone with topical application. It would also appear+ O; x1 A; y+ @- I+ C9 T
that phallic response during puberty is related directly to the
; \! D2 J: x |" j- a# [serum testosterone level. There also is other evidence of local
; L0 ?# m$ p% q0 ?3 b f& V# \( T( wresponse to testosterone with hair growth and with spermato-( b: ?4 V: W% D9 p7 O( Z, Q
genesis. 5• 6
5 l$ f& a( F; a) n1 ~0 fAdministration of larger doses of gonadotropin or systemic; \& @) ]; m$ [; ^# Q1 e
testosterone, as well as topical applications that produce
$ j- f R2 ^& D4 \. c; Ahigher levels of serum testosterone (150 to 900 ng./dl.), will
/ F0 y3 d7 A7 T1 x# xalso produce phallic growth but risks accelerated skeletal
; c7 X. s, P6 I! }7 V# D9 }maturation even after stopping treatment. It would appear
0 D$ H9 e& a- ]1 B+ \1 Uthat this may be avoided by topical applications of testosterone
; T! B9 y1 J- ?, [4 xand monitoring of serum testosterone. Even with this control, X- j! g' }: K8 p
the duration of our therapy did not exceed 3 weeks at any( u6 m. c& M) G5 J/ ?* u
time. It is apparent that the prepuberal male subject may% M! ~) `: \! T- L
suffer accelerated bone growth with testosterone levels near/ R& N2 i; ]2 }1 U/ {0 p
200 ng./dl. When skeletal maturation is complete the level of; m& ` e6 ]5 }3 I- k" p, |3 O
serum testosterone can be maintained in the 700 to 1,300 ng./2 O2 S5 a V: ~ R- t2 U
dl. range to stimulate phallic growth and secondary sexual
. b+ M1 i9 j2 }$ Pchanges. Therefore, after skeletal maturation parenteral tes-( j( V" d6 G3 ^) o8 }0 ?
tosterone may be used to advantage. Before skeletal matura-! G, P! u6 }' G1 b- R( J
tion care must be taken to avoid maintaining levels of serum
9 W5 B3 @( L4 l* H, C: ]# l- I' L# Ltestosterone more than 100 ng./dl. Low-dose gonadotropin
6 _; m" `9 u3 h U) t j: Odepends upon intrinsic testicular activity and may require
" f6 Z$ Y7 e2 Tprolonged administration for any response.* ^9 M5 ~# c/ }) t: k: s# ^+ \
Alternately, topical testosterone does not depend upon tes-
" `2 \9 ~! ~+ z; Iticular function and may provide a more constant level of
4 c7 Y9 Z( n3 f. g, Z' _7 A+ D5 @ `. MREFERENCES
; t7 T" \2 `) [6 G9 m) h1. Immergut, M., Boldus, R., Yannone, E., Bunge, R. and Flocks,2 v: b& g" D v2 J$ F5 S
R.: The local application of testosterone cream to the prepub-
& L9 W6 V. I% v* d+ z& |ertal phallus. J. Urol., 105: 905, 1971.. `0 O* J. X1 X! h& |$ f
2. Guthrie, R. D., Smith, D. W. and Graham, C. B.: Testosterone5 a7 h# [+ u9 r$ A: I4 P1 _3 ]
treatment for micropenis during early childhood. J. Pediat.,6 P$ p& t8 g0 j* u: Q, d0 f
83: 247, 1973.
1 U4 N2 l: n! c/ W3 l3. Jacobs, S. C., Kaplan, G. W. and Gittes, R. F.: Topical testoster-# Y+ a! K" G/ D' R. h; k
one therapy for penile growth. Urology, 6: 708, 1975.! [7 h% Z9 o3 x$ Q3 H) I
4. Wilson, J. D. and Walker, J. D.: The conversion of testosterone) V$ g/ `8 T4 N y( u% V
to 5 alpha-androstan-17 beta-01-3-one (dihydrotestosterone) by
& @( H- E$ {6 n+ W1 F: sskin slices of man. J. Clin. Invest., 48: 371, 1969.
6 D+ @! y4 B2 y7 I6 z8 c8 a; V5. Papa, C. M. and Klingman, A. M.: Stimulation of hair growth
; K8 z, I/ Z ^by topical application of androgens. J.A.M.A., 191: 521, 1965.
) ^+ o9 B7 F$ r, k9 ]6. Gittes, R. F., Smith, G., Conn, C. A. and Smith, F.: Local
+ Y$ C8 x! Y- Tandrogenic effect of interstitial cell tumor of the testis. J.' P0 T# B/ R& m# Z/ {! x6 y) `
Urol., 104: 774, 1970.
" o5 Q, g; v; L: I' C7. Schonfeld, W. A. and Beebe, G. W.: Normal growth and varia-1 U) ?0 E7 F) R2 I% J( N- F; i3 a) w7 g
tion in the male genitalia from birth to maturity. J. Urol., 48: |
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