Ovarian morphology in women with anosmia and hypogonadotropic hypogonadism

Ovarian morphology in women with anosmia and hypogonadotropic hypogonadism R.

L.

GOLDENBERG

R.

D.

POWELL

SAUL

W.

ROSEN

JOHN

R.

MARSHALL*

G.

T.

ROSS

Bethesda, MaTland Ovarian biopsies from jve women with the syndrome of hypogo7lcPdtrapi.c hypogonadim and anosmia who had not previously received ~XO~~YWUSgoraad0twpix.s were evaluatad with special emplursis on follicular [email protected]. Felliculsr &we&pm& past the primordial stage was rarely observed, suggesting that early stages of fidkular maturation require amounts of gonadotropins in excess of those secreted in these wow.

A SY N DROME o F hypogonadism and anosmiaaffecting men more commonly than women and occurring in familial clusters was described by- Kaliman and associates’ in 1944. The syndrome has also been called olfactogenital dysplasia,’and, in the limited number of women with this disorder described in the literature, primary amenorrhea was the usual basisfor seeking medical care. To our knowledge, there are only three reports of ovarian follicular morphology in women with olfactogenital dysplasia who had not received

exogenous gonadotropins prior to biopsy.‘-’ We have performed ovarian biopsiesin the course of diagnostic evaluation of five previously untreated women presenting with primary amenorrhea, anosmia, and hypogonadotropic hypogonadismand now report our finding to add to the limited information on ovarian morphology in this syndrome.

Table I presents pertinent clinical and laboratory data on the five anosmic patients. All patients were greater than 64 inches in height, and luwer-segment length wasgreater than upper-segment length in ali of them. None had fully matured secondary sexual characteristics,although all had phenotypicahy normal immature female internal and external genitals. Skull x-rays and visual field examinations were normal in all patients. The buccat smearwaschromatin positive, and a 46,Xx karyotype was found in c&s from peripheral blood cultures. Urinary 17-ketasteroid and hydroxycorticoid excretion and serum ptotein-bound iodine tests were within normal limits in all five sub-

From the Reproductiun Research Branch, Natimul Instihrk of Child Health and Human Development, the Luboratmy of Pafhdogy, National Cancer In&tie, and the Clinics Em&rin&gy Branch, iV5licmal Institute of Ar&ritis, Met&tic and Digestive Diseases,National Institutes of Health. Receivedfor publication December 8, I975. Accepted Februaq 24, 1976. Re@rint requests: Dr. G. T. Ross, Dep$y Director, The Clinical Center, Natknwt Institutes of Health, Bethesda, Ma$and 20014. *Pm& a&ress: Harbor Generai Hospital, Torrance, California. 91

92

Goldenberg et al

Fig. IA. Section of ovarian biopsy from Case 2. The smooth surface, thin tunica albuginea, and large number ofoocytes all suggest ovarian immatnritv. Neither mature nor involuting corpora lutea are present. Except for a single atretic follicle, there ii no evidence of follicle maturation beyond primary or primordial follicles. (Hematox~lin and eozin. Original magnification ~20.)

Fig. IB. Higher power view of same section. Both primordial antral follicles are present. (Hrmatoxylin and e&n. Original

,jects. Basal levels and response to provocative testing for growth hormone” were normal in the three patients tested. Cytologic examination of vaginal smears showed evidence of marked estrogen deprivation in all five patients. Total urinary gonadotropins were below the limits of detection by a mouse uterine weight assay’ in

every

patients.

24

hour

and

follicle-stimulating

plasma

urine

specimen luteinizing

hormone

assayed hormone

(FSH)

in

all

five

(LH) and concentrations

and primary magnificarion

follicles are seen, but no x It%?.)

were consistently below normal levels by the radioimmunoassay methods used in our laboratory.H. ’ Except for anosmia, the eunuchoidal habitus. absence of secondary sexual development. and low serum and urinary gonadotropins, there were no other physical or endocrinologic abnormalities. Culdoscopic examination and ovarian biopsy were performed on each woman.” The appearance of the ovary at culdoscopy and the microscopic features of the

,

Volume Number

93

Ovarian morphology with anosmia and hypogonadism

126 I

Fig. 2. Section of biopsy of right ovary from Case 2. Arrous indicate two cleftlike structur(‘s interpreted as in\:oluting follicles. The involuting follicle to thr right is in ;I rrlativrlv earl\- s~agc’ 01 itlvolurion. (Hrmatoxylin and eosin. Original magnification x X0.)

Table

I. Clinical

and

laboratorv

tlata

in five

with pritnar):

patients

1 ”

1x 19

67 Ii4

35 35

0% o!:

3 4 5

!?(I 2.4 2.5

titi 69 66

3x St? 3.5

Y/c I ci 0’4

atncnorrlxzt

and anosmia

C1O(X3)

il0 ill)
3.9

(X6) (X3) (X.3) (X3)

Not is c-t i 3

.i.ti

ewlualed (X3) (X IO) (x2)

Vat -rti -.:fi ::4

c\&ited (x:3j ( x I I)) (X2)

*Mouse uterine units. In this assay I(1 m.u.u. represents the lower limit of detection ot gonadotropin ac-ci\it\ ill ;i t’l hour wine sample. to :Milli-lnterrlatiorlal Units, relative to the Second International Reference Preparation. In these assavs. 1 rn1.l:. is r:qclivalent 3.9 ng. of Reference Preparation LER 907 for hLH and to 30 ng. for hFSH.

Table II. Culdoscctpicpritnar~ amenorrhea (kce no. I

and

and

features

CrLldotccJpK

Clusters

1 by 1 by 2 cm. Gth smooth 9 hy I cm. without evidence of follicles

capsule

5

Small, oval without follicles

ot

are

described

evidence

in .Table

II.

All

of primordial

ovaries

capsule without

ovaries

rvrnnen

appeared

immature

Micrwopir

ft~2turc~s

follicles

near tunica

the chrtmologic primordial

proximity the

in five

\\irh

albuginea

Dense clusters of primordial follicles. one follicle with a single layer of cuhoidal granulosa cells surrounding ovum. several involving cystic follicles Dense clusters of primordial follicles near the tunica alhuginca Dense clusters of primordial follicles near the tunica alhuginea, one corpus fihrosum and several involuting cvstic follicles deep in stroma Scattered primordial follicles; one Mlicle n,ith t\\.o l.ty~w of cuboidal granulosa cells --

follicles.

Histologically.

biopsies

cLppPnmncr

3 4

specimens

of ox arian

anosmia

were small and oval and had a smooth visible

microscopic

1 hv 1 ti cm., oval, without evidence of follicles Small, round , smooth capsule

2

biopsy

appearance

fin

.I‘herr

age of’ the patient.

follicles

Mere

densely

to a thin tunica alhuginca \vet-e

very

fer\,

dewloping

In c~-h c-lt15tercd

biopsy. in

close

(Pigs. I A and 1R). tidli~

It’s.

Occasional

94

Goldenberg et al.

involuting cystic follicles were noted (Fig. 2), but there were neither corpora lutea nor corpora albicantia to indicate previous ovulation. The presence of follicles supported the diagnosis of hypogonadotropic hypogonadism. Histologic findings in these patients are similar to those reported previously.*-’

Comment In patients with primary amenorrhea and anosmia, the findings of low gonadotropin levels in serum and urine, absence of other endocrinologic abnormalities, and presence of normal but immature ovaries suggest

that the hypogonadism is the result of an isolated deficiency of gonadotropins. Induction of ovulation with exogenous gonadotropins in simiiar patients”, ” gives further evidence that the defect lies not in the ovary but in the hypothalamic-pituitary unit. Both the number maturing and the extent of maturation of individual follicles were limited prior to treatment tvith gonadotropins. These findings and the occurrenr’c of ovulation after treatment suggest that both preantral and postantral follicle maturation is dependent upon adequate gonadotropin stimulation.

REFERENCES I.

2. 3. 4. 5.

6. 7.

Kallman, F., Schonfeld, W. A., and Barrera, S. E.: Am. J. Ment. Defic. 48: 203, 1944. Gautheir, G.: Acta Neuroveg. 41: 345, 1960. Muller, P.: Gynaecologia 158: 137, 1964. Sparkes, R. S., Simpson, R. W., and Paulsen, C. A.: Arch. Intern. Med. 141: 534, 1968. Greulich, W. W., and Pyle, S. L.: In Radiographic Atlas of Skeletal Development of the Hand and Wrist, Stanford, California, 1955, Stanford University Press. Hembree, W. C., and Ross, G. T.: Lancet 1: 52, 1969. Ross, G. T., Brice, J,, and Reid, R.: In Sunderman, F. W., and Sunderman, F. W., Jr., editors: Laboratory Diagnosis

of Endocrine Disease, St. Louis, 1971, Warren H. Green, Inc., p. 148. 8. Ode& W. D., Ross, G. T., and Rayford, P.: J. Clin. Invest. 46: 248, 1967. 9. Cargille, C. M., Ross, G. T., and Yoshimi, T.: J. C:Iin. Endocrinol. Metab. 29: 12, 1969. 10. Marshall, J. R., and Hammond, C. B.: AM. J. OBSTET. GYNECOL.~~:

1022,1966.

11. Mroueh, A.,and Kase,N.: AM. ~.OBSTET.GYNECOL. 100: 525, 1968. 12. Tagatz, G., Fialkow, P. J., Smith, D., and Spadoni, L.: N. Engl. J. Med. 283: 1326, 1970.