Anosmia and hypogonadism with ovarian mosaicism JAMES R. JONES, M.D. EKKEHARD KEMMANN, M.D. JOSEPH CRESCI, M.D. GEORGE I. SOLISH, M.D. Brooklyn, New York An 18-year-old woman with anosmia and hypogonadotropic hypogonadism is presented. In addition endocrinologic evaluation revealed an apparent deficiency in pituitary growth hormone secretion in response to hypoglycemia and an ovarian insensitivity to exogenous gonadotropins. The ovaries, which on histologic examination appeared to be normal, upon karyotyj1ing showed a chromosomal mosaicism, probably 46,XX/47,XXP.
I N T H E I R c L A s s I c A L treatise on hereditary hypogonadism, Kallmann and associates 1 presented pedigrees of three families, comprised of 62 kindred, in which there were nine individuals with the syndrome of anosmia and hypogonadism. In those rare instances in which chromosomal abnormalities have been described, they have been exclusively limited to anosmic eunuchoid males. All women with this syndrome thus far tested have shown normal leukocytic karyotypes. It is the purpose of this communication to report our finding of an ovarian mosaicism in a patient with anosmia and hypogonadotropic hypogonadism.
For as long as the patient could remember she had been unable to detect odors. There was no other known family history of either anosmia or hypogonadism. At the age of eight years the patient was noted to have congenital lateral nystagmus but this had proved to be of no clinical concern to th(' patient. The patient's mothPr denied any intake of drugs during pregnancy. The mother and father had been 33 and 11 years old, respectively, at the birth of the patient. Physical examination revealed a eunuchoid female (5 feet 6 inches, 126 pounds) with prominent epicanthal folds, low set ears, some elongation of the fronto-occipital head diameter, a high arched palate, and a left septal deviation. There was minimal breast development and only fine, light pubic and axillary hair. The external genitals were female, virginal, and prepubertal. At the apex of the vagina was a hypoplastic cervix. The uterus was small (two inches on sounding), and the adnexa were negative. Neurologic consultation revealed a normal mental status with good intelligence. There was a total lack of sensitivity of the olfactory nerve to the odors of wintergreen, acetone, peppermint, onion, coffee, tobacco, perfume, and alcohol. There was no color blindness but a slight lateral nystagmus was noted. The remainder of the cranial nerves were intact. Electroencephalogram showed a borderline pattern with a slightly excessive theta component. Routine laboratory tests (complete blood count, sequential multiple analyzer 12, urinalysis, chest x-ray), x-rays of the sella turcica and abdomt>n, and intravenous pyelography were entirely normal. Bone age closely matched that of a 13-year-old girl. The patient was admitted to the Clinical Research Center of the Downstate Medical Center for further endocrinologic evaluation. An intravenous insulin tolerance test ( 0.1 units of
Case report Patient J. S., an 18-year-old white college student, was referred to the Gynecologic Endocrine Section of the Downstate Medical Center because of primary amenorrhea. At the age of 13 years scant pubic hair growth was noted but no further breast development or menarche occurred. Because of prominent epicanthal folds and low set ears, leukocytic chromosomal studies wen' carried out revealing a normal 46,XX karyotype. From the Department of Obstetrics and Gynecology, State University of New York, Downstate Medical Center. Received for publication May 7, 1974. Revised July 16, 1974. Accepted July 30, 1974. Reprint requests: Dr. james R. Jones, Department of Obstetrics and Gynecology, State University of New York, Downstate Medical Center, 450 Clarkson Ave., Brooklyn, New York 11203.
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Fig. I. Photomicrograph of ovarian biopsy from patient with anosmia and hypogonadism.
Table I. Effects of insulin-induced hypoglycemia (0.1 unit of regular insulin per kilogram) on human growth hormone (HGH) concentrations in female patient with anosmia and hypogonadism Minutes from intravenous insulin
1Serum glucose (mg. %) Serum HGH (m!Lg/ml.)
- 10 8.'i
8'i l ..'iO
regular insulin per kilogram) resulted in a hypoglycemic level of glucose of 38 mg. per cent within 24 minutes with no significant rise in plasma human growth hormone (Table I ) . Aside fiOm the gonadotropic-ovarian testings, this was the only endocrinopathy found. Further studies of growth hormone secretion are being carried out. An intravenous glucose tolerance test had a K value of I. 7 with a rapidly occurring rise in plasma insulin. Thyroid, adrenal, and pituitary-adrenocorticotropic hormone ( ACTH) reserve function tests were all normal. Upon completion of the above studies, the patient was discharged from the hospital and cycled with ethinyl estradiol and medroxyprogesterone acetate in preparation for clomiphene citrate and human gonadotropin testing. During this period she experienced normal withdrawal bleeding. There were no detectable effects of clomiphene citrate (I 00 mg. per day for five days) on the low baseline plasma concentrations of follicle-stimulating ( FSH ) and luteinizing hormone ( LH ) or on the excretion rates of total estrogens. FSH concentrations and estrogen excretion rates ranged between 3 and 6 mi. U. per milliliter and 2 and 4 IJ.g per 24 hours, respectively, throughout the five days of clomiphene and for ten days thereafter.
The LH concentrations remained undetectable (less than I ml.U. per milliliter) . In addition, no vaginal bleeding was noted following the clomiphene. Human menopausal gonadotropins ( HMG, Pergona! ) were administered in increasing dosages from 150 I.U. to 450 I.U. per day for 14 days. During this 14 day period total urinary estrogen and pregnanediol excretions rates never exceeded 5.0 !lg per 24 hours and 0. 7 mg. per 24 hours, respectively. Two further cycles with the use of Pergonal (450 I.U. per day for 15 days) were carried out, again without changes in steroid excretion and without subsequent vaginal bleeding. No changes in cervical mucus or ovarian size were found throughout the period of gonadotropin administration. Because of the clinical unresponsiveness to gonadotropins, a laparotomy was carried out one week after Pergonal administration. The uterus was found to be small with normal-appearing tubes. The left ovary was elongated to 7 em. and about I em. in thickness. The right ovary was smaller, measuring 5 x I em. Both ovaries were white with numerous surface rugations and no evidence of ovulation. Histologic examination showed numerous oocytes, primary follicles, and some maturing
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Anosmia and hypogonadism with ovarian mosaicism
Fig. 2. Ovarian karyotype of patient with anosmia and hypogonadism.
Graafian follicles (Fig. 1) . Karyotype with the use of trypsin banding of the ovarian tissue revealed mosaicism, 46,XX/ 47,XX, an apparent F group anomaly (Fig. 2) . Chromosomal analysis of the skin revealed the same mosaicism. Repeat leukocytic analysis was 46,XX. Leukocytic karyotypings of the patient's mother, father, and older brother were normal. For the past year the patient has been cycled on estrogen and progestin with normal withdrawal bleeding and moderate development of breast tissue and pubic axillary hair. Comment
The results of the above testings indicate that this patient has anosmia, hypogonadotropic hypogonadism, histologically normal ovaries with poor responsiveness to gonadotropins, a probable deficiency in growth hormone secretion, and an ovarian chromosomal mosaicism with a possible trisomy F. A relative insensitivity of gonadal response to gonadotropins has been described by Bardin and co-workers 2 in six of seven male anosmic, eunuchoid patients. In two female patients, however, Tagatz and associates 3 were successful in inducing ovulation and subsequent pregnancy, indicating that gonadal insensitivity may not be a necessary component of anosmia and hypogonadism. Since histologic examination indicated a morphologic ovarian response to gonadotropins in our patient, it is our opinion that higher doses of Pergonal will induce ovulation.
The growth hormone deficit to which we alluded in our study indeed requires further work-up. Bardin and co-workers 2 and Antaki and colleagues 4 reported normal increments in growth hormone in patients with anosmia and hypogonadotropism. It should be noted, however, that the increases tended to be of relatively low magnitude in some of the patients. In 1973, Zarate and associates 5 demonstrated a limited pituitary gonadotropin response to synthetic LRF in two anosmic, hypogonadal brothers. However, Antaki and associates• have recently demonstrated a normal plasma FSH and LH response to the subcutaneous administration of 100 p.g of synthetic LRF in three patients (two women) . Thus, the issue of pituitary competence in this syndrome is unsettled. There have been no reports at this time of any abnormalities of thyroid or adrenal function in patients with anosmia and hypogonadotropism. The present description of ovarian and skin chromosomal mosaicism is, to our knowledge, the first description of any detectable chromosomal abnormality in a woman with anosmia and hypogonadotropism. The chromosomal anomaly found in our patient was cautiously assigned to the F group, although other possibilities are apparent such as deletions and translocations. Anomalies of the F group chromosomes are rare with no definite phenotype reported. Diverse systems have been re-
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ported to be involved and the relevance of the chromosomal pattern is obscure. In addition, mosaicism is commonly found. 6 Whether this chromosomal anomaly relates to the observed ovarian un-
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responsiveness or the somatic stigma or specifically to the syndrome of anosmia and hypogonadotropism awaits further exploration.
1. Kallmann, F. J., Schoenfeld, W. A., and Barrera, S. E.: Am. J. Ment. Defic. 48: 203, 1944. 2. Bardin, C. W., Ross, G. T., Rifkind, A. B., Cargille, C. M., and Lipsett, M. B.: J. Clin. Invest. 48: 2046, 1969. 3. Tagatz, G., Fialkow, P. ]., Smith, D., and Spadoni, L.: N. Engl. J. Med. 283: 1326, 1970.
4. Antaki, A., Somma, M., Wyman, H., and Van Campenhout, J.: J. Clin. Endocrine!. Metab. 38: 1083, 1974. 5. Zarate, A., Kastin, A. ]., Soria, J., Canales, E. S., and Schaiiy, A. V.: J. Ciin. Endocrinoi. Metab. 36: 612, 1973. 6. Gagnon, F., Archambault, L., Ducharme, J. R., and Katyk-Longtin, N.: Rev. Can. Bioi. 22: 133, 1963.