Isolated Hypogonadotropic Hypogonadism in Male Identical Twins

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Isolated Hypogonadotropic Hypogonadism in Male Identical Twins FLOR GEOLA, MD JEROME M. HERSHMAN, MD Los Angeles IDIOPATHIC HYPOGONADOTROPIC HYPOGONADISM (IHH) is

characterized by the failure of normal secondary sex characteristics to develop at the time of expected puberty. Anosmia is a common finding in patients with IHH (Kallmann's syndrome) and in their eugonadal relatives. Several reports have shown varied laboratory and clinical findings in patients with IHH suggesting a heterogeneous disorder.1'2 It is thought to be a genetic disorder, and both X-linked and autosomal inheritance have been postulated.3-5 Sporadic cases have also been reported.6 In patients with IHH, abnormalities of gonadotropin-releasing hormone (GnRH) secretion are discernible. These include a complete absence of gonadotropin secretion or abnormalities in the amplitude and frequency of pulsatile gonadotropin release and altered bioactivity of the secreted gonadotropin.7 There is a paucity of data regarding the sexual behavior of patients with IHH before treatment. The usual recommended treatment, especially for inducing fertility, is the intravenous administration of human chorionic gonadotropin and human menopausal gonadotropin8 or the pulsatile administration of GnRH.9 Herein we present the first report of sporadic idiopathic hypogonadotropic hypogonadism in identical twin brothers. Surprisingly, spermatogenesis occurred after long-term testosterone treatment in one ofthese patients. Reports of Cases Case I

The patient, a 25-year-old male student, was first seen at He had only a few hairs on the sides of his face and shaved infrequently. He had not noted any other abnormality. He did not smoke. The patient first noted hair growth in his axillary and pubic areas at 13 years of age and had libido and erections beginning at age 14 or 15. He had been married for two years when first seen, and the patient and his wife were interviewed separately concerning their sexual activity. The frequency of sexual relations was three to four times per month. Penetration was normal, and he maintained erections for 6 to 12 minutes during intercourse. He had orgasms that were normal, except that he never ejaculated. Family history. The patient was the result of a normal age 23 because of a lack of facial hair.

(Geola F, Hershman JM: Isolated hypogonadotropic hypogonadism in male identical twins. West J Med 1989 Jan; 150:84-87) From the Endocrinology Section, Wadsworth Veterans Administration Medical Center, Los Angeles, and the Department of Medicine, University of California, Los Angeles, School of Medicine. This work was supported by Veterans Administration Medical Research Funds. Reprint requests to Flor Geola, MD, 1 t600 Wilshire Blvd, Suite 210, Los Angeles, CA 90025.

pregnancy and delivery. No medication was used by his mother during the pregnancy. He had an identical twin (case 2) and a healthy sister. There is no history of abnormal sex characteristics or infertility in the parents, sister, aunt, uncles, grandparents, or brothers of the grandparents. The parents were not consanguineous. Little is known about the other family members because they live on another continent, and information about their health is scanty. No family member (except the brother) has any known medical problem. There is no known neurologic disorder, anosmia, cleft palate, or color blindness, although the relatives were not tested individually. Physical examination. Pertinent findings on examination included eunuchoidal habitus, a height of 188 cm (74 in), scant facial hair, and abundant axillary and pubic hair but with a female escutcheon. The testes measured 2.5 by 1.5 cm and were soft. The prostate was not palpable. There was no gynecomastia. The patient had red-green color blindness. The rest of the examination, including sense of smell and a complete neurologic examination, showed no abnormalities.

Case 2 The twin brother of patient 1 had the same history and physical examination findings. His appearance was identical to that of patient 1, so that they could not be easily distinguished from each other. He was not married and had sexual relations infrequently, but with characteristics similar to those of his brother. He was also color-blind. After the completion of the work-up, therapy for both patients consisting of the intravenous administration of testosterone cypionate (Depo-Testosterone), 200 mg every two to three weeks, was started. Patient 1 has been followed closely. His voice has deepened, and he has noted an increased amount of facial and body hair. He began to have ejaculations after about four or five months, and he also noted a somewhat increased libido, but no other change in his sexual performance.

Materials and Methods Test Procedures The patients were studied on the Special Diagnostic and Treatment Unit of Wadsworth Veterans Administration Medical Center, Los Angeles. On the first day of the study, a needle was inserted in the antecubital vein and was kept patent by a slow saline infusion. After a blood specimen was taken at -15 minutes and 0 minutes, both patients were given a bolus of 200 ,tg of GnRH and 500 ,ug of thyrotropinreleasing hormone (TRH). Blood specimens were then taken at 15, 30, 60, 90, and 120 minutes for luteinizing hormone (LH), follicle-stimulating hormone (FSH), thyroidstimulating hormone (thyrotropin; TSH), and prolactin measurements. The preinjection serum specimens were tested for thyroxine levels, triiodothyronine (T3) uptake, T3 radioimmunoassay, and TSH, prolactin, LH, FSH, growth hormone, and cortisol levels. Aliquots from the - 15-, 0-, and 15-minute specimens were pooled for serum testosterone measurements. The patients continued to receive GnRH, 200-atg boluses, intravenously every 8 hours for the next 72 hours.

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ABBREVIATIONS USED IN TEXT FSH = follicle-stimulating hormone GnRH = gonadotropin-releasing hormone IHH = idiopathic hypogonadotropic hypogonadism LH = luteinizing hormone T3 = triiodothyronine TRH = thyrotropin-releasing hormone TSH = thyroid-stimulating hormone (thyrotropin)

On the second day of the study, after a baseline blood specimen was taken, the patients received 25 units of cosyntropin intravenously and 500 mg of levodopa orally. Blood specimens were drawn at 30, 60, 90, and 120 minutes for serum cortisol and growth hormone measurements. On the fourth day of the study, the last bolus of 200 yg of GnRH was given. Blood specimens were taken at baseline, 30, 60, 90, and 120 minutes for LH and FSH measurements. Because the patients did not ejaculate before therapy, no semen analysis was done before the testosterone injections were started. A semen analysis was done on patient 1 after 11 months of testosterone therapy. Standard radioimmunoassay methods were used for measuring hormone levels. Patient 1 was chromatin-negative and XY karyotype. Patient 2 was not tested in this regard.

Results The basal serum levels of the hormones are shown in Table 1. The responses to the releasing hormones are shown in Figures 1 to 5. The TSH response to TRH (Figure 1) and the cortisol response to adrenocorticotropic hormone (Figure 2) were normal in both patients. The prolactin response to TRH (Figure 3) was slightly blunted (normal peak response > 15 ng per ml). The growth hormone response to levodopa administration was normal (data not shown). The FSH and LH responses to the initial dose of GnRH and the tenth doses (injections every 8 hours for 72 hours) are shown in Figures 4 and 5. The peak elevation of FSH levels (3.3 mIU per ml in both patients) after the first GnRH injec-

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tion rose to 6.7 and to 4.6 mIU per ml in patients 1 and 2, respectively, after the tenth dose. The peak elevation of LH levels (18. 1 and 15. 1 mIU per ml) after the first GnRH dose, however, declined to 14.1 and 13.0 inIU per ml, respectively, after the tenth injection. A semen analysis in patient 1 after 1 1 months of receiving 200 mg of Depo-Testosterone intravenously every two weeks showed a volume of 1.2 ml. The sperm count was 15,250,000 per ml. Only 20% to 30% were highly mobile. More than 50% of the sperm looked normal and mature. Serum LH and FSH levels both remained under 2 mIU per ml. The serum testosterone level rose to 450 to 650 ng per dl.

Discussion This is the first report of identical twin brothers having idiopathic hypogonadotropic hypogonadism. The fact that none of the known relatives of the patients had disorders compatible with IHH or Kallmann's syndrome suggests that these twin brothers probably have sporadic IHH. There is no general agreement as to the mode of its transmission; it is ACTH

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Figure 1.-The serum thyroid-stimulating hormone (TSH) levels rose after 500 Mg of thyrotropin-releasing hormone (TRH) was given intravenously. *-- = patient 1, o--o patient 2 =

Figure 3.-The serum prolactin response to the intravenous administration of 500 Mg of thyrotropin-releasing hormone (TRH) is shown. *-- = patient 1, o--o = patient 2

TABLE 1.-Basal Serum Hormonal Levels in Identical Twins With Idiopathic Hypogonadotropic Hypogonadism Testosterone, ngldl

Patientl ...... 54 Patient 2 ...... 44 Normal values .. 350-1,050

LH,

mrU/mi 1.0 < 1.0 1-15

FSH,

m/U/mi 1.3 1.4 1-15

Thyroxine,

Free Thyroxine

8.7 7.2

9.7 6.9

T3 RIA, ngldl 134 123

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FSH=follicle-stimulating hormone, LH-luteinizing hormone, T3 RIA=triiodothyronine radioimmunoassay

Index

Growth Hormone, ng/mI

Prolactin, ng/ml

Cortisol, mgIdI

2.4 2.2