Testicular Function in Sickle Cell Disease*

Vol.

FERTILITY AND STERILITY Copyright © 1974 The American Fertility Society

25,

No.

12, December 1974 Printed in U.S.A.

TESTICULAR FUNCTION IN SICKLE CELL DISEASE* GERALD FRIEDMAN, M.D.,t RUTH FREEMAN, M.D.,t ROBERT BOOKCHIN, M.D.,t ROBERT BOYAR, M.D.,§ GOLLAPUDI MURTHY, M.D.,t AND LEON HELLMAN, M.D.§

Veterans Administration Hospital, Northport, New York 11768, State University of New York, Stony Brook, New York 11790, Albert Einstein College of Medicine, Bronx, New Yark 10461, and Department of Oncology and Institute for Steroid Research, Monte{wre Hospital and Medical Center, Bronx, New York 10467

It has recently been demonstrated that pharmacologic doses of androgen can increase the total red cell mass of patients with sickle cell anemia. 1 It has also been . shown that androgen administration inhibits formation of irreversibly sickled cells,2 thus increasing red cell survival.3 There are no reported measurements of plasma testosterone or pituitary gonadotropin concentrations in men with sickle cell disease, although clinical hypogonadism and delayed pubescence have been reported4 ,5 in patients with this disorder. The present study was undertaken to study testicular function in adult males with sickle cell disease. M~TERIALS

AND METHODS

Eight black men with sickle cell disease were studied. The patients were from 22 to 34 years old. Seven patients had homozygous sickle cell anemia, and one had sickle cell-B thalassemia disease. Two patients were receiving blood transfusions (Table 1). Patients were questioned as to severity of their hematologic disease (frequency and severity of crises, graded from minimal to marked), pertinent family history, Received March 21, 1974. *Supported in part by National Institutes of Health Training Grant, AM-05435, National Cancer Institute, CA-07304, General Clinical Research Centers, RR-53, and National Heart and Lung Institute, LH-14734. tVA Hospital and SUNY. tAlbert Einstein. § Montefiore.

age at onset of puberty (defined as appearance of body hair and or growth spurt), shaving history, sexual potency, and fertility. Physical examination included testicular size (longest diameter or comparison with Prader's orchidometer), height, lower segment length (pubis to floor), and arm span measurements, and hair pattern determination. Hematologic data were outlined (Table 2); all patiellts had hemoglobin electrophoresis by stafch gel,6 (pH 8.6); and agar gel,7 (pH 6.2), and fetal hemoglobin was quantitated by alkali resistance. 8 Blood was taken from each patient and simultaneous analyses were performed for plasma luteinizing hormone (LH) and follicle-stimulating hormone (FSH) by radioimmunoassay,9,lO and for plasma testosterone, by double isotope derivative analysts (performed by New England Nuclear Labs, Worcester, Mass, using their application of Kliman'sll procedure). Blood was collected between 9 and 11 AM at least three weeks after the last transfusion. Specimens for semen analyses were obtained from masturbation in four patients after one week of sexual abstention. Volume, sperm count (cc/ml), and sperm motility at 0 and 2 hours were measured. RESULTS

The clinical data on these eight patients are summarized in Table 1. Their hematologic data are summarized in Table 2. FSH, LH, testosterone values, and sperm analyses are summarized in Table 3.

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TESTICULAR FUNCTION AND SICKLE CELL

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TABLE 1. Clinical Data of Eight Men With Sickle Cell Disease

'"

Testes Length of lower

Arm

segment

span

(em)

Age at onset of pubertya

91

171

19

171

92

190

17

3

175

95

182

20

4

166

86

175

20

5

159

87

167

18

6 7

165 170

91 87

167 176

17 19

8

172

N.A.d

176

19

Patient no.

Height (em)

1

172

2

(em)

Size (em)

Hair pattern

Shaving frequency

0

Facial

Upper beard Sparse

Every 2 weeks Every Chin 4 weeks Upper lip Chin 0 Upper lip 0 Chin Upper lip Fulle 0 Upper lip 0 beard Every Upper lip 3 days

Right

5.0

4.5 N.A.d

N.A d

4

4.5

5.0 N.A.d

N.A.d

Present

4

4.0

3.5 12

12

None

4

4.0

8-10

None

3

3.0

None None

3 4

5.0 3.5

3.5 8-10 soft 3.5 10 soft 4.5 15 3.5 N.A.d

None

4

5.0

4.0 10

Pubicb

Left

None

3

Present

Right

Volume' (ee) Left

Chest

8-10 15 N.A.d 10

aOnset of pUberty=development of pubic and axillary hair and/or growth spurt. bGraded according to pubic hair ratings of Gardner. 15 cCompared to Prader orchidometer. dN.A.=data not available. eHair growth at onset of transfusions.

The heights of all the patients were in the lower half of the normal range except that of patient 5 who was 159 cm tall. Six of the eight patients had arm spans more than 4 cm greater than their heights. Seven had differences of upper and lower segments greater than 4 cm. All patients noted that they had less facial and body hair and shaved less often than their fathers and brothers. Three out of eight patients had female pubic hair patterns. Testicular size was in the lower normal range in four of the eight men and below normal in the other four. When measured by volume as compared to the Prader orchidometer, only one (patient

6) of five patients had normal adult testicular volumes (15 ml or greater). Seven of eight patients had hemoglobin S-S pattern on hemoglobin electrophoresis; one patient had hemoglobin S-B-thalassemia. Laboratory findings revealed that all patients tested had plasma testosterone concentrations in the normal range with a mean concentration of 0.63 jLg/IOO ml. Plasma FSH ranged from 5.3 to 28.5 mIU/ml, with a mean value of 13.8 mIUI ml. Although two values were higher than normal, both patients had values at other times that were within the normal range. Plasma LH ranged from 4.8 to 34.0

TABLE 2. Hematologic Data of Eight Men with Sickle Cell Disease Hemoglobin

l I

~

Patient no.

Age

Type

Gm

Het

Reticulocyte count (%)

Hemoglobin F (%)

Periodic transfusions

1 2 3 4

23 25 30 25

9.0 6.2 9.0 12.2

28.5 18.5 29.0 40.0

22 15 10 2

5.0 3.3 5.2 3.2

0 0 0 0

5 6 7 8

23 34 22 30

S-S S-S S-S S-B thalassemia S-S S-S S-S S-S

10.8 9.9 9.0 9.8

34.0 30.0 27.0 26.0

13 5 10 9

3.5 1.8 5.0 4.0

0

+ 0

+

1020

December 1974

FRIEDMAN ET AL

TABLE 3. Laboratory Results for Eight Men with Sickle Cell Disease PlasmaFSH (mlU/mll

PlasmaLH (mlU/mll

Plasma testosterone ("g/lOO m!)

Semen analysis (sperm x lO'/mll'

Vol (mll'

34.0 31.5 22.1 22.0 9.3 23.5 5.9 23.8 23.0 16.2 9.4 4.8 12.3 23.6

.58

2

2

.64

14.2

3

N.A.

8.8

3

7 8

12.5 13.0 5.5 6.5 16.3 12.8 6.3 23.5 11.8 7.0 5.3 26.5 16.3 14.8

Mean ± standard deviation Normal

13.8±7.5 5-20

18.7±8.8 5-20

Patient no.

1 2 3 4 5 6

.69

N.A .

N.A.

.42

.71

N.A. 52

N.A. 2

.38 .89

N.A. N.A.

N.A . N.A.

0.63 ±.17 .3-1.0

>20 millionlml

3-5

'f Motility

30-50%

50%

aN.A.=data not available.

mIU/ml, with a mean of 18.7. Eight out of 15 LH determinations were above the upper limits of normal adult males. Only two patients had persistently (two determinations) elevated LH values. Three of the four patients tested had oligospermia. One patient (patient 6) who was maintained on chronic blood transfusion for symptomatic benefit of painful crises, had normal semen analysis, testosterone and LH values. He developed axillary and pubic hair after initiation of periodic blood transfusion at age 29. DISCUSSION

The patients in this study demonstrated clinical findings suggestive of decreased androgen activity, but plasma testosterone concentrations were normal. Three patients were oligospermic; this could have been due to local sickling and secondary tissue hypoxia, although other causes, such as the presence of anemia per se, cannot be ruled out. Pharmacologic doses of androgen administered to patients with sickle cell anemia elicited excellent responses both in terms of red cell mass and parameters of red blood cell survival. 13 ,14 However, it is not known whether recovery or re-

bound increase in spermatogenesis occurs after such therapy. SUMMARY

The testicular function of eight adult black men with sickle cell disease was studied. Plasma testosterone concentrations were within the normal range; plasma FSH concentrations were normal, but two of the eight patients demonstrated elevated LH levels. Oligospermia was present in three of four patients studied. Local ischemia secondary to sickling was postulated as one factor responsible for the findings. REFERENCES 1. Lundh B, Gardner F: The haematological re-

2. 3.

4. 5.

sponse to androgens in sickle cell anemia. Scand J Haematol 7:389, 1970 Isaacs W, Hayhoe E: Steroid hormones in sickle cell disease. Nature 215:1139, 1967. Sergeant G, Sergeant B, Milner P: The irreversibly sickled cell: a determinant of he molysis in sickle cell anemia. Br J Haematol 17: 527, 1969 Windsor T, Burch G: The habitus of patients with sickle cell anemia. Hum BioI 16:99, 1944 Whitten C: Growth status of children with sickle cell anemia. Am J Dis Child 102:101, 1961

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TESTICULAR FUNCTION AND SICKLE CELL

6. Smithies 0: An improved procedure for starch gel electrophoresis, further variations in serum proteins of normal individuals. Biochem J 51: 585, 1959 7. Robinson AR, Robson M, Harrison AP, et al: A new technique for differentiation of hemoglobin. J Lab Clin Med 50(5):745,1957 8. DesForges JF, Merritt JA: Fetal hemoglobin determination by alkali denaturation. In Diagnostic Procedures in Hematology. Chicago, Yearbook Medical Publishers, Inc, 1971 9. Midgley AR: Radioimmunoassay for human follicle stimulating hormones. J Clin Endocrinol 27:295, 1967 10. Midgley AR: Radioimmunoassay: a method for human chorionic gonadotropin and human luteinizing hormone. Endocrinology 79:10, 1966

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11. Kliman B, Peterson RE: Double isotope derivative assay of aldosterone in biological extracts. J BioI Chem 235:1639,1960 12. Santomauro A, Sciarra J, Varma A: A clinical investigation of the semen analysis and postcoital test in the evaluation of male infertility. Fertil Steril 23:245, 1972 13. Lundh B, Gardner F: The effect of testosterone in pharmacological doses on plasma volume and on some serum proteins in patients with sickle cell anemia and in sexually impotent men. Scand J Clin Lab Invest 28:72, 1971 14. Mentzner W, August C, Nathan D: The irreversibly sickled cell. Blood 34:733 (abstract), 1969 15. Gardner LI: Endocrine and Genetic Disease of Children. Philadelphia, W. B. Saunders Co., 3U, 1969