THE ROLE of thyroid hormone in the treatment of male infertility requires

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1 Semen Analysis in Myxedema SOLOMON I. GRIBOFF, M.D. THE ROLE of thyroid hormone in the treatment of male infertility requires further clarification The frequently quoted article by Marine, in which he reported absence of spermatogenesis in a myxedematous male, was published before the recognition of pituitary myxedema in Marine's case, at autopsy, revealed a chromophobe adenoma, and the testicular changes were probably due to hypopituitarism rather than primary myxedema. Maqsood's studies 6-8 on the influence of thyroxine in improving spermatogenesis in the male mouse, rabbit, and ram are not directly related to the human myxedematous male. Turner et al., studying a large series of childless couples, suggested that neither hypothyroidism nor hypometabolism significantly decreases fertility in the male. Tyler observed 28 hypothyroid males among 302 oligospermic patients ( 9.4 per cent). No details were given of the sperm counts and only 9 of the 28 males were said to be improved with thyroid therapy, suggesting that the oligospermia was not due to hypothyroidism since correction of the specific defect by thyroid hormone was not uniformily attained. Tyler believed that some of the encouraging reports on thyroid effectiveness in the male are due to failure to observe an adequate base line before instituting treatment. Pathologic studies 1 of three elderly primary myxedematous males revealed normal testes. One other patient in the series demonstrated atrophic testes with tubules lined only by Sertoli cells, which was probably due to a seminiferous tubular dysgenesis not related to the myxedema. 4 No detailed studies of semen analysis in myxedema have been reported. The present paper describes the semen analysis of 5 patients with primary myxedema in an attempt to clarify the effect of myxedema upon spermatogenesis. CASE REPORTS Patient 1. B. G., age 38, was first seen in March 1957 with complaints of facial puffiness, fatigue, chills, cold intolerance, sluggishness in the mornings, loss of scalp hair, dry skin and lack of sweating, stiffness of the fingers, slower mental processes, From the Endocrine Clinic, Department of Medicine, Long Island Jewish Hospital, New Hyde Park, N. Y., and the Medical Department, Long Beach Memorial Hospital, Long Beach, N. Y. 436

2 VoL. 13, No.5, 1962 MYXEDEMA AND SPERMATOGENESIS 437 harsher voice, and emotional irritability of 1 year duration. There had been progressive loss of libido but ejaculation was still present; weight was unchanged. He had been previously treated for a diffuse toxic goiter with radioactive iodine in 1952, following which he had been told that he had become hypothyroid, with a basal metabolism of -20. Thyroid therapy had been started but he had discontinued the medication for approximately 1 year. Physical examination revealed the classic features of myxedema. The blood pressure was 120/80 and a regular pulse of 72 per minute was noted. There was no evidence of axillary or pubic hair loss and the genitalia were normal. The PBI was 3.2 p.g.% and the basal metabolism was -32. A sperm count revealed a total volume of 1~ cc. and 190 million sperm per cubic centimeter. The patient was placed on L-triiodothyronine, 25 p.g. per day with weekly increments of 25 p.g. until a daily maintenance dose of 100 p.g. was utilized. There was rapid improvement in the symptoms and signs. In particular, libido improved within 2 weeks. The patient has remained clinically well on the L-triiodothyronine since then. SUMMARY. A 38-year-old male with the onset of primary myxedema following radioactive iodine therapy for hyperthyroidism was found to have a normal number ofspenn in his ejaculate. Patient 2. H. W., age 30, was seen in March 1959 with definite myxedema following total thyroidectomy and right radical neck dissection for a mixed papillary and follicular carcinoma with multiple lymph node involvement, performed in December He had received postoperative cobalt therapy to the right side of the neck and upper mediastinum. Total body scanning with use of radioactive iodine failed to reveal any functioning thyroid tissue in February, The patient complained of cold intolerance, weight gain, irritability, insomnia, sluggishness, easy fatigue, mental slowing, dryness of the skin, and puffiness of the face. There was a decrease in libido but ejaculation was present. Myxedema facies, dry coarse skin, thinning of the scalp hair, dry axillae, and sluggish relaxation-phase reflexes were present. The blood pressure was 120/80 and the pulse was regular, with a rate of 60 per minute. The testicles, penis, and axillary and pubic hair were normal. A sperm count was 168 million per cubic centimeter in a 2-cc. volume. He was treated at first with increasing doses of L-triiodothyronine, to 125 p.g. per day with rapid clearing of all symptoms and signs of myxedema. The dosage was changed to desiccated thyroid, 240 mg. daily, in August 1959, and he has been well, without clinical evidence of metastases, to the present time. summary. A 30-year-old male with primary myxedema following total thyroidectomy for thyroid carcinoma was found to have a normal number of sperm in his ejaculate. Patient 3. M. G., age 64, was seen in November 1959 with progressive fatigue, dry skin, cold intolerance, irritability, constipation, and leg muscle cramps of several years duration. Decreased libido for 8 years had been present but ejaculation was possible. Physical examination revealed a weight of 188 lb., height of 5 ft. 5 in., blood pressure of 150/90, pulse 48 and regular, puffy apathetic facies, sparse dry

3 438 GRIBOFF FERTILITY & STERILITY scalp hair, dry cool skin and puffiness of the lower legs without pitting. The genitalia, and axillary and pubic hair were normal. The PBI was 3.9 p.g.%, the radioactive iodine uptake was 10% with no response to 10 units of T.S.H. administered intramuscularly, suggestive of primary thyroid failure. The sperm count was 295 million per cubic centimeter in a total volume of 1 cc. SUMMARY. A 64-year-old male with primary myxedema was found to have a normal number of sperm in his ejaculate. Patient 4. M. F., age 35, presented in February 1960 with symptoms of easy fatigue, sluggishness, cold intolerance, loss of scalp hair, and loss of libido of 5 month's duration. Ejaculation was possible but penile erectile strength had decreased. Progressive weakness, dullness, slow hoarse speech, clumsiness of the hands, dryness of the skin, loss of sweating ability, and constipation were present. Physical examination revealed a dull myxedema facies with prominent puffiness of the face, a yellowish pallor of the face without icterus, dry coarse skin, dry sparse scalp hair, dry axillae, slow hoarse speech, blood pressure of 110/80, and pulse 75 per minute and regular. The genitalia, and axillary and pubic hair were normal. The biceps and knee reflexes revealed a characteristic extremely delayed relaxation phase. The PBI was 2.6 p.g.%; cholesterol, 360 mg.%; basal metabolism, -17; and the carotene test was positive. The radioactive iodine uptake was 1.7% with an insignificant rise to 4% after 10 units of T.S.H. intramuscularly, indicative of primary myxedema. A 24-hour urine for 17-ketosteroids contained 14.8 mg. and the 17-hydroxysteroids were 5.3 mg. (normal values). The skull X-ray revealed a normal sella turcica. The sperm count revealed 200 million sperm per cubic centimeter in a 1.5-cc. volume. The patient was studied with repeated seminal fluid examinations, all 3-5 days after coitus, produced manually into a clean sterile jar, and brought to the office. within 30 min. There were two control examinations before the administration of desiccated thyroid extract-30 mg. daily for 1 week, with increments of 30 mg. every 2 weeks. A daily maintenance dose of 120 mg. was reached after 5 weeks. Eight seminal fluid examinations were performed after the onset of therapy to compare the effects of treatment upon various parameters. No significant changes were present in the number of sperm per total volume of :ejaculate, which remained in the normal range throughout the study ( 125 million per cubic centimeter in a total volume of 3 cc. after 8 months of therapy). The ph remained in the range The number of abnormal sperm forms remained in normal range ( 12 per cent). The sperm motility immediately after passage was. persistently normal, ranging from 80 per cent before therapy to 90 per cent after. therapy and from Grade 3 motility at onset to Grade 4 motility after therapy. '... Rapid loss.of sperm motility and excessive drying of the material under the cover sfp was noted, to the: extent that all sperm motility was gone within 1-2 hours of exposure. Control semen specimens obtained from normal healthy males with proven fertility examined for at least 6 hours at the same time and under the same room conditions did not exhibit this rapid drying and loss of motility, a motility of

4 VoL. 13, No.5, 1962 MYXEDEMA AND SPERMATOGENESIS per cent with Grade 3 activity being present on the exposed slides from 12 nor~ mal males at the end of 4 hours. The abnormal motility pattern in the slides obtained from the myxedematous male became progressively less noticeable under thyroid treatment within 1 month ( 30 per cent motility of Grade 3 activity at 4 hours on the second post-treatment specimen) and disappeared completely after 7 weeks of therapy ( 65 per cent motility of Grade 3 activity at 4 hours on the third post-treatment specimens) (Fig. 1). Clinically and by laboratory studies, the patient had become euthyroid within 2 months of thyroid treatment. SUMMARY. A 35-year-old male with primary myxedema had repeated sperm counts in normal range. Rapid drying of the slides made for the study of spermatozoa motility, and loss of all motility was noted within 1-2 hours of exposure to room air. This phenomenon was not noted in slides from normal fertile males examined at the same time and was completely corrected by thyroid therapy of the myxedematous patient. Patient 5. J.P., age 30, was referred, prior to a second marriage, for semen evaluation in November 1960 because of a previous history of "marital incompatibility" Fig. 1. Patient M.F. Percentage of actively motile sperm in relation to exposure of sperm specimen to air. Curve 1,2 is of control specimens; Curve 3, after adffiinistration of thyroid extract, 30 mg. per day for 7 days and 60 mg. per day for 5 days; Curve 4, after 60 mg. per day for 9 days and 90 mg. per day for 5 days; Curve 5, 90 mg. per day for 9 days and 120 mg. per day for 13 days; Curve 7, 120 mg. per day (continuous); and Curve N, average values for 12 normal healthy adults (age 26-39).

5 440 GRIBOFF FERTILITY & STERILITY and divorce in However, he stated that sexual incompatibility was not the problem and his libido was normal. The semen analysis revealed a ph of 7.5, total volume of 3.5 cc., sperm count of 109 million per cubic centimeter with 20 per cent abnormal forms and 70 per cent motility of Grade 3 activity. However, further observation of the exposed slides revealed a similarity to patient M. F. but to a less severe degree-i.e., a rapid drying of the slide and decrease in sperm motility to below 40 per cent within 2-3 hours of observation. Repeated samples from the original covered jar up to 4 hours after passage revealed normal motility, but these slides on exposure to air for 3 hours revealed the same decrease in sperm motility. Because of these findings the patient was studied for hypothyroidism. In the past year there had been easy fatiguability and a tired feeling after work, requiring a nap in the evening. Cold intolerance, a decrease in sweating, weight gain of 5 lb. and a slowing of his thinking and speaking had also occurred. Physical examination revealed a height of 5 ft. 6 in., weight of 155lb., dry scalp hair, mild puffiness about the face and eyes, dryness of the skin and axillae, cool dry hands, and sluggish relaxation phase reflexes. The blood pressure was 120/80, pulse 80 and regular, and the axillary hair, pubic hair, and genitalia were normal. The blood count and urinalysis were normal. Two PBI tests gave levels of 3.3 and 3.5 p.g.%. The radioactive iodine uptake was 9 per cent in 24 hours. A repeat semen analysis was essentially unchanged from the first examination. The patient was placed on L-triiodothyronine, 50 p.g. per day, for 7 days. The semen analysis then revealed a ph of 7.6; total volume, 3 cc.; sperm count of 135 million per cubic centimeter, with 18 per cent abnormal forms; and 70 per cent motility of Grade 4 activity. Fresh specimens from the original covered specimen jar demonstrated normal motility (over 60 per cent) for at least 6 hours. On the slides exposed to air however, the rapid decrease in sperm motility to below 40 per cent occurred between the third and the fourth hour of observation, approximately one hour later than the two control observations. The patient was placed on 100 p.g. per day of L-triiodothyronine for another 2 weeks and a fourth semen specimen was obtained. The ph was 7.6; total volume, 2 cc.; sperm count, 123 million per cubic centimeter, with 20 per cent abnormal forms and 80 per cent motility of Grade 4 activity. Again the fresh specimens from the original covered specimen jar revealed normal motility for at least 6 hours. Furthermore, the slides exposed to room air continued to demonstrate normal motility at the end of 4 hours ( 70 per cent with Grade 3 motility). These findings, for the first time, compared well with the control normal human semen specimen which was tested under the same conditions and at the same time. The normal control slide had decreased from 90 per cent to 80 per cent activity at the end of 4 hours, with a progressive decrease from Grade 4 to Grade 2 motility (Fig. 2). Clinically, the patient's symptoms and signs of hypothyroidism had disappeared on therapy. summary. A 30-year-old male with a normal sperm count was initially suspected of hypothyroidism because the semen analysis revealed a rapid drying and loss of sperm motility on the exposed slide which was similar to that of patient M.F. The diagnosis was confirmed by thyroid studies. The administration of L triiodothyronine reverted the observed phenomenon of rapid drying and loss of

6 VoL.13, No.5, 1962 MYXEDEMA AND SPERMATOGENESIS 441 sperm motility to normal, as judged by comparison with a control semen specimen from a normal fertile male examined simultaneously with each specimen obtained from the patient < 0 N 80 0 ~ < 70 ::t a.::_ w~ e;z 60 w ~u -~~~:: 50 ~w OD- ::t- 40 (3) >- -I w > 30 i= u < HOURS EXPOSED TO ROOM AIR Fig. 2. Patient J.P. Percentage of actively motile sperm in relation to exposure of sperm specimen to air. Curve 1,2 is of control specimens; Curve 3, after administration of L-triiodothyronine, 50 p.g. per day for 7 days; Curve 4, after 100 p.g. per day for 14 days; and Curve N, average values for 12 normal healthy adults (age 26-39). DISCUSSION The evidence presented in the introduction suggested that hypothyroidism is not a cause of male infertility. The 5 myxedema patients presented in this paper demonstrated normal sperm counts, further substantiating the impression, in this disease, of a normal degree of spermatogenesis, sufficient to fulfill the criteria for fertility in regard to number of spermatozoa. One study 13 has been reported on the use of L-triiodothyronine in hypometabolic, but not hypothyroid, males in which an improvement in sperm motility and sperm count was noted in approximately 70 per cent of the patients who originally had a normal sperm count. However, the other 30 per cent demonstrated poorer semen quality with the therapy. No patients with an abnormally low sperm count in the series demonstrated any improvement with the L-triiodo-

7 442 GRIBOFF FERTILITY & STERILITY thyronine. It is reasonable to state that if the sole cause of poor semen quality is lack of thyroid hormone, the administration of the hormone should be effective in improving all of these specimens. This was not the case, just as in the hypothyroid males reported by Tyler. L-triiodothyronine studies in subfertile, euthyroid males demonstrated an improvement in number of active cells in per cent of the patients However, this effect is not a purely thyroid effect since L-thyroxine did not reveal similar activity and one must postulate a local tissue benefit of L.T. 3 to explain the divergence. With regard to sperm motility, the 2 patients studied in detail here demonstrated a normal motility from the original covered specimen for 6 hours. However, exposure of the semen to room air, while on the slide and under the cover slip, revealed a rapid drying of the material and loss of sperm motility (within 1-2 hours in the severely myxedematous patient, M.F., and within 2-3 hours in the patient with the milder condition, J.P.). This phenomenon was not seen in the slides of normal fertile males examined at the same time and under the same conditions of air temperature, humidity, and air currents. This abnormality was completely corrected by thyroid therapy. Tentatively a lower limit of 40 per cent motility at the end of 4 hours was selected as the division between hypothyroid and euthyroid specimens on the basis of observation in these 2 patients. It is possible that mucoprotein deposits, characteristic of myxedema, were contributing to the viscosity of the seminal fluid. Exposure to the free air might induce evaporation of trapped fluid of the mucoprotein material, thus thickening the seminal fluid and causing the spermatozoa to lose motility. Another cause of the decreased motility of the spermatozoa could be a specific lack of viability under these conditions as a result of thyroid insufficiency. Since these experimental conditions are not comparable to the environment of the female genital tract it is unlikely that this observed phenomenon plays any role in fertility potential. However, if further studies corroborate the finding of markedly decreased sperm motility on exposure to the air, the test may be utilized for the diagnosis of hypothyroidism, since patient J.P. was suspected of having the disease by means of his semen analysis before the history, physical examination, and thyroid studies were performed. Furthermore, the progress of thyroid therapy could be followed in the male by repeated semen studies for the disappearance of this phenomenon. In addition, in spermatozoa from myxedematous males we have a human living cell which is readily available for studies of the local tissue effects of L-triiodothyronine in thyroid insufficiency conditions. The differentiation of primary (thyroid) myxedema from secondary (pituitary) myxedema due to panhypopituitarism is of great importance, since the administration of thyroid hormone to the latter without adequate adrenal steroid replacement can precipitate an adrenal crisis. 10 In a myxe-

8 VoL. 13, No.5, 1962 MYXEDEMA AND SPERMATOGENESIS 443 dematous male with a history of a complete loss of libido the differential diagnosis could be easily made since spermatozoa, demonstrable by semen analysis, would be present in uncomplicated primary myxedema and presumably absent in panhypopituitary myxedema because ()f the concomitant loss of pituitary gonadotropins (which are essential for spermatogenesis) in the latter condition. SUMMARY 1. The sperm counts of 5 myxedematous males were found to be in normal range, supporting the suggestion that hypothyroidism is not a cause of male infertility. 2. Detailed studies of the semen in 2 patients :t;evealed a rapid drying of the seminal fluid on the slides exposed to room air with a concomitant rapid loss of sperm motility. This was not observed in specimens obtained from normal males examined under the same room air conditions. Furthermore, this phenomenon was reverted to normal by thyroid therapy. Future studies in this field are suggested since this phenomenon may be useful in the diagnosis and treatment of male hypothyroidism. 365 W. Penn St. Long Beach, N. Y. REFERENCES l. DouGLASS, R. C., and JACOBSEN, S.D. Pathologic changes in adult myxedema: Survey of 10 necropsies. ]. Clin. Endocrinol. 17:1354, FARRIS, E. J. Advances in the treatment of sterility. Ann. Rev. Med. 7:91, FARRIS, E. J., and CoLTON, S. W. Effects of L-thyroxine and liothyronine on spermatogenesis. ]. Urol. 79:863, GRIBOFF, S. I., and LAWRENCE, R. The chromosomal etiology of congenital gonadal defects. Am. ]. Med. 30:544, HoRRAX, T. M. Liothyronine in the treatment of male infertility. ]. Urol. 80:49, MAQSOOD, M. Thyroxine therapy in male infertility. Nature 168:466, MAQSOOD, M. Influence of thyroid status on spermatogenesis. Science 114:693, MAQSOOD, M. Role of thyroid on maturity and fertility in the male. Fertil. & Steril. 5: 382, MARINE, D. Changes in the interstitial cells of the testes in Gull's disease. A.M.A. Arch. Path. 28:65, MEANS, J. H., HERTZ, S., and LERMAN, J. The pituitary type of myxedema or Simmond's disease masquerading as myxedema. Tr. A. Am. Physicians 55:32, REED, D. C., BROWNING, W. H., and O'DoNNELL, H. F. Male subfertility. Treatment with liothyronine (cytomel). ]. Urol. 79:868, ScHNEEBERG, N. G. The Thyroid Gland and Infertility. Clinical Obstetrics and Gynecology, Roeber, New York, Sept. 1959, p TAYMOR, M. L., and SELENKOW, H. A. Clinical experience with L-triiodothyronine in male infertility. Fertil. & Steril. 9:560, TURNER, V. H., DAVIS, D. D., ZANARTU, J., and HAMBLEN, E. C. Analysis of clinical data on 500 childless couples: Fertile results. South. M. ]. 44:628, TYLER, E. T. The thyroid myth in infertility. Fertil. & Steril. 4:218, 1953.

Hypothyroidism. Causes. Diagnosis. Christopher Theberge

Hypothyroidism. Causes. Diagnosis. Christopher Theberge Hypothyroidism Pronunciations: (Hypothyroidism) Hypothyroidism (under active thyroid) is a condition where the thyroid gland fails to secrete enough of the thyroid hormones thyroxine (T4) and triiodothyronine