Reproductive Manifestations of Thyroid Disease

THYROID DISORDERS

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REPRODUCTIVE MANIFESTATIONS OF THYROID DISEASE Cheri A. Johnson, DVM, MS

Thyroid function and reproductive function have many interactions, the scope and mechanisms of which are not fully understood. There are direct interactions between the thyroid and reproductive hormones. For example, thyrotropin-releasing hormone (TRH) stimulates pituitary release of prolactin (PRL) as well as thyrotropin (TSH), yet TRH does not seem to have a regulatory role in PRL secretionP TRH is found in many extrahypothalamic tissues, including the rat prostate, seminal vesicles, and epididymis, as well as the human placentaY Although TRH is found in the human placenta, it does not appear to regulate human placental lactogen or human chorionic gonadotropin (hCG). Extrahypothalamic TRH is apparently not affected by TSH or the thyroid hormones. Estrogen stimulates pituitary thyrotropin17 and affects gonadotropin release. In dogs, it has been shown that thyroxine (T4 ) is significantly higher during diestrus and during pregnancy than in any other reproductive state.29 Triiodothyronine {T3 ) is also higher during diestrus but not during pregnancy. Thyroid hormones are not different among canine males and females in anestrus, proestrus, or during lactation. Thyroid and reproductive function are both influenced by external factors, such as glucocorticoids, which suppress thyroid hormones and the gonadal steroids.20 These and other observations regarding the thyroid and reproductive hormones have suggested the possibility of cause and effect relationships between thyroid and reproductive disorders. HYPERTHYROIDISM

Hyperthyroidism is rare in dogs, although functional thyroid carcinoma can occur. Iatrogenic hyperthyroidism, from accidental overdose From the Department of Small Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, Michigan VETERINARY CUNICS OF NORTH AMERICA: SMALL ANIMAL PRACTICE VOLUME 24 • NUMBER 3 • MAY 1994

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or misguided attempts to improve coat or fertility, has been reported in dogs. 18 The effects of hyperthyroidism on canine reproduction are unknown. The effects of immune-mediated hyperthyroidism (Graves' disease) on human reproduction have been studied.2• 16 In men, total testosterone is higher than normal but free testosterone is lower. Some men develop gynecomastia and some become impotent. Some women with Graves' disease do not ovulate normally. There is an increased prevalence of low birthweight and neonatal death in children born to hyperthyroid women. Although hyperthyroidism is rare in dogs, iatrogenic changes in thyroid function must often be considered by clinicians working with breeders of purebred dogs. Because hypothyroidism is a very common endocrinopathy, known by some breeders to exist within their bloodlines and known to adversely affect coat quality and fertility, some dogs are treated with thyroid replacement therapy without, or before, confirmation that hypothyroidism exists. Although treatment is presumably aimed at replacing a hormonal deficit, it is possible that any clinical results are due to pharmacologic effects of excess thyroid hormones. Exogenous thyroid hormones cause dose-dependent suppression of all of the loops of the hypothalamic-pituitary-thyroid axis,Z7 which makes evaluating thyroid function in a treated, but unconfirmed, case very difficult. Feline hyperthyroidism is usually a geriatric condition. By the time it occurs, cats are usually already retired from the breeding program. HYPOTHYROIDISM

Hypothyroidism is the most common endocrine disorder in dogs. It is almost always due to primary disease of the thyroid gland. 3 The most common diseases are idiopathic follicular atrophy and lymphocytic thyroiditis. Lymphocytic thyroiditis associated with lymphocytic orchitis has been described as an inherited condition in a colony of Beagles.B Affected dogs had decreased testicular size and subfertility or sterility. Subnormal fertility and poor semen quality has been reported in a colony of Borzois with lymphocytic thyroiditis, but testicular biopsies were not evaluated in those dogs. 18 In both colonies, hypothyroidism did not develop until dogs were 1 to 2 years of age or older. Lymphocytic thyroiditis and lymphocytic orchitis are considered to be immune-mediated diseases. Whether the hypothyroidism itself causes decreased fertility or whether decreased fertility is a result of lymphocytic orchitis that occurs simultaneously with, but not as a direct result of, lymphocytic thyroiditis is unknown. Whether the hypothyroidism in these Beagles and Borzois is representative of canine hypothyroidism in general is also not known. In both colonies, a genetic predisposition for lymphocytic thyroiditis was demonstrated.7· 8• 13 Because there was poor correlation between serum concentrations of thyroid hormone (which were often normal early in the

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course of the disease) and the severity of histologic lesions of the thyroid, and because lymphocytic thyroiditis progressively affects adult animals, dogs may have entered the breeding program before their lymphocytic thyroiditis is recognized, thus perpetuating the trait in the breed. The effects of hypothyroidism on human and animal reproductive function have been studied, but the mechanisms of the interrelationship of gonadal and thyroid functions remain unclear. Hypothyroidism is not always associated with clinical signs of reproductive dysfunction; poor libido and poor semen quality are reportedly associated with hypothyroidism in dogs. 3' 11 ' 13' 18 Yet other studies have failed to demonstrate an association with hypothyroidism and reproductive problems. Of 55 hypothyroid male dogs of various breeds, none was reported to have reproductive abnormalities. 25 Beale et aP surveyed the owners of racing Greyhounds and found that there was no difference in thyroid function between normal dogs and dogs with poor reproductive performance. Of 22 stud dogs between 3 and 10 years of age, 2 were described by the owners as having poor libido, decreased sperm production, or difficulty impregnating bitches. The authors concluded that the poor reproduction in these Greyhounds was due to factors other than hypothyroidism. Experimentally induced hypothyroidism has been shown to adversely affect reproductive function in other species. For example, when thyroidectomy was performed in young rats, gametogenesis and the development of Leydig cells were inhibited. These effects were reversed by the administration of thyroxine for 30 days. 6 Likewise, in goats made hypothyroid with thiourea, libido, ejaculate volume, number of sperm ejaculated, and sperm motility and viability were all diminished, and the number of morphologic defects increased by 90 days. These changes were reversible after the thiourea was discontinued and the animals became euthyroid. Return to normal libido and semen quality occurred after 16 to 24 weeks. 28 Dogs with congenital hypothyroidism have also been studied. An 8-month-old mix-breed dog with congenital hypothyroidism was described as having small, soft, symmetric testes.5 After 8 months of thyroid hormone therapy, the testes had grown to 7.1 g with the dog weighing 7.3 kg. This is similar to testicular size previously reported in normal dogs.Z6 Spermatid numbers, however, were reduced in all cross sections of the testes and were absent in 20%. Greco et aP 5 r~ported congenital hypothyroidism in Giant Schnauzers. Reproductive hormones were evaluated in two of them. Unfortunately the gender and physical appearance of the genitalia of the two were not specified, but basal luteinizing hormone (LH) concentrations and LH response to gonadotropin-releasing hormone (GnRH) were reported to be normal after 2 years of thyroxine therapy. Hypothyroid men reportedly have decreased testosterone, decreased testosterone response to hCG, and increased gonadotropins (LH and follicle-stimulating hormone) when compared with euthyroid men, but this may not be associated with clinical signs or subfertility.21 Three of eight hypothyroid men evaluated also had diminished libido, sperm count, and sperm motility, which improved after 12 weeks of euthyroidism.

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Infertility, prolonged anestrus, short estrus, and poor libido are reportedly associated with hypothyroidism in bitches.3• 11 • 18• 25 An increased occurrence of abortion, stillbirth, and mummified fetuses has been reported in hypothyroid Borzois compared with bitches of other breeds with nonthyroidal disorders in the same colony. 18 Reproductive dysfunction is not always found in hypothyroid bitches. Beale et aP evaluated reproductive performance and thyroid function in Greyhounds and concluded that poor reproductive performance was due to factors other than hypothyroidism in those bitches. Abnormal estrus was reported in only 5 of 53 hypothyroid bitches of various breeds evaluated by Nesbitt et al.25 Goats made hypothyroid with thiourea became anestrual in approximately 6 weeks. Estrus cycles resumed 16 to 18 weeks after thiourea was discontinued and the animals were euthyroid.28 Hypothyroid women may have irregular cycles, including ovulation failure or cessation of cycles.10 When conception does occur, spontaneous abortion, low birthweight, and fetal death are more common in overtly hypothyroid women than in euthyroid individuals. 10• 14• 22• 23 In pregnant women, serum concentrations of T4 and T3 increase during the first 18 weeks of gestation. This increase is due in part to an increase in thyroid-binding globulin (TBG) in response to estrogen. It also may be from TSH-like effects of hCG. 23 At any rate, pregnant women with clinical signs.of impending spontaneous abortion who subsequently did abort had lower T4 and T3, lower TBG, and higher TSH than those who did not subsequently abort. Human chorionic gonadotropin concentrations were similar for both groups. The thyroid hormones are thought to support ovarian granulosa cell function and placental trophoblast function.23 The outcome of pregnancy in women with subclinical hypothyroidism is much better than for those with overt hypothyroidism, but birthweight may still be low. 10 These findings caused concern about whether the dose of thyroid medication for hypothyroid women should be increased during pregnancy.22 Current recommendations are for careful monitoring of maternal thyroid hormone concentrations, especially in early gestation, because the majority of women who are euthyroid during early pregnancy remain euthyroid throughout pregnancy on the same dose of thyroid hormone. 14 Hypothyroidism and Prolactin

Serum concentrations of prolactin are elevated in a minority of people with primary hypothyroidismY Hyperprolactinemia is an important cause of infertility in women, although the mechanisms are not fully understood.24 The primary site of impaired hypothalamic-pituitary-ovarian function is thought to be the hypothalamus because decreased pulsatile secretion of gonadotropin has been found in hyperprolactinemic patients, yet pituitary responsiveness to GnRH is normal. Increased prolactin also decreases the feedback of estrogen on gonadotropin release and has been shown in vitro to directly inhibit progesterone production

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by granulosa cells in some studies.24 Amenorrhea and infertility in hyperprolactinemic women resolve as prolactin declines.U· 24 When hyperprolactinemia occurs as a result of primary hypothyroidism in people, prolactin concentrations decline with thyroid hormone treatment.U These observations in people have led to speculation that infertility in hypothyroid dogs may reflect prolactin's interference with gonadotropin release and gonadal steroid production,3 but hyperprolactinemia in canine hypothyroidism remains to be investigated. The term galactorrhea is usually used to refer to lactation that is not associated with normal pregnancy and parturition. Nonpuerperal galactorrhea is usually accompanied by hyperprolactinemia in humansY Although excess prolactin promotes the continuation of galactorrhea, it is often not adequate by itself to initiate the process. Galactorrhea often does not occur in hyperprolactinemic men or women in the absence of an initiating event involving estrogen or progesterone withdrawalP Galactorrhea has been reported in women and in dogs with hypothyroidism.5· 12• 24 Although false pregnancy, the most common cause of canine galactorrhea, is considered to be a normal event in bitches, some bitches are much more severely affected than usual. False pregnancy occurs at the end of diestrus, as serum concentrations of progesterone .decline.9 Some bitches with pronounced false pregnancy were found to be hypothyroid. When treated with thyroid hormones only, the false pregnancy resolved. 5 Although TRH and prolactin hot measured in these bitches, it was proposed that primary hypothyroidism caused elevated TRH, which in turn caused hyperprolactinemia. Thyrotropin-releasing hormone is known to be a potent stimulus of prolactin secretion in dogs. 19 Excessive prolactin would be expected to perpetuate the galactorrhea of false pregnancy. Observations in people and animals demonstrate a relationship between thyroid and reproductive functions. Clearly thyroid dysfunction does not always result in clinical signs of reproductive disorders or subfertility. Perhaps the thyroid's effect on reproductive performance is a continuum wherein euthyroidism supports optimal reproductive function, but in which clinically significant reproductive dysfunction is likely to be manifested only in patients with overt hypothyroidism. The adverse effects of thyroid dysfunction on reproduction seem to be reversible when euthyroidism is restored. References 1. Beale KM, Bloomberg MS, VanGilder J, et a!: Correlation of racing and reproductive performance in Greyhounds with response to thyroid function testing. J Am Anim Hasp Assoc 28:263-269, 1992 2. Burrow GN: Management of thyrotoxicosis in pregnancy. N Eng! J Med 313:562, 1985 3. Chastain CB: Canine hypothyroidism. JAm Vet Med Assoc 181:349-353, 1982 4. Chastain CB, Schmidt B: Galactorrhea associated with hypothyroidism in intact bitches. JAm Anim Hosp Assoc 16:851, 1980 5. Chastain CB, McNeel SV, Graham CL, et a!: Congenital hypothyroidism in a dog due to iodine organification defect. Am J Vet Res 44:1257- 1265, 1983

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6. Chowdhury AR, Gautam AK, Chatterjee BB: Thyroid-testis interrelationship during the development and sexual maturity of the rat. Arch Androl13:233-239, 1984 7. Conaway DH, Padgett GA, Nachreiner RF: The familial occurrence of lymphocytic thyroiditis in Borzoi dogs. Am J Med Genet 22:409, 1985 8. Conaway DH, Padgett GA, Bi.mton TE, et al: Clinical and histologic features of primary, progressive, familial thyroiditis in a colony of Borzoi dogs. Vet Pathol22:439, 1985 9. Concannon PW, Lein DH: Hormonal and clinical correlates of ovarian cycles, ovulation, pseudopregnancy, and pregnancy in dogs. In Kirk RW (ed): Current Veterinary Therapy X, Philadelphia, WB Saunders Co, 1989, pp 1269-1282 10. Davis LF, Leveno KJ, Cunningham FG: Hypothyroidism complicating pregnancy. Obstet Gynecol 72:108-112, 1988 11. Feldman EC, Nelson RW: Canine female reproduction and canine male reproduction. In Canine and Feline Endocrinology and Reproduction, Philadelphia, WB Saunders Co, 1987, pp 399-524 12. Frantz AG: Prolactin. N Engl J Med 298:201-207, 1978 13. Fritz TE, Lombard LS, Tyler SA, et al: Pathology and familial incidence of orchitis and its relation to thyroiditis in a closed Beagle colony. Exp Mol Pathol24:142-158, 1976 14. Girling JC: The effect of pregnancy on the thyroxine dosage in women with primary hypothyroidism. Br J Obstet Gynaecol99:368-370, 1992 15. Greco DS, Feldman EC, Peterson ME, et al: Congenital hypothyroidism and dwarfism in a family of Giant Schnauzers. J Vet Intern Med 5:57-65, 1991 16. Hudson RW, Edwards AL: Testicular function in hyperthyroidism. J Androl 13:117124,1992 17. Jackson !MD: Thyrotropin releasing hormone. N Eng! J Med 306:145-155, 1982 18. Johnson CA, Grace JA, Probst MR: Effects of maternal illness on perinatal health. Vet Clin North Am 16:555-566, 1987 19. Kaufman J, Olson PN, Reimers TJ, et a!: Serum concentrations of thyroxine, 3,5,3'triiodothyronine, thyrotropin and prolactin in dogs before and after thyrotropin-releasing hormone administration. Am J Vet Res 46:486, 1985 20. Kemppainen RJ, Thompson FN, Lorenz MD, et a!: Effects of prednisone on thyroid and gonadal function in dogs. J Endocrinol96:293-302, 1983 21. Jaya Kumar B, Khurana ML, Ammini AC, eta!: Reproductive endocrine functions in men with primary hypothyroidism: Effect of thyroxine replacement. Horm Res 43:215218, 1990 22. Mandel SJ, Larsen PR, Seely EW, et al: Increased need for thyroxine during pregnancy in women with primary hypothyroidism~ N Eng! J Med 323:91-127, 1990 23. Maruo T, Katayama K, Matuso H, et al: The role of maternal thyroid hormones in maintaining early pregnancy in threatened abortion. Acta Endocrinol127:118-122, 1992 24. Molitch ME: Pregnancy and the hyperprolactinerrHc woman. N Eng! J Med 312:13641370, 1985 25. Nesbitt GH, Izzo J, Peterson L, et al: Canine hypothyroidism: A retrospective study of 108 cases. JAm Vet Med Assoc 177:1117-1121, 1980 26. Olar TT, Amann RP, Pickett BW: Relationships among testicular size, daily production and output of spermatozoa, and extragonadal spermatozoal reserves of the dog. Bioi Reprod 29:1114-1120, 1983 27. Panciera DL, Atkins CE, Bosu WTK, et al: Quantitative morphologic study of the pituitary and thyroid glands of dogs administered L-thyroxine. Am J Vet Res 51:27, 1990 28. Reddi NM, Rajan A: Reproductive behavior and semen characteristics in experimental hypothyroidism in goats. Theriogenology 25:263-274, 1986 29. Reimers TJ, Mummery LK, McCann JP, eta!: Effects of reproductive state on concentrations of thyroxine, 3,5,3'-triiodothyronine and cortisol in serum of dogs. Bioi Reprod 31:148, 1984

Address reprint requests to Cheri A. Johnson, DVM Veterinary Teaching Hospital Michigan State University Wilson Road East Lansing, MI 48824-1314