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Polycystic ovaries, precocious puberty and acquired hypothyroidism: the van wyk and grumbach syndrome
Polycystic Ovaries, Precocious Puberty and Acquired Hypothyroidism: The Van Wyk and Grumbach Syndrome By Anindya Chattopadhyay, Vijaya Kumar, and Mohan Marulaiah Karnataka, India
Long-standing acquired hypothyroidism can rarely be associated with precocious puberty and polycystic ovaries. The authors report such a case, which responded to the simple replacement of thyroid hormone. It is important to look for hypothyroidism in girls with ovarian masses and precocious puberty to avoid surgery on the ovaries.
J Pediatr Surg 38:1390-1392. © 2003 Elsevier Inc. All rights reserved.
P
A diagnosis of Van Wyk and Grumbach syndrome was made, and she was started on thyroid replacement using L-Thyroxine at 0.05 mg once a day initially, and then increased to 0.1 mg/d. She was followed up monthly over the subsequent 2 months; her skin improved, and she stopped menstruating. Over the next 4 months, her height increased by 7 cm and she lost 1.5 kg. USG showed a decrease in size of her ovarian cyst to 1.8 ⫻ 2.5 cms. By 6 months of therapy, her symptoms and abdominal distension had completely disappeared (Fig 2), as had her ovarian cyst on ultrasound scan Her current height is 125 cm, and she weighs 23.1 kg.
RECOCIOUS PUBERTY has been reported as a complication of severe acquired hypothyroidism in children.1 Rarely, multicystic ovaries develop in this condition.2 Although sporadically reported, this entity has been ignored in the pediatric surgical literature. Undiagnosed, this syndrome has led to surgery on the ovaries,3 when all the features in this condition can be reversed with thyroxine hormone replacement. We report such a case and briefly review the literature of this little-understood disorder.
INDEX WORDS: Polycystic ovaries, hypothyroidism, precocious puberty, Van Wyk and Grumbach syndrome.
DISCUSSION CASE REPORT A 9-year-old girl was referred to us with a working diagnosis of hypothyroidism and functioning ovarian tumor for evaluation and consideration for surgery. She had a history of lethargy, lassitude, and dry skin for 1 year. For the last 6 months she had been having cyclical bleeding per vaginum lasting for 3 to 5 days, every month. She also complained of a decreased appetite for the last one month. On examination, she weighed 25.2 kg, and her height was 117 cm, below the fifth percentile for her age. She had coarse, dry flaky skin and was slightly obese (Fig 1). She had mild enlargement of both the breasts, with the breast tissue measuring 3 ⫻ 3 cm. She had no axillary or pubic hair, and there was no clitoromegaly. One could palpate a 6 ⫻ 8 cm firm, nontender, mobile mass in the left iliac fossa. The mass was felt in the pelvis on a rectal examination. Ultrasound scan showed the mass to be a large multiloculated cyst measuring 9 ⫻ 5 ⫻ 2 cms arising from the left ovary. Hormonal profile showed profound hypothyroidism with a grossly raised thyroid-stimulating hormone (TSH) (⬎100 IU/ mL). Follicle-stimulating hormone (FSH) levels were raised (8 mlU/ mL), luteinizing hormone LH was normal (0.4 IU/mL), but her prolactin (PRL) levels were very high (175 ng/mL). Serum estradiol level also was elevated (632 pg/mL). An x-ray for bone age showed retardation of skeletal maturity to 6 to 7 years.
From the Department of Pediatric Surgery, Kasturba Medical College, Manipal, Karnataka, India. Address reprint requests to Anindya Chattopadhyay, Associate Professor, Department of Pediatric Surgery, Kasturba Medical College, Manipal-576119, Karnataka, India. © 2003 Elsevier Inc. All rights reserved. 0022-3468/03/3809-0023$30.00/0 doi:10.1016/S0022-3468(03)00403-2 1390
Van Wyk and Grumbach2 first reported multicystic ovaries with precocious puberty in patients with hypothyroidism. Since then, sporadic reports have appeared in the literature about this condition. The salient diagnostic features of this condition include a long-standing history of hypothyroidism,4,5 high levels of TSH,6 isosexual precocity with a lack of pubic and axillary hair growth,6,7 a delayed bone age6,8 and a failure of increase in the secretion of pituitary gonadotrophin on the administration of GnRH.4 The exact mechanism of the development of the nonclassical endocrine abnormalities remains speculative. Investigators have been divided over the role of PRL in the pathogenesis of the precocious puberty. Those who point to a central role for hyperprolactinemia contend that increased PRL levels are an important part of the syndrome.4,7,9 They hypothesize that pituitary stimulation by thyrotropin-releasing hormone (TRH) leads to increased levels of TSH and PRL,4,8 or a failure of sex steroid metabolism leads to an increase in the secretion of PRL by decreasing the hypothalamic levels of prolactin inhibitory factor (PIF).9 Elevated PRL may enhance the sensitivity of the ovaries to circulating gonadotrophins by increasing ovarian receptors to LH.10 Supporting this hypothesis is the fact that bromocriptine has been shown to inhibit cyst formation in the ovaries of hypothyroid rats.11 Other investigators have failed to show a consistent
Journal of Pediatric Surgery, Vol 38, No 9 (September), 2003: pp 1390-1392
POLYCYSTIC OVARIES AND PRECOCIOUS PUBERTY IN ACQUIRED HYPOTHYROIDISM
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Fig 1. The patient at presentation: note the obesity and breast enlargement.
increase in PRL in patients.5 They postulate that the raised gonadotrophin levels result from an overproduction of multiple pituitary hormones as a result of a lack of specificity in the thyroid feedback mechanism,2 or from an overlap in glycoprotein synthesis,6 or as a result of an excessive production of luteinizing hormone– releasing hormone (LHRH) owing to it’s proximity to the TRH production center.9 The multicystic ovaries may result from elevated levels of circulating gonadotrophins acting on the organ. The cysts resemble lutein cysts seen in Stein-Leventhal syndrome.2 It also is possible that increased sensitivity of the ovaries to the circulating gonadotrophins could result from the hypothyroid state directly12 or via increased PRL.10 However, Hassan et al3 reported that the ovarian enlargement was secondary to a myxedematous infiltration, and ovarian cysts have been reported even in the absence of precocious puberty.13
Fig 2. The patient 6 months after starting L-thyroxine. Note the decreased breast development.
More recently, a direct action of TSH on FSH receptors has been proposed.14 High circulating TSH levels, which are seen in almost all patients in this syndrome, may be the actual mediator of precocity. Although there is little consensus regarding the precise etiopathology of the disorder, the treatment approach is clear. All symptoms subside with thyroxine hormone replacement; the endocrine abnormalities resolve, and even the large cysts in the ovaries disappear.4,5,8,13 Surgery should be considered only for the complications of the ovarian cyst such as torsion. This case highlights the fact that the correlation of grossly enlarged ovaries and hypothyroidism is entrenched sufficiently to warrant a study of thyroid function, if other symptoms are present, before ovarian surgery is entertained.
REFERENCES 1. LaFranchi S: Hypothyroidism, in Behrman RE, Kleigman RM, Jenson HB (eds): Nelson Textbook of Pediatrics. Philadelphia, PA, Saunders, 2000, pp 1698-1704
2. Van Wyk JJ, Grumbach MM: Syndrome of precocious menstruation and galactorrhea in juvenile hypothyroidism: An example of hormonal overlap in pituitary feedback. J Pediatr 57:416-435, 1960
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3. Hansen KA, Tho SPT, Hanly M, et al: Massive ovarian enlargement in primary hypothyroidism. Fertil Steril 67:169-171, 1997 4. Hemady ZS, Siler-Khodr TM, Najjar S: Precocious puberty in juvenile hypothyroidism. J Pediatr 92:55-59, 1978 5. Lindsay AN, Voorhess ML, MacGillivray MH: Multicystic ovaries in primary hypothyroidism. Obstet Gynecol 61:433-437, 1983 6. Evers JLH, Rolland R: Primary hypothyroidism and ovarian activity evidence for an overlap in the synthesis of pituitary glycoproteins. Br J Obstet Gynecol 88:195-202, 1981 7. Barnes ND, Hayles AB, Ryan RJ: Sexual maturation in juvenile hypothyroidism. Mayo Clin Proc 48:849-856, 1973 8. Bhattacharya M, Mitra AK: Regression of precocious puberty in a child with hypothyroidism after thyroxine therapy. Indian Pediatr 29:96-98, 1992 9. Costin G, Kershnar AK, Kogut MD, et al: Prolactin activity in juvenile hypothyroidism and precocious puberty. Pediatrics 50:881889, 1972
CHATTOPADHYAY, KUMAR, AND MARULAIAH
10. Advis JP, Richards JS, Ojeda SR: Hyperprolactinemia induced precocious puberty: Studies on the mechanism(s) by which prolactin enhances ovarian progesterone responsiveness to gonadotrophins in prepubertal rats. Endocrinology 108:1333-13342, 1981 11. Copmann TL, Adams WC: Relationship of polycystic ovary induction to prolactin secretion: Prevention of cyst formation by bromocriptine in the rat. Endocrinology 108:1095-1097, 1981 12. Jones RG: Effects of a pituitary gonadotrophin on the ovaries of hypothyroid rats. Endocrinology 54:464-470, 1954 13. Riddlesberger MM, Kuhn JP, Munschauer RW: The association of juvenile hypothyroidism and cystic ovaries. Radiology 139:77-80, 1981 14. Anasti JN, Flack MR, Froeloich J, et al: A potential novel mechanism for precocious puberty in juvenile hypothyroidism. J Clin Endocrinol Metab 80:276-279, 1995
Long-standing acquired hypothyroidism can rarely be associated with precocious puberty and polycystic ovaries. The authors report such a case, which responded to the simple replacement of thyroid hormone. It is important to look for hypothyroidism in girls with ovarian masses and precocious puberty to avoid surgery on the ovaries.
J Pediatr Surg 38:1390-1392. © 2003 Elsevier Inc. All rights reserved.
P
A diagnosis of Van Wyk and Grumbach syndrome was made, and she was started on thyroid replacement using L-Thyroxine at 0.05 mg once a day initially, and then increased to 0.1 mg/d. She was followed up monthly over the subsequent 2 months; her skin improved, and she stopped menstruating. Over the next 4 months, her height increased by 7 cm and she lost 1.5 kg. USG showed a decrease in size of her ovarian cyst to 1.8 ⫻ 2.5 cms. By 6 months of therapy, her symptoms and abdominal distension had completely disappeared (Fig 2), as had her ovarian cyst on ultrasound scan Her current height is 125 cm, and she weighs 23.1 kg.
RECOCIOUS PUBERTY has been reported as a complication of severe acquired hypothyroidism in children.1 Rarely, multicystic ovaries develop in this condition.2 Although sporadically reported, this entity has been ignored in the pediatric surgical literature. Undiagnosed, this syndrome has led to surgery on the ovaries,3 when all the features in this condition can be reversed with thyroxine hormone replacement. We report such a case and briefly review the literature of this little-understood disorder.
INDEX WORDS: Polycystic ovaries, hypothyroidism, precocious puberty, Van Wyk and Grumbach syndrome.
DISCUSSION CASE REPORT A 9-year-old girl was referred to us with a working diagnosis of hypothyroidism and functioning ovarian tumor for evaluation and consideration for surgery. She had a history of lethargy, lassitude, and dry skin for 1 year. For the last 6 months she had been having cyclical bleeding per vaginum lasting for 3 to 5 days, every month. She also complained of a decreased appetite for the last one month. On examination, she weighed 25.2 kg, and her height was 117 cm, below the fifth percentile for her age. She had coarse, dry flaky skin and was slightly obese (Fig 1). She had mild enlargement of both the breasts, with the breast tissue measuring 3 ⫻ 3 cm. She had no axillary or pubic hair, and there was no clitoromegaly. One could palpate a 6 ⫻ 8 cm firm, nontender, mobile mass in the left iliac fossa. The mass was felt in the pelvis on a rectal examination. Ultrasound scan showed the mass to be a large multiloculated cyst measuring 9 ⫻ 5 ⫻ 2 cms arising from the left ovary. Hormonal profile showed profound hypothyroidism with a grossly raised thyroid-stimulating hormone (TSH) (⬎100 IU/ mL). Follicle-stimulating hormone (FSH) levels were raised (8 mlU/ mL), luteinizing hormone LH was normal (0.4 IU/mL), but her prolactin (PRL) levels were very high (175 ng/mL). Serum estradiol level also was elevated (632 pg/mL). An x-ray for bone age showed retardation of skeletal maturity to 6 to 7 years.
From the Department of Pediatric Surgery, Kasturba Medical College, Manipal, Karnataka, India. Address reprint requests to Anindya Chattopadhyay, Associate Professor, Department of Pediatric Surgery, Kasturba Medical College, Manipal-576119, Karnataka, India. © 2003 Elsevier Inc. All rights reserved. 0022-3468/03/3809-0023$30.00/0 doi:10.1016/S0022-3468(03)00403-2 1390
Van Wyk and Grumbach2 first reported multicystic ovaries with precocious puberty in patients with hypothyroidism. Since then, sporadic reports have appeared in the literature about this condition. The salient diagnostic features of this condition include a long-standing history of hypothyroidism,4,5 high levels of TSH,6 isosexual precocity with a lack of pubic and axillary hair growth,6,7 a delayed bone age6,8 and a failure of increase in the secretion of pituitary gonadotrophin on the administration of GnRH.4 The exact mechanism of the development of the nonclassical endocrine abnormalities remains speculative. Investigators have been divided over the role of PRL in the pathogenesis of the precocious puberty. Those who point to a central role for hyperprolactinemia contend that increased PRL levels are an important part of the syndrome.4,7,9 They hypothesize that pituitary stimulation by thyrotropin-releasing hormone (TRH) leads to increased levels of TSH and PRL,4,8 or a failure of sex steroid metabolism leads to an increase in the secretion of PRL by decreasing the hypothalamic levels of prolactin inhibitory factor (PIF).9 Elevated PRL may enhance the sensitivity of the ovaries to circulating gonadotrophins by increasing ovarian receptors to LH.10 Supporting this hypothesis is the fact that bromocriptine has been shown to inhibit cyst formation in the ovaries of hypothyroid rats.11 Other investigators have failed to show a consistent
Journal of Pediatric Surgery, Vol 38, No 9 (September), 2003: pp 1390-1392
POLYCYSTIC OVARIES AND PRECOCIOUS PUBERTY IN ACQUIRED HYPOTHYROIDISM
1391
Fig 1. The patient at presentation: note the obesity and breast enlargement.
increase in PRL in patients.5 They postulate that the raised gonadotrophin levels result from an overproduction of multiple pituitary hormones as a result of a lack of specificity in the thyroid feedback mechanism,2 or from an overlap in glycoprotein synthesis,6 or as a result of an excessive production of luteinizing hormone– releasing hormone (LHRH) owing to it’s proximity to the TRH production center.9 The multicystic ovaries may result from elevated levels of circulating gonadotrophins acting on the organ. The cysts resemble lutein cysts seen in Stein-Leventhal syndrome.2 It also is possible that increased sensitivity of the ovaries to the circulating gonadotrophins could result from the hypothyroid state directly12 or via increased PRL.10 However, Hassan et al3 reported that the ovarian enlargement was secondary to a myxedematous infiltration, and ovarian cysts have been reported even in the absence of precocious puberty.13
Fig 2. The patient 6 months after starting L-thyroxine. Note the decreased breast development.
More recently, a direct action of TSH on FSH receptors has been proposed.14 High circulating TSH levels, which are seen in almost all patients in this syndrome, may be the actual mediator of precocity. Although there is little consensus regarding the precise etiopathology of the disorder, the treatment approach is clear. All symptoms subside with thyroxine hormone replacement; the endocrine abnormalities resolve, and even the large cysts in the ovaries disappear.4,5,8,13 Surgery should be considered only for the complications of the ovarian cyst such as torsion. This case highlights the fact that the correlation of grossly enlarged ovaries and hypothyroidism is entrenched sufficiently to warrant a study of thyroid function, if other symptoms are present, before ovarian surgery is entertained.
REFERENCES 1. LaFranchi S: Hypothyroidism, in Behrman RE, Kleigman RM, Jenson HB (eds): Nelson Textbook of Pediatrics. Philadelphia, PA, Saunders, 2000, pp 1698-1704
2. Van Wyk JJ, Grumbach MM: Syndrome of precocious menstruation and galactorrhea in juvenile hypothyroidism: An example of hormonal overlap in pituitary feedback. J Pediatr 57:416-435, 1960
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3. Hansen KA, Tho SPT, Hanly M, et al: Massive ovarian enlargement in primary hypothyroidism. Fertil Steril 67:169-171, 1997 4. Hemady ZS, Siler-Khodr TM, Najjar S: Precocious puberty in juvenile hypothyroidism. J Pediatr 92:55-59, 1978 5. Lindsay AN, Voorhess ML, MacGillivray MH: Multicystic ovaries in primary hypothyroidism. Obstet Gynecol 61:433-437, 1983 6. Evers JLH, Rolland R: Primary hypothyroidism and ovarian activity evidence for an overlap in the synthesis of pituitary glycoproteins. Br J Obstet Gynecol 88:195-202, 1981 7. Barnes ND, Hayles AB, Ryan RJ: Sexual maturation in juvenile hypothyroidism. Mayo Clin Proc 48:849-856, 1973 8. Bhattacharya M, Mitra AK: Regression of precocious puberty in a child with hypothyroidism after thyroxine therapy. Indian Pediatr 29:96-98, 1992 9. Costin G, Kershnar AK, Kogut MD, et al: Prolactin activity in juvenile hypothyroidism and precocious puberty. Pediatrics 50:881889, 1972
CHATTOPADHYAY, KUMAR, AND MARULAIAH
10. Advis JP, Richards JS, Ojeda SR: Hyperprolactinemia induced precocious puberty: Studies on the mechanism(s) by which prolactin enhances ovarian progesterone responsiveness to gonadotrophins in prepubertal rats. Endocrinology 108:1333-13342, 1981 11. Copmann TL, Adams WC: Relationship of polycystic ovary induction to prolactin secretion: Prevention of cyst formation by bromocriptine in the rat. Endocrinology 108:1095-1097, 1981 12. Jones RG: Effects of a pituitary gonadotrophin on the ovaries of hypothyroid rats. Endocrinology 54:464-470, 1954 13. Riddlesberger MM, Kuhn JP, Munschauer RW: The association of juvenile hypothyroidism and cystic ovaries. Radiology 139:77-80, 1981 14. Anasti JN, Flack MR, Froeloich J, et al: A potential novel mechanism for precocious puberty in juvenile hypothyroidism. J Clin Endocrinol Metab 80:276-279, 1995