|Year : 2017 | Volume
| Issue : 2 | Page : 81-85
Primary hypothyroidism presenting as a pituitary macroadenoma and precocious puberty
Balram Sharma, Hema Singh, Sanjay Saran, Sandeep Kumar Mathur
Department of Endocrinology, SMS Medical College and Hospitals, Jaipur, Rajasthan, India
|Date of Web Publication||26-May-2017|
Department of Endocrinology, SMS Medical College and Hospitals, Jaipur, Rajasthan
Source of Support: None, Conflict of Interest: None
The association in young females of long-standing primary hypothyroidism, isosexual precocious pseudopuberty, and multicystic enlarged ovaries was first described in 1960 by Van Wyk and Grumbach. In this case study, we report a girl with precocious puberty, poor linear growth, decreased vision, and a large pituitary pseudotumor due to long-standing hypothyroidism with regression of all components following thyroxine (T4) supplementation. This girl aged 12 years and 3 months presented in Endocrinology Department with complaints of early menarche starting at the age of 8 years with normal cycles along with early progressive breast development starting almost simultaneously. On examination, she had a reduced growth for age (<5th centile) with adequate breast development (Tanner Stage 3) but no pubic or axillary hair development. Physical and biochemical examination for blood indices revealed a microcytic hypochromic anemia. Most importantly, she had an elevated thyroid stimulating hormone >150 μIU/ml (0.35–5.5) and a free T4 (FT4) and free triiodothyronine below normal limits suggestive of primary hypothyroidism. Furthermore, serum prolactin levels were elevated along with an elevated serum follicle-stimulating hormone, luteinizing hormone, and estradiol. Multicystic ovaries and a bulky uterus on ultrasound were suggestive of precocious puberty. Magnetic resonance imaging scan of the sella turcica was suggestive of a pituitary macroadenoma. Posttreatment with gluten-free diet, iron supplements, and T4 replacement, her thyroid function, hemoglobin, and prolactin normalized along with a regression in the size of the ovary. Therefore, in patients of this age presenting with a pituitary macroadenoma, anemia, precocious puberty, and primary hypothyroidism, medical management was preferred over neurosurgical intervention so as to avoid permanent hypopituitarism and lifelong hormone replacement therapy.
Keywords: Pituitary macroadenoma, precocious puberty, primary hypothyroidism
|How to cite this article:|
Sharma B, Singh H, Saran S, Mathur SK. Primary hypothyroidism presenting as a pituitary macroadenoma and precocious puberty. Thyroid Res Pract 2017;14:81-5
|How to cite this URL:|
Sharma B, Singh H, Saran S, Mathur SK. Primary hypothyroidism presenting as a pituitary macroadenoma and precocious puberty. Thyroid Res Pract [serial online] 2017 [cited 2020 Jul 11];14:81-5. Available from: http://www.thetrp.net/text.asp?2017/14/2/81/201732
| Introduction|| |
The association in young females of long-standing primary hypothyroidism, isosexual precocious pseudopuberty, and multicystic enlarged ovaries was first described in 1960 by Van Wyk and Grumbach. Since then, sporadic case reports have contributed to clarifying the key features of this syndrome. The unique elements that lead to this diagnosis are follicle-stimulating hormone (FSH)-dominated sexual precocity combined with a delayed bone age in the presence of long-standing untreated hypothyroidism., It is important to recognize this syndrome because initiating simple thyroid hormone replacement completely resolves symptoms and hormone abnormalities, avoiding unnecessary investigations for malignancies or surgical intervention.
We report a girl with precocious puberty, poor linear growth, decreased vision, and a large pituitary pseudotumor due to long-standing hypothyroidism with regression of all components following thyroxine (T4) supplementation.
| Case Report|| |
A female child aged 12 years and 3 months presented in Endocrinology Department with complaints of early menarche starting at the age of 8 years with normal cycles along with early progressive breast development starting almost simultaneously. Her mother also complained of her poor linear growth, frequent headache (without nausea or vomiting), decreased vision, and progressively declining academic performance. She was born through a full-term normal vaginal delivery with a birth weight of 2.67 kg. There was no history of neonatal hypoglycemia or jaundice. Postnatally, all the developmental milestones, both verbal and motor, attained at appropriate age.
There was no history of loss of consciousness, seizures, or gelastic episodes. Her appetite was normal and she did not have excessive somnolence, cold intolerance, or constipation. Her scholastic performance continued to decline.
On examination, her height was 123 cm (<5th centile), weight was 29 kg (10–25th centile) and she had breast development at Tanner's Stage 3 but no pubic or axillary hair development [Figure 1]. Blood pressure was 100/70 with a pulse rate of 60/min. She had pallor, dry scaly skin [Figure 2], and depressed nasal bridge but no thyroid enlargement. Her intelligence quotient was 78 (low average). Neurological examination suggestive of mild decreased temporal visual fields on confrontation test and hung up ankle reflex. Fundus showed mild bilateral temporal disc pallor. However, visual acuity was normal.
|Figure 1: The girl showing short stature, classical hypothyroidism look before thyroxine therapy|
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|Figure 2: The hands of the girl showing short stature, classical hypothyroidism look before thyroxine therapy|
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She had microcytic hypochromic anemia with a hemoglobin level of 4.7 g/dl (normal 12–14 g/dl). Hormonal investigations revealed thyroid stimulating hormone (TSH) >150 μIU/ml (0.35–5.5), free triiodothyronine 1.43 pg/ml (1.8–4.2), and free T4 (FT4) 0.53 ng/dl (0.89–1.76) using chemiluminescence immunoassay with antithyroid peroxidase 99.9 IU/ml suggestive of autoimmune primary hypothyroidism. FSH was 12.29 mIU/ml (0.7–11.1), luteinizing hormone (LH) was 0.13 mIU/ml (0.8–7.6), and prolactin was >200 ng/dl through electrochemiluminescence immunoassay. S. estradiol (E2) was 615 pg/ml (21–312).
Since patient had severe microcytic hypochromic anemia which cannot solely be explained by hypothyroidism, further evaluation for cause of anemia was done. Serum iron was 36 μg/dl (40–150), serum total iron binding capacity 425 μg/dl (200–400), serum ferritin <3 ng/ml, serum Vitamin B12 456 pg/ml (193–982), serum folate 14.57 ng/ml (3–17) all of which is suggestive of iron deficiency anemia. Serum tissue transglutaminase IgA >100 IU/ml. Upper gastrointestinal endoscopy showed D2 - scalloping. Duodenal biopsy - suggestive of celiac disease modified Marsh classification - Grade 3A. These findings are suggestive of celiac disease which can be associated with autoimmune hypothyroidism.
Her radiological investigations revealed a bone age of 8 years (Greulich and Pyle's atlas) [Figure 3]. Ultrasonography (USG) of the pelvis showed a uterine size of 110 mm × 37 mm × 60 mm with enlarged multicystic ovaries (right ovary measuring 95 mm × 41 mm × 74 mm [152 ml] and left ovary 87 mm × 47 mm × 75 mm [165 ml]), i.e., bulky uterus with enlarged for age multicystic ovaries suggestive of precocious puberty [Figure 4]. Perimetry was normal. Electrocardiogram was suggestive of sinus bradycardia with low voltage complexes. Chest X-ray showed cardiomegaly [Figure 5]. USG neck showed hypoplastic thyroid with hypoechoic echotexture, septations with subtle increase in vascularity suggestive of Hashimoto's thyroiditis.
|Figure 3: X-ray wrist and hand showing retarded bone age (chronological age of this patient is 12 years and 3 months)|
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|Figure 4: (a) Ultrasonography of pelvis: Showing cystic changes and enlarged size in left ovary (before thyroxine therapy). (b) Ultrasonography of pelvis: Showing enlarged size and cystic changes of right ovary (before thyroxine therapy)|
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|Figure 5: X-ray skull true lateral view showing increased sellar size because of thyrotroph hyperplasia; X-ray chest showing mild cardiomegaly|
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The magnetic resonance imaging scan of sella revealed lobulated mass lesion in sella and suprasellar region measuring 21 mm × 14 mm × 15 mm showing intense homogeneous contrast enhancement [Figure 6]. Pituitary not visualized separately suggestive of pituitary macroadenoma. Optic chiasma is pushed superiorly and mildly compressed by mass and there is no obvious parasellar extension.
|Figure 6: Magnetic resonance imaging sella showing pituitary hyperplasia looking like pituitary macroadenoma|
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She was treated with strict gluten-free diet, T4 replacement, and iron supplements. During follow-up at 6 months, her thyroid functions normalized, prolactin decreased to 72.5 ng/ml, hemoglobin normalized, repeat USG revealed complete regression of ovarian cysts with normal-sized ovaries and size of pituitary decreased markedly to 11 mm × 11 mm × 8.6 mm (>50% decrease in size) [Figure 7]. Symptoms and signs of hypothyroidism improved dramatically with 3kg weight loss, normal skin appearance, improved height velocity [Figure 8].
|Figure 7: Magnetic resonance imaging images showing reduced size of pituitary after thyroxine therapy (compare with previous magnetic resonance imaging sella)|
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| Discussion|| |
The presence of precocious puberty and bilateral enlarged ovaries and elevated FSH warranted gonadotropin-releasing hormone (GnRH) stimulation test, but the presence of delayed bone age narrows diagnosis to long-standing hypothyroidism. The concomitant presence of celiac disease made the treatment even more challenging as the T4 replacement may alone not be able to reverse the condition till the patient follows strict gluten-free diet which is necessary for proper absorption of the drug. Moreover, the presence of a large macroadenoma like pituitary enlargement threatened the vision of the child. However, we preferred to take a risk of medical management as going for neurosurgical intervention will end up with permanent hypopituitarism with need for lifelong hormonal replacement therapy.
Specific key elements of this disorder are characteristic phenotype, imaging studies, and biochemical changes. Phenotypically, girls show the classical “hypothyroid” appearance, delayed growth, FSH-mediated secondary sexual characteristics with breast development with or without galactorrhea, uterine bleeding but absence of significant pubic or axillary hair development. Boys with this syndrome have macroorchidism without significant virilization, and testicular histology shows a predominance of tubular elements without elevated Leydig cell number, consistent with an FSH-mediated response. Imaging studies typically reveal enlarged multicystic ovaries with follicular development, a pubertal uterus, enlarged pituitary gland, and unique to this cause of sexual precocity, delayed bone age. Biochemically, low FT4 is combined with raised levels of TSH, prolactin, and estradiol. Typically, LH-releasing hormone stimulation shows an FSH-dominated prepubertal response with suppressed LH, confirming GnRH-independent precocious pseudopuberty.
The pathophysiology of the Van Wyk–Grumbach syndrome involves a complex interaction between different hypothalamic–pituitary hormonal axes.
First, in the original description, Van Wyk and Grumbach  hypothesized that there was hormonal overlap in the pituitary feedback mechanism. They tried to explain precocious puberty by an overlap in negative feedback regulation with overproduction of gonadotropins as well as thyrotropin (both share common α-subunit) in response to thyroid deficiency. However, although gonadotropins are elevated in these patients, these have been observed to be GnRH unresponsive or bioinactive in earlier studies. Furthermore, advancement of skeletal maturation characteristically associated with elevated gonadotropin states is not seen. Hence, gonadotropin excess does not appear to cause sexual precocity associated with hypothyroidism.
Second theory states that the glycoproteins TSH, FSH, LH, and human chorionic gonadotropin share a common alpha subunit but have a unique b-subunit that is specific to each hormone. Extreme TSH elevation seen in profound hypothyroidism induces FSH-like effects on the gonads resulting in multicystic ovaries, uterine bleeding, and breast enlargement. Hence, precocious puberty secondary to hypothyroidism behaves like an incomplete form of gonadotropin-dependent precocious puberty.
Third theory proposed that loss of negative feedback from thyroid hormones in primary hypothyroidism not only results in high thyrotropin releasing hormone (TRH) levels, hyperplasia of the TSH-secreting cells in the pituitary but also stimulates prolactin secretion. Prolactin is known to suppress pituitary gonadotropins by slowing GnRH pulse frequency., Slow GnRH pulses preferentially lead to suppression of LH and production of FSH. This differential regulation may explain the discordance between FSH and LH in this syndrome. Pathogenesis of galactorrhea in affected individuals is mediated by hyperprolactinemia. According to prolactin theory, hyperprolactinemia as a result of chronic stimulation of TRH enhances the sensitivity of ovaries to even trace amounts of circulating gonadotropins prepubertally. The increased sensitivity of ovaries to gonadotropins along with extremely elevated TSH having FSH-like effects could have caused multicystic ovaries.
| Conclusion|| |
The pathophysiology of Van Wyk–Grumbach syndrome involves a complex mechanism, which is, at least in part, mediated by the direct action of TSH on FSH receptors. We hypothesize that the “overlap” of hormone actions, as described by Van Wyk and Grumbach, may be exerted on a receptor level, specifically since all hormones involved use G protein – coupled receptors with common intracellular signaling pathways, with the raised TSH being the suspected common culprit. Early recognition and initiation of thyroid hormone replacement can avoid further diagnostic procedure, fear of malignancy and unnecessary surgery, resolve symptoms, and improve final height achieved.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]