An unusual presentation of acquired hypothyroidism: the Van Wyk–Grumbach syndrome

in European Journal of Endocrinology
Authors: E Baranowski and W Högler
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  • Department of Endocrinology and Diabetes, Birmingham Children's Hospital, Steelhouse Lane, Birmingham B4 6NH, UK

(Correspondence should be addressed to E Baranowski; Email: ebaranowski@doctors.org.uk)

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 FSH-dominated sexual precocity combined with a delayed bone age in the presence of hypothyroidism. It is important to recognise this syndrome because initiating simple thyroid hormone replacement completely resolves symptoms and hormone abnormalities, avoiding unnecessary investigations for malignancies or surgical intervention. We describe an 8-year-old girl with autoimmune thyroiditis and severe long-standing hypothyroidism presenting with the clinical features of Van Wyk–Grumbach syndrome, a secondary TSH-secreting adenoma and hyperprolactinaemia. In addition, this girl presented with microcytic anaemia, elevated erythrocyte sedimentation rate (ESR) and two unusual features – a newly developed streaky hyperpigmented skin lesion and parathyroid hormone suppression despite vitamin D deficiency. Thyroxine replacement normalised all hormone abnormalities and shrunk the pituitary adenoma within 9 months, but the new skin lesion persisted. We review the literature and explore the pathophysiology of known and new features that give rise to speculation indicating stimulation of the FSH G protein-coupled receptor by excessive TSH, but LH suppression by hyperprolactinaemia.

Abstract

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 FSH-dominated sexual precocity combined with a delayed bone age in the presence of hypothyroidism. It is important to recognise this syndrome because initiating simple thyroid hormone replacement completely resolves symptoms and hormone abnormalities, avoiding unnecessary investigations for malignancies or surgical intervention. We describe an 8-year-old girl with autoimmune thyroiditis and severe long-standing hypothyroidism presenting with the clinical features of Van Wyk–Grumbach syndrome, a secondary TSH-secreting adenoma and hyperprolactinaemia. In addition, this girl presented with microcytic anaemia, elevated erythrocyte sedimentation rate (ESR) and two unusual features – a newly developed streaky hyperpigmented skin lesion and parathyroid hormone suppression despite vitamin D deficiency. Thyroxine replacement normalised all hormone abnormalities and shrunk the pituitary adenoma within 9 months, but the new skin lesion persisted. We review the literature and explore the pathophysiology of known and new features that give rise to speculation indicating stimulation of the FSH G protein-coupled receptor by excessive TSH, but LH suppression by hyperprolactinaemia.

Introduction

In 1960, Van Wyk and Grumbach first described a syndrome characterised by breast development, uterine bleeding and multicystic ovaries in the presence of long-standing primary hypothyroidism (1). On review of subsequent case reports, specific key elements of this disorder can be distinguished, characterising phenotype, imaging studies and biochemical changes (Table 1). Phenotypically, girls show the classical ‘hypothyroid’ appearance, delayed growth, follicle-stimulating hormone (FSH)-mediated secondary sexual characteristics with breast development with or without galactorrhoea, uterine bleeding but absence of significant pubic or axillary hair development. 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 free thyroxine (T4) is combined with raised levels of thyroid stimulating hormone (TSH), prolactin and oestradiol. Typically, luteinising hormone-releasing hormone (LHRH) stimulation shows an FSH-dominated prepubertal response with suppressed luteinising hormone (LH), confirming gonadotropin-releasing hormone (GnRH)-independent precocious pseudopuberty (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22). Most cases in the literature are secondary to autoimmune thyroid disease but there are some case reports where the syndrome is secondary to unrecognised congenital hypothyroidism (5, 10, 12). It is important to recognise this syndrome as symptoms regress with thyroid hormone replacement and patients spontaneously enter true puberty at an appropriate time (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22).

Table 1

Summary of clinical findings in Van Wyk-Grumbach syndrome.

PhenotypeImagingBiochemistry
Typical hypothyroid appearanceEnlarged ovaries with multiple follicular cystsExtremely raised TSH and low-undetectable free T4
Delayed growthPubertal uterusRaised oestradiol
Precocious uterine bleedingDelayed bone ageHigh/high-normal FSH
Precocious thelarcheEnlarged pituitarySuppressed LH
± GalactorrhoeaFlat response on LHRH stimulation test
Absence of pubic and axillary hairRaised prolactin

The majority of human hormones act through 7-transmembrane G protein-coupled receptors (GPCRs) of which many hundreds are described. They all share common intracellular signalling pathways but little is known about their distribution, activity and cross-reactivity in hormone excess conditions (23).

We present a girl with both typical and unusual features of the Van Wyk–Grumbach syndrome, giving rise to speculation about hormonal overlap at the level of the GPCRs.

Case presentation

A girl aged 8 years and 9 months was referred to the endocrinology department with a suspicion of precocious puberty after having had two episodes, 4 months apart, of per-vaginal bleeding lasting 3–4 days with associated cramp-like abdominal pain. She was of Pakistani origin, born at 37 weeks gestation with a birth weight of 2.36 kg and was of normal intelligence. Apart from mother's pre-eclampsia during pregnancy, there were no antenatal or postnatal difficulties. Routine neonatal blood spot screening was normal. She had no history of visual disturbance or headaches and had been generally well in herself. However, she had experienced some recent weight gain and poor growth, and had been prescribed iron supplements because of suspected iron deficiency anaemia. She had no family history of thyroid disease, autoimmunity or precocious puberty.

On examination, her height was 124.7 cm (9th–25th centile, mid-parental height target range 50th–98th centile), weight was 36.55 kg (91st centile) and she had breast development at Tanner's stage 2, but no pubic or axillary hair development. She also had a large, streaky hyperpigmented skin lesion in her left axilla and flank, which had newly developed over the previous months (Fig. 1).

Figure 1
Figure 1

Newly developed streaky hyperpigmented lesion in the left axilla and chest wall. Full colour version of this figure available via http://dx.doi.org/10.1530/EJE-11-0494.

Citation: European Journal of Endocrinology 166, 3; 10.1530/EJE-11-0494

Baseline LH was 0.2 U/l, FSH 5.0 U/l and oestradiol was <50 pmol/l. Morning cortisol, 17-hydroxyprogesterone, androgens, human chorionic gonadotropin (hCG), α-fetoprotein and IGF1 were normal. Primary hypothyroidism was demonstrated by a free T4 <3.9 pmol/l with a TSH of 995 mU/l. Positive thyroid peroxidase antibodies confirmed autoimmune thyroiditis; TPO antibody titre was 378 kU/l (normal range 0–35 kU/l). Further blood tests highlighted a raised prolactin at 1310 mU/l, deficient vitamin D (16.2 nmol/l) and a suppressed parathyroid hormone (PTH) of 7 ng/l (13–29), in the presence of normal calcium and phosphate. She had a raised white blood cell count of 14.9 gG/l, raised ESR and severe, hyporegenerative, microcytic anaemia (Table 2). LHRH testing showed an FSH-dominated, prepubertal response with a 0–30 min FSH change from 6.7 to 6.5 U/l and an LH change from 0.1 to 0.4 U/l. Her repeat oestradiol was raised (164 pmol/l).

Table 2

Blood test results.

Test (normal range in brackets)Initial results (age 8 y, 9 months) After 3 months of treatmentAfter 9 months of treatment
Free thyroxine (10.7–21.8 pmol/l)<3.910.811.8
TSH (0.40–3.50 mU/l)955.07.9020.7
TPO Ab titre (0–35 kU/l)378
Prolactin (mU/l)1310218198
LH (0.7–2.2 U/l)0.20.5NA
FSH (0.2–6.0 U/l)5.02.44.9
Oestradiol (pmol/l)<50<5054
Calcium (2.20–2.60 mmol/l)2.422.33
Adjusted calcium (2.20–2.60 mmol/l)2.392.33
Phosphate (1.20–1.80 mmol/l)1.191.53
25-Hydroxy vitamin D (>50 nmol/l)16.240.5
Alkaline phosphatase (250–750 IU/l)51011021051
PTH (13–29 ng/l)73254
Calcitonin (0.0–5.0 ng/l)15.84.2
ESR (0–9 mm/h)501828
Haemoglobin (12–14 g/l)8.412.6

TPO Ab, thyroid peroxidase antibody.

A pelvic ultrasound scan found a pubertal uterus in size and appearance, and large, cystic ovaries with multiple dominant follicles (Fig. 2). A later pelvic magnetic resonance imaging (MRI) confirmed these findings. Contrasting with the pubertal development, her bone age was found to be delayed by 3 years. She went on to have an MRI of the brain, which showed a pituitary adenoma measuring 1.7×1.7×1 cm extending up to, but not compressing, the optic chiasm.

Figure 2
Figure 2

The ultrasound scan shows a pubertal uterus in size and appearance, measuring 5.3 cm in length, with a thickened endometrium (1.2 cm). Large, cystic ovaries with multiple dominant follicles were seen with one large thick-walled, irregular, complex cyst associated with the right ovary (4×1.5×2.9 cm), containing a smaller 1.3 cm diameter echogenic cyst within it. The right ovarian volume (including cyst) was 38.1 ml, and the left was 19.4 ml, with the largest follicle on the left measuring 1.4 cm in diameter.

Citation: European Journal of Endocrinology 166, 3; 10.1530/EJE-11-0494

T4 treatment was started, purposely at a low dose of 25 μg (22 mg/m2) and increased gradually to 50, 75 and then 100 μg (88 mg/m2) at her latest visit. Vitamin D deficiency was treated with 30 000 units of ergocalciferol/week and the anaemia with iron supplements. She had no further episodes of vaginal bleeding, and all her biochemistry returned to normal/expected values (Table 2). At her last review after 9 months of replacement therapy, her height was 134.1 cm (25th–50th centile) with a weight of 34.65 kg (75th centile), meaning that she had slimmed from a body mass index of 23.5 to 19.2 kg/m2. The hyperpigmented lesion in the axilla/flank was unchanged. At this point her growth velocity had reached 14 cm/year, but she had now entered true puberty. A repeat brain MRI showed a massive reduction in pituitary size with a large sella and CSF-filled void as remnants of the previous TSH and prolactin hypersecretion.

Discussion

The pathophysiology of the Van Wyk–Grumbach syndrome involves a complex interaction between different hypothalamic–pituitary hormonal axes. In the original description, Van Wyk and Grumbach hypothesised that there was hormonal overlap in the pituitary feedback mechanism. This overlap was thought to be partly at the hormone molecular level, given that both TSH and gonadotropins are glycoproteins, and/or partly due to a lack of specificity at the hypothalamic level (1). TRH-induced TSH excess may be the common stimulator of the FSH receptor and possibly other GPCRs. The fascinating aspect of this syndrome is that TRH-induced hyperprolactinaemia likely suppresses the pituitary gonadotrophic axis, in particular LH, at the same time.

Stimulation of the gonadal FSH receptor by TSH is supported by the specific FSH/oestrogen dominant clinical picture and histopathologic findings. Girls with this syndrome have breast development, follicular cysts and menstruation in the absence of pubic or axillary hair, which depends on adrenal androgens (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22). Histopathological analysis of resected ovaries and ovarian cysts shows cystic follicles and little if any luteinisation. Some reports also noted myxoedematous infiltrates within affected ovaries, suggesting an independent role in cyst formation and abnormal steroidogenesis within the gonad (1, 2, 3, 4, 5, 6, 18). Boys with this syndrome have macroorchidism without significant virilisation, and testicular histology shows a predominance of tubular elements without elevated Leydig cell number, consistent with an FSH-mediated response (24, 25). Thyroid hormone is known to affect testis growth and physiology, particularly during early development (26). The role of thyroid hormone receptors found on Sertoli and Leydig cells, in particular in this syndrome, is currently poorly understood. Because of the gonadal enlargement, and ovarian cyst formation, malignancy is often suspected, especially when accompanied by elevated ESR (7) and anaemia (4, 6, 8, 9, 10), as in our case. Non-recognition can lead not only to a delay in diagnosis but also to unnecessary surgical procedures. Surgery should only be indicated if there is ovarian torsion or if the cystic enlargement does not regress with treatment (4, 6, 9, 11).

The peripubertal phase, where low FSH levels prevail, could be vulnerable to FSH receptor stimulation by TSH (18, 24, 27) with cases very rarely being reported outside of this age group (18, 21, 22). A dose-dependent response of the FSH receptor to TSH is assumed as only very few children, all with extremely high TSH levels, are affected. This hypothesis is well supported by in vitro experiments (24, 27). The glycoproteins TSH, FSH, LH and hCG share a common α-subunit but have a unique β-subunit that is specific to each hormone. They each act through transmembrane GPCRs to activate adenylate cyclase and stimulate cAMP production (23). Anasti et al. (24) showed that recombinant human TSH elicited a dose-dependent response at the human FSH receptor. The TSH concentration required was several orders of magnitude higher than FSH, demonstrating that the FSH-like activity of TSH is very low. They went on to show that TSH and FSH are acting through the same receptor and that TSH competitively antagonises FSH. This response was not generic for all glycoproteins as adenylate cyclase activity in transfected cells was unresponsive to hCG. The concept of overlap between the glycoprotein hormones in times of hormone excess is not unprecedented – for example, hCG is used to stimulate LH receptors as a test of testicular function in boys due to the homology of their β-subunits (28).

To test whether a mutation or allelic variation in affected individuals leaves them more susceptible to TSH acting through the FSH receptor, Ryan et al. (27) sequenced the human FSH receptor gene in eight patients with gonadal hyperstimulation secondary to primary hypothyroidism. They found no mutations and no variance in the sensitivities of different allelic combinations or polymorphisms of the human FSH receptor. They confirmed previous study results that a very high concentration of TSH can directly cause activation of the wild-type FSH receptor (29). One may speculate that TSH could also be acting through its own receptor on the ovary, but this is considered less likely as hypothyroidism more commonly presents with ovarian insufficiency and delayed puberty (17).

The role of prolactin has long been argued in this syndrome, especially as prolactin has not been elevated in every reported case (12). Loss of negative feedback from thyroid hormones in primary hypothyroidism not only results in high TRH levels, hyperplasia of the TSH-secreting cells in the pituitary but also stimulates prolactin secretion (5, 6, 13, 14, 30, 31, 32). In addition, elevated oestrogen concentrations reduce prolactin inhibitory factor via a negative feedback mechanism, causing a further increase in prolactin (8, 33). Prolactin is known to suppress pituitary gonadotropins by slowing GnRH pulse frequency (34, 35, 36). Slow GnRH pulses preferentially lead to suppression of LH and production of FSH (37). This differential regulation may explain the discordance between FSH and LH in this syndrome. Potentially, this discrepancy could also be caused by abnormalities in the activin–inhibin–follistatin axis but these hormones were not measured (37). Cross-reactivity of such excessive TSH with FSH in standard assays is very unlikely but cannot be completely excluded, given the structural similarities between FSH and TSH, which warrants further studies.

Prolactin also sensitises the ovary to circulating gonadotropins and accelerates follicular maturation via a poorly understood mechanism (30, 38). Bromocriptine given to rats with hCG-induced sexual precocity inhibits ovarian cyst formation (30). However, ovarian hyperstimulation is not a recognised feature of prolactinomas, and girls with unrecognised Van Wyk–Grumbach syndrome continued vaginal bleeding despite treatment with bromocriptine (5). One would assume, however, that the pathogenesis of galactorrhoea in affected individuals is mediated by hyperprolactinaemia.

One of the unique diagnostic features of the Van Wyk–Grumbach syndrome is the combination of delayed bone age with apparent sexual precocity. Hypothyroidism leads to arrested growth and bone age delay that appears to outweigh the effect of the sexual precocity and raised circulating oestrogen. Providing thyroid hormone is adequately replaced, and there is enough time for catch up growth before true puberty occurs, it is conceivable that patients can achieve a final height within normal limits (5, 7, 15, 25).

This case presented with some unusual features, namely PTH suppression, streaky newly developed hyperpigmentation and severe anaemia. Lack of TSH causes bone loss (23). TSH in lab studies suppresses bone remodelling (39). There is poor understanding of what TSH excess, and long-standing hypothyroidism, does to bone metabolism. In our patient, TSH appeared to exert PTH-like effects with low phosphate and compensatory raised calcitonin levels whilst her PTH was suppressed, opposite to what would be expected given her vitamin D deficiency. We speculate that this PTH-like effect is exerted via TSH's own GPCR found on osteoblast and osteoclast precursors and less likely via the PTH GPCR because of profound structural difference between TSH and PTH. The fact that PTH increased during T4 replacement despite successful ergocalciferol treatment supports our hypothesis.

The association between localised skin hyperpigmentation and this syndrome was recognised by Van Wyk and Grumbach in one of the cases in their original publication (1) but there has been no mention in the literature since then. The speculated mechanism of development was further hormonal overlapping with the melanocyte-stimulating hormone (MSH) (1). MSH also acts via its GPCR and one could speculate that low-level cutaneous mosaicism of receptor distribution and activity could cause such a streaky hyperpigmentation in cases of TSH excess if homologies or cross-reactivity exist between TSH and MSH, analogous to paraneoplastic phenomena. An alternative hypothesis could be that TSH is stimulating its own epidermal TSH receptor. The presence of a streaky skin hyperpigmentation would obviously suggest a differential diagnosis of McCune Albright syndrome. Although the combination of McCune Albright syndrome and autoimmune thyroiditis may in theory result in a similar clinical picture, this diagnosis can be excluded as the skin lesion was not congenital, there was no evidence of polyostotic fibrodysplasia, bone age was delayed rather than advanced, and all hormone abnormalities vanished with T4 treatment.

Anaemia is not so uncommon in hypothyroidism (40, 41) and has been noted in several case reports of the Van Wyk–Grumbach syndrome (4, 6, 8, 9, 10, 18). The proposed mechanism involves decreased red cell production in response to the reduced metabolic requirements for oxygen in tissues in hypothyroidism (40, 41). In addition, the anaemia may also be exaggerated by menorrhagia, dietary deficiency or pernicious anaemia as part of an autoimmune ‘cluster’ (41).

In 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 hypothesise 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 GPCRs with common intracellular signalling 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 interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

References

  • 1

    Van Wyk JJ, Grumbach MM. Syndrome of precocious menstruation and galactorrhoea in juvenile hypothyroidism: an example of hormonal overlap in pituitary feedback. Journal of Pediatrics 1960 57 416435. doi:10.1016/S0022-3476(60)80250-8.

    • Search Google Scholar
    • Export Citation
  • 2

    Bassam T & Ajlouni K. A case of ovarian enlargement in severe primary hypothyroidism and review of the literature. Annals of Saudi Medicine 2006 26. Downloaded from http://www.saudiannals.net on June 8 2010, IP 194.176.105.45

  • 3

    Hansen KA, Tho SP, Hanly M, Moretuzzo RW, McDonough PG. Massive ovarian enlargement in primary hypothyroidism. Fertility and Sterility 1997 67 169171. doi:10.1016/S0015-0282(97)81876-6.

    • Search Google Scholar
    • Export Citation
  • 4

    Browne LP, Boswell HB, Crotty EJ, O'Hara SM, Birkemeier KL, Guillerman RP. Van Wyk and Grumbach syndrome revisited: imaging and clinical findings in pre- and postpubertal girls. Paediatric Radiology 2008 38 538542. doi:10.1007/s00247-008-0777-1.

    • Search Google Scholar
    • Export Citation
  • 5

    Sanjeevaiah AR, Sanjay S, Deepak T, Sharada A, Srikanta SS. Precocious puberty and large multicystic ovaries in young girls with primary hypothyroidism. Official Journal of Endocrine Practice 2007 13 652655.

    • Search Google Scholar
    • Export Citation
  • 6

    Panico A, Lupoli GA, Fonderico F, Colarusso S, Marciello F, Poggiano MR, Del Prete M, Magliulo R, Iervolino P, Lupoli G. Multiple ovarian cysts in a young girl with severe hypothyroidism. Thyroid 2007 17 12891293. doi:10.1089/thy.2007.0056.

    • Search Google Scholar
    • Export Citation
  • 7

    Niedziela M, Korman E. Severe hypothyroidism due to autoimmune atrophic thyroiditis – predicted target height and a plausible mechanism for sexual precocity. Journal of Pediatric Endocrinology and Metabolism 2001 14 901907. doi:10.1515/JPEM.2001.14.7.901.

    • Search Google Scholar
    • Export Citation
  • 8

    Hunold A, Alzen G, Wudy SA, Bluetters-Sawatzki R, Landmann E, Reiter A, Wagner HJ. Ovarian tumour in a 12-year old female with severe hypothyroidism: a case of Van Wyk and Grumbach syndrome. Pediatric Blood and Cancer 2009 52 677679. doi:10.1002/pbc.21920.

    • Search Google Scholar
    • Export Citation
  • 9

    Indumathi CK, Bantwal G, Patil M. Primary hypothyroidism with precocious puberty and bilateral cystic ovaries. Indian Journal of Pediatrics 2007 74 781783. doi:10.1007/s12098-007-0140-9.

    • Search Google Scholar
    • Export Citation
  • 10

    Ozgen T, Guven A, Aydin M. Precocious puberty in a girl with Down syndrome due to primary hypothyroidism. Turkish Journal of Paediatrics 2009 51 381383.

    • Search Google Scholar
    • Export Citation
  • 11

    Chattopadhyay A, Kumar V, Marulaiah M. Polycystic ovaries, precocious puberty and acquired hypothyroidism: the Van Wyk and Grumbach syndrome. Journal of Pediatric Surgery 2003 38 13901392. doi:10.1016/S0022-3468(03)00403-2.

    • Search Google Scholar
    • Export Citation
  • 12

    Sharma Y, Bajpai A, Mittal S, Kabra M, Menon PSN. Ovarian cysts in young girls with hypothyroidism: follow up and effect of treatment. Journal of Pediatric Endocrinology and Metabolism 2006 19 895900. doi:10.1515/JPEM.2006.19.7.895.

    • Search Google Scholar
    • Export Citation
  • 13

    Takeuchi K, Deguchi M, Takeshima Y, Maruo T. A case of multiple ovarian cysts in a pre-pubertal girl with severe hypothyroidism due to autoimmune thyroiditis. International Journal of Gynaecological Cancer 2004 14 543545. doi:10.1111/j.1048-891x.2004.14318.x.

    • Search Google Scholar
    • Export Citation
  • 14

    Campaner AB, Scapinelli A, Machado RO, Dos Santos RE, Beznos GW, Aoki T. Primary hypothyroidism presenting as an ovarian tumour and precocious puberty in a prepubertal girl. Gynaecological Endocrinology 2006 22 395398. doi:10.1080/09513590600819032.

    • Search Google Scholar
    • Export Citation
  • 15

    Kamboj MK, Musham CK. Case presentation of hypothyroidism with extreme short stature and early puberty. International Journal of Disability and Human Development 2009 8 317320. doi:10.1515/IJDHD.2009.8.3.317.

    • Search Google Scholar
    • Export Citation
  • 16

    Singh BM, Ammini AC, Kriplani A. Ovarian cyst in juvenile hypothyroidism. Archives of Gynaecology and Obstetrics 2005 271 262263. doi:10.1007/s00404-003-0581-y.

    • Search Google Scholar
    • Export Citation
  • 17

    Durbin KL, Diaz-Montes T, Loveless MB. Van Wyk and Grumbach syndrome: an unusual case and review of the literature. Journal of Pediatric and Adolescent Gynaecology 2011 24 e93e96. doi:10.1016/j.jpag.2010.08.003.

    • Search Google Scholar
    • Export Citation
  • 18

    Shu J, Xing L, Zhang L, Fang S, Huang H. Ignored adult primary hypothyroidism presenting chiefly with persistent ovarian cysts: a need for increased awareness. Reproductive Biology and Endocrinology 2011 9 119 doi:10.1186/1477-7827-9-119.

    • Search Google Scholar
    • Export Citation
  • 19

    Sultan A, Velaga MR, Fleet M, Cheetham T. Cullen's sign and massive ovarian enlargement secondary to primary hypothyroidism in a patient with a normal FSH receptor. Archives of Diseases in Children 2006 91 509510. doi:10.1136/adc.2005.088443.

    • Search Google Scholar
    • Export Citation
  • 20

    Wormbecker A, Clarson C. Acquired primary hypothyroidism: vaginal bleeding in a quiet child. Canadian Medical Association Journal 2010 182 588590. doi:10.1503/cmaj.090883.

    • Search Google Scholar
    • Export Citation
  • 21

    Bhansali A, Jayaprakash P, Dutta P, Walia R, Ravikumar P. Precocious puberty and a sellar mass. BMJ Case Reports 2009 bcr03.2009.1677.

  • 22

    Kubota K, Itho M, Kishi H, Igarashi S, Minegishi T. Primary hypothyroidism presenting as multiple ovarian cysts in an adult woman: a case report. Gynaecological Endocrinology 2008 24 586589. doi:10.1080/09513590802288192.

    • Search Google Scholar
    • Export Citation
  • 23

    Kroeze WK, Sheffler DJ, Roth BL. G-protein-coupled receptors at a glance. Journal of Cell Science 2003 116 48674869. doi:10.1242/jcs.00902.

  • 24

    Anasti JN, Flack MR, Froehlich J, Nelson LM, Nisula BC. A potential novel mechanism for precocious puberty in juvenile hypothyroidism. Journal of Clinical Endocrinology and Metabolism 1995 80 276279. doi:10.1210/jc.80.1.276.

    • Search Google Scholar
    • Export Citation
  • 25

    Bruder JM, Samuels MH, Bremner WJ, Ridgway EC, Wierman ME. Hypothyroid-induced macroorchidism: use of a gonadotropin-releasing hormone agonist to understand its mechanism and augment adult stature. Journal of Clinical Endocrinology and Metabolism 1995 80 1116. doi:10.1210/jc.80.1.11.

    • Search Google Scholar
    • Export Citation
  • 26

    Wagner MS, Wajner SM, Maia AL. The role of thyroid hormones in testicular development and function. Journal of Endocrinology 2008 199 351365. doi:10.1677/JOE-08-0218.

    • Search Google Scholar
    • Export Citation
  • 27

    Ryan GL, Feng X, d'Alva CB, Zhang M, Van Voorhis BJ, Pinto EM, Kubias AE, Antonini SR, Latronico AC, Segaloff DL. Evaluating the roles of follicle-stimulating hormone receptor polymorphisms in gonadal hyperstimulation associated with severe juvenile primary hypothyroidism. Journal of Clinical Endocrinology and Metabolism 2007 92 23122317. doi:10.1210/jc.2006-2086.

    • Search Google Scholar
    • Export Citation
  • 28

    Nakamoto JM, Franklin SL & Geffner ME. Puberty. In Pediatric Practice: Endocrinology, 1st edn, ch 7, pp 259–298. Eds MS Kappy, DB Allen & ME Geffner. New York: McGraw-Hill Companies, 2010

  • 29

    De Leener A, Montanelli L, Van Durme J, Chae H, Smits G, Vassart G, Costagliola S. Presence and absence of follicle stimulating hormone receptor mutations provide some insights into spontaneous ovarian hyperstimulation syndrome pathophysiology. Journal of Clinical Endocrinology and Metabolism 2006 91 555562. doi:10.1210/jc.2005-1580.

    • Search Google Scholar
    • Export Citation
  • 30

    Copmann TL, Adams WC. Relationship of polycystic ovary induction to prolactin secretion: prevention of cyst formation by bromocriptine in the rat. Endocrinology 1981 108 10951097. doi:10.1210/endo-108-3-1095.

    • Search Google Scholar
    • Export Citation
  • 31

    Rosenfield RL, Cooke DW & Radovick S. Puberty and its disorders in the female. In Pediatric Endocrinology, 3rd edn, ch 14, pp 530–609. Ed. MA Sperling. Philadelphia Saunders, Elsevier, 2008

  • 32

    Koller K, Renee W, Marjorie W. Thyroid hormones regulate the level of thyrotropin-releasing hormone mRNA in the paraventricular nucleus. PNAS 1987 84 73297334. doi:10.1073/pnas.84.20.7329.

    • Search Google Scholar
    • Export Citation
  • 33

    Costin G, Kershnar AK, Kogut MD, Turkington RW. Prolactin activity in juvenile hypothyroidism and precocious puberty. Pediatrics 1972 56 881889.

  • 34

    Denef C. Paracrinicity: the story of 30 years of cellular pituitary crosstalk. Journal of Neuroendocrinology 2008 20 170. doi:10.1111/j.1365-2826.2008.01676.x.

    • Search Google Scholar
    • Export Citation
  • 35

    Krassas GE, Poppe K, Glinoer D. Thyroid function and human reproductive health. Endocrine Reviews 2010 31 702755. doi:10.1210/er.2009-0041.

  • 36

    Grattan DR, Jasoni CL, Liu XL, Anderson GM, Herbison AE. Prolactin regulation of gonadotropin-releasing hormone neurons to suppress luteinizing hormone secretion in mice. Endocrinology 2007 148 43444351. doi:10.1210/en.2007-0403.

    • Search Google Scholar
    • Export Citation
  • 37

    Thackray VG, Mellon PL, Coss D. Hormones in synergy: regulation of the pituitary gonadotropin genes. Molecular and Cellular Endocrinology 2010 314 192203. doi:10.1016/j.mce.2009.09.003.

    • Search Google Scholar
    • Export Citation
  • 38

    Advis JP, Richards JS, Ojeda SR. Hyperprolactinaemia-induced precocious puberty: studies on the mechanism(s) by which prolactin enhances progesterone responsiveness to gonadotropins in prepubertal rats. Endocrinology 1981 108 13331342. doi:10.1210/endo-108-4-1333.

    • Search Google Scholar
    • Export Citation
  • 39

    Zaidi M, Davies TF, Zallone A, Blair HC, Iqbal J, Moonga SS, Mechanik J, Sun L. Thyroid-stimulating hormone, thyroid hormones and bone loss. Current Osteoporosis Reports 2009 7 4752. doi:10.1007/s11914-009-0009-0.

    • Search Google Scholar
    • Export Citation
  • 40

    Chu JY, Monteleone JA, Peden VH, Graviss ER, Vernava BS. Anaemia in children and adolescents with hypothyroidism. Clinical Paediatrics 1981 20 696699. doi:10.1177/000992288102001102.

    • Search Google Scholar
    • Export Citation
  • 41

    Munro DS & Kennedy RL. Goitre and hypothyroidism. In Clinical Endocrinology, 1st edn, ch 24, pp 293–308. Ed. A Grossman. Oxford: Blackwell Scientific Publications, 1992

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    Newly developed streaky hyperpigmented lesion in the left axilla and chest wall. Full colour version of this figure available via http://dx.doi.org/10.1530/EJE-11-0494.

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    The ultrasound scan shows a pubertal uterus in size and appearance, measuring 5.3 cm in length, with a thickened endometrium (1.2 cm). Large, cystic ovaries with multiple dominant follicles were seen with one large thick-walled, irregular, complex cyst associated with the right ovary (4×1.5×2.9 cm), containing a smaller 1.3 cm diameter echogenic cyst within it. The right ovarian volume (including cyst) was 38.1 ml, and the left was 19.4 ml, with the largest follicle on the left measuring 1.4 cm in diameter.

  • 1

    Van Wyk JJ, Grumbach MM. Syndrome of precocious menstruation and galactorrhoea in juvenile hypothyroidism: an example of hormonal overlap in pituitary feedback. Journal of Pediatrics 1960 57 416435. doi:10.1016/S0022-3476(60)80250-8.

    • Search Google Scholar
    • Export Citation
  • 2

    Bassam T & Ajlouni K. A case of ovarian enlargement in severe primary hypothyroidism and review of the literature. Annals of Saudi Medicine 2006 26. Downloaded from http://www.saudiannals.net on June 8 2010, IP 194.176.105.45

  • 3

    Hansen KA, Tho SP, Hanly M, Moretuzzo RW, McDonough PG. Massive ovarian enlargement in primary hypothyroidism. Fertility and Sterility 1997 67 169171. doi:10.1016/S0015-0282(97)81876-6.

    • Search Google Scholar
    • Export Citation
  • 4

    Browne LP, Boswell HB, Crotty EJ, O'Hara SM, Birkemeier KL, Guillerman RP. Van Wyk and Grumbach syndrome revisited: imaging and clinical findings in pre- and postpubertal girls. Paediatric Radiology 2008 38 538542. doi:10.1007/s00247-008-0777-1.

    • Search Google Scholar
    • Export Citation
  • 5

    Sanjeevaiah AR, Sanjay S, Deepak T, Sharada A, Srikanta SS. Precocious puberty and large multicystic ovaries in young girls with primary hypothyroidism. Official Journal of Endocrine Practice 2007 13 652655.

    • Search Google Scholar
    • Export Citation
  • 6

    Panico A, Lupoli GA, Fonderico F, Colarusso S, Marciello F, Poggiano MR, Del Prete M, Magliulo R, Iervolino P, Lupoli G. Multiple ovarian cysts in a young girl with severe hypothyroidism. Thyroid 2007 17 12891293. doi:10.1089/thy.2007.0056.

    • Search Google Scholar
    • Export Citation
  • 7

    Niedziela M, Korman E. Severe hypothyroidism due to autoimmune atrophic thyroiditis – predicted target height and a plausible mechanism for sexual precocity. Journal of Pediatric Endocrinology and Metabolism 2001 14 901907. doi:10.1515/JPEM.2001.14.7.901.

    • Search Google Scholar
    • Export Citation
  • 8

    Hunold A, Alzen G, Wudy SA, Bluetters-Sawatzki R, Landmann E, Reiter A, Wagner HJ. Ovarian tumour in a 12-year old female with severe hypothyroidism: a case of Van Wyk and Grumbach syndrome. Pediatric Blood and Cancer 2009 52 677679. doi:10.1002/pbc.21920.

    • Search Google Scholar
    • Export Citation
  • 9

    Indumathi CK, Bantwal G, Patil M. Primary hypothyroidism with precocious puberty and bilateral cystic ovaries. Indian Journal of Pediatrics 2007 74 781783. doi:10.1007/s12098-007-0140-9.

    • Search Google Scholar
    • Export Citation
  • 10

    Ozgen T, Guven A, Aydin M. Precocious puberty in a girl with Down syndrome due to primary hypothyroidism. Turkish Journal of Paediatrics 2009 51 381383.

    • Search Google Scholar
    • Export Citation
  • 11

    Chattopadhyay A, Kumar V, Marulaiah M. Polycystic ovaries, precocious puberty and acquired hypothyroidism: the Van Wyk and Grumbach syndrome. Journal of Pediatric Surgery 2003 38 13901392. doi:10.1016/S0022-3468(03)00403-2.

    • Search Google Scholar
    • Export Citation
  • 12

    Sharma Y, Bajpai A, Mittal S, Kabra M, Menon PSN. Ovarian cysts in young girls with hypothyroidism: follow up and effect of treatment. Journal of Pediatric Endocrinology and Metabolism 2006 19 895900. doi:10.1515/JPEM.2006.19.7.895.

    • Search Google Scholar
    • Export Citation
  • 13

    Takeuchi K, Deguchi M, Takeshima Y, Maruo T. A case of multiple ovarian cysts in a pre-pubertal girl with severe hypothyroidism due to autoimmune thyroiditis. International Journal of Gynaecological Cancer 2004 14 543545. doi:10.1111/j.1048-891x.2004.14318.x.

    • Search Google Scholar
    • Export Citation
  • 14

    Campaner AB, Scapinelli A, Machado RO, Dos Santos RE, Beznos GW, Aoki T. Primary hypothyroidism presenting as an ovarian tumour and precocious puberty in a prepubertal girl. Gynaecological Endocrinology 2006 22 395398. doi:10.1080/09513590600819032.

    • Search Google Scholar
    • Export Citation
  • 15

    Kamboj MK, Musham CK. Case presentation of hypothyroidism with extreme short stature and early puberty. International Journal of Disability and Human Development 2009 8 317320. doi:10.1515/IJDHD.2009.8.3.317.

    • Search Google Scholar
    • Export Citation
  • 16

    Singh BM, Ammini AC, Kriplani A. Ovarian cyst in juvenile hypothyroidism. Archives of Gynaecology and Obstetrics 2005 271 262263. doi:10.1007/s00404-003-0581-y.

    • Search Google Scholar
    • Export Citation
  • 17

    Durbin KL, Diaz-Montes T, Loveless MB. Van Wyk and Grumbach syndrome: an unusual case and review of the literature. Journal of Pediatric and Adolescent Gynaecology 2011 24 e93e96. doi:10.1016/j.jpag.2010.08.003.

    • Search Google Scholar
    • Export Citation
  • 18

    Shu J, Xing L, Zhang L, Fang S, Huang H. Ignored adult primary hypothyroidism presenting chiefly with persistent ovarian cysts: a need for increased awareness. Reproductive Biology and Endocrinology 2011 9 119 doi:10.1186/1477-7827-9-119.

    • Search Google Scholar
    • Export Citation
  • 19

    Sultan A, Velaga MR, Fleet M, Cheetham T. Cullen's sign and massive ovarian enlargement secondary to primary hypothyroidism in a patient with a normal FSH receptor. Archives of Diseases in Children 2006 91 509510. doi:10.1136/adc.2005.088443.

    • Search Google Scholar
    • Export Citation
  • 20

    Wormbecker A, Clarson C. Acquired primary hypothyroidism: vaginal bleeding in a quiet child. Canadian Medical Association Journal 2010 182 588590. doi:10.1503/cmaj.090883.

    • Search Google Scholar
    • Export Citation
  • 21

    Bhansali A, Jayaprakash P, Dutta P, Walia R, Ravikumar P. Precocious puberty and a sellar mass. BMJ Case Reports 2009 bcr03.2009.1677.

  • 22

    Kubota K, Itho M, Kishi H, Igarashi S, Minegishi T. Primary hypothyroidism presenting as multiple ovarian cysts in an adult woman: a case report. Gynaecological Endocrinology 2008 24 586589. doi:10.1080/09513590802288192.

    • Search Google Scholar
    • Export Citation
  • 23

    Kroeze WK, Sheffler DJ, Roth BL. G-protein-coupled receptors at a glance. Journal of Cell Science 2003 116 48674869. doi:10.1242/jcs.00902.

  • 24

    Anasti JN, Flack MR, Froehlich J, Nelson LM, Nisula BC. A potential novel mechanism for precocious puberty in juvenile hypothyroidism. Journal of Clinical Endocrinology and Metabolism 1995 80 276279. doi:10.1210/jc.80.1.276.

    • Search Google Scholar
    • Export Citation
  • 25

    Bruder JM, Samuels MH, Bremner WJ, Ridgway EC, Wierman ME. Hypothyroid-induced macroorchidism: use of a gonadotropin-releasing hormone agonist to understand its mechanism and augment adult stature. Journal of Clinical Endocrinology and Metabolism 1995 80 1116. doi:10.1210/jc.80.1.11.

    • Search Google Scholar
    • Export Citation
  • 26

    Wagner MS, Wajner SM, Maia AL. The role of thyroid hormones in testicular development and function. Journal of Endocrinology 2008 199 351365. doi:10.1677/JOE-08-0218.

    • Search Google Scholar
    • Export Citation
  • 27

    Ryan GL, Feng X, d'Alva CB, Zhang M, Van Voorhis BJ, Pinto EM, Kubias AE, Antonini SR, Latronico AC, Segaloff DL. Evaluating the roles of follicle-stimulating hormone receptor polymorphisms in gonadal hyperstimulation associated with severe juvenile primary hypothyroidism. Journal of Clinical Endocrinology and Metabolism 2007 92 23122317. doi:10.1210/jc.2006-2086.

    • Search Google Scholar
    • Export Citation
  • 28

    Nakamoto JM, Franklin SL & Geffner ME. Puberty. In Pediatric Practice: Endocrinology, 1st edn, ch 7, pp 259–298. Eds MS Kappy, DB Allen & ME Geffner. New York: McGraw-Hill Companies, 2010

  • 29

    De Leener A, Montanelli L, Van Durme J, Chae H, Smits G, Vassart G, Costagliola S. Presence and absence of follicle stimulating hormone receptor mutations provide some insights into spontaneous ovarian hyperstimulation syndrome pathophysiology. Journal of Clinical Endocrinology and Metabolism 2006 91 555562. doi:10.1210/jc.2005-1580.

    • Search Google Scholar
    • Export Citation
  • 30

    Copmann TL, Adams WC. Relationship of polycystic ovary induction to prolactin secretion: prevention of cyst formation by bromocriptine in the rat. Endocrinology 1981 108 10951097. doi:10.1210/endo-108-3-1095.

    • Search Google Scholar
    • Export Citation
  • 31

    Rosenfield RL, Cooke DW & Radovick S. Puberty and its disorders in the female. In Pediatric Endocrinology, 3rd edn, ch 14, pp 530–609. Ed. MA Sperling. Philadelphia Saunders, Elsevier, 2008

  • 32

    Koller K, Renee W, Marjorie W. Thyroid hormones regulate the level of thyrotropin-releasing hormone mRNA in the paraventricular nucleus. PNAS 1987 84 73297334. doi:10.1073/pnas.84.20.7329.

    • Search Google Scholar
    • Export Citation
  • 33

    Costin G, Kershnar AK, Kogut MD, Turkington RW. Prolactin activity in juvenile hypothyroidism and precocious puberty. Pediatrics 1972 56 881889.

  • 34

    Denef C. Paracrinicity: the story of 30 years of cellular pituitary crosstalk. Journal of Neuroendocrinology 2008 20 170. doi:10.1111/j.1365-2826.2008.01676.x.

    • Search Google Scholar
    • Export Citation
  • 35

    Krassas GE, Poppe K, Glinoer D. Thyroid function and human reproductive health. Endocrine Reviews 2010 31 702755. doi:10.1210/er.2009-0041.

  • 36

    Grattan DR, Jasoni CL, Liu XL, Anderson GM, Herbison AE. Prolactin regulation of gonadotropin-releasing hormone neurons to suppress luteinizing hormone secretion in mice. Endocrinology 2007 148 43444351. doi:10.1210/en.2007-0403.

    • Search Google Scholar
    • Export Citation
  • 37

    Thackray VG, Mellon PL, Coss D. Hormones in synergy: regulation of the pituitary gonadotropin genes. Molecular and Cellular Endocrinology 2010 314 192203. doi:10.1016/j.mce.2009.09.003.

    • Search Google Scholar
    • Export Citation
  • 38

    Advis JP, Richards JS, Ojeda SR. Hyperprolactinaemia-induced precocious puberty: studies on the mechanism(s) by which prolactin enhances progesterone responsiveness to gonadotropins in prepubertal rats. Endocrinology 1981 108 13331342. doi:10.1210/endo-108-4-1333.

    • Search Google Scholar
    • Export Citation
  • 39

    Zaidi M, Davies TF, Zallone A, Blair HC, Iqbal J, Moonga SS, Mechanik J, Sun L. Thyroid-stimulating hormone, thyroid hormones and bone loss. Current Osteoporosis Reports 2009 7 4752. doi:10.1007/s11914-009-0009-0.

    • Search Google Scholar
    • Export Citation
  • 40

    Chu JY, Monteleone JA, Peden VH, Graviss ER, Vernava BS. Anaemia in children and adolescents with hypothyroidism. Clinical Paediatrics 1981 20 696699. doi:10.1177/000992288102001102.

    • Search Google Scholar
    • Export Citation
  • 41

    Munro DS & Kennedy RL. Goitre and hypothyroidism. In Clinical Endocrinology, 1st edn, ch 24, pp 293–308. Ed. A Grossman. Oxford: Blackwell Scientific Publications, 1992