Case 2 -

Multicystic Ovaries Due to Hypothyroidism Ronald Jaffe, MB. BCh

Case History: A 9-year-old girl presented with a 2-year history of abdominal pain, increasing abdominal girth and fatigue. The physical examination was unremarkable, Tanner stage 0, but she had palpable abdominal masses. A CT scan revealed cystic masses arising from the pelvis to the level of the umbilicus, multiloculated, multicystic and ovarian in origin. The cysts were decompressed laparoscopically and the cyst wall biopsied. The cytology was benign and the cysts were diagnosed as "luteinized follicular cysts", with the note that since they were large and bilateral, a non-ovarian endocrine effect was possible. Within 2 months, the ovarian cysts recurred, larger than before and were removed laparoscopically. The cysts were signed out as "multiple luteinized cysts with a prominent granulosa cell layer", but an expert consultation was sought because of the clinical concern around their rapid re-growth. The consultant diagnosed "multicystic juvenile granulosa cell tumors", the in-house diagnosis was revised accordingly. The slide is from this procedure. A bilateral salpingo-oophorectomy was done, 4 months after first presentation. The diagnosis was "cystic ovaries with multicystic granulosa cell tumor", with a note that suggested that the granulosa cell tumors were on the background of (non-neoplastic) cystic ovaries and that no extra-ovarian spread was present. The consultant confirmed his original diagnosis and agreed that there were also benign cysts. She was treated with Cisplatin, VP-16 and Bleomycin for 6 months and one year later, is well without evidence of disease. Case 2 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer At the time of her first chemotherapy administration, clinical hypothyroidism was suspected. The free T4 was 0.23 ng/dl (0.81-2.06) TSH 2003 uIU/mL (0.700-5.700) prolactin 87.1 ng/mL/ (1.2-11.4) Inhibin A 175.3 (high) Inhibin B 37 (less than 30 pg/mL). She was begun on Synthroid and improved clinically and her pituitary and thyroid tests normalized. Discussion: Multiple ovarian cysts due to hypothyroidism are described extensively in the literature [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29] but the major textbooks are silent on the subject, except for Blaustein. Since the advent of pelvic sonography, more cases have been described suggesting that the condition of cystic ovaries is common in hypothyroidism [10]. The cysts can be massive, and the presentation can be as ovarian masses, torsion, delayed or more commonly precocious puberty and vaginal bleeding. Because the hypothyroidism is commonly the condition under observation, and because the ovarian cysts regress rapidly and completely with thyroid replacement therapy, there are few descriptions of the histopathology of the cysts [1, 2, 4, 13, 20, 22] Gross descriptions reveal multiple cysts that contain clear yellow fluid. The descriptions include "cystic cavities lined by a single layer of ovoid cells...with no evidence of luteinization" [22] and Van Voorhis et al [20] describe the finding in an adult who underwent unilateral salpingo-oophorectomy to remove a necrotic ovary following torsion as "Multiple (hemorrhagic) luteinized follicular cysts were present". The ovarian resection in this instance revealed numerous follicular cysts that had a compact granulosa cell component, 2-3 cell layers thick over a slightly luteinized theca interna. Other cysts had prominent granulosa cell proliferation that had an "immature" appearance with pleomorphism, slightly prominent nucleoli and brisk apoptotic and mitotic activity, sometimes several within a single high-power field. The peripheral granulosa cell layer revealed prominent luteinization. Inhibin A and CD99 staining was intense on these elements confirming their granulosa cell nature [30, 31, 32, 33]. Although these were interpreted as bilateral juvenile granulosa cell tumors at the time, in light of the documentation of hypothyroidism it is overwhelmingly likely that these represent the ovarian cysts of hypothyroidism. The pathophysiology is not clear. Van Wyk [2] described "hormonal overlap" in that TSH, GH, FSH and LH have common alpha chains and it is their β-chains that confer specificity of action. Some cross-reaction of the very high TSH could produce FSH and LH-like activity responsible for the luteinized ovarian cysts [34]. In some of the cases reported, however, FSH levels have been very high. There may, therefore, be some action of thyroid releasing hormone on pituitary cells to stimulate gonadotropin release, FSH and LH. An enlarged pituitary gland or even pituitary adenomas are described in hypothyroidism, some of these also with ovarian cysts [35, 36, 37, 38]. An animal model of hypothyroid rats suggests yet another mechanism in that there is increased sensitivity to FSH because of an increase in the number of ovarian FSH receptors [39]. Combinations of pituitary and local ovarian effects are likely, given the histopathology. More recent functional data from administration of LH and FSH to women have shown that selective LH rise in the late follicular phase favors Inhibin A secretion from more mature follicles while FSH and E [2] in the early follicular phase results in Inhibin B secretion [40]. From this data we can infer that there was indeed FSH and LH effect on the hypothyroid induced cysts. 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