Abstract
Ovarian cysts can be caused by endocrine disorders. Hypothyroidism causing ovarian cysts is an uncommon entity, but rarely does it cause an ovarian cyst which can mimic malignancy. We report three cases of ovarian masses which were referred to our institute suspecting malignancy. These patients on further evaluation were found to have severe hypothyroidism and started on thyroxine supplementation. There was dramatic symptomatic relief as well as resolution of the ovarian masses on subsequent imaging. Hypothyroidism should be considered in the differential diagnosis of bilateral multicystic adnexal masses to avoid inadvertent surgery.
Keywords: Hypothyroidism, Ovarian cyst, Malignancy
Introduction
Ovarian cysts are a common finding in women of the reproductive age group. It is a common cause of gynecological surgery in all age groups. Ovarian cysts can be caused by many reasons. Ovarian cysts arising due to endocrine disorders are mostly benign and usually do not require any surgical intervention unless they present with acute features like torsion, hemorrhage, or rupture.
Primary hypothyroidism is a common endocrine abnormality resulting from thyroid hormone deficiency which can lead to multiple-system impairment. Long-standing hypothyroidism presenting as an ovarian mass has been described as the Van Wyk-Grumbach syndrome in young girls. The main features described are hypothyroidism, isosexual precocious puberty, delayed bone age, and ovarian mass. Reversal to a prepubertal state occurs following thyroid hormone replacement therapy [1].
Although ovarian cysts associated with hypothyroidism is less commonly seen in adults, several cases have been reported where long-standing hypothyroidism can lead to ovarian cysts. Usually, these cysts are self-limiting, benign-appearing, and rarely become symptomatic [2]. Failure to recognize hypothyroidism as an etiology of ovarian cysts could inadvertently lead to unnecessary surgical intervention.
Here we report a series of 3 patients with hypothyroidism who presented with large ovarian mass cases which resolved spontaneously on treatment with thyroid hormone supplementation.
Case 1
A 19-year-old unmarried lady was referred with complaints of mass per abdomen. She had infrequent periods (2–3 months) but normal menstruation that lasted 4–5 days. Her complaints started as a palpable abdominal mass with vague abdominal discomfort lasting for 1 month. Ultrasound revealed bilateral ovarian masses of 12 × 9 cm on the right and 10 × 8 cm on the left. The masses were multiloculated with thick septa and mild ascites. CT evaluation confirmed the USG findings with no enlarged node, no omental thickening, and no evidence of metastasis.
Blood investigations revealed a raised CA-125–292; germ cell markers were normal. Her thyroid function tests revealed markedly elevated TSH and low T3 and T4 (Fig. 1a, b; Table 1).
Fig. 1.
a Case 1—USG image of the right ovary showing multiloculated cystic lesion with thick septa and suspicious solid area. b Case 1—CT image showing bilateral multiloculated ovarian masses
Table 1.
Case 1—blood investigations
CA-125 | 292 (0–35 U/mL) |
CEA | 1.2 (0–3.7 ng/mL) |
Germ cell markers | Normal |
TSH | 130 (0.27–4.2 mIU/mL) |
S T3 | 0.4 (80–200 ng/mL) |
S T4 | 0.34 (5.1–14.1 μg/100 mL) |
She was started on thyroxine supplementation of 100 μg. Repeat USG after 2 weeks showed almost complete resolution of the multiloculated cystic masses to reveal bilateral bulky ovaries of 3 × 4 cm on the left and 4.8 × 3 cm on the right. Her TSH had come down to 2.8. She was kept on further follow-up. Repeat ultrasound taken after 6 months was also normal.
Case 2
A 37-year-old lady was evaluated following complaints of dull aching abdominal pain. She had undergone subtotal hysterectomy at the age of 27 years (2009) for postpartum hemorrhage. She was diagnosed with carcinoma breast at 32 years (2014) and underwent a modified radical mastectomy and was on tamoxifen tablet H/O subtotal hysterectomy in 2009 for PPH.
Her blood investigations showed CA-125–15.3, CEA-1.5, and normal germ cell tumor markers. Her TSH level was 146 mg/mL, FT3-0.2, and FT4-0.6 (Table 2).
Table 2.
Case 2—blood investigations
CA-125 | 15.3 (0–35 U/mL) |
CEA | 1.5 (0–3.7 ng/mL) |
Germ cell markers | Normal |
TSH | 146 (0.27–4.2 mIU/mL) |
S T3 | 0.2 (80–200 ng/mL) |
S T4 | 0.6 (5.1–14.1 μg/100 mL) |
On imaging, USG showed a unilateral ovarian cyst of 7 × 4 cm on the left with thick septa and solid areas and mild ascites.
On CT evaluation, there was a left-sided multiloculated ovarian cyst of 8 × 4 cm with mild ascites, with no enlarged nodes or evidence of mental or intra-abdominal metastasis (Fig. 2a, b).
Fig. 2.
a Case 2—USG image showing multiloculated ovarian cyst of 7 × 4 cm with suspicious solid area. b Case 2—CT image showing multiloculated ovarian cyst with thick septa
She was started on thyroxine 100 μg. She was found to have symptomatic relief and was discharged but kept on follow-up.
Follow-up ultrasound after 2 months showed complete resolution of adnexal masses and normalization of TSH.
Case 3
A 51-year parous postmenopausal lady was evaluated for right lower abdominal pain radiating to the groin for 5 days. She was evaluated outside and referred to our institute suspecting malignancy as ultrasound revealed an ovarian mass.
On further evaluation, she also revealed a history of constipation and cold intolerance. She attained menopause at the age of 48 years. Her blood investigations showed CA-125–393 (Table 3). Her TSH was 110.
Table 3.
Case 3—blood investigations
CA-125 | 393 (0–35 U/mL) |
CEA | 3.5 (0–3.7 ng/mL) |
TSH | 110 (0.27–4.2 mIU/mL) |
S T3 | 0.2 (80–200 ng/mL) |
S T4 | 0.5 (5.1–14.1 μg/100 mL) |
Imaging with ultrasound showed a right adnexal lesion multiloculated lesion of size 14 × 10 cm with solid areas and mild ascites. Her left ovary showed a cystic mass of 4 × 4 cm.
CT evaluation showed a right adnexal poorly defined multiloculated cystic mass—8 × 6 cm. It is seen extending to the umbilical region, encasing jejunal loops. Left ovarian cyst of size—5 × 5 cm with minimal solid areas in POD (Fig. 3a, b).
Fig. 3.
a Case 3—USG showing multiloculated ovarian mass lesion of 10 × 14 cm size. b Case3—CT showing multiloculated ovarian mass lesion of 8 × 6 cm on the right and 5 × 5 cm on the left
She was started on thyroxine supplementation of 200 μg started with nuclear medicine consultation. Her abdominal pain gradually subsided. Ultrasound was taken after 1 week. It showed a lesion in the POD of size 4.3 × 2.2 × 3.1 cm with vascularity suggestive of a bulky ovary, no definite evidence of free fluid in the abdomen or pelvis, and no evidence of any cystic lesion in the pelvis.
She was discharged. Follow-up ultrasound taken after 3 months showed normal uterus and ovaries. Her TSH had come down to 2.3. Her CA-125 values had also normalized. (21.2 IU/mL).
Discussion
Ovarian cyst is a common gynecological concern. The etiology of ovarian cysts can vary greatly including benign or malignant tumors, endometriosis, and inflammation. Some cysts are the direct result of endocrine disorders and mostly do not require surgery unless complicated by hemorrhage, torsion, or rupture. Hypothyroidism is a common endocrinological disorder which can cause reproductive dysfunction like menorrhagia, amenorrhoea, ovulatory dysfunction, and rarely ovarian cyst [3].
Van Wyk and Grumbach syndrome is a well-known endocrine disorder in which concomitant ovarian cyst formation is reported along with juvenile hypothyroidism, reduced bone age, and isosexual precocious puberty. The ovarian enlargement could present as a large ovarian cyst or multicystic ovaries in young girls. Reversal to a prepubertal state occurs following thyroid hormone replacement therapy in these young girls [1].
Although ovarian cysts associated with hypothyroidism is less commonly seen in adults, several cases have been reported where long-standing hypothyroidism can lead to ovarian cysts. Hypothyroidism can lead to ovarian cysts in the early reproductive years, late reproductive years, perimenopausal age group, and rarely in the postmenopausal age group [4].
Usually, these cysts are self-limiting, benign-appearing, and rarely become symptomatic. Failure to recognize hypothyroidism as an etiology of ovarian cysts could inadvertently lead to unnecessary surgical intervention.
There are several hypotheses about the ovarian cyst formation in severe hypothyroidism. [5–7].
Hormonal overlap in the pituitary feedback mechanism, as TSH, GH, FSH, and LH are all glycoprotein with common alpha chain and may thus cross-react. High-serum TSH mimics FSH and LH, leading to a luteinized ovarian cyst.
When there is a change in the pituitary gonadotropin level, there may be an overlap effect in the negative feedback response. As a result, not only TSH but also gonadotropins are stimulated by extremely high TRH, and hence, the remarkable high FSH can stimulate ovarian cyst formation.
FSH receptor activating mutation permitting or amplifying the effect of TSH on the follicles.
TSH sensitizes ovaries to gonadotropin stimulation by stimulating the nuclear thyroid receptors in the granulosa cells leading to ovarian hyperstimulation.
Myxomatous type of infiltration can interfere with steroidogenesis in the ovary and lead to ovarian cyst formation.
Van Wyk and Grumbach first described the relation between ovarian cyst and hypothyroidism in 1960. They proposed a hormonal overlap in the pituitary feedback mechanism which occurs since TSH, GH, FSH, and LH are all glycoproteins with a common alpha chain and may cross-react. High TSH could produce FSH- and LH-like activities leading to luteinization of ovarian cyst. The TRH may also act on pituitary cells to stimulate gonadotropin release and hence FSH and LH [1].
Jing Shu et al. published a case report with ignored adult primary hypothyroidism presenting with persistent ovarian cysts. They discussed the possible pathophysiology of the development of ovarian cysts in patients with primary hypothyroidism. TSH, FSH, and their receptors have related structures. High concentrations of TSH in hypothyroidism can cause the activation of FSH receptors resulting in ovarian hyperstimulation. They concluded that hypothyroidism and other endocrine disorders must be considered in the differential diagnosis of adult patients with ovarian multiple cysts to prevent inadvertent ovarian surgery [8].
Our first case is a young hypothyroid girl with bilateral ovarian masses which is a common scenario encountered. Her ovarian masses and symptoms resolved with treatment with thyroxine.
Our second case is a carcinoma breast-treated patient, on tamoxifen, who presents with an ovarian mass. The dilemma, in this case, was that she is a young carcinoma breast case on tamoxifen. Both carcinoma breast and tamoxifen are known risk factors for the development of borderline/malignant ovarian masses. Even though her serum marker CA-125 level was normal, she is at high risk for malignant ovarian tumors.
But on evaluation, she was found to be hypothyroid and there was a marked resolution of her ovarian cyst with thyroxine supplementation. Hence, she was kept on close follow-up.
Our third patient was a postmenopausal lady who had a high level of CA-125. That makes her at a higher risk for malignant ovarian tumors with higher RMI score. But such high levels of CA-125 have been documented in hypothyroid patients also without any malignancy [9]. Failure to diagnose hypothyroidism in patients with ovarian cysts and elevated CA-125 levels may lead to misdiagnosis of ovarian carcinoma and inadvertent surgery. Thyroid hormone replacement results in normalization of CA-125 as well as the disappearance of ovarian cyst.
Conclusion
Hypothyroidism causing ovarian cysts should always be considered in the differential diagnosis of young females presenting with multiloculated ovarian tumors. Whenever large ovarian cysts are detected in a young female, the possibility of hypothyroidism should be considered and management by thyroid hormone supplementation can result in the regression of cyst and thereby avoidance of unnecessary surgical intervention. So, it is advisable to screen all young females with ovarian cyst for underlying primary hypothyroidism. Surgical exploration in these cases should be performed only when these cysts present with ovarian torsion, hemorrhage, or rupture.
Although uncommon, postmenopausal women with hypothyroidism can also present with ovarian cysts. Hypothyroidism can also cause elevation of tumor markers like CA-125, hence raising suspicion of malignant ovarian cysts. Careful evaluation would be required in such cases to rule out malignancy. In such cases, hypothyroidism should be treated and patients should be kept on close surveillance rather than upfront surgery.
Footnotes
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References
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