Abstract
Long-standing, overt hypothyroidism-induced bilateral multiloculated ovarian cysts represent an infrequent occurrence. Our first case, presented with bilateral complex ovarian masses, exhibited overt hypothyroidism symptoms, including lethargy, weight gain and subfertility, prompting consideration for surgical intervention. Similarly, in the second case, a girl aged 11 years with stunting, delayed bone age and academic challenges was referred for surgical exploration due to bilateral complex ovarian masses. Both cases revealed elevated thyroid-stimulating hormone levels during preoperative workup. Commencing levothyroxine replacement therapy resulted in complete regression of ovarian cysts and substantial symptom improvement within an 8-week timeframe. The third case, a previously diagnosed patient with Hashimoto’s thyroiditis, benefited from the lessons gleaned in managing the initial cases, responding well to levothyroxine therapy, thereby averting the necessity for surgery in all three instances. These cases underscore the significance of considering thyroid function in the evaluation of ovarian masses and highlight the efficacy of levothyroxine replacement therapy in resolving both hypothyroidism and associated ovarian cysts, thereby obviating the need for surgical intervention.
Keywords: thyroid disease, medical management, drug therapy related to surgery, endocrine system, obstetrics and gynaecology
Background
Thyroid disorders can have varied presentations as thyroid-stimulating hormone (TSH) plays a crucial role in regulating the body’s metabolism and maintaining hormonal balance. Disruption of thyroid function can indeed have significant impact on reproductive health causing menstrual irregularity, infertility and premature ovarian insufficiency. Increased TSH contributes to its spill-over effect on follicle-stimulating hormone (FSH) receptors. Increased collagen deposition in ovaries as a result of hypothyroidism has also been suggested. Thyroid disorders can cause ovarian cysts that can be successfully managed medically with thyroid hormone replacement therapy with levothyroxine avoiding the need for surgical intervention.
The persistent presence of complex ovarian cysts raises consideration for surgical management due to the inherent risk of malignancy. However, there is a subset of complex ovarian cysts that are formed secondary to long-standing overt hypothyroidism. The prevalence of Hashimoto’s thyroiditis is 0.5–1.3 per 1000 cases all over the world with an incidence of 3.5 per 1000 cases in women but its correlation with the ovarian cyst is not yet studied in the literature.1 It emphasises the importance of considering the underlying thyroid condition in the evaluation of ovarian masses to prevent unnecessary surgical interventions. The association between hypothyroidism and ovarian cysts can be attributed to myxoedema of ovaries and the similarity between the receptors of FSH and TSH. These findings provide important insight regarding the significance of a thorough preoperative evaluation for hypothyroidism in patients presenting with bilateral multiloculated ovarian cysts. Highlighting the characteristics of ovarian cysts in hypothyroidism, such as thin walls, multilocularity and the absence of papillary excrescences or increased vascularity, with a normal range of tumour markers aids in differentiating them from other types of ovarian masses that may necessitate surgical management. In this report, we present three cases of overt hypothyroidism characterised by bilateral complex ovarian cysts spanning diverse age groups. All three patients harboured underlying Hashimoto’s thyroiditis, and the ovarian cysts exhibited complete regression following thyroxine replacement therapy. Given these findings, a meticulous preoperative assessment for hypothyroidism is advocated in cases presenting with bilateral multiloculated ovarian cysts to prevent surgical intervention and in turn preserve ovarian tissue and ovarian reserve.
Case presentation
Case 1
A nulliparous female in her 20s, married for 2 years, consulted us to obtain a second opinion for surgery after her private practitioner recommended bilateral complex ovarian cystectomy. She noticed a painless abdominal mass 3 months back which was gradually increasing in size along with complaints of swelling all over her body, lethargy, sleepiness most of the time, cold intolerance and excessive weight gain in the last 6 months. In her menstrual history, cycles were prolonged for 40 days however menstrual flow was normal. Her weight was 65 kg with a body mass index (BMI) of 23.1 kg/m2. She had a pulse of 60 beats/min, blood pressure of 110/70 mm Hg and a 16-week-sized cystic, well-defined mass was present on abdominal palpation. On bimanual examination, two separate cystic masses were felt in bilateral adnexa approximately 10 cm in size on each side.
Investigations
Trans-abdominal ultrasound revealed bilateral complex ovarian masses with the size of 11.03 cm×10.16 cm×7.34 cm on the left side (volume 430.65 mL) and 9.7 cm×8.54 cm×7.99 cm on the right side (volume 346.42 mL). Both the masses had multiple thin-walled cysts inside without any papillary excrescences or increased vascularity (figure 1). She had serum TSH of 100 mIU/L (0.27–4.20 mIU/L), serum triiodothyronine (T3) of 0.195 ng/mL (0.8–2.0 ng/mL) and serum thyroxine (T4) of 0.420 μg/dL (5.1–14.1 μg/dL). Her antithyroid peroxidase antibodies were raised to 85.27 IU/mL (normal <35 IU/mL) with a normal level of tumour makers. So a clinical diagnosis of myxoedema secondary to Hashimoto’s thyroiditis was made.
Figure 1.
Bilateral huge ovarian enlargement with multiple septa inside mimicking ovarian hyperstimulation syndrome-like picture.
Treatment
The patient was started on Thyroxine replacement therapy with Levothyroxine 100 μg daily.
Outcome and follow-up
Subsequent to 4 weeks of treatment, a notable amelioration of symptoms was observed concomitant with a reduction in serum TSH levels to 1.5 mIU/L. Furthermore, there was a diminution in ovarian dimensions, measuring 7 cm×6.2 cm×5.0 cm on the left side and 6.2 cm×5.3 cm×4.0 cm on the right side (figure 2). At the 8-week follow-up, serum TSH was recorded at 0.325 mIU/L, serum T3 at 1.92 ng/mL (reference range: 0.8–2.0 ng/mL), and serum T4 at 11.10 μg/dL (reference range: 5.1–14.1 μg/dL). Concurrently, the patient exhibited a weight loss of 5 kg and a complete resolution of myxoedema. The ovarian masses demonstrated a reduction in size to 5.0 cm×4.5 cm×3.8 cm on the left side and 4.8 cm×4.6 cm×3.5 cm on the right side, accompanied by the presence of diminutive cysts (figure 3). The patient was advised to maintain the existing thyroxine dosage, thus averting the need for surgical intervention through the pursuit of conservative therapeutic modalities. Table 1 shows the changes that took place for 8 weeks. At 12 weeks, normal size and morphology of ovaries were seen on ultrasonography.
Figure 2.
Significant regression in size of the cysts inside ovaries after 4 weeks of treatment.
Figure 3.
Further reduction in size of cysts at 8 weeks of treatment.
Table 1.
Findings that illustrate the progression and improvements observed over 8 weeks during thyroxine replacement therapy with levothyroxine 50 μg
| Parameters | At first visit | After 4 weeks | After 8 weeks |
| Weight | 65 kg | 63.2 kg | 60 kg |
| TSH | 100 mIU/L | 1.5 mIU/L | 0.325 mIU/mL |
| T3 | 0.195 ng/mL (0.8–2.0 ng/mL) | 1.92 ng/mL | |
| T4 | 0.420 μg/dL (5.1–14.1 μg/dL) | 11.10 μg/dL | |
| Anit-TPO Ab | 85 IU/mL | ||
| CA-125 | 26 | ||
| USG findings |
|
|
|
Ab, antibody; T3, triiodothyronine; T4, thyroxine; TPO, thyroid peroxidase; TSH, thyroid-stimulating hormone; USG, ultrasonography.
Differential diagnosis
The differential diagnoses of complex ovarian masses were haemorrhagic cysts, mucinous cystadenoma and endometrioma. Ovarian hyperstimulation syndrome (OHSS) was ruled out as there was no treatment history for ovulation induction. Malignant ovarian masses were excluded as tumour markers were normal. Keeping these differential diagnoses in mind, our first patient was referred for excision of masses but in pre-operative workup, TSH was raised exponentially. During the treatment, bilateral complex ovarian cyst resolved completely.
Case presentation
Case 2
A middle childhood girl was referred for surgical exploration due to a substantial bilateral ovarian mass and ascites. She presented with complaints of lethargy, and swelling all over the body and her academic performance was suboptimal. Thelarche occurred at 9 years, followed by menarche at 11 years. Breast development was consistent with Tanner’s stage III, pubic hair at Tanner’s stage I and absent axillary hair. Her height was 129 cm which was at the third percentile, and she exhibited anasarca. Dry thick skin and lustreless hair were evident. Abdominal examination revealed significant distension due to a massive mass extending to the xiphisternum, accompanied by ascites. A provisional diagnosis of Van Wyk-Grumbach syndrome was established.
Investigation
Investigations revealed a TSH concentration of 80.4 mIU/L (reference range: 0.35–5.5 mIU/L), and an antithyroid peroxidase antibody level of 386.5 IU/mL (reference range: <34 IU/mL). Pelvic ultrasonography disclosed a large multiloculated ovarian cyst, measuring 15 cm×10.5 cm×9.7 cm on the right side and 12.2 cm×11.3 cm×8 cm on the left side, alongside mild ascites. Cardiomegaly with mild pericardial and bilateral mid-pleural effusions were also noted. A 2-year delay in bone age was identified on X-ray.
Treatment
The patient was started with evothyroxine 50 μg/day.
Outcome and follow-up
After a 4-week follow-up, significant symptomatic improvement occurred. Complete resolution of ascites, pleural effusion and pericardial effusion was observed. The ovarian mass regressed to 6.9 cm×4.9 cm×4 cm on the right side and 6 cm×4.4 cm×3.8 cm on the left side. The patient was continued with levothyroxine 50 μg. At the 8-week follow-up, with the same dose of thyroxine, cyst size was further reduced to 4.2 cm×3. 2 cm×1.8 cm on the right side and 4.1 cm×3.1 cm×2 cm on the left side. Table 2 summarises the patient’s baseline characteristics, clinical features, laboratory results, imaging findings and treatment outcomes at different time points. At 14 weeks of ultrasonography, normal ovaries were seen with follicles in them.
Table 2.
Summary of the patient’s baseline characteristics, clinical features, laboratory results, imaging findings and treatment outcomes at different time points
| Parameter | Baseline | 4-Week follow-up | 8-Week follow-up |
| TSH concentration | 80.4 mIU/L (high) | 10.32 mIU/mL | 4.4 mIU/mL |
| Anti-TPO Ab level | 386.5 IU/mL (high) | ||
| Imaging findings | |||
| Ovarian cyst (right) | 15 cm×10.5 cm×9.7 cm | 6.9 cm×4.9 cm×4 cm | 4.2 cm×3.2 cm×1.8 cm |
| Ovarian cyst (left) | 12.2 cm×11.3 cm×8 cm | 6 cm×4.4 cm×3.8 cm | 4.1 cm×3.1 cm×2 cm |
| Ascites | Present | Resolved | Resolved |
| Pleural effusion | Present | Resolved | Resolved |
| Pericardial effusion | Present | Resolved | Resolved |
| Cardiomegaly | Present | ||
| Bone age (X-ray) | 2-year delay | ||
| Treatment | |||
| Levothyroxine dose | Not specified | 50 μg/day |
Ab, antibody; TPO, thyroid peroxidase; TSH, thyroid-stimulating hormone.
Differential diagnosis
The differential diagnosis for this middle-aged girl was bilateral complex ovarian malignancy as there were ascites and pleural effusion.
Case presentation
Case 3
A woman in her 40s had a surgical menopause as she underwent a hysterectomy due to heavy menstrual bleeding. She was referred for bilateral complex ovarian masses, possibly indicative of ovarian malignancy. She reported the symptoms of abdominal heaviness, lethargy and easy fatigability. The patient had a documented history of Hashimoto’s thyroiditis and had been receiving treatment with 75 μg of levothyroxine. Her weight was 62 kg and a BMI of 22.8 kg/m².
Investigation
Investigations were conducted, revealing ultrasonographic findings of bilateral enlarged ovaries measuring 5.6 cm×5.1 cm×4.2 cm on the right side and 5.2 cm×4.6 cm×4 cm on the left side, accompanied by multiple cysts and minimal ascites. Despite concerns of ovarian malignancy, all tumour markers, including CA-125 (14 U/mL), CA 19.9 (<1.4 U/mL) and CEA (0.1 ng/mL), yielded negative results. Given her history of Hashimoto’s thyroiditis, a repeat thyroid profile demonstrated elevated levels, with a serum TSH of 131.2 mIU/L, serum T3 of 0.3 ng/mL and serum T4 of 3.2 μg/dL.
Treatment
In response to the hypothyroidism diagnosis, the levothyroxine dosage was increased to 100 μg, and a follow-up ultrasound after 4 weeks revealed a normalisation in ovarian size and a reduction in cyst dimensions. Consequently, the correction of her hypothyroid state obviated the need for major surgery, leading to the resolution of the ovarian mass (figure 4). Table 3 shows investigations at first visit and after 6 weeks of levothyroxine 100 μg.
Figure 4.
Upper two images showing 6 cm×5.1 cm×4.2 cm on the right side and 5.2 cm×4.6 cm×4 cm on the left side with multiple cysts and normal ovaries in the below two images.
Table 3.
Investigation at first visit and resolution seen after 6 weeks after levothyroxine 100 μg
| Clinical findings | At first visit | After 6 weeks |
| Ultrasonographic findings | ||
| Bilateral ovaries | ||
| Right side | 5.6 cm×5.1 cm×4.2 cm | 3 cm×2.2 cm×1.4 cm |
| Left side | 5.2 cm×4.6 cm×4 cm | 3.2 cm×2.1 cm×2.3 cm |
| Ascites | Minimal | Nil |
| Tumour marker results | ||
| CA-125 | 14 U/mL (negative) | |
| CA 19.9 | <1.4 U/mL (negative) | |
| CEA | 0.1 ng/mL (negative) | |
| Thyroid profile | ||
| Serum TSH | 131.2 mIU/L (elevated) | 15.3 mIU/L |
| Serum T3 | 0.3 ng/mL | 96 ng/mL |
| Serum T4 | 3.2 μg/dL | 4.9 μg/dL |
T3, triiodothyronine; T4, thyroxine; TSH, thyroid-stimulating hormone.
Outcome and follow-up
Medical management with levothyroxine resolved the ovarian cysts completely at 6 weeks after treatment. Patient was asked to continue levothyroxine 100 μg and follow-up with endocrinologist for further adjustment of dose of levothyroxine.
Differential diagnosis
A second case involved a middle-aged girl with sizeable ovarian masses appointed for excision. However, the pre-operative evaluation revealed overt hypothyroidism and successful resolution of the ovarian masses occurred following treatment with levothyroxine over 12 weeks. A comprehensive literature review unveiled similar cases in the existing literature. This collective experience guided our approach in the third case, where overt hypothyroidism was considered in the differential diagnosis for bilateral ovarian masses. Before surgical exploration, the patient’s levothyroxine dosage was increased, leading to a substantial reduction in ovarian size, ultimately normalising it and averting the need for surgery.
Discussion
There are multiple aetiologies for the formation of ovarian cysts in Hashimoto’s disease and long-standing hypothyroidism, but the most convincing one is the cross-reactivity of TSH, FSH and luteinising hormone (LH) due to the sharing of a common alpha chain.2 It is also postulated that there are TSH receptors on ovarian follicles, which on binding with TSH sensitises the action of FSH. The third possibility is myxoedematous infiltration of ovarian tissue without luteinisation of theca interna, leading to multiple cysts formation. This hypothesis is supported by the histological examination of ovaries in similar cases where surgery was performed inadvertently. Histology showed only follicular cysts with non-luteinised granulosa cells and edematous stroma.3 All these mechanisms can lead to multiple large cysts inside the ovary mimicking OHSS in the picture. Spontaneous OHSS in long-standing hypothyroidism has been described in the literature.2 4–7 Menstrual irregularities with hypothyroidism are well known but the occurrence is not documented in the literature, therefore the association of hypothyroidism with ovarian cysts is not established.
Bilateral theca lutein cysts can also mimic similar ultrasound appearance, but there was no history of recent pregnancy or vesicular mole in any of the three cases. The second possibility is ovarian hyperstimulation due to gonadotropins, but our patients never received any hormonal treatment.
A prospective study by Muderris et al, where 26 patients had untreated hypothyroidism, found that ovarian volume increased with cyst formation in such patients as compared with controls.8 Once the euthyroid state is achieved, the ovarian volume as well as cystic changes both regress. In most of the cases reported earlier, there was severe hypothyroidism in patients with serum TSH being >100 mIU/L and these regressed over 3–6 months.7 9–11 The prevalence of hypothyroidism and ovarian cysts is not established in the literature and further research is required in the field.
Van Wyk-Grumbach syndrome was first described in the literature in 1960 as a triad of isosexual precocious puberty, large ovarian cysts and delayed bone age in juvenile hypothyroidism.12 FSH response to TRH is augmented in hypothyroidism along with increased sensitivity of the mammotroph, resulting in increased prolactin secretion. This selective FSH responsiveness explains the low levels of LH in such conditions. High TSH in untreated primary hypothyroidism acts on FSH receptors causing increased growth of follicles and increased oestrogen production resulting in the ovarian cyst and peripheral precocious puberty due to structural analogy to FSH. These girls usually develop early secondary sexual characteristics like thelarche, irregular vaginal bleeding and large ovarian cysts.13 In our second case, discordant sexual development characterised by advanced thelarche, and vaginal bleeding without pubarche pointed towards an increased oestrogenic state. This along with delayed skeletal maturation, that is, bone age led us to diagnose Van Wyk-Grumbach syndrome. These patients with ovarian mass can present with acute abdomen and the decision to avoid surgery is a crucial step in management to preserve the ovarian tissue.
Conclusion
In conclusion, our report serves as a valuable contribution to the medical literature, shedding light on the association between hypothyroidism and ovarian cysts and advocating for a cautious approach to the management of such cases. This information can guide healthcare practitioners in making informed decisions and avoiding unnecessary surgeries, thereby reducing potential morbidities and preserving ovarian reserve in affected patients.
Patient’s perspective.
Case 1
I was told to have a high chance of ovarian malignancy as I had a huge ovarian lump and was referred to AIIMS Nagpur for surgery. There, I was found to have severe hypothyroidism, for which I was never investigated and the doctor told me that a trial of thyroid medicines can be given to see the response before deciding on surgery. To my surprise, my weight reduced over 2 months and the abdominal lump regressed to almost half in a month. I started feeling well and my work capacity also improved.
Case 2
My younger daughter had very unusual symptoms, unlike her siblings. She was the shortest in her class and was not performing well in academics. We were shocked to discover that she was carrying a huge lump in her abdomen which might be cancerous. We went to AIIMS Nagpur where we were told that cancer is unlikely as all her symptoms are due to hypothyroidism. My daughter was started on thyroid tablets and all her symptoms resolved over 2 months. We are thankful to the doctors that a big surgery was avoided.
Case 3
I had undergone a hysterectomy 2 years back as I used to have heavy menstrual bleeding, which was not responding to tablets. I have been taking thyroid tablets for 5 years. Recently, I was told that I will need one more surgery as I have developed ovarian cysts which can be cancerous. I made the mistake of not getting a thyroid test done for at least 2 years and when it was done on preoperative evaluation, I discovered that it was abnormal. Doctors told me that we could avoid surgery and thankfully my cysts resolved after treatment.
Learning points.
When ultrasound reveals a complex ovarian mass, investigating long-standing hypothyroidism is crucial, antithyroid peroxidase antibody testing is necessary, especially in cases of overt hypothyroidism.
Positive response to levothyroxine appears in 6–8 weeks, highlighting the need for patient compliance for prolonged treatment.
Opting for surgery in these patients should be avoided to prevent the loss of ovarian tissue, thereby preserving fertility in the long run.
Footnotes
Contributors: AG, SD, MDh and MDa were responsible for drafting of the text, sourcing and editing of clinical images, investigation results, drawing original diagrams and algorithms and critical revision for important intellectual content. AG, SD, MDh and MDa gave final approval of the manuscript.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
Competing interests: None declared.
Provenance and peer review: Not commissioned; externally peer reviewed.
Ethics statements
Patient consent for publication
Not applicable.
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