Practical insights: from irregular menstrual cycle to total thyroidectomy

1. Introduction

The accidental detection of a large multinodular goiter may be done amid investigations for various menstrual cycle anomalies in terms of polycyclic ovaries syndrome or menopause recognition⁽¹⁾. Moreover, the presence of an autoimmune thyroid condition (including with an enlargement of the thyroid gland which is more frequently found in Graves’s diseases rather than in Hashimoto’s chronic thyroiditis) may be associated with another ovarian or pituitary (syndromic or not) condition that involves secondary amenorrhea^(2-4). Of note, severe thyr­oid dysfunction itself, either hypothyroidism/myxedema or hyperthyroidism, might impair the normal function of the gonadal axes as a functional, not lesion-induced negative effect^(5,6).

Another point of dual insights, when it comes to the thyroid and menses topics, is the epidemiological bridge, namely the fact that polycystic ovary syndrome represents the most common ovarian dysfunction that is found in females of reproductive age, while a thyroid nodule represents the most frequent thyroid anomaly, with a general prevalence of 5% and an age-dependent pattern^(7-9).

2. Materials and method

Our objective was to introduce a series of two cases that started as menstrual cycle anomalies and, finally, a larger goiter was detected during specific investigations, followed by total thyroidectomy. Laboratory and imaging findings were provided. The patients agreed for their medical records to be presented. This was a retrospective collection of data. The Local Committee of the “Dr. Carol Davila” Central Military Emergency University Hospital, Bucharest, Romania, approved the presentation of the surgical outcome (number 608/28.6.2023).

3. Results: case series presentation

3.1. Case 1

We present the case of a non-smoking 51-year-old female patient admitted for menses cessation, with the most recent months accompanied by hyperhidrosis and insomnia. Also, she displayed a neck (thyroid) mass with a recent enlargement during the last two months. On admission, the clinical evaluation showed a right cervical mass accompanied by euthyroid status; she described compression symptoms represented by choking sensation and intermittent swallowing disturbances (Figure 1). She had no medical history suggestive for a multinodular goiter or other thyroid conditions, and she has never had any endocrine evaluation. Her family medical history was irrelevant.
 

Currently, leucopenia with neutropenia was found at hemogram assay that was not confirmed at a later evaluation the following day (of note, COVID-19 test was negative). The biochemical assessment revealed normal liver and renal function, together with phosphor-calcium metabolism within normal range (Table 1).
 

Autoimmune thyroid disease was revealed by elevated serum anti-thyroperoxidase antibodies (TPOAb) that was consistent with an autoimmune thyroid background, and a low normal TSH (thyroid stimulating hormone), as well as a mildly increased calcitonin level were found. A high level of FSH (follicle stimulant hormone), of 45 mgUI/mL, confirmed the menopausal status with hypoestrogenic status (Table 2).
 

Neck ultrasound was performed, showing a right thyroid lobe of 2.5/2.6/4.65 cm and a left thyroid lobe of 1.76/1.6/4.7 cm, with hypoechoic, intensely inhomogeneous pattern; on the lower half of the right lobe, there was a conglomerate of 2-3 isoechoic nodules, with resolution areas, vascularized, of 3.7/2.15/2.7 cm, containing microcalcifications with posterior acoustic shadowing and left tracheal deviation; superior to the conglomerate, another mixed nodule of 0.9/0.6/0.8 cm with a tendency to conglomerate with the previous one; on the inferior half of the left lobe, there was a nodular conglomerate of 2.1/1/1.2 cm; no local lymph node enlargement was detected (Figure 2).
 

Due to the presence of a dominant nodule with recent enlargement on a non-endemic multinodular goiter with tracheal deviation (revealed by ultrasound evaluation and clinical compressive effects), the patient was referred to surgery for total thyroidectomy which went well, with early discharge (Figure 3A+B).
 

The postoperative histological examination confirmed an adenomatous multinodular goiter, with anisofollicular adenomatosis, with predominant mesofollicular and macrofollicular pattern, a dominant nodule in the right thyroid lobe displaying hyperplastic epithelial areas with hyperfunctional aspect, cystic dilated follicles, hemorrhage and post-hemorrhage resorption areas, scalloping, siderophages, stromal sclerohyalinisation, minimal interstitial lymphocytic inflammatory infiltrate, intrafollicular macrophage collections and cholesterol crystals; a fragment of parathyroid tissue was found adjacent to the right thyroid lobe. The second opinion was provided and confirmed the presence of anisofollicular coloidocystic multinodular goiter with hyperplastic epithelial areas with hyperfunctional aspect, hemorrhage, perinodular circumscribed sclerosis and a small fragment of pericapsular parathyroid tissue, an overall benign confirmation. Four months following total thyroidectomy, the patient presented for endocrine follow-up. She did not experience post-surgical hypocalcemia (Table 3).
 

Thyroid panel revealed low TSH value while the patient was under 75 µg of levothyroxine daily.  Therefore, she was recommended to decrease the levothyroxine dose to 61.2 µg per day (Table 4).
 

Post-surgical anterior neck ultrasound revealed a right thyroid edema of 0.3/0.4 cm, left thyroid edema of 0.26/0.3 cm, with hypoechoic, inhomogeneous pattern and absent vascularization; no significant laterocervical adenopathy was found (Figure 4).
 

Noting the benign histological features of the thyroid and the absence of remaining thyroid tissue at ultrasonography evaluation, the management was represented by thyroid hormone substitution in order to maintain the TSH level in the normal range and periodical assessment of the thyroid hormones, along with postoperative thyroid area imaging. Menopausal-like symptoms remitted after thyroid removal, thus the lady was not offered any additional hormone (estrogen) replacement therapy.

3.2. Case 2

We present the case of a 22-year-old smoker female admitted for endocrine checkup while she was known with polycystic ovary syndrome and had multiple endocrine and gynecological assessments since her menarche at the age of 15 years old. During these investigations, an accidental multinodular goiter was diagnosed more than five years before. The patient went through multiple endocrine assays during this period, but she refused the surgical treatment with total thyroidectomy that was recommended.

On the current admission, she accused compression symptoms such as choking sensation, together with insomnia, palpitations and epigastralgy. The personal medical history included polycystic ovary syndrome and she followed treatment with oral contraceptives since the age of 12, with a few breaks of 1-2 months, during which she had no menstrual cycle. Her family medical history included the father with type 2 diabetes mellitus and the mother with an autoimmune thyroid disease. The clinical examination showed a large goiter, as well as hirsutism, and acanthosis nigricans of the posterior cervical region, axilla, inguinal crease and elbow crease. Blood pressure was 118/77 mmHg, and she had a mildly increased Body Mass Index of 25.78 kg/m². The biochemistry panel detected only a mild hypoglycemia, the rest of the assays being within normal range (Table 5). 
 

Blood endocrine evaluation revealed normal thyroid function, with TSH of 1.35 µIU/mL (normal range: 0.35-4.94), FT4 (free levothyroxine) of 11.9 pmol/L (normal range: 9-19) and negative thyroid antibodies such as TPOAb of 0.45 IU/mL (normal range: 0-5.61), ATG (anti-thyroglobulin antibodies) of 15.26 IU/mL (normal range: 0-115) and TRAb (anti-TSH Receptor antibodies) of 1.2 IU/L (normal range: 0-1.75). Moreover, hypovitaminosis D was detected: 25-OHD (25-hydroxyvitamin D) of 11.2 ng/mL (normal range: 20-100) – Table 6.
 

The exploration of gonadal axes in terms of FSH and estradiol was not feasible while the subject was under estroprogestatives; the prolactin remained within normal limits; the total testosterone small increase was the hallmark of the polycystic ovary syndrome (Table 7).
 

Oral glucose tolerance test (OGTT) with 75 g glucose administered was performed, and HOMA-IR (Homeostatic Model Assessment for Insulin Resistance) was calculated with a value of 8.6, thus suggestive for insulin resistance (Table 8).
 

Neck ultrasound detected a large, multinodular goiter with hypoechoic, inhomogeneous pattern. Right thyroid lobe of 2.07/2.2/4.84 cm, left thyroid lobe of 2.25/1.95/5.75 cm; right thyroid lobe with two mixed nodules with a tendency to conglomerate, of 1.07/0.8/0.8 cm and 0.9/0.61/1.5 cm, respectively, with increased nodular vascularization, the rest of the lobe presenting five mixt nodules with a maximum diameter of 0.6 cm; the inferior part of the isthmus contained a hypoechoic nodule with resolution areas, increased vascularization and microcalcification and macrocalcifications, with 1.9/1.2/1.92 cm; left thyroid lobe with two hypoechoic nodules in the medium third, of 2/0.9/0.7 cm and 0.6/0.3/1.6 cm, respectively, and another hypoechoic, vascularized nodule of 1.5/0.8/1.7 cm in the superior half of the lobe; no significant adenopathy was found (Figure 5).
 

The patient underwent total thyroidectomy. Transitory post-surgical bilateral recurrent laryngeal nerve paresis was identified, and a progressive remission was registered under oral glucocorticoids for six weeks. The postoperative pathological report showed be­nign features. Two weeks since surgery, the biochemical assay revealed increased levels of total cholesterol and triglycerides and a mildly elevated glycated hemoglobin A1c. She had already started thyroid substitution treatment with 100 µg levothyroxine daily, however TSH was still low at the moment of evaluation. 25-OHD levels remained decreased, noting that she had started vitamin D supplementation two weeks prior (cholecalciferol 2000 UI/day). After two months, neck ultrasound revealed thyroid areas without tissue remnants and small postoperative edema (Figure 6).
 

Levothyroxine replacement with dose adjustment was done in addition to continuing oral contraceptives and vitamin D supplements, along with periodic checkup.

4. Discussion

4.1. Menopause and multinodular goiter

The first case introduced the issue of differentiating compressive thyroid sensation from menopausal-like symptoms which both include a complicated clinical panel. A higher incidence of thyroid nodules is reported in menopause than in women of reproductive age, but the menopausal status itself is not regarded as a specific risk factor for (differentiated) thyroid cancer^(10,11). Despite longstanding goiter, the patient did not complain priorly about neck symptoms, neither she had a specific medical history consistent with this diagnosis. The delayed presentation may be associated with COVID-19 pandemic, as seen in other medical and surgical areas^(12,13). Older approaches suggested TSH suppressive therapy for nodular goiter or isolated thyroid nodules, but nowadays this is less likely to be recommended due to cardiovascular and bone concerns⁽¹⁴⁾.

4.2. Polycystic ovary syndrome and multinodular goiter

On the other hand, the second patient was diagnosed with multinodular endemic goiter at a very young age while she was under surveillance for her polycystic ovaries syndrome. Some studies suggested a correlation between these two conditions, despite the fact that TSH does not serve as a predictor of cardiometabolic complications in this syndrome^(15,16). This lady presented some metabolic traits as seen by increased HOMA-R, and further cardiometabolic surveillance is mandatory. Moreover, the postoperative exposure to glucocorticoids should take into consideration the already described insulin resistance^(17,18). As seen in other types of neck surgery for large masses, a transitory involvement of laryngeal recurrent nerve was described, which is correlated to the preoperative features of the thyroid gland, not to the ovarian dysfunction. Notably, postoperative vitamin D supplements might help the polycystic ovary syndrome, as well^(19,20).

5. Conclusions

Both menopausal status and polycystic ovary syndrome have been reported to be associated with multinodular goiter. The presence of the menstrual cycle anomalies might bring attention to the thyroid status or may require a differentiation of the symptoms, as seen here.  

Abbreviations: TPOAb = anti-thyroperoxidase antibodies; TSH = thyroid-stimulating hormone; FSH = follicle-stimulating hormone; FT4 = free levothyroxine; ATG = anti-thyroglobulin antibodies; TRAb = anti-TSH receptor antibodies; 25OHD = 25-hydroxyvitamin D; OGTT = oral glucose tolerance test.

Corresponding author: Florica Şandru, e-mail: florysandru@yahoo.com

CONFLICT OF INTEREST: none declared.

FINANCIAL SUPPORT: none declared.

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