Severe primary hypothyroidism-related hyperprolactinemia and secondary amenorrhea

1. Introduction

The most frequent cause of hypothyroidism in iodine-sufficient regions is chronic autoimmune thyroiditis, commonly referred to as Hashimoto’s disease, which causes inadequate synthesis and release of thyroid hormones⁽¹⁾. The disease is more common in women, and the prevalence of Hashimoto’s disease varies by area and socioeconomic status; in women, it ranges from 4.8% to 25.8%, and in men, from 0.9% to 7.9%⁽²⁾. Autoimmune thyroiditis is characterized by a particular lymphocytic infiltration of the parenchyma belonging to the thyroid gland and the presence of particular antibodies, mainly antithyroglobulin (ATG) antibodies and antithyroperoxidase (ATPO) antibodies⁽³⁾.

Globally, hypothyroidism has a wide spectrum of clinical manifestations and frequently appears as menses anomalies and reproductive potential impairment in addition to a wide area of clinical elements such as tiredness (81%), dry skin (63%), puffy eyes, depressive symptoms, reduced quality of life, altered cognitive function and memory, weight gain, constipation, increased sensitivity to cold (cold intolerance), reduced hearing, and even voice changes^(4-6).

These clinical features are tidily related to the thyroid hormones-associated roles, since they are important regulators of the metabolic, vascular and cardiac physiology. Therefore, deficiency of thyroid hormones affects the body in many ways, particularly in the cardiovascular system, where they can have a major impact on heart function, with an increased risk for atherosclerosis⁽⁷⁾. Hence, hypothyroidism is associated with different abnormalities in electrocardiography such as delayed intraventricular conduction, flattened P waves, flat or inverted T waves and, traditionally, sinus bradycardia⁽⁸⁾. Also, hypothyroidism is characterized by a decrease in the expression of liver LDL (low-density lipoproteins) receptors and a reduction in the activity of cholesterol-a-monooxygenase, which breaks down cholesterol, resulting in an overall decreased LDL clearance⁽⁹⁾. Therefore, dyslipidemia, particularly hypercholesterolemia, is frequently associated with hypothyroidism and with potential negative effects at the cardiovascular and metabolic level⁽¹⁰⁾. Anemia can be associated with thyroid dysfunction, particularly hypothyroidism, and it impairs the pregnancy outcome in selected (severe) female cases⁽¹¹⁾. Many studies found a correlation between hypothyroidism and vitamin D levels, but, overall, females with vitamin D deficiency are quite frequently found among the population confirmed with low levels of thyroid hormones, particularly primary type of hypothyroidism/myxedema⁽¹²⁾.

The diagnosis of hypothyroidism requires levothyroxine replacement therapy as the standard care; additionally, the decision of lipid lowering drugs for hypercholesterolemia or estroprogestive in cases with myxedema-related amenorrhea is based on individual management, since restoring normal thyroid hormones levels is expected to improve many related aspects^(13,14).

We aim to present an adult female confirmed with severe hypothyroidism due to Hashimoto’s thyroiditis that was associated with hyperprolactinemia which, combined, led to secondary amenorrhea. Additionally, hypercholesterolemia, anemia and vitamin D deficiency were confirmed. The patient’s electrocardiogram showed flattened T waves which were very suggestive of myxedema. This unexpected severity of thyroid hormones deficiency is rarely found nowadays due to active screening protocols and easy access to thyroid assessment; however, in young individuals, the clinical tolerance to associated issues is higher than seen in seniors, thus a delay of diagnosis might be found. Whether this impacts the overall reproductive potential in young females mostly depends on the compliance to lifelong hormonal replacement and surveillance of adequate serum hormonal levels, including during pregnancy.

2. Case presentation

A 26-year-old lady, coming from an endemic area, with no fa­mi­ly history of any endocrine pathology, was admitted for a se­con­da­ry checkup following the detection of an abnormally high TSH (thyroid stimulating hormone) level (above 500 µUI/mL, meaning approximately 100 times increase upper the nor­mal limit), a value that was found during a routine testing.

During examination, the patient revealed typical symptoms and indicators of hypothyroidism. The patient complained of generalized weakness, constipation, hair loss, depression, excessive sleepiness, anorexia, reduced hearing and secondary amenorrhea (she did not take any progestative, neither estroprogestative; she had a negative pregnancy test on current admission). She reported that the symptoms had progressed over the course of a year, and no specific medical therapy was initiated. Medical family history revealed type 1 diabetes mellitus in her mother. The clinical examination of the patient revealed normal vital signs, blood pressure of 113/82 mmHg, and pulse of 60-65 per minute (regular). Her weight was 67 kg and her height was 162 cm, with a Body Mass Index of 25.53 kg/m² and clinical signs of myxedema: minimal periorbital edema, coarse hair, dry skin, and yellow palmar discoloration consistent with hypercarotenemia (Figure 1).

The thyroid gland was not palpable, and no surficial cervicolateral lymphadenopathy was detected. She had a menarche at 12 years old, and normal menstrual cycle until one year prior (nulipara).

The laboratory findings started with the first endocrine assessments, showing a TSH value above 500 µUI/mL (normal range between 0.27 and 4.2 µUI/mL) and fT4 (free levothyroxine) below 0.5 pmol/L (normal range bet­ween 12 and 22 pmol/L) in association with increased he­pa­tic enzymes in terms of AST (aminotransferase) of 41 UI/L (normal range: below 35 UI/L). The current labora­tory evaluation also revealed hypercholesterolemia: total cho­les­te­rol of 558 mg/dL (normal range between 0 and 200 mg/dL), LDL-cholesterol of 475 mg/dL (normal range: 60-160 mg/dL); normochromic macrocytic anemia in terms of hemoglobin of 11.1 g/dL (normal range: 12-15.5 g/dL) while being in secondary amenorrhea, as already men­tioned (Table 1).

Thyroid evaluation showed (once again) severe hypothyroidism, with a low FT4 level of 5.8 pmol/L (normal range: 9-19 pmol/L) with extremely high TSH, above 100 µUI/mL (normal range: 0.35-4.94 µUI/mL; of note, this was a different lab to her prior assays). A subsequent ATPO testing showed high levels of 126.6 UI/mL (normal range: 0-5.61 UI/mL) with normal ATG. A mild hyperprolactinemia was detected, namely a serum prolactin of 40.79 ng/dL (normal range: 3.34-26.72 ng/mL). Plasma morning ACTH (adrenocorticotropic hormone) and cortisol levels were normal, and no further dynamic test was necessary to confirm the normal adrenal function.  Hypovitaminosis D was also detected in terms of 25-hydroxyvitamin D of 19.8 ng/mL (normal range: above 30 ng/mL) without secondary hyperparathyroidism (Table 2).

Thyroid ultrasound showed a hypoechoic pattern suggestive of a thyroid autoimmune disease (Figure 2).

We also performed a cardiologic evaluation, the electrocardiogram revealing flattened T waves, suggestive of myxedema, while the cardiac ultrasound showed no pericardial liquid (Figure 3). 

Oral administration of daily levothyroxine was offered to the young lady, 50 µg/day for the first week, followed by a gradual increase to 100 µg/day; the first checkup of TSH and FT4 was after 6-8 weeks. Soon after the initiation of the thyroid hormone replacement, the menses spontaneously restarted. Further hematologic assessments revealed no particular cause of anemia, thus the reduced general metabolic rate amidst myxedema was considered as the single cause. Life-long surveillance of levothyroxine substitution is required with periodic assays. In case of pregnancy, an increase dose is mandatory. A higher risk than in the general population in order to associate other endocrine autoimmune conditions such as primary adrenal failure or premature ovarian insufficiency is estimated, thus awareness is necessary. Moreover, 2000 UI of daily cholecalciferol was initiated for three months, followed by another three months of 1000 UI/day.

3. Discussion

This case highlights several aspects that are worth being mentioned.

Firstly, primary hypothyroidism leads to increased thyrotropin-releasing hormone (TRH) release from the hypothalamus, which has a trophic effect on thyrotrophs and lactotrophs cells, resulting in increased TSH and prolactin levels. This may potentially lead to pituitary gland enlargement, too. In most severe cases, primary hypothyroidism/myxedema has mild hyperprolactinemia⁽¹⁵⁾.

Hyperprolactinemia is commonly caused by primary hypothyroidism; however, not all patients experience this condition. Of those with overt primary hypothyroidism, up to 40% of patients have been reported to have hyperprolactinemia^(16,17). Long-term hyperprolactinemia can cause hypogonadism and related irregular menstruation, secondary amenorrhea, sexual dysfunction, and even low bone mineral density, osteoporosis and fragility fractures in the long term^(18-20).

Another aspect relates to the importance of autoimmune background in a female of reproductive age due to a higher risk (of four to ten times) of developing another endocrine autoimmune condition, especially Addison’s disease or premature ovarian failure but, also, non-endocrine pathologies such as vitiligo or lupus etc.^(21,22)

Anemia in autoimmune hypothyroidism might be caused by the low level of thyroid hormones as a direct consequence or associated autoimmune anomalies at gastric or intestinal level, also causing B12 vitamin deficiency; alternatively, an incidental cause such as anorexia or minor beta-thalassemia should be taken into consideration^(23,24).

Another important aspect is the admission of a patient with a large area of myxoedema-associated complications that developed them within one year via a progressive onset. Of course, we may conclude that delayed presentation might be related to the medical and social issue that came with a late COVID-19 pandemic reality, as seen in other medical areas, including the thyroid field^(25,26). However, the prognosis was good due to prior irrelevant comorbidities and compliance to the recommendations once the diagnosis was established.

Further on, the young lady was seeking for fertility, and the long-term outcome seems good if hormonal replacement therapy is continued and adjusted over time. The therapeutic use of levothyroxine in pregnancy and newborn is well recognized, with good maternal-fetal outcomes. Controversies around the target TSH amidst gestation are still present. The best surveillance hormone is FT4, not TSH, due to pregnancy-related effects of the maternal estrogens in binding proteins and thyroid hormones-TSH feedback^(27,28). Another aspect to be followed is the correction of hypovitaminosis D to improve the general health, but also to ensure an optimal evolution of the mineral metabolism, including over the pregnancy^(29,30).

4. Conclusions

The late presentation for myxedema complicated with hyperprolactinemia in a young female, associating a large panel of clinical elements, including secondary amenor­rhea that did not require a specific intervention, apart from levothyroxine substitution. A particular contribution to fertility profile and future pregnancy also involves the diagnosis of vitamin D deficiency. 

Abbreviations: ACTH = adrenocorticotropic hormone; ALT = aminotransferase; AST = alanine aminotransferase; ATG = antithyroglobulin antibodies; ATPO = antithyroid peroxidase; FT4 = free levothyroxine; TSH = thyroid stimulating hormone; 25-OHD = 25-hydroxyvitamin D

Acknowledgement. We thank the patient for her written consent to present her medical records and above displayed captures.

Corresponding author: Mara Carsote, e-mail: carsote_m@hotmail.com

Conflict of interest: none declared  
Financial support: none declared
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