Primary amenorrhoea as a manifestation of coeliac disease

Abstract

Coeliac disease is a systemic autoimmune disorder that has a wide range of clinical manifestations that include abdominal pain, diarrhoea, obstipation, weight loss, short stature and even primary amenorrhoea. It can be asymptomatic, which makes it an underdiagnosed disease. We present a case report of a 15-year-old girl who was referred to a paediatric consultation due to primary amenorrhoea. A detailed clinical history revealed poor weight gain. Physical examination showed that secondary sexual characteristics were present and there was a low body mass index. Ultrasonography images and laboratory tests revealed a normal urogenital system and an adequate gonadal function. Coeliac disease antibodies were positive and the diagnosis was confirmed through duodenal biopsy. The symptom resolved with a gluten-free diet. An approach to primary amenorrhoea should always include investigation of a systemic illness as it is a rare but treatable diagnosis.

Background

Primary amenorrhoea is defined by the absence of menses by age 15 years in the presence of normal development and secondary sexual characteristics.¹ It is often, but not exclusively, caused by chromosomal irregularities that lead to primary ovarian insufficiency (eg, Turner syndrome) or anatomic abnormalities (eg, Müllerian agenesis). In the absence of structural defects, diseases that affect the hypothalamic–pituitary–gonadal axis should be considered. Systemic illness, such as coeliac disease (CD), if severe enough, can decrease hypothalamic gonadotrophin-releasing hormone (GnRH) secretion which leads to secondary or primary amenorrhoea.²

CD is a systemic disorder caused by gluten and characterised by the presence of a variable combination of gluten-dependent clinical manifestations, CD-specific antibodies, HLADQ2 or HLA-DQ8 haplotypes and enteropathy.^{3 4} Non-specific symptoms and signs of CD make it a condition difficult to diagnose. Therefore, gynaecological presentations such as infertility, delayed menarche or amenorrhoea should prompt investigation of CD.⁵

Case presentation

A 15-year-old girl was referred to a paediatric consultation due to primary amenorrhoea. Her mother had had a late menarche at 15 years of age. In terms of personal history, she was diagnosed with migraine and referred to a neurologist. In this context, a CT scan of the brain was performed, which excluded brain lesions. There was no medication history. Other than that, she had a history of poor weight gain (weight progression in the third percentile) with an adequate food intake. There was no evidence of gastrointestinal manifestations (namely vomiting, diarrhoea, nausea and abdominal pain) or any other accompanying symptoms.

At observation, she had a weight of 43 kg, height of 161.5 cm (percentile 15–50), body mass index (BMI) of 16 (percentile 3) and presented secondary sexual characteristics (Tanner score of M3P2). The remaining physical examination was normal. There was no evidence of dysmorphism, hirsutism, virilisation or abnormal external genitalia.

Investigations

Laboratory studies revealed normal haemoglobin of 14.5 g/L (reference range 12–16), iron studies showed decreased ferritin of 22 ng/mL (reference range 30–340), elevated total iron binding capacity of 445 g/dL (reference range 291–430), and normal iron of 115 µg/dL (reference range 20–145) and transferrin of 311 mg/dL (reference range 164–324). Tissue transglutaminase IgA antibody was elevated at 40 (considered positive if >10) and total IgA was normal at 127 mg/dL (reference range 55–174). Follicle-stimulating hormone (FSH) was 4.91 mUI/mL, luteinising hormone (LH) was 2.44 mUI/mL, 17-alpha OH progesterone was 0.73 ng/mL, 17-beta oestradiol was 56.49 pg/mL and basal insulin-like growth factor 1 was 288 ng/mL, which were normal values, compatible with her current pubertal stage. Thyroid, renal and liver functions were normal. Pregnancy was excluded. The patient’s karyotype was 46, XX. Further laboratory studies showed that HLA-DR5-DQ7 and HLA-DR7-DQ2, associated with predisposition to CD, were positive.

A pelvic ultrasound revealed uterus and ovaries with the expected dimensions and shape for her current age and pubertal development.

The patient’s bone age was only 1 year less than chronological age, which was considered an irrelevant finding.

An endoscopy was performed and biopsies of duodenum were collected. Biopsy findings were consistent with CD (Marsh classification of histological findings: 3a/3b) and confirmed the diagnosis.

Differential diagnosis

Most causes of amenorrhoea are identifiable through a detailed history, examination and laboratory analysis.⁶

A thorough physical examination is essential. The absence of hirsutism, acne and virilisation made polycystic ovarian syndrome and hyperandrogenism unlikely diagnosis. The gynaecological observation excluded structural causes such as imperforate hymen and müllerian duct anomaly. The pelvic ultrasound confirmed the absence of outflow obstruction and revealed normal pubertal uterus and ovaries.⁷

Serum levels of FSH, LH, prolactin (PRL), thyroid-stimulating hormone (TSH) and free thyroxine were measured to rule out endocrine causes of amenorrhoea (such as ovarian insufficiency, prolactinoma, hypothyroidism).^{6 8} In the presence of normal laboratory and imaging studies, hypothalamic amenorrhoea (HA) would be the next possible cause. HA occurs due to deficient secretion of hypothalamic GnRH, which in turn leads to failure of pituitary gonadotrophin and gonadal steroid release. Genetic causes include Kallman syndrome, Prader-Willi syndrome and other rare syndromes with idiopathic hypogonadotropic hypogonadism, but these are typically associated with additional symptoms such as anosmia, mental retardation, extreme obesity and facial dysmorphia.

Organic diseases of the hypothalamic area (neoplasms, sarcoidosis, tuberculosis, parasitoids and other infiltrating lesions) were also excluded by the absence of lesions in previous brain CT scans.

The most common central causes of amenorrhoea in an adolescent or young adult include constitutional delay of growth and puberty, chronic illness and functional hypothalamic amenorrhoea (which can be weight loss related, stress related or exercise related).⁹ A low BMI or significant decrease in BMI percentile could be suggestive of an eating disorder, female athlete triad or other chronic illnesses. Basic chemistries, complete blood count, inflammatory markers and serum markers of CD can be useful to determine if a chronic illness is thought to be the cause of amenorrhoea.⁹ There was no history of an eating disorder or excessive exercise, so functional HA became unlikely. Other causes of HA include chronic disease and malabsorptive illnesses such as CD.¹⁰ Therefore, CD screening was performed and revealed positive antibodies and predisposing haplotypes. The diagnosis was then confirmed by duodenal biopsy.¹¹

Constitutional delay of growth and puberty could be considered due to the family history of late menarche, if other underlying conditions had been ruled out.¹²

Treatment

After confirmation of the diagnosis of CD, she started a gluten-free diet. Menses typically return after correction of the underlying nutritional deficit, which occurred 10 months after the diet was initiated. Compliance to the gluten-free diet is essential for catch-up growth, weight gain and pubertal maturation.¹³

Outcome and follow-up

The patient is now 16 years old and is still maintaining a gluten-free diet. The most recent laboratory studies showed negative CD anti-tissue transglutaminase antibodies (IgA 11.2 UQ and IgG 4.3 UQ). Her menses are irregular, but she is no longer amenorrhoeic. Her weight (52 kg) and height (165 cm) have increased and she now has an adequate BMI of 19 (p15–50). She maintains a normal pubertal development (current Tanner stage M4P5).

Discussion

There are not many published cases of primary amenorrhoea as a manifestation of CD.

There was a similar case report of a 20-year-old woman with primary amenorrhoea associated with failure of development of secondary sexual characteristic, and a history of weight loss while maintaining a diet with an adequate caloric intake. Laboratory studies revealed microcytic hypochromic anaemia, low levels of FSH and LH levels, normal TSH and PRL levels and positive IgA anti-endomysial antibody. Duodenal biopsy showed villus atrophy, suggestive of CD. The patient’s condition improved markedly and attained menarche after 6 months of a gluten-free diet.¹⁴

Another article reported a case of a 16-year-old teenage girl with weight loss, short stature and amenorrhoea. Further investigation showed delayed bone age versus chronological age and delayed progression into puberty. IgA antitransglutaminase antibodies were positive and intestine biopsy findings were compatible with CD. This was another example of atypical CD that presented with weight loss, short stature and delayed puberty, all of which consequences of the underlying disease. There was improvement with gluten free-diet but menarche was not achieved by the time of the publication.¹³

It is estimated that the prevalence of CD in Portugal is 1:134.¹⁵ Since the number of diagnosed cases in Portugal is less than expected according to the above-mentioned prevalence, there might still be a lot of undiagnosed or misdiagnosed patients. The fact that CD can be oligosymptomatic or asymptomatic contributes to this situation. In fact, it has been reported that one-third of patients with CD might be asymptomatic.¹⁶ Several factors such as site of lesions, length of intestine involved and grade of malabsorption may influence the timing of the first symptoms and delay the diagnosis.¹³ Although the pathogenesis of the different presentations of CD is not completely understood, it is believed that nutritional deficiencies and inflammatory response may explain reproductive manifestations.¹⁷

Learning points.

• Primary amenorrhoea should always prompt investigation. Regular menstruation requires normal hypothalamic–pituitary–ovarian axis, anatomical presence and patency of genital tract, responsive endometrium, 46 XX karyotyping and active support from other endocrine glands like adrenal and thyroid. The approach to amenorrhoea should be systematic and directed at the pathologies that might affect any of the mentioned components.

• Chronic systemic illnesses like diabetes mellitus, inflammatory bowel disease and coeliac disease are associated with malabsorption and caloric deficit, which inhibits hypothalamic secretion and leads to amenorrhoea. Treatment of the underlying illness usually resolves the amenorrhoea.

• Coeliac disease is a systemic disorder caused by gluten and characterised by the presence of a variable combination of gluten-dependent clinical manifestations which include delayed puberty and amenorrhoea. Typical gastrointestinal manifestations may be absent, which is why high level of suspicion is required. Treatment involves a gluten-free diet.