Special Feature

A (Not Really So) Rare Cause of a Common Presentation

By Sarah L. Berga, MD

Menstrual irregularities are arguably the mainstay of gynecologic office practice. The differential diagnosis for this common presentation is quite extensive, but a common cause is reduced central hypothalamic GnRH drive due to "lifestyle issues." This cause is easy to recognize clinically when there is a dramatic loss of weight or the patient tells you that she has been training for a marathon. Weight loss and excess energy expenditure represent forms of metabolic imbalance, and it is now well established that metabolic and nutritional signals modulate the hypothalamic GnRH pulse generator. Depending on the degree of metabolic imbalance and compounding psychogenic factors, the reduction in GnRH may be partial or complete and continuous or intermittent. Menstrual patterns range from luteal insufficiency with preservation of menstrual interval, to prolonged folliculogenesis with a long menstrual interval, or a short menstrual interval due to partial and unsustained folliculogenesis. Indeed, the menstrual interval and flow may vary from cycle to cycle as the extent of GnRH varies from day to day. It takes a minimum of 14 "good days" to grow a follicle and anything less than that may interfere with optimal folliculogenesis. When the lifestyle issues that initiate or maintain the suppression of GnRH are less obvious and the suppression is incomplete, this form of reproductive compromise can be exceedingly difficult to recognize in the office, as neither metabolic imbalance nor GnRH suppression is readily documented using clinical chemistries.

It is not well appreciated that metabolic imbalance can exist in the absence of weight loss. For instance, overnutrition or periodic hypoglycemia from poor control of diabetes may also engender metabolic imbalance without resulting in weight loss or gain. In general, when there is weight loss or low weight, a clinical or subclinical eating disorder needs to be considered; however, not even all weight loss is due to an eating disorder or voluntary food or nutrient restriction. Indeed, there is growing recognition of another form of metabolic compromise that can cause and present as menstrual irregularities, namely adult-onset malabsorption syndromes.

An apparently common cause of malabsorption is food allergies and conditions that masquerade as food allergies, such as lactose deficiency, gastrointestinal infections, cholestasis, metabolic disorders such as galactosemia, and irritable bowel syndromes, including Crohn’s disease. The topic of food allergies was recently extensively reviewed.1 Interestingly, food hypersensitivity reflects a malfunction of the normal immune response to dietary proteins and may range in prevalence from 4-20%. Symptoms vary widely. In children, the typical allergens are egg, milk, peanut, wheat, and soya, whereas in adults, typical allergens are peanuts, tree nuts, and seafood. Arguably, the most insidious of these syndromes is celiac disease, which is an irreversible food allergy to gluten and wheat.

It is commonplace to think of food allergies as presenting in childhood and therefore not the domain of the gynecologist. However, a common presentation of celiac disease is menstrual irregularities, miscarriage, and infertility. Thus, it seems very likely that gynecologists and reproductive endocrinologists will be the physicians who will see and care for these women. Thus, I thought a quick review of this topic might be worthwhile.2 Celiac disease, originally thought to occur only rarely in childhood, is a food allergy to the storage proteins of wheat, which are called glutens, that results in a T-cell mediated chronic inflammatory bowel disorder with an autoimmune component. In adults, the symptoms of celiac disease might include diarrhea, bloating, or abdominal pain with meals, but many of those with celiac disease who do not have obvious gastrointestinal complaints nonetheless suffer the long-term consequences, including metabolic bone disease, osteoporosis, anemia, malaise, autoimmune disorders, folate deficiency, severe liver disease, neurological symptoms, dental disease, and excess mortality primarily due to malignancy, including an 80-fold excess risk of small bowel adenocarcinoma. Even in patients with diarrhea, there tends to be a delay in diagnosis due almost exclusively to physicians failing to test for this condition. Diarrhea represents a late finding and is due to progression of the disease into the distal small bowel. Pregnancy can serve as a trigger for the development of symptoms. Based on symptoms, the disease was previously estimated to occur in 1/3500 people worldwide, but serological screening has revealed the prevalence to be around 1/250 worldwide.

Gynecologic manifestations can include delayed menarche, premature menopause, amenorrhea, recurrent miscarriage, and sexual dysfunction. The potential obstetrical manifestations include intrauterine growth restriction, increased perinatal mortality, and inadequate lactation. Further, there is an excess risk of celiac disease among patients with infertility.3,4

The diagnosis of celiac disease is based on the presence of histological changes in a small bowel biopsy, although there may be false negatives because the disease is patchy. The major histological feature is villous atrophy with crypt hyperplasia and intraepithelial lymphocytosis. In adults, although histological features can improve with a gluten-free diet, they often do not completely normalize. Serological tests have an important role in the diagnosis and management of celiac disease and provide the greatest chance of establishing the diagnosis. The presence of IgA and IgG antibodies against endomysium is almost 100% specific but only 80% sensitive. The total amount of gluten consumed by a patient will alter the results of serological testing. Therefore, other antibody tests should be done, usually anti-gliadin, both IgA and IgG. Total IgA should also be measured, because IgA deficiency is 10-fold higher in those with celiac disease and may render the tests falsely negative.

The treatment is a strict gluten-free diet. Since most commercial flavorings and colorings use gluten, this is a burdensome task. However, with increasing recognition, some commercial manufacturers have begun to accurately label their foods, and some stores even have gluten-free aisles. When a patient with celiac disease is contemplating pregnancy, the obstetrician must be certain to emphasize that it is critical to ensure appropriate folate levels, but the patients must be cautioned to acquire gluten-free vitamins.

In short, although most gynecologists and reproductive endocrinologists may not be aware of it, celiac disease and other food allergies are a relatively common cause of typical reproductive complaints, including menstrual irregularities, amenorrhea, infertility, sexual dysfunction, premature menopause, recurrent miscarriage, and poor obstetrical outcomes. The long-term sequelae of untreated celiac disease are far from benign and therefore, when there is the least suspicion, testing should be done. Certainly, the relatives of anyone with celiac disease must be tested, regardless of the absence or presence of symptoms. To optimally protect the health of women and their infants, it is clear that obstetrician-gynecologists need to become familiar with gynecological manifestations and also to be able to order the appropriate screening tests.

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1. Sicherer SH. Lancet. 2002;360:701-710.

2. Green PR, Jabri B. Lancet. 2003;362:383-391.

3. Collin P, et al. Gut. 1996;39:382-384.

4. Meloni GF, et al. Hum Reprod. 1999;14:2759-2761.