Periodic Fever, Menstrual Cycle-Dependent

A number sign (#) is used with this entry because of evidence that menstrual cycle-dependent periodic fever can be caused by heterozygous mutation in the HTR1A gene (109760) on chromosome 5q11.

Description

Women show menstrual cycle-dependent physiologic changes in relation to sex hormone levels. Because ovulation triggers a significant change in the hormonal milieu that is similar to local inflammation, a 0.5 to 1.0 degree Celsius increase in basal body temperature after ovulation is commonly associated with progesterone secretion and is believed to be triggered by the induction of several inflammatory cytokines. Rare menstrual cycle-dependent febrile episodes have been reported, some of which have shown a luteal-phase-dependent pattern (summary by Jiang et al., 2012).

Clinical Features

Rutanen et al. (1993) reported 2 Finnish women who had recurrent fevers up to 40 degrees Celsius associated with the luteal phase of the menstrual cycle, who also had continuously elevated serum levels of TNF (191160) and IL6 (147620). The first woman developed monthly recurrent fevers, up to 39.5 degrees Celsius and lasting 1 week, at age 17 years; evaluation revealed only mild hypercortisolism. At age 18, she developed severe tremor and ataxia in association with the fever, which continued for a 2-month period. She was found to be pregnant, which was terminated due to her continued fever and neurologic symptoms; after termination, the fever and associated symptoms disappeared, but subsequently the fever and hypercortisolism recurred. Two more pregnancies were associated with fever, tremor, and ataxia, with resolution of symptoms after termination of the pregnancies. Upon recognition of an association between fever and the midluteal phase of the menstrual cycle, progesterone levels were measured and found to be normal. Three more pregnancies were associated with fever and ended in spontaneous abortions at 6 to 7 weeks' gestation. At age 28, the patient still had midluteal phase increases in temperature, but the associated symptoms were markedly milder than in the early years of the disorder. The second patient developed fever, myalgia, and lower extremity weakness after beginning use of a triphasic oral contraceptive at age 18. Evaluation after 6 weeks of continuous fever revealed no infectious focus. The oral contraceptive pill was discontinued, and the patient's symptoms improved dramatically; however, the patient was subsequently readmitted for evaluation several times due to recurrent fevers occurring at days 19 through 25 of the menstrual cycle, concomitant with the highest levels of serum progesterone. No signs of infection were detected and the only abnormal findings were mildly elevated serum cortisol and 11-deoxycorticosterol as well as 24-hour urinary excretion of cortisol. Administration of progesterone and progestins triggered fever in both patients, and treatment with antiprogesterone (RU486) prevented the fever and associated symptoms, which recurred with cessation of RU486. To prevent the endogenous progesterone surge, the first patient also underwent ovarian suppression by treatment with the GnRH (152760) antagonist nafarelin and remained afebrile. Serum levels of TNF and IL6 were consistently elevated in both patients, 4- to 6-fold and 4- to 4.5-fold, respectively, greater than the levels observed in healthy female controls. Rutanen et al. (1993) noted that fever did not appear immediately after ovulation, suggesting that a certain threshold of serum progesterone was required to trigger it.

Nakamura and Hino (2005) reported a 30-year-old Japanese woman who developed recurrent high fevers (greater than 38 degrees Celsius) associated with her menstrual cycle 3 years after being treated with interferon-beta for a hepatitis C infection. The fevers occurred a few days after ovulation, and when ovarian function was suppressed by GnRH agonist (GnRHa), the symptoms disappeared. While in anovulation, the patient received estrogen followed by estrogen with progestogen, which resembles the sex hormone milieu of a normal menstrual cycle without the luteinizing hormone (LH; 152780) surge; this treatment did not induce the symptoms. When human chorionic gonadotropin (hCG; 118860) was injected on the beginning day of estrogen with progestogen following treatment with estrogen alone, the previous symptoms reappeared. However, hCG injection without estrogen priming did not induce symptoms, indicating that the LH surge after estrogen priming caused the symptoms. Measurements of inflammatory cytokines, including TNF, IL6, IL1A (147760), and IL1B (147720), showed that serum levels were highest during the menstrual period, but there were no significant changes on the day when symptoms appeared. After ending 5 months of treatment with GnRHa, the patient had normal menstrual cycles, and although symptoms still occurred, they were mild and did not require treatment.

Yamasaki et al. (2011) described a 14-year-old Japanese girl who presented with a 1-year history of recurrent febrile episodes (39 to 41 degrees Celsius) associated with development of regular menstrual cycles. Recording of basal body temperatures revealed that the fevers occurred for 10 to 12 days, concomitant with the luteal phase of every ovulatory cycle, and disappeared 1 day before the onset of menses. Suppression of the ovulatory cycle with GnRHa abolished the fevers. Yamasaki et al. (2011) noted that unlike the report by Rutanen et al. (1993), in which there was persistent elevation of TNF and IL6 associated with progesterone action, serum levels of inflammatory cytokines in this patient, including TNF, IL1B, IL2 (147680), IL6, IL8 (146930), IL10 (124092), and C-reactive protein (123260), did not change during GnRHa therapy and most were within the normal range before and during GnRHa administration. Yamasaki et al. (2011) concluded that luteal-phase-dependent febrile episodes might be induced by various mechanisms.

Jiang et al. (2012) studied a 33-year-old Taiwanese woman with high fevers (greater than 38 degrees Celsius) in both the pre- and postovulation periods of her menstrual cycle since menarche at 14 years of age. Evaluation for infectious processes was negative, and serologic studies for connective tissue disorders and immunoelectrophoresis were all normal. During her menstrual cycles, extremely high levels of estrogen were observed in the luteal phase, and her fevers were not associated with levels of proinflammatory factors such as IL1B or IL6. GnRHa therapy resulted in complete remission of the fevers in association with ovarian suppression, and administration of a conjugated estrogen, Premarin, on the first day of the menstrual cycle immediately increased her body temperature. However, the progesterone antagonist RU486 had no effect on her fevers; taken together, these findings suggested that estrogen might play a critical role in her fevers. Family history revealed that her father had diabetes and diabetes-associated uremia, and her older brother developed migraines at age 20 years and diabetes at age 32. Her mother and sister were healthy. Because migraine, thermoregulation, and glucose metabolism are associated with human serotonin receptor HTR1A (109760) function, Jiang et al. (2012) administered a serotonin receptor antagonist, buspiron, which resulted in successful remission of the patient's periodic fevers.

Molecular Genetics

In a 33-year-old Taiwanese woman with recurrent fevers associated with her menstrual cycle that were successfully treated with a serotonin receptor antagonist, Jiang et al. (2012) sequenced the serotonin receptor gene HTR1A (109760) and identified a 1-bp deletion in the upstream promoter (-480delA; 109760.0001). The mutation was also identified in her father and brother, who had serotonin-related disorders such as diabetes and migraines, but was not found in her unaffected mother or sister or in 50 unrelated population controls. Jiang et al. (2012) proposed that increased concentrations of estrogen during the pre- and postovulation phases triggered an increase in body temperature in this patient through a failure in the negative feedback pathway of serotonin caused by HTR1A -480delA-mediated deficiency.