CATAMENIAL DIABETIC KETOACIDOSIS

Abstract

Diabetic ketoacidosis (DKA) is a common medical emergency situation. In rare cases, glycemic changes associated with the menstrual cycle may create a predisposing factor for DKA. In the absence of facilitating factors that may cause DKA, catamenial DKA should be considered. In the patients with catamenial DKA, increasing the insulin dose 1-2 days before menstruation may prevent the development of hyperglycemia or DKA associated with menstrual cycle. In this study, we present a 21-year-old female with type 1 diabetes mellitus (DM) that recurrently applied to our hospital due to DKA a few days prior to menstrual bleeding.

INTRODUCTION

Diabetic ketoacidosis (DKA) is an acute metabolic complication characterized by hyperglycemia, moderate / severe ketonemia, ketonuria and metabolic acidosis. DKA can be caused by glycemic changes associated with menstrual cycle in addition to predisposing factors such as inadequate insulin treatment, incompatibility with insulin treatment, a new diagnosis of diabetes mellitus (DM), acute major illnesses (myocardial infarction, cerebrovascular diseases, sepsis, or pancreatitis), drugs affecting carbohydrate metabolism (glucocorticoids, thiazide diuretics, second-generation atypical antipsychotic agents (1), sodium-glucose co-transporter 2 (SGLT2) inhibitors (2), sympathomimetic agents (3)) and eating disorders (4).

The word “catamenial” is derived from “katamenios” in Greek, meaning “once-a-month, monthly”. Many diseases such as epilepsy, pneumothorax, migraine, asthma, rheumatoid arthritis and neuropathy exacerbations may be associated with catamenial. Catamenial hyperglycemia or DKA is used to describe increase in blood glucose concentrations related to menstrual cycle phase changes (5). In this study, we present a 21-year-old female with type 1 diabetes mellitus (DM) that recurrently applied to our hospital due to DKA a few days prior to menstrual bleeding.

CASE REPORT

A 21-year-old female with type 1 DM and a history of DKA recurred 3 to 4 times a year was admitted to the hospital with complaints of nausea, vomiting and abdominal pain that started a few days before menstrual bleeding. The patient, who was diagnosed with type 1 DM in 2009, has been using an insulin pump since then.

There was no history of previous operations and addictions. Her father, uncle and aunt had a history of type 2 DM. Her physical examination results were as follows: pulse rate: 90 bpm; blood pressure: 110/70 mm Hg; respiratory rate: 18 per minute; and body temperature: 36°C. She was normal except for decreased skin turgor and a dry tongue suggesting moderate to severe dehydration. Her laboratory results were as follows: hemoglobin: 11.5 g/dL, leukocyte: 6700/mm³, and platelet: 178,000/mm³, urea: 50 mg/dl, creatinine: 0.8 mg/dL, serum sodium: 139 mEq/dL, potassium: 3.8 mEq/dL, and chloride: 98 Eq/dL. Arterial blood gas analysis revealed pH of 7.25 mEq/dL, bicarbonate of 13.8 mmol/L, anion gap of 15. Urine examination revealed 3 positive glucose and ketones. Any hormonal or other precipitating causes of DKA were ruled out. The follow-up data of the patient are given in Table 1. Her hormone analysis revealed follicle-stimulating hormone (FSH): 2.57 mIU/ mL (normal level, 1.3-23.4 mIU/mL fertile females); luteinizing hormone (LH): 2.73 mIU/mL (normal level, 0.8-15.5 mIU/mL fertile females); prolactin: 18 ng/mL (3.34-26.72); estradiol: 136 pg/L (36.5-246 luteal phase); progesterone: 31.9 ng/L (5.16-18.56 luteal phase). DKA was improved with hydration and insulin infusion.

Table 1.

Laboratory parameters during her 8 days of hospitalization

	Day 1	Day 2	Day 3	Day 4	Day 5	Day 6	Day 7	Day 8
Urine ketone	+++	+++	++	++	++	++	-	-
Plasma glucose level (mg/dL)	431	233	187	92	140	103	240	101
Arterial pH	7.25	7.24	7.37	7.37				7.36
Serum bicarbonate (mEq/L)	13.8	17.9	22.2	23.6				24.2
Anion gap = [Na+ - (Cl-+HCO3- )]	137-(109+13)=15	134-(99+17)=18		140-(106+23)=9				140– (106+24)=10

Our patient had a regular menstrual cycle every 28 days and her menstrual hemorrhage lasted for 5 to 6 days. At the time of her admission to our hospital, she was found to be on the 26^th – 27^th day (late luteal phase) of the menstrual cycle. The patient who had a history of 3-4 hospitalizations due to DKA in the premenstrual period was evaluated as catamenial DKA. The patient was advised to increase the dose of insulin and hydration a few days before menstrual bleeding. In her follow-up period, the patient did not come in a situation of diabetic ketoacidosis in premenstrual period again.

DISCUSSION

Catamenial hyperglycemia or DKA is used to describe increase in blood glucose concentrations related to menstrual cycle phase changes (5). Hyperglycemia or DKA in the late luteal phase was first reported by Harrup and Mosenthal at John Hopkins hospital in 1918 (6). In this study, we present a 21-year-old female with type 1 diabetes mellitus (DM) that recurrently applied to our hospital due to DKA a few days prior to menstrual bleeding. Our patient had a regular menstrual cycle every 28 days and her menstrual hemorrhage lasted for 5 to 6 days. At the time of her admission to our hospital, she was found to be on the 26^th – 27^th day (late luteal phase) of the menstrual cycle. The patient who had a history of 3-4 hospitalizations due to DKA in the premenstrual period was evaluated as catamenial DKA.

In 1942, Cramer et al. reported that 47 % of women during the premenstrual phase admitted due to DKA had no obvious underlying cause, and that they were within the first or second day of their menstrual period (7). Cawood et al. found out that 67% of women with diabetes had changes in blood glucose levels during the premenstrual phase (8). Goldner et al. demonstrated that increased progesterone level was the main reason for DKA and hyperglycemia during the luteal phase (9). Trout et al. investigated the association between intravenous glucose tolerance test and hormones level in different phases of the menstrual cycle. A correlation was found between decreased insulin sensitivity and increased plasma progesterone levels (10). Low-grade inflammation was found to be another possible cause for hyperglycemia and DKA in the premenstrual and menstrual period (11). C-reactive protein level was shown to increase during the premenstrual and menstrual period by Puder et al. (12).

Studies on glycemic changes during the menstrual cycle showed an increased risk of hyperglycemia in early luteal phase (16^th-18^th days of the 28-day menstrual cycle). However, the risk of hypoglycemia was higher during the follicular phase (1^st-12^th days of the 28-day menstrual cycle) and the risk of glucose fluctuations also increased during peri-ovulation phase (13^th-15^th days of the 28-day menstrual cycle) (13).

Catamenial variation in glycemia is associated with the variations in insulin sensitivity, and thus glycemic patterns tend to vary from woman to woman and even during consecutive menstrual cycles (14,10).

Catamenial hyperglycemia and DKA are both diagnosis of exclusion. Any hormonal or other precipitating causes of hyperglycemia such as intercurrent illnesses (i.e., surgery, trauma, myocardial ischemia, pancreatitis), psychological stress, and non-compliance with insulin therapy should be thoroughly investigated and ruled out. While no standard methods are currently available for the diagnosis of catamenial glucose variability, most experts suggest an analysis of menstrual cycle with daily glycemic variability (5,11).

Although there is some evidence of an increased incidence of hyperglycemia or DKA during the premenstrual and menstrual period, their mechanism is not clear yet. In order to prevent catamenial DKA, it is recommended to take some precautions such as an analysis of menstrual cycle, close follow-up of blood glucose, prevention of triggering factors, regular aerobic exercise and increased insulin dose during the premenstrual and menstrual period (5).

Only 9 cases showing a relationship between menstrual cycle and DKA have been reported in the literature so far (Table 2) (5,15). Our study reports significant changes in glucose metabolism associated with the late luteal phase of menstrual cycle.

Table 2.

A summary of the reported cases with catamenial hyperglycemic crisis or DKA

Catamenial DKA
Authors	Publication Year	Age, Country	Clinical Diagnosis
Harrop et al.	1918	18 USA	DKA
Rosenbloom	1921	30 USA	DKA
Peperkorn	1932	19 Germany	DKA
		25	DKA
		32	Hyperglycemic crisis
		49	Hyperglycemic crisis
Morton et al.	1946	31 USA	DKA
Hubble	1954	15 UK	DKA
Green	1958	18 USA	Hyperglycemic crisis
Sandstöm	1969	17 Sweden	DKA
Ovalle et al.	2008	32 USA	DKA
		35	DKA
Gomez et al.	2013	23 USA	DKA
Our case		21	DKA

As a limitation of our study, the routine laboratory tests of our case with the LH, FSH, progesterone and estradiol in luteal phase, follicular phase or pre-ovulatory phase were not present so we couldn’t add this data to the report.

In conclusion, the most important factor in the treatment of DKA is the identification and management of predisposing factors. It should be kept in mind that in fertile women with DKA whose predisposing factors cannot be clearly identified, the menstrual cycle may be a triggering factor of DKA.

Although there are no standard methods for the diagnosis of catamenial hyperglycemia or DKA, the frequent measurement of blood glucose level and an analysis of menstrual cycle are recommended (10,11). In the patients with DM, increasing the insulin dose during the premenstrual and menstrual period may prevent the development of DKA or hyperglycemia associated with menstrual cycle.

Conflict of interest

The authors declare that they have no conflict of interest.