Causes

Researchers are still uncertain about the causes of premenstrual syndrome. Evidence suggests that fluctuations in hormones and brain chemicals play a role.

Activity in the Hypothalamic-Pituitary-Adrenal (HPA) System

The hypothalamic-pituitary-adrenal (HPA) system controls reproduction, appetite, and feelings of well-being. The HPA is also involved in regulating the stress response. A number of reproductive hormones and neurotransmitters (chemical messengers in the brain) play important and complicated interrelated roles in the activity of the HPA system. Disruptions in these chemicals may be important in PMS and premenstrual dysphoric disorder (PMDD).

• Reproductive hormones. The two important female hormones, progesterone and estrogen, are at their highest levels during the premenstrual period. Evidence indicates that an abnormal response to progesterone, rather than estrogen, is the primary factor in PMS.
• Neurotransmitters. Each hormone is involved in the regulation of two neurotransmitters, serotonin and gamma-aminobutyric acid (GABA). These brain chemicals have properties that protect against PMS symptoms.
• Stress hormones.

The exact roles and relationships of any of these substances in PMS or premenstrual dysphoric disorder (PMDD) are still unclear. Evidence increasingly suggests that fluctuations in some of these hormones--not whether they are high or low--may be the important factors in premenstrual problems.

Progesterone and GABA. Changes in progesterone and a potent progesterone derivative called allopregnanolone (ALLO) are proving to play important roles in PMS. ALLO in turn regulates gamma-aminobutyric acid (GABA). Imbalances in the hormones that reduce GABA levels have been associated with depression, anxiety, and agitation. GABA is an amino acid that acts as a neurotransmitter to inhibit transmission of impulses from one nerve cell to another. It plays a very important role in the stress response. An important 2002 study reported lower levels of GABA during menstruation in women with premenstrual dysphoric disorder (PMDD). In fact, GABA may become an important target for drugs aimed at relieving PMDD.

Serotonin. Some women with PMS and premenstrual dysphoric disorder have been found to have abnormal levels of serotonin. Abnormalities in this important neurotransmitter are associated with depression, anger, irritability, poor impulse control, and carbohydrate cravings, all symptoms of PMS.

Stress Hormones. After a stressful event, the HPA system releases certain neurotransmitters called catecholamines, particularly dopamine and epinephrine (adrenaline).

• These chemicals trigger the release of the steroid hormones known as glucocorticoids, which in turn produce cortisol, the primary stress hormone.
• Cortisol activates systems throughout the body to respond to this stressful event (the fight or flight response). Low levels are associated with depression.

One study observed that women with PMS-related depression had lower cortisol levels during the premenstrual phase and higher levels during menstruation compared to women with few PMS symptoms.

Calcium and Magnesium Imbalances

Calcium and magnesium help nerve cells to communicate and blood vessels to widen and narrow. Female hormones, including estrogen, regulate calcium and magnesium. Hormonal swings during the premenstrual phase cause variations in these important minerals. Some researchers believe that imbalances in these minerals may contribute to PMS. (Vitamin D, which is essential for calcium absorption, may also be deficient in women with PMS.)

One study observed very low levels of magnesium and high levels of calcium during the premenstrual phase. Some experts hypothesize that deficiencies in magnesium may be responsible for triggering symptoms. The effects are likely to be more complicated than this, however, since taking calcium supplements appears to reduce PMS symptoms in some women, while taking magnesium seems to have no effect.

Other Physical Factors

Peptides. Some researchers are studying certain peptides that vary during the menstrual cycle among women with and without PMS. These substances include arginine vasopressin (AVP), which affects water retention, and atrial natriuretic peptide (ANP), which increases sodium elimination.

Thyroid Hormone. A few studies report that women with PMS may be more sensitive to variations in thyroid hormone, which can impact both physical and emotional well-being.

Prolactin. Some PMS symptoms, particularly breast pain, may be caused by excess levels of prolactin, a hormone produced by the pituitary gland that stimulates the glands in the breasts.

Endometrial Abnormalities. Results of a study of women who had both PMS and heavy bleeding (menorrhagia) suggested that substances in the endometrium (the lining of the uterus) might cause PMS symptoms.