Various hypotheses have been implicated in the etiology of PMS, including interaction between ovarian steroid hormones, endogenous opioid pep-tides, central neurotransmitters, eicosanoids, and peripheral autonomic and endocrine secretions. Despite all the investigations relating to these diverse fields, there is no firmly established biological pattern for PMS and its pathophysiology still remains obscure.
As early as the 1930s, it was suggested that PMS was caused as a result of excessive levels of the female sex hormones in the blood. Later, deficient blood levels of progesterone were blamed, so that by the 1960s PMS treatment was dominated by progesterone administration. Despite this, the findings from several studies showed no clear link between low blood progesterone levels and the severity of the condition.
More recently, attention has been given to the significance of the oestrogen-to-progesterone ratio as a factor triggering PMS. In particular, it has been postulated that women with PMS-A (anxiety) have increased plasma concentrations of oestrogen relative to progesterone in the luteal phase compared with normal women. One possible mechanism is that low plasma blood levels of oestrogen and progesterone early in the luteal phase in PMS sufferers lead to an increased secretion of gonado-trophic hormones from the pituitary which, in turn, leads to a rise in oestrogen in the late luteal phase, owing to the stimulation of ovarian follicles. These follicles rapidly regress under the influence of the luteal secretion of progesterone. Excess oestrogen in the luteal phase may be the cause of fluid retention, breast tenderness, changes in carbohydrate metabolism, and mood swings associated with PMS. Although the ovarian hormone imbalance hypothesis remains unproven, administration of progesterone in the latter half of the cycle continues to be the first-line treatment for PMS by general practitioners in the UK.
The existence of subgroups of PMS of varying etiology may account for clinical observations that some women with severe premenstrual depression report, paradoxically, a worsening of symptoms during progesterone treatment. Indeed, such women have been reported to respond to oestrogen treatment. Their condition may be linked to progesterone excess, which has been suggested to occur in some women who experience PMS symptoms at midcycle. High luteal progesterone levels may lead to depletion of oestrogen receptors of the hypothalamus, which is consequently less sensitive to oestrogen, requiring a higher midcycle oestrogen surge for normal pituitary response. This is followed by an abrupt and pronounced oestrogen drop at midcycle which may even result in symptoms of hot flushes.
It has been demonstrated that symptoms such as irritability, withdrawal, depression, hopelessness, tension, lack of initiative, and weight gain are linked to changes in urinary potassium/sodium ratio, which in PMS women is higher 3-4 days before the onset of menses and lower for the rest of the cycle compared with that in normal women. The reason for this may lie in the enhanced secretion of angiotensin promoted by higher progesterone levels during the luteal phase of the menstrual cycle.
Angiotensin is a hormone with vasoconstricting properties which acts on the kidneys by constricting efferent arterioles. This reduces blood flow from the kidneys and enhances excretion of the electrolytes sodium and potassium. An electrolyte imbalance occurring in PMS may alter neurotransmitter activity, in particular monoaminergic (noradrenalin and serotonin) and cholinergic neurotransmitters, affecting behavior and mood regulation. Angiotensin is also known to act directly on the adrenal cortex to promote aldosterone release (see below) and may be involved in stimulating antidiuretic hormone (ADH) secretion by the pituitary. Both of these hormones are directly involved in the maintenance of electrolyte balance.
Aldosterone, the steroid hormone secreted by the adrenal cortex, promotes retention of sodium and excretion of potassium by the kidneys. An elevated secretion of aldosterone in the luteal phase would tend to lead to sodium retention and, as a result, promote fluid retention. Whether the high aldosterone levels found in PMS are a consequence of direct adrenal cortex stimulation or are promoted by increased adrenocorticotrophic hormone (ACTH) secretion from the pituitary is unknown, although circulating levels of gonadal hormones are known to influence electrolyte homeostasis via the angiotensin-aldosterone system, as stated above.
Fluctuation in prolactin levels has also been suggested as a cause for PMS. Prolactin is a pituitary hormone which regulates mammary gland development in women and is necessary for successful lactation. Latent hyperprolactinemia is thought to predispose nonlactating women to premenstrual breast pain. Prolactin levels rise acutely due to stress and higher levels promote sodium, potassium, and water retention. Noradrenalin has been implicated in promoting prolactin release, while the presence of dopamine reduces it. Both stress and high oestrogen levels promote noradrenalin secretion, while dopa-mine may be reduced in those consuming a diet low in certain nutrients (see below).
In one study, a high percentage of women with PMS who were treated with thyrotrophin releasing hormone (TRH) were found to have low thyroid function. As thyroid hormone supplementation has been used in the past as antidepressant therapy, some recent studies have attempted to link thyroid dysfunction to PMS. Indeed, there are suggestions that PMS may be an early symptom of a progressive thyroid disorder and the severity of PMS increases as thyroid dysfunction progresses. Nevertheless, the use of thyroid hormone for the treatment of PMS remains controversial.
Opioids, Peptides, and Endorphins
Opioid and neuropeptides receptors are found in nerve synapses of the brain and the gastrointestinal tract, and their suppression by morphine is known to alter the perception of pain. Endorphins are substances also found in the brain and in the pituitary gland that have opiate-like activity. Indeed, the endogenous opioid of the pituitary, fl-endorphin, has been described as the body's own analgesic, absence of which leads to symptoms sometimes described by PMS sufferers: cramping, craving for carbohydrates, insomnia, irritability, and nausea. This observation has led to the hypothesis that fl-endorphin deficiency may be the cause of PMS. If this is the case, then it is only likely to hold true for a minority subgroup of PMS because although lacrimation, diarrhea, and pupillary dilation are common in fl-endorphin deficiency, they are not common in PMS. On the other hand, PMS symptoms such as depression, breast swelling or tenderness, and weight gain are not common features of fl-endorphin withdrawal.
Depression is a commonly reported symptom of PMS. Monoamines, such as noradrenalin and serotonin, are known chemical mediators of mood. Monoamine oxidases (MAOs) and catechol-O-methyl transferase are enzymes that metabolize monoamines and thus decrease the amounts available for neural transmission. Their activity can be affected by the greater fluctuation in progesterone and oestrogen levels found in women with PMS compared with normal women.
Oestrogen suppresses MAO type A activity and increases MAO type B activity. While MAO type A enzymes are involved in the breakdown of adrenalin, noradrenalin, serotonin, and dopamine, MAO type B enzymes deactivate only dopamine. Thus suppression of type A and increase in type B enzyme activity results in excess serotonin, adrenaline, and noradrenalin and a relative deficiency of dopamine, a situation which may trigger anxiety and depression.
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