Author: Gianpiero Pescarmona
Calcium-regulating hormones across the menstrual cycle: evidence of a secondary hyperparathyroidism in women with PMS. 1995
Premenstrual syndrome (PMS) (also called PMT or premenstrual tension) is a collection of physical and emotional symptoms related to a woman's menstrual cycle, symptoms which affect millions of women during their reproductive years.
While most women of child-bearing age (up to 85%) report having experienced physical symptoms related to normal ovulatory function, such as bloating or breast tenderness, medical definitions of PMS are limited to a consistent pattern of emotional and physical symptoms occurring during the luteal phase of the menstrual cycle that interfere with some aspects of normal life. These specific emotional and physical symptoms begin between the ages of 25 and 35 years and vary from woman to woman, but each individual woman's pattern of symptoms is predictable, occurs consistently during the ten days prior to menses, and vanishes either shortly before or shortly after the start of menstrual flow. Two to ten percent of women have significant premenstrual symptoms that are separate from the normal discomfort associated with menstruation in healthy women. Premenstrual dysphoric disorder (PMDD) consists of symptoms are similar to, but more severe than PMS; it's classified as a repeating transitory cyclic disorder with similarities to unipolar depression, and as therapy several antidepressants are approved.
More than 200 symptoms have been associated with PMS, but irritability, tension, and dysphoria are the most prominent. Headache, often of migrainous type, is one of physical symptoms often reported in the diagnostic criteria for PMS. Menstrual migraine is a particular subtype of migraine occurring within the 2 days before and the 3 days after the onset of menses; studies have confirmed the correlation between these two conditions and provide indications for the treatment of MM. Triptans are the gold standard for the acute treatment. Non-steroidal anti-inflammatory drugs have been demonstrated effective in MM prophylaxis. Among natural products there is some evidence of efficacy for magnesium, phytoestrogens and ginkgolide B . The magnesium deficit is one of the components of the pathogenesis of premenstrual disorders. Hypomagnesaemia is a reason of the polymorphism of clinical presentation, structural and functional disorders of nervous system and development of psychopathological constituent of premenstrual disorders in clinics. Ginkgolide B is a herbal constituent extracted from leaves of the ginkgo biloba tree. Studies have shown that ginkgolide B is a specific platelet activating factor (PAF) receptor antagonist, and it suppresses PAF-mediated platelet activation via competitive binding.
The etiology of PMS remains unknown and this syndrome is complex and multifactorial. Although the role of ovarian hormones is unclear, the symptoms of the premenstrual disorders are related to the production of progesterone by the ovary. Infact some evidence suggests that the disorder is related to enhanced sensitivity to progesterone in women with underlying serotonin deficiency.
Progesterone also known as P4 (pregn-4-ene-3,20-dione) is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy (supports gestation) and embryogenesis of humans and other species. In animals progesterone is produced in the ovaries (by the corpus luteum), in the adrenal glands and, during pregnancy, in the placenta. Progesterone is also stored in adipose (fat) tissue. In women, progesterone levels are relatively low during the preovulatory phase of the menstrual cycle, rise after ovulation, and are elevated during the luteal phase. If pregnancy occurs, human chorionic gonadotropin is released maintaining the corpus leuteum allowing it to maintain levels of progesterone. At around 12 weeks the placenta begins to produce progesterone in place of the corpus leuteum and it utilizes maternal cholesterol as the initial substrate.
The most important neurotransmitter systems implicated in the genesis of the PMS symptoms are the GABArgic and the serotonergic systems. Metabolites of progesterone formed by the corpus luteum of the ovary and in the brain bind to a neurosteroid-binding site on the membrane of the gamma-aminobutyric acid (GABA) receptor, changing its configuration, rendering it resistant to further activation and finally decreasing central GABA-mediated inhibition. By a similar mechanism, the progestogens in some hormonal contraceptives are also thought to adversely affect the GABAergic system. The lowering of serotonin can produce PMS-like symptoms and serotonergic functioning seems to be deficient in the brain; accordingly, agents that augment serotonin are efficacious and are as effective even if administered only in the luteal phase. However PMS is ultimately not likely to be related to the dysregulation of individual neurotransmitters. Infact brain imaging studies are beginning to focus attention on the complex brain circuitry underlying affect and behaviour.
As PMS is essentially the result of cyclical ovarian activity, usually ovulation, an effective treatment should inhibit ovulation. This can be done by an oral contraceptive but as these women are progestogen intolerant the symptoms may persist becoming constant rather than cyclical. Alternatively, transdermal estradiol by patch, gel or implant effectively removes the cyclical hormonal changes, which produce the cyclical symptoms. Gonadotropin-releasing hormone is effective in the short term. In the end laparoscopic hysterectomy and bilateral oophorectomy with adequate replacement of estrogen and testosterone should be considered in the severe cases with progestogenic side-effects.
Serotonin is a monoamine neurotransmitter, biochemically derived from tryptophan, which is primarily found in the gastrointestinal (GI) tract, platelets, and in the central nervous system (CNS) of animals including humans, where it has various functions. These include the regulation of mood, appetite, and sleep. Serotonin also has some cognitive functions, including memory and learning. Modulation of serotonin at synapses is thought to be a major action of several classes of pharmacological antidepressants. Selective serotonin re-uptake inhibitors have well-established efficacy for severe premenstrual syndrome and premenstrual dysphoric disorder. Efficacy has been reported with both continuous dosing (all cycle) and intermittent or luteal phase dosing (from ovulation to menses). Anxiolytics, calcium, chasteberry and cognitive-behaviour therapy may also have a role in the treatment of premenstrual symptoms.
Recent studies in rats indicate that levels of glutamate spikes prior to menstruation in the cortex and hippocampus. High glutamate levels have been tied to mood disorders in several studies. Other studies suggest that up to 40% of women with PMS symptoms have a significant decline in their circulating serum levels of beta-endorphin. Beta endorphin is a naturally occurring opioid neurotransmitter which has an affinity for the same receptor that is accessed by heroin and other opiates. Some researchers have noted similarities in symptom presentation between PMS symptoms and opiate withdrawal symptoms. On other study has shown in women with PMS elevated levels of serum pseudocholinesterase. This enzyme is considered a possible marker for trait-anxiety.
Calcium, magnesium, and other elements were studied in the red blood cells and hair of normals and patients with premenstrual syndrome. Significantly lower amounts of calcium, chromium, copper, and manganese were found in the blood of patients with PMS. The significantly lower blood cell calcium level found in these studies may provide additional evidence that PMS may be related to a calcium-deficiency state or a metabolic defect involving calcium.
Dietary restrictions and exercise may also be useful in patients with PMS. Sodium restriction has been proposed to minimize bloating, fluid retention, and breast swelling and tenderness. Caffeine restriction is recommended because of the association between caffeine and premenstrual irritability and insomnia. In epidemiologic and short-term prospective studies, women with PMS who practiced aerobic exercise reported fewer symptoms than control subjects. Dietary supplements that have been evaluated in women with PMS include vitamins (A, E, and B6), calcium, magnesium, multivitamin/mineral supplements, and evening primrose oil.
Poor-quality studies suggest that vitamin B6 use is beneficial in premenstrual syndrome. In nine randomized, controlled clinical trials of vitamin B6 as a single supplement or in a multivitamin, improvement of symptoms was reported, but the poor quality of the trials limits their usefulness. Vitamin E supplementation is a recognized treatment for mastalgia. Supplements of calcium carbonate in a dosage of 1,200 mg per day for three menstrual cycles resulted in symptom improvement. Magnesium in a dosage of 200 to 400 mg per day has shown minimal benefit in alleviating bloating. Evening primrose oil, a prostaglandin precursor, has been studied in women with PMS, and mild relief has been demonstrated in women with breast tenderness.
High dietary intake of vitamin D may reduce the risk of premenstrual syndrome (PMS), perhaps by affecting calcium levels, cyclic sex steroid hormone fluctuations, and/or neurotransmitter function. Between 2006 and 2008, 186 women aged 18-30 (mean age=21.6 years) completed a validated food frequency questionnaire, additional questionnaires to assess menstrual symptoms and other health and lifestyle factors, and provided a fasting blood sample collected during the late luteal phase of their menstrual cycle. Results suggested the possibility of an inverse association between intake of vitamin D from food sources and overall menstrual symptom severity, though were not statistically significant. From among all study participants, 44 women meeting standard criteria for PMS and 46 women meeting control criteria were included in additional case-control analyses. In these women higher intake of vitamin D from foods was associated with a significant lower prevalence of PMS. Late luteal phase 25-hydroxyvitamin D3 levels were not associated with prevalent PMS. Results from this pilot study suggest that a relationship between vitamin D and PMS is possible. This review indicates a possible biochemical mechanism occurring between vitamin D and mood disorders affecting women.
Vitex agnus-castus L. (chaste tree; chasteberry) is a popular herbal treatment used for a range of female reproductive conditions in the North of America and Europe. Trials were conducted to demonstrate the efficacy and safety of Vitex extracts. Eight of them were conducted to investigated premenstrual syndrome, two premenstrual dysphoric disorder and two latent hyperprolactinaemia. For premenstrual syndrome, seven of eight trials found Vitex extracts to be superior to placebo (5 of 6 studies), pyridoxine (1), and magnesium oxide (1). In premenstrual dysphoric disorder, one study reported Vitex to be equivalent to fluoxetine, while in the other, fluoxetine outperformed Vitex. Fluoxetine (also known by the trade names Prozac, Sarafem, Fontex, among others) is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class and it is frequently used to treat major depression, obsessive compulsive disorder,bulimia nervosa, panic disorder, body dysmorphic disorder, premenstrual dysphoric disorder. Adverse events with Vitex were mild and generally infrequent. Despite some methodological limitations, the results from randomised, controlled trials to date suggest benefits for Vitex extracts in the treatment of premenstrual syndrome, premenstrual dysphoric disorder and latent hyperprolactinaemia. The mechanism of action of Vitex Agnus-castus is not fully understood; it has dopaminergic effects resulting in changes of prolactin secretion. At low doses, it inhibits activation of dopamine 2 receptor by competitive binding, causing a slight increase in release of prolactin; in higher concentrations the binding activity is sufficient to reduce the release of prolactin. A decrease of prolactin will influence levels of Follicle-stimulating hormone (FSH) and estrogen in women and testosterone in men. Dopaminergic compounds present in Vitex agnus castus seem likely to be the clinically important compounds which improve premenstrual mastodynia and possibly also psycho-somatic symptoms of PMS.
Also the Olea europea, the olive tree, an ancient tree that originates from the Mediterranean environment of Asia Minor has an important role in the treatment of premenstrual symptoms; the edible olive fruit is a nutrient with proven beneficial effects due to biophenols and squalenes (oleocanthal, tyrosol, hydroxytyrosol, oleuropein) it contains. They provide an exceptional antioxidative activity, removing harmful compounds from the body. Oxidants are essential in the genesis of many diseases and conditions, such as cardiovascular disorders, cancer, osteoporosis, Alzheimer disease, and premenstrual syndrome.
Nonpharmacologic measures should be monitored at least every three months. If symptoms are not adequately relieved, the addition of pharmacologic treatment should be considered.
Nonpharmacologic management with some evidence for efficacy includes cognitive behavioral relaxation therapy, aerobic exercise, as well as calcium, magnesium, vitamin B(6) L-tryptophan supplementation or a complex carbohydrate drink.
Pharmacologic management includes selective serotonin reuptake inhibitors administered daily or premenstrually and serotonergic tricyclic antidepressant; anxiolytics and potassium sparing diuretics have demonstrated mixed results in the literature. Hormonal therapy is geared towards producing anovulation. There is good clinical evidence for GnRH analogs with addback hormonal therapy, danocrine, and estradiol implants or patches with progestin to protect the endometrium. Oral contraceptive pills prevent ovulation and should be effective for the treatment of PMS/PMDD. There is preliminary evidence that a new oral contraceptive pill containing low-dose estrogen and the progestin drospirenone, a spironolactone analog, instead of a 19-nortestosterone derivative can reduce symptoms of water retention and other side effects related to estrogen excess.