menopause The menopause is the term for the stage of life wherein a human female ceases to menstruate, and permanently loses the ability to have children. Strictly, menopause refers to the point at which a woman has not experienced a menstrual period for twelve months; the years of biological disturbances either side of this point are known as the 'perimenopause'.
The endocannabinoid system has a fundamental role to play in all aspects of female fertility, from initial fecundity, to implantation of the developing embryo into the endometrium, to delivery of endocannabinoids via breast milk. As well as all this, the EC system also has a vital role in the cessation of fertility.
What is the menopause?
Prior to the perimenopause, during a phase known as the premenopause, women typically begin to experience irregularities to their menstrual cycle, and levels of hormones begin to fluctuate. The premenopausal stage can last several years before the onset of perimenopause, and may begin to affect an individual as early as age thirty-five.
During postmenopause (the years after menopause), women experience overall lower levels of reproductive hormones, along with an increased propensity for urinary tract infections, weight gain, and various other health complications.
Symptoms of the perimenopause
During the perimenopause, which typically occurs between 45 and 55 years of age, various unpleasant and occasionally debilitating symptoms occur. These symptoms can be roughly divided into three types: vaginal/uterine; other physical; and psychological.
Vaginal/uterine symptoms include vaginal dryness, pain during intercourse, and atrophic vaginitis (a condition whereby the mucous membranes of the vagina, vulva and related tissues become thinner and lose elasticity).
Other physical symptoms include night sweats, heart palpitations, dizziness, headaches, stiffness, back pain, breast pain, urinary incontinence, night sweats, insomnia, and hot flashes. Psychological symptoms include anxiety, depression, lack of focus, memory problems, mood swings, and loss of libido.
Menopause and the endocannabinoid system
There is a relative abundance of research into the complex role the endocannabinoid system plays in female fertility in general, including in the onset of menopause. Existing research has demonstrated that various fundamental changes to the endocannabinoid system and related biological systems occur during the menopause transition.
Menopause carries with it an increased risk of osteoporosis, which is itself thought to be related to changes in EC-system function in the skeletal system. A 2011 study found that in the osteoclasts (cells responsible for resorbing bone) of postmenopausal women diagnosed with osteoporosis, an overexpression of CB2-receptors caused osteoclast overactivity, causing bone to be resorbed too quickly.
Menopause also affects the body’s sensitivity to insulin, and is known to cause insulin resistance (which can in turn lead to the development of diabetes type II) in a large proportion of postmenopausal women. Furthermore, a 2013 Canadian study found that in obese postmenopausal women, those that exhibited insulin resistance also demonstrated higher circulating levels of the endocannabinoid 2-AG in the blood, lower levels of anandamide, and elevated levels of CB1-receptor activity compared with subjects who exhibited insulin sensitivity.
The link between the endocannabinoid system, the menopause transition and the risk of weight gain deserves further investigation. An earlier study, conducted in 2005 in Germany, found that in postmenopausal women, obese subjects exhibited a significant increase in both anandamide and 2-AG compared with non-obese subjects. A corresponding reduction in levels of the endocannabinoid-degrading enzyme FAAH was also observed in obese women.
How genetic variations to the EC system affect menopause
There are also genetic elements controlling the function of the endocannabinoid system at key points in the female reproductive life cycle; research has demonstrated that individuals in possession of certain single-nucleotide polymorphisms (SNPs) differ in their physical response to menopause, in ways determined by the function of the EC system.
A 2010 study into postmenopausal women in Poland found that those in possession of a specific SNP, A3813G, of the gene encoding for expression of cannabinoid receptor type I rendered individuals more likely to experience increased android (central torso) fat deposits.
A 2011 study by the same Polish research team found that a different SNP, RS2023239, of the CNR1 gene may be associated with an increased ‘free androgen index’ in postmenopausal women in possession of it. Increased levels of free androgens (male reproductive hormones such as testosterone) may in turn be associated with an increased risk of cardiovascular disease.
How can cannabis help menopausal women?
The CB2-receptors of the osteoclasts are fundamentally involved with the development of osteoporosis, and it has been shown that SNPs in the CNR2 gene encoding for expression of CB2-receptors are strongly associated with the development of osteoporosis in postmenopausal women.
As well as this, it is also now known that CB1-receptors also have a role to play in the development of osteoporosis: a 2005 study on mice with inactivated CB1-receptors exhibited increased bone mass and were protected from ovariectomy-induced bone loss. Several studies have also shown that antagonists of the CB2-receptors decrease bone loss; thus, inactivation of the CB-receptors appears to be key to reducing the excessive rate of bone resorption that causes osteoporosis.
While limited research into the altered EC-system function in obese postmenopausal women does exist, there are apparently no specific studies into the ability of cannabinoids to control or reverse weight gain in such cases. However, in general terms, it appears that CB-receptor blockers are also key to managing this symptom.
Several studies have demonstrated that the synthetic selective inverse agonist of the CB1-receptor, rimonabant, is capable of causing weight loss in humans, but the drug has been withdrawn from the market due to the potential for serious psychiatric side-effects including suicide ideation.
However, prevalence of obesity in cannabis users is much lower than in the general population, a fact potentially attributable to a synergistic effect of THC combined with CBD; thus, non-synthetic medical cannabis may prove equally if not more effective than any synthetic cannabinoid, and presents far fewer potential side-effects.
Again, no specific studies into the ability of cannabis to ameliorate insomnia in menopausal women exist, but there are several studies attesting to the ability of various cannabinoids and synthetic cannabinoids including anandamide and the THC analogue Marinol to speed onset of sleep, improve restfulness of sleep and reduce likelihood of awaking mid-sleep, as outlined in this 2007 review.
There have been several studies into the relationship between the endocannabinoid system, insulin resistance, and the development of diabetes. It appears that blockers of the CB-receptors are key to managing insulin resistance, as CB2-knockout mice exhibit reduced insulin resistance, and CB1-receptor blockers have been repeatedly shown to mediate diet-induced insulin resistance.
Again, countless studies into the ability of cannabis and cannabinoids to manage pain have been published over the decades, with the general consensus appearing to be that CB-receptors agonists are more useful than blockers in the management of pain. Both CB1-receptor agonists such as anandamide and CB2-receptor agonists such as the synthetic AM1241 have been shown to exert an anti-nociceptive effect in cases of chronic pain.
The precise role of the EC system in mediating anxiety remains somewhat controversial, and appears to be dose-dependent. Low doses of CB-receptor agonists appear to induce a anxiolytic effect, while high doses exert the opposite effect. Furthermore, CB1-receptor inactivation or deletion appears to induce anxiogenic effects.
Loss of libido
The CB1-receptor inverse agonist AM251 has been shown to increase sexual motivation, proceptivity and receptivity in female rats, suggesting a possible role for CB1-receptor blockers in the treatment of loss of libido in human females.
Could cannabis worsen any of the symptoms of menopause?
Cannabis is certainly associated with xerostomia (dryness of the mouth); it has also been widely linked in the popular press to vaginal dryness, although it appears that there is in fact no basis for this claim. A 2009 study entitled ‘Cannabis and Sexual Health’ appears to be the basis, but on closer inspection it is apparent that the association between cannabis use and vaginal dryness was in fact too weak to reach statistical significance. Furthermore, the mechanism underlying vaginal lubrication differs in fundamental ways to salivation.
Indeed, there is evidence that cannabis can in fact enhance sexual arousal, which is more likely to have a beneficial than detrimental effect on the natural processes of vaginal lubrication.
Although the consensus on this is shaky, it does appear that cannabis can trigger acute cardiovascular events in susceptible individuals. It appears that agonists such as THC are more likely to be implicated in such events, and thus it may be advisable to avoid THC if suffering from heart palpitations, particularly if at risk from any pre-existing condition.
In general, it appears that CB-receptor blockers are more useful for the management of menopause-related disorders including osteoporosis, weight gain and loss of libido, whereas agonists such as THC are more useful in the management of pain, anxiety and insomnia.