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What You Should Know About Progesterone and PMS
Besides estrogen, progesterone is the other important ovarian hormone. It is needed to prepare the uterus for the implantation of fertilized eggs. Therefore, progesterone level is normally high during the luteal phase. However, there are indications that progesterone level is lower in women with PMS than in women free of the condition. This quickly leads to estrogen dominance and PMS symptoms during the luteal phase of the menstrual cycle. It follows than that progesterone therapy should help with PMS. But this conclusion has very little support from clinical trials. In what ways should progesterone help PMS? How weak is the evidence for progesterone therapy for PMS? Read on to find out.
by Brad Chase
Progesterone is a steroid hormone belonging to the class of hormones known as progestogens.
Progesterone is closely involved in the menstrual cycle, pregnancy and gestation. The level of progesterone rises during the latter stage of the menstrual cycle just before the start of menstrual flow. Its function then is to prepare the uterus for implantation of fertilized egg by thickening the uterine walls.
Depending on the physiological state of a woman, progesterone can be produced in the ovaries, adrenal gland and/or placenta.
As a female hormone, progesterone balances estrogen. This means that it both complements and counteracts the effects of estrogen.
In fact, the activities of progesterone are enhanced in the presence of estrogen. In addition, estrogen increases the number of progesterone receptors present.
However, the role of progesterone in the body is not restricted to female reproductive health.
Progesterone and some of its metabolites are neuroactive steroids or neurosteroids. When produced in the central nervous system, progesterone is further metabolized to allopregnanolone, an important neurosteroid.
As neurosteroids, progesterone and allopregnanolone are neuroprotective agents. Besides protecting the neurons in the brain, they also improve synaptic functions and the myelination of nerve fibers.
Therefore, progesterone may improve memory and cognitive performance. In addition, it may also function as a mood stabilizer.
The effect of progesterone on the central nervous system is one of the reasons why it is believed to help with PMS symptoms.
Because the core emotional-type PMS symptoms are caused by the interaction between ovarian hormones and neurotransmitters, some experts believe that it is possible to treat PMS with progesterone.
At most times, the level of progesterone in the blood is higher than the blood level of estrogen. This is most likely because progesterone serves as a precursor to a number of hormones include estrogen.
Other hormones synthesized from progesterone are testosterone, cortisol and aldosterone.
Before ovulation, the concentration of progesterone in the blood is less than 1 nanogram per milliliter (ng/ml).
However, as ovulation starts, the production of progesterone shoots up. In the luteal phase, the level of progesterone is 20 ng/ml. Sometimes, blood progesterone level can reach 140 times the level of estrogen. In this phase and at this concentration, progesterone functions purely as an antagonist to estrogen.
A high progesterone level is required to prepare the uterine wall for fertilized egg. When no fertilized egg is implanted after a while, the level of progesterone falls rapidly and menstrual flow begins.
However, studies show that this pattern of progesterone rise and decline differs in women with PMS.
Specifically, progesterone level never rises to optimal levels during the luteal phase in PMS. This quickly results in estrogen dominance rather than progesterone dominance.
When the blood level of progesterone falls, it creates a hormonal profile that is not right for the luteal phase. In addition, all the benefits of high progesterone level at that point in the menstrual cycle are lost.
With no progesterone to hold back the estrogen dominance, the symptoms of PMS quickly develops.
The physiological effects of progesterone in the body suggest that it can help with PMS symptoms.
For example, progesterone is a muscle relaxant. In fact, it is commonly given to pregnant women to delay labor and preterm birth. This suggests that progesterone reduces uterine contraction. Therefore, it can help reduce cramps associated with PMS.
In addition, the anti-inflammatory effect of progesterone may help reduce PMS-related swelling.
By inhibiting prolactin and preventing breast development and milk production, progesterone can also relieve the breast tenderness felt by women with PMS.
Furthermore, progesterone can prevent fluid retention. Progesterone is a potent diuretic and it acts by blocking aldosterone, an adrenal hormone that promotes the retention of sodium and water.
This means that progesterone can reduce extracellular fluid volume. In this way, it can reduce PMS-related water weight and swelling.
In fact, studies show that the drop in progesterone level during the luteal phase in women with PMS triggers a condition known as progesterone withdrawal. Progesterone withdrawal is a compensatory mechanism and it encourages the body to hoard sodium and water through the release of aldosterone.
Lastly, progesterone can relieve PMS symptoms by serving as a neurosteroid with a neuroprotective role.
Studies show that progesterone can be synthesized in the brain. It has an antioxidant property and it can also help protect the brain from edema resulting from injury.
In addition, progesterone is used in the brain to produce allopregnanolone, another important neurosteroid. Allopregnanolone binds to GABA-A (gamma aminobutyric acid-A) receptors to reduce anxiety and improve synaptic activity.
Therefore, progesterone may help reduce some of the emotional-type symptoms of PMS.
Even though all evidence indicates that certain PMS symptoms can be relieved by simply raising progesterone level, there is precious little evidence to support that view.
In fact, the relationships between progesterone, estrogen, other hormones, neurotransmitters and PMS symptoms are so complex that it is quite possible to worsen PMS with progesterone therapy.
It does not help that bioavailability of the hormone from oral and topical progesterone products is low and unpredictable.
In a 2012 article published in the medical journal, Menopause International, a leading expert and professor of obstetrics and gynecology discussed the incidence of premenstrual disorders induced by progesterone in clinical settings.
The author mentioned the role of progesterone in hormonal therapy and how it is commonly recommended in the treatment of endometriosis and heavy menstrual bleeding.
Progesterone is usually given in the form of combined oral contraceptives, progestogen-only contraceptives or direct progestogen therapy. However, such medications can cause or worsen PMS-like symptoms. Even then the author stated the importance of progesterone for protecting the lining of the uterus from the actions of estrogen.
In his recommendation, the author warned that doctors should look out for progesterone-induced PMS and manage it accordingly.
Progesterone is believed to improve mood and cognitive functioning by stimulating the synthesis of allopregnanolone. However, allopregnanolone can have contradictory effects.
For example, this progesterone metabolite can sometimes cause anxiety and reduce anxiety at other times.
A 2006 study published in the journal, Pyschopharmacology, investigated the effect of allopregnanolone concentration on mood in women with menopausal problems.
For the study, the researchers recruited 43 postmenopausal women and gave each of them 2 mg/day of estradiol for 4 treatment cycles. In addition, the participants received one of placebo, 30, 60 and 200 mg/day of oral micronized progesterone.
The results of the study showed that progesterone was only effective for improving mood at particular concentrations. In addition, its effect on mood was even worse than that of estrogen.
Even though this study investigated the effect of progesterone on menopause, its results give an indication of the unpredictable nature of oral progesterone therapy for PMS.
The conclusions of a 2003 published in the journal, Biological Psychiatry, partly explained the failure of progesterone therapy for PMS. The researchers studied the effect of progesterone on GABA-A receptors in the motor cortex with a technique known as TMS (transcranial magnetic stimulation).
The researchers recruited 9 women with PMS and 14 matched women without PMS to serve as control.
After conditioning the women to the TMS technique, the researchers measured brain responses due to the action of progesterone on the GABA-A receptor.
The results showed that both groups responded in the same way during the follicular phase of the menstrual cycle. However, there was a greater inhibition of GABA receptor during the luteal phase among the control subjects than among women with PMS.
The researchers, therefore, concluded that there was abnormal brain response to progesterone during PMS.
This abnormal response may explain why progesterone therapy is not effective for improving PMS symptoms even though there is every indication that it should.
A 2001 review published in the British Medical Journal analyzed the results of past studies that have investigated the efficacy of progesterone and progestogens in the management of PMS.
The reviewers selected 10 clinical trials involving progesterone (suppositories and oral micronized forms) and 4 trials involving progestogens. Overall, the review involved over 900 women.
In their conclusion, the reviewers found that their meta-analyses showed that progesterone and progestogen therapies performed no better than placebos. Therefore, they found no clinical support for the use of progesterone and progestogens in the management of PMS.
More than 10 years later, another review from the Cochrane Collaboration did not show that a decade of more research has found clear benefits for progesterone in the treatment of PMS.
Although this Cochrane review searched from a broader pool of clinical studies, only 2 studies met the Cochrane review criteria for randomized, double-blind and placebo-controlled trials. Even then the 2 studies differed some much in methodology and doses of progesterone that the reviewers could not combine them for their analysis.
One of the studies that made the final cut found that progesterone performed better than placebo in the management of PMS symptoms.
However, the other study found that there was no difference between placebo, oral progesterone and vaginally inserted progesterone in the treatment of PMS.
Therefore, the reviewers concluded that the evidence did not support or refute the benefits of progesterone for PMS.
In addition, the researchers found that neither study investigated the possibility that certain women may benefit from progesterone or investigated claims that higher doses are needed for progesterone to improve PMS symptoms.
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