MEDICAL RESEARCH

NATURAL PROGESTERONE
 
In her book “Once a Month: Understanding and Treating PMS”, Katharina Dalton advocates treatment of PMS with progesterone (sex hormone) during the luteal phase (last 14 days of cycle before menstruation). She asserted that the cause of PMS in certain women was that they didn’t produce enough progesterone during their luteal phase. One site I found said Dalton prescribed 400-1600mg progesterone daily plus 50-200mg of Vitamin B6. However many scientific studies have failed to find any evidence of progesterone’s efficacy and this treatment is now out-dated.

Research on progesterone:

http://www.psychosomaticmedicine.org/cgi/content/full/61/5/676
Actions of progesterone on the body
 
You can buy progesterone creams on the internet. Progesterone can be synthesized from Wild Yam extract but Wild Yam creams do not contain progesterone, unless it has been manufactured and added separately to the cream. These creams are expensive so if you do want to try natural progesterone I would recommend buying it from a reliable source, i.e. your doctor or checking the progesterone content of the cream.

Women don't produce more than 30mg of progesterone a day so it is frustrating that the dose of progesterone, in the form of pessaries, is so high (200mg for Cyclogest). They don't manufacture a lower dose but it is possible to chop the Cyclogest up, however this makes it difficult to insert, and it's difficult to chop them into 4 pieces. Perhaps progesterone creams are better as less progesterone would be absorbed that way so perhaps they would be less sedating. However I still had wild mood swings on the progesterone and there is still no evidence that it helps in PMS. Possibly it works better in combination with oestrogen which increases serotonin (important for mood).

http://www.medicinescomplete.com/mc/bnf/current/PHP4486-progestogens-and-progesterone-receptor-modulators.htm
http://en.wikipedia.org/wiki/Progesterone  
http://www.npis.info/basicprogesterone.htm
http://www.jfponline.com/Pages.asp?AID=1117
http://www.drkaslow.com/html/progesterone.html

This is a good progesterone cream

NEUROTRANSMITTERS
 
Our impulses and emotions are controlled by the passing of electrical signals between neurons (nerve cells) in the brain. Neurons are made up of a cell body, an axon and numerous long dendrites. Electrical signals travel along the dendrites (which are like electrical cables), through the cell body and down the axon. However there is a small gap between the axon of each neuron and the dentrites of neighbouring neurons which the electrical signal needs to cross somehow. This gap is called the synapse. Certain chemicals called neurotransmitters act as chemical messengers which transport signals between the axon of one neuron and the dentrite of another. The surfaces of the neuron cells have sites called receptors which neurotransmitters bind to. Receptor sites can only receive specific types of neurotransmitters. Some examples of neurotransmitters are serotonin, dopamine, GABA and noradrenaline. After the neurotransmitter has attached to a receptor site (and passed on it's chemical message), it releases from the receptor site and floats back into the synapse. Two things can then happen to the neurotransmitter. Either it is broken down by enzymes called monoamine oxidase or it may be sucked back into the synapse that released it.

For further information about the role of specific neurotransmitters on mood and behavior see the following sites:
http://www.benbest.com/science/anatmind/anatmd10.html
http://themedicalbiochemistrypage.org/steroid-hormones.php
http://themedicalbiochemistrypage.org/nerves.php
 
SSRI anti-depressants, such as Prozac/Sarafem, inhibit the re-uptake of serotonin by the axons, and so serotonin builds up in the synapse. MAOI or monoamine oxidase inhibitors are another class of anti-depressants which destroy the enzyme monoamine oxidase so that levels of certain neurotransmitters (serotonin, norepinephrine, and dopamine) build up in the synapse without being destroyed.

Certain hormones which are synthesised in the brain are called neurosteroids. It is becoming clear that neurosteroids can have a profound affect on neuron receptor function. For instance the neurosteroid allopregnanolone, which is derived from progesterone, binds to GABA-A receptors in the brain and enhances their function.

MEDICAL RESEARCH

Some research seems to suggest that women with PMDD either have low levels of, or have an abnormal sensitivity to, fluctuations of the neurosteroid allopregnanolone.

Role of allopregnanolone in PMS ?
Allopregnanolone levels and alcohol 
Anxiolytic effect of progesterone 
Discusses role of neurotransmitters in PMDD, excerpt from a book
E2 and SHBG different in PMDD women
Low dose 2mg of Prozac can increase allopregnanalone levels

Prozac, SSRI's and allopregnanolone:
http://www.sciencedaily.com/releases/1999/11/991110061714.htm
Allopregnanolone supresses sexual behaviour and ovulation
Gonadotrophin releasing_hormone
Dysregulation of the g-aminobutyric acidA/benzodiazepine receptor complex for PMDD
Talks about action of neurosteroids on GABA-A receptors
http://ajp.psychiatryonline.org/article.aspx?articleID=1566973 ?

Researchers on PMDD:

Research by Medello,M.D.
Research by Alessandro Guidotti, M.D.
Research by T Backstrom, M.D.

SSRI'S AND DEPRESSION
 
5HT (serotonin) increases neurogenesis (process of generating new brain cells) and starting this process is thought to be how anti-depressants treat depression. This process takes several weeks though and is clearly not the same process by which SSRI's treat PMS symptoms therefore, and so possibly Prozac's efficacy in treating PMS is not soley to do with serotonin. This is further evidence for allopregnanolone or some other neurochemicals being involved. A doctor suggested to me that an increase in serotonin causes an increase in allopregnanolone? 
http://www.biopsychiatry.com/newbraincell/

Interesting paper on PMDD and PMS
Conclusion from this paper: These data strongly suggest that the GABAergic system is substantially modulated by menstrual cycle phase in healthy women and those with PMDD. Furthermore, they raise the possibility of disturbances in cortical GABA neuronal function and modulation by neuroactive steroids as potentially important contributors to the pathogenesis of PMDD.

NATURAL OESTROGEN
 
The basis behind HRT treatment, with oestrogen, is that fluctuations in oestrogen levels cause fluctuations in serotonin levels in the brain. Serotonin is linked to mood. With the dose of oestrogen given in HRT, the aim is to suppress the natural hormone cycle - to stop your natural oestrogen cycling up and down, and therefore to stop serotonin level fluctuating. So both GABA and serotonin seem to be implicated in PMS. I also take testosterone which influences dopamine levels. Dopamine affects concentration, energy and alertness.
 
TESTOSTERONE

All about testosterone

ENVIRONMENTAL OESTROGENS
 
It may be wise to avoid xenoestrogens: alky phenols in detergents, and methyl paraben, propyl paraben, and butyl paraben found in most skin care products as these can be absorbed by the body.
DO NOT store food in clingfilm or soft plastic and do not cook it in plastic containers.

SUPPLEMENTS THAT MAY AFFECT BRAIN NEUROTRANSMITTER LEVELS

Article on how amino acids and diet can affect mood
(suggests bananas, pecan nuts, rice & beans contain more tryptophan than meat.

GABA:
"GABA (Gamma-aminobutyric acid) is the number one inhibitory (calming) neurotransmitter in the brain. Its function is to decrease neuron activity and inhibit nerve cells from over-firing. GABA supports the brain against stress-related messages from reaching the motor centers of the brain by occupying their receptor sites. Together with L-theanine, GABA supports relaxation without compromising cognitive function.
Research with human volunteers has demonstrated that L-theanine creates its relaxing effect in approximately 30 to 40 minutes after ingestion. The mechanism behind this effect is two-fold:
1) L-theanine directly stimulates production of alpha brain waves, which creates a deep state of relaxation while maintaining mental alertness.
2) L-theanine appears to play a role in the formation of gamma-aminobutyric acid, better known as GABA. GABA acts as a powerful inhibitor of neurotransmitters and helps maintain relaxed levels of neuron activity."
From: http://www.l-theanine.com/intro.htm
L-Theanine may also increase serotonin so is worth trying for PMDD.

Serotonin:
"Tryptophan is still available by prescription. Oddly enough, less is more, with lower doses (one to three gm) more effective than higher doses. Taking the amino acid with carbohydrates helps in its absorption.

Also magnesium, zinc and vitamin B6 are cofactors in serotonin synthesis.
Serotonin synthesis is a 2-step process, the first step of which requires the enzyme tryptophan hydroxylase with oxygen, iron and THB as co-factors. Neither the enzyme nor the co-factors are rate-limiting for either step of these reactions -- virtually all brain tryptophan is converted to serotonin. Serotonin concentration in the brain is far more sensitive to the effects of diet than any other monoamine neurotransmitter -- and can be increased up to 10-fold by dietary supplementation in laboratory animals.
Consumption of a meal that is high in carbohydrate, branch-chained amino acids and tryptophan has a particularly dramatic effect because both glucose from carbohydrate and branch-chained amino acids (especially leucine) increase insulin secretion. Insulin facilitates the transport of the branch-chained amino acids into muscle cells, thereby reducing the competition tryptophan faces for the large neutral amino acid transporter that takes it across the blood-brain barrier. The resultant drowsiness induced by serotonin is a common effect of a large carbohydrate meal. "
From: http://www.benbest.com/science/anatmind/anatmd10.html
L-tryptophan or 5-HTP are pre-cursors to serotonin and have fewer side-effects than SSRI's. You may experience nausea or drowsiness when you first start taking L-tryptophan but apparently this disappears after a week or so..
More about serotonin

This (rather expensive!) supplement by Patrick Holford contains L-Theanine and L-tryptophan (i felt quite stoned/dopey when i tried it, it's quite strong so start on a lower dose than he suggests), or try the amino acids individually at lower doses.

POSSIBLE FUTURE TREATMENTS

Pheromone nasalspray
Vomeropherins (or pheromones)
Pharm company who are researching pheromones
Umercrine Mood

Ganaxolone:
"Ganaxolone (3alpha-hydroxy-3beta-methyl-5alpha-pregnane-20-one), an orally active synthetic analog of the neuroactive steroid allopregnanolone, is a positive allosteric modulator of gamma-aminobutyric acid(A) receptors with anti-convulsant properties."

Company researching Ganaxolone (note Ganaxolone had undergone Phase 1 trials with a different company 10 years ago, they got taken over, and i thought the research had ended. Picamilon may be a safer alternative to this drug for PMDD, however.
http://www.ncbi.nlm.nih.gov/pubmed/17199022
http://journals.prous.com/journals/servlet/xmlxsl/pk_journals.xml_summary_pr?p_JournalId=2&p_RefId=793135&p_IsPs=N

Other anxiolytic drugs:
http://jpet.aspetjournals.org/cgi/content/full/295/1/337 (Co 2-67 49)
http://jpet.aspetjournals.org/cgi/content/full/293/3/1084

MIGRAINES

A lot of women suffer from migraines during there menses - called menstrual migraine.
Webpage on migraines
Hypnosis has been trialed by the Migraine Trust in London and found to be useful, see link:
Hypnosis for migraine

FURTHER LINKS ON NEUROSTEROIDS
 
Serum steroids and PMS
Neurosteroids prevent development of tolerance and aid recovery from benzos
Allopregnanolone affects sleep in tranquiliser-like fashion
Role of allopregnanolone in epilepsy
Allopregnanolone and DHEA role in depression
Preserving brain function
On GABA and anaesthetics (not that relevant really)
On GABA (neuroscience)
Role of 5HT in depression
Further multiple links on allopregnanolone
Allopregnanolone and GABA receptors
GABA and migraines (research)
Etiology of PMS, mentions other hormone systems