Autoimmune Thyroid Disease

An Unfortunate and Lengthy Adventure in Misdiagnosis

Monoamine oxidase and oestrogen

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Why are women more prone to depression and mood disorders than men? And why do more women than men seem to suffer from food chemical related disorders, especially fibromyalgia?

Depressive disorders in women are commonly associated with reproductive events. This association may be due in part to the changing balance between estrogen, progesterone, and other hormones that affect neurotransmitter function throughout a woman’s lifecycle. […] Some data suggest that depression in women tends to respond differently to antidepressant treatment than depression in men, underscoring the need to examine the risk and treatment of depressive disorders in males and females separately. Women have benefited considerably from serotonin reuptake inhibitor anti-depressants that are currently available. These agents appear to be more effective than the older tricyclic antidepressants in treating various depressive disorders that occur commonly or exclusively in women. Additionally, serotonin reuptake inhibitors have increased tolerability in women, who generally experience more adverse effects from tricyclics and monoamine oxidase inhibitors than do men. Estrogen appears to enhance antidepressant response in postmenopausal women receiving estrogen replacement therapy. Special issues related to the treatment of depression in women.

Women have worse responses to monoamine oxidase inhibitors than men do? Why would that be? After all, it’s men who only have one copy of the MAO gene – which resides on the X chromosome.

Estrogen replacement treatment in menopausal women has been reported to have a positive effect on mood states. However, the addition of a progestin partially negates this positive effect in some women. The opposite effects of estrogen and progestin on mood may relate to their opposite effects on adrenergic and serotonergic neural function. In a double-blind, placebo-controlled, crossover study, 38 nondepressed menopausal women were cyclically treated with estrogen and estrogen plus progestin, or with placebo, for five 28-day cycles. This paper identifies the pretreatment attributes of women who do and do not have negative mood responses to progestin, and examines the relationship of these adverse side-effects to platelet monoamine oxidase (MAO), a marker of adrenergic and serotonergic functioning. Adverse mood responses to progestin occur in women with a long duration of menopause, low pretreatment serum estradiol and testosterone levels, high pretreatment serum FSH levels, low pretreatment platelet MAO activity, and pretreatment mood abnormalities. We conclude that adverse mood response to the addition of a progestin occurs in menopausal women who have low pretreatment gonadal hormone levels secondary to a long duration of menopause. Impaired central nervous system adrenergic and serotonergic functioning also may be a factor predisposing to a negative mood response to progestin. Individual differences in changes in mood and platelet monoamine oxidase (MAO) activity during hormonal replacement therapy in menopausal women.

In this case the above study finds that oestrogen decreases monoamine oxidase expression, and progesterone increases monoamine oxidase expression. Hence in these depressed women, decreasing monoamine oxidase activity with oestrogen (effectively giving them an MAOI), elevated their mood. More of the same:

the expression of several genes associated with embryo implantation (i.e. thrombomodulin, monoamine oxidase A, SPARC-like 1) can be induced by P[rogesterone] in vitro Progesterone regulation of implantation-related genes: new insights into the role of oestrogen.

It had previously been reported that estrogen treatment in menopausal women had a positive effect on mood, whereas the combination of estrogen plus a progestin had a negative effect on mood. We found that the women with a long duration of menopause and higher treatment serum estradiol levels had significantly more dysphoria when receiving a combination of estrogen plus progestin than did the women with a short duration of menopause and lower serum estradiol levels. However, both short and long duration menopausal groups showed improvement in mood when estrogen was administered alone. Platelet MAO levels, a marker of adrenergic and serotonergic function thought to relate to mood, were negatively correlated with serum estradiol levels during HRT. We suggest that these paradoxical findings may be secondary to a prolonged estrogen deficiency state in women with a long duration of menopause. Relationships of serum estradiol levels, menopausal duration, and mood during hormonal replacement therapy.

Of course if you have the kind of depressed monoamine oxidase activity that leads to food chemical intolerance, oestrogen is the last thing you need. When I first started to get more severe symptoms (during and shortly after coming off the pill), one of my theories was that I had ‘progesterone deficiency’ – a condition that exists only in alternative medicine. In mainstream medicine, you only have a deficiency or an excess of female hormones if your period has either stopped or your bleeding is abnormally heavy. So when I suggested progesterone deficiency to my (female) doctor at the time, she laughed at me and said hormonal problems were always caused by oestrogen deficiency, and the cure was the pill. Which fortunately I couldn’t take anymore as it had put me in hospital with deep vein thrombosis.

My cycle has always been as regular as clockwork. The pill did change my period – I never used to spot during the week before I was due. It’s only during the last few months that this after-effect of the pill has gone away and I stopped using the pill something like five years or more ago. Apparently some effects of the pill, including loss of sex drive and hormonal changes, can last up to ten years after the pill is discontinued. It’s no wonder so many women have problems getting pregnant these days!

Though I haven’t had my hormone levels tested, I’m fairly sure I have high oestrogen levels. I’m an hourglass shape and have a DD cup size, something that runs in my family. My grandmother had oestrogen-dependent breast cancer. At the time I started to get anxious about post-pill symptoms, progesterone deficiency fitted a lot of my symptoms. Of course I was on warfarin at the same time. Now it turns out that progesterone would have done me some good, by raising my MAO levels. I wonder how many other women with low MAO levels are out there thinking along the same lines as I did about progesterone deficiency?

But of course it’s always a bit more complicated than a simple inverse correlation between oestrogen and MAO:

The serotonin neural system plays a pivotal role in mood, affective regulation and integrative cognition, as well as numerous autonomic functions. We have shown that ovarian steroids alter the expression of several genes in the dorsal raphe of macaques, which may increase serotonin synthesis and decrease serotonin autoinhibition. Another control point in aminergic neurotransmission involves degradation by MAO. This enzyme occurs in two isoforms, A and B, which have different substrate preferences. […] MAO-A and -B mRNAs were detected in the dorsal raphe nucleus (DRN) and in the hypothalamic suprachiasmatic nucleus (SCN), preoptic area (POA), paraventricular nucleus (PVN), supraoptic nucleus (SON), lateral hypothalamus (LH) and ventromedial nucleus (VMN). MAO-A mRNA optical density was significantly decreased by E, P, and E+P in the DRN and in the hypothalamic PVN, LH and VMN. Ovarian hormones had no effect on MAO-B mRNA expression in the DRN. However, there was a significant decrease in MAO-B optical density in the hypothalamic POA, LH and VMN with E, P or E+P treatment. Pixel area generally reflected optical density. CONCLUSIONS: Ovarian steroids decreased MAO-A, but not B, in the raphe nucleus. However, both MAO-A and B were decreased in discrete hypothalamic nuclei by hormone replacement. These data suggest that the transcriptional regulation of MAO by ovarian steroids may play a role in serotonin or catecholamine neurotransmission and hence, mood, affect or cognition in humans. Ovarian steroid regulation of monoamine oxidase-A and -B mRNAs in the macaque dorsal raphe and hypothalamic nuclei.

Estrogen replacement therapy is widely used in postmenopausal women. The current study examines the effect of varying concentrations of estrogen on the levels of activity of monoamine oxidase A and -B in brain and in other tissues. […] High dose estrogen (5 mg/pellet) significantly decreased MAO-B activity and resulted in lesser or insignificant changes in MAO-A activity, respectively in liver (-30%, +1%), kidney (-22%, -11%), and uterus (-57%, -35%) (p Tissue-specific effects of estrogen on monoamine oxidase A and B in the rat.

These are shockingly large percentage changes. It’s the decreased MAO-A activity in the hypothalamus and amygdala that’s particularly interesting, as they are primitive parts of the brain. Hypothalamus, amygdala, and limbic system keep cropping up in my research as sites where the processing of amines and glutamate is altered somehow in food chemical intolerance spectrum syndromes including autism and fibromyalgia. One researcher even thinks that the amygdala is damaged in fibromyalgia. The hypothalamus controls body temperature, hunger, thirst, fatigue, anger, and circadian cycles, and links the nervous system to the endocrine system via the pituary gland. The amygdala plays a role in the processing and memory of emotional reactions.

So the next question is, if oestrogen levels make women more vulnerable than men to amines, why are there something like six male aspergers for every female asperger?

Well we know that asperger’s/autism/schizophrenia/bipolar disorder/epilepsy and other overlapping disorders seem to be connected to changes in dopamine processing in the brain.

This discussion is followed by a more detailed description of estrogen’s actions upon the dopamine transporter, which is hypothesized to serve as one of the major mechanism involved with nigrostriatal dopaminergic neuroprotection. Overall, estrogen appears to inhibit dopamine transporter function by decreasing the affinity of the transporter. Such an effect could prevent neurotoxic agents from entering dopamine nerve terminals, thereby decreasing nigrostriatal neurodegeneration. Neuroprotective effects of estrogen upon the nigrostriatal dopaminergic system.

Women seem to be less vulnerable to some dopamine related disorders because dopamine is processed differently in the presence of oestrogen. They seem to be less likely to suffer the effects of high dopamine. In addition to this, men have a special region on the Y chromosome called the Sex-determining Region Y (SRY), and it is this one region on the Y chromosome that determines whether you develop as a male or a female.

SRY has been linked to the fact that men are more likely than women to develop dopamine-related diseases such as schizophrenia and Parkinson’s disease. SRY makes a protein that controls concentrations of dopamine, the neurotransmitter that carries signals from the brain that control movement and coordination. Sex-determining Region Y (SRY)

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Written by alienrobotgirl

26 January, 2008 at 9:58 pm

Posted in The Genetics of FCI?

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