Extended: New Explanation of Bipolar Disorder in Women: Addiction to Testosterone



Bipolar Disorder, DHEA and Testosterone in Women: Addiction to Testosterone

(Copyright 2006, James Michael Howard, Fayetteville, Arkansas, U.S.A.)

I suggest this disorder may be caused by an inappropriate combination of
stimulation caused by testosterone and dehydroepiandrosterone (DHEA) and
dehydroepiandrosterone sulfate (DHEAS). DHEAS is the large supply of this
hormone in the blood from which the active molecule, DHEA, is converted.
These hormones are connected with mania, depression, and menstrual
problems.

Manic episodes have been connected with the luteal phase of the cycle
(Biological Psychiatry 1993; 33: 194-203). Free testosterone levels were
significantly higher in premenstrual syndrome than controls in the luteal
phase and DHEA levels were significantly higher in PMS in the luteal phase
(Psychoneuroendocrinology 1992; 17: 195-204). A later study also reported
increased DHEA and free testosterone in the luteal phase (Gynecological
Endocrinology 2004; 18: 79-87). DHEA levels are significantly lower during
the luteal phase in "premenopausal healthy women" (Psychological Medicine
2004; 34: 93-102). "Early-onset menstrual dysfunction" has been reported
more often in women with bipolar disorder and women with depression
compared to healthy controls (Journal of Clinical Psychiatry 2006; 67:
297-304). The opposite side of this hypothesis is that low DHEA has been
connected with depression (Archives of General Psychiatry 2005; 62:
154-162). When DHEA is low these individuals feel depression.

Testosterone is high in mania (European Archives of Psychiatry and Clinical
Neuroscience 2003; 253: 193-6). Increased testosterone has been connected
with early puberty and obesity in girls (Journal of Clinical Endocrinology
& Metabolism 2006; February 21). The metabolic syndrome is "alarmingly
high" in bipolar disorder (Bipolar Disorder 2005; 7: 424-30). DHEA is
being considered as a treatment for metabolic syndrome (Journal of the
American Medical Association 2004; 292: 2243-8).

A common treatment for bipolar disorder, valproate, actually causes similar
problems to testosterone. Valproate increases weight gain, testosterone,
and DHEAS (Epilepsia 2004; 45: 1106-15 and New England Journal of Medicine
1993; 329: 1383-8). Valproate increases testosterone during the luteal
phase (Journal of Affective Disorders 2005; 89: 217-25) and contributes to
menstrual abnormalities (Bipolar Disorders 2005; 7: 246-59). However,
valproate is effective in bipolar disorder. The effects of valproate may
be used to "tease" apart the connection of DHEA and testosterone in mania
and depression in bipolar disorder.

Valproate increases DHEAS. This means that valproate is reducing
conversion of DHEAS to DHEA. I suggest a combination of high testosterone
and high DHEA over-stimulate the brain and cause "mania." One treated with
valproate will possibly experience the effects of excessive testosterone
but not the stimulating effects of testosterone and excessive DHEA
simultaneously. Valproate reduces this mania by reducing available DHEA.
Lithium also reduces DHEA. In rats, lithium reduces DHEA and DHEA levels
(International Journal of Neuropsychoparmacology 2004; 7: 71-5). When this
combination of androgens declines, "depression" occurs. I suggest this may
fit type 1 bipolar disorder. Type 2 may represent a state of low DHEA
which results in depression interrupted periodically by the combination of
simultaneous testosterone with a reduced DHEA level.

"The prevalence of the metabolic syndrome in patients with bipolar disorder
is alarmingly high? and The prevalence of obesity is even higher than the
already very high prevalence that has been estimated for the US general
population." (Bipolar Disorders 2005; 7: 424-30). "The odds of having the
MBS [metabolic syndrome] were 3.8 times higher for every quartile increase
in bioavailable testosterone in girls with PCOS?" (J Clin Endocrinol Metab
2006; 91: 492-7). Bipolar disorder is increased in women with polycystic
ovary syndrome (PCOS) (J Affect Disord 2006 Feb 15; Klipstein and Goldberg,
ahead of print at this writing).

The Mechanism: Maybe Bipolar Disorder is Testosterone Addiction

It has been my hypothesis that DHEA is involved in all growth and
development and maintenance of all tissues. My principal hypothesis is
that DHEA optimizes replication and transcription of DNA. At its most
basic level, I suggest cells absorb DHEA for growth. As cells form masses
of cells, cell surface area is reduced so availability of DHEA is reduced
as a consequence. This shifts the cellular mode from growth to
differentiation. That is, lots of DHEA enables the cell to replicate. As
DHEA amounts are reduced, areas of DNA are activated according to their
ability to react to reduced levels of DHEA. That is, DHEA is used for
reduced areas of DNA activation as DHEA is reduced. This is
differentiation; tissue formation.

I suggest the addiction mechanism is controlled by the levels of DHEA that
are available for the neuronal tissues that are involved. A "drug"
attaches to a part of the brain. This reduces available receptors which
respond appropriately. I suggest this triggers recruitment of DHEA by
these brain parts for this purpose. Hence, DHEA levels are increased, the
tissues are activated by the extra DHEA. When the drug is used again, the
process is reinitiated, therefore, eventually requiring more drug. This is
also how I explain growth and development. The involvement of DHEA with
drugs of addiction has been reported. "These results showed that DHEAS
prevented the development of morphine tolerance and dependence and
suggested that the attenuating effects of DHEAS might result from the
regulation of c-fos mRNA expression, which is possibly involved the
signaling activation of ERK, but not of cAMP pathway." (Behav Brain Res
2004; 152: 243-5). This is a "rebound" mechanism, that is, receptors are
closed by drugs of abuse which causes the rebound which stimulates DHEA.

Testosterone has this effect, that is, testosterone is reinforcing: "These
results indicate that testosterone at high doses causes central autonomic
depression, which may be a factor in deaths during self-administration. As
well, the depressive effects of large quantities of testosterone may be
mediated, at least in part, by an opioidergic mechanism." (Neuroscience
2005; 130: 971-81). In the foregoing quotation, an overdose of
testosterone shuts down the nervous system just as does an overdose of
morphine. Testosterone does produce an addictive effect: "?these data
support the hypothesis that testosterone is reinforcing."
(Psychopharmacology (Berl) 2004; 171: 298-305). "We conclude that
pharmacologic testosterone activates select steroid-sensitive brain
regions, as well as midbrain areas involved in reinforcement of
commonly-abused drugs." (Psychoneuroendocrinology 2006; 31: 237-49). "In
particular, substance abuse, especially cocaine abuse or dependence and
alcoholism, is a far more common phenomenon in the population of patients
with bipolar affective disorder than in the general population. ?There is
evidence that bipolar disorder patients with substance abuse have a worse
course of illness." (J Clin Psychopharmacol 1992; 12 (1 Suppl): 17S-22S).

I suggest the individuals who exhibit bipolar disorder are addicted to
testosterone. That is, when testosterone is released in these individuals,
perhaps at ovulation to stimulate libido, their brains over-react with an
abundance of DHEA. This shows as extra DHEA during the luteal phase of the
cycle. This mechanism begins a cycle of DHEA use that results in
over-stimulation of the brain until the adrenal glands are exhausted. This
exhaustion of DHEA availability would be similar to that of cocaine or
methamphetamine use. "Chronic cocaine self-administration induced
elevation in brain DHEA, its sulfate ester, DHEAS, and pregnenolone. The
increased brain DHEA following cocaine self-administration may serve as a
compensatory protective mechanism geared to attenuate the craving for
cocaine. Such anti-craving activity is further enhanced by DHEA treatment
before and during cocaine self-administration." (Eur Neuropsychopharmacol
2005; Maayan, et al., in press at this writing).

The mania is due to overstimulation of testosterone with DHEA and the
depression is caused by exhaustion of the adrenal glands.



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