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


Because of the “new” material of 2012, below, I am  adding more precision to my explanation: I suggest the basis of bipolar disorder is inappropriate production of dehydroepiandrosterone (DHEA) in response to molecular directives involving use of DHEA and production of DHEA.” Copyright 2012


(Copyright 2006, James Michael Howard, Fayetteville, Arkansas, U.S.A.) (Possible New Support Below and more new, 2008)  (New Supporting Work, 2012, below)


POSSIBLE TREATMENT: METFORMIN or FINASTERIDE to reduce testosterone levels that induce mania and DHEA to reduce depression.  (I am working on this at this time; BELOW “POSSIBLE NEW SUPPORT” SECTION.  I will add new material as I find it.)


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.  A possibility for treatment may be DHEA to prevent depression.  It has been found that DHEA may be useful “in controlling cocaine-seeking behavior, by reducing both the desire for cocaine usage and the incidence of replapse” (Neuropsychopharmacology 2006 (January):  Ravid Doron, et al., “DHEA, a Neurosteroid, Decreases Cocaine Self-Administration and Reinstatement of Cocaine-Seeking Behavior in Rats”).  Perhaps taking DHEA may reduce the effects of testosterone in women with bipolar disorder.  Metformin, which reduces testosterone in women with polycystic ovary syndrome (Prilozi 2006; 27: 57-66), may be used to reduce testosterone in women with bipolar disorder.





Testosterone and DHEA both stimulate protein kinase C activity.  Therefore, according to my hypothesis, PKC activity should be increased in bipolar disorder during mania.  Please read the following abstract:


J Psychiatr Res. 2005 Jul;39(4):355-63.


Lithium and valproic acid treatments reduce PKC activation and receptor-G protein coupling in platelets of bipolar manic patients.

Hahn CG, Umapathy, Wang HY, Koneru R, Levinson DF, Friedman E.

Medical College of Pennsylvania, Philadelphia, PA, USA.

Dysregulated protein kinase C (PKC) distribution and activation, and abnormal receptor-G protein coupling, have been implicated in the pathophysiology of bipolar affective disorder (BD). The therapeutic effectiveness of lithium has also been correlated with its ability to reduce PKC activation and G protein-mediated signaling. We examine the cellular distribution and activation of PKC and receptor-G protein coupling in blood platelets from normal controls, patients with BD mania or schizophrenia during treatment-free state, and after lithium or valproic acid administration. PKC activity was measured under basal and 50 nM phorbol 12-myristate, 13-acetate (PMA), 1 microM serotonin or 0.5 U/ml thrombin-stimulated conditions. The coupling of G proteins to serotonin or thrombin receptors were assessed by serotonin or thrombin-mediated [35S]GTPgammaS binding to membrane Galpha proteins. The results demonstrate that membrane-associated PKC activity and stimulus-induced PKC translocation are increased in BD manic, whereas stimulus-elicited PKC translocation is attenuated in schizophrenic patients. Lithium and valproic acid treatments attenuated the stimulus-induced PKC translocations to a similar degree and decreased PKC activity in both cytosolic and membranous fractions after two weeks of drug administration. An increase in 5-HT or thrombin stimulated [35S]GTPgammaS binding to Galpha proteins was detected in BD manic but not in schizophrenic patients although basal [35S]GTPgammaS binding was not different across the diagnostic groups. Lithium and valproic acid treatments similarly reduced receptor-G protein coupling with comparable time courses. Thus, increased membrane-associated PKC, cytosol to membrane PKC translocation and receptor-G protein coupling in platelets of BD manic patients were alleviated by lithium or valproic acid treatments.





Finasteride blocks “5-alpha-reductase” which converts testosterone into dihydrotestosterone.  During treatment for “androgenetic alopecia,” finasteride induced “moderate to severe depression” in 19 of 23 subjects (J Dermatol 2002; 29: 665-9).  This resolved promptly after suspension of finasteride.  So, finasteride reduces mood.  Now, one would not want finasteride during the depression phase of bipolar disorder, but one may want to use finasteride to reduce the excess testosterone of the luteal phase.  Testosterone enhances mood in women so finasteride use would have to be adjusted to maintain a good sense of well-being and mood without mania in women exhibiting bipolar disorder.  I suspect that reducing the excessive effects of testosterone on DHEA levels may reserve DHEA which may reduce subsequent depressions.  Of course, finasteride may be used to reduce excessive testosterone and DHEA to reduce excessive depression during the appropriate parts of the cycle.  THESE ARE IDEAS STIMULATED BY MY HYPOTHESIS REGARDING THE CAUSE OF BIPOLAR DISORDER IN WOMEN.  ONE SHOULD …NOT… TRY THIS “TREATMENT” WITHOUT A PHYSICIAN’S SUPPORT.


Added May 13, 2006:


Brain Behav Immun 200; 14: 49-61


“Modulation of IL-6 production during the menstrual cycle in vivo and in vitro”


“Serum IL-6 [interleukin-6] concentration demonstrated a significant increase in the luteal phase of the MC [menstrual cycle] and was elevated when serum dehydroepiandrosterone (DHEA) was low and vice versa.  DHEA decreased LPS-induced IL-6 secretion at six of seven time points during the MC.  In contrast, beta-estradiol and testosterone increased LPS-induced IL-6 secretion in six of seven time points during the MC (signigicant for testosterone).”


Prog Neuropsychopharmacol Biol Psychiatry 2002; 26: 1167-70


“Interleukin-6 serum levels correlate with response to antidepressant sleep deprivation and sleep phase advance”


“Unstimulated production of interleukine-6 (IL-6) is known to be enhanced in patients affected by a major depressive episode. Recent studies supported a role for basal IL-6 levels in predicting response to antidepressant drug treatments. In a sample of 10 consecutively admitted drug-free bipolar depressed inpatients, we investigated the possible correlation between unstimulated pretreatment production of IL-6 and antidepressant response to a night of total sleep deprivation (TSD) followed by a night of sleep phase advance (SPA), a nonpharmacologic treatment which is known to rapidly improve depressive symptomatology. Changes in perceived mood during treatment were recorded with self-administered Visual Analogue Scales (VAS). We observed a significant inverse correlation between IL-6 serum levels and VAS scores after treatment, meaning that higher IL-6 values before treatment were associated with worse response. This finding is in agreement with previous studies about amitriptyline and lithium antidepressant treatments. Our preliminary finding confirms the clinical value of IL-6 baseline concentration as a predictor of response to antidepressant treatment.”



Front Neuroendocrinol. 2008 Jan 3 [Epub ahead of print]

Anabolic-androgenic steroid dependence? Insights from animals and humans.

Wood RI

Department of Cell & Neurobiology, Keck School of Medicine of the University of Southern California, 1333 San Pablo Street, BMT 401, Los Angeles, CA 90033, USA.

Anabolic-androgenic steroids (AAS) are drugs of abuse. They are taken in large quantities by athletes and others to increase performance, with negative health consequences. As a result, in 1991 testosterone and related AAS were declared controlled substances. However, the relative abuse and dependence liability of AAS have not been fully characterized. In humans, it is difficult to separate the direct psychoactive effects of AAS from reinforcement due to their systemic anabolic effects. However, using conditioned place preference and self-administration, studies in animals have demonstrated that AAS are reinforcing in a context where athletic performance is irrelevant. Furthermore, AAS share brain sites of action and neurotransmitter systems in common with other drugs of abuse. In particular, recent evidence links AAS with opioids. In humans, AAS abuse is associated with prescription opioid use. In animals, AAS overdose produces symptoms resembling opioid overdose, and AAS modify the activity of the endogenous opioid system.

New Support 2012:  My response to Baroni, et al., Frontiers in Child and Neurodevelopmental Psychiatry, “Sleep disturbances in pediatric bipolar disorder: a comparison between bipolar I and bipolar NOS”


I sent the following to Baroni, et al., and the journal:


“Since the mechanism that produces the symptoms of bipolar disorder is not known at this time, perhaps two hypotheses may explain bipolar disorder and the findings of Baroni, et al., Front Psychiatry 2012: "Sleep Disturbances in Pediatric Bipolar Disorder: A Comparison between Bipolar I and Bipolar NOS."


I suggest the basis of bipolar disorder is inappropriate production of dehydroepiandrosterone (DHEA) in response to molecular directives involving use of DHEA and production of DHEA.


It is my hypothesis that bipolar disorder is caused by an endogenous addiction to testosterone.  It is easier to demonstrate in women: .  I think the periodicity of bipolar disorder results from the effects of testosterone on DHEA.  That is, testosterone first stimulates use of DHEA which induces increased brain activation.  When the adrenal glands cannot maintain production of DHEA, DHEA availability fails.  It is known that low DHEA results in depression and some evidence exists that DHEA can cause mania in some situations.  This would explain the cycle of mania and depression of bipolar disorder.


Very briefly, it is my hypothesis that the function of sleep is to produce DHEA which stimulates consciousness ( ).  My mechanism suggests that the light-dark cycle is involved in stimulating DHEA.  This requires melatonin production during the dark phase which then results in the production of DHEA.  The function of sleep is the production of DHEA during the day.  Melatonin cycles during sleep to produce DHEA in increasing amounts until sufficient DHEA is achieved to induce consciousness.  During sleep the periodic cycling increases DHEA which produces REM sleep while periods of melatonin produce SWS because melatonin momentarily reduces DHEA production.  The mechanism is melatonin induced reduction in DHEA which rebounds in response.  This mechanism keeps the brainstem functioning during the deepest SWS periods.


More specifically, it is also my hypothesis that testosterone evolved to direct the cellular use of DHEA caused by increased production of androgen receptors stimulated by testosterone.  (This explanation is available: "DHEA, Estradiol, Testosterone, and the Relevance of Their Ratio …The Androgen Receptor …and the Secular Trend," at: .)


Regarding Baroni, et al., I suggest the function of sleep is the production of DHEA.  Therefore, individuals who produce DHEA rapidly and / or excessively in response to the mechanism of sleep would exhibit increased sleep disturbances characterized by "insomnia and decreased need for sleep."  That is, they produce DHEA in response to the sleep mechanism in such amounts that they do not sleep.  The levels of enuresis reported by Baroni, et al., suggests that sleep in some of these individuals is very deep.  That is, the depth of sleep is so deep that normal response mechanisms do not interrupt sleep with the result that the "rebound" production of DHEA is very high upon awakening.  These both indicate increased production of DHEA.


Since I think testosterone increases androgen receptors through which DHEA activates the brain, this combination of increased production of DHEA as a result of sleep and increased absorption by, and subsequent activation, the brain because of increased androgen receptors adds additional supporting material to my explanation of bipolar disorder and may serve to explain the findings of Baroni, et al.”