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Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2013, 7, 77-79

77

Affective Disorder and Hyperandrogenism

Celen Zerouni2, Elaine Kummerow1, Mariflor Martinez1, Ana Diaz2, Uribe Ezequiel1,2 and
Richard Wix-Ramos1,2,*
1

Universidad de Carabobo, Facultad de Ciencias de la Salud, Departamento de Ciencias Fisiolgicas, Valencia,

Venezuela; 2INSALUD, Hospital Psiquitrico Dr. Jose Ortega Duran, Campus Universitario, Barbula, Venezuela
Received: July 29, 2012; Accepted: August 31, 2012; Revised: November 7, 2012

Abstract: A 40-year-old female patient with bipolar disorder and premenstrual dysphoric disorder did not present any
physical evidence of virilization, treated with quetiapine and lithium carbonate. Laboratory testing showed evidence of
hyperandrogenism (Testosterone levels 88.5ng/dL). After control, testosterone levels were normal (free testosterone 0.20
pg/ml, total testosterone 27.90ng/dl), as free thyroxine levels decreased (T4 0.83ng/dl) and increased progesterone levels
(progesterone 3.80ng/ml). We consider an association between increased androgenic hormone levels in women,
quetiapine and lithium carbonate treatment as well as the presence of an affective disorder and premenstrual dysphoric
disorder. Some relevant patents are also outlined in this review.

Keywords: Affective disorder, hormonal alteration, hyperandrogenism, premenstrual dysphoric disorder, quetiapine and
lithium carbonate treatment.
INTRODUCTION
As one of the most common endocrinopathies, androgen
excess affects approximately 7% of reproductive-aged
women [1]. Among this large cohort of women, the majority
is diagnosed with polycystic ovary syndrome (PCOS) [2].
Successively, Isojarvi et al. reported a high frequency of
polycystic ovaries and/or hyperandrogenism in a large series
of women with epilepsy. The pathogenic mechanisms underlying the association between epilepsy and reproductive endocrine disorders are not yet clear. Antiepileptic drugs
(AEDs), particularly acid valproate (VPA), may mediate this
association [3, 4] however, the association between quetiapine, lithium carbonate with polycystic ovaries and/or
hyperandrogenism remains unknown. There is little available
research that empirically establishes clinical features that
might increase the chances of premenstrual dysphoric disorder (PMDD), since this disease is more likely to occur in
patients with a family history for both, PMDD or major depression [5]. Perhaps the most crucial factor in establishing
diagnosis of PMDD rules out another underlying medical or
psychiatric diagnosis and shows a premenstrual exacerbation
of symptoms. For example, more than 50% of patients suffering from major depression report a clear-cut premenstrual
exacerbation in their depressive symptoms [6]. Our case report presents a patient with bipolar disorder, premenstrual
dysphoric disorder, treated with quetiapine, lithium carbonate was found to have elevated serum testosterone levels.
The relationship among a possible hormonal alteration in
bipolar disorder, PMDD, quetiapine and lithium carbonate
treatment remains unknown. If there any correlation exists
*Address correspondence to this author at the Apartado Postal 3798, El
trigal, Valencia, Venezuela; Tel: 0058-241 8712437 or 0058-4126848439;
Fax: 0058-2418712437; E-mail: richardwix@hotmail.com
2212-3334/13 $100.00+.00

between hormonal alterations and brain function, it could

provide us new information necessary for identifying the
etiology and implementing effective therapies of affective
disorder, premenstrual dysphoric disorder and hyperandrogenism.
Ms. E.K., a 40-year-old Latin-American woman (EK)
was brought by relatives for psychiatric support presenting
symptoms such as irritability, aggressiveness, erratic perambulation, hiporexia and insomnia. At 32 years of age during
late puerperium (2002), the patient presented her first psychotic episode showing irritability, megalomaniac and paranoid delusions, soliloquy, aggressiveness and insomnia. She
was hospitalized and treated with haloperidol 5mg, chlorpromazine 25mg, clonazepan 0.5mg, valproic acid 250mg
and biperidene 2mg (for a period of 3 years). Patient was
diagnosed with puerperal psychosis and was discharged 12
days later in better conditions. In 2005, Ms. E.K., presented a
second psychotic episode with irritability, aggressiveness,
religious delusions, olfactory and auditory hallucinations and
insomnia. She was hospitalized and treated with haloperidol
5mg, carbamazepine, levomepromazine 25mg, aripripazol
15mg, lorazepan 2mg, Tioridazine 100mg and risperidone
2mg and evntually responded to treatment, showing improvement. She was discharged with a diagnosis of bipolar disorder type 1 after 17 hospitalization days. In 2006, at 36
years of age, after interruption of the medical treatment, Ms.
E.K., was again hospitalized for 16 days due to psychotic
symptoms similar to described before. She was treated with
haloperidol 5mg, olanzapine 10mg, lithium carbonate
600mg, levomepromazine 25mg and lorazepan 2mg. The
patient was discharged in better conditions, with the same
last diagnosis, symptoms of aggression, dysphoria increase
during menstruation. She had not history of any other illness
and was considered physically healthy. The physical exami 2013 Bentham Science Publishers

78 Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2013, Vol. 7, No. 1

Zerouni et al.

nation showed no signs of virilization. Her medic-ations at

that time included quetiapine 600 mg, and lithium carbonate
600 mg. EEG and MRI showed no abnormalities, complete
blood count and liver- and kidney-function, glucose; lipid
profile tests were normal, HIV and VDRL nonreactive and
normal urinalysis. Hormonal profile (follicular fase) demonstrated normal thyroid stimulating hormone (TSH) 1.14
uUI/mL (NV 1.0 - 4.0), normal free thyroxine (FT4) 1.1
ng/dl (NV 0.8-1.9), elevated total testosterone 88.5ng/dl (NV
2-80ng/dl), Follicular Stimulating Hormone (FSH) 8.3
mIU/ml (NV 3.0-14.4), Luteinizing Hormone (LH) 3.43
mIU/ml (NV 1-18), LH/FSH ratio 0.41, normal serum
prolactin 9.58 ng/ml (NV 3 - 29), estradiol 27.1 pg/ml VN
(15- 160), basal insulin 3.8 uIU/ml (NV 3-17), basal cortisol
13.8 ug/dl (NV 5-25).

care of endocrinology department for the management of

hormonal alteration and was kept under outpatient
psychiatric control.

We observed normalization of androgens values (one

year after the last hormonal control) treated with quetiapine
600mg, and lithium carbonate 600mg: free testosterone 0.20
pg/ml, total testosterone 27.90 ng/dl, T4 free 0.83 ng/dl
(NV0.89-1.76), DHEA-S 107 ug/dl, normal OGTT, 17 OH
progesterone 0.40ng/dl, LH 6.00 mUI/ml, FSH 13.70
mUI/ml, LH/FSH ratio 0.43, estradiol 20.80 pg/ml, progesterone 3.80 ng/ml (NV 0.0-1.13), androstenedione 1.00
ng/ml, prolactin 9.40 ng/ml, cortisol A.M 11.70 ug/dl, cortisol P.M. 7.60 ug/dl, DHEA-S 107 ug/dl, TSH 1,23 mUI/ml,
FT4 0.83nd/dl (NV 0.89-1.76), thyroglobulin antibodies 0.10
UI/ml, anti-peroxidase antibodies 3.5 UI/ml (negatives).

RECENT PATENTS ON AFFECTIVE DISORDER

AND HYPERANDROGENISM

There are several things we could learn from this case: 1)

hyperandrogenism could modulate affect, 2) hyperandrogenism could have a close relationship between bipolar
affective disorder and premenstrual dysphoric disorder, 3)
Valproic acid is associated with hyperandrogenism however,
the association between quetiapine and lithium carbonate
remain unknow, and 4) Interaction between hyperandrogenism, bipolar affective disorder and premenstrual dysphoric disorder remains unknown. Further research is needed
to resolve these questions, to improve the life quality of
patients and reduce suffering.

Some important patents on diagnosis and treatment of

affective disorder and hyperandrogenism are highlighted
below.
1.

A novel crystalline form of (2-(6-fluoro-1H-indol-3ylsulfanyl)benzyl)methyl amine has been found effective for the
treatment of depression, anxiety,
Alzheimer's disease, psychosis, or sleep disorders [15].

2.

An extract of microalga Aphanizomenon Flos Aquae

Aquae Ralf ex Born and Flah. Var. flos has been
patented for treatment of neurological disease such as
Alzheimer disease, Parkinson disease, multiple sclerosis,
Attention deficit hyperactivity disorder (ADHD),
autism, depression, memory deficiency and affective
disorders [16].

3.

Lakusta et al. have discussed prophylactic treatment for

cognitive-affective disorders [17].

4.

O'Neil has described a model based method by which

optimal treatment dose can be calculated for seasonal
affective disorders [18].

5.

Tejura has explained the use of estrogen derivative for

the treatment of hyperandrogenism and conditions
relating to hyperandrogenism e.g., polycystic ovary
syndrome, ovarian cancer, prostate cancer, obesity and
hiperplasia [19].

DISCUSSION
It is unclear whether the hyperandrogenism was functional or a component of PCOS since we had no basal ovaric
USG report, whether quetiapine and lithium carbonate
caused or represented an incidental finding. Antiepileptic
drugs (AEDs), in particular valproic acid (VPA) may be
associated with hyperandrogenism in women [3, 4]. A
patient was treated with valproic acid for 3 years however;
we could not explain the hyperandrogenism in our patient.
Our patient exhibited hyperandrogenism when she was
treated with quetiapine and lithium carbonate. PCOS is a
heterogeneous disorder with complex pathogenesis, whose
origin is attributed to an ovarian and adrenal disregulation in
androgen sintesis [7, 8]. The amygdala and particularly the
hippocampus contains relatively high concentrations of androgen receptors [9], making these structures critical targets
to androgen action. Furthermore, the anterior hippocampus
has strong reciprocal projections to the HPA axis [10]. These
hippocampal connections to both amygdale and HPA axis
underline the hippocampal role in emotion regulation. Testosterone has been reported to regulate the affect. In elderly
adults, reduced testosterone levels have been proposed as
one of the major mechanisms associated with the dysphoria
that is often observed during the late stages of life [11]. In
addition, testosterone is invoked in the regulation of fear and
anxiety. Testosterone has been associated with both depressive symptoms [11] and with aggressive tendencies [12],
both of which reect emotional disturbances. Our patient in
physical examination did not demonstrate evidence external
signs of virilization, she exhibited elevated levels of testosterone. A connection between PCOS and Bipolar Disorder
(BD) was suggested by Matsunaga and Sarai and further
clari
ed by Rasgon [13, 14]. The patient remained under the

CURRENT & FUTURE DEVELOPMENTS

A laboratory protocol for diagnosis of hyperandrogenism
in women with affective disorder treated with antiepileptic
drugs like valproic acid, quetiapine or lithium carbonate is
warranted.
CONFLICT OF INTEREST
The authors confirm that this article content has no conflicts
of interest.
ACKNOWLEDGEMENTS
We are grateful to Dr. Dalia Unda, Lic. Soraya for helpful comments, suggestions and corrections in the manuscript.

Affective disorder and Hyperandrogenism

Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2013, Vol. 7, No. 1

ABBREVIATIONS
MRI

Magnetic Resonance Imaging

EEG

Electroencephalography

HIV

Human Immunodeficiency Virus

VDRL

Venereal Disease Research Laboratory

ACTH

Adrenocorticotropic hormone

TSH

Thyroid-stimulating hormone

T3

Triiodothyronine

T4

Thyroxine

F.S.H.

Follicular stimulating hormone

L.H

Luteinizing hormone

[7]

[8]
[9]

[10]
[11]

[12]

[13]

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