Gynecological Endocrinology, November 2005; 21(5): 243–247

PREMENSTRUAL SYNDROME

Drospirenone in the treatment of severe premenstrual cerebral edema
in a woman with antiphospholipid syndrome, lateral sinus thrombosis,
situs inversus and epileptic seizures

Gynecol Endocrinol Downloaded from informahealthcare.com by Selcuk Universitesi on 01/30/15
For personal use only.

SVETLANA VUJOVIĆ1, JASNA ZIDVERC2, MILOŠ STOJANOVIĆ1, ZORANA PENEZIĆ1,
MIOMIRA IVOVIĆ1, VLADIMIR ÐUKIĆ1, & MILKA DREZGIĆ1
1

Institute of Endocrinology, Clinical Center of Serbia, Beograd, Serbia and Montenegro, and 2Institute of Neurology,
Clinical Center of Serbia, Beograd, Serbia and Montenegro

Abstract
We report herein the case of 32-year-old woman with situs inversus, thrombophilia, antiphospholipid syndrome and severe
premenstrual syndrome (PMS) with cerebral edema and epileptic seizures prior to menstruation. Seven days prior to regular
menstruation she developed severe PMS, including headache, blurred vision, epileptic seizures, urinary incontinence,
craving for food, depression and irritability. Papilledema was detected. Daily hormone analyses prior to and during
menstruation confirmed an ovulatory cycle with extremely high progesterone, prolactin and insulin levels in the late luteal
phase. From day 29 to day 31, progesterone and insulin decreased sharply and the estradiol/progesterone ratio changed,
leading to epileptic seizures and the peak of her symptoms. Diuretic treatment was administered. All symptoms disappeared
during the first few days of menstruation. A novel oral contraceptive, containing ethinyl estradiol and drospirenone, an
antimineralocorticoid progestogen, was given during the next cycle and hormone analyses were repeated. All symptoms were
reduced significantly and no cerebral edema and epileptic seizures occurred. This is the first report of a woman with severe
PMS and cerebral edema being treated successfully with an oral contraceptive containing drospirenone.

Keywords: Premenstrual syndrome, progesterone, estradiol, cerebral edema, epileptic seizures

Introduction
Premenstrual syndrome (PMS) has been defined as
distressing physical, behavioral and psychological
symptoms, not due to organic disease, which recur
regularly during the same phase of each menstrual
cycle and which disappear or regress significantly
during the remainder of the cycle [1]. Typical physical
signs include symptoms of fluid retention such as
breast tenderness, swelling and abdominal bloating,
weight gain, and headache affecting well-being and
quality of life. Psychological symptoms include irritability, depression, reduced libido and attacks of
bulimia. One consistent endocrine finding in PMS is
that symptom development in the luteal phase
requires ovulation [2]. PMS symptoms do not occur
in anovulatory cycles, before puberty, during pregnancy or after menopause [3], yet will continue after
hysterectomy if ovarian function is maintained [4].
Female-to-male transsexuals have ovulatory cycles,
but no PMS due to the gradual fall of progesterone in
the luteal phase [5].

Alterations in mineralocorticoid metabolism may
be significant in the pathogenesis of PMS. Changes in
the renin – angiotensin – aldosterone system (RAAS)
play an important role during the luteal phase of the
cycle. Aldosterone, the major regulator of blood
volume and potassium homeostasis, acts primarily
through the kidney, causing retention of sodium and
loss of potassium. So, aldosterone antagonism could
be of potential benefit in women with severe PMS.
Oral contraceptives (OCs) are often recommended
to women with PMS, but the progestogenic properties
of OCs vary depending on the molecule from which
they are derived. The development of a new generation
of progestogens with improved receptor selectivity
profiles has been a great challenge. A fourth-generation
progestogen, drospirenone, derived from spironolactone, has partial antimineralocorticoid activity and
weak antiandrogen effects. The antimineralocorticoid
activity is derived from direct competition with
aldosterone for binding to the aldosterone receptor.
Since a number of PMS symptoms appear to be
related to fluid retention, it was anticipated that the

Correspondence: S. Vujović, Institute of Endocrinology, Clinical Center of Serbia, 11 000 Beograd, Dr Subotića 13, Serbia and Montenegro.
Tel: 381 63 8136951. E-mail: vujovic@EUnet.yu
ISSN 0951-3590 print/ISSN 1473-0766 online ª 2005 Taylor & Francis
DOI: 10.1080/09513590500361853

244

S. Vujović et al.

antimineralocorticoid properties of drospirenone
would be particularly effective at relieving symptoms.
The objective of the present study was to evaluate
the effects of a novel OC containing drospirenone on
severe PMS that included epileptic seizures and
intracranial hypertension.

Gynecol Endocrinol Downloaded from informahealthcare.com by Selcuk Universitesi on 01/30/15
For personal use only.

Case report
A 32-year-old woman was the second child of healthy
parents, born from a twin pregnancy. Her twin was lost
during the second trimester of the pregnancy. She had
menarche at 9 years of age and began to experience
PMS 13 years later. During the past 9 years she had
experienced seven spontaneous abortions and undergone premature childbirth. During pregnancy she had
no exacerbations of PMS. Informed written consent
was obtained from this patient.
X-ray and ultrasound examinations revealed situs
organorum inversus completus in the thorax and
abdomen, forked sixth and seventh ribs, coalesced
second and third cervical vertebrae and short third,
fourth and fifth metacarpal bones and phalanges. Her
karyotype was normal – 46,XX. Three years previously
a prothrombin gene mutation (G20210A allele), a singlenucleotide G-to-A transition at position 20 210 in the
sequence of the 30 -untranslated region on chromosome
11, was discovered [6]. She was genotyped by the
polymerase chain reaction method as FVR506Qnegative and FII G20210A-positive in the heterozygous
state. This genetic thrombophilia has been established
as an important risk factor for venous thrombosis [7].
Two years before she developed a cerebral right sinus
thrombosis diagnosed by digital subtraction angiography, one of the rare clinical manifestations of the
antiphospholipid syndrome [8]. The activated partial
thromboplastin time (PTT) was prolonged and lupus
anticoagulant was present, as were antimitochondrial
antibodies. She was treated with repeated cerebrospinal fluid drainage, acetazolamide and later with
intravenous heparin, followed by warfarin.
Seven days prior to each menstruation she developed typical severe PMS symptoms together with
cerebral edema and epileptic seizures, and regularly
spent a few days in hospital receiving emergency
diuretic therapy. Therapy with diuretics (Aldactone1
150 mg), benzodiazepine and fluoxetine during the
luteal phase failed to relieve her PMS symptoms,
which persisted. This investigation was conducted
for scientific rather than clinical reasons.
Clinical examination on admission revealed a
woman with short stature (150 cm) who was overweight (87 kg) and with centripetal fat distribution,
predominantly on the posterior neck and upper trunk.
There were numerous nummular skin changes, predominantly erythematous and prurigous, and dark
older lesions with central necrosis, distributed on the
posterior trunk and the legs. The diagnosis of PMS was
confirmed by a prospective recording of daily symptoms using the Premenstrual Distress Questionnaire

(recording of ten most prevalent symptoms) and the
Moos Menstrual Questionnaire [9]. Each symptom
was scored using the scale 0 ¼ none, 1 ¼ mild,
2 ¼ moderate and 3 ¼ severe, indicating the presence
of severe PMS. Her symptoms were followed up
prospectively daily during the luteal phase, menstruation and first 7 days of the next cycle. Hormone
analyses – follicle-stimulating hormone, luteinizing
hormone, prolactin, estradiol (Figure 1), progesterone
(Figure 2), testosterone and sex hormone-binding
globulin (SHBG) – were performed daily. During this
period she was treated with anticoagulants, with daily
measurements of prothrombin time (PT) and PTT,
and with diuretics, fluoxetine, benzodiazepine and
biguanide. Thyroid, parathyroid and adrenal function
were normal, she did not have diabetes. From day
25 of her ovarian cycle all symptoms worsened,
including irritability, tiredness, mood swings, restlessness, depression, bloatedness and weight gain
(from 87 to 92 kg). Prolactin levels increased from
300 to 500 mIU/l from day 25 to day 27, reaching a
maximum 1 day prior to menstruation, and her
progesterone levels decreased from 280 to 200 nmol/l
during days 25 to 29. During the night from days 29 to
30 she had dyspnea, blurred vision, felt weak and
craved food. Fundoscopic examination revealed bilateral papilledema with decreased visual acuity. At that
time, from the evening to the morning, her progesterone levels decreased rapidly from 200 to 60 nmol/l and
her insulin concentrations from 120 to 20 mIU/l.
Computed tomography of her cranium revealed no
abnormalities. One day prior to menstruation whilst
asleep during night she had a grand mal epileptic
seizure with urinary and fecal incontinence and
transitory cardiac arrhythmia lasting 5 min. Her
prolactin level reached its peak at that time, whilst she
remained normoglycemic and her progesterone levels
decreased from 60 to 1 nmol/l. Cerebral edema was
found. Lumbar puncture revealed raised intracranial
pressure with an increased pressure of 400 mmHg and
she had developed a focal neurological deficit. Cytobiochemical content of cerebrospinal fluid was normal.
Oligoclonal bands were not detected in cerebrospinal
fluid or serum. She was treated with diuretics. All her
symptoms disappeared gradually during the first 3 days
of menstruation.

Figure 1. Estradiol level during the luteal phase (day 20–31) of one
menstrual cycle and the follicular phase (day 1–7) of the next cycle,
before and after administration of Yasmin1 to the patient with
severe premenstrual syndrome and cerebral edema.

Drospirenone and PMS

Gynecol Endocrinol Downloaded from informahealthcare.com by Selcuk Universitesi on 01/30/15
For personal use only.

Figure 2. Progesterone levels during the luteal phase (day 20–31)
of one menstrual cycle and the follicular phase (day 1–7) of the
next cycle, before and after administration of Yasmin1 to the
patient with severe premenstrual syndrome and cerebral edema.

In the next cycle she received a daily oral dose of
30 mg ethinyl estradiol and 3 mg drospirenone
(Yasmin1; Schering AG, Berlin, Germany) on days
1–21, followed by a tablet-free period from day 22 to
day 28. Effects of the treatment were monitored by
means of COPE (Calendar of Premenstrual Experiences) score [10]. Daily hormone measurements
showed an anovulatory cycle, with normal prolactin
and insulin levels, and she lost 5 kg (from 87 to
82 kg) prior to menstruation. She experienced no
PMS symptoms and had no cerebral edema or
epileptic seizures.
Discussion
A case of a 32-year-old woman with lateral sinus
thrombosis (possibly induced by mastoiditis), prothrombin gene mutations and antiphospholipid
syndrome, epileptic seizures and raised intracranial
pressure was referred by neurologists. There were
two possible explanations for this case. The coincidental association of two thrombotic disorders
could have been the cause of her seven spontaneous
abortions and antiphospholipid antibodies could
have been responsible for the thrombotic event.
There are some studies demonstrating anticardiolipin antibodies in 32–40% of patients with idiopathic
intracranial hypertension with normal cerebral
angiograms, suggesting the possibility of a nonocclusive thrombotic pathogenesis of some causes
of intracranial hypertension [11]. However, the fact
that she had exacerbations every month prior to
menstruation implied a possible link between hormonal fluctuations during the menstrual cycle and a
variety of physical, emotional and fluid retentionrelated symptoms.
We confirmed severe PMS in this patient. About
20–30% of all fertile women suffer from PMS [12],
of which about 43% suffer from weight gain and
edema due to water retention, similar to this patient.
Severe symptoms are found in 2–3% of fertile women
such that, on more than two occasions within any
6 months, sufferers are unable to work during the
premenstrual period and their lives are totally
disrupted. The patient reported here spent 5 days
each month in hospital because of intracranial

245

hypertension and cerebral edema associated with
severe PMS.
Many studies implicate progesterone as a provoking factor in PMS. Redei and Freeman [13] found
that premenstrual symptoms occur 3–5 days after the
progesterone plateau, consistent with our finding.
Thus a fall in progesterone may be triggering factor
for PMS symptoms. In addition, increased estradiol
levels during the luteal phase were found to be
positively correlated with the more severe symptoms
when compared with cycles in the same individuals
with low luteal-phase estradiol levels [14]. Some
studies did not find any differences in the plasma
levels of estradiol and progesterone between women
with PMS and controls [15], but levels of those
hormones were measured only once in the luteal
phase. Smith and colleagues [16] suggested the
absence of an abnormality in dynamic ovarian
function as measured by gonadotropin-releasing
hormone (GnRH) stimulation. In contrast, we found
a direct correlation between the progesterone fall,
peaks of prolactin and insulin and epileptic seizures
in our patient. Other studies have confirmed that
progesterone stimulates dopamine release in striatal
tissue [17] and GnRH release from hypothalamic
neurons [18] but inhibits opioid receptor binding
and activity and reduces meningeal release of
substance P [19], thereby inhibiting the development
of neurogenic edema. There is evidence that progesterone metabolites interact with the g-aminobutyric
acid (GABA) receptor subtype A and serotoninergic
systems, and both systems appear to be involved in
the pathophysiology of PMS [20]. Activation of the
GABAA receptor makes the cell membrane permeable to chloride ions and produces strong sedating
and anticonvulsive effects, as was found with our
patient during the progesterone plateau. Thus, the
abrupt decrease of progesterone levels could have
been one of the triggering factors for epileptic
seizures in our patient.
Progesterone increases hypothalamic serotonin
content [21]. Several symptoms encountered in
PMS resemble those of a possible serotoninergic
deficiency. Brzezinski and associates found fenfluramine to be effective in alleviating PMS [22]. This has
been confirmed with tricyclic antidepressants that
have a serotoninergic profile and with selective
serotonin-reuptake inhibitors (SSRIs). Pearlstein
and Stone [23] found that approximately half of their
subjects achieved complete remission of PMS symptoms and concluded that SSRIs should be the firstline treatment for PMS. Unfortunately, this therapy
was unsuccessful in our patient.
Our patient felt depressed during the first 3
months of pregnancy but had no intracranial
hypertension, problems with vision or epileptic
seizures, suggesting that the fall in progesterone
rather than high progesterone levels per se is an
etiological factor for PMS. During pregnancy a
large number of PMS patients report symptom

Gynecol Endocrinol Downloaded from informahealthcare.com by Selcuk Universitesi on 01/30/15
For personal use only.

246

S. Vujović et al.

relief, perhaps due to high and non-fluctuating
levels of estradiol and progesterone [24].
The sex hormones in Yasmin1 interfere with the
RAAS in two ways. First, ethinyl estradiol stimulates
the production of angiotensinogen-induced increases
of angiotensin II, aldosterone and body weight. Second,
drospirenone antagonizes the sodium-retaining effects of ethinyl estradiol, by antimineralocorticoid
effects in the kidneys [25] inducing natriuresis that
partly counteracts the suppressive effect of angiotensin II on renin concentrations. While taking Yasmin1,
our patient’s body weight decreased by 5 kg during
the luteal phase of the cycle. These findings are in
agreement with previous studies [26]. Blood pressure in our patient remained unchanged, as was
observed in other studies [27]. Aldosterone may
possibly have deleterious effect on the vasculature by
modifying endothelial function and affecting vascular
remodeling, particularly by fibrosis. So, aldosterone
antagonism could be of potential benefit in women
with severe PMS.
The brain RAAS had been found to be involved in
the modulation of cardiovascular and fluid–electrolyte homeostasis, generally complementary to the
classical roles of the endocrine RAAS. RAAS has
additionally been implicated in memory, cognition
and stress, modulating the activity of the autonomic
nervous system, the hypothalamic–pituitary axis,
baroreflex sensitivity and vasopressin release. The
brain RAAS is physically separated from the systemic
endocrine RAAS by the blood–brain barrier. Circulating angiotensin II may, however, transmit effects
inside the brain through areas lacking the blood–
brain barrier [28]. Cerebral edema can be partly
explained by effects of the angiotensin II and
drospirenone counteracts it. Angiotensinogen, the
only known source of angiotensin, is produced in the
hypothalamus and brain stem, which are important
for the central control of homeostasis. The involvement of angiotensin II in the circadian regulation of
vascular tone by inducing the circadian expression of
clock genes in vascular smooth muscle has been
recently suggested [29]. Antisense oligodeoxynucleotides against angiotensinogen or AT1 mRNA
administered into the brain reduce hypertension
and may protect spontaneously hypertensive rats
against cerebral ischemia [30]. Therefore, intracranial hypertension and cerebral edema could be partly
explained by this mechanism.
Eriksson and co-workers [31] found that an increase
of free testosterone appears to be associated with
premenstrual irritability, and our study confirms this
(although insignificantly). Drospirenone has antimineralocorticoid activity eight times greater than that of
spironolactone, and antiandrogenic activity five to ten
times greater than that of progesterone, but less than
that of cyproteron acetate [32]. Although weak, this
antiandrogenic activity probably counteracted the
negative effects of androgens on hair growth and skin
in our patient. These changes are probably due to

increased binding to SHBG. Ethinyl estradiol increases
the level of SHBG, but drospirenone does not inhibit
this induction.
As a history of thromboembolic disorders and
existing blood coagulation disorders are contraindications for Yasmin1, medical supervision is
recommended when Yasmin1 is administered to obese
women with epilepsy. Our patient wishes to continue
treatment with Yasmin1 because no other drugs have
helped her and she cannot continue as before. The
prothrombotic effects of OCs may result from changes
in hemostatic parameters (an increase in procoagulant
effects, a decrease in anticoagulant effects, and
equivocal effects on fibrinolysis with increases in
antifibrinolytic activity) [33]. The same dose of anticoagulants in the cycle with/without Yasmin1 indicates
well-maintained hemostatic equilibrium, meaning that
the high rate of turnover of coagulation factors and
similar activation of the coagulatory and fibrinolytic
aspects of the hemostatic system do not translate into
significantly increased risk of venous thromboembolism. Thus, prophylactic fractionated heparin to allow
use of the pill would be the best therapeutic choice.
Conclusion
Dynamic hormonal changes prior to menstruation,
with a crucial progesterone fall, can trigger instability
in serotoninergic homeostasis and changes in mineralocorticoid pathways leading to PMS symptoms,
also including intracranial hypertension, cerebral
edema and epileptic seizures. No sole role of any
system can be assumed. PMS is likely to be a
multifaceted syndrome with impairment in many
biological parameters.
In our patient, administration of Yasmin1 (ethinyl
estradiol and drospirenone) resulted in a significant
reduction in the incidence of severe PMS symptoms
during all phases of the menstrual cycle, but
particularly during the luteal phase. Symptoms of
fluid retention (weight gain, breast tenderness, breast
and abdominal swelling), negative psychological
effects (comprising feelings of loneliness, sadness,
tearfulness, moodiness, anxiety, irritability, restlessness), acne, food craving, and even epileptic seizures
and cerebral edema improved, indicating the beneficial effect of Yasmin1 in one woman. This appears
a useful means to improve the quality of life for our
patient.

References
1. Panay N, Studd J. Progesterone intolerance in the treatment of
severe premenstrual syndrome. In: The 11th World Congress
of Gynecological Endocrinology, 2004, Florence. London:
The Parthenon Publishing Group; 2004. p 177.
2. Hammarback S, Ekholm UB, Backstrom T. Spontaneous
anovulation causing appearance of cyclical symptoms in
women with PMS. Acta Endocrinol 1991;125:132–137.
3. Studd JWW. Premenstrual syndrome. Br Med J 1979;1:410–
415.

Gynecol Endocrinol Downloaded from informahealthcare.com by Selcuk Universitesi on 01/30/15
For personal use only.

Drospirenone and PMS
4. Backstrom T, Boyle H, Baird DT. Persistence of symptoms of
premenstrual tension in hysterectomized women. Br J Obstet
Gynaecol 1981;88:530–536.
5. Vujovic S. No evidence of premenstrual syndrome in femaleto-male transsexuals. Gender Dysphoria 1992;2:56–68.
6. Poort SR, Rosental FR, Reitsma PH, Bertina RN. A common
genetic variation in the 3-transected region of prothrombin
gene is associated with elevated plasma prothrombin level and
increase in venous thrombosis. Blood 1996;88:3698–3703.
7. Soria JM, Almasy L, Souto JC, Tirado I, Borell M, Mateo J,
Slifer S, Stone W, Blangero J, Fountcuberta J. Linkage
analysis demonstrates that the prothrombin G20210A mutation jointly influences plasma prothrombin levels and risk of
thrombosis. Blood 2000;95:2780–2785.
8. Carhuapoma JR, Mitsias P, Levine SR. Cerebral venous
thrombosis and anticardiolipin antibodies. Stroke 1997;28:
2363–2369.
9. Moos RH. The development of a menstrual distress questionnaire. Psychosom Med 1968;30:853–867.
10. Mortola JF, Girton L, Beck L, Yen SS. Diagnosis of
premenstrual syndrome by a simple, prospective and reliable
instrument: the calendar of premenstrual experience. Obstet
Gynecol 1990;76:302–307.
11. Leker RR, Steiner I. Anticardiolipin antibodies are frequently
present in patients with idiopathic intracranial hypertension.
Arch Neurol 1998;55:817–820.
12. Vujovic S. Ultrasongrafske i funkcionale karakteristike ovarijuma u žena sa predmenstrucionim sindromom [dissertation],
Beograd: University of Beograd; 1991.
13. Redei E, Freeman EW. Daily plasma estradiol and progesterone levels over the menstrual cycle and their relation to
premenstrual symptoms. Psychoneuroendocinology 1995;20:
259–267.
14. Hammaback S, Damber JE, Backstrom T. Relationship
between symptom severity and hormone changes in women
with premenstrual syndrome. J Clin Endocrinol Metab 1989;
68:125–130.
15. Backstrom T, Sanders D, Leask R, Davidson D, Warner P,
Bancroft J. Mood, sexuality, hormones and the menstrual
cycle. II. Hormone levels and their relationship to the
premenstrual syndrome. Psychosom Med 1983;45:503–507.
16. Smith MJ, Schmidt PJ, Su T-P, Rubinow DR. Gonadotropin
releasing hormone-stimulated gonadotropin levels in women
with premenstrual dysphoria. Gynecol Endocrinol 2004;19:
335–343.
17. Petitclerc M, Bedard PJ, Di Paolo T. Progesterone releases
dopamine in male and female rat striatum. A behavioural
and microdialysis study. Prog Neuropsychopharmacol Biol
Psychiatry 1995;19:491–497.
18. Sinchak K, Micevych PE. Progesterone blockade of estrogen
activation of m-opioid receptors regulates reproductive
behaviour. J Neurosci 2001;21:5723–5729.
19. Limmroth U, Lee WS, Moskowitz MA. GABA-A receptormediated effects of progesterone, its ring-A-reduced metabolites and synthetic neuroactive steroids on neurogenic oedema
in the rat meninges. Br J Pharmacol 1996;117:99–104.

247

20. Genazzani AR, Stomati M, Morittu A, Bernardi F,
Monteleone P, Casarosa E, Gallo R, Salvestroni C, Luisi M.
Progesterone, progestogens and the central nervous system.
Hum Reprod 2000;15(Suppl): 14–27.
21. Walker RF, Wilson CA. Changes in hypothalamic serotonin
associated with amplification of LH-surges by progesterone in
rats. Neuroendocrinology 1983;37:200–205.
22. Brzezinski AA, Wurtman JJ, Wurtman RJ, Gleason R,
Greenfield J, Nader T. D-Fenfluramine suppresses the
increased calorie and carbohydrate intakes and improves the
mood of women with premenstrual depression. Obstet
Gynecol 1990;76:296–301.
23. Pearlstein TB, Stone AB. Long-term fluoxetine treatment of
late luteal phase dysphoric disorder. J Clin Psychiatry
1994;55:332–335.
24. Corney RH, Stanton R. A survey of 658 women who report
symptoms of premenstrual syndrome. J Psychosom Res 1991;
35:471–482.
25. Oelkers W, Helmerhorst FM, Wuttke W. Effects of an oral
contraceptive containing drospirenone on the rennin–
angiotensin–aldosterone system in healthy female volunteers.
Gynecol Endocrinol 2000;16:204–213.
26. Freeman EW, Kroll R, Rapkin A, Pearlstein T, Brown C,
Parsey K, Zhang P, Patel H, Foegh M; PMS/PMDD Research
Group. Evaluation of a unique oral contraceptive in the
treatment of premenstrual dysphoric disorder. J Womens
Health Gend Based Med 2001;10:561–569.
27. Apter D, Borsos A, Baumgartner W, Melis GB,
Vexiau-Robert D, Colligs-Hakert A, Palmer M, Kelly S.
Effect of an oral contraceptive containing drospirenone and
ethinylestradiol on general wellbeing and fluid-related symptoms. Eur J Contracept Reprod Health Care 2003;8:37–51.
28. Baltatu O, Bade M. Brain rennin–angiotensin system.
Neuroendocrinology 2003;78:253–259.
29. Nanaka E, Emoto N, Iheda K, Fukuya H, Rohman MS,
Raharjo SB, Yagita K, Okamura H, Yokoyama M.
Angiotensin II induces circadian gene expression of clock
genes in culture of vascular smooth muscle cells. Circulation
2001;104:1746–1748.
30. Yamakawa H, Phillips MI, Saavedra JM. Intracisternal
administration of angiotensin II AT (1) receptor antisense
oligodeoxynucleotides protects against cerebal ischemia in
spontaneously hypertensive rats. Regul Pept 2003;111:117–
122.
31. Eriksson KT, Simblad C, Lispo P, Modigh K, Andersch B.
Serum levels of androgen are higher in women with
premenstrual irritability and dysphoria than in controls.
Psychoneuroendocrinology 1992;17:195–204.
32. Muhn P, Fuhrmann U, Fritzemeier KH, Krattenmacher R,
Schillinger E. Drospirenone: a novel progestogen with
antimineralocirticoid and antiandrogen activity. Ann N Y
Acad Sci 1995;761:311–335.
33. Vandenbroucke JP, Rosing J, Bloemenkamp KW, Middeldorp
S, Helmerhorst FM, Bouma BN, Rosendaal FR. Oral
contraceptives and the risk of venous thrombosis. N Engl J
Med 2001;344:1527–1535.