There's a new male contraceptive pill being tested which involves doses
of testosterone - human, I would hope - combined with progestin, a
synthetic progesterone derivative.  Used together, they're reported to
shut down sperm production.

Leaving aside efficacy, I'd like to point out a few things about the
dangers of interfering with the progesterone system.

We discussed in sci.life-extension a few days ago the problems synthetic
progestin posed for women on hormone replacement therapy.  A recent
_Scientific American_ article mentioned problems with one particular
type.  I've heard women link various formulations of birth control pills
to everything from migraines and sex drive to candidiasis (which has a
curious link to sinus infections and TMJ).  I would assume every women
is a mosaic of different genes, so introducing an artificial, not quite
identical, steroid like progestin would negatively affect certain
individuals.  Given that men may soon face the same problem, I decided
to dig a little deeper into this pathway than I already had.

Allopregnanolone (THP), a GABA(A) enhancer, is synthesized from
progesterone by either a 3alpha-HSD or a 5 alpha reductase (5AR) isoform.

5ARs are also responsible for the synthesis of THDOC (another GABA
enhancer) and dihydrotestosterone, the androgen behind prostate cancer
and male-pattern baldness (though thanks to recent research we know DHT
is not responsible for female-pattern baldness and this is why 5AR
inhibitors are ineffective for women). Finasteride/Proscar/propecia and
other 5AR inhibitors have a use in treating benign prostate hyperplasia,
prostate cancer and hair loss because they block the formation of DHT
but this avenue may pose neurological problems because they block
allopregnanolone too.

On the other hand 3alpha-HSD not only synthesizes THP, it also breaks
down DHT in the prostate.  Its effect in the scalp is unknown, but it
has been fingered as something worth looking at as a potential hair loss
inhibitor.  Unfortunately, in the synthesis of THP it's not an equal
partnership.  One study suggests that the bulk of THP synthesis occurs
via 5ARs and not 3alpha-HSD.

Why do we need THP?

THP is anxiolytic (anxiety-reducing), neuroprotective and possibly
antidepressant - all through its GABA(a)-enhancement.  SSRIs may get
their antidepressant effects in part by increasing levels of
progesterone and THP - this despite the fact that SSRIs also appear to
inhibit the actions of at least one 3alpha-HSD in the formation  of THP
(if this inhibition of 3alpha-HSD occurs in the scalp it might explain
why hair loss is associated with chronic SSRI use - taking an SSRI would
elevate DHT in the skin).

Studies in women indicate 19-nor derivatives might be a particularly bad
form of progestin to use given their lack of stimulation for
allopregnanolone levels.  It stands to reason if artificial progestin
somehow jams up the synthesis of THP then all sorts of bad things can
start to happen from having a less efficient inhibitory system.  
Specifically GABAergic signaling has been shown to attenuate the release
of dangerous levels of dopamine, perhaps making it a treatment for both
cocaine addiction and Parkinson's.  GABA enhances memory in aged adults
(although too much GABA can inhibit learning).  GABA also blocks the
release of glutamate in damaging instances of excitotoxic
neurodegeneration and neuropathic pain (TMJ).  THP itself regulates
sleep.  It's involved with well-being, PMS and female sexual health.  
It's even involved in myelin generation and might inhibit the
progression of MS (a wild guess on my part).

It's also true that continuous exposure to elevated levels of
progesterone or THP can actually generate some anxiety, so this is a
carefully balanced system.  There's also some interaction between
estrogen and progesterone levels.  Each gender and each tissue also has
a somewhat different response.

Given all this, what danger does progesterone/progestin administration
pose in males - particularly those with preexisting conditions?  Would
it necessitate some sort of precautionary supplementation with GABA or
L-Theanine or something more potent to regain GABAergic function or
would it be impossible?  What would the long term risks be for
neurodegeneration - especially if you already had some?

Neurosteroids are a pretty muddy and fairly new topic in research.  I've
posted this article in various place in the hopes of getting a reply
from people who have looked at the problem from several other angles.  
I'm in contact with women who suffer TMJ pain and post-partum depression
and I want to help them find answers.  I'm curious to know if I've
bungled the research at all or I've glossed over some pretty big and
necesary parts of the hormone web because this already has some
relevance for my own health.

        __________________ Contraceptive article ___________________
   

http://www.nytimes.com/aponline/international/AP-Australia-Male-Contracep
tive.html

Male Contraceptive Results Show Promise
By THE ASSOCIATED PRESS

Published: October 7, 2003

Filed at 2:03 a.m. ET

SYDNEY, Australia (AP) -- A hormone-based contraceptive treatment that
stops men from producing sperm has prevented pregnancy among 55 couples
during a 12-month test, researchers said Tuesday.

The study, a U.S. government-funded program sponsored by Virginia-based
family planning organization CONRAD, was able to successfully and
reversibly turn off sperm production in the men who took part, said Rob
McLachlan, director of clinical research at Prince Henry's Institute of
Medical Research in Sydney, Australia.
Advertisement


CONRAD often funds medical studies outside of the United States and
works closely with the World Health Organization.

``This is the first time the combination of long-acting testosterone and
a progestin have been used in an effectiveness study, this is the first
to be reported in the world,'' McLachlan said by telephone. ``We're very
pleased and excited the results are so positive.''

It was an 18-month commitment by the 55 couples involved, he said.

The trial was conducted in two phases. The first, over three to six
months, involved taking testosterone and progestin to turn off sperm
production. Then when the sperm count was zero or close to zero, the
12-month trial period began.

``What was unusual was the fact that this was an effectiveness study,''
McLachlan said. ``Once the sperm was suppressed the couples used this as
their (contraceptive) method. Other studies only monitor how far the
sperm count falls.''

Over the 12 months of the trial, the men continually took implants of
testosterone and injections of progestin, a reproductive hormone. The
implants require minor surgery to put them under the skin, McLachlan
said.

``Normally there are signals from the brain to the testes that promote
production of sperm and to make testosterone, which is important for
general health in men -- it gives them strength, energy, sex drive,'' he
said.

``When you give the testosterone and the progestin together, you turn
off the brain signals which normally go to the testicle. As a result the
testicle stops making sperm and stops making testosterone.''

At the end of the trial, the sperm levels of the all the male
participants recovered to the levels they were at before undergoing the
program, McLachlan said, although it took six to 12 months for this to
happen.

McLachlan said the risk of cancer in men taking the contraceptive would
be similar to that of women on female contraception.

Tony Morrow, an endocrinologist from Sydney's Mona Vale hospital, who
was not linked to the research, concurred.

``There's been no evidence reported that higher levels of testosterone
could be related to prostate cancer, if men are on such treatments they
would be monitored,'' he told The AP.

He said more research with larger groups was necessary to evaluate other
possible side effects such as sleep disorders and breathing difficulties.

McLachlan said there are already two pharmaceutical companies interested
in the approach but added it would ``inevitably take several years''
before the contraceptive would reach pharmacy shelves, and more tests
have to be done over longer periods of time.

Considering the limited options for male contraceptives -- condoms and
vasectomies -- this new contraceptive was the most promising male
specific method, McLachlan said.

But Morrow doubted that men would take readily to the new concept.

``I think it's not going to be popular or widespread, because it
involves injections and testosterone implants. I think it is one way
forward because there doesn't seem to be any other way,'' Morrow said.

The study will be published in the October edition of Journal of
Clinical Endocrinology and Metabolism.

   __________________ Abstracts on progesterone and TMJ
___________________

Stomatologiia (Mosk). 2001;80(5):18-21. Related Articles, Links

   [Steroidogenesis disorders in women with temporomandibular
dysfunction]

   [Article in Russian]

   Pisarevskii IuL, Khyshiktuev BS, Belokrinitskaia TE, Semeniuk VM,
Kholmogorov VS.

   The aim of the study was to trace hormone shifts in women suffering
from different manifestation of the TMJ pain dysfunction syndrome.
Levels of some blood steroid hormones (oestradiol, progesterone,
testosterone, cortisol) were determined in 193 female patients aged
14-70. The object of study was blood serum collected in different
menstrual phases. It was found that when pain dysfunction syndrome of
the TMJ was accompanied by intact dentition and orthognathic occlusion
blood steroid levels demonstrated shifts since puberty. In pain
dysfunction syndrome of the TMJ accompanied by occlusal disharmony
steroid shifts were first registered an early reproductive age. In
patients without pain dysfunction syndrome of the TMJ steroid values
remained close to those of healthy control. Shifts in steroid production
may be indicative of impaired steroidogenesis in women with pain
dysfunction syndrome of the TMJ.

   PMID: 11696945 [PubMed - indexed for MEDLINE]

2: J Oral Maxillofac Surg. 2000 Feb;58(2):189-96; discussion 196-7.
Related Articles, Links

   Effect of estrogen replacement on temporomandibular joint remodeling
in ovariectomized rats.

   Yasuoka T, Nakashima M, Okuda T, Tatematsu N.

   Department of Oral and Maxillofacial Surgery, Gifu University School
of Medicine, Japan.

   PURPOSE: The investigation was performed to elucidate the effect of
estrogen on the temporomandibular joint (TMJ) and to evaluate the
therapeutic effect of 17beta-estradiol replacement in growing rats.
MATERIALS AND METHODS: Thirty 4-week-old female albino Wistar rats were
divided into 3 groups. Ten rats were ovariectomized followed by
intramuscular administration of 17beta-estradiol for hormone replacement
(OVX + E2), 10 were sham operated (CTL), and 10 were ovariectomized
without hormone replacement (OVX). Five rats from each group were killed
at 1 and 2 weeks postoperatively, and the serum estrogen was determined
to verify the adequacy of replacement. The temporomandibular joints of
the age-matched sham-operated control and ovariectomized groups were
histomorphometrically evaluated at the same periods. RESULTS: In OVX
animals, the thickness of the articular soft tissue was increased by a
concomitant increase of the transitional and cartilage zones in the
anterior and posterior portions at 1 and 2 weeks postoperatively.
However, the bone volume was decreased in the anterior and posterior
portions at 2 weeks after the surgery and the condyle was flattened.
Replacement with 17beta-estradiol restored most of the histomorphometric
parameters. The thickness of articular soft tissue was increased in the
anterior portion by an increase in the cartilage zone in the OVX + E2
group at 2 weeks postoperatively. Increase of bone volume was found at 2
weeks after hormone replacement with a corresponding increased osteoid
surface and decreased quiescent surface in the central portion at 1 week
postoperatively. A flattened condyle was still noted at 2 weeks
postoperatively in the OVX + E2 animals despite the hormone replacement.
CONCLUSIONS: Estrogen in a physiologic concentration may play an
important role in TMJ remodeling. Progesterone may be indispensable for
remodeling, particularly contributing to morphogenesis.

   PMID: 10670598 [PubMed - indexed for MEDLINE]

3: J Oral Maxillofac Surg. 1996 Jun;54(6):721-7; discussion 727-8.
Related Articles, Links
   Click here to read
   Effects of sex hormones on protein and collagen content of the
temporomandibular joint disc of the rat.

   Abubaker AO, Hebda PC, Gunsolley JN.

   Department of Oral and Maxillofacial Surgery, School of Dentistry,
Medical College of Virginia, Virginia Commonwealth University, Richmond
23298, USA.

   PURPOSE: The effect of sex hormones on the protein and collagen
content of the temporomandibular joint (TMJ) disc of adult male and
female rats. MATERIALS AND METHODS: One hundred forty-four Wistar rats
were assigned to 14 groups of 12 each. Two groups, one female and one
male, served as a control and received no treatment, and two other
groups (one female and one male) received a sham gonadectomy and placebo
hormone. The remaining 10 groups (five males and five females) received
either orchiectomy or ovariectomy, followed by administration of
estrogen, progesterone, combined estrogen and progesterone, or
testosterone. The total protein and collagen content of the TMJ disc
were determined using the calorimetric hydroxyproline method. RESULTS:
The collagen content of TMJ discs of control males was statistically
greater than the collagen content of the control female rats. This
difference disappeared after ovariectomy of females and orchiectomy of
males. Also, there was a general trend for a decrease in collagen and
protein content to be produced by estrogen, progesterone, and by
estrogen combined with progesterone in castrated male and female rats,
and by orchiectomy of male rats. There was also a trend toward an
increase in collagen and protein content after ovariectomy in female
rats and administration of testosterone to castrated male and female
rats. However, the only statistically significant effect of the drugs
tested was that of estrogen combined with progesterone in ovariectomized
female rats (a lowering effect on the total protein) and of estrogen
alone in orchiectomized male rats (a lowering effect on the collagen
content). CONCLUSION: Steroid sex hormones have an effect on the
collagen and protein content of the TMJ disc of the rat as indicated by
the difference in the values between control males and females and by
the disappearance of this difference on castration of both male and
female animals. This was also manifested by the significant effect of
estradiol on collagen content of castrated males, by the effect of
estrogen combined with progesterone on the protein content of castrated
females.

   PMID: 8648477 [PubMed - indexed for MEDLINE]

   __________________ Abstracts on glutamate and TMJ ___________________

J Neurophysiol. 2003 Mar;89(3):1467-77. Related Articles, Links
   Click here to read
   Response properties of TMJ units in superficial laminae at the
spinomedullary junction of female rats vary over the estrous cycle.

   Okamoto K, Hirata H, Takeshita S, Bereiter DA.

   Department of Surgery, Brown Medical School, Rhode Island Hospital,
Providence, Rhode Island 02903, USA.

   Neurons responsive to stimulation of the temporomandibular joint
(TMJ) region were recorded from superficial laminae at the trigeminal
subnucleus caudalis/upper cervical cord (Vc/C(2)) junction region of
cycling female rats under barbiturate anesthesia. To determine if
receptive field (RF) properties or sensitivity to algesic chemicals of
TMJ units vary over the estrous cycle, animals were selected from
proestrous (high estrogen) or early diestrous (low estrogen) stages.
More than 90% of TMJ units from each group received convergent
nociceptive input [wide dynamic range (WDR) or nociceptive specific
(NS)-like] from facial skin. The cutaneous high-threshold RF areas of
WDR units from proestrous rats were 30% larger than diestrous units,
while RF areas of NS units were similar. Bradykinin (BK, 0.1-10 microM)
injection into the TMJ region excited a high percentage of units (>80%
of total) from both groups in a dose-related manner. However, BK-evoked
response magnitude (R(mag), +140%) and duration (+64%) were greater for
proestrous than diestrous units. Both WDR and NS-like TMJ units of
proestrous females displayed enhanced BK-evoked R(mag) values and
response duration. Glutamate or mustard oil excitation of TMJ units was
not affected by stage of the estrous cycle. Several TMJ units from
proestrous and diestrous females were activated antidromically from the
contralateral posterior thalamus, indicating that projection and
nonprojection units were included in the sample population. These
results were consistent with the hypothesis that factors related to
stage of the estrous cycle modify the processing of deep craniofacial
inputs by superficial dorsal horn neurons at the spinomedullary
junction, a key region for the initial integration of sensory signals
from the TMJ.

   PMID: 12626622 [PubMed - indexed for MEDLINE]

2: Brain Res. 2002 Dec 13;957(2):338-44. Related Articles, Links
   Click here to read
   Influence of sex on reflex jaw muscle activity evoked from the rat
temporomandibular joint.

   Cairns BE, Sim Y, Bereiter DA, Sessle BJ, Hu JW.

   Department of Oral Physiology, Faculty of Dentistry, The University
of Toronto, 124 Edward Street, Toronto, ON, Canada.

   Injection of glutamate into the rat temporomandibular joint (TMJ)
evoked a concentration-dependent increase in jaw muscle activity. We
investigated whether there are sex-related differences in
glutamate-evoked jaw muscle activity that are mediated by sex hormones
and whether prior injection of glutamate into the TMJ alters the
magnitude of jaw muscle activity evoked by a subsequent injection of the
algesic and inflammatory compound mustard oil (MO) into the TMJ. The
magnitude of glutamate-evoked digastric and masseter muscle activity was
significantly greater in female than male rats when 1000 mM glutamate
was injected into the TMJ. Gonadectomy significantly reduced the
magnitude of glutamate-evoked digastric muscle activity in female rats.
Treatment of gonadectomized female rats with estrogen (20 microg/day)
increased the magnitude of glutamate-evoked digastric muscle activity.
Glutamate-evoked jaw muscle activity in gonadectomized and
estrogen-treated gonadectomized males was not significantly different
from intact males. Prior injection of glutamate over a concentration
range of 10-1000 mM significantly increased digastric muscle activity
evoked by MO injection into the TMJ 30 min later. In contrast, MO-evoked
masseter muscle activity was significantly increased by prior injection
of 250 mM glutamate only. There were, however, no sex-related
differences in the enhancement of MO-evoked jaw muscle activity by prior
injection of glutamate. These findings indicate that there are
sex-related differences in glutamate-evoked jaw muscle activity that are
dependent on female sex hormones, and increased glutamate concentrations
sensitize the TMJ to noxious chemical stimuli.

   PMID: 12445976 [PubMed - indexed for MEDLINE]

3: Pain. 2002 Jul;98(1-2):89-99. Related Articles, Links
   Click here to read
   Sex differences in amino acid release from rostral trigeminal
subnucleus caudalis after acute injury to the TMJ region.

   Bereiter DA, Shen S, Benetti AP.

   Department of Surgery, Brown Medical School, Rhode Island Hospital,
222 Nursing Arts Bldg., Providence, RI 02903, USA.

   The neurological basis for painful temporomandibular disorders (TMD)
and the higher prevalence of TMD pain in women than men is not known. To
better define the circuitry and neurochemical mechanisms in the lower
brainstem associated with noxious sensory inputs from the
temporomandibular joint (TMJ) region a microdialysis method was used to
measure the release of amino acid transmitters from the ventral
trigeminal subnucleus interpolaris/caudalis transition region
(Vi/Vc-vl). The irritant chemical, mustard oil, was injected into the
TMJ region (TMJ-MO) under barbiturate anesthesia in males and normal
cycling female rats. Males displayed significant increases in glutamate,
serine, and glycine within 15 min after TMJ-MO and increases in
citrulline occurred after a delay of 15-30 min. TMJ-MO did not enhance
amino acid release in diestrus or proestrus females. GABA release was
not affected by TMJ-MO in males or females. Pretreatment with morphine
(3 mg/kg, i.v.) prevented the increase in amino acid release seen after
TMJ-MO in males. Amino acid release at the Vi/Vc-vl transition region
evoked by TMJ-MO also was prevented by prior microinjection of the
GABA(A) receptor agonist, muscimol, into the most caudal portion of Vc
suggesting this region acted as a critical relay for nociceptive inputs
from the TMJ region. These results suggest that glutamatergic mechanisms
acting at the Vi/Vc-vl transition region contribute to processing of
nociceptive signals that arise from the TMJ region. These results also
are consistent with the hypothesis that central neural mechanisms that
integrate nociceptive inputs from deep craniofacial tissues are
different in males and females.

   PMID: 12098620 [PubMed - indexed for MEDLINE]

4: Neuroreport. 2001 Nov 16;12(16):3457-60. Related Articles, Links
   Click here to read
   Sex-related suppression of reflex jaw muscle activity by peripheral
morphine but not GABA.

   Cai BB, Cairns BE, Sessle BJ, Hu JW.

   Faculty of Dentistry, University of Toronto, 124 Edward Street,
Toronto, Ontario M5G 1G6, Canada.

   The present study examined the effect of peripherally applied
morphine and GABA on jaw muscle electromyographic activity reflexly
evoked by co-injection of glutamate into the temporomandibular joint
(TMJ) of lightly anesthetized Sprague-Dawley rats of both sexes. In male
but not female rats, morphine significantly suppressed glutamate-evoked
jaw muscle activity in a dose-dependent and naloxone-reversible manner.
The median suppressive dose (+/- s.e.) for male rats was 12.7 +/- 3.1
microg (digastric muscle) and 12.6 +/- 1.3 microg (masseter muscle).
GABA (5 micromol) significantly reduced glutamate-evoked muscle activity
in both sexes. These data suggest that female rats are considerably less
sensitive than male rats to the suppressive effects of peripherally
applied morphine, but both sexes are equally affected by peripherally
applied GABA.

   PMID: 11733690 [PubMed - indexed for MEDLINE]

5: J Neurophysiol. 2001 Nov;86(5):2393-404. Related Articles, Links
   Click here to read
   Intensity coding by TMJ-responsive neurons in superficial laminae of
caudal medullary dorsal horn of the rat.

   Takeshita S, Hirata H, Bereiter DA.

   Department of Surgery, Brown Medical School, Rhode Island Hospital,
Providence, Rhode Island 02903, USA.

   Temporomandibular disorders (TMD) represent a family of recurrent
conditions that often cause pain in the temporomandibular joint (TMJ)
region and muscles of mastication. To determine if TMJ-responsive
neurons encoded the intensity of pro-inflammatory chemical signals,
dose-effect relationships were assessed after direct injection
bradykinin into the joint space and compared with responses after
injection of glutamate or saline. Neurons were recorded from superficial
laminae of the trigeminal subnucleus caudalis/upper cervical cord
junction region (Vc/C(2)) and identified by palpation of the TMJ region
in barbiturate-anesthetized male rats. The majority (62 of 84) of units
received convergent input from facial skin, while 26% were driven only
by deep input from the TMJ region. Conduction-velocity based on the
latency to firing after electrical stimulation of the TMJ region
indicated 64% of units were driven by A-delta fiber input only.
Bradykinin (0.1-10 microM) excited 69% of neurons tested, and 70% (19 of
27) of these units were activated by the lowest dose (0.1 microM).
Glutamate (50-200 mM) excited 27% of units; however, when tested after
bradykinin, 58% of units were activated by glutamate. Some TMJ units
(17%) were excited by saline injection alone and not enhanced further by
bradykinin or glutamate. Most (88%) TMJ units were activated by
injection of the small fiber excitant, mustard oil (20% solution), into
the TMJ region. Units responsive to bradykinin or glutamate were not
restricted to particular classes [e.g., wide dynamic range (WDR),
nociceptive specific (NS), deep only]. A small percentage of TMJ units
(approximately 15%) were activated antidromically from the contralateral
posterior thalamus. In parallel studies using c-fos immunocytochemistry,
bradykinin (1 microM) injection into the TMJ region produced a greater
number of Fos-positive neurons at the Vc/C(2) region than glutamate (200
mM) or saline. These results revealed two broad classes of TMJ units
that encoded the intensity of pro-inflammatory chemical stimuli applied
to the TMJ region, units that received convergent nociceptive input from
facial skin (i.e., WDR and NS units) and units that responded only to
deep input from the TMJ region. On the basis of encoding properties and
efferent projection status, it is concluded that activation of TMJ units
within the superficial laminae at the Vc/C(2) region contribute to the
diffuse and spreading nature of TMD pain sensation.

   PMID: 11698529 [PubMed - indexed for MEDLINE]

6: Neuroreport. 2001 Jul 3;12(9):1875-8. Related Articles, Links
   Click here to read
   Temporomandibular-evoked jaw muscle reflex: role of brain stem NMDA
and non-NMDA receptors.

   Cairns BE, Sessle BJ, Hu JW.

   Faculty of Dentistry, The University of Toronto, 124 Edward Street,
Toronto, Ontario M5G 1G6, Canada.

   This study investigated the possible involvement of brain stem
excitatory amino acid receptor mechanisms and the trigeminal subnucleus
caudalis (Vc) in temporomandibular joint (TMJ)-evoked reflex jaw muscle
activity. Glutamate injected into the TMJ of anesthetized rats reflexly
evoked activity in the jaw muscles. Application of lidocaine, but not
saline, to the surface of the caudal brainstem overlying Vc
significantly suppressed TMJ-evoked jaw muscle activity, while
application of NMDA or non-NMDA receptor antagonists also significantly
attenuated jaw muscle activity. These results provide evidence that Vc
is a critical relay in the TMJ-evoked reflex activation of the jaw
muscles, and that both NMDA and non-NMDA receptor mechanisms may
contribute to these effects.

   PMID: 11435915 [PubMed - indexed for MEDLINE]

7: J Neurophysiol. 2001 Jun;85(6):2446-54. Related Articles, Links
   Click here to read
   Characteristics of glutamate-evoked temporomandibular joint afferent
activity in the rat.

   Cairns BE, Sessle BJ, Hu JW.

   Faculty of Dentistry, The University of Toronto, Toronto, Ontario
M5G 1G6, Canada.

   Injection of glutamate into the rat temporomandibular joint (TMJ)
capsule can reflexly induce a prolonged increase in the
electromyographic (EMG) activity of the jaw muscles, however, the
characteristics of TMJ afferents activated by glutamate have not been
investigated. In the present study, we examined the effect of glutamate
injection into the TMJ capsule on jaw muscle EMG activity and the
extracellularly recorded activity of single trigeminal afferents that
had receptive fields in the TMJ tissue and antidromically identified
projections to the brain stem subnucleus caudalis (Vc) in rats of both
sexes. Glutamate (0.05--1.0 M, 10 microl) injection into the TMJ capsule
evoked EMG activity in a dose-related manner; however, at concentrations
of 0.5 and 1.0 M, glutamate-evoked digastric muscle responses were
greater in female than in male rats. In experiments where jaw muscle EMG
and afferent activity were recorded simultaneously, glutamate (0.5 M, 10
microl) injection into the TMJ capsule evoked activity in the jaw
muscles as well as in 27 (26 A delta and 1 C-fiber afferent) of 34
trigeminal afferents that could be activated by blunt mechanical
stimulation of the TMJ tissue. In these experiments, glutamate-evoked
jaw muscle activity was significantly increased for 6 min after the
glutamate injection, whereas afferent activity was significantly
increased only during the first minute after the glutamate injection.
The glutamate-evoked afferent activity was inversely related to
conduction velocity and, in afferents with conduction velocities <10
m/s, was significantly greater in female (n = 6) than in male (n = 10)
rats. These results suggest that glutamate excites putative nociceptive
afferents within the TMJ to a greater degree in female than in male
rats. This sex-related difference in afferent discharge may, in part,
underlie sex-related differences in glutamate-evoked jaw muscle EMG
activity.

   PMID: 11387390 [PubMed - indexed for MEDLINE]

8: Anat Rec. 2000 Apr 1;258(4):369-83. Related Articles, Links
   Click here to read
   Increased in vivo levels of neurotransmitters to trigeminal
motoneurons: effects on craniofacial bone and TMJ.

   Byrd KE, Yang L, Yancey KW, Teomim D, Domb AJ.

   Department of Anatomy, Indiana University School of Medicine,
Indianapolis 46202, USA.

   The results of chronic, in vivo delivery of excitatory and
inhibitory neurotransmitter substances upon the craniofacial skeleton
are of ongoing interest to clinician and basic scientist alike. Our
purpose was to document and compare the effects of biodegradable
glycine, glutamate, and thyrotropin-releasing hormone (TRH) microspheres
upon the craniofacial skeleton and TMJ of actively growing rats.
Glycine, glutamate, TRH, and blank microspheres were stereotactically
implanted in proximity to motoneurons within the trigeminal motor
nucleus in order to test the following null hypotheses: (1)
neurotransmitter microspheres implanted near trigeminal motoneurons of
growing rats have no significant effect on the craniofacial skeleton and
temporomandibular joints of implanted animals, and (2) there are no
significant differences between the relative effects of glutamate, TRH
(excitatory to trigeminal motoneurons), and glycine (inhibitory to
trigeminal motoneurons) implants upon the craniofacial skeleton and
temporomandibular joint. Fifty male Sprague-Dawley rats underwent
stereotactic neurosurgery at 35 days; five rats each were killed at 14
and 21 days postoperative for data collection and comparison between
glycine-, glutamate-, TRH-, blank-microsphere, and sham-surgery rats.
Glycine rats had significantly (P < or = 0.05, 0. 01) smaller
implant-side cranial dimensions and mandibular condyles, all glycine
rats showed increased gracility of implant-side bones, and deviation of
their facial skeleton away from the implant-side; this was in contrast
to the generally larger implant-side bony structures in both glutamate
and TRH rats. The two null hypotheses were both rejected. Due to their
inhibitory and excitatory effects upon trigeminal motoneurons,
masticatory muscles, and their neuromuscular generation of biomechanical
forces that affect bone, the neurotransmitter substances glycine,
glutamate, and TRH appear to play an important role in the growth and
development of the mammalian craniofacial skeleton and TMJ. Copyright
2000 Wiley-Liss, Inc.

   PMID: 10737855 [PubMed - indexed for MEDLINE]

9: J Neurophysiol. 1999 Apr;81(4):1966-9. Related Articles, Links
   Click here to read
   Activation of peripheral GABAA receptors inhibits temporomandibular
joint-evoked jaw muscle activity.

   Cairns BE, Sessle BJ, Hu JW.

   Department of Oral Physiology, Faculty of Dentistry, University of
Toronto, Toronto M5G 1G6 Canada.

   We have previously shown that injection of mustard oil or glutamate
into rat temporomandibular joint (TMJ) tissues, an experimental model of
acute TMJ injury, can reflexly induce a prolonged increase in the
activity of both digastric (jaw-opener) and masseter (jaw-closer)
muscles. In this study, GABA was applied to the TMJ region by itself or
in combination with glutamate, and the magnitude of evoked jaw muscle
electromyographic (EMG) activity was measured. Application of GABA alone
to the TMJ region did not evoke significant jaw muscle EMG activity when
compared with normal saline controls. In contrast, co-application of
GABA and glutamate into the TMJ region decreased the magnitude of
glutamate-evoked EMG activity. This GABA-mediated inhibition of
glutamate-evoked EMG activity followed an inverse dose-response
relationship with an estimated median inhibitory dose (ID50) of 0.17 +/-
0.05 (SE) micromol and 0.031 +/- 0.006 micromol for the digastric and
masseter muscles, respectively. Co-administration of the GABAA receptor
antagonist bicuculline (0.05 micromol) but not the GABAB receptor
antagonist phaclofen (0.05 or 0. 15 micromol) reversed the suppressive
actions of GABA, indicating that this action of GABA may be mediated by
peripheral GABAA receptors located within the TMJ region. Our results
suggest that activation of peripheral GABAA receptors located within the
TMJ region could act to decrease the transmission of nociceptive
information.

   PMID: 10200231 [PubMed - indexed for MEDLINE]

10: Arch Oral Biol. 1999 Jan;44(1):27-32. Related Articles, Links
   Click here to read
   Development of inflammation after application of mustard oil or
glutamate to the rat temporomandibular joint.

   Fiorentino PM, Cairns BE, Hu JW.

   Faculty of Dentistry, University of Toronto, Ontario, Canada.

   Application of the small-fibre excitant and inflammatory irritant
mustard oil or the excitatory amino-acid receptor agonist glutamate to
the rat temporomandibular joint (TMJ) region evokes similar changes in
jaw-muscle activity, suggesting that peripheral application of glutamate
may be nociceptive. Application of mustard oil to the TMJ region is also
inflammatory, but, it is not clear if application of glutamate is
equally inflammatory. In this study the extent of plasma-protein
extravasation and oedema induced by mustard oil application to the TMJ
region was compared with that induced by glutamate. Application of
mustard oil resulted in plasma-protein extravasation into the TMJ
tissues and oedema of the TMJ region. In contrast, glutamate did not
cause plasma-protein extravasation or oedema.

   PMID: 10075147 [PubMed - indexed for MEDLINE]

11: J Neurosci. 1998 Oct 1;18(19):8056-64. Related Articles, Links
   Click here to read
   Evidence that excitatory amino acid receptors within the
temporomandibular joint region are involved in the reflex activation of
the jaw muscles.

   Cairns BE, Sessle BJ, Hu JW.

   Department of Oral Physiology, Faculty of Dentistry, The University
of Toronto, Toronto, Ontario M5G 1G6, Canada.

   We have previously shown that injection of the inflammatory irritant
and small-fiber excitant mustard oil (MO) into the temporomandibular
joint (TMJ) region can reflexively induce a prolonged increase in the
activity of both digastric and masseter muscles in rats. It is possible
that peripheral excitatory amino acid (EAA) receptors play a role in
this effect, because MO-evoked increases in jaw muscle activity are
attenuated by preapplication of the noncompetitive NMDA receptor
antagonist MK-801 into the TMJ region. In the present study the EAA
receptor agonists glutamate, NMDA, kainate, and AMPA were applied
locally to the TMJ region. Jaw muscle responses similar to those evoked
by MO application to the TMJ region were achieved with glutamate, NMDA,
AMPA, and kainate. Repeated application of glutamate, NMDA, or AMPA at
intervals of 30 min evoked responses in the ipsilateral jaw muscles that
were of comparable magnitude. Co-application of the NMDA receptor
antagonist DL-2-amino-5-phosphonovalerate (0.5 micromol) significantly
reduced the magnitude of the glutamate- and NMDA-evoked ipsilateral jaw
muscle responses without affecting responses evoked by AMPA. In
contrast, co-application of the non-NMDA receptor antagonist
6-cyano-7-nitroquinoxaline-2,3-dione (1 nmol) significantly reduced the
magnitude of the glutamate- and AMPA-evoked ipsilateral jaw muscle
responses without affecting responses evoked by NMDA. This evidence
suggests that both NMDA and non-NMDA EAA receptor types are located
within the TMJ region and may contribute to jaw muscle activity that can
be reflexively evoked from the TMJ region.

   PMID: 9742172 [PubMed - indexed for MEDLINE]

13: Pain. 1996 Oct;67(2-3):451-9. Related Articles, Links

   Excitatory amino release within spinal trigeminal nucleus after
mustard oil injection into the temporomandibular joint region of the rat.

   Bereiter DA, Benetti AP.

   Department of Neuroscience, Brown University/Rhode Island Hospital,
Providence, RI 02903, USA.

   Inflammation of the temporomandibular joint (TMJ) region evokes pain
and hyperalgesia as well as causing persistent changes in the response
properties of central trigeminal neurons. To determine if excitatory
amino acids have a role in TMJ-induced responses, extracellular
concentrations were measured in microdialysate samples from probes
positioned in the spinal trigeminal nucleus (Vsp) near the transition
region between subnucleus interpolaris and subnucleus caudalis (Vi/Vc)
in chloralose-anesthetized rats. Injection of the selective small fiber
excitant, mustard oil (20 microliters, 20% solution), into the
ipsilateral TMJ region caused a transient (by 10 min) increase in
glutamate (from 0.48 +/- 0.16 to 1.94 +/- 0.78 microM, P < 0.005) and
aspartate (from 0.29 +/- 0.11 to 1.78 +/- 0.82 microM, P < 0.025) among
sites located at the ventrolateral pole of the Vi/Vc transition region
(n = 6). Samples from probes located within the ventral Vsp, but outside
this Vi/Vc transition region (n = 9), did not show significant changes
in amino acid concentrations. Glutamate and aspartate also increased
after mustard oil injections into the contralateral TMJ region.
Dialysate concentrations of serine and taurine did not change
significantly after mustard oil injections. Addition of high potassium
(150 mM) to the perfusate solution caused increases in glutamate and
aspartate regardless of probe location. The transient and selective
release of glutamate and aspartate within the Vi/Vc transition after
acute irritation of the TMJ region is consistent with a proposed role
for excitatory amino acids in mediating noxious sensory input from deep
orofacial structures. Together with previous reports of c-fos
expression, these results suggest that neurons within the ventrolateral
portion of the Vi/Vc transition may serve as a relay site for the
integration of sensory or reflex responses to acute inflammation of the
TMJ region.

   PMID: 8951941 [PubMed - indexed for MEDLINE]

    __________________ Abstracts on allopregnanolone __________________

Eur Neuropsychopharmacol. 2003 Oct;13(5):327-32. Related Articles, Links
   Click here to read
   Brain neurosteroid changes after paroxetine administration in mice.

   Nechmad A, Maayan R, Spivak B, Ramadan E, Poyurovsky M, Weizman A.

   Laboratory of Biological Psychiatry, Felsenstein Medical Research
Center, Petah Tikva, Israel.

   Although it is known that selective serotonin reuptake inhibitors
(SSRIs), as other antidepressants, elevate mood only after 3-4 weeks of
treatment, the mechanism responsible for this delay is not understood.
SSRIs have been demonstrated to alter the levels of neurosteroids such
as allopregnanolone (THP) which possess anxiolytic and mood-elevating
properties. We compared the effect of 9 and 21 days i.p. administration
of paroxetine, a potent SSRI, on the synthesis of THP and its precursor,
5alpha-dihydroprogesterone (DHP), in the mouse cortex, hypothalamus and
olfactory bulb. Cortex, olfactory bulb and hypothalamus synthesized
levels of DHP were significantly raised after 9 days of paroxetine
administration, whereas a significant rise in the THP synthesized level
was observed only after 21 days of treatment. Peripheral synthesis of
DHP, measured by the level in serum, significantly increased after 9
days, but reverted to normal values after 21 days. No increase was
detected in serum THP levels either after 9 or 21 days treatment.
Differences in peripheral and brain synthesis indicates independence in
brain synthesis. The data indicate that paroxetine administration
differentially increases [3H]DHP and [3H]THP content, depending on the
duration of the treatment. Our results suggest that brain THP may be
involved in the antidepressive and anxiolytic activity of paroxetine.

   PMID: 12957330 [PubMed - in process]

Neuropharmacology. 2003 Sep;45(4):461-72. Related Articles, Links
   Click here to read
   Steroid-sensitive GABAA receptors in the fetal sheep brain.

   Crossley KJ, Nitsos I, Walker DW, Lawrence AJ, Beart PM, Hirst JJ.

   Department of Physiology, Monash University, P.O. Box, Building 13F,
Clayton, Victoria 3800, Australia.

   Neuroactive steroids such as allopregnanolone (3 alpha-hydroxy-5
alpha-pregnan-20-one) influence central nervous system (CNS)
excitability by increasing GABA (gamma aminobutyric acid) inhibitory
activity. Allopregnanolone concentrations are higher in the fetal
compared to the adult ovine brain, suggesting that this neurosteroid may
have a role in regulating fetal CNS activity during gestation. We
examined the localisation of allopregnanolone-sensitive GABA(A)
receptors in the fetal brain to determine if their sensitivity to
allopregnanolone changed during late gestation. The binding of [(35)S]
tert-butylbicyclophosothionate (TBPS) was used to identify the
GABA-chloride ion receptor complex in fetal sheep brains at 90-95,
115-120 and 140-145 days gestational age (GA; term approximately 147
days), by autoradiography. Allopregnanolone (200 nM) reduced [(35)S]TBPS
binding by 70-100% throughout the brain at all fetal ages examined. The
levels of [(35)S]TBPS binding increased with advancing gestation in all
regions examined except some areas of the medulla. Functionally related
nuclei and brain areas associated with regulating somato/viscerosensory
functions displayed high levels of [(35)S]TBPS binding from
mid-gestation. These results indicate that allopregnanolone may interact
with GABA(A) receptors to inhibit fetal CNS activity from mid-gestation.
This inhibition may contribute to maintaining the sleep-like behaviour
and low incidence of arousal-type activity typical of fetal life, and
may be neuroprotective by limiting excitatory neurotransmission.

   PMID: 12907307 [PubMed - in process]

Brain Res. 2003 Aug 8;980(2):255-65. Related Articles, Links
   Click here to read
   Neuroactive steroid 3 alpha-hydroxy-5 alpha-pregnan-20-one modulates
ethanol-induced loss of righting reflex in rats.

   Khisti RT, VanDoren MJ, O'Buckley T, Morrow AL.

   Departments of Psychiatry and Pharmacology, Bowles Center for
Alcohol Studies, University of North Carolina at Chapel Hill, School of
Medicine, CB #7178, Chapel Hill, NC 27599-7178, USA.

   Systemic ethanol administration elevates plasma and brain levels of
GABAergic neuroactive steroids, including
3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-THP) that contribute
to specific behavioral actions of ethanol. The present study determined
the effect of adrenalectomy and 5alpha-reductase type-1/type-2 enzyme
inhibition, known to reduce neuroactive steroids, on ethanol-induced
increases in cerebral cortical levels of 3alpha,5alpha-THP and hypnotic
effects in male rats. Systemic ethanol administration to male rats
increases plasma levels of progesterone and corticosterone similar to
acute stress, indicating release of these steroids from adrenal glands.
Adrenalectomy markedly reduced the elevation of cerebral cortical
3alpha,5alpha-THP and plasma progesterone levels and reduced the
duration of ethanol-induced loss of righting reflex. Prior systemic
administration of 5alpha-dihydroprogesterone (10 or 15 mg/kg, i.p.), an
immediate precursor of 3alpha,5alpha-THP, to adrenalectomized rats not
only restored the ethanol-induced increases in cerebral cortical
3alpha,5alpha-THP levels but also reversed the effect of adrenalectomy
on ethanol-induced loss of righting reflex. Prior administration of the
5alpha-reductase inhibitor finasteride (2 x 25, 2 x 75 or 2 x 150 mg/kg,
s.c.) and the 5alpha-reductase type-1 inhibitor SKF-105,111 (50 mg/kg,
i.p.) did not reduce ethanol-induced increases in the cerebral cortical
levels of 3alpha,5alpha-THP at hypnotic doses of ethanol. Furthermore,
these drugs did not alter the duration of loss of righting reflex.
However, significant correlations between cerebral cortical
3alpha,5alpha-THP levels and the duration of loss of righting reflex
were obtained regardless of finasteride administration. These results
demonstrate the contributory role of neuroactive steroids in the
ethanol-induced loss of righting reflex and the source of
ethanol-induced elevation of GABAergic neuroactive steroids.
Ethanol-induced increases in neurosteroids could be pertinent to the
etiology of sleep-related disorders associated with alcoholism.

   PMID: 12867266 [PubMed - indexed for MEDLINE

Eur J Pharmacol. 2003 Aug 8;474(2-3):217-22. Related Articles, Links
   Click here to read
   Protective efficacy of neuroactive steroids against cocaine
kindled-seizures in mice.

   Kaminski RM, Gasior M, Carter RB, Witkin JM.

   NIDA Addiction Research Center, 5500 Nathan Shock Drive, Baltimore,
MD 21224, USA.

   Neuroactive steroids demonstrate pharmacological actions that have
relevance for a host of neurological and psychiatric disorders. They
offer protection against seizures in a range of models and seem to
inhibit certain stages of drug dependence in preclinical assessments.
The present study was designed to evaluate two endogenous and one
synthetic neuroactive steroid that positively modulate the
gamma-aminobutyric acid (GABA(A)) receptor against the increase in
sensitivity to the convulsant effects of cocaine engendered by repeated
cocaine administration (seizure kindling). Allopregnanolone
(3alpha-hydroxy-5alpha-pregnan-20-one), pregnanolone
(3alpha-hydroxy-5beta-pregnan-20-one) and ganaxolone (a synthetic
derivative of allopregnanolone
3alpha-hydroxy-3beta-methyl-5alpha-pregnan-20-one) were tested for their
ability to suppress the expression (anticonvulsant effect) and
development (antiepileptogenic effect) of cocaine-kindled seizures in
male, Swiss-Webster mice. Kindled seizures were induced by daily
administration of 60 mg/kg cocaine for 5 days. All of these positive
GABA(A) modulators suppressed the expression of kindled seizures,
whereas only allopregnanolone and ganaxolone inhibited the development
of kindling. Allopregnanolone and pregnanolone, but not ganaxolone, also
reduced cumulative lethality associated with kindling. These findings
demonstrate that some neuroactive steroids attenuate convulsant and
sensitizing properties of cocaine and add to a growing literature on
their potential use in the modulation of effects of drugs of abuse.

   PMID: 12921865 [PubMed - in process]

Eur J Pharmacol. 2003 Aug 8;474(2-3):217-22. Related Articles, Links
   Click here to read
   Protective efficacy of neuroactive steroids against cocaine
kindled-seizures in mice.

   Kaminski RM, Gasior M, Carter RB, Witkin JM.

   NIDA Addiction Research Center, 5500 Nathan Shock Drive, Baltimore,
MD 21224, USA.

   Neuroactive steroids demonstrate pharmacological actions that have
relevance for a host of neurological and psychiatric disorders. They
offer protection against seizures in a range of models and seem to
inhibit certain stages of drug dependence in preclinical assessments.
The present study was designed to evaluate two endogenous and one
synthetic neuroactive steroid that positively modulate the
gamma-aminobutyric acid (GABA(A)) receptor against the increase in
sensitivity to the convulsant effects of cocaine engendered by repeated
cocaine administration (seizure kindling). Allopregnanolone
(3alpha-hydroxy-5alpha-pregnan-20-one), pregnanolone
(3alpha-hydroxy-5beta-pregnan-20-one) and ganaxolone (a synthetic
derivative of allopregnanolone
3alpha-hydroxy-3beta-methyl-5alpha-pregnan-20-one) were tested for their
ability to suppress the expression (anticonvulsant effect) and
development (antiepileptogenic effect) of cocaine-kindled seizures in
male, Swiss-Webster mice. Kindled seizures were induced by daily
administration of 60 mg/kg cocaine for 5 days. All of these positive
GABA(A) modulators suppressed the expression of kindled seizures,
whereas only allopregnanolone and ganaxolone inhibited the development
of kindling. Allopregnanolone and pregnanolone, but not ganaxolone, also
reduced cumulative lethality associated with kindling. These findings
demonstrate that some neuroactive steroids attenuate convulsant and
sensitizing properties of cocaine and add to a growing literature on
their potential use in the modulation of effects of drugs of abuse.

   PMID: 12921865 [PubMed - in process]

FASEB J. 2003 Aug;17(11):1428-33. Related Articles, Links
   Click here to read
   Differential regulation of steroid 5alpha-reductase isozymes
expression by androgens in the adult rat brain.

   Torres JM, Ortega E.

   Department of Biochemistry and Molecular Biology, Faculty of
Medicine, University of Granada, Avda. de Madrid s/n, 18012 Granada,
Spain.

   The enzyme 5alpha-reductase (5alpha-R) is present in many mammalian
tissues, including the brain. The physiological importance of 5alpha-R
in the brain derives from its capability to convert testosterone (T) to
a more potent androgen, dihydrotestosterone (DHT), and to convert
progesterone and deoxycorticosterone (DOC) to their respective
5alpha-reduced derivatives, precursors of allopregnanolone and
tetrahydroDOC, potent allosteric modulators of the gamma-aminobutyric
acid receptor (GABA(A)-R). 5alpha-R occurs as two isoforms, 5alpha-R
type 1 (5alpha-R1) and 5alpha-R type 2 (5alpha-R2). We studied the
effects of T and DHT on the mRNA levels of both 5alpha-R isozymes in the
prefrontal cortex of the adult rat, using an accurate and precise method
that combines the high specificity of one-step quantitative RT-PCR with
the sensitivity of capillary electrophoresis. Our results demonstrate
that both isozymes of 5alpha-R are expressed in the cerebral cortex of
adult rats. The gene expression of 5alpha-R type 2 is under the positive
control of T and DHT. The gene that codes for 5alpha-R type 1 is not
constitutive, because its expression is negatively regulated by T and
DHT. These results open up a new research line that may lead to a better
understanding of the role of 5alpha-R isozymes in the physiology of the
central nervous system.

   PMID: 12890696 [PubMed - indexed for MEDLINE]

J Neurochem. 2003 Aug;86(4):848-59. Related Articles, Links
   Click here to read
   Progesterone and its metabolites increase myelin basic protein
expression in organotypic slice cultures of rat cerebellum.

   Ghoumari AM, Ibanez C, El-Etr M, Leclerc P, Eychenne B, O'Malley BW,
Baulieu EE, Schumacher M.

   INSERM U488, Bicetre, France.

   We have previously shown that progesterone (PROG) is synthesized by
Schwann cells and promotes myelin formation in the peripheral nervous
system (PNS). We now report that this neurosteroid also stimulates
myelination in organotypic slice cultures of 7-day-old (P7) rat and
mouse cerebellum. Myelination was evaluated by immunofluorescence
analysis of the myelin basic protein (MBP). After 7 days in culture
(7DIV), we found that adding PROG (2(-5) x 10(-5) M) to the culture
medium caused a fourfold increase in MBP expression when compared to
control slices. The effect of PROG on MBP expression involves the
classical intracellular PROG receptor (PR): the selective PR agonist
R5020 significantly increased MBP expression and the PR antagonist
mifepristone (RU486) completely abolished the effect of PROG on this MBP
expression. Moreover, treatment of P7-cerebellar slice cultures from PR
knockout (PRKO) mice with PROG had no significant effect on MBP
expression. PROG was metabolized in the cerebellar slices to
5alpha-dihydroprogesterone (5alpha-DHP) and to the GABAA receptor-active
metabolite 3alpha,5alpha-tetrahydroprogesterone (3alpha,5alpha-THP,
allopregnanolone). The 5alpha-reductase inhibitor L685-273 partially
inhibited the effect of PROG, and 3alpha,5alpha-THP (2(-5) x 10(-5) M)
significantly stimulated the MBP expression, although to a lesser extent
than PROG. The increase in MBP expression by 3alpha,5alpha-THP involved
GABAA receptors, as it could be inhibited by the selective GABAA
receptor antagonist bicuculline. These findings suggest that progestins
stimulate MBP expression and consequently suggest an increase in CNS
myelination via two signalling systems, the intracellular PR and
membrane GABAA receptors, and they confirm a new role of GABAA receptors
in myelination.

   PMID: 12887683 [PubMed - indexed for MEDLINE]

Maturitas. 2003 Jul 25;45(3):231-5. Related Articles, Links
   Click here to read
   Progesterone increase under DHEA-substitution in males.

   Nadjafi-Triebsch C, Huell M, Burki D, Rohr UD.

   MD Gyn/Ob and Consultant in Womens' Health, Basle, Switzerland.

   Two case reports of men suffering from excessive fatigue and
depression are presented, both treated with 50 or 25 mg DHEA per day
over a period of 1 year. Under DHEA treatment one subject reported being
less tired and the other experienced improved well-being without
depressive episodes and an increase in libido. Investigations of sex
hormone parameters in plasma before and under treatment revealed a
decrease of testosterone and an increase of progesterone in both,
possibly dose-dependent to DHEA application. It is hypothesised that the
increase of progesterone is parallel to an increase of its metabolite
allopregnanolone (which was not determined), that might explain the
improvement in well-being. The increase of progesterone under DHEA
supplementation in males should receive further attention.

   PMID: 12818469 [PubMed - in process]

Pharmacol Biochem Behav. 2003 Jul;75(4):889-94. Related Articles, Links
   Click here to read
   Finasteride inhibits the progesterone-induced spike-wave discharges
in a genetic model of absence epilepsy.

   van Luijtelaar G, Budziszewska B, Tetich M, Lason W.

   NICI, Biological Psychology, University of Nijmegen, The
Netherlands.

   Previously, it was found that progesterone aggravates spike-wave
discharges (SWD) in WAG/Rij rats in a nongenomic way. In order to
elucidate whether the regulatory effect of progesterone depends on its
conversion to allopregnanolone, the effect of finasteride, a
5alpha-reductase inhibitor, on progesterone-induced increase in SWD was
studied in the same model for absence epilepsy. Progesterone (10 and 20
mg/kg ip) dose-dependently increased the number of SWD (by 54% and 97%,
respectively) during the first hour postinjection. Pretreatment of rats
with finasteride (50 mg/kg sc) blocked the progesterone-induced
enhancement of SWD. Finasteride alone had no effect on the number of
SWD, up to 24 h following its administration. It is concluded that
finasteride blocked the progesterone-induced increase in SWD, which
indicates that this action of progesterone is mediated by its
neuroactive metabolite allopregnanolone.

   PMID: 12957232 [PubMed - in process

Pharmacol Biochem Behav. 2003 Jul;75(4):831-5. Related Articles, Links
   Click here to read
   Long-term social isolation enhances picrotoxin seizure
susceptibility in mice: up-regulatory role of endogenous brain
allopregnanolone in GABAergic systems.

   Matsumoto K, Nomura H, Murakami Y, Taki K, Takahata H, Watanabe H.

   Department of Pharmacology, Institute of Natural Medicine, Toyama
Medical and Pharmaceutical University, 2630 Sugitani, Toyama, Japan.

   Allopregnanolone (ALLO, 3alpha,5alpha-tetrahydroprogesterone), a
positive allosteric modulator of actions of gamma-aminobutyric acid
GABA) at GABA(A) receptors, is synthesized in the brain from
progesterone by the sequential action of two enzymes: a type I
5alpha-reductase and a 3alpha-hydroxysteroid oxidoreductase. We
previously demonstrated that long-term social isolation of mice caused a
significant decrease in brain ALLO content via suppression of type I
5alpha-reductase and its mRNA expression. In this study, to clarify a
physiological role of endogenous brain ALLO, we investigated changes in
seizure susceptibility of mice following protracted social isolation and
compared with those of mice treated with SKF105111 (SKF), an inhibitor
of types I and II 5alpha-reductase. Social isolation of mice for 7 weeks
prior to the experiments caused a significant increase of seizure
susceptibility to the GABA(A) receptor antagonist picrotoxin but not to
the glycine receptor antagonist strychnine or the glutamate receptor
agonist kainic acid. The change in the seizure susceptibility was
completely reversed by 2.5 mg/kg ip ALLO, a dose that per se had no
effect on picrotoxin-induced seizure. Treatment of mice with SKF (20
mg/kg ip) also reduced a threshold dose of picrotoxin, but not that of
strychnine or kainic acid, which was required to elicit seizure in
group-housed mice. The effect of SKF was attenuated by ALLO (2.5 mg/kg
ip). In contrast, SKF treatment had no effect on picrotoxin-induced
seizure in socially isolated mice. These findings suggest that
endogenous brain ALLO plays a suppressive role in seizure susceptibility
via a positive modulation of GABA(A) receptor function and that social
isolation enhances seizure susceptibility in mice via reduction of
GABA(A) receptor function caused by a decrease of endogenous ALLO.

   PMID: 12957225 [PubMed - in process]

Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):2035-40. Epub 2003 Feb 05.
Related Articles, Links
   Click here to read
   In socially isolated mice, the reversal of brain allopregnanolone
down-regulation mediates the anti-aggressive action of fluoxetine.

   Pinna G, Dong E, Matsumoto K, Costa E, Guidotti A.

   Psychiatric Institute, Department of Psychiatry, College of
Medicine, University of Illinois, Chicago, IL 60612, USA.

   Social isolation (SI) of male mice lasting >4 weeks is associated
with aggression toward intruders and a down-regulation of brain
allopregnanolone (Allo) content. SI of female mice fails to
down-regulate brain Allo content or to induce aggressiveness. Fluoxetine
(Prozac in clinical use) is an S- and R-fluoxetine (FLX) mixture, which
in mammals is metabolized into S- and R-norfluoxetine (NFLX). The S
isomers of FLX and NFLX are more active than their respective R isomers
in normalizing brain Allo down-regulation and in reducing the
aggressiveness induced by SI. Thus, FLX stereospecifically reduces brain
Allo down-regulation and the aggressiveness induced by SI, whereas
serotonin (5-HT) uptake inhibition lacks stereospecificity. The doses of
S-FLX and S-NFLX that reduce aggressiveness and Allo brain content
down-regulation induced by SI are at least one order of magnitude lower
than the doses that block 5-HT reuptake. Doses of imipramine that
inhibit 5-HT uptake neither reduce aggressiveness nor normalize brain
Allo down-regulation. We conclude that Allo brain content normalization
is a better candidate than 5-HT reuptake inhibition to explain the
reduction of aggressiveness elicited by S-FLX and S-NFLX.

   PMID: 12571361 [PubMed - indexed for MEDLINE]

Brain Res. 2003 Jun 20;976(1):1-8. Related Articles, Links
   Click here to read
   Region-specific dysregulation of allopregnanolone brain content in
the olfactory bulbectomized rat model of depression.

   Uzunova V, Ceci M, Kohler C, Uzunov DP, Wrynn AS.

   Novartis Institutes for BioMedical Research, Nervous System,
Novartis Pharma AG, WSJ-386.3.26, CH-4002 Basel, Switzerland.

   Allopregnanolone (ALLO) is one of the most potent positive
endogenous allosteric modulators of the type A gamma-aminobutyric acid
(GABA(A)) receptors. While the robust anxiolytic profile of ALLO has
been extensively characterized in rodents and its antidepressant-like
effect was recently demonstrated in mice, there have been only few
reports on alterations of brain ALLO levels in putative animal models of
depression and anxiety. Removal of the olfactory bulbs of rats produces
one of the most predictive animal models with which to screen for drugs
with potential antidepressant activity following repeated treatment. We
therefore investigated whether the olfactory bulbectomized (OB) rat
model of depression may be associated with alterations of ALLO levels in
whole brain tissue and in different brain regions. We determined ALLO
levels in whole brain, amygdala, frontal cortex, hippocampus, and whole
cerebral cortex of OB or sham-operated rats at 7, 14, or 28 days
following bulbectomy or sham surgery. We observed a significant increase
of whole brain ALLO content at 7 and 28 days post-surgery in the OB
rats. At days 7 and 14 following olfactory bulb removal, ALLO levels
were significantly decreased in amygdala and frontal cortex and
significantly increased in whole cerebral cortex. In the hippocampus we
observed only a tendency for decreased ALLO levels at day 14. Our data
indicates a strong region-specific dysregulation of ALLO homeostasis in
brains of OB rats which may contribute to the formation of the
bulbectomy syndrome via a sustained reduction in physiological
GABA-ergic tone in amygdala and frontal cortex.

   PMID: 12763616 [PubMed - indexed for MEDLINE]

J Pharmacol Exp Ther. 2003 May;305(2):541-8. Epub 2003 Feb 11. Related
Articles, Links
   Click here to read
   Anxiogenic effects of neurosteroid exposure: sex differences and
altered GABAA receptor pharmacology in adult rats.

   Gulinello M, Smith SS.

   Department of Physiology and Pharmacology, State University of New
York Downstate Medical Center, Brooklyn, New York, USA.

   Acute exposure to progesterone or its neurosteroid derivative
allopregnanolone (3alpha,5alpha-THP) is anxiolytic, consistent with the
GABA modulatory effects of 3alpha,5alpha-THP at the GABA(A) receptor.
However, continuous exposure to progesterone increases anxiety in
association with increased expression of the benzodiazepine-insensitive
GABA(A) receptor alpha4 subunit. Furthermore, negative mood symptoms and
altered GABA(A) receptor pharmacology in patients with premenstrual
dysphoric disorder occur in the early luteal phase in association with
peak circulating levels of progesterone and 3alpha,5alpha-THP. Because
sex differences have been reported in steroid-regulated anxiety
responses, the present study investigated the role of sex and
development in the regulation of anxiety after short-term exposure to
3alpha,5alpha-THP. To this end, we compared the effects of hormone
administration in adult male, adult female, and juvenile female rats.
Increased anxiety in the elevated plus maze was evident in all groups
after 48-h exposure to either 3alpha,5alpha-THP or progesterone. At this
time point, alterations in the anxiolytic profile of benzodiazepine
agonists and antagonists were also observed in both adult males and
females in the elevated plus maze. However, sex differences in the
acoustic startle response were observed after short-term hormone
treatment such that only female rats displayed an increased response
indicative of higher anxiety levels. These results suggest that although
neurosteroid exposure may influence both the pharmacological properties
of the GABA(A) receptor and the manifestation of anxiety in both sexes,
the effects of neurosteroids may be modulated in a sex- and
task-specific manner.

   PMID: 12606703 [PubMed - indexed for MEDLINE]

J Steroid Biochem Mol Biol. 2003 Jun;85(2-5):247-55. Related Articles,
Links
   Click here to read
   Structure-function relationships in 3alpha-hydroxysteroid
dehydrogenases: a comparison of the rat and human isoforms.

   Penning TM, Jin Y, Heredia VV, Lewis M.

   Department of Pharmacology, School of Medicine, University of
Pennsylvania, 3620 Hamilton Walk, 19104, Philadelphia, PA, USA

   3alpha-Hydroxysteroid dehydrogenases (3alpha-HSDs) inactivate
steroid hormones in the liver, regulate 5alpha-dihydrotestosterone
(5alpha-DHT) levels in the prostate, and form the neurosteroid,
allopregnanolone in the CNS. Four human 3alpha-HSD isoforms exist and
correspond to AKR1C1-AKR1C4 of the aldo-keto reductase (AKR)
superfamily. Unlike the related rat 3alpha-HSD (AKR1C9) which is
positional and stereospecific, the human enzymes display varying ratios
of 3-, 17-, and 20-ketosteroid reductase activity as well as 3alpha-,
17beta-, and 20alpha-hydroxysteroid oxidase activity. Their k(cat)
values are 50-100-fold lower than that observed for AKR1C9. Based on
their product profiles and discrete tissue localization, the human
enzymes may regulate the levels of active androgens, estrogens, and
progestins in target tissues. The X-ray crystal structures of AKR1C9 and
AKR1C2 (human type 3 3alpha-HSD, bile acid binding protein and
peripheral 3alpha-HSD) reveal that the AKR1C2 structure can bind
steroids backwards (D-ring in the A-ring position) and upside down
(beta-face inverted) relative to the position of a 3-ketosteroid in
AKR1C9 and this may account for its functional plasticity. Stopped-flow
studies on both enzymes indicate that the conformational changes
associated with binding cofactor (the first ligand) are slow; they are
similar in both enzymes but are not rate-determining. Instead the low
k(cat) seen in AKR1C2 (50-fold less than AKR1C9) may be due to substrate
"wobble" at the plastic active site.

   PMID: 12943710 [PubMed - in process]

Neuropsychopharmacology. 2003 Jun;28(6):1207-9. Epub 2003 Apr 02.
Related Articles, Links
   Click here to read
   Alcohol intoxication increases allopregnanolone levels in female
adolescent humans.

   Torres JM, Ortega E.

   Department of Biochemistry and Molecular Biology, Institute of
Neurosciences, School of Medicine, University of Granada, Spain.

   Teenage drinking is a cause of growing concern in industrialized
countries, where almost 35% of alcohol drinkers are under 16 years old.
Increased anxiety, irritability, and depression among adolescents may
induce them to seek the anxiolytic and rewarding properties of alcohol.
We studied the effects of acute alcohol intoxication (AAI) on the plasma
levels of progesterone and allopregnanolone in female adolescents. Blood
samples were drawn from female adolescents who arrived at the emergency
department. One study group was formed by those who arrived with evident
behavioral symptoms of AAI and the other by those arriving for mild
trauma (contusions, sprains) after no consumption of alcohol (controls).
Our results demonstrate that AAI significantly increases serum
progesterone and allopregnanolone levels in both follicular and luteal
phases of the ovarian cycle. Since alcohol and allopregnanolone
positively modulate gamma-aminobutyric acid type A (GABA(A)) receptors,
allopregnanolone may play a major role in the anxiolytic and rewarding
effects of alcohol, either directly or by influencing the sensitivity of
GABA(A)-receptors to alcohol.

   PMID: 12700685 [PubMed - indexed for MEDLINE]

Pediatr Res. 2003 Jun;53(6):956-64. Epub 2003 Mar 19. Related Articles,
Links
   Click here to read
   Changes in 5alpha-pregnane steroids and neurosteroidogenic enzyme
expression in the perinatal sheep.

   Nguyen PN, Billiards SS, Walker DW, Hirst JJ.

   Fetal and Neonatal Research Group, Department of Physiology, Monash
University, Clayton Victoria 3800, Australia.

   Pregnane steroids have sedative and neuroprotective effects on the
brain as a result of interactions with the steroid-binding site of the
GABAA receptor. To determine whether the fetal brain is able to
synthesize pregnane steroids de novo from cholesterol, we measured the
expression of cytochrome P450 side-chain cleavage (P450scc) and
5alpha-reductase type II (5alphaRII) enzymes in fetal sheep from 72 to
144 d gestation (term approximately 147 d) and in newborn lambs at 3 and
19-26 d of age. Both P450scc and 5alphaRII expression was detectable by
90 d gestation in the major regions of the brain and also in the adrenal
glands. Expression increased with advancing gestation and was either
maintained at fetal levels or increased further after birth. In
contrast, the relatively high content (200-400 pmol/g) of
allopregnanolone (5alpha-pregnan-3alpha-ol-20-one), a major sedative
5alpha-pregnane steroid, present throughout the brain from 90 d
gestation to term, was reduced significantly (<50 pmol/g) immediately
after birth. These results suggest that although the perinatal brain has
the enzymes potentially to synthesize pregnane steroids de novo from
cholesterol, either the placenta is a major source of these steroids to
the brain or other factors associated with intrauterine life may be
responsible for high levels of allopregnanolone production in the fetal
brain until birth.

   PMID: 12646725 [PubMed - in process]

Psychiatry Res. 2003 May 30;118(2):107-16. Related Articles, Links
   Click here to read
   Neurosteroid secretion in panic disorder.

   Brambilla F, Biggio G, Pisu MG, Bellodi L, Perna G,
Bogdanovich-Djukic V, Purdy RH, Serra M.

   Dipartimento di Scienze Neuropsichiche, Istituto Scientifico
Ospedale S. Raffaele, Universita' Vita e Salute, Milan, Italy.

   Evidence that neurosteroids have anxiolytic effects in animal models
of anxiety has suggested that alterations of neurosteroid secretion
might be implicated in the pathogenetic mechanisms of anxiety disorders
in humans. In 25 female patients with panic disorder (PD) and 11 healthy
female controls, we measured plasma concentrations of progesterone
(PROG), pregnenolone (PREG), allopregnanolone
(3alpha,5alpha-tetrahydroprogesterone=3alpha,5alpha-THPROG),
dehydroepiandrosterone (DHEA) and tetrahydrodeoxycorticosterone
(3alpha,5alpha-THDOC) during a drug-free month and during the following
month of paroxetine therapy. The neurosteroids were measured during the
early follicular phase, the mid-luteal phase and the premenstrual phase
of both months (days 7, 22 and 27 from the beginning of the cycle).
Significantly higher levels in patients than controls were found in PROG
during the mid-luteal phase of both months, PREG in the premenstrual
phase in the drug-free month, 3alpha,5alpha-THPROG during the follicular
phase of the drug-free month and during the premenstrual phase of the
therapy month, and 3alpha,5alpha-THDOC during the premenstrual phases of
both months. DHEA levels did not differ in patients and controls. These
results suggest that neurosteroids in PD are hypersecreted, possibly as
an attempt to counteract the anxiogenic underlying hyperactivity of the
hypothalamo-pituitary-adrenal axis and to improve a reduced GABA(A)
receptor sensitivity.

   PMID: 12798975 [PubMed - in process]

Front Biosci. 2003 May 1;8:s358-76. Related Articles, Links
   Click here to read
   Sleep and endocrine regulation.

   Steiger A.

   Max Planck Institute of Psychiatry, Department of Psychiatry,
Munich, Germany.

   A bidirectional interaction exists between sleep
electroencephalogram (EEG) and endocrine activity in various species
including humans. Various hormones (peptides, steroids) were shown to
participate in sleep regulation. A keyrole was shown for the reciprocal
interaction between sleep-promoting growth hormone-releasing hormone
(GHRH) and sleep-impairing corticotropin-releasing hormone (CRH).
Changes in the GHRH:CRH ratio result in changes of sleep-endocrine
activity. There is good evidence that the change of this ratio in favor
of CRH contributes to aberrances of sleep during aging and depression.
Besides of GHRH ghrelin and galanin promote SWS, whereas somatostatin is
another sleep-impairing factor. NPY acts as a CRH antagonist and induces
sleep onset. Prolactin enhances rapid eve-movement sleep (REMS) in rats.
SWS is enhanced in patients with prolactinoma. Other studies on the
influence of prolactin of human sleep are lacking. There is a
controversy whether CRH promotes REMS.In humans vasocactive intestinal
polypeptide (VIP) appears to play a role in the temporal organization of
sleep, since after VIP administration the NREMS-REMS cycle decelerated.
Several neuroactive steroids (pregnenolone, progesterone,
allopregnanolone, dehydroepiandrosterone) exert specific effects on
sleep EEG via GABAA receptors. Cortisol appears to enhance REMS. Finally
gonadal hormones participate in sleep regulation. Estrogen replacement
therapy and CRH-1 receptor antagonism in depression are beneficial
clinical applications of the basic research presented here.

   PMID: 12700062 [PubMed - in process]

Pharmacol Biochem Behav. 2003 May;75(2):397-404. Related Articles, Links
   Click here to read
   Anti-conflict-like actions of intralateral septal infusions of
allopregnanolone in Wistar rats.

   Molina-Hernandez M, Tellez-Alcantara NP, Perez Garcia J, Olivera
Lopez JI, Teresa Jaramillo M.

   Laboratorio de Conducta, Instituto de Investigaciones Psicologicas,
Universidad Veracruzana, POB 361, Jalapa, Veracruz 91000, Mexico.

   The aim of the present study was to test the hypothesis that
allopregnanolone infused into the lateral septal nuclei will reduce
conflict-like behavior in ovariectomized rats. The interaction with
systemic administration of several agonists and antagonists of the
GABA-A receptor was assessed. Results showed that intralateral septal
doses of allopregnanolone (1.0 microg, P<.05; 2.0 microg, P<.05) or
systemic injections of allopregnanolone (1.0 mg/kg s.c., P<.05; 2.0
mg/kg s.c., P<.05), diazepam (2.0 mg/kg i.p., P<.05), or muscimol (0.3
mg/kg i.p., P<.05; 0.6 mg/kg i.p., P<.05) reduced conflict-like
behavior. Subthreshold doses of intralateral septal infusions of
allopregnanolone (0.5 microg/side) synergized with systemic subthreshold
doses of GABA-A agonists: allopregnanolone (0.5 mg/kg, P<.05), diazepam
(1.5 mg/kg, P<.05), or muscimol (0.1 mg/kg, P<.05). The GABA-A
antagonists, flumazenil (0.1 mg/kg i.p.) and bicuculline (2.0 mg/kg
i.p.) attenuated the synergism between intralateral septal infusions of
allopregnanolone and diazepam or muscimol, respectively. Conversely,
neither flumazenil (P<.05) nor bicuculline (P<.05) attenuated the
synergism of the combination allopregnanolone (intralateral septum
nuclei; 0.5 microg/side) plus systemic injections of allopregnanolone.
In conclusion, allopregnanolone reduced conflict-like behavior probably
acting at the GABA-A receptors found in the lateral septal nuclei.

   PMID: 12873631 [PubMed - in process]

Epilepsy Res. 2003 Apr;54(1):11-9. Related Articles, Links
   Click here to read
   Allopregnanolone serum levels and expression of 5 alpha-reductase
and 3 alpha-hydroxysteroid dehydrogenase isoforms in hippocampal and
temporal cortex of patients with epilepsy.

   Stoffel-Wagner B, Watzka M, Steckelbroeck S, Ludwig M, Clusmann H,
Bidlingmaier F, Casarosa E, Luisi S, Elger CE, Beyenburg S.

   Department of Clinical Biochemistry, University of Bonn,
Sigmund-Freud-Str. 25, D-53105 Bonn, Germany.

   In the human central nervous system, progesterone is rapidly
metabolised to 5 alpha-dihydroprogesterone which subsequently is further
reduced to allopregnanolone (AP). These conversions are catalysed by 5
alpha-reductase and 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSD).
Although different isoforms of both enzymes have been identified in the
brain, our knowledge of their expression in the human brain remains
limited. The aim of the present study was to investigate the mRNA
expression of 5 alpha-reductase 1 as well as 3 alpha-HSD 1, 2, 3 and 20
alpha-HSD in brain tissue from patients with pharmacoresistant temporal
lobe epilepsy (TLE). Specimens were derived from either the hippocampus
or the temporal lobe cortex and from the tumor-free approach corridor
tissue of patients with brain tumors. Quantification of different mRNAs
was achieved by real time PCR. In addition, we provide data on
simultaneous evaluation of serum AP concentrations. We could demonstrate
that 3 alpha-HSD 1 was not expressed in the hippocampus and temporal
lobe of patients with TLE. In the hippocampus and temporal lobe, the
expression levels of 3 alpha-HSD 2 were about 20% of that in liver
tissue, those of 3 alpha-HSD 3 about 7% and those of 20 alpha-HSD about
2%, respectively. In patients with TLE, expression of 3 alpha-HSD 2 was
significantly higher in the hippocampus than in temporal lobe cortex
tissue (P<0.006). AP concentrations did not correlate significantly with
the mRNA expression levels of 5 alpha-reductase 1, 3 alpha-HSD 2 and 3
and 20 alpha-HSD in any of the patient groups under investigation. In
conclusion, the present study demonstrates mRNA expression of 5
alpha-reductase 1 and 3 alpha-HSD 2 and 3 and 20 alpha-HSD in the
hippocampus and temporal lobe of epileptic patients. These findings
provide further molecular biological evidence for the formation and
metabolism of neuroactive steroids in the human brain.

   PMID: 12742591 [PubMed - indexed for MEDLINE]

Gynecol Endocrinol. 2003 Apr;17(2):159-68. Related Articles, Links
   Click here to read
   Adrenal function under long-term raloxifene administration.

   Genazzani AR, Lombardi I, Borgioli G, di Bono I, Casarosa E,
Gambacciani M, Palumbo M, Genazzani AD, Luisi M.

   Department of Reproductive Medicine and Child Development, Division
of Obstetrics and Gynecology, University of Pisa, Pisa, Italy.

   The aim of the present study was to evaluate the effect of long-term
(12 months) administration of raloxifene hydrochloride (60 mg/day) on
the steroid production of the adrenal cortex and on the
hypothalamic-pituitary-adrenal axis in postmenopausal women. We
performed a basal evaluation, a corticotropin releasing factor (CRF)
(100 microg i.v. bolus) test and a dexamethasone (DXM) (0.25 mg)
suppression-adrenocorticotropic hormone (ACTH) (10 microg i.v. bolus)
stimulation test in 11 postmenopausal women, before and after 3, 6 and
12 months of raloxifene treatment. Raloxifene administration
significantly modified circulating levels of adrenal steroids,
decreasing cortisol (-24%), dehydroepiandrosterone (DHEA) (-36%), and
its sulfate (DHEAS) (-41%), and androstenedione (-29%), and increasing
circulating allopregnanolone (+39%) levels. Progesterone and
17OH-progesterone levels remained unmodified, while estradiol and
estrone levels showed a significant decrease (-51% for estradiol and
-61% for estrone). We also observed an increase in circulating ACTH
(+58%) and beta-endorphin (+120%). No modifications in the hormonal
responses to CRF were observed during the treatment. DXM significantly
suppressed circulating steroids at any time with a lower suppression of
cortisol from the third month and a higher suppression of DHEA at 12
months. ACTH administration was associated with a significantly blunted
cortisol response from the sixth month and a significantly increased
response of allopregnanolone from the third month. The present data
exclude a raloxifene effect on pituitary sensitivity to CRF and
demonstrate a reduced adrenal sensitivity to ACTH, sustained by the
opposite changes in basal cortisol and Delta5 androgens, which were
reduced, and in ACTH and beta-endorphin, which were increased, as well
by the reduced response of cortisol to the direct ACTH stimulus. The
reduction of circulating cortisol levels and cortisol response to the
ACTH challenge suggests that raloxifene protects against the neurotoxic
effects of endogenous glucocorticoids. Furthermore, the progressive
increase in basal allopregnanolone and its increased response to ACTH
indicate that chronic raloxifene administration exerts direct effects on
the pattern of adrenal enzymes, leading to specific changes in the
circulating levels of this anxiolytic progesterone metabolite. The
important reduction in the circulating levels of estradiol and estrone
under long-term raloxifene administration may represent a further
mechanism by which this molecule may exert a protective effect against
breast and endometrial malignancies.

   PMID: 12737677 [PubMed - in process]

J Physiol. 2003 Apr 1;548(Pt 1):233-44. Epub 2003 Feb 14. Related
Articles, Links
   Click here to read
   Neurosteroid regulation of oxytocin and vasopressin release from the
rat supraoptic nucleus.

   Widmer H, Ludwig M, Bancel F, Leng G, Dayanithi G.

   Department of Neurobiology, U-583 INSERM, University of Montpellier
II, Place Eugene Bataillon, F-34095 Montpellier cedex 5, France.

   In adult rats somato-dendritic release of oxytocin and vasopressin
from magnocellular neurones in the supraoptic nucleus of the
hypothalamus has important autoregulatory actions on the neuronal
electrical activity, and in neonatal rats it plays a role in the
development of dendritic arborisation. In the adult, oxytocin effects
are modulated by allopregnanolone via an interaction with inhibitory
GABAA receptors. This study examined the effects of allopregnanolone,
progesterone and 17beta-oestradiol on oxytocin and vasopressin release
from intact isolated supraoptic nuclei and from the neurophypophyses in
rats of differing ages. In supraoptic nuclei from rats of 3-4 weeks old
or less, all three neurosteroids induced oxytocin release from the
isolated supraoptic nucleus, but only allopregnanolone induced
significant release of vasopressin. Surprisingly, in these very young
rats, allopregnanolone-induced oxytocin release was inhibited by GABAA
receptor antagonists as well as by an oxytocin receptor antagonist. By
contrast, in supraoptic nuclei from adult rats allopregnanolone-induced
oxytocin release was much smaller, and was enhanced in the presence of
bicuculline. The GABAA receptor agonist muscimol also induced oxytocin
release from supraoptic nuclei in young rats, but had no effect in adult
rats. Oxytocin cells isolated from young rats showed an increase in
[Ca2+]i in response to both allopregnanolone and muscimol.
Allopregnanolone had no effect on [Ca2+]i or on the release of oxytocin
or vasopressin from neurohypophysial axon terminals in either young or
old rats. We conclude that, in very young rats, (i) neurosteroids induce
oxytocin release from the supraoptic nucleus by a mechanism that partly
depends on the presence of GABA, which in young rats is depolarising to
oxytocin cells, and which also partly depends upon endogenous oxytocin,
and (ii) the effect of allopregnanolone upon oxytocin release changes
with age, as the functional activity of GABAA receptors changes from
excitation to inhibition of oxytocin cells.

   PMID: 12588901 [PubMed - in process]

Arch Gen Psychiatry. 2003 Feb;60(2):161-8. Related Articles, Links
   Click here to read
   Induced panic attacks shift gamma-aminobutyric acid type A receptor
modulatory neuroactive steroid composition in patients with panic
disorder: preliminary results.

   Strohle A, Romeo E, di Michele F, Pasini A, Hermann B, Gajewsky G,
Holsboer F, Rupprecht R.

   Max Planck Institute of Psychiatry, Munich, Germany.

   BACKGROUND: Certain metabolites of progesterone such as
3alpha,5alpha-tetrahydroprogesterone (3alpha,5alpha-THP;
allopregnanolone) and 3alpha,5beta-THP (pregnanolone) are potent,
positive allosteric modulators of gamma-aminobutyric acid type A
receptors. Although animal studies suggest anxiolytic properties of
these endogenous modulators of central nervous excitability, no clinical
data indicate whether they are also involved in the pathophysiology of
anxiety disorders and panic attacks. METHODS: We quantified the
concentrations of 3alpha,5alpha-THP, 3alpha,5beta-THP, the isomer
3beta,5alpha-THP, and their precursors in the plasma of 10 patients with
panic disorder and matched control subjects during panic attacks induced
by means of sodium lactate and cholecystokinin tetrapeptide
administration, using a highly sensitive gas chromatography-mass
spectrometry analysis. RESULTS: Panic attacks induced by sodium lactate
and cholecystokinin tetrapeptide in patients with panic disorder were
accompanied by pronounced decreases in the concentrations of
3alpha,5alpha-THP and 3alpha,5beta-THP and a concomitant increase in the
concentrations of the functional antagonistic isomer 3beta,5alpha-THP,
findings that are compatible with a decreased gamma-aminobutyric
acid-ergic tone. No changes in neuroactive steroid concentrations were
observed after placebo administration in patients with panic disorder or
after placebo, sodium lactate, or cholecystokinin tetrapeptide
administration in controls. CONCLUSIONS: The association between changes
in plasma neuroactive steroid concentrations and experimentally induced
panic attacks and the well-documented pharmacological properties of
these compounds as gamma-aminobutyric acid type A receptor modulators
suggest that neuroactive steroids may play a role in the pathophysiology
of panic attacks in patients with panic disorder.

   PMID: 12578433 [PubMed - indexed for MEDLINE]

Gynecol Endocrinol. 2003 Feb;17(1):65-77. Related Articles, Links
   Click here to read
   Effect of different hormonal replacement therapies on circulating
allopregnanolone and dehydroepiandrosterone levels in postmenopausal
women.

   Bernardi F, Pieri M, Stomati M, Luisi S, Palumbo M, Pluchino N,
Ceccarelli C, Genazzani AR.

   Department of Reproductive Medicine and Child Development,
University of Pisa, Pisa, Italy.

   The effects of hormone replacement therapy (HRT) on the central
nervous system in postmenopausal women might be mediated by changes in
neurosteroid synthesis and/or release. The aim of this study was to
evaluate the impact of HRT on the levels of allopregnanolone, a sedative
anxiolytic GABA(A) agonist steroid, and dehydroepiandrosterone (DHEA), a
GABA(A) antagonist steroid. We evaluated allopregnanolone and DHEA
circulating levels after 1, 3, 6, 9 and 12 months of HRT with ten
different estrogen or estrogen-progestin molecules, regimens and routes
of administration in 186 postmenopausal women. Cortisol, luteinizing
hormone, follicle stimulating hormone, estradiol and progesterone levels
were also evaluated. Allopregnanolone levels significantly increased
during follow-up with all HRT preparations. The addition of progestin
molecules (except for 19-nor derivatives) to transdermal estradiol
administration alone determined a higher increase in allopregnanolone
levels. Transdermal HRT showed a significantly higher percentage change
in allopregnanolone levels compared with oral HRT. DHEA levels showed a
progressive decline starting from the 3-month follow-up, without
significant differences between the transdermal and oral groups, as well
as among the ten groups, independently of the presence and type of
progestin molecule used. In conclusion, HRT strongly modifies
circulating neurosteroid levels in postmenopausal women.

   Publication Types:

       * Clinical Trial
       * Randomized Controlled Trial

   PMID: 12724021 [PubMed - indexed for MEDLINE]

CNS Drugs. 2003;17(5):325-42. Related Articles, Links

   The role of hormones and hormonal treatments in premenstrual
syndrome.

   Backstrom T, Andreen L, Birzniece V, Bjorn I, Johansson IM,
Nordenstam-Haghjo M, Nyberg S, Sundstrom-Poromaa I, Wahlstrom G, Wang M,
Zhu D.

   Department of Clinical Sciences, Obstetrics and Gynecology, Umea
University, Umea, Sweden.

   Premenstrual syndrome (PMS) is a menstrual cycle-linked condition
with both mental and physical symptoms. Most women of fertile age
experience cyclical changes but consider them normal and not requiring
treatment. Up to 30% of women feel a need for treatment. The aetiology
is still unclear, but sex steroids produced by the corpus luteum of the
ovary are thought to be symptom provoking, as the cyclicity disappears
in anovulatory cycles when a corpus luteum is not formed. Progestogens
and progesterone together with estrogen are able to induce similar
symptoms as seen in PMS. Symptom severity is sensitive to the dosage of
estrogen. The response systems within the brain known to be involved in
PMS symptoms are the serotonin and GABA systems. Progesterone
metabolites, especially allopregnanolone, are neuroactive, acting via
the GABA system in the brain. Allopregnanolone has similar effects as
benzodiazepines, barbiturates and alcohol; all these substances are
known to induce adverse mood effects at low dosages in humans and
animals. SSRIs and substances inhibiting ovulation, such as
gonadotrophin-releasing hormone (GnRH) agonists, have proven to be
effective treatments. To avoid adverse effects when high dosages of GnRH
agonists are used, add-back hormone replacement therapy is recommended.
Spironolactone also has a beneficial effect, although not as much as
SSRIs and GnRH agonists.

   Publication Types:

       * Review
       * Review, Tutorial

   PMID: 12665391 [PubMed - indexed for MEDLINE]

J Sex Marital Ther. 2003;29 Suppl 1:95-102. Related Articles, Links

   Serum allopregnanolone levels relate to FSFI score during the
menstrual cycle.

   Nappi RE, Abbiati I, Luisi S, Ferdeghini F, Polatti F, Genazzani AR.

   Department of Obstetrics and Gynecology, IRCCS Policlinico S.
Matteo, University of Pavia, Pavia, Italy.

   The aim of this study was to measure serum allopregnanolone levels
and other hormones in women who completed the Female Sexual Function
Index (FSFI; Rosen et al., 2000) during the follicular or the luteal
phase of the menstrual cycle. Twenty-nine women with a regular menstrual
cycle completed the FSFI during days 5-7 and days 19-21 of their
menstrual cycles. We collected a blood sample on the same days so that
we could determine levels of allopregnanolone (AP),
dehydroepiandrosterone (DHEA), free testosterone (FreeT),
androstenedione (A), and estradiol (E2); we stored serum at--20 degrees
C until we assayed it. We performed statistical analyses by parametric
and nonparametric comparisons and correlations, as appropriate. We found
that the full FSFI score was 23 +/- 11.3 (mean +/- SD; 31% under 95%
confidence interval = 18.7) in our study population. We also found a
significant positive correlation between serum allopregnanolone levels
and each FSFI domain, including full scale score (r = 0.47, p < 0.01),
with the exception of pain. Similarly, we found a positive correlation
between FreeT and each FSFI domain and full scale score (r = 0.55, p <
0.002). We found no significant correlation among FSFI scores and DHEA,
A, or E2 plasma levels. It is interesting to note that FSFI full score
was significantly higher (p < 0.04) in women tested in the luteal phase
compared to women tested in the follicular phase. Serum allopregnanolone
may be relevant to female sexuality directly or by its influence on a
woman's general sense of well-being during the menstrual cycle. Further
studies are required to test the hypothesis that high serum
allopregnanolone levels in the luteal phase play a role in women's
attitudes toward self-report questionnaires on sexual function.

   PMID: 12735093 [PubMed - indexed for MEDLINE]

Neuropharmacology. 2003 Jan;44(1):49-55. Related Articles, Links
   Click here to read
   On the putative physiological role of allopregnanolone on GABA(A)
receptor function.

   Puia G, Mienville JM, Matsumoto K, Takahata H, Watanabe H, Costa E,
Guidotti A.

   The Psychiatric Institute, Department of Psychiatry, University of
Illinois at Chicago, 1601 W. Taylor St. MC912, Chicago, IL 60612, USA.

   To obtain definitive evidence for a physiological allosteric
modulatory role for endogenous brain ALLO on GABA(A) receptor function,
we studied GABA(A) receptor activity under conditions in which the
concentration of endogenous brain ALLO was decreased by about 80% for
longer than 5 h following the administration of SKF 105111-
17beta-17-[bis (1methylethyl) amino carbonyl]
androstane-3,5-diene-3-carboxylic acid (SKF), a potent inhibitor of
5alpha-reductases Type I and II. We used the in situ patch-clamp
technique to record GABA-evoked currents and spontaneous inhibitory
postsynaptic currents (sIPSCs) from pyramidal neurons in neocortical
slices of vehicle- or SKF-treated mice. The potency, but not the
efficacy, of exogenously applied GABA was decreased in slices from mice
treated with SKF. When neocortical slices were treated in vitro for 3 h
with 10 microM SKF, ALLO was also reduced (25-30%) and in addition, the
GABA dose-response curve was shifted to the right; however this shift
was not as marked as the shift in the slices obtained from mice treated
with SKF, in keeping with the smaller decrease of the ALLO content in
these slices. Furthermore, direct application of ALLO to these slices
shifted the dose-response curve of GABA back toward a non-SKF treated
profile. We then analyzed GABAergic sIPSCs in neocortical slices
obtained from vehicle or SKF-treated mice. Mean decay time and charge
transfer were significantly reduced by SKF treatment. The decay of
sIPSCs was best fitted by two exponentials, but only the fast component
was decreased in the SKF group. Direct application of ALLO (100 nM)
normalizes the sIPSC kinetics in slices from ALLO depleted mice. No
changes were detected in the amplitude or frequency of sIPSCs. These
data demonstrate that endogenous ALLO physiologically regulates
spontaneously induced Cl(-) current by acting on a specific recognition
site, which is probably located on GABA(A) receptors (a receptor on a
receptor), thereby prolonging inhibitory currents by facilitating
conformational transition of the GABA-gated Cl(-) channel to an open
state.

   PMID: 12559121 [PubMed - indexed for MEDLINE]

Proc Natl Acad Sci U S A. 1999 Nov 9;96(23):13512-7. Related Articles,
Links
   Click here to read
   Selective serotonin reuptake inhibitors directly alter activity of
neurosteroidogenic enzymes.

   Griffin LD, Mellon SH.

   Department of Obstetrics, Gynecology, and Reproductive Sciences,
University of California, Box 0556, San Francisco, CA 94143-0556, USA.

   The neurosteroid 3alpha-hydroxysteroid-5alpha-pregnan-20-one
(allopregnanolone) acts as a positive allosteric modulator of
gamma-aminobutyric acid at gamma-aminobutyric acid type A receptors and
hence is a powerful anxiolytic, anticonvulsant, and anesthetic agent.
Allopregnanolone is synthesized from progesterone by reduction to
5alpha-dihydroprogesterone, mediated by 5alpha-reductase, and by
reduction to allopregnanolone, mediated by 3alpha-hydroxysteroid
dehydrogenase (3alpha-HSD). Previous reports suggested that some
selective serotonin reuptake inhibitors (SSRIs) could alter
concentrations of allopregnanolone in human cerebral spinal fluid and in
rat brain sections. We determined whether SSRIs directly altered the
activities of either 5alpha-reductase or 3alpha-HSD, using an in vitro
system containing purified recombinant proteins. Although rats appear to
express a single 3alpha-HSD isoform, the human brain contains several
isoforms of this enzyme, including a new isoform we cloned from human
fetal brains. Our results indicate that the SSRIs fluoxetine,
sertraline, and paroxetine decrease the K(m) of the conversion of
5alpha-dihydroprogesterone to allopregnanolone by human 3alpha-HSD type
III 10- to 30-fold. Only sertraline inhibited the reverse oxidative
reaction. SSRIs also affected conversions of androgens to 3alpha- and
3alpha, 17beta-reduced or -oxidized androgens mediated by 3alpha-HSD
type II(Brain). Another antidepressant, imipramine, was without any
effect on allopregnanolone or androstanediol production. The
region-specific expression of 3alpha-HSD type II(Brain) and 3alpha-HSD
type III mRNAs suggest that SSRIs will affect neurosteroid production in
a region-specific manner. Our results may thus help explain the rapid
alleviation of the anxiety and dysphoria associated with late luteal
phase dysphoria disorder and major unipolar depression by these SSRIs.

   PMID: 10557352 [PubMed - indexed for MEDLINE]