Allopregnanolone on Sexual Function

Neurosteroids and libido

Neurosteroids and the proteins responsible for their synthesis from cholesterol are found
in structures critical for sexual desire in males and females, such as the amygdala, medial
preoptic area (MPOA), and ventral medial hypothalamus (VMH). These areas are rich in receptors affected by neurosteroids. Neurosteroids elicit different responses in males and females. Animal studies link neurosteroids to the regulation of the hypothalamic- pituitary-gonadal axis, including both enhancement and suppression of sexual motivation and behavior. For instance, activation of hypothalamic GABA-A receptors by allopregnanolone, a neuroactive metabolite of progesterone, in female rats can lead to suppression of ovulation and can have either positive or negative effects on sexual behavior. The inhibition of gonadotropin-releasing hormone (GnRH) in the hypothalamus by allopregnanolone release can be antagonized by pregnenolone sulfate. In addition, 3á-androstanediol attenuates lordosis and promotes aggression in female rats, probably through GABA-A receptor inhibition in the medial basal hypothalamus and MPOA. Moreover, problems that interfere with sexual behavior and function such as depression and premenstrual syndrome correlate with changes in serum neurosteroid levels in humans. In male mice, a commonly used performance test for sexual behavior involving preference for the odors of estrous females was enhanced by intra-cerebroventricular administration of the progesterone metabolite 3á- hydroxy-4-pregnen-20-one and reduced by pregnenolone sulfate. Because androgens and progesterone are synthesized in the brain, some of the effects of these steroids on sexual behavior may be mediated in part by their local synthesis. For instance, administration of estradiol rapidly induces copulatory behavior in male rats. Although estrogen derived from the aromatization of gonadal testosterone is critical to maintain sensitivity for sexual stimulation in the male, these and later studies suggest that copulatory behavior can be triggered by estrogen produced de novo in the brain itself.

askdrkhaled.com/Male%20sexua … libido.htm

Effect of centrally injected allopregnanolone on sexual receptivity, luteinizing hormone release, hypothalamic dopamine turnover, and release in female rats.
Laconi MR, Cabrera RJ.
Source
Instituto de Medicina y Biología Experimental de Cuyo (IMBECU-CONICET), Cátedra de Farmacología, Facultad de Ciencias Médicas, Mendoza, Argentina.

Abstract
The effect of intracerebroventricular (icv) injection of allopregnanolone (5alpha-pregnan-3alpha-ol-20-one) on the dopaminergic and reproductive function in ovariectomized rats primed with estrogen and progesterone was investigated. Thirty minutes after icv allopregnanolone injection, the sexual receptivity, luteinizing hormone (LH) release, dopamine content, and release in the medial basal hypothalamus (MBH) and preoptic area (POA) were determined. After allopregnanolone injection, LH serum levels were reduced (p < 0.001) and lordosis behavior was inhibited (p < 0.005). Intracerebroventricular injection of bicuculline (a gamma-aminobutyric acidA [GABAA] antagonist) alone was ineffective. The injection of allopregnanolone plus bicuculline blocked the effects of allopregnanolone on sexual receptivity and on LH serum levels. At the same time, endogenous dopamine concentration in both the MBH and POA was augmented (p < 0.005 and p < 0.006, respectively) and the turnover rate decreased in both structures. Moreover, in vitro 3H-dopamine release from MBH and POA was lower in rats injected with allopregnanolone in comparison with vehicle-treated rats. These results suggest that allopregnanolone influences the dopaminergic mechanisms in female rats, which may, in turn, be responsible for the reduced reproductive activity. Allopregnanolone may exert its effects on sexual behavior through GABAA receptor modulation and a decrease in dopaminergic activity in the MBH and POA. These actions could explain the inhibition of LH release.

Neurosteroids Alter γ-Aminobutyric Acid Postsynaptic Currents in Gonadotropin-Releasing Hormone Neurons: A Possible Mechanism for Direct Steroidal Control
Shannon D. Sullivan and Suzanne M. Moenter

  • Author Affiliations

Departments of Internal Medicine and Cell Biology, University of Virginia, Charlottesville, Virginia 22908
Address all correspondence and requests for reprints to: Suzanne M. Moenter, Departments of Internal Medicine and Cell Biology, P. O. Box 800578, University of Virginia, Charlottesville, Virginia 22908. E-mail: smm4n@virginia.edu.
Abstract

Pulsatile GnRH release is required for fertility and is regulated by steroid feedback. Whether or not steroids or their metabolites act directly on GnRH neurons is not well established. In some neurons, steroid metabolites known as neurosteroids modulate the function of the GABAA receptor. Specifically, the progesterone derivative allopregnanolone is an allosteric agonist at this receptor, whereas the androgen dehydroepiandrosterone sulfate (DHEAS) is an allosteric antagonist. We hypothesized these metabolites act similarly on GnRH neurons to modify the response to GABA. Whole-cell voltage-clamp recordings of GABAergic miniature postsynaptic currents (mPSCs) were made from green fluorescent protein-identified GnRH neurons in brain slices from diestrous mice. Glutamatergic currents were blocked with antagonists and action potentials blocked with tetrodotoxin, minimizing presynaptic effects of treatments. Allopregnanolone (5 μM) increased mPSC rate of rise, amplitude and decay time by 15.9 ± 6.1%, 16.5 ± 6.3%, and 58.3 ± 18.6%, respectively (n = 7 cells). DHEAS (5 μM) reduced mPSC rate of rise (32.1 ± 5.7%) and amplitude (27.6 ± 4.3%) but did not alter decay time (n = 8). Effects of both neurosteroids were dose dependent between 0.1 and 10 μM. In addition to independent actions, DHEAS also reversed effects of allopregnanolone on rate of rise and amplitude so that these parameters were returned to pretreatment baseline values (n = 6). These data indicate allopregnanolone increases and DHEAS decreases responsiveness of GnRH neurons to activation of GABAA receptors by differentially modulating current flow through GABAA receptor chloride channels. This provides one mechanism for direct steroid feedback to GnRH neurons.

Steroid hormones and sleep regulation.
Teran-Perez G, Arana-Lechuga Y, Esqueda-Leon E, Santana-Miranda R, Rojas-Zamorano JA, Moctezuma JV.
Source
Departamento de Biologia de la Reproduccion, Universidad Autonoma Metropolitana-Iztapalapa, C.P. 09340 Iztapalapa, D.F. Mexico, Mexico. jvm@xanum.uam.mx.
Abstract
In the search of the sleep substance, many studies have been addressed for different hormones, responsible for sleep-wake cycle regulation. In this article we mentioned the participation of steroid hormones, besides its role regulating sexual behavior, they influence importantly in the sleep process. One of the clearest relationships are that estrogen and progesterone have, that causing changes in sleep patterns associated with the hormonal cycles of women throughout life, from puberty to menopause and specific periods such as pregnancy and the menstrual cycle, including being responsible for some sleep disorders such as hypersomnia and insomnia. Another studied hormone is cortisol, a hormone released in stressful situations, when an individual must react to an extraordinary demand that threatens their survival, but also known as the hormone of awakening because the release peak occurs in the morning, although this may be altered in some sleep disorders like insomnia and mood disorders. Furthermore neurosteroids such as pregnanolone, allopregnanolone and pregnenolone are involved in the generation of slow wave sleep, the effect has been demonstrated in experimental animal studies. Thus we see that the sleep and the endocrine system saved a bidirectional relationship in which depends on each other to regulate different physiological processes including sleep.

Neurosteroids for a successful pregnancy.
Frye CA, Hirst JJ, Brunton PJ, Russell JA.
Source
Department of Psychology, and Biological Sciences, Centers for Life Science and Neuroscience Research, The University at Albany-SUNY, Albany, NY 12222, USA. cafrye@albany.edu
Abstract
Steroid hormones play a critical role in the initiation and maintenance of pregnancy. In particular, the important role that the progesterone metabolite, and neurosteroid, allopregnanolone, may play in fetal and adolescent development is becoming increasingly evident. Unlike steroid hormones, neurosteroids act at nontraditional targets in the central and peripheral nervous systems, including GABA(A) receptor complexes. This commentary discusses the three works in this issue that elucidate the important role of allopregnanolone in the mechanisms that regulate stress hypo-sensitivity of rodents in late pregnancy, neuroprotective effects in fetal sheep exposed to a hypoxic insult, and the continuing role that prefrontal cortex formation of allopregnanolone may play on the cognitive development of gestationally stressed rat offspring, grown to adolescence. The narrative that these works comprise was facilitated by the 5(th) International Meeting on Steroids and the Nervous System (Torino, Italy), which is organized to update our knowledge on the relationships between steroid hormones synthesized in different organs and the nervous system. Topics covered in this most recent meeting included sex differences in, and hormonal influences on, cannabinoid-regulated biology; steroids and pain; the importance of co-regulatory factors for steroid receptor action in the brain; mechanism and role of estrogen-induced nonclassical signaling in the brain; vitamin D as the forgotten neurosteroid; neurosteroids and GABA(A) receptors; and pathogenic mechanisms mediated by glucocorticoid receptors in psychiatric disorders. The 6(th) International Meeting on Steroids and the Nervous System will be held in Torino, Italy in February 2011.

Sex difference in sensitivity to allopregnanolone neuroprotection in mice correlates with effect on spontaneous inhibitory post synaptic currents.
Kelley MH, Kuroiwa M, Taguchi N, Herson PS.
Source
Department of Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Portland, OR 97201, USA.
Abstract
Allopregnanolone (ALLO) is a neurosteroid that has many functions in the brain, most notably neuroprotection and modulation of gamma-amino butyric acid (GABA) neurotransmission. Using a mouse model of cardiac arrest and cardiopulmonary resuscitation, we have previously demonstrated that ALLO protects cerebellar Purkinje cells (PCs) from ischemia in a GABA(A) receptor-dependent manner. In this study we examined the effect of sex on ALLO neuroprotection, observing that low dose ALLO (2 mg/kg) provided greater neuroprotection in females compared to males. At a higher dose of ALLO (8 mg/kg), both sexes were significantly protected from ischemic damage. Using an acute cerebellar slice preparation, whole cell voltage clamp recordings were made from PCs. Spontaneous inhibitory post synaptic currents (IPSCs) were analyzed and the response to physiological ALLO (10 nM) was significantly greater in female PCs compared to male. In contrast, recordings of miniature IPSCs, did not exhibit a sex difference in response to ALLO, suggesting that ALLO affects males and females differentially through a mechanism other than binding postsynaptic GABA(A) receptors. We conclude that the female brain has greater sensitivity to ALLO mediated potentiation of GABAergic neurotransmission, contributing to increased neuroprotection.

Some very nice finds! Lets pray they find something for this upcoming meeting in Italy

Here is an interesting read on pregnenalone.

books.google.com/books?id=3ls82S … ex&f=false

Old thread but figured I’d revive it since everyone is talking about sage.

I’m confused didn’t zulresso get approved???
Can anyone elaborate?

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Zulresso was approved for post partum depression. It requires IV for around 60 hours. Hence, some people here are looking at Zuranolone (Sage-217) another allopregnanolone analogue under development by Sage Therapeutics, which has not yet been approved and recently failed a clinical trial (although there is a bit of debate about this). Zuranolone would be easier to get and easier to take (oral).

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Gotcha, so if zuranolone doesn’t get approved maybe we could try Zulresso as an off label treatment, obviously the cost on this is outrageous but seems like It may be the only option if the other one doesn’t get approved.

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Does anyone know what Melcangi is working on these days and if there are any signs that any other groups have taken up similar lines of inquiry?

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Well, a partial nevermind. I see here that he is still active in this area. Do still wonder if he is the only one looking at that and maybe even more wondering if he might also possibly look at PSSD and PAS patients.

It’s great to see real bio markers. Would be even better if the same were implicated in all 3. I mean from the perspective of that it might triple resources or at least interest in potentially one problem.

https://www.pfsfoundation.org/publications/

Can you plz link me to the study that zuranolone has failed? I will really appreciate it

There’s a link to a summary of the trial in the article

Thx for the link…
Its still hard to know, if SAGE 217 would have any effect on us, since we litereally have no Allo whatsoever, and most of us had no history of depression (Which is a very complex disease) before poisining ourselves with Fin, so Allo may be the missing stuff, that drives our symptoms…
Im 1 Step away from ordering it (Already contacted the company, which is 100% legit, it will cost me 2600 dollars for 1g)…Im still very hesitant to ordering it (Mainly fearing, that SAGE-217 will make no difference, which will put me into a very deep depression, that might end in me killing myself)…Its paradox i know…
I took out of frustration 30mg of 9-MBC, and might experiment with it for 1 week, before settling myself on ordering SAGE-217…Wish me luck guys, i will be happy to be the lab rat, if it means i can find a cure for this shit…I cant even imagine, how much damage this poison did to thousands, if not tens of thousands if young guys…The crash alone must be enough to persecute every single employee in Merck to a life sentence…Please to all who crashed, and everyone thinking of committing suicide, please stay tuned, till i finish my experiments, and then you can decide what to do next…Wish me luck guys

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Thank you very much for sharing what you are going through and what your thoughts on things are. Definitely do not commit suicide yet man. I know it’s unbearable but I do think it is possible to “forget” about PFS for extended periods and be able to enjoy life quite a bit. I know you can’t totally forget but I think being around here and focusing on it does temporarily make things feel worse than they really are. So if you feel like ending it you gotta at least get off this board for a while and try to focus on other things for a while.

I do think the Sage 217 has a reasonable chance of being at least very helpful. I’m thinking about trying it too, though it would need to be a few months from now.

In case it is useful for you to know, although I have tried just about all anti-depressants and basically none of them helped, I did have success with one. Low,dose Amisulpride seems to help my mood a lot. Unfortunately, it causes hyperprolactin, which makes the sexual sides worse, so it’s not a good long-term solution. However, it has been very helpful in keeping going when handicapped by depression. Of course it might not work for you. Just thought I’d give you something to look at in case it might be useful to know. You would want to search for information on it in the context of “dysthymia”, not psychosis. At high doses it operates very differently (psychosis treatment) from how it operates at low doses (dysthymia treatment).

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I don’t know it it’s true that we have no Allo. I have periods where libido is much better than baseline and mood is 80%+, including the last 2 days. And how about all the others who have temporary recovery?

We might just be deficient in it rather than completely lacking it, I’m sure that would cause insane issues. It would explain variety of symptoms because different people will have different levels of allo deficiency. Lack of allo sounds like it explains my muscle twitches, sleep issues and libido problems tbh.

Hope someone tries this soon

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