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INFOMATION:
Medroxyprogesterone acetate (INN, USAN, BAN), also known as 17α-hydroxy-6α-methylprogesterone acetate, and commonly abbreviated as MPA, is a steroidal progestin, a synthetic variant of the human hormone progesterone.[2][3] It is used as a contraceptive, in hormone replacement therapy and for the treatment of endometriosis as well as several other indications.
Medical uses
In females, the most common use of MPA is as an oral or depot-injected contraceptive and also as the progestin component of menopausal hormone replacement therapy to prevent endometrial hyperplasia and cancer. MPA is also used as a treatment for endometriosis, dysmenorrhea, and amenorrhea. MPA, along with other progestins were developed to allow the hormones to be taken orally, as progesterone (the hormone made by the human body) could not be taken orally before the process of micronization was developed.
In males, MPA has been used to control inappropriate sexual behavior to chemically castrate convicted sex offenders.
MPA is an extremely effective contraceptive when used with relatively high doses to prevent ovulation. It has also been used to treat benign prostatic hyperplasia, as a palliative appetite stimulant for cancer patients, and at high doses (800 mg per day) to treat hormone-dependent cancers of primarily the breast, but also other types.
Though not used as a treatment for epilepsy, MPA reduces the frequency of seizures and does not interact with anti-epileptic medications. MPA does not interfere with blood clotting and appears to improve blood parameters for women with sickle cell anemia. Similarly, MPA does not appear to affect liver metabolism, and may improve primary biliary cirrhosis and chronic active hepatitis. Women taking MPA may experience spotting shortly after starting the medication but is not usually serious enough to require medical intervention. With longer use amenorrhoea can occur as can irregular menstruation which is a major source of dissatisfaction, though both can result in improvements with iron deficiency and risk of pelvic inflammatory disease and often do not result in discontinuing the medication. MPA is also prescribed in combination with an estrogen to prevent endometrial hyperplasia in post-menopausal women who are undergoing hormone replacement therapy.
MPA has also been prescribed in hormone replacement therapy for male-to-female transsexuals due to its antiandrogen and progestogen effects.
Pharmacodynamics
Activity profile
MPA acts as an agonist of the progesterone, androgen, and glucocorticoid receptors (PR, AR, and GR, respectively), activating these receptors with EC50 values of approximately 0.01 nM, 1 nM, and 10 nM, respectively. It has very low and likely completely insignificant affinity for the estrogen and mineralocorticoid receptors (ER and MR, respectively). Although the EC50 values of MPA at the PR and the AR and GR are separated by several orders of magnitude, because it is so potent, and because it is used at relatively high doses in humans, it is likely that the overall activation of each of the three receptors is fairly similar.[citation needed] The intrinsic activities of MPA in activating the PR and the AR have been reported to be at least equivalent to those of progesterone and dihydrotestosterone (DHT), respectively, indicating that it is a full agonist of these receptors.
In addition to its direct effects on steroid receptors, MPA, at sufficient doses, inhibits the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes, resulting in a marked suppression of gonadotropin, androgen, estrogen, adrenocorticotropic hormone (ACTH), and cortisol levels as well as concentrations of sex hormone-binding globulin (SHBG). There is evidence that the downregulatory effects of MPA on the HPG axis are mediated by activation of both PRs and ARs in the pituitary gland. Due to its effects on androgen levels, MPA has strong functional antiandrogen properties, and it is used in androgen-sensitive conditions such as precocious puberty in prepubescent boys and hypersexuality in men. In addition, since it affects estrogen levels similarly, unlike many other antiandrogens such as spironolactone and cyproterone acetate which have a high propensity for causing gynecomastia via indirect stimulation of estrogen, MPA is not thought to possess any estrogenic effects. Indeed, due to its inhibitory effects on estrogen levels, it has potent antiestrogenic effects, and has been used to treat precocious puberty in prepubescent girls. Accordingly, MPA should not be used in high doses without an estrogen in women due to the risk of osteoporosis and other symptoms associated with hypoestrogenism.
As mentioned above, MPA is a potent full agonist of the AR. Its activation of the AR has been shown to play an important and major role in its antigonadotropic effects and in its beneficial effects against breast cancer. However, although MPA does have the capacity to cause androgenic side effects such as acne and hirsutism in some patients (especially women), it seldom actually does so, and when it does, the effects tend to be only mild, regardless of the dosage used. In fact, likely due to its suppressive actions on androgen levels, it has been reported that MPA is generally highly effective in improving pre-existing symptoms of hirsutism in women with the condition. Moreover, MPA rarely causes any androgenic effects in children with precocious puberty, even at very high doses. The reason for the general lack of virilizing effects with MPA, despite it binding to and activating the AR with a high affinity and this action playing an important role in many of its physiological and therapeutic effects, is not entirely clear. However, MPA has been found to interact with the AR in a fundamentally different way than other agonists of the receptor such as dihydrotestosterone (DHT). The result of this difference appears to be that MPA binds to the AR with a similar affinity and intrinsic activity to that of DHT, but requires about 100-fold higher concentrations for a comparable induction of gene transcription, while at the same time not antagonizing the transcriptional activity of normal androgens like DHT at any concentration. Thus, this may explain the low propensity of MPA for producing androgenic side effects.
As an agonist of the GR, MPA has glucocorticoid properties, and as a result can cause symptoms of Cushing's syndrome, steroid diabetes, and adrenal insufficiency at sufficiently high doses.
Although MPA and the related drug megestrol acetate (which is a close analogue) have been extensively used as appetite stimulants, the mechanism of action of their beneficial effects on appetite is not entirely clear. However, glucocorticoid, cytokine, and possibly anabolic-related mechanisms are all thought to possibly be involved, and a number of downstream changes have been implicated, including stimulation of the release of neuropeptide Y in the hypothalamus, modulation of calcium channels in the ventromedial hypothalamus, and inhibition of the secretion of proinflammatory cytokines including IL-1α, IL-1β, IL-6, and TNF-α, actions that have all been linked to an increased appetite.
Comparison to medroxyprogesterone
Medroxyprogesterone (MP), the parent drug of MPA, is a metabolite of MPA. While both MP and its acylated derivative MPA bind to the PR and both act as agonists, MPA has approximately 100 fold higher binding affinity and transactivation potency compared to MP. As such, MP is not used clinically, though it has seen some use in veterinary medicine.
Ligand PR Ki (nM) Coactivator recruitment EC50 (nM) Reporter cell line EC50 (nM) Progesterone 4.3 ± 1.0 0.9 ± 0.2 25 ± 11 Medroxyprogesterone acetate 1.2 ± 0.3 0.6 ± 0.08 0.15 ± 0.03 Medroxyprogesterone 241 ± 96 47 ± 14 32 ± 1Pharmacokinetics
MPA is well-absorbed orally and through intramuscular injection, peaking at 2–4 hours for the former. The half life is 12 to 17 hours for an oral dose, and 40 to 50 days for an intramuscular injection. MPA binds to albumin in the blood, and is metabolized primarily through the liver via hydroxylation and conjugation. Intramuscular MPA is released slowly; a 150 mg dose is first detectable in the blood 30 minutes after injection, plateauing at 1.0 ng/mL for three months, followed by a gradual, tapering decline that lasts up to nine months in some women. The high levels of MPA in the blood inhibits luteinizing hormone and ovulation for several months, with an accompanying decrease in serum progesterone to below 0.4 ng/mL. Ovulation resumes when once blood levels of MPA fall below 0.1 ng/ml. Serum estradiol remains at approximately 50 pg/nl for approximately four months post-injection (with a range of 10-92 pg/nL after several years of use), rising once MPA levels fall below 0.5 ng/ml.
Hot flashes are rare while MPA is found at significant blood levels in the body, and the vaginal lining remains moist and creased. The endometrium undergoes atrophy, with small, straight glands and a stroma that is decidualized. Cervical mucus remains viscous. Because of its steady blood levels over the long term and multiple effects that prevent fertilisation, MPA is a very effective means of birth control.
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