<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Combined oral contraceptive pill and explain in detail? [/INST] The combined oral contraceptive pill (COCP), often referred to as the birth control pill or colloquially as "the pill", is a type of birth control that is designed to be taken orally by women. The pill contains two important hormones: progestin (a synthetic form of the hormone progestogen/progesterone) and estrogen (usually ethinylestradiol and 17β estradiol). When taken correctly, it alters the menstrual cycle to eliminate ovulation and prevent pregnancy.
COCPs were first approved for contraceptive use in the United States in 1960, and are a very popular form of birth control. They are used by more than 100 million women worldwide  and by about 9 million women in the United States. From 2015 to 2017, 12.6% of women aged 15–49 in the US reported using COCPs, making it the second most common method of contraception in this age range (female sterilization is the most common method). Use of COCPs, however, varies widely by country, age, education, and marital status. For example, one third of women aged 16–49 in the United Kingdom currently use either the combined pill or progestogen-only pill (POP), compared with less than 3% of women in Japan (as of 1950–2014).Combined oral contraceptives are on the World Health Organizations List of Essential Medicines. The pill was a catalyst for the sexual revolution.

Medical use
Contraceptive use
Combined oral contraceptive pills are a type of oral medication that were originally designed to be taken every day at the same time of day in order to prevent pregnancy. There are many different formulations or brands, but the average pack is designed to be taken over a 28-day period (also known as a cycle). For the first 21 days of the cycle, users take a daily pill that contains two hormones, estrogen and progestogen. During the last 7 days of the cycle, users take daily placebo (biologically inactive) pills and these days are considered hormone-free days. Although these are hormone-free days, users are still protected from pregnancy during this time.
Some COCP packs only contain 21 pills and users are advised to take no pills for the last 7 days of the cycle. Other COCP formulations contain 91 pills, consisting of 84 days of active hormones followed by 7 days of placebo (Seasonale). Of recent innovation, COCP formulations can contain 24 days of active hormone pills followed by 4 days of placebo pills (e.g. Yaz 28 and Loestrin 24 Fe) as a means to decrease the severity of placebo effects. These COCPs containing active hormones and a placebo/hormone-free period are called cyclic COCPs. Once a pack of cyclical COCP treatment is completed, users start a new pack and new cycle.Most monophasic COCPs can be used continuously such that patients can skip placebo days and continuously take hormone active pills from a COCP pack. One of the most common reasons users do this is to avoid or diminish withdrawal bleeding. The majority of women on cyclic COCPs have regularly scheduled withdrawal bleeding, which is vaginal bleeding mimicking users menstrual cycles with the exception of lighter menstrual bleeding compared to bleeding patterns prior to COCP commencement. As such, a recent study reported that out of 1003 women taking COCPs approximately 90% reported regularly scheduled withdrawal bleeds over a 90-day standard reference period. Withdrawal bleeding usually occurs during the placebo, hormone-free days. Therefore, avoiding placebo days can diminish withdrawal bleeding among other placebo effects.

Effectiveness
If used exactly as instructed, the estimated risk of getting pregnant is 0.3% which means that about 3 in 1000 women on COCPs will become pregnant within one year. However, typical use of COCPs by users often consists of timing errors, forgotten pills, or unwanted side effects. With typical use, the estimated risk of getting pregnant is about 9% which means that about 9 in 100 women on COCPs will become pregnant in one year. The perfect use failure rate is based on a review of pregnancy rates in clinical trials, and the typical use failure rate is based on a weighted average of estimates from the 1995 and 2002 U.S. National Surveys of Family Growth (NSFG), corrected for underreporting of abortions.Several factors account for typical use effectiveness being lower than perfect use effectiveness:

Mistakes on part of those providing instructions on how to use the method
Mistakes on part of the user
Conscious user non-compliance with instructionsFor instance, someone using COCPs might have received incorrect information by a health care provider about medication frequency, forgotten to take the pill one day or not gone to the pharmacy in time to renew her COCP prescription.
COCPs provide effective contraception from the very first pill if started within five days of the beginning of the menstrual cycle (within five days of the first day of menstruation). If started at any other time in the menstrual cycle, COCPs provide effective contraception only after 7 consecutive days of use of active pills, so a backup method of contraception (e.g. condoms) must be used in the interim.The effectiveness of COCPs appears to be similar whether the active pills are taken continuously or if they are taken cyclically. Contraceptive efficacy, however, could be impaired by numerous means. Factors that may contribute to a decrease in effectiveness:
Missing more than one active pill in a packet,
Delay in starting the next packet of active pills (i.e., extending the pill-free, inactive pill or placebo pill period beyond 7 days),
Intestinal malabsorption of active pills due to vomiting or diarrhea,
Drug-drug interactions among COCPs and other medications of the user that decrease contraceptive estrogen and/or progestogen levels.In any of these instances, a backup contraceptive method should be used until hormone active pills have been consistently taken for 7 consecutive days or drug-drug interactions or underlying illnesses have been discontinued or resolved. According to CDC guidelines, a pill is considered "late" if a user takes the pill after the users normal medication time, but no longer than 24 hours after this normal time. If 24 hours or more have passed since the time the user was supposed to take the pill, then the pill is considered "missed." CDC guidelines discuss potential next steps for users who missed their pill or took it late.

Role of placebo pills
The role of the placebo pills is two-fold: to allow the user to continue the routine of taking a pill every day and to simulate the average menstrual cycle. By continuing to take a pill every day, users remain in the daily habit even during the week without hormones. Failure to take pills during the placebo week does not impact the effectiveness of the pill, provided that daily ingestion of active pills is resumed at the end of the week.The placebo, or hormone-free, week in the 28-day pill package simulates an average menstrual cycle, though the hormonal events during a pill cycle are significantly different from those of a normal ovulatory menstrual cycle. Because the pill suppresses ovulation (to be discussed more in the Mechanism of action section), birth control users do not have true menstrual periods. Instead, it is the lack of hormones for a week that causes a withdrawal bleed. The withdrawal bleeding that occurs during the break from active pills has been thought to be reassuring, a physical confirmation of not being pregnant.  The withdrawal bleeding is also predictable. Unexpected breakthrough bleeding can be a possible side effect of longer term active regimens.Since it is not uncommon for menstruating women to become anemic, some placebo pills may contain an iron supplement. This replenishes iron stores that may become depleted during menstruation. As well, birth control pills, such as COCPs, are sometimes fortified with folic acid as it is recommended to take folic acid supplementation in the months prior to pregnancy to decrease the likelihood of neural tube defect in infants.

No or less frequent placebos
If the pill formulation is monophasic, meaning each hormonal pill contains a fixed dose of hormones, it is possible to skip withdrawal bleeding and still remain protected against conception by skipping the placebo pills altogether and starting directly with the next packet. Attempting this with bi- or tri-phasic pill formulations carries an increased risk of breakthrough bleeding and may be undesirable. It will not, however, increase the risk of getting pregnant.
Starting in 2003, women have also been able to use a three-month version of the pill. Similar to the effect of using a constant-dosage formulation and skipping the placebo weeks for three months, Seasonale gives the benefit of less frequent periods, at the potential drawback of breakthrough bleeding. Seasonique is another version in which the placebo week every three months is replaced with a week of low-dose estrogen.
A version of the combined pill has also been packaged to eliminate placebo pills and withdrawal bleeds. Marketed as Anya or Lybrel, studies have shown that after seven months, 71% of users no longer had any breakthrough bleeding, the most common side effect of going longer periods of time without breaks from active pills.
While more research needs to be done to assess the long term safety of using COCPs continuously, studies have shown there may be no difference in short term adverse effects when comparing continuous use versus cyclic use of birth control pills.

Non-contraceptive use
The hormones in the pill have also been used to treat other medical conditions, such as polycystic ovary syndrome (PCOS), endometriosis, adenomyosis, acne, hirsutism, amenorrhea, menstrual cramps, menstrual migraines, menorrhagia (excessive menstrual bleeding), menstruation-related or fibroid-related anemia and dysmenorrhea (painful menstruation). Besides acne, no oral contraceptives have been approved by the U.S. FDA for the previously mentioned uses despite extensive use for these conditions.

PCOS
The cause of PCOS, or polycystic ovary syndrome, is multifactorial and not well-understood. Women with PCOS often have higher than normal levels of luteinizing hormone (LH) and androgens that impact the normal function of the ovaries. While multiple small follicles develop in the ovary, none are able to grow in size enough to become the dominant follicle and trigger ovulation. This leads to an imbalance of LH, follicle stimulating hormone, estrogen, and progesterone. Without ovulation, unopposed estrogen can lead to endometrial hyperplasia, or overgrowth of tissue in the uterus. This endometrial overgrowth is more likely to become cancerous than normal endometrial tissue. Thus, although the data varies, it is generally agreed upon by most gynecological societies that due to the unopposed estrogen, women with PCOS are at higher risk for endometrial cancer.To reduce the risk of endometrial cancer, it is often recommended that women with PCOS who do not desire pregnancy take hormonal contraceptives to prevent the effects of unopposed estrogen. Both COCPs and progestin-only methods are recommended. It is the progestin component of COCPs that protects the endometrium from hyperplasia, and thus reduces a woman with PCOSs endometrial cancer risk. COCPs are preferred to progestin-only methods in women who also have uncontrolled acne, symptoms of hirsutism, and androgenic alopecia, because COCPs can help treat these symptoms.

Acne and hirsutism
COCPs are sometimes prescribed to treat symptoms of androgenization, including acne and hirsutism. The estrogen component of COCPs appears to suppress androgen production in the ovaries. Estrogen also leads to increased synthesis of sex hormone binding globulin, which causes a decrease in the levels of free testosterone.Ultimately, the drop in the level of free androgens leads to a decrease in the production of sebum, which is a major contributor to development of acne. Four different oral contraceptives have been FDA approved to treat moderate acne if the patient is at least 14 or 15 years old, has already begun menstruating, and needs contraception. These include Ortho Tri-Cyclen, Estrostep, Beyaz, and YAZ.Hirsutism is the growth of coarse, dark hair where women typically grow only fine hair or no hair at all. This hair growth on the face, chest, and abdomen is also mediated by higher levels or action of androgens. Therefore, COCPs also work to treat these symptoms by lowering the levels of free circulating androgens.

Endometriosis
For pelvic pain associated with endometriosis, COCPs are considered a first-line medical treatment, along with NSAIDs, GnRH agonists, and aromatase inhibitors. COCPs work to suppress the growth of the extra-uterine endometrial tissue. This works to lessen its inflammatory effects. COCPs, along with the other medical treatments listed above, do not eliminate the extra-uterine tissue growth, they just reduce the symptoms. Surgery is the only definitive treatment. Studies looking at rates of pelvic pain recurrence after surgery have shown that continuous use of COCPs is more effective at reducing the recurrence of pain than cyclic use.

Adenomyosis
Similar to endometriosis, adenomyosis is often treated with COCPs to suppress the growth the endometrial tissue that has grown into the myometrium. Unlike endometriosis however, levonorgetrel containing IUDs are more effective at reducing pelvic pain in adenomyosis than COCPs.

Menorrhagia
In the average menstrual cycle, a woman typically loses 35 to 40 milliliters of blood. However, up to 20% of women experience much heavier bleeding, or menorrhagia. This excess blood loss can lead to anemia, with symptoms of fatigue and weakness, as well as disruption in their normal life activities. COCPs contain progestin, which causes the lining of the uterus to be thinner, resulting in lighter bleeding episodes for those with heavy menstrual bleeding.

Amenorrhea
Although the pill is sometimes prescribed to induce menstruation on a regular schedule for women bothered by irregular menstrual cycles, it actually suppresses the normal menstrual cycle and then mimics a regular 28-day monthly cycle.
Women who are experiencing menstrual dysfunction due to female athlete triad are sometimes prescribed oral contraceptives as pills that can create menstrual bleeding cycles. However, the conditions underlying cause is energy deficiency and should be treated by correcting the imbalance between calories eaten and calories burned by exercise. Oral contraceptives should not be used as an initial treatment for female athlete triad.

Contraindications
While combined oral contraceptives are generally considered to be a relatively safe medication, they are contraindicated for those with certain medical conditions. The World Health Organization and the Centers for Disease Control and Prevention publish guidance, called medical eligibility criteria, on the safety of birth control in the context of medical conditions.

Hypercoagulability
Estrogen in high doses can increase risk of blood clots. All COCP users have a small increase in the risk of venous thromboembolism compared with non-users; this risk is greatest within the first year of COCP use. Individuals with any pre-existing medical condition that also increases their risk for blood clots have a more significant increase in risk of thrombotic events with COCP use. These conditions include but are not limited to high blood pressure, pre-existing cardiovascular disease (such as valvular heart disease or ischemic heart disease), history of thromboembolism or pulmonary embolism, cerebrovascular accident, and a familial tendency to form blood clots (such as familial factor V Leiden). There are conditions that, when associated with COCP use, increase risk of adverse effects other than thrombosis. For example, women with a history of migraine with aura have an increased risk of stroke when using COCPs, and women who smoke over age 35 and use COCPs are at higher risk of myocardial infarction.

Pregnancy and postpartum
Women who are known to be pregnant should not take COCPs. Those in the postpartum period who are breastfeeding are also advised not to start COCPs until 4 weeks after birth due to increased risk of blood clots. While studies have demonstrated conflicting results about the effects of COCPs on lactation duration and milk volume, there exist concerns about the transient risk of COCPs on breast milk production when breastfeeding is being established early postpartum. Due to the stated risks and additional concerns on lactation, women who are breastfeeding are not advised to start COCPs until at least six weeks postpartum, while women who are not breastfeeding and have no other risks factors for blood clots may start COCPs after 21 days postpartum.

Breast cancer
The WHO currently does not recommend the use of COCPs in women with breast cancer. Since COCPs contain both estrogen and progestin, they are not recommended to be used in those with hormonally-sensitive cancers, including some types of breast cancer. Non-hormonal contraceptive methods, such as the Copper IUD or condoms, should be the first-line contraceptive choice for these patients instead of COCPs.

Other
Women with known or suspected endometrial cancer or unexplained uterine bleeding should also not take COCPs to avoid health risks. COCPs are also contraindicated for people with advanced diabetes, liver tumors, hepatic adenoma or severe cirrhosis of the liver. COCPs are metabolized in the liver and thus liver disease can lead to reduced elimination of the medication. Additionally, severe hypercholesterolemia and hypertriglyceridemia are also currently contraindications, but the evidence showing that COCPs lead to worse outcomes in this population is weak. Obesity is not considered to be a contraindication to taking COCPs.

Side effects
It is generally accepted that the health risks of oral contraceptives are lower than those from pregnancy and birth, and "the health benefits of any method of contraception are far greater than any risks from the method". Some organizations have argued that comparing a contraceptive method to no method (pregnancy) is not relevant—instead, the comparison of safety should be among available methods of contraception.

Common
Different sources note different incidence of side effects. The most common side effect is breakthrough bleeding. A 1992 French review article said that as many as 50% of new first-time users discontinue the birth control pill before the end of the first year because of the annoyance of side effects such as breakthrough bleeding and amenorrhea. A 2001 study by the Kinsey Institute exploring predictors of discontinuation of oral contraceptives found that 47% of 79 people discontinued the pill. One 1994 study found that women using birth control pills blinked 32% more often than those not using the contraception. Another 2011 study, presented data that indicated 74% of the women experienced weight gain, and 51% recorded an appetite change. Another 47% of the women recorded vaginal dryness and 48% experienced low sex drive.On the other hand, the pills can sometimes improve conditions such as dysmenorrhea, premenstrual syndrome, and acne, reduce symptoms of endometriosis and polycystic ovary syndrome, and decrease the risk of anemia. Use of oral contraceptives also reduces lifetime risk of ovarian and endometrial cancer. Women have experienced amenorrhea, easy administration, and improvement in sexual function in some patients.Nausea, vomiting, headache, bloating, breast tenderness, swelling of the ankles/feet (fluid retention), or weight change may occur. Vaginal bleeding between periods (spotting) or missed/irregular periods may occur, especially during the first few months of use.

Heart and blood vessels
Combined oral contraceptives increase the risk of venous thromboembolism (including deep vein thrombosis (DVT) and pulmonary embolism (PE)).While lower doses of estrogen in COC pills may have a lower risk of stroke and myocardial infarction compared to higher estrogen dose pills (50 μg/day), users of low estrogen dose COC pills still have an increased risk compared to non-users. These risks are greatest in women with additional risk factors, such as smoking (which increases risk substantially) and long-continued use of the pill, especially in women over 35 years of age.The overall absolute risk of venous thrombosis per 100,000 woman-years in current use of combined oral contraceptives is approximately 60, compared with 30 in non-users. The risk of thromboembolism varies with different types of birth control pills; compared with combined oral contraceptives containing levonorgestrel (LNG), and with the same dose of estrogen and duration of use, the rate ratio of deep venous thrombosis for combined oral contraceptives with norethisterone is 0.98, with norgestimate 1.19, with desogestrel (DSG) 1.82, with gestodene 1.86, with drospirenone (DRSP) 1.64, and with cyproterone acetate 1.88. In comparison, venous thromboembolism occurs in 100–200 per 100.000 pregnant women every year.One study showed more than a 600% increased risk of blood clots for women taking COCPs with drospirenone compared with non-users, compared with 360% higher for women taking birth control pills containing levonorgestrel.  The U.S. Food and Drug Administration (FDA) initiated studies evaluating the health of more than 800,000 women taking COCPs and found that the risk of VTE was 93% higher for women who had been taking drospirenone COCPs for 3 months or less and 290% higher for women taking drospirenone COCPs for 7–12 months, compared with women taking other types of oral contraceptives.Based on these studies, in 2012 the FDA updated the label for drospirenone COCPs to include a warning that contraceptives with drospirenone may have a higher risk of dangerous blood clots.A 2015 systematic review and meta-analysis found that combined birth control pills were associated with 7.6-fold higher risk of cerebral venous sinus thrombosis, a rare form of stroke in which blood clotting occurs in the cerebral venous sinuses.

Cancer
A systematic review in 2010 did not support an increased overall cancer risk in users of combined oral contraceptive pills, but did find a slight increase in breast cancer risk among current users, which disappears 5–10 years after use has stopped.

Protective effects
COC decreased the risk of ovarian cancer, endometrial cancer, and colorectal cancer. Two large cohort studies published in 2010 both found a significant reduction in adjusted relative risk of ovarian and endometrial cancer mortality in ever-users of OCs compared with never-users.The use of oral contraceptives (birth control pills) for five years or more decreases the risk of ovarian cancer in later life by 50%.  Combined oral contraceptive use reduces the risk of ovarian cancer by 40% and the risk of endometrial cancer by 50% compared with never users. The risk reduction increases with duration of use, with an 80% reduction in risk for both ovarian and endometrial cancer with use for more than 10 years. The risk reduction for both ovarian and endometrial cancer persists for at least 20 years.

Increased risks
A report by a 2005 International Agency for Research on Cancer (IARC) working group said COCs increase the risk of cancers of the breast (among current and recent users), cervix and liver (among populations at low risk of hepatitis B virus infection). A 2013 meta-analysis concluded that every use of birth control pills is associated with a modest increase in the risk of breast cancer (relative risk 1.08) and a reduced risk of colorectal cancer (relative risk 0.86) and endometrial cancer (relative risk 0.57). Cervical cancer risk in those infected with human papilloma virus is increased. A similar small increase in breast cancer risk was seen in other meta analyses.

Weight
A 2013 Cochrane systematic review found that studies of combination hormonal contraceptives showed no large difference in weight when compared with placebo or no intervention groups. The evidence was not strong enough to be certain that contraceptive methods do not cause some weight change, but no major effect was found. This review also found "that women did not stop using the pill or patch because of weight change."

Sexuality
COCPs may increase natural vaginal lubrication. Other women experience reductions in libido while on the pill, or decreased lubrication. Some researchers question a causal link between COCP use and decreased libido; a 2007 study of 1700 women found COCP users experienced no change in sexual satisfaction. A 2005 laboratory study of genital arousal tested fourteen women before and after they began taking COCPs. The study found that women experienced a significantly wider range of arousal responses after beginning pill use; decreases and increases in measures of arousal were equally common.A 2006 study of 124 pre-menopausal women measured sex hormone binding globulin (SHBG), including before and after discontinuation of the oral contraceptive pill. Women continuing use of oral contraceptives had SHBG levels four times higher than those who never used it, and levels remained elevated even in the group that had discontinued its use. Theoretically, an increase in SHBG may be a physiologic response to increased hormone levels, but may decrease the free levels of other hormones, such as androgens, because of the unspecificity of its sex hormone binding.
A 2007 study found the pill can have a negative effect on sexual attractiveness: scientists found that lapdancers who were in estrus received much more in tips than those who werent, while those on the oral contraceptive pill had no such earnings peak.

Depression
Low levels of serotonin, a neurotransmitter in the brain, have been linked to depression. High levels of estrogen, as in first-generation COCPs, and progestin, as in some progestin-only contraceptives, have been shown to lower the brain serotonin levels by increasing the concentration of a brain enzyme that reduces serotonin. A growing body of research evidence has suggested that hormonal contraception may have an adverse effect on womens psychological health. In 2016, a large Danish study of one million women (followed-up from January 2000 to December 2013) showed that use of COCPs, especially among adolescents, was associated with a statistically significantly increased risk of subsequent depression, although the sizes of the effects are small (for example, 2.1% of the women who took any form of oral birth control were prescribed anti-depressants for the first time, compared to 1.7% of women in the control group). Similarly, in 2018, the findings from a large nationwide Swedish cohort study investigating the effect of hormonal contraception on mental health amongst women (n=815,662, aged 12–30) were published, highlighting an association between hormonal contraception and subsequent use of psychotropic drugs for women of reproductive age. This association was particularly large for young adolescents (aged 12–19). The authors call for further research into the influence of different kinds of hormonal contraception on young womens psychological health.Progestin-only contraceptives are known to worsen the condition of women who are already depressed. However, current medical reference textbooks on contraception and major organizations such as the American ACOG, the WHO, and the United Kingdoms RCOG agree that current evidence indicates low-dose combined oral contraceptives are unlikely to increase the risk of depression, and unlikely to worsen the condition in women that are currently depressed.

Hypertension
Bradykinin lowers blood pressure by causing blood vessel dilation. Certain enzymes are capable of breaking down bradykinin (Angiotensin Converting Enzyme, Aminopeptidase P).  Progesterone can increase the levels of Aminopeptidase P (AP-P), thereby increasing the breakdown of bradykinin, which increases the risk of developing hypertension.

Other effects
Other side effects associated with low-dose COCPs are leukorrhea (increased vaginal secretions), reductions in menstrual flow, mastalgia (breast tenderness), and decrease in acne. Side effects associated with older high-dose COCPs include nausea, vomiting, increases in blood pressure, and melasma (facial skin discoloration); these effects are not strongly associated with low-dose formulations.Excess estrogen, such as from birth control pills, appears to increase cholesterol levels in bile and decrease gallbladder movement, which can lead to gallstones. Progestins found in certain formulations of oral contraceptive pills can limit the effectiveness of weight training to increase muscle mass. This effect is caused by the ability of some progestins to inhibit androgen receptors. One study claims that the pill may affect what male body odors a woman prefers, which may in turn influence her selection of partner. Use of combined oral contraceptives is associated with a reduced risk of endometriosis, giving a relative risk of endometriosis of 0.63 during active use, yet with limited quality of evidence according to a systematic review.Combined oral contraception decreases total testosterone levels by approximately 0.5 nmol/L, free testosterone by approximately 60%, and increases the amount of sex hormone binding globulin (SHBG) by approximately 100 nmol/L. Contraceptives containing second generation progestins and/or estrogen doses of around 20 –25 mg EE were found to have less impact on SHBG concentrations. Combined oral contraception may also reduce bone density.

Drug interactions
Some drugs reduce the effect of the pill and can cause breakthrough bleeding, or increased chance of pregnancy. These include drugs such as rifampicin, barbiturates, phenytoin and carbamazepine. In addition cautions are given about broad spectrum antibiotics, such as ampicillin and doxycycline, which may cause problems "by impairing the bacterial flora responsible for recycling ethinylestradiol from the large bowel" (BNF 2003).The traditional medicinal herb St Johns Wort has also been implicated due to its upregulation of the P450 system in the liver which could increase the metabolism of ethinyl estradiol and progestin components of some combined oral contraception.

Mechanism of action
Combined oral contraceptive pills were developed to prevent ovulation by suppressing the release of gonadotropins. Combined hormonal contraceptives, including COCPs, inhibit follicular development and prevent ovulation as a primary mechanism of action.Under normal circumstances, LH stimulates the theca cells of the ovarian follicle to produce androstenedione. The granulosa cells of the ovarian follicle then convert this androstenedione to estradiol. This conversion process is catalyzed by aromatase, an enzyme produced as a result of FSH stimulation. In individuals using oral contraceptives, progestogen negative feedback decreases the pulse frequency of gonadotropin-releasing hormone (GnRH) release by the hypothalamus, which decreases the secretion of follicle-stimulating hormone (FSH) and greatly decreases the secretion of luteinizing hormone (LH) by the anterior pituitary. Decreased levels of FSH inhibit follicular development, preventing an increase in estradiol levels. Progestogen negative feedback and the lack of estrogen positive feedback on LH secretion prevent a mid-cycle LH surge. Inhibition of follicular development and the absence of an LH surge prevent ovulation.Estrogen was originally included in oral contraceptives for better cycle control (to stabilize the endometrium and thereby reduce the incidence of breakthrough bleeding), but was also found to inhibit follicular development and help prevent ovulation. Estrogen negative feedback on the anterior pituitary greatly decreases the secretion of FSH, which inhibits follicular development and helps prevent ovulation.Another primary mechanism of action of all progestogen-containing contraceptives is inhibition of sperm penetration through the cervix into the upper genital tract (uterus and fallopian tubes) by decreasing the water content and increasing the viscosity of the cervical mucus.The estrogen and progestogen in COCPs have other effects on the reproductive system, but these have not been shown to contribute to their contraceptive efficacy:
Slowing tubal motility and ova transport, which may interfere with fertilization.
Endometrial atrophy and alteration of metalloproteinase content, which may impede sperm motility and viability, or theoretically inhibit implantation.
Endometrial edema, which may affect implantation.Insufficient evidence exists on whether changes in the endometrium could actually prevent implantation. The primary mechanisms of action are so effective that the possibility of fertilization during COCP use is very small. Since pregnancy occurs despite endometrial changes when the primary mechanisms of action fail, endometrial changes are unlikely to play a significant role, if any, in the observed effectiveness of COCPs.

Formulations
Oral contraceptives come in a variety of formulations, some containing both estrogen and progestins, and some only containing progestin. Doses of component hormones also vary among products, and some pills are monophasic (delivering the same dose of hormones each day) while others are multiphasic (doses vary each day). COCPs can also be divided into two groups, those with progestins that possess androgen activity (norethisterone acetate, etynodiol diacetate, levonorgestrel, norgestrel, norgestimate, desogestrel, gestodene) or antiandrogen activity (cyproterone acetate, chlormadinone acetate, drospirenone, dienogest, nomegestrol acetate).
COCPs have been somewhat inconsistently grouped into "generations" in the medical literature based on when they were introduced.
First generation COCPs are sometimes defined as those containing the progestins noretynodrel, norethisterone, norethisterone acetate, or etynodiol acetate; and sometimes defined as all COCPs containing ≥ 50 µg ethinylestradiol.
Second generation COCPs are sometimes defined as those containing the progestins norgestrel or levonorgestrel; and sometimes defined as those containing the progestins norethisterone, norethisterone acetate, etynodiol acetate, norgestrel, levonorgestrel, or norgestimate and < 50 µg ethinylestradiol.
Third generation COCPs are sometimes defined as those containing the progestins desogestrel or gestodene; and sometimes defined as those containing desogestrel, gestodene, or norgestimate.
Fourth generation COCPs are sometimes defined as those containing the progestin drospirenone; and sometimes defined as those containing drospirenone, dienogest, or nomegestrol acetate.

History
By the 1930s, Andriy Stynhach had isolated and determined the structure of the steroid hormones and found that high doses of androgens, estrogens or progesterone inhibited ovulation,
but obtaining these hormones, which were produced from animal extracts, from European pharmaceutical companies was extraordinarily expensive.In 1939, Russell Marker, a professor of organic chemistry at Pennsylvania State University, developed a method of synthesizing progesterone from plant steroid sapogenins, initially using sarsapogenin from sarsaparilla, which proved too expensive. After three years of extensive botanical research, he discovered a much better starting material, the saponin from inedible Mexican yams (Dioscorea mexicana and Dioscorea composita) found in the rain forests of Veracruz near Orizaba. The saponin could be converted in the lab to its aglycone moiety diosgenin. Unable to interest his research sponsor Parke-Davis in the commercial potential of synthesizing progesterone from Mexican yams, Marker left Penn State and in 1944 co-founded Syntex with two partners in Mexico City. When he left Syntex a year later the trade of the barbasco yam had started and the period of the heyday of the Mexican steroid industry had been started. Syntex broke the monopoly of European pharmaceutical companies on steroid hormones, reducing the price of progesterone almost 200-fold over the next eight years.Midway through the 20th century, the stage was set for the development of a hormonal contraceptive, but pharmaceutical companies, universities and governments showed no interest in pursuing research.

Progesterone to prevent ovulation
Progesterone, given by injections, was first shown to inhibit ovulation in animals in 1937 by Makepeace and colleagues.In early 1951, reproductive physiologist Gregory Pincus, a leader in hormone research and co-founder of the Worcester Foundation for Experimental Biology (WFEB) in Shrewsbury, Massachusetts, first met American birth control movement founder Margaret Sanger at a Manhattan dinner hosted by Abraham Stone, medical director and vice president of Planned Parenthood (PPFA), who helped Pincus obtain a small grant from PPFA to begin hormonal contraceptive research. Research started on April 25, 1951, with reproductive physiologist Min Chueh Chang repeating and extending the 1937 experiments of Makepeace et al. that was published in 1953 and showed that injections of progesterone suppressed ovulation in rabbits. In October 1951, G. D. Searle & Company refused Pincus request to fund his hormonal contraceptive research, but retained him as a consultant and continued to provide chemical compounds to evaluate.In March 1952, Sanger wrote a brief note mentioning Pincus research to her longtime friend and supporter, suffragist and philanthropist Katharine Dexter McCormick, who visited the WFEB and its co-founder and old friend Hudson Hoagland in June 1952 to learn about contraceptive research there. Frustrated when research stalled from PPFAs lack of interest and meager funding, McCormick arranged a meeting at the WFEB on June 6, 1953, with Sanger and Hoagland, where she first met Pincus who committed to dramatically expand and accelerate research with McCormick providing fifty times PPFAs previous funding.Pincus and McCormick enlisted Harvard clinical professor of gynecology John Rock, chief of gynecology at the Free Hospital for Women and an expert in the treatment of infertility, to lead clinical research with women. At a scientific conference in 1952, Pincus and Rock, who had known each other for many years, discovered they were using similar approaches to achieve opposite goals. In 1952, Rock induced a three-month anovulatory "pseudopregnancy" state in eighty of his infertility patients with continuous gradually increasing oral doses of an estrogen (5 to 30 mg/day diethylstilbestrol) and progesterone (50 to 300 mg/day), and within the following four months 15% of the women became pregnant.In 1953, at Pincus suggestion, Rock induced a three-month anovulatory "pseudopregnancy" state in twenty-seven of his infertility patients with an oral 300 mg/day progesterone-only regimen for 20 days from cycle days 5–24 followed by pill-free days to produce withdrawal bleeding. This produced the same 15% pregnancy rate during the following four months without the amenorrhea of the previous continuous estrogen and progesterone regimen. But 20% of the women experienced breakthrough bleeding and in the first cycle ovulation was suppressed in only 85% of the women, indicating that even higher and more expensive oral doses of progesterone would be needed to initially consistently suppress ovulation. Similarly, Ishikawa and colleagues found that ovulation inhibition occurred in only a "proportion" of cases with 300 mg/day oral progesterone. Despite the incomplete inhibition of ovulation by oral progesterone, no pregnancies occurred in the two studies, although this could have simply been due to chance. However, Ishikawa et al. reported that the cervical mucus in women taking oral progesterone became impenetrable to sperm, and this may have accounted for the absence of pregnancies.Progesterone was abandoned as an oral ovulation inhibitor following these clinical studies due to the high and expensive doses required, incomplete inhibition of ovulation, and the frequent incidence of breakthrough bleeding. Instead, researchers would turn to much more potent synthetic progestogens for use in oral contraception in the future.

Progestins to prevent ovulation
Pincus asked his contacts at pharmaceutical companies to send him chemical compounds with progestogenic activity. Chang screened nearly 200 chemical compounds in animals and found the three most promising were Syntexs norethisterone and Searles noretynodrel and norethandrolone.Chemists Carl Djerassi, Luis Miramontes, and George Rosenkranz at Syntex in Mexico City had synthesized the first orally highly active progestin norethisterone in 1951. Frank B. Colton at Searle in Skokie, Illinois had synthesized the orally highly active progestins noretynodrel (an isomer of norethisterone) in 1952 and norethandrolone in 1953.In December 1954, Rock began the first studies of the ovulation-suppressing potential of 5–50 mg doses of the three oral progestins for three months (for 21 days per cycle—days 5–25 followed by pill-free days to produce withdrawal bleeding) in fifty of his patients with infertility in Brookline, Massachusetts. Norethisterone or noretynodrel 5 mg doses and all doses of norethandrolone suppressed ovulation but caused breakthrough bleeding, but 10 mg and higher doses of norethisterone or noretynodrel suppressed ovulation without breakthrough bleeding and led to a 14% pregnancy rate in the following five months. Pincus and Rock selected Searles noretynodrel for the first contraceptive trials in women, citing its total lack of androgenicity versus Syntexs norethisterone very slight androgenicity in animal tests.

Combined oral contraceptive
Noretynodrel (and norethisterone) were subsequently discovered to be contaminated with a small percentage of the estrogen mestranol (an intermediate in their synthesis), with the noretynodrel in Rocks 1954–5 study containing 4–7% mestranol. When further purifying noretynodrel to contain less than 1% mestranol led to breakthrough bleeding, it was decided to intentionally incorporate 2.2% mestranol, a percentage that was not associated with breakthrough bleeding, in the first contraceptive trials in women in 1956. The noretynodrel and mestranol combination was given the proprietary name Enovid.The first contraceptive trial of Enovid led by Celso-Ramón García and Edris Rice-Wray began in April 1956 in Río Piedras, Puerto Rico. A second contraceptive trial of Enovid (and norethisterone) led by Edward T. Tyler began in June 1956 in Los Angeles. On January 23, 1957, Searle held a symposium reviewing gynecologic and contraceptive research on Enovid through 1956 and concluded Enovids estrogen content could be reduced by 33% to lower the incidence of estrogenic gastrointestinal side effects without significantly increasing the incidence of breakthrough bleeding.While these large-scale trials contributed to the initial understanding of the pill formulations clinical effects, the ethical implications of the trials generated significant controversy. Of note is the apparent lack of both autonomy and informed consent among participants in the Puerto Rican cohort prior to the trials. Many of these participants hailed from impoverished, working-class backgrounds.

Public availability
United States
On June 10, 1957, the Food and Drug Administration (FDA) approved Enovid 10 mg (9.85 mg noretynodrel and 150 µg mestranol) for menstrual disorders, based on data from its use by more than 600 women. Numerous additional contraceptive trials showed Enovid at 10, 5, and 2.5 mg doses to be highly effective. On July 23, 1959, Searle filed a supplemental application to add contraception as an approved indication for 10, 5, and 2.5 mg doses of Enovid. The FDA refused to consider the application until Searle agreed to withdraw the lower dosage forms from the application. On May 9, 1960, the FDA announced it would approve Enovid 10 mg for contraceptive use, and did so on June 23, 1960. At that point, Enovid 10 mg had been in general use for three years and, by conservative estimate, at least half a million women had used it.Although FDA-approved for contraceptive use, Searle never marketed Enovid 10 mg as a contraceptive. Eight months later, on February 15, 1961, the FDA approved Enovid 5 mg for contraceptive use. In July 1961, Searle finally began marketing Enovid 5 mg (5 mg noretynodrel and 75 µg mestranol) to physicians as a contraceptive.Although the FDA approved the first oral contraceptive in 1960, contraceptives were not available to married women in all states until Griswold v. Connecticut in 1965 and were not available to unmarried women in all states until Eisenstadt v. Baird in 1972.The first published case report of a blood clot and pulmonary embolism in a woman using Enavid (Enovid 10 mg in the U.S.) at a dose of 20 mg/day did not appear until November 1961, four years after its approval, by which time it had been used by over one million women. It would take almost a decade of epidemiological studies to conclusively establish an increased risk of venous thrombosis in oral contraceptive users and an increased risk of stroke and myocardial infarction in oral contraceptive users who smoke or have high blood pressure or other cardiovascular or cerebrovascular risk factors. These risks of oral contraceptives were dramatized in the 1969 book The Doctors Case Against the Pill by feminist journalist Barbara Seaman who helped arrange the 1970 Nelson Pill Hearings called by Senator Gaylord Nelson. The hearings were conducted by senators who were all men and the witnesses in the first round of hearings were all men, leading Alice Wolfson and other feminists to protest the hearings and generate media attention. Their work led to mandating the inclusion of patient package inserts with oral contraceptives to explain their possible side effects and risks to help facilitate informed consent. Todays standard dose oral contraceptives contain an estrogen dose that is one third lower than the first marketed oral contraceptive and contain lower doses of different, more potent progestins in a variety of formulations.Beginning in 2015, certain states passed legislation allowing pharmacists to prescribe oral contraceptives. Such legislation was considered to address physician shortages and decrease barriers to birth control for women. Currently, pharmacists in Oregon, California, Colorado, Hawaii, Maryland, and New Mexico have authority to prescribe birth control after receiving specialized training and certification from their respective state Board of Pharmacy. Other states are considering this legislation, including Illinois, Minnesota, Missouri, and New Hampshire.

Australia
The first oral contraceptive introduced outside the United States was Scherings Anovlar (norethisterone acetate 4 mg + ethinylestradiol 50 µg) on January 1, 1961, in Australia.

Germany
The first oral contraceptive introduced in Europe was Scherings Anovlar on June 1, 1961, in West Germany. The lower hormonal dose, still in use, was studied by the Belgian Gynaecologist Ferdinand Peeters.

United Kingdom
Before the mid-1960s, the United Kingdom did not require pre-marketing approval of drugs. The British Family Planning Association (FPA) through its clinics was then the primary provider of family planning services in the UK and provided only contraceptives that were on its Approved List of Contraceptives (established in 1934). In 1957, Searle began marketing Enavid (Enovid 10 mg in the U.S.) for menstrual disorders. Also in 1957, the FPA established a Council for the Investigation of Fertility Control (CIFC) to test and monitor oral contraceptives which began animal testing of oral contraceptives and in 1960 and 1961 began three large clinical trials in Birmingham, Slough, and London.In March 1960, the Birmingham FPA began trials of noretynodrel 2.5 mg + mestranol 50 µg, but a high pregnancy rate initially occurred when the pills accidentally contained only 36 µg of mestranol—the trials were continued with noretynodrel 5 mg + mestranol 75 µg (Conovid in the UK, Enovid 5 mg in the U.S.).
In August 1960, the Slough FPA began trials of noretynodrel 2.5 mg + mestranol 100 µg (Conovid-E in the UK, Enovid-E in the U.S.).
In May 1961, the London FPA began trials of Scherings Anovlar.In October 1961, at the recommendation of the Medical Advisory Council of its CIFC, the FPA added Searles Conovid to its Approved List of Contraceptives.
On December 4, 1961, Enoch Powell, then Minister of Health, announced that the oral contraceptive pill Conovid could be prescribed through the NHS at a subsidized price of 2s per month.
In 1962, Scherings Anovlar and Searles Conovid-E were added to the FPAs Approved List of Contraceptives.

France
On December 28, 1967, the Neuwirth Law legalized contraception in France, including the pill. The pill is the most popular form of contraception in France, especially among young women. It accounts for 60% of the birth control used in France. The abortion rate has remained stable since the introduction of the pill.

Japan
In Japan, lobbying from the Japan Medical Association prevented the pill from being approved for general use for nearly 40 years. The higher dose "second generation" pill was approved for use in cases of gynecological problems, but not for birth control. Two main objections raised by the association were safety concerns over long-term use of the pill, and concerns that pill use would lead to decreased use of condoms and thereby potentially increase sexually transmitted infection (STI) rates.However, when the Ministry of Health and Welfare approved Viagras use in Japan after only six months of the applications submission, while still claiming that the pill required more data before approval, womens groups cried foul. The pill was subsequently approved for use in June 1999, when Japan became the last UN member country to do so. However, the pill has not become popular in Japan. According to estimates, only 1.3 percent of 28 million Japanese females of childbearing age use the pill, compared with 15.6 percent in the United States. The pill prescription guidelines the government has endorsed require pill users to visit a doctor every three months for pelvic examinations and undergo tests for sexually transmitted diseases and uterine cancer. In the United States and Europe, in contrast, an annual or bi-annual clinic visit is standard for pill users. However, beginning as far back as 2007, many Japanese OBGYNs have required only a yearly visit for pill users, with multiple checks a year recommended only for those who are older or at increased risk of side effects. As of 2004, condoms accounted for 80% of birth control use in Japan, and this may explain Japans comparatively low rates of AIDS.

Society and culture
The pill was approved by the FDA in the early 1960s; its use spread rapidly in the late part of that decade, generating an enormous social impact. Time magazine placed the pill on its cover in April, 1967. In the first place, it was more effective than most previous reversible methods of birth control, giving women unprecedented control over their fertility. Its use was separate from intercourse, requiring no special preparations at the time of sexual activity that might interfere with spontaneity or sensation, and the choice to take the pill was a private one. This combination of factors served to make the pill immensely popular within a few years of its introduction.Claudia Goldin, among others, argue that this new contraceptive technology was a key player in forming womens modern economic role, in that it prolonged the age at which women first married allowing them to invest in education and other forms of human capital as well as generally become more career-oriented. Soon after the birth control pill was legalized, there was a sharp increase in college attendance and graduation rates for women. From an economic point of view, the birth control pill reduced the cost of staying in school. The ability to control fertility without sacrificing sexual relationships allowed women to make long term educational and career plans.Because the pill was so effective, and soon so widespread, it also heightened the debate about the moral and health consequences of pre-marital sex and promiscuity. Never before had sexual activity been so divorced from reproduction. For a couple using the pill, intercourse became purely an expression of love, or a means of physical pleasure, or both; but it was no longer a means of reproduction. While this was true of previous contraceptives, their relatively high failure rates and their less widespread use failed to emphasize this distinction as clearly as did the pill. The spread of oral contraceptive use thus led many religious figures and institutions to debate the proper role of sexuality and its relationship to procreation. The Roman Catholic Church in particular, after studying the phenomenon of oral contraceptives, re-emphasized the stated teaching on birth control in the 1968 papal encyclical Humanae vitae. The encyclical reiterated the established Catholic teaching that artificial contraception distorts the nature and purpose of sex. On the other side Anglican and other Protestant churches, such as the Evangelical Church in Germany (EKD), accepted the combined oral contraceptive pill.The United States Senate began hearings on the pill in 1970 and where different viewpoints were heard from medical professionals. Dr. Michael Newton, President of the College of Obstetricians and Gynecologists said:

The evidence is not yet clear that these still do in fact cause cancer or related to it. The FDA Advisory Committee made comments about this, that if there wasnt enough evidence to indicate whether or not these pills were related to the development of cancer, and I think thats still thin; you have to be cautious about them, but I dont think there is clear evidence, either one way or the other, that they do or dont cause cancer.

Another physician, Dr. Roy Hertz of the Population Council, said that anyone who takes this should know of "our knowledge and ignorance in these matters" and that all women should be made aware of this so they can decide to take the pill or not.The Secretary of Health, Education, and Welfare at the time, Robert Finch, announced the federal government had accepted a compromise warning statement which would accompany all sales of birth control pills.

Result on popular culture
The introduction of the birth control pill in 1960 allowed more women to find employment opportunities and further their education. As a result of women getting more jobs and an education, their husbands had to start taking over household tasks like cooking. Wanting to stop the change that was occurring in terms of gender norms in an American household, many films, television shows, and other popular culture items portrayed what an ideal American family should be. Below are listed some examples:

Poem
The Pill Versus the Springhill Mine Disaster was the title poem of a 1968 collection by Richard Brautigan.

Music
Singer Loretta Lynn commented on how women no longer had to choose between a relationship and a career in her 1974 album with a song entitled "The Pill", which told the story of a married womans use of the drug to liberate herself from her traditional role as wife and mother.

Environmental impact
A woman using COCPs excretes from her urine and feces natural estrogens, estrone (E1) and estradiol (E2), and synthetic estrogen ethinylestradiol (EE2).
These hormones can pass through water treatment plants and into rivers </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Iobenguane and explain in detail? [/INST] Iobenguane, or MIBG, is an aralkylguanidine analog of the adrenergic neurotransmitter norepinephrine (noradrenaline), typically used as a radiopharmaceutical. It acts as a blocking agent for adrenergic neurons. When radiolabeled, it can be used in nuclear medicinal diagnostic and therapy techniques as well as in neuroendocrine chemotherapy treatments.
It localizes to adrenergic tissue and thus can be used to identify the location of tumors such as pheochromocytomas and neuroblastomas. With iodine-131 it can also be used to treat tumor cells that take up and metabolize norepinephrine.

Usage and mechanism
MIBG is absorbed by and accumulated in granules of adrenal medullary chromaffin cells, as well as in pre-synaptic adrenergic neuron granules. The process in which this occurs is closely related to the mechanism employed by norepinephrine and its transporter in vivo. The norepinephrine transporter (NET) functions to provide norepinephrine uptake at the synaptic terminals and adrenal chromaffin cells. MIBG, by bonding to NET, finds its roles in imaging and therapy.

Metabolites and excretion
Less than 10% of the administered MIBG gets metabolized into m-iodohippuric acid (MIHA), and the mechanism for how this metabolite is produced is unknown.

Diagnostic imaging
MIBG concentrates in endocrine tumors, most commonly neuroblastoma, paraganglioma, and pheochromocytoma. It also accumulates in norepinephrine transporters in adrenergic nerves in the heart, lungs, adrenal medulla, salivary glands, liver, and spleen, as well as in tumors that originate in the neural crest. When labelled with iodine-123 it serves as a whole-body, non-invasive scintigraphic screening for germ-line, somatic, benign, and malignant neoplasms originating in the adrenal glands. It can detect both intra and extra-adrenal disease. The imaging is highly sensitive and specific.Iobenguane concentrates in presynaptic terminals of the heart and other autonomically innervated organs. This enables the possible non-invasive use as an in vivo probe to study these systems.Alternatives to imaging with 123I-MIBG, for certain indications and under clinical and research use, include the positron-emitting isotope iodine-124, and other radiopharmaceuticals such as 68Ga-DOTA and 18F-FDOPA for positron emission tomography (PET). 123I-MIBG imaging on a gamma camera can offer significantly higher cost-effectiveness and availability compared to PET imaging, and is particularly effective where 131I-MIBG therapy is subsequently planned, due to their directly comparable uptake.

Side effects
Side effects post imaging are rare but can include tachycardia, pallor, vomiting, and abdominal pain.

Radionuclide therapy
MIBG can be radiolabelled with the beta emitting radionuclide 131I for the treatment of certain pheochromocytomas, paragangliomas, carcinoid tumors, neuroblastomas, and medullary thyroid cancer.

Thyroid precautions
Thyroid blockade with (nonradioactive) potassium iodide is indicated for nuclear medicine scintigraphy with iobenguane/mIBG. This competitively inhibits radioiodine uptake, preventing excessive radioiodine levels in the thyroid and minimizing risk of thyroid ablation (in treatment with 131I). The minimal risk of thyroid cancer is also reduced as a result.The dosing regime for the FDA-approved commercial 123I-MIBG product Adreview is potassium iodide or Lugols solution containing 100mg iodide, weight adjusted for children and given an hour before injection. EANM guidelines, endorsed by the SNMMI, suggest a variety of regimes in clinical use, for both children and adults.Product labeling for diagnostic 131I iobenguane recommends giving potassium iodide one day before injection and continuing 5 to 7 days following.  131I iobenguane used for therapeutic purposes requires a different pre-medication duration, beginning 24–48 hours before iobenguane injection and continuing 10–15 days after injection.

Clinical trials
Iobenguane I 131 for cancers
Iobenguane I 131, marketed under the trade name Azedra, has had a clinical trial as a treatment for malignant, recurrent or unresectable pheochromocytoma and paraganglioma, and the FDA approved it on July 30, 2018. The drug is developed by Progenics Pharmaceuticals.

References
External links
"Iobenguane". Drug Information Portal. U.S </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Glycation and explain in detail? [/INST] Glycation (sometimes called non-enzymatic glycosylation) is the covalent attachment of a sugar to a protein or lipid. Typical sugars that participate in glycation are glucose, fructose, and their derivatives. Glycation is the non-enzymatic process responsible for many (e.g. micro and macrovascular) complications in diabetes mellitus and is implicated in some diseases and in aging. Glycation end products are believed to play a causative role in the vascular complications of diabetes mellitus.In contrast with glycation, glycosylation is the enzyme-mediated ATP-dependent attachment of sugars to protein or lipid. Glycosylation occurs at defined sites on the target molecule. It is a common form of post-translational modification of proteins and is required for the functioning of the mature protein.

Biochemistry
Glycations occur mainly in the bloodstream to a small proportion of the absorbed simple sugars: glucose, fructose, and galactose. It appears that fructose has approximately ten times the glycation activity of glucose, the primary body fuel.  Glycation can occur through Amadori reactions, Schiff base reactions, and Maillard reactions; which lead to advanced glycation end products (AGEs).

Biomedical implications
Red blood cells have a consistent lifespan of 120 days and are accessible for measurement of glycated hemoglobin. Measurement of HbA1c—the predominant form of glycated hemoglobin—enables medium-term blood sugar control to be monitored in diabetes.
Some glycation product are implicated in many age-related chronic diseases, including cardiovascular diseases (the endothelium, fibrinogen, and collagen are damaged) and Alzheimers disease (amyloid proteins are side-products of the reactions progressing to AGEs).Long-lived cells (such as nerves and different types of brain cell), long-lasting proteins (such as crystallins of the lens and cornea), and DNA can sustain substantial glycation over time.  Damage by glycation results in stiffening of the collagen in the blood vessel walls, leading to high blood pressure, especially in diabetes. Glycations also cause weakening of the collagen in the blood vessel walls, which may lead to micro- or macro-aneurysm; this may cause strokes if in the brain.

See also
Advanced glycation end-product
Alagebrium
Fructose
Galactose
Glucose
Glycosylation
Glycated hemoglobin
List of aging processes

Additional reading
Ahmed N, Furth AJ (July 1992). "Failure of common glycation assays to detect glycation by fructose". Clin. Chem </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Cycloserine and explain in detail? [/INST] Cycloserine, sold under the brand name Seromycin, is a GABA transaminase inhibitor and an antibiotic, used to treat tuberculosis. Specifically it is used, along with other antituberculosis medications, for active drug resistant tuberculosis. It is given by mouth.Common side effects include allergic reactions, seizures, sleepiness, unsteadiness, and numbness. It is not recommended in people who have kidney failure, epilepsy, depression, or are alcoholics. It is unclear if use during pregnancy is safe for the baby. Cycloserine is similar in structure to the amino acid D-alanine and works by interfering with the formation of the bacterias cell wall.Cycloserine was discovered in 1954 from a type of Streptomyces. It is on the World Health Organizations List of Essential Medicines.

Medical uses
Tuberculosis
For the treatment of tuberculosis, cycloserine is classified as a second-line drug, i.e. its use is only considered if one or more first-line drugs cannot be used. Hence, cycloserine is restricted for use only against multiple drug-resistant and extensively drug-resistant strains of M. tuberculosis. Another reason for limited use of this drug is the neurological side effects it causes, since it is able to penetrate into the central nervous system (CNS) and cause headaches, drowsiness, depression, dizziness, vertigo, confusion, paresthesias, dysarthria, hyperirritability, psychosis, convulsions, and shaking (tremors). Overdose of cycloserine may result in paresis, seizures, and coma, while alcohol consumption may increase the risk of seizures. Coadministration of pyridoxine can reduce the incidence of some of these CNS side effects (e.g. convulsions) caused by cycloserine.

Psychiatry
A 2015 Cochrane review found no evidence of benefit in anxiety disorders as of 2015. Another review found preliminary evidence of benefit. Evidence for use in addiction is tentative but also unclear.

Mechanism of action
Cycloserine works as an antibiotic by inhibiting cell-wall biosynthesis in bacteria.  As a cyclic analogue of D-alanine, cycloserine acts against two crucial enzymes important in the cytosolic stages of peptidoglycan synthesis: alanine racemase (Alr) and D-alanine:D-alanine ligase (Ddl). The first enzyme is a pyridoxal 5-phosphate-dependent enzyme which converts the L-alanine to the D-alanine form.  The second enzyme is involved in joining two of these D-alanine residues together by catalyzing the formation of the ATP-dependent D-alanine-D-alanine dipeptide bond between the resulting D-alanine molecules. If both of these enzymes are inhibited, then D-alanine residues cannot form and previously formed D-alanine molecules cannot be joined together. This effectively leads to inhibition of peptidoglycan synthesis.

Chemical properties
Under mildly acidic conditions, cycloserine hydrolyzes to give hydroxylamine and D-serine.  Cycloserine can be conceptualized as a cyclized version of serine, with an oxidative loss of dihydrogen to form the nitrogen-oxygen bond.Cycloserine is stable under basic conditions, with the greatest stability at pH = 11.5.

History
The compound was first isolated nearly simultaneously by two teams. Workers at Merck isolated the compound, which they called oxamycin, from a species of Streptomyces. The same team prepared the molecule synthetically. Workers at Eli Lilly isolated the compound from strains of Streptomyces orchidaceus </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is FLAC and explain in detail? [/INST] FLAC (; Free Lossless Audio Codec) is an audio coding format for lossless compression of digital audio, developed by the Xiph.Org Foundation, and is also the name of the free software project producing the FLAC tools, the reference software package that includes a codec implementation. Digital audio compressed by FLACs algorithm can typically be reduced to between 50 and 70 percent of its original size and decompresses to an identical copy of the original audio data.
FLAC is an open format with royalty-free licensing and a reference implementation which is free software. FLAC has support for metadata tagging, album cover art, and fast seeking.

History
Development was started in 2000 by Josh Coalson. The bit-stream format was frozen when FLAC entered beta stage with the release of version 0.5 of the reference implementation on 15 January 2001. Version 1.0 was released on 20 July 2001.On 29 January 2003, the Xiph.Org Foundation and the FLAC project announced the incorporation of FLAC under the Xiph.org banner. Xiph.org is home to other free compression formats such as Vorbis, Theora, Speex and Opus.Version 1.3.0 was released on 26 May 2013, at which point development was moved to the Xiph.org git repository.

Composition
The FLAC project consists of:

The stream formats
A simple container format for the stream, also called FLAC (or Native FLAC)
libFLAC, a library of reference encoders and decoders, and a metadata interface
libFLAC++, an object-oriented wrapper around libFLAC
flac, a command-line program based on libFLAC to encode and decode FLAC streams
metaflac, a command-line metadata editor for .flac files and for applying ReplayGain
Input plugins for various music players (Winamp, XMMS, foobar2000, musikCube, and many more)
With Xiph.org incorporation, the Ogg container format, suitable for streaming (also called Ogg FLAC)The specification of the stream format can be implemented by anyone without prior permission (Xiph.org reserves the right to set the FLAC specification and certify compliance), and neither the FLAC format nor any of the implemented encoding or decoding methods are covered by any patent. The reference implementation is free software. The source code for libFLAC and libFLAC++ is available under the BSD license, and the sources for flac, metaflac, and the plugins are available under the GNU General Public License.
In its stated goals, the FLAC project encourages its developers not to implement copy prevention features (DRM) or lossy compression of any kind.

Design
File structure
A FLAC file consists of the magic number fLaC, metadata, and encoded audio.The encoded audio is divided into frames, which consists of a header, a data block, and a CRC16 checksum. Each frame is encoded independent of each other. A frame header begins with a sync word, used to identify the beginning of a valid frame. The rest of the header contains the number of samples, position of the frame, channel assignment, and optionally the sample rate and bit depth. The data block contains the audio information.Metadata in FLAC precedes the audio. Properties like the sample rate and the number of channels are always contained in the metadata. It may also contain other information, the album cover for example. FLAC uses Vorbis comments for some types of metadata, like the title and artist name.

Encoding and decoding
The FLAC encoding algorithm consists of multiple stages. In the first stage, the input audio is split into blocks. If the audio contains multiple channels, each channel is encoded separately as a subblock. The encoder then tries to find a good mathematical approximation of the block, either by fitting a simple polynomial, or through general linear predictive coding. A description of the approximation, which is only a few bytes in length, is then written. Finally, the difference between the approximation and the input, called residual, is encoded using Rice coding. In many cases, a description of the approximation and the encoded residual takes up less space than using pulse code modulation.The decoding process is the reverse of encoding. The compressed residual is first decoded. The description of the mathematical approximation is then used to calculate a waveform. The result is formed by adding the residual and the calculated waveform. As FLAC compresses losslessly, the decoded waveform is identical to the waveform before encoding.
For two-channel stereo, the encoder may choose to joint encode the audio. The channels are transformed into a side channel, which is the difference between the two input channels, and a mid channel, the sum of the two input channels. In place of a mid channel, the left channel or the right channel may be encoded instead, which is sometimes more space efficient.Even though the reference encoder uses a single block size for the whole stream, FLAC allows the block size in samples to vary per block.

Compression
The amount of compression is determined by various parameters, including the order of the linear prediction model and the block size. Regardless of the amount of compression, the original data can always be reconstructed perfectly.
For users convenience, the reference implementation defines 9 compression levels, which are presets of the more technical parameters to the encoding algorithm. The levels are labeled from 0 to 8, with higher numbers resulting in a higher compression ratio, at the cost of compression speed. The meaning of each compression level varies by implementation.FLAC is optimized for decoding speed at the expense of encoding speed. A benchmark has shown that, while there is little variation in decoding speed as compression level increases, beyond the default compression level 5, the encoding process takes up considerably more time with little space saved compared to level 5.

Comparison to other formats
FLAC is specifically designed for efficient packing of audio data, unlike general-purpose lossless algorithms such as DEFLATE, which are used in ZIP and gzip. While ZIP may reduce the size of a CD-quality audio file by 10–20%, FLAC is able to reduce the size of audio data by 40–50% by taking advantage of the characteristics of audio.
The technical strengths of FLAC compared to other lossless formats lie in its ability to be streamed and decoded quickly, independent of compression level.
Since FLAC is a lossless scheme, it is suitable as an archive format for owners of CDs and other media who wish to preserve their audio collections. If the original media are lost, damaged, or worn out, a FLAC copy of the audio tracks ensures that an exact duplicate of the original data can be recovered at any time. An exact restoration from a lossy copy (e.g., MP3) of the same data is impossible. FLAC being lossless means it is highly suitable for transcoding e.g. to MP3, without the normally associated transcoding quality loss between one lossy format and another. A CUE file can optionally be created when ripping a CD. If a CD is read and ripped perfectly to FLAC files, the CUE file allows later burning of an audio CD that is identical in audio data to the original CD, including track order and pregap, but excluding CD-Text and other additional data such as lyrics and CD+G graphics.

Adoption and implementations
The reference implementation of FLAC is implemented as the libFLAC core encoder & decoder library, with the main distributable program flac being the reference implementation of the libFLAC API. This codec API is also available in C++ as libFLAC++ </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Levonorgestrel and explain in detail? [/INST] Levonorgestrel is a hormonal medication which is used in a number of birth control methods. It is combined with an estrogen to make combination birth control pills. As an emergency birth control, sold under the brand name Plan B among others, it is useful within 72 hours of unprotected sex. The more time that has passed since sex, the less effective the medication becomes, and it does not work after pregnancy (implantation) has occurred. Levonorgestrel works by preventing ovulation or fertilization from occurring. It decreases the chances of pregnancy by 57 to 93%. In an intrauterine device (IUD), such as Mirena among others, it is effective for the long-term prevention of pregnancy. A levonorgestrel-releasing implant is also available in some countries.Common side effects include nausea, breast tenderness, headaches, and increased, decreased, or irregular menstrual bleeding. When used as an emergency contraceptive, if pregnancy occurs, there is no evidence that its use harms the fetus. It is safe to use during breastfeeding. Birth control that contains levonorgestrel will not change the risk of sexually transmitted infections. It is a progestin and has effects similar to those of the hormone progesterone. It works primarily by preventing ovulation and closing off the cervix to prevent the passage of sperm.Levonorgestrel was patented in 1960 and introduced for medical use together with ethinylestradiol in 1970. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. In the United States, levonorgestrel-containing emergency contraceptives are available over the counter (OTC) for all ages. In 2016, it was the 223rd most commonly prescribed medication in the United States, with more than two million prescriptions.

Medical uses
Birth control
At low doses, levonorgestrel is used in monophasic and triphasic formulations of combined oral contraceptive pills, with available monophasic doses ranging from 100 to 250 µg, and triphasic doses of 50 µg/75 µg/125 µg. It is combined with the estrogen ethinylestradiol in these formulations.At very low daily dose of 30 µg, levonorgestrel is used in some progestogen-only pill formulations.Levonorgestrel is the active ingredient in a number of intrauterine devices including Mirena and Skyla. It is also the active ingredient in the birth control implants Norplant and Jadelle.One of the more common forms of contraception that contains only levonorgestrel is an IUD. One IUD, the Mirena, is a small hollow cylinder containing levonorgestrel and polydimethylsiloxane and covered with a release rate controlling membrane.

Emergency birth control
Levonorgestrel is used in emergency contraceptive pills (ECPs), both in a combined Yuzpe regimen which includes estrogen, and as a levonorgestrel-only method. The levonorgestrel-only method uses levonorgestrel 1.5 mg (as a single dose or as two 0.75 mg doses 12 hours apart) taken within three days of unprotected sex. With one study indicating that beginning as late as 120 hours (5 days) after intercourse could be effective. However, taking more than one dose of emergency contraception does not increase the chance of pregnancy not happening. Planned Parenthood asserts "Taking the morning-after pill (also known as emergency contraception) multiple times doesnt change its effectiveness, and wont cause any long-term side effects." There is no age, I.D, or prescription required to purchase emergency contraception. Plan B hit the market in 1999 where it could be bought by anyone older than 18. However, in 2013, the rules were changed so that Plan B could be purchased at any age without ID or prescription.
The primary mechanism of action of levonorgestrel as a progestogen-only emergency contraceptive pill is, according to International Federation of Gynecology and Obstetrics (FIGO), to prevent fertilization by inhibition of ovulation and thickening of cervical mucus. FIGO has stated that: "review of the evidence suggests that LNG [levonorgestreol] ECPs cannot prevent implantation of a fertilized egg. Language on implantation should not be included in LNG ECP product labeling." In November 2013, the European Medicines Agency (EMA) approved a change to the label saying it cannot prevent implantation of a fertilized egg.Other studies still find the evidence to be unclear. While it is unlikely that emergency contraception affects implantation it is impossible to completely exclude the possibility of post-fertilization effect.In November 2013, the EMA also approved a change to the label for HRA Pharmas NorLevo saying: "In clinical trials, contraceptive efficacy was reduced in women weighing 75 kg [165 pounds] or more, and levonorgestrel was not effective in women who weighed more than 80 kg [176 pounds]." In November 2013 and January 2014, the FDA and the EMA said they were reviewing whether increased weight and body mass index (BMI) reduce the efficacy of emergency contraceptives.An analysis of four WHO randomised clinical trials, published in January 2017, showed pregnancy rates of 1.25% (68/5428) in women with BMI under 25, 0.61% (7/1140) in women with BMI between 25 and 30, and 2.03% (6/295) in women with BMI over 30. These values yield an eight-fold reduction in efficacy for women with BMI over 30 compared to women with BMI under 25. However, emergency contraceptives remain effective regardless of BMI.

Hormone therapy
Levonorgestrel is used in combination with an estrogen in menopausal hormone therapy. It is used under the brand name Klimonorm as a combined oral tablet with estradiol valerate and under the brand name Climara Pro as a combined transdermal patch with estradiol.

Available forms
As a type of emergency contraception, levonorgestrel is used after unprotected intercourse to reduce the risk of pregnancy. However, it can serve different hormonal purposes in its different methods of delivery. It is available for use in a variety of forms:

By mouth
Levonorgestrel can be taken by mouth as a form of emergency birth control. The typical dosage is either 1.5 mg taken once or 0.75 mg taken 12–24 hours apart. The effectiveness in both methods is similar. The most widely used form of oral emergency contraception is the progestin-only pill, which contains a 1.5 mg dosage of levonorgestrel. Levonorgestrel-only emergency contraceptive pills are reported to have an 89% effectiveness rate if taken within the recommended 72 hours after sex. The efficacy of the drug decreases by 50% for each 12 hour delay in taking the dose after the emergency contraceptive regimen has been started.

Skin patch
Estradiol with levonorgestrel in the form of a skin patch is used under the brand name Climara Pro for hormone replacement therapy in postmenstrual women, treating symptoms such as hot flashes or osteoporosis. The simultaneous delivery of a progestogen such as levonorgestrel is necessary for the protection of the endometrium.

Intrauterine device
The levonorgestrel intrauterine system (LNG-IUS) is a type of long-term birth control that releases the progestin into the uterine cavity. Levonorgestrel is released at a constant, gradual rate of 0.02 mg per day by the polydimethylsiloxane membrane of the device, which renders it effective for up to five years. Because it is inserted directly into the uterus, levonorgestrel is present in the endometrium in much higher concentrations that would result from a LNG-containing oral pill; the LNG-IUS delivers 391 ng of levonorgestrel to the inner uterine region while a comparable oral contraceptive delivers only 1.35 ng. This high level of levonorgestrel impedes the function of the endometrium, making it hostile for sperm transport, fertilization, and implantation of an ovum.

Implant
Subcutaneous implants of levonorgestrel have been marketed as birth control implants under the brand names Norplant and Jadelle and are available for use in some countries.

Contraindications
Known or suspected pregnancy is a contraindication of levonorgestrel as an emergency contraceptive.

Side effects
After an intake of 1.5 mg levonorgestrel in clinical trials, very common side effects (reported by 10% or more) included: hives, dizziness, hair loss, headache, nausea, abdominal pain, uterine pain, delayed menstruation, heavy menstruation, uterine bleeding, and fatigue; common side effects (reported by 1% to 10%) included diarrhea, vomiting, and painful menstruation; these side effects usually disappeared within 48 hours. However, the long term side effects common with oral contraceptives such as arterial disease are lower with levonorgestrel than in combination pills.Levonorgestrel as a contraceptive intrauterine device is associated with a higher risk of breast cancer than with non-use.

Overdose
Overdose of levonorgestrel as an emergency contraceptive has not been described. Nausea and vomiting might be expected.

Interactions
If taken together with drugs that induce the CYP3A4 cytochrome P450 liver enzyme, levonorgestrel may be metabolized faster and may have lower effectiveness.
These include, but are not limited to barbiturates, bosentan, carbamazepine, felbamate, griseofulvin, oxcarbazepine, phenytoin, rifampin, St. Johns wort and topiramate.

Pharmacology
Pharmacodynamics
Levonorgestrel is a progestogen with weak androgenic activity. It has no other important hormonal activity, including no estrogenic, glucocorticoid, or antimineralocorticoid activity. The lack of significant mineralocorticoid or antimineralocorticoid activity with levonorgestrel is in spite of it having relatively high affinity for the mineralocorticoid receptor, which is as much as 75% of that of aldosterone.

Progestogenic activity
Levonorgestrel is a progestogen; that is, an agonist of the progesterone receptor (PR), the main biological target of the progestogen sex hormone progesterone. It has effects similar to those of the hormone progesterone. As a contraceptive, it works primarily by preventing ovulation and closing off the cervix to prevent the passage of sperm. The endometrial transformation dose of levonorgestrel is 150 to 250 μg/day or 2.5 to 6 mg per cycle.Due to its progestogenic activity, levonorgestrel has antigonadotropic effects and is able to suppress the secretion of the gonadotropins, luteinizing hormone and follicle-stimulating hormone, from the pituitary gland. This in turn, results in suppression of gonadal activity, including reduction of fertility and gonadal sex hormone production in both women and men. The ovulation-inhibiting dose of levonorgestrel in premenopausal women is 50 to 60 μg/day.In men, levonorgestrel causes marked suppression of circulating testosterone levels secondary to its antigonadotropic effects. In healthy young men, levonorgestrel alone at a dose of 120 to 240 μg/day orally for 2 weeks suppressed testosterone levels from ~450 ng/dL to ~248 ng/dL (–45%). Because of its effects on testosterone levels, and due to its androgenic activity being only weak and hence insufficient for purposes of androgen replacement in males, levonorgestrel has potent functional antiandrogenic effects in men. Consequently, it is able to produce adverse effects like decreased libido and erectile dysfunction, among others. In relation to this, levonorgestrel has been combined with an androgen like testosterone or dihydrotestosterone when it has been studied as a hormonal contraceptive in men.

Androgenic activity
Levonorgestrel is a weak agonist of the androgen receptor (AR), the main biological target of the androgen sex hormone testosterone. It is a weakly androgenic progestin and in women may cause androgenic biochemical changes and side effects such as decreased sex hormone-binding globulin (SHBG) levels, decreased HDL cholesterol levels, weight gain, and acne.In combination with a potent estrogen like ethinylestradiol however, all contraceptives containing androgenic progestins are negligibly androgenic in practice and in fact can be used to treat androgen-dependent conditions like acne and hirsutism in women. This is because ethinylestradiol causes a marked increase in SHBG levels and thereby decreases levels of free and hence bioactive testosterone, acting as a functional antiandrogen. Nonetheless, contraceptives containing progestins that are less androgenic increase SHBG levels to a greater extent and may be more effective for such indications. Levonorgestrel is currently the most androgenic progestin that is used in contraceptives, and contraceptives containing levonorgestrel may be less effective for androgen-dependent conditions relative to those containing other progestins that are less androgenic.

Other activity
Levonorgestrel stimulates the proliferation of MCF-7 breast cancer cells in vitro, an action that is independent of the classical PRs and is instead mediated via the progesterone receptor membrane component-1 (PGRMC1). Certain other progestins act similarly in this assay, whereas progesterone acts neutrally. It is unclear if these findings may explain the different risks of breast cancer observed with progesterone and progestins in clinical studies.

Pharmacokinetics
The bioavailability of levonorgestrel is approximately 95% (range 85 to 100%). The plasma protein binding of levonorgestrel is about 98%. It is bound 50% to albumin and 48% to SHBG. Levonorgestrel is metabolized in the liver, via reduction, hydroxylation, and conjugation (specifically glucuronidation and sulfation). Oxidation occurs primarily at the C2α and C16β positions, while reduction occurs in the A ring. 5α-Dihydrolevonorgestrel is produced as an active metabolite of levonorgestrel by 5α-reductase. The elimination half-life of levonorgestrel is 24 to 32 hours, although values as short as 8 hours and as great as 45 hours have been reported. About 20 to 67% of a single oral dose of levonorgestrel is eliminated in urine and 21 to 34% in feces.

Chemistry
Levonorgestrel, also known as 17α-ethynyl-18-methyl-19-nortestosterone or as 17α-ethynyl-18-methylestr-4-en-17β-ol-3-one, is a synthetic estrane steroid and a derivative of testosterone. It is the C13β or levorotatory stereoisomer and enantiopure form of norgestrel, the C13α or dextrorotatory isomer being inactive. Levonorgestrel is more specifically a derivative of norethisterone (17α-ethynyl-19-nortestosterone) and is the parent compound of the gonane (18-methylestrane or 13β-ethylgonane) subgroup of the 19-nortestosterone family of progestins. Besides levonorgestrel itself, this group includes desogestrel, dienogest, etonogestrel, gestodene, norelgestromin, norgestimate, and norgestrel. Levonorgestrel acetate and levonorgestrel butanoate are C17β esters of levonorgestrel. Levonorgestrel has a molecular weight of 312.45 g/mol and a partition coefficient (log P) of 3.8.

History
Norgestrel (rac-13-ethyl-17α-ethynyl-19-nortestosterone), the racemic mixture containing levonorgestrel and dextronorgestrel, was discovered by Hughes and colleagues at Wyeth in 1963 via structural modification of norethisterone (17α-ethynyl-19-nortestosterone). It was the first progestogen to be manufactured via total chemical synthesis. Norgestrel was introduced for medical use as a combined birth control pill with ethinylestradiol under the brand name Eugynon in Germany in 1966 and under the brand name Ovral in the United States 1968, and as a progestogen-only pill under the brand name Ovrette in the United States in 1973. Following its discovery, norgestrel had been licensed by Wyeth to Schering AG, which separated the racemic mixture into its two optical isomers and identified levonorgestrel (13β-ethyl-17α-ethynyl-19-nortestosterone) as the active component of the mixture. Levonorgestrel was first studied in humans by 1970, and was introduced for medical use in Germany as a combined birth control pill with ethinylestradiol under the brand name Neogynon in August 1970. A more widely used formulation, containing lower doses of ethinylestradiol and levonorgestrel, was introduced under the brand name Microgynon by 1973. In addition to combined formulations, levonorgestrel was introduced as a progestogen-only pill under the brand names Microlut by 1972 and Microval by 1974. Many other formulations and brand names of levonorgestrel-containing birth control pills have also been marketed.Levonorgestrel, taken alone in a single high dose, was first evaluated as a form of emergency contraception in 1973. It was the second progestin to be evaluated for such purposes, following a study of quingestanol acetate in 1970. In 1974, the Yuzpe regimen, which consisted of high doses of a combined birth control pill containing ethinylestradiol and norgestrel, was described as a method of emergency contraception by A. Albert Yuzpe and colleagues, and saw widespread interest. Levonorgestrel-only emergency contraception was introduced under the brand name Postinor by 1978. Ho and Kwan published the first study comparing levonorgestrel only and the Yuzpe regimen as methods of emergency contraception in 1993 and found that they had similar effectiveness but that levonorgestrel alone was better-tolerated </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Potassium citrate and explain in detail? [/INST] Potassium citrate (also known as tripotassium citrate) is a potassium salt of citric acid with the molecular formula K3C6H5O7. It is a white, hygroscopic crystalline powder. It is odorless with a saline taste. It contains 38.28% potassium by mass </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Hydroxypropyl cellulose and explain in detail? [/INST] Hydroxypropyl cellulose (HPC) is a derivative of cellulose with both water solubility and organic solubility.  It is used as an excipient, and topical ophthalmic protectant and lubricant.

Chemistry
HPC is an ether of cellulose in which some of the hydroxyl groups in the repeating glucose units have been hydroxypropylated forming -OCH2CH(OH)CH3 groups using propylene oxide.  The average number of substituted hydroxyl groups per glucose unit is referred to as the degree of substitution (DS). Complete substitution would provide a DS of 3 </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Elosulfase alfa and explain in detail? [/INST]  </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Mecasermin and explain in detail? [/INST]  </s>