Drugs Used For Anovulation
This list also comprises most of the drugs used for ovulation induction and IVF treatments

The medication which is most commonly used to treat anovulation is clomifene citrate (or clomid), which has been used since the 1960s. It was first used to treat cases of oligomenorrhea, and it was then applied to the treatment of anovulation. It is relatively easy and convenient to use: factors which contributed to its success. Clomifene citrate has an anti-estrogenic role, and it appears to stimulate the pituitary and therefore affect the ovarian function.It also has an effect on cervical mucus quality and uterine mucosa, which might affect sperm penetration and survival, hence its early administration during the menstrual cycle. Clomifene citrate is a very efficient ovulation inductor, and has a success rate of 67%. Nevertheless, it only has a 37% success rate in inducing pregnancy. This difference may be due to the anti-estrogenic effect which clomifene citrate has on the endometrium, cervical mucus, uterine blood flow, as well as the resulting decrease in the motility of the fallopian tubes and the maturation of the oocytes.

Another anti-estrogenic molecule called tamoxifen is often used in the prevention and treatment of breast cancer. It can therefore also be used to treat patients that have a reaction to clomifene citrate. A third anti-estrogenic compound

Femara (Letrozole) is used also as a substitute for Clomid . Estrogens are produced by the conversion of androgens through the activity of the aromatase enzyme. Letrozole blocks production of estrogens in this way by competitive, reversible binding to the heme of its cytochrome P450 unit. The action is specific, and letrozole does not reduce production of mineralo- or corticosteroids. In contrast, the antiestrogenic action of tamoxifen, the major medical therapy prior to the arrival of aromatase inhibitors, is due to its interfering with the estrogen receptor, rather than inhibiting estrogen production.

Human chorionic gonadotropin (hCG) is a molecule which is structurally similar to luteinizing hormone (LH). LH is secreted by the pituitary just before ovulation occurs, whereas hCG is released during pregnancy. On its own, hCG is not very effective in inducing ovulation, but when combined with clomifene citrate, it is much more effective. HCG should only be administered at certain points in the cycle, around the time of ovulation. A Recombinant version of hCG is available commercially and it is called Ovidrel. Ovidrel works just like hcg but it si more convenient because it does not require mixing.

Human menopausal gonadotropin (hMG) is a very powerful treatment for infertility. It consists of a combination of LH and FSH. From menopause onwards, the body starts secreting LH and FSH in large quantities due to the slowing down of the ovarian function. This excess of hormones is not used by the body and is expelled in the urine. HMG is therefore collected from the urine of menopausal women. The urine then undergoes purification and a chemical treatment. The resulting hMG induces the stimulation of several ovarian follicles. This increases the risk of producing several oocytes during the same cycle, and thus the risk of multiple pregnancies. Commercial names of hMGs are Menopur, Repronex.

Follicle-stimulating hormone (FSH or recombinant FSH) is now used as a replacement for hMG. Although hMG is a combination of FSH and LH, FSH is the main active component that has an effect on ovulation.

Metformin is an oral biguanid used to treat type 2 diabetes that has shown very promising results in the treatment of patients with PCOS. However, some experts question the efficacy of metformin. Though the results from early treatment with metformin were promising, its role and the roles of other similar molecules in reducing insulin levels among patients suffering from PCOS is not very clear.

Several studies indicate that in some cases, a simple change in lifestyle could help patients suffering from anovulation. Consulting a nutritionist, for example, could help a young women suffering from anorexia to put on some weight, which might re-start her menstrual cycle. Conversely, a young overweight woman who manages to lose weight could also relieve the problem of anovulation (losing just 5% of body mass could be enough to re-start ovulation). However, it is widely acknowledged by doctors that it is usually very difficult for PCOS patients to lose weight.

What is the Luteal Phase?

The luteal phase (or secretory phase) is the latter phase of the menstrual cycle(in humans and a few other animals). It begins with the formation of the corpus luteum and ends in either pregnancy or luteolysis. The main hormone associated with this stage is progesterone which is significantly higher during the luteal phase than other phases of the cycle. Some sources define the end of the luteal phase to be a distinct "ischemic phase".

Hormonal events

After ovulation, the pituitary hormones FSH and LH cause the remaining parts of the dominant follicle to transform into the corpus luteum. It continues to grow for some time after ovulation and produces significant amounts of hormones, particularly progesterone, and to a lesser extent, estrogen. Progesterone plays a vital role in making the endometrium receptive to implantation of the blastocyst nd supportive of the early pregnancy; it also has the side effect of raising the woman's basal body temperature.

Several days after ovulation, the increasing amount of estrogen produced by the corpus luteum may cause one or two days of fertile cervical mucus. lower basal body temperatures, or both. This is known as a "secondary estrogen surge".

The hormones produced by the corpus luteum also suppress production of the FSH and LH that the corpus luteum needs to maintain itself. With continued low levels of FSH and LH, the corpus luteum will atrophy.The death of the corpus luteum results in falling levels of progesterone and estrogen. These falling levels of ovarian hormones cause increased levels of FSH, which begins recruiting follicles for the next cycle. Continued drops in levels of estrogen and progesterone trigger the end of the luteal phase: menstruation and the beginning of the next cycle.

The average length of the human luteal phase is fourteen days. Between ten and sixteen days is considered normal, although luteal phases of less than twelve days may make it more difficult to achieve pregnancy. While luteal phase length varies significantly from woman to woman, for the same woman the length will be fairly consistent from cycle to cycle.

The loss of the corpus luteum can be prevented by implantation of an embryo: after implantation, human embryos produce human chorionic gonaotropin (hCG). hCG is structurally similar to LH and can preserve the corpus luteum .Because the hormone is unique to the embryo, most pregnancy tests look for for the presence of hCG. If implantation occurs, the corpus luteum will continue to produce progesterone (and maintain high basal body temperatures) for eight to twelve weeks, after which the placenta takes over this function.

Luteal phase defect

Luteal phase defect (LPD) occurs when the luteal phase is shorter than normal, progesterone levels during the luteal phase are below normal, or both. LPD is believed to interfere with the implantation of embryos.

Can Progestrone Supplementation Prevent Miscarriages?

Based on the Chocrane Database Review the answer is : probably not. But is does seem to prevent further losses in women with 3 or more miscarriages. This is why in the end we end it prescribing it quite liberally. The review states quite clearly that the type of progesterone (vaginal vs injectable) makes no difference in therms of outcome. So don't believe it if they tell you that the oil injection is any better. Abstract is below

Abstract

Background

Progesterone, a female sex hormone, is known to induce secretory changes in the lining of the uterus essential for successful implantation of a fertilised egg. It has been suggested that a causative factor in many cases of miscarriage may be inadequate secretion of progesterone. Therefore, progestogens have been used, beginning in the first trimester of pregnancy, in an attempt to prevent spontaneous miscarriage.

Objectives

To determine the efficacy and safety of progestogens as a preventative therapy against miscarriage.

Search strategy

We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (January 2008), CENTRAL (The Cochrane Library 2006, Issue 4), MEDLINE (1966 to June 2006), EMBASE (1980 to June 2006), CINAHL (1982 to June 2006), NHMRC Clinical Trials Register (June 2006) and Meta-Register (June 2006). We searched references from relevant articles, attempting to contact authors where necessary, and contacted experts in the field for unpublished works.

Selection criteria

Randomised or quasi-randomized controlled trials comparing progestogens with placebo or no treatment given in an effort to prevent miscarriage.

Data collection and analysis

Two review authors assessed trial quality and extracted data.

Main results

Fifteen trials (2118 women) are included. The meta-analysis of all women, regardless of gravidity and number of previous miscarriages, showed no statistically significant difference in the risk of miscarriage between progestogen and placebo or no treatment groups (Peto odds ratio (Peto OR) 0.98; 95% confidence interval (CI) 0.78 to 1.24) and no statistically significant difference in the incidence of adverse effect in either mother or baby.

In a subgroup analysis of three trials involving women who had recurrent miscarriages (three or more consecutive miscarriages), progestogen treatment showed a statistically significant decrease in miscarriage rate compared to placebo or no treatment (Peto OR 0.38; 95% CI 0.20 to 0.70). No statistically significant differences were found between the route of administration of progestogen (oral, intramuscular, vaginal) versus placebo or no treatment.

Authors' conclusions

There is no evidence to support the routine use of progestogen to prevent miscarriage in early to mid-pregnancy. However, there seems to be evidence of benefit in women with a history of recurrent miscarriage. Treatment for these women may be warranted given the reduced rates of miscarriage in the treatment group and the finding of no statistically significant difference between treatment and control groups in rates of adverse effects suffered by either mother or baby in the available evidence. Larger trials are currently underway to inform treatment for this group of women.

Source: Cochrane Database

Metformin treatment before and during IVF or ICSI in women with polycystic ovary syndrome.

It is stll not clear not clear whether addition of metformin to stimulation protocols is beneficial. This very good review from the Cochane Database . the conclusion odf the review was that no evidence exists that metformin treatment before or during ART cycles improves live birth or pregnancy rates.

Gynecology, Federal University of São Paulo (UNIFESP), Av. Dr. Altino Arantes, 865 - ap. 124, São Paulo, Vila Clementino, Brazil, 04042-034. leotso@uol.com.br

BACKGROUND: The use of insulin-sensitising agents, such as metformin, in women with polycystic ovary syndrome (PCOS) who are undergoing ovulation induction or in vitro fertilisation (IVF) cycles has been widely studied. Suppression of insulin levels with metformin might reduce the hyperinsulinaemia and hyperandrogenism suppression of the ovarian response. As a consequence, metformin could improve both pregnancy and live birth rates. OBJECTIVES: To determine the effectiveness of metformin as a co-treatment during IVF or intra-cytoplasmic sperm injection (ICSI) in achieving pregnancy or live birth in women with PCOS. SEARCH STRATEGY: The Menstrual Disorders and Subfertility Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE, EMBASE, LILACS, the meta Register of Controlled Trials, and reference lists of articles were searched (to week 4, September 2008). SELECTION CRITERIA: Types of studies: randomised controlled trials (RCTs) comparing metformin treatment with placebo or no treatment in women with PCOS who underwent IVF or ICSI treatment.Types of participants: women of reproductive age with anovulation due to PCOS with or without co-existing infertility factors.Types of interventions: metformin administered before and during IVF or ICSI treatment.Types of outcome measures: live birth rate, clinical pregnancy rate, miscarriage rate, incidence of ovarian hyperstimulation syndrome (OHSS), incidence of patient-reported side effects, serum estradiol level on the day of trigger, serum androgen level, and fasting insulin and glucose levels. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted the data according to the protocol. The methods of randomisation and allocation concealment, and characteristics of the studied groups were evaluated. MAIN RESULTS: This review found no evidence that metformin treatment before or during assisted reproductive technique (ART) cycles improved live birth or clinical pregnancy rates. The pooled odds ratio (OR) for live birth rate (3 RCTs) was 0.77 ( 95% CI 0.27 to 2.18) and for clinical pregnancy rate (5 RCTS) was 0.71 (95% CI 0.39 to 1.28). The risk of OHSS in women with PCOS and undergoing IVF or ICSI cycles was reduced with metformin (pooled OR 0.27, 95% CI 0.16 to 0.47). AUTHORS' CONCLUSIONS: This review found no evidence that metformin treatment before or during ART cycles improves live birth or pregnancy rates. The risk of OHSS in women with PCOS and undergoing IVF or ICSI cycles was reduced with metformin. Further large RCTs are necessary to definitively answer if the use of metformin in PCOS women undergoing ART improves live birth and pregnancy rates.

source Cochrane Database Syst Rev. 2009 Apr 15;(2):CD006105.

Embryo cryopreservation (a primer)

The first pregnancy derived from a frozen human embryo was reported by Alan Trounson & Linda Mohr in 1983 (although the fetus aborted spontaneously at about 20 weeks of gestation); the first term pregnancies derived from frozen human embryos were reported by Zeilmaker et al. and the first human baby hatched via a rate frozen freezing process was born in 1984. Since then and up to 2008 it is estimated that between 350,000 and half a million IVF babies have been born from embryos controlled rate frozen and then stored in liquid nitrogen; additionally a few hundred births have been born from vitrified oocytes but firm figures are hard to come by.

On the safety of embryo cryopreservation, a 2008 study reported at the ESRE discovered that children born from frozen embryos did “better and had a higher birth weight” than children born from a fresh transfer. The study was conducted out of Copenhagen and evaluated babies born during the years 1995–2006. 1267 children born after Frozen Embryo Transfer (FET), via controlled-rate freezers and storage in liquid nitrogen, were studied and categorised into three groups. 878 of them were born using frozen embryos that were created using standard in vitro fertilisation in which the sperm were placed into a dish close to the egg but had to penetrate the egg on their own. 310 children were born with frozen embryos created using ICSI in which a single sperm was injected into a single egg, and 79 were born where the method of creation of the embryos was not known.

17,857 babies born after a normal IVF/ICSI with fresh embryos were also studied and used as a control group or reference group. Data on all of the children’s outcomes were taken regarding birth defects, birth weights, and length of pregnancy. The results of the study showed that the children who came from frozen embryos had higher birth weights, gave longer pregnancies and produced fewer “pre-term” births. There was no difference in the rate of birth defects whether the children came from frozen embryos or fresh embryos. In the FER group, the birth defect rate was 7.7% compared to the fresh transfer group which was slightly higher at 8.8%. The scientists also found that the risk for multiple pregnancies was increased in the fresh embryo transfers.

Around 11.7% of the ICSI and 14.2% of the IVF frozen cases were multiple pregnancies. In the case of fresh embryos, 24.8% of the ICSI and 27.3% of the IVF were multiple pregnancies. It should also be noted that maternal age was significantly higher in the FER group. This is significant since based on age one would have expected a higher rate of problems and birth defects. The study adds to the body of knowledge suggesting that traditional embryo freezing is a safe procedure. It was unclear however why the frozen embryo children did better than their fresh embryo counterparts

If multiple embryos are generated, patients may choose to freeze embryos that are not transferred. Those embryos are slow frozen and then placed in liquid nitrogen and can be preserved for a long time. There are currently 500,000 frozen embryos in the United States.

The advantage is that patients who fail to conceive may become pregnant using such embryos without having to go through a full IVF cycle. Or, if pregnancy occurred, they could return later for another pregnancy. Spare embryos resulting from fertility treatments may be donated to another woman or couple, and embryos may be created, frozen and stored specifically for transfer and donation by using donor eggs and sperm.

source Wikipedia