Femara (Letrozole) or Clomid (clomiphene) for ovulation inducion: which one is better? Study shows they are equally effective.


Clomifene (INN) or clomiphene (USAN and former BAN) or Clomid or Clomifert is a selective estrogen receptor modulator (SERM) that increases production of gonadotropins by inhibiting negative feedback on the hypothalamus. It is used mainly for ovarian stimulation in female infertility due to anovulation

Letrozole (INN, trade name Femara) is an oral non-steroidal aromatase inhibitor.Estrogens are produced by the conversion of androgens through the activity of the aromatase enzyme. Estrogens then bind to an estrogen receptor, which causes cells to divide.

 Letrozole prevents the aromatase from producing estrogens by competitive, reversible binding to the heme of its cytochrome P450 unit. 

Letrozole has been used for ovarian stimulation by fertility doctors since 2001—having less side-effects than clomifene (Clomid) and less chance of multiple gestation. A Canadian study presented at the American Society of Reproductive Medicine 2005 Conference suggests that Letrozole may increase the risk of birth defect. A more detailed ovulation induction follow-up study found that letrozole, compared with a control group of clomiphene, had significantly lower congenital malformations and chromosomal abnormalities at an overall rate of 2.4% (1.2% major malformations) compared with clomiphene 4.8% (3.0% major malformations).

A recent meta analysis comparing the two treatments for ovulation induction, Clomid vs Femara  , published on RBM  online, suggests that the two treatments are equivalent outcome-wise. Side effects seem to be less for the Femara group.
In my experience the response seem to be very individualized : some patients respond better to Clomid , others to Femara.

Abstract Below

Abstract 

The aim of this study was to systematically compare the clinical efficacy and safety of letrozole with clomiphene citrate for ovulation induction in women with polycystic ovary syndrome (PCOS). The Cochrane Central Register of Controlled Trials, PubMed, EMbase, CBMdisc and CNKI were searched for eligible randomized controlled trials (RCT) comparing letrozole with clomiphene citrate in PCOS patients. Two reviewers independently extracted information and evaluated methodological quality according to the Cochrane Handbook 5.0. Meta-analysis was performed with the fixed-effects model or random-effects model according to the heterogeneity. Six eligible RCT involving 841 patients were included. Letrozole was associated with a number of lower mature follicles per cycle (standardized mean difference, SMD, –1.41; 95% CI –1.54 to –1.28; P < 0.00001) compared with clomiphene citrate. There were no significant differences in pregnancy rate (relative risk, RR, 0.97; 95% CI 0.79 to 1.18), abortion rate (RR 1.38; 95% CI 0.48 to –3.96) and multiple pregnancy rate (RR 0.34; 95% CI 0.07 to –1.72) between the two groups. The evidence from ovulation rates was not enough to support either letrozole or clomiphene citrate. In conclusion, letrozole is as effective as clomiphene citrate for ovulation induction in patients with PCOS

http://www.rbmojournal.com/article/S1472-6483%2811%2900180-5/abstract

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.

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.

Elevated DHEA and PCOS

Good article from Medscape below:

PCOS is characterized by menstrual irregularities and hyperandrogenism. Androgens (testosterone, androstenedione, DHEA, and DHEA sulfate [DHEAS]) are produced by the ovaries and the adrenal glands. In addition, androgens are derived from the peripheral conversion of estrogens. A fraction of the total androgens consists of androgen bound to proteins in the circulation; it is the free, unbound fraction that is responsible for the clinical effects. The adrenal gland produces about 25% of the circulating testosterone, 50% of androstenedione, and 90% of DHEAS. Most patients with PCOS will have increased testosterone levels, but 25% to 50% of them will also have elevated DHEAS.

The exact etiology of adrenal androgen excess is not known. Increased adrenocorticotropic hormone (ACTH) production, increased adrenal sensitivity to ACTH, altered steroidogenic enzyme activity (17-20 lyase, 3-beta-hydroxysteroid dehydrogenase activity), and an overproduction of androgens in response to hyperprolactinemia have all been implicated as potential mechanisms. Others have suggested a role for abnormal glucose metabolism (hyperinsulinemia; insulin resistance is a characteristic feature of PCOS) in the adrenal androgen excess.

A connection between ovarian estrogen production and adrenal androgen synthesis has also been evaluated. Estrogens could have a direct adrenal effect or their effect could be mediated via prolactin. Estrogens are known to increase pituitary prolactin secretion, which in turn will augment adrenal DHEAS output. The induction of hypoestrogenism with gonadotropin-releasing hormone agonist reduces DHEAS levels. Some of these metabolic characteristics may have a genetic background.

These potential pathways leave us with numerous possibilities for medical intervention. Before choosing the treatment, we need to decide what symptom we are planning to manage (eg, infertility, recurrent miscarriage, hirsutism, acne, or menstrual irregularity). If our goal is to restore ovulatory cycles, then selective estrogen receptor modulators (eg, clomiphene citrate [CC]), insulin-sensitizing agents (eg, metformin), gonadotropins, bromocriptine (in the case of hyperprolactinemia), glucocorticoids, aromatase inhibitors, or ovarian drilling could all be offered. Most of these drugs have been shown to be effective in restoring menstrual cyclicity, although their efficacy varies. In addition, they are associated with different risk-benefit profiles. The agent with the least side effects and best safety profile should be chosen first. Because hyperinsulinemia has been suggested as a possible mechanism leading to increased adrenal DHEAS production, the use of metformin is likely to lower DHEAS levels as well. However, it is my opinion that metformin should not be administered with the sole indication to lower high DHEAS levels; treatment should address the patient's complaint. During metformin administration, androgen levels will be reduced, and in over 50% of the patients, ovarian cyclic function will be restored. Metformin administered in early pregnancy will lower miscarriage rates as well.

Glucocorticoids (eg, dexamethasone 0.5-2.0 mg) have been shown to improve menstrual regularity in up to 60% of women with PCOS. However, success rates significantly vary from study to study. The combination of CC and dexamethasone also has been shown to be effective for CC-resistant women with PCOS. At this point, it is unclear which patient might benefit from additional dexamethasone therapy. Biochemical parameters (various baseline androgen levels) were mostly shown not to be predictive of response. It is also unclear which dose of dexamethasone leads to the best results, and for how long it should be administered. Long-term steroid administration is associated with significant side effects (eg, weight gain, osteoporosis, gastrointestinal problems, and glucose intolerance); therefore, its use should be limited. As there are numerous, safer treatment options that are available to manage the various problems that arise among women with PCOS, the use of glucocorticoids should be reserved for those who fail other interventions.

On menstrual and basal body temperature charting


I was searching amazon.com and checking out reviews of fertility books for a future post and found a comment from a reviewer which i think are quite interesting

I have such mixed feelings about the book that I have difficulty writing a balanced review. On one hand, this book contains far more information about the menstrual cycle, ovulation, and BBT charting than any other source I've found. My OB/GYN suggested that I start charting after several months of trying to conceive, but his overview of how to chart and interpret those charts was so brief as to be almost useless. This detailed, thorough book helped fill in many of those gaps.
On the other hand, I was so upset with the tone of the book that I would hesitate to recommend it to anyone. The author assumes that all of her female readers are ignorant victims of the "male-dominated medical establishment," and criticizes women again and again for not knowing every minute detail of their menstrual cycle, which I found silly. After all, I don't know every detail of the inner workings of my digestive tract either--does that make me a victim too?
My more serious objection is the fear tactics that the author uses to scare women away from seeking out medical help with a fertilty problem. I approached my fertility problem this way: I want a baby, and whether it's conceived through medical means or "natural" means does not matter. I agree that charting and lifestyle modifications should be your first step on the road to treatment, but if those methods don't work (which they probably won't if you have a serious fertility problem), you shouldn't be afraid to move on to medical help. After reading this book, I came away thinking that every doctor is arrogant, close-minded, ignorant about basic biology, and out to prescribe unnecessary fertility treatments just to make money. The first OB/GYN I saw wasn't great, but when I switched to a wonderful infertility specialist, everything became easier right away. He suggested that I stop charting because timing wasn't our problem--my husband's low sperm counts were. Quitting charting was the single biggest stress-reliever of my infertilty experience--I no longer felt that it was all "up to me." I'm also happy to report that after two years of trying, I'm finally expecting a baby this summer. My overall recommendation of this book would be to heed the factual information, but ignore the biases of its author.
source : amazon.com

I cannot agree more with this comment. On one side knowledge is power and it is essential for all of us to live mindfully. At the same time we should also approach problems with pragmatism and with an unbiased mind. More to come on this topic

What are the most appropriate treatments for patients with Polycystic Ovary Syndrome (PCO) who desire fertility?

Well ASRM and ESHRE had a consensus meeting last year and here is the abstract (most important points highlighted in bold by me):

Consensus on infertility treatment related to polycystic ovary syndrome.

The treatment of infertile women with polycystic ovary syndrome (PCOS) is surrounded by many controversies. On the basis of the currently available evidence, a group of experts reached a consensus regarding the therapeutic challenges raised in these women. Before any intervention is initiated, preconceptional counseling should be provided emphasizing the importance of lifestyle, especially weight reduction and exercise in overweight women, smoking, and alcohol consumption. The recommended first-line treatment for ovulation induction remains the anti-estrogen clomiphene citrate (CC). Recommended second-line intervention, should CC fail to result in pregnancy, is either exogenous gonadotropins or laparoscopic ovarian surgery (LOS). The use of exogenous gonadotropins is associated with increased chances for multiple pregnancy, and, therefore, intense monitoring of ovarian response is required. Laparoscopic ovarian surgery alone is usually effective in less than 50% of women, and additional ovulation induction medication is required under those circumstances. Overall, ovulation induction (representing the CC-gonadotropin paradigm) is reported to be highly effective with a cumulative singleton live-birth rate of 72%. Recommended third-line treatment is in vitro fertilization (IVF). More patient-tailored approaches should be developed for ovulation induction based on initial screening characteristics of women with PCOS. Such approaches may result in deviation from the above mentioned first-line, second-line, or third-line ovulation strategies in well-defined subsets of patients. Metformin use in PCOS should be restricted to women with glucose intolerance. Based on recent data available in the literature, the routine use of this drug in ovulation induction is not recommended. Insufficient evidence is currently available to recommend the clinical use of aromatase inhibitors for routine ovulation induction. Even singleton pregnancies in PCOS are associated with increased health risk for both the mother and the fetus.

Source : Fertility And Sterility via MEDLINE

I think it is very important to note that this consensus document confirms what most reproductive endocrinologists already know and that is that Metformin (Glucophage) is a lousy fertility drug. For a while it seemed to be very promising and at some point it was being prescribed (by some) to all PCOS patients. But today it is quite clear that only a subgroup of patients will benefit from this drug. More on this in the future!

Clomiphene citrate and intrauterine insemination (IUI): how well does it work?

For those of you out there who have questions on Clomid (Clomiphene Citrate , Serophene) and it's efficacy here is an excellent piece of research out of Harvard Medical School. It is a retrospective study and therefore has limitations but i think it gives a great idea of what the chances are of concieving with clomid. Here is the abstract below (Source Fertility and Sterility via MEDLINE). As usual relevant parts are Highlighted in bold by me.

Clomiphene citrate and intrauterine insemination: analysis of more than 4100 cycles.

OBJECTIVE: To evaluate the outcomes of a large cohort of patients undergoing fertility treatment with clomiphene citrate and intrauterine insemination. DESIGN: A retrospective cohort study. SETTING: Boston IVF, a large university-affiliated reproductive medicine practice. PATIENT(S): A total of 4,199 cycles performed in 1,738 infertility patients between September 2002 and July 2007. INTERVENTION(S): All patients received oral clomiphene citrate, and patients with completed cycles had intrauterine insemination performed. MAIN OUTCOME MEASURE(S): Cumulative and per cycle pregnancy rates achieved among subsets of patients defined by age, completed cycles, and intention to treat (ITT). RESULT(S): For women under age 35 years, 2,351 cycles were initiated in 983 patients. A total of 238 pregnancies ensued, yielding a pregnancy rate (PR) per completed cycle of 11.5% and 10.1% per cycle initiated with ITT. In women aged 35-37 years, 947 cycles in 422 women lead to a PR per completed cycle and ITT of 9.2% and 8.2%, respectively. For patients aged 38-40 years, 614 cycles in 265 women lead to a PR per completed cycle and ITT of 7.3% and 6.5%, respectively. In women aged 41-42 years, 166 cycles in 81 patients lead to a PR per completed cycle and ITT of 4.3% and 3.6%, respectively. For women above age 42 years, 120 cycles in 55 patients lead to a PR per completed cycle and ITT of 1.0% and 0.8%, respectively. On a per-patient treated basis, cumulative PRs were 24.2% under age 35, 18.5% ages 35-37, and 15.1% ages 38-40, whereas only 7.4% ages 41-42 and 1.8% above 42 became pregnant (one pregnancy in 55 patients). CONCLUSION(S): As anticipated, younger patients have a higher PR per cycle than older patients. The PR per cycle for patients who initiate only one or only two treatment cycles is notably higher than the corresponding per cycle rates for cycles 3 through 9. The drop in success per patient among 41- and 42-year-olds is sharp, but the exceptionally low success rate above age 42 suggests that CC with IUI has virtually no place in their treatment.

Overall this is a very good article. I am not sure i agree 100% with all of its conclusions which are a bit drastic.
I do agree, and other data supports this, that most people who get pregnant on clomid get pregnant on the first 3 cycles.
I think that the overall pregnancy rates may vary for different populations and depending on the way physicians practice. For example in my practice were we do not immediately jump to ivf pregnancy rates for inseminations are consistently higher. Some ivf physicians divert patient who have poor prognoses to iui in order not affect their center's pregnancy rates and this lowers the iui rates.
The issue on how to approach the over 42 patients is complex and furthermore (sadly) much has to deal with insurance coverage and resources. Over 42 patients are a heterogeneous group : a minority of them have good ovarian reserve whereas the majority has poor or no reserve. Although patients are very aware of this reality they often opt to try their luck. Obviously this represents a philosophical decision: the pragmatist will opt for oocyte donation whereas the more idealistic will try with their own eggs and a few lucky ones will succeed.
For what pertains the actual benefit of utilizing ovulation induction in the patients over 44 I think the verdict is still not out.