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

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.

Acupuncture and IVF Meta Analisys

the study, from Guy's and St Thomas' Hospital in London, was a review
and meta-analysis of 13 randomised trials involving the use of
acupuncture during IVF treatment and outcome assessment. In total, 2500
women were included.

Further break down of the results into categories including live birth
rate, whether the control groups received no intervention at all or
sham (placebo) needle acupuncture, as well as the types of acupuncture
used, the number of sessions women were given, and who administered the
acupuncture, consistently found no significant difference.

Professor Philip Steer, BJOG Editor-in-Chief said: "Those undergoing
IVF treatment and their clinicians clearly wish for the best possible
outcome, a healthy pregnancy and birth. Over the years there has been
much back and forth regarding whether acupuncture increases the chances
of success.


"This meta-analysis appears to show that, despite its popularity,
acupuncture may have no beneficial effect on IVF after all. Further
work is required in this area to fully establish whether a link does
exist so that women can be assured that they are receiving the most
effective care."

See Abstract of the Study Below

A systematic review and meta-analysis of acupuncture on in vitro fertilisation.
El-Toukhy T, Sunkara S, Khairy M, Dyer R, Khalaf Y, Coomarasamy A
BJOG 2008; DOI: 10.1111/j.1471-0528.2008.01838.x.

Assisted Conception Unit, Guy's and St Thomas' Hospital, London, UK.

Background
Numerous randomised studies have reported pregnancy outcome in women
who received acupuncture during their in vitro fertilisation (IVF)
treatment cycle. Objective The objective of this study was to conduct a
systematic review with meta-analysis of the trials of acupuncture
during IVF treatment on the outcomes of clinical pregnancy and live
birth rates. Search strategy Searches were conducted in MEDLINE,
EMBASE, Cochrane Library, ISI Proceedings and SCISEARCH. Selection
criteria All randomised controlled trials that evaluated the effects of
acupuncture compared with no treatment or sham acupuncture in women
undergoing IVF-intracytoplasmic sperm injection treatment were
included. Data collection and analysis Study selection, quality
appraisal and data extraction were performed independently and in
duplicate. A sensitivity analysis was conducted where the meta-analysis
was restricted to trials in which sham acupuncture was used in the
control group. Meta-regression analysis was used to explore the
association between study characteristics and pregnancy rates. Main
results Thirteen relevant trials, including a total of 2500 women
randomised to either acupuncture or control group, were identified. No
evidence of publication bias was found (Begg's test, P = 0.50). Five
trials (n = 877) evaluated IVF outcome when acupuncture was performed
around the time of transvaginal oocyte retrieval, while eight trials (n
= 1623) reported IVF outcome when acupuncture was performed around the
time of embryo transfer (ET). Meta-analysis of the five studies of
acupuncture around the time of egg collection did not show a
significant difference in clinical pregnancy (relative risks [RR] =
1.06, 95% CI 0.82-1.37, P = 0.65). Meta-analysis of the eight studies
of acupuncture around the time of ET showed no difference in the
clinical pregnancy rate (RR = 1.23, 95% CI 0.96-1.58, P = 0.1). Live
birth data were available from five of the eight studies of acupuncture
around the time of ET. Meta-analysis of these studies did not show a
significant increase in live birth rate with acupuncture (RR = 1.34,
95% CI 0.85-2.11). Using meta-regression, no significant association
between any of the studied covariates and clinical pregnancy rate was
found (P > 0.05 for all covariates). Conclusion Currently available
literature does not provide sufficient evidence that adjuvant
acupuncture improves IVF clinical pregnancy rate.

PMID: 18652588 [PubMed - as supplied by publisher]

Of course we all know that a meta analysis is a statistical execercise with great limitations, nevertheless it is clear that the initial enthusiasm for this practice in IVF needs to be reconsidered.

AMH hormone levels as a predictor of age at menopause

Huge hype today as time Magazine reports about an article from a the in the Journal of Clinical Endocrinology and metabolism.
The scientific article is titled Relationship of Serum Anti-Mullerian Hormone Concentration to Age at menopause. The Abstract of the article is below.

BACKGROUND: Serum anti-Müllerian hormone (AMH) levels are highly correlated with antral follicle counts (AFC), while being menstrual cycle independent and easily measurable. However, AMH, unlike AFC, has not been tested as yet as a predictor of reproductive status. By relating AMH levels to the age distribution of reproductive events like onset of menopause we tested this hypothesis. METHODS: AMH levels were measured in 144 fertile normal volunteers and used to determine an estimate of mean AMH as a function of age. Data on onset of menopause were obtained from the population-based Prospect-Epic cohort. Estimation of an AMH threshold to predict menopause was done by maximum likelihood using the observed (EPIC) and predicted (AMH) distributions of age at menopause. Predictions of age at menopause follow from an individual woman's AMH relative to percentiles of the distribution of AMH for a given age, and the corresponding percentiles of the predicted distribution of age at menopause. RESULTS: There was good conformity between the observed distribution of age at menopause and that predicted from declining AMH levels. CONCLUSION: The similarity between observed and predicted distributions of age at menopause supports the hypothesis that AMH levels are related to onset of menopause. Results of this study suggest that AMH is able to specify a woman's reproductive age more realistically than chronological age alone.

Let me explain the whole thing in simple words. AMH is produced by the ovaries(just as eggs are) as a woman ages the ovaries shrink so threre are less eggs and less AMH. We have known this fact for a long time . What the people in the study have done is they compared numbers in ovulating women to a control group of menopausal women from a different population. So it was not a prospective study. The right way to do this study would be to follow the same women for 20 years or more until they reach menopause.
Thus the study does not add much to our knowledge: as a general rule if you ovaries are getting smaller prematurely or you produce less eggs prematurely or your day 3 fsh goes up prematurely you are more likely to undergo menopause earlier.
So pretty much no news for most women. I think that it is common knowledge that fertility declines with age the decline is sharper after the age of 35 so if you are interested in knowing your status you can go to any reproductive endocrinologist and get any or all of these tests.

Link to Times article

Fertility Clinics Pick Their Costumers

I am proud to say that no patient selection is done at our clinic. But the data below speaks for itself.

Video of Embryo Transfer

this is a video that describes pretty well the process of embryo transfer. As you will be able to see the embryo (or embryos) are gently placed with a catheter approximately 2 centimeters from the top (fundus) of the uterus. They are pretty much planted in a gelatinous substance and therefore do not fall out.

Video explanation of ivf

This one is from youtube. Video created by a doctor in india. Pretty good job

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

On Acupuncture and Infertility (an in depth analysis)

Below you will find an in depth analysis of the available science on acupuncture and IVF. As you probably know i am a fertility specialist with a decade of experience. I use acupuncture daily as part of my practice and my professional experience with it has been very positive . Nevertheless since i have done some reading to see what info was available online on this topic most of what i found was complete junk, advertising ,false promises and unscientific information. This makes me sad because very valuable alternative treatment options often end up on websites like quackwatch because of the misinformation that is spread around online.
Consequently I attemped to fix this problem by reading all the literature currently available on the topic and summarize it in a scientific way, as if i was presenting it to some of my colleagues. So i am sorry if the content at times appears heavy.

What is Acupuncture?

The term "acupuncture" describes a family of procedures involving the stimulation of anatomical points on the body using a variety of techniques. The acupuncture technique that has been most often studied scientifically involves penetrating the skin with thin, solid, metallic needles that are manipulated by the hands or by electrical stimulation.

Practiced in China and other Asian countries for thousands of years, acupuncture is one of the key components of traditional Chinese medicine. In TCM, the body is seen as a delicate balance of two opposing and inseparable forces: yin and yang. The concept of two opposing yet complementary forces described in traditional Chinese medicine. Yin represents cold, slow, or passive aspects of the person, while yang represents hot, excited, or active aspects. A major theory is that health is achieved through balancing yin and yang and disease is caused by an imbalance leading to a blockage in the flow of qi. Yin represents the cold, slow, or passive principle, while yang represents the hot, excited, or active principle. According to TCM, health is achieved by maintaining the body in a "balanced state"; disease is due to an internal imbalance of yin and yang. This imbalance leads to blockage in the flow of qi. In traditional Chinese medicine, the vital energy or life force proposed to regulate a person's spiritual, emotional, mental, and physical health and to be influenced by the opposing forces of yin and yang(vital energy) along pathways known as meridians. Qi can be unblocked, according to TCM, by using acupuncture at certain points on the body that connect with these meridians. Sources vary on the number of meridians, with numbers ranging from 14 to 20. One commonly cited source describes meridians as 14 main channels "connecting the body in a weblike interconnecting matrix" of at least 2,000 acupuncture points.

Source : NIH

Do I Believe In Acupuncture ?

I get asked frequently by patients if I believe in Acupuncture or other alternative treatments. My standard answer to the question is that as a scientist i have no beliefs, i just look at the evidence. Of course as a very open minded person i understand there are different levels of evidence. I also understand that absence of evidence of any treatment's efficacy is not the same thing as proven evidence that it is not efficacious. Therefore i do not discard a treatment option a priori just because there are no randomized double blind prospective studies on the topic published in the New England Journal of Medicine.

So far there have been 6 Prospective Randomized Studies on the role of acupuncture in infertility

These studies do not focus on acupuncture and fertility in general since this kind of study would be very difficult if not impossible to do. Most of the studies have focus a simple question: does acupuncture performed during IVF (In Vitro Fertilization) treatments around the time of embryo transfer (usually one session thirty minutes before and after embryo transfer) increase the chance of pregnancy?

1) The Original Study ("Paulus Study")

This research originated from an original study performed by a German group (Paulus et al.) which is cited pretty much in every website that advertises acupuncture services. In the study (the first randomized, controlled, prospective trial of acupuncture with IVF patients), published in 2002, 165 women undergoing embryo transfer were randomized to receive either 25 minutes of acupuncture or were assigned to a control group, that consisted of resting quietly for the same amount of time both before and after embryo transfer. In this study a significant increase was observed in the clinical pregnancy rate for the acupuncture arm when compared with the control arm (42.5% vs. 26.3%).

As exciting as the study was, there was an important source of criticism in it: the control group was no treatment (rest) rather than placebo (sham acupuncture). Now I do not want to spend much time here explaining what a placebo is but in a nutshell a placebo is a "sham" treatment that has no known effect on a disease, but the receiver of the treatment believes that the placebo is efficacious and thanks to the power of suggestion a treatment effect is observed.

2) The follow up study of the Paulus Group ("Second Paulus study")

Interestingly enough the same group was aware of the fact that a no treatment control group might have constituted a problem and one year later carried out a follow up study with with the placebo control. The study was presented at the annual meeting of the European Society for Human Reproduction and Embryology (ESHRE). In the follow up study 200 patients were randomized to receive either real or sham acupuncture for 25 minutes before and after the IVF Embryo Transfer. The study concluded that there was no statistical difference between the two groups ( 43% vs 37% , p=0.39 ). It is important to note that in this study good quality embryos were used.

It is important to note that the authors of the study hypothesized that the control group may have had higher than expected pregnancy rates due to a possible acupressure effect of the sham acupuncture. This is pure hypothesis though since there was no third group without therapy to compare the outcomes with.

The authors opted never to publish this study with negative outcome as full paper, this is a bit concerning because it may signal bias in favour of acupuncture.

3) The Dieterle Study

This is the third randomized prospective study, the lead author is Stefan Dieterle in Dortmund, Germany. The study included 225 patients.

The protocol consisted of 30 minutes of acupuncture after Embryo Transfer and 3 days later and the addition of a special Chinese medical drug (the seed of Caryophyllaceae) was placed on the patient’s ear at the same time. The control group received different acupuncture points, specifically designed not to influence fertility and making sure that equal numbers of needles were applied to the study and control groups.

The clinical pregnancy rate was 34% in the treatment group vs. 16% in the control group (P<.01). This astounding difference in pregnancy was noticed by the authors. More specifically in the paper they note that "according to the German IVF/ICSI register (2003), the average clinical pregnancy rates for this age are 24.6% for IVF and 22.6% for ICSI". I am quite surprised that the study was not controlled for embryo quality (in fact the words "embryo quality" are not ever mentioned in the paper) although all other major parameters such as age, weight, cause of infertility, type of stimulation, number of ampules etc.., were not statistically different. The authors do not highlight this fact although they mention that thanks to the German Embryo Protection Law, clinics are not allowed to perform embryo selection. Nevertheless this observation leaves the door open to the possibility that the treatment group could have just had better embryos by pure chance.

So rather than looking into the obvious, control for embryo quality, the authors look elsewhere to explain these discrepancies suggesting that the the sham acupuncture group could have had an adverse effect on the pregnancy rate.

4) The Danish Study

This is probably the largest randomized perspective study to date it was conducted by Dr. Lars Westergaard in Denmark and it was sponsored by the Danish government.

Dr. Westergaard randomized 300 IVF patients so that 100 received acupuncture on the day of Embryo Transfer according to the original Paulus protocol, 100 received acupuncture on the day of Embryo Transfer and again 2 days later, and a control group of 100 subjects received no acupuncture at all. The control subjects had 1 hour of bed rest after Embryo Transfer.

It is interesting to note that unlike the previous studies where acupuncture was administered by licensed acupuncturists (and often the same practitioner) in this study, 9 nurses were trained and administered the acupuncture.

Pregnancy rates: both acupuncture groups had statistically significant greater pregnancy rates with( 39% for the single-session acupuncture, 36% for the two-session) the control group that had a clinical pregnancy rate of 24%.

The ongoing pregnancy/delivery rate was statistically significantly higher in the one-session group than in the control group, but there were no differences between the two-acupuncture-session and control group. This observation, along with the observation that pregnancy loss rates were much greater in the 2 session group vs the 1 session group (although not statistically significant) brought up again the question on weather acupuncture days after transfer could potentially have adverse effects.

What I found to be really interesting about this study was the fact that the authors found no difference in implantation rates (gestational sacs/no. of transferred embryos) which is a bit surprising because the theory behind acupuncture is that it may increase implantation.

So again no mention about embryo quality in any of the groups.

Why do I think mentioning embryo quality is important? Because Acupuncture is administered after the embryos are created and therefore it is a key element in determining whether the groups of subjects being compared are really similar.

The Australian Study

228 women were randomized in two groups: acupuncture and sham acupuncture (that means not on acupuncture points known to affect fertility) with placebo needles, these newly developed needles are retractable, so the subjects are not aware of whether they are receiving real acupuncture treatment.

All subjects had three treatment sessions. The first took place on day 9 of stimulating injections, and the second and third were immediately before and after Embryo Transfer.

Although the pregnancy rate was 31% in the acupuncture group and 23% in the control group the difference did not reach statistical significance. The ongoing pregnancy rate at 18 weeks was higher in the treatment group (28% vs. 18%), but the difference was not statistically significant either.

This study also reported embryo quality, no difference of embryo quality being reported in the 2 groups.

This was a well designed and executed study that was designed after the original Paulus study (with some differences such as the day 7 acupuncture). The authors hypothesize that if they had done a study with more subjects and therefore a greater power t detect smalled differences acupuncture may have proven efficacious.

The Harvard Study

This very recent study was conducted by Dr. Alice Domar. Dr Domar is well known worldwide for heading the Mind Body Center for Women's Health at Harvard's affiliated Boston IVF. Dr. Domar was interested in trying to figure out a way to do a good acupuncture study that mimicked a well designed study using a pill. In order to do this blinding was essential so that it would be possible to rule out if the placebo effect was on the part of the patient, the health care team, or a combination of the two.

Dr Domar went about replicating the original Paulus study and to "assess the potential contribution of a placebo effect on the part of the patient, but to control for the placebo effect on the part of the health care team." For this reason all members of the health care team, not only the doctor the doctor performing the transfer(as in prior studies), were blinded to the treatment.

As per Dr. Domar's paper :

In both the Paulus and Dieterle studies the physician performing the embryo transfer was blind but the remainder of the health care team was apparently not. There was no information on staff blinding in the Smith study and in the Westergaard study , blinding could not have taken place as the actual acupuncture sessions were conducted by the clinic nurses themselves. Thus it is possible that there could have been a placebo effect on the part of members of the health care team. This is somewhat doubtful, as one would think that the member of the team who has the greatest potential impact on the results of the embryo transfer would be the physician and this was controlled for in at least two of the studies.

There were no significant differences between the two groups in terms of clinical pregnancy rates with 30.8% ultrasound-confirmed clinical pregnancy for the acupuncture compared to a 33.8% rate in the controls (P=.69).

No difference in early miscarriage rates was noted as well.

On the topic of embryo quality: "Because the Paulus study used only subjects with good quality embryos, a separate analysis was performed on subjects who had at least one good quality embryo transferred. The acupuncture patients in this subgroup had a 42% clinical PR and the control subjects had a 47% rate (P=not significant [NS])".

I was very impressed by Dr. Domar's study, mostly because she is not a member of the alternative medicine denier's gang like the people on Quackwatch. On the contrary she is the kind of person who carries out studies with titles like "Impact of group psychological interventions on pregnancy rates in infertile women", in which she proved that 10 months of psychological intervention increased pregnancy rates in infertile patients. She is the kind of researcher that you would imagine being biased towards an alternative regimen rather than against; however, she is also a good scientist who has written about the need of sticking to good science.



Final Considerations

I think that the existing evidence is suggestive that an acupuncture session at the time of embryo transfer may increase pregnancy rates in IVF. Given the quality of the studies and the fact that they appear to have some methodological limitations, such as selection bias which may have influenced the study findings, it can be argued that the existing evidence is inconclusive.

What is the mechanism of action of acupuncture in IVF?

Based on the existing science we do not really know. Various possibilities have been hypothesized: increased blood flow to the uterus, uterine relaxation (although a large ultrasound study of 163 subjects by the Paulus group confirmed acupuncture treatment does not inhibit uterine motility, interestingly this negative study was also not published and left languishing as an oral presentation at ASRM) or increased release of endorphins, and finally placebo effect.

Lets say that the effect of acupuncture on IVF is due to placebo, if i am a patient should I care?

I say that if it works for you .....you shouldn't care why it works! In fact the more you question the less it is likely to work.

I think that the issue is more relevant for practitioners and it deals more with the ethics of medicine and the philosophy of science.

My good friend Dr. Pati suggested a way to approach this: even if it is placebo effect-if it
works-use it -the power of the mind is limited only by our preconceptions-

Is there any good scientific evidence that Acupuncture may help me even if i am not doing IVF?

All of the evidence currently available at this time is anecdotal, which means that all of the claims that you read on all promotional websites are pretty much unverified claims. As I stated at the beginning of this article, this does not exclude that an effect may be present: it's just not been proven by rigorous scientific methodology (the kind of methodology and rigorous work that you expect and demand your infertility specialists to go by).

What About the Study on the British Medical Journal?

In February 2008 an Article from British Medical Journal presented a meta analysis of the existing studies (excluding the domar study) and concluded that " current estimates of the effects of adjuvant acupuncture on in vitro fertilisation are significant and clinically relevant" .

Since this article is nothing but a cumulative analysis of the above trials and overall does not contradict their outcomes i would argue that id does not add much to the discourse: ultimately if there are methodological flows in the original study a meta-analisys is not going to correct any errors.

Why has Acupuncture become so popular?

Because of the evolving nature of medicine from humanistic to science we have witnessed major change in the role of doctors. Doctors are not healers anymore, they operate according to algorithms. Because of this they are viewed as detached and not caring. So there is an enormous interest in ancient healing practices whose practitioners actually seem to "care" and "listen".

One of the major arguments in favour of acupuncture is that it has been around for thousands of years.

Most alternative treatments and especially the ones which are ancient and have survived to our times have almost no side or adverse effects: this makes a lot of sense if you think about it. Throughout the centuries many other medical treatments in use (application of leeches for example) had major side effects ,and some actually killed people. Therefore any treatments that may have had no effect or minimal effect on whichever ailment ended up appearing much more efficacious just by virtue of contrast.

References

Paulus WE, Zhang M, Strehler E, El-Danasouri I, Sterzik K. Influence of acupuncture on the pregnancy rate in patients who undergo assisted reproduction therapy. Fertil Steril.

Paulus WE, Zhang M, Strehler E, Seybold B, Sterzik K. Placebo-controlled trial of acupuncture effects in assisted reproduction therapy. 2003: Oral presentation, ESHRE, Madrid, Spain, June 2003;18(Suppl1): xviii18.

Dieterle S, Ying G, Hatzmann W, Neuer A. Effect of acupuncture on the outcome of in vitro fertilization and intracytoplasmic sperm injection: a randomized, prospective, controlled study. Fertil Steril. 2006;85:1347–1351.

Smith C, Coyle M, Norman RJ. Influence of acupuncture stimulation on pregnancy rates for women undergoing embryo transfer. Fertil Steril. 2006;85:1352–1358.

Westergaard LG, Mao Q, Krogslund M, Sandrini S, Lenz S, Grinsted J. Acupuncture on the day of embryo transfer significantly improves the reproductive outcome in infertile women: a prospective randomized trial. Fertil Steril. 2006;85:1341–1346.

Domar a., Meshay I, Kelliher J, Alper M, Powers D. The impact of acupuncture on in vitro fertilization outcome. Fertil Steril. 2008; march

Gleicher n. , et al. Background pregnancy rates in an infertile population. Hum Reprod. 1996 May;11(5):1011-2.

Copyright © 2008 Andrea Vidali  All rights reserved.

Are Doctors Miracle Workers?

Interesting article on the New York Times this weekend by David Rieff on the topic of patient physician relationship. Here are a couple of thoughts. More to follow.

Trust Your Doctor?
The article by David Rieff , "Miracle Workers?" , highlights the erosion of the concept of "trust" towards one's physician. Paraphrasing George Simmel, inherent to the nature of trust is an element of faith. This faith is ‘conditional’, in the sense that it rests on the awareness that certain social and legal structures are in place to protect one's interests. One can trust because society is organized to prevent such trust from being abused. Nevertheless, trust entails a relationship between two parties that are on different levels of knowledge and power. When medicine was a humanistic science, doctors were regarded to be the exclusive keepers of their knowledge. This was essential to a patient’s trust.

The ‘exclusivity’ of a doctor’s knowledge no longer exists. Furthermore, modern clinical epistemology has moved the medical discourse from the realm of the "possible" (as I often say to my patients, the answer to any possibilistic question is always yes) to the realm of the “probable”, that is, the quantifiable world of statistics. This shift has been quite positive, allowing more sick people to be treated with more appropriate treatments. In this new paradigm, hope is rooted not in his faith but in knowledge that we are receiving the best treatment available against our disease.

Yet patients still have a longing for the days in which they could simply "trust" their doctor. This longing is partially fulfilled today by alternative medicine, whose language remains the language of the "possible" - the language of faith. Perhaps there is a fundamental human need involved, which the language of the probable and the ‘comfort of statistics’ can never fully assuage.

Effect of cell phone usage on semen analysis: observational study

Another report on cell phone use and male fertility. I had previously reported on this topic on this blog.
This article published on Fertility and Sterility this month (2/2008) is from a reputable institution the Cleveland Clinic and i think it's findings are quite relevant. Here is the Abstract below

Objective

To investigate the effect of cell phone use on various markers of semen quality.

Design

Observational study.

Setting

Infertility clinic.

Patient(s)

Three hundred sixty-one men undergoing infertility evaluation were divided into four groups according to their active cell phone use: group A: no use; group B: <2>4 h/day.

Intervention(s)

None.

Main Outcome Measure(s)

Sperm parameters (volume, liquefaction time, pH, viscosity, sperm count, motility, viability, and morphology).

Result(s)

The comparisons of mean sperm count, motility, viability, and normal morphology among four different cell phone user groups were statistically significant. Mean sperm motility, viability, and normal morphology were significantly different in cell phone user groups within two sperm count groups. The laboratory values of the above four sperm parameters decreased in all four cell phone user groups as the duration of daily exposure to cell phones increased.

Conclusion(s)

Use of cell phones decrease the semen quality in men by decreasing the sperm count, motility, viability, and normal morphology. The decrease in sperm parameters was dependent on the duration of daily exposure to cell phones and independent of the initial semen quality.

I do not think in modern society most people would be able to survive without cell phones. These phones operate between 400 MHz and 2000 MHz frequency bands and emit radiofrequency electromagnetic waves (EMW). Reports of potential adverse effects of radiofrequencyelectromagnetic waves have been reported for a few years now with the gretest concern for the brain.

As the article states

These phones operate at different frequencies in different countries and continents. Exposure of radiofrequency energy depends upon the frequency of the cellular phone. Analog phones operate at 450–900 MHz, digital phones (Global System for Mobile Communications [GSM]) at 850–1900 MHz, and third-generation phones at approximately 2000 MHz . For years the cell phone companies have assured people that cell phones are perfectly safe. For assessing exposure from transmitters located near the body, the most useful quantity is the specific absorption rate (SAR), the amount of radiofrequency energy absorbed from the phone into the local tissues. The SAR of cell phones varies from 0.12 to 1.6 W/kg body weight depending upon the model. In the United States, the upper limit of SAR allowed is 1.6 W/kg .

So pretty much by now we have evidence that excessive phone use may have adverse health effects. I think this study is very relevant because it is the first study that showed what we in medicine call a dose-response relationship . That is the more cell phone usage the less the sperm. For the record the highest users in the study talked on the cell for more than 4 hours per day but an effect was already seen in men who talked for less than 2 hours a day. In the control group were men who reported no cell phone use ( i wonder where they found these guys id did not think they exhisted!)
the study has some limitations: most notably cell use was self reported , and everybody had a different phone, and no account was taken for where the phone was kept when not in use. Nevertheless the message is clear : "The decrease in sperm parameters was dependent on the duration of daily exposure to cell phones and independent of the initial semen quality".

So what to do?
1) Cut down phone use to less than 2 hours/day .
We are frequently lazy. I personally reach for the cell even when i am sitting in my office
2) Do not Keep the phone in your pocket.
Those belt carriers may make you look a bit nerdy but at least you are not applying the phone directly to your testicles!
3) Get a Phone with lower emissions!
Check the information provided below to figure out which phone is best for you.

Below Is The Information that You need if you want to learn more about cell phone emissions
(source: Federal Communication Commission)

Cellular Phone Specific Absorption Rate

The SAR is a value that corresponds to the relative amount of RF energy absorbed in the head of a user of a wireless handset. The FCC limit for public exposure from cellular telephones is an SAR level of 1.6 watts per kilogram (1.6 W/kg). Specific Absorption Rate (SAR) for Wireless Phones and Devices Available at various Web sites.

The easiest way to ascertain SAR for many cellular phones is via the FCC's links to individual manufacturers' Web sites: http://www.fcc.gov/cgb/sar/. On this page you will find links to most manufacturers' Web pages that include SAR information for their phones, along with instructions on how to search each site for SAR information.

You can also obtain SAR information on many cellular phones from the FCC's database if you have the FCC ID number of the phone or device and if it was produced and marketed within the last 1-2 years.

The FCC ID number is usually shown somewhere on the case of the phone or device. In many cases, you will have to remove the battery pack to find the number. Once you have the number proceed as follows. Go to the following Web site: https://fjallfoss.fcc.gov/oetcf/eas/ . Once you are there you will see instructions for inserting the FCC ID number. Enter the FCC ID number (in two parts as indicated: "Grantee Code" is comprised of the first three characters, the "Equipment Product Code" is the remainder of the FCC ID). Then click on "Start Search." The grant of equipment authorization for this particular ID number should appear. Look through the grant for the section on SAR compliance, certification of compliance with FCC rules for RF exposure or similar language. This section should contain the value(s) for typical or maximum SAR for your phone.

For portable phones and devices authorized since June 2, 2000 , maximum SAR levels should be noted on the grant of equipment authorization. For phones and devices authorized between about mid-1998 and June 2000, detailed information on SAR levels is typically found in the "exhibits" associated with the grant of equipment authorization. Therefore, once a grant is accessed these exhibits can be viewed by clicking on the appropriate entry labeled "View Exhibit."

Electronic records for FCC equipment authorization grants were initiated in 1998. Therefore, prior to this date FCC records for grants are in the form of paper records that are not part of our electronic database. At this time, due to staff limitations, we are unable to routinely search through FCC paper records to extract SAR information for grants filed prior to mid- to late-1998.

If you want additional consumer information on safety of cell phones and other transmitting devices please consult the information available below at this Web Site. In particular, you may wish to read or download our OET Bulletin 56 (see "RF Safety Bulletins") entitled: "Questions and Answers about Biological Effects and Potential Hazards of Radiofrequency Electromagnetic Fields." If you have any problems or additional questions you may contact us at RF Safety (rfsafety@fcc.gov) . [ July 18, 2000 ]

You may also wish to consult a consumer update on mobile phone safety published by the U.S. Food and Drug Administration (FDA) that can be found at: www.fda.gov/cdrh/phones .

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.

Three-parent embryo formed in lab

BBC News reports that a Newcastle University team created embryos from 3 parents

Within hours of their creation, the nucleus, containing DNA from the mother and father, was removed from the embryo, and implanted into a donor egg whose DNA had been largely removed.

The only genetic information remaining from the donor egg was the tiny bit that controls production of mitochondria - around 16,000 of the 3billion component parts that make up the human genome.

The embryos then began to develop normally, but were destroyed within six days.

for most of us who work in the field this experiment is no news at all since this is very similar work that was carried out in 2002 called Ooplasmic Transfer also known as Cytoplasm Transfer for the purpose of egg rejuvenating. Sadly the FDA put an end to this excellent and promising work.So once again the US government hampers US research and allows the brits to take over . This is exactly what happened with the first IVF . If you have time check out this brilliant link to PBS on The First IVF and discover how we missed an opportunity.

Ultimately this is work of great interest because it represents an example of human genetic engineering that is applicable and because it is for now limited in it's scope to the treatment of "orphan" (rare) conditions such as mitochondrial diseases .

Surge in older women seeking IVF

The British Human Fertilisation and Embryology Authority reported that here has been a huge rise in demand for fertility treatment among women in their forties.

The BBC News reports that Human Fertilisation and Embryology Authority figures show last year there were 6,174 treatment cycles among women aged 40-45 using their own eggs.In 1991, the comparable figure was just 596 cycles.

check out the data below (source BBC)

1991:
Women aged 40: 210 treatment cycles
Women aged 41: 153
Women aged 42: 115
Women aged 43: 55
Women aged 44: 44
Women aged 45: 19

2006:
Women aged 40: 2,288 treatment cycles
Women aged 41: 1,605
Women aged 42: 1,070
Women aged 43: 682
Women aged 44: 358
Women aged 45: 171

All forms of fertility treatment using own fresh eggs or frozen embryos

Of course this number does not surprise us since we have been observing the same phenomenon in the US. The surge in demand for fertility treatments by older patients is to be put in relation to changing demographics as a consequence of baby boomers
getting older . By definition the last baby boomers were born in 1964 and they are now 43 year old. the next generational wave is of much smaller dimension. these numbers will not change until 20012 according to demographers.

Cleavage stage ("day 3") versus blastocyst stage ("Day 5") embryo transfer in assisted conception.

A recent cochrane database review tackled this topic here is a summary of the findings below:

Abstract

Background

Recent advances in cell culture media have led to a shift in IVF practice from early cleavage embryo transfer to blastocyst stage transfer. The rationale for blastocyst culture is to improve both uterine and embryonic synchronicity and self selection of viable embryos thus resulting in higher implantation rates.

Objectives

To determine if blastocyst stage embryo transfers (ETs) affect live birth rate and associated outcomes compared with cleavage stage ETs and to investigate what factors may influence this.

Search strategy

Cochrane Menstrual Disorders and Subfertility Group Specialised Register of controlled trials, Cochrane Controlled Trials Register (CENTRAL) (The Cochrane Library), MEDLINE, EMBASE and Bio extracts. The last search date was January 2007.

Selection criteria

Trials were included if they were randomised and compared the effectiveness of early cleavage versus blastocyst stage transfers.

Data collection and analysis

Of the 50 trials that were identified, 18 randomised controlled trials (RCTs) met the inclusion criteria and were reviewed. The primary outcome was rate of live birth. Secondary outcomes were rates per couple of clinical pregnancy, multiple pregnancy, high order pregnancy, miscarriage, failure to transfer embryos and cryopreservation. Quality assessment, data extraction and meta-analysis were performed following Cochrane guidelines.

Main results

Evidence of a significant difference in live-birth rate per couple between the two treatment groups was detected in favour of blastocyst culture (9 RCTs; OR 1.35, 95% CI 1.05 to 1.74 (Day 2/3: 29.4% versus Day 5/6: 36.0%)). This was particularly for trials with good prognosis patients, equal number of embryos transferred (including single embryo transfer) and those in which the randomisation took place on Day 3. Rates of embryo freezing per couple was significantly higher in Day 2 to 3 transfers (9 RCTs; OR 0.45, 95% CI 0.36 to 0.56). Failure to transfer any embryos per couple was significantly higher in the Day 5 to 6 group (16 RCTs; OR 2.85, 95% CI 1.97 to 4.11 (Day 2/3: 2.8% versus Day 5/6: 8.9%)) but was not significantly different for good prognosis patients (9 RCTs; OR 1.50, 95% CI 0.79 to 2.84).

Authors' conclusions

This review provides evidence that there is a significant difference in pregnancy and live birth rates in favour of blastocyst transfer with good prognosis patients with high numbers of eight-cell embryos on Day three being the most favoured in subgroup for whom there is no difference in cycle cancellation. There is emerging evidence to suggest that in selected patients, blastocyst culture maybe applicable for single embryo transfer.

My Comments

I think the key words on the author conclusion are "good prognosis patient". that means somebody who had many eggs and many embryos were created. This allows the option of selecting the very best embryos to transfer and obviously increase the chance of a pregnancy for that cycle (possibly foregoing the chance of subsequent frozen cycles). But in the scenario of somebody with 4 average to poor quality embryos on day 3 , attempting to grow them to blastocyst stage is probably not going to change the overall prognosis. What might happen instead it that the embryos may not grow to the fifth day and the patient may not have a transfer: as frustrating as this experience is this may possibly be a better outcome than having a day 3 transfer and going to the whole 14 days of progesterone injections and get a negative beta.

Caffeine and Miscarriages

Today the International Herald Tribune had an article on caffeine and miscarriages. Parts of the article are below.

Too much caffeine during pregnancy may increase the risk of miscarriage, a new study says, and it suggests that pregnant women may want to reduce their intake or cut it out entirely.

Many obstetricians already advise women to limit caffeine, though the subject has long been contentious, with conflicting studies, fuzzy data and various recommendations given over the years.

The new study, being published Monday in the Journal of Obstetrics and Gynecology, finds that pregnant women who consume 200 milligrams or more of caffeine a day - the amount in 10 ounces of coffee or 25 ounces of tea - may double their risk of miscarriage. Ten ounces is equivalent to about 300 milliliters.

Professional groups like the American College of Obstetricians and Gynecologists and the American Society for Reproductive Medicine have not taken official positions on caffeine, representatives said.

On Friday, the March of Dimes Web site said most experts agreed that the amount of caffeine found in 8 to 16 ounces of coffee a day was safe. It noted that some studies had linked higher amounts to miscarriage and low birth weight, but stated: "However, there is no solid proof that caffeine causes these problems. Until more is known, women should limit their caffeine intake during pregnancy."

Now, having reviewed the new study, the March of Dimes plans to change its message, to advise women who are pregnant or trying to conceive to limit their daily caffeine intake to 200 milligrams or less, said Janis Biermann, its senior vice president of education and health promotion.

Li's study included 1,063 pregnant women who were interviewed once about their caffeine intake. At the time of the interview, their median length of pregnancy was 71 days. But 102 had already miscarried - not surprising, because most miscarriages occur very early in pregnancy. Later, 70 more women miscarried, for an overall miscarriage rate of 16 percent for the group, a typical rate.

Of 264 women who said they used no caffeine, 12.5 percent had miscarriages. But the miscarriage rate was 24.5 percent in the 164 women who consumed 200 milligrams or more per day. The increased risk was associated with caffeine itself and not with other known risk factors like the mother's age or smoking habits, the researchers said.

Li said the study had answered an important question that previous research had left unresolved. Women who have morning sickness are less likely to miscarry than those who do not, possibly because the same hormonal changes that cause nausea and vomiting contribute to a healthy pregnancy. But some researchers said morning sickness could lead to misleading results in caffeine studies.

These researchers argued that because they feel ill, some women may consume less caffeine. That tendency may make it appear that they are less likely to miscarry because they avoid caffeine, when the real reason is actually that they started out with healthier pregnancies.

Li said he and his colleagues had carefully analyzed the data and determined that the risk from caffeine was real and could not be explained away by different rates of morning sickness.

Dr. Carolyn Westhoff, a professor of obstetrics and gynecology, and epidemiology, at Columbia University Medical Center in New York, had reservations about the study, noting that miscarriage is difficult to study or explain.

She said most miscarriages resulted from chromosomal abnormalities, and there was no evidence that caffeine could cause those problems.

Of course Dr. Westhhoff is dead on with her comments. The study is at best mildly indicative of an effect . The main reason is that it is a retrospective study . To believe that cutting caffeine would reduce miscarriages by 50% is simply ludicrous.
Nevertheless i would say that it is prudent to reduce caffeine intake to 2 cups per day of regular coffee. That's 1 espresso or 1 "tall latte" for the starbucks drinkers.

Young cancer victims are being denied access to NHS fertility treatment, according to a report by leading doctors in the UK

http://uk.news.yahoo.com/skynews/20080115/tuk-nhs-cancer-treatment-fails-young-vic-45dbed5.html

Cell Phone Use and Infertility

The Daily Mail today reports a study presented t the American Society of Reproductive medicine that finds that cell phone use increases infertility in men .
According to the study those men who made calls on a mobile phone for more than four hours a day had the worst sperm counts and the poorest quality sperm.

Well here is another one of these "fishing expedition type" lifestyles studies that are basically impossible to control (phone usage is based on questionnaires) and that help us very little. What many of these studies do I create panic in people who are already suffering with infertility.
I do agree though that cell phone usage cannot be good for anyone's health so I do not think that cutting down on it is a bed thing

IVF Baby has a Baby of Her Own

The Daily Mail reports today that the First IVF baby , Louise Brown is pregnant.

Louise Brown, the first test-tube baby in the world, has given birth to a child of her own. The boy ­ named Cameron ­ was conceived naturally and without IVF.

He was born weighing 5lb 6oz at St Michael's Hospital in Bristol just before Christmas and Louise describes him as "tiny but perfect" in an interview with The Mail on Sunday.

In the interview, the 28-year-old, whose pioneering conception by in-vitro fertilisation made her famous around the world, also reveals that she thinks it is wrong for parents to use science to choose the sex of their children, and that she was teased at school because she was a "test tube" baby.

Louise's own birth, by Caesarean section in Oldham, Lancashire, caused a media sensation in July 1978. The fertility specialists Patrick Steptoe and Bob Edwards became the first to successfully carry out IVF by extracting an egg, impregnating it with sperm and planting the resulting embryo back into the mother.

As a baby, Louise knew nothing about it, of course, but she has since discovered that media attention makes her uncomfortable. "I don't feel any more special than anyone else," she told The Independent on Sunday three years ago.

Then, she was making her first public appearance as an adult, at Bourn Hall, near Cambridge, the fertility clinic founded by the men who gave her life. The event was to celebrate the 25th anniversary of her birth.

"I just get on with my life ­ normal," she said at the time, visibly shaking as she spoke because she was so nervous about being interviewed. "Mum and Dad didn't treat Natalie any different from me."

Natalie is her younger sister, who was the 40th IVF baby to be born. And Natalie became the first of them all to have a child of her own, giving birth to a girl called Casey in May 1999.

Louise was five when her parents told her how she had been conceived. " They had it all on video, so Mum and Dad showed that to me at home. It was just before I went to school."

Dr Steptoe died in 1988, but Dr Edwards has stayed close to the family and was guest of honour when, in 2004, Louise married Wesley Mullinder. She met her future husband when he was working as a doorman in a nightclub.

Despite lifelong media attention, Louise has always sought to stay private rather than make money from her fame. "I get phone calls from mates saying: 'There was a picture of you in the paper', and I say: 'Was there? OK'."

More than a million people are believed to have been conceived using IVF, and about 9,000 babies a year are born as a result of the procedure in this country. The success rate for women under 35 using their own eggs is approaching 30 per cent.

Asked if she would have the treatment too in order to conceive a baby, the answer Louise Brown gave the IoS in 2003 was an unhesitating: "Yes" . But in the end, to her great but very private joy, it appears not to have been necessary.

Source : the independent UK

Bioidentical Hormones

Here is a recent interview that i did with Dr. Manny on Fox news

Q: What is the logic behind Hormone Replacement therapy in Menopausal Women?

A:Restoration of low thyroid, insulin and cortisol is the medical standard. So, it seems logical to also replace low estrogen, progesterone and testosterone; however the evidence leaves clinicians at a loss for clear direction, because of conflicting results from studies using varying types of hormones, routes and ages.


Q: What are the Normal Hormone Ratios?

A: These are three predominant estrogens in non-pregnant, premenopausal women. These are estrone (E1), estradiol (E2) and estriol (E3) at a ratio of E1 10-20%, E2 10-20% and E3 60-80%. This ratio is protective, since the bulk of estrogen is in the form of the weakest estrogen, E3, which is also the most clot and breast protective. E2 is the strongest estrogen and E1 is the storage form of estrogen, which also has the ability to stimulate breast proliferation and clots. E1 can be metabolized to methylated products, which are excreted safely by the liver, however if the liver systems are overwhelmed or methyl groups are deficient, E1 is converted to quinines (i.e 4-OH or 16-OH) which can be mutagenic and carcinogenic.


Q:What are Bio-identical hormones and how can they mimic protective ratios?

A: Horse-derived, soy and yam hormones do not fit into the human receptor exactly. Bio-identical hormones are exactly identical to the hormones of the human body, molecule by molecule. Since, they fit the hormone receptor like a key fits into its lock the body cannot distinguish between a bio-identical hormone and the hormones it makes itself. It must be clarified that Bio-identical hormones are often created through an artificial process from soy or yam hormones by removing any molecules that do not exist on the human hormone counterpart. They can also be made synthetically in the laboratory, for example there are pharmaceutical grade patches that contain bio-identical 17-beta estradiol.

Q: According to this principle how are Bio-identicals prescribed by doctors who use them today?

A: the goal is to reestablished the normal protective ratio, a 20: 80 ratio of E2 to E3 avoiding E1 altogether.
Transdermal estrogen mimics normal ratios better than oral, since oral estrogen first passes through the liver where 50% is converted into estrone sulfate (E1) before circulating to tissues. Transdermal estrogen enters the circulation at the ratio applied to the skin. A body of literature suggests that transdermal estrogen decreases thrombosis, blood pressure, triglycerides and vascular resistance as opposed to oral estrogen which increases thrombosis, blood pressure, CRP, triglycerides, gallstones and liver binding proteins.
Q: Going back to the large hormone replacement studies that four years ago raised questions about the health risks associated with traditional menopause hormones what has happened since then?

A: The WHI study was a large NIH sponsored study that greatly influenced the way in which American doctors prescribe hormones and the way in which American women receive them with millions of women stopping hormone replacement therapy (HRT) . Like with any medical study there were may problems. They should have studied quality of life.. They should have used estrogens in favorable ratios and transdermally. They should have used a bio- identical progesterone instead of a synthetic, non-bio-identical progestin which is known to be thrombogenic and carcinogenic.They should have started women on hormones before they developed significant vascular disease (by age 55) instead of at average age 63 and average age 71 in the memory study. Also , they should have insisted on media coverage of the positive findings they later found in the estrogen-only arm. Since that study many American women and their doctors have found an alternative in the Bio-identical approach. Unfortunately there are no large studies the size of the WHI study available yet but a large body of evidence points to the potential advantages bio-identical approach. There is no question that more studies on Bio-identicals are needed.

I am primarily a fertility physician and do not consult much on menopausal issues . I believe that one of the finest physicians in this area is Dr. Sangeeta Pati . She is a close friend and a great inspiration to many. Check Dr Pati's website at www.sajune.com

CDC 2003 Report Highlights 1

Here are some highlights from the recent CDC report on fertility clinics. The report goes back to 2003 because they have to wait one year until the baby is born and then another year to collect the data

Do ART success rates differ among women of different ages?

Age <23,>45, Pregnancy rate 3.3%, Live birth rate 1.9%, Singleton live birth rate 1.4%

Please keep in mind that these numbers refer to infertile women trying to conceive so although you cannot extrapolate the rates to the normal population you can probably extrapolate the attrition effect due to age

Some scientific evidence of sperm damage caused by varicocele

Interesting article on the December 2005 of the scientific journal Human Reproduction. The article was designed to determine the extent of sperm nuclear DNA damage in patients with varicocele and to examine its relationship with oxidative stress.
The investigators compared semen of individuals with varicocele with normal controls and concluded that

the presence of a varicocele is associated with high levels of DNA-damage spermatozoa even in the presence of normal semen profile. The results also indicate that oxidative damage is associated with sperm DNA damage in these patients.

An interesting conclusion . Much is said about the role of varicocele and infertility but there is scant evidence of a clear biologic effect so far. The common wisdom is that varicoceles induce an elevation in testicular temperature, but oxidative stress is now a novel theory. Whether treatment of varicocele is beneficial for most patient is still debated .

Source: Hum Reprod. 2005 Dec 16

Male fertility testing home kit goes on sale in the UK

The BBC news reports today that

The world's first over-the-counter home fertility test for men has been developed by scientists at Birmingham University

The test takes an hour, and forces the sample sperm to swim through a mock female cervix. Dependent on how many sperm get through the barrier, the test measures whether or not the male has enough sperm to fertilize an egg

First of all I must say that a similar test is available in the US. Second as far as I am concerned (until clinical studies prove otherwise) all this test does for a man is to confirm whether or not he has any sperm at all. Obviously that is good to know but let me reemphasize that all one will be able to tell by taking the test is that one is not completely infertile not how fertile one is .

SSRI antidepressant and pregnancy risk

The FDA has determined that exposure to paroxetine (Paxil) in the first trimester of pregnancy may increase the risk for congenital malformations, particularly cardiac malformations. At the FDAÂ’s request, the manufacturer has changed paroxetineÂ’s pregnancy category from C to D and added new data and recommendations to the WARNINGS section of paroxetineÂ’s prescribing information. FDA is awaiting the final results of the recent studies and accruing additional data related to the use of paroxetine in pregnancy in order to better characterize the risk for congenital malformations associated with paroxetine.
This is quite relevant because , to my knowledge this is the first time that a SSRI antidepressant is classified as a Fcategoryory D. Many women in their reproductive age do currently take antidepressants and many may be undergoiinfertilityity treatments. At this time women taking paxil and are pregnant or planning a pregnancy should consult their physician and possibly discontinue the drug or switch to another preparation.

Selective serotonin reuptake inhibitors (SSRIs) are a class of antidepressants that evolve their effects at the serotonin transporter. They increase the extracellular level of the neurotransmitter serotonin by inhibiting its reuptake into the presynaptic cell. Examples of SSRI's are
Citalopram (Celexa, Cipramil, Emocal, Sepram)
Escitalopram oxalate (Lexapro, Cipralex)
Fluoxetine (Prozac, Fontex, Seromex, Seronil, Sarafem)
Fluvoxamine maleate (Luvox, Faverin)
Paroxetine (Paxil, Seroxat, Aropax, Deroxat)
Sertraline (Zoloft, Lustral)

For couples having difficulties getting pregnant, the delay in conception may affect their baby's sex

In the study, published in the BMJ, researchers compared information on more than 5,000 Dutch women who gave birth between July 2001 and July 2003.
Among the 498 women who took longer than one year to get pregnant, the percentage of male babies was over 57 percent, compared with 51 percent among the women who took less time to get pregnant.

The proportions of X and Y chromosome bearing sperms in human semen are equal, but more boys than girls are born. Male embryos and fetuses have a greater risk of attrition in utero than their female counterparts, and therefore male excess is likely to be still larger at the time of conception. It remains unexplained, however, what is responsible, presumably at some point between insemination and conception, for the greater probability of Y bearing sperms fusing with the ovum.

Because for couples using fertility treatments in this study there was no link between time to pregnancy and the babyÂ’s sex, the authors arehypothesizingg that it is the fact that y bearing sperms may be better swimmers through thick cervical mucus. I would say interesting hypothesis but still untested.

Soy and fertility report

apparently soy contains a chemical that kills sperm

A natural chemical found in soy, tofu and legumes can potentially damage sperm and lower men's fertility, Reuters reports of new research from King's College London.

The plant chemical, genistein, mimics the effect of the female hormone estrogen and in turn affects sperm in laboratory mice. Tests in humans have shown an even stronger impact than in the rodents. Research leader Lynn Fraser found in lab tests that small amounts of genistein can cause human sperm to "burn out" and lose fertility, reports Reuters

check out the full article

Infertility Boosts Testicular Cancer Risk?


Interesting report from yahoo news

Compared to males in the general population, infertile men, or men with abnormal sperm counts, are 20 times more likely to develop testicular cancer, a new study finds.

It does make sense. Thats why i frequently recommend that patients with abnormal semen see a urologist

Korean cloning paper a fake?

The Associated Press reports that a doctor who provided human eggs for research by cloning pioneer Hwang Woo-suk said in a Thursday broadcast that the South Korean scientist admitted that most of the stem cells produced for a key research paper were faked.

Roh Sung-il, chairman of the board at Mizmedi Hospital, told KBS television that Hwang had agreed to ask the journal Science to withdraw the paper, published in June to international acclaim. Roh was one of the co-authors of the article that detailed how individual stem cell colonies were created for 11 patients through cloning.

Roh also told MBC television that Hwang had pressured a former scientist at his lab to fake data to make it look like there were 11 stem cell colonies.

Reuters also reports that

The daily newspaper Hankyoreh and three South Korean television networks quoted Roh Sung-il as saying that he, stem cell scientist Hwang Woo-suk and another co-author of the landmark 2005 Science paper on tailor-made stem cells had notified the journal that they were withdrawing the paper.

"Professor Hwang admitted to fabrication," Roh said in an appearance on MBC television. Roh, a specialist in fertility studies, was referring to a meeting he had with Hwang earlier in the day.

last minute

Another chapter in the Korean cloning saga

Another article appeared today questioning the work of Korean scientist Hwang Woo-suk. He is the head scientist of the group that recently reported the first ever clonig of a dog in a paper on the journal Nature.

The current debate stems from inconsistencies in the article published in the journal Science titled "Patient-specific embryonic stem cells derived from human SCNT blastocysts". In the publication the team claimed that it had established Eleven hESC lines by somatic cell nuclear transfer (SCNT) of skin cells from patients with disease or injury into donated oocytes. Basically this is what we call "Therapeutic Cloning". All the authors were from Korea with the exception of Dr. Schatten from the US . Dr. Schatten recently made a number of public statements with regards to breaches in ethical standards such as not disclosing the fact that some of the lab techs from Dr. Woo-suk lab donated the eggs .
This is the clear example of a situation in which if one lies (or fails to disclose) on any aspects of a research project (even on things that may be immaterial to the final results) the whole research project becomes vulnerable to criticism.

A Surrogate Dries Her Tears

Interesting article on yesterday's NYT. It's titled "A surrogate dries her tears" . But anybody who knows what surrogacy is would quickly figure out that what this woman did is not traditional surrogacy.
What she did is she got impregnated using donor sperm and HER OWN EGGS and subsequently gave the baby to a couple (they happened to be 2 gay men). So she basically GAVE HER OWN GENETIC BABY UP FOR ADOPTION.
No kidding she felt attachment to the baby! Everybody knows that the way to do this is to use donor eggs to create the embryos so that the surrogate is not carrying her own genetic child.
In any case the article is interesting and it points to a very good reference website called surromomsonline.com.

Does rest after intrauterine insemination help?

I was always doubtful of this and patient frequently ask me the question. So I did a little search and found this interesting article:

A randomized study of the effect of 10 minutes of bed rest after
intrauterine insemination

Objective: To evaluate the effects of 10
minutes of
bed rest after intrauterine insemination (IUI) on the pregnancy
rate.
Design: Prospective randomized study.

Intervention(s): Patients were
prospectively randomized
either to immediate mobilization after IUI (group
I) or to remain in a supine
position for 10 minutes after the procedure
(group II).

Main Outcome
Measure(s): Cumulative pregnancy rate.

Result(s): Ninety-five couples
were included in the analysis. Group
I consisted of 40 couples (90 cycles), and
group II consisted of 55 couples
(120 cycles). The pregnancy rate per couple in
group I (4 of 40 [10%]) was
significantly lower than in group II (16 of 55
[29%]). The pregnancy rate
per cycle in group I (4.4%) was also lower than in
group II (13.3%). With
use of life-table analysis, the cumulative probability of
pregnancy in group
II was significantly higher than in group I.

Conclusion(s): A 10-minute
interval of bed rest after IUI has a positive
effect on the pregnancy rate.

Although it is only one study it is pretty convincing . Additionally it does not seem much of a sacrifice to wait for an additional 10 minutes after having waited for 2 hours in the doctor's waiting room!

The Femara Scare (Now Resolved!)
(Read all way to bottom of article)

Femara (letrozole) has been widely used off label in the recent years for ovulation induction by fertility doctor nationwide.
News Media have been reporting that the

Swiss drug manufacturer Novartis is sending letters to fertility doctors worldwide to reiterate a warning that the drug should not be given to women who may be pregnant, said spokeswoman Kim Fox.

The U.S. label on the drug already warns that it has been associated with birth defects, but concerns arose when a researcher in Canada published a report noting cases where the drug had been given to pregnant women.

Here is the abstract of the report presented at the conference

[O-231] The Outcome Of 150 Babies Following The Treatment With Letrozole Or Letrozole And Gonadotropins.

M. M. Biljan, R. Hemmings, N. Brassard. Montreal Fertility Centre, Montreal, PQ, Canada; St'Mary's Hospital, Montreal, PQ, Canada; Université Laval, Québec, PQ, Canada

Objective: Letrozole is a medication widely used for secondary breast cancer prevention. Recently, this aromatase inhibitor has been used for ovulation induction. In this analysis we report the outcome of 150 babies born as a result of treatment with either letrozole alone or a combination of letrozole and gonadotropins at the Montreal Fertility Centre. Design: Retrospective analysis. Materials and Methods: This analysis includes patients with unexplained infertility and patients with polycystic ovarian disease. As a control group we used patients delivered at “St. Mary’s” hospital in Montreal between 1995 and 2004. The choice of the hospital was deliberate, as “St. Mary’s” hospital delivers mostly low risk babies. Results: During a period of 25 months 171 babies were born as a result of the use of letrozole or letrozole and gonadotropins. Twenty one babies were lost for follow-up. One hundred and fifty babies were compared with a data-base of normal deliveries containing 36,050 deliveries. The median age (M) of treated patients was 35.2 years (interquartile difference (IQD)= 31.4-37.9). We had 110 singleton and 20 twin pregnancies. All twin pregnancies apart of one were conceived following the treatment with letrozole and gonadotropins. The incidence of vaginal bleeding was 36.7% in the first trimester, 7.3% in the second trimester, and 1.3% in the third trimester. Seventy-seven non-diabetic singleton pregnancies were delivered at term. There was no difference in weight between this group and the control. Twenty patients had gestational diabetes. Seventeen patients with gestational diabetes delivered at term. When compared with controls these babies were of a significantly lower birth weight than controls (p<0.002 ci="11.3-136.6)." p="0.25" ci="0.78-4.71)." p="0.0005" ci="2.64-27.0)" p="0.0006" ci="3.30-58.1)">

Although this finding needs to be taken very seriously we need to review the data. this is only an abstract and it is not clear from the abstract what the specifics are about the cardiac and locomotor malformations. Also remember that this is a retrospective study.
I am a bit puzzled by the fact that it is known that Femara has a half life of 2 days so all of it should be out of the body by the time a pregnancy is established therefore there is no clear biological reason on why any effect should be seen .

A Follow Up to This study was announced in 2006 and reversed the findings

Concerns about the use of letrozole, an easy-to-use and inexpensive drug for the treatment of infertility, appear to be unfounded, according to a major study co-authored by Dr. Togas Tulandi, Director of the Division of Reproductive Endocrinology and Infertility, McGill University Health Centre (MUHC), Chief of Obstetrics and Gynecology at the Jewish General Hospital and professor of obstetrics and gynecology at McGill University. The findings, which are currently available in an early online edition of Fertility and Sterility, showed that babies whose mothers were treated with letrozole had the same rate of birth defects as those whose mothers were treated with clomiphene citrate — the low-risk, first-line treatment for infertility for more than 40 years.

"We found no statistically significant difference in the overall rates of major and minor malformations or chromosomal abnormalities between newborns in the two groups," says Dr. Tulandi. "Our findings indicate concerns about a link between letrozole and birth defects are unfounded. This is significant because it confirms that letrozole can indeed be used in the treatment of infertility without increasing risk to the fetus."

The study contradicts an earlier, much smaller study linking letrozole to increased rates of inherited malformations. This study led to widespread concern about the use of letrozole, a drug which has been widely used in the treatment of infertility in recent years.

"There were several methodological problems with the earlier study," says Dr. Tulandi. "For one thing, it compared the incidence of birth defects in children conceived spontaneously with that in children conceived through fertility treatments using letrozole. This is an apples-and-oranges comparison, because there are always fewer birth defects in children conceived spontaneously." The earlier study also compared different age groups between the control and treatment.

The new study, by Dr. Tulandi, Dr. Robert Casper from the Department of Obstetrics and Gynecology at the University of Toronto, and their co-authors examined a total of 911 babies whose mothers were treated for infertility with either letrozole or clomiphene citrate from 2001 to 2005. Five Canadian centres in Quebec and Ontario participated.
(adapted from Press Release)

Letrozole is currently back in my practice!

Yet another celebrity undergoing advanced fertility treatments!

People reported a couple of days ago that Angela Bassett (47) is expecting twins via a surrogate carrier.

"They are expecting twins via a surrogate," says a source close to the 47-year-old star of How Stella Got Her Groove Back and What's Love Got to Do With It.

The source adds: "The babies are due in a couple months."

A publicist for Bassett had no comment.

Now they are not commenting on the source of the oocytes but we can speculate that the source of the oocytes is from an oocyte donor. Obviously this is just speculation but at 47 twin pregnancy would be an extremely unusual event.
this is the typical example of a situation in which celebrities while (rightfully) trying to protect their privacy end up creating false expectations for the public. I would equate it to the statement " I did not have plastic surgery".

Disclaimer

What's the deal with this blog (PLUS A LITTLE DISCLAIMER)?

Every day (or whenever I am able to, given the fact that I work abut 20 hours a day) I will post articles relative to the world of infertility. These will be scientific articles or articles of general interest. The articles will contain comments edited by me.

The goal of this blog is to expand the knowledge of the readers in the area of infertility and advanced reproductive technologies.

Now here is the disclaimer: THE SELECTION OF ARTICLES AND LINKS ARE BASED ON MY PERSONAL OPINIONS AND SCIENTIFIC INTERESTS. IN NO WAY THIS IS MEANT TO BE MEDICAL ADVICE OF ANY KIND. SO IF YOU ARE SUFFERING FROM INFERTILITY I ADVISE YOU TO CONTACT YOUR DOCTOR.

Dr. Andrea Vidali


Andrea Vidali, M.D.
is a partner at American Fertility Services, P.C., which has locations in Manhattan and Hackensack, NJ. At each of these sites he oversees and performs advanced reproductive technologies. Dr. Vidali is also Director of the Reproductive Endocrinology and Infertility Division at Hackensack University Medical Center in Hackensack, NJ, and Director of the Reproductive Endocrinology and Infertility Division at Saint Vincents Catholic Medical Center in New York City. An accomplished laparoscopic surgeon, Dr. Vidali is also Director of the Advanced Laparoscopy Surgery Division at St. Vincents, where he routinely performs operations such as laparoscopic hysterectomy, laparoscopic myomectomy, and excision of severe endometriosis.

Since completing his medical degree at the University of Padova, Italy, Dr. Vidali has focused his career on male and female infertility, reproductive endocrinology, and advanced laparoscopic surgery. After medical school Dr. Vidali completed a two-year postdoctoral fellowship in molecular biology at the National Institute for Cancer Research in Italy. He completed his residency in obstetrics and gynecology at Georgetown University Hospital, in Washington, D.C., followed by a fellowship in reproductive endocrinology at Columbia University College of Physicians & Surgeons.

Dr. Vidali consults and lectures on infertility and in vitro fertilization (IVF) around the world. His research interests include endometriosis, laparoscopic aspects of infertility, and male infertility, in particular azoospermia. Collaborations with academic institutions in Europe and South America allow him to share his expertise with other physicians in the world of infertility. In Brazil, he has been awarded the title of Visiting Professor for his work in teaching laparoscopic surgery by the Hospital Das Clinicas, San Paulo. In Italy, Dr. Vidali collaborated with leading researchers to develop a new model for oocyte freezing.

Dr. Vidali is an active member of the American Society for Reproductive Medicine (ASRM), Society of Laparoendoscopic Surgeons (SLS), European Society of Human Reproduction and Embryology (ESHRE), International Society of Gynecological Endoscopy (ISGE), RESOLVE, and International Council on Infertility Information Dissemination (INCIID). He speaks fluent Italian, Spanish, and Portuguese.