The International Council on Infertility Information Dissemination, Inc

IVF Scholarships from INCIID

"From INCIID the Heart" IVF Scholarship

2019 Scholarships will be reviewed on a rolling basis as they are received each month.

The InterNational Council for Infertility Information Dissemination (INCIID -- pronounced “inside”) has the first and only national program designed to help individuals and couples -- From INCIID the Heart -- It provides an  In Vitro Fertilization (IVF) Scholarship to those in need through donations of funds and treatment from professional members, and consumers.    

 "Infertility care is sometimes portrayed as ‘wealthy couples creating designer babies. But nothing could be further from the truth".  The From INCIID the Heart is an important step in helping to eliminate the barrier preventing many couples from having children.

There are at least 6-7 million infertile couples in the U.S., and of those, approximately two million are unable to conceive without IVF treatment.  The majority have no insurance coverage for IVF and its associated medications, which can range in cost between $18,000 and $25,000 per couple. And  EMD Serono supports the program with donations of ovarian stimulation medications.
 
INCIID continues to gain support for the scholarship from a number of respected IVF clinics in the U.S. to donate their expertise and state-of-the-art facilities for patients who do not have the financial resources. Thes generous reproductive centers support the INCIID mission to help patients build families where they may not have the opportunity without help. The program will cover most of the basic expenses incurred during an IVF cycle.

Couples with financial and medical need may be eligible for participation in the program. The criteria are simple: No insurance covering IVF, Financial Need and Medical Infertility (as defined by the American Society for Reproductive Medicine - ASRM).  Final committee selections and decisions take cost-of-living in different regions of the country into account, applicants who may have student loan debt and a variety of other situations. Each application is processed based on an individual needs assessment.   INCIID required applicants provide copies of their most recent tax returns (2 years) and pay stubs (2 consecutive and most recent pay cycles), and supply a letter from their doctor recommending IVF as medically necessary. Selected recipients partner with INCIID in agreement to fundraise a small amount. 
Our goal is to give those without insurance coverage for IVF an opportunity to fulfill their dream of becoming parents.

For more information and to apply: READ the FAQ (Frequently Asked Questions) FIRST. Once you read the FAQ, download the application located at the end of the FAQ.

* All recipient/finalist cycles are subject to a final medical review and determination on whether the donated treatment is appropriate for the recipient. INCIID  may make changes in policies, procedures, offerings, and requirements at any time. The fundraising agreement in no way guarantees a cycle of IVF.

The application process is on-going. If you want to be considered for the program, please read the FAQ first and then send us your application. Applications are reviewed throughout the year. Before you apply: Please get the latest version of Adobe Reader.

INCIID is grateful to EMD Serono. for their support of this program.

The Role of Metformin in FSH-Treated Women with PCOS Summarized by Christine Schroeder, Ph.D.

Authors and Affiliations: Vincenzo De Leo, Antonio la Marca, Antonino Ditto, Giuseppe Morgante, and Antonio Cianci; Department of Obstetrics and Gynecology, Universities of Siena and Catania, Italy.

Journal: Fertility and Sterility, Volume 72, Number 2, pp. 282-285

Summarized by Christine M. Schroeder, Ph.D.

Polycystic ovarian syndrome (PCOS) is a common cause of menstrual disruption. PCOS is characterized by elevated androgen, insulin, and luteinizing hormone level. Patients also frequently present male pattern hair growth, with amenorrhea, and above-normal weight.

Patients with PCOS frequently experience infertility; additionally their cases can present a challenge to the fertility specialist. These individuals will often respond very slowly to stimulation and tend not to develop dominant follicles. As a result, these patients will often ultimately develop a large number of mature follicles and are at increased risk for hyperstimulation.

Metformin is a drug normally used to treat individuals with non-insulin dependent diabetes. It has multiple actions, including reduction of glucose production in the liver and increasing glucose uptake throughout the body. Metformin also decreases hyperinsulinism, reduces plasma levels of luteinizing hormone (LH), and reduces ovarian androgen production.

The insulin, androgen, and LH-related actions of metformin form the basis for its use for patients with PCOS. The normalization of these hormone levels addresses many of the underlying mechanisms of PCOS. As a result, patients should respond to ovarian stimulation in a more predictable and orderly fashion.

The current study examines whether metformin affects the response to FSH therapy among PCOS patients resistant to clomiphene citrate (CC). The researchers defined CC resistance as a failure to ovulate or conceive on CC dosages of up to 150 mg for three cycles or more. Study participants were 20 women with PCOS who had normal blood pressure, prolactin levels, thyroid function, and ACTH response. Patients were not screened for insulin resistance. All male partners had normal semen analyses, and none of the patients had taken ovulatory medications within two cycles of starting the study.

Participants were randomly assigned to two groups. In the first group ("F-M"), patients underwent two cycles of FSH treatment, then one cycle of metformin treatment, and another cycle of metformin and FSH treatment. The second group ("M-F") received metformin treatment for one cycle, followed by a cycle of metformin and FSH treatment. Thus, the structure of the study was as follows:

 

Group
Cycle One
Cycle Two
Cycle Three
Cycle Four
F-M
FSH only
FSH only
Metformin only
FSH + Metformin
M-F
-----
-----
Metformin only
FSH + Metformin

 

The treatment protocol began patients on one vial of urinary-derived FSH per day. The dosage was increased by one vial per day until detection of an ovarian response. The patient was then maintained on that dosage until the hCG shot was given. The criteria for administering the hCG shot were: (1) the presence of at least one follicle of 18 mm or greater and (2) no more than three follicles greater than or equal to 17 mm. The Metrodin dosage used was 500 mg three times daily.

A preliminary analysis of the results indicated that the two treatment groups did not differ in terms of age, infertility history, body mass index, or hormonal profiles.
In the first FSH-only cycle that the F-M group underwent, one of the patients conceived. A second patient conceived in the next cycle of FSH-only treatment. Therefore, only eight of the ten patients in the F-M group went on to take Metrodin, and the number of cycles analyzed for each of the protocols was:

 

  • FSH-only: 19 cycles (ten in the first F-M group's cycle, and nine in the second)
  • Metformin-FSH: 18 (ten from the M-F group's cycle, and eight from the Metformin-FSH cycle of the F-M group)

Because of the risk that PCOS patients have of responding too strongly to medications, the analyses focused not only the pregnancy rate, but also upon the number of follicles developed, the estradiol levels, and the incidence of cancelled cycles. The results indicated that:

 

  • The daily dose needed to cause a detectable ovarian response was similar in the FSH-only and FSH-Metrodin cycles
  • The estradiol level for the FSH-only cycles was significantly higher, 720 pg/mL versus 450 pg/mL
  • The number of follicles in the FSH-only cycles was significantly higher, 4.5 versus 2.5
  • The number of cycles cancelled due to too many follicles was 31.5% in the FSH-only cycles, compared to none in the FSH-Metformin cycle
  • The pregnancy rates per cycle were similar for both the FSH-only cycles (10.5%) and FSH-Metformin cycles (16.6%; not statistically significant)
  • The hyperstimulation after hCG rate was 26.3% for the FSH-only cycles and 16.6% for the FSH-Metformin cycles (not statistically significant)

 

The researchers concluded that metformin pretreatment appears to result in more orderly follicular growth in FSH-treated patients with PCOS. Additionally, because the patients were not screened for insulin resistance, the results are not specific to only insulin-resistant PCOS patients. Finally, the researchers also noted that metformin does not seem to have teratogenic effects, it is inexpensive, and has minimal side effects. Nonetheless, they recommend additional research involving a larger sample, so that the ideal metformin dosage and duration of treatment can be determined.
 

Note: These sample sizes were very small. With a larger sample, it is likely that the pregnancy and hyperstimulation rates between the two groups would have been significantly different.

Pregnancy Rates after Tubal Reversal

Authors and Affiliations: Tae Ki Yoon, Hae Ree Sung, Hyung Gon Kang, Sun Hee Cha, Chung No Lee, and Kwang Yul Cha; CHA General Hospital and Pochon CHA University (Seoul, Korea).

Journal: Fertility and Sterility, Volume 72, Number 6, pp. 1121-1126.

 

Summarized by Christine M. Schroeder, Ph.D.

Women who desire no additional children often elect to undergo tubal sterilization. Although tubal sterilization is a permanent and effective means of contraception, about one percent of women who undergo it will subsequently seek to have it reversed.

Tubal reversal is accomplished via microsurgical techniques and has traditionally been done via laparotomy Microsurgical instruments have improved sufficiently, however, that reversal can now often be accomplished via laparoscopy, which is less invasive and allows quicker recovery time. Reversal via laparoscopy, however, is more technically demanding and requires a higher level of surgical skill.

The purpose of the current study was to evaluate the outcome of tubal reversal in patients and determine which factors influenced post-reversal pregnancy rates. Participants were 202 women with a mean age of 35 years (ranging from 27 to 45), who had an average of 1.7 children prior to to undergoing sterilization. Sterilization had been accomplished in 100 patients via Fallope ring and via electrocautery in 53 cases, with the remainder of patients undergoing a variety of less common techniques. An average of 8.5 years elapsed between the time of the original surgery and the reversal, with a range of two to 21 years.

Prior to reversal, patients underwent:

  • Hysterosalpingogram
  • Pelvic ultrasound
  • Partner semen analysis
  • Diagnostic laparoscopy, if the method of sterilization was unknown

 

All procedures were set up so that, if accomplishing reversal via laparoscopy was determined to be non-feasible, the procedure could immediately be converted to laparotomy.
One hundred eighty-six patients were followed for a minimum of 12 months after surgery (the remainder were lost to follow-up), and analyses were conducted to examine the effects of the following variables on post-surgery pregnancy rates:

 

  • Original method of sterilization used
  • The location of the tube where reconstruction was carried out
  • Post-surgery tubal length
  • Whether other pelvic pathologies were discovered and removed during surgery
  • Whether one or both tubes were restored to function
  • The age of the patient at surgery

 

Ninety-eight of the 186 patients delivered healthy infants during the follow-up and 31 had ongoing pregnancies at the close of the study. Analyses of the above variables (which took all factors into account simultaneously) indicated two significant effects, age at surgery and whether one or two tubes were successfully repaired:

 

  • Among patients aged 25 to 29 years, the pregnancy rate was 100 percent; 30 to 34 years, 91.9 percent; 35 to 39 years, 79.5 percent; and 40 to 45 years, 70.6 percent.
  • Patients who only had one tube successfully reversed had a pregnancy rate of 60 percent, compared to 87 percent for patients who had both tubes successfully reversed.

 

Based on these results, the authors concluded that in the hands of a skilled and experienced surgeon, a laparoscopic approach to tubal reversal is an effective protocol. They also concluded that, in many cases, the success rates of tubal reversal are far superior to IVF (another treatment of choice for women with tubal sterilization who are now interested in fertility), suggesting that it may be a preferable approach for many patients, especially in view of the fact that tubal reversal does not carry the elevated risk of multiple pregnancy that IVF does.

FET without an GnRH Agonist

Article Title: A flexible protocol for artificial preparation of the endometrium without prior gonadotropin-releasing hormone agonist suppression in women with functioning ovaries undergoing frozen-thawed embryo transfer cycles.

Authors and Affiliations: Alex Simon, Arye Hurwitz, Murshid Pharhat, Ariel Revel, Bat-Sheva Zentner, and Neri Laufer; Department of Obstetrics and Gynecology, Hassadah University Hospital, Mount Scopus (Jerusalem, Israel).

Journal: Fertility and Sterility, Volume 71, Number 4, pp. 609-613.

 

Summarized by Christine M. Schroeder, Ph.D.

Advances in IVF technology and success rates have lead to increasing numbers of patients who have surplus embryos after a fresh IVF cycle. Most commonly, these embryos are cryopreserved for future use.

Patients who undergo transfer of frozen embryos are confronted by several protocol options. Regularly ovulating patients may choose to simply undergo spontaneous ovulation and then have the embryos transferred during the appropriate post-ovulatory time period. Patients with irregular cycles or anovulation, however, must often rely on a medicated frozen embryo transfer (FET) cycle. In these cases, several options are available, including the use Clomid or injectibles to bring about ovulation in the patients, after which appropriately-timed embryo transfer takes place. Like spontaneous unmedicated cycles, however, this protocol can be somewhat unpredictable and patients may have to skip cycles because the timing of ovulation was not as expected.

In an attempt to increase the predictability of FET cycles, many programs have experimented with using a GnRH agonist (e.g., Lupron) in their protocol, as patients using a GnRH agonist are far less likely to experience a spontaneous LH surge. Because of its increased predictability, medicated protocols using GnRH have increased in popularity. The cost and additional effort required by adding a GnRH agonist, as well as several studies questioning its necessity, however, have raise the question of whether it is possible to increase the predictability of a medicated FET cycle without using a GnRH agonist. The purpose of the current study was to investigate one such protocol.

Participants in the study were 140 patients undergoing a total of 185 FET cycles. The mean age of the patients was 30 years. Sixty-six percent of the patients were spontaneously ovulatory, but all had functioning ovaries that were capable of responding to stimulation. Embryos had been frozen between 42 and 72 hours after retrieval in the fresh IVF cycle, and ranged in size from two to eight cells.

 

All patients underwent a similar protocol:

  • Two milligrams of oral estrogen, three times per day, beginning on cycle day one and continuing for between 12 and 20 days (average=15 days).
  • The addition of oral micronized progesterone and vaginal progesterone when the endometrial thickness was eight mm or greater.
  • Transfer of embryos 48 to 72 hours after onset of progesterone supplementation.
  • Cancellation of the cycle if: (1) the endometrium failed to reach eight mm after 20 days of estrogen, (2) if serum progesterone was six nmol/L or greater on the seventh day of estrogen, or (3) if serum progesterone was six nmol/L or greater on the day that progesterone supplementation was to have begun.

 

Participants transferred an average of three embryos. Of the 185 cycles reviewed, eight were canceled - two because of premature elevation of progesterone levels and six because of inadequate endometrial thicknesses.

Analysis of the cycle results showed:

  • A pregnancy rate of 21.7 percent
  • A multiple (twins and triplets) pregnancy rate of 21 percent
  • An ongoing (second trimester) pregnancy rate of 17.7 percent
  • A per-embryo implantation rate of nine percent.

 

Based on these results, the authors concluded that, among patients with functioning ovaries, an FET protocol that does not use a GnRH agonist may be appropriate and effective.

Birthweight and Sex Ratio after Blastocyst Transfer

Article Title: "Birth weight and sex ratio after transfer at the blastocyst stage in humans"

Authors and Affiliations: Yves J.R. Ménénzo, Institut Rhonalpin, Fondation Marcel Mérieux, Bron, France; Jacques Chouteau, Clinique Belledone, Saint-Martin-d'Hères, France; M.J. Torelló, Institut Universitari Dexeus, Barcelona; Ann Girard, Clinique Belledone; and Anna Viega, Universitari Dexeus.

Journal: Fertility and Sterility, Volume 72, Number 2, pp.221-224.

 

Summarized by Christine M. Schroeder, Ph.D.

During selection of embryos for IVF transfer, preference is given to those that cleave more rapidly. In some mammals, research has shown that male embryos have higher initial cleavage rates than female embryos, and that male embryos are thus more likely to be the first to achieve the blastocyst stage. Therefore, it is possible that blastocyst selection procedures in IVF will lead to a higher than expected proportion of male blastocysts being transferred.

Additional research in animals has revealed a higher incidence of overweight males, some with abnormalities, when IVF is used in conjunction with co-culture. It is not clear, however, whether either the potential sex ratio difference or the incidence of overweight males applies to the human population.

The current study examined both the birth weight and the sex ratio of infants who were born after the use of blastocyst transfer. Patients came from three IVF centers, and the infants studied were from three groups1:

  1. The fresh transfer group: Infants who were born following fresh blastocyst transfer with coculture
  2. The frozen transfer group: Infants born following frozen blastocyst transfer
  3. The comparison group: Infants born after spontaneous conception at a university hospital over a seventeen month period

 

The results indicated that:

 

  • The fresh blastocyst group had a significantly higher proportion of males (58.3 percent) than females (41.3 percent)
  • The frozen transfer blastocyst group did not have significantly different proportions of males (51.9 percent) and females (48.1 percent)
  • Male babies in the fresh transfer group had an average birth weight of 2,788 grams, compared to a significantly higher average weight of 3,218 grams in the comparison group (see however, the note regarding birth weight measures at the end of the summary)
  • Male babies in the frozen transfer group also had an average birth weight (3,040 grams) significantly lower than that of the comparison group

 

The researchers concluded that human male embryos do indeed cleave more rapidly in the preimplantation stage than female embryos. As a result, they reach the blastocyst stage sooner and are more likely to be selected for fresh transfer. In contrast, frozen blastocysts transfers were not subject to the same selection criteria - embryos that are frozen general are generally slower-growing and are not subject to the same selection criteria as fresh transfer. As a result, births resulting from frozen transfers did not have a sex ratio significantly different from the spontaneously conceived control group. Finally, blastocyst co-culture does not seem to have the same negative effects in humans that they do in some mammals.

 

Note: This study is interesting, but I think the authors neglected one important factor. The mean birth weights that were analyzed are a combination of babies from both single and multiple pregnancies. Although there is no mention of the fact, it would be reasonable to assume that there was a higher rate of multiple pregnancies in one or both of the blastocyst groups. Since babies from multiple pregnancies usually weigh less than singletons, the higher proportions of multiples in the blastocyst groups very well might have dragged down the average weight of the entire group.
Looking at the average weights they listed for singleton-only pregnancies convinced me even further that the differences might be related to multiples. Among male babies born as singletons, the average weight for the fresh transfer group was 3,191 grams, the average weight for the frozen transfer group was 3,333 grams, and the average weight for the comparison group was 3,308 grams. It is doubtful that these differences would be statistically significant. A similar pattern was also found for female singleton babies.

 


1 There was also a group of infants born after use of sequential media, but the group was much smaller and did not offer the same statistic power for analyses. The analyses of this group were presented in the paper, but are not included in this summary.
 

Your Fertility Your Environment by Shanna H. Swan, Ph.D.

Fertility, the ability of people to produce offspring, was a concept formerly applied only to the female. For example, demographers traditionally defined the fertility rate as the average number of live-born children per woman of reproductive age. However, fertility is one of the few measures that reflect the joint health of two individuals, and we have only recently begun to appreciate the extent to which fertility depends on the health and environment of both the male and female partner, as well as the interaction between partners. Males appear to be solely responsible for infertility in about 20% of infertile couples and contribute to infertility in another 30-40% (Thonneau 1991).

 

Using the demographic definition above, fertility declined 50% worldwide between 1950 and 2000 (Glebatis 1981). Between 1976 and 1998, the percent of women in the United States aged 35-39 who were childless increased from 10.5% to 19.8% (United Nations Populations Information Network 2002). Moreover, the number of annual office visits for infertility increased from 600,000 to 2 million between 1968 and 1990 (Seibel 1997). Recent data from Denmark show a significant decline in teen pregnancies (Jensen 2002) which, the authors argue, reflects a decrease in fecundity. While these data indicate that fertility, at least by the demographers' definition, has declined, they do not answer the following critical question; Are a woman and her partner who desire pregnancy less able to conceive today than a comparable couple of the same age 50 years ago? They also do not address causes of the decline and, in particular, the role of environmental factors which is the focus of this discussion.

 

These trends undoubtedly reflect, at least in part, changes in non-environmental factors that affect a couple's ability and/or desire to conceive. For example, women and their partners may choose to delay childbearing resulting in decreased fertility when their first pregnancy attempt occurs at an older age. Couples may also make life style choices to decrease family size, or not bear children at all. These non-environmental factors, some of which are listed in Table 1, are very difficult to quantify.

 

TABLE 1: NON-ENVIRONMENTAL FACTORS THAT MAY INFLUENCE TRENDS IN FERTILITY 

* Women's education and increasing role in the workforce
* Availability, affordability, attitudes towards and education concerning contraception
* Availability, affordability and attitudes towards assisted reproduction
* A woman or couple's decision to remain childless or to limit population size
* A woman or couple's decision to delay childbearing
* Sexually transmitted diseases 
* Changing attitudes towards marriage, sexual behavior and family size
* Changing attitudes towards elective pregnancy termination
* Decreasing age at which premature infants can survive

 

All of these factors may vary both geographically and temporally, as well as within ethnic/racial groups. Moreover, they are interrelated in complex ways. Several more useful measures of "fertility potential" are available. Fecundity (or fecundability) has been defined as, "the monthly probability of conception in the absence of contraception outside the gestation period and the temporary sterile period following the termination of a pregnancy" (United Nations Populations Information Network 2002). The National Center for Health Statistics uses a measure of decreased fecundity, "impaired fecundity", which they define as a woman's inability to conceive or bear a child to term. The number of cycles of unprotected intercourse without conception, or "time-to-pregnancy" (TTP) is another useful measure and infertility is often diagnosed when TTP exceed 12 months (or cycles).

Changes in fecundity and impaired fecundity in the US have been examined by comparing responses to the National Survey for Family Growth (NSFG) in 1982, 1988 and 1995 (Chandra 1998). This analysis found increases in impaired fecundity over that time period and the authors suggested that this change was due to more couples voluntarily delaying child-bearing. We questioned that interpretation, however, since the greatest increase in impaired fecundity was seen in women under 25, precisely the age group in which subfecundity, because of delayed childbearing, would be least likely (Swan 1999). These data suggest that, at least in the US, fecundity declined between 1982 and 1995. Limited data have recently become available from the sixth cycle of the NSFG (Ventura 2004). However, data on live birth rates between 1990 and 2000 suggest a reversal of the decline seen in previous reports. This reversal is seen across race/ethnic groups and for most age groups. Data on impaired fecundity, perhaps the most relevant statistics for assessing trends in involuntary subfertility, are not yet available but are expected later in 2004. On balance, the limited data available do not allow us to draw any conclusions about trends in fecundity.
 

Since it is so difficult to draw conclusions about trends in fecundity and environmental causes, researchers have examined trends in reproductive parameters which are easier to measure in the hope that these will shed light on the larger problem of fecundity. Trends in sperm counts have been the most widely studied to date. This brief discussion of sperm count decline provides a "case study" of how studies of temporal and geographical variation in a reproductive parameter may give us clues to causes of impaired fecundity.

 

 

Sperm count and fertility

Evaluation of a man's semen quality is an important component of an infertility workup. How strong is the connection between semen quality and fertility? There is no doubt that severely impaired semen quality impairs fecundity, and there is now new evidence that reduced sperm count, even in apparently healthy men, can affect fertility. For example, two studies (Bonde 1998, Zinaman 1996) found that couples stopping contraception in order to become pregnant had a reduced probability of conceiving in the first six months of trying when sperm concentration was low (less than 40 x 106/ml). However, since fecundity is a function of the fertility and sexual function of the couple, sperm concentration may well decline without an accompanying decrease in fertility on the population level if, for example, female fertility increased over the same period.
 
A great deal of research has been conducted on factors affecting semen quality in part because of its link to fecundity. Reduced sperm counts can be caused by a range of factors including genetics, infectious agents (e.g. mumps) and anatomic abnormalities. However, environmental causes have been of primary concern since 1992 when a group of Danish researchers concluded that over the average, sperm count in normal men had declined 1% per year during the past 50 years, and postulated that "environmental influences, particularly compounds with 'estrogen-like activity'" may be responsible (Carlsen 1992). This controversial study produced considerable debate and led us to conduct a reanalysis of the 61 studies (Swan 1997). We concluded that, at least statistically, trends differed geographically and while the average sperm count in the US and Europe had declined significantly, there were not sufficient data to draw any conclusions about other areas. This issue is still controversial and is likely to remain so since historical data are necessarily subject to uncertainty and potential bias.
 
Even if we assume that semen quality has declined, these trend studies do not address the question of whether environmental chemicals can (or have) reduced semen quality. This question was first examined in the workplace, where exposures are usually far higher than those encountered environmentally. There is a large body of literature demonstrating strong relationships between work place exposures and decreases in semen quality and other factors that can affect a couples' fertility. For example, widespread concern was generated in the late 1970's, following reports of sterility and decreased sperm counts in workers exposed to the agricultural nematocide DBCP(Thrupp 1991, Goldsmith 1997, Slutsky 1999). The chlorinated hydrocarbon pesticide chlordecone (kepone) was withdrawn because of its severe effects on semen quality (Faroon 1995). Ethylene dibromide (EDB) was an active component of approximately 100 pesticides. Its use was severely restricted in 1984 due to reduced sperm counts and semen quality (Whorton 1981, Schrader 1988). For a more complete treatment, see Schettler et al Generations at Risk (1999).
 
More recently, adult exposure to several pollutants at low environmental levels have been linked to reduced semen quality. If these exposures have increased over time, these could, in principal, contribute to the reported declines in sperm concentration. For example, after we saw significantly poorer semen quality in men living in agricultural mid-Missouri compared to men living in urban centers, (Swan 2003a) we examined metabolite levels in the men's urine. We found several (alachlor, atrazine and diazinon particularly) to be linked to poor semen quality (Swan 2003b). A range of other low-level environmental exposures have been linked to impaired semen quality including phthalates (Duty 2003), PCBs and DDT (Hauser 2003), maternal smoking (Jensen 2004), water chlorination by-products (Fenster 2003) and air pollution (Evenson 2004).
 
Does it follow that men (or couples) exposed to these environmental chemicals have impaired fecundity? Among Danish couples attempting to conceive for the first time, men whose initial sperm concentration was less than 40 x 106/ml had significantly reduced fecundability and took longer to conceive (Bonde 1998). In mid-Missouri, sperm concentration of 35% of fertile men fell below 40 x 106/ml, a point below which fecundity decreases significantly. Among men living in central Minneapolis, only 19% fell below this cut-off. Since poor semen quality in these men was linked to pesticide exposure, it is plausible -though far from proven- that these chemicals can impair human fecundity.
 
We cannot, however, conclude that a decrease in sperm count directly implies a decrease in fecundity on a population level. Even if semen quality is declining there may be no net decrease in couple fecundity. For example, if couples trying to conceive are better educated (such as through the use of home kits to detect ovulation) this will tend to increase conception success. Increased female fertility, for example, as a result of the declining incidence of sexually transmitted disease, which has occurred in the United States since 1980 (CDC 2000), will also increase couple fecundity.
 

Reproductive factors in the female

Measures of female fertility are more difficult to quantify. For example, a measure analogous to sperm count, ovarian follicular number, is extremely difficult to ascertain even with ultrasound. Thus, this endpoint has been rarely studied. However, failure to conceive may be the reflection of a hidden increase of early pregnancy loss. Several studies have examined early loss and it has been estimated to occur in 20% to 70% of pregnancies (Hakim 1995). Since a marker for early loss must be ascertained in urine samples collected soon after conception, this too is logistically difficult and few studies have related this endpoint to environmental exposures. Endometriosis is a fertility-related endpoint that has been examined with respect to some environmental exposures, notably dioxin. However, human data on this association are conflicting. Alterations in menstrual function, such as short follicular phase, may also contribute to impaired fecundity. These studies are also quite difficult since they require prospective collection of daily urine samples and extensive hormonal analysis. For these reasons, there are far fewer studies of environmental causes of impaired female factors than male. However, it should be noted that many environmental agents that have been shown to adversely effect male fertility have also been related to impaired female reproductive function when that has been examined. Notable examples include; cigarette smoke, radiation, lead, ethylene glycol ethers and water chlorination by-products (total trihalomethane).

 
Factors that may alter a couples' fertility

While we have focused here on environmental exposures, a wide range of environmental, infectious, endocrine, life style and genetic factors may play a role in infertility. These factors may result in a range of clinical endpoints including which can include fetal loss (both subclinical and clinical), menstrual dysfunction, endometriosis, uterine fibroids, and hormonal irregularities. Clearly, a full discussion of all factors and their influence on each of these endpoints is beyond the scope of this brief discussion. However, several general comments may be helpful.
 
Exposure to factors that can alter fertility may occur at any time from gestation to adulthood. While the fetal period has been shown to be the most sensitive for a range of exposures, an adult attempting conception has no control over these. Adults today carry an enormous body burden of chemicals of which we are likely unaware, since these exposures are "invisible" except by examining levels in human samples (such as blood and urine). In a study led by Mount Sinai School of Medicine in New York, in collaboration with the Environmental Working Group and Commonweal, researchers at two major laboratories found an average of 91 industrial compounds, pollutants, and other chemicals in the blood and urine of nine volunteers, with a total of 167 chemicals found in the group (http://www.ewg.org/reports/bodyburden/). Like most of us, the people tested do not work with chemicals on the job and do not live near an industrial facility.
 
While it is not possible to provide full toxicological profiles of the chemicals found to be prevalent today, an overview of the contaminants tested and found most frequently in the Mt. Sinai survey may be useful. PCBs, which were used as industrial insulators and lubricants prior to being banned in the US in 1976, persist for decades in the environment and accumulate up the food chain, to man. A recent study (Hauser 2003) found PCBs to be associated with reduced semen quality. There are 210 different dioxins and furans, which are by-products of PVC production, industrial bleaching, and incineration. These chemicals can also persist for decades in the environment and are found in air, water, soil and food. Dioxins are developmental toxicants affecting the developing endocrine (hormone) system. For example, a significant deficit of male babies was reported among couples exposed to high levels of dioxin (Mocarelli 1996).
 
Organochlorine pesticides (such as DDT and chlordane) also accumulate up the food chain to man and have been shown to cause cancer and numerous reproductive effects. There are a range of organophosphate insecticide metabolites, such as breakdown products of chlorpyrifos and malathion which are potent nervous system toxicants found most commonly as residues in food. Metals, including lead, mercury, arsenic and cadmium have long been shown to cause lowered IQ, developmental delays, behavioral disorders and cancer at doses found in the environment. For lead, most exposures are from lead paint. For mercury, most exposures are from canned tuna. For arsenic, most exposures are from arsenic (CCA) treated lumber and contaminated drinking water. For cadmium, sources of exposure include pigments and bakeware. Phthalates, plasticizers found in a wide range of cosmetic and personal care products, have recently been shown to be associated with reduced semen quality (Duty 2003) and in animal models cause birth defects of male reproductive organs.
Unfortunately, we cannot reduce our body burden of past exposures, most of which persist in the body for decades. Work place exposures, which may be avoidable, can be far higher, and it is in those settings that we have learned much of what we know about human reproductive risks. Workers, particularly those attempting to conceive, should be provided with full information on the reproductive risks of the agents with which they are working. If economics permit, it would be prudent for those of reproductive age to avoid occupational exposure to reproductive toxins.
 
Setting aside fetal and childhood exposures and occupational setting exposures, we are left with exposure to currently used chemicals in the home, the workplace and the surrounding environments. The routes of these exposures (ie water, air, food, skin) are limited. There are steps that one can take to limit exposure via each of these routes. There are several non-governmental organizations that have produced excellent web-based facts sheets for consumers that provide practical information based on good science. These are provided in the

 
What should a concerned couple do in the face of uncertain risks?

The Children's Environmental Health Coalition has complied a check list entitled "Protecting Your Baby from Environmental Toxins During Pregnancy" (http://ecomall.com/greenshopping/checbaby.htm) that recommends limits on certain exposures in our food, air, water and homes. Few of the exposures have been definitively shown to impair fecundity in humans. Nonetheless, it would be prudent for a couple attempting pregnancy to limit their exposure to as many of these as possible. This precautionary action makes sense on several levels. First, while the evidence in humans is absent or weak for many exposures, the animal data is much stronger, and toxicology has traditionally been used as an early step in identifying human risk. Without animal testing we would, for example, have few of the drugs and vaccines we rely on. Second, reducing risk while attempting conception will also limit risk during early fetal development, the most sensitive period, if conception is achieved. Third, the recommendations for decreasing toxic exposures will, at worst, have little effect on health; they are not harmful. Finally, most of the steps to reduce risk are simple and relatively inexpensive.
 

 

APPENDIX

 

Web-based Resources

Food: Food News, an affiliate of the Environmental Working Group (EWG) has compiled a Shoppers Guide for Pesticide in Produce. The report suggests substituting organic for conventional produce that is consistently contaminated with pesticides and, when organic products are not a choice, to consume fruits and vegetables with consistently low pesticide loads (http://www.foodnews.org/walletguide.php). 
Water: The EWG has conducted an extensive survey of drinking water sources by state and compiled the Clean Water Report Card (that will help consumers evaluate the quality of their own drinking water (http://www.ewg.org/reports/reportcard/home.html))
Personal care products: The EWG has conducted an extensive, chemical-by-chemical evaluation of personal care products called Skin Deep (http://www.ewg.org/reports/skindeep). 
Fish consumption: A report with a pocket size shopping guide on contaminants in fish, Healthy Fish, Healthy Families has been compiled Physicians for Social Responsibility (http://www.mercuryaction.org/fish). 
General information on fertility and the environment: 
An excellent overview, Infertility and Related Reproductive Disorders by Ted Schettler includes an excellent discussion of the role of the environment (http://www.protectingourhealth.org/newscience/infertility/2003-04peerrev...).
The Collaborative for Health and the Environment (CHE) maintains a web page that provides accurate and timely information on infertility (http://www.protectingourhealth.org/newscience/infertility/infertilitykno...) and more general information on environment and health www.protectingourhealth.org.

 

References

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* Carlsen, E., Giwercman, A., Keiding, N., & Skakkebaek, N. E. (1992). Evidence for decreasing quality of semen during past 50 years. BMJ (Clinical Research Ed.), 305, 609-613.
* Centers for Disease Control and Prevention (2001). Tracking the hidden epidemics : trends in STDs in the United States 2000. Atlanta, GA: Centers for Disease Control and Prevention.
* Chandra, A. & Stephen, E. H. (1998). Impaired fecundity in the United States: 1982-1995. Family Planning Perspectives, 30, 34-42.
* Duty, S. M., Silva, M. J., Barr, D. B., Brock, J. W., Ryan, L., Chen, Z. et al. (2003). Phthalate exposure and human semen parameters . Epidemiology, 14, 269-277.
* Evenson, D. P., Jost, L. K., Perreault, S. D., Selevan, S. G., & Rubes, J. (2001). Application of the sperm chromatin structure assay to the Teplice Program semen studies: a new method for evaluating sperm nuclear chromatin damage. In Sram, R. J. (Ed.), Teplice program: impact of air pollution on human health (pp. 167-180). Prague: Academia.
* Faroon, O., Kueberuwa, S., Smith, L., & Derosa, C. (1995). ATSDR evaluation of health effects of chemicals. II. Mirex and chlordecone: health effects, toxicokinetics, human exposure, and environmental fate. Toxicology and Industrial Health, 11, 1-203.
* Fenster, L., Waller, K., Windham, G., Henneman, T., Anderson, M., Mendola, P. et al. (2003). Trihalomethane levels in home tap water and semen quality. Epidemiology, 14, 650-658.
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* Jensen, T. K., Jorgensen, N., Punab, M., Haugen, T. B., Suominen, J., Zilaitiene, B. et al. (2004). Association of in utero exposure to maternal smoking with reduced semen quality and testis size in adulthood: a cross-sectional study of 1,770 young men from the general population in five European countries. American Journal of Epidemiology, 159, 49-58.
* Mocarelli, P., Brambilla, P., Gerthoux, P. M., Patterson, D. G. J., & Needham, L. L. (1996). Change in sex ratio with exposure to dioxin. Lancet, 348, 409.
* Schettler, T., Solomon G., Valenti, M., & Huddle, A. (1999). Generations at risk: reproductive health and the environment. Cambridge, MA: MIT Press.
* Schrader SM, Turner TW, & Ratcliffe JM (1988). The effects of ethylene dibromide on semen quality: a comparison of short-term and chronic exposure. Reproductive Toxicology, 2, 191-198.
* Seibel, M. M. (1997). Infertility: a comprehensive text. In Seibel, M. M. (Ed.), Diagnostic evaluation of an infertile couple (pp. 3-28). Stamford, CT: Appleton & Lange.
* Slutsky, M., Levin, J. L., & Levy, B. S. (1999). Azoospermia and oligospermia among a large cohort of DBCP applicators in 12 countries. International Journal of Occupational & Environmental Health, 5, 116-122.
* Swan, S. H., Elkin, E. P., & Fenster, L. (1997). Have sperm densities declined? A reanalysis of global trend data. Environmental Health Perspectives, 105, 1228-1232.
* Swan, S. H. & Hertz-Picciotto, I. (1999). Reasons for infecundity. Family Planning Perspectives, 31, 156-157.
* Swan, S. H., Kruse, R. L., Liu, F., Barr, D. B., Drobnis, E. Z., Redmon, J. B. et al. (2003a). Semen quality in relation to biomarkers of pesticide exposure. Environmental Health Perspectives, 111, 1478-1484.
* Swan, S. H., Brazil, C., Drobnis, E. Z., Liu, F., Kruse, R. L., Hatch, M. et al. (2003b). Geographic differences in semen quality of fertile U.S. males. Environmental Health Perspectives, 111, 414-420.
* Thonneau, P. & Spira, A. (1991). Prevalence of infertility: international data and problems of measurement. European Journal of Obstetrics, Gynecology, and Reproductive Biology, 38, 43-52.
* Thrupp, L. A. (1991). Sterilization of workers from pesticide exposure: the causes and consequences of DBCP-induced damage in Costa Rica and beyond. International Journal of Health Services, 21, 731-757.
* United Nations Population Information Network (POPIN) dictionary of demographic and reproductive health terminology (1990). Retrieved March 29, 2002, from http://www.un.org/popin/
* Ventura, S. J., Abma, J. C., Mosher, W. D., & Henshaw, S. (2004). Estimated pregnancy rates for the United States, 1990-2000: an update. National Vital Statistics Report, 52, 1-9.
* Whorton, D. (1981). The effect of occupation on male reproductive function. In Spira, A. & Jouannet, P. (Eds.), Human fertility factors (pp. 339-348). Paris: Editions INSERM.
* Wilcox, A. J., Weinberg, C. R., O'Connor, J. F., Baird, D. D., Schlatterer, J. P., Canfield, R. E. et al. (1988). Incidence of early loss of pregnancy. The New England Journal of Medicine, 319, 189-194.
* Windham, G. C., Waller, K., Anderson, M., Fenster, L., Mendola, P., & Swan, S. (2003). Chlorination by-products in drinking water and menstrual cycle function. Environmental Health Perspectives, 111, 935-941.
* Zinaman, M. J., Brown, C. C., Selevan, S. G., & Clegg, E. D. (2000). Semen quality and human fertility: a prospective study with healthy couples. Journal of Andrology, 21, 145-153.

Rocket Fuel Masculinizes Fish

Rocket fuel masculinizes fish

 

A contaminant widely found across the U.S. turns female fish into males.

 

 

Researchers have found that perchlorate, a component of rocket fuel, interferes with the endocrine systems of fish. A study published in Environmental Toxicology and Chemistry reports that the chemical affected the sexual development of the threespine stickleback, a common lab fish.

The female fish exposed to perchlorate produced both male and female sexual organs and began behaving like their brethren. The females’ male organs even produced sperm that were capable of fertilization, although the embryos later died.

The doses used in the study were well above what has been found in the environment, but researchers say the study shows that the chemical may be having effects that have not yet been examined. Earlier studies have shown that perchlorate interferes with thyroid hormone production.

For more than a decade, the U.S. EPA has been studying safe exposure standards for perchlorate. Beginning in the 1940s, tons of the chemical were disposed of at military sites across the U.S., where it seeped into groundwater and has since been found in milk. EPA set a reference dose in January 2005, after a National Academies of Sciences report, that temporarily serves as the measure for safe drinking-water levels.

 
doi: 10.1897/05-454R.1
Environmental Toxicology and Chemistry: No. 25, pp. 2087–2096.

 

doi: 10.1897/05-454R.1
Environmental Toxicology and Chemistry: Vol. 25, No. 8, pp. 2087–2096.

PERCHLORATE INDUCES HERMAPHRODITISM IN THREESPINE STICKLEBACKS

Richard R. Bernhardt,1 Frank A. von Hippel,1 and William A. Cresko2

 

1. Department of Biological Sciences, University of Alaska Anchorage, 3211 Providence Drive, Anchorage, Alaska 99508-4614, USA 2. Center for Ecology and Evolutionary Biology, University of Oregon, Eugene, Oregon 97403, USA

(Received 2 August 2005; Accepted 9 January 2006)

Abstract–Recently, concern regarding perchlorate contamination has arisen in many contexts. Perchlorate has many military, commercial, and domestic applications, and it has been found in milk, drinking and irrigation water, and produce. Perchlorate is harmful at low levels, yet it remains unregulated in the United States while the U.S. Environmental Protection Agency attempts to establish acceptable exposure levels. The present study investigated potential reproductive effects on vertebrates using a model fish species, the threespine stickleback (Gasterosteus aculeatus). Sticklebacks were raised from syngamy through sexual maturity in untreated water and in three target concentrations of sodium perchlorate–treated water. Perchlorate was found to interfere with the expression of nuptial coloration, courtship behavior, and normal sexual development. Genetic testing revealed that some females were masculinized to the extent that they produced both sperm and eggs, and histological analysis showed that these individuals had intersexual gonads (ovotestes) containing both oocytes and cells undergoing spermatogenesis. In vitro fertilizations revealed that those gametes were capable of self- and cross-fertilization. However, crosses using sperm derived from genetic females died either during the blastula phase or near the onset of organogenesis. Sperm derived from genetic males produced viable fry when crossed with eggs derived from genetic females from all treatments. To our knowledge, the present study provides the first evidence that perchlorate produces androgenic effects and is capable of inducing functional hermaphroditism in a nonhermaphroditic vertebrate.

Keywords–––Perchlorate     Hermaphroditism     Threespine stickleback     Gasterosteus aculeatus     Endocrine disruption

Premature Maturity

From the New York Times

 
October 17, 2006

 

Preschool Puberty, and a Search for the Causes 
 

By DARSHAK M. SANGHAVI

 

 

Parents often think their children grow up too quickly, but few are prepared for the problem that Dr. Michael Dedekian and his colleagues at the University of Massachusetts Medical School reported recently.

At the annual Pediatric Academic Society meeting in May in San Francisco, they presented a report that described how a preschool-age girl, and then her kindergarten-age brother, mysteriously began growing pubic hair. These cases were not isolated; in 2004, pediatric endocrinologists from San Diego reported a similar cluster of five children.

It turns out that there have been clusters of cases in which children have prematurely developed signs of puberty, outbreaks similar to epidemics of influenza or environmental poisonings. In 1979, the medical journal The Lancet described an outbreak of breast enlargement among hundreds of Italian schoolchildren, probably caused by estrogen contamination of beef and poultry. Similar epidemics in Puerto Rico and Haiti were tracked by the Centers for Disease Control and Prevention in the 1980’s.

Increasingly — though the science is still far from definitive and the precise number of such cases is highly speculative — some physicians worry that children are at higher risk of early puberty as a result of the increasing prevalence of certain drugs, cosmetics and environmental contaminants, called “endocrine disruptors,” that can cause breast growth, pubic hair development and other symptoms of puberty.

Most commonly, outbreaks of puberty in children are traced to accidental drug exposures from products that are used incorrectly. Dr. Dedekian’s first patient was evaluated for possible genetic endocrine problems and a rare brain tumor before the cause of her puberty was discovered. It turned out that her testosterone level was almost 100 times normal, in the range of an adult man. The same problem affected her brother.

The doctors realized that the girl’s father was using a concentrated testosterone skin cream bought from an Internet compounding pharmacy for cosmetic and sexual performance purposes. From normal skin contact with their father, the children absorbed the testosterone, which caused pubic hair growth and genital enlargement. The boy, in particular, also developed some aggressive behavior problems.

Sex hormones are potent because they are easily absorbed through the skin and resist degradation better than many other hormones. Unlike protein-based hormones like insulin, sex hormones like testosterone and estrogen are technically steroids, meaning they are derived from cholesterol.

Primarily made by the liver, cholesterol begins with tiny pieces of sugar that are joined, twisted and oxidized in a dizzying series to make an end product that resembles the interlinked rings of the Olympic emblem. Dr. Joseph L. Goldstein, Nobel Laureate and a biochemist in Texas, once called it “the most highly decorated small molecule in biology,” because 13 Nobel Prizes have been awarded for its study.

Through further processing, primarily in the gonads and adrenal glands, cholesterol is converted into sex hormones like estrogen and testosterone. Kenneth Lee Jones, the former chief of pediatrics at the University of California, San Diego, noted pediatric cases similar to those described by Dr. Dedekian in a 2004 report in the journal Pediatrics.

At that time, unregulated “prohormones” like Andro, famously used by Mark McGwire, the former St. Louis Cardinals power hitter, and banned by federal law in 2005, were available as topical sprays used to enhance libido. Dr. Jones said the sprays used by adults in some households permeated the children’s bedsheets, and the early puberty stopped only when the adults stopped using the sprays and also discarded old sheets.

Testosterone-containing products are not the only trigger of disordered puberty in children.

In a 1998 paper in the journal Clinical Pediatrics, Dr. Chandra Tiwary, the former chief of pediatric endocrinology at Brook Army Medical Center in Texas, reported an outbreak of early breast development in four young African-American girls who used shampoos that contained estrogen and placental extract. The early puberty reversed once the shampoo was stopped.

In the tradition of previous physicians who deliberately exposed themselves to possible pathogens, Dr. Tiwary tried the shampoos on himself. He carefully measured his own levels of various male and female sex hormones to establish his baseline, used the shampoos for a few days, then repeated the tests.

While Dr. Tiwary is quick to admit that his unpublished findings must be interpreted with great caution, some of his sex hormone levels changed by almost 40 percent after he used the shampoos. In some cases, substances other than sex steroids may also disrupt normal sexual development. In Boston at the annual Endocrine Society meeting in June, Clifford Bloch of the University of Colorado School of Medicine presented several cases of young men who had developed marked breast enlargement from using shampoos containing lavender and tea tree oils, which are widely used essential oil additives that present no problem for adults. (Unlike Dr. Dedekian’s cases, these cases were not a result of passive transfer from parents. The boys themselves used the shampoos.)

Dr. Bloch collaborated with scientists at the National Institute of Environmental Health Sciences in North Carolina to test the oils on human breast cells grown in test tubes. Lavender and tea tree oil had the same effect on the cells as estrogen.

Dr. Bloch speculates that the findings, which he is submitting for publication in a peer-reviewed journal, may explain the boys’ breast growth. He noted, however, that cells in a test tube are a far cry from humans, so the relationship of the essential oil to breast growth remains hypothetical.

While pediatric endocrinologists have implicated pharmaceutical or personal care products for causing pubertal problems in children, some environmental scientists also claim that some widespread industrial and pharmaceutical pollutants harm the normal sexual development of fish and animals. By extension, they may also contribute to earlier or disrupted puberty in children, these scientists contend. Robert Havelock, a senior reproductive toxicologist at the Environmental Protection Agency, said these concerns “caused a shift in worry from cancer to noncancer” effects of environmental pollution over the past decade.

In 1994, scientists found that estrogen-like chemicals from plastics manufacturing plants that had contaminated sewers in England caused genetically male fish to develop into females. In the early 1980’s, major spills of the DDT-like pesticide dicofol in Florida led to the “feminization” of the reproductive tracts of male alligators.

Robert Cooper, the chief of endocrinology at the reproductive toxicology division of the Environmental Protection Agency, says various sources of endocrine disruptors, like manufacturing chemicals, may be leaching into the environment. While their relation to pubertal problems in children remains highly speculative, he believes further study is needed.

Past epidemiological evidence, however, does worry Dr. Cooper, because some chemical exposures have been associated with early puberty. In 1973, thousands of Michigan residents ate food contaminated by a flame retardant, PBB, which was later correlated with earlier menstruation in girls. In Puerto Rico, which has some of the world’s highest rates of early puberty, the condition was linked to higher levels of a plasticizer called phthalate in affected children.

Governmental efforts to create a systematic method to assess possible endocrine disruptors from environmental sources have stalled.

In 1996, Congress directed the E.P.A. to develop a comprehensive screening program for possible endocrine disruptors within three years. Dr. Cooper says no such program has begun operation, a failure he attributed largely to stonewalling by chemical industry representatives who serve on an advisory committee for the program. Now the proposed rollout is December

2007, but Dr. Cooper said, “They may be dreaming.” Critics cite the program’s high potential costs and lack of reliable laboratory tests.
Protecting children from endocrine disrupters in cosmetics and prescription drugs may also be difficult in the near future.

In 1989, the Food and Drug Administration proposed allowing up to 10,000 units of estrogen per ounce of cosmetic, the approximate oral daily dose of hormone replacement therapy for postmenopausal women. Dr. Tiwary said that in the early 1990’s he filed an adverse drug report with the agency about hormone-containing shampoos but that to his knowledge, it never came to anything.

Reached by e-mail, a spokeswoman for the F.D.A. said that the agency was “aware of some reports describing premature sexual devolepment” with shampoos but that it had concluded that “there is no reason for consumers to be concerned.”

At this time, “placental materials are neither prohibited by cosmetic regulations nor restricted” by the F.D.A., she wrote.

Dr. Dedekian said that while prohormones like Andro are no longer commercially available, lax regulation of so-called compounding pharmacies allows the manufacture and sale of concentrated testosterone creams, like the one affecting his patient, without government oversight.

Topical lotions and creams containing testosterone may become more common. In 2000, Solvay Pharmaceuticals secured F.D.A. approval for Androgel, a lotion to treat a syndrome the company calls low T, referring to low testosterone. According to the company’s Web site, the condition affects 13 million men over 45. From 2000 to 2004, the number of testosterone prescriptions doubled to over 2.4 million a year.

Solvay Pharmaceuticals referred questions on Androgel’s possible risks to Natan Bar-Chama, an associate professor of urology at Mount Sinai School of Medicine.

Dr. Bar-Chama acknowledged the theoretical risks of transfer of the hormone through skin contact with children, but he said he had never seen a case among the hundreds of men he has treated. He added, however, that it was prudent to take precautions when using the product, including hand-washing after handling the gel and wearing clothing to avoid skin-to-skin contact with others.

In 2003, an Institute of Medicine report stated, “There has been increasing concern about the increase in the number of men using testosterone and the lack of scientific data on the benefits and risks of this therapy.”

Dr. Dan Blazer, a psychiatrist at Duke who was chairman of the committee, said, “In no way did we find a condition that we defined as low T.”

The major clinical trial of Androgel’s effectiveness for low T, published in The Journal of Clinical Endocrinology and Metabolism in 2000, included neither a placebo group (patients who received an inactive dummy lotion) nor a control group (patients who did not have low T) for comparison.

Dr. Ronald Swerdloff, the chief of endocrinology at Harbor-U.C.L.A. Medical Center in Torrance, Calif., and a consultant for Solvay, who ran the study, said the trial was limited in scope since it examined “a new route of administration for an already established drug.

Men who use cell phone have increased risk of infertility

Men who use mobile phones face increased risk of infertility
 

Daily Mail (UK)

by JENNY HOPE

 

Men who use mobile phones could be risking their fertility, warn researchers. A new study shows a worrying link between poor sperm and the number of hours a day that a man uses his mobile phone. Those who made calls on a mobile phone for more than four hours a day had the worst sperm counts and the poorest quality sperm, according to results released yesterday at the American Society for Reproductive Medicine annual meeting in New Orleans.
 
 
Doctors believe the damage could be caused by the electromagnetic radiation emitted by handsets or the heat they generate. The findings suggest millions of men may encounter difficulties in fathering a child due to the widespread use of mobile phones and offers another possible explanation for plummeting fertility levels among British males.
 
 
Sperm counts among British men have fallen by 29 per cent over the past decade, a drop which has also been blamed on increasing obesity, smoking, stress, pollution and 'gender-bending' chemicals which disrupt the hormone system.
 
 
The latest study backs up previous research which indicated a link between mobile phone use and sperm quality, but it is the biggest and best designed to date.
 
 
US researchers in Cleveland and New Orleans, and doctors in Mumbai, India, looked at more than 360 men undergoing checks at a fertility  clinic who were classified into three groups according to their sperm count. Men who used a mobile for more than four hours a day had a 25 per cent lower sperm count than men who never used a mobile. The men with highest usage also had greater problems with sperm quality, with the swimming ability of sperm - a crucial factor in conception - down by a third. They had a 50 per cent drop in the number of properly formed sperm, with  just one-fifth looking normal under a microscope.
 
 
Professor Ashok Agarwal, director of the Reproductive Research Centre at the Cleveland Clinic, Ohio, who led the study, said "Almost a billion people are using cell phones around the world and the number is growing in many countries at 20 to 30 per cent a year. "In another five years the number is going to double. People use mobile phones without thinking twice what the consequences may be. "It is just like using a toothbrush but mobiles could be having a devastating effect on fertility. It still has to be proved but it could have a huge impact because mobiles are so much part of our lives."
 

Altogether 361 men in the study were divided into four groups, with 40 never using a mobile, 107 men using them for less than two hours a day, 100 men using them for two-four hours daily and 114 making calls for four or more hours a day.
 
 
The main finding was that on four measures of sperm potency - count,  motility, viability and morphology, or appearance - there were significant differences between the groups. The greater the use of mobile phones, the greater the reduction in each measure. Prof Agarwal said "This was very clear and very significant.  
 

Many in the lowest group for sperm count would be below normal as defined by the World Health Organisation." The WHO says a normal sperm count is above 20 million per millilitre of seminal fluid. "There was a significant decrease in the most important measures of sperm health with cell phone use and that should definitely be reflected in a decrease in fertility" he said. Motility measures the swimming ability of sperm, viability measures whether non-swimming sperm are still alive while morphology is the appearance compared to the norm.
 

Although the men were seeking fertility treatment at a clinic in Mumbai, not all would have had a problem - it could be their partners, he added. Prof Agarwal said the most likely mechanism was damage to sperm- making cells in the testes caused by electromagnetic radiation or heat, although a fall in hormone production could also affect sperm motility and sperm DNA. He said: "These cells in the testes have been shown to be susceptible to electromagnetic waves in previous research in animals. "Somehow electromagnetic waves may be causing direct damage to these cells and that perhaps causes a decrease in sperm production." Mobiles may also increase temperature in the groin, if a man was wearing it on a belt or carrying it around in a pocket. Prof Agarwal said it was too early to advise men trying to start a family about whether they should limit their mobile phone use. He said "We still have a long way to go to prove this but we have just had  another study approved."
 
 
More than 40 million people in Britain are thought to use mobile phones. Alasdair Philips, director of the consumer pressure group Powerwatch said "It's a plausible link between the amount of time spent using a  mobile phone and a possible effect on male fertility. "The eyes, breasts and testicles are the areas of the body most likely to absorb the energy and many men carry their mobiles attached to their belt."  Sending text messages uses less power than talking but it can be a more intense emission of radiation, especially on trains, he said. "I've seen men on trains spending two or three hours continually texting  with their mobile phones held in their laps, and they press Send in the same position when it starts to seek a signal. "This needs a considerable amount of power within what is effectively a metal box. We advise people to send a text with their arm outstretched  next to the window when travelling on a train" he added. He said local heating of the groin triggered by a mobile phone might also be involved in affecting sperm quality. "Sperm is very temperature sensitive as shown by many studies, and a short-term rise in temperature could be responsible" he added.
 
 
However, Dr Allan Pacey, senior lecturer in andrology at the University of Sheffield, said "This is a good quality study but I don't think it tackles the issue. "If you're using your phone for four hours a day, presumably it is out of your pocket for longer. That raises a big question: how is it that testicular damage is supposed to occur?"  He said mobile phone use may be a marker for other lifestyle factors known to affect sperm quality. "Maybe people who use a phone for four hours a day spend more time sitting in cars, which could mean there's a heat issue. It could be they are more stressed, or more sedentary and sit about eating junk food getting fat. Those seem to be better explanations than a phone causing the damage at such a great distance" he added.

 

From the ASRM Meeting October 2006

Scientists Discover Antioxidents May Cause Fertility Problems

Antioxidants Might Cause Fertility Problems in Females, Scientists Discover

 

ScienceDaily (Jan. 18, 2011) — Antioxidants are sold over the counter everywhere. They're added to food, drink and face cream. But according to Prof. Nava Dekel of the Biological Regulation Department, we still don't have a complete understanding of how they act in our bodies. New research by Dekel and her team, recently published in the Proceedings of the National Academy of Sciences (PNAS), has revealed a possible unexpected side effect of antioxidants: They might cause fertility problems in females.

Common antioxidants include vitamins C and E. These work by eliminating molecules called reactive oxygen species that are produced naturally in the body. Stress can cause these chemically active molecules to be overproduced; in large amounts they damage cells indiscriminately. By neutralizing these potentially harmful substances, antioxidants may, theoretically, improve health and slow down the aging process.

But when Dekel and her research team including her former and present Ph.D. students Dr. Ketty Shkolnik and Ari Tadmor applied antioxidants to the ovaries of female mice, the results were surprising: ovulation levels dropped precipitously. That is, very few eggs were released from the ovarian follicles to reach the site of fertilization, compared to those in untreated ovaries.

To understand what lies behind these initial findings, the team asked whether it is possible that the process of ovulation might rely on the very 'harmful' substances destroyed by antioxidants -- reactive oxygen species.

Further testing in mice showed that this is, indeed, the case. In one experiment, for instance, Dekel and her team treated some ovarian follicles with luteinizing hormone, the physiological trigger for ovulation, and others with hydrogen peroxide, a reactive oxygen species. The results showed hydrogen peroxide fully mimicked the effect of the ovulation-inducing hormone. This implies that reactive oxygen species that are produced in response to luteinizing hormone serve, in turn, as mediators for this physiological stimulus leading to ovulation.

Among other things, these results help fill in a picture that has begun to emerge in recent years of fertility and conception, in which it appears that these processes share a number of common mechanisms with inflammation. It makes sense, says Dekel, that substances which prevent inflammation in other parts of the body might also get in the way of normal ovulation, and so more caution should be taken when administering such substances.

Much of Dekel's research has focused on fertility -- her previous results are already helping some women become pregnant. Ironically, the new study has implications for those seeking the opposite effect. Dekel: "On the one hand, these findings could prove useful to women who are having trouble getting pregnant. On the other, further studies might show that certain antioxidants might be effective means of birth control that could be safer than today's hormone-based prevention."

Dekel and her team are now planning further studies to investigate the exact mechanics of this step in ovulation and to examine its effect on mice when administered in either food or drink. In addition, they plan to collect data on the possible link between females being administered antioxidant supplements and the difficulty to conceive.

Prof. Nava Dekel's research is supported by the M.D. Moross Institute for Cancer Research; the Jeanne and Joseph Nissim Foundation for Life Sciences Research; the Yeda-Sela Center for Basic Research; the Willner Family Center for Vascular Biology -- Head; the Dwek Family Biomedical Research Fund; the Phyllis and Joseph Gurwin Fund for Scientific Advancement; and the J & R Foundation. Prof. Dekel is the incumbent of the Philip M. Klutznick Professorial Chair of Developmental Biology.

 


Story Source: Weizmann Institute of Science.

 


Journal Reference:

1.     K. Shkolnik, A. Tadmor, S. Ben-Dor, N. Nevo, D. Galiani, N. Dekel. Reactive oxygen species are indispensable in ovulation. Proceedings of the National Academy of Sciences, 2011; DOI: 10.1073/pnas.1017213108

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