When you call a reproductive endocrinologist, make sure at least some of the staff and technicians are available seven days a week. “If they’re not,” says Grant, “you’re clearly not in the hands of someone whose priority is getting you pregnant.” After all, you may ovulate on a Saturday or Sunday, and need to be seen for tests or treatments pinned to that day. What’s more, if you have a regular 28-day cycle, the same thing will happen next month and the one after and…
The Hales knew shortly after they were married in 1991 that they were going to need IVF: Jennifer’s tubes, tests had shown, were completely blocked. What they didn’t know, though, was that Andrew also had a problem, something they learned three years later during their first IVF affempt, when only two out of a dozen eggs were successfully fertilized. Two more affempts (one with ICSI, one using frozen embryos) also failed. At that point, the Hales thought they might turn to adoption. But deciding to give IVF with ICSI one more shot, in 1997 they consulted the Pacific Fertility Medical Center in San Francisco. “This time we had an angel on our side,” says Jennifer. Last July 4, Julia Elizabeth Hale was born.
If diagnostic tests show that you have ovulation irregularities, your doctor will probably suggest that you try the drug Clomid (clomiphene citrate, also marketed as Serophene) and have scheduled sex based on when tests show you’re about to ovulate. (“If your doctor simply throws Clomid at you without any testing,” says Dr. Silber, “find another doctor.”)
This is an okay game plan for a limited number of months, up to six, some suggest. Others say even fewer. “If Clomid is going to work,” says Dr. Zouves, “it will do it in three cycles.” Unfortunately, there are doctors who will urge women to keep trying with Clomid, sometimes up to a year—a suggestion that not only won’t help, but could expose you to unnecessary danger, says Carolyn Runowicz, M.D., director of the division of gynecologic oncology at the Albert Einstein College of Medicine and Montefiore Medical Center in New York. (Some studies have shown a link between fertility drugs and ovarian cancer, but until we know—the National Cancer Institute is carrying out long-term studies now—caution seems prudent.)
If Clomid doesn’t work, your doctor may suggest using more powerful ovulation-induction drugs—such as Pergonal (known chemically as hMG, for human menopausal gonadotropin) or Fertinex (chemically, FSH, for follicle-stimulating hormone) to be taken by injection at home. While you’re on these drugs, you need to be monitored with blood tests to make sure hormone levels are rising properly. A few days into treatment, you should also have a transvaginal ultrasound (a sonogram done with a probe inserted vaginally) to check that follicles in your ovary are maturing. Ultrasound is also necessary to check that your ovaries are not becoming enlarged or producing too many follicles—which may lead to a potentially dangerous condition known as ovarian hyperstimulation syndrome.
All these drugs, but especially hMG and FSH, increase your chances of becoming pregnant with multiples. For couples eager to have a baby, having more than one may sound even better (and in a study several years ago, the vast majority of infertility patients surveyed expressed a desire for twins, with half even liking the sound of triplets!). But it’s not ideal. Your pregnancy will be more complicated, you’ll be much more likely to deliver early, and the babies, as a result of their prematurity, may face days, weeks, even months in neonatal intensive care. Then, they’re more likely to have developmental disabilities.
Sometimes fertility drugs are used with an in-office procedure to achieve pregnancy. In this, your husband produces a semen sample (by masturbation) and the doctor treats and inserts the sample directly into your uterus. If your husband also has fertility problems or tests have shown “penetration” problems (his sperm fail to penetrate your egg), the doctor can mix the sample with a variety of substances to help.
How long should you try IUI? Like Clomid, IUI usually works quickly if it’s going to work, says Dr. Silber. “If you haven’t conceived in several cycles, it’s time to move on,” he believes. Other specialists may suggest trying for six months or even a year.
What you need to think about: IUI isn’t cheap, costing anywhere from an estimated $1,400 to $4,000 a month. Unless there’s reason to believe that sperm getting into the uterus is your problem, you might want to cut your losses sooner. Moreover, each insemination cycle exposes you to the potential risks of fertility drugs. By going quickly or even directly to high-tech methods, you limit those risks.
These are the superstars of infertility treatment, the procedures that have made pregnancy possible for couples who, not long ago, had no chances whatever—women whose tubes are completely blocked, for example, or men who produce no sperm at all. Basically, the treatments all start the same way: A woman takes a series of different drugs to stimulate ovulation (and to produce multiple eggs). Then, while she’s sedated, the doctor retrieves the eggs from the ovary.
With IVF, the retrieved eggs are placed in a glass (petri) dish, where they mix with sperm provided by your husband. After two days, the fertilized eggs (now known as embryos) are transferred back to your uterus.
When one of Lisa Daly’s closest friends asked Lisa to hold her newborn son at the baby’s bris (the Jewish rite of circumcision), Lisa initially demurred. “It’s good luck,” her friend insisted. “It means you’ll have your baby soon.” Could that be what would work? Lisa, a registered nurse who specializes in monitoring high-risk pregnancies, and her husband, Ira, now a social studies teacher, had been trying to have a baby for five years. The Queens, New York, couple had undergone test after test, and everything had come back normal. They’d had surgery (a laparoscopy for her, repair of a varicose vein on his testicle for him). Still no pregnancy. Four attempts at intrauterine inseminations, with Clomid to boost ovulation, also failed. Even more heartbreaking, Lisa became pregnant once on her own, and once with Clomid, but miscarried both times. “I just lost it after the second one,” she admits. And then, a month later, only two weeks after holding her friend’s baby, Lisa started another cycle of Clomid and on Rosh Hashanah, the Jewish holy day of renewal, conceived her own son. Jacob Samuel Daly was born on May 27,1997.
If you didn’t like high-school math, you’re going to have a tough time decoding the numbers that fertility centers tout as the basis of their success rates. But it’s more than worth the effort: IVF and its relatives are physically and emotionally demanding procedures, not to mention extremely expensive. Why use up your few chances to get pregnant at a center that isn’t experienced in your problem or that hasn’t had much success generally?
Fortunately, you have help: The Assisted Reproductive Technology Success Rates, a compendium of results from 300 or so clinics that are members of the Society for Assisted Reproductive Technology (SART). You can order copies by phone (888- 299-1585) or click on to the World Wide Web (Actually, it will take lots of clicks: The directory prints Out in three parts, 150 pages each.) And note: As of this printing, the directory currently available is based on 1995 records; the 1996 edition is expected to be available by year’s end. Also, starting with the 1996 directory, centers will be audited (on a random basis) as part of a government crackdown on misleading claims and practices at fertility clinics.
How do you interpret the numbers each center presents? Unscrupulous practitioners would probably like you to focus on one figure only: The number of live births achieved after embryos have been transferred to the mother’s womb. Why not? By definition, that has to be the highest figure, since it would eliminate from consideration all those cycles that had to be canceled at earlier points in the process because things hadn’t gone well—the woman had failed to produce enough good eggs, for example, or the eggs had failed to fertilize.
So the figure that’s generally most meaningful is the one that’s most comprehensive: Number of live births per cycles initiated, a figure that’s popularly called the “take-home baby rate.” But even that number isn’t as revealing as it sounds. Smaller, local centers, for example, may treat couples from the area. If the woman becomes pregnant, fine. If she doesn’t, though, she may move on to a larger clinic, which handles more difficult cases, explains Zev Rosenwaks, M.D., director of the Center for Reproductive Medicine and Infertility at New York Hospital-Cornell Medical Center in New York. The smaller center ends up with a high success rate—but all that reflects is the fact that the clinic’s largely treating couples who get pregnant more easily.
Other more insidious practices can be at work too. Centers have a great stake in publishing high success rates: They could, therefore, be bumping up couples with “easier” cases to the top of a waiting list, in hopes their higher odds will raise the center’s overall success rates. Or centers could be rejecting couples with severe problems or assigning such couples to a “research group,” so their numbers will be kept out of the overall rates. Conversely, centers whose figures seem on the low side may be more accepting of such difficult cases.
“Centers where thousands of IVF cycles have been performed and many hundreds or thousands of women have become pregnant almost surely have mastered IVF,” says Joseph D. Schulman, M.D., director of the Genetics & IVF Institute in Fairfax, Virginia. And look for experience in your particular problem, advises Dr. Kearney.
Knowing certain specifics can signal whether a center is top-notch. Find out what percent of cycles a center cancels, advises Dr. Silber. “If the cancellation rate’s higher than 15 to 20 percent in women under 39, that’s a red flag,” he warns. Similarly, if a center is doing ICSI, embryos should be placed back in the womb successfully nearly all the time. “Failure should occur less than 2 percent of the time,” says Dr. Silber, “and only in patients with few or poor eggs.
Dr Eliran MorHigh numbers of complications signal that a center may not be paying close enough attention. You could ask specifically about ovarian hyperstimulation risk, suggests Dr. Rosenwaks. “With careful monitoring, a center’s rate should be exceedingly low, less than 1 percent.”
Generally, IVF babies are no more likely to suffer birth defects or other abnormalities, studies show. But male babies conceived through ICSI do have a higher risk of certain genetic defects. The reason: Men who have extreme infertility problems (very low sperm counts or no sperm at all) may have an inherited defect on their Y-chromosome, which they in turn may pass to their sons.
In 1995, 28 percent of all assisted-reproductive technology births were twins, triplets, or higher- order births, according to the SART figures. You can avoid the risk of multiple births by limiting the number of embryos that are transferred back to the mother. But then you also cut the chances of success. Is there a happy medium, so to speak? Going beyond mere numbers, some specialists believe that checking the quality of embryos might be the ticket. Last spring, for example, the Northwest Center for Infertility and Reproductive Endocrinology in Margate, Florida, reported that they’d found the best “formula” for maximizing pregnancy rates while limiting higher-order (triplets or more) multiple conceptions:
One way around the problem of multiple births is to transfer a larger number of embryos, then “reduce” the number early in pregnancy (by injecting one or more fetuses with a solution that causes them to die). Aside from the painful emotional issues reduction raises, it is not a panacea: While it does cut your risks, in a study comparing “reduced” twins (from quadruplets) with twins that started out that way, the reduced twins averaged lower weights at birth and were more likely to be delivered early, possibly because of complications from the reduction procedure itself or possibly because of problems related to the implantation of a larger number of fetuses to begin with.
IVF is not like rolling dice, Dr. Kearney explains, where the more rolls, the greater your odds of success. Rather, couples with the fewest problems are more likely to get pregnant ”on an earlier throw”; those who are older or who have more medical problems are less likely. Nor, obviously, do such couples’ chances improve with time.
Finances aside (though with IVF averaging $8,000 to $10,000 per cycle, few couples can put finances aside), the latest numbers suggest that it’s worth trying at least three cycles. A just-released SART study found that success rates remain almost equal for the first two cycles of IVF, and then decline only modestly. After more than four cycles, however, pregnancy rates drop significantly. At that point, couples may want to explore other technologies (such as using donor eggs) or turn their energies to other ways of creating a family or having children in their lives.
There are nearly 300 clinics affiliated with the Society for Assisted Reproductive Technology. How do you choose the best one for you? Start by collecting recommendations from doctors and others you trust, then ask probing questions before signing on with a facility. Also, Assisted Reproductive Technology Success Rates, a directory of data from centers across the country, can point you to clinics achieving higher-than-average pregnancy rates or treating a larger number of couples with particular problems. Based on the most recent directory figures, these ten centers stand out:
Fertility is the natural capacity of a living being to establish the clinical pregnancy through an intricate biological process “reproduction” with the assistance of reproductive system to produce offspring, the real existence of a species. The system has unifying characteristics in males and females of a species including Homo sapiens (humans)—the highest ranked animal species. It controls the development of structural and functional differences between males and females, and influences their behavior.1 Like the other physiological systems in our body, reproductive system also needs efficacious way to care for and to maintain fecundity, which is generally obtained using fertility regulators. Usage of such regulators have risen at least threefold in recent years, where most of the commercially available regulators are synthetic chemicals, often have adverse effects and toxicity. This emphasizes the need for developing biologically active substances as potential fertility regulators from various natural sources. In this regard, the therapeutic potentials of the secondary metabolites or natural products, produced by living organisms in their natural environment, has been considered as one of the best choices. Over the last five decades, research on development of natural fertility regulation have come to the forefront of new therapeutics development in fertility regulation. It has been found that worldwide varied communities are chiefly practicing the plant-based traditional medicines for fertility regulation.2 The purpose of this current chapter is to provide information about natural products involved in fertility regulation. While there are several reports, including many review articles, describing fertility regulatory properties of plants and plant extracts available in the literature, this chapter will only cover isolated natural products with fertility regulatory properties as evident from animal based in vivo studies, and wherever available from human clinical trials.
To understand potential involvement of natural products in the regulation of reproductive physiology and fertility, it is essential to have an idea about the human reproductive system. The following section will briefly discuss the reproductive system and its regulation, current fertility regulators, and inter-relationship between herbs and fecundity.
Fertility has been defined in many ways—from the demographers practice of simply recording the number of children born, to the precise (but difficult to measure) monthly probability of conception. Infertility is likewise variably defined, making comparison of data across studies difficult. Furthermore, there is debate about which measures/indicators/contributors are the most useful to try to track when trying to understand fertility/infertility, fecundity/subfecundity trends.
Fertility is defined as the ability to have a clinical pregnancy, whereas fecundity is clinically defined as the capacity to have a live birth, including gamete production, fertilization and carrying a pregnancy to term. In literature, fertility is often considered as the ability to get pregnant, which is best reflected by time to pregnancy (TTP). Fertility rate is defined as the average number of children per woman in a lifetime. The fertility rate is determined by time to pregnancy, pregnancy outcome (e.g. miscarriages) and personal choice. In women with rheumatoid arthritis (RA) a decreased fertility rate has been described long ago [38]; such decreased fertility may be ascribed, among other factors, to a prolonged TTP [39,40]. For women with IA other than RA, conflicting results have been reported [41,42].
In clinical practice, the decreased fertility observed in women with RA is a concern. In the past, when treatment options during pregnancy and during the preconception period were limited, TTP exceeded more than one year in roughly 40% of women with RA. This was associated with active disease, the use of prednisone in a daily dose exceeding 7.5 mg and the use of non-steroidal anti-inflammatory drugs (NSAIDs) [39]. How active disease may contribute to an increased TTP remains an unanswered question. A reduced ovarian reserve was described in patients with RA and spondyloarthritis (SpA) [43], whereas an inverse correlation between disease activity markers and anti-Müllerian hormone (AMH) levels, suggesting that disease activity can play a role [44]. Circulating interleukin (IL)-6 levels have been shown to correlate with TTP, even after correction for disease activity, suggesting that systemic inflammation may play a role [45]. Interestingly, in a small study, treatment with tumour necrosis factor-inhibitors (TNFi) was associated with a shorter TTP. However, this study was too small to correct for relevant confounders [46]. A decreased intercourse frequency in women with (active) RA has been suggested as an explanation for the lower fertility rate. Although sexual dysfunction is highly prevalent in women with RA, this has mainly been studied in postmenopausal women in long term relationships [47] while data in young RA patients with a wish to conceive are lacking. Lastly, it has been shown that women with RA may enter menopause at an earlier age compared to healthy controls, thereby reducing their reproductive lifespan [38]. This observation was made in times when strict control of disease activity was not common in RA patients; thus it could be envisaged that it provided an extra-articular feature of RA related to chronic elevated disease activity. It is not known whether such observation can be translated to women that have always been treated according to a treat-to-target approach aimed at remission.
In women with systemic lupus erythematosus (SLE), the prevalence of primary infertility does not seem to be different from the general population, while there are several factors that may contribute to secondary infertility: menstrual irregularity or amenorrhea due to severe flares, renal insufficiency-related hypofertility, menstrual disorders (e.g. due to endometriosis) and premature ovarian failure (POF). POF is due to accelerated reduction of the ovarian reserve due to either direct autoimmune oophoritis or to the use of cytotoxic drugs [48]. CYC exposure is one of the causes of premature ovarian failure described in SLE women; it is associated with lower levels of AMH which are directly related to cumulative doses and women’s age at the beginning of treatment [49,50]. It is recommended to offer fertility preservation methods, especially GnRH analogues, to all menstruating women with SLE who are going to receive alkylating agents [51].
Despite all these factors, TTP in women with SLE was found to be normal (except for those women that have been treated with CYC) [52]. Instead, women with SLE have decreased fecundity as a result of a higher rate of miscarriage, a lower rate of live birth and due to personal choices [53].
According to the latest international glossary on infertility and fertility care, infertility is defined as a disease characterized by the failure to establish a clinical pregnancy after 12 months of regular and unprotected sexual intercourse or due to an impairment of a person’s capacity to reproduce, either as an individual or with his or her partner. Female infertility, which is mainly caused by female factors comprising: ovulatory disturbances; decreased ovarian reserve; anatomical, endocrine, genetic, functional or immunological abnormalities of the reproductive system; chronic disease; and sexual conditions incompatible with coitus [80].
Whether the fertility of SS female decreases is inconclusive. Among the SS patients, 5.9 % had chosen not to have children due to the disease, but there was no indication of infertility as judged by the number of pregnancies [12]. More recent study also pointed out the number of pregnancies in SS patients was no less than that in controls, and 24 % of them with more than 3 pregnancies (high parity) [32]. Currently, there is limited evidence that directly indicating the fertility of SS patients is diminished. Karakus et al. [81] reported a significantly shorter duration of menstrual cycle in 24 SS patients compared to controls (26 vs.28 days, P = 0.043), lower serum anti miller hormone level (P = 0.001) and antral follicle count (P = 0.01) and higher luteinizing hormone level (P = 0.019). The volume of right ovary and left ovary was also lower, but did not reach statistical significance.
