Last week a patient presented to my office with a question that made me feel like I was responding to a Dear Abbey letter requesting help to make some crucial life decisions that were related to her reproductive health.  As I pondered her query that I had heard so many times before I wondered how terribly nerve racking it must feel like for this woman.

Dear Fertility Doc,

“I am 39 years old, single and I enjoy my career.  However, I always dreamed I would have children.  Unfortunately, I have not yet met a man that I would feel comfortable with to marry and with whom to have a baby.  What should I do?”

Signed,

At Reproductive Crossroads

The issues that this woman brings up are universal in my practice.  She basically has to weigh her desire to have children now rather than delay, using her own eggs or potentially with an egg donor or to adopt.   She needs to consider the ramifications of taking time off from her career as well as creating a child with donor sperm.  She expressed concern to me that if she were to meet Mister Right how will he respond to this child?  Are there any tests that I can perform that can help this woman make a decision?

First of all, it is imperative in cases like this to do a full fertility screen so that we understand from a fertility perspective how much time she has left and how urgent this patient needs to make a decision.  To assess her fertility I do a Day 3 serum Estradiol and FSH, an AntiMullerian Hormone and a sonographic antral follicle count.  The FSH is regulated by negative feedback from serum Estradiol and inhibin both of which are produced by the granulosa cells of the ovarian follicles.  With diminishing ovarian activity there are fewer follicles, less estradiol and inhibin so with less feedback, the FSH level is high.  Occasionally, in patients with low ovarian activity, often called reserve, a patient may have an ovarian cyst that produces estradiol.  This will lower the FSH level to otherwise normal activity levels even when there is minimal ovarian activity and inhibin.  One would misinterpret the low normal FSH in the presence of higher estradiol which is why this must be measured concurrent with FSH.

AntiMullerian Hormone is also produced by the granulosa cells and low levels therefore indicate depleted ovaries.  Likewise, few antral follicles seen on ultrasound typically performed during the early follicular phase of the cycle will indicate low ovarian reserve.

Once we know a patient’s relative fertility through this screen we need to decide whether she is prepared to delay her career for pregnancy and motherhood or should she do IVF and freeze her embryos thereby freezing her fertility potential at the current state.

Since she is single without a participating partner we would be using the sperm from an anonymous donor.  The specimens are obtained from sperm banks that are certified by New York State by virtue of their screening and testing for infectious and hereditary diseases.  Patients may review what is available from the sperm banks.  They can review on the internet the donor’s demographic information, physical attributes, educational and occupational histories, etc for the offered specimens.

If a woman does not have any infertility issues I would attempt donor insemination.  However, due to her advanced age, I would progress to more aggressive therapies if we were not successful after a few cycles.

A common concern for women in this circumstance is that they may meet their soul mate in the future and he may not be comfortable with a child produced with someone else’s sperm.  This is an issue that is very individual and I can only offer to support the patients as they decide what is best for them.

As she prolongs the decision her fertility is diminishing, and thereby risks not being able to have a child using her own eggs.  If conceiving with one’s own eggs is crucial then she must weigh the downside of conceiving a child from an anonymous donor and if she does so, the potential problems associated with finding a man in the future who she may want to have a family with.

It is enormously stressful making these decisions at these reproductive crossroads.

I discuss these issues with my patients and help them arrive at the decision that is right for them.

You have that dreaded infertility diagnosis, “Over 40 With High FSH Levels.” And there’s no cure or magic herb that will turn back the hands of time. You’re desperate so you are willing to try it all anyway, including acupuncture and some internet recommendations such as DHEA (dehydroepiendosterone).

You hear that you can lower your FSH with DHEA or estrogen. The fact is, however, elevated FSH levels do not cause a problem with conceiving. They are merely a marker of diminishing ovarian reserve, a depletion of ovarian follicles and eggs that, combined with increasing age, means you have very few genetically normal eggs available in your ovaries to achieve a healthy child.

Reproductive endocrinologists typically counsel “Over 40 With High FSH Levels” patients that their chance of successfully achieving a live birth using their own eggs is small and that by using a donated egg from a young, fertile woman they can increase their odds of giving birth to greater than 70 percent per donation. Unfortunately, this comes as a shocking disappointment to most women. It’s often a reason for them to drop out of a doctor’s practice or even quit trying to conceive.

So what do you do when faced with this situation? Your answer needs to be individualized, based on your emotional and financial resources, your motivation and your comfort with using a donated egg.

At our clinic, we try to come up with a strategy with our patients that includes counseling to begin the discussion about donor eggs, as opposed to trying with less chance for successful outcome using a patient’s own eggs, or stopping therapy completely and adopting or living child-free.

Perhaps you will choose a low tech option such as insemination with or without hormonal therapy. Sometimes, the plan will be to blast ahead with the big guns using IVF with full stimulation or with less medication and cost using MicroIVF or Minimal Stimulation IVF. Some patients respond better to different stimulations such as sensitizing with estrace or even DHEA prior to stimulation, using a lupron flare or even using clomid in combination with gonadotropins. Unfortunately, it is hard to predict what will be the optimal stimulation for you until we give it a shot.

The bottom line? There’s no right or wrong choice for you. Remember, a family can look many different ways and still be a healthy, loving unit. Your physician, nurses and counselors are available to assist you and support you with whatever decision you make.

It has become commonplace for women who have been frustrated with repeated unsuccessful attempts to conceive naturally on their own to see their gynecologist who often times will try clomid therapy on them. Clomid, the traditional brand name for clomiphene citrate, is a competitive inhibitor of estrogen. It stimulates the pituitary gland to produce follicle stimulating hormone (FSH) which in turn will stimulate the ovaries to mature follicle(s) containing eggs. Estrogen normally has a negative effect on the pituitary: Clomid blocks estrogen and leads to pituitary FSH production and ovarian stimulation.

Infertility patients — those under 35 having one year and of unprotected intercourse without a resulting pregnancy and those over 35 having six months without pregnancy — have a two to five percent pregnancy rate each month trying on their own without treatment. Clomid therapy increases a couple’s fertility by increasing the number of eggs matured in a cycle and by producing a healthier egg and follicle. The pregnancy rate with clomid therapy alone is approximately ten percent per cycle and 12 -15 percent when combined with intrauterine insemination (IUI). Women who are unable to ovulate on their own experience a 20 percent pregnancy rate per cycle with clomid, the equivalent to that of a fertile couple trying on their own.

Clomid and Your Cervical Mucus

Women who are likely to conceive with clomid usually do so in the first three months of therapy, with very few conceiving after six months. As clomid has an antiestrogen effect, the cervical mucus and endometrial lining may be adversely affected.

Cervical mucus is normally produced just prior to ovulation and may be noticed as a stringy egg white like discharge unique to the middle of a woman’s cycle just prior to and during ovulation. It provides the perfect environment for the sperm to swim through to gain access to a woman’s reproductive tract and find her egg. Unfortunately, clomid may thin out her cervical mucus, preventing the sperm’s entrance into her womb. IUI overcomes this issue through bypassing the cervical barrier and depositing the sperm directly into the uterus.

However, when the uterine lining or endometrium is affected by the antiestrogic properties of clomid, an egg may be fertilized but implantation is unsuccessful due to the lack of secretory gland development in the uterus. The lining does not thicken as it normally would during the cycle. Attempts to overcome this problem with estrogen therapy are rarely successful.

Side Effects

Many women who take clomid experience no side effects. Others have complained of headache, mood changes, spots in front of their eyes, blurry vision, hot flashes and occasional cyst development (which normally resolves on its own). Most of these effects last no longer than the five or seven days that you take the clomid and have no permanent side effect. The incidence of twins is eight to ten percent with a one percent risk of triplet development.

Limit Your Clomid Cycles

Yet, another deterrent to clomid use was a study performed years ago that suggested that women who used clomid for more than twelve cycles developed an increased incidence of ovarian tumors. It is therefore recommended by the American Society of Reproductive Medicine as well as the manufacturer of clomiphene that clomid be used for no more than six months after which it is recommended by both groups that patients proceed with treatment including gonadotropins (injectable hormones containing FSH and LH) to stimulate the ovaries in combination with intrauterine insemination or in vitro fertilization.

Success Rates

For patients who fail to ovulate, clomid is successful in achieving a pregnancy in nearly 70 percent of cases. All other patients average close to a 50 percent pregnancy rate if they attempt six cycles with clomid, especially when they combine it with IUI. After six months, the success is less than five percent per month.

In vitro fertilization (IVF) is a successful alternative therapy when other pelvic factors such as tubal disease, tubal ligation, adhesions or scar tissue and endometriosis exist or there is a deficient number, volume or motility of sperm. Success rates with IVF are age, exam and history dependent. The average pregnancy rate with a single fresh IVF cycle is greater than 50 percent. For women under 35, the pregnancy rate for women after a single stimulation and retrieval is greater than 70 percent with a greater than 60 percent live birth rate at East Coast Fertility.

Young patients sometimes choose a minimal stimulation IVF or MicroIVF as an alternative to clomid/IUI cycles as a more successful and cost effective option as many of these patients experience a 40 percent pregnancy rate per retrieval at a cost today of $3,900.

Today, with all these options available to patients, a woman desiring to build her family will usually succeed in becoming a mom.

These encounters I have with patients are more frequent than they should be. Unfortunately, many women delay seeking help in their efforts to conceive until their age has become significant both because they have fewer healthy genetically normal eggs and because their ability to respond to fertility drugs with numerous mature eggs is depressed. Women often do not realize that fertility drops as they age starting in their 20s but at an increasing rate in their 30s and to a point that may often be barely treatable in their 40s.

A common reason women delay seeking help is the trend in society to have children at an older age. In the 1960’s it was much less common that women would go to college and seek a career as is typical of women today. The delayed childbearing increases the exposure of women to more sexual partners and a consequent increased risk of developing pelvic inflammatory disease with resulting fallopian tube adhesions. When patients have endometriosis, delaying pregnancy allows the endometriosis to develop further and cause damage to a woman’s ovaries and fallopian tubes. They are more likely to develop diminished ovarian reserve at a younger age due to the destruction of normal ovarian tissue by the endometriosis. Even more important is that aging results in natural depletion of the number of follicles and eggs with an increase in the percentage of these residual eggs that are unhealthy and/or genetically abnormal.

Diminished ovarian reserve is associated with decreased inhibin levels which decreases the negative feedback on the pituitary gland. FSH produced by the pituitary is elevated in response to the diminished ovarian reserve and inhibin levels unless a woman has a cyst producing high estradiol levels which also lowers FSH. This is why we assess estradiol levels at the same time as FSH. Anti-Mullerian Hormone (AMH) can be tested throughout a woman’s menstrual cycle and levels correlate with ovarian reserve. Early follicular ultrasound can be performed to evaluate a woman’s antral follicle count. The antral follicle count also correlates with ovarian reserve.

By screening women annually with hormone tests and ultrasounds a physician may assess whether a woman is at high risk of developing diminished ovarian reserve in the subsequent year. Alerting a woman to her individual fertility status would allow women to adjust their family planning to fit their individual needs.

Aggressive fertility therapy may be the best option when it appears that one is running out of time. Ovulation induction with intrauterine insemination, MicroIVF and IVF are all considerations that speed up the process and allow a patient to take advantage of her residual fertility.

With fertility screening of day 3 estradiol and FSH, AMH and early follicular ultrasound antral follicle counts, the biological clock may still be ticking but at least one may keep an eye on it and know what time it is and act accordingly.

At East Coast Fertility, we understand the emotional aspect that accompanies infertility, and we believe it is equally important to support our patients emotionally as well as physically. It is important to understand fertility holistically. In addition to treating the various physical etiologies of infertility, we must take into account the effects of stress and anxiety. Your mind and body work together, not separately. Therefore your thoughts have a direct effect on yourphysiology. When you are experiencing stress, your brain releases stress hormones. These stress hormones function in many ways. One of the stress hormones, cortisol, has been documented to interfere with the release of the reproductive hormones, GnRH (gonadatropin releasing hormone), LH (luteinizing hormone), FSH (follicle stimulating hormone), estrogen, and progesterone. In fact, severe enough stress can completely inhibit the reproductive system. Cortisol levels have also been linked to very early pregnancy loss. For this reason, it has been found extremely helpful when treating infertility, to include mind/body methods and strategies which help to alleviate the stress response that sets off a cascade of hormonal responses which may inhibit fertility.

The mind/body work we teach here at East Coast Fertility includes methods that allow the body to return to a calm and relaxed state, thereby turning off the biochemical stress response and allowing our hormonal physiology to function optimally.  Feelings of anxiety, depression, isolation, and anger are common themes in infertility.  Often, anger masks the feelings of loss experienced month after month of trying to conceive without success. Infertility impacts on one’s marriage, self-esteem, sexual relationship, family, friends, job, and financial security.

One study showed that women going through infertility experience as much depression as women who have been diagnosed with life-threatening illnesses such as metastatic cancer, heart disease, or HIV. When women face these other illnesses, they are likely to seek out the support of their friends and family. The sad aspect of infertility is that although these women are as depressed as those facing life-threatening illnesses, they are far less likely to seek out support from friends and family. Often, thoughts of not living up to the expectation to become pregnant, thoughts such as “why is this happening to me?!”, and the intense emotions of loss related to the thought that one may never have a child, lead to feelings of isolation, anger, and depression.

Although there is a correlation between stress and infertility, the relationship remains complex. However, the research does in fact suggest that psychosocial factors such as depression and anxiety correlate with
lower pregnancy rates following IVF. In addition, of the women who participated in Alice Domar’s Mind/Body program at the Mind/Body institute in Boston, 55% conceived pregnancies that resulted in the birth of a full term baby compared with 20% of the control group.

~ Mind/Body Support Group at East Coast Fertility ~

In our Mind/Body support group, patients experience the opportunity to share information, feelings, or their own personal stories. You may be surprised to see how your support can help others or you may be relieved
to hear others experiencing the same type of thoughts and feelings as you experience. Often, the supportive nature of this group, and the connection that develops between members, fosters a healing process.
Feelings of isolation, anger, and stress are slowly relieved.

Our Mind/Body program focuses on symptom reduction and developing a sense of control over one’s life by utilizing Mind/Body strategies and interventions which elicit the relaxation response. The relaxation
response is actually a physical state that counteracts the stress response. You can think of it as the physiological opposite of the body’s stress response. We cannot be stressed and relaxed at the same time.
Therefore when a person elicits the relaxation response, the body’s stress response is halted, stress hormones diminish. Stress responses such as heart rate, metabolic rate, blood pressure, and shallow breathing decrease. Breathing becomes slower and deeper, so we have more oxygen being delivered to all the cells in the body. The way in which you are taught to elicit the relaxation response is through methods such as: breath focus, guided visual imagery, muscle Relaxation and learned mindfulness, and meditation.

In Mind/Body work, we also work with “cognitive restructuring” which is examining our negative thoughts, seeing where there is distortion, and reframing our thoughts positively and realistically. Often, we have held on to certain negative thoughts and feelings we may have developed years ago. The thought pattern becomes so ingrained in us, that we take it for truth, when in fact, it is a distortion. Cognitive restructuring will help you examine your thoughts and see which are distorted, causing you needless worry, anxiety, or depression. Once you understand how a thought is distorted, you can change those thoughts and alleviate the anxiety attached to them.

Awareness of the mind/body connection allows us to use our minds to make changes in our physiology. This holistic treatment – combining bio-medical science with mind/body medicine deals with the treatment of the whole individual rather than looking only at the physical aspect.  The fact is, body and mind work together. We invite you to take advantage of this unique area of support provided at East Coast Fertility and join our Mind/Body group.

Embryo

Many IVF programs have reintroduced the concept of utilizing a co-culture medium to improve the quality and implantation of embryos. Co-culture is a procedure whereby “helper” cells are grown along with the developing embryo. Today, the most popular cell lines include endometrial cells (from the endometrium, or uterine lining) and cumulus cells from women’s ovaries.  Both cell lines are derived from the patient, thereby eliminating any concerns regarding transmission of viruses. Endometrial cells are much more difficult to obtain and process, while cumulus cells are routinely removed along with the oocytes during IVF retrieval.

Cumulus cells play an important role in the maturation and development of oocytes.  After ovulation cumulus cells normally produce a chemical called Hyaluronan.   Hyaluronan is secreted by many cells of the body and is involved in regulating cell adhesion, growth and development. Recent evidence has shown that Hyaluronan is found normally in the uterus at the time of implantation..

Co-culture of cumulus cells provides an opportunity to detoxify the embryo’s culture medium that the embryos are growing in and produce growth factors important for cell development 1,2.  This may explain why some human embryos can experience improved development with the use of co-culture.

Preparation of co-culture cells starts with separation of the cumulus cells from the oocytes after aspiration of the follicles. These sheets of cells are washed thoroughly and then placed in a solution that permits the sheets to separate into individual cells.  The cells are then washed again and transferred to a culture dish with  medium and incubated overnight. During this time individual cells will attach to the culture dish and create junctions between adjoining cells. This communication is important for normal development. The following morning, cells are washed again and all normally fertilized oocytes (embryos) are added to the dish. Embryos are grown with the cumulus cells for a period of three days to achieve maximum benefit.

Performing co-culture of embryos has improved implantation and pregnancy rates above and beyond those seen with the IVF advances previously described. More importantly, It promises to offer advantages for those patients whose previous IVF cycles were unsuccessful.

References:
1. Barmat LI, Worrilow KC, Paynton BV. Growth factor expression by
human oviduct and buffalo rat liver coculture cells. Fertil Steril 1997;
67:775–9.

2. Fukui Y, McGowan LT, James RW, Pugh PA, Tervit HR. Factors
affecting the in vitro development of blastocysts of bovine oocytes
matured and fertilized in vitro. J Reprod Fertil 1991;92:125–31.