CHAPTER 12 Fertility Challenges

Infertility is defined as the inability to conceive after 12 months of unprotected intercourse in a couple of reproductive age attempting to conceive. Approximately 90% of couples achieve conception within this time, and a further 15% of normally fertile couples take longer than 12 months to become pregnant. Research has shown that even couples in their late thirties have a 91% chance of conceiving naturally within 2 years, and recent studies estimate that an average of 25% to 40% of women have a live birth without treatment during the 3 years after the first infertility consultation, even without treatment. 1 2 3 Nevertheless, of the approximately 60 million women of reproductive age in the United States in 1995, about 1.2 million, or 2%, had had an infertility-related medical appointment within the previous year and an additional 13% had received infertility services at some time in their lives.⁴ This number has increased in recent decades because of societal demographic changes, particularly the aging of the baby boom generation, leading to an increased size of the reproductive age population, and more couples delaying fertility for the sake of careers.¹

Infertility is not synonymous with sterility and it is important to differentiate these terms. Sterility is defined the inability to achieve pregnancy and affects only 1% to 2% of couples.² Primary infertility refers to those who have never before conceived and secondary infertility to those who have achieved conception some time in the past (regardless of pregnancy outcome) and thereafter became infertile.⁵

FEMALE FACTORS AFFECTING FERTILITY

The main types of female infertility include ovulatory disorders (25%) and tubal disease (20% to 25%), including endometriosis (10%). Ovulatory factors are suspected when menstrual abnormalities are reported. Male infertility is the primary cause in approximately 25% of cases and contributes to an additional 15% to 25% of cases. Infertility results from unexplained causes in up to 20% of cases.¹ Thorough evaluation of the couple will point to a probable cause in 85% to 90% of cases.² Ovarian factors are primarily associated with follicular phase disruptions. An inadequate luteal phase is said to account for only 3% to 4% of fertility failure. Examples of all of the factors that account for fertility challenges are listed in Table 12-1.

TABLE 12-1 Causes of Fertility Challenges

FACTOR	EXAMPLES
Ovulatory	Defects of the ovaries Anovulatory cycles Hyperprolactinemia Hypothalamic dysfunction Pituitary dysfunction Gonadal dysgenesis Premature ovarian failure Ovarian resistance
Metabolic	Thyroid disorders Adrenal disorders Liver disease Renal disease Androgen excess (adrenal or neoplastic causes)
Pelvic	Common infection (genitourinary infections such as Chlamydia trachomatis, Ureaplasma urealyticum, Mycoplasma hominis, and Neisseria gonorrhoeae causing inflammation, infections and scar tissue) Chronic inflammation manifesting as pelvic inflammatory disease (PID) Uterine or fallopian adhesions Endometriosis (attributed to 5% of cases of infertility) Fibroids Structural abnormalities
Cervical (evident in only about 3% of cases)	Factors are and can include: Hostile mucus (sperm antibodies, abnormal viscosity or pH) Cervicitis and infections Acquired surgical damage to the mucus producing endocervical glands (cone biopsy, laser ablation, cryotherapy) associated with cervical dysplasia or neoplasia
Immune-mediated	Lack of blocking antibodies Autoimmune disease such as SLE Immunophenotypes Anti-thyroid antibodies Antiphospholipid syndrome (APS)

Data from Kaider A, Kaider B, Janowicz P, et al.: Immunodiagnostic evaluation in women with reproductive failure, Am J Reprod Immunol 42(6):335-346, 1999.

Unexplained and coexisting factors account for approximately 10% of infertility cases and can be a result of environmental and/or occupational exposure to toxicity such as heavy metals, radiation, solvents, DES, smoking, and exogenous androgens and/or estrogens from environmental and food sources. Nutritional deficiency, stress, and age can all contribute to fertility problems. Abnormal body mass index (BMI), including being underweight or overweight, can cause amenorrhea and infertility. The fertility of a woman begins to significantly decline between the ages of 35 to 38 and sharply declines after the age of 40.

MALE FACTORS AFFECTING FERTILITY

Male factors affecting fertility include:

• Endocrine disorders of the hypothalamus, pituitary, adrenal glands, thyroid

• Anatomical disorders of the male reproductive tract

• Sperm abnormalities

• Abnormal spermatogenesis resulting from chromosomal, infection, radiation, or chemical exposure

• Abnormal motility resulting from Kartagener’s syndrome (the absence of cilia), testicular varicoceles, or antibody production (male immune-mediated infertility)

• Sexual dysfunction, including erectile and ejaculatory dysfunction or decreased libido

• Unexplained factors

• Environmental and occupational toxicity such as exposure to heavy metal, DES, radiation, and exogenous androgens and estrogens

• Nutritional deficiency, particularly zinc and selenium

• Psychological stressors

DIAGNOSIS

Initial evaluation of infertility must include a thorough workup of both partners for male and female factors that might cause fertility problems.

Evaluation of Male Factors

Primary evaluation includes:

• A thorough medical history and physical examination

• Semen analysis

A secondary evaluation is recommended and usually includes more holistic measures:

• Genitourinary infection screening

• Heavy metal screening

• Male hormone panel

• Adrenal stress index (ASI)

Semen analysis can rule out the most likely abnormalities in male factors. Sperm count, motility, morphology, pH, and white blood cell count need to be reviewed. If the male has not had a semen analysis within the past 3 months prior to the initial visit to the practitioner, it is suggested that this test be recommended. Spermatogenesis takes approximately 74 days; hence, the viability of the sperm will depend on the environment over the 74-day time frame in which the sperm were developing. If, for example, the man was exposed to dangerous solvents, toxic heavy metals, or radiation, his sperm parameters may reflect abnormalities. The morphology is the most relevant parameter to review, as this indicates the most likely chance of that sperm resulting in conception and hence the actual sperm viability. The percentage morphology reflects the number of normally shaped sperm within the sample.

Several genitourinary infections are known to significantly affect both male and female fertility, including Chlamydia trachomatis, Ureaplasma urealyticum, Mycoplasma hominis, and Neisseria gonorrhoeae. Subclinical infection can contribute to unexplained infertility. Not only can these genitourinary tract infections adversely affect fertility, but they also can potentially cause miscarriage and birth defects.

Evaluation of Female Factors

Primary evaluation should include:

• Thorough medical history and physical examination

• Expanded female hormonal panel

• Evaluation for thyroid disorders

• Evaluation for immunologic disorders, including autoimmune conditions

• Genitourinary infection screening as described above for male evaluation

• Cervical cytology

A secondary evaluation is recommended, especially for unidentified infertility:

• Heavy metal screening

• Salivary adrenal stress index (ASI)

In a tertiary evaluation for pelvic factors, minor surgery is often required. These tests require referral to a reproductive medical specialist. These tests and procedures, although sometimes necessary, are invasive, painful, and expensive:

• Hysterosalpingogram for investigation of tubal patency, congenital malformations, polyps, and distal and proximal occlusions

• Transvaginal ultrasound for detection and monitoring of the developing follicle on the ovary

• Endometrial biopsy sampling to determine the maturation of the endometria

• Laparoscopy for detection of tubal abnormalities such as agglutinated fimbria or adhesions, tubal cysts, and endometriosis

• Serum tests for immune-mediated infertility

Mutual Fertility Testing

The post coital test (Sims-Huhner Test) is an evaluation of the sperm’s interaction within cervical mucus postcoitally. This test is designed to evaluate the number of sperm that survive within the mucus and their duration of survival. This test can rule out parameters such as inadequate quantity and clarity of cervical mucus, spinnbarkeit of greater than 8 cm, and non-forward progressive sperm in the mucus. When the quality and quantity of mucus is good, yet the test results are abnormal, then further evaluation for cervical mucus antisperm antibodies is warranted. It is a debatable test for efficacy but is used to assess cervical hostility to sperm. Hostile mucus can result from the presence of sperm antibodies and/or an unfavorable pH of cervical mucus.

Noninvasive Home Evaluation and Patient Participation: Thermo-Symptal Monitoring and Mucus and Cervical Evaluation for Detection of Ovulation

As fertility evaluation can be physically invasive, traumatic, and cost prohibitive, there are some useful tests women can do themselves at home. One easy technique is Thermo-Symptal monitoring, which involves the monitoring and recording of the basal body temperature (BBT) and recording of cervical mucus secretions on a daily basis throughout the cycle. Although convenient and cost-effective, Thermo-Symptal monitoring requires consistent commitment and a learned awareness of the body’s subtle signs of fertility. This awareness can help the couple refine conception timing and allow the woman sense of participation in her own program toward achieving pregnancy.

Basal Body Temperature Monitoring

The luteal phase of the cycle is characterized by the production of progesterone from the corpus luteum. Progesterone is a thermogenic hormone elevating the core body temperature in the luteal phase of the cycle. When adequate progesterone is produced as a result of ovulation having occurred, the BBT elevates and remains elevated for approximately 10 days after ovulation, until either menses occurs, in which the temperature will drop, or pregnancy is established, in which the temperature will continue to elevate to a third phase as the progesterone continues to be produced into the pregnancy. This elevation in temperature usually occurs 1 to 2 days after ovulation.

Interpretation of the Basal Body Temperature

In the follicular, preovulatory phase of the menstrual cycle in a healthy woman, the temperature reading is approximately 97°F. An increase in temperature greater than 97°F in the luteal phase, after day 13 or 14, is indicative of a normal ovulation in 90% of cases. If the temperature maintains above this temperature after 16 days, this is suggestive of pregnancy. The BBT is measured orally first thing upon waking in the morning, before any activity, with a specific fertility thermometer (thermocrystal basal thermometer). The temperature is best taken at the same time each day, after at least 6 hours of sleep. The routine should commence on the first day of her cycle, which corresponds to the first day of menstrual flow. Sleeping with an electric blanket, heated waterbeds, or other heating or cooling devices near the body may disrupt the BBT and adversely affect the reading; hence, they need to be avoided while monitoring BBT. BBT cannot be used by the couple to predict ovulation; it only confirms ovulation retrospectively by indicating the event of luteinization but is considered a relatively reliable assessment of the preovulatory phase. Therefore, used as a single tool, it proves to be of limited value. When BBT is monitored concurrently with cervical mucus observations, it can be a very informative and valuable tool for the couple.

Monitoring Cervical Mucus Changes

Daily monitoring of the texture, quality, and quantity of cervical mucus secretions can be useful to predict ovulation. Cervical mucus secretions change throughout the cycle under the influence of estrogen and progesterone. Approximately 2 or 3 days before ovulation occurs, the estrogen levels peak and the nature of the mucus changes from a pasty thick or milky consistency to a distinctive “spinnbarkeit”: stretchy mucus (usually 6 to 10 cm) of wet consistency and opaque color. It resembles a similar texture and nature to raw egg white. At this stage of the cycle, the mucus is an optimal reservoir to nourish sperm and encourage their survival for conception. When seen under a microscope, fertile spinnbarkeit mucus dries into a distinctive crystalline fernlike pattern. Small, inexpensive ovulation predictor microscopes for home use are available to assist couples in predicting ovulation. Saliva is usually used on the microscope as an alternative to cervical mucus, because saliva mimics the ferning pattern of the spinnbarkeit at the ovulation time. When estrogen levels are lower in the early follicular phase and midluteal phase of the cycle, the mucus secretions are thin, milky, and sparse in nature. When a woman is monitoring cervical mucus, it is recommended she feel the texture of the mucus (at the vaginal opening) between the forefinger and thumb and not use toilet tissue to collect the sample. It absorbs moisture and may lead to misinterpretation of the mucus viscosity. Home test kits that measure urinary LH levels are available for ovulation prediction. These are single use tests and their disadvantage is the expense when used regularly.

The Texture and Shape of the Cervix

Some women experiencing infertility may produce inadequate quantities of cervical mucus or experience difficulty feeling the texture of the mucus. In this case, she can be taught to feel the texture of the cervix itself. When cervical tissue is not under the influence of peak estrogen levels it feels hard, cartilaginous (imagine feeling the end of the nose; this is a similar texture), and the cervical os is closed. At the time of the LH surge and estrogen peak, the cervix becomes soft, “ripe,” and palpable (imagine feeling the texture of the cheeks; this is a similar texture) and the cervical os is slightly open.

CONVENTIONAL TREATMENT APPROACHES

Despite developments in fertility knowledge and technologies, the overall prognosis for achieving childbirth with reproductive technologies is approximately 50%, and declines as women age. Each treatment option has overt and hidden costs, including emotional, physical, and financial burdens, often without justification because of lack of success. Couples entering fertility treatment need to be fully cognizant of the potential price of treatment in all of these areas, and the benefit vs. costs must be evaluated. Patients must also consider the high frequency and implications of a multiple pregnancy, a common outcome with assisted reproductive technologies. Psychological support should be available to all couples considering reproductive technologies, with no blame laid upon either partner, and a realistic appraisal of the chances for success and failure of treatment honestly provided. Reproductive expert Marcelle Cedars advises, “The option of child-free living should also be included in any discussion. At times couples must be advised to stop treatment if the likelihood for success is quite low. Frequently this is a very difficult time for both the patient and the physician, but fruitless treatment should be avoided.”¹

Ovulatory Factors

The conventional treatment of ovulatory factors is determined by the conclusive diagnosis made after clinical investigation. With conventional infertility therapy, the chances of conception are said to be 15% to 25% per cycle, depending on the degree of drug-induced ovarian stimulation. If failure to conceive after a maximum of 12 cycles persists, then assisted reproductive technology (ART) is recommended as the next option by allopathic medical reproductive specialists.

Ovarian Stimulation Therapy

Induction of ovulation is said to be successful in 90% to 95% of cases with administration of particular pharmaceutical drugs in a given scenario. Each given scenario depends on a specific set of circumstances, such as hormonal imbalances or failure of a prior drug approach.

In cases of elevated FSH, indicating ovarian failure, postmenopause or ovarian resistance, fertility cannot be restored using drugs. Options for these women include adoption, or embryo or egg donation. Success of pregnancy with embryo or egg donation is reported to be approximately 40%, but this does not reflect live birth statistics for the given scenario. This scenario also gives rise to multifactorial ethical, legal, financial, and psychosocial issues. In the case of chronic anovulation with normal FSH and normal prolactin levels, first line therapy is Clomiphene citrate, a nonsteroidal, antiestrogen drug. This drug is prescribed for women with oligomenorrhea, amenorrhea (including polycystic ovarian syndrome and psychogenic amenorrhea), and women who have sufficient estradiol levels or luteal phase deficiency (progesterone failure). This is administered orally at 50 to 250 mg daily orally on days 5 to 10 of the cycle. It is often combined with corticosteroids, estrogen, and midcycle human chorionic gonadotrophin (hcG) and followed up with monthly hormonal testing or ultrasound to establish the drug’s efficacy in stimulating the follicle and ovulation. Clomiphene citrate is reported to be successful in stimulating ovulation in 70% of cases. The pregnancy rate from use of this drug is only 35%. In 50% of women who use Clomiphene citrate, it stimulates more than one follicle, and the incidence of multiple births is 8%. It is recommended that it not be used for longer than six cycles. Use for longer than 12 months may increase the risk of ovarian cancer. Side effects of Clomiphene citrate include hot flashes, breast tenderness, mood swings, visual problems, thick cervical mucus, luteal phase deficiency (although it is routinely prescribed for this problem), ovarian enlargement, abdominal-pelvis bloating, and discomfort. Ovarian hyperstimulation syndrome has been associated with this drug therapy.

Where there is failure to respond to Clomiphene citrate, or in patients with pituitary insufficiency and/or hypothalamic insufficiency, unexplained infertility, or endometriosis, a second line of treatment is used to induce ovarian stimulation: human menopausal gonadotropin (hMG), a pituitary peptide hormone. This is a combination of FSH and LH derived from the urine of menopausal women. Administration is by intramuscular injection one to two times per day at a dose of 75 to 600 IU/day. This drug regime is also used to stimulate the ovaries in preparation for assisted reproductive technology (ART) procedures such as in vitro fertilization (IVF), gamete intrafallopian transfer (GIFT), or zygote intrafallopian transfer (ZIFT). It is said to be successful in stimulating ovulation in 85% to 90% of cases. It increases the multiple pregnancy rates up to 20% and increases the risk of both ovarian hyperstimulation syndrome and ovarian cancer. Side effects include mood swings and ovarian hyperstimulation.

When the diagnosis of hypothalamic dysfunction has been established and ovarian stimulation using Clomiphene citrate fails, the addition of gonadotrophin releasing hormone (GnRH), a hormone produced by the hypothalamus is administered. This is infused by pump into the indwelling and one side effect is potential infection of the indwelling line. This step is said to restore ovulation in nearly all cases. Restoring ovulation does not necessarily result in a successful pregnancy.

When elevated prolactin levels are causing amenorrhea or luteal phase defects are confirmed (e.g., in PCOS), bromocriptine is used. In this circumstance, thyroid function is also evaluated, as primary hypothyroidism can cause elevated prolactin levels. Many pharmaceutical drugs can also cause hyperprolactinemia as a side effect. This needs to be considered and ruled out. Hyperprolactinemia is treated using bromocriptine, a dopamine agonist. Administration is either oral or vaginally at doses of 2.5 mg twice daily or 0.5 mg twice a week. Bromocriptine does not increase the risk of inducing multiple pregnancies. Side effects include weakness, nausea, and nasal congestion.

Pelvic Factors

Endometriosis and the effects of salpingitis are the most common problems causing infertility related to pelvic factors. These affect the structural health of the fallopian tubes, as well as uterine and endometrial tissue. Salpingitis is usually caused by infections with microorganisms such as Neisseria gonorrhea and Chlamydia trichomatosis; other infective organisms include Escherichia coli, Mycoplasma hominis, and Ureaplasma urealyticum.⁷ Bacterial vaginosis is common among these women. Antibiotic drugs are the usual treatment for these infections.⁸ The treatment option for moderate and advanced endometriosis is usually surgical; at the time of a laparoscopy, resection and ablation is performed. Fibroids are usually left untouched and are only addressed if multiple miscarriages have been a problem. ART is available for those who are unable to conceive after surgery for common pelvic factors.

Cervical Factors

Inadequate cervical mucus midcycle is treated in one of two ways. Either low-dose estrogen is given mid to late in the follicular phase or human menopausal gonadotrophin (hMG) is given to stimulate ovarian production of estrogen. If this fails, the couples are recommended to artificial insemination (AI), one of the oldest of the fertility treatments still used. If cervicitis is a possible causal factor, the antibiotic doxycycline is administered. If surgery (commonly cone biopsy or laser ablation) or congenital issues render the endocervical glands absent or damaged, intrauterine insemination (IUI) procedures can result in pregnancy in 20% to 30% of cases within three cycles of treatment. Those who fail to have a positive outcome are offered the possibility of IVF, GIFT, or ZIFT.

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