Female Infertility

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Chapter 34 Female Infertility


The bearing and rearing of children are part of the ultimate life plan for most adults within our society. When those who desire children are unsuccessful in conceiving, their frustration can turn to despair, helplessness, and the need to seek advice from nearly any source: their mothers, their friends, even the mass media. Popular perceptions of the causes and cures of infertility are frequently incorrect and rarely remedial, which only increases our patients’ apprehension. Many patients will therefore present for the medical evaluation of infertility anxious, apprehensive, and full of self-recrimination.

The purpose of the basic infertility workup is thus to (1) identify the likely basis of the underlying obstacle or obstacles and suggest the best evidence-based therapies, and (2) bring understanding and identity to our patients. This regard for the psychological well-being of our patients will help guide them toward successful closure regardless of the eventual success or failure of their treatment.



Infertility is associated with a broad spectrum of definitions and classifications, indicating that it is interpreted very differently by various groups and individuals (Table 34-1). Broadly defined, infertility depicts a diminished capability to conceive and thereby bear children.

Table 34-1 Basic Definitions

Infertility One-year period of unprotected intercourse without successful conception
Subfertility An ability to conceive a pregnancy that is decreased from age-matched and population-matched controls
Fecundability The probability that actions taken in a single menstrual cycle will result in a pregnancy
Fecundity The probability that actions taken in a single menstrual cycle will result in a live birth
Primary infertility A patient who has never been pregnant
Secondary infertility A patient with a previous history of a pregnancy regardless of outcome (i.e., spontaneous abortion, ectopic pregnancy, stillbirth, or live birth)
Chemical pregnancy A pregnancy diagnosed by a positive β-hCG titer that spontaneously aborts before clinical verification by other means such as transvaginal ultrasonography
Clinical pregnancy A pregnancy diagnosed by a positive β-hCG titer and clinically verified, usually with transvaginal ultrasound (i.e., intrauterine sac or fetal cardiac activity) or, in cases of miscarriage, by pathologic examination

The medical definition of infertility is a 1-year period of unprotected intercourse without successful conception. Utilizing this strict interpretation, infertility is a common problem, affecting at least 10% to 15% of all couples. Based on observational data, the remaining 85% to 90% of couples attempting conception will achieve a pregnancy within that 1-year timeframe.1,2

When viewed across the entirety of their reproductive lifetimes, the problem becomes even more common, and up to 25% of women can have an episode of undesired infertility for which they actively seek medical assistance.3 This is because the desire to conceive can change markedly over the reproductive life of a woman, which is generally considered to be between ages 15 and 44. Couples additionally may not actively attempt conception continually during an entire calendar year, but sporadically across a wider timespan.

It must be remembered that infertility is often a reversible state. The capacity to reproduce is a constantly shifting condition where any substantive change can lead to remarkable differences in overall cycle fecundity rates over time. The most appropriate time to pursue an infertility evaluation is therefore at the specific time that the couple is actually attempting to conceive. Laboratory values and symptom complexes can be considered to be accurate reflections of fecundability only over the short term (i.e., 6 months).

Normal Fecundity Rates

Success rates of specific therapies make the greatest sense when practically compared to rates found in natural conditions (i.e., in the “normal couple”) These per cycle rates of achieving conception can provide simple estimates of the efficacy of various treatment protocols and assists patients in choosing an optimum treatment plan. To appreciate the basic differences between such a normal fertile population and those that present with decreased fecundity, one must be able to appropriately define what normal truly is.

Overall birth rates in the United States have changed markedly over the past 200 years due to an innumerable set of changes in physical, environmental, and social circumstances. The first official U.S. census was performed in 1790 and reported an overall crude birth rate of 55 per 1000 population.4

By the last completed U.S. census, the crude birth rate had decreased to only 14.1 per 1000 population, a quarter of its initial value. Changes in the crude birth rate, however, are not reflective of the true nature of fertility in humans as biologic units.

To measure the true reproductive capacities of Homo sapiens sapiens as individual biologic beings, studies of fertility in the so-called natural populations should be closely examined. Natural population is a term given to groups in which couples are generally permitted to reproduce without any societal limitation to reproduction.5

The Hutterites of North America are an often utilized example of such a natural population.68 This sect of Swiss immigrants originally came to the New World in the mid-sixteenth century and eventually settled in several locations, all in the northern United States and southern Canada. The Hutterites are a closed and very close-knit, truly communal society. There are only six surnames within the entire social structure. All families share equally, and there is therefore no direct impetus or incentive to limit the size of the nuclear family unit. Consequently, they absolutely refuse to use contraception. Overall, the average number of pregnancies per female was 15, while the number of live births averaged 11. Remarkably, although the overall rate of infertility was only 2.4%, a marked decrease in fecundity with advancing age has been documented, with 89% of Hutterite women having their last live birth after age 34, 67% bearing children after age 40, and a mere 13% after age 45. We will discuss the effects of advancing age on fertility later in this chapter.

Data from studies such as these have suggested that fertility in women generally peaks between ages 20 and 24.9,10 It remains fairly stable until approximately age 30 to 32, at which time it begins to decline progressively.11,12 This decline accelerates markedly after age 40. At a bottom line, therefore, fecundity rates in women at age 20 approximate 20% per cycle. This is the peak fecundity rate reflected in the natural setting and can be used as the gold standard when comparing success rates. Subsequently, fertility rates decrease by 4% to 8% in women age 25 to 29; 15% to 19% lower by age 30 to 34; 26% to 46% by age 35 to 39, and 95% lower at age 40 to 45.4,13

These fundamental baseline numbers must be fully understood by both practitioner and patients in order to fully understand the meaning of the relative success rates of the therapies that are being recommended. It is impossible to appropriately counsel the patients on any therapy without fully understanding these basic concepts and the overall limitations of the biology of reproduction.

Over short periods of time, any cross-sectional population of infertile couples will behave in a relatively uniform manner; in other words, a statistically constant proportion will conceive with each additional cycle of treatment and follow-up. Over longer periods of time however, cycle fecundability appears to decline markedly and the overall cumulative pregnancy rate eventually plateaus.14,15

The overall pregnancy rate will never reach 100%. This is primarily due to the overall heterogeneity of infertile and subfertile populations as a whole. Those couples with the highest relative fecundity rates achieve pregnancy most rapidly and are therefore removed from the population, leaving only those couples with more serious problems remaining in the infertile pool. As an example, Zinaman and colleagues reported a prospective observational study of 200 healthy couples desiring to achieve pregnancy and followed them conservatively over a period of 12 menstrual cycles.16

The fecundability rates were highest during the first 2 months of follow-up, greater than 25% per cycle, and had dropped drastically by 6 months to less than 10% per cycle. By the end of the trial, the per cycle fecundability rate was only 3% (Table 34-2).

Although this study followed couples without known fertility problems, the same basic tenets can be applied to any therapy eventually recommended to infertile couples. The fecundity rates of individual therapies will reveal this same diminution across time as the natural model. With each failed cycle of therapy, the chances of relative success with the next cycle are decreased. Not all therapies will lead to success in all patients, nor will all patients become pregnant with any therapy. It is imperative that patients fully understand this concept from the very inception of their treatment. It will greatly increase their understanding of the implications of their therapies and make it far easier to understand the possible failure of those therapies when it occurs.


The simplest manner to express the overall causes of medical and environmental conditions that cause infertility is to divide the overall problem into male factors and female factors. One of the broadest investigations concerning these categorizations was conducted by the World Health Organization (WHO) Task Force on the Diagnosis and Treatment of Infertility in 1992.17 Although there were several significant differences in their findings depending on the economic environment of the populations studied, the data was remarkably uniform.

In the developed world, infertility can be attributed solely to the female partner in 37% of couples and solely to the male partner in 8% of couples; factors can be identified in both partners in 35% of couples. No identifiable direct cause of infertility (i.e., unexplained infertility) can be found in 5% of couples.

The actual percentages that individual factors are found to be the primary cause of infertility vary widely between studies. However, in a broad meta-analysis of more than 20 trials studying infertile couples, the following primary diagnoses were found: disorders of ovulation (27%), abnormal semen parameters (25%), abnormalities of the fallopian tube (22%), unexplained infertility (17%), endometriosis (5%), and other (4%).18 An additional cause is cervical factors, including cervical stenosis, which accounts for up to 5% of infertility in many series.19

Direct observations on human populations allow us to group the causes of infertility into five broad categories, listed in Table 34-3. This broad listing of root causes, although perhaps not complete, can be used as a basis for the initial evaluation of the infertile couple. The overall purpose of the evaluation is to determine which of these overall processes needs to be improved, repaired, or overcome to establish a successful pregnancy. Each question asked at the initial interview, each laboratory test requested, every diagnostic procedure performed must always reflect the need to categorize the problem as simply as possible to suggest the appropriate remedy.

Table 34-3 Causes of Infertility

Infertility and Weight

Anovulation, oligo-ovulation, subfertility, and infertility have all been commonly described in women who are significantly above or below their ideal body weight.20

In one study, women with anovulatory infertility were stratified by body mass index (BMI) and compared to normal fertile controls.21 It was clear that the overall risk of ovulatory abnormality was increased with any significant variation from ideal body weight. Obese women (BMI > 27 kg/m2) had a relative risk of anovulatory infertility of 3.1 compared to women closer to their ideal body weight (BMI 20–25 kg/m2). At the same time, women with a BMI lower than 17 kg/m2 had a relative risk of anovulatory infertility of 1.6. Although the relative risk of anovulation was highest in obese women, it was also significantly increased in underweight women as well.


The initial evaluation is by far the most important interview the caregiver will ever have with the infertile couple for several reasons. First, as with any initial visit, it is the primary information gathering occurrence the caregiver will share with the patients. The first evaluation will help identify the specific causes of infertility and suggest the appropriate treatment. As previously stated, with proper evaluation and treatment, the majority of women will become pregnant, and proper categorization will assist in this greatly.

Second, it serves as the beginning of a partnership between caregiver and the couple that will hopefully lead to conception. The first visit helps lay down the sense of understanding and trust necessary between physician and patients, especially in such an emotionally charged situation as infertility. This understanding is vital to overcome much of the misinformation that has been gained by the patients from friends, relatives, and the mass media.

Third, the patients should understand from the initial counseling session that although they have presented asking for medical advice concerning their infertility, the eventual therapeutic decisions are solely theirs to make. In the age of in vitro fertilization/embryo transfer (IVF/ET), intracytoplasmic sperm injection (ICSI), ovum donation, and the other ARTs, there are medical solutions for nearly every cause of infertility or subfertility. The patients have to realize, however, that the ultimate decision concerning what therapies are personally acceptable to them lies only within their hands. They are in control of both the direction and the intensity of suggested therapy and should be counseled to such an extent starting at the first meeting.

Last, this initial evaluation should lay down the guidelines of possibility to the patients. Not all therapies will work in all patients and not all patients will become pregnant regardless of the therapy. The couple should be given a concise outline of the possibilities of care and all of the information necessary to make an intelligent decision concerning their options. When the patients are allowed to have such an involvement in decision making, it allows them to more easily accept the failure of any individual therapy and helps them reach closure if success is never attained.

Primary Elements of the Initial Infertility Evaluation

The initial evaluation consists of seven primary elements (Table 34-4). It is recommended that the entire initial evaluation should be completed before direct recommendations concerning treatment are suggested to the patients. Most patients will accept a temporary delay in their therapies while full evaluation of all aspects of their clinical state is accomplished far easier than they do frequent changes in their protocol interspersed with intermittent testing and analysis.

Table 34-4 Initial Infertility Evaluation

Physical examination
Semen analysis
Tests of hormonal status
Assessment of tubal patency
Tests of ovulatory status
Assessment of luteinization


The data collected as part of a careful medical history will often identify signs and symptoms of a specific disease or cause and focus the evaluation on the factors responsible for the infertility. Many of the answers to the questions that should be asked, especially those concerning medical and family history and any previous evaluations, are more fully answered when the patients are specifically prepared to answer them.

Sending a questionnaire to the patients before their initial evaluation is strongly recommended. By filling out these data sheets before their initial visit, the patients will be forced to (1) find out the answers to the questions that they do not immediately know the answers to, especially those about family history, (2) have collated the data from other physicians concerning testing already performed and other therapies attempted, and (3) be able to better understand the nature of the first evaluation prior to their arrival. There are several versions of preprinted questionnaires available either through the American Society for Reproductive Medicine (ASRM) or from many of the pharmaceutical companies that produce the medications used in ovulation induction.

In the female partner, the relevant medical history concerning the causes and the nature of infertility covers a broad range of subjects.22,23

Attention to detail during this collection of data is imperative.

Family History

Many common genetically determined diseases, such as congenital adrenal hyperplasia, can have a significant effect on ovulation and fecundity. Such family information would be helpful in determining the need for further provocative testing of the proband. Include questions about the following:

Questions should be raised about a familial history of any of the following problems in any population:

Table 34-5 Genetic Screening for Various Ethnic Groups

Ethnic Group Disorder Screening Test
Ashkenazi Jews

African Americans Sickle cell anemia Presence of sickle cell hemoglobin, confirmatory hemoglobin electrophoresis Mediterranean populations Beta-thalassemia electrophoresis Mean corpuscular volume (MCV) < 80%, followed by hemoglobin Southeast Asians Chinese Alpha-thalassemia Hemoglobin electrophoresis if mean corpuscular volume < 80% Cystic fibrosis DNA analysis of specified panel of 25 CFTR gene mutations

Adapted from American Society for Reproductive Medicine: Appendix A: Minimal genetic screening for gamete donors. In 2004 Compendium of ASRM practice committee and ethics committee reports. Fertil Steril 82:S22–S23, 2004.

Sexual History

Coital Frequency and Timing

It is important to be aware of the association of coital timing and the probability of successful conception (Fig. 34-1). Because activated sperm can last for up to 80 hours in the female reproductive tract,40,41 it has long been a general recommendation that intercourse occur at specific times during the menstrual cycle to ensure that at the time of expected ovulation there will be capacitated sperm available for fertilization. There can, however, be a significant diminution of both cycle and overall fecundity rates if coitus becomes too frequent.42,43


Figure 34-1 Probability of conception according to day of coitus in relation to the day of basal body temperature (BBT) rise. Day 0 indicates day of BBT rise.

(Data from From Royston JP: The probability of conception and day of timed intercourse. Biometrics 38:397, 1982.)

It is important to remember that coitus is usually a spontaneous expression of love between two individuals. If their love-making is placed on too specific a timed schedule, it can lead to significant performance anxiety, sexual dysfunction, and a worsening of the problem at hand. This will in turn greatly increase the already high frustration level borne by the couple. Consequently, unless there is marked male factor infertility present, there can be no clear medical justification for advising the avoidance of coitus at any time. It should be suggested to the patients that they make love at least twice a week from the cessation of menses.


Questions concerning painful intercourse should be specific to typify the type of dysfunction that this pain represents.

Is the pain insertional in nature? A lack of lubrication at the initiation of coitus and the pain that it can engender does not necessarily represent the presence of an organic problem specific to the reproductive tract.

Do the patients utilize an artificial lubricant on a regular basis? Although most commercially available vaginal lubricants are not spermicidal in their basic nature, their use can form an amalgam with the semen placed into the vagina during ejaculation. This may lead to a decrease in sperm motility and the number of sperm that enter the cervix. It should be suggested to the patients that alternative methods of increasing vaginal lubrication be used during times of high relative fecundity.

Is there deep thrust dyspareunia? Deep thrust dyspareunia can be a very common gynecologic problem, but it is usually an episodic or intermittent complaint.44

The etiology of this symptom stems from the relative immobility of the pelvic organs and arises from rapid stretching of the uterosacral and cardinal ligaments due to the sudden movement of the cervical/uterine unit during coitus. It can also be caused by direct pressure on nodular lesions of endometriosis in the uterosacral ligaments or in the pouch of Douglas. Deep thrust dyspareunia should raise the suspicion of an organic disease, such as endometriosis or adenomyosis.4548

Is there increased pain with orgasm? Orgasm is physiologic, typified by rhythmic contractions of the orgasmic platform and the uterus, created involuntarily by localized vasocongestion and myotonia.49 These contractions have a recorded rhythmicity of approximately 0.8 seconds, as the tension increment is released in the orgasmic platform, but accumulates slowly and more irregularly in the uterine corpus. The eventual strength of these uterine contractions may be 4 to 5 times the baseline to peak intensity of a labor contraction.50

Localized production of prostaglandins and endoperoxidases in both endometriosis and adenomyosis can intensify these contractions and cause sensitization of C-afferent nerve fibers in the pelvis, thereby eliciting greater pain with each of these individual contractions.51 Marked pain with orgasm may therefore be a diagnostic suggestion of organic disease of the reproductive tract.52