An Overview of Female Infertility

Sandra L. Torrente and Valerie Montgomery Rice Overview

According to the 1995 National Survey of Family Growth, the percentage of women reporting some form of fecundity impairment rose from 8% in 1988 to 10% in 1995 which some believe is related in part to a trend toward delayed child-bearing. Numerous observational studies have demonstrated that 80-90% of couples that have unprotected intercourse for 12 months will conceive. Thus, the accepted definition of an infertile couple is the failure to conceive after 12 months of intercourse without any form of birth control. Evaluation for infertility is indicated for couples who fit this definition as well as those who have significant risk factors for infertility who may have less than 12 months of exposure to the possibility of pregnancy (e.g., history of oligomenorrhea or sexually transmissible infections). The general causes of infertility and the frequencies are listed in Table 13.1. In this chapter we will focus on the female factors affecting infertility (Table 13.2).

An increasing number of women are waiting to start their families until completion of education and/or training, one factor that has led to women seeking pregnancy later in life. In the 1970s women over 35 years of age accounted for 5% of pregnancies and today they account for up to 14% of the pregnancies. Women in general will experience a decreased fecundity rate at 37.5 years of age. This is attributed in great part to a decline in the number of healthy oocytes, directly influencing the rate of conception.

When evaluating a patient for infertility, ideally the medical history and physical exam are obtained from the couple. One must obtain a complete obstetrical and gynecological history from the female. The menstrual history is an excellent indictor of ovulatory status. A complicated obstetrical history may suggest the need for maternal fetal medicine consultation prior to initiating therapy, especially if the planned infertility treatment predisposes to multiple births. The gynecologic history can give clues about risk factors for tubal scarring (Chlamydia infection, surgery for endometriosis) or cervical factor infertility (ablation for abnormal Pap smear).

The sexual history is obviously relevant. The sexual history should include frequency of coitus especially in the periovulatory period. Complaints of sexual dissatisfaction are common among infertile couples who often feel that spontaneity is lost in striving to achieve pregnancy. Dyspareunia may suggest that endometriosis is the problem. Use of a lubricant may affect sperm motility. Finally, the history of contraception use is important to establish if the patient has experienced any complications with hormonal therapy, particularly a deep venous thrombosis. It is not uncommon for couples to seek help from different medical providers; therefore, try to obtain any previous infertility work up the couple has been through.

Table 13.1. General causes of infertility

Female factor Male factor Unexplained factors

Table 13.2. Causes of female infertility

Tubal factor Ovulatory dysfunction

Endometriosis Unexplained

Cervical factor Uterine factor

A general medical history is imperative in determining other major medical problems affecting a patient's fertility. A patient should be in optimal health prior to initiating fertility therapy. Many common chronic medical conditions such as diabetes mellitus, hypertension and obesity will increase a patient's risk for miscarriage and pregnancy complications. Lastly, taking a social history will identify any habits which may influence a patient's fertility. Tobacco, marijuana, and cocaine use will affect fecundity rates in women as well as men. There is a known dose-response relationship between the number of cigarettes smoked and length of time it takes to achieve pregnancy. Marijuana affects the fertility directly by inhibiting secretion of GnRH in both men and women. Cocaine is also known to decrease spermatogenesis.

An example of a history form for an infertile woman is provided in Table 13.3. Steps in the evaluation of infertility are summarized in Table 13.4 and Figure 13.1.

Ovulatory Disorder

Patients with an ovulatory disorder that is not due to ovarian failure have several medical options available. There are three types of ovulatory dysfunction that are classified by the World Health Organization (WHO):

Hypothalamic-Pituitary Failure (Hypogonadotropic Hypogonadal Anovulation)

Patients with this form of anovulation suffer from hypothalamic amenorrhea. Patients will have low estrogen levels, low gonadotropin levels (FSH and LH), normal prolactin levels and will not bleed after a progesterone challenge. The classic patients seen with this disorder are those that suffer from anorexia nervosa, or athletes with a low BMI (<17), and women under high stress.

Treatment

• Lifestyle modification including reducing exercise, improving nutritional intake, and addressing any underlying psychological issue will help return ovulatory function. If lifestyle modification does not improve anovulation use of gonadotropins can be considered. Because of low estrogen levels, these patients do not usually respond to clomiphene.

Table 13.3. Infertility History (female)

Marital History

Married_ # of years_# Prior marriages_

Single_Separated_Divorced_Widowed_

Menstrual History

Last menstrual period_ Regular_yes_no

Menarche_ Intermenstrual bleeding yes_no

Interval__Dysmenorrhea_yes_no

Duration_

Amenorrhea_ primary_secondary_

Virilization:_hirsutism_balding_acne_voice changes

Obstetric History

Gravida:_term_premature_stillborn_spontaneous abortion_induced abortion

Ectopic pregnancies:_right_left

Complications:_pregnancy_postpartum

Gynecologic History

Previous abdominal

or pelvic surgery

_yes

_no

DES exposure

_yes

_no

Endometriosis

_yes

_no

PID

_yes

_no

Abnormal pap

_yes

_no

STD

_yes

_no

Previous Infertility or

Endocrinology Studies

PCT

_yes

_no

Hormonal studies

_yes

_no

HSG

yes

_no

Semen analysis

yes

_no

BBT

_yes

_no

Medication

_yes

_no

Endometrial BX

_yes

_no

Laparoscopy

_yes

_no

Other studies

_yes

_no

Sexual History

Frequency 1

ime per

Contraception:

None_

Satisfied

_yes

_no

Oral contraceptive

_yes

_no

Dyspareunia

yes

_no

IUD

_yes

_no

Diaphragm

_yes

_no

Lubricant use

_yes

_no

Female sterilization

_yes

_no

Male sterilization

_yes

_no

Habits

Cigarettes

_yes

_no

_# per day

Alcohol

yes

_no

# drinks per

Marijuana

_yes

_no

# times used per

Other drugs

_yes

_no

# times used per

Family

Past Medical History

Operations: Hospitalizations: Current medications:

Patient

Family

Birth defects:

Inherited disease (i.e., cystic fibrosis, sickle cell):

Table 13.4. Evaluation of infertility

Test

Serum FSH Hysterosalpingogram

Serum progesterone Serum TSH Serum prolactin Semen analysis on partner

Purpose

Evaluate ovarian reserve

Tubal patency and uterine configuration

Establish ovulation

Confirm euthyroid state

Rule out adenoma

Evaluate male

Time of Cycle

About 7 days after LH surge N/A

Luteal phase N/A

Medical Algorithm
Figure 13.1. Infertility algorithm.

Hypothalamic-Pituitary Dysfunction (Normogonadotropic Normoestrogenic Anovulation)

Patients with this form are usually oligomenorrhea women. Many women in this category have polycystic ovarian syndrome (PCOS) and will have an elevated LH/FSH ratio, elevated androgens, and enlarged ovaries with multiple follicles. Of the three types of ovulatory dysfunction, this is the most common.

Treatment

• Lifestyle style modification for women with anovulatory infertility often consists of weight loss. Women with a BMI>27 and oligomenorrhea should be counseled on weight loss as first line therapy for infertility. A loss of 5-10% of body weight may be enough to restore ovulation.

• Ovulation induction is the initial step taken if weight is not an issue or if the patient remains anovulatory after weight loss. The first line of therapy is clomiphene citrate, a SERM with estrogen antagonist and agonist effects that increases gonadotropin release. Clomiphene is given on cycle days 5 through 9 at a dose of 50 mg/day (if ovulation does not occur in the first cycle the dose is increased in subsequent cycles). The LH surge will occur 3-12 days after the last dose of clomiphene. The LH surge can be determined using urinary ovulation predictor kits. Ovulation can be expected to occur 24-48 hours after detection of a positive result.

Insulin sensitizing agents (Metformin) used concurrently can improve the response to clomiphene in PCOS patients. Metformin works to decrease gluconeogenesis, and intestinal uptake of glucose.

• Once ovulation is established, if the patient does not become pregnant in six cycles, intrauterine insemination (IUI) should be considered.

• If ovulation induction with IUI does not achieve pregnancy after three to six cycles of positive ovulation IVF should be considered.

Ovarian Failure (Hypergonadotropic Hypoestrogenic Anovulation)

Patients with this form of anovulation present with premature ovarian failure Gonadotropin levels are elevated and estrogen levels are low.

Treatment

• Oocyte donation and IVF is highly successful for this group of patients.

Hormone replacement therapy is generally recommended for symptomatic relief and to prevent osteoporosis.

Hyperprolactinemic Anovulation

Patients will present with oligomenorrhea or amenorrhea and sometimes galac-torrhea. Fasting prolactin levels are elevated and estradiol levels are often decreased. First one must rule out a pituitary adenoma with an MRI.

Treatment

• A dopamine agonist is generally the first line treatment.

Tubal Disorders

Infertility occurs when the fallopian tubes or fimbria are scarred or blocked and cannot transport the ovum or sperm, or serve as the site of fertilization. Previous history of salpingitis (tubal infection), pelvic inflammatory disease, endometriosis, or abdominal surgery can all lead to tubal scarring. Seventy-five percent of tubal disease can be attributed to a previous Chlamydia infection, often asymptomatic. The United States Preventative Task Force (USPSTF) recommends that clinicians routinely screen women under the age of 25 and sexually active and other asymptomatic women at increased risk for Chlamydia infection. Hysterosalpingography (HSG) is used to evaluate tubal patency.

Treatment

• Surgical options for tubal repair depend on the site of obstruction and severity of tubal damage.

• Proximal tubal obstruction can be treated with hysteroscopic or fluoroscopically-guided catheterization of the fallopian tube.

• IVF is the treatment of choice for tubal disease that cannot be surgically corrected. If there is a hydrosalpinx present, salpingectomy prior to IVF improves the outcome with IVF.

Endometriosis

Patients with known endometriosis may suffer from infertility, sometimes due to adhesions causing tubal blockage or decreased tubal motility. However, the mechanism of infertility is not understood for patients with mild disease and no apparent anatomic distortion. Some studies suggest that patients with minimal to mild en-dometriosis that do not apparently have tubal blockage still should undergo ablative treatment to reduce endometriosis, as a means of improving fertility.

Treatment

• Laparoscopic resection or ablation of endometriosis and adhesiolysis is preferable to medical treatment for infertile patients.

• Ovulation induction (clomiphene or gonadotropins) and IUI can be offered if there is at least one normal, patent fallopian tube.

• IVF should be offered if surgery and ovulation induction/IUI fail or if the endometriosis is extensive.

Uterine Disorders

Patients with uterine abnormalities will present more likely with recurrent pregnancy loss and not primary infertility. The uterine abnormalities most commonly seen are submucosal leiomyomas, endometrial polyp, septate uterus, and uterine synechiae which all can interfere with implantation.

Treatment

• Leiomyomas—The need for surgery in an otherwise asymptomatic infertile woman depends upon the size and location of the fibroids. Abdominal myomectomy is the treatment of choice for large intramural or subserosal leiomyomas, especially if they distort the endometrial cavity. Small fibroids in these locations do not require treatment. Hysteroscopic myomectomy is preferred for submucosal leiomyomas which are associated with increased miscarriage rate unless resected.

• Endometrial polyps—should be removed by operative hysteroscopy.

• Septa and synechiae—should be treated with hysteroscopic resection.

Cervical Disorders

Unfavorable cervical mucus at midcycle may act as a physical barrier for sperm penetration. Similarly, the cervix may cause infertility in women with stenotic cervical os, cervical surgery or ablation for dysplasia or chronic cervicitis.

Treatment

• Bypass the cervix with IUI and IVF if necessary.

• Treat cervicitis, if present.

Unexplained Infertility

Ten to fifteen percent of couples present with a completely normal workup. Patients in this group may have problems that cannot be detected by available testing: ovum pick up, sperm transport, fertilization or implantation. However, older female age with decreased ovarian reserve or borderline semen parameters are common in couples with this diagnosis. Randomized, controlled clinical trials support the use of superovulation and IUI as first line treatment, resulting in 2-3 fold increase in cycle fecundity depending upon patient selection and the regimen used. Superovulation increases the number of eggs available to the sperm and corrects any subtle ovulation problems. The insemination delivers greater numbers of motile sperm closer to the egg for fertilization.

Treatment

• Clomiphene alone or with IUI is the usually the first line of therapy.

• Gonadotropin therapy with IUI has a higher multiple birth rate and is usually reserved for patients who fail to conceive with clomiphene.

• If three cycles of gonadotropins and IUI fail, ART can be offered.

Definitions

1. Assisted reproductive technologies (ART)—all methods that involve direct retrieval of oocytes from the ovary (see chapter on ART).

2. Basal body temperature (BBT)—a test used to confirm ovulation. Patient is asked to record their oral temperature every morning before arising, starting with the onset of menstrual flow. The rise should be greater than 0.4 degrees Fahrenheit for the ten days or more preceding menses to indicate ovulation.

3. Clomiphene citrate—A selective estrogen receptor modulator (SERM) that acts as an estrogen antagonist and agonist. The agonist effect increases gona-dotropin release. The starting dosage is generally 50 mg/day for 5 days starting on cycle day 5 (see Chapter 15).

4. Fecundability—The probability of achieving a pregnancy within one menstrual cycle.

5. Fecundity—The ability to achieve a live birth within one menstrual cycle.

6. Follicle-stimulating hormone (FSH)—A hormone produced by the pituitary gland. Pharmacologic preparations can be given as to cause follicle recruitment and growth within the ovary.

7. Hysterosalpingogram (HSG)—a radiological test that is performed to identify any uterine cavity or tubal defects.

8. Infertility—One year of unprotected coitus without conception.

9. In vitro fertilization (IVF)—A type of ART that includes ovarian stimulation, egg retrieval and sperm collection, the eggs are fertilized and incubated in the laboratory. Resulting embryos are later transferred to the uterus.

10. Intrauterine insemination (IUI)—Introduction of "washed" sperm into the uterus.

11. Intracytoplasmic sperm injection (ICSI)—Direct injection of a single sperm into an oocyte.

12. Luteinizing hormone (LH)—A hormone produced by the pituitary gland, which causes follicle development, egg maturity, and ovulation. LH can also be given as a medication.

13. Ovarian hyperstimulation syndrome—A complication of ovulation induction therapy. There three grades: mild which consists of mild abdominal pain and the ovaries are <5 cm in diameter on ultrasound exam; moderate which the ovaries measure 5-10 cm in diameter; and severe in which the patient presents with intraperitoneal fluid and may also have oliguria, hypotension, and pleural effusions (see Chapter 15).

14. Post coital test (PCT)—A test to establish if the sperm and cervical mucus are compatible. The test is performed 2-8 hours after intercourse around the time of ovulation and requires a microscopic evaluation of the cervical mucous for the presence of motile sperm. Because of poor reproducibility and lack of predictive power, this test is not routinely recommended in the evaluation of the infertile couple.

Key Points

1. Establish if the cause of infertility is reversible or irreversible. If it is reversible (i.e., PCOS) correct the issue with appropriate medical or surgical therapy. If it is irreversible (i.e., ovarian failure) counsel in regards to ART with possible oocyte donation.

2. The most common cause of female infertility is ovulatory dysfunction. Fortunately with minimally invasive infertility therapy patients can reach a fecundity rate similar to that of couples without fertility problems.

3. Ensure appropriate counseling of the risk involved when using ovulation induction medication and IVF.

4. Women with known endometriosis should have optimal ablation or resection of endometriosis prior to infertility therapy. One must also ensure tubal patency.

Suggested Reading

1. Speroff's, Clinical Gynecologic Endocrinology and Infertility. 7th ed. Lippincott Williams and Wilkins, 2005, [For a thorough review of female infertility, Speroff's 7th ed, is the book all residents should have. It is what one should read during their RE/I rotation. Specifically Chapters 27 and 31 were referenced for this review].

2. ACOG Practice Bulletin #34, February 2002. Management of Infertility Caused by Ovulatory Dysfunction, ACOG Compendium. 2005, [For a much more abbreviated review, but helpful for both interns and residents the ACOG Compendium is what one should read for a quick reference].

3a. Smith S, Pfeifer S, Collins J. Diagnosis and management of female infertility. JAMA 2003; 290:1767-1770.

3b. Lobo R, Potential options for preservation of fertility in women. New England Journal of Medicine 2005; 353:64-73.

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