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Infertility is defined as a failure to
conceive after 1 year of unprotected, appropriately
timed intercourse without conception. The prevalence
of infertility among couples in the United States is
approximately 10%-15%. Possible contributing factors
include advanced maternal age due to delay in child
bearing and a decrease in sexual activity with increasing
length of relationship. The natural fecundity rate (the
percentage of fertile couples achieving a live birth)
per month is estimated at 20%-25%. Life table analysis
reveals that 64% of women with primary unexplained infertility
(when all standard clinical tests yield normal results)
and 79% with secondary infertility (when a previous
pregnancy has occurred) will conceive within 9 years.
Nevertheless, the decision to institute diagnostic tests
and treatment should be made on an individual basis.
This article will address the basic infertility work-up.
Next month we will discuss specific causes and their
evaluation.
Conception and pregnancy are dependent
on a complex interaction of physiologic, anatomic, and
immunologic factors. The man requires normal spermatogenesis,
reproductive anatomy, and sexual function to provide
an adequate number of morphologically normal, motile
spermatozoa in the upper vagina of a woman. The woman
requires a functionally intact hypothalamic-pituitary-ovarian
axis to orchestrate the menstrual cycle and stimulate
normal folliculogenesis, ovulation, and a luteal-phase
hormonal environment. In order for the egg and sperm
to meet in the fallopian tube, the sperm must initially
pass through the cervical mucus, which may be impervious,
depending on the time of the female's menstrual cycle.
The tube must then be mobile and functional to retrieve
the egg. Once fertilized, the "pre-embryo"
travels to the uterus where successful implantation
is contingent on an adequate hormonally stimulated endometrium,
which is maintained by progesterone production from
the corpus luteum. A disruption in any of these steps
can result in infertility.
In 20%-25% of couples, both the man
and woman have reproductive abnormalities. Both female
and male factors each account for 40% of fertility problems.
Other etiologic factors have been studied. Exercise
programs can be associated with menstrual disturbances
and decreased fertility. Strenuous activity can result
in amenorrhea or oligomenorrhea by causing adverse effects
on gonadotropins, androgens, estrogens, and progesterone.
Cigarette smoking has been shown to affect fertility
rates in an inverse ratio; some studies have shown a
possible alteration in tubal physiology, transport,
and cervical mucus as a result of smoking. Sperm parameters,
as shown by semen analysis, have also been adversely
affected by cigarette smoking.
The basic infertility work-up begins with obtaining
a comprehensive medical history from both partners.
In addition to the usual gynecologic history, it is
important to discuss coital frequency and timing, sexual
dysfunction, and use of spermicidal lubricants. Other
areas of importance are endocrinologic abnormalities
including galactorrhea, weight changes, acne, frontal
balding, and hirsutism. The man should also give a fertility
and sexual history. Also, environmental exposures may
lead to an underlying cause. The woman should undergo
a thorough physical examination, including a pelvic
examination with cultures of Chlamydia, gonorrhea, and,
possibly, mycoplasma and urea plasma, as indicated.
If the semen analysis reveals abnormalities, the man's
external genitalia should also be examined to exclude
serious pathology. The couple's medical records of diagnostic
tests should then be reviewed. It is important to provide
appropriate education to assist the infertile patient
or couple in the understanding of the problem, evaluation,
and treatment proposed. Laboratory testing and procedures
will address the etiologic factors.
The male factor is estimated to be
significant in 40%-50% of couples. To determine the
adequacy of the spermatozoa, the man must submit a semen
sample for analysis after at least 2, but no more than
5 days of sexual abstinence. Sperm morphology has shown
to be the most important semen parameter in predicting
fertility rates and pregnancy outcome in assisted reproduction.
Abnormal semen parameters can result from fluctuations
in hormonal levels, from genetic or congenital abnormalities,
and from drug use, infections, previous surgery, and
exposure to occupational and environmental toxins.
Ovulatory dysfunction occurs in approximately
30% of infertile patients. Presumptive evidence of ovulation
is determined by using the basal body temperature (BBT)
chart, steroid or gonadotropin hormone assays, and ultrasound;
by analyzing cervical mucus changes; or by an endometrial
biopsy. A history of regular monthly menses, premenstrual
molimina, and dysmenorrhea are usually indicative of
ovulation. The mid-cycle luteinizing hormone (LH) surge
is the most reliable predictor or ovulation, but its
analysis requires frequent blood sampling and expensive
radioimmunoassay. The determination of BBT is the oldest
and most widely used test, but it is not the most accurate
or reliable method of ovulation detection. Temperature
elevation is secondary to the effect of progesterone
on the hypothalamus. A temperature greater than 98 degrees
Fahrenheit with a rise of 0.4-0.6 degrees Fahrenheit
between 2 consecutive days is characteristic of ovulation.
The BBT predicts the LH surge within 2-3 days. A sustained
elevation of temperature for less than 10 days suggests
a luteal phase deficieny (LPD). A single serum progesterone
reading of greater than 3 ng/mL in the luteal phase
is presumptive evidence of ovulation, and greater than
10 ng/mL virtually excludes a LPD.
The endometrial biopsy is another method of confirming
ovulation but also evaluates the adequacy of the luteal
phase. This test is the histologic means to diagnose
a luteal-phase defect (LPD), however the clinical significance
of LPD is highly dubious. More recently, the lack of
alpha v beta 3 integrin expressed by the endometrium
has been associated with a decreased rate of implantation.
This protein is only expressed during the window of
implantation and its absence is found in 50% of patients
with endometriosis.
Tubal factor infertility, a cause
in 30%-50% of cases, may first be suspected on the basis
of the patient's history. Significant risk factors include
a history of acute salpingitis (often referred to as
pelvic inflammatory disease [PID]), septic abortion,
ruptured appendix, pelvic or tubal surgery, a history
of an ectopic pregnancy, and possibly use of an intrauterine
device. The incidence of infertility after salpingitis
is 11%-12%, 23%, and 54% for one, two, and, at least,
three episodes, respectively. In addition, salpingitis
increases the risk for ectopic pregnancy due to damage
of the tubal mucosa. Nevertheless, about half of the
patients with tubal disease or pelvic adhesions have
a negative history for PID. Hydrosalpinges have been
demonstrated to have a deleterious effect on implantation
either from retrograde toxic fluid or absence of integrin.
Salpingectomy (removing the tube) or salpingostomy (opening
the tube) has been recommended to improve pregnancy
rates naturally or with assisted reproduction.
The uterine factor is a rare cause of
infertility, accounting for only about 2% of cases.
Anatomic causes such as leiomyomas, polyps or, rarely,
adhesions can impair sperm transport or embryo implantation.
Hysterosalpingography (HSG) allows
the diagnosis of uterine and tubal factors. By using
water soluble or oil contrast media, HSG can lead to
identification of intrauterine anomalies and tubal patency.
It has approximately a 75% correlation with laparoscopy
and hysteroscopy for accuracy. The procedure is usually
performed in the follicular phase of the menstrual cycle,
2 to 5 days after cessation of menses. The risk of infection
from the procedure is less than 1% in a low-risk population
and greater than 3% in a high-risk group.
Hysteroscopy and laparoscopy are the final
diagnostic procedures in the basic infertility work
up. Hysteroscopy can lead to identification of intrauterine
adhesions, submucosal leiomyomas, and endometrial polyps.
While viewing the pelvis, a laparoscopy can lead to
a diagnosis of adhesions, endometriosis, or tubal disease.
These procedures not only definitively diagnose uterine
and pelvic factors but also facilitate operative management
by the physician.
In addition to the heretofore outlined work up, the
diagnosis of unexplained infertility may warrant further
investigation. This can include bacteriologic, immunologic,
sperm-penetration, and ultrasound studies. The treatment
of unexplained infertility has included expectant management,
controlled ovarian hyperstimulation (COH) with clomiphene
citrate or gonadotropins, IUI, a combination of COH
and IUI, and In-Vitro Fertilization. As with other diagnoses,
treatment is ultimately determined by thorough consultation
with the patient or couple after all options have been
discussed.
A shorter duration of infertility
upon initial consultation carries a more favorable prognosis.
The physician should individualize treatment and be
realistic. Professionals caring for patients with infertility
should be aware of resources, such as RESOLVE, which
offer emotional support as well as information concerning
adoption.
- Infertility-Discussion
- Female Infertility
- Male Factor Infertility
- Cervical Factor Infertility
- Endometriosis
- PCOS
- Ovulatory Dysfunction
- Tubal Factor Infertility
- Uterine Factor Infertility
- Unexplained Infertility
- Infertility Overview- Samuel Thatcher, MD
- Clomid- Extensive Information at Huntington Reproductive Clomid Web Site
- PRESERVING
REPRODUCTIVE OPTIONS IN ONCOLOGY PATIENTS ,
by Bradford Kolb, M.D., F.A.C.O.G.,
Board Certified, Reproductive Endocrinology and Infertility
- THE
CONTEMPORARY FERTILITY EVALUATION, by Daniel Potter, M.D., F.A.C.O.G.,
Board Certified, Reproductive Endocrinology and Infertility,
Huntington Reproductive Center
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