Infertility
Infertility is defined as a diminished
capacity to conceive and bear a child. It is not equivalent to sterility, the
absolute and irreversible inability to conceive. Clinically, a couple is
considered infertile if they are unable to conceive after 12 months of
unprotected, frequent coitus. Many factors contribute to infertility (Fig.
34.1). Diseases that affect only females account for about half of infertile
couples and diseases that only affect males about one-third. About 10% of
couples will have disorders in both the male and the female partner. Some
10–15% of couples have no identifiable cause for their infertility or will
become pregnant during the evaluation. Specific disorders causing infertility
include those involving each of the major physiologic events necessary to
produce a pregnancy: (i) production of a healthy egg; (ii) production of
healthy sperm; (iii) transportation of the sperm to the site of fertilization;
(iv) transportation of the zygote to the uterus for implantation; (v)
successful implantation in a receptive endometrium; (v) presence of other conditions, some
immunologic, that can interfere with one or more of the other events.
Oocyte abnormalities
The main cause of female
infertility due to oocyte abnormalities is a failure to ovulate regularly or, in
some cases, at all. Those disorders that result in oligo-ovulation or anovulation
are also causes of amenorrhea (see Chapters 30 and 31), and fall into three
categories: hypothalamic dysfunction, pituitary disease and ovarian
dysfunction.
Common hypothalamic causes of
anovulation include abnormalities of weight and body composition, strenuous
exercise, stress and travel. Pituitary or endocrine disorders associated with
anovulation are hyperprolactinemia and hypothyroidism. The two most common
known causes of ovarian dysfunction are polycystic ovary syndrome and premature
ovarian failure. Oocyte abnormalities more complex than simple anovulation
cause the fairly rapid decline in fertility that occurs as women enter their
40s.
Female anatomic abnormalities
Fallopian tubal disease is
usually the result of inflammatory scarring of the fallopian tubes. This may be
caused by pelvic inflammatory disease, appendicitis with rupture, septic
abortion, previous surgery and, occasionally,
previous use of an intrauterine device. The most common site of tubal blockage
is the distal fimbriated end of the tube. These blockages are typically
associated with additional pelvic adhesions and may affect up to 20% of the
women in infertile couples. Purposeful, surgically-induced blockage occurs with
surgical sterilization; some women regret their contraceptive decision
post-tubal sterilization and present to the fertility specialist requesting
reversal.
Endometriosis is a common
disorder, characterized by the presence of tissue resembling endometrium
outside of its normal position lining the uterus. The glands and stroma of
endometriosis are usually respon- sive to gonadal hormones and the biochemical
changes the steroids induce in this ectopic endometrium mimic those seen in
endometrium within the uterine cavity. Increased prostaglandin production by
peri- menstrual and menstrual endometriotic lesions is thought to promote the
inflammation, fibrosis and adhesion formation characteristic of the dis- order.
Endometriosis lesions can be found almost anywhere in the pelvis but are most
common on the peritoneal surfaces covering the pouch of Douglas,
bladder, ovaries, fallopian tubes,
bowel and appendix. Women with endometriosis can
present with pelvic pain, adnexal masses (endometriomas), infertility, or any
combination of these.
Uterine leiomyomas, also
known as fibroids or uterine myomas, are benign smooth muscle tumors of the
uterus. They are the most common pelvic tumor in women, and may be located
anywhere within the wall of the uterus or may hang from a stalk containing the
blood supply to the tumour (pedunculated leiomyomas). Pedunculated leiomyomas
may hang from the outside of the uterus or may project into the endometrial
cavity. Those leiomyomas that distort the uterine cavity (submucosal in
location) or physically obstruct fallopian tubes are most closely associated
with decreased fecundity.
Male factors
A varicocele is a
dilatation of the pampiniform plexus of veins that drain the contents of the
scrotum. Varicoceles appear to reduce semen quality in some men and their
correction improves semen quality. The ultimate effect of correction on
fertility is less clear. Varicoceles may adversely affect semen quality by exposing
the testis to temperatures higher than those in nonaffected men or by exposing
the testis to abnormally high concentrations of gonadotoxic
substances. Both effects appear to result from decreased venous efflux from the
affected testis.
Blockage of the vas deferens or
epididymis can result from con- genital abnormalities (i.e., mutations in the cystic
fibrosis transmembrane regulator gene; Chapter 26), from infection-associated
scarring, or from inadvertent surgical ligation at the time of inguinal
surgery. Purposeful, surgically induced blockage occurs with vasectomy; some
vasectomized men regret their contraceptive decision and present to the
fertility specialist requesting reversal.
Damage to the bladder neck or
injury to the lumbar sympathetic nerves involved in the ejaculation reflex may
cause retrograde ejaculation, as may neurologic conditions such as multiple
sclerosis if they inhibit normal innervation to the bladder neck. With
retrograde ejaculation, sperm pass into the bladder upon ejaculation rather
than exiting from the penile urethra. Therapy is unnecessary if fertility is
not desired. If it is, medical therapies may augment bladder neck closure. If
these fail, sperm may be harvested from alkalinized urine.
Men may also produce very few or
no sperm because of inadequate hormonal stimulation of the testis or because of
gonadal failure. Men with hypogonadotropic hypogonadism may have pituitary
gland or hypothalamic defects (e.g., Kallmann syndrome). They fail to secrete
gonadotropins and so lack appropriate testicular function. These men are good
candidates for treatment with exogenous gonadotropins. Most will respond and
produce viable sperm. Men with gonadal failure (e.g. Klinefelter syndrome;
47XXY; Chapters 26 and 29), have few therapeutic options. Some with
oligospermia or azospermia will never discover the cause of their disorder.
Implantation abnormalities
Implantation abnormalities
encompass a group of endometrial and embryonic defects that interfere with the
complex communication occurring between these entities early in the
postconception period. Luteal phase deficiency (LPD) is the most discussed of
the endometrial disorders that may directly impact implantation. LPD describes
a group of endometrial maturation abnormalities that have been associated with
subfertility and recurrent pregnancy loss. In LPD of ovarian etiology, abnormal
follicular development and ovulation lead to a relative deficiency in
progesterone production. This delays or minimizes the effects of progesterone
in converting the endometrium into a secretory organ receptive to implantation.
Diagnostic tests for the condition are presently suboptimal.
Other factors
Many other factors can influence
fecundity; several of these are immunologic. Antisperm antibodies have been
identified in some patients with infertility but have also been detected in
fertile couples. Their etiologic role and treatment remain unclear.
Inflammatory cells recruited into cervical mucus in response to cervical infections
may affect sperm function, perhaps through release of cytokines. Some women
develop antibodies against negatively charged phospholipids commonly
encountered in cell membranes. These antiphospholipid antibodies can inhibit
placental formation, activate the complement cascade and promote thromboses in
small vessels leading to local ischemia and infarction. Although
antiphospholipid antibodies more typically result in recurrent early miscarriage,
some women experience loss so early as not to know they are even pregnant. In
these women, the antiphospholipid syndrome may initially manifest itself
clinically as infertility.
Genetic abnormalities such as the
androgen insensitivity (Chapter 26)
and gonadal dysgenesis syndromes (Chapters 26 and 27) can also cause infertility. Gonadotoxin exposure,
including exposure to radiation, cigarette smoke and chemotherapeutic agents,
can cause gonadal dysfunction and impaired fertility.
Evaluation and treatment of infertility Evaluation initially involves assessment of the male partner with a semen
analysis and documentation of ovulatory menstrual cycles and patent fallopian
tubes in the female partner. In some couples, additional testing will be
indicated. This may include: anatomic assessment of the uterine cavity,
evaluation of ovarian reserve by measuring serum FSH and estradiol levels in
the early follicular phase of the cycle, determining ovarian antral follicle
counts or random anti-Müllerian hormone (AMH) testing. Laparoscopy and/or
hysteroscopy may be indicated in some patients.
Once the evaluation is complete,
treatment is directed by the findings. Anovulatory or oligoovulatory women are
treated either by correction of any underlying problem such as hyperprolactinemia
or hypothyroidism or by induction of ovulation. Medications used for the
induction of ovulation work by a variety of mechanisms. The most commonly used
is clomiphene citrate, an estrogen partial agonist/ antagonist that acts at the
level of the hypothalamus and pituitary gland to block estrogenic negative
feedback. This increases gonadotropin secretion. Aromatase inhibitors act to
reduce circulating estrogen levels, again blocking negative feedback centrally
and promoting gonadotropin production and release. Both medications require a
functioning hypothalamic–pituitary–ovarian axis. Patients who are not
candidates for, or who fail the prior therapies can be treated with
gonadotropin (FSH +/− LH) injections.
Reproductive tract surgery to
remove endometriosis or a fibroid tumor
may be recommended, although medical therapy for some of these problems is also
available. In the past, tubal reconstructive
surgery was a mainstay of infertility treatment; where readily available,
assisted reproductive techniques like in vitro fertilization (IVF) have
virtually eliminated the need for this approach.
Treatments for male factor
infertility may first address the underlying etiology directly. This may
include medical or surgical therapies, such as correction of a varicocele or
correction of blockage in the vas deferens. More commonly, assisted
reproductive techniques are used to bypass sperm problems. Sperm can be washed,
concentrated and placed directly into the intrauterine cavity using artificial
insemination. The sperm source can be the woman’s partner or a donor.
The widespread availability of
the assisted reproductive technologies has revolutionized infertility
treatment, making pregnancies possible under circumstances never before
considered treatable. The most common treatment approach is IVF, in which
multiple harvested oocytes are fertilized by spermatozoa in the laboratory. The
resulting embryos are grown in the laboratory for 2–5 days, then a group of
embryos is selected and transferred back into the cavity of the uterus.
Standard IVF can be modified in a number of ways. Donor eggs or donor sperm can
be used. In cases of severe male factor infertility, sperm can be injected
directly into the oocyte cytoplasm to effect fertilization (intracytoplasmic
sperm injection, ICSI). These sperm can be immotile. They can be retrieved
directly from the vas deferens, epididymis, or even the testis in men with
obstructive azospermia. Finally, recently developed technology allows genetic
assessment of the embryos created through IVF. Using preimplantation genetic
diagnosis (PGD), a single blastomere is removed from a developing blastocyst
and screened for a variety of selected heritable single gene defects or for
numerical chromosomal content. The results of screening can be used in
selecting those embryos that will be transferred back
to the uterus.
