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Infertility


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.


Infertility, Oocyte abnormalities, Female anatomic abnormalities, Implantation abnormalities, Evaluation and treatment of infertility,

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.