Infertility (Part Two)

Uterine Factors of Infertility

The uterus is the final destination for the embryo and the place where the fetus develops until birth. Thus, uterine factors can be related to primary infertility or to pregnancy failures and premature births. Uterine factors can be congenital or acquired. They can affect the endometrium or myometrium and are responsible for 2-5% of infertility cases.

- Congenital factors

• The development of the Müllerian ducts is responsible for the normal anatomical configuration of the uterus, fallopian tubes, cervix, and upper vagina. The full spectrum of Müllerian congenital anomalies varies from complete absence of the uterus and vagina (Rokitansky-Küster-Hauser syndrome) to minor defects such as a bicornuate uterus and vaginal septa (transverse or longitudinal).
• Most uterine malformations detected over the last 40 years were due to medications. An example is diethylstilbestrol (DES), which between the 1950s-1970s was used to treat patients with frequent abortions, later found to be responsible for malformations of the uterine cervix, disorders of the uterine cavity, fallopian tube dysfunction, menstrual disorders, and the development of clear cell carcinoma of the vagina.
• Preterm birth is associated with cervical incompetence, a unicornuate uterus connected to a blind horn, and uterine septum. The uterine septum may also be responsible for implantation problems and first-trimester abortions.

- Acquired defects

• Endometritis related to traumatic births, dilation and curettage, and instrumentation (e.g., myomectomy) of the endometrial cavity that can create intrauterine adhesions or synechiae, with total or partial obliteration of the endometrial cavity.
• Placental polyps may develop from placental remnants.
• Intrauterine and submucosal fibroids are very common, affecting 25-50% of women. They can cause distortion of the cavity and damage blood supply. They can also cause implantation failure, early miscarriage, premature birth, and placental rupture.

Ovarian Factors of Infertility

Oogenesis occurs in the ovaries from the first trimester of embryonic life and is completed by 28-30 weeks of gestation. By then, approximately 7 million oocytes are present. They are arrested in the prophase stage of the first meiotic division. Later, the number of oocytes decreases due to a continuous process of atresia. At birth, the number of oocytes drops to about 2 million. At menarche, there are about 500,000 oocytes. These oocytes are used throughout the reproductive years until menopause.

The ovulatory process is initiated and controlled by the hypothalamic-pituitary-ovarian axis. From the present follicles each month, only one oocyte is selected, which establishes dominance, and develops until the preovulatory stage. The peak of LH makes the ovulation process possible, by resuming the meiosis of the oocyte, and stimulates the formation of the corpus luteum and subsequent progesterone stimulation.

Ovulation disorders are defined as an alteration in the frequency and duration of the menstrual cycle. Ovulation failure is the most common cause of infertility. Lack of ovulation can be related to primary and secondary amenorrhea, or oligomenorrhea.

Primary amenorrhea can be divided into 2 categories: hypergonadotropic hypogonadism and hypogonadotropic hypogonadism.

Secondary amenorrhea is most often related to disorders of the endocrine system and may be linked to thyroid disorders, adrenal glands, pituitary including tumors. A common cause of secondary amenorrhea is premature ovarian failure, which is the loss of ovarian function around the age of 40 years.

Oligoamenorrhea resulting from dysfunction of the hypothalamic-pituitary-ovarian axis is the most common cause of ovulation disorders related to infertility. Patients may also have symptoms of hyperandrogenism, acne, hirsutism, and hair loss. Obesity is often associated with it and worsens the prognosis. Although these patients are not sterile, their fertility capability is reduced, and the obstetric outcome is poor due to an increased risk of pregnancy loss. Most of these women have polycystic ovary syndrome.

Advanced Age

The prevalence of infertility dramatically increases with age. Also, fertility decreases with the length of marriage due to less frequent intercourse and/or from contraception. Similar facts come from the experience of many IVF programs. Chromosomal anomalies and poor quality of oocytes are two causes of the low quality of embryos, low implantation rate, increased abortions, and decreased birth rates.

Tubal Factors

The fallopian tubes play an important role in reproduction as they transport the embryo from the ampulla where fertilization occurs to the uterine cavity where implantation occurs.

Anomalies or damage to the fallopian tube are related to fertility and are responsible for abnormal implantation (e.g., ectopic pregnancy). Blockage of the distal end of the fallopian tubes results in the accumulation of normally secreted tubal fluid, creating tube distension with subsequent damage to the epithelial linings (hydrosalpinx)

Other tubal factors related to infertility can be both congenital and acquired. Congenital absence of the fallopian tubes may be spontaneous torsion in utero followed by necrosis and reabsorption. Desired tubal ligation and salpingectomy are acquired causes.

Peritoneal Factors

The uterus, ovaries, and fallopian tubes share the same space in the peritoneal cavity. Anatomical defects or physiological disorders of the peritoneal cavity, including infections, adhesions as a result of previous pelvic surgical interventions, can cause infertility. Pelvic inflammatory disease, peritoneal adhesions, endometriosis, and ovarian cyst rupture, all compromise the motility of the fallopian tubes or produce blockage of the fimbriae with the development of hydrosalpinx. Large fibroids, pelvic masses, or blockage of the cul-de-sac interfere with the accumulation of peritoneal fluid and interfere with the release of normal oocytes during ovulation, becoming a mechanical factor for infertility.

Male Factor of Infertility

The male factor of infertility can be divided by pretesticular, testicular, and posttesticular etiology.

Pre-testicular Factors

Pretesticular causes of infertility include congenital or acquired diseases of the hypothalamus, pituitary, or peripheral organs that alter the hypothalamic-pituitary axis. Such disorders include idiopathic hypogonadotropic hypogonadism, prolactinomas, gonadotropin deficiencies, and Cushing's syndrome.

Testicular Factors

Testicular factors can be of genetic or non-genetic nature. Klinefelter's syndrome is the most common chromosomal cause of male infertility and results in primary testicular insufficiency. Non-genetic etiologies include medications, infections, trauma, and varicoceles.

Age also affects male fertility. With increasing age, testosterone levels decrease, gonadotropin levels increase, sperm concentration and semen volume change, and libido decreases. As a result, the incidence of congenital defects increases.

Post-testicular Factors

Post-testicular factors are those that prevent normal sperm transport through the ductal system. Such factors can be congenital or acquired. Males exposed to DES in utero may have ductal obstruction. Congenital bilateral absence of the vas deferens is seen in males with cystic fibrosis. Also, infections, surgical procedures, and trauma can cause blockage of the ducts.