Aetiology
Female infertility aetiologies include cervical/uterine abnormalities, tubal disease, diminished ovarian reserve, ovulatory dysfunction, and unexplained infertility. The most common aetiologies are ovarian dysfunction and diminished ovarian reserve.[10][11] This is partly because age is a major risk factor for infertility and women are significantly delaying the time of first childbirth. It has been clearly demonstrated that fecundity decreases with age and this decrease accelerates at 35 years of age.[12][13] Polycystic ovary syndrome (PCOS) is also a major contributor to ovulatory infertility.[14]
Tubal disease is common in women with a history of sexually transmitted infections; endometriosis also contributes to tubal disorders.[11][14] Cigarette smoking, very high body fat, and decreased body mass may also contribute to a delay in conception.[15][16][17] High or low body fat in women is related to ovulatory dysfunction, while smoking is related to accelerated menopause.
Pathophysiology
Pathophysiology varies according to aetiology.
Group 1: hypothalamic pituitary failure. Hypogonadotrophic anovulation occurs as a result of hypothalamic or pituitary abnormalities; for example, hypothalamic amenorrhoea as a result of very low body mass index or excessive exercise, or hypogonadotrophic hypogonadism.
Group 2: hypothalamic-pituitary-ovarian dysfunction (eugonadotrophic anovulation); for example, PCOS.
Group 3: hypergonadotrophic anovulation; for example, primary ovarian insufficiency or menopause.
Tubal disease
Tubal factor infertility is most often caused by untreated gonorrhoea and chlamydia infections.[19] Chlamydia trachomatis is an obligate intracellular parasite that invades the cervix, uterus, and fallopian tubes. This organism is the leading cause for acute salpingitis worldwide. The manifestation of this disease is varied, ranging from subclinical to an acute tubo-ovarian abscess that can include peritonitis and peri-hepatitis.[20] High anti-chlamydial antibody titres highly correlate to abnormal tubal pathology.[21] The risk of tubal occlusion has been approximated as 10% for an initial episode of salpingitis, and then doubled with every subsequent infection.[22]
Any pelvic infection, including appendicitis and diverticulitis, can damage the fallopian tubes.
Endometriosis
Endometriosis can cause intra-abdominal inflammation and adhesions.[23]
This growth of hormonally responsive endometrial tissue outside the uterus may cause anatomical obstruction of the fallopian tubes. It may also lead to infertility by producing cytokines that may be toxic to sperm or embryos.[5][24] Data from oocyte donation cycles also suggest that a slight impairment in uterine receptivity may contribute to infertility in women with endometriosis.[25]
Age
Age-related decreases in fecundity are caused by declining oocyte numbers and poorer oocyte quality. Oogenesis begins in utero. By month 7 of gestation, mitosis completes and the peak number of oocytes (approximately 7 million) is achieved. Hormone-independent apoptosis begins at this time and continues until menopause, regardless of factors such as contraceptive use and pregnancy. Although the number of oocytes remaining in the ovary (ovarian reserve) impact on pregnancy rates, age also leads to a higher rate of oocyte aneuploidy due to decreased chromosomal crossover, meiotic spindle fragility, and telomeric shortening.[26][27][28] This leads to a high likelihood of implantation failure, miscarriage, and chromosomally abnormal embryos.[12][13][29]
Uterine abnormalities
Uterine abnormalities can be congenital or acquired. Failure of Müllerian duct fusion results in uterine malformations, including uterine didelphys, bicornuate or unicornuate uterus, and uterine septum.[30] Submucosal or intramural leiomyomata may have an impact on implantation or cause tubal obstruction.[31][32]
Endometritis, particularly if associated with a dilation and curettage procedure, can destroy the endometrial lining and cause Asherman's syndrome (intrauterine adhesions).[33] Adenomyosis may cause infertility through reduced endometrial receptivity and alterations in embryo implantation, but the exact mechanisms are unknown.[34]
Classification
Infertility in women[3]
Primary infertility: if a woman is unable to ever conceive a pregnancy, either due to the inability to become pregnant or due to the inability to carry a pregnancy to a live birth.
Secondary infertility: if a woman is unable to bear a child, either due to the inability to become pregnant or due to the inability to carry a pregnancy to a live birth, following a previous pregnancy or previous ability to carry a pregnancy to live birth.
Alternative classifications
The following informal classification of infertility by cause can be useful:
Ovulatory dysfunction: typically associated with irregular menstrual cycles or complete amenorrhoea and accounts for up to 40% of diagnoses in women with infertility.[4] Differential diagnoses include hypothalamic amenorrhoea, polycystic ovary syndrome (PCOS), and primary ovarian insufficiency.
Anatomical infertility: pelvic adhesive disease can decrease fertility by obstructing the fallopian tubes or restricting their movement. Uterine abnormalities, either congenital or acquired (e.g., Asherman's syndrome) may also lead to infertility.
Endometriosis: growth of hormonally responsive endometrial tissue outside the uterus may cause anatomical obstruction of the tubes. It may also lead to infertility by producing cytokines that may be toxic to sperm or embryos.[5]
Unexplained infertility: women with unexplained infertility are thought to be subfertile, with an overall decrease in fecundability. There is no consensus on the definition of unexplained fertility, but normal semen analysis, tubal patency, ovulation status, and uterine cavity assessment are the most commonly applied criteria.[6] The majority of these women will conceive without intervention. However, the proportion of unexplained diagnoses is decreasing as our understanding of fertility improves.
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