Female infertility accounts for about one third of all causes of infertility. It may be due to a range of different causes.
Every month women of child-bearing age release a mature ovum (egg cell) from their ovaries, a process called ovulation. Several ova (egg cells) can sometimes be naturally ovulated at the same time, giving the possibility of a multiple pregnancy. Ovulation usually occurs at mid-cycle (on around day 14). About 36 hours before this, a hormone called luteinising hormone (LH), secreted by the brain, reaches its peak. The most commonly marketed commercial ovulation tests are based on the detection of an LH hormonal peak. Ovulation may also be detected by the increase in another hormone, progesterone, which is measured in the blood on around day 20 of the cycle. A progesterone level of >3 ng/ml on day 20 means that ovulation has taken place, although this does not reveal its quality.
Ovulation is a complex phenomenon which has a number of pre-requisite conditions:
- The presence of a pool of immature follicles (containing immature eggs) in the ovaries. When she reaches menopause, a woman no longer ovulates and her menstruation stops.
- The selection each month of a mature follicle (among several) containing the oocyte that will be ovulated. The growth and selection of this so-called dominant follicle takes place by means of a hormone called FSH, produced by the pituitary gland, or hypophysis, which is located in the brain.
- A peak or surge in the LH hormone.
There may be a failure to ovulate for several different reasons.
Ovarian ageing and premature ovarian failure
The stock of immature eggs is created when a woman is born and it does not regenerate. It gradually runs out, until all these cells are used up at the time of the menopause. Over time there is also a significant reduction in the quality of the ova, especially after the age of 35. One of the first signs of ovarian aging is a shortening of the menstrual cycles (every 23-25 days instead of every 27-35 days). Later, at around the time of the perimenopause, ovulations occur less frequently with longer intervals between menstruations, before they finally stop completely at the menopause. Sometimes, this can happen before the age of 40, a phenomenon that is defined as premature ovarian insufficiency (POI). This can be due to multiple factors, especially genetic, but it can also be induced by toxic treatments that affect ovarian function (chemotherapy, radiotherapy, etc.), or by autoimmune diseases (anti ovarian antibodies).
The complete cessation of ovulation in these situations generally means that it is impossible to offer Assisted Reproductive Technology (ART) techniques using the patient’s own gametes. Couples are therefore advised to opt for oocyte donation. For women who are still ovulating, infertility may be the subject of discussions with healthcare teams so as to determine the best strategy to adopt (ovarian stimulation with scheduled intercourse, intra-uterine insemination, or in vitro fertilisation). The decision depends on the woman’s age, ovarian reserve markers (antral follicle count on ultrasound scan, blood levels of anti-Müllerian hormone) and any other possible causes of infertility (male, fallopian tube abnormalities, endometriosis, etc.).
Note that although ovarian reserve markers provide an indirect estimate of the stock of eggs remaining in the ovaries, they do not identify the quality of the oocyte and therefore cannot predict the chances of pregnancy, whether natural or through ART. They do however make it possible to predict the extent of ovarian response to stimulation (the number of oocytes that can be retrieved by aspiration via a puncture for in vitro fertilisation).
Polycystic ovary syndrome and other causes of ovulation abnormalities
Polycystic ovary syndrome (PCOS) is a hormone disorder of unknown origin, which results in disorders of the menstrual cycle (irregular, lasting over 35 days or even absent), and an increase in production of the so-called androgenic hormones (e.g. testosterone) which may manifest as hyperpilosity or severe acne. The excessive production of androgens within the ovaries leads to excessive follicle growth and a maturation defect which prevents the monthly selection of a mature follicle from which ovulation can take place. As ovulation is rare or absent there is little chance of fertilisation, resulting in infertility. This syndrome is often associated with obesity and insulin resistance.
Note that although the ovarian reserve markers (CFA and AMH) have higher values than normal, this does not mean there is a higher stock of eggs, but merely an excess of growth follicles.
The treatment of ovulation disorders associated with PCOS may require various different therapies such as clomiphene citrate administration, ovarian stimulation by FSH and laparoscopic ovarian drilling. In all cases, any excess in the patient’s body weight should always be reduced.
This condition involves a variety of rare ovulation disorders, related to a dysfunction of the brain system responsible for producing FSH and LH. The main causes are tumours (pituitary adenomas), or genetic and pharmaceutical factors, but there can be certain so-called functional causes, as in the case of eating disorders (e.g. restrictive anorexia).
Depending on the specific case, infertility treatment may require induction of ovulation by a GnRH pump or ovarian stimulation.
Fallopian tube-related infertility
The unobstructed permeability of the fallopian tubes is essential in order for the spermatozoa to reach the ovum and then for the embryo to correctly adhere to the wall of the uterus.
Certain pathologies are responsible for tubal disorders, abnormalities or occlusions, particularly a history of upper genital infection (salpingitis) and ectopic (extra-uterine) pregnancy. In fact, sexually-transmitted infections with chlamydiae trachomatis or other germs (gonococcus, etc.), even though they are sometimes asymptomatic, may cause irreversible damage to the fallopian tube(s) causing more or less severe obstructions. Although proximal obstruction, close to the end of the fallopian tube in contact with the uterus, cannot usually be treated, distal lesions, whether or not they are associated with dilation (hydrosalpinx) may require a surgical intervention. Endometriosis may also be a cause of tubal dysfunction.
A diagnosis of tubal dysfunction requires a hysterosalpingography.
Depending on the case, treatment may require intrauterine insemination (if only one fallopian tube remains normal) or in vitro fertilisation (IVF), but surgery may be necessary in certain situations.
On about the 5th day after fertilisation, the embryo attaches itself to the wall of the uterus, where the endometrium has thickened for about ten days due to the effect of the oestradiol produced by the dominant follicle.
Thus, uterine cavity disorders may disrupt the process of embryonic implantation.
Various different types of endometrial disorder are possible, and they can be classified as “mechanical” or “functional”.
Mechanical causes involve obstacles inside the uterus:
- Uterine fibroids: only those that affect the uterine cavity directly should be treated surgically.
- Uterine polyp: this is a benign tumor resulting from the proliferation of tissue emanating from the mucosa membrane lining of the uterus (endometrium)
- Intrauterine synechiae: this is the formation of intrauterine adhesions, either following a genital infection, or more often after an endo-uterine procedure (curettage, hysteroscopic surgery, etc.)
- Congenital malformations: uterine septum, exposure to diethylstilbestrol (formerly marketed in France as Distilbene).
These abnormalities are diagnosed by means of a diagnostic ultrasound or hysteroscopy. Treatment generally requires surgery before any ART procedure can be carried out.
The “functional” causes relate to clinical situations where no intrauterine mechanical damage has been identified. This is particularly the case of hormonal, inflammatory or autoimmune pathologies. For example, diabetes, hypothyroidism, endometriosis and lupus may especially be to blame. It should be noted that obesity is also associated with embryo attachment failure. In any case, the underlying pathology must be treated, regulated and brought under control.
Idiopathic infertility: “All the test results are normal”
About 10% of infertility remains unexplained, due to the present limits of medical knowledge.
It is important to note that to date there are no reliable fertility markers.
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