Infertility is a disease defined as the absence of pregnancy despite regular unprotected sexual intercourse for a period of at least 12 months.
According to the WHO report, the estimated prevalence of infertility worldwide between 1990 and 2021 is 17.5%, meaning that one person in 6 has had at least one experience of infertility in their lifetime.
Periodic” prevalence, defined as the proportion of the population having suffered from infertility at a given time or over a given period, which may be current or past, is estimated at 12.6%.
Fertility disorders therefore affect almost 1 in 4 couples, and their incidence is increasing due to the rising age of desire for children and environmental factors. Overall, the etiologies of infertility concern women in 25% of cases, men in 25% of cases; they are mixed in 25% of cases and, in 25% of cases, remain unexplained. In fact, both members of the couple should be investigated.
In this section, we will only deal with infertility in women.
What are the causes of female infertility?
There are two main causes of female infertility:
- ovulation disorders: these can be caused by a number of factors: premature ovarian failure, reduced ovarian reserve, chromosomal abnormality, hormonal disorder, polycystic ovary syndrome, sequelae of chemotherapy, radiotherapy or surgery;
- obstructive or mechanical causes:
– endometriosis lesions,
– tubal obstruction, total or partial, secondary to salpingitis, particularly after Chlamydiae infection, surgical sequelae;
– uterine mechanical obstacles: sequelae of conization for cervical cancer, cervical mucus abnormalities, uterine polyps or fibroids, congenital malformation.
In terms of frequency, the two main causes are ovarian disorders (25% of infertility cases, including 70% of polycystic ovary syndrome or PCOS) and endometriosis (around 30% of cases).
When should an infertility assessment be requested, and what clinical, functional and radiological tests should be carried out?
The objectives of an infertility work-up are twofold: to establish a diagnosis and a prognosis before starting a Medically Assisted Reproduction (MAP) procedure.
When to explore?
An infertility work-up is initiated in the absence of an evolving clinical pregnancy after one year of regular intercourse without contraception if the woman is under 35, and after 6 months if the woman is over 35. It must be as complete as possible, to save precious time; it has both diagnostic and prognostic value.
Initial clinical, functional and radiological assessment
Careful questioning should reveal any medical or surgical history, and enable the patient’s cycle rhythm to be established (temperature curve). The clinical examination provides a general assessment and records the patient’s weight and height. According to the latest update of the CNGOF recommendations on first-line management of infertile couples, the Hühner post-coital test to assess the quantity and quality of cervical mucus is no longer recommended as part of the initial assessment of infertile couples.
The radiological examinations recommended as first-line treatment for infertile women are an endovaginal 3D pelvic ultrasound, to diagnose uterine malformations and detect endocavitary pathologies, and a hysterosalpingography to explore tubal permeability, in the absence of any history that might raise suspicion of tubal or pelvic pathology.
FSH (follicle-stimulating hormone)
Despite its considerable variations during and between cycles, FSH is measured on D3 and taken into account in the context of MPA. If elevated, it is indicative of a poor response to ovarian stimulation, but not predictive of the chances of pregnancy.
Estradiol (E2)
Measured on D2 or D3 of the cycle, it is only useful in association with FSH: if elevated, it can “catch up” with certain falsely reassuring (“normal”) FSH levels, in the case of follicular recruitment that has begun too early (feedback from E2, which has lowered FSH). Like FSH, E2 does not predict the chances of pregnancy.
E2 is also useful for predicting the risk of ovarian hyperstimulation and associated thrombo-embolism (proposed threshold: 3500 ng/L).
Biological investigation
In the first-line work-up of an infertile woman, the recommended biological tests are an AMH assay before undergoing MAP treatment, and a vaginal swab for microbiological evaluation in search of bacterial vaginosis.
A more complete hormonal work-up may be carried out at a later stage, including assays of 17-hydroxyprogesterone, total testosterone, delta4-androstenedione, DHEA sulfate, LH, progesterone, TSH and prolactin.
Estimating ovarian reserve: FSH, E2, AMH
Ovarian reserve corresponds to the number of follicles present in the ovaries: it is accurately assessed by anatomopathological counting of primordial follicles on each ovary.
In practice, however, it is assessed clinically (patient’s age), ultrasonographically (DWI) and by biological assays of FSH, E2 and AMH, which indirectly reflect growing follicles.
The aim of this assessment is to diagnose premature ovarian failure, diminished ovarian reserve, polycystic ovary syndrome (PCOS) or hypogonadotropic hypogonadism; the aim is also therapeutic, within the framework of a PGM pathway, making it possible to define good/normal/bad responders to ovarian stimulation, to guide the choice of treatment type and dose, and to identify patients at risk of ovarian hyperstimulation.
AMH (anti-müllerian hormone)
Is very useful, as its plasma concentration follows the follicular decline that occurs with advancing age in women. In addition, it is constant during the cycle and between cycles (or undergoes slight variations, with no impact); however, it is thought to be reduced by long-term contraceptive use.
AMH cannot be used to predict the chances of spontaneous pregnancy (nor can it be used for MAP). However, it is very often prescribed, as its plasma concentration correlates with the percentage of euploid embryos obtained during MPA, and is therefore predictive of a patient’s chances of pregnancy during MPA. AMH predicts ovarian response to stimulation and identifies patients at risk of ovarian hyperstimulation, helping to prevent the associated thrombo-embolic risk.
Other biological tests
17-hydroxyprogesterone (17-OHP)
Should be measured at D3 of the cycle in cases of spanio- or a-menorrhea, or in the presence of signs of hirsutism, to search for PCOS (5 to 10% of women), which can cause fertility problems, or adrenal block, which is rare, but whose differential diagnosis with PCOS must be established:
- 17-OHP < 2 ng/ml: absence of 21-OHase block (phenotype in favor of PCOS) ;
- 17-OHP > 5 ng/ml, 21-OHase block;
- 2 < 17-OHP < 5 ng/ml: perform a Synacthen® test with 17-OHP measurement 1 h after Synacthen® injection: if 17-OHP < 10 ng/ml, no 21-OHase block / a 17-OHP value > 10 ng/ml is in favour of this diagnosis.
Total testosterone, delta-4 androsterone and DHEA sulfate are useful in the diagnosis of biological hyperandrogenism, one of the diagnostic criteria for PCOS (for Nathalie, return link to Campus Endocrino with PCOS). Classically in PCOS, total testosterone is elevated, as are delta-4 androstenedione and SDHEA (17-OHP is normal).
LH is interesting from a pathophysiological point of view, to determine the “LH peak”, but in reality, this peak only occurs in less than 50% of cases (in the other cases, there is a double or even triple peak) and is of little help. In practice, LH is not a marker of ovarian reserve; it could be useful at D3, in association with FSH, as an LH/FSH ratio > 1 is an indirect sign of PCOS.
Progesterone is a steroid hormone derived from the corpus luteum, whose purpose is to enable the transformation of proliferative endometrium into secretory endometrium; but it is not present in the follicular phase, and its serum concentration varies greatly from one woman to another in the luteal phase. Hence the difficulty of defining luteal insufficiency.
Its measurement is of no interest at D3; it should be measured at D20 – D22 on average (to be modulated according to cycle length), in the event of spaniomenorrhea or short cycles. Its purpose is to verify the existence of ovulation (if above 5 ng/ml).
Prolactin should only be measured in the presence of clinical signs: spanio-, a-menorrhea or galactorrhea.
TSH measurement is recommended by the American Thyroid Association in 2017, in all women consulting for infertility, as hypothyroidism is associated with an increased risk of miscarriage.
A vaginal microbiological evaluation with Nugent score and standard bacteriology is recommended in the initial work-up of an infertile woman. Bacterial vaginosis is found in around 20% of infertile women and appears to have a negative impact on IVF success rates, with a significantly increased risk of early miscarriage. Thus, it is currently recommended to treat any symptomatic bacterial vaginosis in infertile women; in an asymptomatic woman, it is also recommended to treat and monitor the outcome of treatment on a repeat vaginal swab to document cure of the vaginosis.
Chlamydia trachomatis serology may be useful in detecting tubal damage secondary to infection by this bacterium. However, given its poor performance, a negative C. trachomatis serology cannot exclude tubal pathology of infectious origin. Furthermore, in infertile women with patent fallopian tubes, a positive C. trachomatis serology cannot be associated with a reduced rate of spontaneous pregnancy or pregnancy through artificial insemination (insufficient data in the literature).
