Fundamentals of female fertility diagnosis

Part three of the expert cycle “Fundamentals of female fertility diagnosis” discusses the female fertility assessment and further diagnosis. The fundamentals of female fertility diagnosis are based on the identification of the cause of infertility. In order to achieve this aim, a medical interview and specialist tests are required.

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Fundamentals of female fertility diagnosis

The difficulties associated with conception are a significant and increasingly frequent problem of today’s world. Contrary to the common opinion, for several dozen years the level of infertility is relatively constant[1]. Meanwhile, diagnostic methods and lifestyle have changed. To a large extent, the problem of infertility results also from the shift in age at which couples decide to become parents. The increasing number of people first seek professional fulfillment and set aside the decision about starting a family. The contributing factors are the increased effectiveness of contraception and better accessibility of counseling for family planning. However, the potential chance of giving birth to a child decreases with age and, in consequence, the percentage of infertile couples grows[2]. We can talk about infertility if a couple does not achieve pregnancy after a year of regular unprotected intercourse. The studies have demonstrated that after this time, about 85% women get pregnant. In the remaining 15%, diagnosis should be initiated in order to identify the cause of the problem[3]. We should always keep in mind the most important rule of patient management in this group. In the case of infertility, we do not diagnose the woman or the man, but the couple as a whole.

The most significant single factor affecting a woman’s fertility is her age. This is why age-related changes are discussed before any other causes of infertility. Over time, a woman’s body experiences changes which decrease her chances for fertilization: the number of ovarian follicles drops – those remaining age, the rate of aneuploidies increases which results in lower chances for fertilization and increased risk of pregnancy loss; sensitivity to gonadotropins decreases. With age, the success rate of assisted reproductive technologies (ART) decreases as well. The numbers of obtained oocytes and available embryos are lower, the incidence of fragmentations and aneuploidies in embryos is higher, and the implantation rate is lower in older than in younger women[4].

The causes of female infertility can be divided into several groups:

1. Ovarian

This group includes ovarian function disorders which lead to very irregular ovulations or their total absence.

In the 16th to 20th week of fetal life, ovaries contain approximately 6-7 millions of primary follicles. In the course of life, this number systematically decreases. A newborn has approximately 1 to 2 million of these follicles. At the time of menarche, there are about 300 thousand of them in ovaries; in the period of menopause – only several hundred thousand of them remain. The follicle pool can fall drastically in the consequence of, for example, surgical interventions within ovaries or their resection. This can result in earlier menopause[5][6]. In the case of unexplained infertility in a woman over 30 years of age, we should always take into account premature ovarian failure and decreased number of follicles in ovaries. In such a case, shortened menstrual cycles due to shorter follicular phase are observed[7].

Ovulation disorders are responsible for up to 40% causes of infertility[8]. Their clinical manifestations include the disturbed rhythm of menstrual bleedings (oligo/amenorrhea, functional bleedings, polymenorrhea). The causes may include thyroid gland diseases, excessive loss of body mass[9], intensive sport activities, polycystic ovary syndrome, hypothalamic pituitary failure, hyperprolactinemia. In exceptional cases, even with regular menstruations, unruptured dominant follicle can undergo luteinization – then regular menstrual cycles without ovulation occur. Ovulation assessment is one of the fundamental tests in the treatment of infertility. The presence of ovulation is confirmed in serial ultrasound examinations carried out on subsequent days of the menstrual cycle, observation of the growth of dominant follicle with simultaneous observation of the quality and quantity of cervical mucus. A patient can carry out the self-observation of the occurrence of ovulatory cycles through the observation of cervical mucus, daily measurements of her body temperature or carrying out ovulation tests. Such observations should be performed preferably in parallel with ultrasound exams to confirm ovulation. Nevertheless, the only indisputable proof of ovulation is pregnancy. If any disorders are confirmed, it is necessary to identify their causes, carry out hormonal tests, and in certain cases exclude, for example, endometriosis, and inflammations. When the causes of anovulation have been identified, treatment can be initiated.

Hormonal disorders being the cause of infertility can be related, among others, to premature ovarian failure, hyperprolactinemia, excessive amount of male sex hormones, abnormal thyroid or adrenal function, insulin resistance. Clinical signs related to these disorders include premenstrual spotting, breast tenderness, shortened menstrual cycles, increasing body hair, acne, tendency to overweight, decreased body mass, dark color of skin in armpits and perineum and others.

2. Tubal (40% causes of infertility[8])

Infertility may be caused by the obstruction of fallopian tubes or pathological changes within lesser pelvis. The symptoms of inflammatory changes are most often pain in lower abdomen and vaginal discharge. They can occur as a complication after surgical treatment, in particular of appendicitis or after gynecological operations.

Tubal patency test is not the first test carried out in the diagnosis of infertility. It should be performed if it is indicated on the basis of data obtained during the medical interview or before performing e.g. intrauterine insemination. Tubal patency assessment is indicated also after ectopic pregnancy.

3. Uterine

This group includes anatomical anomalies which can impair the ability to get pregnant or to maintain pregnancy. These can be congenital defects of uterus, endometrial polyps, uterine fibroids. Each case requires a case-by-case decision whether a given anomaly requires treatment.

4. Cervical

Infertility caused by a cervical factor is related to the presence of an obstacle in the cervical canal of uterus. The most common are mechanical obstacles, adhesions after cervical surgeries, anatomical defects, polyps in the cervical canal.

5. Unexplained infertility (10% [8])

This diagnosis can be made when the presence of ovulations, patency of fallopian tubes and normal structure of uterus has been confirmed, and after semen analysis as well as tests for sperm motility in cervical mucus have been carried out. Special attention should be paid to potential comorbidities, e.g. immune or endocrine disorders, and the patient should be referred to the respective specialist.

When the diagnostic process is initiated, the couple should be made aware of its purpose. When we have already established what forms the barrier for conception, we will be able to assess the prognosis for spontaneous pregnancy and to draw up the most optimal plan of the therapeutic procedure. Our actions should seek answers to several questions:

• Is the ovarian function normal? How big is the ovarian reserve? Are the cycles ovulatory?
• Are fallopian tubes patent?
• Is the structure of the uterus normal?
• What is the real chance of spontaneous pregnancy and of pregnancy after the treatment?

The tests which help to identify the causes of infertility should be started if a woman did not get pregnant after a year of unprotected regular sexual intercourse. Women aged over 35 years should visit the doctor even earlier. From the 35th year of age, a woman’s chances for pregnancy decrease faster and faster. Drastic fall in fertility occurs in the 38th year of age. For these reasons, delaying the start of treatment by mature women may decrease the chances of conception. An earlier visit to a specialist should be paid also by women with disorders of the rhythm of bleedings indicative of oligo/amenorrhea, or with the suspicion or history of uterine or tubal pathologies or endometriosis[10].

The first visit should take place preferably on day 1 to 3 of menstrual cycle. Then, the diagnostic process may be initiated immediately. It usually begins with the detailed interview. A well-conducted interview helps to set a proper direction for the diagnostic process. The physician should obtain information about the patients’ age, age at menarche, rhythm of menstrual bleedings and its disorders, observed signs of ovulation, dysmenorrhea, duration of infertility, obstetric history (miscarriages, ectopic pregnancies), past inflammatory conditions of adnexa, existing or past serious systemic diseases (diabetes, thyroid diseases), sexually transmitted diseases, surgeries (appendectomy, surgeries within ovaries or uterus), number of sexual partners, family history of congenital disorders, use of stimulants and presence of addictions, use of contraceptives and other medications [9][11][12][13]. The first visit should include complete gynecological examination (bimanual exam intravaginal ultrasound, Papp smear, breast examination). The physical examination should also include the assessment of body mass, consistency and size of thyroid gland, any potential signs of hyperandrogenism. With regard to male partner, the interview should be performed in relation to problems with the descent of testes, their inflammatory conditions and other problems as well as surgical interventions in the lower abdominal area.

Laboratory tests, if carried out and interpreted properly, are a very good diagnostic tool. On day 1-3 of the cycle, the following tests should be carried out:

• E2 (estradiol),
• LH, FSH – a very high level of these hormones indicates the ovarian failure. It can mean premature menopause. In such cases, the estrogen level is often low. Slightly increased LH level or relative to FSH increase in the level of LH suggest polycystic ovary syndrome,
• Prolactin and metoclopramide test,
• Testosterone,
• Anti-TPO antibodies and SHBG,
• Inhibin B – a substance produced in ovarian follicles which selectively inhibits FSH secretion from the pituitary gland. The inhibin level decreases with age in connection with the decreasing number of follicles. In consequence, FSH level rises. This test is intended to assess the ovarian reserve[14],
• AMH – the level of this hormone depends more on the reproductive than calendar age and is related to the age at which a woman stops menstruating. It allows the more precise than based on the currently applied methods determination of ovarian reserve and the assessment of what reaction should be expected in the period of hormone drug administration during hormonal stimulation in IUI, IVF or ICSI. In addition, AMH allows to determine, on the basis of its concentration, the end of reproductive period in a woman and thus the beginning of menopause. AMH allows to make proper diagnosis and take the appropriate decision concerning treatment at the outset. The test is carried out on a sample of blood serum and is independent from the patient’s cycle day. Tests for FSH and E2 levels at the beginning of the follicular phase have been carried out for many years for the purposes of ovarian reserve assessment[15].

In case of unexplained infertility, the following additional tests can be considered:

• Immunological tests intended to detect in a woman antisperm antibodies which lead to sperm agglutination preventing fertilization,
• Genetic tests,
• Bacteriological tests intended to detect abnormal vaginal biocenosis allow its proper treatment. Diagnosis includes also tests for infections caused by microorganisms such as: HPV, Chlamydia trachomatis, Ureaplasma urealyticum, Mycoplasma.

As it has been already mentioned, the element of fertility diagnosis is the confirmation of ovulation. The only indisputable proof of ovulation is pregnancy. According to the position expressed by ESHRE, among all hormonal tests only the determination of progesterone in the middle luteal phase provides information whether the cycle is ovulatory. Other tests, such as methods of detecting LH peak, cervical mucus examination, basic temperature measurements, have low sensitivity and specificity. If a patient menstruates regularly, the level of progesterone on day 21 of the cycle is determined. Concentration exceeding 30 nmol/L confirms the occurrence of ovulation in such cycle.

The occurrence of ovulatory cycles is confirmed by:

• regular menstrual cycles with the rhythm of 21 to 35 days,
• presence of abundant, watery cervical mucus 14-16 days before menstruation,
• pain in lower abdomen 14-16 days before menstruation,
• two-phase pattern of the basal body temperature curve.

Further information is provided by ultrasound exam confirming in the ovary the presence of a growing follicle which reaches 16 to 22 mm during the periovulatory period, and the determination of estradiol levels in the periovulatory period (150–400pg/mL).

Examinations with proven importance in the assessment of the anatomical condition of female reproductive organs are ultrasonography, hysterosalpingography, laparoscopy and hysteroscopy.

Ultrasound exam – with this non-invasive technique, we can assess endometrium and the structure of ovaries, number of antral follicles (follicles with dimensions of 2 to 6 mm) and the follicular growth in patients with ovulation disorders or qualified to treatment with assisted reproductive techniques.

Hysterosalpingography (HSG) is a relatively minimally invasive and inexpensive examination imaging uterus and fallopian tubes at the same time. It allows to assess whether the fallopian tubes are patent or whether peritubal adhesions occur. However, it does not show directly periadnexal adhesions or endometriosis. It consists in introducing a contrast medium to the uterus via the uterine cervix and taking X-ray images. HSG provides also information about the shape of and any potential changes in the uterine cavity, such as, for example, uterine septum, fibroids, polyps.

In case of abnormal result, when changes in fallopian tubes are suspected, for the purpose of verification the method of choice is laparoscopy using methylene blue dye injection, and if intrauterine changes are suspected – hysteroscopy. HSG should be carried out only when the result of ultrasound tubal patency test is not clear. The ultrasound exam is a method of choice because it is less invasive and does not expose the patient’s ovaries to X radiation.

Laparoscopy is a surgical procedure during which the assessment of the fallopian tube patency is possible. It consists in introducing a fluid to the uterine cavity and observing its movement to the abdominal cavity. This examination is not without any disadvantages. The procedure is relatively expensive. There is the risk of complications. It does not have 100% sensitivity in identifying the fallopian tube obstruction.

Laparoscopy should be performed in patients with abnormal result of hysterosalpingography or abnormal result of clinical examination. It is also recommended in women who underwent an inflammation of adnexa or surgical treatment, e.g. appendectomy, surgeries within ovaries. This examination can be very useful if the cause of infertility is not clear. The procedure is carried out more often to remove changes in e.g. ovaries or when endometriosis is suspected. It can be combined with hysteroscopy in order to assess the structure of uterine cavity.

Hysteroscopy is an endoscopic procedure intended to assess the structure of uterine cavity; during the procedure, changes occurring in the uterine cavity such as polyps, fibroids and adhesions can be removed. Hysteroscopy performed routinely in all infertile female patients is not justified. This examination should be carried out in case of clinical symptoms or changes confirmed in ultrasound or HSG examination.

In conclusion, the diagnosis of the female factor in infertility should start with the in-depth medical interview and physical examination and the ultrasound assessment of organs within the lesser pelvis. In addition, on day 1 to 3 of the cycle, levels of estradiol, LH, FSH, prolactin, anti-TPO antibodies and SHBG, Inhibin B and AMH should be determined. Currently, PRL in the metoclopramide test is not recommended. In doubtful cases, it is worth to consider testing for macroprolactin. If we suspect any uterine anomalies, the examination which will visualize them is hysterosalpingography or hysteroscopy, while in case of suspected tubal obstruction, we should carry out hysterosalpingography. It allows also to locate the obstruction of the fallopian tube. Finally, once again the most important rule in the diagnosis and treatment of infertility has to be stressed – infertility is a problem of both partners and it should always be perceived as such.

Authors of article: M. Kaszuba A. Litwin, dr hab. n. med. K. Łukaszuk, prof GUM-ed

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