Infertility Evaluation: History, Examination and Tests

An infertility evaluation examines both partners together. It starts with a detailed history and physical examination, then runs two sets of laboratory tests: screening tests that every couple planning a pregnancy should have, and diagnostic tests that find the cause, namely semen analysis for the man and tests of ovulation, tubal patency and the uterine cavity for the woman.

Dr. Soma Singh, Associate Director - IVF & Infertility, Max Super Speciality Hospital, Noida, India, describes history as the key to any clinical condition, in infertility as in medicine and surgery. This article sets out the evaluation she teaches, with the reasoning behind each step. It is part of a series: the overview is in recent advances in the management of an infertile couple, and the male side of the evaluation, including semen analysis reference values and sperm DNA fragmentation, is covered in male infertility evaluation.

When to start an infertility evaluation

The standard trigger is 12 months of regular, unprotected intercourse without a pregnancy. Dr. Singh begins sooner when there is a reason to expect a problem: the woman is over 35, her periods are irregular, her history suggests pelvic infection or endometriosis, she has had ovarian surgery, the man has known or suspected poor semen quality, or either partner has had chemotherapy or radiotherapy.

Taking the history from the woman

The woman's history starts with her age, because age is the most important prognostic factor in any fertility treatment. The questions that follow each have a purpose:

• Duration of infertility. The longer a couple has been trying, the lower the chance of conception, falling by 20 to 25% each year.
• Coital difficulties. Problems with intercourse are a treatable cause that is easily missed if not asked about.
• Menstrual regularity. Regular cycles strongly suggest regular ovulation; irregular cycles point towards ovulatory dysfunction such as polycystic ovary syndrome (PCOS).
• Obstetric history. Previous pregnancies, miscarriages and their outcomes separate primary from secondary infertility.
• Medical and surgical history, including any pelvic or ovarian surgery.
• Lifestyle: smoking, alcohol and recreational drugs.

Taking the history from the man

The man needs an equally detailed history. Male age matters less than female age: Dr. Singh noted that obvious changes in male fertility are rarely seen before about 50. With age, semen volume, sperm motility and the proportion of normally shaped sperm fall, while sperm concentration stays much the same.

The history covers coital problems, previous medical illnesses, previous surgery, past sexually transmitted infections, drug history and lifestyle factors.

The physical examination

Examination of both partners looks for signs of hormonal deficiency, endocrine disease and structural problems.

In the woman:

• Weight and body mass index (BMI). Both underweight and overweight can cause infertility and adverse pregnancy outcomes.
• Secondary sexual characteristics, and whether they are well developed.
• The thyroid, for enlargement.
• The breasts, for any discharge.
• Signs of hyperandrogenism, the excess of male hormones seen in conditions such as PCOS: hirsutism (excess hair growth) and acne.
• A thorough abdominal and pelvic examination, including the vagina and cervix, for structural anomalies.

In the man:

• BMI and body habitus.
• Secondary sexual characteristics, and gynaecomastia (breast enlargement), which Dr. Singh singles out as important.
• Genital examination: the penis, the scrotum, whether both testes are present and in position, their size, and, for a clinician comfortable doing so, palpation of the vas deferens and epididymis to confirm that the cord structures are present.

Not every gynaecologist is well versed in examining the male genitalia. Dr. Singh's practical advice for them is to start with a simple semen analysis. An abnormal reproductive history or an abnormal semen analysis is then the indication for formal evaluation of the man by a urologist or medical specialist.

Preconception screening tests for every couple

Screening tests are not aimed at finding the cause of infertility. They make sure that the couple is fit to conceive and that a pregnancy will be safe. Dr. Singh's panel:

For both partners:

• Blood group.
• Screening for sexually transmitted infections.

For the woman, who will carry the pregnancy:

• Rubella and varicella immunity, so that she can be vaccinated before conceiving if she is not immune.
• Pap smear or liquid-based cytology (LBC) to rule out cervical cancer.
• Haemoglobin electrophoresis to detect an abnormal haemoglobin.
• HbA1c, a measure of average blood sugar over recent months. Strict blood sugar control before conception is essential.
• Thyroid profile.
• Vitamin D. Dr. Singh adds this test because, in her view, vitamin D deficiency can lead to miscarriage.
• Other hormone assays as indicated.

Haemoglobin electrophoresis and thalassaemia carrier screening

Haemoglobin electrophoresis separates the types of haemoglobin in the blood. Dr. Singh uses it before starting any treatment, whether ovulation induction, IUI or IVF, to find out whether the woman carries haemoglobin S (the sickle cell gene), haemoglobin C or thalassaemia trait. If she is a carrier, the man must be tested as well, because the condition is inherited. When both partners carry thalassaemia trait, each child has a 25% chance of thalassaemia major. Such couples may need genetic counselling or pre-implantation genetic testing of their embryos before transfer, as described in the series overview.

Diagnostic tests: finding the cause

Diagnostic tests answer four questions. Is the semen normal? Is the woman ovulating? Are her fallopian tubes open? Is her uterine cavity normal? Further tests follow from the history and examination. Semen analysis, the first and simplest test for the man, is covered in detail in the male infertility article.

Is she ovulating?

A woman with regular monthly periods and premenstrual symptoms is almost certainly ovulating. Where confirmation is needed, the options are:

• Mid-luteal progesterone. Progesterone is measured in the second half of the cycle; a level above 3 ng/mL indicates that ovulation has occurred.
• Urinary LH kits. Commercial kits detect the surge of luteinising hormone (LH) that triggers ovulation. Dr. Singh finds them useful for couples who live apart and meet for only a few days in a month or a year, who need to time intercourse precisely.
• Follicular tracking by transvaginal ultrasound. Serial scans show exactly when ovulation takes place. This is the ideal method, but it is cumbersome, because it requires repeated clinic visits.
• Basal body temperature charting is no longer used.

Are the fallopian tubes open?

Tubal assessment has three main tools, in increasing order of invasiveness:

1. Hysterosalpingography (HSG). An X-ray dye test and the common first-line screening test. It shows the uterine cavity and the tubes, including whether a block is proximal (near the uterus) or distal (at the far end). It is sometimes therapeutic as well: flimsy adhesions or small blocks can clear as the dye is pushed through.
2. Ultrasound tests. In the simpler version, saline is pushed into the uterus during a transvaginal scan; fluid appearing in the pouch of Douglas behind the uterus shows that at least one tube is open, but not which one. Hysterosalpingo-contrast sonography (HyCoSy) uses a contrast medium that is visible on ultrasound, so it shows which tube is patent and which is blocked.
3. Laparoscopy, keyhole surgery through the abdominal wall, is the standard method. It shows the whole pelvis, not just the tubes, and allows tubal blocks to be corrected in the same sitting.

Is the uterine cavity normal?

Fibroids and other uterine anomalies are common, and Dr. Singh assesses the cavity in every woman:

• Transvaginal ultrasound (TVS) is a must at the very first visit for every woman, in any clinic that has an ultrasound machine. It shows the size of the uterus, fibroids and other masses, ovarian cysts and much else in the pelvis.
• HSG, already done for the tubes, also outlines the cavity and is the best initial test.
• Saline infusion sonohysterography (SIS). Saline is instilled through a cannula or a Foley catheter while scanning, which distends and outlines the cavity. It is particularly useful when a small polyp or intrauterine adhesions are suspected.
• Hysteroscopy, which views the cavity directly through the cervix, is the definitive test, but it is a surgical procedure that needs anaesthesia unless it is performed as office hysteroscopy.

Ovarian reserve testing: when it is and is not indicated

Ovarian reserve is the number of eggs remaining in the ovaries. Dr. Singh is clear that testing it is not a screening test and is not indicated for every woman who presents with infertility. She reserves it for women at increased risk of diminished reserve:

• age over 35;
• unexplained infertility;
• a family history of early menopause;
• previous ovarian surgery;
• smoking;
• a poor response to gonadotropin stimulation in the past;
• endometriosis.

Ovarian reserve should always be checked before surgery for endometriosis, because operating on the ovaries can reduce it further. Dr. Tripti Sharan's article on endometriosis, ovarian reserve and fertility covers that decision in depth.

The physiology behind the tests

Each test makes sense against the normal cycle, which Dr. Singh explained in the discussion. Under the influence of follicle-stimulating hormone (FSH) from the pituitary, a cohort of follicles in the ovaries starts to grow each cycle. The follicle most sensitive to FSH dominates; the others regress. The dominant follicle releases one egg at ovulation.

While the follicle grows, it secretes oestrogen, which builds up the endometrium, the lining of the uterus, in preparation for an embryo. After ovulation, the corpus luteum (the remains of the follicle) produces progesterone, which is why a mid-luteal progesterone level confirms ovulation. Fertilisation takes place in the fallopian tube, which is why tubal patency is tested, and the embryo reaches the uterine cavity a few days later and implants, which is why the cavity is assessed. If no pregnancy occurs, the prepared lining is shed as the menstrual period.

From evaluation to treatment

Once the cause is identified, treatment follows a ladder from lifestyle change to medical treatment, surgery and assisted reproduction, described in IUI, IVF and ICSI. For the WHO's own diagnostic sequence and thresholds, Dr. Hrishikesh Pai's article on the WHO infertility workup is a useful companion. Questions from the audience on screening and physiology are collected in the Live Discussion from this masterclass.