Basic Infertility Evaluation - Fertility Tests: https://www.inciid.org

InterNational Council on Infertility Information Dissemination, Inc. (INCIID – pronounced “inside”)

This article is a basic overview or review of an infertility evaluation for those individuals and couples struggling with infertility and trying to conceive or carry a pregnancy to term and delivery.

The American Society of Reproductive Medicine (ASRM) revised the definition of infertility to encourage earlier evaluation and treatment in the highest risk group. Infertility has traditionally been defined as the inability to conceive after twelve months of regular, unprotected intercourse

INCIID suggests seeking evaluation early with a reproductive endocrinologist (RE). Seeking help from a specialist (RE) is particularly important if you are 30 or over and/or have experienced more than one spontaneous abortion (miscarriage).

The following experiences suggest seeking specialized help from a reproductive endocrinologist.

· Regular unprotected intercourse with no pregnancy for a year

· Trying 6 months when 30 years of age or older

· Irregular menstrual cycles

· A history of pelvic pain or other problems such as infection or abdominal or reproductive surgery

· DES Exposure

· Two or more miscarriages (under 30) and one if 30 or older

· Male reproductive problems that may alert you to a problem may include:

• Reproductive surgery • Low sperm count and./or problems with morphology etc. • prostatitis • Urinary infections

Reproductive Endocrinology and Infertility (REI): Why seeing an RE is important.

Education The reproductive endocrinology specialist is usually an Obstetrician-Gynecologist with advanced

education, research and professional skills in the field of Reproductive Endocrinology and Infertility (REI). Reproductive endocrinology is a surgical subspecialty of obstetrics and gynecology that trains physicians in reproductive medicine addressing hormonal functioning as it pertains to reproduction as well as the issue of infertility and multiple pregnancy loss.

Generally, OB/GYN enter into a 3-year fellowship or training program leading to board certification in Reproductive Endocrinology and Infertility by the American Board of Obstetrics and Gynecology. These fellowships provide clinical training in reproductive endocrinology, reproductive surgery, assisted reproductive technology (i.e. IVF and other ART procedures), genetics, embryology, and andrology. The programs are rigorous with comprehensive requirements. The physicians in the program are also required to pass a written examination and an oral exam by a team of REI experts. Once passed the physicians are sub-specialty board certified.

INCIID is often asked, “who is the best”. The most important first decision is seeing a specialist. Seeing an RE is the consummate “gold standard”. OB/GYNs will have some basic knowledge about infertility but that information and practice are minimal. The research required during an REI fellowship will support improved clinical outcomes and fewer clinical errors. This sub-specialty also requires updating physician knowledge to continue to provide evidence-based practice.

When looking for a board-certified reproductive endocrinologist check the Society of Reproductive Endocrinology and Infertility (SREI)website. The SREI required board certification in Obstetrics and Gynecology as well as the RE subspecialty. INCIID also offers a biographical overview including the specialty of physician members who support INCIID’s mission. Search the directory by zip code or state.

Patients should not be shy about asking their fertility doctor if they are “Sub-specialty” board certified as a reproductive endocrinologist.

Many patients are reluctant to switch from their OB/GYN. Some sight the expense. But the business of Obstetrics and Gynecology concentrates on routine gynecological care and delivering babies for their bread and butter. While evaluation of a fertility problem can be expensive, to stay with an OB/GYN can waste valuable time and actually become more expensive.

INCIID stresses the importance of seeking early care with qualified practitioners and outlines the criteria for moving to a specialist.

Having a family is an individual or couples’ decision. Whatever your situation, partners are in this together.

Basic Infertility Evaluation

Please note that every reproductive endocrinologist (RE) has his or her own standard protocol, and the following is intended to be a helpful basic guideline. Patients should be in a partnership with their physician and feel comfortable asking questions about any test or procedure.

FIRST APPOINTMENT: History and Physical Exam

At the first appointment, most REs also do a routine screening of both partners such as HIV, hepatitis, etc. Medical histories for both partners will be taken. Try to keep track of the length of your menstrual cycles for several months beforehand. Charting Basal Body Temps (BBTs) for several months will also give your doctor some insights---as will using home Ovulation Predictor Tests (OPTs) and recording the results. A semen analysis will be scheduled. Some doctors will accept your medical records for review prior to your appointment. If not, bring your medical records with you.

The doctor will generally start with some type of comprehensive questionnaire providing an overview of reproductive history for both partners. He or she may also ask questions about the reproductive history. Some of those questions may include information about:

• Previous pregnancies (if any) • Irregular periods or menstrual cycles • Pre-existing conditions or diagnosis such as polycystic ovary syndrome, pelvic inflammatory

disease, tubal pregnancy, endometriosis • Problems with ovulation, • Male infertility issues, sperm count, motility, urinary or prostate issues

The physician may do a vaginal ultrasound. Consider scheduling the first consultation with the RE during the first or second day of the menstrual cycle. Why? Because during the exam, the doctor may be able to do several tests that are cycle-day specific. Instead of re-scheduling for another date, patients may be able to arrange for time-sensitive tests and move forward with evaluations and a plan more quickly.

Assessment of Ovarian Reserves

Human Ovary Antral Follicle Count (Guided Vaginal Ultrasound)

One test and a good predictor of ovarian reserve is the antral follicle count. The count is done of cycle days 2, 3, or 5 using guided vaginal ultrasound. Antral follicles are immature eggs. The number of immature follicles correlates with ovarian reserves. that looks at the ovaries. Keep in mind that antral follicles vary from month to month.

A vaginal ultrasound can also discover abnormalities within the Pelvis. Infections in the pelvic region often go unnoticed but are a significant cause of infertility (i.e. blocked tubes, uterine scarring, tubal damage, endometriosis, fibroids, adhesions, etc.) If the antral count is too low (generally less than 4 according to Dr. Richard Sherbahn) chances of a successful pregnancy and live birth are low, the higher antral counts can be indicative of PCOS (Poly Cystic Ovarian Syndrome)

Anti-Mullerian Hormone Testing of Ovarian Reserve (AMH) (Blood Test)

The human egg is "housed" inside a structure called the follicle. The follicle is comprised of specialized cells called granulosa cells. The granulosa cells produce a specific hormone directly and predictably linked to egg quality, and that hormone is called AMH. While other means of examining ovarian reserve may offer indirect, and possibly less accurate, less specific, and less predictive tests of egg quality (such as cycle day 3 FSH/estradiol levels and the Clomiphene Citrate Challenge Test), many reproductive endocrinologists believe women are better served by examining their AMH level -- a more direct, more accurate, more specific, and more predictive test of egg quality.

The AMH test has been found particularly useful in the following clinical situations:

·

Women who either need a Clomiphene Citrate Challenge Test (CCCT) or previously had a CCCT and want to confirm/refute the results;

· Women of advanced reproductive age (35 years or older);

· Any women with a diagnosis of "unexplained infertility";

· Women who have shown a poor response to ovulation induction with either Clomid/Serophene or injectable fertility drugs;

· Women who have been told they need IVF with donor eggs -- a normal AMH level may permit them to do IVF with their own eggs, while an abnormal AMH level may confirm the need for IVF with donor eggs

For more information on AMH testing, see the article by Scott Roseff, MD

Day 3 Follicle Stimulating Hormone (FSH) and Estradiol (E2) Testing (Blood Testing)

On the third day of the menstrual cycle, the clinic may draw blood and test the FSH levels. This test is not as reliable as other but can give an indication if a woman is closer to menopause (with low ovarian reserves). FSH is a hormone secreted by the anterior lobe of the pituitary and stimulates the maturing of the ovarian follicles in women. In men, the hormone is important in maintaining spermatogenesis.

Unfortunately, a high FSH is always bad but a good level may not mean there are egg reserves either.

Adding to the confusion is the fact that FSH bounces around quite a bit. One month the result may be a 7 and the next month it may be a 13. For a while, it was thought that waiting for a month to cycle may yield a better level and improve the odds that a given cycle would work. Unfortunately, the intermittent high FSH is as bad a prognostic sign in months where the FSH is normal as in months where the level is high.

For more information on FSH testing read the David Sable, MD article.

Other Blood Work May Be Ordered

(Please also reference educational module on Biotin Interference)

Depending on the individual or couple’s needs, there may be other blood tests ordered. Blood tests that might be needed include:

Luteinizing hormone (LH): A pituitary hormone that stimulates the gonads. In the male LH is necessary for spermatogenesis (Sertoli cell function) and for the production of testosterone (Leydig cell function). In the woman LH is necessary for the production of estrogen. When estrogen reaches a critical peak, the pituitary releases a surge of LH (the LH spike), which releases the egg from the follicle.

LH controls the length and sequence of the female menstrual cycle, including ovulation, preparation of the uterus for implantation of a fertilized egg, and ovarian production of both estrogen and progesterone. Theca cells in the ovary respond to LH stimulation by secretion of testosterone, which is converted into estrogen by adjacent granulosa cells. In women, ovulation of mature follicles on the ovary is induced by a large burst of LH secretion - the preovulatory LH surge. Residual cells within ovulated follicles proliferate to form corpora lutea, which secrete the steroid hormones - progesterone and estradiol. Progesterone is necessary for the maintenance of pregnancy, and, in most mammals, LH is required for continued development and function of corpora lutea. For more information read this article.

Dr. Geoffrey Sher, “It is certainly time for us to reflect seriously on what and why e use specific protocols and drugs in IVF.” Dr. Sher thinks the focus might be better by optimizing ovogenesis rather than simply on how to increase the total egg yield.” He goes on to say he favors the use of FSHr-dominant, long pituitary down-regulation protocols that reduce LH. Dr. Sher is experienced in treating older women. Read more about LH regulation here. Estradiol (E2),

Prolactin is a hormone produced by the pituitary gland. The pituitary gland sits below the hypothalamus at the base of the brain.

Prolactin causes breasts to grow and develop. It also causes milk production in the breasts of a lactating or pregnant woman. Prolactin can be found in both males and females. A blood test will determine the prolactin levels and your doctor will have a normal or out of range level and recommend the best course of action.

During pregnancy prolactin levels increase. After the birth of a baby, a woman’s estrogen and progesterone levels drop and prolactin levels rise. These high levels of prolactin cause milk to “come in” or milk production to begin so a baby can be breastfed. In women who are not pregnant, prolactin is one of the hormones that regulate menstrual cycles. In males, high levels of prolactin may be related to sperm production and sexual dysfunction. For more information on prolactin, read this article by Carolyn Coulam, MD.

Testosterone (T): The male hormone responsible for the formation of secondary sex characteristics and for supporting the sex drive. Testosterone is also necessary for spermatogenesis.

Progesterone (P4): The hormone produced by the corpus luteum during the second half of a woman's cycle. It thickens the lining of the uterus to prepare it to accept implantation of a fertilized egg. It is released in pulses, so the amount in the bloodstream is not constant.

17-hydroxyprogesterone (17-OHP) An over-secretion of androgen can cause elevated 17-OHP levels which can, in turn, interfere with ovulation. This is called congenital adrenal hyperplasia. Once this condition is found it can be corrected with medication to help patients ovulate normally.

Thyroid Releasing Hormone (TRH) and low levels of Thyroxine(T4) can also result in an excess of prolactin (normally produced by the pituitary gland to promote lactation) and TSH both of which can have a negative effect on fertility by preventing ovulation or result in irregular or absent periods.

Thyroid Stimulating Hormone (TSH): Women are far more likely and more often (than men) experience thyroid disease during their reproductive years. The most common test done to assess thyroid function is TSH (Thyroid Stimulating Hormone). TSH is produced by our pituitary

gland. TSH stimulates the thyroid to produce the hormones T4 (thyroxine) that can interfere with ovulation.

Different clinics and laboratories standardize testing in different ways. Below is an overview generally of the ranges for the different levels.

Luteinizing Hormone (LH)

· Follicular Phase (day two or three): <7mIU/ml

· Day of LH Surge: >15mIU/ml

Follicle Stimulating Hormone (FSH)

· Follicular Phase: <13mIU/ml

· Day of LH Surge: >15 mIU/ml

Estradiol

· Day of LH Surge: >100 pg/ml

· Mid Luteal Phase (seven days after O): >60 pg/ml

Progesterone

· Day of LH Surge: <1.5 ng/ml

· Mid Luteal Phase >15 ng/ml

Prolactin:<25 ng/ml Free T3: 1.4 to 4.4 pg/ml Free Thyroxine (T4): 0.8 to 2.0 ng/dl Total Testosterone: 6.0 to 89 ng/dl Free Testosterone: 0.7 to 3.6 pg/ml DHEAS: 35 to 430 ug/dl Androstenedione: 0.7 to 3.1 ng/ml

KEY: < = less than; >= greater than; mIU=milli International Units;

ml=milliliter;

pg=picograms;

ng=nanograms;

uIU=micro International Units;

dl=deciliter; ug=micrograms

Additional Testing

After the initial workup, many doctors continue with some of the following tests.

HYSTEROSALPINGOGRAM (HSG):

This test is used to examine a woman's uterus and fallopian tubes. It is essentially an x-ray procedure in which a radio-opaque dye is injected through the cervix into the uterus and fallopian tubes. This "dye" appears white on the x-ray, and allows the radiologist and your doctor to see if there are any abnormalities, such as an unusually shaped uterus, tumors, scar tissue or blockages in the fallopian tubes. If you are trying to get pregnant in the same cycle as an HSG, make sure to schedule the test PRIOR to ovulation so that there is no danger of "flushing out" a released egg or developing embryo. Although most women report only minor cramping and short-term discomfort during this procedure, some women, especially those who DO have blockages, report intense pain. Speak to your doctor about taking a pain medication about 30 minutes prior to the actual procedure.

Transabdominal Saline Contrast Sonohysterography

Although HSG is the standard screening test for the diagnosis of tubal infertility, there are studies that confirm a higher sensitivity, safety and acceptability of Transabdominal Saline Contrast Sonohysterography (compared to HSG) for the evaluation of tubal patency in infertile women.

This technique uses sound waves to produce pictures of the inside of a woman’s uterus and help diagnose unexplained vaginal bleeding. Hysterosonography is performed very much like a gynecologic exam and involves the insertion of the transducer into the vagina after you empty your bladder.

Using a small tube inserted into the vagina, your doctor will inject a small amount of sterile saline into the cavity of the uterus and study the lining of the uterus using the ultrasound transducer. This can also be injected into the fallopian tubes for evaluation of patency. Ultrasound does not use ionizing radiation, has no known harmful effects, and provides a clear picture of soft tissues that don’t show up well on x-ray images.

This technology is readily available, easy to interpret. It is not only safer and cheaper but it’s as accurate as HSG in evaluating the fallopian tubes and the uterine cavity in infertile patients. Some physicians advocate its use as a replacement. (Read more here.)

HYSTEROSCOPY

(Transabdominal Saline Contrast Sonohysterography can be also used in place of Hysteroscopy)

If a uterine abnormality is suspected after the HSG, your doctor may opt for this procedure, performed with a thin telescope mounted with a fiber optic light, called a hysteroscope. The hysteroscope is inserted through the cervix into the uterus and enables the doctor to see any uterine abnormalities or growths. "Photos" are taken for future reference. This procedure usually is performed in the early half of a woman's cycle so that the build-up of the endometrium does not obscure the doctor's view. However, if the doctor is planning to do an endometrial biopsy at the same time, it is done near the end of the cycle.

LAPAROSCOPY

A narrow fiber optic telescope is inserted through a woman's abdomen to look at the uterus, fallopian tubes, and ovaries and to discern endometriosis or pelvic adhesions, and is the best diagnostic tool for evaluating the ovaries. This test is usually done two or three days before menstruation is expected, and only after an HCG beta blood test ensures the woman is not pregnant

ENDOMETRIAL BIOPSY

In the past, the endometrial biopsy was a routine part of the fertility evaluation, but currently, it is performed mainly on patients at risk for endometrial cancer or with repeated IVF failures. An endometrial biopsy is a simple office-based procedure that is performed just before the onset of a woman's menses.

Baseline tests for follicle stimulating hormone (FSH) and luteinizing hormone (LH) must be done on day three of your cycle. If your consultation should take place before that, you'll be instructed to come in for these tests on day three of your cycle. Additional tests will be conducted on the day of Luteinizing Hormone (LH) surge (mid-cycle), and again about seven days after ovulation.

Luteinizing Hormone (LH)

· Follicular Phase (day two or three): <7mIU/ml

· Day of LH Surge: >15mIU/ml

Follicle Stimulating Hormone (FSH)

· Follicular Phase: <13mIU/ml

· Day of LH Surge: >15 mIU/ml

Estradiol

· Day of LH Surge: >100 pg/ml

· Mid Luteal Phase (seven days after O): >60 pg/ml

Progesterone

· Day of LH Surge: <1.5 ng/ml

· Mid Luteal Phase >15 ng/ml

Prolactin:<25 ng/ml Free T3: 1.4 to 4.4 pg/ml Free Thyroxine (T4): 0.8 to 2.0 ng/dl Total Testosterone: 6.0 to 89 ng/dl Free Testosterone: 0.7 to 3.6 pg/ml DHEAS: 35 to 430 ug/dl Androstenedione: 0.7 to 3.1 ng/ml

KEY: <= less than; >= greater than; mIU=milli International Units; ml=milliliter; pg=picograms; ng=nanograms; uIU=micro International Units; dl=deciliter; ug=micrograms

Semen Analysis

A semen analysis is an important test and it should be done early in the evaluation. If there is a significant sperm problem, the female analysis may be modified to more basic tests and certainly, the analysis should be conducted before more invasive female surgical interventions are attempted.

About a quarter of infertility cases are due to a sperm defect. Almost half of the infertility patient cases will include a sperm deficit as a contributing factor in the causation of infertility. Take a closer look at the male reproductive system and the way sperm

is analyzed here.

Multiple Miscarriages, Stillbirth and Pregnancy Loss

Until the last decade, there was little a couple could do if they suffered from recurrent pregnancy losses. Miscarriages that couldn't be attributed to chromosomal defects, hormonal problems or abnormalities of the uterus were labeled "unexplained," and couples would continue to get pregnant, only to suffer time and again as they lost their babies. New research, however, has provided information on the causes of the heretofore unexplained pregnancy losses allowing more effective treatment enabling women to carry their babies to term. About 15-20% of all pregnancies result in miscarriage, and the risk of pregnancy loss increases with each successive pregnancy loss. For example, in a first pregnancy, the risk of miscarriage is 11-13 %. In a pregnancy immediately following that loss, the risk of miscarriage is 13-17 %. But the risk to a third pregnancy after two successive losses nearly triples to 38 %.

There are a number of tests for multiple pregnancy loss. Those patients with unexplained infertility may also want to read this article by Carolyn Coulam, MD and investigate immunological issues that may curtail or prevent pregnancy. (A list of tests can be found in the article.)

If you have questions about a basic fertility evaluation, please contact INCIID.