- infertility is generally defined as 1 year of unprotected intercourse without conception. Approximately 85-90% of healthy young couples conceive within 1 year.
- Cycle fecundability is the probability that a single cycle will result in pregnancy .
- Cycle fecundity is the probability that a single cycle will result in a live birth.
The Epidemiology of Infertility
- Declining U.S. birth and fertility rates can be attributed to several factors:
1) Greater interest in advanced education and career among women.
2) Later marriage and more frequent divorce.
3) Improvements in contraception and access to family planning services.
4) Delayed childbearing.
5) Decreased family size.
Aging and Female Fertility
- Overall, fertility rates are 4% to 8% lower in women aged 25-29, 15 to 19% lower between ages 30 and 34, 26-46% lower in women aged 35-39, and as niuch as 95% lower between ages 40 and 45.
Physiology of Reproductive Aging
- follicular depletion :During fetal life, germ cells rapidly proliferate by mitosis to yield approximately 6 to 7 million oogonia by 16-20 weeks of pregnancy. From that point forward, the germ cell population begins an inexorable exponential decline via gene-regulated apoptosis.'” Transformed to oocytes after entering the first meiotic division, the number of germ cells falls to between 1 and 2 million at birth and to about 300,000 to 500,000 by the onset of puberty..
- Over the next 35-40 years of reproductive life, only about 400 to 500 oocytes will ovulate; the rest are lost through atresia. During the reproductive years, the rate of follicular depletion is relatively constant and gradual until age 37-38 (when approximately 25,000 oocytes remain) and then accelerates over the 10-15 years preceding menopause. At the time of menopause, fewer than 1,000 follicles remain.
- Endocrynology :As the pace of follicular depletion begins to increase during the later reproductive years, but before any discernible change in menstrual regularity, serum follicle-stimulating hormone (FSH) levels begin to increase; luteinizing hormone (LH) concentrations remain unchanged.
Oocyte and aging folicles
- The available evidence indicates that both the age-related decline in female fertility and the increase in risk of spontaneous miscarriage can be attributed largely to progressive follicular depledon and a high incidence of abnormalities in aging oocytes.
- In sum, αccumulαted evidence strongly suggests that the primary cause ofthe age-dependent decrease in fecundability and increase in the incidence of spontaneous miscarriage is an increasing prevalence of aneuploidy in aging oocytes resulting frotn disordered regulatory mechanisms governing meiotic spindle formation andfunction.
- Aging and uterus:Aging does not appear to have any significant adverse effect on the uterus. Although the prevalence of benign uterine pathology (leiomyomas, endometrial polyps, adenomyosis) increases with age, little evidence exists to indicate it has much overall impact on fertility in women.
Ovarian Reserve Tests
- ovarian reserve; generally describing the size and quality of the remaining ovarian follicular pool.
- an early follicular phase (cycle day 3) serum FSH concentration is the simplest and still most widely applied measure of ovarian reserve.Currently, in most lαborαtories, cycle day 3 serum FSH levels above 10-20 IU/L are considered abnormal
2)clomiphene citrate challenge test:
The clomiphene citrate challenge test is a provocative and even more sensitive test of ovarian reserve that probes the endocrine dynamics of the cycle under both basal and stimulated conditions before (cycle day 3 FSH and estradiol) and after (cycle day 10 FSH) treatment with clomiphene citrate (100 mg/day, cycle days.
4)antimiillerian hormone (AMH) levels
5)The number of small antral follicles
observed by transvaginal ultrasound examination at the outset of the menstrual cycle reflects the size of the resting follicular pool and correlates with age and response to gonadotropin stimulation
- ovarian reserve testing can more strongly be justified for women with any of ‘the following characteristics:
- Age older than 35.
- Unexplained infertility, regardless of age.
- Fαmily history of early menopause.
- Previous ovarian surgery (ovarian cystectomy or drilling, unilateral oophorectomy), chemotherapy, or radiation.
- Demonstrated poor response to exogenous gonadotropin stimuladon.
Guiding Principles in the Evaluation of Infertility
- Lifestyle and Environmental Factors;
2)Substance abuse :smoking
4)potentially harmful occupational and environmental exposures
Normal Reproductive Efficiency
- reproductive efficiency in normally fertile couples averages about 20% and does not exceed approximately 35% even when coitus is carefully timed
- Normal sperm can survive in the female reproductive tract and retain the ability to fertilize an egg for at least 3 and up to 5 days, but an oocyte can be successfully fertilized for only approximately 12-24 hours after it is released. Consequently, in virtually all conception cycles, intercourse occurs sometime within the 6-day interval ending on the day of ovulation.
Indications for Evaluation
- Overall, the likelihood of success without treatment declines by about 5% for each additional year of female partner’s age and by 15-25% for each added year of infertility.
- Evaluation should be offered to all couples who have failed to conceive after a year or more of unprotected intercourse, but a year of infertility should not be regarded as a prerequisite for evaluation. Regardless of age or duration of infertility, immediate evaluation should be offered to women older than age 35, women with irregular or infrequent menses, women with a history of pelvic infection or endometriosis, and in men with known or suspected poor semen quality, because there is no rationale for delay in such circumstances
The Female Infertility Evaluation
- Gravity, parity, pregnancy outcomes, and associated complications.
- Cycle length and characteristics, onset and severity of dysmenorrhea.
- Coital frequency, and any sexual dysfunction.
- Duration of infertility and results of any previous evaluation and treatment.
- Past surgery, its indications and outcome, and past or current medical illnesses, to include episodes of pelvic inflammatory disease or exposure to sexually-transmitted infections.
- Previous abnormal Pap smears and any subsequent treatment.
- Current medications and allergies.
- Occupation and use of tobacco, alcohol, and other drugs.
- Family history of birth defects, mental retardation, early menopause or reproductive failure.
- Symptoms of thyroid disease, pelvic or abdominal pain, galactorrhea, hirsutism, and dyspareunia
- Weight and body mass index.
- Any thyroid enlargement, nodule, or tenderness.
- Breast secretions and their character.
- Signs of androgen excess.
- Pelvic or abdominal tenderness, organ enlargement or mass.
- Vaginal or cervical abnormality, secretions, or discharge.
- Any mass, tenderness, or nodularity in the adnexa or cul-de-sac
- Pap smear
- blood type, Rh factor, and antibody screening (in Rh-negative women) are also recommended, if not already known.
- Screening for cystic fibrosis
- previous rubella infection or vaccination
- Screening for varicella (chickenpox) immunity
- Screening for sexually-transmitted infections (STIs)
1) Male Factor: Abnormalities of Semen Quality
2) Ovarian Factor
Basal Body Temperature (BBT)
during the follicular phase of the cycle, then is modestly higher (0.4°-0.8° over the average preovulatory temperature during the luteal phase
- coital timing can be optimized by suggesting alternate-day intercourse beginning 7 days before the earliest observed rise and ending on the day before the latest observed shift in BBT
- Serum Progesterone Concentration:
- In general, any level greater than 3 ng/mL provides reliable objective evidence that ovulation has occurred
- Therefore, when the serum progesterone concentrαtion is used to document ovulation, the best time to test with the overall length of the menstrual cycle, aiming for approximately a week before the expected menses
- Urinary LH Excretion
- results correlate best with the serum LH peak when testing is performed in the late afternoon or early evening hours (4:00-10:00 P.M.), probably because LH surges often begin in the early morning hours and are not detected in urine until several hours later.
- Ovulation generally follows within 14-26 hours after detection of the urine LH surge and almost always within 48 hours. Consequently, the interval of greatest fertility includes the day of LH surge detection and the following 2 days.
- Endometrial Biopsy and Luteal Phase Deficiency:
- in the absence of treatment with exogenous progesterone or synthetic progestins, a secretory endometrium implies recent
- endometrial dating can not be used to guide the clinical management of women with reproductive failure and should no longer be regarded as an important element of their evaluation.
- Transvaginal Ultrasound and the Luteinized Unruptured Follicle
- The method involves direct observation of a characteristic sequence of changes that occur just prior to and immediately after ovum release
3) Cervical Factor: Abnormalities of Sperm-Mucus Interaction
- Estrogen stimulates cervical mucus production, and, as estrogen levels rise with progressive follicular development, the mucus becomes more abundant, clear, and watery and more easily penetrated by sperm. Progesterone inhibits cervical mucus production and renders it opaque, viscid, and impenetrable
- The postcoital test
4)Uterine Factor: Anatomic and Functional Abnormalities
- Transvaginal Ultrasound and Sonohysterography
- Congenital Uterine Malformations
- Uterine Leiomyomas
- Intrauterine Adhesions (Asherman’s Syndrome)
- Endometrial Polyps
- Chronic Endometritis
5) Tubal Factor: Tubal Occlusion and Adnexal Adhesions
- A history of pelvic inflammatory disease (PID), septic abortion, ruptured appendix, tubal surgery, or ectopic pregnancy suggests the possibility of tubal damage. PID is unquestionably the major cause of tubal factor infertility and ectopic pregnancies.
- Hysterosalpingography (HSG)
- Chlamydia Antibody Tests
- Tubal Surgery in the Era of ART
6) Unexplained Infertility