• Infertility is the absence of pregnancy despite one year of unprotected intercourse. Those who have never had a pregnancy before are called primary infertile, and those who have had at least one pregnancy, whether or not they resulted in a live birth, are called secondary infertile. Couples who can conceive after 12 months are called subfertile.
• Fecundability; The probability of pregnancy occurring in an unprotected menstrual cycle is 20% for women under 35 years of age. Fecundity decreases as women age.
• Fecundity; Unprotected is the probability of a live birth occurring in one menstrual cycle and is less than fecundity.
• Age is the most important indicator of success with both spontaneous and assisted reproductive techniques. Ovarian reserve decreases with age. The decrease in fertility with advancing age is mostly due to the decrease in the number of oocytes.
• 90% of couples achieve pregnancy within one year. In 7.4% of couples of reproductive age, infertility is a health problem.
Causes of infertility
1. Male Factor ---------------------------------------------- ---------------------► 25%
2. Ovulatory Factor ---------------------------------------------- --------------► 27%
3. Tubal / Uterine Factor ------------------------------ ---------- ---- ---------► 22%
4. Other factors ---------------------------------------------- -------------------► 9%
5. Unexplained infertility ---------------------------------------------- --► 17%
Initial Evaluation
• History and physical examination: Both couples should make the initial evaluation.
• Semen analysis: It is the first examination to be done in all infertile couples.
• Investigation of ovarian reserve and ovulation
• Investigation of tubal patency and uterine cavity; HSG is one of the primary tests that should be done.
Because of the low diagnostic value of the postcoital test, it is not used as a standard diagnostic method in the investigation of infertile couples.
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ETIOLOGY |
EVALUATION |
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ovulatory
factor |
Midluteal serum progesterone measurement |
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Use of ovulation kits |
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3rd day FSH (±) E2 measurement (ovarian reserve) |
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AMH measurement (±) |
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TSH, PRL, androstenedione measurement(±) |
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Antral follicle count by ultrasonography (±) |
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Basal body temperature chart (±) |
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tubal/pelvic
factor |
hysterosalpingography |
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Laparoscopy + chromatubation |
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uterine
factor |
hysterosalpingography |
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Transvaginal ultrasonography / Sonohystereography
(saline infusion sonography) |
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MRI (±) |
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Hysteroscopy (±) Laparoscope |
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male
factor |
Semen Analysis |
Male Infertility
• While male factor alone is the cause of 25% of infertility, male factor is observed in approximately 50% of infertile couples. Spermatogenesis occurs in the seminiferous tubules of the testicles. Sertoli cells and Leydig cells are present here. The testicles are under the control of LH and FSH secreted from the pituitary. LH stimulates testosterone synthesis in Leydig cells, and FSH stimulates inhibin synthesis in Sertoli cells.
• FSH and testosterone stimulate spermatogenesis in the seminiferous tubules. Immature spermatogonia turn into spermatocytes as a result of mitotic division, which in turn transform into spermatids containing haploid chromosomes by meiosis. These pass into the epididymis and mature in a period of 2-6 days, and the spermatozoa become more mobile.
• Spermatogonia turn into mature sperm in 64-74 days. By ejaculation, mature spermatozoa are expelled with secretions from the vas deferens, prostate, seminal vesicle, and bulbourethral glands. When semen is excreted, it is a gelatinous mixture of spermatozoa and seminal plasma. Semen undergoes liquefaction in 20-30 minutes due to the proteolytic enzymes in it.
• Sperm in the ejaculate usually do not have fertilization capacity. For this, it is necessary to have capacitation and acrosome reaction. The acrosome is the anterior portion of the sperm head, the equivalent of the Golgi body. It makes a hole in the zona pellucida around the oocyte with its lytic enzymes. The occurrence of some biochemical and electrical events on the outer surface membrane of the sperm is called capacitation. Capacitation takes place in the cervix and tuba.
• After the male's history and physical examination, basal semen analysis (volume, concentration, movement, morphology) is performed. Spermiogram should be done after 2-3 days of sexual abstinence.
Semen Analysis
- Volume---------------------------------------------------► ≥ 1.5 ml
- Sperm count---------------------------------------------► ≥ 15 million/ml
- Motility--------------------------------------------------► ≥ 32% progressive, 40% total motility
- Morphology (strick criterion)-------------------------► ≥ 4% normal morphology
- Leukocytes-----------------------------------------------► < 1 million/ml
- Immunobead or mixed antiglobulin reaction--------► < 50%
- pH---------------------------------------------------------► ≥ 7.2
- Viability--------------------------------------------------► > 58%
- Round cell------------------------------------------------► < 5 million/ml
► Aspermia (anejaculation); It is the absence of the ejaculate.
► Azoospermia; absence of sperm in the ejaculate. The main cause of testicular azoospermia is gonadal insufficiency. The most common cause of posttesticular azoospermia is previous vasectomy operation. 15-20% of infertile men have azoospermia.
► Oligozoospermia; low sperm count. If the total progressive motile sperm count is < 5 million/ml, it is severe oligozoospermia.
► Asthenozoospermia; low sperm motility.
► Teratozoospermia; It is an increase in sperm with abnormal morphology. The most important advantage of the Kruger strick criteria is that there is a correlation between the sperm ratio evaluated as normal and the IVF results.
► Necrozoospermia; is that all sperm are lifeless and immobile.
► Leukocytospermia; an increase in leukocytes in semen.
• In addition, cells other than sperm should be reported in the semen analysis. These cells can be epithelial cells, round cells (immature germ cell or leukocytes), isolated sperm heads or tails. Immature germ cells show testicular damage, while leukocytes show inflammation. The most common colonizing microorganisms are Chlamydia trachomatis, Ureaplasma urealyticum and Mycoplasma hominis.
• Sperm are highly antigenic and if the blood-testicular barrier is destroyed by vasectomy, testicular torsion, infection or trauma, antibodies to sperm develop immediately. Antisperm antibodies reduce the pregnancy rate.
• The presence of trembling sperm in the spermiogram but unable to move forward suggests antibody formation. It is unnecessary to look for these antibodies in the blood of a man or woman. What matters is whether there is anti-sperm antibody in the cervical mucus or semen. Immunobead and mixed agglutination reaction test (sperm MAR test) are used for diagnosis.
• A sperm pH <7 with low volume indicates ejaculatory duct obstruction or absence of the vas deferens.
Etiology
Causes of male infertility
- 1. Those whose cause cannot be determined-------48.5%
- 2. Idiopathic abnormal semen---------------------------26.4%
- 3. Varicocele----------------------------------------------12.3%
- 4. Infections---------------------------------------------- 6.6%
- 5. Immunological factors--------------------------------3.1 %
- 6. Congenital causes--------------------------------------2.1%
- 7. Sexual dysfunction-------------------------------------1.7%
- 8. Endocrine causes---------------------------------------0.6%
The most common causes of male infertility are idiopathic abnormal semen and
varicocele.
• In men, gonadal insufficiency is associated with testicular azoospermia. This condition can be congenital, genetic (Kleinfelter syndrome, microdeletion in Y chromosome), acquired (radiation, chemotherapy treatment, testicular torsion or mumps orchitis) and developmental (undescended testis).
• Microdeletion of Y chromosome is detected in 10-20% of cases with idiopathic azoospermia or severe oligospermia. In the long arm of the Y chromosome, there may be microdeletion in AZF (azoospermia factor) a (proximal), AZF-b (central), AZF-c (distal) regions.
• While sperm can be found in testicular biopsies in 47, XXY Kleinfelter cases, it is unlikely that sperm cells can be found in testicular biopsies, especially in cases with microdeletion in AZF-a and AZF-b regions. AZF-c region microdeletions have a better prognosis.
Medications that can cause male infertility
Those that disrupt spermatogenesis
- Sulfasalazine
- methotrexate
- Nitrofura ntoi n
- colchicine
- Chemotherapy
Those that disrupt ejaculation
- alpha blockers
- antidepressants
- Phenothiazines
Pituitary suppressors
- testosterone injection
- GnRH analogs
Those that cause erectile dysfunction
- beta blockers
- Thiazide diuretics
- metoclopramide
Those with antiandrogenic effects
- cimetidine
- Spironolactone
Those that impair sperm quality
- Cocaine
- Alcohol
- Cigarette
- Marijuana, heroin
Treatment
Infertility due to endocrine and infective causes may respond to treatment.
Clomiphene citrate is useful in idiopathic cases. Surgery can be performed in patients with varicocele.
Treatment in male infertility of male infertility
In idiopathic cases--------------------------Clomiphene
In the presence of antisperm antibodies----------Introuterine insemination (IUI)
In anatomical disorder----------------------Introuterine insemination (IUI)
Abnormal semen analysis-------------Introuterine insemination (IUI)
Poor postcoidal test---------------------Introuterine insemination (IUI)
In unexplained infertility-----------Introuterine insemination (IUI)
• Total progressive motile sperm count (TPMSS) is the most important factor affecting the pregnancy rate and if it is 5-10 million or more, maximum efficiency is achieved in IUI.
• ICSI should be performed if the total progressive motile sperm count is < 2 million or if sperm has been surgically obtained.
Female Infertility
Decreased Ovarian Reserve
• Advanced age (aging in the oocyte) is an important cause of infertility in women. Another factor is the increased risk of abortion with increasing age. In the last 10 years before menopause, follicular loss accelerates, follicular phase shortens, and luteal phase failure is more common. IVF should be performed in women with low ovarian reserve.
Tests used to determine ovarian follicle reserve:
► Basal FSH level (on the 3rd dayof the cycle): FSH is ≥ 8 IU/mL in subfertile women and the rate of spontaneous pregnancy decreases by 7% for each 1 IU/ml FSH level.
► Basal estradiol level (on the 3rd day of the cycle): It reflects follicular development rather than the number of antral follicles. It is often used in combination with FSH level. In women with low ovarian reserve, the basal estrogen level is increased (60-80 pg/ml).
► Clomiphene citrate evaluation test (CCCT): FSH and estradiol levels are measured on the 3rd day. 5-9 of the cycle. Clomiphene 100 mg/day is given orally for 5 days between days. FSH and E2 levels are measured again on the 10th day of the cycle. It is more valuable than the basal FSH value. A FSH value of > 14 IU/L on day 10 following the test or a total FSH total of > 26 IU/L on day 3 to 10 are indicative of low ovarian reserve.
► Serum inhibin B level: It starts to be synthesized in the granulosa cells of the ovarian follicles from the preantral follicle stage and shows the size of the developing follicle cohort. Inhibin B levels are also low in women with low ovarian reserve.
► Serum AMH (anti-Müllerian hormone) level: It is synthesized from granulosa cells in preantral and small antral follicles. AMH level decreases with age and is not detected after menopause. A value of > 3.5 ng/dl indicates good reserve, while a value of <1 ng/dl indicates a decreased ovarian reserve. Unlike other ovarian reserve tests, the AMH level can be measured on any day of the menstrual cycle.
► Antral follicle count on the 3rd day of the cycle with transvaginal ultrasound: It is the number of follicles between 2-10 mm and the basal antral follicle count for each ovary is checked. The number decreases as the reserve decreases, and the risk of IVF failure and cycle cancellation is high if the total antral follicle count is <4.
Ovulatory Factors (Anovulation)
• Ovulatory factors constitute 30-40% of female infertility causes. The fertile period in women is 6 days (days 10-17 of the menstrual cycle). Therefore, the ovulation period should be determined.
Tests used to detect ovulation
► Measurement of LH in serum or urine: After the LH peak is detected, ovulation occurs within 48 hours.
► Basal body temperature: As soon as you wake up from sleep, the measurement is taken orally or rectally. A biphasic pattern in body temperature is observed in women with ovulatory cycles, and an increase of 0.2-0.5 degrees in body temperature is observed after ovulation. If the body temperature rises for 3 consecutive days, ovulation is assumed.
► Evaluation of cervical mucus: In the fertile period, the cervical mucus descends to the introitus, has a slippery and clean appearance, while it is dry and sticky in other periods of the menstrual cycle. The amount of cervical mucus peaks 2-3 days before ovulation.
► Midluteal serum progesterone level: Progesterone more than 3 ng/ml in the midluteal phase (day 21-23 or 7 days after the LH peak) is considered compatible with ovulation.
► Detection of rupture of the dominant follicle by ultrasound: Dominant follicles usually rupture when they reach a diameter of 21-23 mm, followed by minimal fluid in Douglas. The preovulatory follicle reaches a diameter of 17-19 mm in spontaneous cysts and 19-25 mm in diameter in clomiphene-induced cycles.
• Tests used in the differential diagnosis of anovulatory infertility causes:
► Serum FSH level
► Serum PRL level
► Serum TSH level
• In treatment, the underlying disease should be treated (hypothyroidism, hyperprolactinemia) and ovulation induction is used if necessary.
Agents used in ovulation induction
(CC) ovulation induction
0 Clomiphene citrate (CC) is one of the first treatment options for ovulation induction in anovulatory infertility. The use of clomiphene citrate in anovulatory infertility is associated with 50% ovulation, 25% pregnancy and 22% live birth. Its effectiveness decreases in obesity, advanced age and hyperandrogenemia. Multiple pregnancy risk is 8% and most are twin pregnancies
Aromatase enzyme inhibitors (letrozole, anastrazole)
They reduce the level of circulating estrogen by reducing the conversion of androgens to estrogen. As a result, an increase in FSH level occurs.
0 Adverse effects such as thickening of the cervical mucus and thinning of the endometrium during the use of clomiphene are not observed during the use of letrozole. Multiple pregnancy rates are also lower.
In 0 PCOS, more term live births are obtained in ovulation induction with letrozole than with clomiphene.
Gonadotropins
0 FSH and LH play a role in follicle development and selection of the dominant follicle. They are agents of second choice in cases that do not respond to CC. Pure FSH is preferred in PCOS.
0 FSH + LH (hMG) is used in hypogondotropic hypogonadism. Compared to other anovulatory patients, patients with PCOS have a higher risk of ovarian hyperstimulation (4.6%) and multiple pregnancy (36%).
Indications and contraindications for the use of gonadotropins
Indications
1. Patients with PCOS unresponsive to CC + metformin therapy
2. Patients with hypogonadotropic hypogonadism
3. Cases of unexplained infertility
4. In vitro fertilization practice
contraindications
1. Primary ovarian insufficiency
2. Uncontrolled thyroid or adrenal dysfunctions
3. Intracranial lesion (pituitary tumor etc.)
4. Undiagnosed abnormal uterine bleeding
5. Ovarian cyst
6. Hypersensitivity to Gonadotropins
7. Sex hormone-dependent tumors
8. Pregnancy
tamoxifen
0 It has a similar structure to clomiphene and although it does not have negative effects on the endometrium, its success rates are similar to clomiphene.
Tubal Factors
• Distal tubal occlusion is observed in 85% of tubal infertility.
• Tubal activity increases at the time of ovulation, allowing the oocyte to be captured and transported to the ampulla within minutes. It occurs with tubal damage, obstruction, peritubal periovarian adhesions (PIH, surgery, endometriosis, etc.).
• Mycobacterium tuberculosis is the microorganism with the worst prognosis in terms of infertility in PID. However, the microorganisms most associated with PID and infertility are C. trachomatis and N. gonorrhoeae.
• HSG is the first diagnostic method that should be applied to evaluate whether the tuba is open. However, laparoscopy is the gold standard in the definitive diagnosis of tubal and peritoneal factors.
• IVF should be performed in uncorrected tubal occlusions. Performing salpingectomy before IVF increases the chance of success in cases with hydrosalpinges.
Uterine Factors
• They are pathologies seen in 15% of all infertile couples. Endometrial polyps, endometrial hyperplasia, submucous fibroids, intrauterine synechiae and congenital uterine anomalies can cause uterine cavity disorder and cause infertility.
• HSG, hysteroscopy, transvaginal ultrasonography, three-dimensional transvaginal ultrasonography, sonohysterography and MR can be used for diagnosis. The gold standard method to be used in the evaluation of the endometrial cavity is hysteroscopy. The gold standard method in the diagnosis of congenital uterine anomalies is pelvic MRI and it is especially useful in the diagnosis of rudimentary uterine horn.
Luteal Phase Defect (LFD)
• It is characterized by insufficiency in the development of the mature secretory endometrium during the implantation period.
• It can be seen artificially in ovulation inductions with assisted reproductive techniques or gonadotropins. It is seen in 4% of infertile women.
• Diagnostic clues; A midluteal progesterone level is less than 5-10 ng/ml, there is a difference of more than 2 days between the histological and chronological dates of the endometrium, the increase in basal body temperature lasts less than 11 days, and the luteal phase lasts less than 14 days.
• In treatment after the luteinizing hormone peak or hCG injection , Progesterone support should start on day 3-4 and if conception occurs it should continue for at least 8-9 weeks
Peritoneal Factors
• Infertility may occur due to endometriosis and adhesions. Laparoscopy is used to diagnose the presence of peritoneal factor.
Unexplained infertility
• With current techniques, the cause of infertility cannot be understood in nearly '20% of couples.
• Although ovulation induction + IUI with clomiphene, letrozole or gonadotropin is often planned first in the treatment, IVF has recently come to the fore as the first choice.
Asisted Reproductive Techniques(ART)
• GIFT (Gamet Intra-Fallopian Transfer)
• ZIFT (Zygote Intra-Fallopian Transfer)
• IVF/ET (In-vitro Fertilization/Embryo Transfer)
• ICSI (Intra-Cytoplasmic Sperm Injection)
The most important factor in the success of ART is the age of the woman.
Live birth rates per cycle in infertile couples undergoing in vitro fertilization:
Ovulatory dysfunction------------------------------------------------► 37.3%
Male factors------------------------------------------------------------► 35.8%
Endometriosis----------------------------------------------------------► 34.3%
Unexplained infertility------------------------------------------------► 31.8%
Tubal factor-------------------------------------------------------------►30.7%
Multiple factors (male and female)---------------------------------► 27.5%
Uterine factor-----------------------------------------------------------► 26.9%
Multiple factors (female only)---------------------------------------► 23.4%
Decreased ovarian reserve--------------------------------------------► 15.3%
Ovarian hyperstimulation syndrome (OHSS)
• Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic complication of ovulation induction (often gonadotropins). Although its pathophysiology is unknown, it is related to increased local and systemic capillary permeability. As a result, there is a decrease in intravascular volume and an increase in volume in the third space.
• OHSS risk factors include a history of OHSS, high AMH level with polycystic ovarian morphology, many stimulated follicles, polycystic ovary syndrome, high estrogen level, thin and young patient.
• In OHSS, the production of vasoactive substances such as prorenin, angiotensin converting enzyme (ACE), angiotensin-I, II and angiotensinogen increases in the ovaries. However, the main responsible factor in pathophysiology is the increase in VEGF secretion. VEGF secretion from granulosa cells increases with the dose of human chorionic gonadotropin (hCG). VEGF is responsible for the establishment of the clinical picture, especially by causing vasodilation.
Clinic
• It is divided into two clinics according to the start time:
► Early-onset OHSS: Occurs within the first 9 days after oocyte retrieval and due to externally administered hCG. It is associated with high estradiol and many follicles.
► Late-onset OHSS: It occurs after the 9th day and due to increased hCG during pregnancy. It is associated with multiple pregnancy.
classification
Stage I: Abdominal distention
Stage 2: In addition; nausea-vomiting or diarrhea. The ovaries are 5-12 cm in size.
Stage 3: In addition; presence of ascites in the abdomen
Stage 4: In addition; hydrothorax or respiratory distress
Stage 5: In addition; decrease in blood volume, hemoconcentration, renal failure (oliguria), coagulation abnormalities. (thromboembolism).
examinations
• Complete blood count, prothrombin time, partial thromboplastin time, serum electrolytes (in terms of hyponatremia and hyperkalemia), liver function tests, creatinine, BUN, AC X-ray, TV USG, oxygen saturation determination, serum hCG level are checked.
Since the ovaries are extremely fragile in patients with OHSS, pelvic examination should not be performed in these patients and deep abdominal palpation should be avoided. Again, in these cases, surgical intervention should be avoided unless absolutely necessary.
treatment
• There is no specific treatment for OHSS. While mild and moderate stimulation cases are followed up on an outpatient basis , severe hyperstimulation requires hospitalization .
• Even if pregnancy has occurred in critical cases, termination is done. Paracentesis can be applied when abdominal acid is excessive. Fluid imbalance should be corrected and prophylactic anticoagulants should be used due to hypercoagulopathy.