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Infertility
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Infertility The inability to conceive following unprotected sexual intercourse 1 year (age < 35) or 6 months (age >35) Normally a fertile couple has approximately a 20 % chance of conception in each ovulatory cycle
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Infertility Primary infertility Secondary infertility
a couple that has never conceived Secondary infertility infertility that occurs after previous pregnancy regardless of outcome
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Requirements for Conception
normally developed reproductive tract in both the male and female partner normal functioning of an intact hypothalamic-pituitary-gonadal axis supports gametogenesis (the formation of sperm and ova). timing of intercourse Unblocked tubes that allow sperm to reach the egg The sperms ability to penetrate and fertilize the egg Implantation of the embryo into the hormone-prepared endometrium Finally a healthy pregnancy
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Infertility. Statistic
A female factor (ovulatory dysfunction, pelvic factor) is in approximately 50% A male factor (sperm and semen abnormalities) is in approximately 35% Unexplained factors and causes (e.g., coital techniques) related to both partners are in approximately 15%
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Causes for infertility
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Cause of Female Infertility
CONGENITAL OR DEVELOPMENTAL FACTORS Abnormal external genitals Absence of internal reproductive structures HORMONAL FACTORS Anovulation-primary Pituitary or hypothalamic hormone disorder Adrenal gland disorder Congenital adrenal hyperplasia Anovulation-secondary Disruption of hypothalamic-pituitary-ovarian axis Early menopause Amenorrhea after discontinuing OCP Increased prolactin levels TUBAL/PERITONEAL FACTORS Absence of fimbriated end of tube Tubal motility reduced Absence of a tube Inflammation within the tube Tubal adhesions UTERINE FACTORS Developmental anomalies Endometrial and myometrial tumors Asherman syndrome (uterine adhesions or scar tissue)
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Cause of Female Infertility CONGENITAL OR DEVELOPMENTAL FACTORS
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Cause of Female Infertility CONGENITAL OR DEVELOPMENTAL FACTORS
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Cause of Female Infertility CONGENITAL OR DEVELOPMENTAL FACTORS
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Cause of Female Infertility CONGENITAL OR DEVELOPMENTAL FACTORS
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Cause of Female Infertility TUBAL/PERITONEAL FACTORS
Chlamidial infection Pelvic infections (ruptures appendix, STIs)
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Cause of Female Infertility UTERINE FACTORS
Uterine fibroids
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Cause of Female Infertility UTERINE FACTORS
Endometrial tumor
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Cause of Female Infertility UTERINE FACTORS
Asherman syndrome
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Cause of Female Infertility VAGINAL-CERVICAL FACTORS
Vaginal-cervical infection Sperm antibody
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Cause of Male Infertility
STRUCTURAL OR HORMONAL DISORDERS Undescended testes Hypospadias Testicular damage Varicocele Low testosterone levels caused by mumps OTHER FACTORS Endocrine disorders Genetic disorders Psychologic disorders Sexually transmitted infections Exposure of scrotum to high temperatures Exposure to workplace hazards such as radiation or toxic substances SUBSTANCE ABUSE Changes in sperm (Smoking, heroin, marijuana, amyl nitrate, butyl nitrate, ethyl chloride, methaqualone, Monoamine oxidase) Decrease in sperm (Hypopituitarism, Debilitating or chronic disease, Trauma, Gonadotropic inadequacy, Decrease in libido Heroin, methadone, selective serotonin reuptake inhibitors, and barbiturates) Impotence (Alcohol, Antihypertensive medications) OBSTRUCTIVE LESIONS OF THE EPIDIDYMIS AND VAS DEFERENS NUTRITIONAL DEFICIENCIES
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Cause of Male Infertility STRUCTURAL OR HORMONAL DISORDERS
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Evaluation of the Infertile couple
History and Physical exam Semen analysis Thyroid and prolactin evaluation Determination of ovulation Basal body temperature record Serum progesterone Ovarian reserve testing Hysterosalpingogram
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Assessment of woman 1.Age
2. Duration of infertility (length of contraceptive and noncontraceptive exposure) 3. Obstetric A. number of pregnancies, miscaridges and abortion B. Length of time required to initiate each pregnancy C. Complication of pregnancy D. Duration of lactation 4. Gynecologic: detailed menstrual history 5. Previous tests and therapy of infertility 6. Medical: general (chronic&hereditary disease), medication, family problem, sexual development, galactorrhea 7. Surgical: abdominal or pelvic surgery
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1. Follicular development, ovulation, and luteal develop ment are supportive of pregnancy:
a. Basal body temperature (presumptive evidence of ovulatory cycles) is biphasic, with temperature eleva tion that persists for 12 to 14 days before menstruation b. Cervical mucus characteristics change appropriately during phases of menstrual cycle c. Laparoscopic visualization of pelvic organs verifies follicular and luteal development 2. The luteal phase is supportive of pregnancy: a. Levels of plasma progesterone are adequate b. Findings from endometrial biopsy samples are con sistent with day of cycle 3. Cervical factors are receptive to sperm during expected time of ovulation: a. Cervical os is open b. Cervical mucus is clear, watery, abundant, and slip pery and demonstrates good spinnbarkeit and ar borization (fern pattern) c. Cervical examination does not reveal lesions or in fections d. Postcoital test findings are satisfactory (adequate number of live, motile, normal sperm present in cer vical mucus) e. No immunity to sperm demonstrated 4. The uterus and uterine tubes are supportive of preg nancy: a. Uterine and tubal patency are documented by Spillage of dye into peritoneal cavity Outlines of uterine and tubal cavities of adequate size and shape, with no abnormalities b. Laparoscopic examination verifies normal develop ment of internal genitals and absence of adhe sions, infections, endometriosis, and other lesions 5. The male partner's reproductive structures are normal: a. No evidence of developmental anomalies of penis, testicular atrophy, or varicocele (varicose veins on the spermatic vein in the groin) b. No evidence of infection in prostate, seminal vesi cles, and urethra c. Testes are more than 4 cm in largest diameter 6. Semen is supportive of pregnancy: a. Sperm (number per milliliter) are adequate in ejacu late b. Most sperm show normal morphology c. Most sperm are motile, forward moving d. No autoimmunity exists e. Seminal fluid is normal
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Abnormalities of Spermatogenesis
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Normal Sperm made in seminiferous tubules Travel to epididymis to
mature
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Normal Sperm exit through vas deferens
Semen produced in prostate gland, seminal glands, cowpers glands Sperm only 5% of ejaculation Sperm can live 5-7 days
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Semen Analysis (SA) Obtained by masturbation
Provides immediate information Quantity Quality Density of the sperm Morphology Motility Abstain from coitus 2 to 3 days Collect all the ejaculate Analyze within 1 hour A normal semen analysis excludes male factor 90% of the time
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Normal Values for SA Volume Sperm Concentration Motility Viscosity Morphology pH WBC 2.0 ml or more 20 million/ml or more 50% forward progression 25% rapid progression Liquification in min 30% or more normal forms Fewer than 1 million/ml
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Causes for Abnormal SA Abnormal Count No sperm Few sperm
Klinefelter’s syndrome Sertoli only syndrome Ductal obstruction Hypogonadotropic-hypogonadism Few sperm Genetic disorder Endocrinopathies Varicocele Exogenous (e.g., Heat)
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Continues: causes for abnormal SA
Abnormal Morphology Varicocele Stress Infection (mumps) Abnormal Motility Immunologic factors Infection Defect in sperm structure Poor liquefaction Abnormal Volume No ejaculate Ductal obstruction Retrograde ejaculation Ejaculatory failure Hypogonadism Low Volume Obstruction of ducts Absence of vas deferens Absence of seminal vesicle Partial retrograde ejaculation Infection
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Causes for male infertility
42% varicocele repair if there is a low count or decreased motility 22% idiopathic 14% obstruction 20% other (genetic abnormalities)
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Abnormal Semen Analysis
Azoospermia Klinefelter’s (1 in 500) Hypogonadotropic-hypogonadism Ductal obstruction (absence of the Vas deferens) Oligospermia Anatomic defects Endocrinopathies Genetic factors Exogenous (e.g. heat) Abnormal volume Retrograde ejaculation Infection Ejaculatory failure
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Evaluation of Abnormal SA
Repeat semen analysis in 30 days Physical examination Testicular size Varicocele Laboratory tests Testosterone level FSH (spermatogenesis- Sertoli cells) LH (testosterone- Leydig cells) Referral to urology
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Evaluation of Ovulation
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Female Reproductive System
Ovaries Two organs that produce eggs Size of almond 30,000-40,000 eggs Eggs can live for hours
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Menstruation Ovulation occurs 13-14 times per year
Menstrual cycles on average are Q 28 days with ovulation around day 14 Luteal phase dominated by the secretion of progesterone released by the corpus luteum Progesterone causes Thickening of the endocervical mucus Increases the basal body temperature (0.6° F) Involution of the corpus luteum causes a fall in progesterone and the onset of menses
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Ovulation A history of regular menstruation suggests regular ovulation
The majority of ovulatory women experience fullness of the breasts decreased vaginal secretions abdominal bloating Absence of PMS symptoms may suggest anovulation mild peripheral edema slight weight gain depression
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Diagnostic studies to confirm Ovulation
Basal body temperature Inexpensive Accurate Endometrial biopsy Expensive Static information Serum progesterone After ovulation rises Can be measured Urinary ovulation-detection kits Measures changes in urinary LH Predicts ovulation but does not confirm it
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Basal Body Temperature
Excellent screening tool for ovulation Biphasic shift occurs in 90% of ovulating women Temperature drops at the time of menses rises two days after the lutenizing hormone (LH) surge Ovum released one day prior to the first rise Temperature elevation of more than 16 days suggests pregnancy
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Serum Progesterone Progesterone starts rising with the LH surge
drawn between day 21-24 Mid-luteal phase >10 ng/ml suggests ovulation
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Salivary Estrogen: TCI Ovulation Tester- 92% accurate
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Add Saliva Sample
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Non-Ovulatory Saliva Pattern
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High Estrogen/ Ovulatory Saliva Pattern
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Anovulation
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Anovulation Symptoms Evaluation*
Irregular menstrual cycles Amenorrhea Hirsuitism Acne Galactorrhea Increased vaginal secretions Follicle stimulating hormone Lutenizing hormone Thyroid stimulating hormone Prolactin Androstenedione Total testosterone Order the appropriate tests based on the clinical indications
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Anatomic Disorders of the Female Genital Tract
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Sperm transport, Fertilization, & Implantation
The female genital tract is not just a conduit facilitates sperm transport cervical mucus traps the coagulated ejaculate the fallopian tube picks up the egg Fertilization must occur in the proximal portion of the tube the fertilized oocyte cleaves and forms a zygote enters the endometrial cavity at 3 to 5 days Implants into the secretory endometrium for growth and development
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Fertilization
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Implantation
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Acquired Disorders Acute salpingitis Intrauterine scarring
Alters the functional integrity of the fallopian tube N. gonorrhea and C. trachomatis Intrauterine scarring Can be caused by curettage Endometriosis, scarring from surgery, tumors of the uterus and ovary Fibroids, endometriomas Trauma
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Hysterosalpingogram An X-ray that evaluates the internal female genital tract architecture and integrity of the system Performed between the 7th and 11th day of the cycle Diagnostic accuracy of 70%
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Hysterosalpingogram The endometrial cavity Fallopian tubes
Smooth Symmetrical Fallopian tubes Proximal 2/3 slender Ampulla is dilated Dye should spill promptly
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HSG: Tubal Infertility
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??? Unexplained infertility ???
10% of infertile couples will have a completely normal workup Pregnancy rates in unexplained infertility no treatment % clomid and intrauterine insemination 8.3% gonadotropins and intrauterine insemination 17.1% ???
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Treatment of the Infertile Couple
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Inadequate Spermatogenesis
Eliminate alterations of thermoregulation Clomiphene citrate is occasionally used for induction of spermatogenesis 20% success In vitro fertilization may facilitate fertilization Artificial insemination with donor sperm is often successful
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Anovulation Restore ovulation Clomiphene citrate
Administer ovulation inducing agents Clomiphene citrate Antiestrogen Combines and blocks estrogen receptors at the hypothalamus and pituitary causing a negative feedback Increases FSH production stimulates the ovary to make follicles
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Clomid Given for 5 days in the early part of the cycle
Maximum dose is usually 150mg 50mg dose - 50% ovulate 100mg -25% more ovulate 150mg lower numbers of ovulation No changes in birth defects If no pregnancy in 6 months refer for advanced therapies 7% risk of twins 0.3% triplets
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Superovulatory Medications
If no response with clomid then gonadotropins- FSH (e.g. pergonal) can be administered intramuscularly This is usually given under the guidance of someone who specializes in infertility This therapy is expensive and patients need to be followed closely Adverse effects Hyperstimulation of the ovaries Multiple gestation Fetal wastage
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Anatomic Abnormalities
Surgical treatments Lysis of adhesions Septoplasty Tuboplasty Myomectomy Surgery may be performed laparoscopically hysteroscopically If the fallopian tubes are beyond repair one must consider in vitro fertilization
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Assisted Reproductive Technologies (ART)
Explosion of ART has occurred in the last decade. Theses technologies help provide infertile couples with tools to bypass the normal mechanisms of gamete transportation. Probability of pregnancy in healthy couples is 30-40% per cycle, live birth rate 25%. this varies depending on age
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Intrauterine insemination (artificial insemination)
definition: sperm introduced into female reproductive tract by means other than coitus sperm can come from donor / sperm bank or from husband usually, several ejaculations are pooled often used when male has low sperm count or antibodies present in ejaculate
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Artificial Insemination
Sperm donation or sperm aspiration
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In Vitro Fertilization
“test - tube babies” 1st performed in 1978 (Louise Joy Brown) often performed on infertile women with tubal blockage Sperm and egg combined in the lab, fertilization Zygote placed back into the uterus Very expensive and not always successful Oldest woman in the US to give birth using in vitro was 62 years old and an Romanian woman gave birth at 66
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In Vitro Fertilization
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IVF Protocol GnRH agonist (e.g. Lupron) for 7 days
FSH agonist (follistim, Gonal-F, Repronex) until follicles measure mm in diameter hCG given to induce egg maturation Egg retrieval (transvaginally) h later
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IVF protocol sperm and ova added to dish; fertilization occurs 12-14hrs. eggs transferred to new dish and cell division occurs embryos squirted into uterus at 4- to 32-cell stage (optimal: blastocyst stage)
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IVF Protocol, cont’d. 3 to 5 embryos are injected to increase chances of pregnancy woman given progestagen to prevent miscarriage
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IVF Protocol, cont’d. new variations / improvements:
Intracytoplasmic sperm injection (ICSI) use of frozen embryos 27,000 attempts made per year; 18.6% successful (success rates are increasing)
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GIFT and ZIFT GIFT = gamete intrafallopian transfer
useful for tubal blockage ova are collected and inserted into oviducts below point of blockage husband’s sperm are placed in oviduct
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GIFT and ZIFT woman is treated with hormones to prevent miscarriage
4200 attempts made / year; 28% successful ZIFT = zygote intrafallopian transfer ZIFT is like IVF, only zygotes (1 cell stage) are inserted below blockage in oviduct (24% success rate)
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Surrogate mother Woman unable to have children may have IVF in another woman who has the child
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Emotional Impact Infertility places a great emotional burden on the infertile couple. The quest for having a child becomes the driving force of the couples relationship. The mental anguish that arises from infertility is nearly as incapacitating as the pain of other diseases. It is important to address the emotional needs of these patients.
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Conclusion Infertility should be evaluated after one year of unprotected intercourse. History and Physical examination usually will help to identify the etiology. If patients fail the initial therapies then the proper referral should be made to a reproductive specialist.
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Thank You for attention!
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