Download - 2 Non Endocrine Female Infertility.pdf
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INFERTILITY
Rukmono Siswishanto
Obstetric and Gynecology Department Gadjah Mada University/Sardjito Hospital Jogjakarta
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Infertility
No pregnancies occurred in couples who have intercourse without protecBon in a
period of 1 year
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Primary inferBlity Previously had never been pregnant
Secondary inferBlity Previously been pregnant
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INTRODUCTION
q The dilemma of inferBlity vs populaBon overgrowth
q AffecBng around 8% couples • ReproducBve problem 50-‐80 million couples • Two million new inferBle couples per year
q Frequency: 12% (Indonesia), 10-‐15% (USA)
q PrevenBon potenBal
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Fecundability
The probability of being pregnant in a single menstrual cycle
Factors affecBng fecundability Age, Oocyte depleBon, Spontaneous aborBon, Male factor
Fecundity The probability of achieving a live birth within a single cycle
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CHAPTER 2 • Dynamics for Human Growth: Morphologic, Dynamic, and Functional Aspects 27
INITIATION OF THE FOLLICULARGROWTH
Oogenesis and Composition of the Ovarian Reserve
In humans, at the beginning of the fourth week of embry-onic development the primordial germ cells (PGC)migrate to the coelomic epithelium of the gonadal ridges.When sexual differentiation occurs, the PGC continue toproliferate in the embryonic ovary and become oogonia.By the twentieth week of pregnancy, about 7 millionoogonia are present [2]; thereafter oogonia enter meioticprophase, which marks the end of germ cell production.Around the twenty-fourth week of gestation, almost allthese germ cells, now called oocytes, have passed throughthe first four stages of meiosis I and are arrested at thediplotene stage. The oocytes are surrounded by a layer ofepithelial pregranulosa cells to form primordial follicles.Although some of these follicles start to grow almostimmediately, most remain in a resting stage until theyeither degenerate or enter the growth phase. After birththe pool of follicles at the resting stage constitutes theovarian reserve, including primordial follicles in which theoocyte is surrounded by flattened granulosa cells (GC)(Figure 2.3, A), transitory follicles in which the oocyte issurrounded by a mixture of flattened and cuboidal GC(Figure 2.3, B), and small primary follicles in which theoocyte is surrounded by a single layer of cuboidal GC(Figure 2.3, C).
Aging Changes
In humans, as in other mammals, the size of the ovarianreserve decreases drastically with age (Table 2.1). Attritionof the ovarian reserve has started during fetal life, as soonas the twenty-fourth week of pregnancy when the numberof oocytes began to reduce dramatically. At birth the sizeof the ovarian reserve varies among individuals. Althoughfollicular counts have been performed in a small numberof newborn ovaries, it can be proposed from direct counts
[2, 3] and mathematical extrapolation [4] that each ovarycontains between 250,000 and 500,000 resting follicles. Inhumans the rate of follicular depletion might vary amongsubjects and accelerates from approximately 38 years ofage onward, leading to a stock at menopause estimatedbetween less than 100 [4] and 1000 [5] resting follicles per ovary.
Given the age range, comprised between 40 and 60years, for menopause occurence it takes 50% more timefor some women to exhaust their follicle pool than it does for others. This may be related to variable depletionrates, differences in the initial number of resting follicles,or both. The menopausal age of a given woman is corre-lated with the timing of menopause in her mother andsisters, which strongly suggests a genetic component infactors that regulate depletion of the follicle pool. Parityand environmental factors such as nutrition, race, andsocioeconomic status also influence the age at whichmenopause occurs [6]. Among these factors, lifestyle exposures—especially smoking—can hasten menopauseoccurence [7].
In all mammalian species, follicles leave the stock ofresting follicles in a continuous stream, either by apopto-sis or by entry into the growth phase. By taking intoaccount the number of growing follicles within the ovariesthroughout life [4], it can be estimated that more than 90%of the ovarian reserve escapes by apoptosis mainly duringinfancy and early adulthood.
Depletion of the Pool by Atresia
It is now widely accepted that apoptosis, an active energy-consuming process controlled by a number of intracel-lular proteins, is mainly responsible for attrition of theovarian reserve (see Part V for a detailed discussion of follicular apoptosis). Two comments can be made con-cerning apoptosis of nongrowing follicles in humans.Firstly, atresia of these follicles is difficult to appreciate.Careful examinations of the ovarian reserve show that the oocyte is the first cell to disappear, which leads to follicles exhibiting an irregular ring of transformed GC
TABLE 2.1 Total number (¥10–3) of different types of small follicles from humanovaries in various age groups. Values are mean ± SEM; number ofovaries is indicated in parentheses.
Age groups (years)
19–30 31–35 36–40 41–45 !46Follicular types (5) (9) (13) (28) (26)
Primordial 51.9 ± 9.0 19.5 ± 2.8 9.7 ± 1.1 4.9 ± 1.5 1.3 ± 0.2Transitory 21.8 ± 2.7 10.6 ± 1.7 6.0 ± 1.3 3.1 ± 0.7 0.9 ± 0.1Primary 4.9 ± 0.6 2.3 ± 0.3 1.5 ± 0.4 0.7 ± 0.1 0.3 ± 0.1Total 79.6 ± 12.4 33.3 ± 4.0 20.6 ± 3.7 8.9 ± 2.1 2.7 ± 0.4
SEM, standard error to the mean.
Total number (¥10–3) of different types of small follicles from human ovaries in various age groups. Values are mean ± SEM; number of ovaries is indicated in parentheses
Burden of the Disorder
32.7
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72.1
85.4
93.4
0
10
20
30
40
50
60
70
80
90
100
M 1 M 3 M 6 M 12 M 24
Pregnancy %age
90% of couples will conceive a]er 12 months
As many as 10-‐15% of couples experiencing inferBlity
30% inferBlity among women 35-‐44 year old 6
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q Study in Dakota & Montana (USA): -‐ Peak of ferBlity in women: 25 years old -‐ 1/3 women: inferBle starBng from 40
q Intrauterine InseminaBon Programme (France), pregnancy rate a]er 1 year inseminaBon: -‐ 74 % in ≤ 30 years old -‐ 62 % in 30-‐35 years old
q The Importance: -‐ Screening & adequate treatment -‐ Limits of therapy & others alternaBve
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The Importance of Age
Why Infertile
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Causes of Infertility
① Sperm abnormality(male factors)
② Ovulation disorders (ovulation factors)
③ Tubal injury/ occlusion, paratubal adhesion, or endometriosis (tubal & peritoneal factors)
④ Interaction abnormalities between cervical mucus & sperm(cervical factors)
⑤ Rare condition: uterine abnormalities, immunological problems, & infection
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The Cause of Infertility
Male Factors 25 - 40%
Female Factors 40 – 55%
Mix Factors 10%
Unexplained 10%
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10 10
Male
Female
Mix
Unexplained
Prevalence of Female Infertility
Disfunction of Ovulation 30 – 40%
Tubal/ Peritoneal Factors 30 – 40%
Unexplained 10 – 15%
Others 10 – 15%
80 %
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Ovaries Factors
q Anomaly: -‐ UnovulaBon -‐ Luteal phase defect -‐ Amenorea due to low level of estrogen q Test: -‐ cervical mucus -‐ basal body temperature -‐ hormonal vaginal cytology -‐ hormonal test -‐ endometrial biopsy
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Anomaly: obstruc4on due to infec4on, tumor, endometriosis, hydrosalphynx, congenital segmental obstruc4on.
Test: Rubin test, HSG, Laparoscopy & Falloscopy
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Tubal Factors
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Anomaly • Pelvic endometriosis • InflammaBon adhesion • Surgical adhesion Test • Laparoscopy • Surgery
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Peritoneal Factors
Prevalence of Male Infertility
Unknown 48,5%
Idiopathic semen abnormalities 26,4%
Varicocele 12,3%
Infection 6,6%
Immunologic 3,1%
Other acquired 2,6%
Congenital 2,1%
Sexual factors 1,7%
Endocrine disorders 0,6%
>80%
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Normal Semen Analysis
① Volume ≥ 2,0 ml ② Sperm Concentration ≥ 20 juta/ml ③ Motility ≥ 50% ④ Morfology ≥ 30% normal
Normospermia – Oligospermia – Asthenospermia - Teratospermia
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Preparing Semen Analysis
1. Abstinence 2-5 days
2. Directly put into clean container (never use condom)
3. Protect from cold
4. Received at the laboratory within 1 hour
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Management of Infertility
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Management Option
The majority of infertility therapy aimed to condense the time of the pregnancy
without intervention.
For example, attempts to get pregnant before or during the natural decline in
female fecundity
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Management Option: Male
1. Medical therapy(GnRH, CC, phenylepephrine, glucocorticoid)
2. Surgical therapy
3. Arificial insemination
Management Option: Anovulation
1. Medical Therapy
2. Surgical Therapy
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Treatment • OvulaBon factors:
– InducBon of ovulaBon – OperaBve: policysBc ovary
• InducBon of ovulaBon: – clomiphene citrate – Gonadotropin – GnRH – BromocripBn – Dexamethazone
• Surgical treatment: – Laparotomy à Wedge resecBon – Laparoscopy à Wedge resecBon – Electrocauter – Diathermi – VaporizaBon
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• Clomiphene Citrate (CC) 50-‐150 mg given at 5, 6, 7, 8, 9 day of menstrual period
• hMG 2-‐3 ample daily given at 7,8,9,10,11,12,13,14,15 day of menstrual period
• Pure FSH (Metrodin) 75 IU given at 7,8,9,10,11,12,13,14,15 day of menstrual period (= hMG)
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Induction of Ovulation
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Management Option: Tubal & Peritoneal
1. Medical Therapy
2. Surgical Therapy
3. IVF (in vitro fertilization)
Assisted ReproducBve Technology (ART)
• Include: IVF (In Vitro FerBlizaBon) GIFT (Gamete Intra Fallopian Transfer) ZIFT (Zygote Intra Fallopian Transfer) oocyte donor Cryopreserved embryo transfer • IndicaBons: severe damage of the tubes post sterilizaBon the tube InducBon of ovulaBon & inseminaBon: failed ovary failed InferBle due to oocyte factors
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IN VITRO FERTILIZATION
① SBmulaBon of the ovaries with/without central supression
② Oocyte retreieval
③ PreparaBon for the spermatozoa
④ FerBlizaBon and growing embryo
⑤ Embryo transfer & treatment of luteal phase
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Timing for InseminaBon & Embryo Transfer
• PreparaBon for spermatozoa (swimming up/percol) 2 hours before ovum pick up.
• Oocyte incubaBon about 6 hours, depend on the quality • 1 day a]eràobserv is there any ferBlizaBon • Embryo transfer was done a]er concepBon at stage 2-‐4
cells • The next stageà pregnancy rate per transfer increased,
the difficulty is need specific media for the embryo life.
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Medical treatment: the result is poor
• GnRH: hypogonadotropic hypogonadism • Retrograd ejaculaBon: α adrenergic agonist
• Clomiphene citrate: idiopaBc inferBlity • GlucocorBcoid: anBsperm anBbody
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Surgical treatment
• CorrecBon to varicocel and vasectomy , arBficial inseminaBon, ART (IVF, GIFT, MicromanipulaBon)
• ArBficial inseminaBon: intra uterine inseminaBon, intra cervical, intra peritoneal dan intra fallopian tube.
• ArBficial inseminaBon: preparaBon for sample, quanBty of sperm & Bming
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Female Problems
a. Cervical factors b. Uterine factors c. Tubal factors d. Peritoneal factors e. Ovarian factors
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a. Cervical factors
l Poor mucus l Inflammation l Stenosis l Antisperm-Antibody l Estrogen
l Huhner l Culture l Dilatation l Immune test l Antibiotic
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Uterine factors
• Septum • Fibroid • Adhesion • Polyp • Endometriosis
• HSG • Hysteroscopy • Biopsy • OperaBve hysteroscopy
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b. Uterine factors
l about 5% l distorBon uterine cavity due to synechiae, myoma, uterine polyps, endometriBs à defect: implantaBon, growth of concepBon, nutriBon & oxygenaBon of the fetus l Test: HCG l Therapy: operaBve
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Tubal factors
• Tubo Ovarial adhesion • Tubal obstrucBon • Endosalphyng damage • HSG
• Laparoscopy • Salphyngoscopy • Micro laparoscopy • Micro-‐surgery
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OvulaBon factors
• UnovulaBon • Follicle rupture • Lutein • DisfuncBon • Ovary • UnovulaBon
• Endometrial biopsy • Basal body temperature • LH test • Progesteron level • InducBon of ovulaBon • Ultrasound
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FEMALE FACTORS a. Vulva and vagina • < 5% as causal factor • Anomaly: -‐ congenital; vaginal septate, hymen imperforate -‐ infecBon -‐ Phsycogen (vaginismus, disparenia) -‐ C. Albicans and Trichomonas: inferBle due to coital defect
• Treatment depend on the cause: operaBve & medical treatment
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b. Cervical factors • About 5%: cause of inferBly • Some anomalies can be find: canal obstrucBon, cervical mucus anomaly,
malposiBon, atresia, polyps, synechiae & inflammaBon
• Test: -‐ cervical mucus test -‐ postcoital test -‐ in vitro test • Treatment: -‐ operaBve -‐ ArBficial inseminaBon -‐ InducBon of ovulaBonà then:
IVF, GIFT atau ZIFT -‐ InfecBon à culture
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UNEXPLAINED INFERTILITY • Result of all the standard test are normal • About 10-‐15% inferBle couples • Fecundity about 1.5% • 60% couples become pregnant in 3 years with
expectaBve therapy • With ART à become pregnant is higher • Pregnancy rate about 40% a]er 6 periodes of
superovulaBon or 3 periodes in vitro ferBlizaBon • Monthly pregnancy rate: 10-‐15%
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Luteal phase defect
• Progesteron at luteal phase, clomiphene citrate at follicular phase
• Progesteron à IM/Vag. Supp 50-‐100 mg daily IM
• Clomiphene = inducBon of ovulaBon 50 mg daily
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f. InfecBon factors
• Chlamidia trakhomaBs & mycoplasma sp. • 20% acute salphyngiBs due to clamidia (USA) • InferBle couples: become pregnant à 47% mycoplasma + (cervical isolaBon)
• InferBle couples: failed to become pregnant à 53% mycoplasma +
• Treatment depend on the cause
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Tubal Factors l Therapy: opera4ve laparotomy/laparoscopy; • salphygoovorolysis (59% pregnant, Gomel, 1975) • -‐ Fimbrioplasty (48% pregnant, Gomel, 1975) • (31% pregnant, MeTler, et al) • -‐ Salphyngostomy (18% pregnant, Daniell & Herbert) • (29,4% pregnant, Dubuisson) l Therapy for peritoneal factors = tubal factors
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