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LECTURE 3.a.
Female and MaleInfertility
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3
Different definitions of infertility
Time trends and geographic variations ininfertility
Etiology and treatment of male and femalefactor infertility
Adverse effects of infertility treatment
Lecture Objectives
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Inability to achieve a recognized pregnancy after trying toconceive for:
> 1 year (U.S. ACOG) or
> 2 years (WHO)
Primary infertility: no prior pregnancy
Secondary infertility: Prior pregnancy by woman or man
Infecundity: Inability to achieve a live birth
Definitions of infertility
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Definition Prevalence (%)
Ever waited > 24 months 20.6Tried for > 24 months 12.5
Consulted a physician 9.6Diagnosed infertility 6.1
Prevalence of infertility depends on the
specificity of the question asked
Prevalence of Infertility
Depends on the question
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Primary infertility:Absence of a live birth at
specific ages (e.g. > age 30) in non-contracepting population
Secondary infertility:Absence of a live birth> 5 years in persons with prior births
Demographic Definitions
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1965 1982 1988 1995
All 13.3 13.9 13.7 11.9
Primary 2.2 5.8 6.0 5.7
Secondary 11.1 8.1 7.7 6.2
Definition: Inability to conceive >1 year, within past 3
years. NSFG 1965 1995.Source: Chandra. Infertil Repro Clin North Amer 1994;5:283.
U.S. Married Women Aged 15 44 years
Prevalence of Infertility in U.S.
1965 - 1995
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1965 1982 1988 1995
Number(millions)
3.0 2.4 2.3 2.1
Excludes sterilized couples.Source: NSFG 1995.
Numbers of Infertile Women in US
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Demographic:
Delay in marriage (1968 24.9 vs 2002
25.1 yrs)
Delay in first birth 1968 21.4 vs 2002
25.1 yrs Delayed childbearing
shifts first birthsto later ages when fertility is lower
Biologic:
Possible effects of STDs and PID?
U.S. trends in primary infertility
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Decrease in Secondary Infertility
Decrease in family size since 1960s
More couples adopt sterilization to
terminate reproduction and do notrecognize secondary infertility
U.S. Trends in secondary infertility
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Most data come from demographic sources
Proportions childless age 25-34 Proportions with no birth in past 5 years
Range of primary infertility, 3-20+%
Regional variation: Historic Infertility Beltin central Africa
Cameroon, Congo, Uganda
Developing Country trends
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Infertility in Africa decreased in recent
decades Difficult to determine trends from
surveys due to selective inclusion ofcurrently married women (e.g. infertilewomen may often be divorced)
Variation in survey samples over time
Trends in Developing Countries
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Papua New Guinea
Tabar infertility 45% in 1940s decreased to18.5% in one generation following use ofpenicillin for presumptive therapy
Zaire
Equater province infertility 42% in1955,decreased to 9.7% in 1975
Source: WHO Technical Report 1975; No. 582
Trends in Developing Countries
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Etiologic studies require invasive procedures andclinical evaluation
Variability between clinics Type of service (general, specialization)
Triage (selective referral)
Costs and socioeconomic barriers Lack of standardization
Female cause 50-60%
Male cause 40-50%
Etiology of Infertility
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Tubal oculsion due to Pelvic InflammatoryDiseases (PID) Industrialized countries 33% Africa 75%
Ovulatory disorders
30% Endometriosis HIV
Toxic exposures: smoking, glycol ethers, nitrous oxide,
pesticides
Etiology of Infertility in Women
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Pelvic Inflammatory Disease and Infertility
1. Cervical infection (C. trachomatis and/or N. gonorrhoeae)
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Pelvic Inflammatory Disease and Infertility
2. Alteration of cervicovaginal microenvironment, increased pH
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Pelvic Inflammatory Disease and Infertility
3. Overgrowth of vaginal and anaerobic flora, resulting in BV.
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Pelvic Inflammatory Disease and Infertility
4. Progressive ascent of original cervical pathogen and/or BV
anaerobes into the endometrium, fallopian tubes, and the
peritoneal cavity.
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1. Cervix
2. Uterine Cavity3. Fallopian Tubes
4. Abdominal Cavity
Sequence of Extension
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Endocervicitis: May be asymptomatic; vaginaldischarge, cervical inflammation, or infection;local tenderness
Endosalpingitis: Constant bilateral lowerquadrant abdominal pain aggravated by body
motion. Tenderness in one or both adnexalareas. Abscess formation may occur.
Endometriosis: Menstrual irregularity
Peritonitis: Nausea, emesis, abdominaldistention, rigidity, tenderness. Pelvic orabdominal cavity abscess formation may follow.
Clinical Features
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0
5
10
15
20
25
30
35
40
45
50
0 1 2 3+
Number of PID Episodes
Percent
Percent of women with tubal factor infertility following PID,by number of episodes
Source: Westrom LV. Sex Trans Dis 1994;24(2 Suppl):S32-37.
Tubal Factor Infertility & PID
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Pelvic Inflammatory Disease
Hospitalizations of Women 15 to 44 years United
States, 19802003
Note: The relative standard error for these estimates of the total number of acute and
chronic PID cases ranges from 6% to 18%. Data available through 2003.
SOURCE: National Hospital Discharge Survey (National Center for Health Statistics, CDC)
Hospitalizations (in thousands)
Acute, Unspec.
Chronic
0
40
80
120
160
200
1980 82 84 86 88 90 92 94 96 98 2000 02
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Pelvic Inflammatory Disease
Initial Visits to Physicians Offices
Women 15-44 : US, 1980-2004
Note: The relative standard error for these estimates ranges from 19% to30%.
Visits (in thousands)
0
100
200
300
400
500
1980 82 84 86 88 90 92 94 96 98 2000 02 04
SOURCE: National Disease and Therapeutic Index (IMS Health)
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Ectopic Pregnancy
Hospitalizations of Women 15 to 44 UnitedStates, 19802003Hospitalizations (in thousands)
0
20
40
60
80
100
1980 82 84 86 88 90 92 94 96 98 2000 02
Note: Some variations in 1981 and 1988 estimates may be due to changes in sampling
procedures. The relative standard error for these estimates ranges from 8% to 12%. Data
available through 2003.
SOURCE: National Hospital Discharge Survey (National Center for Health Statistics, CDC)
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Risks of subfertility > 1 year
Mother smoker
RR = 1.5 (1.2-2.0)
Father smoker, mother non-smoker
(passive smoking) RR = 1.2 (1.0-1.4)
Source: Hull et al. Fertil Steril 2000;74:725
Smoking and Subfertility
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Microchip Manufacturing: Female Workers
Exposure to Ethylene Glycol Ethers (EGE)
EGEExposure
Subfertility
(Inability to conceive > 1year)(%) RR (CI)
None 9.2 1.0
Low 13.3 1.5 (0.7-3.1)
Medium 13.3 1.8 (0.8-4.3)
High 27.3 4.6 (1.6-13.3)
Source: Correa A, et al. Ethylene glycol ethers and risks of spontaneous
abortion and subfertility.Am J Epidemiol 1996;143:707-17
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Tubal Oculsion
Assisted Reproductive Technologies(ART)
In vitrofertilization (IVF) Gamete intrafallopian transfer (GIFT)
Zygote intrafallopian transfer (ZIFT) Tubal surgery
Treatment of Female Infertility
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In vitro fertilization (IVF)
United States: 1 in 80-100 births now IVF conceptions;100,000 IVF cycles; 48,000 births
(1) Once mature, the eggs
are suctioned from the
ovaries and (2) placed in alaboratory culture dish with
the man's sperm for
fertilization. (3) The dish is
then placed in an incubator.(4) About 2 days later, 3 to
5 embryos are transferred
to the woman's uterus.
Public Domain
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Live births per embryo transfer, by
age of mother and age of donor
Figure 2. Van Vorhiss BJ. Clinical practice. In vitro fertilization. NEJM 2007 Jan 25;356(4):379-86.
Copyright 2007 Massachusetts Medical Society. All Rights Reserved.
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Preconception genetic diagnoses
One or two balstomeres are removed from
the embryo Chromosome identification and evaluation
by fluorescence in situ hybridization (FISH) Current techniques allow evaluation of up
to 10 chromosomes in a single cell
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Ovulation Disorders
Ovulation induction by Clomid, GnRH
Endometriosis Drug treatment (Danazol)
Surgery
Treatment of Female Infertility
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Prognosis varies with:
Age Primary vs. secondary infertility
Duration of infertility Type and severity of pathology
Single vs. multiple causes Male, female, or both affected
Smoking, caffeine, nutrition
Prognosis of Infertility
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Delivery Rates with IVF
No male factor
Age Delivery %
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Live births per embryo transfer ~50%
Pregnancy loss ~ 18%
Multiple births per delivery
31% twins
3% triplets or more
(normal conception, 1% multiple gestations)
Source: Society for Assisted Reprod Technol. Fertil Steril 2000;74:641.
Bradley NEJM 2007;356:379
Outcomes of IVF: U.S.
Percentage of twins after in vitro fertilisation by
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37Copyright 2005 BMJ Publishing Group Ltd.
Kallen, B. et al. BMJ 2005;331:382-383. All Rights Reserved.
Percentage of twins after in vitro fertilisation byyear of birth in Europe
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IVF Pregnancy Outcomes(Shevell Obstet Gybecol 2005;106:1039)
Odds of adverse outcomes IVF vs no ART
Preeclampsia OR 2.7 (1.7-4.4) Preterm labor OR 1.5 (1.0-2.2)
Placental abruption OR 2.4 (1.1-5.2) Placenta previa OR 6.0 (3.4-10.7)
Cesarean section OR 2.3 (1.8-2.9)
L Bi th W i ht d ART (US)
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Low Birth Weight and ART (US)Schieve NEJM2002;346:731-7
N = 42,463 ART vs 3,389,098 naturalconceptions
Risk of low birth weight with ART RR = 2.6(2.4-2.7)
Very low birth weight (
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Birth Defects and ART
N = 837 IVF; 301 ICSI; 4000 natural conceptions All Major Defects:
IVF = 9.0%, ICSI = 8.6%, natural = 4.2%
IVF RR = 2.0 (1.5-2.9); ICSI RR = 2.0 (1.3-3.2)
Musculoskeletal defects: IVF = 3.3%, ICSI =3.3%, natural = 1.1%
Chromosomal defects: IVF = 0.7%, ICSI =
1.0%, Natural = 0.2% VLBW: IVF = 4%, ICSI = 1%, natural= 1.0%
Hansen NEJM2002;346:725-30
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Ovulation induction $1500-5000
Artificial insemination $1000-2000
IVF womans own eggs $12,500-25,000
IVF donor eggs $20,000-35,000
Costs of in vitroFertilization
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Insurance Coverage and IVF: USA 2001
IVF primarily privately funded
3 states full coverage
5 states partial coverage 37 states no coverage
IVF per 1000 women Full coverage 3.8/1000
Partial coverage 1.8/1000
No coverage 1.4/1000
Jain NEJM 2002;347:661
IVF procedures 1996 = 64,036 vs 2001 = 107,587
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Women with recurrent EPLs have no
recognized pregnancy and report delayedconception. If delay >1 year classified asinfertile.
Increased SABs in women with infertility mayreflect a common mechanism of damage to
ovum and fetus such as toxic exposures. e.g., Glycol ethers increase SAB (RR=
2.8) and infertility (RR = 4.6)
Infertility and Pregnancy Loss
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Early Pregnancy Loss (EPL)
No Infertility history EPL = 21.1% Infertility history EPL = 69.7%
Spontaneous Abortion (SAB)
No Infertility history SAB = 14%
Infertility history SAB = 23%
Women with delays in conception have higher rates
of EPLs and SABs
Infertility and Pregnancy Loss
Microchip Manufacturing: Female Workers
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Microchip Manufacturing: Female Workers
Exposure to Ethylene Glycol Ethers (EGE)
EGEExposure
SpontaneousAbortion
Subfertility
(%) RR (CI) (%) RR (CI)
None 14.8 1.0 9.2 1.0
Low 16.0 1.0(0.6-0.7)
13.3 1.5(0.7-3.1)
Medium 18.9 1.4
(0.8-2.6)
13.3 1.8
(0.8-4.3)High 33.3 2.8(1.4-5.6)
27.3 4.6(1.6-13.3)
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Infertility increases with age SABs increase with age
Due to ovum deteriorationwith age
IVF with donation of an ovum from young
women to an older recipient increasespregnancy rates and decreases SABs
Infertility, SABs, and Age
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Male Infertility
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Varicoele 20-40% (importance?)
Infections (e.g. mumps, STD orchitis &
epididymitis, HIV)
Undescended testis
Toxins (e.g. DPCP, glycol ethers)
Etiology of Male Infertility
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Varicocelectomy
7 Randomized trials no benefit
Pregnancy RR = 1.04 (0.7-1.4) Evers & Collins Lancet 2003;361:1849
Artificial insemination by donor or self
Hormone supplements
Intracytoplasmic sperm injection (ICSI)
Treatment of Male Infertility
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Male fertility and time trends in semen
quality
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Male fertility and age, effect of endocrinestatus
Secular trends in semen quality
Testicular development and testicular canceras a marker of adverse effects
Possible effects of environmental factorsincluding environmental estrogens, endocrinedisruptors hypothesis
Factors influencing male fertility
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Sexual activity declines with age
Testosterone decline with age
Semen quality and age
Difficult to estimate male fertility with age,independent of female age-specific fertility Correlation of partners age Only women become pregnant
Ireland and Bangladesh data suggest decline in malefertility > age 50
Male Fertility and Age
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0
100
200
300
400
500
600
700
20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79
Age groups
Num
berofsexualeventsper5years
Male Sexual Activity and Age
Any sexual activity
Sexual intercourse
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0
2
4
6
8
10
12
20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59
Age (years)
PlasmaTestosterone(mg/m
l)
95th
75th
Median
25th
5th
Data Source: Simon D, et al. The influence of aging on plasma sex hormones in men: theTelecom Study. Am J Epidemiol 1992;135;783-91.
Testosterone Level and Age
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Requires sample from masturbation
Assessed by:
Semen volume (normal 5 mL) Sperm count (normal > 20 million/mL)
Motility (>40%) Morphology (50% typical forms)
Assessment of Semen
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Variation in semen quality
Between laboratories and regionally
Season (lower in hot months)
Age (lower with age)
Recent ejaculation (decreased if < 3
days)
Problems in assessment of Semen
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Semen Quality and Age
Young ( 59)
Volume 2.3 mLCount 208 mill
Motility 23.8%
AbnormalMorphology 12.8%
Chromosmal abnormalities
4.8%
Sartorelli, Fertil Steril 2001;76:1119-23
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59
40
50
60
J F M A M J J A S O N D
Calendar Months
30
40
50
60
70
50
60
70
80
50
60
70
80
60
70
80
90
J F M A M J J A S O N D
Calendar Month
70
80
90
100
110
90
100
110
120
120130
140
150
160
170
Data Source: Levine et al. Male factors contributing to the seasonality of human reproduction.Ann NY Acad Sci 1994;709:29-45.
Sperm concentration, millions/ml
MacLeod
Levine (Calgary)
Spira
SL Pol
Tjoa
Levine (New Orleans)
Mortimer
Politoff
Seasonal Variation in Sperm Count
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Meta-analysis and some longitudinal studiessuggest declines in sperm counts of normal
males over time Is this evidence for male reproductive
damage?
Are these trends real?
Consistency between studies Selection effects
Definition of normal
Adjustment for recency of intercourse, ageand season
Time Trends in Semen Quality
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From Carlsen E, et al. Evidence for decreasing quality of semen during
past 50 years. BMJ 1992;305:609-613. Copyright 1992 BMJ. All Rights
Reserved.
Trends in Sperm Count over Time
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Environmental Estrogen Hypothesis
Environmental estrogens may act as
hormonal disruptors: Diet (fat, phytoestrogens)
Synthetic hormones
Estrogenic chemicals (e.g. pesticides,organochlorine and benzene derivatives)
Solvents Fungicide causing azoospermia (DBCP)
Hormonal Disruptors hypothesis
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0
50
100
150
200
250
300
350
1950-
54
1955-
59
1960-
64
1965
Birth Cohort
Sperm
Concentration(x106
/mL)
*
*
** 0
1
2
3
4
5
6
7
8
1950-
54
1955-
59
1960-
64
1965
B i r t h C oh o r t
Sem
en
Volum
e(m
L)
**
*
*
* * *
*
Data Source: Rasmussen et al. No evidence for decreasing semen quality in four birth cohorts
of 1,055 Danish men born between 1950 and 1970 Fertil Steril 1997:68(6):1061.
Concentration of Sperm by Birth Cohort
Problems with Time Trends in Semen
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Studies inconsistent
Variations in definitions of normal (WHOdefinition decreased from 60 to 20
million/mL over time)
Selection of normal men varies betweenstudies (e.g. sperm donors, vasectomycases)
Problems with Time Trends in SemenQuality
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Lack of control for time since last
ejaculation, season, and age
Variation in laboratory methods, and inter-observer variation in sperm counts
Confounding between regions
Problems with Time Trends in Semen
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