Female and Male Infertility

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LECTURE 3.a.

Female and MaleInfertility


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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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2. Alteration of cervicovaginal microenvironment, increased pH


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3. Overgrowth of vaginal and anaerobic flora, resulting in BV.


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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



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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

GNU Free Documentation License
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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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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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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

Female and Male Infertility

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