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LECTURE 3.a.

Female and Male Infertility

3

Different definitions of infertilityTime trends and geographic variations in infertilityEtiology and treatment of male and female factor infertilityAdverse effects of infertility treatment

Lecture Objectives

4

Inability to achieve a recognized pregnancy after trying to conceive 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

5

Definition Prevalence (%)Ever waited > 24 months 20.6Tried for > 24 months 12.5Consulted 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

6

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

7

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

8

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

9

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 births

to later ages when fertility is lower

Biologic: – Possible effects of STDs and PID?

U.S. trends in primary infertility

10

Decrease in Secondary Infertility

– Decrease in family size since 1960’s

– More couples adopt sterilization to terminate reproduction and do not recognize secondary infertility

U.S. Trends in secondary infertility

11

12

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 Belt”in central Africa– Cameroon, Congo, Uganda

Developing Country trends

13

Infertility in Africa decreased in recent decades– Difficult to determine trends from

surveys due to selective inclusion of currently married women (e.g. infertile women may often be divorced)

– Variation in survey samples over time

Trends in Developing Countries

14

Papua New Guinea– Tabar infertility 45% in 1940’s decreased to

18.5% in one generation following use of penicillin 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

15

Etiologic studies require invasive procedures and clinical 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

16

Tubal oculsion due to Pelvic Inflammatory Diseases (PID)– Industrialized countries 33%– Africa 75%

Ovulatory disorders– ∼

30%

EndometriosisHIVToxic exposures:– smoking, glycol ethers, nitrous oxide,

pesticides

Etiology of Infertility in Women

17

Pelvic Inflammatory Disease and Infertility

1. Cervical infection (C. trachomatis and/or N. gonorrhoeae)

18

Pelvic Inflammatory Disease and Infertility

2. Alteration of cervicovaginal microenvironment, increased pH

19

Pelvic Inflammatory Disease and Infertility

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

20

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.

21

1. Cervix2. Uterine Cavity3. Fallopian Tubes4. Abdominal Cavity

Sequence of Extension

22

Endocervicitis: May be asymptomatic; vaginal discharge, cervical inflammation, or infection; local tendernessEndosalpingitis: Constant bilateral lower quadrant abdominal pain aggravated by body motion. Tenderness in one or both adnexal areas. Abscess formation may occur.Endometriosis: Menstrual irregularityPeritonitis: Nausea, emesis, abdominal distention, rigidity, tenderness. Pelvic or abdominal cavity abscess formation may follow.

Clinical Features

23

05

101520253035404550

0 1 2 3+

Number of PID Episodes

Perc

ent

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

24

Pelvic Inflammatory Disease Hospitalizations of Women 15 to 44 years United

States, 1980–2003

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

25

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% to 30%.

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)

26

Ectopic Pregnancy Hospitalizations of Women 15 to 44 United

States, 1980–2003Hospitalizations (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)

27

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

28

Microchip Manufacturing: Female Workers Exposure to Ethylene Glycol Ethers (EGE)

EGE Exposure

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

29

Tubal Oculsion– Assisted Reproductive Technologies

(ART)• In vitro fertilization (IVF)• Gamete intrafallopian transfer (GIFT)• Zygote intrafallopian transfer (ZIFT)

– Tubal surgery

Treatment of Female Infertility

30

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 a laboratory 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

31

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.

32

Preconception genetic diagnoses

One or two balstomeres are removed from the embryoChromosome identification and evaluation by fluorescence in situ hybridization (FISH)Current techniques allow evaluation of up to 10 chromosomes in a single cell

33

Ovulation Disorders– Ovulation induction by Clomid, GnRH

Endometriosis– Drug treatment (Danazol)– Surgery

Treatment of Female Infertility

34

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

35

Delivery Rates with IVF

No male factorAge Delivery %<35 35.735-39 33.540+ 10.3

Male factor infertilityAge Delivery %<35 35.135-39 33.540+ 12.8

ASRM/SART Registry Fertil Steril 2002;77:18-31

36

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.

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 by year of birth in Europe

38

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)

39

Low Birth Weight and ART (US) Schieve NEJM 2002;346:731-7

– N = 42,463 ART vs 3,389,098 natural conceptions

– Risk of low birth weight with ART RR = 2.6 (2.4-2.7)

– Very low birth weight (<1500 gm) RR = 1.8 (1.7-2.0)

– 4.3% of very low birth weight attributable to ART

40

Birth Defects and ARTN = 837 IVF; 301 ICSI; 4000 natural conceptionsAll 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 NEJM 2002;346:725-30

41

Ovulation induction $1500-5000

Artificial insemination $1000-2000

IVF woman’s own eggs $12,500-25,000

IVF donor eggs $20,000-35,000

Costs of in vitro Fertilization

42

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 1.4/1000Jain NEJM 2002;347:661

IVF procedures 1996 = 64,036 vs 2001 = 107,587

43

Women with recurrent EPLs have no recognized pregnancy and report delayed conception. If delay >1 year classified as infertile.Increased SABs in women with infertility may reflect 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

44

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

45

Microchip Manufacturing: Female Workers Exposure to Ethylene Glycol Ethers (EGE)

EGE Exposure

Spontaneous Abortion

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)

46

Infertility increases with ageSABs increase with ageDue to ovum deterioration with age

IVF with donation of an ovum from young women to an older recipient increases pregnancy rates and decreases SABs

Infertility, SABs, and Age

47

Male Infertility

GNU Free Documentation License

48

Varicoele ∼ 20-40% (importance?)

Infections (e.g. mumps, STD orchitis & epididymitis, HIV)

Undescended testis

Toxins (e.g. DPCP, glycol ethers)

Etiology of Male Infertility

49

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

Male fertility and time trends in semen quality

51

Male fertility and age, effect of endocrine status

Secular trends in semen quality

Testicular development and testicular cancer as a marker of adverse effects

Possible effects of environmental factors including environmental estrogens, endocrine disruptors hypothesis

Factors influencing male fertility

52

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 partner’s age– Only women become pregnant

Ireland and Bangladesh data suggest decline in male fertility > age 50

Male Fertility and Age

53

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

ber

of s

exua

l eve

nts

per

5 ye

ars

Male Sexual Activity and Age

Any sexual activity

Sexual intercourse

54

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)

Plas

ma

Test

oste

rone

(mg/

ml)

95th

75th

Median

25th

5th

Data Source: Simon D, et al. The influence of aging on plasma sex hormones in men: the Telecom Study. Am J Epidemiol 1992;135;783-91.

Testosterone Level and Age

55

Birth rates by male age married to women aged 20-29, Ireland 1911

Birth per 1000 by male age

425 411

356

293

0

50

100

150

200

250

300

350

400

450

1 2 3 4

male age

Birt

h/10

00

~40 ~45 ~50 60~

56

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

57

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

58

Semen Quality and Age

Young (<39)Volume 5.3 mLCount 325 millMotility 32.8%Abnormal morphology 11.0%

Chromosomal abnormalities 11.9%

Older men (> 59)Volume 2.3 mLCount 208 millMotility 23.8%AbnormalMorphology 12.8%

Chromosmal abnormalities4.8%

Sartorelli, Fertil Steril 2001;76:1119-23

59

40

50

60

J F M A M J J A S O N DCalendar Months

30

40

50

60

7050

60

70

80

50

60

70

80

60708090

J F M A M J J A S O N DCalendar Month

7080

90100

110

90

100

110

120

120130140150160170

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/mlMacLeod

Levine (Calgary)

Spira

SL Pol

Tjoa

Levine (New Orleans)

Mortimer

Politoff

Seasonal Variation in Sperm Count

60

Meta-analysis and some longitudinal studies suggest 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, age

and season

Time Trends in Semen Quality

61

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

62

“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

63

0

50

100

150

200

250

300

350

1950-54

1955-59

1960-64

1965

Birth Cohort

Sper

m C

once

ntra

tion

(x 1

06 / m

L)

**

**0

1

2

3

4

5

6

7

8

1950-54

1955-59

1960-64

1965

Bi r t h Cohor t

Sem

en V

olum

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

64

Studies inconsistent

Variations in definitions of “normal” (WHO definition decreased from 60 to 20 million/mL over time)

Selection of “normal” men varies between studies (e.g. sperm donors, vasectomy cases)

Problems with Time Trends in Semen Quality

65

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