Understanding Infertility, Evaluations, and Treatment Options

Arlene J. Morales, M.D., FACOG

FER 03520 Infertility DT6 04/11/23 21:45

Understanding Infertility, Evaluations,and Treatment Options

Arlene J. Morales, M.D., F.A.C.O.G.

Fertility Specialists Medical Group, Inc.



What We Will Cover

• Introduction – What is infertility?– Briefly review female reproduction

• Evaluating fertility• Fertility testing• Treatment options

– Common procedures



Introduction

• Definition: The inability of couples of reproductive age to establish a pregnancy within 1 year through unprotected sexual intercourse1

• In the United States, 7.3 million women (12% of women of reproductive age) had difficulty or were unable to get pregnant or carry a baby to term2

• Only 50% receive treatment

• With treatment, 2 of 3 couples will succeed

1. Practice Committee of the American Society for Reproductive Medicine. Fertil Steril. 2008;90(5 suppl):S60. 2. Chandra et al. Vital Health Stat 23. 2005;(25):1.



There Are Multiple Causes of Infertility

14%

6%

6%

7%

1%

6%

11%

13%

18%

19%

Causes of Infertility

Centers for Disease Control and Prevention. 2006 Assisted Reproductive Technology Success Rates: National Summary and Fertility Clinic Reports. 2008. http://www.cdc.gov/ART/ART2006/508PDF/2006ART.pdf. Accessed April 20, 2009.

Tubal factor

Ovaluatory dysfunction

Diminished ovarian reserve

Endometriosis

Uterine factor

Male factorOther causes

Unexplained

Multiple factors(female only)

Multiple factors(male + female)



Decline in Fertility With Age:The Fixed Ovarian Pool BecomesDepleted as Time Passes

Broekmans et al. Trends Endocrinol Metab. 2007;18:58.

0

0.2

0.4

0.6

0.8

1.0

1.2

20 25 30 35 40 45 50

Monthly Fertility Rate

Female age (y)

Rel

ativ

e ra

te



ART: Pregnancy and Birth Rates Still

Decrease With Women’s Age

*For consistency, all percentages are based on cycles started.Centers for Disease Control and Prevention. 2006 Assisted Reproductive Technology Success Rates: National Summary and Fertility Clinic Reports. 2008. http://www.cdc.gov/ART/ART2006/508PDF/2006ART.pdf. Accessed April 20, 2009.

Age (years)

Per

cen

t

60

50

40

30

20

10

0<21 22 24 26 28 30 32 34 36 38 40 42 44 46 48 >48

Pregnancy Live birth Singleton live birth



Determinants of Declining FertilityWith Advancing Age in Women

• Declining oocyte number and ovulatory disturbances

• Declining oocyte quality and increasing chromosomal and genetic mutations

• Luteal phase dysfunction

• Impaired fertilization rates

• Implantation failures

• Poor-quality embryos and genetic abnormalities

• Impaired endometrial receptivity

• Higher incidence of age-related gynecologic problems, including uterine fibroids and polyps

• Declining sexuality

• Increased pregnancy wastage

• Early implantation failures and preclinical losses

• Clinical losses

• Increased incidence of general medical problems accompanying aging (eg, type 2 diabetes mellitus, hypertension)

• High incidence of obstetric complications and poor pregnancy outcomes

Pal and Santoro. Endocrinol Metab Clin North Am. 2003;32:669.



The Female Reproductive Tract

Image on file with Organon, a part of Schering-Plough.



The Ovary

Netter illustrations used with permission of Elsevier Inc. All rights reserved.



The Brain Controls Reproduction

Pituitary

Hypothalamus

Image on file with Organon, a part of Schering-Plough. Netter illustration used with permission of Elsevier Inc. All rights reserved.



Menstrual Cycle

Luteal PhaseFollicular Phase

Day 1 Day 14 Days 21-22or

Days 20-24

LH Surge Implantation

Day 7

Selection ofDominant

Follicle

“Window of Receptivity”

Recruitment of Follicles

Day 28

American Society for Reproductive Medicine. Age and fertility: a guide for patients. 2003. http://www.asrm.org/Patients/patientbooklets/agefertility.pdf. Accessed April 20, 2009.



The Hormones

• Gonadotropin-Releasing Hormone (GnRH)– Released by the hypothalamus, acts on pituitary

– Coordinated pulse frequency

• Follicle-Stimulating Hormone (FSH)– Released by the anterior pituitary, acts on ovary

• Luteinizing Hormone (LH) – Released by the anterior pituitary, acts on ovary

• Estrogen (E2)– Produced by the growing follicle, acts on endometrium

• Progesterone (P4)– Produced by the corpus luteum (CL) and placenta, acts on

endometrium

American Society for Reproductive Medicine. Age and fertility: a guide for patients. 2003. http://www.asrm.org/Patients/patientbooklets/agefertility.pdf. Accessed April 20, 2009.



How Hormones Interact

HypothalamusHypothalamus

PituitaryPituitary

OvaryOvary

FSH & LH

Coordinated GnRH Pulses


Estrogen

Netter illustration used with permission of Elsevier Inc. All rights reserved.

The Cycle:

...Oocyte,

...Uterus, ...Hormones



Normal Fertilization and Implantation




When to Suspect a Problem

• If the woman is under 35 and has tried unsuccessfully to conceive for more than 12 months

• Or if the women is over 35 and has tried for more than6 months

• If the couple meets either of these criteria, then the couple may need to be evaluated

• Although couples frequently turn to their Ob/Gyn for initial fertility guidance, referral to an infertility specialist, a reproductive endocrinologist (RE), may be necessary

Practice Committee of the American Society for Reproductive Medicine. Fertil Steril. 2006;86(5 suppl):S264.Taylor. BMJ. 2003;327:494.



Evaluating Female FertilityClinical Need Routine Tests

First Exam • Patient history and physical exam

Ovulatory status • Midluteal serum progesterone• Ultrasound scanning• Endometrial biopsy• Basal body temperature

Ovarian reserve • Basal LH, FSH, E2, inhibin B, anti-Müllerian hormone, FSH:LH ratio• Clomiphene citrate, exogenous FSH, or GnRH antagonist testing

Uterine factors • Ultrasound scanning• Hysteroscopy• Hysterosalpingography (HSG)

Tubal factors • HSG• Fluoroscopic tubal cannulation• Chromotubation

Bowen et al. Fertil Steril. 2007;88:390. Practice Committee of the American Society for Reproductive Medicine. Fertil Steril. 2006;86(5 suppl):S264. Taylor. BMJ. 2003;327:494.



Endometrial Biopsy

• Delayed endometrial maturation from inadequate P4 production by the CL could cause infertility and early pregnancy loss

• Histologic dating of the endometrium via biopsy has been used for the evaluation of CL function and diagnosis of luteal phase deficiency (LPD)

• However, a single biopsy is not sufficient to make the diagnosis

• Therefore, most REs do not believe that “histologic dating” isa good diagnostic tool

Murray et al. Fertil Steril. 2004;81:1333.



Transvaginal Ultrasound




Hysteroscopy

Polyp

Septum

©Tim Peters and Company, Inc. Peapack, NJ 07977, USA.



Hysterosalpingography (HSG)

©Tim Peters and Company, Inc. Peapack, NJ 07977, USA.



Evaluating Male FertilityClinical Need Routine Tests

First exam • Reproductive/medical history

• Physical examination

Semen analysis • Ejaculate volume

• pH

• Sperm concentration

• Total sperm number

• Percent motility

• Forward progression

• Normal morphology

• Sperm agglutination

• Viscosity

Additional analyses • Basal hormone analysis: FSH, LH, testosterone, prolactin

• Postejaculatory urinalysis

• Ultrasonography

• Testicular biopsy/exploration

• Genetic screening

• Specialized semen and sperm analyses

Male Infertility Best Practice Policy Committee of the American Urological Association; Practice Committee of the American Society for Reproductive Medicine. Fertil Steril. 2006;86(5 suppl):S202. Taylor. BMJ. 2003;327:494.



Male Infertility

Normal sperm quality:Count: >20 × 106/mL

Morphology: >30% Motility: >50%

Image on file with Organon, a part of Schering-Plough

Male Infertility Best Practice Policy Committee of the American Urological Association; Practice Committee of the American Society for Reproductive Medicine. Fertil Steril. 2006;86(5 suppl):S202. Taylor. BMJ. 2003;327:494.



Treatment Options for Infertile CouplesCondition Treatment OptionsFemale infertility

Ovulatory failure or dysfunction OI

Tubal factor COS with IVF

Endometriosis IUI (patent tubes), or COS with IVF

Male infertility

Male subfertility IUI with or without OI

Male factor COS with ICSI

Female and/or male infertility

Unexplained IUI, COS with IVF, or ICSI

National Institute for Clinical Excellence. Fertility assessment and treatment for people with fertility problems. 2004. http://www.nice.org.uk/nicemedia/pdf/CG011fullguideline.pdf. Accessed April 20, 2009.

OI = ovulation induction; COS = controlled ovarian stimulation; IVF = in vitro fertilization;IUI = intrauterine insemination; ICSI = intracytoplasmic sperm injection.



Ovulation Induction

• OI is useful in patients with anovulatory infertility– WHO class I: hypogonadotropic hypogonadism

– WHO class II: polycystic ovary syndrome (PCOS)

• Goal– Stimulate development of a single follicle that will be able to

reach preovulatory size and rupture

• Options– Clomiphene citrate (CC)

– Gonadotropins (hMG/FSH followed hCG)

– GnRH analogue

Messinis. Hum Reprod. 2005;20:2688. Practice Committee of the American Society for Reproductive Medicine. Fertil Steril. 2008;90(5 suppl):S7. Practice Committee of the American Society for Reproductive Medicine. Fertil Steril. 2006;86(5 suppl):S187.



Ovulation Induction: Clomiphene Citrate • CC is an antiestrogen that binds to estrogen receptors and interferes

with estrogen-negative feedback – Results in an alteration in pulsatile GnRH secretion – Leads to increases in gonadotropin secretion and follicular development

• CC is widely used for ovulation induction in women with PCOS and in couples with unexplained infertility

• CC treatment successfully induces ovulation in about 80% of properly selected candidates – Pregnancy rates are much lower (30%-40% per cycle)– 40%-45% of couples can become pregnant within 6 cycles– Failure to conceive after successfully induced ovulation is indication for

further evaluation

• Patient characteristics predictive of poor response to CC:– Hypothalamic disorder– Low estrogen levels– Obesity

American Society for Reproductive Medicine. Medications for inducing ovulation: a guide for patients. 2006. http://www.asrm.org/Patients/patientbooklets/ovulation_drugs.pdf. Accessed April 20, 2009. Case. Can Fam Physician. 2003;49:1465. Practice Committee of the American Society for Reproductive Medicine. Fertil Steril. 2006;86:S187.



Limitations and Risks With CC for OI • CC is generally well tolerated, although some side effects may limit its

efficacy and safety– Short-term, reversible side effects include: hot flashes, mood swings,

visual disturbances, breast tenderness, pelvic discomfort, and nausea– The antiestrogenic effects may negatively impact the uterine lining, leading

to lower pregnancy rates– Risk of multiple pregnancy is increased– Risk of cancer is increased among women who were treated with CC

• Uterine fibroid risk increases with CC treatment• Risk of ovarian cancer increases among women treated with prolonged

CC

• Treatment should be limited to no more than 6 cycles or fewer in consideration of woman’s individual situation– Age, baseline characteristics, etc

Althuis et al. Am J Epidemiol. 2005;161:607.Case. Can Fam Physician. 2003;49:1465.



Ovulation Induction: Gonadotropin Treatment• Optimal for women who have failed CC or who cannot risk waiting • Used in women with inadequate pituitary secretion of LH and FSH

(hypogonadotropic amenorrhea) or PCOS• Agents: FSH, hCG, human menopausal gonadotropin (hMG)• Success rates

– WHO class I: 30% per cycle– WHO class II: 17% per cycle

• May include IUI or natural intercourseOI

American Society for Reproductive Medicine. Medications for inducing ovulation: a guide for patients. 2006. http://www.asrm.org/Patients/patientbooklets/ovulation_drugs.pdf. Accessed April 20, 2009. Practice Committee of the American Society for Reproductive Medicine. Fertil Steril. 2008;90(5 suppl):S7.

hCG



Use of IUI in OI Protocol• Indications

– Unexplained infertility – Male subfertility—mild

oligozoospermia, asthenozoospermia, or teratozoospermia

– Failure to conceive after ovulation induction treatment

– Ejaculatory failure– Retrograde ejaculation

• Procedure– Washed prepared sperm are

deposited in the uterus just before the release of an egg or eggs in a natural or stimulated cycle

• Success rate: up to 15% per cycle

• Significant risk for multiple pregnancy

Rowell and Braude. BMJ. 2003;327:799.

Image on file with Schering-Plough/Organon.



In Vitro Fertilization

Procedure

• Initially used in women with fallopian tube blockage or damage

• Now employed for many causes of infertility (eg, endometriosis, male factor)

• Involves– COS– Egg retrieval– Insemination, fertilization,

embryo culture– Embryo transfer– Cryopreservation of extra

embryos

Risks

• Ovarian hyperstimulation syndrome (OHSS)– Usually not serious and

resolves with outpatient management

– 1%-2% severe requiring hospitalization

– Dose-dependent, avoided by careful titration

• Anesthesia• Multiple births• Ectopic pregnancy• Cost• Psychologic distress

American Society for Reproductive Medicine. Assisted reproduction technologies: a guide for patients. 2008. http://www.asrm.org/Patients/patientbooklets/ART.pdf. Accessed April 20, 2009.



Intracytoplasmic Sperm InjectionIndications

• Very low numbers of motile sperm

• Severe teratospermia• Problems with sperm binding to

and penetrating the egg• Antisperm antibodies• Prior or repeated fertilization

failure with standard IVF methods

• Frozen sperm limited in number and quality

• Obstruction of the male reproductive tract not amenable to repair

Success Rate and Complications

• Fertilization rate: 50%-80%• Live offspring: 20%-40%

(40% in younger women; success declines with maternal age)

American Society for Reproductive Medicine. Intracytoplasmic sperm injection (ICSI). 2008. http://www.asrm.org/Patients/FactSheets/ICSI-Fact.pdf. Accessed April 20, 2009. Campbell and Irvine. Br Med Bull. 2000;56(3):616. Palermo et al. Sem Reprod Med. 2000;18(2):161.



Controlled Ovarian Stimulation: Gonadotropin Treatment • Starts with higher dose of gonadotropins than for OI (COS: 150-225 IU

of FSH; OI: 50-75 IU of FSH)• Needs GnRH analog treatment to prevent interference by endogenous

hormones• COS is followed by oocyte retrieval, IVF, and transfer of embryos

hCG

COS

Arslan et al. Fertil Steril. 2005;84(3):555.Borini and Dal Prato. Reprod Biomed Online. 2005;11:283.



Common Procedures: COS

IVF

or

ICSI

rFSH/hMG

Day 2 or 3of menses

GnRH agonist

Cycle day21-24

Down regulation

Luteal phasesupport

Embryo TransferEmbryo Transfer

GnRH antagonist

Day 6 of FSH

rFSH/hMG

hCGhCG



How can the Ob/Gyn and fertilityspecialist work together to ensure that patients get the most appropriatetreatment as soon as possible?

FertilitySpecialist

Ob-Gyn Patient



Management Algorithm for Ob/Gyn

Hanson and Dumesic. Mayo Clin Proc.1998;73:681.

Refer to fertility specialist

Female <35 years of age1 year of infertility

Female >35 years of age6 months of infertility

Abnormal

SuccessfulUnsuccessful

Initiate prenatal care

Couple attempting conception

Abnormal

Abnormal

Normal

Determine progesterone level 7 days after presumed ovulation

Anovulation or oligo-ovulation without hirsutism

Female physiology: serum-sensitive TSH, FSH, and prolactin levels

Male evaluation: semen analysis

Female anatomy: hysterosalpingography

Ovulation

Consider referral forCOS

Treatment: clomiphene citrate 50-100 mg/d orally for 5 days during menses, for 3 cycles



Summary

• Infertility treatment protocol and success rates are highly dependent on ovarian age – Associated risk factors increase with age (eg, endometriosis) as well

as other risks (chromosomal abnormalities)

• Conduct diagnostic tests after– 1 year of infertility for woman aged <35 years

– 6 months of infertility for woman aged >35 years

• Multiple techniques exist to assess ovulatory function, and several different types of protocols treat female infertility– Most treatments have higher rates of success in younger women

• The Ob/Gyn, fertility specialist, and patient need to work together to determine reasonable expectations and optimal treatment course



Thank You

Arlene J. Morales, M.D., F.A.C.O.G.Fertility Specialists Medical Group, Inc.

Understanding Infertility, Evaluations, and Treatment Options

Health & Medicine

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