Female Infertility

Aka: Female Infertility, Infertility, Subfertility, Assisted Reproductive Technology, Assisted Reproductive Techniques

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II. Definitions

  1. Infertility
    1. No conception in 1 year without Contraception and with regular unprotected intercourse
      1. Primary Infertility: Nulligravida
      2. Secondary Infertility: Prior pregnancies

III. Epidemiology

  1. Affects 12% of couples in the United States (8 to 12% of couples worldwide)

IV. History

  1. History taken with both partners present
  2. Ages of both partners
  3. Medications and substances
    1. Teratogen Exposures (e.g. Isotretinoin, Warfarin, Lithium, Valproate)
    2. Substances (Tobacco, Alcohol, Marijuana, ilicit drug use)
  4. Obstetric History
    1. Prior Pregnancy and outcomes
  5. Sexually Transmitted Infections (STI)
    1. Pelvic Inflammatory Disease
    2. STI symptoms (e.g. Vaginal Discharge, Dysuria, Abdominal Pain, Fever)
  6. Menstrual History
    1. Menarche
    2. Menstrual period timing (i.e. ovulatory cycles)
  7. Male Factors
    1. See Male Infertility
    2. Erectile Dysfunction
    3. Libido
    4. Toxin exposures (e.g. Heavy Metals, Pesticides)
    5. Substances (Tobacco, Alcohol, Marijuana, ilicit drug use)
    6. Childhood illnesses (e.g. mumps, Cryptorchidism)
  8. Sexual History
    1. Number of contiguous months attempting conception
    2. Timing of intercourse in Menstrual Cycle
    3. Frequency of intercourse
      1. Optimally every day or every other day in Ovulation
    4. Lubricant use (spermatotoxic)
    5. Dyspareunia
    6. Technique

V. Exam: Women

  1. Breast Exam
    1. Breast formation
    2. Galactorrhea
  2. Genitourinary Exam
    1. Uterine masses
    2. Vaginal Discharge
  3. Endocrine
    1. Thyromegaly
    2. Hyperandrogenism
      1. Hirsutism
      2. Acne Vulgaris
      3. Clitoromegaly

VI. Exam: Men

  1. See Male Infertility

VII. Causes

  1. General
    1. Infertility is multifactorial in 40% of cases
    2. In at least 25% to 30% of cases, no Infertility cause is identified
  2. Female Infertility Causes
    1. See Female Infertility Causes
    2. Female factors overall account for 35 to 50% of cases
    3. Ovulatory Dysfunction accounts for 21-25% of cases
    4. Tubal factors account for 14-20% of cases
  3. Male Infertility Causes
    1. See Male Infertility
    2. Male factors account for 26-30% of cases (up to 40 to 50% of cases in some studies)

VIII. Evaluation: Indications

  1. Female age <35 years old
    1. Start Infertility evaluation after 12 months of no conception despite regular, unprotected sexual intercourse
  2. Female age 35 to 40 years old
    1. Start Infertility evaluation after 6 months of no conception despite regular, unprotected sexual intercourse
  3. Female age >40 years old
    1. Start evaluation immediately if suspected cause for Infertility (e.g. prior PID, tubal disease, prior Ectopic Pregnancy)
  4. Non-Heterosexual partners
    1. Start evaluation immediately

IX. Evaluation: Male Factor

  1. See Male Infertility
  2. History
    1. Prior conceived children
    2. History of testicular or scrotal surgery
    3. History of testicular infection (Mumps)
  3. Labs
    1. Semen Analysis
    2. Test for Sexually Transmitted Disease
      1. Mandatory for in vitro fertilization

X. Evaluation: Female Factors

  1. History related to Infertility Causes
  2. Confirm Ovulation
    1. See Ovulation
    2. Serum Progesterone (preferred)
      1. See Mid-Luteal Serum Progesterone for protocol
      2. Obtain Serum Progesterone on Day 21 of cycle (or 7 days before anticipated Menses onset)
      3. Serum Progesterone > 5 ng/ml (15.8 nmol/L) suggests Ovulation
    3. Other measures to confirm Ovulation
      1. Basal Body Temperature (not recommended, unreliable)
      2. Urine Luteinizing Hormone
  3. Aproach
    1. See below for evaluations of non-ovulating and ovulating women

XI. Evaluation: Female Factor - Not Ovulating (or Ovulatory Dysfunction)

  1. See Ovulatory Dysfunction
  2. Evaluate for Anovulation causes
    1. Follicle Stimulating Hormone
    2. Serum Prolactin
    3. Thyroid Stimulating Hormone
    4. Midluteal Phase Serum Progesterone (day 21)
      1. Serum Progesterone <3 ng/ml (<9.54 nmol/L) suggests annovulation
  3. Evaluate for Premature Ovarian Failure (age >35 years)
    1. See Premature Ovarian Failure
    2. Serum Follicle Stimulating Hormone (FSH) on Day 3 of cycle
      1. Increased FSH >10 IU/L on day 3 suggests decreased ovarian reserve
      2. Increased FSH >15-29 IU/L on day 3 suggests decreased likelihood of conception
      3. Increased FSH >30-40 IU/L (at any time) and low Serum Estradiol suggests Premature Ovarian Failure
        1. Consider Fragile X Syndrome carrier mutation testing in age <40 years
    3. Serum Estradiol (on Day 3 of cycle if menstruating)
      1. Decreased Serum Estradiol
        1. FSH increased: Premature Ovarian Failure
        2. FSH decreased: Hypothalamic-Pituitary failure
      2. Increased Serum Estradiol > 60-80 pg/ml and normal FSH predicts lower conception rate
        1. Associated with ovarian insufficiency (or decreased ovarian reserve)
    4. Antimullerian Hormone
      1. Antimullerian Hormone < 1.0 ng/ml suggests decreased ovarian reserve
      2. Unreliable marker of fertility in age 30 to 44 years without prior Infertility
        1. (2020) Fertil Steril 114(6): 1151-7 [PubMed]
    5. Other tests (low efficacy)
      1. Clomiphene Citrate (Clomid) challenge
      2. Antral follicle count (by Transvaginal Ultrasound)
        1. Count <5 to 7 suggests decreased ovarian reserve (poor efficacy)
  4. Consider Hyperandrogenism
    1. Serum 17a-Hydroxyprogesterone
    2. Serum Testosterone

XII. Evaluation: Female Factor - Ovulating

  1. Risk Factors for fallopian tube related Infertility cause
    1. Sexually Transmitted Infections and Pelvic Inflammatory Disease
    2. Prior abdominal or pelvic surgery
    3. Endometriosis
    4. Prior Ectopic Pregnancy
  2. Assess tubal patency
    1. No tubal obstruction risk factors
      1. Hysterosalpinography
    2. Tubal obstruction risk factors (Ectopic Pregnancy, pelvic infections, Endometriosis)
      1. Hysteroscopy
      2. Laparoscopy (with dye)
    3. Other first-line measures
      1. Transvaginal Ultrasound
  3. Other measures that are not recommended (do not affect management)
    1. Avoid post-coital Cervical Mucus testing
    2. Endometrial Biopsy for histologic dating
      1. Endometrial Biopsy is only indicated for suspected pathology (e.g. Endometrial Cancer Risk Factors)

XIII. Management

  1. General measures
    1. Tobacco Cessation
    2. Limit Alcohol to <2 drinks per day
    3. Avoid Marijuana
      1. May lower semen count and suppress Ovulation
    4. Target health weight
      1. Goal Body Mass Index (BMI) >20 kg/m2 and <30 kg/m2
      2. Obesity affects both male (semen quality, Erectile Dysfunction) and female (Ovulation, fertilization) factors
        1. Weight loss 5 to 10% improves spontaneous Ovulation and response to Ovulation induction
      3. Low BMI in women (e.g. RED-S) is associated with Anovulation
    5. Profertility Diet
      1. May improve pregnancy rates in women undergoing Assisted Reproductive Technology (ART)
      2. Folic Acid, Vitamin D and Vitamin B12
      3. Diet high in fruits and vegetables
      4. Seafood
      5. Gaskins (2019) Am J Obstet Gynecol 220(6): 567.e1-567.e18 [PubMed]
  2. Treat specific conditions if present
    1. Thyroid Disease (Hypothyroidism, Hyperthyroidism)
    2. Hyperprolactinemia
    3. Hypothalamic-Pituitary Failure
      1. Underweight women or over Exercisers with Amenorrhea, low Serum FSH and low Estradiol
      2. Encourage normalization of weight and moderation of Exercise
    4. Polycystic Ovary Syndrome (PCOS)
      1. Encourage weight loss, Exercise and lifestyle modification
      2. Clomiphene (Clomid)
      3. Letrozole (Femera)
      4. Metformin (Glucophage) 1500 mg daily
        1. Initial studies were promising and did increase Ovulation rates
        2. However does not increase the live birth rate
        3. Lord (2003) BMJ 327: 951 [PubMed]
        4. Sun (2013) Arch Gynecol Obstet 288(2): 423-30 [PubMed]
      5. Laparoscopic Ovarian Drilling
    5. Tubal disease
      1. Tubal repair surgery (tubal cannulation, tubal anastomosis)
      2. In vitro fertilization
    6. Intrauterine Abnormalities (e.g. Uterine Fibroids)
      1. Referral to gynecologic surgery
    7. Endometriosis
      1. Laparoscopic ablation
    8. Male Infertility
      1. Referral to male fertility specialist or urologist
      2. See general measures above (Tobacco Abuse, Obesity, limit Alcohol, avoid Marijuana)
      3. Treat cause (e.g. Varicocele Repair)
      4. Artificial Insemmination, Intrauterine insemination
  3. Ovulatory Dysfunction management
    1. Risk of Ovarian Hyperstimulation Syndrome and Multiple Gestation
    2. Clomiphene Citrate (Clomid) 50 mg (max 100 mg) daily for 5 days (starting on 2 to 5 of cycle)
    3. Letrozole (Femera) 2.5 (max 7.5 mg) daily for 5 days (starting on day 3 of cycle)
    4. Gonadotropins (for central Hypogonadism)
  4. Unexplained or refractory Infertility
    1. Precaution in unexplained Infertility
      1. Intrauterine insemination and Ovulation induction do not increase pregnancy rates
    2. Referral to Assisted Reproductive Technology (ART) as indicated
    3. Ovulatory Dysfunction management (as above)
    4. Intrauterine insemination
    5. In-Vitro Fertilization

XIV. Prognosis

  1. Overall fertility rate with treatment: 50%
  2. Even without treatment, 50% will conceive in the second year of attempting pregnancy
  3. Predictors of lower success rate
    1. Tubal causes of Infertility (20% fertility rate)
    2. Severe Endometriosis (17% fertility rate)
    3. Longer duration of Infertility
    4. No prior fertility history
    5. Women over age 30-35 years
  4. Reference
    1. Collins (2004) Hum Reprod Update 10:309-16 [PubMed]

XV. Complications: Assisted Reproductive Technology (ART)

  1. Ovarian Hyperstimulation Syndrome (OHSS)
  2. Heterotopic Pregnancy
  3. Mulitple Gestation
  4. Ovarian Torsion
    1. Increased risk with Assisted Reproductive Technology (ART), especially with Ovulation induction (e.g. Clomid)
    2. Multiple cysts that form on the stimulated ovary can act as a lead point for torsion

XVI. References

  1. (2012) Fertil Steril 98(2): 302-7 [PubMed]
  2. (2004) Fertil Steril 82(suppl 1):S169-72 [PubMed]
  3. Jose-Miller (2007) Am Fam Physician 75(6):849-58 [PubMed]
  4. Lindsay (2014) Am Fam Physician 91(5): 308-14 [PubMed]
  5. Phillips (2023) Am Fam Physician 107(6): 623-30 [PubMed]

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Related Studies

Ontology: Infertility (C0021359)

Definition (CHV) Unable to produce children
Definition (CHV) Unable to produce children
Definition (MEDLINEPLUS)

Infertility means not being able to become pregnant after a year of trying. If a woman can get pregnant but keeps having miscarriages or stillbirths, that's also called infertility.

Infertility is fairly common. After one year of having unprotected sex, about 15 percent of couples are unable to get pregnant. About a third of the time, infertility can be traced to the woman. In another third of cases, it is because of the man. The rest of the time, it is because of both partners or no cause can be found.

There are treatments that are specifically for men or for women. Some involve both partners. Drugs or surgery are common treatments. Happily, many couples treated for infertility go on to have babies.

NIH: National Institute of Child Health and Human Development
Definition (NCI_NCI-GLOSS) The inability to produce children.
Definition (NCI) Inability to conceive for at least one year after trying and having unprotected sex. Causes of female infertility include endometriosis, fallopian tubes obstruction, and polycystic ovary syndrome. Causes of male infertility include abnormal sperm production or function, blockage of the epididymis, blockage of the ejaculatory ducts, hypospadias, exposure to pesticides, and health related issues.
Definition (MSH) Inability to reproduce after a specified period of unprotected intercourse. Reproductive sterility is permanent infertility.
Concepts Pathologic Function (T046)
MSH D007246
SnomedCT 8619003, 162186008, 289179008, 15296000
English Infertility, Sterility, Sterile, unable to get pregnant, inability to conceive, inability to conceive (symptom), inability to conceive (infertility), Infertility NOS, Infertility [Disease/Finding], Unable (to);conceive, get pregnant unable, unable (to) get pregnant, Unable (to);get pregnant, sterility, Infertility problem, Not fertile, infertility, infertility (symptom), sterile, infertile, Infertile, Cannot achieve a pregnancy, Difficulty conceiving, Infertile (finding), Sterility (finding), Infertility, NOS, Sterility, NOS, Reproductive Sterility, Sterility, Reproductive, unable to conceive
Dutch onvruchtbaarheid NAO, steriliteit, infertiliteit, Infertiliteit, Steriliteit
French Infertilité SAI, Stérilité, Infertilité
German Unfruchtbarkeit NNB, Sterilitaet, Sterilität (Fortpflanzung), Infertilitaet, Unfruchtbarkeit, Kinderlosigkeit, Fruchtbarkeitsstörung, Infertilität, Zeugungsunfähigkeit
Italian Infertilità NAS, Sterilità riproduttiva, Sterilità, Infertilità
Portuguese Infertilidade NE, Esterilidade, Infertilidade
Spanish Esterilidad NEOM, esterilidad (hallazgo), esterilidad, infértil (hallazgo), infértil, Infertilidad, Esterilidad
Japanese 生殖不能, 不妊症ＮＯＳ, ｾｲｼｮｸﾌﾉｳ, ﾌﾆﾝｼｮｳ, ﾌﾆﾝｼｮｳNOS, 不妊性, 不妊, 不妊症
Swedish Barnlöshet
Czech neplodnost, infertilita, Sterilita, Neplodost, Neplodnost NOS
Finnish Hedelmättömyys
Russian BESPLODIE, БЕСПЛОДИЕ
Croatian NEPLODNOST
Polish Niepłodność
Hungarian Infertilitas, Infertilitas k.m.n., sterilitas
Norwegian Infertilitet, Barnløshet, Sterilitet, Ufruktbarhet
Derived from the NIH UMLS (Unified Medical Language System)

Ontology: Female infertility (C0021361)

Definition (MEDLINEPLUS)

Infertility is a term doctors use if a woman hasn't been able to get pregnant after at least one year of trying. If a woman keeps having miscarriages, it is also called infertility. Female infertility can result from physical problems, hormone problems, and lifestyle or environmental factors.

Most cases of infertility in women result from problems with producing eggs. One problem is premature ovarian failure, in which the ovaries stop functioning before natural menopause. In another, polycystic ovary syndrome (PCOS), the ovaries may not release an egg regularly or may not release a healthy egg.

About a third of the time, infertility is because of a problem with the woman. One third of the time, it is a problem with the man. Sometimes no cause can be found.

If you suspect you are infertile, see your doctor. There are tests that may tell if you have fertility problems. When it is possible to find the cause, treatments may include medicines, surgery, or assisted reproductive technologies. Happily, two-thirds of couples treated for infertility are able to have babies.

Dept. of Health and Human Services Office on Women's Health
Definition (MSH) Diminished or absent ability of a female to achieve conception.
Concepts Pathologic Function (T046)
MSH D007247
ICD9 628.9, 628
ICD10 N97 , N97.9
SnomedCT 156065009, 266679002, 156059009, 198472001, 156067001, 6738008
English Infertility, Female, Infertility, female, of unspecified origin, Female infertility, unspecified, female infertility, female infertility (diagnosis), Infertility female, Female infertility NOS, Infertility, Female [Disease/Finding], infertility female, females infertility, Female Infertility, Female infertility NOS (disorder), Infertility - female, Female infertility (disorder), infertility; female, Female infertility, NOS, Female infertility, Infertility, female, Infertility;F
Dutch vrouwelijke onvruchtbaarheid, vrouwelijke onvruchtbaarheid van niet-gespecificeerde oorsprong, infertiliteit; vrouw, Infertiliteit bij vrouw, niet gespecificeerd, onvruchtbaarheid vrouwelijk, Infertiliteit bij vrouw, Infertiliteit van de vrouw
French Stérilité féminine, Infertilité, chez la femme, d'origine non précisée, Infertilité féminine, Infertilité de la femme
German Infertilitaet der Frau, Infertilitaet, weiblich, unspezifischer Ursprung, Sterilitaet der Frau, nicht naeher bezeichnet, Sterilitaet der Frau, Unfruchtbarkeit der Frau, Impotentia gestandi, Fruchtbarkeitsstörung der Frau, Infertilität, weibliche
Italian Infertilità femminile, di origine non specificata, Infertilità femminile
Portuguese Infertilidade feminina de origem NE, Infertilidade feminina, Infertilidade Feminina
Spanish Esterilidad femenina de origen no especificado, Infertilidad femenina, infertilidad femenina, SAI (trastorno), Female infertility NOS, infertilidad femenina, SAI, esterilidad femenina, SAI (trastorno), esterilidad femenina, SAI, infertilidad femenina (trastorno), infertilidad femenina, Esterilidad femenina, Infertilidad Femenina
Japanese 女性不妊症、原因不明, ｼﾞｮｾｲﾌﾆﾝｼｮｳ, ｼﾞｮｾｲﾌﾆﾝｼｮｳｹﾞﾝｲﾝﾌﾒｲ, 女性不妊症, 不妊症-女性, 女性不妊
Swedish Barnlöshet hos kvinnor
Finnish Naisen hedelmättömyys
Russian BESPLODIE ZHENSKOE, БЕСПЛОДИЕ ЖЕНСКОЕ
Czech Neplodnost u ženy, Ženská neplodnost, Neplodnost ženská, blíže neurčeného původu, infertilita ženská, neplodnost ženská, ženská infertilita
Korean 상세불명의 여성 불임증, 여성 불임증
Croatian NEPLODNOST ŽENE
Polish Niepłodność kobieca, Niepłodność żeńska
Hungarian Női infertilitas, női infertilitas, Nem meghatározott eredető nő infertilitas
Norwegian Kvinnelig infertilitet, Infertilitet hos kvinner, Kvinnelig ufruktbarhet, Ufruktbarhet hos kvinner, Ufrivillig barnløshet hos kvinner
Derived from the NIH UMLS (Unified Medical Language System)

Ontology: Subfertility (C0729353)

Concepts Disease or Syndrome (T047)
MSH D007246
SnomedCT 198471008, 313279000
Dutch subfertiliteit
French Subfécondité
German Subfertilitaet
Italian Subfertilità
Portuguese Subfertilidade
Spanish Subfertilidad, fertilidad disminuida, subfertilidad (hallazgo), fertilidad disminuida (hallazgo), subfertilidad
Japanese 低妊孕率, ﾃｲﾆﾝﾖｳﾘﾂ
Czech Subfertilita
English subfertility, Subfertility, Sub-Fertility, Subfertility (finding)
Hungarian Subfertilitas
Norwegian Subfertilitet
Derived from the NIH UMLS (Unified Medical Language System)

Ontology: Reproductive Techniques, Assisted (C0949811)

Definition (MSH) Clinical and laboratory techniques used to enhance fertility in humans and animals.
Concepts Therapeutic or Preventive Procedure (T061)
MSH D027724
Swedish Tekniker för fortplantningshjälp
English REPRODUCTIVE TECHNIQUES ASSIST, ASSIST REPRODUCTIVE TECHNICS, assisted reproductive technique, assisted reproductive techniques, Assisted Reproductive Technic, Assisted Reproductive Technics, Assisted Reproductive Technique, Reproductive Technic, Assisted, Reproductive Technics, Assisted, Reproductive Technique, Assisted, Reproductive Techniques, Assisted, Technic, Assisted Reproductive, Technics, Assisted Reproductive, Technique, Assisted Reproductive, Techniques, Assisted Reproductive, Assisted Reproductive Techniques
Finnish Hedelmättömyyshoidot
Russian REPRODUKTIVNYE METODY VSPOMOGATEL'NYE, РЕПРОДУКТИВНЫЕ МЕТОДЫ ВСПОМОГАТЕЛЬНЫЕ
Japanese 生殖技術-介助, 生殖補助医療, 技術-生殖補助, 生殖医療補助技術, 生殖補助技術, 医学的生殖介助
French Techniques d'assistance à la reproduction, Techniques de reproduction assistée
Czech umělé oplodnění - techniky, reprodukce asistovaná - techniky, techniky asistované reprodukce, asistovaná reprodukce
Croatian ZAČEĆE, POTPOMOGNUTO, METODE
Polish Metody wspomagania rozrodu, Prokreacja medycznie wspomagana, Reprodukcja wspomagana, Techniki reprodukcji wspomaganej medycznie, Metody prokreacji wspomaganej medycznie, Rozród wspomagany
Norwegian Befruktning, assistert, Assistert befruktning, Assisterte reproduksjonsteknikker, Assisterte befruktningsteknikker, Reproduksjon, assistert
German Reproduktionstechniken, assistierte
Italian Tecniche di riproduzione assistita
Dutch ART, Reproductietechnieken, kunstmatige, Voortplantingstechnieken, kunstmatige
Portuguese Técnicas Reprodutivas Assistidas
Spanish Técnicas Reproductivas Asistidas
Derived from the NIH UMLS (Unified Medical Language System)

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