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Evaluation of women with infertility

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Key words: infertility, infertility evaluation, ovulatory dysfunction, ovarian reserve, tubal patency

Advanced practice nurses (APNs) may be the first point of contact in a woman’s lengthy fertility journey. Although caring for a patient with infertility is within the scope of practice of APNs, this process can be intimidating and complex. APNs need to set realistic expectations, educate patients, and provide initial management. The author discusses the initial evaluation of a woman with infertility prior to a referral to a reproductive endocrinology and infertility specialist if necessary.

As many as 15% of couples trying to conceive a child are diagnosed with infertility, defined as the inability to conceive within 1 year despite unprotected intercourse.1 Because advancing maternal age is a driving force in the decline of fertility, the time span in the definition may reasonably be altered to 6 months for women older than 35 years. Overall fertility rates, which peak between the ages of 20 and 24 years, are 4%-8% lower in women aged 24-29, 15%-19% lower in those aged 30-34, 26%-46% lower in those aged 35-39, and as much as 95% lower in those aged 40-45.1 

Infertility is a complex diagnosis that can greatly affect physical, mental, and financial aspects of a couple’s life together.2 In general, infertility is considered a couple’s diagnosis because 35%-40% of cases are due to male factors, 30%-40% to female factors, and up to 30% to a combination of male and female factors or unexplained factors.1 Common causes of infertility in women are ovulatory dysfunction and tubal/peritoneal pathology, and a common cause of infertility in men is a sperm abnormality.3 

Referral to a specialist in reproductive endocrinology and infertility (REI) is considered early in the assessment of infertility in a woman with endometriosis, tubal disease, a history of three or more spontaneous abortions, or previous ovulation induction, or in a case of male factor infertility. When known risk factors exist, or when a woman is older than 35 years, APNs should not wait to initiate assessment and referral until a couple has tried to conceive for a full year. However, women who have not previously tried ovulation induction medications, are anovulatory, have polycystic ovary syndrome (PCOS), or have unexplained infertility may be treated by an APN for 3-6 months prior to referral.4 Male factor infertility may be addressed with an intrauterine insemination if an andrology laboratory is available. Knowing the appropriate components and timing of an infertility assessment is essential.

History

The APN takes a thorough history from each partner. The APN needs to learn how long the couple has been trying to conceive and the results of any previous evaluation to ensure that testing is not repeated unnecessarily.

The woman

A full menstrual history is obtained, including age at menarche, cycle length, characteristics of bleeding, and presence or absence of moliminal symptoms (e.g., bloating, breast tenderness). Absence of moliminal symptoms may suggest anovulation.1 The woman is asked about prior contraception use; her obstetric history, including pregnancy outcomes and complications (e.g., ectopic pregnancy, cesarean delivery, dilation and curettage procedures); past surgeries; current medications; recent weight changes; signs and symptoms of thyroid disease; pelvic or abdominal pain; galactorrhea; hirsutism; and dyspareunia. A history of chlamydia, gonorrhea, or pelvic inflammatory disease (PID) increases the potential for tubal damage and raises suspicion of tubal infertility disease.1,5 

A thorough family history includes a discussion of reproductive outcomes and the existence of birth defects, mental retardation, early menopause, and/or genetic abnormalities.1 The American Congress of Obstetricians and Gynecologists recommends taking a detailed family history and, depending on a woman’s ethnicity, performing preconception carrier screening for cystic fibrosis, sickle cell disease, Tay-Sachs disease, thalassemia, familial dysautonomia, and Canavan disease.6 

The man

Male infertility may be influenced by lifestyle factors (e.g., obesity; use of certain medications, alcohol, or tobacco) or a genetic condition (e.g., cystic fibrosis) or it may be idiopathic. Evaluation begins with a thorough reproductive history to assess for coital frequency and timing, duration of infertility, results of any past evaluations, childhood illnesses (e.g., mumps), systemic illness (e.g., diabetes mellitus, hypertension), past genitourinary surgery (e.g., orchiectomy, hernia repair), sexual history (e.g., erectile dysfunction, history of sexually transmitted infections), and exposure to environmental toxins.7 The history entails a thorough review of systems, a complete family reproductive history, and a social history, including use of recreational drugs, steroids, tobacco, or alcohol (these substances can affect semen parameters).

Physical examination

The woman

The APN performs a targeted physical examination to explore causes of infertility. Weight and body mass index (BMI) are calculated. Ovulatory dysfunction may occur at any BMI level but is more common when it falls outside the healthy range (20-24 kg/m2).1  The thyroid is assessed for enlargement, presence of nodules, or tenderness. Signs of androgen excess (e.g., hirsutism, acne) are noted, as are characteristics of any breast/nipple discharge. Abdominal and bimanual exams are performed to assess for tenderness, organ enlargement, and masses. Pelvic tenderness in the posterior cul-de-sac or uterosacral ligaments may indicate endometriosis. The uterus is palpated for enlargement or immobility, which may indicate fibroids, uterine anomaly, endometriosis, or pelvic adhesions.8 A speculum exam is done to assess the cervix for the presence of abnormalities, secretions, or discharge, which may suggest a pelvic infection.

The man

In the absence of a history of trauma, surgery, genital abnormality, or sexual dysfunction, the physical exam of the man may be deferred pending a semen analysis. An abnormal history or semen analysis finding warrants a physical exam by a urologist or an REI specialist. If a physical exam by the APN is deemed appropriate in a given case, it consists of an inspection of the penis, noting the location of the urethral meatus and the presence of hypospadias; palpation of the testes; ascertainment of the presence and consistency of the vas deferens and the epididymis; and determination of the presence of a varicocele. The APN notes the presence of secondary sex characteristics such as stature, hair distribution, and breast tissue distribution. A digital rectal exam may be considered to evaluate the prostate.1 

Diagnostic testing

Ovulatory function

In order for a woman to conceive, several components are necessary: ovulation, patent Fallopian tubes, a suitable uterine environment, and motile sperm capable of fertilization. Ovulatory dysfunction accounts for up to 40% of female infertility cases and is identified in about 15% of couples.1  Ovulation may be assessed by a mid-luteal progesterone level, an ovulation predictor kit, basal body temperature (BBT) measurements, or mid-cycle ultrasound. In some cases, a menstrual history may be sufficient. If a woman does not have regular and predictable menstrual cycles occurring every 21-35 days, further evaluation is necessary.

A mid-luteal progesterone level is assessed 7 days before expected menses; for a woman with a regular 28-day cycle, progesterone is assessed on cycle day 21.8 For a woman with irregular cycles, this assessment may occur later in the menstrual cycle. A progesterone level greater than 3 ng/mL provides evidence of recent ovulation, although levels greater than 10 ng/mL better reflect good luteal function.9 If the progesterone level is less than 3 ng/mL, the level is rechecked 5-7 days later. If the level remains low, the woman is further evaluated for anovulation.

A woman may choose to use an ovulation predictor kit, also known as a urine luteinizing hormone (LH) kit, to track her ovulation. A woman begins using daily test strips several days before anticipated ovulation to identify the mid-cycle LH surge that precedes ovulation by about 36 hours. The test kit identifies peak fertility as the day of the surge and the following day. The kit is not reliable for all women, particularly those with premature ovarian failure or PCOS, because LH levels may already be elevated.

Although not widely recommended, another option for ovulation detection is the BBT method, an inexpensive way to look retrospectively at the ovulation time frame. An oral temperature is taken at the same time every morning before rising. About 2 days following ovulation, a woman’s temperature rises roughly 0.5° F. Charting this temperature shift can help a woman better identify her ovulation pattern and peak fertility in subsequent months. Of note, evaluating an increase in cervical mucus or using an ovulation predictor kit has been found to be more reliable than BBT in terms of attempting to achieve a pregnancy in the current cycle.10

Ovarian reserve

Oocytes decrease in quantity and quality as women age and are incapable of regenerating. The number of human oocytes peaks at 6-7 million at 20 weeks’ gestation; by the time a female reaches puberty, only 300,000-500,000 oocytes remain. During her lifetime, a woman will ovulate 400-500 eggs. To assess a woman’s fertility potential and determine a treatment plan, the APN must first assess ovarian reserve, which is done by measuring basal follicle-stimulating hormone (FSH), estradiol, and anti-Müllerian hormone (AMH) levels and performing ovarian imaging early in the follicular phase to evaluate the antral follicle count (AFC).

There is debate regarding the age at which to begin ovarian reserve testing. Current thinking is to recommend such testing for women older than 35 years who have not conceived after 6 months of regular unprotected intercourse.11 The APN may consider testing a woman at an earlier age if certain risk factors are present: anovulation, family history of early menopause, certain genetic conditions such as fragile X or Turner syndrome, history of endometriosis or pelvic infection, previous ovarian surgery, history of cancer treated by gonadotoxic therapy or pelvic radiation, and tobacco use.

Ovarian reserve testing is not infallible and it does not determine the end of a woman’s reproductive capability, nor does it predict the rate in which reproductive potential will diminish. The purpose is to assess the quality and quantity of the remaining oocytes to predict reproductive potential and, for the APN, the time to refer to a specialist. When results fall outside the normal range, the APN can encourage the patient to pursue more aggressive treatment options, which often include referral to an infertility specialist. Ovarian reserve can be assessed by measuring/doing the following:

Basal follicle-stimulating hormone/estradiol

Low estradiol levels early in each menstrual cycle trigger increased secretion of gonadotropin-releasing hormone, leading to increased release of FSH. Then, as the developing cohort of follicles produces estradiol and inhibin B, the increased FSH is suppressed by negative feedback. As a woman ages, a smaller cohort of follicles is available to produce estradiol and inhibin B, which increases secretion of FSH. The robust secretion of FSH stimulates rapid follicular growth and higher estradiol levels, resulting in a shorter follicular phase.11

Estradiol and FSH levels are measured on menstrual cycle days 2-4. FSH values greater than 10 mIU/ mL are associated with diminished ovarian reserve and poor response to ovarian stimulation. Because each menstrual cycle can vary, a single elevated FSH level does not predict an inability to conceive and, therefore, has limited reliability.12 During follicular development, estradiol is released from the developing follicles. In the early follicular phase (typically, cycle day 2-4), the estrogen level is usually less than 50 pg/mL. An elevated value (>60-80 pg/mL) may indicate oocyte depletion.13 For measurements to be meaningful, both FSH and estradiol levels are drawn on menstrual cycle days 2-4.

Clomiphene citrate challenge test

The CCCT may be considered for ovarian reserve testing, although it does not clearly improve FSH and estradiol test accuracy for predicting poor ovarian response or pregnancy after in vitro fertilization (IVF).14 The test requires measurement of cycle day 3 FSH and estradiol levels, followed by administration of clomiphene citrate 100 mg on cycle days 5-9. An FSH level is drawn again on cycle day 10; it should remain below 10 mIU/mL. If either the FSH or the estradiol level on day 3 or the FSH on day 10 is elevated, the patient likely has impaired ovarian function and a referral is warranted. Use of the CCCT has declined because newer tests such as AMH and AFC are simpler and have high predictive values.11

Serum anti-Müllerian hormone

Anti-Müllerian hormone is secreted by the granulosa cells of the pre-antral follicles and is reflective of the primordial oocyte pool.15 As women age and the number of oocytes decreases, the AMH level drops as well. The AMH level may be an earlier predictor of decreased ovarian reserve than FSH levels; it begins to decline early in the ovarian aging process, whereas elevated serum FSH levels are not found until cycles are already irregular.16 The advantage of determining the AMH level is that it remains constant throughout the menstrual cycle and may be drawn at any time.11 Evidence suggests that AMH levels may be diminished with oral contraceptive use and in women with obesity.17 By contrast, women with PCOS have been noted to have AMH levels 2-3 times higher than unaffected women. Overall, an AMH value of 1.0 mg/mL predicts an FSH value of 10.0 mIU/mL. Higher AMH levels suggest normal ovarian function, whereas lower levels have been associated with poor ovarian stimulation and poor pregnancy outcomes.18 Women whose levels fall outside the normal range should be referred to an REI specialist.

Antral follicle count

Ultrasound, although expensive, is another useful tool in evaluating ovarian reserve. AFC is the sum of the antral follicles in both ovaries early in the follicular phase (cycle days 1-4). Antral follicles have been defined as measuring 2-10 mm in diameter. A total of 3-6 antral follicles is considered low, and is associated with poor response in IVF. However, a low value is not predictive of a patient’s ability to conceive.19 No single test has 100% specificity and sensitivity; biochemical assays and imaging should be used in combination to most accurately evaluate ovarian reserve.

Tubal patency

Impaired tubal patency is another common cause of infertility. When tubal disease is suspected by patient history (e.g., chlamydia, gonorrhea, PID, previous ectopic pregnancy, tubal surgery), a hysterosalpingogram (HSG) is considered.8 An HSG can evaluate tubal patency and may have some therapeutic benefit. HSG is typically performed in the late follicular phase, or 2-5 days after the end of menstruation. An HSG can document tubal patency and uterine abnormalities, including filling defects (polyps and fibroids) and uterine malformations (e.g., septum, bicornuate uterus). If an abnormality is noted, a referral is warranted.

Semen analysis

For the male partner, a semen analysis is considered early in the evaluation. This analysis is the most accurate evaluation of male fertility and can be used as a cost-effective way to quickly exclude male factors as the cause of a couple’s infertility. If the semen analysis yields normal results, attention is then focused on the female partner.

Prior to semen collection, the male partner should have an abstinence window of 2-5 days (2-3 days is preferred).20 The analysis may be performed in a fertility center or a urology office where an andrology lab is available. The semen sample is collected in a sterile container provided by the lab. If the man chooses to collect the sample outside the lab, it must be kept warm and delivered within 1 hour of collecting. Normal results for a semen analysis include a volume of 1.5 mL or greater, more than 39 million sperm per ejaculate, total motility of 40%, progressive motility (linear movement) of 32%, and 4% normal forms. If the analysis yields abnormal findings, efforts are made to identify modifiable factors to improve the natural ability of the man’s sperm to fertilize an ovum. Because semen samples can fluctuate, the semen analysis is repeated in 4-6 weeks. If results remain abnormal on repeat evaluation, referral to an infertility specialist is advised.7 

Conclusion

A diagnosis of infertility is life altering for many couples, with lasting psychological impact. The cause of infertility is often multifactorial and complex, leading to frustration in both providers and patients. Because of the substantial emotional, financial, and physical burden to patients, providers must practice with a holistic and therapeutic approach. APNs are in an excellent position to provide this holistic care for their patients, addressing aspects of both physical and emotional well-being. Resources for patients are listed in the Box.

Much of fertility testing is cycle dependent and cannot be completed at a single visit. Therefore, a month or more may be spent completing diagnostic testing before treatment takes place. The APN must assess patient expectations and explain that the evaluation takes time. Once test results are received, the APN may decide to treat with ovulation induction medication (e.g., clomiphene citrate) and timed intercourse for several months or refer to an REI specialist. Because of the length and intimacy of the evaluation, patients may feel more comfortable working with an APN with whom they have already established a trusting relationship before referral to a specialist.

References

  1. Fritz MA, Speroff L. Clinical Gynecologic Endocrinology and Infertility. 8th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2011.
  2. Benyamini Y, Gozlan M, Kokia E. Variability in the difficulties experienced by women undergoing infertility treatments. Fertil Steril. 2005;83(2):275-283.
  3. Hull M, Glazener C, Kelly NJ, et al. Population study of causes, treatment, and outcome of infertility. BMJ. 1985;291:1693-1697.
  4. Devine KS. Caring for the infertile woman. MCN Am J Matern Child Nurs. 2003;28(2):100-105.
  5. Akande VA, Hunt LP, Cahill DJ, et al. A cohort study of the prediction of Chlamydia infection causing subfertility, the value of treatment independent management and prognosis for pregnancy in 1119 women following laparoscopy. Presented at: British Congress of Obstetrics and Gynaecology; 2011; Birmingham, UK.
  6. American Congress of Obstetricians and Gynecologists. Preconception Carrier Screening. August 2012.
  7. Practice Committee for the American Society for Reproductive Medicine. Diagnostic evaluation of the infertile male: a committee opinion. Fertil Steril. 2015;103(3):e18-e25.
  8. Practice Committee for the American Society for Reproductive Medicine. Diagnostic evaluation of the infertile female: a committee opinion. Fertil Steril. 2015;103(6):e44-e50.
  9. Quaas A, Dorkras A. Diagnosis and treatment of unexplained infertility. Rev Obstet Gynecol. 2008;1(2):69-76.
  10. Barron ML, Fehring RJ. Basal body temperature measurement: is it useful to couples seeking pregnancy? J Matern Child Nurs. 2005;30(5):290-296.
  11. Practice Committee of the American Society for Reproductive Medicine. Testing and interpreting measures of ovarian reserve: a committee opinion. Fertil Steril. 2015;103(3):e9-e17.
  12. Kwee J, Schats R, McDonnell J, et al. Intercycle variability of ovarian reserve tests: results of a randomized study. Hum Reprod. 2004;19(3):590-595.
  13. Cahill DJ, Wardle PG. Management of infertility. BMJ. 2002;325(7354):28-32.
  14. Hendriks DJ, Mol BW, Bancsi LF, et al. The clomiphene citrate challenge test for the prediction of poor ovarian response and nonpregnancy in patients undergoing in vitro fertilization: a systematic review. Fertil Steril 2006;86(4):807-818.
  15. Nelson SM. Biomarkers of ovarian response: current and future applications. Fertil Steril. 2013;99(4):963-969.
  16. de Vet A, Laven JS, de Jong FH, et al. Antimüllerian hormone serum levels: a putative marker for ovarian aging. Fertil Steril. 2002;77(2):357-362.
  17. Kallio S, Puurunen J, Ruokonen A, et al. Antimüllerian hormone levels decrease in women using combined contraception independently of administration route. Fertil Steril. 2013;99(5):1305-1310.
  18. Singer T, Barad DH, Weghofer A, Gleicher N. Correlation of antimüllerian hormone and baseline follicle stimulating hormone levels. Fertil Steril. 2009;91(6):2616-2619.
  19. Hendriks DJ. Mol BW, Bancsi LF, et al. Antral follicle count in the prediction of poor ovarian response and pregnancy after in vitro fertilization: a meta-analysis and comparison with basal follicle stimulating hormone level. Fertil Steril. 2005:83(2):291-301.
  20. Cooper TG, Noonan E, von Eckardstein S, et al. World Health Organization reference values for human semen characteristics: Hum Reprod Update. 2010;16(3):231-245.

Web resources (for the Box)

B. reproductivefacts.org/Booklet_Infertility_An_Overview/

C. reproductivefacts.org/FACTSHEET_Diagnostic_Testing_for_Female_Infertility/

D. acog.org/Patients/FAQs/Evaluating-Infertility

E. brighamandwomens.org/Departments_and_Services/obgyn/Services/infertility-reproductive-surgery/infertility-services/education-consent-forms.aspx

F. aafp.org/afp/2015/0301/p308-s1.html

G. cdc.gov/reproductivehealth/Infertility/

Researchers provide new insights into age-related female infertility

 

Researchers at the University of Montreal Hospital Research Center (CRCHUM) have discovered a possible new explanation for female infertility. Thanks to cutting-edge microscopy techniques, they observed for the first time a specific defect in the eggs of older mice. This defect may also be found in the eggs of older women. The choreography of cell division goes awry, and causes errors in the sharing of chromosomes. These unprecedented observations are being published today in Current Biology. Read more.

 

World’s first ‘menstrual cycle on a chip’ created to develop individualized treatments for women suffering from reproductive problems

The world’s first ‘menstrual cycle on a chip’ could change the future of research into gynecological problems, scientists claim.

The cube-shaped device, called Evatar, is a palm-sized recreation of the female reproductive tract.

It is made with human tissue cultured from stem cells and contains 3D models of ovaries, fallopian tubes, womb, cervix and vagina, as well as the liver.

The creation of the novel tool marks the first time scientists have been able to mimic the interplay between tissues and hormones.

Researchers plan to use the device to investigate conditions such as endometriosis, fibroids, reproductive organ cancers and infertility.

Dr Teresa Woodruff, a professor of obstetrics and gynecology at Northwestern University in Chicago, Illinois, where the device was created, said: ‘This is nothing short of a revolutionary technology.

‘If I had your stem cells and created a heart, liver, lung and an ovary, I could test 10 different drugs at 10 different doses on you and say, “Here’s the drug that will help your Alzheimer’s or Parkinson’s or diabetes”.

‘This will help us develop individualized treatments and see how females may metabolize drugs differently from males.’

The landmark study shows how the 28-day menstrual cycle can be mimicked using ‘organ on a chip’ technology.

The researchers used human stem cells to culture a combination of tissues of the ovary, fallopian tube, womb, cervix and liver in the device for four weeks.

Each ‘organ’ occupies its own brown cube and a special fluid pumps through each pea-sized organ to perform the function of blood.

The organs are able to communicate with each other via secreted substances, including hormones such as estrogen, to closely resemble how they all work together in the body.

The project is part of a larger effort by the US National Institutes of Health to create a ‘body on a chip’.

Read more at The Daily Mail

 

The role of anti-Müllerian hormone in diagnosing and managing PCOS

Because multiple subjective factors can cloud the diagnosis of polycystic ovary syndrome, anti-Müllerian hormone (AMH) level, an objective value, has been studied as a potential supplement to polycystic ovarian morphology in diagnosing and managing the syndrome. The author reviews recent evidence demonstrating the role of AMH in this regard.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder affecting females of reproductive age and the leading cause of anovulatory infertility.1 Lack of correct diagnosis and management of PCOS can lead to reproductive challenges (e.g., infertility, early miscarriage, gestational diabetes), metabolic disorders (e.g., type 2 diabetes mellitus), or cardiovascular disorders (e.g., hypertension, dyslipidemia).2 Advanced practice nurses (APNs) are tasked with correctly diagnosing and managing PCOS in order to prevent these associated morbidities, which can compromise quality of life.

According to the Rotterdam criteria for diagnosing PCOS, at least two of these three elements must be met: clinical and/or biochemical hyperandrogenism, ovulatory dysfunction, and polycystic ovarian (PCO) morphology.3 PCO morphology has been defined as the presence of more than 12 follicles measuring <10 mm and/or an increased ovarian volume (>10 mL) without a cyst or dominant follicle in either ovary.3 According to Lujan et al,the inclusion of ultrasonographic(USG) evidence of polycystic ovaries as a diagnostic marker has substantially broadened the phenotypic spectrum of PCOS, yet much debate surrounds the validity of these newly identified milder variants of the syndrome.

In light of such concerns, the use of anti-Müllerian hormone (AMH) level as a more reliable marker for PCO morphology than follicle size and number on USG has been investigated in recent studies. Results of these studies indicate a consistent relationship between AMH level and USG estimates of antral follicle count (AFC) and ovarian volume.5-7 Research has shown that serum AMH levels are significantly increased in women with PCOS versus those without PCOS.1,5,6 Although further research is needed, serum AMH measurement may prove to be a useful tool for APNs in diagnosing phenotypes of PCOS that satisfy the Rotterdam criteria.

Development of polycystic ovaries

To appreciate the role of AMH in PCOS, APNs must understand the two-cell, two-gonadotropin model of estrogen synthesis, as well as how disruption of this process may lead to development of polycystic ovaries.8 This model describes the working hormonal balance between the outer theca cell layer and the inner granulosa cell layer in the ovarian follicle; the former cell layer secretes androgens and the latter, estrogens. When luteinizing hormone (LH) stimulates cholesterol in the theca cells, androgen is released. Upon exposure to follicle- stimulating hormone (FSH), androgen is converted into estrogens in the granulosa cells.

When this two-cell, two-gonadotropin process is disrupted, a hormonal imbalance ensues, such that circulating LH concentrations exceed FSH concentrations. Ovarian androgen production increases, resulting in serum androgen excess. The increased androgen stimulates the growth of smaller antral follicles yet inhibits later follicular development and maturation.9 Such arrest in follicle growth can lead to PCO morphology. These smaller antral follicles cannot be released via ovulation or subsequent luteinization.

Function of AMH

Anti-Müllerian hormone has been identified as the hormone secreted by sertoli cells in the male testes during embryonic sexual differentiation.10,11 In females, AMH is a glycoprotein produced by the granulosa cells of antral follicles. The highest level of AMH secretion is evident in antral follicles ≥4 mm in diameter and continues to be expressed until the differentiation stage (8-9 mm), in which FSH selects a dominant follicle for future ovulation.12 Evidence suggests that AMH inhibits follicular growth by inhibiting estrogen secretion in the antral follicles prior to FSH selection. As a result, estrogen and AMH have an inverse relationship; AMH exerts a regulatory function by ensuring that not all primordial follicles are released at once.13

Levels of AMH fluctuate only minimally throughout the menstrual cycle, and not to the same extent as FSH and other pituitary and ovarian hormone levels. AMH levels are noted to be lower in women during pregnancy. These levels decline steadily after age 25 and are undetectable after menopause.14 Information on whether AMH levels are affected by the use of hormonal contraception is conflicting.15,16

Current uses of AMH measurement

Because AMH is secreted by antral follicles prior to the differentiation stage, it is most often used as a clinical biomarker for ovarian reserve in infertility diagnosis and management and in detection of premature ovarian aging.17,18 AMH is an excellent predictor of ovarian responsiveness in ovulation induction and in vitro fertilization, as well as a useful tool to help predict ovarian hyper-stimulation, oocyte yield, and ovarian function pathology in an infertility setting.13,19-21 In addition, AMH may be useful in assessing the need for fertility-preservation strategies and detecting post-chemotherapy or surgical damage to the ovarian reserve.13,22

Use of AMH measurement in diagnosing PCOS

A thorough history, physical examination, and select laboratory tests are important elements in determining the presence of androgen excess and ovulatory dysfunction— two of the three Rotterdam criteria used for PCOS diagnosis.As described earlier, polycystic ovaries, the third criterion, are identified via USG by the presence of more than 12 antral follicles measuring <10 mm and/or an increased ovarian volume (>10 mL) without a cyst or dominant follicle in either ovary. However, USG has potential shortcomings, including sensitivity of the machine, less-than-perfect operator technique, and subjective interpretation of the findings. In addition, transvaginal USG imaging may be inappropriate or less accurate in certain patient populations (e.g., obese persons or those who have never been sexually active).3,4

Determination of a patient’s AMH level, an objective laboratory value, may help minimize the subjectivity of the USG findings. In several studies, a serum AMH level >18 pmol/L, when compared with USG, provided better sensitivity and specificity for PCO morphology in women who met Rotterdam criteria for PCOS.5,23,24 Other studies have been performed to determine the optimal cutoff for the AMH value:

• A meta-analysis of data extracted up until January 2013 showed that an AMH value of 33.6 pmol/L was 82.8% sensitive and 79.4% specific in diagnosing PCOS in symptomatic women.25

• In 2013, a study of 60 infertile women with PCOS showed that an AMH value of 23.8 pmol/L was 98% sensitive and 93% specific in diagnosing PCOS.26

• Another 2013 study, conducted on 59 infertile women, 37 of whom had characteristics of PCOS, showed that an AMH level of 33 pmol/L was 95% sensitive and 95% specific in diagnosing PCOS.1

• In a study conducted in 2011 on 240 patients, an AMH value of 35.7 pmol/L was 92% sensitive and 97% specific in identifying PCO morphology.5

These findings notwithstanding, a standard AMH level for diagnosing PCOS has yet to be established. Furthermore, several limitations preclude AMH from becoming widely utilized for PCOS diagnosis. First, lack of a universally accepted method and assay to measure AMH prevents it from becoming an established diagnostic tool for PCOS.27 Second, because AMH declines with advancing age, the threshold for PCOS diagnosis may need to be modified through the life span.28 Third, research involving the use of AMH level to diagnose PCOS in adolescents is limited.27, 29, 30 Finally, the 2013 Endocrine Society guidelines do not include a recommendation for using AMH measurement as a routine diagnostic tool for PCOS.3

Although AMH level and oligoanovulation are correlated, AMH has not been proven to be an acceptable indicator of ovulatory dysfunction or hyper androgenism.23 Hence, AMH level, if used, should be combined with other laboratory or clinical measures of hyperandrogenism and/or ovulatory dysfunction to maximize its diagnostic sensitivity and specificity. Furthermore, the role of AMH is unclear in diagnosing subtypes of PCOS, especially those that do not present with classic symptoms. Studies have suggested that ovulatory PCOS phenotypes, compared with anovulatory types, are associated with differing levels of serum AMH.31

Use of AMH measurement in gauging response to PCOS treatment

The goal of PCOS treatment is managing symptoms and minimizing co-morbidities. Proper management can reduce the risk for certain gynecologic cancers and infertility. Management should be both individualized and holistic and may include weight reduction through lifestyle modification and use of hormonal contraceptives, metformin, and gonadotropin/estrogen modulators. Current methods of monitoring the effectiveness of these management modalities include patient-reported symptom improvement and menstrual regulation, physical examination for reduction in signs of hyperandrogenism, measurement of insulin and glucose levels, and achievement of successful pregnancy outcome.

Many recent studies have been conducted to assess the relationship between various PCOS management modalities and patients’ AMH levels; the Table (pp 3839) lists a representative sample of such studies.15, 16, 32-37 Additional research is needed to demonstrate the utility of these AMH measurements, especially as compared with current methods (e.g., clinical signs, patient-reported symptoms, other lab test findings) in making decisions about and evaluating the effectiveness of treatment.

Discussion

Based on what is known at this time, use of the AMH level is not recommended as a replacement for any component of the Rotterdam criteria in terms of diagnosing PCOS or as an assessment tool for monitoring the success of existing management modalities. However, AMH may be a useful supplemental tool for APNs because it is an objective and more reliable marker for diagnosing PCO morphology. Indeed, AMH can help providers who are not trained in pelvic or transvaginal USG in diagnosing PCOS. Although more research is needed in this area, AMH may be another component of PCOS diagnosis and management in the future.

Conclusion

Although the Rotterdam criteria are the gold standard for diagnosing PCOS, concern regarding the subjective nature of polycystic morphology on USG has been voiced over the years. An AMH value >35 pmol/L may have the highest sensitivity and specificity in terms of indicating polycystic ovaries. However, data supporting the use of AMH levels to make treatment choices or to monitor the effectiveness of such treatments in females with PCOS are inconclusive. At the very least, findings from studies assessing changes in AMH levels related to specific treatment modalities may offer more insight into the pathophysiology of this complex endocrine disorder.

Tiffany A. Tseng is a women’s health nurse practitioner at HRC Fertility in Pasadena, California. The author states that she does not have a financial interest in or other relationship with any commercial product named in this article.

References

1. Casadei L, Madrigale A, Puca F, et al. The role of serum anti-Müllerian hormone (AMH) in the hormonal diagnosis of polycystic ovary syndrome. Gynecol Endocrinol. 2013;29(6):545-550.

2. Jayasena CN, Franks S. The management of patients with polycystic ovary syndrome. Nat Rev Endocrinol. 2014;10(10):624-636.

3. Legro RS, Arslanian SA, Ehrmann DA, et al. Diagnosis and treatment of polycystic ovary syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2013;98(12):4565-4592.

4. Lujan ME, Chizen DR, Pierson RA. Diagnostic criteria for polycystic ovary syndrome: pitfalls and controversies. J Obstet Gynaecol Can2008;30(8):671-679.

5. Dewailly D, Gronier H, Poncelet E, et al. Diagnosis of polycystic ovary syndrome (PCOS): revisiting the threshold values of follicle count on ultrasound and of the serum AMH level for the definition of polycystic ovaries. Hum Reprod. 2011;26(11):3123-3129.

6. Pigny P, Merlen E, Robert Y, et al. Elevated serum level of anti-mullerian hormone in patients with polycystic ovary syndrome: relationship to the ovarian follicle excess and to the follicular arrest. J Clin Endocrinol Metab. 2003;88(12):5957-5962.

7. Piltonen T, Morin-Papunen L, Koivunen R, et al. Serum anti-Müllerian hormone levels remain high until late reproductive age and decrease during metformin therapy in women with polycystic ovary syndrome. Hum Reprod. 2005;20(7):1820-1826.

8. Hillier SG, Whitelaw PF, Smyth CD. Follicular oestrogen synthesis: the ‘two-cell, two-gonadotrophin’ model revisited. Mol Cell Endocrinol. 1994; 100(1-2):51-54.

9. Vendola KA, Zhou J, Adesanya OO, et al. Androgens stimulate early stages of follicular growth in the primate ovary. J Clin Invest. 1998; 101(12):2622-2629.

10. La Marca A, Stabile G, Artenisio AC, Volpe A. Serum anti-Mullerian hormone throughout the human menstrual cycle. Hum Reprod. 2006; 21(12):3103-3107.

11. Vigier B, Picard JY, Tran D, et al. Production of anti-Müllerian hormone: another homology between Sertoli and granulosa cells. Endocrinology. 1984;114(4):1315-1320.

12. Weenen C, Laven JS, Von Bergh AR, et al. Anti-Müllerian hormone expression pattern in the human ovary: potential implications for initial and cyclic follicle recruitment. Mol Hum Reprod. 2004;10(2):77-83.

13. Dewailly D, Andersen CY, Balen A, et al. The physiology and clinical utility of anti-Müllerian hormone in women. Hum Reprod Update. 2014;20(3):370-385.

14. Leader B, Baker V. Maximizing the clinical utility of antimullerian hormone testing in women’s health. Curr Opin Obstet Gynecol. 2014;26(4):226-236.

15. Somunkiran A, Tavuz T, Yucel O, Ozdemir I. Anti-Müllerian hormone levels during hormonal contraception in women with polycystic ovary syndrome. Eur J Obstet Gynecol Reprod Biol. 2007;134(2):196-201.

16. Panidis D, Georgopoulos NA, Piouka A, et al. The impact of oral contraceptives and metformin on anti-Müllerian hormone serum levels in women with polycystic ovary syndrome and biochemical hyperandrogenemia. Gynecol Endocrinol. 2011; 27(8):587-592.

17. van Rooij IA, Broekmans FJ, Scheffer GJ, et al. Serum antimullerian hormone levels best reflect the reproductive decline with age in normal women with proven fertility: a longitudinal study. Fertil Steril. 2005;83(4):979-987.

18. Lie Fong S, Schipper I, Valkenburg O, et al. The role of anti-Müllerian hormone in the classification of anovulatory infertility. Eur J Obstet Gynecol Reprod Biol. 2015;186:75-79.

19. van Rooij IA, Broekmans FJ, te Velde ER, et al. Serum anti-Müllerian hormone levels: a novel measure of ovarian reserve. Hum Reprod. 2002;17(12):3065-3071.

20. Amer SA, Mahran A, Abdelmaged A, et al. The influence of circulating anti-Müllerian hormone on ovarian responsiveness to ovulation induction with gonadotrophins in women with polycystic ovarian syndrome: a pilot study. Reprod Biol Endocrinol. 2013;11:115.

21. Dąbkowska-Huć A, Lemm M, Sikora J, et al. Anti-Müllerian hormone dynamics during ovulation induction treatment with recombinant follicle-stimulating hormone in women with polycystic ovary syndrome. Endokrynol Pol. 2013; 64(3):203-207.

22. Dunlop CE, Anderson RA. Uses of anti-Müllerian hormone (AMH) measurement before and after cancer treatment in women. Maturitas. 2015;80(3):245-250.

23. Sahmay S, Aydin Y, Oncul M, Senturk LM. Diagnosis of polycystic ovary syndrome: AMH in combination with clinical symptoms. J Assist Reprod Genet. 2014;31(2):213-220.

24. Lauritsen MP, Bentzen JG, Pinborg A, et al. The prevalence of polycystic ovary syndrome in a normal population according to the Rotterdam criteria versus revised criteria including anti-Mullerian hormone. Hum Reprod. 2014;29(4):791-801.

25. Iliodromiti S, Kelsey TW, Anderson RA, Nelson SM. Can anti-Mullerian hormone predict the diagnosis of polycystic ovary syndrome? A systematic review and meta-analysis of extracted data. J Clin Endocrinol Metab. 2013;98(8):3332-3340.

26. Saikumar P, Selvi VK, Prabhu K, et al. Anti mullerian hormone: a potential marker for recruited non growing follicle of ovarian pool in women with polycystic ovarian syndrome. Clin Diagn Res. 2013;7(9):1866-1869.

27. Dewailly D, Lujan ME, Carmina E, et al. Definition and significance of polycystic ovarian morphology: a task force report from the Androgen Excess and Polycystic Ovary Syndrome Society. Hum Reprod Update. 2014;20(3):334-352.

28. Zec I, Tislaric-Medenjak D, Megla ZB, Kucak I. Anti-Müllerian hormone: a unique biochemical marker of gonadal development and fertility in humans. Biochem Med (Zagreb). 2011;21(3):219-230.

29. Cengiz H, Ekin M, Dagdeviren H, et al. Comparison of serum anti-Müllerian hormone levels in normal weight and overweight-obese adolescent patients with polycystic ovary syndrome. Eur J Obstet Gynecol Reprod Biol. 2014;180:46-50.

30. Pinola P, Morin-Papunen LC, Bloigu A, et al. Anti-Müllerian hormone: correlation with testosterone and oligo- or amenorrhoea in female adolescence in a population-based cohort study. Hum Reprod. 2014; 29(10):2317-2325.

31. Alebić MS, Stojanović N, Duhamel A, Dewailly D. The phenotypic diversity in per-follicle anti-Müllerian hormone production in polycystic ovary syndrome. Hum Reprod. 2015;30(8):1927-1933.

32. Neagu M, Cristescu C. Anti-Müllerian hormone—a prognostic marker for metformin therapy efficiency in the treatment of women with infertility and polycystic ovary syndrome. Med Life. 2012;5(4):462-464.

33. Tomova A, Deepinder F, Robeva R, et al. Anti-Müllerian hormone in women with polycystic ovary syndrome before and after therapy with metformin. Horm Metab Res. 2011;43(10):723-727.

34. Kriseman M, Mills C, Kovanci E, et al. Antimullerian hormone levels are inversely associated with body mass index (BMI) in women with polycystic ovary syndrome. J Assist Reprod Genet. 2015;32(9):1313-1316.

35. Piouka A, Farmakiotis D, Katsikis I, et al. Anti-Mullerian hormone levels reflect severity of PCOS but are negatively influenced by obesity: relationship with increased luteinizing hormone levels. Am J Physiol Endocrinol Metab. 2009;296(2):E238-E243.

36. Thomson RL, Buckley JD, Moran LJ, et al. The effect of weight loss on anti-Müllerian hormone levels in overweight and obese women with polycystic ovary syndrome and reproductive impairment. Hum Reprod. 2009;24(8):1976-1981.

37. Mahran A, Abdelmaged A, El-Adawy AR, et al. The predictive value of circulating anti-Müllerian hormone in women with polycystic ovarian syndrome receiving clomiphene citrate: a prospective observational study. J Clin Endocrinol Metab.

Fertility preservation for young cervical cancer survivors

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By Aimee Chism Holland, DNP, WHNP-BC, FNP-BC, RD; Deborah Kirk Walker, DNP, FNP-BC, NP-C, AOCN; Sigrid Ladores, PhD, PNP; and Karen Meneses, PhD, RN, FAAN

About 68% of invasive cervical cancer cases diagnosed in the United States involve women of childbearing age. Current treatment options for young patients with cervical cancer may cause hormonal and/or structural modifications to the reproductive system that could compromise pregnancy potential. Although clinical guidelines are available to help preserve fertility in these patients, gaps in practice remain, suggesting that the fertility-sparing needs of cervical cancer survivors are not routinely met. The authors provide nurse practitioners with current evidence about fertility-sparing treatments and with counseling considerations for young cervical cancer survivors.

Key words: cervical cancer survivor, fertility-sparing treatment, pregnancy, infertility, conization, trachelectomy

Cervical cancer was once the leading cause of gynecologic cancer in the United States. Following introduction of the use of the Pap smear in the 1940s, the incidence of cervical cancer has declined dramatically.<sup.1 Because use of the Pap smear is so effective and so widespread, the diagnosis of cervical cancer, when it is found, is usually made when a woman is younger (and still fertile) and when the disease is at an earlier stage (and therefore more easily treated).

In 2014, the American Cancer Society projected that 12,360 new cases of cervical cancer would be diagnosed in the U.S.2 Approximately 68% of cervical cancer cases are diagnosed in women of childbearing age.3,4 For young women, a diagnosis of cervical cancer once meant a hysterectomy and loss of the ability to bear a child. Today, fertility-sparing treatment (FST) options exist for women with early-stage cervical cancer, as well as more advanced fertility preservation and assisted reproductive technology (ART) approaches for those who are not candidates for FST.5

Young cervical cancer survivors may not know about FST options, and thus fear that treatment for cancer may compromise their future ability to conceive.6 Survivors also tend to be anxious about pregnancy outcomes after completing cancer treatment.7,8 Evidence suggests that they will want to discuss future fertility options with their healthcare provider (HCP).9 The American Society of Clinical Oncology (ASCO) and the American Society of Reproductive Medicine have published guidelines recommending that, prior to treatment, HCPs educate patients diagnosed with cervical cancer about the treatment’s potential effects on their fertility, along with fertility-preservation options.10,11 However, many HCPs are uninformed themselves and do not routinely offer fertility-preservation counseling prior to cancer treatment.12,13 The purpose of this article is to provide HCPs with current evidence about FST for cervical cancer and with counseling recommendations for young cervical cancer survivors.

Diagnosis and staging of cervical cancer

A Pap smear is used to screen for cervical cancer but not to make the diagnosis. A histology report from a cervical biopsy confirms the diagnosis and type of cervical cancer. After diagnosis, a workup is done to determine disease stage (Table 1).5

A clinical staging system is used for cervical cancer (rather than the surgical criteria used for most other gynecologic cancers). Two different staging systems are available. The International Federation of Gynecology and Obstetricsn (FIGO) staging system is based on a physical examination, diagnostic procedures, and imaging studies. Stages IA1, IA2, and IB1 are con­sidered early stages of cervical cancer.5,14 In stages IA1 and IA2, cancer is confined to the cervix and diagnosed only microscopically. Stage IB1 describes cancer confined to the cervix with a clinically visible tumor ?4 cm, stromal invasion that further describe tissue involvement (Table 2).5,15,16

Fertility-sparing cervical cancer treatment

The National Comprehensive Cancer Network (NCCN) recommends cone biopsy or radical trachelectomy for treatment for up to cervical cancer stage IB1 in women who want to preserve their fertility.5 This recommendation has not always existed; trends in surgical management of low-risk early-stage lesions have changed over the past 20 years. Hysterectomy was the only cure for cervical cancer stage IB1 until Dargent developed the fertility-sparing radical vaginal trachelectomy (RVT) technique in 1994.,sup>17 Prior to RVT, women with stage IA1 or IA2 lesions were the only cervical cancer survivors able to preserve their fertility.15

Cone biopsy

This term refers to a wedge-shaped excision of cervical tissue for both diagnostic evaluation and removal of abnormal tissue. Two methods of obtaining a cone biopsy with fertility sparing in mind are cold knife conization (CKC) and the loop electrosurgical excision procedure (LEEP). Cone biopsy is used to treat small lesions when there is no risk of dissecting across a gross neoplasm.5 Given that adequate margins and correct orientation are obtained, CKC and LEEP are appropriate measures for cervical cancer stage IA1 without lymphovascular space invasion.5 Negligible risks exist for cervical cancer stage IA1 recurrence following this treatment.5

Potential risks regarding future fertility following a cone biopsy include cervical stenosis and preterm delivery.18,19 Cervical stenosis occurs in 2%-3% of patients after CKC and in 3%-4% post-LEEP.19 Because of scar tissue formation that can occur after a cone biopsy, fertility may be compromised until the tissue is removed from the cervix. Long and Leeman19 reported that a history of a cone biopsy increased the odds of a preterm delivery by 2.19 (95% confidence interval, 1.93-2.49); risk correlated with the depth of the transformation zone removed. In this study, a greater risk existed for preterm delivery when a cone biopsy sample was thicker than 1.2 cm and larger than 6 cm2. However, Bevis and Biggio18 reported that evidence for the effects of conization procedures on fertility was conflicting because of the different types of procedures performed and the varying quality of control groups.

Fanfani et al20 performed a multicenter retrospective analysis of reproductive outcomes in 23 early-stage cervical cancer survivors who had undergone coni­zation treatment. Among 10 patients who tried to conceive, 6 achieved a spontaneous pregnancy and 4 received conception assistance via in vitro fertilization and embryo transfer (1 of whom achieved a pregnancy). In total, 70% of the young survivors achieved a pregnancy after cone biopsy treatment.

Trachelectomy

This fertility-sparing surgical procedure is performed to eradicate cervical cancer. In an RVT, the uterine corpus, ovaries, and Fallopian tubes are preserved, but the cervix, upper portion of the vagina, and the supporting ligaments are removed. A cerclage is placed at the location of the isthmus to close the opening of the uterus.7 RVT is an option for patients with stage IA2 or IB1 lesions 2 cm and ?4 cm, and provides a larger resection of the parametria.5

Most women who undergo RVT are able to conceive spontaneously, but a small number will require conception assistance.21 The 5-year cumulative pregnancy rate for women trying to conceive post-RVT is 52.8%; the cervical cancer recurrence rate after the procedure continues to be low.7 Potential risks of either trachelectomy procedure with regard to future fertility include miscarriage, preterm delivery, anovulation, and isthmic stenosis.7,21

Koh et al5 reported that, worldwide, more than 300 pregnancies have been confirmed following a trachelectomy for cervical cancer. Risk for second trimester miscarriage following a trachelectomy is 10%. However, 72% of women have carried a pregnancy to term. Park et al22 conducted a retrospective chart review of 55 young early-stage cervical cancer survivors who underwent laparoscopic abdominal trachelectomy. Ten of 18 patients attempting a pregnancy conceived; 6 of the 10 experienced preterm delivery. Overall, 55.6% of the survivors achieved a pregnancy, with 60% delivering preterm.

Fertility preservation procedures

Most women with cervical cancer at stage IB2 or greater are not candidates for FST. Radiation therapy is most often used for patients with higher stage IB disease, often called bulky disease. Radiation therapy is also used following a primary radical hysterectomy or in conjunction with chemotherapy in advanced disease. Radiation that includes the ovaries can damage oocyte quality and sex hormone production. Chemotherapy is not used in patients with milder forms of cervical cancer who are considering FST options.

Women planning to undergo radiation still have fertility preservation options, including the ART procedures of oocyte or embryo cryopreservation prior to cancer treatment.23 Cryopreservation of unfertilized oocytes, as opposed to embryos, may be considered for patients who do not have a male partner, do not wish to use donor sperm, or have religious or ethical reasons for avoiding embryo freezing. Because oocytes are highly sensitive to radiation injury, a procedure called ooph­oropexy (ovarian transposition) may be used. With ooph­oropexy, ovaries are sutured to the posterior uterus to protect them during pelvic radiation.

Before or after cancer treatment, survivors may benefit from ovarian stimulation medications that help promote follicular development. However, guidelines from both the American Congress of Obstetricians and Gynecologists and ASCO indicate insufficient evidence regarding the effectiveness of gonadotropin-releasing hormone analogs to suppress and protect ovarian function during cytotoxic treatment.24

Counseling before treatment

These counseling recommendations concerning fertility preservation were issued by ASCO: (1) Assume that patients with cancer want to discuss fertility preservation; address the possibility of infertility before cancer treatment starts and work with an interdisciplinary team to formulate a plan and make appropriate referrals; (2) Present oocyte and embryo cryopreservation as established fertility preservation methods; (3) Discuss the option of ooph­oropexy when pelvic radiation will be performed; (4) Inform patients of their individual risk for infertility, based on disease stage and treatment, as high, medium, low, or nonexistent; and (5) Inform patients about the use of conservative gynecologic surgery and radiation options.11

Several organizations and advocacy groups are available for young cervical cancer survivors with fertility concerns both before and after treatment (Table 3). ASCO created a video that can educate young patients about fertility preservation options and support networks.

Counseling after treatment

A woman who has undergone FST for cervical cancer faces many challenges. She may experience distress, depression, anxiety, and/or fear, and, depending on her own innate coping ability and her support system, may require psychological assessment and referral. HCPs can evaluate patients for these psychological reactions with tools such as the Functional Assessment of Cancer Therapy-Cervical Cancer Subscale and the NCCN Distress Thermometer for Patients, and make referrals as needed.

Cervical cancer and its treatment can adversely affect sexual health, causing problems such as decreased libido, fatigue, vaginal stenosis, and dyspareunia (Table 4).25-27 Many women hesitate to mention sexual problems on their own, so HCPs need to inquire about them and make referrals to a counselor who specializes in sex therapy, a gynecologist, or a physical therapist who specializes in pelvic pain and sexual dysfunction.* Many of the physical and psychological complaints involving sexual function resolve with-in the first year after treatment but may last up to 2 years or long­er.25,26

With regard to dyspareunia in particular, asking patients whether they experience it is the first step in helping resolve the problem. Nonpharmacologic and pharmacologic treatments, along with alternate positioning during intercourse, can be offered. HCPs can recommend over-the-counter vaginal moisturizers and lubricants to assist with vaginal dryness, dyspareunia, and sexual stimulation. In addition, prescription-strength topical lidocaine, estradiol vaginal cream, or ospemifene may help.

Undergoing ART can be arduous for women who endure painful and costly treatments. As of 2008, only 15 states have mandates that require health insurance carriers to provide full or partial coverage of costs related to infertility treatments.28 Most couples or individual women pay for infertility treatments out of pocket. Each ART cycle requires a woman to invest her body, mind, time, and money to realize her dream of motherhood, and she may be placing herself at risk for developing anxiety and depression.29-31

Even if a woman succeeds in achieving pregnancy through ART, the process is often fraught with anxiety.32,33 Young female cancer survivors have reported that they have a hopeful yet worried outlook on fertility and motherhood.34 This worry is especially true for cervical cancer survivors who have had trachelectomy surgery, as reported by Lloyd et al,7 wherein several participants described how they were fearful during pregnancy and attempted to be “model” pregnant women who followed every recommendation to reduce risks associated with preterm labor and miscarriage.

Consultations with specialists in reproductive endocrinology and/or high-risk obstetrics may be helpful. Pregnancy loss after infertility treatment can be devastating to these women, who view their pregnancy as “precious” and a “miracle,” and can have a profound impact on their psychological well-being.7 HCPs should prompt­ly refer these cancer survivors to mental health counselors who specialize in infertility and pregnancy loss.

Conclusion

Sixty-eight percent of cervical cancer cases diagnosed in the U.S. involve reproductive-aged women.2 Many of these women desire future pregnancies and want to discuss treatment options and future fertility. An interdisciplinary care approach for these women is necessary, with an emphasis placed on both successful cancer treatment and fertility preservation. FST options are available for women with early-stage cancer up to IB1. Fertility preservation procedures are available for women who are not candidates for FST. National guidelines are available regarding treatment and counseling for reproductive-age women with cervical cancer. The role of HCPs such as women’s health nurse practitioners is to educate young cervical cancer patients and survivors about their treatment options, manage pre- and post-treatment care, and provide referrals to specialists as needed.

Aimee Chism Holland is Assistant Professor, Coordinator of the Dual Adult/Gerontology Primary Care and Women’s Health Nurse Practitioner Specialty Track; Deborah Kirk Walker is Assistant Professor; Sigrid Ladores is Assistant Professor; and Karen Meneses is Professor and Associate Dean for Research, all at the School of Nursing at The University of Alabama at Birmingham. The authors state that they do not have a financial interest in or other relationship with any commercial product named in this article.

References

1. American Cancer Society. What is cervical cancer? October 2014. www.cancer.org/cancer/cervicalcancer/detailedguide/cervical-cancer-what-is-cervical-cancer

2. American Cancer Society. What are the key statistics about cervical cancer? October 2014. www.cancer.org/
cancer/cervicalcancer/detailedguide/cervical-cancer-key-statistics

3. Centers for Disease Control and Prevention. Gyencological Cancers: What are the Risk Factors? March 2014. www.cdc.gov/cancer/cervical/basic_info/risk_factors.htm

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5. Koh WJ, Greer BE, Abu-Rustum NR, et al. Cervical cancer. J Natl Compr Canc Netw. 2013;11(3):320-343.

6. Kola S, Walsh JC. Patients’ psychological reactions to colposcopy and LLETZ treatment for cervical intraepithelial neoplasia. Eur J Obstet Gynecol Reprod Biol. 2009;146(1):96-99.

7. Lloyd PA, Briggs EV, Kane N, et al. Women’s experiences after a radical vaginal trachelectomy for early stage cervical cancer. A descriptive phenomenological study. Eur J Oncol Nurs. 2014;18(4):362-371.

8. Wenzel L, Dogan-Ates A, Habbal R, et al. Defining and measuring reproductive concerns of female cancer survivors. J Natl Cancer Inst Monogr. 2005(34):94-98.

9. Maltaris T, Seufert R, Fischl F, et al. The effect of cancer treatment on female fertility and strategies for preserving fertility. Eur J Obstet Gynecol Reprod Biol. 2007;130(2):148-155.

10. Ethics Committee of American Society for Reproductive Medicine. Fertility preservation and reproduction in patients facing gonadotoxic therapies: a committee opinion. Fertil Steril. 2013;100(5):1224-1231.

11. Loren AW, Mangu PB, Beck LN, et al. Fertility preservation for patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2013;31(19):2500-2510.

12. Gorman JR, Usita PM, Madlensky L, Pierce JP. Young breast cancer survivors: their perspectives on treatment decisions and fertility concerns. Cancer Nurs. 2011;34(1):32-40.

13. Kim SS, Klemp J, Fabian C. Breast cancer and fertility preservation. Fertil Steril. 2011;95(5):1535-1543.

14. Lea JS, Lin KY. Cervical cancer. Obstet Gyncol Clin North Am. 2012;39(2):233-253.

15. American Joint Committee on Cancer. What is Cancer Staging? 2014. https://cancerstaging.org/references-tools/Pages/What-is-Cancer-Staging.aspx

16. Pecorelli S. Revised FIGO staging for carcinoma of the vulva, cervix, and endometrium. Int J Gynaecol Obstet. 2009;105(2):103-104.

17. Dargent D, Mathevet P. Schauta’s vaginal hysterectomy combined with laparoscopic lymphadenectomy. Baillieres Best Pract Res Clin Obstet Gynaecol. 1995;9(4):691-705.

18. Bevis KS, Biggio JR. Cervical conization and the risk of preterm delivery. Am J Obstet Gynecol. 2011;
205(1):19-27.

19. Long S, Leeman L. Treatment options for high-grade squamous intraepithelial lesions. Obstet Gynecol Clin North Am. 2013;40(2):291-316.

20. Fanfani F, Landoni F, Gagliardi ML, et al. Sexual and reproductive outcomes in early stage cervical cancer patients after excisional cone as a fertility-sparing surgery: an Italian experience. J Reprod Infertil. 2014; 15(1):29-34.

21. Wong I, Justin W, Gangooly S, et al. Assisted conception following radical trachelectomy. Hum Reprod. 2009;
24(4):876-879.

22. Park JY, Kim DY, Suh DS, et al. Reproductive outcomes after laparoscopic radical trachelectomy for early-stage cervical cancer. J Gynecol Oncol. 2014;25(1):9-13.

23. Wang ET, Pisarska MD. Preserving fertility in women facing cancer. Contemporary OB/GYN. 2013;58(12):22-32.

24. American Congress of Obstetricians and Gynecologists. Committee opinion no. 607: gynecologic concerns in children and adolescents with cancer. Obstet Gynecol. 2014; 124(2 pt 1):403-408.

25. Carter J, Sonoda Y, Baser RE, et al. A 2-year prospective study assessing the emotional, sexual, and quality of life concerns of women undergoing radical trachelectomy versus radical hysterectomy for treatment of early-stage cervical cancer. Gynecol Oncol. 2010;119(2):358-365.

26. Froeding LP, Ottosen C, Rung-Hansen H, et al. Sexual functioning and vaginal changes after radical vaginal trachelectomy in early stage cervical cancer patients: a longitudinal study. J Sex Med. 2014;11(2):595-604.

27. Miller M. Sexual Dysfunction in Women. March 2014. www.clinicalkey.com

28. Henne MB, Bundorf MK. Insurance mandates and trends in infertility treatments. Fertil Steril. 2008;89(1): 66-73.

29. Gonzalez LO. Infertility as a transformational process: a framework for psychotherapeutic support of infertile women. Issues Ment Halth Nurs. 2000;21(6):619-633.

30. Sandelowski M. A theory of the transition to parenthood of infertile couples. Res Nurs Health. 1995;18(2): 123-132.

31. Su TJ, Chen YC. Transforming hope: the lived experience of infertile women who terminated treatment after in vitro fertilization failure. J Nurs Res. 2006;14(1):46-54.

32. Hammarberg K, Fisher JR, Wynter KH. Psychological and social aspects of pregnancy, childbirth and early parenting after assisted conception: a systematic review. Hum Reprod Update. 2008;14(5):395-414.

33. Ladores S. The early postpartum experience of previously infertile mothers. Podium presentation at: 25th International Research Congress, Sigma Theta Tau International: Engaging Colleagues – Improving Global Health Outcomes; July 2014; Hong Kong.

34. Gorman JR, Bailey S, Pierce JP, Su HI. How do you feel about fertility and parenthood? The voices of young female cancer survivors. J Cancer Surviv. 2012;6(2):200-209.

*Editor’s Note: In the current issue of Women’s Healthcare: A Clinical Journal for NPs, Tammy M. DeBevoise, PT, DPT; Angela F. Dobinsky, PT, DPT; Caitlin B. McCurdy-Robinson, PT, DPT; Christina M. McGee, PT, DPT, ATC, LAT; Cody E. McNeely, PT, DPT; Sara K. Sauder, PT, DPT; and Kimberlee D. Sullivan, PT, DPT, WCS, BCB-PMD present a feature-length article on pelvic floor physical therapy.