Continuing Education Activity

As modern women push the initial childbearing age back, age-related fertility decline is increasing among our population. This activity outlines and reviews the key elements of the pathophysiology, the course, and the key evaluation steps for age-related fertility decline. This inevitable process happens to all women as they age. As clinicians, it is critical to recognize important signs to diagnose this phenomenon correctly through history, physical exams, and laboratory exams. It is, however, even more, vital to have a strong working knowledge of the general trend of age-related fertility decline so that appropriate counseling can be undertaken with patients before they reach the point of irreversible fertility loss. This article also highlights the role of the interprofessional team in diagnosing and addressing patients with this problem.

Objectives:

• Describe the etiology of age-related fertility decline.
• Review the pathophysiology of fertility decline with age.
• Identify the key laboratory tests that predict disease trends.
• Summarize the conditions for identifying and treating patients with age-related processes affecting reproduction and help guide reproductive endocrinologist consultation.

Introduction

Females are born with a determinate number of oocytes.[1] In contrast to their male counterparts, females do not create new gametes throughout their lifetime. This number of oocytes peaks at around 20 weeks gestation and decreases with age. The female gametes decline stepwise until approximately age 32, at which point the number of oocytes decreases more quickly until about age 37 when they decrease significantly.[2]

As modern women push the initial childbearing age back, age-related fertility decline is increasing among our population. Given this reality and that there is no cure for this phenomenon, the OBGYN Generalist has an important role in educating patients regarding their potential fecundity starting at an early age and referring patients for further workup in a timely manner.[3]

Etiology

As female humans age, fertility is affected through that process. While in earlier times, a mother at the age of 35 would be a rarity, it is not uncommon for women aged 35 to be conceiving their first or second child nowadays. The decline in fertility is a modern problem that is not always easily solved by artificial reproductive technology.[1] The age-related fertility decline stems from several factors. However, it can be mostly summed up this way: both oocyte quantity and quality decrease with age. Other factors include increased risk of complications, changes in the ovulatory cycle, and a potential decline in uterine health.[4]

The number of gametes is decreased through the process of atresia, with an initial decline from the max number of approximately 6-7 million gametes around 20 weeks gestation to approximately 1 to 2 million oocytes at birth to 300,000 to 500,000 at puberty to 25,000 at 37 years old and around 1,000 at the age of 51.[2] 

There is no known way to slow or reverse this decline in the number of gametes. Additionally, as previously mentioned, the caliber of these oocytes also declines. While the exact mechanism is unknown, this is believed to be related to the changes in circulating hormones, specifically a rising level of follicle-stimulating hormone paired with declining levels of anti-müllerian and inhibin B hormones.[2]

A high-quality oocyte is key for fertility. It has been found that gamete quality is tied closely to the genetics of the gametes, which is more frequently negatively affected in women of increasing age. As a person ages, the chances for chromosomal abnormalities, specifically aneuploidy, increase. The presence of such aneuploidy dramatically affects the quality of an oocyte. This affects fertility as the presence of aneuploidy is a common cause of early miscarriage, attributed to approximately 65 to 75% of early missed abortions and about 35% of clinically recognized abortions. The occurrence of aneuploidy is largely attributed to meiotic nondisjunction due to meiotic spindle changes, but there is very little information regarding how to affect that process. Age is clearly related: in mothers below 25 years of age, there is a rate of down syndrome to be around 2%, and in women greater than 35, that risk jumps to almost 35%.

Epidemiology

While it is clear that the ability to conceive is not the same across all populations and can vary due to many factors, patterns of predicted infertility have been established. Studies have analyzed the average age of infertility in many countries. In Japan, it has been found that fertility was highest at women aged 24 or younger and that their fertility decreased with age, which correlates to similar data from a study on European women.[5] 

As fertility can be linked to many different factors, it is difficult to define the exact prevalence alone for age-related reasons. However, based on data from multiple trials of both insemination and IVF, the chances of conception both naturally and via artificial reproductive technology decrease with age. As many as 10 to 15% of all couples attempting conception have reported difficulties with infertility.[6][7]

Pathophysiology

The pathophysiology of age-related fertility decline in females is multifactorial. A decrease in the number of gametes and the integrity of those gametes is affected by age due to oocyte atresia over time and changes in the meiotic spindle, which can lead to aneuploidy. Other contributing factors include changes in ovulation patterns with age, aging of the uterus, and increased risk for complications.[4]

History and Physical

There are no specific findings on history and physical but rather through laboratory and ultrasound examination.[1]

Evaluation

A provider should think of testing women for decreased ovarian reserve beginning at the age of 35 in women attempting conception; this age parameter may be lowered for women with diminished ovarian reserve risk factors such as having only one ovary, those who have a history of ovarian surgery, anyone exposed to chemotherapy or radiation, as well as those patients who present with unexplained infertility. In any patient 40 years or older who seeks care regarding infertility, it is appropriate to be evaluated immediately. It is important to note that while the tests for ovarian reserve can provide information regarding the number of gametes a woman has left, the values provide no information regarding oocyte quality.[8]

Additionally, testing for ovarian reserve can predict a patient’s potential response to gonadotropin stimulation. Patients with decreased ovarian reserve have been shown to have less likelihood of pregnancy success with artificial reproductive technology. The preferred biomarker to evaluate in patients is the level of the anti-müllerian hormone (AMH), which has been shown to correlate to the available oocyte number. There is an established pattern of predicted AMH value by age, which can guide a patient’s AMH value correlates to the general population’s and thus can guide a physician in diagnosing decreased ovarian reserve.[9]

Treatment / Management

The OBGYN generalist holds an important role as a patient counselor and also as the link to the reproductive endocrinologist. Patient counseling should include general ways to optimize fertility, including maintaining a healthy weight and upholding a healthy lifestyle, including smoking cessation and reduction of alcohol intake.[10] OBGYN physicians should always inform their patients regarding fertility concerns regardless of the patient’s desire to actively achieve pregnancy or not. It is essential to include the decreased pregnancy rates for patients in their 30s and 40s both naturally and using artificial reproductive technology as a part of counseling about birth control in every well-woman visit.[11]

Another important role for the OBGYN generalist is the recognition of age-related fertility decline as a diagnosis for their patients. A prompt evaluation must be undertaken for patients who are 35 years and older who have been unsuccessfully attempting to conceive for six months; this also includes prompt referral to a fertility specialist. Given the more rapidly advancing nature of the disease after age 35, time for evaluation and treatment is of the essence for patients.[11] 

Additionally, one should think of testing women for decreased ovarian reserve beginning at the age of 35; this age parameter may be lowered for women with decreased ovarian reserve risk factors such as having only one ovary, those who have a history of ovarian surgery, anyone exposed to chemotherapy or radiation, as well as those patients who present with unexplained infertility. It is important to note that while the tests for ovarian reserve can provide information regarding the number of gametes a woman has left, the values provide no information regarding oocyte quality. Additionally, testing for ovarian reserve can provide some prediction regarding a patient’s potential response to gonadotropin stimulation as patients with decreased ovarian reserve have been shown to have less likelihood of success of pregnancy with artificial reproductive technology.[8]

The preferred biomarker to evaluate in patients is the level of the anti-müllerian hormone (AMH), which has been shown to correlate to the available oocyte number. There is an established pattern of predicted AMH value by age, which can serve as a guide to where a patient’s AMH value correlates to the general population’s and thus can guide a physician in diagnosing decreased ovarian reserve. The only true treatment for age-related fertility decline due to reduced ovarian reserve is to use donor oocytes. A woman with diminished ovarian reserve should be offered the option of donor oocytes as her successful pregnancy rate is greater than attempts to conceive with her eggs even while using artificial reproductive technology.

Differential Diagnosis

Differential diagnosis of age-related infertility includes true sterility as well as other causes of infertility. It is recommended that female patients have their male counterparts tested via semen analysis as part of the infertility workup. Infertility can be attributed to a myriad of causes. These include a combination of many things, including environmental factors, male factor infertility determined by semen analysis, sexual dysfunction, genetic abnormalities, as well as ovulatory dysfunction, structural abnormalities, and unexplained infertility.[7][12]

Prognosis

While there is no true cure for age-related fertility decline, patients who are promptly evaluated and referred to a reproductive endocrinologist have multiple options open to them for treatment, thanks to the technological advances in the field of assisted reproductive technology. This is important as patients with infertility can be strongly emotionally affected by their diagnosis. Prompt evaluation and referral to a specialist is the best thing that an OBGYN Generalist can do for their patients of advancing age who are seeking fertility. Another factor to consider is that artificial reproductive technology can be prohibitively expensive for patients as insurance often does not cover IVF.[13]

Complications

Potential complications of age-related fertility decline include true inability to conceive, a phenomenon also known as sterility, as well as complications of treatment for infertility. There are increased rates of miscarriage, preterm births, non-severe complications, congenital malformations, and the need for interventions in women who birth children after 40 years old.

Deterrence and Patient Education

The OBGYN generalist holds a vital role as a patient counselor at yearly regular well-women exams. This counseling should include general ways to optimize fertility, including maintaining a healthy weight and upholding a healthy lifestyle, including smoking cessation and reduction of alcohol intake.[10] Each appointment offers an opportunity for the physician to inform their patients about fertility regardless of the patient’s desire to actively achieve pregnancy or not.

Cultural factors of the twenty-first century have led women to not only have fewer children but also begin procreating much later than women of prior generations. Additionally, once infertility is established as a patient’s diagnosis, the treatment options are not often available to all due to high costs and the lack of insurance, which often prohibits access for patients.[13]

Enhancing Healthcare Team Outcomes

While the OBGYN generalist is typically the first line contact for patients attempting conception, all healthcare team members must be aware of their potential to impact a patient's care. Pharmacists play a key role in advising patients regarding their medication choices and the long-term effects some therapies may have on fertility. Additionally, due to the significant potential emotional impact on patients, mental health professionals, as well as chaplains, it can be an immense support to patients dealing with infertility of any kind. A comprehensive, well-rounded health care team will provide important support and appropriate evaluation for the patient dealing with age-related fertility decline.

Review Questions

• Access free multiple choice questions on this topic.
• Comment on this article.

References

1.

Baird DT, Collins J, Egozcue J, Evers LH, Gianaroli L, Leridon H, Sunde A, Templeton A, Van Steirteghem A, Cohen J, Crosignani PG, Devroey P, Diedrich K, Fauser BC, Fraser L, Glasier A, Liebaers I, Mautone G, Penney G, Tarlatzis B., ESHRE Capri Workshop Group. Fertility and ageing. Hum Reprod Update. 2005 May-Jun;11(3):261-76. [PubMed: 15831503]

2.

American College of Obstetricians and Gynecologists Committee on Gynecologic Practice and Practice Committee. Female age-related fertility decline. Committee Opinion No. 589. Fertil Steril. 2014 Mar;101(3):633-4. [PubMed: 24559617]

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Crawford NM, Steiner AZ. Age-related infertility. Obstet Gynecol Clin North Am. 2015 Mar;42(1):15-25. [PubMed: 25681837]

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Rowe T. Fertility and a woman's age. J Reprod Med. 2006 Mar;51(3):157-63. [PubMed: 16674009]

5.

Konishi S, Kariya F, Hamasaki K, Takayasu L, Ohtsuki H. Fecundability and Sterility by Age: Estimates Using Time to Pregnancy Data of Japanese Couples Trying to Conceive Their First Child with and without Fertility Treatment. Int J Environ Res Public Health. 2021 May 20;18(10) [PMC free article: PMC8161326] [PubMed: 34065492]

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Chu KY, Patel P, Ramasamy R. Consideration of gender differences in infertility evaluation. Curr Opin Urol. 2019 May;29(3):267-271. [PubMed: 30720494]

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Tamrakar SR, Bastakoti R. Determinants of Infertility in Couples. J Nepal Health Res Counc. 2019 Apr 28;17(1):85-89. [PubMed: 31110383]

8.

Tal R, Seifer DB. Ovarian reserve testing: a user's guide. Am J Obstet Gynecol. 2017 Aug;217(2):129-140. [PubMed: 28235465]

9.

Lliberos C, Liew SH, Zareie P, La Gruta NL, Mansell A, Hutt K. Evaluation of inflammation and follicle depletion during ovarian ageing in mice. Sci Rep. 2021 Jan 11;11(1):278. [PMC free article: PMC7801638] [PubMed: 33432051]

10.

Quinn MM, Cedars MI. Declining Fertility with Reproductive Aging: How to Protect Your Patient's Fertility by Knowing the Milestones. Obstet Gynecol Clin North Am. 2018 Dec;45(4):575-583. [PubMed: 30401543]

11.

Liu K, Case A., REPRODUCTIVE ENDOCRINOLOGY AND INFERTILITY COMMITTEE. Advanced reproductive age and fertility. J Obstet Gynaecol Can. 2011 Nov;33(11):1165-1175. [PubMed: 22082792]

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Infertility Workup for the Women's Health Specialist: ACOG Committee Opinion, Number 781. Obstet Gynecol. 2019 Jun;133(6):e377-e384. [PubMed: 31135764]

13.

Forti G, Krausz C. Clinical review 100: Evaluation and treatment of the infertile couple. J Clin Endocrinol Metab. 1998 Dec;83(12):4177-88. [PubMed: 9851748]

Disclosure: Amy Owen declares no relevant financial relationships with ineligible companies.

Disclosure: Paul Sparzak declares no relevant financial relationships with ineligible companies.