Causes of Diminished Ovarian Reserve: Risk Factors and Fertility Impact

What Is Diminished Ovarian Reserve?

Every woman is born with her complete lifetime supply of eggs, around one to two million primordial follicles. By the time she reaches puberty, the number drops to around 300,000 to 500,000, and it continues to decline throughout her reproductive years.

Diminished ovarian reserve is diagnosed in women when the follicular pool depletes at a faster rate than expected, as per a woman’s age. It also refers to when the remaining eggs are of insufficient quality to support proper fertilisation and healthy embryo development. While a woman with diminished ovarian reserve can still get pregnant naturally, but the odds are much smaller.

You may not know that you are affected by the condition, as women rarely experience any obvious symptoms other than not getting pregnant despite trying. Regardless, you can still keep an eye out for irregular periods, vaginal dryness, and hot flashes.

How Does Age Affect Ovarian Reserve?

Age is one of the most fundamental and universally applicable causes of diminished ovarian reserve. Reduced egg number and reduced egg quality are progressive, irreversible natural processes that increase significantly in incidence in women from their mid-thirties. Their egg reserve decreases dramatically, and by age 37, women only have approximately 1/10 of their original supply left. Chromosomal abnormalities become increasingly prevalent in the remaining eggs.

Diminished ovarian reserve comprises two components. Firstly, follicular atresia is a natural programmed process of cell death that continues without regard to whether the woman is pregnant or not, or if she is using contraception or any other methods that inhibit ovulation. Secondly, aging oocytes exhibit mitochondrial dysfunction, which impairs their ability to complete meiosis accurately. This increases the risk of aneuploidy (abnormal chromosomal numbers).

Reduced quantity combined with declining quality is why advanced maternal age is linked to lower pregnancy rates, higher miscarriage rates, and increased risk of chromosomal conditions in the children.

What Genetic Conditions Cause Diminished Ovarian Reserve?

Several genetic mutations and chromosomal abnormalities contribute to a rapidly declining ovarian reserve. Some of them are:

• FMR1 Premutation (Fragile X): Premutations in the FMR1 gene, between 55 and 200 copies of the CGG repeat expansion, are clearly correlated with Primary ovarian insufficiency and diminished ovarian reserve. The mechanism is thought to involve RNA toxicity that damages folliculogenesis.
• Turner Syndrome (45, X): This leads to early depletion of follicles from as early as foetal development. Most individuals with Turner syndrome experience premature ovarian insufficiency (POI) in adolescence or early adulthood. 
• Mutations involving BMP15 and GDF9: Bone Morphogenetic Protein 15 (BMP15) and Growth Differentiation Factor 9 (GDF9) are ovarian oocyte-secreted proteins and are crucial for the development and growth of the follicle. Mutations of the gene responsible for BMP15 and GDF9 cause POF and ovarian insufficiency because of their role in follicular maturation and cell communication.
• BRCA1 Mutations: BRCA1 is typically associated with an increased risk of breast and ovarian cancers. This type of mutation is associated with low AMH and AFC levels.
• Others: Mosaic Turner syndrome, trisomy X (47, XXX), and structural aberrations of the X chromosome may also contribute to low ovarian reserve, depending on the extent of the chromosomal abnormality.

How Do Autoimmune Disorders Affect Ovarian Reserve?

The inflammation of the ovaries driven by autoantibodies, also known as autoimmune oophoritis, is a recognised yet underdiagnosed cause of diminished ovarian reserve and POI. In this condition, the immune system targets the ovarian tissue, specifically the granulosa and theca cells surrounding the follicles. This then triggers inflammatory destruction. Autoimmune POI is often linked to other endocrine autoimmune disorders like Addison’s disease.

Other autoimmune conditions that are associated with diminished ovarian reserve include systemic lupus erythematosus (SLE), rheumatoid arthritis, myasthenia gravis, and type 1 diabetes mellitus. However, you must keep in mind that the mechanisms here are usually multifactorial, involving both immune-mediated follicular damage and immunosuppressive medications.

Can Previous Ovarian Surgeries Reduce Egg Quality And Quantity?

Whether it is through direct tissue removal or vascular compromise to the ovarian cortex, prior surgeries near or on the ovaries can pose a high risk of reducing ovarian reserve.

• Ovarian Cystectomy: Surgical excision of ovarian cysts, such as dermoid cysts, serous cystadenomas and haemorrhagic cysts, may inadvertently remove functional ovarian cortical tissue containing primordial follicles. The risk is especially high with the stripping technique routinely used in laparoscopic cystectomy, which has been shown to remove measurable amounts of ovarian cortex with the cyst wall.
• Endometrioma Surgery: Removal of endometriomas (ovarian cysts caused by endometriosis) is especially damaging to ovarian reserve. This may lead to a significant decrease in AMH and AFC after endometrioma cystectomy, with some women suffering a permanent decrease in reserve, especially after bilateral or repeated surgeries.
• Ovarian Torsion Surgery: The twisting of the ovary on its pedicle can cause ischaemic injury. If detorsion is delayed or oophorectomy is done, a considerable loss of follicles may ensue. Even after successful detorsion, ischaemia-reperfusion injury may reduce functional ovarian tissue.
• Hysterectomy: Total hysterectomy, with preservation of the ovaries, has been associated with earlier development of ovarian insufficiency. This may be due to disruption of the uterine-ovarian blood flow via the uterine artery.

Is Endometriosis A Contributing Factor To DOR?

Endometriosis is a condition in which tissue resembling that of the uterine lining grows outside the uterus. This can impair the ovarian reserve either directly or indirectly.

Ovarian endometriomas secrete reactive oxygen species (ROS) and pro-inflammatory mediators, which may have toxic effects on adjacent follicles and accelerate follicular atresia. It has been shown that the follicular fluid of women with endometriosis contains elevated levels of oxidative stress markers that affect oocyte quality, even in morphologically normal follicles.

In addition to direct follicular toxicity, endometriosis causes local inflammation that affects the ovarian microenvironment and granulosa cell function, thereby impairing normal folliculogenesis. Women with endometriosis have consistently lower AMH levels and AFC than age-matched controls without endometriosis, and the decrease is proportional to disease severity.

Does Chemotherapy Or Radiation Damage Ovarian Reserves?

Alkylating agents such as cyclophosphamide, busulfan, and melphalan are the most potent gonadotoxic cytotoxic agents used in chemotherapy. They induce double-strand breaks in DNA in oocytes and granulosa cells, leading to apoptosis and irreversible follicular depletion. The damage depends on the agent, the cumulative dose, and the patient's age at the time of treatment. Platinum-based agents, taxanes, and anthracyclines have intermediate and lower gonadotoxicity.

On the other hand, radiation to the pelvis or the whole abdomen directly irradiates the ovarian follicles, which are highly radiosensitive. Cranial radiation that includes the hypothalamic-pituitary axis can also lead to decreased gonadotropin secretion, resulting in a functional rather than structural decrease in ovarian stimulation.

What Environmental And Toxic Exposures Reduce Ovarian Reserve?

Exposure to environmental toxins may also contribute to low ovarian reserve. The toxins that you should watch out for are the following:

• Endocrine Disrupting Compounds (EDCs): These have been known to disrupt hormone signalling pathways in women. It also inhibits follicular development and ovarian reserve.
• Smoking: It is one of the most studied environmental factors associated with DOR. The polycyclic aromatic hydrocarbons (PAHs) of cigarette smoke are directly toxic to oocytes and speed up follicular apoptosis through the aryl hydrocarbon receptor (AhR) pathway. Smokers have lower AMH levels and AFC and are likely to reach menopause about 1-4 years earlier than non-smokers.
• Heavy Metals: Cadmium, arsenic, and lead have been identified as ovarian toxins. Cadmium is present in cigarette smoke and some occupational exposures. It mimics oestrogen and disrupts ovarian granulosa cell function, resulting in follicular loss.

Can Lifestyle Factors Cause Diminished Ovarian Reserve?

Genetic, medical, and environmental factors aside, a woman’s lifestyle also impacts her ovarian reserve. Even though the lifestyle alone does not lead to diminished ovarian reserve, there are certain practices that can affect ovarian ageing and even exacerbate predisposition.

• Excessively high or low body weight: Extreme body weight can lead to hormonal imbalances that impact ovarian function. Caloric restriction and low body fat inhibit gonadotropin secretion via hypothalamic suppression, while insulin resistance and chronic inflammation associated with obesity may promote follicular depletion.
• Alcohol: Alcohol abuse has been proven to interfere with the hypothalamic-pituitary-ovarian axis and be associated with diminished ovarian reserve in some observational studies. However, unlike smoking, evidence supporting this correlation is rather weak.
• Vitamin D Deficiency: Vitamin D has been found to play a crucial role in ovarian function.Vitamin D deficiency in the body results in decreased AMH levels.

What Is Idiopathic Diminished Ovarian Reserve?

In many cases, particularly those seen in younger women, diminished ovarian reserve does not have an identifiable cause, regardless of investigation. This is known as idiopathic diminished ovarian reserve. It has been hypothesised that in such cases, the cause may lie in unidentified genetic polymorphisms, subclinical autoimmune activity, or subtle mitochondrial dysfunction that is undetectable by current diagnostic tools.

Conclusion

Diminished ovarian reserve is a clinically complex disorder with a broad spectrum of known aetiologies, including advancing age, genetic mutations, autoimmune processes, surgical history, gonadotoxic treatments and environmental exposures. The primary and inevitable reason for the decline of follicles is still age, but many medical and external factors can significantly accelerate this process.

Early assessment of ovarian reserve, especially in women with risk factors for earlymenopausesuch as family history, prior pelvic surgery, cancer treatment or autoimmune disease, allows for timely fertility preservation and better reproductive planning.