Decreased Ovarian Function with Age: Primary Cause
The primary cause of decreased ovarian function with age is the progressive depletion of the ovarian follicle pool, which begins before birth and continues throughout a woman's reproductive lifespan until menopause. 1, 2
Mechanism of Age-Related Ovarian Decline
The fundamental process underlying ovarian aging is straightforward and irreversible:
Women are born with a finite number of primordial follicles that peaks at approximately 300,000 (ranging from 35,000 to 2.5 million) at 18-22 weeks post-conception, after which no new follicles are formed 1
Progressive follicle depletion occurs continuously from birth through menopause, with menstrual irregularity typically beginning when the average number of primordial follicles per ovary decreases to approximately 100 2
The smaller oocyte pool with advancing age makes the ovaries increasingly vulnerable to any additional insults, whether from radiation, chemotherapy, or natural processes 3
Hormonal Cascade of Ovarian Aging
The declining follicle numbers trigger a predictable endocrine sequence:
Inhibin B decreases as the number of small antral follicles declines, since inhibin B is produced by these follicles and serves as a major regulator of FSH secretion 2
FSH levels increase in response to decreased inhibin B, initially acting as a compensatory mechanism to maintain estradiol production in the follicular phase until late in the menopausal transition 2
Estradiol levels eventually decline as the follicle pool becomes critically depleted, though this occurs later in the transition process 2
The ovary becomes the primary source of estrogen in reproductive-age women (secreting 70-500 mcg of estradiol daily depending on cycle phase), but after menopause, most endogenous estrogen comes from peripheral conversion of adrenal androgens to estrone 4
Age-Dependent Vulnerability
Older age at the time of any ovarian insult confers greater risk of ovarian failure due to the already diminished follicle reserve 3:
Radiation doses as low as 5 Gy can affect ovarian function in postpubertal girls, while prepubertal girls require higher doses (≥10 Gy) for similar effects 3
Mathematical modeling demonstrates that sterilizing radiation doses decrease with age: 20.3 Gy in infants, 18.4 Gy at age 10 years, and 16.5 Gy at age 20 years 3
The relative risk of premature ovarian failure increases 1.15-fold with each year of advancing age 3
Clinical Manifestations
The transition to menopause reflects this follicular depletion:
Anovulatory cycles increase in frequency during the last 30 months before final menses, though ovulatory cycles continue to occur episodically even after entering the late menopausal transition 2
Cycle characteristics become unpredictable with marked fluctuations in FSH levels, representing a mixture of ovulatory cycles (with relatively normal FSH) and anovulatory cycles (with markedly elevated FSH and low estradiol) 2
No specific endocrine marker reliably predicts menopause, making FSH or estradiol measurements unreliable for staging individual women regarding their proximity to menopause 2
Important Clinical Caveat
Genetics, measured as family history for age at onset of menopause, is the main determinant of when this follicular depletion reaches critical levels, though physical activity, diet, and lifestyle can influence the timing 1. Women with early menopause are more likely to possess certain genetic polymorphisms, such as the PVUII polymorphic allele for estrogen receptor alpha 5.