Estrogen Deficiency and Secondary Amenorrhea

Pathophysiology

Secondary amenorrhea is often characterized by systemic reductions in estradiol levels, not excess estrogen, particularly in women with functional hypothalamic amenorrhea 1, 2
Low energy availability disrupts the hypothalamic-pituitary-gonadal axis, leading to disruptions in luteinizing hormone pulsatility, which in turn causes menstrual dysfunction manifesting as oligo-amenorrhea 1, 3
These hormonal disruptions result in decreased estradiol and progesterone levels, not increased levels 2

In female athletes, the well-established female athlete triad involves perturbations of energy availability, bone health, and menstrual status 3
Low energy availability causes disruptions of LH pulsatility, which disturbs gonadotropin release, resulting in menstrual dysfunction 3
These hormonal changes include decreased estradiol, decreased progesterone, decreased leptin, increased ghrelin, and other hormonal alterations 2
When estrogen levels are aberrantly subphysiologic, osteoclast activity predominates and bone mass is lost 3

For women with secondary amenorrhea due to low estrogen levels, estrogen replacement therapy may be necessary 4
Treatment of hypogonadism aims to normalize ovarian hormone levels through estrogen replacement with oral, micronized, or transdermal preparations 4
Amenorrhea in contraceptive implant users is generally not harmful and does not require medical treatment 5

Secondary amenorrhea with low estrogen levels increases risk for decreased bone mineral density and stress fractures 3
In the setting of oligo-amenorrhea with low estrogen, bone microarchitecture is negatively affected, leading to decreased trabecular number and cortical thickness 3
These changes result in decreased stiffness and lower failure load, ultimately increasing the incidence of bone stress injury 3

Primary amenorrhea is defined as no menarche by age 15 years, or by age 13 years in the absence of secondary sexual characteristics 6
Secondary amenorrhea affects approximately 3-4% of women in the general population 7

Functional Hypothalamic Amenorrhea (FHA) accounts for 20-35% of secondary amenorrhea cases 7
Polycystic Ovary Syndrome (PCOS) is one of the most common causes of secondary amenorrhea 7
Hyperprolactinemia accounts for approximately 20% of secondary amenorrhea cases 7
Primary Ovarian Insufficiency (POI) is characterized by elevated FSH and LH levels 7
Thyroid dysfunction, including hypothyroidism and hyperthyroidism, can cause amenorrhea 7
Advanced liver disease can cause amenorrhea due to altered estrogen metabolism and disruption of the hypothalamic-pituitary axis 8

Epilepsy can directly affect the hypothalamic-pituitary axis and increase the risk of amenorrhea 9, 10, 11, 12
Athletes with amenorrhea require evaluation for Relative Energy Deficiency in Sport (RED-S) and are at risk for decreased bone density 6, 7
FHA-PCOM is a special entity that affects 40-47% of women with FHA and features characteristics of both FHA and PCOM 7

The first step in diagnosis is a pregnancy test 7
Initial laboratory evaluation should include serum FSH, LH, prolactin, and TSH levels 7
Pelvic ultrasound can be used to evaluate for PCOM and uterine abnormalities 7
Additional testing may include androgen profile for suspected PCOS 7
Progestin challenge test can be used to determine estrogen status 7

Premature Ovarian Insufficiency (POI) is characterized by ovarian failure before age 40, resulting in disruption of the hypothalamic-pituitary axis with low follicle-stimulating hormone and luteinizing hormone, leading to anovulation, amenorrhea, and profoundly low estradiol levels, as reported by the Hepatology journal 13
Turner Syndrome is a specific genetic cause of POI, which requires cardiologist evaluation due to associated congenital heart disease risk, according to the Human Reproduction Update journal 14

Advanced liver disease causes low estradiol through altered estrogen metabolism and disruption of the hypothalamic-pituitary axis, with amenorrhea or oligomenorrhea seen in more than 25% of women with advanced liver disease, as stated in the Hepatology journal 13
Excess alcohol intake affects the hypothalamic-pituitary axis or directly impairs ovarian function, resulting in low estradiol production, as reported by the Hepatology journal 13

For women under 40 with confirmed POI or hypoestrogenism, hormone replacement therapy is strongly recommended to normalize ovarian hormone levels and reduce risk of osteoporosis, cardiovascular disease, and urogenital atrophy, continuing until at least age 51, as recommended by the Human Reproduction Update journal 14
The preferred regimen for hormone replacement therapy is 17-β estradiol (not ethinylestradiol or conjugated equine estrogens), with progestogen added for women with intact uterus, according to the Human Reproduction Update journal 14