I. Clinical manifestations
1.Symptoms
1.1 Menstrual changes: amenorrhea is the main clinical manifestation of POF. POF occurs before puberty as primary amenorrhea, and no secondary sex characteristics development; occurs after puberty as secondary amenorrhea, before 40 years of age, menstruation is terminated, often with secondary sex characteristics development. The age of onset of POF depends on the age of the ovaries.
The age of onset of POF depends on the reserve of primordial follicles in the ovary and the rate of follicular atresia. Low follicular reserve and rapid atresia can lead to premature ovarian failure. Patients with chromosomal defects have congenital ovarian hypoplasia and very poor ovarian reserve, resulting in earlier onset of POF and even failure to reach puberty, resulting in primary amenorrhea. In most patients with POF, the process of ovarian decline is sudden and irreversible, but in a few patients, the process lasts for a period of time, corresponding to the transition to natural menopause.
Occasionally, after the diagnosis of POF, there is a so-called transient recovery of ovarian function, which is manifested by the resumption of normal menstruation, and there are even reports of pregnancy in POF patients, but as the time after the diagnosis of POF increases, the chance of recovery of ovarian function becomes smaller.
1.2 Estrogen deficiency: Due to the decline of ovarian function, POF patients, in addition to infertility, will also be like menopausal women, a group of estrogen deficiency syndrome, such as hot flashes, sweating and other vasodilatory symptoms, depression, anxiety, insomnia, memory loss and other neuropsychiatric symptoms, as well as vulvar itching, vaginal burning, vaginal dryness, painful intercourse and painful urination, urinary urgency, urinary frequency, difficulty in urination and other urogenital tract symptoms. The symptoms of amenorrhea are not always the same. These symptoms are relatively uncommon in patients with POF with primary amenorrhea.
Although the exact cause of POF is not well understood, in addition to drugs, surgery, infection and other clear destructive factors, research suggests that most POF may be related to genetic, endocrine and immune diseases. Some patients with POF may have autoimmune endocrine disorders such as hypoadrenalism (Addison’s disease), diabetes mellitus, hyper- or hypothyroidism, and hyper- or hypoparathyroidism, with hypothyroidism being the most common.
In a prospective NIH study, Kim et al. analyzed 119 patients with POF who had normal karyotype and found that 32 of them had hypothyroidism (27%), 3 had hypoadrenalism (215%), and 3 had diabetes (215%).
Patients with Addison’s disease may have fatigue, weakness, hyperpigmentation, weight loss, and decreased blood pressure; patients with diabetes mellitus may have excessive drinking, polyphagia, polyuria, and weight loss; patients with hyperthyroidism may have excitement, impatience, fear of heat, excessive sweating, polyphagia, and palpitations; patients with hypothyroidism may have weakness, fear of cold, bloating, constipation, unresponsiveness, and mental retardation; patients with hyperparathyroidism may have muscle weakness; and patients with hypoparathyroidism may have muscle weakness. Patients with hyperparathyroidism may have muscle weakness, loss of appetite, nausea and vomiting, sudden aging, memory loss, emotional instability, personality change, general or local bone pain, joint swelling and pain, itchy skin, etc.; patients with hypoparathyroidism may have hand and foot twitching, numbness around the mouth and fingertips, anxiety, sweating, pallor, mental confusion, dry skin, etc.; patients with rheumatoid arthritis may have joint pain and stiffness; Patients with combined systemic lupus erythematosus (SLE) may have fever, rash, arthralgia and other manifestations.
Patients with Turner syndrome may have short stature and mental retardation, as well as webbed neck, barrel-shaped chest, elbow valgus, through-handedness, widely spaced nipples, internal canthus, downward sloping eye fissures, large and low ear shells, low posterior hairline, short fourth and fifth metacarpals and metatarsals, and striated ovaries.
Patients with primary amenorrhea due to chromosomal abnormalities may have underdeveloped secondary sexual characteristics, such as underdeveloped breasts, underdeveloped internal genitalia, and sparse or absent pubic and axillary hair. Pelvic examination may reveal estrogen deficiency, such as vaginal mucosal congestion and submucosal bleeding spots. In rare patients with lymphocytic thyroiditis, enlarged ovaries may be palpable with or without pressure pain.
In addition, the presence of signs of various etiologies should be noted. Patients with Addison’s disease may have fatigue, weakness, skin folds on hands and gingival pigmentation, weight loss, and decreased blood pressure; patients with hyperthyroidism may have protruding eyes, enlarged thyroid glands, and increased heart rate; patients with hypothyroidism may have puffy eyelids, large tongues, thin and dry hair, and loss of the outer 1/3 of the eyebrows, as well as hoarseness, dry skin, and slow heart rate; patients with hyperparathyroidism may have muscle atrophy. Patients with hyperparathyroidism may have muscle atrophy, bone and joint pain; patients with hypoparathyroidism may have positive hand twitch signs; patients with rheumatoid arthritis may have swollen finger joints such as pike shape, or even deformity; patients with SLE have special facial features, such as butterfly-shaped red spots on the cheeks and nose.
3.Laboratory tests
3.1 Sex hormone level measurement: serum hormone level measurement shows elevated FSH level and decreased estrogen level is the most important feature and diagnostic basis of POF patients, generally FSH > 40 U/L, estradiol < 73.2 pmol/L. The most sensitive is the elevated serum FSH level, FSH elevation is the early indicator of POF. The pathophysiological features of this phenomenon are similar to those of the menopausal transition The pathophysiological characteristics of this phenomenon are similar to those of the menopausal transition, during which the residual follicles in the ovary are still intermittently active, resulting in fluctuating and unstable sex hormone levels.
Therefore, a single measurement showing elevated FSH levels cannot conclude that ovarian function is necessarily in complete failure and sometimes repeated measurements are needed. It should be noted that serum FSH levels do not necessarily reflect the number of primordial follicles in the ovary and that elevated FSH is only an indication of the lack of negative feedback from estrogen and inhibitory hormones during the development of the sinus follicle.
3.2 Ultrasonography: In most POF patients, pelvic ultrasound showed shrunken ovaries and uterus and no follicles in the ovaries. However, more than 1/3 of POF patients with normal karyotype have follicles on pelvic ultrasound, and it has been reported that 6 years after the diagnosis of premature ovarian failure, follicles can still be found in the ovaries on ultrasound, but in most women these follicles do not function normally, and there is no correlation between follicle diameter and serum estradiol levels.
There are two explanations for this phenomenon, one may be the presence of residual follicles in the ovaries, and the other may be the so-called “ovarian insensitivity syndrome”, in which follicles are present in the ovaries but are insensitive to FSH and therefore do not develop. This may be related to a defective FSH receptor in the ovary, but the exact cause is not known. It is difficult to differentiate it from POF clinically, and the diagnosis can be made only if a large number of primordial follicles are found on ovarian biopsy. Ultrasonography can also reveal any anatomical abnormalities of the genital tract, such as genital tract malformations and agenesis.
3.3 Bone densitometry OF patients may present with low bone mass and osteoporosis due to low peak bone mass and increased bone loss rate. Young women who develop POF before peak bone formation have a much longer estrogen deficiency than normal menopausal women, and premature estrogen deficiency causes accelerated bone resorption and increased bone loss, thus making them more likely to develop osteoporosis. The literature reports that 2/3 of chromosomally normal women with spontaneous POF have a lower bone mineral density (BMD) than the average value of 1 SD in normal women of the same age, and the change in BMD increases the risk of hip fracture by 216 times.
3.4 Autoimmune and endocrine indexes: The clinical significance of detecting anti-ovarian antibodies is uncertain. Anti-ovarian antibodies do not correlate with the severity of ovarian inflammation and do not predict if and when ovarian failure will occur. Anti-nuclear antibodies may be positive in up to 1/3 of normal women when tested with commercially available kits. Some studies have shown that POF may occur in women with adrenal failure who are positive for steroid cell antibodies.
Patients with suspected autoimmune disease should be tested for autoantibodies, hematocrit, immunoglobulins, and rheumatoid factor. When there are clinical indications, thyroid function (blood thyroid hormone, thyrotropin), adrenal function (blood and urine cortisol, blood electrolytes), parathyroid function (parathyroid hormone) and blood glucose indexes can be measured.
The significance of ovarian biopsy for the diagnosis of POF has not been confirmed because it is not helpful in confirming the staging of POF and there are reports of pregnancy in ovarian biopsies with follicular deficiencies.
Currently, ovarian function can be determined by stimulation tests with GnRH analogs and ovulation tests with clomiphene. The progesterone withdrawal test is of little relevance because some patients with proliferative POF can sometimes produce enough estrogen for a positive progesterone withdrawal test. For some patients with secondary amenorrhea who have not had children and for all patients with primary amenorrhea, karyotype examination should be performed. For patients with Y chromosome, bilateral gonadectomy should be performed as early as possible to prevent the occurrence of gonadal tumors.
Diagnosis of premature ovarian failure
Diagnosis of premature ovarian failure: The accepted diagnostic criteria for premature ovarian failure are at least 4 months of amenorrhea before the age of 40, 2 or more serum FSH > 40 U/L (more than 1 month between tests), and estradiol level < 73.2 pmol/L. History, physical examination and other ancillary laboratory tests may help to diagnose the relevant etiology of the disease.
1. Medical history: Take a detailed history of the patient, including age at menarche, premenstrual status, duration of amenorrhea, any triggers of amenorrhea (mental stimulation, environmental toxins, etc.), history of drug use, history of cancer chemotherapy, radiation therapy, ovarian surgery, pelvic infection, tuberculosis, and history of pregnancy and childbirth. Self-perceived symptoms, such as hot flashes, excessive sweating, insomnia, irritability, impatience, vaginal dryness, painful urination, etc.
Past and present history of mumps and AIDS virus infection, as there is rare ovarian failure secondary to infection. To find out if the patient and her family have any previous or current autoimmune diseases such as Addison’s disease, thyroid disease, diabetes, SLE, rheumatoid arthritis, leukoplakia, Crohn’s disease, and dry syndrome. A few epidemiological studies have shown a familial predisposition to premature ovarian failure, and some studies have shown that hereditary mutations in gonadotropin receptors can lead to premature ovarian failure, so the family history should be carefully questioned, including the menstrual and reproductive status of the mother, sisters and female second-degree relatives and the reproductive status of male relatives.
2. Physical examination: During the general examination, attention should be paid to the general development, intelligence and nutritional status, and the development of breast and pubic hair should be examined and graded according to the Tanner grading scale. The pelvic examination should pay attention to the presence of atrophic vaginitis caused by estrogen deficiency. Patients with autoimmune POF (lymphocytic ovarian disease) may sometimes have enlarged ovaries on pelvic examination. The focus should be on the presence or absence of signs related to the above autoimmune diseases.
In addition to serum sex hormone level measurement, when there are clinical indications, attention should be paid to the examination of related diseases, such as routine blood and urine analysis, blood sedimentation, antinuclear antibody, immunoglobulin and rheumatoid factor test. The presence of pituitary tumors can be identified by magnetic resonance imaging and by stimulation of the production of intact FSH, alpha and beta subunits by thyroid releasing hormone. Bone densitometry should be performed for suspected low bone mass and osteoporosis.
Pelvic ultrasonography is performed to understand the presence of anatomical abnormalities and the presence of follicles. However, in patients with spontaneous POF with normal karyotype, pelvic ultrasound does not change the clinical diagnosis because even if follicles are found, it has not been proven that the ovarian function can be restored with treatment.