Overview of amenorrhea
Amenorrhea caused by organic pathology or dysfunction of the pituitary gland is often triggered by pituitary ischemia, tumors, surgery, etc. Patients are often combined with ovulation disorders, which can easily lead to infertility.
Definition
The causes of amenorrhea involve the gonadal axis and various parts of the reproductive organs, including the hypothalamus, pituitary gland, ovaries, uterus, and lower genital tract. Amenorrhea caused by organic lesions or dysfunctions of the pituitary gland is called “pituitary amenorrhea” [1-2].
Classification
Amenorrhea is classified as primary amenorrhea or secondary amenorrhea based on the presence or absence of previous menstruation. Pituitary amenorrhea is also categorized into these two groups.
Primary amenorrhea: over the age of 14 years with undeveloped secondary sexual characteristics, such as undeveloped breasts, sparse body hair, and low fat distribution in the buttocks and thighs; or over the age of 16 years with developed secondary sexual characteristics and no menstrual flow.
Secondary amenorrhea: menstruation was once present, and menstruation ceased for 6 months after the establishment of normal menstruation or ceased for more than 3 cycles on the original cycle.
Etiology
Organic lesions or dysfunctions of the pituitary gland due to various causes may affect the secretion of gonadotropins, leading to amenorrhea.
Causes
Damage to the pituitary gland
Postpartum hemorrhage causing hypoxic necrosis of the pituitary gland, as in Silhan’s syndrome.
Pituitary surgery or radiation therapy.
Pituitary tumors such as prolactinoma, thyrotropinoma, growth hormone tumor, Cushing’s syndrome.
Pituitary trauma, autoimmune injury, or inflammation.
Primary pituitary hypogonadism
For example, single gonadotropin deficiency.
Pathogenesis
The normal production and continuation of menstruation depends on the interplay between the hypothalamus, pituitary gland, and ovaries, which together form the hypothalamic-pituitary-ovarian (HPO) axis, and problems in any of these areas can lead to amenorrhea.
Normally, the pituitary gland secretes gonadotropins under the action of the hypothalamus, which act on the ovaries to secrete estrogen and progesterone to induce follicular development and cyclic changes in the uterine lining, thus forming the menstrual cycle.
However, if the pituitary gland is diseased and hormone secretion is disturbed or unable to secrete hormones normally, a woman’s menstruation cannot form normally, resulting in amenorrhea [1-5].
Symptoms
Symptoms are mainly amenorrhea and may be combined with other symptoms depending on the cause.
Main symptoms
Primary amenorrhea: over the age of 14 years, the secondary sexual characteristics have not yet developed; or over the age of 16 years, the secondary sexual characteristics have developed, and menstruation has not yet occurred.
Secondary amenorrhea: Normal menstrual cycle has been established, and menstruation has stopped for 6 months or more than 3 cycles on the original cycle.
Other symptoms
Clinical manifestations are related to the location, extent and degree of pituitary damage and destruction, as well as the degree of atrophy of the corresponding target gland of the hypogonadotropic gonadotropin.
Infertility: Infertility can result due to mostly combined ovulation disorders.
Genital and breast atrophy: loss of pubic hair, vaginal dryness, pale pigmentation of vulvar skin and areola, loss of libido; breasts become smaller.
Abnormal milk secretion: no milk after delivery or some patients may have abnormal milk secretion in non-postpartum period.
Endocrine disorders: chills, fatigue, blood pressure fluctuation, dry skin, abnormal blood sugar, tachycardia, hirsutism and acne.
Abnormal growth and development: short stature or excessive length, mandibular hypertrophy, thick hands and feet, etc.
Compression symptoms: Pituitary tumors compressing the optic nerve may present with compression symptoms such as headache, vision or visual field changes.
Consultation
As the pituitary gland secretes many kinds of hormones, there may be many different manifestations at the onset of the disease, so you can consult the corresponding departments according to your symptoms.
Departments
Gynecology
If you have symptoms of amenorrhea or infertility, we recommend that you consult a gynecologist or a gynecologic endocrinologist or reproductive specialist.
Endocrinology
Patients with metabolic disorders such as lactation, fatigue, excessive sweating, high blood pressure, weight loss, hirsutism, acne, etc. are advised to consult an endocrinologist.
Neurosurgery
Imaging suggestive of a pituitary mass requires a visit to the neurosurgery department.
Preparation
Preparation for consultation: registration, preparation of documents, FAQs
Tips for Consultation: Registration, Preparation of Documents, Frequently Asked Questions
Gynecological examination may be required. Please wear loose-fitting clothes.
You may need to check your skin condition, such as the distribution of acne, so please do not wear makeup.
Preparation Checklist
Symptom list
Pay particular attention to the time of onset of symptoms, special manifestations, etc.
Record of menstrual history: including age at menarche, length of period, menstrual cycle, presence of menstrual cramps, amount of menstrual flow, and date of starting and stopping of recent menstruation.
Are there any infertility problems? Is there any atrophy of the breasts? Is there lactation? Is there any vaginal dryness or lightening of the skin color of the vulva? Any loss of libido?
Any delayed or arrested physical development?
Any fear of heat and sweating, weight loss, loss of appetite?
Any other symptoms such as headache, vision loss, etc.?
Medical History Checklist
Marital status and maternal history.
Any history of postpartum hemorrhage especially shock?
Any family history of pituitary disease?
Any history of endocrine system disorders such as diabetes mellitus, thyroid disorders, etc.?
Any history of cranial surgery or radiation therapy?
Checklist
Test results for the last six months, which you can bring with you to the doctor’s office
If you have had sexual intercourse recently, you can test yourself for early pregnancy test to rule out pregnancy initially.
Chromosome test results, if available, may be brought for reference.
Hormone test results from outside hospitals and other imaging tests such as ultrasound of uterine adnexa or CT and magnetic resonance imaging (MRI), if available, may be brought for reference by the doctor.
Medication List
Medications taken in the past 3 months, if available in boxes or packages, you may bring them to the doctor’s office.
Recent medications taken, including name of medication, dosage, frequency, and mode.
Are taking psychoactive drugs such as diazepam, chlorpromazine, etc.?
Are birth control pills, various nutritional supplements taken? Any IUDs or subcutaneous implants?
Diagnosis
The diagnosis of pituitary amenorrhea needs to be made through a detailed history, general physical examination and relevant auxiliary tests, as well as to exclude other possible causes of amenorrhea.
Diagnostic basis
If the patient is a woman of childbearing age, the diagnosis of the following diseases can only be made after first ruling out pregnancy-related diseases and perfecting a negative urine pregnancy test.
Medical history
History of abnormal menstruation.
There may be a history of postpartum hemorrhage or shock, craniocerebral surgery or radiotherapy.
Clinical manifestations
Symptoms.
Age over 14 years, secondary sexual characteristics such as breasts remain undeveloped; or age over 16 years, secondary sexual characteristics have developed and menstruation has not yet occurred; or a normal menstrual cycle has been established but has ceased for 6 months or for more than 3 cycles on the original cycle.
Some patients may have a combination of breast spillage, chills, fatigue, hypotension, dry skin, hypothermia, and weight loss.
Physical Examination
General examination: Check the general condition including mental state, nutrition and health status, intelligence, height, weight, proportion of trunk and limbs, growth characteristics of the five senses and development of secondary sex characteristics (such as hair distribution, breast development, etc.), as well as skin color, vision and sense of smell, thyroid gland, etc., and find out any abnormalities.
Gynecological examination: check the development of internal and external genitalia, such as the size of clitoris, the morphology of labia majora and minora, the distribution of pubic hair, the vagina and hymen, the size of the uterus, pelvic masses, etc., and find out the abnormalities of genital anatomy and other conditions.
Laboratory Tests
Pregnancy test: women of childbearing age who experience amenorrhea should first rule out pregnancy and measure human chorionic gonadotropin (hCG) in blood or urine, a positive test suggests pregnancy.
Measurement of reproductive hormones: follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), estradiol (E2), progesterone (P) and testosterone (T) levels can be measured, which can assist in diagnosis.
Other hormone measurements: Thyroid hormone and adrenaline are measured if necessary to help clarify the cause.
Blood tests: routine blood tests can determine the presence or absence of anemia, and biochemical tests assess whether there are indicators of metabolic abnormalities such as hyperglycemia and hyperlipidemia.
Progesterone test: This test is performed in patients with secondary amenorrhea. If there is no bleeding, estrogen-progestin sequential test should be performed; if there is bleeding, it suggests that the endometrium has been affected by a certain level of estrogen.
Estrogen-progestin sequential test: This test is performed in patients with secondary amenorrhea; if there is no bleeding, it suggests uterine amenorrhea.
Pituitary excitability test: if LH value rises after LH-releasing hormone injection, it indicates that the pituitary gland is functioning normally and the lesion is in the hypothalamus; if there is no increase in LH value or the increase is not significant after several times of repeating the test, it indicates that the pituitary gland is functioning abnormally.
Chromosomal examination: exclude amenorrhea caused by chromosomal abnormality.
Imaging examination
Gynecological ultrasound: it can observe the presence or absence of uterus in the pelvis, uterine morphology, size and thickness of the endometrium, ovarian size, morphology, number of follicles, as well as the presence or absence of ovarian tumors.
Cranial CT or Magnetic Resonance Imaging (MRI): used to find out whether there are tumors and space-occupying lesions in the hypothalamus or pituitary gland.
Differential Diagnosis
Physiologic amenorrhea
Amenorrhea that occurs before puberty, during pregnancy, breastfeeding, or after menopause is considered physiologic amenorrhea and usually requires no management.
Ovarian amenorrhea
Similarity: Both may manifest as amenorrhea and ovulation disorders.
Differences: The disease is caused by ovarian dysfunction, with increased levels of hormone secretion at the pituitary level (and decreased levels of these hormones in pituitary amenorrhea).
Differentiation: A combination of history, clinical presentation, blood hormone tests and imaging can help to differentiate.
Uterine amenorrhea
Similarities: It also presents with amenorrhea.
Difference: Uterine amenorrhea is caused by abnormal endometrial development or other uterine pathologies, and hormone secretion is usually normal.
Differentiation: Vaginal ultrasound and hysteroscopy can observe the condition of the endometrium and uterine cavity to rule out uterine amenorrhea [6-8].
Treatment
Aim of treatment: Correct hormone levels, restore normal menstrual cycle and fertility.
Treatment principle: Individualized treatment for different causes, combined use of symptomatic drugs, surgery and other methods.
General treatment
Lifestyle improvement: combining work and rest, reducing stress, adjusting diet, appropriate exercise, maintaining a healthy weight.
Psychotherapy: remove psychological barriers and support psychotherapy.
Medication
Sex hormone supplementation therapy
Cyclic supplementation of estrogen and progesterone is available. Simulate the hormonal pattern of normal menstrual cycle, give estrogen and progesterone cycle sequential treatment, also known as artificial cycle therapy.
Commonly used estrogens include estradiol valerate, estrone hyperemesis gravidarum, and micronized 17-beta estradiol.
Commonly used progestins include dydrogesterone, medroxyprogesterone acetate, and so on.
Commonly used estrogen and progesterone cycle sequential compound preparations include estradiol and dydrogesterone tablets compound preparation, estradiol valerate tablets and estradiol cyproterone compound preparation.
Ovulation promotion therapy
Applicable to those who have normal uterus and ovaries and have the requirement of fertility, commonly used drugs are as follows:
Clomiphene (also known as Clomiphene): It is suitable for those who have a certain level of estrogen, which can stimulate follicular development and induce ovulation. Similar drugs include tamoxifen citrate, letrozole and bromocriptine.
Gonadotropins: These include purified FSH, urotropin (hMG), etc. They can stimulate follicular growth and maturation, and induce ovulation or super-ovulation, which may lead to multiple pregnancies, ovarian hyperstimulation syndrome, and other adverse effects, and must be administered by an experienced physician with ultrasound and hormone level monitoring.
Other hormonal treatments
Artificial glucocorticoids, such as hydrocortisone and prednisone, are used to replace the lack of cortisol. Due to the potential adverse effects of glucocorticoids, try to use the lowest effective dose possible and limit long-term use as much as possible.
Use thyroid hormone preparations such as levothyroxine sodium salt to replace the patient’s deficient thyroid hormones.
Other symptomatic treatments
When accompanied by hypotension, dilation therapy such as sodium and potassium expansion may be used to appropriately regulate blood pressure. For example, intravenous supplementation of 0.9% saline and sodium lactate Ringer’s solution.
When accompanied by anemia, patients are advised to consume foods rich in iron, folic acid, vitamin B, etc., and take appropriate supplements orally or by injection if necessary.
Patients with depression need to take antidepressant medication, such as fluoxetine, paroxetine, etc. They should strictly follow the doctor’s advice and prescription, and should not adjust the dosage or stop taking the medication on their own.
Surgery or radiotherapy
Depending on the location, size and nature of the tumor as well as the systemic condition, surgical resection of the tumor or radiotherapy is required as appropriate [6,9-11].
Prognosis
With a clear diagnosis and targeted treatment, many patients can regain menstruation and fertility.
Cure
Cure of pituitary amenorrhea varies with individual differences and etiology.
For some patients with pituitary amenorrhea due to, for example, difficult to completely remove tumors, pituitary surgery or radiation therapy damage, long-term hormone replacement therapy or other methods may be needed to maintain menstruation and hormone levels.
Prognostic factors
Prognosis is affected by a variety of factors, such as etiology, age, and timeliness of treatment.
Etiology: Patients with a clear diagnosis and a cause that can be fully resolved have a better prognosis, e.g., a higher likelihood of menstrual recovery after pituitary tumor resection; patients with an unknown etiology are prone to a poorer prognosis.
Age: Younger patients may have a better prognosis because of their higher recovery potential and reproductive ability; older patients, such as those who are nearly menopausal, have a relatively poorer prognosis.
Timeliness of treatment: Timely and targeted treatment has a positive effect on the prognosis, while untimely treatment has a negative effect on the prognosis.
Overall health status of the patient: if the patient has no underlying disease, better nutritional status, and better mental status, the prognosis is likely to be better; on the contrary, the prognosis may be relatively poor.
Harmfulness
Infertility: Ovulation disorders may prevent successful pregnancy.
Fracture: long-term hormonal imbalance may reduce bone density and increase the risk of fracture.
Cardiovascular disease: Long-term hormone imbalance may affect cardiovascular health.
Psychological trauma: some patients may have abnormal appearance and body shape and posture, which may easily cause psychological trauma to patients.
Daily
In pituitary amenorrhea patients, reasonable dietary management and healthy lifestyle have positive significance to the recovery of the body in the course of treatment.
Daily management
Dietary management
Maintain a nutritious and balanced diet with moderate intake of foods rich in protein and estrogen, such as beans, fish, meat and dairy products, which will help the recovery of hormone levels. Pay attention to maintaining a regular diet to prevent obesity or malnutrition.
Life management
Maintain good work and rest habits to avoid the endocrine effects of staying up late and overworking. Strengthen exercise to improve physical fitness. Quit smoking and limit alcohol to avoid bad habits.
Psychological support
Pituitary amenorrhea may have psychological effects on patients, such as anxiety and depression. If necessary, seek help from psychological professionals for psychological treatment.
Disease monitoring
Observe the menstrual cycle, amount, color, and menstrual cramps, and record them for feedback to the doctor during follow-up visits.
Breast symptoms: closely observe whether there is breast swelling and pain, breast spillage, etc.
Reproductive system changes: for example, whether there is any discomfort such as loss of pubic hair, lightening of vulvar skin and vaginal dryness.
Changes in blood pressure and blood sugar: Patients with diabetes and hypertension need to monitor their blood sugar and blood pressure as needed.
Emotional fluctuations: Pay attention to your emotional changes, such as whether you are easily irritable, lost, etc., and make timely psychological adjustments.
Prevention
Pituitary amenorrhea can not be prevented, but should be detected and treated as early as possible.
Perinatal health care
Mothers should have regular checkups and good perinatal care, especially high-risk pregnant women should prevent postpartum hemorrhage and prevent shock.
Growth and development monitoring
Children or adolescents with growth and developmental delays should actively seek professional help and early treatment.
Emotional management
Learn to release stress and maintain a relaxed mood to avoid endocrine imbalance caused by prolonged emotional stress.
Seek psychological counseling when necessary, share emotions with family and friends, and seek help from psychological professionals.
Follow-up and examination
Undergo regular medical checkups and pay attention to the health indicators related to the reproductive system and endocrine system.
For those with a family history of pituitary disease or those who have undergone cranial surgery, regular attention should be paid to the pituitary function and timely evaluation and follow-up should be conducted.
Disease prevention and management
For patients with known pituitary or endocrine disorders, actively cooperate with physicians, follow treatment protocols, and control disease progression.
Proper management of intracranial and extracranial lesions, if there are pituitary tumors and other lesions, should seek medical consultation in time.