It is the situation in which a woman cannot menstruate spontaneously in the reproductive age.
Amenorrhea during lactation and pregnancy is physiological.
Primary Amenorrhea
It is the state of not having menstruation at the age of 15 in those who develop secondary sex characteristics and at the age of 13 in those who do not.
Etiology of primary amenorrhea
1. Gonadal dysgenesis 30% (most common)
2. Müllerian agenesis (RKMH)
3. Testicular feminization
Secondary Amenorrhea
It is the absence of menstruation for at least 3 cycles in a previously menstruating woman.
The most common cause of secondary amenorrhea is pregnancy. Other causes:
1. Chronic anovulation 28%
2. Hypothalamic suppression 10%
3. Anorexia / weight loss 10%
4. Prolactinomas 7.5%
5. Asherman syndrome 7%
6. Hypothyroidism 1%
• The presence of secondary sex characteristics is important in determining the etiology of amenorrhea. In the absence of secondary sex characteristics, it indicates no exposure to estrogen.
Amenorrhea Classification
Hypergonadotropic amenorrhea (FSH > 20 IU/ml):
1. Gonadal dysgenesis (most frequent)
■ Turner syndrome
■ 46.XX pure gonadal dysgenesis
■ 46,XY pure gonadal dysgenesis (Swyer syndrome)
2. Partial deletion of the X chromosome
3. Mosaic structure in sex chromosomes (45X/46XX most common)
4. Fragile X syndrome
5. Gonadotropin receptor mutations
■ LH receptor mutation
■ FSH receptor mutation
6. Resistant ovarian syndrome (Savage Syndrome)
7. Autoimmune oophoritis (Blizzard Syndrome)
8. Galactosemia
9. Enzyme defects
■ 17a-Hydroxylase and 17-20 Desmolase deficiency
■ Aromatase deficiency
■ Congenital lipoid adrenal hyperplasia
10. Radiation and chemotherapy
11. Infections
Hypogonadotropic amenorrhea (FSH<5 IU/ml):
1. Physiological (constitutional) delay (most common)
2. Kallmann syndrome
3. CNS tumors (most common craniopharyngioma)
4. Pituitary lesions
■ Empty sella syndrome
■ Sheehan's syndrome (pituitary apoplexy)
■ Infections (tuberculosis, sarcoidosis)
■ Hand Schüller Christian disease
■ Diabetic vasculitis
■ Sickle cell anemia
■ Pituitary adenomas
■ Pituitary hypoplasia
5. Disruption of hypothalamic GnRH secretion
■ Anorexia nervosa, bulimia, malnutrition
■ Stress, excessive exercise
■ Hyperprolactinemia
■ Hypothyroidism
■ Cushing's syndrome
■ Chronic diseases, neoplasia, malabsorption, marijuana use
■ Obesity
6. GnRH receptor mutation
7. FSH deficiency
Normogonadotropic amenorrhea (FSH 5-20 IU/ml):
1. Müllerian anomalies
■ Imperforate hymen
■ Transverse vaginal septa
■ Absence of cervix or vagina
■ RKMH syndrome
2. Asherman's syndrome
3. Absence of endometrium
4. Complete androgen insensitivity syndrome (testicular feminization)
Hypergonadotropic Amenorrhea (FSH > 20 IU\ML)
► High levels of LH and FSH are seen with primary gonadal insufficiency and consequently impaired gonadal steroid production (decrease in estrogen level) and therefore decreased (-) feedback. 30% of hypergonadotropic amenorrhea are associated with genetic anomalies and are often the cause of primary amenorrhea.
Gonadal Dysgenesis
It is the most common cause of primary amenorrhea and hypergonadotropic hypogonadism (30%). Turner syndrome is most common in gonadal dysgenesis with primary amenorrhea (50%).
Karyotype analysis should be performed in all cases with hypergonadotropic amenorrhea before the age of 30. In the presence of Y chromosome, gonads should be removed because of the risk of malignant transformation (gonadoblastoma, dysgerminoma, choriocarcinoma, yolk sac tumor).
Partial Deletion of X Chromosome
0 The phenotype depends on the size and localization of the lost genetic material.
Mosaism in Sex Chromosomes
0 45X0/46XX mosaicism is most common in primary amenorrhea.
In 0 45X0 /46XY mosaicism, gonadectomy should be performed as soon as the diagnosis is made.
Due to partial deletion of the X chromosome and sex chromosome mosaicism, ovarian failure may occur following the administration of enough estrogen to develop several menses and breasts, and they may present with secondary amenorrhea before the age of 30.
Fragile X Syndrome
0 shows X-linked transmission and occurs due to FMR1 gene inactivation at the Xq27.3 localization. It is a disorder with mental retardation. Primary (premature) ovarian failure is seen in 13-26% of cases.
Gonadotropin Receptor Mutations
Gonads due to LH or FSH receptor mutations do not respond to gonadotropins.
Resistant Ovarian Syndrome (Savage Syndrome)
0 Patients have primordial follicles in their ovaries; however , there is no response to FSH and follicular development cannot continue due to the absence of FSH receptors or the presence of postreceptor defect .
0 A small number of patients with severe congenital receptor defects have primary amenorrhoea and secondary sex characteristics infantilism. However, delayed puberty, normal development of secondary sex characteristics, and primary ovarian failure are seen in partially affected patients.
0 Definitive diagnosis is made by ovarian biopsy, but it is not recommended in practice because it does not change the treatment. Hormone replacement therapy is administered until menopause.
Primary Ovarian Insufficiency and Autoimmune Oophoritis (Blizzard Syndrome)
Primary ovarian failure (Premature ovarian failure)
- The case of entering menopause before the age of forty is called primary ovarian failure. Primary ovarian insufficiency diagnostic criteria; Amenorrhea for more than 4 months is having serum FSH level at menopausal level on two separate measurements and being under 40 years of age.
- In most cases of primary ovarian failure, the cause is unknown (idiopathic). Known causes include sex chromosome disorders (FMR1 premutation, mosaicism, X chromosome deletion, 47XXX), single gene mutations, exposure to toxic agents (radiation, chemotherapy) and autoimmunity. Autoimmune lymphocytic oophoritis is seen in 4% of women with primary ovarian failure.
Smoking reduces the age of menopause but is not expected to cause amenorrhea before age 40.
autoimmune oophoritis
- Normal primordial follicles are found in the ovaries, but there is lymphocytic infiltration around the secondary and antral follicles. While the theca layer is infiltrated with lymphocytes, there is no infiltration in the granulosa layer.
- Estrogen is low, FSH is high.
- Biopsy is not recommended for diagnosis. Antiovarian antibodies are also unreliable in the diagnosis. In those with negative ovarian antibody, oophoritis can be seen on biopsy.
- The most reliable test for diagnosis is antibody positivity against the adrenal gland. The most useful of these antibodies is the measurement of antibodies against 21 hydroxylase; however, the ideal is to show these antibodies by indirect immunofluorescence in the adrenal gland.
- Positive antibodies against 21 hydroxylase in primary ovarian failure cases are an indication of autoimmune oophoritis and the risk of fatal hypoadrenalism. The presence of antithyroid antibody positivity does not indicate that the cause of primary ovarian failure is autoimmune.
- Tests to be performed in the differential diagnosis of primary ovarian insufficiency; FMR1 premutation, karyotype (under 30 years old) and 21 hydroxylase antibodies.
- Primary ovarian failure may be a part of polyglandular autoimmune syndrome and various autoantibodies are positive in 92%. It most often progresses with thyroid pathologies and the picture is often accompanied by hypothyroidism. Therefore, thyroid antibodies (peroxidase and thyroglobulin) should be checked in these patients and annual TSH follow-up should be performed if positive.
- Hypoparathyroidism, adrenal insufficiency, myasthenia gravis, diabetes, autoimmune hemolytic anemia, ITP, rheumatoid arthritis and vitiligo are other accompanying autoimmune diseases.
- In cases diagnosed with primary ovarian failure, some tests are recommended if they are symptomatic because of the possibility of accompanying other autoimmune diseases. These; calcium, phosphorus, albumin
(for parathyroid), FBC, HbAlC (for pancreas), antibodies against 21 hydroxylase, TSH, free T4, thyroid antibodies (for thyroid), ACTH (for adrenal), whole blood (for hemolytic/pernicious anemia) and platelets (for idiopathic anemia) for thrombocytopenia).
- Spontaneous recovery and return of ovarian function are possible. However, in most cases, amenorrhea and infertility are permanent.
galactosemia
0 In galactosemia, which is a rare autosomal recessive disease due to galactose-1-phosphate uridyl transferase enzyme deficiency, primordial follicles are rapidly lost due to the toxic effects of galactose metabolites and primary ovarian failure occurs.
Enzyme Defects
Deficiency of 17α-Hydroxylase and 17,20 desmolase
- As a result of the mutation of the CYP17 gene, the activity of both enzymes is deficient. These enzymes are responsible for steroid production in both the ovary and the adrenal gland.
- Patients may be 46,XX or 46,XY structures, and the presence of a uterus in 46,XX individuals distinguishes them from 46,XY individuals. Both groups of patients have female phenotype, primary amenorrhea and secondary sexual retardation, accompanied by hypertension and hypokalemia.
- Decreased 17-hydroxylase in affected individuals leads to decreased cortisol production and consequently increased ACTH. Response to increased ACTH, as 17 hydroxylase is not required for mineralocorticoid synthesis
As a result, a large amount of mineralocorticoid is released from the adrenal gland, resulting in hypernatremia, hypokalemia, and hypertension.
- These patients have primordial follicles in their ovaries, but gonadotropins cannot be suppressed because sex steroids cannot be produced.
- High progesterone levels are important in diagnosis. The 17-OH progesterone level is also very low.
- In the treatment, glucocorticoids and estrogen should be given.
Aromatase deficiency
- In this rare autosomal recessive disease, testosterone cannot be converted to estrogen and pubertal development is impaired. While cliteromegaly and posterior labioscrotal fusion are seen at birth, breast development does not occur at puberty, primary amenorrhea, virilization, retardation at bone age (no rapid growth) and multicystic ovaries occur.
- Increased gonadotropin (FSH, LH), testosterone and DHEA-S levels are present, and estrogen levels are very low.
Congenital lipoid adrenal hyperplasia
- Cholesterol cannot be converted to pregnenolone in this autosomal recessive disease. Here there is no defect in the p450 scc enzyme; however, there is a mutation in the StAR protein (steriodogenic acute regulatory protein), which enables cholesterol to be transported from the outer mitochondrial membrane to the inner.
- Hyponatremia, hyperkalemia and acidosis are seen in the neonatal period. Both XX and XY individuals are phenotypically female. 46,XY cases do not have a uterus, while 46,XX cases have a uterus.
Radiation and Chemotherapy
The effects of radiation and chemotherapeutic drugs on the ovary depend on age and dose. The stage in which the ovaries are most insensitive to the effects of radiotherapy and chemotherapy is the prepubertal period . Before puberty, amenorrhea may occur before secondary sexual characteristics develop due to severe ovarian damage.
0 The older the cases and the higher the radiation dose, the higher the ovarian damage. The radiation dose that completely terminates ovarian activity is 800 rad. Ovarian damage can be reduced by moving the ovaries out of the pelvis before radiotherapy.
0 The risk of ovarian failure is also high in patients receiving combined chemotherapy, and among the chemotherapeutics, the most toxic agents to the ovary are alkylating agents (especially cyclophosphamide).
0 While ovarian function may return after chemotherapy, loss of ovarian function after radiotherapy is not reversible.
Infections
0 Mumps and HIV infection can cause primary ovarian failure.
Hypogonadotropic Amenorrhea (FSH < 5 IU/ML):
► Most of the cases develop for acquired reasons and present with secondary amenorrhea. The sexual development of the patients is retarded and their gonadotropin levels are low. They may originate from the hypothalamohypophyseal
Physiological (Structural) Delay
0 It is the most common cause of hypogonadotropic amenorrhea. It is due to delayed maturation of the GnRH pulsatile system.
Kallmann Syndrome
0 These patients do not have congenital GnRH. It is the second most common cause of hypothalamic primary amenorrhea. It is accompanied by an olfactory defect (anosmia). There is sexual infantilism, mostly sporadic, but may also be inherited · They respond to pulsatile GnRH therapy and are the most physiological approach to ovulation induction. Estrogen and progesterone should be given to those who do not desire fertility.
CNS Tumors
0 The most common CNS tumor causing primary amenorrhoea is craniopharyngiomas · In addition, germinomas, tubercular or sarcoid granulomas, and dermoid cyst can also cause amenorrhea.
Pituitary Lesions
- Empty Sella Syndrome
- It is the extension of the subarachnoid space into the pituitary fossa due to a congenital sellar diaphragm defect. It can also develop as a result of pituitary surgery, radiotherapy, infarction or tumor. It may be accompanied by amenorrhea.
- Sheehan Syndrome
- It is acute pituitary necrosis due to deep hypotension and hypovolemic shock due to postpartum atony bleeding.
There is postpartum amenorrhea and usually the first sign is the absence of lactation. It may be accompanied by visual disturbances such as headache and narrowing of the visual field. Axillary and pubic hairs fall out, panhypopituitarism develops · The most common deficiencies are in growth hormone and gonadotropins. It is also observed in hypothyroidism.
- Hand Schüller Christian Disease
- Langerhans cell type histiocytosis.
- Infections (tuberculosis, sarcoidosis, encephalitis)
- Diabetic Vasculitis
- Sickle Cell Anemia
- Pituitary Adenoma
Impairment of Hypothalamic GnRH Release
There is a disturbance in the release of 0 GnRH. If the decrease in GnRH pulsatility is very mild, luteal phase disorder occurs, if more prominent, anovulation occurs, and if severe, amenorrhea occurs. They constitute approximately 1:3 of patients with amenorrhea. Increased CRH secretion inhibits gonadotropin secretion by increasing endogenous opiates.
-Anorexia Nervosa Bulumia
- In addition to hypogonadotropic amenorrhea in these patients; Hot-cold intolerance, lanugo feathering, hypotension, bradycardia, hypothyroidism (T3 low, reverse T3 high), osteopenia and diabetes insipidus can also be seen. Due to impaired vitamin A metabolism, serum carotene levels rise, resulting in yellowing of the skin. It is a serious condition with 9% mortality due to hypoglycemia and electrolyte imbalance.
- FSH, LH and estradiol are constantly low and cortisol levels are high in the cases. Anemia, hypoalbuminemia, and hypercholesterolemia are seen.
- Diagnostic criteria for anorexia nervosa:
• Severely low body weight
• Excessive fear of getting fat
• Change in body image perception; Don't see yourself fat even though you're thin
- In bulimia, in addition to amenorrhea, loss of teeth, hypertrophy of the parotid gland, hypokalemia and metabolic alkalosis can be seen.
Stress
- It is the most common cause of acquisition. Due to the increase in endogenous opiates and CRH, GnRH pulsatility decreases and amenorrhea occurs.
Extreme Exercise (Female Athlete Syndrome)
- Causes hypogonadotropic hypogonadism by a mechanism similar to acute weight loss.
hyperprolactinemia
hypothyroidism
Cushing's Syndrome
Chronic Diseases, Neoplasia, Marijuana Use, Malabsorption, Obesity
- Changes in endorphins, cortisol, insulin and IGF cause changes in GnRH pulsatility. It is seen as irregular bleeding with anovulation rather than amenorrhea.
GnRH Receptor Mutation
FSH Deficiency
Normogonadotropic Amenorrhea (FSH 5-20 IU/ML)
► Conditions that cause this type of amenorrhea are usually disorders related to anatomical anomalies. Estrogen, progesterone and gonadotropins are at normal levels, and secondary sexual characters have completed their normal development.
Müller Agenesis (Rokitansky-Küster-Mayer-Hauser Syndrome)
0 The karyotype of the cases is 46,XX and their ovarian functions are normal. However, in these patients with primary amenorrhea, the tuba, uterus and upper part of the vagina are not developed and are in the form of a thin band. Pubic hair growth, breast development and hormonal profile are normal.
0 Although the exact cause is not known, it is thought that there is a mutation in the HOX gene and AMH gene necessary for Müllerian duct development.
0 May be isolated or with other anomalies. There are double collecting ducts in 40% of the patients, pelvic or horseshoe kidney and renal agenesis in 15%, and skeletal anomalies in 5-12% of the patients. Individuals also have abnormal galactose metabolism. In some cases, it may be accompanied by hearing abnormalities.
Asherman Syndrome
0 It is a picture that develops as a result of damage to the basal endometrium after endometrial curettage, cesarean section, myomectomy and metroplasty operations. A similar picture may occur in genital tuberculosis and uterine schistosomiasis.
0 Although amenorrhea is the most prominent clinic, pregnancy loss, dysmenorrhea and hypomenorrhea are also seen.
0 Although it can be diagnosed with hysterosalpingography (HSG}, hysteroscopy is the most sensitive method in diagnosis.
0 With hysteroscopy, adhesions can be opened and treatment can be completed. To prevent re-adhesion of the cavity, an IUD or pediatric foley catheter can be inserted (withdrawn after 7 days). The endometrium is induced by giving the patient a high dose of estrogen (2.5 mg/day) for 2 months. 70-80% of cases can become pregnant, but complications such as abortion, premature labor, placenta accreta, placenta previa and postpartum bleeding may occur during pregnancy.
Transverse Blocking Conditions
0 Imperforate hymen occurs due to the absence of transverse vaginal septum and cervix or vagina.
0 Cyclic pelvic pain, hematocolpos, hematometra or hemoperitoneum may be seen in cases of imperforate hymen and transverse vaginal septum, starting from puberty. Although the uterus and ovaries are normal in ultrasonography, a dense cystic cyst with extension to the dogula is observed (hemtocolpos). The risk of endometriosis is also increased in these patients.
• In all cases of amenorrhea, pregnancy should be ruled out first.
Anenorrhea Treatment
• If possible, the primary cause should be corrected.
• If the primary cause cannot be corrected in hypogonadotropic hypogonadism, combined estrogen and progesterone are used cyclically to initiate, mature and maintain secondary sex characteristics.
• Combined estrogen and progesterone are used cyclically to initiate, mature and maintain secondary sexual characteristics in patients with primary amenorrhoea associated with all gonadal insufficiency and hypergonadotropic hypogonadism. Gonadectomy should be performed in those with a Y cell line.
• In those who want pregnancy; Clomiphene is ineffective in ovulation induction in hypogonadotropic hypogonadism. Human menopausal gonadotropin (hMG) is usually successful. If the pituitary functions are normal, GnRH can be used pulsatilely.
Gonadotropins have no place in the treatment of hypergonadotropic amenorrhea.