Amenorrhea

AMENORRHEA
Ludmila Barbakadze
Ivane Javakhishvili Tbilisi State University Assistant Professor �Medical Doctor at Archil Khomassuridze Institute of Reproductology ,Tbilisi , Georgia.

1. AMENORRHEA Ludmila Barbakadze Ivane Javakhishvili Tbilisi State University Assistant Professor Medical Doctor at Archil Khomassuridze Institute of Reproductology ,Tbilisi , Georgia.

2. Definition: the absence of menstrual bleeding Physiologic states of Amenorrhea: prepubertal age, pregnancy, lactation and postmenopausal females. Non-Physiologic occurs in 5% of reproductive age women. In the absence of pregnancy, the challenge is to determine the exact cause of absent menses. Amenorrhea might be Primary and Secondary

3. . Primary amenorrhea - is the absence of menses by age 16 years, in the presence of normal growth and secondary sexual characteristics. If by age 14 menses has not occurred and the onset of puberty, such as breast development, is absent, a workup for primary amenorrhea should start. Secondary amenorrhea - is defined as the cessation of an established menses – for 3 months in a woman with a regular cycle or 6 months in a women with history of irregular cycle.

4. Causes of primary amenorrhea First , it is imperative to rule out pregnancy. Additional diagnoses of primary amenorrhea usually result from a genetic or anatomic abnormality. The relative prevalence of primary amenorrhea includes: hypergonadotropic hypogonadism (48.5% of cases), hypogonadotropic hypogonadism (27.8%), and eugonadism (pubertal delay with normal gonadotropins ; 23.7%). The hypergonadotropic hypogonadism category includes patients with abnormal sex chromosomes ( ie , Turner syndrome), who make up 29.7% of all primary amenorrhea cases, and those with normal sex chromosomes. The latter group includes both patients who are 46,XX (15.4%) and those who are 46,XY (3.4%).

5. Causes of secondary amenorrhea Disorders associated with a low or normal FSH, which account for 66% of cases of secondary amenorrhea, include the following: Weight loss/anorexia Chronic anovulation including PCOS Hypothyroidism Cushing syndrome Pituitary tumor, empty sella , Sheehan syndrome Disorders in which the FSH is high (12%) include the following: 46,XX spontaneous POI Premature ovarian failure due to abnormal karyotype (45,X mosaic/ring chromosome) Pure gonadal dysgenesis Disorders associated with a high prolactin level make up 13% of cases. Anatomic disorders ( ie , Asherman syndrome) account for 7%. Hyperandrogenic states as a cause of secondary amenorrhea (2%) include the following: Polycystic ovarian syndrome (PCOS) Ovarian tumor Non-classic CAH Undiagnosed Iatrogenic Antipsychotics Cancer   chemotherapy Antidepressants Blood pressure  drugs Allergy medications.

6. Hypothlamic dysfunction (20-30%) hypogonadotropic hypogonadism leads to low gonadotropin (FSH/LH) levels.

7. Types of amenorrhea based on HPO axis etiology Hypothalamic amenorrhea ( 20-30 %) Hypothalamic dysfunction results in decreased GnRH secretion, which affects the pulsatile release of pituitary gonadotropins , LH and FSH, causing anovulation . A common cause of amenorrhea is functional hypothalamic amenorrhea .   Functional hypothalamic amenorrhea can be caused by eating disorders, exercise, or high levels of prolonged physical or mental stress (depression). Hypothyroidism, hyperthyroidism, or any severe chronic medical condition may result in amenorrhea.

8. Idiopathic hypogonadotropic hypogonadism leads to low gonadotropin (FSH/LH) levels. When this occurs with anosmia, it is diagnosed as Kallmann syndrome, the signs of which include midline facial defects, renal agenesis, and neurologic deficiencies. Kallmann syndrome most commonly occurs as an X-linked recessive disorder caused by a  KAL1  defect. In some female athletes excessive exercise and disordered eating cause severe suppression of GnRH , leading to low estradiol levels. This female characterized by low energy availability with or without disordered eating, amenorrhea, and osteoporosis. Anorexia nervosa  is a serious psychiatric disease with severe medical complications including primary amenorrhea (15%), osteopenia (52%), and osteoporosis (35%).

9. Pituitary amenorrhea A deficiency in FSH and LH may result from GnRH receptor gene mutations. Women with these mutations presented with amenorrhea, low FSH and estradiol levels and high LH levels. Primary amenorrhea caused by hyperprolactinemia is a rare condition characterized by the onset of thelarche and pubarche at appropriate ages but arrest of pubertal development before menarche.   Hyperprolactinemia is associated with suppression of the GnRH from the hypothalamus and subsequent inhibition of LH and FSH, suppressed gonadal function and galactorrhea .  Prolactinomas  are the most common cause of persistent hyperprolactinemia .   Prolactinomas are more commonly noted in secondary amenorrhea. Brain injury or cranial irradiation may also result in amenorrhea. Other pituitary causes include empty sella syndrome, pituitary infarct, hemochromatoses , and sarcoidosis . Treatment: HRT. Hypoth-pituitar region imaging to role out CNS lesions.

10. Gonadal failure 35% Hypergonadotropic hypogonadism is characterized by gonads (bands of fibrous tissue in place of the ovary). Synthesis of o ვ arian steroids does not occur. Breast development does not occur because of very low estradiol level. The ext and internal genitalia are fenotipically normal female. Causes: Terner syndrome (45,XO) > 50% of patients with gonadal failure. Outher causes are comonly due to other non- inheareted chromosomal disorders and deletions . Cause of primary amenorrhea. Treatment: Replacement hormonal therapy – developes breast tissue and prevents osteoporosis. The preasense of Y chromosome requires exciton of ganadal tissue to prevent the 25% incidence of malignancy.

11. Ovarian causes of primary amenorrhea Gonadal dysgenesis is characterized by the congenital loss or underdevelopment of germ cells within the gonad during organogenesis. The gonads usually contain only fibrous tissue and are called streak gonads. In females, the most common form of gonadal dysgenesis is Turner syndrome (45,X), in which gonadotropin levels, especially the FSH levels, are high during early childhood and after age 9-10 years. Additional anomalies associated with Turner syndrome include short stature, webbed neck, coarctation of the aorta (10%), renal abnormalities (50%), hypertension, pigmented nevi, short forth metacarpal and metatarsals, Hashimoto thyroiditis, obesity, and osteoporosis. [3]  Depletion of ovarian follicles causes amenorrhea.

12. POI Spontaneous 46,XX primary ovarian insufficiency (POI), is hypergonadotropic hypogonadism, characterized by oligomenorrhea /amenorrhea, estrogen deficiency, and its associated symptoms such as hot flashes, vaginal dryness, dyspareunia, and insomnia.   Autoimmune oophoritis occurs in 3-4% of POI cases. Amenorrhea is also seen in pure 46, XX gonadal dysgenesis and in 46,XY gonadal dysgenesis . These women have significantly elevated FSH levels due to the absence of ovarian follicles and reduction in negative feedback on FSH from estradiol and inhibin A and B. Polycystic ovarian syndrome (PCOS) usually presents as secondary amenorrhea, but in some cases may present as primary amenorrhea.

13. Congenital and anatomical abnormalities Female reproductive tract abnormalities account for about one fifth of primary amenorrhea cases. Cyclic pelvic pain is common in girls with disorders of the reproductive tract involving outflow obstruction. Imperforate hymen causes an outflow obstruction. These patients can have blood in the vagina that collects and can result in a perirectal mass. Transverse vaginal septum can be anywhere along the tract between the hymenal ring and cervix. Vaginal agenesis, or müllerian dysgenesis (also known as Mayer- Rokitansky - Kuster -Hauser [MRKH] syndrome) is caused by agenesis or partial agenesis of the müllerian duct system. It is characterized by congenital aplasia of the uterus and upper two thirds of the vagina in women showing normal development of the secondary sexual characteristics and a normal 46,XX karyotype.The first sign is primary amenorrhea. It affects 1 of 4500 women. It can be associated with renal, vertebral, and, to a lesser extent, auditory and cardiac defects. Treatment: creation of neovagina by surgery.

14. enzyme defects Complete androgen insensitivity syndrome is caused by a defective androgen receptor. Although patients with this syndrome have a 46,XY karyotype the testosterone cannot activate cellular transcription; therefore, the patient has female external genitalia. The testes, located internally and sometimes in the labia or inguinal area, also produce müllerian -inhibiting hormone, so all müllerian -derived structures ( ie , the fallopian tubes, uterus, upper third of the vagina) are absent .

15. Prognosis Amenorrhea has been associated with an increased risk of wrist and hip fractures related to reduced bone density. Young women with ovarian insufficiency that is unresponsive to therapy require hormone replacement to maintain bone density. Adolescence is a critical period for bone accretion as over half of peak bone mass is achieved during the teenage years.   Regular menses is a sign that the ovaries are producing normal amounts of estrogen, androgens, and progesterone, all of which play an important role in building and maintaining bone mass. Late menarche has been associated with a 3-fold increase in the risk of wrist fracture. In some cases, loss of menstrual regularity is an early sign of declining fertility and impending premature ovarian failure. Also in some cases, follicle depletion progresses to cause irreversible infertility. Women with PCOS have many long-term health issues, including higher risk of diabetes and cardiovascular disease, that should be monitored and treated.

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17. Hypogonadotropic hypogonadism includes the following: Congenital abnormalities Endocrine disorders Tumor Systemic illness (2.6%) Eating disorder (2.3%) Congenital abnormalities that can cause hypogonadotropic hypogonadism include the following: Isolated GnRH deficiency (8.3%) Forms of hypopituitarism (2.3%) Congenital central nervous system (CNS) defects (0.8%) Constitutional delay (6%) Endocrine disorders that can cause hypogonadotropic hypogonadism include the following: Congenital adrenal hyperplasia (CAH) (0.8%) Cushing syndrome (0.4%) Pseudohypoparathyroidism (0.4%) Hyperprolactinemia (1.9%) Tumors that can cause hypogonadotropic hypogonadism include the following: Unclassified pituitary adenoma (0.8%) Craniopharyngioma (1.1%) Eugonadism may result from anatomic abnormalities or intersex disorders. Anatomic abnormalities include congenital absence of the uterus and vagina (CAUV; 16.2%) and cervical atresia (0.4%). Intersex disorders include androgen insensitivity (1.5%), 17-ketoreductase deficiency (0.4%), and inappropriate feedback (5.3%).