Menstrual Cycle Regulation and Abnormal Bleeding PDF

MENSTRUAL CYCLE CONTROL Associate Professor Ziya Kalem M.D İSTİNYE UNIVERSITY LIV BAHÇEŞEHİR In order to understand and treat menstrual cycle abnormalities, first of all, it is necessary to know the physiological mechanisms that regulate the normal menstrual cycle. In order to be easy and understa...

MENSTRUAL CYCLE CONTROL Associate Professor Ziya Kalem M.D İSTİNYE UNIVERSITY LIV BAHÇEŞEHİR In order to understand and treat menstrual cycle abnormalities, first of all, it is necessary to know the physiological mechanisms that regulate the normal menstrual cycle. In order to be easy and understandable, it will be appropriate to examine the menstrual cycle in 3 parts. 1. Follicular phase 2. Ovulation 3. Luteal phase  FOLLICULAR PHASE It is the process of selecting a single follicle (dominant follicle) ready for ovulation from a group of immature (immature) follicles and covers a period of 10-14 days, but it should be noted that the recovery of the follicle group including the leader follicle from atresia is due to the rise of the FSH hormone in the late luteal period of the previous cycle. In fact, the time from a primordial follicle to the level of the preovulatory follicle is 85 days.  PRIMORDIAL FOLLICULE In embryonic life, primordial germ cells are formed as a result of the migration of endodermal cells from the yolk sac, allantois, and hindgut to the genital prominence. In the embryo, these cells begin to multiply by mitosis at 6-8 weeks and reach a total of 6-7 million by the 20th week. These cells are surrounded by a single layer of granulosa cells and a primordial follicle pool is formed. During this period, the oocyte is in the diplotene stage of the prophase of the 1st meiosis. By birth, most of these cells undergo atresia, and at birth the approximate number is reduced to 2 million. Until puberty, this number drops to 300-400 thousand. Bu sayıdaki follikül havuzundan üreme hayatı boyunca ortalama 400 follikül ovulasyonla atılır. From this number of follicles pool, an average of 400 follicles are ejected through ovulation throughout the reproductive life. PREANTRAL FOLLİKÜL Preantral follicle occurs as a result of the growth of the oocyte in the primordial follicle, the formation of the zona pellucida membrane around it, the multilayered granulosa cells, and the formation of theca cells from the ovarian stroma outside the basal lamina. Developments up to this stage are independent of FSH, that is, they develop under the influence of paracrine and autocrine factors; these are factors like GDF9, BMP15. FSH receptors first develop on granulosa cells in the preantral follicle, that is, the preantral follicle responds to FSH. The success of a follicle depends on its ability to transform an androgen-dominated microenvironment into an estrogen-dominated microenvironment. High androgen levels suppress aromatase activity and the resulting androgenic environment causes the follicle to undergo atresia.  ANTRAL FOLLICULE Under the synergistic effect of FSH and estrogen, granulosa cells begin to produce an excess of follicular fluid. These fluids, which begin to accumulate in the intercellular space, combine to form a fluid cavity and thus the antral follicle emerges. The follicle fluid contains hormones, cytokines and growth factors, which provide the appropriate environment for the oocyte and surrounding cells to mature properly. In this period, the granulosa cells around the oocyte are called cumulus oophorus. In the presence of FSH, estrogen is concentrated in the follicle fluid. In the absence of FSH, androgen dominance occurs in the follicle fluid. LH is not found in the follicle fluid until the middle of the cycle. If LH occurs early in plasma and antral fluid, mitosis stops in granulosa cells, degeneration begins, and intrafollicular androgen levels increase. In follicles with androgen dominance, estrogen induced mitosis in granulosa cells stops and the oocyte degenerates The steroid hormone concentration in the follicular fluid is hundreds of times higher than in the plasma and reflects the functional capacity of the theca- granulosa cells. Steroid hormone synthesis occurs in two separate functional compartments within the follicle.  TWO CELLS – TWO GONADOTROPINES Aromatase activity is much higher in granulosa cells than in theca cells. In humans, in preantral and antral follicles, LH receptor is found only on theca cells, and FSH receptor is found only on granulosa cells. Androgen is synthesized in theca cells under the influence of LH hormone, and this androgen is converted to estrogen by aromatization induced by FSH in granulosa cells. HYPOTHALAMUS AND GONADOTROPINE RELEASE HORMONE (GNRH=LHRH) The hypothalamus is composed of nerve cell bodies called nuclei. The n.arcuatus in the mediobasal area of the hypothalamus is the main regulator of steroid hormone synthesis and the menstrual cycle. GNRH is synthesized in hypothalamic neurons and transported to the median eminence around primary portal plexuses by axons, and rapidly passes into the portal circulation, stimulating gonadotrope cells in the anterior pituitary lobe, causing FSH, LH synthesis and secretion.  GNRH GnRH is a 10 amino acid decapeptide. Half-life is less than 5 minutes It is secreted pulsatilely. Under the influence of GnRH, first the stored reserve of FSH and LH, and then the synthesized reserve are released from the basophilic cells in the anterior pituitary lobe. Early follicular: 94 min Late follicular:71 min midluteal 103 min late luteal 216 min synthesis of steroid hormones from cholesterol  PREOVULATORY FOLLICULE Granulosa cells enlarge and contain lipid inclusion bodies Vacuoles increase and vascular structures increase in theca cells In the oocyte, meiosis progresses and approaches reduction division. With the effect of LH, luteinization begins in the granulosa cells and as a result, progesterone synthesis begins.  INHIBIN, ACTIVIN, FOLLISTATIN These peptides are secreted by granulosa cells. They are secreted by the effect of FSH. Inhibin inhibits FSH secretion (reciprocal relationship) Activin stimulates FSH secretion Follistatin binds to activin and suppresses FSH secretion. The preovulatory follicle initiates LH secretion, which is necessary for ovulation, with the effect of estradiol secreted by itself.(positive feedback) Ovulation occurs 10-12 hours after the LH peak level or 24 -36 hours after the estrogen peak level, that is, the follicle ruptures. The most reliable indicator for the expected ovulation time is when the LH surge begins, ovulation occurs 34-36 hours after LH begins to rise. The LH surge causes meiosis to start again (but meiosis is completed by expulsion of the second polar body after sperm enters the oocyte) LH increase causes granulosa cells to luteinize and start to secrete progesterone, prostaglandin synthesis increases, plasminogen increases, collagen decompensates and follicle ruptures.  LUTEAL PHASE Before the rupture of the follicle and the expulsion of the ovum, the granulosa cells increase in size and appear vacuolated, and yellow pigment called lutein accumulates in it. After ovulation, the granulosa cells continue to grow and become the corpus luteum with the participation of the theca cells around the follicle. Capillaries penetrate the granulosa cells and reach the follicle cavity, and the cavity is filled with blood, the corpus luteum in this period is called the corpus hemorrhagicum. 8-9 days after ovulation, vascularization peaks in the corpus luteum, and progesterone level also peaks. The luteal phase does not prolong indefinitely even with continued LH stimulation, indicating degeneration of the corpus luteum with an active luteolytic mechanism. 9-11 days after ovulation, corpus luteum functions decrease, the mechanism of this degeneration is unknown. Here, nitric oxide may be effective because NO induces apoptosis in luteal cells. Another mechanism is that estradiol synthesized locally in the corpus luteum causes luteolysis by increasing prostaglandin F2-alpha synthesis. In the luteal phase, estrogen is needed for the formation of progesterone receptors in the endometrium and for endometrial changes with the effect of progesterone. ABNORMAL UTERINE BLEEDING Abnormal uterine bleeding is the most common reason for women of reproductive age to see a doctor Abnormal menstrual bleeding Other causes: Pregnancy, systemic diseases, or cancer In 60% of cases, no pathological findings are found during examination (formerly called dysfunctional bleeding) It should be kept in mind that sometimes there may be more than one cause  Abnormal Uterine Bleeding Definitions Menorrhagia: Used to express menstrual bleeding that is both excessive in amount and prolonged in duration. The defined amount is bleeding over 80 ml in total, but this definition is used in research. In the clinic, the patient's statement is taken into account. A clot in menstrual blood is not abnormal, but it can indicate excessive bleeding Bleeding in the form of squirting or bleeding that constantly leaks from the vulva, called "open-faucet", is always considered abnormal. Submucous myoma Pregnancy complications Adenomyosis Intrauterine devices Endometrial hyperplasia Malignant tumors Coagulation disorders Bleeding not yet classified (dysfunctional bleeding) Hypomenorrhea: It refers to the lack of bleeding, sometimes it is just spotting. It may be due to obstruction in the cervical canal, adhesion in the uterine cavity (Asherman syndrome) or hymenal stenosis. In some patients who use birth control pills, menstrual bleeding may be very little in the form of spotting. Metrorrhagia: (Intermenstrual bleeding) It occurs between menstrual periods. It may be due to pathological reasons such as endometrial polyp, endometrial cancer, but it may be in the form of spotting due to the sudden drop in estrogen after ovulation. In recent years, it has also been seen due to drugs used for postcoital protection. Polymenorrhea: Menstrual cycle intervals shorter than 21 days It is usually associated with anovulation, but it can also be due to a short follicular phase or a short luteal phase. Menometrorrhagia: Bleeding that occurs at irregular intervals and varies in amount and duration. It can be due to pregnancy complications or malignant diseases Oligomenorrhea: Menstrual period intervals longer than 35 days. It usually develops due to anovulation Amenorrhea: It is the condition of not having menstruation for more than 6 months, it can develop due to pregnancy, hypothalamic and pituitary problems, excessive weight loss, menopause Postcoital bleeding: Cervical cancer should be considered until proven otherwise. Other causes may include; infection cervical polyp cervical eversion atrophic vaginitis Cervical smear, colposcopy and biopsy may be required. FIGO 2011 CLASSIFICATION SYSTEM Detailed anamnesis Physical examination Cytological examination Pelvic ultrasound Blood tests Endometrial biopsy Hysteroscopy Dilation-Curettage HISTORY The cause of many vaginal bleedings can only be determined by taking a detailed history. The amount and duration of bleeding, the length of cycle intervals, the amount and duration of intermenstrual bleeding; the time of the last menstruation, the age of the first menstrual period, the age of menopause and whether there is an additional disease should be questioned. In order to understand whether the bleeding is abnormal or a variation of normal, the patient should keep a record of the bleeding pattern. Most women may experience menstrual irregularities that may occur occasionally and are not abnormal. In such cases, depending on the patient's age and the pattern of bleeding, all that needs to be done is to monitor.  PHYSICAL EXAMINATION A mass in the pelvic region of the abdomen and irregular palpation of the uterus suggest myoma. A symmetrically growing uterus is characteristic for adenomyosis or endometrial carcinoma. Lesions in the vulva, vagina and cervix can be recognized on inspection. Decidual reactions in the cervix during pregnancy may be the cause of bleeding A barrel-shaped cervix can be recognized with rectovaginal examination (cervix ca.)  CYTOLOGICAL EXAMINATION Cervical smear, which is used in the diagnosis of asymptomatic intraepithelial lesions, can also be helpful in the screening of endocervical invasive cancers Cervical cytology is not reliable in the diagnosis of endometrial diseases, but if endometrial cells are seen in cytology in a postmenopausal woman who is not taking estrogen, further investigation is required. Even tubal or ovarian cancer can be suspected by looking at cervical cytology. Abnormal findings in cervical smear may require further investigations such as colposcopy, biopsy and HPV testing.  PELVIC ULTRASOUND Pelvic ultrasound is an integral part of the gynecological examination and can be performed vaginally or abdominally. Examination with ultrasound can add many details to the physical examination; endometrial structure, thickness, intramural and submucous myomas, polyps, adnexal masses can be recognized with ultrasound Sonohysterography: Ultrasound is performed simultaneously by injecting fluid into the endometrial cavity through a thin catheter. This technique is more sensitive in detecting problems in the endometrial cavity (polyp, myoma, adhesion..). ENDOMETRIAL BIOPSY It can be done using Novak, Duncan, Kevorkian curettes or Pipelle. If no cause is found and bleeding continues, Hysteroscopy or dilatation curettage is performed. HYSTEROSCOPY The cavity is directly monitored by inserting an endoscopic camera into the endometrial cavity through the cervical canal. It has recently replaced dilatation and curettage because it does not require hospitalization and has a higher diagnostic value.  DILATATION and CURETTAGE For many years it has been used as the gold standard in the diagnosis of abnormal uterine bleeding General anesthesia Local anesthesia Outpatient treatment However, it may be insufficient in focal lesions (such as polyps) MANAGEMENT OF ABNORMAL UTERINE BLEEDING There should be no prejudice when making a diagnosis. Anamnesis and careful pelvic examination Pregnancy? Birth control pill? Intrauterine device (IUD)? Are the cycles ovulatory? Are they anovulatory? The cause of bleeding in ovulatory cycles may be corpus luteum persistence or short luteal phase. In anovulatory cycles, there is irregular shedding in the endometrium, after organic causes are excluded (thyroid, pituitary, adrenal), the patient is given oral contraceptives and progesterone to control bleeding. The development of diagnostic and treatment methods has reduced the number of surgery, like hysterectomy If there is no reason such as submucous myoma, cancer or life-threatening active bleeding, we can prefer hormone preparations or minimally invasive procedures to hysterectomy. Antifibrinolytic agents and prostaglandin synthase inhibitors can be used successfully for menorrhagia. Long-acting intramuscular progestogens (Depo-Provera) or Levanorgestrel-releasing intrauterine devices are as effective as endometrial resection in treating bleeding NON-GYNECOLOGICAL CAUSES Myxoedema Hypothyroidism Liver diseases Blood dyscrasias Excessive weight gain or loss Heavy exercise Drug use (anticoagulants, adrenal steroids  ANOVULATORY (DYSFUNCTIONAL) UTERINE BLEEDING estrogen breakthrough bleeding estrogen withdrawal bleeding progesterone breakthrough bleeding progesterone withdrawal bleeding ANOVULATORY (DYSFUNCTIONAL) UTERINE BLEEDING After pathological causes are ruled out (polyp, myoma etc.), dysfunctional bleeding is diagnosed. Although persistent corpus luteum and short luteal phase are the cause of bleeding in ovulatory patients, the vast majority of patients are anovulatory Although the exact causes of anovulation are unknown, hypothalamic- pituitary axis disorders are the main cause and unopposed estrogen causes excessive growth of the endometrium and eventually, after a certain point, irregular shedding, i.e. bleeding, begins After organic causes are ruled out (thyroid, pituitary, adrenal), the patient is given oral contraceptives and progesterone, the endometrium is transformed from the proliferative phase to the secretory phase and bleeding is controlled TREATMENT In adolescents: In the first years after menarche, cycles are usually irregular because they are anovulatory. Heavy bleeding may occur. After pathological conditions are excluded with examination, ultrasound and blood tests, these patients are treated by giving estrogen. Very rarely, curettage may be required. In excessive bleeding, 25 mg conjugated estrogen can be given intravenously at 4 hour intervals, when bleeding decreases, 2.5 mg orally (at 4-6 hour intervals) is continued for 14-21 days, when bleeding stops, medroxyprogesterone acetate is given 5-10 mg per day for 7-10 days. As an alternative to this treatment, oral contraceptives can be administered 3-4 times a day. After bleeding is brought under control, treatment is continued for 3-4 cycles at the lowest possible dose. If the result of a biopsy is proliferative endometrium, the patient can be given medroxyprogesterone acetate 10 mg for 10 days. If bleeding is not too severe in adolescents, oral contraceptives can be given at normal doses for 3-4 months. Young women: The approach is similar to adolescents in women between the ages of 20-30, but the possibility of organic causes is higher Premenopausal women: This is a group that requires attention because the possibility of endometrial cancer must be excluded. Surgical treatments: Dilation and Curettage Levanorgestrel-containing IUD Endometrial Ablation Myomectomy Hysterectomy POSTMENOPAUSAL BLEEDING Bleeding that occurs 12 months after the last menstrual period is called postmenopausal bleeding. During this period, the FSH value should be above 30 mIU/mL Postmenopausal bleeding is likely to be due to pathological reasons. Any bleeding that occurs after menopause is abnormal. The most common reason is that patients do not use their hormone treatments properly. If endometrial hyperplasia develops in patients under HRT (hormone replacement therapy), the progesterone dose is increased, and if there is atypia in the hyperplasia, hysterectomy is performed. Cracks in the vulva or atrophy in the vagina may cause bleeding. Local or systemic estrogen can be used in these patients In postmenopausal bleeding, fractionated curettage must be performed. In recurrent postmenopausal bleeding, even if the cause is not found, hysterectomy may sometimes be necessary