Menstr uel Cycle and Menstr uel Cycle Abnormalities

Menstruel Cycle and Menstruel Cycle Abnormalities Rukset Attar, MD, PhD Department of Obstetrics and Gynecology

MENSTRUEL CYCLE • Menstruation is the cyclic, orderly sloughing of the uterine lining, in response to the interactions of hormones produced by the hypothalamus, pituitary, and ovaries. • The menstrual cycle may be divided into two phases: • the follicular or proliferative phase, and • the luteal or secretory phase

MENSTRUEL CYCLE • Menstrual cycles that occur at intervals less than 21 days are called polymenorrheic, • and menstrual cycles, which are prolonged more than 35 days, are called oligomenorrheic. • The menstrual cycle is typically most irregular around the extremes of reproductive life, menarche and menopause, due to anovulation and inadequate follicular development. • The luteal phase is relatively constant with a duration of 14 days. • The variability of cycle length is usually derived from varying lengths of the follicular phase of the cycle, ranging from 10 to 16 days.

The Follicular Phase • Between cycle days 5 and 7 and only one follicle is selected from the cohort of recruited follicles to ovulate and the remaining follicles will undergo atresia • By cycle day 8, one follicle exerts its dominance by promoting its own growth and suppressing the maturation of the other ovarian follicles • Serum estrogen levels rise in parallel to the growth of follicle size as well as to the increasing number of granulosa cells

For the positive feedback effect of LH release to occur, estradiol levels must be greater than 200 pg/ml for approximately 50 hours in duration

Ovulation • Ovulation occurs approximately 10-12 hours after the LH peak. • The LH surge is initiated by a dramatic rise of estradiol produced by the preovulatory follicle • To produce the critical concentration of estradiol needed to initiate the positive feedback, the dominant follicle is almost always >15mm in diameter on ultrasound • The LH surge stimulates • luteinization of the granulosa cells • synthesis of progesterone responsible for the midcycle FSH surge • resumption of meiosis and the completion of reduction division in the oocyte with the release of the first polar body

Ovulation • Prostaglandins and proteolytic enzymes such as collagenase and plasmin, are increased in response to LH and progesterone. • Although the precise mechanism is not known, proteolytic enzymes and prostaglandins are activated and digest collagen in the follicular wall, leading to an explosive release of the oocyte-cumulus complex • Prostaglandins may also stimulate ovum release by stimulation of smooth muscle within the ovary. • The point of the dominant follicle closest to the ovarian surface where this digestion occurs is called the stigma

Luteal Phase • After ovulation, the granulosa cells continue to enlarge, become vacuolated in appearance, and begin to accumulate a yellow pigment called lutein. • The luteinized granulosa cells combine with the newly formed theca-lutein cells and surrounding stroma to become what is known as the corpus luteum. • The corpus luteum is a transient endocrine organ that predominately secretes progesterone and its primary function is to prepare the estrogen primed endometrium for implantation of the fertilized ovum. • The basal lamina dissolves and capillaries invade into the granulosa layer of cells in response to secretion of angiogenic factors by the granulosa and thecal cells

Abnormalities of The Menstrual Cycle • Major abnormalities of menstruation during the reproductive years : • amenorrhea and • abnormal uterine bleeding • pregnancy

Amenorrhea • Amenorrhea may be defined as • the absence of menstruation for 3 or more months in women with past menses (i.e., secondary amenorrhea) or • No menses by age 14 in the absence of growth or development of secondary sexual characteristicsor • No menses by age 16 regardless of the presence of normal growth and development of secondary sexual characteristics( primaryamenorrhea)

The basic requirements for normal menstrual function thus include four anatomically and functionally distinct structural components • the genital outﬂow tract including the uterus, • the ovary, • the pituitary, and • the hypothalamus—thus providing a natural and useful hierarchy for organizing the diagnostic evaluation of amenorrhea.

Amenorrhea can result from congenital or acquired disease or dysfunction at any level in the system and can involve more than one mechanismegPCOS involves a number of interrelated pathophysiologicmechanismsoperating at the ovarian, pituitary and hypothalamic level

Accordingly, the many causes of amenorrhea can be categorized according to the site or level of the disorder or disturbance: • Disorders of the genital outﬂow tract and uterus • Disorders of the ovary • Disorders of the anterior pituitary • Disorders of the hypothalamus or central nervous system

Evaluation of Amenorrhea • a careful medicalhistory and physical examination • In those with primary or secondary amenorrhea having a patent vagina and visible cervix, the likelihood of a genital outﬂow tract abnormality is very small. • The only possibilities that need be considered are cervical stenosis and intrauterine adhesions (Asherman syndrome) or other endometrial damage that may result from surgical trauma or infection. • In those with primary amenorrhea • ImperforateHymen • TransverseVaginalSeptum • MüllerianAgenesis • AndrogenInsensitivitySyndrome

Evaluation of Amenorrhea • primary amenorrhea • Gonadaldysgenesis- espTurner S

In women with normal genital tract anatomy and no relevant history to suggest the possibility of cervical stenosis or Asherman syndrome, disorders of the genital outﬂow tract and uterus can be excluded and further stepwise evaluation is required to determine the cause of amenorrhea. Attention now may be focused on the next level of the reproductive system, theovary.

Abnormalities of ovarian function are the most common overall cause of amenorrhea and include a wide variety of disorders ranging from simple chronic anovulation, as in women with PCOS, obesity, thyroid disorders and hyperprolactinemia, to complete ovarian failure relating to chromosomal abnormalities or other genetic disorders such as Fragile X (FMR1) premutations and galactosemia, autoimmune disease, radiation or chemotherapy.

Serum Estradiol Concentration-40 pg/mL clearly suggests the presence of functional ovarian follicles but also is common during a premature or normal perimenopause and occurs sporadically in women with hypothalamic amenorrhea. estrogenic” cervicalmucus progestinchallenge test endometrialthickness,- 6 mm A high serum FSH concentration is a reliable indication of ovarian follicular depletion or failure

Hypogonadotropic state: Prepubertal, Hypothalamic or pituitary dysfunction • Serum FSH<5 IU/L Serum LH<5 IU/L • Hypergonadotropic state: Postmenopausal, Castrate, or Ovarian failure • Serum FSH >20 IU/L Serum LH >40 IU/L • Normal • Serum FSH 5–20 IU/L Serum LH 5–20 IU/L

When evaluation reveals clear evidence of normal ovarian estrogen production and the serum FSH level also is normal, the diagnosis of chronic anovulationis established. • thyroid disorders • prolactin disorders • PCOS, • obesity, • stress or exercise, and • reproductive aging

Themostcommoncauses of sec. amenorrheaare • Cronicavovulation • Hypothalamicsupression • Anorexia/weightloss • Prolactinomas • Asherman • Hypothyroidism

Chronic Anovulation • With inappropriate steroid feedback • Functional androgen excess (PCOS) • Adrenal Hypoplasia • Neoplasms producing androgens or estrogens • Neoplasms producing hCG (including trophoblastic disease) • Liver and renal disease • Obesity • Other endocrine disorders • Thyroid dysfunction • Adrenal hyperfunction

Chronic Anovulation • Hypothalamic • Psychogenic, including pseudocyesis • Exercise-associated • Eating disorders, nutritional • 2° to systemic illness • Hypothalamic neoplasms • Pituitary • Isolated gonadotropin deficiency (including Kallmann syndrome) • Hypopituitarism • Pituitary neoplasms, including microadenomas

When evaluation reveals clear evidence of low ovarian estrogen production and the serum FSH level is consistently high, the diagnosis of ovarian failure is established. • Ovarian Failure

HypergonadothropicAmenorrhea • Gonadaldysgenesis /Turner, 46 xx püre gonadaldysgenesis, 46 Xypuregonadaldysgenesis-Swyer S ) • Fragile X Syndrome • Gonadothyropinreceptormutations ( LH, FSH ) • Resistantovarysyndrome ( Savage S) • Otoimmuneooforitis ( Blizzard S) • Galaktosemia • Enzymedefects- 17-alpha hydroxilase, and 17-20 desmolase, aromatase, konjlipoid adrenal hyperplasia • RT/ CT • İnfections • Complete androgeninsensitivity

Premature Ovarian Failure • Cytogenetic Alterations of the X Chromosome • Mutations of Specific Genes • Enzymatic Defects • Steroidogenic enzyme defects • 17α-Hydroxylase or 17,20-lyase deficiency • 20,22-Desmolase deficiency • Aromatase deficiency • Galactosemia • Defects in Gonadotropin Secretion or Action • Receptor and post-receptor defects • Secretion of biologically inactive gonadotropin • α- or β-Subunit defects

Premature Ovarian Failure • Immune Dysfunction • Association with other autoimmune disorders (15-20% of cases, 4% with steroidogenic cell autoimmunity) • Isolated • In association with congenital thymic aplasia • Physical Insults • Chemotherapeutic (especially alkylating) agents • Ionizing radiation • Viral agents • Surgical extirpation • Gonadotropin-Secreting Pituitary Tumors (Extremely Rare) • Idiopathic

all patients under age 30 with a diagnosis of ovarian failure, a karyotypeshould be obtained to exclude chromosomal translocations, deletions, and mosaicism A karyotypealso identifies those having a Y chromosome in whom gonadectomy is indicated due to the risk for malignant transformation (20–30%). FMR1- fragile X the presence of anti-adrenal antibodies strongly implies autoimmune oophoritisas the cause of POF and identifies women who should be carefully evaluated and followed to exclude adrenal insufficiency-Anti-CYP21

When estrogen levels are clearly low, a serum FSH level in the low normal range (5–10 I/L) • When there is no clear explanation for hypogonadotropic hypogonadism (e.g., signiﬁcant physical, nutritional, or emotional stress) or for hyperprolactinemia (e.g., medications), further evaluation with imaging is indicated to exclude tumors and to help distinguish between pituitary and hypothalamic causes. • Kalmann S, AnorexiaNervosa, Craniopharingeoma, PraderWillie S, emptysella, Sheehan S, İnfectionssuch as tbc, sarcoidosis, HandSchüller Christina disease, physiologic) • The method of choice is MRI (with gadolinium contrast) because it is more sensitive and accurate than other imaging techniques for detection of abnormalities within and near the sellaturcica.

The routine endocrine evaluation of women with amenorrhea includes the measurement of serum • Beta hCG • TSH, • prolactin, • FSH • E2 • Women with pituitary macroadenomasrequire additional evaluation, including a serum free T4, IGF-1 (GH deficiency), and morning cortisol level (6:00–9:00 A.M.) ( Adrenal insufficiency).

Diagnosis • History and physical examination • Body dimensions and habitus • Distribution and extent of terminal androgen-stimulated body hair • Extent of breast development by Tanner staging and the presence or absence of any breast secretions • External and internal genitalia • FSH, TSH, and prolactin • progestin challenge • total testosterone and dehydroepiandrosterone sulfate

Etiology of Abnormal Uterine Bleeding • Organic causes • Associated with disorders of the reproductive tract • Pregnancy-related disorders • Malignancies • Benign uterine abnormalities (i.e., fibroids, polyps) • Iatrogenic causes (i.e., IUDs, estrogens) • Lower genital tract disease • Functional ovarian cysts and other benign ovarian neoplasms • Systemic disease • Coagulation disorders (Primary or secondary) • Thyroid dysfunction • Liver disease • Dysfunctional (anovulatory) uterine bleeding (DUB)

Abnormal Uterine Bleeding • Menorrhagia (hypermenorrhea) is heavy orprolonged menstrual flow • submucousmyomas, • complications of pregnancy, • adenomyosis, • IUDs, • endometrial hyperplasias, • malignanttumors, and dysfunctional bleeding are causes ofmenorrhagia.

Abnormal Uterine Bleeding • Hypomenorrhea (cryptomenorrhea) is unusuallylight menstrual flow, sometimes only spotting. • Anobstruction such as hymenal or cervical stenosis • Uterine synechiae (Asherman’s syndrome) • oral contraceptives occasionally

Abnormal Uterine Bleeding • Metrorrhagia (intermenstrual bleeding) isbleeding occurring at any time between menstrual periods. • Ovulatory bleeding occurs at midcycle as spottingand can be documented with basal body temperatures. • Endometrial polyps and endometrial and cervical carcinomas • Exogenousestrogen administration

Abnormal Uterine Bleeding • Polymenorrhea • Menometrorrhagia • Oligomenorrhea • Contact bleeding (postcoital bleeding) • Cervicalcancer • Cervicaleversion, • cervical polyps, • cervical or vaginal infection(eg, due to Trichomonas), or atrophic vaginitis

Etiology of Abnormal Uterine Bleeding • DUB • results from a functional abnormality of the hypothalamic-pituitary-ovarian axis • the frequency of the various causes of AUB varies with the age of the patient. • DUB is more common early and late in the reproductive years.

Causes of DUB • Prepuberty • Newborn girls sometimes spot for a few days after birth because of placental estrogenic stimulation of the endometrium in utero. • Withdrawal of the estrogen at birth leads to sloughing of the endometrium. • Accidental trauma to the vulva or vagina is the most common cause of bleeding during childhood. • Vaginitis with spotting, most often because of irritation from a foreign body, also may occur. • Prolapse of the urethral meatus and tumors of the genital tract also must be considered in the differential diagnosis.

Causes of DUB • When the bleeding is due to the ingestion of estrogen-containing drugs (typically oral contraceptives) by children, there is rarely significant pubertal development. • Sexual abuse always must be considered in the young girl presenting with abnormal bleeding. • Thus, it is clear that most of the prepubertal causes of bleeding are really not uterine in origin.

Causes of DUB • Adolescents • as many as half of all menstrual cycles are anovulatory when menses begin • Typically, anovulatory bleeding occurs at intervals longer than normal menstrual cycles, while bleeding due to organic causes tends to occur more frequently than regular menses. • In most cases of anovulatory bleeding beginning in adolescence, there is spontaneous resolution. • However, it is important to remember that up to 20% of patients with AUB during the teenage years have a primary coagulation disorder. • It is also important to rule out pregnancy-related bleeding during the reproductive years

Causes of DUB • ReproductiveAges • Exogeneous hormon use • Pregnancy • Anovulation • Fibroids • Servicalandendometrialpolyps • Tiroiddisfunction

Causes of DUB • Perimenapouse • Anovulation • Fibroids • Servicalandendometrialpolyps • Tiroiddisfunction

Causes of DUB • Postmenauposal • Endometrialatrophy • Endometrialpolyp • Malignancy • Hormon therapy • Endometrial hyperplasia clearly is a possibility in women who do not ovulate on a regular basis, even at a much earlier age than 40 • Tumors of otherorganssuch as vulva, vagina, serviks • The finding of endometrial hyperplasia after the menopause always should result in a search for a source of estrogen, either from exogenous therapy or from an endogenous (commonly ovarian) neoplasm.

Diagnosis • history • physical examination • The hemodynamic stability of any patient with abnormal bleeding should be assessed. • The pelvic examination will rule out obvious organic causes. • complete blood count to assess hematological status, • a platelet count and • other coagulation studies to rule out a coagulation defect, • and thyroid function studies to rule out a thyroid abnormality.

Diagnosis • endometrial biopsy • is indicated in any woman over age 35 with AUB, • in any woman with a prolonged history of irregular bleeding, and • in most, if not all, women with severe bleeding • endometrial thickness • there is almost never any significant pathology when the endometrial thickness is less than 5 mm • sometimes termed saline infusion sonography (SIS), • hysteroscopy

New ClassificationSystemfor AUB at reproductiveages • PALM-COEİN Classification • Polyp • Adenomyosis • Leyomioma, • Malignity ve hyperplasia • Coagolopathy • Ovulatuarydysfunction, • Endometrial • Iatrojenik • Nonclassified

PALM: StructurelCausesfor AUB at reproductiveages • Polyp (AUB-B) • Adenomyosis (AUB-A) • Leiomyoma (AUB-L) • Submukousmyoma (AUB-L sm) • Othermyomas (AUB-Lo) • Malignityor hyperplasia (AUB-M)

COEİN: NonstructurelCauses • Coagolopathy (AUB-C) • Ovulatuarydysfunction(AUB-O) • Endometrial (AUB-E) • Iatrogenik (AUB-I) • Nonclassified (AUB-N)

Treatment • Progesteron • Estrogen • COC • PG syntesisinhibitors- NSAIs • LNG-RIA • GnRHanalogs • Danazol • Desmopressin • Antifibrinolitictherapy

Menstr uel Cycle and Menstr uel Cycle Abnormalities