MENSTRUAL CYCLE DISORDERS DIAGNOSIS PETR KREPELKA 1

NORMAL MENSTRUAL CYCLE The mean duration of the MC Mean 28 days (only 15% of ♀) Range 21-35 The average duration of the MC 3-8 days The normal estimated blood loss? Approximately 30 ml Ovulation occurs Usually day 14 34 hrs after the onset of mid-cycle LH surge 2

NORMAL MENSTRUAL CYCLE Regulation of MC Interaction between hypothalamus, pituitary & ovaries Menarche 12.7 Menopause 51.4 3

HYPOTHALAMIC ROLE IN THE MENSTRUAL CYCLE The hypothalamus secretes GnRH in a pulsatile fashion GnRH activity is first evident at puberty Follicular phase GnRH pulses occur hourly Luteal phase GnRH pulses occur every 90-180minutes Loss of pulsatility down regulation of pituitary receptors   secretion of gonadotropins Release of GnRH is modulated by –ve feedback by: steroids gonadotropins Release of GnRH is modulated by external neural signals 4

PHASES OF THE MENSTRUAL CYCLE Ovulation divides the MC into two phases: 1-FOLLICULAR PHASE -Begins with menses on day 1 of the menstrual cycle & ends with ovulation ▲RECRUITMENT FSH  maturation of a cohort of ovarian follicles “recruitment”  only one reaches maturity 5

FOLLICULAR PHASE MATURATION OF THE FOLLICLE (FOLLICULOGENESIS) - FSH  primordial follicle (oocyte arrested in the diplotene stage of the 1st meiotic division surrounded by a single layer of granulosa cells)   1ry follicle (oocyte surrounded by a single layer of granulosa cells basement membrane & theca cells)   2ry follicle or preantral follicle (oocyte surrounded by zona pellucida , several layers of granulosa cells & theca cells)

FOLLICULOGENESIS  tertiary or antral follicle 2ry follicle accumulate fluid in a cavity “antrum” oocyte is in eccentric position surrounded by granulosa cells “cumulous oophorus”

FOLLICULOGENESIS continue to thrive SELECTION -Selection of the dominant follicle occurs day 5-7 -It depends on - the intrinsic capacity of the follicle to synthesize estrogen -high est/and ratio in the follicular fluid -As the follicle mature   estrogen  FSH “-ve feed back on the pituitary”  the follicle with the highest No. of FSH receptors will continue to thrive - The other follicles “that were recruited” will become atretic 8

- LH  theca cells  uptake of cholesterol & LDL  FSH ACTIONS -recruitement -mitogenic effect   No. of granulosa cells  FSH receptor -stimulates aromatase activity  conversion of androgens  estrogens “estrone & estradiol” -  LH receptors - ESTROGEN Acts synergistically with FSH to - induce LH receptors - induce FSH receptors in granulosa & theca cells - LH  theca cells  uptake of cholesterol & LDL  androstenedione & testosterone

FOLLICULOGENESIS OTHER FACTORS THAT PLAY A ROLE IN FOLLICULOGENISIS -INHIBIN Local peptide in the follicular fluid -ve feed back on pituitary FSH secreation Locally enhances LH-induced androstenedione production -ACTIVIN Found in follicular fluid Stimulates FSH induced estrogen production  gonadotropin receptors androgen No real stimulation of FSH secretion in vivo (bound to protein in serum)

PREOVULATORY PERIOD - NEGATIVE FEEDBACK ON THE PIUITARY - estradiol & inhibin -ve feed back on pituitary   FSH -This mechanism operating since childhood - POSITIVE FEEDBACK ON THE PITUITARY   estradiol (reaching a threshold concentration - 200 pg/ml, for 48 hrs )   +ve feed back on the pituitary (facilitated by low levels of progestrone)   LH surge  secretion of progestrone Operates after puberty +ve feed back on pituitary   FSH 11

PREOVULATORY PERIOD LH SURGE Lasts for 48 hrs Ovulation occurs after 34hrs Accompanied by rapid fall in estradiol level Triggers the resumption of meiosis Affects follicular wall  follicular rupture Granulosa cells  lutenization  progestrone synthesis

OVULATION Gentle release of the oocyte surrounded by the cumulus The dominant follicle protrudes from the ovarian cortex Gentle release of the oocyte surrounded by the cumulus granulosa cells Mechanism of follicular rupture 1- Follicular pressure Changes in composition of the antral fluid   colloid osmotic pressure 2-Enzymatic rupture of the follicular wall LH & FSH  granulosa cells  production of plasminogen activator   plasmin   fibrinolytic activity  breake down of F. wall LH   prostglandin E   plasminogen activator   PG F2α   lysosomes under follicular wall 13

LUTEAL PHASE LASTS 14 days FORMATION OF THE CORPUS LUTEUM After ovulation the point of rupture in the follicular wall seals Vascular capillaries cross the basement membrane & grow into the granulosa cells  availability of LDL-cholestrole LH  LDL binding to receptors  3α OH steroid dehydrogenase activity  progestrone The luteal phase is about 14 days in length and ends with the onset of menses. This phase includes the functional lifespan of the corpus luteum, which supports the released ovum by secreting progesterone. Progesterone secretion increases up to 8 days after the LH surge. Smaller increases in 17α-hydroxyprogesterone, estradiol, and estrone occur. Progesterone decreases before menses unless the ovum is fertilized and pregnancy results. A serum progesterone level higher than 10 ng/mL 1 week before menses is probably diagnostic of normal ovulation. Progestins increase basal morning body temperature so that a “thermogenic shift” of more than 0.3° C occurring after a nadir is a presumptive sign of ovulation. Unfortunately, taking basal temperatures on a daily basis is tedious, subject to error, and not very reliable 14

LUTEAL PHASE Marked  in progestrone secretion Progestrone actions: -suppress follicular maturation on the ipsilateral ovary -thermogenic activity  basal body temp -endometrial maturation Progestrone peak 8 days after ovulation (D22 MC) Corpus luteum is sustained by LH It looses its sensitivity to gonadotropins  luteolysis  estrogen & progestrone level  desquamation of the endometrium “menses”

LUTEAL PHASE estrogen & progestrone   FSH &LH The new cycle stars with the beginning of menses If pregnancy occurs  hCG secreation  maintain the corpus luteum

ENDOMETRIAL CHANGES DURING THE MENSTRUAL CYCLE 1-Basal layer of the enometrium -Adjacent to the mometrium -Unresponsive to hormonal stimulation -Remains intact throughout the menstrual cycle 2-Functional layer of the endometrium Composed of two layers: -zona compacta  superficial -Spongiosum layer 17

ENDOMETRIAL CHANGES DURING THE MENSTRUAL CYCLE 1-Follicular /proliferative phase Estrogen  mitotic activity in the glands & stroma   endometrial thickness from 2 to 8 mm (from basalis to opposed basalis layer) 2-Luteal /secretory phase Progesterone - Mitotic activity is severely restricted -Endometrial glands produce then secrete glycogen rich vacules -Stromal edema -Stromal cells enlargement -Spiral arterioles develop, lengthen & coil 18

MENSTRUATION Periodic desquamation of the endometrium The external hallmark of the menstrual cycle Just before menses the endometrium is infiltrated with leucocytes Prostaglandins are maximal in the endometrium just before menses Prostaglandins  constriction of the spiral arterioles ischemia & desquamation Followed by arteriolar relaxation, bleeding & tissue breakdown When estradiol and progesterone decline, the stroma becomes edematous, endometrial and blood vessel necrosis occurs, and bleeding ensues. Local release of prostaglandins may initiate vasospasm with ischemic necrosis and uterine contractions that accompany menstrual flow. Prostaglandin synthetase inhibitors can relieve menstrual cramping. Fibrinolytic activity peaks at the time of menstruation, accounting for the noncoagulability of menstrual blood. The histologic changes are characteristic; therefore, endometrial biopsies can be used to characterize the stage of the cycle and to assess the tissue response to gonadal steroids. 19

Definition of normal menstruation Regularity Frequency - Cycle lenght Duration of menstrual flow Volume of menstrual flow

Describing normal uterine bleeding Regularity of menstruation Regular Iregular Absent Frequency Frequent Normal Infrequent

Describing normal uterine bleeding Duration of menstrual flow Prolonged Normal Shortened Volume of menstrual flow Heavy Light

Nomenclature for normal menstraution Abnormal uterine bleeding Feature Normal Abnormality 1 Abnormality 2 Regularity Regular ±2;20d Iregular variation > 20d Absent Frequency Normal q 24-38d Frequent < 24d Infrequent >38d Duration Normal 4,5-8d Prolonged > 8d Shortened <4,5d Volume Heavy Light 23

Classification of causes of abnormal uterine bleeding PALM - COEIN Polyp Coagulopathy Adenomyosis Ovulatory dysfunction Leiomyoma Submucosal Endometrial Other Iatrogenic Malignancy&hyperplasia Not classified Thesystem ha sbeen approved by the FIGO Executiv eBoardas aFIGO classification system. There are 9 main categories,which are arranged according to the acronym PALM-COEIN(pronounced“pahm-koin”): 24

Myoma classification Submucosal Pedunculated intracavitary 1 Pedunculated intracavitary 1 >50% intracavitary 2 ≤50% intracavitary Other 3 Contacts endometrium, 0% intracavitary 4 Intramural 5 Subserosal ≥50% intramural 6 Subserosal <50% intramural 7 Subserosal pedunculated 8

Initial evaluation. For a diagnosis of chronic abnormal uterine bleeding (AUB), the initial assessment requires the patient to have experienced 1 or a combination of unpredictability, excessive duration, abnormal volume, or abnormal frequency of menses for at least the previous 3 months. Patients should undergo a structured history designed to determine ovulatory function, potential related medical disorders, medications, and lifestyle factors that might contribute to AUB. For those with heavy menstrual bleeding, the structured history should include the questions from Table 1 . Understanding the future fertility desires of the patient will help to frame the discussion of therapy following appropriate investigation. Ancillary investigations should include a hemoglobin and/or a hematocrit assessment, appropriate tests for features that could contribute to an ovulatory disorder (thyroid function, prolactin, and serum androgens), and if the Table 1 -based structured history is positive for coagulopathy either referral to a hematologist or appropriate tests for von Willebrand disease. Reproduced, with permission, from Ref. [11] . Reproduced, with permission, from Ref. [11] . FIGO classification system (PALM-COEIN) for causes of abnormal uterine bleeding in nongravid women of reproductive age Munro, Malcolm G., International Journal of Gynecology & Obstetrics, Volume 113, Issue 1, 3-13 Copyright © 2011

Uterine evaluation. The uterine evaluation is, in part, guided by the history and other elements of the clinical situation, such as patient age, presence of an apparent chronic ovulatory disorder, or presence of other risk factors for endometrial hyperplasia or malignancy. For those at increased risk, endometrial biopsy is probably warranted. If there is a risk of structural anomaly, particularly if previous medical therapy has been unsuccessful, evaluation of the uterus should include imaging, at least with a “screening” transvaginal ultrasound (TVUS) examination. Unless the ultrasound image indicates a normal endometrial cavity, it will be necessary to use either or both hysteroscopy and saline infusion sonography (SIS) to determine whether target lesions are present. Such an approach is also desirable if endometrial sampling has not provided an adequate specimen. Uncommonly, these measures are inconclusive or, in the instance of virginal girls and women, not feasible outside of an anesthetized environment. In these instances, magnetic resonance imaging (MRI) may be of value, if available. Abbreviations: AUB, abnormal uterine bleeding; CA, carcinoma. Reproduced, with permission, from Ref. [11] . Reproduced, with permission, from Ref. [11] . FIGO classification system (PALM-COEIN) for causes of abnormal uterine bleeding in nongravid women of reproductive age Munro, Malcolm G., International Journal of Gynecology & Obstetrics, Volume 113, Issue 1, 3-13 Copyright © 2011

Menstrual cycle disorders Polymenorrhoea Oligomenorrhoea Hypomenorrhoea Amenorrhoea Menorrhagia Hypermenorrhoea Dysmenorrhoea Premenstrual syndrome 28

Polymenorrhoea vs. oligomenorrhoea

Hypermenorrhoea vs. menorrhagia 30

Dysmenorrhoea Painful menstruation Primary – occurs only in ovulatory cycles High level of prostaglandines Secondary Endometriosis Pelvic inflammatory disease Congenital abnormalities 31

Premenstrual syndrome Complex of physical and emotional symptoms that occur cyclic before menstruation Therapy - symptomatic Premenstrual syndrome (PMS), also known as premenstrual tension, is a complex of physical and emotional symptoms that occur repetitively in a cyclic fashion before menstruation and that diminish or disappear with menstruation. 32

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