Physiology of Menstruation PDF

Part II Chapter 5 Physiology of menstruation PHY SIOLOCi YOF MENSTRUATION What is the menstrual cycle? The menstrual cycle Is a complex series of physiologica l changes occurring in wom- en on a monthly basis. The aim of the ovarian component of th...

Part II Chapter 5 Physiology of menstruation PHY SIOLOCi YOF MENSTRUATION What is the menstrual cycle? The menstrual cycle Is a complex series of physiologica l changes occurring in wom- en on a monthly basis. The aim of the ovarian component of the menstrual cycle is to produce a mature ovum in each cycle whereas the uterine components respon- sible for the preparation of the uterine environment as a "nesting place" in the event of fertilization of the produced ovum. The menstrual cycle is orchestrated by the en- docrine system through the complex Interaction of the hypothalamus, pituitary and gonads. The entire cycle lasts around 28 days, with the cycle beginning on the first day of menstruation & ovulation occurring around day 14. Menstruation: Menstruation is the cyclic shedding of secretory endometrium associated with some blood loss as a result of a decline in the estrogen & progesterone production caused by degeneration of the corpus luteum if no pregnancy takes place Ovulatory cycle Day 2 4 8 10 12 14 16 18 20 22 24 26 28 Follicular phase Luteal phase ~] -5 ~ ~~ :c C. lH ~ FSH " l zJ ~ ~ Q 0.! l E ·.5 e.g Menstruation ,li 10 500 so 8 400 40 6 300 30 4.200 20 2 100 I l 10 Hystro Tuts salplngography 'F 'C 98.8 37.1 98.6 37.0 98.4 36.9 98.2 36.8 08.0. _..............._. 36.7 97.8 36.6 97.6 36.4 97.4 36.3 Day Summary of menstrual cycle physiology - - - - - - - - - - - - -11 Part II Chapter 5 Physiology of menstr uation. ts of Three phases The ovary after puberty undergoes monthly cycles, each consis 1. Follicular phase. 2. Ovulation. 3. Luteal phase. A. Follicular P-hase: ·t 'ta At the first day of menstrual blood flow, the hypothalamo-pl UI ry f axis is released f t he from the negative feedback of Estrogen & progesterone due to degenera ,on ° corpus luteum of the previous cycle. The hypothalamus produces Gonadotrophin Releasing Hormone (GnRH~- This bind to the pituitary stimulating release of Follicle Stimulati ng Ho r- mone (FSH)_. FSH binds to the ovaries stimulating. Development of ovarian follicles ( stimulates the growth of 10-20 follicles ) Secretion of estrogen from the growing follicles Secretion of inhibin (inhibits FSH) from the growing follicles Development of ovarian follicles( folliculogenesis)occurs in Three dis- tinct phases: Recruitment Maturation ---+Dominance The follicle most sensitive to FSH becomes dominant & is known as the Graafian follicle (oocyte develops within it) The Graafian follicle continues to secrete increasing amounts of estrogen This inhibits the growth of the other competing follicles (Negative feedback) The Graafian follicle & its supporting follicles- like a bride in her entourage of bridesmaids. This favorite follicle, truly stands upon the shoulders of its contem- poraries. Facts about the Graafian follicle: Contains the primary oocyte Oocyte is surrounded by a hard shell called "Zona Pellucida" (perlucere=to shine through} Oocyte is also surrounded by Granulosa & Theca cells Granulosa cells, under influence of FSH secretes Estradiol Theca cells , under influence of LH, secretes Progesterone (after ovulation) Mature Graafian follicle reaches a size of ±20mm The Two-cell Two gonadotrophin theory of ovarian steroidogenesis: During the follicular phase, LH stimulates the Theca cells to produce androgens (An- drostenedione, Dehydro-epiandrostenedione &Testosterone). These androgens dif- fuse into the Granulosa cells where they are aromatized under the influence of FSH to the most potent estrogen Estradiol (E2). m- - - - - - - - - - - - - - - - - -  Part II Chaptor 5 Phyaloloyy of menntrualion Estrone Estradiol Estrogen causes: Endometrial regeneration and proliferation. Thinning of cervical mucus to allow easier passage of sperm. Initially inhibits FSH production from the pituitary gland {Negative feedback) When it reaches a threshold level (±200pg/ml sustained for 48 hours) causes a sudden spike in LH around day 12 {Positive feedback -+- only one in the cycle) LH surge causes: Changes in the Graafian follicle wall leading to ovulation within ±36 hours. Resumption of meiosis of the oocyte. Conversion of the Graafian follicle into the progesterone producing corpus lute- um. B. Ovulation: Within 24-48 hours of the LH surge, the follicle ruptures releasing a secondary oo- cyte { ovulation occurs at mid cycle about 14 days before the expected cycle). C. Luteal phase: The corpus luteum {Latin for "yellow body"; plural corpora lutea) is a temporary en- docrine structure in female ovaries and is involved in the production of relatively high levels of progesterone and moderate levels of estradiol and inhibin A. It is the remains of the ovarian follicle that has released a mature ovum during a previ- ous ovulation. The corpus luteum is colored because of concentrating carotenoids (including lutein) from the diet and secretes mainly progesterone plus a moderate amount of estrogen that inhibits further release of gonadotropin-releasing hormone {GnRH) and thus secretion of luteinizing hormone (LH) and follicle-stimulating hor- mone (FSH). A new corpus luteum develops with each menstrual cycle. - - - - - - - - - - - - - - - - - - -11 Part II Chapter 5 Physiology of menstruation N.B: VThe constant length of the luteal phase (14 days) V Day of ovulation= Cycle length- 14 V Ovulatory cycles are painful and regular. Increased levels of progesterone results In Three; Endometrium becoming receptive to Implantation of the blastocyst (day~ embryo) Negative feedback causing.decreased LH & FSH (both needep to maintain th e cor- pus luteum) Three extra-uterine changes: Hostile cervical mucus, impermeable to sperms t basal body temperature Changes in vaginal cytology (Maturation index) 4. Increased progesterone levels -.~ LH levels (negative feedback) -+ degenera- tion of the corpus luteum -. Progesterone no longer produced. 5. The falling level of progesterone triggers menstruation & the entire cycle starts again However if an ovum is fertilized it produces HCG which is similar in function to LH, this prevents degeneration of the corpus luteum (continued production of pro- gesterone) which will continue until placental steroidogenesis is well established at ± 9th or 10th week of gestation(Luteo-placental shift) m-------------------  Part II Chapter 5 Physiology of menstru ation 11. THE ENDOMETRIAL CYCLE The uterus has its own cycle which is governed by changes in the ovarian hormones. The endometrium is the part of the uterus most affected by these changes. It is composed of 2 layers. Functional layer: this grows thicker In response to Estrogen& is shed during men- struation Basal layer: this forms the foundation from which the functional layer develops. it does not shed. The endometrial cycle has 3 phases: The proliferative phase should be regarded as the first phase of the construction of a "home" for the fertilized ovum. Up to ovulation time "foundations, walls, roof and plumbing" are built up. Thereafter, (in the secretory phase), the home is made more hospitable by being stocked with food supplies. 1. Proliferative phase: This corresponds to follicular phase of ovarian cycle. Dur- ing the proliferative phase the endometrium is exposed to an increase in estrogen levels. This estrogen causes regen- eration and proliferation of the functional endometrial layer. 2. Secretory phase Proliferative endometrium The secretory phase begins once ovulation has occurred. First sign of ovulation is appearance of subnuclear vacuolation in the endometrial cells. This phase is driven by progesterone produced by the corpus luteum It results in the endometrial glands beginning to se- crete various substances These secretions make the uterus a more welcoming Secretory endometrium environment for an embryo to implant. Window of fertility A woman's most fertile period is between 5 days before ovulation until 1 to 2 days after. Symptoms of approaching ovulation include thinning and increased amount of cervical mucous, and some women experience something called Mittelschmerz which is German for Mid cycle pain. 3. Menstrual phase: At the end of the luteal phase, the loss of the corpus luteum results in decreased progesterone production. The decreasing levels of progesterone cause the spiral arteries in the functional endometrium to undergo vasoconstriction. The loss of - - - - - - - - - - - - -m Part II Chapter 5 Physiology of menstruation hemic necrosis and blood supply causes the functional endometrlum to un d ergo isc 4 sloughing (shedding to be discharged with menstrual blood. Proliferative Luteal phase Feature Menstrual phase phase Thickness of stra- Absent Thin to thick Thickest tum functionale Appearance of en- Portions of the Straight Highly coiled dometrial glands glands in stratum basales Degree of coiling Absent Less coiled Highly coiled of coiled arteries Predominant go- Falling LH, rising FSH LH nadotropin FSH Predominant ovar- Transition from Estrogen Progesterone ian hormone progesterone to estrogen Days of idealized 1-5 5-14 14-28 28-day cycle Viscosity of cervl- Difficult to Thinnest on Increasing viscos- cal secretions determine CD14 ity Phases of uterine cycle Superficial layer (upper 2/3) Deep layer (lower 1/3) It consists of stratum compactum It consists of stratum basale & stratum spongiosum and they together comprise the functional layer of the endometrium. Supplied by the spiral arteries Supplied by the basilar arteries. which undergo vasoconstriction during the secretory phase. During the secretory phase, these basilar arteries remain straight, so the blood sup- This causes necrosis and slough- ply of the basal layer remains intact and ing of these layers during men- thabs why it is not shed during menstrua- struation tion and it serves to regenerate the other layers. Layers of the endometrium 11- - - - - - - - - - - - - - - - - -  Pa r t II Chapter 5 Physiology of menstruation Early menses da 1-4) Blood. Hypoechoic central echo with a thi ck Luteal endometnum hyperechoic endometrlal echo and pos terlor enhancement similar to the luteal phase Late menses (day 3-7) A Single hyperechoic thin line (central en- dometrial echo) Single line late menstrual endometrium Hypoechoic halo Hypoechoic central echo representing blood disappears Anteroposterior thickness of the who(e Three line proliferation endometrium is only 1-3 mm phase endometrium Early follicular phase (day 5-9) Halo present Relatively thin anteroposterior endome- trial thickness (6 mm) Hyperechoic luteal Luteal phase phase endometrlum Maximum endometrial thickness Hyperechoic endometrium Loss of halo E Loss of triple line sign Maximum posterior enhancement Sonograph ic features of the uterine cycle - - - - - - - - - - - - -11 Part 11 Chapter 5 Physiology of menstruation Comparison between Estrogen & Progesterone Estrogen Progesterone Estrogen in greek «Oistros>> Progesterone In greek «Pro= = frenzy, the cause of heat in favor; gestare = to bear Definition i.e. the hormone of preg- in animals during which time only coitus is possible nancy 1. The Graafian follicle. 1. Corpus Luteum. 2. Syncytiotrophoblast of the 2. Syncytiotrophoblast of placenta. the placenta. Sources 3. Adrenal cortex (small 3. Adrenal cortex (small amount). amount). 4. Peripheral adipose tissue 4. Stromal cells of the ovary (small amount). (small amount). Metabolized in the liver and Metabolized in the liver and excreted in bile. excreted in urine as preg- nandiol. 1% free (active) Metabolism 100% protein-bound. (globu- 99% protein-bound (SHBG lin and albumin). and albumin). During pregnancy, it is excret- ed in urine. I 2 peaks: 1 peak: Mean peak before ovulation After CL formation (midlu- Blood Levels (>200 pg/ml) teal ---. >10 ng/ml) Smaller peak after CL forma- tion.  Part II Chapter 6 Physiology of menstruation On the genital system Vagina --+- shift to th e ri ght In Vagina --+- shift to the middle maturation Index I. e. predomi- in maturation index i.e. pre- nant superfici al cell type --+- dominance of Intermediate acidophlllc cells with pyknotic cell type --+ basophilic cells nuclei on clear background --+- wit h ves icular nuclei on proliferation of vaginal epithe- clear back ground. lium --+- ++ Dodderline bacilli increasing vaginal acidity. Cervix --+- progestational cervical mucous (+amount, Cervix --+ estrogenic cervical mucous (tamount, + viscosity, tSpinbarkeit, viscosity, t cellu larity,( -ve) (-ve) terning) +cellularity, (+ve )Spinbarkeit, --+- non-penetrable. (+ve) terning) --+- penetrable. Uterus --+- proliferative en- Uterus --+ secretory endo- dometrium (if unopposed --+ metrium (must be estrogen- endometrial hyperplasia --+- primed). endometrial carcinoma). Actions f Tubes --+- motility and vascu- Tubes --++ motility. larity. General act ion Breast --+- proliferation of the Breasts --+ development of duct system and increased acini. vascularity. Bone and joints --+ relax- Bones and joints --+ increased ation of joints and ligaments. mineralization. GIT-+ decreased motility. GIT-+ increased motility. Metabolic --+ Metabolic --+ Protein --+ anabolic. Thermogenic effect CHO --+ diabetogenic. f Fat -+ HDL and + LDL. (t o.5°C). Fat --+ +HDL and tLoL. t Clotting --+ clotting factors (II, VII, IX and X) and + fibrino- Water and salt retention. lytic activity. Part II Chapter 5 Physiology of menstruation During pregnancy t Size and vascularlty of geni- Prepares the endometri~m tal organs. for implantation and main- tains the decidua. Uterine contractions. Relaxation of uterine mus- Development of the mam- cle and other smooth mus- mary duct system. cles (quiescence). Development of breast acini. Estrogen is Femininity while Progesterone is Motherhood Hypothalamus Anterior lobe of pituitary ◄ ►. Progesterone ~ Suprarenal cortex Ovary Ovary t Placenta, foetus ~Placenta -,. Embedding of ovum, vascularity of uterus, growth of uterus, myometriai control 11- - - - - - - - - - - - - - - - -  Part II Chapter 9 Amenorrhea AMENORRHEA Definition Amenorrhea is defined as the absence of menstruation. It may be classified as ei- ther primary or secondary. There are, of course, physiological situations in which amenorrhea is normal, namely pregnancy, lactation and prior to the onset of pu- berty and after menopause. Absence of menstruation physlologlcal patholog ical 1- before puberty secondary 2-after menopause 3- during pregnancy 4- during lactation true primary cryptomenorrhea amenorrhea Primary amenorrhea It is the absence of menses by the age of 16 with normal secondary sexual charac- teristics or the absence of menses by the age of 14 without secondary sexual char- acteristics. This means that presence of 2ry sex characters is reassuring, and we can wait before starting to investigate. Cryptomenorrhea (False amenorrhea) refer to chapter on Mullerian anomalies '\l Secondary amenorrhea: It is the absence of menstruation for either 6 months or more than the equivalent time of three menstrual cycles in a previously menstruating female. The four-compartment approach in the diagnosis and management of amenorrhea: Menstruation requires an intact outflow tract that connects a healthy functioning uterine cavity with responsive endometrium with the outside i.e., patency and con- tinuity of the vagina and cervix. The source of menstrual blood is the endometrium. - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - El Part II Chapter 9 Amenorrhea This tissue Is stimulated and r gul t d by prop r quantity and sequence of estrogen and progesterone produc d by th ovary. Th s hormones are produced In a cyclic fashion , by the maturing ov rl n folllcl s, nd the corpus luteum. The ovarian cycle Is mainly d t rmlned by cyclic production of two pituitary gonado- , trophic hormones, the folllcl tlmul ting hormon (FSH) and lutelnizlng hormone (LH). The secretion of these two pituitary hormones Is under the control of gonad- ~ otrophin-releaslng hormone (Gn RH), which Is secreted by the neuronal cells of the basal hypothalamus and carried by the blood to the pituitary through the portal cir- culation connecting the hypothalamus and the pituitary. Moreover, a normal female chromosomal pattern, and active support by the thyroid & adrenal glands are of paramount Importance. Gonadolropln- releasing hormone (GnRH) Hypothalamus Compartment IV : Hypothalamus Compartment Ill: Pituitary gland Lutelnlzlng hormone (LH), Adrenal Folllcle-stlmulatJng Pancreas gland hormone (FSH) f\.Nj Thyroid ~ Other endocrine glands ICompartment I: outflow tract and uterus I Four-compartments required for normal menstruation Major Causes of Primary Amenorrhea Compartment I Mullerian agenesis MRKH (2nd most common (Disorders of outflow tract) cause of primary amenorrhea) Androgen insensitivity syndrome (testicular feminization syndrome) 11 - - - - - - - - - - - - - - - - - - - - - - - -  Part II Choptor 9 Amenorrhea Compartment II Gon d I dysgenosls (most common cause of (Disorders of the ovary) 1ry amenorrh a) -. Turner's syndrome (45X) Pure gonad I dy genesis (46XX) Sweyer's syndrome (46XY) Savage syndrome (resistant ovary syndrome Compartment Ill Neoplasla (Disorders of the anterior Prolactinomas/Craniopharyngiomas pituitary) Hypopituitary states, Chiari Fromme! syndrome Compartment IV Kallman syndrome (amenorrhea + anosmia) (Disorders of the CNS) Frohlich's syndrome (Adiposo-genital Dystrophy) Flow-chart for the management of primary amenorrhea Patient with primary amenorrhea History and physical examination Secondary sexual characteristics are present T Measurement of serum gonadotropln (FSH & LH) T Pelvic ultrasound Uterus absent or Uterus present or Reduced Increased (FSH > 20 IU/L abnormal normal (FSH/LH < 5 IU/L) and LH > 40 IU/L) Hypogonadolroplc Hypergonadolroplo Karyolype Outflow obstruction hypogonadlsm hypogonadlsm Karyotypo enelysls T T TT Androgen Insensitivity M0llerlan agenasls Evaluate for secondary lmperforate hymen or 45f° 1 syndrome amenorrhea transverse vaginal septum Premature Turner's ovarian failure Syndrome - - - - - - - - - - - - - - - - - - - - - - - - 11 Part II Chapter 9 Amenorrhea Major Causes of Secondary Amenorrhea Compartment I Asherman>s syndrome (after excessive curet- (Disorders of outflow tract) tage or endometrial TB). Acquired obstruction (gynatresia) of cervi- cal canal causing severe stenosis or atresla e.g following electrocauterization, chemical burns, cervical amputation in Fothergill's op- eration, conization, CIN or genital TB. Compartment II PCOS (Disorders of the ovary) Trauma (surgery or radiotherapy) Infections (mumps, T.B and rarely pyogenic in- fections) Premature ovarian failure. Compartment Ill Hyperprolactinemia. (Disorders of the pituitary) Pituitary adenoma, prolactinoma. Insufficiency as Simmond's disease and Shee- han's syndrome Empty Sella turcica syndrome Infiltrative disease Compartment IV Vigorous exercise/excessive stress (Disorders of the hypothala- Weight loss. mus) Eating disorders (anorexia and bulimia) Tumor (craniopharyngioma and glioma) Radiation Pseudocyesis (false pregnancy) II Infection (TB) Infiltrative diseases (sarcoidosis) 11 - - - - - - - - - - - - - - - - - - - - - - - - -  Part II Chapter 9 Amenorrhea No anatomical abnormality detected on physical examination and pregnancy excluded - TSH prolactln progestatlonal challenge Elevated Prolactln > +Withdrawal -Withdrawal TSH 100 ng/ml bleeding bleed Normal TSH normalprolactin Cycllc estrogen and progesterone - NormalTSH normalprolactln Anovulation +Withdrawal No bleed bleeding iifjjf FSH, LH assay T Low Normal fill ~ r--=r 1-!,.>'~~~~~~~'!1!' } - Normal I Karyotyplng lfage < 30 Flow-chart for the management of secondary amenorrhea Progesterone withdrawal test: This involves giving progestin (such as medroxy- progesterone acetate 10mg) for 5 days, and then stopping it. If the outflow tract (uterus and vagina) is normal, and there is sufficient endogenous estrogen to in- duce endometrial proliferation, progesterone will produce secretory endometrium. On withdrawing the progesterone, the endometrium will break down, and menstrua- tion will occur. ---------------------------m ~art II Chapter 9 Amenorrhea Asherman's syndrome It is among the most important acquired causes of outflow tract abnormalities. It is the presence of intrauterine adhesions, which prevent endometrial prolifer~- tion (and thus menstru~tion). The commonest cause of Asherman's syndrome is vigorous postpartum uterine ~urettage and severe uterine infections including tuberculous endometritis. Clinical picture: Hypomenorrhea up to amenorrhea; Infertility, recurrent mis- carriage Diagnosis TVS, Hysterosalpingography showing "honey-Coomb" appearance; hysteroscopy Treatment by hysteroscopic lysis of adhesions with insertion of mechanical barrier e.g. balloon catheter, or IUD followed by cyclic hormonal therapy to pro- mote endometrial regeneration. Prognosis: poor in cases of amenorrhea Sheehan's syndrome It is a syndrome resulting from ischemic necrosis of the anterior pituitary gland due to spasm in its arterioles occurring at the time of severe hemorrhage or shock complicating childbirth. Only the anterior pituitary is affected because in a parturient, blood supply to the pituitary gland is modified to the advantage of the posterior lobe. Manifestations of the syndrome are likely to appear when around 75% of the gland is destroyed. If ~95% of the gland is affected, picture of Sim- mond's syndrome (Absolute panhypopituitarism) is seen. Symptoms include failure of lactation after delivery, due to low prolactin pro- duction, secondary amenorrhea with low FSH&LH, loss of libido, increased sen.;. sitivity to cold (low TSH). Signs include genital/breast atrophy, loss of axillary& pubic hair, signs of hypo- thyroidism (weakness& lethargy), hypothermia and hypoglycemia. Management is by life-long hormone replacement Kallman's syndrome (Idiopathic.hypogonadotrophic Hypogonadism) Genetic condition characterized by hypogonadotropic hypogonadism and anos- mia. Several genetic variants are present but common event is disruption of the mi.: gration of olfactory nerve cells and GnRH-producing nerve cells in the develop- ing brain. · m -------------------------  Part II Chapter 9 Amenorrhea Eating Disorders: Anorexia and Bulimia nervosa It is a psychiatric disorder with severe physiological consequenc- es characterized by the inability or refusal to maintain a minimally normal weight. Patients have a profoundly disturbed body image as well as an in- tense fear of weight gain despite being moderately underweight. Two subtypes: restricting (limitation of food intake) & Binge- eating (bulimia nervosa) in which there is self-induced vomit- ing. Exercise-associated amenorrhea (Athletic amenorrhea) Deficit resulting from inadequate replenishment of the caloric demands of train- ing. Female athletic triad describes a relationship of eating disorder, osteoporosis (low estrogen leading to fractures), and amenorrhea. Stress-induced amenorrhea Due to stressful situations leading to hypothalamic amenorrhea, eg from exams. Contraception-related amenorrhea Persistence of the negative feedback exerted by the contraceptive agent on the pi- tuitary gland after the stopping of the contraceptive agent. This prevents ovulation leading to amenorrhea for variable durations of time, usually around six months. The presence of the so called post-pill amenorrhea is currently questionable. Treatment of Amenorrhea 1. Treatment of the cause: for example: Surgical resection of intrauterine, cervical, and vaginal adhesions/septa. Treatment of hyperprolactinemia (medical or surgical) Correction of thyroid dysfunction. Psychiatric treatment of eating disorders 2. Induction of ovulation: e.g., PCOS if pregnancy Is desired. 3. Oral contraceptive pills is a good treatment option that can achieve besides the cyclic bleeding, contraception, and f hormone-replacement therapy to maintain body constitution and prevent osteoporosis. - - - - - - - - - - - - - - - - - -- - - - - - - 1 1