[OBS] 01 Ovarian, Endometrial, and Menstrual Cycle.pdf

OBS OBSTETRICS 1 SHIFT 1 LE...

OBS OBSTETRICS 1 SHIFT 1 LESSON Ovarian, Endometrial, and Menstrual Cycle Anne Catherine A. Castro, MD | 08/10/23 01 TABLE OF CONTENTS ❐ Monthly process of endometrial tissue sloughing with 1. Overview of Menstrual Cycle 1 hemorrhage, dependent on sex steroid hormone-directed 1.1. Hypothalamic-Pituitary-Ovarian Axis changes in the blood flow in the spinal arteries 1.2. Menstrual Cycle Spiral Arteries 2. Ovarian Cycle 4 Interspersed between the muscle fibers 2.1. Follicular phase ○ End points located at endometrium 2.2. Ovulation phase ❐ Estrogen o f is responsible for thickening of endometrial lining 2.3. Luteal phase ❐ Progesterone is responsible for the sloughing off of the 3. Endometrial Cycle 9 thickened endometrial lining 3.1. Proliferative phase 3.2. Secretory phase ❐ INFORMATION (2024 Trans) 3.3. Menstruation Menstruation 4. Summary 13 Starts when there is desquamation of the endometrium LEGEND Purpose: To promote a new endometrial growth. ○ Important because the uterus is meant to be a place or ★ Important / Take Note ✤ Textbook Information a sanctuary for a pregnancy to happen ➤ Lecturer’s Verbatim ❐ Other Transes/Resources ○ Regeneration/endometrial growth happens every month after the desquamation to allow another PHASES OF THE MENSTRUAL CYCLE possible pregnancy to happen CYCLE PRE-OVULATION O POST-OVULATION V Ovarian Follicular phase U Luteal phase L A T Proliferative I Uterine Period Secretory phase phase O N Figs. 2-3. Overview of the Menstrual Cycle 1. OVERVIEW OF MENSTRUAL CYCLE PSP Average menstrual cycle: 28 days Menstrual Cycle Day 5 to 7: period of angiogenesis/revascularization to ○ Remarkable coordination of morphologic changes that stop bleeding occurs within the axis of hypothalamus, pituitary and ○ Bleeding cannot happen for entire 28 days, it has to ovaries as well as outside such as uterus and cervix have a period of recovery ○ Divided into 2 cycles Ovarian Cycle Changes that happen to the ovaries Ovulation period divides it into 2 phases ○ Follicular phase ○ Luteal phase Endometrial Cycle Changes that happen to the endometrium ○ Proliferative phase Fig 4.The Menstrual Cycle ○ Secretory phase Blue - most fertile days If corpus luteum (CL) is rescued by the human chorionic gonadotropin (hCG) that continuously secretes progesterone → Decidualization of endometrium occurs If CL production of progesterone drops → Menstruation occurs During menstruation, RBCs are interspersed in the endometrium Proliferative phase: with presence of non-convoluted glands Secretory Phase: more bending and an appearance of Fig 1. Overview of the Menstrual Cycle (Source: Dr. Castro’s plenary lecture) more stroma in endometrium UST MED 2026 | OBSTETRICS 1 1  OBS SHIFT 1 | LESSON 1 | Ovarian, Endometrial, and Menstrual Cycle After ovulation, there is a production of corpus luteum which produces progesterone → produces negative feedback to hypothalamus and anterior pituitary Fig 5.The Endometrium During Menstruation What brings about Menstruation? ① Leukocyte infiltration ○ Key to initiation of extracellular matrix breakdown of the functionalis layer ○ Functionalis layer is shed off; Basalis layer is left behind to help in the regeneration of the endometrium should a pregnancy not occur ① Severe coiling of the arteries → hypoxia of the endometrium ○ Similar to a patient having angina pectoris Endometrial ischemia → tissue degeneration ③ Rupture of an arteriole of a coiled artery with formation of hematoma ○ Superficial endometrium is distended due to hematoma → ruptures Cause for blood clots ④ Leakage from a spiral artery Fig 6. Hypothalamic-Pituitary-Ovarian Axis Functionalisis shed, Basalis left for endometrial growth (Source: Dr. Castro’s plenary lecture) Clinical Application In certain procedures, only the Functionalis layer is scraped off leaving the Basalis layer intact. Doctors avoid the Basalis layer since touching this layer may cause the patient H 1.1. HYPOTHALAMIC-PITUITARY-OVARIAN AXIS APP Hypothalamus secretes Gonadotropin-Releasing Hormone (GnRH) → GnRH stimulates anterior pituitary to secrete FSH, LH, TSH, GH, adrenocorticotropic hormones. ○ FSH and LH: part of HPO axis FSH stimulates granulosa cells of the ovaries to = => hypothalamus ↓ : GnRH secrete estrogen * - - Ant. pituitary : ESH G LH stimulates theca cells of the ovaries to secrete LH 17 granulos estrogen thecaAharon ene androgen & progesterone Androgens are converted into estrogen via the Fig 7. Hypothalamic-Pituitary-Ovarian Axis aromatase enzyme which is produced in the (Source: Dr. Yu’s plenary lecture) granulosa cells ❐ FSH and LH are important to stimulate growing follicles within ❐ Estrogen and progesterone contribute to the ovary menstrual cycle High levels of FSH and LH from the anterior pituitary (but ○ ❐ Posterior pituitary secretes vasopressin and oxytocin more of FSH) → stimulate the ovary to produce a mature After that, there is a negative feedback of estrogen to the follicle hypothalamus As FSH increases, the mature follicle increases in size → ○ If estrogen levels are high, initially, it produces a more estrogen is secreted negative feedback to the anterior pituitary ○ Initially, there is a rise in estrogen, as it increases further, But higher levels produce a positive feedback to the there is a slow negative feedback on FSH anterior pituitary to produce more FSH But there would be further increase in estrogen levels UST MED 2026 | OBSTETRICS 1 2  ↑ FSH StimulatesAmaurefondback - surge - ovulation - development corpus lutum - & progestor i s (luteinization) ↳ inhibits GnRH to produce follicles inhibin OBS SHIFT 1 | LESSON 1 | Ovarian, Endometrial, and Menstrual Cycle more thru Increased levels of estrogen → stimulate anterior pituitary to 1.2. MENSTRUAL CYCLE JMP secrete more FSH and LH (positive feedback) → LH surge → stimulate ovulation → production of corpus luteum FSH and LH levels ○ There is also an increase in FSH but more of LH ○ Initial low level would increase → stimulate high levels of ○ Corpus luteum produces progesterone estrogen → stimulate increase of FSH but more of LH As corpus luteum is produced, there would be high levels of ❐ INFORMATION (2025 Trans) progesterone Ovulation release mature follicle ○ From the extrusion of the mature follicle, the CL comes out which is formerly the graafian follicle > - estrogeenant > - progesterone predominant CL produces increasing amounts of progesterone which will inhibit the GnRH to produce more follicles ○ During this phase, ovary secretes 3 hormones: ③ ⑪ estrogen, inhibin, and progesterone Inhibin: signals the hypothalamus to stop ① producing GnRh → inhibited production of FSH O and LH ○ If fertilization occurs, there would be implantation and patient would become pregnant Pregnant patient will have its CL stay a little longer to produce more progesterone to maintain its pregnancy ○ If NO fertilization, corpus luteum will be produced, the cycle repeats and then patient menstruates Fig 9. The Menstrual Cycle ❐ INFORMATION (2024 Trans) (Source: Dr. Castro’s plenary lecture) How do we measure the amount of menstrual blood the patient has? Menstrual Cycle is composed of 2 cycles There is a study wherein they used a regular pad and an ○ Ovarian Cycle overnight pad in quantifying the amount the patient bleeds. Follicular Phase: NOT fixed This is important because it serves as a guide for the Luteal phase: Fixed (usually takes 14 days) menstrual history of the patient. ○ Endometrial Cycle When we ask about how much the patient bleeds every Proliferative Phase: NOT fixed menstrual cycle, we have to qualify what type of pad she Secretory Phase: Fixed (usually takes 14 days) uses. Follicular and proliferative phase: estrogen predominant ○ Ex. When a patient told you that she soaked 1 whole Luteal and secretory phase: progesterone predominant pad everytime she bleeds, but she only uses a WITHOUT conception, corpus luteum will decrease in size, pantyliner, that may indicate just a small amount atrophy, and die compared to another patient telling she soaked just a ❐ Menstruation will occur and is brought about by middle portion of her overnight pad. pseudoinflammatory events These 2 scenarios are different so we have to be cautious ❐ Infiltration of neutrophils will be 1-2 days before when asking how much the patient bleeds during menstruation menstruation. ❐ Interaction with IL-8, MCP-1 and monocytes will promote infiltration of neutrophils WITH conception, implanted embryo will continue to secrete progesterone from the hCG produced by the embryo Cycle length counting: from 1st day of menstruation to the next 1st day of menstruation Menstrual Cycle Normal Values Average Cycle Length 28 ± 7 days Range 21-35 days Duration 3-7 days 20-80 mL (anything more or less Amount Fig 8. Different mL of dyed liquid applied to different pad sizes. would be abnormal) UST MED 2026 | OBSTETRICS 1 3  OBS SHIFT 1 | LESSON 1 | Ovarian, Endometrial, and Menstrual Cycle > - same Follicular phase Biological clock ○ Reproductive potential Females in utero have a fixed number of oocytes that can be produced. The number decreases up until puberty. ○ In utero: 4 million oocytes ○ At birth: 2 million oocytes (arrested) ○ Puberty: 400,000 oocytes Depleted at around 1000 follicles per month until the age of 35 In a cycle, a cohort of follicles has a capability of producing eggs. ONLY ONE mature follicle can be fertilized ○ If not fertilized, the patient menstruates. Within the reproductive lifespan of a female, she would have released 400 eggs ○ Around 35 years of reproductive age ➤ Reproductive life of females: 33.3 years I Fig 10. The Menstrual Cycle (Source: Dr. Castro’s plenary lecture) gonadotropin Difference between a cycle with conception and without before & In dependent ○ Follicular and proliferative phases remain the same puberty - ○ Changes would be seen at the luteal phase CDF t ➤ For women who are regularly menstruating, it can be determined when she is fertile because the luteal phase is constant and fixed to 14 days. This can be used to predict when I the patient would ovulate S ○ Ex. Patient with an average cycle length of 28 days, the responsa OCCUr AFTER - puberty patient would be ovulating on the 14th day. i ○ Patient with an average cycle of 30 days, the patient would ovulate at day 16 (30 - 14 = G 16) 2. OVARIAN CYCLE JMP Fig 13. Types of follicles/growth of follicles (Source: Dr. Castro’s plenary lecture) ★ Early follicular growth - controlled by locally produced growth ↳ produced by the ovary factors (GDF9 & BMP15) ★ Secondary/Antral & preovulatory follicles - responsive to FSH Gonadotropin Independent ○ Reach the primary or preantral follicle without the stimulation of gonadotropins (FSH and LH) ○ Usually controlled by locally produced factors Growth differentiation factor 9 (GDF9) and Bone Morphogenetic Protein 15 (BMP15) Fig 11. The Ovarian Cycle (Source: Dr. Castro’s plenary lecture) ○ Occur BEFORE puberty Changes that occur within the ovary; the growth of the follicle Primordial Follicle (50 um) and the release of the oocyte Usually grow into early developing follicles Becomes arrested at the primary or preantral follicle up until puberty Early Developing Follicle (100 um) Primary or Preantral Follicle (200 um) Gonadotropin Dependent ○ In need of stimulation of FSH and LH to move from the primary or preantral follicle to the secondary or antral follicle ○ Occur AFTER puberty Secondary or Antral Follicle (500 um) Preovulatory Follicle (20 um) Fig 12. The Development of follicles (Source: Dr. Castro’s plenary lecture) Antrum - fluid filled cavity within the follicle UST MED 2026 | OBSTETRICS 1 4  OBS SHIFT 1 | LESSON 1 | Ovarian, Endometrial, and Menstrual Cycle 2.1. FOLLICULAR PHASE DHP 2. Selection of dominant follicle ~ 1 6. Fig 16. The Selection of a Dominant Follicle (Source: Dr. Castro’s plenary lecture) Fig 14. Ovarian Cycle (Source: Dr. Yu’s plenary lecture) Usually only one dominant follicle is selected from the cohort to complete growth to maturity. There are 3 events that occur during follicular phase ○ Recruitment of a cohort of antral follicles ❐ The one stimulated with the most FSH will be the R S G. ○.. The selection of a dominant follicle graafian follicle (2025 trans) ○ Growth of the selected dominant follicle The other follicles in the cohort become atretic Selection of a dominant follicle from the cohort usually only one becomes a dominant follicle, it selectively grows and the rest of the cohort will eventually die. Fig 15. Recruitment of a Cohort of Antral Follicles (Source: Dr. Yu’s plenary lecture) 5-7 follicles ~ 1. Recruitment of a cohort of antral follicles During each ovarian cycle, a group of antral follicles (cohort) begins a phase of semi-synchronous growth Fig 17. The Development of Follicles (Source: Dr. Castro’s plenary lecture) FSH is required for further development of large antral follicles (cyclic recruitment) ➤ Why do the other follicles in the cohort die while only one Selection window - follicular development from FSH follicle dominates? stimulation This is because of the increase of granulosa cells within Only follicles progressing to this stage develop the capacity to the dominant follicle. produce estrogen. ➤ Granulosa cells produce estrogen. continuous secretion of estrogen from granulosa cells ➤ There are several eggs that die, thousand eggs per cycle ➤ As this dominant follicle increases in size while more estrogen undergo apoptosis. being produced, this initial increase in estrogen would exert a ➤ During each ovarian cycle a group of antral follicles or negative feedback to the anterior pituitary gland so that FSH will secondary follicles begin a semi-synchronous growth upon decrease in number. stimulation of FSH or gonadotropins. ➤ The initial decrease of FSH would be insufficient to stimulate all ➤ FSH stimulation is needed for the ovarian cycle to start. the follicles These groups of antral follicles that are predetermined to Because FSH decreases, there won’t be enough stimulation of other smaller follicles to continue growing>thus,on, - grow at this cycle are called cohorts (5-7 follicles). Only the dominant follicle will survive since it will be the only one stimulated by the FSH. ❐ In one pregnancy, you would only have a single gestation coming from one dominant follicle. (2025 trans) ❐ In some occurrences, there would be two dominant follicles (fraternal twin gestations). (2025 trans) UST MED 2026 | OBSTETRICS 1 5  OBS SHIFT 1 | LESSON 1 | Ovarian, Endometrial, and Menstrual Cycle 3. Growth of the selected dominant follicle Fig 20. Negative Feedback Loop of Inhibin Fig 18. Graafian Follicle (Source: Dr. Castro’s plenary lecture) (Source: Dr. Castro’s plenary lecture) The last event of the follicular phase is the growth of the There would be LH and FSH surge. selected dominant follicle. Aside from the estrogen, inhibin B is also produced ➤ One characteristic change of the dominant follicle is the ○ This is an inhibitor that causes a negative formation of the theca cell layer feedback to your anterior pituitary gland to ○ Surrounds the granulosa cell layer produce less FSH. ○ Differentiates into theca interna and theca externa (recall LH stimulates the theca cell ❐ INFORMATION (2025 Trans) layer) Production of Theca cell layer ○ Surrounds the granulosa layer * 2.1.2. Two-cell-two-gonadotropin theory ○ Rapidly differentiates into: Theca interna - near the granulosa cells Theca externa - exterior part of dominant follicle Theca cell layer responds to LH while granulosa cell responds to FSH which represents the Two-cell-two -gonadotropin theory Two-cell-two-gonadotropin theory Granulosa Cell ○ Granulosa cell is stimulated by FSH which causes the conversion of Androstenedione to gromatase Estradiol ○ The estradiol will diffuse into the basement membrane and goes into the circulation Theca Cell ○ Theca cell is stimulated by LH which causes the conversion of cholesterol to Androstenedione ○ Androstenedione will diffuse into the granulosa stimulates cell which contributes to the higher levels of Fig 19. Two-cell-two-gonadotropin Theory estradiol (Source: Dr. Castro’s plenary lecture) ○ Into some degree the Androstenedione also goes ➤ The Two-cell-two-gonadotropin theory states that during the into the circulation follicular phase, LH stimulates the theca cells to produce androstenedione or androgens from the cholesterol ➤ These androgens traverse the basement membrane and enter the granulosa cell Once inside, FSH stimulates the production of the aromatase enzyme which is the enzyme that converts androstenedione to the estradiol. ➤ This Two-cell-two-gonadotropin theory increases the amount of estradiol essentially available to the body which would go to the circulation and produce an eventual positive feedback to increase the FSH. UST MED 2026 | OBSTETRICS 1 6  OBS SHIFT 1 | LESSON 1 | Ovarian, Endometrial, and Menstrual Cycle 2.2. OVULATION PHASE MDP ❐ INFORMATION (2024 Trans) OVULATION Occurs 24 hours after peak estradiol level, however there is no specific amount for this > - estradiol peak 24hrs after estradiol peak ○ 250 pg/mL of estradiol would already indicate ② 34-36hrs after initial LH rise * a mature follicle ③ 10-12hrs after LH peak Difficult to determine if this is the peak evel so what we usually use is the initial rise of LH as basis for ovulation Occurs 34-36 hours after initial rise of LH, ovulation would occur ○ Basis of OTC ovulation test kits ○ Patient to check their urine for the LH level Two lines will not indicate if it is the surge already or peak but will only indicate adequate amount of LH Occurs 10-12 hours after peak of serum LH ○ Stimulates resumption of meiosis in the ovum and release of the first polar body During ovulation, there is also a rupture of the follicular wall leads to the following: ○ The follicle must rupture in order to release of the cumulus oocyte complex (COC) - this oocyte should be fertilized by the sperm to conceive ○ This is due to the plasminogen activator group AProgesterone and prostaglandins causes rupture the Fig 21. Ovarian-Endometrial Cycle (w/o conception) (Source: Dr. Castro’s plenary lecture) ○ The activation of proteases play a role in the weakening of the follicular wall and eventually leading to its rupture Once you have a mature follicle, the dominant follicle grows and ovulation. into the correct size ○ Dominant follicle of 18 mm above indicates that this is a mature follicle Ovulation (red line) ○ Happens 14 days from the last normal menstrual LMP period If the patient is regularly menstruating in a 28 day cycle, ovulation usually happens along Day 14 (red line) Fig 22. An ovulated cumulus-oocyte complex (Source: Dr. Catro’s plenary lecture) ○ During ovulation, mature follicle ruptures and gives rise to An oocyte is at the center of the complex. Cumulus cells are widely separated from the release of oocytes each other by the hyaluronan-rich extracellular matrix. Oocytes would then be caught within the fimbriated end of the fallopian tube wherein it will ❐ [WILLIAM OBSTETRICS, 25E (2018)] OVULATION (page 82) await the sperm In response to LH, greater progesterone and prostaglandin When you tell your patients who want to conceive that they production by cumulus cells, as well as GDF9 and BMP-15 should try during the ovulation period, how would they by the oocyte activates expression of genes critical to know/estimate? formation of the extracellular matrix by the cumulus complex. 1. Occurs 24 hours after peak estradiol level (violet line) During synthesis of this matrix, cumulus cells lose contact Peak is due to the production of granulosa cells with one another and move outward from the oocyte along 2. Occurs 34-36 hours after initial rise of LH (blue line), the hyaluronan polymer, this process is called expansion. ovulation would occur This results in a 20-fold augmentation of the cumulus This initial rise and LH peak is the guiding complex volume and coincides with an LH-induced principle behind the ovulation test kits remodeling of the ovarian extracellular matrix. Patients would usually start testing at about Day These allow release of the mature oocyte and its 8-9, in order to check if they are starting to have surrounding cumulus cells though the surface epithelium. an LH surge. Once it becomes positive, they can start trying if they want to conceive 3. Occurs 10-12 hours after peak of serum LH (yellow line) → patient ovulates UST MED 2026 | OBSTETRICS 1 7  OBS SHIFT 1 | LESSON 1 | Ovarian, Endometrial, and Menstrual Cycle 2.3. LUTEAL PHASE DBP The progesterone produced in this phase will help develop the endometrium for implantation of the embryo. hCG stimulates the same receptors as LH, which means that it can also trigger the conversion of cholesterol to progesterone, thus sustaining a pregnancy. LuthDue t - Fig 23. Luteal phase (Source: Dr. Castro’s plenary lecture) hCG Development of the corpus luteum (Luteinization) Fig 24. Luteal phase and the hormones produced in this phase Changes during Luteal Phase: (Source: Dr. Castro’s plenary lecture) ① ○ Neovascularization High blood supply within the ovary is due to the ff: 2.3.1. CORPUS LUTEUM HSP Vascular endothelial growth factor (VEGF) Produces progesterone Other angiogenic factors produced by Luteal phase differs when the patient becomes pregnant or theca-lutein and granulosa-lutein cells in not response to LH ② ○ Cells undergo hypertrophy WITH Pregnancy WITHOUT Pregnancy ③ ○ Cells increase capacity to synthesize hormones Corpus luteum is Corpus luteum becomes lifespan of CL Lifespan of the corpus luteum is constant at 14 days. ~ rescued by the human smaller in size and regresses ○ It is fixed that after 14 days of luteinization, the corpus chorionic after ovulation via apoptosis luteum will undergo apoptosis gonadotropin (hCG) Decreased levels of ○ Ex. Patient with an average cycle of 30 days, the patient secreted by the embryo circulating LH together with would ovulate at day 16 (30 - 14 = 16) Corpus luteum will progesterone since the ★ NOTE: Luteal phase is constant in length (14 days)while continuously increase corpus luteum already dies, the follicular phase varies. This is important to know for the production of then the patient will patients trying to conceive. ↑progesterone, thus menstruate as the cycle will supporting the begin again Lifespan of the corpus luteum is dependent on LH and hCG - - pregnancy in response Decreased LH sensitivity of ○ hCG (human chorionic gonadotropin) to embryonic hCG luteal cells If there is fertilization of the egg, the embryo will implant on to the endometrium, then the syncytiotrophoblast will produce hCG to sustain the ❐ INFORMATION (2024 Trans) corpus luteum, preventing its apoptosis Corpus Luteum During the luteal phase, the granulosa cell also responds to ○ Does not produce LH LH (right) ○ Dependent on the amount of LH ○ Luteal phase is progesterone dominant ○ LH converts cholesterol to progesterone. and nCG ○ Progesterone diffuses into the circulation to help support pregnancy ! If the patient is pregnant, the LH receptors within the So granulosa cell also respond to the hCG levels (right) ○ hCG also helps convert cholesterol to progesterone Granulosa-lutein cells have more capacity to produce progesterone as depicted by Figure 24. ○ Due to more enhanced access to more steroidogenic Figure 25. Sonogram of the Corpus luteum and dominant follicle precursors thorough blood-borne, LDL-derived Source: Dr. Castro’s plenary lecture cholesterol. Dominant follicle at the follicular phase (yellow arrow) with other cohorts of follicles (red arrow) that have not been selected to become the dominant follicle, LDL stimulates Cholesterol to become making them smaller than the dominant follicle. When it ruptures, it will become the Progesterone. - corpus luteum (black arrow). The appearance of the corpus luteum has a thick wall with fine lace-like eco pattern. UST MED 2026 | OBSTETRICS 1 8  OBS SHIFT 1 | LESSON 1 | Ovarian, Endometrial, and Menstrual Cycle ❐ INFORMATION (2024 Trans) During the early part of the cycle, estrogen exerts its effects by causing the endometrium to thicken ERα (Estrogen receptor α) - most changes of endometrium ERβ (Estrogen receptor β) - for the glands and stroma Roles of Estrogen: Figure 26. Gross specimen of a Corpus Luteum ○ Synthesis of proteins from receptor-specific gene Source: Dr. Yu’s plenary lecture It is yellowish with an atrophic area in between. transcription ○ At the cell surface: stimulate nitric acid production in endothelial cells 2.3.3. PROGESTERONE HSP Figure 27. Microscopic/Histologic view of the Corpus luteum Source: Dr. Yu’s plenary lecture Appearance of a convoluted lining composed of luteinized granulosa cell with an outer layer of theca cells and an inner layer of fibrous tissue; where the antrum was before containing the follicle that has been released. ❐ INFORMATION (2024 Trans) Sonogram of the Follicle ○ Monitor the follicle size 1mm increase in size of follicle everyday Figure 29. Progesterone Source: Dr. Castro’s plenary lecture ○ If the follicle reaches 18-20mm then it is expected to 2 Types of Receptors: rupture. ○ Progesterone receptor 𝝰 (PR-A) ○ If it doesn’t rupture it defeats its role of releasing the ○ Progesterone receptor 𝛃 (PR-B) ovum at that particular time. Responsible for most of glandular secretion during A pregnancy is not likely to happen luteal phase ○ Signs ovulation has happened sonographically Formation of Corpus Luteum (lacy pattern) ❐ Subnuclear vacuolation Decrease in size of the follicle ○ An important feature that will tell histologically that Fluid in the cul de sac progesterone is already in the system or when ovulation has started. 2.3.2. ESTROGEN HSP Enters the cell via diffusion Main purpose/function: ○ Prepares the endometrium for implantation ○ Helps maintain pregnancy once the embryo is implanted ○ Decreased level of progesterone in patients who did not have fertilization/implantation will lead to menstruation 3. ENDOMETRIAL CYCLE EIP, RRP, FLP ➤ Changes that happen in Endometrial cycle occur together with Figure 28. Estrogen (Source: Dr. Castro’s plenary lecture) Ovarian cycle 17B estradiol (E2) ➤ Because the endometrium is hormone responsive, there is an ○ Most biologically potent/most active form increase in estrogen, which helps in its repair during proliferative ○ Secreted by the granulosa cells of the dominant follicle phase and the luteinized granulosa cells of the corpus luteum ❐ Proliferative phase - preovulatory ○ Two types of receptors both seen in the endometrium: ❐ Secretory phase - postovulatory ER𝝰 ER𝛃 ❐ Dating of the endometrium ○ Functions: ○ Epithelial (glandular) Responsible for follicular growth & endometrial ○ Stromal (mesenchymal) growth/thickening ○ Blood vessels For secondary female sexual characteristics Protective functions for bone, heart, brain & other organs ★ NOTE: When the patient becomes menopausal there will also be a decrease in estrogen. UST MED 2026 | OBSTETRICS 1 9  OBS SHIFT 1 | LESSON 1 | Ovarian, Endometrial, and Menstrual Cycle 3.1. PROLIFERATIVE PHASE EIP - day 5 Re-epithelialization and angiogenesis ○ For cessation of endometrial bleeding Estrogen predominant ○ Induces growth factor gene expression in stromal cells ○ Increase VEGF for angiogenesis ➤ Phase immediately prior to ovulation ➤ Follicular phase production of estradiol ➤ Usually starts around day 5 (day 1 is start of menses) ○ Restoration, revascularization of the endometrium - bleeding Endometrium: thin thickens to stop Glands: tubular, narrow ➤ As level of ↑estrogen rises from the developing follicle, the endometrium begins to regenerate and the bleeding stops Figure 30. The Endometrial Cycle Source: Dr. Yu’s plenary lecture Representation of the relationship of what is going in the follicles of the ovaries and in the glands and the stroma of the endometrium. ❐ In between are the hormones from the anterior pituitary gland wherein the LH and FSH is seen ❐ Coming from the ovaries are the estradiol and progesterone ★ NOTE: One of the crude ways to determine if a patient is ovulating is taking note of the basal body temperature (RED LINE ON THE FIGURE). Sustained increase in temperature indicates ovulation. If basal body temperature is sustained for a longer time, it could indicate that the patient is pregnant because of the thermogenic effects imposed by progesterone. ENDOMETRIUM coiled ↑ L thick glands Figure 32 Endometrium during proliferative phase Proliferative phase shows thin narrow glands that are straight and non-convoluted during the early part of the cycle. This is an effect of estrogen. As the cycle proceeds more convolutions are expected with the glands ❐ Characterized by hyperplasia and increased stromal ground substance ❐ It is more variable between the 2 phases of the endometrial Figure 31. Endometrium during the proliferative and secretory phase cycle (ovarian cycle) Source: Dr Castro’s Lecture; Cunningham et al. Williams Obstetrics 25th Ed. ○ As short as 5 - 7 days ➤ Functionalis layer - Presence of spiral arteries ○ As long as 21 - 30 days ➤ Basalis layer - Contains the basal arteries ❐ Luteal (ovarian cycle) or secretory (endometrial cycle) phase is ➤ The endometrium also contains glands which are elongated constant in duration - 12 - 14 days during the proliferative phase and convoluted during secretory phase. The spiral arteries coil up during the secretory phase - > non-convoluted) proliferative : elongated glands (straight & Secretory : convoluted glands spiral arteries COILED up UST MED 2026 | OBSTETRICS 1 10  OBS SHIFT 1 | LESSON 1 | Ovarian, Endometrial, and Menstrual Cycle 3.2. SECRETORY PHASE RRP ❐ The Menstrual Cycle (Ultrasound (2025 Trans) Proliferative Phase Secretory Phase Early Secretory Phase Glycogen accumulates in the basal portion of glandular epithelium ↓ ○ Creating subnuclear vacuoles and Day 17 pseudostratification & basal portion ○ From direct progesterone action through receptors expressed in glandular cells Vacuoles move to apical portion of secretory More thicker and homogenous Day 18 Presence of a Triple layer & apex portion non ciliated cells absence of a triple layer Glycoprotein and mucopolysaccharide Day 19 contents are released Mitotic activity ceases Mid Secretory Phase Day 21-24 Stroma becomes edematous Stromal cells surrounding the spiral arterioles begin to enlarge Day 22-25 ○ Stromal mitosis becomes apparent Glands exhibit extensive coiling Luminal secretions become visible Late Secretory Phase Predecidual cells surround spiral arterioles Day 23-28 ❐ Continuing growth & development of spiral arteries Figure 34. The Menstrual Cycle (Ultrasound) Irregular menstrual cycle ○ Cannot have a dominant follicle during the secretory phase ○ Cannot have a corpus luteum during the proliferative phase ○ Difficult for the patient to conceive Follicular Phase ○ Presence of growing follicles (upper right image) ○ Endometrium starts to thicken (upper left image) Presence of a dominant follicle enlarged by the estrogen Figure 33. Endometrium during the proliferative and secretory phases (middle right image) the uterus will become trilaminar in the late proliferative stage (middle left image) Proliferative Phase Secretory Phase Presence of a corpus luteum with reticular strands (lower right image) means that the patient has ovulated ○ On the white arrow, presence of fluid means that ovulation has occurred ○ Endometrium is at the secretory phase or hyperechoic in ultrasound (lower left image) Non-convoluted, straight, thin, Coiled, tortuous, thicker and tubular glands darker staining glands recall : non-convoluted elongated glands & proliferative : (straight Secretory : convoluted glands spiral arteries COILED up UST MED 2026 | OBSTETRICS 1 11  OBS SHIFT 1 | LESSON 1 | Ovarian, Endometrial, and Menstrual Cycle 3.2.1. WINDOW OF IMPLANTATIONNFP Occurs in the mid-luteal/secretory phase ○ Day 20-24 or 1 week after ovulation ❐ Period where implantation is best suited to accept embryo or blastocyst ○ Blastocyst - day 5 embryo ○ Usually on the posterior upper third of endometrium, where marked stromal edema and mitosis occurs ★ Characterized by appearance of pinopodes ○ Luminal protrusions that appear on the apical cell surface ○ Aid in preparing the endometrium for blastocyst implantation Coincide with changes in the surface glycocalyx Fig 37. Events following the Window of Implantation. 3.3. MENSTRUATION FLP Infiltration of leukocytes: key to initiation of extracellular matrix breakdown of the functionalis layer CAUSE OF BLEEDING/SLOUGHING ○ Severe coiling of the arteries causes hypoxia of the endometrium → endometrial ischemia → tissue Fig 35. Window of Implantation. The diagram shows the timing of window of degeneration implantation in the ovarian cycle. ○ ★ ONLY Functionalis layer is shed, Basalis left for endometrial growth ❐ CLINICAL APPLICATION (2025 Trans) In certain procedures, only the Functionalis layer is scraped off leaving the Basalis layer intact. Doctors avoid the Basalis layer since touching this layer may cause the patient to have no menses for a while due to acquiring Asherman’s Syndrome Fig 36. Pinopods(top) and Steps in Blastocyst Implantation (bottom) EVENTS AFTER WINDOW OF IMPLANTATION ★ Rescue of corpus luteum and continued Fertilization/ progesterone secretion Pregnancy Endometrium becomes DECIDUALIZED Fig 38. Endometrium during menstruation. ★ Luteolysis and decline in progesterone production MENSTRUATION occurs Endometrium has a pseudoinflammatory No appearance Fertilization ○ Due to infiltration of neutrophils one to two days before menstruation Production of interleukin-8 (IL-8) and monocyte chemotactic attractant -1 (MCP-1) UST MED 2026 | OBSTETRICS 1 12  OBS SHIFT 1 | LESSON 1 | Ovarian, Endometrial, and Menstrual Cycle 3.3.1. PROSTAGLANDINS DURING MENSTRUATION Actual menstrual bleeding follows rupture of spiral arterioles and hematoma formation Hematoma → distention of superficial endometrium → rupture Fissures develop in the adjacent functionalis layer and blood with tissue fragments are sloughed. Hemorrhage stops with arteriolar constriction ➤ Start of a new cycle after menstruation ends (~ day 5), regeneration of the endometrium SUMMARY FLP PHASES OF THE MENSTRUAL CYCLE CYCLE PRE-OVULATION O POST-OVULATION V Ovarian Follicular phase U Luteal phase L A T Fig 39. Arachidonic Pathway Proliferative I Uterine Period Secretory phase phase O PROSTAGLANDINS Increased in production during menstruation N DEC Progesterone → signals production of Cyclooxygenase from arachidonic acid → Prostaglandin production & Causes the ff: promote uterine contraction ○ Vasoconstriction ○ Myometrial contractions ○ Uterine ischemia ○ Upregulation of proinflammatory response Vasoactive peptides that stimulate the endothelin-enkephalinase system → leads to vasoconstriction = Cause of pain during menstruation Painful menstruation is caused by myometrial contractions and uterine ischemia ❐ Patients with heavy menstrual bleeding are given NSAIDs to decrease prostaglandin pathway → DEC pain & bleeding ○ Prostaglandin F2α-induced spiral artery vasoconstriction Fig 41. The menstrual cycle. & 3.3.2. MENSTRUAL BLEEDING ★ IMPORTANT NUMBERS Mean length of menstrual cycle 28 ± 7 days Average duration 3-7 days Average amount 20-80 mL Follicular phase (length) More variable 14 days - ! constant Luteal/Secretory phase (length) (corresponds to life span of corpus luteum) Menstrual cycle length is most variable 2 years following menarche and preceding menopause ○ 2 YEARS AFTER MENARCHE - HPO axis is still immature and may not secrete properly ○ 2 YEARS PRIOR TO MENOPAUSE - FSH starts to increase therefore the cycle length varies Fig 40. Endometrium during menstruation. UST MED 2026 | OBSTETRICS 1 13  OBS SHIFT 1 | LESSON 1 | Ovarian, Endometrial, and Menstrual Cycle ❐ IMPORTANT DATES Q&A (2C) OF THE MENSTRUAL CYCLE (2024 TRANS) What is inhibin A vs B? DAY 1 Endometrial Cycle begins ○ Inhibin A & B are inhibitory and exert a negative feedback to the HPO axis DAY 5 Reepithelialization and Angiogenesis - Proliferative phase DAY 14 Ovulation (28 day cycle) Estrogen DAY 17 Subnuclear Vacuolization ○ E1 - pregnancy DAY 21-24 DAY 22-25 Window of Implantation Apparent Stromal Mitosis I Secretory please ○ E2 estradiol - most potent ○ E3 estriol - menopausal women Things to remember: ❐ CALCULATIONS OF THE MENSTRUAL CYCLE (2024 Trans) ○ Know when the ovulation occurs if the woman has a LMP: Last Menstrual Period normal cycle PMP: Previews Menstrual Period Constant luteal phase Estradiol peak Calculate for the Interval ○ It is the most important information of menstrual history Can a whole cohort be atretic? that is helpful in predicting ovulation and menstruation ○ Only one becomes a dominant follicle, while the rest Determine the time intervals between each becomes atretic menstrual period by using the first day of each ○ Therefore, safeguard the dominant follicle as it becomes LMP and PMP the mature follicle. It will be extruded during ovulation, Calculate the Next Menstrual Period meets the sperm cell for fertilization and form & implants ○ Add the time interval onto the first day of the LMP blastocyst in the endometrium ○ The 1st day of the LMP serves as the 1st day of the interval, thus you will actually be adding: (INTERVAL - 1) For fertile window, how many days will it be before and after Subtract 1 from the interval then add to the LMP ovulation? Calculate the next day of Ovulation ○ Know when the ovulation is to occur and if you plan to ○ subtract 14 days from the calculated next menstrual conceive, perform it nearest to the ovulation. period ○ If you are trying not to conceive and use it as a natural family planning method, refrain any sexual contact during ❐ CLINICAL APPLICATION (2024 Trans) ovulation NSAIDs ○ If a patient complains about very painful menses, doctors FREEDOM WALL prescribe Non-Steroidal Anti-inflammatory Agents (NSAIDs). ○ These block the Cyclooxygenase Pathway which would halt the production of: Prostaglandins (for pain reduction) Thromboxane A2 (to reduce bleeding) Prostacyclin. ○ There will be a resolution to the pain during menses but this may also result in decreased amount of menstrual flow. ○ This may pose the risk of accumulating dirty blood due to insufficient menstrual bleeding. OCPs ○ Patients on Oral Contraceptive Pills (OCPs) do not bleed bright red since the OCPs may contain little estrogen. ○ Does not induce the endometrium to thicken as compared to a patient not taking OCPs. REFERENCES Castro, A. (2023). Online lecture on Ovarian, Endometrial and Menstrual Cycle. TL RRP (C6) TE RVP (C6) UST MED 2026 | OBSTETRICS 1 14