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Harvard-MIT Dvision of Health Sciences and Technology HST .071: Human Reproductive Biology Normal Menstrual cycle Alan Penzias MD Normal Menstrual Cycle – Alan Penzias MD 32 SUMMARY OF THE NORMAL MENSTRUAL CYCLE Teleologically, the purpose of the human menstrual cycle is the production of a fertilizable egg and the development of an appropriate uterine environment for implantation of the resultant embryo (Figure 1). In the human the usual course of events is the production of only one mature egg per menstrual cycle, although occasionally twinning results from the simultaneous ovulation of two or more eggs (dizygotic). The human menstrual cycle, therefore, can be seen as the mechanism whereby only one mature egg (from the 7 million present at the time of maximal oocyte (egg) availability from meiotic division at 6 months of fetal life, is allowed to ovulate each lunar month. Simultaneously a hormonal environment is created which permits implantation in the uterus 7 days after ovulation. The human menstrual cycle is ultimately controlled by the hypothaiamic pulse generator located in the arcuate nucleus. It is modulation of this pulse generator, either directly of through modulation of the signal from this pulse generator at the pituitary target of the message that results in the human menstrual cycle. The signal from the hypothaiamic pulse generator is delivered by means of a decapeptide, the neurohormone gonadotropin releasing hormone (GnRH). Release of GnRH is pulsafile in nature and is the result of multicircuit electrical activity in the GnRH producing cells of the arcuate nucleus. To date no convincing evidence is available that any modulation of this multicircuit activity can increase the synchronized firing rate of GnRH neurons above their intrinsic maximum of approximately once every 75 minutes. (Aspartic acid has been putative in this regard, but solid evidence is lacking). Thus, all modulation of the GnRH signal at the level of the hypothalamus is by slowing of the GnRH pulse generator from its intrinsic rate. The effect of GnRH on the pituitary is to release two glycopeptides, follicle stimulating hormone (FSH) and luteinizing hormone (LH). (Although these hormones are named from their functions in the menstrual cycle, the identical hormones are present in men where they regulate testosterone production and spermatogenesis by the testis). GnRH has been shown to possess a remarkable one to one relationship with LH at the pituitary. That is each pulse of OnRH is accompanied by a imultaneous pulse of LH. FSH is regulated in a more complex fashion with a combined effect of both OnRH and an ovarian peptide called inhibin. The resting stage of the ovarian follicle is termed the primordial follicle. This follicle consists of the oocyte, arrested at the diplotene phase of meiosis I, and a single layer of cuboidal cells - the grannlosa cells. The process of maturation of the follicle is initially gonadotropin (LH and FSH) independent. The length of this gonadotropin independent phase is poorly characterized in the human but may last several months. Follicular maturation is characterized by an increase in the number and functional capacity of 33 33 the granulosa cells. These follicles almost all undergo atresia due to lack of rescue by gonadotropius necessary for continued growth. The determinant of whether a follicle is at the appropriate stage of development to be "rescued" from atresia is the number of FSH receptors, which is in turn dependent on the number of granulosa cells which contain these receptors. Until just prior to its final stage of development, the preovulatory follicle contains FSH receptor but no LH receptor. The process of follicular development and atresia is ongoing from six months of prenatal life until the depletion of all follicles at the time of menopause. It continues through childhood and pregnancy unabated. The precise mechanism which signals cohorts of follicles to initiate growth is unknown, however the number initiating growth is directly proportionate to the remaining pool of follicles. In childhood and during pregnancy all follicles undergo atresia as a result of insufficient FSH to "rescue" these follicles. During the course of the menstrual cycle, however, several of these follicles will have developed to a stage where these is sufficient growth to be sensitive to the circulating levels of FSH. This cohort of follicles are said to be recruited and of them only one will gain,dominance, and the remainder will undergo atresia through a mechanism similar to their non-recruited counterparts. The process by which one follicle gains dominance is the result of positive feedback within the granulosa cells of this follicle. FSH induces its own receptor. The process of FSH induced FSH receptor in the granulosa cells is estrogen dependent, with the predominant estrogen produced by the granulosa cell being estradiol. Thus in the dominant follicle FSH > estradiol > FSH receptor. Concomitantly, estradiol is inhibitory to FSH so that levels of FSH from the pituitary gradually decrease depriving less mature follicles of FSH necessary to prevent their atresia. In this way one dominant pre-ovulatory follicle is produced each cycle. (Administration of excess FSH is the mechanism whereby multiple follicles can be induced for such pregnancy enhancing procedures as in-vitro fertilization). In the process of follicular growth during the first half of the menstrual cycle, the follicular Phase, estradiol levels in the circulation increase approximately 10-fold largely as the result of activity of the dominant pre-ovulatory follicle. The effects of the estradiol are not only to inhibit pituitary FSH but to regulate the pituitary release of LH. At higher levels estradiol is inhibitory to LH, however in a critical range of physiologic estradiol levels achieved during the first haft of the menstrual cycle estmdiol has a unique effect on the pituitary. It increases LH synthesis in response to GnRH, but partially inhibits GnRH-induced LH release. Thus there is in the gonadotroph an increasing "reserve pool~ of synthesized but unreleased LH as the follicular phase of the menstrual cycle progresses. Eventually the "reserve pool~ of LH is saturated and a massive release of LH occurs over a 36 hour period, the so called "LH surge" which is the trigger for ovulation and marks the end of the follicular phase. Prior to the LH surge however, there is a lower level of palsatile release of LH from the gonadotroph. This LH acts upon a second ovarian cell type the theca cell. The theca cell synthesizes androgens, 34 primarily androstenedione from LDL-cholesteml. This androgen serves as the substrate for granulosa cell estradiol production. Thus in the menstrual cycle, the theca cell and granulosa cell operate in concert, giving rise to the two cell theory of ovarian function. The conversion of the theca derived androgens to estrogen is by the aromatization of the first ring of the steroid molecule. The enzyme responsible is therefore called aromatase. Aromatase activity is directly induced by FSH action on the granulosa cell. LH receptor is present at all times on theca cells, and FSH receptors develop in granulosa cells during their maturation from the primordial follicle. At high doses, FSH action on the granulosa cell induces LH receptors. Physiologically, this high degree of FSH activity is attained only by the dominant preovulatory follicle (as a result of a high concentration of FSH receptors) a few days before ovulation. Thus the granulosa cell develops LH receptors a few days prior to the LH surge. The LH surge typically occurs 14 days into the menstrual cycle (which is counted from the first day of menstrual bleeding), although there is a normal physiologic variation in this interval (follicular phase length) from 9-17 days. In contrast the second half of the menstrual cycle (luteal phase) is much more precise physiologically lasting 14 ± 2 days. (A shorter than 12 day luteal phase is considered pathological and termed lnteal phase defect a condition seen repeatedly overseveral menstrual cycles in only 3-4% of women). The LH surge induces proteases, collagenases and tissue plasminogen activators that digest the capsule of the ovary and permit extrusion of the oocyte and a surrounding nest of specialized granulosa cells the cumulus cophorus. Simultaneously, meiotic division proceeds to metaphase of meiosis II where it is arrested until fertilization. The effect of the LB surge is to induce at partial 17 hydroxylase block in the steroidogenic pathway resulting in the production of progesterone as well as estrogen by the remaining theca and granulosa cells. This progesterone production results in a characteristic yellow color of the remaining dominant follicle and from this the name corpus luteum (yellow body) is given to the remains of what was previously the dominant follicle. This second phase of the menstrual cycle is referred to as the luteal phase. The follicular phase of the cycle is therefore estrogen dominated, while the luteal phase is both estrogen and progesterone dominated. The premenstrual syndrome including, breast tenderness, bloating and affective liability are likely to be progesterone induced. Most characteristic of the action of estrogen is the hypertrophy of the uterine lining (endometrium) which grows severifi millimeters in height during the follicular phase. The action of progesterone on the estrogen-primed endometrium is to convert this endometrium into a secretory pattern. The endometrium can be accurately dated in the post ovulatory phase by the presence of initially subnuclear vacuoles in the glandular epithelium which by 4 days past ovulation migrate to the endothelial surface and release their contents. By day 21 of the classic 28 day 35 cycle, these epithelial glands have become tortuous and there is abundant secretion in the lumina, a condition optimal for implantation of the fertilized egg which occurs at this time. (The phases of the endometrial cycle are termed differently than those of the menstrual cycle, with the follicular phase being referred to in the endometrial cycle as the proliferative phase, and the luteal phase as the secretory phase,) In the absence of pregnancy, the life span of the corpus iuteum is self limited. The mechanisms for this are poorly indicated although responsivity to LH has been clearly shown to decline. As a result of this during the last 7 days of the cycle estrogen and progesterone production from the corpus luteum decline. These decreases lead to spasm of the arteries in the blood vasculature which supports the endometrium (either by direct action or through prostaglandin mediated mechanisms) and breakdown of the endometrium occurs leading to menses. In the event pregnancy occurs, a hormone analogous to LH (sharing an identical first 121 amino acids) human chorionic gonadotropin (hCG)is released by the developing embryo into the maternal circulation, hCG has additional scialic acid residues on the C terminal amino acids (not shared by LH) which greatly prolong its half-life and permit maintenance of the corpus luteum and consequently the absence of menses. 36 Learning Objectives Describe the hypothalamic control of the menstrual cycle Understand the role of the pituitary gland in regulating ovarian response Appreciate the steroidogenic capacity of the ovarian follicular unit Reasons to learn about the normal menstrual cycle: You have one You know someone who has one As a physician, you will be a lightening rod for medical questions on any topic including this one Menstrual Cycle Length Age 21-39: 98% CI: 21-35 days Only 15% with 28 day cycle Age 25: 40% with 25-28 day cycles Age 25-35: 60% have 25-28 day cycles o Age < 20 and > 40 Highest incidence of anovulation 37 Elements of cyclic menstruation Hypothalamic Control GnRH pulse generator Pituitary Response Differential release of LH and FSH Ovarian Compliance The foUide unit Theca, Gmnulo, Oocyte Gonadotropin Releasing Hormone (GnRH) 10 Amino Acids (decapeptide) Primarily produced in Arcuate Nucleus T1/2:90 seconds Pulsatile Release Pulse generator located in medial basal hypothalamus (MBH) 38 GnRH Antagonists Hypothalamic Control GnRH Pulsatility Central Modulation α-Adrenergic Norepinephrine Dopaminergic Opioids Hypothal GnRH Central Modulation α-Adrenergic Norepinephrine Dolmminergic Opioids 39 Hypothslamic Control GnRI-I Puisatility Central Modulation α-Adrenergic System Norepinephrine - STIMULATORY FFFECT HOW would you test this hypothesis? Block the adrenergic receptor Look for anatomic connection 40 Dopaminergic Input Dopamine – INHIBITORY EFFECT Cycling and postmenopausal women Mechanism Direct Effect Indirect effect via ENDOGENOUS OPIOIDS Hypothalamic Control GnRH Pulsatility Central Modulation α-Adrenergic System Norepinepbrine - STIMULATORY EFFECT PROPOSED MECHANISM NE neuron inhibits the inhibitory GABA neuron Central Modulation Endogenous Opioid Peptides β-endorphin- INHIBITORY EFFECT Evidence Naloxone (an opioid ANTAGONIST) DA stimulates hypothalamic j3-endorphin release 41 Proopiomelancirtiun (POMC) GnRH Pulsatility 42 Actions of Pulsatile GnRH Synthesis and storeage of LH and FSH Activation mid movement of LH and FSIi from reserve pool to acutc rclc, asablc pool Direct secretion of LH and FSH PITUITARY RESPONSE Regulators of Gonadotropins (LH and FSH) Estrogen Progesterone FSH as a market of reproductive aging Cyclic Gonadotropins The LH Surge Luteal phase temperature shift Hormonal Mediation Estrogen: Modulates LH amplitude Negative feedback on LH (early folllcular) Change to STIMULATORY to induce LH surge (or attenuation of negative feedback) Propsed Mechanism Under influence of E2 GnRH receptor conoentration increases near mid-cycle (self-priming) Critical estradiol level for critical length of time 43 LH Surge Estradiol: Critical concentration (>150 pedna) Critical length of time (>50 hours) Precise Mechani$.m Unknown Surge rarely seen under above conditions during fertility therapy Cyclic Gonadotropins (LH/FSH) Hormonal Mediation Progesterone: Modulates LH frequency At Iow levels, with E2, augments LH surge Induces small FSH surge At post-ovulatory levels: POWERFUL suppressant of LH and FSH o Sites of Action Direct inhibition of GnRH at hypothalamus Antiestrogenic at pituitary 44 Thermogenic Shift Luteal phase (after ovulation) rise in core body temperature Rise of 0.40 -0.6o C Caused by PROGESTERONE o MECHANISM Set point changein thermoregulatory center of hypothalamus Thought to be mediated byopioids, serotonJn and IL-1 Thermogenic shift 45 Hormonal Mediation Progesterone: Clinical application of gonadotropin (LH/FSH) suppression Progestin compounds Birth control pills Depot Provera E2 Regulation of FSH Signs of Reproductive Aging What else regulates FSH level (other than E2)? Inhibin: o Produced by ovarian granulosa cells o Potent inhibitors of FSH Activin o Stimulates FSH release o Much lower quantifies than of inhibin Follistatin o A pituitary single chain glycosylatcd polypetide o Binds activin (therefore favors FSH suppression) 46 Inhibins and Activins Inhibin: o Inhibin A-Mature Follicles, Corpus Luteum o lnhibin B - Smaller Pre-ovulatory follicles (marker of OVARIAN RESERVE) Activin o Activin A & B - Observed in nature o Activin AB - Not observed to occur 47 Reproductive Aging See Santoro N. et al. Fertil Steril 1999, 71 : 658-62. 48 Reproductts Aging Fewer follicledoocytes left in re-serve Less Inhibin B (less suppression of FSH) More lnhibin A (stimulation of FSH release) Inhibin comprised of α & β subunits Activin comprised ofβdimers ? Lessαsubunit therefore moreβdimers Result: Higher FSH Levels GnRH Smnmary Pulsatile release from Arcuate Nucleus Pulse Generator; Medial Basal Hypothalamus oMODULATORS adrenergic: NE – STIMULATORY GABA – INHIBITORY Opioids - INHIBITORY Summary of Key Points Pulsatilc GnRH: critical range for frequency and amplitude GnRH: Positive action on Anterior Htuitary Synthesis, Storeage and Release of LH/FSH LH/ FSH Summary Difti~renfial release to Pulsatile GnRH MODUL ATORS o Estrogen: Inhibitory then STINULATORY o Progesterone: Inhibitory o Inhibin: FSH Inhibitor o Activin: FSH Stimulator o Follistatin: Binds Activin (Favors FSH Inhibition) Summary: Key Points LOW ESTROGEN o Enhances synthesis and storeage of LH/FSH o Inhibits RELEASE of LH/FSH HIGH ESTROGEN o Induces LH Surge at midcycle o Sustained elevation of LH 49 Summary: Key Points LOW PROGFSTERONE o Enhances LH response to GnRH at midcyde o Responsible for midcycle FSH surge HIGH PROGESTERONE (Post-ovulatory) o Powerful inhibitor of LH/FSH release o Direct inhibition of OnRtl at hypothalamus o Antiestrogenie at pituitary Recommended Texts and Investigators Physiology of Reproduction (Knobil and Neill) Clinical Gynecologic Endocrinology and Infertility (Speroff, Glass and Kese) Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management (Yen, Jaffe & Barbieri) Investigators Gary Hodgen AV Schaliy Ernst Knobil 50 IGF, IGF-BP & PAPP-A Products of granulosa cc!Is IGFs stimulate slcroidogcncsis and folliclc development along with Lli and FSII IGF-BP4 modulates the effects of IGF by modulating its bioavailability; low IGF-BP4 means more free IGFs IGF-BP4 proteolysis decreases IGF-BP4 thereby increasing free IGFs IGF-BP4 protcasc rcgcntly identified as PAPP-A (pmggmncy associated se. mm prolein A) 51 IGF and IGF-BP Granulosa ccUs arc the source of' PAPP-A! High PAPP-A conccrttrations seen in dominant follicle l PAPP-A gene expression is restrictcd to hcalthy follicles and corpora lutea2 52 Follicle development Gonadotropin Independent Phase Tonic growth phase Occurs Independent of LH / laSH Oral contraceptive use Pregnancy Class 1 to Class 4 follicles Follicle development Gonadotropin Dependent Phase Requires LH / FSH Class 5 to Class 8 follicles Follicle development Gonadotropin Independent Phase o Tonic growth phase o Occurs independent of LH / FSH Oral contraceptive use Pregnancy o Class 1 to Oass 4 follides Gonadotropin Dependent Phase o Requires LH / FSH o Class 5 to Class 8 follicles Intraovarian Follicle Development Gonadotropin independent development Gonadotropin dependent development LH dependent thecal androgen production FSH dependent granulosa estrogen conversion Intraovarian Follicle Development "Selected" follicle is more efficient at aromatizing estrogen Remaining follicles accumulate androgens o Aromatase cannot keep pace with androgen production o Androgen excess induces atresia o Atresia occurs via apoptosis 53 Intmovarian Follicle Development Gormdotnmin theeapy o ResoJes follicles destined for alresia o FSH component Induces aromatase o MulUple follicles develop Follicle Threshold o Level of FSH required for efficient conversion of androgen to estrogen o Higher close of hMG rescues more follicles o More follicles is not necessarily better 54 Normal Menstrual Cycle Cyclic GnRH Differentiai production of L.H and FSH Ovarian Response Continuous production of inhibin Conversion of androgens to estrogen About 1550 BCE an Egyptian described how lint (fctet) inserted into the vagina could prevent conception. Is this the first description of a tampon? 55 The Abnormal Menstrual Cycle Alan S. Penzias, MD Div. Reproductive Endocrinology Beth Israel Deaconess Medical Center Boston IVF Harvard Medical School Hypothalamic Dysfunction Endogenous Opioids Examples o Anorexia Nervosa o "Stress Induced" o Depression Mechanism o High cortisol states o Increased ACTH production 56 Proopiomelanocortin (POMC) Abnormal menstruation Hypothalamic amenorrhea o Pituitary Disease o Prolactin production o Stalk compression Ovarian Dysfunction o Failure: lack of estrogen / inhibin Hyperandrogenicity Prolactin Regulation 57 Pituitary Disease Hyperprolactinemia o Microadenoma o Prolactin producing macroadenoma o Other macroadenoma with stalk compression Psychotropics Hypothyroidism Prolactin Regulation Prolactin Regulation Harvard-MIT Dvision of Health Sciences and Technology HST .071: Human Reproductive Biology Disorders of Ovulation Peripheral Disorders Thyroid Hypofunction o Associated hyperprolactinemia o Low SHBG Thyroid Hyperfunction Excess SHBG Sex Hormone Binding Globulin Decreased by: o Androgens o Low T4 o Obesity Increased by: o Estrogen o High T4 Impact of SHBG Normal female testosterone level: 50 ngldl (range: 20 - 80 ngldl) Normal mid-cycle female estradiol level: 200 pg/ml (range: 100 - 300) Impact of SHBG 1 ng = 10-9 grams 1 pg = 10-12 grams 50 ng/dl = 50000 pg / 100 mi = 500 pg/ml Impact of SHBG Normal female testosterone level: 500 pg/ml Normal mid-cycle female estradiol level: 200 pg/ml On average, circulating T is 2.5 x higher than circulating estradiol Harvard-MIT Dvision of Health Sciences and Technology HST .071: Human Reproductive Biology Impact of SHBG Testosterone: 99% bound; 1% free Estradiol: 97% bound; 3% free Decreasing the quantity of SHBG present in circulation therefore has a significant impact on the quantity of free testosterone available Impact of Androgens High androgens: adrenal or ovarian feedback on the hypothalamus DECREASING GnRH pulsatility Abnormal Menstruation Peripheral Disorders o Thyroid hypofunction Associated with hyperprolactinemia Low SHBG o Thyroid Hyperfunction Excess SHBG o Adrenal Dysfunction Hyperandrogenism Based on underlying etiology o e.g. PRL, Thyroid, CAH Based on specific goals o Fertility o Cyclicity o Cancer prevention (periodic withdrawal) Based on specific needs o Contraception o Side effect profile o Lifestyle