Menstrual Physiology, Amenorrhea Dra.

Brion October 19, 2011

III-2

MENSTRUAL CYCLE Ideal 28 day cycle. Midcycle is marked by ovulation. Dependent on the interplay of pituitary and ovarian hormones. Predominant hormones involved: o GnRH from the hypothalamus. o FSH and LH from the anterior pituitary gland, secreted in response to GnRH. o Estrogen and Progesterone from the ovary, in response to FSH and LH. MENSTRUAL PHASE FSH Day 1 = 1st day of menses Ovarian Cycle changes during the cycle depends completely on the gonadotropic hormones FSH and LH. Folicular Phase / Endometrial Proliferation Phasepreovulatory:estrogen Luteal Phase / Secretory Phase postovulatory: progesterone Day 4: ovulation day LH surge happens to promote ovulation Estrogen has a rapid increase and then a sudden drop. Then a sudden surge of progesterone happens. Female menstrual cycle is determined by a complex interaction of hormones Predominant hormones involved in the menstrual cycle are GnRH, FSH, LH, estrogen and progesterone GnRH is secreted by the hypothalamus LH and FSH are secreted at the level of the ovary GnRH stimulates the secretion of LH and FSH from the anterior pituitary gland GnRH stimulates the secretion of LH and FSH from the anterior pituitary gland GnRH secreted from the hypothalamus in a pulsatile manner throughout the cycle. Early follicular phase is frequent of GnRH secretion: 1/90 minutes and 1/60 70 minutes Luteal phase decreases with increase in amplitude GnRH induces the release of both FSH and LH, but LH is much more sensitive to change in GnRH levels secreted by the anterior pituitary gland For follicular growth until antrum develops Secretion is highest and most crucial during the first week of the follicular stage of the menstrual cycle o time of follicle recruitment Negative feedback on GnRH. Induce estrogen and progesterone secretion at the level of the ovary. Induces the proliferation of granulose cell expression of LH reception on granulosa cells.

LH

secreted by the anterior pituitary gland required for the growth and preovulatory follicles; and the luteinization and ovulation of the dominant follicles Follicular phase-LH induces androgen synthesis by theca cells o stimulation, proliferation, differentiation and secretion of follicular theca cells and increase on granulose cells Preovulatory LH surge drives the oocyte into the 1st meiotic division and initiates luteinization of thecal and granulose cells. The resulting corpus luteum produces high levels of progesterone and some estrogen

ESTROGEN produced at the level of the ovary and is crucial for the development of the antrum and the maturation of the graafian follicle predominant at the end of the follicular phase directly preceding ovulation Estradiol, the most potent and abundant estrogen, is primarily derived from androgens migrating from the thecal cells to the granulose cells, where they are converted into estradiol by aromatase enzymes. Action of estradiol involves induction of FSH receptor on the granulose cells, proliferation and secretion of the follicular thecal cells At low circulatory levels, estrogen exerts negative feedback on FSH and LH secretion. Estrogen further induces proliferation of more estrogen-granulose cell and the synthesis of estrogen receptors establishing positive feedback loop on itself. In the uterine cycle, estrogen induces proliferation of endometrial glands. PROGESTIN secreted at the level of the ovary by luteinized follicles. first to be stimulated in progestin synthesis: requires p450 enzymes Levels increase prior to ovulation and peaks 5-7 days after. induce migration of blood vessels in the follicle walls and stimulate prostaglandin secretion on follicular tissues During the luteal phase, progesterone induces swelling and increase secretion of the endometrium

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PHASES

AMENORRHEA Absence or cessation of menstrual blood flow during the reproductive period Categories: Physiologic Postpartum lactation Pregnancy Menopause Pathologic - absence of menses due to an anatomic or endocrinologic disorder o Primary Amenorrhea - failure of flow to commence before 16.5 years of age o Secondary Amenorrhea - absence of menses for at least 3 months in woman who previously had regular spontaneous menstrual period o Cases of investigation Primary amenorrhea at age 16 with normal secondary sexual development Primary amenorrhea at age 14 without normal secondary sexual development Amenorrhea for 3 months duration in previously menstruating female PRIMARY AMENORRHEA Grouping with primary amenorrhea with normal external genitalia as the basis of the presence or absence of secondary sexual characteristic (breast) and female external genitalia (uterus) o Breast = estrogen activity= intact HPO axis o Uterus = structurally intact reproductive tract

PROLIFERATIVE PHASE spans period from the end of menses until ovulation increase levels of estrogen induce proliferation in the zona functionalis from the stem cells of the basalis proliferation of the stromal glands and the stromal connective tissue endometrial glands are elongated with narrow lumen and their cells contain some glycogen. Glycogen however is not secreted during the follicular phase Spiral antrum elongate and stimulates the length of the endometrium SECRETORY PHASE from the ovulation and last until the menstrual phase of the next cycle progesterone induces the endometrial glands to secrete glycogen, mucus and other substances These glands become tortuous Without fertilization by day 23 of the menstrual cycle, corpus luteum begins to degenerate and consequently ovarian hormone levels decrease Estrogen and progestin levels decrease, the endometrium undergoes involution Day 25-26 menstrual cycle, endothelia and thromboxane begin to mediate vasoconstriction of the spiral arteries Resulting ischemia may cause early menstrual cramps. By day 28, intense vasoconstriction and subsequent ischemia cause mass apoptosis of the functionalis. MENSTRUAL PHASE spiral arteries rupture due to ischemia apoptosed endometrium is slough off and usually last for four days the functionalis is completely shed as menstrual flow (arterial and venous blood, remnants of endometrial stoma and glands, RBS and WBC).

CATEGORY 1. BREAST ABSENT, UTERUS PRESENT Most common category Primary amenorrhea without breast development / uterus present Serum FSH

LOW / NORMAL Hypogonadotropic

HIGH Hypergonadotropic

Hypogonadism
Prolactin, CT-Scan NORMAL HIGH Pituitary Adenoma

Hypogonadism
BP

NORMAL

HIGH 17-Hydroxylase Deficiency

Non-Prolactin Secreting tumor, Inadequate GnRH

Karyotype Gonadal dysgenesis

Causes: 1.) Hypogonadotropic hypogonadism low FSH, LH; Low estrogen, progesterone CNS tumors o Non prolactin secreting tumor rare, chromophobe adenomas, pharyngiomas

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Pituitary adenomas- MC, elevated prolactin, respond well to bromocripitine, increase PRL inhibit estrogen Congenital anatomic defect Insufficient GnRH secretion due to neurotransmitter defect Inadequate GnRH release or secretion o Eg. Kallmans syndrome (amenorrhea + anosmia) o Normal ovaries but lack gonadotropin-stimulating development o When pregnancy id desired may give pulsating GnRH or HMG stimulate ovulation 2.) Hypergonadotropic Hypogonadism Gonadal failure 60% primary amenorrhea Increased FSH and LH Decrease estrogen and progesterone Result to different syndromes: o Turners syndrome 45X MC chromosomal abnormality causing gonadal failure and primary amenorrhea o 46X, abnormal X (deletional disorder) o Mosaicism (X/XX,X/XX/XXX) structurally abnormal x may be due to deletions in the long or short arms, ring formation or minute fragmentations. short like turners syndrome but with somatic abnormalities o 46XX or 46XY pure gonadal dysgenesis Absent secondary sexual characteristics Gonads are fibrous commonly have Y chromosomes o 46XX with 17-hydroxylase deficiency extremely rare Impaired cortisol production Cortisol and sex steroid replacement Hypertension Lethal when left untreated - hypernatremia and hypokalemia hypertension Early electrolyte intervention MANAGEMENT: o All indications in this category are hypoestrogenic due to CNS abnormalities o Treatment: estrogen/progesterone replacement for withdrawal bleeding and enhance breast development o CATEGORY 2. BREAST PRESENT, UTERUS ABSENT

Absence of androgen receptor synthesis leading to failure of differentiation of male external and internal genitalia o Pubic and axillary hair fail to develop o Abnormal sexual differentiation and a Y chromosome mandates gonadal extirpation because of high risk for malignant degeneration of the dysgenetic gonad; about 20% among AI/TF after 20yo o In this case, gonadectomy done after puberty for endogenous hormonal stimulation of breasts and long bone epiphyses followed by E/P replacement therapy. Congenital absence of uterus (Rokitansky-Kuster_hauser syndrome) o Agenesis, mullerian problem o Uterus and outflow tract fail to develop o Ovaries remain anatomically and endocrinologically functional o Renal and skeletal anomalies - need urogram and skeletal x-ray o Treatment: surgical construction and progressive vaginal dilation - done at sexual debut o

CATEGORY 3. BREST ABSENT, UTERUS ABSENT Karyotype XY Laparoscopy

Testes PRESENT

Testes ABSENT

17,20 Desmolase Deficiency 17-Hydroxylase Deficiency

Agonadism

Testosterone

NORMAL

HIGH

Rare, not enough androgen production Least common Male karyotype: phenotypically female (FSH, testosterone in female range) Estrogen therapy to induce development of breast and enhance female features o 17,20 desmolase deficiency o 17-hydroxylase deficiency with 46XY karyotype leads to inadequate testosterone synthesis and testicular development o Agonadism Gonadectomy: to diminish remaining male hormone effect Probably occurs after MIF elaboration because no female ductal structures are seen Vanishing testes syndrome during embryonic life 46XY but no gonadal tissue laparoscopy

Congenital absence of Uterus

Androgen insensitivity (testicular feminization)

Causes: Androgen insensitivity (testicular feminization) o XY but phenotypically female o X-linked recessive, sex autosomal dominant disorder o Testosterone level normal range for males o Receptor present but insensitive to testosterone

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CATEGORY 4. BREAST PRESENT, UTERUS PRESENT

Prolactin

NORMAL

INCREASED

Hypothalamic, Pituitary, Ovarian, Uterine outflow

Pituitary lesion Prolactinoma

Decrease GnRH Hypothalamic etiology Pituitary etiology Ovarian etiology Uterine ouflow tract cause Causes: o Hyperprolactenimia about 25% cases o Normal prolactin hypothalamic pituitary Management: manage like secondary amenorrhea

Stress and strenuous exercise (self-limiting) o Catecholestrogen levels rises which reduce rate of catecholamine degradation and increase its availability for dopamine synthesis which suppresses GnRH release o Endorphin levels increase during exercise negative action on GnRH secretion and enhance dopamine secretion amenorrhea o Menses return when stress or exercise abates Weight loss o Amenorrhea induced in those with Weight loss in whom Body weight is >15% below Ideal Body Weight o Relatively small proportion of body fat shifts peripheral estrogen metabolism to formation of more catecholestrogen inhibit GnRH release amenorrhea (e.g. anorexia nervosa) Hypothalamic dysfunction o No cyclic pulsatile LH secretion because of abnormal GnRH pulsatility due to transmitter dysfunction o Circulating estradiol level > 40pg/ml (+) progesterone withdrawal bleeding o No bleeding < estrogen pituitary failure o differentiate from hypothalamic-pituitary failure where estradiol levels are <40 pg/ml

SECONDARY AMENORRHEA Definition: absence of menses for at least 3 months in a woman who previously had regular spontaneous menstrual periods Causes: o HPO axis causes, uterus outflow disorder

Pituitary Causes Neoplasms CT scan/MRI o prolactin secreting bromocriptine o nonprolactin secreting surgical Non-neoplastic conditions o excessive hemorrhage, anoxia, thrombotic episodes which cause destruction of Pituitary cells o Sheehans syndrome - related to pregnancy o Simmonds disease unrelated to pregnancy o Due to treatment hormonal replacement, low FSH, LH, ACTH, TSH adrenal insufficiency Note: American Congress of Obstetricians and Gynecologists (ACOG) PITUITARY DYSFUNCTION Hyperprolactinemia Prolactinomas account for 20% of secondary amenorrhea Pituitary adenomas Prolactin-secreting lactotroph-adenomas Non-functional adenomas Functional thyrotroph adenomas (secreting TSH and causing hyperthyroidism) Somatotroph adenomas (secreting GH and causing acromegaly) Corticotroph adenomas (secreting ACTH and causing Cushings disease) Other pituitary masses (craniopharyngiomas, meningiomas, cysts) Pituitary infarct/infiltration Sheehans syndrome, radiation, infiltration (hemachromatosis, lymphocytic) Ovarian causes ovaries unable to secrete estrogen for uterine priming Infections Decreased blood supply after surgery Depletion of follicles after cystectomy Irradiation Systemic Chemotherapy Autoimmune disease

Note: American Congress of Obstetricians and Gynecologists (ACOG) Etiology: o Dont forget PREGNANCY! Most common cause of secondary amenorrhea Rule out with a urine or serum hcg before proceeding o Consider each level of the control of menstrual cycle: Hypothalamus endocrine regulation of the Pituitary menstrual cycle Ovary Uterus responds to endocrine cues from the HPO axis Cervix involved structurally in the Vagina outflow of menstrual blood

Hypothalamic Causes CNS lesions that interfere with GnRH release craniopharyngiomas, granulomatous disease (TB, sarcoidosis) Drugs: o Phenothiazines, Reserpine - cause hyperprolactinemia and inhibit gonadotropin release o OCPs prevent ovulation by suppressing GnRH and Gn action and may persist up to 6 months after stopping the pills post-pill amenorrhea

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Note: American Congress of Obstetricians and Gynecologists (ACOG) OVARIAN DYSFUNCTION Ovarian failure (menopause): 1 year of amenorrhea due to depletion of oocytes Spontaneous: typically occurs at age 52 in American women Premature: < 40 years old Autoimmune conditions o lymphocytic infiltrate in theca cells of ovarian follicles Chemotherapy/radiation Fragile X premutation Karyotypic abnormalities o Turner Syndrome, loss of small portion of X chromosome, mosaic Turner Syndrome, presence of Y chromatin material Surgical Hyperandrogenism Polycystic Ovary Syndrome (PCOS) Accounts for 20% of cases of amenorrhea Manifestations include: o Hirsutism o Acne o Menstrual irregularities o Obesity o Acanthosis nigricans o Premature pubarche, and/or precocious puberty To diagnose, any 2 of 3: o Oligomenorrhea/amenorrhea o Signs of androgen excess o Presence of polycystic ovaries on ultrasound ( 12 follicles)

Uterine and Outflow tract Ashermans syndrome o intrauterine adhesions that interfere with endometrial growth due to D&C pospartum curettage, endometritis esp. TB, myomectomy, metroplasty o adhesiolysis by hystereocopy or D&C indwelling pedia FC for 10 days, AB and high dose estrogen (2.5mg daily for 3 wks with MPA 10 mg OD during the 3rd wk) o Transverse vaginal septum septum at any level of the vaginal canal o Imperforate hymen septum located in the introitus o Cervical stenosis congenital or s/p cautery or conization Note: American Congress of Obstetricians and Gynecologists (ACOG) ASHERMANS SYNDROME Results from acquired scarring of endometrial lining Secondary to postpartum hemorrhage or endometrial infection, followed by instrumentation (i.e. D & C) Diagnosis suggested by: absence of normal uterine stripe on pelvic ultrasound Absence of withdrawal bleeding after sequential administration of estrogen, then progestin. Can confirm diagnosis by Hysteroscopic evaluation

*MPA - medroxyprogesterone acetate

MPA 5-10mg BID X 5days Uterine Bleeding LH High (>25mL) PCOS (LH:FSH = >3) Normal LH FSH Hypothalamic dysfunction Normal to Low High (>30 mIU/mL) Premature Ovarian Follicle (POF) <35 24 hour urine free cortisol NO Uterine Bleeding Pituitary lesion Prolactinoma

Testosterone (ovarian), DHEAS (adrenal)

Normal Induce bleeding, dexamethasone, spironolactone

Prolactin

HypothalamicPituitary Failure
High PRL, CT-Scan, ACTH Reserve test

MPA 10mg/day x 12days

Work-up for Hyperprolactinemia

A gynecologist had become fed up with malpractice insurance and was on the verge of being burned out. Hoping to try another career where skillful hands would be beneficial, he decided to become a Mechanic. He found out from the local technical college what was involved, signed up for evening classes, attended diligently, and learned all he could. When the time for the practical exam approached, the gynecologist prepared carefully for weeks and completed the exam with tremendous skill. When the results came back, he was surprised to find that he had made a score of 150%. Fearing an error, he called the instructor, saying, I dont want to appear ungrateful for such an outstanding result, but I wondered if there had been an error which needed adjusting. The instructor said, During the exam, you took the engine apart perfectly, which was worth 50% of the total mark. You put the eng ine back together again perfectly, which is also worth 50% of the mark. After a pause, the instructor added I gave you an extra 50% because you did all of it through the muffler.

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