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Back to Basics: Gynecology
Dr. John Lamensa Assistant Professor Department of Obstetrics and Gynecology University of Ottawa April 1, 2011
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Overview Normal Menstruation Menstrual Abnormalities Contraception
Sexual development Menstrual cycle Menstrual Abnormalities Amenorrhea Abnormal uterine bleeding PCOS Menopause Contraception Infertility Pelvic Pain Dysmenorrhea Endometriosis Pelvic Mass Ectopic pregnancy Pap smears Vaginal/pelvic infections
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A mother is concerned that her 12-year-old daughter has not had her period yet (the other girls in her daughter’s class have already started theirs). She also thinks her daughter does not show signs of puberty yet. Knowing the first sign at the onset of puberty, you should ask which of the following questions? Has her daughter had any acne? Has her daughter started to develop breasts? Does her daughter have any axillary or pubic hair? Has her daughter started her growth spurt? Has her daughter had any vaginal spotting? Important landmarks of normal development.
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The sequence of events in normal pubertal development are:
Peak growth, pubic hair, breast budding, menarche Breast budding, pubic hair, peak growth, menarche Breast budding, menarche, pubic hair, peak growth Pubic hair, breast budding, menarche, peak growth B- although accelerated growth is before breast; Breast budding usually first recognized pubertal change Menarche usually occurs 2-3 yrs after onset of breast enlargement. Pubertal sequence requires a period of 4.5 years (range 1.5 – 6 years): accelerated growth, breast budding or thelarche (median age 9.8 years), adrenarche (usually appears after the breast bud starts with pubic hair development (median age 10.5 years) with axillary hair growth 2 years later. Adrenal androgens, and to a lesser degree, gonadal androgen secretion cause pubic and axillary hair growth. Adrenarche plays little if any part in skeletal growth. While temporally related to gonadarche, adrenarche is an independent, functionally unrelated biological event. Early growth is triggered by early increases in gonadal estrogen (and GH and IGF-1) from early puberty and maximal growth rate achieved median is 11.4 years. Menarche is a late event (median 12.8 years) occurring after the peak growth has passed, midpuberty, and results from a sufficient gonadal estrogen secretion that proliferates the endometrium. GROWTH: Pubertal growth spurt is associated with an increase in gonadal steroid, then GH, then IGF-1. Normal growth requires the combined action of these three. Ie. Lanon-type dwarfs (genetic defect in GH-receptor and cannot stimulate IGF-1 production) do have some growth from gonadal steroid only. Long-bone growth is exquisitely sensitive to low-dose estrogen. Low-dose stimulate IGF-1. These low- doses are not sufficient to cause breast development. In higher doses, IGF-1 production is inhibited (ie. menarche) and sex steroid doses eventually stimulate epiphyseal fusion. The relationship between menarche and growth spurt is relatively fixed: menarche occurs after the peak in growth velocity has passed. Slower growth, totaling no more than 6cm or 2.5 in. is noted after the initiation of menses. Normal range of menarche in US ( years with a median of 12.8 years. Adolescent girl’s growth spurt occurs 2 years earlier than boys (11-12 years). Her growth peak or maximal rate of change is about 2 years after breast budding and about 1 year before menarche. The final endocrine hallmark of puberty is the positive feedback on the pituitary and hypothalamus.. Menses following menarche are anovulatory for as long as months. Not uncommon for 50% of adolescents to be anovulatory for 4 years after menarche.
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Female Sexual Development
In infancy and pre-puberty, FSH and LH levels are high or low ? Prior to onset of puberty, FSH and LH levels increase or decrease? This stimulates ovaries to produce Physiology of puberty. In infancy and pre-puberty – GnRH (gonadotropin releasing hormone) and (FSH and LH) levels are low. Once born, loss of feedback inhibition of the gonadotropins by maternal and placental hormones, triggers an prompt increase in LH/FSH. This transient increase in estrogen leads to waves of follicular maturation and atresia. Feedback inhibition quickly re-establishes itself and the axis remains quiescent until at least 8 years age. Gonadotropin levels and central inhibitory influence on GnRH secretion are inhibited by extremely low levels of estrogen. Prior to onset of puberty: FSH and LH levels start to increase which stimulates gonads to produce sex steroids from the combined reduction in intrinsic suppression of GnRH and decreased sensitivity to the negative feedback of estrogen. The increased amplitude and frequency of pulsatile GnRH are believed to provoke progressively enhanced responses of FSH and LH secretion. FSH rises initially and plateaus midpuberty; LH rises more slowly and peaks in late puberty. Estradiol levels increase – breast development occurs. Soon enough estrogen available to initiate endometrial growth and menses (usually 2 years after breast budding) Menarche usually follows peak height velocity Adrenarche is a biologically unrelated event, increase in adrenal androgens – leads to pubic and axillary hair development temporally related to other pubertal changes. Growth spurt is superimposed on pubertal process & begins prior to thelarche. estrogen
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A 9 year old girl presents for evaluation of regular vaginal bleeding
A 9 year old girl presents for evaluation of regular vaginal bleeding. History reveals thelarche at age 7 and adrenarche at age 8. Which of the following is the most common cause of this condition in girls? Idiopathic Gonadal tumors McCune-Albright syndrome Hypothyroidism CNS tumors Pubertal changes before the age of 8 years are considered precocious (greater than 2.5 SD from the mean). The most serious ramification is adult short stature. They are transiently tall but have early epiphyseal fusion because of skeletal sensitivites to higher doses of estrogen. Eventually short stature results with 50% less than 5 ft. tall. They have normal reproductive life and is not associated with premature menopause. Increased growth is typically the first sign, followed by breast, and pubarche. Menarche can also be the first sign. Precocity is 5 times more common in girls. True precocious puberty is a GnRH-Dependent event where there is premature activation of the HPO-axis. ii) GnRH-Independent events (precocious pseudopuberty) where sexual maturation may be due to extra pituitary secretion of hCG or sex steroid secretion independent of CNS control or GnRH-Independent. 75% are idiopathic or true (diagnosis of exclusion). Rule out central or peripheral sites involved in disease such as brain, ovary and adrenal gland (GnRH-Independent). b) Gonadal tumors (ovarian and testicular) 11% of girls with precocious puberty. Usually an estrogen-producing neoplasm or cyst. (granulosa or thecal tumor). Gonadoblastomas, teratoma, cystadenomas, gonadoblastomas, even ovarian cancer. Pelvic mass palpable in 80%. c) McCune-Albright Syndrome: 5% of precocity and consists of multiple disseminated cystic bone lesions that easily fracture. Pathology secondary to autononmous, early, ovarian estrogen production. Precocity, café au lait spots, and multiple fractures, should lead to diagnosis. Subsequent loss of GnRH pulsatility and LH/FSH levels stay low. d) Long-standing hypothyroidism. Replacement will stop precocious development. e) CNS tumors are considered central causes but make up only 7% of cases. So idiopathic and CNS tumors total ~80% of cases. Tumours include: hamartoma (most common in girls, hyperplastic congenital malformation of the floor of the third ventricle) craniopharyngioma, astrocytoma, glioma, neurofibroma, epednymoma, and suprasellar teratoma – all usually near the hypothalamus. Nontumorous causes: encephaitis, meningitis, hydrocephalus von Recklinghausen’s disease.
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The most common cause of delayed puberty is:
Turner’s syndrome Craniopharyngioma Constitutional delay Anorexia nervosa Primary hypothyroidism Delayed puberty: difficult definition because of the wide variation in normal development. No secondary sex characteristics by 17 years warrants an evaluation. Failure of growth would suggest this associated with hypergonadotropins. The most common disorder in hypergonadotropic hypogonadism is gonadal dysgenesis leading to ovarian failure. Think Turner’s for those with 45X and is the most common cause of ovarian failure with abnormal chromosomes. b) Most common neoplasm associated with delayed puberty. Tumor of Rathke’s pouch, originating from the pituitary stalk, with suprasellar extension. Imaging reveals an abnormal sella and calcifications in 80% of cases. Treatment consists of combination of surgery and radiation. c) Constitutional or physiologic delay can be regarded as a physiologic variant in development affecting 10%. The typical patient with physiologic delay is short with appropriate bone maturation delay. This hypogonadotrophic hypogonadism presents with decreased LH and depressed FSH.
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Normal Menstrual Cycle
Follicle Numbers: 6-7 million at 20 weeks; 2 million at birth; at puberty; ovulatory events from menarche. Constitutive atresia. Just before and during menses, escape from the negative feedback of estrogen, progesterone, and inhibin results in increased FSH secretion by anterior pituitary. This initial increase in FSH essential for follicular growth and steroidogenesis. Initiation of follicular growth occurs independently of hormone influence. The primordial follicle becomes the primary follicle based on oocyte increase in size and the granulosa cells become cuboidal rather than squamous in shape. FSH-induced aromatization of androgen in the granulosa results in the production of estrogen. Even though the preantral follicle makes androgen and progesterone, significantly more estrogen is made by aromatase conversion to estrogens. With continued growth of the follicle, autocrine/paracrine factors produced within the follicle maintain follicular sensitivity to FSH allowing conversion from an androgen dominant microenvironment to one dominated by estrogen, a change necessary for a complete and successful follicular lifespan. Together, FSH and estrogen increase FSH receptor content of the follicle. The fate of the pre-antral follicle is in delicate balance. At low concentrations, androgens enhance their own aromatization and contribute to estrogen production. At higher levels, the limited capacity of aromatization is overwhelmed, and the follicle becomes androgenic and ultimately atretic. (See PCOS) Continued activity of FSH and activin lead to appearance of LH receptors on granulosa cells, a prerequisite for ovulation and luteinization. Ovulation is triggered by rapid rise in estradiol. A positive response in the anterior pituitary results in mid-cyle LH surge necessary for egg expulsion and corpus luteum formation. A rise in progesterone is followed by a second rise in estradiol, producing the 14 day luteal phase characterized by low FSH and LH levels. The demise of the corpus luteum, concomitant with a fall in hormone levels, allows FSH to increase again to start a new cycle. Rise in FSH recruits ovarian follicular growth, single dominant follicle ovulates. Its “dominance” is a function of achieving the highest aromatase activity. LH receptors in response to FSH. In late follicular phase, activin levels drop (increases aromatase activity and FSH and LH receptor formation) and inhibin levels increase. This leads androgen synthesis in the theca in response to LH and IGF-1 to provide substrate for even greater estrogen production in the granulosa. Rise in estrogen from the granulosa cells of enlarging dominant follicle – proliferation of endometrium. Estrogen peak causes LH surge, ovulation occurs hours after the onset of the LH surge. Surge lasts ~48 hours and a minimum threshold (14-27h) must be maintained for maturation of the oocyte to occur. Menses occurs 14 days after ovulation (fixed). Corpus luteum produces progesterone and estrogen Progesterone – rise in basal body temperature by 0.5 to 1, prepares endometrium for embryo implantation. If no pregnancy, hormone levels decrease, withdrawal of E and P causes constriction of spiral arteries, ischemia, endometrial shedding.
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The initial work-up for a patient with 2° sexual characteristics and amenorrhea include all of the following except: Pregnancy test Pelvic ultrasound Prolactin level Thyrotropin level Assessment of endogenous estrogen status (progestational challenge) a) Pregnancy always need to be ruled out. Need to assess prolactin TSH (rarely abnormal without clinical symptoms) so simple to treat with prompt return to ovulation and estrogen level. e) Sexual development provides evidence of some estrogen production but current E status need to be confirmed either through progesterone withdrawal test or Estradiol levels. Progestational challenge assesses estrogen production and competency of the outflow tract. 5 days of progestin (no estrogens) with a bleed expected within 2-7 days. Bleeding implies anovulation. No bleed implies outflow tract obstruction or lack of estrogen therefore provide an estrogen/progestin cycle over 2 cycles. At this point a bleed implies a functional end-organ and the problem lies either at the ovary or the hypothalamus/pituitary. Check gonadotropins. High= ovarian failure; Low or Normal= hypothalamic cause but consider imaging of the sella turcica. b) A pelvic ultrasound should be considered if anatomic defect is suspected, but not necessarily as initial work-up
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Amenorrhea Primary Amenorrhea Secondary Amenorrhea
No menses by age 13 in the absence of development of secondary sexual characteristics or No menses by age 15 regardless of presence of normal growth and development Secondary Amenorrhea No menses for a length of time equivalent to a total of at least 3 of the previous cycle intervals > 6 months of amenorrhea Old notes say age 14 and 16. Traditionally, investigations are initiated at age16, but secular trends toward earlier menarche, evaluation should begin by age 15 (97% of girls should have experienced menarche).
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Amenorrhea - Etiology PREGNANCY Hypothalamus Pituitary Ovary
ALWAYS NEED TO RULE OUT!! PREGNANCY Extreme Stress, Anorexia nervosa, Tumors, Infection, Congenital (Kallman’s syndrome) Hypothalamus (35%) Prolactin adenomas, 1o hypopituitarism, Sheehan syndrome, (Thyroid) Pituitary (20%) Congenital, Premature Ovarian Failure (autoimmune, infection, irradiation, surgery, chemo) Anovulation (PCOS, tumors) Ovary (20%) Approach is to think in terms of compartments: 1) Disorders of the Outflow tract or uterus 2) Disorders of the Ovary 3) Disorders of the Anterior pituitary 4) Disorders of the CNS (Hypothalamus). Hypothalamic : (hypogonadotropic hypogonadism) have deficiency in GnRH pulsatile secretion. Not testable. Typically it is the diagnosis of exclusion after pituitary testing is negative. Anorexia means underweight. Stress is thought to increase cortisol and CRH. The latter inhibits gonadotropin secretion (augmentation of endogenous opiod secretion). Kallmann’s Syndrome is congenital hypogonadotropic hypogonadism associated with anosmia (amenorrhea with anosmia). They can respond to induction of ovulation but not with Clomid. Pituitary: tumors are usually not malignant but can grow, upwards, and compress optic chiasma leading to the classic bitemporal hemianopsia. Craniopharyngiomas (are calcified and seen on coned views); meningiomas, gliomas, metastatic tumours and chordomas. Prolactin adenomas are the most common pituitary tumor. Sheehan’s Syndrome: acute necrosis of the pituitary gland due to postpartum hemorrhage and shock. The symptoms of hypopituitarism are seen early in the post-partum phase (failure of lactation and loss of pubic and axillary hair) prolactin , TSH and ACTH affected. Ovary: Gonadal dysgensis leads to ovarian streaks with 45X or Turner’s (50%)>mosaics (25%)>46XX (25%) in primary amenorrhea. The reverse if they have secondary amenorrhea. Mosaicism is the presence of multiple cell lines of varying sex chromosome composition. Any Y chromosome requires gonadal excision because a testicular component is a risk for tumor development and heterosexual development. Premature ovarian failure (early depletion of ovarian follicles) before the age of 40. Probably a genetic disorder and unknown generally. Sex chromosome abnormalities can be identified which have accelerated rates of atresia. Uterus/Vagina: Asherman’s syndrome is secondary amenorrhea following the destruction of the endometrium. Usually secondary to intrauterine scarification from curettage. The adhesions partially or completely obliterate the endometrium. Mullerian anomalies: segmental disruptions of the vagina should be ruled out. Mullerian agenesis or Mayer-Rokitansky-Kuster-Hauser syndrome is amenorrhea and no apparent vagina (2nd to gonadal dysgenesis as a cause of primary amenorrhea). They usually have a uterus of some kind. Ovaries and growth are normal. Can have renal and skeletal abnormalities. Androgen insensitivity occurs with no vagina and no uterus. (3rd most common cause of primary amenorrhea). CAI is genetically male but with failure of virilization. They have testes and produce adequate hormone but do not respond to it. Because anti-Mullerian hormone is present they don’t develop uterus, tubes and upper vagina. Gonads removed after puberty because they have a low malignant potential before puberty and are insensitive to testosterone and will develop female without virilizing effects. There is a spectrum and some can have partial androgen response (Incomplete androgen insensitivity) have some androgenization. Gonadectomy not deferred as this will obviate further unwanted virilization. Transmitted by x-linked recessive gene. Congenital Absence, Imperforate hymen, Vaginal septum, Asherman’s syndrome Uterus/vagina (5%) Drugs (Metoclopramide, neuroleptics) Others
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Premature ovarian failure may be due to any of the following except:
Turner’s syndrome Autoimmune dysfunction Hyperandrogenism Radiation exposure C – Hyperandrogenism usually occurs with PCOS, causes anovulation, but not atresia of follicles. The role of androgens in early follicular development complex. Androgens in low concentrations enhance granulosa aromatase activity enhancing estrogen production. In her doses, preantral granulosa cells favor the production of potent androgens rather than estrogens. An androgenic milieu (ie. Low FSH or high LH) antagonizes estrogen-induced granulosa proliferation and will promote degeneration of the oocyte. In the antral follicle, granulosa cells are well established in their preference for producing estrogens. Robust estrogen production is a function of LH-induced thecal production of androgen as substrate for the granulosa cells aromatase. The higher estrogen from the emerging dominant follicle (days 5-7) has an inhibitory effect on pituitary FSH which suppresses other follicle maturation but a stimulatory effect on LH secretion. LH stimulates theca androgen production during the late follicular phase which is typically the substrate for further estrogen. LH also stimulates progesterone production in the granulosa (luteinization).
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Anovulatory, dysfunctional bleeding Coagulopathy Pregnancy
A 15 year old female is brought to the ED because of very heavy vaginal bleeding. Her Hb level is 90 g/L. Each of the following diagnoses should be considered except: Anovulatory, dysfunctional bleeding Coagulopathy Pregnancy Endometrial polyps Thyroid dysfunction D – endometrial polyps are rare in adolescents
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Anovulatory, dysfunctional bleeding Coagulopathy Pregnancy
A 45 year old female is brought to the ED because of very heavy vaginal bleeding. Her Hb level is 90 g/L. What is the least likely diagnosis? Anovulatory, dysfunctional bleeding Coagulopathy Pregnancy Endometrial polyps Thyroid dysfunction D – endometrial polyps are rare in adolescents
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A 14 year old girl is brought to the ED by her mother because she has been bleeding heavily for the past 2 weeks. She experienced menarche 6 months ago and has been very irregular. She denies any other medical problems. She has never been sexually active. She has normal secondary sexual development. Her BP is 100/60 and her pulse is 100. She is 5 ft tall and weighs 95 lbs. Her abdomen is benign. She will not let you perform a speculum or pelvic exam. Which of the following is not indicated in the evaluation of this patient? hCG Bleeding time CBC Type and Screen Estradiol level D – endometrial polyps are rare in adolescents
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Approach to AUB
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Abnormal Bleeding Investigations: hCG CBC, ferritin
TSH, prolactin, coagulation profile Rule out organic diseases: H&P Endometrial biopsy (esp. if > 40 years old) + Ultrasound * post-menopausal bleeding is endometrial cancer until proven otherwise – need tissue diagnosis
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Acute DUB Treatment Severe: Mild: OCP
Cyclic Medroxy Progesterone Acetate (Provera) Severe: Stabilize patient as required (ABC’s) Premarin IV 25 mg q4-6h or high dose OCP + Add OCP or Provera for maintenance D&C if severely ill or unresponsive to medical therapy
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DUB Longterm Treatment
Hormonal Manipulation of Cycle Combined Contraceptives Progesterone only Progesterone IUD (Mirena) GnRH analogue Control of Menorrhagia NSAIDs for menorrhagia Anti-fibrinolytic agents (Cyklokapron) Surgical endometrial ablation hysterectomy
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Polycystic ovarian syndrome Late onset congenital adrenal hyperplasia
A 26 year old G0P0 complains of being too hairy. Her menses have always been irregular occurring every 2 to 6 months. She also complains of acne and is seeing a dermatologist for this. She denies any other medical problems. She is 5’ 5’’ tall, weighs 200 lbs, and her BP is 100/60. On exam, there is sparse hair around the nipples, chin and upper lip. There is no galactorrhea, thyromegaly, or temporal balding. Pelvic examination is normal. Which is the most likely condition in this patient? Idiopathic hirsutism Polycystic ovarian syndrome Late onset congenital adrenal hyperplasia Sertoli-leydig cell tumor of the ovary Adrenal tumor c) Late onset CAH are hirsute because of excess adrenal androgen production, by a deficiency in 21 hydroxylase. (check levels of 17-OH progesterone for CAH). The most common cause of hirsutism in women is anovulation and excessive androgen production by the ovaries. Adrenal causes are uncommon. Hirsutism: implies a vellus to terminal hair transformation in male pattern distribution. Sexual hair is hair that responds to sex steroids. Once influenced by androgens, these final hair characteristics recur in cycles, even in the absence of sustaining androgens. (ie. Castration in a male after puberty with a full distribution of beard and sexual hair won’t stop this process although hairs may slower and finer; Hypertrichosis is a generalized increase in hair of the fetal lanugo type, associated with the use of drugs or malignancy. Vellus hair is the downy hair associated with the pre-pubertal years; Terminal hair is the coarse hair that grows on various parts of the body during the adult years.
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In a woman with PCOS, a systemic manifestation that is the direct effect of the hyperinsulinemic state is: a) hirsutism b) obesity c) acanthosis nigricans d) hyperprolactinemia AC is a characteristic condition that appears in the skin folds, especially of the neck, axillae, and groin and under the breasts. The skin is darkly pigmented and has a velvety appearance. Ethnic prevalence varies estimates 15% of young African-American women demonstrate AC without any medical condition. In PCOS it is a reflection of hyperinsulinemia and results from direct insulin stimulation of the epithelial cells in these areas.
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PCOS - pathophysiology
insulin ↑estrogen ↓FSH + ↑LH anovulation ↑peripheral estrogen ↑androgens from ovary oligomenorrhea The pathogenesis of Anovulation: Evidence implicates insulin and the insulin receptor as well as the steroid enzyme pathways leading to excess ovarian androgen production in the pathophysiology of PCOS. Hirsutism is one of the classic manifestations of PCOS reflecting both an increase in the production of androgens and an increase in the amount of circulating free testosterone. Both of these are likely indirect manifestations of the hyperinsulinemia associated with PCOS. - The fate of the pre-antral follicle is in delicate balance. At low concentrations, androgens enhance their own aromatization and contribute to estrogen production. At higher levels, the limited capacity of aromatization is overwhelmed, and the follicle becomes androgenic and ultimately atretic. Central Defects malfunction of the hypothalamus is a likely and a favorite explanation for ovulatory failure. below threshold GnRH pulsatility leads to no gonadotropin surge. hyperprolactinemia. higher LH pulse frequency and amplitude is also seen in anovulatory women than seen in normal midfollicular phases. (inhibitory). Abnormal feedback signals: estradiol levels may not fall low enough to allow sufficient FSH response for the initiation of follicular growth. Appropriate decline requires reduction in secretion, appropriate clearance and metabolism (affected by liver or thyroid disease), and absence of contributions by extra-gonadal sources. the adrenal indirectly contributes to estrogen levels by conversion of androgen precursors – mainly androstenedione. I.e. Stress may contribute to sustained levels. Adipose tissue can convert androstenedione to estrogen (estrone) hence conversion increases with increasing body weight. Obesity therefore: increases peripheral aromatization of androgens to estrogens; decreases SHBG thus increasing circulating levels of estrogen and testosterone; increased insulin levels can stimulate ovarian stromal tissue production of androgens. estradiol levels may be inadequate for the stimulatory effects necessary to induce ovulatory surge of LH In PCOS the average daily levels estrogen and androgens is higher and dependent upon LH stimulation. LH increases secondary to high estrogen levels which also inhibits FSH. Chronic ovarian exposure to this leads to follicular maturation but incompletely so. These follicles are surrounded by gonadotropic stimulation in the form of LH which leads to thecal secretion of more androgen. This process is self-sustaining because even with atresia there is a new population of follicles to take over. A reduction in SHBG by 50% is seen in anovulatory women and is regulated by testosterone and by hyperinsulinemia which has a direct effect on the liver. Of note, all androgens are increased: testosterone, androstenedione and DHA (ovary) as well as adrenal (DHAS) as is estrogen. HAIR-AN syndrome – hirsutism, anovulation/amenorrhea/infertility, insulin resistance, acanthosis nigricans (darkening of skin folds in intertriginous zones). compensatory response to insulin resistance is hyperinsulinemia which leads to hypertension, increase in TG and decrease in HDL-cholesterol. elevated insulin contributes to hyperandrogenism by: binding to IGF-1 receptors, as opposed to insulin receptor only – the two receptors are similar, which are important in regulating thecal androgen response to LH, decreasing liver production of SHBG; inhibition of liver production of IGF-1 binding-protein. obesity HIRSUTISM INFERTILITY
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Treatment of PCOS Cycle Control Infertility
Weight loss: diet and exercise Cyclic progesterone or OCP to prevent endometrial hyperplasia/ cancer Metformin to insulin levels & ? reduce risk of progression to type 2 diabetes Infertility Ovulation induction: Clomiphene, FSH, LHRH, etc. Metformin to sensitize to ovulation induction Ovarian drilling *Treatment will depend on patient’s immediate concerns and risk factors PCOS is a complex metabolic disorder that includes a range of manifestations. Therapy should not just focus on controlling abnormal bleeding or fostering pregnancy; consider overall health. - Clomid works to increase the levels of FSH. Decreasing testosterone levels by laser drilling (less adhesions) than wedge resection of the ovaries. Oral hyperglycemic agents.
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Treatment of PCOS/Hirsutism
- OCP (specifically Diane-35) antiandrogenic - + spironolactone (inhibits steroid receptor) - Finasteride (5α reductase inhibitor) - Flutamide (androgen reuptake inhibitor) - Mechanical removal of hair The Ferriman-Gallwey score Severity of the hirsutism, as measured by a modified Ferriman-Gallwey score, a method that grades hair growth on a scale of 0 to 4 in nine androgen-sensitive areas. Mild and severe hirsutism are considered to be scores of ≥8-15 and >15, respectively. estrogen-progestin contraceptive as first-line pharmacologic therapy for most women. An anti-androgen is then added after six months if the cosmetic response is suboptimal. For women with hirsutism and contraindications to oral contraceptives, we sometimes use spironolactone alone, but an alternative form of contraception is essential to protect male fetus. Start with an oral contraceptive preparation containing 30 to 35 mcg of ethinyl estradiol combined with a progestin with minimal androgenicity (such as norethindrone, norgestimate, desogestrel, or drospirenone). After six months, if the patient is not satisfied with the clinical response, we typically add spironolactone 50 to 100 mg twice daily; this dose can then be reduced over time as needed. Other antiandrogens that are effective include finasteride and cyproterone acetate (available in most countries, but not the United States). Hirsutism can also be treated by removal of hair by mechanical means such as shaving, waxing, depilatories, electrolysis or laser treatment. - In addition, Vaniqa (eflornithine hydrochloride cream 13.9 percent) is a topical drug that inhibits hair growth. It is not a depilatory, and must be used indefinitely to prevent regrowth.
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The following statements are true except:
Menopause occurs at ~51 years of age as a result of a genetically determined depletion of ovarian follicles responsive to gonadotropins. Menopause occurs earlier in smokers. Loss of ovarian function results in absolute estrogen deficiency. Hormone replacement therapy should not be used for prevention of cardiovascular disease or dementia C – there is still peripheral (adrenal) source of estrogen
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Definitions Menopause Perimenopause
after 12 consecutive months of amenorrhea, resulting from the loss of ovarian follicular activity Menopause occurs with the final menstrual period which is only known with certainty retrospectively one year or more after the event. Perimenopause the period immediately prior to menopause when clinical, biological, and endocrinological features of approaching menopause commence. The “climacteric” should be abandoned to avoid confusion.
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Clinical Conditions In Menopause
Vasomotor symptoms 75% of women > 1 year in 80% of women Major indication for ERT/HRT SSRI, clonidine, gabapentin, black cohosh Urogenital atrophy Lubricants, moisturizers, local estrogen therapy Osteoporosis Ca, Vit D, smoking cessation, exercise Bisphosphonates, ERT/HRT, SERMs (raloxifene) Hot flashes are sudden onset of intense warmth that begins in the chest and may progress to the neck and face. Accompanied by anxiety, palpitations, and profuse sweating. Interfere with work, social life, sleep patterns and her general perception of health. Most women experience these vasomotor symptoms for 6 months to 2 years, although some have them for 10+ years About 75% of women will experience for a median time of 3.8 years The precise cause of vasomotor symptoms is unknown although they appear to have a hypothalamic origin. HT significantly reduces the frequency and severity of hot flashes by about 80% compared to placebo. Alternatives to Estrogen: progestins can be used Provera 20 mg OD; Depo 150 mg q1-3 months; Megace 20 mg OD (80% reduction); Prometrium 200 mg OD (no significant data). Bellergal and Dixarit (clonidine - central alpha agonist) are the only non-hormonal options approved for treatment of symptoms. Clonidine is an old antihypertensive drug and has limited benefit in the treatment of vasomotor symptoms with significant SE. (dizziness, dry mouth, drowsiness and constipation). Stop if no improvement in 2-4 weeks. SSRI – Venlafaxine achieved a 60% reduction in symptoms. Up to 75 mg OD as no increase benefit at higher doses. Paroxetine and fluoxetine are not particularly effective. Gabapentin treats neurologic disorders and neuropathic pain ?mechanism. Reduced by 50% in one RCT. Evidence is lacking for Complementary and Alternative Medicines (CAMs) but Black Cohosh has been shown to provide some benefit for the treatment of menopausal symptoms. Neither the identity of the active compound nor the mechanism has been determined No longterm data, in particular, on endometrium and breast. Hepatotoxicity has been reported.
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HRT Good Bad relief of vasomotor and GU symptoms
Increases BMD, decreases fracture risk Decrease colorectal cancer Bad Increases VTE, CAD, stroke ? Increased risk of breast cancer, ovarian cancer, and dementia No increased risk of endometrial cancer Symptoms of urogenital aging include dyspareunia, vulvar soreness, discharge, urinary frequency and urgency, and/or recurrent UTI. Colorectal cancer reduction in trials show a drop of 30% in current and recent users (within 1 year) or 6 fewer cases / women per year. Cardiovascular HT does not prevent CAD and increases the risk of cardiovascular events in the first year of treatment in older post-menopausal women.HERS study (Heart and E/P replacement study). 6.8 years of observation. Stroke/VTE Estrogen is the likely culprit. The Nurse’s Health Study and WHI (both E alone or E/P arms) show an increased risk of stroke and VTE, especially in older post-menopausal women with risk factors for these conditions. Breast cancer No increase risk in 4 year s or less. Beyond 5 years the relative risk increased 2% per year of use or, in absolute terms, 2, 6, 12 additional cases per 1000 HT users for 5, 10, 15+ years of use, respectively. The increase at 5 years is similar to other lifestyle variables such as fewer pregnancies, reduced breastfeeding, obesity in menopause, excessive alcohol, cigarette use, and lack of regular exercise. Increase risk returns to normal 5 years after cessation. Ovarian cancer rates, from WHI study, show a small but not significant increase in risk from baseline. But baseline rates are so low that these results should be cautiously interpreted. The evidence for HT on improving cognitive function, in healthy post-menopausal women, remains controversial with conflicting evidence. RCTs have not demonstrated improved cognitive function; although short and long-term verbal memory scores are higher. There may even some decline in cognitive function with HT. The same is true for Alzheimer’s the most common form of dementia. ET may actually increase the risk for its development. There may be a benefit in estrogen therapy for the treatment of mild to moderate AD. Estrogen is not currently recommended for reducing the risk of developing dementia in postmenopausal women or for retarding the progression or deterioration in women diagnosed with AD.
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A 42 year old G4P4 woman states her cycles are regular and denies any STIs. Currently she and her husband uses condoms, but they hate the hassle of a coital dependent method. She is interested in a more effective contraceptive method. They do not want any more children. She reports occasional migraine headaches, has had a serious allergic reaction to anesthesia as a child. She is a social drinker and smoker. She weighs 70 kg, her BP is 142/88. Which is the most appropriate contraceptive method for this patient? Combination OCP Diaphragm Transdermal patch Intrauterine device Bilateral tubal ligation
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Contraception Combined Hormonal Progestin Only Intrauterine Devices
OCP Patch Ring Progestin Only Progestin only pill DMPA (Depo-Provera) Intrauterine Devices Copper IUD (Nova-T) Hormonal IUS (Mirena) Barrier Methods Male and female condom, diaphragm, cervical cap, sponge Permanent Sterilization Male Female (Laparoscopic and hysteroscopic)
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Hormonal Contraception
Absolute contraindications Pregnancy Undiagnosed vaginal bleeding Thromboembolic disease Estrogen dependent tumors Coronary/cerebrovascular disease Impaired liver function Uncontrolled hypertension Migraines with neurological symptoms Smoker, age >35 Relative contraindication Migraines (non-focal) Controlled hypertension Hyperlipidemia Sickle cell anemia Gallbladder disease SLE
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Combined hormonal contraceptives:
Decrease the risk of stroke and VTE Should only be started on the first day of a menstrual period Suppress ovulation mainly through an estrogen dominant effect Is contraindicated in women >35 years old Decrease dysmenorrhea, menorrhagia and acne A) STROKE A significantly increased risk of stroke is seen in users of combined OCs that contain more than 50 μg of ethinyl estradiol. Although some studies of low-dose combined OCs report no increase in the risk of stroke, others have reported an increased risk of up to 2-fold. Smoking and hypertension are major risk factors for stroke. Combined OC users with hypertension are at an increased risk of stroke relative to users without hypertension. A meta-analysis published in 2000 reported an odds ratio of 1.93 (95% confidence interval [CI], 1.35–2.74) for current combined OC preparations in studies that controlled for smoking and hypertension. b) Initiation Various start dates for the combined OC are used. Conventionally, the combined OC is started during the first 5 days of the menstrual cycle or on the first Sunday after menses begin. If the combined OC is started within the first 5 days of the menstrual cycle, a backup method of contraception is not necessary for prevention of pregnancy, provided that no pills have been missed. Another alternative is the Quick Start method, where a combined OC user takes her first pill in the health-care provider’s office after ruling out pregnancy. A back-up method of contraception should be used for the first week after combined OC initiation if the Quick Start method is used. This method, with its simple starting instructions, improves compliance, particularly in adolescents, and is not associated with an increase in the incidence of breakthrough bleeding or other side effects. c) MECHANISM OF ACTION The combined OC’s multiple mechanisms of action may contribute to its high efficacy. Its main mechanism of action is to suppress gonadotropin secretion, thereby inhibiting ovulation. Other mechanisms of action include: • Development of endometrial atrophy, making the endometrium unreceptive to implantation • Production of viscous cervical mucus that impedes sperm transport • Possible effect on secretion and peristalsis within the fallopian tube, which interferes with ovum and sperm transport.
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In combined hormonal contraceptives, which of the following is the primary contraceptive effect of the estrogenic component? Conversion of ethinyl estradiol to mestranol Atrophy of the endometrium Suppression of cervical mucus secretion Suppression of LH secretion Suppression of FSH secretion
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Smoking in a woman over 35 years of age Hypertension
A 38 year old G3P3 would like to restart the birth control pill. Her PMHx is significant for hypertension, well controlled with a diuretic, and a seizure disorder. Her last seizure was 12 years ago and currently is on no anti-epileptic medications. She complains of stress related headaches that are relieved with over the counter pain medications. She is divorced, smokes 1 pack of cigarettes per day, drinks 3-4 alcoholic beverages per week. On exam, she weighs 90 kg, her BP is 126/80, and pelvic exam is normal. She has some lower extremity non-tender varicosities. She has taken birth control pills in the past and would like to restart them as they help with her menstrual cramps. Which of the following would contradict the use of combination oral contraceptives in this patient? Varicose veins Tension headaches Seizure disorder Smoking in a woman over 35 years of age Hypertension Smoking is a prominent risk factor for MI; the relative risk of MI in women who smoke is approximately 11. Combined OC use had a compounding effect with heavy smoking, with an odds ratio of 32 (95% CI, 12–81) in heavy smokers when compared to nonsmoking non-users. Thus, age and smoking are the major risk factors for MI in women who consider using combined OCs. Because of the potential for combined OCs to compound theeffects of age and smoking, it is prudent to avoid their use in women over 35 who smoke heavily. Varicose veins embolization does not usually occur in the absence of deep vein involvement. EPILEPSY Combined OCs can be used safely in women with epilepsy. Some drugs reduce the efficacy of combined OCs.80 In this case, the use of combined OCs containing more than 35 μg of ethinyl estradiol may be warranted. It is recommended that injections of DMPA be given every 10 weeks rather than every 12 weeks in women who are receiving antiepileptic drugs that induce hepatic microsomial enzymes. Tension headaches are not related to combined OC use. Migraine headache is associated with an approximately 3-fold increase in risk of ischemic stroke. The risk of stroke is considered higher in women who have migraine with aura (relative risk approximately 6 compared with women without migraine), although not all studies report a difference. The risk of stroke is further increased by the presence of hypertension, smoking, and the use of combined OCs. Migraine is not considered a contraindication to the use of combined OCs in the absence of aura or other risk factors. Combined OC use is generally considered contraindicated in patients with migraine aura. Hypertension when uncontrolled (systolic ≥ 160mm Hg or diastolic ≥ 100mm Hg). Otherwise relative contraindication hypertension (systolic 140–159mm Hg, diastolic 90–99mm Hg). Smoking is qualified when less than 15 cigarettes in women over the age of 35 years.
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True or False about OC The combined OC reduces the risks of ovarian and endometrial cancer. Women on the combined OC should have periodic pill breaks. The combined OC affects future fertility The combined OC causes birth defects if a woman becomes pregnant while taking it The combined OC must be stopped in all women over 35 The combined OC causes acne. True False 1) The risk of ovarian cancer is reduced by at least half in women who use combined OCs. A meta-analysis of 20 studies of combined OC use indicated that the risk of ovarian cancer decreased with increasing duration of OC use, reducing by 10 to 12% after 1 year of use and by approximately 50% after 5 years of use. This reduction in risk persists for 10 to 20 years after combined OC use has been discontinued. The combined OC is associated with a 50% overall reduction in the risk of endometrial cancer and the protective effect persists long after the combined OC is discontinued. 2) This is unnecessary. Pill breaks place a woman at risk for unintended pregnancy and cycle irregularity. 3) The combined OC affects future fertility. Fertility is restored within 1 to 3 months after stopping the combined OC. 4) The combined OC causes birth defects if a woman becomes pregnant while taking it. There is no evidence that the combined OC causes birth defects if it is taken inadvertently during pregnancy. 5) The combined OC must be stopped in all women over 35 years old. Healthy, non-smoking women may continue to use the combined OC until menopause. 6) The combined OC causes acne. Acne improves in women using the combined OC due to a decrease in circulating free androgen. Although all combined OCs will result in an improvement of acne, 2 combined OCs in Canada have received official labelling for the treatment of acne; these 2 OCs contain ethinyl estradiol in combination with either levonorgestrel or norgestimate. The combination pill with cyproterone acetate is indicated for the treatment of severe acne and is also a contraceptive.
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27 year old nulligravid student was “celebrating” with her male partner after passing her exams. Immediately after intercourse she noticed that the condom was broken. Her LMP was 12 days ago. She has regular 28 day cycles with molimina. She normally takes Alesse but had stopped 6 months ago. She pages you at 2 am. She does not want to get pregnant. What would be the appropriate management(s) to offer this couple? (You may chose up to three answers)
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Contraception Urgent pregnancy test (serum)
Suggest expectant management and wait to see if she misses a period If she still has her Alesse tablets, take 5 of these now, and another 5 in 12 hours Insertion of copper containing IUD 0.75 mg Levonorgestrel po now and again in 12 hours Suggest doing a handstand q hourly x 48 hours to prevent implantation
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Emergency Contraception
Yuzpe Method within 72 hours of intercourse 2 Ovral tablets q12h x 2 doses (with Gravol!) 100 µg estradiol µg levonorgestrol (LNG) EACH dose. 6% chance of pregnancy decreases to 2% with Yuzpe recent estimate of pregnancy 3.2% ‘Plan B’ 0.75 mg (LNG) every 12h x 2 doses (less nausea) or 1 double dose of the LNG EC regimen (1.5 mg) may be used, as they have similar efficacy with no difference in side effects. increase in efficacy compared to Yuzpe with 1.1% pregnancy rate. Copper IUD Insertion within 5 days of intercourse (extended up to 7 days in Canada) 1% failure rate Hormonal methods – delay or inhibit ovulation. Yuzpe = 100 mcg estradiol mcg levonorgestrel repeated once initiated within 72 hours but up to 5 days. Ethinyl estradiol plus levonorgestrel (Yuzpe regimen) — The Yuzpe method . Plan B (the only product for EC approved in Canada). LNG method is more effective and associated with fewer side-effects than Yuzpe. But accessibility is occasionally a factor in using the combined BCP. Copper IUD is extremely effective but more invasive approach. Provides for ongoing contraception afterwards and a broader window of protection as can be inserted until day 5 post-ovulation. Antiprogestins (ie. Mifespristone) may be more effective than progestins due to their ability to both delay ovulation and inhibit implantation. A disadvantage of antiprogestins is that the delay in ovulation results in a delay in subsequent menses, which may provoke anxiety about possible pregnancy. Not available in Canada. MECHANISM OF ACTION: The mechanism of action of emergency contraception is uncertain and may vary depending upon the day of the cycle the drug is administered. Oral emergency contraceptives may act by one or more of the following actions: Inhibiting or delaying ovulation; Interfering with fertilization or tubal transport; Preventing implantation by altering endometrial receptivity; Causing regression of the corpus luteum. Direct laboratory evidence overwhelmingly supports the hypothesis that emergency contraceptives work by mechanisms that do not include post-fertilization events. Since these drugs are administered within hours of intercourse and implantation does not occur until approximately five to seven days after ovulation, use of emergency contraception does not interrupt pregnancy and is ineffective after pregnancy has occurred.The primary mechanism of copper intrauterine contraception is to inhibit fertilization. It may also have secondary postfertilization contraceptive effects and can be inserted up to 7 days post coitus (SOGC). Method Dose Reported efficacy: Levonorgestrel 0.75 mg given twice, 12 hours apart, or 1.5 mg single dose (89% effective). Estrogen plus progesterone (Yuzpe regimen) 100 microgram ethinyl estradiol plus 0.5 mg levonorgestrel, each given twice, 12 hours apart ( % effective). efficacy up to 120h but best within 72 hours. Mifepristone Single 600 mg dose (100%). Copper intrauterine device. Inserted within 120 hours after intercourse (Over 90 %). Vomiting If levonorgestrel is vomited within one hour of administration and no antiemetic was given, we suggest giving an antiemetic agent and then repeating the levonorgestrel. If estrogen-progestin pills are vomited within one hour of ingestion and an antiemetic was not taken prophylactically, then an antiemetic can be given and the estrogen-progestin dose repeated. Alternatively, levonorgestrel alone can be administered for emergency contraception. vaginal administration of emergency contraceptives (levonorgestrel, Yuzpe regimen) may also be effective. However, the efficacy of this approach has not been thoroughly investigated and the optimal dose is controversial. We would consider it only as a last resort if premedication with antiemetics was ineffective or use of a copper intrauterine device was unacceptable. Need for additional contraception — Women using emergency contraception pills should be advised that a risk of pregnancy still. There are no absolute contraindications to the use of emergency hormonal contraception except known pregnancy, and this is only because it is ineffective. According to the WHO, there are no known medical contraindications to the use of hormonal EC, aside from allergy to one of the constituents.
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OVRAL AND SUBSTITUTIONS
Brand Pills/Dose EE (μg)/Dose LNG (μg)/Dose Ovral 2 100 500 Alesse 5 Triphasil 4 yellow 120 Triquilar Minovral 4 600 Follow Yuzpe, therefore, repeat dose in 12h.
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An 18 yo university student recently became sexually active and is complaining of severe dysmenorrhea which is not responsive to heating pads and mild analgesics. She does not want to get pregnant. Which of the following is the most appropriate treatment for this patient? NSAIDS Narcotic analgesics Short acting benzodiazepines Combined hormonal contraceptive Selective serotonin reuptake inhibitors (SSRIs) NSAIDs are analgesics which inhibit the cyclooxygenase (COX) enzymes, thereby inhibiting the production of Prostaglandins (non-specific inhibitors of both COX-1 and COX-2). Avoiding the inhibition of platelets and GI toxicity is the reason for COX-2 specific inhibitors such as celebrex and Mobicox. A meta-analysis of 56 trials 59 confirms beyond doubt that all 4 NSAIDs evaluated (naproxen, ibuprofen, mefenamic acid and aspirin) are effective in primary dysmenorrhea. In the systematic review, both naproxen and ibuprofen appeared to be better than aspirin. On a risk-benefit assessment, ibuprofen was better than naproxen because of the side effects of naproxen. Little evidence of superiority of any NSAIDs with regard to either efficacy or safety. Effective treatment is initiated with the onset of bleeding. Oral contraceptives may be recommended for the treatment of primary dysmenorrhea. The added contraceptive advantage may make oral contraceptives a first-line therapy for some women. (I-A)
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A 27 yo woman complains of mood swings, depression, irritability, and breast pain each month in the week prior to her menstrual period. She often calls in sick at work because she cannot function with these symptoms present. Which is the best option for treating this patient? NSAIDS Narcotic analgesics Short acting benzodiazepines Combined hormonal contraceptive Selective serotonin reuptake inhibitors (SSRIs) Managing Premenstrual complaints: Molimina: A normal phenomenon affecting most ovulatory women. Premenstrual symptoms that indicate imminent menstruation: headache, breast pain, bloating, irritability, labile mood. PMS is a combination of physical, psychological and behavioral changes that adversely affect 3-5% of ovulatory women each month in the week(s) leading up to (and sometimes throughout) menstruation. PMDD (premenstrual dysphoric disorder) DSM-IV and requires 5 or more severe symptoms in most cycle for the past year. Linked to ovarian activity as it resolves with medical, surgical or natural menopause. lots of theories about etiology Is a link with fluctuations in serotonin. Diagnosis: H&P Prospective record keeping (PRISM – Prospective Record of th4e Impact and Severity of Menstrual symptoms) calendar. Treatment Supportive measures (validation, education, prospective charting) Lifestyle modifications (decrease caffeine, EtOH, calcium supplements, stress reduction, exercise) Popular but unproven remedies: vaginal progesterone; Evening Primrose oil, and pyridoxine (Vitamin B6) show no effect superior to placebo. Medical treatment: PG Sythetase inhibitors BCP (special effect of drosperinone on mood component) has mixed results in literature but relieves dysmenorrhea and reduce flow – thus improving the summation of premenstrual/menstrual distress. Drosperinone is a unique progestin derived from spironolactone that has anti-androgenic and anti-mineralocorticoid effects. It has similar efficacy on daily symptoms rating similar to SSRI. Anxiolytics/hypnotics Estrogen supplementation at menstruation (for menstrual migraine) Luteal phase Danazol (200 mg for mastalgia). SSRI are second level medical interventions (First in PMDD). Elevate serotonin levels. Become effective in days rather than in 4-8 weeks when used for clinical depression. Accordingly intermittent or luteal phase dosing appears effective. GnRH-agonists/depo-provera, Danazol to suppress ovaries are a 3rd line medical intervention Surgical therapy the ultimate when symptoms are severe and unresponsive to medical therapies other than medical ovarian suppression. Side-effects and cost of continued medical suppression may be prohibitive.
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A 39 yo G3P3 complains of severe, progressive secondary dysmenorrhea and menorrhagia. Pelvic examination demonstrates a tender, diffusely enlarged uterus with no adnexal tenderness. Endometrial biopsy was normal. Which of the following is the most likely diagnosis? Endometriosis Endometritis Adenomyosis Leiomyoma Endometriosis is the presence of functioning endometrial glands and stroma outside of the uterine cavity and often hemosiderin-laden macrophages. Typically found on dependent surfaces in the pelvis and most often affects the posterior cul de sac and ovaries. Unique ability to invade and destroy tissues and cause severe inflammation and adhesion formation. Estimate to affect 7% of US women of reproductive age. Etiology: i) tubal regurgitation ii) lymphatic spread & hematogenous spread iii) direct implantation iv) coelomic metaplasia Diagnosis: dysmenorrhea, dyspareunia, prementrual backache with or without infertility. Endometritis refers to inflammation of the endometrium, the inner lining of the uterus. Pathologists have traditionally classified endometritis as either acute or chronic. Acute endometritis is characterized by the presence of microabscesses or neutrophils within the endometrial glands. chronic endometritis is distinguished by variable numbers of plasma cells within the endometrial stroma. Both present with pain and abnormal bleeding but acute most often has fever associated with it. Typically preceded by PID. Chronic due to a number of etiologies including infection (TB, chlamydia) or foreign bodies including (IUD, submucus fibroids, polyps, radiation). Adenomyosis refers to a disorder in which endometrial glands and stroma are present within the uterine musculature (uterine adenomyomatosis). The ectopic endometrial tissue appears to induce hypertrophy and hyperplasia of the surrounding myometrium, which results in a diffusely enlarged uterus (often termed "globular" enlargement) analogous to the concentric enlargement of the pregnant uterus. However, some women have only small areas of diffuse disease that are only apparent by microscopy, whereas others develop nodules (termed adenomyomas), which clinically resemble leiomyomas. The uterus generally does not exceed the size of a pregnant uterus at 12 weeks of gestation. The pathogenesis of adenomyosis is not known. The two major theories are that it either develops from endomyometrial invagination of the endometrium or de novo from mullerian rests. On gross inspection, the uterus with diffuse adenomyosis is uniformly enlarged and boggy, in contrast to the irregular and firm appearance of the fibroid uterus. Heavy menstrual bleeding and painful menstruation are the major symptoms of adenomyosis, occurring in approximately 60 and 25 percent of women, respectively. Chronic pelvic pain may occur. Newer reports using magnetic resonance imaging (MRI) criteria for diagnosis suggest that the disease may cause dysmenorrhea and chronic pelvic pain in adolescents and younger reproductive-age women than previously appreciated. Menorrhagia is possibly related to the increased endometrial surface of the enlarged uterus, while pain may be due to bleeding and swelling of endometrial islands confined by myometrium. Approximately one-third of women are asymptomatic. A definitive diagnosis of adenomyosis can only be made from histological examination of a hysterectomy specimen. The preoperative diagnosis is suggested by characteristic clinical manifestations (ie, menorrhagia and dysmenorrhea with a uniformly enlarged uterus) in the absence of endometriosis or leiomyomas. MRI is clearly the best imaging technique, but is expensive.
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Pelvic Pain: Differential Diagnosis
CHRONIC: Endometriosis/adenomyosis Dysmenorrhea (cyclic pain) Ovarian cysts Chronic PID Adhesions Uterine prolapse Cancer invasive (late) Fibroids Pelvic congestion syndrome ** RULE OUT PREGNANCY!** ACUTE: Adnexal: Mittelschmerz Ovarian cysts, rupture, torsion Hemorrhage into ovarian cyst or neoplasm Uterine: Degenerating fibroids Torsion of pedunculated fibroid Pyometra/hematometra Infectious Acute PID Endometritis
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Diagnostic laparoscopy for pelvic pain should be performed to:
Evaluate women with cyclic pain who respond to NSAIDs or OCP Initially evaluate women with chronic non-cyclic pelvic pain Biopsy and treat endometriotic lesions Lyse all adhesions C. The diagnosis can only be substantiated by laparoscopy or laparotomy. This will assess the presence and the extent of the disease. Peritoneal biopsy is desirable although not necessary for the diagnosis if recognizable lesions are present. It is used for confirmation in doubtful cases. Endometriosis should be documented carefully by using the revised Classification by the American Society for reproductive medicine. NOT a validated scoring system but is semi-objective means of determining the extent of the disease and provides a quantifiable basis for follow-up comparisons. USS: Endometriomas have a characteristic appearance on ultrasound with irregular edges and internal echoes produced by chronic intracystic bleeding. CA-125 levels are helpful in monitoring severe cases but are not specific to this condition CT and MRI have a limited role in the diagnosis for superficial lesions but are much more helpful in delineating the pathological changes in more extensive disease
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Which of the following statements are true?
Women with endometriosis always have dysmenorrhea or chronic pelvic pain. Minimal or mild endometriosis should never be treated surgically, only medically. The degree of pelvic pain correlates with laparoscopic findings. Medical treatment of endometriosis includes OCP, progestins, GnRH analogues, Danazol. Medical treatment of endometriosis results in long term disease suppression and pain relief after cessation of therapy. A-false B-false C-false D-true E-false Danazol is effective in resolving implants when treating mild or moderate stages of disease and over 80 percent of patients experience relief or improvement of pain symptoms within two months of treatment. significant decrease in the level of pelvic pain, lower back pain, defecation pain, and total pain. The improvement in pain scores was still present six months after discontinuation of danazol therapy. a 19-nortestosterone derivative with progestin-like effects. mechanisms of action include inhibition of pituitary gonadotropin secretion, direct inhibition of endometriotic implant growth, and direct inhibition of ovarian enzymes responsible for estrogen production. divided doses ranging from 400 to 800 mg daily, generally for six months. side effects that can be dose-dependent, and a small percentage of patients discontinue the drug because of them. Side effects include weight gain, muscle cramps, decreased breast size, acne, hirsutism, oily skin, decreased high density lipoprotein levels, increased liver enzymes, hot flashes, mood changes, and depression. Androgenic side effects associated with use of danazol are not treatable except by lowering the dose. GnRH agonists produce hypoestrogenic symptoms, which can be minimized by add-back therapy.
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Endometriosis Abnormal growth of endometrial glands and stroma outside the uterine cavity Pathogenesis is unknown Infertility Dysmenorrhea, dyspareunia, dyschezia On pelvic exam: Tender nodules especially over uterosacrals Uterine retroversion with decreased mobility Adnexal enlargement with tenderness May also be normal Endometriosis is the presence of functioning endometrial glands and stroma outside of the uterine cavity and often hemosiderin-laden macrophages. Typically found on dependent surfaces in the pelvis and most often affects the posterior cul de sac and ovaries. Unique ability to invade and destroy tissues and cause severe inflammation and adhesion formation. Estimate to affect 7% of US women of reproductive age. Etiology: i) tubal regurgitation ii) lymphatic spread & hematogenous spread iii) direct implantation iv) coelomic metaplasia Diagnosis: dysmenorrhea, dyspareunia, prementrual backache with or without infertility. Signs: pelvic nodularity with tenderness, especially over the uterosacral ligaments Uterine retroversion with decreased mobility Adnexal enlargement with tenderness
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Your 43 yo patient would like to get pregnant but is concerned that she may be too old to get pregnant. You recommend that she have her gonadotropin levels be tested. Which day of the menstrual cycle is best to test this? Which day would be best to check her progesterone level to confirm ovulation? (cycle interval 28 days) Day 3 Day 8 Day 14 Day 21 Day 26 A-false B-false C-false D-true E-false
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Infertility - Etiology
Tubal/Pelvic Pathology (35%) Sperm Problems (35%) Unexplained (10-15%) Ovarian Problems (15%)
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Infertility Investigations
Ovaries Day 3 FSH Day 21 progesterone TSH, Prolactin Basal Body Temperature Testes Semen analysis x 2 Tubes HSG/SIS Laparoscopy Sex Timing Frequency Hysterosalpingogram Either water or lipid soluble contrast media can be used. HSG also provides information about the uterine cavity. Women with abnormalities on HSG should be referred to a reproductive endocrinologist to discuss treatment options. - HSG is not useful for detecting peritubal adhesions or endometriosis. Laparoscopy is. Saline infusion sonohysterography (SIS) refers to a procedure in which fluid is instilled into the uterine cavity transcervically to provide enhanced endometrial visualization during transvaginal ultrasound examination. Same as SHG which means ultrasound performed after the instillation of saline. Hysterosalpingo contrast sonography (HyCoSy) has been compared favourably in the literature with hysterosalpingography (HSG). It does not require ionizing radiation and demonstrates the uterus and ovaries.
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Hysterosalpingogram (HSG)
Hysterosalpingogram Either water or lipid soluble contrast media can be used. HSG also provides information about the uterine cavity. Women with abnormalities on HSG should be referred to a reproductive endocrinologist to discuss treatment options. - HSG is not useful for detecting peritubal adhesions or endometriosis. Laparoscopy is.
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Laparoscopy Poorly visualized fimbriae. Suspicious for peritubal disease.
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31 y.o. woman complains of sudden onset of RLQ pain.
pain is constant and worse with movements. no nausea/vomiting. bowel movements are normal. Her LMP was 7 weeks ago, and she has been actively trying to get pregnant. Past medical history is positive for PID requiring hospitalization for IV antibiotics for 4 days. Her vitals are stable, and she is afebrile. She is having mild vaginal bleeding (<1 pad) that started today. The abdomen is tender with guarding.
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What is the most likely diagnosis?
Ruptured ectopic pregnancy Appendicitis Incomplete abortion Ovarian torsion Hydatidiform mole
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Location of Ectopic Pregnancy
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What 3 initial investigations would be most appropriate?
a) CBC b) pelvic ultrasound (endovaginal and transabdominal) c) flat plate (x-ray) of abdomen d) quantitative hCG e) sigmoidoscopy with possible colonoscopy f) IVP with delayed films A,B,D
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In order to help distinguish an IUP from an ectopic pregnancy, the change in hCG levels over 48 hours is observed. What percentage rise in hCG represents the lower limit of normal values for viable IUP? 33% 50% 66% 100% 66% Human chorionic gonadotropin - can be detected in serum and urine as early as eight days after the LH surge, if pregnancy has occurred. The hCG concentration in a normal intrauterine pregnancy rises in a curvilinear fashion until about 41 days of gestation, after which it rises more slowly until approximately 10 weeks, and then declines until reaching a plateau in the second and third trimesters. There is a wide range in the normal hCG level at each week of pregnancy. Studies in viable intrauterine pregnancies have reported the following changes in serum hCG: The mean doubling time ranges from 1.4 to 2.1 days in early pregnancy. In 85 percent of viable intrauterine pregnancies, the hCG concentration rises by at least 66 percent every 48 hours during the first 40 days of pregnancy; only 15 percent of viable pregnancies have a rate of rise less than this threshold. The slowest recorded rise over 48 hours associated with a viable intrauterine pregnancy was 53 percent. The hCG concentration rises at a much slower rate in most, but not all, ectopic and nonviable intrauterine pregnancies. In one series, as an example, only 21 percent of ectopic pregnancies were associated with hCG levels that followed the minimum doubling time of a viable intrauterine pregnancy
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Investigations Hx & P/E hCG quantitative, CBC, blood T&S
Pelvic Ultrasound and the Discriminatory Level an intrauterine pregnancy should be seen if hCG > – IU/L (transvaginal) hCG > IU/L (transabdominal) Serial hCG - normal doubling time is about 2 days inadequate doubling suggests abnormal pregnancy Laparoscopy: definitive diagnosis The discriminatory level/zone is based upon the correlation between visibility of the gestational sac and the hCG concentration, and is of major diagnostic importance. It is defined as the serum hCG level above which a gestational sac should be visualized by ultrasound examination if an intrauterine pregnancy is present.
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Treatment Medical (Methotrexate): 50 mg/m2 (1/10th chemo dose)
serial hCG; weekly F/U 10-15% failure rate, 25% require 2nd dose Criteria: patient clinically stable no FHR hCG <5000 <3.5cm unruptured ectopic pregnancy no hepatic/renal/hematologic disease compliance and F/U essential Surgical Laparoscopy vs laparotomy Salpingectomy vs salpingostomy MTX is a folic acid antagonist widely used for treatment of neoplasia, severe psoriasis, and rheumatoid arthritis. - It inhibits DNA synthesis and cell reproduction, primarily in actively proliferating cells such as malignant cells, trophoblasts, and fetal cells. A review of cohort studies comparing fertility outcome after salpingostomy and salpingectomy for tubal ectopic pregnancy did not find an overall beneficial effect of salpingostomy. - The rate of future intrauterine pregnancy was not consistently higher after salpingostomy than after salpingectomy, whereas the risk of repeat ectopic pregnancy was slightly increased. - Salpingectomy does not appear to compromise the rate of subsequent intrauterine pregnancy in women whose contralateral fallopian tube appears to be normal and avoids the complication of persistent or recurrent ectopic pregnancy in the same tube.
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Ectopic Pregnancy
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A 60 year old woman presents with a pelvic mass
A 60 year old woman presents with a pelvic mass. What percentage of ovarian neoplasms in post-menopausal women are malignant: 5% 10% 30% 50% Adnexal Mass - Compared to < 10% in premenopausal women. - In girls younger than 15 years of age, a high percent of ovarian tumors are malignant. The overall risk of malignancy of an adnexal mass increases with age after menarche: 6 to 11 percent in premenopausal women 29 to 35 percent in postmenopausal women.
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A 10 yo healthy young girl with LLQ pain and left ovarian mass.
21 yo G2P2 with increasing hair growth, more acne, with a 7cm left adnexal mass. A 23 yo woman undergoing laparoscopy for a 5 cm solid right ovarian mass. Pathology shows hair, sebum and thyroid tissue. A 56 yo postmenopausal woman with enlarged uterus, vaginal bleeding, and a 6 cm right adnexal mass. A 10 yo healthy young girl with LLQ pain and left ovarian mass. A 17 yo woman with primary amenorrhea with a pelvic mass. Karyotyping revealed a mosaicism of sex chromosomes (45, X/46, XY) Granulosa tumor Germ cell tumor Gonadoblastoma Sertoli leydig cell tumor Mature teratoma (dermoid cyst) Steroli-Leydig. 2. Mature teratoma 3. Granulosa cell tumor 4. Germ cell tumor 5. Gonadoblastoma. Epithelial ovarian tumors (85%) Germ Cell Tumors (10%) Mature teratoma is a benign germ cell tumor. Malignant germ cell tumors occur principally in the second and third decades of life Accompanied by abdominal pain and 10% present with acute onset secondary to torsion, hemorrhage or rupture. Ovarian germ cell tumors may be associated with elevated hCG, AFP, or LDH. Not typically bilateral. Usually can conserve uninvolved contralateral ovary and uterus to preserve reproductive capability. Chemotherapy as an adjunct to optimal cytoreductive surgery. Dysgerminoma can occur at any age and is one of the most common ovarian neoplasm in pregnancy (also serous cystadenoma). A small portion of dysgerminomas arise is sexually abnormal females, particularly those with mixed gonadal dysgenesis or testicular feminization. In such cases the dysgerminomas often develops in a previously existing gonadoblastoma. A rare ovarian lesion composed of germ cells (resembling those of dysgerminoma) and gonadal stroma cells resembling those of granulosa or Sertoli tumor. (mix of sex chord and germ cell tumor). Sex chromatin shows 45x or macaisicm (45, X/46, XY). Patients have primary amenorrhea, virilization, or developmental abnormalities of the genitalia 80% are phenotypically women; 60% of those are virilized. Stromal tumors (mesenchymal) (5%) include tumours of the female type (granulosa cell tumors and granulosa-theca cell tumors) and male type (Sertolio-Leydig tumors) and rarely lipid cell tumors and gynandoblastoma Granulosa cell tumor is the most common malignant tumor in this group of neoplasms. Throughout first 4 decades. Bilateral in only 5% All granulosa cell tumors should be considered malignant. The adult and juvenile variants with the latter much more likely to result in a malignancy. Therapy: surgical removal , can preserve uterus with full staging. Residual or recurrent disease requires chemotherapy. Young patients may show precocious puberty because these tumors may produce estrogen. In older women, menstrual irregularity or PMB due to estrogen production may be presenting symptom. Sertoli-Leydig tumors occur less frequently that granulosa cell tumors and are rarely bilateral. May produce androgens and can present with masculinization or defeminization
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Ovarian Cysts/Tumors Benign vs. malignant Benign
Physiological (follicular cysts, corpus luteal cysts, hemorrhagic cysts) Endometrioma Benign adenomas Germ cell tumors (dermoid cysts)
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Ovarian Tumors
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Ovarian Tumors
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Use of combination OC therapy Menopause after age 55 NSAIDS
A 30 yo woman came to your office because her 70 yo grandmother recently died from ovarian cancer. You discuss with her the risk factors and prevention of ovarian cancer. Which of the following can decrease a woman’s risk of ovarian cancer? Use of combination OC therapy Menopause after age 55 NSAIDS Nulliparity Ovulation induction medications 1% risk of ovarian cancer in general population. Goes up to 5% with 1 first degree and 7% with 2 or more
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A 50 yo G4 P4 presents for her well-woman examination
A 50 yo G4 P4 presents for her well-woman examination. She has had 4 vaginal deliveries. Her LMP was 1 year ago, she occasionally still has a hot flash. She had a previous laser conization for carcinoma in situ of her cervix 10 years ago. All of her Pap smears have been normal since. How often should she undergo Pap smear testing? Every 3 months Every 6 months Every year Every 2 years Every 3 years 2005 Ontario Cervical Screening Guidelines Note: These recommendations do not apply to those women who have had previous abnormal Pap tests. Screening initiated within 3 years of first vaginal sexual activity Done annually until 3 consecutive negative Pap tests Then every 2-3 years Cessation at age 70 if adequate negative screening (3-4 negatives in last 10 years)
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PAP Smear Management Possible Results (Squamous) within Normal Limits
Atypical Squamous Cells of Undetermined Significance (ASCUS): may favour reactive or premalignant/malignant process Low Grade Squamous Intraepithelial Lesion (LSIL) High Grade Squamous Intraepithelial Lesion (HSIL) Squamous Cell Carcinoma
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A 21 yo woman is seen for a Pap smear showing HSIL, colposcopy confirms a cervical lesion. Which of the following HPV types is often associated with this type of lesion? A 20 yo woman complains of bumps around her vaginal opening which have been getting bigger. On physical exam, there are multiple 2-10 mm lesions around her introitus. Her cervix has no gross lesions. A Pap test showed ASCUS. Reflex HPV testing showed no high risk HPV. Which of the following HPV types is often associated with this? HPV type 6 HPV type 11 HPV type 16 HPV type 42 HPV type 44 High risk 16, 18, 31 With condylomas 6, 11
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Physiologic discharge Candidiasis Bacterial vaginosis Trichomoniasis
A 29 yo G0 complains of a vaginal discharge that is thin, grayish white color. She noticed a slight fishy vaginal odor. She denies vaginal or vulvar pruritis or burning. She is sexually active, but denies STIs in the past. She is on OCP. Last month, she took a course of amoxicillin for a sinus infection. What is the most likely diagnosis? Physiologic discharge Candidiasis Bacterial vaginosis Trichomoniasis Chlamydia On exam, there is a thin copious whitish discharge, vaginal ph is The cervix is not inflamed. Wet smear shows clue cells. Overgrowth of anaerobic bacteria, displacing normal vaginal flora, lactobacillus/ Whiff test with KOH. Treatment with flagyl
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Vulvovaginal candidiasis
Parameter Normal Findings Vulvovaginal candidiasis Bacterial vaginosis Trichomoniasis Symptoms None or mild, transient Pruritus, soreness, change in discharge, dyspareunia Malodorous discharge, no dyspareunia Malodorous, purulent discharge, dyspareunia Signs Normal vaginal discharge: white/ transparent, thick, mostly odorless Vulvar erythema, edema, fissure . Thick, white, adherent, “cottage-cheese” Thin, homogeneous, gray, malodourous discharge Purulent, greenish-yellow discharge, vulvovaginal erythema Vaginal pH > 4.5 Amine Test Negative Positive (about 70-80%) Often positive Saline microscopy PMN:EC ratio <1; rods dominate; squames +++ PMN:EC ratio <1; rods dominate; squames +++;pseudohyphae (about 40 percent); budding yeast for nonalbicans Candida PMN:EC <1; loss of rods; increased coccobacilli;clue cells (>90 percent) PMN ++++; mixed flora; motile trichomonads (60 percent) 10% KOH Pseudohyphae (about 70 percent) Other Culture if microscopy negative Culture of no value If microscopy negative perform culture or rapid antigen/nucleic acid amplification tests Differential Diagnosis Physiologic leukorrhea Contact irritant or allergic vulvar dermatitis, chemical irritation, focal vulvitis (vulvodynia) Purulent vaginitis, DIV, atrophic vaginitis, erosive lichen planus pH Place sample of vaginal secretion on test strip; read while moist pH>4.5 is abnormal (ie. BV, trich or blood) Careful not to sample the cervix as these secretions are basic (pH=7.0). Avoid posterior fornix as cervical secretions collect here. Lubricants, semen, douches and pv medications can alter pH (usually increase) Premenarchal and post-menopausal pH can be normal and elevated (>4.7) Wet Mount Microscopy with saline medium. Low and high power Sample anterior fornix and lateral vaginal walls Place cotton-tipped swab in tube with small amount normal saline and place on slide Looking for: Trichomoniasis: motile organisms; Candida: buds or hyphae; BV: “clue cells” Excess PMNL with normal microscopy suggest cervicitis. Whiff test Sample of vaginal secretions in 10% KOH KOH alkalizes amines, produced by anaerobic bacteria, are volatile and produce sharp, “fishy” odour KOH improves visualization candida.
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GENERAL DIAGNOSTIC APPROACH
Office-based tests are under-utilized: Microscopy not performed in 37% pH not measured in >90% Whiff testing not performed in >90% Medication prescribed in 54% without clinical evaluation. 150 office visits of 52 symptomatic women. Wiesenfeld HC. et al., (1999) Am J Obstet Gynecol; 181:
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Vulvovaginitis Treatment
Candida Intravaginal OTC azole ovules and creams (clotrimazole, miconazole) Fluconazole 150 mg po single dose Bacterial Vaginosis Metronidazole 500 mg po BID for 7days Metronidazole gel 0.75%, 5g pv OD for 5 days Clindamycin cream 2%, 5g pv OD for 7 days (oil-based) Alternatives Metronidazole 2 g PO single dose (85% cure but higher relapse) Clindamycin 300 mg PO for 7 days Trichomonas Metronidazole 2 g po single dose Metronidazole 500 mg BID for 7 days Candida VVC Expect resolution in 2-3 days Topical azoles are recommended in pregnancy. May need up to 7 days. Trichomonas Efficacy is 82-88% for both regimens; increased to 95% if partner also treated Partner should be treated (most are asymptomatic; mild urethritis) with same regimen as case. Reportable in some jurisdictions Follow-up Not unless symptoms recur; usually re-infection Resistance estimated at 5%. Usually respond to high-dose metronidazole.
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19 year old G0 woman presents to the ER with lower abdo/pelvic pain for 2 days. She had developed a fever today and a vaginal discharge. She has recently become sexually active and is not using contraception. A pregnancy test is negative. What is the most likely diagnosis? a) early appendicitis b) chlamydial cervicitis c) disseminated herpes d) PID e) trichomonas vaginitis
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PID Clinical diagnosis
ascending infection to endometrium, tubes, peritoneum spectrum of severity 2/3 asymptomatic, many subtle or mild symptoms. Common: fever > 38.3 lower abdominal/pelvic pain and tenderness (adnexal) cervical motion tenderness on bimanual exam abnormal discharge: vaginal or cervical. Uncommon: nausea, vomiting dysuria irregular vaginal bleeding RUQ pain (Fitz-Hugh-Curtis)
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Reasons for Hospitalization
Pregnancy failed outpatient management of oral antimicrobials unable to tolerate oral meds tubo-ovarian abscess severe illness, nausea/vomiting, high fever immunocompromised previous instrumentation unreliable for follow up or compliance
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A 50 yo woman woman complains of leakage of urine
A 50 yo woman woman complains of leakage of urine. After genuine stress urinary incontinence, which of the following is the most common cause of urinary leakage? Detrusor dyssynergia Urethral diverticulum Overflow incontinence Unstable bladder Fistula
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A 65 yo woman presents for evaluation of pelvic prolapse
A 65 yo woman presents for evaluation of pelvic prolapse. She has a history of well controlled chronic hypertension. She has had 3 SVD, the last baby weighed 9 lbs and required forceps for delivery. She has a Hx of chronic constipation and uses a laxative regularly. She has smoked for 30 years and has a smoker’s cough. She is post-menopausal and has never been on HRT. Which of the following is the LEAST important in the subsequent development of genital prolapse in this patient? chronic cough chronic constipation chronic hypertension childbirth trauma menopause
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Pelvic relaxation
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Predisposing Factors age pregnancy and vaginal childbirth
menopause (↓ estrogen) changes in pelvic anatomy (surgery) obesity chronic cough chronic constipation connective tissue disorders
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Treatment Conservative Surgical Pessary (not useful for rectocele)
Kegels weight loss stool softeners HRT smoking cessation Surgical Vaginal Hysterectomy (for uterine prolapse) Vaginal Repair (anterior, enterocele, and/or posterior repair) Vault suspension Anti-incontinence procedure
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