A. Physiology and Anatomic Components Required for Normal Menses

1. I - Uterus (steroid responsive endometrium) and intact outflow tract
2. II - Gonadotropin responsive ovaries
3. III - Anterior pituitary intact
4. IV - Normally functioning hypothalamus and central nervous system

B. Normal Ovulation

1. Oocytes number ~2 million at birth
2. Control of ovulation by hypothalamic-pituitary interactions with ovary
3. Hypothalamic-Pituitary-Ovarian Axis Overview [2]
   1. Pituitary secretion of follicle stimulating hormone (FSH)
   2. FSH stimulates ovarian follicle development and ovarian estradiol production
   3. Estrogen maintains low FSH levels throughout cycle (negative feedback)
   4. Estrogen stimulates LH surge (in presence of FSH) by pituitary
   5. Ovulation and luteinization of the follicle (formation of corpus luteum)
4. Menopause [2]
   1. Defined as normal loss in oocytes by age ~50
   2. Loss in oocytes leads to lost follicles leads to reduced estradiol and inhibin secretion
   3. Lack of feedback on hypothalamus leads to increased chronic FSH and LH levels
   4. Increased FSH and/or LH, normal or decreased estradiol, amenorrhea
   5. Failure of ovary to properly respond to estrogen and pituitary hormones (FSH, LH)
   6. The process of menopause may take 6-12 months

C. Normal Mensturation
[Figure] "Hormonal Changes During Menses"

1. Characteristics of Normal Menses
   1. Onset of normal menses occurs age 9-12 (called "menarche")
   2. Normal menstrual cycle is 28 days, with normal range 22-40 days
   3. Each cycle is divided into Proliferative, Luteal, Secretory, and Menstrual Phases
   4. Average menstrual blood loss is 40mL (range 25-69mL)
   5. A cyclic loss of >80mL is required to induce iron deficiency anemia
2. Proliferative Phase
   1. For the first 2 weeks of the cycle, uterus is Proliferative and dependent on Estrogen
   2. Pulsatile release of GnRH stimulates release of FSH and LH (gonadotropins)
   3. Activins (produced by ovaries) stimulate production of FSH by pituitary cells
   4. FSH stimulates Estrogen production by granulosa cells
   5. Functionalis layer of uterine endometrium proliferates with tubular and coiled glands
   6. Glands secrete alkaline watery solution which promotes sperm motility
   7. Spiral Arteries are narrow and inconspicuous
   8. Many mitoses seen in the glandular tissue
3. Ovulation occurs ~14 days due to FSH and LH surge and Luteal Phase begins
   1. FSH in combination with estradiol stimulates surge of LH
   2. LH surge stimulates the production of progesterone
   3. Progesterone, made by granulosa cells in corpus luteum, begins to accumulate
   4. Increased progesterone causes increase in basal body temperature (~0.4°F)
   5. This increase in body temperature is the main sign of ovulation
   6. Second estrogen peak also occurs
   7. Endometrial glands become enlarged and more coiled due to progesterone
   8. Gland cells store glycogen in vacuoles (days 17-19)
4. Gland cells in Secretory Phase
   1. Copious secretions to bathe implanted zygote
   2. Glands become enlarged and much more coiled (saw-tooth)
   3. Stromal cells develop vacuolar and eosinophilic changes = predecidualization
5. By day 27 the entire stroma has become predecidualized
6. The uterus is supported by progesterone
   1. Progestational hormones maintain the uterus
   2. Progesterone synthesis by granulosa lutein cells stimulated by FSH and LH
   3. Towards the end of menstrual cycle, LH levels decrease
   4. In pregnancy, trophoblasts make hCG, which serves LH function, maintains corpus luteum
   5. Inhibin A and follistatin levels increase at end of menstrual cycle, reducing FSH [4]
7. In the absence of pregnancy (HCG), newly formed corpus luteum degenerates
   1. Progesterone levels fall
   2. Endometrium undergoes collapse and breakdown
   3. Menses commences on day 28 for 3-7 days
8. Phase of menstrual cycle may affect QTc interval and drug-induced QTc prolongation [9]

D. Abnormal Menstruation

1. Normal duration of a complete cycle is 28 days
2. Irregular Menstrual periods are very common especially in adolescence
   1. Oligomenorrhea is reduction in number of menses over time - cycles >35 days apart
   2. Amenorrhea is lack of menstruation (must miss 2 cycles for diagnosis)
   3. Menorrhagia is excessive menstrual bleeding
   4. Menopause is cessation of menstruation; may take 6-12 months
3. Overview of Causes of Abnormal Menstruation
   1. Hyperandrogenergic chronic anovulation (polycystic ovary syndrome)
   2. Other Endocrinopathies: thyroid disease, prolactin abnormalities, Cushing Syndrome
   3. Abnormalities of hypothalamic-pituitary-adrenal (HPA) axis
   4. High levels of physical activity
   5. Severe weight loss with reduction of body fat leads to repression of menses
   6. This is usually associated with anorexia or bulemia
   7. Excess or chronic high level stress
4. Physical Activity
   1. High levels of activity may lead to repression of menstruation
   2. This is probably related to percentage of body fat
   3. Note that adipose tissue synthesizes estrogen
   4. Lack of fat may lead to estrogen deficiency
5. Failed ovulation is cause of infertility in ~10% of infertile women
6. Menstrual irregularities lasting >6 months should be evaluated
7. Treatment of Menorrhagia
   1. Oral contraceptive agents may be effective
   2. Levonorgestrel releasing intrauterine device as alternative to hysterectomy [5]
   3. Gonadotropin releasing hormone analogs (chemical castration) may be used
   4. Hysterectomy may be considered in severe cases

E. Premenstrual Dysphoric Disorder (PMDD) [3,14]

1. Previously called "Premenstrual Syndrome" (PMS)
2. Symptoms
   1. Occur in most women of reproductive age
   2. Some physical discomfort and/or dysphoria 1-2 weeks before mentruation
   3. This corresponds to the luteal phase of menstrual cycle
3. Etiology
   1. Largely unclear, but given mood components, central nervous system clearly involved
   2. Relationship to declining progesterone levels
   3. Likely role for serotonin in mediating effects of changing hormone levels
   4. Gamma-aminobutyric acid (GABA) levels may also be altered during menstruation
4. Criteria for Severe PMDD from DSM-IV [14]
   1. Require at least one of: depressed mood, dysphoria, anxiety/tension, affect lability, irritability
   2. Require at least four additional symptoms including:
   3. Decreased interest in usual activities
   4. Concentration difficulties
   5. Marked lack of energy
   6. Marked change in appetite, overeating or food cravings
   7. Sleep disturbances: hypersomnia or insomnia
   8. Feeling overwhelmed
   9. Other physical symptoms: myalgias, breast tenderness, bloating, possibly headache (debated)
   10. Affect lability includes: sudden mood swings, crying, feeling out of control
   11. Two cycles of daily charting required to confirm timing of symptoms
   12. Evidence of functional impairment: interferes with work, school, social activities, relationships
5. Diagnosis
   1. Patients should maintain a daily record of symptoms for ~2 months to make diagnosis
   2. Symptoms should be assigned a severity level such as: 0 (none) to 4 (severe)
   3. This record should be reviewed in order to make diagnosis
   4. Patients with some of the symptoms who do not meet full DSM-IV criteria may have mild- moderate PMDD
   5. Pre- and post-menstrual scores are obtained and pre- should be >50% higher than post
   6. In addition, treatment effect should be assessed with scores taken while on medicines
6. Treatment
   1. Vitamin B6 50mg po qd to bid alleviates general symptoms, especially depression [5]
   2. Short courses of antidepressants (usually SSRI's) may be useful during luteal phase
   3. Fluoxetine (Prozac®, Sarafem®) 20mg po qd improved tension, irritability, dysphoria [10]
   4. Fluoxetine is approved as Sarafem (10mg, 20mg capsules) for PDD [7]
   5. Fluoxetine, sertraline, paroxetine and citalopram are recommended at low doses [3]
   6. Fuoxetine dose >20mg qd had no added benefits but increased side effects [10]
   7. Overall, various SSRI's are very effective in PMS when used chronically or intermittently [6]
   8. Second line: clomipramine (tricyclic) 24mg qd starting, 50-75mg divided thereafter
   9. Alternative second line: alprazolam (Xanax®), 0.50-0.75mg qd starting
   10. Oral contraceptives are often extremely helpful
   11. Aerobic exercise 3-5 times per week also helps many women
   12. Third line treatment with leuprolide 3.75mg IM q month in severe and resistant cases
   13. Longer acting NSAIDs are often helpful for physical symptoms
   14. Spironolactone (Aldactone®), an aldosterone antagonist, reduces bloating and breast pain [14]

F. Menstrual Migraine [10]

1. Introduction
   1. Includes pure menstrual and menstrually related migraine
   2. Usually occurs without aura and longer duration than non-menstrual migraine
   3. Usually more resistant to treatment than non-menstrual migraine
2. Migraine Without Aura - Definition
   1. At least 5 long-lasting (4-72 hour) migraine attacks
   2. At least 2: Unilateral location, moderate to severe pain, pulsating, aggrevated by physical activity
   3. At least 2 during attack: nausea, vomiting, photophobia, phonophobia, osmophobia
   4. Attacks not attributed to other disorder
3. Pure Menstrual Migraine - Definition
   1. Migraine without aura that occurs exclusively on day 1±2 of menstruation
   2. At least 2 of 3 menstrual cycles
   3. No migraine occurs on other times of the cycle
4. Menstrually Related Migraine - Definition
   1. Migraine without aura on days 1±2 of menstrual cycle
   2. At least 2 of 3 consecutive menstrual cycles
   3. Additional attacks of migraine with or without aura occur at other times of the cycle
5. Treatment with triptans and other agents as with typical migraine
6. Prophylaxis [10]
   1. Estrogen (oral contraceptives) of limited value in recent studies
   2. Naratriptan and frovatriptan have shown good prophylactic activity [11,12]
   3. Naratriptan (Amerge®) 1mg po bid two days before initiation of menstruation reduced migraine rates from 50% to 25% [10,11]
   4. Frovatriptan (Frova®) 5mg loading dose day 1, then 2.5mg po qd or bid through day 5 of menstruation significantly reduces migraines and functional disability [10,12]
   5. Frovatriptan 2.5mg bid is superior to 2.5mg once daily for menstrual migraines [10]

References

1. Davis A. 1997. JAMA. 277(16):1308
2. Weiss G, Skurnick JH, Goldsmith LT, et al. 2004. JAMA. 292(24):2991
3. Grady-Weliky TA. 2003. NEJM. 348(5):433
4. Muttukrishna S, Knight PG, Groome NP, et al. 1997. Lancet. 349:1285
5. Wyatt KM, Dimmock PW, Jones PW, O'Brien PM. 1999. Brit Med J. 318:1375
6. Comess KA, DeRook FA, Russell ML, et al. 2000. Am J Med. 109(5):351
7. Fluoxetine for Premenstrual Dysphoric Disorder. 2001. Med Let. 43(1096):5
8. Hurskainen R, Teperi J, Rissanen P, et al. 2001. Lancet. 357(9252):273
9. Rodriguez I, Kilborn MJ, Liu XK, et al. 2001. JAMA. 285(10):1322
10. Steiner M, Steinberg S, Stewart D, et al. 1995. NEJM. 332(23):1529
11. Brandes JL. 2006. JAMA. 295(15):1824
12. Drugs for Migraine. 1998. Med Let. 40(1037):97
13. Almotriptan and Frovatriptan. 2002. Med Let. 44(1124):19
14. Yonkers KA, O'Brien PM, Eriksson E. 2008. Lancet. 371(9619):1200