1
Q
Primary vs. Secondary Amenorrhea
A
Primary - no menses by 14 and no secondary sexual characteristics OR no menses by 16 with secondary sexual characteristics
Secondary - previous history of menstruation with no menses for 3 cycles (or 6 months)
2
Q
Outline the control pathway from the CNS to the uterus
A
CNS –> Hypothalamus (GnRH) –> Anterior Pituitary (FSH/LH) –> Ovaries (estrogen/progesterone) –> uterus –> menses
*estrogen and progesterone feedback on the hypothalamus and pituitary
3
Q
Important ROS Questions to rule out a hypothalamic cause?
A
- radiation, trauma, diet, stress, chronic illness, eating disorders, headache, vision changes, anosmia (Kallman’s)
4
Q
Important things to examine on physical?
A
- growth record, neuro, thyroid, tanner staging, abdo exam, genitals (estrogen status, imperforate hymen), acne, hirsutism
5
Q
Important labs/ tests?
A
- day 3 FSH/LH/PRL/TSH/E2
- day 21 progesterone/ BHCG
- CBC, ferritin, VW factor, coags, renal/liver, pap/swabs
- karyotype
- progesterone challenge (helps determine estrogen status)
- androgens (DHEA, testosterone, 17-OH progesterone) if symptoms
- pelvic U/S, MRI head if progesterone challenge (-)
6
Q
Hyper vs Hypogonadotropic Hypogonadism
A
Hyper –> ovaries are failing (FSH/LH high, estradiol low)
–> do a karyotype (can have chromosome issue)
Hypo –> CNS failing (FSH/LH low, estradiol low)
*43% of primary amenorrhea is HYPER, 31% is HYPO, 26% is EU (chronic anovulation/ outflow tract issue)
7
Q
Examples of HYPOgonadotropic Hypogonadism
A
- structural or endocrinologic CNS issue (test with MRI head) OR stress/anorexia/excessive exercise/hypothyroidism/etc.
- adenoma, prolactinoma, craniopharyngioma, FSHB mutation, idiopathic
- Kallman’s –> isolated GnRH deficiency, anosmia, mid face defects
- Sheehan’s –> pituitary stops working after significant blood loss during childbirth
8
Q
Examples of EUgonadotropic Eugonadism (causes of bleeding)
- common tests
- elaborate on each and tx
A
- PCOS –> 2 of Androgen excess, ovulatory dysfunction, polycystic ovaries
- tx with regular progestin withdrawal (prevents endometrial hyperplasia)
- Hyperprolactinemia –> high PRL and low/normal FSH/LH
- can be caused by meds, prolactinoma, hypothyroidism
- treat with dopamine agonist (bromocriptine, cabergoline)
- Outflow Tract Abnormalities –> congenital (imperforate hyymen, vaginal septum, cervical or mullerian agenesis) or acquired (Ashermann’s intrauterine adhesions)
- test with physical exam, TSH/PRL/androgens/ progesterone challenge, U/S
9
Q
How does a progesterone challenge test work?
A
- gives an estimate of the concentration of estrogen (confirms estrogen primed uterus)
- medroxyprogesterone 5-10mg or micronized progesterone 200-300mg daily for 5-10 days
- A positive response is normal withdrawal bleeding for 3-5 days about 2-10 days after the end of the progestin
- A positive repsonse suggests E2 is >50pg/mL
10
Q
What is Mullerian Agenesis (MRKH)?
- Tx?
A
- defect in the AMH gene
- will have normal breasts, ovaries, pubic hair
- NO uterus, cervix, upper vagina
- renal and skeletal abnormalities are also common
Tx - vaginal dilators (#1), psych support, fertility counselling, surgical neovagina
11
Q
Primary Ovarian Insufficiency (POI) - the only example of HYPERgonadotropic Hypogonadism
- two diff types and their different causes
A
- causes menopause before age 40
Normal Karyotype
–> chemo/radiation, ovarian surgery, gonadal dysgenesis, infectious oophoritis (mumps) fragile X, Addison’s, thyroid, SLE, T1DM, myasthenia gravis (lots of autoimmune causes)
*Fragile X –> CGG repeats in the FMR1 gene, most common inherited cause of low IQ and autism
Abnormal Karyotype
- Turner’s –> 45XO or mosaic variations, short, webbed neck, low ears/hairline, wide nipples/ shield chest, absent sexual development in some
- treat with hormones/pubertal induction/ gonadectomy/ fertility - Androgen Insensitivity Syndrome –> 46XY, X-linked recessive, mutation in gene for androgen receptor
- inguinal testes (no sperm), breasts, no pubic hair/uterus, blind vagina
- treat with gonadectomy if complete, virilization - Androgen Synthesis Disorder –> 5alpha-reductase deficiency (testosterone cannot be converted to DHT), autosomal recessive
- male internally, female externally
- treat by virilizing at puberty
12
Q
General treatments for:
- HYPOgonadotropic hypogonadism
- HYPERgonadotropic hypogonadism
- EUgonadotropic eupogonadism
A
HYPO –> get back to weight you had regular cycle with, decrease stress, ovulation induction with gonadotropins (clomiphene citrate, metformin, drilling if pregnant)
HYPER –> psych, hormones until menopause (combo OCPs), pubertal induction, contraception discussions
EU –> thyroid replacement, dopamine agonist for hyperprolactinemia, healthy weight, regular progestin withdrawal for PCOS, ovulation induction if pregnant
13
Q
- If uterus absent, what tests should you order?
- If withdrawal bleeding on progetserone bleeding is present and normal LH/FSH?
- both deficient estrogen or progesterone can lead to…
*Bright red bleed is likely…
A
- karyotype, serum T/E2, LH/FSH
- chronic anovulation
- bleeding
- acute
14
Q
Abnormal Uterine Bleeding Defintion
A
- change in the frequency/ duration/ amount of menses
- chronic if over 6 months
- peak prevalence prior to menopause
15
Q
Most common causes of hysterectomies?
A
- menorrhagia, fibroids
16
Q
Overview of the menstrual cycle
A
- LH peak during ovulation (and smaller FSH peak)
- must have estrogen exposure first, then both E+P, then withdrawal of both
- in the early follicular phase the endometrium is thin, in the luteal phase it is thick
17
Q
Factors that stop bleeds vs. promote bleeds?
A
Stop
–> progesterone dependent (early)
–> normal coagulation cascade (late)
–> Endothelin-1 and PG-F2a (vasoconstriction)
Promote
–> excess PGE2 and PG12 (vasodilate)
–> excess plasminogen activators (breakdown clot)
–> deficiencies in endometrial repair
*see higher levels of PGE2 and PG12 in women with menorrhagia
18
Q
Typical length of cycles over time?
A
- first 5-7 years are commonly longer (though some will have short) due to immature HPO axis
- slowly become shorter with more cycle per year
- 8-10 years before menopause they lengthen again (less quality and quantity of eggs)
19
Q
Menopause
A
- Permanent loss of menses due to loss of follicular activity
- 12 months of amenorrhea (since LMP) with no obvious pathological cause (still need contraception if ur still bleeding!)
- 99% of menopause is after 40, average age is 51.5
- low estrogen and high FSH
20
Q
Length of a menstrual cycle and amount of blood lost
A
- typically every 28 days (+/- 7)
- lasts 4 days (+/- 2)
- 40cca (+/- 20)
*after ovulation is fixed (13-15d), but beforehand is variable
21
Q
Definition of an Irregular Cycle
A
- in first 1-3 years –> under 21 days or over 45 days
- between 3 years and menopause –> under 21 days or over 35 days
- ANY cycle over 90 days or less than 8 a year
*a signal of oligo/anovulation
22
Q
Definition of:
- Menorrhagia
- Metrorrhagia
- Menometrorrhagia
A
- over 7 days or over 80cc bleeding at regular intervals
- bleeds at irregular but frequent intervals, variable amounts
- prolonged uterine bleeds at irregular intervals
23
Q
PALM-COIEN
A
Structural –> Polyps, Adenomyosis, Leiomyoma, Malignancy/ hyperplasia
Non-Structural –> Coagulopathy, Ovulatory dysfxn, Iatrogenic, Endometrial, Not yet classified
*always want to exclude pregnancy or cancer!
24
Q
Drugs that may cause AUB?
A
- SSRIs/TCAs, anticonvulsants, anticoagulants, contraception, steroids, antispychotics, tamoxifen
- chasteberry, ginseng, danshen
25
When is anovulatory bleeding considered normal (physiological)?
- Adolescence, perimenopause, lactation, pregnancy
26
Common unique causes of bleeding for:
- at birth
- 48-52
- 52+
- at birth - estrogen withdrawal
- 48-52 - an-ovulation due to perimenopause, endometrial hyperplasia, cervical and endometrial cancer
- 52+ - hormone therapy, vaginal/endometrial atrophy, endometrial cancer
27
Perimenopause
- typically ~5 years
- early on has variable cycle length, but overall lenghtneing (40-50 days)
- late has 2 or more skipped cycles (anovulation), erratic menstruation
- FSH and LH increase (though also fluctuating), estrogen fluctuates widely but is long term decreasing
*cannot predict menopause based on FSH
- may be most symptomatic during this time!
28
Signs of Hypothalamic Amenorrhea
- GnRH pulsatility is low, LH/FSH low, estrogen very low
- thin endometrium, vaginal atrophy, low bone density
29
PCOS
- hyper-estrogenic endometrium with failure of regular exposure to progesterone (THICK)
- normal FSH and estrogen, LH can be increased, increased androgens
- risk of endometrial hyperplasia and cancer
30
Investigations for structural problems? Indications for endometrial biopsy?
- Pelvic/ transvaginal U/S, saline infusion sonogram, hysteroscopy, biopsy
- tend to have normal ovulatory cycles
- 40+, failure of tx, hx of anovulatory cycles, significant bleeding outside of menses, post-menopause, endometrial thickness over 4mm on TVUS (although honestly do it even if its smaller)
- over 90kg, nulliparous, PCOS, DM (risks for endometrial cancer)
31
Endometritis/ Cervicitis
- signs
- common causes
- purulent discharge, post-coital bleeding, pelvic tenderness, fever
- commonly chlamydia and gonorrhea
32
HPV
- high risk strains
- low risk strains
- virility factors
- can cause oropharyngeal (80% men), anal, penile, vulvar, cervical cancers and lead to genital warts, can be asymptomatic
- most common STI (50% of people get it)
High risk - 16/18/31/33/45/52/58 (cancers)
Low risk - 6/11 (genital warts, respiratory papillomatosis, oral/conjunctival papillomas)
* 16 and 18 are most common
- E6/E7 oncoprotein mediate cervical cancer --> interfere with tumor supressor proteins, insert into DNA, lead to dysplasia, once it invades (cancer)
33
LSIL vs HSIL (cytology findings)
- low grade intraepithelial lesion --> CIN I, mild cervical dysplasia, HPV infection and virus production
- high grade intraepithelial lesion --> CIN II (moderate cervical dysplasia, no virus production), CIN III (severe cervical dysplasia/ carcinoma in situ/ invasive carcinoma - increased E6/7 and viral DNA integration)
*LSIL/HSIL are cytology (pap) terms, CIN is a histology term
34
Risks for HPV/ Cervical Cancer
- early age first sexual activity (lower immune response), mutliple partners, multiparity, long term OC use, immune compromise (smoking, steroids, DM, HIV, renal failure)
35
HPV Vaccine
- different forms
- schedule
- best prevention for cervical cancer
- greatest benefit if before onset of sexual activity
- non-infectious recombinant vaccine
HPV2 (Cervarix) - 16/18, 10-25 females
HPV4 (Gardisil) - 6/11/16/18, 9-26 males and females
HPV9 (Gardisil-9) - 6/11/16/18/31/33/45/52/58 (prevents 90% of cancers)
9-14 --> 2 doses at 0/6m
15+ --> 3 doses at 0/2/6m
also 3 doses if HIV, stem cell/ organ transplant, immune deficits
*currently gender neutral vaccination in grade 6 in BC, available to women/queer men/HIV/transgender 9-26 for free
36
Secondary Prevention of HPV
- visual inspection with acetic acid (VIA)
- cytology (pap smear, very specific but low Sn)
- HPV testing (High Sn, slightly lower SP, actually more effective) done every 5 years
37
Treatment for Surgical Dysplasia
- LEEP (loop electrosurgical excisional procedure) for stage IIB (cancer outside cervix)
38
When to screen for cervical cancer?
- Anyone with a cervix starting at 25 or 3 years after 1st sexual activity (even if same sex, transgender, received the vaccine)
- Not necessary if no sexual contact or TOTAL hysterectomy
- Discontinue at 69 (as long as 3 negative paps in the last 10 years)
- Done yearly until 3 negative results in a row, then every 3 years
39
If uterus is bigger than expected for GA?
- twins, pelvic mass, molar pregnancy, wrong dates
40
Gestational Trophoblastic Disease (GTD)
- group of diseases that occur during pregnancy as a result of abnormally proliferating trophoblast cells
- pre-malignant --> hydatidiform mole or molar pregnancy (partial/ complete)
- malignant --> gestational trophoblastic neoplasia (GTN)
*high risk picture --> uterine bleeding, profuse vomiting, 42 yo at 10w gestation
41
Normal journey from zygote onwards (this is all occuring before implantation)
- what forms the embryo vs palcenta?
- what produces BHCG?
- Zygote --> 12-16 cells Morula --> fluid filled cavity Blastocyst
- Inner Cells --> embryoblasts (become embryo)
- Outer cells --> trophoblasts (become placenta)
- trophoblasts differentiate into cyto and syncitiotrophoblasts which invade the endometrium to the maternal spiral arteries (very agressively invasive)
- syncitio produce BHCG which maintains the corpus luteum and progesterone until placenta is fully formed, also responsible for morning sickness
42
Hydatidiform Moles
- what are they?
- two different types
- abnormal fertilization resulting in atypical trophoblast cell proliferation, tumours that arise from gestational tissue
- Complete Mole --> ovum fertilized by haploid sperm which then duplicates OR fertilized by 2 sperm (ovum nucleus deactivated or absent)
- 46XX or rarely 46XY, paternal origin
- absent fetus, large uterus, BHCG over 100,000
- widespread villous edema, marked trophoblast atypia, snowstorm pattern on U/S
-15-20% GTN risk
- Partial Mole --> ovum fertilized by 2 haploid sperm (haploid ovum nucleus still activated)
- 69XXX or rarely 69XXY, maternal (1) and paternal (2) origin
- present fetus, small uterus, BHCG under 100,000
- focal villous edema, mild trophoblast atypia, multicystic placenta on U/S
- 1-5% GTN risk
43
Common clincial presentation of a complete mole
- test to order and why?
- missed/late periods, vaginal bleeding in the first trimester, hyperemesis, abdominal pain, HYPERth sx, large uterus, absent fetal HR, ovarian enlargement on U/S, snowstorm pattern on U/S
- order TSH as it bears structural resemblance to BHCG, and BHCG can bind to the TSH receptor and cause elevated T4 and low TSH
44
Risks for molar pregnancy
What is considered high risk?
- previous molar pregnancy
- extremes of reproductive age (under 20 over 36), asian and hispanic heritage
45
Management of Molar Pregnancy
- prepare for complications with TH/T4/BHCG/CXR, etc.
- suction and curettage under general anesthesia, send tissue for pathology
- Post-evacuation contraception and BHCG @48h, weekly until undetectable, monthly for 6m (serial BHCG helps monitor for persistent malignant disease as it is a tumor marker for GTD, also want to take contraception to ensure an increase in BHCG isn't because of a new pregnancy)
--> OCP or injectable medroxyprogesterine acetate is preferred, IUDs not recommended (perforation)
- in subsequent pregnancies, need U/S @6-8 weeks and BHCG measured 6 weeks post-partum
46
Gestational Trophoblastic Neoplasia (GTN)
- 3 diff types
- prognosis
- how to dx
- treatment
- more common after a molar pregnancy but can happen at any time
- invasive mole (more common in complete)
- choriocarcinoma
- placental site trophoblastic tumor (rare)
- over 95% 5 year survival, fertility is unaffected, normal offspring, 98% will have normal pregnancy after
- high risk if metastases (lungs most common), BHCG over 40,000, over 4 months since pregnancy, failed chemo
- over 10% increase in BHCG for 3+ values over 2 weeks OR
- plateau of BHCG for 4 measurements over 3 weeks
OR
- BHCG remains high for 6 months
OR
- histological carcinoma of choriocarcinoma
*other investigations include CXR (CT/MRI of abdo/pelvis/head) if abnormal, NEVER biopsy
Tx
--> low risk --> single chemo agent (methotrexate or actinomycin D)
--> high risk --> combo chemo (MTX, actinomycin D, and cyclophosphamide)
*radiotherapy if cerebral metastases
47
Ovarian Reserve
- how to test
- ovaries contain all eggs at birth (1-2 million, actually more as a fetus @20 weeks), menopause has under 1000
- test with day 3 FSH, over 20 is menopausal
- antral follicle count
- Anti-mullerian hormone (AMH) - made by the granulosa cells of pre/small antral follicles, 0.1pmol/L (low) is menopausal
48
What causes accelerated loss of primordial follicles?
- smoking
- chemo, pelvic radiation
- ovarian surgery
- potentially autoimmunity
*Primordial follicle --> prenatal follicle --> antral follicle --> preovulatory follicle
49
What produces LH/FSH and what do they control?
LH - stimulate theca cells in ovarian stroma (androgens)
FSH - stimulate granulosa cells in ovarian follicle (estrogens)
*both from anterior pituitary
50
Explain the mechanism that results in low estrogen high FSH in menopause
- no oocytes --> no follicles --> no granulosa cells --> no estrogen and no inhibin B
- inhibin B normally lowers FSH level (also a marker of follicle #)
51
Symptoms of Menopause
- vasomotor --> hot flashes, night sweats, issues sleeping
- psych --> worse PMS, depression, irritable, poor memory and concentration (best predictor is prior depression)
- sexual dysfxn --> dyspareunia, dryness, low libido
- somatic --> headache, dizziness, arthralgias, palpitations, dry itchy skin
- stress incontinence > urge incontinence
- weight gain (~5lbs) due to lower metabolism and shift in fat composition
52
Hot Flashes
- physiology
- tx
- heat starting in chest and rising, last 3-4 minutes, +/- anxiety and palpitations
- #1 reason for hormone therapy, 80% of women
- likely hypothalamic, thermoregulatory dysfunction due to low estrogen
- narrowing of the thermoneutral zone, kisspeptin (hypertrophy, interact more with thermoregulatory centers), neurokinin B, dynorphin neurons
- some placebo effect
- evidence - weight loss, CBT, clinical hypnosis
- meh - mindfulness, paced respiration, soy and ferment extract
* can also try SNRIs/SSRIs/gabapentin/clonidine/oxybutynin
53
Hormone Therapy
- goals
- schedule
- if under 45?
- examples (estrogen, progesterone, other)
- aim is to lower estrogen deficiency symptoms, treat urogenital atrophy, and prevent osteoporosis
- for estrogen no specific time frame or dose, can continue past 65+, do NOT give if asx
- Cyclic --> daily estrogen and progesterone 12-14 days a month, will induce withdrawal bleeding
- Continuous --> daily estrogen and daily progesterone, no bleeding
- if under 45, hormone REPLACEMENT therapy until average age of menopause (premature menopause has risk of osteoporosis, CV disease, low cognition, early mortality)
Estrogen
- most potent is ethinyl estradiol (synthetic 17B-estradiol), though actually not included in guidelines. Can be given PO, transdermal patch, transdermal gel, injection
- also premarin (conjugated estrogen)
Progesterone
- want enough to prevent endometrial hyperplasia
- oral medroxyprogesterone, oral micronized progesterone, Norethindrone acetate, Levonorgestrel IUD (Mirena/Kyleena - Mirena is higher dose)
Other
- Tibolone - estrogenic, progestogenic, and androgenic properties
- Tissue Specific Estrogen Complex - selective estrogen receptor modulator which prevents endometrial hyperplasia
*do not need endometrial protection with progesterone with these
54
When should you consider transdermal hormone therapy?
- smoker, shift worker, high TGs, HTN, gallbladder disease, sexual dysfucntion, migraines, malabsorption, high VTE risk, metabolic syndrome
55
Endometrial Cancer
- risks
- sx
- dx
- tx - if premenopausal?
- most common gyne cancer in Canada
- average age is 63, only 15-20% are premenopausal
- NO SCREENING
- risks --> unopposed estrogen (thickens lining), menopause after 55, nulliparity, chronic anovulation, HTN, DM, obesity, tamoxifen, HNPCC syndrome
- sx --> 90% have AVB, asymptomatic post-menopausal bleeding with endometrial cells on pap, perimenopausal AUB with abnormal endometrial cells
- dx --> endometrial biopsy (can be done in office)
- also useful: history and physcial, speculum exam, dilation and curettage, hysteroscopy
- pelvic U/S can only reduce suspicion (endometrium should be under 5mm)
- tx
--> low risk --> hysterectomy and BSO
--> high risk --> hysterectomy, BSO, assessment of LNs, +/- omentectomy
- radiotherapy THEN chemotherapy with increasing stage and risk factors
- if premenopausal or grade 1A, can give fertility preserving options --> high dose progestins (Mirena IUD/ Megace), may cause weight gain/ HTN/ VTE
56
Staging of Endometrial Cancer (FIGO)
- Surgical
- 1A - only endometrium
- 1B - spread to myometrium
- 2 - spread to cervix
- 3A - spread to ovary
- 3B - vagina
- 3C - spread to lymph nodes
- 4A - bladder/bowel
- 4B - other organs
* EC extends through the uterus, spreads to the tubes/ovaries/LNs, and eventually the blood
57
What does follow-up for endometrial cancer look like?
- pelvic exam every 3-4 months for 2 years, then every 6 months for 3/5 years
- most patients with recurrence will be bleeding
- Paps/ blood/imaging are NOT helpful
- encourage patients to lose weight, manage HTN/DM, lower CV risks (leading cause of death after EC treatment)
58
Screening for breast cancer? Colorectal cancer?
- mammogram every 2 years from 50-79
- FIT test every 2 years from 50-74
59
Lynch Syndrome
- screening
- when to test
- tx
- inherited DNA mismatch repair mutation
- increased risk of endometrial, colorectal, and ovarian cancer
- test if 3 family members, 2 generations, 1 under 50
- test even if already diagnosed with EC!
- screening - colonscopy every 2 years 25-40, annual after 40, annual TVUS and endometrial biopsy 35+, immunohistochemistry for mismatch repair (absence of 4 MMR proteins in tumor), tumor infilitrating lymphocytes and dedifferentiated carcinoma on histology
- ASA for CRC and OCP and ASA for EC/OC
- tx --> colectomy, hysterectomy, BSO
60
Most common cause of post-menopausal bleeding?
- benign endometrial carcinoma
61
Fibroids
- sx
- dx
- very common and often asymptomatic
- common sx are menorrhagia, pelvic pain, infertility, pregnancy loss
- often first indication is on bimanual exam, but best diagnostic test is TVUS
62
Benign vs. Malignant Postmenopausal Bleed
Benign --> atrophic vaginitis, cervical/uterine polyp, fibroids
Malignant --> endometrial cancer/hyperplasia, cervical cancer, vaginal/vulvar cancer
63
What to do if abnormal pap smear?
Send for colposcopy
64
Staging Cervical Cancer
- need a biopsy with stroma to determine premalignancy vs. cancer
- can be done with LEEP or MRI/PET scan
0 - carcinoma in situ (100% survival)
I - confined to cervix
II - beyond cervix but not to pelvic wall or lower 2/3 of vagina
III - pelvic wall or lower 1/3 of vagina
IV - bladder, rectum, metastasis (7% survival)
65
Symptoms, Diagnosis, and Treatment for Cervical Cancer
Sx --> bleeding (especially post-coital), discharge
Dx --> Colposcopy and biopsy
Stage I --> radical hysterectomy (ovaries included), bilateral pelvic lymphadenopathy and sentinel pelvic nodes
Stage II-IV --> ONLY radio and chemotherapy
66
AUB investigations in perimenopause
- BHCG, CBC, ferritin, TSH, prolactin, U/S, endometrial biopsy, pap
- FSH/LH/est/progest are useless as widely fluctuating
67
Contraception in older age
- Absolute contraindications for estrogen contraception
- Age alone is not a contraindication for contraception, but CV risks increase so often switch to progesterone only
- smoker over 35, personal VTE Hx, migraine with aura, under 6 weeks postpartum, BP >160/100, ischemic heart disease, prior stroke, breast cancer, severe cirrhosis/DM
68
Vasomotor Sx Tx
- HT w estrogen is the most effective treatment for vasomotor symptoms (not at high enough dose to help with contraception or AUB)
- cold showers, dress warm, avoid coffee/alcohol/ smoking, CBT, sleep, healthy diet/ exercise, hypnosis, etc.
- low dose combined pill/patch/ring, venlafaxine, clonidine
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