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Clomid Gonadotropins: injectible fertility drugs and OHSS
Abnormal bleeding CAH
Dr. Speroff's conference notes Fibroids and GnRH addback
OC/BCP If you miss BCP's, other info
SHBG and IR Infertility related tests, terms, and info

Dr. Leon Speroff has written a "Bible" for ob/gyn. Its called: "Clinical Gynecologic Endocrinology and Infertility". Published in 1999 by Lippincott, Williams & Wilkins, it is used for treatment and reference purposes by a good number of OB/GYN's. If you are looking for why your doctor is doing what they are doing, then this page might help. I read through the book and tried to pull out information that would be useful to you. The numbers in parenthesis are the page numbers for reference should you need it.

PCO related info
Women who have these problems (anovulation, hyperandrogenism, etc.) can get a reduction in life expectancy due to coronary and diabetic problems. Therefore, it is best for the doctor to "aggressively" persue treatment (507). PCO women are at a higher risk for developing GD: gestational diabetes (developing diabetes when you get pregnant) (510). Losing weight (to the point of going below a BMI of 27) (1106) is going to help. At this point insulin resistance is not detected (510).
The ovary is the major source of the high levels of testosterone, with the most common cause being chronic anovulation and high levels of androgen production. DHT is the major problem causing the hair to grow from the fine vellus hairs to the darker, courser terminal hairs. The higher the DHT, the more hair growth. (528). The most common complaints of women with increased androgens are: hirsutism, acne, oily skin, increased libido, and clitoromegaly. (529) About 70% of women with anovulation develop hirsutism. Dehydroepiandrosterone is a food supplement - it can cause hirsutism and acne. Hirsutism that develops rapidly after 25 yrs of age is usually an androgen producing tumor. Tests include: testosterone, 17-OHP, prolactin, thyroid and TSH (suggests hyperinsulinemia tests also) (530). LH is the a main cause of androgens for hirsutism (544). For hirsuitism, the first choices: low dose OC/BCP for 6 months (560). If this doesn't work, add spironolactone or finasteride. There is no clinical evidence one works better than the other so choose whatever drug by cost and side effects. The exception to this is that finasteride may be better for idiopathic hirsutism. In one study, flutamide restored ovulation in all the women (497). It can be liver toxic, however, so your liver enzymes should be tested (540). Spironolactone is also good drug to use at 200 mg daily for hirsutism (546). It beat out Flutamide in comparisons (549), but you must use a contraceptive with it. Finasteride works as well as spironolactone, but its action is to block the testosterone from becoming a chemical called dihydrotestosterone. This is the chemical that grows the 'terminal' or dark, course hairs. The best OC/BCP contains desogestrel, gestodene, and norgestimate, but this is not always proven in studies (544). Although Cimetidine works, it is the least potent (550). If you are in Europe, Cyproterone Acetate in Diane/Diane-35/Dianette (OC/BCP) works very well for hirsutism (545). There is little to no problems with using low dose OC/BCP, because there is little to no measureable difference in insulin resistance. Spironolactone and flutamide don't cause any insulin resistance problems either (508-9).
(529) Acanthosis nigricans (gray brown velvet discoloration at the groin, neck, vulva, and armpits), being overweight and hirsuit practically equals IR and hyperinsulinemia. 35 to 60% of PCO women are overweight (492). Another study also mentions that obese and "non obese" women have success with metformin treatment (506). It is ok to assume "ALL overweight, anovulatory women with polycystic ovaries are hyperinsulinemic" (534).
Metformin is mentioned, along with sources on ovulation and pregnancy in "a significant number" of them. (505). Several studies are noted, in that some patients respond and some don't, including those who are overweight and non-overweight (1106-1107). PCO women, regardless of weight, but who have IR, have a greater response to ACTH than plain anovulatory patients with normal insulin levels (539). The women most likely to not respond to Clomid are those are hyperandrogenic and overweight (possibly insulin resistant). A suggestion for those who are hyperandrogenic is to use dexamethasone (1105), .5 mg at bedtime (1107). Bromocriptine (or cabergoline) has been mentioned as another possible for PCO women, because it brings down the LH levels, but is controversial (1108). Women with PCO need to be watched more carefully on injectible fertility drugs as they are at greater risk for the potentially fatal Ovarian Hyperstimulation Syndrome or OHSS. Start monitoring on day 4 or 5 (1111). (1135) says the initial dose of gonadotropin is 225-300 iu/daily, except for the young and those with PCO, who need a lower dose (75 - 150) on injectible drugs.
The defect of PCO is not in the P450c17 gene, but in the P450scc gene. (499) This makes a big difference as to where you are going to look for future treatments.
(1106) Ratio's of less than 4.5 are considered IR. This is the fasting glucose:insulin ratio. (798) Two factors of insulin resistance are the amount of carbs in the diet, and amt. of daily exercise. To measure IR, take the ratio of fasting glucose to fasting insulin. If its lower than 4.5, its indicative of IR.
(1099) GnRH is already operating at maximum capacity in PCO women (personal note: this might be why Clomid doesn't work for a lot of PCO women). It only magnifies an ordinary cycle. (1100) It is suggested to have a semen analysis before this. (Personal note: it makes sense - if there is little semen, why waste time with Clomid, since that isn't where you would need help.) The stats (1100) say that 75% of pregnancies occur during the first 3 months of treatment, and then persue a workup only if the patient has ovulated and not become pregnant.

Clomid:
(1102) Clomid
starts on day 5 (no documented differences on starting anywhere between days 2 thru 5), at 50 mg dose. If no ovulation, up it to 100 mg. If you don't get ovulation, keep upping the dose in 50 mg increments to 200 or 250 mg. The highest dose that causes ovulation should be tried 3 to 4 times before going on. (Personal note: Dr. Speroff does state that this goes against what is recommended by the manufacturers, but Clomid does mess up the cervical fluid, making it hostile to sperm if given so many months in a row.) If you do ovulate, have sex every other day for 1 week starting on the last day of meds (personal note: should be day 10).
(1104) If having no success with Clomid, do ultrasounds to check for cysts. (Personal note: this will more than likely not be covered by insurance for Americans.) With no other infertility problem other than anovulation, a pregnancy rate is 60 to 75% for 6 months of Clomid. If you've not become pregnant in 6 months, you probably won't on Clomid. (1105) The women most likely to not respond to Clomid are those are hyperandrogenic and overweight (possibly insulin resistant). (1105) A suggestion for those who are hyperandrogenic is to use dexamethasone. (1106) The body mass goal for those women with insulin resistance is under 27 on a BMI scale for drugs to work.

(1110): The list of gonadotropins, FSH/LH, and their regular names used on infertility discussions:
Menopausal gonadotropins: Pergonal, Humegon, Repronex
Purified FSH: Metrodin
High purified FSH: Fertinex, Metrodin HP
Recombinant FSH: Puregon, Gonal-F, Follitism
HCG: Pregnyl, Profasi
(1111) Recombinant FSH does better with IVF. Outside of that, its up to the doctor to decide which is best. You should see your doctor on the 7th day, to decide what to do next. You get seen then every 1 to 2 days. Women with PCO need to be watched more carefully as they are at greater risk for the potentially fatal Ovarian Hyperstimulation Syndrome or OHSS. Start monitoring them at day 4 or 5. (1112) You never know what you are going to get because the ovaries react differently every month. You can do back to back cycles, and studies have shown a greater chance of getting pregnant if you do this. On day 7, estrogen should be between 1000 and 1500. Anything over is getting close to OHSS, and at 2000, you shouldn't get a HCG shot to ovulate. (1113) You have the best chance of getting pregnant with your endometrium lining being at 9 to 10 mm or more. (1115) The signs of the previously mentioned OHSS: abdominal distention, weight gain. This is potentially life threatening, so go to a hospital if you feel you have it, or have it checked out immediately.

Abnormal bleeding:
(577) Problems with abnormal bleeding
normally occur when you are younger than 20 and older than 40. This is typical. A normal cycle lasts from 2 to 7 days, with 4 to 6 being the average. Anything less or more is abnormal. 24 to 35 day cycles are normal, anything else needs an evaluation. The levels of PAI-1 may govern the amount of bleeding. If you have PCO, this might be a concern. The definitions of abnormal bleeding problems are as follows:
(566) Dysmenorrhea: pain with menstruation. Prostaglandins cause this problem.
(579) Oligomenorrhea: any cycle that lasts greater than 35 days.
Polymenorrhea: any cycle that last less than 24 days.
Menorrhagia: regular intervals for periods, excessive flow and duration.
Metrorrhagia: irregular intervals for periods, excessive flow and duration.
(567) If you have painful periods and NSAID drugs don't help, consider a laparoscopy to determine the cause of the problem. It is possible that endometriosis or pelvic inflammatory diseases are present. (568) For menstrual headaches, a drug called sumatriptan can be used. (Personal note: sometimes a dose of estrogen can help. In the birth control pill Mircette, you have several days of just estrogen only during the 'break time', which supposedly helps.) (140) Excessive bleeding changes how much prostaglandin you produce. This is why you normally hurt so bad when you have a heavy period. Dr. Speroff divides up problems with periods into 4 areas: the vaginal canal area, the ovary or not ovulating, the pituitary gland, and the hypothalamus (pg 424). The first thing that should be done is exclude pregnancy. Next are blood tests of TSH, prolactin, and a progesterone challenge (pg 424). (Starting on pg 424) The progesterone challenge test is not a blood test, but is where you are given something like Provera/Prometrium and see if you produce a 'withdrawal' bleed in 2 to 7 days. You should have some amount of bleeding. There are two situations where this may not happen, the first particularly important for PCO women. If the endometrium is decidualized due to high androgen levels/anovulatory times, you may not get a bleed. (The other is an adrenal problem.) There is a very SHORT period of time from progession of normal endometrium (the lining of the uterus) to cancer, so it is possible a doctor would want to check for this. He does also mention on pg 427 that sometimes this bleed can trigger ovulation - I've heard of it happening in women on some email lists and discussions. If a withdrawal bleed hasn't been produced, a pituitary tumor check is in order. Also, the tract itself will have to be checked, to make sure that the blood can freely outflow. Once that has been checked, its time to look at the FSH and LSH levels. A normal adult female should have a FSH and LH between 5 and 20. Anything less and the pituitary is messed up. Anything more and the ovaries have probably stopped working. On page 430, he does say that lung cancer can produce gonadotropins (personal note: maybe if that type of cancer is in the family, it should be mentioned to your practioner to check.)
(434) Autoimmune diseases can occur that cause abnormal bleeding and the following is a list to check for them: calcium, phosphorus, fasting glucose (personal note: I would also add insulin and insulin/glucose ratio), morning cortisol, Free T4, TSH, thyroid antibodies, CBC and sedimentation rate, total protein, albumin/globulin ratio, rheumatoid factor, and antinuclear antibodies. ACTH may not be necessary he says, but ovarian failure precedes adrenal failure. The last part: page 453 talks about bromocriptine, which is used to treat high prolactin levels. About 10% of patients can't tolerate this drug due to nausea, headache and faintness, dizziness, fatigue, nasal congestion, vomiting, etc. Try to take it with a drink or snack, but lowering the dose and building up might also help. Some patients can't take this drug at all. Dr. Speroff says (455) there is a new drug out called cabergoline or dostinex, (Personal note: written up in the Fertility and Sterility magazine in Feb 1999). It has been used with some success in PCO women also, but tends to not give these side effects.

(535) CAH is an inherited enzyme defect.

Notes from Dr. Speroff during a conference:
The treatment of choice for galactorrhea is cabergoline. Bromocriptine and cabergoline if given vaginally decrease side effects. Sometimes creeping up on the dosage will also avoid side-effects. Women over 60 should have an annual TSH. Patients on thyroid Rx need yearly TSHs. Measure FSH at age 50 in patients on OCs at the end of the pill free week, if over 20 switch from OCs to HRT. Also if E2 is less than 30 switch. Mammograms should be ordered annually starting at age 40. The relative hyperinsulinemia of menopause is responsible for weight gain at that time of life. Any of the SSRIs are effective in relieving vasomotor symptoms of the menopause especially in patients who can't take E. Patients on tamoxifen should have an annual endometrial stripe and not wait for bleeding as possible CA may be advanced by that time. Twice yearly IV injections of bisphosphonates will probably replace current regimens. Soy has little effect on bone density, ipriflavone (a synthetic) has. The reason obese patients gain back weight after weight loss is they can't respond to leptin. There is a question about MPA negating some of the positive effects of E in HRT. Suggests other progestational agents than MPA in high risk patients. FemHrt, a light version of LoEstrin will probably replace Prempro as the HRT of choice. Expects MPA to be out of favor in a year or two. Patients who have idiopathic venous thrombosis should be screened by a hematologist for thrombogenic conditions. If + they may need an anticoagulant and HRT. HRT probably decreases the risk of Parkinson's. Patients on tamoxifen have decreased tooth loss because of better bone. Hispanic patients who have gestational diabetes and are breast feeding should not have the progestin only pill as it seems to accelerate the development of DM.

Fibroids:
(149) African American women are 2 to 3 times more likely to get fibroids compared to white, Hispanic and Asian groups. If you are African American, this might be something to check into if you have having heavy, painful periods. (My personal note, fibroids that grow near the cervix (or on it) can cause continence problems.) It takes an average of 2 full term pregnancies, smoking and low weight lessen the risk for fibroids. (My personal note: I don't think he's suggesting anyone go out and smoke.) Dr. Speroff recommended 'add back therapy' if you use GnRH agonists (Lupron and other similar drugs) to shrink fibroids. (My personal note: what happens is that Lupron tends to be very tough on the system, causing: bad hot flashes, mood swings, etc. To allieviate these problems, you take one of the menopausal drugs (Premarin type) and 'add back' the hormones to the system, in a small and controlled way. Its enough to get rid of the worst part of the Lupron problems, but manageable enough to not give you your symptoms back.) Dr. Speroff mentions the newer Cetrorelix drug - it is an antagonist (vs. Lupron agonist) and the action of Cetrorelix is the same as Lupron, without the 'flare' effect. (My personal note: the 'flare' effect is that when you start out on these meds, sometimes the initial effect is too 'charge up' the hormones, giving you a large dose of them. This tends to be painful, which is why Cetrorelix was created.)

OC/BCP:
(898) The general effect of OC/BCP is to worsen insulin resistance. The progesterone in the OC/BCP does this. The low dose pills appear to not have this effect. He does state that changes in how carbs work are in the non-diabetic range. Although there are changes, Dr. Speroff states they are minimal. (899) The liver is affected most by estrogen (in the pill). If you have a tendancy to gall stones, then in the first few years, you have a greater risk of developing them, but some studies verify this and some dont. (914) There is NO reason to recommend free time away from the pill. Taking the pill at the same time every day helps with problems of breakthrough bleeding. (544) The best OC/BCP contains desogestrel, gestodene, and norgestimate, but this is not always proven in studies. (Personal note: PCO women have better luck with the desogestrel types of OC/BCP.)

(915) If you miss pills:
For 1 pill missed: take the missed one ASAP and keep on going. No backup is needed.
For 2 pills missed: if during the first 2 weeks: take 2 pills daily for 2 days and keep on going. Use an alternate method of contraception for 7 days just in case.
For 2 pills missed: if during week 3: if you started on day 1 of your period: start a new pack. Use an alternate method of contraception for 7 days and starting immediately.
For 2 pills missed: if during week 3: if you did a Sunday start: take a daily pill until Sunday and then start a new pack. Use an alternate method of contraception for 7 days and starting immediately.
For 3 or more pills missed: if you started on day 1 of your period: start a new pack and use an alternate method of contraception for 7 days.
For 3 or more pills missed: if you did a Sunday start: take a daily pill until Sunday and then start a new pack. Use a backup method of contraception for 7 days and starting immediately.
(916) For episodes of gastroenteritis use a 7 day backup method of contraception EVEN IF YOU TOOK YOUR PILLS.
(916) Breakthrough bleeding (bleeding when you aren't supposed to) does NOT mean that the pill is not working. Also, doubling of the pills really doesn't help, and switching isn't a good idea. Its best to let things just take a bit to work out. (Personal note: speaking from personal experience, if its a problem, ask for a change.)
(917) For low dose pills where you've not missed one this is generally caused because the estrogen part of the pill isn't strong enough to produce a 'good' endometrium to shed.
(918) No weight gain has been associated with any pill. Acne improves no matter what the pill.
(926) Progesterone only mini-pills and their progesterone compounds:
Micronor, NorQD, Noriday: norethnidrone
Microval: norgestrel
Ovrette, neogest: levonorgestrel
Exluton: lynestrenol
Femulen: ethynodial diacetate
CerazetteR: desogestrel
Note that these pills must be taken at the same time every day.
(927) Look for a lot more cysts on these pills, so this may not be a good option for PCO women. (928) Levonorgestrel minipills can cause acne. (547) Available in Europe: Cyproterone Acetate in Diane/Diane-35/Dianette (OC/BCP) works very well for hirsutism.

SHBG and IR:
(46) "an important mechanism for a reduction in circulating SHBG levels is insulin resistance and hyperinsulemia (independant of age and weight). This relationship between the levels of insulin and SHBG is so strong that SHBG concentrations are a marker for hyperinsulinemic insulin resistance and a low level of SHBG is a predictor for the development of Type II diabetes.". A personal suggestion, you might want to quote this if you doctor doesn't want to test your SHBG levels. Also, he says that "both total and unbound testosterone are normal in only a few women with hirsuitism." Another case where your levels of these hormones should be checked out.

Infertility related tests information:
(136) suggests an endometrial biopsy about 2 to 3 days before your period to diagnose luteal phase defects". (A personal suggestion, you might want to quote this if you doctor doesn't do this test.) (227) LH surges for ovulation tend to occur starting at 3 am, or usually between midnight and 8 am in 66% of women, in the morning in spring, evening in winter/autumn. From July to Feb, about 90% of women ovulate during the hours of 4 to 7 am, during spring, 50% do between midnight and 11 am. On page 232 he states that 11 to 17 days is a normal luteal time. In other words, you should get your period from 11 to 17 days after ovulation and be ok.
Page 1134 lists the terms:

IVF: InVitro fertilization: fertilization in laboratory
GIFT: Gamete IntraFallopian Transfer: putting eggs and sperm into the Fallopian tubes
ZIFT: Zygote IntraFallopian Transfer: putting fertilized eggs into the Fallopian tubes
TET: Tubal Embryo Transfer: putting embryos into the Fallopian tubes
POST: Peritoneal Oocyte and Sperm Transfer: putting eggs and sperm in the pelvic cavity
ICSI: Intracytoplasmic Sperm Injection: putting 1 sperm into the egg
TESE: Testicular Sperm Extraction: removal of sperm from testes
MESA: Microsurgical Epididymal Sperm Aspiration

Page 1134 lists the tests: HIV-1, 2, HTLV-1, Hepatitis B antigen, Hepatitis B and C antibodies, Chlamydia, Syphilis, Gonorrhea, Cytomegalovirus.
Page 1136 gives recommended follicle sizes of 18 mm for a dominant one, and several others at 14. This is when you get the HCG shot. Your endometrium should be at least 8 mm for and if its less than 6, you have a reduced chance for pregnancy. (1037) dispels some myths on infertility: anxiety and nervousness don't cause it (its an organic disease like a cold or an infection; adoption doesn't get you pregnant; D&C's don't help, matter of fact one study indicated the opposite - it makes it worse; and retroverted uteri are not infertility causers.

Last Update: Feb. 20, 2003