CC resistance

What History & Examination for a case with persistent CC resistance?? _ Age at menarche, Cycle regularity, Menst—quantity of Loss / .pain, Hirsutism, Galactorrhoea, Problems with sexual activity, Occupation, previous pregnancies. Duration of subfertility, operations, Drug/ alcohol./ smoking/ medical disorders/ contraceptive use/ Previous Tr of subfertility, Oligomenorrhoea implies-periods occurring between  (35-180 days) : But Ameno implies no period continuously for 6 months

What to examine clinically?? To

examine:- A) Wt, Height, BMI- Wt in Kg ÷ Ht in meter².   Normal will be 20-25; Overweight is 25.1 to 30 & Obesity is >  signify clinical IR-. So must must insist on wt loss  B) Any acanthosis C) what is the waist circumference?-if if above 88 cm & later metformin.

Pre-induction Investigations:-Don't forget to get 1) AMH 2) What is her age, 3) baseline FSH, 4) LH 5)  E2 6) T4 (Total) and 7) FPG :Insulin ratio(Roy-34-in suspected PCOS). 6) What’s the tubal status? HSG is best and can pick up PID, Cavitary disorders, . The initial step of HSG prior tock are 1) H/O. STI 2) H/O/ CS or complicated delivery 3) Endometriosis 4) H/O Ectopic operation / App open.5) Even per tubal adhesions may be picked up by good quality HSG. 7) Role of PCT:-debatable, but have an important role when man can’t produce semen at Lab.

 In proposed CC cycles:-better to use micro Prog in previous cycle. If Primolut ten there can be embryonic loss in that cycle. If no response think of- five common causes of anovulation- obesity, hyper-LH/ Insulin/ Androgen/ hyperprolactinaemia. Is she really a case of Anovulation ?? The four common causes of anovulation as suggested by WHO are A) WHO Group-I: - HP Failure (Low gonadotrophins with amenorrhoea), B) WHO Group-II: HP dysfunction e.g., PCOS:- evidenced by normal E 2 , normal FSH . As a matter of fact about 90%of anovulation is of this type –clinically represented by oligo ameno, and rarely ameno, C) WHO Group –IIIWHO Group III:- Primary Ov failure. POF, Nat meno, Turners syn. Ameno, Low E2, High FSH-A better marker will be low AMH than low FSH... Hot flushes. Primary Ov failure. POF, Nat meno, Turners syn. Quite often in cases of WHO Group III-the cause remains uncertain--D) WHO Group-IV- Hyperprolactinaemia.(PRL level will have to be twice the upper limit). E) WHO group-V:- Outflow Tract Obstruction. FSH is Normal, No PCT neither withdrawal bleeding with combined E & P; Usually Primary ameno, Rarely Anchorman’s Syndrome.

How to know that she is a case of anovulation & needs CC induction??.  Ans:  A regular cycle length of 24-35 days, painful periods and serum progesterone of 8 ng/ml or 25 n.mol/L or more in regular cycle will exclude the possibility of anovulation as the cause subfertity. Prog test should be done 7 days before the expected period i.e. day 28 if her usual cycle length is 35 days. If C length is > 35 days then first P may be estimated on day 28 and then repeated after 7 days. Where cycle length is >  P testing unnecessary,  then anovulation diag is obvious 60 days

Once the diag of anovulation is confirmed then next step will be the type of anovulation- Then only Formulate Tr plan. A) WHO Group I:- (Hypogonadotrophic Hypogonadism) Diag by very low gonadotrophins. Ca uses are A) HYPOTHALAMIC:-stress, Wt elated, Kallmann’s syn with anosmia, debilitating systemic diseases. Few cases are idiopathic. B) Pit:-Sheehan’s syndrome, Pit radiation. May opt for Pulsatile GnRH if Hypo is the cause of Hypogonadotrophic Hypogonadism, but conventional HMG will be equally effective in both Pit/ Hypo cases of Hypogonadotrophic Hypogonadism. B) WHO Group II:- Dysfunction :- What is PCOS ?? It (PCOS) comprises about 75% of women suffering from infertility due to anovulation. Oligo-ameno (35-180days) is usual rarefy ameno. Tr is 1) Life style modifications 2) CC. Anastrazole 3) insulin lowering agents, 4) LOD 5) Gonadotrophins.

The diag of PCOS may be done without blood sampling but traditionally / customarily one estimates LH, FSH, T4 (Total) and FPG: Insulin ratio. But FSH & E2 will be normal. Biochemical (Raised total Test, androstenedione & FAI) / Clinical Hyperandrogenism (Acne, Hirsutism, alopecia) & USG e/o PCOS. = (> 12 follicles per Ov measuring 2-9 main dia, or increased Ov volume ). But CAH, Cushing’s have to be eliminated. WHO Group III:- Primary Ov failure. POF, Nat meno, Turners syn. Ameno, Low E2, High FSH-A better marker will be low AMH than low FSH... Hot flushes. Primary Ov failure. POF, Nat meno, Turners syn. Quite often in cases of WHO Group III-the cause remains uncertain. WHO Group IV: - Hyperprolactinaemia. In 30 % of cases raised PRL is seen. Not to tr> 50. Exclude Hypothyroidism, phenothiazines intake, MRI as 50% will have microadenoma (< 10 mm).

Flow Chart after confirming anovulatory cause of subfertility.- Step 1:- PRL- Go for Bromocriptine/ Cabergolin.  then estimateàStep 2:- A) Normal PRL-but Oestradiol low Hypothalamic Pit Failure. B)àLowàFSH  but  Normal PRL-but Oestradiol low  Primary Ovarian Failure.  High  FSH is Therefore diag of cause of anovulation is easy and can be pinpointed by couple of days. Then estimate PRL if PCT is +ve then (scuff E2 is present and excludes G P disorders) The other way of diagnosing cause of anovulation:- Modified plan with minimum Lab cost: Plan is if there is mod Oligomenorrhoea -Prog Challenge Test- If withdrawal bleed is +ve But if no PCT is –Ve then possibilities are 1) Hypergonadotropic Hypogonadism (high FSH), 2) Hypogonadotropic Hypogonadism. But if the sec ameno is >  6 months to follow the above scheme & investigation for outflow tract Obstruction. By definition amenorrhoea implies absence of menst >6 months. cc+inj r-FSH ,do follicular monitoring and accordingly add r-FSH/ primary infertility wad pcod. Did not respond to 100mg of clomiphene. Before going for hMG is there any other protocol. She is also taking tab. Metformin and syrup m2 tone. What is her age, baseline FSH, LH, e2? For how long she is taking metformin and what dose C) For pcod FSH is better than hMG A) Cc+metformin or B) cc+steroids As she is already taking cc+metformin, start with D) cc+inj r-FSH ,do follicular monitoring and accordingly add r-FSH/HMG Don't forget to get AMH E) Try Myoinosital+Nacetylcystine combination for 2-3 months and then try induction with 200mg of cc.

Flow Chart about etiology on Oligomenorrhoea.  Ans: LH, FSH,TT, Free Test, 17-OH P, FBS  A) firstly try to exclude PCS by Signs of hyperandrogenism, Clinical/ biochemical hyperandrogenismàHP Dysfunction is likely cause   Step-1:- PRL, Second Step 2:-Normal &  I impending Ov failure  Insulin(LH not necessary),B) No PCOS—estimate FSH—High When to stop CC and proceed for r-FSH (r-FSH is better in PCOS cases than HMG? 1) If no response with 150 mg CC- CC resistance. 2) ET persistently <  proceed for HMG in third cycle. Don’t push on such thin ET more than two cycles. 3) No conception after six Ov cycles. 7mm in mid cycle-more than one cycle When to add met as well? - When profound CC resistant. including those related to stress, exercise and eating disorders, treatment with gonadotropins is effective in patients with low FSH levels, but it must be started at a low dose because of the possibility that ovaries unaccustomed to FSH. In cases of obese PCOS as many as 80% will have hyperinsulinaemia, and in normal wt PCOS the prevalence of hyperinsulinaemia will be about 30-40%. But insulin testing is usually not done due too complicated Lab procedures. LH Value in PCOS?? About 50% will have LH value > 10 IU/Lit. In such cases OI will not be successful and miscarriage rate will be high. Better IVF. One can use Micro Prog / OCP in previous cycle. When to do Total Tetsos & 17-OH P? If rapidly progressing hyperandrogenic symptoms then these two tests may be done. Other Rare Lab Tests? Lipid profile, Homocysteine, Plasminogen Activator Inhibitor-1