Anovulation

Posted On April 24, 2018 by Dr.Shobhana Mohandas

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Anovulation is one of the commonest factors treated in infertility.  It is known that women ovulate infrequently and modern life requires the couple to stay separately quite often.  Therefore ovulation inducing drugs are given commonly to women when they come for infertility evaluataion, more so , because it is easily prescribed.

Evaluation of ovulation:

History: Irregular periods are suggestive of anovulation.  Women who are having regular menstrual cycles (frequency of 23-35days, with no more than 2-3 days variation each month) have a greater than 95% chance that they are ovulating.

Basal body temperature chart: The temperature of the woman is taken everyday before rising from bed and noted.  Just after ovulation the temperature rises by 0.2-0.5⁰ C and remains higher than the preovulatory phase.  It is a retrospective diagnosis and very strainful to the patient, but in patients who cannot are not willing for serial vaginal USG, this could be used as a fairly good method of documenting ovulation.

Serum progesterone measurements:A serum progesterone value greater than 30nmol/L suggests ovulation

Endometrial biopsy: A secretory endometrium in the second half of the cycle suggests ovulation. It is an invasive method and is not resorted to in current day practice.

Urinary LH kits: Urinary LH is measured using reagent strips by the patient herself .   The testing should be carried out at the same time every day starting two to three days before expected ovulation.  A colour change predicts ovulation in 12-24 hours. This is a prospective test and ovulation cannot be confirmed , as increase in LH levels may not always end in ovulation.

Ultrasound: The preovulatory follicle grows at a rate of 2-3 mm per day and is 17-25mm at the time of ovulation.Pregnancy is associated with follicles of larger size at the time of ovulation and usually those greater than 20mm.  Ultrasound features of ovulation include a reduction in size of the follicle associated with loss of definition of the folllicular wall, together with the presence of fluid in the pouch of Douglas and even multiple echoes in the follicle.  Ultrasound assessment is usually carried out one or two days before expected ovulation and repeated one or two days after ovulation. The pre-ovulatory endometrium changes its texture after ovulation and is another indicator of ovulation on ultrasonography.

Anovulation could be suspected in a patient who has irregular or scanty menstruation. A normally cycling woman could have regular periods occuring at the interval of 28-35 days.

Clinical examination:A proper clinical examination could give clues regarding the etiology of the ovulatory disorder.

Bodymass: Obesity is usually associated with anovulation, being more of a central obesity.

Hirsuitism:  The raised androgen levels in PCOD  patients is associated with hirsuitism.  Acanthosis Nigricans:These are hyperpigmented patches on the dorsal surfaces of the  body.

Breasts: The breasts should always be examined in all infertile patients. Expression of  the nipples may reveal galactorrhoea, which may be a sign of subtle hyperprolactinaemia. This should be differentiated from the pathological nipple discharges.

Thyroid swelling: Any thyroid swelling should be looked for and investigated.

Diagnosis of anovulation:

Urinary LH kits or serial ultrasonography could be used to make a presumptive diagnosis of ovulation and to time ovulation.   Vaginal sonography has an edge over abdominal sonography for follicular study as the follicles and the endometrium are depicted much more clearly by the vaginal probe.

Hormone profile:

Serum prolactin levels- to determine hyperprolactinaemia.

Serum FSH levels on day3- To determine premature ovarian failure(FSH>40IU),

 diminished ovarian resereve(FSH-15-20IU), hypogonadotropism,etc.

Serum LH levels – (>10IU in midfollicular phase suggestive of PCOD).

LH/FSH ratio greater than 3 is suggestive of PCOD.

Serum DHEAS (Dehydroepiandrosterone)levels –(>10micromole /L suggestive of adrenal involvement)

Serum T3,T4,TSH levels- To diagnose hypothyroidism.

GTT- To diagnose insulin resistance in PCOD.

Insulin levels->30mu/L fasting suggestive of hyperinsulinaemia which may lead to PCOD.

Candidates for ovulation induction:

Ovulation induction should be considered only in patients who have ovulatory disorders. The administration of Clomiphene citrate(The first line of therapy in anovulation) to normally ovulating women does not increase the pregnancy rate in infertile women ⁽⁵⁾ as shown in controlled studies. This principle may have to be waived in patients undergoing treatment with Artificial Reproductive Technology. In patients undergoing intrauterine insemination, results are improved when their ovaries are stimulated artificially.  In patients undergoing IVF ET/ICSI, the cycles are planned so that a certain number of patients can have their ovum pickups done on the same day simultaneously.

Ovulatory disorders:

Ovulation can be presumed to occur when menstrual cycles occur regularly at intervals of 28 to 35 days.

Ovulatory disorders could be:

1. a) Oligoovulation where ovulation occurs in lesser frequency as compared to normal population,
2. b) Anovulation where ovulation does not take place at all
3. c) Luteal phase defects, where ovulation takes place, but there is defective formation and growth of the corpus luteum, which normally forms after ovulation.

Some of the ovulatory disorders are described below.

Polycystic ovarian syndrome:This is a common condition among anovulatory patients        and affects 6-10% of all women(13). The finding of polycystic ovaries may appear in many an ultrasonography report and to the uninitiated doctor, it may sound like a cystic disease of the ovary. Polycystic ovarian syndrome is in fact a disease where there is hormonal imbalance, leading to the development of multiple follicles in the ovary.

Pathology: In the normally ovulating ovary there may be multiple follicles seen on USG before day 7 of the menstrual period. One of them become dominant and ovulates. In polycystic ovaries, the ovarian size is increased,the multicystic appearance of the ovaries persist, and there is no dominance of any one follicle and consequently there is no ovulation.

Endocrinology:The endocrinology of this syndrome is too complex to be described in this book. In short, there is hyperandrogenemia, normal or elevated oestrogen levels, raised LH secretion with alteration of the normal relationship between LH and FSH leading to a raised LH: FSH ratio. Recently it has been found that some of these patients have insulin resistence, leading to hyperinsulinaemia. This leads to hyperandrogenism of PCOS. The high levels of androgenic hormones interferes with the pitutary ovarian axis leading to increased LH levels, anovulation, amenorrhoea and infertility.

Clinical findings:Polycystic ovarian syndrome has a gradual onset in young women with mild hirsuitism which gradually increases and comes to medical attention 1 year after onset.  The onset of symptoms is typically in the decade between 15 and 25 years. Some women have acne in addition to hirsuitism.  Some women with PCOS have Acanthosis nigracans.   Women with PCOS tend to be obese.  Amenorrhoea or an irregular menstrual pattern may be the presenting symptom.  They may come with infertility. Sometimes in addition to reduced conception, pregnancy outcome may also be adversely affected with miscarriage rates as high as 65% being reported.

Diagnosis: An ultrasound examination demonstrating greater than 10 to 15 follicles in each ovary, raised androstenedione and testosterone levels, with an LH: FSH ratio greater than 2:1.

Clomiphene citrate: Clomiphene citrate (CC) is a synthetic nonsteroidal estrogen agonist-antagonist.

Action: It mimics the appearance of estrogen and tricks the body, mainly the hypothalamus to believe that oestrogen levels are higher than what it actually is. It occupies estrogen receptors leading to the production of gonadotropin releasing hormones from the hypothalamus and gonadotropins from the pituitary, resulting in formation of a dominant follicle,subsequently followed by ovulation.

Indication: Clomiphene citrate is most effective and should be considered the initial treatment of choice for women with anovulation or oligo-ovulation associated with normal endogenous estrogen production and normal levels of FSH (WHO group 2). Clinically, this represents the large and heterogeneous group of women with polycystic ovary disease.

Dose:The initial recommended dosage is 50 mg once daily for 5days; therapy can be initiated on cycle days 3, 4, or 5.  In the absence of documented ovulation, the clomiphene citrate dosage should be increased to 100 mg daily for 5 days. An additional 25% of patients will ovulate if the dosage of Clomiphene citrate is increased to 100 mg daily for 5 days.  Gysler et al reported that 26% of patients who eventually ovulated required a daily dosage of 150 mg or more.  Once the minimal effective dose to induce ovulation has been determined, there is no advantage to increasing the dosage in subsequent cycles, even in the absence of pregnancy. Treatment with clomiphene citrate should be continued for three to six ovulatory cycles. Approximately 90% of clomiphene-induced pregnancies occur within four to six ovulatory cycles. Detection of ovulation should be sought during each cycle. In most patients, ovulation takes place approximately 5 to 12 days after the last treatment dose.

Monitoring cycles:Different strategies may optimize the timing of intercourse or intrauterine inseminations. These include frequent intercourse after cycle day 10, BBT charting, measurement of urinary or serum LH, or serial ultrasound monitoring. Contraindications; Clomiphene is contraindicated in moderate to large ovarian cysts,   pregnancy, organic intracranial lesions,  pituitary macroadenomas, liver disease, uncontrolled thyroid or adrenal dysfunction, visual disturbances and undiagnosed abnormal uterine bleeding.

Clomiphene failures:

Insulin lowering agents: Recent literature has shown that one of the major biochemical features   of polycystic ovary syndrome is insulin resistance accompanied by compensatory hyperinsulinemia (elevated fasting blood   insulin levels).  Hyperinsulinemia produces the hyperandrogenism of polycystic ovary syndrome, interfering with the pituitary ovarian axis, leading to increased LH levels, anovulation, amenorrhea, and infertility.  It has been shown that lowering serum insulin concentrations with metformin (Glyciphage 1500 mg a day) or troglitazone (Rezulin 400 mg a day) ameliorates hyperandrogenism, by reduction of ovarian enzyme activity that results in male hormone production.   Out of these, Metformin is available in India as 500mg and 850mg tablets.  The dose is 500-850mg three times daily.  It has been shown to reverse the endocrine abnormalities seen with PCOD in 2-3 months time. The therapy reduces hirsutism, obesity, blood pressure, triglyceride levels, and facilitates reestablishment of the normal pituitary_ovarian cycle, thus often allowing resumption of normal ovulatory cycles and pregnancy. , When given to non_diabetic patients, neither metformin nor troglitazone lowers blood sugar   while both appear to be very safe. In the first week of taking the medication, people will often experience upset stomach or   diarrhea, which usually resolves after the first week. For those on metformin, starting with one pill daily the first week and increasing to twice a day during the second week can minimize this side effect. Patients with reduced renal function (creatinine >1.5 or creatinine clearance <60%) are at a higher risk for a rare side effect of metformin therapy called lactic   acidosis, and the drug should be given cautiously, if at all, to such patients. Metformin given during pregnancy has not shown increased incidence of congenital anomalies in the fetus.  Recurrent abortions caused due to PCOD can benefit from Metformin therapy.

Once simple measures fail to effect ovulation in the infertile patient, there are two options left, a)Treatment with gonadotopin injections,either  HMG(Human Menopausal gonadotropins ) or FSH(Follicle stimulating hormone) b) Drilling of the ovaries laparascopically.

Treatment with Gonadotropins: HMG or FSH are given singly or in adjunct to Clomiphene citrate with ultrasound monitoring. A dose of 75IU or 150IU is started on day 2 or 3 and given daily or alternate days , with doses being adjusted according to the growth of follicle seen on Ultrasonography and serum estrogen levels, if same day results are available.   Gonadotropin injections are costly, between Rs2500-Rs10,000 per cycle depending on the drug used and the response.In case of failures, the whole  treatment has to be repeated in subsequent months.

Treatment with gonadotropins can be supplemented with Gonadotropin releasing hormones given simultaneously by various protocols.

Laparoscopic drilling:  A few holes are made into the surface of the ovary, draining the subcapsular cysts, and reducing the intraovarian androgen levels, thus facilitating ovulation.  Spontaneous ovulation rates ranges from 55-92% and overall pregnancy rates ranges from 56-76%.  The mean duration of ovulation ranged from 20-40 days postoperatively in one particular study.  Thus if the husband is staying away from the wife, the procedure is ideally performed 1 month before he comes home.  Usually the effect of drilling in producing ovulation lasts for more than a year.  Gjonnaess followed a large cohort of women and his data suggest that of the women who ovulate in response to ovarian drilling, only 3-4% stop ovulating in the subsequent year.  This is where laparoscopic drilling scores over gonadotropin administration.  The patient has to spend only once for the surgery, while in gonadotropin administration, the patient has to repeatedly spend huge amounts month after month in case of failures.

Polycystic ovarian syndrome affects 5-10% of all reproductive age women¹    The basic pathological findings in PCOS include, elevated LH levels, and subsequently elevated androgen levels, like testosterone and dehydroepiandrostenedione.  There is increased resistance to insulin, which can be aggravated by obesity.  All these factors need to be addressed while treating a patient with PCOS.

Patient with PCOS who desire preg­nancy are candidates for the medical induction of ovula­tion. The traditional drugs used in the treatment of anovulation in a patient of PCOD include clomiphene citrate, Metformin, Steroids, Anti obesity agents, Gonadotropins and GnRh analogues and antagonists. However, Clomiphene citrate on prolonged therapy can adversely affect the endometrium and Metformin is sometimes not tolerated by  patients.  The other drugs useful in this scenario are enumerated below.

Raloxifene:  Clomiphene citrate (CC), the traditionally used ovulogen,  is a selective estrogen-receptor modulator (SERM), and it presumably works to induce ovulation by inhibiting negative endogenous estrogen feedback on the hypothalamicpituitary axis, resulting in an increase in follicle-stimulating hormone (FSH) secretion, follicular growth, and ovulation.  However, endometrial receptivity decreases and miscarriage rates are high with the use of this agent.  Raloxifene is a SERM approved for the treatment of osteoporosis in postmenopausal women , with antiestrogenic effects at the

level of the hypothalamus and/or pituitary similar to CC. Raloxifene may have a favorable impact on markers of endometrial receptivity compared with CC, and it has been shown to increase FSH levels in premenopausal women.  Ernesto de Paula Guedes Neto et al² have, in a study, proved that 100 mg of Raloxifene for five days  is as efficacious as clomiphene in inducing ovulation, with a more favourable effect on the endometrium.

 

Pioglitazone: Hyperinsulinemia caused by insulin resistance in PCOD causes hyperandrogenemia.  Metformin is traditionally used to improve this resistance and lower the blood glucose levels.  However, many patients cannot tolerate the side effects of Metformin and some are resistnant to it .  Pioglitazone is another insulin sensitizing agent which can be used to improve ovulation in PCOS.  Its action is different from Metformin. It acts after insulin binding by insulin receptors to improve the action of insulin, reduces its resistance to hormones, and inhibits glucose production in the liver³.  pioglitazone may be

effective in cases of dexamethasone- or metformin-resistant PCOS in the dose of 30 mg per day.

Atrovastatin and Simvastatin^4,5: The cholesterol lowering Statins, Atorvastatin in the dose of 20 mg or Simvastatin 20 mg per day has been found to be effective in reducing inflammation, biochemical hyperandrogenemia, and metabolic parameters in patients with PCOS after a 12-wk period.  Homocysteine levels have also been found to be lower with the use of Statins in PCOS patients.

Insositol:  The inositol phosphoglycans (IPGs) are putative mediators in a nonclassic insulin signaling cascade for glucose uptake and use.Insulin-resistant women with PCOS display decreased insulin stimulated release of d-chiro-inositol (DCI)-containing IPGs(DCI-IPGs) during an oral glucose tolerance test (OGTT), which was related to impaired coupling between insulin action and the release of the DCI-IPG. Oral nutritional supplementation with inositol, part of the vitamin B complex (B8) and an intracellular second messenger, was demonstrated to enhance insulin sensitivity and improve the clinical and hormonal characteristics of patients with PCOS   In addition, inositol supplementation was shown to restore spontaneous ovulation with the consequent increase in conception, either alone or when combined with gonadotropin.⁶

Multivitamins: Jorge et al,⁷ in a prospective study concluded that consuming multivitamin supplements at least three times per week was associated with a reduced risk of ovulatory infertility. This association appeared to be mediated in part by folic acid.

Vitamin D3: Selimoglu et al have, using a single dose of 300,000 units of 25-hydroxyvitamin vitamin D3 orally, in PCOS women in a study, concluded that PCOS women are mostly deficient in vitamin D3 and supplementing them with vitamin D3, can have a beneficial effect in improving insulin resistance in obese women with PCOS¹² .

N-Acetyle cysteine:  N- acetyle cysteine as an adjunct to clomiphene citrate or Metformin could improve insulin sensitivity in PCOS subjects^8,9,10.  1.8gm/day in normal weight women (600mg three times a day)and 3 gm/day in extremely obese women for 5 to 6 weeks are the dosages recommended.

Arginine: Nitric oxide (NO) has a positive role in oocyte maturation and ovulation.  L-Arginine is a positive NO enhancer.  In one study, Eight patients with PCOS displaying oligo-amenorrhea from at least 1 yr underwent a combined treatment with N-acetylcysteine (NAC) (1200 mg/day) plus L-arginine (ARG) (1600 mg/day) for 6 months. It concluded that prolonged treatment with NAC+ARG might restore gonadal function in PCOS¹¹. This effect seemed associated to an improvement in insulin sensitivity

.When faced with a patient with severe PCOS, and achieving pregnancy with standard treatment seems difficult, it would be helpful to supplement the patient with adjuvants that may help reduce insulin sensitivity, and help oocyte maturation and ovulation, with positive effects on the endometrium. Replacing Clomiphene and Metformin with Raloxifene or Pioglitazone are options worth trying in selected cases.

Luteal phase defect:

Pathology: Luteal phase defect (LPD) refers to a relative deficiency in the secretion of

progesterone by the corpus luteum.The defective functioning of the corpus luteum leads to inadequate development of the endometrium,poor implantation and pregnancy wastage.  The most accurate diagnosis of luteal phase defect can be done by dating the endometrium on the 23^rd to 24^th day of the cycle and it is seen to lag behind by 2 days.  It is not always practical.

Clinical picture: Luteal phase defects manifests as unexplained infertility and pregnancy wastage. Thinning of the endometrium found on transvaginal sonography may be suggestive.  In early pregnancy recurrent losses (3 abortions in succession) the incidence of LPD could be 20-40%. The incidence among subjects with unexplained infertility, employing endometrial biopsy as diagnostic measure, is in the range of 10-20%.

Associated pathologies:Luteal phase dysfunction may be associated with several clinical entities, including mild or intermittent hyperprolactinemia (of any cause), strenuous physical exercise,inadequately treated 21-hydroxylase deficiency, and habitual abortion.

Treatment:

1. a)In patients with abnormal ovulation, Clomiphene citrate should be administered.
2. b)In patients with normal ovulation, progesterone supplemetation should be given in the second half of the cycle.  Micronised progesterone could be given in the dose of 100mg twice daily. Vaginal administration of this drug has better absorption compared to the oral route.
3. c)In cases of LPD associated with mild hyperprolactinaemia, Bromocriptine should be added to treatment.
4. d)Administration of additional HCG injections in the latter half of the cycle.
5. e)As a last resort, gonadotropin supplimentation could be tried.

Hyperprolactinaemia:

Aetiology:Numerous clinical conditions may cause elevated

prolactin levels, among them pituitary tumors, certain medications, chest wall trauma,

Chronic renal insufficiency, hypothyroidism, empty sella syndrome, pituitary stalk

transection, and occasionally nonpituitary tumors.

Presentation: Hyperprolactinaemia  presents with hypoestrogenism,menstrual irregularities(Oligomenorrhoea or secondary amenorrhoea),anovulation and galactorrhea. Galactorrhea is not present always. Subtle ovulatory dysfunctions such as follicular dysfunction and luteal phase deficiency are the other well-recognised manifestations of this endocrinopathy, which present as ‘Unexplained infertility’.  Hence prolactin determinations are essential in all patients with these disturbances.

Bromocryptine: Bromocryptine is a dopamine agonist and inhibits the production of prolactin. Hyperprolactinaemia with infertility has extremely high pregnancy rates when treated with Bromocryptine. Bromocryptine could be admininistered to patients with galactorrhoea, specially when infertile, even if prolactin levels are normal.Treatment with Bromocryptin could be useful in some cases of corpus leuteum insufficiency presenting as unexplained infertility.  In cases of failed induction of ovulation with Clomiphene citrate, one of the ways of improving results could be by adding Bromocryptine.

Dose: The optimal dose of Bromocryptine is 2.5mg twice daily.  It could be either taken orally or placed in the vagina, from where it is absorbed.  Oral administration could result in side effects like severe nausea, vomiting,giddiness,constipaton, abdominal bloating, etc.  Starting the drug at a low dose, once a day, could reduce the severity of side effects. The drug could be started in a dose of 1.25 mg once daily after food, and gradually increased to 1.25 mg twice daily over 2 days and finally reach the dose of 2.5mg twice daily.

Dose:  Often the dosage range required to restore ovulation is between 2.5mg to 7.5mg daily.  Serum prolactin level should be redetermined after 3-4 weeks of treatment.  Usually 2.5mg twice daily is needed to normalise  prolactin levels, but some patients can be maintained on dosages as low as 1.25 mg at bedtime.

Duration of treatment:  Although B romocriptine therapy usually restores ovulatory cycles after approximately 2 months, with or without the normalization of serum prolactin levels, alternative ovulation induction agents such as clomiphene citrate or gonadotropin therapy should be added if it does not.  Alternate treatment options should also be considered after 4-6 months of ovulatory cycles without conception. Bromocryptin therapy could be stopped once the patient becomes pregnant, but continuation should be strongly considered for patients with macroadenomas to minimize pregnancy-associated complications. Administration does not cause increased risks for miscarriage,adverse obstetric outcomes, or congenital anomalies.(Kistner)

Premature ovarian failure:

Pathology:  When premature menopause occurs before the age of 35,it is due to premature ovarian failure.

 Clinical picture: The patients present with secondary amenorrhoea. On testing the FSH and LH levels in the serum they are found to be raised and in the menopausal range

Etiology:It may be caused by genetic defects,infectious and iatrogenic destruction of primordial follicles as a result of mumps oophoritis,irradiation or chemotherapy. It has also been hypothesized that it may be an autoimmune disease. There could be other autoimmmune disorders assossiated with it like Addison disease,thyroiditis, hypoparathyroidism, diabetes, pernicious anemia, myasthenia gravis, and vitiligo. Associated diseases:Because of the associated polyendocrine autoimmune syndromes, patients should be screened for diabetes, anemia, thyroid, adrenal, and parathyroid insufficiency.

Treatment:  Accepting an ovum from a donor and going in for IVF-ET is the only option out in patients suffering from infertility.  Any other diseases which may be associated with POF should be meticulously looked for and treated.

 

Diminished Ovarian Reserve

Recently, a subgroup of patients with unexplained infertility has been described as

having incipient ovarian failure or diminished ovarian reserve (Toner et al, 1991). These

patients have elevated FSH levels on day 3 that are greater than 15 to 20 mIU/mL.

They often have normal ovulation and menstrual cycles, but they respond poorly to

human menopausal gonadotropins. As do patients with POF, these patients have an

extremely poor chance for future fertility in the absence of IVF with donor oocytes.

F Hypothalamic Amenorrhea

Pathology:There is reduced production of Gonadotropin releasing hormones from the hypothalamus and consequently reduced production of gonadotropins, leading to reduced follicular development,anovulation and amenorrhoea.

Endocrinology&diagnosis: In contrast to polycystic ovarian syndrome (PCOS), hypothalamic amenorrhea is associated with a hypoestrogenic state. Normal or low gonadotropin levels and the absence of progestin-induced bleeding confirm the diagnosis.

Aetiology:Common causes of hypothalamic amenorrhea include exercise, weight loss, and stress. It has a better prognosis compared to premature ovarian failure.

Treatment: Gonadotropin injections given along  with monitoring of follicular growth and estrogen levels may result in ovulation.

G Thyroid Disease

Hyperthyroidism and hypothyroidism may be associated with menstrual irregularities and ovulatory dysfunction.

Euthyroid:Many practitioners give tablets of thyroxine empirically to infertile women even though they are euthyroid.  This sort of treatment remains unsubstantiated.

Clinical hypothyroidism:Patients with clinical hypothyroidism may benefit from thytoid hormone replacement with a resumption of normal ovulatory function.

Subclinical hypothyroidism: The role of thyroid hormone therapy for patients with subclinical hypothyroidism (i.e. elevated TSH level and normal thyroxine and triiodothyronine levels) remains unclear and warrants further investigation.

Treatment: Eltroxin should be started in the dose of 0.1mg/day . The dose could be increased to 2 or 3 tablets /day till the patient becomes euthyroid .

H Adrenal Disease: Certain disorders of adrenal gland like Addison disease, Cushing syndrome,etc can be associated with ovulatory disorders.

 Clomiphene failures:

The following alternatives may be tried.

1. a)When standard doses of Clomiphene does not result in ovulation, extending the course to 14 days has been shown to be effective in some patients.
2. b)Clomiphene may be combined with a single dose of hCG (5000-10,000IU).Serial ultrasound examination should be done and hCG given on he day the follicular diameter exceeds 18mm.
3. c)Serum Dehydro epiandrostenedione levels(DHEAS is an adrenal androgen) should be estimated. If it is >2umg/ml, an adrenal involvement could be presumed. In such cases, adding Dexamethasone 0.5mg daily should be considered
4. d)If the tri-iodo-thyronine levels are below 80ng/ml, combining Clomiphene with throxine, 0.1mg/day will help.
5. e)Clomiphene can be combined with Gonadotropins.  The required dose of gonadotropins is reduced when clomiphene is combined.
6. f)Combining Bromocriptine with clomiphene in patients with normal prolactin levels is not supported by current literature.

References:

1.Serdar.E.B, Physiology and pathology of the female reproductive axis: Melmed: Williams Textbook of endocrinoloty, 12^th ed. Copyright 2011 Saunders,, An imprint of Elsevier.

2. Ernesto de Paula Guedes Neto et al: Prospective, randomized comparison between raloxifene and clomiphene citrate for ovulation induction in polycystic ovary syndrome.Fertility and Sterility:Vol. 96, No. 3, September 2011 .7.6333333333

3.Hirotaka Ota et al, Successful pregnancies treated with pioglitazone in infertile patients with polycystic ovary syndrome : Fertil Steril_ 2008;90:709–13.

4. Sathyapalan T – J Clin Endocrinol Metab – 01-Jan2009; 94(1): 103-8.
5. Cemil Kayaet al: Fertility and Sterility Volume 92, Issue 2, August 2009, Pages 635-642.
6. Giuseppe Morgante et al, The role of inositol supplementation in patients with polycystic ovary syndrome, with insulin resistance, undergoing the low-dose gonadotropin ovulation induction regimen:Fertility Sterility 2011.

7.Jorge E.Chavarno et al., Use of multivitamins, intake of B vitamins, and risk of ovulatory infertility: Fertil

Steril:  2008;89:668–76.

8. Fulghesu AM : N-acetyl-cysteine treatment improves insulin sensitivity in women with polycystic ovary syndrome – Fertil Steril – 01-JUN-2002;
9. Badawy A : N-Acetyl cysteine and clomiphene citrate for induction of ovulation in polycystic ovary syndrome: a cross-over trial. Acta Obstet Gynecol Scand – 01-JAN-2007; 86(2): 218-22.
10. Rizk AY: N-acetyl-cysteine is a novel adjuvant to clomiphene citrate in clomiphene citrate-resistant patients with polycystic ovary syndrome.  Fertil Steril – 01-FEB-2005; 83(2): 367-70.
11. Masha A : acetylcysteine and L-arginine restores gonadal function in patients with polycystic ovary syndrome.  J Endocrinol Invest – 01-DEC-2009; 32(11): 870-2.

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