Evaluation of ovulation:
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
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
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
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
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
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
examination:A proper clinical examination
could give clues regarding the etiology of the ovulatory disorder.
Obesity is usually associated with anovulation, being more of a
Hirsuitism: The raised androgen levels
in PCOD patients is
associated with hirsuitism.
Acanthosis Nigricans:These are hyperpigmented patches on the
dorsal surfaces of the
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.
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
prolactin levels- to determine hyperprolactinaemia.
levels on day3- To determine premature ovarian
levels – (>10IU in midfollicular phase suggestive of PCOD).
ratio greater than 3 is suggestive of PCOD.
DHEAS (Dehydroepiandrosterone)levels –(>10micromole /L suggestive
of adrenal involvement)
T3,T4,TSH levels- To diagnose hypothyroidism.
diagnose insulin resistance in PCOD.
levels->30mu/L fasting suggestive of hyperinsulinaemia which may
lead to PCOD.
Candidates for 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
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.
can be presumed to occur when menstrual cycles occur regularly at
intervals of 28 to 35 days.
disorders could be:
Oligoovulation where ovulation occurs in lesser frequency as
compared to normal population,
Anovulation where ovulation does not take place at all
phase defects, where ovulation takes place, but there is defective
formation and growth of the corpus luteum, which normally forms
the ovulatory disorders are described below.
ovarian syndrome:This is a common condition among anovulatory
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
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.
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
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.
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.
citrate: Clomiphene citrate (CC) is a
synthetic nonsteroidal estrogen agonist-antagonist.
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.
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.
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.
measures fail to effect ovulation in the infertile patient, there
are two options left, a)Treatment with gonadotopin
HMG(Human Menopausal gonadotropins ) or FSH(Follicle
stimulating hormone) b) Drilling of the ovaries
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.
with gonadotropins can be supplemented with Gonadotropin releasing
hormones given simultaneously by various protocols.
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 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
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.
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
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
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
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
Atrovastatin and Simvastatin4,5: 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.
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
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.
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 .
acetyle cysteine as an adjunct to clomiphene citrate or Metformin
could improve insulin sensitivity in PCOS subjects8,9,10.
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
Nitric oxide (NO) has a positive role
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
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
Pathology: Luteal phase defect (LPD)
refers to a relative deficiency in the secretion of
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 23rd to
24th day of the cycle and it is seen to lag behind by 2
days. It is not always
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%.
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.
In patients with abnormal ovulation, Clomiphene citrate
should be administered.
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
In cases of LPD associated with mild hyperprolactinaemia,
Bromocriptine should be added to treatment.
Administration of additional HCG injections in the latter
half of the cycle.
As a last resort, gonadotropin supplimentation could be
Aetiology:Numerous clinical conditions may
levels, among them pituitary tumors, certain medications, chest wall
renal insufficiency, hypothyroidism, empty sella syndrome, pituitary
transection, and occasionally
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 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.
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.
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
Pathology: When premature menopause
occurs before the age of 35,it is due to premature ovarian
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
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
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
a subgroup of patients with unexplained infertility has been
incipient ovarian failure or diminished ovarian reserve (Toner et
al, 1991). These
have elevated FSH levels on day 3 that are greater than 15 to 20
often have normal ovulation and menstrual cycles, but they respond
menopausal gonadotropins. As do patients with POF, these patients
poor chance for future fertility in the absence of IVF with donor
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.
Gonadotropin injections given along with monitoring of
follicular growth and estrogen levels may result in ovulation.
and hypothyroidism may be associated with menstrual irregularities
and ovulatory dysfunction.
practitioners give tablets of thyroxine empirically to infertile
women even though they are euthyroid. This sort of treatment
hypothyroidism:Patients with clinical
hypothyroidism may benefit from thytoid hormone replacement with a
resumption of normal ovulatory function.
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 .
Disease: Certain disorders of adrenal gland like Addison disease,
Cushing syndrome,etc can be associated with ovulatory
following alternatives may be tried.
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.
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.
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
If the tri-iodo-thyronine levels are below 80ng/ml, combining
Clomiphene with throxine, 0.1mg/day will help.
Clomiphene can be combined with Gonadotropins. The required dose of
gonadotropins is reduced when clomiphene is combined.
Combining Bromocriptine with clomiphene in patients with
normal prolactin levels is not supported by current literature.
1.Serdar.E.B, Physiology and pathology
of the female reproductive axis: Melmed: Williams Textbook of
endocrinoloty, 12th 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.
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Successful pregnancies treated with pioglitazone in infertile
patients with polycystic ovary syndrome : Fertil Steril_
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