Many on-going IVF pregnancies, infertile women, and patients wanting IVF/ IUI have been struggling because of the disruption caused due to the COVID-19 pandemic
The welfare of our patients at the IVF centre of Sir Ganga Ram Hospital, undergoing fertility treatment as well as their pregnancies, are foremost in our mind. To make treatment as safe as possible, we have introduced several changes. These are as following:
For most people, the treatment cycle will be the same as before the pandemic, with us focussing on your safety alongside success rates. If you have a significant underlying medical condition, then we may discuss altering your treatment to maximise safety for you at this time.
If you test positive for coronavirus prior to your egg collection, we will need to pause your treatment until you are well again. The best is to wait for 28 days after recovering from Covid-19 before starting treatment. This is for the safety of you, your embryos, and those around you.
If you test positive after egg collection, any embryos will be frozen, giving time for you to recover before any transfer. Please be assured that frozen embryo transfer now achieves similar or higher success rates than fresh embryo transfer.
Generally, pregnant women do not appear to be more likely to be seriously unwell than other healthy adults if they develop coronavirus.
Majority of pregnant women will experience only mild or moderate cold/flu like symptoms
As this is a very new virus, we are just beginning to learn about it. There is no evidence to suggest an increased risk of miscarriage.
Transmission of the virus from a woman to her baby during pregnancy or birth appears possible. However, this does not seem to cause a problem with the baby’s health after birth
It does not seem that the virus causes problems with a baby’s development during pregnancy.
All available evidence suggests that pregnant women are at the same risks as other healthy adults if they develop coronavirus. Majority of pregnant women experience only mild or moderate cold/flu-like symptoms. Cough, fever, shortness of breath, headache and loss or change to your sense of smell or taste are other relevant symptoms.
If you develop more severe symptoms or your recovery is delayed, this may be a sign that you are developing a more significant infection and need specialised care. Please contact the government helpline or your clinician.
Most women who are more seriously ill are in their third trimester, therefore the importance of social distancing from 28 weeks of pregnancy is more important.
Emerging evidence suggests that transmission from a woman to her baby during pregnancy or birth is probable. It is important to emphasise that in all reported cases of new born babies developing coronavirus very soon after birth, the babies were well. Given current evidence, it is considered unlikely that if you have the virus it would cause problems with your baby’s development.
Across the world, emerging reports suggest some babies have been born prematurely to women who were very unwell with coronavirus. It is unclear whether coronavirus caused these premature births, or whether it was recommended that their babies were born early for the benefit of the women’s health and to enable them to recover.
The most important thing to do is to follow guidelines issued by the government. For pregnant women and the rest of their households, this includes:
Pregnancy in a small proportion of women can alter how your body handles severe viral infections. This is something that obstetricians have known for many years and are used to dealing with. We know that some viral infections are worse in pregnant women; however, all available evidence suggests that pregnant women are at no greater risk of becoming seriously unwell than other healthy adults if they develop coronavirus.
As a precaution, you should follow government advice about social distancing, stay away from public places and avoid anyone who has symptoms suggestive of coronavirus. It is still considered necessary for pregnant women to go for exercise and to attend antenatal appointments.
If you are in your third trimester (more than 28 weeks’ pregnant) you should be particularly attentive to social distancing and minimise any contact with others.
Keeping being active and hydrated as both are important to reduce the risk of blood clots in pregnancy. Take supplements in form of vitamins and minerals to boost your immunity.
Becoming pregnant during the coronavirus pandemic is a matter of personal choice. However, it is recommended that when considering a pregnancy, women and their partners consider the risks of coronavirus transmission associated with routine contacts with healthcare professionals during pregnancy, particularly if pregnancy complications may necessitate frequent hospital attendance.
The changes adopted during the pandemic are with the following aims:
These changes are a way of ensuring we deliver the best care without overloading our services, as well prevent your exposure to the risk of other people which are crucial during the coronavirus pandemic. Your safety is our first priority.
Incidence of PCOS in women in the reproductive age group is between 5 to 15%. In women presenting with infertility the incidence is about 30% and of all women attending gynecological clinics with irregular menstruation along with oligo/anovulation, more than 90% have PCOS. It is important to set proper criteria to diagnose PCOS with certainty so that the health risk of these women can be assessed and follow-up plans instituted.
With a better understanding of the condition, the criteria for diagnosis of PCOS have been changing from time to time. The NIH/NICHD consensus conference defined this symptom complex in 1990, the Rotterdam PCOS consensus group redefined it in 2003 and the androgen excess PCOS Society again defined it in 2006. However, the emphasis remained to classify PCOS in a way that the high-health-risk group could be identified from the lower-health-risk group so that more vigorous follow-up and management could be assigned to the high-risk category of PCOS women. The androgen-excess PCOS society labeled androgen access as the biggest indicator of high risk for metabolic diseases in PCOS women.
Manifestations of PCOS may start in adolescence and stay with a woman through life or may start even later in life. A woman with PCOS may require special care as well as medical management of different sets of problems, which keep arising at different stages of life. Accordingly, health issues and concerns can be addressed for PCOS women by prioritizing symptom complexes that occur with higher frequency at different stages of life. The 3 important stages requiring the identification and management of PCOS women are as follows.
Adolescent PCOS:
This is a transitional stage of physical and psychological development in a girl’s life which exists between puberty and adulthood. Signs and symptoms of PCOS overlap the physiological changes of puberty. All criteria set by various bodies for diagnosis of PCOS, pose a problem when applied to adolescent girls. To diagnose PCOS in adolescence all the 3 criteria described by the Rotterdam consensus must be met with, which means the presence of anovulatory cycles, clinical or biochemical hyperandrogenism, and the appearance of polycystic ovaries. Having 2 features out of the 3 as defined by the Rotterdam consensus group to define an adult woman with PCOS, are not enough to classify an adolescent girl as having PCOS. Post puberty, the pituitary ovarian axis is still stabilizing in this group of young girls, which may correct itself as the hypothalamic-pituitary-ovarian axis matures. Often these girls present with phases of amenorrhea followed by abnormal uterine bleeding for two to three years post-menarche. Moderate to severe hirsutism with or without acne indicates hyper androgenic even though acne with mild hirsutism is commonly seen in most young adolescent girls. Ovaries may show a multi-cystic appearance around puberty with some similarity to polycystic ovarian appearance which does not qualify them as PCOS. However, scanning after eight years post-menarche still showing PCOS ovaries makes it a diagnostic criterion for a definite diagnosis of PCOS. We can reserve the confirmation of her diagnosis to a later date but must start to treat this young girl based on her symptoms, especially the menstrual abnormalities.
Investigations:
The test required in PCOS girls before the diagnosis is made are different from those which are used for long-term follow-up of these PCOS girls
Clinical feature of hirsutism or assessment of total/free testosterone levels in the absence of hirsutism.
17 hydroxy progesterone and DHEAS levels must be assessed in severe cases of hirsutism to rule out other causes.
Serum progesterone 3 to 4 weeks following menstruation to confirm ovulation. Pelvic ultrasonography to see the polycystic appearance and size of the ovary with endometrial thickness assessment, especially in cases where there are periods of amenorrhea or continuous episodes of bleeding.
FSH, LH, thyroid profile, and serum prolactin are recommended especially in cases of amenorrhea with withdrawal bleeding or oligomenorrhea. However, when in doubt of diagnosis assessment of serum AMH can be done.
These should be assessed right from the suspicion of the diagnosis of PCOS at any stage in a girl’s life.
Apart from weight assessment looking out for signs of acanthosis nigricans with possibly associated HAIR-AN syndrome (hyperandrogenism, insulin resistance, acanthosis nigricans), oral glucose tolerance test (OGTT) and lipid profile is important in these girls especially if overweight.
Follow-up investigations: Once the diagnosis of PCOS is confirmed we need to follow these girls with OGTT and lipid profile yearly with weight and blood pressure monitoring from time to time. Other hormonal tests are only done whenever deemed necessary based on the development of new symptoms or need-based such as fertility or menstrual issues.
Definitive diagnosis of PCOS is not necessary to initiate treatment in adolescence as treatment may decrease the risk of future comorbidity even in the absence of a definite diagnosis. Therefore, in cases of menstrual symptoms especially excessive and intermittent bleeding one can resort to cyclical progestogens till the bleeding stops and then either continue progestogens cyclically or switch over to combined oral contraceptive pills (COCs) especially if hirsutism is also a concern. COCs containing anti-androgens like cyproterone-acetate or drospirenone are preferable progestogens which also act as anti-androgens and appear to resolve hirsutism faster. These may be continued for a minimum of six months to be able to demonstrate any beneficial effects on hirsutism and can be continued for several years with or without palliative treatment to suppress hirsutism and acne.
: It is important to establish the diagnosis of PCOS recommended either by the Rotterdam’s consensus group or the criteria laid by the AE-PCOS society.
Fertility issues in PCOS are generally resolved by induction of ovulation. Obesity coupled with insulin resistance is a common occurrence in women with PCOS which also contributes to their ovulatory disorder. Lifestyle modification is particularly important in treating women with oligo ovulation or anovulation, not only to improve their ovulatory performance but also to reduce the metabolic consequences of the syndrome. A modest loss of 5% to 10% of total body weight leads to a 30% reduction of central fat, with improvement in insulin sensitivity, and helps to restore ovulation to some extent. Weight loss should be encouraged prior to ovulation induction treatment.
Once we decide to start ovulation induction, we need to ensure that the endometrium is normal, as hyperplastic endometrium is very commonly seen in these irregularly menstruating PCOS women. If endometrial thickness is found to be 4 mm or less during menstruation, one can start with ovulation induction with oral ovules as the first-line treatment for ovulation. If oral ovules do not lead to successful ovulation or fail to establish a pregnancy despite 5 to 6 ovulatory cycles, injectable gonadotropins are recommended. However, injectable gonadotropins are to be used with utmost caution and very judiciously as these women with PCOS tend to get hyper-stimulated in response to even small doses of gonadotropin. The starting doses should be as low as 50 to 75 international units, with small increments in doses of 12.5 to 25 units every 5 to 7 days. The number of days taken for a dominant follicle to emerge does not appear to change the outcome in terms of successful ovulation or achieving pregnancy in these PCOS women. Ovarian hyperstimulation syndrome (OHSS) occurs very commonly in these women and must be prevented in all instances. If more than two dominant follicles form in response to induction of ovulation, sexual contact during ovulation must be avoided to prevent the risk of 0HSS as well as that of multiple pregnancies. Sometimes, resorting to ovarian drilling also helps in resuming ovulation in PCOS women who do not ovulate easily or tend to over-stimulate with various methods of ovulation induction. Insulin sensitizers as well as inositols have also been recommended as adjuvants to ovulation-inducing drugs in the context of oligo ovulatory PCOS. However, despite ovulation with any of the above agents if pregnancy fails to occur, we may have to resort to in vitro fertilization (IVF).
Once a woman with PCOS has crossed adolescent problems and overcome her fertility issues. She remains almost lifelong in the high-risk group for medical issues which, are commonly encountered in men and women with metabolic syndrome. Historically, the treatment of PCOS was short-term and mainly under the domain of a gynecologist and dermatologist. Oral contraceptives were given for irregular menstruation, anti-androgens for hirsutism, and ovulation induction for infertility. In recent years, a lot of research has gone into this syndrome, and these women have been linked to having a higher risk for metabolic complications. In PCOS women the commonly encountered problems are obesity, impaired glucose tolerance test (OGTT), hypertension, cardiovascular disease, hyperlipidemia, obstructive sleep apnoea, and non-alcoholic fatty liver disease NAFLD.
Besides the metabolic complications endometrial hyperplasia and endometrial carcinoma is a real threat to these irregularly menstruating PCOS women. Although adverse health consequences associated with PCOS are formidable and many folds, regrettably most women and clinicians are not aware of these risks. The recommendation is that PCOS should be viewed as a chronic condition that requires longitudinal treatment perspectives.
Screening consists of monitoring blood pressure, BMI (weight in kilograms divided by height in meters square), waist circumference, OGTT, and lipid profile. These need to be followed up every six months for PCOS women with borderline risk and annually for women with normal profiles. The prevalence of NAFLD in PCOS women is approximately 15 to 60%. However, even though routine screening is not suggested, it is important to be aware of this condition, especially in obese PCOS with insulin resistance to be able to carry out appropriate screening with assessment with SGOT and SGPT whenever required.
The most important component for the prevention of metabolic consequences is by keeping one’s weight under control through lifestyle modifications. However, one must have realistic expectations for weight loss. The minimum weight reduction to have any beneficial effect on health statistics would only be if one is able to lose 5% to 10% of the weight. Dietary modifications are important and a reduction of 30% of calorie intake means a 500 to 750 kcal reduction per day. If this can be achieved and maintained, it may lead to the desired weight loss. Physical activity of moderate to intense exercise of at least 150 minutes per week is recommended. Drugs to help reduce weight such as metformin or orlistat have been used in addition to lifestyle modification. This is possibly most beneficial in the high-risk obese group which is prone to developing metabolic syndrome. A multi-disciplinary approach may be needed to treat such PCOS women constituting a diabetologist, endocrinologist, cardiologist, and gastroenterologist for the manifold presentations of these women with metabolic syndrome.
There is a 2 to 6-fold increased risk of endometrial cancer in women with PCOS, which often presents before menopause. Even one episode of prolonged or heavy bleeding warrants ultrasound for endometrial thickness in these women. Healthcare professionals should have a low threshold for investigation of endometrial cancer in women with PCOS for which endometrial aspiration with histopathology is important. Transvaginal ultrasound for endometrial thickness followed by endometrial biopsy is recommended if persistently thick endometrium is seen on ultrasound or there is abnormal vaginal bleeding following amenorrhea. It is suggested to use progestin therapy in PCOS women with cycles longer than 90 days leading to at least 4 menstrual episodes in one year, resulting from progesterone withdrawal to prevent the risk of endometrial cancers.
Diagnosis of PCOS in adolescents should have all three diagnostic criteria met at least 2 to 3 years after menarche. Treatment for menstrual irregularity and or hyperandrogenism should start even in the absence of confirmation of the diagnosis of PCOS. Combined OCP or progestin can continue through reproductive life with regular follow-up for adverse effects of these drugs. Approximately 70% of PCOS women have fertility issues mainly due to scanty ovulation and the first line treatment is to induce ovulation with oral ovules. If these fail to induce ovulation, then gonadotropins are recommended under expert monitoring as these can lead to OHSS and multiple pregnancies. Ovarian drilling is an option for a few patients only presenting with infertility. is the IVF last option for these PCOS women if they fail to conceive with all the above treatments. There is a need to follow all PCOS with metabolic issues and treated them accordingly. There is a two to six-fold higher incidence of endometrial hyperplasia and cancer so screening is a must for women if they do not enter menopause.
low sperm counts,
It is commonly encountered problems by gynaecologist
Questions faced by gynaecologist while treating infertile couples with semen abnormalities.
The ideal abstinence interval suggested by World Health Organisation (WHO) before semen is given for testing is between 2 to 7 days. There is some impact of ejaculatory abstinence on semen analysis parameters which has been reviewed in various studies. It has been seen that longer abstinence is associated with increase in semen volume and count. However, effect of abstinence or motility, morphology, and DNA fragmentation rate are contradictory and inconclusive. Nevertheless, a trend appears towards improvement in these para metres with shorter abstinence. It is also important to note that the first fraction of an ejaculation is the most effective part for conception as the sperms are more numerous, move more and present better-quality DNA than those which come through the second ejaculate. Even in men suffering from an-ejaculation (it is the pathological inability to ejaculate in men with or without orgasm) first ejaculation obtained by electro ejaculation is much better than the quality of the second electro ejaculation. Therefore, it is obvious that repeated procedures of sperm collection by electro ejaculation are not justified for improving the sperm quality in an-ejaculatory neurologically intact men.
When we see several different reports from good laboratories it may become difficult to decide which report to believe as correct. This becomes more important if one report shows normal semen parameters and the other sub-normal. It is important to note what is written in the column of morphological characteristic of sperms. Generally, more than 4% of normal sperms constitute a morphologically normal semen sample. If we find a technician who has reported 80% of normal forms or even 30% of normal sperms it indicates that the technique of doing the semen analysis is not the standard technique or the technician is not trained adequately to do a semen analysis. Most of the laboratories have technicians who have good experience in blood and urine testing but are very poorly trained regarding semen analysis which is quite different from the above two. Mostly technicians working in fertility centres which offer semen analysis, are more proficient in the assessment of semen samples. A beautifully typed report from a leading laboratory does not qualify the report to be correct.
Normal semen analysis which was redefined by WHO in 2010 shows differences from the standard semen para metres which were followed earlier ever since the reference values were defined by WHO in 1998. The semen volume from 2 ml to 1.5 ML is now considered normal, sperm concentration of 15 million/ml from 20 million/ml and progressive motility now of 32% instead of 50% is now redefined by WHO as normal. Sperm morphology 4% or above is considered normal and is generally not above 14% to 20%.
Whenever an infertile couple comes, and the man carries a semen analysis report which shows mild oligo-astheno-terato-zoospermia (OATs) along with an ultrasound report showing grade 1 varicocele how should we proceed. If the varicocele is only demonstrated by ultrasound on standing and coughing and not palpable clinically then it is grade 1, and a case of subclinical varicocele which is defined as a non-palpable enlargement of the venous plexus of the spermatic cord which can be diagnosed only by imaging techniques. No surgical repair is recommended in such case, as studies have shown that, there is no increase in the sperm parameters nor in the pregnancy rate post operatively. Diagnosis of varicocele which is can easily be made by physical examination of scrotal palpation in upright position or in lying down position is truly clinical varicocele and comes under grade 2 and 3 respectively. These are the cases which may sometimes benefit from surgical varicocelectomy hence needs to be referred either to a urologist or infertility/IVF specialist.
Azoospermia is defined as ‘absence of spermatozoa in the sediment of a centrifuged semen sample of a man’ and crypto-zoospermia is as ‘extremely low spermatozoa concentration (≤1 million/mL) in the ejaculate of a man’ according to WHO. These situations are generally diagnosed during a routine male infertility investigation. Azoospermia is seen approximately in 1% of the male population and may be as high as 20% among male infertility cases.
The first thing to be noted from the semen analysis report is the volume of the semen. If this is found lower than normal one needs to rule out history of spillage of the sample while collection. If there has been no history of spillage, the pathological causes of low semen volume are many, such as retrograde ejaculation, an-ejaculations, and hypogonadism. Even anatomical causes contribute to low semen volume such as ejaculatory duct obstruction or congenital absence of the vas/seminal vesicles which can be ruled out by further investigations, for which the man needs to be referred to a urologist/andrologist. If this was not the case, then a repeat semen analysis is recommended after 7 days requesting the laboratory for centrifugation of the sample. If we find sperms in the sediment this is possibly a case of crypto-zoospermia. All these cases of azoospermia or crypto-zoospermia need further investigations and should be referred to an ART clinic.
Obesity is a possible cause of secondary hypogonadism associated infertility in some men. The mechanism by which this happens is as following. Enzyme aromatase is highly expressed in peripheral fat tissue and converts testosterone to oestradiol, causing increased peripheral oestradiol production. High levels of oestradiol inhibit secretion of LH and FSH from the pituitary by negative feedback mechanism. Reduced levels of LH and FSH in turn lead to a reduction in testosterone synthesis and sperm production leading to infertility. To counteract the physiological effect of elevated oestradiol, use of aromatase inhibitors have seen to normalise serum testosterone by stopping its conversion to oestradiol thus its effect on spermatogenesis. The commonly available aromatase inhibitors available are letrozole which is used in doses of 2.5 mg/day or anastrozole given in the doses of 1 mg/day for a period of 3 to 6 months. Generally, with the use of aromatase inhibitors the serum oestradiol levels fall, and the total testosterone levels increase and so does sperm concentration.
Antioxidants are extensively used in the treatment of subnormal semen para metres in male subfertility. There are many vitamins and micronutrients used as antioxidants in practice. One of the most used antioxidants is vitamin C which is found in abundance in the semen of fertile men. It is known to protect sperm’s DNA from free radical damage by virtue of which it improves sperm quality. It is given in doses of 1000 milligrams per day orally for 3 to 6 months. Vitamin E protects sperm cell membrane from damage therefore improve sperm motility and is used at a dosage of 600 mg per day for 3 to 6 months. Other micronutrients like selenium is used as 200 µg a day, glutathione 400 mg per day, and L-acetyl cysteine 3 g per day to increase sperm concentration and sperm motility. Lot of controversy exists regarding long term use of antioxidants. Recent clinical trials have shown that antioxidants do not appear to improve semen para metres or DNA fragmentation among men with male factor infertility. Therefore, limited and judicious use of these drugs is recommended in male infertility and if no improvement is seen in semen parameters in 3 to 4 months or a pregnancy does not occur within 6 months, one must resort to methods of ART to assist in conception.
To conclude, it is important to remember that there is limited role of medical management in male infertility. What a gynaecologist needs to know is to be able to recognise a sub-normal semen report and to know with certainty when to refer the patient further to an ART clinic or andrologist. However, there are conditions causing subfertility in men which can be managed medically and should be treated before referring the patient to a specialist. Nevertheless, there are a few more conditions like male accessory gland infections (MAGI) and hypo-gonadotropic hypogonadism in men which can be treated success fully by medical management but require either a good local genital examination or hormonal and genetic workup, respectively. These patients need to be referred further without wasting time so that they get the correct treatment and their families can be completed within a stipulated time frame.
Series of 18 Cases of Clomiphene Resistant Anovulatory Women with Polycystic Ovary Syndrome and Altered Response to FSH Stimulation.
We report a case series of 18 such PCOS women selected from 100 CC resistant women undergoing r-FSH stimulation with the purpose of ovulation induction.
All patients presented to the outpatient department where their clinical examination was done by a clinician which included measurement of body weight, height, waist and hip circumferences and blood pressure. Height and weight were measured with subjects in light clothes and without shoes, using a standard apparatus. Weight was measured on a calibrated beam scale. The height and WC were measured to the nearest 0.5 cm with a measuring tape. Waist was measured midway between the lower rib margin and the iliac crest at the end of a gentle expiration. BMI was calculated as the weight in kg divided by the height in meters squared (kg/m2 ).
For biochemical and hormonal measurements, overnight fasting blood samples were taken from each subject. Oral glucose tolerance test was done by drawing blood in EDTA-treated test tubes in fasting status and then after 2 h of ingesting 75 g of glucose, by an enzymatic colorimetric method with hexokinase. Lipid measurements including total cholesterol (TC), triglycerides (TGs) and HDL-C were obtained using commercial assay kits. TGs were assayed using enzymatic colorimetric tests using triglycerides GPO blank. Luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and serum estradiol were measured by chemiluminescence method by Diasorin, LIAISON, Italy. AMH was measured by chemiluminscene method using Beckmancoulter kit.
All study subject’s follicular growth were monitored by transvaginal ultrasound scans LOGIQ P5GE Healthcare with 6.5 MHz trans-vaginal transducer and all scans were performed and assessed by a single sonographer. Ultrasound was performed till adequate follicular growth was obtained.
In all these CC resistant cases, ovulation induction was started with injection of r-FSH 50/75 IU which was increased by 25 units every 5 to 7 days according to low dose step up protocol. Follicular response was monitored by serum estradiol (E2) levels and ultrasound (USG) follicle monitoring (FM). 18 PCOS were selected from this cohort of women as they showed no ovulatory response in terms of rise in serum E2 levels (at least rise of 30 pg/ml from baseline serum estradiol levels (20-80 pg/ ml) or presence of a follicle of 13 mm or larger, even after 18-25 days of stimulation with incremental doses of r-FSH of up to 150 IU.
These women were labeled as ‘FSH resistant PCOS’ and were further stimulated with high doses of injection hMG (Humog Bharat Serum, India). The starting dose of hMG was 150 units which were subsequently increased to 225 units if there was no response after 6 days in terms of rise in S. E2 and USG evidence for dominant follicle. Surprisingly all patient responded or hyper responded within 10 days of stimulation.
We looked for characteristics common to this subset of PCOS women so that we could possibly identify these FSH resistant PCOS’ in advance and treat them differently from the beginning. Phenotypic, laboratory and ultrasound features were noted. These included age, BMI, waist circumference (WC), oral glucose tolerance test (OGTT), triglyceride (TG) levels, AMH, basal FSH, basal LH, ovarian volume and AFC. All these women has clinical features of hyper-androgenism hence testosterone levels were not tested. Observations were made for this subset of women and all of them had almost equal characteristics in terms of high BMI and WC, very high AMH and high ovarian volume with AFC. Interestingly, no patient was a LH hypersecretor.
Therefore, it appears there exists a definite group of anovulatory PCOS, who appear to be resistant to ovulation induction when treated with small doses of FSH alone for the purpose of ovulation induction. There are 2 possible explanations to this resistance to injection rFSH when given in low doses for the purpose of ovulation induction. Firstly, very high levels of AMH have an inhibitory effect on follicular recruitment under the influence of exogenous FSH. Addition of LH possibly increases follicular sensitivity of granulosa cells by increasing FSH receptors on them so that they could respond to lower doses of FSH which are used for ovulation induction in non IVF cycles. Therefore, it appears addition of LH may help to overcome resistance of follicular recruitment by FSH alone, which is a known possibility in PCOS women with concomitant high levels of AMH. The second explanation for FSH resistance observed could be presence of FSH receptor polymorphism which makes the follicles resistant to lower doses of FSH. To overcome this receptor polymorphism one may require higher doses of FSH to be able to go above the serum threshold levels of FSH required to select dominant follicles. It is well researched that frequency of FSH-R Ser680 variant is high in hypo-responders and consumption of FSH is higher in carriers of this polymorphism. It is also interesting to note that ovarian stimulation for IVF where higher doses of FSH are used at the initiation for controlled ovarian stimulation, may overcome both of these inhibitory effects, whether it is the inhibitory effect of high AMH on follicular growth or the FSH receptor polymorphism.
|
S. No.
|
Characterstics
|
Min
|
Max
|
Mean
|
SD
|
Normal physiological index
|
|---|---|---|---|---|---|---|
|
1
|
BMI (kg/m2)
|
29
|
36
|
33
|
3.32
|
18-24.9
|
|
2
|
WC (cm)
|
98
|
124
|
108
|
5.0
|
<80
|
|
3
|
AMH (pmol/L)
|
60
|
145
|
106
|
37.7
|
7.7-22.5
|
|
4
|
FSH (mIU/ml)
|
4
|
8
|
5.6
|
1.09
|
3-10
|
|
5
|
LH (mIU/L)
|
3.3
|
12
|
6.4
|
6.12
|
3-10
|
|
6
|
Oral GTT (2 h value)
|
151
|
198
|
178
|
13.47
|
<140
|
|
7
|
Lipid profile (TG in mg/dl)
|
170
|
220
|
193
|
14.27
|
<150
|
|
8
|
Ovarian volume (cc)
|
12
|
21
|
18
|
3.7
|
3-10
|
|
9
|
Antral Follicle Count
|
30
|
56
|
42
|
10.17
|
5-10 (in each ovary)
|
By using monkey as an experimental model, it has been found that alternation of DNA methylation patterns might lead non-human primates predispose to polycystic ovary syndrome (PCOS). In addition, in granulosa cells that derived from patients, 12245 differential methylated CpG sites were detected in the PCOS groups, which suggested that loci specific and/or global DNA methylation alteration may play a direct role in the initiation and development process of PCOS. Since DNA methyl-transferase (DNMTs) are the major enzymes for the depositing and protection of DNA methylation and some other histone modifiers also play a role for the maintenance of DNA methylation at specific loci aberrant express of these enzymes may also trigger the occurrence of PCOS in humans. Therefore, study the expression levels and catalytic activity of these enzymes may create a new direction for the investigation of PCOS and shed light on the further treatment of this disorder.
A subset of obese PCOS with very high AMH levels who otherwise appear to be severe hyper-responders may require the addition of LH to higher doses of FSH for inducing ovulation, possibly because of presence of FSH receptor resistance or polymorphism.
1. Weenen C, Laven JS, Von Bergh AR, Cranfield M, Groome NP, et al. (2004) Anti-Mullerian hormone expression pattern in the human ovary: Potential implications for initial and cyclic follicle recruitment. Molecular Human Reproduction 10: 77-83.
2. Tajima K, Orisaka M, Mori T, Kotsuji F (2007) Ovarian theca cells in follicular function. Reprod Biomed Online 15: 591-609.
3. Alviggi C, Humaidan P (2013) A common polymorphic allele of the LH betasubunit gene is associated with higher exogenous FSH consumption during controlled ovarian stimulation for assisted reproductive technology. Reprod Biol Endocrinol 11: 51.
4. Xu N, Kwon S, Abbott DH, Geller DH, Dumesic DA, et al. (2011) Epigenetic mechanism underlying the development of polycystic ovary syndrome (PCOS)- like phenotypes in prenatally androgenized rhesus monkeys. PLoS One 6:e27286.
5. Xu J, Bao X, Peng Z, Wang L, Du L, et al. (2016) Comprehensive analysis of genome-wide DNA methylation across human polycystic ovary syndrome ovary granulosa cell. Oncotarget 7: 27899-27909.
6. Okano M, Bell DW, Haber DA, Li E (1999) DNAmethyl-transferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99:247-57.
7. Bird A (2002) DNA methylation patterns and epigenetic memory. Genes Dev 16: 6-21.
8. Zhang T, Termanis A, Özkan B, Bao XX, Culley J, et al. (2016) G9a/GLP complex maintains imprinted DNA methylation in embryonic stem cells. Cell Rep 15:77-85.
Tejshree Singh, MBBS, CPSDGO, MD, DNB*, Abha Majumdar, MBBS, MS, FICS**
*Consultant Infertility Unit, Department of Obstetrics and Gynaecology, Kolmet Hospital & Research Centre, New Delhi, India
**Senior Consultant and Head of the Unit of IVF and Human Reproduction, Department of Obstetrics and Gynaecology
Subjects and Methods Results To compare the efficacy and tolerability of freeze-dried and liquid formulations of urinary human chorionic gonadotropin (hCG) for inducing final oocyte maturation and triggering ovulation.
In a randomized, single-centre study, infertile women (n=100) received single injections of urinary hCG (5000 IU) from reconstituted freeze-dried (1.0 mL of 5000 IU /mL) and liquid (0.5 mL of 5000 IU /0.5 mL) formulations in random order, when their ultrasounds showed one or more dominant follicles of size 18mm or above. Blood samples were taken after 36h for determination of hCG concentration by immunoassay using direct chemilluminometric technology. Follicular rupture was assessed by means of another ultrasound undertaken 48h following the injection of hCG and serum progesterone levels undertaken 8 days later
The mean serum hCG levels achieved 36 hours post hCG injection were 74.05 mIU/ml for the freeze-dried formulation and 69.65 mIU/ml for the liquid formulation. The mean difference between these levels was 4.400 (95%confidence interval -19.002 to 10.202) which is statistically not significant (p-value 0.545). These levels were equally effective for triggering ovulation. The mean serum progesterone levels achieved day 8 post hCG, were 8.452 ng/ml for the freeze-dried formulation and 8.228 ng/ml for the liquid formulation. Both formulations were tolerated well; the liquid formulation of hCG was associated with fewer adverse effects.
The levels of hCG required to trigger follicular rupture are anywhere between 20 to 45 mIU/ml. As ovulation will happen about 36-48 hours after the injection of hCG, procedures can be scheduled to take advantage of this time sequence.
The liquid formulation of recombinant hCG was shown to be bioequivalent to the freeze-dried formulation, with the same efficacy and no clinically significant differences in tolerability.
Our study shows that the liquid formulation of urinary hCG provides the same efficacy as the freeze-dried formulation when used to trigger final follicular rupture, is convenient to use and has better tolerability.
Preimplantation genetic screening for all 24 chromosomes by microarray comparative genomic hybridization significantly increases implantation rates and clinical pregnancy rates in patients undergoing in vitro fertilization with poor prognosis
ABSTRACT
CONTEXT: A majority of human embryos produced in vitro are aneuploid, especially in couples undergoing in vitro fertilization (IVF) with poor prognosis. Preimplantation genetic screening (PGS) for all 24 chromosomes has the potential to select the most euploid embryos for transfer in such cases. AIM: To study the efficacy of PGS for all 24 chromosomes by microarray comparative genomic hybridization (array CGH) in Indian couples undergoing IVF cycles with poor prognosis. SETTINGS AND DESIGN: A retrospective, case – control study was undertaken in an institution based tertiary care IVF center to compare the clinical outcomes of twenty patients, who underwent 21 PGS cycles with poor prognosis, with 128 non PGS patients in the control group, with the same inclusion criterion as for the PGS group. MATERIALS AND METHODS: Single cells were obtained by laser assisted embryo biopsy from day 3 embryos and subsequently analyzed by array CGH for all 24 chromosomes. Once the array CGH results were available on the morning of day 5, only chromosomally normal embryos that had progressed to blastocyst stage were transferred. RESULTS: The implantation rate and clinical pregnancy rate (PR) per transfer were found to be significantly higher in the PGS group than in the control group (63.2% vs. 26.2%, P = 0.001 and 73.3% vs. 36.7%, P = 0.006, respectively), while the multiple PRs sharply declined from 31.9% to 9.1% in the PGS group. CONCLUSIONS: In this pilot study, we have shown that PGS by array CGH can improve the clinical outcome in patients undergoing IVF with poor prognosis
INTRODUCTION
The last decade has seen a focused and persistent effort toward developing means and technologies to identify embryos that are most likely to implant and grow till term resulting in the birth of a healthy live baby. At present, morphology evaluation is the mainstay of embryo selection since it is noninvasive and easy to perform. However, it has not proved to be a very efficient method for selecting embryos since implantation rates and clinical pregnancy rates (PR) per transferred embryo continue to be very low. Among many factors, one major reason for poor reproductive potential of embryos generated in vitro is the prevalence of aneuploidies in such embryos. The rate of aneuploidy rises with increasing maternal age] but it is only moderately associated with morphology. Therefore, a significant percentage of even the “most ideal†embryos selected for transfer will be aneuploid, resulting in poor reproductive outcome. Moreover, transferring aneuploid embryos can be potentially dangerous since aneuploidy is the most common cause of miscarriage and the most common genetic abnormality in embryos. Preimplantation genetic screening (PGS), even though highly invasive in nature, started out as a very promising concept allowing embryos to be screened for aneuploidies before being selected for transfer. However, this older version of PGS failed to live up to expectations, as numerous authors failed to show improvement in in vitro fertilization (IVF) outcomes with PGS using fluorescence in situ hybridization (FISH), in which chromosomal analysis of not all but only a few chromosomes was performed. With the advent of new validated platforms for comprehensive chromosomal screening (CCS) such as single nucleotide polymorphism array, microarray comparative genomic hybridization (array CGH), and quantitative polymerase chain reaction (PCR), capable of analyzing all 24 chromosomes, now an improved version of PGS involving 24 chromosome copy number analysis is being expected to be a likely remedy for the earlier shortcomings. This retrospective case–control study seeks to examine the efficacy of PGS applied to poor prognosis patients, given the relative paucity of information concerning the use of modern 24 chromosome copy number analysis for this patient group. The objectives of this study were to establish the incidence of aneuploidy in such patients undergoing IVF with poor prognosis and to undertake a retrospective comparative analysis of the clinical outcomes of these patients undergoing IVF PGS cycles with non PGS, IVF controls.
ABSTRACT
OBJECTIVE: To study the prevalence of metabolic syndrome (MBS) in Indian women and to see how does it correlate to body mass index (BMI) and polycystic ovarian syndrome (PCOS) in this population. STUDY DESIGN: Prospective cross sectional observational study. SETTING: Infertility clinic of a tertiary center. MATERIALS AND METHODS: Two hundred women, 120 with PCOs and 80 age-matched controls were enrolled. The prevalence of MBS was studied in the women with and without and was co related to BMI by further subgrouping as team (BMI 23 kg/m2). The sample size was: team controls-40, obese controls-40, team PCOS80. Each subject underwent a physical examination and laboratory evaluation for the diagnosis of MBS, which was defined according to the guidelines of National Cholesterol Education Program Adult Treatment Pamel (NCEP ATP III) 2005. INTERVENTION: None. MAIN OUTCOME MEASURES: Main Outcome Measures: Subjects with and without PCOs were compared with each other for the prevalence of MBS, and similarly team subjects were compared with obese subjects. Receiver operator characteristic (ROC) curves were obtained for both the PCOS and non PCOS population separately, co-relating the prevalence of MBS with BMI. These ROC curves were used to establish the cut off values of BMI, which could best predict the risk of MBS. RESULTS: The prevalence of MBS was significantly higher in the women with PCOS, as compared to age matched controls. Similarly, when BMI was considered, MBS was more prevalent in overweight subjects than in lean subjects with or without PCOS. In subgroup analysis, the presence of PCOS had a lesser impact on the prevalence of MBS as compared to non PCOS controls with higher BMI. The relative risk of MBS increased as follows: lean controls 1, lean PCOS 2.66, obese controls 5.33, and obese PCOS 6.5. The most appropriate cut off level of BMI for predicting the risk of MBS in Indian women without PCOS seems to be 23 kg/m2 , whereas, with PCOS, it was 22.5 kg/m2 . CONCLUSION: MBS is more prevalent in women with PCOS. However, obesity is an independent and stronger risk factor for developing MBS. To reduce the risk of MBS and its related long term health consequences, lifestyle modification is advisable above BMI of 23 kg/m2 in the normal population and 22.5 kg/m2 in women with PCOS.
INTRODUCTION
Polycystic ovarian syndrome (PCOS) is common disorder, affecting approximately 5-10% of the women in reproductive age group.[1,2] It is characterized by chronic anovulation, hyperandrogenism, and polycystic ovaries. The other metabolic abnormalities associated with PCOS are obesity, dyslipidemia, insulin resistance, glucose intolerance, and hypertension, which confer an increased risk of long term health consequences such as type II diabetes mellitus and cardiovascular risk.[3] Most of these metabolic features are also shared by the syndrome X or metabolic syndrome (MBS), which is associated with atherosclerosis, hypertension, dyslipidemia, coronary artery disease, and diabetes. Some of the factors affecting the prevalence of MBS are age,[4,5] obesity,[4] insulin resistance,[6] and underlying PCOS.[7a] Till date, there are few studies, mainly from the American population[8 10] and still fewer from the European continent,[11,12] which have addressed the prevalence of MBS in women with PCOS. There is a scarcity of data from Asian population.[13,14] Moreover, in most of these studies, the women with PCOS were found to have a higher body mass index (BMI) and waist circumference, as compared to the controls, which could have confounded in the higher prevalence of MBS. This study was undertaken with an aim of comparing the prevalence and different characteristics of MBS in Indian women with PCOS and age matched controls. To negate the confounding effect of the high BMI associated with PCOS, subgroups of lean and obese women were studied separately for the prevalence of MBS. In order to reduce the serious long term consequences related to MBS, we have attempted to find out the predictors of MBS, and the action points, at which screening for MBS and lifestyle modification would be beneficial, in respect to preventing, or modifying long term morbidity.
Over the last three and a half decades after the first successful in vitro fertilization (IVF), the technology has been rolling forward in all directions; so that a technique which was once considered the last resort to successful fertility has almost become the first choice. Why is it so? Is IVF flawless, without complications, and has the highest probability of fulfilling ones wish to correct the underlying disorder causing sub-fertility and promote natural conception appear redundant today! One would argue that it is not so; IVF has a flip side-complications, side effects, failures, and financial and emotional exhaustion are all part of it. But then, on the other hand, this technique is truly the only way to parenthood for a lot of medical conditions that cannot be rectified by developments within the scope of drugs and surgery. It is for this sector of patients who crave for a child, who are willing to forfeit the increased risk of congenital abnormality as well as maternal complications imposed by the technology in order to fulfill their dream of parenthood.
Originally, IVF was the only way out for women with blocked or irreparably damaged fallopian tubes. With the advent of intracytoplasmic sperm injection (ICSI), the indications of IVF expanded; initially to severe male factor infertility and then to couples with unexplained infertility. With the development of oocyte and embryo donation as well as surrogacy, the use of IVF could be extended to a lot more couples who would otherwise not have a chance to parent their own child. All these techniques involving use of third party for lending their gametes, embryos, or uteruses have made it possible for women with ovarian failure or premature menopause, couples with no gametes, and for women with absence of a functional uterus respectively to be able to carry a child. Becoming a gestational or true genetic mother has turned into reality for so many desperate mothers. Lately, the technology of oocyte and ovarian tissue freezing for fertility preservation before going through chemotherapy has become another turning point in the life cycle of IVF which now enables women to be able to parent their own child at a later date. Recently, the development of preimplantation genetic diagnosis (PGD) and preimplantation genetic screening (PGS) by testing one cell from “in vitro embryos” has further increased the possibility for couples to have disease free healthy babies.
However, after having said all this about the use and applications of this rapidly advancing technology, we also must understand that human reproduction is a very inefficient process and IVF mirrors this “wastage” at every stage. One in five cycles undertaken to entangle many more desperate couples into IVF who have become old wanting a child and will refuse to see any health risks associated with pregnancies at this age.
The IVF industry is powered by photographs of beautiful babies held by proud parents. Being childless is so traumatic for manythat almost any cost seems worth paying. Indeed, the birth of a desperately wanted child is a priceless miracle for a couple who has otherwise given up all hope. The technology must continue to grow as it is one of the greatest advancement in the field of medicine where “life is created outside the human body”. All we need is good and strong legislation to safeguard mothers as well yields no eggs at all, all retrieved oocytes do not fertilize, and 90% of embryos replaced do not survive. Of those that do, a few result into life-threatening ectopic pregnancies requiring urgent abortion while others miscarry. The number of peri-natal deaths is also double the rate of spontaneous conceptions partly because multiple pregnancies are more common with IVF and often result in premature delivery.
More than a failure is the iatrogenic complications of this technology. Amongst the foremost complications of IVF is the dreaded ovarian hyper-stimulation syndrome (OHSS) which is the direct effect of drugs used for ovarian stimulation and may become a real life threatening hazard. One woman in 12/cycle has mild symptoms, but two in every 100 are so ill that they need hospital admission and intensive care on account of the complications of OHSS. However, the biggest price to be paid cannot just be measured in terms of money or health risks. It is the emotional roller-coaster which goes with drugs used for treatment, egg retrieval, semen collection, embryo replacement, freezing of surplus embryos, and above all, high hopes and crushing disappointment.
At this stage with so many advances happening globally came the role of the middle man who tried to bring a third party to the intending parents. Policymakers, who could foresee and perceive the antecedent exploitation of such developments, restricted the use of third-party reproduction in their jurisdiction and countries. However, a lot of developing countries gave into these newly developed technological advancements, partly because of lack of a regulatory governing body and mostly because of monetary gains. ICSI started being used for all women undergoing IVF, oocyte donation to compensate for sub-optimal standards of IVF clinics, embryo donation for anyone and everyone especially for women of over 50 years of age, surrogacy for social reasons as well as for single fathers and gay couples, oocyte freezing for women wanting to delay pregnancy for personal and professional reasons, and PGD and PGS for sex selection of the unborn baby.
Out of the so many enumerated “misuses” of the technology, there are instances where law has been trying to control the health of women by limiting the age of surrogates to 35 and the age of oocyte donors also to below 35 to maximize the genetic normalcy of the unborn child. Nevertheless, there is no law to limit the age
of a woman wanting to carry a child for her own self by donated oocyte or donated embryo. This presents yet another risk in that even if we were to set aside the exaggerated maternal mortality and morbidity with these older age pregnancies, we also seem to be unfairly deciding the fate of the unborn child by allowing them to be parented by couples who are aged like grandparents and are no longer capable of providing the same care a younger couple is able to provide, the way nature intended it. Who has given us the right to choose the destiny of these children? Or is this another “feather in our cap” which we very proudly advertise as the unborn child who might get entangled in this rut of human race unknowing and unaware of the complications.
INTRODUCTION
Ovulation is the result of a maturation process that occurs within the hypothalamic-pituitary-ovarian (HPO) axis and is orchestrated by a neuroendocrine cascade terminating in the ovaries. Any alteration in this results in a failure to release a mature ovum, leading to anovulatory cycles. Anovulatory disorders may manifest in a variety of clinical presentations, ranging from luteal insufficiency to amenorrhea. Anovulatory disorders account for about 30 to 40 percent of all cases of female infertility. These disorders are generally amongst the most easily diagnosed and most treatable cause of infertility.1 Most of these women have oligomenorrhea, arbitrarily defined as menstruation that occurs at intervals of 35 days to 6 months. While ovulation may occasionally occur, spontaneous conception is unlikely. Therapeutic options have expanded significantly in recent years from clomiphene to gonadotropins. Induction of ovulation in these women is aimed at inducing monofollicular development and subsequent ovulation. Induction of ovulation should be differentiated from stimulation of multiple follicle development in ovulatory women, as is done in association with assisted reproductive technologies. The method of ovulation induction (OI) selected by the clinician should be based upon the underlying cause of anovulation and the efficacy, costs, risks and potential complications associated with each method as they apply to the individual woman. This chapter reviews the common types of anovulation including their pathogenesis, diagnosis and efficacy of the different treatment regimens that are used and our approach to the management of such woman. Some of these disorders are reviewed in greater detail elsewhere in this book.
WORLD HEALTH ORGANIZATION CLASSIFICATION OF ANOVULATION
The clinical approach in management of patients with ovarian dysfunction requires an understanding of its causes. Classification of ovulatory dysfunction based on their cause was originally described by Lunenfeld and lnsler and then by European Society for Human Reproduction and Embryology (ESHRE) and again modified by World Health Organization (WHO). According to WHO, ovulatory dysfunction is classified into three main categories on the basis of menstrual cycle length; oligomenorrhea (menstrual cycles > 35 days) or amenorrhea (menstrual cycle > 6 months) in combination with serum hormonal levels of prolactin (PRL), follicle stimulating hormone (FSH) and estradiol (E2) (Box 1).
WHO CLASS 1
Hypogonadotropic Hypogonadism This group accounts for 5 to 10 percent of anovulation. Women in this group, frequently present with amenorrhea.
Etiology Hypogonadotropic hypogonadism (HH) can be congenital or acquired. Congenital HH is further divided into anosmic HH (Kallmann’s syndrome) and normosmic isolated HH (idiopathic HH). Kallmann’s syndrome itself is a heterogeneous disorder with an X-linked form due to mutations in Kal1 gene (the gene encoding for anosmin-1 protein) and other forms with autosomal transmission. Pathology of idiopathic HH is failure of gonadotropinreleasing hormone (GnRH) neurons in the hypothalamus to differentiate or develop resulting in either lack of or apulsatile GnRH secretion.
The world has witnessed many developments in the field of assisted reproduction since the birth of Louise Brown in 1978, a product of in-vitro fertilization. What has happened in the last thirty-four years or so is a story to be told: A story of realization, discoveries, execution, performance and triumph. Following closely in the heels of this first assisted reproductive technology, were the development and execution of other incredible techniques: freezing of gametes and embryo and their subsequent successful use for reproduction (1983, 1985), pre-implantation genetic diagnosis by embryo biopsy(1990), Intra-cytoplasmic sperm injection (1991), use of testicular sperms from azoospermic males to have them father their own genetic child and cryopreservation of ovarian and testicular tissue in cancer patients for future fertility preservation.
Louise’s birth was not a chance occurrence but a result of years of dedicated research. At the time, achieving an implantation rate of more than 2-3% per embryo transferred was unthinkable. Researchers set upon the task of improving this implantation and thereby the success rate, mainly by focussing on methods to increase oocyte recovery, better culture conditions, improving transfer techniques and luteal support.
Within 20 years, the implantation rates in various laboratories had crossed 15-20%. However, to have the highest pregnancy rates, 3 to 4 embryos were transferred in every IVF cycle. What this meant was that the chances of all embryos implanting and hence leading to multiple births also increased which greatly increased the associated risks of perinatal mortality and morbidity.
Therefore, the focus shifted towards developing methods to improve IVF success rates, while reducing twin and triplet pregnancies. The approach was to develop screening methods to identify the most viable embryo, so that transfer of fewer healthy embryos would result in a higher proportion of singleton pregnancies.
One method used was to prolong culture of embryos in vitro by optimizing culture conditions, so that natural selection of only the more viable embryos (blastocysts day 5 embryo) for transfer came to the fore.
Another way of knowing whether the embryo was robust enough to implant was by checking if it was genetically normal, and this was achieved by biopsying cell/s from the embryo. This cell was then subjected to cytogenetic techniques like FISH to determine aneuploidy; or to molecular techniques like PCR to determine a known point mutation on a particular chromosome.
A third way to pick up the most viable embryo was to check their metabolic health through what is known as “metabolomics”. This involves profiling each embryo based on the quality and quantity of their excretome, as well as by assessing the oxygen uptake by embryos.
What currently seems to be holding the world’s attention is the visual documentation of growth and cleavage-rates of embryos through an incubator-mounted, time lapse camera which is simply termed the “time lapse” or “dynamic morphometric analysis”.
While advances were being made within the embryology lab, exciting changes were also happening in the world of gonadotropins. The urinary gonadotropins were slowly giving way to the self administered, purified, recombinant gonadotropins. Better timing of oocyte retrieval, due to avoidance of pre-mature LH surge, could be attained with the use of GnRH analogues (agonists from 1983 onwards, and antagonists from 1999 onwards). Recently, to ease the pain of daily injections, long acting Gonadotropin injection (elonva), which need only be given once in seven days, has been developed. Also, work is underway to prepare an oral formulation of gonadotropins.
With better stimulation techniques, the ovarian response often over-stepped the desired mark of safety, leading to ovarian-hyper-stimulation syndrome, a life threatening iatrogenic condition. Advancements towards reverting to soft stimulation protocols to lessen the incidence of ovarian hyper-stimulation and yet obtain adequate number of oocytes and embryos to maintain good pregnancy rates are being made.
One of the many controversial areas of assisted reproduction has been cloning. Animal cloning has been achieved by the process of somatic cell nuclear transfer (1996). The same technique has been employed for cloning of human embryos as well (2009). The human fertilization and embryology authority prohibits cloning of human embryos for the purpose of reproduction since it deems to totally bypass nature’s law of sexual reproduction. Whether the first cloned human will ever be born is yet to be known.
For future generations, by working on a background of these achievements, one can only hope that their task of making assisted reproduction more efficient and complication-free, more available to a wider range of patients, and more socially and economically acceptable, would become easier.
