Preliminary study indicates that Resveratrol is effective in correcting PCOS Abnormalities.

Courtesy: www.pexels.com

Clinical pearls:

• Resveratrol in a dose of 1500 mg/day reduced the levels of Testosterone and DHES by 23.1% and 22.1% in a small pilot study of patients with PCOS.
• It also improved the insulin resistance and decreased serum insulin levels significantly.

Resveratrol found in grapes and red wine can help to reverse the hormonal imbalance found in women with PCOS says the results of small pilot study published online October 18,2016 in  The Journal of Clinical Endocrinology& Metabolism.

Polycystic ovary syndrome (PCOS) is a complex endocrine disorder and affects 1 in 15 women worldwide with less than  50% of women diagnosed. [1] It is responsible for 70 percent of infertility issues in women who have difficulty ovulating, per the PCOS Foundation.[2] It has been recognized and diagnosed for 75 years. Genetic and environmental factors play a part in its causation, but the exact etiology remains unknown.

It has a multifactorial etiology that involves genetic, environmental and hormonal imbalance. Androgen excess is clearly the culprit but insulin resistance also plays a major role in its causation. 

Although large number of women with obesity have PCOS, not all obese women have PCOS. Apart from infertility, PCOS is responsible for many chronic conditions. As per NIH, women with PCOS constitute the largest group at risk for developing CVD and Type 2 DM. More than half will be diagnosed with prediabetic or diabetic before the age of 40 years. [3]

Treatment is currently directed at symptoms rather than treating the pathophysiology which remains largely unknown. Lifestyle modification, weight loss and metformin have all shown to decrease androgen, improve insulin sensitivity and bring about ovulation.

Resveratrol is an antioxidant compound found in many foods like dark chocolate, blueberries, raspberries, including peanuts and pistachio beside grapes and red wine.  It is known to have anti-inflammatory and anti-proliferative property well known to cause apoptosis in cancer cells. In 2010 a study by researchers at University of California School of Medicine, Department of Gynecology and Obstetrics, showed that in-vitro animal studies resveratrol could counteract the negative effect of insulin on ovarian cells and preventing excess proliferation of the theca interstitial ovarian cells.

The recent study is a randomized, double-blind, placebo-controlled trial that evaluated the effects of resveratrol over a period of 3 months at Department of Reproductive Medicine, University of California, San Diego, La Jolla, CA.

The study included 34 patients diagnosed with PCOS as per the Rotterdam criteria,[4] each having at least 2 of the following three clinical or chemical hyperandrogenism; oligo- or amenorrhea; and/or polycystic ovaries as viewed by transvaginal ultrasound.

All study participants were evaluated at baseline and after 3 months for BMI, hirsutism, acne score, Insulin levels, OGTT and other metabolic and endocrine abnormalities.

Participants were then randomly assigned to receive either placebo or 1500 mg/day of oral micronized transresveratrol. Over the course of the studies 3 women were lost to follow-up and one became pregnant, so the final analysis includes 15 women in each arm.

The primary endpoint of the study was changes in testosterone levels (T).

It was seen that resveratrol was significantly effective in bringing down the serum testosterone levels in the study group. Women on resveratrol experienced an average of 23.1% decline of total T levels (.53 ng/mL at baseline to 0.41 ng/ml) which was significantly more than what was observed by use of OC pills and metformin (19%)  over a 12-month period.[5] For women in placebo group no change in T levels was seen. Similarly, serum DHES levels decreased by 22.1% for women taking resveratrol (8.05 μmol/L at baseline to 6.26 μmol/L after 3 months).

Resveratrol also decreased the serum fasting insulin levels and exert a positive increase in Insulin Sensitivity Index of by 66%.

“It is apparent that resveratrol significantly reduces serum levels of T and DHEAS, suggesting an effect on ovarian as well as adrenal androgen production” the authors quoted.

In a press releases accompanying the article, the study’s senior author Dr.  Antoni J. Duleba said “Our study is the first clinical trial to find resveratrol significantly lowers PCOS patients’ levels of testosterone as well as dehydroepiandrosterone sulfate (DHEAS), another hormone that the body can convert into testosterone. This nutritional supplement can help moderate the hormone imbalance that is one of the central features of PCOS.”

He also stated the need for more studies before a recommendation can be made for its use in clinical practice.

The authors reported having no relevant conflicts of interest.

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[1] http://www.pcosfoundation.org/what-is-pcos

[2] http://www.pcosfoundation.org/about-pcos

[3] https://prevention.nih.gov/docs/programs/pcos/FinalReport.pdf

[4] Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod. 2004;19:41– 47

[5] Glintborg D, Altinok ML, Mumm H, Hermann AP, Ravn P, Andersen M. Body composition is improved during 12 months’ treatment with metformin alone or combined with oral contraceptives compared with treatment with oral contraceptives in polycystic ovary syndrome. J Clin Endocrinol Metab. 2014;99:2584 –2591

Vitamin D and Human Reproduction—Evolving perspectives

We are all well versed with the role of Vitamin D in maintaining calcium and phosphorus homeostasis and promoting bone mineralization. Its deficiency is linked to many chronic diseases of the cardiovascular and metabolic systems.

Evidence from animal and human studies suggests that vitamin D plays a very important role in human fertility and neonatal development. This steroid hormone has Vitamin D receptors (VDR) at multiple sites in the body including ovary, particularly the granulosa cells, endometrium and placenta.

It plays a very important role in ovarian steroidogenesis. [1] It deficiency contribute to development of insulin resistance and impaired glucose metabolism in patients with Polycystic Ovary Syndrome (PCOS). Therapeutic efficacy of supplementation with Vitamin D to improve insulin resistance, bring about ovulation and regularize menstruation in PCOs patients have been documented.[2] [3]

Observations also shows that lower 25(OH)D levels put women at higher risk of developing uterine fibroids, both in black and white ethnicities. In these women, the growth and size of the fibroid is also directly related to decreased levels of Vitamin D. Animal studies and human in vitro studies have shown the beneficial effect Vitamin D supplementation in inhibition of development and/or growth of uterine fibroids.[4] [5]

A recent study by Harris HR et al demonstrated that women within the highest quintile of Vitamin D blood values have one fourth the risk of developing endometriosis as compared to those in lowest quintile.[6]

It also plays a role in Body Mass Index (BMI) as per a recent meta-analysis, every 10% increase in BMI leads to 4% decrees in Vitamin D concentration.[7]

It’s role in male reproductive physiology is well documented by the fact that it’s level directly correlate with sperm motility and morphology.

As per Hill’s criteria a causal relationship between Vitamin D deficiency and negative outcome in IVF is explained but further research into knowing the magnitude of association is needed.[8]

A systemic review and meta-analysis by Lerchbaum E and Obermayer-Pietsch B published in Eur J Endocrinol May 1, 2012 concludes that Vitamin D plays an important role in Human reproduction and advocates the need of further research in therapeutic benefits of Vitamin D supplementation in such patients.  

Another review by Vanni et al published in the Reproductive Biology and Endocrinology, 2014 emphasizes the importance of supplementation of Vitamin D in IVF settings because consisting evidence documenting the increase incidence of gestational diabetes, IUGR, pre-eclampsia and preterm births in patients deficient in Vitamin D.[9]

The authors opine that although drastic improvements in reproductive failure may not be achieved solely by supplementing Vitamin D, but its addition to any fertility regimen is cheap, effective and without any side effects. It is easily correctable by simple oral supplementation.

Dosage up to 4000 IU is safe, without any side effects and effectively improve maternal vitamin D status. [10]

Results of double blind randomized trial entitled “Vitamin D during IVF” is still awaited.[11]

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[1]Anagnostis P, Karras S, Goulis DG: Vitamin D in human reproduction: a narrative review. Int J Clin Pract. 2013, 67 (3): 225-235

[2] Selimoglu H, Duran C, Kiyici S, Ersoy C, Guclu M, Ozkaya G, Tuncel E, Erturk E, Imamoglu S: The effect of vitamin D replacement therapy on insulin resistance and androgen levels in women with polycystic ovary syndrome. J Endocrinol Invest. 2010, 33 (4): 234-238.

[3] Wehr E, Pieber TR, Obermayer-Pietsch B: Effect of vitamin D3 treatment on glucose metabolism and menstrual frequency in polycystic ovary syndrome women: a pilot study. J Endocrinol Invest. 2011, 34 (10): 757-63.

[4] Bläuer M, Rovio PH, Ylikomi T, Heinonen PK: Vitamin D inhibits myometrial and leiomyoma cell proliferation in vitro. Fertil Steril. 2009, 91 (5): 1919-1925.

[5] Halder SK, Osteen KG, Al-Hendy A: Vitamin D3 inhibits expression and activities of matrix metalloproteinase-2 and −9 in human uterine fibroid cells. Hum Reprod. 2013, 28 (9): 2407-2416.

[6]  Harris HR, Chavarro JE, Malspeis S, Willett WC, Missmer SA: Dairy-food, calcium, magnesium, and vitamin D intake and endometriosis: a prospective cohort study. Am J Epidemiol. 2013, 177 (5): 420-430.

[7] Vimaleswaran KS, Berry DJ, Lu C, Tikkanen E, Pilz S, Kiraki LT, Cooper JD, Dastani Z, Li R, Houston DK, Wood AR, Michaëlsson K, Vandenput L, Zgaga L, Yerges-Armstrong LM, McCarthy MI, Dupuis J, Kaakinen M, Kleber ME, Jameson K, Arden N, Raitakari O, Viikari J, Lohman KK, Ferrucci L, Melhus H, Ingelsson E, Byberg L, Lind L, Lorentzon M, et al: Causal relationship between obesity and vitamin D status: bi-directional Mendelian randomization analysis of multiple cohorts. PLoS Med. 2013, 10 (2): e1001383-

[8] Hill AB: The environment and disease: association or causation?. Proc R Soc Med. 1965, 58: 295-300.

[9] Aghajafari F, Nagulesapillai T, Ronksley PE, Tough SC, O’Beirne M, Rabi DM: Association between maternal serum 25-hydroxyvitamin D level and pregnancy and neonatal outcomes: systematic review and meta-analysis of observational studies. BMJ. 2013, 26 (346): f1169-

[10] Wagner CL, McNeil R, Johnson DD, Husley TC, Ebeling M, Robinson C, Hamilton SA, Hollis BW: Health characteristics and outcomes of two randomized vitamin D supplementation trials during pregnancy: a combined analysis. J Steroid Biochem Mol Biol. 2013, 136: 313-320.

[11] https://clinicaltrials.gov/ct2/show/NCT01019785

da Vinci robotic system saves fertility after reanastomosis following segmental resection of tubal ectopic pregnancy.

Clinical pearls:

• da Vinci-guided reanastomosis after segmental resection of tubal pregnancy is feasible for salvaging tubal patency and fertility in patients with absent or defective contralateral tubal function.

Patients with a single functional fallopian tube can be benefited by use of da Vinci robotic system for segmental resection and end to end reanastomosis of tubal ectopic pregnancy with higher chances of recovering the tubal patency after surgery.

The prevalence of ectopic pregnancy in women attending the emergency department with first trimester pain and bleeding is 6 to 16%.[i] The last CDC statistic quote the prevalence at 20 per 1000 pregnancies while the NHS shows that there are 11,000 ectopic pregnancies in U.K each year. [ii]

The occurrence of ectopic pregnancy in one tube increases the patients chance of getting ectopic in contralateral tube by 6-7-fold because both tube share similar pathology. Conventional option that are in frequent use includes methotrexate (MTX) therapy, salpingotomy, and milking of the ectopic implant. However, these options are not used very commonly due to delay in diagnosis of most ectopic pregnancies. They are diagnosed at a stage when rupture is imminent, thus limiting the use of options that can preserve the tube.

Researchers at the Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea reported results of a retrospective study of 17 patients who underwent segmental resections of tubal pregnancy followed by end-to-end reanastomosis over a period of 1.5 years. The paper was published in the October issue of Journal of Medicine.[iii]

The inclusion criteria for patients in the study are those diagnosed with tubal pregnancy actively seeking to conceive afterwards with stable vital signs, ages under 40 years, those with spontaneous or post-MTX rupture, presence of fetal heartbeat, and serum hCG levels initially over 5000 mIU/mL or elevated hCG levels despite MTX therapy. 

Exclusion criteria were pregnancy very near to corneal end or occupying fimbria, severe pain with tachycardia ,hypotension due to hemoperitoneum greater than 500 mL, size of ectopic pregnancy more than 5 cm and those patients suitable for MTX therapy ( without rupture and  preoperative serum hCG levels of less than 1500 mIU/mL)  as well as those with declining hCG level of more than 50% after 48 hours.

Out of 17 patients initially recruited, 14 patients underwent the procedure with 3 patients had to undergo salpingectomies due to intraoperative findings.

All surgeries were performed by team skilled in Robotic, Minimal Invasive Gynecological surgery as well as laparoscopic tubal anastomosis following tubal recanalization using the da Vinci robotic system (Intuitive Surgical, Mountain View, CA).[iv]

These patients were followed up for a period of 2 years for recovery of tubal patency, surgical complications, pregnancy and live births rates. 

Out of 14 patients who underwent surgery, only 11 were included in the final follow-up, as two patients were confirmed at surgery to have patent contralateral tube, and one did not desire immediate conception.

A HSG performed at 6 months’ follow-up showed 100% patency.

The cumulative pregnancy rate at 24 months was 63.64% (7/11) with no repeat tubal pregnancy. Follow-up beyond 24moths led to additional intrauterine pregnancies but they were not included in the study statistics.

The researchers stressed the need for additional future trials with larger number of patients to accumulate solid data on end to end reanastomosis after tubal resection surgery.

The authors concluded “tubal reanastomosis after segmental resection of tubal pregnancy using the da Vinci system is a feasible means of salvaging fallopian tube integrity and fertility in those with a single viable fallopian tube, demonstrating natural pregnancy rates compatible with that of conventional reanastomosis for tubal ligation.”

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[i] http://www.uptodate.com/contents/ectopic-pregnancy-incidence-risk-factors-and-pathology

[ii] http://www.nhs.uk/conditions/Ectopic-pregnancy/Pages/Introduction.aspx

[iii] http://journals.lww.com/md-journal/Fulltext/2016/10110/Robot_assisted_segmental_resection_of_tubal.5.aspx

[iv] http://www.davincisurgery.com/da-vinci-gynecology/

Is CA 125 a non-invasive, accurate rule in test for endometriosis: a systematic review and meta-analysis.

Clinical pearls:

• CA 125 serves as a good rule in diagnostic marker for endometriosis at levels ≥ 30 units/ml in women presenting with symptoms and negative sonography. 

It is estimated that 10% of women have endometriosis during the reproductive years with a total of more than 10 million women in US suffering with it currently. It is the number one cause of infertility with high prevalence of 25-30% among infertile women.

Physicians often suspect endometriosis on the basis of history, symptoms, direct visualization, sonography or physical findings.[1]

It is challenging to make a confirm diagnosis unless a sample is obtained by laparoscopic surgery and histology is done. The test in invasive, expensive, and involves surgery that has its own complications. Hence it is often underdiagnosed or the diagnosis is delayed. According to Ballweg ML, an analysis of 7000 confirmed cases showed that the average time to diagnose is >9 years. [2] 

The delay results in symptom deterioration and diseases progression.

The investigators wanted to find out whether a simple, non-invasive blood test can rule out endometriosis. This will save time, money and also better unable the physician to formulate a management plan in such patients.

Research into mechanism of endometriosis have led to the discovery of potential serum markers used for diagnosing the disease.

CA-125 serum concentration has been associated with many gynecological diseases.  CA-125 antigen is expressed in many tissues derived from coelomic epithelia like ovary, fallopian tube, ovary, peritoneum and endometrium.[3] It is the most investigated and studied noninvasive marker for diagnosis of endometriosis. But, studies have come up with varied results that are not consistent and cannot be applied for ruling out endometriosis.

A systemic review and meta-analysis published in the British Journal of Obstetricsand Gynecology evaluates the diagnostic accuracy of CA 125 for endometriosis.[4]

This meta-analysis includes 22 studies with a total of 3626 subjects with surgically diagnosed endometriosis. The patients were classified into mild (stage I-II) and severe (stage III-IV) according to classification by American fertility society.

In the final analysis 14 studies with 2920 subjects (1584 with endometriosis, 1336 controls) were analyzed to assess the presence of endometriosis at CA 125 cut-off value of ≥ 30 units/ml.

The review found that CA125 showed increasing sensitivity as the disease stage 24.8% at stage I–II versus 63.1% at stage III–IV with an average sensitivity of 52.4%.

The authors concluded that at value of ≥ 30 units/ml Ca 125 serves as good rule in test in patients with symptoms but unfortunately CA 125 < 30 units/ml, does not rule out endometriosis with 49% of those with a negative test may still have endometriosis.

Other markers that are currently investigated are human epididymis protein 4 and miRNA which hold vast potential to be an accurate bio-marker in future.

In the absence of other noninvasive test at present, the investigators advocate that CA 125 ≥ 30 units/ml is highly specific for endometriosis in symptomatic women with a negative USG. These patients should be provided with early treatment plans with medical and surgical options.

In patients with CA 125 levels < 30 units/ml, further investigations are required.

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[1] http://www.endtoendo.com/Endometriosis_Prevalence_End_to_Endometriosis.html

[2] https://www.ncbi.nlm.nih.gov/pubmed/15157638

[3] Jacobs I. Screening for ovarian cancer by CA-125 measurement. Lancet 1988;1:889

[4] http://onlinelibrary.wiley.com/doi/10.1111/1471-0528.14055/full

News from American Society for Reproductive Medicine (ASRM) 2016 Scientific Congress—Pesticides residue in fruits and vegetables linked to lower probability of Live Birth.

Clinical Pearls:

• Higher preconception consumption of Fruits and Vegetable, that have high pesticide residue results in lower probability of livebirth after ART.

American Society for Reproductive Medicine (ASRM) 2016 Scientific Congress is currently ongoing at (October 15 – 19) Salt Lake City, Utah. Some selected abstract and news from the conference.

A prospective cohort study by Chiu Y et al. examined the association between preconception intake of Fruits and Vegetables(FV) that has high pesticides residue and outcome of pregnancies conceived by assisted reproductive techniques. [1]

The study subjects included 300 women who underwent 493 ART cycles at an academic center between 2007-2015.  Food intake was systematically documented by filling a food questionnaire.

Surveillance data from US Department of Agriculture was used to classify food into high and low-to-moderate (L-M) pesticide residues.

Medical records of the academy were used to provide information on implantation, live birth and clinical pregnancy. Pregnancy loss was defined as loss after a positive pregnancy test. Linear regression was used to analyze the result after adjusting for age, BMI, race, smoking, physical activity, total energy intake, alcohol intake, dietary patterns, infertility diagnosis and stimulation protocol.

Out of 493 ART cycles,287 women (58%) had a positive β-hCG with 202 (41%) giving birth to live born infants.

The high pesticide intake was divided into quartiles based on daily consumption of the Fruits and Vegetables. The highest probability of live birth per ART was seen in quartile 1-2 (46-47%) whereas the lowest probability was seen in the 4^th quartile (30%). The association was explained because of higher consumption (≥1.6 servings/d) of FV by women in 4^th quartile as compared to women in the first quartile who only consumed <0.7 servings/day. (P,trend=0.01).

Consumption of FV with Low to moderate pesticide residue did not affect the outcome of ART. 

  

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[1] http://www.fertstert.org/article/S0015-0282(16)61491-7/fulltext

News from American Society for Reproductive Medicine (ASRM) 2016 Scientific Congress— Laparoscopic surgery or ART directly---What comes first in patients with Unexplained Infertility.

Clinical Pearls:

• Both the procedure resulted in pregnancy rate at par with each other, but the researchers advocate doing diagnostic and therapeutic laparoscopy first in patients with unexplained infertility.  

American Society for Reproductive Medicine (ASRM) 2016 Scientific Congress is currently ongoing at (October 15 – 19) Salt Lake City, Utah. Some selected abstract and news from the conference.

It is always an obstetrician dilemma whether to perform laparoscopy first or go for ART in patient diagnosed with unexplained infertility.

 A randomized prospective clinical trial results by Algergawy  A.et al. presented on October 18, 2016 evaluated the outcome of these two approaches.[1]

The study involved a cohort of 423 patients who were diagnosed with unexplained infertility based on normal HSG findings, regular ovulation, normal hormonal profile and normal male partner. These women were randomized into two groups. Women who underwent COH followed by IUI for 3 cycles and then ICSI constituted group 1 (205). The second group (218) consists of women who underwent laparoscopy (Diagnostic and therapeutic).

86 women (41.95%) in the first group conceived within 1 year, 26 cases (12.6%) by IUI. and 60 cases (29.26%) by ICSI.

In the second group, diagnostic laparoscopy revealed multiple pathology like mild to moderate endometriosis, severe endometriosis and hypoplastic fallopian tube. Adhesiolysis, ablation and excision of endometriotic implant was performed. The overall pregnancy rate in group 2 was 84 cases (38.53%). 

Although the pregnancy rate in both group is at par, laparoscopy resulted in better diagnosis of causes of unexplained infertility resulting in better management of cases. It also enabled spontaneous pregnancy in significant number of patients thus avoiding psychological, emotional and physical trauma of ART. It also avoids the many complications of ART like OHSS and multiple pregnancy.

If the patient of unexplained infertility does not conceive after laparoscopy, then ART can always be performed when needed and previous diagnostic laparoscopy facilitates the results of ART.

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[1] http://www.fertstert.org/article/S0015-0282(16)61545-5/fulltext

News from American Society for Reproductive Medicine (ASRM) 2016 Scientific Congress-- Low AMH levels predict poor outcome in patients undergoing IVF-ET.

Clinical Pearls:

• Patients aged >34 years with low AMH levels displayed poorer IVF-ET outcome particularly, higher miscarriage rates that is not dependent on age and ovarian response to COH.

American Society for Reproductive Medicine (ASRM) 2016 Scientific Congress is currently ongoing (October 15 – 19) at  Salt Lake City, Utah. Some selected abstract and news from the conference.

Anti-Müllerian Hormone (AMH) has long been known to provide insight into ovarian function. It is produced by small, growing follicles, thus providing us with quantitative information on ovarian reserve.

While AMH levels predict the treatment outcome in controlled ovarian hyperstimulation, no data is available on its role in predicting miscarriages in patients undergoing IVF-ET. [1] Researchers are more and more interested to evaluate its role in oocyte competence and embryo health.

Results of a prospective study by  Tarasconi B et al at the ASRM 2016 conference shows the role played by levels of AMH and subsequent miscarriage rate in patients undergoing IVF-ET. [2] The paper is also published in a special supplement of Journal Fertility and Sterility.

The study authors examined 2,365 infertile women undergoing 2,688 IVF-ET cycles. All the women included in the study had serum AMH tested as reference with ELISA. Women were classified into 3 age groups: ≤33 years (n=1,033), 34-36 years (n=690) and ≥37 years (n=965) and into 3 different AMH groups: Low AMH (0.04-1.60 ng/mL; n=540), Intermediate AMH (1.61-5.59 ng/mL; n=1,608), and High AMH (5.60-35.00 ng/mL; n=540).

After analyzing the data by binary logistic regression, it was seen that clinical pregnancy and live birth rate were directly proportional to levels of AMH, with miscarriage rate being highest in the low AMH level group.

The results were statistically significant in older women in the two age groups of 34-36 years and ≥37 years.

When the whole population was included as one variable, regression analysis showed direct association between patient’s AMH levels and rate of miscarriages independent of age and number of oocyte retrieved.

The study findings support the hypothesis that AMH levels are biomarker of oocyte and embryo reproductive health beside predicting number of oocyte obtained by COH. 

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[1]https://www.ncbi.nlm.nih.gov/pubmed/23644117 accessed on October17, 2016.

[2] http://www.fertstert.org/article/S0015-0282(16)61512-1/fulltext

Rekovelle (Follitropin delta) granted marketing authorization by European Medicines Agency.

Follitropin delta (Rekovelle, Ferring Pharmaceuticals A/S) is a novel human recombinant follicle-stimulating hormone (rhFSH) indicated for use in controlled ovarian stimulation (COS) in women undergoing assisted reproductive technology (ART) therapy such as in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI).

Follitropin delta is available as solution for injection (12 µg/0.36 ml, 36 µg/1.08 ml and 72 µg/2.16 ml) It is a recombinant human follicle-stimulating hormone (FSH) belonging to the pharmacotherapeutic class of gonadotropins (ATC code: G03GA10). The amino acid sequences of the two FSH subunits in follitropin delta are identical to the endogenous human FSH sequences.[1]

It can be administered as tailored regimen to each individual patient based on the measurement of the woman’s serum anti-Müllerian hormone (AMH) and Body Mass Index (BMI).

Personalized treatment is a novel approach to the management of patients undergoing Assisted Reproductive Techniques (ARTs), with the ultimate goal of helping couples to conceive in an efficient and safe manner.

The approval comes in wake of results of Phase III (Evidence-based Stimulation Trial with Human rFSH in Europe and Rest of World) (ESTHER) trials of follitropin delta for pregnancy-related complexities which was presented at the 32^nd Annual Meeting of the European Society of Human Reproduction and Embryology (ESHRE) in Helsinki, Finland.[2]

ESTHER-1 is a multicentric, randomized, assessor-blind, controlled trial conducted in Europe and other centers in the world. The study involved 1,326 patients from 37 fertility clinics in 11 countries between ages 18 to 40 undergoing their first cycle of in-vitro fertilization (IVF) or intracytoplasmic injection (ICSI).[3]

Patients were administered with an individualized dosing regimen of follitropin delta which was fixed throughout stimulation compared with daily follitropin alfa dose of 150 IU (11 µg) for the first five days, (conventional dosing regimen) which was open to dose adjustments after five days.

The number of oocytes retrieved and blastocysts obtained were similar for both the arms of the trial (10.0 and 10.4).

More patients using the individualized regimen of Folliotropin delta obtained the target oocytes number of 8-14 as compared to using conventional regimen. (p<0.05). The study arm also has less incidences of OHSS (p<0.05).

The ongoing pregnancy as well as well as ongoing implantation rates were also similar in both the groups.

Data from the ESTHER-2 trial in which a subset of women underwent additional assessor-blind stimulation cycles (a total of 513 in cycle 2, and 188 in cycle showed no increased immunogenicity risk.[4]

The most common side effects are ovarian hyperstimulation syndrome (OHSS), headache, nausea, fatigue pelvic discomfort and pelvic or adnexal pain,

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[1] http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_-_Initial_authorisation/human/003994/WC500214216.pdf

[2] Nyboe Andersen A and Arce JC on behalf of the ESTHER-1 trial group. Efficacy and safety of follitropin delta in an individualised dosing regimen: A randomised, assessor-blind, controlled phase 3 trial in IVF/ICSI patients (ESTHER-1). Poster presented at 32nd Annual Meeting of the European Society of Human Reproduction and Embryology (ESHRE) in Helsinki, 3–6 July 2016. 

[3] ESTHER-1 trial. www.clintrials.gov Available at: https://clinicaltrials.gov/ct2/show/NCT01956110. Last accessed: October 2016

[4] ESTHER-2 trial. www.clintrials.gov. Available at: https://clinicaltrials.gov/ct2/show/NCT01956123. Last accessed: October 2016