Friday, September 30, 2016

First healthy ‘Three parent baby ‘born in US after spindle nuclear transfer.

A healthy baby boy was born on April 6 to a mother whose two children have died previously at age of 8months and 6 years due to Leigh syndrome. She also had history of four spontaneous abortions.

Leigh syndrome is a debilitating disease with damage is to the basal ganglia and brainstem. Symptoms are the fatigue and weakness typical of mitochondrial diseases, plus double vision, drooping eyelids, trouble swallowing, dystonia of the upper arms, and gradual motor deterioration.

The cause of this syndrome is single-base mutation in a mitochondrial gene that encodes subunit 6 of the ATPase gene. The newborn's mother carries that mutation. 

Mutations in mitochondrial DNA are maternally inherited and are responsible for causing many debilitating disorders without definitive treatment. Diseases of the mitochondria appear to cause the most damage to cells of the brain, heart, liver, skeletal muscles, kidney and the endocrine and respiratory systems.

Mitochondrial replacement therapy, has been shown to be a novel technology in minimizing mutated mtDNA transmission from oocytes to pre-implantation embryos.

This past February, after a yearlong debate the United Kingdom became the first [1]country to legalize mitochondrial replacement therapy (MRT), also known as mitochondrial DNA replacement, which can be used to make “three-parent babies.”

The procedure is still controversial in US, US FDA ascertaining in 2015 that more data is needed before legalizing the procedure while Institute of Medicine concluding in 2016 that it can be allowed under limited condition.

In this technique the nucleus of an affected woman's extracted egg is removed and is put into the enucleated egg of another woman, which contains her mitochondria. The child would thus be genetically related to three people, which is why the media often refers to "three-parent babies" or "three-parent in vitro fertilization."

 The procedure can be carried out in one of the two ways.
1) Spindle Nuclear Transfer(SNT).
2) pronuclear transfer (PNT).

The simpler of the two is called maternal spindle transfer (MST). First, doctors use standard IVF treatment to collect eggs from the mother. They then remove the nucleus from one of the mother’s eggs and transfer it into a healthy donor egg that has had its own nucleus removed. The reconstituted egg holds all of the mother’s healthy nuclear DNA, or 99.8% of her genes, plus the donor’s healthy mitochondria. This egg is then fertilized with the father’s sperm and the embryo is implanted into the woman like any other IVF embryo.

John Zhang, MD, PhD performed the procedure in Mexico to avoid legal issues. The paper is published in current issue of Fertility and Sterility.[2] In this case, the mother carried the mutation with 24.5% mtDNA displaying the altered gene. Due to religious reasons the parents opted for Spindle Nuclear Transfer(SNT).  

Five metaphase II oocytes were subjected to meiotic SNT and fertilized by ICSI.  Four of the embryos developed into blastocysts, PGS showed that one blastocyst was euploid (46XY), while the rest were aneuploidy. The single euploid was transferred which resulted in an uneventful pregnancy.

Only 2% of baby’s mitochondria had mother’s mutation.The baby is currently 3 months old and is very healthy.


Premenopausal Bilateral Oophorectomy accelerates aging and incidence of 18 chronic morbidities.

Clinical Pearls:

  • Women who had bilateral oophorectomy before menopause experienced increased risk of depression, hyperlipidemia, cardiac arrhythmias, coronary artery disease, arthritis, asthma, chronic obstructive pulmonary disease, and osteoporosis. (hazard ratio, 1.22; 95% CI, 1.14-1.31; P<.001). 
  • The younger the age at oophorectomy, the stronger the association with these chronic conditions.
  • In these group of women, the risk of occurrence of many chronic condition was reduced by supplementing estrogen therapy.
  • Study provides definitive evidence against use of bilateral oophorectomy as a means to prevent ovarian cancer in average risk premenopausal women.

Bilateral Oophorectomy is often chosen by many  as a method for prevention of ovarian cancer in premenopausal women who are at average risk of ovarian cancer. The procedure gained popularity in US when Angelina Jolie came forward about her own experiences 2 years back.She  is a carrier of mutation in BRCA1 gene putting her high risk for ovarian and breast cancer. [1]

The current guidelines from the American College of Obstetricians and Gynecologists read, "The most effective method of preventing ovarian cancer is surgical removal of the ovaries and fallopian tubes. ...The potential benefit in cancer risk reduction for premenopausal women at average risk of ovarian cancer must be balanced with the consequences of premature loss of estrogen production."

However, in practice many doctors advise patients in favor of removal of both ovaries to eliminated the risk of  getting ovarian cancer. 

Many societies around the world have formulated guidelines so that the surgery is only performed in absolutely indicated patients like BRCA1 positive patients, but the practice still continues.

Observational studies have also documented the beneficial role of estrogen in keeping chronic morbidities at bay in women who undergo bilateral oophorectomy before the age of 46 years.

The present study was prompted because of uncertainties in the risk/benefit ratio of bilateral oophorectomy for preventing ovarian cancer and the role played by estrogen in delaying many chronic morbidities which may be sign of cellular and tissue aging.

The study was published in the recent issue of Mayo Clinic Proceedings.[2]

The researchers used the Rochester Epidemiology Project records-linkage system to recruit 1653 women who underwent bilateral oophorectomy before the age of 50 years between 1988-2007 in Olmsted County, Minnesota. Each subject was than randomly matched to a control, who was also born in the same year (±1 year), but did not have bilateral oophorectomy. They were followed up for approximately 14 years to study 18 comorbidities.

At baseline it was observed that women who underwent bilateral oophorectomy were Caucasians, less educated, had increased BMI and were heavy smokers as compared to referral women. They were also more likely to suffer from mental, Cardiometabolic and somatic disorders at the time of surgery.

Researchers used inverse probability weighting to balance the baseline risk factors and individual characteristics thereby minimizing their effects as potential confounders.

Women who had bilateral oophorectomy before menopause experienced increased risk of depression, hyperlipidemia, cardiac arrhythmias, coronary artery disease, arthritis, asthma, chronic obstructive pulmonary disease, and osteoporosis. (hazard ratio, 1.22; 95% CI, 1.14-1.31; P<.001). 

The younger the age at oophorectomy, the stronger the association with these chronic conditions.

In these group of women, the risk of occurrence of many chronic condition was reduced by supplementing estrogen therapy.

The researchers proposed three possible mechanisms to explain the results of the study. Although inverse probability weighting was used to rule out confounding and bring the observational study close to RCT for interpretation as possible, genetic, environmental and lifestyle factors may have acted as confounders.

Premature and abrupt decline in estrogen levels may have led to increase in ‘epigenetic age’ serving as a bio-marker for accelerated aging.

Oophorectomy leads to loss of protective effect of other ovarian hormones progesterone, testosterone, or inhibin and disrupts the hypothalamic-pituitary axis.

The study had several strengths and limitations. As all the data was extracted electronically it eliminates the recall bias and non- participation of the subjects. Study may have underestimated those conditions which do not have any medical code, as the data was extracted form records.  Statistical power was limited for some associations for the time the women were followed. It may become significant if they are followed for longer period of time.

To Conclude, the study results along with results of the earlier studies provides definitive evidence against use of bilateral oophorectomy as a means to prevent ovarian cancer in average risk premenopausal women. Study also emphasizes the protective effect estrogen may exert to delay cellular and tissue level aging which is manifested as increased risk of multiple morbidities.  


Wednesday, September 28, 2016

ACOG updates the committee opinion and expands antenatal corticosteroids recommendations for late preterm births.

American College of Obstetricians and Gynecologists (ACOG) recently updated its committee opinion for administration of prenatal corticosteroids and expanded it to high risk women for late preterm birth (34 0/7 - 36 6/7 weeks).

“Providing women’s health care providers with evidence-based techniques to successfully manage instances of preterm birth is a top priority for ACOG,” said one of the Committee Opinion authors, 

Dr. Yasser El-Sayed, MD, FACOG. “Through the new committee opinion we are expanding an existing therapy, based on recent data, to improve outcomes in more clinical settings. It’s an important step in getting more mothers and babies the care they need to be healthy.”[1]

This new Committee Opinion replaces ACOG’s Practice Advisory on Antenatal Corticosteroid Administration in the Late Preterm Period, originally issued on April 4, 2016.[2]

These recommendations follow the results of significant Antenatal Late PretermSteroids (ALPS) trial, published earlier this year.[3] The committee opinion now includes recommendations that support the administration of antenatal corticosteroids in certain populations during the late preterm birth period, or between 34 and 37 weeks of gestation.

The recommendation also holds good in multiple gestation.

Corticosteroids given late preterm significantly reduced the rate of neonatal respiratory complications like transient tachypnea of the newborn, surfactant use, and bronchopulmonary dysplasia. Studies also show lower rates of intracranial hemorrhage, necrotizing enterocolitis, and mortality. The only side effect is neonatal hypoglycemia which should be monitored closely.

As per the news release “The document also re-emphasizes ACOG’s recommendation to consider antenatal corticosteroids for pregnant women at risk of preterm delivery starting at 23 weeks of gestation, based on a family’s decision regarding resuscitation.”

The ACOG recommendations in the October issue of journal of Obstetrics and Gynecology[4]: It states: 

  • A single course of corticosteroids is recommended for pregnant women between 24 0/7 weeks and 33 6/7 weeks of gestation, including for those with ruptured membranes and multiple gestations. It may be considered for women starting at 23 0/7 weeks of gestation who are at risk of preterm delivery within 7 days, based on a family’s decision regarding resuscitation. 
  • A single course of betamethasone is recommended for pregnant women between 34 0/7 weeks and 36 6/7 weeks of gestation at risk of preterm birth within 7 days, and who have not received a previous course of antenatal corticosteroids.
  • Treatment should consist of either two 12-mg doses of betamethasone given intramuscularly 24 hours apart or four 6-mg doses of dexamethasone administered intramuscularly every 12 hours.
  • Scheduled repeat course or serial courses are not recommended.
  • A single repeat course of antenatal corticosteroids should be considered in women who are less than 34 0/7 weeks of gestation who have an imminent risk of preterm delivery within the next 7 days, and whose prior course of antenatal corticosteroids was administered more than 14 days previously. Rescue course corticosteroids could be provided as early as 7 days from the prior dose, if indicated by the clinical scenario.
  • Evidence is insufficient at present for giving a rescue or repeat course in patients with preterm pre labor rupture of membranes (PROM), hence no recommendation is made.
  • ACOG advocates continuous long term monitoring of patients who received corticosteroids.  


Morning Sickness in early pregnancy linked to lower risk of miscarriages and still births.

Nausea and vomiting in early pregnancy affects 50-80% of pregnant women. Researchers have linked its etiology to imbalance in carbohydrate metabolism, rising hormonal levels in pregnancy, psychosomatic factors  evolutionary survival adaptation which protects pregnant mothers and their babies from food poisoning

 Few  observational studies in the past have documented that incidence of pregnancy loss is lower in patients who have morning sickness in first trimester.

A new study published in the in the journal JAMA Internal Medicine[1] found that women who suffer from nausea and vomiting in the first trimester have 50% less chance of miscarriage.

The study is a result of secondary data analysis of a Randomized Control Trial (RCT) examining Effects of Aspirin in Gestation and Reproduction (EAGeR) Trial.[2] The EAGeR study is a multi-site, double-blinded randomized trial designed to assess the effects of low-dose aspirin on implantation and pregnancy outcome carried out by researchers at NIH's Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and other institutions.

The secondary analysis was limited to women who had a pregnancy confirmed by positive human chorionic gonadotropin (hCG) test, had a history of at least one pregnancy loss. A total of 797 study subjects was recruited. The women kept a daily diary for nausea and vomiting from week 2 to week 8 of pregnancy, and monthly thereafter.

Out of 797 pregnancies, 188 ended in loss (23.6%), and at the end of 8 weeks about 57.3 percent of the women reported experiencing nausea and 26.6 percent reported nausea with vomiting. 
In this cohort of women, it was seen that nausea alone or nausea with vomiting during pregnancy were associated with nearly 50%-75% reduction in the risk for pregnancy loss. When the analysis was done for peri-implantation pregnancy loss, the results were similar but they were not statistically significant.

Younger women (age <25 years) suffered much more with nausea and vomiting as compared to older women.

The association persisted even after accounting for confounding factors like maternal stress, alcohol intake, caffeine intake, smoking, fetal sex, multiple-fetal gestation, and karyotype.

Stefanie Hinkle, the lead author and a researcher at the national institute said "Our study evaluates symptoms from the earliest weeks of pregnancy, immediately after conception, and confirms that there is a protective association between nausea and vomiting and a lower risk of pregnancy loss.” But, was not sure whether the study results could be applied to primigravida.

She also went to stress that women with no nausea or vomiting should not be alarmed as a result of this study. "Every pregnancy is different and just because they don't have symptoms doesn't mean they're going to have a pregnancy loss," Hinkle said.[3]

The study was also followed by an accompanying editorial by Siripanth Nippita, MD, and Laura E. Dodge, ScD, MPH, from the Department of Obstetrics and Gynecology, Beth Israel Deaconess Medical Center. They said "This study's contribution to the existing literature is valuable for several reasons. It builds on a prior cohort study by Sapra et al and similarly enrolled a large sample of women before conception."

They further quote “The widespread availability of sensitive urine hCG tests coupled with real-time electronic data capture using mobile phone apps or similar technology has the potential to improve data quality and eliminate recall bias. Given these methodologic advantages over previous investigations, we hope that such studies can further deepen our understanding of the underlying causes of [nausea and vomiting in pregnancy]."

The researchers also urged women with nausea and vomiting in pregnancy to seek medical consultation since it negatively affects the quality of life.

[3] Stefanie N. Hinkle, Sunni L. Mumford, Katherine L. Grantz, Robert M. Silver, Emily M. Mitchell, Lindsey A. Sjaarda, Rose G. Radin, Neil J. Perkins, Noya Galai, Enrique F. Schisterman. Association of Nausea and Vomiting During Pregnancy With Pregnancy LossJAMA Internal Medicine, 2016; DOI: 10.1001/jamainternmed.2016.5641

Monday, September 26, 2016

Guidelines revised for preventing thromboembolism in pregnancy.

Obstetric Venous thromboembolism (VTE) is a leading cause for maternal morbidity and mortality. Venous thromboembolism encompasses deep vein thrombosis(DVT) and pulmonary embolism (PE) complicates 0.5 to 3.0 per 1,000 pregnancies.[1] PE is the seventh leading cause of maternal mortality and contributes to 9% of maternal deaths.[2]

Maternal deaths due to VTE are preventable by forming and implementing comprehensive guidelines for prophylaxis of thromboembolism. But, presently sufficient clinical trial data remains unavailable to formulate VTE prophylaxis guidelines in pregnancy.

In US only women who are at high risk for VTE receive pharmacologic prophylaxis, thereby increasing the rate of obstetric VTE in the last decade.

On the contrary, RCOG guidelines in U.K recommend screening and assessment of antepartum and postpartum women for at risk for VTE. Due to regular assessment many women receive pharmacologic thromboprophylaxis, bringing down the rates of VTE since the release of the guidelines.

Observational data support risk-factor-based prophylaxis in bringing down the incidence of VTE, hence the National Partnership for Maternal Safety under the guidance of the Council on Patient Safety in Women's Health Care developed safety bundle. Safety bundle supports routine risk evaluation for obstetric patients with pharmacological and mechanical thromboprophylaxis when needed. [3] It outlines simple practices that can be implemented in every maternal units, adapting according to the healthcare resources available in each community.

The article was published in October issue of Obstetrics and Gynecology journal.[4] The bundle is grouped into 4 domains: Readiness, Recognition, Response, and Reporting and Systems Learning. 

Readiness: Every Unit should use standard VTE risk assessment tool during prenatal outpatient visits, antepartum admissions to hospital, post labor and post cesarean stay in hospitals and 6 weeks postpartum.

Recognition and Response: Once the risk assessment is done, physicians should use patients Caprini[5] or Padua score[6] to identify those patients who will need thromboprophylaxis according to clinical situation and risk score. The thromboprophylaxis guidelines are as advocated by ACOG, American College of Chest Physicians and RCOG.

  • Antepartum outpatient prophylaxis: women with a history of multiple VTE or thrombophilia episodes low-molecular-weight (LMW) heparin or unfractionated heparin (UFH) is recommended.
  • Antepartum Inpatients for more than 3 days: Women who are not at risk for bleeding or imminent childbirth, prophylaxis with daily LMW heparin or twice-daily UFH is advocated.
  • Women with a history of VTE who are undergoing a trial of vaginal birth are given intrapartum mechanical thromboprophylaxis using pneumatic compression devices while in bed. After the delivery, LMW heparin or UFH can be for those at high risk for VTE based on RCOG criteria or a Padua score of 4 or greater.
  • Those women undergoing an operative delivery are prescribed mechanical thromboprophylaxis using pneumatic compression. Once the surgery is over, they can also be given LMW heparin or UFH, based on RCOG criteria or modified Caprini scores.
  • RCOG criteria also advocates that all women who are undergoing operative delivery may be routinely prescribed LMW heparin or UFH due to complications with mechanical prophylaxis.
  • Women with repeated history of VTE, high-risk thrombophilia, or VTE with acquired thrombophilia can be put on extended 6-week treatment-dose of LMW heparin or UFH postpartum.

Reporting and Systems Learning: All centers should meticulously keep records of patients receiving prophylaxis for VTE, adverse reactions and complications.  Routine audits should be performed to check whether physicians are evaluating, assessing the risk factors for VTE and planning the treatment accordingly.

However, in an accompanying editorial Baha M. Sibai, MD, from the University of Texas Medical School at Houston, and Dwight J. Rouse, MD, MSPH, associate editor for Obstetrics & Gynecology, have expressed concern that the widespread use pharmacological prophylaxis may do more harm than good. 

The authors are specially concerned with 3 days’ prophylaxis for antepartum hospitalized patients and women at high risk for VTE and have undergone vaginal birth.

They were especially worried about following the RCOG criteria of pharmacological prophylaxis after cesarean delivery, which would apply to more than half of the C.S. patients in the US. 

According to the editorial analysis” approximately 1 million women would require pharmacologic prophylaxis to prevent even one maternal death from cesarean delivery–associated pulmonary embolism."

Nevertheless, they advocate the use of mechanical prophylaxis in all obstetrics units’ post-cesarean and building a database of huge obstetric patients in whom the mechanical method was used. In the future, this large data base created can be used to assess the pros and cons of using pharmacological prophylaxis in obstetrics patients.

[1] Snow V, Qaseem A, Barry P, et al., for the American College of Physicians, American Academy of Family Physicians Panel on Deep Venous Thrombosis/Pulmonary Embolism. Management of venous thrombo-embolism: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med. 2007;146(3):204–210....
[2] The Confidential Enquiry into Maternal and Child Health (CEMACH). Saving mothers’ lives: reviewing maternal deaths to make motherhood safer — 2003–2005: the seventh report on confidential enquiries into maternal deaths in the United Kingdom. London: CEMACH, 2007

Sunday, September 25, 2016

Novel Investigational antibiotic for Gonorrhea holds a promise for future with 100% cure rate.

Gonorrhea is one of the most common STD in US. Recently public health officials have identified cluster of gonorrhea cases in Hawaii that show decreasing susceptibility to ceftriaxone and high level of resistance to azithromycin. [1] 

Currently a combination of ceftriaxone and azithromycin is the last available option for treating gonorrhea and investigators believe that they will run out of this option in near future. Left untreated, gonorrhea can lead to serious health problems including infertility, pelvic inflammatory disease and life-threatening ectopic pregnancy in women.

  • One third of the new gonorrhea infection are resistant to at least 1 drug.
  • It is the most common communicable disease in the US, with an estimated 820,000 new infections each year.
  • We are only left with 1 treatment option for gonorrhea out of 5 reported by CDC in 2006 due to development of resistance by the bacteria.

Hence, researchers have renewed interest in development of new drug for gonorrhea. At the 2016 STD Prevention Conference, researchers from Louisiana State University presented results of phase 2 clinical trials of experimental oral antibiotic that was safe and effective in treating uncomplicated gonorrhea. Unlike any other marketed antibiotic, the new drug dubbed as ETX0914 is a novel spiropyrimidinetrione, that acts by inhibiting deoxyribonucleic acid biosynthesis by accumulation of double strand cleavages. [3]

In a small clinical trial, a total of 179 participants (167 men and 12 women) were randomized approximately 70:70:40 to receive either 2000mg or 3000mg ETX0914 orally or 500mg ceftriaxone in a single intramuscular injection.

Patients were followed up for safety, microbiological and clinical cure rates. The drug was well tolerated with only mild gastrointestinal side effects.

All patients receiving 3g ETX0914 (47/47) and 98 percent of patients in the 2g group (48/49) were cured. 

The trials lead investigator Stephanie N. Taylor, M.D., professor of medicine and microbiology at Louisiana State University Health Sciences Center said “We are very pleased with these results and look forward to seeing ETX0914 advance through additional clinical studies.”

The combination therapy of azithromycin and ceftriaxone recommended by CDC is still effective, but “ will eventually fail” says  Jonathan Mermin, MD, director of the CDC's center for HIV/AIDS, viral hepatitis, STD, and TB prevention quotes "In the battle between humans and pathogens," he said, "gonorrhea is a formidable opponent."


Friday, September 23, 2016

US- FDA gives clearance to new 5-year contraceptive device Kyleena.

US-FDA approved a new contraceptive device called Kyleena by Bayer Pharmaceuticals preventing pregnancy for 5 years. [1]

Kyleena belongs to the category of Long acting contraceptive device (LARC) and will be available in the market by prescription from October. The small, flexible, plastic IUD contains 19.5 mg of a progestin hormone levonorgestrel.

According to recent data the use of long-acting reversible contraception (LARCs) has increased nearly five-fold in the last decade.

 Kyleena or other   hormonal IUCD are marginally more effective than copper IUCD as they better control the blood flow.

After using Kyleena for some time, women are likely to experience fewer days of spotting and bleeding or may experience amenorrhea. Regular period resumes after removal of the device.

"Data show that the use of effective, long-acting birth control methods including intrauterine devices – or IUDs – have helped to reduce unintended pregnancies in the United States but we still have a long way to go," said Anita L. Nelson, M.D., Professor and Chair, Obstetrics and Gynecology at Western University of Health Sciences, Pomona, Calif on Bayer’s website. "Kyleena is highly effective at preventing pregnancy and may be an appropriate choice for women who want a low-dose, non-daily birth control method”. [2]


New International Menopause Society (IMS) guidelines affirms the safety of menopausal HT.

The International Menopause Society (IMS) recently released 2016 Global Consensus Statement on Menopausal Hormone Therapy (MHT).[1]  The IMS brought together 7 international societies, including European Menopause and Andropause Society and the North American Menopause Society to formulate comprehensive, evidence based guidelines with practice essentials to help and guide physicians across the globe in managing women through menopause transition and beyond.

The guidelines are aimed at helping women across the globe to prevent chronic diseases due to aging along with treatment of troublesome menopausal symptoms. 

The term Menopausal Hormone Therapy (MHT) includes estrogen, progesterone and combined therapies.

The recommendations simply provide an overview of basic principles of hormone therapy which can be modified and adapted according to the geographical region, country specific belief and practices, basic infrastructure of healthcare and the variation and availability of the hormones. It also simply provides consensus and is not a replacement for the detailed guidelines issued by each individual societies.

Professor Rod Baber, IMS President, commented “I believe the new Global Consensus is a major step forward in the management of menopausal women as it provides women and their doctors with internationally endorsed guidance”.[2]

General principles that governs the use of MHT

The option of starting MHT should be decided according to the need of each patient depending upon age, time elapsed since menopause, the symptoms, risk of VTE, breast and gynecological malignancies and CVD.

It should be a part of overall life style change and management including diet, exercise and smoking cessation for prevention of postmenopausal osteoporosis.

MHT include a range of hormonal products that can be administered by various routes. It includes Tibolone or CE/BZA too when available. Each product has its own side effects, and risk/benefit rations.

MHT should always begin with the lowest possible dose that alleviates the symptoms with minimum side effects. The route of administration should be tailored to individual need, preference and side effects. 

The benefit/risk ratio should be assessed annually for each patient. The duration of the treatment should be planned accordingly with the lowest possible dose schedule. Some women may require longer duration of treatment for relief of Vaso Motor symptoms (VMS).

Use of estrogen as single systemic agent is only advocated in case of patients who have undergone hysterectomy, concomitant use of progesterone is always advocated with intact uterus unless CE is combined with BZA for uterine protection. 

Testosterone only therapy or in combination with MHT is only indicated in selective postmenopausal women with sexual interest/arousal disorder.

Use of custom compound hormone therapy is not recommended because of batch to batch variability, lack of regulation standards for safety, efficacy and purity.  

Safety data on use of MHT for breast cancer survivor is limited currently. It’s use in such patients can only be undertaken after discussing it with patient’s oncologist when complementary options have exhausted.   

Benefit/risk profile for MHT

Quality of life, sexual satisfaction, mood changes, joint pain and sleep disturbances may improve with MHT.

MHT with Tibolone and combination of Conjugated Equine estrogen and bazedoxifene (CE/BZA) is effective in treatment of osteoporosis. It has consistently seen to be effective in reducing the risk of vertebral, hip and other osteoporosis-related fractures in post-menopausal women.

MHT is the only therapy that is effective in preventing fractures in postmenopausal women with mean T-score in normal or osteopenic range. It should be initiated before the age of 60 or 10 years within menopause for at risk women for osteoporosis. 

If started after the age of 60 years, it is considered the second line of therapy and risk/ benefit ratio should be compared with other first line drugs.

The most effective treatment of VMS at any age is Tibolone and combination of Conjugated Equine estrogen and bazedoxifene (CE/BZA). Symptomatic women derive maximum benefits if treatment is started within 10 years of menopause or before the age of 60 years.

Vulvovaginal atrophy(VVA) is now considered a component of genitourinary syndrome of menopause (GSM). MHT including Tibolone relieves the symptoms of VVA. Topical estrogen preparations are first line of treatment in patients with only local vaginal dryness, dyspareunia or recurrent UTI. Ospemifene, a selective estrogen receptor modulator (SERM) is also licensed in some countries for treatment of dyspareunia due to VVA.

Many observational studies, RCTs and meta-analysis provides data that shows consistent benefits in standard dose estrogen alone group as compared to estrogen plus progestogen MHT in decreasing myocardial infarction and all-cause mortality when initiated before age of 60 or within 10 years of menopause.

The risk of VTE and ischemic stroke increases with oral MHT as compared with transdermal therapy (0.05 mg twice weekly or lower) when started before the age of 60 years.

The risk of breast cancer with MHT in women over the age of 50 years is a complex issue. Estrogen only MHT in women with hysterectomy shows a lower risk as compared to combine therapy the medroxyprogesterone acetate in the women’s health initiative study (WHI). However, the risk of < 1.0 per 1000 women per year is less than that associated with sedentary life style, alcohol consumption and obesity.

Women who experience a natural or iatrogenic menopause before the age of 45, particularly before the age of 40 face a consistent high risk for cardiovascular disease, osteoporosis, mood disorders and dementia. Results of observational studies have shown that these women benefit from MHT, but they have to be confirmed by RCTs. MHT can be prescribed till the age of natural menopause. 

In women with major depressive disorders, antidepressant therapy remains the first line of treatment, although MHT can be used to improve mood in women with anxiety/depressive symptoms.  MHT initiated in early menopause and after the age of 65 years also does not have significant effect on cognition and increase the risk of dementia.  Although some observational studies have shown that early initiation may prevent Alzheimer’s disease in later life.


Wednesday, September 21, 2016

Building strong bones with biologics- Romosozumab significantly decreases fracture risk in osteoporotic postmenopausal women.

Clinical Pearls:

  • Currently, no osteoanabolic treatment exists for osteoporosis, other than parathyroid hormone.
  • Romosozumab is the first humanized, osteoanabolic, anti-sclerostin monoclonal antibody which binds and inhibits sclerostin leading to increases in bone formation and decrease in bone reabsorption.
  • This regimen is a new approach in treating osteoporosis whereby patients received sequential anabolic therapy with two biologic agents-Romosozumab and Denosumab. 
  • One year of treatment with Romosozumab resulted in clinically significant lower risk of vertebral and clinical fractures in postmenopausal women and resulted in substantial gains in Bone Mineral Density (BMD) at the spine and hip. 

According to the statistics by International Osteoporosis Foundation (IOF) [1]It is estimated that osteoporosis affects 200 million women worldwide, affecting one tenth of women over the age of 60, one fifth over the age of 70, two-fifth over the age of 80 and nearly two-third over the age of 90.[2] 

Nearly 1 in 3 women over the age of 50 will suffer osteoporotic fractures during her life time. Fewer than 25% of patients suffering osteoporotic fractures receive treatment after the incidence and even among those who start the treatment, majority of the patients terminate it prematurely.

Currently, other than the parathyroid hormone analogs all treatments aimed at osteoporosis are antiresorptive. Researchers have spent resources on development of anabolic therapies, which led them to novel therapeutic approach in the treatment of osteoporosis - sclerostin inhibition. Sclerostin is secreted by osteocytes and acts by inhibiting Wnt signaling, thereby preventing osteoblast development and function.

Romosozumab is the first humanized, osteoanabolic, anti-sclerostin monoclonal antibody which binds and inhibits sclerostin leading to increases in bone formation and decrease in bone reabsorption.[3] 

The Fracture Study in Postmenopausal Women with Osteoporosis (FRAME) is an international, randomized, double-blind, placebo-controlled, parallel-group phase 3 trial. The landmark study aims to evaluate the effect of 1 year of Romosozumab (at a dose of 210 mg, administered subcutaneously monthly) on development of fractures in post-menopausal women with osteoporosis. The FRAME trial recruited 7180 postmenopausal women between 55 -90 years of age and they were randomized to receive either 210 mg of Romosozumab placebo once a month for 12 months.

The study findings were presented at the at the American Society for Bone and Mineral Research (ASBMR) 2016 Annual Meeting.[4] The results were also published simultaneously in The New England Journal of Medicine.[5]

After I year of therapy with the monoclonal antibody treatment, patient received 2 doses of denosumab 60 mg subcutaneously at an interval of 6months. This regimen is a new approach in treating osteoporosis whereby patients received sequential anabolic therapy with two biologic agents.

The results were statistically significant since the relative risk of new vertebral fractures was reduced by 75% and the relative risk of a clinical fracture by 36% through 12 months compared to those receiving placebo.

The study met the coprimary end points of reducing the cumulative incidence of new vertebral fractures at the end of 1 year and 24 months. By reducing the incidence of clinical fractures (vertebral and non-vertebral) at the end of 12 months’ secondary end point werealso met, however when only incidence of non-vertebral fractures was analyzed, the study was short of meeting the goal.

In the study Romosozumab did reduce non-vertebral fractures but the data was not statistically significant. This was explained due to the geographical location of the study population. Majority of the study subjects were from Latin America were the incidence of non-vertebral fracture is extremely low. When the analysis was conducted after excluding the Latin American cohort, Romosozumab led to a significant 42% reduction in the risk of nonvertebral fractures over 1 year compared with placebo patients.

The clinical benefits seen in trials were also supported by lab results of increase in bone-formation marker P1NP and decrease in bone-resorption marker β-CTX during the 12 months’ period of therapy.

Adverse events were reported in control as well as placebo groups equally. Hypersensitivity reactions were more common in the Romosozumab group along with single incidence of jaw bone necrosis and atypical femoral fracture.

In an accompanying editorial, Dr Rosen and Dr Ingelfinger quote "The long-term treatment of osteoporosis remains challenging, and Romosozumab may be one answer. More trials are needed before we can embrace a new approach."

The study received funding from Amgen and UCB Pharma as well as Dr Cosman received personal fees from Amgen and other pharma company. The editorial authors are employee of NEJM.  

[2] Kanis JA (2007) WHO Technical Report, University of Sheffield, UK: 66.