Osteoporosis drug Romosozumab receives marketing approval in Japan

Monoclonal antibody romosozumab gains first-ever marketing approval in Japan for the treatment of osteoporosis in patients at high risk of fracture announced Amgen and UCB in a joint press release. The drug will be known as Evenity in Japan and would be developed by Amgen Astellas BioPharma K.K.–a joint venture between Amgen and Astellas Pharma Inc., headquartered in Tokyo.

Romosozumab has a dual effect on the bone– it works by binding and inhibiting the activity of the protein sclerostin which increases bone formation and decreases bone breakdown.

Japanese people have the longest life expectancy in the world and with that comes the burden of osteoporotic fractures. In Japan, the osteoporotic fracture is the leading cause of disability that requires long term nursing home care.

"The approval of EVENITY in Japan is a significant milestone that reinforces our commitment to bringing effective treatments to the millions of patients who suffer from osteoporosis," said David M. Reese, M.D., executive vice president of Research and Development at Amgen in a news release.

"A patient with a prior osteoporotic fracture is twice as likely to suffer another fracture if left undiagnosed and without appropriate treatment. With this approval, physicians in Japan now have a new medicine to help patients reduce their risk of fracture."

The approval is based on results of two phase 3 clinical trials– FRAME and BRIDGE. The FRActure study in postmenopausal woMen with ostEoporosis (FRAME), included 7,180 postmenopausal women with osteoporosis. The women received romosozumab 210 mg s.c. or placebo once monthly for 12 months, followed by denosumab 60 mg s.c. once every 6 months in both groups for 12 months. The drug significantly increased spine and hip BMD and reduced vertebral and clinical fracture risk.

The BRIDGE study (placeBo-contRolled study evaluating the efficacy anD safety of romosozumab in treatinG mEn with osteoporosis) involved 245 men with osteoporosis (163 romosozumab, 82 placebo) randomized 2:1 to receive either 210 mg romosozumab or placebo subcutaneously once monthly for 12 months. Men on Romosozumab showed a significant bone mineral density (BMD) gains at the lumbar spine, total hip and femoral neck compared to placebo at six and 12 months.

The approval is also significant because FDA rejected Amgen’s initial marketing application for Romosozumab in the US because of cardiovascular side effects of the drug in ARCH trial. The drug is also under regulatory review in Europe.

The Japanese Pharmaceuticals and Medical Devices Agency undertook a thorough review of the safety profile of EVENITY, including the cardiovascular safety findings in the ARCH trial.

Toshio Matsumoto, M.D., Ph.D., emeritus professor of Tokushima University and the advisor of the university's Fujii Memorial Institute of Medical Sciences said in the press release, "Physicians have been waiting for a new therapeutic option. I have great hope that the approval of EVENITY will help reduce the fracture risk for patients in Japan."

"Patients with a prior fracture face the risk of having another fracture and particularly stand to benefit from the option of a new bone-forming agent," he further added.

Meanwhile, During the second review cycle, the US Food and Drug Administration (FDA) Bone, Reproductive, and Urologic Drugs Advisory Committee (BRUDAC) recently voted in favor of approving Amgen and UCB’s romosozumab (EVENITY) In the US for the treatment of postmenopausal women with osteoporosis at high risk for fracture. The committee indicated that the drug benefits for treatment of postmenopausal osteoporosis outweigh its risk.

Press release

FDA approves elagolix (Orilissa), the first and only oral treatment for endometriosis pain

The U.S. Food and Drug Administration (FDA) today approved ORILISSA™ (elagolix), the first and only oral gonadotropin-releasing hormone (GnRH) antagonist especially useful in the management of women with moderate to severe endometriosis pain— announced AbbVie and Neurocrine Biosciences.

Orilissa represents the first FDA approved oral treatment for endometriosis in over a decade and is expected to be available in U.S. retail pharmacies in early August 2018.

The drug is available in two oral dosages-150 mg once daily and 200 mg twice daily, taken with or without food roughly at the same time every day.

The FDA approval is supported by the results of 2 of the largest, randomized, double-blind, placebo-controlled phase 3 trials conducted to date, which evaluated nearly 1,700 women with moderate to severe endometriosis pain. Women either received 150 mg, 200 mg (952 women) or a placebo (734 women) and were evaluated at the end of 3 months.

Of the women in the treatment arm, 475 received a 150-mg daily dose, while and 477 received a 200-mg twice-daily dose.

Clinical trial results demonstrate that Orilissa significantly reduced all the 3 types of pain commonly associated with endometriosis— daily menstrual pelvic pain, non-menstrual pelvic pain, and pain with sex (p <0.001). Furthermore, women on 200 mg dose showed a significant reduction in dyspareunia as compared to placebo.

The most significant side effect observed with elagolix is dose-dependent decreases in bone mineral density; limiting the treatment to either 150 mg daily for up to 24 months or 200 mg twice daily for up to 6 months.

Bone mineral density loss is not entirely reversible on stopping the treatment. Other adverse effects are reported in 5% of patients and include hot flashes/night sweats, headache, and nausea, difficulty sleeping, an absence of periods, anxiety, joint pain, depression and mood changes.

"ORILISSA represents a significant advancement for women with endometriosis and physicians who need more options for the medical management of this disease," said Michael Severino, M.D., Executive Vice President, Research and Development and Chief Scientific Officer, AbbVie. "The approval of ORILISSA demonstrates AbbVie's continued commitment to address serious diseases and unmet needs."

"Endometriosis is often characterized by chronic pelvic pain that can impact women's daily activities," Hugh Taylor, MD, study investigator from Yale University School of Medicine in New Haven, Connecticut, said in the release. "Women with endometriosis may undergo multiple medical treatments and surgical procedures seeking pain relief, and this approval gives physicians another option for treatment based on a woman's specific type and severity of endometriosis pain."

AbbVie is going to role in an application for the approval of elagolix in Uterine Fibroids too; the drug has already shown promising results in initial trials conducted by the drug manufacturer.

AbbVie press release

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USPSTF issues draft recommendations on low-dose vitamin D and calcium for fracture prevention

http://www.huffingtonpost.com/ellen-sarver-dolgen/vitamin-d-calcium-supplements_b_3543283.html

The USPSTF today issued draft recommendations for effectiveness and potential harm of prescribing Vitamin D and Calcium in community dwelling men and pre-and post-menopausal women for the primary prevention of fractures.

Aging population, low bone mass and falls all contribute to a substantial health burden of fractures. Nearly 1 in 2 women older than 50 years of age will experience a fracture during her life time.

Currently, Vitamin D and Calcium supplementation are often advised for postmenopausal women to prevent fractures.

USPSTF recommendations on efficacy of Calcium and Vitamin D in preventing fractures are based on data from a total of 41,772 women across eight 8 RCTs with mean age between 53 to 80 years while for assessing the harm it reviewed the evidence from 9 RCTs with a total of 39,659 subjects, which also included 5,991 men.

The review of evidence concluded:

USPSTF found sufficient evidence to recommend against daily supplementation of 400 IU or less of vitamin D combined with 1,000 mg or less of calcium in prevention of fractures in postmenopausal women.

Evidence is also insufficient to make recommendations for greater than 400 IU of vitamin D and greater than 1000 mg of calcium supplementation in postmenopausal women.

At this time, there is insufficient evidence to determine the balance of benefits and harms of prescribing vitamin D and calcium supplementation, alone or combined, for the primary prevention of fractures in men and premenopausal women.

USPSTF found sufficient evidence that supplementation with vitamin D and calcium increases the incidence of kidney stones, although the magnitude of this harm was small.

This recommendation does not apply to persons living in institutional or nursing home care or with a history of osteoporotic fractures or those who are at increased risk for falls. It also does not apply to persons with a diagnosis of osteoporosis or vitamin D deficiency.

USPSTF recommends screening for osteoporosis in women aged 65 or older and in younger women if they have a high fracture risk. Evidence is insufficient to recommend for or against screening for vitamin D deficiency in asymptomatic adults.

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Quick facts about Bone Health: News from ASBMR 2017 annual meeting

https://www.spine-health.com

The 2017 annual meeting of American Society for Bone and Mineral Research took place from September 8-11 at Denver, Colorado, USA.

It is world’s largest and most diverse meeting in the bone, mineral and musculoskeletal research field.

Some interesting facts about bone health:

Bone mass peaks around age 30 and slowly starts to decline, the rate of loss accelerated in the first few years after menopause.

http://silverfoxvet.net

Experts recommend testing for BMD in women who have suffered any fracture at age 45 or older and at age 50 for women who have a family history of hip fractures or other bone-related disease.

All women above the age of 65 should have a baseline BMD testing done. However, after a fracture 4 out of 5 women over 67 are not treated or tested for osteoporosis.

US and other countries round the globe will see a steep rise in osteoporotic fractures because of rise in aging population. Nearly 1 in 3 women and 1 in 5 men over the age of 50 will suffer an osteoporotic fracture.

Osteoporosis affects nearly 10 million Americans while another 34 million have low bone mass predisposing them to fracture risk.

Worldwide a fragility fracture occurs every 3 secs, amounting to more than 8.9 million fractures annually.

Institute of Medicine recommends that adults 19 years of age and older require about 600-800 International Units of vitamin D daily and 1000-1200 mg. of calcium daily through food and with supplements if needed.

By 2050, the worldwide incidence of hip fracture in men is projected to increase by 310% and 240% in women, compared to rates in 1990.

Endocrine Society issues guidelines for management of menopausal symptoms in breast cancer survivors

Women experiencing menopausal symptoms after receiving treatment for breast cancer should be managed with life-style changes instead of hormonal therapy says the first ever set of professional guidelines issued by the Endocrine Society.

Increasing incidence of breast cancer and improved survival have led to increasing number of women survivors who have a long life ahead, while experiencing the side effects of cancer chemotherapy.  

It is estimated that there are 9.3 million breast cancer survivors worldwide, who experience menopausal symptoms or clinical manifestations of estrogen deficiency.

The comprehensive review was published August 02, 2017 in Endocrine Society’s Journal of Clinical Endocrinology & Metabolism.

Premenopausal women diagnosed with breast cancer experience abrupt onset of estrogen depletion symptoms after treatment with chemotherapy. Just like women experiencing natural menopause these women develop vulvovaginal atrophy (VVA), vasomotor symptoms (VMS), osteopenia, and osteoporosis, CVDs and psychological symptoms like sleep disorders, mood changes and depression.

These women cannot be treated with Hormonal Replacement Therapy (HRT) like their counterparts with natural menopause.

The study’s first author, Richard J. Santen, M.D., of the University of Virginia Health System in Charlottesville, VA said in a News Release by Endocrine Society “Following breast cancer, women should generally not be treated with menopausal hormone therapy but should instead focus on lifestyle modifications such as smoking cessation, weight loss, and regular physical activity.”

“Pharmacologic agents are also available to treat women with severe symptoms. The most important thing to remember is that therapy must be individualized based on each woman’s needs and goals,” he further added.

The author and his colleagues reviewed randomized controlled clinical trials (RCTs), observational studies, evidence- based guidelines, and expert opinion from professional societies to formulate the guidelines.

1) Life style modification advised for all breast cancer survivors include weight management, regular physical activity, smoking and alcohol cessation, vitamin D and calcium supplementation and eating healthy diet.

2) Sleep and other psychomotor symptoms should be treated with mind-brain-behavior or nonhormone, pharmacologic therapy.

3) Vasomotor symptoms respond well to selective serotonin /noradrenaline reuptake inhibitors and gabapentenoid agents.

4) A variety of non-hormonal treatments are available for treating osteoporosis like bisphosphonates, including zoledronic acid (Reclast) and denosumab (Prolia).

5) Treatment of VVA is a grey zone, low dose estrogen applied vaginally is absorbed in blood and although the blood levels are within normal limits, it could still potentially stimulate occult breast cancer cells. Hence, it is not generally advised, especially those on aromatase inhibitors.

6) Intravaginal DHEA and oral ospemiphene is often prescribed to relieve dyspareunia but their safety is still not established in breast cancer survivors.

7) Vaginal laser therapy is being used, but still more data is needed to document its efficacy.

8) Researchers are looking into other therapies in near future like lasofoxifene, neurokinin B inhibitors, stellate ganglion blockade, vaginal testosterone, and estetrol.

9) The most important recommendation is treatment should be individualized according to need of each patient.

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.

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[1] http://www.imsociety.org/manage/images/pdf/fd28270c02bdca95a58a471e1719e9b4.pdf

[2] http://www.imsociety.org/manage/images/pdf/d9cfd8c2b902d63b0c1bb0ada805240d.pdf

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.  

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[1] https://www.iofbonehealth.org/facts-statistics

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

[3] http://www.ncbi.nlm.nih.gov/pubmed/24842796

[4] http://www.asbmr.org/meetings/annualmeeting.aspx

[5] http://www.nejm.org/doi/full/10.1056/NEJMoa1607948#t=article

Forever Young--------- Secret to fountain of youth using ovarian tissue transplant to stall menopause

The dramatic increase in average life expectancy during the 20th century ranks as one of society’s greatest achievements. Most babies born in 1900 did not live past 50! But currently worldwide, the average life expectancy at birth is 71.0 years (68.5 years for males and 73.5 years for females) over the period 2010–2013 according to United Nations World Population Prospects.

Japanese women took the top spot in average life expectancy worldwide for the third consecutive year by living up to average age of 86.83 years. Women, who tend to outlive men, will comprise the bulk of the older adult population and it is predicted that women will live up to 100 by the year 2055.

According to National Institute on Aging, the “oldest old” (people aged 85 or older) constitute 8 percent of the world’s 65-and-over population: 12 percent in more developed countries and 6 percent in less developed countries.

Assuming the median age for the onset of menopause is 51; women will spend about 40 years in menopause deprived of naturally produced oestradiol and progesterone, leading to an increasing incidence of menopause-related disorders such as osteoporosis, dementia, neuromuscular degenerations, cardiovascular diseases and lack of general well-being.

Currently, exogenous oestradiol is being used in its various forms as a preventive as well as curative modality.

This article by Andersen  C.Y and Kristensen S.G in August issue of Reproductive Bio-Medicine Online  discusses a radical new method to postpone menopause. It is based on the hypothesis that ovarian cortical tissue freezing in order to permit future transplantation can become a possible option for a great number of women for postponing menopause and thus alleviating its sequelae.

The surplus ovarian follicles in youth could be cryopreserved, to be used after natural menopause

Currently the main use of ovarian tissue preservation is to preserve the fertility in patients with malignancy  but the endocrine potential of the preserved cryo tissue can be exploited for a more physiological solution to menopause related medical problems.

This appealing technology is already available, but it is to be seen whether it works to postpone menopause, possible in those patients who already have done ovarian preservation.

The ovaries of a newborn female contain a million eggs in the form of resting follicles. An average women will ovulate on an average 450 times from puberty to menopause, the rest 99.9% of eggs will undergo degeneration.

Many of the follicles constituting this enormous loss possess the ability for growth and development and hence sex-steroid secretion, but may not contain oocytes best suited for reproduction.

It is also known that a woman with one ovary is as fertile as women with both the ovaries, according to a large study by Lass et al, 1997 in Journal of Human Reproduction.

Two large studies by  (Bjelland et al, 2014, Yasui et al, 2012) also proved that the age of menopause is only one year earlier for women with one ovary as compared to her normal counterpart.

All the information about safety and efficacy of the re-transplanted ovaries comes from patients affected by cancer who cryopreserved ovarian tissue prior to gonadotoxic insults (chemotherapy or radiotherapy).

It is seen that menstruation cycle is reestablished in most patients with a clinical pregnancy rate of 30% is achieved.

Current experience from the author’s center shows that the re-transplanted ovaries functioned normally for 6-11 years. .

It is noticeable that tissue in these patients has been transplanted with the intention of providing fertility, which requires a larger pool of follicles (i.e. more tissue) to be transplanted than for providing menstrual cycles alone. Therefore the longevity of this tissue if the aim was to postpone menopause would probably be longer.

In addition, ovarian tissue will start to work in most places in the body and may be transplanted subcutaneously during local anaesthesia. In this way natural fertility will be avoided and will prevent senior women from becoming pregnant.

The risks associated with extending the menstrual cycle past the age of natural menstrual cycles may augment the risk for cancers like breast cancer? In recent years much of the risk of breast cancer due to MHT has been alleviated. What about the uterus and the cervix? Should hysterectomy and mastectomy be a part of ovarian transplantation to treat menopause in order to reduce the late-onset risks of cancer?

Careful consideration, individually tailored advice and close monitoring are needed for women who may want to use their ovarian tissue for postponing menopause.

Thousands of women worldwide have already had ovarian tissue frozen for fertility preservation due to different malignancies. For various reasons, a large number of these women will not have used their tissue by the time they reach menopause, either prematurely or at the expected time of menopause and will have tissue available for continued ovarian function. Some of them might want to use it for postponing menopause. They will indeed have this opportunity available without experiencing additional risks and may represent a group of patients in which initial results can be obtained.

Furthermore cryopreservation of isolated human pre-antral follicles is now also available which implies that a predetermined number of follicles may be transplanted in small alginate beads just a few microlitres in size.

Currently, the only use of ovarian cryopreservation is for fertility preservation, but in near future transplantation of frozen-thawed ovarian tissue may serve as a physiological solution to prevent the massive medical legacy of osteoporosis and other menopause-related disorders in the ageing population.

The unanswered questions at present are i) Does the grafted tissue carries a higher risk of malignancy? (ii)The functional integrity of the tissue in women who are menopausal? and (iii) How many women will be attracted to postponed menopause, with continued menstruation?

It is also thoughtful to think of other aspects of this procedure such as these patients sometimes have other co- morbidities that must be taken into account. Access to healthcare will be another challenge as well as whether it will be covered by insurance or not?

If proven successful, will it save billions of dollars in healthcare spending due to morbidities of menopause like CVD and osteoporosis?

The aim of this article was to open up a discussion about the new endeavor of technical opportunity to postpone menopause further? In the future, will it be possible to utilize the enormous loss of human follicles that naturally occur to avoid menopause for prolonged periods of time?

In principle the authors see no reasons why ovarian transplants to treat menopause ought not be pursued. But before going forward a large number of issues need to be addressed and the foremost is to show this form of transplantation is really a useful tool in alleviating the debilities associated with menopause without causing or exacerbating other health risks.

Only then it could be offered as therapy!

References:

• http://www.telegraph.co.uk/news/politics/11348561/Average-life-expectancy-heading-for-100.htm
• https://www.nia.nih.gov/research/publication/global-health-and-aging/living-longer
• http://www.japantimes.co.jp/news/2015/07/31/national/social-issues/japanese-women-top-life-expectancy-third-year/
• http://www.nhs.uk/news/2015/09September/Pages/UK-womens-life-expectancy-second-worst-in-Western-Europe.aspx
• https://www.google.com/?gws_rd=ssl#q=average+life+expectancy+in+world
• http://www.rbmojournal.com/article/S1472-6483%2815%2900249-7/fulltext
• Lass et al, 1997Lass, A., Paul, M., Margara, R., and Winston, R.M. Women with one ovary have decreased response to GnRHa/HMG ovulation protocol in IVF but the same pregnancy rate as women with two ovaries. Hum. Reprod. 1997; 12: 298–300
• Bjelland, E.K., Wilkosz, P., Tanbo, T.G., and Eskild, A. Is unilateral oophorectomy associated with age at menopause? A population study (the HUNT2 Survey). Hum. Reprod. 2014; 29: 835–841
• Yasui, T., Hayashi, K., Mizunuma, H., Kubota, T., Aso, T., Matsumura, Y., Lee, J.S., and Suzuki, S. Factors associated with premature ovarian failure, early menopause and earlier onset of menopause in Japanese women. Maturitas. 2012; 72: 249–255
• Donnez, J., Dolmans, M.M., Pellicer, A., Diaz-Garcia, C., Ernst, E., Macklon, K.T., and Andersen, C.Y. Fertility preservation for age-related fertility decline. Lancet. 2015; 385: 506–507
• Stoop, D., Cobo, A., and Silber, S. Fertility preservation for age-related fertility decline. Lancet. 2014; 384: 1311–1319
• Camboni, A., Van Langendonckt, A., Donnez, J., Vanacker, J., Dolmans, M.M., and Amorim, C.A. Alginate beads as a tool to handle, cryopreserve and culture isolated human primordial/primary follicles. Cryobiology. 2013; 67: 64–6