Menopause is related to lifespan in all species. When they begin to undergo menopause, B6J mice deteriorate in physical activity at 525 days approximately, and die at 636 days approximately. That is, after their ovaries are depleted of follicles, the mice themselves become less active and frail. When we transplanted ovaries from young B6J mice who were only 70-140 days old, the old mice began to cycle again and were truly rejuvenated. They now lived to 915 days approximately, a 44 per cent increase in lifespan approximately (Kagawa et al).
Does this have any application to humans in view of the negative recommendations of the famous WHI study of 2003, in which the usage of HRT in the united states dropped from almost 40 per cent of women to only 4 per cent now? Are these women who were scared by the WHI study, doomed to a briefer life span because of this hormonal deprivation, an outcome which this mouse study would suggest will occur to them? Indeed,can we possibly extend not only the reproductive lifespan of woman, but their lifespan in general by transplantation of a young ovary, and could this just be one of their own ovaries (or just a small piece of one of their own ovaries), frozen when they were young? 50 per cent of women born today may live to 100. they will not want to be in menopause for half their life. HRT or transplantation of ovary tissue frozen when they were young may improve these odds.
We looked at our current results with transplantation of fresh and frozen ovary tissue in humans, and were amazed to see how very long these pieces of ovarian tissue last whether fresh or frozen (Anderson et al RBMOnline; Silber et al Fertil Steril, Molec Human Reprod, New Engl J Med). We have shown that cryopreservation of ovary from young women undergoing cancer treatment or tixic therapy for multiple sclerosis, or who have to put off childbearing for personal reasons, or for Turners Syndrome patients is very robust and successful, with almost all such grafts working after thaw and transplantation. What about if this could be used to prolong the reproductive lifespan of women and to even eliminate menopause, and lengthen life?
In a total of 11 fresh transplants (9 isografts and 2 allografts) in otherwise menopausal women, we have reported consistently a very robust finding that FSH and ovulatory cycling resumes at exactly 4.5 months. I does not matter what the case. Cycling and hormone production and usually eventually pregnancy resume by 4.5 months. the same results were observed in 6 frozen ovary transplants. thus far we have 14 healthy babies from these transplants. from all around the world thus far there are over 30 babies from frozen ovarian grafts and including fresh, there are over 40 healthy babies. all 17 of our human transplants resulted in normal cycling by 4.5 months, and the AMH rose as the the FSH came down to normal always at 4.5 months. patients lose no eggs from ischemia time of the grafting process we have found, and with vitrification they lose no eggs from the freezing and thawing process. most grafts composed of only a fourth of an ovary, lasted about 8 years or longer.
at the istanbul meeting, i then described in detail the process of ovarian tissue vitrification, thawing, and transplantation. i dont have time or space for going over those details here, but all are welcome to spend a few days with us in st louis, and that will be plenty of time to learn these relatively easy techniques.
this means that if patients were to have ovarian tissue frozen to preserve their fertility, they might never have to go through menopause. we know that unilateral oophorectomy does not hasten menopause or make it come any earlier, via compensatory mechanisms which slow down follicle recruitment when the total follicle count is reduced. so at 50 when they would otherwise go through menopause, they could have a pieces of ovary tissue transplanted back, not just for fertility in older years, but even to maintain hormonal function without exogenous HRT.
So does this not contradict what we thought about HRT from the WHI study in 2003? The tragic impact of the 2003 WHI study is that now only 5 per cent approximately of American women use HRT, and they are suffering because of it (Sprague, BL, obster Gynecol 2012; 120:595-603). Since the scare created by the WHI study originally in 1999, HRT has diminished dramatically and we are seeing more hip fractures, more breast cancer, more vaginal atrophy and urinary infections, more heart disease, and even earlier dementia because of this (Rossouw et al JAMA 2002; 288: 321). The WHI paper was hyped prematurely with a PR blitz, but in fact subsequent papers showed no increased risk of coronary heart disease or breast cancer, and in fact the risk of breast cancer was decreased by being on estrogen alone. without HRT the risk is increased( Gottlieb, WSJ, aug 30, 2007; Stevenson et al Atherosclerosis. 2009 dec; 207(2):336-340). Osteoporosis really took off after women stopped HRT after the WHI study (Islam, s, menopause.2009;16:77-83; Karim, R, menopause. 2011;18:1172-1177).
A huge meta-analysis showed dramatic reduction in coronary heart disease in women who were on HRT (Saltpeter, SR et al. J. Gen. Intern. Med. 2006;21:363-366). This was verified the next year by the WHI itself (JAMA 2004 apr;291: 1701-1712; JAMA 2007 apr; 297: 1465-1477). The dramatic reduction in breast cancer in women on estrogen was strongly verified in 2012 (Anderson, g; Lancet Oncology 2012;13: 476-486). The WHI study and the way it was reported was strongly condemned in 2011 thus: "The excessive conservatism engendered by the presentation to the media of the first results of the WHI in 2002 has disadvantaged nearly a decade of women who may have missed the potential therapeutic window to reduce their future cardiovascular, fracture, and dementia risk" ( Sturdee and Pines. Climacteric 2011; 14: 302-320). Many of the "substitute treatments proposed to make up for stopping HRT have produced disastrous increases in disease. For example it was suggested that women take calcium supplements to increase the lost bone from not taking estrogen. but this resulted in a dramatic increase in myocardial infarction ( Boland et al, BMJ 2008;336:262).
Four different prospective studies ( Nurse's 1985, Kaiser Walnut Creek, 1987, LRC, 1988, Leisure World 1988, Upsalla, 1992, Nurse's, 2000) before WHI demonstrated lower risk of heart disease in those on HRT. but these were women who started HRT right near the time of menopause, not 12 years later, as was the case with the discredited WHI study. More recently a huge meta-analysis verifed a reduced risk of coronary artery disease in women on HRT (Hsia J et al, Arch Intern Med 2006;166:357-365). Skin thickness has been shown to deteriorate with menopause but not with women on HRT (Chen L Skin Res Technol 2001;7:95-97). Breast cancer decreases in women on estrogen compared to those not treated (Stefanick et al JAMA 2006;295: 1647-1657). Even the teeth are better in women on estrogen (Birkenfeld et al. Menopause 1999;6: 129-133). Estrogen treatment lessens aging eye disease (Guaschino et al. Menopause. 2003;10:53-57). Wound healing is faster in women on estrogen ( Ashcroft et al. Am J. Pathol. 1999;155:1137-1146). Connective tissue collagen is stronger and thicker in women on estrogen ( Brit J Obstet Gynecol, 1985: 92: 256-259). So many studies both before and after the WHI study have shown dramatically better health in all ways for women who are not deprived of hormones when they reach menopause.
Our simple mouse study, which shows over a 40 per cent increase in longevity for older mice given ovaries from young mice, supports in a simple way that hormone deprivation in menopause compromises health and even longevity for menopausal women.
Dr Sherman Silber, Infertility Center of St Louis, St Lukes Hospital, USA
www.infertile.com
