Eur J Endocrinol. 2012 May;166(5):765-78. doi: 10.1530/EJE-11-0984. Epub 2012 Jan 24.
Vitamin D and fertility: a systematic review.
Lerchbaum E1, Obermayer-Pietsch B.
Vitamin D has been well-known for its function in maintaining calcium and phosphorus homeostasis and promoting bone mineralization. There is some evidence that in addition to sex steroid hormones, the classic regulators of human reproduction, vitamin D also modulates reproductive processes in women and men.
The aim of this review was to assess the studies that evaluated the relationship between vitamin D and fertility in women and men as well as in animals.
We performed a systematic literature search in Pubmed for relevant English language publications published until October 2011.
RESULTS AND DISCUSSION:
The vitamin D receptor (VDR) and vitamin D metabolizing enzymes are found in reproductive tissues of women and men. Vdr knockout mice have significant gonadal insufficiency, decreased sperm count and motility, and histological abnormalities of testis, ovary and uterus. Moreover, we present evidence that vitamin D is involved in female reproduction including IVF outcome (clinical pregnancy rates) and polycystic ovary syndrome (PCOS). In PCOS women, low 25-hydroxyvitamin D (25(OH)D) levels are associated with obesity, metabolic, and endocrine disturbances and vitamin D supplementation might improve menstrual frequency and metabolic disturbances in those women. Moreover, vitamin D might influence steroidogenesis of sex hormones (estradiol and progesterone) in healthy women and high 25(OH)D levels might be associated with endometriosis. In men, vitamin D is positively associated with semen quality and androgen status. Moreover, vitamin D treatment might increase testosterone levels. Testiculopathic men show low CYP21R expression, low 25(OH)D levels, and osteoporosis despite normal testosterone levels.
Int J Fertil. 1991 Jan-Feb;36(1):36-8.
Vitamin B12 deficiency and infertility: report of a case.
Sanfilippo JS1, Liu YK.
An oligomenorrheic infertile patient with evidence of vitamin B12 (cobalamin) deficiency is described. Treatment consisted of clomiphene citrate, human chorionic gonadotropin (hCG), conjugated estrogens, dexamethasone, and ferrous sulfate. Pregnancy occurred after 1,000 micrograms of vitamin B12 was added to the treatment regimen. We believe the patient’s infertility was in part related to the megaloblastic anemia. A possible correlation between vitamin B12 deficiency and failure to ovulate is presented.
Andrologia. 2009 Feb;41(1):46-50. doi: 10.1111/j.1439-0272.2008.00895.x.
Prevalence of low serum cobalamin in infertile couples.
Pront R1, Margalioth EJ, Green R, Eldar-Geva T, Maimoni Z, Zimran A, Elstein D.
A high prevalence of low levels of cobalamin (B12) had been found in a survey of multi-ethnic normal individuals in Israel. The purpose of this study was to investigate the incidence of cobalamin deficiency among Israeli couples suffering from infertility. All couples seen at the in vitro fertilization clinic at an urban hospital (Shaare Zedek Medical Center) in Jerusalem for a 6-month period were invited. Mean cobalamin levels were 259.2 pg ml(-1) in males and 275.1 pg ml(-1) in females (normal >200 pg ml(-1)), 35.5% of 172 men and 23.3% of 223 females had cobalamin deficiency (P = 0.01). There were 171 couples with complete demographic questionnaires and cobalamin values for each partner. In 74 couples (43.3%), one partner was cobalamin deficient, with no significant difference between those with unexplained infertility versus those with explained infertility; and in 13 couples, both partners were cobalamin deficient. Thirty-nine per cent of all men with an abnormal semen analysis had cobalamin deficiency, a finding that requires further investigation. This study questions whether higher rates of male infertility in Israel are partially ascribable to cobalamin deficiency. Recommendation for supplementation in both males and females to achieve high-normal levels of cobalamin would be prudent.
Int J Gen Med. 2011; 4: 99–104.
Published online 2011 Jan 23. doi: 10.2147/IJGM.S16275
Selenium–vitamin E supplementation in infertile men: effects on semen parameters and pregnancy rate
Mohammad K Moslemi1,2 and Samaneh Tavanbakhsh3
This article has been cited by other articles in PMC.
Infertility is an important medical and social problem that has an impact on well-being. A significant development in the last 10 years in the study of human infertility has been the discovery that oxidative sperm DNA damage has a critical role in the etiology of poor semen quality and male infertility. Selenium (Se) is an essential element for normal testicular development, spermatogenesis, and spermatozoa motility and function. The predominant biochemical action of Se in both humans and animals is to serve as an antioxidant via the Se-dependent enzyme glutathione peroxidase and thus protect cellular membranes and organelles from peroxidative damage. We explored the efficacy of Se in combination with vitamin E for improving semen parameters and pregnancy rates in infertile men.
Clin Endocrinol (Oxf). 2012 Sep;77(3):343-50. doi: 10.1111/j.1365-2265.2012.04434.x.
Vitamin D in the aetiology and management of polycystic ovary syndrome.
Thomson RL1, Spedding S, Buckley JD.
Vitamin D deficiency is common in women with polycystic ovary syndrome (PCOS), with the 67-85% of women with PCOS having serum concentrations of 25-hydroxy vitamin D (25OHD) <20 ng/ml. Vitamin D deficiency may exacerbate symptoms of PCOS, with observational studies showing lower 25OHD levels were associated with insulin resistance, ovulatory and menstrual irregularities, lower pregnancy success, hirsutism, hyperandrogenism, obesity and elevated cardiovascular disease risk factors. There is some, but limited, evidence for beneficial effects of vitamin D supplementation on menstrual dysfunction and insulin resistance in women with PCOS. Vitamin D deficiency may play a role in exacerbating PCOS, and there may be a place for vitamin D supplementation in the management of this syndrome, but current evidence is limited and additional randomized controlled trials are required to confirm the potential benefits of vitamin D supplementation in this population.
© 2012 Blackwell Publishing Ltd.
Reprod Biomed Online. 2014 Jun;28(6):743-7. doi: 10.1016/j.rbmo.2014.01.019. Epub 2014 Feb 25.
Role of dehydroepiandrosterone in improving oocyte and embryo quality in IVF cycles.
Zangmo R1, Singh N2, Kumar S1, Vanamail P1, Tiwari A1.
The purpose of this study was to evaluate the role of dehydroepiandrosterone (DHEA) on the number and quality of oocytes and embryos in poor responders undergoing IVF cycles. A total of 50 patients with a history of poor ovarian response in the previous cycle(s) were enrolled in a prospective cohort study. They were treated with oral micronized DHEA 25mg three times a day for 4 months. Oocyte and embryo number and quality were recorded before and after treatment. The results were analysed using Student’s paired t-test. After treatment with DHEA, a significant increase in number of mature follicles was seen in the post treatment period (⩽ 35 years P<0.001; ⩾ 36 years P = 0.002). There were significant increases in numbers of oocytes retrieved, fertilization rates and, consequently, the total number of embryos available. More embryos were vitrified among patients ⩽ 35 years (P<0.001) post treatment, and clinical pregnancy rate in this group was 26.7%. DHEA treatment resulted in a higher number of oocytes retrieved, oocytes fertilized, embryos overall and of grade-I embryos. It can help in increasing pregnancy rate in poor responders. This study was performed to evaluate the role of dehydroepiandrosterone (DHEA) treatment on the number and quality of oocytes and embryos in poor responders undergoing IVF cycles. Fifty patients with a history of poor ovarian response in the previous cycle(s) were enrolled in the study and a prospective cohort study was performed. Patients were prescribed oral micronized DHEA 25mg three times a day for 4 months. Oocytes and embryos in terms of both number and quality were measured before and after treatment. A significant increase in mean number of mature follicles was seen in the post-treatment group. There was a significant increase in the number of oocytes retrieved, fertilization rates and, consequently, in the total number of embryos available after treatment with DHEA. More embryos were vitrified post treatment and the overall pregnancy rate was 20%. DHEA resulted in a significant improvement in the numbers of oocytes retrieved, oocytes fertilized, embryos and grade-I embryos. DHEA can help improve pregnancy rate in poor responders with history of previous failed IVF cycles.
J Assist Reprod Genet. 2007 Dec; 24(12): 629–634.
Published online 2007 Dec 11. doi: 10.1007/s10815-007-9178-x
Update on the use of dehydroepiandrosterone supplementation among women with diminished ovarian function
David Barad,corresponding author1,2,5,6 Hyama Brill,3,5,6 and Norbert Gleicher4,5,6
This article has been cited by other articles in PMC.
We assessed the role of DHEA supplementation on pregnancy rates in women with diminished ovarian function.
This is a case control study of 190 women with diminished ovarian function. The study group includes 89 patients who used supplementation with 75 mg daily of oral, micronized DHEA for up to 4 months prior to entry into in vitro fertilization (IVF). The control group is composed of 101 couples who received infertility treatment, but did not use DHEA. The primary outcome was clinical pregnancy after the patient’s initial visit. We developed a Cox proportional hazards model to compare the proportional hazards of pregnancy among women using DHEA with the controls group.
Cumulative clinical pregnancy rates were significantly higher in the study group (25 pregnancies; 28.4% vs. 11 pregnancies; 11.9%; relative hazard of pregnancy in study group (HR 3.8; 95% CI 1.2–11.8; p < 0.05).
DHEA treatment resulted in significantly higher cumulative pregnancy rates. These data support a beneficial effect of DHEA supplementation among women with diminished ovarian function.
Keywords: Dehydroepiandrosterone, Diminished ovarian reserve, Infertility, In vitro fertilization, Pregnancy rates, Age, Life table analysis
Med J Armed Forces India. 2015 Jul;71(3):274-7. doi: 10.1016/j.mjafi.2014.12.022. Epub 2015 Feb 25.
Dehydroepiandrosterone: A panacea for the ageing ovary?
Naredi N1, Sandeep K2, Jamwal VD3, Nagraj N4, Rai S4.
Considerable improvements and advancements have been made in the treatment of infertility but poor ovarian reserve whether due to prematurely or a physiologically ageing ovary, continues to be one of the few unresolved problems of modern infertility care. Fertility researchers had been active for quite some time to find a way to help reverse the effects of ageing on the ovaries but none made an impact till the introduction of Dehydroepiandrosterone [DHEA]. DHEA a mild, and therapeutically well tolerated, male hormone has emerged as a real potential candidate to reverse the effects of ageing on ovaries. Apart from this, DHEA has also been postulated to improve egg and embryo quality, pregnancy rates and time to conception and reduces miscarriage rates. This review attempts to highlight the mechanism of action of this drug, its indications and its current status for treating women with decreased ovarian reserve.
DHEA; Dehydroepiandrosterone; Premature ovarian ageing
PMID: 26288496 [PubMed] PMCID: PMC4534532 [Available on 2016-07-01]
J Steroid Biochem Mol Biol. 2015 Jan;145:213-25. doi: 10.1016/j.jsbmb.2014.06.003. Epub 2014 Jul 5.
DHEA, DHEAS and PCOS.
Goodarzi MO1, Carmina E2, Azziz R3.
Approximately 20-30% of PCOS women demonstrate excess adrenal precursor androgen (APA) production, primarily using DHEAS as a marker of APA in general and more specifically DHEA, synthesis. The role of APA excess in determining or causing PCOS is unclear, although observations in patients with inherited APA excess (e.g., patients with 21-hydroxylase deficient congenital classic or non-classic adrenal hyperplasia) demonstrate that APA excess can result in a PCOS-like phenotype. Inherited defects of the enzymes responsible for steroid biosynthesis, or defects in cortisol metabolism, account for only a very small fraction of women suffering from hyperandrogenism or APA excess. Rather, women with PCOS and APA excess appear to have a generalized exaggeration in adrenal steroidogenesis in response to ACTH stimulation, although they do not have an overt hypothalamic-pituitary-adrenal axis dysfunction. In general, extra-adrenal factors, including obesity, insulin and glucose levels, and ovarian secretions, play a limited role in the increased APA production observed in PCOS. Substantial heritabilities of APAs, particularly DHEAS, have been found in the general population and in women with PCOS; however, the handful of SNPs discovered to date account only for a small portion of the inheritance of these traits. Paradoxically, and as in men, elevated levels of DHEAS appear to be protective against cardiovascular risk in women, although the role of DHEAS in modulating this risk in women with PCOS remains unknown. In summary, the exact cause of APA excess in PCOS remains unclear, although it may reflect a generalized and inherited exaggeration in androgen biosynthesis of an inherited nature.
Copyright © 2014 Elsevier Ltd. All rights reserved.
Trends Endocrinol Metab. 2011 Mar;22(3):103-9. doi: 10.1016/j.tem.2010.12.002. Epub 2011 Feb 1.
Metabolic syndrome and oocyte quality.
Cardozo E1, Pavone ME, Hirshfeld-Cytron JE.
Metabolic syndrome affects one in four women in the USA, and the incidence is rising every year. Metabolic syndrome is strongly associated with development of coronary artery disease and diabetes. Women of reproductive age are not spared from the complications of metabolic syndrome, which overlaps with obesity and polycystic ovary syndrome (PCOS), both of which are linked to infertility and poor reproductive outcome. Therefore, the relationship between the metabolic syndrome and reproductive dysfunction is an active area of study. In this review, we discuss the animal and human data available to determine if the abnormality is at the level of the ovary and/or endometrium, and discuss the underlying mechanisms causing the associated poor reproductive outcomes.
Copyright © 2010 Elsevier Ltd. All rights reserved.
PMID: 21277789 [PubMed – indexed for MEDLINE]
BMJ. 1998 Aug 1; 317(7154): 329–332.
Polycystic ovarian syndrome: the metabolic syndrome comes to gynaecology
Zoe E C Hopkinson, clinical research fellow,a Naveed Sattar, specialist registrar in clinical biochemistry,b Richard Fleming, consultant grade biochemist,a and Ian A Greer, Muirhead professor of obstetrics and gynaecologya
This article has been cited by other articles in PMC.
Polycystic ovarian syndrome is the most common form of anovulatory infertility.1 Its association with menstrual disturbance and altered hormonal parameters leads many affected women of reproductive age to attend a gynaecology or infertility clinic. The aetiology of the condition is unknown, but recent evidence suggests that the principal underlying disorder is one of insulin resistance, with the resultant hyperinsulinaemia stimulating excess ovarian androgen production. Associated with the prevalent insulin resistance, these women exhibit a characteristic dyslipidaemia and a predisposition to non-insulin dependent diabetes and cardiovascular disease in later life. Thus, polycystic ovarian syndrome seems to have many of the hallmarks of the metabolic syndrome.2–4 This article focuses on the recent change in attitudes to polycystic ovarian syndrome arising from the link with insulin resistance—a concept that not only has major implications for the health of affected women but also offers a potential for new treatments.
It is evident that polycystic ovarian syndrome should no longer be considered a purely gynaecological disorder
Affected women seem to have subclinical insulin resistance and a form of the metabolic syndrome that manifests itself in early adult life with gynaecological symptoms
They may therefore gain particular benefit from early screening for cardiovascular risk factors, particularly glucose intolerance
Intervention with insulin sensitising agents, such as metformin, may play a major role in the future treatment of this condition, with the potential capacity to improve both endocrine and metabolic disturbances and reduce the risk of vascular disease
This approach may replace therapies used to treat individual components of polycystic ovarian syndrome such as hirsutism which may reflect a “downstream” feature of this complex metabolic syndrome
Diabetologia. Author manuscript; available in PMC 2015 Jun 1.
Published in final edited form as:
Diabetologia. 2015 Apr; 58(4): 707–715.
Published online 2015 Jan 18. doi: 10.1007/s00125-015-3493-z
History of infertility and risk of type 2 diabetes mellitus: a prospective cohort study
Deirdre K. Tobias,1,2 Audrey J. Gaskins,2,3 Stacey A. Missmer,3,4,5 Frank B. Hu,2,3,4 JoAnn E. Manson,1,3 Germaine M. Buck Louis,6 Cuilin Zhang,6 and Jorge E. Chavarro2,3,4
We sought to evaluate the relationship between delayed conception and type 2 diabetes risk, given that there are plausible underlying mechanisms linking the two, including inflammation and insulin resistance.
Participants of the Nurses’ Health Study II prospective cohort were included if they were free of chronic disease (cardiovascular disease, type 2 diabetes, cancer) at baseline. Biennial questionnaires updated information on infertility status (>12 months attempted pregnancy), lifestyle characteristics and several health-related outcomes. Self-reported cases of diabetes were confirmed using a follow-up questionnaire. Multivariable Cox proportional hazards models were used to compute the HRs and 95% CIs).
Incident type 2 diabetes occurred in 5,993 of the 112,106 participants over 24 years of follow-up (1989–2013). A history of infertility was reported in 27,774 (24.8%) women and was associated with a 20% greater risk of developing diabetes, compared with those never reporting infertility (HR 1.20 [95% CI 1.14, 1.28]), after adjusting for age, lifestyle factors, marital status, oral contraceptive use, family history of diabetes and BMI. Compared with women without a history of infertility, the causes of infertility associated with a higher diabetes risk were ovulation disorders (HR 1.43 [95% CI 1.29, 1.58]) and tubal factor (HR 1.34 [95% CI 1.13, 1.58]). Cervical factor (HR 1.06 [95% CI 0.81, 1.40]) and endometriosis (HR 1.06 [95% CI 0.89, 1.27]) were not associated, while male factor infertility was associated with a modestly higher diabetes risk (HR 1.15 [95% CI 1.00, 1.33]).
These novel findings suggest a history of infertility, particularly that related to ovulation disorders and tubal blockage, is significantly associated with a higher risk of type 2 diabetes.
Keywords: Epidemiology, Fertility, Gestational diabetes, Infertility, Life course epidemiology, Ovulatory disorders, Prospective cohort, Reproductive health, Type 2 diabetes
BMJ. 2006 Feb 25; 332(7539): 434–435.
Should obese women with polycystic ovary syndrome receive treatment for infertility? Given the risks such women will face in pregnancy, they should lose weight first?
Adam H Balen, professor of reproductive medicine and surgery
General Infirmary, Leeds LS2 9NS
Martin Dresner, consultant anaesthetist, Eleanor M Scott, senior lecturer in diabetes and endocrinology, and James O Drife, professor of obstetrics and gynaecology
General Infirmary, Leeds LS2 9NS
This article has been cited by other articles in PMC.
Polycystic ovaries are seen at ultrasound in 20-25% of women, and the prevalence of polycystic ovary syndrome (PCOS) seems to be rising because of the current epidemic of obesity.1 The syndrome accounts for 90-95% of women who attend infertility clinics with anovulation. The considerable risks in pregnancy associated with obesity are not usually appreciated when patients with PCOS attend clinics and request fertility treatment. Is it appropriate to offer treatment or to insist on weight loss? Or does any overweight woman have the right to receive treatment, irrespective of the possible outcome?
The syndrome is defined by any two out of the following criteria: infrequent or absent menstruation, indicating anovulation; hyperandrogenism; and polycystic ovaries diagnosed by ultrasound after the exclusion of other aetiologies of menstrual disturbance and hyperandrogenism.2 At least 40% of women with PCOS are obese,1 and they are more insulin resistant than weight matched women with normal ovaries. Increasing abdominal obesity is correlated with reduced menstrual frequency and fertility, together with greater insulin resistance.1,3
Pregnancy carries considerable risks for women who are obese; these include increased rates of congenital anomalies (neural tube and cardiac defects), miscarriage, gestational diabetes, hypertension, and problems during delivery.4,5 Pregnancy exacerbates any underlying insulin resistance, and as a result women with PCOS and obesity have an increased risk of gestational diabetes.6
Increasingly many of these young women also have type 2 diabetes. If the diabetes is diagnosed before conception, patients are often treated for the coexistent features of the metabolic syndrome with statins, angiotensin converting enzyme (ACE) inhibitors, metformin, and thiazolidinediones, all of which are contraindicated in pregnancy. Because these women have irregular menstruation it is not uncommon, if they do conceive, for them not to realise until after organogenesis has occurred. Unfortunately type 2 diabetes is still commonly regarded as being “mild diabetes” but the outcomes of pregnancy in women with type 2 diabetes are much worse than in the general population and are at least equivalent to, if not slightly worse than, in women with type 1 diabetes.7
Overweight mothers are more likely than others to have hypertension and thromboembolism, leading to a higher risk of maternal mortality. In 2000-2, of the 261 deaths reported to the UK Confidential Enquiry into Maternal Health,8 78 women (35%) were obese, compared with 23% of women in the general population, and of these more than a quarter had a body mass index greater than 35. Some of the women who died were so obese that they required special equipment for delivery or special arrangements for caesarean section because their weight exceeded the maximum for the operating table.8
Several studies have shown that weight loss in women with PCOS improves the endocrine profile, the menstrual cycle, the rate of ovulation, and the likelihood of a healthy pregnancy.9 Even a modest loss of 5% of total body weight can achieve a reduction of central fat, an improvement in insulin sensitivity, and restoration of ovulation. Lifestyle modification is clearly a key component for the improvement of reproductive function in overweight women with anovulation and PCOS.10
Such women should be encouraged to lose weight before having treatments to induce ovulation (such as clomifene citrate or gonadotrophins), both to improve the likelihood of ovulation and to enhance ovarian response. Monitoring treatment is also harder in obese women because their ovaries are more difficult to see on ultrasound scans, thus raising the risk of missing multiple ovulation and multiple pregnancy. National guidelines in the United Kingdom for managing overweight women with PCOS advise weight loss, preferably to a body mass index of less than 30, before starting drugs for ovarian stimulation.10
The use of insulin lowering or sensitising agents has excited much interest in the management of PCOS. Metformin inhibits hepatic production of glucose, thereby decreasing insulin secretion, and enhances insulin sensitivity in cells. A systematic review concluded that metformin benefits women with PCOS by reducing serum insulin concentrations and thereby lowering androgen levels, facilitating ovulation, and improving reproductive outcomes.11 Metformin seems to be less effective for women with anovulation and extreme obesity, although perhaps a higher dose is required than currently prescribed.12
Many obese women who wish to conceive are now prescribed metformin, often at body weights greater than would be permissible for treatment to induce ovulation. Those who ovulate and conceive while remaining obese will have to face considerable additional risks during pregnancy. Is it ethical to treat these women with metformin unless they have already lost weight? At the very least the risks of the pregnancy to mother and child should be explained, understood, and actively managed before embarking on treatment. The importance of encouraging and achieving weight loss as first line treatment cannot be overestimated. We suggest that women with obesity and PCOS should defer even treatment with metformin until they reach a target body mass index of 35 or less.