Sex hormones in women with kidney disease

INTRODUCTION

Chronic kidney disease (CKD) in women is often accompanied by menstrual and fertility disorders as a consequence of kidney-mediated endocrine disturbances. Although nephrologists are often viewed as primary care providers for their patients [1], discussion of menopause, pregnancy, contraception and gynecological issues is uncommon [2]. In a study of 100 women with CKD with and without a functioning kidney transplant referred to a gynecology clinic by a nephrologist, menstrual disorders accounted for 39% and menopause 12% of the referrals [3]. However, gynecological assessment revealed that 85% of these women reported menstrual disorders and more than a third were postmenopausal, with 20% of the postmenopausal women <40 years of age, highlighting that the nephrologist may underappreciate the extent of gynecological disorders in this population. A study examining gynecological and reproductive issues in 76 women <55 years of age with end-stage kidney disease (ESKD) reported amenorrhea in 58% and menopause in 28% of patients [2], again underscoring the high prevalence of disorders of sexual endocrinology in the women with CKD (Figure 1).

FIGURE 1:

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Gonadotropin, estradiol and progesterone levels throughout life and on dialysis in the premenopausal years [4]. (Reprinted with permission.) E2, estradiol; FSH, follicle-stimulating hormone; LH, luteinizing hormone; P, progesterone.

The kidney is a key regulator of sex hormones in patients with CKD [4]. The onset of kidney disease results in ovarian dysfunction in women, largely through disruption of the normal hypothalamus–pituitary–gonadal axis, with the magnitude of dysfunction seemingly directly related to the degree of CKD (Figure 2). Thus, disturbances in the menstrual cycle and fertility become increasingly common as CKD progresses in women and amenorrhea and infertility are the norm once ESKD is reached [2]. In a study of 238 women with ESKD on hemodialysis >45 years of age who were amenorrheic, 65% reported amenorrhea due to ‘natural menopause’ (i.e. not related to surgery or other medical intervention) at a mean age of 45.9 years [5], a marked divergence from the average age of menopause of 51 years in the general population [6]. While it is possible that women with ESKD become menopausal at an earlier age due to the comorbid conditions and treatments leading to CKD, including systemic lupus erythematosus [7], diabetes [8, 9] and smoking [10], the presence of CKD itself also appears to impair sex hormone production and function.

FIGURE 2:

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The hypothalamic–pituitary–gonadal axis in women with kidney disease. CKD, chronic kidney disease; FSH, follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone.

The relationship between the kidney and the hypothalamic–pituitary axis is complex. In addition to adversely affecting gonadal function, CKD equally modifies nongonadal hormones, such as those within the hypothalamic–pituitary–thyroidal and hypothalamic–pituitary–adrenal axes [11]. How the kidney both affects and is affected by sex hormones in women will be the focus of this review.

HOW KIDNEY DISEASE AFFECTS SEX HORMONES

The absence of menses for 1 year accompanied by an increase in follicle-stimulating hormone (FSH) levels to >30 mIU/L is considered consistent with menopause [6]. However, a small study of hemodialysis-dependent women [12] reported that while serum FSH levels were >100 mIU/L in all women of postmenopausal age, levels were substantially lower (13.4 ± 1.5 mIU/mL) in premenopausal women despite more than half being amenorrheic, the implication being that permanent cessation of menses does not necessarily imply menopause and ovarian failure in this population.

The limited literature examining sex hormones in those with CKD focuses largely on ESKD patients; information about fertility and related gynecological issues throughout the stages of CKD is lacking. The available studies support defects in the hypothalamus as a cause of failure of the hypothalamic–pituitary–gonadal axis, although the exact mechanisms remain to be elucidated.

As CKD progresses, tonic release of gonadotropin-releasing hormone (GnRH) regulating basal secretion of the gonadotropins, luteinizing hormone (LH) and FSH appears to remain normal, but there is loss of the normal cyclic release of GnRH by the hypothalamus, leading to loss of normal pulsatile gonadotropin secretion by the pituitary and resulting in impaired ovulation. Why cyclic release of GnRH is compromised in the setting of CKD is unclear, but hyperprolactinemia and high levels of GnRH and LH caused by reduced clearance have been implicated (Figure 2). Treatment with peritoneal or conventional hemodialysis does not restore hypothalamic–pituitary–ovarian function; however, treatment with increased intensity of hemodialysis [13] and kidney transplantation [14] often, but not always [3], restores menses and fertility.

Although it is unclear at what threshold of kidney dysfunction prolactin levels begin to increase [15], hyperprolactinemia in CKD is the consequence of both reduced renal clearance and upregulated production of prolactin due to CKD-mediated inhibition of dopaminergic activity [16]. As a result of increased prolactin levels, normal cyclic GnRH secretion decreases, resulting in the loss of pulsatile LH and FSH release, ultimately leading to the decline and eventual absence of estradiol release and an ensuing lack of progestational changes in the endometrium. The outcome is irregular menses, anovulation, amenorrhea and infertility in women with CKD. However, treatment with bromocriptine in three patients with ESKD and hyperprolactinemia reduced prolactin levels but did not result in a consistent effect on gonadotropin responses [12], suggesting that factors other than hyperprolactinemia are involved in the ovarian dysfunction of CKD.

The sex hormone levels of women with ESKD, and probably nondialysis-dependent CKD, do not vary as would be normally expected during a healthy menstrual cycle. Although levels of plasma estradiol, progesterone and FSH in women of premenopausal age with ESKD are similar to those observed in the follicular phase of the menstrual cycle in healthy age-matched controls, estradiol levels fail to increase and peak midcycle [12]. Similarly, while follicular phase LH levels are greater in women with ESKD compared with controls, levels are low when compared with the normal midcycle LH surge [12].

In a study of eight women of premenopausal age with ESKD and four age-matched healthy controls, the pattern of gonadotropin release in response to stimulation with ethinyl estradiol was strikingly different between the two groups. The ESKD group did not demonstrate the expected initial suppression followed by the normal surge of plasma LH and FSH in response to estrogen [12] further highlighting that the ovulatory and menstrual irregularities observed in the CKD population are likely to be the consequence of hypothalamic and pituitary, rather than ovarian, dysfunction. Further supporting the hypothesis that primary ovarian function appears to be preserved in the setting of CKD is the fact that as plasma LH and FSH levels rise in response to the administration of the antiestrogenic agent clomiphene citrate, estradiol levels also increase, suggesting that the ovary remains responsive to gonadotropins [12].

Despite anovulatory menstrual cycles, the endometrium of women with CKD remains responsive to ovarian sex hormones, as premenopausal women with ESKD developed vaginal spotting in response to ethinyl estradiol [12]. A study of 75 women of reproductive age with ESKD reported that while endometrial reactivity to circulating estrogens was preserved, pathological endometrium morphology was a common finding in this population compared with age-matched healthy controls [17], though registry data have not shown a higher standardized incidence of endometrial cancer in women with CKD [18]. Of note, compared with the general population, cervical cancer incidence is higher in the female dialysis population [19] and is presumed due to relative immunosuppression in the setting of a viral-mediated cancer.

Estradiol, estrone and estrone sulfate are the primary circulating estrogens in women, although the amount of estrone relative to estradiol increases with menopause [20]. Oral administration of estradiol or conjugated equine estrogens results in a high estrone:estradiol ratio, whereas use of nonoral routes results in approximately equal amounts of each compound. While little estradiol and estrone are excreted in the urine, the presence of kidney disease alters the pharmacokinetics of both endogenous and exogenous forms of estradiol. Free and total estradiol plasma concentrations are higher in women with ESKD both at baseline and after an oral estradiol dose, but no change occurs in estrone concentrations. Neither estradiol nor estrone is removed by dialysis, suggesting that women with CKD should receive a 50% reduced oral estradiol dose [20].

HOW SEX HORMONES AFFECT THE KIDNEY

It has been previously suggested that CKD progresses more slowly in women compared with men [21, 22], though the relationship between sex, sex hormones and diabetic kidney disease remains unclear [23, 24]. However, while the recent Chronic Kidney Disease Prognosis Consortium study [25], a meta-analysis including more than 2 million participants, showed an increased risk of all-cause and cardiovascular mortality in men compared with women at all levels of estimated glomerular filtration rate (eGFR), there was no evidence of a sex difference in associations of eGFR and urinary albumin; creatinine ratio with end-stage renal disease, even after stratifying by age to account for the potential impact of menopause. However, the incidence and prevalence of renal replacement therapy in men exceeds that in women [26, 27].

The impact of sex hormones on kidney function and disease remains an area not without controversy; if female sex is renoprotective, whether this protection is mediated by lack of testosterone or the presence of estrogen is unclear and is an area of active investigation [28]. Estradiol exerts its actions via estrogen receptor (ER) α and ERβ, with ERα being more predominant in the kidney of female rats and ERβ more common in the kidney of male rats [29], though the exact biological actions mediated via these receptors are largely unknown. ERs are present in the mesangial, endothelial and vascular smooth muscle cells of the kidney [30]. As has been reviewed elsewhere [31], sex hormones have been shown in animal studies to affect a number of renal cellular processes by influencing both the synthesis and activity of a number of cytokines, growth factors and vasoactive agents. Estrogen plays a significant role in determining renin–angiotensin system activity and transduction of transforming growth factor-β signal and is involved in the regulation of genes involved in extracellular matrix metabolism [31]. Estrogen deficiency can accelerate the progression of glomerulosclerosis in susceptible mice. For example, ovariectomized ROP Os/+ mice developed more severe glomerulosclerosis and kidney dysfunction than age-matched female controls [32]. Other rodent models have shown positive effects of estrogen replacement; estradiol therapy after ovariectomy has been demonstrated to normalize the diminished renal functional reserve in oophorectomized Wistar rats [33], to lessen glomerular damage in uninephrectomized, spontaneously hypertensive rats [34] and to reduce glomerulosclerosis in aging Dahl salt-sensitive rats [35]. Interestingly, while continuous treatment with exogenous estradiol after ovariectomy in ROP Os/+ mice prevented microalbuminuria and excess extracellular matrix accumulation, intermittent treatment with estradiol showed no effect [36], suggesting that the timing of initiation, pattern and duration of hormone therapy may play a role in the potential preservation of kidney function. However, not all studies have shown a renoprotective effect of estradiol. Female mice transgenic for an ERα gene deletion show podocyte damage and apoptosis, which was prevented by ovariectomy and reproduced in B6 mice by testosterone supplementation [37]. In contrast, female ERα knockout mice were protected from the development of albuminuria and glomerulosclerosis associated with diabetes, suggesting that ERα mediates a pathophysiogical effect on the diabetic female kidney. Other studies have supported an adverse effect of estrogen on the kidney in the setting of diabetes. Puberty has been reported to herald the onset of diabetic nephropathy [38], particularly in girls, with the decline in kidney function accelerating after puberty in women compared with age-matched men [38, 39], suggesting that estradiol may have a detrimental effect on kidney function in women with diabetes. While treatment of streptozotocin-induced diabetic rats with 17β-estradiol decreased glomerulosclerosis, tubulointerstitial fibrosis and albuminuria [40–43], the converse was observed in Cohen rats, with ovariectomy reducing and 17β-estradiol exacerbating diabetic renal disease [44]. Furthermore, treatment with testosterone in ovariectomized Cohen rats resulted in progressive kidney damage [45]. The possibility of strain-specific effects of sex hormones has been raised, and also that ovariectomy itself may be renoprotective by removing the source of testosterone production [46]. Diabetes itself alters sex hormone production in both women and men and sex hormone levels are associated with diabetes risk and glycemic control [47]. In women, a systematic review suggested that higher testosterone levels are associated with increased diabetes risk [48], but a more recent prospective study reported that neither estrogen nor testosterone levels predict diabetes risk in women [49]. Women with types 1 and 2 diabetes often present with clinical manifestations of impaired ovarian function [23, 47], and estradiol has been reported as higher [48, 50], lower [51] or similar [52] and testosterone higher [48, 53] in women with diabetes compared with nondiabetic age-matched controls; as renal function was not reported in these studies, it is not possible to differentiate potential kidney-mediated compared with diabetes-mediated sex hormone alterations. The role of sex hormones in diabetic kidney disease thus remains controversial and further study is required in this area.

EXOGENOUS SEX HORMONES

The results from in vitro and animal studies have not translated directly to humans. While endogenous estradiol may be renoprotective in women [54], the use of exogenous sex hormones is more controversial. Studies examining the roles of endogenous and exogenous estradiol in kidney health and disease have at times reported differing if not directly opposing results, which likely reflect variations in the type and formulation of sex hormone, route of administration, timing of initiation and duration of use [55].

Oral contraceptive

In the general population, the use of oral contraceptives (OCs) is associated with a small but detectable increase in blood pressure [56] and a slightly increased risk of hypertension [57]. Nonoral administration of sex hormones for contraception, however, is not associated with increased blood pressure [58], likely reflecting avoidance of the ‘first-pass effect’ via hepatic metabolism. While we are not aware of any studies specifically examining the effects of OC use in the population with CKD, administration has been associated with an increased renal tubular responsiveness to changes in sodium intake leading to an increased GFR and filtration fraction [59], an increase in renal nitric oxide [60] and and an increase in renin–angiotensin activity (RAS) [56, 61–64], which has been linked to a greater risk of diabetic nephropathy [62]. In a large cross-sectional study, OC use was associated with a 1.90 odds ratio of albuminuria, with a nonstatistically significant trend toward a greater association between higher doses of ethinyl estradiol and risk [65]. Of note, the dose and type of the progestin included in the OC has also been implicated in the increased RAS activity associated with OC use [66]. Blood pressure returns to baseline with cessation of the OC [57], and 6 months after OC withdrawal, a decreased GFR but no change in albumin excretion was observed in 13 hypertensive young women [67]. A systematic review concluded there was limited evidence on both oral and transdermal contraceptive use among kidney transplant recipients, but the available literature suggested that both were effective in terms of preventing pregnancy, with no overall changes in biochemical measures [68].

Postmenopausal hormone therapy

The rate of progression of CKD may be slower in women compared with men, although this relative protection appears to diminish with age and potentially with menopause [54], suggesting that estradiol, levels of which drop by 80% in menopause [47], is the renoprotective agent. However, human studies have reported conflicting results with the use of exogenous estrogen. The use of oral estrogen in an elderly community-dwelling population has been associated with faster loss of kidney function [69]. While a cross-sectional study of 1518 postmenopausal women reported a positive association between hormone therapy use and albuminuria, with an odds ratio of 2.56 (95% CI 1.32–4.97) in women with >5 years of postmenopausal therapy compared with nonusers [65], data from the Nurses' Health Study demonstrated that >6 years of postmenopausal therapy use was associated with a lower urinary albumin:creatinine ratio in nondiabetic women [70]. In a cross-sectional study of 1044 older postmenopausal community-dwelling women, estrogen users had better eGFR and blood pressure than did nonusers. However, 10-year follow-up of 443 participants showed improved blood pressure and decreased urinary albumin excretion among mostly long-term current users, with no difference in GFR by estrogen use [71]. A study of 16 diabetic and hypertensive early postmenopausal women described increased creatinine clearance and decreased urinary protein excretion 3.5 months after initiation of postmenopausal hormone therapy [72]. A case–control study reported greater creatinine clearance in hormone therapy users compared with nonusers [65]. In contrast, postmenopausal women on hormone therapy in the Insulin Resistance Atherosclerosis Study had a significantly reduced risk and amount of albuminuria at 5 years compared with nonusers, but no differences were observed in kidney function [73]. A 6-month randomized controlled study in postmenopausal women with type 2 diabetes showed no effect of treatment with conjugated equine estrogen and medroxyprogesterone acetate on urinary albumin excretion [74]. These divergent results may reflect important factors pertaining to postmenopausal hormone therapy, such as route of administration, timing of initiation and type of concomitant progestin therapy, which were not always reported in these studies, all of which can contribute to the wide variations in outcomes [55, 75].

SEX HORMONE USE IN CKD

Sexual dysfunction is common in ESKD [76]. Amenorrheic young women with ESKD on dialysis have lower trabecular bone mineral density (BMD) and evidence of increased bone resorption when compared with regularly menstruating women on dialysis [77]. However, there are limited studies evaluating therapies, including hormone therapy, to treat hypogonadal signs and symptoms in the CKD population [78]. In a study of 255 women with ESKD ≥45 years of age, 54% stated they would not take postmenopausal hormone therapy if prescribed by their nephrologist [5]. Perhaps as a consequence of patients' unwillingness, postmenopausal hormone therapy is rarely prescribed in women with ESKD [5, 79]. In a nonrandomized study, 13 women with ESKD on hemodialysis with secondary amenorrhea and estradiol levels <30 pg/mL were treated with transdermal 17β-estradiol and cyclic addition of nortisterone acetate and compared with 10 control women with ESKD on hemodialysis over a 12-month period [80]. The women treated with hormone therapy all resumed regular menses, demonstrated a decrease in prolactin levels and experienced a significant increase in lumbar spine BMD, libido and quality of life compared with controls. While hormone therapy was reportedly well-tolerated, two patients from the treatment group withdrew due to persistent headache and dizziness and recurrent vascular access thromboses. Eleven postmenopausal women with ESKD on hemodialysis were treated with 2 mg daily of oral, micronized estradiol for 8 weeks accompanied by medroxyprogesterone in a randomized, placebo-controlled crossover study [81]. An improved cardiovascular lipid profile was demonstrated with treatment and no significant adverse events were observed. A recent systematic review highlighted that studies examining the use of hormone therapy in patients with CKD are largely limited to the ESKD population and report only surrogate outcomes [82]. There have been no studies examining the direct effect of hormonal therapy on clinical outcomes such as cardiovascular morbidity and mortality, fracture risk, access thrombosis and quality of life in patients with CKD or ESKD. This paucity of studies contributes to the clinician's uncertainty as to whether treatment with sex hormones may be of benefit or harmful in this high-risk population.

The safety and efficacy of the selective estrogen receptor modulator (SERM) raloxifene has been studied in both the ESKD on dialysis and nondialysis-dependent CKD populations. In a small prospective, blinded, placebo-controlled study, 50 postmenopausal women on chronic hemodialysis with proven severe osteopenia or osteoporosis by bone densitometry were randomized to placebo or raloxifene 60 mg/day for 1 year [83]. The authors reported a significant increase in trabecular BMD and a decrease in bone resorption markers and low-density lipoprotein cholesterol values, although no data on outcomes such as fracture risk or cardiovascular events were included in the study. The effect of raloxifene on the rate of change of BMD, incidence of fractures and adverse events by stage of CKD was examined over 3 years in a post hoc analysis of the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, a multicenter, randomized, placebo-controlled trial of 7705 postmenopausal women (ages 31–80 years) with osteoporosis [84]. Raloxifene increased both hip and spine BMD and reduced the risk for vertebral fractures among individuals with CKD. Furthermore, the effect of raloxifene on hip BMD was greater among those with mild to moderate CKD. Although the number of adverse events increased as kidney function declined, adverse events were similar between the raloxifene and placebo groups within each category of kidney function, suggesting that at least in terms of bone protection, raloxifene may be a safe therapy in women with CKD. A subsequent post hoc analysis of the MORE trial examined the effect of raloxifene on kidney function and reported that treatment with the lower SERM dose was renoprotective [85]. The 3-year mean decrease of eGFR was 0.98 mL/min/1.73 m2 for the placebo group compared with 0.56 mL/min/1.73 m2 for the raloxifene 60 mg group and 0.55 mL/min/1.73 m2 for the raloxifene 120 mg group, with a nonstatistically significant trend toward greatest benefit in those with baseline CKD. Furthermore, the authors also reported a lower incidence of adverse events related to CKD in the treatment groups compared with placebo.

HYPOESTROGENISM AS A RISK FACTOR FOR NONCARDIOVASCULAR DISEASE

In contrast to the general population, younger women with ESKD on dialysis have a higher risk of mortality compared with both age-matched men with ESKD and women from the general population, largely due to noncardiovascular causes such as malignancy and infection [86–88]. The reasons for this sex disparity in survival are unclear, but may include higher arteriovenous fistula failure to mature rates in women [26, 89, 90], resulting in greater hemodialysis catheter use [26, 91] and the presence of underlying multisystem disease. Significantly increased cancer risks, including the lower genital tract in women, have been observed in younger ESKD patients [19]. In comparison with the background population, the excess cancer risk in both women and men was highest in the group 0–34 years of age and gradually declined with increasing age [19].

Whether sex hormones play a role in the increased risk of infection and malignancy in younger women with ESKD is unclear. Sex hormones modulate immune system activity [92, 93], which could contribute to this risk. Generally, estrogen stimulates while testosterone impairs production of immunoglobulins by plasma cells [92]. Estrogen stimulates monocytes to produce IL-10, which in turn leads to IgG and IgM B-cell secretion [94]. Estrogen upregulates the expression of mediators of B-cell survival and impairs mediators of B-cell apoptosis. In patients with systemic lupus erythematosus, estrogen increased the production of anti-double-stranded DNA autoantibodies [95]. In addition, the numbers of T-regulatory cells, which control expansion of the peripheral T-cell pool and its response to infections, vary with the menstrual cycle and are greatest when estrogen levels are highest [96]. However, how estrogen modulates T-cell biology has yet to be fully elucidated, as there appears to be a biphasic response to estrogen by T-cells, with differing responses depending on estrogen level [92]. Conversely, estrogen can also have a suppressive effect on the immune system, as estrogen downregulates transcription of the FcyRIIIA gene, which then reduces IL-1β, IL-6 and TNF secretion [97]. Cytokine production and neutrophil activity are inversely related to estrogen levels throughout the menstrual cycle [98]. Of note, healthy premenopausal women mount stronger immune responses to infection compared with men [99]. However, after menopause there is an increase in the incidence of chronic inflammatory disease in women that equals or exceeds that of men [99] and initiation or suspension of hormone therapy in postmenopausal women is associated with changes in the immune response [100], suggesting that estrogen status could play a role in the increased risk of noncardiovascular disease observed in younger women with ESKD, though this remains speculative at this point.

HYPOESTROGENISM AS A CARDIOVASCULAR RISK FACTOR

There is overwhelming evidence suggesting a cardioprotective function for endogenous ovarian sex hormones, and in particular estradiol, in women without kidney disease [101]. The fact that postmenopausal women with CKD are significantly younger when they experience cessation of menses [2, 3] is of particular relevance, as an earlier age of menopause is associated with an increased risk of cardiovascular mortality [101], the most common cause of death of women with CKD [86]. In the general population, women of premenopausal age are relatively protected in terms of cardiovascular disease compared with age-matched men. In contrast, women <45 years of age with ESKD receiving dialysis have similar rates of cardiovascular mortality to their male counterparts [86], suggesting that the hypoestrogenism associated with kidney disease may adversely affect cardiovascular risk in this population. As alterations of sex steroids in women with CKD are not well characterized, it is unclear at what stage kidney disease begins to adversely affect the hypothalamic–pituitary–gonadal axis, with some studies suggesting alterations in the hormonal milieu occurring early [15]. In a small prospective observational study of 78 women of postmenopausal age with nondialysis-dependent CKD (n = 11), ESKD on dialysis (n = 41) or kidney transplant (n = 26), a nonsignificant trend was observed between both estradiol (P = 0.08) and estrone (P = 0.09) and mortality over a median follow-up of 8.4 years [102]. However, in a prospective study of 147 prevalent postmenopausal hemodialysis patients followed up for 32 ± 16 months, a U-shaped association between baseline endogenous serum estradiol levels and cardiovascular and overall mortality was found [103]. These findings suggest that there may be an optimal range of estradiol in the ESKD population, at least in women of postmenopausal age, or that other confounding factors modify the relationship between estradiol and cardiovascular risk. Of note, hyperprolactinemia has been associated with mortality and cardiovascular events in the setting of CKD [104], offering a potential therapeutic target for cardiovascular and kidney disease prevention [105].

SUMMARY

A summary of outcomes that have been associated with low estrogen in women with CKD is outlined in Table 1. Premature menopause associated with hypoestrogenism is underrecognized but common in women with CKD and ESKD. Declining kidney function negatively impacts the hypothalamic–pituitary–gonadal axis, resulting in anovulatory cycles, early menopause and increased symptoms consistent with menopause, as well as a potentially increased risk of endometrial malignancies. However, the hypothalamic dysfunction associated with kidney disease appears to be at least partially reversible with more intensive hemodialysis and kidney transplantation. The use of oral forms of contraception should be viewed with caution in the population at risk of kidney disease, but balanced with the health concerns of an unplanned pregnancy in this population. The onset of menopause may in itself accelerate the progression of kidney disease, although whether postmenopausal hormone therapy reverses this risk is controversial. Kidney disease–mediated premature menopause may increase cardiovascular risk. However, while hormonal therapy with estrogens may positively affect quality of life and sexual desire and may prevent loss of bone mass in postmenopausal women with ESKD, currently available data in the healthy postmenopausal population do not support use of this therapy for chronic disease prevention, although it could be appropriate for symptom management in some women [75]. The potential risk of thromboembolic disease with the use of postmenopausal hormone therapy remains a particular concern in the population with ESKD, at least with oral forms of treatment. Of note, the use of transdermal estradiol is associated with a significantly lower incidence of venous thromboembolism compared with oral estrogen use [106], highlighting that nonoral forms of treatment may be a more appropriate form of hormone therapy in the population with CKD. Furthermore, age and the number of years since menopause are both important factors to consider when interpreting the current postmenopausal hormone therapy data. The concept that initiation of hormone therapy in younger and recently menopausal women may provide benefit while concomitantly increasing risk in older postmenopausal women is referred to as the ‘timing hypothesis’ [107]. A recent review reports a survival benefit [relative risk (RR) 0.70 (95% CI 0.52–0.95)] and decreased coronary heart disease [(RR 0.52 (95% CI 0.29–0.96)] in the subgroup of healthy women or women with preexisting heart disease who initiate hormone therapy within 10 years of menopause [108], suggesting that hormone treatment may play a protective role, but only in specific populations. Given the high prevalence of sex hormone–mediated pathophysiology, symptoms and potentially risk in the population with kidney disease, large randomized controlled trials examining the effects of nonoral estradiol in younger, perimenopausal women with CKD are required to establish the true benefits and adverse effects of hormone treatment in this high-risk population.