Reproductive Health in Women with Kidney Disease

Menstrual abnormalities, including oligomenorrhea, polymenorrhea, and irregular menses, have adverse health effects and worsen the quality of life of women with kidney disease. Early menopause, defined as menopause before 45 years, leads to a decline in ovarian hormones, which is associated with a higher risk of cardiovascular disease, reduction in bone mineral density, cognitive impairment, changes in mood, and sexual dysfunction. Because menstruation is associated with ovulation, menstrual disturbances are closely correlated with infertility. Additionally, early menopause decreases reproductive lifespan, resulting in unexpected infertility not reversible by traditional fertility treatments (1).

In this issue of CJASN, Rytz et al. (2) conducted a systematic review and meta-analysis of 35 studies to understand menstrual abnormalities and the reproductive lifespan in women of childbearing age with nondialysis CKD, dialysis-dependent CKD, or kidney transplants. About two thirds of women undergoing dialysis had menstrual abnormalities, with high rates of irregular menses and amenorrhea among those on hemodialysis. Women on peritoneal dialysis had significantly higher rates of menstrual irregularities as compared with women on hemodialysis (19%–47% versus 75%) (2). Women with CKD, including those with kidney failure, are at higher risk of menstrual abnormalities and reduced fertility due to disruption of the hypothalamic-pituitary gonadal axis. Uremia leads to decreased estrogen and progesterone levels, increased luteinizing hormone levels, and lack of cyclic luteinizing hormone release, which is necessary for ovulation. With kidney disease, there is a decrease in the clearance of prolactin, resulting in hyperproteinemia. Underlying comorbidities of autoimmune disease and use of immunosuppressive medications, like cyclophosphamide, to treat them also increase the risk of menstrual abnormalities (3). The reasons for the higher rates of menstrual abnormalities in women on peritoneal dialysis versus hemodialysis remain unclear, especially because patients on peritoneal dialysis likely have higher residual kidney function. Peritoneal dialysis is associated with lower rates of conception, hypothesized due to the use of hypertonic dextrose solutions and fluid in the peritoneal cavity, which interferes with the transit and implantation of the ovum to the uterus (4). Because menstrual abnormalities are associated with reduced fertility, differences in the sex hormonal status by dialysis modalities may be a contributing factor with peritoneal dialysis not being very effective in preserving residual kidney function and promoting prolactin excretion as postulated, but the exact pathophysiology needs further study.

Kidney transplantation rapidly restores the hypothalamic-pituitary-gonadal axis, with a return of circulating sex hormones to normal levels as early as a few weeks to 6 months post-transplant. Improvement in libido and correction of menstrual abnormalities can be seen in 50%–60% of patients with CKD following a successful kidney transplant (5,6). On the contrary, the systematic review reported only a 7%–30% decrease in menstrual abnormalities following a kidney transplant. Although only 30% of patients had improvement in amenorrhea following a kidney transplant, no differences were found in the prevalence of oligomenorrhea, polymenorrhea, or irregular menses between the pretransplantation and post-transplantation populations. Why was there no improvement in menstrual disorders other than amenorrhea with kidney transplantation? Kidney transplantation restores the function of the endocrine system but does not fully reverse the morphologic damage done to the gonads by uremic toxins. Additionally, the degree of improvement of reproductive function and the normalization of hormonal status can be affected by the health of the allograft, the original cause of kidney failure (such as SLE), the presence of comorbidities (such as diabetes, hypertension, and anemia), the use of certain medications (such as β-blockers and corticosteroids), and psychologic factors, such as depression. Moreover, using immunosuppressants, such as cyclophosphamide, before receiving a kidney transplant can result in premature ovarian failure (7). The authors did not study the effect of these potentially relevant factors on menstrual disturbances, which may have contributed to the persistence of menstrual abnormalities post-transplantation.

Although it remains unknown when precisely the disruption of the hypothalamic gonadal axis occurs with kidney disease, conception rates decrease with the progression of kidney disease. Additionally, the rates of adverse maternal and fetal outcomes are higher with greater severity of CKD, implying that the degree of kidney function is associated with both decline in fertility and menstrual abnormalities (8). The authors did not determine the prevalence of menstrual abnormalities in the nondialysis, nontransplant CKD population, which remains a significant limitation. Information on menstrual irregularities stratified by CKD stages is critical to counsel our women patients with kidney disease regarding menstrual health, fertility, and contraception.

Women with kidney disease get earlier menopause, and on average, women on dialysis undergo menopause 4–5 years earlier than the general population (9). Ages of menarche and menopause did not differ between women with CKD and those who were on dialysis or had received kidney transplantation. Study heterogeneity likely contributed to this, with most women with kidney failure reaching menopause before the initiation of dialysis (2). However, as expected, the overall reproductive lifespan length in women with CKD was significantly shorter at approximately 32 years, as compared with approximately 37 years for women in the general population.

Although the reproductive lifespan was not stratified by CKD stage, dialysis, or transplant status, these findings have important implications, possibly predisposing women with kidney disease to a higher risk of cardiovascular disease.

It should be noted that some of these women may have been advised to use sustained contraception, especially in cases of advanced CKD, in cases of autoimmune diseases at risk of progression with pregnancy, in the initial postkidney transplant period, or if taking teratogenic medications. However, less than half of the included studies reported hormone therapy/contraceptive use. Counseling regarding contraceptive use should be provided to all women with kidney disease, especially to prevent unplanned pregnancies, which occurs with all stages of CKD. Although CKD is associated with menstrual disorders, which adversely affect fertility, there is a return of reproductive function following a kidney transplant. Also, history of kidney disease is associated with a higher risk of adverse pregnancy outcomes of preeclampsia, preterm births, still births, and higher neonatal mortality. It is of paramount importance that women are counseled about the effect of kidney disease on maternal and fetal outcomes and that pregnancies in this high-risk population are planned. Contraceptive use among those with kidney failure remains low, ranging between 5% and 10% compared with 60% in the general population (10). Nephrologists do not routinely discuss contraception with their women patients of childbearing age, and patients are often not aware of changes in their reproductive function with CKD and kidney transplant. Therefore, the provision of safe and effective contraception should be readily available to women with kidney disease. Because the decision to proceed with or delay conception is highly individualized, contraceptive decision making should balance patient acceptability and safety. The barrier method is not an optimal contraception due to high failure rates. Intrauterine devices or progesterone-only methods remain the preferred contraceptive methods for women with kidney disease (10).

Given the paucity of data on the extent of menstrual abnormalities, this review increases our understanding of menstrual health in women with kidney disease. Although the study had some limitations of significant statistical heterogeneity, lack of a consistent definition for menstrual abnormalities, and a wide range of publication dates, the authors should be commended for highlighting the critical knowledge gap in menstrual health with this important work.

In summary, menstrual abnormalities are common in women with kidney disease, negatively affecting their quality of life. There remains a need to increase awareness regarding menstrual and reproductive health among patients and health care providers. Physicians can manage women with kidney disease by being cognizant of this risk, including screening for cardiovascular disease, osteoporosis, and disorders of mood and cognition in women with premature menopause. Hormone replacement therapy can be offered after weighing the risks and benefits. Counseling about reproductive lifespan can help patients make informed decisions about their options for fertility, including the timing of conception, cryopreservation of eggs, and use of contraception. Future research should emphasize the risks of premature menopause and menstrual abnormalities in women stratified by stages of CKD and transplant status and investigate their pathophysiology and risk reduction strategies.

Disclosures

S. Shah reports honoraria from Advances in Chronic Kidney Disease, AstraZeneca Pharma, Otsuka Pharma, and Vifor Pharma and speakers bureau for AstraZeneca. The remaining author has nothing to disclose.

Funding

S. Shah is supported by National Heart, Lung, and Blood Institute grant 1K23HL151816-01A1.

Author Contributions

S. Shah conceptualized the study, was responsible for project administration, was responsible for validation, was responsible for visualization, and provided supervision; R. Gumber and S. Shah wrote the original draft; and S. Shah reviewed and edited the manuscript.