Prevalence of HIV-associated menstrual abnormalities in Nigeria

The prevalence of HIV-associated menstrual irregularities and disorders has been examined among HIV-positive women of reproductive age (15–45 years), and findings varied between 29 and 76%, substantially exceeding those reported in studies conducted in developed nations [9, 15, 22, 23]. The observed menstrual disorders included intermenstrual bleeding, menorrhagia, hypermenorrhea, amenorrhea, oligomenorrhea, and secondary dysmenorrhea [6, 9, 15, 22, 23]. According to Ezechi et al. [15] the most common menstrual irregularities and disorders reported among HIV seropositive women were irregular periods (7.9%), oligomenorrhea (6.4%), amenorrhea (3.8%), and secondary dysmenorrhea (2.6%), with an overall 29.1% prevalence for menstrual irregularities among WLHIV. In contrast, the seronegative group exhibited lower rates of 4.4%, 3.9%, 1.8%, and 1.9% for the named disorders. This study found no significant difference in the prevalence of heavy or intermenstrual bleeding but noted higher rates of amenorrhea and irregular menstrual cycles among WLHIV compared to HIV seronegative individuals [15]. In 2013 and 2017, Ukibe et al. presented two different studies with a prevalence of 76% (163 of 214) and 40% (18 of 35) in Nnewi Anambra State of South-Eastern Nigeria, respectively [9, 23]. The decrease in the latter may be attributed to its small sample size. Notably, Osun State in the Southwest had a significantly higher prevalence of 70.2% (167 of 238), as highlighted by Adebimpe et al. in 2014 [22].

Patterns and contributing etiologies of menstrual abnormalitiesPatterns of menstrual abnormalities among WLHIV in Nigeria

A study assessing menstrual cycle patterns among Nigerian WLHIV who were symptomatic but not on ART, symptomatic on ART, and non-infected control subjects reported secondary amenorrhea as the commonest observed menstrual disorder (40.5%), followed by hypomenorrhea (20.3%), dysmenorrhea (16.5%), polymenorrhea (3.7%) [9], and hypermenorrhea (3.7%). These findings were in keeping with those of previous studies where amenorrhea was the most prevalent menstrual disorder among WLHIV [8, 10, 24]. A similar study conducted among WLHIV in Benue and Lagos States [22] revealed that about one-third of the respondents reported a change in their menstrual pattern since commencing ART, and pattern changes included irregular menstruation, amenorrhea, lighter than normal menstruation (oligomenorrhea) and menorrhagia. These findings were also in keeping with a previous study that suggested a strong association between ART adherence and menstrual disturbances among WLHIV [8]. It surmised that WLHIV classified as non-adherent, with calculated adherence levels below 95%, were seven times more likely to experience menstrual irregularities than their adherent counterparts. Furthermore, the prevalence and patterns of menstrual disorders varied significantly among WLHIV based on the duration of ART. Women who had been on ART for over 5 years exhibited a higher prevalence and diversity of menstrual irregularities and disorders compared to those who had been on ART for a shorter duration; although the authors did not state whether this was a consequence of longer duration of disease or if adherence rates over this period were considered [22]. Ezechi et al. reported that over 700 of approximately 2500 participants experienced a form of menstrual disorders [15]. Among these, irregular periods, oligomenorrhea, and amenorrhea were ranked the top three symptoms, respectively, whereas menorrhagia and dysmenorrhea were the least reported menstrual disorders [15]. The median age of study respondents was 32.7 for the seropositive cohort and 33.2 for the control negatives. The ART regimen respondents received was not stated across reviewed studies. In addition, a closer look at the trends and patterns reveals that many WLHIV in Nigeria and globally of reproductive age often suffer from other systemic complications such as weight loss, depressive conditions, and substance abuse [8, 14, 15].

Contributing etiology to reported menstrual irregularities

The etiology of menstrual irregularities among WLHIV remains unclear. However, several contributing factors have been outlined (Fig. 1). The literature suggests the presence of menstrual irregularities in patients with background immunosuppression. This is often a result of increased viral load and decreased CD4 count levels. The level of immunosuppression, mirrored by the degree of viremia and CD4 count, is relative to patient adherence to ART. CD4 cells are crucial immune system cells targeted by HIV. Low CD4 count, which implies a weakened immune system, can disrupt hormonal regulation in the body, leading to menstrual irregularities. A study among Nigerian WLHIV found that amenorrhea and irregular menstruation were as high as 80.7% and 81.7%, respectively, among the ART naïve group when compared with a control ART adherent group that recorded just about 22% and 18% prevalence, respectively [6]. Similarly, another study found that WLHIV who were adherent to ART with consequent high CD4 counts had a very low percentage (< 20%) of menstrual irregularities [25]. In contrast, those who were ART-naive or reported suboptimal ART adherence with increased viral load counts and low CD4 counts had reported one or more menstrual irregularities or disorders [3]. The direct pharmacological effects of ART on the menstrual cycle remain unclear. While few studies have investigated potential associations between ART use and menstrual cycle characteristics, others have consistently reported no direct effect of ARTs on menstrual cycle length, regularity, or bleeding patterns [8].

Fig. 1

Factors contributing to menstrual abnormalities among Nigeria WLHIV. WLHIV women living with HIV

Additionally, ovarian dysfunctions linked to HIV infection and related comorbidities have contributed significantly to menstrual irregularities among WLHIV. This is usually a consequence of the dysregulation of hormones produced by the ovaries. Studies have demonstrated that WLHIV who experience abnormal menstruation exhibit fluctuating levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, and prolactin [9, 15, 26]. Two studies have produced conflicting results as regards levels of these hormones among HIV-infected patients. Oghundahunsi et al. suggested low levels of FSH, LH, and increased prolactin levels [27]; Rose NU et al. found significantly higher than normal levels of FSH, LH, and prolactin in HIV clients across both phases of the menstrual cycle when compared with the controls [9]. Research findings have associated HIV infection and ART use with a spectrum of endocrine and metabolic dysfunctions. Hypogonadism, characterized by reduced testosterone levels, has been associated with weight loss and a decline in CD4 cell counts [28, 29]. Testosterone deficiency observed in HIV seropositive males and females can manifest in a range of symptoms including wasting syndrome, fatigue, anemia, depression, and decreased libido, all of which are common complications of HIV infection. These hormonal imbalances often result in menstrual disorders, including amenorrhea, oligomenorrhea, and irregular menstrual cycles. Hyperprolactinemia, particularly, is a known disruptor of the menstrual and reproductive cycles, with research indicating its profound impact on hormonal balance and menstrual function. The exact mechanisms underlying these hormonal changes are still being investigated, but several factors may contribute. HIV infection can directly disrupt the hypothalamic-pituitary-ovarian (HPO) axis, the intricate signaling pathway that regulates reproductive hormones. In addition, HIV infection makes women more susceptible to various opportunistic infections [23], such as tuberculosis. These infections can cause widespread inflammation, with increased production of pro-inflammatory cytokines that may disrupt the delicate hormonal balance necessary for regular menstrual cycles [23]. In addition, treatment for some opportunistic infections can have side effects that contribute to menstrual irregularities. HIV-associated inflammation and immune dysregulation may further impair hormonal production and release.

Furthermore, in evaluating the possible etiology of menstrual disorders among WLHIV, it is imperative to consider confounding variables like body mass index (BMI). More WLHIV have lower BMI when compared to their seronegative counterparts [15]. These low BMI and poor nutritional status can contribute to menstrual irregularities, particularly amenorrhea. A longitudinal study revealed that severe weight loss was a common occurrence, affecting one-third of the WLHIV population, and was linked to amenorrhea [30]. A study investigating the link between low BMI and the occurrence of amenorrhea revealed that up to 38% of WLHIV with a BMI below 90% of their ideal weight reported experiencing the absence of menstruation or those with irregular frequencies [13]. Other potential contributing factors may include the use of illicit drugs among patients with a psychiatric disorder as well as anxiety about health conditions [31, 32]. Additionally, anemia of chronic disease (ACD) associated with chronic HIV infection may contribute to the prevalence of amenorrhea [33]. Exposure to a variety of stressors can lead to an increase in the release of stress hormones, which negatively affects the gonadotrophin-releasing hormones. This can result in menstrual irregularities or even the complete cessation of menstruation [34]. Diagnostic modalities should consider eliminating other possible causes of amenorrhea and menstrual irregularities, like the use of hormonal or intrauterine contraceptive methods, coexisting uterine fibroids, and women who may be pregnant or lactating when managing these conditions.

Determinants and impact of menstrual disorders among WLHIVClinical and patient-related factors

The pathogenesis of menstrual disorders in WLHIV is a multifaceted phenomenon influenced by a complex interplay of clinical, therapeutic, and patient-related factors. Many studies have demonstrated an association between CD4 cell count and menstrual disorders among WLHIV. In particular, low CD4 cell counts have been shown to significantly elevate the risk of menstrual irregularities, underscoring the profound influence of the immune system on women's reproductive health. Research has demonstrated that both overweight and underweight conditions can lead to menstrual irregularities. However, underweight individuals living with HIV are at a higher risk of experiencing amenorrhea and irregular menstrual cycles. Although ART has reduced the incidence of menstrual disorders among WLHIV, there have been reported changes in menstruation patterns upon commencement of ART [8, 35]. High viral load and low CD4 + cell counts have been implicated as major contributors to menstrual irregularities in WLHIV by causing cytopenias [36]. Thrombocytopenia due to bone marrow suppression associated with HIV has also been reported as a contributing factor [37]. Zidovudine has been shown to raise platelet counts, without necessarily demonstrating a corresponding antiviral effect in about 40–60% of the patients, and reported as a choice treatment for HIV-associated thrombocytopenia [38]. Lamivudine, zidovudine, and nevirapine have been reported as post-treatment predictors of anemia [35].

Impact of menstrual irregularities on PLHIV

Abnormal menstruation can lead to anemia, reduced fertility, and an overall reduction of quality of life. Iron deficiency anemia commonly results from prolonged and heavy menstrual bleeding [39]. Anemia in WLHIV not only contributes to an increased rate of infertility but has been linked to the early onset of menopause and ovarian insufficiency [10, 25]. While most ART can effectively resolve anemia, ART-naivety or poor adherence can exacerbate the condition due to the immunosuppressive state caused by untreated HIV, which further compounds anemia-associated complications. Physical health and mental well-being are affected as a result of abnormal menstruation, especially prolonged amenorrhea, lasting over 12 months [40]. Other factors such as oral contraceptive pills (OCPs), use of medications and recreational drugs, mental illness, and profound stress also contribute to the prolonged amenorrhea observed in WLHIV [41]. A compelling association exists between amenorrhea and lower educational attainment in women, a finding that mirrors the link between menopause and lower socioeconomic status and education level [42]. While the underlying biological mechanisms remain elusive, this association highlights the intricate interplay between social and biological factors in the menstrual health of WLHIV.

Interventions for menstrual abnormalities among WLHIV and therapeutic effectiveness

Women's experiences with HIV infection and associated complications necessitate tailored and targeted healthcare services that address their specific needs. Pharmacological and nonpharmacological strategies have been utilized in the management of menstrual disorders among WLHIV, and both approaches have proven to be effective in their holistic care. Pharmacological interventions such as hormone replacement therapy (HRT) and ART adjustment to minimize side effects have been proven effective. The use of integrase strand transfer inhibitors (INSTIs) led to notable improvements in the overall well-being of WLHIV, with observed weight gain, and and the resolution of previously experienced menstrual irregularities [15, 43]. Various etiologic factors attributed to menstrual abnormalities were found to be significantly mitigated with high adherence to ART. A study revealed that WLHIV with menstrual disorders exhibited significantly lower adherence rates to ART compared to women without these disorders [3]. Similarly, pharmacotherapy has been deployed to manage coexisting comorbidities like osteopenia and osteoporosis, which may be caused by low estrogen levels among WLHIV. Bisphosphonates, such as alendronate sodium, risedronate, and ibandronate, have demonstrated remarkable efficacy and safety in increasing BMD when administered alongside calcium and vitamin D supplementation [44, 45]. These medications effectively inhibit osteoclast activity, reducing bone resorption and promoting bone formation. Selective estrogen receptor modulators (SERMs), including raloxifene and tamoxifen, have also emerged as valuable therapeutic options for managing osteoporosis among WLHIV [45]. Nonpharmacological methods involve lifestyle adjustments, nutritional support, and stress reduction techniques [46]. It is pertinent that clinicians conduct pregnancy investigations for all HIV-infected women of childbearing potential presenting with current amenorrhea, irrespective of their history of sexual activity or contraceptive use, to exclude amenorrhea due to pregnancy. Serum FSH may be useful in diagnosing early menopause if suspected in the setting of prolonged amenorrhea [44].

The use of HRT and ART adjustments has shown positive outcomes in restoring menstruation among PLHIV with menstrual irregularities, particularly amenorrhea [47]. A study model incorporating only HIV-seropositive women found that higher CD4 cell counts were associated with a lesser occurrence of menstrual irregularities compared to women with lower CD4 cell counts (less than 200/mm3). Separate analysis revealed that the longer the duration of ART, the lower the risk of amenorrhea. In addition, women with lower CD4 cell counts (200–500/mm3) who were ART-naive or non-compliant were more likely to experience oligomenorrhea [47]. However, Fumaz et al. reported that ART use for 2–4 years and above was protective against oligomenorrhea and intermenstrual bleeding [3]. Lifestyle changes and nutritional support have also yielded promising results, promoting overall health and potentially alleviating amenorrhea. The level of therapeutic effectiveness may vary among individuals, making it essential to personalize treatment strategies.

Research gaps and prospects

Previous studies faced certain limitations, including a lack of information on other potential causes of menstrual disorders, particularly amenorrhea and irregular cycles, and specific ART regimens used by respondents. Much of the research on menstrual disorders in WLHIV was conducted during the early epidemic, a time marked by a higher prevalence of advanced disease and wasting syndrome in WLHIV. There is a need for extended research to further explore the intricate interplay between major systems such as the renal, pituitary, thyroid and parathyroid, hypothalamic, and hepatobiliary systems in the setting of HIV infections and ART use to better understand the underlying factors contributing to menstrual irregularities. Existing studies have highlighted several gaps, including the need for more robust, diverse, and representative sample populations for a more comprehensive understanding of the subject. Moreover, the heightened prevalence of menstrual irregularities and subsequent infertility among WLHIV who are adherent to ART with undetectable viral loads remains unclear and needs further investigation.

Future research should explore preventive therapies to reduce the incidence of menstrual irregularities among WLHIV. Developing guidelines for gynecological care tailored to WLHIV in Nigeria is a promising direction. Recent longitudinal studies assessing the current effects and trends of HIV infection, and treatment with combined ART on the menstrual cycle are crucial. Clinicians should take a holistic approach when evaluating amenorrhea and other menstrual irregularities in HIV-positive women, considering the patient's overall health and potential contributing factors, such as substance use, medications, and opportunistic infections. A complete diagnostic workup is necessary to determine the cause of the menstrual disorder, as symptoms may mimic those of co-existing pregnancy, ovarian cyst, ovarian failure, or menopause. Lastly, exploring stress levels and markers of chronic anovulation, such as the presence of multiple follicles on ultrasound, and ruling out thyroid disease and disorders of prolactin secretion in this group is necessary.