Perimenopause as an obesogenic sensitive period: Contributions to elevated cardiovascular risk

Abstract

Background

Perimenopause, encompassing the period of progressive menstrual irregularity preceding a woman’s final menstrual cycle and extending 12 months thereafter, is associated with an acceleration in atherosclerotic cardiovascular disease (CVD) risk, attributable in part to redistribution of body fat. During perimenopause, even in the context of minimal-to-modest weight gain, women experience an expansion of visceral adipose tissue. Concomitantly, women often experience a reduction in gluteofemoral subcutaneous adipose tissue. This pattern of fat redistribution is associated with a greater prevalence of CVD risk factors and a higher incidence of CVD events. Here we present a case of disproportionate weight gain and fat redistribution in a woman newly initiating a long-acting injectable antipsychotic medication with mild-to-moderate obesogenic effects during perimenopause.

Clinical Presentation

A 46-year-old woman with schizoaffective disorder and primary hypothyroidism on levothyroxine presented to her endocrinologist with concerns of weight gain. She also reported vasomotor symptoms and oligomenorrhea. For management of schizoaffective disorder, she was engaged in psychiatric counseling and had initiated a monthly, extended-release aripiprazole lauroxil injectable, within the year. On physical examination, her weight had increased by 9.2 kilograms, shifting her to an overweight body mass index. Fat distribution was notably centripetal, but there was no other Cushing’s stigmata. Laboratory evaluation revealed thyroid stimulating hormone within normal limits, an elevated follicle stimulating hormone level, and an undetectable antimullerian hormone level. Human chorionic gonadotropin test was negative, and neither prolactin nor 24-hour urine free cortisol levels were elevated. Ultimately, her psychiatrist discontinued the long-acting aripiprazole therapy while continuing counseling. Greater than two years post medication discontinuation, she has not achieved significant weight loss, despite augmented physical activity and implementation of dietary changes.

Conclusions

In a perimenopausal woman, initiation of a medication with mild-to-moderate obesogenic effects potentially precipitated a dramatic weight gain (10x above the potential magnitude described in package insert), and despite medication discontinuation and lifestyle interventions, excess weight was not shed. While the menopausal transition is not typically associated with significant weight gain, the clinical case described suggests that perimenopausal factors may have contributed to medication-induced weight gain, which was predominantly centrally distributed. As metabolic memory in adipocytes can impede meaningful weight loss, this case highlights perimenopause as a critical period of heightened metabolic sensitivity to pharmacologic insult. Clinicians of perimenopausal patients should exercise caution in initiating medications with obesogenic side effects. When such medications are necessary, ongoing evaluation of cardiometabolic risk indices and support for concomitant salutary lifestyle modifications are advised.

1. Introduction

Perimenopause, the transitional phase surrounding the final menstrual period, characterized by progressive menstrual irregularity and declining gonadal function, is associated with modest weight gain coupled with more substantial metabolic alterations. These metabolic changes, heavily driven by changes in body composition, exacerbate the risk of cardiovascular disease (CVD) among peri‑ and post-menopausal women.

Here, we re-present [1] - and now discuss - a case of unanticipated, disproportionate weight gain in a perimenopausal woman following initiation of long-acting injectable aripiprazole lauroxil, an antipsychotic generally perceived to stimulate, at most, mild-to-moderate weight gain. This case highlights perimenopause as a potential obesogenic sensitive period and underscores the need for clinical vigilance when prescribing agents with potential metabolic consequences during this time.

2. Case presentation

A 46-year-old woman with schizoaffective disorder and primary hypothyroidism on levothyroxine presented to her endocrinologist with progressive weight gain and an inability to lose weight.

Approximately one year prior, her psychiatrist initiated her on an extended-release injectable suspension of aripiprazole lauroxil 882 mg/month, as treatment for schizoaffective disorder. Four months before the start of this medication, the patient reported worsening menstrual irregularity and vasomotor symptoms. Antimullerian hormone (AMH) levels at the time were 0.17ng/mL. Throughout the ensuing year, her vasomotor symptoms worsened and her AMH level fell to undetectable. Overall, over the past year of therapy with aripiprazole lauroxil, the patient’s weight had increased from 62.0 kg to 71.2 kg, a total gain of 9.2 kg. This level of weight gain was >10-fold higher than that which is described as a potential side effect of aripiprazole. Notably, the same medication had been administered to the patient years earlier, when she was pre-menopausal, over an approximately 2-year duration, and treatment at that time was accompanied by a much more modest weight gain of 1.8 kg.

On physical exam, the patient’s body mass index (BMI) was 26.1 kg/m², in the overweight category, compared to a starting BMI of 22.8 kg/m² (normal-weight category). Fat distribution was predominantly central, without other stigmata of Cushing’s disease. Additional laboratory evaluation revealed: Human chorionic gonadotropin (hcg) level was negative, and neither prolactin nor 24-hour urine free cortisol levels were elevated. Thyroid stimulating hormone (TSH) level was 1.1 mIU/mL (normal range: 0.4–5.0mIU/mL) and free thyroid hormone 4 (FT4) level was 1.4 ng/dL (normal range: 0.9–1.8ng/dL). Follicle stimulating hormone (FSH) level was elevated at 71.3 IU/mL.

Though her cholesterol and blood pressure remained largely unchanged through the course of aripiprazole therapy, her hemoglobin A1c increased to 5.8 %, placing her in the prediabetes range (pre-treatment hemoglobin A1c had been 5.1 %). The long-acting aripiprazole therapy was discontinued by her psychiatrist, and she remained engaged in counseling, off pharmacotherapy. Greater than two years post medication discontinuation, despite dietary interventions including consultation with a nutritionist for dietary counseling/advice and increased physical activity (walking >30 min most days), weight loss has not been achieved.

3. Discussion

Understanding how a woman’s stage of reproductive aging may influence her cardiometabolic risk requires careful consideration of the stages of menopause and the associated physiologic changes. In this regard, foundational knowledge has emerged from the Study of Women’s Health Across the Nation (SWAN). Launched in 1994, SWAN followed 3302 women aged 42–52 years, collecting detailed clinical and laboratory data longitudinally. These data facilitated the development of the Stages of Reproductive Aging Workshop (STRAW) staging system [2] (summarized in Fig. 1). STRAW defines three reproductive aging phases (reproductive, menopausal transition, and postmenopause), further subdivided into ten stages based on clinical and hormonal features. Beginning at menarche (the onset of menstrual bleeding), the reproductive phase (comprising Stages –5, –4, –3a, and –3b) spans the early to late reproductive years. The menopausal transition (Stages –2 and –1) entails ovarian follicular depletion and is marked by progressive menstrual irregularity. This transition culminates in the final menstrual period (Stage 0), defined retrospectively after 12 consecutive months without menses. Postmenopause (Stages +1a to +2) follows the final menstrual period and is characterized by estradiol decline and FSH elevation [3]. Hormone levels typically stabilize within two years after the final menstrual period. Perimenopause encompasses the menopausal transition (Stages –2 and –1) through the final menstrual period and the following 12 months of amenorrhea required to define it. Pronounced menstrual irregularity and hormonal fluctuations represent hallmarks of perimenopause.

Fig. 1.

Summary of the STRAW+10 framework for reproductive aging, highlighting perimenopause.

The Stages of Reproductive Aging Workshop (STRAW+10) framework delineating the continuum of reproductive aging into three broad phases: 1) reproductive, 2) menopausal transition, and 3) postmenopause - further subdivided into ten stages defined by menstrual and hormonal characteristics. The menopausal transition, comprising Stages –2 and –1, marks the onset of ovarian follicular depletion and is characterized by progressive menstrual irregularity and fluctuating estradiol and FSH levels. Perimenopause encompasses this transition period through the final menstrual period and the subsequent 12 months of amenorrhea. This dynamic interval is distinguished by pronounced hormonal variability and evolving physiologic changes that may influence cardiometabolic health [Adapted from Harlow et al., 2012, J Clin Endocrinol Metab]. Created in BioRender. Stockman, S. (2026) https://BioRender.com/ejztxyu.

The median age of the final menstrual period in U.S. women is approximately 51 years, yet as STRAW staging illustrates, reproductive aging represents a prolonged transition wherein hormonal fluctuations influence cardiometabolic health risks. Epidemiological studies consistently demonstrate that postmenopausal women experience a significant increase in CVD risk compared to their premenopausal counterparts [4]. The landmark 1976 Framingham Heart Study revealed that women aged 40–54 years who had undergone natural menopause exhibited a two- to six-fold higher incidence of CVD relative to premenopausal women [5]. Further, within each specific chronologic age group brackets, postmenopausal (vs. premenopausal) women exhibited higher rates of CVD, even after adjusting for traditional cardiovascular risk factors [5]. These findings suggest an independent contribution of reproductive aging to CVD risk, above and beyond the known contribution of chronologic aging. In recognition of this point, the American Heart Association now includes menopause as a female-specific CVD risk factor, underscoring the importance of considering reproductive aging in cardiovascular risk assessments [4].

Though the mechanisms by which reproductive aging influences CVD risk are not completely understood, a combination of hormonal, metabolic, and vascular changes are thought to contribute. Perimenopausal decline in estrogen contributes to unfavorable shifts in the lipid milieu, as circulating levels of total cholesterol, LDL cholesterol, triglycerides [6], and apolipoprotein B [7] increase, and as the cardioprotective capacity of HDL cholesterol declines [8]. Estrogen loss also impairs endothelial function, potentially by altering redox balance and increasing oxidative stress [9,10]. Declining estrogen levels are also accompanied by increases in systolic and diastolic blood pressure, a phenomenon partially reversed by estrogen replacement [11,12]. Many of these changes occur independently of chronological aging, suggesting that the hormonal changes contribute – directly or indirectly – to worsening cardiovascular risk in midlife women [4,13].

During perimenopause, weight gain is generally modest and largely due to chronological aging [14], while concomitant changes in body composition may be profound and at least partially due to hormonal fluctuations [15]. In SWAN, entry into the menopausal transition was associated with accelerated increases in fat mass, with the rate of total fat gain approximately twice that observed during the premenopausal period [16]. Abdominal fat gain predominated, with waist circumference increasing by an average of 2.2 cm over three years [17]. These observations reflect reproductive aging-associated hormonal changes: declining estrogen levels are known to promote a shift in adipose tissue distribution from subcutaneous gluteofemoral depots to central visceral adipose tissue (VAT) [18,19]. Specifically, lower estrogen levels trigger increased production of bone marrow–derived adipocytes, which are associated with VAT expansion and impaired tissue function [20,21]. Additionally, lower estrogen levels result in relative androgen excess, further favoring visceral fat deposition [22,23]. Hormonally-driven perimenopausal shifts in fat distribution, favoring VAT, contribute to adverse cardiometabolic changes, as outlined below. Meanwhile, VAT independently predicts CVD risk, even after adjusting for total adiposity and conventional CVD risk factors [24].

Increased VAT, a body composition consequence of reproductive aging, can lead to deleterious metabolic consequences [25] (Fig. 2). VAT is highly metabolically active, with an elevated rate of lipolysis that increases circulating free fatty acids (FFAs) [26]. These FFAs drive hepatic insulin resistance through enhanced fatty acid flux to the liver and subsequent lipid metabolite accumulation [27]. Resultant compensatory hyperinsulinemia promotes de novo lipogenesis and inhibits lipolysis, further favoring adipose tissue expansion [28]. Additionally, as VAT secretes lower levels of the satiety hormone leptin (compared to subcutaneous gluteofemoral adipose tissue) [29], perimenopausal relative VAT excess may impair appetite regulation, contributing to caloric excess and ensuing weight gain.

Fig. 2.

Mechanisms supporting perimenopause as an obesogenic sensitive period.

Perimenopause represents a critical window of heightened metabolic sensitivity, during which physiologic and behavioral changes converge to promote weight gain and increased central adiposity. The preferential accumulation of visceral adipose tissue (VAT) increases free fatty acid flux, driving hepatic insulin resistance, compensatory hyperinsulinemia, and further adipose expansion. VAT also secretes less leptin than subcutaneous fat, impairing appetite regulation and predisposing to caloric excess. Simultaneously, menopause accelerates skeletal muscle loss, reducing basal metabolic rate and energy expenditure, thereby favoring positive energy balance. Behavioral changes during this transition, including sleep disturbances and declining physical activity, further compound weight gain and adverse downstream cardiometabolic sequalae. Created in BioRender. Stockman, S. (2025) https://BioRender.com/nersh4f.

Meanwhile, a second body composition consequence of reproductive aging entails the gradual loss of skeletal muscle, with deleterious metabolic consequences. Basal metabolic rate reflects the energy required to maintain basic physiological functions at rest [30] and accounts for the majority of total daily energy expenditure [31]. Skeletal muscle is the major determinant of the basal metabolic rate and subsequent energy expenditure [32]. While skeletal muscle loss occurs with chronologic aging, menopause accelerates this decline beyond that of normal aging, thus contributing directly to a reduced basal metabolic rate [33,34]. Without meaningful dietary adjustments, reduced energy expenditure can create a positive energy balance, promoting weight gain.

In addition to physiologic changes, the perimenopausal period is characterized by behavioral changes, including sleep disturbances, which can disrupt metabolic regulation and contribute to reductions in physical activity, thereby promoting weight gain. Over 25 % of perimenopausal women experience sleep disturbances severe enough to impair daytime functioning [35,36]. Sleep disruptions are associated with alterations in appetite-regulating hormones, including decreased leptin and increased ghrelin, promoting heightened hunger and caloric intake [37]. Poor sleep additionally impairs glucose tolerance and insulin sensitivity, while promoting systemic inflammation [38,39]. Concurrently, physical activity declines during the menopausal transition [40]. For midlife women, barriers to regular exercise include not only fatigue, but also competing demands of home and caregiving [41]. Reproductive aging-associated hormonal changes may additionally reduce motivation and contribute to exercise intolerance, further deterring physical activity and promoting a positive energy balance that favors weight gain [11].

Medications known to promote mild-to-modest weight gain may exert amplified obesogenic effects among women traversing menopause. Data from the Women’s Health Initiative show that postmenopausal women taking weight-promoting medications such as antidepressants and insulin (vs. women not taking such medications) experienced greater increases in body weight and waist circumference over three years, with risk rising in parallel with the number of medications used [6]. Additional studies emphasize the critical role of menopausal stage when considering pharmacologic effects on body weight and adiposity. For example, in a study focused on women with HIV, initiation of integrase strand transfer inhibitors during perimenopause resulted in marked increases in both BMI and waist circumference [42,43]. Further, the rate of BMI and waist circumference increase varied by menopausal stage, with the most pronounced chronologic age–adjusted increases occurring among women in the late perimenopause and diminishing as women progressed into the later postmenopausal stage. Together, these findings suggest that pharmacologic exposures specifically during perimenopause may exacerbate physiologic and/or behavioral changes, promoting excess weight gain and central adiposity.

Of note, the case presented in this review suggests that even medications generally perceived to precipitate only mild-to-moderate weight gain may, when administered to perimenopausal women, contribute to substantial weight gain. In our case, the patient was initiated on aripiprazole lauroxil 882mg/month, which is typically associated with modest weight increase, as compared to other antipsychotic medications. In studies of aripiprazole lauroxil, patients treated for 12 weeks demonstrated a mean (SD) increase in body weight of 0.86 (3.7) kg [44], significantly less than the 9.2 kg weight gain observed in the presented case. One reason weight increase associated with use of this medication is typically mild-to-moderate is that the drug exerts only partial (as opposed to complete) agonism at the 5-HT2C receptor and D2 receptor, conferring a lower risk of hyperphagia and metabolic disturbance. We infer that any agent or stimuli capable of increasing appetite or energy intake may exacerbate weight gain disproportionately in the perimenopausal obesogenic-sensitive period.

In our patient’s case, many factors may have contributed to disproportionate weight gain. She did endorse a modest increase in appetite following initiation of the long-acting antipsychotic, which may have promoted a positive energy balance. The effects of a positive energy balance, in turn, were likelyfurther amplified by changes in body composition and metabolism which typically accompany perimenopause. The patient’s comorbid conditions could have also contributed to disproportionate weight gain. For example, autoimmune thyroid disease, such as the patient had, has been associated with systemic inflammation, which may predispose to weight gain independent of biochemical euthyroidism [45]. Intermittent undertreatment of autoimmune hypothyroidism, in the context of suboptimal levothyroxine adherence, may also have contributed. In addition, the patient’s underlying schizoaffective disorder introduced psychotropic-related factors such as emotional lability, psychosocial stress, and stress-mediated hormonal changes, which can adversely affect weight regulation and metabolic health. While this case cannot establish a singular cause for the patient’s disproportionate weight gain, the magnitude of weight gain observed following initiation of the long-acting antipsychotic during the perimenopausal transition, particularly in contrast to her prior exposure to the same medication in the setting of longstanding hypothyroidism and schizoaffective disorder, supports a clinically meaningful interaction between weight promoting agents and reproductive stage–specific metabolic vulnerability.

Despite discontinuing the offending medication and implementing intensive lifestyle changes, the patient in this case was unable to achieve weight loss, reflecting the challenges of reversing perimenopausal weight gain. Patient-oriented studies show that weight loss is often accompanied by disproportionate reductions in energy expenditure [[46], [47], [48]], which cannot be fully explained by changes in body composition [49]. Meanwhile, emerging in vitro evidence suggests that adipocyte molecular memory of weight-gain induced metabolic adaptations hinders sustained weight loss. Obesity induces lasting epigenetic and transcriptional changes that persist after weight loss, priming adipose tissue for maladaptive metabolic responses to future nutritional cues, including increased glucose uptake and enhanced lipid accumulation [50]. Such maladaptive metabolic responses in adipocytes, along with an overall reduced energy expenditure following weight loss, shift the body toward a higher fat and weight set point. This phenomenon may contribute to challenges in sustaining or building upon transient weight loss among individuals who have gained weight. Taken together, these observations underscore the importance of recognizing perimenopause as an obesogenic sensitive period, during which women are particularly vulnerable to weight gain, especially in response to pharmacologic exposures. For perimenopausal women, prevention of excess weight gain, potentially through avoidance of weight-promoting pharmacotherapy, is critical.

When administration of weight-promoting medication during the perimenopausal transition is unavoidable, incorporating targeted lifestyle interventions can counteract the heightened risk of weight gain and support metabolic health. The Women’s Healthy Lifestyle Project, a randomized control trial evaluating the impact of a 5-year behavioral dietary and physical activity program on weight and body composition established that weight gain and increased waist circumference during the perimenopausal period can be mitigated by lifestyle intervention [51]. An additional case-control study examining the effects of an individually-designed nutrition plan on body weight among postmenopausal women treated with antipsychotic medications further highlights a role for nutritional intervention in helping to preclude medication-induced gains in BMI and body fat [52].

A combination of lifestyle and appetite-suppressive or weight-loss medications may help attenuate weight gain among perimenopausal women receiving medications with mild-to-moderate obesogenic effects. For example, in a randomized controlled trial of adults (∼50 % women) requiring antipsychotic therapy, the combination of lifestyle intervention and the anti-hyperglycemic, mildly anorexigenic agent metformin forestalled weight gain more effectively than either lifestyle or metformin alone [53]. Intriguingly, more recent work suggests that the weight-reducing effects of select anorexigenic medications in women may depend, in part, upon the hormonal milieu. Among postmenopausal women randomized to the glucagon-like peptide-1 receptor agonist (GLP1RA) tirzepatide alone or tirzepatide coupled with estrogen-based hormonal replacement therapy (HRT), the proportion of women achieving ≥20 % weight loss was significantly higher in the combination therapy arm (45 % vs. 18 %) [54]. Further research is needed to identify optimal strategies to prevent weight gain among women transitioning through perimenopause, particularly those requiring pharmacologic agents with known obesogenic potential (e.g., antipsychotics, anticonvulsants, beta-blockers, corticosteroids).

Perimenopause represents a critical, yet underrecognized, window of sensitivity for the development of weight gain, accumulation of visceral fat, and associated metabolic disturbances. The profound hormonal shifts characteristic of this transition disrupt energy balance through multifaceted mechanisms, rendering women uniquely susceptible to obesogenic stimuli. The presented case underscores how the metabolically deleterious effects of obesogenic medications may be amplified during perimenopause, via recalcitrant weight gain of unexpected magnitude. Clinicians caring for women at midlife should regularly assess a woman’s stage of reproductive aging, counsel on anticipated metabolic changes, endorse positive lifestyle modification, and, if possible, avoid prescribing medications with known obesogenic effects during perimenopause. When initiation of such medications is unavoidable, lifestyle interventions, potentially coupled with concurrent anti-obesity therapy, may help mitigate or even prevent medication-related weight gain, fat redistribution, and downstream metabolic and cardiovascular sequelae. Recognizing and addressing perimenopause as a critical period of metabolic sensitivity is essential to improving long-term cardiometabolic health outcomes in women.

CRediT authorship contribution statement

Margot E. Manning: Writing – review & editing, Writing – original draft, Data curation, Conceptualization. Sara L. Stockman: Writing – review & editing, Writing – original draft, Validation, Data curation, Conceptualization. Markella V. Zanni: Writing – review & editing, Validation, Supervision, Resources, Conceptualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.