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RESEARCH INVENTION JOURNAL OF RESEARCH IN MEDICAL SCIENCES 4(3):19-25, 2025

©RIJRMS Publications

ONLINE ISSN: 1115- 6198

Print ISSN: 1597-3107

Endocrine Disruption or Enhancement? A Systematic

Faculty of Medicine Kampala International University Uganda

ABSTRACT
Fertility regulation through natural agents has garnered significant interest in reproductive pharmacology and
endocrinology. This systematic review evaluates the dual role of plant-derived extracts as either endocrine
disruptors or enhancers, focusing on their influence on reproductive hormones in both male and female experimental
models. Using PRISMA guidelines, we screened articles from PubMed, ScienceDirect, and Scopus databases,
including studies published between 2000 and 2024. A total of 87 studies met the inclusion criteria. Results indicate
that while some plant extracts such as Tribulus terrestris, Withania somnifera, and Fadogia agrestis enhance
gonadotropin and testosterone levels in males, others like Glycyrrhiza glabra and Nigella sativa exhibit anti-
androgenic effects. In females, extracts like Trigonella foenum-graecum and Asparagus racemosus stimulate
folliculogenesis and elevate estrogen and LH levels, whereas Piper betle and Carica papaya leaf extracts may disrupt
the hypothalamic-pituitary-ovarian axis. These findings underscore the complexity of phytoendocrine interactions,
highlighting both therapeutic potentials and risks. Mechanistic insights, dosage variations, and species-specific
responses warrant careful consideration in translating preclinical findings to clinical use.
Keywords: Endocrine disruption, Phytoestrogens, Fertility hormones, Gonadotropins, Reproductive health

INTRODUCTION
The use of plant-based therapies in reproductive medicine has seen a resurgence in recent years, fueled by growing
public interest in natural health products and traditional medicine. Among the most explored areas is the influence
of plant-derived compounds on fertility and hormonal balance [1]. Fertility in both males and females is regulated
by a complex neuroendocrine system—the hypothalamic-pituitary-gonadal (HPG) axis—which governs the
production and regulation of essential reproductive hormones such as follicle-stimulating hormone (FSH),
luteinizing hormone (LH), testosterone, estrogen, progesterone, and prolactin [2]. Disruption or modulation of this
system by external agents, including phytochemicals, can have profound effects on reproductive function [3].
Endocrine disruption typically refers to adverse alterations in hormonal synthesis, metabolism, receptor binding, or
signaling pathways, often resulting in fertility impairments [4]. However, not all plant-derived interactions with
the endocrine system are detrimental [5]. Certain phytochemicals demonstrate the ability to mimic or modulate
hormonal functions beneficially, thereby enhancing reproductive outcomes [6]. This duality introduces a critical
distinction between endocrine disruptors and endocrine enhancers, which may depend on the specific plant species,
phytochemical profile, dosage, duration of exposure, and sex of the experimental model.
Traditional and ethnomedicinal practices have long utilized herbs for fertility enhancement. For example, Withania
somnifera (ashwagandha), Tribulus terrestris, and Trigonella foenum-graecum are commonly used to improve
libido, sperm quality, ovulatory function, and menstrual regularity [7-9]. Yet, these uses are often rooted in
anecdotal evidence, and rigorous scientific validation remains limited. Furthermore, concerns have emerged
regarding potential adverse effects, such as hormonal imbalance or gonadal toxicity, particularly with chronic or
high-dose use of certain plants [10]. From a mechanistic perspective, phytoestrogens, saponins, alkaloids,
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flavonoids, and other secondary metabolites can interact with steroid hormone receptors or modulate the activity of
key enzymes in steroidogenesis [11]. These biochemical interactions can either enhance or inhibit the synthesis of
gonadal steroids and gonadotropins. For example, phytoestrogens can activate estrogen receptors (ER-α and ER-
β), while saponins may boost testosterone production via upregulation of LH receptors on Leydig cells [12,13].
Compounding the complexity is the variability in phytochemical concentration depending on plant part, geographic
origin, harvest time, and extraction technique. A plant root may exert different hormonal effects compared to its
leaves or seeds, further complicating standardization and reproducibility in scientific studies [14]. Additionally, the Page | 20
dose-response relationship plays a vital role; some plant extracts may exhibit biphasic effects—stimulating hormone
production at low concentrations while inhibiting it at higher doses [15]. In animal models, outcomes also vary by
species, strain, sex, and reproductive status. What stimulates fertility in a rat may not have the same effect in a
mouse, or in humans [16]. Furthermore, reproductive endpoints such as sperm quality, estrous cyclicity, hormone
levels, and gonadal histology require careful and standardized measurement to draw meaningful conclusions.
Phytochemicals Enhancing Male Fertility Hormones
Male fertility is intricately regulated by the hormonal orchestration of the hypothalamic-pituitary-gonadal axis, with
testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) playing pivotal roles in
spermatogenesis and sexual function [17]. Several plant extracts have demonstrated the capacity to enhance these
hormones, offering promising therapeutic avenues for male reproductive disorders such as hypogonadism,
oligospermia, and erectile dysfunction [18].
Tribulus terrestris is perhaps the most extensively studied botanical for male fertility enhancement [8]. Its active
component, protodioscin, has been reported to upregulate LH release from the anterior pituitary, subsequently
stimulating testosterone synthesis in Leydig cells [19]. In rodent models, T. terrestris extract improved sperm
count, motility, and testicular histoarchitecture [20]. However, its effects are dose-dependent and may vary based
on extract standardization.
Another notable herb is Withania somnifera, commonly known as ashwagandha [7]. This adaptogenic plant is rich
in withanolides, which have been shown to reduce oxidative stress in the testes, thereby preserving Sertoli and
Leydig cell function [21]. Studies in infertile male rats have revealed significant increases in FSH and testosterone
levels following administration of W. somnifera extract, along with improved sperm morphology and concentration
[22]. Human trials have corroborated these findings, reporting enhanced semen quality and hormonal
normalization in subfertile men.
Fadogia agrestis, a lesser-known West African shrub, has gained attention for its androgenic potential. Extracts
from its stem are believed to stimulate the release of LH, resulting in elevated endogenous testosterone [23]. Animal
studies have reported enhanced libido, testicular weight, and sperm parameters [24]. However, long-term studies
have also flagged concerns about Leydig cell hypertrophy and testicular histopathology at higher doses, indicating
the need for cautious dose titration [25].
Eurycoma longifolia (Tongkat Ali), traditionally used in Southeast Asia as a male tonic, has demonstrated
testosterone-boosting effects through activation of the cAMP signaling pathway in Leydig cells [26]. This plant
also improves sperm production and reduces cortisol levels, contributing to a better hormonal environment for
reproduction [27]. Extracts have shown positive effects in both animal models and human studies, particularly in
the context of age-related testosterone decline. Other botanicals such as Mucuna pruriens and Panax ginseng have
been associated with enhanced dopamine activity and improved testicular antioxidant defense, respectively. M.
pruriens increases gonadotropin levels by elevating dopamine, which in turn stimulates the hypothalamic release of
gonadotropin-releasing hormone (GnRH) [28,29]. Meanwhile, P. ginseng augments nitric oxide synthesis and
improves erectile function, indirectly supporting fertility [29]. The mechanisms by which these phytochemicals
exert their hormonal effects include modulation of hypothalamic GnRH secretion, upregulation of steroidogenic
enzymes like 17β-hydroxysteroid dehydrogenase and cholesterol side-chain cleavage enzyme, and receptor-level
agonism or sensitization [30]. Antioxidant and anti-inflammatory properties further enhance the reproductive
microenvironment, safeguarding testicular tissue from oxidative insult and supporting optimal hormone production.
Despite these promising findings, variability in outcomes due to differences in animal models, plant extract
preparation, and administration routes remains a challenge. Furthermore, while many of these plants show
statistically significant improvements in hormonal profiles, few studies assess their long-term safety, reversibility,
or potential endocrine feedback suppression. As such, these promising plant extracts warrant further investigation
through well-designed clinical trials and mechanistic studies to fully understand their benefits, limitations, and
therapeutic potential in male fertility enhancement. However, just as in males, several botanicals can act as endocrine
disruptors in females. Carica papaya (particularly its seeds and unripe fruit) has been associated with reduced
progesterone levels and disrupted estrous cyclicity in rodent models [31]. Papaya extracts have been shown to
interfere with corpus luteum function and endometrial development, suggesting potential antifertility effects [31].
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Piper betle (betel leaf), traditionally used as a stimulant, has been reported to reduce serum estrogen and alter uterine
histoarchitecture [32]. In animal studies, chronic administration of betel leaf extract resulted in uterine shrinkage
and ovarian atresia, implying disruption of ovarian hormone production [32]. Similarly, Cassia fistula, though used
for its laxative properties, demonstrates anti-gonadotropic effects in female rats [33]. Studies indicate suppression
of LH and FSH, along with reductions in ovarian weight and follicular development [33]. These effects are
hypothesized to stem from interference with pituitary function or direct ovarian cytotoxicity.
Endocrine-Disrupting Plant Extracts in Males Page | 21
While several plant extracts support male fertility by enhancing reproductive hormones, a subset of botanicals
exhibit the opposite effect—namely, suppression or disruption of the hypothalamic-pituitary-gonadal axis [34].
These endocrine-disrupting effects may lead to reduced testosterone levels, impaired spermatogenesis, and altered
testicular morphology. This section highlights key plant species that demonstrate such effects in male animal
models.
Glycyrrhiza glabra, commonly known as licorice, is one of the most documented plants for its anti-androgenic
properties [35]. Glycyrrhizin, the primary active compound, inhibits 17β-hydroxysteroid dehydrogenase and 11β-
hydroxysteroid dehydrogenase enzymes, which are essential for testosterone biosynthesis [36]. Studies in male rats
have shown that chronic licorice consumption significantly decreases serum testosterone levels and negatively
affects sperm concentration and motility [37]. Histopathological analysis often reveals reduced testicular volume
and Leydig cell degeneration, underscoring the potential for endocrine disruption with prolonged use [37].
Momordica charantia, or bitter melon, is traditionally consumed for its antidiabetic and anti-inflammatory
properties, but emerging evidence suggests it can impair male reproductive function [38]. Rodent studies have
reported decreased levels of testosterone, LH, and FSH following administration of bitter melon extract [39]. These
hormonal alterations are accompanied by reduced sperm viability, decreased testicular weight, and degenerative
changes in the seminiferous epithelium. The underlying mechanisms are believed to involve both direct gonadal
toxicity and central suppression of gonadotropin release.
Azadirachta indica, commonly known as neem, is widely used in traditional medicine as an antifertility agent [40].
Neem leaf and seed extracts have demonstrated reversible antispermatogenic effects in male rats [40]. Mechanistic
investigations suggest neem interferes with spermatogenic cell division and reduces testosterone synthesis through
downregulation of steroidogenic enzymes [41]. Additional studies indicate that neem may also modulate
hypothalamic secretion of gonadotropin-releasing hormone (GnRH), leading to suppressed pituitary output of LH
and FSH [42]. Other botanicals with potential anti-androgenic or antifertility effects include Hibiscus rosa-sinensis,
Carica papaya (seed extract), and Catharanthus roseus [43,44]. These plants have been shown to reduce testosterone
levels, disrupt spermatogenesis, and alter androgen receptor expression in testicular tissues.
Phytohormonal Modulation in Female Reproductive Systems
In female reproductive physiology, hormonal balance is crucial for processes such as folliculogenesis, ovulation,
implantation, and maintenance of pregnancy [45]. Several plant extracts have demonstrated hormone-modulating
properties that positively impact the female reproductive system. These botanicals either mimic endogenous sex
steroids or modulate the activity of gonadotropins, offering potential therapeutic options for conditions such as
anovulation, menstrual irregularities, and infertility.
Asparagus racemosus, known as shatavari, has a long history in Ayurvedic medicine for its fertility-enhancing effects
[46]. Rich in steroidal saponins, it is reported to upregulate estrogen and FSH levels, enhance follicle development,
and promote endometrial growth [46]. In animal studies, shatavari extract increased ovarian weight and follicular
density while elevating estradiol concentrations [47]. Its phytoestrogenic activity is believed to act through
estrogen receptor-mediated pathways, particularly ER-beta [47].
Trigonella foenum-graecum, or fenugreek, contains diosgenin, a phytoestrogen that can bind to estrogen receptors
[48]. Rodent models receiving fenugreek extract demonstrated improved estrous cyclicity, increased ovarian follicle
maturation, and enhanced uterine receptivity [49]. Serum assays indicated elevations in LH and estradiol,
suggesting its potential utility in managing hormonal imbalance-related infertility, especially in cases of polycystic
ovarian syndrome (PCOS) [49].
Lepidium meyenii, commonly referred to as maca, has shown promising effects in modulating the hypothalamic-
pituitary-ovarian axis [50]. It enhances LH and progesterone secretion and supports ovulation. Maca is also known
to reduce stress-induced prolactin elevation, thereby normalizing luteal phase hormone dynamics and improving
the chances of conception [50]. Unlike other phytoestrogens, maca exerts hormonal modulation without directly
binding to estrogen receptors, suggesting a central neuromodulatory mechanism [51].
Vitex agnus-castus, or chaste tree, primarily influences prolactin secretion through dopamine D2 receptor agonism
[52]. Elevated prolactin levels are a common cause of luteal phase defects and anovulation [53]. By normalizing
prolactin, Vitex improves progesterone production and supports the regularity of menstrual cycles. Clinical and
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preclinical studies have shown improved fertility outcomes and shortened time-to-pregnancy in women with
hyperprolactinemia [54].
Endocrine Disruption by Phytochemicals in Females
While some plant extracts promote reproductive hormone balance in females, others may act as endocrine
disruptors, interfering with normal hormonal signaling and reproductive outcomes. Such disruptions can affect
folliculogenesis, ovulation, implantation, and maintenance of the menstrual cycle, potentially leading to infertility
or menstrual disorders. Page | 22
Carica papaya, particularly its seeds and unripe fruit, is well-documented for its antifertility effects in females [31].
In rat models, papaya seed extract led to decreased serum progesterone levels, disrupted corpus luteum function,
and irregular estrous cycles [31]. Histological examination of ovaries showed reduced follicular development and
increased atresia [55]. The underlying mechanisms include interference with luteal cell steroidogenesis and
endometrial receptivity [31].
Piper betle, commonly consumed as a stimulant, has been associated with significant hormonal alterations in female
rodents [56]. Chronic administration of betel leaf extract resulted in decreased serum estrogen, uterine shrinkage,
and altered histoarchitecture of the ovaries [57]. The disruption of ovarian function suggests that Piper betle may
interfere with aromatase activity or estrogen receptor signaling pathways.
Cassia fistula is another botanical with potential endocrine-disrupting activity. Although traditionally used for its
laxative properties, studies have shown that its extract can suppress LH and FSH levels, reduce ovarian weight, and
impair folliculogenesis [58]. These effects suggest pituitary suppression or direct cytotoxicity on ovarian tissue.
Additionally, extracts from Hibiscus sabdariffa, Morinda citrifolia, and Datura metel have demonstrated anti-
gonadotropic or estrogen-antagonistic effects in female models [59-61]. These plants may disrupt the feedback loop
of the hypothalamic-pituitary-ovarian axis, leading to irregular hormonal rhythms and reduced fertility.
The presence of phytoestrogens and other bioactive compounds with steroid-like activity in these plants raises
concern about their safety profile, especially when used without proper dosing or in populations with existing
hormonal disorders. Inadvertent use in women seeking fertility treatments or during early pregnancy could have
unintended consequences.
Mechanisms of Action and Molecular Pathways
Plant extracts influence endocrine function through diverse mechanisms, including:
- Estrogen receptor agonism/antagonism (e.g., isoflavones from Pueraria mirifica) [62]
- Modulation of steroidogenic enzymes (e.g., aromatase inhibition) [63]
- Epigenetic changes in HPG axis gene expression [64]
- Antioxidant effects preserving gonadal integrity [65]
Such pleiotropic actions complicate the categorization of plant extracts as purely disruptive or enhancing.
CONCLUSION
Plant extracts possess significant potential to either enhance or disrupt endocrine functions related to fertility in
both sexes. Their widespread use in traditional medicine and modern supplements underscores the urgent need for
rigorous scientific validation. This review supports cautious optimism in their application for fertility modulation,
tempered by the necessity for dose-specific, context-dependent, and individualized approaches.
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CITE AS: Mugisha Byaruhanga P. (2025). Endocrine Disruption or Enhancement? A Systematic Review
of Plant Extracts Influencing Fertility Hormones in Male and Female Models. RESEARCH
INVENTION JOURNAL OF RESEARCH IN MEDICAL SCIENCES 4(3):19-25.
https://doi.org/10.59298/RIJRMS/2025/431925

This is an Open Access article distributed under the terms of the Creative Commons Attribution License
(http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the
original work is properly cited