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Table 1 Summarizing the effects of sex related hormones and the analogues of them in the cardiotoxicity induced by chemotherapeutic agents

From: A comprehensive review on the effects of sex hormones on chemotherapy-induced cardiotoxicity: are they lucrative or unprofitable?

Ref.

Study model

Drug

Dosage / administration route

Outcome of therapy

[48]

Pooled data analysis from six phase 3 prospective RCT.

2,328 men with pathologically confirmed prostate cancer and naïve to androgen deprivation therapy (ADT).

Randomization: Men were randomized to receive either a GnRH agonist or a GnRH antagonist for 3–7 months

GnRH Antagonist: Degarelix (n = 1491).

GnRH Agonists:

Leuprolide (n = 379).

Goserelin (n = 458).

Antiandrogen (Bicalutamide): Given to some patients for 1 month as flare protection.

GnRH Antagonist (Degarelix): Administered as per study protocol, details on specific dosage were not provided.

GnRH Agonists (Leuprolide, Goserelin): Administered as per study protocol, with some patients also receiving bicalutamide for 1 month.

Administration Route: Not explicitly mentioned, but typically these are administered via injection.

Men with preexisting cardiovascular disease treated with a GnRH antagonist had a significantly lower risk of cardiac events within 1 year compared to those treated with GnRH agonists (Hazard Ratio: 0.44; 95% CI, 0.26–0.74; p = 0.002).

The absolute risk reduction was 8.2%, with a number needed to treat of 12.

Cardiac events occurred only in the longer trials; none occurred in the shorter trials.

Conclusion: GnRH antagonists may reduce the number of cardiac events in men with preexisting cardiovascular disease compared to GnRH agonists.

[53]

Prospective cohort study

3,637 community-dwelling men aged 70–88 years.

Duration: Mean follow-up was 5.1 years (range 0.1–7.2 years).

Primary Focus: Testosterone and its associated hormones (SHBG and LH)

Testosterone, SHBG, and LH levels were assessed in participants.

IHD Events: 17% of men experienced an ischemic heart disease (IHD) event, with 160 of these being fatal.

Testosterone: Higher levels of total and free testosterone were associated with fewer IHD events, but these associations disappeared after adjusting for prevalent IHD and other cardiovascular risk factors.

SHBG: No link was found between SHBG levels and IHD events.

LH: Higher LH levels were associated with increased risk of IHD events, both before and after adjusting for other factors.

[82]

Observational study of 37,443 men with local or regional prostate cancer.

Androgen deprivation therapy (ADT) with:

1.Gonadotropin-releasing hormone (GnRH) agonists

2.Oral antiandrogens

Combined androgen blockade (GnRH agonists + oral antiandrogens)

3.Orchiectomy

GnRH Agonists: Administered as injections with dosage intervals accounted for by estimating treatment duration.

Oral Antiandrogens: Administered orally, with treatment duration accounting for persistent effects up to 8 weeks after the last dose.

Orchiectomy: Surgical removal, with patients remaining in this treatment category permanently.

GnRH Agonists: Associated with increased risks of diabetes (adjusted hazard ratio [aHR] = 1.28), coronary heart disease (aHR = 1.19), myocardial infarction (aHR = 1.28), sudden cardiac death (aHR = 1.35), and stroke (aHR = 1.22).

Combined Androgen Blockade: Increased risk of coronary heart disease (aHR = 1.27).

Orchiectomy: Increased risks of coronary heart disease (aHR = 1.40) and myocardial infarction (aHR = 2.11).

Oral Antiandrogen Monotherapy: Not associated with significant increases in any outcomes studied.

[87]

The study involved male ARKO mice (androgen receptor knockout mice) and their wild-type (WT) littermates.

Additionally, Rat H9c2 cardiac myoblast cells were used in cell culture experiments.

Doxorubicin (DOX)

Mice: 20 mg/kg DOX administered via intraperitoneal (i.p) injection.

Cell Culture: H9c2 cells were treated with DOX at a concentration of 1 µM.

Mice:

DOX treatment reduced the survival rate of both male WT and male ARKO mice, with a significantly lower survival rate in ARKO mice (28% vs. 68% in WT).

DOX treatment caused early-phase left ventricular dysfunction, more severe in ARKO mice.

ARKO mice exhibited more pronounced mitochondrial damage, increased cardiac superoxide production, and higher levels of lipid peroxidation in response to DOX.

DOX treatment led to increased apoptosis of cardiac cells in both WT and ARKO mice, but ARKO mice showed a significantly higher number of apoptotic cells and a lower Bcl-2-to-Bax ratio.

DOX treatment resulted in suppressed Akt phosphorylation and reduced Tfam expression in the myocardium of ARKO mice, indicating greater susceptibility to DOX -induced cardiotoxicity.

Cell Culture:

Testosterone, when used as an AR agonist in H9c2 cells, enhanced Akt phosphorylation and Tfam expression via an AR- and PI3K-dependent pathway, indicating a protective mechanism against DOX -induced cardiotoxicity.

[108]

Prospective, longitudinal study

Population: Elderly Swedish men and women (opposite-sex twins)

Age: 71 to 80 years at baseline; 82.4 years at follow-up

Sample Size: 425 subjects (230 men, 195 women) at baseline; 277 subjects (132 men, 145 women) at follow-up

Hormone Studied: Progesterone (physiologic concentrations)

Administration Route: Natural physiologic serum concentrations measured; no external administration

Time Points: Baseline (1996) and 8-year follow-up (2004)

Higher serum progesterone levels were significantly associated with increased mortality (P < 0.001) and congestive heart failure (CHF) (P < 0.01) at follow-up.

The association with CHF remained significant even after adjusting for inflammatory markers (CRP), cystatin, and insulin levels.

Conclusion: Elevated physiologic concentrations of progesterone in elderly individuals were associated with an increased prevalence of CHF and higher mortality rates, independent of other risk factors.

[110]

Experimental Design: The study included:

Principal study with 8 nonpregnant, 10 pregnant, and 6 nonpregnant progesterone-treated rats.

Preliminary study with 6 additional nonpregnant rats.

Control studies with 1 nonpregnant, 1 pregnant, and 1 progesterone-treated nonpregnant

Cocaine HCl

Cocaine Concentrations: Ranging from 10^-16 M to 10^-4 M, added to the muscle bath at 30-minute intervals.

Progesterone Dosage (for pretreatment): 7 mg/kg, administered intramuscularly for 3 consecutive days.

Nonpregnant Rats: Muscles remained functional up to 10^-4 M cocaine. Positive inotropy (increased dT/dt) was observed up to 10^-7 M, with negative inotropy at higher concentrations.

Pregnant and Progesterone-Treated Nonpregnant Rats: All muscles became nonfunctional at 10^-5 M cocaine. These groups exhibited only negative inotropy with increasing cocaine concentrations.

Proportion of Nonfunctional Muscles: Significant differences were observed among the groups at certain cocaine concentrations.

Parameter Measurements: Peak tension (PT), time to peak tension (TPT), and rate of tension formation (dT/dt) were used to assess muscle response. The negative inotropy in pregnant and progesterone-treated groups was due to decreased PT and TPT.

[111]

Rat Papillary Muscles

Groups:

Untreated (Control) (n = 12)

Progesterone (7 mg/kg) for 3 days (n = 12)

Progesterone (7 mg/kg) for 3 days + RU 486 (10 mg/kg) for 3 days (n = 12)

Progesterone (7 mg/kg) for 3 days + single low dose RU 486 (10 mg/kg) (n = 6)

Progesterone (7 mg/kg) for 3 days + single high dose RU 486 (50 mg/kg) (n = 6)

RU 486 (10 mg/kg) for 3 days (n = 6)

RU 486 (10 mg/kg) for 3 days without exposure to cocaine (n = 6)

Progesterone: 7 mg/kg

RU 486 (Mifepristone):

Low dose: 10 mg/kg

High dose: 50 mg/kg

Progesterone: Administered daily for 3 days

RU 486:

Administered daily for 3 days or as a single dose 1 h before decapitation.

RU 486 Reversal of Progesterone-Enhanced Cardiotoxicity: RU 486 treatment effectively reversed the increased sensitivity to cocaine-induced cardiotoxicity that was observed in rats pretreated with progesterone.

Functionality at Higher Cocaine Concentrations: Papillary muscles from rats treated with RU 486 (either for 3 days or as a single high dose) remained functional at significantly higher cocaine concentrations (up to 10^-3 M) compared to those treated with progesterone alone, which became nonfunctional at much lower concentrations (around 10^-7 M).

Positive Inotropy with High-Dose RU 486: The group treated with a single high dose of RU 486 exhibited a biphasic response, showing positive inotropy at lower cocaine concentrations, followed by negative inotropy at higher concentrations. This pattern was absent in the group treated with a single low dose of RU 486, which only displayed negative inotropy.

RU 486 Alone: In the absence of cocaine, RU 486 alone did not significantly affect papillary muscle contractility, indicating that its protective effects are specific to the context of cocaine exposure.

[130]

Female Sprague-Dawley rats were used, weighing between 225–250 g.

The rats were utilized to study the synthesis, release, and effects of oxytocin (OT) in the heart.

Oxytocin (OT).

Peripheral injection of oxytocin was administered intravenously (i.v.) in previous studies referenced.

During the experiment, OT was also analyzed through heart homogenates, perfusion of isolated hearts, and RT-PCR of cardiac tissues.

OT was synthesized and released by the rat heart, particularly in the atria.

OT presence in the heart influenced the release of atrial natriuretic peptide (ANP).

Peripheral injection of OT in rats decreased mean arterial pressure in a biphasic manner: an initial pressor effect followed by a prolonged decrease in arterial pressure.

OT’s natriuretic properties may contribute to blood volume regulation.

OT was shown to reduce heart rate and force of atrial contractions, suggesting a role in cardiac output and blood volume reduction

[131]

the study involved adult female and immature female Sprague Dawley rats.

The immature female rats were specifically implanted with a silastic tube containing diethylstilbestrol (DES), an estrogen analogue, for 48 h.

Diethylstilbestrol (DES), an estrogen analogue

The DES was administered via implantation in a silastic tube for 48 h.

DES also increased oxytocin (OT) levels in the vena cava from 3497 ± 350 to 7756 ± 445 pg/mg protein but did not affect OT concentration in the aorta.

[145]

To investigate the therapeutic effects of liraglutide, oxytocin, and granulocyte colony-stimulating factor (G-CSF) in a doxorubicin (DXR)-induced cardiomyopathy rat model.

40 male Sprague–Dawley rats.

40 male Sprague–Dawley rats.

Groups:

Normal Group: 8 rats with no treatment.

DXR Group: 32 rats administered with doxorubicin to induce cardiomyopathy, divided into 4 subgroups:

Placebo (DXR + Saline): 8 rats treated with 0.9% NaCl saline solution.

DXR + LIR: 8 rats treated with liraglutide.

DXR + OX: 8 rats treated with oxytocin.

DXR + G-CSF: 8 rats treated with filgrastim (G-CSF).

Doxorubicin (DXR)

Liraglutide (LIR)

Oxytocin (OX)

Filgrastim (G-CSF)

Placebo

Doxorubicin (DXR):

Dosage: 2.5 mg/kg/day intraperitoneally (i.p.), administered every other day for 6 doses (total dose 15 mg/kg).

Liraglutide (LIR):

Dosage: 1.8 mg/kg/day i.p. for 15 days.

Oxytocin (OX):

Dosage: 160 µg/kg/day i.p. for 15 days.

Filgrastim (G-CSF):

Dosage: 100 µg/kg/day i.p. for 15 days.

Placebo:

Dosage: 0.9% NaCl saline solution, 1 ml/kg/day i.p. for 15 days.