INTRODUCTION:

Infertility affects 20% to 30% of women globally who are of reproductive age, making it a major global health concern. The World Health Organization (WHO) defines infertility as the difficulty in achieving pregnancy after a year of engaging in unprotected sexual intercourse. This condition affects an individual's capacity to reproduce, whether independently or alongside a partner^1,2.

Worldwide, 8 to 14 percent of couples of childbearing age experience infertility issues³. Approximately half of infertility instances are due to male factors, either solely (around 30%) or in combination with female issues (about 20%)³._. Roughly 30 percent of male infertility cases lack a clear reason for abnormal sperm characteristics, even after extensive testing⁴. This situation is referred to as "idiopathic infertility"⁵. The causes of infertility are intricate, involving hormonal disturbances such as polycystic ovarian syndrome (PCOS), physical irregularities like uterine fibroids and endometriosis, genetic factors, as well as external influences such as pollutants and lifestyle habits⁶. Infertility and unfavorable reproductive outcomes have been repeatedly linked to a number of lifestyle-related variables, such as poor preconception nutrition, obesity, stress, and anxiety^7–9. Considering the crucial roles that vitamins and minerals have in various body functions, the status of micronutrients is a significant changeable element that could influence female fertility. Adequate levels of these micronutrients are necessary for the quality, maturation, fertilization, and implantation of oocytes. Additionally, antioxidants help reduce oxidative stress, a recognized contributor to infertility. Research has shown that certain women of childbearing age and those experiencing infertility often display inadequate levels of particular micronutrients, which could impede their chances of becoming pregnant¹⁰.

A). Hormonal therapies:

1. Aromatase Inhibitors:

The two primary estrogens in males are estrone and 17β-estradiol (E2). Aromatase is an enzyme belonging to the cytochrome P450 family, present in various tissues and organs such as the testicles, fat tissue, liver, and brain. It facilitates the transformation of testosterone and androstenedione¹¹. Medications for AIS inhibit the conversion of androgens into estrogens by hindering aromatase function. Examples of non-steroidal drugs that lead to reversible inhibition of this enzyme are letrozole and anastrozole, which are frequently used in medical settings. These drugs have been utilized to address unexplained male infertility to promote LH production and subsequently enhance testosterone levels within the testes, supporting sperm production by minimizing the negative feedback effect of estrogens on the hypothalamus-pituitary-gonadal axis¹².

1.1. Letrozole:

Letrozole serves as an aromatase inhibitor and belongs to the cytochrome P450 enzyme superfamily, which consists of hemoproteins¹³. It plays a crucial role in the limiting phase of estrogen production, particularly in transforming testosterone into estradiol (E2) and androstenedione into estrone¹⁴. Aromatase inhibitors represent a novel class of drugs utilized in fertility therapies, offering benefits such as oral usage, affordability, user-friendliness, and minimal side effects. Compared to injectable gonadotropins, letrozole stands out due to its cost-effectiveness, simplicity in application, and reduced adverse reactions. Recent studies suggest that letrozole can be considered a primary treatment option for women experiencing ovulatory issues. Estradiol, generated by the granulosa cells in the ovaries, hinders the secretion of follicle-stimulating hormone (FSH) by the pituitary gland through a negative feedback loop. Aromatase inhibitors disrupt this feedback inhibition on the hypothalamic-pituitary axis by blocking the conversion of androgens into estrogens, leading to an increase in FSH levels. This rise in FSH enhances the androgen levels in the ovaries, improving their sensitivity to FSH and promoting the growth of ovarian follicles. This process illustrates the potential of aromatase inhibitors in fostering follicular development and improving reproductive outcomes¹⁵. Common side effects include gastrointestinal issues, fatigue, hot flashes, headaches, and back pain¹⁶.

1.2. Clomiphene Citrate:

CC is a nonsteroidal medication that indirectly promotes ovulation. For many years, it has been utilized extensively to aid with reproductive technology and encourage ovulation. Patients with anovulatory diseases and polycystic ovarian syndrome (PCOS) benefit most from it¹⁷. It connects to raloxifene and tamoxifen as a specific estrogen receptor modulator (SERM)¹⁸. Depending on the specific tissue involved, these medications can exhibit both promoting and blocking effects as opposed antagonists at estrogen receptors. By enhancing natural gonadotropin activity, leading to increased FSH and LH levels, CC specifically opposes estrogen's negative feedback on the hypothalamus, thereby enhancing ovarian stimulation¹⁹. Headaches, mood fluctuations, and vision abnormalities are examples of transient adverse effects. Numerous studies suggest that CC may have teratogenic, cytotoxic, genotoxic, and embryotoxic effects²⁰.

2. Selective Estrogen Receptor Modulators (SERMs):

SERMs operate in a way similar to AIs by blocking estrogens from causing negative feedback at the level of the hypothalamus and pituitary gland. When this negative feedback decreases, the production of GnRH and gonadotropins rises²¹. Theoretically, an increase in FSH would enhance spermatogenesis by influencing Sertoli cells, while an elevation in LH would activate Leydig cells and increase testosterone levels²². Due to this mechanism, the treatment is not effective for men whose hypothalamic-pituitary axis is altered, such as those with congenital or acquired hypogonadotropic hypogonadism, or for infertile patients with elevated endogenous gonadotropin levels (primary hypogonadism)²¹. Clomiphene and tamoxifen are the primary drugs studied and used within this category. Clomiphene is particularly noted as the most widely prescribed treatment for idiopathic male infertility, at least per a survey conducted in the United States²³. Unlike AIs, estrogen antagonists can lead to an increase in both testosterone and estrogen levels²⁴. Nonetheless, these medications are generally considered safe. Possible side effects of clomiphene and tamoxifen include nausea, hot flashes, headaches, vision changes, and cardiovascular issues, but these are uncommon and typically short-lived²⁵.

3. Follicle Stimulating Hormone:

Human FSH is a type of gonadotropin consisting of two glycoprotein subunits, α and β, that are bound together without covalent bonds. Out of the 92 amino acids in the α subunit, two are modified with carbohydrates. Similarly, the β subunit contains 111 amino acids, of which two also undergo carbohydrate modification²⁶. The anterior pituitary gland is responsible for producing the hormone FSH, which, alongside LH, regulates the activity of the gonads in both males and females. FSH encourages the growth of Sertoli cells, triggers mitosis in spermatogonia, and supports the development of cells in the testis up to the round spermatid phase²⁷. Furthermore, FSH and testosterone appear to facilitate spermiogenesis by regulating the attachment of round spermatids to Sertoli cells²⁸. It has indeed been demonstrated that a temporary decrease in FSH and testosterone can result in failure of sperm production due to issues with the final separation of spermatids from the Sertoli cells²⁹. Recent studies have shown that FSH can enhance sperm quality and/or increase conception rates in men suffering from normal gonadotropic oligozoospermia^30,31. Additionally, patients facing sperm maturation arrest and azoospermic individuals who undergo testicular sperm extraction (TESE) have experienced better fertilization and pregnancy rates when treated with FSH before assisted reproductive technologies³².

4. Luteinizing Hormone:

Lutropin Alpha, also known as Luveris, represents a synthetic variant of LH that plays a crucial role in the maturation of ovarian follicles in females. It is administered alongside follitropin alfa to address infertility in women who have low levels of LH. The gene for human LH is integrated into the DNA of eukaryotic cells in recombinant human LH (r-hLH), which is one of the pharmacy-grade forms of LH created through biotechnology currently available. Studies suggest that Luveris can enhance the developmental ability of prophase bovine immature oocytes in vitro, an effect that is likely increased when combined with FSH (Gonal-F)³³.

5. Gonadotrophin-Releasing Hormone Agonists:

To improve sperm quality and increase chances of pregnancy, people facing unexplained infertility started receiving treatment with gonadotropins and gonadotropin-releasing hormone (GnRH) analogues starting in the 1950s³⁴. However, because of the uncomfortable way it had to be injected, the use of GnRH was slowly phased out. Human chorionic gonadotropin (HCG) was used to treat male infertility until the end of the 1970s, either by itself³⁵ or in conjunction with human menopausal gonadotropin (hMG)³⁶. When urofollitropin, a hormone with FSH-like action that was isolated from menopausal women's urine, became accessible in the middle of the 1980s, it was used experimentally to treat oligoasthenozoospermia³⁷. Recombinant FSH was discovered in the 2000s³⁹, although pure FSH was discovered in the latter part of the 1990s³⁸. Biosimilar FSH mulations have just entered the market⁴⁰. Although recombinant luteinizing hormone (LH) is also available, its short half-life (~10h) prevents it from being employed in clinical practice⁴¹.

5.1. Leuprorelin (Leuprolide Acetate):

Leuprolide is a synthetic hormone analog that is used in transgender hormone treatment and to treat a number of illnesses, such as endometriosis, breast cancer, and uterine fibroids^42,43. This drug is injected subcutaneously or intramuscularly⁴⁴. Leuprolide, a GnRH analog, lowers gonadotropin levels, which in turn lowers levels of estradiol and testosterone⁴⁵. Hot flashes, mood swings, sleeplessness, migraines, and injection site discomfort are common adverse effects of leuprolide⁴⁶. Leuprolide acetate is an agonist of the GnRH receptorInitially, it triggers the release of gonadotropins from the pituitary gland, such as FSH and LH, leading the testes and ovaries to generate increased levels of steroids. This results in heightened levels of dihydrotestosterone in men and estrogen in women. However, when leuprolide is administered consistently, it reduces the production of LH and FSH, which subsequently lowers estrogen levels in women and testosterone levels in men⁴⁷.

5.2. Synarel (Nafarelin Acetate):

One drug that functions as a GnRH agonist is nafarelin. It is mostly used to treat diseases like precocious puberty and endometriosis⁴⁸. It is also used as part of hormone treatment for transgender people, to treat uterine fibroids, and to control ovarian stimulation during IVF operations⁴⁹. A nasal spray is used to deliver the medication, usually two or three times a day⁵⁰.

6. Human Chorionic Gonadotropin:

The cells known as trophoblasts, which are the first to surround the embryo—especially the syncytiotrophoblast —create human chorionic gonadotropin (hCG), a hormone vital for detecting pregnancy. Following implantation, these cells contribute to the formation of the placenta⁵¹. hCG is also employed in medical contexts to trigger ovulation and boost testosterone production since it shares a similar structure with LH. Various organizations often collect urine samples to obtain hCG for fertility treatments due to its high levels in pregnant women. After suitable pretreatment with human menotropins, drugs such as Varel (CG) and Pregnyl (CG) are commonly utilized to promote ovulation and support conception in women with infertility due to a lack of ovulation, provided the infertility is not due to primary ovarian failure⁵².

7. Combination therapy:

Research has explored various empirical treatments for unexplained male infertility, including different combinations of hormone therapies alongside antioxidants⁵³. A significant study involving 212 participants found that tamoxifen (20 mg per day), which acts as an estrogen blocker and enhances FSH and LH in adult males, combined with testosterone undecanoate (120mg daily) for a duration of six months, notably improved sperm concentration and the rate of spontaneous pregnancies (33.9% compared to 10.3%, RR 3.195, 95% CI 2.615–3.765). Another research project indicated that the combination of tamoxifen (20 mg daily) and testosterone undecanoate (120mg daily), compared to a placebo, led to substantial increases in sperm concentration, motility, normal morphology, functional percentage, and testicular volume. Furthermore, this study revealed that combining tamoxifen with testosterone outperformed either treatment used alone in enhancing the functional fraction of sperm⁵⁴.

In a randomized controlled trial with 30 participants, clomiphene citrate (25mg) along with vitamin E (400 mg) taken daily resulted in significant increases in sperm concentration and pregnancy rates (36.7% versus 13.3%, OR 3.76, 95% CI 1.03–13.64) compared to a placebo⁵⁵. Many potential treatment combinations remain unexplored, although some combinations have shown to be moderately effective in addressing idiopathic infertility.

B.) non-hormonal therapies:

1. Antioxidants:

Many studies have been published that investigate the underlying causes of infertility in couples, particularly focusing on how oxidative stress (OS) plays a role in women's infertility⁵⁶. Oxidative stress leads to cellular harm, which happens when there is an imbalance between the ability of the body to neutralize harmful substances and the production of reactive oxygen species (ROS)⁵⁷. Reactive oxygen species (ROS) naturally occur as a consequence of cells needing oxygen for survival. While a certain level of ROS is essential for the normal functioning of cells, including reproductive ones, too much can be harmful, potentially damaging DNA and leading to cell death. Increased levels of ROS can be triggered by both internal and external factors^.58. Common external elements that often cause oxidative stress in reproductive cells include smoking, drinking alcohol, environmental pollutants, poor nutrition, and weight problems. Conditions such as infections, chronic diseases, and autoimmune disorders are examples of internal contributors⁵⁹. At appropriate levels, reactive oxygen species (ROS) are vital for communication processes involved in oocyte development, follicle growth, the breakdown of the corpus luteum, and the development of the placenta. Conversely, excessive ROS can have harmful consequences. It is crucial to maintain ROS at a balanced level due to their significant influence on reproductive functions⁶⁰.

Balanced levels of reactive nitrogen and oxygen species (RNOS) are important for signaling different aspects of women's reproductive health. They play a role in ovulation within the ovaries and help the uterine lining to heal and regenerate after menstruation without causing scarring. Additionally, they assist in various activities such as energy production, blood vessel growth (angiogenesis), and controlling inflammation throughout different phases of the menstrual cycle, all of which certainly affect fertility⁶¹. To counteract oxidative damage or stress, the body has developed an antioxidant defense system. Antioxidants can directly neutralize reactive oxygen species (ROS), rendering them harmless and repairing the resulting harm⁶². The body naturally contains both enzymatic and non-enzymatic antioxidants. Examples of enzymatic antioxidants include catalase, superoxide dismutase, glutathione peroxidase, and glutathione reductase. Non-enzymatic antioxidants include compounds like ascorbic acid (Vitamin C), alpha-tocopherol (Vitamin E), ferritin, and transferrin⁶³.

1.1 Carnitines:

Carnitine is a type of short-chain amino acid and carboxylic acid that belongs to the methylamine group. It acts as a carrier, transporting fatty acids into the mitochondria where they can be utilized for ATP production. The two main forms of carnitine found in human bodies are L-carnitine and L-acetylcarnitine⁶⁴. L-carnitine also exhibits antiapoptotic effects because it can inhibit cell death triggered by FAS-FAS ligand and caspase 3, 7, and 8⁶⁵. In male reproductive health, carnitine is present in significant quantities within the epididymis, making it a marker for epididymal function⁶⁶. In fact, men experiencing epididymitis showed lower levels of L-carnitine in their semen. Research indicates that adding L-carnitine can improve sperm quality after removing harmful agents such as bacteria or inflammation^67-69. Evidence from studies shows that incubating sperm with carnitine enhances their motility, suggesting that carnitine plays a role in managing sperm development and agility⁷⁰.

1.2 Coenzyme Q10:

Coenzyme Q10 (CoQ10) is a natural, fat-soluble antioxidant that regulates the outer mitochondrial membrane's permeability and the electron transport chain during respiration⁷¹. The link between CoQ10 levels and hydrogen peroxide (H2O2) indicates that CoQ10 not only helps prevent the formation of hyperoxides but also shields cells from oxidative damage⁷². An in vitro study showed that combining CoQ10 with zinc and D-aspartic acid reduced lipid peroxidation in sperm from both asthenozoospermic patients and men without sperm motility issues. In this latter group, sperm motility significantly improved. This resulted in a higher percentage of motile sperm following the swim-up technique across all test groups⁷³. Oral intake of CoQ10 has been proven to enhance sperm metrics, including concentration, motility, and morphology^74-76 as well as improve pregnancy rates⁷⁷among patients with idiopathic oligoasthenoteratozoospermia (OAT). However, another study indicated that, despite a notable increase in the antioxidant capacity of seminal plasma, there were no significant changes in the sperm characteristics of individuals with idiopathic OAT after CoQ10 treatment⁷⁸. A meta-analysis of three controlled trials found significant improvements in sperm concentration and motility, but there was no improvement in sperm morphology and success rates for conception⁷⁹.

1.3 Myoinositol:

Myoinositol is part of the B vitamin family and serves as a precursor for phosphatidylinositol polyphosphates, which are important for intracellular signaling^76-80. This compound not only has antioxidant properties but also contributes to cell shape and development, including the formation of cell membranes, lipid creation, and cell replication⁸¹. Myoinositol may be essential for regulating fluid levels because of its osmotic properties⁸². Moreover, it appears to influence human sperm's movement, chemical response, and response to temperature changes. Sperm thermotaxis is crucial for fertilization, as it promotes the movement of sperm from cooler areas to warmer ones, like the oviduct during ovulation⁸³.

The flagellum facilitates movement by gaining motility via the interaction of inositol 1,4,5-triphosphate with its receptors, leading to the inflow of calcium ions⁸³. In particular, inositol triphosphate receptors located in the head of the sperm encourage the influx of calcium, which alters the function of various enzymes, such as phospholipase C, protein kinase C, and phospholipase A2. These enzymes play a role in the sperm's connection to the zona pellucida and in the release of the contents of the acrosome⁸⁴. Although one study did not show an increase in sperm motility⁸⁶, the treatment with oral myoinositol was found to be safe and effective in improving semen quality^85-88. When myoinositol was given, levels of gonadotropin, inhibin B, and testosterone in the serum increased. However, data regarding pregnancy rates is lacking^85,87. Consequently, further investigation is necessary.

1.4 Vitamins C and E:

Ascorbic acid, commonly referred to as vitamin C, is a mildly acidic, water-soluble compound that can combat hydrogen peroxide, superoxide, and hydroxyl radicals. By eliminating free hydroxyl radicals and superoxide anions, vitamin E (α-tocopherol), which is fat-soluble, can prevent the peroxidation of membrane phospholipids⁸⁹. Studies have shown that the proportion of active spermatozoa is closely linked to the levels of both vitamins in semen^90,91, and these levels tend to be reduced in individuals with abnormal sperm characteristics compared to those with normal sperm counts⁹². Furthermore, research indicates an inverse relationship between vitamin C content and sperm DNA fragmentation index⁹⁴, along with a direct relationship to the amount of morphologically sound spermatozoa⁹³. Investigations into the connections between these two vitamins or between a vitamin and other antioxidants tend to show greater consistency^99-103, yet there is a lack of in vivo studies exploring the effectiveness of treatments that use only one vitamin^90,95-98.

1.5 Carotenoids:

Vegetables with colors like yellow, red, orange, and pink contain natural antioxidants called carotenoids. Reduced sperm motility has been linked to their dietary deficit^89. Carotenoids are the source of vitamin A, sometimes referred to as retinol. It controls several stages of spermatogenesis and the proliferation of epithelial cells ^81. Men with lower retinol serum concentrations have been found to have worse-quality sperm⁸⁹. Due to its ability to neutralize singlet oxygen, lycopene, a type of carotenoid present in fruits and vegetables, plays a role in the human redox defense mechanism¹⁰⁴. Research indicates that incorporating lycopene into cryoprotectant during cryopreservation lessens oxidative stress damage inflicted by reactive oxygen species on the sperm plasma membrane, prevents oxidative harm to sperm mitochondria, and improves the ability of sperm to withstand apoptosis¹⁰⁵.

1.6 Omega-3 fatty acids:

It has been suggested that omega-3 polyunsaturated fatty acids in the diet possess properties that combat inflammation and oxidative damage^106,107. This research looked into how omega-3 fatty acids affect semen qualities through a double-blind, placebo-controlled, randomized trial involving 238 men experiencing unexplained infertility¹⁰⁸. For a duration of 32 weeks, participants in the treatment group received a daily dose of 1.84 grams of docosahexaenoic (DHA) and eicosapentaenoic (EPA) acids. The results showed significant enhancements in sperm concentration, movement, and structure among those receiving treatment. Furthermore, the treatment group exhibited notably higher levels of EPA and DHA in their seminal plasma, red blood cells, and sperm. After the treatment period, this group also demonstrated higher activity levels of catalase-like enzymes and superoxide dismutase (SOD). There was a positive correlation between sperm characteristics and the levels of EPA and DHA in the seminal plasma¹⁰⁸.

1.7 N-acetyl cysteine (NAC):

NAC serves as a precursor to reduced glutathione (GSH), which can help restore this vital antioxidant function¹⁰⁹. Additionally, NAC can directly eliminate reactive oxygen species (ROS)^109-111. Given that NAC has been shown to improve the survival rate of germ cells within seminiferous tubules¹¹², boost sperm mobility, and reduce ROS in semen¹¹¹, it has been explored as a potential treatment for male idiopathic infertility. In two randomized, placebo-controlled trials involving men with unexplained infertility, taking NAC (600mg each day for six months) noticeably improved sperm parameters and the oxidative status of semen^114,113. Although data regarding pregnancy outcomes is lacking, it is essential to evaluate how NAC affects male idiopathic infertility comprehensively.

1.8 Trace elements:

Selenium, a crucial micronutrient, affects spermatogenesis, sperm function, and the development of testicles. It is an essential component of selenoproteins, which include various enzymes that protect against oxidative stress, such as glutathione peroxidase¹¹⁴. The deficiency of selenium has been connected to alterations in sperm shape and movement, difficulties in sperm production and maturation, and a reduction in testis size¹¹⁵.

Like selenium, zinc plays a role in various enzymes crucial for cell replication, DNA repair and synthesis, as well as protection against oxidative stress (including superoxide dismutase). Men with idiopathic infertility often have lower seminal zinc levels compared to fertile individuals¹¹⁶. Approximately 100 metalloenzymes require zinc to function, and it is involved in vital biological processes like protein production and DNA synthesis. Zinc works alongside other antioxidants and has its own antioxidant actions¹¹⁷. It's believed that zinc can occupy sites that would otherwise bind copper and iron, preventing lipid peroxidation associated with these metals¹¹⁷.

Low levels of zinc in seminal plasma have been linked to male infertility¹¹⁸. Higher zinc levels in seminal plasma are strongly associated with increased sperm concentration and healthy sperm morphology. Initial findings suggest that zinc supplementation may enhance sperm concentration, movement, and structure^119,120.

2. Probiotics and prebiotics:

Recent studies have revealed that the gut microbiota plays several significant roles in the body. It seems to influence not just digestive processes but also the immune response, the formation of organs, the stability of tissues, cancer development, bone density, metabolic functions, and even behavior¹²¹. Regarding hormone regulation, the gut microbiota releases an enzyme called β-glucuronidase, which converts estrogens into their active states, thus managing estrogen levels. As a result, imbalances in the gut can lead to fluctuations in circulating estrogen¹²². This disruption might be connected to the underlying causes of various health issues in women, including obesity, metabolic syndrome, endometriosis, polycystic ovary syndrome, endometrial hyperplasia, cancer, and infertility¹²². While no studies have specifically investigated the link between gut microbiota and male infertility, there is a possibility that the microbiota influences the feedback systems of the hypothalamus and pituitary gland by regulating estrogen levels¹²³.

3. Anabolic steroids:

Anabolic steroids are synthetic forms of testosterone that have been modified to enhance the hormone's muscle-building (anabolic) properties instead of its masculine (androgenic) characteristics. The steroid hormone testosterone is created in the human body from cholesterol, which serves as the foundation for all steroid hormones found in humans. In men, the Leydig cells in the testes and the adrenal glands are responsible for the biosynthesis of testosterone; in women, this production occurs only in the adrenal glands. Testosterone is fundamentally derived from the two main precursors, androstenediol and androstenedione. Along with testosterone, there is also some production of 5-dihydrotestosterone (DHT) and its isomer epitestosterone, with a ratio of 30:1¹²⁴.

Androgenic effects:

The primary sexual characteristics in males develop due to testosterone. The development of male genitalia is aided by the combination of testosterone and a polypeptide factor known as Mullerian regression factor (MRF). Following this, testosterone solely governs the growth of external genitalia. The Leydig cells release minimal amounts of testosterone from the time of birth until puberty¹²⁴.

THERAPEUTIC USE:

1. Men's replacement treatment:

When puberty is postponed or the testicles are surgically taken out because of a tumor or injury, anabolic steroids can be given to stimulate sexual growth. In this case, the replacement therapy continues for life¹²⁴.

2. Women's replacement treatment:

Sexual infantilism is an uncommon disease in which a young girl does not produce testosterone, progesterone, or estradiol. Her libido develops as a result of her testosterone problems. Some postpartum and postmenopausal women experience libido decline. Testosterone treatment has been demonstrated to increase sex desire in each of these situations¹²⁵.

SIDE EFFECTS:

Abuse of anabolic steroids has several adverse effects.

1. Heart:

Anabolic steroids cause the body to retain more sodium chloride through the kidneys, which causes water retention and an increase in blood volume. Although it doesn't always happen, these two conditions can lead to hypertension¹²⁶.

2. Clotting of blood:

Only one documented case exists of a sports person consuming anabolic steroids and passing away due to a stroke, though this number may be higher among those addicted to steroids¹²⁶.

3. Issues with the liver:

Orally active anabolic steroids, especially the 17 methyl variants, are closely linked to hepatic cancer, jaundice, and the deadly degenerative liver disease petiocis hepatis¹²⁷.

4. Adverse sexual consequences:

In one research by Holma, long-term use of high dosages of anabolic steroids resulted in a 73% decrease in sperm counts and three cases of azoospermia, or total lack of sperm. The quantity of immotile sperm increased by 10% and the number of motile sperm decreased by 30%, even among those who had sperm. Male fertility was thus significantly decreased, supporting several clinical accounts of the same phenomenon¹²⁷.

5. Impact on libido:

It is believed that testosterone influences libido in both men and women, at least somewhat. Elevated blood levels of anabolic steroids decrease libido and inhibit the body's normal production of testosterone¹²⁶.

6. Gynaecomastia:

Men who are attempting to enhance their use of anabolic steroids might face this opposing condition. This relates to the growth of breast tissue. The primary reason for this condition among anabolic steroid users is the transformation of the drug into oestradiol by liver aromatase enzymes, which then promotes the development of breast tissue¹²⁴.

7. Control of blood sugar:

Increased insulin resistance brought on by anabolic steroids can lower glucose tolerance and ultimately result in secondary diabetes with type II symptoms¹²⁴.

8. Behavioral and psychological effects:

It's uncertain how anabolic steroids affect behavior and how they may contribute to the development of mental illness. According to big research conducted in the USA, 25% of anabolic steroid abusers had a mood illness of some kind, ranging from serious depression to bipolar disorder to mania¹²⁸.

c). Targeted drug therapies:

1. Metformin:

As an antihyperglycemic medication, metformin lowers insulin levels, increases tissue sensitivity to insulin, and inhibits the liver's ability to produce glucose. Metformin has been proven effective in addressing hyperinsulinemia while lowering ovarian androgen levels, LH, and sex hormone-binding globulin (SHBG), in individuals with PCOS¹²⁹. It also encourages the return of normal ovulation and menstrual periods. Metformin and CC together improve the ovulatory response in obese PCOS women, as shown by Nestler et al¹³⁰ 39% (19/49) of patients reported experiencing nausea and stomach discomfort, which are common adverse effects of metformin. However, these side effects were usually temporary and mostly happened within the first two weeks of therapy¹³¹.

2. Dopamine agonist:

Because dopamine may reduce the production and release of prolactin releasing factors through D2-like receptors, it functions as a prolactin-inhibiting factor¹³². Among them, ergoline derivatives like cabergoline and bromocriptine are commonly used. According to studies, by preventing excessive prolactin release, these drugs successfully reduce prolactinomas and restore normal gonadal function. Dopamine agonists like cabergoline and bromocriptine can help regular menstrual cycles and promote ovulation by lowering prolactin levels, which can interfere with ovulation¹³³.

3. Anti-inflammatory treatment:

3.1 Corticosteroids:

Anti-sperm antibodies (ASA) decrease chances for natural conception by hindering sperm movement and function. For male infertility associated with ASA, corticosteroids have been explored as a specific approach^134,135. The use of Prednisolone for over three months offers only modest benefits. Despite potential serious side effects, such as weight gain, widespread infections, and avascular necrosis (AVN) of the femoral head, Prednisolone is not considered an ideal option for men facing infertility due to ASA¹³⁶.

3.2 non-steroidal anti-inflammatories (NSAIDs):

Leukocytes are commonly found in the seminal fluid of infertile men, and they have been shown to negatively affect sperm functionality¹³⁷. However, the connection between bacterial leukocytospermia and male infertility remains uncertain^138,139. Empirical treatment with NSAIDs has been applied for infertility linked to bacterial leukocytospermia. In two studies, administering 25 mg of COX-2 inhibitors (rofecoxib) daily for a month significantly reduced leukocytospermia and improved sperm qualities (normal shape, motility, and count)¹⁴⁰. To confirm whether these enhancements in sperm qualities lead to increased fertility, randomized controlled trials focusing on live birth rates as the main outcome are necessary.

4. Antibiotics:

Genitourinary (GU) infections might contribute to male infertility. According to Gallegos et al., such infections can diminish sperm count, shape, and motility while raising sperm DNA fragmentation. Treating GU infections with appropriate antibiotics has been shown to significantly lower sperm DNA fragmentation and improve sperm count and motility. Selecting the right antibiotic is crucial since various antibiotic classes vary greatly in their ability to penetrate different regions of the male digestive tract. Empirical antibiotic treatment has been used for infertile men exhibiting low-level leukocytospermia (0.2-1.0 106 WBC/mL). Doxycycline not only has a broad spectrum of antibacterial effects but also specifically reduces the production of reactive oxygen species by leukocytes. It appears that antibiotics can effectively treat those with low-level leukocytospermia¹⁴¹.

CONCLUSION:

The field of reproductive healthcare is changing significantly, and new therapy approaches are giving infertile people new hope. Clinical results in fertility control have improved because of innovations in pharmacological interventions, such as focused medication treatments like metformin for PCOS and enhanced hormonal therapy. Dietary therapies and nutraceuticals, especially antioxidants like CoQ10, omega-3 fatty acids, N-acetyl cysteine (NAC), carotenoids, vitamins C and E, myoinositol, and carnitines have been shown to promote ovarian function and reduce reproductive damage caused by oxidative stress¹⁴². Similarly, new opportunities for probiotic-based treatments targeted at enhancing reproductive health have been presented by the growing importance of the gut and vaginal microbiota in fertility control^143,144. With a paradigm shift toward precision medicine, regenerative techniques, and bioengineered reproductive tissues, the future of reproductive healthcare appears bright. The next phase of fertility control will be greatly influenced by the ethical integrity, accessibility, and long-term safety of these breakthroughs and therapeutic treatments as research advances.

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Received on 22.01.2026 Revised on 28.02.2026

Accepted on 31.03.2026 Published on 04.07.2026

Available online from July 18, 2026

Asian J. Pharm. Tech. 2026; 16(3):271-281.

DOI: 10.52711/2231-5713.2026.00039

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