Myo-Inositol (ProFecund Ino) – Obtaining a Pregnancy in Women with Polycystic Ovary Syndrome

Abstract

Polycystic ovary syndrome (PCOS), affecting 5–10% of women, is characterized by irregular ovulation and excess androgen hormones. The multifactorial causes include hormonal imbalances, insulin resistance, genetics, and obesity. Diagnosis involves identifying criteria like oligo/anovulation, hyperandrogenism, and micropolycystic ovarian appearance. Traditional treatments include progesterone-based medication and oral contraceptives. However, fertility-focused treatments such as clomiphene, metformin, purified FSH, or LH are administered for those seeking to restore fertility. This article explores “ProFecund Ino,” a myo-inositol-based treatment for PCOS. It touts benefits such as improved hormonal balance, regulated menstrual cycles, stimulated ovulation, enhanced insulin sensitivity, and positive effects on the nervous system. The study involving 200 women with PCOS showed a 38% pregnancy rate with ProFecund Ino and additional pregnancies resulted from ovarian stimulation and IVF procedures. The conclusion underscores the efficacy of myo-inositol-based treatments in conjunction with assisted reproductive techniques, significantly increasing pregnancy chances for women with PCOS.

1. Introduction

Also known as Stein-Leventhal syndrome or chronic hyperandrogenic anovulation, polycystic ovary syndrome (PCOS) is an endocrinological condition characterized by the absence of ovulation and the presence of excessive amounts of androgenic hormones in the female body.

Clinically, PCOS is manifested by amenorrhea (lack of menstrual cycles) or irregular menstrual cycles, accompanied by obesity and manifestations caused by excess androgen hormones (acne, hirsutism, etc.).

2. Epidemiology

PCOS affects 5–10% of the total female population worldwide and up to 26.7% of the female population of childbearing age (15–44 years) [1].

It is estimated that 70% of women with PCOS are still undiagnosed [2].

PCOS symptoms most frequently occur in girls with recent menses and in women in the premenstrual period (with worsening symptoms, especially pelvic pain).

3. Causes and risk factors

The exact cause is not fully elucidated. However, certain favorable factors can be described:

• Disorders of the metabolism of androgen and estrogen hormones;

• Insulin resistance and hyperinsulinemia;

• The genetic factor;

• Obesity.

4. Signs and symptoms

1. Amenorrhea (absence of menstrual cycles) or irregular menstrual cycles;

2. Clinical signs caused by excess androgen hormones (hirsutism—increased body hair, increased muscle mass, acne, alopecia, hoarseness of voice);

3. Obesity.

5. Diagnosis

According to the Rotterdam Consensus of 2003 still in force, the diagnosis of polycystic ovary syndrome (PCOS) is made in the presence of at least two of the following three criteria:

1. Oligo/Anovulation—consequence of ovulatory dysfunction, they are present in about 75% of patients; the remaining 25%, with rhythmic periods, have subclinical oligo/anovulation confirmed by repeated low progesterone levels on day 21 of the menstrual cycle;

2. Clinical and/or biochemical hyperandrogenism—highlighted by the increased value of free testosterone is found in 60–80% of PCOS patients. Among the clinical signs of hyperandrogenism, hirsutism is considered the most relevant (60% of patients), which is evaluated by the modified Ferriman-Gallwey score (mFG). It can associate acne (15–25%) and androgenetic alopecia (5%);

3. Ovaries with a micropolycystic appearance—the micropolycystic appearance of the ovaries is detected by transvaginal ultrasound in 75% of PCOS patients, consisting of at least one ovary with a volume > 10 cm3 or presenting at least 12 follicles with a diameter between 2 and 9 mm.

6. Treatment

Classic treatment includes progesterone-based medication (Medroxyprogesterone) and oral contraceptives.

In the case of women who want to regain their fertility (with the hope of obtaining a future pregnancy), antiestrogens (clomiphene), metformin, and purified FSH or LH are administered.

7. ProFecund Ino

7.1 Active ingredients per daily dose

• Myo-inositol 4000 mg

• Vitex agnus-castus 40 mg

• QuatrefolicTM 755 mcg (400 mcg folate)

• Vitamin B2 2.8 mg

• Stevia rebaudiana and fructose (sweeteners) and lemon flavor.

7.2 Mode of presentation

Box with 30 sachets of 3 g of product.

7.3 Administration method

Two sachets per day.

The recommended courses for obtaining a stable result over time are three months.

7.4 Benefits

• Improving female hormonal balance and maintaining a balanced level of testosterone and estrogen (menstrual cycle disorders, premenstrual syndrome, premenopause, hirsutism, acne) [1];

• Regulation of the menstrual cycle and ovulation [2];

• Stimulation of oocyte maturation and increase in the number of oocytes (after ovarian stimulation) [3];

• Improvement of insulin sensitivity [1];

• Optimum functioning of the nervous system and improvement of the emotional state by facilitating the transmission of nerve impulses and improving the sensitivity of brain receptors to serotonin [4, 5];

• Reduces fatigue and protects cells against oxidative stress [5].

8. Myo-inositol

8.1 Definition

Myo-inositol is a pseudovitamin consisting of nine molecules with a similar structure (isomers), found especially in cereals and citrus fruits.

Usually, the term inositol is used for the stereoisomer myo-inositol.

With a similar structure to glucose, inositol is involved in cell signal transmission.

8.2 Indications

8.2.1 Adjuvant in PCOS

One of the causes of polycystic ovary syndrome is insulin resistance. Myo-inositol contributes to increasing insulin sensitivity and improving the activity of insulin receptors.

Also, it contributes to changing the FSH/LH ratio, lowering the testosterone level, and restoring the normal menstrual cycle.

8.2.2 Pregnancy

In pregnant women carrying fetuses with neural tube defects, low levels of inositol have been observed compared to women with normal pregnancies. Inositol can prevent a wide range of neural tube defects resistant to folic acid supplementation.

8.3 Interactions and adverse effects

This shows a high safety profile for most adults. Among the possible side effects that may occur when taking it are nausea and dizziness, fatigue, or headache.

It is considered safe to be given in hospital to premature babies with ARDS (acute respiratory distress syndrome).

In the case of bipolar affective disorders, it is recommended to avoid the administration of inositol, as it may trigger the worsening of symptoms.

No interactions with other drugs are known to date.

9. Vitex agnus-castus

9.1 Characteristics

• Shrub 2–4 m high

• Fruit of chastity/ monks’ pepper/ lambing

• Mediterranean and Asian countries

• Blooms in summer

• Goddess Hera—born under a Vitex tree

• Used by Hippocrates

• Mentioned in Materia Medica (Dioscorides)

• Ancient Greece—female adornment during festivals held in honor of Demeter (god of agriculture, fertility, and marriage)

9.2 Mechanism of action

Vitex agnus-castus is not a hormone. Vitex acts on the hypothalamus and pituitary gland where it improves specific hormone secretion or the transmission of the necessary chemical signals to the ovaries for the release of estrogens and progesterone.

$$\text{Vitex agnus-castus }\to -LH\text{and}\downarrow FSH\to \text{prepares the body for ovulation}.$$

9.3 Vitex and progesterone

Vitex potentiates the hormones involved in ovulation, also participating in the rebalancing of the hormonal balance:

• is effective in regulating pituitary function;

• normalization of estrogen and progesterone levels.

Vitex is highly effective in maintaining adequate progesterone levels during the luteal (postovulatory) phase, levels necessary for pregnancy.

9.4 Interactions and other side effects

• No known drug-extract interactions have been reported for Vitex in humans

  Careful use is recommended when prescribed among:

  • dopamine agonists;

  • hormone replacement therapy (estroprogestant combinations used in the treatment of menopause) due to the mechanisms of action.

• Side effects associated with Vitex extracts are mild, reversible, and uncommon.

• Gastrointestinal disorders or headaches in less than 2% of patients.

10. Quatrefolic

Whereas folic acid requires three intermediate steps to reach the level of active folate, L-Methylfolate (Quatrefolic) is a metabolized folic acid, which leads to its immediate and complete absorption as biologically active folate.

10.1 Benefits: Increased solubility in water

• QuatrefolicTM—100 times more soluble in water compared to the calcium salt of (6S)5- methyl tetrahydrofolic acid—MetafolinTM.

• The high solubility in water of the product means a complete absorption at the level of intestinal cells, facilitating faster access to blood circulation and improving bioavailability at the level of the body.

• Before ingestion, once dissolved in a liquid (water, tea, etc.), the pH of QuatrefolicTM is protected from hydrolytic degradation, which makes it easy to administer.

10.2 Benefits: Increased bioavailability

• The bioavailability of QuatrefolicTM is visibly increased compared to MetafolinTM and folic acid

10.3 Safety of use

• 2010 – USA: GRAS (Generally recognized as safe)

  • “For use as a source of folate in conventional and medical foods”

• 2013 – EUROPE: EFSA Positive Scientific Opinion trend

  • “As a source of folate added for nutritional purposes to food”

• 2014 – EUROPE: EFSA Novel Food approval

  • “As a source of folate added for nutritional purposes to food supplements”

• 2015 – EUROPE: EFSA Novel Food (Annex II to Directive 2002/46/EC)

  • “As a source of folate added for nutritional purposes to food supplements”

10.4 Medical uses of quatrefolic

• preconception (planned pregnancy);

• pregnancy;

• breastfeeding;

• newborns, children or adults with folic acid deficiency;

• macrocytic anemia;

• hyperhomocysteinemia.

11. Vitamin B2 (riboflavin)

It is a water-soluble vitamin with an important role in the proper functioning of the entire human body. Water-soluble vitamins, such as vitamin B2, are transported through the bloodstream, and the amount that is no longer needed is eliminated from the body through urine.

Another important aspect is that people must consume vitamin B2 every day, because the body can only store small amounts, and the reserves of this nutrient are consumed quickly.

11.1 Mechanism of action

It acts as an antioxidant, which controls the presence of harmful free radicals inside our body. Riboflavin is necessary for the production of an antioxidant called glutathione, which acts as a “destroyer” of free radicals and, at the same time, detoxifies the liver.

There are many diseases that can be prevented with the help of an adequate dose of riboflavin. This vitamin is also useful in the treatment of genital conditions:

Helps overall metabolism to convert macronutrients: carbohydrates, lipids, and proteins into energy. It also participates in improving the immune system, helps the body to balance acidity, and is important for hair, nails, and eyes.

11.2 Vitamin B2: deficiency

• Stomatitis, the tongue may become red and sore throat, chapped lips and inflammation in the corners of the mouth may occur;

• Eyes may start to sting, redden, water, and become sensitive to light;

• The symptoms, listed above, not taken into account can lead to blood loss;

• Infants whose mothers are deficient in vitamin B2 or have a diet low in vitamin B2 (less than 1.2 mg per day) during pregnancy have a higher risk of certain birth defects.

11.3 Studies

Numerous clinical studies have shown that riboflavin functions as an antioxidant nutrient, effectively mitigating lipid peroxidation and reducing oxidative reperfusion injury. Additionally, a lack of riboflavin may elevate the susceptibility to specific forms of cancer.

Riboflavin may also have neuroprotective effects in certain neurological conditions (e.g., Parkinson’s disease, migraine, and multiple sclerosis) through its role.

Less well known is the fact that vitamin B2 provides growth stimulants for children and helps support healthy vision along with vitamin A.

12. Gonal

12.1 Description

Gonal-F (follitropin alpha) is a human follicle-stimulating hormone (FSH) gonadotropin, which is a glycoprotein hormone produced using recombinant DNA technology.

Follitropin alfa possesses a dimeric structure composed of two glycoproteins, the α- and β-subunits, which are non-covalently linked and not identical. The α-subunit comprises 92 amino acids, while the β-subunit has 111 amino acids. Both their primary and tertiary structures closely resemble those of human follicle-stimulating hormone.

The biological activity of follitropin alfa in vivo has been standardized against the initial International Standard for Recombinant Human Follicle-Stimulating Hormone, established in 1995 by the Expert Committee on Biological Standards of the World Health Organization.

It is important to note that Gonal-F does not contain any luteinizing hormone (LH) activity.

Gonal-F is a sterile, freeze-dried powder designed for subcutaneous injection following reconstitution. Each Gonal-F multidose vial is supplied with 600 IU (equivalent to 44 micrograms) or 1200 IU (equivalent to 87 micrograms) of follitropin alfa, which delivers 450 IU (about 33 micrograms) or 1050 IU (around 77 micrograms) of follitropin alfa, respectively. These vials also contain 30 milligrams of sucrose, 1.11 milligrams of dibasic sodium phosphate dihydrate, and 0.45 milligrams of monobasic sodium phosphate monohydrate.

12.2 Indications

Gonal-F is indicated for:

• Inducing ovulation and promoting pregnancy in women with oligo-anovulatory infertility, where infertility arises from functional issues (and not due to primary ovarian failure);

• Stimulating the development of multiple follicles in ovulatory infertile women as a component of assisted reproductive technology treatments;

• Inducing spermatogenesis in infertile men with azoospermia (no measurable sperm in semen) and primary or secondary hypogonadotropic hypogonadism when infertility is not a result of primary testicular failure.

12.3 Mechanism of action

Gonal-F encourages the growth of ovarian follicles in women who do not suffer from primary ovarian failure. To trigger the final maturation of the follicle and induce ovulation when a natural LH surge is absent, human chorionic gonadotropin (hCG) is administered after Gonal-F, but only when patient monitoring reveals that adequate follicular development has occurred.

In men with hypogonadotropic hypogonadism, Gonal-F is effective in stimulating spermatogenesis.

13. Cetrotide

13.1 Description

Cetrotide is a medication employed to prevent premature ovulation, which refers to the premature release of eggs from the ovaries. This medication is typically given to women who are undergoing ovarian stimulation treatment, a fertility procedure aimed at stimulating the ovaries to produce a greater number of eggs.

Cetrotide’s active ingredient is cetrorelix.

13.2 Mechanism of action

The active ingredient in Cetrotide, cetrorelix, functions by inhibiting the actions of luteinizing hormone-releasing hormone (LHRH) within the body. LHRH regulates the production and release of another hormone known as luteinizing hormone (LH), which is responsible for initiating the process of ovulation. In the context of fertility treatment, ovarian stimulation is utilized to encourage the ovaries to generate a greater number of eggs. By blocking the effects of LHRH, Cetrotide effectively suppresses the production of LH, thereby preventing premature ovulation. This is important because premature ovulation can result in the release of immature and unsuitable eggs for use in assisted reproductive techniques like in vitro fertilization (IVF).

14. Study objective

This study aims to increase the chances of obtaining a pregnancy in women diagnosed with polycystic ovary syndrome.

15. Materials and method

This prospective, interventional study had a duration of 24 months, was conducted between January 2021 and February 2023, and was carried out in four national medical centers in Bucharest:

1. Regina Maria – “Unirea” Medical Center;

2. Emergency Clinical Hospital “Sfantul Pantelimon”;

3. CMI “Al Jashi Issam”;

4. “Nicolae Malaxa” Clinical Hospital

To this purpose, a group of 200 women (aged between 22 and 36 years old) were included.

16. Inclusion criteria

1. Age between 22 and 36 years old.

2. Female, in a relationship.

3. Women with polycystic ovary syndrome (PCOS).

4. The desire to have children and unprotected sexual intercourse 2–3 times a week.

5. Normal values for the partner’s semen analysis.

17. Results and discussions

The number of pregnancies installed versus women included in the study: out of the total number of 200 patients who have finalized the study:

• 38% (76) got pregnant by the end of it;

• 76% of the remaining patients (94) continued IVF protocol and managed to obtain a pregnancy;

• 15% will continue with another IVF procedure.

Our study was based on a batch of 200 patients with the environment of origin as shown below (Figure 1 and Table 1):

Figure 1.

Patients distribution by living environment.

Total patients 200
Urban	Rural
120	80

Table 1.

Patients distribution by living environment.

Our batch of patients was divided between smokers and non-smokers as shown below (Figure 2 and Table 2):

Figure 2.

Smokers vs. nonsmokers distribution.

Total patients 200
Smokers	Nonsmokers
100	100

Table 2.

Smokers vs. nonsmokers distribution.

The batch presented a small percentage of obese patients (Figure 3 and Table 3):

Figure 3.

Normal weight vs. obesity distribution.

Total patients 200
Normal weight	Obesity
190	10

Table 3.

Normal weight vs. obesity distribution.

Out of the 200 women participating in the study, 6% presented comorbidities during their pregnancies. Ten of them presented thrombophilia and two of them gestational diabetes, as shown in Figure 4 and Table 4.

Figure 4.

Comorbidities.

Total patients 200
Normal	Thrombophilia	Gestational diabetes
188	10	2

Table 4.

Comorbidities.

After undergoing between three and six months of ProFecund Ino treatment, 70% of the patients presented follicular quality improvement (Figure 5 and Table 5).

Figure 5.

Follicular quality.

Follicular quality total patients 200
No changes	Quality improvement
60	140

Table 5.

Follicular quality.

In total, 38% out of all included patients (76) obtained pregnancy after only following the proposed treatment with ProFecund Ino. All of the 76 patients were at most 32 years old at the time of pregnancy diagnostic (Table 6).

Total patients 200
Pregnancies	No pregnancy
76	124

Table 6.

ProFecund Ino ONLY.

The remaining 124 patients continued the ProFecund Ino treatment and started ovarian stimulation with medium dose Gonal F (Follitropin Alpha) and Cetrotide, followed by an IVF procedure. This led to another 94 pregnancies, which represents 76% of the remaining batch. Thirty of the patients (24%) did not obtain a pregnancy and will continue the ProFecund Ino treatment and will undergo a new procedure (Table 7).

Total patients 124
Pregnancies	No pregnancy
94	30

Table 7.

IVF + Profecund Ino.

18. Conclusions

Patients with polycystic ovary syndrome who underwent the myo-inositol (ProFecund Ino – women, ProFecund B – men with relatively good sperm quality) treatment (both partners for at least four months) managed to obtain a pregnancy in 38% of the cases (Figures 6 and 7).

Figure 6.

ProFecund Ino ONLY.

Figure 7.

IVF + ProFecund Ino.

IVF treatment succeeded in 47% of the total cases after undergoing ProFecund Ino treatment, proceeding with a medium dose of Follitropin Alpha – (Gonal 200 IU) for 7 to 8 days, followed by inhibition with Cetrotide (Cetrorelix) starting on the sixth day of the stimulation process. On the aspiration day, the follicle presented a better quality.

Patients who presented thrombophilia (5%) received antithrombotic treatment with an antiplatelet agent (Aspirin, 75 mg daily) and anticoagulant agent (Clexane, 4000UI daily) associated with progesterone. All 10 patients managed to get pregnant and had a full-term delivery.

Patients with gestational diabetes did not necessitate insulin, glucose levels were managed with strict diet.

All patients who carried their pregnancies to term showed an improvement in their polycystic ovary syndrome.

As shown in Figure 8 and Table 8, the main purpose of the study was achieved by obtaining a pregnancy in 85% of the participants and by being able to fulfill their wish of completing their family.

Figure 8.

Overall results.

Total patients 200
Pregnancies	Unsuccessful
170	30

Table 8.

Overall results.