Hormonal Imbalance – The Root Cause

Women between their mid-forties to fifties will invariably experience a sudden change in their mood, disturbed sleep patterns, flushing cheeks, hot flashes in the face, neck and chest, bone fragility, weight issues, vaginal dryness, and repeated bouts of anxiety, restlessness, and overall weakness. This is natural for all women (who have not undergone hysterectomy or oophorectomy) and is known as menopause. It is diagnosed after a whole year of cessation of menstrual cycles.

In 2021, women aged 50 and above comprised 26% of the female population globally and more than 6 million women enter menopause annually, which is predicted to increase to 1.2 billion menopausal and post-menopausal women by 2030.(1) (2)

The root cause of menopause is a steep reduction in levels of estrogen and progesterone, two main hormones secreted by the ovary during the first and second half of the menstrual cycle respectively. Estrogen and progesterone are promoters of several crucial functions in the body like muscle health regulation, secretion of serotonin and norepinephrine (two of the “happy hormones” in the body), neuroprotection and cognizance, protecting the genito-urinary tract, and bone health. Hence, an abrupt reduction of estrogen and progesterone leads to menopausal symptoms, that last a decade.

In some cases, the symptoms are not severe and do not affect daily lifestyles. Routine activities like meditation, a nutritious diet, practising any destressing hobby, exercising, and walking, can help relieve a lot of stress and ensure a person’s mental well-being.

However, for a lot of women, the symptoms are severe and they are bound to consult a specialist to cope with the sudden changes in the body. A specialist or an ob-gynae will prescribe either non-hormonal or hormonal medication depending on the patient’s age, medical history, and severity of symptoms.

HRT: Replenishing The Body’s Hormone Reserves

Hormonal medication for menopause is referred to as hormone replacement therapy (HRT) as it involves replacing the body’s hormone reserves with artificial, commercialised hormones synthesized in laboratories from plant and animal sources. Traditional HRT consists of conjugated estrogen and progesterone with extra structural groups attached to them but does not alter their molecular properties. (3)

The most common hormone conjugates used for traditional HRT include conjugated equine estrogens (CEE), which are extracted from the urine of pregnant mares consisting of equilin sulfate (native to horses) and estrone sulfate. (4) CEE has been used in two of the largest HRT trials so far - the Woman Health Initiative (WHI) study and another Danish study, and is also one of the most prescribed HRT drugs by physicians. (5) (6) (7)

What Is BHRT?

Bioidentical hormone therapy refers to hormones synthesised in a laboratory from plant sources. However, there is a specified process of extraction, and packaging involved.(4) As suggested by the names, bioidentical hormones are identical in molecular structure and have similar receptors as human, endogenous hormones.

It is important to mention in this regard that other hormone supplements are also made from plant sources like yam and black cohosh, like isoflavones, and sold as “natural” and “herbal” alternatives to traditional hormone therapy, but are synthetic in their chemical nature due to high levels of processing, and vary greatly from the endogenous or even the bioidentical hormones. (8) (9)

The most common contenders for BHRT include estrone sulfate, estropipate, 17β-estradiol, estriol, progesterone, testosterone, and dehydroepiandrosterone (DHEA). Out of these, estropipate (E1), and 17β-Estradiol (E2) have cleared the required safety and efficacy parameters, and are available in the market on being approved by the FDA. (10) Estriol (E3) is not FDA-approved yet but is used widely in Europe. Bioidentical hormone dosage matters the most when it comes to adjusting risks depending on age and medical history.

It is also important to know that several pharmacies use compounded bioidentical hormones (CBHT) by mixing different proportions of the bioidentical estrogens (for example: bi-estrogen or bi-est is composed primarily of estriol, estrone and 17β-estradiol in an 8:1:1 ratio) and claim them to be safer than BHRT and HRT. The safety and efficacy details of such compounds are debatable and are subject to further research. (11)

HRT And BHRT: The Benefits

Both HRT and BHRT have their respective benefits.

HRT Benefits:

Traditional HRT benefits have been assessed in multiple clinical trials as they were the primary choice of hormone replacement for women undergoing menopause. (6) (12) It was seen that

• Some clinical trials showed that HRT alleviated menopausal symptoms like hot flashes, mood swings and night sweats
• When implemented at the right time, HRT benefits patients with bone density issues and has a protective role in osteoporosis for women aged under sixty years
• HRT may also have some protective effects on cardiovascular health provided the dosing is accurate and the duration is between three to five years; a CEE and cyclic medroxyprogesterone combination does so by lowering the levels of low-density lipoprotein (LDL, or bad cholesterol) and increasing the levels of high-density lipoprotein (HDL, good cholesterol) (all participants in this study were between 45-64 years old)

BHRT Benefits:

The research on BHRT is comparatively less as it is a more recent intervention. Nonetheless there are encouraging results to promote their use among patients who are not suited for traditional hormone therapy due to health reasons. Additionally, hormone therapy approved by the FDA will have sufficient backing in terms of safety and efficacy. Bioidentical hormones benefit people in the following ways,(10) (13) (14)

• BHRT had a cardioprotective and anti-hypertensive effect on menopausal women when a combination of 17β-estradiol with drospirenone (a synthetic form of progesterone) was administered
• The benefits of estriol in managing vaginal atrophy in menopausal women was evident from vaginal cytology, cervical mucus and clinical and colposcopic findings
• Another clinical trial involved pregnant women with relapsing-remitting multiple sclerosis were given estriol for a year showed suppressed delayed-hypersensitivity reaction response, decreased interferon-γ levels, and shrinkage of brain lesions indicating estriol’s protective role in immunity as well; albeit this was a small study
• A valid argument while discussing the benefits of bioidentical hormones is that they have been proven to be at par with the traditional conjugated hormone therapy, and even better in some cases in terms of safety profiles in managing menopause syndromes when used in lower doses and without contraindications for less than five years

HRT And BHRT: The Risks

Both HRT and BHRT have their own sets of adverse effects and risks as well, depending on individual medical histories, age of administration, dosage, and duration.(4) (11)

HRT Risks

• The most common HRT side effects include nausea, bloating, weight gain, facial hair, and general weakness
• Women in clinical studies with an average age of sixty and above have had risks of venous thromboembolism and cardiovascular disease with oral formulations of CEE
• Women starting estrogen therapy after a decade of entering menopause are also at an increased risk of ischaemic stroke and cognitive disorders
• Unopposed systemic estrogen therapy has been linked to increased risks of endometrial cancer and continuous, concomitant use of estrogen and progesterone beyond five years has been linked to a slightly high risk of breast cancer
• There is a fixed dosing of conjugate hormones and hence dosing cannot be modified to suit individual needs

BHRT Risks

• Some side effects of bioidentical hormones are like those of traditional ones – acne, weight gain, mood swings, nausea, and bloating
• Bioidentical hormones are still under clinical trials for safety and efficacy which makes their use and dosing dubious in multiple cases
• The fact that compounding bioidentical hormones is a practice in most pharmacies without being regulated by the FDA makes its dosing even more tricky than standardised doses of the FDA-approved hormones
• The use of Estriol (E3) as a bioidentical hormone is not regulated by the FDA but it is used as a major component of compounded drugs (bi-est and tri-est)

Final Verdict

There are hormone replacement therapy side effects for every routine, but whether it outweighs the hormone therapy benefits is what needs to be assessed by practitioners. What works out for one individual may not work for the other. Traditional and bioidentical hormone replacement risks are still under extensive research and are subject to age, dosage, and duration of therapy.

The only guideline here is both traditional and bioidentical hormone replacement therapy benefits patients who are on the younger spectrum of menopause patients (till the fifties), and if there is a history of heart disease, blood clots, breast cancer, dementia, endometrial cancer, or uterine cancer along with old age (sixties and above) there are more chances of both forms of therapy being counter-productive.

It is always advised that everyone should report to their general physicians and gynecologists at the very instant they feel that menopause symptoms are bothering their lifestyle majorly. Self-medication is extremely injudicious. So is the thought that because one is undergoing menopause, one must need to replenish hormone reserves artificially. Our body is designed to heal from every condition and menopause is only natural.

The Bottom Line Remains…

All FDA-approved hormone therapies – be it traditional hormone replacement or bioidentical hormone replacement, can only be used to manage menopause symptoms for a limited time, and is not a cure to menopause. Just like menopause is a natural process and not a diagnosis.