Indian doctors more confident about oestrogen therapy for menopause as USFDA may scrap black box warning

USFDA, in a discussion telecast publicly last month, said local oestrogen therapy, such as vaginal cream, is safe & the risks of hormone replacement therapy were overstated.

Graphic by ThePrint

New Delhi: The United States Food and Drug Administration (USFDA) has declared its plan to remove the currently mandated, strictest health warning on oestrogen replacement therapies. The development has triggered a debate around the treatment, once widely used to manage menopausal symptoms but later linked to harmful side effects, such as cancer.

The USFDA, in 2003, mandated a black box warning—the highest level of warning associated with approved drugs when proven to be associated with serious or life-threatening adverse events—on all menopause treatments containing oestrogen, regardless of form or absorption rates.

The move came after the findings of a Women’s Health Initiative (WHI) study—the largest-ever randomised controlled trial of hormone therapy in 2002—went public. The study found a combined oestrogen-progestin therapy linked to a rise in heart attacks and strokes, and a slightly elevated risk of breast and endometrial cancers. 

However, the FDA panel, which held a discussion telecast publicly last month, was of the view that at least local oestrogen therapy, such as vaginal cream, is safe and should not carry the same warnings as systemically delivered oestrogen via patches or pills taken orally.

The panel suggested that the risks associated with hormone replacement therapy (HRT) likely were overstated.

The FDA has now invited submission of broad, public comments on the risks and benefits related to menopause hormone therapy, including “data that could support updates to the labelling of such products”.

Typically occurring between the ages of 45 and 55, menopause is the cessation of menstruation and the decline in ovarian function. This biological process comes with hormonal fluctuations, mainly the lowering of oestrogen and progesterone levels, which can lead to a variety of physical and psychological symptoms. 

A hallmark symptom of menopause is hot flashes, characterised by sudden waves of heat, flushing, and sweating, often accompanied by palpitations and feelings of anxiety. Additionally, many women experience night sweats while the drop in oestrogen levels has links to a marked rise in mood swings and behavioural changes, vaginal dryness, adverse bone health, cardiovascular events, and the risk of breast cancer. 

HRT had been a common approach since the 1970s to manage menopausal symptoms by supplementing the body with oestrogen, progesterone, or both. However, since 2000, following the WHI findings, most doctors and patients worldwide have been cautious in recommending or using it, and its popularity has dramatically dropped. 

In India, where HRT is available in the form of pills, vaginal creams, and topical cream applied on the arms, but no implants or patches, like in the US, there is no country-specific box warning, which is mandatory for the products in India.

India never updated the official regulatory stance to reflect the advanced risk-benefit understanding associated with the treatment. However, experts maintained that clinicians had been hesitant in prescribing it.

Now, many, including those in India, believe the situation will change.

“I am glad at the development concerning the warning status related to HRT for menopause,” Dr Archana Dwiwedi, the chair of the mid-life committee in the Federation of Obstetric and Gynaecological Societies of India (FOGSI), told ThePrint.

A large number of women undergoing menopause or post-menopause can benefit majorly from HRT but remain deprived of it, mainly on account of evidence that may now be outdated, she said, adding that current scientific understanding is that HRT’s benefits for most women far outweigh the risks.

‘Evolving’ evidence

In 1991, the National Institutes of Health in the US launched the WHI, a $625 million, long-term, randomised controlled study to investigate ways to prevent the leading causes of death and disability in postmenopausal women.

The WHI recruited 1,61,808 postmenopausal women aged 50 to 79 for its study, and over 68,000 participated in one of three clinical trial arms—hormone therapy, diet modification, or calcium and vitamin D supplementation. 

The hormone therapy trial, intended to last nine years, would evaluate the long-term health impacts of the two most common HRT regimens at the time—conjugated equine estrogen (CEE-oestrogen derived from the urine of pregnant mares) plus progestin, or synthetic progesterone for women with a uterus and CEE alone for others who underwent a hysterectomy and no longer had a uterus.

Eleven years later, the NIH announced that it was stopping the oestrogen-plus-progestin arm of the trial early, citing increased rates of blood clots, stroke, heart attacks, and breast cancer in women taking the combined hormone therapy.

These findings led to a dramatic shift in the usage pattern of HRT globally, with a large number of patients and doctors abandoning it overnight.

However, experts now say the WHI findings have since come under intense scrutiny, and an understanding has evolved that the results, which profoundly impacted the use of HRT, could have been skewed.

For instance, the trial participants were old—63-year-olds on average—who in any case have a high baseline risk for cardiovascular conditions. 

Also, a follow-up study, which came out in 2024, concluded that HRT is safe and beneficial for most healthy women with bothersome menopause symptoms if they start it in the years shortly after menopause begins. 

“The latest versions of HRT are also far safer and can make life easier for a high percentage of women, who face bothersome health challenges in the menopause stage, which severely affects their quality of life,” Dwiwedi said. 

There, however, are some sceptics too.

“I suspect the pharmaceutical industry pushed the latest FDA development. While the FDA panel batting for warning labels in the HRT shared a lot of anecdotal evidence to suggest they are safe, why was there not any scientific presentations to back those claims?” asked a gynaecologist with AlIMS Delhi, who did not wish to be named.

However, while there is no clarity on whether the FDA will remove the requirement of black box warnings on all HRT for menopause, several of the panel members made a strong case for at least local oestrogen therapies, with comparatively low level of oestrogen, for symptoms such as vaginal dryness and urinary issues, as opposed to systemic therapies in the form of pills and implants. 

Some Indian clinicians agree with this argument.

Vaginal oestrogen cream, mainly prescribed based on requirement, is not for a systemic replacement of oestrogen, but for local reasons, such as dryness or burning sensation, or poor urinary control or poor comfort level in terms of intercourse, said gynaecologist Dr Hemanandini Jayaraman from Manipal Hospital in Bengaluru.

She said that the absorption of vaginal creams into the body is negligible, so no enhanced risk or risk factors are associated with the creams, which women generally use for local reasons.

“As far as continuing the vaginal application is concerned, if a patient gets symptomatic relief, which is extremely good, it can be safely pursued for a longer duration of time,” the clinician added.

However, she also maintained that HRT, even in the form of oral prescription, could be safe provided there is regular monitoring of the users.

Attitudes towards HRT in India

India has nearly 15 crore women estimated to be postmenopausal, and roughly 30-40 percent of them could be considered potential candidates for HRT.

“These are women who are symptomatic and have no contraindications, such as prior hormone-sensitive cancers or high clotting risk, typically considered suitable candidates for HRT,” the Federation of Obstetrics & Gynaecological Societies of India (FOGSI) member said.

However, according to estimates, less than five percent of women receive HRT. 

Currently, India follows a global prescription for norms for hormone therapy, including the USFDA as well as European guidelines. And while there is no equivalent to the FDA’s black box warning on systemic risks like breast cancer, stroke, or clots here, the Indian drug monographs and medical literature still describe side effects for estrogen therapy, such as deep vein thrombosis, hypertension, breast and endometrial cancer, and dementia.

Moreover, the guidelines from Indian expert groups mirror international concerns about systemic oestrogen use in women with certain risk factors, usually after age 60 or more than 10 postmenopause years, pointed out Dr Sweta Kumar, a gynaecologist and obstetrician with Surya Mother and Child Super Speciality Hospital in Pune.

While many gynaecologists in India are aware of HRT and do prescribe it to some patients, a significant number are hesitant or prefer alternative options. Younger or less experienced clinicians tend to be more cautious, and alternative therapies are still quite common in practice, Kumar said.

According to the 2025 national cross-sectional survey of 514 young Indian obstetricians-gynaecologists, the combined oestrogen-progestin therapy for vasomotor symptoms was recommended by 83 percent of the practitioners with three years‘ or below-three years’ experience. When their experience range was seven to 10 years, fewer practitioners, 77 percent, recommended it. 

Moreover, younger doctors (0–3 years) were found less likely to support early initiation of therapy—30 percent of them—compared to more experienced ones—49 percent of them. 

A large number of patients also find HRT risky and are hesitant to use it, Dr N.S. Saradha, a senior gynaecologist with SIMS Hospital in Chennai, underlined. 

“Women experiencing early or surgical menopause, accelerated bone loss, and high risk of osteoporosis benefit the most from HRT. I hope with the evolving understanding around HRT, both doctors and patients can make informed decisions on its usage,” Saradha said.

(Edited by Madhurita Goswami)