In the early twentieth century US, Jean Paul Pratt and Edgar Allen conducted clinical experiments on women who had abnormal menstrual cycles. During the clinical tests, researchers injected the hormone estrogen into their patients to alleviate their menstrual ailments, which ranged from irregular cycles to natural menopause. The hormone estrogen plays a prominent role in the menstrual cycle by signaling the tissue lining the uterus (endometrium) to thicken in preparation for possible pregnancy. In their clinical tests, Pratt and Allen showed that injecting estrogen into female human subjects restored their normal menstrual cycle, removed symptoms such as hot flashes, and caused uterine tissue to grow. The clinical tests conducted by Pratt and Allen provided experimental evidence and justification for the injection of isolated estrogen in women to alleviate, for a short amount of time, different menstrual problems, and it contributed to later hormone therapy research.

Estrogen plays a key role in the regulation of gene transcription. This is accomplished by its ability to act as a ligand and to bind to specific estrogen receptor (ER) molecules, such as ERα and ERβ, which act as nuclear transcription factors. There are three major nuclear estrogen receptor protein domains: the estrogen binding domain, the protein interaction domain, and the DNA binding domain. The domain responsible for the regulation of transcription is the DNA binding domain, which binds to DNA sequences called estrogen-responsive elements (EREs), found in enhancer regions of specific genes. By the binding of estrogen or an estrogen mimic to these enhancers, the target genes become activated and the proteins produced are involved in numerous cellular processes. With an estrogen mimic or xenoestrogen, such as diethylstilbestrol (DES), the negative regulation of certain genes during embryonic development can be devastating to the developing anatomy, especially the reproductive system.

The figure depicts three different molecular structures of estrogen found in mammals’ that differ by the arrangement of bonds and side groups. The molecular structures of the three estrogen molecules differ by the arrangement of chemical bonds and side groups attached to the core steroid structure, cholesterol, which contains three cyclohexane rings and one cyclopentane ring.

Hormone replacement therapy, or HRT, is a form of medication often used to treat the symptoms of menopause. According to the National Institute on Aging, menopause is the point in a female’s life twelve months after she has had her last period. The time leading up to menopause, often called perimenopause, is a transition stage when levels of sex hormones, namely estrogen and progesterone, begin to fall. For approximately eighty-five percent of menopausal females, that decline results in symptoms such as vaginal dryness, shifting moods, and hot flashes, or an abrupt feeling of warmth typically in the upper body. HRT replenishes a person’s sex hormones, and though there are many methods of HRT, people most commonly take a pill that contains either estrogen only or both estrogen and progesterone. HRT has evolved scientifically but has at times resulted in controversy over potential side effects. Despite historical controversy, as of 2024, researchers recognize that with careful consideration of an individual's health conditions and history, HRT can be an effective treatment for menopausal symptoms.