From Menarche to Menopause: The Story of Progesterone

The hormone progesterone frequently is discussed with regard to menstruation, fertility, pregnancy, and contraception during reproductive years or in the context of hormone replacement therapy (HRT) with estrogen in menopause. Women, however, often have questions as to the nature of “natural” progesterone as compared with a progestin, which is a synthetic version, or why the route of administration may at times create different reactions, risks, and benefits.

Progesterone’s role in the menstrual cycle is well understood. The reproductive cycle is controlled by a small group of neurons in the hypothalamus called the KNDy neurons (kisspepsin, neurokinin B, and dynorphin), which become active at puberty. Under their control, gonadotrophin-releasing hormone neurons in the hypothalamus activate the pituitary to release follicle-stimulating hormone (FSH) and luteinizing hormone (LH) to stimulate the ovaries to advance follicle development. During the follicular or growth phase of the menstrual cycle, estrogen secretion from the ovaries acts on the endometrium, the lining of the uterus, to thicken it by converting short, straight, narrow glands in the decidua to long, tortuous glands. A spike of LH leads to extrusion of the ovum (ovulation). The fimbria of the fallopian tubes captures the ovum and, if sperm are available, fertilization can follow. The ovarian site of ovulation, now called the corpus luteum, begins to produce progesterone to further develop the endometrium in order to maintain the anticipated early pregnancy. With failure of fertilization, estrogen and progesterone levels fall, decidual ischemia develops, and menses results.
Discerning the biologic effect of progesterone can first be traced to R. deGraaf (1672) and later to L.A. Prenent and G. Born (1898). Others, in the early 1900s, wrote of the effects of secretions from the corpus luteum upon the endometrium. Then, in 1929, G.W. Corner and W.A. Allen demonstrated the importance of the corpus luteum for maintaining the early pregnancy.

But understanding the structure of the hormone and not just its actions was achieved by R.E. Marker at The Pennsylvania State College (later University) who started with Sarsasapogenin, a plant steroid isolated from Sarsaparilla. He produced progesterone in a three-step chemical process that became known as the “Marker Degradation.” Using Sarsasapogenin and its laboratory manipulation, however, was very expensive. The next historical step was to utilize the Beth root from the lily family to produce Diogenin, a compound which previously had been isolated by the Japanese from a yam of the Dioscorea family. Then, in 1941, Marker learned of a plant called Cabeza de Negro, also of the Dioscorea family, existing in Veracruz, Mexico. When no United States company was interested, Marker returned to Mexico and dried ten tons of it to make 3 kilograms of progesterone. Through the 1940s, Marker formed or joined several companies as other investigators began taking the lead to economically develop progesterone production from plants.

Synthetic progestins, in contrast, were birthed in a laboratory. Scientists, applying techniques used to convert testosterone to estrone and estradiol, coupled with additional known chemical steps, produced norethindrone. Norethindrone, a progestin, is one of the two active components (along with an estrogen) of the first oral contraceptive pills (OCP). Later generations of progestins in OCPs and HRT formulations differed from each other in their affinities for estrogen, androgen, and progesterone receptors with resulting differing side effects. With the ability to inhibit ovulation, alone or in combination with estrogens, progestins now are accepted as critical components of oral contraceptives, intrauterine devices, and progesterone contraceptive implants.

The role of progesterone and progestins in menopause medicine as part of HRT, however, has been more controversial. Progesterone was not always a part of HRT. The effectiveness of estrogen to reduce menopausal symptoms led the Food and Drug Administration (FDA) to approve diethylstilbestrol (DES) in 1941 and Premarin® in 1942. As a result, estrogen use soared in the 1960s and early 1970s until mid-1970 when reports of estrogen-related endometrial hyperplasia and cancer began to appear. The addition of a progestin to counter the stimulatory effect of estrogen on the endometrium resulted in PremPro®, a combination of Premarin®, a conjugated group of estrogens derived from the urine of pregnant mares and medroxyprogesterone acetate, a progestin. This product was employed in the Women’s Health Initiative (WHI), a study with the intent to prove the efficacy of menopausal hormones for bone and heart health. Instead it demonstrated a small increased risk of breast cancer, a shocking result that was not found in the second arm of that study that only employed Premarin® for women who did not have a uterus. The use of all HRT plummeted after 2002 when the results were published and the study prematurely stopped. Today, current thinking is that the responsible agent was the progestin when combined with Premarin®.

Modern HRT requires that a menopausal woman with a uterus who is on estrogen must take some type of progesterone. While progestins are still used by some, oral micronized progesterone has become the standard. Some have used a daily dose of 100 mg. Others use 200 mg for 14 days at the end of every three months. But, premenstrual-like discomfort often is described as a side effect of this higher dose. Because oral progesterone must be absorbed by the intestine and has a “first pass” through the liver, this route often is bypassed by using progesterone as a vaginal suppository. Studies of infertility patients on progesterone indicate that the vaginal route is a more effective way to deliver progesterone to the uterus.

The science of hormones continues to have its champions and its critics. Still, progress is being made as scientists and clinicians combine laboratory and clinical studies to improve women’s health.

James Woods | 5/12/2017

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