Other Hormonal Modifiers

Updated: Mar 12, 2019

Obesity

The next hormonal modifier I want to address is obesity, focusing here on the negative hormonal changes that occur as body fat levels increase. It's important to realize that, in some cases, the presence of the hormonal modifier may be causing a woman's predisposition to obesity. PCOS is a common one and it's overall effects on a woman's physiology, especially combined with the modern diet and lifestyle, put woman at risk for fat gain to begin with and this becomes a vicious cycle where PCOS causes insulin resistance which causes the PCOS to worsen, worsening the insulin resistance, etc. But even when PCOS or another hormonal modifier is not present, as women begin to gain excessive amounts of fat, there are a variety of hormonal changes that start to occur and much of this is due to the development of insulin resistance. Both progesterone and estrogen levels may go up and the production of androgens may increase as well creating a state of elevated testosterone/androgen levels, causing a PCOS-like state.

Obesity, like PCOS, is also associated with infertility and other pregnancy related problems. Ovulation may be impaired, the risk of miscarriage is increased and this is all fundamentally related to the hormonal changes that occur, and primarily the insulin resistance that tends to develop. For women wanting to become pregnant, this presents a problem but, as with PCOS, the loss of even moderate amounts of weight/fat drastically improves the situation.

Overall, increasing levels of body fat create an androgen-like physiology and the insulin resistance that will usually be present will create an effective luteal phase physiology.

Age Related Changes in Women's Physiology

In addition to the above modifiers, which can occur at any age in women, there are also a number of age-related changes that occur in a woman's physiology over her lifespan. Here I am only focusing on those changes that occur later in life such as peri-menopause and menopause itself. At perimenopause, a woman's reproductive function begins to decrease, a process referred to as the climacteric. Effectively, a woman runs out of potential follicles/eggs to fertilize and this signals the reproductive system to shut down at which point her estrogen and progesterone production is nearly eliminated. This is yet another place where women and men differ significantly. As I discussed in earlier blogs, with increasing age a man's testosterone levels are reduced (which some are calling andropause to liken it to menopause) but at no point does it drop to zero. In contrast, at menopause, a woman's reproductive hormone production essentially stops.

Regardless, the menopausal transition that a woman undergoes has a profound impact on her overall physiology although this is another area of some complexity as there are four different situations that have to be considered. These include perimenopause, the time before true menopause occurs which has both an early and late phase along with menopause itself. After menopause, women who go on Hormone Replacement Therapy (HRT) show a different physiology than those women who do not. I should mention that in addition to the profound changes that are occurring in a woman's hormones at this time, there are other changes that are simply age-related that also contribute to the changes in physiology.

Perimenopause

Perimenopause literally means near menopause and refers to the changes that occur as a woman begins the transition into menopause itself. While perimenopause is typically thought to occur in the 50's, it is possible for some women to enter peri-menopause in their 40's or even 30's. The entire perimenopausal period can last anywhere from 12 months up to four years and is divided into an early- and late-phase depending on the specific hormonal profile which is seen. Unfortunately, only blood work to determine the actual levels of estrogen and progesterone can pinpoint exactly where a woman is at this time. During perimenopause, cycles may become infrequent or change in length and some cycles will be anovulatory with no egg being released.

If there is a perceived "benefit" to peri-menopause it's that falling estrogen may decreases PMS symptoms. At the same time, other symptoms, similar to what is seen postmenopausally often appear. Hot flashes, sleep problems, mood changes, a decline in sexual interest and function and a loss of bone density may all occur. The occurrence of these symptoms, especially the easily observable ones, can actually act as an indicator that peri-menopause has started; blood work would support or confirm this.

In early perimenopause estrogen levels can start to shift up and down but there is typically a decrease in progesterone without much change in estrogen levels. For that reason, I will consider early peri- menopause to be an estrogen-like situation, creating an effectively follicular-phase physiology. In late perimenopause, estrogen starts to drop along with the drop in progesterone and this will create a state of relative hyperandrogenism. Androgen levels are not elevated above normal but their effects become relatively dominant unless hormone replacement is begun.

Late perimenopause is often accompanied by the beginnings of a change in body weight, body fat and fat distribution and this is due to the drop in estrogen levels. Muscle loss often accelerates and with this metabolic rate can begin to slow down. Fat gain may start to occur with a shift in body fat from the lower body to around the midsection and this is typically accompanied by the development of insulin resistance. For this reason I will consider the late perimenopausal woman to to have a hyperandrogenic/progesterone-like hormonal state with an effective luteal phase physiology. This will be altered if Hormone Replacement Therapy (HRT) is begun.

Menopause

Once a woman has not had a menstrual cycle for 12 months after entering perimenopause, she is considered to have entered menopause and to be postmenopausal Here, the same side effects that may have started in perimenopause can become more pronounced . This includes hot flashes, mood swings, depression, vaginal dryness, cloudy thinking and many others. Her reproductive system has effectively shut off completely and her hormone production drops significantly. Her estrogen levels will continue to drop from the peri-menopausal level and can be as low as 95% below her pre-menopausal levels. Her progesterone levels will already have dropped since there are no longer follicles being released or implanting with no development of the corpus luteum.

After menopause, testosterone levels may be slightly higher than average and this can happen for a few reasons. Some women will have had PCOS to begin with but there can be reasons such as testosterone secreting tumors which are present. Even without those medical conditions being present, postmenopausal women often see a slight increase in testosterone levels after menopause before levels fall gradually over the next five years. The consequence of the above is that the immediate postmenopausal women will develop the same type of hyperandrogenic state I described previously. This will put the postmenopausal woman in an effectively luteal-phase physiology.

This includes the development of insulin resistance along with a shift from the typical female lower body fat pattern to a more male-like central body fat pattern. Along with this comes an increase in heart disease risk. In addition to this shift in body fat patterning, there is often an increase in body weight and total body fat levels as well with a reduction in energy expenditure and metabolic rate. The lack of estrogen also causes an accelerated rate of bone loss increasing a woman's risk of developing osteopenia or osteoporosis. A majority of these effects are reversed by the use of hormone replacement therapy (HRT).


Hysterectomy

Before finishing up the blog with a brief discussion of HRT, I want to address one other potentially major hormonal modifier that women might encounter (outside of the myriad medical conditions) and that is a hysterectomy. Usually done for medical reasons, a hysterectomy refers to a surgery where part or all of a woman's reproductive organs are removed. In a full hysterectomy, the ovaries, uterus and cervix are all removed and this brings on a state identical to menopause described above (it may be referred to as surgical menopause). But there is also a partial hysterectomy where only the uterus is removed, leaving the cervix and ovaries intact. This decreases levels of both estrogen and progesterone which necessitates estrogen- only Hormone Replacement Therapy (HRT). While often thought to occur later in life, hysterectomies may be required at any time during a woman's reproductive life.

Hormone Replacement Therapy (HRT)

As women approach and enter the menopausal transition, the issue of whether or not to begin hormone replacement therapy (HRT) arises. Like hormonal BC, HRT has typically contained a synthetic form of estrogen, typically conjugated equine estrogen (CEE), along with the same progestin found in the Depo-Provera shot. The goal here is to reduce or eliminate the many negative effects that often occur at menopause due to the reduction/near elimination of a woman's estrogen and progesterone production. There is also some interest in androgen replacement for postmenopausal women.

The topic of HRT is one filled with some controversy and I want to look at some of the arguments both in favor of and against the use of HRT after menopause. In favor or HRT is the fact that it can reverse or at least attenuate many of the negative effects that occur at menopause in terms of body weight, body fat, increased heart disease risk, etc. I'd note that this is only true if HRT is started fairly early after menopause occurs. Just as with BC, HRT does not appear to cause any weight gain outside of what typically occurs with age. At the same time, there is a long-standing concern with the potential of HRT to increase the risk of breast cancer.

Much of this concern comes from one of the earliest study on long-term HRT use, the Women's Health Initiative (WHI) study which was actually terminated due to an increase in breast cancer risk among the study subjects. These results caused a drastic decrease in the use of HRT which has been accompanied by decreased incidence of breast cancer. However, re-analysis of the WHI and other studies suggest that the benefits outweigh the risks so long as HRT is begun shortly after menopause occurs with the health risks only increasing substantially in women over 60-70 years of age.

Without meaning to trivialize breast cancer in any way, there is the fact that heart disease is a far more common cause of death after menopause than breast cancer. Since I have no intention of giving recommendations as to whether any woman should or should not use HRT, I only mention this as it may impact on the choice of any individual woman's choice of whether or not to use HRT. A woman with a familial history or genetic risk (i.e. BRCA mutation) for breast cancer might make a very different choice regarding HRT than one without that risk or with a family history of heart disease, for example. With time, there may be the potential to identify who is or is not not a good candidate for HRT based on this and other factors . As with the newer forms of BC that include low- or ultra-low dose estrogens and different types of progestins, newer forms of HRT are in development and these seem to show similar benefits to the older forms with fewer side-effects.