Jango Bio

Hormone Imbalance

The hormones that regulate reproduction in humans promote growth and development early in life, in order for us to become reproductive adults, but later in life they fall out of balance and can cause or accelerate disease conditions.


 

Hypothalamic-pituitary-gonadal (hpg) hormones

There are dozens of hormones produced by the body along what is known as the hypothalamic-pituitary-gonadal (HPG) axis. These hormones govern stages of growth, development, and maturation in order to ensure that the individual reaches sexual maturity and is able to reproduce. During this period, feedback mechanisms keep the HPG axis in balance. This balance is maintained until the point of reproductive maturity, past which levels of HPG hormones diverge from the youthful state. As an individual ages, cells in the gonads (ovaries for females ; testes for males) begin to die off and become dysfunctional, causing hypogonadism and consequent dysregulation of the HPG axis. Women possess at birth ~1,000,000 ovarian follicles, a number that is reduced to ~65,000 by age 35, with virtually none remaining by age 51 (i.e. menopause; Left figure below). In men, there is progressive loss of Sertoli cells, Leydig cells, germ cells and support cells, along with specific pathological changes within those cells. This is associated with reduced testicular size, sperm quality, and testosterone levels declining by 0.9-1.6% per year after age 30 (i.e. andropause; Right figure below).

 

The model of establishment and decline of human primordial follicle population from conception to the menopause that has the best fit to data from 325 ovaries of varying ages. Age-related Decline in Ovarian Follicles in Women (adapted from Wallace and Kelsey, 2010; PlosOne).

Age-related Decline in Circulating Testosterone in Men (adapted from Vermeleun, 1996, Declining Androgens with Age: An Overview. In Vermeulen, A. & Oddens, & B. J. (Eds.), Androgens and the Aging Male (pp. 3-14). New York: Parthenon Publishing.)

 

 

imbalance of reproductive hormones in women is associated with mortality

During the reproductive period of a woman's life there is a regular cycling of HPG hormones that regulates the menstrual cycle. As her reproductive time comes to a close, and she enters into menopause, hormone levels begin to diverge from their normal range into a dyotic phase characterized by decreased circulating sex steroids (estrogens/progesterone and inhibins) but increased circulating gonadotropin, GnRH and activin. These changes are associated with biological aging, also known as 'senescence' (Left figure below). As an example of the consequences of these hormonal changes, consider the Nurses' Health Study published in 2009. In this study, 29,380 women who were having their uterus removed for a benign condition were observed for incidence of other diseases and overall mortality. Roughly half (55.6%) had both ovaries removed, whereas the other half (44.4%) had their ovaries conserved, and the two groups were compared across a range of conditions including heart disease, stroke, and mortality. During the 24 years of follow-up with these patients, among the patients who kept their ovaries 1242 died, whereas among the patients who had both ovaries removed 1955 died (Right table below). This controlled longitudinal study indicates that the induction of hormone dysregulation with oophorectomy (ovary removal) leads to an increased incidence of death.

 

Schematic of Circulating Hormonal Changes that Occur With Menopause (from Atwood and Bowen, 2011; Experimental Gerontology)

Removal of Ovaries Increases the Incidence of Death (Adapted from Parker et al., 2009; Obstetrics & Gynecology)

 

 

Imbalance OF reproductive HORMONES IN MEN IS ASSOCIATED WITH MORTALITY

During the early-reproductive period of a man's life HPG hormone levels are stable. Around the age of 30, hormone levels begin to progressively diverge from their normal range, characterized by decreased levels of sex steroids (testosterone and inhibins) but increased levels of gonadotropin, GnRH and activin. These changes persist throughout adult life (Left figure below). As an example of the consequences of these hormonal changes, consider the following study published in 2006, where mortality was assessed among male veterans over the age of 40 who had previously had their testosterone levels measured repeatedly over 5 years with up to 8 years follow-up. The data (Right figure below) demonstrated that men with low testosterone levels were at greater risk of death (34.9%) versus those with normal testosterone levels (20.1%). These data indicate with a high degree of confidence (P=0.001) that reduced endogenous levels of testosterone contribute to male mortality.

 

Schematic of Circulating Hormonal Changes that Occur During Andropause (from Atwood and Bowen, 2011; Experimental Gerontology)

Cumulative Survival as a Function of the Age-related Decline in Circulating Testosterone in Men (adapted from Shores et al. 2006, Arch Intern Med)

 

 

Gonadal transplantation in animal models increases life expectancy

In animals, re-establishment of the negative feedback loops in the HPG axis of post-reproductive mice (22 months of age) following transplantation with reproductively viable ovaries from  young mice (3 months of age) has been demonstrated to extend lifespan by up to 40% (Cargill et al, 2003 ; Mason et al. 2009). This method of hormone replacement therapy allows re-establishment of the entire HPG axis, including replacement of all gonadal hormones necessary for the negative feedback loops within the hypothalamus and pituitary.

 

Ovarian Transplantation Increases Healthspan and Lifespan in Mice (from Cargill et al, 2003; Aging Cell)

Ovary Age Predicts Life Expectancy in Mice (from Cargill et al, 2003; Aging Cell)

 

 

heterochronic parabiosis in animal models suggests a role for blood-borne factors in aging

By connecting the blood streams of a young and an old animal together ('heterochronic parabiosis'), scientists have shown that young blood can rejuvenate old tissues. First described by Paul Bert in 1864 and refined in 1933 by Bunster and Meyer, parabiosis is a surgical union of two organisms such as mice that allows sharing of the blood circulation, which includes all the sex hormones. When the parabiotic partners are a young mouse and an old mouse, after a short period of time the old mouse begins to exhibit the healthy cellular structures of the young mouse. Hair growth, muscle tone and cognitive ability in the old mouse begin to mimic that of the young mouse. When the same mice are later separated, the cellular structures of the old mouse revert to reflect the chronological age of the mouse. Moreover, studies have demonstrated that the older partners of heterochronic parabiosis lived four to five months longer than controls (Ludwig et al., 1972). Such has become the importance of ‘young blood’ that Alkahest has initiated Phase I clinical trials to test this product in the treatment of Alzheimer's Disease. Our approach differs in that we aim to circumvent the practical, ethical, and immunological challenges that would be associated with clinical application of parabiosis or gonadal transplants by instead developing stem cell therapies.