Introduction

Menopause refers to a physiological event occurring naturally in middle-aged women, and which marks the end of the female’s fertility period and reproductive capacity . Etymologically, the term ‘menopause’ is derived from ‘menos’, Greek for month and ‘pausos’, Greek for ending. It is thus defined as the permanent, irreversible cessation of menses brought about by a decline in ovarian follicular activity .

Menopause occurs, on average, at the age of 51, but varies among women, ranging from 45 up to 56 years of age. It is recognised clinically retrospectively, after a year or more of amenorrhea, for which no pathological diagnosis or physiological cause has been found.

Physiological changes in the menopause

The menopausal transition is a gradual endocrinological modification preceding menopause. This progressive continuum of somatic and psychological alterations leads fertile women experiencing, regular and predictable menses typical of normal cyclic activity of the ovary to their last menstruation related to ovarian senescence and thus menopause.

The decrease in the number of ovarian follicles accounts for a decline in oestradiol synthesis. As a consequence, a negative feedback mechanism comes into play, which results in more follicle-stimulating hormone being released by the pituitary gland to try and stimulate ovarian function. Meanwhile, oestradiol levels continue to decrease, until the level is too low to stimulate endometrial proliferation and hence menstruation stops.

Gonadotrophin secretion in turn stimulates the ovarian stroma to undergo steroidogenesis and form androgen precursor, androstenedione. The latter is converted to estrone, by the process of extraglandular and extrahepatic aromatisation, occurring mainly in muscle and adipose tissue. As oestrone (the form of oestrogen found in menopausal women) is less potent than oestradiol (the form of oestrogen occurring in premenopausal women), the level of active oestrogen in the body is decreased. Thus, perimenopausal age is characterised by a decrease in oestradiol production, increase in follicle-stimulating hormone and luteinising hormone levels, and elevated oestrone synthesis.

In a typical menstrual cycle, the corpus luteum produces progesterone, which converts the endometrium to its secretory stage and opposes oestrogen action of certain tissues. Menopause is characterised by anovulatory cycles, during which no corpus lutei are produced, and hence progesterone synthesis comes to a halt. During perimenopause, decreasing levels of progesterone means that oestrogen is unopposed, resulting in accumulation of endometrial lining and thus irregular bleeding, characteristic of this phase.

Such endocrine changes during the climacteric, particularly oestrogen deficiency, are often responsible for the clinical signs and symptoms that many women experience, collectively referred to as menopausal syndrome. Such symptoms may start as early as 10 years before menopause.

The immediate symptoms resulting from decreased oestrogen levels include vasomotor signs, such as hot flushes and night sweats. Some women also report psychological symptoms such as tiredness, depressed mood, mood swings, loss of libido, lethargy, insomnia, anxiety, irritability, and difficulties with short-term memory and concentration.

A common intermediate complication of menopause is organ atrophy, particularly urogenital atrophy, which occurs form rapid loss of collagen as a result of oestrogen deficiency . Vaginal atrophy often presents with vaginal dryness and burning, pruritus, and dyspareunia. Lower urinary tract atrophy, in turn, results in urgency, frequency, dysuria, and incontinence. Moreover, declining collagen quantity in the cardinal and uterosacral ligaments, caused by low oestrogen levels, may cause uterine prolapse . Collagen deposition in the dermis also decreases gradually, causing skin to wrinkle and become translucent and fragile, making it more prone to trauma, bleeding, and infection.

Body weight increases in menopausal women, with fat being mainly deposited in the abdominal region. This results in an increase in the waist-to-hip circumference ratio, and thus a change from the gynecoid to the android body shape.

Hormonal changes may also lead to chronic, long-term health problems, which include osteoporosis, cardiovascular complications, and Alzheimer’s disease. Although clinically silent for some years, these may have an even larger effect on a woman’s quality and quantity of life than the short-term complications .

Physiological changes in the menopause

The menopausal transition is a gradual endocrinological modification preceding menopause. This progressive continuum of somatic and psychological alterations leads fertile women experiencing, regular and predictable menses typical of normal cyclic activity of the ovary to their last menstruation related to ovarian senescence and thus menopause.

The decrease in the number of ovarian follicles accounts for a decline in oestradiol synthesis. As a consequence, a negative feedback mechanism comes into play, which results in more follicle-stimulating hormone being released by the pituitary gland to try and stimulate ovarian function. Meanwhile, oestradiol levels continue to decrease, until the level is too low to stimulate endometrial proliferation and hence menstruation stops.

Gonadotrophin secretion in turn stimulates the ovarian stroma to undergo steroidogenesis and form androgen precursor, androstenedione. The latter is converted to estrone, by the process of extraglandular and extrahepatic aromatisation, occurring mainly in muscle and adipose tissue. As oestrone (the form of oestrogen found in menopausal women) is less potent than oestradiol (the form of oestrogen occurring in premenopausal women), the level of active oestrogen in the body is decreased. Thus, perimenopausal age is characterised by a decrease in oestradiol production, increase in follicle-stimulating hormone and luteinising hormone levels, and elevated oestrone synthesis.

In a typical menstrual cycle, the corpus luteum produces progesterone, which converts the endometrium to its secretory stage and opposes oestrogen action of certain tissues. Menopause is characterised by anovulatory cycles, during which no corpus lutei are produced, and hence progesterone synthesis comes to a halt. During perimenopause, decreasing levels of progesterone means that oestrogen is unopposed, resulting in accumulation of endometrial lining and thus irregular bleeding, characteristic of this phase.

Such endocrine changes during the climacteric, particularly oestrogen deficiency, are often responsible for the clinical signs and symptoms that many women experience, collectively referred to as menopausal syndrome. Such symptoms may start as early as 10 years before menopause.

The immediate symptoms resulting from decreased oestrogen levels include vasomotor signs, such as hot flushes and night sweats. Some women also report psychological symptoms such as tiredness, depressed mood, mood swings, loss of libido, lethargy, insomnia, anxiety, irritability, and difficulties with short-term memory and concentration.

A common intermediate complication of menopause is organ atrophy, particularly urogenital atrophy, which occurs form rapid loss of collagen as a result of oestrogen deficiency . Vaginal atrophy often presents with vaginal dryness and burning, pruritus, and dyspareunia. Lower urinary tract atrophy, in turn, results in urgency, frequency, dysuria, and incontinence. Moreover, declining collagen quantity in the cardinal and uterosacral ligaments, caused by low oestrogen levels, may cause uterine prolapse . Collagen deposition in the dermis also decreases gradually, causing skin to wrinkle and become translucent and fragile, making it more prone to trauma, bleeding, and infection.

Body weight increases in menopausal women, with fat being mainly deposited in the abdominal region. This results in an increase in the waist-to-hip circumference ratio, and thus a change from the gynecoid to the android body shape.

Hormonal changes may also lead to chronic, long-term health problems, which include osteoporosis, cardiovascular complications, and Alzheimer’s disease. Although clinically silent for some years, these may have an even larger effect on a woman’s quality and quantity of life than the short-term complications .

Skin ageing and menopause

The human skin can be described as a sheet-like single organ formed from a group of cells having different embryonic origin. These cells exist as a complex mosaic in complete harmony under normal conditions . Three important factors affect skin ageing. These are the natural process of ageing (known as chronological ageing), decreased oestrogen (which typically happens in women after menopause), and harmful environmental factors like ultraviolet radiation .

The skin ages through two major processes: the intrinsic and extrinsic processes. Intrinsic ageing varies among individuals and depends on the genetic make-up. This type of ageing cannot be avoided. In contrast, extrinsic skin ageing can be modulated depending lifestyle. Extrinsic cutaneous ageing is a type of premature skin ageing it occurs by exposing the skin to harmful environmental factors, such as poor nutrition, smoking, sun exposure and large alcohol intake .

Gross anatomy and characteristics of ageing skin

General appearance and structure of skin after menopause

Skin that has undergone intrinsic ageing sometimes looks nearly as smooth and flawless as normal skin except, for a few exaggerated expression lines . Several changes, however, occur to the skin after menopause, and the appearance of skin may change quite significantly. With the onset of menopause, the skin becomes dry because the functions of the sebaceous glands and sweat glands decline, and with time they become unresponsive to stimuli. This is sometimes associated with decreased oestrogen levels .

The skin becomes rapidly thinner after menopause at a rate similar to the decrease in bone mass. The reduction in thickness cannot be attributed to age alone but also to the decrease of skin collagen . The thickness of the skin decreases by 1.13% every year in the postmenopausal period, whereas the collagen content decreases by 2.1% every post-menopausal year . The decline in skin collagen and skin thickness is reflected in dry, flaky, wrinkled and easily bruised skin . Menopause brings with it changes in collagen metabolism. The postmenopausal period is marked by low amounts of soluble collagen and slower turnover and collagen synthesis. This manifests itself in decreased skin resilience and pliability . The skin loses its suppleness, and many women complain of intense tingling and formication owing to the effect on the neurovascular network in the skin.

Young skin is rich in oestrogen receptors, and oestrogen binds actively and is metabolised by the skin. The reduction in oestrogen that occurs in the perimenopause leads to a decrease in the number and density of hair follicles in the scalp . Oestrogen and androgen receptors are present in skin fibroblasts . Changes in oestrogen with the onset of menopause alter the skin vascularisation and the connective tissue in the dermis. Changes in the ground substance occur as a result of increase in hydorxyproline turnover and mucopolysaccharide incorporation. When oestrogen therapy is administered for 6 weeks, the number of capillaries increase and atrophy of the epidermis disappears. Also, collagen fibres appear less fragmented. Both oestriol succinate and oestradiol valerate have shown to thicken the epidermis . It is the decrease in collagen content and change in skin elasticity that contribute to the appearance of old skin .

Changes in skin histology

Mechanism of intrinsic skin ageing

The main theory that is believed to contribute to the ageing process of skin is the accumulation of reactive oxygen species (ROS) that results from damage of cells throughout life that are accompanied by oxidative metabolism . This oxidation that occurs in cells damages the DNA causing mutations, oxidises proteins which then lose their function, and also oxidises lipids found in membranes, which lose their transport capacity and have distorted transmembrane signalling .

The micro-inflammatory model of skin ageing

External stimuli such as cigarette smoke and ultraviolet radiation, together with internal stimuli, such as psychological stress and hormone changes that accompany menopause, induce nerve endings to release various neuropeptides into the skin . These neuropeptides increase the synthesis of adhesion molecules, which are responsible for the first step in the inflammatory process. Adhesion molecules enable circulating monocytes and granulocytes to roll over, adhere and diapedese through the endothelial wall of blood vessels and migrate into the dermis. These white blood cells produce and secrete proteases and ROS that in turn change the turnover of the proteins of the dermis and also damage cells in the skin. The damaged cells are stimulated to release leukotrienes and prostaglandins. These chemicals act as stimuli on the mast cells and induce the secretion of histamine and the cytokine tumour necrosis factor-alpha, which in turn stimulate endothelial cells to produce intra-cellular adhesion molecule-1 and also help liberate P-selectins. A second set of immune cells is stimulated to migrate, causing more inflammation and the process goes on and on. The final result would be an imbalance in the degradation and synthesis of elastin and collagen fibres. As the fibroblasts in old age are unable to synthesise these fibres, this inflammatory process causes ageing of the skin, with a change in the composition of the dermis and epidermis, skin thickness, and elastic properties of the skin . ( Fig. 1 )

The micro-inflammatory model of skin ageing.

Collagen and menopause

Collagen is the most abundant protein found in humans. It is the main structural element in the skin and provides support and strength . The skin contains around 40% of the total body collagen. In the dermis 97.5% of the fibrous protein is collagen. Collagen in the skin is composed of two basic alpha chains. Both alpha 1 and alpha 2 chains are each made up of a little bit more than 1000 amino acid residues. The alpha chains form a triple helix, making collagen a very strong structure. Around 25% of the amino acids in collagen are proline and hydroxyproline .

Twelve types of collagen molecules have been identified in human skin . Collagen type I constitutes 90% of the total collagen in the body and is the major type found in the skin. Changes in collagen with menopause not only affect the skin but also bones and tendons, two tissues where collagen type I is found in a high concentration. The molecular formula of collagen type I is [α1(I) ₂ α2(I)], meaning that it consists of two alpha 1 chains and one alpha 2 chain. Collagen type III is found in the uterus, muscles, lung, liver and large arteries besides skin. Its molecular formula is [α1(III) ₃ ] and it consists of three identical alpha 1 chains .

The DEJ contains collagen type IV. This type of collagen is responsible for stability of the main skin layers. Skin wrinkles contain abnormal amounts of this type of collagen. The base of a wrinkle contains less collagen type IV than the flanks. This can reduce the stability of the DEJ and quicken the process of wrinkle formation. The stratum basale, the deepest layer of the skin epidermis, is fixed to the papillary dermis below it via anchoring fibrils. These are composed mainly of collagen type VII. The formation of wrinkles could occur as a result of breakdown of these fibrils, which dissolve the bonding between the epidermal and dermal layers .

The collagen composition varies with age, and this is believed to occur via ‘gene switching’. In young age, one has a high amount of collagen type III, but with age it decreases . As one ages, the rate of translation and post-translational enzymes decrease, and hence the total amount of collagen around the whole body decreases. Using collagen markers, osteoclastic activity after menopause increased more than osteoblastic activity. The enzymes prolyl hydroxylase and lysyl hydroxylase, both involved in the formation of collagen, decrease more with age than collagen hydroxylysyl glycosyltransferases. Throughout life, even in old age, a considerable amount of collagen is degraded and replaced. With oestrogen replacement therapy, the osteoblastic activity increased more than osteoclastic activity, resulting in an increase in thickness of the dermis of the skin . The quality of the collagen fibres also changes with age. The fibres become thick and group together in rope-like bundles. They appear disorganised compared with younger skin .

With ageing, the level of the transcription factor c-jun increases, whereas the level of c-fos remains the same as found in young skin . In contrast, other investigators reported that even the transcription factor c-fos is found in higher amounts in old skin compared with young skin . These two transcription factors enhance the formation of activator protein-1. This protein triggers the expression of matrix metalloprotein (MMP) genes and consequently the levels of MMPs especially MMP-1 and MMP-9 are higher compared with levels in young skin . These MMPs increase the synthesis of collagenases and gelatinases, the enzymes that breakdown collagen. Exposure to ultraviolet radiation accelerates these processes .